Nucleophilic trifluoromethylation of imines under acidic conditions

Article abstract of DOI:10.1002/ejoc.200800820

A general method for the trifluoromethylation of imines by using Me ₃SiCF₃ under acidic conditions is described. The reaction is promoted by hydrofluoric acid generated in situ from KHF₂ and either TFA or TfOH. A new chemoselectivity pattern was achieved, as the C=N bond was found to be more reactivate than the carbonyl group. The trifluoromethylation reaction is believed to proceed by concerted transfer of the CF₃ group from the silicon atom to the iminium electrophile. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800820

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800820
Nucleophilic Trifluoromethylation of Imines under Acidic Conditions
Vitalij V. Levin,[a] Alexander D. Dilman,*[a] Pavel A. Belyakov,[a] Marina I. Struchkova,[a]
and Vladimir A. Tartakovsky[a]
Keywords: Fluorine / Imines / Schiff bases / Silicon / Trifluoromethylation
A general method for the trifluoromethylation of imines by
reactivate than the carbonyl group. The trifluoromethylation
using Me3SiCF3 under acidic conditions is described. The re- reaction is believed to proceed by concerted transfer of the
action is promoted by hydrofluoric acid generated in situ
from KHF2 and either TFA or TfOH. A new chemoselectivity
pattern was achieved, as the C=N bond was found to be more
CF3 group from the silicon atom to the iminium electrophile.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Herein we report the first example of nucleophilic tri-
fluoromethylation proceeding in the presence of strong pro-
tic acids. A switch from basic to acidic conditions leads to
a new selectivity profile with the benefits of substrate scope
and functional group compatibility issues.
Introduction
As a result of the importance of compounds bearing a
trifluoromethyl group for the pharmaceutical and agro-
chemical industries,[1] the development of trifluoromethyl-
ation reactions has been a subject of intense investigation.[2]
Among different approaches for the introduction of a CF3
group into organic molecules, the methodology of nucleo-
philic trifluoromethylation by using the Ruppert–Prakash
reagent (Me3SiCF3)[3] has gained particular attention in re-
cent years.[4–6]
Indeed, Me3SiCF3 is an available, shelf-stable, and easy-
to-handle compound, and its nucleophilic reactivity is un-
covered by Lewis basic activators, such as fluoride ions. The
Lewis base mediated reactions of Me3SiCF3 proceed
through the generation of five-coordinate species, which
serve as CF3 carbanion equivalent [Equation (1)].
In contrast to the well-elaborated trifluoromethylation of
carbonyl compounds,[3b,4,5a,5b] reactions of the C=N bond
with Me3SiCF3 are limited. Thus, only biased substrates
such as nitrones,[9] azomethines activated by chelating
Lewis acids,[10] and iminium ions[11] undergo smooth tri-
fluoromethylation. Concerning neutral imines, their reactiv-
ity strongly depends on the substituent at the nitrogen
atom. Substrates bearing an electron-withdrawing substitu-
ent react easily,[5b,12] whereas imines with an aryl group re-
act under the more drastic conditions of naked fluoride ion
activation.[13] At the same time, substrates possessing an
alkyl or benzyl group at the nitrogen atom, which cannot
stabilize the incipient negative charge, are unreactive, and
their reactions with Me3SiCF3, as well as those with other
trifluoromethylating reagents, have not been described.
Within the framework of our studies on trifluoromethyl-
ation[10,11a,11b] and pentafluorophenylation[14] of C=N
bonds with the use of silicon reagents we demonstrated that
N,N-dialkyliminium ions readily react with Me3SiCF3 in
the presence of potassium fluoride if DMF is used as the
solvent.[11a] This prompted us to test the behavior of imin-
ium ions generated by protonation of imines under similar
conditions.
(1)
Despite the fact that five-coordinate intermediates with
a CF3 group at the silicon atom have been identified,[7] the
mechanism of their reaction with electrophiles has not been
studied. Usually, it is implied that a free CF3 carbanion is
formed in this process. In accord with this notion is the
considerable basicity of the Me3SiCF3/Lewis base system,
which readily abstracts acidic protons to provide trifluoro-
methane,[8] thereby limiting the scope of this methodology.
Results and Discussion
It was rewarding to find that when a solution of imine 1a
in DMF was successively treated with an excess amount of
trifluoroacetic acid (TFA), Me3SiCF3, and KF at 23 °C
product 2a was obtained in 86% yield [Equation (2)]. Be-
cause TFA and KF are expected to afford a solution of hy-
[a] N. D. Zelinsky Institute of Organic Chemistry,
119991 Moscow, Leninsky prosp. 47, Russia
Fax: +7-499-135-53-28
E-mail: adil25@mail.ru
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Nucleophilic Trifluoromethylation of Imines under Acidic Conditions
drofluoric acid, the use of KHF2 in the presence of a reduced process, we proposed that its reactivity could be increased by
amount of acid was tested and shown to provide identical using a stronger acid. After considerable experimentation it
results. Consequently, KHF2 was used for further studies.
was determined that employment of triflic acid in acetonitrile
containing DMF (3 equiv.) afforded amine 2b in 83% iso-
lated yield (Table 1, Entry 7). In this case, DMF exhibits an
accelerating effect on the trifluoromethylation, although de-
composition of the silane is accelerated as well, and as a
result, three equivalents of Me3SiCF3 should be used for
complete conversion.
Because optimal conditions require expensive triflic acid
and an excess amount of the silane, we felt that cheaper pro-
tocols with the use of TFA (Table 1, Entries 3 and 4) could
also be evaluated upon studying trifluoromethylation of
more active imines.
A variety of imines were involved in the trifluoromethyl-
ation reaction with Me3SiCF3 (Table 2). Imines bearing elec-
tron-rich aromatic rings at the carbon atom turned out to be
most reactive and furnished products in high yield within 3 h
in the presence of TFA.
(2)
It is worthy to note that these trifluoromethylation reac-
tions occur under acidic conditions defined by an excess
amount of TFA. To get a better understanding of this pro-
cess, a brief screen of reaction parameters was undertaken.
Interesting results were obtained on changing the order of
mixing: the combination of KHF2 and TFA in DMF gave a
clear solution. Subsequent treatment of this solution with
Me3SiCF3, stirring for 30 min at 0 °C, and addition of imine
Importantly, acid-sensitive furan and acetal fragments are
1a led to recovered imine, indicating that the silane was de- tolerated under the reaction conditions (Table 2, Entries 4,
stroyed by the hydrofluoric acid. However, when the same 9, 13). Substrates bearing benzyl, alkyl, cycloalkyl, and allyl
experiment was performed in acetonitrile product 2a was ob- substituents at the nitrogen atom also work well in this pro-
tained in 90% yield. The latter observation suggests that Me3- cess. However, the benzhydryl group tends to decrease the
SiCF3 and HF are compatible in acetonitrile. A more decisive product yield (Table 2, Entry 9 vs. Entries 10–12). The imine
piece of evidence supporting this conclusion was provided by derived from glycine afforded the corresponding trifluoro-
NMR spectroscopy. Thus, by mixing KHF2, TFA methyl derivative, albeit in moderate yield (Table 2, Entry 22),
(1.7 equiv.), and Me3SiCF3 (2 equiv.) in CD3CN and by which may be associated with the electron-withdrawing effect
1
monitoring the resulting homogeneous solution by H and of the methoxycarbonyl group. It should be pointed out that
19F NMR spectroscopy it was found that almost no decom- substrate may contain an unprotected hydroxy group both
position of the silane occurred within 1 h at room tempera- in the aromatic ring (Table 2, Entries 23 and 24) and in the
ture and only after 3 d was half of the silane converted into substituent at the nitrogen atom, although in the latter case
Me3SiF.
the yield was modest (Table 2, Entries 25 and 26).
Imine 1b containing a nitro group instead of a methoxy
Imines derived from tertiary and α-branched aliphatic al-
group turned out to be much less reactive, and no product dehydes were successfully involved in the trifluoromethyl-
was formed in DMF. Therefore, for this substrate we decided ation reaction (Table 2, Entries 27 and 28). At the same
to optimize the reaction conditions (Table 1). When the reac- time, reaction of α-unbranched substrate 1x under the stan-
tion was performed in MeCN, product 2b was furnished in dard conditions did not give the expected product. Instead,
71% yield after stirring for 15 h at room temperature we isolated amine 3, which is formed through initial aldol-
(Table 1, Entry 3). On the basis of the assumption that the ization, followed by trifluoromethylation of the α,β-unsatu-
protonated imine serves as the electrophilic species in this rated imine [Equation (3)].
Table 1. Trifluoromethylation of imine 1b.
Solvent
Acid
Acid
[equiv.]
KHF2
[equiv.]
Silane
[equiv.]
Time
[h]
Yield of 2b
[%][a]
1
2
3
4
5
6
7
DMF
MeCN
MeCN
MeCN/DMF (3 equiv.)
