An efficient and convenient method for synthesizing new derivatives of pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepine-5,10-dione via Sonogashira, Suzuki-Miyaura, and Stille cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2012.09.041

An efficient method for synthesizing new pyrido[2,3-e]pyrrolo[1,2-a][1,4] diazepine-5,10-dione derivatives starting from l-proline methyl ester and 2-aminonicotinic acid is presented. This method employs Pd-catalyzed cross-coupling reaction on the corresponding brominated compound 4 (key intermediate). Sonogashira, Stille, and Suzuki-Miyaura cross-coupling reactions are used to generate products 5a-g, 6, 7a-c, and 8a-e, in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.09.041

Tetrahedron Letters 53 (2012) 6401–6405
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and convenient method for synthesizing new derivatives of
pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepine-5,10-dione via Sonogashira,
Suzuki–Miyaura, and Stille cross-coupling reactions
Abderrahman El Bouakher a,b, Gildas Prié b, Mina Aadil a, Said Lazar a, Ahmed El Hakmaoui a,
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 EA 6306 IMT, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, Université de Tours, 37200 Tours, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2012
Revised 6 September 2012
Accepted 11 September 2012
Available online 18 September 2012
An efficient method for synthesizing new pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepine-5,10-dione deriva-
tives starting from L-proline methyl ester and 2-aminonicotinic acid is presented. This method employs
Pd-catalyzed cross-coupling reaction on the corresponding brominated compound 4 (key intermediate).
Sonogashira, Stille, and Suzuki–Miyaura cross-coupling reactions are used to generate products 5a–g, 6,
7a–c, and 8a–e, in good to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminonicotinic acid
(S)-3-Bromo-7,8,9,9a-tetrahydro-5H-pyrido
[2,3-e]pyrrolo[1,2-a][1,4]
diazepine-5,10(11H)-dione
C–C Cross-coupling reactions
The development of new approaches for the efficient construc-
tion of a number of heterocycles continues to be essential for
accessing natural products and their structural analogs.
Benzodiazepines form a well-known and widely applied class of
biologically active compounds1 and are representatives of the
family of privileged structures.2 Discovered in the 1960s,3 the
pyrrolobenzodiazepines (PBDs) are an important class of
sequence-selective DNA-interactive agents that bind covalently
to guanine bases within the minor groove of DNA.4 The
pyrrolo[1,2-c][1,4]-benzodiazepine ring system is part of the
naturally-occurring DNA-interactive antitumor antibiotics known
as the ‘anthramycines’ (Fig. 1).5 They are produced by various
Starting from these data reported in the literature, the aim of
our research was the synthesis of compounds containing the
pyrrolo[1,2-c]1,4-diazepine ring and heterocyclic nuclei.
We decided to synthesize their pyridine analogs PPDs (pyr-
idopyrrolodiazepines), compounds not or less described in the lit-
erature up to now.
Recently, and continuing our work on new N-containing hetero-
cyclic compounds, we reported a preliminary work describing the
access to new pyrido[3,2-e][1,4]diazepine-2,5-diones and
pyrido[2,3-e][1,4]diazepine-2,5-dione derivatives.9
In the present Letter we wish to describe our results in
extension of the cited methodology to the preparation of new 3-
substitued-7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a]-
[1,4]diazepine-5,10(11H)-diones 4, 5, 6, 7, 8. The latter were
synthesized starting from commercially available 2-aminonicotinic
Streptomyces species and the biosynthesis of
a number of
pyrrolo[1,2-c][1,4]-benzodiazepine rings has been studied.6
Numerous studies have demonstrated that anthramycin binds
in the narrow groove of DNA. The model proposed for attachment
of anthramycin to DNA involves a covalent aminal linkage between
the 2-amino group of the guanidine and C-11 of anthramycin,7 and
was confirmed by a NMR study of an anthramycin-DNA adduct.8
acid 1. Compound 1 was coupled with L-proline methyl ester in
DMF, HOBt, EDC, and Et3N, at room temperature to provide amide
2, which was brominated with 1.1 equiv of NBS in CHCl3 under
OH
H
N
OCH3
H3CO
N
⇑
Corresponding authors. Tel.: +212 523314705; fax: +212 523315353 (M.A.);
tel.: +33 24 736 7227; fax: +33 24 736 7229 (M.-C.V.-M.).
