Group-assisted purification (GAP) chemistry for dihydrofurans: Water as a medium for catalyst free synthesis in a one pot four component reaction

Article abstract of DOI:10.1039/c4gc00388h

A simple, catalyst free, water mediated, one pot four component, green protocol was developed for title compounds 7 starting from aromatic aldehydes (1), malononitrile (2), 1,3-diones (3) and N-chlorosuccinimide (NCS) in a sequential addition reaction at

Full text of DOI:10.1039/c4gc00388h

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Group-assisted purification (GAP) chemistry for
dihydrofurans: water as a medium for catalyst free
synthesis in a one pot four component reaction†
Cite this: Green Chem., 2014, 16,
3237
Madhu Chennapuram,a Narender Reddy Emmadi,a Chiranjeevi Bingi,a
Jagadeesh Babu Nanubolub and Krishnaiah Atmakur*a,c
A simple, catalyst free, water mediated, one pot four component, green protocol was developed for title
compounds 7 starting from aromatic aldehydes (1), malononitrile (2), 1,3-diones (3) and N-chlorosuccini-
mide (NCS) in a sequential addition reaction at ambient temperature. The approach presented herein, for
the first time, is through an unusual rearrangement where NCS was reacted with 2-amino-7,7-dimethyl-
5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4), which was formed by the Knoevenagel
condensation of aldehyde and malononitrile followed by the Michael addition of 3. In addition, this novel
protocol is compatible with various aldehydes and active C–H functional derivatives, accomplishes high
yields and follows the GAP chemistry principle. Interestingly, compound 4 when reacted with NCS in
alcohol medium gave 2-cyano-6,6-dimethyl-4-oxo-3-aryl-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxy-
late (5).
Received 5th March 2014,
Accepted 2nd April 2014
DOI: 10.1039/c4gc00388h
www.rsc.org/greenchem
interrupted Feist–Benary reaction.15 However, most of the
strategies require using a base or a metal catalyst and an
Introduction
In modern heterocyclic chemistry furan scaffolds occupy a pro-
minent position principally because of their presence in many
natural products and biologically active compounds.1 Among
this class of compounds, dihydrofurans are one of the impor-
tant compounds commonly found in a large variety of natu-
rally occurring substances.2 Furthermore, dihydrofurans are
subunits of a range of biologically active compounds3 and also
serve as extremely important intermediates in organic syn-
thesis4 as they can be transformed into an array of highly func-
tionalized tetrahydrofurans.5 In fact, a number of synthetic
strategies have been reported6,7 for synthesis of functionalized
dihydrofuran derivatives including the Feist–Benary and the
interrupted Feist–Benary (FB) reaction,8 CAN mediated oxi-
dative cycloaddition of 1,3-dicarbonyls to conjugated com-
pounds,9 DABCO promoted reaction of pyridinium salts with
enones,10,11 olefin metathesis,12 Pd catalyzed coupling–cycliza-
tion of 2-(2′,3′-allenyl)acetylacetates,13 copper catalyzed asym-
metric cycloaddition,14 and the ionic liquid promoted
organic solvent and follow a traditional approach. Usually, tra-
ditional organic syntheses adopt a “stop-and-go” approach,
which involves the purification of intermediates to avoid the
compatibility issues of the consecutive reactions.
On the other hand, purification processes are often time
consuming and expensive. In addition, organic solvents con-
tribute the lion’s share to the pollution problem in practical
organic synthesis.16 In this instance, water is the solvent of
choice as an ideal organic reaction demands that it would
proceed neat, that is, without any solvent or preferably in an
environmentally benign solvent such as water. Moreover, water
is considered as a cheap, safe, natural, non-flammable, environ-
mentally benign and abundantly available green solvent.17
Additionally, multicomponent reactions (MCRs) effectively
answer the issues of traditional approaches and have become
an increasingly powerful tool18 in organic, combinatorial and
medicinal chemistry because of their atom economy, conver-
gence, multiple bond forming efficiency19 and other suitable
characteristics from the green chemistry point of view.20 These
features make MCRs well suited for easy construction of diver-
sified heterocyclic scaffolds.21 With this background, and also
as a part of our research programme on the synthesis of bio-
active molecules in a multicomponent one pot reaction,22
herein we report the synthesis of functionalized 2,3-dihydro-
furans for the first time by a green, novel and efficient, water
mediated, catalyst free one pot four component reaction.
aDivision of Crop Protection Chemicals, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500 007, India
bLaboratory of X-ray crystallography, CSIR-Indian Institute of Chemical Technology,
Tarnaka, Hyderabad 500 007, India
cAcSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
E-mail: srikrishnua@yahoo.com; Fax: +91 40 27193382; Tel: +91 40 27191436
†CCDC 979361 and 982398. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4gc00388h
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Results and discussion
Before embarking on preparation of the title compounds 7 by
water mediated reaction, 2-amino-7,7-dimethyl-5-oxo-4-phenyl-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4) was prepared
in higher yield (84%) by reacting benzaldehyde (1), malono-
nitrile (2) and 5,5-dimethylcyclohexane-1,3-dione (3) in water
at reflux temperature (Scheme 1).23
In an effort to construct further a ring system over 4, it was
treated with N-chlorosuccinimide (NCS) in ethanol at room
temperature (Table 1) and ethyl 2-cyano-6,6-dimethyl-4-oxo-
3-phenyl-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5a)
was obtained in high yields within 0.5 h. Surprised over the
unusual formation of the ring contraction product 5a in con-
trast to a similar literature report,24 the same reaction was
repeated in methanol and gratifyingly obtained a methyl ester
(5b). The structure of 5 was well characterized by NMR and
mass spectra. However, IR spectra indicated a very low intense
signal for the –CN functional group. Finally, the structure of a
representative compound 5h was unambiguously confirmed by
single crystal X-ray diffraction analysis (Fig. 1).
Fig. 1 ORTEP diagram of compound 5h.25
peroxide (TBHP) in combination with sodium chlorite. It is
interesting to mention that the reaction with NBS (Table 1,
entry 2) resulted in formation of two products, i.e. 5a (50%)
and 6a (33%), whereas with NIS (Table 1, entry 3), compound
6b was obtained in poor yields. However, reaction with I2
(Table 1, entry 4) afforded 5a in 33%, whereas the reaction of 4
with sodium chlorite independently, as well as in combination
with TBHP and also with sodium hypochlorite, at ambient
and reflux temperature could not give any product. With
these results in hand, the NCS reaction was further
studied using n-propanol, isopropanol, n-butanol, and isobuta-
nol as the solvent and obtained the corresponding esters
(5c–f). Furthermore, this method was generalised by reacting
different chromenes 4 with NCS, varying substitution on the
phenyl ring, in ethanol and the results 5g–m are shown in
Table 2.
