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DOI: 10.1002/asia.201000310

Multicomponent Reactions for the Synthesis of Heterocycles

Bo Jiang,[a] Trideep Rajale,[b] Walter Wever,[b] Shu-Jiang Tu,*[a] and Guigen Li*[b]

2318  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2010, 5, 2318 – 2335
 Abstract: Multicomponent domino reactions (MDRs)
serve as a rapid and efficient tool for the synthesis of ver-
satile heterocycles, particularly those containing structural
diversity and complexity, by a one-pot operation. These
reactions can dramatically reduce the generation of chem-
ical wastes, costs of starting materials, and the use of
energy and manpower. Moreover, the reaction period can
Introduction
Heterocycles constitute the largest diversity of organic mole-
cules of chemical, biomedical, and industrial significance.[1–3]
They widely exist in numerous natural products, such as vi-
tamins, hormones, antibiotics, alkaloids, herbicides, and
dyes.[2] They are also among the most frequently encoun-
tered scaffolds in numerous drugs and pharmaceutically rel-
evant substances.[3] In the past several decades, a significant
number of efforts have been made on the discovery and de-
velopment of more efficient pharmaceuticals, pesticides, in-
secticides, rodenticides, and weed killers by following well-
studied natural models and biochemical pathways in living
cells.[2] In addition, a series of libraries consisting of hetero-
cycles have been successfully established for the structure-
activity-relationship studies (SAR) for drug design and syn-
thesis.[3] Meanwhile, the diversity-oriented synthesis (DOS)
continues to be an area of importance at the interface of or-
ganic synthesis and chemical biology.[4] While DOS plays an
important role in searching for new bioactive small mole-
cules with functional and stereochemical diversity,[5] more
efficient multicomponent domino reactions (MDRs) for the
synthesis of a series of heterocycles, particularly functional-
ized multiheterocycles, have been in high demand.
In the past several years, the development of new multi-
component domino reactions has become an active and
challenging topic in modern organic chemistry;[1] they can
readily provide greater atom-economic access to a diverse
spectrum of compounds and their libraries for screening. A
MDR can be defined as the process by which three or more
reactants are assembled into a structure with functional di-
versity and complexity in a one-pot operation without
adding any reactants or changing conditions during the
whole reaction process.[6] Noticeably, MDRs show the syn-
thetic advantages over conventional reactions in regard to
[a] Dr. B. Jiang, Prof. Dr. S.-J. Tu
School of Chemistry and Chemical Engineering
Xuzhou Normal University
Xuzhou 221116, Jiangsu, (P. R. China)
Fax: (+ 86)-516-83500065
E-mail: laotu@xznu.edu.cn
[b] T. Rajale, W. Wever, Prof. Dr. G. Li
Department of Chemistry and Biochemistry
Texas Tech University
Lubbock, TX 79409-1061 (USA)
Fax: (+ 1) 806-742-1289
E-mail: guigen.li@ttu.edu
Chem. Asian J. 2010, 5, 2318 – 2335  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
be substantially shortened. This Review covers recent ad-
vances on multicomponent domino reactions for the con-
struction of five-, six-, and seven-membered heterocyclic
skeletons and their multicyclic derivatives.
Keywords: domino reactions · green chemistry · heterocy-
cles · microwave irradiation · multicomponent reactions
simplicity, efficiency, selectivity, convergence, and atom-
economy.[7] The mechanisms of multicomponent domino re-
actions are often complex and consist of many continuous
steps. Ideally, all or most steps during multicomponent reac-
tions (MCRs) processes would reach reversible equilibriums
with the last step being irreversible, leading to the final
products. Furthermore, multicomponent domino reactions
are preferred to not have the need of organic solvents for
which one reactant directly serves as the reaction media, or
they can take place simply in water. In these cases, the prod-
ucts could precipitate out from the reaction mixture, which
enables purification simply by filtration and washing without
the need of chromatography or recrystallization. To this day,
several excellent review articles on MCRs or MDRs have
been published.[8–9] In the present review, we summarize the
MDRs for the synthesis of heterocycles that have mainly ap-
peared in the past two years.
