Efficient atom economical one-pot multicomponent synthesis of densely functionalized 4H-chromene derivatives

Article abstract of DOI:10.1016/j.tet.2011.06.021

A sequential one-pot, atom economical three component reaction yielding medicinally promising ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-5-oxo-5,6,7, 8-tetrahydro-4H-chromene-4-carboxylate derivatives (4a-f) through a tandem Michael addition-cyclization reaction starting with structurally diverse cyclohexane-1,3-dione, diethyl acetylene dicarboxylate, and malononitrile has been carried out in different organic bases under solvent free condition for the optimization of maximum yield. All the formed 4H-chromenes were characterized by spectral and X-ray methods.

Full text of DOI:10.1016/j.tet.2011.06.021

Tetrahedron 67 (2011) 6057e6064
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient atom economical one-pot multicomponent synthesis of densely
functionalized 4H-chromene derivatives
,
Muthusamy Boominathan a, Muthupandi Nagaraj a, Shanmugam Muthusubramanian a
*
,
Rajaputi Venkatraman Krishnakumar b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b Department of Physics, Thiagarajar College, Madurai 625009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequential one-pot, atom economical three component reaction yielding medicinally promising ethyl
2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate de-
rivatives (4aef) through a tandem Michael additionecyclization reaction starting with structurally di-
verse cyclohexane-1,3-dione, diethyl acetylene dicarboxylate, and malononitrile has been carried out in
different organic bases under solvent free condition for the optimization of maximum yield. All the
formed 4H-chromenes were characterized by spectral and X-ray methods.
Received 3 March 2011
Received in revised form 6 June 2011
Accepted 9 June 2011
Available online 22 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
(PCO), a great number of 4H-chromene derivatives have been
identified and verified to possess effective relaxant activity on
Highly functionalized 4H-chromenes occur commonly in nu-
merous natural compounds,1,2 showing significant biological ac-
tivities and extensive applications in pharmaceutical uses,3 such as
anticoagulant, spasmolytic, diuretic, antiancaphylactia, and anti-
cancer.4e8 Besides, 4H-chromenes can be employed as cosmetics or
pigments,9,10 and utilized as potential biodegradable agrochemi-
cals.11 These compounds have potential application as cognitive
enhancers for the treatment of neurodegenerative diseases, in-
cluding Alzheimer’s disease, as well as for the treatment of
schizophrenia and myoclonus.1 Chromene pharmacophore can also
serve as useful building blocks in the generation of a variety of
natural products showing molluscicidal, antibacterial, antitumor,
antiallergic, antibiotic, hypolipidemic, and immunomodulating
activities.12e14 Recent SAR studies on 4H-chromene derivatives A
(UCPH-101), B, and C (SV30) (Fig. 1) reveal that they are potential
inhibitors of EAAT1 (Excitatory amino acid transporters), anti-
cancer agent and Bcl-2 inhibitor, respectively.15 Also compounds D
(HA 14-1) and E (Fig. 1) have potent biological activities.1,15 Pyrano
[2,3-b]pyridines and pyrano[2,3-d]pyrimidine derived from 2-
amino-4H-chromenes possess antibacterial and fungicide activ-
ity.16,17 Several 4H-chromene derivatives are useful as photoactive
materials undergoing novel photochemical ring contraction to
cyclobutenes from the triplet state.6,18 Since the discovery of cro-
makalim as a typical ATP-sensitive potassium channel opener
blood vessels, cardiac muscle, and other smooth muscles.
Drugs having 4H-chromene moiety are being used in the
treatment of a number of diseases, such as hypertension, asthma,
ischemia, and urinary incontinence.19e23 4H-Chromene derivatives
are administrated for treating a disorder responsive to the positive
modulation of AMPA receptor in suffering animals.24 The synthesis
of 4H-chromenes by one-pot strategy has been reported using
TMG-[bmim][X] and [2-aemim][PF6] as catalyst25,26 under micro-
wave radiation. Only few reports exist in the literature in which
organic catalysts, for example, tetrabutylammonium fluoride
(TBAF), tetrabutylammonium bromide (TBABr), iodine, (S)-proline,
iminium-allenamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
rare earth perfluorooctanoates, and hexadecyltrimethylammonium
bromide have been employed for the synthesis of 4H-
chromenes.27e31,35c The 4H-chromene moiety could also be
designed by polymer-supported palladacycles with alkenes or
allenes,32 microwave-assisted liquid-phase,33 and solid-phase like
KFealumina.6,7,34 Because of their important use in pharmaceutical,
great effort have been focussed toward developing new synthetic
approaches for the construction of this privileged structure.
