Copper-Catalyzed Asymmetric Silylation of Propargyl Dichlorides: Access to Enantioenriched Functionalized Allenylsilanes

Article abstract of DOI:10.1002/anie.201908343

A copper-catalyzed silylation of propargyl dichlorides was developed to access chloro-substituted allenylsilanes under mild reaction conditions. Moreover, enantioenriched chloro-substituted allenylsilanes can be synthesized in moderate to high yields and good enantioselectivities with this protocol.

Full text of DOI:10.1002/anie.201908343

COMMUNICATIONS
DOI: 10.1002/adsc.201900904
Copper-Catalyzed Reaction of Aryl Isocyanides with Active
Methylene Isocyanides and Arylsulfonothioates: Synthesis of
Sulfur-Containing Trisubstituted Imidazoles
Pei Xu,a Yi-Ming Zhu,a Xing-Jia Li,a Fei Wang,a Shun-Yi Wang,a,* and
Shun-Jun Jia,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science
& Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, People’s
Republic of China
E-mail: shunyi@suda.edu.cn; shunjun@suda.edu.cn
Manuscript received: July 22, 2019; Revised manuscript received: August 26, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900904
addition to construct imidazoles have been reported in
the literature (Scheme 1, b). To the best our knowl-
Abstract: A Copper-catalyzed reaction of aryl
isocyanides with active methylene isocyanides and
edge, there are no multi component reactions based on
arylsulfonothioates is developed for the synthesis of
isocyanide-isocyanide [3+2] cycloaddition.
sulfur-containing trisubstituted imidazoles. This re-
CÀ S bond formation reactions have attracted in-
creasing attention for their importance in natural
products and functional materials.[9] The most classical
method for the building CÀ S bond usually utilizing
mercaptans which have the unpleasant odor. In the past
few years, arylsulfonothioates as thiolating agents have
received increasing attention from the synthetic com-
munity of researchers.[10–14] Many groups such as Xu’s
group,[10] Song’group,[11] Orru’s group,[12] Hosoya’s
group,[13a] and Reddy’s group[13b] have been success-
fully constructed sulfur-containing compounds with
arylsulfonothioates. Very recently, the reactions involv-
action not only forms new CÀ C, CÀ N, and CÀ S
bonds in one step, but also provides a new strategy
for the construction of trisubstituted imidazoles
based on the isocyanide-isocyanide [3+2] cyclo-
addition.
Keywords: Copper-catalyzed; Aryl isocyanides; Ac-
tive methylene isocyanides; Arylsulfonothioates; Sul-
fur-containing trisubstituted imidazoles
Imidazoles are one of the important classes of ing arylsulfonothioates have been well studied in our
heterocyclic compounds which can be found in
numerous pharmaceutical molecules.[1] For example,
Losartan[2] and Econazole[3] frameworks are imida-
zoles, which have anticancer and antiallergic activities,
respectively. Imidazoles have been also served as
ligands in transition-metal-catalyzed reactions.[4] In
addition, imidzaoles can catalyze organic reactions by
themselves.[5] During the past decade, different meth-
ods have been developed to the synthesis of
imidazoles.[6] In these methods, the [3+2] cyclo-
addition of active methylene isocyanides and “C=N” is
a highly atomic economic method.[7,8] The “C=N”
bond of imines,[7a] carbodiimides,[7b] isothiocynates,[7c,d]
benzothiazoles,[7e] ketenimines,[7f] and isocyanides[8]
have been succesfully appied to [3+2] cycloaddition
to construct imidazoles (Scheme 1, a). While, there are
Scheme 1. Isocyanides-“C=N” [3+2] cycloaddition to imida-
zoles.
