Diisopropyl azodicarboxylate mediated selective dehydrogenation of 2-amino-3-cyano 4H-chromenes

Article abstract of DOI:10.1016/j.tetlet.2017.03.049

Selective dehydrogenation of 2-amino-3-cyano 4H-chromenes to the corresponding 2-iminochromenes mediated by diisopropyl azodicarboxylate under neutral conditions is reported. The dehydrogenation reaction is compatible with phenolic hydroxyl group and gene

Full text of DOI:10.1016/j.tetlet.2017.03.049

Accepted Manuscript
Diisopropyl azodicarboxylate mediated selective dehydrogenation of 2-ami-
no-3-cyano 4H-chromenes
Himanshu Sharma, Mohini Mourya, Debanjan Guin, Yogesh C. Joshi,
Mahabeer P. Dobhal, Ashok K. Basak
PII:
S0040-4039(17)30351-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.049
TETL 48750
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 February 2017
14 March 2017
16 March 2017
Please cite this article as: Sharma, H., Mourya, M., Guin, D., Joshi, Y.C., Dobhal, M.P., Basak, A.K., Diisopropyl
azodicarboxylate mediated selective dehydrogenation of 2-amino-3-cyano 4H-chromenes, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.049
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Graphical Abstract
Diisopropyl azodicarboxylate mediated
selective dehydrogenation of 2-amino-3-
cyano 4H-chromenes
Himanshu Sharma, Mohini Mourya, Debanjan Guin, Yogesh C. Joshi, Mahabeer P. Dobhal, Ashok K. Basak*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Diisopropyl azodicarboxylate mediated selective dehydrogenation of 2-amino-3-
cyano 4H-chromenes
Himanshu Sharma,a Mohini Mourya,a Debanjan Guin,a Yogesh C. Joshi,a Mahabeer P. Dobhalb and Ashok
K. Basak*a
aDepartment of Chemistry, University of Rajasthan, JLN Marg, Jaipur-302004, India
bSuresh Gyan Vihar University, Jagatpura, Jaipur-302025, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Selective dehydrogenation of 2-amino-3-cyano 4H-chromenes to the corresponding 2-
iminochromenes mediated by diisopropyl azodicarboxylate under neutral conditions is reported.
The dehydrogenation reaction is compatible with phenolic hydroxyl group and generates
iminochromene in high yields. The methodology provides an easy access to coumarin and N-
tosyl 2-amino-3-cyano-4-aryl 4H-chromenes
Received in revised form
Accepted
Available online
Keywords:
2-Amino-3-cyano-4-aryl 4H-chromene
Diisopropyl azodicarboxylate
2-Iminochromene
Selective Dehydrogenation
N-Tosyl 2-animo-3-cyano-4-aryl 4H-chromene
Natural and synthetically available 2-amino-3-cyano-4-aryl
4H-chromenes and their derivatives are considered as important
heterocyclic compounds because of their widespread biological
activities such as anticancer, antimicrobial, antifungal,
antioxidant and antirheumatic activities.1 Chromenes possessing
antagonist activity for anti-apoptotic Bcl-2 proteins have been
reported. The pro-apoptatic activity of several chromenes have
also been reported which make them as potential anticancer
therapeutic agents.2 Dehydrogenation of 2-amino-3-cyano-4-aryl
4H-chromenes generate corresponding 2-iminochromenes which
on acidic hydrolysis provide biologically important coumarins.3
Studies by Cai et. al. showed that coumarins act as potent
apoptosis inducer with significant advantage over the
corresponding chromenes.4 Cai et al. reported the
dehydrogenation of 2-amino-3-cyano-4-aryl 4H-chromenes using
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Scheme 1).4a
During our study on iodine mediated synthesis of coumarins
from chromenes, we observed the formation of 2-iminochromene
under anhydrous conditions (Scheme 1).5 The iminochromene
could be isolated in good yields after aqueous Na2S2O3 work-up.
Previous work:
N
N
O
NH2
CN
O
NH
CN
DDQ
a)
DCM, rt
Ar
Ar
b)
I2
O
NH2
CN
O
NH
toluene
reflux
CN
Ar
Ar
O
This work:
HO
c)
O
NH2
CN
HO
NH
CN
DIAD
DMF, rt
Ar
Ar
Scheme 1
: Synthetic methods for 2-iminochromene from chromene
Besides the well-known Mitsunobu reaction, diethyl
azodicarboxylate and its congeners have been used for various
dehydrogenation reactions such as dehydrogenation of alcohols,
thiols, hydroxylamines and hydrazines.6 Diethyl azodicarboxylate
have also been employed for dehydrogenation of tertiary amines7
and N-alkyl tetrahydroisoquinolines.8 This report describes the
efficient dehydrogenation of 2-amino-3-cyano 4H-chromenes to
the corresponding iminochromenes using