2. Results and discussion
As part of our continued interest to achieve high atom economic
reactions, a multicomponent organic base mediated solvent free
synthesis of medicinally promising ethyl 2-amino-3-cyano-4-(2-
ethoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-4-car-
boxylate derivatives (4aef) under one-pot condition by the
* Corresponding author. E-mail address: muthumanian2001@yahoo.com (S.
Muthusubramanian).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.021

6058
M. Boominathan et al. / Tetrahedron 67 (2011) 6057e6064
OMe
OMe
MeO
Br
EtOOC
COOEt
CN
O
Br
CN
CN
O
SV30
NH2
O
NH2
O
NH2
N
C
B
A
OH
OH
CN
EtOOC
CN
Br
COOEt
NH2
O
HN
HA-14-1
N
O
NH2
E
D
Fig. 1. Selected examples of 4H-chromenes with biological and pharmacological activity.
reaction of a variety of cyclohexane-1,3-diones (1aef) with diethyl
acetylenedicarboxylate (2) and malononitrile (3) has been de-
veloped. The reaction mixture was thoroughly ground with cata-
lytic amount (0.3 equiv) of organic base at room temperature and
then heated to 80 ꢀC over a water bath. Rapid formation of 4H-
chromene, yield ranging from 79 to 90% (Table 1), has been noticed
within 30 min under the solvent free condition. All the synthesized
4H-chromene derivatives (4aef) (Scheme 1) are unknown and
completely characterized by spectral and single crystal X-ray
analysis.
We speculate that the anion generated from the malononitrile
(3) by methylamine attacks diethyl acetylenedicarboxylate to give
Michael adduct F. The enolic form of cyclohexane-1,3-dione reacts
with Michael adduct F leading to intermediate G. The migration of
lone pair from oxygen leading to an intramolecular Michael addi-
tionecyclization giving ultimately the 4H-chromene system (4aef).
The sequence of the reactions is presented in Scheme 2.
From the crystal structure (Fig. 2) (see the Supplementary data
for more details, crystal data has CCDC number; CCDC-792844), it
is clear that the methylene carbethoxy and carbethoxy groups are
attached to C-4 of 4H-chromene system. The cyclohexenone ring
has a half-chair/sofa conformation. The spectral data also supports
the assigned structure.
The complete assignment of all hydrogens and carbons is pos-
sible with a set of two dimensional NMR experiments. Fig. 3 shows
all the 2D connectivities between various carbon nuclei.
In the formation of 4b, 4c, and 4d, the reaction is diaster-
eoselective giving one diastereomer in each case. Though single
crystal could not be grown for any of these compounds, the ste-
reochemistry of these compounds can be assumed to the one in
which the substituent at C-7 occupying an equatorial like orienta-
tion and is cis to the carbethoxy group at C-4 as in the crystal
structure of 4f. The influence of the organic base on the MCR-like
transformation has been investigated in detail with 4f and it is
found that methylamine is the catalyst of choice. Triethylamine has
also been found to be ideal, while other bases lead to relatively
lower yields. These findings are summarized in Table 2. The opti-
mized reaction time is 30 min at 80 ꢀC.
The same reaction has been carried out with 4-tert-butylcyclo-
hexanone (1g), in the place of 1,3-diketone. Here again, the reaction
went in the expected direction, but with low yield (42%). The
product formed, ethyl 2-amino-6-tert-butyl-3-cyano-4-(2-ethoxy-
2-oxoethyl)-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate,
(5;
Scheme 3) has been confirmed by spectral data. This reaction shows
that the presence of the second carbonyl group is not essential for
4H-chromenes formation, though the reaction course is definitely
being influenced by the second carbonyl group.
When the malononitrile component in the above reaction is
replaced by other substrates with an active methylene (viz, ethyl
cyanoacetate and ethyl bromoacetate), differently substituted 4H-
chromene skeleton can be expected. Changing one of the compo-
nent in classical reaction of this type is quite common and such
a variation has led to variety of derivatives35 like spiro[acenaph-
thylene-1,10-pyrano[2,3-c]pyrazolo-2-carbonitrile36
Spiro-oxindoles-4H-chromenes,37
derivatives.
2,3-dihydro-4H-chromene-4-
ones, 2,3-dihydro-4-pyridinones,38 bis(4H-chromene), 4H-benzo
[g]chromene,39 N-arylquinoline derivatives,31 annulated 4H-chro-
menes,40 dihydropyrano[4,3-b]pyranes,41 and 4-ferrocenyl-4H-
chromene42 are all prepared by varying one of the component in
classical 4H-chromene synthesis.
