Benzotrifluoride: A Useful Alternative Solvent for Organic Reactions Currently Conducted in Dichloromethane and Related Solvents

Full text of DOI:10.1021/jo9620324

450
J . Org. Chem. 1997, 62, 450-451
results suggest that benzotrifluoride shows good potential
as a solvent for many types of organic reactions.8c
We first examined some common derivatization reac-
tions of alcohols. Standard acylation,10,11 tosylation,12 and
silylation13 reactions all occur in BTF in comparable
yields and reaction times to their counterparts in CH2Cl2.
The results of these experiments are described in the
Supporting Information.
Ben zotr iflu or id e: A Usefu l Alter n a tive
Solven t for Or ga n ic Rea ction s Cu r r en tly
Con d u cted in Dich lor om eth a n e a n d
Rela ted Solven ts
Akiya Ogawa and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
We next checked some representative procedures for
the oxidation of alcohols. The Swern oxidation is a well-
known method for the conversion of alcohols to aldehydes
or ketones, and it is typically performed below -60 °C
in order to avoid the decomposition of unstable interme-
diates.14 However, Swern and co-workers reported that
the use of excess amounts of reagents enables the
oxidation at higher temperatures. Thus, we examined
the Swern oxidation of a secondary alcohol in BTF at -27
°C. Vigorous gas evolution (presumably CO and CO2)
occurred when dimethyl sulfoxide (DMSO) was added to
the BTF solution of oxalyl chloride (1.3 equiv to the
alcohol) at -27 °C. Immediately, 2-octanol was added
to the mixture at -27 °C. Subsequent addition of Et3N
and workup provided a 76% yield of 2-octanone (eq 1).
The oxidation of 2-octanol in CH2Cl2 under similar
conditions gave rise to 2-octanone in 71% yield.
Received October 31, 1996 (Revised Manuscript Received
December 17, 1996)
Dichloromethane is one of the most popular solvents
in organic synthesis1 because of its good dissolving power
for organic molecules, its favorable physical properties,
and its inertness toward many types of reagents and
reaction conditions.2 Its weak Lewis basicity makes it
especially attractive for organometallic and Lewis acid
reactions,3 and it is also commonly used in oxidations4
and functional group interconversions.5 However, the
toxicity of dichloromethane coupled with its low boiling
point (40 °C) can pose problems.6 Thus, the development
of other solvents that can substitute for dichloromethane
is a useful goal. In this paper, we report that benzotri-
fluoride7 (C6H5CF3, BTF, 1) is a potentially valuable
alternative solvent to CH2Cl2.
BTF is a clear, free-flowing liquid with a boiling point
of 102 °C, a melting point of -29 °C, and a density of 1.2
g/mL (25 °C). It is a robust compound with a relatively
low toxicity and price.8 J udging from empirical measures
of solvent polarity,2b,c BTF is slightly more polar than
fluorobenzene, THF, and ethyl acetate, very similar to
pentafluorobenzene, and slightly less polar than chloro-
form, pyridine, and dichloromethane.7b Despite these
favorable properties, BTF is not used as a solvent in
organic synthesis. Our recent success in using BTF as
a hybrid organic/fluorous solvent9 showed that it is
capable of dissolving a wide variety of organic com-
pounds. This suggested that the potential of BTF as a
solvent for standard organic synthesis was unappreci-
ated. To evaluate this potential, we selected a series of
representative transformations from the literature and
conducted pairs of reactions differing only in the substi-
tution of benzotrifluoride for dichloromethane. The
The Dess-Martin oxidation is another mild and con-
venient method for the oxidation of alcohols to alde-
hydes.15 The oxidation of a benzylic alcohol with Dess-
Martin reagent (1.1 equiv) was performed by using BTF
and CH2Cl2 at room temperature. As shown in eq 2, this
oxidation proceeded smoothly in both solvents to yield
the corresponding aromatic aldehyde in 92% and 96%
yield, respectively.
