Furan ring opening-pyrrole ring closure: A new route to pyrrolo[1,2- d ][1,4]benzodiazepin-6-ones

Article abstract of DOI:10.1055/s-0030-1260204

A new method for the synthesis of pyrrolo[1,2-d][1,4]benzodiazepines is described. The method is based on the acid-catalyzed recyclization of N-[2-(5-alkyl-2-furyl)phenyl]-2-aminoacetamides and permits the formation of both diazepine and pyrrole rings in

Full text of DOI:10.1055/s-0030-1260204

PAPER
3547
Furan Ring Opening–Pyrrole Ring Closure: A New Route to
Pyrrolo[1,2-d][1,4]benzodiazepin-6-ones
S
ynthesisof Py
a
d
]
t
[
1,4]be
y
nzodiazepin-
a
6-ones na A. Nevolina,a Vitaly A. Shcherbinin,a Olga V. Serdyuk,b Alexander V. Butin*a
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University, Moskovskaya st. 2,
Krasnodar 350072, Russian Federation
Fax +7(861)2596592; E-mail: alexander_butin@mail.ru; E-mail: av_butin@yahoo.com
Department of Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation
b
Received 18 July 2011
amides 2 (Scheme 1).10 This process represents a domino
reaction, in which the furan ring opening, pyrrole form-
ation, and diazepine ring closure take place in one pot. Ex-
tending our research in this field, herein we present an
Abstract: A new method for the synthesis of pyrrolo[1,2-
d][1,4]benzodiazepines is described. The method is based on the
acid-catalyzed recyclization of N-[2-(5-alkyl-2-furyl)phenyl]-2-
aminoacetamides and permits the formation of both diazepine and
pyrrole rings in one pot. The reaction proceeds via furan ring open- application of this methodology to the synthesis of pyrro-
ing to give the diketone moiety followed by consecutive reactions
of the free amino group with both carbonyl functions.
lo[1,2-d][1,4]benzodiazepines.
As starting compounds for the synthesis of pyrrolo[1,2-
Key words: furans, ring opening, ring closure, fused-ring system,
d][1,4]benzodiazepines, we have used 2-(2-aminoar-
pyrrolo[1,2-d][1,4]benzodiazepines, Paal–Knorr reaction
yl)furans 3, which were obtained according to the known,
simple procedure.11 Treatment of anilines 3a–f with 2-
(phthalimido)acetyl chloride (4) in benzene afforded
amides 5a–f (Scheme 2, Table 1). Refluxing compounds
5 in an ethanolic solution of hydrazine hydrate for a short
time led to corresponding amines 6a–f. The amines 6 were
refluxed in a mixture of acetic acid and hydrochloric acid
(5:1) for 40 minutes. Then, sodium hydrogen carbonate
was added to the cooled reaction mixture in the amount
Pyrrolo[1,4]diazepines represent an important class of
compounds that are extensively utilized in pharmacology
and medicine. Among them, the most frequently studied
are the ‘anthramycins’ produced by Streptomyces sp.1,2
These natural antitumor antibiotics are pyrrolo[2,1-
c][1,4]benzodiazepine derivatives.3 It is also known that
pyrrolo[1,2-a][1,4]benzodiazepines exhibit a wide spec-
which is required to neutralize hydrochloric acid only (if
trum of biological activity.4 On the other hand, pyrro-
acetic acid was also neutralized, yields of the goal prod-
lo[1,2-d][1,4]benzodiazepines are less well-studied,5
ucts dropped significantly). The target pyrrolodiazepines
8a–f were isolated in moderate yields after reflux of the
obtained reaction mixture for 20 minutes. It should be not-
though some of them reveal antiviral (including anti-HIV-
1) activity.5c
Most known methods for the synthesis of pyrrolodiaz- ed that moderate yields of the products 8 were caused by
epines are based on the annulation of a diazepine ring to incomplete conversion of furans 6 into diketones 7. In-
pyrrole moiety.6 To the best of our knowledge, only one deed, the starting compounds 6 can be isolated from the
method for the synthesis of pyrrolobenzodiazepines, reaction mixture. A possible reason seems to be the con-
based on the intramolecular Paal–Knorr reaction leading jugation of the furan and the aromatic ring. This fact is in
to the simultaneous formation of pyrrole and diazepine accordance with the results obtained previously.9c
rings, has been hitherto described.7 This approach is un-
In summary, the proposed previously methodology of
der-investigated, which is evidently related to the fact that
one-pot furan ring opening, pyrrole ring closure, and diaz-
the procedure for the synthesis of suitable 1,4-dicarbonyl
epine formation is a common approach to pyrrolodiaz-
compounds is quite time-consuming.
