Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Triflates-Triggered Intermolecular Cyclization of Carbodiimides Leading to 2‑Aminoquinazolinone and 2,4-Diaminoquinazoline Derivatives Xiaowei Zhang,† Sheng Wang,† Yu Liu,† and Chanjuan Xi*,†,‡ †
MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *
ABSTRACT: A triflate-triggered intermolecular cyclization of carbodiimides to provide 2-amino-4-imino-quinazolines, which could be easily transformed to 2-aminoquinazolinones and 2,4diaminoquinazolines in high yield, has been reported. A variety of functional groups are tolerated in the 2-amino-4iminoquinazoline scaffolds.
Q
uinazoline scaffolds are important nitrogen-containing heterocycles widely existing in natural products,1 such as chrysogine 11a and l-vasicinone 2,1b as well as drugs,2 such as methaqualone 3 as a type of hypnotic,2b gefitnib 4 and erlotinib 5 as anticancer clinical candidates, 2d compound 6 as acetylcholinesterase inhibitors,2e and compound 7 as potent antimicrobial agents2f (see Figure 1). The quinazoline derivatives generally display a broad range of bioactivities,3 for instance, antimicrobial,3a antiinflammatory,3b antifungal,3c antibacterial,3d and antitumor.3e Among the family of the
quinazoline scaffolds, 2-aminoquinazolinones and 2,4-diaminoquinazolines have received particular interest, because of their vital pharmacological activity. Consequently, numerous synthetic methods have been developed in the previous literature.4 The most common approaches to the 2-aminoquinazolinones involve a reaction4a between amines and isatoic anhydrides that could be prepared from cyclization of 2-aminobenzoic acid or its derivatives with carboxylic acid derivatives or orthoesters.5 Amination of quinazolinones to provide the corresponding 4amino quinazoline derivatives were also demonstrated.6 Moreover, there are several effective metal-catalyzed protocols for preparing 2-aminoquinazolinones in recent years.7 Nevertheless, some of these reported methods suffer from drawbacks, such as harsh conditions, long reaction times, tedious workup conditions, and unsatisfactory yields. From the viewpoint of sustainable chemistry, the development of a general, efficient, concise, easy workup, and metal-free pathway toward 2-amino4-imino-quinazoline derivatives is still highly desirable, especially for the drug screen without trace metals, although several methods to reach 4-imino-quinazoline have been reported.8 As part of our ongoing interest to develop convenient and diverse route under metal-free conditions for synthesis of heterocycles, we have developed methyl trifluoromethanesulfonate (MeOTf)-induced annulation of alkynes and isothiocyanates or nitriles to afford various heterocycles, such as quinolines,9a indenones,9b,c and pyrroles.9d Herein, we describe the triflate esters (ROTf)-triggered intermolecular cyclization of carbodiimides to provide 2-amino-4-iminoquinazolines in high yield within high selectivity. Furthermore,
Figure 1. Examples of biologically active compounds.
Received: January 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00314 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
aforementioned results, the optimal condition is shown in entry 17 in Table 1. Under the optimized conditions, a study on the substrate scope was carried out. First, a variety of N,N′-diarylcarbodiimides was studied as examples. Generally, the reaction proceeded smoothly with any diarylcarbodiimides to afford the corresponding 2-amino-4-imino-quinazolines (3), which could be hydrolyzed to generate the corresponding 2-aminoquinazolinones (4). The representative results are shown in Scheme 1. When diarylcarbodiimides with para-substituents,
the 2-amino-4-imino-quinazolines could be easily transformed to 2-aminoquinazolinones and 2,4-diaminoquinazolines after hydrolysis. On the basis of our former research work on triflate-triggered annulation,9 we initially explored the reaction of N,N′diphenylcarbodiimide 1a (0.5 mmol) and MeOTf 2a (0.5 mmol) in dichloroethane (DCE) as solvent in a sealed tube at 100 °C for 12 h, 2-amino-4-imino-quinazoline 3aa was observed by NMR in 10% yield (Table 1, entry 1). We Table 1. Optimization of Cyclization of N,N′Diarylcarbodiimidesa
Scheme 1. Scope of Cyclization of N,N′Diarylcarbodiimidesa
entry
temp [°C]
time [h]
solvent
ratio, 1a:2a
yieldb [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
100 100 100 100 100 100 100 100 100 100 100 100 100 120 130 120 120 120
12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 18 24 30
DCE DCE THF CH3CN DMF DMSO CH2Cl2 CHCl3 CCl4 n-hexane DCE DCE DCE DCE DCE DCE DCE DCE
1.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.0:1.0 2.2:1.0 2.4:1.0 2.6:1.0 2.4:1.0 2.4:1.0 2.4:1.0 2.4:1.0 2.4:1.0
10 53 NR NR NR NR 38 25 10 28 67 72 71 77 75 81 88 (73) 80
a
The reaction was performed with MeOTf (0.5 mmol) in 2 mL of solvent. bThe yield was evaluated by 1H NMR with dibromomethane (CH2Br2) as an internal standard. Isolated yield was given in parentheses based on MeOTf.
