Silver-Induced [3+2] Cycloaddition of Isocyanides with Acyl Chlorides: Regioselective Synthesis of 2,5-Disubstituted Oxazoles

Article abstract of DOI:10.1002/cctc.201900965

A silver-induced cycloaddition of isocyanides with acyl chlorides has been developed. This transition metal-catalyzed strategy provides an effective and scalable approach for the formation of 2,5-disubstituted oxazoles in good to high yields. The employed silver-based MOF catalyst can be efficiently recycled without compromising the yield.

Full text of DOI:10.1002/cctc.201900965

Accepted Article
Title: Silver-Induced [3+2] Cycloaddition of Isocyanides with Acyl
Chlorides: Regioselective Synthesis of 2,5-Disubstituted
Oxazoles
Authors: Jian-Quan Liu, Xuanyu Shen, Andrey Shatskiy, Enlong Zhou,
Markus Kärkäs, and Xiang-Shan Wang
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: ChemCatChem 10.1002/cctc.201900965
Link to VoR: http://dx.doi.org/10.1002/cctc.201900965
A Journal of
www.chemcatchem.org

10.1002/cctc.201900965
ChemCatChem
COMMUNICATION
Silver-Induced [3+2] Cycloaddition of Isocyanides with Acyl
Chlorides: Regioselective Synthesis of 2,5-Disubstituted
Oxazoles
Jian-Quan Liu,[a,b] Xuanyu Shen,[a] Andrey Shatskiy,[b] Enlong Zhou,[c]* Markus D. Kärkäs,[b]* Xiang-
Shan Wang[a]*
Abstract: A silver-mediated cycloaddition of isocyanides with acyl
chlorides has been developed. This transition metal-catalyzed
strategy provides an effective and scalable approach for the
formation of 2,5-disubstituted oxazoles in good to high yields. The
employed silver-based MOF catalyst can be efficiently recycled
without compromising the yield.
Isocyanides are versatile starting materials and have been
widely applied in the synthesis of nitrogen-containing motifs.[1,2]
Among the reported manifolds, the [3+2] dipolar cycloaddition
reactions constitute an appealing route for construction of N-
heterocyclic skeletons.[3] However, most of these protocols are
associated with poor regioselectivity (Figure 1a).[4] Thus, altering
the reaction conditions to selectively favor formation of one
regioisomer is an ongoing challenge in isocyanide chemistry.
The cycloaddition reaction of isocyanides with acyl chlorides
is well established and has been widely investigated to generate
4,5-disubstituted oxazoles (Figure 1b).[5,6] In 2009, El Kaïm and
coworkers reported the regioselective cycloaddition to furnish
2,5-disubstituted oxazoles. The reaction was presumed to
proceed via the corresponding imidoyl chloride,[7] which in the
presence of 2,6-lutidine could cyclize to give the corresponding
cycloaddition adduct (Figure 1c).[8] In terms of the scope, the
protocol is generally limited to benzyl isocyanides, and a
catalytic protocol remains elusive. Herein, we disclose
a
practical silver-mediated cycloaddition between a wide array of
isocyanides and acyl chlorides (Figure 1d).
Metal-organic frameworks (MOFs) are assembled from
metal ions or clusters coordinated with multidentate organic
ligands.[9] Owing to their high surface area, tunable porosity, and
versatile architecture, MOFs can act as templates or hosts to
Figure 1. Cycloaddition reactions of isocyanides with acyl chlorides.
direct the formation of surfactant-free metal nanoparticles with
tuneable size and uniform shape, which may lead to unexpected
synergistic catalysis with improved efficiency and selectivity.[10]
On the basis of these precedents and our continued efforts in
metal-catalyzed cyclization manifolds, we wondered if silver-
containing MOFs could mediate the cycloaddition of isocyanides
and acyl chlorides. To our delight, treatment of benzoyl chloride
(1a) and ethyl isocyanoacetate (2a) in the presence of AgMOF-1
(for details see the Supporting Information), afforded 2,5-
disubstituted oxazole 3a in 37% isolated yield along with a
significant amount of 4a (29%; Table 1, Entry 1).