only five methodologies based on the concept of two
components of isocyanide-isocyanide [3+2] cyclo-
Adv. Synth. Catal. 2019, 361, 1–6
1
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
group.[14] In addition, our group has focused on the instead of Cu2O, the reaction proceed smoothly to give
reactions of isocyanides for the decade.[15] As our 4a in 64% yield (Table 1, entry 2). Other copper
ongoing interest in the reaction of isocyanides, we catalysts including Cu, CuI, CuO as well as nickel
introduce arylsulfonothioates to the isocyanide- catalyst NiO and iron catalyst Fe(acac)3 were also
isocyanide [3+2] cycloaddition system. Herein, we investigated under similar reaction conditions (Table 1,
describe a reaction of aryl isocyanides with active entries 3–7). However, all these catalysts were not
methylene isocyanides and arylsulfonothioates to con- effective. Screening different amounts of the Cu2O
struct sulfur-containing trisubstituted imidazoles revealed that 15 mol% of Cu2O was the ideal amount
(Scheme 1, c). This reaction provides a novel strategy (Table 1, entries 8–9). Other solvents such as THF,
for the construction of trisubstituted imidazoles elicited a similar reactivity, while DCE, Toluene,
through new CÀ C, CÀ N, and CÀ S bonds formation.
DMSO or DMF could not improve the yield of the
At the beginning, we tried the reaction of 1- target product (Table 1, entries 10–14). Notably, in-
isocyano-4-nitrobenzene 1a, methyl 2-isocyanoacetate creasing the concentration of the reaction revealed that
2a and S-phenyl benzenesulfonothioate 3a in the 1 mL of CH3CN was the ideal amount (Table 1,
presence of 10 mol% of Cu2O in CH3CN to optimize entry 15). Screening the temperature of this reaction
°
the reaction (Table 1, entry 1). To our delight, the revealed that 80 C was the optimal reaction temper-
desired product methyl 1-(4-nitrophenyl)-5-(phenyl- ature (Table 1, entries 16–17). We try to employ S-
thio)-1H-imidazole-4-carboxylate (4a) was formed in phenyl methanesulfonothioate to improve atomic uti-
74% yield after 4 h. The structure of 4a was confirmed lization, but 4a was obtained in 73% yield (Table 1,
by NMR, HRMS and X-ray analysis (see the Support- entry 18). Therefore, the optimized reaction conditions
ing Information). When CuTC applied to the reaction included 1-isocyano-4-nitrobenzene 1a (0.2 mmol),
methyl 2-isocyanoacetate 2a (0.3 mmol) and S-phenyl
benzenesulfonothioate 3a (0.3 mmol) in the presence
Table 1. Optimization of the reaction conditions.[a]
°
of 15 mol% of Cu2O in 1.0 mL CH3CN at 80 C.
With the optimized conditions established, we first
investigated the substrate scope of isocyanides 1 and 2
(Table 2). The reaction of 1-isocyano-4-methylbenzene
1b with methyl 2-isocyanoacetate 2a and S-phenyl
benzenesulfonothioate 3a failed to give the desired
product 4b under the optimized conditions. The
reactions of the halogen group (Br, I) substituted ary
isocyanides with 2a and 3a could furnish the corre-
Entry Catalyst (mol%) Solvent (mL) T ( C) Yield[b] (%)
°
1
Cu2O (10)
CuTC (10)
Cu (10)
CH3CN (2)
CH3CN (2)
CH3CN (2)
CH3CN (2)
CH3CN (2)
CH3CN (2)
CH3CN (2)
CH3CN (2)
CH3CN (2)
THF (2)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
74
64
2
3
trace
ND
ND
ND
ND
78
73
77
45
70
59
75
81
71
78
73
4
CuI (10)
Table 2. Substrate scope of isocyanides.[a,b]
5
6
CuO (10)
NiO (10)
7
8
9
Fe(acac)3 (10)
Cu2O (15)
Cu2O (20)
Cu2O (15)
Cu2O (15)
Cu2O (15)
Cu2O (15)
Cu2O (15)
Cu2O (15)
Cu2O (15)
Cu2O (15)
10[c]
11[d]
12
13[e]
14[f]
15
16
17
DCE (2)
Toluene (2)
DMSO (2)
DMF (2)
CH3CN (1)
CH3CN (1)
CH3CN (1)
CH3CN (1)
18[g] Cu2O (15)
[a] Reaction conditions: 1 a (0.2 mmol, 1.0 equiv.), 2 a
(0.3 mmol, 1.5 equiv.), 3a (0.3 mmol, 1.5 equiv.), catalyst,
solvent, argon atmosphere, temperature, 4 h.
[b] Isolated yield.
[c] THF=Tetrahydrofuran.
[d] DCE=1,2-Dichloroethane.
[e] DMSO=Dimethyl sulfoxide.
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), 3a
[f] DMF=N,N-Dimethylformamide.
