Silver-Catalyzed [3+2] Cycloaddition of Azomethine Ylides with Isocyanides for Imidazole Synthesis

Article abstract of DOI:10.1002/adsc.201700447

A silver-catalyzed aerobic oxidative [3+2] cycloaddition of azomethine ylides with aryl or heteroaryl isocyanides has been developed. The reaction represents a novel protocol for the efficient and practical synthesis of 1,2-diarylimidazoles bearing a broad range of substituents in good to excellent yields under mild conditions. The practicability of this cycloaddition was shown by a gram-scale synthesis and a double cycloaddition for the construction of highly conjugated polyarylimidazole systems. (Figure presented.).

Full text of DOI:10.1002/adsc.201700447

Title: Silver-Catalyzed [3+2] Cycloaddition of Azomethine Ylides with
Isocyanides for Imidazole Synthesis
Authors: Zhongyan Hu, Jinhuan Dong, and Xianxiu Xu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700447
Link to VoR: http://dx.doi.org/10.1002/adsc.201700447

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Silver-Catalyzed [3+2] Cycloaddition of Azomethine Ylides with
Isocyanides for Imidazole Synthesis
Zhongyan Hu,a,b Jinhuan Dongb and Xianxiu Xu a,b,*
a
Jilin Province Key Laboratory of Organic Functional Molecular Design and Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China
xuxx677@sdnu.edu.cn
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized
b
Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of
Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A silver-catalyzed aerobic oxidative [3+2] this cycloaddition was shown by a gram-scale synthesis and
cycloaddition of azomethine ylides with aryl or heteroaryl a double cycloaddition for the construction of highly
isocyanides was developed. The reaction represents a novel conjugated polyarylimidazole systems.
protocol for the efficient and practical synthesis of 1,2-diaryl
imidazoles bearing a broad range of substituents in good to
excellent yields under mild conditions. The practicability of
Keywords: azomethine ylides; [3+2] cycloaddition;
imidazoles; isocyanides; silver catalysis
azomethine ylides are versatile nitrogen-based 1,3-
dipoles employed in dipolar cycloadditions.[10,11] In
particular, the reaction of azomethine ylides with
alkenes provides a powerful method for both racemic
and asymmetric syntheses of pyrrolidines with up to
four contiguous stereocenters (Scheme 1, eq 1).[11,12]
Electron-deficient alkenes[11,12] and alkynes[11,13] are
the most widely used dipolarophiles in such
cycloadditions. However, only a few examples
involving heteroatom-containing dipolarophiles such
as imines[14] and aldehydes[15] have been reported
(Scheme 1, eq 2). In 2012, Hashmi and co-workers
reported the use of Au(I) isocyanide complexes as
dipolarophiles in [3+2] cycloaddition with
azomethine ylides for the synthesis of saturated
NHC–Au(I) complexes (Scheme 1, eq 3).[16] In
addition, a [3+1] cycloaddition of azomethine ylides
with isocyanides was developed by Foucaud and co-
workers,[17] and a Lewis acid-catalyzed [3+1+1]
cycloaddition involving azomethine ylides and
aliphatic isocyanides was reported by Soeta, Ukaji
and co-workers.[18] Although the syntheses of
Introduction
Imidazoles make up an important class of five-
membered azaheterocycles with significant biological
activities.[1] Among
their
derivatives,
1,2-
diarylimidazoles show a broad range of biological
activities. Some of these compounds have been used
as antagonists of the cannabinoid CB1 receptor,[2]
selective inhibitors of COX-2,[3] clozapine-like mixed
activities at dopamine D2, serotonin and GABAA
receptors.[4,5] Considerable attention has therefore
been focused on the synthesis of these privileged
scaffolds.[2-8]
alkylation/cyclization/dehydration
Generally,
sequential
reactions of
diarylamidines and 2-halomethylketones (or analogs)
are used for the synthesis of 1,2-diarylimidazoles.[2-
4,6c-f] The annulation of N-chloro-N'-arylbenzamidines
and electron-rich alkenes provides an alternative
method for synthesizing these frameworks.[7]
Recently, N-arylation of 2-aryl imidazoles[6a,b,8] and
C2-arylation of N-aryl imidazoles[6a,b,9] have been
used to prepare these compounds. However, most of
these methods suffer from drawbacks such as lack of
readily available precursors, low overall yields or
regioselectivity issues. The development of efficient,
regiospecific, and general methods for the synthesis
of 1,2-diarylimidazoles from readily available
starting materials is therefore still needed.
