Facile and efficient synthesis of 3,4,5-substituted furan-2(5H)-ones by using β-cyclodextrin as reusable catalyst

Article abstract of DOI:10.1016/j.tet.2009.04.081

3,4,5-Substituted furan-2(5H)-one derivatives were synthesized by using β-cyclodextrin as a catalyst in water via biomimetic approach. β-Cyclodextrin can be recovered and reused.

Full text of DOI:10.1016/j.tet.2009.04.081

Tetrahedron 65 (2009) 5251–5256
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Facile and efficient synthesis of 3,4,5-substituted furan-2(5H)-
ones by using b-cyclodextrin as reusable catalyst
*
S. Narayana Murthy, B. Madhav, A. Vijay Kumar, K. Rama Rao, Y.V.D. Nageswar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
3,4,5-Substituted furan-2(5H)-one derivatives were synthesized by using
water via biomimetic approach. -Cyclodextrin can be recovered and reused.
Ó 2009 Elsevier Ltd. All rights reserved.
b-cyclodextrin as a catalyst in
Received 9 January 2009
Received in revised form 23 April 2009
Accepted 24 April 2009
b
Available online 3 May 2009
HO
Br
O
1. Introduction
O
Br
O
Furan-2(5H)-ones have attracted the attention of several organic
chemists as valuable targets due to their presence as a subunit in
many natural products isolated from a variety of sources like
sponges, algae,1 animals,2 plants3 and insects.4 According to the
literature reports this subunit is present in as many as more than
13,000 natural products.5 This coreunit isthe keystructuretoinduce
a wide range of biological activities like antimicrobial,6 antifungal,7
anti-inflamatory,8 anticancer9 and anti-viral HIV-1.10 Butenolide
synthon is the core structural unit found in many bioactive natural
products such assarcophine1 andrubrolide2, whichisisolatedfrom
the colonial tunicate Ritterela rubra,11,12 as well as in synthetic drug
benfurodil hemisuccinate 3 (EucilatÒ).
O
O
Br
O
Br
HO
1
2
O
O
COOH
CH3
O
O
CH3
3
In view of the biological activity associated with butenolide
synthon researchers have developed a number of methodologies
to construct substituted furan-2(5H)-one unit. Domschke et al.
developed a methodology for the synthesis of 2(5H)-furanone,
which describes the method in short.13 Liu et al. described the
synthesis of 2(5H)-furanone by refluxing furfural with hydrogen
peroxide followed by oxidation leading to a mixture of 2(3H) and
2(5H)-furanones.14 Chunling Fu et al. developed a protocol for the
synthesis of 4-iodofuran-2(5H)-ones from iodolactonisation of
allenoates with molecular iodine.15
Sweeney et al. reported the first preparation of 3,4-bistributyl-
stannyl 2(5H)-furanones by reacting TBS as well as THP protected
butynoate with hexabutylditin in the presence of PdCl2(PPh3)2
leading to substituted acrylate intermediate, which upon treating
under a variety of conditions yielded desired furanone synthon.16
More recently Mauro et al. described the construction of furanone
system via ring-closing metathesis catalyzed by the first generation
Grubbs’ catalyst.17 The above-mentioned methodologies suffer from
certain limitations like multistep strategies, use of costly metal cat-
alysts and highly volatile solvents. Thus, in view of these short-
comings there is need to develop mild and environmentally benign
methodology to synthesize furanones, by replacing organic solvents
with water using a recyclable activator as a part of green chemical
approach.
Presently organic reactions in aqueous phase have attracted
attention because of the added advantages of water as an envi-
ronmentally benign and economically affordable solvent. However
the fundamental problem in performing the reaction in water is
that many organic substrates are hydrophobic and insoluble in
water. In continuation of our efforts towards developing bio-
mimetic approaches,18 through supramolecular catalysis and also
to overcome the drawbacks of the existing methodologies for the
synthesis of furanones, we report herein, the synthesis of fur-
anones in presence of
catalyst.
b-cyclodextrin, as recyclable supramolecular
* Corresponding author. Tel.: þ91 40 27191654; fax: þ91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.081

5252
S. Narayana Murthy et al. / Tetrahedron 65 (2009) 5251–5256
2. Results and discussion
groups of
Fig. 1.
b-CD, which further reacts with aldehyde as indicated in
Cyclodextrins are cyclic oligosaccharides possessing hydro-
phobic cavities. They are torus-like macro rings consisting of six
All reactions were carried out with a catalytic amount (10 mol %)
-CD in water. But for NMR studies inclusion complex was pre-
pared by taking
-CD and aniline in 1:1 ratio. A comparison of 1H
of
b
(
a
-CD), seven (
b
-CD), eight (
g
-CD) 1,4-linked
a
-
D
-glucopyranose
b
units. Cyclodextrins and modified cyclodextrins have attracted
much attention as aqueous based hosts for inclusion complex
phenomenon with a wide variety of guests. Inclusion complex
formation occurs as a result of interaction between hydrophobic
cavity of CD and hydrophobic portion of guest. These bind the
substrates selectively and catalyze the chemical reactions by su-
pramolecular catalysis involving reversible formation of host–
guest complex with the substrate by non-covalent bonding as
seen in the enzyme complexation process. These features of CDs
attracted us to investigate reactions, under biomimetic
conditions.
