Carbon-sulfur bond formation via iridium-catalyzed asymmetric allylation of aliphatic thiols

Article abstract of DOI:10.1021/ol200197v

An iridium-catalyzed regio- and enatioselective allylation with aliphatic thiols as the nucleophile in dichloromethane has been accomplished; and the branch products were obtained in 34-80% yields with up to 94/6 b/l and 98% ee.

Full text of DOI:10.1021/ol200197v

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1514–1516
Carbon-Sulfur Bond Formation via
Iridium-Catalyzed Asymmetric Allylation
of Aliphatic Thiols
Ning Gao, Shengcai Zheng, Weikang Yang, and Xiaoming Zhao*
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai 200092,
People’s Republic of China, and Key Laboratory of Fluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, People’s Republic of China
xmzhao08@mail.tongji.edu.cn
Received January 21, 2011
ABSTRACT
An iridium-catalyzed regio- and enatioselective allylation with aliphatic thiols as the nucleophile in dichloromethane has been accomplished; and
the branch products were obtained in 34-80% yields with up to 94/6 b/l and 98% ee.
The exploration of transition metal-catalyzed allylations
for the construction of carbon-sulfur bonds is of wide-
spread interest due to the growing need for versatile, mild,
and selective methods in the preparation of organosulfur
compounds.1 Iridium-catalyzed reactionsofthistypeusing
an unsymmetrically substituted allylic substrate normally
formthe branchproductalongwiththelinearproduct, and
their enantioselectivity could be controlled by tuning the
catalyst system.2 Since sulfur compounds, particularly
aliphatic thiols, are well-known metal catalyst poisons,3
their use as nucleophiles in this type of transformation
remains a considerable challenge. While carbon-sulfur
bond formation with aromatic thiols (e.g. 4-chlorothiophe-
nol, 2-pyridinethiol, 2-pyrimidinethiol, and thiophenol) has
been investigated in this context,4 the employment of
more basic aliphatic thiols, which failed to conduct an
allylation catalyzed by palladium catalyst,4a for the
(2) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int.
Ed. 2004, 43, 2426–2428. (b) Alexakis, A.; Polet, D. Org. Lett. 2004, 6,
3529–3531. (c) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
17192–17193. (d) Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 7720–7721. (e) Helmchen, G.; Dahnz, A.; Duebon, P.; Schelwies,
M.; Weihofen, R. Chem. Commun. 2007, 675–691. (f) He, H.; Zheng, X.;
Li, Y.; Dai, L.; You, S. Org. Lett. 2007, 9, 4339–4341. (g) Liu, W.; He, H.;
Dai, L.; You, S. Org. Lett. 2008, 10, 1815–1818. (h) Liu, W.; He, H.; Dai,
L.; You, S. Synthesis 2009, 2076–2082. (i) He, H.; Liu, W.; Dai, L.; You,
S. J. Am. Chem. Soc. 2009, 131, 8346–8347. (j) Liu, W.; Zheng, S.; He,
H.; Zhao, X.; Dai, L.; You, S. Chem. Commun. 2009, 6604–6607. (k)
Spiess, S.; Raskatov, J. A.; Gnamm, C.; Broner, K.; Helmchen, G.
Chem.;Eur. J. 2009, 15, 11087–11090. (l) Ohmura, T.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 15164–15165. (m) Shu, C. T.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2004, 43, 4794–4796. (n) Lyothier, I.; Defieber,
C.; Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45, 6204–6206. (o)
Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett.
2007, 9, 3949–3951. (p) Ueno, S.; Hartwig, J. F. Angew. Chem., Int. Ed.
2008, 47, 1928–1931. (q) Ueda, M.; Hartwig, J. F. Org. Lett. 2010, 12,
92–94.
(3) (a) Hegedus, L. L.; McCabe, R. W. Catalyst Poisoning; Marcel
Dekker: New York, 1984. (b) Hutton, A. T. In Comprehensive Coordination
Chemistry; Wilkinson, G., Gillard, R. D., McCleverty, J. A., Eds.; Pergamon:
Oxford, U.K., 1984; Vol. 5, p 1151.
(4) (a) Frank, M.; Gais, H. J. Tetrahedron: Asymmetry 1998, 9, 3353–
3357. (b) Gais, H. J.; Spalthoff, N.; Thomas, J.; Frank, M.; Raabe, G.
Tetrahedron Lett. 2000, 41, 3809–3812. (c) Gais, H.-J.; Thomas, J.;
Spalthoff, N.; Gerhards, F.; Frank, M.; Raabe, G. Chem.;Eur. J. 2003,
9, 4202–4221. (d) Zheng, S.; Gao, N.; Liu, W.; Liu, D.; Zhao, X.; Cohen,
T. Org. Lett. 2010, 43, 4454–4457.
(1) (a) For a review in the area, see: Kondo, T.; Mitsdo, M. Chem.
