Furan ring opening-pyrrole ring closure: A new synthetic route to aryl(heteroaryl)-annulated pyrrolo[1,2-a][1,4]diazepines

Article abstract of DOI:10.1039/c002994g

A method of synthesis of pyrrolo[1,2-a][1,4]benzodiazepines is described. This method is based on the recyclization of N-(furfuryl)anthranilamides under treatment with an aq. HCl/AcOH system and allows one to form both diazepine and pyrrole rings in one step. The reaction proceeds via furan ring opening into a diketone moiety followed by consecutive interaction of the NH₂-group with both carbonyl functions. The process is not efficient in the presence of alkyl or aryl groups on amide nitrogen due to competitive furfuryl cation elimination. But alkylation of pyrrolo[1,2-a][1,4]benzodiazepines yields efficiently the corresponding N-alkyl derivatives. Steric effects also prevent cyclization due to reversibility of diazepine ring formation under these reaction conditions. However, the corresponding pyrrolo[1,2-a][1,4] benzodiazepines can be obtained by a stepwise process, i.e., 1) furan ring opening with aq. HCl/AcOH and 2) cyclization of isolated aminodiketones under treatment with glacial acetic acid. Another efficient procedure for the synthesis of pyrrolo[1,2-a][1,4]benzodiazepines consists of acid-catalyzed furan ring opening of N-(furfuryl)-2-nitrobenzamides followed by treatment of the formed nitrodiketone with Fe/AcOH. It leads to a one pot reduction of nitro group to amine, cyclization into diazepine and pyrrole ring formation. This procedure is efficient both for substrates with steric demands and for N-alkyl- or N-aryl-N-(furfuryl)amides. The proposed approach can be also applied to the synthesis of parent pyrrolo[1,2-a][1,4]diazepines or their analogues annulated to heterocycles. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c002994g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Furan ring opening–pyrrole ring closure: a new synthetic route to
aryl(heteroaryl)-annulated pyrrolo[1,2-a][1,4]diazepines†
Alexander V. Butin,*a Tatyana A. Nevolina,a Vitaly A. Shcherbinin,a Igor V. Trushkov,b,c Dmitry A. Cheshkovd
and Gennady D. Krapivina
Received 15th February 2010, Accepted 14th May 2010
First published as an Advance Article on the web 4th June 2010
DOI: 10.1039/c002994g
A method of synthesis of pyrrolo[1,2-a][1,4]benzodiazepines is described. This method is based on the
recyclization of N-(furfuryl)anthranilamides under treatment with an aq. HCl/AcOH system and
allows one to form both diazepine and pyrrole rings in one step. The reaction proceeds via furan ring
opening into a diketone moiety followed by consecutive interaction of the NH2-group with both
carbonyl functions. The process is not efficient in the presence of alkyl or aryl groups on amide nitrogen
due to competitive furfuryl cation elimination. But alkylation of pyrrolo[1,2-a][1,4]benzodiazepines
yields efficiently the corresponding N-alkyl derivatives. Steric effects also prevent cyclization due to
reversibility of diazepine ring formation under these reaction conditions. However, the corresponding
pyrrolo[1,2-a][1,4]benzodiazepines can be obtained by a stepwise process, i.e., 1) furan ring opening
with aq. HCl/AcOH and 2) cyclization of isolated aminodiketones under treatment with glacial acetic
acid. Another efficient procedure for the synthesis of pyrrolo[1,2-a][1,4]benzodiazepines consists of
acid-catalyzed furan ring opening of N-(furfuryl)-2-nitrobenzamides followed by treatment of the
formed nitrodiketone with Fe/AcOH. It leads to a one pot reduction of nitro group to amine, cyclization
into diazepine and pyrrole ring formation. This procedure is efficient both for substrates with steric
demands and for N-alkyl- or N-aryl-N-(furfuryl)amides. The proposed approach can be also applied to
the synthesis of parent pyrrolo[1,2-a][1,4]diazepines or their analogues annulated to heterocycles.
1-c][1,4]benzodiazepine derivatives. While isomeric pyrrolo[1,
2-a][1,4]benzodiazepines have been less studied, it has been
Introduction
demonstrated that these compounds have CNS activity4–6 be-
ing potent sedative,6–8 anticonvulsant,7,8 myorelaxant,8,9 and
psychotropic9–11 agents. Moreover, pyrrolo[1,2-a][1,4]benzo-
diazepine derivatives showed antiinflammatory,6 analgesic,11,12 and
fungicidal13 activity.
[1,4]Benzodiazepines are psychoactive drugs showing anxiolytic,
sedative, hypnotic, amnesic, muscle relaxant, and other kinds of
physiological activities.1 On the other hand, the pyrrole moiety is
an important part of various medicines, such as Atorvastatin,
Dividol, Ketorolac, Pyrvinium, Sunitinib, Tolmetin, etc. The
combination of [1,4]benzodiazepine and pyrrole fragments in
one molecule might both increase the known activities of these
pharmacophores and induce some other physiological effects.
One of the methods for this combination is annulation of the
pyrrole ring to the [1,4]benzodiazepine moiety. Among these
compounds, the most studied ones are “anthramycins” produced
by Streptomyces sp.2,3 These antitumor antibiotics are pyrrolo[2,
The methods of pyrrolo[1,2-a][1,4]benzodiazepines synthesis
are mainly based on the use of 1-[2-(a-aminoalkyl)phenyl]pyrroles
which form the target diazepines by Pictet–Spengler condensa-
tion with aldehydes (method a on Scheme 1),7,11,13–15 Bischler–
Napieralski reaction of the corresponding amide (method b),4–6,15,16
or the intramolecular condensation with carbonyl moiety at
C2 atom of the pyrrole ring (method c).17 Not only a-aminoalkyl
group but also imines (methods d and e),18 oximes (method
f )18c,19 and amides20 might participate in these reactions. An
analogous reaction can be also performed when the pyrrole
ring consists of nucleophilic fragment and N-aryl substituent
has an electrophilic moiety (method g),8,21 this process has been
also realized under conditions of four-component Ugi reaction
(method h).22 Some other methods of the synthesis of pyrrolo[1,
2-a][1,4]benzodiazepines and their analogues wherein benzene
ring is replaced by heterocycles have been described too.23
All these methods include the formation of diazepine ring
from 1-arylpyrroles. However, pyrroles are very susceptible to
acids and other electrophilic agents. Moreover, the use of these
approaches is restricted due to the complexity of 1-arylpyrrole
synthesis. Recently we proposed a principally new approach
to the construction of pyrrolo[1,2-a][1,4]benzodiazepine scaffold
aResearch Institute of Heterocyclic Compounds Chemistry, Kuban State
Technological University, Moskovskaya st. 2, Krasnodar, 350072, Russian
Federation. E-mail: alexander_butin@mail.ru; Fax: +7 861 2596592;
Tel: +7 861 2559556
bDepartment of Chemistry, M.V. Lomonosov Moscow State University,
Leninskie Gory 1/3, Moscow, 119991, Russian Federation
cLaboratory of Chemical Synthesis, Federal Research Center of Pediatric
Hematology, Oncology and Immunology, Leninskii av. 117/2, Moscow,
105062, Russian Federation
dState Scientific Research Institute of Chemistry and Technology of Orga-
noelement Compounds, Entuziastov Shosse, 38, Moscow, 111123, Russian
Federation
† Electronic supplementary information (ESI) available: IR, MS, NMR
(1H and 13C) data as well as elemental analysis of synthesized compounds,
results of ab initio calculations. CCDC reference numbers 761545–761546.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c002994g
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Scheme 3 Synthesis of N-(furfuryl)anthranilamides 1 from furfurylamine
2a and 2-(phthalimido)benzoyl chlorides 3. Reagents and conditions: a)
benzene, rt, 1.5 h, 66% 4a, 72% 4b; b) N2H4·H2O, EtOH, rt, 15 min, 90%
1a, 92% 1b.
further reduced to anthranilamides 1 by hydrazine hydrate in the
R
R ꢀ
presence of RANEYꢀ nickel (Scheme 4). Both approaches allow
Scheme 1 The main methods of pyrrolo[1,2-a][1,4]benzodiazepine unit
synthesis.
one to synthesize amides 1 in good yields. Therefore, the selection
of the synthetic method is determined by the accessibility of the
starting ortho-substituted benzoic acids only. The obtained results
are summarized in Table 1.
based on the acid-catalyzed recyclization of N-(2-aminobenzoyl)-
5-methylfurfurylamine which allows one to form simultaneously
both diazepine and pyrrole rings (Scheme 2).24 This method allows
us to obtain a broad scope of pyrrolo[1,2-a][1,4]benzodiazepines
from cheap starting compounds. Now we have applied this method
to a broad range of substrates bearing various substituents in the
furan moiety, in benzoyl group, at the amide nitrogen and at a-
carbon atom. Herein, we describe the results of this investigation
in detail.
