Rhodium-catalyzed homodimerization–cyclization reaction of two vinyl isocyanides: a general route to 2-(isoquinolin-1-yl)oxazoles

Abstract

A novel rhodium-catalyzed homodimerization–cyclization reaction of two vinyl isocyanides has been developed for the first time. In this reaction, the highly reactive 1,4-diazabutatriene intermediates generated by the homodimerization of two vinyl isocyanides could undergo a novel type of intramolecular tandem cyclization and provides a new and highly efficient method for the construction of 2-(isoquinolin-1-yl)oxazoles by formation of three new bonds and two rings from readily available acyclic starting materials in a single step.

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Isocyanides are useful building blocks in organic synthesis because of their unique modes of reaction.¹ Accordingly, significant advances have been made in isocyanide-based multicomponent reactions,² [3 + 2]-cycloaddition of activated methylene isocyanides with polar multiple bonds,³ transition metal-catalyzed isocyanide insertion⁴ and radical insertions.⁵ In stark contrast, reports on coupling-cyclization of two isocyanides are rare.^6–10 In this context, the coupling-cyclization of two isocyanides using 1,4-diazabutatriene species generated in situ from the dimerization of isocyanides as key intermediates has emerged as an efficient protocol for the synthesis of fused heterocyclic compounds.^7–10 In 1999, Beckert provided evidence for the existence of 1,4-diazabutatriene by reduction of bis-imidoyl chlorides of oxalic acid.⁷ Subsequently, the groups of Cheng and Kobayashi independently reported the related coupling-cyclization reactions of 2-pyridylisonitriles or o-isocyanostyrenes.⁸ Recently, Xu's and Li's groups developed a new cross-cyclization from nonsymmetrical 1,4-diazabutatriene generated by the heterodimerization of two different isocyanides,⁹ respectively. However, all of the above reactions were limited to functionalized aryl isocyanides.^7–9 To the best of our knowledge, so far only one example of a homodimerization–cyclization reaction based on 1,4-diazabutatriene generated by the dimerization of nonaromatic isocyanides was described. The pioneering work by Lange and Höfle reported a homodimerization–cyclization reaction of two imidoyl isocyanides and 2,2′-diphenyl-4,4′-biquinazoline in 38% yield (Scheme 1, eqn (1)).¹⁰ Thus, the development of new coupling-cyclization of nonaromatic isocyanides, especially vinyl isocyanides, remains a challenging task. As a continuation of our studies on isocyanide chemistry,¹¹ herein, we report a rhodium-catalyzed coupling-cyclization based on the homodimerization of two vinyl isocyanides (Scheme 1, eqn (2)). In this reaction, the highly reactive 1,4-diazabutatriene intermediate generated by the dimerization of two vinyl isocyanides undergoes a novel type of intramolecular tandem cyclization to furnish 2-(isoquinolin-1-yl)oxazoles in good to high yields.

Scheme 1 Homodimerization–cyclization reaction of two imidoyl isocyanides or vinyl isocyanides.

The isoquinoline skeleton is a privileged structure that is commonly found in numerous synthetic and natural products.¹² Similar to the isoquinoline skeleton, the oxazole unit is a ubiquitous heterocyclic scaffold found in many bioactive natural products and pharmaceutical drugs.¹³ As a consequence, the combination of these two structural features within a single framework giving novel oxazole-isoquinolines has potential for biological and pharmacological activities. To date, only one method has been reported for the synthesis of 2-(isoquinolin-1-yl)oxazoles based on the cycloaddition of isoquinoline Reissert salts with acetylenic aldehydes.¹⁴ Our reaction provides a new and highly efficient approach for the construction of 2-(isoquinolin-1-yl)oxazoles via a rhodium-catalyzed cascade cyclization strategy by formation of three new bonds and two rings from readily available acyclic starting materials in a single step (Scheme 1, eqn (2)).

