One-pot access to dihydrofurans via tandem oxidative difunctionalization and ring contraction of aminopyrans

Article abstract of DOI:10.1039/c4ob00324a

An operationally simple and efficient protocol for the construction of dihydrofuran derivatives has been accomplished via a sequential addition of N-chlorosuccinimide and a base to 2-amino-4H-pyran derivatives in alcohol medium. The one-pot protocol proceeding via tandem oxidative difunctionalization and ring contraction provides an entirely new strategy for the construction of the dihydrofuran skeleton. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00324a

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
“One-pot” access to dihydrofurans via tandem
oxidative difunctionalization and ring contraction
of aminopyrans†
Cite this: Org. Biomol. Chem., 2014,
12, 4412
Santhosh Reddy Mandha,a Manjula Alla*a and Jagadeesh Babu Nanubolub
Received 12th February 2014,
Accepted 9th April 2014
An operationally simple and efficient protocol for the construction of dihydrofuran derivatives has been
accomplished via a sequential addition of N-chlorosuccinimide and a base to 2-amino-4H-pyran deriva-
tives in alcohol medium. The one-pot protocol proceeding via tandem oxidative difunctionalization and
ring contraction provides an entirely new strategy for the construction of the dihydrofuran skeleton.
DOI: 10.1039/c4ob00324a
www.rsc.org/obc
Attention is now focused on the newly functionalized
derivatives. It is envisioned that 2-amino-3-chloro-2-alkoxy-4-
Introduction
Aminopyrans are attention worthy heterocyclic molecules due aryl-2,3-dihydro-4H-benzo[h]chromene-3-carbonitrile analogs
to their unique applications in the field of synthetic organic might be good substrates for base catalyzed dehydrohalogena-
chemistry,1 cosmetics,2 agrochemicals3 and medicinal chemi- tion. Since the chemical reactivity of the pyran ring towards
stry.4 They are allied with numerous types of biological activi- strong bases such as alcoholic NaOH–KOH is well known13
ties such as antimicrobial,5 anticancer,6 anti-inflammatory,7 (i.e., ring opening and recyclization to 2-alkoxypyridines), a
fungicidal,8 molluscicidal,9 anticonvulsant,10 inhibitors of deliberate usage of mild bases was envisaged for
human Chk1 kinase,11 etc., which sustains the interest in this dehydrohalogenation.
class of molecules. In recent years though a great effort has
gone into improvising synthetic procedures for easy access to
aminopyrans, they are largely handicapped by the unusual
Results and discussion
reactivity and weak stability of the aminopyran ring towards
many reagents. The pyran ring is known to open and recyclize
To begin with, the dehydrohalogenation was attempted on 2a
in the presence of a variety of reagents such as strong acids,
(2-amino-3-chloro-2-ethoxy-4-phenyl-2,3-dihydro-4H-benzo[h]-
bases, nucleophiles, etc. From this perspective, our laboratory
chromene-3-carbonitrile) with piperidine as a base in solvent
has been actively pursuing the synthesis and reactivity of these
methanol at room temperature. The reaction mixture turned to
versatile substrates. Recently a mild method for oxidative
a clear brown colored solution, followed by the precipitation of
difunctionalization of 2-amino-4H-pyrans has been developed
product after 10 hours. The spectral data of the product
by our group employing iodobenzene diacetate (IBD) and
showed some unusual features. In the 1H-NMR spectra of start-
N-chlorosuccinimide (NCS) in an alcoholic medium.12 Herein
ing material 2a, the pyran (4H) proton which is observed as a
2-amino-4H-pyrans are shown to undergo geminal dialkoxyla-
singlet (δ = 4.91 ppm) is deshielded (δ = 5.17 ppm) for the
tion with an unusual 1,2-amino migration in the presence of
product (Fig. 1). Similarly the –OCH2 protons of the ethoxy
iodobenzene diacetate and addition of chlorine and alkoxy
group in 2a appeared as two multiplets integrating for one
groups takes place across the chromene double bond when
proton each (δ = 4.10–4.01 and δ = 3.68–3.60 ppm, respect-
NCS is employed.
ively), indicating that they are diastereotopic and attached to
an sp3 chiral carbon. However in the product the –OCH2
protons of the ethoxy group appear only as a multiplet inte-
aCrop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka,
Hyderabad, India. E-mail: manjula@iict.res.in; Tel: +91 4027191441
grating for two protons (δ = 4.50–4.38 ppm). A new distinct
singlet in the downfield region (δ = 8.17 ppm) is indicative of
an –NH proton.
Mass spectrometry showed the molecular ion peak [M + H]
at m/z ∼ 343 and no [M + 2] peak indicating the loss of a chlor-
ine atom in the form of HCl. Since the pyran (4H) proton is
intact, it was concluded that a proton was lost from the –NH2
bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Tarnaka, Hyderabad, India
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of all the new compounds and CIF files for the compounds 3h and
6. CCDC 938721 and 938722. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4ob00324a
4412 | Org. Biomol. Chem., 2014, 12, 4412–4420
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Optimization of reaction conditionsa on highly functionalized
pyran derivatives
Entry Base
Solvent
MeOH
Time
48 h
Yield (%) of 3a
1
2
3
4
5
6
7
8
9
Pyridine
Imidazole
Triethylamine (TEA) MeOH–EtOH 12 h
Piperidine
K2CO3
—
—
70
78
—
—
—
MeOH–EtOH 48 h
MeOH–EtOH 10 h
Fig. 1 Comparison of 1H-NMR spectra of the product with the
substrate.
MeOH
MeOH
MeOH
—
24 h
24 h
24 h
20 min 62
30 min 77
Na2CO3
NaHCO3
Alc. KOHb
Alc. KOHc
—
group and therefore the product should either have structure A
or structure B (Fig. 2).
a Conditions: 2a (1 mmol), base (1.1 mmol), rt. b 1 N methanolic KOH
(1 mmol) was used. c 0.1 N methanolic KOH (1 mmol) was used.
Owing to the fact that the ethoxy group is still attached to
one of the diastereomeric centres in structure A, the change in
the –OCH2 protons in 1H-NMR pattern cannot be accounted
for, thus ruling out structure A as the product. In structure B,
the ethoxy group is directly attached to an sp2 hybridized
carbon, which indicates that only one signal should appear for
the –OCH2 protons. However, the appearance of a multiplet
signal instead of a clear quartet in the 1H-NMR spectrum indi-
cates that the multiplicity of the –OCH2 protons in structure B
is probably due to the influence of the asymmetric quaternary
carbon of the dihydrofuran system. Since structure B satisfies
the 1H-NMR spectral parameters, it is inferred that 2,3-di-
hydrofuran is indeed the product formed. Additional proof for
the 2,3-dihydrofuran system was obtained from the X-ray crys-
tallography data.
