Highly efficient conversion of fused 2-amino-4-aryl-4H-chromene-3- carbonitriles into fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles using Vilsmeier conditions

Article abstract of DOI:10.1016/j.tetlet.2013.05.030

A simple, mild, and highly efficient protocol for the synthesis of fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles has been developed starting from fused 2-amino-4-aryl-4H-chromene-3-carbonitriles utilizing Vilsmeier conditions.

Full text of DOI:10.1016/j.tetlet.2013.05.030

Accepted Manuscript
Highly efficient conversion of fused 2-amino-4-aryl-4H-chromene-3-carboni‐
triles into fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles using Vilsmeier
conditions
Janardhan Banothu, Ravibabu Velpula, Rajitha Gali, Rajitha Bavantula, Peter
A. Crooks
PII:
S0040-4039(13)00787-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.030
TETL 42930
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 April 2013
7 May 2013
11 May 2013
Please cite this article as: Banothu, J., Velpula, R., Gali, R., Bavantula, R., Crooks, P.A., Highly efficient conversion
of fused 2-amino-4-aryl-4H-chromene-3-carbonitriles into fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles using
Vilsmeier conditions, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.030
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Highly efficient conversion of fused 2-amino-
4-aryl-4H-chromene-3-carbonitriles into
fused 2-oxo-4-aryl-2H-chromene-3-
Leave this area blank for abstract info.
carbonitriles using Vilsmeier conditions
Janardhan Banothu,a Ravibabu Velpula,a Rajitha Gali,a Rajitha
Bavantula,a* Peter A. Crooksb
R
R
O
CN
CN
O
SOCl2/DMF
120 oC, 60-90 min
O
NH2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Highly efficient conversion of fused 2-amino-4-aryl-4H-chromene-3-carbonitriles
into fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles using Vilsmeier conditions
Janardhan Banothu,a Ravibabu Velpula,a Rajitha Gali,a Rajitha Bavantula,a* Peter A. Crooksb
a Department of Chemistry, National Institute of Technology, Warangal-506 004, A.P., India
b Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR-72205, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple, mild and highly efficient protocol for the synthesis of fused 2-oxo-4-aryl-2H-
chromene-3-carbonitriles has been developed starting from fused 2-amino-4-aryl-4H-chromene-
3-carbonitriles utilizing Vilsmeier conditions.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles
Fused 2-amino-4-aryl-4H-chromene-3-carbonitriles
Vilsmeier conditions
Coumarins are important class of oxygen-containing
heterocycles, which are mainly found in plants of the family
malononitrile as a by-product under basic conditions in 35%
yield, although to-date, there are no direct reports on the efficient
synthesis of fused 2-oxo-4-aryl-2H-chromene-3-carbonitriles
under mild conditions. Thus, there is a need for the development
of new and efficient methods for the preparation of such
compounds in high yields and under mild reaction conditions.
Rutaceae and Apiaceae. Coumarins possess
a variety of
therapeutic and pharmacological properties.1 Recently, polycyclic
coumarins such as (+)-Calanolide-A, which has been isolated
from Calophyllum lanigerum trees, were found to be highly
effective against HIV.2 Other coumarin derivatives such as
Warfarin, Geiparvarin and Novobiocin (Fig 1) are prominent
drugs with anticoagulant, antiproliferative and antibiotic
activities, respectively. In addition, coumarins are widely used as
additives in foods, perfumes, cosmetics, optical brighteners, and
dispersed fluorescence and lasers dyes.3
In continuation of our research towards the synthesis of
biologically potent molecules from the readily available
substrates,13 herein we report a new, facile and rapid conversion
of fused 2-amino-4-aryl-4H-chromene-3-carbonitriles into their
corresponding fused 2-oxo-4-aryl-2H-chromene-3-carbonitrile
counterparts under Vilsmeier conditions.
O
O
2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (1a-i) and
OH
H2N
O
O
O
OH
O
OH
H
N
O
3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles
(3a-d)
OH
O
O
O
O
O
were synthesized via three-component condensation of α/β-
naphthol, arylaldehydes and malononitrile in refluxing ethanol
under basic conditions.14 Compound 1a-i and 3a-d on reaction
O
O
O
O
Geiparvarin
Warfarin
Novobiocin
Figure 1. Biologically potent coumarin derivatives
o
with thionyl chloride in dimethylformamide at 120 C afforded
Generally, coumarins can be synthesized utilizing the Pechmann
reaction,4 Knoevenagel condensation reactions,5 Claisen
rearrangement chemistry,6 Perkin reaction,7 and Wittig8 and
Reformatsky9 reactions, as well as other catalytic cyclization
reactions.10 Among these, the Pechmann reaction is often the
method of choice because it is simple and straight forward, and
involves the condensation of phenols with β-ketoesters in the
presence of a variety of acidic condensing agents.
the corresponding 2-oxo-4-aryl-2H-benzo[h]chromene-3-carbo-
nitriles (2a-i) and the 3-oxo-1-aryl-3H-benzo[f]chromene-2-
carbonitriles (4a-d) in good yields (Scheme 1 and 2, Table 1).
R
R
OH
CN
O
CN
SOCl2/DMF
CN
CN
EtOH, Et3N
R
CHO
120 oC, 60-90 min
O
O
NH2
Reflux, 1-6 hr
1 (a-i)
2(a-i)
Several methods have been reported for the synthesis of fused 2-
oxo-2H-chromene-3-carbonitriles which utilize expensive and
hazardous catalysts, and which afford only poor yields, even after
prolonged reaction times.11 Recently, Nermien and co-workers12
reported the formation of substituted 2-oxo-4-aryl-2H-chromene-
3-carbonitriles by the condensation of phenol with arylidene
Scheme 1. Synthesis of 2-oxo-4-aryl-2H-benzo[h]chromene-3-
carbonitriles
Corresponding author. Tel.: 0091-0870-2459445; fax: 0091-0870-2459547; e-mail: rajitabhargavi@yahoo.com

2
Tetrahedron Letters
R
R
From the IR spectrum of the product, the disappearance of two
SOCl2/DMF
CN
OH
CN
CN
CN
EtOH, Et3N
absorption bands at 3323 and 3171 cm-1 for the NH2 in the
starting material, and at the same time, the appearance of a strong
band at 1724 cm-1 for C=O of lactone moiety, and a medium
band at 2228 cm-1 for the C≡N group was indicative of product
formation. From the 1H NMR spectrum, the absence of one
singlet at 4.85 ppm (proton attached to 14th carbon) and 7.15 ppm
(two amine protons) in the starting material, and the
disappearance of signals at 40.4 ppm (14th carbon) and 56.3 ppm
(13rd carbon) and the presence of signals at 164.1 ppm (14th
carbon) and 157.1 ppm (12nd carbon) in the 13C NMR spectra also
confirm the formation of compound 2a, and rule out the
sulfoxido analog 5 as the product. In addition, the molecular ion
peak from the mass spectral and the elemental analysis data are
consist with the formation of product 2a.
CHO
R
120 oC, 60-90 min
Reflux, 4-8 hr
O
O
3 (a-d)
NH2
O
4(a-d)
Scheme 2. Synthesis of 3-oxo-1-aryl-3H-benzo[f]chromene-2-
carbonitriles
Table 1. Synthesis of fused 2-oxo-4-aryl-2H-chromene-3-
carbonitriles.
Entrya
R
Product Time
(min)
Yieldb
(%)
94
1
2
3
4
5
6
7
8
C6H5
2-ClC6H4
4-ClC6H4
60
75
60
60
60
75
90
90
60
75
75
90
75
2a
2b
2c
2d
2e
2f
2g
2h
2i
4a
4b
4c
4d
92
96
Utilizing these optimal conditions (i.e. 3 mmol of SOCl2 in DMF
at 120 C), we have synthesized a variety of fused 2-oxo-4-aryl-
4-OCH3C6H4
3,4-(OCH3)2 C6H3
4-CH3C6H4
4-OHC6H4
3-NO2C6H4
4-OH-3-OCH3C6H3
C6H5
4-OHC6H4
3-NO2C6H4
4-OH-3-OCH3C6H3
92
93
o
2H-chromene-3-carbonitriles (2a-i and 4a-d) in good yields and
short reaction times (Table 1). The structures of all these newly
synthesized compounds were confirmed by their spectral and
analytical properties.
90
88
90
90
9
10
11
12
13
88
88
Ph
Ph
Ph
O
CN
O
CN
NH
S
SOCl2
DMF
86
90
X
O
O
NH2
O
N
H
O
aReaction conditions: Fused 2-amino-4-aryl-4H-chromene-3-
2a
1a
5
carbonitrile (1 mmol), thionylchloride (3 mmol), DMF (5mL),
SOCl2
AcOH, Reflux, 24 h
120 oC.
bIsolated yields.
Ph
O
N
Ghorab and co-workers15 have reported the synthesis of sulfoxido
derivatives by the reaction of 3-amino-6,7,8,9-tetrahydro-6-oxo-
NH
CH3
O
5-aryl-5H-thiazolo[2,3-b]quinazoline-2-carboxamides
with
6
thionyl chloride. The interesting feature of these molecules
prompted us to investigate similar reaction conditions on fused 2-
amino-4-aryl-4H-chromene-3-carbonitriles without conversion of
the nitrile moiety into amide functionality. Thus, we carried out
Scheme 3. Reaction of 2-amino-4-phenyl-4H-benzo[h]chromene-
3-carbonitrile under different solvent conditions.
The proposed reaction pathway for the formation of fused 2-oxo-
4-aryl-2H-chromene-3-carbonitriles is shown in Scheme 4.
Initially, Vilsmeier formylation likely occurs on the free amine of
the starting material, followed by hydration and subsequent
elimination of formamide, to afford the final product in good
yield.
this reaction utilizing
1 mmole of 2-amino-4-phenyl-4H-
benzo[h]chromene-3-carbonitrile (1a) and 5mL of neat thionyl
chloride and observed several unidentified products. We
subsequently carried out the same reaction (1:1 ratio of 1a and