Scheme
2
Synthesis of pyrrolo[1,2-a][1,4]benzodiazepines via
N-(furfuryl)anthranilamide recyclizations.
Results and discussion
Scheme 4 Synthesis of 1 from furfurylamines 2 and o-nitrobenzoyl
chlorides 5. Reagents and conditions: a) benzene, rt, 1.5 h; b) N2H4·H2O,
Synthesis of N-(furfuryl)anthranilamides
R ꢀR
RANEYꢀ Ni, EtOH, reflux, 30 min.
The proposed method for the pyrrolo[1,2-a][1,4]benzodiazepine
synthesis consists of acid-catalyzed recyclization of N-(furfuryl)-
anthranilamides 1. These substrates were synthesized from fur-
furylamines 225 by two procedures. The first one is based
on the transformation of anthranilic acid derivatives into
2-(phthalimido)benzoyl chlorides 3 followed by reaction with
5-methylfurfurylamine (2a) with formation of amides 4. The
target anthranilamides 1a,b were obtained from 4a,b by amine
deprotection using a common procedure26 (Scheme 3).
To the better understanding the title recyclization, we also syn-
thesized N-substituted-N-(furfuryl)anthranilamides 8. N-Alkyl
derivatives 8a–c were obtained by reaction of 6a with the
corresponding alkyl halides in the presence of sodium hydride
followed by reduction of the formed adducts 7a–c with a hydrazine
R
R ꢀ
hydrate/RANEYꢀ nickel system (Scheme 5).
N-(4-Chlorophenyl)-N-(5-methylfurfuryl)anthranilamide 8d
was synthesized from 5-methylfurfural 9 using the sequence
presented in Scheme 6.
The second method consists of acylation of furfurylamines 2
with 2-nitrobenzoyl chlorides 5 yielding amides 6 which were
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Table 1 Synthesis of amides 6 and 1
Yield of Yield of
Products R
R1 R2
R3
R4
R5
6, %a
1, %a
1
2
3
4
5
6
7
8
9
6a/1a
6c/1c
6d/1d
6e/1e
6f/1f
6g/1g
6h/1h
6i/1i
Me
Me
Me
Me
Me
Et
t-Bu
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
Cl
H
H
94
91
84
73
95
89
89
75
89
94
92
90
93
96
91
OMe OMe H
H
H
H
H
H
H
H
H
H
H
OMe H
OMe 68
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
82
86
92
82
63
90
6j/1j
p-ClC6H4
Me
Me
H
Me
Ph
10 6k/1k
11 6l/1l
a Isolated yield.
Scheme 6 Synthesis of amide 8d. Reagents and conditions: a) TsOH,
benzene, reflux, 2 h; b) NaBH4, EtOH, rt, 35 min, 55% over two steps;
R ꢀR
c) 5a, benzene, rt, 1.5 h, 86%; d) N2H4·H2O, RANEYꢀ Ni, EtOH,
reflux, 30 min, 72%.
Scheme 5 Synthesis of amides 8a–c. Reagents and conditions: a) RHal,
NaH, THF, rt, 24 h; 86% 7a (MeI), 83% 7b (EtBr), 62% 7c (BnCl); b)
R ꢀR
N2H4·H2O, RANEYꢀ Ni, EtOH, reflux, 30 min; 82% 8a, 76% 8b,
85% 8c.
Recyclization of N-(furfuryl)anthranilamides
Earlier we have shown that furan derivatives containing nucle-
ophilic centers recyclized under treatment with Brønsted acids
into new heterocyclic systems.27 We investigated the possibility of
the related recyclization of N-(furfuryl)anthranilamides using the
model substrate 1a. We found that 1a rearranged into pyrrolo[1,
2-a][1,4]benzodiazepine 13a in moderate yield under heating at
◦
60–70 C in AcOH in the presence of conc. HCl for 4–5 h.24 At
room temperature this reaction proceeded much more slowly and
went to completion after 24 h only but the temperature decrease
influenced by-processes even more efficiently. It allowed us to
obtain product 13a in 72% yield. The structure of 13a was assigned
Fig. 1 Single-crystal X-ray structure of 13a.
1
from H and 13C NMR spectra and unambiguously proved by
single crystal X-ray data28 (Fig. 1).†
of N-furfurylamide 1f with aq. HCl/AcOH. Diketone 14f was
isolated in this reaction in a yield of 32%. Amide 1h failed to form
diazepine at all, diketone 14h being the single reaction product
in this case. When we used N-furfurylamides 1i–l as substrates,
neither pyrrolodiazepines 13 nor diketones 14 were isolated from
the reaction mixtures. Products of destruction were only formed
from these substrates under the studied reaction conditions.
The isolation of diketones 14 in the reactions of
N-furfurylamides 1e,f,h allows us to suppose that these com-
pounds are intermediates in the transformation of 1 into 13. To
prove it, we investigated the reaction mixtures under the conditions
To determine the scope of this reaction, we studied the recy-
clization of the synthesized N-(furfuryl)amides 1 into pyrrolo[1,
2-a][1,4]benzodiazepines 13 under the optimized reaction condi-
tions (Table 2). We found that compounds 1b–d,g were trans-
formed into the corresponding pyrrolobenzodiazepines in 65–78%
yield. However, in the case of substrate 1e, which has a methyl
group at the C3 atom of the anthranilic acid moiety, the yield of the
target diazepine 13e was 11% only. The main product in this reac-
tion was uncyclized diketone 14e. Only traces of pyrrolodiazepine
13f were found in the reaction mixture formed after treatment
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Table 2 Acid-catalyzed recyclization of N-(furfuryl)anthranilamides 1
into pyrrolo[1,2-a][1,4]benzodiazepines 13
This sequence of transformation (furan–diketone–pyrrole) is
quite standard but usually it is realized as the stepwise procedure
with isolation of the intermediate diketones.29 To the best of our
knowledge, there are only two examples of similar intramolecular
furan into pyrrole transformations without isolation of dicarbonyl
intermediates.30
We failed to isolate imines 15 from the reaction mixtures. We
believe it is a result of the reversibility of the diazepine ring
formation when the reactions were performed in the presence of
hydrochloric acid. As a result, the lifetime of this intermediate
is small enough. The formed diazepines 15 can either further
cyclize with the formation of the pyrrole ring leading to 13, or
can decompose back to aminodiketones 14. Indeed, when the
anthranilic acid moiety has a substituent in the position ortho to
the amine function (amides 1e,f), the yields of pyrrolodiazepines
drop significantly. The cyclizations of 15e,f proceeded slowly than
their hydrolysis, and the main products in these reactions were
diketones 14e,f. Similarly, the hydrolysis of 15h to 14h is faster
than its cyclization into 13h. These results can be explained by the
steric effects of the substituents which can influence both kinetic
and thermodynamic characteristics of the reaction. To shed more
light on this problem, we performed ab initio quantum chemical
calculations on 13, 15 and tetrahedral intermediates 16 (Fig. 2) at
MP2/6-311G** level.31 The selected method of calculation allows
one to reproduce well the experimental geometry of 13a (Fig. 1).
