Trifluoromethylation of salicyl aldimines

Article abstract of DOI:10.1021/jo701734d

(Chemical Equation Presented) A method for the nucleophilic trifluoromethylation of salicyl aldimines, which do not contain an activating group at the nitrogen atom, has been described. The reaction proceeds through the initial generation of intramolecula

Full text of DOI:10.1021/jo701734d

Trifluoromethylation of Salicyl Aldimines†
Trifluoromethyltrimethylsilane, Me3SiCF3, turned out to be
an especially useful reagent as an equivalent of trifluoromethyl
carbanion for the direct introduction of the CF3 group.4a-c,5 The
reactions using Me3SiCF3 are usually performed in the presence
of Lewis base, and processes of this type are very well
establishedforthetrifluoromethylationofcarbonylcompounds.4a-c,6
At the same time, analogous addition of CF3-carbanion to imines
has a number of limitations associated mainly with low reactivity
of C,N double bond.
Thus, while strongly biased substrates such as azirines,7
imines of perfluorinated ketones,8 or N-tosylated or sulfinylated6b,9
imines can be successfully trifluoromethylated using Me3SiCF3,
imines having an aryl group at nitrogen are markedly less
reactive. In the latter case, the reaction requires employment of
fluoride ion for the activation of Me3SiCF3 and proceeds with
moderate yield.10,11 Reactions of imines bearing an N-alkyl
fragment with Me3SiCF3 are expected to be even more difficult
and, to the best of our knowledge, are not described.
Alexander D. Dilman,*,‡ Dmitry E. Arkhipov,‡
Vitalij V. Levin,‡ Pavel A. Belyakov,‡
Alexander A. Korlyukov,§ Marina I. Struchkova,‡ and
Vladimir A. Tartakovsky‡
N. D. Zelinsky Institute of Organic Chemistry,
119991 Moscow, Leninsky prosp. 47, Russian Federation, and
A. N. NesmeyanoV Institute of Organoelement Compounds,
119991 Moscow, VaViloV str. 28, Russian Federation
adil25@mail.ru
ReceiVed August 8, 2007
The studies performed by our group have demonstrated that
the iminium cations serve as good electrophiles for the interac-
tion with fluorinated silanes in the presence of weak Lewis
bases, though these investigations mainly focused on the transfer
of C6F5 group.12,13
In this respect, it seemed reasonable to propose that the
electrophilicity of imines can be increased by complexation with
Lewis acids.14 However, the major problem in this case is that
to activate Me3SiCF3 rather strong Lewis bases such as fluoride,
alkoxide, carbonate, or acetate anions are required (Scheme 1,
path a).15 As a result, given that the activation of both imine
and the silane constitute an equilibrium processes, the Lewis
A method for the nucleophilic trifluoromethylation of salicyl
aldimines, which do not contain an activating group at the
nitrogen atom, has been described. The reaction proceeds
through the initial generation of intramolecular boron
complex followed by interaction with Me3SiCF3 activated
by sodium acetate.
(5) For the first synthesis of Me3SiCF3, see: Ruppert, I.; Schlich, K.;
Volbach, W. Tetrahedron Lett. 1984, 24, 2195.
Organofluorine compounds have gained considerable attention
due to their importance for the pharmaceutical and agrochemical
industries.1 In particular, substances with trifluoromethyl group,
as well as methods for their preparation, have become a subject
of intense investigations in recent years.2-4
(6) For recent comprehensive studies, see: (a) Prakash, G. K. S.; Panja,
C.; Vaghoo, H.; Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.;
Mathew, T.; Olah, G. A. J. Org. Chem. 2006, 71, 6806. (b) Kawano, Y.;
Kaneko, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79, 1133.
(7) Felix, C. P.; Khatimi, N.; Laurent, A. Tetrahedron Lett. 1994, 35,
