A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

Article abstract of DOI:10.1016/j.tetlet.2011.07.098

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5- diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-p

Full text of DOI:10.1016/j.tetlet.2011.07.098

Tetrahedron Letters 52 (2011) 5077–5080
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A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones
and pyrido[2,3-e][1,4]diazepine-2,5-diones
Abderrahman El Bouakher a,b, Hélène Laborie b, Mina Aadil a, Ahmed El Hakmaoui a, Said Lazar c,
b,
Mohamed Akssira a, , Marie-Claude Viaud-Massuard
⇑
⇑
a Laboratoire de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 20800 Mohammedia, Morocco
b Laboratoire de Synthèse Organique et Thérapeutique, UMR CNRS 6239 Génétique-Immunothérapie-Chimie et Cancer, UFR des Sciences Pharmaceutiques,
Université de Tours, 37200 Tours, France
c Laboratoire de Biochimie, Environnement & Agroalimentaire, URAC 36, Université Hassan II Mohammedia-Casablanca, BP 146, 20800 Mohammedia, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]dia-
Received 26 April 2011
Revised 20 July 2011
Accepted 22 July 2011
Available online 29 July 2011
zepine-2,5-diones 9, is reported using the condensation of
1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and
9 were also synthesized by peptide coupling of -amino acid methyl ester derivatives with b-amino acids
(2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).
a-amino acid methyl ester derivatives with
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azaisatoic anhydride
Heterocyclization
Pyrido[3,2-e][1,4]diazepine-2,5-diones
Pyrido[2,3-e][1,4]diazipine-2,5-diones
The wide range of biological activities displayed by benzodiaz-
epine-derived compounds makes benzodiazepine scaffolds, partic-
ularly 1,4-benzodiazepine systems, some of the most important
structures for drug discovery.1,2 Thus, in addition to the well-
known anxiolytic,3 sedative,4 and anticonvulsant,5 activities of
the classic benzodiazepines, several 1,4-benzodiazepine deriva-
tives have also demonstrated activity as antitumor antibiotics,6
and anti-HIV agents.7,8 However, many undesirable effects have
been associated with the use of benzodiazepines. Thus, intensive
attempts have been made to discover new synthetic routes to ac-
cess this type of skeleton and to produce modified ring systems
with potential new activities.9 In particular, heterocycle-fused dia-
zepine derivatives, such as the pyrido-diazepines, have exhibited
new pharmacological activities.10
Two methods were used to prepare compounds 8 and 9. The
starting compound in method A was 3-N-Boc amino pyridine-2-
carboxylic acid.13 This was converted into azaisatoic anhydride 4
ingoodyieldsbyan excessof thionylchlorideundermethylene chlo-
ride reflux for 18 h. (Scheme 1). Compound 4 was then condensed
with appropriate methyl ester of
a-amino acids under N,N-
dimethylformamide reflux for 24 h. After purification by
chromatography, a series of pyrido[3,2-e][1,4]diazepine-2,5-diones
8a–h14 were obtained as shown in Table 1.
For the preparation of pyrido[2,3-e][1,4]diazepine-2,5-dione 9
regioisomers, we started from 2-amino nicotinic acid 2, which
was converted to 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione 5 in ethyl
chloroformate for 12 h at 100 °C.15 Under the same conditions, the
methyl ester derivatives of
a-amino acids were condensed with
Our ongoing research program for new bioisosters of 1,4-
benzodiazepines led us to develop a short and convenient synthesis
of new pyrido[3,2-e][1,4]-diazepine-2,5-diones and pyrido[2,3-e]
[1,4]diazepine-2,5-diones.
azaisatoic anhydride 5 (Scheme 1) to give after purification a series
of pyrido[2,3-e][1,4]diazepine-2,5-dione16 9a–h compounds, as
shown in Table 1.
