Nucleophilic trifluoromethylation using trifluoromethyl iodide. A new and simple alternative for the trifluoromethylation of aldehydes and ketones

Article abstract of DOI:10.1021/ol016933x

(Matrix Presented) A novel method for nucleophilic trifluoromethylation of aldehydes and ketones, based on photoinduced reduction of trifluoromethyl iodide by tetrakis(dimethylamino)ethylene (TDAE), is presented.

Full text of DOI:10.1021/ol016933x

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4271-4273
Nucleophilic Trifluoromethylation Using
Trifluoromethyl Iodide. A New and
Simple Alternative for the
Trifluoromethylation of Aldehydes and
Ketones
Samia A1ıt-Mohand,† Naoto Takechi,† Maurice Me´debielle,‡ and
,†
William R. Dolbier, Jr.*
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611-7200, and
UniVersite´ Claude Bernard-Lyon 1, Laboratoire SERCOF (UMR CNRS 5622),
Batiment E. CheVreul, 43, Bd du 11 noVembre 1918, F-69622 Villeurbanne, France
wrd@chem.ufl.edu
Received October 18, 2001
ABSTRACT
A novel method for nucleophilic trifluoromethylation of aldehydes and ketones, based on photoinduced reduction of trifluoromethyl iodide by
tetrakis(dimethylamino)ethylene (TDAE), is presented.
Compounds containing the trifluoromethyl group are of great
interest in the pharmaceutical and agrochemical industry.
Among the numerous methods for incorporation of the
trifluoromethyl group into organic compounds,1 one of the
most useful involves the use of reagents that effectively
synthetic chemists around the world. Because of its diversity
of applicability, deriving from extensive recent work by the
groups of Prakash,2 Shreeve,3 and others,2,3 (trifluoromethyl)-
trimethylsilane (Me3SiCF3) is generally considered to be the
most effective reagent of this type, but recent advances from
Langlois’ group on the use of trifluoroacetaldehyde hemi-
aminals and their derivatives as trifluoromethylating reagents
in reactions with nonenolizable aldehydes and ketones have
also sparked considerable interest.4,5
Trifluoromethyl iodide has previously been used for the
purpose of nucleophilic trifluoromethylation of carbonyl
compounds, via its derived organozinc reagent. However,
the required use of ultrasound for these reactions, developed
by Kitazume and Ishikawa, seems to have limited their use
by synthetic chemists.6,7
-
generate the unstable CF3 anion as an in situ species for
the purpose of nucleophilic trifluoromethylation of electro-
philic substrates such as aldehydes and ketones. Because of
the limited number of such reagents and because of specific
limitations that pertain to each, there remains considerable
interest in the development of new trifluoromethyl anion
reagents that might offer an experimental or cost advantage.
We wish to report, at this time, a novel use of the currently
relatively inexpensive compound, trifluoromethyl iodide, as
a ready source of a new trifluoromethyl anionic reagent that
adds to aldehydes and ketones to provide addition products
in very good to excellent yield.
Beginning in 1998, we demonstrated in a series of papers
that tetrakis(dimethylamino)ethylene (TDAE) could be used
Currently, there are two major, preferred trifluoromethyl
anion methodologies that receive most of the attention from
(2) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757-786.
(3) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613-7632.
(4) Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848-
8856.
† University of Florida.
‡ Universite´ Claude Bernard-Lyon 1.
(1) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555-
6666.
(5) Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001,
1467-1471.
10.1021/ol016933x CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/04/2001

as an effective reductant to generate synthetically competent
nucleophilic heterocyclic difluoromethyl anions from chloro-
and bromodifluoromethyl precursors.8,9 It was a natural
extension to determine whether a combination of TDAE and
trifluoromethyl iodide could be used to generate synthetically
competent trifluoromethyl anions. Pawelke earlier demon-
strated that the combination of CF3I and TDAE could be
used to prepare CF3TMS from TMSCl.10
Initial results were, however, quite discouraging, because
when TDAE was added to a solution of benzaldehyde and
trifluoromethyl iodide in dry DMF at -35 °C and the
solution allowed to warm with stirring to room temperature,
although the reagents were totally consumed, the desired
trifluoromethyl addition product was obtained in only poor
yield. (Petrov has very recently reported a similar result in
a paper that appeared as our own work was nearing
completion.)11
Table 1. Photopromoted Nucleophilic Trifluoromethylation of
Aldehydes and Ketones Using CF3I/TDAE Reagenta
NMR
yield
isolated
yield
products
R1
R2
114
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
H
H
H
80
89
89
95
91
quant
91
74
82
78
81
82
90
86
93
86
68
78
73
78
79
215
p-Cl-Ph
p-CN-Ph
p-F-Ph
o-Br-Ph
1-naphthyl
4-Me2N-1-naphthyl
3-thienyl
2-furanyl
4-pyridyl
PhCHdCH
2-OMe-PhCHdCH
Ph
PhCHdCH
i-C3H7
c-C6H11
n-C3H7
Ph
316
416
515
617
7b
815
916
10b
114
12b
134
144
1518
1614
1716
1814
194
2014
83
68
65
52
68
15
18
65
76
53
48
53
CH3
73
quant
fluorenyl
(CH2)5
194
2014
In contrast to the results obtained when the reaction is
carried out thermally, when the same reaction is carried out
at -20 °C, under irradiation by a sun lamp,12 its outcome
was remarkably improved, with a yield of 80% being
obtained. Subsequent reactions carried out in this manner
with a large number of aldehydes and ketones exhibited
similar success, as indicated in Table 1 below. A representa-
tive procedure is given in a footnote.13
a All products except 7, 10, and 12 have been previously reported, with
appropriate references being given. b The mp’s and 1H, 13C, and 19F NMR
spectra of the new products are given in ref 19.
which presumably is the active trifluoromethylating agent.8
Although DMF is presently the preferred solvent, the reaction
(13) Synthesis of 1-Phenyl-2,2,2-trifluoroethanol. Into a three-necked
flask equipped with a dry ice reflux condenser and a nitrogen inlet were
added, at -35 °C, 15 mL of anhydrous DMF, benzaldehyde (1 mL, 9.8
mmol), and CF3I (1.8 mL, 21.6 mmol). The solution was stirred and
maintained at this temperature for 15 min, and then to it was added TDAE
(5 mL, 21.5 mmol) at -20 °C. A red color developed with formation of a
white precipitate. The solution was vigorously stirred at -20 °C for 10
min and then was irradiated by a sun lamp for 8 h, during which time the
mixture warmed to room temperature. The resulting orange-red solution
was then filtered, and the solid washed with ether. The DMF solution was
then hydrolyzed with water, and the resulting aqueous mixture was extracted
with ether (3 times). The combined ether solutions were washed with brine
(5 times) and dried over MgSO4. The solvent was removed, and the crude
product was purified by silica gel chromatography (CH2Cl2/hexane ) 8:2)
to give 1-phenyl-2,2,2-trifluoroethanol in a yield of 78%.
(14) Krishnamurthy, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem.
1991, 56, 984-989.
The yields derived under photochemical conditions were
generally far superior to those that could be obtained in the
absence of light, and for most substrates examined the yields
