Asymmetric synthesis of 2-substituted pyrrolidines by addition of Grignard reagents to γ-chlorinated N-tert-butanesulfinyl imine

Article abstract of DOI:10.1039/b917435d

A highly diastereoselective addition of various Grignard reagents to chiral γ-chlorinated N-tert-butanesulfinyl imine resulting in the formation of 2-substituted pyrrolidines is reported. This method is general and also efficient for the preparation of both enantiomers of 2-aryl, 2-alkyl and 2-vinyl substituted pyrrolidines in high yields.

Full text of DOI:10.1039/b917435d

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Asymmetric synthesis of 2-substituted pyrrolidines by addition
of Grignard reagents to c-chlorinated N-tert-butanesulfinyl iminew
Leleti Rajender Reddy* and Mahavir Prashad
Received (in College Park, MD, USA) 25th August 2009, Accepted 4th November 2009
First published as an Advance Article on the web 24th November 2009
DOI: 10.1039/b917435d
A
highly diastereoselective addition of various Grignard
reagents to chiral c-chlorinated N-tert-butanesulfinyl imine
resulting in the formation of 2-substituted pyrrolidines is
reported. This method is general and also efficient for the
preparation of both enantiomers of 2-aryl, 2-alkyl and 2-vinyl
substituted pyrrolidines in high yields.
2-Substituted pyrrolidines constitute an important structural
motif in biologically active compounds as they are found in a
wide variety of natural products,1 pharmaceuticals,2 and
effective chiral controllers in asymmetric synthesis.3 Particularly,
these compounds are pharmaceutically relevant, as over 200
compounds containing this pharmacophore are currently in
advanced biological testing.4 Known synthetic methods of
these privileged structures, suffer from either long synthetic
sequences, low yields, lack of generality or modest selectivity.5
Recently, Merck scientists have reported6 an elegant method
for the asymmetric synthesis of 2-arylpyrrolidines in a highly
enantioselective manner but this method also has some
limitations: it is limited to the synthesis of only the
(R)-enantiomer of aryl pyrrolidines, and it utilizes s-BuLi.7
We reasoned that a direct method to access enantioenriched
2-substituted pyrrolidines would be the asymmetric addition
of Grignard reagents to Ellman’s type g-chlorinated
N-tert-butanesulfinyl imine (1) followed by cyclization.
Whereas the diastereoselective addition of Grignard reagents
to Ellman’s aldimines (2)8 is well established, the asymmetric
addition of Grignard reagents to Ellman’s type g-chlorinated
Scheme 2 Synthesis of g-chloro N-sulfinyl aldimine (SS)-1 and
g-chloro N-sulfinyl aldimine (RS)-1.
N-tert-butanesulfinyl imine (1) followed by cyclization has not
been described (Scheme 1) to our knowledge.9 Herein, we
report a general and a practical method for the diastereoselective
addition of Grignard reagents to Ellman’s type g-chlorinated
N-tert-butanesulfinyl imine (1), followed by cyclization in a
one-pot procedure to give 2-substituted pyrrolidines.
g-Chloro N-sulfinyl aldimine (SS)-110 was synthesized in
high yield via condensation of 4-chlorobutanal (5) (1.0 equiv.)11
with (SS)-tert-butanesulfinamide (1.0 equiv.)12 in the presence
Table 1 Ring closing of chiral d-chloro sulfinamide 3a by treatment
with base
Temp. Time/
h
a
Yield %
Entry Sulfinamide Base
1C
Solvent
1
2
3
4
5
3a
3a
3a
3a
3a
BuLi
NaH
LiHMDS 23
ꢀ78 (0) 1
ꢀ78 (0) 1
THF
THF
THF
MeCN
65
79
98
76
1
NEt3
KOH
D
D
12
12
THF–H2O 85
a
Isolated yield of analytically pure products.
Scheme 1 Ellman’s aldimines and retrosynthetic analysis
Chemical Research and Development, Novartis Pharmaceuticals
Corporation, One Health Plaza, East Hanover, New Jersey 07936,
USA. E-mail: Rajender.leleti@novartis.com
w Electronic supplementary information (ESI) available: Complete
experimental procedures, characterization data, copies of NMR
spectra and single X-ray crystallographic data for compound 4b.
CCDC 747534. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b917435d
Scheme 3 Reaction of various Grignard reagents with g-chlorinated
N-tert-butanesulfinyl imines.
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of 1.1 equiv. of Ti(OEt)4 in THF at room temperature for 12 h.
