Mannich-Type Reaction with Trifluoromethylated N,O-Hemiacetal: Facile Preparation of β-Amino-β-trifluoromethyl Carbonyl Compounds

Article abstract of DOI:10.1021/ol005812e

(Matrix Presented) On treatment of silyl enolates and an N,O-hemiacetal, derived from trifluoroacetaldehyde ethyl hemiacetal and p-anisidine, with GaCl₃ (0.2 equiv) and C₆H₅COCl (0.2 equiv) in propionitrile, Mannich-type r

Full text of DOI:10.1021/ol005812e

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1577-1579
Mannich-Type Reaction with
Trifluoromethylated N,O-Hemiacetal:
Facile Preparation of
â-Amino-â-trifluoromethyl Carbonyl
Compounds
Jun Takaya, Hirotaka Kagoshima, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin UniVersity,
1-5-1, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received March 15, 2000
ABSTRACT
On treatment of silyl enolates and an N,O-hemiacetal, derived from trifluoroacetaldehyde ethyl hemiacetal and p-anisidine, with GaCl3 (0.2
equiv) and C H COCl (0.2 equiv) in propionitrile, Mannich-type reaction took place smoothly to afford â-amino-â-trifluoromethyl carbonyl
6
5
compounds in high yields.
There is currently widespread interest in organofluorine
compounds not only because of their usefulness in the field
of material science but also for their diverse biological
activities and potential for clinical and other applications.
Development of efficient methods for the preparation of
organofluorine compounds thus continues to be an important
goal of synthetic organic chemistry.1 The synthesis of amino
compounds bearing a trifluoromethyl moiety is a significant
aspect of organofluorine chemistry. Nucleophilic addition of
organometallics toward imines derived from trifluoroacetal-
dehyde should provide easy access to the N-2,2,2-trifluoro-
ethylamines. However, this is hampered for the following
reasons: (1) trifluoromethylated imines are labile due to the
exceptionally high electrophilicity; (2) trifluoroacetaldehyde
itself, being volatile gas, is not easy to handle. To overcome
the former difficulty, N,O-acetal2 and N,N-acetal3 were
employed. With respect to the latter issue, commercially
available trifluoroacetaldehyde ethyl hemiacetal4 has been
employed as a starting material.
As part of our continued interest in the development of
the activation of the CdN bond and subsequent addition of
organometallics such as silyl enolates5 and allylic organo-
metallics,6 we focused on the Mannich-type reaction of silyl
(2) (a) Costerousse, G.; Teutsch, G. Tetrahedron 1986, 42, 2685. (b)
Fuchigami, T.; Nakagawa, Y.; Nonaka, T. J. Org. Chem. 1987, 52, 5489.
(c) Fuchigami, T.; Ichikawa, S.; Konno, A. Chem. Lett. 1989, 1987. (d)
Ishii, A.; Higashiyama, K.; Mikami, K. Synlett 1997, 1381. (e) Ishii, A.;
Miyamoto, F.; Higashiyama, K.; Mikami, K. Tetrahedron Lett. 1998, 39,
1199.
(3) Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39, 9151.
(4) For the use of trifluoroacetaldehyde ethyl hemiacetal as a starting
material for the trifluoromethylated compounds, see: Kubota, T.; Iijima,
M.; Tanaka, T. Tetrahedron Lett. 1992, 33, 1351. Funabiki, K.; Nojiri, M.;
Matsui, M.; Shibata, K. J. Chem. Soc., Chem. Commun. 1998, 2051.
Funabiki, K.; Matsunaga, K.; Matsui, M.; Shibata, K. Synlett 1999, 1477.
Loh, T.-P.; Li, X.-R. Tetrahedron 1999, 55, 5611. Kumadaki, I.; Jonoshita,
S.; Harada, A.; Omote, M.; Ando, A. J. Fluorine Chem. 1999, 97, 61.
Sakuma, K.; Kuki, N.; Kumo, T.; Takagi, T.; Koyama, M.; Ando, A.;
Kumadaki, I. J. Fluorine Chem. 1999, 93, 165. Gong, Y.; Kato, K.; Kimoto,
H. Synlett 1999, 1403. Ishii, A.; Mikami, K. J. Synth. Org. Chem. Jpn.
2000, 58, 324.
(5) Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999, 1045. Akiyama,
T.; Takaya, J.; Kagoshima, H. Synlett 1999, 1426. Akiyama, T.; Takaya,
J.; Kagoshima, H. Chem. Lett. 1999, 947. Akiyama, T.; Takaya, J.;
Kagoshima, H. Tetrahedron Lett. 1999, 40, 7831.
(6) Akiyama, T.; Iwai, J. Synlett 1998, 273. Akiyama, T.; Iwai, J.; Onuma,
Y.; Kagoshima, H. J. Chem. Soc., Chem. Commun. 1999, 2191.
(1) Fluoroorganic Chemistry. Synthetic Challenge and Biomedicinal
Rewards, Tetrahedron Symposia in Print No. 58. Resnati, G.; Soloshonok,
V. A., Eds. Tetrahedron 1996, 52, 1-300.
10.1021/ol005812e CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/10/2000

Table 1. Effect of Lewis Acid
Next, Mannich-type reaction of a silyl enol ether (3a) with
1 was studied under the influence of 0.5 equiv of Lewis acid
in propionitrile and the results are shown in Table 1.
Although conventional Lewis acids such as TiCl4 and ZnI2
were not effective, use of either BF3‚OEt2 or InCl3 afforded
an adduct (4a) in a good yield. GaCl3 exhibited the highest
activity and afforded 3a quantitatively.10
Mannich-type reactions with other silyl enolates were
studied and the results are shown in Table 2. Although 0.5
equiv of GaCl3 sufficed for 3a, the yields dropped signifi-
cantly with another silyl enol ether (3b) (entry 2). Gratify-
ingly, use of 1.0 equiv of GaCl3 resulted in the formation of
the adducts in excellent yields with various kinds of silyl
enol ethers as well as ketene silyl acetals though the
stereoselectivity was modest.
Although present Mannich-type reaction provides easy
access to â-amino-â-trifluoromethyl carbonyl compounds in
excellent yields, use of equimolar amount of promoter is not
advantageous. For example, Mannich-type reaction of 1 with
3a under the influence of 0.2 equiv of GaCl3 afforded 4a in
18% yield. To decrease the amount of GaCl3, we screened
several additives and found that the combined use of GaCl3
(0.2 equiv) and PhCOCl (0.2 equiv) efficiently promoted the
Mannich-type reaction to afford 4 in high yields. The results
of the Mannich-type reaction under the influence of the
GaCl3-C6H5COCl system are shown in Table 3. Mannich-
type reaction took place smoothly to afford the corresponding
adducts in high yields in all of the cases examined, exhibiting
stereoselectivity comparable to those with 1.0 equiv of GaCl3.
enolate with an aldimine derived from trifluoroacetaldehyde.7
We have found that an N,O-hemiacetal (1) is readily available
by simply mixing trifluoroacetaldehyde ethyl hemiacetal and
an amine followed by removal of the solvent. It is noted
that 1 can be stored without significant decomposition in a
refrigerator.8 Furthermore, Mannich-type reaction with the
N,O-hemiacetal proceeded smoothly under the influence of
GaCl3 to afford â-amino-â-trifluoromethyl carbonyl com-
pounds in excellent yields.
At the outset, trifluoroacetaldehyde ethyl hemiacetal was
treated with p-anisidine (1.0 equiv) in diethyl ether in the
presence of MS 4A at room temperature for 1.5 h. Removal
of the sieves by filtration and subsequent evaporation of the
solvent afforded 1 in 97% yield. The N,O-hemiacetal was
used without further purification. While preparation of an
aldimine (2), derived from trifluoroacetaldehyde and p-
anisidine, requires high temperature, acid catalyst, and careful
distillation,9 1 is much superior to 2 in terms of its ease of
preparation and higher stability.
Table 2. Results of the Mannich-Type Reaction by Means of GaCl3
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Org. Lett., Vol. 2, No. 11, 2000

nucleophilic addition of silyl enolates. Interestingly, treatment
of 3a and 2 with GaCl3 (0.5 equiv) in propionitrile at room
temperature for 1.0 h led to the preferential formation of 6
in 75% yield7 and 4a was not obtained at all. Use of GaCl3
(0.2 equiv) and PhCOOH (1.0 equiv) furnished 4a in 79%
yield. It is considered that present Mannich-type reaction of
1 with GaCl3 proceeded by way of 2 and the actual activator
would be a strong protic acid such as H+GaCl3X- (X ) OH
or C6H5COO). In the case of the GaCl3-PhCOCl protocol,
PhCOCl facilitated the generation of 2 by way of O-
benzoylation and thus liberated HX (X ) PhCOO or Cl)
would form H+GaCl3X- to afford 4.
Table 3. Results of the Mannich-Type Reaction Employing
GaCl3-PhCOCl
In summary, we have reported Mannich-type reaction of
silyl enolates with N,O-hemiacetal derived from trifluoro-
acetaldehyde ethyl hemiacetal. Salient features of the present
protocol are (1) the facile synthesis and high stability of the
N,O-hemiacetal as a synthetic equivalent of trifluoromethy-
lated aldimine and (2) the ability to obtain Mannich adducts
exclusively without concomitant formation of the cyclization
product.
The N-aryl substituent was readily removed to give free
â-amino carbonyl compounds. Treatment of 4a with cerium
ammonium nitrate (CAN) in acetonitrile-water (9:1) at 0
°C for 1 h led to the smooth deprotection of the p-
methoxyphenyl group to afford a â-amino-â-trifluoromethyl
ketone (5) in a good yield.11
Supporting Information Available: Experimental pro-
cedures and spectra data for the Mannich adducts. Complete
analytical data of 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
The present addition reaction is considered to proceed by
OL005812E
in situ generation of an aldimine (2) and subsequent
(7) Lewis acid mediated Mannich-type reaction of a silyl enol ether with
an N,O-acetal (CF3CH(OCH3)NEtPh), prepared by means of electrochemical
method, was reported, wherein a cyclization product was obtained prefer-
entially accompanied by a Mannich adduct.2b
(8) For the use of N,O-hemiacetal in Mannich-type reactions, see:
Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org.
Chem. 1999, 64, 2168. Ferraris, D.; Young, B.; Dudding, T.; Drury, W. J.,
III; Lectka, T. Tetrahedron 1999, 55, 8869.
(9) Abouabdellah, A.; Be´gue´, J.-P.; Bonnet-Delpon, D.; Nga, T. T. T. J.
Org. Chem. 1997, 62, 8826.
(10) For the use of GaCl3 as a promoter, see: Yamaguchi, M.; Kido,
Y.; Hayashi, A.; Hirama, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1313.
Yamaguchi, M.; Tsukagoshi, T.; Arisawa, M. J. Am. Chem. Soc. 1999, 121,
4074.
(11) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120,
431.
Org. Lett., Vol. 2, No. 11, 2000
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