Catalytic, enantioselective, intramolecular carbosulfenylation of olefins

Article abstract of DOI:10.1021/ja401867b

The first catalytic, enantioselective carbosulfenylation of alkenes with an aromatic nucleophile is described, using a BINAM-based selenophosphoramide catalyst. E-Alkyl- and aryl-substituted alkenes afforded tetrahydronaphthalenes with complete diastereospecificity, and generally high enantiomeric ratios.

Full text of DOI:10.1021/ja401867b

Communication
pubs.acs.org/JACS
Catalytic, Enantioselective, Intramolecular Carbosulfenylation of
Olefins
Scott E. Denmark* and Alex Jaunet
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S
* Supporting Information
sulfenylphthalimide, 1, is susceptible to catalysis by Lewis
bases and the intermediate thiiranium ions are stable12a and can
be captured enantiospecifically with a variety of heteroatom
nucleophiles.12b These insights led to the development of the
first catalytic, enantioselective sulfenoetherification of un-
activated double bonds using 1, MsOH, and a chiral
selenophosphoramide as the Lewis base.12c In continuation of
these studies we sought to expand the scope of the asymmetric
sulfenofunctionalization13−15 to include carbocyclizations with
aromatic nucleophiles. Although such transformations are
known, no examples of catalytic, enantioselective cyclizations
are on record.
ABSTRACT: The first catalytic, enantioselective carbo-
sulfenylation of alkenes with an aromatic nucleophile is
described, using a BINAM-based selenophosphoramide
catalyst. E-Alkyl- and aryl-substituted alkenes afforded
tetrahydronaphthalenes with complete diastereospecificity,
and generally high enantiomeric ratios.
he reaction of sulfur(II) electrophiles with alkenes1 to
T
afford sulfenofunctionalized products has been thoroughly
studied since the 1960s primarily in the context of investigating
the chemistry of thiiranium ions.2 These reactive intermediates
can be generated by a variety of different sulfenylating reagents
(Scheme 1). In addition to the wide range of nucleophiles that
have been employed in intermolecular sulfenofunctionalization
reactions, the intramolecular capture (sulfenocyclization
reactions) can be effected with sulfenylating agents to form
carbocycles and heterocycles. Moreover, sulfenium-initiated
cyclizations have also been successful with polyolefins5 and
electron-rich arenes.6 Several examples of nucleophilic opening
of chiral thiiranium ions are reported. However, these species
are generated by anchimerically assisted ionization of
enantiomerically enriched hydroxy sulfides formed from
asymmetric dihydroxylation of alkenes.7 These enantiomerically
enriched thiiranium ions have been captured with various
nucleophiles in inter- and intramolecular fashion.8 However,
only two reports of direct, enantioselective methylsulfenylation
reactions have been reported, both employing stoichiometric
reagents.9
In view of the conditions reported for the sulfenoether-
ification, the initial conditions for the sulfenocarbocyclization of
alkene 2a employed 1 (1.0 equiv), MsOH (1.0 equiv), and
Lewis base (10 mol %) in CDCl3 at −20 °C. A number of chiral
phosphoramides were tested to develop an asymmetric variant
of the intramolecular sulfenocarbocyclization. The initial survey
of Lewis bases was carried out with E/Z mixtures of the starting
material 2a. The trans/cis ratio of the diastereomeric products
1
3a was determined by H NMR spectroscopic analysis of the
purified material, and the enantiomeric composition of the
products was determined by chiral stationary phase supercritical
fluid chromatographic (CSP-SFC) analysis (Table 1). The
exclusive formation of trans- and cis-1,2-disubstituted-1,2,3,4-
tetrahydronaphthalenes from E- and Z-olefins respectively is in
accordance with the anticipated diastereospecificity character-
istic of other seleno-11 and thiofunctionalizations.12 Chiral
Lewis base (R)-4a afforded cyclized products 3a with moderate
enantioselectivity for the major product, trans-3a (Table 1,
entry 1). However, the minor product, cis-3a, was produced in
racemic form.
Scheme 1
Increasing the size of the ring to the azepane catalyst (R)-4b
led to higher enantioselectivity for trans-3a but gave cis-3a in
racemic form (entry 2). A further increase in the size of the ring
with azocane catalyst (R)-4c achieved slightly reduced
enantioselectivity in the formation of trans-3a (entry 3). cis-
3a was still obtained with moderate enantioselectivity. Use of
acyclic, branched and secondary external amines with
diisopropylamino-substituted selenophosphoramide (R)-4d
afforded reasonable enantioselectivity for trans-3a (entry 4).
