Magnesium-promoted Additions of Difluoroenolates to Unactivated Imines

Abstract

Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic structures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that using magnesium salts and organic bases, unactivated imines will react with difluoroenolates, generated under exceedingly mild conditions. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-β-amino-carbonyl groups. This method provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones without the need of protecting groups or the use of activated imines. Moreover, we have applied this strategy to create analogues of the dual orexin receptor antagonist, almorexant, in only two synthetic steps.

Graphical Abstract

INTRODUCTION

Organic compounds displaying fluorine are particularly valuable in the pharmaceutical, chemical, and agrochemical industries, because the presence of fluorine on a molecule can drastically improve its chemical and biological properties.^1–3 Specifically in drug development, nearly 25% of all marketed drugs contain at least one fluorine atom.^4–6 Numerous efforts for the synthesis of fluorine-containing organic compounds have been reported, yet it is challenging to create some complex fluorinated structures.^7,8 For example, there are vastly more methods for the synthesis of molecules displaying a trifluoromethyl group or a single fluorine than a difluoromethylene group. A primary reason is the difluoromethyl group is not a terminal group; and therefore, newer strategies such as late-stage fluorination cannot be readily applied. A uniquely appealing type of difluorinated compound is a difluoro-β-amino acid, and the typical synthetic target is an α,α-difluoro-β-amino-carbonyl group. These building blocks have found potential use as difluorinated drug leads^9,10 and enzyme inhibitors (Figure 1).^11–13

Figure 1.

Examples of compounds displaying α,α-difluoro-β-amino-carbonyl groups.

The synthesis of α,α-difluoro-β-amino-carbonyl groups relies heavily on the addition of difluoroenolates to imines that are activated with protecting groups on nitrogen. Although the protecting groups assist in enhancing the reactivity (i.e., electrophilicity) of the imine, the utility of protecting groups continues to decline as two protection/deprotection steps must be added into the overall synthetic plan. The addition of difluoroenolates to unprotected, hence unactivated imines, is quite desirable but remains synthetically challenging. Currently, there are only two strategies to unite a difluoroenolate with an unactivated imine: 1) Reformatsky additions of bromodifluoroethyl acetate^14–19 and bromodifluormethyl ketones^20,21 2) Mukaiyama additions of difluoroenoxy silanes (Figure 2). Typically, Reformatsky reactions with bromodifluoroethyl acetate are vigorous and therefore provide the cyclized lactam.^14,15 A diastereoselective variants have been reported,^16–18 and an indium-promoted version of the Reformatsky process has been developed to favor the amino-adduct rather than the lactam.¹⁹ This chemistry has been extended to bromodifluoromethyl ketones in which the unactivated imines react in the presence of copper and zinc.^20,21 Unfortunately, all of these reactions are restricted to a few esters or ketones that bear the requisite bromodifluoromethyl group. The traditional Mukaiyama addition of difluoroenoxysilanes to unactivated imines is limited to a single example in the literature,²² because these imines easily hydrolyze under typical reaction conditions.²³ Although the addition of the Ruppert-Prakash reagent (i.e., CF₃SiMe₃) to acyl silanes followed by treatment of nucleophilic fluorine can generate reactive difluoroenoxysilanes in situ that add to unactivated imines,²⁴ more effective methods are clearly needed. In order to address these deficiencies, we have devised a method that unleashes difluoroenolates under mild conditions yet tunes the reactivity to the unactivated imine. Moreover, we have applied this strategy to produce an α,α-difluoro-β-amino-carbonyl analogue of a drug candidate in only two synthetic steps.

Figure 2.

Two existing methods to prepare α,α-difluoro-β-amino-carbonyl groups from unactivated imines.

In 2011, we reported a mild approach for the generation of difluoroenolates from highly α-fluorinated gem-diols following the release of trifluoroacetate (Figure 3).²⁵ These difluoroenolates subsequently react with aldehydes,^25,26 halogenation reagents,^27,28 trifluoromethyl ketones,²⁹ and disulfides³⁰ and can be quenched with water³¹ or D₂O.³² This approach has been expanded to monofluoroenolates.^33,34 The difluoroenolates also add to activated imines, such as N-sulfonyl,^35,36 N-tosyl,³⁶ N-Boc,³⁵ and N-sulfinyl imines,³⁷ using the originally reported conditions of LiBr/Et₃N.²⁵ These reactions provide the β-amino-α,α-difluoroketones, bearing the corresponding N-substituent, in high yields. Additional studies on the fragmentation of highly α-fluorinated gem-diols have described a novel photoredox-mediated addition to iminiums derived in situ from tetrahydroquinolines;³⁸ however, a general method to add difluoroenolates produced from highly α-fluorinated gem-diols to imines without the need of protecting/activating groups is not currently available.

Figure 3.

Preparation of α,α-difluoro-β-aminocarbonyl groups from highly α-fluorinated gem-diols.

Herein, we describe a simple and mild method to add difluoroenolates, produced from the release of trifluoroacetate from highly α-fluorinated gem-diols, to unactivated imines. This task is accomplished by using magnesium salts and base. Also, we have applied this methodology to synthesizing derivatives of tetrahydroisoquinolines, and particularly, we have produced an α,α-difluoro-β-amino-carbonyl derivative of the drug candidate, almorexant, using these iminoaldol reactions.

RESULTS AND DISCUSSION

Our initial studies began by examining the scope of reactivity of the fluorinated gem-diol 1²⁵ with activated imines using the reported conditions of LiBr/Et₃N (Table 1).^35–37 Imines 2–4 displaying an N-Boc,³⁵ N-tosyl,³⁶ or N-sulfonyl^35,36 substituent participated in yields similar to the reported values. Moreover, the oxaziridine 5 also is a suitable electrophile for this process and provides the same product 9 as direct addition to the N-sulfonylimine 4. This type of addition to an oxaziridine has not been reported from a fluorinated gem-diol, to our knowledge. Also, the diazodicarboxylate 6 reacts with the difluoroenolate in the presence of LiBr and Et₃N to produce hydrazine 10. This reactivity with azodicarboxylates has been recently reported using difluoroenoxysilanes as the difluoroenolate source,³⁹ but it is not known in the literature from highly α-fluorinated gem-diols. Although these iminoaldol-type reactions demonstrate and expand the existing scope for the case of LiBr/Et₃N using activated imines, additional reactivity can be easily tuned by selecting different reagents.

Table 1.

LiBr/Et₃N Promoted Additions of Difluoroenolates Derived from Highly α-Fluorinated gem-Diols.

^aYields determined by ¹⁹F NMR using trifluorotoluene as the internal standard.