a Reaction conditions: diarylcarbodiimide 1 (1.2 mmol), triflate 2 (0.5 mmol), DCE (2 mL), 120 °C, N2, 24 h. The yield was evaluated by 1H NMR with CH2Br2 as internal standard. Isolated yield was given in parentheses. bCombined NMR yield of two isomers.
detected that the product 3aa contained two molecules of 1a. When 2 equiv of 1a and 1 equiv of 2a were used, the reaction proceeded smoothly, and 3aa was obtained in 53% NMR yield (Table 1, entry 2). Then, different solvents were screened, such as tetrahydrofuran (THF), acetonitrile (CH3CN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichlomethane (CH2Cl2), trichloromethane (CHCl3), tetrachloromethane (CCl4), and n-hexane (Table 1, entries 3−10). DCE was found to be the superior solvent for this reaction (Table 1, entry 2). To further improve the yield of product, a ratio of substrates was investigated (Table 1, entries 11−13). A satisfactory yield could be obtained when diphenylcarbodiimide (1a) and MeOTf (2a) were used in 2.4/1 ratio (Table 1, entry 12). When the reaction temperature was enhanced to 120 °C and 130 °C, the yield of 3aa was improved to 77% and 75%, respectively (Table 1, entries 14 and 15). Furthermore, the effect of reaction time was also examined (Table 1, entries 16− 18), the yields of 3aa increased to 88% when reaction was treated for 24 h (Table 1, entry 17). Based on the
such as methyl and chloro groups, were employed, the corresponding 2-amino-4-imino-quinazolines 3ba and 3ca were formed in 80% and 93% NMR yields, respectively. When bis(4-fluorophenyl)methanediimine 1d was employed, the 3da was obtained in 86% NMR yield. During the isolation on silica gel, a mixture of 3da and 4da was obtained. To obtain sole product, the reaction mixture was hydrolyzed using a MeOH−HCl aqueous solution to afford 4da in 60% isolated yield after purifization on silica gel. Diarylcarbodiimides with strong electron-withdrawing group such as trifluoromethyl in the para-position afforded the corresponding 3ea in trace amount, and the starting materials remained based on GC-MS. When di-o-tolylmethanediimine (1f) was used, a mixture of two products was observed in NMR with a ratio of ∼1:1. In B
DOI: 10.1021/acs.orglett.8b00314 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 2. Scope of Cyclization of N,N′-Diarylcarbodiimides and N,N′-Dialkylcarbodiimidesa
addition, two peaks were shown in GC-MS with the same molecular weight, which indicated that two isomers may formed in trans and cis. Notably, only one product 4fa was obtained in 70% isolated yield after hydrolysis and purification. To our delight, the crystal of 3ca was suitable for single-crystal analysis, and its structure was fully characterized by X-ray diffraction (XRD) analysis. The structure of 3ca clearly shows the formation of the 2-amino-4-imino-quinazoline skeleton. Then, we utilized EtOTf instead of MeOTf to facilitate cyclization and 3ab was gained in 85% NMR yield. Furthermore, we tried PhOTf as a triflate reagent; unfortunately, the reaction did not proceed, and the starting materials remained. To further extend the substrate scope, we attempted asymmetry carbodiimides possessing aliphatic and aromatic substituents, such as N-cyclohexyl-N-phenylcarbodiimide 1g and N-butyl-N-phenylcarbodiimide 1h. Both reactions proceeded to give a complex and inseparable mixture. Moreover, we tried the combination of two different carbodiimides. When diphenylcarbodiimide 1a and diisopropylcarbodiimide (DIC) 1i were mixed with a 1:1 ratio in the reaction, the unexpected product N2,N4-diisopropyl-N2-methylquinazoline-2,4-diamine 5aia was obtained in 15% isolated yield after hydrolysis. The formation of 5aia may be attributed to