For example, according to our calculations, the pyrrole ring is tilted
vs. the benzene ring by 47.7◦, with the corresponding experimental
value being 47.6◦.28
Yield of Yield of
Substrate R
R1 R2
R3
R4
R5
13, %a 14, %a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Cl
H
H
H
72
65
75
78
11
—
—
—
—
20
32
—
57
—
—
—
—
OMe OMe H
H
Me
OMe H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe traces
H
H
H
H
H
H
H
H
H
H
H
H
70
—
—
—
—
—
t-Bu
H
10 1j
11 1k
12 1l
p-ClC6H4
Me
Me
Me H
Ph
H
a Isolated yield.
of the partial conversion of 1. Indeed, we isolated diketone 14c
under these conditions and assigned its structure using spectral
data. Using this compound as reference, we found by TLC analysis
that diketones 14 are present in the reaction mixtures for all
the studied processes of diazepines 13 formation. Therefore, we
can state that the first step of the title recyclization is furan ring
opening leading to 14. The formed diketones react with the amine
function of the anthranilic acid moiety by intramolecular Paal–
Knorr reaction yielding pyrrolodiazepines 13 (Scheme 7).
Fig. 2 Structures optimized at MP2/6-311G** level.
According to our calculations, the cyclization of 15a into 16a
is a slightly exothermic process (DE = -2.8 kJ mol-1). Oppositely,
the transformations of 15e into 16e and 15h into 16h are slightly
endothermic (+5.5 and +0.4 kJ mol-1, respectively). The tilting
angle between the pyrrole and benzene rings can be also considered
as a measure of the steric effects in 16 and 13. This angle is 28.3◦
in the most stable conformer of 16a, 37.8◦ in 16e, and 59.2◦ in 16h.
Dehydration of 16 into 13 is exothermic for all studied substrates
(-17.5, -17.8 and -9.7 kJ mol-1 for 16a, 16e, and 16h, respectively).
Therefore, it is possible to conclude that the steric effects definitely
influence the stability of the intermediates 16 and the products 13
but these effects are relative small. The total energy changes in the
transformations of 15 into 13 were calculated to be -20.3 kJ mol-1,
-12.3 kJ mol-1, and -9.3 kJ mol-1 for 13a, 13e, and 13h, respectively.
It means that the obtained results cannot be explained on the
basis of thermodynamic effects only. At least, the formation of
13 from 15 is exothermic and, therefore, can be realized for all
studied substrates. We supposed that hydrolysis of imines 15 to
aminodiketones 14 should compete with their cyclizations to 13
to a small extent only if hydrochloric acid is absent in the reaction
Scheme 7 The possible mechanism of pyrrolodiazepine 13 formation.
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mixture. Indeed, the treatment of diketones 14e,f with glacial acetic
acid for 2 h leads to 13e,f in high yield (Scheme 8).
Chart 1 Furfuryl cations formed from 1a–f (21a), 1j (21b), 1k (21c) and
1l (21d).
Scheme 8 Transformation of diketones14e,f into pyrrolodiazepines 13e,f.
The moderate yields of the target pyrrolodiazepines by
HCl/AcOH-catalyzed recyclizations of 1e,f are the result of the
concurrent decomposition of N-furfurylamides. The presence of
a substituent in the position ortho to the amine function decreases
the rate of 14 into 13 cyclization. As a result, the back reaction of
14 into 1 competes efficiently with this process. But different sites of
1 can be protonated by acid. The protonation at the C5 atom of the
furan ring leads to cation 17 and, after its hydrolysis, to diketone
14. The protonation of the NH2 group (formation of 18) is the
preferable process but fails to give any product. And lastly, the
protonation of the amide oxygen yields cation 19. This process is
very important as it is accompanied by N–C bond breaking which
yields anthranilamide 20 and furfuryl cation 21 (Scheme 9) and, as
a result, leads to the tar formation. When we tried to perform the
recyclizations of 1j–l, we isolated only anthranilamide 20a (R2 =
R5 = H). This can be explained by the increased stability of cations
21b–d in comparison to 21a (Chart 1).
1a–f were treated with acid. We also failed to obtain the
recyclization products for substrates 8a–d bearing alkyl or aryl
substituents at the amide nitrogen atom. The significant tar
formation due to a-C–N bond fragmentation leading to cation
21a formation was found in these cases. The detailed analysis of
the reaction mixture for 8b transformation allowed one to identify
N-ethylanthranilamide.
The intermediate 21a is formed in the reactions of 8a–d but
not in the transformations of 1a–f. We believe it is related to
the nature of the second substituent at the amide nitrogen atom.
Indeed, protonation of amide oxygen atom can be accompanied
by N–C bond breaking with formation of cation 21 and amide 20
or by N deprotonation yielding hydroxyimine 22 (Scheme 9).
The last process is predominant for reactions of 1a–f. However,
this deprotonation is impossible for products of the amide oxygen
protonation in 8a–d. As a result, the intermediate decomposes into
amide and ArCH2+ cation which leads to realization of various by-
processes.
In other words, the formation of these relatively stable cations
was competing efficiently with the transformation of 1j–l into
pyrrolobenzodiazepines but this process was not important when
This problem can be solved in a straightforward manner.
N-Alkylpyrrolobenzodiazepines 23a–c,e can be easily synthesized
Scheme 9 The possible acid-catalyzed transformations of N-(furfuryl)anthranilamides 1.
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Table 3 Transformation of N-(furfuryl)-2-nitrobenzamides 6 into ni-
trodiketones 24 and then to pyrrolo[1,2-a][1,4]benzodiazepines 13
from the corresponding NH-analogues 13 by treatment with alkyl
halides in the presence of sodium hydride. We demonstrated the
efficiency of this approach using 13a and a series of alkylating
agents. The synthesized 23 were isolated in good to excellent yields
(Scheme 10).
Scheme 10 Synthesis of N-alkylpyrrolo[1,2-a][1,4]benzodiazepines
23a–c,e by alkylation of compound 13a. Reagents and conditions: a) RX,
NaH, THF, rt, 95% 23a (MeI, 6 h), 93% 23b (EtBr, 6 h); 85% 23c (BnCl,
48 h); 67% 23e (ICH2CO2Et, 24 h).
Entry Substrate
R
R1
R2
H
Yield of 24, %a Yield of 13, %a
Synthesis of pyrrolo[1,2-a][1,4]benzodiazepines from
N-(furfuryl)-2-nitrobenzamides
1
2
3
4
5
6a
6e
6h
6k
6l
Me
Me
t-Bu
Me
Me
H
H
H
Me
Ph
75
81
80
19
81
67
Me 79
H
H
H
43
42
40
The recyclizations of the substrates 1e,f,h–l and 8a–d were not
efficient due to their protonation at the amide oxygen atom
with the formation of cations 21 and their decomposition to the
anthranilamides and furfuryl cations. We supposed that this pro-
tonation would be depressed if an electron releasing ortho amino
group could be changed for an electron withdrawing substituent.
To prove it, we treated N-(5-methylfurfuryl)-2-nitrobenzamide
(6a) with HCl/AcOH under the same reaction conditions. Indeed,
we isolated diketone 24a in 75% yield. Encouraged by this
result, we performed similar transformations with nitrobenza-
mides 6e,h,k,l. All of them have substituents which prevented
the efficient recyclization of the corresponding anthranilamides 1.
Some quantity of 2-nitrobenzamide was formed in these reactions
but we isolated nitrodiketones 24 in moderate yields too (Table 3).
When a solution of 24 in AcOH was heated with Fe to reflux and
then the reaction mixture kept for 1 h at room temperature, the
target pyrrolobenzodiazepines 13 were formed via reduction to 14
and their one pot cyclization (Table 3).
a Isolated yield.