Rev. 2000, 100, 3205–3220. (b) Eichelmann, H.; Gais, H. J. Tetrahedron:
Asymmetry 1995, 6, 643–646. (c) Trost, B. M.; Krische, M. J.; Radinov,
R.; Zanoni, G. J. Am. Chem. Soc. 1996, 118, 6297–6298. (d) Trost, B. M.;
Crawley, M. L.; Lee, C. B. J. Am. Chem. Soc. 2000, 122, 6120–6121. (e)
Felpin, F. X.; Landais, Y. J. Org. Chem. 2005, 70, 6441–6446. (f)
Chandrasekhar, S.; Jagadeshwar, V.; Saritha, B.; Narsihmulu, C.
J. Org. Chem. 2005, 70, 6506–6507. (g) Jegelka, M.; Plietker, B. Org.
Lett. 2009, 11, 3462–3465. (h) Alexey, B.; Zaitsev, H. F.; Caldwell, P. S.;
Pregosin, L. F. V. Chem.;Eur. J. 2009, 15, 6468–6477. (i) Kondo, T.;
Morisaki, Y.; Uenoyama, S.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc.
1999, 121, 8657–8658. (j) Xu, Q.; Liu, W.; Dai, Li.; You, S. J. Org. Chem.
2010, 75, 4615–4618. (k) Xu, Q.; Dai, L.; You, S. Org. Lett. 2010, 12,
800–803.
r
10.1021/ol200197v
Published on Web 02/24/2011
2011 American Chemical Society

Table 1. Reaction Optimization for the Iridium-Catalyzed
Asymmetric Alkylation of Sodium Cyclohexanethiolate 3aa
entry
L
solvent additive temp (°C) yield (%)b 4a/5ac ee (%)d
1
2
3
4
5
6
7
8
9
L1 DCM CsF
L2 DCM CsF
L3 DCM
15
15
15
15
15
15
15
15
15
25
0
36
95/5
82
NRe
72
91/9
92/8
93/7
92/8
96
98
97
95
L3 DCM CsF
L4 DCM CsF
L5 DCM CsF
L6 DCM CsF
L3 DCM CsCl
L3 DCM LiCl
78
Figure 1. Chiral Ligands L1-L6.
77
33
NRe
64
88/12
90/10
88/12
88/12
96
96
96
96
In the first instance, we began with a study on aliphatic
thiols as the nucleophile. Thus, an allylation of (E)-cinnayl
methyl carbonate 2a with sodium cyclohexanethiolate 3a
as the model reaction in the presence of [Ir(COD)Cl]2
(1 mol %), ligand L17 (2 mol %), and cesium fluoride
(CsF) in dichloromethane (DCM) was performed at 15 °C.
To our delight, the corresponding products were obtained
in 36% yield with 95:5 4a:5a and 82% ee (entry 1),
indicating that the chiral amine of L1 alone could induce
the good ee value of the branch product 4a. Inspired by
these results, a range of the varying ligands such as L2,8
L3,9,10 L4,9 L5,10 and PHOX ligand L611 (see Figure 1)
were further evaluated and the preliminary results were
illustrated in Table 1. The reactions with ligands L3 and L4
afforded the branch product 4a in 72-78% yields with
excellent regio- and enatioselectivity (entries 3-5). How-
ever, the iridium complex generated from either a stereo-
chemically simpler ligand L2 or PHOX ligand L6 totally
failed to promote this allylation (entry 2 vs entry 7). In
addition, the use of a sterically hindered ligand L5 in this
allylation led tothe desiredproducts inpoor yield (entry 6).
Finally, L3 was chosen as the optimal ligand for further
exploration. In our previous study on the iridium-cata-
lyzed allylation of thiophenol, we found that CsF has
strong influences on the efficiency and regioselectivity.4d
As a result, we investigated the effect of additives, solvents,
and temperature on this allylation. As shown in Table 1,
the use of additives including CsF, CsCl, and LiCl merely
had slight influences on both yield and regioselectivity
(entries 4, 8, and 9). Interestingly, the desired products
were also obtained in 72% yield with 91:9 4a:5a and 96%
ee without the use of any additive (entry 3 vs entry 4).
