Bargellini condensation of coumarins. Expeditious synthesis of o-carboxyvinylphenoxyisobutyric acids

Article abstract of DOI:10.1016/j.tetlet.2005.10.045

Condensation of coumarins with chloroform and acetone in the presence of a base furnished o-carboxyvinylphenoxyisobutyric acids in good yields. The diacid 7a was transformed in a few high yielding steps to the marine sesquiterpene helianane underscoring t

Full text of DOI:10.1016/j.tetlet.2005.10.045

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8741–8743
Bargellini condensation of coumarins. Expeditious synthesis of
o-carboxyvinylphenoxyisobutyric acids
Prabir K. Sen,a Bidyut Biswasb and Ramanathapuram V. Venkateswaranb,*
aChemistry Department, Haldia Government College, Midnapore, West Bengal, India
bDepartment of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 25 July 2005; revised 6 October 2005; accepted 12 October 2005
Abstract—Condensation of coumarins with chloroform and acetone in the presence of a base furnished o-carboxyvinylphenoxy-
isobutyric acids in good yields. The diacid 7a was transformed in a few high yielding steps to the marine sesquiterpene helianane
underscoring the importance of this new protocol.
Ó 2005 Elsevier Ltd. All rights reserved.
Bargellini reported1 the interesting condensation of
phenol with chloroform and acetone in the presence of
sodium hydroxide to yield a-phenoxyisobutyric acid 1
(Scheme 1). This pointed to a general conversion of
alcohols to a-alkoxyisobutyric acid systems which could
be de-alkoxylated to a methacrylic acid. Later investiga-
tors have improved upon this observation with better
yields obtained from condensation with acetonechloro-
form (chloretone) and application to a variety of alco-
hols and carbonyl substrates.2 Further transformations
of the phenoxyisobutyric acids to provide an alternative
to the Birch reduction have also been described.3
However, the potential of this useful transformation in
synthesis has not been thoroughly investigated. The
isolation of heliannuol A 24, an important allelochemi-
cal from cultivar sun flowers and helianane 3 from a
marine sponge,5 both of which contain an a-phenoxy-
isobutyl component are good choices as substrates for
the exploration of this methodology for their synthesis.
Various researchers have exploited this reaction to
incorporate a gem-dimethyl functionality into a ring sys-
tem.6 We have also applied7 this methodology in our
synthesis of heliannuol A wherein the styrenol(s) 4 were
subjected to a Bargellini condensation with chloroform
and acetone in the presence of sodium hydroxide to fur-
nish the phenoxyisobutyric acid(s) 5 (Scheme 2) which
were elaborated to the natural product. Styrenol 4a itself
was obtained from decarboxylative alkaline hydrolysis
of coumarin 6a. It occurred to us that direct condensa-
tion of coumarin with chloroform and acetone in the
HO
O
O
OH
3
2
OH
O
R
R
CO2H
1
OH
O
CO2H
Scheme 1. Reagents and conditions: (i) CHCl3, powdered NaOH,
acetone, reflux 6 h; (ii) HCl.
4
5
a
R = H
Keywords: Coumarins; Bargellini condensation; a-Carboxyvinylphen-
oxyisobutyric acids; Helianane.
b R = OMe
*
Scheme 2. Reagents and conditions: (i) CHCl3, powdered NaOH,
Corresponding author. Tel.: +91 33 24734971; fax: +91 33
acetone, reflux 6 h; (ii) HCl.
24732805; e-mail: ocrvv@mahendra.iacs.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.045

