A facile asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines

Article abstract of DOI:10.1021/jo902710s

Chemical Reaction Reprentation A new and general method for asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines from a single starting material is described. Reductive cyclization of (Ss)-γ-chloro-N- tertbutanesulfinyl ketimines with LiBHEt₃ in THF at -78 to 23 °C afforded (S_s,R)-N-tert-buta.nemnnyl-2-substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99:1). The diastereoselectivity is controlled effectively by the choice of reducing agent. Thus, the corresponding epimers of (3 to DIBAL-H/LiHMDS. Deprotection of N-fe/ f-butanesulfinyl-2-substituted pyrrolidines using 4 N HCl in dioxane and MeOH gave the corresponding enantiomers of 2-substituted pyrrolidines in quantative yield. This method was found to be effective for a variety of substrates including aromatic, heteroaromatic, and aliphatic substituents. Extension of this methodology to the formation of 2-substituted piperidines is also illustrated. Reductive cyclization of (5s)-<5-chloroN- tetr-butanesulfinyl ketimine with LiBHEt₃ in THF at -78 to 23 °C or DIBAL-H/LiHMDS in toluene at -78 to 0 °C afforded the (Ss,R?)-N-tert-butanesulfinyl-2-substituted piperidines in excellent yield (98%) and with high diastereoselectivity (99:1) or (Ss,S)-.N-tert-butanesulfmyl- 2substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively.

Full text of DOI:10.1021/jo902710s

pubs.acs.org/joc
A Facile Asymmetric Synthesis of Either Enantiomer of
2-Substituted Pyrrolidines
Leleti Rajender Reddy,* Sonia G. Das,† Yugang Liu, and Mahavir Prashad
Chemical Research and Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East
Hanover, New Jersey 07936. †Current address: Department of Medicinal Chemistry, College of Pharmacy,
University of Minnesota, 308 Harvard St. SE, Minneapolis, MN 55455.
rajender.leleti@novartis.com
Received January 4, 2010
A new and general method for asymmetric synthesis of either enantiomer of 2-substituted pyrroli-
dines from a single starting material is described. Reductive cyclization of (SS)-γ-chloro-N-tert-
butanesulfinyl ketimines with LiBHEt3 in THF at -78 to 23 °C afforded (SS,R)-N-tert-butanesulfi-
nyl-2-substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99:1).
The diastereoselectivity is controlled effectively by the choice of reducing agent. Thus, the
corresponding epimers of (SS,S)-2-substituted pyrrolidines were synthesized in good yields
(87-98%) and with high diastereoslectivity (1:99) by simply switching the reducing agent from
LiBHEt3 to DIBAL-H/LiHMDS. Deprotection of N-tert-butanesulfinyl-2-substituted pyrrolidines
using 4 N HCl in dioxane and MeOH gave the corresponding enantiomers of 2-substituted
pyrrolidines in quantative yield. This method was found to be effective for a variety of substrates
including aromatic, heteroaromatic, and aliphatic substituents. Extension of this methodology to the
formation of 2-substituted piperidines is also illustrated. Reductive cyclization of (SS)-δ-chloro-
N-tert-butanesulfinyl ketimine with LiBHEt3 in THF at -78 to 23 °C or DIBAL-H/LiHMDS in
toluene at -78 to 0 °C afforded the (SS,R)-N-tert-butanesulfinyl-2-substituted piperidines in
excellent yield (98%) and with high diastereoselectivity (99:1) or (SS,S)-N-tert-butanesulfinyl-2-
substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively.
Introduction
compounds containing this pharmacophore are currently
in advanced stages of biological testing.13 In addition, these
compounds are effective chiral controllers and thus play an
important role in asymmetric synthesis.14 As a result, the
Enantiomerically pure 2-substituted pyrrolidines are ubi-
quitous structural motifs found in a wide variety of natural
products1-3 and pharmaceutical drugs.4-12 Over 4000
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Published on Web 03/04/2010
DOI: 10.1021/jo902710s
r
2010 American Chemical Society

Rajender Reddy et al.
JOCArticle
SCHEME 1
SCHEME 2. Synthesis of Chlorinated N-tert-Butanesulfinyl
Ketimines (SS)-3a-3p
synthesis of these compounds has been an active area of
research. Known synthetic methods of these privileged
structures suffer from either long synthetic sequences, low
yields, lack of generality, or modest selectivity.15,16 The
classical approach to obtain enantiomerically pure 2-sub-
stitued pyrrolidines is by resolution of the racemate via
diastereoselective salt formation. However, the maximum
theoretical yield for resolution is only 50%. Campos et al.
have reported17 an elegant method for asymmetric synthesis
of 2-substituted pyrrolidines in a highly enantioselective
manner. This method employs (-)-sparteine mediated en-
antioselective lithiation of N-Boc-pyrrolidine, followed by
transmetalation and Pd-catalyzed Negishi coupling. This
method is limited to the synthesis of (R)-aryl pyrrolidines
due to the lack of inexpensive alternatives for (þ)-spar-
teine.21 In addition, it utilizes s-BuLi, which is a pyrophoric
liquid and restricted from use on a large scale.18 Recently, we
reported19 an asymmetric synthesis of 2-substituted pyrroli-
dines by addition of Grignard reagents to γ-chloro N-tert-
butanesulfinyl aldimine followed by base-catalyzed cycliza-
tion. This method provides either enantiomer of 2-substi-
tuted pyrrolidines by changing the chiral starting material.
Thus, development of an asymmetric synthesis to provide
either enantiomer of 2-substituted pyrrolidines from the
same starting material still remains an elusive challenge.
We reasoned that a direct method to access either enantio-
mer of 2-substituted pyrrolidines would be via asymmetric
reductive cyclization of γ-chloro-N-tert-butanesulfinyl keti-
mines 3, and this asymmetric reductive cyclization of 3 to
either diastereomers of 2-substituted pyrrolidines has not
been described to our knowledge.20 Herein, we report a
versatile and practical method for diastereoselective reduc-
tive cyclization of (SS)-γ-chlorinated N-tert-butanesulfinyl
ketimines (3) to give either diastereomer of 2-substituted
pyrrolidines (4 or 5) in a single step with high yields (Scheme 1).
The tert-butanesulfinyl group not only induces excellent dia-
stereoselectivity but also serves as an efficient low molecular
weight protecting group for the nitrogen for future modifica-
tions of the 2-substituted pyrrolidines, if needed.
Results and Discussion
Synthesis of γ-Chlorinated N-tert-Butanesulfinyl Ketimines
(SS)-3a-3p. Two methodologies were investigated for the
synthesis of γ-chlorinated N-tert-butanesulfinyl ketimines
(SS)-3a-3p by condensation of appropriate ketones 6a-6p21
with (S)-tert-butanesulfinamide22 7 (Scheme 2). An initial
attempt to synthesize 3a under heterogeneous conditions23
using pyridinium p-toluenesulfonate as a catalyst and
magnesium sulfate as a water scavenger was unsuccessful.
However, a subsequent trial using homogeneous condi-
tions24 that utilized Ti(OEt)4 as both a Lewis acid and a
water scavenger furnished 3a in 90% yield. Since this
approach was straightforward and provided 3a with excel-
lent yields, it was employed to prepare aryl sulfinyl ketimines
3a-3i, heteroaryl sulfinyl ketimine 3j, and aliphatic sulfinyl
ketimines 3k and 3p. In the same way, the δ-chlorinated
N-tert-butanesulfinyl ketimine (SS)-3m, ε-chlorinated
N-tert-butanesulfinyl ketimine (SS)-3n, ζ-chlorinated N-tert-
butanesulfinyl ketimine (SS)-3o, and dechlorinated N-tert-
butanesulfinyl ketimine (SS)-3p were synthesized via con-
densation of (S)-tert-butanesulfinamide 7 with ketones
6m-6p, respectively. In all cases, the products were isolated
in analytically pure form by extractive workup followed by
flash chromatography. 1H NMR analysis revealed that
sulfinyl ketimines 3a-3p existed solely as the (E)-isomer,
(13) MDL Drug Data Report; M.I.S., Inc.: San Leandro, CA, 2009.
(14) Whitesell, J. K. Chem. Rev. 2002, 89, 1581–1590.
(15) Brinner, K. M.; Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109–
2113.
(16) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715–721.
(17) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen,
C.-y. J. Am. Chem. Soc. 2006, 128, 3538–3539.
(18) (a) Anderson, N. G. Practical Process Research & Development;
Academic Press: San Diego, 2000. (b) Repic, O. Principles of Process Research
and Chemical Development in the Pharmaceutical Industry; John Wiley & Sons,
Inc.: New York, 1998.
(19) Reddy, L . R.; Prashad, M. Chem. Commun. 2010, 222.
(20) Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.; Faul,
M. M. The J. Org. Chem. 2006, 71, 6859–6862.
(21) Ketones are commercially available from several companies.
(22) Both (SS)-tert-butanesulfinamide and (SS)-tert-butanesulfinamide
are readily available commercially from various companies ($1800/kg).
(23) Fei, Z.; Wu, Q.; Zhang, F.; Cao, Y.; Liu, C.; Shieh, W.-C.; Xue, S.;
McKenna, J.; Prasad, K.; Prashad, M.; Baeschlin, D.; Namoto, K. J. Org.
Chem. 2008, 73, 9016–9021.
(10) Winn, M.; von Geldern, T. W.; Opgenorth, T. J.; Jae, H.-S.; Tasker,
A. S.; Boyd, S. A.; Kester, J. A.; Mantei, R. A.; Bal, R.; Sorensen, B. K.;
Wu-Wong, J. R.; Chiou, W. J.; Dixon, D. B.; Novosad, E. I.; Hernandez, L.;
Marsh, K. C. J. Med. Chem. 1996, 39, 1039–1048.
(11) Xue, C.-B.; Chen, X.-T.; He, X.; Roderick, J.; Corbett, R. L.;
Ghavimi, B.; Liu, R.-Q.; Covington, M. B.; Qian, M.; Ribadeneira, M. D.;
Vaddi, K.; Trzaskos, J.; Newton, R. C.; Duan, J. J. W.; Decicco, C. P. Bioorg.
Med. Chem. Lett. 2004, 14, 4453–4459.
(12) Lin, N.-H.; Carrera, G. M.; Anderson, D. J. J. Med. Chem. 2002, 37,
3542–3553.
(24) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984–995.