The structure of 13h was unambiguously proved by single crystal
X-ray analysis† (Fig. 3).28 The angle between the planes of the
benzene and pyrrole rings in this structure is 56.6◦, in good
accordance with the calculated value (58.0◦). The steric effect
of the tert-butyl group is also revealed by significant elongation
of some bonds in 13h vs. 13a. For example, the N2–C6 (using
˚
numeration on Fig. 1 and 3) bond length is 1.420 A in 13a
Fig. 3 Single-crystal X-ray structure of 13h.
˚
but 1.431 A in 13h. Similar elongation was also found for N2–
C12, C10–C11, C11–C12, and, especially, for the C12–C13 bond,
nitropyrazole-5-carbonyl chlorides 2632 as the starting com-
pounds. They were transformed into the correspond-
ing N-(furfuryl)amides 27 which were further reduced to
4-aminopyrazol-5-carboxamides 28. We found that 28 recyclized
smoothly into pyrazolo[3,4-f ]pyrrolo[1,2-a][1,4]diazepines 29 in
good yields under treatment with hydrochloric acid in AcOH
(Scheme 12). The bulky tert-butyl substituent at the C3 atom
of the pyrazole ring in 28b has no significant effect on this
transformation. This is explained by the larger distance between
ortho substituents in five-membered pyrazole cycle in comparison
with six-membered benzene ring.
˚
namely C–CH3 distance in 13a is 1.486 A and C–CMe3 bond
˚
length is 1.528 A.
This approach was found to be also efficient for the direct
synthesis of N-alkylpyrrolo[1,2-a][1,4]benzodiazepines 23 from
N,N-disubstituted o-nitrobenzamides 7 (Scheme 11).
Synthesis of other pyrrolo[1,2-a][1,4]diazepines
To determine the scope of the applicability of the proposed
method, we studied the recyclization of heterocyclic ana-
logues of N-(furfuryl)anthranilamides. We selected 1-methyl-4-
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HCl/AcOH yields 5-methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-
a][1,4]diazepin-3-one (33) (Scheme 13).
Conclusions
We developed a principally new approach to the synthesis of
the biologically active pyrrolo[1,2-a][1,4]diazepines. Contrary to
the known methods of synthesis of these compounds, diazepine
and pyrrole rings are formed in one pot as a result of a
domino reaction sequence “furan ring opening–diazepine ring
closure–pyrrole ring closure”. The proposed method allows one
to synthesize pyrrolo[1,2-a][1,4]diazepines and their derivatives
annulated to aromatic and heteroaromatic rings in good yields.
Yields of pyrrolobenzodiazepines are lower if the starting com-
pounds contain substituents hampering cyclizations due to steric
effects. However, the corresponding pyrrolobenzodiazepines were
synthesized in good yields by furan ring opening of N-(furfuryl)-
2-nitrobenzamides followed by nitro group reduction and in situ
cyclization of the formed aminodiketones.
Scheme 11 Synthesis of N-substituted pyrrolo[1,2-a][1,4]benzodia-
zepines 23 from nitrobenzamides 7. Reagents and conditions: a) HCl,
AcOH, rt, 24 h, 70% 25a, 80% 25d; b) Fe, AcOH, heating to reflux, then
rt, 1 h, 63% 23a, 77% 23d.
Experimental
General procedures
NMR spectra were recorded with a Bruker DPX 300 (300 MHz
1
for H and 75 MHz for 13C NMR) spectrometer in CDCl3 or
DMSO-d6 at room temperature; the chemical shifts (d) were
1
measured in ppm with respect to the solvent (CDCl3: H: d =
1
7.25 ppm, 13C: d = 77.0 ppm; DMSO-d6: H: d = 2.50 ppm,
13C: d = 39.5 ppm). Coupling constants (J) are given in Hz.
Multiplicities of signals are described as follows: s = singlet,
d = doublet, t = triplet, q = quadruplet, m = multiplet, dd =
double doublet, dq = double quadruplet, br = broadened. IR
spectra were measured as KBr plates on InfraLUM FT-02 and
InfraLUM FT-801 instruments. Mass spectra were recorded on a
Kratos MS-30 instrument with 70 eV electron impact ionization
at 200 ◦C. Melting points (uncorrected) were determined in open
capillaries with Electrothermal 9100 melting point apparatus.
Column chromatography was performed on silica gel KSK (50–
160 mm, LTD Sorbpolymer). Acyl chlorides 3, 5, and 30 were
obtained by treatment of the corresponding acids with thionyl
chloride according to published procedure.33 Amines 2a–d,f,g were
synthesized by published methods.25 Other starting compounds
Scheme 12 Synthesis of pyrazolo[3,4-f ]pyrrolo[1,2-a][1,4]diazepines 29.
Reagents and conditions: a) benzene, 1.5 h, 63% 27a, 88% 27b; b)
R ꢀR
N2H4·H2O, RANEYꢀ Ni, EtOH, reflux, 30 min; 79% 28a, 87% 28b;
c) HCl, AcOH, rt, 24 h, 83% 29a, 76% 29b.
Moreover, we applied the developed approach to the syn-
thesis of a pyrrolo[1,2-a][1,4]diazepine which is not annulated
to other rings. To realize this idea, we acylated 5-methylfur-
furylamine (2a) with 3-(phthalimido)propionyl chloride (30).
Phthalimide protecting group was then changed for the
acid-labile Boc substituent using a standard two-step pro-
cedure. The treatment of the obtained carbamate 32 with
Scheme 13 Synthesis of pyrrolo[1,2-a][1,4]diazepine 33 from furfurylamine 2a and b-alanine derivative 30. Reagents and conditions: a) benzene, rt, 1.5 h,
93%; b) N2H4·H2O, EtOH, rt, 2 h; c) Boc2O, rt, 1 h, 76% over two steps; d) HCl, AcOH, rt, 8 h, 41%.
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are available commercially. All reactions were carried out using
freshly distilled and dry solvents.
starting compound and stirred at room temperature until full
conversion (15 min, TLC monitoring). The main part of solvent
was evaporated under reduced pressure. Residue was poured into
cold water (50 mL). Precipitate was filtered, washed with water,
dried and recrystallized from aqueous ethanol.
General procedure A for synthesis of N-(furfuryl)amides 4, 6, 27,
and 31
To benzene solution of furfurylamine (2) was added dropwise
under stirring a solution of acyl chloride (1.1 equiv) in benzene
(for ca. 30 min). The reaction mixture was stirred for 1 h at
room temperature. Saturated NaHCO3 solution (100 mL) was
added, mixture was vigorously stirred for 30 min. The formed
precipitate was filtered off; filtrate was extracted with benzene
(3 ¥ 30 mL). The combined organic phases were washed with
water and dried over anhydrous Na2SO4. Solvent was evaporated
under reduced pressure. Residue and precipitate were combined.
The crude product was purified by flash chromatography on silica
gel using the specified eluent or recrystallization from the specified
solvents.
2-Amino-5-bromo-N-[(5-methyl-2-furyl)methyl]benzamide (1b).
Obtained according to General procedure B from 4b (5 g,
11.4 mmol); 92% (3.25 g); white solid; mp 126–127 ◦C
(EtOH); dH (300 MHz, CDCl3) 2.28 (3H, s, Me), 4.50 (2H, d,
3J = 5.1 Hz, CH2), 5.54 (2H, br s, NH2), 5.91 (1H, d, 3J = 3.3 Hz,
HFur), 6.16 (1H, d, 3J = 3.3 Hz, HFur), 6.23 (1H, br t, 3J = 5.1 Hz,
NH), 6.51 (1H, d, 3J = 8.7 Hz, HAr), 7.26 (1H, dd, 3J = 8.7 Hz, 4J =
2.1 Hz, HAr), 7.40 (1H, d, 4J = 2.1 Hz, HAr); dC (75 MHz, CDCl3)
13.5, 36.8, 106.3, 107.5, 108.7, 117.1, 118.8, 129.6, 135.0, 147.7,
148.9, 152.2, 167.7; nmax (KBr)/cm-1 3457, 3354, 3283, 1623, 1573,
1537, 1250, 1017, 894, 819, 787; m/z (EI) 310/308 (M+, 17/18%),
200/198 (12/12), 110 (90), 95 (100), 43 (22); Found: C, 50.64; H,
4.22; N, 9.12. Calc. for C13H13BrN2O2: C, 50.51; H, 4.24; N, 9.06%.