In order to establish the optimum reaction conditions for
5, catalyst screening studies were conducted in ethanol at
room temperature employing NBS, NIS, I2 and sodium chlo-
rite, and sodium hypochlorite and aqueous tert-butyl hydro-
At this stage, attention was directed to treat compound 4
with NCS in water as a solvent presuming to yield a carboxylic
acid 8 instead of an ester 5.
Scheme 1
Accordingly compound 4 was treated with NCS (1 equiv.) in
water at room temperature and surprisingly 7 was obtained, at
variance with the expected product in 7 h (Scheme 2).
However, 1.2 equivalents of NCS could bring down the
reaction time to 3 h. Having obtained compound 7 in water
mediated reaction, we next scrutinized the solvent ratio in
combination with 25% and also with 50% ethanolic water
independently and obtained the combination of products 5
and 7 in 30%, 35% and 29%, and 42% yields respectively.
Similar yields were also observed with 25% and 50% methano-
lic water.
Table 1 Optimization of reaction conditionsa
Product
Entry
Reagent
Time (h)
5a (%)
6 (%)
The structure of 7 was confirmed by NMR, IR, and mass
spectroscopy and also by X-ray crystallography analyses
(Fig. 2). Next, our studies were directed to prepare 7 by four
component one pot reaction in water. Thus a model reaction
was attempted with benzaldehyde (1) (1 mmol), malononitrile
(2) (1 mmol), and dimedone (3) (1 mmol) in water at reflux
temperature followed by NCS (1.2 mmol) in sequential
addition at ambient temperature. Amazingly, this reaction
resulted in product 7 in high yields (Table 3).
1
2
3
4
5
6
7
NCS
NBS
NIS
I2
NaClO2
NaOCl
NaClO2–TBHP
0.5
1.0
1.0
1.0
6.0
6.0
6.0
79
50
—
33
—
—
—
—
33 (6a: X = Br)
20 (6b: X = I)
—
—
—
—
a Unless otherwise indicated, the reaction was performed by treating 4
(1.7 mmol) and the corresponding reagent (1.7 mmol) in ethanol at
room temperature.
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Table 2 Scope of alcohols and the
synthesize compound 5a
R
functional group on
4
to
Table 2 (Contd.)
Entry
9
R
Alcohol
Ethanol
Product (5)
Yieldb (%)
80
Entry
1
R
Alcohol
Ethanol
Product (5)
Yieldb (%)
79
4-NO2
H
2
3
4
5
6
7
H
Methanol
n-Propanol
Isopropanol
n-Butanol
Isobutanol
Ethanol
70
72
62
58
68
69
10
11
3-OPh
2-CF3
Ethanol
Ethanol
65
63
H
H
12
13
4-OMe
Ethanol
Ethanol
69
71
H
4-Me
H
a Unless otherwise indicated, the reaction was performed with
compound 4 (1.7 mmol) and NCS (1.7 mmol) in the corresponding
alcohol at room temperature open to air for 0.5 h. b Yields are given for
isolated products.
4-F
Captivated by the exceptional formation of 7 in a water
mediated, four component, one pot, catalyst free, eco-friendly
reaction in high yields, the generality and scope of this proto-
col were demonstrated by synthesizing a series of dihydrofuran
derivatives (7aa–7am & 7b–d). A wide range of aldehydes
including an aliphatic aldehyde (7am) and different active C–H
functional derivatives such as 3a, 3b, and 3c were well toler-
ated under this set of reaction conditions and furnished 7 in
good yields (Table 4). Pure products were obtained by simple
filtration and washed with water and hexanes. It is noteworthy
8
4-Br
Ethanol
76
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Table 3 Scope of aldehydes to synthesize compound 7a,b
Scheme 2
Fig. 2 ORTEP diagram of compound 7aa.25
that this protocol followed the GAP chemistry process, which
avoids traditional purification methods such as column
chromatography and recrystallization.
Furthermore, compound 7 was subjected to hydrolysis with
concentrated HCl and also with sulphuric acid to get an acid
8. However, these studies were unsuccessful. In the light of
sequential formation of 4, followed by the unexpected ring
contraction product 7 in one pot reaction, a plausible mechan-
ism has been proposed for the title compounds. As per the
established chemistry, the reaction begins with the formation
of the Knoevenagel product A followed by the Michael addition
of C–H functional derivatives leading to B which on intramole-
cular cyclization followed by a 1,3 proton shift provides the
a Unless otherwise indicated, the reaction was performed with
aldehyde 1 (3.7 mmol), malononitrile 2 (3.7 mmol) and dimedone 3
(3.7 mmol) in water (40 mL) at reflux temperature for 3 h followed by
addition of NCS (4.5 mmol) at RT and stirred for 3 h. b Yields are given
for isolated pure products.
evidence for the proposed mechanism. On the other hand, for-
mation of 5 is presumably attributable to the hydrolysis of
aminonitrile compound (4). This, on treatment with NCS gives alkoxyimine (similar to E) due to the increase in acidity during
C, which on C–O bond dissociation propelled by water, leads
to intermediate D. Then the subsequent attack of the hydroxyl
the course of the reaction, as the pH of the alcoholic medium
changed from 4.95 (before addition of NCS) to 1.23 on
functional group on nitrile carbon and elimination of HCl completion of the reaction and also there was no possibility
facilitate the formation of the five member ring E, which tauto-
merises to the desired product 7.
for tautomerism. A similar situation was observed in water
mediated reaction of 7, where the pH changed from 5.02
Furthermore, the presence of succinimide protons at 9.32 to 1.60 at the end of the reaction. Nevertheless, the possible
and 2.75 ppm in the 1H NMR spectrum of the crude product 7,
which had disappeared on washing with water and hexanes, is
tautomerism of hydroxy imine
(Scheme 3).
E probably leads to 7
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Table 4 Scope of active methylene compounds to synthesize 7a
pot four component reaction following GAP chemistry. High
yields and compatibility are the added advantages of this pro-
tocol which can be exploited further.
Experimental section
General
Entry
1
3
Product 7
Yield (%)
69
Melting points were measured by CINTEX programmable
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra of samples in CDCl3 and DMSO-d6 were recorded on
AVANCE-300 MHz and 500 MHz spectrometers. Chemical
shifts (δ) are reported relative to TMS (δ = 0.0) as the internal
standard. Mass spectra were recorded on ESI spectrometers.
All high resolution mass spectra were recorded on the QSTAR
XL Hybrid MS/MS System (Applied Biosystems/MDS Sciex, Foster
City, USA), equipped with an ESI source (IICT, Hyderabad). IR
were recorded on Thermo Nicolet nexus 670 spectrometer using
KBr pellets. pH of the reaction medium was recorded on an EI
digital pH meter (model no. 112) using standardised buffers
4 and 9. TLC was performed on Merck 60 F-254 silica gel plates.
The chemicals used in this work were obtained from commer-
cial channels and were used without purification.
2
3
58
52
a Unless otherwise indicated, the reaction conditions are the same as
in Table 3.
General procedure for the preparation of ethyl 2-cyano-6,6-
dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexahydrobenzofuran-2-
carboxylate (5)
To
a suspension of 2-amino-7,7-dimethyl-5-oxo-4-phenyl-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4) (500 mg,
1.7 mmol) in 5 mL of ethanol in a round bottomed flask was
added N-chlorosuccinimide (226 mg, 1.7 mmol) and the
homogeneous solution was stirred at room temperature, open
to air. After completion of the reaction as indicated by TLC,
the separated solid was filtered, washed with (2 × 2 mL) cold
ethanol and dried to yield the pure product 5.
Ethyl 2-cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexa-
hydrobenzofuran-2-carboxylate (5a). Isolated as a yellow solid;
yield 79%; m.p. 110–112 °C; IR (KBr): 3002, 2963, 2937, 2274,
1764, 1660, 1387, 1230, 1126, 1036, 971, 730, 700 cm−1 1H
;
NMR (500 MHz, CDCl3): δ 7.42–7.33 (m, 3H), 7.20 (d, J = 8.24
Hz, 2H), 4.71 (s, 1H), 4.44–4.35 (m, 2H), 2.62–2.50 (m, 2H),
2.34–2.22 (m, 2H), 1.38 (t, J = 7.17 Hz, 3H), 1.22 (s, 3H), 1.16 (s,
3H) ppm; 13C NMR (125 MHz, CDCl3): δ 193.0, 175.0, 164.0,
135.2, 129.0, 128.0, 113.3, 112.4, 85.4, 64.3, 55.2, 51.0, 37.1,
34.2, 28.5, 28.4, 14.0 ppm; ESI-MS: m/z 340 [M + H]+; HRMS
(ESI) Anal. calcd for C20H22NO4 m/z 340.1543 [M + H]+, found
340.1585.
Scheme 3 Plausible reaction mechanism for compound 7.
Methyl 2-cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexa-
hydrobenzofuran-2-carboxylate (5b). Isolated as a colourless
solid; yield 70%; m.p. 125–127 °C; IR (KBr): 3027, 2961, 2932,
2877, 2189, 1771, 1651, 1455, 1390, 1251, 1223, 1128, 1031,
Conclusions
1
972, 727, 697 cm−1; H NMR (300 MHz, CDCl3): δ 7.41 (d, J =
In summary, we have improved the yields of 4 up to 84% in
water mediated reaction at reflux temperature and developed a
simple, efficient, catalyst free green protocol for the synthesis
of dihydrofurans (7) for the first time in water mediated one
6.79 Hz, 3H), 7.22 (d, J = 7.55 Hz, 2H), 4.73 (s, 1H), 3.99 (s,
3H), 2.60 (s, 2H), 2.32 (s, 2H), 1.26 (s, 3H), 1.19 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ 193.0, 175.0, 165.0, 135.2, 129.0,
128.0, 112.4, 85.4, 55.3, 55.0, 51.0, 37.2, 34.3, 30.0, 28.5 ppm;
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ESI-MS: m/z 326 [M + H]+; HRMS (ESI) Anal. calcd for (s, 2H), 2.30 (s, 2H), 1.41 (t, J = 7.16 Hz, 3H), 1.24 (s, 3H), 1.17
C19H20NO4 m/z 326.1392 [M + H]+, found 326.1392. (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 193.1, 175.0, 162.0,
Propyl 2-cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexa- 130.0, 116.0, 113.3, 112.5, 85.4, 64.5, 55.0, 51.0, 37.31, 34.3,
hydrobenzofuran-2-carboxylate (5c). Isolated as a yellow solid; 29.5, 28.5, 14.0 ppm; ESI-MS: m/z 358 [M + H]+; HRMS (ESI)
yield 72%; m.p. 149–153 °C; IR (KBr): 2983, 2937, 2140, 1764, Anal. calcd for C20H21FNO4 m/z 358.1455 [M + H]+, found
1660, 1387, 1230, 1126, 730, 700 cm−1
CDCl3): δ 7.45–7.32 (m, 3H), 7.19 (d, J = 9.06 Hz, 2H), 4.70 (s,
;
1H NMR (300 MHz, 358.1454.
Ethyl 3-(4-bromophenyl)-2-cyano-6,6-dimethyl-4-oxo-2,3,4,5,6,7-
1H), 4.32 (t , J = 6.60 Hz, 2H), 2.65–2.49 (m, 2H), 2.29 (s, 2H), hexahydrobenzofuran-2-carboxylate (5h). Isolated as a colour-
1.87–1.72 (m, 2H), 1.23 (s, 3H), 1.17 (s, 3H), 1.01 (t, J = 7.36 Hz, less solid; yield 76%; m.p. 141–144 °C; IR (KBr): 2959, 2897,
3H) ppm; 13C NMR (75 MHz, CDCl3): δ 198.0, 175.0, 164.1, 2873, 2185, 1919, 1764, 1649, 1391, 1250, 1218, 1208, 837,
1
135.3, 129.0, 128.0, 113.3, 112.4, 85.4, 70.0, 55.3, 51.0, 37.1, 544 cm−1; H NMR (300 MHz, CDCl3): δ 7.53 (d, J = 8.30 Hz,
34.2, 28.5, 28.4, 20.0, 10.0 ppm; ESI-MS: m/z 354 [M + H]+; 2H), 7.08 (d, J = 8.49 Hz, 2H), 4.67 (s, 1H), 4.48–4.37 (m, 2H),
HRMS (ESI) Anal. calcd for C21H24NO4 m/z 354.1707 [M + H]+, 2.68–2.48 (m, 2H), 2.28 (s, 2H), 1.40 (t, J = 7.17 Hz, 3H), 1.22
found 354.1707.
