New stable reagents for the nucleophilic trifluoromethylation. Part 2: Trifluoromethylation with silylated hemiaminals of trifluoroacetaldehyde

Article abstract of DOI:10.1016/S0040-4039(00)01552-5

New reagents for the nucleophilic trifluoromethylation have been easily synthesized from fluoral hemiketal. They provide silylated trifluoromethylcarbinol from non-enolizable carbonyl compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01552-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8777–8780
New stable reagents for the nucleophilic
trifluoromethylation. Part 2: Trifluoromethylation with
silylated hemiaminals of trifluoroacetaldehyde
T. Billard,* B. R. Langlois* and G. Blond
Laboratoire de Synthe`se, Electrosynthe`se et Re´activite´ des Compose´s Organiques Fluore´s (UMR 5622),
Universite´ Claude Bernard–Lyon I, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
Received 12 July 2000; accepted 12 September 2000
Abstract
New reagents for the nucleophilic trifluoromethylation have been easily synthesized from fluoral
hemiketal. They provide silylated trifluoromethylcarbinol from non-enolizable carbonyl compounds.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: trifluoromethylation; fluoral; hemiaminal; trifluoromethylcarbinol.
Because of the specific properties of the CF3 moiety, its introduction in organic compounds
represents, at present, a classical modification used in the screening of new bio-active com-
pounds.1 Among the panel of available methods for introducing this group, the nucleophilic
strategy is one of the most popular.
In our quest for new nucleophilic trifluoromethylating reagents, we have recently shown that
2,2,2-trifluoro-1-morpholinoethyl trimethylsilyl ether (1) constitutes a stable new reagent2 which
trifluoromethylates non-enolizable carbonyl compounds to provide the corresponding silylated
trifluoromethylcarbinols, in the same way as Ruppert’s reagent.3
Nevertheless, this reagent was obtained from gaseous fluoroform which is not very easy to
handle.
Scheme 1. Retrosynthesis of 1
* Corresponding authors. Fax: +33 4 72 43 13 23; e-mail: billard@univ-lyon1.fr; bernard.langlois@univ-lyon1.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01552-5

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When looking at compound 1 from a retrosynthetical point of view, it can also be considered
as a silylated hemiaminal arising from trifluoroacetaldehyde (fluoral) (Scheme 1).
Fluoral itself is a very electrophilic gaseous compound which is conveniently available in its
methyl hemiketal form that we planned to use for the synthesis of 1. Usually, this hemiketal
generates free fluoral by distillation of over P2O5 but some authors described its direct reaction
in the presence of dessicants.4
Indeed, the reaction of methyl hemiketal of fluoral with morpholine led to hemiaminal (2)
which was silylated with N-trimethylsilyl imidazole, under neutral conditions, to yield 1 (Scheme
2).
Scheme 2. Synthesis of 1 from methyl hemiketal of fluoral
By the same procedure, another silylated hemiaminal (3)5,6 was synthesized from N-benzyl
piperazine (Scheme 3). Like 1, 3 is a stable compound which can be easily purified and stored
for a long time.
Scheme 3. Synthesis of 3 from methyl hemiketal of fluoral
Although 1 behaves as an efficient trifluoromethylating reagent, the necessity to use two
equivalents of it (versus substrate) constitutes a disadvantage. In this respect, the reactivities of
compounds 3 and 1 were compared with benzophenone (Table 1).
It appears from Table 1 that, at 80°C, which was the optimal temperature previously
determined for reacting 1, similar results were obtained with one equivalent of 3 and two
equivalents of 1 (entries 1 and 2). Moreover, in contrast to 1, the reactivity of 3 was not affected
when lowering the temperature to 60°C (entry 3). Thus 3 exhibits a better reactivity than 1.
The exact reason for this difference is not yet completely understood. Nevertheless, it can be
suggested that 1 could form a dimer because of the strong interaction between oxygen and
silicium, whereas this phenomenon should be less important with 3, first because of the weaker
interaction between nitrogen and silicium and, furthermore, because of the steric hindrance
introduced by the benzyl group (Scheme 4). This hypothesis justifies the use of 2 equivalents of
1. A better understanding of this mechanism is under study in our laboratory.

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Table 1
Comparative study of the reactivities of 1 and 3
Entry
q (°C)
4a (%)
From 1 (×equiv.)
From 3 (×equiv.)
1
2
3
4
5
80
80
60
50
40
57 (1)
80 (2)
70 (2)
55 (2)
19 (2)
86 (1)
85 (1)
57 (1)
28 (1)
Scheme 4. Dimeric forms of 1 and 3
Reagent 3 has also been opposed to other carbonyl compounds (Table 2).
As shown in Table 2, non-enolizable ketones and aldehydes provided a-trifluoromethylated
carbinols in good isolated yields. It can be noticed that for the less reactive substrates, the yield
can be improved by increasing the temperature from 60 to 80°C (entries 2 and 5). Concerning
the trifluoromethylation of enolizable carbonyl compounds, the reaction follows a different
route which leads to b-(trifluoromethyl)-b-(piperazino)carbonyl compounds. This process will be
reported in a future paper.
In conclusion, we have shown that 1 and 3 constitute powerful trifluoromethylating reagents
towards non-enolizable ketones and aldehydes. They are easy to handle and readily prepared
from the liquid and commercially available methyl hemiketal of fluoral.

8780
Table 2
Reaction of 3 with carbonyl compounds
References
1. (a) Filler, R.; Kobayashi, Y.; Yagulpolskii, Y. L. Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: Amsterdam, 1993. (b) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New York, 1994. (c) Hudlicky, M.; Pavlath, A.
E. Chemistry of Organic Fluorine Compounds II. A Critical Review; ACS Monograph 187; American Chemical
Society: Washington DC, 1995.
2. Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101–2103.
3. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–786.
4. (a) Ishii, A.; Higashiyama, F.; Mikami, K. Synlett 1997, 1381–1382. (b) Ingrassia, L.; Mulliez, M. Synthesis 1999,
1731–1738.
5. Typical procedure for the preparation of 3: To a solution of N-benzylpiperazine (14.77 g, 84 mmol) in CH2Cl2 (80
,
,
mL; dried over 4 A molecular sieves), were added 4 A molecular sieves, followed by methyl hemiketal of fluoral
(12 g, 92 mmol). The reaction mixture was stirred at room temperature for 48 h then filtered and evaporated in
vacuo. The residue was dissolved in CH2Cl2 and the hemiaminal of fluoral was precipitated by pentane to yield
17.56 g of a white solid. N-Trimethylsilyl imidazole (9.38 mL, 64 mmol) was added at 0°C to a solution of this
white solid in THF (30 mL, freshly distilled over sodium/benzophenone). After 20 min at 0°C, stirring was
continued for 5 h at room temperature. Then, the reaction mixture was treated with pentane and 6% aqueous
NaHCO3. The organic layer was washed twice with 6% aqueous NaHCO3 and dried over Na2SO4. After
evaporation in vacuo, 3 was obtained as a yellow oil (20.81 g, 71%).
1
6. Spectral data of 3: H NMR: l 7.24–7.42 (massif, 5H); 4.47 (q, 1H, J=5.7 Hz); 3.55–3.54 (2s, 2H); 2.85 (dt, 2H,
J=10.8 Hz, J=4.9 Hz); 2.78 (dt, 2H, J=10.9 Hz, J=4.8 Hz); 2.49 (t, 4H, J=4.6 Hz); 0.22 (S, 9H). 13C NMR:
l 138.40; 129.64; 128.67; 127.53; 123.93 (q, J=286.8 Hz); 85.69 (q, J=32.4 Hz); 63.49; 53.64; 47.82; 0.36. 19F
.
29
+
’
NMR: l −76.85 (d, J=5.7 Hz). Si NMR: l 21.14. Mass spectra: m/z 346 (M ); 277; 175; 91; 73; 42; 28. Anal.
calcd for C16H25F3N2OSi: C (55.47%) H (7.27%) N (8.09%). Found: C (55.56%) H (7.53%) N (8.33%).