two carbodiimide molecules through intermolecular metathesis reaction, which has been reported by Meyer.10 In order to improve the reaction, we further optimized the reaction condition based on possible mechanism (see Tables S1 and S3 in the Supporting Information). As a result, the reaction was conducted at 140 °C for 12 h with the addition of diphenylcarbodiimide (1a), DIC (1i), and MeOTf in 1.2:3:2 ratio, only 5aia was detected in 90% NMR yield after treated by MeOH−HCl aqueous solution. It is noteworthy that a mixture of compound 3aia (minor) and product 5aia (major) was obtained in NMR and GC-MS without treatment by the MeOH−HCl aqueous solution. Having identified the optimized reaction conditions (see Table S3), ranges of diarylcarbodiimides and dialkylcarbodiimides were investigated and the representative results are shown in Scheme 2. Reaction of DIC 1i and diarylcarbodiimides 2 with para-substituents such as methyl, methoxyl, chloro, and fluoro groups afforded the corresponding 2,4-diaminoquinazolines (5aia−5dia, 5hia) in high yields. When EtOTf was employed in this reaction, the product 5aib was also isolated in 75%. The structure of 5aib was fully characterized by XRD analysis and it clearly displayed the skeleton of 2,4-diaminoquinazoline. When N,N′-dicyclohexylcarbodiimide (DCC) 1j was used in the reaction and the corresponding 2,4-diaminoquinazolines (5aja, 5bja, 5dja, 5hja) were also formed in satisfactory yields. Unfortunately, when ditert-butylcarbodiimide 1k was used, the corresponding 2,4diaminoquinazoline 5aka was not observed, which may be attributed to steric hindrance. Furthermore, when dibutylcarbodiimide 1l was used, the product 5ala was isolated in 62% yield. Notably, in the reaction, we did not observed any 2aminopyrimidines, which could be generated from carbodiimides and diaryliodonium salts.11 On the basis of the above results and related precedents, a plausible mechanism is proposed as follows (Scheme 3). First, methylation of the carbodiimide by MeOTf affords carbenium ion A. Then, another molecular carbodiimide attacks the carbon atom of A to afford intermediate B. Next, the nucleophilic nitrogen atom attacks the carbenium in B to form four-membered intermediate C, which is followed by ring
a
Reaction conditions: diarylcarbodiimide 1 (0.3 mmol), dialkylcarbodiimide 1′ (0.75 mmol), triflate 2 (0.5 mmol), DCE (2 mL), 140 °C, N2, 12 h. The yield was evaluated by 1H NMR with CH2Br2 as internal standard. Isolated yield was given in parentheses.
Scheme 3. A Plausible Mechanism of the Reactions
opening with C−N bond cleavage to form carbenium D. Finally, intramolecular Friedel−Crafts reaction of D affords quinazolinone imine 3, which undergoes hydrolysis with MeOH−HCl aqueous solution to form 2-amino-quinazolinone 4 (R = aryl group) and 2,4-diamino-quinazoline 5 (R = alkyl C
DOI: 10.1021/acs.orglett.8b00314 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Ronsisvalle, G. Farmaco 1999, 54, 780. (c) Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.; Conte, L.; Ramis, J.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem. 1998, 41, 1869. (d) Kung, P.-P.; Casper, M. D.; Cook, K. L.; Wilson-Lingardo, L.; Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, R.; Cook, P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705. (e) Tsou, H.-R.; Mamuya, N.; Johnson, B. D.; Reich, M. F.; Gruber, B. C.; Nilakantan, F.; Ye, R.; Shen, R.; Discafani, C.; Deblanc, R.; Davis, R.; Koehn, F. E.; Greenberger, L. M.; Wang, Y.