Water-based biphasic media for exothermic reactions: Green chemistry strategy for the large scale preparation of clofibric acid and analogues

Article abstract of DOI:10.1016/j.tetlet.2005.03.025

A water-based biphasic reaction process has been developed for conducting exothermic reactions without organic solvents. This procedure is rapid, simple, and suitable for small scale synthesis as well as larger (multi-molar) scale reactions. The preparation of several hundred grams of clofibric acid and analogues by this eco-friendly and energy-efficient procedure is described. Smaller amounts of these compounds were prepared by the friction-activated 'Grindstone Chemistry' method described previously.

Full text of DOI:10.1016/j.tetlet.2005.03.025

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3011–3013
Water-based biphasic media for exothermic reactions:
green chemistry strategy for the large scale preparation
of clofibric acid and analogues
Ajay K. Bose,* Maghar S. Manhas, Subhendu N. Ganguly, Suhas Pednekar and
Arun Mandadi
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology Hoboken, NJ 07030, USA
Received 16 December 2004; revised 4 March 2005; accepted 4 March 2005
Available online 19 March 2005
Abstract—A water-based biphasic reaction process has been developed for conducting exothermic reactions without organic sol-
vents. This procedure is rapid, simple, and suitable for small scale synthesis as well as larger (multi-molar) scale reactions. The prep-
aration of several hundred grams of clofibric acid and analogues by this eco-friendly and energy-efficient procedure is described.
Smaller amounts of these compounds were prepared by the friction-activated ꢀGrindstone Chemistryꢁ method described previously.
Ó 2005 Elsevier Ltd. All rights reserved.
Current publications indicate renewed interest in deriva-
tives of clofibric acid (4) which were used in earlier times
as hyperlipidimia controlling drugs.1 Thus, Glaxo-
SmithKline chemists have described a method for
improving the earlier synthesis of 2-methyl-2-aryloxy-
propanoic acids (3) because of the present interest in this
class of compounds for the potential treatment of type II
diabetes.2 The intermediate selected by them is 2-bromo-
2-methylpropanoic acid (2) which is allowed to react
with a phenolic compound (1). Reagent 2 is quite expen-
sive and large volumes of organic solvents (2-butanone
in particular) are also required (Scheme 1). It is worth
noting that warming the reaction mixture to 50 °C is
indicated although the reaction is stated to be quite
exothermic.
An alternative synthesis of clofibric acid and analogues
is the Bargellini reaction3 published in 1906. This reac-
tion involves the interaction of a phenol with acetone
and chloroform in presence of sodium hydroxide. Heat-
ing under reflux for several hours and fairly lengthy
work up provided low yields of clofibric acid and ana-
logues. We attempted improvement of this reaction by
using protocols developed in our laboratory. In preli-
minary work we noticed that this reaction is quite
exothermic.
Water-based biphasic reaction media for exothermic
reactions: We have recently studied the large-scale
preparation of coumarin-3-esters4a (5) and dihydro-
pyrimidinones4b (6) (Schemes 2 and 3).
COOH
O
OH
COOR1
Br
NaOH, 2 butanone
R
R
+
1
2
3
4 R = p-Chloro
Scheme 1.
Keywords: 2-Methyl-2-aryloxypropanoic acids; Exothermic reaction; Water-based biphasic reaction media; Clofibric acid; Energy-efficient process.
*
Corresponding author. Tel.: +1 201 2165547; fax: +1 201 2168240; e-mail: abose@stevens.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.025