In the same way, the g-chloro N-sulfinyl aldimine (RS)-1, was
synthesized via condensation of 5 with (RS)-tert-butanesulfin-
amide (Scheme 2).
at room temperature for 1 h with 1.5 equiv. of LiHMDS in
THF (Table 1, entry 3).
Experimentally, it was shown that the crude d-chloro sulfin-
amide 3a could also be converted to the corresponding
2-phenylpyrrolidine 4a in high yield (91% in two steps) and
with a high diastereomeric ratio (dr 97 : 3) by stirring at room
temperature for 1 h in the presence of 1.5 equiv. of LiHMDS.
More importantly, no epimerization reaction occurred during
the cyclization (Scheme 3).
Treatment of g-chloro N-sulfinyl aldimine (SS)-1 (1.0 equiv.)
with phenylmagnesium chloride (6a, 1.5 equiv.) in CH2Cl2 at
ꢀ78 1C for 5 h followed by NH4Cl work-up afforded the crude
d-chloro sulfinamide 3a in high diastereomeric ratio (dr 97 : 3).13
The diastereoselectivity of the reaction was determined to be
1
97 : 3 by H NMR analysis of the crude product. A series of
Encouraged by these results, we turned our attention to
other substituted aromatic Grignard reagents. Interestingly, a
large number of substituted aromatic Grignard reagents, such
as p-methoxy-, p-methyl-, p-bromo-,14p-tert-butyl-reagents,
reacted cleanly with g-chlorinated N-(tert-butanesulfinyl)
imine (1) followed by base-catalyzed cyclization leading to
corresponding 2-arylpyrrolidines 4b–4e (Table 2, entries 2–5)
in good yields (83–89%) and high diastereomeric ratios (up to
96 : 4). 2-(p-Bromophenyl)-pyrrolidine (SS,S)-4b was obtained
as a colorless crystalline solid (mp 110–112 1C). The structure
and absolute stereochemistry of (SS,S)-4b was confirmed by
single crystal X-ray diffraction analysis (Fig. 1).z
bases (BuLi, NaH, LiHMDS, Et3N, and KOH) were investi-
gated in different solvents to facilitate the cyclization reaction
of pure d-chloro sulfinamide (SS,S)-3a towards 2-phenyl-
pyrrolidine (SS,S)-4a. Addition of 1.1 equiv. of BuLi in THF
at ꢀ78 1C and subsequently warming to 0 1C for 1 h provided
(SS,S)-4a in 65% yield (Table 1, entry 1). Better results were
obtained if NaH was used as a base under the latter conditions
(Table 1, entry 2). Heating 3a for 12 h in boiling CH3CN, in
the presence of 4 equiv. of Et3N, afforded 76% of corresponding
(SS,S)-4a (Table 1, entry 4). In the same way, heating of 3a for
12 h in boiling H2O–THF (1 : 1), in the presence of 3 equiv. of
KOH, afforded 85% of corresponding (SS,S)-4a (Table 1,
entry 5). Best results were obtained if (SS,S)-3a was stirred
Similarly, reaction of aliphatic Grignard reagents such as
cyclohexylmagnesium chloride (6f) and tert-butylmagnesium
Table 2 Asymmetric addition of various Grignard reagents to g-chlorinated N-tert-butanesulfinyl imine
Entry
Substrate (1)
Reagent (6)
Product (4)c
Yield (%)a
drb
1
2
3
4
5
1a
1a
1a
1a
1a
6a: R = H
4a
4b
4c
4d
4e
91
83
86
88
85
97 : 3
95 : 5
95 : 5
96 : 4
94 : 6
6b: R = Br
6c: R = Me
6d: R = OMe
6e: R = t-Bu
6
1a
6f
3f
90
97 : 3
7
8
1a
1a
6g
6h
4g
4h
84
82
95 : 5
92 : 8
9
10
11
Enantiomer of 1a
Enantiomer of 1a
Enantiomer of 1a
6a
6b
6d
Enantiomer of 4a
Enantiomer of 4b
Enantiomer of 4d
90
85
83
97 : 3
95 : 5
96 : 4
a
b
c
Isolated yield of analytically pure products. The diastereoselectivity was determined by 1H NMR. dr relative to sulfur. All reactions were
performed using 1.2 equiv. of Grignard agent at ꢀ78 1C for 5 h. Followed by isolation of crude product and cyclization using LiHMDS, rt, 1 h in
THF unless otherwise stated.
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In summary, we have described an efficient, highly diastereo-
selective addition of various Grignard reagents to chiral
g-chlorinated N-(tert-butanesulfinyl) imine affording enantio-
merically pure 2-substituted pyrrolidines. This method is
useful for the preparation of both enantiomers of 2-substituted
pyrrolidines. Extension of this work is currently under way in
our laboratory.
