Design, synthesis, and applications of chiral N-2-phenyl-2-propyl sulfinyl imines for group-assisted purification (GAP) asymmetric synthesis

Article abstract of DOI:10.1021/jo400354r

A new chiral (R_s)-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 which contains a newly generated polar group 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.

Full text of DOI:10.1021/jo400354r

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Article
Design, synthesis and applications of chiral N-2-phenyl-2-propyl sulfinyl
imines for Group-Assisted Purification (GAP) asymmetric synthesis
Suresh Pindi, Jianbin Wu, and Guigen Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400354r • Publication Date (Web): 15 Mar 2013
Downloaded from http://pubs.acs.org on March 15, 2013
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Design, synthesis and applications of chiral N-2-
phenyl-2-propyl sulfinyl imines for Group-Assisted
Purification (GAP) asymmetric synthesis
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Suresh Pindi,† Jianbin Wu† and Guigen Li*,†, ‡
†Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
‡Institute of Chemistry & BioMedical Sciences (ICBMS), Nanjing University, Nanjing 210093, P. R.
China
E-mail: guigen.li@ttu.edu.
RECEIVED DATE
*CORRESPONDING AUTHOR FAX: 001-806-742-1289.
Table of Contents (TOC) graphic:
O
S
O
S
Me
Me
Toluene
NH
N
MgBr
R
+
Me
R'
rt, 30- 50 min
Me
R
(GAP)
>99%de)
R'
(91%
-
quant; 92
-
Chromophorable, stable and GAP
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 (Rs)-thiosulfinate was also
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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.
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KEYWORDS: N-sulfinyl imine, sulfinamide, group-assisted purification (GAP), allylic amines
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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,4 N-
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
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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.
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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
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solubility so that the GAP chemistry can be accomplished more efficiently (Scheme 1).
Scheme 1
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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
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
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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.
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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 SN2 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).
Scheme 3
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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).
Table 1 Results of N-(Rs)-2-phenylpropyl-2-sulfinyl imines
Entry
Aldehyde or
ketone
R2
R3
Product
Yield (%)a
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Phenyl
1-Naphthyl
2-Me-phenyl
4-Me-phenyl
4-F-phenyl
2-furyl
H
H
8a
8b
8c
8d
8e
8f
98
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92
52
45b
80c
3
H
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4
H
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H
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H
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7g
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iso-butyl
H
8g
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8
Cyclohexyl
trans-PhCH=CH
Phenyl
H
9
H
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7j
Me
H
8j
7k
7l
-COOEt
8k
8l
4-NO2-phenyl
H
aIsolated yields after column chromatography. 4 Å M.S. were used instead of Ti(OEt)4.
b
cReaction carried out at room temperature.
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
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stereochemically efficient under room temperature conditions, or, very low temperature is
necessary.
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Initially, we began our investigation with the addition of allylmagenisium bromide to N-sulfinyl
imine 8a in THF as solvent at -78 ºC. Although the product was formed in a quantitative yield,
no diastereoselectivity (~1:1) was observed. However, when the reaction was performed at 0 ºC,
the diastereoselectivity was enhanced to 5:1, and at room temperature it was further improved to
8:1. Raising the temperature to 50 ºC 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.
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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
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give in >99 % purity without the use of column chromatography or recrystallization, which also
belongs to the GAP chemistry as defined broadly.
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Table 2 Results of the allylmagnesium Grignard addition reaction to N-(Rs)-2-phenylpropyl-2-
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sulfinyl imines
Entry
Imine
8a
Product
9a
% yielda,b
Quant
Quant
95
% dec
> 99
> 99
> 99
97
1
2
8b
8c
9b
3
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4
8d
8e
9d
99
5
9e
94
98
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96
98
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8g
8h
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Quant
99
98
8
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97
9
9i
94
92
10
8j
9j
91
> 99
aIsolated yields after washing with hexanes. combined yields of both the diastereomers.
b
cDiastereoselectivity was determined by using H-NMR of crude samples; >99% de means only
1
on isomer was observed.
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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).
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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
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Me
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N
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Br
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
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points were uncorrected. High-resolution mass spectra for all the new compounds were collected
on a Q-TOF.
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Synthesis of disulfide 220
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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
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under reduced pressure to afford crude (Rs)-thiosulfinate 4 as white solid, which was washed
with hexanes to provide 7.9 g (75 %) of pure (Rs)-thiosulfinate 4 with 85 % ee. The enantiomeric
excess was further improved to 99 % by washing with hexanes twice (10 mL of hexanes required
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i
for 1.0 g of thiosulfinate). HPLC Diacelchiralpak AS-H column, 98:2 Hexanes/ PrOH; 1.0
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mL/min, 230 nm, tR= 14.7 min; tS= 19.1 min;
[α
]
+126.2 (c = 1.0, CHCl3); H NMR (CDCl3,
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400 MHz): δ = 1. 63 (s, 3H), 1.77-1.82 (m, 9H), 7.24-7.41 (m, 1H); C 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
i
white solid with 94 % ee. HPLC, Diacelchiralpak AS-H column, 93:7 Hexanes/ PrOH; 1.0
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mL/min, 254 nm, tS= 4.8 min; tR= 7.2 min;
[α
]
-31.8 (c = 1.0, CHCl3); H 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),
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7.28-7.34 (m, 1H), 7.35-7.40 (m, 3H). C NMR (CDCl3, 100 MHz): δ = -4.7, -4.2, 17.5, 22.0,
5
6
22.4, 25.5, 62.8, 127.7, 127.8, 128.2, 136.7; HRMS (TOF ES+): m/z calcd for C15H28NOSSi
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[(M+H)+], 298.1661; found, 298.1669.
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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
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column, 93:7 Hexanes/ iPrOH; 1.0 mL/min, 254 nm, tR= 21.0 min; tS= 24.9 min;
[α
]
-100.2 (c
= 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 1.52 (s, 3 H), 1.60 (s, 3 H), 3.69 (br, 2H) 7.24-
13
7.27 (m, 1H), 7.31-7.39 (m, 4H). C 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 (Rs)-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.
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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.
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Compound 8a: White crystalline solid; Mp 119-121 ºC;
[α
]
+17.7 (c = 1.0, CHCl3); H 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-
13
7.68 (m, 2H), 8.29 (s, 1H); C 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.
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Compound 8b: Pale yellow solid; Mp 98-103 ºC;
[α
]
+34.5 (c = 1.0, CHCl3); H 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-
13
7.86 (m, 2H), 7.96 (d, J= 8.2 Hz, 1H), 8.70-8.73 (m, 1H), 8.82 (s, 1H); C 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.
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Compound 8c: Sticky liquid;
[α
]
-53.9 (c = 1.0, CHCl3); H 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.
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Compound 8d: White solid; Mp 93-95 ºC;
[α
]
+ 58.3 (c = 1.0, CHCl3); 1H NMR (CDCl3, 400
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7
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-
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7.46 (m, 2H), 7.61- 7.63 (m, 2H), 8.26 (s, 1H); C NMR (CDCl3, 100 MHz): δ = 21.1, 21.6,
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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.
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Compound 8e: White crystalline solid; Mp 63-65 ºC;
[α
]
+20.1 (c = 2.7, CHCl3); H 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-
13
7.38 (m, 2H), 7.64- 7.67 (m, 2H), 8.10 (s, 1H); C 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.
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Compound 8f: Light yellow solid; Mp 119-120 ºC;
[α
]
+105.8 (c = 1.0, CHCl3); H 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),
13
7.36-7.38 (m, 2H), 7.57-7.58 (m, 1H), 7.99 (s, 1H); C 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.
