Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process★

doi:10.6023/A23040164

Abstract

Pyrrolo[3,2-d]pyrimidin-4-ones are valuable structural motifs in many bioactive compounds and pharmaceuticals. Such structures have received extensive attentions from synthetic community. Two general strategies have been developed for the formation of the fused pyrimidine-pyrrole structure: one is to construct the pyrimidine ring from substituted pyrroles, and the other is to construct the pyrrole ring from 5,6-functionalized pyrimidines. However, these methods have generally required multiple synthetic steps and the use of starting materials with uncommon functional groups, and also suffered with other drawbacks such as harsh reaction conditions and limited substrate scope. Thus, it is highly desirable to develop facile and practical approaches for the construction of structural diversified pyrrolo[3,2-d]pyrimidin-4-ones. Very recently, we have developed an alkyne-isocyanide [3＋2] cycloaddition/Boulton-Katritzky rearrangement/ring expansion reaction for the synthesis of 9-deazaguanines from 1,2,4-oxadiazole-derived propiolamides with isocyanides. Different from traditional Boulton-Katritzky rearrangement (BKR), which is to form stable five-membered rings, the method provides a facile access to fused heterocycles via forming an unstable BKR spirocyclic intermediate and followed by a spontaneous ring expansion via acyl migration. In this work, to further expand the scope of this method, the [3＋2] cycloaddition/BKR-ring expansion reactions of isoxazole-derived propiolamides with isocyanides were developed. The reactions were performed with CuI as the catalyst and Cs₂CO₃ as the base in toluene/N,N-dimethylformamide (DMF) (1∶3, V∶V) at room temperature for the alkyne-isocyanide [3＋2] cycloaddition and then at 110 ℃ for the BKR-ring expansion process. A variety of isoxazole- derived propiolamides and isocyanides were well tolerated in the reactions and afforded the desired pyrrolo[3,2- d]pyrimidin-4-one products in satisfactory yields. The control experiments were performed to elucidate the reaction process: copper catalyst is used only for the alkyne-isocyanide [3＋2] cycloaddition, but no necessary for the base-promoted BKR-ring expansion process. Compared to the traditional methods for such skeletons, the approach features readily available starting materials, broad substrate scope, short steps, and structural diversification.

Key words: alkyne-isocyanide [3＋2] cycloaddition, Boulton-Katritzky rearrangement (BKR), ring expansion, pyrrolo[3,2-d] pyrimidin-4-one, cascade reaction

Cite this article

Jianghao Luo, Haowen Ma, Jiehao Zhang, Wei Zhou, Qian Cai. Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★[J]. Acta Chimica Sinica, 2023, 81(8): 898-904.

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Fig. & Tab. 6

Figure 1. Examples of pyrrolo[3,2-d]pyrimidin-4-one-related bioactive compounds

Figure 2. An alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction for the construction of pyrrolo[3,2-d]pyrimidin-4-one derivatives

Entry	Catalyst	Solvent (V∶V)	Base
1^c	CuI	Tol/DMF (1∶3)	Cs₂CO₃	Trace	90
2^d	CuI	Tol/DMF (1∶3)	Cs₂CO₃	Trace	88
3^e	CuI	Tol/DMF (1∶3)	Cs₂CO₃	64	18
4	CuI	Tol/DMF (1∶3)	Cs₂CO₃	79	Trace
5^f	CuI	Tol/DMF (1∶3)	Cs₂CO₃	74	Trace
6	CuBr	Tol/DMF (1∶3)	Cs₂CO₃	59	Trace
7	Cu₂O	Tol/DMF (1∶3)	Cs₂CO₃	46	Trace
8	CuI	Tol	Cs₂CO₃	12	83
9	CuI	DMF	Cs₂CO₃	67	Trace
10	CuI	DMSO	Cs₂CO₃	61	Trace
11	CuI	Tol/DMF (1∶3)	LiO^tBu	42	Trace
12	CuI	Tol/DMF (1∶3)	NaOH	48	Trace

Table 1. Optimization of reaction conditions for alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction

Figure 3. Substrate scope for alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction

Figure 4. Gram-scale reaction and synthetic transformation of 3a

Figure 5. Control experiments for alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction

References 13

[1]	(a) Bantia S.; Miller P. J.; Parker C. D.; Ananth S. L.; Horn L. L.; Kilpatrick J. M.; Morris P. E.; Hutchison T. L.; Montgomery J. A.; Sandhu J. S.; Int. Immunopharmacol. 2001, 1, 1199;
	(b) Theoclitou M.-E.; Aquila, B.; Block, M. H.; Brassil, P. J.; Castriotta, L.; Code, E.; Collins, M. P.; Davies, A. M.; Deegan, T.; Ezhuthachan, J.; Filla, S.; Freed, E.; Hu, H.; Huszar, D.; Jayaraman, M.; Lawson, D.; Lewis, P. M.; Nadella, M. V. P.; Oza, V.; Padmanilayam, M.; Pontz, T.; Ronco, L.; Russell, D.; Whitston, D.; Zheng, X. J. Med. Chem. 2011, 54, 6734;
	(c) Laufersweiler M. C.; Wang Y.; Soper D. L.; Suchanek M. K.; Fancher A. N.; Lu W.; Wang R. L.; Oppong K. A.; Ellis C. D.; Baize M. W.; O'Neil S. V.; Wos J. A.; Demuth T. P. Bioorg. Med. Chem. Lett. 2005, 15, 4322. doi: 10.1016/j.bmcl.2005.06.046
[2]	(a) Semeraro T.; Lossani A.; Botta M.; Ghiron C.; Alvarez R.; Manetti F.; Mugnaini C.; Valensin S.; Focher F.; Corelli F.; J. Med. Chem. 2006, 49, 6037;
	(b) Rodrigues M. V. N.; Barbosa, A. F.; da Silva, J. F.; dos Santos, D. A.; Vanzolini, K. L.; de Moraes, M. C.; Corrêa, A. G.; Cass, Q. B. Bioorg. Med. Chem. 2016, 24, 226;
	(c) Tian C.; Wang, M.; Fang, F.; Zhang, Z.; Wang, X.; Liu, J. Eur. J. Med. Chem. 2017, 138, 630;
	(d) Gangjee A.; Li, W.; Yang, J.; Kisliuk, R. L. J. Med. Chem. 2008, 51, 68;
	(e) Huang L.; Li, H.; Li, L.; Niu, L.; Seupel, R.; Wu, C.; Cheng, W.; Chen, C.; Ding, B.; Brennan, P. E.; Yang, S. J. Med. Chem. 2019, 62, 4526;
	(f) Zeng S.; Xie H.; Zeng L.-L.; Lu X.; Zhao X.; Zhang G.-C.; Tu Z.-C.; Xu H.-J.; Yang L.; Zhang X.-Q.; Hu W. Bioorg. Med. Chem. 2013, 21, 1749. doi: 10.1016/j.bmc.2013.01.062
[3]	(a) Imai K.-I. Chem. Pharm. Bull. 1964, 12, 1030 doi: 10.1248/cpb.12.1030
	(b) Taylor, E. C.; Young, W. B.; Ward, C. C. Tetrahedron Lett. 1993, 34, 4595;.
	(c) Taylor, E. C.; Young, W. B. J. Org. Chem. 1995, 60, 7947;.
	(d) Elliott, A. J.; Montgomery, J. A.; Walsh, D. A. Tetrahedron Lett. 1996, 37, 4339;.
	(e) Furneaux, R. H.; Tyler, P. C. J. Org. Chem. 1999, 64, 8411;.
	(f) Liu, M.-C.; Luo, M.-Z.; Mozdziesz, D. E.; Sartorelli, A. C. Synth. Commun. 2002, 32, 3797;.
	(g) Elliott, A. J.; Morris, P. E.; Petty, Jr. S. L.; Williams, C. H. J. Org. Chem. 1997, 62, 8071;.
	(h) Kwong, C. D.; Elliot, A. J.; Montgomery, J. A. J. Labelled Cpd. Radiopharm. 1998, 41, 879;.
	(i) Shih H.; Cottam H. B.; Carson D. A. Chem. Pharm. Bull. 2002, 50, 364. doi: 10.1248/cpb.50.364
[4]	(a) Boulton A. J.; Katritzky A. R.; Hamid A. M. J. Chem. Soc. C 1967, 2005;
	(b) Afridi, A. S.; Katritzky, A. R.; Ramsden, C. A. J. Chem. Soc., Perkin Trans. 1 1976, 315;.
	(c) For a book: Comprehensive Heterocyclic Chemistry II, Eds.: Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Elsevier, Amsterdam, 1996, Vols. 1-9.
[5]	For selected reviews and examples of rearrangement with isoxazoles and 1,2,4-oxadiazoles, see: (a) Pace, A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74, 351;
	(b) Martorana, A.; Piccionello, A. P.; Buscemi, S.; Giorgi, G.; Pace, A. Org. Biomol. Chem. 2011, 9, 491;.
	(c) Martorana, A.; Pace, A.; Buscemi, S.; Piccionello, A. P. Org. Lett. 2012, 14, 3240;.
	(d) Hu, F.; Szostak, M. Adv. Synth. Catal. 2015, 357, 2583;.
	(e) Jones R. C. F.; Chatterley A.; Marty R.; Owton W. M.; Elsegood M. R. J. Chem. Commun. 2015, 51, 1112. doi: 10.1039/C4CC07999J
[6]	For selected reviews on ring expansion reactions, see: (a) Lu, B.-L.; Dai, L.; Shi, M. Chem. Soc. Rev. 2012, 41, 3318;
	(b) Mack, D. J.; Njardarson, J. T. ACS Catal. 2013, 3, 272;
	(c) Biletskyi, B.; Colonna, P.; Masson, K.; Parrain, J.-L.; Commeiras, L.; Chouraqui, G. Chem. Soc. Rev. 2021, 50, 7513;
	(d) Li, D.; Zang, W.; Bird, M. J.; Hyland, C. J. T.; Shi, M. Chem. Rev. 2021, 121, 8685;
	(e) Nanda, T.; Fastheem, M.; Linda, A.; Pati, B. V.; Banjare, S. K.; Biswal, P.; Ravikumar, P. C. ACS Catal. 2022, 12, 13247;
	(f) Ye J. Chin. J. Org. Chem. 2021, 41, 1755. doi: 10.6023/cjoc202100030
[7]	For selected examples on ring expansion reactions, see: (a) Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858;
	(b) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260;
	(c) Chen, G.-Q.; Zhang, X. N.; Wei, Y.; Tang, X.-Y.; Shi, M. Angew. Chem., Int. Ed. 2014, 53, 8492;
	(d) Pan, D.; Wei, Y.; Shi, M. Org. Lett. 2016, 18, 3930;
	(e) Chen, G.-Q.; Fang, W.; Wei, Y.; Tang, X.-Y.; Shi, M. Chem. Sci. 2016, 7, 4318;
	(f) Pan, D.; Wei, Y.; Shi, M. Org. Lett. 2017, 19, 3584;
	(g) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 1680;
	(h) Zhuo, C.-X.; Wu, Q.-F.; Zhao, Q.; Xu, Q.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 8169;
	(i) Zhuo, C.-X.; Cheng, Q.; Liu, W.-B.; Zhao, Q.; You, S.-L. Angew. Chem., Int. Ed. 2015, 54, 8475;
	(j) Wu, Q.; Zheng, C.; Zhuo, C.-X.; You, S.-L. Chem. Sci. 2016, 7, 4453;
	(k) Wang, Y.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 15093;
	(l) Zheng, C.; You, S.-L. Acc. Chem. Res. 2020, 53, 974;
	(m) George, J.; Kim, H. Y.; Oh, K. Adv. Synth. Catal. 2016, 358, 3714;
	(n) George, J.; Kim, H. Y.; Oh, K. Org. Lett. 2017, 19, 628;
	(o) Ramu, G.; Ambala, S.; Nanubolu, J. B.; Babu, B. N. RSC Adv. 2019, 9, 35068;
	(p) Ramu, G.; Tangella, Y.; Ambala, S.; Babu, B. N. J. Org. Chem. 2020, 85, 5370;
	(q) Moisan, L.; Wagner, M.; Comesse, S.; Doris, E. Tetrahedron Lett. 2006, 47, 9093;
	(r) Pesquet, A.; Daїch, L. Van Hijfte, J. Org. Chem. 2006, 71, 5303;
	(s) Shang, S.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Angew. Chem., Int. Ed. 2014, 53, 6216;
	(t) Guo, X.; Xing, Q.; Lei, K.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Adv. Synth. Catal. 2017, 359, 4393;
	(u) Mamedov, V. A.; Mamedova, V. L.; Qu, Z.-W.; Zhu, H.; Galimullina, V. R.; Korshin, D. E.; Khikmatova, G. Z.; Litvinov, I. A.; Latypov, S. K.; Sinyashin, O. G.; Grimme, S. J. Org. Chem. 2021, 86, 13514;
	(v) Mandal, S.; Pramanik, A. J. Org. Chem. 2022, 87, 9282;
	(w) Zhu W.-K.; Xu L.-W. Chin. J. Org. Chem. 2023, 43, 362. (in Chinese) doi: 10.6023/cjoc202300003
	( 祝炜柯, 徐利文, 有机化学, 2023, 43, 362.)
[8]	For recent reviews on heterocyclic dearomatization: (a) Roche, S. P.; Porco, J. A. Angew. Chem., Int. Ed. 2011, 50, 4068;
	(b) Donohoe, T. J.; Pullin, R. D. C. Chem. Commun. 2012, 48, 11924;
	(c) Ding, Q.; Zhou, X.; Fan, R. Org. Biomol. Chem. 2014, 12, 4807;
	(d) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc.Chem. Res. 2014, 47, 2558;
	(e) Liang, X.-W.; Zheng, C.; You, S.-L. Chem. Eur. J. 2016, 22, 11918;
	(f) Sun, W.; Li, G.; Hong, L.; Wang, R. Org. Biomol. Chem. 2016, 14, 2164;
	(g) Zheng, C.; You, S.-L. Chem 2016, 1, 830;
	(h) Wu W.-T.; Zhang L.-M.; You S.-L. Acta Chim. Sinica 2017, 75, 419. (in Chinese) doi: 10.6023/A17020049
	( 吴文挺, 张立明, 游书力, 化学学报, 2017, 75, 419.)
[9]	Luo J.; Ma H.; Wu K.; Ao Y.; Zhou W.; Cai Q. Org. Lett. 2023, 25, 2123. doi: 10.1021/acs.orglett.3c00575
[10]	For selected reviews on alkyne-isocyanide [3＋2] cycloaddition, see: (a) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235;
	(b) Boyarskiy, V. P.; Bokach, N. A.; Luzyanin, K. V.; Kukushkin, V. Y. Chem. Rev. 2015, 115, 2698;
	(c) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.; Novellino, E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295;
	(d) Luo J.; Chen G.-S.; Chen S.-J.; Li Z.-D.; Liu Y.-L. Chem. Eur. J. 2021, 27, 6598. doi: 10.1002/chem.v27.22
[11]	For selected examples, see: (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260;
	(b) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664;
	(c) Gao, M.; He, C.; Chen, H.; Bai, R.; Cheng, B.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 6958;
	(d) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953;
	(e) Qi, X.; Zhang, H.; Shao, A.; Zhu, L.; Xu, T.; Gao, M.; Liu, C.; Lan, Y. ACS Catal. 2015, 5, 6640;
	(f) Xiao, P.; Yuan, H.; Liu, J.; Zheng, Y.; Bi, X.; Zhang, J. ACS Catal. 2015, 5, 6177;
	(g) Dong, J.; Bao, L.; Hu, Z.; Ma, S.; Zhou, X.; Hao, M.; Li, N.; Xu, X. Org. Lett. 2018, 20, 1244;
	(h) He, X.-L.; Zhao, H.-R.; Song, X.; Jiang, B.; Du, W.; Chen, Y.-C.; ACS Catal. 2019, 9, 4374;
	(i) Zheng, S.-C.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2019, 58, 1494;
	(j) Liu, J.-Q.; Chen, X.; Shatskiy, A.; Kärkäs, M. D.; Wang, X.-S. J. Org. Chem. 2019, 84, 8998;
	(k) Wang Y.; Zhou Y.; Song Q. Chem. Commun. 2020, 56, 6106. doi: 10.1039/D0CC01919D
[12]	Bird C. W. Tetrahedron 1985, 41, 1409. doi: 10.1016/S0040-4020(01)96543-3
[13]	CCDC 2258385 (3j) contains the supplementary crystallographic data for this paper.

串联炔-异氰[3＋2]环加成/Boulton-Katritzky重排/扩环反应构建吡咯并[3,2-d]嘧啶-4-酮化合物^★