Synthesis of Pyrimidopyrrolopyridazines via a Tandem Reaction of

6 days ago - College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058 , P.R. China. ⊥ State Key Laboratory of Innovative Natural Medi...
3 downloads 3 Views 746KB Size
Download PDF
Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Synthesis of Pyrimidopyrrolopyridazines via a Tandem Reaction of Heterocyclic Ketene Aminals with 1,2-Diaza-1,3-dienes Menghao Zhao,† Xia Li,† Jiaan Shao,§ Wenteng Chen,∥ Ning Xie,⊥ Hu Yuan,*,† Qingyan Sun,*,† and Weidong Zhang*,†,‡ †

Innovation Center of Chinese Medicine, China State Institute of Pharmaceutical Industry, Shanghai 201203, P.R. China ‡ Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China § Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, 310018, P.R. China ∥ College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, P.R. China ⊥ State Key Laboratory of Innovative Natural Medicine and TCM Injections, Jiangxi Qingfeng Pharmaceutical Co., Ltd., Ganzhou 341000, Jiangxi, China S Supporting Information *

ABSTRACT: A tandem reaction of heterocyclic ketene aminals and 1,2-diaza-1,3-dienes was developed for the expedient synthesis of pyrimidopyrrolopyridazine derivatives. This process involved an intramolecular conjugate addition followed by CuCl2-catalyzed hydrazone formation.

N

fused polycyclic systems containing pyridazine8 and other nitrogen heterocycles (e.g., pyrimidine and pyrrole)9 are rare in the literature. Expanding the structural diversity may facilitate the study of the biology of this class of compounds. Herein, we report a tandem reaction of heterocyclic ketene aminals and 1,2-diaza-1,3-dienes for preparing novel pyrimidopyrrolopyridazine derivatives. Heterocyclic ketene aminals (HKAs, Figure 2)10 possess an electron-rich carbon that can serve as a nucleophile,11 and 1,2-diaza-1,3-dienes (DDs, Figure 2)12 can be viewed as hydrazide precursors with electrophilic properties.13 These two classes of

itrogen heterocycles are an important class of structural motifs in natural1 and synthetic2 compounds of biological interest. Pyridazine-containing polycyclic compounds have received considerable attention because of their broad range of biological activities,3 including diuretic,4 anti-HIV,5 GABAA receptor agonistic,6 and platelet aggregation inhibitory properties7 (Figure 1). However, efficient methods for the construction of

Figure 2. Hypothesis of a reaction of HKAs and DDs. Received: April 7, 2018

Figure 1. Selected bioactive compounds bearing pyridazine-fused cores. © XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01094 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters building blocks have found use in the construction of various heterocyclic systems.14 We envisaged that the reaction of HKAs and DDs may produce a conjugate adduct that could further undergo pyridazine and pyrrole formation to give an interesting 6,5,6-tricyclic skeleton, as illustrated in Figure 2. Notably, a 5,5,6-tricyclic system could also be generated through different cyclization pathways. Initially, a model reaction of HKA 1a and DD 2a was performed. A preliminary screen of solvents and temperatures was examined; the reaction proceeded well in CH3CN at room temperature to deliver 3a (Table 1, entries 1−8). Encouraged Figure 3. X-ray structure of 4a.

Table 1. Optimization of the Reaction Conditionsa

entry

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

CH3CN THF MeOH DMF THF CH3CN MeOH toluene CH3CN CH3CN CH3CN THF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

additive

T (°C)

DIPEA AcONa t-BuONa NaH (0.1equiv) CuCl2 (0.1 equiv) CuCl2 (0.1 equiv) CuCl2 (0.1 equiv) ZnCl2 (0.1 equiv) AcOH (0.1 equiv) Pd(OAc)2 (0.2 equiv) AlCl3 (0.2 equiv) Cu(OAc)2 (0.2 equiv) BF3·Et2O (0.2 equiv) FeCl3 (0.2 equiv) CuBr2 (0.2 equiv) CuCl2 (0.2 equiv) CuCl2 (0.5 equiv) CuCl2 (1.0 equiv)

rt rt rt rt reflux reflux reflux reflux rt rt 50 rt rt 50 reflux 50 50 50 50 50 50 50 50 50 50 50