imidazolidines[14]
and
saturated
NHC–Au(I)
complexes[16] via cycloaddition of azomethine ylides
have been documented (Scheme 1, eq 2 and 3), the
catalytic synthesis of imidazoles from the
cycloaddition of azomethine ylides and isocyanides
has not been reported.[19] During the course of our
studies of isocyanide-based annulations[20] and
inspired by Hashmi’s work,[16] we developed a one-
step silver-catalyzed aerobic oxidative 1,3-dipolar
cycloaddition of azomethine ylides with isocyanides
1,3-Dipolar cycloadditions are fundamental
organic reactions for the construction of five-
membered heterocycles.[10] In this context,
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
for the efficient and practical synthesis of 1,2-
diarylimidazoles (Scheme 1, eq 3). Cyclizations of
isocyanides with activated methylene isocyanides[21]
or propargylamines[22] have recently been reported for
1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene),
AuCl(PPh3) and Au2O3 were also screened (Table 1,
entries 15−17); imidazole 3aa was not detected, and
hydrolysis of both isocyanide 2a and imino ester 1a
the synthesis of 2-unsubstituted imidazoles. This [3+2] was observed.
cycloaddition not only represents a novel, simple, and
Table 1. Optimization of Reaction Conditions[a].
general approach for the synthesis of imidazoles with
a wide range of substituents at the 2-position, but also
considerably expands the scope of azomethine ylide-
based 1,3-dipolar cycloadditions.
En. Cat.
Sol.
Temp. Time Yield
(oC)
(h)
(%)[b]
34
1
Ag2CO3
1,4-dioxane 25
1,4-dioxane 40
1,4-dioxane 60
1,4-dioxane 40
26
2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
AgNO3
AgF
8
85
3
12
18
6
38
78[c]
4
5
THF
40
40
40
40
70
6
CH3CN
DCE
6
73
7
3
61
8
toluene
7
60
9
1,4-dioxane 40
1,4-dioxane 40
1,4-dioxane 40
1,4-dioxane 40
1,4-dioxane 40
1,4-dioxane 40
1,4-dioxane 40
13
5
74
10
11
12
13
14
15
16
8
24
24
60
48
12
12
12
48
Ag2O
13[d]
24[e]
ND[f]
ND[g]
ND[h]
ND[i]
Cu2O
CuCl
Scheme 1. Cycloadditions of azomethine ylides.
[IPrAu]Cl
AuCl(PPh3) 1,4-dioxane 40
Au2O3 1,4-dioxane 40
Results and Discussion
17
[a]
Reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol),
Initially, the reaction of imino ester 1a with 4-
benzoyl phenyl isocyanide 2a was used as a model
reaction to optimize the reaction conditions (Table 1).
Under catalysis with Ag2CO3 (30 mol%), the reaction
of 1a (0.36 mmol) and 2a (0.3 mmol) gave imidazole
3aa in 34% yield after stirring for 26 h at room
temperature in 1,4-dioxane (Table 1, entry 1). When
the reaction temperature was elevated to 40 °C, the
yield of 3aa increased to 85% (Table 1, entry 2).
However, when the temperature was further elevated
to 60 °C, silver mirror was observed and 3aa was
obtained in 38% yield even when the reaction time
was prolonged to 12 h (Table 1, entry 3). This result
is consistent with Bi’s finding that one equivalent of
Ag2CO3 was needed when the reaction was
performed at higher temperatures.[19] Decreasing the
amount of Ag2CO3 to 20 mol% led to a lower yield
(Table 1, entry 4). Selected solvents, i.e., THF,
acetonitrile, 1,2-dichloroethane and toluene were
examined, but all gave 3aa in lower yields (Table 1,
entries 5−8). AgOAc (Table 1, entry 9), AgNO3
(Table 1, entry 10), AgF (Table 1, entry 11), Ag2O
(Table 1, entry 12), Cu2O (Table 1, entry 13) and
CuCl (Table 1, entry 14), were less effective catalysts
than Ag2CO3. Gold catalysts such as [IPrAu]Cl (IPr =
Ag2CO3 (0.09 mmol), solvent (2 mL), air atmosphere.
[b] Yield of isolated product.
[c] Ag2CO3 (20 mol%) was used.
[d] 1a was recovered in 78% yield.
[e] 4aa was obtained in 45% yield.
[f]
ND = not detected.
[IPrAu]Cl (5 mol%) was used, IPr = 1,3-bis(2,6-
diisopropylphenyl) imidazol-2-ylidene.
[h] AuCl(PPh3) (5 mol%) was used.
[i] Au2O3 (5 mol%) was used.
[g]
With the optimal conditions in hand (Table 1, entry
2), the scope of viable imino ester substrates 1 was
examined; the results are summarized in Scheme 2. A
wide range of substrates 1 were tolerated in this
reaction, and a series of 2-substituted imidazoles
(3ba–ta) were produced in good to high yields from
the reactions of isocyanide 2a with a wide range of
imino esters 1 bearing various R1 groups, e.g., para-
(1b−e),[23] ortho- (1f), and meta- (1g) substituted
aryls, di- (1h and 1i) and tri- (1j) substituted phenyls,
2-naphthyl (1k), heteroaryl groups (1l, 1m and 1n),
2-ferrocenyl (1o), and alkyl groups (1p and 1q).
Alkoxycarbonyl-substituted substrates (1a−r) and the
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
cyano-substituted imine 1s were also tolerated in this
[3+2] cycloaddition, but the yield of 3sa was low.
Reactions of CF3-substituted imine 1t with
isocyanide 2a did not give the corresponding
trifluoromethylated imidazole 3ta. This is probably
because it is more difficult to form the corresponding
azomethine ylide from cyano-substituted imine 1s
and CF3-substituted imine 1t than from ester-
substituted imines under these conditions.
imidazoles 3aq and 3ar in high yields. Heteroaryl
isocyanides 2s–v also afforded the corresponding
imidazoles 3as–av in moderate yields. When tert-
butyl isocyanide and cyclohexyl isocyanide were
used in this [3+2] cycloaddition, the desired
imidazole products were not detected.
Scheme 3. Scope of isocyanides 2.
Control experiments were performed to clarify the
reaction mechanism. The reaction of imino ester 1a
with isocyanide 2a in a nitrogen atmosphere for 2 h at
40 °C gave intermediate 4aa in 82% yield (Scheme 4,
eq 1); 4aa was converted to imidazole 3aa in 92%
yield under the standard conditions (Scheme 4, eq 2).
These results show that 4aa is probably the reactive
intermediate in this [3+2] cycloaddition reaction.
Furthermore, when 2.0 equivalents of 2,2,6,6-
tetramethyl-1-piperidinyloxy or 2,6-di-tert-butyl-4-
methylphenol were added to the standard reaction,
3aa was obtained in 55% and 65% yields,
respectively (Scheme 4, eq 3), indicating that this
transformation probably does not proceed via a
radical pathway.
A possible mechanistic pathway based on the
present and previously reported results[21,22] is shown
in Scheme 5. Initially, the azomethine ylide dipole A
is formed by coordination to silver and
deprotonation.[24] Intermediate A attacks silver-
activated isocyanides B, giving the imidoyl-silver
intermediate C.[22,25] Protonation of C generates
dipole D, which resonates with structure E. Two
pathways are then possible. In pathway a,
intramolecular nucleophilic addition occurs to give
dihydroimidazole-silver complex F, and protonolysis
by AgHCO3 regenerates the catalyst Ag2CO3 and
delivers dihydroimidazole G,[26] which produces the
final imidazole 3 by aerobic oxidative aromatization.
Scheme 2. Scope of imino esters 1.
The scope of the reaction was then evaluated with
respect to isocyanides 2 (Scheme 3). The reaction
tolerated a wide range of aryl and heteroaryl
isocyanides 2. Aryl isocyanides 2 with electron-
withdrawing, -donating and -neutral groups at the
para position gave 2-substituted imidazoles 3ab–af
in good to high yields. Aryl isocyanides 2 bearing
substituents at the meta position, such as PhCO (2g),
CO2Et (2h) and Br (2i) afforded the corresponding
imidazoles 3ag–ai in good yields. The ortho-
substituted 2-benzoyl- (2j), 2-chloro- (2k), and 2-
methoxy- (2l) aryl isocyanides gave the 2-substituted
imidazoles 3aj–al in moderate yields. In the
cycloaddition of 1a with 2j, as well as the imidazole
product 3aj, the intermediate (Z)-ethyl 3-[(2-
benzoylphenyl)amino]-2-[(E)-benzylideneamino]-
acrylate 4aj was isolated in 35% yield. The structure
of 4aj was determined using X-ray diffraction.[23] The
disubstituted aryl isocyanides 2m and 2n and
trisubstituted aryl isocyanides 2o and 2p produced the
corresponding 2-substituted imidazoles 3am–ap in
good to high yields. In addition, the reactions of -
and -naphthyl isocyanides 2q and 2r gave
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
Alternatively, intermediate E can be reversibly
protonated by AgHCO3 to afford the diamino acrylate
intermediate 4 (pathway b).
