A formal (5+1) annulation reaction from heterodimerization of two different isocyanides: stereoselective synthesis of 2: H -benzo [b] [1,4]oxazin-2-one

Article abstract of DOI:10.1039/c9cc06678k

A novel (5+1) annulation reaction of functionalized 2-isocyanophenyloxyacrylate and aromatic, aliphatic isocyanides has been disclosed. This domino reaction involves the unusual heterodimerization of two different isocyanides and allows for a quick access to many 2H-benzo[b][1,4]oxazin-2-one derivatives.

Full text of DOI:10.1039/c9cc06678k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
A formal (5+1) annulation reaction from
heterodimerization of two different
isocyanides: stereoselective synthesis of
2H-benzo[b][1,4]oxazin-2-one†‡
Cite this: Chem. Commun., 2019,
55, 12243
Received 28th August 2019,
Accepted 18th September 2019
ab
Shikuan Su,ab Jie Hu,a Yongmei Cui,a Chongrong Tang,a Yali Chen*ab and Jian Li
*
DOI: 10.1039/c9cc06678k
rsc.li/chemcomm
A novel (5+1) annulation reaction of functionalized 2-isocyanophenyl- investigated, thus lending more support to the reaction
oxyacrylate and aromatic, aliphatic isocyanides has been disclosed. mechanism.12–14 Compared with the popularity of homo-
This domino reaction involves the unusual heterodimerization dimerization between two same isocyanides, the coupling of
of two different isocyanides and allows for a quick access to many two different isocyanides seemed far more difficult and only
2H-benzo[b][1,4]oxazin-2-one derivatives.
limited examples of heterodimerization were reported.15–18
Among them, Yamamoto and co-workers reported a copper-
Isocyanides as highly valuable building blocks have been widely catalyzed [3+2] annulation of aryl isocyanides and activated methy-
used in various carbon–carbon and carbon–heteroatom bond lene isocyanide for imidazole synthesis (Scheme 1, eqn (1)).15,16
forming reactions.1,2 Isocyanides possess structurally unique This was a pioneering contribution involving two different
divalent carbon, which makes them good components in a isocyanides, whereas no 1,4-diazabutatriene intermediate from
multicomponent reaction.3 As such, the classical four-component heterodimerization of two isocyanides was formed.
Ugi and three-component Passerini reactions have found applica-
Indeed, a special polarized reactivity of the isocyano group
tion in many fields such as asymmetric synthesis,4 and the total was fully exemplified in such a case. Of late, Xu and co-workers
synthesis of natural products5 and macrocycles.6 In addition, the reported an unprecedented heterodimerization of 2-isocyano-
past years have witnessed a rapid growth of metal-, Lewis acid- chalcone and another isocyanide to synthesize pyrrolo[3,4-b]-
catalyzed isocyanide insertion reactions7,8 and the related radical indoles.17 After that, Xu and co-workers reported another
processes.9
interesting [4+2] annulation of aryl and heteroaryl isocyanide
On the other hand, the exploration of a new reactivity profile with substituted isocyanoacetamides to synthesize pyridine-fused
of isocyanide has attracted considerable attention and has carbo- and heterocycles (Scheme 1, eqn (2)).18,19 From the above-
become a persistent research area in isocyanide chemistry.10 mentioned description, the study on the heterodimerization of two
In this regard, studies on coupling and cross-cycloaddition
between two isocyanides have a long history and many important
achievements have been developed.11–14 Importantly, the first
successful example can be dated back to 1977 when Lange and
co-workers disclosed their work on homodimerization of imidoyl
isocyanide.11 In this work, an unstable 1,4-diazabutatriene inter-
mediate was proposed to interpret the synthesis of symmetrical
4,40-bis-quinazolines. After that, other similar processes were also
a School of Materials Science and Engineering, Shanghai University,
99 Shangda Road, Shanghai 200444, P. R. China. E-mail: yalichen@shu.edu.cn
b Department of Chemistry, Center for Supramolecular Chemistry and Catalysis,
College of Sciences & Institute for Sustainable Energy, Shanghai University,
99 Shangda Road, Shanghai 200444, P. R. China. E-mail: lijian@shu.edu.cn
† In memory of Professor Yongmin Zhang.
