New multicomponent cyclization: Domino synthesis of pentasubstituted pyridines under solvent-free conditions

Article abstract of DOI:10.1039/c0ob01258k

An efficient methodology for the synthesis of highly functionalized pyridine derivatives starting from readily available common reactants has been developed under microwave irradiation and solvent-free conditions. The new domino reaction enables successfu

Full text of DOI:10.1039/c0ob01258k

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New multicomponent cyclization: domino synthesis of pentasubstituted
pyridines under solvent-free conditions†
Bo Jiang,a Xiang Wang,a Feng Shi,a Shu-Jiang Tu*a and Guigen Li*b
Received 28th December 2010, Accepted 5th April 2011
DOI: 10.1039/c0ob01258k
An efficient methodology for the synthesis of highly func-
tionalized pyridine derivatives starting from readily available
common reactants has been developed under microwave irra-
diation and solvent-free conditions. The new domino reaction
enables successful assembly of five new r bonds including
two C–N bonds in a one-pot operation. A new mechanism
has been proposed, which involves a novel reaction and se-
quence consisting of deprotonation–imine formation–anionic
carbonyl addition.
new practical multicomponent syntheses serving for medicinal,
industrial and agricultural research.8–10
In the past several years, our group and several others have
developed a series of multicomponent domino reactions that
provide easy access to useful functionalized multiple ring struc-
tures of chemical and pharmaceutical interest.11–14 For example, a
new four-component domino reaction was established providing
an easy access to multifunctionalized quinazoline derivatives11a
and tricyclo[6.2.2.01,6]dodecanes.11b Recently, we have also found
that the domino reaction of Meldrum’s acid, aromatic aldehy-
des and electron-rich heteroaryl-amines in the aqueous phase
under microwave irradiation (MW) led to the formation of
multifunctionalized spiro{[1,3]dioxane-pyridine}-4,6-diones with
high chemo- regio- and stereoselectivity and good yields.11d As a
continuation of our research devoted to the development of multi-
component domino reactions,11–13 in this communication we would
like to report another new four-component domino reaction for
the synthesis of polyfunctionalized pyridine derivatives that are of
chemical and biomedical importance. The reaction was achieved
by reacting malononitrile, cycloketones and ammonium acetate
in a one-pot operation under microwave irradiation (MW) in the
absence of any strong acids or metal catalysts (Scheme 1).
The search for efficient formations of multifunctionalized complex
products by using simple reactants has been an active objective
in organic synthesis.1 In this regard, multi-component domino
reactions that are very useful for the total syntheses of natural
products and versatile building blocks have become increas-
ingly attractive because of their green characteristics of atom-
economy, bond-forming economy and structural economy.2–5
These reactions can avoid time-consuming and costly processes for
purification of various precursors and tedious steps of protection
and deprotection of functional groups. In addition, these reactions
are environmentally friendly, and often proceed with excellent
chemoselectivities.6 Therefore, the design of new selective domino
reactions is a continuing challenge at the forefront of organic
chemistry.
It is well-known that malononitrile can serve as an exceptionally
versatile compound; it has been extensively used as a reactant
or intermediate in organic synthesis. It exhibits unique reactivity
due to the fact that the strongly electron-withdrawing cyano
group can activate the methylene CH2 (pKa = 11.2); its cyano
group can be a good leaving group for substitution reactions
with its polar multiple bonds being suitable for nucleophilic
additions.7 Both methylene group and cyano group can participate
in condensation reactions to give a variety of addition products
and heterocyclic compounds.8 This exceptional behavior further
makes malononitrile an important candidate for the design of
Scheme 1
When a mixture of malononitrile, cyclopentanone and an
excess amount of ammonium acetate was heated in HOAc at
150 ◦C for 30 min under microwave irradiation, the pyridine
derivative, 3a (2,4-diamino-6-(4-cyclopentylidenebutyl)pyridine-
3,5-dicarbonitrile) was readily obtained in 57% yield. This product
1
has been fully characterized by H- and 13C-NMR, HR-MS and
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal Univer-
sity, Xuzhou 221116, Jiangsu, P. R. China. E-mail: laotu@xznu.edu.cn;
Fax: +86-516-83500065
IR spectral analysis. Furthermore, it has been unambiguously
determined by X-ray structural analysis as shown in Fig. 1.
Encouraged by this initial result, we then made many efforts
on optimizing reaction conditions. As shown in Table 1, the
use of ammonium acetate allowed the direct conversion of
cyclopentanone 1a to give the corresponding polysubstituted
bDepartment of Chemistry and Biochemistry, Texas Tech University, Lub-
bock, Texas 79409-1061, USA. E-mail: guigen.li@ttu.edu; Fax: +1 806-
742-3015
† CCDC reference number 806791. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob01258k
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was determined to be 2.3 : 1, but the major isomer needs further
investigation.
The unusual feature of forming 3a–3f is shown by the fact that
two cycloketones were simultaneously converted to a polysub-
stituted pyridine structure, one of them unexpectedly occurred
via ring opening. It should be pointed out that this phenomenon
has not been observed in known cyclization reactions of mal-
ononitrile during the formation of carbocyclic and heterocyclic
compounds.15–18 The use of other cyclic ketones and their func-
tionalized counterparts for this domino reaction will be studied in
due course.
Fig. 1 The ORTEP drawing of 3a.
Similar to our previous four-component domino process,7 the
present reaction also showed the following attractive characteris-
tics: (1) the environmentally friendly process in which water is the
major by-product without additional use of organic solvent during
the reaction process; (2) the convenient work-up which only needs
simple filtration since the products directly precipitate out after
the reaction is finished19–21 and when its mixtures are diluted with
cold water; (3) readily available starting materials of malononitrile,
cycloketones, and ammonium acetate; (4) high atom-economy and
bond-forming economy. Moreover, the two C O bonds and one
C–C bond of cycloketones were cleaved and five new s bonds were
formed. The novelty of the present domino reaction is shown by
the fact that multiple chemical bonds breaking and forming were
simultaneously achieved in an intermolecular manner and in a
one-pot operation.
Table 1 Optimization of reaction conditions
Entry
Solvent
equiv
Time/min
Yield/%
1
2
3
4
5
HOAc
DMF
Ethylene alcohol
Water
Solvent-free
6.0
6.0
6.0
6.0
6.0
30
35
32
30
30
57
48
42
37
81
Table 2 The domino synthesis of compounds 3 at 150 ◦
C
On the basis of the resulting products, a reasonable mechanism is
proposed as shown in Scheme 2 and represented by the formation
of 3a. During the ring closure domino process, the condensation of
malononitrile with cyclopentanone is the initial step to form inter-
mediate A. The [4 + 2] cycloaddition of two molecules of A occurs
and leads to the formation of spirocyclic intermediate B¢, to which
ammonia was added to give C. Intramolecular Michael addition
of C leads to the formation of D, followed by isomerization of the
imines which results in the ring-opening of 1,2-dihydropyridine
intermediate E which is subjected to dehydration to give the final
product 3a. Interestingly, several similar structures to D have been
proposed in our previous work in which final products were also
confirmed by X-ray structural analysis.11a–b Pleasantly, an isomeric
3a, 30 min, yield 81%
3b, 30 min, yield 87% 3c, 36 min, yield 76%a
3d, 40 min, yield 67%
3e, 45 min, yield 52% 3f, 48 min, yield 41%
a Yield of the mixture of two diastereoisomers.
pyridines 3a in a yield of 81% under solvent-free and microwave
irradiation conditions (Table 1, entry 5). Other polar solvents, such
as DMF, ethylene alcohol and water gave lower yields of 37%–57%
under MW irradiation for 30 min (Table 1, entries 1–3). The use of
more than 6 equiv of ammonium acetate did not result in higher
chemical yields.
We next investigated the substrate scope of this domino reaction
by subjecting a series of cycloketones 1b–f to the reactions with
malononitrile 2 in the presence of ammonium acetate under
the optimal conditions. During the domino process of forming
compounds 3, it was interesting to observe that the smaller
cycloketones such as cyclobutanone 1b and cyclopentanones
1a, 1c showed faster reaction rates and led to higher chemical
yields (76%–87%, Table 2) than their larger counterparts such as
cyclohexanones 1d, 1e and 1f that led to slower reaction rates
and lower chemical yields (41%–67%, Table 2). Based on 1H-
NMR analysis (see spectrum in Supporting Information), the
diastereoselectivity of 3c derived from 3-methylcyclopentanone 1c
Scheme 2
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intermediate 3aB has been successfully isolated and can support
the above proposed mechanism. The reaction of isolated 3aB with
ammonium acetate under similar conditions resulted in the ring-
opening product 3a in 83% yield (Scheme 3). It should be pointed
out that the tandem ring-opening from intermediate D is truly
novel sequence which will be further studied in our labs.
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Scheme 3
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Conclusion
In summary, a new multicomponent domino reaction of two moles
of malononitrile with two moles of cycloketones and NH4OAc
has been developed. The new reaction can be easily performed
within a short period under microwave irradiation and solvent-free
conditions to afford highly substituted 2,4-diaminopyridine-3,5-
dicarbonitriles. A logical mechanism has proposed and supported
by a successful isolation of a key intermediate. In addition, a
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Acknowledgements
We are grateful to financial support from the National Science
Foundation of China (Nos. 21072163 and 21002083), Science
Foundation in Interdisciplinary Major Res. Project of XZNU (No.
09XKXK01), Doctoral Research Foundation of Xuzhou Normal
Univ. (XZNU, No. 10XLR20), Robert A. Welch Foundation (D-
1361), and NIH (R03DA026960).
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