Synthesis of tricyclic 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines

Article abstract of DOI:10.1021/ol050181f

(Chemical Equation Presented) A novel methodology was developed for the efficient synthesis of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. The key is the intramolecular Friedel-Crafts cyclization of 5-amino-4-(N-substituted) anilino-6-chloropyrimidine w

Full text of DOI:10.1021/ol050181f

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1541-1543
Synthesis of Tricyclic
4-Chloro-pyrimido[4,5-b][1,4]benzodiazepines
Jianxin Yang, Xin Che, Qun Dang, Zhonglin Wei, Shu Gao, and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery, Jilin UniVersity,
75 Jinlai Street, Changchun, Jilin 130012, P. R. China
xbai@jlu.edu.cn
Received January 28, 2005
ABSTRACT
A novel methodology was developed for the efficient synthesis of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. The key is the intramolecular
Friedel Crafts cyclization of 5-amino-4-(N-substituted)anilino-6-chloropyrimidine with either a carboxylic acid or its derivatives to construct
−
the 4-chloro-pyrimido[4,5-b][1,4]benzodiazepine core. Subsequent nucleophilic substitution allows the introduction of one more diversity point
in the target molecules. This strategy provides an efficient method to access a library of compounds based on privileged substructures that
are of great interest in drug discovery.
The construction of privileged structures is an important
strategy in medicinal chemistry. Benzodiazepines were first
coined as the archetypal privileged substructure by Evans et
al. in 1988.1,2 These compounds have shown a variety of
biological effects predominately ascribed to their actions in
the central nervous system. For example, Clozapine, Olan-
zapine and Quetiapine are used to treat schizophrenia;
Clonazepam, Diazepam, Lorazepam, Nitrazepam, and Ox-
azepam are used as antianxiety drugs. In addition, they are
the basis of cholecystokinin receptor (CCK) A and B
antagonists,3 oxytocin antagonists,4 and inhibitors of protein-
DNA interactions.5 There are four points of diversity in
4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. For instance,
the 4-chloro group can be easily converted to other groups
by either a substitution reaction with a nucleophile (such as
an amine, alcohol, and phenol) or by Suzuki-Miyaura cross-
coupling reactions with boronic acids.6 Several reports have
been devoted to the synthesis of various tricyclic 1,4-
benzodiazepines,7-9 but there is no report describing the
preparation of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines.10
(6) (a) Chorvat, R. J.; Bakthavatchalam, R.; Beck, J. P.; Gilligan, P. J.;
Wilde, R. G.; Cocuzza, A. J.; Hobbs, F. W.; Cheeseman, R. S.; Curry, M.;
Rescinito, J. P.; Krenitsky, P.; Chidester, D.; Yarem, J. A.; Klaczkiewicz,
J. D.; Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.; Fernandez, C. H.;
Zaczek, R.; Fitzgerald, L. W.; Huang, S.; Shen, H. L.; Wong, Y. N.; Chien,
B. M.; Quon, C. Y.; Arvanitis, A. J. Med. Chem. 1999, 42, 833. (b)
Gundersen, L.; Nissen-Meyer, J.; Spilsberg, B. J. Med. Chem. 2002, 45,
1383. (c) Oh, C.; Kim, H.; Lee, S.; Oh, C.; Yang, B.; Rhee, H. J.; Cho, J.
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 345. (d) Havelkova, M.;
Hocek, M.; Cesnek, M.; Dvorak, D. Synlett 1999, 1145.
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893.
(2) Abrous, L.; Hynes, J., Jr.; Friedrich, S. R.; Smith, A. B.; Hirschmann,
R. Org. Lett. 2001, 3, 1089.
(7) (a) Morita, K.; Kobayashi, S.; Shimadzu, H.; Ochiai, M. Tetrahedron
Lett. 1970, 11, 861. (b) Kobayashi, S. Chem. Lett. 1974, 967. (c) Kobayashi,
S. Bull. Chem. Soc. Jpn. 1975, 48, 302.
(8) (a) Hunziker, V. F.; Ku¨nzle, F.; Schindler, O.; Schmutz, J. HelV.
Chim. Acta 1964, 47, 1163. (b) Eyrolles, L.; Kagechika, H.; Kawachi, E.;
Fukasawa, H.; Iijima, T.; Matsushima, Y.; Hashimoto, Y.; Shudo, K. J.
Med. Chem. 1994, 37, 1508.
(9) Frederick, J. P.; William, H. T. (Bristol-Myers). Eur. Pat. Appl. DE
19742418285 19740416, 1974; Chem. Abstr. 1975, 82, 73045.
(10) Chebanov, V. A.; Desenko, S. M.; Shishkin, O. V.; Kolos, N. N.;
Komykhov, S. A.; Orlov, V. D.; Meier, H. J. Heterocycl. Chem, 2003, 40,
25.
(3) 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.
(4) (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,
1301.
(5) 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.
10.1021/ol050181f CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

Herein, we report an efficient method for the synthesis of
4-chloro-pyrimido[4,5-b][1,4]benzodiazepines from com-
mercial 4,6-dichloro-5-nitropyrimidine, which can be readily
converted to 4-amino-pyrimido[4,5-b][1,4]benzodiazepines
as depicted in Scheme 1.
Scheme 3
Scheme 1
This synthesis was inspired by an unexpected observation
during the preparation of various purine libraries.11 As shown
in Scheme 2, when 5-amino-4 anilino-6-chloro-pyrimidine
to form compound 9, which is subsequently dehydrated to
produce compound 4.0.
On the basis of the above analysis, a facile synthesis of
4-chloro-pyrimido[4,5-b][1,4]benzodiazepine (4) was envis-
aged as shown in Scheme 4. While reaction of 5-amino-4,6-
Scheme 2
Scheme 4
(3.0) was treated with benzoic acid and POCl3/PPA to
prepare 6-chloropurine (6), the desired product was ac-
companied by a small contaminant that was isolated and
characterized as 4-chloro-11-benzoyl-6-phenyl-pyrimido[4,5-
b][1,4]benzodiazepine (4.0).
A plausible mechanism for the formation of compound
4.0 is proposed as shown in Scheme 3. It was rationalized
that under the purine formation conditions of refluxing
POCl3/PPA, a small amount of diamine 3.0 was converted
to diacylated product 7. Compound 7 could not undergo
cyclization to a purine ring; however, it was able to undergo
an intramolecular Friedel-Crafts reaction in acidic condition
(11) Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; Bai, X. J. Comb. Chem.
In press.
dichloro-pyrimidine (1.0) with N-methyl-aniline failed to give
1542
Org. Lett., Vol. 7, No. 8, 2005

the desired aminated product,12 utilization of a known two-
step process provided 6-chloro-4,5-diamino pyrimidines (3)
(R2 ) CH3).13,14
to those with either no substitution (compounds 4.1-4.6, R3
) H) or an electron-withdrawing group (compounds 4.13-
4.18, R3 ) F). These results are consistent with the proposed
Friedel-Crafts reaction mechanism shown in Scheme 3,
since electron-donating groups should activate the aromatic
ring toward electrophilic substitution reactions. When R4 was
aliphatic (4.1, 4.2, 4.7, 4.8, 4.13, 4.14), the reactions
proceeded faster than when R4 was aromatic (4.3-4.6, 4.9-
4.12, 4.15-4.18). On the other hand, the yields of the
aromatic acids (except p-nitrobenzoic acid) (4.6, 4.12, 4.18)
were higher presumably due to the stablization effect caused
by conjugation of the aromatic ring. When R4 was an
aromatic group substituted with electron-donating groups,
the yields were highest (4.5, 4.11, 4.17). When R4 was
substituted with an electron-withdrawing group (NO2) (4.6,
4.12, 4.18), the yields were lowest. These results are also
consistent with a Friedel-Crafts-type mechanism since
electron-donating group R4 activates the benzene ring and
stabilized the carbon cation intermediate 6 and the electron-
withdrawing group R4 destabilizes it.
Commercial 4,6-dichloro-5-nitro-pyrimidine 1 was treated
with N-methylbenzenamines to give pyrimidines 2 in high
yields, and the nitro group was easily reduced by Fe/NH4Cl
in good chemical yield. Two cyclization conditions were
studied for the formation of tricyclic 4-chloro-pyrimido[4,5-
b][1,4]benzodiazepines. When pyrimidine 3.1 and benzoic
acid were treated with PPA in refluxing xylene for 5 h,
4-hydroxy-11-methyl-6-phenyl-pyrimido[4,5-b][1,4]-
benzodiazepine (4.19) resulted in 61% isolated yield. Com-
pound 4.19 could be readily converted to 4-chloro-11-methyl-
6-phenyl-pyrimido[4,5-b][1,4] benzodiazepine (4.3) by
treatment with POCl3. Alternatively, the two-step transfor-
mation could be achieved using PPA/POCl3 in a one-pot
procedure to give 4.3 in 74% yield. This observation was
consistent with what was observed during the preparation
of a purine library.11
Under the POCl3/PPA conditions, 6-chloro-4,5-diamino
pyrimidines 3 (R2 ) CH3) reacted with various acids or its
derivatives to yield the desired 4-chloro-pyrimido[4,5-b][1,4]
benzodiazepine ring system (Table 1).
To test the reactivity of the 4-Cl group in tricyclic
4-chloro-pyrimido[4,5-b][1,4]benzodiazepines, nuclephilic
substitution reactions were conducted with amines as shown
in Scheme 5. As expected, good chemical yields were
Table 1. Formation of Tricyclic
4-Chloro-pyrimido[4,5-b][1,4]benzodiazepines
Scheme 5
compd
R3
R4
X
yield (%)
time
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
F
F
F
F
F
CH3CH2CH2
CH3
Ph
4′-F-C6H4
4′-CH3-C6H4
4′-NO2-C6H4
CH3CH2CH2
CH3
Cl
60
52
74
79
90
38
65
57
85
88
97
49
50
45
88
81
90
37
45 min
30 min
5 h
5 h
5 h
12 h
30 min
30 min
5 h
5 h
5 h
12 h
1 h
30 min
5 h
5 h
5h
OAc
OH
OH
OH
OH
Cl
OAc
OH
OH
OH
OH
Cl
OAc
OH
OH
OH
OH
obtained for compounds 5.1 and 5.2.
In conclusion, a novel methodology for the preparation
of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines was devel-
oped. This new method utilizes readily available 4,6-
dichloro-5-nitropyrimidine, amines, and carboxylic acids (or
its derivatives) and generates the desired heterocycles in good
to high yields. The resulting 4-chloro-pyrimido[4,5-b][1,4]-
benzodiazepines can be subjected to nucleophilic substitution
to yield products with more diversity. This strategy provides
an efficient way to access a library of compounds based on
privileged substructures that are of great interest in drug
discovery.
4.9
Ph
4.10
4.11
4.12
4.13
4.14
4.15
4.16
4.17
4.18
4′-F-C6H4
4′-CH3-C6H4
4′-NO2-C6H4
CH3CH2CH2
CH3
Ph
4′-F-C6H4
4′-CH3-C6H4
4′-NO2-C6H4
F
12h
Acknowledgment. This work was supported by the Nat-
ional Natural Science Foundation of China (#20232020), Jilin
Provincial Fund for Young Talented Scientists (#20010105),
and Changchun Discovery Sciences, Ltd.
Higher yields of the products (4.7-4.12) were observed
when R3 was an electron-donating group (CH3) compared
(12) Tanji, K.; Satoh, R.; Higashino, T. Chem. Pharm. Bull. 1992, 40,
227.
(13) Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.; Han, N.;
Hurt, R.; Jenkins, T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno, O.; Santora, V.
J.; Sonnenberg, J. D.; Karbon, W. J. Med. Chem. 2000, 43, 4288.
(14) Caron, S.; Vazquez, E. J. Org. Chem. 2003, 68, 4104.
Supporting Information Available: Experimental details
and compound characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL050181F
Org. Lett., Vol. 7, No. 8, 2005
1543