[g] S-phenyl methanesulfonothioate instead of S-phenyl benze-
nesulfonothioate.
(0.3 mmol), Cu2O (15 mol%.), CH3CN (1 mL), 80 C, 4 h,
°
argon atmosphere.
[b] Isolated yield.
Adv. Synth. Catal. 2019, 361, 1–6
2
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
sponding products 4c and 4h in 20% and 25% yield,
respectively. The results indicated that the electron-
withdrawing group on the aryl ring has significant
effect on the cross-cycloaddition reaction. Then, a
series of electron-withdrawing groups (CN, CF3,
COMe, CO2Et) substituted aryl isocyanides have been
subjected to the reactions with 2a and 3a. It should be
noted that the desired products 4d, 4e, 4f, 4g were
obtained in 54%-75% yield. When the nitro group
shifted to the ortho or meta position of the aryl ring,
the reaction proceeded smoothly to give the desired
product 4i and 4j in 80% and 62% yields, respectively.
Scheme 2. Scale-up synthesis and transformations of 4a.
The reaction of the multifunctionalized 3-isocyano- tion tolerated electron-donating (Me, OMe) or elec-
[1,1’-biphenyl]-2-carbonitrile 1k with 2a and 3a led to tron-withdrawing (Cl, Br, F, NO2) substituents on the
the desired product 4k in 72% yield. It is worth aryl ring, giving the desired products 4p, 4q, 4r, 4t,
mentioning that there are two halogen groups (I and 4u, 4v and 4w in 59% to 83% yields. To our delight,
Cl) of the aryl isocyanide as the substrate the the amino group, which has active hydrogen atom, at
corresponding product 4l was obtained in moderate the para-position of the aryl ring could reacted
yield. Unfortunately, the reaction of tert-butyl smoothly. It should be noted that S-(thiophen-2-yl)
isocyanide with 2a and 3a failed to give the benzenesulfonothioate 3j reacted with 1a and 2a
corresponding product. We also explored the scope of under the standard reaction conditions to give 4x in
active methylene isocyanides. The imidazole product 82% yield. Next, we turned our attention to the S-alkyl
could be obtained in good yield when using ethyl 2- benzenesulfonothioate. When S-propyl benzenesulfo-
isocyanoacetate 2b as the substrate. Additionally, other nothioate was employed in the reaction with 1a and
active
methylene
isocyanides
such
as
1- 2a under the optimized conditions, we couldn’t
((isocyanomethyl)sulfonyl)-4-methylbenzene 2c and isolated the pure desired product. Unfortunately, the
2-isocyano-1-morpholinoethan-1-one 2d were em- reaction of Se-phenyl benzenesulfonoselenoate with 1a
ployed in the reaction, the desired products 4n and 4o and 2a failed to give the selenium functionalized
were performed in 19% and 32% yields, respectively.
imidazole due to the different reactivity of Se-phenyl
To further evaluate the scope of this method, benzenesulfonoselenoate.
differently substituted arylsulfonothioates were exam-
To demonstrate the synthetic potential of our
ined, and most of the tested substrates smoothly method, we tried to amplify the model reaction of 1a,
underwent to afford the corresponding products under 2a and 3a under the standard reaction conditions in
the optimal conditions (Table 3). Explicitly, the reac- 4 mmol scale. Fortunately, 4a could be observed in
73% yield (Scheme 2). In addition, the oxidation
reaction of 4a with 3-Chloroperoxybenzoic acid (m-
CPBA) proceeded smoothly to afford methyl 1-(4-
Table 3. Substrate scope of S-aryl arylsulfonothioate.[a,b]
nitrophenyl)-5-(phenylsulfonyl)-1H-imidazole-4-car-
boxylate 5 in 74% yield (Scheme 2).
In order to understand the reaction mechanism, a
series of controlled experiments have been conducted
(Scheme 3). It was found that no reaction occurred
between 1a and 3a under the standard reaction
conditions (Scheme 3, a). A similar result was
observed when 2a was applied to the reaction with 3a
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3
°
(0.3 mmol), Cu2O (15 mol%.), CH3CN (1 mL), 80 C, 4 h,
argon atmosphere.
[b] Isolated yield.
Scheme 3. Control experiments.