2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[(5-methyl-2-furyl)-
methyl]benzamide (4a). Synthesized according to General
procedure A from 5-methylfurfurylamine (2a) (5 g, 45 mmol;
solution in 50 mL of benzene) and 2-(1,3-dioxo-1,3-dihydro-
2H-isoindol-2-yl)benzoyl chloride (3a) (14.15 g, 49.5 mmol;
solution in 100 mL of benzene); eluent: CH2Cl2–petroleum
ether (1 : 2); 66% (10.7 g); colorless needles; mp 146–147 ◦C
(CH2Cl2-petroleum ether); dH (300 MHz, CDCl3) 2.19 (3H, s,
General procedure C for synthesis of amides 1
R
R ꢀ
Hydrazine hydrate (1.5 mL) and RANEYꢀ nickel (0.5 g) was
added to a solution of amide 6 (1 g) in ethanol (20 mL); reaction
mixture was refluxed until full conversion of substrate (30 min,
TLC control). Nickel was filtered off. Filtrate was evaporated to
volume of ca. 5 mL and poured into water (30 mL). The precipitate
was filtered, air-dried and purified by flash chromatography on
silica gel using the specified eluent or by recrystallization from the
specified solvents.
3
3
Me), 4.38 (2H, d, J = 5.4 Hz, CH2), 5.81 (1H, d, J = 3.0 Hz,
HFur), 6.05 (1H, d, 3J = 3.0 Hz, HFur), 6.30 (1H, br t, 3J = 5.4 Hz,
NH), 7.35–7.38 (1H, m, HAr), 7.45–7.50 (1H, m, HAr), 7.56–7.61
(1H, m, HAr), 7.63–7.66 (1H, m, HAr), 7.72–7.79 (2H, m, HPht),
7.87–7.93 (2H, m, HPht); dC (75 MHz, CDCl3) 13.4, 36.9, 106.2,
108.3, 123.7 (2C), 128.1, 129.0, 129.8, 129.9, 131.3, 131.9 (2C),
133.9, 134.2 (2C), 148.8, 151.7, 166.4, 167.4 (2C); nmax (KBr)/cm-1
3346, 1711, 1665, 1524, 1381, 1299, 1111, 1083, 1017, 804, 720;
m/z (EI) 360 (M+, 5%), 250 (7), 110 (100), 76 (11), 43 (8); Found:
C, 70.14; H, 4.44; N, 7.80. Calc. for C21H16N2O4: C, 69.99; H,
4.48; N, 7.77%.
2-Amino-N-[(5-methyl-2-furyl)methyl]benzamide
(1a).
Synthesized according to General procedure
C
from 6a
(1 g, 3.84 mmol); 95% (0.84 g); white solid; mp 62–63 ◦C (aq.
EtOH); dH (300 MHz, CDCl3) 2.25 (3H, s, Me), 4.50 (2H, d, 3J =
3
5.4 Hz, CH2), 5.50 (2H, br s, NH2), 5.89 (1H, d, J = 3.0 Hz,
HFur), 6.12 (1H, d, 3J = 3.0 Hz, HFur), 6.44 (1H, br t, 3J = 5.4 Hz,
NH), 6.56–6.62 (1H, m, HAr), 6.63–6.66 (1H, m, HAr), 7.14–7.20
(1H, m, HAr), 7.29–7.32 (1H, m, HAr); dC (75 MHz, CDCl3) 13.4,
36.6, 106.2, 108.3, 115.6, 116.4, 117.2, 127.2, 132.3, 148.7, 149.3,
151.9, 168.9; nmax (KBr)/cm-1 3370, 3300, 3271, 1635, 1528, 1447,
1300, 1255, 782, 749; m/z (EI) 230 (M+, 30%), 120 (45), 110 (100),
95 (68), 92 (38), 65 (59), 43 (37); Found: C, 67.60; H, 6.24; N,
12.19. Calc. for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17%.
N-[(5-Methyl-2-furyl)methyl]-2-nitrobenzamide
(6a).
Obtained according to General procedure A from (2a) (5 g,
45 mmol; solution in 50 mL of benzene) and 2-nitrobenzoyl
chloride (5a) (9.3 g, 49.5 mmol, solution in 50 mL of benzene);
94% (10.96 g); white solid; mp 117–118 ◦C (CH2Cl2–petroleum
ether); dH (300 MHz, CDCl3) 2.21 (3H, s, Me), 4.47 (2H, d,
3
3J = 5.4 Hz, CH2), 5.87 (1H, d, J = 3.0 Hz, HFur), 6.14 (1H, d,
General procedure D for alkylation of N-(furfuryl)amide 6a
3
3J = 3.0 Hz, HFur), 6.45 (1H, br t, J = 5.4 Hz, NH), 7.43–7.46
Sodium hydride (0.7 g, 60% dispersion in mineral oil) was added
portionwise at 15 ◦C to a solution of 6a (3 g, 11.5 mmol) in
THF (60 mL). Reaction mixture was stirred for 10 min, then alkyl
halide (23 mmol) was added. Mixture was stirred for 1 d (TLC
control), poured carefully into water (150 mL) and kept overnight
for THF evaporation. Product was extracted with ethyl acetate
(5 ¥ 30 mL, TLC control). The combined organic phases were dried
with anhydrous Na2SO4; solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel using the specified eluent and recrystallized from the
specified solvents.
(1H, m, HAr), 7.48–7.54 (1H, m, HAr), 7.57–7.63 (1H, m, HAr),
7.95–7.98 (1H, m, HAr); dC (75 MHz, CDCl3) 13.4, 37.2, 106.3,
108.7, 124.4, 128.7, 130.4, 132.5, 133.6, 146.3, 148.4, 152.0, 166.1;
nmax (KBr)/cm-1 3281, 1640, 1543, 1523, 1353, 1297, 786, 750;
m/z (EI) 242 (M+-18, 44), 169 (50), 155 (45), 150 (16), 141 (24),
134 (64), 110 (66), 104 (47), 95 (69), 76 (80), 65 (38), 51 (100),
43 (98); Found: C, 60.03; H, 4.67; N, 10.80. Calc. for C13H12N2O4:
C, 60.00; H, 4.65; N, 10.76%.
General procedure B for synthesis of N-(furfuryl)anthranilamides
1a,b
Hydrazine hydrate (5 mL) was added to solution of 4 in ethanol
N-Methyl-N-[(5-methyl-2-furyl)methyl]-2-nitrobenzamide (7a).
(50 mL). The reaction mixture was heated until dissolution of
Synthesized according to General procedure D using methyl
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iodide (3.26 g, 23 mmol); eluent: benzene–petroleum ether (1 : 1).