‡ Electronic supplementary information (ESI) available: NMR, HRMS (ESI) and
X-ray crystal structure data (CIF) for compound 3a, 4n. CCDC 1906923 (3a) and
Scheme 1 Representative examples involving the coupling of two different
1906924 (4n). For ESI and crystallographic data in CIF or other electronic format
isocyanides.
see DOI: 10.1039/c9cc06678k
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 12243--12246 | 12243

View Article Online
Communication
ChemComm
different isocyanides was still at its infant stage. In addition, some
strategies also suffered from insufficient atom economy and limited
isocyanide scope. As a continuation of our previous research,20
herein we report a new (5+1) annulation based on the heterodimer-
ization of our newly designed 2-isocyanophenyloxyacrylate and
common isocyanides (Scheme 1, eqn (3)).
We initially examined the model reaction of ethyl 3-(2-isocyano-
phenoxy)acrylate (1a) and tert-butyl isocyanide (2a) to optimize
the reaction conditions. Treatment with the mixture in toluene
at 100 1C essentially afforded a new annulation product 3a in 8%
yield (Table 1, entry 1). Next, several other solvents were screened
to enhance the yield of compound 3a. To our delight, the yield
of 3a could be significantly increased when the reactions
were performed in DMF (N,N-dimethylformamide) and DMA
(N,N-dimethylacetamide), respectively (Table 1, entries 6 and 7).
Further experimental results also revealed that the present
reaction was very sensitive to the reaction temperature. Pleasingly,
compound 3a was isolated in 71% when the mixture was heated
at 130 1C in DMA (Table 1, entry 9). During our optimization,
different catalysts were also screened (see the ESI‡ for details).
The scope of the reaction was subsequently investigated with
respect to 2-isocyanophenyloxyacrylate 1 under the optimized
conditions. As shown in Scheme 2, a series of substituted
2-isocyanophenyloxyacrylate 1 having chloro, bromo, methyl,
methoxyl, cyano, ester, and acetyl groups at positions 5 (3a–3f),
6 (3g), 4 (3h–3j), and 3 (3k–3l) on the aromatic ring of the
substrate were first examined.21 All reactions worked well to
produce the desired product, thus providing a good compatibility.
Additionally, the replacement of the ester moiety in substrate
2-isocyanophenyloxyacrylate 1 from OMe to OEt or Ot-Bu was
Scheme 2 Scope of the reaction with respect to 2-isocyanophenyl-
oxyacrylate 1. a Reaction conditions A: 0.3 mmol of 2-isocyanophenyl-
oxyacrylate 1, 0.6 mmol tert-butyl isocyanide 2a, and 0.6 mmol H2O in
3 mL DMA, 130 1C, 24 hours. Yields of the product after silica gel
chromatography.
conducted and the corresponding reactions proceeded smoothly substrate 1a under the optimized conditions. In this regard,
to afford products 3n and 3o, respectively. aromatic isocyanides 2 bearing electron-withdrawing or donating
As shown in Scheme 3, the present reaction tolerated a wide groups at para- (4a–4e), meta- (4f–4g), ortho- (4h–4j) were proved to be
range of isocyanides 2 upon a reaction with functionalized effective isocyanide components. Then, several disubstituted- and
trisubstituted aromatic isocyanides including 3,4-dichlorophenyl
isocyanide 2l, 2,4-dichlorophenyl isocyanide 2m, 2,6-dimethyl-
phenyl isocyanide 2n, 4-bromo-2,6-dimethylphenyl isocyanide
Table 1 Reaction optimizationa
2o, and a-naphthyl isocyanide 2p were used to react with 1a to
produce the corresponding products 4k–4o.21 The structure of
compounds 4n was unambiguously confirmed by single crystal
X-ray analysis.21 Next, the scope of the reaction with respect to the
aliphatic isocyanide 2 was examined. Accordingly, commonly
Entry
Solvent
Temp (1C)
Yieldb (%)
used isocyanides including some sterically hindered admantyl
isocyanide 2s and 1,1,3,3-tetramethylbutyl isocyanide 2t were well
tolerated to form 2H-benzo[b][1,4]oxazin-2-one derivatives (4p–4s).
To gain more insight into the present reaction, several
mechanistic experiments and control experiments were carried
out. The isotope experiment demonstrated that O18 was incorporated
into the resulting [O18]-3a when H2O18 was used as the third
component (Scheme 4, eqn (1)). Moreover, H/D exchange was
also observed when D2O was added to the mixture of 1a and 2a
(Scheme 4, eqn (2)). These results indicated that water was
involved in the present conversion as a component. Moreover,
no obvious influence was observed when excessive radical
scavenger TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) was
added to the pre-formed solution of 1a and 2a under standard
1
2
3
4
5
6
7
8
Toluene
1,4-Dioxane
DME
Diglyme
DMSO
DMF
DMA
DMA
DMA
DMA
100
100
100
100
100
100
100
120
130
140
80
8
15
13
6
0
31
42
49
71
59
Trace
Trace
9
10
11
12c
DMA
DMA
130
a
All reactions were carried out with 0.3 mmol of 2-isocyanophenyl-
oxyacrylate 1a, 0.6 mmol tert-butyl isocyanide 2a, and 0.6 mmol H2O in
b
3 mL solvent. Yields of the product after silica gel chromatography.
c
No extra H2O was added.