Evaluation of other catalysts prepared from branched secondary
amines allowed the identification of the diisobutyl-derived
catalyst (S)-4e, which afforded excellent enantioselectivity for
trans-3a (entry 5). Further extension to the diisoamylamine-
As part of a broadly based program to apply the concept of
Lewis base activation of Lewis acids10 to the reactions of main
group elements, we have investigated the chemistry of
selenium(II)11 and sulfur(II)12 electrophiles. From extensive
preparative and mechanistic studies, we have discovered that
the functionalization of isolated alkenes with N-phenyl-
Received: February 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja401867b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Survey of Chiral Lewis Bases in Sulfenocarbocyclization of 2a
a
b
1
Reaction conditions: 2a (0.12 mmol), 1 (0.12 mmol), CDCl3 (0.2 M), −20 °C. E/Z ratio of the starting material was determined by H NMR
c
d
spectroscopic analysis. The trans/cis ratios of the cyclization products were determined by 1H NMR spectroscopic analysis. The enantiomeric ratio
was determined by CSP-SFC analysis. Reactions were completed in 24 h. Reactions were completed in 48 h.
e
f
derived catalyst (S)-4f afforded results similar to those obtained
with the azepane catalyst (R)-4b for trans-3a and a slight
improvement for cis-3a (entry 6). The use selenophosphor-
amide catalysts (R)-4g and (S)-4h derived from linear
dialkylamines afforded excellent enantioselectivities for trans-
3a (entries 7 and 8) but lower enantioselection than that
obtained with (S)-4e bearing a diisobutylamino group.
With a highly enantioselective Lewis base catalyst in hand,
the diversity of the substituent patterns on the alkene as well as
the nucleophilicity of the aromatic residue needed for effective
cyclization were explored. Surprisingly, however, upon scaling
the reactions to 1.0 mmol, the enantioselectivities decreased.
Consequently, the critical reaction parameters had to be re-
evaluated, in particular the acid source and loading.16 After
extensive optimization it was found that EtSO3H (0.75 equiv)
served effectively and reproducibly as the Brønsted acid for
cyclization. Using 10 mol % of catalyst (S)-4e, EtSO3H (0.75
equiv) and (E)-2a substrate afforded excellent enantioselection
of trans-3a (96:4) with high conversion (Table 1, entry 9).
Lowering the loading of (S)-4e to 5 and 2 mol % afforded
enantiomeric ratios of 71:29 and 67:33, respectively (entries 10
and 11).
bearing linear, β-branched, and alicyclic substituents (E)-3b−
(E)-3d afforded cyclized products trans-3b−trans-3d in
moderate yields but excellent levels of enantioselectivity and
reacted with similar rates (entries 3−5). The length of the alkyl
chain on the alkene did not influence the rate or
enantioselectivity of the reaction. However, the presence of a
chlorine atom on the alkyl chain ((E)-2c) decreased the rate of
the reaction while maintaining a high level of enantioselectivity.