Construction of Five-Membered Heterocycles
Heterocycles with One Heteroatom
Five-membered heterocycles bearing one heteroatom are
abundant in nature and are known for their diverse biologi-
cal properties.[10] Among these derivatives, pyrroles, furans,
and thiophenes exhibit a wide range of applications as ver-
satile pharmacophores and precursors for the synthesis of
natural products.[2] An interesting synthesis of these hetero-
cycles by MDRs has been recently achieved by reacting fu-
maryl chloride with primary amines and alkyl acetoacetate
as reported by Alizadeh and co-workers (Scheme 1).[11] This
multicomponent cyclocondensation was performed under
solvent-free conditions at room temperature to afford penta-
substituted pyrroles 1 in 70–85 % chemical yields.
The group of Pan and Wu developed the synthesis of iso-
indolinones 2 with high diastereoselectivity (diastereomeric
excess (de) up to 99 %) in 32–67 % yields through a multi-
Scheme 1.
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component reaction of o-phthalaldehyde, N-alkyl/aryl-sub-
stituted urea, and an aromatic aldehyde in the presence of a
catalytic amount of trimethylsilyl chloride (TMSCl) at ambi-
ent conditions (Scheme 2).[12] Other syntheses involve the
Scheme 2.
reaction of 2-benzylidenemalononitrile with aldehydes and
amino acids to yield 4-phenylpyrrole-3-carbonitriles 3 in re-
fluxing toluene (Scheme 3)[13] and the reaction of 1,3-dike-
Shu-Jiang Tu was born in 1957 in Jiangsu
(China) and received his B.Sc. in 1983.
He was appointed as Assistant Professor
at the Xuzhou Normal University in 1999
and was promoted to full Professor in
2003. His current interests are the devel-
opment of new synthetic methods, green
chemistry, and microwave multicompo-
nent syntheses.
Guigen Li was born in Jiangsu Province,
P.R. China. He obtained B.Sc. and M.S.
degrees in China. He received his PhD
degree at the University of Arizona (with
Prof. Victor J. Hruby). He did his post-
doctoral research at the Scripps Research
Institute (with Prof. K. Barry Sharpless).
He joined the Department of Chemistry
and Biochemistry at Texas Tech Universi-
ty in 1997 as an Assistant Professor and is
currently Professor. His research interests
are focused on: the discovery of new
chiral and achiral reagents and methodol-
ogies, asymmetric synthesis and catalysis,
and bioorganic and medicinal chemistry
by the use of the principles of organic
chemistry on molecular level.
Abstract in Chinese:
2320 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
S.-J. Tu, G. Li et al.
Scheme 3.
tones with aldehydes and amines to afford polysubstituted
pyrroles 4 (28 examples) with high regioselectivity
(Scheme 4).[14] Good to excellent yields (75–98 %) have
been achieved by using a low-valent titanium promoter at a
Scheme 4.
Bo Jiang was born in 1981 in Jiangsu
(China). He received his PhD in 2010
from the Suzhou University under the su-
pervision of Prof. Shu-Jiang Tu and Prof.
Guigen Li. His research interests include
multicomponent reactions, domino reac-
tions, and the innovation of synthetic
methods.
Trideep Rajale received his M.Sc. (Organ-
ic Chemistry) degree from the University
of Pune (India) in 2002 and M.S. (Phar-
maceutical Sciences) from the University
of Montana in 2010. He is currently pur-
suing his PhD under the guidance of
Prof. Guigen Li at Texas Tech University.
His research interests include asymmetric
synthesis and catalysis, multicomponent
domino reactions, and chiral phosphonyl
imine chemistry.
Walter Wever was born in 1985 in Guatema-
la City (Guatemala). He received his Bache-
lors of Science in Chemistry at Texas Tech
University in 2008. He is currently pursuing
his PhD degree in Organic Chemistry under
the supervision of Prof. Guigen Li at Texas
Tech University. His research projects in-
clude asymmetric catalysis, chiral phosphon-
yl imine chemistr, and microwave-assisted
multicomponent domino reactions.
Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles
fast reaction rate; the reaction can be completed within
15 min to afford highly functionalized pyrroles. Hashemi
et al. recently reported the synthesis of 2-alkyl-5-aryl-
(1H)pyrrole-4-ol derivatives 5 by reacting b-dicarbonyl com-
pounds with arylglyoxals in the presence of ammonium ace-
tate in water at room temperature (Scheme 5).[15]
Scheme 5.
The mono- or bis(aminomethylated) pyrroloindoles 6 (or
7) were obtained in moderate to excellent yields through
the controlled Mannich-type reaction and cyclization of 4,6-
diethynyl-1,3-phenylenediamine or its pyridine congener
with paraformaldehyde and secondary amines
(Scheme 6).[16] The domino reaction catalyzed by CuI was
performed in toluene/dioxane (1:1) at 80 8C to give pyrrolo
derivatives. These synthetic methodologies provide a power-
ful tool for the divergent preparation of pyrroloindole and
dipyrrolopyridine derivatives.
Scheme 6.
There are 30 examples of polysubstituted dihydropyrroles
8 synthesized by Jiang et al. in 60–98 % yields by using
easily available but-2-ynedioates, amines, and aldehydes at
room temperature or at 70 8C (Scheme 7).[17] Based on the
effects of different substrates, additives, reaction times, and
temperatures, two different pathways were proposed, for
which one involves a domino hydroamination/nucleophilic
addition/amidation–cyclization process and another under-
Scheme 7.
Chem. Asian J. 2010, 5, 2318 – 2335  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
goes a hydroamination/amidation/intramolecular cyclization/
imine–enamine tautomerization sequence resulting in tetra-
and pentasubstituted 9, respectively. In addition, the in vitro
biological screening against HIV-1 has shown that 22 of
these dihydropyrrole analogues exhibited significant activity
with IC50 values in the micromolar range (38–58 mm).
Chebanov et al. investigated the multicomponent reac-
tions of 3-amino-1,2,4-triazoles/5-aminotetrazole with phe-
nylpyruvic acids and aromatic aldehydes by using conven-
tional thermal heating, ultrasonification, and microwave die-
lectric heating. Two different reaction pathways for these cy-
clocondensations were established depending on the temper-
ature regime and building-block selection. The reaction of
the starting materials at room temperature proceeds by for-
mation of an azomethine intermediate, ultimately providing
triazolopyrimidinecarboxylic acids of type 10. At high tem-
peratures, the multicomponent cyclocondensation of the
same building blocks proceeds through a different pathway
yielding pyrrolones of type 9 (Scheme 8).[18]
Scheme 8.
Furans, another class of heterocycles, are versatile phar-
macophores possessing a variety of biological activities.[19]
Furans are generally prepared from 1,4-dicarbonyl com-
pounds by using acid catalysts. Furans can also be synthe-
sized through a multicomponent reaction in a one-pot oper-
ation. However, because of their sensitivity to acids, the syn-
thesis of furans remains a challenge. With this in mind, Ali-
zadeh et al. reported a simple isocyanide-based multicompo-
nent synthesis of bis(aminofuran)bicinchoninic amide
derivatives 11. The reaction of isocyanides with dialkyl ace-
tylenedicarboxylates and bicinchoninic acid (BCA) was car-
ried out in MeCN/THF at 25 8C for 36 h (Scheme 9).[20]
Later on, Esmaeili et al. successfully synthesized highly
functionalized g-spiroiminolactones 12 through a three-com-
ponent reaction of benzofuran-2,3-dione derivatives with di-
alkyl acetylenedicarboxylates and alkyl isocyanides in re-
fluxing CH2Cl2 (Scheme 10).[21] In this reaction, the ester
carbonyl group of the benzofuran-2,3-dione derivative is in-
corporated into a two-atom assembling unit to yield the de-
sired compounds in 55–75 % yields. This reaction provides
the first example of an ester group participating in an isocy-
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Scheme 9.
Scheme 10.
anide-based multicomponent process. In addition, the isocy-
anide-based multicomponent reaction of isocyanides with di-
alkyl acetylenedicarboxylates and acetic anhydride in
CH2Cl2 at room temperature produces furan-3,4-dicarboxy-
lates 13 in 47–60 % yields (Scheme 11).[22]
Scheme 11.