CONH2
O
E-mail addresses: akssira@uh2m.ac.ma (M. Akssira), mcviaud@univ-tours.fr,
marie-claude.viaud-massuard@univ-tours.fr (M.-C. Viaud-Massuard).
Figure 1. Structure of anthramycin
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.041

6402
A. El Bouakher et al. / Tetrahedron Letters 53 (2012) 6401–6405
O
O
mild conditions at room temperature for 30 min. The brominated
CO2H
NH2
N
Br
N
b
product 3 was obtained in a good yield (90%). Cyclization of com-
pound 3 was performed in DMF under reflux for 18 h. After evap-
oration of the solvents and recrystallization in EtOH, the reaction
mixture was simply cooled to room temperature and filtered to
give the pure (S)-3-bromo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]-
pyrrolo[1,2-a][1,4]diazepine-5,10(11H)-dione 410 in 70% yield
(Scheme 1). The structure of compounds 4 was assigned by 1H
NMR, 13C NMR, and X-ray (Fig. 2).
a
N
1
CO2CH3
CO2CH3
N
NH2
N
NH2
2
3
c
O
O
R
Br
N
d
N
N
N
N
N
H
Palladium(0)-catalyzed carbon–carbon (Csp2–Csp2) bond-
forming processes are widely used in synthetic chemistry.11
Sonogashira,12 Stille, and Suzuki–Miyaura13 cross-coupling reac-
tions have found extensive use in natural product synthesis and
for the construction of complex molecules.14
O
O
H
5a-g, 8a-e
4
Scheme 1. Reagents and conditions: (a) EDC, 1.2 equiv; HOBt, 1.2 equiv; L-proline
methyl ester, 1.2 equiv; DMF; Et3N; 12 h; rt. (b) NBS, 1.1 equiv; CHCl3; 0.5 h; rt. (c)
DMF; 18 h; reflux. (d) For conditions and reaction times, see footnote of Table 1.
Sonogashira cross-coupling reactions
Sonogashira cross-coupling reactions were first achieved on
compound 4. This reaction was performed with terminal alkynes
(1.2 equiv), copper iodide (10 mol %), and 5 mol % of Pd(PPh3)4 in
a mixture of DMF/Et3N (1:1) at 100 °C for 2 h. The desired
compounds 5a–g (Scheme 1) were isolated in excellent yields
(76–96%).15 (Table 1).
Sequentially, compound 5a was desilylated (Scheme 2) using
tetrabutylammonium fluoride (TBAF) in THF at room temperature
for 40 min to furnish the terminal alkyne 6 in excellent yield
(95%).16 Finally, compounds 7a–c can readily be achieved with
good yields (75–80%) by reaction of terminal alkyne 6 with the
Figure 2. Single-crystal X-ray analysis of 4.
Table 1
Pd-catalyzed cross coupling reactions on compound 4
O
O
Br
R
(a) or (b) or (c) or (d)
N
N
H
N
N
O
O
4
5Ha-g, 7a-c, 8a-e
Product 5,7 and 8
(H3C)3Si
Entry
1
R
Conditions
a
N° yield (%)
5a (96)
O
N
(H3C)3Si
N
O
N
O
H
N
OH
HO
9
2
3
4
a
a
a
5b (90)
5c (80)
5d (92)
N
N
H
O
O
N
9
N
N
O
H
N
O
N
N
O
H
O
N
5
6
a
a
5e (95)
5f (88)
N
N
O
H
F3C
O
N
F3C
N
N
O
H

A. El Bouakher et al. / Tetrahedron Letters 53 (2012) 6401–6405
6403
Table 1 (continued)
Entry
R
Conditions
a
Product 5,7 and 8
N° yield (%)
H3CO
O
N
H3CO
7
5g (76)
N
N
O
H
N
O
N
8
9
b
b
7a (80)
7b (76)
N
N
N
O
H
O
H2N
H2N
O
N
N
N
O
H
H
N
N
N
O
N
O
N
10
b
7c (75)
N
O
N
O
N
H
N
N
O
H
O
11
12
13
c
c
c
8a (85)
8b (95)
8c (90)
N
N
O
H
(H3C)3Si
O
N
(H3C)3Si
N
N
H
O
O
N
H3C–
N
N
H
O
HN
O
N
HN
14
15
d
d
8d (50%)
8e (52)
N
N
O
H
O
N
OBn
N
N
OBn
O
H
(a) Alkyne, 1.2 equiv; Pd(PPh3)4, 0.05 equiv; CuI, 0.1 equiv; DMF/ Et3N (1:1); 2 h; 100 °C. (b) (i) ethynyl-trimethylsilane, 1.2 equiv; Pd(PPh3)4, 0.05 equiv; CuI, 0.1 equiv; DMF/
Et3N (1:1); 2 h; 100 °C; (ii) Bu4NF, 1.5 equiv; THF; 40 min; rt; (iii) 3-bromoquinoline or 3-bromoaniline or compound 4, 1 equiv; Pd(PPh3)4, 0.05 equiv; CuI, 0.1 equiv; DMF/
Et3N (1:1); 2 h; 100 °C. (c) RSnBu3, 1.5 equiv; Pd(PPh3)2Cl2, 0.1 equiv; DMF; 1.5 h; reflux. (d) RB(OH)2, 1.2 equiv; K2CO3, 2 equiv; Pd(PPh3)4, 0.05 equiv; DME; 4 h; 100 °C.
