Direct trifluoromethylation of nitriles promoted by tetrabutylammonium bifluoride

Article abstract of DOI:10.1055/s-0029-1217824

The direct trifluoromethylation of nitriles using TMSCF3 is reported. This reaction is promoted by TBABF and provides ,-bistrifluoromethylated amines in moderate to good yields. The reaction conditions are mild and tolerate a range of functional groups. T

Full text of DOI:10.1055/s-0029-1217824

2518
LETTER
Direct Trifluoromethylation of Nitriles Promoted by Tetrabutylammonium
Bifluoride
D
irec
t
Trifluorom
e
d
thylation of
rNitriles ian Huang,* Huan-Qiu Li, Walter Massefski, Eddine Saiah
Chemical Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA
Fax +1(617)6655682; E-mail: ahuang@wyeth.com
Received 29 April 2009
ate to good yields in the presence of tetrabutylammonium
bifluoride (TBABF).
Abstract: The direct trifluoromethylation of nitriles using TMSCF3
is reported. This reaction is promoted by TBABF and provides a,a-
bistrifluoromethylated amines in moderate to good yields. The reac-
tion conditions are mild and tolerate a range of functional groups.
The X-ray crystal structure of a bistrifluoromethylamine was ob-
tained.
During the course of a medicinal chemistry project, we
were interested in preparing fluorinated amines. Very few
routes for the synthesis of a,a-bis(trifluoromethyl)benzyl-
amines have been reported. One such synthesis is based
on the reaction of hexafluoroimine with an aromatic hy-
drocarbon under extremely vigorous Friedel–Crafts con-
ditions (AlCl3 as a catalyst at temperatures between 150–
200 °C in an autoclave).12 The yields ranged from 15–
43%. Another route reported by Nesi et al. involved a
multistep conversion of bistrifluoromethyl alcohols to the
corresponding bistrifluoromethylamines via triflates fol-
lowed by the displacement to azides and ultimately reduc-
tion to the amines.13
Key words: a,a-bistrifluoromethylated amines, nitriles, tetrabutyl-
ammonium bifluoride, trifluoromethyltrimethylsilane
Fluorinated molecules often display unique properties
that make them suitable for numerous applications in
pharmaceuticals,1,2 agrochemicals,3 and materials sci-
ence.4 Perfluoroalkyl-containing molecules often exhibit
behavior distinct from their hydrocarbon counterparts.
For instance, moieties such as the trifluoromethyl group
can dramatically influence the polarity, solubility, chemi-
cal reactivity, and intermolecular interactions of an entire
molecule.5 Straightforward and reliable procedures for the
introduction of the trifluoromethyl group are highly desir-
able.6,7 In recent years the utilization of trifluoromethyl-
trimethylsilane (TMSCF3), also known as the Ruppert–
Prakash reagent, as a nucleophilic trifluoromethylating re-
agent has become the method of choice for introducing
trifluoromethyl groups into various organic compounds.
Because of the electrophilic nature of the carbonyl carbon,
aldehydes and ketones are very reactive to nucleophilic at-
tack by TMSCF3 in the presence of a fluoride source such
as tetrabutylammonium fluoride (TBAF).8 Esters and
nitrones were initially thought to be deactivated towards
TMSCF3 but were subsequently reported to be good
substrates affording trifluoromethyl ketones9 and tri-
fluoromethylhydroxylamines10 in good yields. Simple
amides are less reactive due to the electron donation from
the adjacent nitrogen which leads to deactivation of the
carbon–nitrogen bond.6 With such deactivated substrates,
little conversion to product is observed, or low to moder-
ate yields are obtained with the addition of additives such
as TMS-imidazole to trap unstable intermediates.10,11 The
direct trifluoromethylation of nitriles to yield a,a-bistri-
fluoromethylated amines has not been reported in the lit-
erature. We wish to report herein the discovery that a,a-
bistrifluoromethylated amines can be obtained in moder-