Encouraged by these findings further examination of the
reaction conditions was pursued. First, several AgMOFs with
different Ag loadings were screened (Table 1, Entries 2–4; for
details see the Supporting Information). AgMOF-3 displayed the
highest catalytic activity towards the 2,5-disubstituted oxazole 3a,
[a]
Dr. J.-Q. Liu, X. Shen, Prof. X.-S. Wang
School of Chemistry and Chemical Engineering, Jiangsu Key
Laboratory of Green Synthesis for Functional Materials, Jiangsu
Normal University
Xuzhou Jiangsu 221116, P. R China
E-mail: xswang1974@yahoo.com
Dr. J.-Q. Liu, Dr. A. Shatskiy, Dr. M. D. Kärkäs
Department of Chemistry, Organic Chemistry, KTH Royal Institute of
Technology, SE-100 44 Stockholm, Sweden
E-mail: karkas@kth.se
[b]
[c]
Prof. E. Zhou
College of Chemistry and Material Science, Shandong Agricultural
University
Taian, Shandong 271000, P. R. China
E-mail: iamelzhou@njtech.edu.cn
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900965
ChemCatChem
COMMUNICATION
while the other screened AgMOF catalysts inferior activity. Next,
the solvent effect was evaluated, demonstrating that the use of
1,4-dioxane greatly increased the yield of 3a to 83% while nearly
completely suppressing the formation of 4a (Table 1, Entry 5). In
contrast, aprotic polar solvents, such as DCE and CH3CN, had a
negative effect and delivered 3a in only 62% and 53% yields,
respectively (Table 1, Entries 6 and 7). Furthermore, the protic
polysubstituted acyl chlorides were well-tolerated, showing no
deleterious steric effects. Analogously, the fused aryl product 3k
(R = 2-naphthyl) could also be produced in 67% yield. Next,
heteroaryl acyl chlorides containing furyl (1o) and pyridyl (1n)
motifs were subjected to the cyclization, leading to moderate
yields of the corresponding products 3o and 3n, respectively.
Subsequently, several aliphatic acyl chlorides (1p–1s) including
n
i
t
solvent EtOH only offered trace amounts of 3a (Table 1, Entry 8). benzyl, Bu, Bu, and Bu were investigated, and were efficiently
In the absence of a silver catalyst the cycloaddition was entirely
suppressed (Table 1, Entry 9). In contrast, several commercially
available silver catalysts, including Ag2CO3, AgNO3 and AgOAc,
only afforded the Nef and Schollkopf products (Table 1, Entries
10–12). A control experiment between 1a and 2a under El
Kaïm’s reaction conditions[8] failed to produce the desired
product 3a (Table 1, Entry 13). Thus, AgMOF-3 (100 mg) in 1,4-
dioxane (2.0 mL) and a temperature of 80 °C was selected as
the optimal reaction conditions.
converted to the corresponding 2,5-disubstituted oxazoles 3p–
3s in good to high yields. Besides ethyl isocyanoacetate (2a),
other isocyanides, such as methyl isocyanoacetate (2b), tert-
butyl isocyanoacetate (2c), TosMIC (2d) and benzyl isocyanide
(2e), were also treated with benzoyl chloride (1a) under the
optimal reaction conditions. To our delight, the corresponding
products were obtained in 52–83% yields. Finally, the structure
of compound 3 was also confirmed through single-crystal X-ray
diffraction analysis for compound 3b (CCDC 1831231, see the
Supporting Information).
Table 1. Optimization of reaction conditions.[a]
Entry
Solvent
Yield (%)[b]
[Ag] (mg)
3a
4a
1[c]
2[c]
3[c]
4[c]
5[c]
AgMOF-1
AgMOF-2
AgMOF-3
AgMOF-4
AgMOF-3
DMF
37
29
DMF
45
79
68
83
62
53
16
DMF
trace
11
DMF
1,4-dioxane
DCE
trace
trace
trace
6[c]
7[c]
8[c]
9
10[d]
11[d]
AgMOF-3
AgMOF-3
AgMOF-3
–
CH3CN
EtOH
trace
trace
0
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
0
0
94
0
Ag2CO3
AgNO3
0
12[d]
13[e]
AgOAc
0
0[f]
97
0[f]
–
[a] Reactions were performed on a 0.5 mmol scale, at 0.25 M (with respect to
1a). [b] Isolated yields. [c] Reactions were performed with 100 mg catalyst (3.7
mol% Ag). [d] Reactions were performed with 10 mol% catalyst. [e] Reaction
performed in the presence of 2,6-lutidine. [f] Yields determined by 1H NMR.
Having established the optimal reaction conditions, the
scope with respect to the acyl chloride component was initially
examined. As summarized in Scheme 1, all the reactions
proceeded smoothly and afforded the desired 2,5-disubstituted
oxazoles in moderate to high yields within 2–5 h under an Ar
atmosphere. Aromatic acyl chlorides bearing electron-donating
groups, such as Me and MeO, electron-withdrawing groups,
such as CO2Et and NO2, as well as halogens (e.g. Br, Cl) on the
arene were shown to be competent reaction partners in this
transformation. In addition, ortho-, meta-, para- and
Scheme 1. Scope of silver-induced cycloaddition of isocyanides with acyl
chlorides.
