Benzodiazepines have been the first class of molecules
recognized as privileged structures.4 This term was in fact coined
by Evans as a single molecular framework able to provide
ligands for diverse receptors. This conclusion followed the
observation that 1,4-benzodiazepin-2-ones were able to bind to
cholecystokinin (CCK) and to several central nervous system
receptors.5 The benzodiazepine ring is contained in molecules
that bind G-protein-coupled receptors and6 in several drugs used
for central nervous system diseases,7 and it has found applica-
tions for the synthesis of peptidomimetics,8 peptide antagonists,9
inhibitors of DNA interactions,10 antiviral or antimalarial
compounds,11 and many other potentially active molecules.12
Despite the impressive diversity of benzodiazepines prepared
to date, a great deal of work has been directed toward the
synthesis of 1,4-benzodiazepin-2,5-diones,13 presumably as a
result of the relatively easy synthetic procedure available. The
corresponding 1,4-benzodiazepin-2-ones have not been widely
explored, and few examples deal with the 5- or 3-substituted
ring.14
Rapid Approach to 3,5-Disubstituted
1,4-Benzodiazepines via the Photo-Fries
Rearrangement of Anilides
Serena Ferrini, Fabio Ponticelli, and Maurizio Taddei*
Dipartimento di Chimica and Dipartimento Farmaco Chimico
Tecnologico, UniVersita` degli Studi di Siena, Via A. Moro,
53100 Siena, Italy
ReceiVed July 11, 2006
The classical approach to this system is based on the acylation
of o-aminophenones with R-amino acids followed by ring
(3) Chen, G.; Zheng, S.; Luo, X.; Shen, J.; Zhu, W.; Liu, H.; Gui, C.;
Zhang, J.; Zheng, M.; Puah, C. M.; Chen, K.; Jiang, H. J. Comb. Chem.
2005, 7, 398 and references therein. Rishton, G. M. Drug DiscoVery Today
2003, 8, 86.
(4) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893.
Different anilides derived from carboxylic acids and substi-
tuted anilines have been submitted to the photochemically
induced Fries rearrangement giving the corresponding o-
amino phenones under conditions that are compatible with
the presence of acid-labile groups (such as N-Boc or
TBDMSO) on R1 and R3. These compounds, not easily
obtained in other ways, are useful building blocks for the
preparation of benzocondensated heterocycles. After coupling
with N-Boc amino acids and TFA-mediated deprotection,
the products cyclized to the corresponding 3,5-disubstituted
1,4-benzodiazepin-2-ones, privileged structures predomi-
nantly active in the central nervous system. The same results
were obtained by coupling with N-Cbz-protected R-amino
acids followed by microwave assisted hydrogenolysis. When
the Fries rearrangement was carried out on the anilide derived
from N-Boc-Ala-OH and the further coupling done with
N-Cbz-(OMe)Asp-OH, the formed benzodiazepines could
be inserted in a peptide chain for the preparation of
conformationally constrained peptidomimetics.
(5) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(6) (a) Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000,
35, 289. (b) Abrous, L.; Hynes, J., Jr.; Friedrich, S. R.; Smith, A. B.;
Hirschmann, R. Org. Lett. 2001, 3, 1089.
(7) Campiani, G.; Butini, S.; Fattorusso, C.; Catalanotti, B.; Gemma,
S.; Nacci, V.; Morelli, E.; Cagnotto, A.; Mereghetti, I.; Mennini, T.; Carli,
M.; Minetti, P.; Di Cesare, M. A.; Mastroianni, D.; Scafetta, N.; Galletti,
B.; Stasi, M. A.; Castorina, M.; Pacifici, L.; Vertechy, M.; Serio, S. D.;
Ghirardi, O.; Tinti, O.; Carminati, P. J. Med. Chem. 2004, 47, 143 and
references therein.
(8) (a) Micale, N.; Vairagoundar, R.; Yakovlev, A. G.; Kozikowski, A.
P. J. Med. Chem. 2004, 47, 6455. (b) Nakayama, K.; Kawato, H. C.; Inagaki,
H.; Ohta, T. Org. Lett. 2001, 3, 3447.
(9) (a) Evans, B.; Pipe, A.; Clark, L.; Banks, M. Bioorg. Med. Chem.
Lett. 2001, 11, 1297. (b) Wyatt, P. G.; Allen, M. J.; Chilcott, J.; Hickin,
G.; Miller, N. D.; Woollard, P. M. Bioorg. Med. Chem. Lett. 2001, 11,
1307.
(10) Stevens, S. Y.; Bunin, B. A.; Plunkett, M. J.; Swanson, P. C.; Ellman,
J. A.; Glick, G. D. J. Am. Chem. Soc. 1996, 118, 10650.
(11) (a) De Corte, B. L. J. Med. Chem. 2005, 48, 1689. (b) Micale, N.;
Kozikowski, A. P.; Ettari, R.; Grasso, S.; Zappala, M.; Jeong, J.-J.; Kumar,
A.; Hanspal, M.; Chishti, A. H. J. Med. Chem. 2006, 49, 3064.
(12) For some recent selected examples, see: (a) Hadac, E. M.; Dawson,
E. S.; Darrow, J. W.; Sugg, E. E.; Lybrand, T. P.; Miller, L. J. J. Med.
Chem. 2006, 49, 850. (b) Primofiore, G.; Da Settimo, F.; Taliani, S.; Salerno,
S.; Novellino, E.; Greco, G.; Cosimelli, B.; Besnard, F.; Costa, B.; Montali,
M.; Martini, C. J. Med. Chem. 2005, 48, 2936. (c) Abrous, L.; Jokiel, P.
A.; Friedrich, S. R.; Hynes, J., Jr.; Smith, A. B., III; Hirschmann, R. J.
Org. Chem. 2004, 69, 280. (d) Wu, Z.; Ercole, F.; Fitzgerald, M.; Perera,
S.; Riley, P.; Campbell, R.; Pham, Y.; Rea, P.; Sandanayake, S.; Mathieu,
M. N.; Bray, A. M.; Ede, N. J. J. Comb. Chem. 2003, 5, 166.
(13) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513 and references therein.
See also: Tucker, H.; Le Count, D. J. In ComprehensiVe Heterocyclic
Chemistry II; Katritzy, A. R., Rees, C. W., Eds.; Elsevier: Amsterdam, 1996;
Vol. 9, p 151.
The formation of new core structures for the preparation of
focalized libraries is becoming an important target in preparative
combinatorial chemistry.1 The scaffolds required must be cyclic,
be present at a relatively low molecular weight, contain
heteroatoms as H-bond acceptors, and possess two or more
functionalizable positions for parallel decoration.2 Druglike
shapes are also particularly appreciated in scaffolds prepared
for hit discovery.3
(1) Schneider, G.; Schneider, P. In Chemogenomics in Drug DiscoVery,
Methods and Principles in Medicinal Chemistry; Kubini, H., Muller, G.,
Eds.; Wiley-VCH: New York, 2004; Vol. 22, p 341.
(2) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. T. AdV.
Drug DeliVery ReV. 1997, 23, 3.
10.1021/jo0614442 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/26/2006
J. Org. Chem. 2006, 71, 9217-9220
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