Compounds 8 and 9 were also obtained using method B starting
While several strategies for accessing 1,4-benzodiazepine-
diones11 are known, only a few synthetic pathways have been
reported to yield fused pyridodiazepines.12
from b-amino acid (2 or 3) and a-amino acid methyl ester
derivatives, in N,N-dimethylformamide using hydroxybenzotria-
zole, ethylcyclodicarboxylate and Et3N, at room temperature. The
intermediate products (6 or 7) were engaged in the cyclization
reaction using NaH in THF (Scheme 1).17 After purification by chro-
⇑
Corresponding authors. Tel.: +212 523314705; fax: +212 52331 5353 (M.A.);
tel.: +33 24 736 7227; fax: +33 24 736 7229 (M.-C.V.-M.).
matography,
a series of pyrido[2,3-e][1,4]diazepine-2,5-diones
9a–h and pyrido[3,2-e][1,4]diazepine-2,5-diones 8a–h were ob-
tained as shown in Table 1.
E-mail addresses: akssira@uh2m.ac.ma (M. Akssira), mcviaud@univ-tours.fr,
marie-claude.viaud-massuard@univ-tours.fr (M.-C. Viaud-Massuard).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.098

5078
A. E. Bouakher et al. / Tetrahedron Letters 52 (2011) 5077–5080
Y
X
NH2
Y
X
NHR
1 : X = N, Y = CH, R = Boc
2 : X = CH, Y = N, R = H
3 : X = N, Y = CH
2 : X = CH, Y = N
CO2H
CO2H
i or ii
Method B
iv
Method A
H
N
Y
X
O
Y
X
NH2
CO2CH3
4 : X = N, Y = CH ; 80%
5 : X = CH, Y = N ; 60%
6 : X = N, Y = CH ; 70-80%
7 : X = CH, Y = N ; 70-80%
O
N
R1
O
O
R2
iii
v
H
O
N
Y
R1
R2
8 : X = N, Y = CH ; 44-75%
9 : X = CH, Y = N ; 40-70%
N
X
O
Scheme 1. Method A: to prepare 4 starting from 1: (i) SOCl2/CH2Cl2, 18 h, 50 °C; to prepare 5 starting from 2: (ii) Ethyl chloroformate/toluene, 12 h, 100 °C; (iii) the methyl
ester of various a-amino acids, DMF, Et3N, 24 h, reflux. Method B: (iv) the methyl ester of various a-amino acids, HOBt, EDC, DMF, Et3N, overnight, rt; (v) THF, NaH, rt.
Table 1
Results of synthesis compounds 8 and 9 by two methods
Entry
a-Amino acid methyl ester
Product 8
Method
Yield (%)
Product 9
Method
Yield (%)
H
N
O
N
O
H
A
B
75
55
A
B
70
60
1
L
-Proline methyl ester
N
N
N
N
N
H
O
N
N
N
H
9a
O
8a
H
O
Sarcosine
O
A
B
70
56
A
B
66
69
N
N
2
3
N
H
9b
O
O
8b
H
Methyl indoline-2-carboxylate
O
A
B
50
0
A
B
40
0
N
O
H
N
N
N
H
O
N
N
N
N
O
O
H
9c
8c
H
O
O
O
A
B
65
60
A
B
66
55
N
H
N
4
5
Methyl piperidine-2-carboxylate
N
N
H
N
H
9d
O
8d
H
N
O
A
B
55
50
A
B
50
44
H
NH
SCH3
SCH3
L
-Methionine methyl ester
-Phenylalanine methyl ester
NH
H
O
N
O
H
8e
9e
A
B
51
50
A
B
50
48
H
O
H
O
N
NH
6
L
NH
8f
N
H
O
N
N
O
H
9f
A
B
48
50
A
B
45
46
H
O
H
O
N
NH
NH
NH
7
8
L
-Tryptophane methyl ester
NH
N
N
H
N
N
N
O
O
9g
H
8g
H
O
O
H
A
B
49
44
A
B
50
40
N
NH
L-Leucine methyl ester
NH
H
O
N
O
H
9h
8h
A: Condensation of the methyl ester of various
B: Peptide coupling of methyl ester of various
a
-amino acids with azaisatoic anhydride (44–75%).
a-amino acid with b-amino acid (2 or 3) and cyclization by NaH in THF at rt (40–70%).

