Primary 1,2-diamine catalysis III: An unexpected domino reaction for the synthesis of multisubstituted cyclohexa-1,3-dienamines

Article abstract of DOI:10.1039/c0ob00089b

The first organocatalyzed multicomponent domino reactions of aryl ketones, aldehydes and malononitrile were carried out successfully to afford multisubstituted cyclohexa-1,3-dienamines in satisfactory yields.

Full text of DOI:10.1039/c0ob00089b

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Primary 1,2-diamine catalysis III: an unexpected domino reaction for the
synthesis of multisubstituted cyclohexa-1,3-dienamines†
Junfeng Wang, Qin Li, Chao Qi, Yi Liu, Zemei Ge* and Runtao Li*
Received 6th May 2010, Accepted 18th July 2010
DOI: 10.1039/c0ob00089b
The first organocatalyzed multicomponent domino reactions
of aryl ketones, aldehydes and malononitrile were carried
out successfully to afford multisubstituted cyclohexa-1,3-
dienamines in satisfactory yields.
Scheme 1 Multicomponent reactions of aryl ketones.
Creation of highly functionalized and diversified molecules1
from simple starting materials while combining economic2 and
environmental aspects3 is highly desirable in modern organic
chemistry and still remains a great challenge.4 From this per-
spective, organocatalyzed multicomponent reactions (MCRs)
involving domino processes must be competent to come close
to reaching this ideal goal. MCRs5 meet the economic desires,
for they can avoid time-consuming and costly processes for
purification of various precursors and tedious steps of protection
and deprotection of functional groups.6 And organocatalyzed
reactions are always environmentally friendly processes with the
benefits of easy operation, ready availability, and low toxicity of
catalysts.7 Hence, domino reactions catalyzed by organocatalysts
have emerged as a powerful tool in organic synthesis during
the past few years.8 Herein, we wish to report the first primary
1,2-diamine catalyzed three component domino reactions of
aryl ketones, aldehydes and malononitrile for the construction
of multifunctional useful molecules cyclohexa-1,3-dienamines 3
(Scheme 1).
81%) (Scheme 2, 1),9 because we have used this catalytic system
successfully in the asymmetric Michael addition reactions of
chalcones with cyclopentanone10a and 2(5H)-furanones,10b respec-
tively. However, it was surprising to find that under the chiral
1,2-diaminocyclohexane-hexanedioic acid catalyst, the reaction of
acetophenone 1a with alkylidenemalonitrile 5a did not produce
the expected asymmetric Michael addition product 6a. On the
contrary, a racemic cyclohexa-1,3-dienamine 3a was obtained as
the main product. Meanwhile, using ethanediamin-acetic acid as
the catalyst also led to the same result (see ESI†).
Compounds 3 belong to typical acceptor–donor–accept sys-
tems, which are the basis for artificial photosynthetic systems,
materials presenting semiconducting or nonlinear optical proper-
ties and molecular electronic devices.11 Both 3 and their aroma-
tization products 4 are useful intermediates for building blocks
for cyclophanes to create a large molecular cavity and host–
guest complex.12 In addition, their biaryl unit is represented in
several types of compounds of current interest including natural
products, polymers, advanced materials, liquid crystals, ligands
and molecules of medicinal interest.12,13 Therefore, numerous
reports have described their synthesis.11–14 However, most methods
involved cumbersome procedures, costly reagents and low yields,12
such as preformation of the precursors arylidenemalonoditriles 5
is always necessary. The reaction between malononitrile and a,b-
unsaturated ketones could also gave compounds 4, however the
yields were very poor.12,14c,15 Furthermore, compounds 3 are prone
to aromatization by the elimination of hydrogen cyanide affording
compounds 4. In some instances the driving force of aromatiza-
tion is so enhanced that the intermediate diaryl cyclohexadiene
derivatives 3 cannot be isolated and the reaction affords only
Our original aim was to explore whether the chiral 1,2-
diaminocyclohexane-hexanedioic acid system could catalyze the
asymmetric Michael addition reactions of aryl ketones with
alkylidenemalonitrile 5, which has been reported by Chen’s group
using a chiral primary amine 9-amino-9-deoxyepicinchonine as
catalyst in middle yields (48–85%) and enantioselectivities (71–
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing,
100191, P. R. China. E-mail: Lirt@mail.bjmu.edu.cn, Zmge@bjmu.edu.cn;
Fax: +86-10-82716956; Tel: +86-10-82801504
† Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/c0ob00089b
Scheme 2 Reactions of acetophenone 1a with alkylidenemalonitrile 5a.
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Table 1 Catalyst and solvent screening for the domino reactions
Table 2 Three component domino reactions of aryl ketones, aldehydes
and malononitrile
Entry
Cat.
Solvent
Time/h
3a Yield (%)d
Entrya
R1
R2
Time/h
Yield (%)b
a
1
—
II
MeOH
MeOH
MeOH
MeOH
MeOH
CHCl3
THF
72
15
15
15
15
36
36
36
36
trace
90
complex
complex
complex
trace
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
15
12
12
10
10
15
18
18
14
13
12
18
12
12
12
32
3a, 90
3b, 92
3c, 95
3d, 89
3e, 91
3f, 88
3g, 86
3h, 90
3i, 96
3j, 93
3k, 93
3l, 91
3m, 89
3n, 95
3o, 95
3p, 86
2b
3c
4c
5c
6b
7b
8b
9b
2-ClPh
3-ClPh
4-MePh
Me(CH2)9
Ph
2-ClPh
3-ClPh
3-BrPh
4-ClPh
4-MePh
Ph
III
IV
V
Ph
II
II
II
II
4-MePh
4-MePh
4-MePh
4-MePh
3-ClPh
3-ClPh
4-FPh
4-FPh
3,4-diClPh
3,4-diClPh
3,4-diMeOPh
complex
trace
DMSO
H2O
e
—
9
a No catalyst used; b The loading of HOAc is 40 mol%; c The loading of
HOAc is 20 mol%; d Isolated yields of the corresponding product; e No
product 3a observed.
10
11
12
13
14
15
16
3-FPh
Ph
3-ClPh
Ph
4.14e Just recently, Yan et al. reported a multicomponent domino
reaction of malononitrile, benzaldehyde and ethyl a-bromoacetate
(or chloroacetonitrile) in refluxing acetonitrile, affording 2,6-
dicyanoanilines 4 in 31–53% yields.16 However, only very few
domino reactions are known for the synthesis of compounds 3
from alkyl ketones with moderate yields,17 and unfortunately, aryl
ketones employed in these one-pot multicomponent reactions are
unprecedented.
Inspired by the unexpected formation of 3a and Yan’s multi-
component domino reaction,16 we reasoned that the synthesis of
multisubstituted cyclohexa-1,3-dienamines 3 would be achieved
through organocatalyzed multicomponent reactions of aryl ke-
tones, aldehydes and malononitrile.
Therefore, the reaction of acetophenone 1a with benzaldehyde
2a and malononitrile was selected as the model reaction to
examine various amine-acid catalysts and solvents. As listed in
Table 1, except ethanediamine, all the other simple primary amine,
secondary amine and tertiary amine catalysts gave unsatisfactory
results, affording a complex mixture of at least four products (Table
1, entries 2–4). The screening of different solvents was also carried
out using 20 mol% of ethanediamine and 40 mol% of acetic acid as
catalyst at room temperature (Table 1, entries 1 and 5–8). Among
the screened solvents, only the protic polar solvent MeOH gave
the valuable result (Table 1, entry 1).
Subsequently, the substrate scope of aryl ketones and aldehydes
was studied under the optimized reaction conditions (20 mol% of
ethanediamine and 40 mol% of HOAc as the catalyst, methanol as
solvent and the reactions were carried out at room temperature).
Much to our delight, all the reactions were carried out smoothly
in excellent yields (Table 2). The properties and position of the
substituents on the aromatic ring for aryl ketones and aromatic
aldehydes do not have obvious influence on the reaction rate and
yields (Table 2, entries 2–4, 6–16). Meanwhile, alkyl aldehyde
was also investigated giving the corresponding cyclohexa-1,3-
a All the reactions were conducted at room temperature; b Isolated yields
of the corresponding products.
dienamine derivatives in satisfactory yield (Table 2, entry 5). What
is more exciting is that the pure products could be obtained by
simple filtration and/or recrystallization after reaction (except 3e,
which is obtained as a colorless oil).
Two possible pathways (I and II) based on enamine and
hydrogen bonding activation of substrates were proposed for the
formation of compounds 3 as shown in Scheme 3. Inspired by
Chen’s work,9 aryl ketone donors were proposed to be activated
through enamine intermediate A, which then reacted with alkyli-
denemalonitrile 5 to form product 6. Then under the catalytic
system, 6 reacted with malononitrile to form the key intermediate
B, which then transformed easily to 3 (mechanism-I). However, the
proposed mechanism-I did not seem to make sense, for compound
6a was not observed in this process monitored by TLC and the
reaction of 6a and malononitrile could not be facilitated under
the catalytic system (Scheme 3). Excluding the enamine activation
of substrates, the hydrogen bonding between primary amine18
and cyano group might be a reasonable explanation (mechanism-
II). For only the primary diamine catalyst could catalyze the
reaction effectively, therefore, we proposed that both substrates
5 and 8 were linked together through hydrogen binding by the 1,2-
diamine catalyst. Moreover, using the mechanism-II, we could also
understand why the racemic product 3a was obtained under the
chiral 1,2-diaminocyclohexane-hexanedioic acid catalyst, because
the long distance between the reacting centers and the chiral
centers makes the steric effect unimportant.
In order to explore the action of acid additive, the domino
reaction of 1a, 2a and malononitrile was carried out, using only
20 mol% ethanediamine as the catalyst (Scheme 4). Without
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Scheme 4 The domino reaction catalyzed only by ethanediamine.
acid additive, though the reaction still proceeded smoothly, the
aromatization product 4a appeared in 21% yield accompanied by
an unidentified by-product after 8 h. Obviously, the acid additive
HOAc in the reaction functioned to inhibit the elimination of
HCN efficiently (the aromatization process).
In conclusion, primary 1,2-diamine was proven to be efficient in
activating ketone substrates once more. The first organocatalyzed
multicomponent domino reactions of aryl ketones, aldehydes
and malononitrile were conducted to form multi-substituted
cyclohexa-1,3-dienamines 3 in satisfactory results. The possible
mechanisms were proposed.
This research was supported by the funds of National Nat-
ural Science Foundation of China (No. 20972005), and Na-
tional Key Technology R&D Program; Contract grant number:
2007BAI34B00).
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4242 | Org. Biomol. Chem., 2010, 8, 4240–4242
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The Royal Society of Chemistry 2010
©