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SCHEME 3. Asymmetric Reductive Cyclization of γ-Chlori-
nated N-tert-Butanesulfinyl Ketimine (SS)-3a by using LiBHEt3
TABLE 1. Reductive Cyclization of Sulfinyl Ketimine (SS)-3b Using
Various Metal Hydrides
entry
reducing agent
solvent
conversion (%)
4b:5ba,c
1
L-Selectride
NaBH4
LiBH4
9-BBN
LiAlH4
THF
THF
THF
THF
THF
THF
toluene
100
98
99:1
2b
3
40:60
35:65
38:62
18:82
4:96
100
100
100
100
100
4
5
6
7
DIBAL-H
DIBAL-H
1:99
aAll reactions were performed using 1.5 equiv of reducing agent at
-78 °C for 3 h, followed by isolation of crude product and cyclization
using LiHMDS, rt, 1 h in dry THF, unless stated otherwise indicated. b10
equiv of MeOH was used. cThe diastereoselectivity was determined by
1H NMR analysis. The “99:1 or 1:99” denotes that signals for only one
diastereomer were observed.
and the corresponding (Z)-sulfinyl ketimines were not
observed.
Asymmetric Reductive Cyclization of γ-Chlorinated N-tert-
Butanesulfinyl Ketimines (SS)-3a-3p. With the sulfinyl keti-
mines in hand, the preparation of 2-substituted pyrrolidines
via asymmetric reduction of the γ-chloro N-tert-butanesul-
finyl ketimines was explored. Reduction of sulfinyl ketimine
(SS)-3a with 1.1 equiv of LiBHEt3 in dry THF at -78 °C for
3 h followed by extractive workup afforded the crude
γ-chloro sulfinamide (SS,R)-8a in quantitative yield with
little or no formation of the ring-closed product, i.e., pyrro-
lidine (SS,R)-4a (Scheme 3). Gratifyingly, further stirring the
crude γ-chloro sulfinamide 8a with a strong base such as
LiHMDS in THF at rt for 1 h afforded the desired pyrroli-
dine (SS,R)-4a in 90% overall yield from 3a with a high
diastereomeric ratio of 99:1 (Scheme 3). The diastereoselec-
SCHEME 4. Asymmetric Reductive Cyclization of γ-Chlori-
nated N-tert-Butanesulfinyl Ketimine (SS)-3a using DIBAL-H
and LiHMDS
1
tivity of the reaction was determined on the basis of H
NMR analysis of the crude product. The (R)-1-((S)-tert-
butylsulfinyl)-2-(4-bromophenyl)pyrrolidine (4a) was obtained
as a colorless crystalline solid (mp 120-122 °C). The structure
and absolute configuration of (SS,R)-4a was confirmed by
single crystal X-ray diffraction analysis (see Supporting
Information). Further optimization of this (3a to 4a) two-step
process to one step was achieved by warming the reaction
mixture at -78 to 23 °C followed by stirring for 1 h, yielded
pyrrolidine (SS,R)-4a in a single step in 96% yield with a high
diastereoselectivity of 99:1.
Thrilled with these results, a series of metal hydrides were
screened to further elaborate this reduction and test the
possibility of stereoselectivity reversal. A series of reducing
agents, such as L-Selectride, NaBH4, LiBH4, 9-BBN,
NaBH3CN, LiAlH4, and DIBAL-H, were studied in the
reduction of γ-chloro N-tert-butanesulfinyl ketimines 3b in
THF for 3 h at -78 °C. Selectivity was monitored after
cyclization of crude sulfinamide 8b to the desired crude
pyrrolidines 4b and 5b by using 1.5 equiv of LiHMDS.
(Table 1). Reduction with L-Selectride provided a similar
result as LiBHEt3 (99:1 dr, Table 1, entry 1). We were
gratified to find the reversal of diastereoselectivity with a
ratio of 40:60 (4b/5b) when NaBH4 was used as a reducing
agent (Table 1, entry 2). Replacing NaBH4 with LiBH4
resulted in a slightly better outcome with a 35:65 dr
(Table 1, entry 3). Reduction using a sterically hindered
reducing agent like 9-borabicyclo[3.3.1]nonane (9-BBN)
failed to show any improvement (38:62 dr, Table 1, entry 4).
Interestingly, LiAlH4 showed an improved diastereoselectivity
of 18:82 dr, (Table 1, entry 6). To our delight, when DIBAL-H
was used, a marked enhancement in diastereoselectivity was
observed with a diastereomeric ratio of 4:96 (Table 1, entry 7).
The diastereoselectivity was further improved to 1:99 when the
reduction was conducted in toluene instead of THF (Table 1,
entry 8).
Pleased with these results, we focused our efforts on
developing a single-step method to yield 5b with high dia-
stereoselectivity. Unlike the LiBHEt3 conditions, pyrrolidine
5b was not observed during the reduction of sulfinyl ketimine
3a with DIBAL-H at -78 °C for 3 h followed by warming to
rt and stirring for 1-12 h. We reasoned that the low basicity
of the corresponding aluminum complex may inhibit the
cyclization. With this rationale the addition of LiHMDS to
the reaction mixture followed by warming the reaction
mixture from -78 to 23 °C led to complete cyclization. Thus,
in one pot we were able to synthesize (SS,S)-5a in a 90%
2238 J. Org. Chem. Vol. 75, No. 7, 2010

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JOCArticle
TABLE 2. Asymmetric Reductive Cyclization of γ-Chlorinated N-tert-
Butanesulfinyl Ketimine (SS)-3a-3l with LiBHEt3 and DIBAL-H/
LiHMDS
applicability (Table 2). In the LiBHEt3 mediated reductive
cyclization of phenyl γ-chloro N-tert-butanesulfinyl keti-
mine 3b, substitiuents such as OMe, Me, t-Bu, OH, Cl, Br,
F, etc. in the para and meta positions of the phenyl ring
(3c-3i) were well tolerated, and high diastereoselectivity
(99:1 dr) and high yields were obtained in every instance.
(Table 2, entries 3-6). Similarly, treatment 3c-3i with
DIBAL-H/LiHMDS afforded the corresponding 2-aryl sub-
stituted pyrrolidines (5c-5i) in 88-94% yields with high
diastereoselectivity (99:1 dr). Furthermore, heteroaryl keti-
mine 3j, when treated with LiBHEt3 or DIBAL-H/
LiHMDS, also underwent stereoselective reductive cycliza-
tion to afford 4j or 5j with diastereomeric ratio of 99:1 and
1:99 in 93% and 95% yields, respectively (Table 2, entry 10).
In addition, these reactions were also found to be tolerant to
aliphatic ketimines (Table 2, entries 11 and 12). Treatment of
cyclohexyl sulfinyl ketimine 3k with LiBHEt3 or DIBAL-H/
LiHMDS also afforded the corresponding pyrrolidines 4k or
5k in 94% and 95% yield with diastereomeric ratios of
99:1 and 1:99, respectively (Table 2, entry 10). However, when
methyl ketimine 3l was subjected to LiBHEt3 conditions, the
reverse stereoselective product, i.e., (R)-1-((S)-tert-butyl-
sulfinyl)-2-methylpyrrolidine (SS,R-5l) was obtained with
slightly lower diastereoselectivities (8:92 dr) in 88% yield
(Table 2, entry 12). In the same way, treatment of 3l with
DIBAL-H/LiHMDS afforded the reverse stereoselective pro-
duct, i.e., (S)-1-((S)-tert-butylsulfinyl)-2-methyl-pyrrolidine
(SS,S-4l) with 89% yield and diastereomeric ratio of 91:9
(Table 2, entry 12). Thus, as summarized in Table 2, all reactions
took place readily and afforded the corresponding pyrrolidines
in good to excellent yields with high diastereoselectivities.
Asymmetric Synthesis of 2-Substituted Piperidines and
Azepanes. Extension of this methodology to the asymmetric
LiBHEt3
DIBAL-H
entry
R
product yielda (dr)b product yielda (dr)b
1
2
3
4
5
6
7
8
4-BrC6H4
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
96 (99:1)
94 (99:1)
92 (99:1)
90 (99:1)
93 (99:1)
98 (99:1)
92 (99:1)
98 (99:1)
93 (99:1)
93 (99:1)
94 (99:1)
88 (8:92)
5a
5b
5c
5d
5e
5f
5g
5h
5i
90 (1:99)
92 (1:99)
93 (1:99)
87 (1:99)
91 (1:99)
94 (1:99)
90 (1:99)
93 (1:99)
98 (1:99)
95 (1:99)
95 (1:99)
89 (91:9)
4-MeC6H4
4-MeOC6H4
4-tBuC6H4
4-HOC6H4
3-MeOC6H4
4-ClC6H4
4-FC6H4
2-thienyl
C6H11
9
10
11
12
4j
4k
4l
5j
5k
5l
Me
aIsolated yield of analytically pure products. bThe diastereoselectivity
was determined by 1H NMR analysis. The “99:1 or 1:99” denotes that
signals for only one diastereomer were observed; dr relative to sulfur.
yield with a high diastereomeric ratio of 1:99 (Scheme 4).
The structure and absolute configuration of (SS,S)-5a was
confirmed by comparing the 1H NMR, 13C NMR, and
specific rotation data with literature data.19
Scope of the Reaction. With optimized one-step processes
to access either of the two diastereomers of 2-substituted
pyrrolidines (SS,R)-4 and (SS,S)-5 starting from N-sulfinyl
ketimines 3, a variety of γ-chlorinated N-tert-butanesulfinyl
ketimines (SS)-3 were used as substrates to probe the general
SCHEME 5. Asymmetric Synthesis of 2-Subtituted Piperidines
J. Org. Chem. Vol. 75, No. 7, 2010 2239

Rajender Reddy et al.
JOCArticle
synthesis of 2-substituted piperidines, azepanes, and azocines
was investigated. Reduction of δ-chlorinated N-tert-butane-
sulfinyl ketimine (3m) withLiBHEt3 at -78 °C for 3 h followed
by increasing the reaction temperature to rt and stirring over-
night led to the desired 2-phenyl piperidine 10m with high
diastereoselectivity (99:1) and 94% yield (Scheme 5). Likewise,
treatment of 3m with DIBAL-H/LiHMDS afforded reversal
of diastereofacial selectivity, and 2-phenyl piperidine 11m was
obtained with dr of 1:99 in 92% yield (Scheme 5). Excited by
these results, we moved on to the preparation of larger ring
systems like azepanes (seven-membered) and azocines (eight-
membered). Treatment of ε-chlorinated N-tert-butanesulfinyl
ketimine (3n) with LiBHEt3 at -78 °C for 3 h afforded the ε-
chloro sulfinamide 12n in quantitative yield and high diaster-
eoselectivity (99:1 dr). However, ensuing efforts to cyclize 12n
by warming the reaction to rt and stirring for 2 days failed to
afford the cyclized azepane ring. Prolonged stirring of 12n with
LiBHEt3 at rt led to the dechlorinated side product 13n
(Scheme 5). Similarly, treatment of 3n with DIBAL-H at
-78 °C for 3 h also led to complete conversion of 3n to 14n,
but subsequent treatment with LiHMDS at rt and stirring for 2
days did not result in the cyclized azepane (Scheme 5). A series
of other bases (BuLi, NaH, LiHMDS, Et3N, and KOH) were
investigated in different solvents to promote cyclization of 12n
and 14n to the seven-membered ring; however, no cyclization
was occurred (see the Supporting Information). We reasoned
that the increased strain coupled with high activation energy of
the transition state may inhibit the cyclization. Similar results
were obtained with ζ-chlorinated N-tert-butanesulfinyl
ketimine(SS)-3o.