Cyclopropyl substrate (E)-2e bearing branching at the allylic
position led to a good yield and enantioselectivity (entry 6),
whereas common cycloalkyls (five- and six-membered) gave
lower yields and enantioselectivities (entries 7 and 8). If the
alkene contained a tert-butyl substituent, no cyclization
occurred. Cyclization of substrates 2h and (E)-2i containing
geminally disubstituted alkenes allowed formation of quater-
nary carbon centers in good yields. Trisubstituted alkenes were
more reactive than disubstituted E-alkenes, but the enantio-
selectivities were lower (entries 9 and 10). Interestingly,
byproducts resulting from proton-initiated cyclization reaction
were formed in 2−8% yield with trisubstituted alkenes.18
The next stage of the investigation focused on the scope of
(E)-aryl-substituted alkenes that could participate in the
cyclization (Table 2). Substrates (E)-2j, (E)-2k, and (E)-2l
bearing no substituents or electron-donating substituents
afforded cyclization products in good yields and enantio-
selectivities (entries 11−13). As was observed with trisub-
stituted alkenes, increasing the electronic density of the double
bond led to faster cyclization. However, substrate (E)-2m
bearing a methyl group in the ortho position reacted slowly, but
with good enantioselectivity (entry 14). Substrate (E)-2n
At this point, the generality of this transformation was
investigated. Gratifyingly, application of the optimized con-
ditions to a large variety of E-alkyl- and aryl-substituted alkenes
afforded the cyclized products in moderate to excellent yields
(50−92%) with good to excellent enantioselectivities and as
single (trans) diastereomer (Table 2). For example, under these
conditions E-methyl-substituted alkene (E)-2a formed trans-3a
in excellent yield and enantioselectivity. Unactivated E-alkenes
B
dx.doi.org/10.1021/ja401867b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Cyclization with Alkyl- and Aryl-Substituted Alkenes17
ab
,
c
entry
substrate
R1
R2
product
time, d
temp, °C
er
yield, %
1
(E)-2a
(Z)-2a
(E)-2b
(E)-2c
(E)-2d
(E)-2e
(E)-2f
(E)-2g
2h
CH3
H
H
trans-3a
cis-3a
3
1
3
6
3
3
3
3
1
2
2
2
1
3.5
2
6
3
−20
0
97:3
92
91
73
63
77
88
2
CH3
H
52:48
96:4
3
n-C5H11
trans-3b
trans-3c
trans-3d
trans-3e
trans-3f
trans-3g
3h
−20
20
4
(CH2)3Cl
i-Bu
H
94:6
5
H
−20
−20
0
96:4
6
cyclopropyl
cyclopentyl
cyclohexyl
CH3
H
95:5
d
7
H
82:18
85:15
80:20
71:29
94:6
50
e
8
H
0
70
f
9
CH3
CH3
H
−20
−20
−20
−20
−20
−20
−20
20
90
g
10
11
11
13
14
15
16
17
(E)-2i
(E)-2j
(E)-2k
(E)-2l
(E)-2m
(E)-2n
(E)-2o
(E)-2p
C6H5
trans-3i
trans-3j
trans-3k
trans-3l
trans-3m
trans-3n
trans-3o
trans-3p
82
C6H5
90
86
86
4-CH3C6H4
4-CH3OC6H4
2-CH3C6H4
2-naphthyl
4-NC-C6H4
4-CF3C6H4
H
94:6
H
92:8
h
H
92:8
82
i
H
89:11
89:11
92:8
61
H
83
85
H
20
a
b
The enantiomeric ratio was determined by CSP-SFC analysis. The absolute configurations of the products were assigned by comparison of their
c
d
e
CD spectra with that of trans-3b. Yields of analytically pure products. Unreacted starting material was recovered (15%). Unreacted starting
f
g
material was recovered (16%). An 8% yield of protiocyclization product was isolated. A 2% yield of protiocyclization product was isolated.
h
i
Unreacted starting material was recovered (4%). Unreacted starting material was recovered (36%).
bearing a 2-naphthyl substituent afforded good selectivity but in
lower yield (entry 15). Finally, alkenes (E)-2o and (E)-2p
bearing electron-deficient aromatic groups furnished nearly
identical enantioselectivities in very slow reactions (entries 16
and 17). The very slow cyclization (even at room temperature)
of E-styrenes bearing electron-withdrawing substituents could
be ascribed to the electron-deficient nature of the alkene, which
would slow the formation of the thiiranium species.
Scheme 2
The final exploration of substrate scope was carried out with
less monosubstituted aryl groups. Substrates bearing a methoxy
group in the 3-position with respect to the tethered alkene
afforded a mixture of cyclized products 6−9, with both n-pentyl
((E)-5b) and phenyl ((E)-5j) substituents (Scheme 2). With
(E)-5b, a 3:1 ratio of 6/7 was produced in good yields and
enantioselectivities (entry 1). However, substrate (E)-5j
bearing a phenyl substituent afforded a 1:1 ratio of 8/9, but
good enantioselectivity was still achieved for both constitutional
isomers.
In conclusion, the first catalytic, asymmetric carbosulfenyl-
ation of olefins has been accomplished by using a cocatalytic
system of a Brønsted acid (EtSO3H) and a chiral Lewis base
(S)-4e. This method enables efficient access to enantioenriched
trans-tetrahydronaphthalenes with complete diastereo-
specificity, generally high enantiomeric ratios, and a broad
substrate scope with E-olefins. Formation of quaternary centers
was achieved in moderate enantioselectivities. Further inves-
tigations aimed at expanding the scope of the reaction along
with studies on the origins of the enantioselectivity, and the
importance of the role played by the Brønsted acid will be
reported in due course.
