A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

Article abstract of DOI:10.1016/j.tet.2012.09.079

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro- 5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.

Full text of DOI:10.1016/j.tet.2012.09.079

Tetrahedron 68 (2012) 9572e9577
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel and convenient method for the synthesis of new derivatives
of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione
,
b
b
b
b,
*
ꢀ a
Abderrahman El Bouakher a , Gildas Prie , Mina Aadil , Said Lazar , Mohamed Akssira
,
Marie-Claude Viaud-Massuard a
EA 6306 IMT, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, Universite de Tours, 37200 Tours, France
,
*
a
ꢀ
b
ꢀ
Laboratoire de Chimie Bioorganique & Analytique, URAC 22, Universite 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:
Received 28 June 2012
Received in revised form 14 September 2012
Accepted 16 September 2012
Available online 23 September 2012
A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine de-
rivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via
peptide coupling of L-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular
cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]dia-
zepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-
pyridopyrrolodiazepines derivatives 5aem, 6aei, 7, and 8aec. This strategy provides an efficient
method to access a library of compounds based on privileged substructures that are of great interest in
drug discovery.
Keywords:
3-Aminopyridine-2-carboxylic acid
Bromination
2-Bromo-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-
dione
Ó 2012 Elsevier Ltd. All rights reserved.
CeC Cross-coupling reactions
1. Introduction
pyrrolo[1,2-a][1,4]diazepine-6,11-dione A by reaction of 1H-pyrido
[3,2-d][1,3]oxazine-2,4-dione with L
-proline methyl ester.6
The construction of privileged structures is an important strat-
egy in medicinal chemistry. 1,4-Benzodiazepines were first coined
as the archetypal privileged substructure by Evans et al. in 1988.1,2
In the area of molecular recognition, there is growing interest in
ring systems, such as the pyrrolo[2,1-c][1,4]-benzodiazepines
(PBDs), which can recognize and bind specific sequences of DNA.
Such compounds are potential regulators of gene expression with
possible applications in the treatment of certain genetic disorders,
including some cancers.3 They also are highly selective anti-
infective agents, and can be used as affinity-cleavage reagents in
molecular biology.4 The PBD ring system is also found in natural
antitumor antibiotics obtained from Streptomyces species, such as
anthramycin.5 Hence, synthesis of 1,4-pyridodiazepine derivatives
provides an interesting challenge in medicinal chemistry, but the
synthesis of 1,4-pyridodiazepine-6,11-diones remains very com-
plicated, and is rarely reported in the literature. Our group recently
reported the synthesis of 6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
2. Results and discussion
In our aim to synthetize new pyrido[3,2-e]pyrrolo[1,2-a][1,4]
diazepine-6,11-dione derivatives, we tried to halogenate com-
pound A. Attempts with NBS, Br2 or NIS (Table 1) under several
conditions were not successful (no reaction).
We present here an efficient method for the synthesis of com-
pound 4, which was performed starting from 3-aminopyridine-2-
carboxylic acid 1, the latter being obtained from commercially
available pyridine-2,3-dicarboxylic acid.7 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 mild conditions at room temper-
ature for 30 min. The brominated product 3 was obtained in an
excellent yield (95%). Cyclization of compound 3 was performed in
DMF under reflux for 18 h. After evaporation of the solvents and
recrystallization in EtOH, the reaction mixture was simply cooled to
room temperature and filtered to give the pure (S)-2-bromo-
6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-
6,11-dione 4 in 75% yield (Scheme 1). The structure of compound 4
was assigned by 1H NMR, 13C NMR, HSQC, and 13C J-Mod. In order to
confirm the stereoselectivity of the reaction, the enantiomeric
* Corresponding authors. Tel.: þ212 523314705; fax: þ212 52331 5353 (M.A.);
tel.: þ33 24 736 7227; fax: þ33 24 736 7229 (M.-C.V.-M.); e-mail addresses:
akssira@uh2m.ac.ma (M. Akssira), marie-claude.viaud-massuard@univ-tours.fr,
mcviaud@univ-tours.fr (M.-C. Viaud-Massuard).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.079

A. El Bouakher et al. / Tetrahedron 68 (2012) 9572e9577
9573
Table 1
Halogenation tests of compound A
H
O
O
H
NBS
or Br2
N
N
Z
N
N
N
N
or NIS
O
O
A
Z = Br or I
Entry
Reaction conditions
N-Iodosuccinimide, DMF, rt, 12 h
Results
1
2
3
4
5
6
7
NR
NR
NR
NR
NR
NR
NR
N-Iodosuccinimide, DMF, 60 ꢀC, 20 h
N-Bromosuccinimide, DMF, rt, 12 h
N-Bromosuccinimide, DMF, 60 ꢀC, 24 h
N-Bromosuccinimide, CHCl3, 60 ꢀC, 20 h
Br2, acetic acid, rt, 24 h
Br2, acetic acid, 70 ꢀC, 24 h
Fig. 1. ORTEP view of compound (S)-4.
NR: no reaction.
and aqueous solution of K2CO3 (2 equiv) in DME at 100 ꢀC for 4 h.
The desired compounds 5bef and 5hel were then isolated in ex-
cellent yields (79e98%). The Stille cross-coupling reactions of
compound 4 were performed with different tributylstannyl re-
agents RSnBu3 (1.5 equiv), and 10 mol % of PdCl2(PPh3)2 in DMF
under reflux to yield compounds 5a, 5g and 5m (60e95%). The
results are summarized in Table 3.
As an alternative to Suzuki and Stille processes, Sonogashira
cross-coupling reactions of compounds 4 were investigated 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 6aei were isolated in good to excellent yields
(76e98 %) (Table 4).
