2,6-Pyridinedicarboxylic acid as organocatalyst for the synthesis of 1,5-benzodiazepines through one-pot reaction

Article abstract of DOI:10.1016/j.tetlet.2013.05.148

2,6-Pyridinedicarboxylic acid has been found to be an effective and efficient organocatalyst for the synthesis of 1,5-benzodiazepine derivatives from o-phenylenediamine, β-ketoesters, and aromatic aldehydes by employing one-pot three-component reaction. The catalyst plays a crucial role for the regioselective C-C bond formation at the γ position of β-ketoesters. The salient features of this present protocol are simple reaction procedure, requirement of cost-effective catalyst, good yields, and applicable to a wide range of substrates.

Full text of DOI:10.1016/j.tetlet.2013.05.148

Accepted Manuscript
2,6-Pyridinedicarboxylic acid as organocatalyst for the synthesis of 1,5-benzo‐
diazepines through one-pot reaction
Mohan Lal, R. Sidick Basha, Satavisha Sarkar, Abu T. Khan
PII:
S0040-4039(13)00939-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.148
TETL 43048
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 March 2013
29 May 2013
31 May 2013
Please cite this article as: Lal, M., Sidick Basha, R., Sarkar, S., Khan, A.T., 2,6-Pyridinedicarboxylic acid as
organocatalyst for the synthesis of 1,5-benzodiazepines through one-pot reaction, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.05.148
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Graphical Abstract
2,6-Pyridinedicarboxylic acid as organocatalyst for the synthesis of 1,5-
benzodiazepines through one-pot reaction
Mohan Lal, R. Sidick Basha, Satavisha Sarkar and Abu T. Khan*

2,6-Pyridinedicarboxylic acid as organocatalyst for the synthesis of 1,5-
benzodiazepines through one-pot reaction
Mohan Lal, R. Sidick Basha, Satavisha Sarkar and Abu T. Khan*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan)
This work is dedicated to my mentor, Professor Goverdhan Mehta, on the occasion of his 70th
anniversary.
Abstract
2,6-Pyridinedicarboxylic acid has been found to be an effective and efficient organocatalyst for
the synthesis of 1,5-benzodiazepine derivatives from o-phenylenediamine, β-ketoesters and
aromatic aldehydes by employing one-pot three-component reaction. The catalyst plays a crucial
role for the regioselective C-C bond formation at the γ position of β-ketoesters. The salient
features of this present protocol are simple reaction procedure, requirement of cost-effective
catalyst, good yields and applicable to a wide range of substrates.
Keywords: 2,6-Pyridinedicarboxylic Acid, Organocatalyst, β-Ketoesters, 1,5-Benzodiazepines,
Multicomponent reactions.
Organocatalyst containing acidic hydrogen(s) might interact with substrates having basic
functional groups to catalyze a wide variety of reactions and they are extremely useful in organic
synthesis.1 They have the ability to transfer proton in the transition state as well as to stabilize the
reactive intermediate through hydrogen-bond formation.2 Organocatalyzed cascade reactions
usually avoid costly protection/deprotection steps and less time consuming.3 As a matter of fact,

they have been extensively utilized for the synthesis of biologically active natural products and
asymmetric synthesis.4 A few years ago, 2,6-pyridinedicarboxylic acid (2,6-PDCA) has been
explored as bifunctional organocatalyst for hydrophosphonylation of aldehydes and ketone5a and
Michael-type Friedel-Crafts reaction.5b We conceived that 2,6-pyridinedicarboxylic acid (2,6-
PDCA) might be a useful organocatalyst for the synthesis of 1,5-benzodiazepine derivatives
from β-ketoesters. Recently, various research groups have demonstrated the usefulness of β-
ketoesters for the synthesis of numerous heterocyclic compounds by employing multicomponent
reactions (MCRs).6 We have also shown that β-ketoesters are valuable starting material for the
synthesis of substituted pyrroles7 and highly substituted piperidine derivatives8 involving C-C
bond formation either at α position7 or both at the α and γ position8 of β-ketoesters. However, the
selective C-C bond formation particularly at the γ position of β-ketoesters is relatively less
explored. In 2007, Kita et al. first reported9a the synthesis of seven membered 1,4-azepanes
through multicomponent reaction from 1,2-ethylenediamine, β-ketoesters and aromatic
aldehydes in the presence of 10 mol% p-toluene sulfonic acid (p-TSA) involving C-C bond
formation at the γ position of β-ketoesters. They have reported only 23% yield of the product 4b
when the similar reaction was carried out with o-phenylenediamine instead of 1,2-
ethylenediamine with methylacetoacetate and benzaldehyde using 10 mol% p-TSA as catalyst.9b
However, the same research group successfully accomplished the synthesis of various 1,5-
benzodiazepine using pentafluorobenzoic acid as catalyst from o-phenylenediamine, β-ketoesters
and aromatic aldehydes.9b At the same time, Rodriguez and his co-workers also demonstrated9c,9d
the synthesis of 1,4-diazepane derivatives from 1,2-ethylenediamine, β-ketoesters and aromatic
aldehydes in presence of 4 Å molecular sieves in toluene under reflux conditions. They have also
noticed that similar reaction was unsuccessful with o-phenylenediamine, acyclic β-ketoesters and