ASSOCIATED CONTENT
* Supporting Information
Full experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
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).
■
C
dx.doi.org/10.1021/ja401867b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Indolones: (g) Han, Z.; Chen, W.; Dong, S.; Yang, C.; Liu, H.; Pan, Y.;
Yan, L.; Jiang, Z. Org. Lett. 2012, 14, 4670−4673. (h) Li, X.; Liu, C.;
Xue, X.-S.; Cheng, J.-P. Org. Lett. 2012, 14, 4374−4377. (i) Wang, C.;
Yang, X.; Loh, C. C. J.; Raabe, G.; Enders, D. Chem.Eur. J. 2012, 18,
11531−11535. (j) Cai, Y.; Li, J.; Chen, W.; Xie, M.; Liu, X.; Lin, L.;
Feng, X. Org. Lett. 2012, 14, 2726−2929.
(14) For a report of catalytic, enantioselective oxysulfenylation of
unactivated alkenes under chiral Brønsted acid catalysis, see: Guan, H.;
Wang, H.; Huang, D.; Shi, Y. Tetrahedron 2012, 68, 2728−2735.
(15) For catalytic desymmetrization of meso-thiiranium ions, see:
(a) Hamilton, G. L.; Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008,
110, 14984−14986. (b) Lin, S.; Jacobsen, E. N. Nature Chem. 2012, 4,
817−824.
(16) A complete disquisition of these studies and the mechanistic
implications of the role of the Brønsted acid will be disclosed in a full
account of this work.
REFERENCES
■
(1) de la Mare, P. B. D.; Bolton, R. In Electrophilic Additions to
Unsaturated Systems, 2nd ed.; de la Mare, P. B. D., Bolton, R., Eds.
Elsevier: Amsterdam, 1982; Vol. 9, pp 198−246.
(2) (a) Schmid, G. H. In Supplement A: The chemistry of double
bonded functional groups; John Wiley & Sons: London, 1989; Vol. 2,
Part 1, pp 679−731. (b) Schmid, G. H.; Garratt, D. G. In The chemistry
of double-bonded functional groups Part 2; John Wiley & Sons: London,
1977; pp 725−912. (c) Lucchini, V.; Modena, G.; Pasquato, L. Gazz.
Chim. Ital. 1997, 127 (4), 177−188. (d) Rayner, C. M. In Organosulfur
Chemistry: Synthetic Aspects; Page, P., Ed.; Academic Press: London,
1995; pp 89−131. (e) Modena, G.; Pasquato, L.; Lucchini, V.
Phosphorus, Sulfur Silicon Relat. Elem. 1994, 95−6, 265−282.
(f) Capozzi, G.; Modena, G.; Pasquato, L. In The Chemistry of
Sulphenic Acids and Their Derivatives Patai, S., Ed.; John Wiley & Sons
Ltd.: West Sussex, 1990; pp 403−516. (g) Harring, S. R.; Edstrom, E.
D.; Livinghouse, T. Adv. Heterocycl. Nat. Prod. Synth. 1992, 2, 299−
376. (h) Capozzi, G.; Modena, G. Organic Sulfur Chemistry: Theoretical
and Experimental Advances; Bernardi, F., Csizmadia, I. G., Mangini, A.,
Eds.; Elsevier: Amsterdam, 1985; Vol. 19, pp 246−298.
(3) (a) Drabowicz, J.; Lyzwa, P.; Mikolajczyk, M. In The Chemistry of
Sulphenic Acids and Their Derivatives; Patai, S., Ed.; John Wiley & Sons
Ltd.: West Sussex, 1990; pp 187−220. (b) Drabowicz, J.; Kielbasinski,
P.; Mikolajczyk, M. In The Chemistry of Sulphenic Acids and Their
Derivatives; Patai, S., Ed.; John Wiley & Sons Ltd.: West Sussex, 1990;
pp 221−292.