12244 | Chem. Commun., 2019, 55, 12243--12246
This journal is ©The Royal Society of Chemistry 2019

View Article Online
ChemComm
Communication
Scheme 5 Proposed mechanism.
compound 5 might be the possible intermediate. The control
experiment also revealed that oxygen was indispensible to the
present transformation (see the ESI‡ for details).
Based on the aforementioned experimental results and
literature precedent,11–18,20,22,23 a plausible reaction mecha-
nism is proposed in Scheme 5. The present annulation starts
from the nucleophilic attack of isocyanide 2 towards the iso-
cyano carbon atom in 2-isocyanophenyloxyacrylate 1a.11–14,20a
As such, the heteorodimerization process essentially leads to the
generation of a very reactive 1,4-diazabutatriene tautomer A,
which can be considered as a specific 1,3-dipole.17 Next, intra-
molecular Michael addition takes place to produce an unstable
six-membered intermediate B followed by subsequent ring
opening and cyclization to form 2H-benzo[b][1,4]oxazin-2-
one D via intermediate C. In the presence of water, the carbon
nitrogen double bond in D undergoes hydrolysis to deliver E by
the elimination of primary amine as a byproduct.22 According to
our analysis, N–Hꢀ ꢀ ꢀN type hydrogen bonding is formed between
D and the eliminated amine, and thus enables the occurance of
a regioselective Michael addition. As shown in Scheme 5, the
resulting intermediate F experiences neutralization.23 Finally,
the dehydrogenation with the aid of oxygen yields the final
products 3–4.
Scheme 3 Scope of the reaction with respect to the scope of isocyanide 2.
Reaction conditions A. Yields of the product after silica gel chromatography.
In conclusion, we have described an unprecedented (5+1)
annulation reaction with isocyanophenyloxyacrylate and
isocyanide. This domino reaction involves the unusual hetero-
dimerization of two different isocyanides and the in situ C–N
bond cleavage of the isocyano group, which represents a novel
reactivity profile of isocyanide. High synthetic efficiency is
also exhibited by the cleavage and the formation of multiple
C–O, C–C, and C–N bonds. Additionally, this strategy also
features broad isocyanide scope, excellent atom economy,
and stereoselectivity. Further investigation of the reaction
mechanism and potential application are still underway in
Scheme 4 Mechanistic studies and control experiments.
conditions (Scheme 4, eqn (3)), thus ruling out the possibility of our laboratory.
a radical process. To find out the real intermediate of the
The authors gratefully acknowledge financial support from
present reaction, the compound 5 was synthesized and used the National Natural Science Foundation of China (21272146).
to react with tert-butyl amine 6 under the optimized conditions. This work was also sponsored by the Natural Science Founda-
In such a case, product 3n was isolated albeit somewhat in a tion of Shanghai (18ZR1413900) and the Shanghai Pujiang
lower yield (Scheme 4, eqn (4)). This result also suggested that Program (17PJD016).
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 12243--12246 | 12245

View Article Online
Communication
ChemComm
J. Am. Chem. Soc., 2013, 135, 4708; (c) N. Chatani, M. Oshita,
M. Tobisu, Y. Ishii and S. Murai, J. Am. Chem. Soc., 2003,
125, 7812; (d) M. Tobisu, A. Kitajima, S. Yoshioka, I. Hyodo,
M. Oshita and N. Chatani, J. Am. Chem. Soc., 2007, 129, 11431;
(e) J. D. Winkler and S. M. Asselin, Org. Lett., 2006, 8, 3975.
Conflicts of interest
There are no conflicts to declare.
Notes and references
9 (a) B. Zhang and A. Studer, Chem. Soc. Rev., 2015, 44, 3505;
(b) H. Jiang, Y. Cheng, R. Wang, M. Zheng, Y. Zhang and S. Yu,
Angew. Chem., Int. Ed., 2013, 52, 13289; (c) M. Tobisu, K. Koh,
T. Furukawa and N. Chatani, Angew. Chem., Int. Ed., 2012, 51, 11363.
10 For examples that isocyano group behaves as polarized triple bond,
see: (a) S. Tong, Q. Wang, M.-X. Wang and J. Zhu, Angew. Chem., Int.
Ed., 2015, 54, 1293; (b) S. Tong, Q. Wang, M.-X. Wang and J. Zhu,
Chem. – Eur. J., 2016, 22, 8332; For the employment of isocyano
group as N1 synthon:, see: (c) Z. Liu, X. Zhang, J. Li, F. Li, C. Li, X. Jia
and J. Li, Org. Lett., 2016, 18, 4052; For examples that using
isocyanide as cyano source, see: (d) G. Qiu, X. Qiu, J. Liu and
J. Wu, Adv. Synth. Catal., 2013, 355, 2441; (e) S. Xu, X. Huang,
X. Hong and B. Xu, Org. Lett., 2012, 14, 4614; ( f ) J. Peng, J. Zhao,
Z. Hu, D. Liang, J. Huang and Q. Zhu, Org. Lett., 2012, 14, 4966.
1 For reviews, see: (a) Isocyanide Chemistry: Applications in Synthesis
and Materials Science, ed. V. Nenajdenko, Wiley-VCH, Weinheim,
2012; (b) G. Qiu, Q. Ding and J. Wu, Chem. Soc. Rev., 2013, 42, 5257;
(c) A. V. Lygin and A. de Meijere, Angew. Chem., Int. Ed., 2010,
49, 9094.
2 For recent examples, see: (a) S.-C. Zheng, Q. Wang and J. Zhu,
Angew. Chem., Int. Ed., 2019, 58, 1494; (b) W.-K. Yuan, T. Cui, W. Liu,
L.-R. Wen and M. Li, Org. Lett., 2018, 20, 1513; (c) Z.-Y. Gu, Y. Liu,
F. Wang, X. Bao, S.-Y. Wang and S.-J. Ji, ACS Catal., 2017, 7, 3893;
(d) W. Kong, Q. Wang and J. Zhu, Angew. Chem., Int. Ed., 2016,
´
55, 9714; (e) U. M. V. Basavanag, A. Santos, L. El Kaim, R. Gamez-
˜
Montano and L. Grimaud, Angew. Chem., Int. Ed., 2013, 52, 7194.
3 For reviews, see: (a) Multicomponent Reactions in Organic Synthesis,
ed. J. Zhu, Q. Wang and M.-X. Wang, Wiley-VCH, Weinheim,
Germany, 2015; (b) E. Ruijter, R. Scheffelaar and R. V. A. Orru,
Angew. Chem., Int. Ed., 2011, 50, 6234; (c) A. Domling, Chem. Rev.,
2006, 106, 17.
4 (a) Q. Wang, D.-X. Wang, M.-X. Wang and J. Zhu, Acc. Chem. Res.,
2018, 51, 1290; (b) J. Zhang, P. Yu, S.-Y. Li, H. Sun, S.-H. Xiang,
J. Wang, K. N. Houk and B. Tan, Science, 2018, 361, 1087;
(c) S. E. Denmark and Y. Fan, J. Am. Chem. Soc., 2003, 125, 7825.
5 (a) A. Endo, A. Yanagisawa, M. Abe, S. Tohma, T. Kan and
T. Fukuyama, J. Am. Chem. Soc., 2002, 124, 6552; (b) B. B. Toure
and D. G. Hall, Chem. Rev., 2009, 109, 4439; (c) J. Isaacson and
¨
11 G. Hofle and B. Lange, Angew. Chem., Int. Ed. Engl., 1977, 16,
727–728.
¨
12 M. Wenzel, F. Lehmann, R. Beckert, W. Gu¨nther and H. Gorls,
¨
Monatsh. Chem., 1999, 130, 1373.
13 K. Kobayashi, J. Yonemori, A. Matsunaga, T. Kitamura, M. Tanmatsu,
O. Morikawa and H. Konishi, Heterocycles, 2001, 55, 33.
14 N. Shao, G.-X. Pang, X.-R. Wang, R.-J. Wu and Y. Cheng, Tetrahedron,
2010, 66, 7302.
15 (a) C. Kanazawa, S. Kamijo and Y. Yamamoto, J. Am. Chem. Soc.,
`
2006, 128, 10662; (b) M.-A. Bonin, D. Giguere and R. Roy, Tetrahe-
´
dron, 2007, 63, 4912; (c) B. Pooi, J. Lee, K. Choi, H. Hirao and
S. H. Hong, J. Org. Chem., 2014, 79, 9231.
Y. Kobayashi, Angew. Chem., Int. Ed., 2009, 48, 1845.
6 (a) R. Madhavacharya, E. M. M. Abdelraheem, A. Rossettia,
A. Twarda-Clapac, B. Musielak, K. Kurpiewska, J. Kalinowska-
16 Y. Gao, Z. Hu, J. Dong, J. Liu and X. Xu, Org. Lett., 2017, 19, 5292.
17 Z. Hu, H. Yuan, Y. Men, Q. Liu, J. Zhang and X. Xu, Angew. Chem.,
Int. Ed., 2016, 55, 7077.
18 Z. Hu, J. Dong, Y. Men, Z. Lin, J. Cai and X. Xu, Angew. Chem., Int.
Ed., 2017, 56, 1805.
19 A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko,
Chem. Rev., 2010, 110, 5235.
´
¨
Tłusik, T. A. Holak and A. Domling, Angew. Chem., Int. Ed., 2017,
56, 10725; (b) E. M. M. Abdelraheem, M. P. de Haan, P. Patil,
´
¨
K. Kurpiewska, J. Kalinowska-Tłusik, S. Shaabani and A. Domling,
Org. Lett., 2017, 19, 5078; (c) E. Marsault and M. L. Peterson, J. Med.
Chem., 2011, 54, 1961.
20 (a) J. Hu, Y. Fei, H. Zhao, Z. Wang, C. Li and J. Li, Chem. Commun.,
2019, 55, 8394; (b) H. Yuan, C. Tang, S. Su, L. Cui, X. Jia, C. Li and
J. Li, Chem. Commun., 2019, 55, 7231; (c) S. Su, J. Li, M. Sun, H. Zhao,
Y. Chen and J. Li, Chem. Commun., 2018, 54, 9611; (d) F. Li, P. Hu,
M. Sun, C. Li, X. Jia and J. Li, Chem. Commun., 2018, 54, 6412;
(e) T. Jin, Z. Tang, J. Hu, H. Yuan, Y. Chen, C. Li, X. Jia and J. Li, Org.
Lett., 2018, 20, 413.
7 (a) B. Song and B. Xu, Chem. Soc. Rev., 2017, 46, 1103; Pd: (b) W. Hu,
M. Li, G. Jiang, W. Wu and H. Jiang, Org. Lett., 2018, 20, 3500;
(c) J. Wang, S. Luo, J. Huang, T. Mao and Q. Zhu, Chem. – Eur. J.,
2014, 20, 11220; (d) T. Vlaar, R. C. Cioc, P. Mampuys, B. U. W. Maes,
R. V. A. Orru and E. Ruijter, Angew. Chem., Int. Ed., 2012, 51, 13058;
Ag: (e) J. Liu, Z. Fang, Q. Zhang, Q. Liu and X. Bi, Angew. Chem., Int.
Ed., 2013, 52, 6953; ( f ) M. Gao, C. He, H. Chen, R. Bai, B. Cheng and
A. Lei, Angew. Chem., Int. Ed., 2013, 52, 6958; Ni: (g) W.-K. Yuan,
Y. F. Liu, Z. Lan, L.-R. Wen and M. Li, Org. Lett., 2018, 20, 7158; Co:
(h) Q. Gao, P. Zhou, F. Liu, W.-J. Hao, C. Yao, B. Jiang and S.-J. Tu,
Chem. Commun., 2015, 51, 9519; (i) T.-H. Zhu, S.-Y. Wang, T.-Q. Wei
and S.-J. Ji, Adv. Synth. Catal., 2015, 357, 823.
21 CCDC 1906923 and 1906924 for compounds 3a, 4n contain the
supplementary crystallographic data for this paper‡.
ˇ
22 (a) R. Zupet and M. Tisler, J. Org. Chem., 1994, 59, 507; (b) Y.-Y. Ding,
D.-F. Xu, S.-S. Meng, Y. Li and J.-L. Zhao, Adv. Synth. Catal., 2018,
360, 664.
8 (a) Y. Tian, L. Tian, X. He, C. Li, X. Jia and J. Li, Org. Lett., 2015, 23 Y. Z. Xia, Y. Liang, Y. Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu,
17, 4874; (b) C.-H. Lei, D.-X. Wang, L. Zhao, J. Zhu and M.-X. Wang,
Y. H. Li and Z.-X. Yu, J. Am. Chem. Soc., 2007, 129, 3470.
12246 | Chem. Commun., 2019, 55, 12243--12246
This journal is ©The Royal Society of Chemistry 2019