aromatic aldehydes for the synthesis of 1,5-benzodiazepine with 4 Å molecular sieves.9d
Although these methods are quite useful,9 still there is a further scope to devise a newer
methodology for the synthesis of 1,5-benzodiazepine derivatives using other inexpensive catalyst
due to their wide pharmacological activities such as anti-convulsant, anti-inflammatory,
analgesic, anti-anxiety, anti-depressive, anti-biotics,10 anti-cancer11 and anti-viral (HIV) agents.12
In recent times, MCRs have been explored for the synthesis of heterocyclic compounds due to
their diversity, good yields, high selectivity and atom-economy, and high bond forming
efficiency.13 Recently, our research group introduced several reagents as catalysts in
multicomponent reactions for the synthesis of new heterocyclic entities.14 In this paper, we report
2,6-PDCA catalyzed one-pot synthesis of 1,5-benzodiazepine derivatives using o-
phenylenediamine, β-ketoesters and aromatic aldehydes as shown in Scheme 1.
Scheme 1
To find out a suitable reaction conditions, various trial reactions were carried out using a
combination of o-phenylenediamine, methylacetoacetate and 4-chlorobenzaldehyde using
different mol % of catalyst as shown in Table 1. We have observed that 20 mol % of 2,6-PDCA
catalyst is sufficient to obtain maximum yield. Subsequently, similar reaction was examined
with different catalysts such as benzoic acid, 2-nitrobenzoic acid, pyridine-2-carboxylic acid,
and 2,5-pyridinedicarboxylic acid. We have obtained much lower yield of 1,5-benzodiazepine
derivative (4a) with other catalysts. To verify the role of 2,6-PDCA, we have also carried out
similar reaction with isophathalic acid and it provided 32% yield of the desired product 4a. We
presume low yield of the product formation in isophathalic acid, may be due to lower acidity as
compared to 2,6-pyridinedicarboxylic acid. Interestingly, 2-nitrobenzoic acid, which has almost

similar acidity like 2,6-PDCA also did not provide the desired product 4a (Table 1, entry 7) in
good yield. From this observation, we propose that both acidity and formation of intermolecular
hydrogen bonding of the organocatalyst play a crucial role for the formation of desired product.
In the present methodology, we did not obtain 1,5-benzodiazepine derivative 5a, which might
also be possible through α-adduct. Perhaps it is getting converted into the γ-adduct 4a at higher
temperature, which was also observed by Kita and his co-workers,9b due to intramolecular
hydrogen bonding between NH and C=O in the product 4a.
Table 1
After optimization of the reaction conditions, the reaction of o-phenylenediamine, methyl
acetoacetate and benzaldehyde was performed under identical manner and it afforded the desired
product 4b in 62% yield. Encouraged by the above two successful results, a wide variety of
aromatic aldehydes containing different substituents such as –Br, -NO2, -Me, -OMe, -OH groups
at various positions in the aromatic ring were conducted with o-phenylenediamine and methyl
acetoacetate with 20 mol% 2,6-PDCA under similar conditions and the desired products 4c-i
(Table 2, entries 3-9) were isolated in good yields.
Table 2
To verify the generality and further scope of the present protocol, similar reactions were
executed with various heterocyclic aldehydes, o-phenylenediamine and methyl acetoacetate in
presence of 20 mol% of 2,6-PDCA under identical reaction conditions. The products (4j-m)
were obtained in good yields which are mentioned in Table 2 (entries 10-13). The scope of the
reaction was further examined by performing the reaction with different β-ketoesters, o-
phenylenediamine and 4-chlorobenzaldehyde by employing 20 mol % of 2,6-PDCA under