When ethyl cyanoacetate was used instead of malononitrile, the
reaction proceeded smoothly yielding diethyl 2-amino-4-(2-
ethoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3,4-di-
carboxylate, (6; Scheme 4). However, when ethyl bromoacetate was
employed in the place of malononitrile, the course of the reaction is
different and the expected 4H-chromenering is not generated. The
product, obtained in trace amount, has been identified as 1,5-
dimethyl pyrrolo[4,3,2-de]quinoline-2,4(1H,5H)-dione (7; Scheme
5) by spectral analysis.
It has been found that 7 is not reported in literature, though this
nucleus itself can be generated from indole derivatives.43 From
Scheme 5, it is clear that ethyl bromoacetate has not participated in
the reaction; rather, the reaction is a multicomponent-like con-
densation involving methylamine. Indeed, a stoichiometric re-
action of 1a and 2 with methylamine delivers 7 in 68% yields.
Unfortunately, when the reaction was carried out with other

M. Boominathan et al. / Tetrahedron 67 (2011) 6057e6064
6059
Table 1
R
O
The isolated yield of 4H-chromene derivatives
NC
R
R
Entry
Substrate
Product
Yield %
B
CN
R
COOEt
NC
3
O
O
HO
COOEt
CN
N
2
1f
F
1
81
R
R
O
O
O
O
NH2
R
R
4a
CN
CN
H
COOEt
O
COOEt
CN
O
NH2
O
O
NH
G
2
83
R
R
R
R
O
NH2
O
O
O
H
4b
CN
CN
COOEt
O
O
NH2
O
NH2
O
COOEt
CN
4f
Scheme 2. Plausible mechanism for the formation of 4.
R=COOEt
3
4
5
79
84
82
O
NH2
O
4c
COOEt
O
O
COOEt
CN
Ph
O
NH2
Ph
O
4d
COOEt
O
O
COOEt
CN
O
O
NH2
4e
COOEt
O
O
COOEt
CN
6
90
O
NH2
O
Fig. 2. ORTEP diagrams of 4f.
4f
primary amines, no fruitful result has been obtained. The reaction
of dimedone, diethyl acetylenedicarboxylate, and methylamine has
also not gone in the expected line with no conversion of the sub-
strates even after considerable time. A possible explanation for the
formation of 7 is depicted in Scheme 6.
COOEt
O
O
We have also studied variation of the alkyne part of the three
component reaction, replacing diethyl acetylenedicarboxylate with
phenylacetylene. Here, it is not a multicomponent reaction, but
a two component reaction with participation of methylamine
yielding 5,5-dimethyl-3-(methylamino)cyclohex-2-enone44 8 in
trace amount (Scheme 7). Clearly, the acetylenic carbon of phenyl
acetylene is not electrophilic enough to undergo attack by the
1,3-diketone anion.
COOEt
CN
EtO
O
N
CH3NH2
neat
R1
R2
R1
R2
O
O
NH2
O
OEt
N
70-80 o
C
R3 R4
4a-f (79 - 90%)
Scheme 1. Formation of 4H-chromene system (4aef).
R3
R4
1a-f
3
2

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M. Boominathan et al. / Tetrahedron 67 (2011) 6057e6064
O
by the third component (Scheme 9). When the reaction was tested
4.07,2H(m)
60.2
with cyclopentane-1,3-dione (1i) under the same conditions, the
methylamine salt of diethyl 2-(2,5-dioxocyclopentyl)maleate (10)
was obtained. In this case, cyclopentane-1,3-dione reacts with
diethyl acetylenedicarboxylate (2) to form 2-(2,5-dioxocyclopentyl)
maleate and the subsequent removal of second hydrogen leads to
carbanion forming an ammonium salt with methylamine
(Scheme 10). This stable carbanion is reluctant to undergo further
reaction as in the case of Scheme 9.
3.05,1H(d)
3.23,1H(d)
O
1.20,3H(t)
14.0
4.72,2H(m)
62.0
170.6
O
O
38.2
1.25,3H(t)
14.1
O
171.0
2.29,2H(s)
111.8
CN
116.8
196.3
42.8
50.7
32.1
60.6
With a linear 1,3-diketone like acetylacetone, diethyl acetylene
dicarboxylate is not incorporated to generate the 4H-chromene
system. Rather only dihydropyridine 1145,46 (Scheme 11) has been
obtained in trace. While using the calculated moles of methyl-
amine, we got 76% of 11.
