A Practical Synthesis of Terminal Vinyl Fluorides

Abstract

The synthesis of di- and trisubstituted vinyl fluorides with high isomeric purity remains a challenge for organic synthesis. While many methods exist to access these compounds, separation of the desired isomer from the minor isomer and/or starting materials often is difficult. Herein we report a practical method to access di- and trisubstituted vinyl fluorides via a selective Horner-Wadsworth-Emmons olefination/hydrolysis, which provides crystalline 2-fluoroacrylic acids in high (>98%) E-isomeric purity. A subsequent silver catalyzed stereoretentive decarboxylation provides the title substances with high isomeric purity and without the need for tedious chromatography to remove the minor isomer. The process was amenable to a variety of aldehydes and ketones and provided a diverse array of di- and trisubstituted vinyl fluorides. The sequence was applied to the synthesis of antibacterial and anti-inflammatory compounds.

GRAPHICAL ABSTRACT

INTRODUCTION

The incorporation of fluorine into organic molecules often results in advantageous modulation of physical properties.¹ This has resulted in the growing presence of fluorine in pharmaceuticals,² agrochemicals³ and organic materials.⁴ Among the plethora of fluorine containing functional groups, terminal monofluoroalkenes are of interest due to their applications in materials science, synthetic methodology and medicinal chemistry.⁵ Several biologically active compounds bearing trisubstituted (1-3) or disubstituted (4-6) terminal vinyl fluorides are shown in Figure 1.⁶

Figure 1.

Biologically active compounds containing terminal vinyl fluorides.

The geometry of the vinyl fluoride is often critically important to biological activity, and consequently synthetic methods to access these structures with high isomeric purity are desired.^6b To support a recent drug development program, we required a safe and scalable route to trisubstituted terminal vinyl fluorides with high isomeric purity. A survey of the literature revealed a diverse set of approaches, but many raised concerns regarding safety and/or scalability. A selection of published protocols is shown in Figure 2. The Wittig reaction using a fluoromethyl triphenylphosphonium salt was first reported by Schlosser in 1969 (Figure 2A).⁷ Variations of this reagent were subsequently developed but generally provide low selectivities.⁸ In 2016, Hoveyda reported cross metathesis approaches to both Z and E disubstituted vinyl fluorides (Figure 2B).⁹ High selectivities were obtained, but the reaction required a non-commercially available catalyst and was limited to disubstituted products, and in the case of E-vinyl fluorides, a vinyl chloride byproduct was formed which could prove difficult to separate from the desired product.

Figure 2.

Selected methods for terminal vinyl fluoride synthesis (A-D) and our olefination/decarboxylation approach (E).

The hydrodefluorination of 1,1-difluoroalkenes (Figure 2C) was demonstrated by the groups of Ito and Shi in 2017 and can provide E or Z products depending on reaction conditions but is limited to disubstituted vinyl fluoride products.¹⁰ Hu and co-workers reported an olefination using fluoromethylsulfoximine 7 in 2017 (Figure 2D).¹¹ This procedure gave high selectivity for both ketones and aldehydes. The non-commercial availability of the reagent 7 and its 5-step preparation, as well as the requirement to use 7 as the limiting reagent with the ketone in two-fold excess nonetheless presented obstacles to employing this process on large scale.^11b The preparation and Horner-Wadsworth-Emmons (HWE) reaction of triethyl 2-fluorophosphonoacetate 8 were first reported by Machleidt and Wessendorf in 1964 (Figure 2E).¹² The wide commercial availability and low cost of 8 made it an attractive reagent for introduction of the fluorovinyl group from a ketone or aldehyde starting material. We reasoned that if this olefination could be developed with high selectivity and coupled with stereoretentive decarboxylation of the derived carboxylic acid, it would constitute a practical route to vinyl fluoride products. Herein we report the development of this route to di- and trisubstituted terminal vinyl fluorides by a highly selective olefination of ketones or aldehydes using 8, subsequent hydrolysis to the crystalline α-fluoroacrylic acids, and stereospecific Ag-catalyzed decarboxylation.¹³

RESULTS AND DISCUSSION

Initial work focused on optimization of the HWE reaction of acetonaphthone 9 with phosphonate 8 (Table 1). The base was screened first, using 2 equiv of 8 in THF at 0 °C. The use of n-BuLi or alkali metal HMDS derivatives gave modest selectivities around 85:15 favoring E-10a (entries 1–4). We next examined Grignard reagents as bases. In 1998, Sano reported the use of i-PrMgBr as base to give Z-selectivity in the reaction of 8 with aldehydes.¹⁴ In 2008, Davies described the highly E-selective reactions of non-fluorinated phosphonates with aldehydes using MeMgBr as base.¹⁵ When we applied alkyl Grignard bases to the reaction of 8 with ketone 9, a significant improvement in selectivity was observed (entries 5–8). i-PrMgCl gave a 96:4 E/Z ratio of 10a in 88% assay yield. Using MeMgCl gave a higher assay yield of 98% with similar selectivity (95:5, entry 6). The halide counterion had a slight effect on selectivity and yield, with MeMgBr (entry 7) being optimal at 96:4 selectivity and 97% yield. The use of dibutylmagnesium (entry 9) proceeded in high yield but decreased selectivity. The use of an alkylzinc bromide (entry 10) or dimethylzinc (entry 11) was less effective compared to Grignard reagents. A brief examination of other solvents (entries 12–15) showed none to be as effective as THF, although DME did provide high selectivity (97:3, entry 15). Finally, the effect of temperature was examined (entries 16–18). Lowering the temperature to –20 °C resulted in incomplete conversion, although with slightly increased selectivity (97:3, entry 16). Increasing the temperature to 40 °C gave the highest assay yield (99%, entry 17) while maintaining the selectivity observed at 0 °C (96:4) but increasing further to 50 °C resulted in a drop in assay yield and selectivity (entry 18). Thus, the optimal conditions were MeMgBr as base and THF as solvent at a reaction temperature of 40 °C (entry 17).¹⁶

Table 1.

Optimization of olefination reaction conditions.

entry	base	solvent	T (°C)	yield (%)a	E/Zb,c
1	n-BuLi	THF	0	81	85:15
2	LiHMDS	THF	0	85	84:16
3	NaHMDS	THF	0	90	87:13
4	KHMDS	THF	0	73	86:14
5	i-PrMgCl	THF	0	88	96:4
6	MeMgCl	THF	0	98	95:5
7	MeMgBr	THF	0	97	96:4
8	MeMgI	THF	0	88	95:5
9	Bu2Mg	THF	0	98	92:8
10	n-PrZnBr	THF	0	44	85:15
11	Me2Zn	THF	0	81	93:7
12	MeMgBr	toluene	0	79	94:6
13	MeMgBr	NMP	0	66	91:9
14	MeMgBr	2-MeTHF	0	79	93:7
15	MeMgBr	DME	0	79	97:3
16	MeMgBr	THF	−20	86d	97:3
17	MeMgBr	THF	40	99	96:4
18	MeMgBr	THF	50	93	95:5

^aAssay yield from ¹⁹F NMR using benzotrifluoride as internal standard.

^bE/Z ratio from ¹⁹F NMR of crude product.

^cStereochemistry was confirmed by ¹H-¹⁹F HOESY experiments.

^dConversion of 9 to 10a from HPLC (220 nm).

Applying the reaction conditions developed for ketones to the olefination of 4-bromobenzaldehyde 11 showed moderate (80:20) selectivity favoring the Z-isomer (Scheme 1A).^13a Alternatively, the use of n-BuLi as base at low temperature (–78 °C) gave the E-isomer with high selectivity (98:2).¹⁷ The stereochemistry was confirmed by ¹H–¹⁹F HOESY experiments and single crystal X-ray structure analysis of the derived acid of Z-12a (vide infra). By contrast, olefination of 11 with triethyl-2-phosphonopropionate 14 gave the product E-13 in >45:1 E-selectivity using either MeMgBr or n-BuLi as the base (Scheme 1B).

Scheme 1.

Olefination of aldehyde 11 with 8 and 14 using MeMgBr or n-BuLi as base. ^aAfter purification >98:2 Z:E.

The basis for the E/Z selectivity, especially the changes with different bases, was investigated computationally. Calculations were performed with Gaussian¹⁸ B3LYP-D3/6–31G(d,p)¹⁹ with an SMD²⁰ solvation model. The energy diagram for reaction of the lithium and magnesium phosphonates are shown in Figure 3. Coordination of solvent to the Li or BrMg counterions was required to account for the observed trends. Specifically, two THF molecules remained coordinated throughout the reaction. The substrates (A) undergo a precoordination to form B followed by a transition state C for addition of the anion to the aldehyde via a staggered transition state where the metal coordinates the oxygens of the ester, phosphonate, and aldehyde (Scheme 2). The adduct D, then proceeds to a four-membered transition state E (Scheme 2) which gives rise to formation of the alkene.

Figure 3.

Relative Gibbs free energy (kcal/mol) profile diagram of the formation of olefin from the Mg/Li fluoro- and methyl-phosphonates (SMD_(THF)/B3LYP-D3/6–31G**).

Scheme 2.

Reaction pathways of PhCHO with 2-fluoro and 2-methyl phosphonoacetates.

For the reactions of stabilized ylides, the initial addition of the anion is reversible and the selectivity-determining step is typically elimination from the oxaphosphetane via transition state E.²¹ For the α-methylphosphonate 14, this expected trend holds for both the lithium and bromomagnesium phosphonates (Figure 3B) and the E-isomer is the major adduct from each (Scheme 1B). The transition state E has fewer steric interactions en route to the E-isomer as the larger groups (-CO₂Me, -Ph) are trans disposed (Scheme 2B). There are, however, some notable differences between the two pathways. The barrier for the addition of the methyl-substituted phosphonate anion to the aldehyde is significantly higher for the lithium case which can be attributed to the lower Lewis acidity of lithium (NBO charge +0.88) vs magnesium (NBO charge +1.69).

For the α-fluorophosphonate 8, the turnover determining transition state (TDTS) differs depending on the metal counterion employed. With MeMgBr, the expected trend holds in that alkene elimination via E is selectivity determining (left side of Figure 3A) and leads to the Z-isomer with the larger groups (-CO₂Me, -Ph) trans disposed. In this case, steric interactions are again minimized in the oxaphosphetane transition state E (bottom of Scheme 2A). With n-BuLi, the selectivity determining step for α-fluorophosphonate 8 is transition state C (right side of Figure 3A). Steric interactions are minimized in the staggered approach that ultimately leads to the E-isomer (Scheme 2A).

This change of selectivity determining transition state for the fluoro-substituted phosphonates was investigated further. For the initial addition of the anion to the aldehyde, the barrier is again significantly higher for the lithium vs the magnesium case due to greater Lewis acidity of the latter. However, the barriers are generally lower for the fluoro-substituted phosphonate than for the methyl-substituted phosphonate anion. Apparently, the lower nucleophilicity of the fluoro-substituted phosphonate (NBO charge on enolic carbon: F = –0.32 ± 02, Me = –0.76 ± 01) is offset by the greater steric size of the methyl vs fluoro group. This substituent enters into particularly close proximity to the aldehyde groups due to the non-parallel approach of the phosphonate anion along the Dunitz-Bürgi angle to engage π* of the aldehyde. A distortion interaction analysis highlights this effect (see Supporting Information) where the aldehyde undergoes greater distortion with the methyl-substituted phosphonate anion (average = 14.9 kcal/mol) vs the fluoro analog (average = 7.8 kcal/mol).

The hydrolysis of esters in the products from the above reactions was performed using LiOH in aqueous EtOH or i-PrOH, and upon completion of the reaction, acidification usually resulted in crystallization of the product acids in high yield and often with increased isomeric purity (up to >98:2 E/Z).²² For example, hydrolysis of esters 15a and 26a gave the corresponding acids 15b and 26b as single E-isomers on acidification (Scheme 3). Alternatively, the acids could be recrystallized to achieve the desired purity: acid 18b of 95:5 isomeric purity was upgraded to the pure E-isomer (>98:2) after a recrystallization from heptane. This favorable property of the α-fluoroacrylic acids eliminated the need for chromatography for removal of the minor isomer.

Scheme 3.

Hydrolysis of esters to crystalline acids and recrystallization to upgrade isomeric purity.

With the optimal reaction conditions in hand, the scope of the olefination/hydrolysis was explored (Table 2). For a variety of aryl alkyl and heteroaryl alkyl ketones, the olefination proceeded with E/Z selectivity of ≥90:10, with the highest selectivity observed for the sterically hindered 24a (single E-isomer). The olefination proceeded with uniformly high selectivity for electron poor (17a and 22a) and electron rich (16a and 21a) substrates. The olefination of vinyl alkyl ketones resulted in dienes 28a and 29a, with lower selectivity for the less sterically differentiated substrate 29a. The acids were often obtained as pure E-isomers (E/Z >98:2 by ¹⁹F NMR) after crystallization from the reaction mixture on acidification. For substrates 17b, 19b and 28b, the olefination and hydrolysis steps were telescoped (unpurified ester was taken directly into hydrolysis) and the overall yield of acid from ketone is given.

Table 2.

Scope of olefination/hydrolysis of ketones.^a

^aFor olefination products, yield of purified product, reaction E/Z selectivity, and E/Z isomeric purity of purified product [brackets] are given. When E/Z selectivity was the same for the reaction and purified product, no bracketed ratio is given. For carboxylic acid products, yield of purified product is given followed by E/Z isomeric purity of product. E/Z ratio from ¹⁹F NMR of crude product (esters) and isolated product (acids). For detailed reaction conditions, see the Experimental Section.

^bUnpurified ester taken directly into hydrolysis. Yield of acid is the overall yield from ketone.

The olefination/hydrolysis sequence was next applied to a selection of aldehydes (Table 3). As observed for olefination of aldehyde 11, the use of n-BuLi gave uniformly high E-selectivity for aryl, heteroaryl and alkyl aldehydes.¹⁵ The application of MeMgBr as base for olefination gave complimentary results, favoring the Z-isomers Z-12a and Z-30a and with modest selectivity (80:20 and 83:17, respectively). As observed for the ketone substrates, hydrolysis of the esters usually resulted in single E-isomers after isolation by crystallization directly from the reaction mixtures.

Table 3.

Scope of olefination/hydrolysis of aldehydes.^a

^aFor olefination products, yield of purified product, reaction E/Z selectivity, and E/Z isomeric purity of purified product [brackets] are given. When E/Z selectivity was the same for the reaction and purified product, no bracketed ratio is given. For carboxylic acid products, yield of purified product is given followed by E/Z isomeric purity of product. E/Z ratio from ¹⁹F NMR of crude product (esters) and isolated product (acids). For detailed reaction conditions, see the Experimental Section.

^bOlefination was performed using MeMgBr as base.

Single crystal X-ray structures were obtained for acids E-16b and Z-12b (Scheme 4) which confirmed the geometry assignments of the olefins.

Scheme 4.

X-ray crystal structures of acids E-16b and Z-12b

The decarboxylation of three α-fluoroacrylic acids was reported in 1967 by Elkik using a mixture of Cu powder and CuSO₄ (36 mol % Cu in total) in quinoline at 205–210 °C.²³ Subsequent to Elkik’s pioneering work, only stoichiometric decarboxylations have been reported.²⁴ With the hopes of identifying milder conditions with lower temperature and catalyst loading, we embarked on a screen of catalysts for decarboxylation, using 10b of 96:4 E/Z purity as substrate (Table 4).²⁵ For the initial screen, 50 mol % of catalyst was used in NMP (3 volumes) at 130 °C, with the reaction progress and the E/Z ratio of the product determined by HPLC analysis. Of the Cu catalysts screened, Cu₂O was most effective, giving full conversion after 24 h with a slight drop in isomeric purity (94:6, entry 1). Silver salts are well known to promote decarboxylation, and a screen of various Ag salts gave some excellent results.²⁶ Ag(I) salts with low pK_a counterions gave low conversions (entries 6–8), but with retention of the starting olefin isomer ratio. AgNO₃ gave complete conversion after just 1.5 h, but with significant erosion of isomeric purity (76:24, entry 9). The more basic catalysts Ag₂CO₃ and Ag₂O (entries 10–11) also gave full conversion in 1.5 h and with only slight loss of geometric integrity (95:5 and 94:6, respectively). AgOAc proved to be the optimal silver catalyst, giving full conversion in 1.5 h with no loss of isomeric purity (entry 12). The use of Pd, Fe or Ir catalysts was ineffective (entries 13–15). Interestingly, Rh(nbd)₂BF₄ gave a moderate conversion after 24 h and with increased isomeric purity (99:1, entry 16). The Wilkinson catalyst, however, gave no reaction (entry 17).

Table 4.

Decarboxylation catalyst screen.

entry	catalyst	Conversion (%)a			E/Zb
		1 h	4 h	24 h
1	Cu2O	-	28	100	94:6
2	CuO	-	0	1	87:13
3	Cu(OAc)2	-	1	45	94:6
4	CuOAc	-	0	0	-
5	CuTCc	-	5	50	95:5
6	AgOTs	-	8	21	96:4
7	AgBF4	-	-	25	96:4
8	AgOTf	5	-	27	96:4
9	AgNO3	100d	-	-	76:24
10	Ag2CO3	100d	-	-	95:5
11	Ag2O	100d	-	-	94:6
12	AgOAc	100 d	-	-	96:4
13	Pd(OAc)2	-	0	0	-
14	Fe(acac)3	-	0	0	-
15	[Ir(cod)Cl]2	-	0	0	-
16	Rh(nbd)2BF4	-	15	55	99:1
17	Rh(PPh3)3Cl	-	0	0	-

^aConversion of 10b to 10c as measured by HPLC (220 nm).

^bE/Z ratio from HPLC.

^cCopper(I) thiophene-2-carboxylate.

^dConversion after 1.5 h.

We next performed a solvent screen using the optimal catalyst AgOAc with a 50 mol % loading (Table 5). DMAc and DMSO were effective solvents for the reaction, but with slight reduction in isomeric purity (entries 2 and 3). The use of quinoline and pyridine gave a slower reaction but with retention of isomeric integrity (entries 4 and 5). The reaction proceeded but very slowly in 1-pentanol (entry 6). Decarboxylation was significantly retarded in propionic acid due to competitive binding to Ag (entry 7). Low conversion was observed in xylene due to the poor solubility of the catalyst (entry 8).

Table 5.

Decarboxylation solvent screen.

entry	solventa	Conversion (%)b			E/Zc
		2 h	4 h	24 h
1	NMP	100	-	-	96:4
2	DMAc	100	-	-	95:5
3	DMSO	100	-	-	94:6
4	quinoline	90	100	-	96:4
5	pyridine	75	98	100	96:4
6	1-pentanol	-	12	51	96:4
7	propionic acid	0	1	7	98:2
8	p-xylene	0	3	3	97:3

^aThree volumes of solvent relative to 10b.

^bConversion of 10b to 10c as measured by HPLC (220 nm).

^cE/Z ratio from HPLC.

Finally, the loading of AgOAc was optimized (Table 6). Using 15 or 10 mol % catalyst, the reaction reached complete conversion after 1 h (entries 1 and 2). Lowering further to 5 mol % (entry 3) resulted in high but incomplete conversion after 1 h, with the reaction reaching completion by 2 h. The use of only 2.5 mol % catalyst drastically slowed the reaction, with it stalling at 22% conversion after 1 h (entry 4). Increasing the concentration of the reaction by using two instead of three volumes of NMP did not enable complete conversion with 2.5 mol % catalyst (entry 5) but with 5 mol % complete conversion was achieved in 1 h (entry 6). In all cases, isomeric purity was fully retained.

Table 6.

