Unexpected formation of substituted anilides via reactions of trifluoroacetanilides with lithium reagents

Article abstract of DOI:10.1039/a808004f

Reactions of trifluoroacetanilides with various organolithium reagents give the corresponding substituted anilides in good yields.

Full text of DOI:10.1039/a808004f

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Unexpected formation of substituted anilides via reactions of
trifluoroacetanilides with lithium reagents
Keith Smith,* Gamal A. El-Hiti† and Anna Hamilton
Department of Chemistry, University of Wales Swansea,‡ Swansea, UK SA2 8PP
Received (in Cambridge) 15th October 1998, Accepted 9th November 1998
Table 1 Yields of substituted anilides from trifluoroacetanilides 6
according to Eqn. (3)
Reactions of trifluoroacetanilides with various organo-
lithium reagents give the corresponding substituted
anilides in good yields.
Yield
(%)a
Product
R
RЈ
X
Mp (ЊC)
Dilithiotrifluoroacetanilide has recently been used as a syn-
thetic intermediate in a variety of total syntheses of large
natural products.1–4 The dilithio reagent 2 was generated via
deprotonationandbromine–lithiumexchangefromN-(2-bromo-
phenyl)trifluoroacetamide (1) using a combination of methyl-
lithium and tert-butyllithium [Eqn. (1)], according to a method
originally developed by Wender and White.5
4
7
H
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
H
H
6-Me
H
H
6-Me
H
84
93
60
77
71
55
78
91–92 (lit.,8 93)
68–69 (lit.,8 72–73)
Oil
Me
Me
H
Me
Me
H
8
9
131–132 (lit.,8 131–132)
158–160 (lit.,8 145)
Oil
10
11
12
t-Bu
119 (lit.,9 118–120)
a Yield of isolated, purified product.
H
N
CF3
N
CF3
C
O
C
i, MeLi, -78 °C
OLi
ii, t-BuLi, -78 °C
(1)
H
Br
Li
N
CF3
C
O
1
2
In one of the recent syntheses, an attempt was made to gen-
erate the dilithio reagent 2 directly from trifluoroacetanilide (3)
using MeLi and t-BuLi.2 However, reaction of the intermediate
obtained with 2-bromoindan-1-one gave only 17% of the pro-
duct and trifluoroacetanilide (80%) was recovered unreacted.
Because of our own interest in the use of doubly lithiated
anilides and related compounds for organic synthesis6 we also
became interested in dilithio reagent 2 and wanted to obtain
it directly from trifluoroacetanilide (3) so that the process
could be more readily applied to other substituted trifluoro-
acetanilides. We therefore attempted the double lithiation of 3
with different lithiating reagents but could not achieve success-
ful ortho-lithiation under any conditions we tried. With lithium
diisopropylamide, no reaction occurred under the conditions
tried. However, the reaction proceeded in an unexpected
manner with alkyllithiums.
3
n-BuLi, 0 °C
BunLi
-
N
N
C
CF3
CF3
C
O–
O
pathway (b)
pathway (a)
–
Bun
CF3
N
C
N
C
O
–O
Bun Li
-CF3-
Thus, when 3 was reacted with n-BuLi (2 equiv.) in THF,
valeranilide (4) was obtained in 84% yield after purification
[Eqn. (2)]. n-BuLi had evidently acted overall as a nucleophile
Bun
–
N
Bun
N
C
C
O
O
–
NHCOCF3
NHCOBun
i, n-BuLi, THF
ii, H3O+
5
(2)
Scheme 1
3
4 (84%)
NHCOCF3
R
NHCOR'
i, R'Li, THF
ii, H3O+
rather than a lithiating agent, although it is likely that the
mechanism involves initial deprotonation at nitrogen.
Following lithiation at nitrogen there are two alternative
mechanisms to account for the product. One involves nucleo-
philic attack of the n-butyllithium at the carbonyl group, then
elimination of trifluoromethyl anion to give monoanion 5
(pathway a, Scheme 1). The other involves elimination of tri-
fluoromethyl anion to give phenyl isocyanate and then nucleo-
philic addition of n-butyllithium (pathway b, Scheme 1) to give
the same anion, 5. Protonation of anion 5 leads to the observed
product, 4.
X
X
(3)
R
6
7-12
yields of the isolated substituted anilides 7–12 are reported in
Table 1.
As can be seen from Table 1, the reaction is reasonably gen-
eral, accommodating substituents on the aniline ring and both
alkyl and phenyl groups in the acyl moiety. This therefore repre-
sents another possible method for the synthesis of anilides.7
Only reactions of tert-butyllithium proved to be not very
general. As indicated, when unsubstituted trifluoroacetanilide 6
was reacted with tert-butyllithium, N-pivaloylaniline 12 was
The generality of the reaction was investigated by applying
it to various substituted trifluoroacetanilides (6) and differ-
ent lithium reagents; n-BuLi, PhLi and t-BuLi [Eqn. (3)]. The
J. Chem. Soc., Perkin Trans. 1, 1998, 4041–4042
4041