The optimization of the equivalents of the CuCl2 demonstrated that 0.2 equiv are favorable for the formation of 4a (Table 1, entry 24). With the optimized conditions in hand, the scope of substrates was further explored. As shown in Table 2, various R1 substituents in HKAs were tolerated in this reaction (Table 2, entries 1−33). The incorporation of electron-deficient benzene rings or heterocyclic rings as the R1 substituent slightly reduced the yields (Table 2, entries 5, 7, and 17). The R2 and R3 substituents on HKAs showed no significant effect on the reaction yield, while R4 substituents on HKAs resulted in a much lower isolated yield of 4d′, 4e′, and 4f′, which might be attributed to the steric effects (Table 2, entries 30−32). Meanwhile, the substrate scope of DDs were also examined. It was found that different carbon-chain alkyl substituents as R5 afforded the corresponding products smoothly. Based on the above results, a possible mechanism is proposed in Scheme 1. First, a 1,4-conjugated addition of HKA 1

yieldb (%) 3a, 3a, 3a, 3a, 3a, 3a, 3a, 3a, 3a, 3a, 3a, 3a, 3a, 4a, 4a, 4a, 3a, 3a, 3a, 3a, 3a, 3a, 4a, 4a, 4a, 4a,

70 51 32 36 6 30 8 4 60 20 18 7 40 55 35 47 53 49 34 40 27 34 56 62 51 24

Scheme 1. Proposed Mechanism for the Formation of 4

a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol) in solvent with additive. bYields of isolated product 3a or 4a.

to DD 2 produces intermediate I-1.15 Subsequent intramolecular aminolysis of the intermediate I-1 affords I-2. The rapid oxidation of I-2 prevents its transformation though pathway A and generates the stable product 3. Chelation of CuCl2 with 3 then mediates the intramolecular cyclization of I-3 to afford I-4. Finally, aromatization with concomitant loss of a carbamate residue in I-4 provides the desired pyrimidopyrrolopyridazine 4. In conclusion, we developed an efficient and straightforward approach for the synthesis of pyrimidopyrrolopyridazine derivatives. This tandem transformation was initiated by CuCl2 from HKAs with DDs at mild conditions. The broad applicability of

by these results, more efforts were made in order to further cyclization of 3a to tri-ring fused compound. Additives such as bases, acid, and metal were tested. As listed in Table 1, the reaction failed to further transform in the presence of various bases with 3a as the major products (Table 1, entries 9−12). Instead, when 0.1 equiv of CuCl2 was added and the reaction temperature was raised to 50 °C, a new compound was formed as the major product 4a with a yield of 55% (Table 1, entry 14). This new compound 4a was further characterized by X-ray crystallography (Figure 3). Moreover, the isolated yields of 4a did not significantly improve by increasing the temperatures or replacement with other additives (Table 1, entries 16−23). B

DOI: 10.1021/acs.orglett.8b01094 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 2. Synthesis of Pyrimidopyrrolopyridazines 4 from HKAs 1 and DDs 2a

HKAs 1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

1a 1b 1c 1d 1e 1f 1g 1c 1d 1f 1a 1c 1a 1f 1d 1b 1h 1i 1i 1i 1j 1j 1j 1k 1k 1k 1l 1l 1l 1m 1m 1m 1n

DDs 2

R1

R2

R3

R4

phenyl 4-methylphenyl 4-chlorophenyl 3-chlorophenyl pyridin-3-yl naphthalen-2-yl 4-nitrophenyl 4-chlorophenyl 3-chlorophenyl naphthalen-2-yl phenyl 4-chlorophenyl phenyl naphthalen-2-yl 3-chlorophenyl 4-methylphenyl thiophene-2-yl phenyl phenyl phenyl 4-methylphenyl 4-methylphenyl 4-methylphenyl 4-chlorophenyl 4-chlorophenyl 4-chlorophenyl naphthalen-2-yl naphthalen-2-yl naphthalen-2-yl phenyl phenyl phenyl Me

H H H H H H H H H H H H H H H H H Me Me Me Me Me Me Me Me Me Me Me Me H H H H

H H H H H H H H H H H H H H H H H Me Me Me Me Me Me Me Me Me Me Me Me H H H H

H H H H H H H H H H H H H H H H H H H H H H H H H H H H H Et Et Et H

entry

2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2c 2c 2c 2c 2c 2c 2a 2c 2b 2a 2b 2c 2a 2b 2c 2a 2b 2c 2a 2b 2c 2a

products 4 R5

4

yieldb (%)

Me Me Me Me Me Me Me Et Et Et Et n-pr n-pr n-pr n-pr n-pr n-pr Me n-pr Et Me Et n-pr Me Et n-pr Me Et n-pr Me Et n-pr Me

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v 4w 4x 4y 4z 4a′ 4b′ 4c′ 4d′ 4e′ 4f′ 4g′

61c 65 58 60 35 65 38 52 53 60 50 54 52 56 52 53 42 60 55 57 58 52 53 52 50 51 57 60 50 28 21 17 61

a Reagents and conditions: 1 (0.2 mmol), 2 (0.2 mmol), CuCl2 (0.04 mmol), CH3CN (5 mL), 50 °C. bIsolated yields. cReaction condition of 4a: 1a (1.0 mmol), 2a (1.0 mmol), CuCl2 (0.2 mmol), CH3CN (25 mL), 50 °C.

Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

the reaction is remarkable for the rapid synthesis of novel heterocycles with important biological activities.

■

■

ASSOCIATED CONTENT

* Supporting Information S

AUTHOR INFORMATION

Corresponding Authors

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01094. Detailed experimental procedures and full spectroscopic data for all new compounds (PDF)

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected].

Accession Codes

Menghao Zhao: 0000-0003-1883-8234 Hu Yuan: 0000-0002-9962-3114

ORCID

CCDC 1819613 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge

Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b01094 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

■

G.-Y.; Gong, M.; Yue, J.-F.; Yang, X.-X.; Zhou, S.-L.; Du, W.; Chen, Y.C. Org. Lett. 2017, 19, 1874−1877. (13) (a) Li, M.; Zhou, Z.-M.; Wen, L.-R.; Qiu, Z.-X. J. Org. Chem. 2011, 76, 3054−3063. (b) Yu, F.; Yan, S.; Hu, L.; Wang, Y.; Lin, J. Org. Lett. 2011, 13, 4782−4785. (14) (a) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.; Lillini, S.; Mantellini, F.; Palacios, F.; de Los Santos, J. M. J. Org. Chem. 2006, 71, 5897−5905. (b) Attanasi, O. A.; Baccolini, G.; Boga, C.; De Crescentini, L.; Filippone, P.; Mantellini, F. J. Org. Chem. 2005, 70, 4033−4037. (c) Attanasi, O. A.; Bartoccini, S.; Favi, G.; Giorgi, G.; Perrulli, F. R.; Santeusanio, S. J. Org. Chem. 2012, 77, 1161−1167. (d) Attanasi, O. A.; Favi, G.; Filippone, P.; Golobic, A.; Stanovnik, B.; Svete, J. J. Org. Chem. 2005, 70, 4307−4313. (e) Santeusanio, S.; Majer, R.; Perrulli, F. R.; De Crescentini, L.; Favi, G.; Giorgi, G.; Mantellini, F. J. Org. Chem. 2017, 82, 9773−9778. (f) Attanasi, O. A.; Ballini, R.; De Crescentini, L.; Filippone, P.; Mantellini, F. J. Org. Chem. 1999, 64, 9653−9657. (g) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Santeusanio, S. J. Org. Chem. 2002, 67, 8178−8181. (15) Attanasi, O. A.; Favi, G.; Geronikaki, A.; Mantellini, F.; Moscatelli, G.; Paparisva, A. Org. Lett. 2013, 15, 2624−2627.

ACKNOWLEDGMENTS The work was supported by the Professor of Chang Jiang Scholars Program, NSFC (81520108030, 21472238), Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products (16DZ2280200), the Scientific Foundation of Shanghai China (13401900103, 13401900101), the Open Project of State Key Laboratory of Innovative Natural Medicine, and TCM Injections (QFSKL2017001).