Catalyst loading optimization for decarboxylation.

entry	mol % AgOAc	Conversion (%)a			E/Zb
		1 h	2 h	3 h
1	15.0	100	-	-	96:4
2	10.0	100	-	-	96:4
3	5.0	96	100	-	96:4
4	2.5	22	22	22	96:4
5	2.5c	23	23	23	96:4
6	5.0 c	100	-	-	96:4

^aConversion of 10b to 10c as measured by HPLC (220 nm).

^bE/Z ratio from HPLC.

^cTwo volumes of NMP instead of three volumes.

The decarboxylation was then applied to the α-fluoroacrylic acid substrates using the optimized reaction conditions (Table 7). A variety of aryl, heteroaryl and vinyl substituted α-fluoroacrylic acids underwent decarboxylation to yield the corresponding trisubstituted vinyl fluorides in good yields. In all cases except 27c, the isomeric purity of the starting acrylic acid was completely preserved in the trisubstituted vinyl fluoride product. In the case of 27c, the isomeric purity decreased from 92:8 to 81:19 during the decarboxylation. We attribute this anomaly to interaction of the thiophilic silver catalyst with the sulfur atom of the thiophene ring. Notably, the decarboxylation was not perturbed by the presence of other groups known to coordinate or react with silver, such as an aryl bromide (18c, 22c, 25c), an alkyne (23c), a nitrile (24c), and a quinoline nitrogen (26c). The reaction also gave access to unusual terminal monofluoro 1,3-dienes (28-29c).

Table 7.

Silver catalyzed decarboxylation of α-fluoroacrylic acids to trisubstituted vinyl fluorides.^a

^aAssay yields from ¹⁹F NMR versus PhCF₃ are given in brackets, isolated yields are given with no brackets. E/Z isomeric purity of isolated product is given under yields. Isomeric purity determined by ¹⁹F NMR.

^bE/Z ratio degraded from 92:8 to 81:19 during the reaction. The minor isomer was removed by chromatography. For detailed reaction conditions, see the Experimental Section.

The decarboxylation was applied to aldehyde-derived α-fluoroacrylic acids with similar success (Table 8). Both aryl and alkyl substituted fluoroalkenes were amenable to the decarboxylation. The pure E and pure Z isomers of 12b and 30b were converted to the corresponding vinyl fluorides with the isomeric purity completely maintained. Decarboxylation of E-12b and E-30b was facile with only 5 mol % catalyst loading whereas the reaction of isomeric Z-12b and Z-30b required 50 mol % of AgOAc and higher dilution due to lower solubility of the corresponding Ag carboxylate intermediates. Higher reaction temperature (140–145 °C) and increased catalyst loading was also required for efficient decarboxylation of alkyl substituted fluoroacrylic acids (33–35b).

Table 8.

Silver catalyzed decarboxylation of α-fluoroacrylic acids to disubstituted vinyl fluorides.^a

^aAssay yields from ¹⁹F NMR versus PhCF₃ are given in brackets, isolated yields are given with no brackets. E/Z isomeric purity of isolated product is given under yields. Isomeric purity determined by ¹⁹F NMR. For detailed reaction conditions, see the Experimental Section.

^bAgOAc loading of 50 mol %.

The overall method as described above was applied to the synthesis of the BPAO inhibitor 2 (Scheme 5).^6b Olefination of bromoacetophenone 36 gave the ester 37 with a 90:10 Z/E reaction selectivity which was upgraded to a 97:3 Z/E after purification. Displacement of the bromide with di-tert-butyliminodicarboxylate gave 38, which was converted to the mono-Boc acid 39 with aqueous LiOH. The minor E-isomer of 39 was not detectable in the product due to isolation of both 38 and 39 by crystallizations which effectively purged the minor isomer. Decarboxylation of 39 gave a 93% yield of 40 with complete retention of geometric purity. Finally, Boc deprotection yielded the target compound 2 in high yield.

Scheme 5.

Application of HWE/hydrolysis/decarboxylation to the synthesis of BPAO inhibitor 2.

The protocol was also applied to the synthesis of an intermediate en route to LuxS inhibitor 5 (Scheme 6).^6e Periodate cleavage of diol 41²⁷ in EtOH/water gave the aldehyde 42 along with its ethyl hemiacetal. This mixture was taken directly into the olefination with 8 using n-BuLi as base to provide ester 43 with 92:8 E/Z selectivity in 85% yield from 41. Hydrolysis gave the acid 44 (E/Z = 94:6), which upon decarboxylation furnished 45 in 79% yield and as a single isomer after purification. Compound 45 can be converted to 5 by literature methods.^6e

Scheme 6.

Application of HWE/hydrolysis/decarboxylation to the formal synthesis of LuxS inhibitor 5.

CONCLUSION

In summary, a HWE olefination/hydrolysis/decarboxylation sequence has been developed for the preparation of di- and trisubstituted terminal monofluoroalkenes. The olefination reaction exhibits high E-selectivity for ketone substrates using MeMgBr as base and for aldehyde substrates using n-BuLi as base. Upon hydrolysis, the derived α-fluoroacrylic acids are crystalline solids which may be isolated by direct crystallization from the reaction mixture upon acidification, often with an upgrade in isomeric purity. The acids can also be recrystallized to upgrade isomeric purity if necessary. A silver catalyzed decarboxylation was developed which proceeds with retention of olefin configuration under relatively mild reaction conditions. Importantly, the reagent 8 used for the HWE olefination is inexpensive and widely available. This protocol provides a practical method for accessing α-fluoroacrylic acids and terminal di- and trisubstituted vinyl fluorides with high geometric purity without recourse to difficult chromatography for separation of isomers.

EXPERIMENTAL SECTION

General Information.

All starting materials, reagents and solvents were purchased from commercial sources and used as received unless otherwise noted. For reactions requiring heating, an oil bath was used as the heat source. ¹H, ¹⁹F and ¹³C NMR spectra were recorded using Bruker DRX 400 or 500 MHz spectrometers. ¹H and ¹³C chemical shifts are referenced to internal solvent resonances (CHCl₃ ¹H, δ = 7.26 ppm; CDCl₃ ¹³C, δ = 77.0 ppm) and reported relative to SiMe₄; multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet) and brs (broad signal). Coupling constants, J, are reported in Hertz. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. Flash chromatography was performed on a Combi-Flash automated system with silica columns. High-resolution accurate mass (HRAM) was performed on both a Thermo LTQ FT-ICR mass spectrometer using DART source ionization in positive/negative ion modes and on a Thermo Scientific Exactive GC/MS using positive ion electron ionization (EI). Melting points were measured using a differential scanning calorimeter TA instrument DSC 2500.

General Procedure for Horner-Wadsworth-Emmons Reaction of Ketones with Triethyl 2-fluoro-2-phosphonoacetate and MeMgBr in THF.

A round bottom flask is charged with triethyl 2-fluoro-2-phosphonoacetate (1.7–4.5 equiv) and THF (0.3 M rel to ketone substrate). The solution is cooled to 0 to −5 °C. MeMgBr (3.4 M in 2-MeTHF, 1.7–4.5 equiv) is then added dropwise maintaining internal temperature below 10 °C. The reaction mixture is warmed to rt and stirred for 10 min, then heated to 40 °C and stirred for another 10 min. A solution of ketone (1.0 equiv) in THF (1 M) is added dropwise, and the reaction mixture is stirred for 0.5–3 h. After reaction is complete, judged by HPLC or GC analysis, the mixture is cooled to rt. The reaction mixture is quenched with 10% aq. NH₄Cl solution and extracted with EtOAc. Organic phase is dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography.

Ethyl (E)-2-fluoro-3-(naphthalen-2-yl)but-2-enoate (10a).

The reaction between acetonaphthone 9 (10.0 g, 58.75 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (23.8 mL; 117.50 mmol; 2.0 equiv) and MeMgBr (33.8 mL, 117.50 mmol, 3.48 M in 2-MeTHF, 2.0 equiv) was run at 40 °C for 30 min. ¹⁹F NMR of the crude: mixture of stereoisomers in 20.6:1 (95:5) dr. The product was obtained as a colorless oil after purification by silica gel column chromatography eluting with 0–5% EtOAc in hexanes (14.90 g, 98% yield, mixture of stereoisomers in 20.9:1 (95:5) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.90–7.79 (m, 3H), 7.69 (d, J_HF = 1.0 Hz, 1H), 7.55–7.47 (m, 2H), 7.35 (dd, J = 8.4 Hz, J = 1.7 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.27 (d, J = 4.5 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5 (d, J = 36.1 Hz), 144.5 (d, J = 252.3 Hz), 135.8 (d, J = 5.5 Hz), 132.9, 132.6, 131.2 (d, J = 17.2 Hz), 127.8, 127.59, 127.52, 126.2 (d, J = 3.3 Hz), 126.12, 126.07, 125.7 (d, J = 3.0 Hz), 60.9, 19.2 (d, J = 6.5 Hz), 13.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.1 (d, J_HF = 4.4 Hz); Z-isomer: −125.3 (s). HRMS (DART) calcd for C₁₆H₁₆O₂F [M+H]⁺: 259.1129, found 259.1129.

Ethyl (Z)-3-(4-bromophenyl)-2-fluoroacrylate (Z-12a).

The reaction between 4-bromobenzaldehyde (4.25 g, 22.97 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (7.0 mL; 34.46 mmol; 1.5 equiv) and MeMgBr (9.90 mL, 34.46 mmol, 3.40 M in 2-MeTHF, 1.5 equiv) was run at −40 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 4.0:1 (80:20) dr. The product Z-12a was obtained as a white solid after purification by silica gel column chromatography eluting with 0–2% MTBE in hexanes (4.60 g, 73% yield, single Z-isomer (>98:2 dr)). mp 62.1–63.6 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.56–7.46 (m, 4H), 6.85 (d, J_HF = 34.7 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.1 (d, J = 34.2 Hz), 147.4 (d, J = 269.1 Hz), 132.0, 131.6 (d, J = 8.3 Hz), 130.0 (d, J = 4.4 Hz), 124.0 (d, J = 3.9 Hz), 116.3 (d, J = 4.7 Hz), 62.0, 14.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.0 (d, J_HF = 34.7 Hz). NMR spectra matched reported data.³⁰

Ethyl (E)-3-(4-bromophenyl)-2-fluoroacrylate (E-12a).

The reaction between 4-bromobenzaldehyde (3.0 g, 16.21 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (4.93 mL; 24.32 mmol; 1.5 equiv) and n-BuLi (9.0 mL, 24.32 mmol, 2.71 M in hexanes, 1.5 equiv) was run at −78 °C to −20 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 35.5:1 (97:3) dr. The product E-12a was obtained as a colorless oil after purification by silica gel column chromatography eluting with 0–2% MTBE in hexanes (4.14 g, 94% yield, mixture of stereoisomers in 34.5:1 (97:3) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.50–7.44 (m, 2H), 7.38–7.31 (m, 2H), 6.81 (d, J_HF = 21.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.3 (d, J = 35.7 Hz), 147.2 (d, J = 257.6 Hz), 131.3 (d, J = 3.1 Hz), 131.2, 129.9 (d, J = 9.7 Hz), 122.9, 120.4 (d, J = 26.8 Hz), 61.8, 13.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −115.9 (d, J_HF = 21.9 Hz), Z-isomer: −124.0 (d, J_HF = 34.7 Hz). NMR spectra matched reported data.²⁸

Reaction of triethyl 2-phosphonopropionate (14) with 4-bromobenzaldehyde. Ethyl (E)-3-(4-bromophenyl)-2-methylacrylate (E-13).

Using MeMgBr as base:

The reaction between 4-bromobenzaldehyde (1.00 g, 5.40 mmol, 1 equiv) and reagent prepared from triethyl 2-phosphonopropionate (1.74 mL; 8.11 mmol; 1.5 equiv) and MeMgBr (2.33 mL, 8.11 mmol, 3.48 M in 2-MeTHF, 1.5 equiv) was run at −40 °C with warming to rt. ¹H NMR of the crude: >45:1 dr. The product E-13 was obtained as a colorless oil after purification by silica gel column chromatography eluting with 2–5% EtOAc in hexanes (1.35 g, 93% yield). Using n-BuLi as base: The reaction between 4-bromobenzaldehyde (1.00 g, 5.40 mmol, 1 equiv) and reagent prepared from triethyl 2-phosphonopropionate (1.74 mL; 8.11 mmol; 1.5 equiv) and n-BuLi (3.24 mL, 8.11 mmol, 2.50 M in hexanes, 1.5 equiv) was run at −78 °C with warming to rt. ¹H NMR of the crude: >45:1 dr. The product E-13 was obtained as a colorless oil after purification by silica gel column chromatography eluting with 2–5% EtOAc in hexanes (1.33 g, 91% yield). NMR spectra for E-13 prepared by both methods matched reported data.²⁹

Ethyl (E)-2-fluoro-3-phenylbut-2-enoate (15a).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (591 μL, 2.91 mmol, 1.7 equiv) and THF (4.9 mL). The solution was cooled to 0 to −5 °C. MeMgBr (985 μL, 2.91 mmol, 2.96 M in Et₂O, 1.7 equiv) was added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then heated to 40 °C and stirred for another 10 min. A solution of acetophenone (200 μL, 1.71 mmol, 1.0 equiv) in THF (1.7 mL) was added dropwise, and the reaction mixture was stirred for 15 min. The mixture was cooled to rt, quenched with sat. aq. NH₄Cl solution (10 mL) and extracted with EtOAc (2 × 10 mL). The organic phase was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by quantitative ¹⁹F NMR which showed a mixture of stereoisomers in 15.5:1 (94:6) dr. The residue was purified by silica gel column chromatography eluting with 0–2% EtOAc in hexanes to afford 15a as a colorless liquid. Mixture of stereoisomers in 15.9: 1 (94:6) dr (341.6 mg, 96% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.30 (m, 3H), 7.23–7.14 (m, 2H), 4.05 (q, J = 7.2 Hz, 2H), 2.15 (d, J_HF = 4.4 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 160.5 (d, J = 36.2 Hz), 144.2 (d, J = 251.7 Hz), 138.5 (d, J = 5.5 Hz), 131.3 (d, J = 17.0 Hz), 128.0, 127.7, 127.3 (d, J = 3.1 Hz), 60.9, 19.2 (d, J = 6.6 Hz), 13.5; ¹⁹F NMR (470 MHz, CDCl₃) δ −123.9 (s). NMR spectra matched reported data.³⁰

Ethyl (E)-3-(benzo[d][1,3]dioxol-5-yl)-2-fluorobut-2-enoate (16a).

The reaction between 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (3.0 g, 18.28 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (8.15 mL; 40.21 mmol; 2.2 equiv) and MeMgBr (11.6 mL, 40.21 mmol, 3.48 M in 2-MeTHF, 2.2 equiv) was run at 40 °C for 2 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 17.9:1 (95:5) dr. The product 16a was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 2–8% EtOAc in hexanes (3.88 g, 84% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 6.78 (d, J = 7.9 Hz, 1H), 6.70–6.60 (m, 2H), 5.96 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.10 (d, J_HF = 4.5 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5 (d, J = 35.8 Hz), 147.3, 147.2, 144.3 (d, J = 252.6 Hz), 131.9 (d, J = 5.8 Hz), 131.0 (d, J = 17.6 Hz), 121.0 (d, J = 3.2 Hz), 108.2 (d, J = 3.3 Hz), 108.0, 101.1, 70.0, 19.3 (d, J = 6.4 Hz), 13.7; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.4 (q, J_HF = 4.5 Hz). HRMS (DART) calcd for C₁₅H₁₉O₂BrF [M+H]⁺: 329.0547, found 329.0550.

Ethyl (E)-3-(4-bromophenyl)-2-fluorohept-2-enoate (18a).

The reaction between 1-(4-bromophenyl)pentan-1-one (3.0 g, 12.44 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (6.31 mL; 31.10 mmol; 2.5 equiv) and MeMgBr (9.15 mL, 31.10 mmol, 3.40 M in 2-MeTHF, 2.5 equiv) was run at 40 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 17.1:1 (94:6) dr. The product 18a was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 5% MTBE in hexanes (3.77 g, 92% yield, mixture of stereoisomers in 20.5:1 (95:5) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.50–7.45 (m, 2H), 7.06–6.99 (m, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.60–2.40 (m, 2H), 1.41–1.23 (m, 4H), 1.06 (t, J = 7.1 Hz, 3H), 0.93–0.79 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.3 (d, J = 36.2 Hz), 144.2 (d, J = 254.1 Hz), 136.1 (d, J = 5.8 Hz), 134.4 (d, J = 17.1 Hz), 131.1, 129.5 (d, J = 3.1 Hz), 121.6, 61.0, 32.0 (d, J = 4.8 Hz), 28.7 (d, J = 2.0 Hz), 22.2, 13.59, 13.56; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.3 (t, J_HF = 3.5 Hz); Z-isomer: −124.2 (s). HRMS (DART) calcd for C₁₅H₁₉O₂BrF [M+H]⁺: 329.0547, found 329.0550.

Ethyl (E)-2-fluoro-4-methyl-3-phenylpent-2-enoate (20a).

The reaction between isobutyrophenone (3.0 g, 20.2 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (10.26 mL, 50.6 mmol, 2.5 equiv) and MeMgBr (17.1 mL, 50.6 mmol, 2.96 M in Et₂O, 2.5 equiv) was run at 40 °C for 30 min. ¹⁹F NMR of the crude: mixture of stereoisomers in 11.6:1 (92:8) dr. The product 20a was obtained as a colorless oil after purification by silica gel column chromatography eluting with 0–5% EtOAc in hexanes (4.37 g, 11.6:1 (92:8) dr, 91% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.29 (m, 3H), 7.11–7.03 (m, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.31 (dsept, J = 7.0 Hz, J_HF = 0.5 Hz 1H), 1.02 (d, J = 7.0 Hz, 6H), 0.96 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.7 (d, J = 36.9 Hz), 143.7 (d, J = 253.0 Hz), 139.8 (d, J = 14.0 Hz), 134.7 (d, J = 5.6 Hz), 128.3 (d, J = 3.2 Hz), 127.5, 127.2, 60.8, 28.9 (d, J = 5.1 Hz), 20.1 (d, J = 2.0 Hz), 13.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −126.2 (d, J_HF = 5.0 Hz); Z-isomer: −121.3 (s). NMR spectra matched reported data.³⁰

Ethyl (E)-3-cyclopropyl-2-fluoro-3-(4-methoxyphenyl)acrylate (21a).

The reaction between cyclopropyl(4-methoxyphenyl) ketone (4.0 g, 22.70 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (19.6 mL; 96.48 mmol; 4.25 equiv) and MeMgBr (27.7 mL, 96.48 mmol, 3.48 M in 2-MeTHF, 4.25 equiv) was run at 70 °C overnight. ¹⁹F NMR of the crude: mixture of stereoisomers in 11.0:1 (92:8) dr). The product 21a was obtained as a white solid after purification by silica gel column chromatography eluting with 1–5% EtOAc in hexanes (4.46 g, 74% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 6.95–6.87 (m, 2H), 6.87–6.79 (m, 2H), 3.99 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.29–2.10 (m, 1H), 1.00 (t, J = 7.1 Hz, 3H), 0.83–0.70 (m, 2H), 0.44–0.31 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.3 (d, J = 35.1 Hz), 159.0, 145.2 (d, J = 251.6 Hz), 136.9 (d, J = 13.4 Hz), 129.9 (d, J = 3.2 Hz), 124.6 (d, J = 5.1 Hz), 113.1, 60.6, 55.0, 13.6, 11.7 (d, J = 9.4 Hz), 4.8 (d, J = 1.2 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −131.2 (s). HRMS (DART) calcd for C₁₅H₁₈O₃F [M+H]⁺: 265.1235, found 265.1235.

Ethyl (Z)-3-(4-bromophenyl)-2,4,4,4-tetrafluorobut-2-enoate (22a).