NMR spectra of aniline,
(Table 3).
b-CD and b-CD/aniline complex was done
In the 1H NMR spectrum (in DMSO-d6) of aniline, the aro-
matic protons from ortho position appear as
a doublet at
6.61 ppm (J¼8.2 Hz), while meta and para protons appear as
triplets at 7.06 (J¼7.4 Hz) and 6.55 (J¼6.7 Hz), respectively.
Amine protons in aniline appear as singlet at 5.05 ppm. The 1H
NMR spectrum of b-CD/aniline inclusion complex shows upfield
shift of aromatic protons as well as amine protons of aniline. This
upfield shift of aniline protons can be due to the inclusion of
aniline inside
protons due to the incorporation inside the
protons located in the
-CD cavity (C3–H and C5–H) are also
shifted upfield due to magnetic anisotropy caused by the guest
(aniline) molecule.19
-CD was recovered and reused. After the
reaction, the reaction mass was cooled to room temperature and
-CD was filtered and washed with ice-cold water and dried. The
recovered -CD was further used with the same substrates as
a catalyst and checked for the yields and catalytic activity of
recovered catalyst ( -CD). As shown in Table 1, the yields of
b
-CD cavity. Apart from the upfield shift of aniline
In general, model reaction was carried by in situ formation of
b
-CD cavity, the
b
-cyclodextrin complex of aniline in water at 50 ꢀC, followed by
b
successive addition of diethylacetylenedicarboxylate and benzal-
dehyde while stirring at 60–70 ꢀC to yield corresponding 3,4,5-
substituted furan-2(5H)-one in almost quantitative yield (Scheme
1) (Table 2, entry 1, 85%) after 12 h. Controlled reaction in water as
well as in neat indicated no product formation, even after pro-
longed reaction times (24–30 h). Next, the scope of this novel
transformation to construct 3,4,5-substituted furan-2(5H)-one
b
b
b
b
3,4,5-substituted furan-2(5H)-one after two to three recycles
were almost same (Table 1).
CH3
H
O
O
NH2
O
COOEt
COOEt
3. Conclusion
NH
β−CD (10 mol%)
water
In conclusion we have demonstrated an elegant and simple
method for the synthesis of furanone synthon in one pot by using b-
O
O
60-70 °C
cyclodextrin as a reusable catalyst and water as a reaction medium.
This methodology also overcomes the formation of unwanted
products, lower yields, high temperature etc., thus making an
ecofriendly procedure, which will be a useful addition to green
chemistry.
Scheme 1.
derivatives with various substituted anilines and substituted al-
dehydes was evaluated by keeping diethylacetylenedicaboxylate
as a common substrate (Table 2). In general, all the reactions were
very clean, and the 3,4,5-substituted furan-2(5H)-one derivatives
were obtained in high yields with good amount of catalyst re-
covery. The results showed that the substitution group played
a major role in governing the reactivity of the substrate as well as
product yield. The reaction with electron donating group on ani-
line gave good yield (Table 2, entry 10, 88%), while with electron
withdrawing groups, such as para-chloro and para-fluoro (Table 2,
entries11 and 12), yields decreased due to electronic factors. With
aliphatic amines such as benzylamines and n-alkylamines the
reaction was very sluggish. All products were characterized by 1H,
4. Experimental
4.1. General
1H NMR spectra were recorded on Brucker’s Gemini-200 MHz or
Varian’s Avance-300 MHz spectrometer in CDCl3 with TMS as an
internal standard. Mass spectra were recorded on Finnigan MAT
1020 mass spectrometer operating at 70 eV. IR spectra were
recorded using Thermo Nicolet Nexus 670 FT-IR spectrometer. El-
emental analyses were carried out by using Elementar-Vario MICRO
Cube model available at IICT, Hyderabad.