Further, to simplify and broaden the optimization studies
we have directed our focus on to the one-pot multicomponent
protocol with 2-amino-4H-pyran analogs as starting materials.
A sequential addition of NCS followed by the addition of piper-
idine in alcohol medium without isolating the 2-amino-3-
chloro-2-alkoxy-benzo[h]chromene-3-carbonitrile analogs was
attempted to check the feasibility of the one-pot approach. In
congruence with the anticipation, the one-pot oxidative difunc-
tionalization followed by the ring contraction was facile and
aminopyran 1a was transformed to dihydrofuran 3a in high
yield (Table 2).
Once the optimized reaction conditions were established
(Table 2, entries 1 & 4), the scope of the one-pot protocol was
scrutinized by varying the aryl substituent on the aminopyran
Encouraged by these results the standardization of the reac-
tion protocol was carried out in an alcoholic medium by
employing various organic and inorganic bases (Table 1).
When pyridine and imidazole were used as the bases, the pro-
Table 2 Optimization of reaction conditions under one-pot
gress of reaction was negligible even after 48 hours. The reac- conditionsa
tion proceeded to completion in 12 hours when triethylamine
was used as the base. In case of piperidine the reaction pro-
ceeds to completion in 10 hours with better yields. Inorganic
bases especially carbonates did not facilitate the rearrange-
ment. Even though the reaction was rapid in alcoholic potass-
ium hydroxide, yields were comparatively poor due to the
formation of side products.
Entry
Base
Timeb
Yield (%) of 3a
1
2
3
4
5
Piperidine
5 h
6 h
24 h
5 h
77
70
—
76
Triethylamine (TEA)
Pyridine
Aqueous KOHc
Methanolic KOHd
6 h
Mixture of products
a Conditions: 1 (5 mmol), NCS (5.5 mmol), base (6 mmol), rt.
b Reaction time for the base to carry out the transformation. c 1 N
aqueous KOH (10 mmol) was used. d 1 N methanolic KOH (6 mmol)
was used.
Fig. 2 Expected structures for the product.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4412–4420 | 4413

View Article Online
Paper
Organic & Biomolecular Chemistry
derivative employing piperidine as a base and an alcohol as
the solvent. It is worth mentioning that a variety of aryl substi-
tutions both electron rich and electron deficient are tolerated.
Heteroaryl substituents like thiophen-2-yl and pyridin-3-yl also
bestowed the desired products 3c, 3f and 3k, respectively, in
satisfactory yields (Scheme 1).
Furthermore, the versatility of this method was extended by
carrying out a one-pot reaction on amino-1H-pyrans. Under
optimized reaction conditions, a sequential addition of NCS
followed by the addition of piperidine led to the formation of
the dihydrofurans 5(a–d) from 4(a–d), respectively, in satisfac-
tory yields irrespective of the aryl ring substituent (Scheme 2).
On the basis of the above experimental observations, a
mechanistic rationale for the ring contraction of a pyran to a
dihydrofuran has been arrived at (Scheme 3). Initially amino-
pyran undergoes oxidative difunctionalization with NCS in the
presence of an alcohol solvent.12 Subsequent addition of base
to the aminopyran leads to proton abstraction from the amino
group. This leads to a cascade pyran ring opening by the clea-
Scheme 2 One-pot synthesis of dihydrofurans from amino-1H-pyran
derivatives.
Scheme 3 Plausible mechanism for the formation of dihydrofurans.
vage of the (C2–O1) bond, and ring closure of the (O1–C3) bond
to dihydrofuran via elimination of HCl. The sequential
elementary processes lead to formation of the ring contracted
dihydrofuran carbimidate ester.
Attention was focused on the alcoholic KOH reactions
where the formation of more than one product was observed.
The minor product was identified as the compound formed by
partial hydrolysis of the cyanide group, probably due to the
basicity of alcoholic KOH. A detailed study was attempted on
the variation of the product ratios by varying both the number
of equivalents and concentration of alcoholic KOH. It was
found that 0.1 N methanolic KOH (Table 3, entry 3) was best
suited for formation of product 3a exclusively by restricting the
cyanide hydrolysis. It was observed that when an excess
amount of methanolic KOH was used as a base (Table 3, entry
5), ethyl 2-cyano-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-2-
carbimidate (3a) formed initially (monitored by TLC) was com-
pletely converted into dimethyl 3-phenylnaphtho[1,2-b]furan-
2,2(3H)-bis(carbimidate) (6). However, the methanolic KOH
transformations were not extendable to one-pot tandem oxi-
dative difunctionalization and ring contraction.
With the optimized conditions in hand, for alcoholic KOH
ring contraction reactions, highly functionalized pyran deriva-
tive compounds like 2a, 2b, 2e and 2f were treated with 1 N
methanolic KOH (3 mmol) to obtain the products 6, 7, 8 and
9, respectively, in good yields. An additional feature observed
Scheme 1 Synthesis of dihydrofurans from 4H-pyran derivatives.
4414 | Org. Biomol. Chem., 2014, 12, 4412–4420
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 3 Optimization of reaction under methanolic KOH conditions
Yield (%) of
product
Entry
Base
Time
3a
6
1
2
3
4
5
Methanolic KOHa
Methanolic KOHb
Methanolic KOHc
Methanolic KOHd
Methanolic KOHe
20 min
30 min
30 min
45 min
36 h
62
70
77
70
–
20
14
Traces
Traces
75
Fig. 5 The ORTEP diagram of 6 with the atom-numbering scheme. Dis-
placement ellipsoids are drawn at the 30% probability level and H atoms
are shown as small spheres of arbitrary radius. The two intramolecular
N–H⋯O hydrogen bonds are indicated by dotted lines [bond distances
N–H, H⋯O, N⋯O and angle ∠N–H⋯O parameters are 0.87 Å, 2.26 Å,
2.722(2) Å, 116° for N1–H1N⋯O1 and 0.91 Å, 2.21 Å, 2.707(2) Å, 114° for
N2–H2N⋯O1, respectively].
Substrate (2a) in 1 mmol scale. a 1 N methanolic KOH (1 mmol) was
used. b 0.5 N methanolic KOH (1 mmol) was used. c 0.1 N methanolic
KOH (1 mmol) was used. d 0.05 N methanolic KOH (1 mmol) was used.
e 1 N methanolic KOH (3 mmol) was used.
in these reactions was transesterifications which were preva-
lent whenever the alkoxy group of carbimidate ester and alco-
holic solvent were different (Fig. 3).