28.0
1.13,3H (s)
158.8
NH2
162.9
O
4.89,2H(s)
27.9
1.10,3H(s)
40.6
2.39,1H(d)
2.48,1H(d)
3. Conclusion
In summary, an atom economic method for the synthesis of
highly substituted 4H-chromene derivatives in high yield has been
developed. This is the first report to generate 4H-chromene from
acetylene precursors. The reaction condition has been optimized
with different bases. The final products have many reactive sites
and may serve as useful synthons to construct additional rings. The
scope of the reaction has been explored by varying the different
components of this multicomponent reaction and the results have
been summarized.
Fig. 3. HMBC correlation with 1H and 13C NMR of 4f (Rose and green arrows show two
and three bond connectivities, respectively).
Table 2
Screening of base on reaction for the preparation of 4f
Entry
Base
Yield of 4f (%)
1
2
3
4
5
6
7
Methylamine
Benzylamine
Triethylamine
Pyrrolidine
Piperidine
DBU
90
83
88
80
76
78
74
4. Experimental section
4.1. General
DABCO
Melting points were measured in open capillary tubes and are
uncorrected. The 1H NMR, 13C NMR, DEPT, H,H-COSY, C,H-COSY, and
HMBC spectra were recorded on a Bruker (Avance) 300 MHz NMR
instrument using TMS as internal standard and DMSO-d6 as sol-
vent. Standard Bruker software was used throughout. Chemical
COOEt
O
EtO
O
N
COOEt
CN
CH3NH2
neat
70-80 oC
O
O
NH2
OEt
N
3
shifts are given in parts per million (d scale) and the coupling
1g
5
2
constants are given in Hertz. Infrared spectra were recorded on an
SHIMADZU FT IR instrument (in KBr pellet). Band positions are
reported in reciprocal centimeters (cmꢁ1). Silica gel-G plates
(Merck) were used for TLC analysis with a mixture of petroleum
ether (60e80 ꢀC) and ethyl acetate as eluent. Elemental analyses
were performed on a PerkineElmer 2400 Series II Elemental CHNS
analyzer.
Scheme 3. Reaction of 2 and 3 with 1g.
COOEt
COOEt
EtO
O
O
O
O
COOEt
COOEt
CH3NH2
neat
4.2. General procedure for the synthesis of ethyl 2-amino-3-
cyano-4-(2-ethoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-4-carboxylate derivatives (4)
N
70-80 o
C
O
NH2
O
OEt
84%
6
1a
2
Scheme 4. Reaction of 1a and 2 with ethyl cyanoacetate.
To a mixture of cyclic 1,3-dione (7.1 mmol), diethyl acetylene
dicarboxylate (7.1 mmol), and malononitrile (7.1 mmol) was added
methylamine (2.1 mmol) dropwise at room temperature. The re-
action mixture was thoroughly ground and heated to 80 ꢀC for
30 min. Then molten mass was allowed to cool to room tempera-
ture and the resulting mixture was poured into water and the
product was extracted with a minimum amount of chloroform,
dried over sodium sulfate and crystallized in 3:2 chloroform/ethyl
acetate to yield pure derivative of ethyl 2-amino-3-cyano-4-(2-
ethoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-4-car-
boxylate (4). Spectroscopic data for all the compounds are given
below.
N
O
EtO
O
O
O
COOEt
Br
CH3NH2
neat
O
70-80 o
C
OEt
N
O
1a
2
7
Scheme 5. Formation of pyrroloquinoline-2,4-dione 7.
When the 1,3-diketone taken is indane-1,3-dione, again the re-
action is a not a multicomponent reaction, but a two component one
yielding diethyl 4-oxo-4H-indeno[1,2-b]furan-2,3-dicarboxylate 9
(Scheme 8). The internal cyclization seems to be preferred to attack
4.2.1. Ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-4-carboxylate (4a). The title compound
was prepared according to general procedure in Section 4.2 using
cyclohexane-1,3-dione. The resulting mixture was poured into

M. Boominathan et al. / Tetrahedron 67 (2011) 6057e6064
6061
EtOOC
O
O
O
O
O
EtO
O
O
CH3NH2
-EtOH
O
NH
O
N
1a
OEt
OEt
H
N
COOEt
CH3NH2
O
COOEt
O
H
O
O
O
N
N
N
N
O
N
O
air oxidation
-EtOH
N
N
O
O
7
Scheme 6. Proposed mechanism for the formation of 7.