The reaction between 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one (4.0 g, 15.81 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (8.0 mL; 39.52 mmol; 2.5 equiv) and MeMgBr (11.6 mL, 39.52 mmol, 3.40 M in 2-MeTHF, 2.5 equiv) was run at 40 °C for 30 min. ¹⁹F NMR of the crude: mixture of stereoisomers in 25.8:1 (96:4) dr. The product 22a was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 5% MTBE in hexanes (4.56 g, 85% yield, mixture of stereoisomers in 25.8:1 (96:4) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.59–7.52 (m, 2H), δ 7.18–7.09 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 158.7 (d, J = 34.5 Hz), 149.6, (dq, J = 285.1 Hz, J = 2.4 Hz), 131.6, 131.0 (d, J = 3.4 Hz), 127.5 (d, J = 2.5 Hz), 123.9, 121.6 (q, J = 275.4 Hz), 120.5 (dq, J = 32.9 Hz, J = 9.4 Hz), 62.6, 13.3; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −107.3 (q, J = 24.3 Hz), −60.5 (d, J = 24.3 Hz); Z-isomer: δ −105.7 (q, J = 10.0 Hz), −58.5 (d, J = 10.0 Hz). HRMS (DART) calcd for C₁₂H₁₀O₂BrF₄ [M+H]⁺: 340.9795, found 340.9796.

1-(3,5-Dimethylphenyl)hept-5-yn-1-one.

To a suspension of Mg turnings (489.5 mg, 20.13 mmol, 1.04 equiv) in THF (5 mL) was added 1,2-dibromoethane (63 µL, 0.73 mmol, 0.04 equiv) and the mixture was heated to 50 °C and stirred for 15 min. A solution of 1-bromo-3,5-dimethylbenzene (2.63 mL, 19.36 mmol, 1 equiv) in THF (20 mL) was then added dropwise maintaining steady solvent boiling. After complete addition the reaction mixture was stirred at 50 °C for 30 min. The resultant Grignard reagent was titrated with salicylaldehyde phenylhydrazone: 0.765 M solution was obtained. Grignard reagent (13.8 mL, 10.56 mmol, 1.0 equiv.) was added dropwise to a solution of 2-methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate³¹ (3.0 g; 11.62 mmol; 1.1 equiv) in THF (20 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min and then warmed to room temperature and stirred for additional 30 min. The reaction mixture was quenched with 10% aq. NH₄Cl solution and extracted with MTBE (2 × 30 mL). Combined organic extracts were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5–30% EtOAc in hexanes to afford the title ketone as a pale yellow oil (1.56 g, 63% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 2H), 7.19 (s, 1H), 3.06 (t, J = 7.3 Hz, 2H), 2.37 (s, 6H), 2.29–2.21 (m, 2H), 1.90 (apparent quintet, J = 7.0 Hz, 2H), 1.78 (t, J = 2.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 200.3, 138.1, 137.1, 134.5, 125.8, 78.5, 76.3, 37.4, 23.5, 21.2, 18.3, 3.4. HRMS (DART) calcd for C₁₅H₁₉O [M+H]⁺: 215.1430, found 215.1431.

Ethyl (E)-3-(3,5-dimethylphenyl)-2-fluoronon-2-en-7-ynoate (23a).

The reaction between 1-(3,5-dimethylphenyl)hept-5-yn-1-one (1.50 g, 7.00 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (3.3 mL; 16.10 mmol; 2.3 equiv) and MeMgBr (4.6 mL, 16.10 mmol, 3.48 M in 2-MeTHF, 2.3 equiv) was run at 40 °C for 2 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 22.0:1 (96:4) dr. The product 23a was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 0–2% MTBE in hexanes (1.95 g, 92% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 6.94 (s, 1H), 6.74 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.63–2.53 (m, 2H), 2.31 (s, 6H), 2.18–2.08 (m, 2H), 1.76 (t, J = 2.5 Hz, 3H), 1.62–1.48 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.6 (d, J = 36.6 Hz), 144.3 (d, J = 252.4 Hz), 137.3, 136.7 (d, J = 5.3 Hz), 134.8 (d, J = 15.7 Hz), 129.3, 125.5 (d, J = 3.0 Hz), 78.2, 75.9, 60.8, 31.7 (d, J = 5.2 Hz), 26.3 (d, J = 2.1 Hz), 21.1, 18.5, 13.5, 3.3; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.9 (s). HRMS (DART) calcd for C₁₉H₂₄O₂F [M+H]⁺: 303.1755, found 303.1755.

Ethyl (Z)-3-(1-cyanocyclohexyl)-2-fluoro-3-(4-methoxyphenyl)acrylate (24a).

The reaction between 1-(4-methoxybenzoyl)cyclohexane-1-carbonitrile³² (1.0 g, 4.11 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (3.75 mL, 18.5 mmol, 4.5 equiv) and MeMgBr (5.31 mL, 18.5 mmol, 3.48 M in 2-MeTHF, 4.5 equiv) was run at 40 °C for 18 h. ¹⁹F NMR of the crude: single stereoisomer (>98:2 dr). The product 24a was obtained as a colorless oil after purification by silica gel column chromatography eluting with EtOAc in hexanes (1.33 g, 98% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 7.01 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.12–1.97 (m, 2H), 1.83–1.64 (m, 5H), 1.49–1.33 (m, 2H), 1.18–1.03 (m, 1H), 1.02 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.9 (d, J = 35.3 Hz), 159.6, 147.0 (d, J = 269.0 Hz), 132.2 (d, J = 9.5 Hz), 129.9 (d, J = 3.5 Hz), 125.1 (d, J = 5.8 Hz), 120.6, 113.6, 61.5, 55.1, 41.6 (d, J = 1.7 Hz), 34.3 (d, J = 2.1 Hz), 24.6, 22.7, 13.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −111.4 (s). HRMS (DART) calcd for C₁₉H₂₃O₃NF [M+H]⁺: 332.1657, found 332.1657.

Ethyl (E)-3-(4-bromophenyl)-2-fluoro-4-phenylbut-2-enoate (25a).

The reaction between 1-(4-bromophenyl)-2-phenylethan-1-one (4.0 g, 14.54 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (5.9 mL; 29.08 mmol; 2.0 equiv) and MeMgBr (8.4 mL, 29.08 mmol, 3.48 M in 2-MeTHF, 2.0 equiv) was run at 40 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 13.2:1 (93:7) dr. The product 25a was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 0–5% MTBE in hexanes (4.94 g, 94% yield, mixture of stereoisomers in 13.3:1 (93:7) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.31 (m, 2H), 7.27–7.13 (m, 3H), 7.06–6.97 (m, 2H), 6.84–6.75 (m, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.79 (d, J_HF = 3.6 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 160.4 (d, J = 36.2 Hz), 144.3 (d, J = 255.8 Hz), 136.3 (d, J = 2.5 Hz), 135.6 (d, J = 5.3 Hz), 132.8 (d, J = 17.0 Hz), 131.0, 129.7 (d, J = 3.1 Hz), 129.1 (d, J = 1.1 Hz), 128.5, 126.7, 121.8, 61.3, 38.6 (d, J = 5.1 Hz), 13.6; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.3 (t, J_HF = 3.2 Hz); Z-isomer: −122.6 (s). HRMS (DART) calcd for C₁₈H₁₇O₂BrF [M+H]⁺: 363.0391, found 363.0391.

Ethyl (E)-2-fluoro-3-(quinolin-3-yl)but-2-enoate (26a).

The reaction between 1-(quinolin-3-yl)ethan-1-one (4.0 g, 23.37 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (8.1 mL; 39.72 mmol; 1.7 equiv) and MeMgBr (11.7 mL, 39.72 mmol, 3.40 M in 2-MeTHF, 1.7 equiv) was run at 40 °C for 30 min. ¹⁹F NMR of the crude: mixture of stereoisomers in 9.8:1 (91:9) dr. The product 26a was obtained as a light brown oil after purification by silica gel column chromatography eluting with 40% MTBE in hexanes (4.88 g, 81% yield, mixture of stereoisomers in 11.3:1 (92:8) dr). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J_HF = 2.2 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.91 (d, J_HF = 2.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.63 (ddd, J = 8.5 Hz, J = 6.9 Hz, J = 1.4 Hz, 1H), 7.47 (ddd, J = 8.1 Hz, J = 6.9 Hz, J = 1.0 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 2.17 (d, J_HF = 4.5 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.9 (d, J = 35.7 Hz), 149.6 (d, J = 2.9 Hz), 147.1, 145.0 (d, J = 255.4 Hz), 133.7 (d, J = 3.5 Hz), 131.3 (d, J = 5.4 Hz), 129.4, 129.0, 127.9 (d, J = 5.4 Hz), 127.6, 127.1, 126.7, 61.1, 19.0 (d, J = 6.4 Hz), 13.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −120.4 (q, J_HF = 4.5 Hz); Z-isomer: −123.7 (s). HRMS (DART) calcd for C₁₅H₁₅O₂NF [M+H]⁺: 260.1081, found 260.1082.

Ethyl (E)-3-(benzo[b]thiophen-2-yl)-2-fluorobut-2-enoate (27a).

The reaction between 1-(benzo[b]thiophen-2-yl)ethan-1-one (4.0 g, 22.70 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (9.2 mL; 45.39 mmol; 2.0 equiv) and MeMgBr (13.0 mL, 45.39 mmol, 3.48 M in 2-MeTHF, 2.0 equiv) was run at 40 °C for 30 min. ¹⁹F NMR of the crude: mixture of stereoisomers in 10.9:1 (92:8) dr. The product 27a was obtained as a pale yellow oil after purification by silica gel column chromatography eluting with 2–8% EtOAc in hexanes (5.97 g, 99% yield, mixture of stereoisomers in 10.9:1 (92:8) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.79 (m, 1H), 7.78–7.72 (m, 1H), 7.40–7.29 (m, 2H), 7.25 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.25 (d, J_HF = 4.7 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.2 (d, J = 35.7 Hz), 145.5 (d, J = 257.6 Hz), 140.1, 139.3, 138.9 (d, J = 6.7 Hz), 124.5, 124.3, 123.9 (d, J = 21.6 Hz), 123.64, 123.63 (d, J = 3.5 Hz), 122.0, 61.4, 19.3 (d, J = 6.4 Hz), 13.7; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −116.9 (q, J_HF = 4.7 Hz); Z-isomer: −116.4 (q, J_HF = 3.2 Hz). HRMS (DART) calcd for C₁₄H₁₄O₂FS [M+H]⁺: 265.0693, found 265.0694.

Ethyl (E)-2-fluoro-2-(4a-methyl-5-oxo-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-ylidene)acetate (29a).

The reaction between Wieland-Miescher ketone (4.0 g, 22.44 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (8.2 mL; 40.40 mmol; 1.8 equiv) and MeMgBr (11.6 mL, 40.40 mmol, 3.48 M in 2-MeTHF, 1.8 equiv) was run at −40 °C for 30 min. ¹⁹F NMR of the crude: mixture of double bond isomers in 3.47:1 (78:22) dr. The product 29a was obtained as a colorless oil after purification by silica gel column chromatography eluting with 3–10% EtOAc in hexanes (5.98 g, 99% yield, mixture of double bond isomers in 3.44:1 (78:22) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.84–2.71 (m, 1H), 2.71–2.56 (m, 2H), 2.49–2.34 (m, 2H), 2.34–2.20 (m, 1H), 2.11–1.99 (m, 1H), 1.92–1.74 (m, 2H), 1.71–1.56 (m, 1H), 1.38–1.25 (m, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 212.7, 161.2 (d, J = 33.7 Hz), 151.2 (d, J = 12.4 Hz), 142.0 (d, J = 252.9 Hz), 129.5 (d, J = 18.1 Hz), 118.6 (d, J = 2.5 Hz), 61.0, 50.2, 37.9, 32.0, 28.7 (d, J = 1.6 Hz), 24.0, 23.6 (d, J = 1.4 Hz), 19.5 (d, J = 8.1 Hz), 14.1; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −129.6 (m); Z-isomer: −132.5 (d, J_HF = 4.2 Hz). HRMS (DART) calcd for C₁₅H₂₀O₃F [M+H]⁺: 267.1391, found 267.1392.

Ethyl (Z)-2-fluoro-3-(naphthalen-2-yl)acrylate (Z-30a).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (7.79 mL, 38.42 mmol, 1.5 equiv) and THF (80 mL). The solution was cooled to −10 °C. MeMgBr (11.0 mL, 38.42 mmol, 3.48 M in 2-MeTHF, 1.5 equiv) was added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then cooled to −78 °C. A solution of 2-naphthaldehyde (4.0 g, 25.61 mmol, 1.0 equiv) in THF (23 mL) was added dropwise, and the reaction mixture was linearly warmed to rt over 2 h. The mixture was quenched with sat. aq. NH₄Cl solution (50 mL) and extracted with MTBE (2 × 30 mL). Organic phase was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by quantitative ¹⁹F NMR: mixture of stereoisomers in 4.82:1 (83:17) dr. The residue was purified by silica gel column chromatography eluting with 0–2% MTBE in hexanes to afford the product Z-30a as a white solid (4.64 g, 74% yield, single Z-isomer (>98:2 dr)). mp 68.4–70.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.91–7.75 (m, 4H), 7.57–7.46 (m, 2H), 7.09 (d, J_HF = 35.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.4 (d, J = 34.2 Hz), 147.1 (d, J = 267.8 Hz), 133.5 (d, J = 1.9 Hz), 133.1, 130.7 (d, J = 8.1 Hz), 128.7 (d, J = 4.6 Hz), 128.5, 128.4, 127.6, 127.2, 126.8 (d, J = 8.5 Hz), 126.5, 117.6 (d, J = 4.6 Hz), 61.9, 14.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −125.2 (d, J_HF = 35.3 Hz). Both ¹H and ¹³C NMR spectra matched reported data.³³

General Procedure for Horner-Wadsworth-Emmons Reaction of Aldehydes with Triethyl 2-fluoro-2-phosphonoacetate and n-BuLi in THF. Ethyl (E)-2-fluoro-3-(naphthalen-2-yl)acrylate (E-30a).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (5.84 mL, 28.81 mmol, 1.5 equiv) and THF (50 mL). The solution was cooled to −78 °C. n-BuLi (10.63 mL, 28.81 mmol, 2.71 M in hexanes, 1.5 equiv) was added dropwise maintaining internal temperature below 0 °C. The reaction mixture was warmed to rt and stirred for 10 min, then cooled to −78 °C. A solution of 2-naphthaldehyde (3.0 g, 19.21 mmol, 1.0 equiv) in THF (26 mL) was added dropwise, and the reaction mixture was linearly warmed to 10 °C over 2 h. The mixture was quenched with sat. aq. NH₄Cl solution (50 mL) and extracted with MTBE (2 × 30 mL). The organic phase was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by quantitative ¹⁹F NMR: mixture of stereoisomers in 40.0:1 (98:2) dr. The residue was purified by silica gel column chromatography eluting with 0–2% MTBE in hexanes to afford product E-30a as a white solid (4.59 g, 98% yield, mixture of stereoisomers in 40.0:1 (98:2) dr. mp 31.3–32.7 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 7.89–7.79 (m, 3H), 7.60 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 7.56–7.47 (m, 2H), 7.08 (d, J_HF = 22.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5 (d, J = 36.1 Hz), 147.0 (d, J = 255.1 Hz), 133.1, 132.8, 129.5 (d, J = 3.5 Hz), 128.3 (d, J = 9.5 Hz), 128.2, 127.6, 127.4, 127.0 (d, J = 2.1 Hz), 126.7, 126.3, 121.5 (d, J = 26.3 Hz), 61.6, 13.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −116.5 (d, J_HF = 22.4 Hz); Z-isomer: −125.2 (d, J_HF = 35.3 Hz). Both ¹H and ¹³C NMR spectra matched reported data.³³

Ethyl (E)-3-(benzo[d][1,3]dioxol-4-yl)-2-fluoroacrylate (31a).

The reaction between benzo[d][1,3]dioxole-4-carbaldehyde (3.0 g, 19.98 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (6.08 mL; 29.97 mmol; 1.5 equiv) and HexLi (12.5 mL, 29.97 mmol, 2.40 M in hexanes, 1.5 equiv) was run at −78 °C to −30 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 34.8:1 (97:3) dr. The product 31a was obtained as a colorless oil after purification by silica gel column chromatography eluting with 5–7% EtOAc in hexanes (4.90 g, >99% yield, mixture of stereoisomers in 36.1:1 (97:3) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.03–6.97 (m, 1H), 6.84–6.73 (m, 3H), 5.94 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.3 (d, J = 36.0 Hz), 148.1 (d, J = 257.1 Hz), 147.1, 145.7 (d, J = 2.7 Hz), 122.6 (d, J = 2.6 Hz), 121.1, 113.9 (d, J = 27.9 Hz), 113.3 (d, J = 9.9 Hz), 108.7, 100.9, 61.6, 13.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −115.4 (d, J_HF = 20.7 Hz), Z-isomer: −123.9 (d, J_HF = 35.5 Hz). HRMS (DART) calcd for C₁₂H₁₂O₄F [M+H]⁺: 239.0714, found 239.0715.

Ethyl (E)-3-(benzofuran-2-yl)-2-fluoroacrylate (32a).

The reaction between benzo[b]furan-2-carboxaldehyde (5.0 g, 34.21 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (10.4 mL; 51.31 mmol; 1.5 equiv) and n-BuLi (18.9 mL, 51.31 mmol, 2.71 M in hexanes, 1.5 equiv) was run at −78 °C to −20 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 21.6:1 (96:4) dr, 98% yield. The product 32a was obtained as a pale yellow oil after purification by silica gel column chromatography eluting with 0–3% MTBE in hexanes (7.1 g, 89% yield, single stereoisomer (>98:2 dr). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 8.3 Hz, J = 0.8 Hz, 1H), 7.34 (ddd, J = 8.3 Hz, J = 7.2 Hz, J = 1.3 Hz, 1H), 7.28–7.21 (m, 1H), 6.89 (d, J_HF = 21.9 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.3 (d, J = 33.7 Hz), 154.9 (d, J = 2.3 Hz), 146.9 (d, J = 262.0 Hz), 147.5 (d, J = 10.6 Hz), 128.8, 125.8, 123.1, 121.9, 111.8 (d, J = 7.1 Hz), 111.5 (d, J = 33.5 Hz), 111.1, 61.9, 14.1; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −116.5 (d, J_HF = 21.9 Hz). HRMS (DART) calcd for C₁₃H₁₂O₃F [M+H]⁺: 235.0765, found 235.0766.

Ethyl (E)-3-cyclopropyl-2-fluoroacrylate (33a).

The reaction between cyclopropane carboxaldehyde (2.13 mL, 28.53 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (8.7 mL; 42.80 mmol; 1.5 equiv) and HexLi (17.8 mL, 42.80 mmol, 2.40 M in hexanes, 1.5 equiv) was run at −78 °C to −30 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 40.7:1 (98:2) dr. The product 33a was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 4–7% Et₂O in pentane (4.28 g, 95% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 5.27 (dd, J_HF = 20.3 Hz, J = 10.9 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.52–2.39 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.02–0.89 (m, 2H), 0.56–0.43 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.5 (d, J = 34.4 Hz), 146.6 (d, J = 246.3 Hz), 129.6 (d, J = 21.8 Hz), 61.2, 14.1, 8.4 (d, J = 7.2 Hz), 8.1 (d, J = 1.1 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −127.1 (dd, J_HF = 20.3 Hz, J_HF = 1.8 Hz). HRMS (DART) calcd for C₈H₁₂O₂F [M+H]⁺: 159.0816, found 159.0816.

Ethyl (E)-3-cyclopentyl-2-fluoroacrylate (34a).

