Lewis base catalyzed, enantioselective, intramolecular sulfenoamination of olefins

Article abstract of DOI:10.1021/ja5046296

A method for the enantioselective, intramolecular sulfenoamination of various olefins has been developed using a chiral BINAM-based selenophosphoramide, Lewis base catalyst. Terminal and trans disubstituted alkenes afforded pyrrolidines, piperidines, and

Full text of DOI:10.1021/ja5046296

Communication
pubs.acs.org/JACS
Lewis Base Catalyzed, Enantioselective, Intramolecular
Sulfenoamination of Olefins
Scott E. Denmark* and Hyung Min Chi
Department of Chemistry, University of Illinois UrbanaChampaign, Urbana, Illinois 61801, United States
S
* Supporting Information
for the enantioselective, intramolecular sulfenoamination of
olefins.10 Using an achiral sulfenylating reagent in concert with a
chiral Lewis base catalyst, an intermediate thiiranium ion is
generated which is subsequently captured with a pendant amine-
based nucleophile (Scheme 2).
ABSTRACT: A method for the enantioselective, intra-
molecular sulfenoamination of various olefins has been
developed using a chiral BINAM-based selenophosphor-
amide, Lewis base catalyst. Terminal and trans disub-
stituted alkenes afforded pyrrolidines, piperidines, and
azepanes in high yields and high enantiomeric ratios via
enantioselective formation and subsequent stereospecific
capture of the thiiranium intermediate with the pendant
tosyl-protected amine.
Scheme 2
itrogen-containing, saturated heterocycles such as piper-
Nidines, pyrrolidines, and azepanes are commonly found in
many biologically active natural products and pharmaceutical
compounds.1,2 The chemical and biological properties of these
molecules can be greatly influenced by the location and
configuration of carbon and heteroatom substituents.2d Accord-
ingly, numerous strategies have been developed to generate
stereodefined, saturated, nitrogen heterocycles with various
types of substitution.3
As a part of an ongoing program in these laboratories on the
concept of Lewis base activation of Lewis acids,4 we have focused
on the activation of group 16 electrophiles with chiral Lewis
bases.5 Recent reports have described the catalytic, enantio-
selective sulfenoetherification6 and carbosulfenylation7 of olefins
(Scheme 1). These reactions proceed via the enantioselective
generation of thiiranium ions8 that are constitutionally and
configurationally stable at low temperatures which allows them
to be captured by nucleophiles without racemization.9
In the studies of sulfenoetherification and carbosulfenylation
reactions, it was shown that a Brønsted acid coactivator was
required. As a result, for the sulfenoamination reactions, the
amine-based nucleophile needed to be not only sufficiently
nucleophilic to form the C−N bond but also sufficiently non-
basic to avoid protonation under the acidic conditions. To satisfy
those criteria, a series of amines were selected as candidates for
the nucleophile: sulfonamides, benzamides, carbamates, and
phosphinic amides (Chart 1).
Chart 1
The research reported herein expands upon the previous
sulfenofunctionalization reactions to develop a catalytic method
To evaluate the reactivity of the nucleophiles, each substrate
was subjected to the reaction conditions developed for the
sulfenofunctionalization reactions (Table 1).6,7 Preliminary
evaluation of the protected amine substrates 5−11 with
sulfenylating agent 2 (phenylthiophthalimide, PhthSPh) in the
presence of an achiral Lewis base catalyst (tetrahydrothiophene,
THT) and a Brønsted acid (MsOH) at room temperature
showed that sulfonamides 5−7 rapidly formed piperidines in
good yields (entries 1, 3, and 5). Although both tosylamide 5 and
nosylamide 6 displayed excellent reactivity in the presence of
THT, tosylamide 5 possessed a lower background rate when the
Lewis base was omitted (entries 2 and 4). Cyclizations of
benzamide 8 (entry 7) and benzyl carbamate 9 (entry 8) were
slow under the reaction conditions such that 48 h were required
Scheme 1
Received: May 8, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja5046296 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
to reach high conversions. Unsurprisingly, tert-butylcarbamate
10 (entry 9) and diphenylphosphinic amide 11 (entry 10)
decomposed under the acidic reaction conditions.