(s, 3H), 1.17 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 193.0,
Isopropyl 2-cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7- 175.0, 164.0, 134.3, 132.2, 130.0, 123.1, 113.1, 112.4, 85.2, 64.5,
hexahydrobenzofuran-2-carboxylate (5d). Isolated as a yellow 55.0, 51.0, 37.2, 34.3, 28.4, 29.0, 14.0 ppm; ESI-MS: m/z 440
solid; yield 62%; m.p. 121–123 °C; IR (KBr): 2989, 2964, 2168, [M + Na]+; HRMS (ESI) Anal. calcd for C20H20BrNO4Na m/z
1762, 1650, 1386, 1261, 1226, 1105, 729, 699 cm−1
(300 MHz, CDCl3): δ 7.43–7.34 (m, 3H), 7.19 (d, J = 9.30 Hz,
;
1H NMR 440.0467 [M + Na]+, found 440.0474.
Ethyl 2-cyano-6,6-dimethyl-3-(4-nitrophenyl)-4-oxo-2,3,4,5,6,7-
2H), 5.25–5.17 (m, 1H), 4.67 (s, 1H), 2.63–2.52 (m, 2H), hexahydrobenzofuran-2-carboxylate (5i). Isolated as a colour-
2.34–2.26 (m, 2H), 1.41 (d, J = 6.25 Hz, 3H), 1.37 (d, J = less solid; yield 80%; m.p. 152–154 °C; IR (KBr): 2963, 2877,
6.25 Hz, 3H), 1.24 (s, 3H), 1.17 (s, 3H) ppm; 13C NMR (75 MHz, 2214, 1771, 1659, 1526, 1348, 1224, 1111, 985, 730 cm−1
;
CDCl3): δ 193.0, 175.0, 163.5, 137.0, 135.3, 129.0, 128.0, 113.2, 1H NMR (300 MHz, CDCl3): δ 8.27 (d, J = 8.30 Hz, 2H), 7.39 (d,
112.5, 86.0, 73.0, 55.3, 51.0, 37.2, 34.2, 29.0, 21.3 ppm; ESI-MS: J = 8.30 Hz, 2H), 4.82 (s, 1H), 4.45 (q, J = 6.79 Hz, 2H),
m/z 354 [M + H]+; HRMS (ESI) Anal. calcd for C21H24NO4 m/z 2.72–2.51 (m, 2H), 2.31 (s, 2H), 1.42 (t, J = 6.79 Hz, 3H), 1.25 (s,
354.1715 [M + H]+, found 354.1705.
3H), 1.19 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 193.0,
Butyl 2-cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexa- 175.4, 163.5, 149.0, 142.3, 130.0, 113.0, 112.2, 85.0, 65.0, 55.0,
hydrobenzofuran-2-carboxylate (5e). Isolated as
a
yellow 51.0, 37.2, 34.4, 29.0, 28.5, 13.86 ppm; ESI-MS: m/z 385
liquid; yield 58%; IR (KBr): 2964, 2874, 2181, 1763, 1658, 1460, [M + H]+; HRMS (ESI) Anal. calcd for C20H21N2O6 m/z 385.1394
1
1389, 1221, 1123, 730, 698 cm−1; H NMR (500 MHz, CDCl3): [M + H]+, found 385.1401.
δ 7.43–7.34 (m, 3H), 7.19 (d, J = 6.56 Hz, 2H), 4.69 (s, 1H), 4.36
Ethyl 2-cyano-6,6-dimethyl-4-oxo-3-(3-phenoxyphenyl)-2,3,4,5,6,7-
(t, J = 6.56 Hz, 2H), 2.68–2.50 (m, 2H), 2.35–2.25 (m, 2H), hexahydrobenzofuran-2-carboxylate (5j). Isolated as a brown
1.79–1.71 (m, 2H), 1.49–1.36 (m, 2H), 1.23 (s, 3H), 1.17 (s, 3H), viscous liquid; yield 65%; IR (KBr): 2959, 2897, 2873, 2222,
0.98 (t, J = 7.35 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): 1919, 1764, 1649, 1391, 1250, 1218, 1208, 837, 544 cm−1 1H
;
δ 192.8, 174.0, 164.0, 135.2, 129.0, 127.7, 113.2, 112.3, 67.9, NMR (300 MHz, CDCl3): δ 7.43–7.20 (m, 3H), 7.13–6.89 (m,
64.2, 55.1, 50.56, 37.0, 34.0, 30.3, 28.9, 18.5, 13.4 ppm; ESI-MS: 5H), 6.80 (d, J = 7.36 Hz, 1H), 4.68 (s, 1H), 4.37 (q, J = 6.98 Hz,
m/z 368 [M + H]+; HRMS (ESI) Anal. calcd for C22H26NO4 m/z 2H), 2.51 (s, 2H), 2.26 (s, 2H), 1.34 (t, J = 5.66 Hz, 3H), 1.12
368.1856 [M + H]+, found 368.1878.
(s, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ 193.1, 175.3,
sec-Butyl 2-cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7- 175.2, 164.0, 158.0, 157.2, 155.3, 137.2, 130.4, 129.5, 123.2,
hexahydrobenzofuran-2-carboxylate (5f). Isolated as a yellow 119.0, 118.0, 113.0, 112.3, 85.3, 64.3, 55.0, 51.0, 37.0, 34.1,
liquid; yield 68%; IR (KBr): 3031, 2963, 2875, 2230, 1753, 1720, 28.3, 28.2, 14.0 ppm; ESI-MS: m/z 432 [M + H]+; HRMS (ESI)
1
1655, 1389, 1221, 757, 699 cm−1; H NMR (500 MHz, CDCl3): Anal. calcd for C26H26NO5 m/z 432.1811 [M + H]+, found
δ 7.42–7.34 (m, 3H), 7.19 (d, J = 8.24 Hz, 2H), 4.70 (s, 1H), 432.1812.