The reaction between cyclopentane carboxaldehyde (2.72 mL, 25.47 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (7.75 mL; 38.21 mmol; 1.5 equiv) and HexLi (15.9 mL, 38.21 mmol, 2.40 M in hexanes, 1.5 equiv) was run at −78 °C to −30 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 23.6:1 (96:4) dr. The product 34a was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 4–7% EtOAc in hexanes (4.58 g, 97% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 5.81 (dd, J_HF = 21.8 Hz, J = 10.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.47–3.32 (m, 1H), 1.97–1.83 (m, 2H), 1.74–1.53 (m, 4H), 1.39–1.18 (m, 5H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.1 (d, J = 35.7 Hz), 146.2 (d, J = 250.7 Hz), 128.6 (d, J = 16.5 Hz), 61.2, 36.2 (d, J = 4.8 Hz), 33.6 (d, J = 2.2 Hz), 25.3, 14.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.4 (d, J_HF = 21.8 Hz), Z-isomer: −132.0 (d, J_HF = 33.5 Hz). HRMS (DART) calcd for C₁₀H₁₆O₂F [M+H]⁺: 187.1129, found 187.1129.

Ethyl (E)-2-fluoro-5-phenylpent-2-enoate (35a).

The reaction between 3-phenylpropionaldehyde (2.97 mL, 22.36 mmol, 1 equiv) and reagent prepared from triethyl 2-fluoro-2-phosphonoacetate (6.8 mL; 33.54 mmol; 1.5 equiv) and HexLi (14.0 mL, 33.54 mmol, 2.40 M in hexanes, 1.5 equiv) was run at −78 °C to −30 °C for 1 h. ¹⁹F NMR of the crude: mixture of stereoisomers in 15.1:1 (94:6) dr. The product 35a was obtained as a pale yellow liquid after purification by silica gel column chromatography eluting with 5–7% EtOAc in hexanes (4.44 g, 89% yield, mixture of stereoisomers in 17.6:1 (95:5) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.27 (m, 2H), 7.25–7.18 (m, 3H), 5.94 (dt, J_HF = 21.3 Hz, J = 8.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.91–2.82 (m, 2H), 2.81–2.74 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.8 (d, J = 35.8 Hz), 147.3 (d, J = 252.2 Hz), 140.6, 128.4, 126.1, 122.3 (d, J = 18.6 Hz), 61.3, 35.2 (d, J = 2.3 Hz), 27.1 (d, J = 5.1 Hz), 14.1; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −121.7 (d, J_HF = 21.3 Hz), Z-isomer: −129.6 (d, J_HF = 33.1 Hz). NMR spectra matched reported data.³⁰ HRMS (DART) calcd for C₁₃H₁₆O₂F [M+H]⁺: 223.1129, found 223.1130.

General Procedure for Ester Saponfication.

To a solution of ethyl ester (1 equiv) in EtOH (~0.5 M) was added a solution of LiOH•H₂O (2.0 equiv) in water (volume ratio EtOH/H₂O = 2:1) at 0 °C. The reaction mixture was warmed to r.t and stirred until completion as determined by HPLC or GC. The reaction mixture was diluted with water and cooled to 10 °C. Conc. HCl (2.2 equiv) was added dropwise maintaining internal temperature below 25 °C. The resultant slurry was warmed to rt and diluted further with water. The slurry was filtered and the solid was washed with 25 wt.% EtOH in H₂O. The solid was dried to afford the carboxylic acid product.

(E)-2-Fluoro-3-(naphthalen-2-yl)but-2-enoic acid (10b).

Saponification of ester 10a (15.1 g, 58.07 mmol, 20.9:1 (95:5) dr) in EtOH/water afforded carboxylic acid 10b as a white solid (12.1 g, 21.1:1 (95:5) dr, 91% yield). mp 170.3–171.6 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.85–7.77 (m, 3H), 7.68 (s, 1H), 7.49–7.42 (m, 2H), 7.31 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 5.13–4.75 (brs, 1H), 2.20 (d, J = 4.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 163.7 (d, J = 36.5 Hz), 146.2 (d, J = 250.5 Hz), 137.5 (d, J = 5.6 Hz), 134.6, 134.3, 132.8 (d, J = 17.6 Hz), 129.1, 128.7 (2C), 127.6 (d, J = 3.2 Hz), 127.3 (2C), 127.1 (d, J = 2.9 Hz), 19.6 (d, J = 6.9 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −123.5 (q, J_HF = 4.4 Hz); Z-isomer: −124.6 (s). HRMS (DART) calcd for C₁₄H₁₂O₂F [M+H]⁺: 231.0816, found 231.0816.

(E)-3-(4-Bromophenyl)-2-fluoroacrylic acid (E-12b).

Saponification of ester E-12a (1.05 g, 3.85 mmol, 34.5:1 (97:3) dr) in EtOH/water afforded carboxylic acid E-12b as a white solid (0.80 g, > 98:2 dr, 85% yield). mp 149.1–150.6 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.05–8.94 (brs, 1H); 7.55–7.43 (m, 2H), 7.40–7.29 (m, 2H), 6.97 (d, J_HF = 21.8 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.7 (d, J = 36.8 Hz), 145.9 (d, J = 253.9 Hz), 131.45, 131.43 (d, J = 3.6 Hz), 129.1 (d, J = 9.2 Hz), 123.6; 123.5 (d, J = 26.8 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −116.3 (d, J_HF = 21.8 Hz). HRMS (DART) calcd for C₉H₇O₂BrF [M+H]⁺: 244.9608, found 244.9609.

(Z)-3-(4-Bromophenyl)-2-fluoroacrylic acid (Z-12b).

Saponification of ester Z-12a (4.53 g, 16.59 mmol, > 98:2 dr) in EtOH/water afforded carboxylic acid Z-12b as a white solid (3.97 g, > 98:2 dr, 98% yield). mp 226.5–227.5 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.56 (apparent s, 4H), 6.94 (d, J_HF = 35.0 Hz, 1H) 5.32–4.69 (brs, 1H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 164.0 (d, J = 35.3 Hz), 149.1 (d, J = 265.5 Hz), 133.2, 133.0 (d, J = 8.3 Hz), 131.8 (d, J = 4.3 Hz), 124.9 (d, J = 3.9 Hz), 117.3 (d, J = 4.8 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −124.7 (d, J_HF = 35.0 Hz). NMR spectra matched reported data.³⁴

(E)-2-Fluoro-3-phenylbut-2-enoic acid (15b).

To a solution of ethyl ester 15a (5.85 g, 28.09 mmol; 1 equiv) in EtOH (60 mL) was added a solution of LiOH•H₂O (2.36 g; 56.19 mmol; 2.0 equiv) in water (40 mL) at 0 °C. The reaction mixture was warmed to r.t and stirred for 2 h. After reaction completion the reaction mixture was diluted with water (50.0 mL) and cooled to 10 °C. Conc. HCl (5.1 mL; 61.81 mmol; 2.2 equiv) was added dropwise maintaining internal temperature below 25 °C. The resultant slurry was warmed to rt. Water (50.0 mL) was added dropwise, and the slurry was stirred for another 0.5 h. The slurry was filtered and the solid was washed with 25 wt.% EtOH in H₂O (2 × 15 mL). The solid was dried on a Buchner funnel for 2 h and then at 50 °C in a vacuum oven overnight to afford carboxylic acid 15b as a white solid (4.81 g, 95% yield, >98:2 dr). mp 131.8–133.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.46–9.19 (brs, 1H), 7.40–7.30 (m, 3H), 7.38–7.28 (m, 3H), 7.20–7.11 (m, 2H), 2.16 (d, J_HF = 4.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.2 (d, J = 36.6 Hz), 143.3 (d, J = 248.6 Hz), 137.7 (d, J = 5.1 Hz), 135.0 (d, J = 17.0 Hz), 128.2, 128.1, 127.3 (d, J = 3.1 Hz), 19.9 (d, J = 6.6 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.1 (q, J_HF = 4.5 Hz). HRMS (DART) calcd for C₁₀H₁₀O₂F [M+H]⁺: 181.0659, found 181.0660.

(E)-3-(Benzo[d][1,3]dioxol-5-yl)-2-fluorobut-2-enoic acid (16b).

Saponification of ester 16a (3.7 g, 14.67 mmol, >98.2 dr) in 2-PrOH/water afforded carboxylic acid 16b as a white solid (3.0 g, >98.2 dr, 92% yield). mp 161.2–163.1 °C; ¹H NMR (400 MHz, CDCl₃) δ 6.76 (d, J = 8.0 Hz, 1H), 6.73–6.63 (m, 2H), 5.91 (s, 2H), 5.44–4.64 (brs, 1H), 2.08 (d, J_HF = 4.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.9 (d, J = 36.6 Hz), 148.9, 148.8, 146.0 (d, J = 250.0 Hz), 133.6 (d, J = 5.9 Hz), 132.5 (d, J = 17.9 Hz), 122.4 (d, J = 3.2 Hz), 109.5 (d, J = 3.2 Hz), 109.0, 102.6, 19.6 (d, J = 6.8 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.5 (q, J_HF = 4.3 Hz). HRMS (DART) calcd for C₁₁H₁₀O₄F [M+H]⁺: 225.0558, found 225.0558.

General Procedure for Telescoped Horner-Wadsworth-Emmons Reaction and Ester Saponification. (E)-2-Fluoro-3-(4-nitrophenyl)but-2-enoic acid (17b).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (1.04 mL, 5.15 mmol, 1.7 equiv) and THF (8 mL). The solution was cooled to 0 to −5 °C. MeMgBr (1.74 mL, 5.15 mmol, 2.96 M in Et₂O, 1.7 equiv) was then added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then heated to 40 °C and stirred for another 10 min. A solution of 4-nitroacetophenone (500 mg, 3.03 mmol, 1.0 equiv) in THF (4 mL) was added dropwise, and the reaction mixture was stirred for 15 min. The reaction mixture was cooled to rt and concentrated under reduced pressure to minimum volume. 2-PrOH (10 mL) was added, and the mixture was concentrated again. The reaction mixture was diluted with 2-PrOH (5 mL) and cooled to 10 °C. A solution of NaOH (726.6 mg; 18.17 mmol; 6 equiv) in H₂O (1.2 mL) was added, and resultant slurry was warmed to rt and stirred at rt for 1 h. Conc. HCl (1.6 mL; 19.70 mmol; 6.5 equiv) was added, and the reaction mixture was slowly concentrated under reduced producing a yellow precipitate of the product. The mixture was filtered, and the filter cake was washed twice with water (5 mL) and then with heptane (5 mL). The solid was dried on a Buchner funnel for 1 h then at 50 °C in a vacuum oven overnight to afford crude acid 17b (yellow solid, 636.7 mg, 93% yield). Crude acid was obtained as 12.7:1 (93:7) mixture of E/Z isomers (¹⁹F NMR). Its stereochemical purity was increased by recrystallization as follows. Crude acid 17b (970.0 mg) was dissolved in 2-PrOH (3.00 mL) at 70 °C. Heptane (18 mL) was slowly added at 70 °C. The reaction mixture was gradually cooled to rt and the resultant slurry was stirred for 2 h. The slurry was filtered, and the filter cake was washed with a minimum amount of 2-PrOH/heptane mixture (6:1 v/v), then with heptane (5 mL). The solid was dried in high vacuum to afford the acid (yellow solid, 609.7 mg, single isomer (>98:2 dr)). The mother liquor was concentrated and the residue was recrystallized from 2-PrOH (800 μL) and heptane (6 mL) following the same procedure to afford the second crop of product (yellow solid, 220 mg, >98:2 dr). Combined mass: 829.7 mg, 86% yield, 80% overall yield from 4-nitroacetophenone. mp 192.9–194.4 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 8.20 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.63–4.34 (brs, 1H), 2.15 (d, J_HF = 3.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 162.9 (d, J = 35.8 Hz), 148.8, 146.4 (d, J = 255.0 Hz), 147.3 (d, J = 5.9 Hz), 130.9 (d, J = 19.2 Hz), 130.2 (d, J = 3.2 Hz), 124.4, 19.1 (d, J = 6.8 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −122.2 (q, J_HF = 3.8 Hz). HRMS (DART) calcd for C₁₀H₇O₄NF [M-H]^–: 224.0365, found 224.0364.

(E)-3-(4-Bromophenyl)-2-fluorohept-2-enoic acid (18b).

Saponification of ester 18a (3.0 g, 9.11 mmol, 20.5:1 (95:5) dr) in 2-PrOH/water afforded crude carboxylic acid as an off-white solid (2.56 g, 93% yield). The crude acid was recrystallized from heptane to afford 18b as a single stereoisomer (2.18 g, 85% recovery, 79% overall yield, >98:2 dr). ¹H NMR (400 MHz, CDCl₃) δ 11.44–10.75 (brs, 1H), 7.52–7.40 (m, 2H), 7.07–6.92 (m, 2H), 2.72–2.31 (m, 2H), 1.53–1.09 (m, 4H), 1.05–0.67 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.5 (d, J = 36.9 Hz), 143.2 (d, J = 250.5 Hz), 138.2 (d, J = 17.0 Hz), 135.4 (d, J = 5.4 Hz), 131.3, 129.3 (d, J = 3.0 Hz), 122.2, 32.7 (d, J = 4.8 Hz), 28.7 (d, J = 1.9 Hz), 22.3, 13.6; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.8 (t, J_HF = 3.4 Hz); Z-isomer: −124.6 (s). HRMS (DART) calcd for C₁₃H₁₅O₂BrF [M+H]⁺: 301.0234, found 301.0234.

(E)-2-Fluoro-3-(o-tolyl)pent-2-enoic acid (19b).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (6.8 mL, 33.63 mmol, 2.5 equiv) and THF (50 mL). The solution was cooled to 0 to −5 °C. MeMgBr (11.4 mL, 33.63 mmol, 2.96 M in Et₂O, 2.5 equiv) was then added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then heated to 40 °C and stirred for another 10 min. A solution of 2-methylpropiophenone (2.0 mL, 13.45 mmol, 1.0 equiv) in THF (10 mL) was added dropwise, and the reaction mixture was stirred for 30 min. An aliquot of reaction mixture was analyzed by quantitative ¹⁹F NMR: ester 19a was formed as a mixture of stereoisomers in 96:4 dr. The reaction mixture was cooled to rt and concentrated under reduced pressure to a minimum volume. 2-PrOH (20 mL) was added, and the mixture was concentrated again. The reaction mixture was diluted with 2-PrOH (10 mL) and cooled to 10 °C. A solution of NaOH (4.30 g; 107.6 mmol; 8 equiv) in H₂O (10 mL) was added, and resultant slurry was warmed to rt and stirred at rt overnight. conc. HCl (9.4 mL; 114.3 mmol; 8.5 equiv) was added, and the reaction mixture was slowly concentrated under reduced pressure giving a biphasic mixture (water/oil). EtOAc (30 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 10 mL). Combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure to an oil. The oil was treated with 3 M NaOH (9.0 mL; 26.9 mmol; 2 equiv.) and the mixture was extracted with MTBE (20 mL). The aqueous phase was acidified with 3 M HCl (9.9 mL; 29.6 mmol; 2.2 equiv) at 10 °C which resulted in formation of a slurry. The slurry was filtered and the filter cake was washed with water. The solid was dried on a Buchner funnel for 2 h then at 50 °C in vacuum oven overnight to afford crude acid 19b as an off white solid (2.78 g, 99% yield). Crude acid was obtained as 96.5:3.5 mixture of E/Z isomers (¹⁹F NMR). The crude acid was recrystallized from a hot (65 °C) mixture of heptane (10 mL) and IPAc (0.5 mL) to afford 19b as a white solid (2.25 g, 81% recovery, 80% overall yield from 2-methylpropiophenone, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 11.57–9.26 (brs, 1H), 7.25–7.07 (m, 3H), 6.93 (d, J = 7.4 Hz, 1H), 2.78–2.56 (m, 1H), 2.52–2.28 (m, 1H), 2.19 (s, 3H), 1.00 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.2 (d, J = 37.0 Hz), 143.3 (d, J = 249.3 Hz), 139.5 (d, J = 15.3 Hz), 135.8 (d, J = 5.1 Hz), 134.7 (d, J = 2.6 Hz), 130.0, 127.8, 127.4 (d, J = 3.3 Hz), 125.4, 25.8 (d, J = 5.5 Hz), 19.3, 11.1 (d, J = 2.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −126.8 (s). HRMS (DART) calcd for C₁₂H₁₄O₂F [M+H]⁺: 209.0972, found 209.0973.

(E)-2-Fluoro-3-(o-tolyl)pent-2-enoic acid (19b).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (6.8 mL, 33.63 mmol, 2.5 equiv) and THF (50 mL). The solution was cooled to 0 to −5 °C. MeMgBr (11.4 mL, 33.63 mmol, 2.96 M in Et₂O, 2.5 equiv) was then added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then heated to 40 °C and stirred for another 10 min. A solution of 2-methylpropiophenone (2.0 mL, 13.45 mmol, 1.0 equiv) in THF (10 mL) was added dropwise, and the reaction mixture was stirred for 30 min. An aliquot of reaction mixture was analyzed by quantitative ¹⁹F NMR: ester 19a was formed as a mixture of stereoisomers in 96:4 dr. The reaction mixture was cooled to rt and concentrated under reduced pressure to a minimum volume. 2-PrOH (20 mL) was added, and the mixture was concentrated again. The reaction mixture was diluted with 2-PrOH (10 mL) and cooled to 10 °C. A solution of NaOH (4.30 g; 107.6 mmol; 8 equiv) in H₂O (10 mL) was added, and resultant slurry was warmed to rt and stirred at rt overnight. conc. HCl (9.4 mL; 114.3 mmol; 8.5 equiv) was added, and the reaction mixture was slowly concentrated under reduced pressure giving a biphasic mixture (water/oil). EtOAc (30 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 10 mL). Combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure to an oil. The oil was treated with 3 M NaOH (9.0 mL; 26.9 mmol; 2 equiv.) and the mixture was extracted with MTBE (20 mL). The aqueous phase was acidified with 3 M HCl (9.9 mL; 29.6 mmol; 2.2 equiv) at 10 °C which resulted in formation of a slurry. The slurry was filtered and the filter cake was washed with water. The solid was dried on a Buchner funnel for 2 h then at 50 °C in vacuum oven overnight to afford crude acid 19b as an off white solid (2.78 g, 99% yield). Crude acid was obtained as 96.5:3.5 mixture of E/Z isomers (¹⁹F NMR). The crude acid was recrystallized from a hot (65 °C) mixture of heptane (10 mL) and IPAc (0.5 mL) to afford 19b as a white solid (2.25 g, 81% recovery, 80% overall yield from 2-methylpropiophenone, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 11.57–9.26 (brs, 1H), 7.25–7.07 (m, 3H), 6.93 (d, J = 7.4 Hz, 1H), 2.78–2.56 (m, 1H), 2.52–2.28 (m, 1H), 2.19 (s, 3H), 1.00 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.2 (d, J = 37.0 Hz), 143.3 (d, J = 249.3 Hz), 139.5 (d, J = 15.3 Hz), 135.8 (d, J = 5.1 Hz), 134.7 (d, J = 2.6 Hz), 130.0, 127.8, 127.4 (d, J = 3.3 Hz), 125.4, 25.8 (d, J = 5.5 Hz), 19.3, 11.1 (d, J = 2.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −126.8 (s). HRMS (DART) calcd for C₁₂H₁₄O₂F [M+H]⁺: 209.0972, found 209.0973.

(E)-2-Fluoro-4-methyl-3-phenylpent-2-enoic acid (20b).

