Design, synthesis and applications of chiral N-2-phenyl-2-propyl sulfinyl imines for Group-Assisted Purification (GAP) asymmetric synthesis

Abstract

A new chiral (Rs)-2-phenyl-2-propyl sulfinamide has been designed and synthesized; its derived aldimines and ketimines have been applied for asymmetric addition reaction with allylmagnesium bromide. The reaction was conveniently performed at room temperature to give a series of homoallylic amines in high yields (up to quant) and diastereoselectivity (up to >99 % de). The pure products were obtained by relying on Group-Assisted Purification (GAP) chemistry to avoid traditional purification methods of column chromatography or recrystallization. The conversion of disulfide to (R_s)-thiosulfinate was also confirmed to be of the GAP chemistry in which washing crude product can generate pure enantiomer. The absolute stereochemistry has been determined by X-ray analysis.

Introduction

The imine chemistry has been one of the most important topics in modern organic and medicinal chemistry.¹ The resulting chiral amino compounds are valuable synthetic building blocks and have been widely transformed into many natural products and medicinal targets.² Design of chiral N-protected imines and their applications to asymmetric reactions have dramatically advanced the asymmetric fields in the past several decades.³ The search for greener chiral imines with high efficiencies for asymmetric synthesis is still remained challenging. In the past several years, we have designed several chiral N-protected imines including N-phosphonyl,⁴N-phosphoryl,⁵ and N-phosphinyl⁶ auxiliaries. We successfully utilized them to many asymmetric transformations with good to excellent yields and diastereoselectivities without using traditional purification methods, which resulted in a new concept called Group-Assisted Purification (GAP) chemistry.^6-8 By paying attention to this concept, the products can be purified by simply washing with the common solvents to save materials (silica gels, solvents, energy and manpower) substantially. If products appear in the form of oil/liquid, washing can be performed via extractions in separation funnels. The GAP chemistry requires adequate control not only on the physical solubility but also on chemical reactivity and stereoselectivity of both reagents and resulting products. In former, products must be soluble in some common solvents (e.g., THF and DCM) to enable further reactions, but they should not be dissolved well in some other solvents (petroleum ethers, hexane and their co-solvents with EtOAc, etc) to enable simple washing for purification. In latter, the auxiliary-anchored reactants should have efficient reactivity toward various species and show efficient asymmetric induction to ensure the formation of excess amounts of desired isomeric products. In addition, the auxiliary group should be tolerable to many reaction conditions for further transformations; and preferably they be recovered for recycling.

Chiral N-phosphonyl and N-phosphinyl imine-based synthesis has been proven to meet the above requirements both physically and chemically.^4,6 For example, when chiral N-phosphonyl imines were subjected to the reaction with 2-lithio-1,3-dithianes via a special operation by slowly adding the solution of imines into that of lithium anions, the resulting umpolung products, α-amino-1,3-dithianes, were obtained in up to 82% yields and >99:1 diastereoselectivities by following the GAP chemistry process.^7b The pure chiral products can be easily generated by washing their crude products with hexane or the co-solvent of hexane-EtOAc to avoid the traditional purification of chromatography or recrystallization. Besides the use of chiral N-phosphonyl auxiliaries, we also applied their achiral N-phosphonyl counterpart to asymmetric catalysis of Strecker reaction. When achiral N-phosphonyl imines were utilized as the electrophiles to react with Et₂AlCN in the presence of chiral catalysts such as primary free natural amino acids, amino alcohols or BINOLs, the reaction was conducted to give excellent chemical yields and complete enantioselectivity.^7e,7f The achiral N-phosphonyl group also enabled the purification to be performed simply by the GAP process. In addition, achiral N-phosphonyl auxiliary can be readily cleaved under mild condition with the quantitative recovery of N,N^’-bis(naphthalen-1-ylmethyl)ethane-1,2-diamine via one-time extraction with n-butanol.

We believe that the unique polarity of P=O bond in which negative and positive charges are heavily localized on oxygen and phosphorous atoms is responsible for the solid product formation to enable the GAP purification. In N-phosphonyl auxiliaries, N,N-diamino groups donate electron density to stabilize the positively charged phosphorous center, which can indirectly increase electron density on terminal oxygen atom. In the solid state, the polarization effect between highly packed molecules is anticipated to further polarize the P=O bond which would be closer to be a single bond arrangement; this situation would be different in solution phase, particularly, when P=O bond exists in N-phosphonyl imines. The above hypothesis can be proven by the observation in which N-phosphonyl imines usually cannot be synthesized via GAP chemistry operation. A similar situation exists in the “S=O” bond polarization in thiooxime S-oxides, which makes the “S=O” bond to be as described as “S⁺-O^-”.^7,9

Based on the above analysis, we anticipated that the GAP chemistry phenomenon would exist in sulfinyl imine-based organic synthesis for making chiral amine compounds. In the meanwhile, we would like to design new sulfinyl imines by taking advantages of p-toluenesulfimines (aromatic chromophore) and t-butanesulfinyl imines (chemical stability) to modify their solubility so that the GAP chemistry can be accomplished more efficiently (Scheme 1).

Scheme 1.

Considering the availability of starting materials, we first focused on the study of the new chiral N-2-phenyl-2-propyl sulfinamide, its derived imines and their applications to the asymmetric reaction with allylmagnesium bromide. In this paper, would like to report our first results of this study as represented by Scheme 2 and results summarized in Tables 1 and 2.

Scheme 2.

Table 1.

Results of N-(R_s)-2-phenylpropyl-2-sulfinyl imines

Entry	Aldehyde or ketone	R2	R3	Product	Yield (%)a
1	7a	Phenyl	H	8a	98
2	7b	1-Naphthyl	H	8b	97
3	7c	2-Me-phenyl	H	8c	89
4	7d	4-Me-phenyl	H	8d	96
5	7e	4-F-phenyl	H	8e	98
6	7f	2-furyl	H	8f	92
7	7g	iso-butyl	H	8g	87
8	7h	Cyclohexyl	H	8h	88
9	7i	trans-PhCH=CH	H	8i	92
10	7j	Phenyl	Me	8j	52
11	7k	-COOEt	H	8k	45b
12	7l	4-NO2-phenyl	H	8l	80c

^aIsolated yields after column chromatography.

^b4 Å M.S. were used instead of Ti(OEt)₄.

^cReaction carried out at room temperature.

Table 2.

Results of the allylmagnesium Grignard addition reaction to N-(R_s)-2-phenylpropyl-2-sulfinyl imines

Entry	Imine	Product	% yielda,b	% dec
1	8a	9a	Quant	> 99
2	8b	9b	Quant	> 99
3	8c	9c	95	> 99
4	8d	9d	99	97
5	8e	9e	94	98
6	8f	9f	96	98
7	8g	9g	Quant	98
8	8h	9h	99	97
9	8i	9i	94	92
10	8j	9j	91	> 99

^aIsolated yields after washing with hexanes.

^bcombined yields of both the diastereomers.

^cDiastereoselectivity was determined by using ¹H-NMR of crude samples; >99% de means only on isomer was observed.

Results and Discussion

The synthesis of chiral (Rs)-2-phenyl-2-propyl sulfinamide was started from thiol 1 which is commercially available (Scheme 3). Thiol 1 was treated with 30 % aqueous hydrogen peroxide in the presence of NaI to give the disulfide 2. Asymmetric oxidation of disulfide 2 was accomplished with 30 % aqueous H₂O₂ in presence of vanadylacetoacetate and chiral ligand 3 to afford corresponding (Rs)-thiosulfinate 4 in 75 % yield and 85% ee.⁹ The enantiomeric excess was further improved to reach over 99% ee by washing this product with hexane twice as determined by chiral HPLC (AS-H column);¹⁰ Interestingly, this preparation serves as another example of GAP chemistry in non-imine based reactions. We believe this GAP phenomenon of enhancing % ee would have an extensive scope for other reactions and their resulting chiral products in asymmetric synthesis.

Scheme 3.

Surprisingly, the conversion of (Rs)-thiosulfinate 4 to sulfonamide 6 via the substitution reaction using Li/ liq.NH₃ failed to give the desired product, but this worked well in the preparation of t-butylsulfinamide. Treating thiosulfinate ester 4 with benzylamine in presence of n-BuLi led to formation of benzyl protected sulfinamide in a quantitative yield; Unfortunately, the next step of cleavage of benzyl group via catalytic hydrogenation failed, for which the possible toxic effect on catalyst by S=O group might be responsible.¹¹ The next attempt is to use LiHMDS as a stronger electrophile to react with thiosulfinate ester, but the extremely bulky N(SiMe₃)₂ group prevented the S_N2 reaction to occur. However, this nucleophile works well with p-tolenesulfinyl substrate of Andersen reagent.^8,12 Then the less bulky TBDMS-NH₂ (1.0 N solution in THF) which was freshly prepared¹³ was then utilized as the nucleophile in presence of n-BuLi. We were pleased that TBDMS-attached sulfinamide 5 was successfully obtained in a good yield of 93% without the observation of racemization. The subsequent mild deprotection of TBDMS using tetrabutylammonium fluoride (TBAF) gave (Rs)-2-phenyl-2-propyl sulfinamide 6 in 53 % overall yield and excellent enantiomeric excess (Scheme 3).

N-2-Phenyl-2-propyl-sulfinyl imines were readily synthesized by the condensation reaction of N-2-phenyl-2-propyl-sulfinyl amide with various aldehydes with the aid of Ti(OEt)₄.¹⁴ As shown in Table 1, both aldehydes and ketones are suitable for forming sulfinyl imines with the new N-2-phenyl-2-propyl-sulfinyl amide. In general, good to excellent yields (80 - 98%) were achieved with both aromatic and aliphatic aldehydes (entries 1-9, 12, Table 1). In two cases of acetophenone and glyoxamte, moderate yields of 52% and 45%, respectively, have achieved under the conditions above (entries, 10 and 11, Table 1).

The new chiral 2-phenyl-2-propyl sulfinyl imines are examined for its first application to the asymmetric addition reaction by allylmagnesium bromide. The resulting N-protected homoally amines from this reaction are very useful building blocks for a wide range of pharmaceuticals and biologically active substances;¹⁵ and have been transformed into nitrogen containing heterocycles, such as enantiopure C₂-symmetrical trans-2,5-disubstituted pyrrolidines, to serve as organocatalysts, chiral catalytic ligands and as chiral auxiliaries.¹⁶ Traditionally, allylation of imines through C-C bond formation by allylmetal reagents (such as allylindium, allylmagnesium and allyzinc) is used to make homoallyl amines.¹⁷ However, very few such syntheses were stereochemically efficient under room temperature conditions, or, very low temperature is necessary.

Initially, we began our investigation with the addition of allylmagenisium bromide to N-sulfinyl imine 8a in THF as solvent at -78 °C. Although the product was formed in a quantitative yield, no diastereoselectivity (~1:1) was observed. However, when the reaction was performed at 0 °C, the diastereoselectivity was enhanced to 5:1, and at room temperature it was further improved to 8:1. Raising the temperature to 50 °C did not give any diastereoselectivity enhancement. With this observation on hand, we then investigated the solvent effects. Several other solvents, such as toluene, benzene, dichloromethane and ether were screened at r.t. It was found that among these solvents, toluene led to best outcomes in terms of good yields (quant) and complete diastereoselectivity (>99% de) while others gave either poor yields or lower diastereoselectivity.

With the optimized condition in hand, we examined the substrate scope of various imines under the conditions above. As revealed in Table 2, excellent diastereoselectivities were achieved for all cases that were studied. In general, the substituent on aromatic rings of new 2-phenyl-2-propyl sulfinyl imines in regard to the nature and position does not have significant effects on asymmetric induction. For those imines tethered with reactive substituents, such as 4-nitro and – CO₂Et (8k and 8l, Table 1) failed to give clean desired products for this reaction. Importantly, the pure homoallylic amine products were obtained following the GAP chemistry purification without the use of traditional purification methods of column chromatography or recrystallization. The crude solid products were simply washed with minimum amounts of hexnane or heptanes to afford pure products and isomers. For homoallylic amino products formed in oils, washing combined organic phases containing the product with water in separation funnel can also give in >99 % purity without the use of column chromatography or recrystallization, which also belongs to the GAP chemistry as defined broadly.

The absolute stereochemistry of this reaction has been unambiguously determined by X-ray structural analysis of a sample of 9a, which shows the sulfur center to be R and the resulting new chiral carbon center as S configuration (CCDC number 917467).

The deprotection of sulfinyl group of 9a was conducted by the treatment with hydrogen chloride in methanol solution to give the free homoallyl amine 10 after neutralization was performed by using sodium hydroxide (Scheme 4). The optical rotation of resulting free amino product was compared with that of an authentic sample,¹⁸ which can further confirm the absolute stereochemistry of this reaction.

Scheme 4.

The resulting stereochemistry can be explained with a chair like transition state showed in the Figure 1,¹⁹ in which magnesium metal co-ordinates with both nitrogen and oxygen atoms to anchor the attack of nucleophile from Si face of the imine electrophile leading to the S stereochemical induction.

Figure 1.

Transition state for allylmagnesium bromide addition

Conclusions

In summary, the design and synthesis of new chiral N-(Rs)-2-phenyl-2-propylsulfinyl amide and their derived imines have been successfully conducted; and the first application of chiral N-(Rs)-2-phenyl-2-propylsulfinyl imines to the asymmetric addition reactions was performed by using allylamagnesium Grignard reagent to give good yields and excellent diastereoselectivities. The new auxiliary enables the purification of resulting homoallylic amine products to be performed via the economical and environmental friendly GAP operation in which washing the crude product with minimum amounts of common solvents can led to pure products. Further extension of the GAP chemistry to asymmetric synthesis using other sulfinyl imines is currently being explored in our labs.^21-22

Experimental Section

General

All chemicals and solvents were used as received without further purification unless otherwise stated. The NMR spectra were recorded on 400 MHz spectrometer, chemical shifts (δ) were expressed in ppm, and J values were given in Hz, and deuterated CDCl₃ was used as solvent. The reactions were monitored by thin layer chromatography (TLC) using silica gel. The melting points were uncorrected. High-resolution mass spectra for all the new compounds were collected on a Q-TOF.

Synthesis of disulfide 2²⁰

To a stirred solution of thiol 1 (78.8 mmol) in 240 mL of ethyl acetate was added NaI (236 mg, 1.57 mmol), and to this reaction mixture 30 % aq. H₂O₂ (8.9 mL, 78.8 mmol) was added slowly at room temperature. Reaction mixture was stirred at room temperature for 18 hours. At this stage, saturated aq. Na₂S₂O₃ was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude mixture was purified by column chromatography with pure hexanes as eluent to give 9.29 g (78 %) of disulfide 2.

¹H NMR (CDCl₃, 400 MHz): δ = 1.75 (s, 12 H), 7.42-7.44 (m, 2H), 7.49 –7.54 (m, 4H), 7.67–7.69 (m, 4H). ¹³C NMR (CDCl₃, 100 MHz): δ = 29.5, 52.2, 127.1, 127.4, 128.4, 128.5, 145.9. HRMS (TOF ES+): m/z calcd for C₁₈H22S₂ [M⁺], 302.11630; found, 302.11695.

Synthesis of thiosulfinate 4⁹

100 mL schlenk flask was loaded with ligand 3 (62.8 mg, 0.1719 mmol) and vanadylacetylacetanoate (44 mg, 0.165 mmol). Acetone (20 mL) was added and stirred the resulting dark-green solution at room temperature for 30 minutes, while open to the air. To this solution, disulfide 2 (10 g, 33.05 mmol) was added. The resulting mixture was cooled to 0 °C and 30 % aq. H₂O₂ was added slowly with syringe pump over 20 hours. The dark-brown color solution was stirred for another 26 hours at 0 °C. The reaction was quenched with saturated aq. Na₂S₂O₃, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The organic layer was evaporated under reduced pressure to afford crude (R_s)-thiosulfinate 4 as white solid, which was washed with hexanes to provide 7.9 g (75 %) of pure (R_s)-thiosulfinate 4 with 85 % ee. The enantiomeric excess was further improved to 99 % by washing with hexanes twice (10 mL of hexanes required for 1.0 g of thiosulfinate). HPLC Diacelchiralpak AS-H column, 98:2 Hexanes/ ⁱPrOH; 1.0 mL/min, 230 nm, t_R= 14.7 min; t_S= 19.1 min; ${\left[\alpha \right]}_D^{25}+126.2(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1. 63 (s, 3H), 1.77-1.82 (m, 9H), 7.24-7.41 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.8, 24.4, 31.0, 31.9, 53.3, 65.5, 126.6, 126.7, 127.4, 128.1, 128.3, 128.4, 139.8, 145.1; HRMS (TOF ES⁺): m/z calcd for C₁₈H₂₃OS₂ [(M+H)⁺], 319.1190; found, 319.1187.

Synthesis of TBDMS protected sulfinamide 5

TBDMS-NH₂ was prepared from TBDMS-Cl by known literature method.¹³ Freshly synthesized 1M solution of TBDMS-NH₂ (35.1 mL, 35.1 mmol) in THF was taken in a dry round bottomed flask under argon. To this solution, 1.6 M n-BuLi (22.0 mL, 35.16 mmol) was added drop wise at -78 °C, and the mixture was stirred at the same temperature. After 30 minutes the pre dissolved solution of 94 % ee thiosulfinate 4 (2.8 g, 8.79 mmol,) in THF was added slowly at -78 °C. The reaction temperature raised to room temperature slowly, and stirred until the starting material consumed, monitored by TLC. At this stage, reaction quenched with 1 mL aq. NH₄Cl solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, and evaporated under reduced pressure to afford crude TBDMS protected sulfinmaide 5. The crude product was purified by column chromatography to get 2.45 g (93 %) of compound 5 as white solid with 94 % ee. HPLC, Diacelchiralpak AS-H column, 93:7 Hexanes/ ⁱPrOH; 1.0 mL/min, 254 nm, t_S= 4.8 min; t_R= 7.2 min; ${\left[\alpha \right]}_D^{25}\text{-}31.8(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 0.02 (d, J = 10.1 Hz, 6 H), 0.76 (s, 9 H), 1.52 (s, 3H), 1.65 (s, 3H), 2.48 (br, 1H), 7.28-7.34 (m, 1H), 7.35-7.40 (m, 3H). ¹³C NMR (CDCl₃, 100 MHz): δ = -4.7, -4.2, 17.5, 22.0, 22.4, 25.5, 62.8, 127.7, 127.8, 128.2, 136.7; HRMS (TOF ES⁺): m/z calcd for C₁₅H₂₈NOSSi [(M+H)⁺], 298.1661; found, 298.1669.

Synthesis of sulfinamide 6

A dry round bottom flask was charged with TBDMS protected sulfinamide 5 (1.32 g, 4.44 mmol), and THF (23 mL) under argon and was added TBAF (5.33 mL, 5.33 mmol) at 0 °C. After 1hour, TLC indicated that all starting material was consumed. Then the reaction was quenched with 1 mL of water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, and evaporated under reduced pressure to afford crude sulfinmaide 6. The crude product was purified by column chromatography with ethyl acetate as eluent to afford pure sulfinamide 6 0.8 g (98 %) with 94 % ee starting from 94 % ee thiosulfinate 4, and it was further improved to more than 99 % ee by washing with hexane. HPLC, Dsiacelchiralpak OD-H column, 93:7 Hexanes/ ⁱPrOH; 1.0 mL/min, 254 nm, t = 21.0 min; t_S= 24.9 min; ${\left[\alpha \right]}_D^{25}\text{-}100.2(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.52 (s, 3 H), 1.60 (s, 3 H), 3.69 (br, 2H) 7.24-7.27 (m, 1H), 7.31-7.39 (m, 4H). ¹³C NMR (CDCl₃, 100 MHz): δ = 21.7, 22.5, 61.0, 127.3, 127.5, 127.7, 136.5; HRMS (TOF ES⁺): m/z calcd for C₉H₁₄NOS [(M+H)⁺], 184.0796; found, 184.0790.