Adv. Synth. Catal. 2019, 361, 1–6
3
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
temperature. The system was evaporated under the reduced
pressure directly. The residue was purified by flash column
chromatography with ethyl acetate and petroleum ether as
eluents to afford pure product 4a.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21971174, 21672157, 21542015 and
21772137), PAPD, the Projiec of Scientific and Technologic
Infrastructure of Suzhou (SZS201708), the Major Basic
Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 16KJA150002),
Soochow University, and State and Local Joint Engineering
Laboratory for Novel Functional Polymeric Materials for
financial support. We thank Nan Jiang in this group for
reproducing the result of 4d, 4i, 4k and 4x.
Scheme 4. Proposed reaction mechanism.
(Scheme 3, b). After that, we prepared ethyl 1-(4-
nitrophenyl)-1H-imidazole-4-carboxylate 6 according
to the literature reported by Yamamoto’s group.[8b]
However, the reaction of 6 with 3a failed to afford the
target product 4k under the standard conditions
(Scheme 3, c). This result indicates that the 1,4-
disubtituted imidazole is not the intermediate of this
reaction.
Based on the above experiment results and related
literatures,[8b,10a,12a] we proposed a plausible reaction
mechanism for this Cu(I)-catalyzed reaction
(Scheme 4). First, the intermediate A or its tautomer A’
is generated by the reaction of methyl 2-isocyanoace-
tate 2a and Cu2O. Then, the nucleophilic addition of A
or A’ to 1-isocyano-4-nitrobenzene 1a gives intermedi-
ate B. Subsequently, this intermediate B produces the
copper intermediate C through intramolecular addition.
Finally, S-phenyl benzenesulfonothioate 3a reacts with
intermediate C to furnish the product 4a and releases
the Cu species to complete the catalytic cycle.
In summary, we have developed a method to
construct sulfur-containing trisubstituted imidazoles by
the reaction of aryl isocyanides, active methylene
isocyanides and arylsulfonothioates in the presence of
Cu2O. This reaction not only forms CÀ C, CÀ N, and
CÀ S bonds in one step, but also provides a novel
strategy for the construction of trisubstituted imida-
zoles based on the isocyanide-isocyanide [3+2] cyclo-
addition.
References
[1] L. Zhang, X.-M. Peng, G. L. V. Damu, R.-X. Geng, C.-
H. Zhou, Med. Res. Rev. 2014, 34, 340.
[2] J. P. Habashi, D. P. Judge, T. M. Holm, R. D. Cohn, B. L.
Loeys, T. K. Cooper, L. Myers, E. C. Klein, G. Liu, C.
Calvi, M. Podowski, E. R. Neptune, M. K. Halushka, D.
Bedja, K. Gabrielson, D. B. Rifkin, L. Carta, F. Ramirez,
D. L. Huso, H. C. Dietz, Science 2006, 312, 117.
[3] L. Leclercq, V. Nardello-Rataj, Eur. J. Pharm. Sci. 2016,
82, 126.
[4] D. Janssen-Müller, C. Schlepphorst, F. Glorius, Chem.
Soc. Rev. 2017, 46, 4845.
[5] D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T.
Rovis, Chem. Rev. 2015, 115, 9307.
[6] A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Ge-
vorgyan, Chem. Rev. 2013, 113, 3084.
[7] a) X. Zhang, X. Wang, Y. Gao, X. Xu, Chem. Commun.
2017, 53, 2427; b) G. Sapuppo, Q. Wang, D. Swinnen, J.
Zhu, Org. Chem. Front. 2014, 1, 240; c) W. Hao, J.
Zeng, M. Cai, Chem. Commun. 2014, 50, 11686; d) K.
Yan, D. Yang, W. Wei, P. Sun, Y. Lu, H. Wang, Org.
Chem. Front. 2016, 3, 556; e) J. Wang, J. Li, Q. Zhu,
Org. Lett. 2015, 17, 5336; f) J. Cai, H. Bai, Y. Wang, X.
Xu, H. Xie, J. Liu, Chem. Commun. 2019, 55, 3821.
[8] a) R. Grigg, M. I. Lansdell, M. Thornton-Pett, Tetrahe-
dron 1999, 55, 2025; b) C. Kanazawa, S. Kamijo, Y.
Yamamoto, J. Am. Chem. Soc. 2006, 128, 10662; c) B.