Saponification of ester 20a (4.37 g, 18.49 mmol, 11.6:1 (92:8) dr) in EtOH/water afforded carboxylic acid 20b as a white solid (3.38 g, 11.6:1 (92:8) dr, 88% yield). The product was recrystallized from IPAc (1V) and heptane (15 V) to improve stereochemical purity to 18.4:1 (95:5) dr (2.61 g, 77% recovery, 68% overall yield). E-isomer: ¹H NMR (400 MHz, CDCl₃) δ 11.15–9.85 (brs, 1H), 7.36–7.27 (m, 3H), 7.06–6.97 (m, 2H), 3.29 (dsept, J = 7.0 Hz, J_HF = 0.8 Hz, 1H), 1.00 (d, J = 7.0 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5 (dd, J = 37.5 Hz, J = 7.1 Hz), 142.8 (d, J = 250.1 Hz), 143.3 (d, J = 14.0 Hz), 133.9 (d, J = 5.3 Hz), 128.0 (d, J = 3.1 Hz), 127.7, 127.6, 29.4 (d, J = 5.1 Hz), 20.0 (d, J = 2.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −126.7 (s); Z-isomer: −121.3 (s). HRMS (DART) calcd for C₁₂H₁₄O₂F [M+H]⁺: 209.0972, found 209.0973.

(E)-3-Cyclopropyl-2-fluoro-3-(4-methoxyphenyl)acrylic acid (21b).

Saponification of ester 21a (4.36 g, 16.50 mmol, >98.2 dr) in EtOH/water afforded carboxylic acid 21b as a white solid (3.51 g, >98.2 dr, 90% yield). mp 157.2–158.9 °C; ¹H NMR (400 MHz, CDCl₃) δ 12.06–10.81 (brs, 1H), 6.96–6.84 (m, 2H), 6.84–6.74 (m, 2H), 3.79 (s, 3H), 2.45–1.96 (m, 1H), 0.94–0.71 (m, 2H), 0.53–0.30 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.2 (d, J = 35.9 Hz), 159.2, 144.3 (d, J = 247.2 Hz), 140.7 (d, J = 13.3 Hz), 129.8 (d, J = 3.1 Hz), 123.8 (d, J = 4.8 Hz), 113.3, 55.1, 12.3 (d, J = 9.4 Hz), 5.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −131.2 (s). HRMS (DART) calcd for C₁₃H₁₄O₃F [M+H]⁺: 237.0922, found 237.0922.

(Z)-3-(4-Bromophenyl)-2,4,4,4-tetrafluorobut-2-enoic acid (22b).

Saponification of ester 22a (3.0 g, 8.80 mmol, 25.8:1 (96:4) dr) in 2-PrOH/water afforded carboxylic acid 22b as an off-white solid (2.52 g, 25.8:1 (96:4) dr, 92% yield). ¹H NMR (400 MHz, MeOH-d₄) δ 7.60–7.53 (m, 2H), δ 7.24–7.16 (m, 2H), 5.46–4.94 (brs, 1H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 161.3 (d, J = 34.3 Hz), 152.2, (dq, J = 284.3 Hz, J = 2.6 Hz), 132.8, 132.7 (d, J = 3.4 Hz), 129.4 (d, J = 3.2 Hz), 124.8, 123.5 (q, J = 274.7 Hz), 121.0 (dq, J = 32.4 Hz, J = 9.7 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −107.5 (q, J = 24.0 Hz), −61.6 (d, J = 24.0 Hz); Z-isomer: δ −105.6 (q, J = 10.3 Hz), −59.8 (d, J = 10.3 Hz). HRMS (DART) calcd for C₁₀H₄O₂BrF₄ [M-H]^–: 310.9336, found 310.9336.

(E)-3-(3,5-Dimethylphenyl)-2-fluoronon-2-en-7-ynoic acid (23b).

Saponification of ester 23a (1.90 g, 6.28 mmol, >98.2 dr) in EtOH/water afforded carboxylic acid 23b as a white solid (1.68 g, >98.2 dr, 98% yield). mp 88.3–90.3 °C; ¹H NMR (400 MHz, CDCl₃) 6.95 (s, 1H), 6.74 (s, 2H), 2.66–2.54 (m, 2H), 2.30 (s, 6H), 2.17–2.06 (m, 2H), 1.75 (t, J = 2.5 Hz, 3H), 1.58–1.47 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.2 (d, J = 37.0 Hz), 143.3 (d, J = 248.8 Hz), 138.5 (d, J = 15.7 Hz), 137.6, 136.0 (d, J = 5.0 Hz), 129.8, 125.4 (d, J = 2.8 Hz), 78.1, 76.2, 32.4 (d, J = 5.2 Hz), 26.3 (d, J = 1.7 Hz), 21.2, 18.6, 3.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −125.1 (s). HRMS (DART) calcd for C₁₇H₁₈O₂F [M-H]^–: 273.1296, found 273.1295.

(Z)-3-(1-Cyanocyclohexyl)-2-fluoro-3-(4-methoxyphenyl)acrylic acid (24b).

Saponification of ester 24a (1.1 g, 3.32 mmol, >98.2 dr) in EtOH/water afforded carboxylic acid 24b as a white solid (1.0 g, >98.2 dr, 99% yield). mp 156.5–157.6 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.73–8.78 (brs, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H), 2.12–1.92 (m, 2H), 1.82–1.61 (m, 5H), 1.48–1.30 (m, 2H), 1.18–0.97 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.9 (d, J = 36.2 Hz), 159.8, 146.0 (d, J = 266.2 Hz), 135.3 (d, J = 9.3 Hz), 129.6 (d, J = 3.4 Hz), 124.4 (d, J = 5.4 Hz), 120.3, 113.8, 55.2, 42.0 (d, J = 1.7 Hz), 34.2 (d, J = 1.9 Hz), 24.5, 22.7; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −111.9 (s). HRMS (DART) calcd for C₁₇H₁₉O₃NF [M+H]⁺: 304.1344, found 304.1344.

(E)-3-(4-Bromophenyl)-2-fluoro-4-phenylbut-2-enoic acid (25b).

Saponification of ester 25a (4.75 g, 13.08 mmol, 13.3:1 (93:7) dr) in EtOH/water afforded carboxylic acid 25b as a white solid (3.95 g, 14.9:1 (94:6) dr, 91% yield). mp 139.1–141.5 °C; ¹H NMR (400 MHz, CDCl₃) 9.57–8.49 (brs, 1H), 7.40–7.33 (m, 2H), 7.27–7.15 (m, 3H), 7.04–6.96 (m, 2H), 6.83–6.74 (m, 2H), 3.81 (d, J_HF = 3.6 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.9 (d, J = 37.0 Hz), 143.3 (d, J = 252.6 Hz), 136.2 (d, J = 16.7 Hz), 135.9 (d, J = 2.4 Hz), 134.8 (d, J = 5.0 Hz), 131.2, 129.6 (d, J = 3.1 Hz), 129.1, 128.6, 126.9, 122.3, 39.1 (d, J = 5.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.7 (t, J_HF = 3.3 Hz); Z-isomer: −122.9 (s). HRMS (DART) calcd for C₁₆H₁₃O₂BrF [M+H]⁺: 335.0078, found 335.0078.

(E)-2-Fluoro-3-(quinolin-3-yl)but-2-enoic acid (26b).

Saponification of ester 26a (4.70 g, 58.07 mmol, 11.3:1 (92:8) dr) in 2-PrOH/water afforded carboxylic acid 26b as a white solid (3.60 g, >98:2 dr, 86% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (d, J_HF = 2.0 Hz, 1H), 8.30 (d, J_HF = 1.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82–7.71 (m, 1H), 7.67–7.57 (m, 1H), 4.65–2.66 (brs, 1H), 2.21 (d, J_HF = 4.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 161.1 (d, J = 35.4 Hz), 150.2 (d, J = 2.6 Hz), 146.6, 145.2 (d, J = 253.8 Hz), 134.0 (d, J = 3.4 Hz), 131.7 (d, J = 5.8 Hz), 129.7, 128.6, 128.2, 127.6 (d, J = 19.1 Hz), 127.1, 126.9, 19.0 (d, J = 6.4 Hz); ¹⁹F NMR (376.5 MHz, DMSO-d₆) δ −119.2 (q, J_HF = 4.4 Hz); Z-isomer: −121.6 (s). HRMS (DART) calcd for C₁₃H₁₁O₂NF [M+H]⁺: 232.0768, found 232.0769.

(E)-3-(Benzo[b]thiophen-2-yl)-2-fluorobut-2-enoic acid (27b).

Saponification of ester 27a (4.97 g, 18.80 mmol, 10.9:1 (92:8) dr) in EtOH/water afforded carboxylic acid 27b as a pale yellow solid (3.96 g, 10.9:1 (92:8) dr, 89% yield). mp 140.6–142.7 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.81–7.77 (m, 1H), 7.75–7.70 (m, 1H), 7.34–7.27 (m, 2H), 7.26 (s, 1H), 5.45–4.58 (brs, 1H), 2.20 (d, J_HF = 4.7 Hz, 3H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 163.2 (d, J = 36.1 Hz), 147.4 (d, J = 256.3 Hz), 141.7, 141.1, 140.3 (d, J = 6.8 Hz), 125.8, 125.6, 125.1 (d, J = 3.1 Hz), 124.9, 123.1, 19.6 (d, J = 6.8 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −117.2 (q, J_HF = 4.7 Hz); Z-isomer: −115.3 (q, J_HF = 3.1 Hz). HRMS (DART) calcd for C₁₂H₈O₂FS [M-H]^–: 235.0235, found 235.0234.

(E)-3-(Cyclohex-1-en-1-yl)-2-fluorobut-2-enoic acid (28b).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (3.94 mL, 19.45 mmol, 2.5 equiv) and THF (25 mL). The solution was cooled to 0 to −5 °C. MeMgBr (6.57 mL, 19.45 mmol, 2.96 M in Et₂O, 2.5 equiv) was added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then heated to 40 °C and stirred for another 10 min. A solution of 1-cyclohexenyl methyl ketone (966 mg, 1.0 mL, 7.78 mmol, 1.0 equiv) in THF (6 mL) was added dropwise, and the reaction mixture was stirred for 30 min. An aliquot of reaction mixture was analyzed by quantitative ¹⁹F NMR: ester 28a was formed as a mixture of stereoisomers in 12.7:1 (93:7) dr. The reaction mixture was cooled to rt and concentrated under reduced pressure to a minimum volume. 2-PrOH (20 mL) was added, and the mixture was concentrated again. The reaction mixture was diluted with 2-PrOH (35 mL) and cooled to 10 °C. A solution of NaOH (2.81 g; 70.01 mmol; 9 equiv) in H₂O (15 mL) was added, and resultant slurry was warmed to rt and stirred at rt for 3 h. conc. HCl (6.07 mL; 73.90 mmol; 9.5 equiv) was added dropwise at 5–10 °C, and the reaction mixture was slowly concentrated under reduced pressure producing a sticky solid. EtOAc (30 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 10 mL). Combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure to a brown oil. To this oil was added sat. aq. NaHCO₃ solution (10 mL). The reaction mixture was stirred until gas evolution ceased, and then extracted twice with EtOAc. 2-PrOH (3 mL) was added to the aqueous phase, and the resultant solution was concentrated under vacuum to ~10 mL volume. To this solution was added conc. HCl dropwise at 5–10 °C until pH ~2. A pale yellow solid was filtered, washed with a small amount of water, then with heptane. The solid was dried in high vacuum to give the acid 28b in >98:2 dr (830.9 mg, 58% overall yield from 1-cyclohexenyl methyl ketone). mp 103.1–105.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 12.41–11.18 (brs, 1H), 5.71–5.24 (m, 1H), 2.23–1.97 (m, 4H), 1.93 (d, J_HF = 4.2 Hz, 3H), 1.75–1.62 (m, 2H), 1.62–1.49 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.1 (d, J = 36.7 Hz), 142.6 (d, J = 247.0 Hz), 137.7 (d, J = 14.0 Hz), 135.3 (d, J = 4.2 Hz), 124.7 (d, J = 2.9 Hz), 27.2 (d, J = 2.6 Hz), 25.1, 22.5, 21.6, 17.6 (d, J = 6.2 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −128.6 (s). HRMS (DART) calcd for C₁₀H₁₄O₂F [M+H]⁺: 185.0972, found 185.0973.

(E)-2-Fluoro-2-(4a-methyl-5-oxo-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-ylidene)acetic acid (29b).

Saponification of ester 29a (4.85 g, 18.20 mmol, 3.44:1 (78:22) dr) in EtOH/water afforded carboxylic acid 29b as a white solid (3.39 g, 9.97:1 (91:9) dr, 78% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (s, 1H), 6.24–4.95 (brs, 1H), 2.92–2.76 (m, 1H), 2.76–2.57 (m, 2H), 2.55–2.39 (m, 2H), 2.39–2.24 (m, 1H), 2.17–2.02 (m, 1H), 1.99–1.76 (m, 2H), 1.75–1.57 (m, 1H), 1.34 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 212.9, 165.5 (d, J = 35.4 Hz), 152.6 (d, J = 12.4 Hz), 141.3 (d, J = 247.6 Hz), 132.3 (d, J = 18.0 Hz), 118.6 (d, J = 2.2 Hz), 50.3, 37.9, 32.1, 28.6 (d, J = 1.2 Hz), 23.9, 23.7 (d, J = 1.1 Hz), 19.8 (d, J = 7.9 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −129.5 (m); Z-isomer: −132.7 (d, J_HF = 3.9 Hz). HRMS (DART) calcd for C₁₃H₁₆O₃F [M+H]⁺: 239.1078, found 239.1078.

(E)-2-Fluoro-3-(naphthalen-2-yl)acrylic acid (E-30b).

Saponification of ester E-30a (4.59 g, 18.79 mmol, 98:2 dr) in EtOH/water afforded carboxylic acid E-30b as a white solid (3.91 g, > 98:2 dr, 96% yield). mp 151.1–152.7 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.97 (s, 1H), 7.84–7.72 (m, 3H), 7.63 (dd, J = 8.6 Hz, J = 1.6 Hz, 1H), 7.49–7.39 (m, 2H), 7.10 (d, J_HF = 23.0 Hz, 1H), 5.23–4.76 (brs, 1 H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 163.5 (d, J = 36.7 Hz), 149.0 (d, J = 253.6 Hz), 134.7, 134.5, 130.8 (d, J = 3.6 Hz), 130.2 (d, J = 9.7 Hz), 129.4, 128.7, 128.5, 128.4 (d, J = 2.2 Hz), 127.8, 127.4, 122.4 (d, J = 27.2 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −116.3 (d, J_HF = 23.0 Hz). HRMS (DART) calcd for C₁₃H₈O₂F [M-H]^–: 215.0514, found 215.0513.

(Z)-2-Fluoro-3-(naphthalen-2-yl)acrylic acid (Z-30b).

Saponification of ester Z-30a (4.34 g, 17.77 mmol, > 98:2 dr) in EtOH/water afforded carboxylic acid Z-30b as a white solid (3.80 g, > 98:2 dr, 99% yield). mp 187.9–190.0 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 8.04 (s, 1H), 7.86–7.76 (m, 3H), 7.73 (dd, J = 8.7 Hz, J = 1.6 Hz, 1H), 7.54–7.41 (m, 2H), 7.09 (d, J_HF = 35.6 Hz, 1H), 5.33–4.71 (brs, 1H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 164.4 (d, J = 35.3 Hz), 148.8 (d, J = 264.1 Hz), 135.1 (d, J = 1.9 Hz), 134.7, 131.8 (d, J = 7.9 Hz), 130.2 (d, J = 4.6 Hz), 129.7, 129.6, 128.8, 128.5, 127.80 (d, J = 7.4 Hz), 127.77, 118.7 (d, J = 4.7 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −126.1 (d, J_HF = 35.6 Hz). NMR spectra matched reported data.²⁴

(E)-3-(Benzo[d][1,3]dioxol-4-yl)-2-fluoroacrylic acid (31b).

Saponification of ester 31a (4.56 g, 9.14 mmol, 34.5:1 (97:3) dr) in EtOH/water afforded carboxylic acid 31b as a white solid (3.54 g, > 98:2 dr, 88% yield). mp 149.0–150.1 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.02–6.96 (m, 1H), 6.82–6.73 (m, 3H), 5.92 (s, 2H), 5.14–4.90 (brs, 1H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 163.4 (d, J = 36.6 Hz), 150.2 (d, J = 255.1 Hz), 148.8, 147.3 (d, J = 2.5 Hz), 123.8 (d, J = 2.7 Hz), 122.3, 115.0 (d, J = 10.2 Hz), 114.6 (d, J = 28.5 Hz), 109.7, 102.3; ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −115.8 (d, J_HF = 21.0 Hz). HRMS (DART) calcd for C₁₀H₆O₄F [M-H]^–: 209.0256, found 209.0255.

(E)-3-(Benzofuran-2-yl)-2-fluoroacrylic acid (32b).

Saponification of ester 32a (7.1 g, 30.31 mmol, > 98:2 dr) in EtOH/water afforded carboxylic acid 32b as a white solid (5.86 g, > 98:2 dr, 94% yield). mp 183.8–185.2 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.69 (s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.31–7.21 (m, 1H), 7.21–7.10 (m, 1H), 6.84 (d, J_HF = 22.1 Hz, 1H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) δ 163.1 (d, J = 34.7 Hz), 156.3 (d, J = 2.2 Hz), 149.2 (d, J = 260.7 Hz), 149.3 (d, J = 11.0 Hz), 130.2, 126.9, 124.3, 122.8, 112.5 (d, J = 7.1 Hz), 112.0, 111.7 (d, J = 34.5 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −115.0 (d, J_HF = 22.1 Hz). HRMS (DART) calcd for C₁₁H₈O₃F [M+H]⁺: 207.0452, found 207.0452.

(E)-3-Cyclopropyl-2-fluoroacrylic acid (33b).

To a solution of ester 33a (4.18 g; 26.43 mmol, 98:2 dr) in EtOH (45 mL) was added a slurry of LiOH•H₂O (2.22 g; 52.85 mmol; 2 equiv) in H₂O (45 mL) at 0 °C. The reaction mixture was warmed to rt and stirred for 3.5 h. H₂O (56 mL) was added, and the mixture was extracted with hexanes (20 mL). Layers were separated, and the aqueous phase was concentrated under reduced pressure to remove almost all EtOH. The solution was acidified with conc. HCl (4.77 mL; 58.14 mmol; 2.2 equiv) which resulted in separation of the product as an oil. The aqueous phase was then saturated with NaCl and reaction mixture was extracted twice with MTBE (2 × 25 mL). MTBE extracts were dried over Na₂SO₄. Solid was filtered, and the filtrate was concentrated under reduced pressure to afford the product 33b as a white solid. The solid was dried at 40 °C in vacuum oven overnight (3.25 g, > 98:2 dr, 95% yield). mp 101.4–102.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 12.11–11.54 (brs, 1H), 5.46 (dd, J_HF = 19.8 Hz, J = 11.1 Hz, 1H), 2.55–2.37 (m, 1H), 1.09–0.92 (m, 2H), 0.63–0.49 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.1 (d, J = 35.6 Hz), 145.7 (d, J = 241.7 Hz), 133.1 (d, J = 21.5 Hz), 8.9 (d, J = 6.9 Hz), 8.6 (d, J = 1.1 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −127.9 (dd, J_HF = 19.8 Hz, J_HF = 1.7 Hz). HRMS (DART) calcd for C₆H₆O₂F [M-H]^–: 129.0357, found 129.0357.

(E)-3-Cyclopentyl-2-fluoroacrylic acid (34b).

