Alkoxide- and hydroxide-induced nucleophilic trifluoromethylation using trifluoromethyl sulfone or sulfoxide

Article abstract of DOI:10.1021/ol035045u

(Matrix presented) The first alkoxide- and hydroxide-induced nucleophilic trifluoromethylation of carbonyl compounds, disulfides, and other electrophiles, using phenyl trifluoromethyl sulfone 1a (sulfoxide 1b) is reported. The trifluoromethyl sulfone 1a or sulfoxide 1b acts as a CF₃ ^- synthon. Both sulfone 1a and sulfoxide 1b are commercially available and can also be conveniently prepared from trifluoromethane. The new methodology provides a convenient route for efficient trifluoromethylation.

Full text of DOI:10.1021/ol035045u

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3253-3256
Alkoxide- and Hydroxide-Induced
Nucleophilic Trifluoromethylation Using
Trifluoromethyl Sulfone or Sulfoxide
G. K. Surya Prakash,* Jinbo Hu, and George A. Olah
Donald P. and Katherine B. Loker Hydrocarbon Research Institute and Department of
Chemistry, UniVersity of Southern California, Los Angeles, California 90089-1661
gprakash@usc.edu
Received June 10, 2003
ABSTRACT
The first alkoxide- and hydroxide-induced nucleophilic trifluoromethylation of carbonyl compounds, disulfides, and other electrophiles, using
phenyl trifluoromethyl sulfone 1a (sulfoxide 1b) is reported. The trifluoromethyl sulfone 1a or sulfoxide 1b acts as a “CF3-” synthon. Both
sulfone 1a and sulfoxide 1b are commercially available and can also be conveniently prepared from trifluoromethane. The new methodology
provides a convenient route for efficient trifluoromethylation.
In the past two decades, organofluorine compounds have
attracted much attention due to their unique properties and
unusual reactivities.1 Among them, trifluoromethyl group
(CF3)-containing compounds are of particular importance for
different applications in the fields of materials, pharmaceu-
ticals, and agrochemistry. Although many trifluoromethyla-
tion methods have appeared in the literature, including
organometallic,2 nucleophilic,3 electrophilic,4 and radical
trifluoromethylations,5 fluoride-induced nucleophilic trifluo-
romethylation with (trifluoromethyl)trimethylsilane (TMS-
CF3) developed by us previously is considered to be a
straightforward, convenient, and versatile method.3 TMS-
CF3 was commonly prepared from ozone-depleting trifluo-
romethyl halides, but recently, we reported its non-Freon-
based preparation.6
Since the 1990s, there has been increasing research interest
in trifluoromethylation using trifluoromethane (CF3H) as a
trifluoromethylating precursor. CF3H has low toxicity and
is not ozone-depleting. It is a side-product of the multistep
industrial synthesis of Teflon.7a The efficient production of
CF3H has been disclosed via fluorination of methane with
hydrogen fluoride and chlorine.7b Shono and co-workers8
used electrochemically reduced 2-pyrrolidone base to depro-
tonate CF3H to generate the trifluoromethyl anion equivalent
that reacts with aldehydes and ketones. Troupel et al.9 also
reported that cathodic reduction of iodobenzene generates a
strong base, which deprotonates CF3H, inducing its addition
to aldehydes. Thereafter, two research groups carried out
extensive studies on the nucleophilic trifluoromethylation
(1) (a) Hiyama, T., Ed. Organofluorine Compounds. Chemistry and
Applications; Springer: New York, 2000. (b) Banks, R. E., Smart, B. E.,
Tatlow, J. C., Eds. Organofluorine Chemistry: Principles and Commercial
Applications; Plenum Press: New York, 1994. (c) Welch, J. T.; Eshwara-
krishman, S., Eds. Fluorine in Bioorganic Chemistry; Wiley: New York,
1991. (d) Liebman, J. F., Greenberg, A., Dolbier, W. R., Jr., Eds. Fluorine-
Containing Molecules. Structure, ReactiVity, Synthesis, and Applications;
VCH: New York, 1988.
(2) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(3) (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757. (b)
Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123. (c)
Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989,
111, 393. (d) Krishnamurti, R.; Bellew D. R.; Prakash G. K. S. J. Org.