2
diisopropyl azodicarboxylate (DIAD) in a polar aprotic solvent
at ambient temperature.
chromene 4b underwent dehydrogenation reaction in 3 hours
A
three-component condensation among an aldehyde,
malononitile and α-naphthol in presence of piperazine hydrate in
ethanol at room temperature provided chromene 4e in good yields
(Scheme 1).9 The synthetic method was also found to be suitable
to generate chromenes from a wide range of aldehydes using
resorcinol and β-naphthol. During our investigation on Mitsunobu
reaction for the
N-alkylation of chromene 4a with 2-chloro ethanol using DIAD,
we observed the formation of 2-iminochromene 5a. Controlled
experiments showed that diisopropyl azodicarboxylate alone was
responsible for the dehydrogenation of the chromene to the
corresponding iminochromene. A short screening of solvents
showed that the dehydrogenation reaction could be carried out in
several solvents. Dehydrogenation reactions in non-polar solvents
are usually slower and require elevated temperature. Reaction in
refluxing toluene was complete within 3 hours (entry a, Table 1)
whereas reaction in 1,2-dichloroethane required 6 hours for
completion (entry c, Table 1). Dehydrogenation reaction can also
be carried out in non-nuleophilic polar protic solvents in good
yields (entries e-f, Table 1). However, the reaction rate increases
dramatically in polar aprotic solvents (entries h-k, Table 1). Thus,
the reaction in DMF (0.5 M) was complete within 2 hours at room
o
temperature (20 C) to generate the iminochromene 5a in 88%
yields (entry h, Table 1). The dehydrogenation reaction in DMSO,
NMP and DMPU also yielded similar results.
To evaluate the scope of dehydrogenation reaction, first a series
of chromenes generated from different aldehydes, malonitrile and
α-naphthol were treated with DIAD in DMF at room temperature.
As presented in Table 2, most of the iminichromenes could be
isolated in high yields. The reaction works equally well with
substrates derived from aldehydes having electron donating and
electron withdrawing groups in the benzene ring. While

3
chromene 4c required 5 hours for completion. Chromene 4e that
contain a nitro group at 4-position in the benzene ring underwent
smooth dehydrogenation reaction in hours to give
2
iminochromene 5e in 86% yields. Chromene 4f that contain an
indole moiety underwent quick dehydrogenation and the product
was isolated in 68% yields. The product must be isolated as soon
as the reaction is complete. On stirring for longer hours, the
iminochromene 5f gets converted into a polar unidentified
product. Chromene 4g having pyridyl group at 4-position
underwent slow dehydrogenation and the corresponding
iminochromene was isolated in very high yields (88%) after 10
hours. The dehydrogenation reaction was also successful with
chromene 4h containing a cyclohexyl group at 4-position.
However, the iminochromene 5h having fair solubility in diethyl
ether-hexanes mixture was isolated in moderate yields (64%). We
also tested chromenes 4i-4m generated from resorcinol that
contains a phenolic hydroxyl group for the DIAD mediated
dehydrogenation reaction. Except chromene 4l, most of the
iminochromenes were isolated in high yields. No dehydrogenation
of the phenolic hydroxyl group was observed. The
dehydrogenation reactions of chromenes (4n, 4o) derived from β-
naphthol were unusually slow and less effective. For example,
chromene 4n on treatment with DIAD showed approximately 30%
conversion (by TLC analysis) after stirring for 48 hours. Similar
results were obtained with chromene 4o.
Most of the
dehydrogenation reactions were very clean and only
iminochromenes could be detected. Due to extended conjugation
of the π-electrons of aryl rings, the iminochromenes appeared as
intense yellow solids.
H
O
NH
CN
O
N
H
H
CN
7
Ar
H
H
i
N
CO2 Pr
6
Ar
N
8
i
CO2 Pr
O
NH
CN
iPrO2C
iPrO2C
i
CO2 Pr
H
NH
NH
10
O
NH
CN
N
N
H
+
8
i
CO2 Pr
11
9
R'
Ar
Scheme 3
: Mechanism of DIAD mediated dehydrogenation of chromene
The plausible mechanism of the dehydrogenation reaction is
outlined in Scheme 3. We believe that the dehydrogenation of the
tautomeric form 7 of chromene 6 occurs via a concerted
mechanism to generate imino chromene 9 and reduced-DIAD 10.
For chromenes derived from β-naphthol, dehydrogenation of
intermediate 11 would be difficult due to steric crowding of the
aryl groups.
HO
O
NH2
HO
O
O
DIAD (1.2 eq)
DMF, rt, 2 h
CN
CN
then 2N aq. HCl
rt, 2 h
4j
12
Cl
Cl
82%
Cl
Cl
Scheme 4
: One-pot conversion of chromene to coumarin

4
The DIAD mediated dehydrogenation reaction can be used for
References and notes
one-pot conversion of 2-amino-3-cyano-4-aryl 4H-chromenes to
the corresponding coumarins.10,11 For example, chromene 4j when
treated with DIAD in DMF generated iminochromene 5j which on
treatment with 2N aq. HCl in-situ generated coumarin 12 in 82%
yields (Scheme 4). Aqueous HCl must be added after complete
dehydrogenation of chromene takes place.
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iminochromene 14. Chromenes, under these conditions, fail to
generate measurable amount of N-tosylated compound 15. The N-
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cyano 4H-chromenes to the corresponding coumarins.
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Supplementary data is available for the manuscript

5
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12. Experimental procedure for the dehydrogenation of chromene 4a:
To a stirred solution of chromene 4a (300 mg, 0.83 mmol) in
DMF (1.6 mL) was added DIAD (200 µL, 0.84 mmol) at rt. The
reaction mixture was stirred at rt until complete conversion took
place (ca. 3 hours). Then the mixture was slowly diluted with 50%
ether in hexanes (15 mL) with vigorous stirring. The yellow solid
that separated out was filtered off and titurated with 50% ether in
hexanes to obtain chromene 5a (260 mg, 88%) as a yellow solid
(Please see the supplementary information for spectral data).

10
Highlights:
1. Selective dehydrogenation chromenes
2. 2-Iminochromene synthesis in high yields
3. One-pot conversion of chromene to
coumarin
4. Synthesis of novel N-tosyl chromenes
5. Chromene as a reducing agent