configuration of 12 was determined by reductive removal of the
sulfide group and comparison of the optical rotation of the
resulting piperidine to literature values.11
During the reaction optimization studies, isomerization of
piperidine 12 to a pyrrolidine was observed. The combination of
THT and 1.0 equiv of MsOH afforded piperidine 12
quantitatively in 5 min at rt (Scheme 3). However, piperidine
12 isomerized into a 1:2.8 mixture of 12 and pyrrolidine 13 by
allowing the mixture to stir for 12 h. Independent treatment of
either 12 or 13 with 1.0 equiv of MsOH at rt resulted in the
establishment of an equilibrium mixture of 12/13 (1:2.8) after 12
h.12 The isomerization of 12 to 13 alleviates the steric
interactions between the N-tosyl group and the 2-phenyl group
in piperidine 12.13
Table 1. Survey of Amine Protecting Groups
a
d
entry
substrate (R)
Lewis base
time
yield, %
b
b
b
1
2
3
4
5
6
7
8
9
10
5 (Ts)
THT
none
THT
none
THT
none
THT
THT
THT
5 min
93
c
f
5 (Ts)
48 h
4
6 (Ns)
5 min
95
c
f
6 (Ns)
48 h
11
7 (Tris)
7 (Tris)
8 (Bz)
5 min
84
Scheme 3
c
f
48 h
2
b
48 h
86
81
b
9 (Cbz)
10 (Boc)
11 (DPP)
48 h
e
e
−
−
−
−
e
e
THT
b
a
Conversion monitored by TLC. The time full conversion observed.
The time reaction was quenched. Isolated yields. Decomposed
under the reaction conditions. Determined by integration of the H
NMR spectra of crude reaction mixtures.
c
d
e
f
1
Identification of the optimal catalyst involved a survey of
various BINAM-derived selenophosphoramides bearing differ-
ent dialkylamine substituents (Table 2). Azepane-substituted
selenophosphoramide (R)-3a, which was employed in the
analogous sulfenoetherification reaction,6 afforded 12 with an
11:89 e.r. (entry 1). The reaction with diisobutylamine-
substituted selenophosphoramide (S)-3b, which was employed
in the carbosulfenylation reaction, afforded the same yield and
selectivity as (R)-3a (entry 2). Selenophosphoramides with less
bulky substituents, (S)-3c, resulted in a slightly eroded
enantiomeric ratio (entry 3). Azocane-substituted catalyst (S)-
3d and diisopentylamine-substituted selenophosphoramide (S)-
3e afforded the product in lower yields but improved the
enantioselectivities of 91:9 and 93:7 e.r., respectively (entries 4
and 5). Interestingly, diisopropylamine-substituted seleno-
phosphoramide (S)-3f, bearing the most sterically encumbered
substituent adjacent to the nitrogen, afforded the best enantio-
meric ratio of 95:5 e.r. but at a lower rate. The absolute
In view of the MsOH-induced isomerization of the product,
additional studies were performed to evaluate the optimal acid
loading for the sulfenoamination reaction (Table 3). With 1.0
equiv of MsOH at 0 °C, isomerization of 12 to 13 was observed.
However, using less than 1.0 equiv of MsOH greatly reduced the
amount of product isomerization. Whereas reactions with
loadings of 0.5 and 0.75 equiv of MsOH afforded comparable
results (entries 2 and 3), 0.5 equiv led to slightly higher
enantioselectivity. The reaction with 0.25 equiv of MsOH
displayed a slightly slower reaction rate, reaching full conversion
at 24 h (entry 4). Although the reaction with 0.10 equiv gave high
e.r., the reaction rate was unacceptably slow (entry 5).
Table 3. Survey of Acid Loadings
Table 2. Survey of Chiral Lewis Base Catalysts
ab
,
b
c
entry
MsOH, equiv
conv, %
endo:exo
e.r.
1
2
3
4
5
1.00
0.75
0.50
0.25
0.10
100
100
100
98
85.7:14.3
98.9:1.1
99.2:0.8
99.4:0.6
99.5:0.5
91.6:8.4
92.9:7.1
93.5:6.5
93.6:6.4
93.9:6.1
69
a
The conversion was monitored by 1H NMR spectroscopy (6, 12, and
a
b
b
1
entry
catalyst, R2
yield, %
e.r.
24 h). Determined by H NMR spectroscopy of the crude mixture.
c
The enantiomeric ratio was determined by CSP-SFC analysis.
1
2
3
4
5
6
(R)-3a, (CH2)6
(S)-3b, (i-Bu)2
(S)-3c, n-Bu, Et
(S)-3d, (CH2)7
(S)-3e, (i-amyl)2
(S)-3f, (i-Pr)2
90
88
79
67
82
75
11.5:88.5
89.4:10.6
88.1:11.9
91.4:8.6
92.8:7.2
94.6:5.4
The scope of the reaction with various olefins was investigated
next (Table 4). The influence of the electronic properties of the
alkene on reaction rate and stereoselectivity was examined first.
Substrate 14, with a 4-anisyl-substituted double bond possessing
greater electron density than 5, showed comparable reactivity
with a slight drop in enantioselectivity (entry 2). In contrast,
a
b
Isolated yields. The enantiomeric ratio was determined by CSP-SFC
analysis.