Chem. 1991, 56, 984.
(4) (a) Umemoto, T. Chem. ReV. 1996, 96, 1757. (b) Umemoto, T.;
Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156. (c) Umemoto, T.; Gotoh,
Y. Bull. Chem. Soc. Jpn. 1987, 60, 3307. (d) Shreeve, J. M.; Yang, J.-J.;
Kirchmeier, R. L. U.S. Patent 6215021, 2001.
(5) (a) Dolbier, W. R., Jr. Chem. ReV. 1996, 96, 1557. (b) Dolbier, W.
R., Jr. Top. Curr. Chem. 1997, 192, 97.
(6) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.
(7) (a) Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron
Lett. 1998, 39, 2973. (b) Webster J. L.; Lerou, J. J. U.S. Patent 5,446,218,
1995.
(8) Shono, T.; Ishifume, M.; Okada, T.; Kashimura, S. J. Org. Chem.
1991, 56, 2.
(9) Barhdadi, R.; Troupel, M.; Perichon, J. Chem. Commun. 1998, 1251.
10.1021/ol035045u CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003

using CF3H as a precursor. Normant and co-workers7a,10 have
demonstrated the trifluoromethylation of aldehydes by CF3H/
potassium dimsylate in DMF. They suggested that the CF3 /
bond of sulfone 1a or sulfoxide 1b. The generation of
pseudohalide CF3 species is somewhat similar to the
-
-
reaction between benzenesulfonyl halides with alkoxides.
Nucleophilic displacement of the trifluoromethyl group has
been reported for trifluoromethyl aryl sulfones with sodium
methoxide.16 Similar reaction between trifluoromethyl aryl
sulfone and Grignard reagents has been reported for the
preparation of sulfones.17 More recently, Cheburkov et al.
reported that perfluoroalkyl sulfones react with metal hy-
droxides in water or alcohol solution and with ammonia to
form fluorinated sulfonic acid derivatives.18 However, alkox-
ide- and hydroxide-induced nucleophilic trifluoromethylation
using trifluoromethyl sulfones or sulfoxides has not been
previously reported.
DMF adduct was the key intermediate in the trifluoromethyl
transfer process. Roques, Langlois, and co-workers11 reported
the nucleophilic trifluoromethylation of carbonyl compounds
-
and disulfides with CF3H and different bases in DMF. CF3 /
N-formylmorpholine adduct was also developed as a stable
reagent for the trifluoromethylation of nonenolizable carbonyl
compounds.12 Under similar consideration, piperazino hemi-
aminal of trifluoroacetaldehyde was also used as a trifluo-
romethylating agent.13a,b However, trifluoromethane-derived
methods have their drawbacks: first of all, trifluoromethane
is a low-boiling gas (bp -84 °C) and thus its handling as a
reagent in the laboratory is not convenient; second, the quoted
trifluoromethylations do not work well with enolizable
carbonyl compounds.
Trifluoromethyl iodide (CF3I) has also been successfully
used as a nucleophilic trifluoromethylating agent under the
activation of electron-donating tetrakis-(dimethylamino)ethy-
lene (TDAE).14a Motherwell and Storey14b reported the nucle-
ophilic trifluoromethylation using trifluoromethylacetophe-
none-N,N-dimethyl-trimethylsilylamine adduct. Langlois and
co-workers also have reported nucleophilic trifluoromethy-
lations of nonenolizable carbonyl compounds using trifluo-
roacetic acid derivatives,13c,d trifluoromethanesulfinic acid
derivatives,13e and trifluoroacetophenone.13f More recently,
a nucleophilic trifluoromethylation method using trifluoro-
actetamides from amino alcohols was reported.13g
Herein, we wish to report the first alkoxide- and hydroxide-
induced nucleophilic trifluoromethylation of carbonyl com-
pounds, disulfides, and other electrophiles, using trifluoro-
methyl phenyl sulfone 1a (sulfoxide 1b). The trifluoromethyl
-
sulfone 1a or sulfoxide 1b can be used as a “CF3 ” synthon.
Both phenyl trifluoromethyl sulfone 1a and sulfoxide 1b are
commercially available (bp 203 °C/760 mmHg for 1a, bp
85∼87 °C/10 mmHg for 1b) and can also be conveniently
prepared from trifluoromethane in high yields.19 Thus, the
new methodology provides a convenient route for efficient
nucleophilic trifluoromethylation.
