An efficient synthesis of pyrido-imidazodiazepinediones

Article abstract of DOI:10.1016/j.tetlet.2012.12.087

We herein report the synthesis of a series of 12 optically pure 3,4-dihydro-1H-pyrido-[1′,2′:1,2]-imidazo[ 4,5-d][1,3]diazepine-2,5- diones, which form a new family of azaheterocycle-fused [1,3]diazepines. The key step of the synthesis consists in a selec

Full text of DOI:10.1016/j.tetlet.2012.12.087

Tetrahedron Letters 54 (2013) 1364–1367
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An efficient synthesis of pyrido-imidazodiazepinediones
Dominique P. Arama, Vincent Lisowski, Eliana Scarlata, Pierre Fulcrand, Ludovic T. Maillard,
⇑
Jean Martinez, Nicolas Masurier
Institut des Biomolécules Max-Mousseron (IBMM), UMR 5247, Universités Montpellier I et II, 15 Avenue Charles Flahault, 34093 Montpellier, France
a r t i c l e i n f o
a b s t r a c t
We herein report the synthesis of a series of 12 optically pure 3,4-dihydro-1H-pyrido-[10,20:1,2]-imi-
dazo[4,5-d][1,3]diazepine-2,5-diones, which form a new family of azaheterocycle-fused [1,3]diazepines.
The key step of the synthesis consists in a selective C-acylation of 2-amino-imidazo[1,2-a]pyridine by
various natural amino-acids, followed by an intracarbonylation reaction.
Article history:
Received 21 November 2012
Accepted 21 December 2012
Available online 4 January 2013
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diazepinones
Friedel–Crafts acylation
Imidazo[1,2-a]pyridine
Polyfused heterocycles
Urea derivatives
The diazepine scaffold is one of the classical examples of privi-
leged structures, which has proved its effectiveness in a number of
pharmaceutical drugs and still continues to attract much interest
today in medicinal chemistry.1,2 Aryldiazepine ring systems
achieved popularity first in the 1960s with diazepam as the first
orally active benzo[1,4]diazepinone anxiolytic by interaction with
GABA receptor. This scaffold was further shown to interact with
multiple receptor types with high affinity3 and has been used in
the design of enzyme inhibitors4–7 and protein–DNA interaction
inhibitors.8 Beyond benzo[1,4]diazepines, [1,4]diazepines fused
with various heterocyclic ring systems such as imidazole,9–14 in-
dole,15 pyrrole,16 pyridine,17 pyrazole,18,19 thiophene,20–23 etc. have
been investigated.
Among the different classes of diazepines, the [1,3]diazepines
have been studied to a minor extent although their representatives
(benzo-, thiazolo-, and imidazo-fused) exhibit various biological
activities including cytotoxic,24 anti-HIV,25 AMP deaminase inhibi-
tor,26 anti-HCV,27 lymphocyte-specific kinase (Lck) inhibitors.28
The [1,3]diazepin-2-one scaffold can also be found in natural prod-
ucts29 or in synthetic compounds with pharmacological activities,
like calcitonin gene-related peptide (CGRP) receptor antagonists,30
dopamine D2 partial agonists,31 or HIV protease inhibitors32
(Fig. 1). Therefore, development of new fused [1,3]diazepin-2-one
scaffolds, incorporating an urea moiety in the diazepine core could
be of interest to access new bioactive compounds.
the synthesis is a Friedel–Crafts acylation at the C-3 position of
the easily accessible 2-amino-imidazo[1,2-a]pyridine.34,35 In con-
tinuation of this study, we describe herein the synthesis of imi-
dazo[1,2-a]pyridine-based
compounds 1, Fig. 1).
[1,3]diazepin-2,5-diones
(target
The synthesis of target compounds 1 was envisioned from 2-
amino-imidazo[1,2-a]pyridine 3, according to the strategy de-
picted in Scheme 1. Imidazo[1,2-a]pyridine (IP), an aza analog of
H
N
O
O
N
N
NH
O
HO
H
N
O
CGRP receptor antagonist
NH
OH
Isoaquiledine
N
N
NH
O
O
N
N
H
F
Dopamine D2 partial agonist
N
NH
O
N
We recently reported the synthesis of an original series of opti-
NH
cally pure imidazopyrido[1,3]diazepin-5-ones.33 The key step of
O
R
Target compounds 1
⇑
Corresponding author. Tel.: +33 4 11 75 96 42; fax: +33 4 11 75 96 41.
E-mail address: nicolas.masurier@univ-montp1.fr (N. Masurier).
Figure 1. Representative examples of [1,3]diazepin-2-ones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.087

D. P. Arama et al. / Tetrahedron Letters 54 (2013) 1364–1367
1365
N
N
NH2
NH
N
Selective
Intramolecular
carbonylation
N
O
N
NH2
N
C-acylation
NH2
NH
O
O
3
R
R
2
1
Scheme 1. Retrosynthetic approach for the synthesis of target compounds 1.
indole, is known to be an electron-rich aromatic ring with particu-
lar reactivity at C-3 position for aromatic substitution.36,37 This C-3
position can be easily acylated (vs amine acylation) by a selective
Friedel–Crafts acylation, by simple carboxylic acid activation of
amino acid derivatives, leading to diamines 2.33 Subsequent intra-
carbonylation of appropriate diamines 2 could lead to urea deriva-
tives 1.
2-Amino-IP 3 was synthesized according to our previously
described procedure.33 Intermediate 3 was selectively acylated at
C-3 position using a set of N-Boc-protected amino acids (Scheme 2).
Natural amino acids bearing alkyl (Ala, Val, Ile), aromatic (Phe, Trp),
sulfur-containing (Met), alcohol-containing (Thr), acid-containing
(Asp), base-containing (Lys) side chains, and the cyclic amino acid
(Pro) were examined. Activation of the N-protected amino acid
was performed using EDCI/HOBT in DCM at room temperature.
Reactions were monitored by TLC on alumina oxide with DCM/
EtOH (99:1 v/v) as eluent and by HPLC. Each crude 4 was purified
by chromatography on neutral alumina oxide.38 For all used ami-
no-acids, C-3 addition compounds 4a–l were obtained in good to
high yields (64–97%). N-addition side-products were only detected
as traces by LC–MS in accordance with previous results.33 After Boc
removal by HCl treatment, the resulting hydrochloride salt was
neutralized with aqueous ammonia and the solution was extracted
with chloroform. 2-Amino-3-acyl-imidazo[1,2-a]pyridines 2a–l
were isolated without further purification.
To study the experimental conditions of [1,3]diazepin-
2,5-diones 1 formation, diamine derivative 2a was first reacted
with 1,10-carbonyldiimidazole (CDI) in acetonitrile at room tem-
perature (Scheme 3). Compound 1a was isolated in 64% yield, but
the LC–MS analysis of the crude revealed the presence of another
compound, which was assumed to be the reaction intermediate 5
(Scheme 3). The electrospray mass spectrum showed a molecular
ion at m/z 375 corresponding to the addition of one imidazo-
carbonyl moiety on compound 2a. However, attempts to isolate
this intermediate failed. In order to identify the site of carbonyl-
ation, compound 2a was reacted with CDI in acetonitrile. After
2 h, 1 equiv of benzylamine was added, to trap intermediate 5.
Compound 6 was isolated in 34% yield after purification by chro-
N
BocAAOH
N
NH2
NH2
N
EDCI, HOBt
NEt3, DCM
N
NR2Boc
3
O
R1
N
matography on neutral alumina oxide (Scheme 3). The 1H–13
C
4a-l
HMBC analysis of 6 showed a correlation between the CH of the
a
N
phenylalanine residue (5.20 ppm) and the urea carbonyl signal
(158.9 ppm), which unambiguously proved the N-activation posi-
tion. This result confirmed that the aromatic amine in position 2
of the IP nucleus still remained moderately reactive, as it was al-
ready observed for the Friedel–Crafts acylation reaction.
1. HCl
2. NH4OH
NH
NH2
CDI
ACN, 60°C
O
N
N
NH
R
NR2H
O
O
R1
2a-l
1a-l
To optimize the cyclization reaction, compound 2a was reacted
with CDI at 60 °C for 2 h and compound 1a was isolated in good
yield (78%). Under these conditions, no trace of compound 5 was
detected by the LC–MS analysis. Thus, the scope of the reaction
was extended to other 2-amino-3-acylimidazo[1,2-a]pyridines
2b–l.39 Conversion of diamines 2b–l was quantitative as proved
by HPLC monitoring and the urea derivatives 1b–l were easily iso-
lated by filtration in 40–99% yields (Table 1).
g
a
: R2=H, R1 = (L)-(CH2)4NHCbz
: R2=H, R1 = (L)-CH2C6H5
h: R2=H, R1 = (L)-CH2CO2Bn
b: R2=H, R1 = (L)-CH3
i: R2=H, R1 = (L)-CH(CH3)CH2CH3
c: R2=H, R1 = (L)-CH(CH3)2
j
d
: R2=H, R1 = (D)-CH(CH3)CH2CH3
: R2=H, R1 = (L)-CH2CH(CH3)2
k: R2=H, R1 = (L)-CH(OBn)CH3
e: R2=H, R1 = (L)-(CH2)2SCH3
l
f
: R1,R2 = [(CH2)3]c
: R2=H, R1 = (L)-CH2-indole
Scheme 2. Synthesis of 3,4-dihydro-1H-pyrido[10,20:1,2]imidazo-[4,5-d][1,3]diaze-
pine-2,5-diones 1a–l.
N
N
N
NH2
NH2
NH
NH2
CDI
N
O
N
N
H
N
ACN, RT
NH
N
N
+
O
O
O
O
1a (64%)
5
2a
BnNH2
N
NH2
N
H
H
N
N
O
O
: key 1H-13C HMBC correlation
6 (34%)
Scheme 3. Cyclization study at room temperature.

1366
D. P. Arama et al. / Tetrahedron Letters 54 (2013) 1364–1367
Table 1
Synthesized compounds 1a–l
Table 1 (continued)
Compounds
Yield (%)
Structure
Yield (%)
40
Compounds
Structure
N
N
NH
O
N
NH
O
N
1k
NH
OBn
NH
NH
O
1a
78
O
N
O
N
N
1l
99
N
NH
O
O
N
N
O
1b
1c
93
NH
O
N
NH
NH
In summary, we have developed a practical sequence for the
synthesis of the IP-fused [1,3]diazepine-2,5-dione heterocyclic
scaffold. From an initial C-3 acylation of 2-aminoIP by Boc-amino
acids and after removal of the amino protecting group, the dia-
mines were engaged in an intramolecular carbonylation to access
a library of 12 urea compounds in 40ꢀ99% overall yields. In light
of the remarkable biological activities of diazepine derivatives,
these unusual heterocycle fused [1,3]diazepines are currently un-
der investigation for their pharmacological potentialities.
60
86
68
O
N
NH
O
N
NH
1d
1e
O
N
NH
Supplementary data
O
N
N
NH
Supplementary data (including 1H and 13C NMR data for all new
derivatives) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.087.
O
SMe
N
NH
O
References and notes
NH
O
1f
89
1. Sternbach, L. H. J. Med. Chem. 1979, 22, 1–7.
2. Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.; Cho, Y.; Chong, S.;
Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S. H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.;
Mitt, T.; Patel, M.; Penhallow, B. A.; Ricca, C.; Rose, W. C.; Schmidt, R.;
Slusarchyk, W. A.; Vite, G.; Manne, V. J. Med. Chem. 2000, 43, 3587–3595.
3. Bolli, M. H.; Marfurt, J.; Grisostomi, C.; Boss, C.; Binkert, C.; Hess, P.; Treiber, A.;
Thorin, E.; Morrison, K.; Buchmann, S.; Bur, D.; Ramuz, H.; Clozel, M.; Fischli,
W.; Weller, T. J. Med. Chem. 2004, 47, 2776–2795.
4. Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.;
Lewis, H. D.; Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. S. J. Med.
Chem. 2003, 46, 2275–2278.
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. J. Med. Chem. 1988, 31, 2235–
2246.
6. Evans, B. E.; Bock, M. G.; Rittle, K. E.; DiPardo, R. M.; Whitter, W. L.; Veber, D. F.;
Anderson, P. S.; Freidinger, R. M. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 4918–
4922.
7. Micale, N.; Vairagoundar, R.; Yakovlev, A. G.; Kozikowski, A. P. J. Med. Chem.
2004, 47, 6455–6458.
8. Rodriguez, I. B.; Procopio, J. R.; Hernandez, L. H.; Fresenius, Z. Anal. Chem. 1987,
328, 117–119.
9. Hosmane, R. S.; Bhan, A.; Karpel, R. L.; Siriwardane, U.; Hosmane, N. S. J. Org.
Chem. 1990, 55, 5882–5890.
10. Daly, J. W.; Hide, I.; Bridson, P. K. J. Med. Chem. 1990, 33, 2818–2821.
11. Hosmane, R. S.; Bhan, A. J. Heterocycl. Chem. 1990, 27, 2189–2196.
12. Bridson, P. K.; Weirich, T. P. J. Heterocycl. Chem. 1988, 25, 1179–1182.
13. Ivanov, E. I. Khim. Geterotsikl. Soedin. 1998, 828–831.
14. Ivanov, E. I.; Kalayanov, G. D.; Yaroshchenko, I. M. Khim. Geterotsikl. Soedin.
1990, 997–998.
N
H
N
NH
O
N
1g
1h
56
62
NH
O
CbzHN
N
N
NH
O
NH
O
BnO
O
N
NH
O
O
N
1i
1j
53
60
NH
O
N
NH
NH
N
15. Garcia, C. J. Heterocycl. Chem. 1973, 10, 51–53.
16. Funke, C.; Es-Sayed, M.; De Meijere, A. Org. Lett. 2000, 2, 4249–4251.
17. Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997,
62, 1240–1256.
O
18. Baraldi, P. G.; Manfredini, S.; Periotto, V.; Simoni, D.; Guarneri, M.; Borea, P. A. J.
Med. Chem. 1985, 28, 683–685.

D. P. Arama et al. / Tetrahedron Letters 54 (2013) 1364–1367
35. Hamdouchi, C.; Sanchez, C.; Ezquerra, J. Synthesis 1998, 867–872.
1367
19. Lee, J. Y.; Kim, Y. C. ChemMedChem 2009, 4, 733–737.
20. Brouillette, Y.; Lisowski, V.; Fulcrand, P.; Martinez, J. J. Org. Chem. 2007, 72,
2662–2665.
36. Masurier, N.; Moreau, E.; Lartigue, C.; Gaumet, V.; Chezal, J. M.; Heitz, A.;
Teulade, J. C.; Chavignon, O. J. Org. Chem. 2008, 73, 5989–5992.
37. Chaubet, G.; Maillard, L. T.; Martinez, J.; Masurier, N. Tetrahedron 2011, 67,
4897–4904.
21. Brouillette, Y.; Martinez, J.; Lisowski, V. J. Org. Chem. 2009, 74, 4975–4981.
22. Brouillette, Y.; Sujol, G.; Martinez, J.; Lisowski, V. Synthesis 2009, 389–394.
23. Brouillette, Y.; Verdie, P.; Martinez, J.; Lisowski, V. Synlett 2008, 2360–2364.
24. Rotas, G.; Natchkebia, K.; Natsvlishvili, N.; Kekelidze, M.; Kimbaris, A.;
Varvounis, G.; Mikeladze, D. Bioorg. Med. Chem. Lett. 2005, 15, 3220–3223.
25. Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.;
Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C. H.; Weber, P. C.;
Jackson, D. A.; Sharpe, T. R.; Erickson-Viitanen, S. Science 1994, 263, 380–384.
26. Bookser, B. C.; Kasibhatla, S. R.; Appleman, J. R.; Erion, M. D. J. Med. Chem. 2000,
43, 1495–1507.
38. General procedure for the synthesis of 2-amino-3-acyl-imidazo[1,2-a]pyridines
4a–l: To
a suspension of 0.5 g of trifluoro-N-imidazo[1,2-a]pyridin-2-yl-
acetamide33 (2.18 mmol) in 9 mL of aqueous 5 N sodium hydroxide solution
was added 0.5 mL of THF. The solution was stirred at 40 °C for 2 h. The solution
was extracted with dichloromethane (3 ꢁ 20 mL). The organic layer was dried
over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was
dissolved in 20 mL of dichloromethane and 2.4 mmol of BocAAOH (1.1 equiv),
325 mg (2.4 mmol, 1.1 equiv) of HOBt, 460 mg (2.4 mmol, 1.1 equiv) of EDCI,
27. El-Subbagh, H. I.; Hassan, G. S.; El-Azab, A. S.; Abdel-Aziz, A. A. M.; Kadi, A. A.;
Al-Obaid, A. M.; Al-Shabanah, O. A.; Sayed-Ahmed, M. M. Eur. J. Med. Chem.
2011, 46, 5567–5572.
28. Takayama, T.; Umemiya, H.; Amada, H.; Yabuuchi, T.; Koami, T.; Shiozawa, F.;
Oka, Y.; Takaoka, A.; Yamaguchi, A.; Endo, M.; Sato, M. Bioorg. Med. Chem. Lett.
2010, 20, 112–116.
29. Chen, S. B.; Gao, G. Y.; Leung, H. W.; Yeung, H. W.; Yang, J. S.; Xiao, P. G. J. Nat.
Prod. 2001, 64, 85–87.
30. Boehringer Ingelheim Pharma GmbH & Co. KG, Eur. Pat. Appl. EP 2065382 A1,
2009.
31. Magano, J.; Acciacca, A.; Akin, A.; Collman, B. M.; Conway, B.; Waldo, M.; Chen,
M. H.; Mennen, K. E. Org. Process Res. Dev. 2009, 13, 555–566.
32. Gupta, S. P.; Babu, M. S. Bioorg. Med. Chem. 1999, 7, 2549–2553.
33. Masurier, N.; Aruta, R.; Gaumet, V.; Denoyelle, S.; Moreau, E.; Lisowski, V.;
Martinez, J.; Maillard, L. T. J. Org. Chem. 2012, 77, 3679–3685.
34. Hamdouchi, C.; De Blas, J.; Ezquerra, J. Tetrahedron 1999, 55, 541–548.
and 334 lL of triethylamine (243 mg, 2.4 mmol, 1.1 equiv) were added at 0 °C.
The solution was stirred at rt for 4 h. The solution was then washed with
saturated NaHCO3 solution (2 ꢁ 50 mL). The organic layer was dried over
Na2SO4, filtered, and the solvent was concentrated in vacuo. The residue was
purified by chromatography (Al2O3, DCM/EtOH 99/1 v/v) to offer 4a–l.
39. General procedure for the synthesis of 1,3-diazepine-2,5-diones 1a–l. A solution of
150 mg of compound 4a–l in 3 mL of 12 N hydrochloric acid was stirred a room
temperature for 1 h. The solution was treated with 28% aqueous ammonia
solution and then extracted with chloroform (3 ꢁ 20 mL). The organic layer
was dried over Na2SO4, filtered, and the solvent was concentrated in vacuo to
lead compounds 2a–l, which were used in the next step without further
purification. To
a solution of the appropriate diamine 2a–l in 5 mL of
acetonitrile was added 1.1 equiv of carbonyldiimidazole (CDI). The solution
was stirred at 60 °C until completion of the reaction (HPLC monitoring). After
cooling to rt, the precipitate was collected by filtration, washed with
diethylether, and dried in vacuo to give 1a–l.