HETEROCYCLES

Communication | Special issue | Vol. 82, No. 1, 2010, pp. 305-311
Received, 23rd June, 2010, Accepted, 26th July, 2010, Published online, 27th July, 2010.
DOI: 10.3987/COM-10-S(E)66

■ Synthesis of 2,3,4-Tri-Substituted 3,4-Dihydroquinazolines via Tandem Nucleophilic Addition/Epoxy Ring-Opening Cyclization Methodology Using N-(2-Oxiranylphenyl)carbodiimides with Nucleophiles

Takao Saito,* Tatsuya Ote, Masahiro Shiotani, Hiroko Kataoka, Takashi Otani, and Noriki Kutsumura

Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

N-(2-Oxiranylphenyl)carbodiimides, which were synthesized via an aza-Wittig reaction of the corresponding functionalized iminophosphoranes with aromatic and aliphatic isocyanates, underwent O-, S-, C-, or N-nucleophilic addition onto a cumulene, followed by an epoxy ring-opening cyclization with the newly formed NH-nucleophile in a one-pot reaction to furnish 2,3-disubstituted 4-(hydroxymethyl)-3,4-dihydroquinazolines in a highly stereospecific manner.

We have been interested in the chemistry of functionalized (conjugated) heterocumulenes such as carbodiimides, and their use as key substrates for the synthesis of nitrogen heterocycles.1 Considerable advances in the chemistry have been made.2 For examples, the synthetic approaches used included an aza-Wittig reaction of iminophosphoranes with isocyanates to generate functionalized carbodiimides, followed by the use of various ring-forming transformations such as (a) electrocyclization,1a-c,3 (b) intra-1b-d,4 or (c) intermolecular Diels-Alder type reaction,1a,c,5 and (d, e) various types of cyclizations (various bond-forming reactions, e.g., nucleophilic addition/substitution,1e-g,3a,6 and Pauson-Khand reaction1h-j,7) in tandem with the heterocumulene functionality and adjacent available functional group, to furnish nitrogen heterocycles A (Chart 1). Our ongoing program to develop a useful synthetic method based on this concept of a functionalized carbodiimide-mediated, tandem annulation strategy for

heterocyclic synthesis prompted us to seek a suitable new functional group that could play an important part in the ring-forming reaction in tandem.
Scheme 1 depicts our new strategy. A nucleophile initially adds to the cumulene carbon of the (2-oxyranylphenyl)carbodiimide I to give the intermediate II, the newly formed NH-nucleophilic center, which subsequently attacks the epoxy ring resulting in a ring-opening cyclization in a permitted 6-exo-tet manner to produce 4-(hydroxymethyl)dihydroquinazoline III. Herein, we report the results of this new synthetic approach to dihydroquinazolines having a β-amino-alcohol unit.
First, the key substrates 6-7, epoxy-carbodiimides bearing a variety of substituents (R, R1, R2), were prepared from o-aminobenzyl alcohol (1) according to the route shown in Scheme 2.

Oxiranylcarbodiimides 6-7 obtained in this way were allowed to react initially with alcohol nucleophiles; the results are summarized in Table 1. The reaction with methanol or o-chlorophenol in the presence of the corresponding sodium alcoholate or phenolate proceeded slowly to afford the dihydroquinazolines 9 and 10/10’ in good to moderate yields (Table 1, runs 1–6).8 The presence of the base is necessary because the reaction without the base did not proceed even at 110 °C for 10 h. We believe that the reaction is initiated by nucleophilic addition onto the cumulene bond to form the intermediate 8, followed by the intramolecular nucleophilic attack at the proximal epoxy ring by the newly formed amine nucleophile, with simultaneous epoxy ring-opening to produce the dihydroquinazolines 9 and 10/10’. The exclusive formation of the erythro-isomer from trans-6/7 and threo-isomer from cis-7 confirms that the

intramolecular nucleophilic substitution in the epoxy ring-opening process proceeded with complete inversion of the stereogenic center at the epoxy-2-position. Similarly, the oxiranylcarbodiimides 6-7 also reacted with dodecanethiol and benzenethiol to afford the dihydroquinazolines 11 and 12/12’ stereospecifically in good yields (runs 7–12).8 It is noteworthy that the reaction with benzenethiol proceeded even in the absence of an amine base (Et3N) (runs 9 and 11). The reaction with carbon nucleophiles was also examined. Treatment with Grignard reagents RMgBr (R = Me, n-Hex, Ph) or enolate anions derived from acetonitrile and acetophenone failed. However, reaction with stable enolate anions derived from 1,3-diketones successfully resulted in the formation of the expected C-attacking quinazoline products 13 and 14/14’ (runs 13–16).

The carbodiimides 7a(cis) and 7b reacted rapidly with a secondary amine, piperidine, at 0 °C for 10 min to give the corresponding dihydroquinazolines 16’a and 16b, respectively, in fairly good yield (Table 2, runs 1–2). The reaction apparently proceeded through the guanidine intermediate 15, in which an epoxy ring-opening cyclization via path “a” by NHR attack was involved. The reaction of carbodiimides 7c, 7d and 7a(cis) (R = aryl) and 7f and 7f(cis) (R = allyl) with a primary amine (R4 = H: allyl amine, cyclohexyl amine) also produced the corresponding quinazolines 16c, d, f and 16’f, g similarly via the path “a” in 15 with the ambidentate nucleophilic guanidines (runs 3, 4, 6, 7 and 9). In contrast, the reaction of carbodiimides 7e and 7e(cis) bearing a bulky substituent (R = cyclohexyl group) with a less bulky allyl amine yielded quinazolines 17e and 17’e via the alternative path “b” by NHR3 attack in 15 (runs 5 and 8). Similarly, the reaction of trans-[(3-ethoxycarbonyloxyran-2-yl)phenyl]carbodiimides 6a-d with a primary amine (allyl amine, cyclohexyl amine, aniline) resulted in the formation of quinazolines 18 or 19 (runs 10–15). The preferred formation of either 16/18 or 17/199 may be ascribed principally to the steric hindrance of the NHR(R3) group rather than to its nucleophilicity,10 if the allyl group is relatively bulkier than a phenyl group under the conditions in 15.
In summary, we have developed the functionalized carbodiimide-mediated tandem nucleophilic addition /epoxy ring-opening cyclization method for stereospecific synthesis of 2,3-disubstituted 4-(hydroxymethyl)-3,4-dihydroquinazolines.

References

1. (a) T. Saito, M. Nakane, M. Endo, H. Yamashita, Y. Oyamada, and S. Motoki, Chem. Lett., 1986, 135; CrossRef (b) T. Saito, H. Ohmori, E. Furuno, and S. Motoki, J. Chem. Soc., Chem. Commun., 1992, 22; CrossRef (c) T. Saito, T. Ohkubo, H. Kuboki, M. Maeda, K. Tsuda, T. Karakasa, and S. Satsumabayashi, J. Chem. Soc., Perkin Trans. 1, 1998, 3065; CrossRef (d) T. Saito, H. Ohmori, T. Ohkubo, and S. Motoki, J. Chem. Soc., Chem. Commun., 1993, 1802; CrossRef (e) S. Hirota, R. Kato, M. Suzuki, Y. Soneta, T. Otani, and T. Saito, Eur. J. Org. Chem., 2008, 2075; CrossRef (f) S. Hirota, T. Sakai, N. Kitamura, K. Kubokawa, N. Kutsumura, T. Otani, and T. Saito, Tetrahedron, 2010, 66, 653; CrossRef (g) T. Saito and K. Tsuda, Tetrahedron Lett., 1996, 37, 9071; CrossRef (h) T. Saito, N. Furukawa, and T. Otani, Org. Biomol. Chem., 2010, 8, 1126; CrossRef (i) T. Saito, M. Shiotani, T. Otani, and S. Hasaba, Heterocycles, 2003, 60, 1045; CrossRef (j) T. Saito, K. Sugizaki, T. Otani, and T. Suyama, Org. Lett., 2007, 9, 1239; and references cited therein. CrossRef
2. For reviews see, (a) P. Molina and M. J. Vilaplana, Synthesis, 1994, 1197; CrossRef (b) P. M. Fresneda and P. Molina, Synlett, 2004, 1; CrossRef (c) S. Eguchi, ARKIVOC, 2005, (ii), 98; (d) S. Eguchi, Top. Heterocycl. Chem., 2006, 6, 113; CrossRef (e) F. Palacios, C. Alonso, D. Aparicio, G. Rubiales, and J. M. de los Santos, Tetrahedron, 2007, 63, 523. CrossRef
3. (a) J. Barluenga, M. Ferrero, and F. Palacios, J. Chem. Soc., Perkin Trans. 1, 1990, 2193; CrossRef (b) P. Molina, J. Alcantara, and C. Lopez-Leonardo, Tetrahedron, 1997, 53, 3281. CrossRef
4. (a) M. Alajarin, P. Molina, and A. Vidal, J. Nat. Prod., 1997, 60, 747; CrossRef (b) K. Nagamatsu, A. Serita, J.-H. Zeng, H. Fujii, N. Abe, and A. Kakehi, Heterocycles, 2006, 67, 337; CrossRef (c) C. Shi, Q. Zhang, and K. K. Wang, J. Org. Chem., 1999, 64, 925; CrossRef (d) X. Lu, J. L. Petersen, and K. K. Wang, J. Org. Chem., 2002, 67, 7797; CrossRef (e) M. Schmittel, J.-P. Steffen, D. Rodriguez, B. Engelen, E. Neumann, and M. E. Cinar, J. Org. Chem., 2008, 73, 3005, and references cited therein. CrossRef
5. (a) T. Okawa, N. Osakada, S. Eguchi, and A. Kakehi, Tetrahedron, 1997, 53, 16061; CrossRef (b) H. Wamhoff and A. Schmidt, J. Org. Chem., 1993, 58, 6976; CrossRef (c) M. A. Arnold, K. A. Day, S. G. Duron, and D. Y. Gin, J. Am. Chem. Soc., 2006, 128, 13255. CrossRef
6. (a) T. Okawa, M. Kawase, S. Eguchi, A. Kakehi, and M. Shiro, J. Chem. Soc., Perkin Trans. 1, 1998, 2277; CrossRef (b) M. Noguchi, H. Okada, M. Watanabe, K. Okuda, and O. Nakamura, Tetrahedron, 1996, 52, 6581; CrossRef (c) P. Molina, M. Alajarin, and A. Vidal, Tetrahedron, 1989, 45, 4263; CrossRef (d) J. M. Quintela, R. Alvarez-Sarandes, M. C. Veiga, and C. Peinador, Heterocycles, 1997, 45, 1319; CrossRef (e) J.-F. Zhao, C. Xie, S.-Z. Xu, M.-W. Ding, and W.-J. Xiao, Org. Biomol. Chem., 2006, 4, 130. CrossRef