H
(2H, m, CH2), 2.58 (2H, t, J¼6 Hz, CH2), 3.05 (1H, d, J¼16.2 Hz,
CHaHbCOOEt), 3.18 (1H, d, J¼15.9 Hz, CHbHaCOOEt), 4.07 (2H, m,
CH2), 4.17 (2H, m, CH2), 5.15 (2H, s, NH2); 13C NMR (75 MHz, CDCl3)
O
O
N
CH3NH2
neat
d
13.9, 14.0, 19.9, 26.9, 36.7, 38.5, 42.9, 59.9, 60.2, 62.0, 112.8, 116.8,
70-80 o
C
158.8, 164.6, 170.5, 171.2, 196.2; m/z (ESþ) ([MþH]þ) found 349.4.
Ph
O
N
N
H
C17H20N2O6 requires 348.1.
8
3
1f
4.2.2. Ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-7-methyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate (4b). The title
compound was prepared according to general procedure in Section
4.2 using 5-methylcyclohexane-1,3-dione. The resulting mixture
was poured into water and the product was extracted with a min-
imum amount of chloroform, dried over sodium sulfate and the
crude product was purified by crystallization in 3:2 chloroform/
ethyl acetate as colorless solid; mp 178e180 ꢀC; [Found: C, 59.62; H,
6.10; N, 7.68, C18H22N2O6 requires C, 59.66; H, 6.12; N, 7.73]; IR (KBr,
Scheme 7. Reaction of 1f and 3 with phenyl acetylene.
O
O
O
EtO
O
O
N
CH3NH2
COOEt
COOEt
neat
70-80 oC
OEt
N
O
78%
2
9
3
1h
Scheme 8. Reaction of indane-1,3-dione with 2 and 3.
pellet) 3373, 3203, 2981, 1724 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
1.11 (3H, m, CHCH3), 1.23 (6H, m, 2ꢂ CH3), 2.21 (1H, m, CHCH3),
2.32 (2H, m, CH2), 2.53 (2H, m, CH2), 3.06 (1H, d, J¼16.2 Hz,
CHaHbCOOEt), 3.18 (1H, d, J¼15.9 Hz, CHbHaCOOEt), 4.07 (2H, m,
CH2), 4.18 (2H, m, CH2), 5.04 (2H, s, NH2); 13C NMR (75 MHz, CDCl3)
water and the product was extracted with a minimum amount of
chloroform, dried over sodium sulfate and the crude product was
purified by crystallization in 3:2 chloroform/ethyl acetate as col-
orless solid; mp 118e120 ꢀC; [Found: C, 58.57; H, 5.77; N, 8.01,
C17H20N2O6 requires C, 58.61; H, 5.79; N, 8.04]; IR (KBr, pellet) 3325,
d
13.9, 14.0, 20.3, 27.6, 34.9, 38.2, 38.6, 44.8, 60.2, 60.4, 62.0, 112.5,
116.8, 158.8, 163.9, 170.5, 171.1, 196.1.
3199, 2966, 1735 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.21 (3H, t,
4.2.3. Ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-7-ethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate (4c). The title
J¼3.6 Hz, CH3), 1.25 (3H, t, J¼5.7 Hz, CH3), 2.23 (2H, m, CH2), 2.43
O
O
O
O
O
O
H
COOEt
COOEt
OEt BH+
-:B
COOEt
COOEt
-BH+
EtO
O
O
H
O
O
BH+
-:B
COOEt
COOEt
COOEt
COOEt
air oxidation
O
O
9
Scheme 9. Proposed mechanism for the formation of 9.

6062
M. Boominathan et al. / Tetrahedron 67 (2011) 6057e6064
O
CHbHaCOOEt), 4.07 (2H, m, CH2), 4.20 (2H, m, CH2), 5.05 (2H, s,
NH2); 13C NMR (75 MHz, CDCl3) 13.9, 14.0, 23.7, 24.1*, 33.3, 38.6,
O
EtO
O
N
d
CH3NH3
COOEt
CH3NH2
40.5, 43.2, 60.1, 60.4, 61.8, 111.1, 116.8, 158.8, 162.6, 170.6, 171.1,
200.9.
neat
70-80 oC
COOEt
O
OEt
N
O
1i
89%
O
4.2.6. Ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate
(4f). The title compound was prepared according to general pro-
cedure in Section 4.2 using 5,5-dimethylcyclohexane-1,3-dione.
The resulting mixture was poured into water and the product was
extracted with a minimum amount of chloroform, dried over so-
dium sulfate and the crude product was purified by crystallization
in 3:2 chloroform/ethyl acetate as colorless solid; mp 238e239 ꢀC;
[Found: C, 60.57; H, 6.39; N, 7.40. C19H24N2O6 requires C, 60.63; H,
6.43; N, 7.44]; IR (KBr, pellet) 3319, 3253, 2970, 1732 cmꢁ1; 1H NMR
10
2
3
Scheme 10. Reaction with cyclopentane-1,3-dione (1i).