Product was isolated as white solid by recrystallization from
petroleum ether below 0 ◦C; 86% (2.72 g); mp 73–74 ◦C;
dH (300 MHz, CDCl3) (two rotamers) 2.24/2.29 (3H, s, Me),
2.77/3.11 (3H, s, NMe), 4.17/4.72 (2H, br s/s, CH2), 5.86/5.94
(1H, d, J = 3.0 Hz, HFur), 6.01/6.27 (1H, d, J = 3.0 Hz, HFur),
7.39–7.42/7.51–7.54 (1H, m, HAr), 7.52–7.58/7.54–7.60 (1H, m,
HAr), 7.67–7.73/7.68–7.74 (1H, m, HAr), 8.17–8.20/8.20–8.23
(1H, m, HAr); dC (75 MHz, CDCl3) (two rotamers) 13.5/13.6,
32.3/35.6, 43.2/47.7, 106.2/106.4, 109.7/109.9, 124.6/124.7,
128.2/128.7, 129.7/129.8, 132.9/133, 134.3/134.5, 144.9/145.3,
147.0/147.9, 152.2/152.7, 167.7/167.7; nmax (KBr)/cm-1 1648,
1564, 1520, 1488, 1424, 1400, 1348, 1284, 1224, 1028, 800; m/z
(EI) 274 (M+, 15%), 257 (22), 150 (10), 134 (15), 123 (82), 104 (14),
95 (100), 76 (26), 65 (13), 51 (39), 43 (46); Found: C, 61.68; H, 5.26;
N, 10.26. Calc. for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21%.
dissolved in benzene–petroleum ether (1 : 1) mixture and filtered
through pad of silica gel. Solvent was evaporated under reduced
pressure. The obtained product (3.2 g, 86%) was used for further
transformations without additional purification.
3
3
General procedure E for acid-catalyzed recyclization of amides
1 into pyrrolo[1,2-a][1,4]benzodiazepine-6-ones 13
Mixture of amide 1 (1 g), glacial acetic acid (20 mL) and conc.
HCl (3 mL) was stirred at room temperature for 24 h (TLC
control). Then reaction mixture was poured into water (100 mL)
and neutralized to pH ~ 7 with NaHCO3. The formed precipitate
was filtered, washed with water and air-dried. Residue was purified
by flash chromatography on silica gel using the specified eluent and
crystallized from the specified solvents.
1-Methyl-4,5-dihydro-6H -pyrrolo[1,2-a][1,4]benzodiazepin-6-
one (13a). Synthesized according to General procedure E from
1a (1 g, 4.34 mmol); eluent: benzene; 72% (0.66 g); white solid; mp
235–236 ◦C (benzene–petroleum ether); dH (300 MHz, CDCl3)
2-Amino-N-methyl-N-[(5-methyl-2-furyl)methyl]benzamide (8a).
Synthesized according to General procedure C from 7a (1 g,
3.65 mmol); eluent: CH2Cl2–petroleum ether (1 : 1). Aniline 8a
was isolated as light-yellow oil in 82% yield (0.73 g). dH (300 MHz,
CDCl3) 2.25 (3H, s, Me), 2.97 (3H, s, NMe), 4.33 (2H, s, CH2), 4.50
(2H, br s, NH2), 5.88 (1H, d, 3J = 3.0 Hz, HFur), 6.10 (1H, d, 3J =
3.0 Hz, HFur), 6.65–6.71 (2H, m, HAr), 7.09–7.15 (2H, m, HAr); dC
(75 MHz, CDCl3, 40 ◦C) 13.5, 32.9/36.4, 43.6/47.9, 106.2, 109.3,
116.5, 117.3, 120.0, 127.9, 130.5, 145.4, 148.4, 152.1, 171.1; nmax
(KBr)/cm-1 3456, 3352, 1624, 1592, 1496, 1456, 1400, 1264, 1220,
1064, 1020, 784, 756; m/z (EI) 244 (M+, 10%), 124 (100), 120 (39),
95 (80), 92 (25), 65 (29), 43 (20); Found: C, 68.87; H, 6.72; N,
11.28. Calc. for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47%.
3
2.30 (3H, s, Me), 4.09 (2H, d, J = 6.0 Hz, CH2), 5.98 (1H, d,
3J = 3.3 Hz, HPyr), 6.01 (1H, d, 3J = 3.3 Hz, HPyr), 7.25–7.28 (1H,
m, HAr), 7.35–7.41 (1H, m, HAr), 7.52–7.57 (1H, m, HAr), 7.92
(1H, br t, 3J = 6.0 Hz, NH), 7.93–7.97 (1H, m, HAr); dC (75 MHz,
CDCl3) 14.0, 38.0, 104.9, 109.5, 124.9, 126.2, 129.4 (2C), 131.2,
131.4, 132.7, 135.8, 170.7; nmax (KBr)/cm-1 3260, 1656, 1628, 1584,
1492, 1464, 1444, 1408, 1336, 1208, 796, 764; m/z (EI) 212 (M+,
100%), 197 (69), 183 (31), 168 (36), 154 (48), 77 (24), 63 (16), 51
(37); Found: C, 73.52; H, 5.45; N, 13.19. Calc. for C13H12N2O: C,
73.57; H, 5.70; N, 13.20%.
Cyclization of aminodiketones 14 into pyrrolo[1,2-
a][1,4]benzodiazepine-6-ones 13
4-Chloro-N-[(5-methyl-2-furyl)methyl]aniline (12)
A
solution of 4-chloroaniline (10) (11.5 g, 90 mmol),
7,10-Dimethoxy-1-methyl-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]-
5-methylfurfural (9) (9.91 g, 90 mmol) and TsOH (0.4 g) in benzene
(90 mL) was refluxed with a Dean–Stark trap for 2 h. Solvent
was evaporated under reduced pressure. The formed imine 11 was
dissolved in ethanol (100 mL). Sodium borohydride (2 g) was
added to this solution portionwise for 5 min. Reaction mixture
was stirred at room temperature for 30 min (TLC control), poured
into cold water (100 mL) and neutralized with aqueous acetic
acid (1 : 1) to pH ~ 7. Product was extracted with ethyl acetate
(3 ¥ 50 mL); the combined organic fractions were dried over
Na2SO4. Solvent was removed using rotary evaporator. Residue
was distilled under vacuum. Product 12 was obtained as light-
yellow oil (11 g, 55%); bp 205–210 ◦C/10 Torr. It was used for
further transformations without additional purification.
benzodiazepin-6-one
(13f). 2-Amino-3,6-dimethoxy-N-(2,5-
dioxohexyl)benzamide (14f) (0.2 g, 0.65 mmol) was dissolved
in glacial acetic acid (5 mL) and stirred at room temperature
for 2 h (TLC control). Then reaction mixture was poured into
water (20 mL) and neutralized to pH ~ 7 with NaHCO3. The
formed precipitate was filtered, washed with water and air-dried.
The residue was purified by flash chromatography on silica gel
using benzene–petroleum ether (1 : 1) as eluent. Product 13f was
isolated as a beige solid in 62% yield (0.11 g). Mp 166–167 ◦C
(ethyl acetate–petroleum ether); dH (300 MHz, CDCl3) 2.12
(3H, s, Me), 3.73 (3H, s, OMe), 3.89 (3H, s, OMe), 3.93 (1H, dd,
3J = 6.3 Hz, 2J = 15.9 Hz, CH2), 4.07 (1H, dd, 3J = 6.3 Hz, 2J =
15.9 Hz, CH2), 5.89 (1H, d, 3J = 3.3 Hz, HPyr), 6.01 (1H, d, 3J =
3.3 Hz, HPyr), 6.40 (1H, br t, 3J = 6.3 Hz, NH), 6.94 (1H, d, 3J =
9.3 Hz, HAr), 7.03 (1H, d, 3J = 9.3 Hz, HAr); dC (75 MHz, CDCl3)
13.0, 38.5, 55.9, 56.5, 105.4, 107.1, 110.8, 114.0, 121.1, 125.9,
132.4, 133.1, 146.8, 151.3, 167.9; nmax (KBr)/cm-1 3229, 1647,
1519, 1490, 1445, 1265, 1114, 1054, 1004, 796, 751; m/z (EI) 272
(M+, 100%), 257 (37), 242 (37), 228 (44), 213 (36), 199 (27), 170
(12), 154 (11), 45 (14); Found: C, 66.29; H, 6.05; N, 10.19. Calc.
for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29%.