double cycloadditions of imino esters 1 with
biisocyanides 2x and 2y were performed to construct
polyarylbiimidazoles 6, which have extended
conjugated
systems
(Scheme
6,
bottom).
Biimidazoles 6ax, 6bx, 6ex and 6ay were obtained in
moderate yields under the optimal conditions.
Scheme 6. Gram-scale synthesis and double cycloaddition.
Conclusion
Scheme 4. Control experiments.
In summary, a silver-catalyzed [3+2] cycloaddition of
azomethine ylides with aryl or heteroaryl isocyanides
was developed. This new reaction provides a general
and efficient strategy for the synthesis of 1,2-diaryl
imidazoles in a single operation from readily
available starting materials. Unusual reactivity
profiles of isocyanides, which acted as dipolarophiles,
were observed. The practicability of this
cycloaddition was shown by a gram-scale synthesis
and double cycloaddition for the construction of
highly conjugated polyarylimidazole systems.
Investigation of [3+2] cycloaddition of other 1,3-
dipoles with isocyanides is ongoing.
Experimental Section
Typical Procedure for Synthesis of Imidazole 3aa
Ag2CO3 (24.7 mg, 0.09 mmol) was added to a solution of
(E)-ethyl 2-(benzylideneamino)acetate (1a) (68.7 mg, 0.36
mmol) and (4-isocyanophenyl)(phenyl)methanone (2a)
(62.1 mg, 0.3 mmol) in 1,4-dioxane (2.0 mL) in a sealed
tube. The mixture was heated at 40 °C under stirring. TLC
indicated that substrate 2a was consumed in 8 h. The
resulting mixture was concentrated in vacuo. Purification
of the crude product using flash column chromatography
(silica gel; petroleum ether:ethyl acetate = 8:1(v/v)) gave
3aa (101 mg, 85% yield) as a white solid. m. p.
145−146 °C; 1H NMR (600 MHz, CDCl3) δ 1.40 (t, J = 7.2
Hz, 3H), 4.42 (q, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 2H),
7.31−7.34 (m, 3H), 7.41 (d, J = 7.2 Hz, 2H), 7.49 (t, J =
7.8 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 7.2 Hz,
2H), 7.83 (d, J = 7.2 Hz, 2H), 7.89 (s, 1H); 13C NMR
(CDCl3, 151 MHz) δ 14.4, 60.7, 125.3, 127.8, 128.3, 128.4,
Scheme 5. Proposed mechanism.
To evaluate the practicability of the present [3+2]
cycloaddition, a gram-scale synthesis of ethyl 2-(4-
bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-
imidazole carboxylate 3cw was performed (Scheme 6,
top). Imidazole 3cw has an enhanced ability to
potentiate -aminobutyric acid (GABA)-evoked
currents in Xenopus laevis oocytes expressing
recombinant human GABAA receptors with potency
(EC50 = 0.19 μM) and efficacy (388%).[5] In addition,
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
128.9, 129.1, 129.3, 129.8, 131.3, 132.8, 134.0, 136.7,
Tamura, K. Miyamoto, R. W. Stevens, J. Med. Chem.
2004, 47, 720; e) J. H. M. Lange, H. H. Van
Stuivenberg, H. K. A. C. Coolen, T. J. P. Adolfs, A. C.
McCreary, H. G. Keizer, H. C. Wals, W. Veerman, A. J.
M. Borst, W. de Loof, P. C. Verveer, C. G. Kruse, J.
Med. Chem. 2005, 48, 1823; f) Y. Li, Y. Fu, C. Ren, D.
Tang, P. Wu, X. Meng, B. Chen, Org. Chem. Front.
2015, 2, 1632; g) S, C. Shilcrat, M. K. Mokhallalati, J.