similar reaction conditions. The desired products (4n-r) were obtained in good yields, which are
shown in Table 3 (entries 1-5). We have not explored the reaction with other substituted o-
phenylenediamine because it provides inseparable mixture of regio-isomers. However, we are
trying to separate them, which will be disclosed later on in case we are successful.
Table 3
1
From H NMR of the crude reaction mixture, it was noted that we have obtained
exclusively (Z) configuration of the product 4n due to intermolecular hydrogen bonding. Further,
the structural assignment of compound 4n and especially (Z) configuration of the double bond in
the cases of acyclic β-ketoester is determined based on X-ray analysis (Figure 1)
Figure 1
Compound 4n has both type of hydrogen bonding interaction one intra-molecular between N1
H···O1 (N1 H = 0.885 Å; N1 O1 = 2.722 Å, ∠ N H···O = 138.71°) and N4 H···O2 (N4-H =

0.884 Å; N4 O2 = 2.718 Å, ∠ N H···O = 132.65°). Another inter-molecular hydrogen bonding
interaction between O of C=O and N H of other benzodiazepine molecule N H···O (N3 H =
0.863 Å; N3 O2 = 2.932 Å, ∠ N H···O = 139.77°) as shown in Figure 1.16
The stereochemistry between aryl group and the ring juncture in compound 4q was also
established through single XRD data as shown in Figure 2.16
Figure 2
We have observed from XRD structure that the benzylic proton and homobenzylic proton is in
trans-diaxial orientation, which was also reported by Fujioka et al. in cases of cyclic β-
ketoesters. Compound 4q also have intra-molecular hydrogen bonding between N2 H···O3 (N2

H = 0.860 Å; N2 O3 = 2.634 Å, ∠ N2 H···O3 = 132.46°). It was observed that torsional angle
(H-21 C-21 C-20 H-20) for the solid state structure of 4q was determined to be 171.34, which is
3
consistent with the observed JH20-H21 coupling constant of 11.2 Hz, which is in full agreement
with the trans configuration. We have also noted in the compound 4r that coupling constant
value 10.4 Hz for the benzylic proton and homobenzylic proton.
The formation of the product, 1,5-benzodiazepines (4), can be proposed as follows: At first o-
phenylenediamine reacts with β-ketoester to give mono enaminoester A (Scheme 2).
Scheme 2
Then, it reacts with an aromatic aldehyde to form imine-enaminoester product B, which was
proved unequivocally by isolation of the intermediate product B by Kita et al.9b It may also
undergo cyclization reaction either at the α position to afford 1,5-benzodiazepine derivative 5 or
at the γ position to give 1,5-benzodiazepines (4). However, the product 5 undergoes conversion
into the compound 4 during heating, which was also noted by Kita et al.9b Then, the intermediate
B undergoes protonation at the iminium nitrogen atom17 in presence of organocatalyst, 2,6-
pyridinedicarboxylic acid and perhaps it also stabilizes the intermediate C through hydrogen

bonding. Finally, the intermediate C undergoes concomitant cyclization to form intermediate D
through γ-selective C-C bond formation and it forms 1,5-benzodiazepine derivative 4 from
intermediate D by 1,5-hydrogen shift. We have tried to isolate the intermediate C by co-
crystallization, but it was unsuccessful.
In summary, we have demonstrated a simple synthetic protocol for the synthesis of 1,5-
benzodiazepine derivatives catalyzed by 2,6-PDCA as organocatalyst, from o-phenylenediamine,
β-ketoesters and aromatic aldehydes through one-pot MCRs reactions. We have demonstrated
the γ-selective product formation by employing organocatalyst 2,6-PDCA as catalyst with a
variety of aldehydes and esters, which was earlier failure in p-toluene sulfonic acid (p-TSA) and
4 Å molecular sieves in toluene under reflux conditions. In addition, our protocol requires
inexpensive catalyst as compared to pentafluorobenzoic acid. The present protocol provides good
yields with different kind of aldehydes and β-ketoesters. We are currently working for proving
the mechanism as well as asymmetric synthesis, which will be disclosed in full paper.
Acknowledgments
ML, RSB and SS are thankful to CSIR, New Delhi for their research fellowships. The authors
are grateful to the Department of Science and Technology (DST) for providing single XRD
facility under FIST programme to the Department of Chemistry as well as to the Director, IIT
Guwahati for providing general facility. We are thankful to the referees’ for their valuable
comments and suggestions.
Supporting Information