N-(4-Chlorophenyl)-N-[(5-methyl-2-furyl)methyl]-2-
nitrobenzamide (7d)
Solution of 2-nitrobenzoyl chloride (5a) (2.05 g, 11 mmol) in 30 mL
of benzene was added dropwise for 30 min to benzene solution
(50 mL) of furfurylaniline 12 (2.22 g, 10 mmol) under stirring. The
reaction mixture was stirred for 1 h at room temperature. Saturated
NaHCO3 solution (100 mL) was added, mixture was vigorously
stirred for 30 min. Organic phase was separated, aqueous phase
was extracted with benzene (3 ¥ 30 mL). The combined organic
phases were washed with water and dried over anhydrous Na2SO4.
Solvent was evaporated under reduced pressure. Residue was
General procedure F for alkylation of 13a
Sodium hydride (0.56 g, 60% dispersion in mineral oil) was added
portionwise at 15 ◦C to a solution of 13a (2 g, 9.42 mmol) in
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THF (40 mL). Reaction mixture was stirred for 10 min, then alkyl
halide (18.84 mmol) was added. Mixture was stirred until full
conversion of substrate (6–48 h, TLC control), poured carefully
into water (100 mL) and kept overnight for THF evaporation.
The formed precipitate was filtered off, air-dried and purified by
flash chromatography on silica gel using the specified eluent and
recrystallized from the specified solvents.
mixture was poured into cold water (100 mL) and neutralized
to pH ~ 7 with NaHCO3. The formed precipitate was filtered
off and carefully washed with hot ethyl acetate (5 ¥ 30 mL).
The combined organic fractions were dried over Na2SO4. Solvent
was evaporated under reduced pressure. Residue was purified by
flash chromatography on silica gel using the specified eluent and
crystallized from the specified solvents.
1,5-Dimethyl-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-
6-one (23a). Synthesized according to General procedure F using
methyl iodide (2.67 g, 18.84 mmol); 6 h; eluent: ethyl acetate–
petroleum ether (1 : 1), 95% (2.02 g); colorless plates; mp 156–
157 ◦C (ethyl acetate–petroleum ether); dH (300 MHz, CDCl3)
1,4-Dimethyl-4,5-dihydro-6H -pyrrolo[1,2-a][1,4]benzodiazepin-
6-one (13k). Synthesized according to General procedure H from
(24k) (1 g, 3.42 mmol); eluent: ethyl acetate–petroleum ether (1 : 2);
colorless prisms; 81% (0.62 g); mp 201–202 ◦C (ethyl acetate–
petroleum ether); dH (300 MHz, CDCl3) 1.63 (3H, d, 3J = 6.9 Hz,
CHMe), 2.28 (3H, s, Me), 4.31 (1H, dq, 3J = 6.0 Hz, 3J =
6.9 Hz, CHMe), 5.99 (1H, d, 3J = 3.3 Hz, HPyr), 6.02 (1H d, 3J =
3.3 Hz, HPyr), 6.90 (1H, br d, 3J = 6.0 Hz, NH), 7.24–7.27 (1H, m,
HAr), 7.35–7.41 (1H, m, HAr), 7.51–7.57 (1H, m, HAr), 7.93–7.96
(1H, m, HAr); dC (75 MHz, CDCl3) 13.9, 15.7, 43.8, 102.1, 109.2,
125.0, 126.2, 129.4, 129.9, 130.9, 131.2, 135.7, 137.6, 169.6; nmax
(KBr)/cm-1 3160, 1648, 1604, 1520, 1488, 1460, 1404, 1320, 1288,
1160, 772, 704; m/z (EI) 226 (M+, 67%), 211 (100), 184 (57), 167
(18), 77 (22), 43 (50); Found: C, 74.48; H, 6.59; N, 12.22. Calc. for
C14H14N2O: C, 74.31; H, 6.24; N, 12.38%.
2
2.31 (3H, s, Me), 3.13 (3H, s, NMe), 3.92 (1H, d, J = 15.6 Hz,
CH2), 4.32 (1H, d, 2J = 15.6 Hz, CH2), 6.01 (1H, d, 3J = 3.3 Hz,
HPyr), 6.07 (1H, d, 3J = 3.3 Hz, HPyr), 7.24–7.27 (1H, m, HAr), 7.34–
7.39 (1H, m, HAr), 7.48–7.54 (1H, m, HAr), 7.90–7.94 (1H, m, HAr);
dC (75 MHz, CDCl3) 13.9, 34.6, 46.0, 105.1, 109.2, 124.2, 126.1,
129.3, 130.6, 130.8, 131.2, 135.1(2C), 167.7; nmax (KBr)/cm-1 1628,
1520, 1488, 1456, 1408, 1392, 1336, 1232, 1148, 784, 760, 712; m/z
(EI) 226 (M+, 96%), 211 (100), 197 (10), 184 (25), 168 (36), 154
(52), 99 (13), 84 (15), 77 (21), 51 (26), 42 (43); Found: C, 74.32; H,
6.41; N, 12.33. Calc. for C14H14N2O: C, 74.31; H, 6.24; N, 12.38%.
1-Methyl-N-[(5-methyl-2-furyl)methyl]-4-nitro-1H-pyrazole-5-
carboxamide (27a). Synthesized according to General procedure
A from 2a (2 g, 18 mmol; solution in 30 mL of benzene) and
1-methyl-4-nitro-1H-pyrazole-5-carbonyl chloride (26a) (3.76 g,
19.8 mmol; solution in 30 mL of benzene); eluent: CH2Cl2–
petroleum ether (1 : 1); 63% (3.02 g); beige plates; mp 109–110 ◦C
(CCl4); dH (300 MHz, CDCl3) 2.24 (3H, s, Me), 4.11 (3H, s, Me),
4.55 (2H, d, J = 5.4 Hz, CH2), 5.88 (1H, d, J = 3.0 Hz, HFur),
6.17 (1H, d, 3J = 3.0 Hz, HFur), 8.05 (1H, s, HHet), 8.22 (1H, br t,
3J = 5.4 Hz, NH); dC (75 MHz, CDCl3) 13.5, 37.0, 41.3, 106.3,
109.0, 132.2, 133.1, 136.3, 147.7, 152.4, 156.5; nmax (KBr)/cm-1
3296, 1640, 1572, 1564, 1532, 1508, 1468, 1396, 1392, 1316, 1192,
828, 796; m/z (EI) 246 (M+-18, 30%), 136 (82), 108 (25), 95 (52),
83 (46), 67 (39), 53 (50), 43 (100); Found: C, 49.71; H, 4.50;
N, 21.08. Calc. for C11H12N4O4: C, 50.00; H, 4.58; N, 21.20%.
General procedure G for furan ring opening in
N-(furfuryl)-2-nitrobenzamides 6
Mixture of N-(furfuryl)-2-nitrobenzamide 6 (1 g), glacial acetic
acid (20 mL) and conc. HCl (3 mL) was stirred at room
temperature until full conversion of starting compound (24 h, TLC
control). Then reaction mixture was poured into water (100 mL)
and neutralized to pH ~ 7 with NaHCO3. The formed precipitate
was filtered off, washed with water and air-dried. If product was
not precipitated, it was extracted with ethyl acetate (4 ¥ 30 mL), the
combined organic phases were dried with Na2SO4 and evaporated.
In both cases residue was purified by flash chromatography on
silica gel using the specified eluent. Solvent was evaporated under
reduced pressure to 1/3 of the initial volume. Mixture was kept
until crystallization of product.