However, it is well known, that furan derivatives can
Table 1 Yields of Compounds 5a–f, 6a–f, and 8a–f
serve as precursors of 1,4-diketones.8 This feature of the
Entry R1
R2
Products 5, 6, 8 Yield (%)
furan ring has already been used in a two-step synthesis of
pyrrolodiazepines.4b,9 In this procedure, pyrrole deriva-
tives were initially obtained and the diazepine ring was
annulated in the next step. Recently, we have developed a
simple and efficient method for the synthesis of pyrro-
lo[1,2-a][1,4]diazepines 1 which is based on the acid-
catalyzed recyclization of the corresponding N-furfuryl-
5
6
8
1
2
3
4
5
6
H
Me
Me
Me
Me
Et
a
b
c
d
e
f
73
78
85
82
84
75
83
84
88
80
82
85
31
34
36
42
30
29
Me
Cl
OMe
H
SYNTHESIS 2011, No. 21, pp 3547–3551
x
x.
x
x
.
2
0
1
1
Advanced online publication: 02.09.2011
DOI: 10.1055/s-0030-1260204; Art ID: Z70611SS
© Georg Thieme Verlag Stuttgart · New York
Cl
Et

3548
T. A. Nevolina et al.
PAPER
R
NH2
NH2
O
N
H
H
R
N
R
N
O
O
N
O
O
O
H
2
1
Scheme 1 A new method for the formation of pyrrolo[1,2-a][1,4]diazepine moiety via the furan ring opening–pyrrole ring closure sequence
O
O
N
R1
NH2
R1
NH
NH2NH2 H2O
PhtNCH2COCl (4)
O
O
EtOH, reflux, 5 min
benzene, r.t., 20 min
R2
O
R2
3a–f
5a–f
O
O
O
H
NH2
NH2
R1
N
1) AcOH, HCl
reflux, 40 min
R1
NH
R1
NH
O
AcOH
reflux, 20 min
O
N
O
2) NaHCO3
R2
R2
R2
6a–f
7
8a–f
Scheme 2 Synthesis of pyrrolo[1,2-d][1,4]benzodiazepin-6-ones 8a–f from furans 3a–f
1H NMR (300 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 4.48 (s, 2
H, CH2), 6.26 (d, J = 3.3 Hz, 1 H, HFur), 6.80 (d, J = 3.3 Hz, 1 H,
epines. We showed here that it can be applied to the
synthesis of pyrrolo[1,2-d][1,4]benzodiazepines.
HFur), 7.25–7.29 (m, 2 H, HAr), 7.36–7.40 (m, 1 H, HAr), 7.67–7.71
(m, 1 H, HAr), 7.86–7.90 (m, 2 H, HPht), 7.91–7.95 (m, 2 H, HPht),
9.92 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.3, 40.6, 108.2, 110.2, 123.2
(2 C), 126.0 (2 C), 126.4, 127.2, 127.9, 131.7 (2 C), 132.0, 134.6 (2
C), 148.4, 151.6, 165.5, 167.6 (2 C).
MS (EI, 70 eV): m/z (%) = 360 (100) [M+], 284 (34), 267 (32), 237
(21), 226 (19), 207 (35), 200 (40), 172 (52), 160 (80), 101 (31), 82
(22), 76 (58), 59 (77), 57 (54), 43 (35).