B
dx.doi.org/10.1021/ja5046296 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 4. Scope of the Enantioselective Intramolecular Sulfenoamination Reaction
a
b
c
Isolated yields of analytically pure material. Constitutional selectivity determined by 1H NMR spectroscopy of the crude mixture. The
enantiomeric ratio of the major constitutional isomer was determined by CSP-SFC analysis, and the absolute configurations of the products were
d
assigned by analogy to 12. Incomplete conversion on quenching at 48 h.
substrate 16, bearing a strongly electron-withdrawing 4-
trifluoromethylphenyl substituent, afforded only a 39% yield
after 48 h (54% conv., entry 3). Interestingly, the observed e.r.
(91.9:8.1) for 17 was comparable to that for 15. It is important to
note that substrates 5, 14, and 16 (entries 1, 2, and 3) afforded
piperidines, as established by 1H NMR spectroscopy. Substrate
18 bearing a non-conjugated olefin afforded a mixture of endo
and exo products in a 1:3 ratio in good yields and excellent e.r.’s
(entry 4). The reduced endo to exo ratio is likely due to the less-
biased electron density of the alkene. In contrast, isopropyl-
substituted olefin 20 showed a much greater exo selectivity
(along with a high yield and e.r.), thus implicating an important
role for the steric bulk of the substituent (entry 5). Interestingly,
the reaction of 22, containing 2,2-dimethyl substitution on the
tether, afforded a good yield and retained the excellent
enantioselectivity (entry 6). However, substrate 24, with 1,1-
dimethyl substitution in the tether, resulted in a lower
enantioselectivity (entry 7). Other olefins with different
substitution patterns were also investigated. Olefin (Z)-5 reacted
slowly (75% conv. in 48 h) with poor enantioselectivity
C
dx.doi.org/10.1021/ja5046296 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(62.8:37.2) (entry 8). The reaction of terminal olefin 27 gave a
good yield and high enantioselectivity of 92.5:7.5 with exclusive
exo cyclization (entry 9). Carboxamide 29 afforded the product
in good yield with constitutional selectivity, but showed
diminished e.r. (entry 10). Presumably, protonation of the
carbonyl group attenuates the nucleophilicity of the nitrogen and
prevents rapid capture of the intermediate thiiranium ion, thus
allowing racemization.
The influence of tether length on cyclization was also
investigated. Two-carbon-tethered substrate 31 cyclized to
pyrrolidine 32 in 86% yield and 91.3:8.7 e.r. with complete
endo selectivity (entry 11). Interestingly, four-carbon-tethered
substrate 33 showed the impact of conjugation on biasing the
two olefinic carbons by affording exclusively azepane 34 (entry
12). The structure and the absolute configuration of 34 were
established by X-ray crystallography.14 In contrast, the non-
conjugated substrates 35 and 37 afforded only piperidine
products via exo cyclization, indicating the preference to form
the six-membered rings for dialkyl-substituted olefins. Addition-
ally, reactions with both 35 and 37 gave the products in good
yields and excellent enantioselectivities.
AUTHOR INFORMATION
Corresponding Author
sdenmark@illinois.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health for generous
financial support (R01 GM85235). Dedicated to Prof. John A.
Katzenellenbogen on the occasion of his 70th birthday.
REFERENCES
■
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The proposed catalytic cycle for the sulfenoamination reaction
is shown in Figure 1.15 Sulfenylating agent 2 is activated with
MsOH and then transfers the sulfenyl moiety to the Lewis base
(S)-3f, forming the chiral sulfenylating complex i.7c Subsequent
transfer of the sulfenium ion from i to the alkene furnishes the
enantioenriched chiral thiiranium ion intermediate ii. Finally,
capture of the thiiranium ion with the pendant tosylamide and
subsequent deprotonation affords the enantioenriched product.
(4) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560−1638. (b) Gutmann, V. The Donor-Acceptor Approach to
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Figure 1. Proposed catalytic cycle for the sulfenoamination.
(12) See the Supporting Information.
(13) Li, L.; Wang, H.; Huang, D.; Shi, Y. Tetrahedron 2012, 68, 9853−
In conclusion, a Lewis base catalyzed, enantioselective,
intramolecular sulfenoamination of unactivated olefins has
been developed. The reaction produces saturated N-heterocyclic
rings with high enantioselectivities for a wide range of trans
olefins. Extensions to intermolecular sulfenoamination reactions
are under investigation.
9859.
(14) The crystallographic coordinates of 34 have been deposited with
the CCDC; deposition no. 981943. These data can be obtained free of
charge via from the Cambridge Crystallographic Data Centre, at www.
ccdc.cam.ac.uk/conts/retrieving.html or deposit@ccdc.cam.ac.uk.
(15) The kinetic, spectroscopic, structural, and computational
characterization of this catalytic cycle has been completed and submitted
for publication.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures, characterization data, and X-ray
coordinates for 34. This material is available free of charge via the
Internet at http://pubs.acs.org.
D
dx.doi.org/10.1021/ja5046296 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX