Copper-catalyzed enantioselective carbenoid insertion into S-H bonds

Article abstract of DOI:10.1039/b911670b

An asymmetric carbenoid insertion into S-H bonds catalyzed by copper-chiral spiro bisoxazoline complexes has been developed, in which a series of α-mercaptoesters were produced in high yields with moderate to good enantioselectivities (up to 85% ee); this

Full text of DOI:10.1039/b911670b

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Copper-catalyzed enantioselective carbenoid insertion into S–H bondswz
Yong-Zhen Zhang, Shou-Fei Zhu, Yan Cai, Hong-Xiang Mao and Qi-Lin Zhou*
Received (in College Park, MD, USA) 16th June 2009, Accepted 22nd July 2009
First published as an Advance Article on the web 11th August 2009
DOI: 10.1039/b911670b
An asymmetric carbenoid insertion into S–H bonds catalyzed by
copper–chiral spiro bisoxazoline complexes has been developed,
in which a series of a-mercaptoesters were produced in high
yields with moderate to good enantioselectivities (up to 85% ee);
this result represents the best enantioselectivity in the catalytic
asymmetric carbenoid S–H bond insertion reaction.
Scheme 1
degeneration of the metal-associated ylide to free ylide, which
The catalytic asymmetric insertion of metal carbenoids into
1
1
lowers the efficiency of chiral induction (Scheme 1). In fact,
the catalytic asymmetric S–H bond insertion reaction remains
a great challenge nowadays.
X–H (X = C, Si, N, O, S, etc.) bonds is a very powerful
organic transformation for preparing highly versatile building
1
blocks and has drawn considerable attention. Various chiral
We have recently developed highly enantioselective copper–
chiral spiro bisoxazoline complexes as efficient catalysts for
dirhodium catalysts have been developed for highly enantio-
2
selective C–H bond insertion with quite a broad substrate
4
b,c
5a
and N–H bond insertion reactions. We found that
3
O–H
scope. Very recently, breakthroughs in asymmetric Si–H,
4
5
the chiral spiro bisoxazoline ligands with a rigid spirobiindane
backbone enhanced the stability of the copper catalysts and
performed an efficient chiral induction in the copper carbenoid
insertion reactions. The unique characteristics of the spiro
bisoxazoline ligands provide a good opportunity for developing
a highly enantioselective S–H insertion reaction. In this
communication, we report an asymmetric S–H bond insertion
reaction catalyzed by copper complexes of chiral spiro
bisoxazolines. Under mild reaction conditions, the copper-
catalyzed S–H bond insertion of carbenoids generated in situ
from a-diazoesters with mercaptans and thiophenols works
smoothly to yield a-mercaptocarbonyl compounds in high yields
with unprecedentedly high enantioselectivities (up to 85% ee).
The insertion reaction of benzyl a-diazopropionate (1a) and
benzyl mercaptan (2a) was first performed in chloroform at
60 1C with a copper catalyst generated in situ from 5 mol%
O–H and N–H bond insertion reactions have also been
achieved by using chiral copper or dirhodium catalysts. Chiral
a-mercaptocarbonyl compounds are ubiquitous structural
6
subunits in biologically active compounds and the catalytic
asymmetric S–H bond insertion reaction provides an efficient
approach for their construction. However, a highly enantio-
selective catalyst for the asymmetric carbenoid insertion into
7
S–H bonds has not been developed yet. The first catalytic
asymmetric S–H bond insertion reaction was reported by
8
Brunner et al. using a chiral copper–Schiff base catalyst,
albeit with enantioselectivities only up to 13.8% ee. Simonneaux
9
and co-workers investigated the S–H bond insertion reaction
of ethyl a-diazopropionate and thiophenols by using a
chiral porphyrin–ruthenium(II) complex as the catalyst, and
obtained an enantioselectivity of 8% ee. After screening
1
0
numerous chiral copper and rhodium catalysts, Wang et al.
1
F
2
CuCl, 6 mol% ligand and 6 mol% NaBAr
(Scheme 2).
archived 23% ee in the asymmetric S–H bond insertion
reaction of a-diazophenylacetate and thiophenols catalyzed
by Rh (S-DOSP) . This is, to the best of our knowledge, the
Various chiral bisoxazoline ligands with spirobiindane backbones
developed by us were compared. As shown in Table 1, spiro
2
4
highest enantioselectivity ever reported in the catalytic
asymmetric S–H bond insertion reaction. The low level of
enantiocontrol observed in S–H bond insertion reactions
may be partially attributed to two reasons. First, the high
coordination ability of the sulfur atom to the transition metal
may destroy the active chiral catalyst. Second, the relatively
high stability of the sulfonium ylide may increase the trend of
State Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, China.
E-mail: qlzhou@nankai.edu.cn; Fax: +86 22-23506177;
Tel: +86 22-23500011
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details and data for new compounds. See DOI: 10.1039/b911670b
Scheme 2
5
362 | Chem. Commun., 2009, 5362–5364
This journal is ꢀc The Royal Society of Chemistry 2009

Table 1 Cu-catalyzed asymmetric S–H bond insertion of benzyl
a-diazopropionate with benzyl mercaptan: optimization of the
reaction conditions
Table 2 Cu-catalyzed asymmetric S–H bond insertion of a-diazoesters
with arylmethylene mercaptans
a
a
1
R
2
R
Entry
Ar
Product Yield (%) ee (%)
Temp./ Time/ Yield ee
h
b
(%) (%)
c
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Bn
Et
Bu
C
C
C
6
6
6
H
H
H
5
5
5
3a
3b
3c
3d
3e
3f
3g
3h
3i
82
91
62
73
86
87
70
59
64
83
88
71
61
81
73
83
85
83
68
78
44
77
73
77
52
61
Entry [Cu]
Ligand
(S ,S,S)-4a
Solvent 1C
t
1
2
3
4
5
6
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
a
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
60
60
60
60
60
60
1
82
72
70
79
46
46
81
9
55
48
41
0
(R
a
,S,S)-4a
,S,S)-4b
,S,S)-4c
,S,S)-4d
12
12
12
48
12
Bn 4-MeOC
Bn 4-ClC
Bn 2-MeC
Bn 2-ClC
Me
Me
Me
Me
Me
Me
6
H
4
(S
(S
(S
(S
a
6
H
4
6 4
H
a
a
a
6
H
4
,S,S)-Ph- CHCl
C
6
H
5
C
C
C
C
C
C
6
H
6
H
6
H
6
H
6
H
6
H
5
5
5
5
5
5
Binabox
(R ,S,S)-Ph- CHCl
Binabox
9
2-MeC
2-ClC
2-MeOC
3-MeOC
4-MeOC
6
H
4
7
CuCl
a
3
60
48
72
0
10
11
12
13
6
H
4
3j
3k
3l
6
6
6
H
H
H
4
4
4
t
8
9
1
1
1
1
1
1
1
1
1
CuCl
CuCl
CuCl
CuPF
(S,S)- Bu-Box CHCl
3
3
3
3
3
3
60
60
60
60
60
60
40
60
40
80
80
48
1
1
1
1
1
3
3
3
58
80
79
85
85
85
81
81
78
22
83
80
79
80
80
72
76
81
81
70
d
(S
(S
(S
(S
(S
(S
(S
(S
(S
(S
a
a
a
a
a
a
a
a
a
a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
,S,S)-4a
CHCl
CHCl
CHCl
CHCl
CHCl
3m
e
0
1
2
3
4
5
6
7
8
a
Reaction conditions were the same as those in Table 1, entry 17. All
reactions were completed within 2 h.
6
Cu(OTf)
2
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
2
CH Cl
DCE
2
2
lower (entries 14 and 15). The reaction temperature had a
negligible effect on the enantioselectivity of the reaction, while
a higher reaction temperature apparently increased the
reaction rate. For instance, when the reaction was heated to
vigorous reflux in a sealed Schlenk tube in an 80 1C oil bath,
full conversion was achieved within 30 min without diminishing
the enantioselectivity (entry 17). Reducing the catalyst loading
to 1 mol%, the reaction could also be finished in 1 h, but with
a slightly lower yield and enantioselectivity (entry 18).
CHCl
CHCl
CHCl
3
3
3
0.5 82
74
f
1
a
F
Reaction conditions: [Cu] : ligand : NaBAr : 1a : 2a = 0.01 : 0.012 :
b
c
Isolated yield. Determined
0.012 : 0.2 : 0.2 mmol, in 2 mL CHCl
3
.
d
6
by chiral HPLC using a Chiralcel OJ-H column. AgSbF instead of
e
f
NaBAr
F F
was used. AgOTf instead of NaBAr was used. 1 mol%
catalyst was used.
bisoxazoline ligands showed high reactivity and good
enantioselectivity in S–H bond insertion reactions. The
We next investigated the substrate scope of the S–H bond
insertion reaction. The insertion reactions of various
substituted benzyl mercaptans and different a-diazoesters were
conducted under the optimal reaction conditions (Table 2).
The a-diazopropionate with a less sterically hindered ethyl
group gave a higher yield, but a slightly lower ee value (91%
combination of chiralities in the ligand (S ,S,S)-4a rather than
a
(
R ,S,S)-4a is matched in terms of reactivity as well as
a
enantioselectivity (entries 1 and 2). Among the spiro bisoxazoline
ligands tested, (S ,S,S)-4a with phenyl substituents on the
a
2
t
oxazoline rings gave the highest reactivity and enantio-
selectivity (82% yield, 81% ee). The bisoxazoline ligands with
t
other scaffolds such as Ph-Binabox and Bu-Box were also
yield, 73% ee, entry 2). By increasing the size of R to Bu, an
enantioselectivity as high as 83% ee was achieved, although
the yield was lower (entry 3). The substituted benzyl mercaptans
were then examined in the S–H bond insertion reaction (entries
4–7). All the benzyl mercaptans underwent the insertion reaction
smoothly and the corresponding insertion products were
obtained with good yields. The electronic effect of the benzyl
mercaptan substituent on the enantioselectivity was negligible.
The reactions of 4-methoxybenzyl mercaptan and 4-chloro-
benzyl mercaptan gave similar ee values (85 and 83% ee,
respectively; entries 4 and 5). Substitution at the ortho position
of benzyl mercaptan resulted in a lower enantioselectivity,
indicating the existence of a negative steric effect on the
evaluated in the S–H bond insertion reaction under identical
reaction conditions. The reaction became sluggish and very
poor enantioselectivities were observed in the presence of
those ligands. This result indicated that the chiral spirobiin-
dane structure of the ligands is essential for obtaining high
enantioselectivity in the copper-catalyzed carbenoid insertion
into S–H bonds. The additive NaBArF played an important
role in the reaction. No reaction took place under the
conditions of entry 1 in the absence of NaBAr
F
. When
F
, similar
AgSbF and AgOTf were used instead of NaBAr
6
1
yields and enantioselectivities were obtained (entries 9 and 10).
To further improve the enantioselectivity of S–H bond
insertion, the reaction conditions were carefully optimized by
mercaptan substrate (entries 6 and 7). The R group of the
diazo compounds has a great influence on both reactivity and
enantioselectivity in the S–H bond insertion reaction. When
1
benzyl a-diazobutyrate (R = ethyl) was used, only benzyl
using ligand (S
a
,S,S)-4a. A variety of copper salts were tested
as catalyst precursors and essentially identical results were
obtained (entries 11–13). Besides chloroform, the reaction can
also be performed smoothly in boiling CH Cl or DCE;
2-butenoic ester, the b-elimination product of the carbenoid,
was isolated. By changing R from a methyl to a phenyl group,
1
2
2
the corresponding a-mercaptoesters were obtained in moderate
yields with 44% ee (entry 8). Surprisingly, substitutions at the
however, the enantioselectivity of the reaction became slightly
This journal is ꢀc The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5362–5364 | 5363

ortho position of 2-aryl-2-diazoacetates, regardless of their
electronic and steric properties, significantly enhanced the
enantioselectivity (entries 9–11). In contrast, the meta- or
para-substituted aryl diazoacetates only gave modest enantio-
selectivities under the identical reaction conditions (entries 12
and 13).