3303.
(8) (a) Banks, R. E.; Besheesh, M.; Lawrence, N. J.; Tovell, D. J. J.
Fluorine Chem. 1999, 97, 79. (b) Petrov, V. A. Tetrahedron Lett. 2000,
41, 6959.
(9) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77. (b)
Kawano, Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 422. (c)
Kawano, Y.; Mukaiyama, T. Chem. Lett. 2005, 34, 894.
(10) (a) Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org. Lett. 2006, 8,
3589. (b) Blazejewski, J.-C.; Anselmi, E.; Wilmshurst, M. Tetrahedron Lett.
1999, 40, 5475.
(11) Nitrones represent another class of substrates with activated C,N
double bond, which can be trifluoromethylated using t-BuOK; see: Nelson,
D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001, 66, 2572.
(12) (a) Dilman, A. D.; Belyakov, P. A.; Korlyukov, A. A.; Struchkova,
M. I.; Tartakovsky, V. A. Org. Lett. 2005, 7, 2913. (b) Dilman, A. D.;
Levin, V. V.; Karni, M.; Apeloig, Y. J. Org. Chem. 2006, 71, 7214. (c)
Dilman, A. D.; Levin, V. V.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Synthesis 2006, 447. (d) Levin, V. V.; Dilman, A. D.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Antipin, M. Y.;
Tartakovsky, V. A. Synthesis 2006, 489. (e) Dilman, A. D.; Arkhipov, D.
E.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Russ. Chem.
Bull. 2006, 55, 517. (f) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.;
Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. MendeleeV
Commun., 2007, 105. (g) Dilman, A. D.; Gorokhov, V. V.; Belyakov, P.
A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2006, 47, 6217.
(13) In a recent contribution from Makosza and co-workers, pyridinium
salts were shown to be active electrophiles for the interaction with Me3-
SiCF3 activated by KF/Ph3SnF; see: Loska, R.; Majcher, M.; Makosza,
M. J. Org. Chem. 2007, 72, 5574.
† This paper is dedicated to Professor Herbert Mayr on the occasion of his
60th birthday.
‡ N. D. Zelinsky Institute of Organic Chemistry.
§ A. N. Nesmeyanov Institute of Organoelement Compounds.
(1) (a) Dolbier, W. R. J. Fluorine Chem. 2005, 126, 157. (b) Fluorine
in Bioorganic Chemistry; Welch, C. T., Eswarakrishnan, S., Eds.; John
Wiley & Sons: New York 1991. (c) Hiyama, T. Organofluorine Com-
pounds: Chemistry and Applications; Springer, Berlin, 2000. (d) Uneyama,
K. Organofluorine Chemistry; Blackwell Publishing: Oxford, UK, 2006.
(2) Radical trifluoromethylation: (a) Gagosz, F.; Zard, S. Z. Org. Lett.
2003, 5, 2655. (b) Itoh, Y.; Houk, K. N.; Mikami, K. J. Org. Chem. 2006,
71, 8918. (c) Mikami, K.; Tomita, Y.; Ichikawa, Y.; Amikura, K.; Itoh, Y.
Org. Lett. 2006, 8, 4671. (d) Petrick, V.; Cahard, D. Tetrahedron Lett. 2007,
48, 3327.
(3) Electrophilic trifluoromethylation (a) Yagupol’skii, L. M.; Kon-
dratenko, N. Y.; Timofeeva, G. N. Zh. Org. Khim. 1984, 20, 115. (b)
Umemoto, T.; Ishihara, S. J. Fluorine Chem. 1999, 98, 75. (c) Yang, J. J.;
Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998, 63, 2656. (d) Ma,
J.-A.; Cahard, D. J. Org. Chem. 2003, 68, 8726.
(4) Nucleophilic trifluoromethylation: (a) Prakash, G. K. S.; Yudin, A.
K. Chem. ReV. 1997, 97, 757. (b) Prakash, G. K. S.; Mandal, M. J. Fluorine
Chem. 2001, 112, 123. (c) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000,
56, 7613. (d) Langlois, B. R.; Billard, T.; Roussel, S. J. Fluorine Chem.
2005, 126, 173. (e) Xu, W.; Dolbier, W. R., Jr. J. Org. Chem. 2005, 70,
4741. (f) Nowak, I.; Robins, M. J. J. Org. Chem. 2007, 72, 2678. (g) Tyrra,
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M. J. Fluorine Chem. 2007, 128, 813.
10.1021/jo701734d CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
8604
J. Org. Chem. 2007, 72, 8604-8607

SCHEME 1. Trifluoromethylation of Imines
FIGURE 1. X-ray structure of chelate 2a presented in thermal
ellipsoids at 50% probability (except hydrogen atoms).
TABLE 1. Reaction of Complex 2a with Me3SiCF3
acid and base will quench each other (path b). Herein we report
another approach, where the activation of the imine occurs
intramolecularly through the chelation with adjacent hydroxyl
group, thereby allowing for the favorable Lewis acid/Lewis base
combination (path c).
We began our studies from the interaction of N-methylimines
of benzaldehyde and salicyl aldehyde with Me3SiCF3. Boron
trifluoride etherate and sodium acetate6b were used for the
activation of imines and silane, respectively, performing the
reaction in DMF at room temperature (eq 1).
entry
solvent
AcONa (equiv)
time
1 h
15 min
15 min
15 min
6 h
yield of 3a,a %
1
2
3
4
5
6
DMF
DMF
THF
MeCN
DMF
DMF
4
4
4
4
0.1
-
88
85
-
<5b
73
11b
6 h
a Isolated yield. b Yield determined by NMR with internal standard.
17
amine 3a in 88% yield after workup with aq Na2CO3 (Table
1, entry 1). Dimethylformamide was found to be the best solvent,
with tetrahydrofuran and acetonitrile being completely inef-
ficient.18 Trifluoromethylation can be performed even with
catalytic amount of AcONa, but longer reaction time is needed
(entry 5).
Though the boron chelate 2a can be trifluoromethylated quite
cleanly, its isolation in individual form is inconvenient, and a
more practical one-step protocol is desired. A series of experi-
ments was performed to optimize trifluoromethylation procedure
involving quantitative generation of complex 2a (Table 2).
Treatment of imine 2a with 1.2 equiv of potassium tert-
butoxide followed by addition of 2.5 equiv of boron trifluoride
presumably gave a solution of complex 2a together with KBF4.
Subsequent addition of Me3SiCF3 (2.5 equiv) and sodium acetate
(4 equiv) provided amine 3a in 58% yield (entry 1). The yield
of the final product could be increased when the generation of
boron chelate and trifluoromethylation are performed in different
solvents (entry 2). After further optimization, it was found that
employment of Hu¨nig’s base in dichloromethane for 2 h,
evaporation of solvent, and addition of DMF, Me3SiCF3, and
sodium acetate furnished the target product in 86% isolated yield
(entry 4).
While only traces of product were observed with benzaldi-
mine, the reaction of salicyl aldimine provided the corresponding
trifluromethylated amine in 21% isolated yield. The presence
of o-hydroxy group clearly suggested the possibility of inter-
mediate formation of difluoroboron ether capable of chelation
with the imine nitrogen. The boron chelate 2a was synthesized
from N-methylsalicylaldimine by means of silylation with
subsequent silicon/boron exchange (eq 2).
Complex 2a was isolated in individual form as stable and
moisture insensitive compound, and its structure was established
by NMR spectroscopy and X-ray diffraction analysis (Figure
1).16
It was rewarding to find that complex 2a smoothly reacted
with Me3SiCF3 in the presence of sodium acetate providing
(14) (a) For example, BF3 efficiently promotes addition of organometallic
reagents to imines. Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org. Chem.
2005, 70, 2335. (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) For BF3-
mediated addition of perfluoroalkyllithiums to imines see: Uno, H.; Okada,
S.; Shiraishi, Y.; Shimokawa, K.; Suzuki, H. Chem. Lett. 1988, 7, 1165.
However, trifluoromethyllithium and magnesium reagents are highly
unstable and cannot be used.
(15) The reactions of Me3SiCF3 are believed to proceed through the five-
coordinate siliconate species. For mechanistic discussions, see ref 6 and:
(a) Maggiarosa, N.; Tyrra, W.; Naumann, D.; Kirij, N. V.; Yagupolskii, Y.
L. Angew. Chem., Int. Ed. 1999, 38, 2252. (b) Kolomeitsev, A.; Bissky,
G.; Lork, E.; Movchun, V.; Rusanov, E.; Kirsch, P.; Ro¨schenthaler, G.-V.
Chem. Commun. 1999, 1017.
(16) For chelate boron complexes derived from salicyl aldimines, see:
(a) Keizer, T. S.; De Pue, L. J.; Parkin, S.; Atwood, D. A. J. Organomet.
Chem. 2003, 666, 103. (b) Mitra, A.; DePue, L. J.; Struss, J. E.; Patel, B.
P.; Parkin, S.; Atwood, D. A. Inorg. Chem. 2006, 45, 9213. (c) Vedejs, E.;
Chapman, R. W.; Lin, S.; Mu¨ller, M.; Powell, D. R. J. Am. Chem. Soc.
2000, 122, 3047.
(17) Special experiments demonstrated that no trifluoromethylation of
2a with Me3SiCF3 occurs on workup with saturated aqueous Na2CO3.
(18) It was demonstrated by Mukaiyama that for successful activation
of Me3SiCF3 by acetate anion it is necessary to employ sodium or potassium
acetate in DMF or tetrabutylammonium acetate in any other solvent, thereby
suggesting that the role of DMF is merely to solvate the alkali metal cation;
see ref 6b.
J. Org. Chem, Vol. 72, No. 22, 2007 8605

TABLE 2. One-Pot Procedure for the Synthesis of 3a
aromatic substituents, cyclopropyl and allyl groups, as well
as acid-sensitive acetal fragment and furyl ring (entries 3
and 9). However, imine derived from 2-hydroxynaphtaline-
1-carbaldehyde and p-methoxyaniline turned out to be com-
pletely unreactive. The reason for this failure is not clear
at present. Unfortunately, other types of imines bearing
adjacent hydroxyl function such as imines obtained from
benzaldehyde and o-aminophenol, aminoethanol, or 3-
amino-1-propanol also did not give the products of trifluoro-
methylation.
It should be pointed out that the presented method for the
synthesis of compounds 3a-k is advantageous over that
mentioned in the literature. Thus, the Lewis acid mediated
interaction of phenol with imines of trifluoroacetaldehyde was
reported, but in all cases mixtures of ortho- and para-substituted
products were obtained with the yields of ortho isomers not
exceeding 25%.19
time, h
entry
base
solvent
step (a)
step (b)
yield of 3a,a %
1
2
3
4
t-BuOK
t-BuOK
EtN(i-Pr)2
EtN(i-Pr)2
DMF
THF
DMF
CH2Cl2
1
1
1
2
1
1
1
3
58
79
70
86
a Isolated yield.
TABLE 3. Trifluoromethylation of Salicyl Aldiminesa
Besides the trifluoromethyl group, pentafluorophenyl-, dichlo-
rofluromethyl-, and trichloromethyl groups can be transferred
from corresponding silanes using the above-described procedure
(eq 3). However, allyltrimylsilane did not afford the allylation
product.
In summary, a new approach for the trifluoromethylation of
unreactive CdN double bond using Me3SiCF3 furnishing amines
with R-CF3-group has been described. The intramolecular
activation of the imines through the formation of difluoroboron
chelates constitutes the key feature of the described reaction.
Our future studies will be devoted to the employment of the
chelation-induced activation of CdN double bond in the
trifluoromethylation processes.
Experimental Section
Trifluromethylation of Salicyl Aldimines. General Procedure.
BF3‚OEt2 (317 µL, 2.5 mmol) was added dropwise to a solution of
imine 1 (1.0 mmol) and EtN(i-Pr)2 (198 µL, 1.2 mmol) in CH2Cl2
(2 mL) at 0 °C, and the mixture was stirred for 2 h at room
temperature. The solvent was evaporated in a vacuum followed by
successive addition of DMF (2 mL), Me3SiCF3 (370 µL, 2.5 mmol),
and AcONa (328 mg, 4 mmol), and the resulting mixture was stirred
for 3 h at room temperature. For the workup, saturated aqueous
Na2CO3 (1 mL) was added dropwise, and the mixture was diluted
with water (10 mL), extracted with ether/hexanes (1 : 1, 4 × 5
mL), and dried (Na2SO4). Evaporation of the solvent afforded crude
product, which was chromatographed on silica gel eluting with
hexanes/ethyl acetate.
2-[2,2,2-Trifluoro-1-(methylamino)ethyl]phenol (3a). Chro-
matography: hexanes/EtOAc, from 10:1 to 3:1, Rf ) 0.37 (hexanes/
a First step: 1.2 equiv of EtN(i-Pr)2, 2.5 equiv of BF3‚OEt2, 0.5 M
CH2Cl2, rt, 2 h. Second step: 2.5 equiv of Me3SiCF3, 4 equiv of AcONa,
0.5 M DMF, rt, 3 h. b Isolated yield.
1
EtOAc, 4:1). Mp: 58-59 °C. H NMR (250 MHz, CDCl3): 2.30
(br s, ∆ν1/2 ) 200 Hz, 1H), 2.49 (s, 3H), 4.20 (q, 1H, J ) 7.7),
6.82-6.93 (m, 2H), 7.07 (d, 1H, J ) 7.2), 7.28 (t, 1H, J ) 7.2),
10.72 (br s, ∆ν1/2 ) 160 Hz, 1H). 13C NMR (CDCl3): 33.6, 66.8
(q, J ) 29.3), 114.0, 117.1, 119.2, 124.9 (q, J ) 282), 130.5, 131.0,
158.2. 19F NMR (CDCl3): -76.0 (d, J ) 7.7). Anal. Calcd for
Under the optimized conditions, a variety of imines entered
into reaction with boron trifluoride and Me3SiCF3 affording
products of trifluoromethylation in excellent yields (Table 3).
The nitrogen atom of the substrate may have aliphatic and
(19) (a) Gong, Y.; Kato, K.; Kimoto, H. Bull. Chem. Soc. Jpn. 2002,
75, 2637. (b) Gong, Y.; Kato, K.; Kimoto, H. Synlett 2000, 1058.
8606 J. Org. Chem., Vol. 72, No. 22, 2007

C9H10F3NO (205.18): C, 52.68; H, 4.91; N, 6.83. Found: C, 52.54;
H, 4.92; N, 6.84.
Supporting Information Available: Experimental procedures;
spectroscopic, analytical, and X-ray data (CIF) for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the Ministry
of Science (Project No. MK-4483.2007.3) and the Russian
Academy of Sciences (program #8).
JO701734D
J. Org. Chem, Vol. 72, No. 22, 2007 8607