M. D. Fortunak, L. N. Pridgen, J. Org. Chem. 1997, 62,
8449; h) K. H. Bleicher, F. Gerber, Y. Wüthrich, A.
Alanine, A. Capretta, Tetrahedron Lett. 2002, 43, 7687;
i) S.-H. Lee, K. Yoshida, H. Matsushita, B. Clapham, G.
Koch, J. Zimmermann, K. D. Janda, J. Org. Chem.
2004, 69, 8829; j) B. Hu, Z. Wang, N. Ai, J. Zheng, X.-
H. Liu, S. Shan, Z. Wang, Org. Lett. 2011, 13, 6362; k)
Z. Zhang, S. Fang, Q. Liu, G Zhang, J. Org. Chem.
2012, 77, 7665.
137.5, 140.6, 147.7, 162.7, 195.0; HRMS (ESI-TOF) m/z
+
calculated for C25H21N2O3 ([M+H]+) 397.1547, found
397.1564.
Acknowledgements
Financial support provided by the NSFC (21672034), the Natural
Sciences Foundation of Jilin Province (20160101330JC) and
Shandong Normal University (108-100801) is gratefully
acknowledged. We thank Helen McPherson, PhD, from Liwen
Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing
the English text of a draft of this manuscript.
References
[1] a) N. X. Huang, L. Liu, In Comprehensive Heterocyclic
Chemistry III, Vol. 4 (Eds.: A. R. Katritzy, C. A.
Ramsden, E. F. V. Scriven, R. J. K. Taylor), Pergamon,
Oxford, 2008, pp. 143–364; b) M. R. Grimmett, In
Science of Synthesis (Ed. R. Neier), Georg Thieme
Verlag: Stuttgart, 2002, Vol. 12, pp 325−528; c) G.
Parkin, Chem. Rev. 2004, 104, 699; d) G. C. Fortman, S.
P. Nolan, Chem. Soc. Rev. 2011, 40, 5151; e) J. P.
Hallett, T. Welton, Chem. Rev. 2011, 111, 3508; f) L. D.
Luca, Curr. Med. Chem. 2006, 13, 1.
[7] a) E. Rossi, E. Pini, Tetrahedron 1996, 52, 7939; b) L.
Citerio, D. Pocar, M. L. Saccarello, R. Stradi,
Tetrahedron 1979, 35, 2375; c) R. Stradi, G. Verga,
Synthesis 1977, 688.
[8] a) M. T. Wentzel, J. B. Hewgley, R. M. Kamble, P. D.
Wall, H. C. Kozlowski, Adv. Synth. Catal. 2009, 351,
931; b) B. Sezen, D. Sames, J. Am. Chem. Soc. 2003,
125, 10580.
[2] a) B. Dick, V. S. Goodfellow, T. Phillips, J. Grey, M.
Haddack, M. Rowbottom, G. S. Naeve, B. Brown, J.
Saunders, Bioorg. Med. Chem. Lett. 2004, 14, 1151; b)
J. H. M. Lange, H. H. van Stuivenberg, H. K. A. C.
Coolen, T. J. P. Adolfs, A. C. McCreary, H. G. Keizer,
H. C. Wals, W. Veerman, A. J. M. Borst, W. de Looff,
P. C. Verveer, C. G. Kruse, J. Med. Chem. 2005, 48,
1823.
[9] a) L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W.
McCroskey, S. M. Hannick, L. Gherke, R. B. Credo,
Y.-H. Hui, K. Marsh, R. Warner, J. Y. Lee, N.
Zielinsky-Mozng, D. Frost, S. H. Rosenberg, H. L.
Sham, J. Med. Chem. 2002, 45, 1697; b) F. Bellina, S.
Cauteruccio, L. Mannina, R. Rossi, S. Viel, Eur. J. Org.
Chem. 2006, 693; c) F. Bellina, S. Cauteruccio, R.
Rossi, Eur. J. Org. Chem. 2006, 1379; d) I.
Langhammer, T. Erker, Heterocycles 2005, 65, 2721; e)
F. Bellina, C. Calandri, S. Cauteruccio, R. Rossi,
Tetrahedron 2007, 63, 1970.
[3] a) I. K. Khanna, R. M. Weier, Y. Yu, X. D. Xu, F. J.
Koszyk, P. W. Collins, C. M. Koboldt, A. W.