4.18–4.90 (m, 2H), 2.63–2.52 (m, 2H), 2.33–2.25 (m, 2H),
Ethyl 2-cyano-6,6-dimethyl-4-oxo-3-(2-(trifluoromethyl)phenyl)-
2.12–2.03 (m, 1H), 1.24 (s, 3H), 1.17 (s, 3H), 1.01 (s, 3H), 1.00 2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5k). Isolated
(s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 193.1, 175.0, 164.0, as a yellow liquid; yield 63%; IR (KBr): 2962, 2937, 2222, 1751,
135.2, 129.0, 128.0, 113.3, 112.3, 85.4, 77.1, 74.0, 55.2, 51.0, 1657, 1490, 1387, 1299, 964, 853 cm−1 1H NMR (500 MHz,
;
37.1, 34.1, 28.4, 28.0, 19.0 ppm; ESI-MS: m/z 368 [M + H]+; CDCl3): δ 7.74 (d, J = 7.78 Hz, 1H), 7.57 (t, J = 7.62 Hz, 1H),
HRMS (ESI) Anal. calcd for C22H26NO4 m/z 368.1867 [M + H]+, 7.46 (t, J = 7.62 Hz, 1H), 7.25 (d, J = 7.93 Hz, 1H), 5.19 (s, 1H),
found 368.1868.
4.43–4.33 (m, 2H), 2.63–2.50 (m, 2H), 2.29 (s, 2H), 1.36 (t, J =
Ethyl 2-cyano-3-(4-fluorophenyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7- 8.08 Hz, 3H), 1.22 (s, 3H), 1.16 (s, 3H) ppm; 13C NMR
hexahydrobenzofuran-2-carboxylate (5g). Isolated as a colour- (125 MHz, CDCl3): δ 192.3, 175.0, 163.5, 134.1, 132.4, 129.1,
less solid; yield 74%; m.p. 137–138 °C; IR (KBr): 2962, 2937, 129.0, 126.4, 126.4, 114.0, 112.2, 86.0, 64.4, 51.0, 50.2, 37.1,
2187, 1751, 1657, 1490, 1387, 1299, 964, 853 cm−1 1H NMR 34.3, 30.0, 29.0, 28.3, 13.5 ppm; ESI-MS: m/z 408 [M + H]+;
;
(300 MHz, CDCl3): δ 7.17 (q, J = 5.2 Hz, 2H), 7.09 (t, J = HRMS (ESI) Anal. calcd for C21H21NO4F3 m/z 408.1423
8.49 Hz, 2H), 4.70 (s, 1H), 4.43 (q, J = 7.17 Hz, 2H), 2.59 [M + H]+, found 408.1424.
3242 | Green Chem., 2014, 16, 3237–3246
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Ethyl
2-cyano-3-(4-methoxyphenyl)-6,6-dimethyl-4-oxo- colourless solid; yield 74%; m.p. 233–235 °C; IR (KBr): 3365,
1H NMR
2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5l). Isolated as 3197, 2960, 2262, 1711, 1646, 1246, 851 cm−1
;
a brown solid; yield 69%; m.p. 128–130 °C; IR (KBr): 2973, (300 MHz, CDCl3 + DMSO-d6): δ 7.89 (s, 2H), 7.16 (d, J = 8.68
2943, 2245, 1889, 1735, 1646, 1456, 1232, 1122, 1037, 876, Hz, 2H), 6.88 (d, J = 8.68 Hz, 2H), 4.79 (s, 1H), 3.79 (s, 3H),
1
756 cm−1; H NMR (500 MHz, CDCl3): δ 7.12 (d, J = 8.69 Hz, 2.68–2.61 (m, 2H), 2.68 (s, 2H), 1.23 (s, 3H), 1.16 (s, 3H) ppm;
2H), 6.91 (d, J = 8.69 Hz, 2H), 4.66 (s, 1H), 4.45–4.34 (m, 2H), 13C NMR (75 MHz, CDCl3 + DMSO-d6): δ 192.5, 178.4, 173.4,
3.79 (s, 3H), 2.62–2.49 (m, 2H), 2.28 (s, 2H), 1.32 (t, J = 7.17 Hz, 166.2, 159.0, 129.0, 128.1, 113.5, 113.4, 113.0, 86.3, 54.6, 54.5,
3H), 1.22 (s, 3H), 1.15 (s, 3H) ppm; 13C NMR (125 MHz, 53.1, 50.6, 36.0, 29.1, 28.2, 28.0 ppm; ESI-MS: m/z 341
CDCl3): δ 193.0, 174.6, 164.1, 160.0, 129.0, 127.2, 114.3, 113.4, [M + H]+; HRMS (ESI) Anal. calcd for C19H21N2O4 m/z 341.1495
85.6, 64.2, 55.1, 54.8, 51.0, 34.2, 28.5, 28.4, 13.8 ppm; ESI-MS: [M + H]+, found 341.1496.
m/z 370 [M + H]+; HRMS (ESI) Anal. calcd for C21H24NO5 m/z
2-Cyano-6,6-dimethyl-3-(4-nitrophenyl)-4-oxo-2,3,4,5,6,7-hexa-
hydrobenzofuran-2-carboxamide (7ac). Isolated as a colour-
370.1649 [M + H]+, found 370.1653.
Ethyl
hydrobenzofuran-2-carboxylate (5m). Isolated as a pale yellow 2964, 2876, 2213, 1712, 1656, 1494, 1114, 976, 733, 682 cm−1
solid; yield 71%; m.p. 122–125 °C; IR (KBr): 2962, 2935, 2225, 1H NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.26 (s, 1H), 8.24 (s,
1898, 1749, 1653, 1608, 1465, 1251, 1120, 1027, 836, 763 cm−1
1H), 7.95 (d, J = 7.74 Hz, 2H), 7.50 (d, J = 7.74 Hz, 2H), 4.93 (s,
2-cyano-6,6-dimethyl-4-oxo-3-p-tolyl-2,3,4,5,6,7-hexa- less solid; yield 75%; m.p. 250–252 °C; IR (KBr): 3345, 3185,
;
;
1H NMR (300 MHz, CDCl3): δ 7.14 (d, J = 7.62 Hz, 2H), 6.92 1H), 2.80–2.59 (m, 2H), 2.31 (s, 2H), 1.23 (s, 3H), 1.16 (s, 3H)
(d, J = 8.69 Hz, 2H), 4.66 (s, 1H), 4.46–4.34 (t, J = 6.25 Hz, ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): δ 193.2, 175.5,
2H), 2.65–2.48 (m, 2H), 2.34 (s, 3H), 2.29 (s, 2H), 1.42 (t, J = 166.0, 148.0, 144.1, 130.0, 124.0, 114.0, 112.4, 86.0, 54.1, 51.0,
6.56 Hz, 3H), 1.23 (s, 3H), 1.16 (s, 3H) ppm; 13C NMR 37.0, 34.1, 28.4, 28.3 ppm; ESI-MS: m/z 356 [M + H]+, HRMS
(75 MHz, CDCl3):
δ
193.0, 174.7, 164.1, 138.7, 132.2, (ESI) Anal. calcd for C18H18N3O5 356.1241 [M + H]+, found
129.6, 127.6, 113.4, 112.5, 85.5, 64.2, 55.0, 51.0, 37.1, 34.2, 356.1251.