8742
P. K. Sen et al. / Tetrahedron Letters 46 (2005) 8741–8743
presence of a base would provide a novel one-step route
to an a-phenoxyisobutyric acid with the additional
advantage of an acrylic acid functionality on the adja-
cent carbon atom of the phenyl ring for further useful
transformations. We describe in this letter, the realiza-
tion of this process and demonstrate the utility of this
strategy by application to the synthesis of the natural
product helianane 3.
CO2Me
CO2Me
i
CO2Me
CO2Me
O
O
10
11
ii
Interaction of 4,7-dimethylcoumarin 6a with chloroform
and acetone in the presence of sodium hydroxide fol-
lowed by acidic work up afforded diacid 7a in 75% yield
as a crystalline solid. The corresponding dimethyl ester
10, prepared from reaction with diazomethane, was fully
characterized by its analytical and spectral data. The
methodology was extended to a variety of coumarins
6a–d and in all cases the desired diacids 7a–d were
obtained in yields ranging from 70–75%. The ben-
zocoumarins 8a–b also responded identically to the reac-
tion conditions affording the expected diacids 9a–b in
65–70% yields. Thus, the direct Bargellini condensation
with coumarins provides a useful single-step procedure
for the preparation of highly functionalized phenoxy
acids (Scheme 3).
R
R
iv
O
O
R = OH
R = O
12
13
14
iii
v
vi
3
O
15
Scheme 4. Reagents and conditions: (i) 10% Pd–C, H2, MeOH, 5 h,
99%; (ii) LAH, Et2O, reflux, 4 h, 98%; (iii) (COCl)2, DMSO, Et3N,
À78 °C to rt, 5 h, 93%; (iv) methyltriphenylphosphonium iodide, n-
BuLi, THF, 0 °C, 5 h, 70%; (v) catalyst B, CH2Cl2, rt, 6 h, 85%; (vi)
10% Pd–C, H2, MeOH, 5 h, 92%.
Pcy3
Ru
N Mes
Mes N
Cl
Cl
Cl
Ru
Pcy3
Ph
Cl
Ph
Pcy3
titative yield which was reduced to diol 128 with lithium
aluminium hydride in excellent yield (98%). This diol
underwent smooth oxidation under Swern conditions
to dialdehyde 138 (93%) which on a double Wittig reac-
tion afforded diene 148 in 70% yield. This diene had pre-
viously been taken to helianane 3 by Snieckus et al.6b
We also carried out the ring-closing metathesis reaction.
However, employing GrubbsÕ first generation catalyst A
for this cyclization failed to generate any cyclized alkene
and furnished only a complex product profile. Employ-
ing the later version of the catalyst, catalyst B, led to a
smooth ring-closing reaction to afford the cyclized
alkene 158 in 85% yield. Catalytic hydrogenation of this
alkene furnished helianane 3, which was spectro-
scopically identical with a sample we had previously syn-
thesized9 and also with the natural product itself
(Scheme 4).5
Catalyst A
Catalyst B
The utility of this novel preparative procedure was dem-
onstrated through the application of one of the product
diacids to prepare helianane 3. Catalytic hydrogenation
of diester 10 furnished the saturated diester 118 in quan-
R1
R1
R2
R3
i.
CHCl3,NaOH,
acetone
R2
R3
CO2H
CO2H
ii.
HCl
O
O
O
7
6
R1 = R3 = Me, R2 = H
R1 = R2 = Me, R3 = H
R1 = H, R2 = OMe, R3 = H
R1 = R2 = Me, R3 = OMe
(75%)
a
b
(72%)
(70%)
(75%)
c
d
In summary, we have described a novel one-step conver-
sion of coumarins to usefully functionalized diacids
employing the Bargellini condensation and have demon-
strated its synthetic utility. Investigations employing
other lactone types (including dihydrocoumarins, higher
homologues, etc.) and a variety of carbonyl compounds
are expected to further expand the utility of this proto-
col and these are being actively pursued.
O
CO2H
R
R
CO2H
i.
CHCl ,
acetone
O
NaOH,
3
O
ii.
HCl
9
8
Acknowledgements
a
R = H
(65%)
(70%)
b R = Me
P.K.S. thanks the UGC, for a Minor Research Grant.
B.B. thanks the CSIR, for a research fellowship.
Scheme 3.

