Stereoselective Synthesis of (Sulfonimidoyl)cyclopropanes with (R)-PhSO(NTs)CH2Cl and α,β-Unsaturated Weinreb Amides: Tuning the of Selectivity between C-Cl and C-S Bond Cleavage

Article abstract of DOI:10.1002/ejoc.201501611

(Sulfonimidoyl)cyclopropanes have become the subject of special interest since they combine the advantages of two chemical leads (cyclopropane and sulfoximine). However, their synthesis is limited, and the stereoselective synthesis of optically enriched (sulfonimidoyl)cyclopropanes still remains an unsolved task. Here we report the first stereoselective (sulfonimidoyl)cyclopropanation reaction using α,β-unsaturated Weinreb amides and (R)-PhSO(NTs)CH₂Cl [(R)-1]. This reaction possesses a broad substrate scope, and the products can be easily transformed into other useful cyclopropyl-containing and/or sulfonimidoyl-containing compounds. The Weinreb amide group and the counter cation of the base were found to be important for the selective C-Cl bond cleavage. The first (sulfonimidoyl)cyclopropanation of α,β-unsaturated carbonyl compounds with (R)-PhSO(NTs)CH₂Cl was achieved to afford optically enriched (sulfonimidoyl)cyclopropanes in good yields with excellent diastereoselectivities. The reaction shows a broad substrate scope. The Weinreb amide group and the counter cation of the base were found to be important for the selective C-Cl bond cleavage.

Full text of DOI:10.1002/ejoc.201501611

DOI: 10.1002/ejoc.201501611
Communication
Cyclopropanation
Stereoselective Synthesis of (Sulfonimidoyl)cyclopropanes with
(R)-PhSO(NTs)CH2Cl and α,ꢀ-Unsaturated Weinreb Amides:
Tuning the of Selectivity between C–Cl and C–S Bond Cleavage
Xiao Shen,[a] Qinghe Liu,[a] Wei Zhang,[a] and Jinbo Hu*[a]
Abstract: (Sulfonimidoyl)cyclopropanes have become the sub- reb amides and (R)-PhSO(NTs)CH2Cl [(R)-1]. This reaction pos-
ject of special interest since they combine the advantages of
two chemical leads (cyclopropane and sulfoximine). However,
their synthesis is limited, and the stereoselective synthesis of
optically enriched (sulfonimidoyl)cyclopropanes still remains an
unsolved task. Here we report the first stereoselective (sulfon-
imidoyl)cyclopropanation reaction using α,ꢀ-unsaturated Wein-
sesses a broad substrate scope, and the products can be easily
transformed into other useful cyclopropyl-containing and/or
sulfonimidoyl-containing compounds. The Weinreb amide
group and the counter cation of the base were found to be
important for the selective C–Cl bond cleavage.
Introduction
The cyclopropyl group is an important pharmacophore, and
many well-established drugs, such as Odanacatib, Singulair and
Ciprofloxacin contain this prestigious group.[1] Recently, sulfox-
imines have gained increasing attention in drug design because
of their unique physical, chemical, and biological properties.[2]
In this context, (sulfonimidoyl)cyclopropanes have become the
subject of special interest since they combine the advantages
of two chemical leads. Several methods were reported on the
nonstereoselective synthesis of (sulfonimidoyl)cyclopropanes,[3]
but the stereoselective synthesis of optically enriched (sulfon-
imidoyl)cyclopropanes still remains an unsolved task.[4] In 1993,
Jackson reported an addition/elimination reaction between α-
phenylthio-substituted vinylsulfoximine and [(phenylsulfonyl)-
(phenylthio)methyl]lithium, but the (sulfonimidoyl)cyclopro-
pane was obtained (75 % yield) with only 3:1 diastereomeric
ratio (dr).[4a] Craig's transannular, decarboxylative Claisen rear-
rangement reaction of an unsaturated ε-lactone bearing an α-
arylsulfonimidoyl substituent afforded a (sulfonimidoyl)cyclo-
propane in 69 % yield, with only 3:2 dr.[4b] Herein, we report a
conceptually different approach for the synthesis of optically
enriched (sulfonimidoyl)cyclopropanes through the use of (R)-
PhSO(NTs)CH2Cl and (R)-PhSO(NTBS)CH2Cl reagents [see
Scheme 1 (b)]. Our Michael addition/elimination strategy distin-
guishes itself by operational simplicity, broad substrate scope,
and excellent stereoselectivity.