The addition of the fluorinated gem-diol 1²⁵ and N-benzylidenebenzylamine 11 in the presence of Et3N and LiBr or LiCl failed to provide any of the desired product 12 (Table 2, entries 1–2). This lack of reactivity using lithium salts and unactivated imines has been previously reported.³⁵ We hypothesized that these entries (i.e., 1–2, Table 2) and the results in Table 1 were due to the fact that lithium salts activate the lone pairs of electrons associated with oxygen atoms whereas magnesium salts activate lone pairs of electrons on nitrogen. Indeed, the advantages of magnesium salts have been demonstrated in similar carbon-carbon bond forming process.^40,41 Accordingly, exchanging lithium salts with MgBr₂, MgCl₂, and MgI₂ (i.e., entries 3–5, respectively) enabled addition to the unactivated imine 11 and production of the desired adduct 12 in 43–74% yields. Further optimizations revealed that 60 °C was the optimal temperature in the presence of MgI₂ and product 12 was produced in 95% yield as determined by¹⁹F NMR. Isopropyl magnesium chloride also provided the product 12 (entry 10), as Grignard reagents are a functional class of bases for generating fluorinated nucleophiles.⁴²

Table 2.

Optimization of Imino-aldol Process

Entry	Additive	Imine (equiv.)	Temp	Yieldb
1	LiBr	1.2	rt	0%
2	LiCl	1.2	rt	0%
3	MgBr2	1.2	60 °C	50%a
4	MgCl2	1.2	60 °C	74%a
5	MgI2	1.2	rt	43%
6	MgI2	2.0	rt	62%
7	MgI2	2.0	40 °C	66%
8	MgI2	2.0	60 °C	73% (95%)a
9	i-PrNMgCl·LiClc	2.0	60 °C	4%
10	i-PrMgCl·LiBrc	2.0	rt	54%

^aYields determined by ¹⁹F NMR using trifluorotoluene as the internal standard.

^bIsolated yields.

^cEt₃N was not added.

We have previously reported the preparation of many highly α-fluorinated gem-diols 1, 13–17.^25,27,28 The scope of the magnesium-promoted additions of unactivated imine 11 and difluoroenolates derived from these highly α-fluorinated gem-diols was characterized and is displayed in Table 3. A substantial range of isolated yields (15–85%) of the β-amino-α,α-difluoro ketones 12, 18–22 was observed. Typically, aromatic groups (1, 13, 15, and 16) were fully compatible with the imino-aldol process mediated by the release of trifluoroacetate and isolated yields were 49–85%; however, alkyl substrates 14 and 17 provided the lowest yields of 15% and 25%, respectively. This disparity demonstrates the scope of process when varying only the α-fluorinated gem-diol.

Table 3.

Magnesium-promoted Addition of Highly α-Fluorinated gem-Diols to the Unactivated Imine 11^a

^aReactions were typically performed with MgI₂ (4.2 equiv.) and Et₃N (2.1 equiv.), see Supporting Information for details.

^bIsolated yields.

Next, the scope of reactivity of unactivated imines 23–29 with the gem-diol 1 was investigated using the magnesium-promoted aldol reaction (Table 4). The effects of both of the substituents on the imine were examined by varying alkyl groups as well as aryl groups with electron-donating and electron-withdrawing substituents. Flame-dried magnesium iodide was needed to obtain good yields in some examples.⁴⁰ In the case of imine 23, with a phenyl groups at each substituent, the product 30 was obtained in 59% isolated yield. The presence of an electron-donating methoxy group on phenyl imine 24 enabled a higher yield of 79% whereas the presence of an electron-withdrawing fluorine on the phenyl imine 32 resulted in a similar yield of 64%. On the hand, the methoxylphenyl imine 26 bearing a N-fluorophenyl substituent gave a high yield of 78%, yet the bis-methoxylphenyl imine 27 resulted in a lower 38% yield. Imines bearing a N-t-butyl group (28, entry 6) or N-benzyl group (29, entry 7) produced yields of 30 and 61%, respectively. This method provides quick access to useful quantities of compounds bearing α,α-difluoro-β-amino-carbonyl groups, and thus, X-ray structures of 30, 31, and 32 were obtained.

Table 4.

Magnesium-promoted Addition of Highly α-Fluorinated gem-Diol 1 to the Unactivated Imines 23–29^a

^aReactions were typically performed with MgI₂ (4.2 equiv.) and Et₃N (2.1 equiv.), see Supporting Information for details.

^bIsolated yields.

The trifluoroacetate-release mediated imino aldol reaction using unactivated imines has substantial potential in the creation of α,α-difluoro-β-amino-carbonyl groups on organic molecules. A previous report demonstrated the utility of the trifluoroacetate-release aldol reaction in adding difluoroenolates to iminiums derived in situ from N-substituted tetrahydroisoquinoline using visible light-induced photoredox catalysis.³⁸ We envisioned that the magnesium-initiated process could be analogously applied to dihydroisoquinolines to provide tetrahydroisoquinolines. Using this approach, the gem-diol 1 was added to dihydroisoquinoline 37 in the presence of MgI₂ and Et₃N to provide the corresponding tetrahydroisoquinoline α,α-difluoro ketones 38 in good 84% yield (Scheme 1). Suzuki–Miyaura cross-coupling of 38 with vinyltrifluoroborate⁴³ provided the tetrahydroisoquinoline 39 in 40% yield and demonstrates structural variants of tetrahydroquinolines can be quickly created.

Scheme 1.

Imino-aldol addition of gem-diol 1 with dihydroisoquinoline 37

Tetrahydroisoquinolines are a valuable class of heterocycle that appears in bioactive natural products, such as the ecteinascidins,⁴⁴ as well as drug discovery (Figure 4).⁴⁵ Notably, almorexant belongs to a class of drugs that act as dual orexin receptor antagonist for treatment of sleep disorders and displays a key tetrahydroisoquinoline.⁴⁶ There are few reported enantioselective syntheses of almorexant that involved key steps such as asymmetric transfer hydrogenation,⁴⁷ asymmetric allylic amidation,⁴⁸ and asymmetric induction with N-tert-butanesulfinamide.⁴⁹ In addition, several almorexant analogues have been synthesized and reported.⁵⁰

Figure 4.

Structure of biologically active molecules displaying a tetrahydroisoquinoline.

We envisioned a strategy to produce derivatives of almorexant using the magnesium-promoted reaction between a fluorinated gem-diol and a dihydroquinoline (Scheme 2). Furthermore, this approach would be short and not require any protecting groups. Accordingly, the known fluorinated gem-diol 40³⁸ and 6,7-dimethoxy-3,4-dihydroisoquinoline 41 were treated with MgI₂ and Et₃N and gave the α,α-difluoro-β-aminoketone 42. Next, 42 was coupled using the literature method⁴⁸ to amide 43⁵⁰ to give a 2.2:1 mixture of diastereomers and the major isomer was purified in 28% isolated yield. Accessing the almorexant derivative 44 in two synthetic steps is a functional demonstration of this method and displays how the unique α,α-difluoro-β-amino-carbonyl group integrates into known bioactive structures.

Scheme 2.

Two-step, protecting group-free synthesis of fluorinated almorexant analogue 44.

CONCLUSIONS

In summary, we have reported a new protocol to synthesize β-amino-α,α-difluoro ketones using magnesium-promoted additions of difluoroenolates with unactivated imines. The difluoroenolates were unleashed from highly α-fluorinated gem-diols using only MgI₂ and Et₃N following the release of trifluoroacetate. This process eliminates the need of an imine with an activating N-substituent or a protecting group. This approach is compatible with many alkyl and aryl substituted imines and gem-diols. It can be easily integrated into drug discovery, and we have demonstrated its potential use in the synthesis of the analogues of almorexant in only two steps. These reactions further establish the role of releasing trifluoroacetate in the presence of mild reagents, such as a salt and an organic base, to generate valuable and reactive difluoroenolates.

