Preparation of TMS protected trifluoromethylated alcohols using trimethylamine N-oxide and trifluoromethyltrimethylsilane (TMSCHF3)

Article abstract of DOI:10.1016/S0022-1139(03)00104-0

A catalytic trifluoromethylation of aldehydes using trimethylamine N -oxide and trifluoromethyltrimethylsilane (TMSCF₃) is described. Aromatic, aliphatic and α,β-unsaturated aldehydes provided good to excellent yields of the corresponding trifl

Full text of DOI:10.1016/S0022-1139(03)00104-0

Journal of Fluorine Chemistry 123 (2003) 61–63
Preparation of TMS protected trifluoromethylated alcohols using
trimethylamine N-oxide and trifluoromethyltrimethylsilane (TMSCF3)
G.K. Surya Prakash*, Mihirbaran Mandal, Chiradeep Panja,
Thomas Mathew, George A. Olah
Donald P. and Katherine B. Loker Hydrocarbon Research Institute, Department of Chemistry,
University of Southern California, University Park, Los Angeles, CA 90089-1661, USA
Received 12 February 2003; received in revised form 4 April 2003; accepted 4 April 2003
Dedicated to Professor Eric Banks on the occasion of his 70th birthday
Abstract
A catalytic trifluoromethylation of aldehydes using trimethylamine N-oxide and trifluoromethyltrimethylsilane (TMSCF3) is described.
Aromatic, aliphatic and a,b-unsaturated aldehydes provided good to excellent yields of the corresponding trifluoromethylated products.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Aldehydes; Trifluoromethyltrimethylsilane; Trimethylamine N-oxide; Catalytic CF3 transfer; Nucleophilic trifluoromethylation
1. Introduction
similar fashion using oxygen nucleophiles that can act as
true catalysts. Our final aim is to eventually use this chem-
istry to achieve facile enantioselective CF3 transfer [5]. Here
we disclose our preliminary results towards this approach.
After our initial discovery in 1989 [1], TMSCF3 has been
developed into a versatile reagent for the facile introduction
of the trifluoromethyl moiety into organic molecules. In
general carbonyl compounds, esters, activated imines and
related electrophiles undergo smooth reaction under the
initiation by fluoride sources [2,3]. A variety of fluoride
sources such as organic TBAF, TBAT, TMAF as well as CsF
have proven to be efficient in various cases. Metal alkoxides
were also found as initiators for the nucleophilic trifluoro-
methylation reactions [1]. Although, the yields of the tri-
fluoromethylated adducts with a variety of electrophiles
were high, the reactions were not catalytic in initiators.
Furthermore, due to the basic nature of these initiators
we sought a milder process. A true catalytic process of
stereoselective trifluoromethylation reaction is yet to be
realized.
Recent advances in Lewis base catalyzed organic trans-
formation for the silylated species [4] that take advantage of
the high strength of the Si–O bond as well as judicious
selection of kinetic reactivity can also be applied to trifluor-
omethyltrimethylsilane (TMSCF3) chemistry [2]. We have
envisioned that we would be able to activate TMSCF3 for
trifluoromethide transfer to the carbonyl compounds in a
2. Results and discussion
To validate our outlined approach we have screened the
reactivity of commercially available amine oxides such as
pyridine N-oxide, p-chloropyridine N-oxide, N,N-dimethyl-
pyridine N-oxide as well as hexamethylphosphoramide.
Attempts with stoichiometric amounts of HMPA gave only
<10% conversion after 48 h with representative aldehyde 1a.
The probable explanation for this low yield conversion is the
poor electrophilicity of TMSCF3. Though it is hard to find a
system more nucleophilic than HMPA, we expected that
trialkyl amine N-oxides to be more nucleophilic compared to
aromatic N-oxides and therefore we tested the use of tri-
methylamine N-oxide for the activation of TMSCF3. In fact
in the presence of stoichiometric amount of trimethylamine
N-oxide complete conversion of the aldehyde 1a to the
corresponding TMS protected alcohol 2a was observed. It
is very important to note that no free alcohol was observed,
indicating true catalysis (vide supra). Further study of the
reaction conditions significantly lowered the amount of
amine oxide to 50 mol%. A typical reaction procedure is
reported in Section 4. Table 1 shows the scope of the reaction
* Corresponding author. Tel.: þ1-213-740-5984; fax: þ1-213-740-6270.
E-mail address: gprakash@usc.edu (G.K.S. Prakash).
0022-1139/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00104-0