Arene ring fused furans or dihydrofurans are found in a
wide range of natural products and as a key structural unit in
many of the biologically and pharmaceutically active organic
molecules.14–16 Many approaches for the construction of this
class of compounds are available in literature.17 However, the
construction of a dihydrofuran ring by contraction of pyran
ring has no precedence in the literature. Even more unusual is
the presence of a stable carbimidate ester, which is due to the
hydrogen bonding between the proton of the carbimidate
(–NH) and the oxygen of the dihydrofuran ring. Further, con-
clusive proof for the carbimidate ester of dihydrofuran and a
transesterified product was obtained from X-ray crystallogra-
phy data of 3h and 6, respectively (Fig. 4 and 5).
Fig. 3 Substrate scope of transesterified products.
The carbimidate ester could be cleaved to a simple ester in
a facile manner with 10% dil. HCl in acetone or methanol
solvent (Scheme 4).
Fig. 4 The ORTEP diagram of 3h with the atom-numbering scheme.
Displacement ellipsoids are drawn at the 30% probability level and
H atoms are shown as small spheres of arbitrary radius. An intramolecu-
lar N–H⋯O hydrogen bond is indicated by dotted lines [bond distances
N1–H1, H1N⋯O1, N1⋯O1 and angle ∠N1–H1N⋯O1 parameters are
0.90 Å, 2.22 Å, 2.720(2) Å and 114°, respectively].
Scheme 4 Hydrolysis of carbimidate ester.
Org. Biomol. Chem., 2014, 12, 4412–4420 | 4415
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
Organic & Biomolecular Chemistry
cm−1) 3318, 2983, 1968, 1675, 1375, 858; H NMR (300 MHz,
CDCl3) δ: 8.17 (s, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.89 (d, J =
1
Conclusions
In summary, a novel and efficient methodology for the con- 8.3 Hz, 1H), 7.65–7.53 (m, 3H), 7.43–7.36 (m, 3H), 7.27–7.21
struction of dihydrofuran derivatives has been achieved by (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 5.17 (s, 1H), 4.50–4.38 (m,
tandem oxidative difunctionalization and ring contraction of 2H), 1.45 (t, J = 7.5 & 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
aminopyran analogs. The protocol illustrates the atypical reac- δ: 164.4, 152.6, 137.1, 134.5, 129.3, 128.9, 128.8, 127.0, 126.7,
tivity of 4H-pyrans with N-chlorosuccinimide and base under 123.7, 122.0, 121.0, 120.1, 119.6, 114.3, 85.1, 64.0, 58.9, 14.0;
one-pot conditions. In depth investigation of the methodology MS (ESI): m/z 343 (M + H)+; HRMS ESI (M + H)+ m/z calcd for
focussed on various basic media led to the accomplishment of C22H19N2O2 (M + H)+ 343.1441, found 343.1431.
some unusual dihydrofuran frameworks.
Ethyl
2-cyano-3-(4-chlorophenyl)-2,3-dihydronaphtho[1,2-b]-
furan-2-carbimidate (3b). Yield: 1.50 g (80%); mp 101–103 °C;
IR (neat, cm−1) 3315, 2989, 1908, 1665, 1386, 859; 1H NMR
(300 MHz, CDCl3) δ: 8.19 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.90
(d, J = 7.1 Hz, 1H), 7.65–7.54 (m, 3H), 7.38 (d, J = 8.5 Hz, 2H),
7.18 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 5.15 (s, 1H),
Experimental
General consideration
4.44 (qd, J = 7.2 & 2.2 Hz, 2H), 1.45 (t, J = 7.2 & 7.0 Hz, 3H); 13
C
All reactions were performed under RT conditions and open to
air. Melting points were determined in open capillary tubes
and are uncorrected. 1H NMR (300 MHz, 500 MHz) and 13C
NMR (75 MHz, 125 MHz) spectra were recorded in CDCl3.
Chemical shifts are given in δ values referenced to the solvent.
All the yields mentioned in the data are that of isolated crude
products unless otherwise mentioned. However the recrystalli-
zations of the products were carried out from methanol or
ethanol.
General procedure for preparation of starting materials [1(a–j)].
All the substrates 1(a–i) were prepared according to our
reported procedure.12 Compound 1j was prepared according to
the procedure reported in literature.18
General procedure for the synthesis of compounds 3(a–n).
With piperidine as a base: to a suspension of the 2-amino-4H-
pyran analog (5 mmol) in alcohol (10 mL), N-chlorosuccini-
mide (5.5 mmol) was added at room temperature. After
3 hours of stirring, piperidine (6 mmol) was added and stirred
at the same temperature for 5–6 hours, till the product is com-
pletely precipitated out. The reaction mixture was filtered, and
washed with ethanol to separate the desired product (or)
recrystallized from ethanol to afford the pure product [3(a–n)].
With aqueous KOH as a base: to a suspension of the
2-amino-4H-pyran analog (5 mmol) in alcohol (10 mL),
N-chlorosuccinimide (5.5 mmol) was added at room tempera-
ture. After 3 hours of stirring, 1 N aqueous KOH (10 mmol)
solution was added and the resulting mixture was stirred at
the same temperature for 6 hours. After the completion of the
reaction as indicated by TLC, 10 mL of water was added to the
reaction mixture. The solid product was filtered, and washed
with ethanol to give the desired product (or) recrystallized
from ethanol to afford the pure product [3(a–n)].
NMR (75 MHz, CDCl3) δ: 164.1, 152.7, 135.6, 134.9, 134.7,
130.6, 129.1, 128.1, 127.2, 126.8, 124.0, 121.7, 121.0, 120.1,
119.1, 114.2, 84.8, 64.0, 58.3, 14.0; MS (ESI): m/z 377 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C22H18N2O2Cl (M + H)+
377.1051, found 377.1048.
Ethyl
2-cyano-3-(thiophen-2-yl)-2,3-dihydronaphtho[1,2-b]-
furan-2-carbimidate (3c). Yield: 1.44 g (83%); mp 153–155 °C;
IR (neat, cm−1) 3317, 2983, 1677, 1376, 853; 1H NMR
(300 MHz, CDCl3) δ: 8.17 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.90
(d, J = 8.7 Hz, 1H), 7.63–7.56 (m, 3H), 7.37 (dd, J = 5.0 & 1.4 Hz,
1H), 7.27–7.24 (m, 1H), 7.09–7.05 (m, 2H), 5.45 (s, 1H), 4.45
(m, J = 7.2 & 4.2 Hz, 2H), 1.48 (t, J = 7.2 & 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 164.0, 152.4, 139.7, 134.8, 128.2, 128.1,
127.3, 127.2, 126.8, 126.7, 123.7, 121.9, 121.1, 120.1, 119.0,
114.0, 85.1, 64.1, 53.9, 14.0; MS (ESI): m/z 349 (M + H)+; HRMS
ESI (M + H)+ m/z calcd for C20H17N2O2S (M + H)+ 349.1005,
found 349.0997.
Isopropyl 2-cyano-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-2-
carbimidate (3d). Yield: 1.40 g (79%); mp 170–172 °C; IR (neat,
1
cm−1) 3322, 2980, 1970, 1669, 1338, 846; H NMR (500 MHz,
CDCl3) δ: 8.15 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.9
Hz, 1H), 7.63–7.54 (m, 3H), 7.43–7.38 (m, 3H), 7.26–7.21 (m,
2H), 7.10 (d, J = 8.4 Hz, 1H), 5.30 (sep, J = 6.2 Hz, 1H), 5.14 (s,
1H), 1.46 (d, J = 6.2 Hz, 3H), 1.40 (d, J = 6.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 163.8, 152.7, 137.2, 134.6, 129.3, 128.9,
128.8, 128.1, 127.0, 126.7, 123.7, 122.1, 121.1, 120.2, 119.6,
114.4, 85.2, 71.2, 58.9, 21.6, 21.2; MS (ESI): m/z 357 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C23H21N2O2 (M + H)+
357.1598, found 357.1588.
Methyl
2-cyano-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-2-
carbimidate (3e). Yield: 1.33 g (81%); mp 154–155 °C; IR (neat,
1
cm−1) 3300, 2995, 1960, 1675, 1381, 722; H NMR (500 MHz,
From highly functionalized pyran derivatives: to the highly
functionalized pyran analog12 [5 mmol], in ethanol (10 mL),
piperidine (6 mmol) was added at room temperature. The reac-
tion mixture was stirred at room temperature, till the product
is completely precipitated out. The reaction mixture was fil-
tered and recrystallized from ethanol to afford the pure
product.
CDCl3) δ: 8.21 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.88 (d, J =
8.1 Hz, 1H), 7.63–7.54 (m, 3H), 7.41–7.36 (m, 3H), 7.25–7.20
(m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 5.16 (s, 1H), 4.01 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ: 165.0, 152.5, 137.0, 134.5, 129.2,
128.8, 128.0, 127.0, 126.7, 123.8, 121.9, 120.9, 120.0, 119.6,
114.2, 85.0, 58.8, 55.1; MS (ESI): m/z 329 (M + H)+; HRMS ESI
(M + H)+ m/z calcd for C21H17N2O2 (M + H)+ 329.1284, found
329.1284.
Ethyl 2-cyano-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-2-carbi-
midate (3a). Yield: 1.32 g (77%); mp 164–166 °C; IR (neat,
4416 | Org. Biomol. Chem., 2014, 12, 4412–4420
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Methyl
2-cyano-3-(thiophen-2-yl)-2,3-dihydronaphtho[1,2-b]- IR (neat, cm−1) 3305, 2956, 1669, 1385, 812; 1H NMR
furan-2-carbimidate (3f). Yield: 1.33 g (80%); mp 176–178 °C;
IR (neat, cm−1) 3316, 2952, 1901, 1670, 1342, 865; 1H NMR
(300 MHz, CDCl3) δ: 8.22 (s, 1H), 8.11 (d, J = 7.1 Hz, 1H), 7.90
(d, J = 7.1 Hz, 1H), 7.65–7.54 (m, 3H), 7.39–7.34 (m, 1H),
7.28–7.22 (m, 1H), 7.10–7.05 (m, 2H), 5.45 (s, 1H), 4.03 (s, 3H);
13C NMR (75 MHz, CDCl3) δ: 164.7, 152.4, 139.6, 134.8, 128.2,
128.1, 127.4, 127.2, 126.8, 126.7, 123.8, 121.9, 121.1, 120.1,
119.1, 113.9, 85.1, 55.1, 53.8; MS (ESI): m/z 335 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C19H15N2O2S (M + H)+
335.0848, found 335.0844.
(500 MHz, CDCl3) δ: 8.66 (d, J = 5.0 Hz, 1H), 8.61 (d, J = 2.0 Hz,
1H), 8.28 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz,
1H), 7.65–7.57 (m, 3H), 7.54–7.51 (m, 1H), 7.36–7.32 (m, 1H),
7.06 (d, J = 8.0 Hz, 1H), 5.20 (s, 1H), 4.02 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 164.4, 152.7, 150.6, 150.3, 136.6, 134.7,
132.8, 128.1, 127.3, 126.9, 124.2, 123.7, 121.3, 121.0, 120.1,
118.4, 114.1, 84.7, 56.8, 55.2; MS (ESI): m/z 330 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C20H16N3O2 (M + H)+
330.1237, found 330.1239.
Methyl 2-cyano-3-(4-cyanophenyl)-2,3-dihydronaphtho[1,2-b]-
Methyl
2-cyano-3-(4-nitrophenyl)-2,3-dihydronaphtho[1,2-b]- furan-2-carbimidate (3l). Yield: 1.50 g (85%); mp 189–191 °C;
IR (neat, cm−1) 3305, 2947, 2225, 1676, 1382, 814; 1H NMR
(300 MHz, CDCl3) δ: 8.28 (s, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.91
(d, J = 7.2 Hz, 1H), 7.75–7.57 (m, 5H), 7.37 (d, J = 8.1 Hz, 2H),
7.05 (d, J = 8.3 Hz, 1H), 5.23 (s, 1H), 4.02 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 164.2, 152.8, 142.2, 134.8, 132.7, 130.1,
128.1, 127.4, 127.0, 124.3, 121.4, 121.0, 120.1, 118.3, 118.2,
113.9, 113.0, 84.4, 58.5, 55.3; MS (ESI): m/z 354 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C22H16N3O2 (M + H)+
354.1237, found 354.1235.
furan-2-carbimidate (3g). Yield: 1.68 g (90%); mp 185–187 °C;
IR (neat, cm−1) 3325, 2946, 1960, 1670, 1379, 817; 1H NMR
(300 MHz, CDCl3) δ: 8.30 (s, 1H), 8.27 (d, J = 8.3 Hz, 2H), 8.13
(d, J = 8.3 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.68–7.57 (m, 3H),
7.44 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 1H), 5.29 (s, 1H),
4.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 164.1, 152.8, 148.1,
144.1, 134.8, 130.3, 128.1, 127.5, 127.1, 124.4, 124.0, 121.3,
121.0, 120.1, 118.3, 113.9, 84.3, 58.2, 55.3; MS (ESI): m/z 374
(M + H)+; HRMS ESI (M + H)+ m/z calcd for C21H16N3O4
(M + H)+ 374.1135, found 374.1136.
