A facile synthesis of novel cyclic esters of γ-keto acid derivatives by heck coupling reaction

Article abstract of DOI:10.1002/jhet.1898

γ-Keto acids and esters are highly useful compounds in organic synthesis, because a number of five-membered carbocycles and various other heterocycles can be readily obtained from them. A number of γ-keto acids derivatives have been synthesized with high

Full text of DOI:10.1002/jhet.1898

E354
A Facile Synthesis of Novel Cyclic Esters of g-Keto Acid Derivatives by
Vol 51
Heck Coupling Reaction
a
a
b
*
Nellisara D. Shashikumar, G. Krishnamurthy, and Halehatti S. Bhojyanaik
aDepartment of Chemistry, Sahyadri Science College(Autonomous), Shimoga 577203, Karnataka, India
bDepartment of PG Studies and Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu University,
Shankaraghatta 577 451, Shimoga, Karnataka, India
*
E-mail: gkmnaik_sahyadri@yahoo.co.in
Received August 13, 2012
DOI 10.1002/jhet.1898
Published online 25 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
g-Keto acids and esters are highly useful compounds in organic synthesis, because a number of five-membered
carbocycles and various other heterocycles can be readily obtained from them. A number of g-keto acids deriva-
tives have been synthesized with high yield by Heck coupling reaction with different alkenes using Pd(OAc)2 as
catalyst in dioxane solvent. The obtained products were characterized by elemental analysis, IR, proton NMR,
and mass spectral studies.
J. Heterocyclic Chem., 51, E354 (2014).
INTRODUCTION
reactions wherein the lability of halides are found to
be useful to obtain the novel derivatives.
Among the class of oxygen heterocycles, benzoanne-
lated butyrolactones (phthalides) are of considerable inter-
est, because of their natural occurrence and wide range of
biological activity [1–13]. They are active human CCR5
receptor antagonist, an important anti-HIV-1 target,
which interferes with HIV entry into cells (fuscinarin)
[2]. Some members of this group are cytotoxic [7–12] or
antibacterial [13,14]. The 3-butylphthalide is a constituent
in the Chinese folk medicine extracted from celery seed
oil [15], reduces brain damage in mice [16], has been used
for seasoning and flavoring purposes, shows anticonvul-
sant action [17], increases the duration of anesthesia [18],
and exhibits cerebral anti-ischemic action [19–24]. The
biological activity is strongly dependent on their configura-
tion; hence, the synthesis of the asymmetric compounds of
biological interest is highly desirable. The g-keto acids and
esters are highly useful compounds in organic synthesis,
because a number of five-membered carbocycles such
as cyclopentane-1,3-diones and cyclopentenones and
various other heterocycles such as g-lactones, butenolides,
g-lactams, and thiophenes were readily obtained from
them. However, by this method, levulinic acid derivatives
bearing substituents on their a-position, b-position, and/
or g-position were not easily convertible because of their
methodological limitations.
Over the past three decades, the Heck reaction has become
one of the most fundamental metal-catalyzed C–C bond form-
ing processes for the synthesis of complex molecules [25–35].
It has had a huge impact on organic synthesis despite the
disadvantages that the overall coupling of the two fragments
requires two discrete activation steps: (1) the formation of
an aryl or vinyl halide and (2) the union of two reactants with
Pd(0) catalyst.
RESULTS AND DISCUSSION
The starting materials 3-bromophthalide (7a) and o-benzoyl-
benzoic acid (4) required for the synthesis of the derivatives
of g-keto acids were prepared by the literature methods
[36,37]. The 3-bromophthalide was found to be a suitable
reagent, and its feasibility for the Heck reaction was studied.
After obtaining good results, o-benzoylbenzoic acid (4) was
cyclized using SOCl2, which produced 3-chloro-3-phenyl-2-
benzofuran-1(3H)-one (6) (Scheme 1).
The obtained pseudocyclic ester chloride was further
coupled with alkenes using Pd(OAc)2 catalyst in the pres-
ence of tri-o-tolylphosphine as ligand and TEA in dioxane
solvent (Scheme 2). The yield of the products was low when
the reaction was carried out in acetonitrile and DMF
solvents, whereas in dioxane medium, it was increased to
about 70% (Table 1). The obtained products were purified
by column chromatography.
