Alcohol reduction of enamines

Article abstract of DOI:10.1016/j.tetlet.2010.05.053

Primary or secondary alcohols will reduce enamines to their corresponding saturated amines when heated in a microwave apparatus at a temperature of 160 °C for a period of one hour.

Full text of DOI:10.1016/j.tetlet.2010.05.053

Tetrahedron Letters 51 (2010) 3762–3764
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Alcohol reduction of enamines
*
A. Gilbert Cook
Department of Chemistry, Valparaiso University, Valparaiso, IN 46383, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Primary or secondary alcohols will reduce enamines to their corresponding saturated amines when
heated in a microwave apparatus at a temperature of 160 °C for a period of one hour.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 April 2010
Revised 5 May 2010
Accepted 12 May 2010
Available online 20 May 2010
Keywords:
Enamines
Alcohols
Microwave
Reduction
Enamines are typically reduced to saturated amines either by
hydride transfer to a previously formed iminium salt or by catalytic
hydrogenation.1 The source of hydride ions can be from metal hy-
drides,2 formic acid,3 phosphorous acid,4 the Hantzsch ester,5 or
secondary amines.6
However, all the hydride reductions require the use of fairly
strong acids to form the iminium ion. This can be a problem for
acid-sensitive molecules. The catalytic hydrogenation involves
expensive catalysts which are not ‘green’.
The method of enamine reduction reported here does not in-
volve strong acid catalysis and does not use expensive metal cata-
lysts. Rather it uses inexpensive, green alcohols as a neutral
medium and reagent. For example, 1-(1-cyclohexen-1-yl)pyrroli-
dine (1) is reduced with 100% conversion to 1-cyclohexylpyrrol-
idine (2) by heating the enamine with methanol at 160 °C in a
microwave reactor7 for one hour (Scheme 1).
A wide variety of enamines and primary alcohols are reduced by
this method as shown in Table 1. Most secondary alcohols are less
effective than primary alcohols and tertiary alcohols are com-
pletely ineffective in reducing enamines as shown in Table 2. There
seems to be a correlation between the basicity of the enamine8 and
the ease of reduction by alcohols with the most basic enamine
being the most readily reduced.
reactor at 160 °C (Scheme 3). When ethanol-d was used, labeled
amines 3 and 4 are formed in 1:3 ratio with an overall 79% conver-
sion. This shows that protonation is the first step of the reaction
The large amount of 4 formed as compared to 3 shows that exten-
sive equilibration between the enamine and the iminium ion takes
place before the rate-determining hydride reaction occurs in the
second step. When ethanol-d6 was used, labeled amine 5 was
formed showing that the hydride transfer is the second, rate-deter-
mining step of the reaction. Further proof of this mechanism is that
there is an isotope effect in the second, rate-determining step of
the reaction. This isotope effect is shown by the fact that the two
reactions, one using normal ethanol and the other using ethanol-
d6 but identical enamines, under identical microwave, temperature
conditions produce different amounts of reduction products over
an identical period of time. The normal ethanol reaction produced
six times as much reduction product as the deuterated ethanol
reaction.
This alcohol reduction reaction is also stereospecific as shown
by the reduction of 2-N-hexamethylenimine[2.2.1]hept-2-ene (7)
with ethanol at 160 °C in a microwave apparatus to produce the
endo isomer of 2-N-hexamethyleniminobicyclo[2.2.1]heptane (8)
(Scheme 4). The product must be formed by exo addition of
The mechanism for the reaction is shown in Scheme 2. The sec-
ond step in this reaction mechanism involving a hydride transfer is
the rate-determining step. The proof for this reaction mechanism is
given by treating 1-(1-cyclohexen-1-yl)pyrrolidine (1) with etha-
nol-d and ethanol-d6 in separate experiments using the microwave
CH3OH
N
N
160°
C
microwaves
100 % conversion
2
1
* Tel.: +1 219 464 5389; fax: +1 219 464 5489.
E-mail address: Gil.Cook@valpo.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.053

