Although trifluoromethylated nicotinic acids or their
derivatives have been prepared by various methods, very
n-butyl-vinylether 6 in dichloromethane to give the vinylog-
ous butoxyiminium chloride 7, which was then reacted
directly without isolation with the ꢀ-ketoester 4a in the
presence of triethylamine, with the temperature maintained
below 3 °C. The resulting adduct 8a was then quenched with
1 N aqueous HCl solution. Somewhat surprisingly, hydrolysis
of iminium salt 8a did not lead to the formation of the
expected terminal aldehyde 3a. Instead, the yellowish-orange
dimethylamino compound 9a was obtained as a mixture of
(2E,4E) and (2Z,4E) geometric isomers in a fairly good yield
of 56%. The stereochemistry of both isomers was proven
4
few approaches to the preparation of 2a-c have been
5
described in the literature. The existing syntheses of
compounds 2a-c are based on very expensive starting
materials that are neither readily available from commercial
sources or easily prepared. Furthermore, the previously
described methods would not be appropriate for larger-scale
operations, due to the employment of very low temperatures,
long reaction times, dispensing of air-sensitive alkyllithium
reagents, and quenching with solid carbon dioxide. Thus,
we directed our efforts to designing more convenient and
practical synthetic methods to prepare 2-(trifluoromethyl)nic-
otinic acid derivatives 2a-c.
9
by NOESY NMR experiments.
The versatile intermediate 9a was smoothly converted to
the pyridyl ester 2a in excellent yield of 90% upon heating
at 70 °C in the presence of excess aqueous ammonium
hydroxide in ethanol (Scheme 2).
Scheme 2
. Vinylogous Vilsmeier reaction of Ethyl
4
,4,4-Trifluoro-acetoacetate and 2-(Trifluoroacetyl)-acetonitrile
Figure 1. Retrosynthetic analysis of compounds 2a and 2b.
Our retrosynthetic analysis is presented in Figure 1. Ethyl
4
,4,4-trifluoro-acetoacetate 4a seemed to us to represent a
particularly convenient raw material, as it is relatively cheap
and abundantly available in bulk. We envisioned that the
pyridyl ester 2a could be easily accessed via a short, two-
step process involving a Vilsmeier-type reaction of 4a with
an alkyl vinyl ether followed by cyclization of the resulting
dienyl aldehyde 3a with a source of ammonia.
6
7
Vilsmeier reactions of ketones and ꢀ-ketoesters have
been well-known in the literature for decades. However,
formylation reactions using vinylogous iminium salts are
8
usually limited to more reactive substrates, and a powerful
activating group is normally required to achieve a successful
vinylogous Vilsmeier reaction.
The Vilsmeier reagent 5 (freshly prepared by the reaction
of DMF with oxalyl chloride) was treated with 1.3 equiv of
Subsequently, we modified this procedure to directly obtain
the nitrile 2b. Analogous Vilsmeier-type vinylogous formy-
1
0
lation of 2-(trifluoroacetyl)-acetonitrile 4b gave the cor-
responding vinyl nitrile 9b, which was isolated as bright-
yellow crystals in 51% yield. Only one stereoisomer was
9
¨
observed by NMR when the cyano staring material 4b was
(
4) (a) Miller, P. European Patent EP 1340747, 2003. Chem. Abstr. 2003,
1
39, 214341. (b) Cooke, J. WB.; Coleman, M. J.; Caine, D. M.; Jenkins,
used. The subsequent cyclization reaction was effected in a
mixture of methanol and aqueous ammonium hydroxide at
60 °C, leading to formation of the required nitrile 2b in 65%
yield.
Although the obtained yields are slightly lower, nitrile 2b
can thereafter be directly converted to the amidoxime 2d in
one step by reaction with hydroxylamine.
K. P. Tetrahedron Lett. 1998, 39, 7965. (c) Cocco, M. T.; Congiu, C.; Onnis,
V. J. Het. Chem. 1995, 543. (d) Katsuyama, I.; Ogawa, S.; Nakamura, H.;
Yamaguchi, Y.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K.
Heterocycles 1998, 48, 779. (e) Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.;
Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K. Synthesis 1997, 11,
1
2
321. (f) Goble, S. D.; Pasternak, A.; Mills, S. G.; Zhou, C.; Yang, L. WO
004082616A2, 2004. Chem. Abstr. 2004, 141, 314341.
(
5) (a) Schlosser, M.; Marull, M. Eur. J. Org. Chem. 2003, 8, 1569. (b)
Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem. 2003,
8
5
, 1559. (c) Loska, R.; Majcher, M.; Makosza, M. J. Org. Chem. 2007, 72,
Finally, an alternative route to the key intermediates 9a
and 9b was investigated as outlined in Scheme 3. These
574. (d) Shigehara, I.; Makajima, T.; Nishide, H.; Tanimura, T. Japanese
Patent 03081263, 1989. Chem. Abstr. 1989, 115, 183112. (e) Caroll, W.;
Perez-Medrano, A.; Florjancic, A.; Nelson, D.; Peddi, S.; Li, T.; Bunnelle,
E.; Hirst, G.; Li, B. US Patent 0052374, 2006. Chem. Abstr. 2006, 144,
(9) See Supporting Information.
2
92764. (f) Roy, P. J.; Dufresne, C.; Lachance, N.; Leclere, J. P.; Boisvert,
(10) Sumimoto Shinzaburo, A.; Ichiro Ishizuka, T.; Hiroyuki Kai, K.;
Shiro Ueda, O.; Akira Takase, K. European Patent EP 220947, 1987. Chem.
Abstr. 1987, 107, 134298.
M.; Wang, Z.; Leblanc, Y. Synthesis 2005, 16, 2751.
ˇ
6) (a) Zemli cˇ ka, J.; Arnold, Z. Collect. Czech. Chem. Commun. 1961,
(
2
6, 2852. (b) Marson, C. Tetrahedron 1992, 48, 3659.
(11) (a) Schr o¨ der, L. US Patent 4987232, 1991. Chem. Abstr. 1990, 113,
191170. (b) Schr o¨ der, L. European Patent EP 462639, 1991. Chem. Abstr.
1992, 116, 128679.
(
(
7) Gagan, J.; Lane, A.; Lloyd, D. J. Chem. Soc. 1970, C, 2484.
8) Jutz, C. Chem. Ber. 1958, 91, 850.
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Org. Lett., Vol. 10, No. 9, 2008