Aerobic, Cu-catalyzed desulfitative C-C bond-forming reaction of ketene dithioacetals/vinylogous thioesters and arylboronic acids

Article abstract of DOI:10.1039/c1cc11382h

A new Cu-catalyzed thioorganic-boronic acid desulfitative C-C bond-forming reaction involving ketene dithioacetals/ vinylogous thioesters is reported to proceed without the assistance of ligating S-pendant. Vinylogous thiolesters and tetrasubstituted olefins were prepared by this reaction in which Cu catalyst plays a dual role under aerobic conditions.

Full text of DOI:10.1039/c1cc11382h

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Aerobic, Cu-catalyzed desulfitative C–C bond-forming reaction of ketene
dithioacetals/vinylogous thioesters and arylboronic acidsw
Ying Dong,a Mang Wang,*ab Jun Liu,a Wei Maa and Qun Liu*a
Received 10th March 2011, Accepted 12th May 2011
DOI: 10.1039/c1cc11382h
A new Cu-catalyzed thioorganic–boronic acid desulfitative C–C
bond-forming reaction involving ketene dithioacetals/ vinylogous
thioesters is reported to proceed without the assistance of
ligating S-pendant. Vinylogous thiolesters and tetrasubstituted
olefins were prepared by this reaction in which Cu catalyst plays
a dual role under aerobic conditions.
the synthesis of vinylogous thioesters8 and tetrasubstituted
olefins9 from readily available sulfur substrates (Scheme 1C).
The starting materials, ketene dithioacetals 1, were
conveniently prepared by the published protocols in high
yields.10 Initially, the reaction of diethyl 2-(bis(benzylthio)-
methylene) malonate 1a (1.0 mmol) and p-chlorophenylboronic
acid 2a (3.0 mmol) in DMF was investigated as a model
system to screen Cu catalysts and reaction conditions
(Table 1). Only small amount of homocoupling product of
2a, 4,40-dichlorobiphenyl, was obtained when the reaction was
carried out at 60 1C for 30 h under open air with 0.1 or
0.2 equiv. of Cu(OAc)2 as catalyst (entries 1 and 2). To our
delight, the desired product, vinylogous thioester 3a, could be
isolated in 43% yield at 100 1C for 60 h catalyzed by 0.2 equiv.
of Cu(OAc)2 (entry 3). Increasing the catalyst amount or
elevating temperature proved to facilitate the coupling
(entries 4–6). With 0.3 equiv. of Cu(OAc)2 at 130 1C for
60 h, 3a was obtained in 70% yield (entry 7). However, higher
temperature led to decreasing yield (entry 8) as a large amount
of biphenyl was formed. Additionally, higher yield of 3a could
be achieved with 6.0 equiv. of 2a (entry 9). It should also be
noted that aerobic conditions proved to be required for the
catalytic cycle since 3a was obtained only in 10% yield under
Transition metal-catalyzed C–C bond-forming reactions involving
boronic acids offer particular advantages in terms of tolerance
towards a variety of functional groups.1 Therefore, Pd-catalyzed
thioester–boronic acid desulfitative coupling for the synthesis of
ketones developed by Liebeskind and Srogl in 20002a has earned a
place in the list of this rapidly growing field.2,3 All published
thioorganic–boronic acid couplings have required catalytic
quantities of Pd0 and at least stoichiometric amounts of CuI under
neutral, anaerobic conditions (Scheme 1A), except for a recent
example of aerobic PdII and CuII co-catalyzed coupling of
mercaptoacetylenes and arylboronic acids.4 In 2007, Liebeskind
and coworkers reported an aerobic Cu-catalyzed, Pd-free coupling
of thioesters with boronic acids.5a This low-cost catalytic cross-
coupling is mechanistically unique and is of key interest to the
synthetic community,5b however, the method is severely limited to
thioesters5 and requires an initial buildup of a precursor with
appropriately positioned S-pendant, for example, S-aryl-NHtBu
thiosalicylamides, acting as a templating ligand for Cu catalyst
(Scheme 1B).5 Clearly, it is in great demand to expand the scope of
this cheap pathway, especially to expand its thioorganics to those
compounds without having to incorporate the S-pendant.3,5
As part of our continuing research on the chemistry of
functionalized ketene dithioacetals,6,7 we report herein an aerobic
Cu-catalyzed thioorganic–boronic acid coupling involving ketene
dithioacetals/vinylogous thioesters. Different from the previous
reports (Scheme 1A and 1B),2–5 this Pd-free coupling procedure
represents a dual catalysis of Cu for the activation of
thioorganics under aerobic conditions without the assistance of
S-pendant and provides a novel C–C bond-forming method for
a Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: wangm452@nenu.edu.cn
b State Key Laboratory of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, China
w Electronic supplementary information (ESI) available: All the
relevant synthetic details as well as NMR spectra for all new
compounds. See DOI: 10.1039/c1cc11382h
Scheme 1 Thioorganic–boronic acid C–C couplings.
c
7380 Chem. Commun., 2011, 47, 7380–7382
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Table 1 Screening of reaction conditionsa
Table 2 Cu(OAc)2-catalyzed desulfitative coupling reaction of 1
and 2a
Entry
1
EWG1, EWG2
R
2, R1
Yield (%)b
Entry
Cat. (equiv.)
T/1C