7. (a) C. Mukai, T. Yoshida, M. Sorimachi, and A. Odani, Org. Lett., 2006, 8, 83; CrossRef (b) D. Aburano, T. Yoshida, N. Miyakoshi, and C. Mukai, J. Org. Chem., 2007, 72, 6878. CrossRef
8. The structures 9-14 were determined spectroscopically. 12a (Table 1, run 10): Colorless oil; 1H NMR (CDCl3, 500.0 MHz) δ 0.87 (t, J = 6.9 Hz, 3H), 1.25-1.35 (m, 18H), 1.56-1.63 (m, 2H), 2.44 (brs, 1H, OH), 2.93 (ddd, J = 6.9, 8.1, 12.9 Hz, 1H), 3.19 (ddd, J = 6.6, 8.1, 12.9 Hz, 1H), 4.55 (d, J = 6.8 Hz, 1H, H-4), 4.75 (d, J = 6.8 Hz, 1H, CH-O), 6.64-6.66 (m, 2H, Ar), 6.72 (d, J = 7.4 Hz, 1H, Ar), 6.99 (dt, J = 1.2, 7.4 Hz, 1H, Ar), 7.13-7.15 (m, 3H, Ar), 7.21 (d, J = 7.8 Hz, 1H, Ar), 7.26-7.35 (m, 6H, Ar). 13C NMR (CDCl3, 125.65 MHz) δ 14.1 (CH3), 22.6 (CH2), 28.9 (CH2), 29.1 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 31.3 (CH2), 31.8 (CH2), 69.7 (CH, C-4), 74.2 (CH, C-O), 122.0 (C), 123.2 (CH, Ar), 123.8 (CH, Ar), 126.7 (CH, Ar), 127.0 (2CH, Ph), 127.1 (CH, Ar), 127.4 (2CH, Ph), 127.9 (CH, Ar), 128.2 (2CH, Ph), 128.7 (2CH, Ph), 128.8 (CH, Ar), 140.3 (C, Ph), 142.6 (C, Ph), 143.9 (C), 158.7 (C). IR (neat): 3401, 3062, 2923, 2854, 2360, 1527, 1481, 1257 cm-1. ESI-MS: Calcd for C33H43N2OS (M + H)+ 515.3096, found 515.3107. 12’a (Table 1, run 12): Colorless oil; 1H NMR (CDCl3, 600.13 MHz): δ 0.87 (t, J = 7.0 Hz, 3H), 1.25-1.30 (m, 16H), 1.35-1.39 (m, 2H), 1.62-1.67 (m, 2H), 2.72 (brs, 1H, OH), 2.94 (ddd, J = 6.8, 8.2, 12.9 Hz, 1H), 3.24 (ddd, J = 6.3, 8.2, 13.0 Hz, 1H), 4.62 (d, J = 8.4 Hz, 1H, H-4), 4.69 (d, J = 8.4 Hz, 1H, CH-O), 6.12 (d, J = 7.4 Hz, 1H), 6.75 (ddd, J = 2.0, 6.5, 7.4 Hz, 1H, Ar), 7.02 (d, J = 7.0 Hz, 2H, Ph), 7.17-7.23 (m, 6H, Ar), 7.31 (dd, J = 7.5, 8.0 Hz, 2H, Ph), 7.46 (d, J = 7.8 Hz, 2H, Ph). 13C NMR (CDCl3, 150.9 MHz): δ 14.1 (CH3), 22.7 (CH2), 28.9 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 29.7 (CH2), 31.3 (CH2), 31.9 (CH2), 69.8 (CH, C-4), 74.3 (CH, C-O), 122.0 (C), 123.2 (CH, Ar), 123.8 (CH, Ar), 126.7 (CH, Ar), 127.0 (2CH, Ph), 127.1 (CH, Ar), 127.4 (2CH, Ph), 127.9 (CH, Ar), 128.2 (2CH, Ph), 128.7 (2CH, Ph), 128.8 (CH, Ar), 140.0 (C, Ph), 142.4 (C, Ph), 144.8 (C), 157.3 (C). IR (neat): 3216, 3062, 2923, 2854, 2360, 1527, 1481, 1257 cm-1. ESI-MS: Calcd for C33H42N2NaOS (M + Na)+ 537.2916, found 537.2909.
9. The structures 16-19 were determined spectroscopically (in particular, the observed correlation for NOESY and HMBC measurements between H-4/HC(Ar-N(3)) and H-4/C-N(3), respectively).
10. Similar observations and arguments have been reported. See lit.1f and G. Blanco, N. Segui, J. M. Quintela, C. Peinador, M. Chas, and R. Toba, Tetrahedron, 2006, 62, 11124. CrossRef