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obtained in 78% isolated yield. However, the reactions of tert-
butyllithium with substituted trifluoroacetanilides 6 gave com-
plicated mixtures of products under the general reaction condi-
tions. We have not attempted to try to find conditions under
which these reactions can give a single product.
Wales Swansea, for recording mass spectra for us. We also
thank the EPSRC and the University of Wales for grants that
enabled the purchase of NMR equipment used in the course
of this work. G. A. El-Hiti thanks the University of Wales
Swansea for financial support.
Notes and references
Conclusion
† Permanent address; Department of Chemistry, Faculty of Science,
Tanta University, Tanta, Egypt.
‡ Formerly known as the University College of Swansea.
In many cases the reactions of trifluoroacetanilides with
organolithium reagents lead to useful yields of anilides formally
derived by replacement of the trifluoromethyl group by the
organic group from the organolithium reagent.
1 D. W. Brown, P. R. Graupner, M. Sainsbury and H. G. Shertzer,
Tetrahedron, 1991, 47, 4383.
2 J. Graham, A. Ninan, K. Reza, M. Sainsbury and H. G. Shertzer,
Tetrahedron, 1992, 48, 167.
Experimental
3 K. D. Raner and A. D. Ward, Aust. J. Chem., 1991, 44, 1749.
4 C. L. Francis and A. D. Ward, Aust. J. Chem., 1994, 47, 2109.
5 P. A. Wender and A. W. White, Tetrahedron, 1983, 39, 3767.
6 K. Smith and G. J. Pritchard, Angew. Chem., 1990, 102, 298; Angew.
Chem., Int. Ed. Engl., 1990, 29, 282; K. Smith, D. Anderson and
I. Matthews, J. Org. Chem., 1996, 61, 662; Sulfur Lett., 1995, 18, 79;
K. Smith, G. A. El-Hiti, M. F. Abdel-Megeed and M. A. Abdo,
J. Org. Chem., 1996, 61, 647, 656; J. Chem. Soc., Perkin Trans. 1, 1995,
1029; K. Smith, C. M. Lindsay, I. K. Morris, I. Matthews and
G. J. Pritchard, Sulfur Lett., 1994, 17, 197; K. Smith, A. P. Shukla and
I. Matthews, Sulfur Lett., 1996, 20, 121.
General procedure for the preparation of substituted anilides
To a cooled solution (0 ЊC) of substituted trifluoroacetanilide
(1.0 mmol) in THF (10 ml) was added a solution of lithium
reagent (2.0 mmol). The solution was stirred at 0 ЊC for 1 h and
then left overnight at room temperature. The reaction mixture
was diluted with ethyl acetate (10 ml) and quenched with satur-
ated ammonium chloride solution (5 ml). The organic layer was
separated, dried (MgSO4) and the solvent was removed under
reduced pressure. The crude material was purified by column
chromatography using dichloroethane–ethyl acetate (1:1) to
give the substituted anilide.
7 H. M. Meshram, Synth. Commun., 1990, 20, 3253.
8 Properties of Organic Compounds, CD ROM Databases, CRC Press
Inc., 1993, ver. 3.1.
9 W. Führer and H. W. Gschwend, J. Org. Chem., 1979, 44, 1133.
Acknowledgements
Communication 8/08004F
We thank the EPSRC Mass Spectrometry Service, University of
4042
J. Chem. Soc., Perkin Trans. 1, 1998, 4041–4042