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
2a: 4-ClC6H4
2b: Ph
2c: 3-NO2C6H4 3c: 58 (79)
3a: 70 (83)
3b: 61 (71)
1
2
3
4
5
6
7
8
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(OAc)2 (0.3)
Cu(O2CCF3)2 (0.3)
CuSO4 (0.3)
60
60
30
30
60
60
30
40
60
60
60
60
60
60
60
60
60
30
ndc
ndc
43d
51e
61
2d: 4-MeC6H4
3d: 64 (78)
3e: 60 (82)
3f: 57 (77)
3g: 61 (78)
3h: 59 (74)
ndc
3i: 71 (86)
3j: 72 (82)
3k: 63 (77)
3l: 41 (51)
3m: 60 (76)
3n: 55 (67)
3o: 62 (78)
100
100
130
130
130
Reflux
130
130
130
130
130
130
130
130
1a CO2Et, CO2Et
Bn 2e: 3-MeC6H4
2f: 2-MeC6H4
2g: 4-PhC6H4
2h: 2-naphthyl
2i: (E)-styryl
Me 2b: Ph
Et
62
70f
29
9
10
11
12
13d
14e,f
15e,f
16d,f
1b CO2Et, CO2Et
1c CO2Et, CO2Et
1d CO2Me, CO2Me Bn
1e MeCO, MeCO
1f CO2Et, MeCO
1g MeCO, PhCO
1h CO2Et, NO2
9
83g
10h
58
10
11
12
13
14
15
16
Bn
Me
Bn
Me
56
49
44
9.0
ndc
CuTc (0.3)
CuMeSal (0.3)
CuBr (0.3)
CuBr2 (0.3)
a
Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), DMF (4.0 mL),
17
1i
Bn
ndc
b
air. Isolated yield. Not detected. 1a was recovered in 34% yield.
e
c
d
f
1a was recovered in 25% yield. Thioether was isolated in 71%
18
19
1j MeCO, —
1k CO2Et, —
Me
Me
ndc
ndc
g
yield. Yield with 6.0 equiv. of 2a. Yield under N2.
h
a
Reaction conditions:
1
(1.0 mmol),
2
(3.0 mmol), Cu(OAc)2
b
(0.3 mmol), DMF (4.0 mL), 130 1C, air, 60 h. Isolated yield. Yield
in parentheses was obtained by using up to 6.0 equiv. of 2. Not
N2 (entry 10). Similar to the previous results,5a,c thioether was
obtained as a by-product in the reaction (entry 7). Next,
different Cu catalysts were examined. As presented in Table 1,
Cu(O2CCF3)2, CuSO4, copper(I)-thiophene-2-carboxylate
(CuTC), and CuI-3-methylsalicylate (CuMeSal) were effective
catalysts and gave 3a in 44–58% yields (entries 11–14). However,
CuBr was less effective and CuBr2 was ineffective for the
reaction (entries 15 and 16).5a
c
d
e
detected. Reaction was performed at 110 1C for 30 h. Reaction was
performed at 110 1C for 50 h. Yield based on a mixture of two
isomers.
f
thioesters were not obtained from those ketene dithioacetals
having a cyclic 1,3-dicarbonyl unit (1i, entry 17) or bearing
only one EWG (1j and 1k, entries 18 and 19). It is necessary to
point out that the formation of biphenyls can not be avoided
in all cases because Cu salt is also an efficient catalyst for the
homocoupling of boronic acids.12
Dieter et al. reported the synthesis of vinylogous thioesters
by the reaction of organocuprates with a-oxo ketene dithioacetals
under N2.11 However, our approach creates a newly catalytic
pathway for preparing vinylogous thioesters8 by the conjugate
addition using boronic acids as mild nucleophiles1 and represents
the first example of Cu-catalyzed desulfitative C–C coupling
under Pd-free conditions without the assistance of ligating
S-pendant group. Thus, the scope of the reaction was explored
under the conditions as described in Table 1, entry 7,
considering both the yield and the amount of boronic acids.
The results shown in Table 2 suggested that the reaction of
ketene dithioacetal 1a with boronic acids 2 bearing phenyl
(entry 2), electron-deficient (entries 1 and 3) and electron-rich
aryl group (entries 4–8) could afford the desired vinylogous
thioesters 3a–h in good yields. However, alkenyl boronic acid,
such as (E)-styrylboronic acid 2i, was proven ineffective
(entry 9). It was found that higher yields of 3 could be
obtained in the case of substrates 1 with dimethylthio/
diethylthio functional groups (entry 2 vs. entries 10 and 11).
Similarly, vinylogous thioesters 3k and 3l were obtained in
63% and 41% yield, respectively, from 2b with 1d and 2b with
1e (entries 12 and 13). In addition, reactions of 2b with ketene
dithioacetals 1f–h bearing two different EWGs afforded
3m–o in good yields (entries 14–16). Whereas, the vinylogous
It was found that the yields of 3 could be increased by
10–20% (Table 2, yields in parentheses) when 6.0 equiv. of
boronic acids 2 was used. It is worth emphasizing that these
Cu-catalyzed reactions are controllable and the double C–C
coupling products, tetrasubstituted olefins 4, are detected only
in trace amounts even if a large excess of boronic acids were
used. By contrast, the Pd-catalyzed, Cu-mediated couplings of
bisarylthio cyclobutenediones with boronic acids were difficult
to ensure the formation of mono cross-coupling products
(Scheme 1A).2b
The significance of tetrasubstituted olefins is reflected in
their presence in drugs, for example, tamoxifen (an essential
drug for the treatment of breast cancer).13 Nevertheless, the
synthesis of tetrasubstituted olefins is one of the most challenging
subjects because of the paucity of synthetic access.9,13,14
Fortunately, we found that tetrasubstituted olefin 4a could
be obtained in 47% isolated yield by further treatment of 3b
(0.5 mmol) with 2b (1.5 mmol) in DMF at 130 1C for 30 h in
the presence of Cu(OAc)2 (0.15 mmol) under open air. Similarly,
tetrasubstituted olefins 4b–e were successfully synthesized in
48–57% isolated yields, respectively (Scheme 2).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7380–7382 7381