General procedure for the synthesis of (R_s)-2-phenylpropyl-2-sulfinyl imines¹⁴

To a stirred solution of sulfinamide 6 (150 mg, 0.818 mmol), in freshly distilled dichloromethane (20 mL), was added respective aldehyde (1.636 mmol), Ti(OEt)₄ (1.22 mL, 5.81 mmol) under argon. The flask was fitted with condenser and refluxed the reaction for 12-16 hours. Then the reaction was quenched with water (5 mL), and the precipitate was filtered through celite pad. The filter cake was washed with dichloromethane, and the filtrate was extracted with the same. The organic layer was dried over anhydrous Na₂SO₄, and evaporated under reduced pressure to afford crude sulfinyl imine. The crude product was purified by column chromatography and hexanes, ethyl acetae mixture (4:1) was used as an eluent mixture to get corresponding sulfinyl imines. In case of glyoxymate, for the synthesis of its imine M.S (4 Å) was used instead of Ti(OEt)₄.

Compound 8a: White crystalline solid; Mp 119-121 °C; ${\left[\alpha \right]}_D^{25}+17.7(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.69 (s, 3 H), 1.75 (s, 3 H), 7.22-7.31 (m, 3H), 7.37-7.46 (m, 5H), 7.65-7.68 (m, 2H), 8.29 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.1, 21.8, 64.4, 127.3, 127.5, 127.8, 128.7, 129.1, 132.2, 133.8, 138.1, 162.6; HRMS (TOF ES⁺): m/z calcd for C₁₆H₁₈NOS [(M+H)⁺], 272.1109; found, 272.1101.

Compound 8b: Pale yellow solid; Mp 98-103 °C; ${\left[\alpha \right]}_D^{25}+34.5(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.68 (s, 3 H), 1.82 (s, 3 H), 7.22-7.35(m, 3H), 7.45-7.53 (m, 5H), 7.82-7.86 (m, 2H), 7.96 (d, J= 8.2 Hz, 1H), 8.70-8.73 (m, 1H), 8.82 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 19.9, 22.6, 64.4, 124.7, 125.0, 126.3, 127.3, 127.6, 127.8, 128.0, 128.6, 129.1, 130.9, 132.5, 133.3, 133.7, 138.6, 162.8. HRMS (TOF ES⁺): m/z calcd for C₂₀H₂₀NOS [(M+H)⁺], 322.1266; found, 322.1256.

Compound 8c: Sticky liquid; ${\left[\alpha \right]}_D^{25}\text{-}53.9(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.68 (s, 3 H), 1.74 (s, 3 H), 2.37 (s, 3 H), 7. 15-7. 17 (m, 2H), 7.21-7.24 (m, 2H), 7.27- 7.33 (m, 3H), 7.37-7.40 (m, 2H), 7.71-7.73 (m, 1H), 8.49 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 19.6, 21.2, 21.9, 64.3, 126.1, 127.4, 127.5, 127.8, 129.2, 131.1, 131.9, 161.6. HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₀NOS [(M+H)⁺], 286.1266; found, 286.1255.

Compound 8d: White solid; Mp 93-95 °C; ${\left[\alpha \right]}_D^{25}+58.3(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.73 (s, 3 H), 1.79 (s, 3 H), 2.43 (s, 3 H), 7.25-7. 29 (m, 3H), 7.33-7.37 (m, 2H), 7.43-7.46 (m, 2H), 7.61- 7.63 (m, 2H), 8.26 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.1, 21.6, 21.8, 64.3, 127.4, 127.5, 127.8, 129.2, 129.4, 131.4, 138.2, 143.0, 162.4; HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₀NOS [(M+H)⁺], 286.1266; found, 286.1261.

Compound 8e: White crystalline solid; Mp 63-65 °C; ${\left[\alpha \right]}_D^{25}+20.1(\mathrm{c}=2.7,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.68 (s, 3 H), 1.74 (s, 3 H), 7.05-7.11 (m, 2H), 7.21-7.30 (m, 3H), 7.36-7.38 (m, 2H), 7.64- 7.67 (m, 2H), 8.10 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.2, 21.9, 64.5, 115.9, 116.1, 127.3, 127.6, 127.8, 130 (d, J = 2.8 MHz), 131.3 (d, J= 8.5 MHz), 138.0, 161.2, 163.8, 166.3; HRMS (TOF ES⁺): m/z calcd for C₁₆H₁₇NOFS [(M+H)⁺], 290.1015; found, 290.1014.