To a solution of ester 34a (4.49 g; 24.11 mmol; 96:4 dr) in EtOH (45 mL) was added a slurry of LiOH•H₂O (2.02 g; 48.22 mmol; 2 equiv) in H₂O (45 mL) at 0 °C. The reaction mixture was warmed to rt and stirred for 4 h. H₂O (56 mL) was added, and the mixture was extracted with hexanes (20 mL). Layers were separated, and the aqueous phase was concentrated under reduced pressure to remove almost all EtOH. The solution was acidified with conc. HCl (4.36 mL; 53.04 mmol; 2.2 equiv) which resulted in formation of a slurry. The slurry was filtered, and the solid was washed with water. It was then dried on a Buchner funnel for 2 h followed by at 40 °C in a vacuum oven overnight. This yielded a first crop of 34b as a white solid (3.361 g), >98:2 dr. The combined filtrate and wash were concentrated under reduced pressure to a volume of ~30 mL which resulted in precipitation of a second crop of product. The solid was filtered and washed with water. It was then dried on a Buchner funnel for 2 h followed by at 40 °C in a vacuum oven overnight. This yielded a second crop of 34b as a white solid (163.7 mg), >98:2 dr. Combined yield of 34b: 3.53 g; 92% yield, single stereoisomer (>98:2 dr). ¹H NMR (400 MHz, CDCl₃) δ 12.21–11.88 (brs, 1H), 6.00 (dd, J_HF = 21.3 Hz, J = 10.5 Hz, 1H), 3.52–3.32 (m, 1H), 2.02–1.81 (m, 2H), 1.80–1.48 (m, 4H), 1.41–1.16 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.7 (d, J = 37.1 Hz), 145.4 (d, J = 246.2 Hz), 131.8 (d, J = 16.5 Hz), 36.4 (d, J = 4.5 Hz), 33.6 (d, J = 2.1 Hz), 25.3; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.6 (dd, J_HF = 21.3 Hz, J_HF = 1.2 Hz). HRMS (DART) calcd for C₈H₁₀O₂F [M-H]^–: 157.0670, found 157.0670.

(E)-2-Fluoro-5-phenylpent-2-enoic acid (35b).

To a solution of ester 35a (4.34 g; 19.53 mmol; 94:6 dr) in EtOH (45.0 mL) was added a slurry of LiOH•H₂O (1.64 g; 39.05 mmol; 2 equiv) in H₂O (45.0 mL) at 0 °C. The reaction mixture was warmed to rt and stirred for 2 h. H₂O (58.0 mL) was added, and the mixture was extracted with hexanes (20 mL). Layers were separated, and the aqueous phase was concentrated under reduced pressure to remove almost all EtOH. The solution was then acidified with conc. HCl (3.53 mL; 42.96 mmol; 2.2 equiv) which resulted in separation of the product as an oil. The mixture was extracted twice with EtOAc (2 × 25 mL). EtOAc extracts were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford 35b as a pale yellow oil. The oil solidified after standing overnight in the freezer. It was then dried at 40 °C in a vacuum oven overnight (3.72 g, 98% yield, mixture of stereoisomers in 18.3:1 (95:5) dr). ¹H NMR (400 MHz, CDCl₃) δ 12.07–10.87 (brs, 1H), 7.41–7.31 (m, 2H), 7.31–7.20 (m, 3H), 6.16 (dt, J_HF = 20.7 Hz, J = 8.0 Hz, 1H), 2.98–2.88 (m, 2H), 2.88–2.78 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.3 (d, J = 37.1 Hz), 146.4 (d, J = 248.6 Hz), 140.3, 128.5, 128.4, 126.3, 125.8 (d, J = 18.2 Hz), 35.1 (d, J = 2.2 Hz), 27.3 (d, J = 4.7 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −122.1 (d, J_HF = 20.7 Hz), Z-isomer: −130.7 (dd, J_HF = 32.6 Hz, J_HF = 2.2 Hz). HRMS (DART) calcd for C₁₁H₁₀O₂F [M-H]^–: 193.0670, found 193.0670.

General Procedure for Ag-Catalyzed Decarboxylation.

A reaction vial was charged with acid (1 equiv), AgOAc (5 mol%), and NMP (2V). The vial was inerted and placed into a preheated 130 °C oil bath. The reaction mixture was stirred for 4 h under positive Ar pressure. It was then cooled to 0 °C and PhCF₃ was added as an internal standard. The mixture was diluted with CDCl₃ and analyzed by quantitative ¹⁹F NMR to obtain the assay yield. The reaction mixture was directly loaded on a silica gel column using minimum amount of CH₂Cl₂. It was purified by column chromatography and the fractions containing product were concentrated under reduced pressure with a cold 0–4 °C rotovap bath (ice/water) to afford the product.

(E)-2-(1-Fluoroprop-1-en-2-yl)naphthalene (10c).

Decarboxylation of 10b (2.0 g, 8.69 mmol, 21.1:1 (95:5) dr) was carried out with 5 mol% of AgOAc (72.5 mg, 0.43 mmol) in NMP (4 mL, 2V) at 130 °C for 4 h. The product 10c was obtained as a white solid after purification by silica gel column chromatography eluting with 0–2% EtOAc in hexanes (1.59 g, 98% yield, mixture of stereoisomers in 21.4:1 (95:5) dr). mp 36.8–39.2 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.88–7.78 (m, 3H), 7.75 (s, 1H), 7.53–7.42 (m, 3H), 7.07 (d, J_HF = 84.9 Hz, 1H), 2.22–2.11 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.4 (d, J = 258.4 Hz), 134.8 (d, J = 8.8 Hz), 133.4, 132.7, 128.1, 127.9, 127.5, 126.3, 125.8, 124.5 (d, J = 4.4 Hz), 123.8 (d, J = 2.0 Hz), 120.0 (d, J = 10.0 Hz), 12.1 (d, J = 6.1 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −130.4 (dq, J_HF = 84.9 Hz, J_HF = 3.6 Hz); Z-isomer: −128.3 (dq, J_HF = 84.7 Hz, J_HF = 4.6 Hz). NMR spectra matched reported data.^11a HRMS (EI) calcd for C₁₃H₁₁F [M]⁺: 186.0839, found 186.0839.

(E)-1-Bromo-4-(2-fluorovinyl)benzene (E-12c).

Decarboxylation of acid E-12b (250 mg, 1.02 mmol, > 98:2 dr) was carried out with 5 mol% of AgOAc (8.51 mg, 0.051 mmol) in NMP (0.5 mL, 2V) at 130 °C for 2.5 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 181.0 mg, 88% NMR yield, single stereoisomer (> 98:2 dr). The product E-12c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 0–1% Et₂O in pentane (176.3 mg, 86% yield, single stereoisomer (> 98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.39 (m, 2H), 7.16 (dd, J_HF = 82.6 Hz, J = 11.4 Hz, 1H), 7.15–7.08 (m, 2H), 6.34 (dd, J_HF = 18.6 Hz, J = 11.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 150.4 (d, J = 260.7 Hz), 131.9, 131.6 (d, J = 12.1 Hz), 127.6 (d, J = 3.1 Hz), 121.2 (d, J = 2.1 Hz), 113.0 (d, J = 16.7 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −128.2 (dd, J_HF = 82.6 Hz, J_HF = 18.6 Hz). NMR spectra matched reported data.^10a HRMS (EI) calcd for C₈H₆BrF [M]⁺: 199.9631, found 199.9631.

(Z)-1-Bromo-4-(2-fluorovinyl)benzene (Z-12c).

Decarboxylation of acid Z-12b (250 mg, 1.02 mmol, > 98:2 dr) was carried out with 50 mol% of AgOAc (85.1 mg, 0.51 mmol) in NMP (2.0 mL, 8V) at 140 °C for 8 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 171.22 mg, 84% NMR yield, single stereoisomer (> 98:2 dr). The product Z-12c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 0–1% Et₂O in pentane (167.0 mg, 81% yield, single stereoisomer (> 98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 7.34–7.26 (m, 2H), 7.24–7.16 (m, 2H), 6.50 (dd, J_HF = 82.4 Hz, J = 5.4 Hz, 1H), 5.40 (dd, J_HF = 44.1 Hz, J = 5.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.7 (d, J = 271.5 Hz), 131.6, 131.5 (d, J = 1.4 Hz), 130.3 (d, J = 7.3 Hz), 121.3 (d, J = 3.6 Hz), 109.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −120.9 (dd, J_HF = 82.4 Hz, J_HF = 44.1 Hz). NMR spectra matched reported data.^10a HRMS (EI) calcd for C₈H₆BrF [M]⁺: 199.9631, found 199.9633.

(E)-(1-Fluoroprop-1-en-2-yl)benzene (15c).

A reaction vial was charged with acid 15b (200.0 mg; 1.11 mmol; 100.0 mol%, >98:2 dr), AgOAc (9.26 mg; 0.06 mmol; 5 mol%), and NMP (0.40 mL, 2V). The vial was inerted and placed into a preheated 130 °C oil bath. The reaction mixture was stirred for 4 h under positive Ar pressure. It was then cooled to 0 °C and PhCF₃ (34.8 mg) was added as an internal standard. The mixture was diluted with CDCl₃ and analyzed by quantitative ¹⁹F NMR: m(prod) = 138.3 mg, 92% NMR yield, single stereoisomer (>98:2 dr). The reaction mixture was directly loaded on a silica gel column using minimum amount of CH₂Cl₂. It was purified by column chromatography eluting with pentane. Fractions containing product were concentrated under reduced pressure with a cold 0–4 °C rotovap bath (ice/water) to afford 15c as a colorless volatile liquid (123.0 mg, 81% yield, >98:2 dr). ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.25 (m, 5H), 6.90 (dq, J_HF = 85.1 Hz, J_HH = 1.5 Hz, 1H), 2.05 (dd, J_HF = 3.7 Hz, J_HH = 1.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 146.0 (d, J = 257.8 Hz), 137.6 (d, J = 8.9 Hz), 128.5, 127.4, 125.9 (d, J = 3.2 Hz), 120.0 (d, J = 9.8 Hz), 12.2 (d, J = 6.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −131.2 (dq, J_HF = 85.1 Hz, J_HF = 3.7 Hz). NMR spectra matched reported data.³⁵ HRMS (EI) calcd for C₉H₉F [M]⁺: 136.0683, found 136.0683.

(E)-5-(1-Fluoroprop-1-en-2-yl)benzo[d][1,3]dioxole (16c).

Decarboxylation of acid 16b (250.0 mg, 1.12 mmol, >98:2 dr) was carried out with 5 mol% of AgOAc (9.31 mg, 0.06 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4.0 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 179.81 mg, 90% NMR yield, single stereoisomer (>98:2 dr). The product 16c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 1–5% MTBE in hexanes (165.9 mg, 83% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 6.84 (dq, J_HF = 85.2 Hz, J = 1.5 Hz, 1H), 6.82–6.75 (m, 3H), 5.96 (s, 2H), 2.01 (dd, J_HF = 3.7 Hz, J = 1.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 147.8, 147.0, 145.4 (d, J = 257.1 Hz), 131.6 (d, J = 8.8 Hz), 119.8 (d, J = 10.2 Hz), 119.3 (d, J = 1.8 Hz), 108.3, 106.4 (d, J = 3.0 Hz), 101.0, 12.5 (d, J = 5.8 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −132.1 (dq, J_HF = 85.2 Hz, J_HF = 3.7 Hz). HRMS (DART) calcd for C₁₀H₉O₂F [M]⁺: 180.0581, found 180.0582.

(E)-1-(1-Fluoroprop-1-en-2-yl)-4-nitrobenzene (17c).

Decarboxylation of acid 17b (250.0 mg, 0.89 mmol, >98:2 dr) was carried out with 5 mol% of AgOAc (7.41 mg, 0.04 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4.0 h. The product 17c was obtained as a yellow solid after purification by silica gel column chromatography eluting with 0–2% EtOAc in hexanes (159.0 mg, 99% yield, single stereoisomer (>98:2 dr)). mp 59.8–61.3 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.26–8.11 (m, 2H), 7.50–7.42 (m, 2H), 7.03 (dq, J_HF = 83.0 Hz, J = 1.4 Hz, 1H), 2.08 (dd, J_HF = 3.7 Hz, J = 1.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 147.9 (d, J = 263.7 Hz), 147.0, 144.3 (d, J = 9.5 Hz), 126.3 (d, J = 3.3 Hz), 123.9, 119.0 (d, J = 11.4 Hz), 11.9 (d, J = 5.9 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −124.9 (dq, J_HF = 83.0 Hz, J_HF = 3.7 Hz). ¹H and ¹⁹F NMR spectra matched reported data.^11a HRMS (DART) calcd for C₉H₉O₂NF [M+H]⁺: 182.0612, found 182.0612.

(E)-1-Bromo-4-(1-fluorohex-1-en-2-yl)benzene (18c).

Decarboxylation of acid 18b (250.0 mg, 0.83 mmol, >98:2 dr) was carried out with 5 mol% of AgOAc (6.93 mg, 0.05 mmol) in NMP (0.5 mL, 2V) at 130 °C for 5.5 h. The product 18c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with hexanes (190.6 mg, 89% yield, single stereoisomer (>98:2 dr)). mp 102.9–104.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.41 (m, 2H), 7.21–7.09 (m, 2H), 6.77 (d, J_HF = 85.0 Hz, 1H), 2.73–2.33 (m, 2H), 1.53–1.15 (m, 4H), 1.07–0.69 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.9 (d, J = 259.9 Hz), 135.7 (d, J = 9.6 Hz), 131.7, 128.4 (d, J = 3.1 Hz), 124.4 (d, J = 9.9 Hz), 121.3, 29.8 (d, J = 2.1 Hz), 26.1 (d, J = 3.9 Hz), 22.3, 13.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −130.0 (dt, J_HF = 85.0 Hz, J_HF = 2.8 Hz). HRMS (EI) calcd for C₁₂H₁₄BrF [M]⁺: 256.0257, found 256.0261.

(E)-1-(1-Fluorobut-1-en-2-yl)-2-methylbenzene (19c).

Decarboxylation of acid 19b (650.0 mg, 3.12 mmol, >98:2 dr) was carried out with 15 mol% of AgOAc (78.5 mg, 0.47 mmol) in NMP (1.3 mL, 2V) at 130 °C for 18 h. The product 19c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with pentane (346.2 mg, 68% yield, single stereoisomer (>98:2 dr)). mp 107.6–109.1 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.26–7.12 (m, 3H), 7.12–7.06 (m, 1H), 6.45 (d, J_HF = 86.4 Hz, 1H), 2.47 (ddq, J = 7.6 Hz, J_HF = 2.7 Hz, J = 0.9 Hz, 2H), 2.31 (s, 3H), 0.96 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.4 (d, J = 259.8 Hz), 136.8 (d, J = 2.9 Hz), 135.9 (d, J = 9.9 Hz), 130.3 (d, J = 3.0 Hz), 130.1, 127.5, 125.8 (d, J = 7.9 Hz), 125.4, 21.5 (d, J = 3.8 Hz), 19.7, 12.0 (d, J = 2.2 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −131.7 (dt, J_HF = 86.4 Hz, J_HF = 2.0 Hz); HRMS (EI) calcd for C₁₁H₁₃F [M]⁺: 164.0996, found 164.0996.

(E)-(1-Fluoro-3-methylbut-1-en-2-yl)benzene (20c).

Decarboxylation of acid 20b (250 mg, 1.20 mmol, 18.4:1 (95:5) dr) was carried out with 10 mol% of AgOAc (20.0 mg, 0.12 mmol) in NMP (0.5 mL, 2V) at 130 °C for 5 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 139.5 mg, 71% NMR yield, 17.9:1 (95:5) dr. The product 20c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 0–1% Et₂O in pentane (108.6 mg, 55% yield, >98:2 dr). ¹H NMR (400 MHz, CDCl₃) δ 7.34–7.25 (m, 3H), 7.23–7.16 (m, 2H), 6.47 (d, J_HF = 85.6 Hz, 1H), 3.07 (sept, J = 7.0 Hz, 1H), 1.13 (d, J = 7.0 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.4 (d, J = 261.4 Hz), 136.2 (d, J = 10.7 Hz), 130.8 (d, J = 6.6 Hz), 129.0 (d, J = 3.1 Hz), 128.0, 127.3, 28.1 (d, J = 2.1 Hz), 21.2 (d, J = 2.6 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −130.5 (d, J_HF = 85.6 Hz), Z-isomer: −138.2 (dd, J_HF = 85.3 Hz, J_HF = 4.1 Hz); HRMS (EI) calcd for C₁₁H₁₃F [M]⁺: 164.0996, found 164.0996.

(E)-1-(1-Cyclopropyl-2-fluorovinyl)-4-methoxybenzene (21c).

Decarboxylation of acid 21b (250.0 mg, 0.55 mmol, >98:2 dr) was carried out with 10 mol% of AgOAc (8.83 mg, 0.05 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4.5 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 170.33 mg, 84% NMR yield, single stereoisomer (>98:2 dr). The product 21c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 1–4% Et₂O in hexanes (162.8 mg, 80% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 7.22–7.14 (m, 2H), 6.90–6.83 (m, 2H), 6.69 (d, J_HF = 84.8 Hz, 1H), 3.82 (s, 3H), 1.95–1.77 (m, 1H), 0.86–0.72 (m, 2H), 0.57–0.42 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.1, 146.4 (d, J = 260.7 Hz), 129.8 (d, J = 3.2 Hz), 127.3 (d, J = 9.1 Hz), 125.3 (d, J = 6.0 Hz), 113.5, 55.2, 9.2 (d, J = 4.6 Hz), 4.9 (d, J = 3.1 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −133.8 (d, J_HF = 84.8 Hz). HRMS (DART) calcd for C₁₂H₁₄OF [M+H]⁺: 193.1023, found 193.1024.

(Z)-1-Bromo-4-(1,3,3,3-tetrafluoroprop-1-en-2-yl)benzene (22c).

Decarboxylation of acid 22b (250.0 mg, 0.80 mmol, 25.8:1 (96:4) dr) was carried out with 5 mol% of AgOAc (6.66 mg, 0.04 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4.5 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 193.2 mg, 90% NMR yield, mixture of stereoisomers in 25.2:1 (96:4) dr. The product 22c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 1% Et₂O in pentane (167.4 mg, 78% yield, mixture of stereoisomers in 26.2:1 (96:4) dr). The minor stereoisomer can be separated by silica gel column chromatography eluting with pentane. ¹H NMR (400 MHz, CDCl₃) δ 7.57–7.51 (m, 2H), δ 7.23–7.17 (m, 2H), 6.81 (dq, J_HF = 77.0 Hz, J_HF = 0.6 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 151.9, (dq, J = 288.4 Hz, J = 3.1 Hz), 132.0, 130.8 (d, J = 3.0 Hz), 127.7 (dq, J = 6.1 Hz, J = 1.2 Hz), 123.8, 122.0 (q, J = 273.8 Hz), 116.8 (dq, J = 32.2 Hz, J = 1.2 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −111.3 (dq, J_HF = 77.0 Hz, J = 23.7 Hz), −59.7 (d, J = 23.7 Hz); Z-isomer: δ −123.6 (dq, J_HF = 77.6 Hz, J = 7.7 Hz), −63.4 (d, J = 7.7 Hz). HRMS (EI) calcd for C₉H₅BrF₄ [M]⁺: 267.9505, found 267.9509.

(E)-1-(1-Fluorooct-1-en-6-yn-2-yl)-3,5-dimethylbenzene (23c).

Decarboxylation of acid 23b (150.0 mg, 0.55 mmol, >98:2 dr) was carried out with 10 mol% of AgOAc (9.13 mg, 0.05 mmol) in NMP (0.3 mL, 2V) at 130 °C for 3.0 h. The product 23c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 0–2% MTBE in hexanes (96.2 mg, 76% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) 6.94 (s, 1H), 6.92–6.65 (m, 3H), 2.68–2.55 (m, 2H), 2.32 (s, 6H), 2.19–2.08 (m, 2H), 1.79 (t, J = 2.5 Hz, 3H), 1.65–1.52 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.9 (d, J = 259.0 Hz), 138.0, 136.1 (d, J = 9.0 Hz), 129.1, 124.5 (d, J = 3.0 Hz), 124.4 (d, J = 8.7 Hz), 78.8, 75.7, 27.2 (d, J = 2.2 Hz), 25.7 (d, J = 4.3 Hz), 21.3, 18.4, 3.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −131.1 (d, J_HF = 85.7 Hz). HRMS (DART) calcd for C₁₆H₂₀F [M+H]⁺: 231.1544, found 231.1544.