Methyl 2-cyano-3-(4-fluorophenyl)-2,3-dihydronaphtho[1,2-b]-
Methyl 3-(4-chlorophenyl)-2-cyano-2,3-dihydronaphtho[1,2-b]- furan-2-carbimidate (3m). Yield: 1.49 g (86%); mp 131–133 °C;
IR (neat, cm−1) 3317, 2942, 1892, 1674, 1383, 862; 1H NMR
(300 MHz, CDCl3) δ: 8.22 (s, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.90
furan-2-carbimidate (3h). Yield: 1.55 g (86%); mp 150–152 °C;
IR (neat, cm−1) 3330, 2950, 1993, 1669, 1327, 816; 1H NMR
(300 MHz, CDCl3) δ: 8.23 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.90
(d, J = 7.5 Hz, 1H), 7.66–7.55 (m, 3H), 7.38 (d, J = 8.3 Hz, 2H),
7.18 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 5.14 (s, 1H),
4.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 164.8, 152.6, 135.5,
135.0, 134.7, 130.6, 129.2, 128.1, 127.2, 126.8, 124.0, 121.7,
121.0, 120.1, 119.1, 114.1, 84.8, 58.2, 55.2; MS (ESI): m/z 363
(M + H)+; HRMS ESI (M + H)+ m/z calcd for C21H16N2O2Cl (M +
H)+ 363.0894, found 363.0901.
(d, J = 7.3 Hz, 1H), 7.66–7.54 (m, 3H), 7.25–7.18 (m, 2H),
7.14–7.04 (m, 3H), 5.16 (s, 1H), 4.02 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ: 164.9, 163.9, 162.0, 152.6, 134.7, 132.9, 131.0, 130.9,
128.1, 127.1, 126.8, 124.0, 121.8, 121.1, 120.1, 119.3, 116.0,
115.6, 114.2, 85.0, 58.1, 55.2; MS (ESI): m/z 347 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C21H16N2O2F (M + H)+
347.1190, found 347.1184.
Methyl 3-(4-chlorophenyl)-2-cyano-6-methoxy-2,3-dihydrobenzo-
Methyl 2-cyano-3-(4-methylphenyl)-2,3-dihydronaphtho[1,2-b]- furan-2-carbimidate (3n). Yield: 1.18 g (69%); mp 111–112 °C;
IR (neat, cm−1) 3292, 2947, 1663, 1500, 1327, 823; 1H NMR
(300 MHz, CDCl3) δ: 8.12 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.17
furan-2-carbimidate (3i). Yield: 1.33 g (78%); mp 118–120 °C;
IR (neat, cm−1) 3330, 2949, 1907, 1668, 1380, 861; 1H NMR
(300 MHz, CDCl3) δ: 8.20 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.88
(d, J = 7.3 Hz, 1H), 7.65–7.52 (m, 3H), 7.25–7.06 (m, 5H), 5.13
(s, 1H), 4.00 (s, 3H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ:
165.1, 152.5, 138.7, 134.5, 134.0, 129.6, 129.1, 128.1, 127.0,
126.7, 123.7, 122.0, 121.0, 120.1, 119.8, 114.3, 85.2, 58.6, 55.1,
21.2; MS (ESI): m/z 343 (M + H)+; HRMS ESI (M + H)+ m/z calcd
for C22H19N2O2 (M + H)+ 343.1441, found 343.1445.
Methyl 3-(4-bromophenyl)-2-cyano-2,3-dihydronaphtho[1,2-b]-
furan-2-carbimidate (3j). Yield: 1.74 g (86%); mp 136–138 °C;
IR (neat, cm−1) 3318, 2952, 1678, 1381, 816; 1H NMR
(500 MHz, CDCl3) δ: 8.23 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.89
(d, J = 7.7 Hz, 1H), 7.64–7.56 (m, 3H), 7.53 (d, J = 8.8 Hz, 2H),
7.11 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 7.7 Hz, 1H), 5.13 (s, 1H),
4.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 164.7, 152.6, 136.0,
134.7, 132.1, 130.9, 128.1, 127.2, 126.8, 124.0, 123.2, 121.7,
121.0, 120.1, 119.1, 114.1, 84.7, 58.2, 55.2; MS (ESI): m/z 407
(M + H)+; HRMS ESI (M + H)+ m/z calcd for C21H16N2O2Br (M +
H)+ 407.0389, found 407.0392.
(d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.66–6.58 (m, 2H),
4.88 (s, 1H), 3.97 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ: 164.8, 161.7, 135.7, 134.9, 130.6, 129.1, 125.8, 117.5,
97.0, 56.9, 55.7, 55.1; MS (ESI): m/z 343 (M + H)+; HRMS ESI
(M + H)+ m/z calcd for C18H16N2O3Cl (M + H)+ 343.0844, found
343.0842.
General procedure for the synthesis of compounds 5(a–d).
Compounds 4(a–d) were prepared according to the procedure
reported in the literature.19 To a suspension of 3-amino-1-aryl-
1H-benzo[f]chromene-2-carbonitrile analog [4(a–d), 3 mmol]
in methanol (5 mL), N-chlorosuccinimide (3 mmol) was
added. After stirring for half an hour at room temperature,
piperidine (3.6 mmol) was added to the reaction mixture. The
resulting mixture was stirred at room temperature, till the
product is precipitated out. The solid precipitate was filtered
and washed with cold methanol or ethanol to afford the pure
product 5(a–d).
Methyl 2-cyano-1-phenyl-1,2-dihydronaphtho[2,1-b]furan-2-car-
bimidate (5a). Yield: 0.767 g (78%); mp 160–162 °C; IR (neat,
cm−1) 3317, 2951, 2230, 1961, 1669, 1379, 812; 1H NMR
Methyl
2-cyano-3-(pyridin-3-yl)-2,3-dihydronaphtho[1,2-b]-
furan-2-carbimidate (3k). Yield: 1.36 g (83%); mp 141–143 °C;
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4412–4420 | 4417

View Article Online
Paper
Organic & Biomolecular Chemistry
(300 MHz, CDCl3) δ: 8.15 (s, 1H), 7.92–7.83 (m, 2H), 7.41–7.17
(m, 9H), 5.32 (s, 1H), 4.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ:
165.0, 154.8, 137.0, 131.5, 130.8, 129.6, 129.0, 128.9, 128.8,
128.7, 127.5, 124.4, 122.9, 117.6, 114.1, 111.4, 84.8, 57.5, 55.3;
MS (ESI): m/z 329 (M + H)+; HRMS ESI (M + H)+ m/z calcd for
C21H17N2O2 (M + H)+ 329.1284, found 329.1276.