EXPERIMENTIAL SECTION

N-(1-(4-Chlorophenyl)-2,2-difluoro-3-(naphthalen-2-yl)-3-oxopropyl)-4-methylbenzene-sulfonamide 8.⁵¹

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)butan-1-one 1^25,27 (65.7 mg, 0.205 mmol), N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide 3 (133 mg, 0.452 mmol) and LiBr (101 mg, 1.16 mmol) in THF (3 mL) was added was Et₃N (60 μL, 0.43 mmol) dropwise. After 5 min, the reaction was quenched with saturated aqueous NH₄Cl (5 mL), and the resultant mixture was extracted with EtOAc (5 mL × 5). The organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash column chromatography (9:1–8:2 hexanes/EtOAc) afforded the title compound 8 as a yellow solid in 84% yield (86.1 mg): mp 143–145 °C; ¹H NMR (300 MHz, CDCl₃) 8.47 (s, 1H), 8.00–7.82 (m, 4H), 7.72–7.50 (m, 4H), 7.19 (s, 4H), 7.09 (d, J = 8.1 Hz, 2H), 5.66 (d, J = 9.5 Hz, 1H), 5.26 (td, J = 12.2, 9.5 Hz, 1H), 2.32 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 188.3 (t, J_CF = 29.1 Hz, 1C), 143.7, 136.9, 136.1, 134.9, 132.8, 132.1, 130.1, 130.0 (3C), 129.7, 129.4 (2C), 129.0, 128.6 (3C), 127.8, 127.0 (3C), 124.4, 116.1 (t, J_CF = 262.1 Hz, 1C), 59.6 (t, J_CF = 25.4 Hz, 1C), 21.4; ¹⁹F NMR (282 MHz, CDCl₃) −103.87 (dd, J_FF = 284.0, J_HF = 11.8 Hz, 1F), −105.92 (dd, J_FF = 284.2, J_HF = 12.6 Hz, 1F); IR (film) ν_max 3584, 3234, 3055, 2974, 2920, 1702 cm^–1; HRMS (ESI) m/z calcd for C₂₆H₂₀O₃NSClF₂Na (M+Na)⁺ 522.0718, found 522.0721.

N-(2,2-Difluoro-3-(naphthalen-2-yl)-3-oxo-1-phenylpropyl)benzenesulfonamide 9.⁵¹

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (30 mg, 0.09 mmol) and N-benzylidenebenzenesulfonamide 4 (28 mg, 0.11 mmol) in THF (620 μL) was added LiBr (24 mg, 0.28 mmol), and the mixture was stirred for 10 min at rt. Next, Et₃N (26 μl, 0.19 mmol) was added dropwise, and after 5 min, the reaction mixture was quenched with saturated aqueous NH₄Cl (3 mL). The resultant mixture was extracted with EtOAc (2 mL × 3). The organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash chromatography (2:1:1 hexane/Et₂O/CHCl₃) afforded the title compound 9 as a colorless solid in 87 % yield (37 mg): mp 132–135 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.46 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.88–7.82 (m, 3H), 7.71–7.61 (m, 3H), 7.57 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.1 Hz, 1H), 7.31–7.18 (m, 7H), 5.73 (m, 1H), 5.32 (td, J = 12.2, 9.9 Hz, 1H); ¹³C NMR (125 MHz CDCl₃) 188.6 (t, J_CF = 29.0 Hz, 1C), 140.1, 136.0, 132.7 (t, J_CF = 4.3 Hz, 1C), 132.5, 132.4, 132.1, 130.1, 129.6, 129.3, 128.8, 128.7 (2C), 128.6, 128.5 (2C), 128.4 (2C), 127.7, 127.1, 126.9 (2C), 124.4, 116.3 (t, J_CF = 261.9 Hz, 1C), 60.2 (t, J_CF = 25.0 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ −103.77 (dd, J_FF = 280, J_HF = 12.0 Hz, 1F), −105.48 (dd, J_FF = 280, J_HF = 12.8 Hz, 1F); IR (film) ν_max 3272, 1696, 1331, 1284, 1166 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₅H₁₉F₂NO₃SNa [M+Na]⁺ 474.0951, found 474.0962.

N-(2,2-Difluoro-3-(naphthalen-2-yl)-3-oxo-1-phenylpropyl)benzenesulfonamide 9.

2,2,4,4,4-Pentafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)butan-1-one 1^25,27 (8 mg, 0.02 mmol) was azeotroped with toluene (3 × 1 mL) and dissolved in THF (0.3 mL). Next, the solution was added to a flask containing LiBr (8.0 mg, 0.92 mmol) and cooled to −78 °C under an argon atmosphere. A solution of Davis oxaziridine D1 (14 mg, 0.054 mmol), that was azeotroped with toluene (3 × 1 mL) and dissolved in THF (0.20 mL), was added dropwise to the reaction mixture and stirred for 15 min at −78 °C. Next, Et₃N (5 μL, 0.04 mmol) was added, and the resultant mixture was allowed to warm slowly to rt and stirred for 24 h at rt. Then, the reaction mixture was quenched with saturated NH₄Cl solution (5 mL), extracted with EtOAc (3 × 10 mL), washed with brine (3 × 5 mL), and dried over Na₂SO₄. The organics were concentrated under reduced pressure and purified by preparative TLC using 30% EtOAc in hexanes to give the title compound 9 as a colorless solid (6 mg, 57%).

Diisopropyl 1-(1,1-difluoro-2-(naphthalen-2-yl)-2-oxoethyl)hydrazine-1,2-dicarboxylate 10.

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)butan-1-one 1^25,27 (30 mg, 0.094 mmol) and LiBr (35 mg, 0.40 mmol) in THF (0.8 mL) at rt was added diisopropyl azodicarboxylate (40 μL, 0.20 mmol) followed by Et₃N (28 μL, 0.20 mmol). The reaction mixture was warmed to 60 °C for 30 min. Then, the reaction mixture was cooled to rt, quenched with 1 mL of saturated NH₄Cl solution (5 mL), extracted with EtOAc (3 × 10 mL), washed with brine (3 × 5 mL), dried over Na₂SO_4, and concentrated under reduced pressure. Purification by SiO₂ flash chromatography using 5–10% EtOAc in hexanes provided the title compound 10 as a colorless oil (35 mg, 91 %): ¹H NMR (500 MHz, CDCl₃) δ 9.17 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 6.88 (s, 1H), 5.13 (qu, J = 6.2 Hz, 1H), 4.82 (t, J = 5.6 Hz, 1H), 1.34 (d, J = 4.6 Hz, 6H), 1.11 (d, J = 6.0 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 181.8 (t, J_CF = 29.4 Hz, 1C), 155.5, 152.1, 135.8, 132.7, 132.4, 130.3, 129.1, 129.0, 128.4, 127.6, 126.8, 124.5, 112.7 (t, J_CF = 259.6 Hz, 1C), 73.4, 70.8, 21.9, 21.8, 21.3, 21.2; ¹⁹F NMR (470 MHz, CDCl₃) δ −86.96 (d, J_FF= 190.5 Hz, 2F); IR ν_max 3319, 2984, 2934, 1736, 1717, 1628, 1428, 1376, 1249, 1104, 1045 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₀H₂₁F₂N₂O₅ [M–H]^– 407.1419, found 407.1418.

