Modular synthesis of sulfonyl benzoheteroles by silver-catalyzed heteroaromatization of propargylic alcohols with p -toluenesulfonylmethyl isocyanide (TosMIC): Dual roles of TosMIC

Article abstract of DOI:10.1021/ol5031316

A new silver-catalyzed heteroaromatization of propargylic alcohols with p-toluenesulfonylmethyl isocyanide (TosMIC) has been developed that provides an efficient and modular approach to sulfonyl benzoheteroles. For the first time, TosMIC plays a dual role in one reaction: sulfonyl source and ligand. An unprecedented deoxysulfonylation/hydration/condensation reaction pathway is disclosed.

Full text of DOI:10.1021/ol5031316

Letter
pubs.acs.org/OrgLett
Modular Synthesis of Sulfonyl Benzoheteroles by Silver-Catalyzed
Heteroaromatization of Propargylic Alcohols with
p‑Toluenesulfonylmethyl Isocyanide (TosMIC): Dual Roles of TosMIC
Jianquan Liu,† Zhenhua Liu,† Peiqiu Liao,† and Xihe Bi*,†,‡
†Department of Chemistry, Northeast Normal University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A new silver-catalyzed heteroaromatization of propargylic
alcohols with p-toluenesulfonylmethyl isocyanide (TosMIC) has been
developed that provides an efficient and modular approach to sulfonyl
benzoheteroles. For the first time, TosMIC plays a dual role in one reaction:
sulfonyl source and ligand. An unprecedented deoxysulfonylation/hydration/
condensation reaction pathway is disclosed.
enzoheteroles such as benzofurans, indoles, and benzothio-
Bphenes not only are ‘privileged structures’ encountered in
numerous natural products and synthetic functional molecules1
but also function as valuable intermediates in organic synthesis.2
In the past decade, substantial advances in the transition-metal-
catalyzed synthetic methods for these heterocycles have been
witnessed.3 Among these, intra- and intermolecular heteroar-
omatization using alkynes may be one of the most popular
synthetic strategies.4−6 For intramolecular heteroaromatization
reactions, it is well recognized that the activation of the alkynyl π-
bond is initiated by the coordination of a π-electrophilic
transition-metal (TM) catalyst to the CC triple bond,
followed by the generation of an (alkenyl)metal intermediate
(Figure 1a). Despite the impressive progress, the methods
allowing for the modular synthesis of benzoheteroles simply by
changing the heteroatom center under the same catalytic
conditions are rare.7 Propargylic alcohols are readily available
bifunctional building blocks; recently, the exploration of their
Figure 1. Synthesis of benzoheteroles by transition-metal-catalyzed
intramolecular heteroaromatization of alkynes.
synthetic potency has attracted much attention.8 As part of our
continued efforts to develop novel reactions using functionalized
alkynes,9 we herein report a new silver-catalyzed heteroaroma-
Ag2CO3 in the presence of 2 equiv of H2O afforded 3-
sulfonylated benzofuran 3a in 80% yield. The structure of
compound 3a was unambiguously confirmed by X-ray diffraction
(XRD) analysis. This reaction represents a new route to access
benzofurans. Therefore, we carried out an extensive optimization
of the reaction conditions (for the details, see the Supporting
Information). Finally, the yield was improved to 95% under the
optimal conditions (Ag3PO4 (10 mol %), H2O (2.0 equiv), 1,4-
dioxane, 100 °C). Subsequently, two questions related to the
reaction mechanism were raised: (1) how the Ts group was
transferred to the 3-position of benzofurans; (2) whether the
tization reaction of propargylic alcohols with p-toluenesulfonyl-
methyl isocyanide (TosMIC), thus providing a conceptually
novel and modular approach to pharmaceutically relevant
sulfonyl benzoheteroles (Figure 1b).10 An unprecedented
reaction pathway, different from the classical intramolecular
heteroaromatization of alkynes, is disclosed. TosMIC plays a dual
role as the sulfonyl source and ligand. To the best of our
knowledge, this is the first example in which TosMIC plays such a
role in one reaction, even though it has been widely used in
organic synthesis.11
Recently, we and the Lei group realized the first silver-
catalyzed [3 + 2] cycloaddition reaction of alkynes with
isocyanides.9c,d When we tried to expand the substrate scope
to propargylic alcohol 1a, unexpectedly, the reaction catalyzed by
Received: October 27, 2014
© XXXX American Chemical Society
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Letter
heteroaromatization followed the classical TM-catalyzed cycliza-
tion pathway. To elucidate these mechanistic questions, the
following experimental investigations were carried out.
decompose to formaldehyde and a Ts group, probably
accompanied by the generation of a cyanide ion (CN−).13
Furthermore, when quenching the reaction mixture of 1a and 2a
in 15 min, a key intermediate, Ts-1a, was obtained in 26% yield
(eq 4). Clearly, a deoxysulfonylation process occurred in the
initial stage of the reaction.
After identifying the first step in the reaction as deoxysulfo-
nylation, we turned our attention to the subsequent hetero-
aromatization pathway starting from intermediate Ts-1a, which
was synthesized by a reported method.14 The critical role of H2O
in the heteroaromatization of Ts-1a was established: in the
presence of H2O, 3a could be obtained in nearly quantitative
yield (97%), whereas, in the absence of H2O, 3a was obtained in a
poor yield (15%) (eq 5). These results demonstrated Ts-1a to be
the reaction intermediate and also proved the necessity of H2O as
the additive. Interestingly, no reaction occurred in the absence of
TosMIC, thus suggesting that TosMIC acted as a ligand in the
cyclization of TS-1a. This assumption was further confirmed
using aryl isocyanide (2e) instead of TosMIC, which afforded 3a
in 89% yield (eq 6). Although isocyanide−metal complexes are
common in organometallic chemistry,15 to the best of our
knowledge, the use of TosMIC as a ligand in transition-metal-
catalyzed reactions has not been reported.16 The cyclization of
Ts-1a probably proceeded through an unusual hydration/
condensation cascade. Such a hypothesis was confirmed by the
reaction of deuterium-labeled compound [D]-Ts-1a, which only
afforded benzofuran 3a in 92% yield without deuterium
incorporation, while [D]-3a that was expected to be formed by
the addition of alkynes and isomerization was not found (eq 7).17
The classical process was further excluded by the reaction of Int-
1a, which only afforded [OH]-3a in 85% yield by a reported 1,3-
hydroxyl transfer process, while the 3a yield was 0% (eq 8).18
Based on the above results, a plausible mechanism was
proposed (Scheme 2). The domino reaction starts with the
As shown in Scheme 1, first, we found that, in the absence of
TosMIC, the reaction of 1a under the optimized reaction
Scheme 1. Mechanistic Investigations
Scheme 2. A Plausible Reaction Mechanism
reaction of propargylic alcohol 1a with TosMIC 2a to yield the
intermediate Ts-1a by deoxysulfonylation, in which TosMIC acts
as the sulfonyl source. Next, the regioselective hydration of Ts-1a
with H2O takes place using TosMIC as the ligand, thus affording
enol A. The regioselectivity of the reaction can be attributed to
the directing effect of the Ts group. Following keto−enol
tautomerism, α-Ts ketone intermediate B is formed. Finally,
benzofuran 3a is formed by a sequential addition/elimination
cascade (i.e., condensation reaction).19
Next, the substrate scope of propargylic alcohols that could be
used in this domino heteroaromatization reaction was
investigated (Scheme 3). A range of substrates (1b−1q) were
converted into the corresponding benzofuran products (3b−3q)
in synthetically useful yields using the initial optimized reaction
conditions. A range of R groups including (hetero)aryl, fused
conditions failed, thus demonstrating the necessity of TosMIC
(eq 1). Furthermore, instead of TosMIC, other reported Ts
sources such as TsNa and TsNHNH2 were investigated;12
however, either no desired product 3a was obtained or no
reaction occurred (eq 2). To capture the side product from
TosMIC, a TosMIC derivative 2d with a large biphenyl tail was
designed and prepared. Delightfully, the reaction of 1a with 2d
smoothly proceeded to afford product 3a in a slightly decreased
yield (81%); importantly, an aldehyde byproduct 4 was isolated
in 90% yield (eq 3). This result suggests that TosMIC may
B
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Letter
Scheme 3. Synthesis of 3-Sulfonyl Benzofurans, Indoles, and
Benzothiophenes
Scheme 4. Synthesis of 2-Sulfonylmethyl Benzofurans and
Indoles
a
a
a
Isolated yields.
benzofurans (5a−5k) and indoles (5l−5q) in moderate to high
yields (48−92%). The structure of compound 5e was
unambiguously established by XRD analysis. Notably, com-
pounds 5 are newly substituted benzoheteroles.21 The easy
availability of sulfonyl benzoheteroles 5 opens new synthetic
opportunities for a suitable functionalization at the 2-position
because of the well-known ability of the arenesulfonyl moiety as a
good leaving group.22 Therefore, an alkylation reaction of the
benzofuran 5a was realized under radical conditions by the
substitution of the Ts group with a hydrogen atom leading to the
2-alkyl benzofuran derivative 6a; meanwhile, triarylmethane 6b
was obtained by the palladium-catalyzed coupling reaction with
phenylboronic acid.23
a
Isolated yields.
aryl, and alkyl were compatible with the cyclization reaction
conditions. Substrate 1j containing a terminal alkyne unit (i.e., R
= H) also smoothly participated in the reaction with TosMIC,
thus affording the corresponding 2-methyl-3-sulfonyl benzofuran
3j in 97% yield. Moreover, a benzofuran dimer 3k was prepared
in 72% yield starting from a bispropargylic alcohol substrate.
Furthermore, wide variation of the substituents on the benzene
ring including electron-donating (e.g., MeO and t-Bu) and
-withdrawing groups (e.g., Br, Cl, and NO2) allowed the
formation of diverse highly functionalized benzofurans (3l−
3q) in moderate to excellent yields. To our delight, this method
was also capable of preparing 3-sulfonyl benzothiophenes (3r−
3t) and indoles (3u−3z) simply by changing the heteroatoms.
Sulfonyl benzoheteroles are pharmaceutically important;10
however, the reported synthetic methods are mostly limited to
the sulfonylation on a benzoheterole skeleton.19 Herein, we
developed a straightforward method for the synthesis of such
compounds from acyclic precursors.
The preliminary mechanistic studies on the heteroaromatiza-
tion of propargylic alcohols 4 suggested a similar reaction
pathway to that of propargylic alcohols 1. For example, the
deoxysulfonylated intermediate TS-4a was smoothly converted
into the desired product 5a in 83% yield in the presence of
TosMIC, whereas no reaction occurred without TosMIC.
To expand the scope of this methodology, propargylic alcohols
(4) were synthesized by the Sonogashira coupling of terminal
propargylic alcohols with the corresponding ortho-halophenols/
anilines.20 Structurally, the positions of the hydroxyl group and
CC triple bond are interchanged in propargylic alcohols 4 and
1. As shown in Scheme 4, under slightly modified reaction
conditions, to our delight, they were also useful for the
heteroaromatization with TosMIC to afford 2-sulfonylmethyl
In conclusion, we have developed a novel silver-catalyzed
heteroaromatization reaction of propargylic alcohols and
TosMIC, which provides a very convenient and modular
approach to a range of functionalized benzoheteroles including
benzofurans, indoles, and benzothiophenes. For the first time,
C
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Letter
Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. J. Med. Chem.
2003, 46, 2482.
(11) Tandon, V. K.; Rai, S. Sulfur Rep. 2003, 24, 307.
(12) Tang, S.; Wu, Y.; Liao, W.; Bai, R.; Liu, C.; Lei, A. Chem. Commun.
2014, 50, 4496.
(13) (a) Peng, J.; Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Org.
Lett. 2012, 14, 4966. (b) Vishnu, G.; Srivastava, P.; Dhar, L.; Yadav, S.
Tetrahedron Lett. 2011, 52, 4622.
(14) Reddy, M. A.; Reddy, P. S.; Sreedhar, B. Adv. Synth. Catal. 2010,
352, 1861.
the role of TosMIC was found to be twofold, as the sulfonyl
source and ligand. A mechanistically novel deoxysulfonylation/
hydration/condensation reaction pathway, different from the
classical transition-metal-catalyzed intramolecular heteroaroma-
tization of alkynes, was disclosed. Considering the practicality
and novelty of this method and the extreme importance of
benzoheteroles in medicinal chemistry and material science, the
methodology described here undoubtedly will find wide
applications in future synthetic endeavors.