Dimethyl
3-(4-chlorophenyl)naphtho[1,2-b]furan-2,2(3H)-bis-
(carbimidate) (7). Yield: 0.283 g (72%); mp 132–134 °C; IR
(neat, cm−1) 3237, 2941, 2849, 1664, 1348, 1099, 940; H NMR
1
(300 MHz, CDCl3) δ: 8.18 (d, J = 7.9 Hz, 1H), 8.13 (s, 1H), 7.99
(s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.64–7.47 (m, 3H), 7.21 (d, J =
8.5 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 2H),
Methyl 1-(4-chlorophenyl)-2-cyano-1,2-dihydronaphtho[2,1-b]- 5.33 (s, 1H), 3.90 (s, 3H), 3.29 (s, 3H); 13C NMR (125 MHz,
furan-2-carbimidate (5b). Yield: 0.955 g (88%); mp 167–169 °C;
IR (neat, cm−1) 3322, 2960, 1908, 1683, 1312, 821; 1H NMR
(300 MHz, CDCl3) δ: 8.18 (s, 1H), 7.92–7.83 (m, 2H), 7.39–7.30
(m, 5H), 7.19–7.11 (m, 3H), 5.30 (s, 1H), 4.01 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 164.6, 154.8, 135.4, 134.8, 131.8, 130.8,
130.1, 129.4, 129.3, 129.0, 127.7, 124.5, 122.7, 117.0, 114.0,
111.4, 84.5, 56.8, 55.3; MS (ESI): m/z 363 (M + H)+; HRMS ESI
(M + H)+ m/z calcd for C21H16N2O2Cl (M + H)+ 363.0894, found
363.0892.
CDCl3) δ: 168.4, 165.8, 152.3, 137.2, 134.4, 133.5, 130.5, 128.2,
126.7, 126.4, 123.3, 122.3, 121.6, 121.1, 120.3, 92.6, 54.7, 54.0,
53.3; MS (ESI): m/z 395 (M + H)+; HRMS ESI (M + H)+ m/z calcd
for C22H20N2O3Cl (M + H)+ 395.1157, found 395.1138.
Dimethyl 3-(4-methylphenyl)naphtho[1,2-b]furan-2,2(3H)-bis-
(carbimidate) (8). Yield: 0.282 g (79%); mp 136–138 °C; IR
1
(neat, cm−1) 3320, 2941, 1902, 1662, 1435, 1099, 934; H NMR
(500 MHz, CDCl3) δ: 8.17 (d, J = 8.2 Hz, 1H), 8.13 (s, 1H), 7.96
(s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60–7.45 (m, 3H), 7.09 (d, J =
Methyl 2-cyano-1-(4-methoxyphenyl)-1,2-dihydronaphtho[2,1-b]- 8.4 Hz, 1H), 7.02 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 7.6 Hz, 2H),
5.31 (s, 1H), 3.89 (s, 3H), 3.27 (s, 3H), 2.27 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 168.8, 166.1, 152.2, 137.2, 135.5, 134.3,
furan-2-carbimidate (5c). Yield: 0.848 g (79%); mp 140–142 °C;
IR (neat, cm−1) 3319, 2941, 1892, 1677, 1381, 862; 1H NMR
(300 MHz, CDCl3) δ: 8.13 (s, 1H), 7.90–7.82 (m, 2H), 7.39–7.06
(m, 6H), 6.88 (d, J = 8.6 Hz, 2H), 5.29 (s, 1H), 4.00 (s, 3H), 3.79
(s, 3H); 13C NMR (75 MHz, CDCl3) δ: 165.1, 159.8, 154.7, 131.4,
130.8, 129.9, 129.7, 128.9, 127.5, 124.3, 123.0, 117.8, 114.4,
114.2, 111.5, 85.1, 57.0, 55.1; MS (ESI): m/z 359 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C22H19N2O3 (M + H)+
359.1390, found 359.1384.
129.0, 128.7, 128.1, 126.4, 126.2, 123.0, 122.6, 122.2, 121.1,
120.3, 92.8, 54.6, 54.4, 53.3, 21.0; MS (ESI): m/z 375 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C23H23N2O3 (M + H)+
375.1703, found 375.1704.
Dimethyl 3-(thiophen-2-yl)naphtho[1,2-b]furan-2,2(3H)-bis(car-
bimidate) (9). Yield: 0.267 g (73%); mp 134–136 °C; IR (neat,
1
cm−1) 3319, 2944, 2841, 2230, 1663, 1433, 1081, 936; H NMR
Methyl 2-cyano-1-(4-cyanophenyl)-1,2-dihydronaphtho[2,1-b]- (300 MHz, CDCl3) δ: 8.17 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.96
furan-2-carbimidate (5d). Yield: 0.868 g (82%); mp 188–190 °C;
IR (neat, cm−1) 3316, 2960, 2230, 1955, 1683, 1314, 821;
1H NMR (300 MHz, CDCl3) δ: 8.23 (s, 1H), 7.96–7.86 (m, 2H),
7.68 (d, J = 8.3 Hz, 2H), 7.42–7.30 (m, 5H), 7.07 (d, J = 7.5 Hz,
1H), 5.38 (s, 1H), 4.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ: 164.1, 155.0, 142.0, 132.7, 132.1, 130.8, 129.6, 129.1, 127.8,
124.6, 122.4, 118.1, 116.2, 113.7, 112.8, 111.4, 84.1, 57.0, 55.3;
MS (ESI): m/z 354 (M + H)+; HRMS ESI (M + H)+ m/z calcd for
C22H16N3O2 (M + H)+ 354.1237, found 354.1230.
General procedure for the synthesis of biscarbimidate
esters (6–9). To the highly functionalized pyran analog
[1 mmol], 1 N solution of methanolic KOH (3 mmol)
was added and the resulting mixture was stirred at room
temperature for 36 hours. The resultant reaction mixture was
concentrated, 20 mL of CHCl3 was added and filtered
to remove KOH residue. The filtrate was concentrated and
recrystallized from methanol or ethanol to give the pure
product (6–9).
(s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.63–7.48 (m, 3H), 7.25–7.15
(m, 2H), 6.93–6.87 (m, 1H), 6.73 (d, J = 3.0 Hz, 1H), 5.64 (s,
1H), 3.89 (s, 3H), 3.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ:
168.3, 165.7, 152.1, 141.4, 134.5, 128.1, 127.1, 126.7, 126.5,
126.3, 125.4, 123.1, 122.5, 121.7, 121.1, 120.4, 92.5, 54.6, 53.5,
49.5; MS (ESI): m/z 367 (M + H)+; HRMS ESI (M + H)+ m/z calcd
for C20H19N2O3S (M + H)+ 367.1110, found 367.1108.
General procedure for the hydrolysis of carbimidate esters,
synthesis of compounds (10–12). 10% Dilute HCl (5 mL) was
added to a carbimidate analog [1 mmol] in acetone (5 mL),
and stirred at room temperature for 20–30 minutes. The resul-
tant mixture was filtered and washed with cold methanol or
recrystallized from methanol to afford the pure product
[10–12].