Representative Reaction Procedure for Trifluoroacetate Release/Imino-Aldol Reaction.

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (50 mg, 0.16 mmol) and N-benzylidinebenzylamine 11 (62 μL, 0.33 mmol) in THF (1.0 mL) was added MgI₂ (182 mg, 0.656 mmol). The resultant mixture was stirred for 2 min at rt. Then, the mixture was warmed to 60 °C for 1 min and then Et₃N (46 μL, 0.33 mmol) was added. After 5 min of stirring at 60 °C, the reaction was quenched with saturated aqueous NH₄Cl (1.5 mL) and the resultant mixture was extracted with EtOAc (10 mL × 3). The organics were dried over Na₂SO₄ and concentrated under reduced pressure. The mixture was then treated with saturated NaHSO₃ solution (15 mL) and stirred vigorously for 18 h. Next, the mixture was extracted with EtOAc (10 mL × 3). The organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash chromatography (9:1:0.01 hexanes/EtOAc/Et₃N) afforded the product 12 as a colorless solid in 73% yield (45.8 mg).

3-(Benzylamino)-2,2-difluoro-1-(naphthalen-2-yl)-3-phenylpropan-1-one 12.⁵¹

See representative reaction procedure: mp 96–98 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.49 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.91–7.86 (m, 3H), 7.64 (m, 1H), 7.56 (m, 1H), 7.46‒7.36 (m, 5H), 7.09‒7.03 (m, 5H), 4.48 (dd, J = 20.1, 7.7 Hz, 1H), 3.76 (d, J = 13.1 Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 1.82 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 190.3 (t, J_CF = 28.4 Hz, 1C), 138.6, 135.7, 134.4, 132.2, 132.1, 130.4, 130.0, 129.1 (2C), 129.0, 128.7, 128.6 (2C), 128.4, 128.2 (4C), 127.7, 127.0, 126.8, 124.8, 118.1 (t, J_CF= 258.5 Hz, 1C), 63.8 (t, J_CF = 24.3 Hz, 1C), 50.9; ¹⁹F NMR (282 MHz, CDCl₃) δ −102.7 (dd, J_FF = 268.4, J_HF = 7.6 Hz, 1F), −115.3 (dd, J_FF = 268.4, J_HF = 20.1 Hz, 1F); IR (film) ν_max 1701, 1626, 1455, 1114, 698 cm^–1; HRMS (EI-BE) m/z calcd for C₂₆H₂₂F₂NO (M+H)⁺ 402.1669, found 402.1664.

3-(Benzylamino)-1-(4-chlorophenyl)-2,2-difluoro-3-phenylpropan-1-one 18.⁵¹

See representative reaction procedure. To a solution of 1-(4-chlorophenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 13^25,27 (30.9 mg, 0.101 mmol) and N-benzylidinebenzylamine 11 (38 μL, 0.20 mmol) in THF (680 μL) was added MgI₂ (112 mg, 0.404 mmol). The mixture was warmed to 60 °C for 1 min and then Et₃N (30 μL, 0.20 mmol) was added. SiO₂ flash chromatography (9:1:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 18 as a colorless oil (33.1 mg) in 85% yield: ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J = 8.4 Hz, 2H), 7.47‒7.36 (m, 7H), 7.22‒7.17 (m, 3H), 7.10‒7.04 (m, 2H), 4.38 (dd, J = 20.7, 7.2 Hz, 1H), 3.77 (d, J = 13.1 Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 2.11 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 189.3 (t, J_CF = 27.5 Hz, 1C), 140.4, 138.5, 134.2, 131.6 (2C), 131.1, 129.0 (2C), 128.9 (2C), 128.8, 128.6 (2C), 128.3 (2C), 128.2 (2C), 127.2, 117.8 (t, J_CF = 255.0 Hz, 1C), 63.4 (t, J_CF = 22.5 Hz, 1C), 50.8; ¹⁹F NMR (282 MHz, CDCl₃) δ −102.8 (dd, J_FF = 268.7, J_HF = 6.5 Hz, 1F), ‒116.4 (dd, J_FF = 268.5, J_HF = 18.6 Hz, 1F); IR (film) ν_max 1693, 1444, 1266, 1039, 699 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₂H₁₉ClF₂NO (M+H)⁺ 386.1123, found 386.1131.

1-(Benzylamino)-2,2-difluoro-5-methyl-1-phenylhexan-3-one 19.

See representative reaction procedure. To a solution of 1,1,1,3,3-pentafluoro-2,2-dihydroxy-6-methylheptan-4-one 14²⁵ (32.6 mg, 0.130 mmol) and N-benzylidinebenzylamine 11 (51 μL, 0.27 mmol) in THF (1.0 mL) was added MgI₂ (152 mg, 0.547 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (38 μL, 0.27 mmol) was added. SiO₂ flash chromatography (100% hexanes–5:5:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 19 as a colorless oil (6.3 mg) in 15% yield: ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.38 (m, 3H), 7.35 (d, J = 7.6 Hz, 2H), 7.32–7.25 (m, 3H), 7.19 (d, J = 6.9 Hz, 2H), 4.22 (dd, J = 20.6, 7.6 Hz, 1H), 3.73 (d, J = 13.0 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 2.52 (dd, J = 18.1, 6.9 Hz, 1H), 2.39 (dd, J = 18.1, 6.4 Hz, 1H), 2.16 (septet, J = 6.6 Hz, 1H), 1.68 (br s, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 201.5 (dd, J_CF = 31.1, 26.5 Hz, 1C), 139.0, 134.4, 128.9 (2C), 128.7, 128.6 (2C), 128.4 (2C), 128.3 (2C), 127.3, 116.4 (dd, J_CF = 260.0, 256.6 Hz, 1C), 62.8 (dd, J_CF = 26.4, 21.6 Hz, 1C), 51.0, 46.7, 23.4, 22.4 (2C); ¹⁹F NMR (376 MHz, CDCl₃) δ ‒109.9 (dd, J_FF = 258.6, J_HF = 7.5 Hz, 1F), ‒123.6 (dd, J_FF = 258.8, J_HF = 20.5 Hz, 1F); IR (film) ν_max 2959, 1740, 1455, 1124 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₀H₂₄F₂NO (M+H)⁺ 332.1826, found 332.1828.

1-(Benzo[b]thiophen-3-yl)-3-(benzylamino)-2,2-difluoro-3-phenylpropan-1-one 20.