(15) Luzyanin, K. V.; Pombeiro, A. J. L. In Isocyanide Chemistry:
Applications in Synthesis and Material Science, 1st ed.; Nenajdenko, V.,
Ed.; Wiley-VCH Verlag GmbH & Co.: 2012; pp 531−550.
(16) For Ito’s catalyst using tert-alkyl isocyanide as a ligand, see: Ito, Y.;
Suginome, M.; Murakami, M. J. Org. Chem. 1991, 56, 1948.
(17) Wongsa, N.; Sommart, U.; Ritthiwigrom, T.; Yazici, A.;
Kanokmedhakul, S.; Kanokmedhakul, K.; Willis, A. C.; Pyne, S. G. J.
Org. Chem. 2013, 78, 1138.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectra copies. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(18) Li, X.; Xue, J.; Chen, R.; Li, Y. Synlett 2012, 23, 1043.
(19) Xiao, F.; Chen, H.; Xie, H.; Chen, S.; Yang, L.; Deng, G. Org. Lett.
2014, 16, 50.
*E-mail: bixh507@nenu.edu.cn.
Notes
́
(20) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084.
(21) Li, Y.; Shi, F.; He, Q.; You, S. Org. Lett. 2009, 11, 3182.
(22) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press:
Oxford, 1993.
The authors declare no competing financial interest.
(23) Nambo, M.; Crudden, C. M. Angew. Chem., Int. Ed. 2014, 53, 742.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21172029, 21202016,
21372038), the MEPRC (NCET-13-0714), and the Jilin
Provincial Research Foundation for Basic Research
(20140519008JH).
REFERENCES
■
(1) Bronner, S. M.; Im, G. Y. J.; Garg, N. K. Heterocycles in Natural
Product Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: 2011.
(2) (a) Bartoli, G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev. 2014, 43,
4728. (b) Shiri, M. Chem. Rev. 2012, 112, 3508.
(3) For recent reviews, see: (a) Zeng, X. Chem. Rev. 2013, 113, 6864.
(b) Chinchilla, R.; Najera, C. Chem. Rev. 2014, 114, 1783.
́
(4) For examples of benzofuran synthesis, see: (a) Nakamura, I.;
Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022.
(b) Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
̈
(c) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387.
(d) Han, Z.; Zhang, L.; Li, Z.; Fan, R. Angew. Chem., Int. Ed. 2014, 53,
6805 and references cited therein.
(5) For examples of indole synthesis, see: (a) Takeda, A.; Kamijo, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662. (b) Shimada, T.;
Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (c) Liu,
B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013, 135,
16625 and references cited therein.
(6) For examples of benzothiophene synthesis, see: (a) Nakamura, I.;
Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473. (b) Liu,
K.; Jia, F.; Xi, H.; Li, Y.; Zheng, X.; Guo, Q.; Shen, B.; Li, Z. Org. Lett.
2013, 15, 2026 and references cited therein.
(7) (a) Syu, S.; Lee, Y.; Jang, Y.; Lin, W. Org. Lett. 2011, 13, 2970.
(b) Qin, X.; Cong, X.; Zhao, D.; You, J.; Lan, J. Chem. Commun. 2011,
47, 5611.
(8) For examples, see: (a) Nagashima, Y.; Hirano, K.; Takita, R.;
Uchiyama, M. J. Am. Chem. Soc. 2014, 136, 8532. (b) Collins, B. S. L.;
Suero, M. G.; Gaunt, M. J. Angew. Chem., Int. Ed. 2013, 52, 5799.
(9) (a) Fang, Z.; Liu, J.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2014, 53,
7209. (b) Liu, Z.; Liu, J.; Zhang, L.; Liao, P.; Song, J.; Bi, X. Angew.
Chem., Int. Ed. 2014, 53, 5305. (c) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.;
Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953. (d) Gao, M.; He, C.; Chen,
H.; Bai, R.; Cheng, B.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 6958.
(10) (a) Zhou, N.; Zeller, W.; Krohn, M.; Anderson, H.; Zhang, J.;
́
Onua, E.; Kiselyov, A. S.; Ramirez, J.; Halldorsdottir, G.; Andresson, T.;
Gurney, M. E.; Singh, J. Bioorg. Med. Chem. Lett. 2009, 19, 123.
(b) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa, S.;
D
dx.doi.org/10.1021/ol5031316 | Org. Lett. XXXX, XXX, XXX−XXX