Majority of the reported work on g-keto acids were
concerned to only the kinetic studies such as esterifica-
tion of g-keto acids and hydrolysis of the esters. In con-
trast, we have synthesized the new derivatives by
introducing g-keto acid halides by the Heck coupling
The IR spectra of the compounds were taken as KBr
pellet, which exhibit absorption band in the ranges of
© 2014 HeteroCorporation

August 2014
A Facile Synthesis of Novel Cyclic Esters of g-Keto Acid Derivatives by Heck Coupling
E355
Reaction
Table 1
Scheme 1. Preparation of g-keto acid chlorides.
O
Percentage yield and purity of 9a in different solvents.
O
O
COOH
SOCl2
MDC,
O
R
O
Solvent
% Yield
Purity*
Cl
R
6
OH
R
5
DMF
42
39
75
95.6
99.7
98.5
4
Acetonitrile
Dioxane
where R = -C6H5
*HPLC purity after column purification
1800–1780 cmÀ1 and 1230–1220 cmÀ1 due to C═O and
C–O stretching, respectively. The appearance of a new
absorption band at 1665 cmÀ1 spectrum of the products is
due to C═C str, and a band at 944 cmÀ1 is due to –HC═ str.
In the spectrum of the products, a band at 643 cmÀ1 is
not obtained, which confirms the formation product with
Hence, the recent study helps in obtaining new good
intermediates.
EXPERIMENTAL
1
the elimination of halogen. The H NMR spectra of the
All the reagents and solvents were used as received from
commercial suppliers, unless otherwise stated. All chemicals
used for the synthesis were of analytical grade or laboratory
grade and procured from HiMedia Laboratories Pvt. Ltd.,
India, Sigma Chemical Co., USA, E. Merck, Germany, and
Sarabhai Merck Company, India, and specialty chemicals are
procured as samples from the commercial suppliers (SD fine
Chemicals, Mumbai, IN). All equipment was inspected visually
for cleanliness and integrity before use. Mass spectra of the syn-
thesized compounds were recorded on an Agilent 6320 Ion Trap
mass spectrometer. IR spectra were recorded on a Shimadzu IR-
compounds were taken in DMSO-d6 or CDCl3. The spec-
1
tral data are compiled in Table 2. The H NMR spectra
of the compounds 9a–c showed a doublet in the range
of d 6–6.8 for the rigid proton attached to the lactone
ring. The spectra of compounds 9d–f showed two doub-
lets in the range of d 5.70–6.55 due to the proton of
Ar–HC═C– and Ar–C═CH–, respectively. All the aromatic
protons appeared as multiplet between d 7.3 and 8.1. Trans
coupling of the alkenes has been confirmed by J coupling
values. The mass spectra were analyzed in LC–MS, and
the compounds showed [M+ 1] molecular ion peak that
is in agreement with the mass of the product. The data are
compiled in Table 2.
1
470 spectrometer. H NMR spectra were recorded on a Bruker
DRX-300 Avance spectrometer at 300.13 MHz.
Analytical HPLC was performed on an Agilent 1200 system
with UV detection at a wavelength of 230 nm using Inertsil 3V
ODS 5 m, 4.6 mm  250 mm column, and eluting with the 0.1%
o-phosphoric acid solution/acetonitrile (7:3). Melting point was
determined using a Buchi melting point B-540 model and are
uncorrected.
CONCLUSION
Conversion of o-benzoylbenzoic acid (4) to acid chloride
(6). o-Benzoylbenzoic acid (4, 0.01 mol) was dissolved in
dichloromethane (MDC) (20 mL) in a three-necked round
bottom flask fitted withreflux condenser and CaCl2 guard tube.
About 5 mL of thionyl chloride was added and refluxed for 3 h.
The reaction was monitored by TLC. After the completion of
reaction, the excess thionyl chloride and the solvent were
The Heck reaction of phthalide derivatives has been
studied for substituting alkene group by using Pd(OAc)2
in dioxane and characterized by the elemental analysis,
IR, H NMR, and mass spectral studies. The obtained
product can be used as effective intermediates by transfor-
mation to obtain substituted heterocyclic compounds.
1
Scheme 2. Heck coupling reaction of g-keto acid halides.
O
O
Pd(OAc) TEA
O
O
+
R
dioxane,
tri- o -tolylphosphine
X
R
R
R
7a,b
8 a-c
9 a-f
Where
7a R= -H, X= -Br
7b R= -C H X= -Cl
9
a
b
c
d
e
f
R
-H
-H
-H
-C H
-C H
-C H
R
-C H
-COOEt
-CH O-COMe
-C H
-COOEt
-CH O-COMe
8
a
b
c
R
-C H
-COOEt
-CH O-COMe
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E356
N. D. Shashikumar, G. Krishnamurthy, and H. S Bhojyanaik
Vol 51
Table 2
Elemental analysis, 1H NMR, and mass spectral data of synthesized compounds.
Elemental
analysis
Sl.
no.
mp
Product
C
H
1H NMR
m/z
(ꢀC)
9a
81.08
5.23
d 4.38 (t, 1H, –CH═C–Ar, J = 11.52), d 5.98 (d, 1H, –C═CH–Ar), 236.3
96–98
(81.34) (5.12) d 7.2 (d, 1H, rigid H), d 7.2–7.5 (m, 9H, Ar–H)
9b
9c
66.01
4.65
d 3.78 (s, 3H, –CH3), d 6.83 (m, 2H, –CH═CH–, J = 11.68), d 6.86 218.2
83–85
76–78
(66.05) (4.62) (d, 1H, rigid H), d 7.2–7.8 (m, 4H, Ar–H)
67.21
5.18
d 2.58 (s, 3H, –CH3), d 4.40 (d, 2H, –CH2–), d 6.3–6.4 (m, 2H, – 232.2
(67.23) (5.21) CH═CH–, J = 11.6), d 6.58 (d, 1H, rigid H), d 7.8–7.9 (m, 2H, Ar–
H), d 8.0–8.1 (d, 2H, Ar–H)
9d
9e
84.53
5.21
d 5.65 (d, 1H, –C═CH–Ar, J = 12.56), d 6.58 (d, 1H, –CH═C–Ar), 312.4 119–121
(84.59) (5.16) d 7.2–8.2 (m, 14H, Ar–H)
73.45
4.72
d 2.47 (s, 3H, –CH3), d 6.45(s, 1H, –CH═C–COOMe, J = 12.68),
294.3 105–107
(73.46) (4.79) d 7.27 (d, 1H, –C═CH–COOMe), d 7.3–8.0 (m, 9H, Ar–H)
9f
73.96
5.27
d2.45 (s, 3H, –CH3), d4.52 (d, 2H, –CH2–), d5.79 (d, 1H, –
308.3
98–100
(74.01) (5.23) C═CH–CH2–, J = 12.43), d 7.26 (s, 1H, –CH═C–CH2–), d 7.3–
8.1 (m, 9H, Ar–H
removed by distillation under reduced pressure. Yield 87%, mp
52–55 ꢀC [26,36].
Acknowledgments. The authors are thankful to Dr. K. S. Rao,
Vice President, and Dr. K. Sridhara, General Manager, and
also the management of Alkem Laboratories Ltd., R&D
Center, Bangalore, Karnataka, India, for their support to
complete this work.
General procedure for the Heck coupling reaction 9a–f. A
mixture of alkenes 8a–c (10 mmol), pseudocyclic ester halides 7a, b
(10 mmol), palladium acetate (0.09 g), tri-o-tolylphosphine (1.86 g),
and TEA (9 mL) in dioxane (30 mL) was heated to 85 ꢀC under
nitrogen for 18 h. The reaction mixture was cooled to ambient
temperature and filtered, and the filter cake was washed with
dioxane (5 mL). The combined washings and filtrate were
concentrated in vacuum to obtain a semisolid substance. The
material was purified by column chromatography by eluting with
ethyl acetate/hexane.