Sequentially, compound 6a was desilylated using tetrabuty-
lammonium fluoride (TBAF) in THF at room temperature for 40 min
to furnish the terminal alkyne 7 in excellent yield (98%). Finally,
synthesis of compounds 8aec could readily be achieved in good
yields (70e85%) by a reaction of terminal alkyne 7 with the cor-
responding brominated heteroaromatic reagents using standard
Sonogashira conditions. The isolated yields of products 8aec are
shown in Table 5.
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.
excess of crude product 4 was determined by chiral HPLC (Table 2)
and an ORTEP analysis of compound (S)-4 was done (Fig. 1). Pure
samples of (R) and (S)-2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-
e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (R)-4 and (S)-4 were
prepared in good yields by cyclization, respectively, of (R) and (S)-
3. Conclusion
methyl
1-(2-amino-5-bromobenzoyl)pyrrolidine-2-carboxylate
(R)-3 and (S)-3 under DMF reflux for 18 h.
In conclusion, we have developed an efficient synthetic method
to access new 2-substituted-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
pyrrolo[1,2-a][1,4]diazepine-6,11-diones derivatives. This new
Table 2
Chiral HPLC of compound (S)-4 and (R)-4
method utilizes 3-aminopyridine-2-carboxylic acid 1 and L-proline
methyl ester to give compound 2. The bromination of 2 by NBS
under mild and rapid conditions gave compound 3, which was
cyclized in DMF under reflux for 18 h to give chiral (S)-2-bromo-
6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-
6,11-dione 4 (80%). This method opens the way to a general syn-
thesis of functionalized 1,4-pyridodiazepines, major skeletons for
designing biologically active compounds. Further studies and in-
vestigation of the properties of these molecules are currently in
progress in our laboratory.
Amides
Cyclization products
Yield (%)
tR (min)
ee (%)
(S)-3
(R)-3
(S)-4
(R)-4
75
70
7
8.5
>99.5
>99.5
Analytical HPLC was carried out using a LaChrom Elite system equipped with
a VWRL-2130 pump, a VWRL-2200 autosampler at 4 ꢀC, a VWR L-400 UV 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,
250ꢁ4.6 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
4. Experimental section
4.1. General
volume was 10 mL.
All reactions were carried out under an inert atmosphere. 1H
NMR and 13C NMR were recorded on a Bruker Avance DPX300
spectrometer (300 MHz 1H, 75 MHz 13C), the deuterated solvents
indicated were used. For the purification chromatography, silica gel
(60e200 mesh) was used. Thin layer chromatography (TLC) was
carried out on Merck silica gel 60F254 precoated plates. Melting
points were determined in open capillary tubes and are
Palladium-catalyzed cross-coupling reactions represent an im-
portant method for carbonecarbon bond formation of heterocy-
cles.8 The Suzuki and Stille reactions were first achieved on
compound 4. The efficient Suzuki cross-coupling of compound 4
was performed with boronic acids (1.2 equiv), 5 mol % of Pd(PPh3)4

9574
A. El Bouakher et al. / Tetrahedron 68 (2012) 9572e9577
Table 3
Table 4
Suzuki and Stille reactions on 4
Sonogashira reactions on 4
Entry
Condition
R
Product
Yield (%)
Entry
1
R
Product
Yield (%)
98
(H3C)3Sie
6a
1
2
(b)
(a)
5a
5b
85
98
2
3
4
6b
6c
6d
95
80
90
3
4
(a)
(a)
5c
80
79
5d
5
6
6e
6f
96
90
5
6
(a)
(a)
5e
5f
81
97
7
8
6g
6h
95
89
7
8
(b)
(a)
5g
5h
70
90
9
6i
90
Reagents and conditions: (a) alkyne, 1.2 equiv; Pd(PPh3)4, 0.05 equiv; CuI, 0.1 equiv;
DMF/Et3N (1:1); 2 h; 100 ꢀC.
9
(a)
(a)
5i
5j
97
98
Table 5
Synthesis of compounds 8aec from 6a
10
11
12
13
(a)
(a)
(b)
5k
5l
90
96
60
Entry
RBr
Product
Yield (%)
5m
1
2
8a
8b
85
70
Reagents and conditions: (a) RB(OH)2, 1.2 equiv; Na2CO3, 2 equiv; Pd(PPh3)4,
0.05 equiv; DME; 4 h; 100 ꢀC. (b) RSnBu3, 1.3 equiv; Pd(PPh3)2Cl2, 0.1 equiv; DMF;
1.5 h; reflux.
4
3
8c
70
uncorrected. HRMS were performed on a Thermo Q Exactive LC-MS
HR/AM Orbitrap. Commercial starting materials and dry solvents
were obtained and used as received. Chemicals products were
obtained from the following sources: Aldrich and Acros organics.
Reagents and conditions: (a) Bu4NF, 1.5 equiv; THF; 40 min; rt. (b) RBr, 1 equiv;
Pd(PPh3)4, 0.05 equiv; CuI, 0.1 equiv; DMF/Et3N (1:1); 2 h; 100 ꢀC.
chromatography to yield the title compound as a yellow oil
(3.71 g, 75%). Compound 2 (2.7 g, 10.8 mmol) was treated with
NBS (2.12 g, 11.88 mmol) in chloroform (40 mL) at room temper-
ature during 30 min to give compound 3 as an orange oil, which
was purified by silica gel chromatography (3.37 g, 95%). The cy-
clization of compound 3 was obtained by heating in DMF (20 mL)
at 160 ꢀC for 18 h. After evaporation of solvents and re-
crystallization in EtOH, the reaction mixture was allowed to cool
to room temperature, and then filtered to give the pure (S)-2-
bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]
diazepine-6,11-dione 4 (2.13 g, 70%).