Potassium tert-butoxide (tBuOK) was first used as a
nucleophile to attack the sulfur center of phenyl trifluoro-
methyl sulfone 1a generating trifluoromethyl anion (Scheme
1). Into an equimolar mixture of sulfone 1a and benzaldehyde
4 in DMF at -50 °C was slowly added a DMF solution of
tBuOK (2 molar equiv). The reaction mixture was stirred at
-50 °C for 1 h and then warmed to room temperature over
a period of 2 h. 1-Phenyl-2-trifluoromethylethanol 5 was
produced in 71% yield (Scheme 2).
We previously reported a reductive trifluoromethylation
using trifluoromethyl sulfides, sulfoxides and sulfones as
trifluoromethyl (CF3) group precursors.6 However, under the
reductive condition, where magnesium metal was used, the
reaction only worked with chlorosilanes as electrophiles,
while attempts to react with carbonyl compounds failed. We
anticipated that by using a nucleophilic base such as
alkoxides, the carbon-sulfur bond of trifluoromethyl phenyl
sulfone 1a or sulfoxide 1b can be cleaved to give a
Scheme 2. Trifluoromethylation of PhCHO with 1a
-
trifluoromethyl anion (CF3 ) synthon that can undergo
addition to carbonyl compounds (Scheme 1). The driving
Scheme 1. Mechanistic Consideration
Shono and co-workers8 found that when they used CF3H/
tBuOK/DMF to react with benzaldehyde at -50 °C, benzyl
(13) (a) Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001,
1467. (b) Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67, 997. (c)
Langlois, B. R.; Billard, T. Synthesis 2003, 185. (d) Jablonski, L.; Joubert,
J.; Billard, T.; Langlois, B. R. Synlett 2003, 230. (e) Inschauspe, D.; Sortais,
J.-P.; Billard, T.; Langlois, B. R. Synlett 2003, 233. (f) Jablonski, L.; Billard,
T.; Langlois, B. R. Tetrahedron Lett. 2003, 44, 1055. (g) Joubert, J.; Roussel,
S.; Christophe, C.; Billard, T.; Langlois, B. R.; Vidal, T. Angew. Chem.,
Int. Ed. 2003, 42, 3133.
force of this substitution is the formation of a strong S-O
bond (348∼551 kJ/mol)15 and the high polarity of the C-S
(14) (a) Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W., Jr.
Org. Lett. 2001, 3, 4271. (b) Motherwell, W. B.; Storey, L. J. Synlett 2002,
646.
(10) Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L.Tetrahedron
2000, 56, 275.
(11) (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. (b) Large,
S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848. (c) Roques,
N.; Russell, J.; Langlois, B.; Saint-Jalmes, L.; Large, S. PCT Int. Appl.
1998, WO 9822435. (d) Roques, N.; Mispelaere, C. Tetrahedron Lett. 1999,
40, 6411.
(15) Dean, J. A. Lange’s Handbook of Chemistry, 14th ed.; McGraw-
Hill: New York, 1992; p 4.34.
(16) Shein, S. M.; Krasnopol’skaya, M. I.; Boiko, V. N. Zh. Obshei.
Khim. 1966, 36, 2141.
(17) Steensma, R. W.; Galabi, S.; Tagat, J. R.; McCombie, S. W.,
Tetrahedron Lett. 2001, 42, 2281.
(12) Billard, T. B.; Langlois, B. R. Org. Lett. 2000, 2, 2101.
3254
Org. Lett., Vol. 5, No. 18, 2003

Table 1. Trifluoromethylation of Benzaldehyde by PhSO2CF3 Induced by Alkoxide or Hydroxide
benzaldehyde
sulfone 1a
alkoxide
solvent
temperature
time
yield (5,%)
a
b
c
d
e
f
1 equiv
3 equiv
1 equiv
3 equiv
3 equiv
3 equiv
1 equiv
1 equiv
2 equiv
1 equiv
1 equiv
1 equiv
t-BuOK (2 equiv)
t-BuOK (2 equiv)
t-BuOK (2 equiv)
MeONa (3 equiv)
KOH (8 equiv)
DMF
DMF
DMF
DMF
DMF
DMSO
-50 °C
-30 °C to rt
-50 °C to rt
-30 °C to rt
rt
1 h
30 min
3 h
3 h
20 h
1 h
71
91
84
30
45
76
t-BuOK (2 equiv)
rt
a Yields were determined by 19F NMR on the basis of the amount of 1a used.
alcohol and benzoic acid were formed by the competing
Cannizzaro reaction. Russell and Roques11a repeated the
reaction using excess CF3H (9.5 equiv) and BuOK (2.2
We also attempted to carry out the reaction by using a
catalytic amount of tBuOK. However, when a small amount
of tBuOK was introduced, only a low yield of product 5 was
obtained (after hydrolysis), which can be monitored by 19F
t
equiv) at - 50 °C, and 67% yield of trifluoromethylated
product 5 was formed and no benzyl alcohol was detected.
They mentioned that the high reaction temperature with
excess base could lead to Cannizzaro reaction and jeopardize
the nucleophilic trifluoromethylation. In our reaction, as
shown in Scheme 2, only traces of benzoic acid and benzyl
alcohol were detected by NMR. This implies that in our
reaction at low temperature, the Cannizzaro reaction rate is
much slower than the tert-butoxide-induced trifluoromethy-
lation process. The reaction conditions have been optimized
(Table 1). When excess benzaldehyde was introduced, the
yield of product 5 could be improved in terms of the amount
of sulfone 1a used (Table 1, entry b).
t
NMR. Introduction of additional BuOK increased the
product yield, and an excellent yield of 5 was achieved when
t
excess BuOK was used.
An excess of tBuOK (2 equiv) was found to be helpful to
achieve high yields in the trifluoromethylation reactions.
There are several reasons and advantages. tBuOK reacts with
water readily and may be partially hydrolyzed during storage
and handling. Furthermore, excess tBuOK also removes the
moisture from the solvent and reagents. More importantly,
t
excess BuOK in the reaction mixture eliminates the pos-
-
sibility of hydrolysis of CF3 to form CF3H. It is known
t
that CF3H can be deprotonated by BuOK and undergo
Besides tBuOK, sodium methoxide (CH3ONa) and potas-
sium hydroxide (KOH) were tried as nucleophiles (Table 1,
entries d and e). Both of them worked but gave lower yields.
There are several possible reasons. First of all, both sodium
methoxide and KOH cannot readily dissolve in DMF, which
affects the reaction rate. Second, unlike potassium tert-
butoxide, sodium methoxide may react with benzaldehyde
via a Meerwein-Pondorff-Verley-type reduction pathway.20
trifluoromethylation of carbonyl compounds,9-11 Thus, the
present methodology allows the preparation of trifluoro-
methylated products in high yields in the case of noneno-
lizable aldehydes (Table 2, entries 1-5). Similarly, noneno-
lizable ketones can also be easily trifluoromethylated using
this methodology (Table 2, entries 7-12). Since there is no
t
Cannizarro reaction between ketones and BuOK, these
reactions can be carried out even at higher temperatures (such
as 25 °C). Due to the lower reactivity of ketones compared
with aldehydes, the ketone reactions need a slightly longer
time (2-3 h) to go to completion. However, with enolizable
aldehydes and ketones, only low yield (10-30%) of tri-
fluoromethylated products were observed, because of the
competing and facile aldol reactions.
t
Third, KOH has lower nucleophilicity than BuOK, so the
reaction rate can be slow. Here, Cannizzaro reaction may
still happen as a competing side-reaction, but it should not
be a dominating factor to affect the yield since excess
benzaldehyde is present.21
It is worth noting that DMF is not the only convenient
solvent for the reaction. Dimethyl sulfoxide (DMSO) was
also used, and the reaction worked well (Table 1, entry f).
It is noteworthy that phenyl trifluoromethyl sulfoxide 1b
worked equally well as 1a, and similar trifluoromethylations
were observed with aldehyde and ketone (Table 2, entries 6
and 13).
-
This indicates that the CF3 /DMF adduct7a,10,11a is not a
necessary intermediate for this new type of nucleophilic
trifluoromethylation. From a mechanistic point of view,
however, it can be reasonably postulated that the intermediate
species 2 (in Scheme 1) is formed and could act as a real
trifluoromethylating agent.
