Solvent-free mechanochemical and one-pot reductive benzylizations of malononitrile and 4-methylaniline using Hantzsch 1,4-dihydropyridine as the reductantt

Article abstract of DOI:10.1039/b502662h

The properties of Hantzsch 1,4-dihydropyridine, which possesses excellent reducibility, were investigated. The synthesis of benzyl malononitriles and anilines were also studied. Direct reductive benzylizations of malononitrile and 4-methylaniline by aromatic aldehydes were achieved using a Hantzsch 1,4-dihydropyridine as the reductant. It was observed that there is no need for the separation of the in situ generated benzylidene malononitriles and p-tolylamines.

Full text of DOI:10.1039/b502662h

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C O M M U N I C A T I O N
Solvent-free mechanochemical and one-pot reductive benzylizations
of malononitrile and 4-methylaniline using Hantzsch
1,4-dihydropyridine as the reductant†
Ze Zhang, Jie Gao, Jing-Jing Xia and Guan-Wu Wang*
Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
E-mail: gwang@ustc.edu.cn; Fax: (+86) 551 360 7864; Tel: (+86) 551 360 7864
Received 23rd February 2005, Accepted 14th March 2005
First published as an Advance Article on the web 4th April 2005
Under mechanical milling conditions, direct reductive
benzylizations of malononitrile and 4-methylaniline by
aromatic aldehydes were achieved using a Hantzsch 1,4-
dihydropyridine as the reductant.
Chemical hydrogenations of double bond-containing com-
pounds including imines, benzylidenemalononitriles and vari-
ous other a,b-unsaturated systems often involve the use of metal
catalysts1 or stoichiometric amount of metal hydrides.2 In these
cases there are some drawbacks, such as the use of expensive
and even toxic metals, relatively low chemoselectivity and so on.
To circumvent these problems one of the best alternatives is to
apply organoreductants, which have been arousing great interest
in recent years.3 As a typical example among these organoreduc-
Scheme 1
tants, Hantzsch 1,4-dihydropyridine (HEH), which possesses
vigorously at a rate of 1800 rounds per minute (30 Hz) at room
excellent reducibility, has been investigated to a great extent.4
But in most cases it was used as model of hydride-reduction
cofactor NAD(P)H to mimic biological reductions of various
unsaturated compounds. Tremendous efforts were made to study
mainly the mechanistic details of these systems5 and relatively
little attention has been paid to the application of HEH as a
reducing agent in organic synthesis. In recent years there have
been some developments in this field,6,7 especially with the most
recent applications in the selective reduction of a,b-unsaturated
aldehydes.3a,8 Although these attempts have achieved good to
excellent results, there are still some limitations, including the
use of organic solvents, the need of excessive HEH or protection
under an inert atmosphere and relatively long reaction times.
In the course of our study on mechanical organic synthesis9
we were inspired to perform these reactions using a mechanical
milling technique, which supplies a completely solvent-free and
thus environmentally friendly condition. Traditionally, benzyl
malononitriles and anilines were synthesized by the reduction
of benzylidene malononitriles and anilines, which should be
prepared in advance due to the susceptibility of the aldehydes to
common metal-containing reductants. In this communication,
we report a direct reductive benzylization process in which a
mixture of an aldehyde and malononitrile (or 4-methylaniline)
and is directly treated with Hantzsch 1,4-dihydropyridine in a
one-pot fashion, under mechanical milling conditions.
temperature for 90 min. The results are summarized in Table 1.
Table 1 Direct reductive benzylization of malononitrile by various
aromatic aldehydes using HEH 2 as the reductant
Product 3
R
Yield (%)a,(b)
3a
3b
3c
3d
3e
3f
4-Cl
4-Br
97 (82)
98 (83)
98 (87)
98 (86)
98 (86)
98 (71)
95 (54)
98 (72)
68 (—)
0
4-NO2
4-CN
3-NO2
2-NO2
3,4-Cl
2,4-Cl
H
3g
3h
3i
3j
4-N(CH3)2
a Isolated yield from direct separation of the reaction mixtures by
flash column chromatography over silica gel with petroleum ether–
ethyl acetate as the eluent. b Isolated yield from the following procedure:
the reaction mixtures were immersed in 20 mL of diluted hydrochloric
acid (5%) with the aid of ultrasonic irradiation, then the desired solid
products were collected by Bu¨chner filtration, washed with H2O and
dried in a desiccator.
We found that all the aldehydes were not reduced under these
conditions; that is, the reduction was completely selective for
aldehyde-derived benzylidene malononitriles. From Table 1 it
can be seen that in most cases the reactions afforded exclusively
the redox products 3 and 4 in nearly quantitative yields. The
desired products, benzyl malononitriles 3, were isolated from
direct separation of the reaction mixtures by flash column
chromatography. Most of them could also be obtained by
following a more straightforward and easy work-up procedure,
as shown in Table 1, which may be more practical without regard
to the relatively lower yields. Furthermore, this reaction system
exhibits a significant substituent effect, which can be easily
understood from the fact that the aldehydes bearing electron-
withdrawing groups show obviously higher reactivities than
The direct reductive benzylization of malononitrile
(Scheme 1) was investigated first. In a typical procedure, a
mixture of aldehyde 1 (0.5 mmol), malononitrile (0.5 mmol) and
Hantzsch 1,4-dihydropyridine 2 (0.51 mmol) was introduced,
together with a stainless ball of 7.0 mm diameter, into a stainless
jar (5 mL).The same mixture was also introduced into a second,
parallel jar. The two reaction vessels were closed and fixed on
the vibration arms of a ball-milling apparatus (Retsch MM200
mixer mill, Retsch GmbH, Haan, Germany) and were vibrated
† Electronic supplementary information (ESI) available: melting point
for compounds 3 and 5, and spectral data for compounds 3f–3h, 5g and
5h. See http://www.rsc.org/suppdata/ob/b5/b502662h/.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 1 7 – 1 6 1 9
1 6 1 7
©