Initially, the tandem cyclization reaction of vinyl isocyanide 1a was investigated to optimize the reaction conditions. When 1a (0.2 mmol) was heated at 160 °C in toluene for 12 h, the 2-(isoquinolin-1-yl)oxazole 2a was obtained in 22% yield (Table 1, entry 1). The yield of 2a was increased to 74% in the presence of [(C₆H₅)₃P]₃RhCl (1 mol%) under otherwise identical conditions as mentioned above (entry 4). Decreasing the reaction temperature led to comparatively lower yields of 2a (entries 2 and 3). Further increasing the amount of [(C₆H₅)₃P]₃RhCl did not improve the yield of 2a (entry 5). Other catalysts, such as [Cp*RhCl₂]₂, [Rh(COD)Cl]₂, [Rh(nbd)Cl]₂ and ReCl₃ were less effective (entries 6–9). Among the solvents tested, toluene seemed to be the best choice. Other solvents, such as o-xylene, MeCN and DMF gave lower product yields (entries 10, 11 and 13). No desired product 2a was observed when the reaction was performed in DMSO (entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	[M] (mol%)	Temp.	Solvent	t/h	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), catalyst (0.002–0.01 mmol), at 100–160 °C in solvent for 12–18 h in a sealed tube. [Cp*RhCl2]2 = bis[(pentamethylcyclopentadienyl)dichloro-rhodium], [Rh(COD)Cl]2 = chloro(1,5-cyclooctadiene)rhodium(I) dimer, [Rh(nbd)Cl]2 = bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloride dimer. b Estimated by ^1H NMR spectroscopy using dimethyl phthalate as an internal standard. c Isolated yield.
1	—	160	Toluene	12	22
2	[(C6H5)3P]3RhCl (1)	100	Toluene	18	49
3	[(C6H5)3P]3RhCl (1)	130	Toluene	12	58
4	[(C6H5)3P]3RhCl (1)	160	Toluene	12	74^c
5	[(C6H5)3P]3RhCl (5)	160	Toluene	12	73
6	[Cp*RhCl2]2 (1)	160	Toluene	12	32
7	[Rh(COD)Cl]2 (1)	160	Toluene	12	48
8	[Rh(nbd)Cl]2 (1)	160	Toluene	12	48
9	ReCl3 (1)	160	Toluene	12	22
10	[(C6H5)3P]3RhCl (1)	160	o-Xylene	12	54
11	[(C6H5)3P]3RhCl (1)	160	MeCN	12	16
12	[(C6H5)3P]3RhCl (1)	160	DMSO	12	—
13	[(C6H5)3P]3RhCl (1)	160	DMF	12	16

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With the optimized reaction conditions in hand, the scope of the reaction was examined and the results are summarized in Table 2. The tandem reaction showed broad tolerance for vinyl isocyanides. Various diaryl ketone-derived vinyl isocyanides 1a–g undergo efficient dimerization–cyclization reactions to give the corresponding 2-(isoquinolin-1-yl)oxazoles 2a–g in good to high yields. In addition, the electronic properties of aromatic rings can affect this transformation. No reaction was observed when vinyl isocyanides containing strong electron-withdrawing substituents on the aromatic rings, such as ethyl 3,3-bis(4-cyanophenyl)-2-isocyanoacrylate, ethyl 3,3-bis(4-methoxycarbonylphenyl)-2-isocyanoacrylate and ethyl 2-isocyano-3,3-bis(4-nitrophenyl)acrylate, were employed as partners under optimal conditions. It is noteworthy that the dimerization–cyclization reaction of substrates 1f and 1g with differently substituted aromatic rings also proceeded smoothly, resulting in an expected mixture of 2-(isoquinolin-1-yl)oxazoles 2f/2f′ and 2g/2g′ with moderate regioselectivities, which could not be separated by silica gel column chromatography. Furthermore, the regioselectivity of this reaction mainly depends on the electronic properties of the substituents on both aromatic rings. Similarly, aliphatic aryl ketone-derived vinyl isocyanides 1h and 1i were suitable for this reaction, generating the desired 2-(isoquinolin-1-yl)oxazoles 2h and 2i in 75% and 64% yields, respectively. More importantly, in the case of aryl and heteroaryl aldehyde-derived vinyl isocyanides 1j–o, the dimerization–cyclization reaction also worked well, affording the desired products 2j–o in moderate to high yields.¹⁵ In addition, methyl ester- or amide-based vinyl isocyanides 1p and 1q also smoothly underwent this transformation, affording the corresponding products 2p and 2q in 72% and 69% yields, respectively (Table 2). In addition, we found that the dimerization–cyclization reaction is easy to scale-up. A scale-up reaction of 1d (4.0 mmol, 1.22 g) was carried out for 12 h under otherwise identical conditions as mentioned above, furnishing 1.49 g of the desired product 2d in 61% yield.

Table 2 Rhodium-catalyzed homodimerization–cyclization of vinyl isocyanides 1^a,b

a Reaction conditions: 1 (0.2 mmol), [(C₆H₅)₃P]₃RhCl (0.002 mmol), at 160 °C in toluene for 12–16 h in a sealed tube. b Isolated yield. c The ratio was determined by the ¹H NMR spectroscopy of the crude reaction mixtures.