A. E. Bouakher et al. / Tetrahedron Letters 52 (2011) 5077–5080
5079
Acknowledgements
We gratefully acknowledge that this work was funded by the
Moroccan Ministry of Education, CNRST, through project URAC
22, and RéPAM, through a doctoral Grant. We gratefully acknowl-
edge Renaud Respaud for HPLC experiments and Dr. Hassan Allou-
chi for X-ray analysis.
Thanks also to Monika Ghosh for the translation assistance.
References and notes
1. 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, 2235–2246.
2. Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289–298.
3. Davidson, J. R. J. Clin. Psychiatry 2001, 62, 46–50.
Figure 1. Single-crystal X-ray analysis of 8a.
4. McCall, W. V. J. Clin. Psychiatry 2001, 62, 27–32.
5. Hanley, D. F.; Pozo, M. Int. J. Clin. Pract. 2000, 54, 30–35.
6. Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 433–465.
7. De Clercq, E. Antiviral Res. 1998, 38, 153–179.
8. Hsu, M. C.; Schutt, A. D.; Holly, M.; Slice, L. W.; Sherman, M. I.; Richman, D. D.;
Potash, M. J.; Volsky, D. J. Science 1991, 254, 1799–1802.
Table 2
Result of condensation of L, D, and DL-proline methyl esters with azaisatoic anhydride
Entry
Proline methyl ester
Product
Yields (%)
ee (%)
9. Some review articles on the synthesis of 1, 4-benzodiazepines: (a) Joshi, B.;
Chauhan, M. Ind. J. Heterocycl. Chem. 1996, 6, 157–164; (b) Walser, A.; Fryer, R. I.
Chem. Heterocycl. Compd. 1991, 50, 431–543; (c) Walser, A.; Fryer, R. I. Chem.
Heterocycl. Compd. 1991, 50, 545–629; (d) Walser, A.; Fryer, R. I. Chem.
Heterocycl. Compd. 1991, 50, 631–848; (e) Walser, A.; Fryer, R. I. Chem.
Heterocycl. Compd. 1991, 50, 849–946; (f) Bunin, B. A.; Plunkett, M. J. Methods
Enzymol. 1996, 267, 448–465.
1
2
3
8a
75
77
80
96
98
0
L
-Proline methyl ester
8a0
8a00
D
-Proline methyl ester
DL-Proline methyl ester
10. Fiakpvi, C. Y.; Phillips, O. A.; Murthy, K. S. K.; Knavs, E. E. Drug Des. Discovery
1993, 10, 45–55.
H
H
O
N
Proline methyl ester
DMF/TEA
N
O
11. (a) Beccalli, E. M.; Broggini, G.; Paladino, G.; Pilati, T.; Pontremoli, G.
Tetrahedron: Asymmetry 2004, 15, 687–692; (b) Surman, M. D.; Mulvihill, M.
J.; Miller, M. J. Org. Lett. 2002, 4, 139–141; (c) Abrous, L., Jr.; Hynes, J.;
Friederich, S. R.; Smith, A. B., III; Hirschmann, R. Org. Lett. 2001, 3, 1089–1092;
(d) Matthews, J. M.; Dyatkin, A. B.; Evangelisto, M.; Gauthier, D. A.; Hecker, L.
R.; Hoekstra, W. J.; Liu, F.; Poulter, B.; Sorgi, K. L.; Maryanoff, B. E. Tetrahedron:
Asymmetry 2004, 15, 1259–1267; (e) Hemming, K.; Loukou, C. Tetrahedron
2004, 60, 3349–3357; (f) Herrero, S.; Garcıa-Lopez, M. T.; Herranz, R. J. Org.
Chem. 2003, 68, 4582–4585; (g) De Silva, R. A.; Santra, S.; Andreana, P. R. Org.
Lett. 2008, 10, 4541–4544; Shaabani, A.; Maleki, A.; Mofakham, H. J. Comb.
Chem. 2008, 10, 595–598.
O
N
N
N
O
O
4
8 a-a''
Scheme 2. Condensation of L, D, and DL-proline methyl esters with azaisatoic
anhydride 4 in DMF under reflux (see Ref. 14).
The structures of compounds 8 and 9 were determined from
spectroscopic data, and the structure of product 8a obtained from
methods A and B was confirmed by single-crystal X-ray analysis,
which is shown in Figure 1.
12. (a) Beccalli, E. M.; Broggini, G.; Paladino, G.; Zoni, C. Tetrahedron 2005, 61, 61–
68; (b) Legerèn, L.; Dominguez, D. Tetrahedron Lett. 2010, 51, 4053–4057.
13. Akssira, M.; Dahdouh, A.; Kasmi, H.; Boumzebra, M.; Canonne, P. Heterocycles
1993, 36, 1305–1314.
14. General procedure for the preparation of compounds 8a–h
The composition of the crude product 8a was determined by
HPLC18 (Table 2). Pure samples of (S)-6a,7,8,9-tetrahydro-5H-pyr-
ido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (8a) and (R)-
6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-
6,11-dione (8a0)and (R,S)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyr-
rolo[1,2-a][1,4]diazepine-6,11-dione (8a00) were prepared by con-
densing L-proline methyl ester, D-proline methyl ester and DL-
proline methyl ester respectively with azaisatoic anhydride 4 (
Scheme 2) according to the procedure used as references.
In several cases, method A gave better yields than the method B,
this fact is depending on the reactivity of azaisatoic anhydride.
Isatoic anhydrides (analogs of azaisatoic anhydrides) are known
to be extremely versatile reagents, useful in the preparation of a
variety of heterocyclic systems.19 Previous studies have shown that
Method A: A suspension of azaisatoic anhydride (0.48 g, 2.9 mmol) and
a-
amino acid methyl ester (3.5 mmol) in 10 mL of DMF and 2 mL of Et3N was
heated under reflux for 24 h. The solvent was evaporated, and the crude
product was purified by chromatography to give 8.
Method B: To
20 mmol) in anhydrous DMF (100 mL) was added EDC (4.2 g, 22 mmol),
HOBt (2.97 g, 22 mmol) and triethylamine (8.2 mL, 60 mmol). -Amino acid
a solution of 3-aminopyridine-2-carboxylic acid (2.74 g,
a
methyl ester (22 mmol) was added, and the reaction mixture was stirred
overnight. Water (100 mL) was added, and the mixture was extracted with
methylene chloride (4 ꢀ 100 mL), dried over MgSO4 and concentrated. The
compound was purified by silica gel chromatography to give the oil-like open
product 6; this was then dissolved in THF (125 mL) under argon. Sodium
hydride (0.93 g, 60% dispersion in oil, 26.8 mmol) was added, and the reaction
mixture was stirred overnight. Water (5 mL) was carefully added, and the
resulting white precipitate was collected. The precipitate was dissolved in
ethyl acetate (200 mL), washed with water (50 mL) and brine (50 mL), dried
over MgSO4 and concentrated to give product 8.
Compound 8a: mp 245–247 °C; 1H NMR (DMSO-d6, dppm) d: 1.81 (m, 2H);
1.93 (m, 2H); 3.52 (m, 2H); 4.24 (d, 1H); 7.55 (m, 2(1Hpy)); 8.48 (dd, 1Hpy);
10.56 (1H); 13C NMR (DMSO-d6) d: 23.28; 26.24; 47.23; 56.33; 126.62; 130.04;
these compounds react efficiently with
a-amino acids in one-pot
to give 1,4-benzodiazepine-2,5-diones.20
134.19; 143.29; 145.87; 163.15; 171.27; IR, (KBr):
m 3124 (NH), 1693,
1620 cmꢁ1 (two carbonyl groups); MS, m/z: 217.
In conclusion, the new pyrido[3,2-e][1,4]-diazepine-2,5-diones
and pyrido[2,3-e][1,4]diazepine-2,5-diones were efficiently syn-
thesized by condensing 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione
Compound 8e: oil; 1H NMR (DMSO-d6, dppm) d: 2–2.06 (m, 2H); 2.06 (s, 3H);
2.61–2.66 (m, 2H); 434–4.4 (m, 1H); 7.53 (dd, 1Hpy); 7.81 (dd, 1Hpy); 8.57 (dd,
1Hpy); 8.71 (2 (1H), NH); 13C NMR(DMSO-d6) d: 14.86; 29.14; 30.84; 55.86
and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione with appropriate
a-
124.18; 129.55; 134.53; 147.71; 148.87; 162.77; 173.54; IR, (KBr):
m 3300
(NH), 1775, 1714 cmꢁ1(two carbonyl groups); MS, m/z: 251.
amino acid methyl ester derivatives. Pyrido[2,3-e][1,4]diazepine-
2,5-diones and pyrido[3,2-e][1,4]diazepine-2,5-diones, were ob-
tained very efficiently from b-amino acid (2 or 3) by coupling with
15. Sonnenburg, R.; Neda, I.; Fisher, A.; Jones, P. G.; Schmutler, R. Chem. Ber. 1995,
128, 628–634.
16. General procedure for the preparation of compounds 9a–h (See Ref. 14)
Compound 9b: mp 209 °C; 1H NMR (DMSO-d6, dppm) d: 3.12 (s, 3H); 3.94 (s,
2H); 7.3 (dd, 1Hpy); 8.17 (dd, 1Hpy); 8.52 (dd, 1Hpy); 10.88 (s, 1H); 13C NMR
(DMSO-d6) d: 36.37; 52.79; 120.31; 121.5; 141.04; 149.3; 152; 165.89; 170.03;
a-amino acid methyl esters and a final cyclization under basic con-
ditions (NaH/THF). The work reported here provides an efficient
and inexpensive procedure for the synthesis of bioisosters of 1,4-
benzodiazepines.
IR, (KBr):
17. Paulis, H.; WO 2008/009122 A1 24.01. 2008.
m
3066 (NH), 1665,1740 cmꢁ1(two carbonyl groups); MS, m/z: 191.

5080
A. E. Bouakher et al. / Tetrahedron Letters 52 (2011) 5077–5080
18. Analytical HPLC was carried out using a LaChrom Elite system equipped with a
VWRL-2130 pump, VWRL-2200 autosampler at 4 °C, VWR L-400 UV
Proportions of enantiomers (R)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo
[1,2-a][1,4]diazepine-6,11-dione (2 mg/mL), 98% R, 2% S. (S)-6a,7,8,9-tetra-
hydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione had retention
times of 6.4 and 8.6 min (2 mg/mL),: 4% R, 96% S. (RS)-6a,7,8,9-tetrahydro-5H-
pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione had retention times of
6.4 and 8.6 min (2 mg/mL), 50% R, 50% S.
a
a
detector. The chromatographic data was processed using EZChrom Server
software. The UV detection was carried out at 254 nm. The column was a
Chiralpak IA (Daicel, 250 mm ꢀ 4.6 mm), thermostated at 25 °C. The mobile
phase was a mixture of Heptane/Ethanol/Methanol (50:25:25 v/v/v). The flow
rate was 1 mL/min. The injection volume was 5
lL.
19. Coppola, G. M. Synthesis 1980, 505–536.
Retention times for (R)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo
[1,2-a][1,4]diazepine-6,11-dione and (S)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
pyrrolo[1,2-a][1,4]diazepine-6,11-dione were 6.4 and 8.6 min, respectively.
20. Jadidi, K.; Ghahremanzadeh, R.; Asgari, D.; Eslami, P.; Arvin-Nezhad, H.
Monatsh. Chem. 2008, 139, 1229–1232.