A. Gilbert Cook / Tetrahedron Letters 51 (2010) 3762–3764
3763
Table 1
Microwave reductions of enamines using primary alcohols
Enamine
Xa
Alcohol
Temperature (C)
Time (h)
Reductionb (%)
1
1
Methanol
Benzyl Alcohol
160
160
1
1
100
100
X
1
2
4
4
3
Ethanol
Ethanolc
Ethanolc
Ethanol
Ethanol
160
160
160
160
210
1
1
1
3
1
79
68
13
26
15
Ethanolc
Ethanol
Ethanol
160
160
160
1
1
1
100
42
4
X
1
2
2
X
X
—
Ethanol
160
1
9
N
a
1 = pyrrolidine, 2 = hexamethylenimine, 3 = morpholine, 4 = piperidine.
Determined by GC/MS using Agilent 7890A GC with a Phenomenex Zebron ZB-5 30-meter column and Agilent 5975 MSD. The appearance of the enamine ‘parent ketone’
b
in the spectrum was assumed to come from hydrolysis of the enamine during the reaction by traces of water in the alcohol and was considered to be non-reduced enamine
when calculating the percent reduction.
c
Used Aldrich anhydrous ethanol with <0.005% water.
Table 2
H
N
CH CH OH
Secondary/tertiary alcohol reductions of 1-(1-cyclohexen-1-yl)pyrrolidine (1)
3
2
N
Alcohol
Reductiona,b (%)
Time (h)
160 °C
microwaves
7
8
t-Butanol
1-Octanol
2-Pentanol
2-Pentanol
2-Pentanol
(À)-Mentholc
0
35
2
8
36
100
1
5
1
6
0.5
1
Scheme 4.
Table 3
Thermo reduction of 1-(1-cyclohexen-1-yl)pyrrolidine (1) using ethanol
a
b
c
Microwave, 160 °C.
See footnote b of Table 1.
Microwave, 220 °C, cyclohexane solvent.
Temperature (C)
Time (h)
Reductiona (%)
25
25
78
78
78
20
96
2
18
42
0
<1
7
43
62
a
See footnote b of Table 1.
+
N
N
-
+
CH3CH2O
+
CH3CH2OH
hydride. The identity of this product was shown by comparison
with an authentic sample.9
Heating an enamine in a microwave reactor at 160 °C for one
hour with toluene solvent and no alcohol present produced no
reduction products. Allowing an enamine to stand in ethanol at
room temperature for four days produced essentially no reduction
product. When this ethanolic enamine solution was refluxed
(78 °C), it resulted in a 62% reduction of the enamine after 42 h
(see Table 3).
-
+
N
O
O
N
H
CH CH
3
+
H
CH
CH
3
All of the enamine reactants and amine products have been pre-
viously reported in the literature.
Scheme 2.
CD CD OD
3
2
N
CH CH OD
3
2
N
N
N
D
D
D
D
D
+
160°C
D
160 °C
D
microwaves
D
D
D
microwaves
5
4
3
1
Scheme 3.

3764
A. Gilbert Cook / Tetrahedron Letters 51 (2010) 3762–3764
5. Pandit, U. K.; Mas Cabre, F. R.; Gase, R. A.; de Nie-Sarink, M. J. J. Chem. Soc., Chem.
References and notes
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Automatic Temperature Control.
8. Cook, A. G.; Absi, M. L.; Bowden, V. K. J. Org. Chem. 1995, 60, 3169.
9. Cook, A. G.; Schulz, C. R. J. Org. Chem. 1967, 33, 473.
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ed.; Dekker: New York, 1988; Chapter 5; Pitacco, G.; Valentin, E. In The Chemistry
of Enamines, Part 2; Rapport, Z., Ed.; Wiley: New York, 1994. Chapter 17.
2. Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.; Stercho, Y. P. J. Org. Chem.
1983, 48, 3412.
3. Leonard, N. J.; Sauers, R. R. J. Am. Chem. Soc. 1957, 79, 6210.
4. Redmore, D. J. Org. Chem. 1978, 43, 992.