4.2. Preparation of (S)-2-bromo-6a,7,8,9-tetrahydro-5H-pyr-
ido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (4)
To a solution of 3-aminopyridine-2-carboxylic 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 CH2Cl2, dried over
MgSO4, and concentrated. Compound 2 was purified by silica gel

A. El Bouakher et al. / Tetrahedron 68 (2012) 9572e9577
9575
4.2.1. (S)-Methyl 1-(3-aminopicolinoyl)pyrrolidine-2-carboxylate
(2). Yield 75%; as oil; 1H NMR (300 MHz, CDCl3):
2H), 2.45e2.50 (m, 1H), 3.46e3.53 (m, 1H), 3.65e3.71 (m, 1H), 4.34
(d, J¼6.3 Hz, 1H), 7.54 (dd, J¼7.9, 4.7 Hz, 1H), 7.66 (d, J¼8.6 Hz, 1H),
8.22 (d, J¼8.6 Hz, 1H), 8.42e8.45 (m, 1H), 8.64 (dd, J¼4.7, 1.6 Hz,
1H), 9.26 (d, J¼1.6 Hz, 1H), 10.67 (s, NH); 13C NMR (75 MHz, DMSO-
d¼1.90e2.3 (m,
4H), 3.68 (s, 3H), 3.83e3.86 (m, 1H), 3.95e4.00 (m, 1H), 5.01e5.05
(m, 1H), 5.26 (br s, NH2), 6.99e7.00 (m, 1H), 7.78 (dd, J¼4.3, 1.5 Hz,
1H), 7.95 (dd, J¼4.3, 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
¼22.0,
d6):
d
¼23.3, 26.3, 47.3, 56.5, 123.5, 124.3, 131.3, 133.5, 133.7, 134.3,
32.0, 48.0, 52.0, 60.0, 124.2, 126.0, 135.7, 136.7, 167.5, 173.7; MS (EI,
143.1, 148.1, 149.9, 150.4, 163.0, 171.2; HRMS-FIA (m/z): [MþH]þ
CHCl3): m/z¼249.
calcd for C16H14N4O2: 295.1189, found: 295.1188.
4.2.2. (S)-Methyl 1-(3-amino-6-bromopicolinoyl)pyrrolidine-2-
4.3.4. (S)-2-(2-(Benzyloxy)phenyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5e). Yield 81%; mp
carboxylate (3). Yield 95%; as oil; ½a D20
ꢂ
ꢃ24 (c 4, CHCl3); for (R)-3
½
a 2D0
ꢂ
þ23.65 (c 4, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼1.92e2.07
263 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d¼1.78e1.87 (m, 1H),
(m, 2H), 2.03e2.28 (m, 2H), 3.77 (s, 3H), 3.82e3.91 (m, 1H),
4.02e4.09 (m, 1H), 5.08e5.12 (m, 1H), 5.10 (br s, NH2), 6.92e6.96
1.93e2.03 (m, 2H), 2.45e2.50 (m, 1H), 3.44e3.51 (m, 1H),
3.63e3.69 (m, 1H), 4.29 (d, J¼6.2 Hz, 1H), 5.21 (s, 2H), 7.05e7.13 (m,
1H), 7.24 (d, J¼8.2 Hz, 1H), 7.31e7.47 (m, 6H), 7.53 (d, J¼8.6 Hz, 1H),
7.77 (d, J¼6.7 Hz, 1H), 8.04 (d, J¼8.6 Hz, 1H), 10.57 (s, NH); 13C NMR
(m, 1H), 7.20e7.26 (m, 1H); 13C NMR (75 MHz, CDCl3):
d¼25.2, 29.3,
49.1, 52.6, 58.9, 106.3, 116.1, 138.3, 149.9 (2C), 154.8, 172.8; HRMS-
FIA (m/z): [MþH]þ calcd for C12H14BrN3O3: 328.0291, found:
328.0293.
(75 MHz, DMSO-d6):
d
¼23.3, 26.3, 47.3, 56.4, 70.3, 113.7, 121.4,
127.6, 127.8, 128.0, 128.3, 128.9, 129.7, 130.7, 131.3, 132.6, 137.4,
142.8, 151.4, 156.3, 163.2, 171.1; HRMS-FIA (m/z): [MþH]þ calcd for
C24H20N3O3: 400.1656, found: 400.1654.
4.2.3. (S)-2-Bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-
a][1,4]diazepine-6,11-dione (4). Yield 75%; mp 342 ꢀC; ½a D20
þ150 (c
ꢂ
0.3, DMF); for (R)-4 ½a D20
ꢂ
ꢃ149.50 (c 0.3, DMF); 1H NMR (300 MHz,
4.3.5. (S)-2-(2-Bromophenyl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5f). Yield 97%; mp 281 ꢀC;
DMSO-d6):
d
¼1.75e1.84 (m, 1H), 1.90e2.03 (m, 2H), 2.45e2.48 (m,
1H), 3.43e3.48 (m, 1H), 3.59e3.66 (m, 1H), 4.32 (d, J¼6.1 Hz, 1H),
1H NMR (300 MHz, DMSO-d6):
d
¼1.74e1.88 (m, 1H), 1.90e2.07 (m,
7.50 (d, J¼8.5 Hz, 1H), 7.77 (d, J¼8.5 Hz, 1H), 10.67 (br s, NH); 13C
2H), 2.50e2.54 (m, 1H), 3.42e3.51 (m, 1H), 3.63e3.70 (m, 1H), 4.32
(d, J¼6.3 Hz, 1H), 7.37e7.42 (m, 1H), 7.49e7.57 (m, 2H), 7.65 (d,
J¼8.5 Hz,1H), 7.75e7.83 (m, 2H),10.69 (br s, NH); 13C NMR (75 MHz,
NMR (75 MHz, DMSO-d6):
d
¼23.3, 26.2, 47.4, 56.3, 131.1, 133.7,
134.3, 135.7, 143.4, 161.8, 171.0; HRMS-FIA (m/z): [MþH]þ calcd for
C11H10BrN3O2: 296.0029, found: 296.0032.