Veenhuizen, W. E. Perkins, J. J. Casler, J. L. Masferrer,
Y. Y. Zhang, S. A. Gregory, K. Seibert, P. C. Isakson,
J. Med. Chem. 1997, 40, 1634; b) I. K. Khanna, Y. Yu,
R. M. Huff, R. M. Weier, X. Xu, F. J. Koszyk, P. W.
Collins, J. N. Cogburn, P. C. Isakson, C. M. Koboldt, J.
L. Masferrer, W. E. Perkins, K. Seibert, A. W.
Veenhuizen, J. Yuan, D.-C. Yang, Y. Y. Zhang, J. Med.
Chem. 2000, 43, 3168; c) X. de Leval, J. Delarge, F.
Somers, P. de Tullio, Y. Henrotin, B. Pirotte, J.-M.
Dogné, Curr. Med. Chem. 2000, 7, 1041.
[10] For reviews, see: a) M. S. Singh, S. Chowdhury, S.
Koley, Tetrahedron 2016, 72, 1603; b) H.-U. Reissig,
R. Zimmer, Angew. Chem. 2014, 126, 9864; Angew.
Chem. Int. Ed. 2014, 53, 9708; c) J. Adrio, J. C.
Carretero, Chem. Commun. 2014, 50, 12434; d) R.
Huisgen, Angew. Chem. 1963, 75, 604; Angew. Chem.
Int. Ed. 1963, 2, 565.
[11] For reviews, see: a) K. V. Gothelf, K. A. Jørgensen,
Chem. Rev. 1998, 98, 863; b) T. Hashimoto, K.
Maruoka, Chem. Rev. 2015, 115, 5366.
[4] B. Asproni, A. Pau, M. Bitti, M. Melosu, R. Cerri, L.
Dazzi, E. Seu, E. Maciocco, E. Sanna, F. Busonero, G.
Talani, L. Pusceddu, C. Altomare, G. Trapani, G.
Biggio, J. Med. Chem. 2002, 45, 4655.
[12] For a review, see: G. Pandey, P. Banerjee, S. R. Gadre,
Chem. Rev. 2006, 106, 4484.
[13] a) F. Shi, S.-W. Luo, Z.-L. Tao, L. He, J. Yu, S.-J. Tu,
L.-Z. Gong, Org. Lett. 2011, 13, 4680; b) F. Shi, G.-J.
Xing, W. Tan, R.-Y.Zhu, S. Tu, Org. Biomol. Chem.
2013, 11, 1482; c) Z. Wang, Y. Shi, X. Luo, D.-M. Han,
W.-P. Deng, New J. Chem. 2013, 37, 1742; d) F. Shi,
R.-Y. Zhu, X. Liang, S.-J. Tu, Adv. Syn. Catal. 2013,
355, 2447; e) F.-F. Tang, W.-L. Yang, X. Yu, W.-P.
Deng, Catal. Sci. Technol. 2015, 5, 3568.
[5] B. Asproni, G. Talani, F. Busonero, A. Pau, S. Sanna,
R. Cerri, M. P. Mascia, E. Sanna, G. Biggio, J. Med.
Chem. 2005, 48, 2638.
[6] For reviews, see: a) F. Bellina, R. Rossi, Adv. Synth.
Catal. 2010, 352, 1223; b) F. Bellina, S. Cauteruccio, R.
Rossi, Tetrahedron 2007, 63, 4571; for articles, see: c)
T. Mano, R. W. Stevens, K. Ando, K. Nakao, Y.
Okumura, M. Sakakibara, T. Okumura, T. Tamura, K.
Miyamoto, Bioorg. Med. Chem. 2003, 11, 3879; d) T.
Mano, Y. Okumura, M. Sakakibara, T. Okumura, T.
[14] a) S. P. Swain, Y.-C. Shih, S.-C. Tsay, J. Jacob, C.-C.
Lin, K. C. Hwang, J.-C. Horng, J. R. Hwu, Angew.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
Chem. 2015, 127, 10064; Angew. Chem. Int. Ed. 2015,
2017, 56, 1805; b) Z. Hu, H. Yuan, Y. Men, Q. Liu, J.
Zhang, X. Xu, Angew. Chem. 2016, 128, 7193; Angew.
Chem. Int. Ed. 2016, 55, 7077; c) X. Xu, L. Zhang, X.
