One pot iridium-catalyzed asymmetrical double allylations of sodium sulfide: A fast and economic way to construct chiral C2-symmetric bis(1-substituted-allyl)sulfane

Article abstract of DOI:10.1039/c1cc11930c

One pot asymmetrical double allylations of sodium sulfide catalyzed by an iridium complex along with a combination of caesium fluoride and water in dichloromethane have been realized and the double allylation products with two C-S bond chiral centers were obtained in 67-99% yields with b/l 81/19-99/1, dr 85/15-99/1, and 96-99% ee.

Full text of DOI:10.1039/c1cc11930c

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One pot iridium-catalyzed asymmetrical double allylations of sodium
sulfide: a fast and economic way to construct chiral C2-symmetric
bis(1-substituted-allyl)sulfanew
Shengcai Zheng,a Weiqing Huang,a Ning Gao,a Ruimin Cui,a Min Zhanga and
Xiaoming Zhao*a
Received 6th April 2011, Accepted 3rd May 2011
DOI: 10.1039/c1cc11930c
One pot asymmetrical double allylations of sodium sulfide
catalyzed by an iridium complex along with a combination of
caesium fluoride and water in dichloromethane have been
realized and the double allylation products with two C–S bond
chiral centers were obtained in 67–99% yields with b/l
81/19–99/1, dr 85/15–99/1, and 96–99% ee.
Preliminary studies using sodium hydrogensulfide 2a as the
nucleophile and [Ir(COD)Cl]2/phosphoramidite ligand 1a10,11
as the catalyst for an allylation of allylic carbonate 3a were
performed (Table 1). Initially examining this reaction in
dichloromethane (DCM) at room temperature formed the black
precipitate and no desired product was observed (entry 1). The
utilization of sodium sulfide 2b instead of 2a produced the
complex products (entry 2). Interestingly, the reaction with
Cs2CO3 afforded the double allylation product 4a with two
C–S bond chiral centers in 20% yield with 4a/5a 99/1, 93/7 dr,
and 99% ee (entry 3). Further screening of several additives
including CsF, KF, CsCl, and LiCl revealed that the reaction
with CsF furnished the highest yield (39%) with 4a/5a 99/1,
The allyl sulfides, the important organosulfur components of
garlic oil, have received great attention because of their anti-
cancer activity.1 Especially chiral allicin and diallyl sulfides are
most abundant in the garlic oil.2 Organosulfur compounds with
a chiral carbon–sulfur bond are of great importance to
organocatalysis3 and medicinal chemistry.4 Therefore, a new
synthetic method for the preparation of chiral allyl sulfides is very
desirable. Obviously, transition metal-catalyzed asymmetrical
allylation of a sulfur nucleophile is a straightforward access for
the preparation of chiral allyl sulfides.5 However, few studies
on this context were disclosed presumably since sulfur nucleo-
philes can poison transition metal catalysts.6
Table 1 Optimizing reaction conditions for Ir-catalyzed double
allylations of sodium sulfide 2a
Iridium-catalyzed asymmetric allylic substitution has become
an efficient way to synthesize chiral allylic compounds with
both high regioselectivity and enantioselectivity. A wide range
of carbo7 and heteroatom (e.g., N,8 O,9 and S)5l–p nucleophiles
have been extensively investigated during the past decade. The
utilization of an inorganic sulfur nucleophile (e.g., Na2S) in
enantioselective allylic substitution is even more intriguing and
atom-economical. Nevertheless, until today there is no report
that sodium sulfide can serve as a nucleophile in transition-
metal-catalyzed allylation substitutions. Herein we first report
the highly efficient iridium-catalyzed double allylations of
sodium sulfide with a variety of allyl methyl carbonates with
excellent regio-, diastereo-, and enantioselectivity.
Yieldc
(%)
eee
Entry Add.b
Sol.(s)
NaNu 2
4a/5ad dre (%)
1
2
—
—
DCM
DCM
DCM
DCM
DCM
DCM
DCM
NaHS
Na2S
Na2S
Na2S
Na2S
Na2S
Na2S
N.R. —
Comp. —
—
—
—
—
3
4
5
Cs2CO3
CsF
KF
20
39
22
34
8
42
83
64
499/1 93/7 499
499/1 98/2 499
—
97/3
499/1 87/13 94
— 97/3 499
84
6
7
CsCl
LiCl
—
8f
9f
10
11
12
13
14
H2O/DCM Na2S
H2O/DCM Na2S
499/1 97/3 499
499/1 97/3 499
CsF
CsOHÁH2O DCM
Na2S
499/1 98/2
92
CsF
—
DCM
DCM
THF
Na2SÁ9H2O 99
Na2SÁ9H2O 34
Na2SÁ9H2O 24
Na2SÁ9H2O 33
499/1 98/2 499
—
—
—
98/2 499
94/6 499
91/9 499
a Department of Chemistry, Tongji University, 1239 Siping Road,
Shanghai, 200092, PR. China. E-mail: xmzhao08@mail.tongji.edu.cn
b Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, PR. China
w Electronic supplementary information (ESI) available: Experimental
procedures and analysis data for new compounds, CIF file of (R,R)-6f.
CCDC 819903. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc11930c.
CsF
CsF
Toluene
a
Reaction conditions: 1 mol% of [Ir(COD)Cl]2, 2 mol% of 1a,
b
200 mol% of 2a, and 100 mol% of 3a (0.1 M) at 25 1C. 300 mol%
of additive for entries 2–6, 8–10, and 11–13. Isolated yields. Deter-
c
d
mined by 1H NMR of the crude reaction mixture. Determined by a
e
f
chiral HPLC analysis (Chiralpak AD–H column). H2O/DCM = 1/20.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6969–6971 6969

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dr 98/2, and 99% ee (entries 4–7). Using H2O/DCM12 as the
solvents led to somewhat improved yield (42%) of 4a (entry 8).
It is noted that a combination of CsF and H2O dramatically
enhanced the yield from 42% to 83% (entry 8 vs. entry 9). The
employment of the more basic CsOHÁH2O reduced the yield to
64% (entry 9 vs. entry 10). We were gratified to discover that
the use of a more economic reagent, sodium sulfide hydrate
(Na2SÁ9H2O) 2c, along with CsF gave much better results than
that of anhydrous sodium sulfide 2b without influencing regio-,
diastereo-, and enantioselectivity (entry 11 vs. entry 9). In
contrast, a significant decrease in the reaction efficiency was
observed in the absence of CsF under identical conditions
(entry 11 vs. entry 12). These results strongly suggest that an
optimal and small amount of water together with CsF is very
beneficial to Ir-catalyzed allylation of sodium sulfide. Other
solvents such as THF and toluene were also used but poor
results were obtained (entries 13 and 14). Thus, the reaction
conditions presented in entry 11 of Table 1 were defined as the
standard conditions for further study.
Further evaluation of the varied chiral ligands 1a,10,11 1b,11
1c,10 1d,13 and 1e14 (Fig. 1) was carried out under the
optimized conditions. All of 1a–1c gave the same excellent
regio-, diastereo-, and enantioselectivity and only 1a resulted
in 99% yield (entries 1–3, Table 2). Notably, the reaction
completely failed when 1d was tested (entry 4); and the
reaction with a stereochemically simpler ligand 1e afforded
the desired products in 81% yield and 99% ee but with a lower
diastereoselectivity (entry 5).
Table 3 Ir-catalyzed regio-, diastereo-, and enantioselective double
allylations of sodium sulfide hydrate with allyl methyl carbonatesa
Entry
R
4
Yieldb (%) 4/5c
DL/mesod eed (%)
1
2
3
4
5
6
7
8
4-MeOC6H4 4a 99
3-MeOC6H4 4b 99
499/1 97/3
499
97
499
96
499
499
499
499
98
499/1 97/3
499/1 96/4
96/4 95/5
499/1 96/4
98/2 97/3
97/3 96/4
499/1 99/1
81/19 85/15
87/13 89/11
4-MeC6H4
Ph
4-ClC6H4
4-BrC6H4
4c 99
4d 99
4e 80
4f 72
3-CF3C6H4 4g 67
2-Thienyl
Et
Me
4h 77
4i 84
9
10e
4j
—
99
Reaction conditions:a 1 mol% of [Ir(COD)Cl]2, 2 mol% of 1a, 300 mol%
of CsF, 300 mol% of 2b, and 100 mol% 3 (0.1 M) in DCM at
b
c
25 1C. Isolated yields. Determined by 1H NMR of the crude reaction
mixture. Determined by a chiral HPLC analysis. Determined by
d
e
1H NMR and HPLC of a derivative 6j because of the volatilization of 4j.
electron-donating groups (e.g., 4-OMe, 3-OMe, and 4-Me) on
the phenyl ring yielded the desired products in 99% yields
with excellent regioselectivity (96/4–99/1), diastereoselectivity
(95/5–97/3) and enantioselectivity (96–99% ee) (entries 1–4).
The hetero- and aromatic allyl methyl carbonates 3e–h with
electron-withdrawing groups (e.g., 4-Cl, 4-Br, and 3-CF3) on
the phenyl ring afforded the desired products 4e–h in 67–80%
yields with excellent regioselectivity (97/3–99/1), diastereo-
selectivity (96/4–99/1) and enantioselectivity (499% ee)
(entries 5–8). The aliphatic allylic carbonates are the effective
substrates as well as the inseparable products 4i15 and 4j16 with
a small amount of the linear product were observed in these
cases (entries 9–10).
Having established the optimal conditions, we further
explored the scope and generality of this allylation (Table 3).
The phenyl- and aromatic allyl methyl carbonates 3a–d with
Moreover, X-ray diffraction analysis of compound 6f,
generated from 4f in the enantiopure form, reveals its absolute
configuration as (R,R) (see the ESIw).
The power of this methodology was demonstrated by a fast,
efficient, and economical synthesis of a 4-carbon building block,
2,5-disubstituted-2,5-dihydrothiophene1,1-dioxide 7,17 an equi-
valent of 2,5-disubstituted tetrahydrothiophene18 which is a
dienophile as well. The ring-closing metathesis (RCM) of
(S)-3-((S)-but-3-en-2-ylsulfonyl)but-1-ene 6j, which was
prepared via an allylation of 3j with 2b under the optimal
conditions, followed by the oxidation in one pot, with a Grubbs
catalyst furnished (2S,5S)-2,5-dimethyl-2,5-dihydrothiophene1,
1-dioxide 7j17a in 86% yield with 94% ee (Scheme 1). To the
best of our knowledge, this is the first sample for RCM of 6 to 7
in the enatiopure form. In addition, subsequent reduction18
Fig. 1 Chiral ligands 1a–e.
Table 2 Screening chiral ligandsa
Entry Ligand T/h Yieldb (%) 4a/5ac DL/mesod eee (%)
1
2
3
4
5
1a
1b
1c
1d
1e
36
48
48
48
48
99
74
99
N. R.f
81
99/1
99/1
99/1
—
98/2
98/2
98/2
—
499
499
499
—
99/1
80/20
499
a
b
Reaction conditions as described in entry 11 of Table 1. Isolated
yields. Determined by 1H NMR of the crude reaction mixture.
d
c
Determined by a chiral HPLC analysis. e Determined by a chiral HPLC
f
analysis (Phenomenex cellulose-1). N. R. = no reaction.
Scheme 1 The ring-closing metathesis of 6j.
c
6970 Chem. Commun., 2011, 47, 6969–6971
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and hydrogenation of 7j could furnish (2S,5S)-2,5-dimethyl-
tetrahydrothiophene which has been widely used as a C2 catalyst
for the asymmetric epoxidation of aldehydes.3a–c
6 (a) L. L. Hegedus and R. W. McCabe, Catalyst Poisoning,
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In conclusion, we have developed highly regio-, diastereo-,
and enantioselective iridium-catalyzed double allylations of
sodium sulfide hydrate with a variety of allyl methyl carbonates.
This is the first example that sodium sulfide is used as an
atom-economical inorganic nucleophile in transition-metal-
catalyzed allylation substitutions. It is interesting to note that
the double allylation reaction efficiently generates two C–S
chiral centers in one pot. This work also highlights the impor-
tance of an optimal amount of water in iridium-catalyzed
allylation reactions when sodium sulfide is employed as an
inorganic sulfur nucleophile. We are currently investigating
applications of this methodology to generate chiral allylic
sulfides with unique and additional functionalities.
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We gratefully acknowledge Pu Jiang Program of Shanghai
(2010), Innovative Program of Shanghai Education Committee
(09ZZ36), the NSFC (20942003), 985 Program of Tongji
University for generous financial support.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6969–6971 6971