Hydrogen peroxide/dichloromethane (H2O2/CH2Cl2) is
one of the most used oxidation systems, and it is therefore
important to learn whether hydrogen peroxide can be
used in BTF. For this purpose, we selected the selenoxide
elimination reaction from an R-seleno ketone. Upon
treatment of R-(phenylseleno)butyrophenone with 30%
H2O2 in BTF in the presence of pyridine, the correspond-
ing R,â-unsaturated ketone was produced in almost
quantitative yield (eq 3).16
(1) (a) Trost, B. M., Ed. Comprehensive Organic Synthesis; Pergamon
Press: Oxford, 1991. (b) Katritzky, A. R., Meth-Cohn, O., Rees, C. W.,
Eds. Comprehensive Organic Functional Group Transformations;
Pergamon Press: Oxford, 1995. (c) Paquette, L. A., Ed. Encyclopedia
of Reagents for Organic Synthesis; J ohn Wiley & Sons: Chichester,
1995.
(2) (a) Riddick, J . A.; Bunger, W. B. Organic Solvents; J ohn Wiley
& Sons: New York, 1970. (b) Reichardt, C. Solvents and Solvent Effects
in Organic Chemistry; VCH: Weinheim, 1988. (c) Reichardt, C. Chem.
Rev. 1994, 94, 2319.
(3) Schinzer, D., Ed. Selectivities in Lewis Acid Promoted Reactions;
Kluwer Academic: Dordrecht, 1989.
(4) Hudlicky, M. Oxidations in Organic Chemistry; ACS Monograph
186; American Chemical Society: Washington, DC, 1990.
(5) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; J ohn Wiley & Sons: New York, 1991.
(6) Edwards, P. R.; Campbell, I.; Milne, G. S. Chem. Ind. 1982, 619.
(7) (a) The IUPAC name of benzotrifluoride is (trifluoromethyl)-
benzene, and it is also called R,R,R-trifluorotoluene. We use the name
benzotrifluoride because it is prevalent in the organofluorine literature.
(b) The dipole moment and dielectric constant of BTF are 2.86 D and
9.18 (at 30 °C), respectively. (c) Commercial BTF was purified by
refluxing over phosphorus pentoxide for
distillation.
a
few hours followed by
(10) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
(11) Ho¨fle, G.; Steglich, W. Synthesis 1972, 619.
(12) Hwang, C. W.; Li, W. S.; Nicolaou, K. C. Tetrahedron Lett. 1984,
25, 2295.
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99.
(14) Okuma, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(15) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899. (c) Dess, D. B.;
Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(8) (a) Hudlicky, M. Chemistry of Organic Fluorine Compounds, 2nd
ed.; Ellis-Horwood: New York, 1992. (b) Olah, G. A., Chamber, R. D.,
Surya Prakash, G. K., Eds. Synthetic Fluorine Chemistry; Wiley: New
York, 1992. (c) Banks, R. E., Smart, B. E., Tatlow, J . C., Eds. Organic
Fluorine Chemistry. Principles and Applications; Plenum: New York,
1994.
(9) (a) Curran, D. P.; Hadida, S. J . Am. Chem. Soc. 1996, 118, 2531.
(b) Curran, D. P. Chemtracts-Org. Chem. 1996, 9, 75. (c) Curran, D.
P.; Hoshino, M. J . Org. Chem. 1996, 61, 6480.
S0022-3263(96)02032-4 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 3, 1997 451
roethane as the solvent. This gave 2-benzoyl-4-tert-
butylanisole in 66% yield. In contrast, an equimolar
reaction of 4-tert-butylanisole and benzoyl chloride in a
refluxing BTF (102 °C) was complete after 1 day, and
2-benzoyl-4-tert-butylanisole was isolated in 81% yield.
