Rhodium-catalyzed asymmetric arylation of N -(tert -butanesulfinyl)imines with sodium tetraarylborates

Article abstract of DOI:10.1021/jo2024224

A diastereoselective rhodium-catalyzed arylation of N-(tert-butanesulfinyl) imines with sodium tetraarylborates is described. This method is general for constructing various chiral α-branched amines and 2-substituted pyrrolidines with high diastereoselectivity. A practical asymmetric approach to access chiral amines has been developed involving the use of air-stable Rh catalysts and reagents and in the absence of an external ligand.

Full text of DOI:10.1021/jo2024224

Article
pubs.acs.org/joc
Rhodium-Catalyzed Asymmetric Arylation of N-(tert-
Butanesulfinyl)imines with Sodium Tetraarylborates
Leleti Rajender Reddy,* Aditya P. Gupta,† Eric Villhauer,‡ and Yugang Liu
Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, United States
S
* Supporting Information
ABSTRACT: A diastereoselective rhodium-catalyzed aryla-
tion of N-(tert-butanesulfinyl)imines with sodium tetraarylbo-
rates is described. This method is general for constructing
various chiral α-branched amines and 2-substituted pyrroli-
dines with high diastereoselectivity. A practical asymmetric
approach to access chiral amines has been developed involving
the use of air-stable Rh catalysts and reagents and in the
absence of an external ligand.
INTRODUCTION
RESULTS AND DISCUSION
■
■
Chiral α-branched amines and 2-substituted pyrrolidines are
highly important structural motifs in the pharmaceuticals
industry1 and are present in many drugs, drug candidates,
and natural products. Some examples are naturally occurring
cytokine modulator (−)-cytoxazone,2 the third-generation
antihistamine levocetirizine,3 the histamine H1-receptor antag-
onist (S)-cetirizine dihydrochloride,4 the nonpeptide selective
opioid receptor agonist SNC80,5 and the selective Kv1.5
blocker BMS-394136.6 Therefore, general methods for their
asymmetric synthesis are a formidable challenge in synthetic
organic chemistry. The stereoselective addition of organmetallic
reagents to carbon−heteroatom double bonds represents one
of the most straightforward approaches.7 However, despite
recent advances in the synthesis of functionalized Grignard and
organlithium reagents, these methods are plagued by inherent
functional group instability and modest selectivity.8 A more
functional group tolerant method remains highly desirable. In
recent years, transition-metal-catalyzed additions of organboron
reagents to carbon−heteroatom double bonds are of increasing
interest in organic chemistry.9 The major limitations associated
with these protocols are the difficulties associated with the
scale-up,10 due to moisture-sensitive unstable reagents and
catalysts, requiring a glovebox or sealed tube reaction
conditions. We reasoned that a simple air-stable catalyst like
[Rh(Cl)(cod)]2 would promote the coupling of sodium
tetraarylborates with N-(tert-butanesulfinyl)imines to give α-
branched amines and 2-substituted pyrrolidines, which has not
been described in the literature to the best of our knowl-
edge.11−13 Herein, we report a straightforward, scalable, and
highly diastereoselective method that provides entry to
enantioenriched α-branched amines and 2-substituted pyrroli-
dines in high yields and in the absence of an exogenous
ligand.14
Initially, we chose N-(tert-butanesulfinyl)-4-methylphenylimine
(1a) as a model substrate and attempted the addition of an air-
stable sodium tetraphenylborate 2a (1.2 equiv) in the presence
of air-stable [Rh(OH)(cod)]2 (2 mol % Rh) in dioxane at 65
°C for 24 h. Under these conditions, no reaction was observed,
and the starting material was recovered (Table 1, entry 1). No
significant improvement was detected when MeOH was used as
an additive (Table 1, entry 2). Gratifyingly, 45% of product 3a
was formed with ≥98:2 diastereomeric ratio in the presence of
[Rh(Cl)(cod)]2 in dioxane at 65 °C for 24 h (Table 1, entry 3),
and similar results were observed with water as an additive
(Table 1, entry 4). The best results (95% of product 3a with
≥98:2 diastereomeric ratio) were obtained by using MeOH as
an additive in the presence of [Rh(Cl)(cod)]2 in dioxane at 65
°C for 24 h (Table 1, entries 6), and analogous results (90% of
product 3a with ≥98:2 diastereomeric ratio) were obtained by