■

REFERENCES

(1) For selected reviews, see: (a) Cimmino, A.; Evidente, A.; Mathieu, V.; Andolfi, A.; Lefranc, F.; Kornienko, A.; Kiss, R. Nat. Prod. Rep. 2012, 29, 487−501. (b) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675−696. (2) For selected reviews, see: (a) Han, Y.-T.; Jung, J.-W.; Kim, N.-J. Curr. Org. Chem. 2017, 21, 1265−1291. (b) Farghaly, T.; Dawood, K.; Shaaban, M. Curr. Org. Synth. 2015, 12, 230−260. (c) Remennikov, G. Y. J. Heterocycl. Chem. 2017, 54, 2575−2597. (d) Liu, T.; Fu, H. Synthesis 2012, 44, 2805−2824. For select examples, see: (e) Lotfata, A.; Rimaz, M.; Baradarani, M. M. J. Heterocycl. Chem. 2018, 55, 603− 609. (f) Beryozkina, T. V.; Kolos, N. N.; Bakulev, V. A. Chem. Heterocycl. Compd. 2016, 52, 651−657. (3) (a) Huang, C.; Yan, S.-J.; Zeng, X.-H.; Dai, X.-Y.; Zhang, Y.; Qing, C.; Lin, J. Eur. J. Med. Chem. 2011, 46, 1172−1180. (b) Chelini, A.; Brogi, S.; Paolino, M.; Di Capua, A.; Cappelli, A.; Giorgi, G.; Farzad, M.; Di Cesare Mannelli, L.; Micheli, L.; Ghelardini, C.; Anzini, M. J. Med. Chem. 2017, 60, 5216−5221. (c) Frederick, R.; Dumont, W.; Ooms, F.; Aschenbach, L.; Van der Schyf, C. J.; Castagnoli, N.; Wouters, J.; Krief, A. J. Med. Chem. 2006, 49, 3743−3747. (4) Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.; Kinoshita, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y. J. Med. Chem. 1999, 42, 779−783. (5) Porcari, A. R.; Ptak, R. G.; Borysko, K. Z.; Breitenbach, J. M.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2000, 43, 2457−2463. (6) Russell, M. G.; Carling, R. W.; Atack, J. R.; Bromidge, F. A.; Cook, S. M.; Hunt, P.; Isted, C.; Lucas, M.; McKernan, R. M.; Mitchinson, A.; Moore, K. W.; Narquizian, R.; Macaulay, A. J.; Thomas, D.; Thompson, S. A.; Wafford, K. A.; Castro, J. L. J. Med. Chem. 2005, 48, 1367−1383. (7) Cignarella, G.; Barlocco, D.; Pinna, G. A.; Loriga, M.; Tofanetti, O.; Germini, M.; Sala, F. J. Med. Chem. 1986, 29, 2191−2194. (8) (a) Jia, H.; Dai, G.; Weng, J.; Zhang, Z.; Wang, Q.; Zhou, F.; Jiao, L.; Cui, Y.; Ren, Y.; Fan, S.; Zhou, J.; Qing, W.; Gu, Y.; Wang, J.; Sai, Y.; Su, W. J. Med. Chem. 2014, 57, 7577−7589. (b) Lucas, M. C.; Bhagirath, N.; Chiao, E.; Goldstein, D. M.; Hermann, J. C.; Hsu, P. Y.; Kirchner, S.; Kennedy-Smith, J. J.; Kuglstatter, A.; Lukacs, C.; Menke, J.; Niu, L.; Padilla, F.; Peng, Y.; Polonchuk, L.; Railkar, A.; Slade, M.; Soth, M.; Xu, D.; Yadava, P.; Yee, C.; Zhou, M.; Liao, C. J. Med. Chem. 2014, 57, 2683−2691. (9) For selected reviews, see: (a) Heinisch, G.; Haider, N. Heterocycles 1993, 35, 519−538. (b) Svete, J. J. Heterocycl. Chem. 2005, 42, 361−373. (10) For selected reviews, see: Huang, Z.-T.; Wan, M.-X. Heterocycles 1994, 37, 1233−1262. (11) For selected reviews, see: (a) Wang, K.-M.; Yan, S.-J.; Lin, J. Eur. J. Org. Chem. 2014, 2014, 1129−1145. (b) Yang, L.-F. Synlett 2014, 25, 2964−2965. (12) For selected reviews, see: (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009, 2009, 3109−3127. For select examples, see: (b) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Foresti, E.; Mantellini, F. J. Org. Chem. 2000, 65, 2820−2823. (c) Attanasi, O. A.; Filippone, P.; Fiorucci, C.; Foresti, E.; Mantellini, F. J. Org. Chem. 1998, 63, 9880−9887. (d) Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.; Spinelli, D. Org. Lett. 2008, 10, 1983−1986. (e) Attanasi, O. A.; Favi, G.; Filippone, P.; Mantellini, F.; Moscatelli, G.; Perrulli, F. R. Org. Lett. 2010, 12, 468−471. (f) Ran, D

DOI: 10.1021/acs.orglett.8b01094 Org. Lett. XXXX, XXX, XXX−XXX