NMR spectra were recorded with a Bruker DPX 300 (300 MHz for
1H and 75 MHz for 13C NMR) spectrometer at r.t.; measured with
respect to the solvent [CDCl3, d = 7.25 (1H), 77.2 (13C); DMSO-d6,
d = 2.50 (1H), 39.5 (13C)]. IR spectra were measured as KBr plates
on a Bruker Alpha FT-IR spectrophotometer. Mass spectra were re-
corded on a Kratos MS-30 instrument with 70 eV electron-impact
ionization at 200 °C. Melting points (uncorrected) were determined
in capillaries with an Electrothermal 9100 capillary melting point
apparatus. Column chromatography was performed on silica gel
KSK (50–160 mm, LTD Sorbpolymer). All reactions were per-
formed using freshly distilled and dry solvents. PE = petroleum
ether.
Anal. Calcd for C21H16N2O4: C, 69.99; H, 4.48; N, 7.77. Found: C,
70.17; H, 4.57; N, 7.96.
2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[5-methyl-2-(5-
methyl-2-furyl)phenyl]acetamide (5b)
White wool; yield: 4.67 g (78%); mp 248–249 °C.
IR (KBr): 3256, 1728, 1668, 1579, 1536, 1416, 952, 714 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.29 (s, 3 H, CH3), 2.37 (s, 3
H, CH3), 4.46 (s, 2 H, CH2), 6.23 (d, J = 3.3 Hz, 1 H, HFur), 6.72 (d,
J = 3.3 Hz, 1 H, HFur), 7.10 (d, J = 8.1 Hz, 1 H, HAr), 7.19 (s, 1 H,
HAr), 7.56 (d, J = 8.1 Hz, 1 H, HAr), 7.86–7.90 (m, 2 H, HPht), 7.91–
7.95 (m, 2 H, HPht), 9.86 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.3, 20.5, 40.6, 108.0, 109.4,
123.2 (2 C), 123.4, 125.9, 127.2, 128.2, 131.7 (2 C), 131.9, 134.6 (2
C), 136.7, 148.6, 151.2, 165.5, 167.6 (2 C).
Compounds 3 were synthesized according to the previously pub-
lished procedure.11
N-[2-(5-Alkyl-2-furyl)phenyl]-2-(1,3-dioxo-1,3-dihydro-2H-
isoindol-2-yl)acetamides 5a–f; General Procedure
A soln of 2-(phthalimido)acetyl chloride (4, 4.5 g, 20.1 mmol) in
benzene (100 mL) was added dropwise under stirring to a soln of fu-
ran 3 (16 mmol) in benzene (25 mL) at r.t. The mixture was stirred
at r.t. for 20 min (TLC monitoring). Then, it was poured into H2O
(150 mL), NaHCO3 (4 g) was added, and the mixture was vigorous-
ly stirred for 30 min. The precipitate was collected by filtration,
washed with H2O (100 mL) and dried. The crude product was puri-
fied by flash chromatography (silica gel, 1,4-dioxane–PE, 3:1) and
recrystallized (1,4-dioxane–PE, 2:1).
MS (EI, 70 eV): m/z (%) = 374 (100) [M+], 186 (47), 160 (30), 144
(13), 104 (14), 76 (33), 75 (18), 59 (35), 43 (58), 42 (34).
Anal. Calcd for C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C,
70.42; H, 4.68; N, 7.45.
2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[2-(5-methyl-2-
furyl)phenyl]acetamide (5a)
White solid; yield: 4.20 g (73%); mp 237–238 °C.
IR (KBr): 3225, 1730, 1667, 1548, 1536, 1416, 953, 760, 707 cm–1.
N-[5-Chloro-2-(5-methyl-2-furyl)phenyl]-2-(1,3-dioxo-1,3-di-
hydro-2H-isoindol-2-yl)acetamide (5c)
Pale beige solid; yield: 5.36 g (85%); mp 221–223 °C.
Synthesis 2011, No. 21, 3547–3551 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[1,2-d][1,4]benzodiazepin-6-ones
3549
IR (KBr): 3245, 1724, 1668, 1578, 1533, 1418, 1097, 952, 715
cm–1.