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those without substituents or bearing electron-donating groups.
For example, benzaldehyde afforded only 68% of product 3i and
4-dimethylaminobenzaldehyde did not give any desired product.
It is worth pointing out that the Hantzsch 1,4-dihydropyridine
employed here also acted as a base to catalyze the Knoevenagel
condensation step, similar to that catalyzed by piperidine.10 To
confirm this point we have carried out controlled reactions
of aldehydes with malononitrile in the absence of and in the
presence of a catalytic amount (5 mol%) of HEH 2 under the
same conditions, which afforded only trace and quantitative
amount of benzylidene malononitriles, respectively.
To further investigate the reactivity of HEH 2 as a reducing
agent in organic synthesis, we extended its applications to imines.
However, the reaction hardly proceeded without the addition of
any additive. To improve this poorness, we have investigated the
addition of various Lewis acids. The catalytic effect of several
Lewis acids (25 mol%) on the one-pot mechanical reduction of in
situ generated imine (3-nitro-benzylidene-p-tolylamine) from 3-
nitrobenzaldehyde and 4-methylaniline with HEH 2 (Scheme 2)
for 90 min was examined to sort out the best catalyst, and the
results are listed in Table 2.
Scheme 3
Table 3 Direct reductive benzylization of 4-methylaniline by various
aromatic aldehydes using HEH 2 as the reductant
Product 5
R
Yield (%)a
5a
5b
5c
5d
5e
5f
3-NO2
4-Br
4-NO2
4-CN
4-Cl
2-NO2
2,4-Cl
3,4-Cl
H
98
96
95
96
94
95
97
98
62
0
5g
5h
5i
5j
4-N(CH3)2
a Isolated yield from direct separation of the reaction mixtures by
flash column chromatography over silica gel with petroleum ether–ethyl
acetate as the eluent.
It is known that Hantzsch 1,4-dihydropyridine 2 is prone
to oxidation even in the presence of air. On the other hand,
traditional reactions involving HEH 2 were most commonly
performed in organic solvents and the reaction time was very
long. Therefore, treatment of these reactions often used largely
excessive HEH or inert gases such as nitrogen and argon. In
the present protocol, all the reactions were performed under
solid-state conditions without any organic solvent at room
temperature, the reaction time was relatively short (90 min) and
1.02 molar equivalent of HEH is enough to promote the reaction
completely, even without protection by any inert gas.
In summary, we present here the first example of Hantzsch
1,4-dihydropyridine used in mechanochemical organic synthesis.
The present work has successfully developed a more straightfor-
ward method for the synthesis of benzyl malononitriles and
anilines. There is no need for the separation of the in situ gen-
erated benzylidene malononitriles and p-tolylamines and good
to excellent yields of benzylated products can still be achieved
in a one-pot process. Furthermore, the reductant Hantzsch 1,4-
dihydropyridine demonstrates a complete selectivity, for there
is no reduction of any other functional group such as aldehyde,
nitro or cyano groups. All of these advantages make this protocol
a promising and thus appealing alternative both in academic
research and in practical processes.
Scheme 2
Table 2 Catalytic activity of various Lewis acids in the reducion of
in situ generated 3-nitro-benzylidene-p-tolylamine using HEH 2 as the
reductant
Entry
Catalyst (25 mol%)
Yield (%)
1
2
3
4
5
6
7
8
9
None
Trace
52
48
98
28
34
37
88
39
CeCl3·H2O
NiCl2·6H2O
ZnCl2
CuSO4·5H2O
Cu(OAc)2·H2O
Co(OAc)2·4H2O
p-CH3–C6H4SO3H
H3BO3
It can be seen from Table 2 that all the additives can promote
the reaction to a certain extent, but it is obvious that ZnCl2 (entry
4) and p-toluene sulfonic acid (entry 8) demonstrate superior
catalytic activity among them. This result prompted us to select
ZnCl2 as the catalyst for further study; that is, we used ZnCl2 to
catalyze the direct mechanical benzylization of 4-methylaniline
by various aldehydes with HEH 2 as the reductant for 90 min
(Scheme 3).
The experimental procedure is similar to that of malononitrile
as discussed above, except that products 5 were obtained just by
column chromatography since they are more inclined to change
in the presence of HCl. As expected, very good results were
achieved and are summarized in Table 3. Here again, the same
significant substituent effect was observed, just as that observed
in the reactions of malononitrile.
Acknowledgements
We are grateful for the financial support from National Science
Fund for Distinguished Young Scholars (20125205), Fund for
Innovative Research Groups of National Science Foundation
of China (20321101) and Anhui Provincial Bureau of Human
Resources (2001Z019).
1 6 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 1 7 – 1 6 1 9

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Y. Kawai, N. Yamazaki, Y. Mikata and M. Okamura, J. Am. Chem.
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