DMSO-d6):
d
¼23.3, 26.3, 47.3, 56.5, 121.5, 127.5, 128.4, 130.2, 130.9,
132.2, 133.4, 133.5, 140.4, 142.7, 153.6, 162.9, 171.2; HRMS-FIA (m/z):
[MþH]þ calcd for C17H14BrN3O2: 372.0342, found: 372.0343.
4.3. General procedure for Suzuki cross-coupling reactions of
compound 4 with arylboronic acids
4.3.6. (S)-2-(3-Nitrophenyl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
To a solution containing 4 (150 mg, 0.5 mmol) in DME (4 mL)
were successively added the desired boronic acid (1.2 equiv),
Pd(PPh3)4 (29 mg, 0.05 equiv), and 2 mL of an aqueous solution of
potassium carbonate (140 mg, 2 equiv). The reaction mixture was
stirred at 100 ꢀC for 4 h. After the complete disappearance of 4,
water (8 mL) and CH2Cl2 (10 mL) were added. After extraction with
CH2Cl2 (3ꢁ10 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 5bef, 5hel.
pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5h). Yield 90%; mp 280 ꢀC;
1H NMR (300 MHz, DMSO-d6):
d
¼1.79e1.88 (m, 1H), 1.95e2.06 (m,
2H), 2.50e2.53 (m, 1H), 3.49e3.55 (m, 1H), 3.66e3.72 (m, 1H), 4.35
(d, J¼6.2 Hz, 1H), 7.69 (d, J¼8.6 Hz, 1H), 7.82 (dd, J¼7.9, 8.0 Hz, 1H),
8.30 (d, J¼8.0 Hz, 1H), 8.31 (d, J¼8.6 Hz, 1H), 8.54 (d, J¼7.9 Hz, 1H),
8.90e8.93 (m, 1H), 10.73 (s, NH); 13C NMR (75 MHz, DMSO-d6):
d
¼23.3, 26.3, 47.3, 56.5, 121.3, 123.6, 124.2, 131.0, 131.4, 133.0, 134.1,
139.6, 143.0, 148.9, 149.4, 162.9, 171.1; HRMS-FIA (m/z): [MþH]þ
calcd for C17H14N4O4: 339.1088, found: 339.1087.
4.3.7. (S)-2-(1H-Indol-5-yl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
4.3.1. (S)-2-Phenyl-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-
pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5i). Yield 97%; mp 282 ꢀC;
a][1,4]diazepine-6,11-dione (5b). Yield 98%; mp 310 ꢀC; 1H NMR
1H NMR (300 MHz, DMSO-d6):
d
¼1.76e1.88 (m, 1H), 1.95e2.05 (m,
(300 MHz, DMSO-d6):
d
¼1.78e1.88 (m, 1H), 1.91e2.03 (m, 2H),
2H), 2.50e2.57 (m, 1H), 3.48e3.54 (m, 1H), 3.65e3.71 (m, 1H), 4.32
(d, J¼6.7 Hz,1H), 6.53 (s,1H), 7.40 (s,1H), 7.48 (d, J¼8.5 Hz,1H), 8.58
(d, J¼8.5 Hz, 1H), 7.90 (d, J¼8.6 Hz, 1H), 8.11 (d, J¼8.6 Hz, 1H), 8.31
(s, 1H), 10.54 (s, NH), 11.25 (s, NH); 13C NMR (75 MHz, DMSO-d6):
2.45e2.50 (m, 1H), 3.42e3.53 (m, 1H), 3.65e3.71 (m, 1H), 4.32 (d,
J¼6.2 Hz, 1H), 7.42e7.54 (m, 3H), 7.63 (d, J¼8.6 Hz, 1H), 8.08e8.15
(m, 3H), 10.61 (s, NH); 13C NMR (75 MHz, DMSO-d6): 23.3, 26.3,
47.3, 56.5, 123.1, 126.9, 129.3, 129.7, 131.2, 133.2, 138.0, 142.8, 152.1,
163.2, 171.2; HRMS-FIA (m/z): [MþH]þ calcd for C17H15N3O2:
294.1237, found: 294.1237.
d
¼23.3, 26.3, 47.2, 56.5, 102.5, 112.0, 119.1, 120.5, 122.5, 126.8, 128.4,
129.2, 131.1, 132.1, 137.0, 142.6, 153.9, 163.5, 171.2 HRMS-FIA (m/z):
[MþH]þ calcd for C19H16N4O2: 333.1346, found: 333.1344.
4.3.2. (S)-4-(6,11-Dioxo-6,6a,7,8,9,11-hexahydro-5H-pyrido[3,2-e]
pyrrolo[1,2-a][1,4]diazepin-2-yl)benzaldehyde (5c). Yield 80%; mp
4.3.8. (S)-2-o-Tolyl-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-
a][1,4]diazepine-6,11-dione (5j). Yield 98%; mp 278 ꢀC; 1H NMR
277 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼1.78e1.88 (m, 1H),
(300 MHz, DMSO-d6):
d
¼1.78e1.87 (m, 1H), 1.90e2.06 (m, 2H), 2.36
1.94e2.03 (m, 2H), 2.50e2.53 (m, 1H), 3.44e3.52 (m, 1H),
3.65e3.72 (m,1H), 4.35 (d, J¼6.2 Hz,1H), 7.67 (d, J¼8.6 Hz,1H), 8.05
(d, J¼8.6 Hz, 2H), 8.26 (d, J¼8.6 Hz, 1H), 8.33 (d, J¼8.3 Hz, 2H), 10.08
(s, 3H), 2.45e2.50 (m, 1H), 3.42e3.51 (m, 1H), 3.63e3.69 (m, 1H),
4.30e4.34 (m, 1H), 7.24e7.36 (m, 3H), 7.42 (d, J¼6.4 Hz, 1H), 7.63 (d,
J¼8.4 Hz, 1H), 7.71 (d, J¼8.4 Hz, 1H), 10.63 (s, NH); 13C NMR
(s, CHO), 10.70 (s, NH); 13C NMR (75 MHz, DMSO-d6):
d
¼23.3, 26.3,
(75 MHz, DMSO-d6):
d¼20.7, 23.3, 26.3, 47.3, 56.4, 126.3, 126.8,
47.3, 56.4, 123.9, 127.5, 130.5, 131.2, 134.0, 136.7, 143.1, 143.2, 150.6,
163.0, 171.2, 193.3; HRMS-FIA (m/z): [MþH]þ calcd for C18H15N3O3:
322.1186, found: 322.1186.
128.9, 130.0, 130.5, 131.2,132.6, 136.1,139.4, 142.5, 155.1, 163.1,171.2;
HRMS-FIA (m/z): [MþH]þ calcd for C18H17N3O2: 308.1393, found:
308.1390.
4.3.3. (S)-2-(Pyridin-3-yl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyr-
4.3.9. (S)-2-(4-Hydroxyphenyl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-
rolo[1,2-a][1,4]diazepine-6,11-dione (5d). Yield 79%; mp 301 ꢀC; 1H
e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5k). Yield 90%; mp
NMR (300 MHz, DMSO-d6):
d
¼1.74e1.87 (m, 1H), 1.93e2.06 (m,
385 ꢀC; 1H NMR (300 MHz, DMSO-d6, 25 ꢀC):
d¼1.78e1.87 (m, 1H),

9576
A. El Bouakher et al. / Tetrahedron 68 (2012) 9572e9577
1.91e2.01 (m, 2H), 2.47e2.50 (m, 1H), 3.42e3.52 (m,1H), 3.63e3.96
(m, 1H), 4.29 (d, J¼6.1 Hz, 1H), 6.87 (d, J¼8.7 Hz, 2H), 7.55 (d,
J¼8.6 Hz, 1H), 7.10e8.03 (m, 3H), 9.80 (s, OH), 10.53 (s, NH); 13C
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 1e2 h. Water (8 mL) and CH2Cl2 (10 mL) were added.
After extraction with CH2Cl2 (3ꢁ10 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 6aei.
NMR (75 MHz, DMSO-d6):
d
¼23.3, 26.3, 47.2, 56.4, 116.0, 122.0,
128.4, 129.0, 131.0, 132.1, 142.6, 152.4, 159.1, 163.3, 171.1; HRMS-FIA
(m/z): [MþH]þ calcd for C17H15N3O3: 310.1186, found: 310.1183.
4.3.10. (S)-2-(4-Methoxyphenyl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-
e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5l). Yield 96%; mp 290 ꢀC;
1H NMR (300 MHz, DMSO-d6):
d
¼1.78e1.87 (m, 1H), 1.90e2.08 (m,
2H), 2.46e2.50 (m, 1H), 3.63e3.69 (m, 2H), 3.82 (s, 3H), 4.27 (d,
J¼6 Hz, 1H), 7.04e7.07 (m, 2H), 7.56 (d, J¼8.6 Hz, 1H), 8.03e8.07 (m,
4.5.1. (S)-2-((Trimethylsilyl)ethynyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (6a). Yield 98%; mp
3H); 13C NMR (75 MHz, DMSO-d6):
d¼23.3, 26.3, 47.2, 55.7, 56.5,114.6,
219 ꢀC (decomposition); 1H NMR (300 MHz, DMSO-d6):
d
¼0.26 (s,
122.3,128.3,130.6,131.3,133.2,142.6,151.6,160.6,163.4,171.1; HRMS-
9H), 1.75e1.84 (m, 1H), 1.90e2.03 (m, 2H), 2.45e2.50 (m, 1H),
3.40e3.48 (m, 1H), 3.61e3.67 (m, 1H), 4.30 (d, J¼7 Hz, 1H), 7.52 (d,
J¼8.5 Hz, 1H), 7.65 (d, J¼8.5 Hz, 1H), 10.71 (s, NH); 13C NMR
FIA (m/z): [MþH]þ calcd for C18H17N3O3: 324.1343, found: 324.1342.
4.4. General procedure for Stille cross-coupling reactions of
compound 4 with tributylstannyl reagents
(75 MHz, DMSO-d6):
d
¼0.1, 23.3, 26.2, 47.3, 56.3, 94.5, 104.1, 129.7,
130.5, 133.9, 137.7, 148.5, 162.4, 171.1; HRMS-FIA (m/z): [MþH]þ
calcd for C16H19N3O2Si: 314.1319, found: 314.1321.
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,
0.1 equiv) and an appropriate tin reagent (1.3 equiv) for 1.5 h. Re-
moval of DMF gave the crude product, which was partitioned be-
tween CH2Cl2 and a 10% aqueous solution of ammonium hydroxide.
The organic layer was washed with water and brine, then dried
over magnesium sulfate. CH2Cl2 was concentrated under reduced
pressure and the residue was purified by flash column chroma-
tography (silica gel, gradient elution ethyl acetate/cyclohexane) to
give the final products 5a, 5g or 5m.
