Highly efficient microwave-accelerated preparation of β-ketoimines

Article abstract of DOI:10.1016/j.tetlet.2007.09.143

We present here a new and efficient methodology for the β-ketoimine ligand with microwave heating system. The new method showed faster reaction rates, higher yields, and selectivities of the desired compounds in the absence of solvents.

Full text of DOI:10.1016/j.tetlet.2007.09.143

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8281–8284
Highly efficient microwave-accelerated
preparation of b-ketoimines
Dong Hwan Lee,a Sang-Eon Park,a Kyuho Cho,b Younsoo Kim,b
Taimur Athara and Ik-Mo Leea,*
aDepartment of Chemistry, Inha University, 253 Yonghyundong, Namku, Incheon 402-751, Republic of Korea
bSamsung Electronics Co., San #24 Nongseo-dong, Giheung-gu, Yongin City, Gyeonggido 449-711, Republic of Korea
Received 14 August 2007; revised 15 September 2007; accepted 25 September 2007
Abstract—We present here a new and efficient methodology for the b-ketoimine ligand with microwave heating system. The new
method showed faster reaction rates, higher yields, and selectivities of the desired compounds in the absence of solvents.
Ó 2007 Elsevier Ltd. All rights reserved.
The application of microwaves, as an efficient heating
source for organic reactions,1 was recognized in the
mid 1980s. Over 3500 papers describing successful reac-
tions with dramatically enhanced reaction rates have
been published. High yields, clean reactions, employ-
ment of milder and less toxic reagents and solvents,
and simple experimental procedures are known advanta-
ges of this heating technology and this methodology has
been considered one of the most important tools in the
green organic synthesis.2 This technology has also been
adopted successfully in the solid-phase organic synthesis
(SPOS), regarded as one of the key tools for combinato-
rial chemistry for generating libraries of small organic
molecules.3
dense memory required in this field incited the develop-
ment of new processes such as metalloorganic chemical
vapor deposition (MOCVD) or atomic layer deposition
(ALD). Many of the stable and volatile precursors suit-
able to these processes contain b-diketonate analogs.
Modification of this type of ligands introduced various
kinds of b-ketoiminate or b-diketiminate ligands and
complexes of special groups including group 2 was
extensively reviewed.5 The advent of single-site catalysts
with non-cyclopentadienyl (Cp) ligands for olefin poly-
merization has extended the application of these ligands.
Asymmetric analogues have shown the potential for the
asymmetric synthesis.
However, further application of these ligands, especially
b-ketoiminates with bulky substituents has been
deterred by low overall yields and long reaction time.
It has been shown by Varma et al.6,7 that condensation
reactions between primary and secondary amines or
sulfonylamines and aldehydes or ketones are substan-
tially accelerated by microwaves under solvent-free
conditions. Analogous condensation reactions with
hydrazine8 or carboxylic acids9 have been reported to
proceed with more enhanced efficiency on microwave
heating. With help of domestic microwave oven,
Hamelin et al. prepared some b-ketoimines from acetyl-
acetone and high boiling amines,10 and Braibante et al.
also reported the synthesis of b-enamino carbonylic
compounds from cyclic or acyclic, a-chloro-substituted
b-dicarbonyl compounds and amines or ammonium
acetates in the presence of K-10 montmorillonite with
high yields.11
Various polydentate ligands have been used to increase
the stability of the complexes by anchoring the coordi-
nation sites and chelate effect. Among these polydentate
ligands, b-diketonate ligands have drawn much interest
due to their unique resonance stability and they have
been investigated with virtually every metal and metal-
loid in the periodic table. These extensive works have
been well reviewed in as early as late 70s.4 Recent
revived attention to this research field can be mostly
attributed to the explosive development in the informa-
tion industry. Very high integrated circuit and highly
Keywords: Microwave-assisted synthesis; b-Ketoimine, b-diketone,
amines, condensation reaction.
*
Corresponding author. Tel.: +82 32 860 7682; fax: +82 32 867
5604; e-mail: imlee@inha.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.143