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Compound 8g: Colorless liquid;
[α
]
-230.5 (c = 1.0, CHCl3); 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-
13
7.33 (m, 1H), 7.35-7.41 (m, 4H), 7.72 (t, J = 5.5 Hz, 1H); C 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.
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Compound 8h: White solid; Mp 38-40 ºC;
[α
]
-197.0 (c = 1.0, CHCl3); 1H NMR (CDCl3, 400
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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.
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Compound 8i: Light yellow solid; Mp 98-100 ºC;
[α
]
-219.7 (c = 1.0, CHCl3); H 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.
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Compound 8j: Pale yellow liquid;
[α
]
-223.6 (c = 1.0, CHCl3); 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
13
Hz, 2H); C 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.
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Compound 8k: Colorless liquid;
[α
]
-127.0 (c = 1.0, CHCl3); 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,
13
1H); C 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.
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Compound 8l: Yellow color solid; Mp131-133 ºC;
[α
]
+102.8 (c = 1.85, CHCl3); H NMR
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8
9
(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.
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General procedure for the addition of allylmagnesium bromide unto (Rs)-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 x 5 mL of ethyl acetate. The combined organic layers were washed with water (1 x 5 mL),
brine solution (1 x 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.
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Compound 9a: White solid; Mp109-110 ºC;
[α
]
-77.6 (c = 1.0, CHCl3); H 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),
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7.35-7.42 (m, 3H), 7.45- 7.47 (m, 2H); C NMR (CDCl3, 100 MHz): δ = 22.4, 23.3, 43.3, 56.3,
5
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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+):
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m/z calcd for C19H24NOS [(M+H)+], 314.1579; found, 314.1573.
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Compound 9b: Pale yellow solid; Mp114-116 ºC;
[α
]
-99.7 (c = 1.0, CHCl3); 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.
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Compound 9c: White solid; Mp 75-78 ºC;
[α
]
-76. 0 (c = 2.0, CHCl3); 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),
13
7.46- 7.48 (m, 2H); C 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.
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Compound 9d: colorless liquid;
[α
]
-52. 8 (c = 1.4, CHCl3); 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,
13
2H); C 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.
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Compound 9e: Crystalline solid; Mp 76-81 ºC;
[α
]
-72. 5 (c = 1.35, CHCl3); 1H NMR (CDCl3,
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6
7
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),
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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,
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2H), 7.35-7.45 (m, 5H); C 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.
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Compound 9f: Light yellow color liquid;
[α
]
-52. 3 (c = 1.18, CHCl3); H 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,
13
6H); C 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
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D
Compound 9g: Colorless liquid;
[α
]
-56. 4 (c = 2.25, CHCl3); 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),
13
7.28-7.37 (m, 3H), 7.41-7.43 (m, 2H); C 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.
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Compound 9h: Colorless liquid;
[α
]
-70. 4 (c = 2.25, CHCl3); H 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-
13
5.51(m, 1H), 7.27-7.32 (m, 1H), 7.34-7.38 (m, 2H), 7.42-7.44(m, 2H); C NMR (CDCl3, 100
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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.
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Compound 9i: Pale yellow color liquid;
[α
]
-76. 4 (c = 2.15, CHCl3); H 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),
13
7.33-7.45 (m, 7H), 7.50-7.52 (m, 2H); C 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.
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Compound 9j: Light pink color liquid; Mp 116-119 ºC;
[α
]
-52.5 (c = 1.0, CHCl3); H 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,
13
2H); C 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.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from NIH (R21DA031860-01, Li, USA), Robert
A. Welch Foundation (D-1361, Li, USA) and Jiangsu Rennovation Team Program (China) for
their generous support. We also thank NSF grant CHE-1048553 and CRIF program (USA) for
supportinbg NMR facility. We thank Dr. David B. Cordes for X-ray analysis and our co-workers
Dr. Jianbo Xie and Dr. Gaunghui An for their assistance.
Supporting Information Available. 1H and 13C NMR spectra of all pure products are available
free of charge via the Internet at http://pubs.acs.org.
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