(17) The relative configuration of tetrahydronaphthalenes was
1
confirmed by correlation of the H NMR chemical shifts of HC(3)
with known products trans-2a and cis-2a.6,18 The absolute config-
uration of (−)-trans-3k was determined to be (1R,2R) by X-ray
crystallographic analysis of the derived sulfone trans-12. The
crystallographic coordinates of trans-12 have been deposited with
the Cambridge Crystallographic Data Centre; deposition no. 913987.
These data can be obtained free of charge via from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223-336-033; via www.ccdc.cam.ac.uk/conts/
retrieving.html or deposit@ccdc.cam.ac.uk.
(4) Hogg, D. R. In The Chemistry of Sulphenic Acids and Their
Derivatives; Patai, S., Ed.; John Wiley & Sons Ltd.: West Sussex, 1990;
pp 361−402.
(18) See the Supporting Information.
(5) (a) Moore, J. T.; Soldi, C.; Fettinger, J. C.; Shaw, J. T. Chem. Sci.
2013, 292−296. (b) Edstrom, E. D.; Livinghouse, T. J. Org. Chem.
1987, 52, 949−951. (c) Masaki, Y.; Hashimoto, K.; Sakuma, K.; Kaji,
K. Tetrahedron Lett. 1982, 1481−1484.
(6) Edstrom, E. D.; Livinghouse, T. J. Am. Chem. Soc. 1986, 108,
1344−1346.
(7) (a) Toshimitsu, A.; Hirosawa, C.; Tamao, K. Synlett 1996, 465−
467. (b) Toshimitsu, A.; Abe, H.; Hirosawa, C.; Tamao, K. J. Chem.
Soc., Perkin Trans. 1 1994, 3465−3471. (c) Toshimitsu, A.; Hirosawa,
C.; Tamao, K. Tetrahedron 1994, 50, 8997−9008. (d) Toshimitsu, A.;
Hirosawa, C.; Tanimoto, S. Chem. Lett. 1992, 239−242. (e) Toshi-
mitsu, A.; Abe, H.; Hirosawa, C.; Tanimoto, S. J. Chem. Soc., Chem.
Commun. 1992, 284−285. (f) Toshimitsu, A.; Hirosawa, C.;
Tanimoto, S. Tetrahedron Lett. 1991, 32, 4317−4320.
(8) (a) Branchaud, B. P.; Blanchette, H. S. Tetrahedron Lett. 2002, 43,
351−353. (b) Ono, N.; Kaminura, A.; Sasatami, H.; Kaji, A. J. Org.
Chem. 1987, 52, 4135−4137.
(9) (a) Archer, N. J.; Rayner, C. M.; Bell, D.; Miller, D. Synlett 1994,
617−619. (b) Pasquato, L.; Modena, G. Chem. Commun. 1999, 1469−
1470.
(10) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560−1638.
(11) (a) Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem. Soc.
2010, 132, 15752−15765. (b) Denmark, S. E.; Collins, W. R. Org. Lett.
2007, 9, 3801−3804.
(12) (a) Denmark, S. E.; Collins, W. R.; Cullen, M. D. J. Am. Chem.
Soc. 2009, 131, 3490−3491. (b) Denmark, S. E.; Vogler, T. Chem.
Eur. J. 2009, 15, 11737−11745. (c) Denmark, S. E.; Kornfilt, D. J. P.;
Vogler, T. J. Am. Chem. Soc. 2011, 133, 15308−15311.
(13) Enantioselective sulfenylation of activated alkenes derived from
aldehydes, ketones, and amides has also been reported recently.
Aldehydes: (a) Zhao, G. L.; Rios, R.; Vesely, J.; Eriksson, L.; Cordova,
́
A. Angew. Chem., Int. Ed. 2008, 47, 8468−8472. (b) Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794−797. Ketones: (c) Lin, A.; Fang, L.; Zhu, X.; Zhu, C.;
Cheng, Y. Adv. Synth. Catal. 2011, 353, 545−549. (d) Polaske, N. W.;
Dukey, R.; Nichol, G. S.; Olenyuk, B. Tetrahedron: Asymmetry 2009,
20, 2742−2750. (e) Fang, L.; Lin, A.; Hu, H.; Zhu, C. Chem.Eur. J.
2009, 15, 7039−7043. (f) Sobhani, S.; Fielenbach, D.; Marigo, M.;
Wabnitz, T. C.; Jorgensen, K. J. Chem.Eur. J. 2005, 11, 5689−5694.
D
dx.doi.org/10.1021/ja401867b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX