4056
L. Legerén, D. Domínguez / Tetrahedron Letters 51 (2010) 4053–4057
1999, 42, 1951–1964; (c) Rahman, K. M.; Thompson, A. S.; James, C. H.;
17. A similar strategy has previously been reported by Beccalli et al. for the
synthesis of dibenzo[b,e][1,4]diazepinones [(a) Beccalli, E. M.; Broggini, G.;
Paladino, G.; Zoni, C. Tetrahedron 2005, 61, 61–68], and by Carlier and Clement
for the preparation of 1,4-benzodiazepin-3-ones [(b) Clement, E. C.; Carlier, P.
R. Tetrahedron Lett. 2005, 46, 3633–3635].
Narayanaswamy, M.; Thurston, D. E. J. Am. Chem. Soc. 2009, 131, 13756–13766;
(d) Kamal, A.; Rajender, D.; Reddy, D. R.; Reddy, M. K.; Balakishan, G.; Shaik, T.
B.; Chourasia, M.; Sastry, G. N. Bioorg. Med. Chem. 2009, 17, 1557–1572; (e) Hu,
W.-P.; Liang, J.-J.; Kao, Ch.-L.; Chen, Y.-Ch.; Chen, Ch.-Y.; Tsai, F.-Y.; Wu, M.-J.;
Chang, L.-S.; Chen, Y.-L.; Wang, J.-J. Bioorg. Med. Chem. 2009, 17, 1172–1180.
3. (a) Kaneko, T.; Wong, H.; Doyle, T. W. Tetrahedron Lett. 1983, 24, 5165–5168;
(b) Kamal, A.; Shankaraiah, N.; Reddy, K. L.; Devaiah, V. Tetrahedron Lett. 2006,
47, 4253–4257; (c) Kamal, A.; Ramana, A. V.; Reddy, K. S.; Ramana, K. V.; Babu,
A. H.; Prasad, B. R. Tetrahedron Lett. 2004, 45, 8187–8190.
4. Anxiolytic effects: (a) Wright, W. B., Jr.; Brabander, H. J.; Greenblatt, E. N.; Day,
I. P.; Hardy, R. A., Jr. J. Med. Chem. 1978, 21, 1087–1089; Binding to DNA: (b)
Foloppe, M. P.; Rault, S.; Thurston, D. E.; Jenkins, T. C.; Robba, M. Eur. J. Med.
Chem. 1996, 31, 407–410; Antileishmanial agents: (c) Clark, R. L.; Carter, K. C.;
Mullen, A. B.; Coxon, G. D.; Owusu-Dapaah, G.; McFarlane, E.; Duong Thi, M. D.;
Grant, M. H.; Tettey, J. N. A.; Mackay, S. P. Bioorg. Med. Chem. Lett. 2007, 17,
624–627; Antitubercular activity: (d) Kamal, A.; Reddy, K. L.; Devaiah, V.;
Shankaraiah, N.; Reddy, G. S. K.; Raghavan, S. J. Comb. Chem. 2007, 9, 29–42.
5. (a) Zhang, J.; Goodloe, W. P.; Lou, B.; Saneii, H. Mol. Divers. 2000, 5, 127–130;
We recently reported the synthesis of 5-aryl derivatives by cyclodehydration of
amidoalcohols: (b) Legerén, L.; Gómez, E.; Domínguez, D. Tetrahedron Lett.
2008, 49, 7174–7177; (c) Legerén, L.; Domínguez, D. Tetrahedron 2010, 66,
2718–2722.
18. Heinzman, S. W.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 6801–6802.
19.
A similar approach has recently been reported for the synthesis of 1,4-
benzodiazepin-3-ones: (a) Rosenström, U.; Sköld, C.; Lindeberg, G.; Botros, M.;
Nyberg, F.; Karlén, A.; Hallberg, A. J. Med. Chem. 2004, 47, 859–870; (b)
Rosenström, U.; Sköld, C.; Plouffe, B.; Beaudry, H.; Lindeberg, G.; Botros, M.;
Nyberg, F.; Wolf, G.; Karlén, A.; Gallo-Payet, N.; Hallberg, A. J. Med. Chem. 2005,
48, 4009–4024; (c) Deschrijver, T.; Verwilst, P.; Broos, K.; Deckmyn, H.;
Dehaen, W.; De Borggraeve, W. M. Tetrahedron 2009, 65, 4521–4529.
20. Smith, L., II; Wong, W. C.; Kiselyov, A. S.; Burdzovic-Wizemann, S.; Mao, Y.; Xu,
Y.; Duncton, M. A. J.; Kim, K.; Piatnitski, E. L.; Doody, J. F.; Wang, Y.; Rosler, R. L.;
Milligan, D.; Columbus, J.; Balagtas, C.; Lee, S. P.; Konovalov, A.; Hadari, Y. R.
Bioorg. Med. Chem. Lett. 2006, 16, 5102–5106.
21. For recent reviews of Cu-catalysed N-arylation, see: (a) Ley, S. V.; Thomas, A.
W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (b) Monnier, F.; Taillefer, M.
Angew. Chem., Int. Ed. 2008, 47, 3096–3099; (c) Evano, G.; Blanchard, N.; Toumi,
M. Chem. Rev. 2008, 108, 3054–3131; (d) Ma, D.; Cai, Q. Acc. Chem. Res. 2008,
41, 1450–1460; For Pd-catalysed N-arylation: (e) Jiang, L.; Buchwald, S. L. In
Metal Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds., 2nd
ed.; Wiley-VCH: Weinheim, 2004.
22. For precedents of copper-catalysed intramolecular N-arylation of amines
leading to seven-membered rings, see: (a) Ma, D.; Xia, Ch. Org. Lett. 2001, 3,
2583–2586; (b) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett
2002, 231–234.
23. (a) Yeh, V. S. C.; Wiedeman, P. E. Tetrahedron Lett. 2006, 47, 6011–6016; (b) Ma,
D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453–2455.
24. For precedents of palladium-catalysed N-arylation of amines leading to seven-
membered rings, see: (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348–1350; (b) Qadir, M.; Priestley, R. E.; Rising,
T. W. D. F.; Gelbrich, T.; Coles, S. J.; Hursthouse, M. B.; Sheldrake, P. W.;
Whittall, N.; Hii, K. K. Tetrahedron Lett. 2003, 44, 3675–3678; (c) Omar-Amrani,
R.; Schneider, R.; Fort, Y. Synthesis 2004, 2527–2534; (d) Carril, M.; SanMartin,
R.; Churruca, F.; Tellitu, I.; Domínguez, E. Org. Lett. 2005, 7, 4787–4789; (e)
Carril, M.; SanMartin, R.; Domínguez, E.; Tellitu, I. Tetrahedron 2007, 63, 690–
702.
6. Mishra, J. K.; Garg, P.; Dohare, P.; Kumar, A.; Siddiqi, M. I.; Ray, M.; Panda, G.
Bioorg. Med. Chem. Lett. 2007, 17, 1326–1331.
7. De la Fuente, M. C.; Domínguez, D. Tetrahedron 2009, 65, 3653–3658.
8. PBD bioisosters have been obtained by replacing ring A with a number of
different heteroarenes, as follows. Thiophene or pyrrole: (a) Correa, A.; Tellitu,
I.; Domínguez, E.; Moreno, I.; SanMartín, R. J. Org. Chem. 2005, 70, 2256–2264;
(b) Jolivet-Fouchet, S.; Fabis, F.; Rault, S. Tetrahedron Lett. 1998, 39, 5369–5372;
Pyrazole: (c) Baraldi, P. G.; Leoni, A.; Cacciari, B.; Manfredini, S.; Simoni, D.;
Bergomi, M.; Menta, E.; Spinelli, S. J. Med. Chem. 1994, 37, 4329–4337; Pyridine,
pyrazine or pyrimidine: (d) Thurston, D. E.; Bose, D. S.; Howard, P. W.; Jenkins,
T. C.; Leoni, A.; Baraldi, P. G.; Guiotto, A.; Cacciari, B.; Kelland, L. R.; Foloppe, M.-
P.; Rault, S. J. Med. Chem. 1999, 42, 1951–1964. However, no 5-deoxy
heteroanalogues related to 1 have been reported.
9. Wang, H.; Jiang, Y.; Gao, K.; Ma, D. Tetrahedron 2009, 65, 8956–8960.
10. (a) Foranalternativeapproachtoheterocycle-fusedpyrrolo[2,1-c][1,4]diazepines
see the work of Domínguez and Tellitu in Ref. 8a. Their elegant method is based on
cyclization by aromatic amidation mediated by electrophilic substitution, a route
that is not viable for electron-poor aromatics such as the pyrido-fused derivative
1; (b) The 3-bromo derivative of 1 has been prepared by an alternative approach
involving heterocyclization by intramolecular N-acylation: Berman, J.; Sampson,
P.; Pauls, H. W.; Ramnauth, J.; Manning, D. D.; Surman, M. D.; Xie, D.; Decornez, H.
Y. PCT Int. Appl. 2004, WO 2004052890.
25. In fact compound 11 exists exclusively in Z conformation with respect to the
amide bond, that is, with the largest groups anti to each other, since there was
no splitting of any signals in its 1H NMR spectrum.
