Nucleophilic trifluoromethylation of acyl chlorides using the trifluoromethyl iodide/TDAE reagent

Article abstract of DOI:10.1016/S0040-4039(02)00800-6

Chemoselective bis-trifluoromethylation of acyl chlorides using the CF₃I/TDAE-derived nucleophilic trifluoromethyl anion reagent is reported. Very high yields are obtained of an ester product formed by sequential nucleophilic bis-trifluoromethylation, followed by acylation of the resultant alcoholate.

Full text of DOI:10.1016/S0040-4039(02)00800-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4317–4319
Nucleophilic trifluoromethylation of acyl chlorides using the
trifluoromethyl iodide/TDAE reagent
Naoto Takechi,a Samia A¨ıt-Mohand,a Maurice Me´debielleb and William R. Dolbier, Jr.a,*
aDepartment of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
bUniversite´ Claude Bernard-Lyon 1, Laboratoire SERCOF (UMR CNRS 5622), Batiment E. Chevreul, 43, Bd du 11 novembre
1918, F-69622 Villeurbanne, France
Received 1 April 2002; revised 19 April 2002; accepted 23 April 2002
Abstract—Chemoselective bis-trifluoromethylation of acyl chlorides using the CF3I/TDAE-derived nucleophilic trifluoromethyl
anion reagent is reported. Very high yields are obtained of an ester product formed by sequential nucleophilic bis-trifluoromethyl-
ation, followed by acylation of the resultant alcoholate. © 2002 Elsevier Science Ltd. All rights reserved.
In spite of the widespread application of (tri-
fluoromethyl)trimethylsilane (Me3SiCF3) as a nucle-
ophilic trifluoromethylating agent and the numerous
papers on the subject,1–3 there has been only one, brief
mention of its reactions with acyl chlorides, that by
Krishnamurti, Bellew, and Prakash in 1991.4 In this
paper, it was claimed that the reaction of Me3SiCF3
with benzoyl chloride led to competitive single and
double addition, to form ketone and alcohol products,
respectively. However, neither yields nor experimental
details were provided.
Curious about the lack of literature on the reaction,5,6
and recognizing that a chemoselective reaction with
acyl chlorides could be quite useful, we decided to take
a close look at the reaction of our recently developed
CF3I/TDAE-derived trifluoromethyl anion reagent with
acyl chlorides. Using our usual conditions of 2.2 equiv.
of CF3I and TDAE in DMF at −20°C (but no light),
warming to room temperature and then stirring at
room temperature for 2 h, led to rather disappointing
results, with only 5% of alcohol 1 being formed, along
with a second product in 44% yield.7 Isolation and
* Corresponding author. Fax: 352-846-1962; e-mail: wrd@chem.ufl.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00800-6

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N. Takechi et al. / Tetrahedron Letters 43 (2002) 4317–4319
characterization of the major product demonstrated
that it was not the expected ketone, but instead the
benzoate ester (2) of alcohol 1.8
quence, so that ester 2 is essentially the only observed
product of the reaction in DME when the stoichiometry
is fulfilled.
Trying other solvents and conditions, it was quickly
determined that 1,2-dimethoxyethane (DME) was the
preferred solvent for this reaction, with a quantitative
yield of benzoate ester 2 being obtained in an overnight
reaction at room temperature. Further optimization
indicated that stirring at room temperature for 2 h was
sufficient, and that, unlike in the earlier reported reac-
tion with aldehydes and ketones, the reaction with
benzoyl chloride was not enhanced by light.9
The reaction appears to be general for aroyl chlorides,
as indicated by the examples given below, and prelimi-
nary results indicate that aliphatic acyl chlorides can
also be acceptable substrates. Thus, use of isobutyryl
chloride in the reaction produced ester 3 as the only
observable product in 34% yield.
Lastly, when n-C3F7I was used in place of CF3I in this
reaction, a good yield of a mixture of ester and alcohol,
plus rearranged ketone10,11 were obtained, as shown
below. Apparently, steric influences serve to minimize
the final acylation step, and the product of rearranged
i-C3F7− anion addition must be sterically inhibited from
further alkylation. Recently Petrov reported related
It should be noted that, with only 2.2 equiv. of CF3I
−
being used and 2 equiv. of CF3 anion reagent being
required stoichiometrically, this reaction must be very
efficient with respect to the utilization of the tri-
fluoromethyl anion. When the reaction was carried out
using an insufficient amount of trifluoromethyl anion
reagent (i.e. 1.1 equiv. of both CF3I and TDAE), 2 was
still the major product (22%), with but 3% of the
ketone being formed.
−
−
results for the addition of C2F5 and i-C3F7 anions to
benzoyl chloride.6
The high chemoselectivity exhibited in this reaction
clearly indicates that the mechanistic sequence of steps
−
in the reaction, involving initial CF3 addition, loss
of Cl−, second addition of CF3 , and finally acyl-
−
ation, must become progressively faster along the se-

N. Takechi et al. / Tetrahedron Letters 43 (2002) 4317–4319
4319
Although this clean reaction of trifluoromethyl anion
with acyl chlorides may find little synthetic use, consid-
ering the fact that half of the acyl chloride is consumed
in acylating the alcoholate to form the ester product,
the obtained esters can nevertheless be readily con-
verted to the respective bis-trifluoromethyl-substituted
alcohols by transesterification using methanolic KOH.
6. Petrov, V. A. Tetrahedron Lett. 2001, 42, 3267–3289.
7. All yields reported in this paper were determined by 19F
NMR using trifluoromethylbenzene as internal standard.
8. Ester 2 was characterized by NMR and mass spectrome-
1
try: white solid, mp 46–47°C; H NMR, l 8.14 (m, 2H),
7.69 (m, 1H), 7.54 (m, 2H), 7.39–7.50 ppm (m, 5H); 19F
NMR, l −70.7 ppm (s); 13C NMR, l 162.1, 134.6, 130.5,
130.4, 129.1, 128.8, 128.3, 127.3, 126.9, 122.1 (q, J=288
Hz), 83.8 (m, J=30 Hz); HRMS (EI), calcd for
C16H10O2F6: 348.0585; found: 348.0585.
Acknowledgements
9. Typical reaction procedure: Into
a 3-necked flask
equipped with a dry ice reflux condenser and nitrogen
inlet were added, at −35°C, 8 mL of anhydrous DME,
benzoyl chloride (0.50 mL, 4.3 mmol), and CF3I (1.86 g,
9.5 mmol). The solution was stirred and warmed to
−20°C, and then to it was added TDAE (2.20 mL, 9.5
mmol) at −20°C. The reaction mixture was vigorously
stirred and warmed to rt. It was then stirred at rt for 2 h
and the resulting orange-red solution was filtered, and the
solid was washed with ether. The ether solution was
washed with water, and the resulting aq. solution was
extracted with ether. The combined ether solutions were
washed with brine (three times) and dried over Na2SO4.
The solvent was removed, and the crude product ana-
lyzed by 19F NMR to determine the yield (using tri-
fluoromethylbenzene as internal standard).
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’).
References
1. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757–786.
2. Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613–
7632.
3. Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001,
112, 123–131.
10. The rearranged ketone undoubtedly derived from isomer-
ization of the n-C3F7 anion to the i-C3F7 anion by the
well-precedented anionic mechanism involving elimina-
tion/addition of fluoride ion.11
11. Chambers, R. D.; Vaughan, J. F. S. In Organofluorine
Chemistry. Fluorinated Alkenes and Reactive Intermedi-
ates; Chambers, R. D., Ed.; Springer: Berlin, 1997; Vol.
192, pp. 1–88.
4. Krishnamurthy, R.; Bellew, D. R.; Prakash, G. K. S. J.
Org. Chem. 1991, 56, 984–989.
5. To our knowledge, the only other related work is that of
Petrov, who obtained a 56% yield of ketone from the
reaction of benzoyl chloride with 1 equiv. of i-C3F7I/
TDAE, whereas its reaction with 2 equiv. of C2F5I/
TDAE led to a mixture of ketone and alcohol products
(33 and 17% yield, respectively).6