P. K. Sen et al. / Tetrahedron Letters 46 (2005) 8741–8743
8743
(d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 19.8,
21.0, 25.1, 25.1, 29.8, 41.1, 51.2, 52.2, 78.5, 116.5, 122.1,
126.7, 132.9, 136.3, 152.5, 173.1, 175.0; HRMS (ES +ve)
calcd for C17H25O5 [M+H]+ 309.1703, found 309.1719. For
12: 1H NMR (300 MHz, CDCl3): d 1.16 (d, J = 6.5 Hz,
3H), 1.17 (s, 3H), 1.29 (s, 3H), 1.37–1.46 (m, 1H), 1.64–1.71
(m, 1H), 2.21 (s, 3H), 3.17–3.25 (m, 1H), 3.38–3.64 (m, 4H),
6.77 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 7.6 Hz,
1H); 13C NMR (75 MHz, CDCl3): d 20.9, 21.6, 22.4, 24.3,
27.2, 42.5, 60.6, 71.1, 81.5, 122.8, 124.7, 126.8, 136.3, 137.4,
153.1; HRMS (ES +ve) calcd for C15H25O3 [M+H]+
References and notes
1. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329–339.
2. Weizmann, C.; Sulzbacher, M.; Bergmann, E. J. Am. Chem.
Soc. 1948, 70, 1153–1158.
3. Corey, E. J.; Barcza, S.; Klotmann, G. J. Am. Chem. Soc.
1969, 91, 4782–4786.
4. Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M.
G.; Fronzek, F. R. Tetrahedron Lett. 1993, 34, 1999–
2002.
5. Harrison, B.; Crews, P. J. Org. Chem. 1997, 62, 2646–2648.
6. (a) Grimm, E. L.; Levac, S.; Trimble, L. A. Tetrahedron
Lett. 1994, 35, 6847–6850; (b) Stefinovic, M.; Snieckus, V.
J. Org. Chem. 1998, 63, 2808–2809.
253.1804, found 253.1797. For 13: IR (Neat) 1732 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.28 (d, J = 6.9 Hz, 3H),
1.46 (s, 6H), 2.22 (s, 3H), 2.55–2.75 (m, 2H), 3.69–3.76 (m,
1H), 6.39 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 7.07 (d,
J = 7.7 Hz, 1H), 9.69 (t, J = 1.9 Hz, 1H), 9.82 (s, 1H);
13C NMR (75 MHz, CDCl3): d 21.0, 21.8, 22.2, 22.4, 28.1,
51.3, 83.3, 117.1, 123.4, 127.7, 132.9, 137.4, 152.8, 202.6,
204.0. For 14: 1H NMR (300 MHz, CDCl3): d 1.18 (d,
J = 6.9 Hz, 3H), 1.48 (s, 6H), 2.10–2.43 (m, 2H), 2.25 (s,
3H), 3.20–3.27 (m, 1H), 4.93 (d, J = 11.3 Hz, 1H), 5.00 (d,
J = 18.8 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.22 (d,
J = 17.6 Hz, 1H), 5.69–5.89 (m, 1H), 6.16 (dd, J = 10.9,
17.6 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.86 (s, 1H), 7.04 (d,
J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 20.6, 21.6,
27.8, 27.8, 32.4, 42.0, 79.6, 113.2, 115.7, 120.0, 122.5, 126.9,
135.8, 135.8, 138.3, 145.5, 153.9. For 15: 1H NMR
(300 MHz, CDCl3): d 1.26 (d, J = 6.9 Hz, 3H), 1.40(s,
3H), 1.62 (s, 3H), 2.29 (s, 3H), 2.85–3.43 (m, 3H), 5.27 (d,
J = 10.8 Hz, 1H), 5.61–5.74 (m, 1H), 6.75 (s, 1H), 6.88 (d,
J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 21.3, 25.5, 28.9, 29.7, 29.8, 34.5,
81.6, 125.7, 127.9, 130.8, 131.2, 135.1, 136.0, 137.4; 152.9;
HRMS (ES +ve) calcd for C15H21O [M+H]+ 217.1593,
found 217.1587.
7. Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V. Chem.
Commun. 2002, 634–635.
8. All new compounds reported here gave analytical and
spectral data consistent with the assigned structures. Select-
ed spectral data: For 7a: IR (KBr) 1695 (br), 1715,
2974 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.59 (s, 6H),
;
2.17 (s, 3H), 2.29 (s, 3H), 5.99 (s, 1H), 6.53 (s, 1H), 6.80(d,
J = 7.8, 1H), 6.97 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 21.4, 24.8, 25.0, 27.1, 79.0, 116.5, 117.6, 122.3,
127.9, 128.4, 138.7, 150.3, 155.1, 169.8, 177.3; HRMS (ES
+ve) calcd for C15H19O5 [M+H]+ 279.1237, found
279.1236. For 10: IR (CHCl3) 1715, 1738 cmÀ1; H NMR
1
(300 MHz, CDCl3): d 1.52 (s, 6H), 2.16 (s, 3H), 2.28 (s, 3H),
3.55 (s, 3H), 3.75 (s, 3H), 5.91 (s, 1H), 6.53 (s, 1H), 6.78 (d,
J = 7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 21.3, 25.1, 25.9, 25.9, 50.6, 52.2,
79.2, 117.9, 118.1, 122.4, 128.3, 130.1, 138.1, 151.2, 154.4,
165.8, 174.9; HRMS (ES +ve) calcd for C17H23O5 [M+H]+
307.1546, found 307.1540. For 11: IR (CHCl3) 1738 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.26 (d, J = 6.9 Hz, 3H),
1.63 (s, 6H), 2.24 (s, 3H), 2.45 (dd, J = 9.1, 15.0Hz, 1H),
2.70(dd, J = 5.5, 15.0Hz, 1H), 3.51–3.88 (m, 1H), 3.64 (s,
3H), 3.76 (s, 3H), 6.40(s, 1H), 6.73 (d, J = 7.8 Hz, 1H), 7.04
9. Sabui, S. K.; Venkateswaran, R. V. Tetrahedron Lett. 2004,
45, 9653–9655.