An efficient microwave method for the synthesis of imines

Article abstract of DOI:10.1071/CH14659

A large variety of aryl and heterocyclic chiral and achiral imines can be generated simply, efficiently, and cleanly through the use of microwave irradiation and the use of a small amount of molecular sieve. Reactions are rapid and complete in a matter of minutes, and can be quantitative, reducing significantly the time and amount of solvents used in compound isolation and purification.

Full text of DOI:10.1071/CH14659

CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 844–848
Communication
http://dx.doi.org/10.1071/CH14659
An Efficient Microwave Method for the Synthesis of Imines
A
A
A B
,
Emily C. Border, Victoria L. Blair, and Philip C. Andrews
A
School of Chemistry, Monash University, Clayton, Vic. 3800, Australia.
Corresponding author. Email: phil.andrews@monash.edu
B
A large variety of aryl and heterocyclic chiral and achiral imines can be generated simply, efficiently, and cleanly through
the use of microwave irradiation and the use of a small amount of molecular sieve. Reactions are rapid and complete in a
matter of minutes, and can be quantitative, reducing significantly the time and amount of solvents used in compound
isolation and purification.
Manuscript received: 14 November 2014.
Manuscript accepted: 12 January 2015.
Published online: 4 March 2015.
Imines are highly useful precursors for the synthesis of sec-
ondary amines, chiral amines, and important biological mole-
cules such as alkaloids.[1] Traditionally imines are synthesised
by the condensation of an aldehyde or ketone with a primary
amine (Scheme 1), although there are many other variations in
the recent literature, including the oxidative coupling of amines
with primary alcohols in the presence of various catalysts,[2] the
reduction of nitro compounds,[3] and many other alternatives.[4]
The more traditional condensation reaction between a primary
amine and carbonyl compound generally involves stirring or
heating to reflux for extended periods to drive the equilibrium
forward, and often requires the use of materials such as
molecular sieves (MS), zinc chloride, alumina, CuSO4, titanium
chloride and apparatus such as a Dean–Stark apparatus.[5]
The use of microwave (MW) irradiation has improved the
efficiency and yields of many reactions since its introduction
into organic synthesis, often by reducing reaction times and the
need for solvents.[6] There have been a small number of
examples of microwave-assisted methods for the synthesis of
imines, where the general trend is solvent-free microwave
reactions in the presence of a catalyst.[7]
use of magnesium perchlorate as a catalyst.[11] Although these
methods are successful, reaction times, workup procedures, and
the use of expensive or dangerous materials make them less
desirable. Herein, we report an efficient and simple microwave
synthesis method for the synthesis of a large range of functio-
nalised imines.
By altering the reaction variables of time, temperature, and
solvent in a microwave reactor, an efficient synthesis has been
developedusingcommonlyfoundreagents withinthelaboratory.
This convenient method has led to the quantitative synthesis of a
large library of chiral and achiral imines in significantly reduced
times frames. The amine and aldehyde are reacted in a micro-
˚
wave reactor with 3 A molecular sieves in DCM at 508C (maxi-
mum of 300 W) for 10 min (Scheme 2). The reaction mixture is
filtered and the solvent removed to give, in often quantitative
yield, a product in which no further purification is required.
Table 1 compares the synthesis of 1a with previously
reported imine synthesis methods. It is clear that this new
method A has various synthetic advantages and improvements
compared with other pre-existing methods. For example: the use
of microwave irradiation significantly reduces reaction times
from days to minutes (methods A and B); no perchlorates, which
alone are hazardous due to their explosive nature when heating
is involved,[11] need to be used (method A versus D and E);
and no workup or purification steps are required unlike methods
B–E, where extraction, recrystallisation,[9] or distillation[10] is
necessary.
One of the current areas of interest within our group is chiral
secondary and tertiary amines derived from (S)-N-a-methyl-
benzylamine and their metallation chemistry with alkali metals.
In the process, the focus has shifted to a set of imines, (S)-N-
(methoxybenzylidene)-a-methylbenzylamines, due to their
similarities with (S)-N-(methylbenzyl)benzylamine which has
been studied in detail within our group.[8] Classical methods for
the synthesis of (S)-N-a-methylbenzylamine derived imines
include reaction with an aldehyde by stirring the reaction in
NH2
DCM, 3 Å MS,
[9]
˚
dichloromethane (DCM) and 4 A molecular sieves for 48 h,
300 W, 50ЊC,
heating in DCM for 30 min in the presence of K2CO3,[10] or the
10 min
N
ϩ
O
OMe
OH
H
O
1a ϭ p-OMe
1b ϭ o-OMe
1c ϭ m-OMe
RЈ
RЈ
R
H
R ϩ RЈNH2
N
H
R
N
ϪH2O
OMe
Scheme 1. Imine equilibrium.
Scheme 2. The microwave synthesis of 1a, 1b, and 1c.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

Efficient Microwave-Assisted Synthesis of Imines
845
Table 1. Comparison of the new method (A) with previous methods
(B–E) for the synthesis of 1a
Table 2. The library of imines synthesised, their reaction times, and
conversions
Method Catalyst
˚
Solvent Temp [8C] Time
Yield [%]
Amine
Aldehyde
Product, time, conversionA
A
A
B
C
D
E
3 A MS, MW
˚
4 A MS
DCM
DCM
DCM
DCED
DCED
50
10 min 98
1
2
PhCH(CH3)NH2
4-(MeO)-PhCH¼O
20–25
40B
48 h
30 min
8 h
86–96[9]
C [10]
–
100[11]
90[11]
N
K2CO3
O
Mg(ClO4)2
Mg(ClO4)2
20–25
84
10 min, 100 %
1 h
AMicrowave irradiation.
O
PhNH2
4-(MeO)-PhCH¼O
BHeated on a steam bath.
CYields not reported.
N
DDCE ¼ dichloroethane.
10 min, 100 %
O
To determine the versatility of this method, a range of
functionalised and unfunctionalised amines and aldehydes were
reacted as summarised in Table 2. In 26 of the 32 entries,
essentially quantitative conversion to the imine product was
achieved.
The general trend appears to be that the aldehydes that
possess a phenyl functionality work better than those without.
However, when the aldehyde was substituted with a strong
electron withdrawing group on the phenyl ring (entries 13–16
and 25–28) the reaction required longer reaction times.
Similarly, the presence of a heteroatomic group on the
aldehyde (entries 17–20 and 25–28), also requires longer reac-
tion times for higher conversion rates to be achieved. Interest-
ingly, with pyridine substituted aldehydes, particularly low
product conversions are seen, even after extended reaction times
and with higher temperatures, with the recovery of unreacted
starting products primarily isolated.
Looking into the literature, the most similar microwave
methods reported would be that of Varma et al.[7b] or Bekdemir
and Efil.[12] Both reactions are solvent-free, with either K-10
clay or catalytic amounts of b-ethoxyethanol (b-EE) used,
respectively (Scheme 3). While solvent-free reactions are desir-
able, most still require extraction and separation from the
catalyst, which ironically involve solvent. In the case of our
method (A), using a solvent is beneficial as it permits the easy
workup of the reaction mixture, simply via filtration and the
removal of the solvent. However it is also beneficial that
uniform heating throughout the reaction mixture is able to occur
giving a greater energy transfer,[13] a likely contribution to why
these imines can be synthesised in a quick manner in the
presence of a common dehydrating agent. Overall our method
demonstrates short reaction times, with minimal workup proce-
dures. The versatility of this simple method as a highly useful
tool for the synthesis of aryl-based imines is highlighted by the
variety of successful imines synthesised.
3
4
5
CH2¼CHCH2NH2 4-(MeO)-PhCH¼O
N
10 min, 100 %
HO
N
HO(CH2)2NH2
4-(MeO)-PhCH¼O
2-(OH)-PhCH¼O
O
10 min, 100 %
PhCH(CH3)NH2
N
HO
10 min, 100 %
6
7
PhNH2
2-(OH)-PhCH¼O
N
OH
10 min, 100 %
CH2¼CHCH2NH2 2-(OH)-PhCH¼O
N
OH
10 min, 100 %
HO
N
8
9
HO(CH2)2NH2
2-(OH)-PhCH¼O
2-(Br)-PhCH¼O
HO
10 min, 100 %
PhCH(CH3)NH2
N
Br
10 min, 100 %
Following on from the success of the aldehydes, the reaction
was next extended to ketones, notoriously less reactive and
10 PhNH2
2-(Br)-PhCH¼O
N
harder to convert to imines compared with aldehydes.[14]
A
Br
series of reaction conditions were trialled using cyclohexanone
and (S)-N-a-methylbenzylamine as the two starting materials, as
summarised in Table 3. Of all the conditions tested the most
10 min, 100 %
˚
suitable reaction conditions were found to be 3 A molecular
11 CH2¼CHCH2NH2 2-(Br)-PhCH¼O
sieves, 808C, in EtOH for 10 min. An array of reactions was
conducted using these conditions; however, no other ketone
reaction proceeded to give any conversion to the final imine
product. Full details of all tested reactions are provided in the
Supplementary Material.
N
Br
10 min, 100 %
(Continued)

846
E. C. Border, V. L. Blair, and P. C. Andrews
Table 2. (Continued)
Table 2. (Continued)
Amine
12 HO(CH2)2NH2
Aldehyde
Product, time, conversionA
HO
Amine
Aldehyde
Product, time, conversionA
2-(Br)-PhCH¼O
25 PhCH(CH3)NH2
2-(CF3)-PhCH¼O
N
N
Br
F3C
10 min, 100 %
N
30 min, 100 %
13 PhCH(CH3)NH2
4-(NO2)-PhCH¼O
4-(NO2)-PhCH¼O
26 PhNH2
2-(CF3)-PhCH¼O
N
NO2
CF3
30 min, 100 %
30 min, 100 %
NO2
14 PhNH2
27 CH2¼CHCH2NH2 2-(CF3)-PhCH¼O
N
N
CF3
30 min, 97 %
30 min, 100 %
NO2
15 CH2¼CHCH2NH2 4-(NO2)-PhCH¼O
HO
N
28 HO(CH2)2NH2
29 PhCH(CH3)NH2
30 PhNH2
2-(CF3)-PhCH¼O
C4H4S-2-CH¼O
C4H4S-2-CH¼O
N
F3C
30 min, 100 %
30 min, 100 %
HO
N
16 HO(CH2)2NH2
17 PhCH(CH3)NH2
4-(NO2)-PhCH¼O
C5H5N-2-CH¼O
NO2
S
N
30 min, 100 %
30 min, 100 %
N
S
N
N
30 min, 11 %
30 min, 100 %
18 PhNH2
C5H5N-2-CH¼O
N
N
N
S
31 CH2¼CHCH2NH2 C4H4S-2-CH¼O
N
30 min, 7 %
30 min, 100 %
S
19 CH2¼CHCH2NH2 C5H5N-2-CH¼O
32 HO(CH2)2NH2
C4H4S-2-CH¼O
N
N
HO
30 min, 43 %
30 min, 100 %
HO
ADetermined by 1H NMR spectroscopy.
20 HO(CH2)2NH2
21 PhCH(CH3)NH2
C5H5N-2-CH¼O
N
N
30 min, 12 %
Method 1:
K-10 clay,
O
NH2
MW, 3 min
H
N
CH3CH¼CHCH¼O
ϩ
N
30 min, 89 %
N
Method 2:
β-EE,
MW, 1 min
HO
HO
Method 1: 96 %
Method 2: 97 %
22 PhNH2
CH3CH¼CHCH¼O
Scheme 3. Microwave synthesis of imines in the literature: via K-10
clay[7b] or catalytic b-ethoxyethanol.[12]
30 min, 61 %
N
In general, the synthesis of imines from ketones is much
more difficult than from aldehydes. This is due to ketones
having a lower reactivity and thus requiring higher tempera-
tures, longer reaction times, and often the use of catalysts.[14]
Even though this microwave method doesn’t give a full conver-
sion, the reaction can be done in 10 minutes, followed by a
distillation to obtain the pure compound.
23 CH2¼CHCH2NH2 CH3CH¼CHCH¼O
30 min, 99 %
HO
24 HO(CH2)2NH2
CH3CH¼CHCH¼O
N
30 min, 96 %
(Continued)

Efficient Microwave-Assisted Synthesis of Imines
847
Table 3. Systematic approach to improving the reaction of a ketone
with an amine, with the most successful highlighted
Acknowledgements
We would like to thank the Australian Research Council for financial
support.
Temp [8C]
Solvent
Time [min]
ConversionA [prod : smB]
References
50
50
50
70
70
70
80
80
80
DCM
DCM
DCM
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
10
20
30
10
20
30
10
20
30
28 : 72
62 : 38
66 : 34
49 : 51
64 : 36
41 : 59
78 : 22
63 : 37
58 : 42
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