COOEt
O
O
COOEt
CN
CN
CH3NH2
2
3
neat
70-80 oC
N
H
O
(300 MHz, CDCl3)
d 1.10 (3H, s, CH3), 1.13 (3H, s, CH3), 1.20 (3H, t,
O
NH2
O
J¼6.6 Hz, CH3), 1.25 (3H, t, J¼6.4 Hz, CH3), 2.29 (2H, s, CH2), 2.39
(1H, d, J¼17.7 Hz, CHaHb), 2.48 (1H, d, J¼17.7 Hz, CHbHa), 3.09 (1H, d,
J¼16.5 Hz, CHaHbCOOEt), 3.23 (1H, d, J¼16.5 Hz, CHaHbCOOEt), 4.07
(2H, m, CH2), 4.20 (2H, m, CH2), 4.72 (2H, s, NH2); 13C NMR (75 MHz,
11
1j
Scheme 11. Formation of dihydropyridine 11.
CDCl3)
d 14.0, 14.1, 27.9, 28.0, 32.1, 38.2, 40.6, 42.8, 50.7, 60.2, 60.6,
compound was prepared according to general procedure in Section
4.2 using 5-ethylcyclohexane-1,3-dione. The resulting mixture was
poured into water and the product was extracted with a minimum
amount of chloroform, dried over sodium sulfate and the crude
product was purified by crystallization in 3:2 chloroform/ethyl
acetate as colorless solid; mp 120e122 ꢀC; [Found: C, 60.59; H,
6.40; N, 7.41.C19H24N2O6 requires C, 60.63; H, 6.43; N, 7.44]; IR (KBr,
62.0, 111.8, 116.8, 158.8, 162.9, 170.6, 171.0, 196.3; m/z (ESþ)
([MþH]þ) found 377.4. C19H24N2O6 requires 376.1.
4.2.7. Ethyl 2-amino-6-tert-butyl-3-cyano-4-(2-ethoxy-2-oxoethyl)-
5,6,7,8-tetrahydro-4H-chromene-4-carboxylate (5). The title com-
pound was prepared according to general procedure in Section 4.2
using 4-tert-butylcyclohexanone. The resulting mixture was
poured into water and the product was extracted with a minimum
amount of chloroform, dried over sodium sulfate and the crude
product was purified by crystallization in 3:2 chloroform/ethyl
acetate as colorless solid; mp 156e158 ꢀC; IR (KBr, pellet) 3365,
pellet) 3375, 3249, 2981, 1734 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
0.94 (3H, t, J¼7.3 Hz, CH3), 1.27 (6H, m, 2ꢂ CH3), 1.46 (2H, m, CH2),
2.14 (2H, m, CH2), 2.36 (1H, m, CH), 2.53 (2H m, CH2), 3.08 (1H, d,
J¼16.2 Hz, CHaHbCOOEt), 3.19 (1H, d, J¼16.2 Hz, CHbHaCOOEt), 4.06
(2H, m, CH2), 4.18 (2H, m, CH2), 4.91 (2H, s, NH2); 13C NMR (75 MHz,
3180, 2970, 1718 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
0.85 (9H, s, 3ꢂ
CDCl3)
d
11.2, 14.3, 14.5, 28.2, 30.0, 34.5, 34.6, 39.0, 43.3, 60.6, 61.6,
CH3), 1.30 (6H, m, 2ꢂ CH3), 1.70e2.45 (m, 7H, 3ꢂ CH2, CH), 2.95 (1H,
d, J¼15.9 Hz, CHaHbCOOEt), 3.42 (1H, d, J¼15.9 Hz, CHbHaCOOEt),
4.25 (4H, m, 2ꢂ CH2), 5.50 (2H, s, NH2); 13C NMR (75 MHz, CDCl3)
62.4, 113.2, 117.0, 159.1, 164.4, 170.9, 171.4, 196.4.
4.2.4. Ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-5-oxo-7-
phenyl-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate (4d). The ti-
tle compound was prepared according to general procedure in
Section 4.2 using 5-phenylcyclohexane-1,3-dione. The resulting
mixture was poured into water and the product was extracted with
a minimum amount of chloroform, dried over sodium sulfate and
the crude product was purified by crystallization in 3:2 chloroform/
ethyl acetate as colorless solid; mp 137e139 ꢀC; [Found: C, 65.03; H,
5.67; N, 6.58. C23H24N2O6requires C, 65.08; H, 5.70; N, 6.60]; IR (KBr,
d
13.6, 13.7, 22.7, 26.9*, 27.6, 28.9, 32.2, 36.7, 44.4, 55.1, 61.6, 62.7,
62.9, 115.0, 120.5, 127.9, 144.1, 166.5, 168.2.