using EtOH as a additive (Table 1, entries 5). The addition of
MeOH or EtOH to the reaction mixture might help the
solubility of sodium tetraarylborates.11 Under these optimal
reaction conditions, <10% of 3a was formed by using
phenylboronic acid, phenylboronic acid pinacol ester, or
phenylboronic acid MIDA ester as a nucleophile (Table 1,
entries 7−9). A somewhat lower yield of 3a was obtained with
potassium tetraphenylboranate (Table 1, entry 10). The
structure and absolute configuration of (RS, R)-3a was
1
confirmed by comparing the H NMR, 13C NMR, and specific
rotation data with literature data.15
With optimal reaction conditions identified, the scope of the
methodology was investigated by phenylation of various N-
(tert-butanesulfinyl)aldimines (Table 2). Interestingly, a large
Received: November 24, 2011
Published: December 20, 2011
© 2011 American Chemical Society
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Table 1. Rhodium-Catalyzed Addition of Phenylboron Reagents to 1a: Effect of Catalyst and Nucleophile
a
b
entry
Rh catalyst
Ph−B
Ph4BNa
additive
yield (%)
dr
1
2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
[Rh(Cl)(cod)]2
none
0
5
Ph4BNa
MeOH
none
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
3
Ph4BNa
45
50
90
95
8
4
Ph4BNa
H2O
5
Ph4BNa
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
6
Ph4BNa
7
PhB(OH)2
PhB(MIDA)
c
8
10
6
d
9
PhB(OR)2
10
Ph4BK
72
≥98:2
d
a
b
c
1
Isolated yield. The diastereoselectivity was determined by H NMR analysis of crude product. Phenylboronic acid MIDA ester (OR)2 =
OCH2CMe2CH2O.
a
Table 2. Rhodium-Catalyzed Asymmetric Synthesis of α-Branched Amine
b
c
entry
1
Ar
Ph (2a)
product
yield (%)
dr
1
2
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
95
91
92
95
90
92
93
95
94
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
2a
3
2a
4
2a
5
2a
6
2a
7
1g
1h
1a
1a
2a
3g
3h
3i
8
2a
9
4-FC6H4 (2b)
3-MeC6H4 (2c)
10
3j
92
a
b
c
All reactions were performed as described in Table 2 on a 2.0 mmol scale, unless otherwise noted. Isolated yield. The diastereoselectivity was
determined by H NMR analysis of crude product. The “≥98:2” dr denotes that signals for only one diastereomer were observed.
1
variety of substituted aromatic N-(tert-butanesulfinyl)aldimines,
such as p-fluoro, m-fluoro, p-methyl, p-chloro, α-naphthyl
derivatives, reacted cleanly with 2a leading to the correspond-
ing α-branched amines 3a−e (Table 2, entries 1−5) in
excellent yields (90−95%) and high diastereomeric ratios (dr
≥98:2). In the same way, aliphatic N-(tert-butanesulfinyl)-
aldimines such as cyclohexylaldimine 1g and n-hexylaldimine
1h smoothly reacted with 2a affording the corresponding α-
branched amines 3g and 3h (Table 2, entries 7 and 8) in 93%
and 95% yield, respectively (dr ≥98:2). The heterocyclic N-
(tert-butanesulfinyl)aldimine 1f also reacted with 2a to form
amine 3f (Table 2, entry 6) in 92% yield with dr ≥98:2.
Encouraged by these results, we turned our attention to
examining other substituted aromatic borate reagents. Fascinat-
ingly, other substituted aromatic borate reagents, such as
sodium tetrakis(p-fluorophenyl)borate 2b or sodium tetrakis-
(m-methylphenyl)borate 2c, reacted smoothly with 1a to
obtain the corresponding α-branched amines 3i−j (Table 2,
entries 9 and 10) in high yields (90−92%) and high
diastereomeric ratios (≥98:2).
To broaden the scope of this method, we investigated the
asymmetric synthesis of 2-substituted pyrrolidines under
optimal reaction conditions. Reaction of γ-chlorinated N-(tert-
butanesulfinyl)imine 1i (1 equiv) with 2a (1.2 equiv) in the
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presence of [Rh(Cl)(cod)]2 (2 mol % Rh) and MeOH (2.0
equiv) in dioxane at 65 °C for 24 h afforded amine 4a with high
diastereomeric ratio (dr ≥98: 2). The crude amine 4a was
converted to the corresponding pyrrolidine 5a in high yield
(91% for two steps) by stirring at room temperature for 1 h in
presence of 2.0 equiv of LiHMDS. More importantly, no
epimerization occurred during the cyclization. The structure
and absolute configuration of (RS, S)-5a was confirmed by
chlorinated N-(tert-butanesulfinyl)imine 1j was coupled with 2a
and followed by base treatment which afforded piperidine 6a in
high yield (88% for two steps) with high diastereomeric ratio
(dr ≥98: 2).
