Preparation of fluoroalkyl imines, amines, enamines, ketones, α-amino carbonyls, and α-amino acids from primary enamine phosphonates

Article abstract of DOI:10.1021/jo048682m

A simple method for preparation of fluoroalkyl β-enaminophosphonates 1 from alkylphosphonates 2 and perfluoroalkyl nitriles 3 is reported. Olefination reaction of functionalized phosphates 1 with aldehydes gives α,β-unsaturated imines 5. Acid hydrolysis of these fluoroalkyl derivatives 5 affords α,β-unsaturated ketones 6, while their selective reduction with hydrides leads to the formation of allylamines 7, enamines 8, and saturated ketones 9 or amines 10. Selective oxidative cleavage of the carbon-carbon double bond of allylamines 7 gives fluorinated α-amino aldehydes 12, α-amino ketones 13, or α-amino acid derivatives 14.

Full text of DOI:10.1021/jo048682m

Preparation of Fluoroalkyl Imines, Amines, Enamines, Ketones,
r-Amino Carbonyls, and r-Amino Acids from Primary Enamine
Phosphonates†
Francisco Palacios,* Ana Mar´ıa Ochoa de Retana, Sergio Pascual, and Julen Oyarzabal
Departamento de Quı´mica Orga´nica I, Facultad de Farmacia, Universidad del Pa´ıs Vasco,
Apartado 450, 01080 Vitoria, Spain
qoppagaf@vc.ehu.es
Received July 30, 2004
A simple method for preparation of fluoroalkyl â-enaminophosphonates 1 from alkylphosphonates
2 and perfluoroalkyl nitriles 3 is reported. Olefination reaction of functionalized phosphates 1 with
aldehydes gives R,â-unsaturated imines 5. Acid hydrolysis of these fluoroalkyl derivatives 5 affords
R,â-unsaturated ketones 6, while their selective reduction with hydrides leads to the formation of
allylamines 7, enamines 8, and saturated ketones 9 or amines 10. Selective oxidative cleavage of
the carbon-carbon double bond of allylamines 7 gives fluorinated R-amino aldehydes 12, R-amino
ketones 13, or R-amino acid derivatives 14.
Introduction
carbon bonds formation reaction with electrophilic re-
agents.7,8 However, primary enamines, despite their
potential interest as synthons in organic synthesis for
the preparation of acyclic and cyclic derivatives, have
been less studied, given that they are not stable unless
conjugated with an electron-withdrawing group on the
â-carbon atom.9 In this context, we have used function-
alized aminophosphorus derivatives for the preparation
of three-,10 five-,11 and six-membered12 phosphorus-
substituted nitrogen heterocycles, as well as the synthesis
of stable primary enamines13 derived from phosphonates
and phosphazenes in the â position and their synthetic
The development of efficient and mild methods for
organofluorine compound synthesis represents a broad
area of organic chemistry since the incorporation of a
fluorine-containing group into an organic molecule dra-
matically alters its physical, chemical, and biological
properties.1 These changes in properties make them
suitable for diverse applications in synthetic, agricultural,
and medicinal chemistry as well as in materials science.2
Among them, special interest has been focused in devel-
oping synthetic methods for the preparation of fluori-
nated building blocks since they can be used for the
efficient and/or selective preparation of fluorine-contain-
ing molecules with biological activity and commercial
applications.3
(4) For an excellent review, see: Rappoport, Z. In The Chemistry of
Enamines. The Chemistry of Functional Groups; Patai, S., Rappoport,
Z., Eds.; John Wiley: Chichester, 1994.
(5) For recent reviews, see: (a) Stanovnik, B.; Svete, J. Chem. Rev.
2004, 104, 2433. (b) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42,
975.(c) Elassar, A. Z. A.; El-Khair, A. A: Tetrahedron 2003, 59, 8463.
(6) For reviews, see: (a) Shatzmiller, S.; Lidor, R. in ref 1, Part 2,
1994; p 1507. (b) Martin S. F. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2,
p 475.
(7) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273. (b) Stork, G. Med. Res. Rev. 1999, 19, 370. (c) Cuvigny, T.;
Normant, H. Synthesis 1977, 198. (d) Stork, G.; Brizzolarra, A.;
Landesman, H.; Szmuszkovicz, J.; Terrele, R. J. Am. Chem. Soc. 1963,
85, 207.
(8) (a) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E.; Ferna´ndez,
A. Tetrahedron 2001, 56, 3131. (b) Palacios, F.; Aparicio, D.; Garc´ıa,
J.; Vicario, J.; Ezpeleta, J. M. Eur. J. Org. Chem. 2001, 3357. (c)
Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E. Eur. J. Org. Chem.
1998, 1413, 3. (d) Palacios, F.; Aparicio, D.; Garc´ıa, J. Tetrahedron
1996, 52, 9609.
(9) (a) Novak, B. M.; Cafmayer, J. J. Am. Chem. Soc. 2001, 123,
11083. (b) Erker, G.; Riedel, M.; Koch, S.; Jo¨edicke, T.; Wu¨erthwein,
E. U. J. Org. Chem. 1995, 60, 5284.
(10) (a) Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.; de los
Santos, J. M.; Gil, J. I.; Lopez de Munain, R. J. Org. Chem. 2002, 67,
7283. (b) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta, J.
M. J. Org. Chem. 2000, 65, 3213.
(11) (a) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J.
M. Tetrahedron: Asymmetry 2002, 13, 2541. (b) Palacios, F.; Aparicio,
D.; de los Santos, J. M. Tetrahedron 1999, 55, 13767. (c) Palacios, F.;
Pagalday, J.; Piquet, V.; Dahan, F.; Baceiredo, A.; Bertrand, G. J. Org.
Chem. 1997, 62, 292.
Moreover, enamines have attracted a great deal of
attention in recent years because of their range of
applications,4,5 and especially metaloenamines,6 carban-
ions derived from enamines or enolizable imines, are
useful substrates for the regio- and stereoselective carbon-
* To whom correspondence should be addressed. Tel: 34-945-
013103. Fax: 34-945-013049.
† In memory of our college Dr. Juan Carlos Del Amo, Universidad
Complutense of Madrid, who died March 11, 2004.
(1) (a) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrish-
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Chemical Society: Washington D.C., 1991.
(2) (a) Chambers, R. D. Fluorine in Organic Chemistry, 2nd ed.;
Blackwell: London, 2004 (b) Organofluorine Compounds: Chemistry
and Applications; Hiyama, T., Ed.; Springer: Berlin, 2000. (c) Asym-
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Directions; Ramachandran, P. V., Ed.; American Chemical Society:
Washington D.C., 1999.
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Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A.,
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Synthesis and Applications; Kukhar, V. P., Soloshonok, V. A., Eds.;
Wiley: New York, 1995. (c) Banks, R. E.; Smarts, B. E.; Tatlow, J. C.
Organofluorine Chemistry: Principles and Commercial Applications;
Plenum: New York, 1994.
10.1021/jo048682m CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/09/2004
J. Org. Chem. 2004, 69, 8767-8774
8767

Palacios et al.
use for the preparation of functionalized acyclic com-
pounds14 and phosphorus-containing heterocycles.15 With
this in mind, we are interested in the design of stable
primary â-enaminophosphonates containing fluoroalkyl
substitents for the following reasons: (a) these primary
enamines contain a stabilizing group, the phosphonate
in the â position, that could favor the isolation and
stabilization of the primary enamine;9 (b) these reagents
could be very interesting synthons for the preparation
of heterocycles in a way similar to that described for
enamines;5,6 (c) the presence of the phosphonyl group
opens up the possibility of the use of these substrates
for olefination reactions (Wadsworth-Emmons reaction),
and therefore, they might be used as building blocks for
the stereoselective carbon-carbon double bond construc-
tion;16 (d) phosphorus substituents could regulate impor-
tant biological functions and increase biological activity,
in a way similar to that reported for pharmaceuticals;17
(e) the R-fluoroalkyl group could affect to the stability of
the primary enamine group. Moreover, as far as we know,
only â-fluoro-substituted primary enamines,18a,b R,â-
fluorodisubstituted primary enamines,18c and three types
of R-fluoro substituted primary enamines containing a
sulfinyl,19a an alkoxycarbonyl,19b-e and a carbonyl group19f,g
have been reported, and one example of preparation of a
fluorinated primary enamine containing a phosphonate
group by reaction of 1,2,3,3,3-pentafluoropropenyl phos-
phonates with ammonia has been described.19h
FIGURE 1. Design and synthetic strategy.
SCHEME 1. Synthesis of â-Enaminophosphonates
1
Continuing with our interest in the design of new
phosphorus-substituted building blocks and in this case
containing also fluoroalkyl substituents, we report here
an easy and selective synthesis of primary â-enamino-
phosphonates containing fluoroalkyl substituents in the
R position I (Figure 1), as well as their use as versatile
tools for the formation of fluoro-containing derivatives
such as imines V, nitrogen derivatives, and R-aminocar-
bonyl compounds (see Figure 1). Retrosynthetically, we
envisaged obtaining primary enamines I through simple
addition of fluoroalkyl nitriles IV to metalated alkyl
phosphonates in a way similar to that reported for simple
primary enamines derived from phosphazenes and phos-
phonates.13 Olefination reaction of enamines I with
aldehydes II and the use of R,â-unsaturated imines V as
intermediates for the preparation of fluoroalkyl substi-
tuted saturated and allylamines, enamines, saturated
and unsaturated ketones, R-amino-aldehydes, R-ami-
noketones, and R-amino acids is also explored.20
(12) (a) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M. J. Org.
Chem. 2002, 67, 2131. (b) Palacios, F.; Ochoa de Retana, A. M.; Gil, J.
I.; Lopez de Munain, R. Org. Lett. 2002, 4, 2415. (c) Palacios, F.; Ochoa
de Retana, A. M.; Oyarzabal, J. Tetrahedron 1999, 55, 5947.
(13) (a) Palacios, F.; Oyarzabal, J.; Ochoa de Retana, A. M. Tetra-
hedron Lett. 1996, 37, 4577. (b) Barluenga, J.; Lopez, F.; Palacios, F.;
Cano, F. H.; Foces, M. C. J. Chem Soc, Perkin Trans. 1 1988, 2329.
(14) (a) Lo´pez, F.; Pela´ez, E.; Palacios, F.; Barluenga, J.; Garc´ıa, J.;
Tejerina, B.; Garc´ıa, A. J. Org. Chem. 1994, 59, 1984.
(15) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Lopez de
Munain, R. Tetrahedron Lett. 2002, 43, 5917. (b) Palacios, F.; Ochoa
de Retana, A. M.; Oyarzabal, J. Tetrahedron 1999, 55, 3091. (c)
Barluenga, J.; Lo´pez, F.; Palacios, F. Tetrahedron Lett. 1987, 28, 2875.
(16) Johnson, A. W.; Kaska, W. C.; Starzewski, K. A. O.; Dixon, D.
A. Ylides and Imines of Phosphorus; John Wiley & Sons: New York,
1993; pp 307-358.
(17) (a) Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in
Everyday Living; American Chemical Society: Washington D.C., 1987.
(b) Handbook of Organophosphorus Chemistry; Engel, R., Ed.; Marcel
Dekker: New York, 1992.
(18) (a) Hojo, M.; Masuda, M.; Okada, E. Tetrahedron Lett. 1989,
45, 6173. (b) Wanner, M. J.; Hageman, J. M.; Koomen, G. J.; Pandit,
U.K. J. Med. Chem. 1980, 23, 85. (c) Krespan, C. G. J. Org. Chem.
1969, 34, 42. (b) Doussot, P.; Portella, Ch. J. Org. Chem. 1993, 58,
6675.
(19) (a) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Neille, S. V.;
Zanda, M.; Cavicchio, G.; Crucianelli, M. J. Org. Chem. 1996, 61, 3375.
(b) Bouillon, J. P.; Maliverny, C.; Janusek, Z.; Viehe, H. G. Bull. Soc.
Chim. Fr. 1997, 134, 47. (c) Lee, L. F.; Howe, R. K. J. Org. Chem. 1984,
49, 4780. (d) Cen, W.; Ni, Y.; Shen, Y. J. Fluorine Chem. 1995, 73,
161. (e) Fustero, S.; Piera, J.; Sanz-Cervera, J. F.; Catalan, S.; Ramirez
de Arellano, C. Org. Lett 2004, 6, 1417. (f) Luo, B. H.; Guan, H. P.;
Hu, C. M. Synlett 1997, 1261. (g) Lee, L. F.; Sing, Y. L. J. Org. Chem.
1990, 55, 380. (h) Von Allwo¨nden, U.; Ro¨schenthaler, G. V. Chem. Zeitg.
1988, 112, 69.
Results and Discussion
Synthesis of (Z)-Primary â-Enaminophospho-
nates 1 from Phoshonates 2 and Fluoroalkylnitriles
3. We first explored the preparation of the (Z)-primary
â-enaminophosphonates 1. Reaction of fluoroalkylnitriles
3
21 (R1 ) CF3, C2F5, C7F15, CH2F) with diethyl alkylphos-
honates 2 (R1 ) H, CH3) in the presence of base (MeLi
or LDA)22 in an inert atmosphere gave after workup
trifluoromethyl-substituted â-enaminephosphonates 1
(Scheme 1) in good yields (see Table 1, entries 1-6), in a
way similar to that previously reported for other phos-
phorus derivatives.13 Spectroscopic data are consistent
(20) For a preliminary communication, see: Palacios, F.; Pascual,
S.; Oyarzabal, J.; Ochoa de Retana, A. M Org. Lett. 2002, 4, 769.
(21) C7F15CN was purchased from Lancaster, and FCH2CN was
purchased from Aldrich. However, CF3CN and C2F5CN were freshly
prepared by dehydration of the corresponding amides (CF3CONH2,
C2F5CONH2): Reisner, D. B.; Horning, E. C. Organic Syntheses;
Wiley: New York, 1963; Collect. Vol. IV, pp 144-145.
(22) CF3CN and C2F5CN are gases and were bubbled though the
solution of phosphonates 2 in the presence of MeLi. However, C7F15
-
CN and FCH2CN are liquid and were added to the solution of
phosphonates 2 in the presence of LDA.
8768 J. Org. Chem., Vol. 69, No. 25, 2004

Preparation of Compounds from Primary Enamine Phosphonates
TABLE 1. Synthesis of Fluorinated Primary
Enaminophosphonates 1
SCHEME 2. Preparation of r,â-Unsaturated
Imines 5 and Ketones 6
entry
compd
R1
RF
base
yielda (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
CF3
MeLi
MeLi
LDA
LDA
MeLi
LDA
81
85
87
79
42
82
H
C2F5
C7F15
CH2F
CF3
H
H
CH3
CH3
C7F15
a Yields refer to isolated compounds.
with the proposed structure and indicate that they were
isolated as the Z-isomers. Thus, for compound 1a, only
one signal was observed in 31P (δP ) 21.9 ppm) and 19F
NMR (δP ) -104.8 ppm). Likewise, in the 1H NMR
spectrum a well-resolved doublet at δH ) 4.34 ppm (2JPH
) 8.7 Hz) for the vinylic proton was observed, while the
13C NMR spectrum showed absorptions at δC ) 77.0 ppm
(1JPC ) 192.9 Hz, 3JFC ) 3.6 Hz, 2JPC ) 5.6 Hz) and at δC
TABLE 2. Preparation of Fluorinated r,â-Unsaturated
Imines 5
entry compd R1
R2
RF E/Z ratioa yieldb (%)
2
) 149.5 ppm (2JPC ) 33.2 Hz, JFC ) 7.6 Hz) for vinylic
1
2
3
4
5a
5b
5c
5d
H
H
H
p-CH3Ph
CF3
1/2
1/2
1/2
1/5
91 (57)c
85
carbon atoms, and at δC ) 120.0 ppm (1JFC ) 276.4 Hz,
3JPC ) 28.7 Hz) for the fluoromethyl group. 13C-31P
coupling constant (3JPC) in the range of 25-30 Hz showed
that the fluoro-substituted alkyl group (RF) and the
phosphorus atom in enamines 1 are related trans.23
Formation of primary enamines 1 can be assumed to
proceed via protonation of ketimino intermediates 4,
followed by prototropic tautomerization of â-iminophos-
phonates (Scheme 1). The scope of the reaction was not
limited to R-trifluoromethylenamines 1a,e (RF ) CF3) (see
Table 1, entries 1, 5), since perfluoroalkyl- 1b (RF ) C2F5),
1c,f (RF ) C7F15) (see Table 1, entries 2, 3, and 6), and
R-monofluoromethylenamines (RF ) CH2F) 1d (see Table
1, entry 4) were also prepared.
Synthesis of N-Nonsubstituted Fluoroalkyl R,â-
Unsaturated Imines 5 and R,â-Unsaturated Ketones
6. R,â-Unsaturated fluroalkyl ketones are key intermedi-
ates in organic synthesis for the preparation of acyclic
and heterocyclic derivatives24 and in medicinal chemis-
try25 and have been prepared from boronic acids,26a
esters,26b,c enamines,26d-f tellurides,26g or from trifluoro-
methyl ketones.26h-j However, while N-methyl-27a,b and
PhCHdCH CF3
2-thienyl
CH3 p-CH3Ph
C2F5
CF3
83 (51)c
87
a E/Z isomer ratio from 1H NMR. b Yields of crude isolated
compounds. c Yields of pure compounds isolated at reduced pres-
sure (10-5 Torr).
N-phenyl-unsaturated27c,d imines has been prepared, the
N-nonsubstituted fluoroalkyl R,â-unsaturated imines
have not been described.20 With this in mind, we thought
that fluorinated unsaturated imines could be prepared
from fluoroalkyl substituted primary enamino phospho-
nates 1 by olefination reaction with aldehydes in a way
similar to that reported for other enamines,8a,c while
fluorinated unsaturated ketones could be prepared by
olefination reaction of the same enamines 1 and subse-
quent acid hydrolysis.
Reaction of primary enamines 1a,b (R1 ) H) with
butyllithium, followed by the addition of aromatic and
heteroaromatic aldehydes, gave N-nonsubstituted fluoro-
alkyl R,â-unsaturated imines 5 (Scheme 2, Table 2,
entries 1-3) in a stereoselective fashion and in good
yields. 1-Azabutadienes 5 are unstable, but they can be
isolated (see experimental part) and kept in the refrig-
erator 2-3 days. However, for our subsequent synthetic
purposes they can be used without isolation. These
imines 5 are obtained as a mixture of E and Z isomers
toward the CdN bouble bond (see Table 2). Vicinal 3JHH
coupling constants in the range of 16-17 Hz between the
vinylic protons of 5 are consistent with the E configura-
tion of the carbon-carbon double bond.8c,d The reaction
can also be extended to 3-methyl-substituted primary
enamine 1e (R1) CH3) to obtain C-3-substituted 1-aza-
1,3-butadiene 5d (see Table 2, entry 4). Formation of
compounds 5 can be explained by olefination reaction of
enamines 1.
(23) (a) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron
1994, 50, 12727. (b) Duncan, M.; Gallager, M. J. Org. Magn. Reson.
1981, 15, 37.
(24) (a) For a review see: Nenajdenko, V. G.; Sanin, A. V.; Balen-
kova, E. S. Russ. Chem. Rev. 1999, 68, 437. For recent contributions,
see: (b) Peng, W.; Zhu, S. Tetrahedron 2003, 59, 4641. (c) Andrew, R.
J.; Mellor, J. M. Tetrahedron 2000, 56, 7267. (d) Funabiki, K.;
Nakamura, H.; Matsui, M.; Shibata, K. Synlett 1999, 756.
(25) For recent contributions, see: (a) Yoshimatsu, M.; Hibino, M.
Chem. Pharm. Bull. 2000, 48, 1395. (b) Bishop, L. P.; Magss, J. L.;
O’Neill, P. M.; Park, B. K. J. Pharm. Exp. Ther 1999, 289, 511. (c)
Boger, D. L.; Sato, H.; Lerner, A. E.; Austin, B. J.; Patterson, J. E.;
Patricelli, M. P.; Cravatt, B. F. Bioorg. Med. Chem. Lett. 1999, 9, 265.
(d) Kawase, M.; Harada, H.; Saito, C.; Cui, J. M.; Tani, S. Bioorg. Med.
Chem. Lett. 1999, 9, 193.
(26) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) Singh, R. P.; Ca, G. F.; Kichmeier, R. L.; Sheeve, J. M. J.
Org. Chem. 1999, 64, 483. (c) Wiedemann, W.; Heiner, T.; Mloston,
G.; Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. Engl. 1998,
37, 820. (d) Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7261.
(e) Sanin, A. V.; Nenajdenko, V. G.; Smolko, K.; Denisenko, D. I.;
Balenkova, E. S. Synthesis 1999, 842. (f) Huang, W. S.; Yuan, C. Y. J.
Chem. Soc., Perkin Trans. 1 1995, 741. (g) Mo, X. S.; Huang, Y. Z.
Synlett 1995, 180. (h) Xu, Y.; Dolbier, W. R. Tetrahedron Lett. 1998,
39, 9151. (i) Linderman, R. J.; Jamois, E. A.; Tennyson, S. D. J. Org.
Chem. 1995, 59, 957. (j) Hata, H.; Kobayashi, T.; Amii, H.; Uneyama,
K.; Welch, J. T. Tetrahedron Lett. 2002, 43, 6099.
These results prompted us to extend this reaction and
to explore whether fluorinated primary â-enaminophos-
(27) (a) Yamasaki, Y.; Maekawa, T.; Ishihara, T.; Ando, T. Park, B.
K. Chem. Lett. 1985, 1387. (b) Ishihara, T.; Maekawa, T.; Ando, T.
Park, B. K. Tetrahedron Lett. 1983, 24, 1387. (c) Huang, W. S.; Yuan,
C. Y. J. Chem. Soc., Perkin Trans. 1 1995, 741. (d) Mae, M.; Matsuura,
M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002, 43, 2069.
J. Org. Chem, Vol. 69, No. 25, 2004 8769

Palacios et al.
TABLE 3. Preparation of Fluorinated r,â-Unsaturated
SCHEME 3. Reactivity of r,â-Unsaturated Imines
5
Ketones 6
entry
compd
R1
R2
RF
yielda (%)
1
2
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
p-CH3Ph
PhCHdCH
2-Fur
CF3
CF3
CF3
CF3
CF3
CH2F
C2F5
C2F5
CF3
CF3
CF3
76
84
63
65
83
56b
82
64
71
62
71
H
3
H
4
H
p-FPh
5
H
c-C6H11
p-FPh
6
H
7
H
p-CH3Ph
2-thienyl
p-CH3Ph
2-Fur
8
H
9
CH3
CH3
CH3
10
11
6j
6k
PhCHdCH
a Yields refer to isolated compounds. b Yields from phosphonate
TABLE 4. Preparation of Fluorinated Allyl Amines 7
2.
entry
compd
R1
R2
RF
yielda,b (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
H
p-CH3Ph
PhCHdCH
p-CH3Ph
p-FPh
PhCHdCH
p-FPh
CF3
65
54
73
52
54
57c
71
53
phonates 1 could also be useful intermediates for the
preparation of R,â-unsaturated ketones 6. Treatment of
primary enamines 1 with butyllithium, followed by the
addition of aldehydes and acid hydrolysis (H2SO4 5 M),
afforded a stereoselective synthesis of R,â-unsaturated
ketones 6a-k (Scheme 2), obtained only as the E isomers
(see Table 3). Formation of compounds 6 can be explained
by olefination reaction of enamines 1, followed by hy-
drolysis of the N-unsubstituted 1-azadienes 5. Ketones
6 can also be obtained in “one-pot” reaction from phos-
phonates 2, by subsequent addition of base, fluoronitriles,
aldehydes, and acid hydrolysis (Table 3, entry 6).
Synthesis of Allylamines 7, Enamines 8, Ketones
9, and Saturated Amines 10. Imines are starting
materials for the preparation of amines,4 and in our case
the presence of a conjugate C-C double bond opens the
possibility not only of selective 1,2-reduction but also of
1,4-reduction,28 as well as C-N and C-C double-bond
reduction to obtain saturated amines. For this reason,
we explored the regioselective reduction of R,â-unsatur-
ated imines 5 because we thought these substrates could
be used for the preparation of allylamines, enamines, and
saturated amines containing fluoroalkyl-substituted sub-
stituents. Fluorinated allylamine derivatives represent
an important class of compounds for their pharmacologi-
cal interest given their activities as irreversible inhibitors
of serine proteases29a and monoamine oxidases.29b,c In this
context, secondary trifluoromethyl allylamines have been
prepared by Lewis acid-catalyzed addition of acetylenes
to trifluoroacetaldehyde N,N-aminals,30a by vinylmagne-
sium bromide addition to N-acylimines derived from
trifluoroacetaldehyde generated “in situ”30b or by nucleo-
philic trifluoromethylation of N-tosylaldimines30c and
optically active sulfinyl-aldimine.30d
H
CF3
H
C2F5
C2F5
C7F15
CH2F
CF3
H
H
H
7g
7h
CH3
CH3
p-CH3Ph
2-Fur
CF3
a Yields refer to isolated compounds. b Yields from enamines 1.
c Yields from phosphonates 3 (“one-pot” procedure).
hydride, and DIBAL were studied, and the best results
were observed when R,â-unsaturated imines were gener-
ated “in situ” from enaminephosphonates 1 and sodium
borohydride in methanol at very low temperature (-78
°C) was used. Reaction of primary enamines 1a-d (R1
) H) with butyllithium, followed by the addition of
aromatic and heteroaromatic aldehydes and subsequent
treatment of the reaction mixture with NaBH4 in metha-
nol at -78 °C, gave primary fluoroalkyl allylamines 7a-f
(Scheme 3) in a stereoselective fashion (1,2-addition) and
3
in good yields (Table 4, entries 1-6). Vicinal JHH
coupling constants in the range of 16-17 Hz between the
vinylic protons of amines 7 are consistent with the E
configuration of the carbon-carbon double bond. The
reaction can also be extended to 3-methyl-substituted
primary enamine 1e (R1 ) CH3) to obtain C-â-substituted
allylamine 7g,h (see Table 4, entries 7, 8). From a
preparative point of view, it is noteworthy that the
synthesis of allylamines 7 does not require the isolation
and purification of enamines 1 and that they can be
obtained in a “one-pot” reaction from phosphonates 3,
when after the addition of base and fluronitriles 2, a
subsequent addition of aldehydes and hydride is carried
out (Table 4, entry 6). Therefore, this procedure is quite
general and highly selective affording exclusively the E
stereoisomer not only of R-trifluoromethyl allylamines
7a,b,g,h (RF ) CF3), but also of perfluoroalkyl 7c,d,e (RF
) CnF2n+1, n ) 2, 7) and of R-monofluoromethyl allyl-
amines 7f (RF ) CH2F).
We explored initially the selective 1,2 reduction (Cd
N) of imines 5. Sodium borohydride, sodium cyanboro-
(28) For an example of selective 1,2- and 1,4-addition of organo-
lithium reagents to unsaturated aldimines, see: Tomioka, K.; Shioya,
Y.; Nagaoka, Y.; Yamada, K. J. Org. Chem. 2001, 66, 7051 and
references cited therein.
(29) (a) Ohba, T.; Ikeda, E.; Wakayama, J.; Takei, H. Bioorg. Med.
Chem. Lett. 1996, 6, 219. (b) Palfreyman, M. G.; McDonald, I. A.; Bey,
P.; Danzin, C.; Zreika, M.; Cremer, G. J. Neural. Transm., Suppl. 1994,
41, 407. (c) Bey, P.; Fozard, J.; Lacoste, J. M.; McDonald, I. A.; Zreika,
M.; Palfreyman, M. G. J. Am. Chem. Soc. 1984, 27, 9.
(30) (a) Xu, Y.; Dolbier, W. R. J. Org. Chem. 2000, 65, 2134. (b)
Weygand, F.; Steglich, W.; Oettmeir, W.; Maierhofer, A.; Loy, R. S.
Angew. Chem., Int. Ed. Engl. 1966, 5, 600. (c) Prakash, G. K. S.;
Mandal, M.; Olah, G. A. Synlett, 2001, 77. (d) Prakash, G. K. S.;
Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847.
Subsequently, we studied the selective 1,4 reduction
of conjugated imines 5, because by means of this process
we might obtain the until now unknown fluoroalkyl-
substituted enamines 8 without stabilizing groups in â
position. Lithium aluminum hydride and borane were
explored, and the best results were observed when R,â-
unsaturated imines 5 were reduced with borane at low
temperature. Addittion of BH3‚Me2S on R,â-unsaturated
imines 5 generated “in situ” from primary enamines 1a,b
8770 J. Org. Chem., Vol. 69, No. 25, 2004

Preparation of Compounds from Primary Enamine Phosphonates
TABLE 5. Preparation of Fluorinated Enamines 8
SCHEME 4. Preparation of r-Aminocarbonyl
Derivatives 12-14
entry compd R1
R2
RF 7/8 ratioa yieldb (%)
1
2
3
4
5
8a
8b
8c
8d
8e
H
H
H
p-CH3Ph
CF3 10/90
53c,d (58)d,e
PhCHdCH CF3 34/66
30c,f
2-thienyl
CH3 p-CH3Ph
C2F5 5/95
CF3 10/90
CF3 17/83
41c,f
31c,f
CH3 2-Fur
23c,f
a Calculated from 1H and 19F NMR spectra of crude reaction
mixture. b Yields refer to isolated compounds. c Yields of compound
8 from enamines 1. d Purified by column chromatography. e Yield
of compounds 8 from imines 5. f Purified by vacuum distillation
(10-5 Torr).
TABLE 6. Preparation of Fluorinated Saturated
Ketones 9 and Amines 10
entry compd
R1
R2
RF
yielda (%)
1
2
3
4
5
6
9a
H
p-CH3Ph
CF3
65
60
Table 6, entries 4, 6). Amines 10 can also be obtained in
a “one-pot” reaction from phosphonates 1, by subsequent
addition of base, aldehydes, and catalytic reduction of the
C-C double bond (see Table 6, entries 4, 6). Therefore,
not only â-enamino phosphonates 1, but also unsaturated
imines 5 can be synthetic intermediates (Scheme 3) for
the preparation of allylamines 7, enamines 8, saturated
fluoroalkyl ketones 9, and amines 10.
9b
H
H
H
H
PhCHdCH CF3
9c
2-thienyl
p-CH3Ph
p-FPh
C2F5 53
CF3
82b (65)c (75)d (69)e
C2F5 77b
CF3
82b (75)d (69)e
10a
10b
10c
CH3 p-CH3Ph
a Yields refer to isolated compounds. b Yields of compound 10
from allylamine 7. c Yields of compound 10 from enamine 8.
d Yields of compound 10 from unsaturated imines 5. e Yields of
compound 7 from enamines 1.
Synthesis of Fluoroalkyl Substituted R-Aminoal-
dehydes 12, -ketones 13, and -acids 14. Fluorinated
allylamines 7 can be used as building blocks for the
preparation of fluorine-containing R-amino-carbonyl com-
pounds and R-amino acids by oxidative cleavage reaction
of the carbon-carbon double bond. Allylamines 7a (R1
) H) and 7g (R1 ) CH3) were converted into the benzyl
carbamates 11 by reaction with benzyl chloroformiate,
and then the double bond of C-â-unsubstituted allylamine
11a (R1 ) H) was selectively cleaved by ozonolysis (O3)
in the presence of triphenylphosphine at low temperature
(-78 °C) to give the N-Cbz R-amino aldehyde containing
a trifluoromethyl group in the R position 12 (R1 ) H)31
in good yields (73%). Similarly, the oxidation of N-
protected (Cbz) allylamine containing a methyl group in
the â position 7g (R1 ) CH3) with ozone and triphenyl-
phosphine led to the formation of fluorinated R-amino
ketone 13 (R1 ) CH3) (82%). However, when the double
bond was cleaved using the Sharpless (RuCl3-sodium
periodate) method32 the corresponding N-Cbz R-amino
acid 14 was obtained (65%) (Scheme 4). Fluorine-contain-
ing amino acids and aldehydes are important compounds
in organic synthesis and in medicinal chemistry3a,b and
several methods of preparation of these compounds have
been described in recent years.3a,b,33,34 However, as far
as we know, only one example of synthesis of an alkyl
R-fluoroalkyl R-amino ketone35 have been described.
(R1 ) H) led to the formation (1,4-addition) of primary
fluoroalkyl enamines 8a-e (Scheme 3) as major products
(Table 5, entries 1-5), with a small proportion of allyl-
amines 7 (1,2-addition). Both products can be separated
and isolated through column chomatography or distilla-
tion at reduced pressure (10-5 Torr). A similar yield was
obtained when the process was performed with R,â-
unsaturated imine 5a (see Table 5, entry 1). Spectroscopic
data are consistent with the proposed structure and
indicate that enamines 8 were isolated as the Z-isomers
on the basis of NOE experiments. Thus, in mass spec-
trometry compound 8a showed the molecular ion (m/e
215, 54%) and only one signal was observed in 19F NMR
(δP ) -71.2 ppm) for this compound 8a. Likewise, the
1H NMR spectrum showed a triplet at δH ) 5.16 ppm
(3JHH ) 7.3 Hz) for the vinylic proton, while in the 13C
NMR spectrum absorptions at δC ) 104.7 ppm and at δC
) 131.3 ppm (2JFC ) 31.7 Hz) for vinylic carbon atoms
were observed. As far as we know, this process represent
the first synthesis of fluoroalkyl enamines 8 without an
electron withdrawing group in â position. In this case,
fluoroalkyl group in R seems to stabilize the primary
enamino group of these substrates.
These compounds 8 can be used as starting material
for the preparation of saturated ketones. Acid hydrolysis
of enamines 8 (Scheme 3) with 5 M H2SO4 in ether and
at room temperature gave fluoroalkyl-substituted ketones
9 (see Table 6, entries 1-3). Moreover, not only allyl-
amines 7 but also enamines 8 can be used for the
preparation of saturated fluoroalkylamines 10 (Scheme
3). Selective reduction of the C-C double bond of allyl-
amines 7 can be achieved at room temperature by its
catalytic reduction in the presence of palladium on carbon
and acetic acid as solvent, and saturated fluoroalkyl-
amines 10 are obtained (see Table 6, entries 4-6).
Likewise, saturated amines can also be prepared by
catalytic reduction (Pd/C) either of enamines 8 in ethanol
(see Table 6, entry 4) or of R,â-unsaturated imines 5 (see
(31) The oxidation of the R-amino aldehyde to the corresponding
R-amino acid takes place very easily in the presence of air.
(32) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J. Org. Chem. 1981, 46, 3936. (b) Palacios, F.; Alonso, C.; Amezua,
P.; Rubiales, G. J. Org. Chem. 2002, 67, 1941.
(33) (a) Fustero, S.; Navarro, A.; Pina, B.; Soler, J. G.; Bartolome,
A.; Asensio, A.; Simo´n, A.; Bravo, P.; Fronza, G.; Volonteiro, A, Zanda,
M. Org. Lett. 2001, 3, 2621. (b) Davis, F. A.; Srirajan, V.; Titus, D. D.
J. Org. Chem. 1999, 64, 6931.
(34) (a) Bravo, P.; Crucianelli, M.; Fronza, G.; Zanda, M. Synlett
1996, 249. (b) Bravo, P.; Crucianelli, M.; Farina, A.; Valdo Meille, S.;
Volonterio, A.; Zanda, M. Eur. J. Org. Chem. 1998, 435. (c) Abouab-
dellah A.; Welch, J. T. Tetrahedron: Asymmetry 1994, 5, 1005. (d) Van
Hijfte, L.; Heydt, V.; Kolb, M. Tetrahedron Lett. 1993, 34, 4793.
(35) Panzeri, A.; Nesi, M.; Di Salle, E. PCT Int. Appl. WO 9403476,
1994; Chem. Abstr. 1994, 121, 134563.
J. Org. Chem, Vol. 69, No. 25, 2004 8771

Palacios et al.
extracted with CH2Cl2 and filtered through Celite and con-
centrated under vacuum. 1-Azabutadienes 5 are unstable, but
they can be isolated and kept in the refrigerator for 2-3 days.
SCHEME 5. Synthetic Applications of
â-Enaminephosphonates or of Their Precursors
(Fluoronitriles and Phosphonates)
4-p-Tolyl-2-trifluoromethyl-1-aza-1,3-butadiene (5a) (388
mg, 91%) obtained as a pale yellow oil: bp 40-41(10-5 Torr);
1
IR (neat) 3293, 2981, 1600 cm-1; H NMR (300 MHz, CDCl3)
δ 10.45 (bs, 1H, NH), 10.31 (bs, 1H, NH), 7.59 (d, J ) 16.5 Hz,
1H, dCH), 7.43-7.36 (m, 5H, dCH, Har), 7.17 (d, J ) 7.8 Hz,
4H, Har), 6.82 (d, J ) 16.5 Hz, 1H, dCH), 6.58 (d, J ) 16.6
Hz, 1H, dCH), 2.35 (s, 6H, 2 × CH3); 13C NMR (75 MHz,
CDCl3) δ 163.7 (q, J ) 31.7 Hz, CdN), 162.2 (q, J ) 31.7 Hz,
CdN), 141.1 (CH), 140.9 (Car-C), 140.5, 139.9 (dCH), 132.0
(Car-C), 131.4, 129.6 (Car-C), 129.5, 127.8, 127.7, 120.1 (q, J
) 279.5 Hz, CF3), 118.2 (q, J ) 281.5 Hz, CF3), 118.1 (dCH),
117.6, 21.2 (2 × CH3); 19F NMR (282 MHz, CDCl3) δ -73.9,
-72.2; MS(EI) m/z 214 (M+ + 1, 100).
General Procedure for the Preparation of Fluori-
nated R,â-Unsaturated Ketones (6). Butyllithium (1.6 M
in hexanes) (5 mmol) was added to a solution of fluorinated
enaminophosphonate 1 (5 mmol) in THF at 0 °C and under
N2 atmosphere. The mixture was stirred for 1 h at the same
temperature. Then, a solution of the corresponding aldehyde
(5 mmol) in THF (15 mL) was added, and the reaction was
stirred at room temperature until TLC showed the disappear-
ance of the enamino phosphonate 1. A solution of H2SO4 5 M
(3 mL) was added, and the reaction was stirred for 1 h. The
organic layer was extracted with Et2O, washed with water,
dried over anhydrous MgSO4, and filtered, and the solvent was
evaporated under vacuum. The crude product was purified by
chromatography using silica gel (hexane/ethyl acetate).
Conclusions
In conclusion, the first synthesis of fluoroalkyl N-
nonsubstituted R,â-unsaturated imines 5 (X ) NH) is
described. The process involves the olefination reaction
of easily available â-enaminephosphonates with alde-
hydes and under mild reaction conditions or the reaction
of fluoronitriles and alkyl phosphonates in the presence
of base and subsequent addition of aldehydes (Scheme
5). These imines 5 (X ) NH) are versatile intermediates
for the preparation of fluorinated R,â-unsaturated ke-
tones 6 (X ) O), as well as for the synthesis of nitrogen
derivatives such as allylamines 7, primary enamines 8,
saturated amines 10, and R-amino carbonyl derivatives
12-14. Simple fluorinated building blocks are useful
compounds not only for their application in organic
synthesis2,3 but also for their biological activities.1-3
These results may expand the scope and potential of
fluorine preparative organic synthesis.
(E)-1,1,1-Trifluoro-4-p-tolyl-3-buten-2-one (6a) (325 mg,
76%) obtained as a pale yellow oil: Rf 0.87 (ethyl acetate); IR
1
(neat) 2936, 1598, 1194 cm-1; H NMR (300 MHz, CDCl3) δ
7.88 (d, J ) 15.9 Hz, 1H, CH), 7.48-7.17 (m, 4H, Harom), 6.91
(d, J ) 15.9 Hz, 1H, dCH), 2.34 (s, 3H, CH3); 13C NMR (75
MHz, CDCl3) δ 179.9 (q, J ) 34.7 Hz, CdO), 150.2 (dCH),
143.5 (Carom), 130.3-129.3 (Carom), 116.4 (q, J ) 290.5 Hz, CF3),
115.5 (CH), 21.6 (CH3); 19F NMR (282 MHz, CDCl3) δ -78.3.
Anal. Calcd for C11H9F3O: C, 61.68; H, 4.20. Found: C, 61.65;
H, 4.14.
Experimental Section
General Procedure for the Preparation of Fluori-
nated Allylic Amines (7). Butyllithium (1.6 M in hexanes)
(5 mmol) was added to a solution of fluorinated enaminophos-
phonate 1 (5 mmol) in THF at 0 °C and under N2 atmosphere.
The mixture was stirred for 1 h at the same temperature.
Then, a solution of the corresponding aldehyde (5 mmol) in
THF (15 mL) was added, and the reaction was stirred at room
temperature until TLC showed the disappearance of the
enaminophosphonate 1. The reaction was cooled to -78 °C,
and NaBH4 (10 mmol) and MeOH (25 mL) were added. After
1 h at -78 °C, the mixture was warmed to rt, 3% HCl (15 mL)
was added, and stirring was continued for 1 h. The mixture
was made alkaline (pH 12) with NaOH pellets and extracted
with EtOAc (3 × 50 mL). The combined organic extracts were
dried over anhydrous MgSO4 and filtered, and the solvent was
evaporated under vacuum. The crude product was purified by
chromatography using silica gel (hexane/ethyl acetate).
1,1,1-Trifluoro-4-p-tolyl-3-buten-2-amine (7a) (322 mg,
75%) obtained as a pale yellow oil: Rf 0.85 (ethyl acetate); IR
(neat) 3371, 3294, 2927, 1121 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.88 (d, J ) 15.9 Hz, 1H, CH), 7.11-7.24 (m, 4H, Harom),
6.67 (d, J ) 16.1 Hz, 1H, CH), 6.03 (dd, J ) 16.1, 6.5 Hz, 1H,
CH), 3.87 (m, 1H, CH), 2.28 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3) δ 121.1-138.3 (Carom), 55.9 (q, J ) 30.2 Hz, CH), 21.1
(CH3); 19F NMR (282 MHz, CDCl3) δ -78.1. Anal. Calcd for
C11H12F3N: C, 61.39; H, 5.62; N, 6.51. Found: C, 61.47; H,
5.67; N, 6.59.
General Procedure for Preparation of Fluorinated
â-Enaminophosphonates (1). A solution of diethylphospho-
nate 2 (5 mmol) in THF (10 mL) was added to a solution of
base (MeLi or LDA) (5 mmol) in THF (15 mL) at -78 °C and
under N2 atmosphere. The mixture was stirred for 1 h at -78
°C. Then the corresponding fluorinated nitrile 3 was added
into the solution. The reaction was allowed to warm to room
temperature. The resulting mixture was washed three times
with water (20 mL), extracted with CH2Cl2, dried over anhy-
drous MgSO4, filtered, and concentrated under vacuum. The
crude product was purified by chromatography using silica gel
(hexane/ethyl acetate).
Diethyl 2-amino-2-trifluoromethylethenylphospho-
nate (1a) (1.00 g, 81%) obtained as a white solid: mp 63-65
°C; IR (KBr) 3348, 3206, 1217, 1042 cm-1; 1H NMR (300 MHz,
CDCl3) δ 5.83 (bs, 2H, NH2), 4.34 (d, J ) 8.7 Hz, 1H, CH),
3.96 (m, 4H, OCH2), 1.25 (m, 6H, CH3); 13C NMR (75 MHz,
CDCl3) δ 149.5 (dq, J ) 33.2, 7.6 Hz, C-N), 120.0 (dq, J )
276.4, 28.7 Hz, CF3), 77.0 (d, J ) 192.6 Hz, CH), 61.6 (OCH2),
16.1 (CH3); 31P NMR (120 MHz, CDCl3) δ 21.9; 19F NMR (282
MHz, CDCl3) δ -72.3. Anal. Calcd for C7H13F3NO3P: C, 34.02;
H, 5.30; N, 5.67. Found: C, 34.14; H, 5.25; N, 5.73.
General Procedure for the Preparation of Fluori-
nated R,â-Unsaturated Imines (5). Butyllithium (1.6 M in
hexanes) (2 mmol) was added to a solution of fluorinated
enaminophosphonate 1 (5 mmol) in THF at 0 °C and under
N2 atmosphere. The mixture was stirred for 1 h at the same
temperature. Then, a solution of the corresponding aldehyde
(2 mmol) in THF (15 mL) was added, and the reaction was
stirred at room temperature until TLC showed the disappear-
ance of the enaminophosphonate 1. The resulting mixture was
General Procedure for the Preparation of Fluori-
nated Enamines (8). Butyllithium (1.6 M in hexanes) (2
mmol) was added to a solution of fluorinated enaminophos-
phonate 1 (2 mmol) in THF at 0 °C and under N2 atmosphere.
The mixture was stirred for 1 h at the same temperature.
8772 J. Org. Chem., Vol. 69, No. 25, 2004

Preparation of Compounds from Primary Enamine Phosphonates
Then, a solution of the corresponding aldehyde (2 mmol) in
THF (6 mL) was added, and the reaction was stirred at room
temperature until TLC showed the disappearance of the
enamino phosphonate 1. The reaction was cooled to -78 °C,
BH3‚SMe2 1.0 M in CH2Cl2 (2.22 mL, 2.22 mmmol) was added,
and the reaction was stirred at -78 °C until TLC showed the
disappearance of the R,â-unsaturated imine 5. A solution of
NaHCO3 (10 mL) was added, and the reaction was warmed to
rt. The organic layer was extracted with Et2O, washed with
water, dried over anhydrous MgSO4, and filtered, and the
solvent was evaporated under vacuum. The crude product was
purified by vacuum distillation or by chromatography using
silica gel (hexane/ethyl acetate).
δ 137.7 (Carom), 135.6, 129.2 (Carom), 128.3, 126.8 (q, J ) 281.5
Hz, CF3), 52.9 (q, J ) 28.7 Hz, C-CF3), 31.4(CH2), 31.1 (CH2),
20.9 (CH3); 19F NMR (282 MHz, CD3OD) δ -79.2. Anal. Calcd
for C11H14F3N: C, 60.82; H, 6.50; N, 6.45. Found: C, 60.55;
H, 6.44; N, 6.56.
General Procedure for the Preparation of Benzyloxy-
carbonyl Allylamines (11). NaHCO3 (92 mg, 1.1 mmol) was
added to a solution of corresponding allylamines 7 (1 mmol)
in THF (4 mL) at 0 °C. Then a solution of benzyl chloroformiate
(0.20 mL, 1.35 mmol) in THF (4 mL) was added by dripping.
The reaction was stirred at room temperature until TLC
showed the disappearance of the allylamines 7. The organic
layer was extracted with ethyl acetate (2 × 50 mL), washed
with saturated solution of NaCl, dried over anhydrous MgSO4,
and filtered, and the solvent was evaporated under vacuum.
The crude product was purified by chromatography using silica
gel (hexane/ethyl acetate).
N-Benzyloxycarbonyl-1,1,1-trifluoro-4-p-tolyl-3-buten-
2-amine (11a). The general procedure was followed using
1,1,1-trifluoro-4-p-tolyl-3-buten-2-amine 7a. Chromatographic
purification gave 283 mg (81%) of compound 11a as a white
solid: Rf 0.58 (hexane/ethyl acetate,7/3); mp 142-144 °C; IR
(neat) 3296, 3036, 2964, 1695, 1541, 1244 cm-1; 1H NMR (300
MHz, CD3OD) δ 7.36 (s, 5H, Harom), 7.27 (d, J ) 8.1 Hz, Harom),
7.14 (d, J ) 8.1 Hz, Harom), 6.71 (d, J ) 15.9 Hz, 1H, dCH),
6.04 (dd, J ) 15.9, 6.1 Hz, 1H, dCH), 5.04-5.11 (m, 2H, NH,
CHCF), 2.34 (s, 3H, CH3); 13C NMR (75 MHz, CD3OD) δ 155.5
(CdO), 138.6 (Carom), 135.7(dC), 132.5, 129.3 (Carom), 128.5,
128.3, 128.1, 126.6, 124.4 (q, J ) 282.0 Hz, CF3), 117.8 (dC),
67.6 (CH2O), 54.7 (q, J ) 31.7 Hz, CH-NH2), 21.1 (CH3); 19F
NMR (282 MHz, CD3OD) δ -76.4. Anal. Calcd for C19H18F3-
NO2: C, 65.32; H, 5.19; N, 4.01. Found: C, 65.45; H, 5.14; N,
4.06.
General Procedure for the Preparation of Fluoro-
alkyl-Substituted R-Aminoaldehyde (12) and Ketone
(13). O3 was bubbled through a solution of corresponding
benzyloxycarbonyl allylamines 11 (1 mmol) in CH2Cl2 (16 mL)
and methanol (4 mL) at -78 °C until TLC showed the
disappearance of the allylamines 11. Then PPh3 (1 mmol) in
THF (4 mL) was added. The reaction was stirred for 2 h at
room temperature. The solvent was evaporated under vacuum,
and the crude product was purified by chromatography using
silica gel (hexane/ethyl acetate). R-Aminoaldehyde 12 and
ketone 13 are unstable and can be oxidized to compound 14
very easily in the presence of air.
1,1,1-Trifluoro-4-p-tolyl-2-buten-2-amine (8a) (228 mg,
53%) obtained as a pale yellow oil: Rf 0.62 (hexane/ethyl
1
acetate,7/3); IR (neat) 3463, 3378, 2923, 1115 cm-1; H NMR
(300 MHz, CD3OD) δ 7.00-7.06 (m, 4H, Harom), 5.16 (t, J )
7.3 Hz, 1H, dCH), 3.22 (d, J ) 7.3 Hz, 2H, CH2), 3.13 (bs, 2H,
NH2), 2.25 (s, 3H, CH3); 13C NMR (75 MHz, CD3OD) δ 135.9
(Carom), 131.3 (q, J ) 31.7 Hz, dC), 129.3 (Carom), 128.0, 122.0
(q, J ) 272.4 Hz, CF3), 104.7 (dCH), 30.6 (CH2), 20.9 (CH3);
19F NMR (282 MHz, CD3OD) δ -71.2. Anal. Calcd for
C11H12F3N: C, 61.39; H, 5.62; N, 6.51. Found: C, 61.58; H,
5.55; N, 6.39.
General Procedure for the Preparation of Fluori-
nated Saturated Ketones (9). A solution of H2SO4 5M (0.5
mL) was added to a solution of fluorinated enamine 8 (1 mmol)
in Et2O The mixture was stirred for 2 h at room temperature.
The organic layer was extracted with Et2O (3 × 10 mL),
washed with water, dried over anhydrous MgSO4, and filtered,
and the solvent was evaporated under vacuum. The crude
product was purified by chromatography using silica gel
(hexane/ethyl acetate).
1,1,1-Trifluoro-4-p-tolyl-2-butanone (9a) (140 mg, 65%)
obtained as a pale yellow oil: Rf 0.52 (hexane/ethyl acetate,7/
3); IR (neat) 3013, 1750, 1120 cm-1; 1H NMR (300 MHz, CD3-
OD) δ 7.01-7.11 (m, 4H, Harom), 2.87-2.96 (m, 4H, 2 × CH2),
2.24 (s, 3H, CH3); 13C NMR (75 MHz, CD3OD) δ 190.7 (q, J )
35.2 Hz, CdO), 135.2 (Carom), 129.3 (Carom), 128.1, 115.5 (q, J
) 292.1 Hz, CF3), 38.1(CH2), 27.8 (CH2), 20.8 (CH3); 19F NMR
(282 MHz, CD3OD) δ -79.6. Anal. Calcd for C11H11F3O: C,
61.11; H, 5.13. Found: C, 61.42; H, 5.06.
General Procedure A for the Preparation of Fluori-
nated Saturated Amines (10). To a solution of corresponding
fluorinated allylic amine 7 (1 mmol) and Pd/C (0.1 mmol) in
acetic acid (6 mL) was applied 80 psi of hydrogen, and the
reaction mixture was stirred until TLC showed the disappear-
ance of the allylic amine 7. A saturated solution of Na2CO3
(15 mL) was added, and the reaction was filtrated through
Celite. The organic layer was separated, dried over anhydrous
MgSO4, and filtered, and the solvent was evaporated under
vacuum. The crude product was purified by by chromatography
using silica gel (ethyl acetate).
General Procedure B for Preparation of Fluorinated
Saturated Amines (10) from R,â-Unsaturated Imine (5).
To a solution of corrresponding R,â-unsaturated imine 5 (1
mmol) and Pd/C (0.1 mmoles) in ethanol (6 mL) was applied
80 psi of hydrogen, and the reaction was stirred until TLC
showed the disappearance of the imine 5. Then the reaction
was filtrated through Celite, and the solvent was evaporated
under vacuum. The crude product was purified by vacuum
distillation or by chromatography using silica gel (ethyl
acetate) to afford compounds 10.
2-(N-Benzyloxycarbonylamino)-3,3,3-trifluoropropa-
nal (12). The general procedure was followed using N-benzyl-
oxycarbonyl-1,1,1-trifluoro-4-p-tolyl-3-buten-2-amine 11a. Chro-
matographic purification gave 190 mg (73%) of compound 12
as a pale yellow oil: Rf 0.11 (hexane/ethyl acetate,7/3); IR
(neat) 3310, 2964, 1723, 1692, 1537, 1184 cm-1; 1H NMR (300
MHz, CD3OD) δ 9.69 (s, 1H, CHO), 7.25-7.35 (m, 5H, Harom),
5.15 (s, 2H, CH2), 4.16-4.45 (m, 1H, CH-CF3); 13C NMR (75
MHz, CD3OD) δ 190.1 (CdO), 155.5 (COO), 135.3 (Carom), 128.6
(Carom), 128.5, 128.2, 120.7 (q, J ) 283.0 Hz, CF3), 68.1 (CH2O),
61.5 (q, J ) 29.7 Hz, CH-NH); 19F NMR (282 MHz, CD3OD)
δ -71.3.
3-(N-Benzyloxycarbonylamino)-4,4,4-trifluoro-2-bu-
tanone (13). The general procedure was followed using
N-benzyloxycarbonyl-1,1,1-trifluoro-3-methyl-4-p-tolyl-3-buten-
2-amine 11b. Chromatographic purification gave 225 mg (82%)
of compound 13 as a white solid: Rf 0.48 (hexane/ethyl
acetate,7/3); mp 105-106 °C; IR (neat) 3314, 2966, 1732, 1695,
1,1,1-Trifluoro-4-p-tolyl-2-butanamine (10a). The gen-
eral procedure A was followed using 1,1,1-trifluoro-4-p-tolyl-
3-buten-2-amine 7a. Chromatographic purification gave 178
mg (82%) of compound 10a as a pale yellow oil: Rf 0.41
(hexane/ethyl acetate,7/3); IR (neat) 3406, 3330, 2925, 1121
cm-1; 1H NMR (300 MHz, CD3OD) δ 7.02 (s, 4H, Harom), 2.97-
3.04 (m, 1H, CH), 2.74-2.83 (m, 1H, CH2), 2.56-2.66 (m, 1H,
CH2), 2.24 (s, 3H, CH3), 1.88-2.00 (m, 1H, CH2), 1.51-1.64
(m, 1H, CH2), 1.18 (bs, 2H, NH2); 13C NMR (75 MHz, CD3OD)
1
1541 cm-1; H NMR (300 MHz, CD3OD) δ 7.36 (s, 5H, Harom),
5.78 (bs, 1H, NH), 5.15 (s, 2H, CH2), 5.06 (q, J ) 7.3 Hz, 1H,
CH), 2.40 (s, 3H, CH3); 13C NMR (75 MHz, CD3OD) δ 197.2
(CdO), 155.6 (COO), 135.3 (Carom), 128.5 (Carom), 128.3, 128.1,
122.7 (q, J ) 283.0 Hz, CF3), 67.7 (CH2O), 60.9 (q, J ) 30.7
Hz, CH), 28.7 (CH3); 19F NMR (282 MHz, CD3OD) δ -71.6.
Anal. Calcd for C12H12F3NO3: C, 52.37; H, 4.39; N, 5.09.
Found: C, 52.51; H, 4.28; N, 5.17.
J. Org. Chem, Vol. 69, No. 25, 2004 8773

Palacios et al.
Supporting Information Available: Experimental pro-
cedures and characterization data (1H NMR, 13C NMR, IR, and
19F NMR) for compounds 1b-f, 5b-d, 6b-k, 7b-h, 8b-e,
9b,c, 10a-c, 11b, and 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Direccio´n General
de Investigacio´n del Ministerio de Ciencia y Tecnolog´ıa
(MCYT, Madrid DGI, PPQ2003-00910) and the Univer-
sidad del Pa´ıs Vasco (UPV, GC/ 2002) for supporting
this work. S.P. thanks Universidad del Pa´ıs Vasco for
a predoctoral fellowship.
JO048682M
8774 J. Org. Chem., Vol. 69, No. 25, 2004