Reversal diastereoselectivity between the organomagnesium and organolithium reagents on Chiral N-tert-butylsulfinylaldimines for the preparation of chiral amines

Article abstract of DOI:10.1080/00397911.2014.909487

The asymmetric synthesis of both the enantiomer of chiral amines from the single chiral source of N-tert-butylsulfinylaldimines (3) by simply changing the organometallic reagents through diastereoselective addition. An efficient enantioselective synthesis of chiral amines including (S)-3-methyl-1-(2- piperidin-1-yl-phenyl)butyl amine (6a), a key intermediate to prepare antidiabetic drug repaglinide (1), is reported.

Full text of DOI:10.1080/00397911.2014.909487

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Reversal Diastereoselectivity
Between the Organomagnesium and
Organolithium Reagents on Chiral N-
Tert-Butylsulfinylaldimines for the
Preparation of Chiral Amines
Chinnapillai Rajendiran a , Periyandi Nagarajan a , A. Naidu b & P. K.
Dubey b
a Suven Life Sciences Ltd., Research and Development Center ,
Hyderabad , India
b Department of Chemistry , J.N.T. University , Hyderabad , India
Accepted author version posted online: 09 Jun 2014.Published
online: 08 Aug 2014.
To cite this article: Chinnapillai Rajendiran , Periyandi Nagarajan , A. Naidu & P. K. Dubey (2014)
Reversal Diastereoselectivity Between the Organomagnesium and Organolithium Reagents on Chiral
N-Tert-Butylsulfinylaldimines for the Preparation of Chiral Amines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:20, 2936-2942,
DOI: 10.1080/00397911.2014.909487
To link to this article: http://dx.doi.org/10.1080/00397911.2014.909487
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Synthetic Communications1, 44: 2936–2942, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.909487
REVERSAL DIASTEREOSELECTIVITY BETWEEN THE
ORGANOMAGNESIUM AND ORGANOLITHIUM
REAGENTS ON CHIRAL N-TERT-
BUTYLSULFINYLALDIMINES FOR THE PREPARATION
OF CHIRAL AMINES
Chinnapillai Rajendiran,1 Periyandi Nagarajan,1 A. Naidu,2
and P. K. Dubey2
1Suven Life Sciences Ltd., Research and Development Center, Hyderabad,
India
2Department of Chemistry, J.N.T. University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract The asymmetric synthesis of both the enantiomer of chiral amines from the single
chiral source of N-tert-butylsulfinylaldimines (3) by simply changing the organometallic
reagents through diastereoselective addition. An efficient enantioselective synthesis of
chiral amines including (S)-3-methyl-1-(2-piperidin-1-yl-phenyl)butyl amine (6a), a key
intermediate to prepare antidiabetic drug repaglinide (1), is reported.
Keywords 1-(2-Bromophenyl)piperidine;
n-butyraldehyde; n-propionaldehyde; S(–)-tert-butanesulfinamide; titanium tetraethoxide
isobutyraldehyde;
isovaleraldehyde;
Received December 5, 2013.
Address correspondence to Chinnapillai Rajendiran, Suven Life Sciences Ltd., R&D Center, Plot
No. 18, Phase-III, IDA, Jeedimetla, Hyderabad 500055, India. E-mail: nagarajan@suven.com
2936

ASYMMETRIC SYNTHESIS OF CHIRAL AMINES
2937
INTRODUCTION
In recent years the asymmetric synthesis of chiral amines occupied a prominent
place in synthetic organic chemistry. The diasteroselective addition of organometal-
lic reagents to chiral sulfinimines is a useful method for the preparation of chiral
amine as a building block for many pharmaceutically important chiral drugs and
intermediates. Ellman’s groups has popularized the use of chiral auxiliaries tert-
butanesulfinamide for the synthesis of optically active amines.[1] Both enantiomers
of (R)- and (S)-tert-butane sulfinamide are readily available, easy to remove by
acidic conditions, and excellent asymmetric chiral auxiliaries for the preparation
of enantiopure amines.
Recently we have reported[2] the diastereoselective synthetic method for the
preparation of both enantiomers of chiral amines (6a and 8a) from a single chiral
aromatic N-tert-butyl sulfinylaldimines source by simply changing the aliphatic
organometallic reagents such as isobutyl magnesium bromide and isobutyllithium.
(S)-3-Methyl-1-(2-piperidin-1-yl-phenyl)butylamine (6a) is a key raw material for
the preparation of the drug repaglinide (1), which is used for lowering the blood
glucose levels in patients suffering from type II diabetes mellitus (NIDDM)[3–7]
(Figs. 1 and 2).
In continuation of our studies on chiral amine synthesis, we further investi-
gated an efficient method to synthesize chiral amines that would enable us to
prepare both the product antipodes in high stereoselectivity and also could be
amenable to preparing a variety of chiral amine of both isomers. The studies
relate to the preparation of chiral amines from aliphatic aldehydes of the general
formula 2 and aromatic halides of the general formula 4 as starting materials. As
expected we found that the reverse diastereoselective nucleophilic addition of
organic metallic reagents to aliphatic N-tert-butylsulfinylaldimines (3) gave chiral
amines. Herein we report the diastereoselective addition of organomagnesium
reagents and organolithium reagents to same chiral aliphatic N-tert-butylsulfiny-
laldimines as the key step in the construction of both enantiomers of the same
chiral amines.
Figure 1. Structure of repaglinide.