CONCLUSION
■
In conclusion, we have developed an efficient, highly
diastereoselective rhodium-catalyzed asymmetric arylation of
N-(tert-butanesulfinyl)imines with sodium tetraarylborates to
afford enantiomerically pure amines and 2-substituted
pyrrolidines. This method enables the practical asymmetric
synthesis of α-branched amines and 2-substituted pyrrolidines,
promoted via air-stable catalyst and reagents and in the absence
of external ligand. This method has been found to be effective
for a variety of substrates, and extension of this work is
currently underway in our laboratory.
1
comparing the H NMR, 13C NMR, and specific rotation data
with literature data.16 In the same way, reaction 1i with several
substituted aromatic borate reagents, such as 2b, sodium
tetrakis(p-methylphenyl)borate 2d, sodium tetrakis(p-
methoxyphenyl)borate 2e, sodium tetrakis(p-chlorophenyl)-
borate 2f, sodium tetrakis(m-methoxyphenyl)borate 2g, and
sodium tetrakis(p-tert-butylphenyl)borate 2h gave pyrrolidines
5b−g (Table 3) in high yields (83−89%) and high
EXPERIMENTAL SECTION
Table 3. Rhodium-Catalyzed Asymmetric Synthesis of 2-
Substituted Pyrrolidines
■
General Information. All reactions were performed under dry
nitrogen gas in glassware that was flame-dried and equipped with a
magnetic stirring bar. Thin-layer chromatography (TLC) was
performed using silica gel 60 F254 precoated plates (0.25 mm).
Flash chromatography was performed using silica gel (40 μm particle
size). All compounds were judged pure by TLC analysis (single spot/
two solvent systems) using a UV lamp or PMA for detection purposes.
1H and 13C NMR spectra were recorded on an FT-NMR spectrometer
at 500 and 125 MHz, respectively. High-resolution mass spectroscopy
(HRMS) was carried out in electrospray mode. All reagents were
purchased from commercial suppliers and used without further
purification. Unless indicated otherwise, the reaction temperatures
refer to internal reaction temperatures. Sodium tetraarylborates 2c−
h,17−19 (RS)-γ-chlorinated N-(tert-butanesulfinyl)imine (1i),16b (RS)-δ-
chlorinated N-(tert-butanesulfinyl)imine (1j),16a and imines 1a−h20
were synthesized according to literature procedures.
General Procedure (GP1) for the Synthesis Amines. To a
solution of imine 1 (2.0 mmol) in dioxane (5 mL) under nitrogen
were added borate 2 (2.4 mmol), methanol (4.0 mmol), and
[Rh(Cl)(cod)]2 (2 mol %). The reaction mixture was then stirred at
65 °C for 24 h. After completion, the reaction was allowed to cool to
room temperature and diluted with isopropyl acetate (30 mL). The
reaction mixture was washed with 20% KHSO4 solution (2 × 30 mL)
and water (20 mL). The organic phase was evaporated under vacuum
to dryness to obtain the crude product. The crude product was
purified by flash column chromatography (silica gel, 10−40% ethyl
acetate in heptanes) to afford the pure product 3.
(R)-2-Methyl-N-[(R)-Phenyl(p-tolyl)methyl]propane-2-sulfinamide
(3a). Following the general procedure (GP1), the reaction of imine 1a
(0.450 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol) afforded
pyrrolidine 3a (0.57 g, 95%) as a white solid: mp = 58−59 °C; [α]20
D
= −65.9 (c 0.8, CHCl3); 1H NMR (501 MHz, CDCl3) δ ppm 7.40 (d,
J = 7.25 Hz, 2 H), 7.29−7.34 (m, 2 H), 7.21−7.27 (m, 3 H), 7.12 (d, J
= 8.20 Hz, 2 H), 5.61 (d, J = 2.52 Hz, 1 H), 3.68 (d, J = 1.89 Hz, 1 H),
2.30 (s, 3 H), 1.25 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ ppm
141.5, 139.8, 129.5, 128.5, 127.8, 127.2, 61.9, 55.8, 22.7, 21.0; HRMS
(EI) calcd for C18H24NOS [M + H] 302.1579, found 302.1582.