FIGURE 1. Proposed transition states for the reduction of sulfinyl
ketimines (SS)-3.
poorly coordinating and rapidly reacting LiBHEt3 was
posed to attack the electrophilic carbon atom in a sterically
controlled fashion via an open transition state.
Hence, delivery of the hydride would occur from the same
face as the sulfur lone pair to give the (SS,R) diastereomer
(Figure 1, TS 2).
SCHEME 7. Selective Deprotection of Sulfinyl Group
SCHEME 6. Reduction of Dechlorinated N-tert-Butanesulfinyl
Ketimine (SS)-3p
Deprotection To Generate Single Enantiomers of 2-Sub-
tituted Pyrrolidines. Finally, dissolving 4a in methanol fol-
lowed by treatment with 4 M HCl for 30 min led to cleav-
age of the sulfinyl group resulting in the formation of the
(R)-2-(4-bromophenyl) pyrrolidine (17a) as a single enantio-
mer in 98% yield (Scheme 7). The other diastereomer 5a also
underwent smooth deprotection to afford (S)-2-(4-
bromophenyl)pyrrolidine (ent-17a) in 97% yield. The chloro
substituted pyrrolidine 4h and 5h were also tested under these
conditions and were found to give similar results. In the same
way, treatment of 4l or 5l with 4 M HCl (dioxane) in
methanol for 30 min afforded the (S)-2-(4-bromophenyl)-
pyrrolidine (17l) or (R)-2-(4-bromophenyl)pyrrolidine (ent-
17l) in 95% and 92% yields, respectively. The absolute
configuration of (S)-17l and (R)-ent-17l was confirmed by
comparing the specific rotation data with literature data.25
Thus, the sulfinyl group can be cleaved readily under mild
acidic conditions to provide the respective amines in excel-
lent yields.
Mechanistic Rationale/Reasoning. Intrigued by the rever-
sal of diastereofacial selectivity upon changing reducing
agents from LiBHEt3 to DIBAL-H, we pursued the reason
for this diastereoselective switch. To exclude the role of the
chloro group in the diastereoselectivity of the reducing
agents, we synthesized the dechlorinated ketimine 3p
(Scheme 6). Reduction of 3p with DIBAL-H and LiBHEt3
using the conditions mentioned earlier resulted in the for-
mation of 15p and 16p, respectively, with high diastereos-
electivity (Scheme 6), demonstrating that the chloro group
does not play a role. We propose that the DIBAL-H reaction
proceeds through a closed transition state where the alumi-
num metal coordinates with the sulfinyl oxygen directing the
hydride attack from the si face of the imine bond to
give the (SS,S) diastereomer (Figure 1, TS 1). Alternatively,
(25) (a) Kim, M.-J.; Lim, G-B; Whang, S-Y; Ku, B.-C.; Choi, J.-Y.
Bioorg. Med. Chem. Lett. 1996, 6, 71. (b) Kostyanovsky, R. G.; Gella,
I. M.; Markov, V. I; Samojlova, Z. E. Tetrahedron 1974, 30, 39.
2240 J. Org. Chem. Vol. 75, No. 7, 2010

Rajender Reddy et al.
JOCArticle
SCHEME 8. Asymmetric Reductive Cyclization of Methyl Ketimine 3l and Selective Deprotection of Sulfinyl Group
Conclusion. In conclusion, we have developed a highly
efficient, versatile one-step process for asymmetric synthesis
of either stereoisomer of 2-substituted pyrrolidines from the
same starting material with excellent yields and high diaster-
eoselectivety. This method was also applied for the asym-
metric synthesis of both diastereomers of 2-substituted
piperidines with good yields and excellent diastereoselectivety.
This method was found to be effective for a variety of
substrates incorporating various aromatic and aliphatic sub-
stituents. Extension of this work is currently underway in our
laboratory.
1.36 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 178.0, 137.5,
131.7, 128.7, 127.4, 57.9, 44.6, 31.6, 30.0, 22.7. HRMS (EI)
calcd for C14H21NOSl [M þ H] 286.1024, found 286.1032.
(S,E)-N-(4-Chloro-1-p-tolylbutylidene)-2-methylpropane-2-
sulfinamide (3c). Following the general procedure (GP1),
the reaction of 4-chloro-1-p-tolyl-butan-1-one (6c) (25 g,
127.0 mmol) with (SS)-tert-butanesulfinamide (23.1 g, 190.6
mmol) and Ti(OEt)4 (57.9 g, 254.2 mmol) gave 34.3 g (90%) of
pure γ-chloro N-sulfinyl ketimine (SS) 3c as viscous oil,
[R]25D = -17.5 (c 1.03, MeOH). 1H NMR (501 MHz, CDCl3)
δ ppm 7.74-7.83 (m, 2 H), 7.24 (d, J = 8.20 Hz, 2 H),
3.59-3.67 (m, 2 H), 3.22-3.49 (m, 2 H), 2.40 (s, 3 H),
2.08-2.25 (m, 2 H), 1.34 (s, 9 H). 13C NMR (125 MHz,
CDCl3) δ ppm 178.0, 142.4, 134.8, 129.4, 127.5, 57.7, 53.4,
44.7, 31.7, 30.0, 22.7, 21.4. HRMS (EI) calcd for
C15H23NOSCl [M þ H] 300.1189, found 300.1176.
Experimental Section
General Procedure (GP1) for the Synthesis of γ-Chloro
N-Sulfinyl Ketimine 3. A 500 mL, three-necked, round-bottomed
flask was charged with 1-(4-bromophenyl)-4-chlorobutan-1-one
6a (40.0 mmol), THF (100 mL), tert-butanesulfinamide 7 (60.0
mmol), and Ti(OEt)4 (80.0 mmol) under nitrogen atm. The
reaction mixture was then heated at reflux at 65 °C for 48 h. After
completion, the reaction was allowed to cool to rt. Isopropyl
acetate (100 mL) and saturated NaCl solution (100 mL) were then
added to this mixture and stirred for 1 h. The solids were removed
by filtration, and the filtrate was washed with water (2 ꢀ 50 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% ethyl acetate in heptanes)
to afford the pure γ-chloro N-sulfinyl ketimine 3a.
(S,E)-N-(4-Chloro-1-(4-methoxyphenyl)butylidene)-2-methyl-
propane-2-sulfinamide (3d). Following the general procedure
(GP1), the reaction of 4-chloro-1-(4-methoxyphenyl)butan-1-
one (6d) (25 g, 117.5 mmol) with (SS)-tert-butanesulfinamide
(21.37 g, 176.32 mmol) and Ti(OEt)4 (57.9 g, 235.1 mmol) gave
31.56 g (85%) of pure γ-chloro N-sulfinyl ketimine (SS) 3d as
viscous oil, [R]25 = -28.3 (c 1.15, MeOH). 1H NMR (501
D
MHz, CDCl3) δ ppm 7.83-7.91 (m, 2 H), 6.88-6.97 (m, 2 H),
3.86 (s, 3 H), 3.59-3.68 (m, 2 H), 3.19-3.47 (m, 2 H), 2.07-2.27
(m, 2 H), 1.32 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm
178.0, 162.6, 130.0, 129.4, 114.4, 57.5, 55.4, 53.4, 44.8, 31.7, 29.9,
22.6. HRMS (EI) calcd for C15H23NO2SCl [M þ H] 316.1138,
found 316.1125.
(S,E)-N-(4-Chloro-1-(4-bromophenyl)butylidene)-2-methylpro-
pane-2-sulfinamide (3a). Following the general procedure (GP1),
the reaction of 4-chloro-1-(4-bromophenyl)-butan-1-one (6b)
(25.5 g, 100.0 mmol) with (SS)-tert-butanesulfinamide (13.3 g,
110.0 mmol) and Ti(OEt)4 (34.5g, 150.0mmol) gave 30.6g (84%)
of pure γ-chloro N-sulfinyl ketimine (SS) 3a as white solid, mp =
48-50 °C, [R]25D = -24.2 (c 1.10, MeOH). 1H NMR (501 MHz,
CDCl3) δ ppm 7.66-7.86 (m, 2 H), 7.56 (d, J = 8.51 Hz, 2 H),
3.57-3.70 (m, 2 H), 3.19-3.51 (m, 2 H), 2.01-2.28 (m, 2 H),
1.24-1.42 (m, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 176.8,
136.3, 131.9, 128.9, 126.5, 58.0, 44.5, 31.5, 29.8, 22.7. HRMS (EI)
calcd for C14H20NOSBrCl [M þ H] 364.0120, found 364.0138.
(S,E)-N-(4-chloro-1-phenyl)butylidene)--2-methylpropane-2-
sulfinamide (3b). Following the general procedure (GP1), the
reaction of 4-chloro-1-phenyl-butan-1-one (6b) (18.2 g,
100.0 mmol) with (SS)-tert-butanesulfinamide (13.3 g, 110.0
mmol) and Ti(OEt)4 (34.5 g, 150.0 mmol) gave 25.9 g (91%) of
pure γ-chloro N-sulfinyl ketimine (SS) 3b as white solid, mp =
(S,E)-N-(1-(4-tert-Butylphenyl)-4-chlorobutylidene)-2-methyl-
propane-2-sulfinamide (3e). Following the general procedure
(GP1), the reaction of 1-(4-tert-butylphenyl)-4-chlorobutan-1-
one (6e) (10 g, 41.885 mmol) with (SS)-tert-butanesulfinamide
(7.614 g, 62.83 mmol) and Ti(OEt)4 (19.112 g, 83.77 mmol) gave
13.6 g (90%) of pure γ-chloro N-sulfinyl ketimine (SS) 3e as
viscous oil, [R]25D = -18.9 (c 1.0, MeOH). 1H NMR (501 MHz,
CDCl3) δ ppm 7.76-7.90 (m, 2 H), 7.45 (d, J = 7.57 Hz, 2 H),
3.59-3.69 (m, 2 H), 3.21-3.51 (m, 2 H), 2.08-2.27 (m, 2 H), 1.34
(s, 18 H). 13C NMR (125 MHz, CDCl3) δ ppm 177.8, 155.3,
134.7, 127.3, 125.6, 57.7, 53.4, 44.7, 34.9, 31.7, 31.1, 28.1, 22.7.
HRMS (EI) calcd for C18H29NOSCl [M þ H] 342.1653, found
342.1657.