28.5, 28.4, 21.1, 13.8 ppm; ESI-MS: m/z 354 [M + H]+; HRMS
3-(4-Chlorophenyl)-2-cyano-6,6-dimethyl-4-oxo-2,3,4,5,6,7-
(ESI) Anal. calcd for C21H24NO4 m/z 354.1699 [M + H]+, found hexahydrobenzofuran-2-carboxamide (7ad). Isolated as
a
354.1702.
colourless solid; yield 73%; m.p. 278–280 °C; IR (KBr): 3360,
3172, 2965, 2873, 2283, 1713, 1651, 1223, 975, 657 cm−1 1H
NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.16 (s, 1H), 8.02 (s, 1H),
7.36 (d, J = 8.30 Hz, 2H), 7.21 (d, J = 8.30 Hz, 2H), 4.78 (s, 1H),
2.67–2.53 (m, 2H), 2.26 (s, 2H), 1.22 (s, 3H), 1.15 (s, 3H) ppm;
;
General procedure for the preparation of 2-cyano-6,6-
dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexahydrobenzofuran-2-
carboxamide (7)
To a round bottomed flask equipped with a reflux condenser 13C NMR (75 MHz, CDCl3 + DMSO-d6): δ 192.1, 174.0, 166.0,
and a stopper were added benzaldehyde 1 (400 mg, 3.7 mmol), 135.0, 133.2, 133.0, 129.1, 113.3, 112.3, 86.0, 53.5, 50.4, 36.4,
malononitrile 2 (248 mg, 3.7 mmol), and water (40 mL) and 33.5, 30.2, 28.0 ppm; ESI-MS: m/z 345 [M + H]+; HRMS (ESI)
stirred for around 15 min at room temperature. To this Anal. calcd for C18H18N2O3Cl m/z 345.1000 [M + H]+, found
was added 5,5-dimethylcyclohexane-1,3-dione (3) (527 mg, 345.1007.
3.7 mmol), and the reaction mixture was heated to reflux while
3-(4-Bromophenyl)-2-cyano-6,6-dimethyl-4-oxo-2,3,4,5,6,7-
stirring for 3 h. The reaction completion was monitored by hexahydrobenzofuran-2-carboxamide (7ae). Isolated as
a
TLC. Then the heterogeneous reaction mixture mass was colourless solid; yield 75%; m.p. 296–298 °C; IR (KBr): 3356,
allowed to cool down to room temperature, and to it N-chloro- 3168, 2964, 2869, 2222, 1715, 1651, 1468, 1386, 1222, 975, 975,
succinimide (603 mg, 4.5 mmol) was added under continued 656 cm−1 1H NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.19 (s,
;
stirring. After completion of the reaction (by TLC, in 3 h), the 1H), 8.06 (s, 1H), 7.51 (d, J = 8.12 Hz, 2H), 7.15 (d, J = 8.30 Hz,
separated solid was collected on a Buchner funnel after 2H), 4.75 (s, 1H), 2.80–2.59 (m, 2H), 2.25 (s, 2H), 1.22 (s, 3H),
washing with water (2 × 10 mL) and hexanes (10 mL) to yield 1.17 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6):
the pure product 7.
2-Cyano-6,6-dimethyl-4-oxo-3-phenyl-2,3,4,5,6,7-hexahydro- 86.4, 54.2, 51.1, 37.0, 34.2, 29.0, 28.0 ppm; ESI-MS: m/z 388
benzofuran-2-carboxamide (7aa). Isolated as
colourless [M + H]+; HRMS (ESI) Anal. calcd for C18H18O3N2Br m/z
solid; yield 76%; m.p. 203–205 °C; IR (KBr): 3368, 3151, 2966, 389.0495 [M + H]+, found 389.0504.
2798, 2217, 1718, 1649, 1223, 641 cm−1 1H NMR (500 MHz,
2-Cyano-3-(4-fluorophenyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-
CDCl3 + DMSO-d6): δ 7.65 (s, 2H), 7.41–7.23 (m, 5H), 4.88 (s, hexahydrobenzofuran-2-carboxamide (7af). Isolated as
1H), 2.65–2.55 (m, 2H), 2.28 (s, 2H), 1.24 (s, 3H), 1.17 (s, 3H) colourless solid; yield 72%; m.p. 265–267 °C; IR (KBr): 3367,
ppm; 13C NMR (125 MHz, CDCl3 + DMSO-d6): δ 192.2, 178.5, 3184, 2963, 2874, 2262, 1649, 1222, 843, 655 cm−1 1H NMR
δ 193.0, 175.0, 166.4, 136.4, 132.0, 130.4, 122.1, 114.2, 113.0,
a
;
a
;
174.0, 166.0, 136.4, 128.2, 127.9, 127.0, 113.5, 112.6, 86.1, 54.1, (300 MHz, CDCl3 + DMSO-d6): δ 7.94 (s, 1H), 7.64 (s, 1H) 7.25
50.5, 36.4, 36.2, 29.1, 28.1, 28.0 ppm; ESI-MS: m/z 311 (q, J = 5.28 Hz, 2H), 7.07 (t, J = 8.68 Hz, 2H), 4.85 (s, 1H),
[M + H]+; HRMS (ESI) Anal. calcd for C18H19N2O3 m/z 311.1390 2.65–2.55 (m, 2H), 2.27 (s, 2H), 1.23 (s, 3H), 1.16 (s, 3H) ppm;
[M + H]+, found 311.1395.