(R)-2-Methyl-N-[(R)-phenyl(p-fluorophenyl)methyl]propane-2-
sulfinamide (3b). Following the general procedure (GP1), the
reaction of imine 1b (0.455 g, 2.0 mmol) with borate 2a (0.82 g,
2.4 mmol) afforded pyrrolidine 3b (0.55 g, 91%) as a white solid: mp
1
= 65−66 °C; [α]20 = −70.8 (c 1.2, CHCl3); H NMR (501 MHz,
D
CDCl3) δ ppm 7.22−7.42 (m, 7 H), 6.90−7.04 (m, 2 H), 5.62 (d, J =
2.84 Hz, 1 H), 3.72 (d, J = 2.84 Hz, 1 H), 1.24 (s, 9 H); 13C NMR
(125 MHz, CDCl3) δ ppm 163.2, 161.2, 141.1, 138.6, 138.5, 134.2,
129.0 (d, J = 8.25 Hz,), 127.8, 115.7 (d, J = 21.08 Hz,), 61.6, 55.9,
22.6; HRMS (EI) calcd for C17H21NOSF [M + H] 306.1328, found
306.1330.
diastereomeric ratios (≥98:2). To further extend this method-
ology, we also examined the asymmetric synthesis of 2-
substituted piperidines. Under optimal reaction conditions, δ-
(R)-2-Methyl-N-[(R)-phenyl(m-fluorophenyl)methyl]propane-2-
sulfinamide (3c). Following the general procedure (GP1), the
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reaction of imine 1c (0.455 g, 2.0 mmol) with borate 2a (0.82 g, 2.4
(R)-2-Methyl-N-[(S)-m-tolyl(p-tolyl)methyl]propane-2-sulfina-
mide (3j). Following the general procedure (GP1), the reaction of
imine 1a (0.450 g, 2.0 mmol) with borate 2b (0.90 g, 2.4 mmol)
mmol) afforded pyrrolidine 3c (0.56 g, 92%) as a viscous oil: [α]20
=
D
−52.3 (c 1.1, CHCl3); 1H NMR (501 MHz, CDCl3) δ ppm 7.38 (d, J
= 7.25 Hz, 2 H), 7.28−7.34 (m, 2 H), 7.21−7.27 (m, 2 H), 7.14−7.19
(m, 1 H), 7.05−7.10 (m, 1 H), 6.86−6.93 (m, 1 H), 5.62 (d, J = 3.15
Hz, 1 H), 3.84 (d, J = 2.84 Hz, 1 H), 1.23 (s, 9 H); 13C NMR (125
MHz, CDCl3) δ ppm 163.9, 161.9, 145.2, 140.8, 130.4 (d, J = 8.25
Hz,), 128.7, 127.9, 127.2, 123.0, 114.7 (d, J = 21.08 Hz,), 114.2 (d, J =
22.9 Hz,),, 61.8, 55.9, 22.6; HRMS (EI) calcd for C17H21NOSF [M +
H] 306.1328, found 306.1326.
1
afforded pyrrolidine 3j (0.58 g, 92%) as a viscous oil: H NMR (501
MHz, CDCl3) δ ppm 7.29 (d, J = 8.20 Hz, 2 H), 7.09−7.23 (m, 5 H),
7.04 (d, J = 6.94 Hz, 1 H), 5.56 (d, J = 2.21 Hz, 1 H), 3.66 (d, J = 1.58
Hz, 1 H), 2.32 (s, 3 H), 2.30 (s, 3 H), 1.25 (s, 98 H); 13C NMR (125
MHz, CDCl3) δ ppm 142.6, 138.5, 138.4, 137.3, 129.2, 128.7, 128.1,
127.9, 127.8, 124.1, 61.9, 55.8, 22.7, 21.4, 21.1; HRMS (EI) calcd for
C19H26NOS [M + H] 316.1735, found 316.1738.