Methyl
2-cyano-3-(thiophen-2-yl)-2,3-dihydronaphtho[1,2-b]-
furan-2-carboxylate (10). Yield: 0.321 g (96%); mp 176–178 °C;
IR (neat, cm−1) 2956, 1770, 1252, 1095, 709; 1H NMR
(300 MHz, CDCl3) δ: 8.09–8.04 (m, 1H), 7.90–7.86 (m, 1H),
Dimethyl 3-phenylnaphtho[1,2-b]furan-2,2(3H)-bis(carbimidate) 7.61–7.53 (m, 3H), 7.39–7.34 (m, 1H), 7.29–7.26 (m, 1H),
(6). Yield: 0.270 g (75%); mp 186–188 °C; IR (neat, cm−1) 3325,
2945, 2843, 1667, 1434, 1082, 938; H NMR (500 MHz, CDCl3)
7.10–7.05 (m, 2H), 5.66 (s, 1H), 4.00 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ: 165.3, 153.0, 138.7, 134.8, 128.2, 128.0, 127.5, 127.1,
126.9, 126.6, 123.5, 121.6, 121.4, 120.2, 118.9, 113.4, 86.2, 54.6,
53.4; MS (ESI): m/z 358 (M + Na)+; HRMS ESI (M + H)+ m/z
calcd for C19H13NO3SNa (M + Na)+ 358.0508, found 358.0501.
1
δ: 8.19 (d, J = 8.2 Hz, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.86 (d, J =
8.2 Hz, 1H), 7.62–7.47 (m, 3H), 7.24–7.20 (m, 3H), 7.11–6.99
(m, 3H), 5.34 (s, 1H), 3.90 (s, 3H), 3.23 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 168.7, 166.0, 152.2, 138.5, 134.3, 129.6,
129.1, 128.1, 128.0, 127.6, 126.5, 126.2, 123.0, 122.6, 122.0,
121.0, 120.3, 92.7, 54.7, 54.6, 53.2; MS (ESI): m/z 383 (M + Na)+;
HRMS ESI (M + H)+ m/z calcd for C22H20N2O3Na (M + Na)+
383.1366, found 383.1352.
Methyl
2-cyano-3-(4-nitrophenyl)-2,3-dihydronaphtho[1,2-b]-
furan-2-carboxylate (11). Yield: 0.362 g (97%); mp 185–187 °C;
IR (neat, cm−1) 2958, 1768, 1251, 1047, 806; 1H NMR
(300 MHz, CDCl3) δ: 8.27 (d, J = 9.0 Hz, 2H), 8.12–8.07 (m, 1H),
7.92–7.88 (m, 1H), 7.64–7.55 (m, 3H), 7.45 (d, J = 9.0 Hz, 2H),
4418 | Org. Biomol. Chem., 2014, 12, 4412–4420
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
7.09 (d, J = 8.3 Hz, 1H), 5.50 (s, 1H), 4.02 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ: 165.2, 153.4, 148.3, 143.4, 134.9, 130.3,
128.0, 127.4, 126.9, 124.2, 124.0, 121.4, 121.1, 120.2, 118.1,
113.5, 85.4, 57.7, 54.8; MS (ESI): m/z 397 (M + Na)+; HRMS ESI
(M + H)+ m/z calcd for C21H14N2O5Na (M + Na)+ 397.0795,
found 397.0790.
Methyl 2-cyano-1-(4-cyanophenyl)-1,2-dihydronaphtho[2,1-b]-
furan-2-carboxylate (12). Yield: 0.343 g (97%); mp 188–190 °C;
IR (neat, cm−1) 2957, 2228, 1767, 1251, 1051, 751; 1H NMR
(300 MHz, CDCl3) δ: 7.92 (d, J = 9.0 Hz, 1H), 7.90–7.87 (m, 1H),
7.68 (d, J = 8.5 Hz, 2H), 7.40–7.32 (m, 5H), 7.10 (d, J = 7.4 Hz,
1H), 5.52 (s, 1H), 3.99 (s, 3H); 13C NMR (75 MHz, CDCl3) δ:
165.4, 155.7, 141.5, 132.9, 132.2, 130.7, 129.6, 129.2, 127.9,
124.5, 122.4, 118.2, 116.1, 113.3, 113.1, 111.7, 84.1, 57.0, 54.9;
MS (ESI): m/z 377 (M + Na)+; HRMS ESI (M + H)+ m/z calcd for
C22H16N3O2 (M + Na)+ 377.0902, found 377.0900.
2 The Chemistry of Heterocyclic Compounds Chromenes, Chro-
manes, and Chromones, ed. G. P. Ellis, A. Weissberger and
E. C. Taylor, John Wiley, New York, 1977, ch. II, p. 11.
3 E. A. A. Hafez, M. H. Elnagdi, A. G. A. Elagemey and
F. M. A. A. El-Taweel, Heterocycles, 1987, 26, 903.
4 (a) E. Maalej, F. Chabchoub, M. J. Oset-Gasque,
M. Esquivias-Perez, M. P. Gonzalez, L. Monjas, C. Perez,
C. De los Rios, M. I. Rodriguez-Franco, I. Iriepa,
I. Moraleda, M. Chioua, A. Romero, J. Marco-Contelles and
A. Samadi, Eur. J. Med. Chem., 2012, 54, 750;
(b) N. R. Kamdar, D. D. Haveliwala, P. T. Mistry and
S. K. Patel, Eur. J. Med. Chem., 2010, 45, 5056;
(c) W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang, Y. Wang,
J. Zhao, S. Jia, J. Herich, D. Labreque, R. Storer,
K. Meerovitch, D. Bouffard, R. Rej, R. Denis, C. Blais,
S. Lamothe, G. Attardo, H. Gourdeau, B. Tseng,
S. Kasibhatla and S. X. Cai, J. Med. Chem., 2004, 47, 6299;
(d) W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang, J. Zhao,
C. Crogan-Grundy, L. Xu, S. Lamothe, H. Gourdeau,
R. Denis, B. Tseng, S. Kasibhatla and S. X. Cai, J. Med.
Chem., 2007, 50, 2858.
