Synthesis of 1,1′-Diarylethanes and Related Systems by Displacement of Trichloroacetimidates with Trimethylaluminum

Abstract

Benzylic trichloroacetimidates are readily displaced by trimethylaluminum under Lewis acid promoted conditions to provide the corresponding methyl substitution product. This method is a convenient way to access 1,1′-diarylethanes and related systems, which play a significant role in medicinal chemistry, with a number of systems owing their biological activity to this functionality. Most benzylic substrates undergo ready displacement, with electron deficient systems being the exception. Use of an enantiopure imidate showed significant racemization, implicating the formation of a cationic intermediate.

Graphical Abstract

Trichloroacetimidates are often used to activate alcohols as leaving groups, commonly being displaced by heteroatom nucleophiles like alcohols,¹ carboxylic acids,² thiols³ and amines.⁴ This chemistry is especially important in the synthesis of carbohydrates.⁵ Imidate displacement is facilitated by rearrangement of the leaving group to trichloroacetamide, providing an additional thermodynamic driving force to drive the displacement. The imidate structure also features a basic nitrogen, which is readily activated by catalytic amounts of Brønsted or Lewis acids. Trichloroacetimidates are easily formed from alcohols from the inexpensive trichloroacetonitrile, and the imidates can be generated in situ,⁶ providing a method to use inexpensive and readily available alcohols as alkylating agents under mild conditions.

While the use of imidates to form ethers, sulfides and substituted amines has become well known, it is more rare to displace trichloroacetimidates with carbon nucleophiles. As trichloroacetimidates are typically activated with Lewis acids, a carbon nucleophile must be compatible with these conditions. Typically, these substitutions are limited to Friedel-Crafts type processes with electron rich aromatic rings acting as nucleophiles,^3h,7 although there have been reports of silyl enol ethers, allylsilanes and allylstannanes being effective nucleophiles under Lewis acid catalysis.^6b,8 Currently there are no reports on the displacement of trichloroacetimidates with stoichiometric amounts of alkylmetal reagents.

Recently investigations into increasing the scope of nucleophiles that may be used in the displacement of trichloroacetimidates were undertaken. This project began as a new entry into the synthesis of 1,1′-diarylethane systems, as 1,1′-diarylethanes are an important functionality in many biologically active molecules⁹ like those shown in Figure 1.¹⁰ Typically these systems are accessed by hydrogenation of an alkene,¹¹ displacement of a leaving group (like a halide,¹² ammonium salt¹³ or ether¹⁴) or through Friedel-Crafts processes,¹⁵ however displacement of the imidate may also provide access to these systems if a compatible alkylmetal nucleophile could be invoked.

Figure 1.

Biologically Active 1,1′-Diarylethanes

A survey of the literature suggested that trimethylaluminum may be a good candidate for this study as this reagent is readily available. Additionally, trimethylaluminum addition reactions are tolerant of and accelerated by exogenous Lewis acids,¹⁶ which are also known to facilitate trichloroacetimidate displacements. Trimethylaluminum has been used as a source of methyl anion previously to displace halides,¹⁷ sulfonates,^17b,18 and Meldrum’s acid derivatives.¹⁹ This reagent has also been shown to open benzylic epoxides²⁰ and benzylic sulfites,²¹ with the addition of the new methyl group occurring preferentially at the benzylic position in these cyclic systems. Yields in these displacements and ring openings tend to be highest when the leaving group is tertiary or benzylic,^17c,22 and most studies indicate that the trimethylaluminum is adding to carbocations that are formed in situ. This mechanism is supported by the rearrangement of some tertiary allylic chlorides during the addition reaction.²³

Initially, the reaction of trimethylaluminum with diphenylmethyl trichloroacetimidate 6a was studied (Table 1). Solvent effects were observed to be prevalent in the substitution, as only DCM provided 1,1-diphenylethane 7a in appreciable yield at room temperature (entries 1–5). More polar solvents like Et₂O, THF and MeCN may coordinate to the trimethylaluminum and lower reactivity, reducing conversion. Alternatively, the less polar toluene may disfavor formation of the diphenylmethyl carbocation, which may be necessary for product formation. Heating the reaction in toluene did provide some product, however no conversion was observed in refluxing THF. In order to improve the yield, the use of Lewis acid promoters was explored. Initially TMSOTf and BF₃•OEt₂ were evaluated, as these Lewis acids are commonly employed with trichloroacetimidates.^16a,16c,16d With TMSOTf, however, the major product was the rearranged trichloroacetamide 8a, and this product was also a significant in the reaction with BF₃•OEt₂. This product has recently been observed to occur when trichloroacetimidate 6a is treated with a Lewis acid.²⁴ A number of other Lewis acids were then screened for their ability to facilitate the substitution reaction (entries 11–15) at the expense of the rearrangement. From these results aluminum trichloride emerged as the most promising promoter, providing the desired product 7a in a 91% yield (entry 11). Omission of the trimethylaluminum was also explored, with mainly rearrangement of the imidate to the acetamide being observed under these conditions (entry 16), as has been described previously.²⁴

Table 1.

Addition of Trimethylaluminum to Trichloroacetimidate 6a

entry	conditionsa	promoterb	yield 7a	yield 8a
1	toluene, rt, 24h		0	0
2	DCM, rt, 4h		68	13
3	Et2O, rt, 24 h		0	0
4	THF, rt, 18 h		0	0
5	MeCN, rt, 30 min		0	60
6	toluene, reflux, 22 h		23	13
7	DCM, reflux, 22h		27	25
8	THF, reflux, 22 h		0	0
9c	DCM, rt, 30 min	TMSOTf	0	50
10c	DCM, rt, 30 min	BF3•OEt2	37d	63d
11c	DCM, rt, 30 min	AlCl3	91	8
12c	DCM, rt, 30 min	SnCl2	56d	44d
13c	DCM, rt, 30 min	ZnF2	68	0
14c	DCM, rt, 30 min	ZnI2	68	0
15c	DCM, rt, 30 min	Sc(OTf)3	45	0
16	DCM, rt, 30 min	AlCl3	0	60e

^aAlMe₃ (1.5 equiv) was added at 0 °C and then the reaction was warmed to the reported temperature.

^bOne equiv of the Lewis acid was added.

^c3 Equiv of AlMe₃ was used.

^dRatio of products observed in the crude ¹H NMR.

^eNo AlMe₃ was added.

The scope of the displacement with respect to trichloroacetimidate was then investigated (Table 2). Initially diarylmethane-type trichloroacetimidates bearing different functionality on the aromatic rings were evaluated. Alkyl, aryl and methoxy functionalized aromatic substrates all provided the corresponding methylated products in good yield (entries 2–5). In the case of the methoxy containing imidate 6e some rearrangement (28%) to the corresponding trichloroacetamide was observed. In the other examples in Table 2 only trace amounts of the rearranged product was observed, evidently this rearrangement is most competitive in highly activated electron rich systems. The conditions were also compatible with aryl halides (entries 6–8). Incorporation of stronger electron withdrawing groups on one of the aromatic rings was also tolerated in the diarylmethyl imidate substitutions, with nitro and trifluoromethyl groups not troubling the displacement (entries 9 and 10). These results are similar to Friedel-Crafts reactions that have been reported with electron-poor trichloroacetimidates, which also proceed in good yield.²⁵ Larger bicyclic aromatic systems like naphthalene and benzothiophene were incorporated without issue (entries 11–14). The synthesis of the benzothiophene containing 1,1′-diarylethane 7n is notable, as this compound is an intermediate in the synthesis of benzothiophene 5, a compound designed to treat insomnia.²⁶

Table 2.

Addition of Trimethylaluminum to Trichloroacetimidates

Entry	R1	R2	Yield
1	Ph	Ph	91 (7a)
2	4-MePh	Ph	65 (7b)
3	2-MePh	Ph	70 (7c)
4	4-(Ph)Ph	Ph	91 (7d)
5	4-OMePh	Ph	64a (7e)
6	3-ClPh	Ph	92 (7f)
7	4-BrPh	Ph	86 (7g)
8	3-FPh	Ph	87 (7h)
9	4-NO2Ph	Ph	66 (7i)
10	3,5-CF3Ph	Ph	95 (7j)
11	2-naphthyl	Ph	57 (7k)
12	1-naphthyl	Ph	57 (7l)
13	3-benzothienyl	Ph	57 (7m)
14	3-benzothienyl	4-FPh	71 (7n)
15	4-(Ph)Ph	Me	87 (7o)
16	4-(Ph)Ph	n-Bu	97 (7p)
17	4-(Ph)Ph	i-Pr	90b (7q)
18	2-naphthyl	Et	60 (7r)
19	3-benzothienyl	Et	62 (7s)
20	3,4-OMePh	H	92c,d (7t)
21	4-OMePh	H	52c,e (7u)
22	4-(Ph)Ph	H	81c,f (7v)
23	1-naphthyl	H	60c,f (7w)
24	2-naphthyl	H	49c,g (7x)
25	3-benzothienyl	H	62c,h (7y)
26	4-NO2Ph	H	0 (7z)
27	Ph2CH	H	0 (7aa)

^aSome rearrangement product 8e (28%) was also isolated.

^bReaction started at −20 °C and allowed to warm to rt.

^cNo aluminium trichloride was added.

^dReaction performed for 15 min at 0 °C.

^eReaction performed for 15 min at −20 °C.

^fReaction performed for 4 h at 0 °C.

^gReaction started at −10 °C and allowed to warm to 5 °C.

^hReaction performed for 30 min at −20 °C.

With the success of diarylmethyl trichloroacetimidates in the methylation reaction, attention was focused on less activated substrates. Additionally, the diarylmethanes cannot undergo competing elimination reactions, so some systems that could be susceptible to elimination were evaluated (Table 2, entries 15–19). Most of these substrates performed well, including the hindered substrate 6q. Substitution with imidate 6q had to be started at a lower temperature, as when the reaction was started at 0 °C the alkene derived from elimination of the imidate was the major product. Primary benzylic trichloroacetimidates (Table 2, entries 20–26) were more reactive and did not require the addition of aluminum trichloride to provide the ethyl-substituted aromatics in useful yields. In addition, many of the primary imidate substitutions were initiated at low temperatures to avoid decomposition and/or elimination. In the case of 4-nitrobenzyl trichloroacetimidate no reaction occurred, with only starting material being recovered. Attempts to force substitution of imidate 6z by heating the reaction in DCE at reflux also gave no reaction. The aliphatic imidate 6aa was also unreactive and only returned starting material, highlighting the requirement for benzylic activation of the imidate.

Tertiary benzylic trichloroacetimidates and allylic trichloroacetimidates were also evaluated as substrates (Scheme 1). Displacement of the tertiary benzylic trichloroacetimidate 9 (prepared from the known alcohol²⁷) may provide an expeditious route to analogs of physostigmine.²⁸ Attempts to convert imidate 9 to the desired methyl compound were unsuccessful, as only the corresponding chloride 10 was obtained. Although chloride displacement of trichloroacetimidates is known with HCl,²⁹ the formation of chloride 10 was unexpected as trimethylaluminum typically is a better nucleophile than the chloride ion. Attempts to achieve methyl substitution using other Lewis acid promoters with less nucleophilic counterions (TMSOTf, Zn(OTf)₂) provided starting material at room temperature or below. Alternatively, heating chloride 10 with two equiv of trimethylaluminum in refluxing DCE only returned starting material, and no methylation product was detected. While the displacement of tertiary chlorides with trimethylaluminum has been reported, the reactions are slower in the presence of Lewis basic functional groups like amides.^17c This result was rationalized by complexation of the trimethylaluminum to the carbamate leading to a slower substitution reaction. In the more complex system 9 when the trimethylaluminum is complexed with the carbamate, ester and sulfonamide, displacement by the methyl group may be decelerated leading to the formation of chloride 10. The formation of chloride 10 also suggests that the corresponding chlorides may be intermediates in the methyl displacement reaction. To investigate this possibility, chlorodiphenylmethane was treated with trimethylaluminum (DCM room temp, 0 °C – rt) which resulted in the formation of 1,1′-diphenylethane 7a in 65% yield, supporting the possibility that if the chloride was formed it would be rapidly displaced by trimethylaluminum. Attempts to isolate chlorodiphenylmethane by treating imidate 6a with AlCl₃ in DCM gave predominantly the rearrangement product, acetamide 8a (60% yield, Table 1, entry 16). Only trace amounts of chlorodiphenylmethane in the crude ¹H NMR. We are therefore unable to unambiguously assess whether the corresponding chloride is an intermediate in the transformation, and it is also unclear why chloride displacement is favored over imidate rearrangement or elimination for imidate 9.

Scheme 1.

Attempted Methylation of 9 and Methylation of 11

Evaluation of the imidate of allylic alcohol 11 was stymied by the instability of the trichloroacetimidate, which readily decomposed. Adopting the procedure of Dalla and co-workers,^6b where the imidate was formed and used without purification in the alkylation reaction, gave alkene 12 as the sole product of the reaction in 63% yield over two steps. Interestingly, none of the direct substitution product 13 was detected in the crude ¹H NMR.

As shown in Table 2, imidates that are precursors to relatively stable carbocations tend to provide higher yields in the substitution reaction. This is consistent with the reaction proceeding through an S_N1-type pathway, where the imidate ionizes and the resulting cation is trapped by the trimethylaluminum. Additionally, the formation of the more hindered allylic substitution product 12 (Scheme 1) indicates that sterics is not a controlling factor in the substitution reaction, which is also consistent with an S_N1 pathway. To further test this hypothesis the enantioenriched imidate (S)-15 was prepared from the known aminoalcohol³⁰ and subjected to the reaction conditions, providing the product 16 in 49% yield (Scheme 2). Analysis of the reaction product by chiral HPLC showed a racemic mixture, providing further support for an S_N1-type mechanism being operative.

Scheme 2.

Substitution Using a Chiral Trichloroacetimidate

The use of triethylaluminum as the nucleophile in the imidate substitution was also briefly evaluated. In contrast to trimethylaluminum (Table 1, entry 2), treatment of imidate 6a with triethylaluminum provided the rearranged acetamide 7a (60%) as the major product of the reaction (Scheme 3). While a trace amount of the ethyl addition product 17 was observed, it was contaminated with the reduction product diphenylmethane 18, which was difficult to separate. This product may arise from β-hydride delivery, as has been observed in the reaction of triethylaluminum with benzylic halides.^17a Triethylaluminum has also been previously reported to reductively open epoxides³¹ and reduce activated alcohols to alkanes³² through a similar mechanism. Given the predominant rearrangement product, the added complexity of the competitive reduction, and the difficulty in separating the ethyl addition and reduction products, the use of triethylaluminum was not explored further.

Scheme 3.

Use of Triethylaluminum in the Substitution

The Lewis acid promoted addition of trimethylaluminum to trichloroacetimidates provides a useful method for the transformation of alcohols to the corresponding methyl analogs. This work represents the first conditions for the displacement of trichloroacetimidates with an alkylmetal reagent. The transformation most likely proceeds through cationic intermediates, and therefore performs best in benzylic or allylic systems. Increasing steric demands around the site of rearrangement was detrimental to the yield of the transformation. This reaction is especially useful in the synthesis of 1,1′-diarylethanes and related systems, which are important functionality in drug discovery. The reactivity of trichloroacetimidates with other organometallic reagents (specifically organozinc and organocopper reagents) is now being explored, and the results of these studies will be reported in due course.