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To test the synthetic utility of the present protocol, the intramolecular cyclization of 2 was further investigated. As shown in Scheme 2, the hydrolysis of 2a or 2d (0.5 mmol) in the presence of NaOH (1.0 mmol) in refluxing C₂H₅OH–H₂O (10 mL, v/v = 1/1) provided the 1-(oxazol-2-yl)isoquinoline-3-carboxylic acids 3a and 3d in 99% and 98% yields (Scheme 2), respectively. In addition, we found that the intramolecular cyclization reactions of 3a and 3d proceeded smoothly to provide 7H-indeno[2,1-c]isoquinolin-7-ones 4a and 4d in 57% and 53% yields, respectively, via a sequential acyl chlorination and intramolecular Friedel–Crafts acylation reaction in the presence of SOCl₂ (1.0 eq.) and AlCl₃ (1.0 eq.) in dichloromethane (DCM) at room temperature for 12 h (Scheme 2), respectively. Undoubtedly, the above reaction provides a novel and efficient method for the synthesis of 7H-indeno[2,1-c]isoquinolin-7-ones under mild conditions.¹⁶

Scheme 2 Potential synthetic applications of 2.

To further probe the mechanisms for the formation of 2, some control experiments were performed (Scheme 3). When the dimerization–cyclization reaction of 1a was carried out under an atmosphere of nitrogen under otherwise identical conditions, the desired product 2a was produced in 70% yield (Scheme 3, eqn (1)). Similarly, product 2a was obtained in 68% yield when 2,6-di-tert-butyl-4-methylphenol (BHT, 1.0 eq.) was used as a radical inhibitor under the optimized conditions (Scheme 3, eqn (2)). These results imply that a radical process is not involved.

Scheme 3 Control experiments for mechanistic studies.

On the basis of the above experimental results together with related reports,^{7–10,11c,17} a possible mechanism of this homodimerization–cyclization is proposed in Scheme 4. Initially, the coordination of [(C₆H₅)₃P]₃RhCl with vinyl isonitrile 1 generates intermediate A,^11c which undergoes migratory insertion to produce 1,4-diazabutatriene intermediate B. Subsequently, intermediate B undergoes efficient 6π electrocyclization to afford intermediate C, followed by a 1,3-proton shift to give intermediate D. Likely activated by rhodium, the carbonyl oxygen atom of intermediate D attacks the carbon atom of the carbon–nitrogen double bond to form intermediate E.¹⁷ During this process, the rhodium catalyst dissociates to complete the catalytic cycle. Finally, intermediate E undergoes isomerization, followed by protonation to produce the corresponding 2-(isoquinolin-1-yl)oxazoles 2 (Scheme 4).

Scheme 4 Proposed mechanisms for the formation of 2.

In addition, the fluorescence properties of compound 2a in the solid state under the excitation of ultraviolet light were investigated. We found that powder 2a exhibits blue fluorescence at λ_max 440 nm (Fig. 1), which implies that this compound 2a may be a promising candidate in the field of optoelectronic materials.¹⁸

Fig. 1 Normalized emission spectra of compound 2a.

Conclusions

In conclusion, we have developed a novel rhodium-catalyzed homodimerization–cyclization reaction of two vinyl isocyanides. Importantly, this reaction provides a simple and highly efficient method for the construction of 2-(isoquinolin-1-yl)oxazoles from readily available acyclic starting materials in a single step. This new strategy allows the formation of three new bonds and two rings via a sequential intermolecular coupling and intramolecular tandem cyclization. This reaction features readily available substrates, wide substrate scope, good functional group tolerance, and high efficiency. Further studies on other cascade cyclizations based on isocyanides are currently underway.

Experimental section

General procedure for the preparation of 2 (2a as an example)

To a solution of ethyl 2-isocyano-3,3-diphenylacrylate 1a (0.2 mmol, 55.4 mg) in toluene (2.0 mL) was added [(C₆H₅)₃P]₃RhCl (1.8 mg, 0.002 mmol). The reaction mixture was stirred for 12 h at 160 °C in a 10 mL sealed tube. After the reaction was complete, the reaction mixture was poured into saturated aqueous NaCl (5.0 mL) and extracted with CH₂Cl₂ (2.0 mL × 3). The combined organic extracts were dried over anhydrous Mg₂SO₄, filtered and concentrated under reduced pressure to yield the crude product, which was purified by chromatography (ethyl acetate/petroleum ether = 1/5, V/V) to give 2a (82.1 mg, 74%) as a yellow solid. R_f = 0.45 (ethyl acetate/petroleum ether: 3/10). Mp. 60–61 °C; ¹H NMR (600 MHz, CDCl₃) δ: 9.58 (d, J = 8.5 Hz, 1H), 7.72–7.69 (m, 1H), 7.67–7.64 (m, 2H), 7.49 (d, J = 7.2 Hz, 3H), 7.41 (d, J = 7.8 Hz, 4H), 7.36–7.35 (m, 2H), 7.32 (t, J = 7.7 Hz, 4H), 7.23 (t, J = 7.3 Hz, 2H), 5.47 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ: 166.95, 155.86, 150.09, 144.27, 142.72, 141.63, 136.64, 136.08, 134.13, 130.73, 129.87, 129.41, 129.00, 128.29, 128.22, 128.09, 127.94, 126.55, 126.46, 126.38, 120.34, 70.29, 61.37, 47.22, 15.02, 13.69; HRMS (ESI-TOF): [M + Na]⁺ calculated for C₃₆H₃₀N₂NaO₄⁺: 577.2098, found: 577.2104.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

Financial support of this research from the National Natural Sciences Foundation of China (21871044 and 21472017) and the Natural Sciences Foundation of Jilin Province (20190201073JC) is greatly acknowledged.

Notes and references

1. For recent reviews, see: (a) Isocyanide Chemistry Applications in Synthesis and Materials Science, ed. V. Nenajdenko, Wiley-VCH, Weinheim, 2012; (b) A. V. Lygin and A. D. Meijere, Angew. Chem., Int. Ed., 2010, 49, 9094; (c) S. Chakrabarty, S. Choudhary, A. Doshi, F.-Q. Liu, R. Mohan, M. P. Ravindra, D. Shah, X. Yang and F. F. Fleming, Adv. Synth. Catal., 2014, 356, 2315.
2. (a) J. Zhu and H. Bienaymé, Multicomponent Reactions, Wiley-VCH, Weinheim, 2005; (b) A. Dömling, Chem. Rev., 2006, 106, 17; (c) L. Banfi and R. Riva, in Organic Reactions, ed. A. B. Charette, Wiley, New York, 2005, vol. 65, p. 1; (d) A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168.
3. (a) D. V. Leusen and A. M. V. Leusen, Org. React., 2001, 57, 417; (b) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235.
4. For reviews, see: (a) V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin and V. Y. Kukushkin, Chem. Rev., 2015, 115, 2698; (b) G. Qiu, Q. Ding and J. Wu, Chem. Soc. Rev., 2013, 42, 5257; (c) S. Lang, Chem. Soc. Rev., 2013, 42, 4867; (d) T. Vlaar, E. Ruijter, B. U. W. Maes and R. V. A. Orru, Angew. Chem., Int. Ed., 2013, 52, 7084.
5. For a review, see: B. Zhang and S. Armido, Chem. Soc. Rev., 2015, 44, 3505.
6. (a) Z. Hou, J. Dong, Y. Men, Z. Lin, J. Cai and X. Xu, Angew. Chem., Int. Ed., 2017, 56, 1805; (b) C. Kanazawa, S. Kamijo and Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662; (c) B. Pooi, J. Lee, K. Choi, H. Hirao and S. H. Hong, J. Org. Chem., 2014, 79, 9231; (d) M.-A. Bonin, D. GiguHre and R. Roy, Tetrahedron, 2007, 63, 4912; (e) R. Grigg, M. I. Lansdell and M. Thornton-Pett, Tetrahedron, 1999, 55, 2025.
7. M. Wenzel, F. Lehmann, R. Beckert, W. Günther and H. Gürls, Monatsh. Chem., 1999, 130, 1373.
8. (a) N. Shao, G.-X. Pang, X.-R. Wang, R.-J. Wu and Y. Cheng, Tetrahedron, 2010, 66, 7302; (b) K. Kobayashi, J. Yonemori, A. Matsunaga, T. Kitamura, M. Tanmatsu, O. Morikawa and H. Konishi, Heterocycles, 2001, 55, 33.
9. (a) Z. Hu, H. Yuan, Y. Men, Q. Liu, J. Zhang and X. Xu, Angew. Chem., Int. Ed., 2016, 55, 7077; (b) S. Su, J. Hu, Y. Cui, C. Tang, Y. Chen and J. Li, Chem. Commun., 2019, 55, 12243.
10. G. Höfle and B. Lange, Angew. Chem., Int. Ed. Engl., 1977, 16, 727.
11. For selected recent examples, see: (a) L. Zhang, T. Liu, Y. M. Wang, J. Chen and Y.-L. Zhao, Org. Lett., 2019, 21, 2973; (b) Y. Yu, Y. Zhang, Z. Wang, Y.-X. Liang and Y.-L. Zhao, Org. Chem. Front., 2019, 6, 3657; (c) X.-B. Bu, Z.-X. Zhang, Q.-Q. Peng, X. Xu and Y.-L. Zhao, J. Org. Chem., 2019, 84, 53; (d) X.-B. Bu, Z. Wang, X.-D. Wang, X.-H. Meng and Y.-L. Zhao, Adv. Synth. Catal., 2018, 360, 2945; (e) X.-B. Bu, Y. Yu, B. Li, L. Zhang, J.-J. Chen and Y.-L. Zhao, Adv. Synth. Catal., 2017, 359, 351; (f) X.-B. Bu, Z. Wang, Y.-H. Wang, T. Jiang, L. Zhang and Y.-L. Zhao, Eur. J. Org. Chem., 2017, 1132.
12. For selected reviews, see: (a) F. Pan, C. Shu and L.-W. Ye, Org. Biomol. Chem., 2016, 14, 9456; (b) M. Giustiniano, A. Basso, V. Mercalli, A. Massarotti, E. Novellino, G. C. Tron and J. Zhu, Chem. Soc. Rev., 2017, 46, 1295; (c) B. Zhang and A. Studer, Chem. Soc. Rev., 2015, 44, 3505; (d) L. Ackermann, Acc. Chem. Res., 2014, 47, 281; (e) A. Zhang, J. L. Neumeyer and R. J. Baldessarini, Chem. Rev., 2006, 107, 274; (f) P. G. Baraldi, M. A. Tabrizi, S. Gessi and P. A. Borea, Chem. Rev., 2008, 108, 238; (g) K. W. Bentley, Nat. Prod. Rep., 2006, 23, 444; (h) F. Dzierszinski, A. Coppin, M. Mortuaire, E. Dewailly, C. Slomianny, J.-C. Ameisen, F. DeBels and S. Tomavo, Antimicrob. Agents Chemother., 2002, 46, 3197.
13. For selected reviews, see: (a) A. Ibrar, I. Khan, N. Abbas, U. Farooq and A. Khan, RSC Adv., 2016, 6, 93016; (b) A. V. Gulevich, A. S. Dudnik, N. Chernyak and V. Gevorgyan, Chem. Rev., 2013, 113, 3084; (c) D. C. Palmer and E. C. Taylor, The Chemistry of Heterocyclic Compounds Oxazoles: Synthesis, Reactions, and Spectroscopy, Wiley, 2004, vol. 60; (d) Y. Hu, X. Xin and B. Wan, Tetrahedron Lett., 2015, 56, 32; (e) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180; (f) P. Wipf, Chem. Rev., 1995, 95, 2115; (g) I. J. Turchi and M. J. S. Dewarb, Chem. Rev., 1975, 75, 389.
14. A. W. Bridge, M. B. Hursthouse, C. W. Lehmann, D. J. Lythgoe and C. G. Newton, J. Chem. Soc., Perkin Trans., 1993, 1, 1839.
15. CCDC 1887535† (2k) contains the supplementary crystallographic data in the Cambridge Crystallographic Data Centre.
16. (a) A. E. Wendlandt and S. S. Stahl, J. Am. Chem. Soc., 2014, 136, 11910; (b) Z. Shi and F. Glorius, Chem. Sci., 2013, 4, 829.
17. (a) D. Bonne, M. Dekhane and J. Zhu, Angew. Chem., Int. Ed., 2007, 46, 2485; (b) J. Wang, S. Luo, J. Huang, T. Mao and Q. Zhu, Chem. – Eur. J., 2014, 20, 11220.
18. For selected reviews, see: (a) O. Ostroverkhova, Chem. Rev., 2016, 116, 13279; (b) C. Wang, H. Dong, W. Hu, Y. Liu and D. Zhu, Chem. Rev., 2018, 118, 3447; (c) W. Wu, R. Tang, Q. Li and Z. Li, Chem. Soc. Rev., 2015, 44, 3997; (d) Z. Yang, Z. Mao, Z. Xie, Y. Zhang, S. Liu, J. Zhao, J. Xu, Z. Chi and M. P. Aldred, Chem. Soc. Rev., 2017, 46, 915.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data of 2. CCDC 1887535. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9qo01229j

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