4.5.2. (S)-2-(Phenylethynyl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]
pyrrolo[1,2-a][1,4]diazepine-6,11-dione (6b). Yield 95%; mp 314 ꢀC;
1H NMR (300 MHz, DMSO-d6):
d
¼1.76e1.86 (m, 1H), 1.92e2.05 (m,
2H), 2.45e2.50 (m, 1H), 3.40e3.50 (m, 1H), 3.60e3.71 (m, 1H), 4.34
(d, J¼6.4 Hz, 1H), 7.47e7.48 (m, 3H), 7.57e7.64 (m, 3H), 7.76 (d,
J¼8.4 Hz, 1H), 10.73 (s, NH); 13C NMR (75 MHz, ]DMSO-d6):
¼23.3,
d
26.2, 47.3, 56.4, 88.7, 88.9, 121.7, 129.4, 129.7, 130.0, 130.6, 132.2,
133.7, 138.1, 143.6, 162.5, 171.1; HRMS-FIA (m/z): [MþH]þ calcd for
C19H15N3O2: 318.1237, found: 318.1237.
4.4.1. (S,E)-2-(2-(Trimethylsilyl)vinyl)-6a,7,8,9-tetrahydro-5H-pyrido
4.5.3. (S)-4-((6,11-Dioxo-6,6a,7,8,9,11-hexahydro-5H-pyrido[3,2-e]
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5a). Yield 85%; mp
pyrrolo[1,2-a][1,4]diazepin-2-yl)ethynyl)benzaldehyde
(6c). Yield
208 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼0.17 (s, 9H), 1.77e1.85 (m,
80%; mp 221 ꢀC (decomposition); 1H NMR (300 MHz, DMSO-d6):
1H), 1.92e2.01 (m, 2H), 2.45e2.5 (m, 1H), 3.40e3.49 (m, 1H),
3.62e3.68 (m, 1H), 4.27 (d, J¼6.2 Hz, 1H), 6.97 (s, 2H), 7.51 (d,
J¼8.4 Hz, 1H), 7.69 (d, J¼8.4 Hz, 1H), 10.58 (s, NH); 13C NMR
d
¼1.77e1.82 (m, 1H), 1.92e2.02 (m, 2H), 2.45e2.50 (m, 1H),
3.44e3.46 (m, 1H), 3.63e3.69 (m, 1H), 4.34 (d, J¼6.1 Hz,1H), 7.61 (d,
J¼8.2 Hz, 1H), 7.80e7.88 (m, 3H), 7.98 (d, J¼7.7 Hz, 2H), 10.05 (s,
(75 MHz, DMSO-d6):
d
¼0.8, 23.3, 26.2, 47.2, 56.4, 124.1, 130.7, 133.1,
CHO), 10.76 (s, NH); 13C NMR (75 MHz, DMSO-d6):
d
¼23.3, 26.2,
134.9, 142.8, 142.8, 151.5, 163.1, 171.1; HRMS-FIA (m/z): [MþH]þ
47.4, 56.4, 87.9, 91.9, 127.5, 130.1, 130.2, 130.6, 132.9, 133.7, 136.5,
137.5, 143.7, 162.4, 171.1, 193.0; HRMS-FIA (m/z): [MþH]þ calcd for
C20H15N3O3: 346.1186, found: 346.1186.
calcd for C16H21N3O2Si: 316.1476, found: 316.1473.
4.4.2. (S)-2-Vinyl-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a]
[1,4]diazepine-6,11-dione (5g). Yield 70%; mp 250 ꢀC; 1H NMR
4.5.4. (S)-2-(Pyridin-3-ylethynyl)-6a,7,8,9-tetrahydro-5H-pyrido
(300 MHz, DMSO-d6):
d
¼1.79e1.85 (m, 1H), 1.89e2.00 (m, 2H),
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (6d). Yield 85%; mp
2.45e2.50 (m, 1H), 3.43e3.49 (m, 1H), 3.61e3.68 (m, 1H), 4.27 (d,
J¼6.1 Hz, 1H), 5.51 (dd, J¼10.9, 1.3 Hz, 1H), 6.18 (dd, J¼17.6, 1.3 Hz,
1H), 6.81 (dd, J¼17.6, 10.9 Hz, 1H), 7.52 (d, J¼8.5 Hz, 1H), 7.71 (d,
321 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d¼1.74e1.86 (m, 1H),
1.92e2.02 (m, 2H), 2.45e2.50 (m, 1H), 3.44e3.49 (m, 1H), 3.62e3.68
(m, 1H), 4.37 (d, J¼5.9 Hz, 1H), 7.51 (s,1H), 7.60 (d, J¼8.2 Hz,1H), 7.79
(d, J¼8.1 Hz,1H), 8.05 (d, J¼7.1 Hz,1H), 8.62e8.68 (m,1H), 8.80e8.84
J¼8.5 Hz, 1H), 10.56 (s, NH); 13C NMR (75 MHz, DMSO-d6):
¼23.3,
d
26.2, 47.2, 56.4, 119.2, 123.8, 130.6, 133.1, 136.5, 142.7, 151.6, 163.1,
171.2; HRMS-FIA (m/z): [MþH]þ calcd for C13H13N3O2: 244.1080,
found: 244.1079.
(m, 1H), 10.75 (s, NH); 13C NMR (75 MHz, DMSO-d6):
47.4, 56.4, 85.7, 91.5, 119.0, 124.2, 129.9, 130.6, 134.0, 137.5, 139.4,
143.6, 150.1, 152.3, 162.4, 171.1; HRMS-FIA (m/z): [MþH]þ calcd for
C18H14N4O2: 319.1189, found: 319.1190.