(S,E)-N-(4-Chloro-1-(4-hydroxyphenyl)butylidene)-2-methyl-
propane-2-sulfinamide (3f). Following the general procedure
(GP1), the reaction of 5-chloro-1-(4-hydroxy-phenyl)butan-1-
one (6f) (10 g, 50.34 mmol) with (SS)-tert-butanesulfinamide
(9.15 g, 75.51 mmol) and Ti(OEt)4 (22.969 g, 100.68 mmol) gave
35-36 °C, [R]25 = -20.9 (c 1.10, MeOH). 1H NMR (501
D
MHz, CDCl3) δ ppm 7.79-7.96 (m, 2 H), 7.33-7.56 (m, 3 H),
3.57-3.72 (m, 2 H), 3.23-3.54 (m, 2 H), 2.07-2.28 (m, 2 H),
9.87 g (65%) of pure γ-chloro N-sulfinyl ketimine (SS) 3f as a
D
1
solid, mp = 88-90 °C, [R]25 = -52.0 (c 1.04, MeOH). H
J. Org. Chem. Vol. 75, No. 7, 2010 2241

Rajender Reddy et al.
JOCArticle
NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1 H), 7.81 (d, J =
7.58 Hz, 2 H), 6.86 (d, J = 8.84 Hz, 2 H), 3.71 (t, J = 6.57 Hz, 2
HRMS (EI) calcd for C14H27NOSCl [M þ H] 292.8883, found
292.8885.
H), 3.10-3.33 (m, 2 H), 1.88-2.12 (m, 2 H), 1.21 (s, 9 H). 13
C
(S,E)-N-(4-Chloro-1-methyl)-2-methylpropane-2-sulfinamide
(3l). Following the general procedure (GP1), the reaction of
4-chloro-1-methyl-butan-1-one (61l) (12.0 g, 100.0 mmol) with
(SS)-tert-butanesulfinamide (13.3 g, 110.0 mmol) and Ti(OEt)4
(34.5 g, 150.0 mmol) gave 18.8 g (85%) of pure γ-chloro
NMR (125 MHz, DMSO-d6)) δ ppm 178.9, 161.2, 129.6, 127.7,
115.4, 56.3, 44.7, 31.5, 29.4 22.0. HRMS (EI) calcd for
C14H21NO2SCl [M þ H] 302.0982, found 302.1011.
(S,E)-N-(4-Chloro-1-(3-methoxyphenyl)butylidene)-2-methyl-
propane-2-sulfinamide (3g). Following the general procedure
(GP1), the reaction of 5-chloro-1-(3-methoxyphenyl)butan-1-
one (6g) (5 g, 23.51 mmol) with (SS)-tert-butanesulfinamide
(4.27 g, 35.26 mmol) and Ti(OEt)4 (10.72 g, 47.02 mmol) gave
6.08 g (82%) of pure γ-chloro N-sulfinyl ketimine (SS) 3g as a
N-sulfinyl ketimine (SS) 3l as a viscous liquid, [R]25 = -21.1
D
(c 1.60, MeOH). 1H NMR (501 MHz, CDCl3) δ ppm 3.60 (t, J =
6.31 Hz, 2 H), 2.60 (t, J = 7.09 Hz, 2 H), 2.35 (s, 3 H), 2.00-2.16
(m, 2 H), 1.24(s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 183.8,
56.3, 44.2, 39.9, 27.9, 23.3, 22.1. HRMS (EI) calcd for
C9H19ClNOS [M þ H] 224.0876, found 224.0861.
viscous liquid, [R]25 = -10.4 (c 1.42, MeOH). 1H NMR
D
(501 MHz, CDCl3) δ ppm 7.40-7.49 (m, 2 H), 7.34 (t, J =
7.88 Hz, 1 H), 7.03 (d, J = 7.25 Hz, 1 H), 3.83 (s, 3 H), 3.60-3.66
(m, 2 H), 3.23-3.48 (m, 2 H), 2.08-2.25 (m, 2 H), 1.33 (s, 9 H).
13C NMR (125 MHz, CDCl3) δ ppm 177.7, 159.7, 138.9, 129.6,
119.8, 117.5, 112.6, 57.9, 55.3, 44.6, 31.7, 30.0, 22.7. HRMS (EI)
calcd for C15H23NO2SCl [M þ H] 316.1133, found 316.1134.
(S,E)-N-(4-Chloro-1-(4-chlorophenyl)butylidene)-2-methyl-
propane-2-sulfinamide (3h). Following the general procedure
(GP1), the reaction of 4-chloro-1-(4-chlorophenyl)butan-1-one
(6h) (10 g, 46.06 mmol) with (SS)-tert-butanesulfinamide (8.374 g,
69.95 mmol) and Ti(OEt)4 (21.018 g, 92.12 mmol) gave 13.7 g
(93%) of pure γ-chloro N-sulfinyl ketimine (SS) 3h as a white
color solid, mp = 40-42 °C, [R]25D = -26.9 (c 1.12, MeOH). 1H
NMR (501 MHz, CDCl3) δ ppm 7.75-7.88 (m, 2 H), 7.41 (d, J =
8.51 Hz, 2 H), 3.59-3.69 (m, 2 H), 3.23-3.49 (m, 2 H), 2.04-2.25
(m, 2 H), 1.32 (s, 9 H). 13C NMR(125 MHz, CDCl3) δ ppm 176.8,
138.0, 135.9, 129.0, 128.7, 58.0, 44.6, 31.6, 29.8, 22.7. HRMS (EI)
calcd for C14H20NOSCl2 [M þ H] 320.06378, found 320.0638.
(S,E)-N-(4-Chloro-1-(4-fluorophenyl)butylidene)-2-methyl-
propane-2-sulfinamide (3i). Following the general procedure
(GP1), the reaction of 4-chloro-1-(4-fluorophenyl)butan-1-one
(6i) (10 g, 49.84 mmol) with (SS)-tert-butanesulfinamide (9.06 g,
74.76 mmol) and Ti(OEt)4 (22.74 g, 99.68 mmol) gave 14.2 g
(94%) of pureγ-chloroN-sulfinyl ketimine (SS) 3i asa white color
solid, mp= 38-40 °C,[R]25D = -40.7 (c 1.05, MeOH). 1H NMR
(501 MHz, CDCl3) δ ppm 7.85-7.96 (m, 2 H), 7.12 (t, J = 8.51
Hz, 2 H), 3.60-3.70 (m, 2 H), 3.23-3.49 (m, 2 H), 2.08-2.26 (m,
2 H), 1.35 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 176.8,
165.9, 163.9, 133.7, 129.8, 129.7, 115.8, 115.7, 115.4, 57.8, 44.6,
31.6, 29.9, 22.7. HRMS (EI) calcd for C14H20NOSClF [M þ H]
304.0938, found 304.0926.
(S,E)-N-(5-Chloro-1-phenylpentylidene)-2-methylpropane-2-
sulfinamide (3m). Following the general procedure (GP1), the
reaction of 5-chloro-1-phenylpentan-1-one (6m) (10 g, 50.84
mmol) with (SS)-tert-butanesulfinamide (9.24 g, 76.26 mmol)
and Ti(OEt)4 (23.2 g, 101.68 mmol) gave 13.72 g (90%) of pure
γ-chloro N-sulfinyl ketimine (SS) 3m as a viscous liquid,
[R]25D = þ23.6 (c 1.02, MeOH). 1H NMR (501 MHz, CDCl3)
δ ppm 7.78-7.91 (m, 2 H), 7.39-7.51 (m, 3 H), 3.51-3.61 (m, 2
H), 3.14-3.37 (m, 2 H), 1.78-1.95 (m, 4 H), 1.33 (s, 9 H). 13
C
NMR (125 MHz, CDCl3) δ ppm 179.0 137.7, 131.5, 128.6,
127.3, 57.7, 44.3, 32.3, 31.3, 25.9, 22.7. HRMS (EI) calcd for
C
15H23NOSCl [M þ H] 300.1183, found 300.1184.
(S,E)-N-(6-Chloro-1-phenylhexylidene)-2-methylpropane-2-
sulfinamide (3n). Following the general procedure (GP1),
the reaction of 6-chloro-1-phenylhexan-1-one (6n) (10 g,
47 mmol) with (SS)-tert-butanesulfinamide (8.6 g, 71.4 mmol)
and Ti(OEt)4 (20.71 g, 94 mmol) gave 13.42 g (90%) of pure
γ-chloro N-sulfinyl ketimine (SS) 3n as a viscous liquid,
[R]25D = þ12.4 (c 1.22, MeOH). 1H NMR (501 MHz, CDCl3)
δ ppm 7.83 (br. s., 2 H), 7.40-7.51 (m, 3 H), 3.57 (none, 1 H),
3.51 (t, J = 6.46 Hz, 2 H), 3.23-3.34 (m, 1 H), 3.12-3.22 (m, 1
H), 1.77-1.85 (m, 2 H), 1.65-1.74 (m, 2 H), 1.54-1.63 (m,
2 H), 1.35 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 179.5,
137.8, 131.5, 128.6, 127.3, 57.3, 44.7, 32.2, 32.0, 27.9, 27.0,
22.7. HRMS (EI) calcd for C16H25NOSCl [M þ H] 314.1345,
found 314.1347.
(S,E)-N-(7-Chloro-1-phenylhexylidene)-2-methylpropane-2-
sulfinamide (3o). Following the general procedure (GP1), the
reaction of 7-chloro-1-phenylheptan-1-one (6o) (11.5 g, 50.0
mmol) with (SS)-tert-butanesulfinamide (9.0 g, 75.0 mmol) and
Ti(OEt)4 (22.8 g, 100.0 mmol) gave 14.5 g (89%) of pure γ-chloro
N-sulfinyl ketimine (SS) 3o as a viscous liquid, [R]25 = þ29.0
(S,E)-N-(4-Chloro-1-(thiophen-2-yl)butylidene)-2-methylpro-
pane-2-sulfinamide (3j). Following the general procedure (GP1),
the reaction of 4-chloro-1-(thiophen-2-yl)butan-1-one (6j) (5 g,
26.5 mmol) with (SS)-tert-butanesulfinamide (4.817 g, 39.75
mmol) and Ti(OEt)4 (12.09 g, 53.0 mmol) gave 7.5 g (97%) of
pure γ-chloro N-sulfinyl ketimine (SS) 3j as a viscous liquid,
[R]25D = -90.0 (c 1.06, MeOH). 1H NMR (501 MHz, CDCl3) δ
ppm 7.58 (d, J = 3.15 Hz, 1 H), 7.50 (d, J = 5.04 Hz, 1 H),
7.07-7.12 (m, 1 H), 3.60-3.70 (m, 2 H), 3.33-3.42 (m, 1 H), 3.23
(dd, J = 10.72, 5.67 Hz, 1 H), 2.15-2.35 (m, 2 H), 1.30 (s, 9 H).