2938
C. RAJENDIRAN ET AL.
Figure 2. Structure of (S)-3-methyl-1-(2-piperidin-1-yl-phenyl)butylamine.
RESULTS AND DISCUSSION
Several resolution methods have been reported for the preparation of enantio-
pure chiral amine 6a.[8–13] Kinetic resolution of racemic mixture of enantiomers is
one of the current method for preparing enantiomerically pure chiral amines. How-
ever, these processes suffer from disadvantages of poor yields and required multiple
purifications. As part of our research program we aimed to develop the stereocon-
trolled synthesis of chiral amines used in the bioactive molecules. We previously
reported good results on diastereoselectivity in preparing the chiral amines in our
earlier research using chiral aromatic N-tert-butylsulfinylaldimines. Herein we
attempted to use the same strategy by using aliphatic N-tert-butylsulfinylaldimines
of the formula 3 to get the both the enantiomers by changing the nucleophilic
sources.
Condensation of isoveraldehyde (2a) with S(–)-tert-butanesulfinamide in the
presence of titanium tetraethoxide as a water scaventure in tetrahydrofuran (THF)
Scheme 1. Diastereoselective reaction of organometallic reagents with N-tert-butylsulfinylaldimines.

ASYMMETRIC SYNTHESIS OF CHIRAL AMINES
2939
Table 1. Diastereoselective reaction of organomagnesium reagents with N-tert-butylsulfinylaldimine
(3a–3d)
Chiral HPLC (%)
Entry
R
R0
R00
R000
-H
Product
R
S
SOR Yield (%)
1
2
-CH2CH(CH3)2
-CH2CH(CH3)2
-H
-H
6a
6b
10.29
89.71
92.82
þ5.4
76.8
61.4
-H
6.66
þ17.8
3
4
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-H
-Cl
-H
-H
-H
-H
-H
6c
6d
6e
6f
8.44
19.17
10.67
7.69
91.56
80.83
85.94
92.31
85.16
93.67
87.00
98.12
99.05
þ20.4
þ15.3
þ17.0
þ6.0
47.4
62.6
53.9
70.0
53.1
73.8
65.0
70.0
68.6
5
-Cl
-H
-H
-Cl
6
-H
7
-CH3
-H
-H
-H
-CH3
-H
-H
-H
6g
6h
6i
14.84
6.33
þ16.9
þ5.5
8
9
-CH3
-H
-OCH3
13.00
1.88
0.95
þ5.7
10
11
-H
-H
-OCH3
-H
6j
6k
þ21.8
þ14.8
12
13
-CH2CH(CH3)2
-CH2CH(CH3)2
-H
-H
-H
-H
6l
38.72
13.76
61.28
86.24
þ4.1
44.8
61.9
6m
þ18.5
14
15
-CH2CH(CH3)2
-CH2CH3
-H
-H
-H
6n
6o
3.05
1.30
96.95
98.70
þ14.3
þ5.1
72.7
62.1
-H
16
17
18
-CH2CH3
-CH2CH3
-CH2CH3
-H
-CH3
-H
-H
-H
-H
-H
-H
6p
6q
6r
—
4.85
10.94
100.0
95.15
89.06
þ15.7
þ15.3
þ11.2
72.3
76.4
75.0
-CH3
19
-CH(CH3)2
-H
-H
6s
39.57
60.43
þ2.7
57.6
20
21
22
-CH(CH3)2
-CH(CH3)2
-CH(CH3)2
-H
-CH3
-H
-H
-H
-H
-H
-H
6t
6u
6v
—
3.23
15.84
100.0
96.77
84.16
þ3.6
þ8.3
þ3.5
81.7
73.8
80.3
-CH3
23
-CH2CH2CH3
-H
-H
6w
1.54
98.46
þ5.8
58.7
24
25
26
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-H
-CH3
-H
-H
-H
-H
-H
-H
6x
6y
6z
0.98
—
99.02
100.0
96.29
þ14.6
þ10.0
þ12.4
87.8
79.3
76.0
-CH3
3.71
solvent at reflux temperature gave N-tert-butylsulfinylaldimine (3a). The addition of
Grignard reagent 2-piperidin-1-yl-phenylmagnesium bromide (prepared from
1-(2-bromophenyl)-piperidine (4a) and magnesium in THF solvent) to sulfinylaldi-
mine (3a) to get diastereosulfinamine (5) and hydrolysis with alcoholic hydrochloric
acid gave a major chiral amine S-Isomer (6a). Similarly the addition of 2-piperidin-1-
yl-phenyllithium reagent (prepared from 1-(2-bromophenyl)-piperidine (4a) and
n-butyllithium in THF solvent at ꢀ40 to ꢀ60 ꢁC) to sulfinylaldimine (3a) to get
sulfinamine (7) followed by hydrolysis gave the major R-chiral amine (8a). Hence
we could achieve both enantiomers of chiral amines (6a and 8a) from the single chiral
sulfinylaldimine (3a) source. Further we confirmed the product of (S)-chiral amine
(6a) obtained from this method by making the drug repaglinide (1).
Having discovered the encouraging results from our results, we have extended
our studies to generalize and understand the diastereoselectivity on N-tert-butyl

2940
C. RAJENDIRAN ET AL.
Table 2. Diastereoselective reaction of organolithium reagents with N-tert-butylsulfinyl aldimine (3a–3d)
Chiral HPLC (%)
Entry
R
R0
R00
R000
-H
Product
R
S
SOR Yield (%)
1
2
-CH2CH(CH3)2
-CH2CH(CH3)2
-H
-H
8a
8b
67.38
82.13
32.62
17.87
ꢀ2.5
ꢀ10.1
69.2
65.3
-H
3
4
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH(CH3)2
-H
-Cl
-H
-H
-H
-H
-H
8c
8d
8e
8f
66.87
54.98
71.70
68.38
54.25
72.89
72.21
73.85
82.66
33.13
45.02
28.30
31.62
45.75
27.11
27.79
26.15
17.34
ꢀ10.4
ꢀ2.4
ꢀ8.5
ꢀ7.9
ꢀ1.1
ꢀ2.1
ꢀ8.3
ꢀ8.9
ꢀ5.8
58.7
64.7
56.6
61.9
47.8
79.7
59.0
57.7
60.4
5
-Cl
-H
-H
-Cl
6
-H
7
-CH3
-H
-H
-H
-CH3
-H
-H
-H
8g
8h
8i
8
9
-CH3
-H
-OCH3
10
11
-H
-H
OCH3
-H
8j
8k
12
13
-CH2CH(CH3)2
-CH2CH(CH3)2
-H
-H
-H
-H
8 l
62.48
59.54
37.42
40.46
ꢀ3.1
38.4
66.1
8 m
ꢀ8.2
14
15
-CH2CH(CH3)2
-CH2CH3
-H
-H
-H
8n
8o
85.95
54.86
14.05
45.14
ꢀ9.3
ꢀ1.2
75.9
65.7
-H
16
17
18
-CH2CH3
-CH2CH3
-CH2CH3
-H
-CH3
-H
-H
-H
-H
-H
-H
8p
8q
8r
100.0
95.11
87.85
–
ꢀ15.3
ꢀ13.7
ꢀ9.9
88.6
82.3
79.5
4.89
12.15
-CH3
19
-CH(CH3)2
-H
-H
8 s
83.52
16.48
ꢀ3.5
66.5
20
21
22
-CH(CH3)2
-CH(CH3)2
-CH(CH3)2
-H
-CH3
-H
-H
-H
-H
-H
-H
8t
8u
8v
98.09
66.44
77.02
1.91
33.56
22.98
ꢀ4.2
ꢀ4.5
ꢀ3.2
80.1
78.4
75.6
-CH3
23
-CH2CH2CH3
-H
-H
8w
57.21
42.19
ꢀ1.1
63.2
24
25
26
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-H
-CH3
-H
-H
-H
-H
-H
-H
8x
8y
8z
62.90
53.01
52.91
37.10
46.99
47.91
ꢀ3.7
ꢀ0.3
ꢀ0.9
88.7
85.2
81.1
-CH3
sulfinylaldimine (3a) by carrying out the experiments with different aromatic halides
(4b–4n). All the halides gave the expected reverse diastereoselectivity in the reactions.
Further we extended with different aliphatic N-tert-butylsulfinylaldimines (3b–3d)
prepared from n-propanaldehyde (2b), isobutyraldehyde (2c), and n-butyraldehyde
(2d), which were reacted with organometallic reagents prepared from aromatic halides
(4a, 4c, 4g, and 4i) and gave the expected distereoselectivity. In brief the organomag-
nesium reagents provided greater diastereoselectivities and organolithium reagents
substantially lower diastereoselectivities in the preparation of chiral amines. These
reactions are summarized in Scheme 1, and the results are tabulated in Tables 1 and 2.
CONCLUSIONS
In conclusion, we have demonstrated and expanded our earlier study to reverse
the diastereoselectivity of organometallic anions to chiral N-tert-butylsulfinylaldimines

ASYMMETRIC SYNTHESIS OF CHIRAL AMINES
2941
to get the enantiomers of chiral amines. This procedure gives good yield with good
diastereoselectivity and can be applied to prepare the optically active pure chiral
amines of both enantiomers, which is highly useful for synthetic organic chemistry.
EXPERIMENTAL
Melting points were taken on a Branstead melting-point apparatus (model
9300) in open capillary tubes and are uncorrected. Infrared (IR) spectra were
1
recorded as neat or KBr using a Perkin-Elmer 2000 FT-IR spectrometer. Both H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker
NMR spectrometer instrument. Deuterated reagents were used as solvents and tetra-
methylsilane (TMS) was used as internal reference standard. Chemical shift values
are expressed in parts per million (d) values and coupling constants are expressed
in hertz. All mass spectra were recorded using the electrospray ionization (ESI) tech-
nique on an API 2000, ABS triple quadrupole instrument. Chiral high-performance
liquid chromatography (HPLC) was done using a chiral Cel OD-H 250 ꢂ 436 mm
column. The purity of all the compounds was routinely checked by thin-layer
chromatography (TLC) on silica-gel-coated plates. Column chromatography was
performed using 60- to 120-mesh silica gel and executed under nitrogen pressure
(flash chromatography) conditions, using commercial grade solvents as eluents.
All reagents and solvents employed were of commercial grade and were used as such,
unless otherwise specified.
General Procedure for Making N-tert-Butylsulfinylaldimine (3a–3d)
Titanium tetraethoxide (2.0 eq.) was added to a stirred solution of aldehydes
(2a–2d) and S(–)-tert-butanesulfinamide (1.1 eq.) in THF at room temperature.
The mixture was refluxed until completion, the reaction mass was cooled, and
saturated sodium chloride solution was added. The reaction mass was filtered
through celite and the aqueous layer was extracted with ethyl acetate. The
organic layer was concentrated and purified through column chromatography to
get 3a–3d.
General Procedure for the Reaction of Grignard Reagents with
N-tert-Butyl Sulfinylaldimines
The Grignard reagents were prepared from aromatic halides (4a–4n) (3.0 eq.)
using magnesium (3.05 eq.) in THF and then added to a stirred solution of N-tert-
butylsulfinylaldimines (3a–3d) (1.0 eq.) in THF at ꢀ5 to 5 ꢁC. The mixture was
stirred for 1.0 h and warmed to room temperature. The reaction mass was quenched
in saturated ammonium chloride solution and stirred at room temperature. The
organic layer was separated and the aqueous layer was extracted in dichloromethane.
The organic extracts were washed with water and concentrated. This sulfinylamine
(5) was treated with IPA-HCl and stirred for 1.0 h. After completion of the reaction,
the mass was concentrated, stirred with ethyl acetate, and filtered to get 6a–6z.

2942
C. RAJENDIRAN ET AL.
General Procedure for the Reaction of Organolithium Reagents with
N-tert-Butyl Sulfinylaldimines
N-Butyllithium in hexanes (1.6 M, 2 eq.) was added slowly to a stirred solution
of aromatic halides (4a–4n) (2.0 eq.) in THF at ꢀ40 to ꢀ50 ꢁC, and the mass was
stirred for 1.0 h at ꢀ40 to ꢀ50 ꢁC. N-tert-Butylsulfinylaldimines (3a–3d) was added
slowly at 40 to ꢀ50 ꢁC and stirred for 1–2 h. The reaction mass was quenched by
adding saturated ammonium chloride solution, warmed to room temperature, and
extracted in toluene. The organic extracts were washed with water and concentrated.
This sulfinylamine (7) was treated with IPA-HCl and stirred for 1.0 h. After
completion of the reaction, the mass was concentrated, stirred with ethyl acetate,
and filtered to get 8a–8z.
ACKNOWLEDGMENT
The authors greatly acknowledge Mr. Venkat Jasti, CEO, Suven Life Sciences
Ltd., Hyderabad, for providing excellent facilities to carry out this work.
SUPPORTING INFORMATION
1
Full experimental details, H NMR and 13C NMR spectra, and chiral HPLC
data can be accessed on the publisher’s website.
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