3012
A. K. Bose et al. / Tetrahedron Letters 46 (2005) 3011–3013
sodium hydroxide in 300 mL of water) and the solution
COOEt
Piperidine
H2O
CHO
COOEt
COOEt
was chilled. A mixture of acetone (8 mol, 590 mL), chlo-
roform (3 mol, 240 mL) and water 700 mL were added
with vigorous stirring while using a cooling bath for
the reaction mixture. The initial temperature was
18 °C and the final temperature rose to 28 °C. The loss
of chloroform and acetone by evaporation was thus
eliminated by keeping the reaction mixture at a low
temperature. This reaction was conducted in a hood.
+
O
5
O
OH
(90 %) yield, mp 93 oC
Scheme 2.
Both of these reactions are exothermic. We have found
that the heat produced in exothermic reactions can be
conveniently removed by a large volume of water that
is mixed intimately with the solvent-free organic re-
agents.4 A suitable reaction vessel and a powerful stirrer
are the equipments needed. This method has been found
to be efficient for allowing water-immiscible organic re-
agents to participate in exothermic reactions without the
presence of an organic solvent.
After 25 min of stirring, the aqueous reaction mixture
was acidified with cold hydrochloric acid when the 2-
methyl-2-aryloxypropanoic acid separated as a light,
yellow colored, thick liquid that was left overnight in a
refrigerator. A solid material was thus obtained which
was dissolved in sodium bicarbonate solution and repre-
cipitated by acidification with cold hydrochloric acid
(Scheme 4). The product, which was a white solid, was
filtered, washed thoroughly with cold water and
air-dried. The yield was 66%, mp 119 °C (lit.2 mp 120–
121 °C).
The method used (Bargellini reaction3) by Gilman and
Wilder5 for clofibric acid (and analogues) involved heat-
ing the reagents under reflux for 4 h, and the yield was
37.2%.5 We have successfully employed our water-based
biphasic reaction for preparing large quantities of 4 and
analogues more efficiently as described below.
This method is suitable for conducting the reaction
in a larger scale. Thus, 0.5 kg of clofibric acid was pre-
pared by using this low temperature, water-based
biphasic reaction. This method is more efficient than
the procedures described earlier for clofibric acid
and analogues.2,5
The synthesis of clofibric acid and analogues presented a
problem for us because two of the reagents (acetone and
chloroform) are fairly volatile. This problem was solved
by conducting the preparative reaction below 30 °C by
using a cooling bath for the reaction vessel. After some
experimentation the following convenient procedure
was developed for the preparation of clofibric acid and
analogues on several hundred grams scale.
Grindstone Chemistry Procedure. In the course of studies
on exothermic reactions we have devised methods for
modifying some widely used conventional procedures
to make them more energy efficient. One such method
is known in our laboratory by the descriptive name of
ꢀgrindstone chemistryꢁ which is a more evolved version
of the method of Toda, Tanaka and coworkers for sol-
vent-free reactions by grinding solids together.6 We have
shown that reactions between solid/solid, solid/liquid,
A preparative reaction (Scheme 4) was conducted on
2 M scale (257 g of chlorophenol). The phenol was
dissolved in dilute sodium hydroxide solution (300 g of
R
CHO
X
O
O
PTSA, H2O
EtOOC
R
NH2
OEt H2N
+
NH
+
R'
Stir 15 min
N
H
6
X
R' = Me, Ph
R = H, 4OH,
4Cl, 4NO2
R'
X = O, S
Scheme 3.
COOH
O
OH
CHCl3, NaOH (7.5mol)
H2O (1000mL)
O
+
Cl
Cl
yield 66%, m.p 119 oC
stir rt, 20 min
4
257 g,
2moles
neutralize with HCl
reported2 m.p 119-120 oC
Scheme 4.

A. K. Bose et al. / Tetrahedron Letters 46 (2005) 3011–3013
Table 1. Grindstone synthesis of para-substituted analogues of clofibric acid
3013
Entry
para-Substituted analogue of clofibric acid
Mp (°C)
Mp (°C)5
Yield (%)
Present work
Reported5
1
2
3
4-Fluoro
4-Bromo
4-Iodo
83
134–135
131–133
83
135
135
73
70
32.3
39.6
37.8
79.8
and even liquid/liquid can be conducted by grinding
with the help of coarsely crystalline MgSO4Æ7H2O or
sand as a friction enhancing agent.7
procedure is greener because no phase transfer catalyst
is needed and the purification of the product is simpler.8
The reaction is also energy efficient.
Noting that the formation of 2-methyl-2-aryloxypropa-
noic acid is highly exothermic, we submitted to vigorous
mixing (as an alternative to grinding) a mixture of 1 mol
(128.56 g, 1 mol) of p-chlorophenol (1), sodium hydrox-
ide pellets (150 g, 3.75 mol), excess of acetone 232 g,
295 mL), and chloroform (179 g, 120 mL). The temper-
ature of the reaction mixture rose rapidly and acetone
and chloroform started to vaporize. This reaction was
allowed to proceed for about 25 min. After the appro-
priate work up the reaction product proved to be
2-methyl-2-aryloxypropanoic acid of good quality; after
one recrystallization from dichloromethane/hexane the
pure product was obtained in 69% yield.
Acknowledgements
We are grateful to the Union Mutual Foundation for
financial support. We thank Stevens Institute of Tech-
nology for laboratory facilities. We are thankful to
Dr. Mark Cardillo and Dr. F. T. Jones for useful
discussions.
References and notes
1. Witiak, D. J.; Feller, D. R.; Stratford, E. S.; Hackney, R.
E.; Nazareth, R.; Wagner, G. J. Med. Chem. 1971, 14, 754.
2. Davis, R. D.; Fitzgerald, R. N.; Guo, J. Synthesis 2004,
1959.
3. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 337.
4. (a) Unpublished work; (b) Bose, A. K.; Manhas, M. S.;
Pednekar, S.; Ganguly, S. N.; Dang, H.; He, W.; Mandadi,
A. Tetrahedron Lett. 2005, 46, 1901.
By using molar amounts of the substituted phenols, ana-
logues of clofibric acid substituted in the para-position
by the following groups were prepared by the ꢀgrind-
stone chemistryꢁ method in good yield after 10–15 min
of reaction: bromo-, iodo-, and fluoro- (see Table 1).
5. Gilman, H.; Wilder, G. R. J. Am. Chem. Soc. 1955, 77,
6644.
6. Tanaka, K. Solvent free Organic Synthesis; Wiley-VCH:
Weinheim, 2003.
7. Bose, A. K.; Pednekar, S.; Ganguly, S. N.; Chakraborty,
G.; Manhas, M. S. Tetrahedron Lett. 2004, 45, 8351.
8. This is green chemistry Part 3. For part 2, see Ref. 4.
In summary, 10 g of clofibric acid and derivatives can be
conveniently prepared by grindstone chemistry. For
larger quantities, it is more convenient to utilize the
water-based biphasic medium protocol. For reactions
involving water and an organic solution, the conven-
tional method is to use a phase transfer catalyst. Our