13
C NMR, IR and mass spectrometry. The catalytic activity of the
b
-CD was established by the fact that no lactone formation was
observed in the absence of -cyclodextrin even after longer re-
action times. The evidence for the formation of 3,4,5-substituted
furan-2(5H)-ones in presence of
-CD was supported by 1H NMR
studies of inclusion complex between aniline and -CD. The
hydrophobic environment of -CD facilitates the formation of
4.2. General procedure for the synthesis of 3,4,5-substituted
furan-2(5H)-ones
b
b
4.2.1. Typical example: synthesis of ethyl 2,5-dihydro-5-oxo-2-
phenyl-4-(phenylamino)furan-3-carboxylate (Table 2, entry 1)
b
b
b-Cyclodextrin (0.113 g, 0.1 mmol (10 mol %)) was dissolved in
lactones via inclusion complex of aniline/diethylethylenedicar-
boxylate carbanion stabilized by the primary and secondary –OH
water (15 mL). To this clear solution, aniline (0.093 g, 1.0 mmol) was
added and stirred for 2 min, and then diethylacetylenedicarboxylate
(0.170 g, 1.0 mmol) followed by benzaldehyde (0.106 g, 1.0 mmol)
were added, after which the reaction mixture was heated at 60–
70 ꢀC until completion of the reaction as indicated by TLC. The re-
Table 1
Recyclability of
b-CD
Cycles
Yield (%)
Catalyst recovered (%)
action mixture was cooled to the room temperature and b-CD was
filtered, the aqueous phase was extracted with ethyl acetate
(3ꢁ10 mL). The organic layers were washed with water, saturated
brine solution and dried over anhydrous Na2SO4. The combined or-
ganic layers were evaporated under reduced pressure and the
Native
85
83
80
80
93
91
89
86
1
2
3

S. Narayana Murthy et al. / Tetrahedron 65 (2009) 5251–5256
5253
Table 2
-CD catalyzed synthesis of 3,4,5-substituted furan-2(5H)-ones
b
Entry
Anilines
Aldehydes
Products
Time (h)
12
Yielda (%)
CH3
NH
O
O
NH2
CHO
1
85
O
O
O
CH3
NH
CHO
O
NH2
NH2
NH2
NH2
NH2
2
3
4
5
6
13.5
13.5
14
81
81
81
80
81
Me
Me
O
O
O
CH3
O
CHO
NH
O
O
CH3
NH
O
Ph
O
CHO
O
Ph
O
O
O
CH3
O
O
CHO
CHO
NH
13
Cl
Cl
O
O
CH3
O
O
NH
12
EtO
EtO
O
O
CH3
NH
O
O
CHO
NH2
NH2
NH2
7
15
16
15
12
13
80
78
80
88
80
MeO
MeO
O
O
CH3
NH
O
O
CHO
CHO
8
O
O
CH3
NH
O
O
9
O
O
CH3
NH
O
O
NH2
CHO
10
11
H3C
O
CH3
O
CH3
NH
O
O
NH2
CHO
CHO
Cl
O
Cl
O
CH3
NH
O
O
NH2
12
12.5
79
F
O
F
O
(continued on next page)

5254
S. Narayana Murthy et al. / Tetrahedron 65 (2009) 5251–5256
Table 2 (continued )
Entry
Anilines
Aldehydes
Products
CH3
Time (h)
13
Yielda (%)
O
O
NH2
CHO
NH
13
14
80
I
O
I
O
CH3
NH
O
O
NH2
CHO
CHO
12
14
82
83
n-C4H9
O
n-C4H9
Cl
O
CH3
NH
O
NH2
O
15
Cl
O
O
a
Isolated yields.
1.33 (m, 6H, 2CH3), 2.54 (q, 2H, J¼8.0 Hz, CH2), 4.18 (q, 2H, J¼7.3 Hz,
OCH2), 5.65 (s, 1H, benzylic), 6.99–7.11 (m, 5H, arom.), 7.19–7.27 (m,
2H, arom.), 7.45 (d, J¼8.0 Hz, 2H, arom.); dC (300 MHz, CDCl3) 13.9,
15.1, 28.3, 61.2, 96.0, 122.1, 125.6, 127.3, 127.9, 128.8, 132.4, 137.1,
144.3, 156.2, 163.4, 165.0; MS m/z (ESI): 374 ([MþNa]þ).
O
H
O
H
O
O
O
NH
O
4.2.3. Ethyl 2,5-dihydro-5-oxo-4-(phenylamino)-2-p-
tolylfuran-3-carboxylate (3)
H O
Yield 0.27 g (81%). Found: C, 71.12; H, 5.59; N, 4.21. C20H19NO4
requires C, 71.20; H, 5.68; N, 4.15%. Rf (70% EtOAc/n-hexane) 0.25;
nmax (KBr) 3397, 2922, 1718, 1683, 1586, 1492, 1244 cmꢂ1
; dH
Figure 1. Plausible mechanistic pathway.