As a heterogeneous catalyst, AgMOF-3 could also easily be
recycled from the reaction mixture by centrifugation. To further
evaluate the catalytic activity and practicability of the developed
protocol, recycling tests with catalyst AgMOF-3 for the
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900965
ChemCatChem
COMMUNICATION
cycloaddition between 1a and 2a were carried out. As shown in
Figure 2, catalyst AgMOF-3 could be recovered and reused at
least four times without significant decrease in the catalytic
activity. These results highlight the practicality and the stability of
the AgMOF-3 catalyst under the employed reaction
conditions.[10b]
Scheme 3. Mechanistic probes.
Then, the AgMOF catalyst interacts with 6 to form a nitrilium
intermediate 7. A subsequent 1,3-H shift occurs to give
intermediate 8,[13e] which can be transformed to the desired
product 3 through two possible pathways. One pathway is
similar to El Kaïm’s work (Pathway B) in which species 8
undergoes a deprotonation sequence to form nitrilium adduct 10
that subsequently cyclizes to form the desired product 3.[8] The
other pathway (Pathway A) involves intramolecular nucleophilic
addition from 8 to generate the cyclized cationic intermediate
9.[13d] Finally, the target product 3 is produced via a proton shift
process along with regeneration of the AgMOF catalyst.[15]
These two reaction pathways are all reasonable and account for
the outcome in the abovementioned deuterium-labeling
experiment (Scheme 3).
Figure 2. Recycling tests with AgMOF-3 for cycloaddition of 1a and 2a.
The feasibility of the process was further demonstrated
through a gram-scale application (Scheme 2). For this purpose,
the reaction between 1a and 2a was carried out on a 20 mmol
scale under the optimal reaction conditions. Delightedly, the
corresponding oxazole 3a was isolated in 70% yield, even in the
presence of merely 1.85 mol% Ag (100 mg AgMOF-3 per 1
mmol 1a). Then, treatment of 3a with 100 equivalents of
morpholine led to the synthesis of amide 5a, a potentially
biologically active compound.[11]
Scheme 2. Gram-scale cycloaddition between 1a and 2a.
Subsequently, the reaction mechanism was explored
(Scheme 3). Initially, the commonly used radical-trapping
reagents 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and
butylhydroxytoluene (BHT) were added to the reaction
system.[12] In both systems, the desired product 3a was formed
in good yields, which strongly indicate that the silver-induced
reactions do not involve a free radical pathway. Next, a
deuterium labeling experiment in which 2.0 equivalents of D2O
were added to the reaction between 1a and 2a under the
standard conditions. This experiment revealed that the
deuterium incorporation in 3a was 41%. Collectively, these
results differ from the simple alkali-promoted approaches.[6–8]
Scheme 4. Proposed mechanistic pathways.
In summary, we have developed
a
silver-induced
Based on the experimental observations and related
literature precedents,[13,14] a plausible reaction mechanism was
conceived (Scheme 4). First, exposure of isonitrile 2 to acyl
chloride 1 furnishes the α-keto imidoyl halide intermediate 6.
cycloaddition of acyl chlorides with isocyanides, providing a
practical and scalable method for the construction of
synthetically useful 2,5-disubstituted oxazoles. For the first time,
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900965
ChemCatChem
COMMUNICATION
1836; d) V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin and V. Y.
Kukushkin, Chem. Rev. 2015, 115, 2698; e) B. Zhang and A. Studer,
Chem. Soc. Rev. 2015, 44, 3505; f) B. Song and B. Xu, Chem. Soc.
Rev. 2017, 46, 1103.
an improved and regioselective cyclization of isocyanides with
acyl chlorides has been realized using a silver-based MOF
catalyst. The strategy features a broad substrate scope, good
functional group compatibility, and allows catalyst recycling.
Considering the practicality and scalability of the process, the
methodology described herein undoubtedly will find wide
applications in future synthetic endeavors.
[2]
[3]
Isocyanide Chemistry (Eds: V. G. Nenajdenko), Wiley-VCH, Weinheim,
2012.
S. Chakrabarty, S. Choudhary, A. Doshi, F.-Q. Liu, R. Mohan, M. P.
Ravindra, D. Shah, X. Yang, F. F. Fleming, Adv. Synth. Catal. 2014,
356, 2135.
[4]
[5]
Y. Wang, R. K. Kumar, X. Bi, Tetrahedron Lett. 2016, 57, 5730.
a) M. Suzuki, T. Iwasaki, M. Miyoshi, K. Okumura, K. Matsumoto, J.