13C NMR (125 MHz, CDCl3) δ ppm 172.3, 144.9, 132.3, 129.6,
128.0, 58.0, 44.6, 32.1, 30.6, 22.5. HRMS (EI) calcd for
C12H19NOS2Cl [M þ H] 292.0597, found 292.0573.
D
(c 1.02, MeOH). 1H NMR (501 MHz, CDCl3) δ ppm 7.74-7.92
(m, 2 H), 7.35-7.53 (m, 3 H), 3.51 (t, J = 6.78 Hz, 2 H),
3.06-3.36 (m, 2 H), 1.62-1.85 (m, 4 H), 1.40-1.54 (m, 4 H),
1.32 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 179.8, 137.9,
131.4, 128.5, 127.4, 57.5, 44.9, 32.4, 29.0, 28.4, 26.5, 22.7. HRMS
(EI) calcd for C17H27ClNOS [M þ H] 328.1502, found 328.1504.
(S,E)-2-Methyl-N-(1-phenylbutylidene)propane-2-sulfinamide
(3p). Following the general procedure (GP1), the reaction of 1-
phenylpentan-1-one (6p) (10 g, 67.47 mmol) with (SS)-tert-
butanesulfinamide (12.16 g, 101.20 mmol) and Ti(OEt)4
(30.786 g, 134.94 mmol) gave 15.6 g (92%) of pure γ-chloro
N-sulfinyl ketimine (SS) 3p as a viscous liquid, [R]25D = þ30.4
(c 1.63, MeOH). 1H NMR (501 MHz, CDCl3) δ ppm 7.78-7.92
(m, 2 H), 7.37-7.52 (m, 3 H), 3.20-3.32 (m, 1 H), 3.07-3.20 (m,
1 H), 1.65-1.78 (m, 2 H), 1.32 (s, 9 H), 1.03 (t, J = 7.41 Hz, 3 H).
13C NMR (125 MHz, CDCl3) δ ppm 180.0, 138.2, 131.4, 128.5,
127.4, 57.3, 34.3, 22.6, 22.2, 14.2. HRMS (EI) calcd for
C14H22NOS [M þ H] 252.1422, found 252.1414.
(S,E)-N-(4-Chloro-1-cyclohexyl-butylidene)-2-methylpropane-
2-sulfinamide (3k). Following the general procedure (GP1), the
reaction of 4-chloro-1-cyclohexyl-butan-1-one (6k) (9.1 g, 50.0
mmol) with (SS)-tert-butanesulfinamide (9.06 g, 74.76 mmol)
and Ti(OEt)4 (22.74 g, 99.68 mmol) gave 13.2 g (90%) of pure
γ-chloro N-sulfinyl ketimine (SS) 3k as a viscus oil, [R]25
=
D
-32.8 (c 1.02, MeOH). 1H NMR (501 MHz, DMSO-d6) δ ppm
3.63-3.76 (m, 2 H), 2.62-2.74 (m, 2 H), 2.20-2.33 (m, 1 H),
2.00-2.11 (m, 2 H), 1.76-1.87 (m, 2 H), 1.53-1.69 (m, 3 H),
1.16-1.36 (m, 5 H), 1.12 (s, 9 H). 13C NMR (125 MHz, DMSO-
d6) δ ppm 168.7, 55.9, 48.7, 44.5, 32.7, 27.68, 25.4, 24.4, 21.7.
General Procedure (GP2) for the Synthesis of 2-Substituted
Pyrrolidines 4. LiBHEt3 was added to a solution of ketimine 3a
(5 mmol) in THF (15 mL) at -78 °C under nitrogen. After
stirring for 3 h at -78 °C, the reaction mixture was warmed to rt
and stirred for 1 h. On completion, the reaction was quenched
2242 J. Org. Chem. Vol. 75, No. 7, 2010

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JOCArticle
with saturated NH4Cl solution (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 column
chromatography (silica gel, ethyl acetate/hexanes) to afford the
pure 2-substituted pyrrolidines 4.
General Procedure (GP3) for the Synthesis of 2-Substituted
Pyrrolidines 5. To a solution of ketimine 3a (5 mmol) in toluene
(15 mL) at -78 °C was added DIBAL-H under nitrogen. After
stirring for 3 h at -78 °C, the reaction mixture was warmed to rt
followed by addition of LiHMDS (7.5 mmol) and stirred for 1 h.
On completion, the reaction was quenched with saturated
KþNaþ tartarate solution (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 column
chromatography (silica gel, ethyl acetate/hexanes) to afford
the pure 2-substituted pyrrolidines 5.
reaction of γ-chloro N-sulfinyl ketimine (SS) 3c (1.49 g,
5.0 mmol) with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF)
afforded pyrrolidine 4c (1.21 g, 92%) as a white solid, mp =
1
62-64 °C, [R]25 = þ144.6 (c 1.03, MeOH). H NMR (501
D
MHz, CDCl3) δ ppm 7.17 (d, J= 8.2 Hz, 2 H), 7.11 (d, J= 8.2
Hz, 2 H), 4.60 (t, J = 7.41 Hz, 1 H), 3.83-3.92 (m, 1 H),
2.92-3.01 (m, 1 H), 2.32 (s, 3 H), 2.15-2.25 (m, 1 H),
1.93-2.01 (m, 1 H), 1.72-1.90 (m, 2 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
C
15H24NOS [M þ H] 266.1573, found 266.1574.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-mehtylphenyl)-
pyrrolidine (5c). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3b (1.49 g,
5.0 mmol) with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene)
and followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-bromophenyl)-
pyrrolidine (4a). Following the general procedure (GP2), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3a (1.82 g, 5.0
mmol) with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF)
afforded pyrrolidine 4a (1.58 g, 96%) as white solid, mp =
afforded pyrrolidine 5c (1.39 g, 93%) as white solid, mp = 96-
D
1
98 °C, [R]20 = -159.0 (c 0.8, MeOH). H NMR (501 MHz,
CDCl3) δ ppm 7.09-7.17 (m, 4 H), 5.02 (dd, J = 8.04, 2.68 Hz, 1
H), 3.62-3.70 (m, 1 H), 3.50-3.57 (m, 1 H), 2.32 (s, 3 H),
2.08-2.18 (m, 1 H), 1.77-1.90 (m, 2 H), 1.70-1.78 (m, 1 H),
1.06 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 141.5, 136.0,
129.0, 126.4, 57.5, 57.4, 54.5, 36.6, 24.1, 23.1, 23.0. HRMS (EI)
calcd for C15H24NOS [M þ H] 266.1579, found 266.1569.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-methoxyphenyl)-
pyrrolidine (4d). Following the general procedure (GP2), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3d (1.57 g,
5.0 mmol) with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF)
afforded pyrrolidine 4d (1.26 g, 90%) as a white solid, mp =
61-63 °C, [R]25D = þ123.2 (c 1.0, MeOH). 1H NMR (400 MHz,
CDCl3) δ ppm 7.18-7.23 (m, 2 H), 6.82-6.87 (m, 2 H),
4.52-4.61 (m, 1 H), 3.83-3.90 (m, 1 H), 3.78 (s, 3 H),
2.91-3.00 (m, 1 H), 2.14-2.24 (m, 1 H), 1.92-2.02 (m, 1 H),
1.70-1.90 (m, 2 H), 1.09 (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 þ H] 282.1528,
found 282.1527.
120-122 °C, [R]25 = þ152.3 (c 1.13, CHCl3). 1H NMR
D
(501 MHz, CDCl3) δ ppm 7.44 (d, J = 8.51 Hz, 2 H), 7.17
(d, J = 8.51 Hz, 2 H), 4.59 (t, J = 7.25 Hz, 1 H), 3.83-3.96 (m,
1 H), 2.89-3.05 (m, 1 H), 2.17-2.30 (m, 1 H), 1.68-2.02 (m, 3
H), 1.10 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 142.3,
131.4, 128.9, 121.0, 68.7, 57.2, 42.1, 35.9, 26.3, 23.8. HRMS
(EI) calcd for C14H21BrNOS [M þ H] 330.0522, found
330.0527.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-bromophenyl)-
pyrrolidine (5a). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3a (3.65 g,
10.0 mmol) with DIBAL-H (12.0 mL, 12.0 mmol, 1.0 M in
toluene) and followed by LiHMDS (15.0 mL, 15.5 mmol, 1.0
mL in THF) afforded pyrrolidine 5a (2.91 g, 90%) as white solid,
mp = 100-112 °C, [R]25D = -164.3 (c 1.13, CHCl3). 1H NMR
(501 MHz, CDCl3) δ ppm 7.38-7.49 (m, 2 H), 7.14 (d, J = 8.51
Hz, 2 H), 5.02 (dd, J = 8.20, 2.84 Hz, 1 H), 3.49-3.69 (m, 2 H),
2.16 (dd, J = 11.98, 9.14 Hz, 1 H), 1.64-1.96 (m, 3 H), 1.05 (s, 9
H). 13C NMR (125 MHz, CDCl3) δ ppm 143.7, 131.4, 128.2,
120.3, 57.4, 56.9, 54.8, 36.4, 24.1, 23.0. HRMS (EI) calcd for
C14H21BrNOS [M þ H] 330.0527, found 330.0539.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-methoxyphenyl)-
pyrrolidine (5d). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3d (1.57 g,
5.0 mmol) with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene)
and followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
afforded pyrrolidine 5d (1.22 g, 87%) as white solid, mp =
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-phenyl-pyrrolidine (4b).
Following the general procedure (GP2), the reaction of γ-chloro
N-sulfinyl ketimine (SS) 3b (1.42 g, 5.0 mmol) with LiBHEt3
1
85-87 °C, [R]25 = -140.8 (c 1.09, MeOH). H NMR (501
D
MHz, CDCl3) δ ppm 7.16 (d, J = 8.83 Hz, 2 H), 6.83-6.87 (m,
2 H), 4.99 (dd, J = 7.88, 2.84 Hz, 1 H), 3.79 (s, 3 H), 3.62-3.70
(m, 1 H), 3.47-3.55 (m, 1 H), 2.07-2.17 (m, 1 H), 1.78-1.91 (m,
2 H), 1.69-1.76 (m, 1 H), 1.06 (s, 9 H). 13C NMR (125 MHz,
CDCl3) δ ppm 158.2, 136.6, 127.6, 113.7, 57.4, 55.1, 54.2, 36.6,
24.1, 23.1. HRMS (EI) calcd for C15H24NO2S [M þ H] 282.1528,
found 282.1532.
(6.0 mL, 6.0mmol, 1.0M inTHF) afforded pyrrolidine4b(1.17 g,
1
94%) as a viscous liquid, [R]25 = þ121.6 (c 1.05, CHCl3). H
D
NMR (501 MHz, CDCl3) δ ppm 7.14-7.40 (m, 5 H), 4.64 (t, J =
7.25 Hz, 1 H), 3.83-3.99 (m, 1 H), 2.91-3.04 (m, 1 H), 2.19-2.34
(m, 1 H), 1.71-2.01 (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 þ H] 252.1439, found
252.1422.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-tert-butylphenyl)-
pyrrolidine (4e). Following the general procedure (GP2), the
reaction of γ-chloroN-sulfinyl ketimine (SS) 3e (1.70 g, 5.0 mmol)
with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded
pyrrolidine 4e (1.42 g, 93%) as a white solid, mp = 45-50 °C,
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-phenyl-pyrrolidine
(5b). Following the general procedure (GP3), the reaction of
γ-chloro N-sulfinyl ketimine (SS) 3b (1.42 g, 5.0 mmol) with
DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed
by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF) afforded
pyrrolidine 5b (1.15 g, 92%) as white solid, mp = 80-81 °C,
[R]25D = -140.0 (c 1.07, CHCl3). 1H NMR (501 MHz, CDCl3)
δ ppm 7.16-7.34 (m, 5 H), 5.07 (dd, J = 8.04, 2.68 Hz, 1 H),
3.61-3.71 (m, 1 H), 3.52-3.60 (m, 1 H), 2.16 (dd, J = 11.35,
8.51 Hz, 1 H), 1.71-1.92 (m, 3 H), 1.05 (s, 9 H). 13C NMR (125
MHz, CDCl3) δ ppm 143.1, 126.8, 125.0, 55.9, 55.9, 53.3, 35.1,
22.6, 21.5. HRMS (EI) calcd for C14H22NOS [M þ H]
252.1402, found 252.1413.
[R]25 = 110.5 (c 1.0, MeOH). 1H NMR (400 MHz, CDCl3) δ
D
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), 3.85-3.92 (m, 1 H), 2.93-3.01 (m, 1 H),
2.17-2.25 (m, 1 H), 1.91-2.00 (m, 1 H), 1.74-1.91 (m, 2 H), 1.31
(s, 9 H), 1.11 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 150.0,
140.1, 126.7, 125.1, 57.2, 42.0, 35.8, 34.4, 31.5, 31.4, 26.2, 23.9.
HRMS (EI) calcd for C18H30NOS [M þ H]308.2043, found
308.2046.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-tert-butylphenyl)-
pyrrolidine (5e). Following the general procedure (GP3), the reac-
tion of γ-chloro N-sulfinyl ketimine (SS) 3e (1.70 g, 5.0 mmol)
with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-methylphenyl)-
pyrrolidine (4c). Following the general procedure (GP2), the
J. Org. Chem. Vol. 75, No. 7, 2010 2243

Rajender Reddy et al.
JOCArticle
followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
afforded pyrrolidine 5e(1.39 g, 91%) as white solid, mp =
(400 MHz, CDCl3) δ ppm 7.21 (dd, 4 H), 4.55 (t, 1 H),
3.79-3.87 (m, 1 H), 2.87-2.96 (m, 1 H), 2.14-2.23 (m, 1 H),
1.63-1.97 (m, 3 H), 1.05 (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 þ H] 286.1032,
found 286.1028.
55-60 °C, [R]25 = -141.0 (c 1.12, MeOH). 1H NMR
D
(501 MHz, CDCl3) δ ppm 7.31 (d, J = 8.20 Hz, 2 H), 7.16 (d,
J = 8.20 Hz, 2 H), 5.02 (dd, J = 8.04, 2.36 Hz, 1 H), 3.63-3.70
(m, 1 H), 3.48-3.54(m, 1 H), 2.09-2.16 (m, 1 H), 1.74-1.88 (m, 3
H), 1.31 (s, 9 H), 1.07 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ
ppm 149.3, 141.2, 126.1, 125.1, 57.8, 57.4, 54.1, 36.4, 34.4, 31.3,
24.1, 23.1. HRMS (EI) calcd for C18H30NOS [M þ H] 308.2048,
found 308.2043.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-chlorophenyl)-
pyrrolidine (5h). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3h (1.59 g,
5.0 mmol) with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene)
and followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
afforded pyrrolidine 5h (1.32 g, 93%) as white solid, mp =
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-hydroxylphenyl)-
pyrrolidine (4f). Following the general procedure (GP2), the
reaction ofγ-chloroN-sulfinylketimine (SS) 3f(1.50 g, 5.0 mmol)
with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded
pyrrolidine 4f (1.30 g, 98%) as a white solid, mp = 150 °C,
[R]25D = þ137.4 (c 0.93, MeOH). 1H NMR (501 MHz, CDCl3) δ
ppm 7.13 (d, J = 8.51 Hz, 2 H), 6.82 (d, J = 8.51 Hz, 2 H), 6.50
(br. s., 1 H), 4.53-4.56 (m, 1 H), 3.84-3.89 (m, 1 H), 2.94-3.01
(m, 1 H), 2.18-2.23 (m, 1 H), 1.95-2.01 (m, 1 H), 1.74-1.87 (m,
2 H), 1.12 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 155.6,
134.4, 128.5, 115.2, 68.7, 57.2, 42.2, 35.7, 26.3, 23.8. HRMS (EI)
calcd for C14H22NO2S [M þ H] 268.1371, found 268.1364.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-hydroxyphenyl)-
pyrrolidine (5f). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3f (1.50 g, 5.0
mmol) with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and
followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
afforded pyrrolidine 5f (1.25 g, 94%) as white solid, mp = 185
95-102 °C, [R]25 = -145.6 (c 0.75, MeOH). 1H NMR
D
(400 MHz, CDCl3) δ ppm 7.26-7.31 (m, 2 H), 7.16-7.21 (m,
2 H), 5.04 (dd, J = 7.96, 2.65 Hz, 1 H), 3.50-3.69 (m, 1 H),
2.07-2.23 (m, 1 H), 1.65-1.94 (m, 3 H), 1.05 (s, 9 H), 1.05 (s,
9 H). 13C NMR (125 MHz, CDCl3) δ ppm 143.2, 132.2, 128.5,
127.9, 57.5, 56.9, 54.9, 36.5, 24.1, 23.0. HRMS (EI) calcd for
C14H21NOSCl [M þ H] 286.1032, found 286.1034.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-fluorophenyl)-
pyrrolidine (4i). Following the general procedure (GP2), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3i (1.51 g, 5.0 mmol)
with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded
pyrrolidine 4i (1.25 g, 93%) as a white solid, [R]25 = þ127.4
D
(c 1.18, MeOH). 1H NMR (400 MHz, CDCl3) δ ppm 7.21-7.30
(m, 2 H), 6.95-7.04 (m, 2 H), 4.58-4.64(m, 1 H), 3.82-3.93 (m, 1
H), 2.92-3.01 (m, 1 H), 2.20-2.29 (m, 1 H), 1.93-2.01 (m, 1 H),
1.70-1.91 (m, 2 H), 1.09 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ
ppm 163.2, 160.8, 138.9, 128.8, 128.7, 115.2, 115.0, 68.5, 57.2,
42.0, 36.0, 26.3, 23.8. HRMS (EI) calcd for C14H21NOSF [M þ
H] 270.1322, found 270.1321.
°C, [R]25 = -124.4 (c 1.02, MeOH). 1H NMR (501 MHz,
D
CDCl3) δ ppm 8.07 (s, 1 H), 7.08 (d, J = 8.51 Hz, 2 H), 6.83 (d,
J = 8.83 Hz, 2 H), 4.87 (dd, J = 7.57, 3.15 Hz, 1 H), 3.69-3.76
(m, 1 H), 3.40-3.47 (m, 1 H), 2.13 (dd, J = 11.98, 7.88 Hz, 1 H),
1.81-1.92 (m, 2 H), 1.73-1.81 (m, 1 H), 1.13 (s, 9 H). 13C NMR
(125 MHz, CDCl3) δ ppm 155.8, 134.6, 127.8, 115.5, 60.0, 57.8,
51.9, 36.2, 24.0, 23.4. HRMS (EI) calcd for C14H22NO2S [M þ
H] 268.1371, found 268.1365.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-chlorophenyl)-
pyrrolidine (5i). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3i (1.51 g, 5.0 mmol)
with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and
followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(3-methoxyphenyl)-
pyrrolidine (4g). Following the general procedure (GP2), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3g (1.57 g,
5.0 mmol) with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF)
afforded pyrrolidine 5i (1.31 g, 98%) as white solid, mp =
1
80 °C, [R]25 = -146.5 (c 1.0, MeOH). H NMR (501 MHz,
D
CDCl3) δ ppm 7.19-7.24 (m, 2 H), 6.97-7.02 (m, 2 H), 5.04 (dd,
J = 7.88, 2.84 Hz, 1 H), 3.62-3.69 (m, 1 H), 3.51-3.56 (m, 1 H),
2.12-2.19 (m, 1 H), 1.76-1.92 (m, 2 H), 1.68-1.76 (m, 1 H), 1.05
(s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 162.5, 160.5, 140.3,
128.0, 128.0, 115.2, 115.0, 57.4, 57.0, 54.5, 36.5, 24.1, 23.0. HRMS
(EI) calcd for C14H21NOSF [M þ H] 270.1322, found 270.1320.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-thiophenyl-pyrroli-
dine (4j). Following the general procedure (GP2), the reaction of
γ-chloro N-sulfinyl ketimine (SS) 3j (1.45 g, 5.0 mmol) with
LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded pyrroli-
dine 4j (1.19 g, 93%) as a viscous liquid, [R]25D = þ98.5 (c 1.21,
MeOH). 1H NMR (501 MHz, CDCl3) δ ppm 7.19 (dd, J = 4.26,
1.73 Hz, 1 H), 6.90-6.96 (m, 2 H), 4.94 (t, J = 6.46 Hz, 1 H),
3.78-3.86 (m, 1 H), 2.91-2.98 (m, 1 H), 2.22-2.30 (m, 1 H),
1.85-2.03 (m, 3 H), 1.14 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ
ppm 147.9, 126.6, 124.4, 65.1, 57.5, 41.4, 35.8, 26.7, 23.7. HRMS
(EI) calcd for C12H20NOS2 [M þ H] 258.0986, found 258.0979.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2thiophenyl-pyrrolidine
(5j). Following the general procedure (GP3), the reaction of
γ-chloro N-sulfinyl ketimine (SS) 3j (1.45 g, 5.0 mmol) with
DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed
by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF) afforded
pyrrolidine 5j (1.22 g, 95%) as white solid, mp = 125-130 °C,
[R]25D = -130.2 (c 0.98, MeOH). 1H NMR (501 MHz, CDCl3) δ
ppm 7.15 (d, J = 5.04 Hz, 1 H), 6.91-6.95 (m, 1 H), 6.87 (d, J =
3.15 Hz, 1 H), 5.24-5.28 (m, 1 H), 3.60-3.66 (m, 1 H), 3.43-3.49
afforded pyrrolidine 4g (1.28 g, 92%) as a white solid, mp =
1
45-50 °C, [R]25 = þ152.8 (c 1.12, MeOH). H NMR (501
D
MHz, CDCl3) δ ppm 7.23 (t, J = 7.88 Hz, 1 H), 6.82-6.91 (m,
2 H), 6.75-6.81 (m, 1 H), 4.63 (t, J = 7.09 Hz, 1 H), 3.86-3.92
(m, 1 H), 3.80 (s, 3 H), 2.95-3.00 (m, 1 H), 2.22-2.27 (m, 1 H),
1.94-2.00 (m, 1 H), 1.77-1.89 (m, 2 H), 1.12 (s, 9 H). 13C NMR
(125 MHz, CDCl3) δ ppm 159.2, 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 þ H] 282.1528, found 282.1519.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(3-methoxyphenyl)-
pyrrolidine (5g). Following the general procedure (GP3), the
reaction of γ-chloro N-sulfinyl ketimine (SS) 3g (1.57 g, 5.0 mmol)
with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed
by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF) afforded
pyrrolidine 5g (1.26 g, 90%) as a viscous liquid, [R]25
=
D
1
-131.0 (c 1.21, MeOH). H NMR (501 MHz, CDCl3) δ ppm
7.22 (t, J = 7.88 Hz, 1 H), 6.80-6.86 (m, 2 H), 6.75 (dd, J = 8.20,
2.52 Hz, 1 H), 5.03-5.05 (m, 1 H), 3.80 (s, 3 H), 3.61-3.68 (m,
1 H), 3.53-3.58 (m, 1 H), 2.11-2.19 (m, 1 H), 1.72-1.92 (m, 3 H),
1.07 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ ppm 159.6, 146.4,
129.4, 118.9, 112.4, 111.6, 57.4, 55.1, 54.9, 36.5, 24.2, 23.0. HRMS
(EI) calcd for C15H24NO2S [M þ H] 282.1528, found 282.1516.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-(4-chlorophenyl)-
pyrrolidine (4h). Following the general procedure (GP2),
the reaction of γ-chloro N-sulfinyl ketimine (SS) 3h (1.59 g,
5.0 mmol) with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF)
afforded pyrrolidine 4h (1.39 g, 98%) as a white solid, mp =
(m,1H), 2.07-2.15 (m, 1 H), 1.87-1.96(m,3H), 1.12(s, 9 H). 13
C
NMR (125 MHz, CDCl3) δ ppm 148.9, 126.7, 123.8, 123.6, 57.6,
54.1, 53.9, 36.7, 24.2, 22.9. HRMS (EI) calcd for C12H20NOS2
[M þ H] 258.0981, found 258.0979.
75-77 °C, [R]25 = þ111.9 (c 1.09, MeOH). 1H NMR
D
2244 J. Org. Chem. Vol. 75, No. 7, 2010

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JOCArticle
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-cyclohexyl-pyrroli-
dine (4k). Following the general procedure (GP2), the reaction
of γ-chloro N-sulfinyl ketimine (SS) 3k (1.44 g, 5.0 mmol) with
LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded pyrroli-
H), 1.57-1.66 (m, 1 H), 1.43-1.55 (m, 1 H), 1.13 (s, 9 H). 13C
NMR (125 MHz, CDCl3) δ ppm 141.8, 128.4, 128.2, 127.3, 65.4,
58.1, 43.8, 34.4, 25.5, 24.1, 23.2. HRMS (EI) calcd for
C15H24NOS [M þ H] 266.1579, found 266.1550.
dine 4k (1.20 g, 94%) as a viscous liquid, [R]25 = þ106.0
(S)-2-Methyl-propane-2-sulfinic Acid [(R)-6-Chlro-1-phenyl-
hexyl]amide (12n). Following the general procedure (GP2), the
reaction of chloro N-sulfinyl ketimine (SS) 3m (1.56 g, 5.0 mmol)
with LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded amide
12n (1.48 g, 94%) as a viscous liquid. 1H NMR (501 MHz,
CDCl3) δ ppm 7.24-7.35 (m, 5 H), 4.32-4.38 (m, 1 H), 3.46 (t,
J = 6.62 Hz, 2 H), 3.40 (d, J = 2.84 Hz, 1 H), 1.75-1.88 (m,
2 H), 1.66-1.75 (m, 2 H), 1.37-1.47 (m, 2 H), 1.27-1.37 (m,
1 H), 1.19-1.24 (m, 1 H), 1.17 (s, 9 H). 13C NMR (125 MHz,
CDCl3) δ ppm 141.9, 128.4, 127.5, 59.2, 55.4, 44.8, 38.5, 32.2,
26.5, 25.2, 22.5. HRMS (EI) calcd for C16H27NOSCl [M þ H]
316.1502, found 316.1499.
D
(c 0.75, MeOH). 1H NMR (501 MHz, CDCl3) δ ppm 3.68-3.79
(m, 1 H), 3.45-3.52 (m, 1 H), 2.59-2.69 (m, 1 H), 1.73-1.83 (m,
4 H), 1.65-1.72 (m, 4 H), 1.54-1.63 (m, 1 H), 1.40-1.51 (m, 1
H), 1.21 (s, 9 H), 1.07-1.18 (m, 3 H), 0.89-1.05 (m, 2 H), 13
C
NMR (125 MHz, CDCl3) δ ppm 70.7, 57.7, 42.6, 42.3, 30.4, 27.2,
26.8, 26.7, 26.6, 26.5, 26.2, 24.0. HRMS (EI) calcd for
C14H28NOS [M þ H] 258.1892, found 258.1890.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-cyclohexyl-pyrroli-
dine (5k). Following the general procedure (GP3), the reaction
of γ-chloro N-sulfinyl ketimine (SS) 3k (1.45 g, 5.0 mmol) with
DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed by
LiHMDS (7.5 mL, 7.5 mmol, 1.0 M in THF) afforded pyrroli-
dine 5k (1.22 g, 95%) as a viscous liquid, [R]25D = -40.9 (c 1.05,
(S)-2-Methyl-propane-2-sulfinic Acid [(S)-6-Chlro-1-phenyl-
hexyl]amide (14n). Following the general procedure (GP3), the
reaction of chloro N-sulfinyl ketimine (SS) 3m (1.56 g, 5.0 mmol)
with DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and
followed by LiHMDS (7.5 mL, 7.5 mmol, 1.0 mL in THF)
afforded amide 14n (1.20 g, 93%) as a viscous liquid. 1H NMR
(501 MHz, CDCl3) δ ppm 7.25-7.37 (m, 5 H), 4.31-4.35 (m,
1 H), 3.46 (t, J = 6.62 Hz, 2 H), 3.40 (d, J = 3.47 Hz, 1 H),
1.98-2.07 (m, 1 H), 1.66-1.78 (m, 3 H), 1.35-1.47 (m, 2 H),
1.25-1.32 (m, 1 H), 1.23 (s, 9 H), 1.09-1.19 (m, 1 H). 13C NMR
(125 MHz, CDCl3) δ ppm 142.4, 128.7, 127.8, 127.1, 58.9, 55.6,
44.8, 36.3, 32.3, 26.6, 24.9, 22.6. HRMS (EI) calcd for
C16H27NOSCl [M þ H] 316.1502, found 316.1498.
1
CHCl3). H NMR (501 MHz, CDCl3) δ ppm 3.53-3.63 (m,
1 H), 3.30-3.39 (m, 1 H), 3.14-3.23 (m, 1 H), 1.60-1.83 (m,
10 H), 1.23-1.32 (m, 2 H), 1.20 (s, 9 H), 1.05-1.17 (m, 1 H),
0.89-1.06 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ 62.7, 57.5,
50.0, 41.5, 30.7, 27.4, 27.2, 26.6, 26.5, 26.3, 25.2, 23.4. HRMS
(EI) calcd for C14H28NOS [M þ H] 258.1892, found 258.1858.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-methyl-pyrrolidine
(4l). Following the general procedure (GP2), the reaction of
γ-chloro N-sulfinyl ketimine (SS) 3l (1.11 g, 5.0 mmol) with
LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded pyrroli-
dine 4l (0.83 g, 88%) as a viscous liquid, [R]25D = þ32.5 (c 0.89,
1
MeOH). H NMR (501 MHz, CDCl3) δ ppm 3.77-3.84 (m,
(S)-2-Methyl-propane-2-sulfinic Acid[(R)-1-Phenyl-butyl]amide
(15p). Following the general procedure (GP2), the reaction of
chloro N-sulfinyl ketimine (SS) 3p (1.26 g, 5.0 mmol) with
LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded amide 15p
(1.20 g, 95%) as a viscous liquid, [R]25D = þ89.3 (c 1.05, MeOH).
1H NMR (501 MHz, CDCl3) δ ppm 7.31-7.35 (m, 2 H),
7.26-7.30 (m, 3 H), 4.35-4.40 (m, 1 H), 3.36 (br. s., 1 H),
1.72-1.83 (m, 2 H), 1.24-1.36 (m, 1 H), 1.19 (s, 9 H), 0.89 (t,
J = 7.25 Hz, 3 H). 13C NMR (125 MHz, CDCl3) δ ppm 142.1,
128.3, 127.6, 127.5, 59.2, 55.4, 40.9, 22.5, 19.2, 13.8. HRMS (EI)
calcd for C14H24NOS [M þ H] 254.1579, found 254.1569.
(S)-2-Methyl-propane-2-sulfinic Acid [(S)-1-Phenyl-butyl]amide
(16p). Following the general procedure (GP3), the reaction of
chloro N-sulfinyl ketimine (SS) 3p (1.26g, 5.0mmol) withDIBAL-
H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed by LiHMDS
1 H), 3.49-3.57 (m, 1 H), 3.04-3.14 (m, 1 H), 1.77-1.95 (m,
3 H), 1.47-1.54 (m, 1 H), 1.22 (d, J = 6.62 Hz, 3 H), 1.19 (s,
9 H). 13C NMR (125 MHz, CDCl3) δ ppm 60.7, 57.2, 54.7, 47.1,
41.3, 33.5, 24.0, 23.5, 20.4. HRMS (EI) calcd for C9H20NOS
[M þ H] 190.1258, found 190.1266.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-methyl-pyrrolidine
(5l). Following the general procedure (GP3), the reaction of
γ-chloro N-sulfinyl ketimine (SS) 3l (1.11 g, 5.0 mmol) with
DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed by
LiHMDS (7.5 mL, 7.5 mmol, 1.0 M in THF) afforded pyrro-
lidine 5l (0.85 g, 89%) as a viscous liquid, [R]25D = þ83.6 (c 1.38,
1
CHCl3). H NMR (501 MHz, CDCl3) δ ppm 3.69-3.75 (m,
1 H), 2.73-2.80 (m, 1 H), 1.96-2.04 (m, 1 H), 1.82-1.91 (m, 1
H), 1.67-1.78 (m, 1 H), 1.34-1.45 (m, 1 H), 1.18 (s, 9 H), 1.17
(d, J = 5.99 Hz, 3 H). 13C NMR (125 MHz, CDCl3) δ ppm 60.6,
56.6, 41.2, 33.7, 25.9, 23.7, 22.0. HRMS (EI) calcd for
C9H20NOS [M þ H] 190.1258, found 190.1260.