SOCl2) in a variety of different solvents such as ethanol, acetic
acid, acetonitrile, benzene, water and dimethylformamide at the
solvent reflux temperature. Unexpectedly, utilizing DMF we
obtained the desired product 2a in good yield (88%) after a short
reaction time (1 h); we also observed that none of the remaining
solvents produced even a trace amount of 2a, even after 24 h at
reflux. Interestingly, in acetic acid, we obtained a product in 32%
yield, which we later confirmed to be the chromeno pyrimidinone
6 (Scheme 3).
SOCl2 + DMF
Cl
CH3
R
O
R
H
R
H
N
CN
CN
CHO
CN
H
CH3
_
CHO H2
O
N
H
N
O
NH2
O
H
H
From the above observations, we determined that the reaction
proceeds through the formation of Vilsmeier’s reagent. In order
to determine optimal conditions, the above reaction was carried
out at different temperatures and we were able to observe a
R
R
CN
CN
CHO
-NH2CHO
O
O
O
H
N
H
O
o
maximal yield of 94% at 120 C. Furthermore, in an effort to
Scheme 4. Proposed mechanism for the formation of fused 2-
oxo-4-aryl-2H-chromene-3-carbonitriles
improve the yield, we increased the amount of thionyl chloride
and observed no change in the product yield but saw a significant
o
decrease in the reaction time. Thus, maximal yield at 120 C for
In conclusion, we have developed a simple, efficient and fast
method for the synthesis of fused 2-oxo-4-aryl-2H-chromene-3-
carbonitriles in good yield under Vilsmeier conditions. Further
expansion of this reaction and biological applications of these
molecules are currently in progress in our laboratory.
60 min was observed with 3 mmol of thionylchloride. We also
observed a decrease in yield when the reaction temperature was
>120 oC and the amount of thionylchloride was >3 mmol, coupled
with the formation of unidentified impurities. We also carried out
the reaction with phosphorus oxychloride (3 mmol) in place of
thionyl chloride, but this reaction required longer reaction times
(3-4 h) for complete conversion.
Acknowledgements

3
We would like to thank the late Prof. A. Srikrishna, Indian
Institute of Science, Bangalore for his guidance in arriving at the
structures. The author JB thanks The Ministry of Human
Resource Development, RV and RG thanks to UGC for the
research fellowships. Fruitful suggestions and comments of the
reviewers are gratefully acknowledged.
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Supplementary data
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16. General experimental procedure: Thionyl chloride (3 mmol)
was added drop-wise to 2-amino-4-aryl-4H-benzo[h]chromene-3-
carbonitrile/3-amino-1-aryl-1H- benzo[f]chromene-2-carbonitrile
(1 mmol) dissolved in 5 mL of DMF. After complete addition the
mixture turned yellow in colour, and was heated at 120 oC for an
appropriate time, as shown in Table 1. After completion of the
reaction (monitered by TLC), the mixture turned to a green color.
The mixture was cooled to ambient temperature and poured into
ice cold water. The solid that separated out was filtered, washed
with water and purified over coloumn chromatography using 5%
ethyl acetate/hexane as eluent to afford the pure product.
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