Compound 8f: Light yellow solid; Mp 119-120 °C; ${\left[\alpha \right]}_D^{25}+105.8(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.70 (s, 6 H), 6.49-6.50 (m, 1 H), 6.83-6.84 (m, 1 H), 7.22-7.30 (m, 3H), 7.36-7.38 (m, 2H), 7.57-7.58 (m, 1H), 7.99 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.2, 21.9,64.7, 112.3, 118.6, 127.5, 127.6, 127.8, 137.7, 146.7, 149.6, 150.6; HRMS (TOF ES⁺): m/z calcd for C₁₄H₁₆NO₂S [(M+H)⁺], 262.0902; found, 262.0900.

Compound 8g: Colorless liquid; ${\left[\alpha \right]}_D^{25}\text{-}230.5(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 0.88 (t, J = 6.4 Hz, 6H), 1.73 (s, 3H), 1.74 (s, 3H), 1.81-1.91 (m, 1H), 2.16-2.21 (m, 2H), 7.31-7.33 (m, 1H), 7.35-7.41 (m, 4H), 7.72 (t, J = 5.5 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.6, 21.8, 22.3, 22.5, 25.9, 44.6, 63.1, 127.3, 127.5, 127.8, 137.9, 169.5; HRMS (TOF ES⁺): m/z calcd for C₁₄H₂₂NOS [(M+H)⁺], 252.1422; found, 252.1419.

Compound 8h: White solid; Mp 38-40 °C; ${\left[\alpha \right]}_D^{25}\text{-}197.0(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.04-1.27 (m, 6H), 1.62-1.72 (m, 10H), 2.17-2.21 (m, 1H), 7.27-7.31 (m, 1H), 7.32-7.39 (m, 4H), 7.57 (d, J = 4.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.5, 22.1, 25.2, 25.7, 28.7, 28.8, 43.8, 63.1, 127.4, 127.5, 127.7, 137.8, 172.6. HRMS (TOF ES⁺): m/z calcd for C₁₆H₂₄NOS [(M+H)⁺], 278.1579; found, 278.1570.

Compound 8i: Light yellow solid; Mp 98-100 °C; ${\left[\alpha \right]}_D^{25}\text{-}219.7(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.73 (s, 3 H), 1.78 (s, 3 H), 6.96-7.03 (m, 1 H), 7. 09-7. 13 (m, 1H), 7.31-7.37 (m, 1H), 7.40-7.54 (m, 9H), 8.11 (d, J = 9.2 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 20.9, 21.8,64.2, 125.2, 127.2, 127.5, 127.7, 127.8, 128.7, 130.0, 134.7, 138.1, 146.2, 163.6; HRMS (TOF ES⁺): m/z calcd for C₁₈H₂₀NOS [(M+H)⁺], 298.1266; found, 298.1273.

Compound 8j: Pale yellow liquid; ${\left[\alpha \right]}_D^{25}\text{-}223.6(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.76 (s, 3H), 1.78 (s, 3H), 2.16 (s, 3H), 7.21-7.37 (m, 5H), 7.41-7.43 (m, 3H), 7.69 (d, J = 7.8 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 18.6, 19.4, 22.9, 64.5, 127.2, 127.6, 127.6, 128.1, 128.3, 131.5, 138.2, 139.2, 176.2. HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₀NOS [(M+H)⁺], 286.1266; found, 286.1255.

Compound 8k: Colorless liquid; ${\left[\alpha \right]}_D^{25}\text{-}127.0(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.29 (t, J = 7.3 Hz, 3H), 1.72 (d, J = 3.2 Hz, 6H), 4.25-4.28 (m, 2H), 7.25-7.32 (m, 5H), 7.51 (d, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 14.0, 21.4, 22.7, 62.2, 65.9, 127.4, 127.9, 128.1, 136.6, 155.1, 160.8; HRMS (TOF ES⁺): m/z calcd for C₁₃H₁₈NO₃S [(M+H)⁺], 268.1007; found, 268.1012.

Compound 8l: Yellow color solid; Mp131-133 °C; ${\left[\alpha \right]}_D^{25}+102.8(\mathrm{c}=1.85,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.72 (s, 3H), 1.79 (s, 3H), 7.19-7.29 (m, 3H), 7.34-7.36 (m, 2H), 7.79 (d, J = 8.2 Hz, 2H), 8.24-8.26(m, 3H);.¹³C NMR (CDCl₃, 100 MHz): δ = 21.6, 22.0, 65.3, 124.0, 127.2, 127.8, 127.9,, 129.7, 137.4,, 138.6, 149.6, 160.3; HRMS (TOF ES⁺): m/z calcd for C₁₆H₁₇N₂O₃S [(M+H)⁺], 317.0960; found, 317.0969.