Org. Chem. 1973, 38, 3571; b) S. Maeda, M. Suzuki, T. Iwasaki, K.
Matsumoto, Y. Iwasawa, Chem. Pharm. Bull. 1984, 32, 2536; c) W. L. F.
Armarego, H. Taguchi, R. G. H. Cotton, S. Battiston, L. Leong, Eur. J.
Med. Chem. 1987, 22, 283; d) J. Tang, J. G. Verkade, J. Org. Chem.
1994, 59, 7793; e) M. Baumann, I. R. Baxendale, S. V. Ley, C. D. Smith,
G. K. Tranmer, Org. Lett. 2006, 8, 5231; f) W.-S. Huang, Y.-X. Zhang,
C.-Y. Yuan, Syn. Commun. 1996, 26, 1149; g) W.-S. Tian, T.
Livinghouse, J. Chem. Soc., Chem. Commun. 1989, 13, 819.
a) U. Schöllkopf, R. Schröder, Angew. Chem. 1971, 83, 358; Angew.
Chem., Int. Ed. 1971, 10, 333; b) U. Schöllkopf, P.-H. Porsch, Chem.
Ber. 1973, 106, 3382; c) R. Schröder, U. Schöllkopf, E. Blume, I. Hoppe,
Justus Liebigs Ann. Chem. 1975, 533; d) J. Rachoń, U. Schöllkopf,
Justus Liebigs Ann. Chem. 1981, 1186.
Experimental Section
Preparation of AgMOFs: MIL-101 was synthesized according to a
reported procedure.[16] Subsequently, the activated MIL-101 powder (100
mg) was immersed in acetonitrile (8 mL) containing various amounts of
silver nitrate (20 mg, 40 mg, 60 mg and 80 mg for preparation of AgMOF-
1, AgMOF-2, AgMOF-3, and AgMOF-4, respectively). The mixture was
stirred for 24 hours at room temperature. After the impregnation, the
suspension was centrifuged to separate the solid and washed with
CH3CN. The as-synthesized sample was further dried at 150 °C for 8 h,
followed by treatment with a H2/Ar stream (50 ml⋅min–1/50 ml⋅min–1) at
200 °C for 3 h to yield the desired AgMOF. Finally, the sample was kept
under an Ar atmosphere for further use.
[6]
[7]
[8]
J. U. Nef, Justus Liebigs Ann. Chem. 1892, 270, 267.
Typical procedure for synthesis of 3 (with 3a as an example): To a
mixture of 1a (58 μL, 0.5 mmol) and 2a (67 μL, 0.6 mmol) in 1,4-dioxane
(2.0 mL) was added AgMOF-3 (100 mg, 3.7 mol% Ag). The reaction
mixture was stirred at 80 °C under an Ar atmosphere until substrate 1a
was consumed as indicated by TLC (about 3 h). The resulting mixture
was concentrated under reduced pressure and the residue was taken up
in CH2Cl2. The combined organic layers were washed with brine, dried
over MgSO4 and concentrated under reduced pressure. Purification of
the crude product by column chromatography (silica gel; petroleum
ether/ethyl acetate 5:1) afforded compound 3a in 83% yield as a yellow
solid. m.p. 54–55 °C; 1H NMR (400 MHz, CDCl3): δ 7.76 (t, J = 5.2 Hz,
2H), 7.53 (s, 1H), 7.45–7.39 (m, 3H), 4.50 (q, J = 7.2 Hz, 2H), 1.46 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 101 MHz): δ 155.7, 154.3, 151.6, 129.8,
129.0, 126.6, 125.1, 123.8, 62.6, 14.2; HRMS (ESI-TOF) m/z calculated
for C12H12NO3 [M+H]+: 218.0817, found: 218.0816.
A. Dos Santos, L. El Kaïm, L. Grimaud, C. Ronsseray, Chem. Commun.
2009, 3907.
[9]
a) R. V. Jagadeesh, K. Murugesan, A. S. Alshammari, H. Neumann,
M.-M. Pohl, J. Radnik, M. Beller, Science. 2017, 358, 326; b) K. Natte,
H. Neumann, R. V. Jagadeesh, M. Beller, Nature Commun. 2017, 8,
1344; c) R. V. Jagadeesh, H. Junge, M. Beller, Nature Commun. 2014,
5, 4123; d) H. Furukawa, K. E. Cordova, M. O’Keeffe, O. M. Yaghi,
Science 2013, 341, 1230444.