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Therefore, it is easy to understand that substrates 1 having
an acyclic 1,3-dicarbonyl and related functionality, which
coordinate with CuII in a bidentate fashion, show higher
reactivity towards the desulfitative coupling than those having
cyclic 1,3-dicarbonyl unit or only one carbonyl group (Table 2,
entries 1–16 vs. 17–19).16
In conclusion, we have developed a new Cu-catalyzed
thioester–boronic acid desulfitative C–C bond-forming
reaction under neutral, aerobic conditions. This reaction
expands the scope of sulfur substrates by using attractive,
readily available ketene dithioacetals and involves a duel
catalysis of Cu for the activation of thioorganics under
Pd-free conditions without using S-pendant. By this reaction
a series of vinylogous thiolesters and tetrasubstituted olefins
were prepared with low cost and easy to handle catalysts.5
Further studies are in progress.
Scheme 2 Synthesis of tetrasubstituted olefins.
On the basis of all of the results mentioned above and
related reports,3,5 the mechanism for the desulfitative C–C
bond-forming reaction is proposed in Scheme 3. The first two
steps are similar to the mechanism proposed by Liebeskind5a
and involves, (1) the initial activation of thioorganics (ketene
dithioacetal 1 or vinylogous thiolester 3) by coordination to
CuI oxygenate to form intermediate A which is oxidized to a
higher oxidation state CuII/III intermediate B under aerobic
conditions, (2) further coordination of B to boronic acid to
afford intermediate C in which the nucleophilic R2 is directed
toward the b-position of the enone. Differently, however, the
coupling product 3 or 4 could not be formed at this stage
because further activation is necessary.
We gratefully acknowledge NNSFC-20972029/21072027
and the Fundamental Research Funds for the Central
Universities (NENU-STC08007 and 10JCXK009) for funding
support of this research.
Notes and references
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Cabrera, J. Org. Chem., 2007, 72, 8539.
As shown in Scheme 3, an additional activation of inter-
mediate C by CuII is required to afford more reactive
CuII-coordination intermediate D, thereby enhancing the
electrophilicity of the enone and facilitating the consequent
conjugated addition–elimination procedure (D - 3/4). In fact,
the two times catalytic activations of thioorganics require a
little more amount of Cu catalyst. Finally, the catalytic cycle is
completed by reaction of the CuII/III-thiolate E, released from
the reaction, with the second (sacrificial) equivalent of the
boronic acid to generate a thioether15 and a CuI oxygenate.
´
3 H. Prokopcova and C. O. Kappe, Angew. Chem. Int. Ed., 2009, 48,
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4 A. Henke and J. Srogl, Chem. Commun., 2011, 47, 4282.
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´
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(b) H. Junjappa, H. Ila and C. V. Asokan, Tetrahedron, 1990, 46,
5423.
7 For selected recent reports, see: (a) M. Wang, Z. Fu, H. Feng,
Y. Dong, J. Liu and Q. Liu, Chem. Commun., 2010, 46, 9061;
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Scheme 3 Proposed mechanism.
c
7382 Chem. Commun., 2011, 47, 7380–7382
This journal is The Royal Society of Chemistry 2011