Supplementary data (X-ray crystallographic data (CIF files) of 4n and 4q, spectral data of all
1
compounds and copies of H, 13C NMR and HRMS spectra of products associated with this
paper can be found, in the online version, at doi:
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7. Khan, A. T.; Lal, M.; Bagdi, P. R.; Basha, R. S.; Saravanan, P.; Patra, S. Tetrahedron
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Org. Chem. 2008, 73, 8398.
9. (a) Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Org. Lett. 2007, 9, 1687. (b)
Murai, K.; Nakatani, R.; Kita, Y.; Fujioka, H. Tetrahedron 2008, 64, 11034. (c) Sotoca,
E.; Constantieux, T.; Rodriguez, J. Synlett 2008, 1313. (d) Sotoca, E.; Allais, C.;
Constantieux, T.; Rodriguez, J. Org. Biomol. Chem. 2009, 7, 1911.
10. Knabe, J.; Buech, H. P.; Bender, S. Arch. Pharm. 1995, 328, 59.
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via Multicomponent Reaction I & II, Springer: New York. 2010.
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15. General Procedure for the synthesis of 1,5-benzodiazepines - Into an oven dried 25 mL
round bottomed flask was taken a mixture of o-phenylenediamine (1.0 mmol) and β-
ketoesters (1.0 mmol) in 3 mL of dichloroethane. Then, organocatalyst 2,6-
pyridinedicarboxylic acid (34 mg, 0.2 mmol) was added into it and the reaction mixture
was kept for stirring at room temperature. After 2 h of stirring, aromatic aldehyde (1
mmol) was added into it and the reaction mixture was refluxed in a pre-heated oil-bath.
After completion of the reaction, dichloroethane was removed in rotary evaporator and
the crude residue was purified through a silica gel column chromatography. The desired
product 4 was obtained in good yield after eluting with ethyl acetate and hexane (1:9)
mixture. Compound 4a 9b : Yield = 0.230 g (70%), Pale yellow oily, IR (KBr) νmax 1161,
1
1232, 1266, 1489, 1588, 1615, 1648, 2851, 2925, 3365 cm-1. H NMR (400 MHz,
CDCl3): δ 2.51-2.64 (m, 2H), 3.66 (brs, 3H), 4.52 (s, 1H), 4.84 (dd, J = 7.6, 4.8 Hz, 1H),
6.77 (d, J = 7.6 Hz, 1H), 6.90-7.0 (m, 3H), 7.30 (brs, 4H), 10.17 (brs, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 40.1, 50.6, 64.7, 84.4, 121.2, 122.2, 122.7, 125.3, 127.8, 129.0,
130.4, 133.8, 138.0, 143.1, 158.3, 170.7 ppm. HRMS (ESI) calcd for C18H17ClN2O2 [M +
H]+: m/z = 329.1057; found: 329.1042. Anal. Calcd for C18H17ClN2O2: C, 65.75; H, 5.21;
N, 8.52%; found C, 65.54; H, 5.06; N, 8.38%. Compound 4n: Yield = 0.212 g (62%),
Crystalline solid, mp 116-119οC, IR (KBr) νmax 1161, 1234, 1435, 1505, 1618, 1644,
1
1725, 2949, 3444 cm-1. H NMR (400 MHz, CDCl3): δ 1.28 (t, 3H), 2.56 (dd, J = 14.0
Hz, 8.0 Hz, 1H), 2.61 (dd, J = 14.0 Hz, 5.2 Hz, 1H), 3.64 (s, 1H), 4.11-4.18 (m, 2H), 4.54
(s, 1H), 4.83-4.87 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.91-7.01 (m, 3H), 7.32 (s, 4H),