General Procedure (GP2) for the Synthesis 2-Substituted
Pyrrolidines. To a solution of amine 1 (2.0 mmol) in dioxane (5 mL)
under nitrogen were added borate 2 (2.2 mmol), methanol (4.0
mmol) and [Rh(Cl)(cod)]2 (2 mol %). The reaction mixture was then
heated at reflux at 65 °C for 24 h. After completion, the reaction was
allowed to cool to room temperature and diluted with isopropyl
acetate (30 mL). The reaction mixture was washed with 20% KHSO4
solution (2 × 30 mL) and water (20 mL). The organic phase was
evaporated under vacuum to dryness to obtain the crude product 4.
The crude product was taken in 10 mL of THF, followed by addition
of LiHMDS (4.0 mmol) at 23 °C and stirred for 1 h at at 23 °C. On
completion, the reaction was quenched with saturated NH4Cl solution
(20 mL) and ethyl acetate (20 mL). The organic layer was then
separated, washed with water and dried under vacuum to give crude
product. The crude product was purified by flash column
chromatography (silica gel, 10−40% ethyl acetate in heptanes) to
afford the pure product 5.
(R)-2-Methyl-N-[(R)-phenyl(p-chlorophenyl)methyl]propane-2-
sulfinamide (3d). Following the general procedure (GP1), the
reaction of imine 1d (0.485 g, 2.0 mmol) with borate 2a (0.82 g,
2.4 mmol) afforded pyrrolidine 3d (0.61 g, 95%) as a pale yellow solid:
mp = 78−80 °C; [α]20D = −64.1 (c 0.9, CHCl3); 1H NMR (501 MHz,
CDCl3) δ ppm 7.19−7.45 (m, 9 H), 5.61 (d, J = 3.15 Hz, 1 H), 3.70
(d, J = 2.52 Hz, 1 H), 1.24 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ
ppm 141.2, 140.9, 129.0, 128.7, 127.8, 61.7, 55.9, 22.6; HRMS (EI)
calcd for C17H21NOSCl [M + H] 322.1032, found 322.1033.
(R)-2-Methyl-N-[(R)-phenyl(2-naphthyl)methyl]propane-2-sulfi-
namide (3e). Following the general procedure (GP1), the reaction of
imine 1e (0.518 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol)
afforded pyrrolidine 3e (0.60 g, 90%) as a viscous oil: [α]20D = −75.3
(c 0.6, CHCl3); 1H NMR (501 MHz, CDCl3) δ ppm 7.70−7.83 (m, 4
H), 7.37−7.51 (m, 5 H), 7.32 (t, J = 7.57 Hz, 2 H), 7.18−7.27 (m, 1
H), 5.80 (d, J = 2.52 Hz, 1 H), 3.84 (d, J = 2.52 Hz, 1 H), 1.25 (s, 9
H); 13C NMR (125 MHz, CDCl3) δ ppm 141.2, 140.0, 133.3, 132.9,
128.8, 128.6, 128.1, 127.8, 127.7, 126.4, 126.2, 126.0, 125.3; HRMS
(EI) calcd for C21H24NOS [M + H] 338.1579, found 338.1571.
(R)-2-Methyl-N-[(R)-phenyl(2-furyl)methyl]propane-2-sulfina-
mide (3f). Following the general procedure (GP1), the reaction of
imine 1f (0.4 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol) afforded
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-phenylpyrrolidine (5a).
Following the general procedure (GP2), the reaction of γ-chloro N-
sulfinylimine 1i (0.418 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol)
and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0 mL in THF)
afforded pyrrolidine 5a (0.455 g, 91%) as a viscous liquid: [α]25
=
D
pyrrolidine 3f (0.51 g, 92%) as a viscous oil: [α]20 = −41.2 (c 1. 0,
1
−120.1 (c 1.1, CHCl3); H NMR (501 MHz, CDCl3) δ ppm 7.16−
7.37 (m, 5 H), 4.64 (t, J = 7.25 Hz, 1 H), 3.84−3.95 (m, 1 H), 2.90−
3.06 (m, 1 H), 2.16−2.33 (m, 1 H), 1.70−2.07 (m, 3 H), 1.10 (s, 9
H); 13C NMR (125 MHz, CDCl3) δ ppm 143.3, 128.2, 127.2, 69.3,
57.2, 42.1, 35.9, 26.3, 23.8; HRMS (EI) calcd for C14H22NOS [M +
H] 252.1439, found 252.1432.
D
1
CHCl3); H NMR (501 MHz, CDCl3) δ ppm 7.19−7.50 (m, 6 H),
6.29 (dd, J = 3.15, 1.89 Hz, 1 H), 6.10 (d, J = 3.15 Hz, 1 H), 5.62 (d, J
= 3.78 Hz, 1 H), 3.89 (d, J = 3.15 Hz, 1 H), 1.22 (s, 9 H); 13C NMR
(125 MHz, CDCl3) δ ppm 154.4, 142.6, 139.0, 128.5, 128.2, 110.3,
107.9, 56.7, 55.9, 22.5; HRMS (EI) calcd for C15H20NO2S [M + H]
278.1215, found 278.1208.
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-(p-fluorophenyl)-
pyrrolidine (5b). Following the general procedure (GP2), the reaction
of γ-chloro N-sulfinylimine 1i (0.418 g, 2.0 mmol) with borate 2b
(0.94 g, 2.4 mmol) and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0
mL in THF) afforded pyrrolidine 5b (0.49 g, 92%) as a viscous liquid:
[α]25D = −123.2 (c 1.2, MeOH); 1H NMR (400 MHz, CDCl3) δ ppm
7.18−7.34 (m, 2 H), 6.87−7.07 (m, 2 H), 4.54−4.70 (m, 1 H), 3.83−
3.97 (m, 1 H), 2.90−3.03 (m, 1 H), 2.15−2.30 (m, 1 H), 1.66−2.04
(m, 3 H), 1.09 (s, 9 H);13C NMR (125 MHz, CDCl3) δ ppm 163.2,
160.6, 138.9, 128.8 (d, J = 8.25 Hz,), 115.5 (d, J = 21.08 Hz,),, 68.5,
57.2, 42.0, 36.0, 26.3, 23.6; HRMS (EI) calcd for C14H21NOSF [M +
H] 270.1322, found 270.1319.
(R)-2-Methyl-N-[(S)-phenyl(cyclohexyl)methyl]propane-2-sulfina-
mide (3g). Following the general procedure (GP1), the reaction of
imine 1g (0.4 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol) afforded
1
pyrrolidine 3g (0.448 g, 93%) as a viscous oil: H NMR (501 MHz,
CDCl3) δ ppm 7.18−7.37 (m, 5 H), 4.14 (dd, J = 7.25, 2.52 Hz, 1 H),
3.52 (d, J = 1.58 Hz, 1 H), 1.89 (d, J = 12.61 Hz, 1 H), 1.71−1.81 (m,
1 H), 1.55−1.70 (m, 3 H), 1.38−1.50 (m, 1 H), 1.20−1.30 (m, 1 H),
1.18 (s, 9 H), 0.96−1.14 (m, 2 H), 0.78−0.93 (m, 1 H); 13C NMR
(125 MHz, CDCl3) δ ppm 140.7, 128.4, 128.02, 127.3, 64.0, 55.4, 44.5,
29.9, 29.4, 26.2, 22.5; HRMS (EI) calcd for C17H27NOS [M + H]
294.1892, found 294.1885.
(R)-2-Methyl-N-[(S)-1-phenylhexyl]propane-2-sulfinamide (3h).
Following the general procedure (GP1), the reaction of imine 1 h
(0.4 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol) afforded
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-(p-methylphenyl)-
pyrrolidine (5d). Following the general procedure (GP2), the reaction
of γ-chloro N-sulfinylimine 1i (0.418 g, 2.0 mmol) with borate 2d
(0.955 g, 2.4 mmol) and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0
1
pyrrolidine 3h (0.533 g, 95%) as a viscous oil: H NMR (501 MHz,
CDCl3) δ ppm 7.17−7.37 (m, 5 H), 4.24−4.44 (m, 1 H), 3.38 (d, J =
1.89 Hz, 1 H), 1.69−1.86 (m, 2 H), 1.21−1.41 (m, 6 H), 1.15 (s, 9 H),
0.75−0.93 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ ppm 142.1,
128.3, 127.6, 127.4, 59.2, 55.4, 38.8, 31.5, 25.6, 22.5, 22.3, 13.9; HRMS
(EI) calcd for C16H28NOS [M + H] 282.1892, found 282.1887.
(R)-2-Methyl-N-[(S)-p-fluorophenyl(p-tolyl)methyl]propane-2-sul-
finamide (3i). Following the general procedure (GP1), the reaction of
imine 1a (0.450 g, 2.0 mmol) with borate 2b (0.94 g, 2.4 mmol)
afforded pyrrolidine 3i (0.599 g, 94%) as a viscous oil: 1H NMR (501
MHz, CDCl3) δ ppm 7.37 (dd, J = 8.51, 5.36 Hz, 2 H), 7.19−7.30 (m,
2 H), 7.13 (d, J = 7.88 Hz, 2 H), 7.00 (t, J = 8.67 Hz, 2 H), 5.59 (d, J =
2.21 Hz, 1 H), 3.67 (d, J = 1.58 Hz, 1 H), 2.31 (s, 3 H), 1.25 (s, 9 H);
13C NMR (125 MHz, CDCl3) δ ppm 163.1, 161.2, 139.5, 137.7, 137.2,
mL in THF) afforded pyrrolidine 5d (0.47 g, 89%) as a white solid:
1
mp = 62−65 °C; [α]25 = −145.0 (c 1.5, MeOH); H NMR (501
D
MHz, CDCl3) δ ppm 7.14−7.20 (m, 2 H), 7.05−7.14 (m, 2 H), 4.60
(t, J = 7.41 Hz, 1 H), 3.81−3.95 (m, 1 H), 2.89−3.04 (m, 1 H), 2.32
(s, 3 H), 2.22 (dd, J = 11.19, 4.89 Hz, 1 H), 1.68−2.04 (m, 3 H), 1.10
(s, 9 H); 13C NMR (125 MHz, CDCl3) δ ppm 140.2, 136.7, 128.9,
127.1, 69.0, 57.1, 42.0, 35.9, 26.3, 23.8, 21.0; HRMS (EI) calcd for
C15H24NOS [M + H] 266.1573, found 266.1570.
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-(p-methoxyphenyl)-
pyrrolidine (5e). Following the general procedure (GP2), the reaction
of γ-chloro N-sulfinylimine 1i (0.418 g, 2.0 mmol) with borate 2e
(1.05 g, 2.4 mmol) and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0
mL in THF) afforded pyrrolidine 5e (0.518 g, 92%) as a white solid:
1
129.6, 129.0 (d, J = 7.33 Hz,), 127.0, 115.4 (d, J = 21.08 Hz), 61.1,
55.8, 22.6, 21.04; HRMS (EI) calcd for C18H23NOSF [M + H]
320.1484, found 320.1487.
mp = 60−62 °C; [α]25 = −122.0 (c 1.2, MeOH); H NMR (500
D
MHz, CDCl3) δ ppm 7.19−7.24 (m, 2 H), 6.81−6.88 (m, 2 H), 4.55−
4.60 (m, 1 H), 3.81−3.92 (m, 1 H), 3.79 (s, 3 H), 2.90−3.01 (m, 1 H),
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Article
2.13−2.24 (m, 1 H), 1.91−2.03 (m, 1 H), 1.71−1.92 (m, 2 H), 1.08
(s, 9 H); 13C NMR (125 MHz, CDCl3) δ ppm 158.7, 135.0, 128.3,
113.6, 68.6, 57.0, 55.1, 41.9, 35.9, 26.3, 23.8; HRMS (EI) calcd for
C15H24NO2S [M + H] 282.1528, found 282.1530.
ACKNOWLEDGMENTS
■
We thank Dr. Mahavir Prashad, Dr. Prasad Kapa, and Dr.
Ravinder Raju for valuable suggestions.
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-(p-chlorophenyl)-
pyrrolidine (5f). Following the general procedure (GP2), the reaction
of γ-chloro N-sulfinylimine 1i (0.418 g, 2.0 mmol) with borate 2f (1.10
g, 2.4 mmol) and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0 mL in
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(1) (a) Over 5000 compounds containing these pharmacophores are
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THF) afforded pyrrolidine 5f (0.525 g, 92%) as a white solid: mp =
1
74−76 °C; [α]25 = −110.5 (c 1.2, MeOH); H NMR (400 MHz,
D
CDCl3) δ ppm 7.13−7.40 (m, 4 H), 4.51−4.71 (m, 1 H), 3.83−3.97
(m, 1 H), 2.89−3.11 (m, 1 H), 2.17−2.31 (m, 1 H), 1.64−2.06 (m, 3
H), 1.10 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ ppm 141.8, 132.9,
128.6, 128.4, 68.6, 57.2, 42.1, 36.0, 26.3, 23.8; HRMS (EI) calcd for
C14H21NOSCl [M + H] 286.1032, found 286.1034.