d
¼23.3, 26.2,
4.4.3. (S)-2-(2-Methylprop-1-enyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (5m). Yield 60%; mp
4.5.5. (S)-2-(4-Hydroxybut-1-ynyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (6e). Yield 96%; mp
201 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d¼1.76e1.85 (m, 1H), 1.92 (s,
3H), 1.94e2.00 (m, 2H), 2.15 (s, 3H), 2.45e2.50 (m, 1H), 3.40e3.49
(m, 1H), 3.60e3.66 (m, 1H), 4.26 (d, J¼6.2 Hz, 1H), 6.29 (s, 1H), 7.38
(d, J¼8.5 Hz, 1H), 7.47 (d, J¼8.5 Hz, 1H), 10.48 (s, NH); 13C NMR
273 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼1.72e1.82 (m, 1H),
1.94e2.05 (m, 2H), 2.45e2.50 (m, 1H), 2.57e2.60 (m, 2H),
3.43e3.51 (m, 1H), 3.59e3.69 (m, 3H), 4.26e4.30 (m, 1H), 4.98 (s,
OH), 7.50 (d, J¼7.8 Hz, 1H), 7.57 (d, J¼7.8 Hz, 1H), 10.63 (s, NH); 13C
(75 MHz, DMSO-d6):
126.5, 130.2, 131.3, 141.4, 142.3, 153.0, 163.2, 171.1; HRMS-FIA (m/z):
[MþH]þ calcd for C15H17N3O2: 272.1393, found: 272.1389.
d
¼20.2, 23.3, 26.2, 27.81, 47.2, 56.4, 123.8,
NMR (75 MHz, DMSO-d6):
d
¼23.3, 23.5, 26.2, 47.3, 56.3, 59.9, 80.9,
89.1, 129.4, 130.5, 133.2, 138.8, 143.3, 162.5, 171.1; HRMS-FIA (m/z):
[MþH]þ calcd for C15H15N3O3: 286.1186, found: 286.1188.
4.5. General procedure for Sonogashira cross-coupling re-
actions of compound 4 with terminal alkynes
4.5.6. (S)-2-((4-(Trifluoromethyl)phenyl)ethynyl)-6a,7,8,9-
tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione
(6f). Yield 90%; mp 343 ꢀC; 1H NMR (300 MHz, DMSO-d6):
Compound 4 (150 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 0.05 equiv),
and copper(I) iodide (9.6 mg, 0.01 equiv) were added in sequence in
d¼1.77e1.86 (m, 1H), 1.93e2.03 (m, 2H), 2.47e2.50 (m, 1H),

A. El Bouakher et al. / Tetrahedron 68 (2012) 9572e9577
9577
3.36e3.50 (m,1H), 3.63e3.69 (m,1H), 4.34 (d, J¼6.3 Hz,1H), 7.61 (d,
J¼8.5 Hz, 1H), 7.81e7.87 (m, 5H), 10.76 (s, NH); 13C NMR (75 MHz,
HRMS-FIA (m/z): [MþH]þ calcd for C13H12N3O2: 242.0924, found:
242.0923.
DMSO-d6):
d
¼23.3, 26.2, 47.4, 56.4, 87.2, 90.9, 124.3 (q, J¼272 Hz,
4.7. General procedure to prepare compounds 8aec
CF3), 126.0 (q, J¼1 Hz), 126.2 (q, J¼4 Hz), 129.8 (q, J¼32 Hz), 130.1,
130.6, 133.0, 134.1, 137.4, 143.6, 162.4, 171.1; HRMS-FIA (m/z):
[MþH]þ calcd for C20H14N3O2F3: 386.1111, found: 386.1110.
See general procedure for Sonogashira cross-coupling reactions
of compound 4 with terminal alkynes (see Section 4.5.).
4.5.7. (S)-2-(Thiophen-3-ylethynyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (6g). Yield 98%; mp
4.7.1. (S)-2-(Quinolin-3-ylethynyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (8a). Yield 85%; mp
307 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼1.76e1.86 (m, 1H),
313 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼1.77e1.86 (m, 1H),
1.92e2.02 (m, 2H), 2.45e2.50 (m, 1H), 3.40e3.49 (m, 1H),
3.62e3.68 (m, 1H), 4.33 (d, J¼6.4 Hz, 1H), 7.33 (d, J¼4.9 Hz, 1H), 7.57
(d, J¼8.5 Hz, 1H), 7.69e7.74 (m, 2H), 8.03 (d, J¼1.8 Hz, 1H), 10.70 (s,
1.93e2.03 (m, 2H), 2.45e2.50 (m, 1H), 3.42e3.51 (m, 1H),
3.64e3.70 (m, 1H), 4.36 (d, J¼6.6 Hz,1H), 7.63 (d, J¼8.4 Hz, 1H), 7.70
(t, J¼7.5 Hz, 1H), 7.84e7.87 (m, 2H), 8.00e8.12 (m, 2H), 8.73 (s, 1H),
NH); 13C NMR (75 MHz, DMSO-d6):
88.2, 120.6, 127.8, 129.5, 130.1, 130.6, 131.9, 133.6, 138.2, 143.6, 162.5,
171.1; HRMS-FIA (m/z): [MþH]þ calcd for C17H13N3O2: 324.0801,
found: 324.0804.
d
¼23.3, 26.2, 47.3, 56.4, 84.6,
9.05 (s, 1H), 10.77 (s, NH); 13C NMR (75 MHz, DMSO-d6):
d
¼23.3,
26.3, 47.4, 56.4, 86.3, 91.5, 115.9, 127.2, 128.2, 128.7, 129.4, 130.0,
130.6, 131.5, 134.0, 137.6, 139.7, 143.7, 147.1, 151.9, 162.4, 171.1;
HRMS-FIA (m/z): [MþH]þ calcd for C22H16N4O2: 369.1346, found:
369.1346.