(300 MHz, CDCl3) 1.27 (t, 3H, J¼8.0 Hz, CH2CH3), 2.24 (s, 3H, CH3),
4.11 (q, 2H, J¼7.3 Hz, OCH2), 5.61 (s, 1H, benzylic), 6.98–7.34 (m, 9H,
arom.); dC (300 MHz, CDCl3) 13.9, 20.8, 61.9, 122.2, 127.6, 128.0,
128.2, 129.3, 134.0, 135.2, 165.9, 169.1; MS m/z (ESI): 360
([MþNa]þ).
resulting crude product was purified by column chromatography by
using ethyl acetate and hexane (7:3) as eluent to give the title
compound (Table 2, entry 1) (0.274 g, 85%). Found: C, 70.49; H, 5.0;
N, 4.29. C19H17NO4 requires C, 70.58; H, 5.3; N, 4.33%. Rf (70% EtOAc/
n-hexane) 0.25; nmax (KBr) 3292, 1716, 1684, 1655 cmꢂ1
; dH
4.2.4. Ethyl 2-(4-(benzyloxy)phenyl)-2,5-dihydro-5-oxo-4-
phenylamino)furan-3-carboxylate (4)
(300 MHz, CDCl3) 1.19 (t, 3H, J¼6.6 Hz, CH2CH3), 4.16 (q, 2H, J¼7.3 Hz,
OCH2), 5.69 (s, 1H, benzylic), 7.03–7.32 (m, 5H, arom.), 7.45 (m, 5H,
arom.); dC (300 MHz, CDCl3) 13.9, 61.2,113.1,122.2,125.8,127.5,128.5,
128.9,135.0,136.2, 156.3, 162.9, 165.1; HRMS m/z calcd for C19H17NO4
([MþH]þ): 324.1250, found 324.1235.
Yield 0.34 g (81%). Found: C, 71.03; H, 5.49; N, 4.19. C26H23NO5
requires C, 71.71; H, 5.40; N, 3.26%. Rf (70% EtOAc/n-hexane) 0.21;
nmax (KBr) 3159, 2922, 1719, 1684, 1548, 1496, 1266 cmꢂ1
; dH
(300 MHz, CDCl3) 1.28 (t, 3H, J¼6.0 Hz, CH2CH3), 4.11 (q, 2H,
J¼6.7 Hz, OCH2), 4.91 (s, 2H, OCH2C6H5), 6.77 (s, 1H, benzylic), 7.07–
7.46 (m, 14H, arom.); dC (300 MHz, CDCl3) 14.7, 61.8, 70.2,111.3,
114.5, 118.2, 122.5, 126.2, 127.0,127.5,128.9, 132.3, 139.2, 144.9, 160.3,
166.9, 169.2; MS m/z (ESI): 452 ([MþNa]þ).
4.2.2. Ethyl 2-(4-ethylphenyl)-2,5-dihydro-5-oxo-4-
(phenylamino)furan-3-carboxylate (2)
Yield 0.28 g (81%). Found: C, 71.72; H, 6.12; N, 3.92. C21H21NO4
requires C, 71.78; H, 6.02; N, 3.99%. Rf (70% EtOAc/n-hexane) 0.22;
nmax (KBr) 3292, 1716, 1684, 1655 cmꢂ1
; dH (300 MHz, CDCl3) 1.13–
4.2.5. Ethyl 2-(4-chlorophenyl)-2,5-dihydro-5-oxo-4-
(phenylamino)furan-3-carboxylate (5)
Table 3
Yield 0.28 g (80%).Found: C, 63.71; H, 4.46; N, 3.93. C19H16ClNO4
requires C, 63.78; H, 4.51; N, 3.91%. Rf (70% EtOAc/n-hexane) 0.25;
400 MHz 1H chemical shifts of aniline and
b
-CD protons in free and complexed statea
-CD/aniline complex Dd
34
Protons
Aniline
b-CD
b
nmax (KBr) 3286, 2924, 1680, 1539, 1238 cmꢂ1
; dH (300 MHz, CDCl3)
H-ortho
H-meta
H-para
–NH2
C1
C2
C3
C4
C5
C6
O2
O3
O6
2646
2826
2621
2015
2612
2800
2594
1932
1980
1339
1461
1321
1444
1452
2293
2273
1793
1.19 (t, 3H, J¼6.7 Hz, CH2CH3), 4.20 (q, 2H, J¼6.7 Hz, OCH2), 5.71 (s,
1H, benzylic), 7.11–7.45 (m, 9H, arom.); dC (300 MHz, CDCl3) 14.0,
60.8, 114.6, 122.2, 126.0, 129.0, 133.8, 134.2, 135.9, 137.2, 146.3, 165.0,
169.1; MS m/z (ESI): 380 ([MþNa]þ).
26
27
83
1926
1346
1464
1327
1442
1448
2292
2272
1796
ꢂ54
7
ꢂ4
ꢂ6
ꢂ2
ꢂ4
ꢂ1
ꢂ1
3
4.2.6. Ethyl 2-(4-ethoxyphenyl)-2,5-dihydro-5-oxo-4-
(phenylamino)furan-3-carboxylate (6)
Yield 0.29 g (81%). Found: C, 68.62; H, 5.71; N, 3.80. C21H21NO5
requires C, 68.65; H, 5.76; N, 3.81%. Rf (70% EtOAc/n-hexane) 0.20;
nmax (KBr) 3443, 2924, 1681, 1595, 1240 cmꢂ1
; dH (300 MHz, CDCl3)
1.07 (t, 3H, J¼6.7 Hz, CH2CH3),1.30 (t, 3H, J¼6.7 Hz, CH2CH3), 4.10 (q,
a
Chemical shifts expressed in hertz with reference to DMSO-d6.
2H, J¼6.7 Hz, OCH2), 4.18 (q, 2H, J¼6.7 Hz, OCH2), 6.01 (s, 1H,

S. Narayana Murthy et al. / Tetrahedron 65 (2009) 5251–5256
5255
benzylic), 6.89 (d, 2H, J¼7.5 Hz, arom.), 7.04 (t, 1H, J¼6.7 Hz, arom.),
7.21–7.38 (m, 2H, arom.), 7.49–7.52 (m, 2H, arom.), 7.66 (d, 2H,
J¼7.5 Hz, arom.); dC (300 MHz, CDCl3) 14.3,14.8, 61.1, 64.8, 114.1,
116.2, 119.5, 125.6, 126.3, 126.9, 127.9, 132.2, 144.9, 145.2, 156.1,
164.9, 169.7; MS m/z (ESI): 390 ([MþNa]þ).
14.4, 61.9, 116.1, 117.3, 123.5, 127.6, 132.9, 140.3, 145.1, 153.6, 167.4,
170.1; MS m/z (ESI): 364 ([MþNa]þ).
4.2.13. Ethyl 4-(4-iodophenylamino)-2,5-dihydro-5-oxo-2-
phenylfuran-3-carboxylate (13)
Yield 0.35 g (80%). Found: C, 50.78; H, 3.7; N, 3.14. C19H16INO4
requires C, 50.80; H, 3.59; N, 3.12%. Rf (70% EtOAc/n-hexane) 0.23;
4.2.7. Ethyl 2,5-dihydro-2-(4-methoxyphenyl)-5-oxo-4-
(phenylamino)furan-3-carboxylate (7)
nmax (KBr) 3289, 2922, 1724, 1679, 1651 cmꢂ1
; dH (200 MHz, CDCl3)
Yield 0.28 g (81%).Found: C, 67.92; H, 5.46; N, 3.91. C20H19NO5
requires C, 67.98; H, 5.42; N, 3.96%. Rf (70% EtOAc/n-hexane) 0.21;
1.25 (t, 3H, J¼7.5 Hz, CH2CH3), 4.11 (q, 2H, J¼6.7 Hz, OCH2), 5.57 (s,
1H, benzylic), 7.16–7.47 (m, 9H, arom.); dC (200 MHz, CDCl3) 14.1,
61.9, 80.7, 114.9, 117.6, 123.4, 125.8, 127.5, 128.1, 129.7, 134.8, 136.5,
137.4, 141.2, 149.7, 166.3, 169.7; MS m/z (ESI): 472 ([MþNa]þ).
nmax (KBr) 3291, 2928, 1719, 1676, 1548, 1496 cmꢂ1
; dH (300 MHz,
CDCl3) 1.20 (t, 3H, J¼6.7 Hz, CH2CH3), 3.71 (s, 3H, OCH3), 4.19 (q, 2H,
J¼6.7 Hz, OCH2), 5.63 (s, 1H, benzylic), 6.70 (d, 2H, J¼8.3 Hz, arom.),
6.98–7.10 (m, 2H, arom.), 7.21–7.29 (m, 3H, arom.), 7.45 (d, 2H,
J¼7.5 Hz, arom.); dC (300 MHz, CDCl3) 14.3, 55.7, 61.5, 114.6, 124.8,
127.3, 128.9, 141.8, 145.2, 150.6, 167.3, 171.9; MS m/z (ESI): 376
([MþNa]þ).
4.2.14. Ethyl 4-(4-butylphenylamino)-2,5-dihydro-5-oxo-2-
phenylfuran-3-carboxylate (14)
Yield 0.31 g (82%).Found: C, 72.74; H, 6.62; N, 3.61. C23H25NO4 C,
72.80; H, 6.64; N, 3.69%. Rf (70% EtOAc/n-hexane) 0.25; nmax (KBr)
3321, 2923, 2853, 1680, 1593, 1238 cmꢂ1
; dH (300 MHz, CDCl3) 0.87
4.2.8. Ethyl 2,5-dihydro-2-(naphthalen-1-yl)-5-oxo-4-
(phenylamino)furan-3-carboxylate (8)
(t, 3H, J¼6.7 Hz, (CH2)3CH3), 1.26 (m, 5H, (CH2)2CH2CH3þOCH2CH3),
1.49 (m,2H, CH2CH2CH2CH3), 2.47 (t, 2H, J¼6.7 Hz, CH2(CH2)2CH3),
4.13 (q, 2H, J¼6.7 Hz, OCH2), 5.67 (s, 1H, benzylic), 7.02–7.35 (m, 9H,
arom.); dC (300 MHz, CDCl3) 14.1 22.6, 34.3, 35.7, 61.6, 114.6, 118.9,
126.8, 127.4, 129.6, 132.3, 134.2, 140.1, 145.2, 147.3,165.9, 170.6; MS
m/z (ESI): 402 ([MþNa]þ).
Yield 0.29 g (78%).Found: C, 73.95; H, 5.10; N, 3.74. C23H19NO4
requires C, 73.98; H, 5.13; N, 3.75%. Rf (70% EtOAc/n-hexane) 0.25;
nmax (KBr) 3239, 2936, 1720, 1678, 1547, 1496 cmꢂ1
; dH (200 MHz,
CDCl3) 1.25 (t, 3H, J¼5.8 Hz, CH2CH3), 3.87 (br s, NH), 4.09 (q, 2H,
J¼6.6 Hz, OCH2), 6.63 (s, 1H, benzylic), 6.93–7.82 (m, 12H, arom.),
8.35 (d, 2H, J¼8.0 Hz, arom.); dC (200 MHz, CDCl3) 13.3, 60.9, 121.1,
122.7, 123.4, 125.4, 126.3,128.8,128.9,132.2, 133.8, 136.4, 144.1, 165.7,
169.7; MS m/z (ESI): 396 ([MþNa]þ).
4.2.15. Ethyl 4-(3-chlorophenylamino)-2,5-dihydro-5-oxo-2-
phenylfuran-3-carboxylate (15)
Yield 0.29 g (83%).Found: C, 63.74; H, 4.48; N, 3.90. C19H16ClNO4
requires C, 63.78; H, 4.51; N, 3.91%. Rf (70% EtOAc/n-hexane) 0.25;
4.2.9. Ethyl 2,5-dihydro-2-(naphthalen-3-yl)-5-oxo-4-
(phenylamino)furan-3-carboxylate (9)
nmax (KBr) 3393, 2919, 1686, 1593, 1240 cmꢂ1
; dH (300 MHz, CDCl3)
1.29 (t, 3H, J¼7.0 Hz, CH2CH3), 4.05 (q, 2H, J¼7.0 Hz, OCH2), 5.72 (s,
1H, benzylic), 6.98–7.35 (m, 5H, arom.), 7.68–7.71 (m, 4H, arom.); dC
(300 MHz, CDCl3) 14.4, 61.2, 114.3, 115.6, 117.8, 123.6, 126.3, 127.4,
128.9, 135.2, 140.3, 145.1, 167.3, 170.1; MS m/z (ESI): 380 ([MþNa]þ).
Yield 0.29 g (80%). Found: C, 73.96; H, 5.14; N, 3.73. C23H19NO4
requires C, 73.98; H, 5.13; N, 3.75%. Rf (70% EtOAc/n-hexane) 0.25;
nmax (KBr) 3236, 2931, 1723, 1670, 1621, 1490 cmꢂ1
; dH (300 MHz,
CDCl3) 1.23 (t, 3H, J¼6.9 Hz, CH2CH3), 4.12 (q, 2H, J¼7.1 Hz, OCH2),
5.84 (s, 1H, benzylic), 6.97–7.75 (m, 12H, arom.); dC (300 MHz,
CDCl3) 14.5, 61.4, 116.8, 122.5, 126.7, 127.3, 129.3, 131.2, 133.7, 135.1,
144.3, 144.9, 166.7, 171.3; MS m/z (ESI): 396 ([MþNa]þ).
4.3. Preparation of
b-CD/aniline inclusion complex
b-CD (1.135 g, 1 mmol) was dissolved in water (15 mL) by
warming at 60 ꢀC to get clear solution Aniline (0.093 g, 1 mmol)
was added drop wise, the mixture was allowed to stir for 30 min at
60 ꢀC and then cooled to room temperature. It was further cooled
overnight in refrigerator. The obtained solid was filtered, dried and
analyzed by 1H NMR spectroscopy.