H, HAr), 7.86–7.90 (m, 2 H, HPht), 7.91–7.96 (m, 2 H, HPht), 10.06
(s, 1 H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.37 (s, 3 H, CH3), 4.50 (s, 2
H, CH2), 6.27 (d, J = 3.3 Hz, 1 H, HFur), 6.85 (d, J = 3.3 Hz, 1 H,
HFur), 7.34 (dd, J = 2.4, 8.7 Hz, 1 H, HAr), 7.49 (d, J = 2.4 Hz, 1 H,
HAr), 7.68 (d, J = 8.7 Hz, 1 H, HAr), 7.86–7.90 (m, 2 H, HPht), 7.91–
7.96 (m, 2 H, HPht), 10.06 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.3, 40.6, 108.3, 110.9, 123.3
(2 C), 126.3, 127.0, 127.5 (2 C), 130.9, 131.7 (2 C), 133.2, 134.6 (2
C), 147.4, 152.1, 165.9, 167.5 (2 C).
13C NMR (75 MHz, DMSO-d6): d = 12.0, 20.8, 40.6, 106.9, 110.7,
123.3 (2 C), 124.5, 126.2, 126.9, 127.6, 130.9, 131.7 (2 C), 133.2,
134.6 (2 C), 147.3, 157.5, 165.8, 167.5 (2 C).
MS (EI, 70 eV): m/z (%) = 410/408 (32/92) [M+], 242 (62), 222
(67), 220 (100), 206 (30), 166 (15), 160 (96), 133 (20), 104 (25), 76
(10), 59 (17), 43 (59), 42 (34).
Anal. Calcd for C22H17ClN2O4: C, 64.63; H, 4.19; N, 6.85. Found:
C, 64.54; H, 4.27; N, 7.02.
MS (EI, 70 eV): m/z (%) = 396/394 (34/100) [M+], 186 (47), 160
(30), 144 (13), 104 (14), 76 (33), 75 (18), 59 (35), 43 (58), 42 (34).
2-Amino-N-[2-(5-alkyl-2-furyl)phenyl]acetamides 6a–f; Gener-
al Procedure
Anal. Calcd for C21H15ClN2O4: C, 63.89; H, 3.83; N, 7.10. Found:
C, 63.58; H, 3.89; N, 7.00.
Hydrazine hydrate (4 mL) was added to a soln of amide 5 (8 mmol)
in EtOH and the mixture was refluxed for 5 min (TLC monitoring).
Then the mixture was evaporated under reduced pressure. CCl4 (40
mL) was added to the residue and it was stirred vigorously. The ob-
tained solid was collected by filtration and washed with CCl4
(3 × 40 mL). The organic fractions were evaporated under reduced
pressure. The residue was dissolved in EtOAc, passed through a pad
of silica gel, and concentrated.
2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[5-methoxy-2-(5-
methyl-2-furyl)phenyl]acetamide (5d)
White wool; yield: 5.12 g (82%); mp 190–191 °C.
IR (KBr): 3249, 1725, 1669, 1583, 1541, 1416, 1293, 1237, 1036,
952, 715 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.36 (s, 3 H, CH3), 3.75 (s, 3
H, OCH3), 4.47 (s, 2 H, CH2), 6.21 (d, J = 3.3 Hz, 1 H, HFur), 6.64
(d, J = 3.3 Hz, 1 H, HFur), 6.87 (dd, J = 2.7, 8.7 Hz, 1 H, HAr), 7.03
(d, J = 2.7 Hz, 1 H, HAr), 7.57 (d, J = 8.7 Hz, 1 H, HAr), 7.86–7.90
(m, 2 H, HPht), 7.91–7.95 (m, 2 H, HPht), 9.86 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.3, 40.6, 55.3, 107.9, 108.5,
112.2, 112.3, 123.2 (2 C), 127.4 (2 C), 131.7 (2 C), 133.4, 134.6 (2
C), 148.5, 150.8, 158.2, 165.5, 167.5 (2 C).