MeCN
TFA
TFA
TFA
1.25
1.25
1.5
1.25
1.6
1.25
1.6
0.75
0.75
1
0.75
1.5
0.75
1.5
1.5
1.5
2
1.5
3
1.5
3
1
–
15
15
3
24
24
24
69
71
48
63
53
83
TFA
TfOH
TfOH
TfOH
DMF
MeCN/DMF (3 equiv.)
[a] Isolated yield.
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A. D. Dilman et al.
SHORT COMMUNICATION
Table 2. Trifluoromethylation of aldimines.
[a] Isolated yield. [b] The product of the trifluoromethylation of cinnamaldehyde (ca. 20%) was also formed.
Table 3. Trifluoromethylation of ketimines.
(3)
Several ketimines were also tested in the trifluoromethyl-
ation process, and the corresponding products with a four-
substituted carbon atom were produced in reasonable yields
(Table 3). This is the first example of addition of Me3SiCF3
to unactivated ketimines.[15]
As the carbonyl group is more reactive than the C=N
bond in the presence of basic activators for Me3SiCF3, it
could be expected that in the presence of acid the reactivity
order will be reversed. Indeed, trifluoromethylation of imine
6 bearing ketone and azomethine moieties in the presence of
TFA/KHF2 occurred smoothly leading to amino ketone 7 [a] Isolated yield.
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Nucleophilic Trifluoromethylation of Imines under Acidic Conditions
Scheme 1. Chemoselective trifluoromethylation.
(Scheme 1).[16,17] In contrast, the reaction mediated by
Bu4NF affected only the keto group to give silyl ether 8 as
the initial product. Compound 8 decomposes upon silica gel
chromatography, and its yield was determined by NMR
spectroscopy. Nevertheless, the desilylation and acidic treat-
ment of a crude sample allowed isolation of aldehyde 9.
Concerning the mechanism of the trifluoromethylation,
we believe that the process is mediated by hydrofluoric acid
produced from KHF2 and TFA (Scheme 2).
Conclusions
In summary, we demonstrated for the first time that nu-
cleophilic trifluoromethylation can be performed under
acidic conditions. The concerted transfer of the CF3 carb-
anion from the silicon atom to the iminium electrophile is
believed to be responsible for the efficiency of the reaction.
This methodology broadens significantly the scope of the
trifluoromethylation of the C=N bond, and it offers a new
selectivity profile for the application of the Ruppert–Prak-
ash reagent.
Experimental Section
Representative Procedure
Method A: Trifluoroacetic acid (96 µL, 1.25 mmol) was added to a
mixture of imine (1 mmol) and KHF2 (59 mg, 0.75 mmol) in aceto-
nitrile (2 mL) and DMF (232 µL, 3 mmol) at 0 °C, and the suspen-
sion was stirred for 5 min. Me3SiCF3 (221 µL, 1.5 mmol) was
added, the cooling bath was removed, and the mixture was stirred
for 3 h at room temperature. For the workup, saturated aqueous
Na2CO3 (0.5 mL) was added dropwise, and the mixture was stirred
for an additional 2 min, diluted with water (7 mL), and extracted
with diethyl ether/hexane (1:1, 3ϫ5 mL). The combined organic
phase was filtered through Na2SO4 and concentrated under vac-
uum, and the crude product was chromatographed on silica gel.
Scheme 2. Reaction mechanism.
The interaction of HF with the imine generates an imin-
ium ion and the hydrodifluoride anion, which acts as a Lewis
basic activator with respect to the silane. It seems that con-
certed transfer of the CF3 group from the silicon atom to the
iminium electrophile takes place.[18] Otherwise, if the free tri-
fluoromethyl carbanion were generated, it would be readily
quenched by the excess amount of TFA.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for all com-
pounds.
Acknowledgments
In accord with this mechanism is the observation that the
reaction proceeds faster with more basic imines. To gain sup-
port for the ability of the hydrodifluoride anion to activate
This work was supported by the Ministry of Science (project MK-
4483.2007.3), Russian Academy of Sciences (program # 8), Russian
Science Support Foundation, and the Russian Foundation for Ba-
the silane, we carried out the reaction of preformed N- sic Research (project 08-03-00428).
methyl-N-benzyliminium salt 10 with Me3SiCF3 in the pres-
ence of KHF2 in acetonitrile and obtained expected product
11 in 85% yield [Equation (4)].
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SHORT COMMUNICATION
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[15]
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[16] The contribution of attack on the keto group did not exceed
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[17] In fact, even benzaldehyde was found to be unreactive under
the conditions of methods B and C. However, by using method
A, trifluoromethylation occurred slowly with 20% conversion
to the corresponding 2,2,2-trifluoro-1-phenylethanol.
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Received: August 26, 2008
Published Online: September 25, 2008
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