We thank Dr Kapa Prasad and Dr Oljan Repic for suggestions.
Notes and references
Fig. 1 X-ray crystal structure of 4b.
z Single crystals of C14H20BrNOS 4b were recrystallised from ethyl
acetate, mounted in inert oil and transferred to the cold gas stream of
the diffractometer. Crystal structure determination of 4b: Crystal data.
C14H20BrNOS, M = 330.29, orthorhombic, a = 6.1888(4), b =
10.0920(6), c = 24.6826(17) A, U = 1541.61(17) A3, T = 298(2) K,
space group P212121, Z = 4, 3679 reflections measured, 3654 unique
(Rint = 0.034) which were used in all calculations. The final wR(F2)
was 0.077 (all data) and R/(F0) was 0.071 (all data).
1 For examples, see: (a) A. Elbein and R. I. Molyneux, in Alkaloids,
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Biology, ed. G. A. Cordell, Academic Press, San Diego, 2000,
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Fig. 2 Possible transition state A.
2 (a) R. L. Elliott, H. Kopeka, N.-H. Lin, Y. He and D. S. Garvey,
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4 MDL Drug Data Report, MDL Information Systems, Inc.,
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2109–2113; (b) S. Wu, S. Lee and P. Beak, J. Am. Chem. Soc., 1996,
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6 K. R. Campos, A. Klapars, J. H. Waldman, P. G. Domer and
C. Chen, J. Am. Chem. Soc., 2006, 128, 3538–3539.
7 (a) Using this method, (S)-enatiomer is difficult to prepare because
(+)-sparteine is not easily available. (b) s-BuLi is a pyrophoric
liquid and restricted from use on a large scale.
8 (a) F. A. Davis, R. E. Reddy, J. M. Szewczyk, G. V. Reddy,
P. S. Portonovo, H. Zhang, D. Fanelli, R. T. Reddy, P. Zhou and
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(e) P. Zhou, B.-C. Chen and F. A. Davis, Tetrahedron, 2004, 60,
8003 and references cited therein.
9 (a) Q. Chen, J. Li and C. Yuan, Synthesis, 2008, 2986–2990;
(b) B. Denolf, S. Mangelinckx, K. W. Toernroos and N. De
Kimpe, Org. Lett., 2006, 8, 3129–3132.
10 F. A. Davis, K. R. Prasad, M. B. Nolt and Y. Wu, Org. Lett., 2003,
5, 925–927.
11 4-Chlorobutanal is commercially available from several companies
or by synthesis: M. Vuagnoux-d’Augustin and A. Alexakis,
Chem.–Eur. J., 2007, 13, 9647–9662.
12 (SS(-tert-Butanesulfinamide is readily available commercially from
various companies ($1800/kg).
Scheme 4 Deprotection of sulfinyl group.
chloride (6g) smoothly reacted with (SS)-1, followed by the
cyclization affording the corresponding 2-cyclohexylpyrrolidine
4f and 2-tert-butylpyrrolidine 4g in 90% and 84% yield
(dr 97 : 3 and 95 : 5), respectively (Table 2, entries 6, 7). Likewise,
reaction of (SS)-1 with vinylmagnesium chloride (6h) and
followed by the cyclization also proceeded to 2-vinylpyrrolidine
(4h) in 82% yield with dr 92 : 8 (Table 2, entry 8).
Noticeably, the reaction of (RS)-1 with phenylmagnesium
chloride (6a), followed by cyclization, smoothly proceeded to
the enantiomer of 2-phenylpyrrolidine (ent-4a) in 90% yield
with dr 97 : 3 (Table 2, entry 9). Similarly the reaction of (RS)-1
with 6b and 6d followed by cyclization afforded the enantiomer
of 2-(4-bromophenyl)pyrrolidine (ent-4b) and enantiomer of
2-(4-methoxyphenyl)pyrrolidine (ent-4d) in 85% and 88%
yield (dr 95 : 5 and 96 : 4), respectively. (Table 2, entry 10, 11).
A possible mechanistic model to explain the observed stereo-
selectivity is depicted in Fig. 2, which involves a chair-like
transition state (A).8b
Finally, the sulfinyl group can be cleaved readily under mild
acidic conditions to provide free amine 7 in quantitative yield
(Scheme 4).
13 A lower diastereoselectivity was obtained in solvents such as THF,
diethyl ether and TBME.
14 G. P. Schiemenz, Org. Synth., 1973, 5, 496.
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This journal is The Royal Society of Chemistry 2010
224 | Chem. Commun., 2010, 46, 222–224