62
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 123 (2003) 61–63
Table 1
and yields of the products. As it is evident from entry 2, there
is no significant influence of bulky substitutents on the
reaction yield. Aromatic aldehydes with electron withdraw-
ing as well as electron donating groups react equally well
in the amine oxide catalyzed reaction. Aldehyde with a
protons 1g provides the product 2g without any side reac-
tion albeit in moderate yield. The probable path for the
observed catalysis by trimethylamine oxide is depicted in
Scheme 1.
Trifluoromethylation of aldehydes using trimethylamine oxide
Entry Aldehydes TMS protected alcohols
Yields (%)
77
1
2
3
80
76
We propose that trimethylamine oxide-complexed
TMSCF3 3 is in equilibrium with the starting materials
and this complex trifluoromethylates the aldehydes to
generate the complex 4, which on fragmentation provides
the TMS protected alcohols and amine oxide. The reaction
however, is very sluggish with ketones due to their low
electrophilicity.
3. Conclusions
4
5
85
74
In summary, we have developed an efficient catalytic
method for the preparation of TMS protected trifluro-
methylated alcohols from a variety of aldehydes using
trimethylamine N-oxide as a recoverable nucleophilic
catalyst. The present methodology is applicable for base
sensitive substrates. Our studies to apply this reaction to
asymmetric synthesis using chiral amine oxides is currently
underway.
6
7
79
55
4. Experimental
4.1. Typical reaction procedure for amine oxide
catalyzed TMSCF3 addition to carbonyl compounds
In a flame dried flask were taken 1 mmol of aldehyde and
0.5 mmol of trimethylamine oxide in 6 ml dry THF and
stirred for 0.5 h. Subsequently, 3 mmol of neat TMSCF3 was
added to the reaction mixture. The flask was closed with
a rubber septum and the reaction mixture was stirred for
12 h at room temperature. After all the starting material was
consumed, the reaction mixture was evaporated to dryness
and the residue was washed several times with diethyl ether.
Further recrystallization from ether or flash chromatography
afforded the pure TMS protected alcohols. Melting points
reported are uncorrected.
2a: White solid, mp 62 8C, 1H NMR (300 MHz, CDCl3 as
solvent and TMS as standard): d 0.13 (s, 9H), 5.08 (q,
J ¼ 6:8 Hz, 1H), 7.40–7.61 (m, 3H), 7.82–7.91 (m, 4H);
13C NMR (75 MHz, CDCl3 as solvent and TMS as stan-
2
dard): d ꢀ0.24, 73.48 (q, J(C, F) ¼ 32.2 Hz), 124.3 (q,
1J(C, F) ¼ 282 Hz), 124.8, 126.3, 126.6, 127.3, 127.7,
128.1, 128.2, 132.9, 133.0, 133.7; 19F NMR (282.2 MHz,
CDCl3 as solvent and CFCl3 as standard): d ꢀ78.6 (3J(F,
H) ¼ 5.1 Hz); HRMS (EI) m/z 298.1004, calcd for C15H17-
F3OSi 298.1001.
Scheme 1.

G.K.S. Prakash et al. / Journal of Fluorine Chemistry 123 (2003) 61–63
63
2b: Yellowish liquid, 1H NMR d 0.09 (s, 9H), 3.77 (s, 3H),
References
3.79 (s, 3H), 5.51 (q, J ¼ 6:5 Hz, 1H), 6.80–6.88 (m, 2H),
7.15 (m, 1H); 13C NMR d ꢀ0.401, 55.6, 56.2, 65.9
(q, 2J(C, F) ¼ 32.7 Hz), 111.8, 114.3, 115.2, 124.5 (q,
1J(C, F) ¼ 283 Hz), 151.1, 153.7; 19F NMR d ꢀ78.9
(3J(F, H) ¼ 5.9 Hz); HRMS (EI) m/z 308.1061, calcd for
C13H19F3O3Si 308.1055.
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9H), 6.56 (q, J ¼ 7:7 Hz, 1H), 7.47–7.61 (m, 4H), 8.03 (d,
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1
125.4, 125.5 (q, J(C, F) ¼ 281 Hz), 127.1, 127.9, 128.7,
129.7, 130.3, 130.5, 130.9, 131.2, 131.9; 19F NMR d ꢀ74.78
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C19H19F3OSi 348.1157.
¨
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2.61 (m, 1H), 2.82 (m, 1H), 3.91 (m, 1H), 7.17–7.30
(m, 5H); 13C NMR d ꢀ0.40, 31.1, 32.2, 70.5 (q, 2J(C,
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1
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276.1157.
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Acknowledgements
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3137;
Support of our work by the Loker Hydrocarbon Research
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