(7.5 mL, 7.5 mmol, 1.0 mL in THF) afforded amide 16p (1.18 g,
1
93%) as a viscous liquid, [R]25 = þ20.2 (c 1.02, MeOH). H
D
NMR (501 MHz, CDCl3) δ ppm 7.24-7.35 (m, 5 H), 4.31-4.37
(m, 1 H), 3.43 (d, J = 3.47 Hz, 1 H), 1.94-2.04 (m, 1 H),
1.67-1.75 (m, 1 H), 1.21 (s, 9 H), 1.10-1.20 (m, 1 H), 0.88 (t,
J = 7.41 Hz, 3 H). 13C NMR (125 MHz, CDCl3) δ ppm 142.6,
128.6,127.7, 127.1, 58.9, 55.6, 38.8, 22.6, 18.9, 13.8. HRMS (EI)
calcd for C14H24NOS [M þ H] 254.1579, found 254.1574.
General Procedure (GP4) for Deprotection of the tert-Butane-
sulfinyl Group from 4 and 5. To a solution of 4 or 5 (2 mmol) in
MeOH (10 mL) was added 4 M HCl solution (in dioxane, 2 mL).
After the mixture was stirred at room temperature for 30 min,
the mixture was concentrated to dryness and carefully dissolved
in water (20 mL). The aqueous layer was washed with ethyl
acetate (2 ꢀ 20 mL) and neutralized with 6 N NaOH solution to
pH ∼13. Then, the resulting aqueous solution was extracted
with ethyl acetate (3 ꢀ 30 mL). The combined organic layers
were washed with brine and then dried over anhydrous Na2SO4.
The organic layer was concentrated to dryness to obtained pure
2-substituted pyrrolidins 17 or ent-17.
(R)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-phenyl-piperidine
(10m). Following the general procedure (GP2), the reaction of γ-
chloro N-sulfinyl ketimine (SS) 3m (1.49 g, 5.0 mmol) with
LiBHEt3 (6.0 mL, 6.0 mmol, 1.0 M in THF) afforded piperidine
10m (1.24 g, 94%) as a white solid, mp = 45-50 °C, [R]25
=
D
-116.9 (c 1.16, MeOH). 1H NMR (501 MHz, CDCl3) δ ppm 7.43
(d, J = 8.20 Hz, 2 H), 7.36 (t, J = 7.72 Hz, 2 H), 7.20-7.27 (m, 1
H), 4.68 (t, J = 4.10 Hz, 1 H), 3.29 (dd, J = 8.04, 3.31 Hz, 2 H),
2.16-2.23 (m, 1 H), 2.00-2.09 (m, 1 H), 1.56-1.70 (m, 4 H),
1.42-1.52 (m, 1 H), 1.15 (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 þ H] 266.1579, found 266.1563.
(S)-1-((S)-2-Methyl-propane-2-sulfinyl)-2-phenyl-piperidine
(11m). Following the general procedure (GP3), the reaction of
γ-chloro N-sulfinyl ketimine (SS) 3m (1.49 g, 5.0 mmol) with
DIBAL-H (6.0 mL, 6.0 mmol, 1.0 M in toluene) and followed by
LiHMDS (7.5 mL, 7.5 mmol, 1.0mLinTHF) afforded piperidine
11m (1.21 g, 92%) as white solid, mp = 50-55 °C, [R]25
=
(R)-2-(4-Bromophenyl)-pyrrolidine (17a). Following the gen-
eral procedure (GP4), the reaction of 4a (658 mg, 2.0 mmol) with
4 M HCl solution (in dioxane, 2 mL) gives the (R)-2-(4-
bromophenyl)-pyrrolidine 17a (440 mg, 97%) as viscous oil,
D
1
-108.0 (c 1.04, MeOH). H NMR (501 MHz, CDCl3) δ ppm
7.22-7.36 (m, 5 H), 4.14 (dd, J = 8.51, 4.10 Hz, 1 H), 3.31-3.36
(m, 1 H), 2.93-3.01(m, 1 H), 1.89-1.97 (m, 2 H), 1.73-1.84 (m, 2
J. Org. Chem. Vol. 75, No. 7, 2010 2245

Rajender Reddy et al.
JOCArticle
[R]25D = þ52.1 (c 1.01, CH2Cl2). 1H NMR (501 MHz, CDCl3) δ
ppm 7.40 (d, J = 8.51 Hz, 2 H), 7.22 (d, J = 8.20 Hz, 2 H), 4.05
(t, J = 7.72 Hz, 1 H), 3.10-3.24 (m, 1 H), 2.92-3.04 (m, 1 H),
δ ppm 7.21-7.36 (m, 4 H), 4.09 (t, J = 7.72 Hz, 1 H), 3.11-3.28
(m, 1 H), 2.85-3.08 (m, 1 H), 2.10-2.25 (m, 1 H), 1.74-1.99 (m,
3 H), 1.45-1.69 (m, 1 H). 13C NMR (125 MHz, CDCl3) δ ppm
143.6, 132.2, 128.3, 127.8, 61.8, 46.9, 34.5, 25.5. HRMS (EI)
calcd for C10H13ClN [M þ H] 182.0731, found 182.0733.
(R)-2-Methyl-pyrrolidine (ent-17l). Following the general
procedure (GP4), the reaction of 5l (378 mg, 2.0 mmol) with
4 M HCl solution (in dioxane, 2 mL) gives the (R)-2-methyl-
pyrrolidine ent-17l (138 mg, 92%) as viscous oil, [R]25D = -31.2
(c 1.19, hexane). 1H NMR (501 MHz, CDCl3) δ ppm 2.97-3.13
(m, 2 H), 2.82 (q, J = 8.41 Hz, 1 H), 1.81-1.92 (m, 1 H),
2.08-2.23 (m, 1 H), 1.72-2.01 (m, 3 H), 1.43-1.67 (m, 1 H). 13
C
NMR (125 MHz, CDCl3) δ 144.1, 131.2, 128.2, 120.2, 61.8, 46.9,
34.4, 25.5. HRMS (EI) calcd for C10H13BrN [M þ H] 226.0231,
found 226.0229.
(S)-2-(4-Bromophenyl)-pyrrolidine (ent-17a). Following the
general procedure (GP4), the reaction of 5a (658 mg, 2.0 mmol)
with 4 M HCl solution (in dioxane, 2 mL) gives the (S)-2-(4-
bromophenyl) pyrrolidine ent-17a (442 mg, 98%) as viscous oil,
[R]25D = -51.9 (c 1.27, CH2Cl2). 1H NMR (501 MHz, CDCl3) δ
ppm 7.41 (d, J = 8.20 Hz, 2 H), 7.22 (d, J = 8.20 Hz, 2 H), 4.05
(t, J = 7.57 Hz, 1 H), 3.11-3.21 (m, 1 H), 2.91-3.05 (m, 1 H),
1.66-1.82 (m, 2 H), 1.59 (br. s., 1 H), 1.18 (m and d, 4 H). 13
C
NMR (125 MHz, CDCl3) δ ppm 54.5, 46.7, 33.7, 25.7, 21.2.
HRMS (EI) calcd for C5H12N [M þ H] 86.0954, found 86.0970.
(S)-2-Methyl-pyrrolidine (17l). Following the general proce-
dure (GP4), the reaction of 4l (378 mg, 2.0 mmol) with 4 M HCl
solution (in dioxane, 2 mL) gives the (S)-2-methyl-pyrrolidine
2.08-2.27 (m, 2 H), 1.69-1.98 (m, 2 H), 1.43-1.67 (m, 1 H). 13
C
NMR (125 MHz, CDCl3) δ 144.0, 131.3, 126.2, 120.3, 61.8, 46.9,
34.4, 25.5. HRMS (EI) calcd for C10H13BrN [M þ H] 226.0226,
found 226.0228.
17l (142 mg, 95%) as viscous oil, [R]25 = þ30.9 (c 1.02,
D
1
(R)-2-(4-Chlorophenyl)-pyrrolidine (17h). Following the gen-
eral procedure (GP4), the reaction of 4h (570 mg, 2.0 mmol) with
4 M HCl solution (in dioxane, 2 mL) gives the (R)-2-(4-
chlorophenyl)-pyrrolidine 17h (347 mg, 96%) as viscous oil,
[R]25D = þ41.1 (c 1.05, CH2Cl2). 1H NMR (501 MHz, CDCl3) δ
ppm 7.21-7.38 (m, 4 H), 4.09 (t, J = 7.72 Hz, 1 H), 3.09-3.27
(m, 1 H), 2.90-3.07 (m, 1 H), 2.08-2.27 (m, 1 H), 1.70-2.03 (m,
3 H), 1.49-1.71 (m, 1 H). 13C NMR (125 MHz, CDCl3) δ ppm
143.5, 132.2, 128.9, 127.8, 61.8, 46.9, 34.4, 25.5. HRMS (EI)
calcd for C10H13ClN [M þ H] 182.0697, found 182.0696.
(S)-2-(4-Chlorophenyl)-pyrrolidine (ent-17h). Following the
general procedure (GP4), the reaction of 5h (570 mg, 2.0 mmol)
with 4 M HCl solution (in dioxane, 2 mL) gives the (S)-2-(4-
bromophenyl) pyrrolidine ent-17 h (343 mg, 95%) as viscous oil,
[R]25D = -40.9 (c 1.15, CH2Cl2). 1H NMR (501 MHz, CDCl3)
hexane). H NMR (501 MHz, CDCl3) δ ppm 2.97-3.13 (m, 2
H), 2.76-2.88 (m, 1 H), 1.81-1.93 (m, 1 H), 1.56-1.81 (m, 3 H),
1.07-1.25 (m, 4 H). 13C NMR (125 MHz, CDCl3) δ ppm 54.4,
46.7, 33.6, 25.6, 21.1. HRMS (EI) calcd for C5H12N [M þ H]
86.0947, found 86.0970.
Acknowledgment. We thank Dr. Kapa Prasad for valu-
able suggestions.
Supporting Information Available: Complete experimental
procedures, characterization data, copies of NMR spectra, and
single X-ray crystallographic data for compound 4a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2246 J. Org. Chem. Vol. 75, No. 7, 2010