3
3
N-(2,5-Dioxohexyl)-2-nitrobenzamide (24a). Synthesized ac-
cording to General procedure G from 6a (1 g, 3.84 mmol); eluent:
ethyl acetate–petroleum ether (1 : 1); 75% (0.8 g); colorless needles;
mp 119–120 ◦C (ethyl acetate–petroleum ether); dH (300 MHz,
CDCl3) 2.18 (3H, s, Me), 2.71–2.75 (2H, m, CH2), 2.81–2.85
4-Amino-1-methyl-N-[(5-methyl-2-furyl)methyl]-1H-pyrazole-
5-carboxamide (28a). Synthesized according to General pro-
cedure C from 27a (1 g, 3.79 mmol); 79% (0.7 g); colorless
needles; mp 101–102 ◦C (aq. EtOH); dH (300 MHz, CDCl3) 2.24
(3H, s, Me), 2.92 (2H, br s, NH2), 4.12 (3H, s, Me), 4.49 (2H, d,
3
3
3J = 5.7 Hz, CH2), 5.88 (1H, d, J = 3.0 Hz, HFur), 6.11 (1H, d,
(2H, m, CH2), 4.43 (2H, d, J = 4.5 Hz, CH2), 6.64 (1H, br t,
3J = 4.5 Hz, NH), 7.53–7.61 (2H, m, HAr), 7.65–7.70 (1H, m,
HAr), 8.04–8.07 (1H, m, HAr); dC (75 MHz, CDCl3) 29.6, 33.5,
36.9, 49.5, 124.5, 128.7, 130.6, 132.2, 133.7, 146.4, 166.3, 203.8,
206.8; nmax (KBr)/cm-1 3276, 1732, 1712, 1648, 1520, 1412, 1364,
1312, 1240, 856, 792, 716; m/z (EI) 248 (M+-30, 4%), 162 (22),
150 (100), 134 (40), 120 (94), 104 (66), 99 (85), 92 (54), 76 (46),
65 (25), 51 (93), 43 (32); Found: C, 56.26; H, 5.13; N, 10.19. Calc.
for C13H14N2O5: C, 56.11; H, 5.07; N, 10.07%.
3J = 3.0 Hz, HFur), 7.17 (1H, s, HHet), 8.55 (1H, br t, 3J = 5.7 Hz,
NH); dC (75 MHz, CDCl3) 13.5, 35.8, 40.2, 106.2, 108.1, 127.0,
127.1, 133.1, 149.4, 151.9, 159.9; nmax (KBr)/cm-1 3348, 3280, 1652,
1640, 1616, 1568, 1548, 1424, 1356, 1312, 1292, 1204, 1024, 980,
912, 812; m/z (EI) 234 (M+, 17%), 124 (11), 110 (52), 95 (100), 69
(10), 53 (11), 42 (36); Found: C, 56.43; H, 6.16; N, 24.03. Calc. for
C11H14N4O2: C, 56.40; H, 6.02; N, 23.92%.
3,9-Dimethyl-5,6-dihydropyrazolo[3,4-f ]pyrrolo[1,2-a][1,4]di-
azepin-4(3H)-one (29a). Synthesized according to General pro-
cedure E from 28a (1 g, 4.27 mmol); eluent: benzene; 83%
(0.77 g); white solid; mp 179–180 ◦C (benzene–petroleum ether);
dH (300 MHz, CDCl3) 2.37 (3H, s, Me), 4.16 (3H, s, Me), 4.17
General procedure H for synthesis of
pyrrolo[1,2-a][1,4]benzodiazepine-6-ones 13 from nitrodiketones 24
Iron powder (3 g) was added to solution of nitrodiketone 24 (1 g) in
glacial acetic acid (20 mL). Reaction mixture was heated to reflux
and then stirred at room temperature for 1 h (TLC control). Then
3
(2H, d, J = 6.0 Hz, CH2), 5.96–5.99 (2H, m, HPyr), 7.24 (1H,
3
br t, J = 6.0 Hz, NH), 7.60 (1H, s, HHet); dC (75 MHz, CDCl3)
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13.9, 38.2, 39.6, 105.7, 108.6, 123.8, 126.5, 129.0, 129.4, 129.9,
162.5; nmax (KBr)/cm-1 3200, 1656, 1564, 1528, 1432, 1412, 1392,
1340, 1328, 1208, 788, 748, 692; m/z (EI) 216 (M+, 100%), 201
(20), 187 (25), 172 (10), 109 (11), 93 (11), 77 (15), 65 (16), 52 (23),
42 (24); Found: C, 61.44; H, 5.82; N, 25.99. Calc. for C11H12N4O:
C, 61.10; H, 5.59; N, 25.91%.
Pyrrolodiazepine 33 was obtained as white solid (0.24 g, 41%). Mp
194–195 ◦C; dH (300 MHz, CDCl3) 2.19 (3H, s, Me), 2.90–2.94
(2H, m, CH2), 4.00–4.05 (2H, m, CH2), 4.31 (2H, d, 3J = 5.7 Hz,
3
3
CH2), 5.79 (1H, d, J = 3.3 Hz, HPyr), 5.85 (1H, d, J = 3.3 Hz,
HPyr), 7.16 (1H, br t, 3J = 5.7 Hz, NH); dC (75 MHz, CDCl3) 12.2,
34.1, 39.3, 40.9, 105.3, 105.8, 126.9, 129.9, 174.3; nmax (KBr)/cm-1
3200, 1664, 1508, 1476, 1440, 1424, 1388, 1348, 1312, 1248, 1200,
1172, 1100, 776; m/z (EI) 164 (M+, 60%), 162 (51), 149 (39), 136
(30), 120 (67), 109 (100), 106 (90), 95 (42), 93 (48), 77 (47), 66 (41),
59 (29), 55 (66), 42 (46); Found: C, 65.67; H, 7.30; N, 17.06. Calc.
for C9H12N2O: C, 65.83; H, 7.37; N, 17.06%.
3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[(5-methyl-2-furyl)-
methyl]propanamide (31). Obtained according to General
procedure A from 2a (5 g, 45.05 mmol; solution in 50 mL
of benzene) and 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)propanoyl chloride (30) (11.77 g, 49.56 mmol, solution in
50 mL of benzene); eluent: ethyl acetate–petroleum ether (1 : 1).
Compound 31 was isolated as colorless needles in 93% yield
(13.07 g). Mp 176–177 ◦C (EtOH); dH (300 MHz, CDCl3) 2.20
(3H, s, Me), 2.60–2.65 (2H, m, CH2), 3.98–4.02 (2H, m, CH2),
Acknowledgements
We thank the Russian Foundation of Basic Research (grant
nos. 07-03-00352-a and 10-03-00254-a), the Federal Agency for
Education (Rosobrazovanie) (grant no 2.1.1/4628), and Bayer
HealthCare AG (Germany) for financial support of this work.
Dr V.E. Zavodnik is acknowledged for X-ray crystal structure
determination.
3
3
4.33 (2H, d, J = 5.4 Hz, CH2), 5.83 (1H, d, J = 3.0 Hz, HFur),
5.95 (1H, br t, 3J = 5.4 Hz, NH), 6.05 (1H, d, 3J = 3.0 Hz, HFur),
7.66–7.72 (2H, m, HPht), 7.78–7.85 (2H, m, HPht); dC (75 MHz,
CDCl3) 13.4, 34.2, 34.6, 36.5, 106.2, 108.3, 123.2 (2C), 131.9,
133.9 (2C), 149.0, 151.8, 168.0, 169.2 (2C); nmax (KBr)/cm-1 3416,
1720, 1647, 1026, 998, 866, 803, 717; m/z (EI) 312 (M+, 42%),
160 (34), 110 (100), 95 (16), 76 (12), 55 (10), 43 (18); Found: C,
65.39; H, 5.30; N, 8.94. Calc. for C17H16N2O4: C, 65.38; H, 5.16;
N, 8.97%.
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3
CH2), 5.18 (1H, br s, NH), 5.86 (1H, d, J = 3.0 Hz, HFur), 6.03
3
(1H, br s, NH), 6.07 (1H, d, J = 3.0 Hz, HFur); dC (75 MHz,
CDCl3) 13.5, 28.3 (3C), 36.0, 36.5 (2C), 79.2, 106.2, 108.3, 149.1,
151.9, 156.0, 171.1; nmax (KBr)/cm-1 3344, 3318, 1685, 1633, 1530,
1452, 1366, 1325, 1283, 1253, 1231, 1174, 1023, 786; m/z (EI) 282
(M+, 16%), 227 (24), 226 (100), 208 (42), 182 (66), 152 (24), 137
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