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-(m-methoxyphenyl)-
pyrrolidine (5g). Following the general procedure (GP2), the reaction
of γ-chloro N-sulfinylimine 1i (0.418 g, 2.0 mmol) with borate 2g
(1.05 g, 2.4 mmol) and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0
mL in THF) afforded pyrrolidine 5g (0.51 g, 91%) as a white solid:
1
mp = 45−46 °C; [α]25 = −152.8 (c 1.2, MeOH); H NMR (501
D
MHz, CDCl3) δ ppm 7.18−7.29 (m, 1 H), 6.72−6.94 (m, 3 H), 4.63
(t, J = 7.09 Hz, 1 H), 3.86−3.98 (m, 1 H), 3.80 (s, 3 H), 2.88−3.11
(m, 1 H), 2.24 (dd, J = 11.03, 5.36 Hz, 1 H), 1.68−2.05 (m, 3 H), 1.12
(s, 9 H); 13C NMR (125 MHz, CDCl3) δ ppm 159.6, 145.0, 129.3,
119.5, 112.9, 112.4, 69.2, 57.2, 55.1, 42.1, 35.8, 26.2, 23.8; HRMS (EI)
calcd for C15H24NO2S [M + H] 282.1528, found 282.1524.
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(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-(p-tert-butylphenyl)-yr-
rolidine (5h). Following the general procedure (GP2), the reaction of
γ-chloro N-sulfinyl imine 1i (0.418 g, 2.0 mmol) with borate 2h (1.3 g,
2.4 mmol) and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0 mL in
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A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5405.
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te, A.; Boezio, A.
THF) afforded pyrrolidine 5h (0.55 g, 89%) as a white solid: mp =
1
48−50 °C; [α]25 = −113.1 (c 1.5, MeOH); H NMR (400 MHz,
D
(c) Hermanns, N.; Dahmen, S.; Bolm, C.; Brase, S. Angew. Chem., Int.
CDCl3) δ ppm 7.33 (d, J = 8.34 Hz, 2 H), 7.21 (d, J = 8.34 Hz, 2 H),
4.64 (t, J = 6.95 Hz, 1 H), 3.79−3.96 (m, 1 H), 2.88−3.03 (m, 1 H),
2.13−2.28 (m, 1 H), 1.70−2.07 (m, 3 H), 1.32 (s, 9 H), 1.11 (s, 9 H);
13C NMR (125 MHz, CDCl3) δ ppm 150.0, 140.1, 126.7, 125.1, 69.0,
57.2, 42.0, 35.8, 34.4, 31.4, 26.2, 23.9; HRMS (EI) calcd for
C18H30NOS [M + H] 308.2043, found 308.2041.
(S)-1-((R)-2-Methylpropane-2-sulfinyl)-2-phenylpiperidine (6a).
Following the general procedure (GP2), the reaction of δ-chloro N-
sulfinylimine 1j (0.445 g, 2.0 mmol) with borate 2a (0.82 g, 2.4 mmol)
and followed by LiHMDS (4.0 mL, 4.0 mmol, 1.0 mL in THF)
̈
Ed. 2002, 41, 3692−3694. (d) Akullian, L. C.; Snapper, M. L.;
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Chem. Soc. 2004, 126, 8128. (b) Tokunaga, N.; Otomaru, Y.;
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afforded pyrrolidine 6a (0.46 g, 88%) as a white solid: mp = 48−51
1
°C; [α]25 = +114.1 (c 1.0, MeOH); H NMR (500 MHz, CDCl3) δ
D
ppm 7.40 (d, J = 8.20 Hz, 2 H), 7.38 (t, J = 7.72 Hz, 2 H), 7.21−7.28
(m, 1 H), 4.67 (t, J = 4.10 Hz, 1 H), 3.28 (dd, J = 8.04, 3.31 Hz, 2 H),
2.15−2.24 (m, 1 H), 2.00−2.10 (m, 1 H), 1.55−1.71 (m, 4 H), 1.42−
1.51 (m, 1 H), 1.14 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ ppm
140.2, 128.5, 127.4, 126.6, 58.7, 31.2, 25.6, 23.0, 20.4; HRMS (EI)
calcd for C15H24NOS [M + H] 266.1579, found 266.1569.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rajender.leleti@novartis.com.
Notes
†Summer Intern (2010 and 2011): Undergraduate Student
from New York University, New York, NY 10012.
‡Summer Intern (2010): Undergraduate Student from
University of Chicago, Chicago, IL 60637.
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