26. Typical procedure for SNAr leading to (7aS)-6-methyl-5,6,7a,8,9,10-hexahydro-7H-
pyrido[3,2-f]pyrrolo[1,2-a][1,4]diazepin-7-one (3a): A solution of chloroamide
14a (85 mg, 0.33 mmol) in DMSO (4 mL) was treated with dehydrated NaI
(50 mg, 0.33 mmol) and Et3N (0.047 mL, 0.33 mmol) and stirred at 110 °C for
24 h. The resulting mixture was cooled, treated with NaCl (10 mL) and
extracted with AcOEt (5 ꢃ 5 mL). The combined organic layers were dried with
anhydrous Na2SO4, filtered, and concentrated. Purification by flash
chromatography (SiO2, 94:6 CH2Cl2/MeOH) afforded diazepinone 3a (41 mg,
11. (a) Melnyk, P.; Gasche, J.; Thal, C. Synth. Commun. 1993, 23, 2727–2739; (b)
Chelucci, G.; Baldino, S.; Pinna, G. A.; Sechi, B. Tetrahedron Lett. 2008, 49, 2839–
2843.
12. For precedents of copper-catalysed intramolecular N-arylation of amides and
carbamates leading to seven-membered rings, see: (a) Cuny, G.; Bois-Choussy,
M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475–14484; (b) Yang, T.; Lin, Ch.; Fu,
H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781–4784.
57%) as oil. ½a 2D0
ꢁ
ꢂ35.8 (c 1, CH2Cl2), >98% ee. IR (CHCl3) 2926, 1690 (C@O),
1410, 1163 cmꢂ1
.
1H NMR (CDCl3), d: 8.06 (dd, J = 4.8 and 1.6 Hz, 1H, H2), 7.11
13. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727–7729.
(dd, J = 7.1 y 1.6 Hz, 1H, H4), 6.45 (dd, J = 7.1 y 4.8 Hz, 1H, H3), 5.38 (d,
J = 16.4 Hz, 1H, H5), 5.03 (dd, J = 6.8 y 4.6 Hz, 1H, H7a), 3.70–3.57 (m, 2H, CH2),
3.62 (d, J = 16.4 Hz, 1H, H5), 3.07 (s, 3H, NMe), 2.70–2.62 (m, 1H), 2.08–1.97 (m,
2H, CH2), 1.95–1.86 (m, 1H). 13C NMR/DEPT (CDCl3), d: 169.37 (CO), 155.98
(C11a), 147.99 (C2), 136.11 (C4), 114.47 (C4a), 111.29 (C3), 57.56 (C7a), 52.96 (C5),
48.82 (C10), 34.24 (NMe), 28.35 (C8), 23.08 (C9). MS (CI) (m/z): 218 ([M+H]+,
14. The construction of seven-membered rings by palladium-catalysed
intramolecular N-arylation of amides and carbamates is less common, as
these substrates are more challenging than amines: (a) Yang, B. H.; Buchwald,
S. L. Org. Lett. 1999, 1, 35–37; (b) Kitamura, J.; Hashimoto, A.; Yoshikawa, S.;
Odaira, J.-I.; Furuta, T.; Kan, T.; Tanaka, K. Synlett 2006, 115–117; (c) Cropper, E.
L.; Yuen, A.-P.; Ford, A.; White, A. J. P.; Hii, K. K. Tetrahedron 2009, 65, 525–530.
15. Experimental procedure for the Pd-catalysed amidation leading to (9aS)-
5,7,8,9,9a,11-hexahydro-10H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-one
(1): A mixture of chloroamide 7 (75 mg, 0.313 mmol), K2CO3 (133 mg, 2 equiv),
Pd(OAc)2 (6 mg, 0.08 equiv) and BINAP (390 mg, 2 equiv) in dioxane (4 mL)
was stirred under argon in a sealed tube at 120 °C. After 24 h the resulting
mixture was filtered through Celite (finally washed with 10 mL of CH2Cl2), and
the pooled filtrate and washings were concentrated under reduced pressure
and purified by flash chromatography (SiO2, 93:7 CH2Cl2/MeOH), affording
100), MS (EI) (m/z): 217 (23). HRMS (CI) calcd for
C
12H16N3O ([M+H]+):
218.1293, found: 218.1297. HRMS (EI) calcd for C12H15N3O [M+]: 217.1215,
found: 217.1214.
27. Enantiomeric separation was carried out by chiral HPLC using a Chiralcel OD-H
column eluted with n-hexane/2-propanol (gradient from 70:30 to 60:40) and
UV detection at 254 nm.
28. For preparation of 4b (Hal = Br): Robichaud, J.; Bayly, Ch. I.; Black, W. C.;
Desmarais, S.; Léger, S.; Massé, F.; McKay, D. J.; Oballa, R. M.; Pâquet, J.;
Percival, M. D.; Truchon, J.-F.; Wesolowski, G.; Crane, Sh. N. Bioorg. Med. Chem.
Lett. 2007, 17, 3146–3151; For preparation of 4b (Hal = Cl): Bertini, V.;
Luccesini, F.; Pocci, M.; De Munno, A. Heterocycles 1995, 41, 675–688.
29. For a general discussion of the reactivity of halopyridines in the SNAr reaction,
see: (a) Boulton, A. J.; McKillop, A. Reactivity of Six-membered Rings. In
Comprehensive Heterocyclic Chemistry; Katritsky, A., Rees, Ch. W., Eds.;
Pergamon Press, 1984; Vol. 2, pp 59–62; (b) Toshikazu, I.; Matsumoto, K. In
Organic Synthesis at High Pressures; Matsumoto, K., Acheson, R. M., Eds.; Wiley:
New York, 1991; pp 201–212.
diazepinone 1 (64 mg, 90% yield) as a white solid: mp 129–131 °C; ½a D20
ꢁ
+208.4
.
(c 1, CH2Cl2), >98% ee. IR (KBr) 3066, 2924, 1665 (C@O), 1592, 1383 cmꢂ1
1H
NMR d: 9.65 (br s, 1H, NH), 8.43 (dd, J = 4.9 and 1.5 Hz, 1H, H2), 7.59 (dd, J = 7.5
and 1.5 Hz, 1H, H4), 7.05 (dd, J = 7.5 and 4.9 Hz, 1H, H3), 3.97 (d, J = 13.2 Hz, 1H,
H5), 3.76 (d, J = 13.2 Hz, 1H, H5), 3.61 (dd, J = 7.9 and 3.5 Hz, 1H, H9a), 2.97–2.90
(m, 1H), 2.86–2.79 (m, 1H), 2.57–2.47 (m, 1H), 2.06–1.86 (m, 3H). 13C NMR/
DEPT d: 173.02 (CO), 151.10 (C), 147.60 (CH), 138.47 (CH), 123.79 (C), 119.50
(CH), 64.13 (CH), 55.02 (CH2), 54.56 (CH2), 25.97 (CH2), 23.58 (CH2). MS (CI) (m/
z): 204 ([M+H]+, 100), 188 (10). HRMS (CI) calcd for C11H14N3O [(M+H)+]:
204.1137, found: 204.1133.
30. Procedure for Pd-catalysed N-arylation leading to (7aS)-6-methyl-5,6,7a,8,9,10-
hexahydro-7H-pyrido[4,3-f]pyrrolo[1,2-a][1,4]diazepin-7-one (3b): A solution of
bromoamide 14b (79 mg, 0.26 mmol) in toluene (6 mL) was added to a mixture
of Pd(OAc)2 (12 mg, 0.05 mmol), KOtBu (65 mg, 0.53 mmol) and BINAP (65 mg,
0.10 mmol), and the mixture was stirred under argon in a sealed tube at 110 °C.
After 5 h it was cooled, and the reaction was quenched with H2O (10 mL). After
extraction with CH2Cl2 (3 ꢃ 10 mL), the combined organic layers were washed
with brine (3 ꢃ 10 mL), dried with anhydrous Na2SO4, filtered and
concentrated. Purification by flash chromatography (SiO2, 95:5 CH2Cl2/
16. HPLC was performed on a Chiralcel OD-H column eluted with an n-hexane/2-
propanol gradient (from 80:20 to 50:50) at 0.5 mL/min, with UV detection at
254 nm. These conditions had been optimized for dibenzazepinones using a
mixture of (5R,11aS)- and (5S,11aS)-5-phenyl-2,3,5,10,11,11a-hexahydro-1H-
pyrrolo[2,1-c][1,4]benzodiazepin-11-ones, which were prepared in racemic
form from 2-aminobenzophenone and DL-proline following our previously
described procedure (Ref. 5b). Under these conditions other racemic
pyrrolodibenzazepinones have also been resolved successfully (Ref. 5c).
MeOH) afforded diazepinone 3b (25 mg, 44%) as oil.
½
a 2D0
ꢁ
ꢂ111 (c 0.2,
CH2Cl2). IR (CHCl3) 2926, 1663 (C@O), 1426, 1085 cmꢂ1
.
1H NMR d: 7.86 (br