Cyclocarbopalladation/cross-coupling cascade reactions in sulfide series: Access to sulfur heterocycles

Article abstract of DOI:10.1021/ol501165h

Cyclocarbopalladation/cross-coupling cascade reactions were applied for the first time in a sulfur series and represent an efficient route to access sulfur heterocycles. Stille or Suzuki-Miyaura cross-coupling was successfully used as the final reaction.

Full text of DOI:10.1021/ol501165h

Letter
pubs.acs.org/OrgLett
Cyclocarbopalladation/Cross-Coupling Cascade Reactions in Sulfide
Series: Access to Sulfur Heterocycles
Thomas Castanheiro, Morgan Donnard, Mihaela Gulea,* and Jean Suffert*
́ ́ ́
Laboratoire d’Innovation Therapeutique, UMR 7200 CNRS-Unistra, Faculte de Pharmacie, Universite de Strasbourg, 74 Route du
Rhin, Illkirch, France
S
* Supporting Information
ABSTRACT: Cyclocarbopalladation/cross-coupling cascade reactions were applied
for the first time in a sulfur series and represent an efficient route to access sulfur
heterocycles. Stille or Suzuki−Miyaura cross-coupling was successfully used as the final
reaction. The products are original benzothiolane and isothiochromane scaffolds with
a stereodefined tetrasubstituted exocyclic double bond. To illustrate the application of
this method to the synthesis of bioactive molecules, a sulfur analogue of the anticancer
agent tamoxifen was prepared as a potential selective estrogen-receptor modulator.
ne of the main reasons for the continuous and
Ospectacular progress in the field of palladium-catalyzed
reactions is their high tolerance of various functionalized
substrates. However, as far as the development of these
reactions involving organosulfur substrates is concerned, the
deactivation of the catalyst caused by the thiophilicity of
palladium has been a limiting factor. This problem has been
successfully overcome, and during the recent decades many
palladium-catalyzed syntheses of sulfur-containing compounds
have been described, in particular via C−S bond formation.1
On the other hand, despite the interest of sulfur heterocycles as
constituents of a large number of drug structures,2 their
synthesis by using palladium cross-coupling reactions remains
limited.3 Among the various palladium-catalyzed processes, the
cascade cyclizations represent a powerful tool to access
efficiently and with step-economy complex carbocyclic and
heterocyclic molecules from simple starting materials.4 The
potential of this method has not been fully exploited in
heterocycle synthesis, and as far as the synthesis of sulfur
heterocycles by using this approach is concerned, only one
example can be considered as a cascade process: the
intermolecular C−S bond formation/thiacyclization domino
reaction described by Paradies in 2011.3h Otherwise, an original
tandem Pd-catalyzed C−S/C−C coupling on gem-dibromo-
vinyl substrates was reported by Lautens in 2009.3f Although
several cyclocarbopalladation/cross-coupling cascade reactions
leading to nitrogen and oxygen heterocycles have been
reported,5,6 examples in the sulfur series are still missing. To
the best of our knowledge, the reaction described herein
represents the first example of this type of palladium-catalyzed
cascade cyclization, leading to sulfur heterocycles.
isothiochromane) bearing an exocyclic, stereodefined, all-
substituted double bond7 (Scheme 1).
Scheme 1. Expected Pd-Catalyzed Processes
One key point of the method would be the competition
between the cascade and the direct coupling reactions
(formation of product A vs B), as the presence of the metal-
chelating sulfur function on the substrate could influence the
course of the process. The expected products of type A are
rarely encountered scaffolds, different from benzothiophenes
that are obtained by the existing metal-catalytic routes.
We first prepared a range of six starting sulfides 1a−f bearing
on sulfur a 2-bromophenyl or benzyl group and an alkyne with
various R1 substituents (Figure 1).
In our first series of experiments, we attempted a
cyclocarbopalladation/Stille coupling cascade (Table 1).
We envisioned that reacting the appropriate starting sulfide
bearing an alkyne substituent with a coupling partner in the
presence of a palladium catalyst would result in a cyclo-
carbopalladation/cross-coupling cascade, yielding a benzene-
fused five or six-membered sulfur ring (i.e., benzothiolane or
Figure 1. Starting sulfides 1.
Received: April 23, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
(Table 1, entry 8), which is highly acid-sensitive (fast
decomposition is observed if the CDCl3 for the NMR analysis
is not neutralized prior to use). The cascade reaction was found
to be effective also in the case of benzyl ynethioether 1d,
affording heterocycle 2dA (Table 1, entry 9). The scope of the
method was then examined with benzyl propargyl sulfides 1e,f,
which are presumed to react via a 6-exo-dig cyclization to access
6-membered sulfur heterocycles, namely isothiochromanes.
Thus, by reacting 1e and 1f with 2-furylstannane, the desired
products 2eA and 2fA were obtained in good yields (Table 1,
entries 10 and 11). The vinyl derivative 4eA obtained from 1e
isomerized fast, and the product was isolated and characterized
by NMR spectroscopy as a mixture of E/Z isomers in a 3/1
ratio, in 61% yield (Table 1, entry 12). Interestingly, by reacting
1e with the allyltributylstananne, the expected product 5eA was
obtained together with a secondary product, in a ratio of 2/1
(Table 1, entry 13). We were not able to separate these
compounds by column chromatography (same Rf in pure
heptane); however, they could be characterized from the NMR
spectra of the mixture. The unexpected product was found to
be the cyclopropyl derivative 6eA. Its formation occurs
probably via a 4-membered palladacycle intermediate.10
Instead of using the benzene as the solvent, we attempted the
reaction by using 2-methyltetrahydrofuran in one case. Under
these conditions, the reaction between 1e and 2-furyltributyl-
stananne also worked well, leading to a mixture of products
2eA/2eB in a 9/1 ratio. The heterocyclic product 2eA was
isolated in a 70% yield.
To extend the method to other cross-coupling reactions and
also to avoid the difficulty in the product isolation using
stannanes, the cyclocarbopalladation/Suzuki−Miyaura cascade
reaction was investigated. A screening of various reaction
conditions was done for the reaction between sulfide 1b and
phenylboronic acid to reach a complete conversion and a high
selectivity in product A.11 The best result was obtained with
Pd(PPh3)4 as the catalyst and with K3PO4 as the base, in a
mixture of 2-methyltetrahydrofuran/water 98/2 at 130 °C
during 2 or 3 h under microwave irradiation12 (Table 2, entry
1). Under these conditions, a mixture of products 7bA and 7bB
in a 9:1 ratio was obtained. The separation of the two products
having similar polarity was difficult; however, we isolated the
desired heterocycle 7bA pure, in 66% yield. We then submitted
to the same reaction substrates 1c−f (Table 2, entries 2−5).
Ynethioether 1d led only to the cyclic compound 7dA,
however, with a low yield of 30%, due to the difficult
purification of the product (Table 2, entry 3). The 6-membered
sulfur heterocycles 7eA and 7fA were obtained from 1e and 1f,
respectively, with high selectivity and in good yield (Table 2,
entries 4 and 5).
Table 1. Cyclocarbopalladation/Stille Coupling
a
entry
sulfide
R2
product
2aA
yield (%)
1
1a
1a
1a
1a
1b
1b
1b
1c
1d
1e
1f
2-furyl
2-thienyl
vinyl
65
77
51
62
52
63
2
3aA
4aA
5aA
2bA
4bA
5bA
2cA
2dA
2eA
2fA
3
4
allyl
5
2-furyl
vinyl
6
d
7
allyl
38
8
2-furyl
2-furyl
2-furyl
2-furyl
vinyl
61
59
81
70
61
9
10
11
12
13
b
1e
4eA
c
e
1e
allyl
5eA + 6eA
nd
a
b
c
Isolated yield. Mixture of E/Z isomers in a 3/1 ratio. The ratio 5/6
d
e
was 2/1. The conversion was 50%. Not determined.
Cascade reaction conditions that are classically used in our
laboratory8 were applied and optimized for the reaction
between sulfide 1a bearing a trimethylsilyl group on the triple
bond and 2-furyltributylstannane as the coupling partner. The
best results were obtained with 10 mol % of Pd(PPh3)4 as
catalyst, with 1.3 equiv of stannane, in benzene, under
microwave irradiation at 115 °C, and 3 h are necessary for a
complete conversion9 (Table 1, entry 1). Only the desired five-
membered sulfur heterocyclic product 2aA formed by a 5-exo-
dig cyclization/Stille cascade process was obtained, without any
trace of product of type B resulting from a direct coupling.
Although the conversion was total, the isolated yield was
moderate (65%) because of the difficulty in separation from the
crude mixture of the nonpolar product and the stannane
derivatives. Sulfide 1a was then reacted in the same conditions
with 2-thienyl, vinyl, and allylstannane, leading to the
corresponding cyclic products 3aA, 4aA, and 5aA (Table 1,
entries 2−4). Just after purification, the vinyl derivative 4aA was
characterized as the E isomer, but after a few hours,
isomerization occurred (due probably to the conjugated dienic
We next investigated the effect of varying the boronic acid.
By using electron-rich or electron-poor arylboronic acids, the
reaction with sulfide 1e worked well, and the selectivity in
product A was high to total (Table 2, entries 6−12). The
coupling can also take place with a sterically congested partner
such as 2,4-dimethoxyphenylboronic acid (Table 2, entry 12).
In some cases, products A and B were inseparable due to their
similar polarity (Table 2, entries 4, 6, and 7). One limitation
was revealed in the reaction involving 1e and 4-carboxyphe-
nylboronic acid (Table 2, entry 8). In this case, the
cyclocarbopalladation was followed by the protonation of the
vinylic carbon (probably by the carboxylic acid) and not by the
coupling reaction. In consequence, instead the expected
1
structure) and a mixture of E/Z isomers was observed by H
NMR spectroscopy.
The other sulfides were then involved in the cascade process.
With sulfide 1b, the reactions with the same stannanes worked
similarly to those with 1a and led to the corresponding
products 2bA, 4bA, and 5bA (Table 1, entries 5−7). The
reaction between sulfide 1c and 2-furylstannane led to 2cA
1
product, we identified by H NMR the protonated product
B
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Organic Letters
Letter
It is important to notice that the obtained products are
unstable under basic conditions (aqueous 1 M NaOH
solution), leading to an unidentified mixture of compounds.
Finally, to illustrate the application of this method to the
synthesis of potentially bioactive molecules, we have prepared
compound 19 as an analogue of the anticancer agent tamoxifen
(Scheme 2). A four-step sequence was used: demethylation of
Table 2. Cyclocarbopalladation/Suzuki−Miyaura Coupling
Scheme 2. Tamoxifen and a Sulfur Analogue; Synthesis of
Compound 19
a
entry
sulfide
R2
A/B
product A
yield (%)
1
2
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
9:1
1:0
7bA
7cA
7dA
7eA
7fA
66
79
30
91
81
83
86
nd
69
86
67
60
nd
64
73
55
3
1:0
4
20:3
1:0
5
6
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
4-FC6H4
4-CF3OC6H4
4-CO2HC6H4
4-CO2MeC6H4
3-NO2C6H4
10:1
10:1
8eA
9eA
d
7
8
9
1:0
1:0
1:0
1:0
1:1
1:0
1:0
1:0
11eA
12eA
13eA
14eA
10
11
12
3-CF3C6H4
2,4-(MeO)2C6H3
2-furyl
b
e
13
2eA
S-(2-bromo-5-methoxybenzyl) thioacetate 15 to give the
corresponding 5-hydroxy derivative 16, S-alkylation and
subsequent O-alkylation to obtain the appropriate cascade
precursor 18, and a palladium-catalyzed cyclization/Suzuki
cascade process (Scheme 2). The desired product 19 was
obtained in 42% overall yield.
In summary, cyclocarbopalladation/cross-coupling cascade
reactions were applied for the first time in a sulfur series and
enabled the access to sulfur heterocycles. The process works
efficiently via either 5-exo or 6-exo-dig cyclization and is
compatible with Stille and Suzuki−Miyaura cross-coupling
reactions, thereby enabling the introduction of a large variety of
substituents. By this method, we obtained original structures
containing a benzene-fused 5- or 6-membered sulfur hetero-
cycle and a stereodefined tetrasubstituted exocyclic double
bond. Due to their structural particularities, such compounds
could be interesting candidates as selective estrogen receptor
modulators (SERMs). Thus, compound 19 was prepared as a
sulfur analogue of tamoxifen and is presently under biological
investigations. Current studies are focused on exploiting this
method to access various more complex sulfur heterocycles.
c
e
14
15
16
vinyl
4eA
c
e
allyl
5eA
e
cyclopropyl
6eA
a
A: cascade product. B: direct coupling product. The A/B ratio was
b
measured by NMR 1H. PdCl2/SPHOS was used as the catalyst.
c
d
R2BF3K was used as the boron reagent. Instead the desired product,
e
compound 10 was obtained; see ref 13. See structure in Table 1.
10.13 On the other hand, as expected, the replacement in the
coupling partner of the carboxylic acid by the methyl ester
group, led to product 11eA (Table 2, entry 9).
To compare the efficiency of the Stille and Suzuki reactions
in this process, 2-furylboronic acid was reacted with 1e, and we
found that the Suzuki conditions led only to product 2eB
resulting from the direct cross-coupling. By replacing the
Pd(PPh3)4 catalyst by PdCl2/SPHOS, an equimolar mixture of
2eA and 2eB was obtained (Table 2, entry 13).14 As a
reminder, only the desired heterocycle 2eA was formed by
Stille coupling with 2-furylstannane (Table 1, entry 10).
The two possible routes, Stille vs Suzuki coupling, were also
compared for the synthesis of compounds 4eA, 5eA, and 6eA
starting from 1e. Trifluoroborate salts were used as coupling
partners to introduce vinyl and allyl substituents (Table 2,
entries 14 and 15). The vinyl derivative 4eA was obtained as a
mixture of E/Z isomers in a ratio of 3/1 and 64% yield (Table
2, entry 14), similarly to the previous results using Stille
coupling (see Table 1, entry 12). The allyl derivative 5eA was
obtained as a single product (Table 2, entry 15), without the
secondary cyclopropyl derivative 6eA obtained by using the
allylstananne (see Table 1, entry 13). Product 6eA was also
obtained independently, by reacting 1e with cyclopropylbor-
onic acid (Table 2, entry 16).
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectra data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gulea@unistra.fr.
*E-mail: jean.suffert@unistra.fr.
C
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Organic Letters
Letter
(10) For this type of reaction, see: (a) Hegedus, L. S.; Darlinton, W.
H.; Russell, C. E. J. Org. Chem. 1980, 45, 5193−5196. (b) Satake, A.;
Nakata, T. J. Am. Chem. Soc. 1998, 120, 10391−10396.
(11) The optimization of the reaction conditions for the cyclization/
Suzuki−Miyaura cascade is given in the Supporting Information
(Table 1).
(12) The reaction can be performed under oil bath heating but
requires 5−12 h for a similar result.
(13) See the scheme of the reaction and the structure of compound
10 in the Supporting Information.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project wass supported by the University of Strasbourg
(IDEX grant for T.C.) and the CNRS (Centre National de
Recherche Scientifique). We thank Cyril Antheaume and
Patrick Wehrung (University of Strasbourg) for analytical
studies and Elsa Cece (Master student at the university of
Strasbourg) for helpful experiments.
(14) See the scheme of the reaction in the Supporting Information.
DEDICATION
■
Dedicated to Professor Max Malacria (ICSN, University of
Paris 6) on the occasion of his 65th birthday
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D
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