4.2.8. Diethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3,4-dicarboxylate (6). The title com-
pound was prepared according to general procedure in Section 4.2
using cyclohexane-1,3-dione. The resulting mixture was poured
into water and the product was extracted with a minimum amount
of chloroform, dried over sodium sulfate and the crude product was
purified by crystallization in 3:2 chloroform/ethyl acetate as col-
orless solid; yield 84%; mp 127e129 ꢀC; [Found: C, 57.67; H, 6.33; N,
3.45. C19H25NO8 requires C, 57.71; H, 6.37; N, 3.54]; IR (KBr, pellet)
pellet) 3392, 3213, 2981, 1725 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
1.24 (6H, m, 2ꢂ CH3), 2.27 (4H, m, 2ꢂ CH2), 3.12 (1H, d, J¼16.2 Hz,
CHaHbCOOEt), 3.20 (1H, d, J¼16.2 Hz, CHbHaCOOEt), 3.40 (1H, m,
CH), 4.09 (2H, m, CH2), 4.18 (2H, m, CH2), 4.97 (2H, s, NH2), 7.31 (5H,
3373, 3230, 2983, 1730 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.17 (3H,
m, ArH); 13C NMR (75 MHz, CDCl3)
d
13.9, 14.0, 34.4, 37.9, 38.6, 43.0,
t, J¼6.3 Hz, CH3), 1.27 (6H, m, 2ꢂ CH3), 2.01 (2H, m, CH2), 2.40 (2H,
m, CH2), 2.55 (2H, t, J¼6.3 Hz, CH2), 3.05 (1H, d, J¼15.3 Hz,
CHaHbCOOEt), 3.25 (1H, d, J¼15.3 Hz, CHbHaCOOEt), 4.14 (6H, m, 3ꢂ
43,7, 60.2, 60.4, 62.1, 112.7, 116.6, 126.5*, 127.3, 128.8*, 141.5, 158.8,
163.8, 170.5, 171.0, 195.2.
CH2), 6.54 (2H, s, NH2); 13C NMR (75 MHz, CDCl3) 13.8, 14.2*, 19.8,
d
4.2.5. Ethyl 2-amino-3-cyano-4-(2-ethoxy-2-oxoethyl)-8,8-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-4-carboxylate
(4e). The title compound was prepared according to general pro-
cedure in Section 4.2 using 4,4-dimethylcyclohexane-1,3-dione.
The resulting mixture was poured into water and the product was
extracted with a minimum amount of chloroform, dried over so-
dium sulfate and the crude product was purified by crystallization
in 3:2 chloroform/ethyl acetate as colorless solid; mp 238e240 ꢀC;
[Found: C, 60.61; H, 6.38; N, 7.39. C19H24N2O6 requires C, 60.63; H,
6.43; N, 7.44]; IR (KBr, pellet) 3365, 3319, 2970, 1729 cmꢁ1; 1H NMR
27.2, 37.3, 39.0, 43.6, 59.6, 59.8, 61.0, 78.4, 115.3, 158.8, 164.1, 168.2,
171.5, 173.5, 196.2.
4.2.9. 1,5-Dimethylpyrrolo[4,3,2-de]quinoline-2,4(1H,5H)-dione
(7). The title compound was obtained by the general procedure in
Section 4.2 using cyclohexane-1,3-dione. The resulting mixture was
poured into water and the product was extracted with a minimum
amount of chloroform, dried over sodium sulfate and the crude
product was purified by crystallization in 3:2 chloroform/ethyl
acetate as colorless solid; mp 212e214 ꢀC; [Found: C, 67.24; H, 4.68;
N, 13.05. C12H10N2O2 requires C, 67.28; H, 4.71; N, 13.08]; IR (KBr,
(300 MHz, CDCl3)
d 1.10 (3H, s, CH3), 1.11 (3H, s, CH3), 1.23 (6H, m,
2ꢂ CH3), 1.86 (2H, t, J¼6.4 Hz, CH2), 2.58 (2H, t, J¼6.4 Hz, CH2), 3.05
pellet) 3137, 3230, 2939, 1728 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
(1H, d, J¼15.9 Hz, CHaHbCOOEt), 3.16 (1H, d, J¼16.2 Hz,
d
3.34 (3H, s, NCH3), 3.68 (3H, s, NCH3), 6.65 (1H, d, J¼8.4 Hz, ArH),

M. Boominathan et al. / Tetrahedron 67 (2011) 6057e6064
6063
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6.95 (1H, d, J¼8.4 Hz, ArH), 7.14 (1H, s, CH), 7.51 (1H, t, J¼8.4 Hz,
ArH); 13C NMR (75 MHz, CDCl3)
26.6, 29.6, 102.2, 107.9, 108.9,
119.3, 133.5, 136.7, 137.1, 141.4, 163.8, 165.7.