Experimental Section

General Procedure for Trichloroacetimidate Synthesis

A flame dried flask was charged with the alcohol starting material (1 equiv) under argon. Dry DCM was then added to form a 0.5 M solution, and the flask was cooled to 0 °C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.2 equiv) was then added to the solution, followed by trichloroacetonitrile (1.5 equiv). The reaction mixture was monitored by TLC until no more alcohol starting material was detected. The reaction mixture was then concentrated in vacuo, and the residue was purified by silica gel column chromatography using the listed solvent system to provide the desired trichloroacetimidates. Imidates 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6j, 6l, 6m, 6n, 6o, 6p, 6q, 6r, 6s, 6t, 6w, 6x, 6y, 6z, 6aa, 9 and 15 were synthesized from the corresponding alcohols using the general procedure. Imidates 6a,^1c 6i,²⁴ 6k,³³ 6u,³⁴ and 6v,³⁵ were synthesized according to literature protocols.

(4-Methylphenyl)(phenyl)methyl 2,2,2-trichloroacetimidate (6b)

Purified by silica gel chromatography (10% ethyl acetate/1% triethylamine/89% hexanes). Viscous oil (1.17 g, 87%). IR (DCM) 3340, 1662, 1286, 1066, 998 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.43-7.41 (m, 2H), 7.36- 7.25 (m, 5H), 7.15 (d, J = 7.9 Hz, 2H), 6.91 (s,1H), 2.32 (s, 3H); ¹³C{¹H} NMR (100 MHz CDCl₃) δ 161.3, 139.9, 137.8, 136.8, 129.2, 128.4, 127.9, 127.0, 126.8, 91.6, 81.3, 21.6. Anal. calcd for C₁₆H₁₄Cl₃NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 56.32; H, 3.84; N, 4.44.

(2-Methylphenyl)(phenyl)methyl 2,2,2-trichloroacetimidate (6c)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Clear oil (2.38 g, 92%); TLC R_f = 0.59 (10% ethyl acetate/90% hexanes); IR (DCM) 3339, 3053, 3032, 2983, 1664, 1286, 1265, 1075, 913, 741 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.39 (brs, 1H), 7.46-7.43 (m, 1H), 7.38-7.28 (m, 5H), 7.24-7.16 (m, 3H), 7.12 (s, 1H), 2.37 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.3, 138.9, 137.5, 136.2, 130.5, 128.4, 128.1, 128.0, 127.3, 127.2, 126.1, 91.6, 79.0, 19.4. Anal. calcd for C₁₆H₁₄Cl₃NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 56.00; H, 3.96; N, 4.44.

[1,1′-Biphenyl]-4-yl](phenyl)methyl 2,2,2-trichloroacetimidate (6d)

Purified by silica gel chromatography (1% triethylamine/99% hexanes); White solid (0.35 g, 75%); IR (DCM) 3339, 3052, 1664, 1493, 1265, 1075, 984, 798, 739, 703 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 8.42 (brs, 1H), 7.58-7.29 (m, 14H), 6.97 (s, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.4, 141.0, 140.7, 139.8, 138.8, 128.9, 128.6, 128.2, 127.5, 127.4, 127.2, 127.0, 91.7, 81.3 (one aromatic resonance was unresolved). Anal. calcd for C₂₁H₁₆Cl₃NO: C, 62.32; H, 3.99; N, 3.46. Found: C, 62.50; H, 3.98; N, 3.59.

(4-Methoxyphenyl)(phenyl)methyl 2,2,2-trichloroacetimidate (6e)

Purified by silica gel chromatography (1% ethyl acetate/1% triethylamine/98% hexanes); Yellow viscous oil (1.32 g, 92%); IR (DCM) 3335, 1663, 1609, 1512, 1268, 1054, 915, 739 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 7.42-7.25 (m, 7H), 6.90-6.86 (m, 3H), 3.79 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.4, 159.4, 140.0, 131.9, 128.6, 128.5, 127.9, 126.8, 113.9, 91.7, 81.2, 55.3. Anal. calcd for C₁₆H₁₄Cl₃NO₂: C, 53.58; H, 3.93; N, 3.91. Found: C, 53.83; H, 3.67; N, 4.15.

(3-Chlorophenyl)(phenyl)methyl 2,2,2-trichloroacetimidate (6f)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Viscous oil (1.23 g, 78%); TLC R_f = 0.65 (10% ethyl acetate/90% hexanes); IR (DCM) 3341, 1664, 1354, 1266, 1007, 791, 720, 701 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.44 (brs, 1H), 7.41 (d, J = 8.9 Hz, 3H), 7.37-7.21 (m, 6H), 6.90 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.2, 141.9, 139.1, 134.5, 129.9, 128.7, 128.4, 128.3, 127.1, 127.0, 125.1, 91.4, 80.6. Anal. Calcd for C₁₅H₁₁Cl₄NO: C, 49.62; H, 3.05; N, 3.86. Found: C, 49.85; H, 3.25; N, 4.00.

(4-Bromophenyl)(phenyl)methyl 2,2,2-trichloroacetimidate (6g)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); White solid (2.08 g, 90%); TLC R_f = 0.59 (10% ethyl acetate/90% hexanes); IR (DCM) 3054, 2986, 2305, 1667, 1487, 1421, 1265, 705 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.43 (brs, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.34-7.29 (m, 7H), 6.89 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.2, 139.2, 138.8, 131.7, 128.7, 128.6, 128.3, 126.9, 122.1, 91.4, 80.7. Anal. Calcd for C₁₅H₁₁BrCl₃NO: C, 44.21; H, 2.72; N, 3.44. Found: C, 44.18; H, 2.98; N, 3.76.

(3-Fluorophenyl)(phenyl)methyl 2,2,2-trichloroacetimidate (6h)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Clear oil (0.97 g, 56%); TLC R_f = 0.61 (10% ethyl acetate/90% hexanes); IR (DCM) 3054, 1666, 1076, 999, 797, 735 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.44 (brs, 1H), 7.43-7.41 (m, 2H), 7.38-7.28 (m, 4H), 7.21-7.13 (m, 2H), 7.00-6.95 (m, 1H), 6.92 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 162.8 (d, J = 245.1 Hz), 161.2, 142.3, 142.3, 139.1, 130.1, 130.0, 128.6, 128.3, 127.0, 122.5, 114.9 (d, J = 21.0 Hz), 113.9 (d, J = 22.2 Hz), 91.4, 80.6. Anal. Calcd for C₁₅H₁₁Cl₃FNO: C, 51.98; H, 3.20; N, 4.04. Found: C, 52.06; H, 3.02; N, 4.06.

[3,5-Bis(trifluoromethyl)phenyl](phenyl)methyl 2,2,2-trichloroacetimidate (6j)

Purified by silica gel chromatography (10% ethyl acetate/1% triethylamine/89% hexanes); Off-white solid (1.25 g, 89%); TLC R_f = 0.52 (10% ethyl acetate/90% hexanes); IR (DCM) 3342, 1668, 1625, 1379, 963, 798 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.89 (s, 2H), 7.82 (1H), 7.42-7.36 (m, 5H), 7.03 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.9, 142.5, 137.9, 132.0 (q, J = 45.0 Hz), 129.0, 128.9, 123.2 (q, J = 361.7 Hz), 122.1 (hept, J = 4.9 Hz), 91.1, 79.0 (two aromatic resonances did not resolve). Anal. Calcd for C₁₇H₁₀Cl₃F₆NO: C, 43.95; H, 2.17; N, 3.01. Found: C, 43.83; H, 2.07; N, 3.14.

(Naphthalen-1-yl)(phenyl)methyl 2,2,2-trichloroacetimidate (6l)

Purified by silica gel chromatography (1% triethylamine/99% hexanes); Clear oil (1.84 g, 70%); TLC R_f = 0.61 (10% ethyl acetate/90% hexanes); IR (DCM) 3055, 1665, 1265, 1074, 981, 735 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 8.47 (brs, 1H), 8.08-8.05 (m, 1H), 7.88-7.83 (m, 1H), 7.70 (s, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.49-7.44 (m, 5H), 7.37-7.29 (m, 3H), 7.23 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.5, 139.1, 134.8, 133.9, 130.9, 129.1, 128.8, 128.5, 128.1, 127.3, 126.4, 126.0, 125.8, 125.2, 124.0, 91.6, 79.2. Anal. Calcd for C₁₉H₁₄Cl₃NO: C, 60.26; H, 3.73; N, 3.70. Found: C, 60.20; H, 3.85; N, 3.92.

(1-Benzothiophen-3-yl)(phenyl)methyl 2,2,2-trichloroacetimidate (6m)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Viscous oil (0.34 g, 61%); IR (DCM) 3335, 1664, 1264, 702, 563, 484 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.49 (brs, 1H), 7.86-7.84 (m, 1H), 7.78-7.75 (m, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.40-7.32 (m, 7H), 7.25 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.4, 140.7, 138.2, 137.3, 134.5, 128.6, 128.5, 127.3, 125.9, 124.7, 124.3, 122.9, 122.7, 91.6, 77.2. Anal. Calcd for C₁₇H₁₂Cl₃NOS: C, 53.08; H, 3.14; N, 3.64. Found: C, 53.29; H, 2.92; N, 4.01.

(1-Benzothiophen-3-yl)(4-fluorophenyl)methyl 2,2,2-trichloroacetimidate (6n)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Clear oil (0.90 g, 71%); TLC R_f = 0.76 (10% ethyl acetate/90% hexanes); IR (DCM) 3338, 3052, 1665, 1606, 1510, 1265, 1071 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 8.50 (brs, 1H), 7.87-7.83 (m, 1H), 7.72-7.68 (m, 1H), 7.52-7.47 (m, 2H), 7.37 (d, J = 0.9 Hz, 1H), 7.35-7.31 (m, 3H), 7.06 (tt, J = 9.8, 2.9 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.7 (d, J = 246.3 Hz), 161.3, 140.7, 137.1, 134.2, 134.0, 129.3 (d, J = 6.7 Hz), 125.7, 124.7, 124.3, 122.9, 122.6, 115.6 (d, J = 29.0 Hz), 91.5, 77.4. Anal. Calcd for C₁₇H₁₁Cl₃FNOS: C, 50.71; H, 2.75; N, 3.48. Found: C, 50.77; H, 2.70; N, 3.53.

1-(1,1′-Biphenyl]-4-yl)ethyl 2,2,2-trichloroacetimidate (6o)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Off white solid (1.06 g, 81%); IR (DCM) 3333, 1661, 1661, 798, 765, 702, 650 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.33 (brs, 1H), 7.60-7.57 (m, 4H), 7.49 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.3 Hz, 2H), 7.36-7.32 (m, 1H), 6.03 (q, J = 6.5 Hz, 1H), 1.69 (d, J = 6.6 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.7, 140.9, 140.8, 140.4, 128.8, 127.4, 127.3, 127.1, 126.3, 91.8, 77.0, 22.1. Anal. Calcd for C₁₆H₁₄Cl₃NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 56.00; H, 3.96; N, 4.44.

1-(1,1′-Biphenyl]-4-yl)pentyl 2,2,2-trichloroacetimidate (6p)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); White solid (0.71 g, 60%); TLC R_f = 0.68 (10% ethyl acetate/90% hexanes); IR (DCM) 3339, 2954, 2927, 2859, 1661, 1300 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.27 (brs, 1H), 7.57 (d, J = 8.2 Hz, 4H), 7.47-7.32 (m, 4H), 7.34-7.32 (m, 1H), 5.87-5.84 (m, 1H), 2.12-2.03 (m, 1H), 1.92-1.84 (m, 1H), 1.51-1.34 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.7, 140.7, 140.7, 139.5, 128.7, 127.1, 127.1, 126.5, 91.8, 80.8, 36.6, 27.6, 22.4, 14.0 (one aromatic resonance was not resolved). Anal. Calcd for C₁₉H₂₀Cl₃NO: C, 59.32; H, 5.24; N, 3.64. Found: C, 59.58; H, 5.31; N, 3.45.

1-(1,1′-Biphenyl]-4-yl)-2-methylpropyl 2,2,2-trichloroacetimidate (6q)

Purified by silica gel chromatography (10% ethyl acetate/1% triethylamine/89% hexanes); White solid (2.00 g, 66%), TLC R_f = 0.42 (10% ethyl acetate/90% hexanes); IR (DCM) 3339, 2967, 1661, 1487, 1300, 1058, 990 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.16 (s,1H), 7.53-7.49 (m, 4H), 7.37-7.34 (m, 4H), 7.28-7.26 (m, 1H), 5.52 (d, J = 7.1 Hz, 1H), 2.16 (octet, J = 6.8 Hz, 1H), 1.02 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.8, 140.8, 140.7, 138.2, 128.8, 127.4, 127.3, 127.2, 126.9, 92.0, 85.6, 34.4, 19.0, 18.3. Anal. Calcd for C₁₈H₁₈Cl₃NO: C, 58.32; H, 4.89; N, 3.78. Found: C, 58.50; H, 4.69; N, 3.90.

1-(Naphthalen-2-yl)propyl 2,2,2-trichloroacetimidate (6r)

Purified by silica gel chromatography (1% triethylamine/99% hexanes); Yellow oil (1.39 g, 96 %); TLC Rf = 0.62 (10% ethyl acetate/90% hexanes); IR (DCM) 3332, 2972, 1663, 1073, 831, 797, 704 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 8.26 (brs, 1H), 7.85-7.81 (m, 4H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.48-7.45 (m, 2H), 5.92 (m,1H), 2.20-2.09 (m, 1H), 2.05-1.94 (m, 1H), 1.03 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.8, 137.5, 133.08, 133.06, 128.2, 128.0, 127.7, 126.2, 126.0, 125.4, 124.0, 91.9, 82.3, 29.8, 10.0. Anal. Calcd for C₁₅H₁₄Cl₃NO: C; 54.49; H, 4.27; N, 4.24. Found: C, 54.42; H, 4.36; N, 4.31.

1-(1-Benzothiophen-3-yl)propyl 2,2,2-trichloroacetimidate (6s)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/94% hexanes); Yellow viscous oil (2.38 g, 91%); IR (DCM) 3340, 2972, 1664, 1428, 1082, 976, 760 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 8.32 (brs, 1H), 7.94-7.91 (m, 1H), 7.85-7.82 (m, 1H), 7.45 (s, 1H), 7.37-7.30 (m, 2H), 6.24 (t, J = 8.1 Hz, 1H), 2.30-2.02 (m, 2H), 1.02 (t, J = 9.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.9, 140.7, 137.1, 134.9, 124.5, 124.1, 123.6, 122.9, 122.5, 91.9, 77.9, 28.1, 10.0. Anal. Calcd for C₁₃H₁₂Cl₃NOS: C, 46.38; H, 3.59; N, 4.16. Found: C, 46.03; H, 3.60; N, 3.95.

3,4-Dimethoxybenzyl 2,2,2-trichloroacetimidate (6t)

Purified by silica gel chromatography (30% ethyl acetate/1% triethylamine/69% hexanes); Yellow oil (3.00 g, 90%); TLC R_f = 0.28 (20% ethyl acetate/80% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.38 (brs, 1H), 7.01-6.98 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 3.89 (s, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.4, 149.1, 149.0, 127.9, 120.8, 111.3, 111.0, 91.5, 70.8, 55.85, 55.83. Anal. Calcd for C₁₁H₁₂Cl₃NO₃: C, 42.27; H, 3.87; N, 4.48. Found: C, 42.39; H, 3.59; N, 4.59.

1-(Naphthalen-1-yl)ethyl 2,2,2-trichloroacetimidate (6w)

Purified by silica gel chromatography (10% ethyl acetate/1% triethylamine/89% hexanes); Light brown oil (5.64 g, 85%); TLC Rf = 0.56 (10% ethyl acetate/90% hexanes); IR (DCM) 3338, 1662, 1512, 1301, 1085, 774, 648 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.47 (brs, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.56-7.44 (m, 3H), 5.77 (s, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 162.8, 133.7, 131.6, 130.9, 129.5, 128.7, 127.3, 126.5, 126.0, 125.2, 123.7, 91.5, 69.5. Anal. Calcd for C₁₃H₁₀Cl₃NO: C, 51.60; H, 3.33; N, 4.63. Found: C, 51.83; H, 3.28; N, 4.77.

1-(Naphthalen-2-yl)ethyl 2,2,2-trichloroacetimidate (6x)

Purified by silica gel chromatography (10% ethyl acetate/1% triethylamine/89% hexanes); White solid (1.89 g, 99%), TLC R_f = 0.70 (20% ethyl acetate/80% hexanes); IR (DCM) 3335, 3053, 1665, 1305, 1081, 817, 649 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.42 (brs, 1H), 7.90 (s, 1H), 7.87-7.84 (m, 3H), 7.54 (dd, J = 8.4, 1.4 Hz, 1H), 7.50-7.48 (m, 2H), 5.50 (s, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.6, 133.2, 133.1, 132.9, 128.4, 128.0, 127.7, 127.0, 126.3, 126.3, 125.5, 91.4, 70.9. Anal. Calcd for C₁₃H₁₀Cl₃NO: C, 51.60; H, 3.33; N, 4.63. Found: C, 51.71; H, 3.52; N, 4.84.

(1-Benzothiophen-3-yl)methyl 2,2,2-trichloroacetimidate (6y)

Purified by silica gel chromatography (10% ethyl acetate/1% triethylamine/89% hexanes); Off white solid (1.92 g, 68%); TLC R_f = 0.48 (10% ethyl acetate/90% hexanes); IR (DCM) 3340, 3052, 2984, 2304, 1664, 1460, 1295, 1265, 1076, 799, 737, 705 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.46 (brs, 1H), 7.88-7.86 (m, 2H), 7.56 (s, 1H), 7.43-7.36 (m, 2H), 5.57 (s, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 162.7, 140.5, 137.8, 130.3, 126.5, 124.7, 124.4, 122.9, 122.0, 91.0, 65.3. Anal. Calcd for C₁₁H₈Cl₃NOS: C, 42.81; H, 2.61; N, 4.54. Found: C, 43.17; H, 2.43; N, 4.61.

4-Nitrobenzyl 2,2,2-trichloroacetimidate (6z)

Purified by silica gel chromatography (20% ethyl acetate/1% triethylamine/79% hexanes); Yellow solid (3.75 g, 97%); TLC R_f = 0.23 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.25 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 5.45 (s, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.1, 147.8, 142.7, 127.9, 123.8, 90.9, 69.1. Anal. Calcd for C₉H₇Cl₃N₂O₃: C, 36.33; H, 2.37; N, 9.42. Found: C, 36.27; H, 2.30; N, 9.48.

2,2-Diphenylethyl 2,2,2-trichloroacetimidate (6aa)

Purified by silica gel chromatography (5% ethyl acetate/1% triethylamine/89% hexanes); Clear oil (0.31 g, 87%); IR (DCM) 3337, 1663, 1081, 798 cm⁻¹; TLC R_f = 0.68 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.32-7.20 (m, 10H), 4.81 (d, J = 7.3 Hz, 2H), 4.54 (t, J = 7.2 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.8, 141.0, 128.5, 128.4, 126.8, 91.3, 71.6, 49.5. Anal. Calcd for C₁₆H₁₄Cl₃NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 55.93; H, 3.92; N, 4.07.

(2S,3aS,8aS)-dimethyl 8-(phenylsulfonyl)-3a-(2,2,2-trichloro-1-iminoethoxy)-3,3a,8,8a -tetrahydropyrrolo[2,3-b] indole-1,2(2H)-dicarboxylate (9)

Purified by silica gel chromatography (40% ethyl acetate/1% triethylamine/59% hexanes); White foamy solid (0.08 g, 60%); TLC R_f = 0.57 (50% ethyl acetate/50% hexanes); [α]_D²¹ = +85.1 (c = 1.6, CHCl₃); IR (DCM) 3434, 2090, 1642 cm^{−1; 1}H NMR (400 MHz, CDCl₃, 50 °C) δ 8.49 (s, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.54-7.44 (m, 4H), 7.39-7.30 (m, 2H), 7.07 (td, J = 7.7, 1.1 Hz, 1H), 6.71 (s, 1H), 4.83 (d, J = 9.0 Hz, 1H), 3.51 (brs, 3H), 3.26 (s, 3H), 3.17 (d, J = 12.9 Hz, 1H), 3.03 (dd, J = 12.8, 9.2 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, 50 °C) δ 170.3, 159.1, 154.4, 144.8, 144.4, 132.5, 131.5, 129.0, 127.7, 126.6, 125.5, 124.3, 116.3, 93.4, 90.8, 81.6, 58.6, 52.7, 52.2, 39.3. Anal. Calcd for C₂₂H₂₀Cl₃N₃O₇S: C, 45.81; H, 3.49; N, 7.28. Found: C, 45.95; H, 3.37; N, 7.31.

3-(N-Methylbenzenesulfonamido)-1S-(thiophen-2-yl)propyl 2,2,2-trichloroacetimidate (15)

Purified by silica gel chromatography (20% ethyl acetate/1% triethylamine/79% hexanes); Yellow oil (0.25 g, 85%); TLC R_f = 0.62 (40% ethyl acetate/60% hexanes); [α]_D²⁵ = +32.5 (c = 0.4, DCM); IR (DCM) 3375, 1693, 1335, 1163, 1109, 834 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.46 (brs, 1H), 7.81-7.79 (m, 2H), 7.63-7.52 (m, 3H), 7.31 (dd, J = 5.1, 1.1 Hz, 1H), 7.18 (d, J = 3.4 Hz, 1H), 7.01 (q, J = 3.6 Hz, 1H), 6.28 (q, J = 4.9 Hz, 1H), 3.21 (t, J = 6.9 Hz, 2H), 2.81 (s, 3H), 2.47-2.38 (m, 1H), 2.32-2.24 (m, 1H); ¹³C{¹H} NMR (100MHz, CDCl₃) δ 161.1, 141.4, 137.4, 132.7, 129.1, 127.4, 126.6, 126.5, 125.7, 91.4, 73.5, 46.8, 35.5, 35.3. Anal. Calcd for C₁₆H₁₇Cl₃N₂O₃S₂: C, 42.16; H, 3.76; N, 6.15. Found: C, 42.16; H, 3.82; N, 6.12. The enantiomeric purity of this material was verified by NMR using the chiral shift reagent Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate] i.e. Eu(hfc)₃. The addition of 0.8 equiv of Eu(hfc)₃ gave separation of the imidate NH peak at ~8.4 ppm in the ¹H NMR (see supporting spectra for details).

General Procedures for the Displacement of Trichloroacetimidates with Trimethylaluminum

Method A

Aluminium trichloride (1 eq) was dissolved in dry DCM (0.162 M) under argon in a flame dried flask. Trimethylaluminium (3 equiv, 2M in hexanes) was slowly added and the mixture was stirred for 5 min. After cooling to 0 °C the trichloroacetimidate (1 equiv) was added. The reaction mixture was then allowed to warm to rt. After 15 min the reaction was quenched with 10% aq. HCl. The mixture was poured into water and extracted with DCM (3x). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was then purified by silica gel chromatography using the eluent listed for each example. Compounds 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j, 7k, 7l, 7m, 7n, 7o, 7p, 7r, 7s, 10, and 16 were obtained by this method.

Method B

Trimethylaluminium (3 equiv, 2M in hexanes) was suspended in dry DCM (0.162 M) under argon in a flame dried flask. The temperature of the reaction was then cooled to the temperature noted in Table 2. The trichloroacetimidate was the added. The reaction was monitored by TLC, and quenched with the addition of 10% aq. HCl after the time listed in Table 2. The quenched mixture was poured into water and extracted with DCM (3x). The organic extracts were then dried using Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography using the eluent listed for each example. Compounds 7q, 7t, 7u, 7v, 7w, 7x, 7y were obtained using this method.

1,1- Diphenylethane (7a)³⁶

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes); Clear viscous oil (0.04 g, 91%); ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.08 (m, 10H), 4.07 (q, J = 7.2 Hz, 1H), 1.56 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.4, 128.4, 127.7, 126.1, 44.8, 21.9.

1-Phenyl-1-(p-tolyl)ethane (7b)³⁶

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes). Clear oil (0.03 g, 65%); TLC R_f = 0.74 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.07 (m, 9H), 4.12 (q, J = 7.2 Hz, 1H), 2.3 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.6, 143.4, 135.5, 129.0, 128.3, 127.6, 127.5, 125.9, 44.4, 21.9, 21.0.

1-Phenyl-1-(o-tolyl)ethane (7c)^11c

Purified by silica gel chromatography (100% hexanes). Clear viscous oil (0.08 g, 70%); TLC R_f = 0.83 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.27- 7.11 (m, 9H), 4.30 (q, J = 7.2 Hz, 1H), 2.22 (s, 3H), 1.60, (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 146.3, 144.0, 136.2, 130.5, 128.4, 127.8, 126.8, 126.2, 126.1, 125.9, 41.1, 22.2, 19.8.

4-(1-Phenylethyl)biphenyl (7d)³⁷

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes); Clear viscous oil (0.04 g, 91%); TLC R_f = 0.69 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 8.4, 1.4 Hz, 2H), 7.51-7.49 (m, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.32-7.16 (m, 8H), 4.18 (q, J = 7.2 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.2, 145.5, 141.0, 139.0, 128.7, 128.4, 128.0, 127.6, 127.1, 127.0, 127.0, 126.1, 44.5, 21.9.

4-(1-Phenylethyl)anisole (7e)³⁸

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes); Clear viscous oil (0.03 g, 64%); TLC R_f = 0.37 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.12 (m, 7H), 6.83-6.81 (m, 2H), 4.10 (q, J = 7.2 Hz, 1H), 3.77 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.8, 146.8, 138.6, 128.5, 128.3, 127.5, 125.9, 113.7, 55.2, 43.9, 22.1.

1-Chloro-3-(1-phenylethyl)benzene (7f)

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes); Clear viscous oil (0.11 g, 92%); IR (DCM) 3434, 2090, 1642 cm⁻¹; 2968,1594, 1493, 1475, 1426, 1082, 791; TLC R_f = 0.73 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.26 (m, 2H), 7.20-7.13 (m, 5H), 7.09-7.07 (m, 2H), 4.10 (q, J = 7.2 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 148.5, 145.5, 134.2, 129.7, 128.6, 127.8, 127.6, 126.4, 126.3, 125.9, 44.6, 21.7. Calcd for C₁₄H₁₃Cl: C, 77.59; H, 6.05; Found: C, 77.33; H, 5.76

1-Bromo-4-(1-phenylethyl)benzene (7g)³⁹

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.11 g, 86%); TLC R_f = 0.71 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.21-7.16 (m, 3H), 7.07 (d, J = 8.4 Hz, 2H), 4.09 (q, J = 7.2 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 145.7, 145.4, 131.5, 129.4, 128.5, 127.6, 126.3, 119.9, 44.3, 21.8.

1-Fluoro-3-(1-phenylethyl)benzene (7h)

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.04 g, 87%); TLC R_f = 0.66 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.26 (m, 2H), 7.23-7.17 (m, 4H), 6.99 (d, J = 7.7 Hz, 1H), 6.92-6.83 (m, 2H), 4.13 (q, J = 7.2 Hz, 1H), 1.62 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 163.0 (d, J = 244.5 Hz), 149.0, 145.6, 129.7, 128.5, 127.6, 126.3, 123.3, 114.5 (d, J = 22.5 Hz), 112.8 (d, J = 22.4 Hz), 44.5, 21.7. Anal. Calcd for C₁₄H₁₃F: C, 83.97; H, 6.54. Found: C, 83.88; H, 6.22.

1-Nitro-4-(1-phenylethyl)benzene (7i)⁴⁰

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes); Yellow oil (0.08 g, 66%); TLC R_f = 0.55 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J = 8.8, Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 7.24 (t, J = 7.1 Hz, 2H), 7.18-7.12 (m, 3H), 4.18 (q, J = 7.2 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.1, 146.4, 144.5, 128.7, 128.5, 127.6, 126.7, 123.7, 44.7, 21.5.

1-(1-Phenylethyl)-3,5-bis(trifluoromethyl)benzene (7j)

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.13 g, 95%); TLC R_f = 0.57 (100% hexanes); IR (DCM) 2801, 1420, 1374, 1280, 1173, 1134, 897, 701 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H), 7.76 (s, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.25-7.18 (m, 3H), 4.26 (q, J = 7.2 Hz, 1H), 1.68 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 148.9, 144.2, 131.7 (q, J = 44.6 Hz)), 128.9, 127.8 (q, J = 3.4 Hz), 127.5, 126.9, 123.5 (q, J = 361.0 Hz), 120.3 (hept, J =5.2), 44.7, 21.6. Anal. Calcd for C₁₆H₁₂F₆: C, 60.38; H, 3.80. Found: C, 60.65; H, 3.75.

2-(1-Phenylethyl)-naphthalene (7k)⁴¹

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.07 g, 57%); TLC R_f = 0.52 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.76 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.42-7.38 (m, 2H), 7.30-7.24 (m, 5H), 7.20-7.16 (m, 1H), 4.30 (q, J = 7.2 Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 146.3, 143.8, 133.6, 132.2, 128.5, 128.0, 127.81, 127.78, 127.62, 126.9, 126.2, 126.0, 125.4, 44.9, 21.8 (one aromatic resonance was not resolved).

1-(1-Phenethyl)-naphthalene (7l)⁴²

Purified by silica gel chromatography (2% ethyl acetate/98% hexanes); Clear viscous oil (0.07 g, 57%); TLC R_f = 0.73 (10% ethyl acetate/90% hexanes). ¹H NMR (400 MHz, CDCl₃) δ 8.02-7.04 (m, 1H), 7.84-7.82 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47-7.39 (m, 4H), 7.25-7.22 (m, 4H), 7.17-7.13 (m, 1H), 4.91 (q, J = 7.1 Hz, 1H), 1.76 (d, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.6, 141.5, 134.0, 131.7, 128.7, 128.4, 127.6, 127.0, 125.9, 125.8, 125.4, 125.3, 124.3, 123.9, 40.5, 22.5.

3-(1-Phenylethyl)-benzo[b]thiophene (7m)⁴³

Purified by silica gel chromatography (2% ethyl acetate/98% hexanes); White foam (0.07 g, 57%); TLC R_f = 0.38 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.81 (m, 1H), 7.55-7.53 (m, 1H), 7.29-7.15 (m, 8H), 4.43 (q, J = 7.1 Hz, 1H), 1.73 (d, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 145.4, 140.7, 140.6, 138.6, 128.6, 127.4, 126.3, 124.2, 123.8, 122.8, 122.5, 121.5, 39.6, 22.4.

3-(1-(4-Fluorophenyl)ethyl)-benzo[b]thiophene (7n)^14a

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.09 g, 71%); TLC R_f = 0.76 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.27-7.13 (m, 5H), 6.91 (t, J = 8.7 Hz, 2H), 4.39, (q, J = 7.0 Hz, 1H), 1.67 (d, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.5 (d, J = 242.3 Hz), 141.2, 140.8, 140.4, 138.5, 128.9, 124.3, 123.9, 122.9, 122.5, 121.6, 115.4 (d, J = 21.7 Hz), 38.9, 22.5.

4-Isopropylbiphenyl (7o)⁴⁴

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.10 g, 87%); TLC R_f = 0.55 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3 Hz, 3H), 2.94 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 7.0 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.1, 141.3, 138.8, 128.8, 127.2, 127.1, 127.0, 126.9, 33.9, 24.1.

1-(1-Methylpentyl)-4-phenyl-benzene (7p)

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.12 g, 97%); TLC R_f = 0.64 (100% hexanes); IR (DCM) 3027, 2957, 2926, 2856, 1486, 1455, 1008, 837, 732 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.60-7.58 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.4, Hz, 2H), 7.34-7.30 (m, 1H), 7.26-7.24 (m, 2H), 2.72 (hextet, J = 6.8 Hz, 1H), 1.65-1.56 (m, 2H), 1.33-1.15 (m, 7H), 0.87 (t, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 147.2, 141.2, 138.7, 128.7, 127.4, 127.0, 126.9, 39.6, 38.2, 30.0, 22.8, 22.3, 14.1 (one aromatic resonance was unresolved). Anal. Calcd for C₁₈H₂₂: C, 90.70; H, 9.30. Found: C, 90.79; H, 9.37.

4-(3-methylbutan-2-yl)-1,1′-biphenyl (7q)

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.065 g, 90%); TLC R_f = 0.45 (100% hexanes); IR (DCM) 3416, 2960, 2872, 1598, 1486 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 7.7 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.25 (d, J = 9.1Hz, 2H), 2.50 (quintet, J = 7.1 Hz, 1H), 1.81 (octet, J = 6.6 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 146.3, 141.2, 138.6, 128.7, 128.1, 127.02, 127.00, 126.8, 46.6, 34.5, 21.3, 20.2, 18.9. Anal. Calcd for C₁₇H₂₀: C, 91.01; H, 8.99. Found: C, 91.18; H, 8.75.

2-(1-Methylpropyl)-naphthalene (7r)^14a

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.07 g, 60%); TLC R_f = 0.71 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.75 (m, 3H), 7.60 (s, 1H), 7.41 (qd, J = 6.9, 1.4 Hz, 2H), 7.33 (dd, J = 8.5, 1.6 Hz, 1H), 2.75 (sextet, J = 7.0 Hz, 1H), 1.74-1.62 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 145.1, 133.6, 132.2, 127.8, 127.6, 127.5, 125.9, 125.7, 125.2, 125.0, 41.8, 31.0, 21.9, 12.3.

3-(1-Methylpropyl)-benzo [b] thiophene (7s)^14a

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.07 g, 62%); TLC R_f = 0.65 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.86-7.84 (m, 1H), 7.79-7.77 (m, 1H), 7.38-7.30 (m, 2H), 7.06 (s, 1H), 3.09 (sextet, J = 6.8 Hz, 1H), 1.89-1.79 (m, 1H), 1.71-1.60 (m, 1H), 1.35 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 142.5, 140.7, 138.9, 124.0, 123.7, 122.9, 121.9, 119.6, 34.7, 29.8, 20.3, 12.0.

4-Ethyl-1,3-dimethoxybenzene (7t)⁴⁵

Purified by silica gel chromatography (5% ethyl acetate/95% hexanes); Clear viscous oil (0.08 g, 92%); TLC R_f = 0.66 (20 ethyl acetate/80% hexanes). ¹H NMR (400 MHz, CDCl₃) δ 6.80 (d, J = 8.6 Hz, 1H), 6.74-6.73 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.60 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.8, 147.0, 137.0, 119.5, 111.3, 111.3, 56.0, 55.8, 28.5, 15.8.

4-Ethylanisole (7u)⁴⁶

Purified by silica gel chromatography (4% ethyl acetate/96% hexanes); Clear viscous oil (0.05 g, 52%); TLC R_f = 0.78 (10% ethyl acetate/90% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.10 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.77 (s, 3H), 2.58 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.7, 136.4, 128.7, 113.8, 55.3, 28.0, 15.9.

4-Ethylbiphenyl (7v)⁴⁴

Purified by silica gel chromatography (1% ethyl acetate/99% hexanes); Clear viscous oil (0.09 g, 81%); TLC R_f = 0.68 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) 7.59-7.57 (m, 2H), 7.52-7.50 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.33-7.26 (m, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 143.4, 141.2, 138.6, 128.7, 128.3, 127.1, 127.0, 127.0, 28.5, 15.6.

1-Ethylnapthalene (7w)⁴⁷

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.062 g, 60%); TLC R_f = 0.66 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 8.2 Hz, 1H), 7.85-7.83 (m, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.52-7.44 (m, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.33 (d, J = 6.9 Hz, 1H), 3.12 (q, J = 7.5 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 140.3, 133.9, 131.8, 128.8, 126.4, 125.7, 125.4, 124.9, 123.8, 25.9, 15.1 (one aromatic resonance was unresolved).

2-Ethylnapthalene (7x)⁴⁸

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.05 g, 49%); TLC R_f = 0.62 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.74 (m, 3H), 7.60 (s, 1H), 7.41-7.33 (m, 2H), 7.33 (dd, J = 8.4, 1.2 Hz, 1H), 2.80 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.7, 133.7, 131.9, 127.8, 127.6, 127.4, 127.1, 125.8, 125.5, 125.0, 29.0, 15.5.

3-Ethyl-benzo[b]thiophene (7y)⁴⁹

Purified by silica gel chromatography (100% hexanes); Clear viscous oil (0.08 g, 62%); TLC R_f = 0.57 (100% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.83 (m, 1H), 7.74-7.72 (m, 1H), 7.38-7.30 (m, 2H), 7.06 (s, 1H), 2.85 (qd, J = 7.5, 1.0 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 140.6, 139.1, 138.7, 124.2, 123.8, 122.9, 121.7, 120.2, 21.8, 13.4.