4.2.10. Ethyl 4-(p-tolylamino)-2,5-dihydro-5-oxo-2-phenylfuran-
3-carboxylate (10)
Yield 0.29 g (88%).Found: C, 71.18; H, 5.63; N, 4.09. C20H19NO4
requires C, 71.20; H, 5.68; N, 4.15%. Rf (70% EtOAc/n-hexane) 0.25;
nmax (KBr) 3297, 1712, 1687, 1642 cmꢂ1
; dH (200 MHz, CDCl3) 1.27 (t,
3H, J¼6.6 Hz, CH2CH3), 2.24 (s, 3H, CH3), 4.11 (q, 2H, J¼7.3 Hz,
OCH2), 5.61 (s,1H, benzylic), 6.98–7.34 (m, 9H, arom.); dC (200 MHz,
CDCl3) 13.9, 20.8, 61.9, 122.2, 127.6, 128.0, 128.2, 129.3, 133.9, 135.2,
165.5, 171.3; MS m/z (ESI): 360 ([MþNa]þ).
Acknowledgements
We thank CSIR, New Delhi, India for awarding fellowships to
S.N.M., B.M. and UGC for awarding fellowship to A.V.K.
4.2.11. Ethyl 4-(4-chlorophenylamino)-2,5-dihydro-5-oxo-2-
phenylfuran-3-carboxylate (11)
Supplementary data
Yield 0.28 g (80%).Found: C, 63.76; H, 4.51; N, 3.89. C19H16ClNO4
requires C, 63.78; H, 4.51; N, 3.91%. Rf (70% EtOAc/n-hexane) 0.25;
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.04.081.
nmax (KBr) 3293, 2918, 1681, 1586, 1239 cmꢂ1
; dH (300 MHz, CDCl3)
1.20 (t, 3H, J¼6.9 Hz, CH2CH3), 4.23 (q, 2H, J¼8.0 Hz, OCH2), 5.71 (s,
1H, benzylic), 7.29–7.57 (m, 9H, arom.); dC (300 MHz, CDCl3) 14.2,
61.7, 114.3, 115.3, 117.4,123.9, 126.3, 127.3, 128.3, 129.2, 140.3, 145.3,
167.8, 171.4; MS m/z (ESI): 380 ([MþNa]þ).
References and notes
1. (a) Schmitz, F. J.; Kraus, K. W.; Ciereszko, L. S.; Sifford, D. H.; Weinheimer, A. J.
Tetrahedron Lett. 1966, 7, 97; (b) Cimino, G.; De Stefano, S.; Minale, L.; Fattorusso,
E. Tetrahedron 1972, 28, 333; (c) Cafieri, F.; Fattorusso, E.; Santacroce, C.; Minale, L.
Tetrahedron 1972, 28, 1579; (d) Faulkner, D. J. Tetrahedron Lett. 1973, 14, 3821; (e)
Rothberg, I.; Shubiak, P. Tetrahedron Lett. 1975, 16, 769; (f) Cimino, G.; De Steffano,
S.; Guerriero, A.; Minale, L. Tetrahedron Lett. 1975, 16, 1417; (g) Fusetani, N.;
Takahashi, M.; Matsunaga, S. Tetrahedron 1994, 50, 7765.
2. (a) Guo, Y. W.; Gavagnin, M.; Mollo, E.; Trivellone, E.; Cimino, G. J. Nat. Prod.
1999, 62, 1194; (b) Pupo, M. T.; Vieira, P. C.; Fernandes, J. B.; Silva, M. F. G. F.
Phytochemistry 1998, 48, 307; (c) Takeda, K.; Sakurami, K.; Ishii, H. Tetrahedron
1972, 28, 3757.
4.2.12. Ethyl 4-(4-fluorophenylamino)-2,5-dihydro-5-oxo-2-
phenylfuran-3-carboxylate (12)
Yield 0.26 g (79%). Found: C, 66.83; H, 4.74; N, 4.08. C19H16 FNO4
requires C, 66.86; H, 4.72; N, 4.10%. Rf (70% EtOAc/n-hexane) 0.24;
nmax (KBr) 3392, 2935, 1709, 1680, 1584, 1486 cmꢂ1
; dH (300 MHz,
CDCl3) 1.29 (t, 3H, J¼7.2 Hz, CH2CH3), 4.10 (q, 2H, J¼7.1 Hz, OCH2),
3. (a) Min, B. S.; Lee, S. Y.; Kim, J. H.; Kwon, O. K.; Park, B. Y.; An, R. B.; Lee, J. K.; Moon,
H. I.; Kim, T. J.; Kim, Y. H.; Joung, H.; Lee, H. K. J. Nat. Prod. 2003, 66, 1388; (b)
5.58 (s, 1H, benzylic), 6.89–7.39 (m, 9H, arom.); dC (300 MHz, CDCl3)

5256
S. Narayana Murthy et al. / Tetrahedron 65 (2009) 5251–5256
Raghavan, S.; Joseph, S. C. Tetrahedron: Asymmetry 2003, 14, 101; (c) Boalino, D.
M.; Connolly, J. D.; McLean, S.; Reynolds, W. F.; Tinto, W. F. Phytochemistry 2003,
Xu, G.; Nguyen, D.; Castoro, J.; Pierce, M. E.; Confalone, P. N. Tetrahedron Lett.
2003, 44, 247.
64, 1303; (d) Gouda, Y. G.; Abdel-baky, A. M.; Darwish, F. M.; Mohamed, K. M.;
Kasai, R.; Yamasaki, K. Phytochemistry 2003, 63, 887; (e) Ming, D. S.; Lopez, A.;
Hilhouse, B. J.; French, C. J.; Hudson, J. B.; Towers, G. H. N. J. Nat. Prod. 2002, 65,
1412; (f) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
4. (a) Reichstein, T. Cron. Chim. 1967, 15, 3; (b) Chem. Abstr. 1970, 72, 77821n.
5. This statistic number is based on a survey of the ISIS database.
6. (a) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998, 39,
7799; (b) Grossmann, G.; Poncioni, M.; Bornand, M.; Jolivet, B.; Neuburger, M.;
Sequin, U. Tetrahedron 2003, 59, 3237; (c) Levy, L. M.; Cabrera, G. M.; Wright, J. E.;
Seldes, A. M. Phytochemistry 2003, 62, 239.
7. (a) Hein, S. M.; Gloer, J. B.; Koster, B.; Malloch, D. J. Nat. Prod. 2001, 64, 809; (b)
Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Kubanova, P.; Butcha, V. Bioorg.
Med. Chem. 2003, 11, 2843.
8. Padakanti, S.; Pal, M.; Yeleswarapu, K. R. Tetrahedron 2003, 59, 7915.
9. (a) Hoye, T. R.; Tan, L. Tetrahedron Lett. 1995, 36, 1981; (b) Takahashi, S.; Kubota,
A.; Nakata, T. Tetrahedron Lett. 2002, 43, 8661; (c) Bellina, F.; Falchi, E.; Rossi, R.
Tetrahedron 2003, 59, 9091.
11. Miao, S.; Andersen, R. J. J. Org. Chem. 1991, 56, 6275.
12. For the first synthesis of rubrolide C and the diacetates of rubrolides A, D and E
see: Kotora, M.; Negishi, E. Synthesis 1997, 121.
13. Domschke, G. Z. Chem. 1976, 16, 13.
14. Cao, R.; Liu, C.; Liu, L. Org. Prep. Proced. Int. 1996, 28, 215.
15. Fu, C.; Ma, S. Eur. J. Org. Chem. 2005, 3942.
16. (a) Hollingworth, G. J.; Perkins, G.; Sweeney, J. B. J. Chem. Soc., PerkinTrans.11996,
913; (b) Mabon, R.; Richecoeur, A. M. E.; Sweeney, J. B. J. Org. Chem.1999, 64, 328;
(c) Mabon, R.; Richecoeur, A. M. E.; Sweeney, J. B. Tetrahedron 2002, 58, 9117.
17. Bassetti, M.; D’Annibale, A.; Fanfoni, A.; Minissi, F. Org. Lett. 2005, 7, 1805.
18. (a) Surendra, K.; Krishnaveni, N. S.; Arjun Reddy, M.; Nageswar, Y. V. D.; Rao, K.
R. J. Org. Chem. 2003, 68, 9119; (b) Surendra, K.; Krishnaveni, N. S.; Nageswar, Y.
V. D.; Rao, K. R. J. Org. Chem. 2003, 68, 4994; (c) Surendra, K.; Krishnaveni, N. S.;
Arjun Reddy, M.; Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68, 2058; (d)
Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Adv. Synth. Catal. 2004, 346, 346; (e)
Sridhar, R.; Srivivas, B.; Pavan Kumar, V.; Prakash Reddy, V.; Vijay Kumar, A.;
Rama Rao, K. Adv. Synth. Catal. 2008, 350, 1489.
10. (a) Hanessian, S.; Park, R. Y.; Yang, R. Y. Synlett 1997, 351; (b) Hanessian, S.; Park,
R. Y.; Yang, R. Y. Synlett 1997, 353; (c) Choudhury, A.; Jin, F.; Wang, D.; Wang, Z.;
19. Grigoras, M.; Conduruta, D. G. J. Inclusion Phenom. Macrocycl. Chem. 2006,
54, 101.