Another advantage of the reaction is the simple workup
procedure. Since the byproduct of the reaction is tert-butyl
benzenesulfonate, it can be readily hydrolyzed into tert-butyl
alcohol and benzenesulfonic acid derivatives. Aqueous
washing thus can remove most of the byproducts and
simplifies the purification process.
(18) Barrera, M. D.; Cheburkov, Y.; Lamanna, W. M. J. Fluorine Chem.
2002, 117, 13.
(19) Trifluoromethyl phenyl sulfide, sulfoxide, and sulfone are all
commercially available. A number of reports on their preparation have
appeared in the literature. See: (a) ref 11 (a). (b) Gerard, F.; Jean-Mannel,
M.; Laurent, S.-J. Eur. Pat. Appl. 1996, EP 733614. (c) Chen, Q.-Y.; Duan,
J.-X. Chem. Commun. 1993, 918. (d) Yang, J.-J.; Kirchmeier, R. L.; Shreeve,
J. M. J. Org. Chem. 1998, 63, 2656.
(20) Hassner A., Stumer, C., Eds. Organic Syntheses Based on Name
Reactions and Unnamed Reactions; Pergamon: New York, 1994; p 251.
(21) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53.
The novel trifluoromethylating method was also found to
work with disulfides. As shown in Scheme 3, PhSO2CF3
t
(1 equiv) and BuOK (2 equiv) reacted with diphenyl
disulfide (6, 1.2 equiv) at temperatures between -30 °C and
room temperature in 30 min to give quantitative conver-
sion (87% isolated) of trifluoromethyl phenyl sulfide 7
Org. Lett., Vol. 5, No. 18, 2003
3255

Scheme 3. Trifluoromethylation of PhSSPh with 1a
Table 2. Reaction of Trifluoromethyl Phenyl Sulfone (1a)
or Sulfoxide (1b) (2 equiv) with Nonenolizable Carbonyl
Compounds (1 equiv) and BuOK (2.5 equiv) in DMF between
t
-50 °C and Room Temperature
The 1a/tBuOK trifluoromethylation method was also
applied to other systems. For instance, methyl benzoate can
be trifluoromethylated to generate 2,2,2-trifluoroacetophe-
none in 30% yield at temperatures between -50 and -20
°C. CF3Cu can be generated in situ with 1a/tBuOK and
copper iodide (CuI) and then further react with iodobenzene
at 80 °C for 20 h to give R,R,R-trifluorotoluene in 26% yield.
We also attempted the use of other types of sulfones such
as methyl trifluoromethyl sulfone (1c) as the trifluoromethy-
lating agent. When diphenyl disulfide was used as the model
substrate, however, the reaction only gave a minimal yield
of product 7 (∼ 2%). This is probably due to the facile
deprotonation of the methyl group by tBuOK, leading to other
products.
In summary, potasium tert-butoxide-induced trifluoro-
methylation using phenyl trifluoromethyl sulfone (PhSO2-
CF3, 1a) or sulfoxide (PhSOCF3, 1b) enables us to transfer
CF3 group into nonenolizable carbonyl compounds and
disulfides in high yields. Since both compounds 1a and 1b
are stable high-boiling liquids that can be readily produced
from nonozone-depleting trifluoromethane, the reported new
trifluoromethylating method offers an inexpensive and
convenient synthetic methodology. Investigations to extend
the scope of this novel type of fluoroalkylation methodology
to reactions such as difluoroalkylation using difluoromethyl
sulfones or sulfoxides are underway.
Acknowledgment. Support of our work in part by Loker
Hydrocarbon Research Institute is gratefully acknowledged.
Supporting Information Available: General experimen-
tal paragraph; experimental procedures for trifluoromethy-
a Isolated yields. b CFCl3 was used as an internal reference. c Determined
by 19F NMR using PhOCF3 as an internal standard.
1
lation with 1a (1b)/tert-BuOK, and H, 19F, and 13C NMR
and Mass characterization data of the isolated products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19F NMR: - 43.3 ppm). This reaction was even more facile
than that of carbonyl compounds.
OL035045U
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Org. Lett., Vol. 5, No. 18, 2003