13C NMR (75 MHz, CDCl3 + DMSO-d6): δ 192.2, 174.1, 166.1,
2-Cyano-3-(4-methoxyphenyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7- 160.2, 133.1, 130.0, 129.1, 115.2, 114.1, 113.4, 86.0, 53.5, 50.5,
hexahydrobenzofuran-2-carboxamide (7ab). Isolated as
a
36.3, 34.0, 28.1, 27.1, 27.0 ppm; ESI-MS: m/z 329 [M + H]+;
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HRMS (ESI) Anal. calcd for C18H18FN2O3 m/z 329.1296 3365, 2964, 2201, 1744, 1658, 1517, 1389, 1211, 762, 631 cm−1
[M + H]+, found 329.1299. 1H NMR (300 MHz, CDCl3 + DMSO-d6): δ 9.02 (s, 1H), 7.38 (s,
2-Cyano-6,6-dimethyl-4-oxo-3-p-tolyl-2,3,4,5,6,7-hexahydro- 2H), 6.83 (d, J = 7.91 Hz, 1H), 6.66 (d, J = 6.98 Hz, 2H), 4.70 (s,
benzofuran-2-carboxamide (7ag). Isolated as colourless 1H), 3.82 (s, 3H), 2.80–2.61 (m, 2H), 2.26 (s, 2H), 1.23 (s, 3H),
solid; yield 70%; m.p. 242–246 °C; IR (KBr): 3338, 2960, 2869, 1.16 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6):
2218, 1715, 1651, 1469, 1396, 1268, 975, 656 cm−1 1H NMR δ 192.2, 174.1, 164.1, 147.4, 126.5, 120.5, 115.4, 113.0, 112.5,
;
a
;
(300 MHz, CDCl3 + DMSO-d6): δ 8.11 (s, 1H), 7.96 (s, 1H), 7.17 111.4, 85.3, 55.4, 54.4, 36.5, 43.0, 28.1, 28.0 ppm; ESI-MS: m/z
(d, J = 7.93 Hz, 2H), 7.10 (d, J = 8.12 Hz, 2H), 4.72 (s, 1H), 357 [M + H]+; HRMS (ESI) Anal. calcd for C19H21O5N2 m/z
2.80–2.50 (m, 2H), 2.34 (s, 3H), 2.29 (s, 2H), 1.27 (s, 3H), 1.18 357.1445 [M + H]+, found 357.1456.
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): δ 192.3,
2-Cyano-3-(4-hydroxy-3,5-dimethoxyphenyl)-6,6-dimethyl-4-oxo-
174.1, 166.1, 137.3, 133.5, 130.3, 129.0, 128.7, 127.5, 127.0, 2,3,4,5,6,7-hexahydrobenzofuran-2-carboxamide (7al). Isolated
115.3, 114.1, 113.0, 54.0, 50.0, 36.4, 28.1, 28.0, 26.6 ppm; as a brown solid; yield 68%; m.p. 162–165 °C; IR (KBr): 3422,
ESI-MS: m/z 325 [M + H]+; HRMS (ESI) Anal. calcd for 3268, 2960, 2200, 1708, 1648, 1517, 1118, 972, 616 cm−1
;
C19H21N2O3 m/z 325.1546 [M + H]+, found 325.1552.
2-Cyano-3-(4-hydroxyphenyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7- 1H), 6.42 (s, 2H), 4.67 (s, 1H), 3.81 (s, 6H), 2.80–2.61 (m, 2H),
hexahydrobenzofuran-2-carboxamide (7ah). Isolated as
2.26 (s, 2H), 1.24 (s, 3H), 1.16 (s, 3H) ppm; 13C NMR (75 MHz,
yellow solid; yield 69%; m.p. 264–266 °C; IR (KBr): 3471, 3329, CDCl3 + DMSO-d6): δ 192.4, 174.0, 162.2, 146.0, 135.3, 126.0,
1H NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.08 (s, 2H), 7.95 (s,
a
3289, 2984, 2873, 2274, 1719, 1641, 1514, 1219, 976, 536 cm−1
;
114.0, 113.0, 105.0, 86.4, 56.0, 51.0, 37.0, 35.5, 28.5, 28.0 ppm;
1H NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.08 (s, 1H), 7.95 (s, ESI-MS: m/z 387 [M + H]+; HRMS (ESI) Anal. calcd for
1H) 7.00 (d, J = 8.30 Hz, 2H), 6.77 (d, J = 8.30 Hz, 2H), 6.54 (s, C20H23N2O6 m/z 387.1564 [M + H]+, found 387.1563.
1H), 4.65 (s, 1H), 2.68–2.61 (m, 2H), 2.26 (s, 2H), 1.21 (s, 3H),
1.13 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): benzofuran-2-carboxamide (7am). Isolated as
δ 192.3, 173.5, 166.2, 157.2, 129.0, 128.2, 127.0, 115.1, 114.1, solid; yield 56%; m.p. 120–125 °C; IR (KBr): 3316, 3166, 2961,
113.0, 112.0, 86.5, 54.0, 51.0, 36.4, 33.5, 28.1, 28.0 ppm; 2874, 2243, 1774, 1710, 1641, 1393, 1206, 1106, 650 cm−1
ESI-MS: m/z 327 [M + H]+; HRMS (ESI) Anal. calcd for 1H NMR (500 MHz, CDCl3): δ 6.68 (s, 1H), 6.47 (s, 1H), 3.66 (s,
C18H19N2O4 m/z 327.1344 [M + H]+, found 327.1343.
1H), 2.44 (s, 2H), 2.26 (s, 2H), 2.09–1.70 (m, 2H), 1.63–1.35 (m,
2-Cyano-6,6-dimethyl-4-oxo-3-propyl-2,3,4,5,6,7-hexahydro-
a
colourless
;
2-Cyano-3-(4-cyanophenyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7- 2H), 1.14 (s, 3H), 1.11 (s, 3H), 0.96 (t, J = 7.17 Hz, 3H) ppm;
hexahydrobenzofuran-2-carboxamide (7ai). Isolated as a col- 13C NMR (125 MHz, CDCl3): δ 193.8, 171.5, 166.9, 114.5, 113.7,
ourless solid; yield 70%; m.p. 235–237 °C; IR (KBr): 3339, 85.2, 51.2, 48.9, 37.3, 34.2, 33.6, 28.6, 20.0, 13.8 ppm; ESI-MS:
3167, 2965, 2225, 2199, 1714, 1654, 1503, 1389, 1224, 1114, m/z 277 [M + H]+; HRMS (ESI) Anal. calcd For C15H21N2O3 m/z
1
977, 666 cm−1; H NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.33 277.1546 [M + H]+, found 277.1543.