4.5.8. (S)-2-(Hept-1-ynyl)-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyr-
rolo[1,2-a][1,4]diazepine-6,11-dione (6h). Yield 89%; mp 174 ꢀC; 1H
4.7.2. (S)-2,20-(Ethyne-1,2-diyl)bis(6a,7,8,9-tetrahydro-5H-pyrido
NMR (300 MHz, CDCl3):
d
¼0.87 (t, J¼6.6 Hz, 3H), 1.23e1.30 (m,
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione) (8b). Yield 70%; mp
12H), 1.34e1.41 (m, 2H), 1.51e1.60 (m, 2H), 1.96e2.07 (m, 3H),
2.35 (t, J¼7.0 Hz, 2H), 2.68e2.85 (m, 1H), 3.59e3.68 (m, 1H),
3.83e3.89 (m, 1H), 4.12 (d, J¼6.3 Hz, 1H), 7.44 (d, J¼8.4 Hz, 1H),
7.65 (d, J¼8.4 Hz, 1H), 9.66 (s, NH); 13C NMR (75 MHz, CDCl3):
375 ꢀC; 1H NMR (300 MHz, DMSO-d6):
1.92e2.02 (m, 4H), 2.45e2.50 (m, 2H), 3.45e3.50 (m, 2H),
3.63e3.69 (m, 2H), 4.36 (d, J¼4.2 Hz, 2H), 7.62 (d, J¼8.4 Hz, 2H),
7.83e7.96 (m, 2H), 10.76 (s, 2NH); 13C NMR (75 MHz, DMSO-d6):
d
¼1.77e1.85 (m, 2H),
d
¼14.1, 19.3, 22.7, 23.3, 26.3, 28.3, 29.0, 29.2, 29.3, 29.5, 29.6, 31.9,
d
¼23.3, 26.3, 47.4, 56.4, 87.4, 130.2, 130.7, 134.2, 137.2, 143.7, 162.4,
47.5, 56.6, 79.4, 92.5, 129.4, 130.4, 132.0, 140.6, 142.7, 163.2, 170.8;
HRMS-FIA (m/z): [MþH]þ calcd for C23H31N3O2: 382.2489, found:
382.2492.
171.1; HRMS-FIA (m/z): [MþH]þ calcd for C24H20N6O4: 457.1619,
found: 457.1619.
4.7.3. (S)-2-(Pyrimidin-2-ylethynyl)-6a,7,8,9-tetrahydro-5H-pyrido
[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (8c). Yield 70%; mp
4.5.9. (S)-2-(3-Cyclohexylprop-1-ynyl)-6a,7,8,9-tetrahydro-5H-pyr-
ido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione (6i). Yield 90%; mp
320 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼1.74e1.85 (m, 1H),
278 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
¼0.98e1.30 (m, 5H),
1.90e2.02 (m, 2H), 2.45e2.50 (m, 1H), 3.45e3.50 (m, 1H),
3.63e3.69 (m, 1H), 4.36 (d, J¼6.0 Hz, 1H), 7.51e7.95 (m, 4H), 8.90 (d,
1.49e1.57 (m, 1H), 1.60e1.72 (m, 3H), 1.79e1.83 (m, 3H), 1.91e2.02
(m, 2H), 2.36 (d, J¼6.6 Hz, 2H), 2.45e2.50 (m, 1H), 3.40e3.45 (m,
1H), 3.60e3.66 (m,1H), 4.29 (d, J¼6.2 Hz,1H), 7.49 (d, J¼8.4 Hz,1H),
7.56 (d, J¼8.4 Hz, 1H), 10.62 (s, NH); 13C NMR (75 MHz, DMSO-d6):
J¼4.6 Hz, 1H), 10.81 (s, NH); 13C NMR (75 MHz, DMSO-d6):
¼23.3,
d
26.2, 47.4, 56.3, 84.9, 87.1, 121.8, 130.6, 130.7, 134.7, 136.5, 143.9,
152.0, 158.4, 162.3, 171.1; HRMS-FIA (m/z): [MþH]þ calcd for
C17H13N3O2: 320.1142, found: 320.1123.
d
¼23.3, 26.0, 26.2, 26.2, 26.5, 32.6, 37.1, 47.3, 56.3, 81.4, 90.0, 129.4,
130.4, 133.1, 138.9, 143.3, 162.6, 171.1; HRMS-FIA (m/z): [MþH]þ
calcd for C20H23N3O2: 338.1863, found: 338.1797.
Acknowledgements
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 acknowledge
4.6. Preparation of compound 7
To a thoroughly degassed (argon, 10 min) solution of 6a (0.25 g,
0.79 mmol) in dry THF (10 mL) was added tetrabutylammonium
fluoride (0.35 mL, 1.5 equiv) in THF (1 M). The reaction was stirred
at room temperature until the starting material had completely
disappeared (40 min). The reaction mixture was concentrated un-
der vacuum then CH2Cl2 (10 mL) and an aqueous solution (10%) of
ammonium chloride (10 mL) were added. After extraction with
CH2Cl2 (3ꢁ10 mL), the combined organic layers were dried over
MgSO4 and the solvent was removed under reduced pressure to
give compound 7 (0.19 g, 98%).
ꢀ
Dr. Renaud Respaud for HPLC experiments, Dr. Stephane Massip
from university of Bordeaux for X-ray analysis and Monika Ghosh
for the translation assistance.
References and notes
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4.6.1. (S)-2-Ethynyl-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo
[1,2-a][1,4]diazepine-6,11-dione (7). Yield 98%; mp >400 ꢀC; 1H
NMR (300 MHz, DMSO-d6):
d
¼1.75e1.84 (m, 1H), 1.92e2 (m, 2H),
2.45e2.5 (m, 1H), 3.39e3.48 (m, 1H), 3.61e3.67 (m, 1H), 4.31 (d,
J¼6.5 Hz, 1H), 4.39 (s, 1H), 7.55 (d, J¼8.4 Hz, 1H), 7.69 (d, J¼8.4 Hz,
1H), 10.67 (br s, NH); 13C NMR (75 MHz, DMSO-d6):
d¼23.3, 26.2,
8. Reviews: (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Perga-
mon: Oxford, 2000; (b) Kalinin, V. N. Synthesis 1992, 5, 413e432.
47.3, 56.3, 80.7, 82.7, 129.9, 130.6, 134.0, 137.5, 143.5, 162.4, 171.1;