4688
H. Xu et al. / Tetrahedron Letters 49 (2008) 4687–4689
Encouraged by the results presented above, we next probed the
Route I
scope of the reaction with a variety of halogen-substituted aro-
matic aldehydes 1, stabilized carbanions, 2, and amines 3 (Table
1). All reactions were conducted in EtOH at 80 °C with MV irradia-
tion. In each case, smooth reactions occurred to generate desired
products 4 in high yields (72–90%) with short reaction times. Vari-
ations in the form of cyanoacetic acid esters/cyanoacetamides 2
and cyclic secondary amines 3 used in reaction with 4-fluorobenz-
aldehyde 1a had a limited effect on reaction yields (Table 1, entries
1–12). It is realized that when acyclic secondary and primary
amines were employed, a complicated reaction mixture was ob-
served. One possible reason is that generally higher reaction yields
are achieved for Knoevenagel condensation with cyclic secondary
amines than non-cyclic secondary and primary amines. More sig-
nificant was the observation that the MV-facilitated three-compo-
nent reactions could apply for much less reactive chloro- and
bromo-aromatic aldehyde substrates for SNAr reactions (entries
13 and 14). In these instances, the reaction occurred in good yields
(72% and 83%, respectively) in spite of relatively long reaction
times. However, no reactions were seen when the reaction was
performed under traditional heat conditions.
N
H
CN
F
F
3a
CN
+
OEt
Knoevenagel
reaction
CO2Et
2a
CHO
O
1a
5a
SNAr reaction
N
N
H
CN
OEt
4a
O
Route II
F
CN
S
NAr reaction
N
+
CHO
+
N
H
3a
CO2Et
CHO
1a
6a
2a
In the ‘one-pot’ transformation, two reaction pathways (routes I
and II) could be possible (Scheme 2). In route I, the Knoevenagel
condensation proceeds first and then is followed by the SNAr sub-
stitution. Alternatively, the SNAr process occurs prior to the Knoe-
venagel condensation (route II). To verify the reaction mechanism,
we conducted two experiments and found that route I was a likely
one. Treatment of pure preformed 5a, produced from reaction of 4-
fluorobenzaldehyde 1a with ethyl cyanoacetate 2a using Et3N as
catalyst, with piperidine in refluxing ethanol gave rise to the SNAr
product 4a in high yield.8 However, no reaction between 4-fluoro-
benzaldehyde 1a and piperidine was observed under the same
reaction conditions. The presumable reason for the Knoevenagel
condensation and then subsequent SNAr process is that the Knoe-
venagel condensation product (e.g., 5a) is more reactive than alde-
hyde 1a for the SNAr substitution due to its strong electron-
withdrawing ability in addition to resonance effect.
Knoevenagel
reaction
N
N
CN
3a
H
OEt
4a
O
Scheme 2. Reaction pathways.
In summary, we have developed a new microwave-assisted
three-component Knoevenagel-nucleophilic aromatic substitution
reaction of 4-halobenzaldehyde, cyanoacetic acid ester/cyanoacet-
amide, and cyclic secondary amines. The process affords one-pot
process for the domino formation of one carbon-carbon double
bond and one carbon–nitrogen bond. Taking the advantage of
microwave irradiation, reaction times can be significantly reduced
in high yields, and more significantly the less reactive 4-chloro and
bromo-benzaldehydes can effectively participate in the process.
Further expanding the scope of the powerful MV, assisted multi-
component reactions is underway in our laboratory.
Table 1
Scope of MV-facilitated three-component Knoevenagel/aromatic nucleophilic substi-
tution reactiona
Y
MV
Y
X
n = 0-1
CN
Z
5-10 min
Acknowledgment
N
+
CHO
+
CN
n = 0-1
N
H
EtOH
We are grateful for financial support from the National Science
Foundation of China (20572023).
Z
4
3
1a, X = F
2a, Z = CO2Et
1b, X = Cl 2b, Z = CO2Me Y = CH2 and O, NR
1c, X = Br 2c, Z = CONH2
References and notes
Entry
1 and 2
Amines 3
4
t (min)
Yieldb (%)
1. (a) For recent reviews of microwave-assisted synthesis, see: Ondruschka, B.;
Bonrath, W.; Stuerga, D. Microwaves in OrganicSynthesis, (2nd ed.) 2006, 1, 62.;
(b) Zhang, M.; Xu, X.; Zhao, Z.; Zhang, M. Huaxue Tongbao 2007, 70, 513; (c)
Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563; (d) Glasnov, T. N.; Kappe,
C. O. Macromol. Rap. Commun. 2007, 28, 395; (e) Baxendale, I. R.; Hayward, J. J.;
Ley, S. V. Comb. Chem. High Throughput Screening 2007, 10, 802; (f) Cravotto, G.;
Cintas, P. Chem. Eur. J. 2007, 13, 1902; (g) Strauss, C. R.; Varma, R. S. Top. Curr.
Chem. 2006, 266, 199; (h) Zhang, W. Top. Curr. Chem. 2006, 266, 145; (i) Kappe, C.
O. Chimia 2006, 60, 308.
2. For selected recent examples, see: (a) Sheibani, H.; Saljoogi, A. S.; Bazgir, A.
ARKIVOC 2008, 115; (b) Benjamin, E.; Hijji, Y. Molecules 2008, 13, 157; (c)
Sharma, A.; Mehta, V. P.; Van der Eycken, E. Tetrahedron 2008, 64, 2605; (d)
Kahveci, B.; Ozil, M.; Serdar, M. Heterocycl. Chem. 2008, 19, 38; (e) Li, J.; Ye, D.;
Liu, H.; Luo, X.; Jiang, H. Synth. Commun. 2008, 38, 567; (f) Wei, T.-B.; Zhang, Z.-
R.; Shi, H.-X.; Cui, W.-H.; Zhang, Y.-M. Youji Huaxue 2008, 28, 145; (g) Lu, Z.-P.;
Zhang, X.-Y.; Yang, H. Youji Huaxue 2008, 28, 89; (h) Panunzio, M.; Bandini, E.;
D’Aurizio, A.; Martelli, G.; Tamanini, E.; Xiao, S.-Y.; Xia, Z.-N. Youji Huaxue 2008,
28, 60; (i) Ollevier, T.; Nadeau, E. Tetrahedron Lett. 2008, 49, 1546; (j)
Hricoviniova, Z. Tetrahedron: Asymmetry 2008, 19, 204; (k) Besson, T.; Chosson,
E. Comb. Chem. High Throughput Screening 2007, 10, 903; (l) de la Hoz, A.; Diaz-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a,2a
1a,2a
1a,2a
1a,2a
1a,2a
1a,2a
1a,2b
1a,2b
1a,2b
1a,2c
1a,2c
1a,2c
1b,2a
1c,2a
Piperidine
Morpholine
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4a
4a
5
5
5
5
5
90
86
85
86
80
84
85
84
83
75
78
75
72
83
N-Methylpiperazine
Pyrrolidine
N-Ethylpiperazine
N-Phenylpiperazine
Piperidine
Morpholine
N-Methylpiperazine
Piperidine
5
10
10
10
5
5
5
Morpholine
N-Methylpiperazine
Piperidine
30
30
Piperidine
Reaction carried out in MeOH.
a
Unless specified, see Ref. 5 for detailed reaction procedure.
Isolated yield based crystallization without column chromatography.
b