Amines 6a,b,e were obtained as chromatographically pure light-
yellow oils and used for the next step without additional purifica-
tion. The compounds 6c,d,f were recrystallized (EtOAc–PE, 1:1).
2-Amino-N-[5-chloro-2-(5-methyl-2-furyl)phenyl]acetamide
(6c)
Cream plates; yield: 1.86 g (88%); mp 105–106 °C.
IR (KBr): 3412, 3258, 1673, 1574, 1515, 1456, 1411, 1260, 1028,
909, 815, 783 cm–1.
MS (EI, 70 eV): m/z (%) = 390 (100) [M+], 347 (13), 299 (11), 264
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 3.50 (s, 2 H,
CH2), 6.09 (d, J = 3.3 Hz, 1 H, HFur), 6.52 (d, J = 3.3 Hz, 1 H, HFur),
7.05 (dd, J = 2.1, 8.4 Hz, 1 H, HAr), 7.43 (d, J = 8.4 Hz, 1 H, HAr),
8.57 (d, J = 2.1 Hz, 1 H, HAr), 10.46 (s, 1 H, NH).
(14), 246 (10), 203 (15), 160 (94), 89 (13), 59 (29), 43 (24).
Anal. Calcd for C22H18N2O5: C, 67.69; H, 4.65; N, 7.18. Found: C,
67.90; H, 4.74; N, 7.20.
13C NMR (75 MHz, CDCl3): d = 13.7, 45.6, 107.7, 109.2, 119.0,
2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[2-(5-ethyl-2-fur-
yl)phenyl]acetamide (5e)
White solid; yield: 5.03 g (84%); mp 219–220 °C.
IR (KBr): 3257, 1730, 1667, 1535, 1415, 1287, 952, 760, 716 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.5 Hz, 3 H, CH3),
2.73 (q, J = 7.5 Hz, 2 H, CH2), 4.48 (s, 2 H, CH2), 6.27 (d, J = 3.3
Hz, 1 H, HFur), 6.82 (d, J = 3.3 Hz, 1 H, HFur), 7.26–7.29 (m, 2 H,
HAr), 7.37–7.40 (m, 1 H, HAr), 7.67–7.70 (m, 1 H, HAr), 7.86–7.90
(m, 2 H, HPht), 7.91–7.95 (m, 2 H, HAr), 9.92 (s, 1 H, NH).
121.1, 123.9, 127.9, 133.7, 134.7, 149.4, 152.4, 171.2.
MS (EI, 70 eV): m/z (%) = 266/264 (36/100) [M+], 247 (30), 235
(29), 207 (77), 195 (38), 193 (42), 166 (70), 164 (59), 143 (40), 128
(32), 102 (27), 70 (22), 59 (29), 43 (43), 42 (45).
Anal. Calcd for C13H13ClN2O2: C, 58.99; H, 4.95; N, 10.58. Found:
C, 59.11; H, 5.15; N, 10.74.
2-Amino-N-[5-methoxy-2-(5-methyl-2-furyl)phenyl]acetamide
13C NMR (75 MHz, DMSO-d6): d = 12.1, 20.8, 40.6, 106.7, 110.0,
123.2 (2 C), 126.0, 126.1, 126.4, 127.2, 127.8, 131.7 (2 C), 132.0,
134.6 (2 C), 148.3, 157.1, 165.5, 167.5 (2 C).
MS (EI, 70 eV): m/z (%) = 374 (100) [M+], 214 (14), 198 (29), 186
(68), 172 (29), 170 (29), 160 (45), 133 (45), 117 (21), 105 (32), 77
(40), 59 (19), 43 (18), 42 (20).
(6d)
Beige prisms; yield: 1.66 g (80%); mp 99–101 °C.
IR (KBr): 3406, 3277, 1690, 1575, 1517, 1474, 1422, 1301, 1169,
1031, 789 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.26 (s, 3 H, CH3), 3.40 (s, 2 H,
CH2), 3.73 (s, 3 H, OCH3), 5.97 (d, J = 3.3 Hz, 1 H, HFur), 6.30 (d,
J = 3.3 Hz, 1 H, HFur), 6.57 (dd, J = 2.7, 8.7 Hz, 1 H, HAr), 7.31 (d,
J = 8.7 Hz, 1 H, HAr), 8.10 (d, J = 2.7 Hz, 1 H, HAr), 10.41 (s, 1 H,
NH).
Anal. Calcd for C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C,
70.52; H, 4.92; N, 7.39.
13C NMR (75 MHz, CDCl3): d = 13.6, 45.7, 55.4, 105.7, 107.4,
N-[5-Chloro-2-(5-ethyl-2-furyl)phenyl]-2-(1,3-dioxo-1,3-dihy-
dro-2H-isoindol-2-yl)acetamide (5f)
White wool; yield: 4.90 g (75%); mp 225–226 °C.
107.5, 110.6, 113.6, 128.3, 135.3, 150.4, 151.4, 159.6, 171.2.
MS (EI, 70 eV): m/z (%) = 260 (100) [M+], 243 (12), 230 (20), 202
(47), 189 (50), 160 (84), 118 (18), 101 (19), 77 (17), 71 (31), 59
(43), 43 (73).
IR (KBr): 3246, 1724, 1674, 1577, 1531, 1417, 1265, 1197, 950,
716 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.5 Hz, 3 H, CH3),
2.73 (q, J = 7.5 Hz, 2 H, CH2), 4.50 (s, 2 H, CH2), 6.29 (d, J = 3.3
Hz, 1 H, HFur), 6.86 (d, J = 3.3 Hz, 1 H, HFur), 7.34 (dd, J = 2.1, 8.7
Hz, 1 H, HAr), 7.50 (d, J = 2.1 Hz, 1 H, HAr), 7.69 (d, J = 8.7 Hz, 1
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.82; H, 6.46; N, 10.99.
2-Amino-N-[5-chloro-2-(5-ethyl-2-furyl)phenyl]acetamide (6f)
Colorless prisms; yield: 1.90 g (85%); mp 64–65 °C.
Synthesis 2011, No. 21, 3547–3551 © Thieme Stuttgart · New York

3550
T. A. Nevolina et al.
PAPER
IR (KBr): 3404, 3247, 1673, 1574, 1516, 1462, 1413, 1261, 1041,
820, 801, 781 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 4.47 (s, 2 H,
CH2), 6.06 (d, J = 3.6 Hz, 1 H, HPyr), 6.32 (d, J = 3.6 Hz, 1 H, HPyr),
7.02 (d, J = 2.1 Hz, 1 H, HAr), 7.18 (dd, J = 2.1, 8.4 Hz, 1 H, HAr),
7.48 (d, J = 8.4 Hz, 1 H, HAr), 7.96 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 12.1, 47.8, 107.0, 108.9, 121.4,
123.6, 125.9, 129.4, 129.9, 130.0, 132.8, 133.3, 168.5.
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.5 Hz, 3 H, CH3),
2.71 (q, J = 7.5 Hz, 2 H, CH2), 3.50 (s, 2 H, CH2), 6.10 (d, J = 3.3
Hz, 1 H, HFur), 6.54 (d, J = 3.3 Hz, 1 H, HFur), 7.06 (dd, J = 2.4, 8.4
Hz, 1 H, HAr), 7.44 (d, J = 8.4 Hz, 1 H, HAr), 8.56 (d, J = 2.4 Hz, 1
H, HAr), 10.50 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 12.0, 21.4, 45.6, 106.1, 109.1,
119.1, 121.1, 124.0, 128.0, 133.7, 134.7, 149.2, 158.1, 171.2.
MS (EI, 70 eV): m/z (%) = 280/278 (32/100) [M+], 248 (32), 232
(32), 221 (87), 206 (48), 193 (59), 164 (40), 128 (29), 101 (22), 71
(33), 57 (31), 43 (46).
MS (EI, 70 eV): m/z (%) = 248/246 (33/100) [M+], 219 (14), 217
(14), 205 (10), 203 (13), 76 (15), 71 (21), 43 (27), 42 (19).
Anal. Calcd for C13H11ClN2O: C, 63.29; H, 4.49; N, 11.36. Found:
C, 63.26; H, 4.42; N, 11.37.
9-Methoxy-3-methyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-
6(7H)-one (8d)
Colorless needles; yield: 0.61 g (42%); mp 184–185 °C.
Anal. Calcd for C14H15ClN2O2: C, 60.33; H, 5.42; N, 10.05. Found:
C, 60.19; H, 5.43; N, 9.89.
IR (KBr): 3215, 1690, 1616, 1581, 1522, 1468, 1281, 1242, 1038,
802, 751 cm–1.
3-Alkyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-6(7H)-ones 8a–f;
General Procedure
1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 3.82 (s, 3 H,
OCH3), 4.46 (s, 2 H, CH2), 6.04 (d, J = 3.6 Hz, 1 H, HPyr), 6.23 (d,
J = 3.6 Hz, 1 H, HPyr), 6.57 (d, J = 2.4 Hz, 1 H, HAr), 6.79 (dd,
J = 2.4, 8.4 Hz, 1 H, HAr), 7.46 (d, J = 8.4 Hz, 1 H, HAr), 8.79 (s, 1
H, NH).
13C NMR (75 MHz, CDCl3): d = 12.0, 47.8, 55.5, 105.3, 106.5,
108.2, 112.0, 118.1, 128.6, 130.0, 130.3, 133.8, 159.1, 169.1.
Concd HCl (5 mL) was added to a soln of amine 6 (6 mmol) in
AcOH (25 mL), and the mixture was refluxed for 40 min (TLC
monitoring). Then, NaHCO3 (5 g) was added to the mixture and it
was refluxed for 20 min, poured into H2O (150 mL), and neutralized
till pH ~7. The obtained solid was collected by filtration, washed
with H2O (50 mL), dried, and purified by flash chromatography (sil-
ica gel, benzene–PE, 1:1); compounds 8 were recrystallized (ben-
zene–PE, 1:1).
MS (EI, 70 eV): m/z (%) = 242 (100) [M+], 227 (13), 213 (8), 200
(11), 198 (11), 43 (30), 42 (16).
3-Methyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-6(7H)-one (8a)
White wool; yield: 0.39 g (31%); mp 213–214 °C.
IR (KBr): 3189, 1700, 1514, 1402, 1027, 804, 747 cm–1.
Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.49; H, 5.92; N, 11.77.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 4.48 (s, 2 H,
CH2), 6.06 (d, J = 3.6 Hz, 1 H, HPyr), 6.33 (d, J = 3.6 Hz, 1 H, HPyr),
7.02–7.05 (m, 1 H, HAr), 7.18–7.29 (m, 2 H, HAr), 7.54–7.57 (m, 1
H, HAr), 8.40 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 12.1, 47.9, 106.6, 108.6, 121.6,
125.1, 125.6, 127.5, 128.8, 129.6, 130.4, 132.6, 169.0.
3-Ethyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-6(7H)-one (8e)
Beige needles; yield: 0.41 g (30%); mp 159–160 °C.
IR (KBr): 3224, 1671, 1582, 1510, 1472, 1405, 1216, 1024, 748
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 7.5 Hz, 3 H, CH3),
2.61 (q, J = 7.5 Hz, 2 H, CH2), 4.36 (s, 2 H, CH2), 5.98 (d, J = 3.6
Hz, 1 H, HPyr), 6.25 (d, J = 3.6 Hz, 1 H, HPyr), 6.93–6.96 (m, 1 H,
HAr), 7.08–7.18 (m, 2 H, HAr), 7.44–7.47 (m, 1 H, HAr), 8.76 (s, 1 H,
NH).
13C NMR (75 MHz, CDCl3): d = 13.9, 19.8, 47.9, 106.7, 107.0,
121.9, 125.2, 125.8, 127.7, 129.0, 130.8, 132.9, 136.0, 169.4.
MS (EI, 70 eV): m/z (%) = 212 (100) [M+], 184 (34), 168 (12), 150
(13), 103 (33), 75 (18), 59 (14), 43 (26), 42 (51).