See representative reaction procedure. To a solution of 1-(benzo[b]thiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 15²⁷ (31 mg, 0.10 mmol) and N-benzylidinebenzylamine 11 (38 μL, 0.20 mmol) in THF (570 μL) was added MgI₂ (112 mg, 0.402 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (28 μL, 0.20 mmol) was added. SiO₂ flash chromatography (9:1:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 20 as a pale yellow solid (26.7 mg) in 69% yield: mp 106–108 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J = 8.2 Hz, 1H), 8.40 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.44–7.35 (m, 5H), 7.16–6.99 (m, 5H), 4.43 (dd, J = 19.8, 8.0 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 2.02 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 184.7 (dd, J_CF = 29.0, 27.9 Hz, 1C), 140.0 (t, J_CF = 9.0 Hz, 1C), 138.9, 138.7, 137.2, 134.5, 129.8, 129.1 (2C), 128.7, 128.6 (2C), 128.1 (4C), 127.1, 126.1, 125.7, 125.3, 122.1, 117.7 (dd, J_CF = 260.4, 256.8 Hz, 1C), 63.7 (dd, J_CF = 26.2, 22.0 Hz, 1C), 50.7; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.8 (dd, J_FF = 263.0, J_HF = 7.5 Hz, 1F), −116.1 (dd, J_FF = 263.0, J_HF = 18.8 Hz, 1F); IR (film) ν_max 1675, 1458, 1106, 698 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₄H₂₀F₂NOS (M+H)⁺ 408.1234, found 408.1235.

1-(Benzo[d][1,3]dioxol-5-yl)-3-(benzylamino)-2,2-difluoro-3-phenylpropan-1-one 21.⁵¹

See representative reaction procedure. To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 16²⁵ (16 mg, 0.05 mmol) and N-benzylidinebenzylamine 11 (20 μL, 0.105 mmol) in THF (800 μL) was added MgI₂ (57 mg, 0.205 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 5 min and then Et₃N (14 μL, 0.10 mmol) was added. Preparative TLC (8:2 hexanes/EtOAc) afforded the desired product 21 as a colorless solid (12 mg) in 61% yield: mp 89–91 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.40 (m, 5H), 7.24–7.19 (m, 3H), 7.14–7.09 (m, 2H), 6.82 (d, J = 8.3 Hz, 1H), 6.07 (dd, J = 5.7, 1.3 Hz, 2H), 4.39 (dd, J = 20.0, 7.6 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 2.18 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 188.1 (t, J_CF = 28.8 Hz, 1C), 152.5, 148.0, 138.8, 134.5, 129.1 (2C), 128.6, 128.5 (2C), 128.2 (4C), 127.5, 127.1, 126.7, 117.8 (t, J_CF = 258.4 Hz, 1C), 109.5, 108.0, 102.0, 63.7 (t, J_CF = 23.7 Hz, 1C), 50.8; ¹⁹F NMR (470 MHz, CDCl₃) δ ‒102.5 (dd, J_FF = 269.1, J_HF = 7.3 Hz, 1F), ‒114.53 (dd, J_FF = 269.1, 20.0 Hz, 1F); IR (film) ν_max 1693, 1444, 1265, 1039, 699 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₃H₂₀F₂NO₃ (M+H)⁺ 396.1411, found 396.1405.

1-(Adamantan-1-yl)-3-(benzylamino)-2,2-difluoro-3-phenylpropan-1-one 22.

See representative reaction procedure. To a solution of 1-(adamantan-1-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 17^25,27 (35 mg, 0.11 mmol) and N-benzylidinebenzylamine 11 (42 μL, 0.23 mmol) in THF (570 μL) was added MgI₂ (126 mg, 0.452 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (31 μL, 0.23 mmol) was added. SiO₂ flash chromatography (100% hexanes–5:5:0.01 hexanes/CH₂Cl₂/Et₃N) afforded the title compound 22 as a colorless solid (10.8 mg) in 25% yield: mp 104–106 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.16 (m, 10H), 4.39 (dd, J = 20.2, 8.4 Hz, 1H), 3.72 (d, J = 13.0 Hz, 1H), 3.54 (d, J = 13.0 Hz, 1H), 2.02 (s, 3H), 1.88 (q, J = 12.4 Hz, 6H), 1.79 (br s, 1H), 1.71 (q, J = 12.0 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 204.6 (dd, J_CF = 28.4, 25.3 Hz, 1C), 139.3, 134.8, 129.1, 128.4 (4C), 128.3 (2C), 128.2 (2C), 127.1, 118.7 (dd, J_CF = 264.1, 259.9 Hz, 1C), 62.9 (dd, J_CF = 25.4, 21.1 Hz, 1C), 51.1, 46.5, 36.9 (3C), 36.4 (3C), 27.7 (3C); ¹⁹F NMR (376 MHz, CDCl₃) δ −103.8 (dd, J_FF = 270.7, J_HF = 7.5 Hz, 1F), −116.9 (dd, J_FF = 268.8, J_HF = 20.7 Hz, 1F); IR (film) ν_max 2907, 2852, 1716, 1454, 1114 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₆H₃₀F₂NO (M+H)⁺ 410.2295, found 410.2279.

2,2-Difluoro-1-(naphthalen-2-yl)-3-phenyl-3-(phenylamino)propan-1-one 30.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (24 mg, 0.075 mmol), 4Å molecular sieves (100 mg), and N-benzylideneaniline 23 (27 mg, 0.15 mmol) in THF (1.5 mL) was added flame-dried MgI₂ (84 mg, 0.302 mmol), and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (21 μL, 0.15 mmol) was added. The crude mixture was recrystallized from chloroform and hexanes to afford the title compound 30 as a yellow solid (17 mg) in 59% yield. Recrystallization from a solution of hexanes and CH₂Cl₂ (by slow evaporation) provided a crystalline solid suitable for X-ray structure analysis: mp 149–151 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 7.98–7.83 (m, 4H), 7.64 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.38–7.28 (m, 3H), 7.10 (t, J = 7.9 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 7.8 Hz, 2H), 5.38 (dt, J = 17.4, 8.9 Hz, 1H), 4.60 (d, J = 8.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 189.9 (dd, J_CF = 29.5, 27.9 Hz, 1C), 145.5, 135.8, 134.5, 132.4 (dd, J_CF = 5.0, 4.4 Hz, 1C), 132.2, 130.1, 130.0, 129.3, 129.2 (2C), 128.7, 128.7 (2C), 128.6 (2C), 128.5, 127.7, 127.0, 124.6, 118.9, 117.5 (dd, J_CF = 260.8, 259.3 Hz, 1C), 114.2 (2C), 60.6 (dd, J_CF = 25.7, 22.6 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ ‒103.6 (dd, J_FF = 272.0, J_HF = 8.8 Hz, 1F), ‒112.2 (dd, J_FF = 272.1, J_HF = 17.1 Hz, 1F); IR (film) ν_max 1694, 1455, 1285, 1105 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₅H₂₀F₂NO (M+H)⁺ 388.1513, found 388.1506.

2,2-Difluoro-3-(4-methoxyphenyl)-1-(naphthalen-2-yl)-3-(phenylamino)propan-1-one 31.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (32 mg, 0.10 mmol) and N-(4-methoxybenzylidene)aniline 24 (44 mg, 0.21 mmol) in THF (1.0 mL) was added MgI₂ (115 mg, 0.414 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (29 μL, 0.21 mmol) was added. SiO₂ flash chromatography (9:1:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 31 as a dark orange solid (32.5 mg) in 79% yield. Recrystallization from a solution of hexanes and CH₂Cl₂ (by slow evaporation) provided a crystalline solid suitable for X-ray structure analysis: mp 126–128 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.52 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 5.7 Hz, 1H), 7.87 (d, J = 5.1 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.11 (t, J = 7.9 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.9 Hz, 2H), 5.34 (dt, J = 16.3, 8.0 Hz, 1H), 4.58 (d, J = 7.3 Hz, 1H), 3.76 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 189.9 (dd, J_CF = 29.2, 28.1 Hz, 1C), 159.8, 145.6, 135.8, 132.4 (t, J_CF = 4.5 Hz, 1C), 132.1, 130.1, 130.0, 129.7 (2C), 129.3, 129.2 (2C), 128.5, 127.7, 127.0, 126.3, 124.6, 118.8, 117.5 (t, J_CF = 259.8 Hz, 1C), 114.2 (2C), 114.1 (2C), 60.0 (dd, J_CF = 25.7, 22.9 Hz, 1C), 55.2; ¹⁹F NMR (470 MHz, CDCl₃) δ ‒104.2 (dd, J_FF = 270.4, J_HF = 9.1 Hz, 1F), ‒112.1 (dd, J_FF = 270.4, J_HF = 16.6 Hz, 1F); IR (film) ν_max 1694, 1626, 1465, 1106, 692 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₆H₂₂F₂NO₂ (M+H)⁺ 418.1619, found 418.1613.

3-((3,4-Dimethylphenyl)amino)-2,2-difluoro-3-(4-fluorophenyl)-1-(naphthalen-2-yl)propan-1-one 32.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (29 mg, 0.09 mmol), 4Å molecular sieves (100 mg), and 3,4-dimethyl-N-(4-fluorobenzylidene)aniline 25 (44 mg, 0.19 mmol) in THF (1.7 mL) was added flame-dried MgI₂ (107 mg, 0.385 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (25 μL, 0.19 mmol) was added. The crude mixture was recrystallized from chloroform and hexanes to afford the title compound 32 as a pale yellow solid (25 mg) in 64% yield. Recrystallization from a solution of hexanes and CH₂Cl₂ (by slow evaporation) provided a crystalline solid suitable for X-ray structure analysis: mp 141–143 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.54 (s, 1H), 7.96 (dd, J = 15.4, 8.6 Hz, 2H), 7.88 (t, J = 7.3 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 6.1 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.41 (s, 1H), 6.32 (d, J = 8.1 Hz, 1H), 5.32 (dt, J = 17.7, 7.3 Hz, 1H), 4.36 (d, J = 7.7 Hz, 1H), 2.10 (s, 3H), 2.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 189.6 (dd, J_CF = 29.3, 27.7 Hz, 1C), 162.8 (d, J_CF = 247.5 Hz, 1C), 143.3, 137.4, 135.9, 132.3 (t, J_CF = 4.5 Hz, 1C), 132.2, 130.5 (d, J_CF = 2.5 Hz, 1C), 130.2, 130.2 (d, J_CF = 8.0 Hz, 2C), 130.1, 130.0, 129.4, 128.6, 127.7, 127.2, 127.0, 124.6, 117.4 (t, J_CF = 248.5 Hz, 1C), 116.1, 115.6 (d, J_CF = 21.6 Hz, 2C), 111.5, 60.1 (dd, J_CF = 26.0, 22.7 Hz, 1C), 19.9, 18.6; ¹⁹F NMR (470 MHz, CDCl₃) δ ‒103.0 (dd, J_FF = 272.9, 1F), ‒113.3 (dd, J_FF = 272.2, J_HF = 15.7 Hz, 1F), ‒114.4 (s, 1F); IR (film) ν_max 1692, 1507, 1212, 1063 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₇H₂₃F₃NO (M+H)⁺ 434.1732, found 434.1725.

2,2-Difluoro-3-((4-fluorophenyl)amino)-3-(4-methoxyphenyl)-1-(naphthalen-2-yl)propan-1-one 33.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (32 mg, 0.10 mmol) and N-(4-methoxybenzylidene)-4-fluoroaniline 26 (48 mg, 0.21 mmol) in THF (570 μL) was added MgI₂ (115 mg, 0.414 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (29 μL, 0.21 mmol) was added. SiO₂ flash chromatography (9:1:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 33 as a dark orange oil (33.5 mg) in 78% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.50 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.89–7.81 (m, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 6.87 (d, J = 7.7 Hz, 2H), 6.80 (t, J = 8.7 Hz, 2H), 6.55 (m, 2H), 5.23 (dt, J = 17.0, 8.5 Hz, 1H), 4.44 (d, J = 8.6 Hz, 1H), 3.76 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 189.9 (t, J_CF = 28.9 Hz, 1C), 159.9, 156.5 (d, J_CF = 236.9 Hz, 1C), 141.9 (d, J_CF = 1.9 Hz, 1C), 135.8, 132.4 (dd, J_CF = 5.2, 4.3 Hz, 1C), 132.2, 132.0, 130.1, 130.0, 129.7 (2C), 128.5, 127.7, 127.0, 126.1, 124.6, 117.5 (t, J_CF = 259.9 Hz, 1C), 115.7 (d, J_CF = 22.5 Hz, 2C), 115.3 (d, J_CF = 7.5 Hz, 2C), 114.1 (2C), 61.0 (dd, J_CF = 25.9, 22.8 Hz, 1C), 55.2; ¹⁹F NMR (376 MHz, CDCl₃) δ ‒103.9 (dd, J_FF = 271.8, J_HF = 8.6 Hz, 1F), ‒112.4 (dd, J_FF = 271.8, J_HF = 16.9 Hz, 1F), ‒127.1 (sept, J = 3.8 Hz, 1F); IR (film) ν_max 1692, 1626, 1114 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₆H₂₁F₃NO₂ (M+H)⁺ 436.1524, found 436.1515.

2,2-Difluoro-3-(4-methoxyphenyl)-3-((4-methoxyphenyl)amino)-1-(naphthalen-2-yl)propan-1-one 34.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (35 mg, 0.11 mmol) and N-(4-methoxybenzylidene)-4-methoxyaniline 27 (55 mg, 0.23 mmol) in THF (570 μL) was added magnesium iodide (127 mg, 0.455 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (32 μL, 0.23 mmol) was added. SiO₂ flash chromatography (8:2:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 34 as a dark orange oil (12.3 mg) in 25% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.51 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.88 (dd, J = 8.2, 5.5 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 8.9 Hz, 2H), 5.21 (dd, J = 17.6, 8.6 Hz, 1H), 4.25 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 190.0 (dd, J_CF = 29.5, 27.7 Hz, 1C), 159.8, 153.0, 139.5, 135.8, 132.3 (dd, J_CF = 5.3, 3.9 Hz, 1C), 132.2, 130.3, 130.0, 129.7 (2C), 129.3, 128.5, 127.7, 127.0, 126.5, 124.7, 117.7 (dd, J_CF = 260.8, 258.2 Hz, 1C), 115.9 (2C), 114.7 (2C), 114.1 (2C), 61.2 (dd, J_CF = 26.0, 22.4 Hz, 1C), 55.6, 55.2; ¹⁹F NMR (470 MHz, CDCl₃) δ ‒103.6 (dd, J_FF = 270.1, J_HF = 8.5 Hz, 1F), ‒113.3 (dd, J_FF = 270.0, J_HF = 17.6 Hz, 1F); IR (film) ν_max 1693, 1509, 1114 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₇H₂₄F₂NO₃ (M+H)⁺ 448.1724, found 448.1721.

3-(tert-Butylamino)-2,2-difluoro-1-(naphthalen-2-yl)-3-phenylpropan-1-one 35.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (32 mg, 0.10 mmol) and N-benzylidene-tert-butylamine 28 (37 μL, 0.21 mmol) in THF (570 μL) was added MgI₂ (115 mg, 0.414 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for1 min and then Et₃N (29 μL, 0.21 mmol) was added. SiO₂ flash chromatography (9:1:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 35 as a colorless solid (10.7 mg) in 30% yield: mp 106–108 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.94–7.84 (m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.45–7.43 (m, 2H), 7.41–7.29 (m, 3H), 4.63 (dd, J = 22.0, 6.5 Hz, 1H), 1.83 (br s, 1H), 0.84 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 192.0 (dd, J_CF = 30.5, 26.5 Hz, 1C), 138.3, 135.6, 132.2, 132.0 (t, J_CF = 2.9 Hz, 1C), 131.9, 131.4, 129.9, 128.9, 128.7 (2C), 128.4 (2C), 128.2, 127.7, 126.8, 125.1, 118.3 (dd, J_CF = 260.9, 257.3 Hz, 1C), 59.5 (dd, J_CF = 26.9, 21.2 Hz, 1C), 51.5, 30.0 (3C); ¹⁹F NMR (376 MHz, CDCl₃) δ ‒100.9 (dd, J_FF = 258.8, J_HF = 6.4 Hz, 1F), ‒117.5 (dd, J_FF = 258.8, J_HF = 22.2 Hz, 1F); IR (film) ν_max 1698, 1456, 1108, 1077 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₃H₂₄F₂NO (M+H)⁺ 368.1826, found 368.1825.

(4E,6E)-3-(Benzylamino)-2,2-difluoro-1-(naphthalen-2-yl)octa-4,6-dien-1-one 36.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (20 mg, 0.06 mmol) and N-(hexa-2,4-dien-1-ylidene)-1-phenylmethanamine 29 (30 mg, 0.16 mmol, 5:1 (2E,4E)-isomer/(2E,4Z)-isomer mixture*) in THF (1 mL) was added flame-dried MgI₂ (56 mg, 0.20 mmol) and the mixture was stirred for 2 min at rt. The resultant mixture was warmed to 60 °C for 1 min and then Et₃N (14 μL, 0.10 mmol) was added. SiO₂ flash chromatography (9:1:0.01 hexanes/Et₂O/Et₃N) afforded the title compound 36 as a yellow oil in 61% yield (12 mg, 5:1 mixture of isomers*): ¹H NMR (500 MHz, CDCl₃) δ 8.57* (s, 1H), 8.55 (s, 1H), 8.03 (dd, J = 8.7, 1.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.65 (td, J = 7.5, 1.1 Hz, 1H), 7.57 (td, J = 7.5, 1.2 Hz, 1H), 7.13–7.03 (m, 5H), 6.56* (dd, J = 15.2, 11.0 Hz, 1H), 6.24 (dd, J = 15.1, 10.4 Hz, 1H), 6.15 (qd, J = 12.5, 1.3 Hz, 1H), 5.79 (dq, J = 13.2, 6.6 Hz, 1H), 5.54 (dd, J = 14.7, 8.8 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.83 (m, 1H), 3.60 (d, J = 13.2 Hz, 1H), 1.80 (d, J = 6.6 Hz, 3H), 1.61 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 190.1 (t, J_CF = 28.2 Hz, 1C), 138.9, 136.8, 135.7, 132.2, 132.0, 131.5, 130.5, 130.0, 129.1, 128.4, 128.1 (2C), 128.1 (2C), 127.7, 126.9, 126.8, 124.8, 123.0, 118.1 (t, J_CF = 257.4 Hz, 1C), 62.2 (dd, J_CF = 26.3, 22.4 Hz, 1C), 50.5, 18.2, 13.6; ¹⁹F NMR (470 MHz, CDCl₃) δ ‒103.2 (dd, J_FF = 268.9, J_HF = 7.5 Hz, 1F), ‒115.5 (dd, J_FF = 268.9, J_HF = 18.8 Hz, 1F); IR (film) ν_max 1700, 1454, 1116, 990, 699 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₅H₂₄F₂NO (M+H)⁺ 392.1826, found 392.1841. * denotes minor isomer.

2-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-difluoro-1-(naphthalen-2-yl)ethenone 38.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalene-2-yl)butan-1-one 1^25,27 (92.6 mg, 0.289 mmol) and 5-bromo-3,4-dihydroisoquinoline 37 (127 mg, 0.605 mmol) in THF (1.7 mL) was added MgI₂ (340 mg, 1.22 mmol) and the mixture was stirred for 5 min at rt. The resultant mixture was warmed to 60 °C for 5 min and then Et₃N (85 μL, 0.61 mmol) was added. SiO₂ flash chromatography (5:5:0.01 hexanes/CH₂Cl₂/Et₃N) afforded the title compound 38 as a pale yellow solid (101.7 mg) in 84% yield: mp 112–114 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.63 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.41 (dd, J = 7.7, 2.7 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 4.89 (dd, J = 21.0, 8.2 Hz, 1H), 3.26 (m, 1H), 3.02 (m, 1H), 2.85–2.66 (m, 2H), 1.89 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 190.6 (dd, J_CF = 29.8, 27.8 Hz, 1C), 136.8, 135.8, 132.2 (t, J_CF = 8.3 Hz, 1C), 132.1, 131.9, 130.6, 130.0, 129.2, 128.5, 127.7 (2C), 127.6, 126.9 (2C), 125.7, 124.8, 118.9 (dd, J_CF = 265.1, 258.5 Hz, 1C), 57.1 (t, J_CF = 23.4 Hz, 1C), 39.5, 29.6; ¹⁹F NMR (376 MHz, CDCl₃) δ ‒96.0 (dd, J_FF = 270.5, J_HF = 7.2 Hz, 1F), ‒110.4 (dd, J_FF = 270.5, J_HF = 21.0 Hz, 1F); IR (film) ν_max 1698, 1440, 1173, 754 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₁H₁₇BrF₂NO (M+H)⁺ 416.0462, found 416.0448.

2,2-Difluoro-1-(naphthalen-2-yl)-2-(5-vinyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethan-1-one 39.

To a solution of 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-difluoro-1-(naphthalen-2-yl)ethenone 38 (23.5 mg, 0.056 mmol) in THF (0.3 mL) and water (40 μL), PdCl₂ (4.1 mg, 0.023 mmol), PPh₃ (5.8 mg, 0.02 mmol), Cs₂CO₃ (67.6 mg, 0.207 mmol), and potassium vinyltrifluoroborate (9.7 mg, 0.07 mmol) were added, and the resultant mixture was allowed to stir for 23 h at 85 °C in a sealed tube. The reaction mixture was warmed to rt, quenched with water (2 mL), and extracted with CH₂Cl₂ (2 mL). The aqueous layer was extracted with CH₂Cl₂ (2 mL × 3). The organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash chromatography (100:0.01 CH₂Cl₂/Et₃N) afforded the title compound 39 as a pale yellow oil (8.3 mg) in 40% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.61 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.90 (dd, J = 17.3, 11.0 Hz, 1H), 5.62 (d, J = 17.3 Hz, 1H), 5.32 (d, J = 10.9 Hz, 1H), 4.93 (dd, J = 20.6, 8.3 Hz, 1H), 3.26 (m, 1H), 3.00 (m, 1H), 2.79–2.70 (m, 2H), 1.89 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 190.9 (dd, J_CF = 29.7, 27.7 Hz, 1C), 137.2, 135.7, 134.7, 134.1, 132.2, 132.1 (dd, J_CF = 5.1, 4.0 Hz, 1C), 130.8, 130.0, 129.7, 129.1, 128.4, 128.2, 128.1, 127.7, 126.9, 125.7, 125.3, 124.9, 116.3 (dd, J_CF = 264.6, 258.5 Hz, 1C), 57.4 (t, J_CF = 23.6 Hz, 1C), 39.6, 26.1; ¹⁹F NMR (376 MHz, CDCl₃) δ ‒96.6 (dd, J_FF = 268.8, J_HF = 5.6 Hz, 1F), ‒110.6 (dd, J_FF = 268.8, J_HF = 20.5 Hz, 1F); IR (film) ν_max 2923, 1698, 1627, 1466, 1074, 736 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₃H₂₀F₂NO (M+H)⁺ 364.1513, found 364.1510.

2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-difluoro-1-(4-(trifluoromethyl)-phenyl)ethan-1-one 42.

See representative reaction procedure. To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(4-(trifluoromethyl)phenyl)butan-1-one 40³⁸ (117 mg, 0.345 mmol) and 6,7-dimethoxy-3,4-dihydroisoquinoline 41 (139 mg, 0.728 mmol) in THF (2.5 mL) was added MgI₂ (469.5 mg, 1.688 mmol) and the mixture was stirred for 5 min at rt. The resultant mixture was warmed to 60 °C for 5 min and then Et₃N (101 μL, 0.723 mmol) was added. SiO₂ flash chromatography (5:5:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 42 as a pale yellow solid (49.2 mg) in 34% yield: mp 128–130 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 2.4 Hz, 1H), 6.62 (s, 1H), 4.74 (dd, J = 21.2, 7.6 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.12 (m, 1H), 2.95 (dt, J = 3.2, 1.3 Hz, 1H), 2.63 (dt, J = 1.1, 1.0 Hz, 2H), 1.62 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 191.2 (dd, J_CF = 31.6, 27.8 Hz, 1C), 148.7, 147.2, 136.8, 134.6 (d, J = 32.9 Hz, 1C), 130.0 (td, J_CF = 2.5, 1.2 Hz, 2C), 129.6, 125.4 (td, J_CF = 3.7, 3.6 Hz, 2C), 124.8 (t, J_CF = 287.7 Hz, 1C), 120.7, 118.9 (dd, J_CF = 264.7, 256.9 Hz, 1C), 111.7, 111.1 (d, J = 5.6 Hz, 1C), 56.5 (t, J_CF = 23.8 Hz, 1C), 56.0, 55.8, 39.8, 28.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −64.4 (s, 3F), ‒97.2 (dd, J_FF = 265.9, J_HF = 6.2 Hz, 1F), ‒113.3 (dd, J_FF = 265.9, J_HF = 21.1 Hz, 1F); IR (film) ν_max 2927, 1714, 1518, 1465, 1129, 732 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₀H₁₉F₅NO₃ (M+H)⁺ 416.1285, found 416.1281.

(2R)-2-(1-(1,1-Difluoro-2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide 44.

To a solution of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-one 42 (12.1 mg, 0.029 mmol) and (S)-2-(methylamino)-2-oxo-1-phenylethyl 4-methylbenzenesulfonate 43⁴⁸ (10.2 mg, 0.032 mmol) in CH₃CN (1.0 mL) was added i-Pr₂NEt (10 μL, 0.06 mmol). The resultant mixture was stirred for 26 h at 85 °C. Then, reaction mixture was cooled to rt and concentrated under reduced pressure. The mixture was washed with saturated aqueous Na₂CO₃ (5 mL) and extracted with EtOAc (5 mL). The organics were dried over Na₂SO₄ and concentrated under reduced pressure to give a 2.2:1 mixture of diastereomers. SiO₂ flash chromatography (5:5:0.01 hexanes/EtOAc/Et₃N) afforded the title compound 44 as a colorless oil (4.6 mg, major isomer) in 28% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 7.7 Hz, 2H), 6.69 (s, 1H), 6.52 (m, 1H), 6.45 (d, J = 7.5 Hz, 2H), 6.37 (d, J = 2.4 Hz, 1H), 4.19 (s, 1H), 3.91 (s, 3H), 3.89 (m, 1H), 3.79 (s, 3H), 3.52 (m, 1H), 3.12 (m, 1H), 2.92 (dd, J = 14.8, 7.0 Hz, 1H), 2.79 (d, J = 4.9 Hz, 3H), 2.58 (dd, J = 17.4, 5.6 Hz, 1H), 2.18 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 189.3 (t, J_CF = 27.5 Hz, 1C), 171.2, 149.5, 147.4, 135.6, 135.5 (d, J_CF = 32.9 Hz, 1C), 134.8, 129.4 (dt, J_CF = 2.6, 2.3 Hz, 2C), 129.1 (2C), 128.9, 128.6 (2C), 128.5, 127.8, 126.2 (dt, J_CF = 3.7, 3.6 Hz, 2C), 124.7 (t, J_CF = 283.3 Hz, 1C), 118.3 (t, J_CF = 263.3 Hz, 1C), 111.5, 111.1 (d, J_CF = 3.3 Hz, 1C), 69.7, 60.5 (dd, J_CF = 28.0, 23.1 Hz, 1C), 56.1, 55.8, 42.3, 29.7, 25.9; ¹⁹F NMR (376 MHz, CDCl₃) δ ‒64.3 (s, 3F), ‒95.4 (dd, J_FF = 259.9, J_HF = 10.2 Hz, 1F), ‒106.6 (dd, J_FF = 259.5, J_HF = 20.9 Hz, 1F); IR (film) ν_max 2922, 1712, 1664, 1466, 1116, 701 cm^–1; HRMS (ESI-TOF) m/z calcd for C₂₉H₂₈F₅N₂O₄ (M+H)⁺ 563.1969, found 563.1968.