Changing the temperature had a dramatic effect on the
77
10 L3 DCM CsF
11 L3 DCM CsF
12 L3 DCM CsF
68
55
-25
15
15
NRe
trace
trace
13 L3 THF
CsF
66/34
54/46
14 L3 PhMe CsF
a Reaction conditions: 1 mol % of [Ir(COD)Cl]2, 2 mol % of L, 200
mol % of 2a, 100 mol % of 3a, and 300 mol % of additive. b Isolated
yields. c Determined by 1H NMR of the crude reaction mixture. d De-
termined by the chiral HPLC analysis. e NR = no reaction.
preparation of functionalized allyl alkyl sulfides by
iridium catalysis is relatively unexplored.4
Our laboratory has started with a program aimed at
the development of asymmetric allylation for car-
bon-sulfur bond formations.4d In connection with
this program, we envisioned an access to the enantio-
selective synthesis of allyl alkyl sulfide by iridium-
catalyzed allylation. Although allyl alkyl sulfides are
key components of bioactive molecules5 and serve as
versatile synthetic intermediates,6 only direct asym-
metric catalytic methods have been identified for their
preparation.4 Herein, we report that chiral monoden-
tate phosphoramidite-ligated iridium complex cata-
lyzes the enantioselective allylation of allylic alcohol
derivatives with aliphatic thiols.
(5) (a) Trost, B. M.; Keeley, D. E. J. Org. Chem. 1975, 40, 2013–2013.
(b) Hall, I. H.; Lee, K.-H.; Mar, E. C.; Starnes, C. O.; Waddell, T. G. J.
Med. Chem. 1977, 20, 333–337. (c) Shimazaki, M.; Hasegawa, J.; Kan,
K.; Nomura, K.; Nose, Y.; Kondo, H.; Ohashi, T.; Watanabe, K. Chem.
Pharm. Bull. 1982, 30, 3139–3146. (d) Bashiardes, G.; Davies, S. G.
Tetrahedron Lett. 1987, 28, 5563–5564. (e) Trail, P. A.; Willner, D.;
Lasch, S. J.; Henderson, A. J.; Hofstead, S.; Casazza, A. M.; Firestone,
R. A.; Helistrom, I.; Hellstrom, K. E. Science 1993, 261, 212–215. (f)
Shinde, P. D.; Mahajan, V. A.; Borate, H. B.; Tillu, V. H.; Bal, R.;
Chandwadkar, A.; Wakharkar, R. D. J. Mol. Catal. A: Chem. 2004, 216,
(7) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 9, 1375–1378.
(8) Hoen, R.; Berg, M.; Bernsmann, H.; Minnaard, A. J.; Vries, G. J.;
€
115–119. (g) For review see: Enders, D.; Luttgen, K.; Narine, A. A.
Fering, L. B. Org. Lett. 2004, 6, 1433–1436.
Synthesis 2007, 959–980.
(9) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A.
Synthesis 2004, 2586–2590.
(6) (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147–
155. (b) Grobel, B. T.; Seebach, D. Synthesis 1977, 357–402. (c) Metzner,
€
(10) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.;
Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878.
(11) (a) Matt, P. v.; Pfaltz, A. Angew. Chem., Int. Ed 1993, 32, 566–
568. (b) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1995, 34, 1769–1772.
P.; Thillier, A. Sulfur Reagents in Organic Synthesis; Academic Presss:
London, U.K., 1994; p 75. (d) Dai, C.; Zhu, S.; Yu, Z.; Cohen, T. J. Am.
Chem. Soc. 2001, 123, 30–34. (e) Ager, B. J.; Bourque, L. E.; Buchner,
K. M.; Woerpel, K. A. J. Org. Chem. 2010, 75, 5729–5732.
Org. Lett., Vol. 13, No. 6, 2011
1515

74% yield and 98% ee with slightly lower regioselectivity
(86/14) (entry 7). Notably, the reaction of the aliphatic
carbonate 2h or 2j (entry 8 vs entry 10) occurred in good
yield with high enantioselectivity, although the regios-
electivity was lower (71:29 to 77:23). Sodium prop-2-
ene-1-thiolate 3b is an effective nucleophile as well
(entries 9 and 10).
Table 2. Ir-Catalyzed Asymmetric Allylation of Sodium Ali-
phatic Thiolates a
The branch products 4 generated in this way are highly
useful intermediates for the synthesis of biologically active
sulfur compounds,5 especially biotin analogues.12 To de-
monstrate the synthetic potential of 4, a representative
example for the preparaton of compound 7 with a biotin
core is illustrated in eq 1. The ring-closing metathesis
(RCM) of (3-(allylsulfonyl)pent-4-enyl)benzeneacyclic
sulfone with Grubbs’ catalyst, which was made from the
enantioenriched allyl(5-phenylpent-1-en-3-yl)sulfane 4i13
by the oxidation with mCPBA, afforded the cyclic sulfone
712g,14, in two steps with 76% yield and 97% ee.