Pooi, J. Lee, K. Choi, H. Hirao, S. H. Hong, J. Org.
Chem. 2014, 79, 9231; d) H. Wang, R. K. Kumar, Y. Yu,
L. Zhang, Z. Liu, P. Liao, X. Bi, Chem. Asian J. 2016,
11, 2841; e) Z. Hu, J. Dong, Y. Men, Z. Lin, J. Cai, X.
Xu, Angew. Chem. 2017, 129, 1831; Angew. Chem. Int.
Ed. 2017, 56, 1085.
Experimental Section
General procedure for the synthesis of methyl 1-(4-nitro-
phenyl)-5-(phenylthio)-1H-imidazole-4-carboxylate (4a): In
a 25 mL Schlenk tube, to a mixture of 1-isocyano-4-nitro-
benzene (1a, 0.2 mmol, 1 equiv.), methyl 2-isocyanoacetate
(2a, 0.3 mmol, 1.5 equiv.), S-phenyl benzenesulfonothioate (3a,
0.3 mmol, 1.5 equiv.), Cu2O (0.03 mmol, 15 mol%), were added
[9] I. P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011, 111,
1596.
[10] a) W. Wang, X. Peng, F. Wei, C.-H. Tung, Z. Xu, Angew.
Chem. 2016, 128, 659; Angew. Chem. Int. Ed. 2016, 55,
649; b) X. Peng, C. Ma, C.-H. Tung, Z. Xu, Org. Lett.
°
in 1 mL CH3CN. The reaction mixture was stirred at 80 C
under argon atmosphere. After 4 h, the system cooled to room
Adv. Synth. Catal. 2019, 361, 1–6
4
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
2016, 18, 4154; c) H. Li, C. Shan, C.-H. Tung, Z. Xu, [13] a) K. Kanemoto, S. Yoshida, T. Hosoya, Org. Lett. 2019,
Chem. Sci. 2017, 8, 2610; d) S. Huang, H. Li, T. Xie, F.
Wei, C.-H. Tung, Z. Xu, Org. Chem. Front. 2019, 6,
1663.
21, 3172; b) R. J. Reddy, A. H. Kumari, J. J. Kumar,
J. B. Nanubolu, Adv. Synth. Catal. 2019, 361, 1587.
[14] Y. Fang, T. Rogge, L. Ackermann, S.-Y. Wang, S.-J. Ji,
Nat. Commun. 2018, 9, 2240.
[11] a) W. Kong, H. An, Q. Song, Chem. Commun. 2017, 53,
8968; b) W. Kong, C. Yu, H. An, Q. Song, Org. Lett. [15] a) T.-H. Zhu, S.-Y. Wang, T.-Q. Wei, S.-J. Ji, Adv. Synth.
2018, 20, 4975; c) C. Rao, S. Mai, Q. Song, Chem.
Commun. 2018, 54, 5964.
Catal. 2015, 357, 823; b) P. Xu, T.-H. Zhu, T.-Q. Wei,
S.-Y. Wang, S.-J. Ji, RSC Adv. 2016, 6, 32467; c) P. Xu,
F. Wang, T.-Q. Wei, L. Yin, S.-Y. Wang, S.-J. Ji, Org.
Lett. 2017, 19, 4484; d) P. Xu, Y.-M. Zhu, F. Wang, S.-Y.
Wang, S.-J. Ji, Org. Lett. 2019, 21, 683.
[12] a) P. Mampuys, Y. Zhu, T. Vlaar, E. Ruijter, R. V. A.
Orru, B. U. W. Maes, Angew. Chem. 2014, 126, 13063;
Angew. Chem. Int. Ed. 2014, 53, 12849; b) P. Mampuys,
Y. Zhu, S. Sergeyev, E. Ruijter, R. V. A. Orru, S. V.
Doorslaer, B. U. W. Maes, Org. Lett. 2016, 18, 2808.
Adv. Synth. Catal. 2019, 361, 1–6
5
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
Copper-Catalyzed Reaction of Aryl Isocyanides with Active
Methylene Isocyanides and Arylsulfonothioates: Synthesis of
Sulfur-Containing Trisubstituted Imidazoles
Adv. Synth. Catal. 2019, 361, 1–6
P. Xu, Y.-M. Zhu, X.-J. Li, F. Wang, S.-Y. Wang*, S.-J. Ji*