-F.; Wissner, A. J. Med. Chem. 2001, 44, 2719. (4) (a) Errede, L. A.; McBrady, J. J.; Oien, H. T. J. Org. Chem. 1977, 42, 656. (b) Wu, J.; Du, X.; Ma, J.; Zhang, Y.; Shi, Q.; Luo, L.; Song, B.; Yang, S.; Hu, D. Green Chem. 2014, 16, 3210. (c) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M. Tetrahedron Lett. 2005, 46, 7051. (d) Yin, P.; Liu, N.; Deng, Y.; Chen, Y.; Deng, Y.; He, L. J. Org. Chem. 2012, 77, 2649. (e) Harris, N.; Smith, C.; Bowden, K. J. Med. Chem. 1990, 33, 434. (5) (a) Filachione, E. M.; Lengel, J. H.; Fisher, C. H. J. Am. Chem. Soc. 1944, 66, 494. (b) Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T. Tetrahedron Lett. 2008, 49, 7033. (c) Kalusa, A.; Chessum, N.; Jones, K. Tetrahedron Lett. 2008, 49, 5840. (6) Shen, Z.; He, X.; Dai, J.; Mo, W.; Hu, B.; Sun, N.; Hu, X. Tetrahedron 2011, 67, 1665. (7) For examples, see: (a) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829. (b) Xu, L.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 1150. (c) Parua, S.; Das, S.; Sikari, R.; Sinha, S.; Paul, N. D. J. Org. Chem. 2017, 82, 7165. (d) Liu, M.; Shu, M.; Yao, C.; Yin, G.; Wang, D.; Huang, J. Org. Lett. 2016, 18, 824. (8) (a) Qiu, G.; Liu, G.; Pu, S.; Wu, J. Chem. Commun. 2012, 48, 2903. (b) Feng, J.; Wu, X. Org. Biomol. Chem. 2015, 13, 10656. (c) Quintero, C.; Valderrama, M.; Becerra, A.; Daniliuc, C. G.; Rojas, R. S. Org. Biomol. Chem. 2015, 13, 6183. (d) Mirallai, S.; Manos, M.; Koutentis, P. J. Org. Chem. 2013, 78, 9906. (e) Naganaboina, V.; Chandra, K.; Desper, J.; Rayat, S. 2011, 13, 3718. (f) Pang, X.; Chen, C.; Su, X.; Li, M.; Wen, L. Org. Lett. 2014, 16, 6228. (g) Ramanathan, M.; Liu, Y.; Peng, S.; Liu, S. Org. Lett. 2017, 19, 5840. (h) Mirallai, S.; Koutentis, P. J. Org. Chem. 2015, 80, 8329. (i) Szczepankiewicz, W.; Kuznik, N. Tetrahedron Lett. 2015, 56, 1198. (9) (a) Zhao, P.; Yan, X.; Yin, H.; Xi, C. Org. Lett. 2014, 16, 1120. (b) Yan, X.; Zou, S.; Zhao, P.; Xi, C. Chem. Commun. 2014, 50, 2775. (c) Zhao, P.; Liu, Y.; Xi, C. Org. Lett. 2015, 17, 4388. (d) Liu, Y.; Yi, X.; Luo, X.; Xi, C. J. Org. Chem. 2017, 82, 11391. (e) Liu, Y.; Zhao, P.; Zhang, B.; Xi, C. Org. Chem. Front. 2016, 3, 1116. (f) Yan, X.; Yi, X.; Xi, C. Org. Chem. Front. 2014, 1, 657. (g) Wang, S.; Shao, P.; Du, G.; Xi, C. J. Org. Chem. 2016, 81, 6672. (10) (a) Bell, S. A.; Meyer, T. Y.; Geib, S. J. J. Am. Chem. Soc. 2002, 124, 10698. (b) Bell, S. A.; Geib, S. J.; Meyer, T. Y. Chem. Commun. 2000, 16, 1375. (11) Chi, Y.; Yan, H.; Zhang, W.; Xi, Z. Chem.Eur. J. 2017, 23, 757.
group). The mechanisms of hydrolysis of 3 to form 2-aminoquinazolinone 4 and 2,4-diamino-quinazoline 5 were descripted in Table S2 in the Supporting Information. The intermolecular metathesis reaction between two carbodiimides has been reported.10 To further understand the metathesis reaction between diarylcarbodiimide and dialkylcarbodiimide, we drew the reaction mechanism as shown in Table S1. In conclusion, we have developed an alkyltriflate-induced intermolecular cyclization of carbodiimides to provide 2-amino4-imino-quinazolines in high yield. This cyclization represents a general entry to the synthesis of 2-amino-quinazolinone and 2,4-diamino-quinazolines with a one-pot reaction under metalfree conditions.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00314. Experimental procedures, full characterization including 1 H NMR, 13C NMR, and 19F data for all new compounds, copies of spectra for all compounds (PDF) Accession Codes
CCDC 1819546 and 1819548 contain 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 Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chanjuan Xi: 0000-0002-9602-7309 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 91645120 and 21472106). We thank Mr. Chenqi Wang (Tsinghua University) for the preparation of two starting materials.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00314 Org. Lett. XXXX, XXX, XXX−XXX
