Bischler-Napieralski cyclocondensation in the synthesis of new 11H-pyrimido[4,5-b][1,4]benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2008.10.026

A synthetic strategy based on nitrosation-aminolysis-nitroso reduction and Bischler-Napieralski cyclocondensation has been developed for the synthesis of a family of 2-amino-4-methoxy-11H-pyrimido[4,5-b][1,4]benzodiazepines.

Full text of DOI:10.1016/j.tetlet.2008.10.026

Tetrahedron Letters 49 (2008) 7271–7273
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bischler–Napieralski cyclocondensation in the synthesis
of new 11H-pyrimido[4,5-b][1,4]benzodiazepines
a
b
a,c
Justo Cobo a, , Manuel Nogueras , John N. Low , Ricaurte Rodríguez
*
a Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
b Department of Chemistry, University of Aberdeen, Old Aberdeen, AB24 3UE Scotland, UK
c Departamento de Química, Universidad Nacional de Colombia, Bogotá AA 14490, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
A
synthetic strategy based on nitrosation–aminolysis–nitroso reduction and Bischler–Napieralski
Received 4 September 2008
Revised 2 October 2008
Accepted 6 October 2008
Available online 11 October 2008
cyclocondensation has been developed for the synthesis of a family of 2-amino-4-methoxy-11H-pyr-
imido[4,5-b][1,4]benzodiazepines.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of my ever loved
wife Alma Sully Marcillo Rivera
Keywords:
Bischler–Napieralski cyclocondensation
Pyrimidobenzodiazepines
Nitrosation
2-Aminopyrimidines
Aminolysis
Pyrimidine-fused compounds are of general interest in medici-
nal chemistry and chemical biology, due to their wide range of bio-
logical activities.1 In particular, pyrimidobenzodiazepines have
attracted the attention of chemists for many years.2 Figure 1
displays some examples of pyrimidobenzodiazepine derivatives,
which have shown interesting pharmacological properties, such
as antihypoxic and antipyretic (A);3 analgesic (B);1c gastric secre-
tion inhibition (C);4 and immunosuppressive activity (D), com-
pound D showed about two times higher activity than cyclo-
sporine A when it was tested in mice.5
In our ongoing investigation on the preparation of pyrimidine
fused to diazepine systems,6 we have improved the method of
Bai and co-workers (Scheme 1)7 in order to afford new 11H-pyrim-
ido[4,5-b][1,4]benzodiazepine derivatives by starting from other
more versatile commercially available pyrimidines.
Figure 1. Examples of bioactive pyrimidobenzodiazepines.
We have made two modifications. Firstly, we have used the
commercially available 2-amino-4,6-dimethoxypyrimidine, in which
there is an amino group at C2, which is used as pharmacophoric
residue in this kind of compounds, and it brings an additional point
of further diversification.
Secondly, we have used a methodology implemented by our
Scheme 1. Synthesis of pyrimidobenzodiazepines from 4,6-dichloro-5-nitro-
pyrimidine.
group,8 that is based on a nitrosation strategy instead of nitration,
to activate aminolysis of methoxy groups in order to introduce an
aniline residue at C4 (Scheme 2), and so affording a procedure of
* Corresponding author. Tel.: +34 953212695; fax: +34 953211876.
E-mail address: jcobo@ujaen.es (J. Cobo).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.026

7272
J. Cobo et al. / Tetrahedron Letters 49 (2008) 7271–7273
Table 1
Reaction yields in the direct cyclocondensation of 4 to 11H-pyrimido[4,5-b][1,4]-
benzodiazepines 6 and via precursors 5
Entry
Ar
Yields
4?612
4?510
5?611
a
b
c
d
e
f
g
h
i
C6H5
52
60
74
84
50
62
87
71
64
50
73
82
92
—
—
—
—
—
—
—
76
80
80
4-Cl–C6H4
4-NO2–C6H4
4-CF3–C6H4
3-NO2–C6H4
4-Br–C6H4
4-Me–C6H4
4-MeO–C6H4
2-F–C6H4
j
4-F–C6H4
Scheme 2. Syntheses of 11H-pyrimido[4,5-b][1,4]benzodiazepines from 2-amino-
4,6-dimethoxypyrimidine.
higher application than that started from the highly activated 4,6-
dichloro-5-nitropyrimidine.
Therefore, following the mentioned strategy and after reducing
the C5-nitroso group we were able to obtain triaminopyrimidine 4
in an excellent yield (96%).9 This compound was then used to pro-
vide new pyrimidobenzodiazepines by reaction with acid deriva-
tives. Our first attempt was the preparation of three different
amide derivatives 5a–c by reaction of 4 with corresponding
benzoyl chlorides,10 which then underwent a cyclization reaction
under Bischler–Napieralski conditions (POCl3) to yield the new
desired 11H-pyrimido[4,5-b][1,4]benzodiazepines 6a–c (Scheme
2), with no presence of by-product purine derivatives (see Fig. 2).11
We then decided to explore the one-step cyclocondensation to
obtain directly compounds 6 from compound 4, so we carried
out the reaction of 4 with the corresponding acid derivatives under
the cyclization conditions (POCl3) yielding the expected com-
pounds 6a–c12 (Table 1).
By comparing both procedures, the yields to get 6a–c from 4 are
found to be nearly identical. Other acidic compounds were used to
produce pyrimidobenzodiazepines 6d–j in acceptable to good
yields by direct cyclocondensation from derivative 4.
It is important to note that formation of the intermediate amide
derivatives 5 prior to cyclization to form the desired compounds 6
appears to be an unnecessary step, but this step can be very useful
in cases where the 4,5-diamino analogs of 4 are not stable and can-
not be isolated. Formation of amide 5 helps to stabilize these ana-
logs and hence increases the final yield.
Figure 3. Ortep drawing of structure for compound 6i.13
In a general view, this strategy can be of a broader application
starting from substituted 4-alkoxy or 4-chloropyrimidines, and re-
ported derivatives 6 incorporate two new points of diversity on the
pyrimidobenzodiazepine framework (at C2–NH2 and N(11)–H
positions), which afford the opportunity of introducing new sub-
stituents. This, in principle, widens the range of compounds which
may be synthesized and tested in biological studies. On the other
hand, the methoxy at C4 can be readily hydrolyzed, and, in fact,
if after processing the cyclization reaction with water and base,
the mixture is left for one day and pyrimidobenzodiazepin-4-one
8 is isolated (Fig. 2).
It is worthy of notice that the use of polyphosphoric acid (PPA)
for cyclization is not working unlike Bai’s methodology (PPA/
POCl3); under these conditions they reported the formation of pur-
ines like 7 if there is a secondary amino group at C4.7c In fact, we
have also noted that the presence of a Brønsted acid favors the
formation of purine 7 as the major product (see Fig. 2).
The structure of pyrimidobenzodiazepines 6 was unambigu-
ously confirmed by single crystal X-ray diffraction analysis of
derivative 6i (Fig. 3).
In conclusion, we have developed a synthetic route with two
alternatives having as key steps, the selective monosubstitution
of methoxy group in 5-nitrosopyrimidines and Bischler–Napieral-
ski cyclocondensation with acid derivatives for obtaining new pyr-
imidobenzodiazepine derivatives in acceptable yields. These new
compounds may be useful in the field of medicinal chemistry since
they belong to the so-called bicyclic privileged structures,6,14
which have several points of diversification.
Acknowledgments
J.C. and M.N. thank the Consejería de Innovación, Ciencia y
Empresa (Junta de Andalucía, Spain), the ‘Universidad de Jaén’
Figure 2. By-products in the preparation of 2-amino-4-methoxy-11H-pyrimido-
[4,5-b][1,4]benzodiazepines.

J. Cobo et al. / Tetrahedron Letters 49 (2008) 7271–7273
7273
2H), 3.78 (s, 3H), 5.57 (s, 2H), 6.87 (t, 1H, 8 Hz), 7.21 (t, 2H, 8 Hz), 7.69 (d, 2H,
8 Hz), 7.86 (s, 1H). 13C NMR (DMSO-d6) d: 159.06, 155.41, 151.75, 141.09,
128.34, 120.76, 118.97, 101.26, 52.89. MS m/z (assignation, abundance %): 231
(M+, 100), 230 (14) 216 (Mꢀ15, 7), 215 (Mꢀ16, 7), 119 (12), 104 (29), 93 (4), 86
(21), 77 (C6H5þ, 32), 43 (CHNO+, 30); HRMS calcd for C11H13N5O: 231.1120,
found 231.1150.
and its ‘Servicios Técnicos de Investigación’ for financial support.
R.R. thanks ‘Universidad Nacional de Colombia’ for financial sup-
port, and ‘Fundación Carolina’ for a fellowship to carry out his post-
graduate studies at ‘Departamento de Química Inorgánica
Orgánica, Universidad de Jaén’.
y
10. General procedure for the synthesis of N-(2-amino-4-methoxy-6-phenyl-
aminopyrimidin-5-yl)benzamides (5a–c). To
a solution of compound 4
(0.217 g, 0.938 mmol) in pyridine (9 mL), the appropriate benzoyl chloride
derivative (1.22 mmol) was added and the mixture stirred for 1 h. An ice-water
mixture was added on the reaction mixture and the precipitated solid was
filtered off and dried to afford compounds 5. Data for N-(2-amino-4-methoxy-6-
phenylaminopyrimidin-5-yl)benzamide 5a. White solid. Yield 73%, mp: 187–
189 °C. 1H NMR (DMSO-d6) d: 3.73 (s, 3H), 6.27 (s, 2H), 6.92 (m, 1H), 7.22 (m,
2H), 7.40–7.70 (m, 5H), 7.95–8.05 (m, 2H), 8.13 (s, 1H), 9.06 (s, 1H). 13C NMR
(DMSO-d6) d: 53.0, 91.4, 120.6, 121.6, 128.0, 128.05, 128.1, 131.2, 134.34,
140.5, 158.5, 160.4, 165.2, 166.2. MS m/z þ(assignation, abundance %): 230
([MꢀPhCO]+, 4), 105 (PhCO+, 100), 77 (C6H5 38), 57 (C2H3NO+, 84).
Supplementary data
Full experimental details and characterization data (1H and 13C
NMR, MS, and HRMS spectra) for all new compounds are supplied.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.026.
References and notes
11. General procedure for the synthesis of 2-amino-4-methoxy-6-aryl-11H-pyr-
imido[4,5-b][1,4]benzodiazepines
6 from compounds 5. A mixture of 5a–c
(0.396 mmol) and POCl3 (5 mL) was heated between 80 and 90 °C for the
appropriate time: 1.5 h for 5a; 2.0 h for 5b, and 2.5 h for 5c (TLC monitoring).
The mixture was cooled down, then a mixture of ice-water was added and
neutralized with solid K2CO3. A solid precipitated when the pH was basic (ca.
9), the solid was filtered off and washed several times with water, that after
drying and recrystallization from methanol afforded compounds 6. Data for 2-
amino-4-methoxy-6-phenyl-11H-pyrimido[4,5-b][1,4]benzodiazepine 6a.Yellow
solid. Yield 76%, mp >300 °C. 1H NMR (DMSO-d6) d: 3.87 (s, 3H), 6.27 (s, 2H),
6.81 (dd, 1H, 7.8 Hz, 1.3 Hz), 6.91 (ddd, 1H, 7.8 Hz, 7.5 Hz, 0.8 Hz), 6.98 (d, 1H,
7.5 Hz), 7.30 (ddd, 1H, 7.8 Hz, 7.5 Hz, 1.6 Hz). 7.38–7.43 (m, 3H), 7.50–7.56 (m,
3H). 13C NMR (DMSO-d6) d: 53.2, 108,6, 120.9, 121.9, 127.0, 127.7, 128.4, 128.9,
130.6, 131.4, 140.76, 150.5, 160.3, 160.5, 163.8, 165.6. MS m/z (assignation,
abundance %): 318 (M+1, 20) 317 (M, 100), 316 (M–1, 56), 301 (M–16, 7), 77
(C6H5þ, 17), 57 (C2H3NO+, 7), 43 (CHNO+, 22). HRMS calcd for C18H15N5O:
317.1277; found: 317.1262.
1. For examples see: (a) Wang, S.; Folkes, A.; Chuckowree, I.; Cockcroft, X.; Sohal,
S.; Miller, W.; Milton, J.; Wren, S. P.; Vicker, N.; Depledge, P.; Scott, J.; Smith, L.;
Jones, H.; Mistry, P.; Faint, R.; Thompson, D.; Cocks, S. J. Med. Chem. 2004, 47,
1329–1338; (b) McGuigan, C.; Pathirana, R. N.; Snoeck, R.; Andrei, G.; DeClercq,
E.; Balzarini, J. J. Med. Chem. 2004, 47, 1847–1851; (c) Gangjee, A.; Zeng, Y.;
McGuire, J. J.; Mehraein, F.; Kisliuk, R. L. J. Med. Chem. 2004, 47, 6893–6901.
2. (a) Freidinger, R. M.; Evans, B. E.; Bock, M. G. Eur. Pat. Appl.: EP 92-305501
19920616, 1992; Chem. Abstr. 1993, 118, 139861. (b) Di Braccio, M.; Grossi, G.;
Roma, G.; Vargiu, L.; Mura, M.; Marongiu, M. E. Eur. J. Med. Chem. 2001, 36, 935–
949; (c) Schaefer, H.; Riedel, R.; Klemm, K.; Senn-Bilfinger, J.; Eltze, M. Eur. Pat.
Appl. EP 80-104589 19800804, 1981; Chem. Abstr. 1981, 95, 132969; (d)
Kobayashi, S. Chem. Lett. 1974, 9, 967–970; (e) Kobayashi, S. Bull. Chem. Soc. Jpn.
1975, 48, 302–306.
3. Juby, P. F.; Hudyma, T. W. Eur. Pat. Appl. DE 74-2418285 19740416, 1974;
Chem. Abstr. 1975, 82, 73045.
12. General procedure for the synthesis compounds 6 from compound 4. A mixture of
4. Dlugosz, A. Arch. Pharm. 1990, 323, 59–60.
4
(0.200 g; 0.864 mmol), the corresponding benzoic acid derivative (1.73
mmol) and POCl3 (5 mL) was heated between 80 and 90 °C for 1.5–3 h. The
mixture was cooled down, then mixture of ice-water was added and
5. Dlugosz, A. Pol. Pat. Appl. 94-302380 19940223, 1998; Chem Abstr. 1998, 129,
4665.
a
6. (a) Insuasty, B.; Insuasty, H.; Quiroga, J.; Nogueras, M.; Sánchez, A.; Lopez, M. D.
J. Heterocycl. Chem. 1999, 36, 933–936; (b) Insuasty, B.; Argoti, J. C.; Gómez, S.;
Quiroga, J.; Martinez, R.; Ángeles, E.; Gabino, R.; Nogueras, M.; Sánchez, A. J.
Heterocycl. Chem. 1998, 35, 1397–1399; (c) Insuasty, B.; Ramos, M.; Moreno, R.;
Quiroga, J.; Sánchez, A.; Nogueras, M.; Hanold, N.; Meier, H. J. Heterocycl. Chem.
1995, 32, 1229–1233; (d) Insuasty, B.; Ramos, M.; Quiroga, J.; Sánchez, A.;
Nogueras, M.; Hanold, N.; Meier, H. J. Heterocycl. Chem. 1994, 31, 61–64.
7. (a) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X. Org. Lett. 2005, 7, 1541–
1543; (b) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem. 2005, 7,
813–815; (c) Che, x.; Zheng, L.; Dang, Q.; Bai, X. Tetrahedron 2006, 62, 2563–
2568; (d) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem. 2006, 8,
381–387.
neutralized with solid K2CO3. A solid precipitated when the pH was basic (ca.
9), the solid was filtered off and washed several times with water, that after
drying and recrystallization from methanol afforded compounds 6. Data for
2-amino-6-(2-fluorophenyl)-4-methoxy-11H-pyrimido[4,5-b][1,4]benzodiazepine
6i. Reaction time 1.5 h. Reddish solid. Yield 64%, mp >300 °C. 1H NMR (DMSO-
d6) d: 3.81 (s, 3H), 6.47 (s, 2H), 6.61 (d, 1H, 8 Hz), 6.81 (t, 1H, 8 Hz), 6.89 (d, 1H,
8 Hz), 7.16–7.24 (m, 2H), 7.28 (t, 1 H, 8 Hz), 7.45–7.54 (m, 2H), 7.67 (s, 1H). 13C
NMR (DMSO-d6) d: 53.5, 108,2, 115.7, 120.6, 122.6, 124.4, 128.4, 129.6, 130.8,
131.4, 131.9, 148.7, 159.7, 160.8, 161.0, 166.1. MS m/z (assignation, abundance
%): 336 (M+1, 23), 335 (M+, 100), 334 (Mꢀ1, 23), 305 (Mꢀ30, 18), 240
([MꢀC6H4F]+, 4), 95 ([C6H4F]+, 13), 76 (C6H4þ, 9), 57 (C2H3NO+, 33); 43 (CHNO+,
67), 42 (CH2N2+, 27). HRMS calcd for C18H14FN5O: 335.1182, found: 335.1195.
Crystallographic data for 6i were collected at 120 K on a Bruker Nonius 0Kappa
8. (a) Marchal, A.; Melguizo, M.; Nogueras, M.; Sánchez, A.; Low, J. N. Synlett 2002,
255–258; (b) Melguizo, M.; Marchal, A.; Nogueras, M.; Sánchez, A.; Low, J. N. J.
Heterocycl. Chem. 2002, 39, 97–103.
CCD area diffractometer using Mo K
a X-ray radiation (k = 0.71073 ÅA) and
9. 2,4,5-Triamino-6-methoxy-N4-phenylpyrimidine (4). After preparation of 2,4-
diamine-6-methoxy-5-nitroso-N4-phenylpyrimidine (3) starting from 2-
amino-4,6-dimethoxypyrimidine by nitrosation and aminolysis with aniline,
that we have previously reported.7 Then, an aqueous ammonium sulfide
solution was added (15 mL, 20% w/w) to a solution of (3) (0.500 g, 2.04 mmol)
in methanol (15 mL). This mixture was stirred at room temperature for 4 h, the
volume was reduced under reduced pressure and cooled in a refrigerator for
several hours. Compound 4 precipitated as a white solid, which was filtered off
and dried. Yield 98% (0.46 g), mp: 139–141 °C. 1H NMR (DMSO-d6) d. 3.47 (s,
deposited at Cambridge Crystallographic data Center (CCDC reference:
686626).
13. Displacement ellipsoids are drawn at the 50% probability level and H are
represented as small spheres at arbitrary radii. The 2-fluorophenyl substituent
is disordered in two positions with occupancies of 0.75 for fluoride at C62
(represented in Fig. 3), and 0.25 for fluoride at C66.
14. (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930;
(b) Abrous, L.; Hynes, J., Jr.; Friedrich, S. R.; Smith, A. B.; Hirschmann, R. Org.
Lett. 2001, 3, 1089–1091.