5 (a) M. Kidwai, S. Saxena, M. K. R. Khan and S. S. Thukral,
Bioorg. Med. Chem. Lett., 2005, 15, 4295; (b) P. W. Smith,
S. L. Sollis, P. D. Howes, P. C. Cherry, I. D. Starkey,
K. N. Cobley, H. Weston, J. Scicinski, A. Merritt,
A. Whittington, P. Wyatt, N. Taylor, D. Green, R. Bethell,
S. Madar, R. J. Fenton, P. J. Morley, T. Pateman and
A. Beresford, J. Med. Chem., 1998, 41, 787.
6 (a) S. R. Mandha, S. Siliveri, M. Alla, V. R. Bommena,
M. R. Bommineni and S. Balasubramanian, Bioorg. Med.
Chem. Lett., 2012, 22, 5272; (b) J.-L. Wang, D. Liu,
Z.-J. Zheng, S. Shan, X. Han, S. M. Srinivasula, C. M. Croce,
E. S. Alnemri and Z. Huang, Proc. Natl. Acad. Sci. U. S. A.,
2000, 97, 7124.
7 (a) M. E. A. Zaki, H. A. Soliman, O. A. Hiekal and
A. E. Rashad, Z. Naturforsch., C: Biosci., 2006, 61, 1;
(b) S. C. Kuo, L. J. Huang and H. Nakamura, J. Med. Chem.,
1984, 27, 539.
Acidic hydrolysis of 6a
Dimethyl 3-phenylnaphtho[1,2-b]furan-2,2(3H)-dicarboxylate
(13). 10% Dilute HCl (5 mL) was added to the biscarbimidate
analog [5a, 1 mmol] in methanol (5 mL), and stirred at room
temperature for 20 minutes. The resultant mixture was filtered
and washed with cold methanol to give the pure product [13].
Yield: 0.330 g (91%); mp 133–135 °C; IR (neat, cm−1) 2952,
1
1745, 1300, 1278, 1100, 1053, 746; H NMR (500 MHz, CDCl3)
δ: 8.17 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.55–7.46
(m, 3H), 7.29–7.23 (m, 3H), 7.18–7.12 (m, 3H), 5.75 (s, 1H),
3.89 (s, 3H), 3.22 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 168.1,
166.2, 153.6, 137.8, 134.4, 129.4, 128.2, 127.9, 127.8, 126.4,
125.9, 122.4, 122.3, 121.7, 120.9, 120.2, 94.2, 55.1, 53.7, 52.3;
MS (ESI): m/z 385 (M + Na)+; HRMS ESI (M + H)+ m/z calcd for
C22H18O5Na (M + Na)+ 385.1046, found 385.1045.
Acknowledgements
We thank the Director, I.I.C.T. and Head, Crop Protection
Chemicals Division, for the facilities and S.R.M. thanks the
Council of Scientific and Industrial Research (CSIR), India, for
the financial support.
8 (a) M. A. Al-Haiza, M. S. Mostafa and M. Y. El-Kady, Mole-
cules, 2003, 8, 275; (b) T. A. Nakib, V. Bezjak, S. Rashid,
B. Fullam and M. J. Meegan, Eur. J. Med. Chem., 1991, 26,
221.
9 (a) F. M. Abdelrazek, P. Metz, O. Kataeva, A. Jager and
S. F. El-Mahrouky, Arch. Pharm., 2007, 340, 543;
(b) F. M. Abdelrazek, P. Metz, N. H. Metwally and S. F. El-
Mahrouky, Arch. Pharm., 2006, 339, 456.
Notes and references
1 (a) P. Bhattacharyya, K. Pradhan, S. Paul and A. R. Das,
Tetrahedron Lett., 2012, 53, 4687; (b) H. Hayour,
A. Bouraiou, S. Bouacida, F. Berree, B. Carboni, T. Roisnel 10 K. C. Joshi, R. Jain and K. Sharma, J. Indian Chem. Soc.,
and A. Belfaitah, Tetrahedron Lett., 2011, 52, 4868; 1988, 65, 202.
(c) A. Solhy, A. Elmakssoudi, R. Tahir, M. Karkouri, 11 N. Foloppe, L. M. Fisher, R. Howes, A. Potter,
M. Larzek, M. Bousmina and M. Zahouily, Green Chem.,
2010, 12, 2261; (d) F. K. Mohammed, A. Y. Soliman,
A. G. S. Robertson and A. E. Surgenor, Bioorg. Med. Chem.,
2006, 14, 4792.
A. Ssawy and M. G. Badre, J. Chem. Pharm. Res., 2009, 1, 12 S. R. Mandha, M. Alla, V. R. Bommena, J. B. Nanubolu,
213; (e) N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko, S. K. Lingala and S. Yarasi, J. Org. Chem., 2012, 77, 10648.
M. Yu. Antipin, I. V. Magedov and A. Kornienko, J. Org. 13 H. H. Otto, O. Rinus and H. Schmelz, Monatsh. Chem.,
Chem., 2007, 72, 3443; (f) N. Martin, C. Seoane and
J. L. Soto, Tetrahedron, 1988, 44, 5861.
1979, 110, 115.
14 B. M. Fraga, Nat. Prod. Rep., 1992, 9, 217.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4412–4420 | 4419

View Article Online
Paper
Organic & Biomolecular Chemistry
15 A. T. Merritt and S. V. Ley, Nat. Prod. Rep., 1992, 9, 243.
16 S. Ohkawa, K. Fukatsu, S. Miki, T. Hashimoto,
J. Sakamoto, T. Doi, Y. Nagai and T. Aono, J. Med.
Chem., 1997, 40, 559.
X.-S. Li, D.-C. Xu, M.-M. Ge, W.-D. Zhu and J.-W. Xie, J. Org.
Chem., 2010, 75, 8716; (f) P. Xie, Y. Huang and R. Chen,
Org. Lett., 2010, 12, 3768; (g) F. Bertolini and M. Pineschi,
Org. Prep. Proced. Int., 2009, 41, 385.
17 (a) U. A. Kshirsagar, C. Regev, R. Parnes and D. Pappo, Org. 18 M. M. Kandeel and A. M. Kamal, Eur. J. Med. Chem., 2013,
Lett., 2013, 15, 3174; (b) C. Huo, J. An, W. Chaang, X. Jia, 59, 183.
L. Kang and M. Wu, Tetrahedron, 2013, 69, 6375; 19 (a) X.-Y. Meng, H.-J. Wang, C.-P. Wang and Z.-H. Zhang,
(c) C. Huo, X. Xu, X. An, X. Jia, X. Wang and C. Wang,
J. Org. Chem., 2012, 77, 8310; (d) S. A. Snyder, A. Gollner
and M. I. Chiriac, Nature, 2011, 474, 461; (e) L.-P. Fan, P. Li,
Synth. Commun., 2011, 41, 3477; (b) M. M. Heravi,
K. Bakhtiari, V. Zadsirjan, F. F. Bamoharram and
O. M. Heravi, Bioorg. Med. Chem. Lett., 2007, 17, 4262.
4420 | Org. Biomol. Chem., 2014, 12, 4412–4420
This journal is © The Royal Society of Chemistry 2014