d
4.2.10. 5,5-Dimethyl-3-(methylamino)cyclohex-2-enone (8). White
solid; mp 154e156 ꢀC (lit.153e154 ꢀC);44 1H NMR (300 MHz, CDCl3)
11,
d
1.06 (6H, s, 2ꢂ CH3), 2.17 (2H, s, CH2), 2.21 (2H, s, CH2), 2.80 (3H, d,
J¼4.5 Hz, NCH3), 5.07 (1H, s, CH), 5.67 (1H, s, NH); 13C NMR
(75 MHz, CDCl3)
d
28.2*, 29.5, 32.7, 43.2, 50.2, 94.8, 164.3, 196.7.
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4.2.11. Diethyl 4-oxo-4H-indeno[1,2-b]furan-2,3-dicarboxylate
(9). The title compound was obtained by the general procedure
in Section 4.2 using cyclohexane-1,3-dione. The resulting mixture
was poured into water and the product was extracted with a min-
imum amount of chloroform, dried over sodium sulfate and the
crude product was purified by crystallization in 3:2 chloroform/
ethyl acetate as colorless solid; yield 78%; mp 157e159 ꢀC; [Found:
C, 64.94; H, 4.45. C17H14O6 requires C, 64.97; H, 4.49]; IR (KBr,
pellet) 3421,1749,1706,1687,1429 cmꢁ1; 1H NMR (300 MHz, CDCl3)
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d
1.35 (3H, t, J¼7.2 Hz, CH3), 1.44 (3H, t, J¼7.2 Hz, CH3), 4.35 (2H, q,
J¼7.2 Hz, CH2), 4.51 (2H, q, J¼7.2 Hz, CH2), 7.49 (1H, t, J¼7.5 Hz, ArH),
7.59 (1H, t, J¼7.5 Hz, ArH), 7.70 (1H, d, J¼7.5 Hz, ArH), 8.18 (1H, d,
J¼7.5 Hz, ArH); 13C NMR (75 MHz, CDCl3)
d
13.7, 13.8, 62.0, 62.1,
106.1, 114.6, 119.1, 122.9, 124.1, 132.1, 134.5, 135.7, 138.9, 151.3, 156.2,
165.8, 187.5.
4.2.12. Methanaminium
2,5-dioxocyclopentan-1-ide (10). Yield 89%; white solid; 1H NMR
(300 MHz, DMSO-d6)
1.30 (6H, m, CH3), 2.17 (4H, s, 2ꢂ CH2), 2.49
(3H, s, CH3), 4.04 (2H, q, CH2), 4.21 (2H, q, CH2), 6.97 (1H, s, CH), 7.69
(3H, s, NH3); 13C NMR (75 MHz, DMSO-d6)
14.2, 14.7, 23.9, 33.9,
1-(1,4-diethoxy-1,4-dioxobut-2-en-2-yl)-
d
d
58.6, 59.5, 100.7, 105.6, 145.4, 167.6, 169.0, 199.4.
4.2.13. 4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile
(11). White solid; mp 287e289 ꢀC (lit. 285e286 ꢀC);45,46 1H NMR
(300 MHz, DMSO-d6) d 2.29 (3H, s, CH3), 2.37 (3H, s, CH3), 6.03 (1H,
s, CH); 13C NMR (75 MHz, DMSO-d6)
d 18.1, 19.8, 99.0, 106.7, 114.6,
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149.5, 159.1, 160.6.
*One carbon has merged with other.
24. Konkoy, C. S.; Fick, D. B.; Cai, S. X.; Lan, N. C.; Keana, J. F. W. U.S. Patent
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The authors thank DST, New Delhi for assistance under the
IRHPA program for the NMR facility. We thank School of Physics,
Madurai Kamaraj University, for the single crystal X-ray analyses.
Financial support from UGC, New Delhi to M.B. is gratefully ac-
knowledged for the award of a junior Research Fellowship.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.06.021.
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