carbenoid S–H bond insertion reactions. A broad range of
mercaptans and thiophenols underwent the insertion reaction
with carbenoids generated in situ from a-diazoesters to produce
a-mercaptoesters in high yields with moderate to good
enantioselectivities (up to 85% ee). This provides an efficient
and direct approach to the preparation of enantioenriched
a-mercaptoester derivatives. The unprecedented enantiocontrol
in the catalytic asymmetric S–H bond insertion reaction further
demonstrates that the chiral spiro bisoxazoline ligands have
great potential applications in metal carbenoid transfer reactions.
We thank the National Natural Science Foundation of
China (Grant No. 20721062, 20532010, 20702025), the Major
Basic Research Development Program (Grant No.
2006CB806106), the ‘‘111’’ project (B06005) of the Ministry
of Education of China.
In addition to benzyl mercaptans, various thiophenols and
aliphatic mercaptans were also examined in the S–H bond
insertion reaction with carbenoids derived from benzyl
a-diazopropionate (Table 3). All the tested thiophenols under-
went the S–H insertion reactions, affording the S–H bond
insertion products in high yields (76–92%) with good enatio-
selectivities (60–72% ee, entries 1–8). Aliphatic mercaptans are
also suitable substrates for the S–H bond insertion reaction
and the desired products were isolated in high yield, while the
enantioselectivities were low (entries 9 and 10). The use of
sterically hindered mercaptans greatly improved the enantio-
selectivity of the reaction. For example, the bulky trityl thiol
afforded S–H bond insertion product in 77% ee (entry 12).
To further demonstrate the potential utilities of the copper-
catalyzed asymmetric S–H bond insertion reaction, the
synthesis of optically active a-unprotected thiol esters was
performed. The protecting group of 3y was removed by using
Notes and references
1 For reviews, see: (a) M. P. Doyle, M. A. McKervey and T. Ye,
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Diazo Compounds, Wiley, New York, 1998, Chapters 3 and 8;
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7e
3
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3
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2
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4
4
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´
,
Entry
RS–H
SH
Product
Yield (%)
ee (%)
´
1
1
2
3
4
5
6
7
8
9
C
6
H
5
3n
3o
3p
3q
3r
90
83
80
76
85
76
92
81
86
84
85
57
69
72
62
62
60
60
60
67
17
32
61
77
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A. Y. Jeng, Bioorg. Med. Chem. Lett., 2002, 12, 3059–3062;
4-MeOC
4-ClC
3-MeOC
3-ClC
2-MeOC
2-ClC
2,6-Cl
6
4
6
4
6
4
H
4
SH
SH
SH
SH
SH
SH
SH
6
H
(
d) R. V. Bikbulatov, F. Yan, B. L. Rothb and J. K. Zjawiony,
H
4
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6
H
H
4
3s
3t
6
H
7
2
C
6
H
3
3u
3v
3w
3x
3y
n
BuSH
BuSH
PrSH
i
i
10
11
12
1
986, 51, 3664–3671; (b) H. Schedel, P. J. L. M. Quaedflieg,
Q. B. Broxtermann, W. Bisson, A. L. L. Duchateau, I. C.
3
Ph CSH
a
Reaction conditions were the same as those in Table 1, entry 17.
All reactions were completed within 2 h.
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2
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8
9
7
55–764.
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´
, P. L. Maux and G. Simonneaux,
1
1
0 X.-M. Zhang, M. Ma and J.-B. Wang, Arkivoc, 2003, 2, 84–91.
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ꢁ
Scheme 3
12 BAr
F
= tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
5
364 | Chem. Commun., 2009, 5362–5364
This journal is ꢀc The Royal Society of Chemistry 2009