[10] a) R. V. Jagadeesh, A.-E. Surkus, H. Junge, M.-M. Pohl, J. Radnik, J.
Rabeah, H. Huan, V. Schünemann, A. Brückner, M. Beller, Science.
2013, 342, 1073; b) X.-H. Liu, J.-G. Ma, Z. Niu, G.-M. Yang, P. Cheng,
Angew. Chem. 2015, 127, 1002; Angew. Chem. Int. Ed. 2015, 54, 988.
[11] M. Krasavin, M. Korsakov, M. Dorogov, T. Tuccinardi, N. Dedeoglu and
C. T. Supuran, Eur. J. Med. Chem. 2015, 101, 334.
[12] T. J. Montavon, J. Li, J. R. Cabrera-Pardo, M. Mrksich, S. A. Kozmin,
Nat. Chem. 2012, 4, 45.
[13] a) M. Westling, R. Smith, T. Livinghouse, J. Org. Chem. 1986, 51, 1159;
b) S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew. Chem. 2015, 127,
1309; Angew. Chem. Int. Ed. 2015, 54, 1293; c) J. Liu, Z. Liu, P. Liao, L.
Zhang, T. Tu, X. Bi, Angew. Chem. 2015, 127, 10764; Angew. Chem.
Int. Ed. 2015, 54, 10618; d) Z. Hu, J. Dong, X. Xu, Adv. Synth. Catal.
2017, 359, 3585; e) J.-Q. Liu, X. Shen, Y. Wang, X.-S. Wang, X. Bi,
Org. Lett. 2018, 20, 6930; f) J.-Q. Liu, X. Chen, X. Shen, Y. Wang, X.-S.
Wang, X. Bi, Adv. Synth. Catal. 2019, 361, 1543; g) J.-Q. Liu, X. Chen,
A. Shatskiy, M. D. Kärkäs, X.-S. Wang, J. Org. Chem. DOI:
10.1021/acs.joc.9b00528.
Acknowledgements
This work was supported by NSFC of China (No. 21702078),
NSF of Jiangsu Province (No. BK20170231, BK20170968),
Natural Science Foundation of Jiangsu Higher Education
Institution (17KJA150003), the open project of Jilin Province Key
Laboratory of Organic Functional Molecular Design & Synthesis
(130028830) and KTH Royal Institute of Technology. The
Wenner-Gren Foundations and the Olle Engkvist Byggmästare
Foundation are kindly acknowledged for postdoctoral fellowships
to J.L. and A.S., respectively.
[14] a) J. Daru, Z. Benda, Á. Póti, Z. Novák and A. Stirling, Chem. Eur. J.
2014, 20, 15395; b) Z. Hu, J. Dong, Y. Men, Z. Lin, J. Cai, X. Xu,
Angew. Chem. 2016, 128, 7193; Angew. Chem., Int. Ed. 2016, 55,
7077; c) Z. Hu, J. Dong, Y. Men, Z. Lin, J. Cai, X. Xu, Angew. Chem.
2017, 129, 1381; Angew. Chem. Int. Ed. 2017, 56, 1805.
Keywords: acyl chlorides • cycloaddition • isocyanides
oxazoles • silver
•
[15] The presence of HCl can prevent the isocyanide to react completely
with the acyl chloride. However, the presence of HCl α-keto imidoyl
halides presumably proceed to form nitrilium intermediates.
[16] G. Férey, C. Mellot-Draznieks, C. Serre, F. Millange, J. Dutour, S.
Surblé, I. Margiolaki, Science 2005, 309, 2040.
[1]
a) S. Lang, Chem. Soc. Rev. 2013, 42, 4867; b) G. Qiu, Q. Ding and J.
Wu, Chem. Soc. Rev. 2013, 42, 5257; c) U. K. Sharma, N. Sharma, D.
D. Vachhani and E. V. Van der Eycken, Chem. Soc. Rev. 2015, 44,
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900965
ChemCatChem
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jian-Quan Liu, Xuanyu Shen, Andrey
Shatskiy, Enlong Zhou,* Markus D.
Kärkäs,* Xiang-Shan Wang*
Page No. – Page No.
Silver-Induced [3+2] Cycloaddition of
Isocyanides with Acyl Chlorides:
Regioselective Synthesis of 2,5-
Disubstituted Oxazoles
A practical and efficient approach for the formation of 2,5-disubstituted oxazoles
has been achieved using a heterogeneous AgMOF catalyst, thereby addressing the
limitations of current methods. The developed strategy features a broad substrate
scope, good functional group compatibility, and is also amenable to catalyst
recycling.
This article is protected by copyright. All rights reserved.