(s, 2H), 7.82 (d, J = 8.12 Hz, 2H), 7.43 (d, J = 8.12 Hz, 2H), 4.83
2-Cyano-4-oxo-3-phenyl-2,3,4,5,6,7-hexahydrobenzofuran-
(s, 1H), 2.80–2.61 (m, 2H), 2.35–2.15 (m, 2H), 1.19 (s, 3H), 1.11 2-carboxamide (7b). Isolated as a colourless solid; yield 69%;
(s, 3H) ppm; 1H NMR (300 MHz, CDCl3 + DMSO-d6) (D2O m.p. 189–191 °C; IR (KBr): 3368, 3156, 2955, 2192, 1716, 1650,
1
exchange): δ 7.81 (d, J = 7.36 Hz, 2H), 7.44 (d, J = 7.55 Hz, 2H), 1385, 1177, 1128, 961, 698 ppm; H NMR (300 MHz, CDCl3 +
4.84 (s, 1H), 2.76–2.53 (m, 2H), 2.38–2.13 (m, 2H), 1.19 (s, 3H), DMSO-d6): δ 8.15 (s, 2H), 7.32 (d, J = 6.42 Hz, 3H), 7.18 (d, J =
1.12 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): 6.79 Hz, 2H), 4.67 (s, 1H), 2.87–2.59 (m, 2H), 2.38 (q, J =
δ 192.4, 175.0, 166.0, 142.0, 132.2, 129.1, 118.1, 114.0, 112.0, 6.78 Hz, 2H), 2.10 (q, J = 5.85 Hz, 2H) ppm; 13C NMR (75 MHz,
111.2, 86.0, 54.0, 50.5, 36.3, 34.0, 28.2, 28.0 ppm; ESI-MS: m/z CDCl3 + DMSO-d6): δ 193.0, 175.4, 166.1, 136.5, 128.3, 128.2,
336 [M + H]+; HRMS (ESI) Anal. calcd for C19H18N3O3 m/z 128.0, 114.0, 113.6, 86.1, 54.3, 36.3, 23.0, 21.0 ppm; ESI-MS:
336.1362 [M + H]+, found 336.1341.
2-Cyano-3-(2,4-dihydroxyphenyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7- 283.1077 [M + H]+, found 283.1080.
hexahydrobenzofuran-2-carboxamide (7aj). Isolated as 2-Cyano-6-methyl-4-oxo-3-phenyl-3,4-dihydro-2H-furo[3,2-c]-
m/z 283 [M + H]+; HRMS (ESI) Anal. calcd for C16H15N2O3 m/z
a
brown solid; yield 65%; m.p. 234–236 °C; IR (KBr): 3399, 3259, pyran-2-carboxamide (7c). Isolated as a colourless solid; yield
2962, 2217, 1708, 1653, 1520, 1393, 1213, 968, 618 cm−1
;
1H 58%; m.p. 251–253 °C; IR (KBr): 3323, 3274, 3166, 2198, 1695,
NMR (300 MHz, CDCl3 + DMSO-d6): δ 8.01 (s, 1H), 7.93 (s, 1H), 1589, 1250, 1123, 701, 577 cm−1; H NMR (300 MHz, CDCl3 +
6.63 (d, J = 7.93 Hz, 1H), 6.52 (d, J = 1.88 Hz, 1H), 6.36 (d, J = DMSO-d6): δ 8.19 (s, 1H), 8.09 (s, 1H), 7.40 (q, J = 6.98 Hz, 3H),
8.12 Hz, 1H), 4.43 (s, 1H), 2.80–2.50 (m, 2H), 2.17 (s, 2H), 1.21 7.27 (d, J = 9.06 Hz, 2H), 6.33 (s, 1H), 4.99 (s, 1H), 2.35 (s, 3H)
(s, 3H), 1.12 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO- ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): δ 169.0, 167.0,
d6): δ 193.0, 174.0, 166.5, 145.1, 145.0, 128.0, 119.0, 115.5, 165.2, 159.0, 135.1, 128.4, 128.3, 113.2, 100.0, 95.1, 87.0, 53.5,
115.3, 113.0, 87.0, 54.0, 50.1, 36.5, 34.0, 28.4, 28.1 ppm; 20.0 ppm; ESI-MS: m/z 297 [M + H]+; HRMS (ESI) Anal. calcd
ESI-MS: m/z 343 [M + H]+; HRMS (ESI) Anal. calcd for for C16H13N2O4 m/z 297.0487 [M + H]+, found 297.0876.
1
C18H19N2O5 m/z 343.1294 [M + H]+, found 343.1294.
4-Acetyl-2-cyano-5-methyl-3-phenyl-2,3-dihydrofuran-2-carbox-
2-Cyano-3-(4-hydroxy-3-methoxyphenyl)-6,6-dimethyl-4-oxo- amide (7d). Isolated as a colourless solid; yield 52%; m.p.
2,3,4,5,6,7-hexahydrobenzofuran-2-carboxamide (7ak). Iso- 157–159 °C; IR (KBr): 3399, 3164, 2257, 1719, 1679, 1601, 1381,
1
lated as a brown solid; yield 67%; m.p. 201–204 °C; IR (KBr): 1319, 1223, 1191, 939, 637 cm−1; H NMR (500 MHz, CDCl3 +
3244 | Green Chem., 2014, 16, 3237–3246
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Paper
DMSO-d6): δ 11.14 (s, 2H), 7.67–7.45 (m, 5H), 5.14 (s, 1H), 2.68
(s, 3H), 2.14 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3 + DMSO-
d6): δ 193.0, 178.5, 167.0, 165.3, 138.0, 129.0, 128.1, 114.2,
114.0, 84.0, 57.0, 29.2, 14.1 ppm; ESI-MS: m/z 271 [M + H]+;
HRMS (ESI) Anal. calcd for C15H15N2O3 m/z 271.1077 [M + H]+,
found 271.1082.
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Acknowledgements
We thank Dr V. J. Rao, Head Crop Protection Chemicals
Division for encouragement and Director CSIR-IICT for
support. We are grateful to SERB-DST, New Delhi for financial
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