Liu, L. Pan, Q. Liu, Angew. Chem. 2013, 125, 9441;
Angew. Chem. Int. Ed. 2013, 52, 9271; d) Y. Li, X. Xu,
J. Tan, C. Xia, D. Zhang, Q. Liu, J. Am. Chem. Soc.
2011, 133, 1775; e) J. Tan, X. Xu, L. Zhang, Y. Li, Q.
Liu, Angew. Chem. 2009, 121, 2912; Angew. Chem. Int.
Ed. 2009, 48, 2868.
54, 9926; b) Q.-H. Li, L. Wei, X. Chen, C.-J. Wang,
Chem. Commun. 2013, 49, 6277; c) H. Xie, J. Zhu, Z.
Chen, S. Li, Y. Wu, J. Org. Chem. 2010, 75, 7468; d)
W.-J. Liu, X.-H. Chen, L.-Z. Gong, Org. Lett. 2008, 10,
5357.
[15] a) S. Chen, V. Bacauanu, T. Knecht, B. Q. Mercado,
R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2016,
138, 12664; b) I. V. Voznyi, M. S. Novikov, A. F.
Khlebnikov, J. Kopf, R. R. Kostikov, Russ. J. Org.
Chem. 2004, 40, 199; c) M. S. Novikov, I. V. Voznyi,
A. F. Khlebnikov, J. Kopf, R. R. Kostikov, J. Chem.
Soc. Perkin Trans. 1 2002, 1628; d) A. Padwa, W. Dent,
J. Org. Chem. 1987, 52, 235; e) S. Kanemasa, K. Doi,
E. Wada, Bull. Chem. Soc. Jpn. 1990, 63, 2866.
[21] a) C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am.
Chem. Soc. 2006, 128, 10662; b) B. Pooi, J. Lee, K.
Choi, H. Hirao, S. H. Hong, J. Org. Chem. 2014, 79,
9231.
[22] S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew.
Chem. 2015, 127, 1309; Angew. Chem. Int. Ed. 2015,
54, 1293.
[16] a) A. S. K. Hashmi, D. Riedel, M. Rudolph, F.
Rominger, T. Oeser, Chem. -Eur. J. 2012, 18, 3827; b)
R. Manzano, T. Wurm, F. Rominger, A. S. K. Hashmi,
Chem. -Eur. J. 2014, 20, 6844; c) R. Manzano, F.
Rominger, A. S. K. Hashmi, Organometallics 2013, 32,
2199.
[23] CCDC 1527553 (3ca) and 1528640 (4aj) contain the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[17] J. Charrier, A. Foucaud, H. Person, E. Loukakou, J.
Org. Chem. 1983, 48, 481.
[24] W. Zeng, Y.-G. Zhou, Org. Lett. 2005, 7, 5055.
[25] a) P. Xiao, H. Yuan, J. Liu, Y. Zheng, X. Bi, J. Zhang,
ACS Catal. 2015, 5, 6177; b) X. Qi, H. Zhang, A. Shao,
L. Zhu, T. Xu, M. Gao, C. Liu, Y. Lan, ACS Catal.
2015, 5, 6640.
[18] T. Soeta, Y. Miyamoto, S. Fujinami, Y. Ukaji,
Tetrahedron 2014, 70, 6623.
[19] During our manuscript preparation, Bi and co-workers
reported a silver and DBU promoted azomethine-
isocyanide [3+2] cycloaddition; see: X. Huang, X.
Cong, P. Mi, X. Bi, Chem. Commun. 2017, 53, 3858.
[26] G is the proposed intermediate. When the reaction of
1a and 2a was performed under standard conditions
under the nitrogen atmosphere for 8 h, 3aa was
obtained in 35% yield along with 4aa in 60% yield, and
the intermediate G was not obtained.
[20] a) Z. Hu, J. Dong, Y. Men, Z. Lin, J. Cai X. Xu,
Angew. Chem. 2017, 129, 1831; Angew. Chem. Int. Ed.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700447
Advanced Synthesis & Catalysis
FULL PAPER
Silver-Catalyzed [3+2] Cycloaddition of
Azomethine Ylides with Isocyanides for Imidazole
Synthesis
Adv. Synth. Catal. Year, Volume, Page – Page
Zhongyan Hu, Jinhuan Dong and Xianxiu Xu*
7
This article is protected by copyright. All rights reserved.