REFERENCES AND NOTES
[1] (a) Games, D. E. Aromat Heteroaromat Chem 1974, 2, 447. (b)
Murray, R. D. H. Aromat Heteroaromat Chem 1976, 4, 414. (c) Gilchrist,
T. L. J Chem Soc Perkin Trans 1 1999, 2849. (d) Ghosh, S.; Banerjee, I.;
Baul, S. Tetrahedron 1999, 55, 11537.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

August 2014
A Facile Synthesis of Novel Cyclic Esters of g-Keto Acid Derivatives by Heck Coupling
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Reaction
[2] Yoganathan, K.; Rossant, C.; Ng, S.; Huang, Y.; Butler, M. S.;
Buss, A. D. J Nat Prod 2003, 66, 1116.
[3] Chatterjee, P.; Franklin, M. R. Drug Metab Dispos 2003, 31, 1391.
[4] Zhou, J.; Gupta, K.; Yao, J.; Ye, K.; Panda, D.; Giannakakaou,
P.; Joshi, H. C. J Biol Chem 2002, 277, 39777.
7664. (f) Knepper, K.; Ziegert, R. E.; Brase, S. Tetrahedron 2004, 60,
8591. (g) Tanaka, K.; Osaka, T.; Noguchi, K.; Hirano, M. Org Lett
2007, 9, 1307. (h) Chang, H. T.; Jeganmohan, M.; Cheng, C. H. Chem
Eur J 2007, 13, 4356. (i) Everaere, K.; Mortreux, A.; Carpentier, J. F.
Adv Synth Catal 2003, 345, 67.
[5] Shode, F. O.; Mahomed, A. S.; Rogers, C. B. Phytochemistry
2002, 61, 955.
[24] Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J
Org Chem 2010, 75, 368.
[6] Arnone, A.; Assante, G.; Nasini, G.; VajnadePava, O. Phytochem-
istry 1990, 29, 613.
[7] Wild, D.; Toth, G.; Humpf, H. U. J Agric Food Chem 2002,
50, 3999.
[8] Holler, U.; Gloer, J. B.; Wicklow, D. T. J Nat Prod 2002, 65, 876.
[9] Arnone, A.; Assante, G.; Nasini, G.; Strada, S.; Vercesi, A. J
Nat Prod 2002, 65, 48.
[10] Arai, M.; Tomoda, H.; Okuda, T.; Wang, H.; Tabata, N.;
Masuma, R.; Yamaguchi, Y.; Omura, S. J Antibiot 2002, 55, 172.
[11] Puder, C.; Zeeck, A.; Beil, W. J Antibiot 2000, 53, 329.
[12] Palermo, J. A.; Rodriguez, B.; Maria, F.; Spagnuolo, C.;
Seldes, A. M. J Org Chem 2000, 65, 4482.
[25] Buhler, K. U. Spezialplaste, Berlin: Akademie 1978. Trans-
lated under the title Teplo- i termostoikie polimery, Moscow Khimiya
1984, 856.
[26] Puzin, Y. I.; Chebaeva, T. V.; Galinurova, E. I.; Muslukhov,
R. R.; Monakov, Y. B.; Syrkin A. M. Rus J Org Chem 2004, 40, 8, 1129.
[27] (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J Am Chem Soc
2004, 126, 14370. (b) Burstein, C.; Glorius, F. Angew Chem Int Ed
2004, 43, 6205. (c) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org Lett
2004, 6, 4143. (d) Floreancig, P. E.; Wang, L. Org Lett 2004, 6, 4207.
(e) Fukuzawa, S.; Miura, M.; Saitoh, T. J Org Chem 2003, 68, 2042. (f)
Chhor, R. B.; Nosse, B.; Sörgel S.; Böhm, C.; Seitz, M.; Reiser, O. Chem
Eur J 2003, 9, 260. (g) Buchwald, S. L.; Speilvogel, D. J. J Am Chem Soc
2002, 124, 3500. (h) Mandal, S. K.; Amin, S. R.; Crowe, W. E. J Am
Chem Soc 2001, 123, 6457.
[13] Brady, S. F.; Wagenaar, M. M.; Singh, M. P.; Janso, J. E.;
Clardy, J. Org Lett 2000, 2, 4043.