corresponding brominated heteroaromatic products using stan-
dard Sonogashira conditions. The isolated yields of products 7a–c
are shown in Table 1.17
an aqueous solution of K2CO3 (2 equiv) in DME at 100 °C for 4 h.
The desired compounds 8d–e (Scheme 1) were isolated in moder-
ate yields (50–52%) as shown in Table 1.19
In conclusion, we have developed an efficient, inexpensive, and
experimentally simple synthetic method to access new 3-
substitued-7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a]-
[1,4]diazepine-5,10(11H)-dione derivatives. This new method
Stille cross-coupling reactions
As shown in Table 1, treatment of compound 4 with various
organotin reagents RSnBu3 afforded in excellent yields (85–95%)
the corresponding products 8a–c (Scheme 1) in the presence of
10 mol % of PdCl2(PPh3)2 under refluxing DMF. The isolated yields
of products 8a–c are shown in Table 1.18
utilizes 2-aminonicotinic acid 1 and L-proline methyl ester to give
compound 2. The bromination of 2 by NBS under mild and rapid
conditions gives compound 3, which is cyclized in DMF under
reflux for 18 h to give chiral (S)-3-bromo-7,8,9,9a-tetrahydro-
5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepine-5,10(11H)-dione
4
Suzuki–Miyaura cross-coupling reactions
(70%). This method opened the way to the general synthesis of
functionalized 1,4-pyridodiazepines, major skeletons for designing
biologically active compounds. Further studies and investigation of
the properties of these molecules are currently in progress in our
The efficient Suzuki cross-coupling of compound 4 was per-
formed with boronic acids (1.2 equiv), 5 mol % of Pd(PPh3)4 and

6404
A. El Bouakher et al. / Tetrahedron Letters 53 (2012) 6401–6405
11. For recent reviews on this topic, see (a) Alberico, D.; Scott, M. E.; Lautens, M.
O
(H3C)3Si
O
H
Chem. Rev. 2007, 107, 174–238; (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318–5365; (c) Nicolaou, K. C.; Bulger, P.
G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442–4489.
a
N
N
N
N
N
N
12. For recent reviews on Sonogashira reaction, see (a) Doucet, H.; Hierso, J.-C.
Angew. Chem. Int. Ed. 2007, 46, 834–871; (b) Chinchilla, R.; Nàjera, C. Chem. Rev.
2007, 107, 874–922.
O
H
O
H
5a
6
13. For reviews on Suzuki reaction, see (a) Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, 41, 1461–1473; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457–2483; (c) Weng, Z.; Teo, S.; Hor, T. S. A. Acc. Chem. Res. 2007, 40, 676–684.
14. For representative papers on the Sonogashira cross-coupling reactions, see (a)
Yi, C. Y.; Hua, R. M. J. Org. Chem. 2006, 71, 2535–2537; (b) Liang, Y.; Xie, Y.-X.;
Li, J.-H. J. Org. Chem. 2006, 71, 379–381; (c) Lipshutz, B. H.; Chung, D. W.; Rich,
B. Org. Lett. 2008, 10, 3793–3796.
b
O
R'
N
15. General Procedure for Sonogashira Cross-Coupling reactions of compound 4 with
Terminal Alkynes.
N
N
O
H
Compound
4 (150 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), and
7a-c
copper(I) iodide (9.6 mg, 0.05 mmol) were added in sequence in a round-
bottomed flask. The vessel was then sealed with rubber septum, evacuated,
and backfilled with Argon. Anhydrous DMF (2 mL) was added followed by TEA
(2 mL). The terminal alkyne (1.3 equiv) was then added, and the reaction
mixture was heated to 100 °C for 1–2 h. Water (8 mL) and CH2Cl2 (10 mL) were
added. After extraction with CH2Cl2 (3 ꢁ 10 mL), the combined organic layers
were dried over MgSO4, and the solvent was removed under reduced pressure.
The crude material was purified by column chromatography to yield
compounds 5a–g.
Scheme 2. Reagents and conditions: (a) Bu4NF, 1.5 equiv; THF; 40 min; rt. (b) 3-
bromoquinoline or 3-bromoaniline or compound 4, 1 equiv; Pd(PPh3)4, 0.05 equiv;
CuI, 0.1 equiv; DMF/Et3N (1:1); 2 h; 100 °C.
laboratory. The work reported here provides an efficient and
inexpensive procedure for the synthesis of bioisosters of
1,4-benzodiazepines.
Compound 5a: Yield 96%; mp 226 °C; ½a D20
ꢀ
+296.38 (c 2.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d = 0.27 (s, 9H), 2.00–2.15 (m, 3H), 2.82–2.87 (m, 1H), 3.60–
3.70 (m, 1H), 3.79–3.86 (m, 1H), 4.08–4.11 (m, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.73
(d, J = 2.2 Hz, 1H), 10.30 (s, NH); 13C NMR (75 MHz, CDCl3): d = 0.2, 23.4, 26.5,
47.7, 57.1, 99.3, 99.8, 117.0, 120.6, 144.1, 146.9, 154.2, 163.2, 170.0; HRMS-FIA
(m/z): [M+H]+ Calculated for C16H19N3O2Si: 314.1319, Found: 314.1318.
16. Preparation of compound 6.
Acknowledgments
To a thoroughly degassed (argon, 10 min) solution of 5a (0.25 g, 0.79 mmol) in
dry THF (10 mL) was added 0.35 mL (1.5 equiv) of tetrabutylammonium
fluoride in THF (1 M). The reaction was stirred for 40 min at room temperature
until the starting material had completely disappeared (TLC, 2:98 MeOH/DCM).
The reaction mixture was concentrated under vacuum. Dichloromethane
(10 mL) and an aqueous solution (10%) of ammonium chloride (10 mL) were
added. After extraction with CH2Cl2 (3 ꢁ 10 mL), the combined organic layers
were dried over MgSO4 and the solvent was removed under reduced pressure.
The crude material was purified by column chromatography to give compound
We gratefully acknowledge that this work was funded by the
Moroccan Ministry of Education, CNRST, through project URAC
22 and RePAM, through a doctoral Grant. We gratefully acknowl-
edge Hafid Zouihri for X-ray analysis. Thanks also to Monika Ghosh
for the translation assistance.
References and notes
6 (0.18 g, 95%). Yield 95%; mp 408 °C; ½a D20
ꢀ
+5.33 (c 0.3, DMF); 1H NMR
(300 MHz, [D6]DMSO): d = 1.75–1.84 (m, 1H), 1.91–2.01 (m, 2H), 2.50–2.54 (m,
1H), 3.41–3.50 (m, 1H), 3.57–3.63 (m, 1H), 4.3 (d, J = 6.4 Hz, 1H), 4.48 (s, 1H),
8.2 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 11.13 (s, NH); 13C NMR (75 MHz,
[D6]DMSO): d = 23.5, 26.2, 47.5, 56.9, 79.9, 84.6, 114.6, 121.3, 142.9, 148.3,
154.3, 162.9, 170.8; HRMS-FIA (m/z): [M+H]+ Calculated for C13H11N3O2:
242.0924, Found: 242.0924.
1. (a) Da Settimo, F.; Taliani, S.; Trincavelli, M. L.; Montali, M.; Martini, C. Curr.
Med. Chem. 2007, 14, 2680; (b) Bacon, E. R.; Chatterjee, S.; Williams, M. In
Comprehensive Medicinal Chemistry II; Elsevier: Amsterdam, 2006; Vol. 6, p 139.
2. Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudiniere, R. F. J. Comb.
Chem. 2000, 2, 513.
3. Leimgruber, W.; Batcho, A. D.; Czajkowski, R. C. J. Am. Chem. Soc. 1968, 90, 5641.
4. Thurston, D. E. In Molecular Aspects of Anticancer Drug-DNA Interactions; Neidle,
S., Waring, M. J., Eds.; The Macmillan Press Ltd.: London, 1993; Vol. 1, p 54.
5. Thurston, D. E.; Subhas Bose, D. Chem. Rev. 1994, 94, 433–465.
6. (a) Hurley, L. H. Acc. Chem. Res. 1980, 13, 263; (b) Hurley, L. H.; Speedie, M. K.
Antibiot. IV. Biosynth. 1981, 261–294.
7. (a) Hurley, L. H.; Petrusek, R. L. Nature 1979, 282, 529–531; (b) Petrusek, R. L.;
Anderson, G. L.; Garner, T. F.; Fannin, Q. L.; Kaplan, D. J.; Zimmer, S. G.; Hurley,
L. H. Biochemistry 1981, 20, 1111–1119.
8. Graves, E. G.; Pattaroni, C.; Krishnan, B. S.; Ostrander, J. M.; Hurley, L. H.; Krugh,
T. R. J. Biol. Chem. 1984, 8202–8209.
17. See general procedure for Sonogashira cross-coupling reactions of compound 4
with Terminal Alkynes.
Compound 7a: Yield 75%; mp 290 °C; 1H NMR (300 MHz, [D6]DMSO): d = 1.77–
1.86 (m, 1H), 1.89–2.04 (m, 2H), 2.50–2.57 (m, 1H), 3.44–3.53 (m, 1H), 3.57–
3.67 (m, 1H), 4.33 (d, J = 6.0 Hz, 1H), 7.67–7.72 (m, 1H), 7.81–7.87 (m, 1H),
8.03–8.08 (m, 2H), 8.38, (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.81 (d,
J = 2.3 Hz, 1H), 9.06 (d, J = 2.1 Hz, 1H), 11.20 (s, NH); 13C NMR (75 MHz,
[D6]DMSO): d = 23.5, 26.3, 47.6, 57.0, 88.9, 90.1, 114.6, 116.4, 121.4, 127.2,
128.1, 128.6, 129.3, 131.3, 139.2, 142.7, 146.9, 148.8, 152.0, 154.1, 163.0,
170.7; HRMS-FIA (m/z): [M+H]+ Calculated for C22H16N4O2: 369.1346, Found:
369.1345.
9. El Bouakher, A.; Laborie, H.; Aadil, M.; Elhakmaoui, A.; Lazar, S.; Akssira, M.;
Viaud-Massuard, M.-C. Tetrahedron Lett. 2011, 52, 5077–5080.
10. Preparation of compound 4.
18. General procedure for Stille cross-coupling reactions.
Compound 4 (150 mg, 0.5 mmol) was heated to 150 °C in dry DMF (3 mL)
under argon in the presence of PdCl2(PPh3)2 (34.5 mg, 0.05 mmol) and an
appropriate tin reagent (0.65 mmol) for 1.5 h. Removal of DMF gave the crude
product, which was partitioned between dichloromethane and 10% aqueous
ammonium hydroxide. The organic layer was washed with water and brine,
and dried over magnesium sulfate. Dichloromethane was concentrated under
reduced pressure and the residue was purified by flash column
chromatography (silica gel, gradient elution ethyl acetate/cyclohexane) to
give the final product 8a-c.