10.20 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 14.7, 40.1, 59.1, 64.7, 84.8, 121.07,
122.2, 122.7, 125.2, 127.8, 129.1, 130.5, 133.8, 137.9, 143.2, 158.1, 170.4 ppm. HRMS
(ESI) calcd for C19H19ClN2O2 [M + H]+: m/z = 343.1213; found: 343.1196. Anal. Calcd
for C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17%; found C, 66.46; H, 5.48; N, 8.08%.
16. The X-ray crystal structures were determined with a diffractometer. Complete
crystallographic data of 4n (CCDC No. 827828) and 4q (CCDC No. 930463) for the
structural analysis have been deposited to the Cambridge Crystallographic Data Centre,
copies of this information may be obtained free of charge from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
1223-336033, e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
17. HA, K. Acta Cryst. 2012, E68, o196.

Scheme 1. 2,6-Pyridinedicarboxylic acid catalyzed synthesis of 1,5-benzodiazepine derivatives.

Table 1. Optimization of reaction condition for the synthesis of 1,5-benzodiazepine 4a.a
Entry
Organocatalyst used
No Catalyst
Mol%
-
Time / h
% Yieldb
NR
48
1
2
3
4
5
6
7
12
7
2,6-PDCA
10
2,6-PDCA
15
6
55
2,6-PDCA
20
5
70
2,6-PDCA
30
5
69
Benzoic acid
2-Nitrobenzoic acid
20
8
21
20
8
26

8
9
Pyridine-2-carboxylic acid
2,5-PDCA
20
20
20
8
7
8
25
35
32
10
Isophathalic acid
a The reactions were performed using 1 mmol scale of o-phenylenediamine (1), methyl acetoacetate (2),
and 4-chlorobenzaldehyde (3a) in DCE from room temperature to reflux condition. bIsolated yield.
Table 2. Synthesis of 1,5-benzodiazepines using a combination of o-phenylenediamine, methyl
acetoacetate and aromatic aldehydes in presence of 20 mol % 2,6-PDCA.15
Entry
1
Aldehyde (3)
Compound (4)a
Time (h)
%Yieldb
5
70
3a
3b
4a
2
4.5
62
4b

3
4
68
3c
4c
4
4.5
68
3d
4d
5
6
7
HN
NH
O
4
62
71
70
OMe
NO2
3e
4e
2.5
3.5
3f
4f
3g
4g

8
9
4
66
72
3h
4h
3.5
3i
4i
10
11
12
HN
NH
NH
O
4
3
55
61
55
OMe
3j
4j
3k
4k
HN
NH
O
3.5
OMe
3l
N
H
4l

13
4
74
3m
4m
a The reactions were performed in 1 mmol scale involving β-ketoesters, o-phenylenediamine and aromatic aldehyde.
b Isolated yield.
Table 3. Formation of 1,5-benzodiazepines by employing o-phenylenediamine, 4-
chlorobenzaldehyde with different β-ketoesters.15
S.No
1
β-ketoester (2)
Compound (4)a
Time (h)
4.5
% Yieldb
62
2b
4n

2
3
4
5
4
5
66
64
2c
4o
4p
4q
4r
2d
5.5
64
64
2e
4
2f
aThe reactions were carried out in 1 mmol scale of β-ketoesters, o-phenylenediamine and 4-chlorobezaldehyde.
bIsolated yield.

(a)

(b)
Figure 1. (a) ORTEP molecular structure of 4n and (b) Intra (light blue color) and inter (pink
color) hydrogen bonding interactions between two molecules of 4n (CCDC 827828).16
(a)

(b)
Figure 2. (a) ORTEP molecular structure of 4q and (b) Shows Intra molecular hydrogen bond
(light green color) between NH and ester CO group in the compound 4q and exhibits trans
configuration between aryl group and the ring juncture of the product 4q (CCDC No. 930463).16

H
O
O
NH2
2,6-PDCA
DCE
N
H2N
O
+
OR
NH2
OR
A
2
1
CHO
R1
3
H
HN
NH
OR
N
N
O
X
O
OR
R1
R1
HO
B
O
N
- adduct
5
HO
O
O
O
N
H
N
OH
HN
H
O
O
N
HN
H
R1
OR
O
-2,6-PDCA
D
OR
R1
C
H
HN
N
O
OR
adduct
-
R1
4
Scheme 2. Mechanism for the formation of 1,5-benzodiazepines 4