entry
R1
R2 time (h) 4 (%)b
4/5c
ee (%) d
1
2
3
4
5
6
7
8
9
Ph
C6H11
12
12
12
36
36
12
12
12
12
12
a, 72 91/9
96
96
98
97
95
98
98
95
94
95
3-MeOC6H4 C6H11
4-MeOC6H4 C6H11
4-MeC6H4 C6H11
b, 78 84/16 (91/9) e
c, 71 94/6
d, 74 93/7
4-ClC6H4
4-BrC6H4
2-thienyl
C6H11
C6H11
C6H11
e, 71 88/12 (92/8) e
f, 80 86/14 (90/10)e
g, 74 86/14
PhCH2CH2 C6H11
4-BrC6H4 allyl
h, 56 71/29f
i, 60 94/6
10 PhCH2CH2 allyl
j, 34 77/23f
a Reaction conditions: 1 mol % of [Ir(COD)Cl]2, 2 mol % of L3, 200
mol % of 2, and 100 mol % 3 (0.10 M) in DCM at 15 °C. b Isolated yields.
c Determined by 1H NMR of the crude reaction mixture. d Determined
by a chiral HPLC analysis. e 300 mol % of CsF was used in this case.
f Determined by GC-MS.
In summary, we have developed an asymmetric iridium-
catalyzed allylic alkylation of aliphatic thiols. The allyl
alkyl sulfides were achieved in 34-80% yields with up to
94:6 b:l and 98% ee. To the best of our knowledge, this is
the first example that good yields and excellent regio- and
enantioselectivities are simultaneously realized in the en-
antioselective transition metal-catalyzed allylations of ali-
phatic thiols. An important use of the branch product was
discussed.
efficiency and regioselectivity (entries 4 and 10-12).
Furthermore, the survey of solvents indicated that DCM
is the optimal solvent (entries 3 and 4). Other solvents such
as THF and toluene were not effective (entries 13 and 14).
The scope and generality ofthis method for a diversity of
allylic substrates and aliphatic thiols was further explored
under the optimized reaction conditions described in entry
3 of Table 1. As demonstrated in Table 2, the phenyl and
aryl allyl methyl carbonates 2a-f with either electron-poor
groups (e.g., 4-Cl and 4-Br) or electron-rich groups (e.g.,
4-OMe, 3-OMe, and 4-Me) on the phenyl ring using
sodium cyclohexanethiolate3aaffordedthecorresponding
products in 71-80% yields with both excellent regio- and
enantioselectivities (entries 1-6). In contrast, the reaction
in the presence of CsF led to 4-7% improvement of the
regioselectivity with a slight influence on the yield and
anitioselectivity (entries 2, 5, and 6). Using 2-thienyl allyl
methyl carbonate 2g resulted in the desired products in
Acknowledgment. We gratefully acknowledge the
NSFC (20942003), Innovative Program of Shanghai Edu-
cation Committee (09ZZ36), 985 Program of Tongji Uni-
versity, Key Laboratory of Fluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, State Key Laboratory of Fine Chemicals, and
Dalian University of Technology (KF1006) for generous
financial support.
Supporting Information Available.
Experimental
procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(12) (a) Ghosh, A. K.; Thompson, W. J.; Munson, P. M.; Liu, W.;
Huff, J. R. Bioorg. Med. Chem. Lett. 1995, 5, 83–88. (b) Kim, C. U.;
McGee, L. R.; Krawczyk, S. H.; Harwood, E.; Harada, Y.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Cherrington, J. M.;
Xiong, S. F.; Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.;
Erickson, J. W. J. Med. Chem. 1996, 39, 3431–3434. (c) Richter, H. G. F.;
Angehrn, P.; Hubschwerlen, C.; Kania, M.; Page, M. G. P.; Specklin, J.-
L.; Winkler, F. K. J. Med. Chem. 1996, 39, 3712–3722. (d) Buynak, J. D.;
Vogeti, L.; Chen, H. Org. Lett. 2001, 3, 2953–2956. (e) Li, H.; Zu, L.; Xie,
H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833–1835. (f) Li,
H.; Zu, L.; Oh, K. Org. Lett. 2007, 9, 2973–2975. (g) Watanabe, N.;
Kikuchi, M.; Maniwa, Y.; Ijuin, H. K.; Matsumoto, M. J. Org. Chem.
2010, 75, 879–884.
(13) The dienne 4i has been prepared in racemic form from an alkenyl
alcohol by the Mitsunobu reaction and the conversion of the thiolester
to the sulfide in two steps; see: Yao, Q. Org. Lett. 2002, 4, 427–430.
(14) The cyclic sulfone 7 has been prepared in racemic form from 4i
through the oxidation of 4i, followed by the ring-closing metathesis with
Grubbs catalyst: (a) Yao, Q. Org. Lett. 2002, 4, 427–430. (b) Mwangi,
M. T.; Schulz, M. D.; Bowden, N. B. Org. Lett. 2009, 11, 33–36. (c)
Brant, M. G.; Bromba, C. M.; Wulff, J. E. J. Org. Chem. 2010, 75, 6312–
6315.
1516
Org. Lett., Vol. 13, No. 6, 2011