1,2-Dimethyl (2S)-8-(benzenesulfonyl)-3a-chloro-1H,2H,3H,3aH,8H,8aH-pyrrolo[2,3-b] indole -1,2-dicarboxylate (10)

Purified by silica gel chromatography (20% ethyl acetate/80% hexanes); White solid (0.06 g, 80%); [α]_D²⁴ = +38.2 (c = 1.2, DCM); TLC R_f = 0.33 (50% ethyl acetate/50% hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 7.40-7.34 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.20 (s, 1H), 4.66 (d, J = 8.7 Hz, 1H), 3.70 (s, 3H), 3.13 (s, 3H), 3.09-3.12 (m, 1H), 2.95-2.86 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.0, 154.3, 142.2, 139.0, 133.3, 132.1, 131.3, 128.9, 127.3, 125.8, 124.4, 118.4, 86.3, 71.4, 59.3, 53.1, 52.3, 43.0. HRMS (ESI) (m/z): calcd for C₂₀H₁₉ClN₂O₆SNa (M+Na⁺): 473.0544. Found: 473.0541.

N-Methyl-N-[3-(thiophen-2-yl)butyl]benzenesulfonamide (16)

Purified by silica gel chromatography (20% ethyl acetate/80% hexanes); Clear oil (0.070 g, 49%), TLC R_f = 0.62 (50% ethyl acetate/50% hexanes); IR (DCM) 2923, 1446, 1340, 1164, 735, 691 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.06-7.04 (m, 1H), 6.84 (t, J = 3.5 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 3.07 (sextet, J = 6.9 Hz, 1H), 2.93 (td, J = 7.4, 1.9 Hz, 2H), 2.63 (s, 3H), 1.84-1.71 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 150.6, 137.5, 132.5, 129.0, 127.4, 126.6, 123.1, 122.8, 48.4, 37.0, 34.9, 32.6, 23.1. Anal. Calcd for C₁₅H₁₉NO₂S₂: C, 58.22; H, 6.19; N, 4.53. Found: C, 58.10; H, 6.14; N, 4.89; Chiral HPLC analysis: OJ column (hexane/i-PrOH = 91/9, 0.9 mL/min, 254 nm, 25 °C): t_r = 20.4, 22.2 min.

1-(Benzenesulfonyl)-1,2,3,4-tetrahydropyridin-4-ol (11)

IBX (1.170 g, 4.17 mmol) was dissolved in dry DMSO (3.3 ml) and warmed to 75 °C for 5 min. The known 1-(benzenesulfonyl)-4-piperidone⁵⁰ (0.500 g, 2.08 mmol) was added and the reaction was allowed to proceed for 14 h at 75 °C. The reaction mixture was then poured into sat. aq. NaHCO₃ solution and partitioned with ethyl acetate. The organic phase was then filtered through Celite with ethyl acetate, and then the filtrate was washed with water and brine. The organic layer was then dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (40 % ethyl acetate/60% hexanes) to provide crude 1-(benzenesulfonyl)-2,3-dehydro-4-piperidone as an off-white solid (0.297 g, 60%). A portion of this solid (0.200 g, 0.83 mmol) was then dissolved in 2 mL of MeOH. The reaction was cooled to 0°C and CeCl₃•7H₂O (0.313 g, 0.83 mmol) was added followed by NaBH₄ (0.032 g, 0.83 mmol). Reaction mixture was then allowed to warm to room temperature. After 30 min the reaction was poured into water and extracted with ethyl acetate (3x). The combined organic layers were then dried (Na₂SO₄), filtered and concentrated. The residue was purified by silica gel chromatography (50% ethyl acetate/50% hexanes) to provide alcohol 11 as white solid (0.191 g, 95%)

11. TLC R_f = 0.20 (40% ethyl acetate/60% hexanes); IR (DCM) 3398, 1643, 1446, 1170, 935 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 7.80-7.78 (m, 1H), 7.63-7.50 (m, 3H), 6.81 (d, J = 8.3 Hz, 1H), 5.13 (ddd, J = 8.3, 4.8, 1.1 Hz, 1H), 4.12 (brs, 1H), 3.73-3.66 (m, 1H), 3.14 (td, J = 11.9, 3.2 Hz, 1H), 1.86-1.64 (m, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) 137.9, 133.1, 129.3, 127.7, 127.0, 108.8, 59.9, 39.2, 30.0. Anal. Calcd for C₁₁H₁₃NO₃S: C, 55.21; H, 5.48; N, 5.85. Found: C, 54.82; H, 5.40; N, 6.25.

1-(Benzenesulfonyl)-4-methyl-1,2,3,4-tetrahydropyridine (12)

Alcohol 11 (0.150 g, 0.632 mmol) was dissolved in 1.1 mL of dry DCM under argon. The reaction was cooled to 0 °C and DBU (20 μL, 0.131 mmol) was added followed by trichloroacetonitrile (70 μL, 0.698 mmol). The reaction mixture was then allowed to warm to rt and stirred for 15 min. In a separate flask AlCl₃ (84 mg, 0.632 mmol) was dissolved in DCM (2 mL) and AlMe₃ (0.94 mL, 2M in hexanes, 1.92 mmol) was added. After 5 min the solution containing the trimethylaluminum was added to the imidate formed in the first solution at 0°C. After 5 min the reaction was quenched with 1 M HCl and the mixture extracted with DCM (3x). The combined organic layers were then dried (Na₂SO₄), filtered and concentrated. The residue was purified by silica gel chromatography (15% ethyl acetate/85% hexanes) to provide alkene 12 as yellow oil (94 mg, 63%).

12. TLC R_f = 0.25 (20% ethyl acetate/80% hexanes); IR (DCM) 3033, 2974, 2931, 1446, 1328, 1279,1213, 1164, 1105, 980 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 5.67-5.57 (m, 2H), 4.44 (brs, 1H), 3.85 (dd, J = 5.9, 1.4 Hz, 1H), 3.19-3.12 (m, 1H), 1.97-1.79 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.5, 132.3, 129.4, 129.0, 126.8, 124.4, 49.6, 37.8, 23.7, 20.4. Anal. Calcd for C₁₂H₁₅NO₂S: C, 60.73; H, 6.37; N, 5.90. Found: C, 60.46; H, 6.46; N, 5.86.

N-[3S-Hydroxy-3-(thiophen-2-yl)propyl]-N-methylbenzenesulfonamide (14)

(S)-3-(Methylamino)-1-(2-thienyl) propan-1-ol⁵¹ (0.200 g, 1.17 mmol) was dissolved in dry DCM (5 mL) and cooled to 0 °C. Pyridine (0.113 ml, 1.46 mmol) was then added followed by benzenesulfonyl chloride (0.246 mg, 1.39 mmol). The reaction mixture was then allowed to warm to rt and stirred for 14 h. The reaction mixture was then poured into water and extracted with ethyl acetate (3x). This organic extracts were then dried (Na₂SO₄), filtered, concentrated in vacuo. Purification by silica gel chromatography (40% ethyl acetate/60% hexanes) gave sulfonamide S1 as a white solid (0.33 g, 90%).

14. TLC R_f = 0.45 (40% ethyl acetate/60% hexanes); [α]_D²⁴ = −7.4 (c = 0.8, DCM); IR (DCM) 3499, 2925, 1446, 1331, 1160, 1089, 737, 691 cm^{−1; 1}H NMR (300 MHz, CDCl₃) δ 7.74-7.71 (m, 2H), 7.61-7.48 (m, 3H), 7.30 (d, J = 5.0 Hz, 1H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H), 6.93 (dd, J = 3.4, 1.0 Hz, 1H), 4.49 (dd, J = 8.1, 5.3 Hz, 1H), 3.24- 3.14 (m, 1H), 2.85-2.73 (m, 1H), 2.62 (s, 3H), 2.14-2.01 (m, 1H), 1.93- 1.82 (m,1H). ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 144.7, 137.4, 132.5, 129.0, 127.4, 126.7, 126.4, 125.5, 71.8, 47.3, 36.8, 34.9. Anal. Calcd for C₁₄H₁₇NO₃S₂: C, 54.00; H, 5.50; N, 4.50. Found: C, 53.72; H, 5.82; N, 4.38.