Scheme 1. Fluorocyclopropanation and (sulfonimidoyl)cyclopropanation of
α,ꢀ-unsaturated Weinreb amides.
Sulfoximines have been used in nucleophilic alkylidene
transfer reactions, and C–S bond cleavage of the sulfoximines
took place in all of these reactions.[5a–5c,5e–5g,6b,6e,6f] Taking ad-
vantage of the better leaving-group ability of the PhSO(NTs)
functionality (compared to fluorine), we had developed the first
enantioselective fluorocyclopropanation reaction of α,ꢀ-unsatu-
rated Weinreb amides with (R)-PhSO(NTs)CH2F with excellent
stereoselectivity [Scheme 1, (a)].[6b] Only C–S bond cleavage
was found in this fluorocyclopropanation.[6b] However, the cy-
clopropanation reactions reported herein show that the chemo-
selectivity between C–Cl and C–S bond cleavage of (R)-
PhSO(NTs)CH2Cl can be tuned by changing either the counter
cation of the base or the Michael acceptor.
[a] Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences,
345 Ling-Ling Road, Shanghai 200032, P. R. China
E-mail: jinbohu@sioc.ac.cn
http://hujinbo.sioc.ac.cn/en/
Results and Discussion
Optically pure chloromethyl sulfoximine (R)-1 was readily pre-
pared from (S)-2 by a trichlorination/dechlorination process in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501611.
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72 % yield, albeit the direct chlorination of (S)-2 with LiHMDS/ 4 in moderate to excellent yield (62–98 %) and with good to
NCS gave only < 21 % yield of (R)-1 (Scheme 2).[7] With (E)-3-(4- excellent diastereoselectivities (93:7 to > 99:1 dr). The reaction
fluorophenyl)-N-methoxy-N-methylacrylamide (3a) as a model tolerates alkenyl, alkynyl, bromo, chloro, fluoro, methoxy, and
substrate, we investigated its (sulfonimidoyl)cyclopropanation thiophen-2-yl groups.
A naphthyl-substituted unsaturated
reaction with (R)-1 (Table 1). It was found that the metal cations Weinreb amide was also successfully cyclopropanated to give
remarkably affect the chemoselectivity between C–Cl and C–S product 4i in 88 % yield with a 99:1 dr. This cyclopropanation
bond cleavage of (R)-1. When KHMDS was used as a base, the reaction is also amenable to alkyl-substituted unsaturated
expected (sulfonimidoyl)cyclopropane 4a was isolated in 63 % Weinreb amides to give the (sulfonimidoyl)cyclopropanes in
yield with 85:15 dr, and chlorocyclopropanation product 5 was 62–98 % yields, with 98:2–99:1 dr (Table 2, 4j–4m). It is worth
also obtained in 27 % yield with 95:5 dr and 3 % ee (Table 1, noting that the diastereoselectivity of our previous fluorocyclo-
Entry 1). When the counter cation of the base was changed propanation of substrate 3j with (R)-PhSO(NTs)CH2F is much
from potassium to sodium, the yield of 5 decreased to 5 %, but lower than that of the present (sulfonimidoyl)cyclopropanation
the yield of compound 4a increased to 78 % (Table 1, Entry 2). of 3j with (R)-PhSO(NTs)CH2Cl, indicating the different reactivity
When LiHMDS was used as a base, compound 4a was formed of the two sulfoximine reagents.[6b] The absolute configuration
in 89 % yield with > 99:1 dr, and < 1 % yield of 5 was ob- of product 4c was confirmed by its single-crystal X-ray structure
served(Table 1, Entry 3). Further investigation showed that analysis (Table 2), and the others were assigned by analogy.
when HMPA was added as co-solvent, the yield of (sulfonimid-
Table 2. (Sulfonimidoyl)cyclopropanation of α,ꢀ-unsaturated Weinreb am-
oyl)cyclopropane 4a decreased to 64 %, and the yield of chloro-
cyclopropane 5 increased to 22 % (Table 1, Entry 4).
ides.[a]
Scheme 2. Synthesis of (R)-1.