of alcohols were comparable to those obtained in analogous
CF3TMS reactions.
The mechanism of the reaction appears to proceed via an
initially formed charge-transfer complex (red color) between
CF3I and TDAE, followed by stepwise, photoinduced single-
electron transfers of two electrons from TDAE to CF3I to
form a complex between CF3- anion and TDAE+2 dication,
(15) Matsuda, T.; Harada, T.; Nakajima, N.; Itoh, T.; Nakamura, K. J.
Org. Chem. 2000, 65, 157-163.
(16) Tordeux, M.; Francese, C.; Wakselman, C. J. Chem. Soc., Perkin
Trans. 1 1987, 1951-1957.
(17) Pirkle, W. H.; Hoekstra, M. S. J. Org. Chem. 1974, 39, 3904-
3906.
(18) Dolbier, W. R., Jr.; Burkholder, C. R.; Piedrahita, C. A. J. Fluorine
Chem. 1982, 20, 637-647.
1
(19) Compound 7: light orange solid, mp 85-86 °C; H NMR δ 8.26
(6) Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186-
5191.
(m, 1H), 7.85 (m, 1H), 7.66 (d, J ) 7.9 Hz, 1H), 7.50 (m, 2H), 7.00 (d, J
) 7.9 Hz, 1H), 5.66 (q, J ) 6.6 Hz, 1H), 3.60 (br s, 1H), 2.88 (s, 6H); 19
F
(7) For related work using CF3Br, see: Francese, C.; Tordeux, M.;
Wakselman, C. J. Chem. Soc., Chem. Commun. 1987, 642-643.
(8) Burkholder, C. R.; Dolbier, W. R., Jr.; Me´debielle, M. J. Org. Chem.
1998, 63, 5385-5394.
(9) Burkholder, C. R.; Dolbier, W. R., Jr.; Me´debielle, M. J. Fluorine
Chem. 2001, 109, 39-48.
(10) Pawelke, G. J. Fluorine Chem. 1991, 52, 229.
(11) Petrov, V. A. Tetrahedron Lett. 2001, 42, 3267-3289.
(12) A temperature of -20 °C was chosen for the photoinduced process
in order to minimize the extent of thermal decomposition of the charge-
transfer complex, which occurs at room temperature.
NMR δ -77.07 (d, J ) 6.7 Hz); 13C NMR δ 152.0, 132.3, 128.5, 126.7,
126.5, 125.9, 125.0, 124.8 (q, J ) 269 Hz), 124.4, 113.1, 69.5 (q, J ) 33
Hz), 45.0 ppm. Compound 10: white solid, mp 76-77 °C; 1H NMR δ 8.5
(br s, 2H), 7.52 (d, J ) 5.4 Hz, 2H), 5.08 ppm (q, J ) 6.5 Hz, 1H); 19F
NMR δ -78.2 ppm (d, J ) 6.5 Hz); 13C NMR δ 148.9, 145.3, 124.0 (q, J
) 270 Hz), 122.9, 70.8 (q, J ) 32 Hz). Compound 12: cream solid, mp
1
63.5-64.5 °C; H NMR δ 7.45 (dd, J ) 7.6, J ) 1.7 Hz, 1H), 7.30 (m,
1H), 7.17 (d, J ) 16 Hz, 1H), 6.86 (m, 2H), 6.26 (dd, J ) 16.1, J ) 6.5
Hz, 1H), 4.64 (m, 1H), 3.85 (s, 3 H), 2.40 (d, J ) 5.5 Hz, 1H); 19F NMR
δ -79.41 (d, J ) 6.5 Hz); 13C NMR δ 157.1, 131.7, 129.9, 127.4, 127.0,
124.2 (q, J ) 275 Hz), 121.2, 121.2, 120.7, 110.9, 72.1 (q J ) 32 Hz).
4272
Org. Lett., Vol. 3, No. 26, 2001

also gives good results when other solvents are used. For
example, in the reaction with aldehyde 6, a 53% yield was
obtained in dimethoxyethane (DME), and a 72% yield when
DME/HMPA (1:1) was used. Therefore, there is no need to
invoke the intermediacy of Langois’ CF3- adduct with DMF
in these reactions. Additional mechanistic studies are in
progress.
The success of the reaction with aliphatic aldehydes and
ketones appears to be dependent on the kinetic acidity of
their carbonyl R-H’s, with poor results being obtained
generally for aldehydes having a RCH2CHO structure and
for methyl ketones.
In conclusion, this new procedure for nucleophilic tri-
fluoromethylation of aldehydes and ketones, because of the
high yields generally obtained, should provide a relatively
inexpensive synthetic alternative to the currently popular
CF3TMS method.
Acknowledgment. The authors acknowledge, with thanks,
the financial support of this work, in part, by the National
Science Foundation. M.M. would also like to thank the
CNRS for partial support of this work through a research
grant (Aide aux Jeunes Equipes-Appel d'Offres 2000)
OL016933X
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