A Lewis acid-induced Diels-Alder reaction was also
conducted, as shown in eq 7. According to the litera-
To extend the utility of BTF to carbon-carbon bond-
forming reactions, we investigated some important Lewis
acid-assisted reactions including the Sakurai and Mu-
kaiyama reactions. The reaction of mesityl oxide with a
slight excess allyltrimethylsilane (1.2 equiv) in BTF was
performed in the presence of TiCl4 (1 equiv). This
mixture was heterogeneous (a white precipitate was
formed when TiCl4 was added to a solution of mesityl
oxide in BTF), but the desired reaction took place at room
temperature, affording 4,4-dimethyl-6-hepten-2-one in
64% yield (eq 4).17 In contrast, the parallel reaction in
CH2Cl2 was homogeneous, and the yield of the allylation
product was a little bit higher (72%).
ture,21 a mixed solvent consisting of CH2Cl2 and hexane
(7:1) was used for this reaction. When the reaction of
the pantolactone acrylate with cyclopentadiene (1.1
equiv) in the presence of TiCl4 (10 mol %) was carried
out at -10 °C using a BTF/hexane mixture, the desired
Diels-Alder adduct was produced as a single isomer in
73% yield. A similar reaction in CH2Cl2/hexane also
proceeded stereoselectively, but the yield of the adduct
was lower in comparison with BTF.
The results suggest that benzotrifluoride has the
potential to become a generally useful solvent. It can be
considered as a replacement not only for dichloromethane,
but also for other chloro- and chlorofluorocarbon solvents
and for hydrocarbon solvents like benzene, toluene,
hexane, etc. However, at least three limitations are
already evident with benzotrifluoride. First, the freezing
point (-29 °C) is too high for certain applications (this
problem can presumably be solved by using cosolvents
to depress the freezing temperature). Second, benzotri-
fluoride will certainly be sensitive to some kinds of
reducing conditions. While things like hydride reductions
and hydrometalations may succeed, reactions occurring
by electron transfer (for example, dissolving metal reduc-
tions) will probably fail because benzotrifluoride will be
reduced. In this respect, benzotrifluoride resembles
dichloromethane, not benzene and toluene. Third, in
addition to its reaction with AlCl3,19 benzotrifluoride is
hydrolyzed by aqueous acid at high temperatures.8
It is clearly inappropriate to draw sweeping conclusions
about the scope and limitations of benzotrifluoride as a
solvent on the basis of the results of a dozen or so pairs
of reactions. However, it already appears that BTF may
be an interesting solvent for small-scale applications, and
the results suggest that further investigation of the short
and long term toxicity profile, the cost and environmental
impact of disposal, and the potential for recycling of BTF
are worthwhile with and eye toward larger scale applica-
tions.
In the standard Mukaiyama reaction between silyl enol
ethers and aldehydes, â-hydroxy ketones are formed as
major products with the formation of R,â-unsaturated
ketones as byproducts. The TiCl4-induced reaction of a
silyl enol ether of cyclohexanone with 2-phenylpropional-
dehyde in CH2Cl2 afforded the aldol product (68%) and
the R,â-unsaturated ketone (29%) (eq 5).18 In contrast,
a similar reaction in BTF gave rise to R,â-unsaturated
ketone as the major product (84%). Stereoselectivities
(syn/anti, E/Z) in both products were roughly comparable.
Aluminum chloride (AlCl3) is typically used for Friedel-
Crafts reactions; however, it is known that BTF reacts
with AlCl3 at ambient temperature.19 With this limita-
tion in mind, we examined the zinc chloride-catalyzed
Friedel-Crafts reaction between 4-tert-butylanisole and
benzoyl chloride (eq 6).20 In the literature, the ZnCl2-
Ack n ow led gm en t. We thank the National Science
Foundation and the National Institutes of Health for
funding this work. A.K. thanks Osaka University
Engineering Society for financial support of his travel.
Su p p or tin g In for m a tion Ava ila ble: Contains details of
the acylation, tosylation, and silylation reactions of alcohols
(2 pages).
catalyzed benzoylation of 4-tert-butylanisole was per-
formed at 138 °C for 2 days by employing sym-tetrachlo-
J O9620324
(16) (a) Reich, H. J .; Wollowitz, S. Org. React. 1993, 44, 1. (b) Reich,
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(19) (a) Henne, A. L.; Newman, M. S. J . Am. Chem. Soc. 1938, 60,
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(21) Poll, T.; Sobczak, A.; Hartmann, H.; Helmchen, G. Tetrahedron
Lett. 1985, 26, 3095.