8282
D. H. Lee et al. / Tetrahedron Letters 48 (2007) 8281–8284
In connection of our previous efforts to prepare various
derivatives of b-ketoiminates to the application of noble
MOCVD precursors and polymerization catalysts,12 we
have tried to find a way to prepare these ligands,
especially with bulky substituents, more efficiently.
Herein we report that the preparation of b-ketoimines
assisted by microwave heating can result in higher yields
and shorter reaction times than conventional condensa-
tion reactions.
microwave cavity (CEM Co., Discover). When micro-
wave was irradiated at a power of 150 W or 300 W,
the temperature was raised from room temperature to
130 °C. Once the predetermined temperature was
reached, the reaction mixture was held at that tempera-
ture for 5 min. After allowing the mixture to cool to
room temperature, the reaction vessel was opened
and then the yield and selectivity were confirmed by
1H NMR (Varian Unity Inova 400 (400.265 MHz) or
Varian Gemini 2000 (199.976 MHz)).
Typical preparative procedures are as follows: In a
10-mL glass tube were placed CH3C(O)CH2C(O)CH3
(1.0 g, 10 mmol), (2-NH2CH2)Pyridine (1.10 g, 1.0
mmol), HCl (2–3 drop), and a magnetic stir bar. The
vessel was sealed with a septum and placed into the
As shown in Table 1, microwave-assisted preparation
proceeds much faster with high yield and selectivity irre-
spective of the natures of b-diketones or amines used.
However, 1,3-diphenyl-1,3-propandione (runs 14–20),
Table 1. Comparison between microwavea and conventional synthetic methods (GM)b
R1
R2
R1
R2
microwave
+
H2N
R3
130oC , 150W
O
HN
O
O
R3
Run
b-Diketone
Amine
R3
GM
Microwave
Selectivity (%)
R1
R2
Me
Yield (%)
Yield (%)
1
2
3
4
5
6
7
8
9
Me
(CH2)2OH
9013a
8913a
6413b
9013c
9513c
7013c
6613d
7013d
8813d
—
—
—
—
7813c
—
88
90
81
98
98
95
96
89
92
77
93
87
96
83
81
78
95
85
91
82
60*
68*
65*
76*
93
93
97
87
76
59
100
92
99
94
91
100
100
100
100
100
100
100
95
100
100
100
100
100
100
100
100
92
CH2CH(Me)OH
C(Me)2CH2OH
(CH2)2OMe
(CH2)3OMe
o-CH2(C6H4)OMe
2-(CH2)pyridine
2-(CH2)2pyridine
CH(Me)CH2OMe
p-PhOMe
CHMe2
CMe3
(CH2)2Me
(CH2)3OMe
CH2CH(Me)OH
CH(Me)CH2OMe
2-(CH2)pyridine
2-(CH2)2pyridine
o-CH2(C6H4)OMe
2-Me-6-OMe–Ph
(CH2)2OH
CH2CH(Me)OH
2-(CH2)pyridine
2-Pyridine
(CH2)2OH
CH2CH(Me)OH
(CH2)2OMe
CH(Me)CH2OMe
(CH2)3OMe
2-(CH2)pyridine
(CH2)2OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Ph
Ph
3013c
6613d
3413d
5113c
5313c
—
90
100
100
100
100
100
100
100
100
100
100
95
t-Bu
i-Pr
t-Bu
i-Pr
3.613b
—
—
8413b
8513b
82
81
CF3
Ph
CF3
Me
4113c
—
80
—
—
3313c
8913b
7813e
100
100
100
100
100
CH2CH(Me)OH
2-(CH2)pyridine
(CH2)2OH
t-Bu
Me
CH2CH(Me)OH
a Molar ratio b-diketone (10 mmol), amine(11 mmol), reaction time: 5 min, temperature: 130 °C, microwave power: 150 W, no solvent, isolated yield.
Selectivity: [b-ketoimine]/([b-ketoimine] + [b-diketimine])determined by 1H NMR.
b General organic synthesis of several steps.
* Reaction time: 1 h, 10 equiv of pyridine.

D. H. Lee et al. / Tetrahedron Letters 48 (2007) 8281–8284
8283
2,6-tetramethyl-3,5-heptadione (TMHD) (runs 21–24),
or hexafluoroacetylacetone (runs 29–30) showed lower
yields than acetylacetone (runs 1–13). It appears that
some electronic effects (generally, lower yields with elec-
tron withdrawing substituent on b-diketones) may work
in the first two cases but steric effect may be the reason
for the lower yield in the TMHD cases. Meanwhile,
almost quantitative yields were obtained in the cases
of 2,6-dimethyl-3,5-heptadione (runs 25–28) and the
steric effect on the yield is doubtful. It is worth reminding
that reaction time is 1 h in the TMHD reactions but it is
only 5 min in other ones. For the steric effect by the sub-
stituents of amines, it is not easy to find the trends from
the experimental results; with acetylacetone two methyl
groups attached to the a-carbon of the hydroxyalkyl-
amines reduced the yield (from 85% to 65%) significantly
(runs 1 and 3) but for simple alkylamines, steric bulki-
ness induces erratic results (93%, 87%, 96% for i-Pr,
t-Bu, n-Pr, respectively) (runs 11–13) or a minor change
was induced for alkoxyalkylamines (runs 4 and 6). The
effect by the substituent on b-carbon appears to be
negligible (runs 1, 2 and 25, 26) but in some cases, signif-
icant effect was observed (runs 31 and 32). With 2,6-di-
methyl-3,5-heptadione, one methyl group is enough to
reduce the yield by 10% (runs 27 and 28), while with
1,3-diphenyl-1,3-propandione, the presence of one
methyl shows less effect (runs 14 and 16). The effect of
alkyl chain length also appears to be erratic. Moreover,
dissymmetric b-diketones give b-ketoimines where
amines are introduced to the side of less bulky substi-
tuent, Me (runs 31–35), which were confirmed by
NOE experiments.
The reason for the lower yield except steric factor in the
TMHD reactions cannot be proposed yet. However, as
mentioned before, substitution of t-Bu with i-Pr in
b-diketones greatly improve the yield and reaction time.
Volatility of b-diketones may be another reason. Since
the pressure reaction cell with a screw sealed lid was
not employed, evaporation of b-diketones after absorp-
tion of microwave radiation may occur. Even though
the boiling points of acetylacetone, 1,3-diphenyl-1,3-
propandione, hexafluoroacetylacetone, TMHD, and
2,6-dimethyl-3,5-heptadione are quite different (140 °C,
219–221 °C (18 mmHg), 70–71 °C, 72–73 °C (6 mmHg)
and 66 °C (8 mmHg), respectively), more volatile (or
Table 2. Preparation results with various experimental factorsa
microwave
O
HN
+
NH2
N
O
O
N
Run
Amine (equiv)
1.0
HCl
Power (W)
T (°C)
Time (min)
Yield (%)
Selectivityb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
No
60
100
150
130
130
60
80
100
130
5
74
82
22
35
48
36
68
92
91
78
94
86
91
84
96
78
88
98
95
91
43
80
95
74
88
99
97
100
100
100
100
100
100
100
98
93
90
99
90
1
2
5
10
20
5
150
200
130
200
300
150
60
100
150
200
300
150
99
90
1.1
1.2
130
130
5
5
100
100
99
100
100
95
100
100
100
100
100
100
100
1.0
Yes
60
80
100
130
5
1
2
5
5
150
a Molar ratio b-diketone (11 mmol = 1.1 equiv), amine (10 mmol = 1.0 equiv), HCl (0.2 mmol), isolated yield.
b Selectivity: [b-ketoimine]/([b-ketoimine] + [b-diketimine]) determined by 1H NMR.HCl: 16 M aqueous solution.Conventional synthesis: EtOH,
80 °C, HCOOH, 24 h, isolated yield: 66%.

8284
D. H. Lee et al. / Tetrahedron Letters 48 (2007) 8281–8284
low bp) b-diketones still produce the product much
higher yield in much less time. Volatility of b-diketones
after absorption of microwave radiation may not be
determined by their boiling point only. In the TMHD
reactions, much more amines were left and significant
amount of TMHD was solidified on the surface of watch
glass, which is placed on top of the reaction flask and
cooled by dry ice after irradiation for 1 h even though
equal equivalents of reactants were used. In these cases,
10 equiv of pyridine or triethylamine are used to get
significant amounts of corresponding b-ketoimines. The
role of extra amines is not clear but formation of ammo-
nium salts between amines and b-diketones may be
expected and volatility can be reduced. Braibante et al.
also used the same strategy to improve the yield of reac-
tion employing low boiling amines.11 He used ammo-
nium acetates for amines to obtain b-ketoimines with
improved yields. However, no peak assignable to this
Supplementary data
Spectroscopic data for all new compounds prepared.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.09.143.
References and notes
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6284; (b) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman,
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1665–1692; (e) Kappe, C. O.; Stadler, A. Microwaves in
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salt in the H NMR spectrum of the product between
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(g) Microwaves in Organic Synthesis; Loupy, Andre, Ed.;
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In Table 2, effects of various reaction factors are sum-
marized. The effect of reaction time on the yield was
monitored and it was found that yield increased with
the increase of reaction time up to 5 min but slowly
decreased after that time (150 W, 130 °C). The yields
also increased with the increase of microwave power
until 150 W and decreased again with further increase
of power but small differences in yields indicate that
the effect of microwave power may be not significant.
However, this effect depends on the amount of amines.
When 1.0 equiv of amine is used, 150 W is the optimal
power but 200 W is the optimal power with 1.2 equiv
of amines. Generally addition of HCl (0.2 mmol, 16 M
aqueous solution) enhanced the yields significantly in
all the temperature ranges tested and the yield increased
with the temperature but the effect of temperature above
the optimal one (130 °C) is negative. Addition of more
amines resulted in higher yield and slightly excess b-di-
ketones have been used for the easy purification of the
products.
10. Texier-Boullet, F.; Rechsteiner, B.; Hamelin, J. Tetra-
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In summary, various b-ketoimines were obtained in the
absence of solvent but with the aid of microwave in
much less reaction time with higher yields. It is found
that this method can be applicable irrespective of the
nature of b-diketones and amines.
13. (a) Doherty, R. J.; Errington, N.; Housley, J.; Ridland,
W.; Clegg, M. R. J. Organometallics 1999, 18, 1018–1029;
(b) Lim, S. K. M.S. Thesis, Inha University (2001); (c)
Hwang, Y. J. M.S. Thesis, Inha University (2002); (d) Lee,
D. H. M.S. Thesis, Inha University (2004); (e) Fustero, S.;
Torre, M. G.; Pina, B.; Fuentes, A. S. J. Org. Chem. 1999,
64, 5551–5556.
Acknowledgments
Authors show their appreciation for the financial sup-
port of Samsung Electronics Co. (2005–2006) and T.
Athar thanks for the Brain Pool Fellow (2006).