Our initial attempts to effect the trifluoromethylation of
nitriles using 1 M THF solution of TBAF and TMSCF3
(Table 1, entry 1) led only to starting material. Attempts
to dry THF solutions of TBAF using molecular sieves or
magnesium sulfate (MgSO4) did not result in any im-
provement. Substitution of TBAF by tetramethylammo-
nium fluoride (TMAF) also failed to yield any detectable
Table 1 Evaluating Reaction Conditions for Nitrile Trifluorometh-
ylation
CF3
Me3SiCF3, initiator
R
CN
R
NH2
CF3
THF, 0 to 25 °C
Entrya
R
H
H
Initiator
Yield (%)b
1
2
3
4
5
6
7
8
TBAF 1M THF
solid TBAF hydrate
solid TBAF hydrate
‘dried’ TBAFc
–
(5)
(10)
46
Ph
H
Ph
‘dried’ TBAFc
55
Me
SMe
Br
‘dried’ TBAFc
48
‘dried’ TBAFc
80
‘dried’ TBAFc
63
a Reactions were performed with 3 equiv of TMSCF3 and 2 equiv of
specified tetraalkylammonium fluoride in anhyd THF at 25 °C.
b Isolated yields; values in parentheses denote percent conversions
based on integration of unpurified 1H NMR spectrum.
c Heated under vacuum until reaching melting point, cooled and used
directly
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Advanced online publication: 17.08.2009
DOI: 10.1055/s-0029-1217824; Art ID: S04909ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Trifluoromethylation of Nitriles
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amount of product. Low but detectable conversion was of ammonium ions susceptible to E2 elimination. In fact,
observed when solid TBAF was used (entries 2 and 3).
TBABF is isolated after heating TBAF at temperatures
between 44–77 °C. This led us to wonder if the actual pro-
moter for the direct trifluoromethylation of nitriles to the
bistrifluoromethylamines was TBABF. We performed 19F
NMR experiments in THF to investigate the composition
of the ‘dried solid TBAF’ and the major peak observed
was a doublet at d = –149 ppm (JHF = 123 Hz), which is
consistent with the formation of TBABF.14 Based on this
finding, we decided to investigate the use of pure TBABF
as a promoter for the direct trifluoromethylation of nitriles
to bistrifluoromethylamines. TBABF has been reported to
be a mild and efficient fluorinating agent16 with good sol-
ubility in organic solvents such as THF and displays good
thermal stability at temperatures below 140 °C. To the
best of our knowledge, TBABF has not been reported to
initiate trifluoromethylation reactions of C=O or C=N
TBAF is an extremely hygroscopic material, and we rea-
soned that further drying solid TBAF hydrate could lead
to improved yields. Solid TBAF was therefore heated un-
der vacuum until the material melted, cooled, and used di-
rectly. We were gratified to observe moderate to good
yields of the desired a,a-bistrifluoromethylamines (Table
1, entries 4–8). The fluorinated products are easily detect-
ed by NMR and are characterized by a broad singlet by 1H
NMR at d = 2.1–2.3 ppm and a septet by 13C NMR at d =
63–65 ppm.
References both to the difficulty of removing water from
tetraalkylammonium fluorides and to their instability are
well documented in the literature.14 Fry el al.15 concluded
that it is very unlikely that pure, anhydrous tetraalkylam-
monium fluoride salts have ever been produced in the case
Table 2 Trifluoromethylation of Various Nitriles Promoted by TBABF
Entrya
Substrate
Product
Conversion (%)b Yield (%)c
CF3
1
69
92
57
86
27
75
64
77
58
78
52
79
18
63
54
75
N
NH2
CF3
CF3
NH2
CF3
2
3
4
5
6
7
8
N
CF3
NH2
CF3
O
N
O
CF3
NH2
CF3
N
CF3
NH2
CF3
CF3
NH2
CF3
CF3
NH2
N
N
N
F
N
F
Cl
N
N
Cl
CF3
CF3
Br
Br
Br
Br
NH2
CF3
CF3
NH2
CF3
9
91
92
76
82
N
N
N
O
O
S
S
10
O
O
CF3
NH2
CF3
N
a Reactions were performed in anhyd THF with 5 equiv of TMSCF3 and 2.1 equiv of TBABF from 0–25 °C, 2 h.
b Conversion based on integration of unpurified 1H NMR spectrum and LC-MS analysis.
c Unoptimized yields.
Synlett 2009, No. 15, 2518–2520 © Thieme Stuttgart · New York

2520
A. Huang et al.
LETTER
groups with TMSCF3. We treated a variety of nitriles with showed that TBABF could be used instead of TBAF in the
TMSCF3 and commercially available TBABF as a pro- trifluoromethylation of aldehydes and ketones. Further
moter in anhydrous THF at room temperature, and our expansion of the reaction scope using electrophiles such
findings are summarized in Table 2.17
as imines and nitrones and examination of other perfluo-
roalkylation reactions will be reported in due course.
Evaluation of the reaction scope highlights a substrate
profile that tolerates a variety of substitutions. In general,
the yields vary from moderate to high. Electron-with-
drawing groups are likely to polarize the nitrile bond,
which would facilitate the trifluoromethylation reaction
(entries 6–10). In the case of electron-donating groups, the
observed yields were low to moderate, with the dimethy-
laniline being the least reactive substrate tested. The X-
ray structure18 of the sulfonamide product (Table 2, entry
10) was obtained and unambiguously shows the formation
of the bistrifluoromethylated amine.
Acknowledgment
We thank Tarek Mansour, Neelu Kaila, Kathy Lee, and Zhao-Kui
Wan for helpful discussions.
References and Notes
(1) See Special Issue, Fluorine in Life Sciences: ChemBioChem
2004, 5, 557.
(2) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(3) Hiyama, T. In Organofluorine Compounds: Chemistry and
Applications; Yamamoto, H., Ed.; Springer: New York,
2000.
(4) Reichenbächer, K.; Süss, K. I.; Hulliger, J. Chem. Soc. Rev.
2005, 34, 22.
(5) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(6) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(7) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
(8) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am.
Chem. Soc. 1989, 111, 393.
(9) Wiedmann, J.; Heiner, T.; Mloston, G.; Prakash, G. S. K.;
Olah, G. A. Angew. Chem. Int. Ed. 1998, 37, 820.
(10) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001,
66, 2572.
(11) Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org. Lett. 2006, 8,
3589.
With a few exceptions, N–H imines have been reported as
unstable and difficult to isolate. However, Gosselin et al.19
reported that solvolysis of N-TMS-ketimines in MeOH
proceeds readily with cleavage of the nitrogen–silicon
bond and isolation of stable N–H trifluoromethylimines.
We believe that the trifluoromethylation reaction goes
through similar intermediates (Figure 1) where the initial
addition of the CF3 group to the nitrile provides trifluo-
romethylimine intermediates followed by a second CF3
addition to afford the desired bistrifluoromethylamines.
F3C
N
F3C
NH
SiMe3
Ar
Ar
(12) Gale, D. M.; Krespan, C. G. J. Org. Chem. 1968, 33, 1002.
(13) Nesi, M.; Brasca, M. G.; Longo, A.; Moretti, W.; Panzeri, A.
Tetrahedron Lett. 1997, 38, 4881.
Figure 1 Potential imine intermediates for the addition of TMSCF3
to aryl nitriles
(14) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050.
(15) Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48, 2112.
(16) Bosh, P.; Camps, F.; Chamarro, E. Tetrahedron Lett. 1987,
28, 4733.
(17) Typical Procedure for Trifluoromethylation of Various
Nitriles Promoted by TBABF
Since the discovery of the direct trifluoromethylation
reaction of carbonyl compounds with TMSCF3 by
Prakash et al.,8 the most commonly used sources of fluo-
rine include TBAF and cesium fluoride. We wondered if
TBABF could also catalyze the trifluoromethylation of al-
dehydes and ketones. Examples of substrates containing
an aldehyde and a ketone are shown in Scheme 1. 2-Naph-
thylaldehyde and 2¢-acetonaphthone reacted in the pres-
ence of TMSCF3 and a catalytic amount of TBABF to
provide the desired trifluoromethyl alcohols in 95% and
92% yields, respectively.
Biphenyl-4-carbonitrile (110 mg, 0.61 mmol) was dissolved
in THF (4 mL). Under nitrogen at 0 °C (trifluoromethyl)tri-
methylsilane (0.45 mL, 3.05 mmol, 5 equiv) was added. To
this mixture was then added TBAF·HF (0.360 g, 1.28 mmol,
2.1 equiv) solution in THF (4 mL). The cooling bath was
removed, and the reaction mixture was stirred at 25 °C for 2
h. The reaction mixture was concentrated under rotary
vacuum to give a light yellow gum. Column chromatog-
raphy of the residue (silica gel, hexane–EtOAc = 5:1)
provided 2-biphenyl-4-yl-1,1,1,3,3,3-hexafluoropropan-2-
amine (154 mg, 79%) as a white solid. 1H NMR (400 MHz,
CDCl3): d = 7.83 (d, J = 8.3 Hz, 2 H), 7.63–7.69 (m, 2 H),
7.56–7.63 (m, 2 H), 7.42–7.50 (m, 2 H), 7.35–7.42 (m, 1 H),
2.20 (br s, 2 H). 13C NMR (101 MHz, CDCl3): d = 143.2,
140.3, 129.7, 129.3, 128.3, 128.2, 127.7, 127.6, 124.3 (q,
J = 286.9 Hz), 65.4 (spt, J = 27.8 Hz). HRMS (ESI+): m/z
calcd for C15H12F6N [M + H]+: 320.08684; found [M + H]+:
320.08670.
HO
O
R
1. TMSCF3
TBABF(cat.)
0 °C to r.t., 2 h
R
CF3
2. TBAF
R = H, yield = 95%
R = Me, yield = 92%
Scheme 1 TBABF-catalyzed trifluoromethylation of aldehydes and
ketones
(18) CCDC 729907 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(19) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen,
C.; Volante, R. P. Org. Lett. 2005, 7, 355.
In conclusion, we report the first example of direct triflu-
oromethylation of nitriles using TMSCF3. This reaction is
promoted by TBABF and provides bistrifluomethylated
amines in moderate to good yields. TBABF is not as hy-
droscopic as TBAF and is more thermally stable. We also
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