Table 1. Counter cation effect on the chemoselectivity between C–Cl and C–
S bond cleavage of (R)-PhSO(NTs)CH2Cl in its reaction with α,ꢀ-unsaturated
Weinreb amide 3a.[a]
[a] Experimental procedure: to a mixture of (E)-3-(4-fluorophenyl)-N-methoxy-
N-methylacrylamide (3a) (0.5 mmol) and (R)-1 (0.65 mmol, 1.3 equiv.) in sol-
vent at –78 °C was added base (THF solution, 0.6 mmol, 1.2 equiv.); after
20 min, the dry-ice bath was removed and the reaction mixture was stirred
at room temp. for 2 h. [b] Yield refers to isolated yield and the dr, which
[a] Yield refers to isolated yields of the mixture of diastereoisomers; the dr of
the isolated product was determined by 1H NMR spectroscopy. [b] (S)-1 was
used instead of (R)-1.
refers to the ratio of major diastereoisomer to all other diastereoisomers, was
determined by 19F NMR spectroscopy. [c] The ee of the major diastereoisomer
was determined by chiral HPLC. n.d. = not determined.
The substrate scope of the (sulfonimidoyl)cyclopropanation
The Ts protecting group in sulfoximine (R)-1 can be easily
reaction was tested under the conditions described in Table 1, removed with H2SO4 (18.4 M), providing the opportunity to syn-
Entry 3. As shown in Scheme 4, the reaction turned out to be thesize other N-protected optically pure chloromethyl sulfoxim-
general, and chloromethyl sulfoximine (R)-1 could react with a ines. According to a two-step process shown in Scheme 4, N-
variety of structurally diversified α,ꢀ-unsaturated Weinreb am- TBS-substituted sulfoximine (R)-6 was obtained in 88 % yield
ides to afford the corresponding (sulfonimidoyl)cyclopropanes without loss of optical purity at the sulfur stereogenic center.
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Sulfoximine (R)-6 can also undergo cyclopropanation reaction rated ketone 9 under similar reaction conditions (Scheme 6). In
with α,ꢀ-unsaturated Weinreb amide 3a to afford the (sulfonim- contrast to the exclusive formation of (sulfonimidoyl)cyclopro-
idoyl)cyclopropane 4n in 90 % yield and with a 92:8 dr, and the pane 4b in the reaction of (R)-1 with N-methoxy-N-methyl-
major diastereoisomer was isolated in 84 % yield (Scheme 3).
cinnamamide (3b), both (sulfonimidoyl)cyclopropane 10 and
chlorocyclopropane 11 formed in the reaction of (R)-1 and 9.
Interestingly, when 2-benzylidenemalononitrile (12) was ap-
plied to the reaction of (R)-1 under the same conditions, a dif-
ferent chemoselectivity was observed, that is, the sulfonimidoyl
group, instead of the chlorine atom, served as a leaving group.
The two diastereoisomers of chlorocyclopropane 14 were sepa-
rated by silica gel column chromatography to afford the trans
isomer (major product) in 64 % yield, with a 72 % ee, and the
cis isomer (minor product) in 32 % yield, with a 50 % ee
(Scheme 6). The absolute configurations of the two isomers of
14 were confirmed by their single-crystal X-ray structure analy-
sis (see Supporting Information).[10]
Scheme 3. Synthesis of sulfoximine (R)-6 and its application in the synthesis
of (sulfonimidoyl)cyclopropane 4n.
The reaction between optically pure sulfoximine (S)-2 and
α,ꢀ-unsaturated Weinreb amide 3a afforded cyclopropane 7 in
86 % yield with a > 99:1 dr, but only moderate enantioselectiv-
ity was observed (53 % ee, Scheme 4).[8] However, when com-
pound 4a was treated under easy-to-handle reductive desulfon-
imidoylation conditions by using Mg/BrCH2CH2Br/MeOH, the
sulfonimidoyl group could be removed to afford compound 7
in 76 % yield with a > 99:1 dr, and a > 99 % ee (Scheme 4).
Scheme 6. Substrate effects on the chemoselectivity between C–Cl and C–S
bond cleavage of (R)-1 in its reaction with different Michael acceptors.
The selectivity between C–Cl and C–S bond cleavages in the
cyclopropanation reactions of α,ꢀ-unsaturated Weinreb amides
3, α,ꢀ-unsaturated ketone 9, and 2-benzylidenemalononitrile
12 is intriguing. Although further study is needed to elucidate
the detailed mechanism, we propose that a chelated intermedi-
ate, such as A in Figure 1, is involved in the reaction of sulfox-
imine (R)-1 with α,ꢀ-unsaturated Weinreb amides. Sulfoximines
are coordinative and have been widely used as ligands in Lewis
acid mediated reactions.[11] Although a steric repulsion be-
tween the sulfonimidoyl group and Ph can be envisioned in A,
the complexation of the lithium ion with the sulfonimidoyl
group probably make it more preferable than B (see Fig-
ure 1).[12]The proposal of chelated intermediates is supported
by the following experimental results: (1) the ratio of 4a/5 in-
creased when the cation of the base changed from the less
coordinating K ion to the more coordinating Na and Li ions
(Table 1, Entries 1–3);[12] (2) addition of the coordinating solvent
HMPA decreased the ratio of 4a/5 (Table 1, Entry 4). Our pro-
posal is also in accordance with Pyne's mechanistic proposal for
Scheme 4. Preparation of cyclopropane 7.