To a solution of 2-amino nicotinic acid (2.74 g, 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). L-proline methyl ester (22 mmol) was then
added, and the reaction mixture was stirred overnight. Water (100 mL) was
added, and the mixture was extracted with methylene chloride, dried over
MgSO4, and concentrated. Compound
2 was purified by silica gel
chromatography (silica gel, 90:10 ethyl acetate/cyclohexane) to yield the
title compound as a yellow oil (3.71 g, 75%). Compound 2 (2.7 g, 10.8 mmol)
was reacted with NBS (2.12 g, 11.88 mmol) in chloroform (40 mL) at room
temperature during 30 min to give compound 3 as an orange oil, which was
purified by silica gel chromatography (silica gel, 80:20 ethyl acetate/
cyclohexane) (3.19 g, 90%). The cyclization of compound 3 was obtained by
heating in (20 mL) DMF at 160 °C for 18 h. After evaporation of solvents and
recrystallization from EtOH, the reaction mixture was allowed to cool to room
temperature, and then filtered to give the pure (S)-3-bromo-7,8,9,9a-
Compound 8b: Yield 95%; m.p. 259 °C; ½a D20
ꢀ
+6.35 (c 0.3, CHCl3); 1H NMR
(300 MHz, CDCl3): d = 0.18 (s, 9H), 2.02-2.17 (m, 3H), 2.79-2.87 (m,1H), 2.62-
3.71 (m, 1H), 3.81-3.88 (m, 1H), 4.11 (d, J = 7.1 Hz, 1H), 6.66 (d, J = 19.2 Hz, 1H),
6.89 (d, J = 19.2 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 10.45 (s,
NH); 13C NMR (75 MHz, CDCl3): d = 1.4, 23.5, 26.5, 47.7, 57.2, 121.1, 131.0,
134.0, 137.7, 137.8, 147.1, 150.1, 164.0, 170.2; HRMS-FIA (m/z): [M +H]+
Calculated for C16H21N3O2Si: 316.1476, found: 316.1479.
19. General procedure for Suzuki cross-coupling reactions of compound
4 with
tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepine-5,10(11H)-dione
4
Arylboronic Acids.
(2.28 g, 75%).
To
a solution containing 4 (150 mg, 0.5 mmol) in DME (4 mL) were
Compound 4: Yield 75%; m.p. 234 °C; ½a D20
ꢀ
+279.36 (c 1.1, DMF); 1H NMR
successively added the desired boronic acid (0.065 mmol), Pd(PPh3)4 (29 mg,
0.025 mmol), and 2 mL of aqueous solution of potassium carbonate (140 mg,
1 mmol). The reaction mixture was stirred at 100 °C for 4 h. After the complete
disappearance of 4 (TLC, 5:95 MeOH/DCM), water (8 mL) and CH2Cl2 (10 mL)
were added. After extraction with CH2Cl2 (3 ꢁ 10 mL), the combined organic
layers were dried over MgSO4, and the solvent was removed under reduced
(300 MHz, [D6]DMSO): d = 1.75–1.84 (m, 1H), 1.87–2.03 (m, 2H), 2.50–2.54 (m,
1H), 3.34–3.50 (m, 1H), 3.57–3.64 (m, 1H), 4.30 (d, J = 5.9 Hz, 1H), 8.30 (d,
J = 2.5 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 11.06 (s, NH); 13C NMR (75 MHz,
[D6]DMSO): d = 23.5, 26.3, 47.6, 56.9, 114.6, 123.3, 142.0, 147.9, 152.7, 162.6,
170.7; HRMS-FIA (m/z): [M+H]+ Calculated for C11H10BrN3O2: 296.0029, found:
296.0032.

A. El Bouakher et al. / Tetrahedron Letters 53 (2012) 6401–6405
6405
pressure. The crude material was purified by column chromatography to yield
compounds 8d–e.
(m, 7H), 7.92 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d = 24.7, 29.7, 47.9, 59.9, 70.6, 112.8, 120.7, 121.6, 122.6, 124.9, 127.0,
127.5, 128.0, 128.6, 129.7, 129.7, 136.4, 138.1, 140.4, 152.1, 155.6, 164.2;
HRMS-FIA (m/z): [M+H]+ Calculated for C24H21N3O3: 400.1656, Found:
400.1660.
Compound 8e: Yield 52%; mp 160 °C; 1H NMR (300 MHz, CDCl3): d = 1.75-1.83
(m, 1H), 1.94–2.06 (m, 1H), 2.21–2.33 (m, 2H), 2.95–3.02 (m, 1H), 3.50–3.58
(m, 1H), 4.72–4.75 (m, 1H), 5.05–5.13 (m, 2H), 7.03–7.08 (m, 2H), 7.32–7.38