General procedure for the addition of allylmagnesium bromide unto (R_s)-2-phenylpropyl-2-sulfinyl imines

A 25 mL flame dried round bottomed flask was charged under argon with N-sulfinyl imine (0.11 mmol), and freshly distilled toluene (10 mL). At room temperature allylmagnesium bromide (0.22 mmol, 1.0 M solution in ether) was added slowly. Completion of the starting material was monitored by thin layer chromatography. At this stage saturated ammonium chloride (1mL) was added to the reaction mixture. 3.0 mL of water was then added to the reaction and extracted with 2 × 5 mL of ethyl acetate. The combined organic layers were washed with water (1 × 5 mL), brine solution (1 × 5 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated and the crude mixture was co-concentrated with hexanes. The products were dried under high vacuum. The solid products were washed with minimum amount of hexanes or heptanes to afford pure product without column chromatography. The oil products obtained in this addition reaction were also more than 99 % pure after washing with water and co-concentration with hexanes were performed.

Compound 9a: White solid; Mp109-110 °C; ${\left[\alpha \right]}_D^{25}\text{-}77.6(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.56 (s, 3 H), 1.63 (s, 3 H), 2.14- 2.22 (m, 1H), 2.33- 2.38 (m, 1H), 3.05 (s, 1H), 4.24- 4.27 (m, 1H), 4.76- 4.84 (m, 2H), 5.36- 5.41 (m, 1H), 7.13-7.15(m, 2H), 7.23-7.29 (m, 3H), 7.35-7.42 (m, 3H), 7.45- 7.47 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.4, 23.3, 43.3, 56.3, 61.7, 119.0, 127.3, 127.5, 127.7, 127.9, 128.2, 128.3, 133.3, 137.2, 141.5; HRMS (TOF ES⁺): m/z calcd for C₁₉H₂₄NOS [(M+H)⁺], 314.1579; found, 314.1573.

Compound 9b: Pale yellow solid; Mp114-116 °C; ${\left[\alpha \right]}_D^{25}\text{-}99.7(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.58 (s, 3 H), 1.65 (s, 3 H), 2.34- 2.41 (m, 1H), 2.56- 2.60 (m, 1H), 3.24 (d, J = 2.3, 1H), 4.79- 4.87 (m, 2H), 5.11-5.14 (m, 1H), 5.41- 5.46 (m, 1H), 7.27-7.28 (m, 1H), 7.34-7.51 (m, 8H), 7.74 (d, J = 8.2, 1H), 7.83-7.85 (m, 1H), 8.05-8.07 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.5, 23.1, 42.1, 52.7, 61.8, 119.1, 122.9, 124.8, 125.1, 125.5, 126.0, 127.7, 127.9, 128.3, 128.9, 130.7, 133.3, 133.8, 137.0, 137.3; HRMS (TOF ES⁺): m/z calcd for C₂₃H₂₆NOS [(M+H)⁺], 364.1735; found, 364.1733.

Compound 9c: White solid; Mp 75-78 °C; ${\left[\alpha \right]}_D^{25}\text{-}76.0(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.56 (s, 3 H), 1.64 (s, 3 H), 2.11- 2.20 (m, 1H), 2.31- 2.36 (m, 4H), 3.05 (s, 1H), 4.51-4.53 (m, 1H), 4.78- 4.84 (m, 2H), 5.37- 5.44 (m, 1H), 7.09-7.15 (m, 4H), 7.35-7.42 (m, 3H), 7.46- 7.48 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 19.2, 22.2, 23.4, 42.0, 51.8, 61.6, 118.9, 125.9, 126.7, 127.1, 127.6, 127.8, 128.2, 130.3, 133.3, 135.6, 137.1, 139.3; HRMS (TOF ES⁺): m/z calcd for C₂₀H₂₆NOS [(M+H)⁺], 328.1735; found, 328.1734.

Compound 9d: colorless liquid; ${\left[\alpha \right]}_D^{25}\text{-}52.8(\mathrm{c}=1.4,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.56 (s, 3 H), 1.63 (s, 3 H), 2.13- 2.20 (m, 1H), 2.31- 2.37 (m, 4H), 3.03 (s, 1H), 4.21- 4.23 (m, 1H), 4.76- 4.83 (m, 2H), 5.37- 5.41 (m, 1H), 7.02-7.09 (m, 4H), 7.35-7.41 (m, 3H), 7.45-7.47 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.1, 22.3, 23.3, 43.3, 56.0, 61.6, 118.9, 127.2, 127.7, 127.8, 128.2, 129.0, 133.4, 137.1, 137.2, 138.4; HRMS (TOF ES⁺): m/z calcd for C₂₀H₂₆NOS [(M+H)⁺], 328.1735; found, 328.1745.

Compound 9e: Crystalline solid; Mp 76-81 °C; ${\left[\alpha \right]}_D^{25}\text{-}72.5(\mathrm{c}=1.35,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.55 (s, 3 H), 1.63 (s, 3 H), 2.10- 2.18 (m, 1H), 2.29- 2.34 (m, 1H), 3.06 (s, 1H), 4.21- 4.24 (m, 1H), 4.77- 4.85 (m, 2H), 5.33- 5.40 (m, 1H), 6.92-6.97 (m, 2H), 7.05-7.09 (m, 2H), 7.35-7.45 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.4, 22.9, 43.2, 55.6, 61.7, 115.1, 115.3, 119.2, 127.6, 127.9, 128.3, 128.8, 128.9, 133.1, 137.1, 137.2, 160.8, 163.3; HRMS (TOF ES⁺): m/z calcd for C₁₉H23NOFS [(M+H)⁺], 332.1484; found, 332.1492.

Compound 9f: Light yellow color liquid; ${\left[\alpha \right]}_D^{25}\text{-}52.3(\mathrm{c}=1.18,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.55 (s, 3 H), 1.65 (s, 3 H), 2.36- 2.45 (m, 2H), 2.94 (d, J = 4 Hz, 1H), 4.34- 4.38 (m, 1H), 4.78-4.86 (m, 2H), 5.36- 5.43 (m, 1H), 6.06-6.07 (m, 1H), 6.26-6..27 (m, 1H), 7.31-7.46 (m, 6H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.0, 23.7, 39.6, 51.3, 61.8, 107.2, 109.9, 119.2, 127.6, 127.8, 128.2, 132.6, 136.9, 141.9, 153.9; HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₂NO₂S [(M+H)⁺], 304.1371; found, 304.1371

Compound 9g: Colorless liquid; ${\left[\alpha \right]}_D^{25}\text{-}56.4(\mathrm{c}=2.25,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 0.74-0.84 (m, 6H), 1.05-1.21 (m, 2H), 1.44-1.51 (m, 1H), 1.56 (s, 3H), 1.65 (s, 3H), 2.12- 2.16 (m, 2H), 2.56 (d, J = 7.3 Hz, 1H), 3.19- 3.22 (m, 1H), 4.75-4.86 (m, 2H), 5.45- 5.52 (m, 1H), 7.28-7.37 (m, 3H), 7.41-7.43 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 21.9, 22.6, 22.9, 23.1, 24.3, 40.7, 44.2, 52.8, 61.9, 118.6, 127.5, 127.7, 128.1, 133.4, 137.5; HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₈NOS [(M+H)⁺], 294.1892; found, 294.1890.

Compound 9h: Colorless liquid; ${\left[\alpha \right]}_D^{25}\text{-}70.4(\mathrm{c}=2.25,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 0.69-0.88 (m, 2H), 0.96-1.14 (m, 3H), 1.27-1.32 (m, 1H), 1.44-1.53 (m, 2H), 1.57-1.65 (m, 9H), 2.01-2.17 (m, 2H), 2.55 (d, J= 6.4 Hz, 1H), 2.93-2.98 (m, 1H), 4.69-4.83 (m, 2H), 5.43-5.51(m, 1H), 7.27-7.32 (m, 1H), 7.34-7.38 (m, 2H), 7.42-7.44(m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.8, 22.9, 26.1, 26.2, 26.4, 28.3, 28.8, 36.9, 40.9, 58.9, 62.0, 118.3, 127.5, 127.6, 128.1, 134.0, 137.6; HRMS (TOF ES⁺): m/z calcd for C₁₉H₃₀NOS [(M+H)⁺], 320.2048; found, 320.2058.

Compound 9i: Pale yellow color liquid; ${\left[\alpha \right]}_D^{25}\text{-}76.4(\mathrm{c}=2.15,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.66 (s, 3 H), 1.72 (s, 3 H), 2.14- 2.21 (m, 1H), 2.30- 2.36 (m, 1H), 2.9 (s, 1H), 4.87-4.95 (m, 2H), 5.51- 5.58 (m, 1H), 5.90- 5.95 (m, 1H), 6.49-6.53 (m, 1H), 7.27-7.31 (m, 1H), 7.33-7.45 (m, 7H), 7.50-7.52 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.4, 23.4, 41.1, 55.1, 61.6, 118.9, 126.4, 127.6, 127.8, 128.2, 128.4, 129.6, 132.1, 133.0, 136.4, 137.2; HRMS (TOF ES⁺): m/z calcd for C₂₁H₂₆NOS [(M+H)⁺], 340.1735; found, 340.1729.

Compound 9j: Light pink color liquid; Mp 116-119 °C; ${\left[\alpha \right]}_D^{25}\text{-}52.5(\mathrm{c}=1.0,{\mathrm{CHCl}}_3)$; ¹H NMR (CDCl₃, 400 MHz): δ = 1.62 (d, J = 4.1 Hz, 6H), 1.67 (s, 3 H), 2.37- 2.49 (m, 2H), 3.22 (br, 1H), 4.82- 4.87 (m, 2H), 5.23- 5.31 (m, 1H), 7.15-7.24 (m, 5H), 7.32-7.42 (m, 3H), 7.47-7.50 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.5, 23.1, 27.7, 49.0, 59.7, 62.4, 120.3, 126.1, 126.7, 127.6, 127.7, 128.1, 128.3, 132.4, 137.9, 145.4; HRMS (TOF ES⁺): m/z calcd for C₂₀H₂₆NOS [(M+H)⁺], 328.1735; found, 328.1741.