temperature over an extended amount of time (ca. 4 days).8,9
Moreover, the large majority of the reported aldehyde enamines
were only purified by distillation, which limits greatly the
application of these preparation methods to small and volatile
molecules. The limitations of these methods, coupled to the
isolation restrictions, probably explain why aldehyde enamines
have never met the level of utilization of ketone enamines.10
We report herein the development of a very mild, rapid, and
highly chemoselective formation of enamines derived from
aldehydes, with a close to stoichiometric amount of secondary
amine. We tested a series of secondary amines (dibenzylamine,
diethylamine, morpholine, or pyrrolidine) in the condensation
reaction with various aldehydes. Conversions to the enamines
range from 87 to 100% with only 1.2 equiv of amine in the
presence of molecular sieves after 1 h at 0 °C (Table 1, entries
1-9). These very mild reaction conditions contrast markedly
with reported procedures that require heat or excess of amine
for an extended period of time. In fact, we even observed a
Highly Chemoselective Formation of Aldehyde
Enamines under Very Mild Reaction Conditions
Guillaume Be´langer,* Michae¨l Dore´, Fre´de´ric Me´nard, and
Ve´ronique Darsigny
Laboratoire de Synthe`se Organique et de De´Veloppement de
Strate´gies de Synthe`se, De´partement de Chimie, UniVersite´ de
Sherbrooke, 2500 bouleVard UniVersite´, Sherbrooke, Que´bec,
J1K 2R1, Canada
ReceiVed May 30, 2006
1
drop in conversion yields and less clean H NMR spectra of
reaction aliquots when the condensations were run at elevated
temperature (80 °C) or for an extended period of time.11 The
need for molecular sieves was verified: a conversion of 49%
was obtained after 1 h in the absence of molecular sieves
compared to 92% with the dehydrating agent (entry 1, see
footnote). Chloroform turned out to be the solvent of choice:
the condensation of dibenzylamine and hydrocinnamaldehyde
went up to 92% conversion in chloroform (entry 1), whereas
82 and 84% conversions were obtained when dichloromethane
and 1,2-dichloroethane were used, respectively, with the latter
showing a less clean reaction profile.12 With the more hindered
diphenylacetaldehyde, although the condensation with 1.2 equiv
of pyrrolidine was quantitative after 1 h (entry 9), 4 equiv of
the bulkier dibenzylamine was necessary to get 84% conversion
after 4 h (entry 10). However, when nonconjugated enamines
were generated, even from hindered aldehydes, such as cyclo-
hexanecarbaldehyde, the reaction still proceeded rapidly and
quantitatively (entry 4). Not surprisingly, when the less nucleo-
philic N-methylaniline was used, the conversion to the corre-
sponding enamine 11 was much slower (35% after 1 h) but
could be raised to 88% upon treatment with 3 equiv of amine
for 2 h (entry 11). We were only able to isolate and purify
Although ketone enamines are widely used in organic
synthesis, aldehyde enamines are rarely employed due to the
limitations of their preparation using known methods (need
for acid or base, excess of amine, and/or elevated temper-
ature). We have successfully developed rapid and particularly
mild condensation conditions (1 h, 0 °C, 1.2 equiv of amine)
leading to di- and trisubstituted enamines with excellent
conversion (84-100%). Remarkably high chemoselectivity
was observed with complete discrimination between aldehyde
and ketone, among other functional groups positively tested.
Enamines are of great utility in organic synthesis. They are
employed as nucleophiles in various addition reactions,1 and
we recently used them in intramolecular Vilsmeier-Haack
addition to activated amides.2 Although the preparation and use
of ketone enamines are well documented in the literature,3
enamines derived from aldehydes bring up a much greater
challenge.4 The usual conditions to prepare aldehyde enamines
involve either strong Lewis acids (TiCl4, AlCl3, SnCl4, etc.)5
or Brønsted acids (AcOH, PTSA) in refluxing solvent (benzene,
toluene, or xylene).6 The preparation of aldehyde enamines was
also effected in basic conditions (K2CO3), either in refluxing
xylene7 or with a large excess of secondary amine at room
(6) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207.
(7) Allinger, N. L.; Graham, J. C.; Dewhurst, B. B. J. Org. Chem. 1974,
39, 2615.
(8) Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J. Org. Chem.
1964, 29, 801.
(9) To the best of our knowledge, only one paper reports reaction
conditions using molecular sieves and a secondary amine (piperidine, 1.1
equiv) in ether at low temperature for the preparation of a fairly hindered
enamine as a single example. See: White, J. D.; Ruppert, J. F.; Avery, M.
A.; Torii, S.; Nokami, J. J. Am. Chem. Soc. 1981, 103, 1813.
(10) Although aldehyde hydrazones can be used for alkylation reactions,
strongly basic conditions are required to generate the corresponding
nucleophile (Davenport, K. G.; Eichenauer, H.; Enders, D.; Newcomb, M.;
Bergbreiter, D. E. J. Am. Chem. Soc. 1979, 101, 5654), which is not always
appropriate (e.g., in Vilsmeier-Haack cyclization, ref 2).
(11) At 80 °C without molecular sieves, the conversion was fast, but
the reaction was less clean than at 0 °C, and the generated enamines
decomposed extensively over time.
(1) For a review on electrophilic and nucleophilic substitution and
addition reactions of enamines, see: Hickmott, P. W. In The Chemistry of
Enamines, Part 1; Rappoport, Z., Ed.; John Wiley & Sons: New York,
1994; Chapter 14, p 727.
(2) (a) Be´langer, G.; Larouche-Gauthier, R.; Me´nard, F.; Nantel, M.;
Barabe´, F. Org. Lett. 2005, 7, 4431. (b) Be´langer, G.; Larouche-Gauthier,
R.; Me´nard, F.; Nantel, M.; Barabe´, F. J. Org. Chem. 2006, 71, 704.
(3) (a) Hamadouche, M.; El Abed, D. J. Soc. Chim. Tun. 1999, 4, 337.
(b) EÅ ervinka, O. In The Chemistry of Enamines, Part 1; Rappoport, Z.,
Ed.; John Wiley & Sons: New York, 1994; Chapter 9, p 467.
(4) Enamines derived from simple aldehydes are often unstable, being
easily hydrolyzed, oxidized, or polymerized; see ref 3b.
(12) We are confident that the reaction is not catalyzed by traces of acid
in the chloroform or leaching from the molecular sieves since no conversion
to the desired enamine was observed when p-toluenesulfonic acid or BF3‚
OEt2 was added to the reaction mixture.
(5) White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213.
10.1021/jo0611061 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/18/2006
J. Org. Chem. 2006, 71, 7481-7484
7481