(Z)-1-(2-Fluoro-1-(4-methoxyphenyl)vinyl)cyclohexane-1-carbonitrile (24c).

Decarboxylation of acid 24b (250 mg, 0.82 mmol, >98:2 dr) was carried out with 5 mol% of AgOAc (6.88 mg, 0.04 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4.5 h. The product 24c was obtained as a white solid after purification by silica gel column chromatography eluting with 1–6% EtOAc in hexanes (204.9 mg, 96% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 10.73–8.78 (brs, 1H), 7.17–7.07 (m, 2H), 6.92–6.80 (m, 2H), 6.47 (d, J_HF = 82.8 Hz, 1H), 3.79 (s, 3H), 2.15–2.00 (m, 2H), 1.79–1.63 (m, 5H), 1.63–1.47 (m, 2H), 1.24–1.04 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.5, 147.8 (d, J = 275.4 Hz), 131.5 (d, J = 3.3 Hz), 125.2 (d, J = 9.7 Hz), 124.6 (d, J = 1.7 Hz), 121.6, 113.4, 55.1, 40.1 (d, J = 2.6 Hz), 34.7 (d, J = 2.9 Hz), 24.6, 22.7; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −117.1 (d, J_HF = 82.8 Hz). HRMS (DART) calcd for C₁₆H₁₉ONF [M+H]⁺: 260.1445, found 260.1446.

(E)-1-Bromo-4-(1-fluoro-3-phenylprop-1-en-2-yl)benzene (25c).

Decarboxylation of acid 25b (250.0 mg, 0.55 mmol, 14.9:1 (94:6) dr) was carried out with 10 mol% of AgOAc (12.44 mg, 0.07 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4.0 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 191.2 mg, 88% NMR yield, mixture of stereoisomers in 15.2:1 (94:6) dr. The product 25c was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 0–2% MTBE in hexanes (177.0 mg, 82% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) 7.41–7.36 (m, 2H), 7.27–7.21 (m, 2H), 7.20–7.13 (m, 3H), 7.12–7.08 (m, 2H), 6.97 (d, J_HF = 84.5 Hz, 1H), 3.85 (d, J_HF = 2.9 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.6 (d, J = 261.9 Hz), 138.2 (d, J = 2.5 Hz), 135.0 (d, J = 8.7 Hz), 131.6, 128.5, 128.4, 128.3 (d, J = 4.1 Hz), 126.2, 122.8 (d, J = 9.6 Hz), 121.4, 32.6 (d, J = 4.7 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −128.9 (dt, J_HF = 84.5 Hz, J_HF = 2.8 Hz). HRMS (EI) calcd for C₁₅H₁₂BrF [M]⁺: 290.0101, found 290.0103.

(E)-3-(1-Fluoroprop-1-en-2-yl)quinoline (26c).

Decarboxylation of acid 26b (250.0 mg, 1.08 mmol, >98:2 dr) was carried out with 15 mol% of AgOAc (27.1 mg, 0.16 mmol) in NMP (0.75 mL, 3V) at 130 °C for 6 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 175.8 mg, 87% NMR yield, single stereoisomer (>98:2 dr). The product 26c was obtained as a white solid after purification by silica gel column chromatography eluting with 5–10% EtOAc in hexanes (178.3 mg, 88% yield, single stereoisomer (>98:2 dr)). mp 58.0–59.9 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.88 (d, J_HF = 2.3 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.97 (d, J_HF = 2.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 (ddd, J = 8.4 Hz, J = 7.0 Hz, J = 1.4 Hz, 1H), 7.52 (ddd, J = 8.0 Hz, J = 7.0 Hz, J = 1.0 Hz, 1H), 7.06 (dq, J_HF = 83.6 Hz, J = 1.5 Hz, 1H), 2.13 (dd, J_HF = 3.6 Hz, J = 1.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.4 (d, J = 2.2 Hz), 147.4, 146.9 (d, J = 261.2 Hz), 132.1 (d, J = 4.8 Hz), 130.4 (d, J = 8.7 Hz), 129.3, 129.2, 127.8, 127.7, 127.0, 117.6 (d, J = 11.2 Hz), 12.0 (d, J = 5.9 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −127.1 (dq, J_HF = 83.6 Hz, J_HF = 3.6 Hz); Z-isomer: −126.1 (dq, J_HF = 83.7 Hz, J_HF = 4.8 Hz). NMR spectra matched reported data.³⁶ HRMS (DART) calcd for C₁₂H₁₁NF [M+H]⁺: 188.0870, found 188.0870.

(E)-2-(1-Fluoroprop-1-en-2-yl)benzo[b]thiophene (27c).

Decarboxylation of acid 27b (250.0 mg, 1.06 mmol, 10.9:1 (92:8) dr) was carried out with 5 mol% of AgOAc (8.83 mg, 0.05 mmol) in NMP (0.5 mL, 2V) at 130 °C for 2.0 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 181.6 mg, 89% NMR yield, mixture of stereoisomers in 4.3:1 (81:19) dr. The isomers were separated by silica gel column chromatography eluting with 0–1% MTBE in hexanes (E-27c: 142.4 mg, white solid, 70% yield, >98:2 dr; Z-27c: 32.5 mg, white solid, 16% yield, 43.7:1 dr). E-isomer: mp 79.9–80.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.78 (m, 1H), 7.78–7.73 (m, 1H), 7.43–7.33 (m, 2H), 7.25 (dq, J_HF = 82.9 Hz, J = 1.4 Hz, 1H), 7.26 (s, 1H), 2.20 (dd, J_HF = 3.6 Hz, J = 1.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.9 (d, J = 262.6 Hz), 140.1 (d, J = 8.5 Hz), 139.8, 138.1, 124.6, 124.4, 123.1, 122.0, 120.6 (d, J = 8.0 Hz), 115.7 (d, J = 13.8 Hz), 11.9 (d, J = 5.7 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −129.2 (dq, J_HF = 82.9 Hz, J_HF = 3.6 Hz); HRMS (EI) calcd for C₁₁H₉FS [M]⁺: 192.0404, found 192.0406. Z-isomer: ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.79 (m, 1H), 7.79–7.73 (m, 1H), 7.39–7.28 (m, 3H), 6.73 (dq, J_HF = 82.7 Hz, J = 1.5 Hz, 1H), 2.04 (dd, J_HF = 4.4 Hz, J = 1.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.1 (d, J = 269.2 Hz), 139.9 (d, J = 9.0 Hz), 138.9, 137.9 (d, J = 4.7 Hz), 124.5, 124.3, 123.5 (d, J = 1.8 Hz), 122.0, 121.9 (d, J = 5.1 Hz), 112.4 (d, J = 2.1 Hz), 15.3 (d, J = 7.5 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −120.3 (dq, J_HF = 82.7 Hz, J_HF = 4.4 Hz). HRMS (EI) calcd for C₁₁H₉FS [M]⁺: 192.0404, found 192.0402.

(E)-1-(1-Fluoroprop-1-en-2-yl)cyclohex-1-ene (28c).

Decarboxylation of acid 28b (650.0 mg, 3.53 mmol, >98:2 dr) was carried out with 5 mol% of AgOAc (29.45 mg, 0.18 mmol) in NMP (1.3 mL, 3V) at 130 °C for 4 h. The product 28c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 0–1% Et₂O in pentane (427.8 mg, 86% yield, single stereoisomer (>98:2 dr)). ¹H NMR (400 MHz, CDCl₃) 6.73 (d, J_HF = 86.3 Hz, 1H), 5.90–5.64 (m, 1H), 2.21–2.01 (m, 4H), 1.77 (dd, J_HF = 3.6 Hz, J = 1.4 Hz, 3H), 1.71–1.63 (m, 2H), 1.63–1.53 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.5 (d, J = 253.2 Hz), 132.7 (d, J = 6.9 Hz), 124.0 (d, J = 9.3 Hz), 120.9 (d, J = 7.8 Hz), 25.8, 25.3, 22.6, 22.3, 9.5 (d, J = 8.1 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −137.6 (d, J_HF = 86.3 Hz, 1H). HRMS (EI) calcd for C₉H₁₃F [M]⁺: 140.0996, found 140.0997.

(E)-6-(Fluoromethylene)-8a-methyl-3,4,6,7,8,8a-hexahydronaphthalen-1(2H)-one (29c).

Decarboxylation of acid 29b (250 mg, 1.05 mmol, 9.97:1 (91:9) dr) was carried out with 25 mol% of AgOAc (43.8 mg, 0.26 mmol) in NMP (0.5 mL, 2V) at 130 °C for 4 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 154.5 mg, 76% NMR yield, mixture of stereoisomers in 8.93:1 (90:10) dr. The product 29c was obtained as a colorless liquid after purification by silica gel column chromatography eluting with 3–8% EtOAc in hexanes (146.7 mg, 72% yield, mixture of stereoisomers in 7.89:1 (89:11) dr). ¹H NMR (400 MHz, CDCl₃) δ 6.53 (d, J_HF = 84.2 Hz, 1H), 5.70 (s, 1H), 2.71–2.49 (m, 3H), 2.40–2.23 (m, 2H), 2.18–2.06 (m, 1H), 2.05–1.93 (m, 1H), 1.86–1.75 (m, 1H), 1.75–1.65 (m, 1H), 1.65–1.51 (m, 1H), 1.26 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 213.6, 145.2 (d, J = 257.2 Hz), 142.6 (d, J = 13.9 Hz), 119.1 (d, J = 11.6 Hz), 118.3 (d, J = 9.2 Hz), 50.2, 38.1, 31.2, 29.0, 24.5 (d, J = 0.8 Hz), 24.0 (d, J = 1.4 Hz), 17.1 (d, J = 4.8 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −136.5 (m, J_HF = 84.2 Hz); Z-isomer: −138.7 (d, J_HF = 84.4 Hz). HRMS (EI) calcd for C₁₂H₁₅OF [M]⁺: 194.1101, found 194.1103.

(E)-2-(2-Fluorovinyl)naphthalene (E-30c).

Decarboxylation of acid E-30b (250 mg, 1.16 mmol, > 98:2 dr) was carried out with 5 mol% of AgOAc (9.65 mg, 0.58 mmol) in NMP (0.5 mL, 2V) at 130 °C for 3 h. The product E-30c was obtained as a white solid after purification by silica gel column chromatography eluting with 0–1% Et₂O in hexanes (193.8 mg, 97% yield, single stereoisomer (> 98:2 dr). mp 72.0–72.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.74 (m, 3H), 7.66 (s, 1H), 7.52–7.36 (m, 3H), 7.32 (dd, J_HF = 83.1 Hz, J = 11.4 Hz, 1H), 6.56 (dd, J_HF = 19.5 Hz, J = 11.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 150.5 (d, J = 259.3 Hz), 133.6, 132.7 (d, J = 1.3 Hz), 130.1 (d, J = 11.7 Hz), 128.5, 127.70, 127.68, 126.5, 125.9, 125.7 (d, J = 5.0 Hz), 123.3 (d, J = 1.4 Hz), 114.1 (d, J = 16.2 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −129.4 (dd, J_HF = 83.1 Hz, J_HF = 19.5 Hz). NMR spectra matched reported data.³⁷ HRMS (EI) calcd for C₁₂H₉F [M]⁺: 172.0683, found 172.0682.

(Z)-2-(2-Fluorovinyl)naphthalene (Z-30c).

Decarboxylation of acid Z-30b (250 mg, 1.16 mmol, > 98:2 dr) was carried out with 50 mol% of AgOAc (96.5 mg, 0.58 mmol) in NMP (2.0 mL, 8V) at 145 °C for 10 h. The product Z-30c was obtained as a white solid after purification by silica gel column chromatography eluting with 0–1% Et₂O in hexanes (171.9 mg, 86% yield, single stereoisomer (> 98:2 dr)). mp 59.8–61.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.88–7.79 (m, 3H), 7.75–7.68 (m, 1H), 7.54–7.45 (m, 2H), 6.75 (dd, J_HF = 82.7 Hz, J = 5.4 Hz, 1H), 5.79 (dd, J_HF = 44.8 Hz, J = 5.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.5 (d, J = 270.9 Hz), 133.4, 132.6 (d, J = 1.8 Hz), 130.1 (d, J = 1.7 Hz), 128.1, 128.0, 127.9 (d, J = 7.2 Hz), 127.6, 126.7 (d, J = 7.2 Hz), 126.2, 126.1, 110.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −121.7 (dd, J_HF = 82.7 Hz, J_HF = 44.8 Hz). NMR spectra matched reported data.^10a HRMS (EI) calcd for C₁₂H₉F [M]⁺: 172.0683, found 172.0682.

(E)-4-(2-Fluorovinyl)benzo[d][1,3]dioxole (31c).

Decarboxylation of acid 31b (250 mg, 1.19 mmol, > 98:2 dr) was carried out with 5 mol% of AgOAc (9.9 mg, 0.06 mmol) in NMP (0.5 mL, 2V) at 130 °C for 3 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 173.4 mg, 88% NMR yield, single stereoisomer (> 98:2 dr). The product 31c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 3–6% Et₂O in pentane (169.4 mg, 86% yield, single stereoisomer (> 98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (dd, J_HF = 84.1 Hz, J = 11.3 Hz, 1H), 6.83–6.77 (m, 1H), 6.75–6.71 (m, 1H), 6.71–6.66 (m, 1H), 6.29 (dd, J_HF = 20.5 Hz, J = 11.3 Hz, 1H), 6.00 (s, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.0 (d, J = 260.1 Hz), 147.4, 144.0 (d, J = 2.0 Hz), 121.8, 121.2 (d, J = 3.8 Hz), 115.1 (d, J = 12.3 Hz), 109.3 (d, J = 18.3 Hz), 107.3 (d, J = 2.1 Hz), 100.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.9 (dd, J_HF = 84.1 Hz, J_HF = 20.5 Hz). HRMS (EI) calcd for C₉H₇O₂F [M]⁺: 166.0425, found 166.0425.

(E)-2-(2-Fluorovinyl)benzofuran (32c).

Decarboxylation of acid 32b (200 mg, 0.97 mmol, > 98:2 dr) was carried out with 5 mol% of AgOAc (8.1 mg, 0.049 mmol) in NMP (0.4 mL, 2V) at 130 °C for 4 h. ¹⁹F NMR of the crude with PhCF₃ as an internal standard: m(prod) = 121.6 mg, 77% NMR yield, single stereoisomer (> 98:2 dr). The product 32c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 0–1% Et₂O in pentane (114.0 mg, 73% yield, single stereoisomer (> 98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.48 (m, 1H), 7.45 (ddd, J_HF = 82.0 Hz, J = 11.1 Hz, J = 0.6 Hz, 1H), 7.44–7.39 (m, 1H), 7.29–7.24 (m, 1H), 7.23–7.17 (m, 1H), 6.55 (s, 1H), 6.34 (ddd, J_HF = 17.1 Hz, J = 11.1 Hz, J = 0.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.6, 152.1 (d, J = 264.4 Hz), 150.2 (d, J = 13.1 Hz), 128.6, 124.5 (d, J = 0.8 Hz), 122.9, 120.5, 110.8, 104.9 (d, J = 9.9 Hz), 104.2 (d, J = 20.6 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −126.1 (dd, J_HF = 82.0 Hz, J_HF = 17.1 Hz). HRMS (EI) calcd for C₁₀H₇OF [M]⁺: 162.0475, found 162.0476.

(E)-(2-Fluorovinyl)cyclopropane (33c).

Note: due to the low b.p. of the product two reactions were run side by side: one to calculate NMR assay yield, and one to isolate the product as a solution in CDCl₃ for product characterization. A reaction vial was charged with acid 33b (1.00 g; 7.69 mmol, 1 equiv), AgOAc (641.38 mg; 3.84 mmol; 50.0 mol%), and NMP (2.00 mL; 2.00 V). The vial was inerted with argon, sealed, and placed to a preheated to 145 °C oil bath. The reaction mixture was stirred at 145 °C for 4 h. The reaction mixture was cooled to 0 °C, and the vial was opened to release CO₂. To the first reaction vial was added PhCF₃ (77.77 mg) as internal standard, and the mixture was diluted with CDCl₃. The mixture was analyzed by quantitative ¹⁹F NMR: m(prod) = 111.0 mg, 67% NMR assay yield; >98:2 dr. The second reaction mixture was subjected to distillation. The product 33c was isolated as a colorless volatile liquid by bulb-to-bulb distillation from the reaction mixture (40–50 °C bath / 50 torr) using liquid nitrogen to cool the receiver. The distillation receiver was warmed to 5 °C and the product 33c was dissolved in CDCl₃ to avoid product loss as it has a low b.p. ¹H NMR (400 MHz, CDCl₃) δ 6.59 (ddd, J_HF = 85.1 Hz, J = 11.0 Hz, J = 0.8 Hz, 1H), 5.08 (ddd, J_HF = 18.4 Hz, J = 11.0 Hz, J = 8.3 Hz, 1H), 1.27–1.16 (m, 1H), 0.72–0.63 (m, 2H), 0.37–0.24 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.3 (d, J = 250.4 Hz), 115.4 (d, J = 12.5 Hz), 6.8 (d, J = 13.6 Hz), 5.6 (d, J = 1.5 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −134.4 (dd, J_HF = 85.1 Hz, J_HF = 18.4 Hz). Attempts to obtain HRMS data were not successful for this compound.

(E)-(2-Fluorovinyl)cyclopentane (34c).

A reaction vial was charged with acid 34b (250.0 mg; 1.58 mmol, 1 equiv), AgOAc (131.91 mg; 0.79 mmol; 50.00 mol%), and NMP (0.50 mL; 2.00 V). The vial was inerted with argon, sealed, and placed to a preheated to 140 °C oil bath. The reaction mixture was stirred at 140 °C for 3 h. The reaction mixture was cooled to 0 °C, and the vial was opened to release CO₂. Product 34c was isolated as a colorless volatile liquid by bulb-to-bulb distillation from the reaction mixture (40–50 °C bath / 10 torr) using liquid nitrogen to cool the receiver (160.5 mg, 89% yield, single stereoisomer (> 98:2 dr)). ¹H NMR (400 MHz, CDCl₃) δ 6.51 (ddd, J_HF = 86.1 Hz, J = 11.1 Hz, J = 1.0 Hz, 1H), 5.35 (ddd, J_HF = 19.7 Hz, J = 11.1 Hz, J = 8.7 Hz, 1H), 2.40–2.26 (m, 1H), 1.85–1.73 (m, 2H), 1.72–1.50 (m, 4H), 1.32–1.20 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 147.7 (d, J = 252.0 Hz), 116.2 (d, J = 8.0 Hz), 36.5 (d, J = 8.8 Hz), 33.4 (d, J = 2.2 Hz), 24.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −133.4 (dd, J_HF = 86.1 Hz, J_HF = 19.7 Hz). HRMS (EI) calcd for C₇H₁₁F [M]⁺: 114.0839, found 114.0841.

(E)-(4-Fluorobut-3-en-1-yl)benzene (35c).

Decarboxylation of acid 35b (250 mg, 1.29 mmol, 18.3:1 (95:5) dr) was carried out with 50 mol% of AgOAc (107.4 mg, 0.64 mmol) in NMP (0.5 mL, 2V) at 145 °C for 6 h. The product 35c was obtained as a colorless volatile liquid after purification by silica gel column chromatography eluting with 2–4% Et₂O in pentane (177.3 mg, 92% yield, mixture of stereoisomers in 18.1:1 (95:5) dr). ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.28 (m, 2H), 7.27–7.16 (m, 3H), 6.52 (dd, J_HF = 85.6 Hz, J = 11.1 Hz, 1H), 5.41 (ddt, J_HF = 18.9 Hz, J = 11.1 Hz, J = 7.7 Hz, 1H), 2.75–2.67 (m, 2H), 2.31–2.20 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.3 (d, J = 37.1 Hz), 146.4 (d, J = 248.6 Hz), 140.3, 128.5, 128.4, 126.3, 125.8 (d, J = 18.2 Hz), 35.1 (d, J = 2.2 Hz), 27.3 (d, J = 4.7 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −129.8 (dd, J_HF = 85.6 Hz, J_HF = 18.9 Hz). HRMS (EI) calcd for C₁₀H₁₁F [M]⁺: 150.0839, found 150.0840.

Ethyl (Z)-4-bromo-2-fluoro-3-phenylbut-2-enoate (37).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (30.6 mL, 150.72 mmol, 2.0 equiv) and THF (250 mL). The solution was cooled to 0 to −5 °C. MeMgBr (43.3 mL, 150.72 mmol, 3.48 M in 2-MeTHF, 2.0 equiv) was added dropwise maintaining internal temperature below 10 °C. The reaction mixture was warmed to rt and stirred for 10 min, then cooled to 0 °C. A solution of 2-bromoacetophenone (15.0 g, 75.36 mmol, 1.0 equiv) in THF (50 mL) was added dropwise over 30 min. The reaction mixture was warmed to rt and stirred for 20 min. The mixture was quenched with 10% aq. NH₄Cl solution (200 mL), and phases were separated. Aqueous phase was extracted with MTBE (2 × 50 mL). The combined organic phases were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by quantitative ¹⁹F NMR: mixture of stereoisomers in 8.6:1 dr. The residue was purified using silica gel column chromatography eluting with 1–4% EtOAc in hexanes to afford two fractions: less polar fraction (colorless liquid, 1.88 g, E-37) and more polar fraction (Z-37, colorless liquid, mixture of stereoisomers in 30.6:1 (97:3) dr (19.79 g, 91% yield). Polar isomer was used directly in the next step without further purification. Z-37, major: ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.34 (m, 3H), 7.30–7.23 (m, 2H), 4.29 (d, J_HF = 3.5 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.8 (d, J = 35.7 Hz), 145.9 (d, J = 265.1 Hz), 134.6 (d, J = 4.0 Hz), 129.8 (d, J = 13.9 Hz), 128.5, 128.3 (d, J = 3.1 Hz), 128.1, 61.6, 28.8 (d, J = 8.4 Hz), 13.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −117.0 (t, J_HF = 3.5 Hz); HRMS (DART) calcd for C₁₂H₁₃O₂BrF [M+H]⁺: 287.0078, found 287.0078. E-37, minor: ¹H NMR (400 MHz, CDCl₃) δ 7.49–7.33 (m, 5H), 4.81 (d, J_HF = 1.8 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.7 (d, J = 33.8 Hz), 145.4 (d, J = 266.9 Hz), 134.1, 130.6 (d, J = 15.1 Hz), 129.1, 128.5, 128.2 (d, J = 3.7 Hz), 62.1, 29.5 (d, J = 5.2 Hz), 14.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −118.9 (s).

Ethyl (Z)-4-(bis(tert-butoxycarbonyl)amino)-2-fluoro-3-phenylbut-2-enoate (38).

A flask was charged with bromide 37 (17.0 g, 59.21 mmol, 1 equiv; mixture of stereoisomers in 30.6:1 (97:3) dr), Boc₂NH (15.4 g, 71.05 mmol, 1.2 equiv), Bu₄NI (2.2 g; 5.92 mmol, 10.0 mol%), and MEK (140.0 mL). The solution was cooled to 0 °C and Cs₂CO₃ (28.9 g, 88.81 mmol, 1.5 equiv) was added. The reaction mixture was warmed to rt and stirred for 3 h 15 min. The reaction mixture was cooled to 0 °C and quenched with 10% aq. NH₄Cl solution (100 mL). The layers were separated and the organic phase was distilled to 2–3 volumes (~40–50 mL) under vacuum at 60 °C. A heptane/MEK mixture (100 mL, 2:1 v/v) was added. The solution was distilled to about 2 volumes (35 mL) and the resultant solution was diluted with heptane (70 mL) at 60 °C. The mixture was linearly cooled to 0 °C over 1 h. The slurry was filtered. Solid was washed with cold (~ 5 °C) heptane/MEK (50:1 v/v) solvent mixture. It was then dried in vacuum oven at 40 °C overnight to afford the first crop of the product. Crop 1: 17.80 g, white solid, > 98:2 dr. The mother liquor was concentrated to a volume of ~20 mL and the residue was recrystallized from heptane/MEK (50:1 v/v) to afford a second crop of the product. Crop 2: 4.44 g, white solid, > 98:2 dr. Combined weight of 38: 22.24 g, 84.3 wt.% purity, >98:2 dr, 75% yield. The product was used in next step without further purification. A 100 mg sample of crop 1 was purified by silica gel column chromatography for analytical purposes. Eluent: 8–10% EtOAc in hexanes. White solid. ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.25 (m, 3H), 7.15–7.06 (m, 2H), 4.77 (d, J_HF = 2.7 Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 1.37 (s, 18H), 0.96 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.1 (d, J = 36.0 Hz), 151.7, 144.2 (d, J = 257.3 Hz), 133.3 (d, J = 4.9 Hz), 131.4 (d, J = 12.8 Hz), 128.4 (d, J = 3.1 Hz), 127.8, 127.7, 82.5, 61.0, 45.1 (d, J = 9.0 Hz), 27.7, 13.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −123.4 (s). HRMS (DART) calcd for C₁₈H₂₃O₆NF [M+H-C₄H₈]⁺: 368.1504, found 368.1505.

(Z)-4-((tert-Butoxycarbonyl)amino)-2-fluoro-3-phenylbut-2-enoic acid (39).

To a solution of 38 (21.74 g, 84.3 wt.%, 43.33 mmol, 1 equiv) in EtOH (170.0 mL) was added a solution of LiOH•H₂O (8.60 g; 204.97 mmol; 4.73 equiv) in H₂O (131.0 mL) at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h (complete saponification). The reaction mixture was heated to 60 °C and stirred for 13.5 h (complete Boc-cleavage). The reaction mixture was cooled to 10 °C and 1 M HCl (205.0 mL; 204.97 mmol; 4.73 equiv) was added dropwise. A solvent mixture consisting of EtOH (30.00 mL) and H₂O (66.00 mL) was added. The resultant slurry was stirred for 0.5 h and H₂O (71.0 mL) was added dropwise over 30 min (final dilution 25 wt.% EtOH in H₂O). The slurry was stirred for 0.5 h and then filtered. The solid was washed with aq. EtOH (25 wt.% EtOH). It was then dried on a Buchner funnel for 1 h and then in a vacuum oven at 40 °C overnight. Crop 1: white solid (8.09 g, > 98:2 dr). The mother liquor was slowly acidified to pH = 3 with 1 M HCl at 10 °C and extracted with EtOAc. Combined extracts were dried over MgSO₄, filtered, and concentrated under reduced pressure. Crude product was recrystallized from EtOH/H₂O solvent system (final dilution 25 wt.% EtOH in H₂O) to obtain the second crop. Crop 2: white solid (3.32 g, > 98:2 dr). Combined weight of 39: 11.41 g, 89% yield. The compound exists as a mixture of Boc rotamers. mp 138.0–139.0 °C; ¹H NMR (400 MHz, CD₃CN) δ 7.38–7.27 (m, 3H), 7.21–7.10 (m, 2H), 5.38–5.14 (brs, 1H), 4.17–4.06 (m, 2H), 1.29 (s, 9H); ¹³C{¹H} NMR (100 MHz, CD₃CN) δ 161.9 (d, J = 36.7 Hz), 157.0, 145.7 (d, J = 255.3 Hz), 136.0 (d, J = 5.2 Hz), 134.0 (d, J = 14.1 Hz), 129.9 (d, J = 2.8 Hz), 129.23, 129.19, 80.0, 41.4 (d, J = 9.1 Hz), 28.9; ¹⁹F NMR (376.5 MHz, CD₃CN) δ −123.5 (s). HRMS (DART) calcd for C₁₅H₁₇O₄NF [M-H]^–: 294.1147, found 294.1147.

tert-Butyl (Z)-(3-fluoro-2-phenylallyl)carbamate (40).

A reaction flask was charged with 39 (2.0 g, 6.77 mmol, 1 equiv, >98:2 dr), AgOAc (113.0 mg, 0.68 mmol, 10 mol%), and NMP (4.0 mL, 2V). The flask was inerted and placed into preheated to 130 °C oil bath. The reaction mixture was stirred for 3 h under positive Ar pressure. After this time the reaction mixture was cooled to rt Celite was added, and the mixture was diluted with EtOAc (20 mL). The mixture was filtered, and the filter pad was washed with EtOAc. Combined filtrates were washed twice with water (10 mL). The organic phase was separated, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0–1% EtOAc in CH₂Cl₂ to afford 40 as a beige solid (1.59 g, 93% yield, > 98:2 dr). mp 78.4–80.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.57–7.07 (m, 5H), 6.84 (d, J_HF = 83.7 Hz), 4.83–4.37 (brs, 1H), 4.37–4.06 (m, 2H), 1.40 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 155.6, 147.4 (d, J = 264.2 Hz), 134.1 (d, J = 8.0 Hz), 128.7, 127.9, 126.9, 122.5 (d, J = 7.1 Hz), 79.4, 36.3 (d, J = 5.1 Hz), 28.3; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −128.4 (dt, J_HF = 83.7 Hz, J_HF = 2.5 Hz). NMR spectra matched reported data.^11a HRMS (EI) calcd for C₁₀H₁₀O₂NF [M-C₄H₈]⁺: 195.0690, found 195.0692.

(Z)-3-Fluoro-2-phenylprop-2-en-1-amine hydrochloride (2)^6b.

To a solution of 40 (851 mg, 3.39 mmol, 1 equiv) in MeOH (5.00 mL) was added HCl (4.0 M in dioxane, 4.2 mL; 16.93 mmol, 5 equiv), and the mixture was stirred at rt overnight. Reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOH (3 mL). MTBE (13 mL) was added dropwise over 30 min, and the slurry was stirred for 1 h. The slurry was filtered, and the filter cake was washed with MTBE. The main crop was obtained as a white solid (482.2 mg). The mother liquor was concentrated under reduced pressure to a minimal volume and the residue was diluted with MTBE. The slurry was stirred for 30 min and then filtered. The second crop was obtained as a white solid (92.4 mg). Combined weight of 2: 575.2 mg, 91% yield, > 98:2 dr. mp 160.6–162.0 °C; ¹H NMR (400 MHz, MeOH-d₄) δ 7.51–7.35 (m, 5H), 7.20 (d, J_HF = 82.5 Hz), 5.08–4.58 (brs, 3H), 4.13 (dd, J_HF = 2.9 Hz, J = 0.7 Hz, 2H); ¹³C{¹H} NMR (100 MHz, MeOH-d₄) 151.6 (d, J = 268.6 Hz), 133.7 (d, J = 7.1 Hz), 130.4, 130.0, 128.3 (d, J = 3.1 Hz), 119.9 (d, J = 6.5 Hz), 36.2 (d, J = 7.6 Hz); ¹⁹F NMR (376.5 MHz, MeOH-d₄) δ −124.0 (d, J_HF = 82.5 Hz). HRMS (EI) calcd for C₉H₉NF [M-H]⁺: 150.0714, found 150.0714.

(3aR,5S,6aR)-2,2-Dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (42).

To a solution of diol 41 (446.0 mg, 2.18 mmol, 1 equiv) in EtOH (5.00 mL) and H₂O (2.50 mL) was added NaIO₄ (583.9 mg, 2.73 mmol, 1.25 equiv) at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h. The mixture was filtered through a plug of celite and the celite plug was washed with EtOH. The filtrate was concentrated under reduced pressure to remove EtOH and water. The residue was chased twice with anhydrous THF. The crude product was suspended in anhydrous THF and was filtered through a plug of celite. The celite plug was washed with THF. Combined filtrates were passed through a 0.45 micron filter and concentrated under reduced pressure to a minimal volume. The crude product solution (a mixture of aldehyde 42 and its ethyl hemiacetal) was used in the next step without further purification.

Ethyl (E)-3-((3aR,5S,6aR)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-fluoroacrylate (43).

A round bottom flask was charged with triethyl 2-fluoro-2-phosphonoacetate (1.19 mL, 5.89 mmol, 2.70 equiv) and THF (10 mL). The solution was cooled to −78 °C. n-BuLi (2.47 mL, 5.89 mmol, 2.39 M in hexanes, 2.70 equiv) was added dropwise. The reaction mixture was warmed to 0 °C and stirred for 10 min, then cooled to −78 °C. A solution of aldehyde 42 (~376 mg, ~2.18 mmol, 1.0 equiv), which was prepared as described above, was diluted with THF (2.0 mL) and added dropwise at −78 °C. The reaction mixture was linearly warmed to 0 °C over 1 h. The mixture was quenched with 10 wt.% aq. NH₄Cl solution (20 mL) and extracted with EtOAc (2 × 20 mL). Organic phase was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by quantitative ¹H NMR: mixture of stereoisomers in 12.8:1 (93:7) dr. The residue was purified by silica gel column chromatography eluting with 15–18% EtOAc in hexanes to afford 43 as a colorless oil (481.9 mg, 85% yield, mixture of stereoisomers in 12.0:1 (92:8) dr (from integration of quantitative ¹H NMR spectrum. Note: the ratio of stereoisomers by integration of quantitative ¹⁹F NMR spectrum is higher due to an overlapping signal of an impurity)). ¹H NMR (400 MHz, CDCl₃) δ 5.90 (dd, J_HF = 19.4 Hz, J = 8.1 Hz, 1H), 5.83 (d, J = 3.8 Hz, 1H), 5.48 (ddd, J = 10.9 Hz, J = 8.1 Hz, J = 4.5 Hz, 1H), 4.76–4.72 (m, 1H), 4.29 (dq, J = 7.1 Hz, J = 0.5 Hz, 2H), 2.34 (ddd, J = 13.3 Hz, J = 4.5 Hz, J = 4.5 Hz, 1H), 1.58 (ddd, J = 13.3 Hz, J = 10.9 Hz, J = 4.7 Hz, 1H), 1.51 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.30 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 160.1 (d, J = 35.6 Hz), 147.6 (d, J = 258.2 Hz), 121.8 (d, J = 20.6 Hz), 111.3, 105.5, 80.4, 72.3 (d, J = 8.8 Hz), 61.9, 39.1 (d, J = 2.9 Hz), 26.7, 26.1, 14.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −119.6 (d, J_HF = 19.4 Hz), Z-isomer: −124.5 (d, J_HF = 33.1 Hz). HRMS (DART) calcd for C₁₂H₁₈O₅F [M+H]⁺: 261.1133, found 261.1134.

(E)-3-((3aR,5S,6aR)-2,2-Dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-fluoroacrylic acid (44).

To a solution of ethyl ester 43 (890.6 mg, 3.42 mmol; 1 equiv, mixture of stereoisomers in 12.0:1 (92:8) dr) in EtOH (10 mL) was added a slurry of LiOH•H₂O (315.9 mg; 7.53 mmol; 2.20 equiv) in water (5.0 mL) at 0 °C. The reaction mixture was warmed to r.t and stirred overnight. The reaction mixture was diluted with water (10.0 mL) and concentrated under reduced pressure to remove almost all EtOH. It was then extracted with MTBE (10 mL) and diluted with brine (20.0 mL). The mixture was cooled to 10 °C and conc. HCl (620 µL; 7.53 mmol; 2.20 equiv) was added dropwise. The mixture was extracted twice with EtOAc (20 mL). EtOAc extracts were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford 44 as a colorless viscous oil. The oil solidified after standing overnight in a freezer. The solid was dried under vacuum for 2 h (775.5 mg, 98% yield, mixture of stereoisomers in 15.4:1 (94:6) dr (from integration of quantitative ¹H NMR spectrum. Note: the ratio of stereoisomers by integration of quantitative ¹⁹F NMR spectrum is higher due to an overlapping signal of an impurity)). ¹H NMR (400 MHz, CDCl₃): δ 11.05–10.51 (brs, 1H), 6.03 (dd, J_HF = 19.1 Hz, J = 8.1 Hz, 1H), 5.86 (d, J = 3.7 Hz, 1H), 5.50 (ddd, J = 10.9 Hz, J = 8.1 Hz, J = 4.5 Hz, 1H), 4.82–4.74 (m, 1H), 2.38 (ddd, J = 13.4 Hz, J = 4.5 Hz, J = 4.5 Hz, 1H), 1.62 (ddd, J = 13.4 Hz, J = 10.9 Hz, J = 4.7 Hz, 1H), 1.51 (s, 3H), 1.32 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 163.9 (d, J = 36.4 Hz), 147.1 (d, J = 256.6 Hz), 123.7 (d, J = 20.6 Hz), 111.7, 105.5, 80.5, 72.4 (d, J = 8.6 Hz), 38.9 (d, J = 2.7 Hz), 26.6, 26.1; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −119.1 (d, J_HF = 19.1 Hz), Z-isomer: −125.1 (d, J_HF = 32.7 Hz). HRMS (DART) calcd for C₁₀H₁₄O₅F [M+H]⁺: 233.0820, found 233.0820.

(3aR,5S,6aR)-5-((E)-2-Fluorovinyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (45).

A reaction vial was charged with acid 44 (250.0 mg, 1.08 mmol, 1 equiv, mixture of stereoisomers in 15.4:1 (94:6) dr), AgOAc (89.9 mg, 0.54 mmol, 50 mol%), and NMP (0.50 mL, 2V). The vial was inerted and placed into preheated to 140 °C oil bath. The reaction mixture was stirred for 3 h under positive Ar pressure. It was then cooled to 0 °C and PhCF₃ (53.9 mg) was added as an internal standard. The mixture was diluted with CDCl₃ and analyzed by quantitative ¹⁹F NMR: m(prod) = 178.2 mg, 88% NMR yield, mixture of stereoisomers in 15.3:1 (94:6) dr). The reaction mixture was directly loaded on a silica gel column using a minimum amount of CH₂Cl₂. It was purified by column chromatography eluting with 20–30% MTBE in hexanes to afford two fractions: major less polar isomer (white foam, 160.2 mg, 79% yield, >98:2 dr), minor isomer (white foam, 8.9 mg, 4.4% yield, >98:2 dr). Analytical data of the major isomer: ¹H NMR (400 MHz, CDCl₃) δ 6.74 (ddd, J_HF = 82.7 Hz, J = 11.1 Hz, J = 0.8 Hz, 1H), 5.79 (d, J = 3.7 Hz, 1H), 5.36 (ddd, J_HF = 16.9 Hz, J = 11.1 Hz, J = 8.2 Hz, 1H), 4.75–4.69 (m, 1H), 4.57 (ddd, J = 10.9 Hz, J = 8.2 Hz, J = 4.3 Hz, 1H), 2.14 (ddd, J = 13.4 Hz, J = 4.3 Hz, J = 4.3 Hz, 1H), 1.60 (ddd, J = 13.4 Hz, J = 10.9 Hz, J = 4.7 Hz, 1H), 1.49 (s, 3H), 1.29 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 151.7 (d, J = 260.9 Hz), 111.0, 110.8 (d, J = 11.9 Hz), 105.1, 80.3, 73.0 (d, J = 14.4 Hz), 39.8 (d, J = 2.3 Hz), 26.5, 25.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −125.7 (dd, J_HF = 82.7 Hz, J_HF = 16.9 Hz). NMR spectra matched reported data.^6e.^9b HRMS (EI) calcd for C₈H₁₀O₃F [M-CH₃]⁺: 173.0608, found 173.0609.

Data Availability Statement.

The data underlying this study are available in the published article and its Supporting Information.