The Weinreb amide group has been proven to be a powerful
functional group for synthetic transformations.[9] To further
demonstrate the potential applications of our cyclopropanation
method, we studied the reaction of (sulfonimidoyl)cyclopro-
pane 4a with organolithium reagents. After treating phenyl-
acetylene with nBuLi at –78 °C to room temp. for 0.5 h, com-
pound 4a was added at –78 °C, and the solution was stirred
for 2 h. Eventually, compound 8 was obtained in 77 % yield
(Scheme 5).
Scheme 5. Synthetic application of product 4h.
Encouraged by the successful stereoselective synthesis of
(sulfonimidoyl)cyclopropanes with α,ꢀ-unsaturated Weinreb
amides, we tried the reaction between (R)-1 and α,ꢀ-unsatu-
Figure 1. Proposed intermediates.
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account for the decreased selectivity for the C–Cl bond cleav-
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Conclusions
An efficient synthesis of enantiomerically enriched (sulfonimid-
oyl)cyclopropanes with broad substrate scope, good yields, and
excellent diastereoselectivities by the reaction between opti-
cally pure chloromethyl sulfoximines and α,ꢀ-unsaturated Wein-
reb amides has been disclosed. To the best of our knowledge,
this is the first (sulfonimidoyl)cyclopropanation reaction of
Michael acceptors. The counter cation of the base and the
Weinreb amide group were found to be important for the se-
lective C–Cl bond cleavage of (R)-PhSO(NTs)CH2Cl. The easy re-
moval of the sulfonimidoyl group and the transformation of the
Weinreb amide functionality demonstrate the synthetic utility
of this method.
CCDC 1448852 (for 4c), 1448777 (for trans-14), and 1448778 (for cis-
14) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[7] C. R. Johnson, A. Tanerman, Synthesis 1982, 286.
[8] Less than 36 % ee was reported for an enantioselective cyclopropanation
of α,ꢀ-unsaturated carbonyl compounds with an optically active methyl
sulfoximinium salt, see: C. R. Johnson, C. W. Schroeck, J. Am. Chem. Soc.
1968, 90, 6052.
[9] For reviews, see: a) M. Mentzel, H. M. R. Hoffmann, J. Prakt. Chem. 1997,
339, 517; b) V. K. Khlestkin, D. G. Mazhukin, Curr. Org. Chem. 2003, 7,
967; c) S. Balasubramaniam, I. S. Aidhen, Synthesis 2008, 23, 3707.
[10] The absolute configurations of compounds 10, 11 and 13 have not been
confirmed.
Acknowledgments
Support of our work by the National Basic Research Program of
China (2015CB931900 and 2012CB215500), the National Natural
Science Foundation of China (21372246, 21302206, and
21421002), the Shanghai STCSM program (15XD1504400), the
Chinese Academy of Sciences, and the Syngenta PhD Student-
ship (to X. S.) is gratefully acknowledged.
[11] For reviews, see ref.[5c,5d]; for selected examples, see ref.[5g] and: a) C.
Bolm, O. Simic, J. Am. Chem. Soc. 2001, 123, 3830; b) M. Langner, C.
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6110; c) M. Frings, I. Thome, C. Bolm, Beilstein J. Org. Chem. 2012, 8,
1443.
[12] Li–O coordination was found to be very important for the stabilization
of crowded tetrahedral carbonyl addition intermediates, see: a) X. Shen,
L. Zhang, Y. Zhao, L. Zhu, G. Li, J. Hu, Angew. Chem. Int. Ed. 2011, 50,
2588; Angew. Chem. 2011, 123, 2636; b) X. Shen, C. Ni, J. Hu, Helv. Chim.
Acta 2012, 95, 2043; c) X. Shen, C. Ni, J. Hu, Chin. J. Chem. 2013, 31, 878.
[13] S. G. Pyne, Z. M. Dong, B. W. Skelton, A. H. White, J. Org. Chem. 1997,
62, 2337.
Keywords: Cyclopropane · Sulfoximine · Cyclopropanation ·
C–Cl bond cleavage · C–S bond cleavage
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Received: December 28, 2015
Published Online: January 26, 2016
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