Regio- and enantioselective iridium-catalyzed allylation of thiophenol: Synthesis of enantiopure allyl phenyl sulfides

Article abstract of DOI:10.1021/ol101915b

A highly regio- and enantioselective allylic alkylation of sodium thiophenoxide has been realized by [Ir(COD)Cl]₂/phosphoramidite along with CsF as an additive, producing highly enantioenriched allyl phenyl sulfide compounds with up to 99% ee.

Full text of DOI:10.1021/ol101915b

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4454-4457
Regio- and Enantioselective
Iridium-Catalyzed Allylation of
Thiophenol: Synthesis of Enantiopure
Allyl Phenyl Sulfides
Shengcai Zheng,† Ning Gao,† Wei Liu,† Dongge Liu,† Xiaoming Zhao,*,† and
Theodore Cohen‡
Department of Chemistry, Tongji UniVersity, 1239 Siping Road,
Shanghai 200092, P. R. China, State Key Laboratory of Fine Chemicals,
Dalian UniVersity of Technology, 158 Zhongshan Road, Dalian 116012, P. R. China,
and Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh,
PennsylVania 15260, United States
xmzhao08@mail.tongji.edu.cn; xzhao619@hotmail.com
Received June 3, 2010
ABSTRACT
A highly regio- and enantioselective allylic alkylation of sodium thiophenoxide has been realized by [Ir(COD)Cl]2/phosphoramidite along with
CsF as an additive, producing highly enantioenriched allyl phenyl sulfide compounds with up to 99% ee.
Iridium-catalyzed enantioselective allylic substitutions have
been developed as a powerful and general method to synthesize
chiral allylic compounds with both high regioselectivity and
high enantioselectivity. A wide range of carbo-1 and heteroa-
toms2 (e.g., N, O, and SO2) nucleophiles has been studied during
the past decade, but neither aliphatic nor aromatic thiol
nucleophiles have yet been reported. It is well-known that thiols
can poison transition-metal catalysts,3 which imposes a con-
siderable challenge to the study of metal-catalyzed enantiose-
lective allylation substitution reactions. Although the transition-
metal-catalyzed allylations of sulfur nucleophiles to form achiral
allyl sulfides and sulfones have been extensively investigated,4
only a few enantioselective allylations of sulfur nucleophiles
have been reported; these use Pd catalysis,5 and the enantiose-
lectivities and product yields varied from poor to excellent
depending on reaction conditions and substrates.5a Furthermore,
† Tongji University.
‡ University of Pittsburgh.
(1) (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.sEur. J.
2009, 15, 11087–11090.
(2) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–
15165. (b) Shu, C. T.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43,
4794–4796. (c) Lyothier, I.; Defieber, C.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2006, 45, 6204–6206. (d) Pouy, M. J.; Leitner, A.; Weix, D. J.;
Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9, 3949–3951. (e) Ueno, S.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 1928–1931. (f) 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.
10.1021/ol101915b  2010 American Chemical Society
Published on Web 09/23/2010

only sulfinates and more acidic aromatic thiols such as 4-chlo-
rothiophenol, 2-mercaptopyridine, and 2-mercaptropyrimidine
were effective in these palladium-catalyzed enantioselective
systems,5a,c and no reactions took place for more basic
aliphatic thiols and thiophenol, probably due to competitive
coordination to the palladium catalysts between these thiol
substrates and chiral ligands.5a,6
amount of 2a gave the best regioselectivity (94/6) for the
branched isomer 4a without significantly influencing either
efficiency or enantioselectivity (entry 13 versus entry 4).
Conducting the reaction below ambient temperature proved
deleterious to both yields and selectivity (entries 16 and 17).
A variety of chiral ligands 1a,8,9 1b,9 1c,8 and 1d10 (Figure
1) was evaluated using the optimized conditions listed in
Herein, we report the formation of chiral allylic phenyl
sulfides via iridium-catalyzed enantioselective allylations of
sodium thiophenoxide 3. This represents the first example
of the use of transition-metal-catalyzed enantioselective
allylations of thiophenol to form allyl phenyl sulfides in good
yields and with excellent enantioselectivities. Important
potential uses of such products are discussed below.
We first aimed at optimizing reaction conditions for the
enantioselective iridium-catalyzed allylations of sodium thiophe-
noxide 37 to form allyl phenyl sulfides. We initially found that
the reaction of (E)-cinnamyl methyl carbonate 2a with 3 in the
presence of [Ir(COD)Cl]2 and the chiral ligand 1a8,9 in CH2Cl2
furnished a mixture of 4a and 5a in poor yield and regioselec-
tivity, but excellent enantioselectivity for the branched isomer
4a (entry 1, Table 1). Many additives such as Cs2CO3, CsF,1c
Figure 1. Chiral ligands1a-e.
Table 1. Optimizing Reaction Conditions for Ir-Catalyzed
Allylations of NaSPh 3a
entry 13 of Table 1, and 1a gave the best yield and regio-
and enantioselectivity (Table 2). It should be noted that reactions
completely failed when 1d was employed (entry 4).
yieldc
eee
Table 2. Screening Chiral Ligandsa
entry additiveb
solvent
CH2Cl2
2a/3 temp, °C (%) 4a/5ad (%)
entry
ligand
time (h)
yieldb (%)
4a/5ac
eed (%)
1
2
none
none
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
25
25/75 90
9/91
CH3CN
28
1
2
3
4
1a
1b
1c
1d
10
22
12
48
72
62
94/6
93/7
92/8
97
95
97
3
Cs2CO3 CH2Cl2
67
67/33
4
5
CsF
TBAF
AgBr
CsCl
LiCl
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CCl4
ClCH2CH2Cl 1.2/1
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
82
89/11 97
f
52
6
16
94/6
NRe
7
38
67/33
85/15
93/7
8
18
a Reaction conditions: as listed in entry 13, Table 1. b Isolated yields.
c Determined by 1H NMR of the crude reaction mixture. d ee of 4a was
determined by chiral HPLC analysis (Phenomenex Celluolose-1). e NR )
no reaction.
9
56
10
11
12
13
14
15
16
17
NRg
78
92/8
1.2/1
2/1
3/1
1/2
2/1
2/1
NRg
72
94/6
97
75
90/10
80/20
93/7
40
20
(4) (a) 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.sEur. J. 2009, 15, 6468–
6477. (i) Kondo, T.; Morisaki, Y.; Uenoyama, S.; Wada, K.; Mitsudo, T.
J. Am. Chem. Soc. 1999, 121, 8657–8658.
-25
trace
a Reaction conditions: 1 mol % of [Ir(COD)Cl]2, 2 mol % of 1a, 120
mol % of 2a, and 100 mol % of 3 (0.1 M) at 25 °C. b 300 mol % of additive
for entries 3-17. c Isolated yields. Determined by H NMR of the crude
reaction mixture. e Determined by chiral HPLC analysis (Phenomenex
Celluolose-1). f Complex products were observed. g NR ) no reaction.
d
1
TBAF, CsCl, AgBr, and LiCl were screened (entries 3-8), and
only CsF led to a substantial increase in both efficiency and
regioselectivity (entry 4 versus entry 1). The use of ClCH2CH2Cl
as a solvent gave very similar results to those in CH2Cl2 but a
better yield than CHCl3 (entries 4, 9, and 11). The reactions
completely failed when THF and CCl4 were employed as
solvents (entries 10 and 12). The use of a 2-fold amount of 3
led to a significant decrease in yield (entry 15), but a 2-fold
(5) (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.sEur. J. 2003, 9,
4202–4221.
(6) (a) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598–
11599. (b) Ruiz, J.; Cutillas, N.; Sampedro, J.; Lo´pez, G.; Hermoso, J. A.;
Mart´ınez-Ripoll, M. J. Organomet. Chem. 1996, 526, 67–72.
(7) Various alkali-metal (Li, Na, and K) salts of thiophenol were tested,
and we found that sodium thiophenoxide 3 gave the best result.
Org. Lett., Vol. 12, No. 20, 2010
4455

