NHC-Ni(II) Catalyzed Cyclopropene-Isocyanide [5+1] Benzannulation


Cyclopropenes are highly active building blocks in organic synthesis and frequently use for preparing cyclic compounds via [3+2], [2+3], [3+4] and other modes of cycloaddition.[1-4] The [5+1]-cycloaddition of cyclopropenes was rarely reported owning to the high homo-dimerization and polymerization reactivity of the cyclopropenes. Exceptional examples are those using CO as a reaction partner like the Dotz benzannulation and the Semmelhack/Wulff 1,4-hydroquinones synthesis.[5-7] The needs of stoichiometric amount of Cr/Mo/W(CO)n complexes and toxic CO gas have restricted the application of this method.

Fig. 1 [5+1] benzannulation of cyclopropene 1) Semmelhack/Wulff 1,4-hydroquinones synthesis from cyclopropene and CO. 2) (NHC)Ni(II) catalyzed cyclopropene-isocyanide [5+1] benzannulation.

As a continuation of our (NHC)Ni(II)-catalyzed strained cyclic olefin chemistry,[8, 9] we investigated the (NHC)Ni(II) potential in directing a cross-reaction between highly reactive cyclopropene and isocyanide.[10-12] Surprisingly, unlike the cyclopropene-alkyne cross-reaction that gave us a diene product, the reaction gave us a highly substituted naphthamine. The product structure is comparable with the Semmelhack/Wulff 1,4-hydroquinones synthesis by CO complexes. Subsequent optimization gave us a unique way to prepare functionalized arylamines or endocyclic dienes with high yield and good selectivity. The large steric hindrance of NHC (IPentAn) plays a key role to inhibit the cyclopropene homo-dimerization, the cyclopropene rearrangement to indene derivatives and isocyanide oligomerization.

Compared to traditional analogs, this synthetic method has several notable features: 1) it employs catalytic amount of Ni(II) as catalyst ; 2) it has broad substrates scopes and is compatible with many functional groups, including halide, ester, cyanide, heteroaryl and alkene; 3) it provides novel endocyclic 1,3-dienes bearing spiro-ring structures when ß,ß-disubsituted vinyl cyclopropenes are used; 4) it provides an access to diarylamines with a large steric hindrance, which are difficult to synthesis via traditional Buchwald-Hartwig couplings; and 5) it provides regioselective ring-opening when a cyclopropene bearing a trisubstituted olefin is used.

Fig. 2 Scope of (NHC)Ni(II) catalyzed cyclopropene-isocyanide [5+1] benzannulation

The heteroaromatic compounds and naphthamine products obtained from this method are potentially useful in medicinal, photochemical and material chemistry.[13, 14] For example, product 3rb bearing 2,3-dihydro-1H-phenalenes, which is a common motif in OLEDs. A solvent-controlled highly regioselective bromination on unsymmetric diaryl amine was also developed for higher functional product synthesis.

Fig. 3 Solvent-controlled regioselective bromination.

For more details, especially on substrate scope and mechanistic studies please see our article: https://www.nature.com/articles/s41467-022-31896-y


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[2] Rubin, M.; Rubina, M.; Gevorgyan, V., Chemical Reviews, (2007) 107, 3117.

[3] Li, P. H.; Zhang, X. Y.; Shi, M., Chem Commun, (2020) 56, 5457.

[4] Vicente, R., Chemical Reviews, (2021) 121, 162.

[5] Dotz, K. H., Angew Chem Int Edit, (1975) 14, 644.

[6] Semmelhack, M. F.; Ho, S.; Cohen, D.; Steigerwald, M.; Lee, M. C.; Lee, G.; Gilbert, A. M.; Wulff, W. D.; Ball, R. G., J. Am. Chem. Soc., (1994) 116, 7108.

[7] Dotz, K. H.; Tomuschat, P., Chem Soc Rev, (1999) 28, 187.

[8] Huang, J. Q.; Ho, C. Y., Angew. Chem. Int. Ed., (2019) 58, 5702.

[9] Huang, J. Q.; Ho, C. Y., Angew. Chem. Int. Ed., (2020) 59, 5288.

[10] Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W., J. Am. Chem. Soc., (1988) 110, 6818.

[11] Qiu, G. Y. S.; Ding, Q. P.; Wu, J., Chem Soc Rev, (2013) 42, 5257.

[12] Collet, J. W.; Roose, T. R.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A., Angew. Chem. Int. Ed., (2020) 59, 540.

[13] Zhang, Z. Y.; Wu, Y. S.; Tang, K. C.; Chen, C. L.; Ho, J. W.; Su, J. H.; Tian, H.; Chou, P. T., J. Am. Chem. Soc., (2015) 137, 8509.

[14] Cerchia, C.; Nasso, R.; Mori, M.; Villa, S.; Gelain, A.; Capasso, A.; Aliotta, F.; Simonetti, M.; Rullo, R.; Masullo, M.; et al., J. Med. Chem., (2019) 62, 7089.

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