Anal. Calcd for C13H12N2O: C, 73.57; H, 5.70; N, 13.20. Found: C,
73.47; H, 5.82; N, 13.30.
MS (EI, 70 eV): m/z (%) = 226 (67) [M+], 211 (100), 183 (9), 45
(14), 43 (31), 41 (17).
3,9-Dimethyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-6(7H)-one
(8b)
Colorless needles; yield: 0.46 g (34%); mp 218–219 °C.
IR (KBr): 3192, 1694, 1523, 1400, 1027, 812, 750 cm–1.
Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C,
74.65; H, 6.51; N, 12.27.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 6 H, 2 CH3), 4.46 (s, 2 H,
CH2), 6.05 (d, J = 3.6 Hz, 1 H, HPyr), 6.29 (d, J = 3.6 Hz, 1 H, HPyr),
6.85 (d, J = 1.2 Hz, 1 H, HAr), 7.02 (dd, J = 1.2, 7.8 Hz, 1 H, HAr),
7.44 (d, J = 7.8 Hz, 1 H, HAr), 8.56 (s, 1 H, NH).
9-Chloro-3-ethyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-6(7H)-
one (8f)
Colorless needles; yield: 0.45 g (29%); mp 195–196 °C.
13C NMR (75 MHz, CDCl3): d = 12.1, 21.0, 47.9, 105.9, 108.4,
121.9, 122.3, 126.6, 128.7, 129.1, 130.5, 132.5, 137.7, 169.1.
IR (KBr): 3184, 1697, 1573, 1509, 1458, 1401, 1098, 814, 796, 748
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.30 (t, J = 7.5 Hz, 3 H, CH3),
2.71 (q, J = 7.5 Hz, 2 H, CH2), 4.46 (s, 2 H, CH2), 6.08 (d, J = 3.6
Hz, 1 H, HPyr), 6.34 (d, J = 3.6 Hz, 1 H, HPyr), 7.07 (d, J = 2.1 Hz, 1
H, HAr), 7.17 (dd, J = 2.1, 8.4 Hz, 1 H, HAr), 7.48 (d, J = 8.4 Hz, 1
H, HAr), 9.01 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 226 (100) [M+], 198 (24), 113 (24), 59
(60), 56 (33), 43 (59), 42 (31).
Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C,
74.40; H, 6.12; N, 12.21.
13C NMR (75 MHz, CDCl3): d = 13.7, 19.6, 47.6, 106.9, 107.1,
9-Chloro-3-methyl-5H-pyrrolo[1,2-d][1,4]benzodiazepin-
6(7H)-one (8c)
White solid; yield: 0.53 g (36%); mp 245–247 °C.
IR (KBr): 3180, 1696, 1578, 1509, 1405, 1102, 813, 750 cm–1.
121.5, 123.5, 125.8, 129.6, 129.8, 132.7, 133.5, 136.2, 169.0.
MS (EI, 70 eV): m/z (%) = 262/260 (24/65) [M+], 247/245 (38/100),
231 (13), 210 (14), 182 (17), 181 (25), 154 (14), 130 (14), 43 (25).
Anal. Calcd for C14H13ClN2O: C, 64.50; H, 5.03; N, 10.74. Found:
C, 64.54; H, 4.90; N, 10.62.
Synthesis 2011, No. 21, 3547–3551 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[1,2-d][1,4]benzodiazepin-6-ones
3551
Marichal, P.; Sipido, V.; Terence, G.; Nash, R.; Corens, D.;
Richards, R. D. Bioorg. Med. Chem. Lett. 2005, 15, 3453.
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Acknowledgment
We thank the Russian Ministry of Education and Science (Federal
Special Program, procedure 1.3.2., state contract No.
14.740.11.0717) and Russian Foundation of Basic Research (grant
10-03-00254-a) for financial support of this work.
(6) For review, see: Timoshenko, D. O. Adv. Heterocycl. Chem.
2008, 96, 1.
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Synthesis 2011, No. 21, 3547–3551 © Thieme Stuttgart · New York