Having established the optimized reaction conditions,
we turned to a survey of the scope and generality of
iridium-catalyzed enantioselective allylations of sodium
thiophenoxide. As shown in Table 3, all aromatic and
Table 3. Enantioselective Ir-Catalyzed Allylations of NaSPh
with Allyl Methyl Carbonatesa
entry
R
time (h)
4b (%)
4/5c
eed (%)
1e
2
3
4
5
6
7
8
9
Ph
2
4
4
3
4
3
4
3
10
5
a, 72
b, 68
c, 79
d, 70
e, 67
f, 73
g, 69
i, 72
h, 60
j, 70
94/6
97
99
95
90
98
96
97
99
47
91
98
Figure 2. Structure of (S)-4f (thermal ellipsoids are set at 30%
probability).
3-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
3-CF3C6H4
2-thienyl
2-ClC6H4
n-Pr
92/8
93/7e
94/6
91/9
enantiopure form (4f was obtained by recrystallization
from isopropyl alcohol) has been determined by X-ray
diffraction analysis, which reveals its absolute configu-
ration as S. Recently, the origin of enantioselectivity in
iridium-catalyzed enantioselective allylic substitutions was
described by the Hartwig group based on the single-crystal
structure of an elegantly designed allyliridium intermediate
complex.13 The stereochemistry of iridium-catalyzed al-
lylation of sodium thiophenoxide with the chiral phos-
phoramidite ligand (S,S,Sa)-1a completely supports their
explanation.
90/10
98/2e
90/10
90/10
87/13
91/9e
10
11
Me
5
k, 60
a Reaction conditions: 1 mol % of [Ir(COD)Cl]2, 2 mol % of 1a, 300
mol % of CsF, 200 mol % of 2, and 100 mol % 3 (0.1 M) in CH2Cl2 at 25
°C. b Isolated yields. c Determined by 1H NMR of the crude reaction mixture.
d ee of 4 was determined by chiral HPLC analysis; see the Supporting
Information for details. e Determined by GC-MS.
We envision very significant synthetic uses of highly
enantioenriched allyl phenyl sulfides 4 generated in this
way. In order to demonstrate some of these, we have
converted the terminally unsubstituted enantioenriched
3-phenylthio-1-butene 4k into enantioenriched trans-4-
phenylthio-2-pentene-1-ol 6a using the metathesis devel-
oped by Davis14 that works particularly well for allyl
phenyl sulfides; this representative example is demon-
strated in eq 1. Compound 6a is an apt example since it
has been prepared15 by a considerably longer route from
lactic acid and has been converted to trans-2-phenythio-
3-pentene, demonstrating its potential for conversion to
other enantioenriched substrates.
heteroaromatic allyl methyl carbonates 2a-i with either
electron-donating groups (e.g., 4-OMe, 3-OMe, and 4-Me)
or electron-withdrawing groups (e.g., 4-Cl, 4-Br, and
3-CF3) on the phenyl ring gave the branched allylic
sulfides 4a-i in good yields (67-79%) and with excellent
enantioselectivities (90-99% ee, entries 1-8). The reac-
tion also worked well with the aromatic substrate 2h with
an o-Cl group on the phenyl ring but with lower
enantioselectivity (47% ee, entry 9). The unfavorable ortho
substituent effect is in accord with the previously reported
iridium-catalyzed asymmetric allylic substitution
reactions.1j When the same reaction with 2h was per-
formed using the ligand (R,Ra)-1e11,1h rather than 1a, the
result was far inferior; the yield of 4 + 5 was only 5% even
after twice the time used in the experiment with ligand 1a.
The aliphatic allylic carbonates 2j12 and 2k are effective
substrates as well (entries 10 and 11).
The single-crystal structure (Figure 2) (see the Sup-
porting Information for details) of compound 4f in
In summary, we report the formation of a variety of allyl
phenyl sulfides via the enantioselective iridium-catalyzed
allylation of sodium thiophenoxide. To the best of our
knowledge, this is the first example in which both good yields
and excellent enantioselectivities are simultaneously achieved
in the enantioselective transition-metal-catalyzed allylations
(8) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A.
Synthesis 2004, 2586–2590.
(9) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878.
(10) (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.
(11) The ligand (R,Ra)-1e was effective in improving the enantioselec-
tivity of the branched product in the Ir-catalyzed o-chlorophenylallylation
of indole as indicated in reference 1h.
(13) Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. J. Am. Chem.
Soc. 2009, 131, 7228–7229.
(12) Compound 4j has been prepared in racemic form from 2j by Pd-
catalyzed allylation of thiophenol; the yield was very low due to the
unfavorable regioselectivity. Goux, C.; Lhoste, P.; Sinou, D. Tetrahedron
1994, 50, 10321–10330.
(14) Lin, Y. A.; Chalker, J. M.; Floyd, N.; Bernardes, G. J. L.; Davis,
B. G. J. Am. Chem. Soc. 2008, 130, 9642–9643.
(15) Bach, T.; Ko¨rber, C. J. Org. Chem. 2000, 65, 2358–2367.
4456
Org. Lett., Vol. 12, No. 20, 2010

of thiophenol. Some possible important uses of the products
are discussed.
Laboratory of Fine Chemicals, and Dalian University of
Technology for generous financial support. We also thank
Prof. Shuli You of SIOC for generously offering the
phosporamidite ligand (R,Ra)-1e.
Acknowledgment. We gratefully acknowledge the NSFC
(20342003), Innovative Program of Shanghai Education
Committee (09ZZ36), Pu Jiang Program of Shanghai
(2010), 985 Program of Tongji University, Key Laboratory
of Fluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, State Key
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL101915B
Org. Lett., Vol. 12, No. 20, 2010
4457