[28] (a) Dounay, A. B.; Overman, L. E. Chem Rev 2003, 103,
2945. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem Rev 2000, 100,
3009. (c) de Meijere, A, Meyer, F. E. Angew Chem 1994, 106, 2473;
Angew Chem Int Ed Engl 1994, 34, 2379. (d) Moritani, I.; Fujiwara, Y.
Tetrahedron Lett 1967, 1119. (e) Fujiwara, Y.; Moritani, I.; Danno, S.;
Asano, R.; Teranishi, S. J Am Chem Soc 1969, 91, 7166. (f) Zhang, H.;
Ferreira, E. M.; Stoltz, B. M. Angew Chem 2004, 116, 6270; Angew
Chem Int Ed, 2004, 43, 6144.
[29] (a) Tsuji, J. Palladium Reagents and Catalysts: New Perspec-
tives for the 21st Century; Wiley–VCH 2004, p 670. (b) Blatcher P. Glaxo
Group Limited WO199509166 1995, 9.
[30] Trost, B. M.; Verhoeven, T. R. Organopalladium compounds
in organic synthesis and in catalysis. In Comprehensive Organometallic
Chemistry; Abel, E.W., Ed.; Pergamon: Oxford, 1982.
[31] Miyaura, N.; Suzuki, A. Chem Rev 1995, 95, 2457.
[32] Tietze, L. F.; Petersen, S. Eur J Org Chem 2001, 9, 1619.
[33] Cianga, I.; Yagci Y. Eur Polymer J 2002, 38, 695.
[34] Busacca, C. A.; Eriksson, M. C.; Fiaschi, R. Tetrahedron Lett
1999, 40, 3101.
[35] Miller, J. A.; Farrell, R. P. Tetrahedron Lett 1998, 39, 7275.
[36] Puzin, Yu. I.; Egorov, A. E.; Kraikin, V. A. Eur Polym J 2001,
37, 1165.
[14] Dekker, K. A.; Inagaki, T.; Gootz, T. D.; Kanede, K.; Nomura,
E.; Sakakibara, T.; Sakemi, S.; Sugie, Y.; Yamauchi, Y.; Yoshikawa, N.;
Kojima, N. J Antibiot 1997, 50, 833.
[15] Barton, D. H. R.; de Vries, J. X. J Chem Soc 1963, 1916.
[16] Chong, Z.; Feng, Y. Chin Med J 2000, 113, 613.
[17] Yu, S.; You, S.; Chen, H. Yaoxue Xuebao, Chem Abstr 1984,
101, 222490c.
[18] Sato, H.; Yorozu, H.; Yamaoka, S. Biomed Res 1993, 14, 385.
[19] Wang, X. W. Drugs Future 2000, 25, 16.
[20] Liu, Z.; Song, Y.; Wang, W.; Chen, W.; Wang, X. Zhong-
caoyao 1982, 13, 17.
[21] Peter J.C., Jonathan S., Margaret A.B. J Org Chem 2010, 75, 7388.
[22] (a) Kosaka, M.; Sekiguchi, S.; Naito, J.; Uemura, M.; Kuwahara,
S.; Watanabe, M.; Harada, N.; Hiroi, K. Chirality 2005, 17, 218. (b) Pedrosa,
R.; Sayalero, S.; Vincente, M. Tetrahedron 2006, 62, 10400. (c) Karnik, A.
V.; Kamath, S. S. Synthesis 2008, 1832.
[23] (a) Ramachandran, P. V.; Chen, G. M.; Brown, H. C. Tetrahe-
dron Lett 1996, 37, 2205. (b) Kitamura, M.; Okhuma, T.; Inoue, S.; Sayo,
N.; Kumobayshi, H.; Akutagawa, S.; Takaya, H.; Noyori, R. J Am Chem
Soc 1998, 110, 629. (c) Lei, J.G.; Hong, R.; Yuan, S. G.; Lin, G. Q.
Synlett 2002, 927. (d) Witulski, B.; Zimmermann, A. Synlett 2002,
1855. (e) Trost, B. M.; Weiss, A. H. Angew Chem Int Ed 2007, 46,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet