assumed to proceed via protonation of enamino intermediates
5, formed by prototropic tautomerization of imines 4 (Scheme
2). The scope of the reaction was not limited to R-trifluoro-
methyl-enamines 1a,d (RF ) CF3), since perfluoroalkyl- 1b,c
(RF ) CnF2n+1, n ) 2, 7) and R-monofluoromethyl-enamines
1e (RF ) CH2F) were also prepared.
Fluorinated allylamines and R,â-unsaturated fluoralkyl
ketones represent an important class of compounds in organic
synthesis17a and in medicinal chemistry.17b,18 In this context,
secondary trifluoromethyl allylamines have been prepared
by Lewis acid-catalyzed addition of acetylenes to trifluoro-
acetaldehyde N,N-aminals,19a by vinylmagnesium bromide
addition to N-acyl imines derived from trifluoroacetaldehyde
generated in situ,19b or by nucleophilic trifluoromethylation
of N-tosyl aldimine,19c while R,â-unsaturated fluoroalkyl
ketones have been prepared from esters,20a,b enamines,20c-e
tellurides,20f or R-acetylenic trifluoromethyl ketones.20g,h With
this in mind, we thought that fluorinated allylamines and
unsaturated ketones could be prepared from fluoroalkyl-
substituted primary enamino phosphonates 1.
Table 2. Preparation of Fluorinated Carbonyl Compounds and
Allylic Amines
compd
R1
R2
RF
yield, %a
6a
6b
6c
6d
6e
6f
8a
8b
8c
8d
8e
8f
H
H
H
H
CH3
CH3
H
H
H
p-Me-Ph
Ph-CHdCH
p-Me-Ph
p-F-Ph
CF3
CF3
C2F5
CH2F
CF3
65
54
73
57b
53
71
76
82
56b
83
81
62
2-Fur
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-F-Ph
R2 ) c-C6H11
Ph-CHdCH
2-Fur
CF3
CF3
C2F5
CH2F
CF3
C7F15
CF3
H
H
CH3
a
b
Yields refer to isolated compounds. “One pot” procedure from
phosphonate 2.
Emmons olefination reaction of enamines 1 to give N-
unsubstituted 1-azadienes 7, followed by subsequent selective
hydride reduction of the imine carbon-nitrogen double bond
of unstable heterodienes 7. From a preparative point of view,
it is noteworthy that the synthesis of allylamines 6 does not
require the isolation and purification of enamines 1 and that
they can be obtained in a “one pot” reaction from phos-
phonates 2, when after the addition of base and fluronitriles
3 a subsequent addition of aldehydes and hydride is carried
out (Table 2). Therefore, this procedure is quite general and
highly selective, affording exclusively the E stereoisomer
not only of R-trifluoromethyl allylamines 6a,b,e,f (RF ) CF3)
but also of perfluoroalkyl 6c (RF ) C2F5) and of R-mono-
fluoromethyl allylamines 6d (RF ) CH2F).
Reaction of primary enamines 1 with butyllithium, fol-
lowed by addition of aromatic and heteroaromatic aldehydes,
and subsequent treatment of the reaction mixture with NaBH4
in methanol gave primary fluoroalkyl allylamines 6a-f
(Scheme 3, Table 2) in a stereoselective fashion and in good
Scheme 3a
These fluorinated allylamines 6 can be used as building
blocks for the preparation of fluorine-containing R-amino
aldehyde, R-amino ketone, and R-amino acids by an oxida-
tive cleavage reaction of the carbon-carbon double bond.
These results prompted us to extend this reaction to the
preparation of R,â-unsaturated ketones 8. Treatment of
primary enamines 1 with butyllithium, followed by addition
(20) (a) Singh, R. P.; Ca, G. F.; Kichmeier, R. L.; Sheeve, J. M. J. Org.
Chem. 1999, 64, 483. (b) Wiedemann, W.; Heiner, T.; Mloston, G.; Prakash,
G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. 1998, 37, 820. (c) Andrew,
R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7261. (d) Sanin, A. V.;
Nenajdenko, V. G.; Smolko, K.; Denisenko, D. I.; Balenkova, E. S. Synthesis
1999, 842. (e) Huang, W. S.; Yuan, C. Y. J. Chem. Soc., Perkin Trans. 1
1995, 741. (f) Mo, X. S.; Huang, Y. Z. Synlett 1995, 180. (g) Xu, Y.;
Dolbier, W. R. Tetrahedron Lett. 1998, 39, 9151. (h) Linderman, R. J.;
Jamois, E. A.; Tennyson, S. D. J. Org. Chem. 1995, 59, 957.
(21) General procedure for the preparation of allylamines 6: Butyl-
lithium (1.6 M in hexanes) (3.12 mL, 5 mmol) was added to a solution of
fluorinated enaminophosphonate 1a (1.23 g, 5 mmol) in THF (15 mL) at 0
°C under an N2 atmosphere. The mixture was stirred for 1 h at the same
temperature. Then, a solution of p-methylbenzaldehyde (600 mg, 5 mmol)
in THF (15 mL) was added and the reaction was stirred at room temperature
until TLC showed the disappearance of 1a. The reaction was cooled to
-78 °C; NaBH4 (386 mg, 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) to give pure 6a (699
mg, 3.25 mmol).
a (a) i. Base, -78 °C; ii. RFCN; (b) H2O; (c) BuLi, 0 °C; (d)
R2CHO; (e) NaBH4, MeOH, -78 °C; (f) H3O+; (g) MeCN, BuLi,
-78 °C.
yields.21 Vicinal 3JHH coupling constants in the range of 16-
17 Hz between the vinylic protons of 6a-d are consistent
with the E configuration of the carbon-carbon double bond.
Formation of compounds 6 can be explained by Horner-
(17) (a) Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ. Chem.
ReV. 1999, 68, 437. (b) Yoshimatsu, M.; Hibino, M. Chem. Pharm. Bull.
2000, 48, 1395.
(18) Ohba, T.; Ikeda, E.; Wakeyama, J.; Takei, H. Bioorg. Med. Chem.
Lett. 1996, 6, 219.
(19) (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.
Org. Lett., Vol. 4, No. 5, 2002
771