Wang and co-workers presented an efficient methodology
for the oxidative addition reaction of various aldehydes with
5,5-dimethylcyclohexane-1,3-dione and 1,3-indandione to se-
lectively afford spiro-dihydrofuran 14 and cyclopropane 15
derivatives, promoted by molecular iodine and dimethylami-
nopyridine (DMAP) under mechanical milling conditions
(Scheme 12).[23] The products (23 examples) were obtained
in good to excellent yields (60–92 %). Various aromatic al-
dehydes with substituents exhibiting different electronic
properties reacted smoothly and efficiently under the pres-
ent conditions to afford the corresponding dihydrofuran
products in good to excellent yields. The aldehyde with an
electron-withdrawing group gave a higher yield than that
Scheme 12.
2322 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
S.-J. Tu, G. Li et al.
bearing an electron-donating
group. Aliphatic aldehydes and
heteroaromatic aldehydes were
also tolerated in this reaction.
Thiophenes are of considera-
ble interest because of their di-
verse range of biological and
physical properties. The general
synthetic approach to these het-
erocycles involves functionali-
zation at the a- and b-positions of the sulfur atom in the
preconstructed thiophene nucleus[24] or through the con-
struction of a thiophene ring from appropriately substituted
open chain precursors.[25] The latter has become more attrac-
tive for its general applicability in the attainment of more
complicated substitution patterns.[26] Recently, Yan et al. de-
scribed the multicomponent reaction of 1,3-thiazolidine-
dione with malononitrile and aromatic aldehydes in the
presence of different organic amines, which selectively pro-
vided dihydrothiophene 16 and spirocyclohexano-1,3-thia-
zole 17 derivatives in 10–59 % yields (Scheme 13).[27] Secon-
Scheme 13.
dary amines, such as pyrrolidine, piperidine, morpholine,
and dimethylamine, and primary amines, such as benzyla-
mine, can well result in dihydrothiophene derivatives 16. Ar-
omatic aldehydes, with either electron-donating or -with-
drawing substituents, showed similar reactivity and efficien-
cy for this synthesis. Bulky diethylamine, diisopropylamine,
and 1,4-diazabicycloACHTUNGRE[2.2.2]octane yielded spirocyclohexano-
1,3-thiazole 17. This reaction provides an effective and con-
venient synthetic strategy for the construction of dihydro-
thiophene and spirocyclohexano-1,3-thiazole scaffolds, albeit
the yield is relatively low. The same authors reported a simi-
lar version of dihydrothiophene 18 by using aromatic
amines instead of secondary amines, which was further oxi-
dized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
in CH3CN to generate thiophene derivatives (Scheme 14).[28]
Heterocycles with Two Heteroatoms
The imidazoles, pyrazoles, oxazoles, isoxazoles, and thiazoli-
dinones, which contain two heteroatoms, are an important
class of heterocycles that display many important pharmaco-
logical properties and play crucial roles in some biochemical
Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles
Scheme 14.
processes.[29] Many methods for imidazole synthesis have ap-
peared in the literature, including a hetero-Cope rearrange-
ment,[30] four-component condensation of arylglyoxals, the
combination of primary amines, carboxylic acids, and isocya-
nides on Wang resin,[31] the reaction of N-(2-oxo)-amides
with ammonium trifluoroacetate,[32] the use of 1,2-amino al-
cohols in the presence of PCl5,[33] and the combination of di-
ketones, aldehydes, amines, and ammonium acetate.[34] Re-
cently, Tu and Lis groups established a concise and efficient
four-component domino approach to highly substituted 2-
(2’-azaaryl)imidazoles 19 under solvent-free and microwave-
irradiation conditions.[35] The four-component reaction offers
several advantages, including a broad scope of substrates for
which a wide range of common commercial aromatic alde-
hydes and heteroaryl nitriles can be used with shorter reac-
tion times (15–34 min). The desired products were obtained
in good to excellent chemical yields without the tedious
workup isolations. A new mechanism involving an umpo-
lung has been proposed for this reaction (Scheme 15).
Scheme 15.
Imidazolines are considered as privileged structural func-
tionalities owing to their presence in a majority of biologi-
cally active compounds, as well as their immense role in
asymmetric synthesis as chiral auxillaries and chiral re-
agents. Li and co-workers have established a direct three-
component electrophilic reaction of a,b-unsaturated ketones
and esters without the use of any metal catalysts. The mech-
anism involving the formation of an aziridinium ion as an in-
termediate has been proposed to explain the resulting regio-
and stereoselectivity.[36] Li and Pan have recently reported a
method for an efficient diamination of alkenes for the syn-
thesis of substituted imidazolines.[37] The CuI–PPh3-catalyzed
reaction in which N,N-dibromo-p-toluenesulfonamide serves
as a nitrogen/halogen source produced substituted imidazo-
lines 20 in modest to good yields (50–80 %) with excellent
regio- and stereoselectivity (Scheme 16). The scope of the
reaction can be extended to a variety of olefins, including
a,b-unsaturated ketones, a,b-unsaturated esters, and simple
alkenes.
Chem. Asian J. 2010, 5, 2318 – 2335  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 16.
Zhu and co-workers have reported that upon heating a
mixture of 2-aminopyridine (2-aminopyrazine or 2-amino-
pyrimidine), aromatic aldehyde, and imidazoline-2,4,5-trione
under solvent-free conditions afforded imidazoACHTUNGRE[1,2-a]pyri-
dine derivatives 22 in excellent yields. The one-pot multi-
component reaction was performed at 200 8C for 5 min, pro-
ducing the desired compounds (17 examples) in 92–97 %
yields (Scheme 17).[38]
Scheme 17.
The synthesis of pyrazoles via [3+2] atom fragments has
been well investigated by Katritzky and co-workers. In this
method, b-diketones or their derivatives are condensed with
hydrazine to form the five-membered ring.[39] The titanium-
catalyzed three-component coupling of a primary amine, an
alkyne, and isonitrile followed by treatment with hydrazines
afforded pyrazoles 22, as reported by Odoms group. Modi-
fications on the catalyst resulted in good control of regiose-
lectivity for some of the substrates (Scheme 18).[40]
Scheme 18.
Recently, Orru and co-workers have described a synthesis
of 2-substituted oxazoles 23 and 2H-2-imidazolines 24 by
using a multicomponent reaction of amines, aldehydes, or
ketones and a-acidic isocyano amides or esters
(Scheme 19).[41] By optimizing the reaction conditions, the
product formation can be fully controlled and directed
quantitatively to the desired heterocyclic scaffold. They
found that AgI (or CuI) catalysis produces 24, whereas ap-
plication of a Bronsted acid (NEt3·HCl) and/or use of an
aprotic solvent (DMF) can selectively yield corresponding
23. This method results in considerable chemical diversity
showing four functional regions in two distinct scaffolds.
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Scheme 19.
The same group presented a similar approach to dihydroox-
azolopyridines 25 through a multicomponent reaction of iso-
cyano dihydropyridones with aldehydes and amines
(Scheme 20).[42]
Scheme 20.
Thiazolidinones have been conveniently synthesized by a
three-component condensation of a primary amine, an alde-
hyde, and a mercaptoacetic acid.[43] Favi and co-workers de-
scribed a new three-component synthesis of 5-hydrazinoal-
kylidene rhodanine derivatives 26 by starting from aliphatic
primary amines, carbon disulfide, and 1,2-diaza-1,3-dienes
(Scheme 21; DIPEA = N,N-diisopropylethylamine).[44] The
Scheme 21.
authors optimized the reaction of benzylamine with carbon
disulfide and 1,2-diaza-1,3-diene at room temperature in
THF without the use of any base. The best yields of the de-
sired product were achieved when the starting components
were used in the ratio 1.5:1/3. The reaction proceeds well in
both the solution and solid phase. Similarly, a simple and
highly efficient one-pot synthesis of 2-thioxo-1,3-thiazolidin-
4-ones 27 through the multicomponent condensation of a
primary amine with carbon disulfide and fumaryl chloride in
water was also described by Alizadeh et al. (Scheme 22).[45]
Scheme 22.
2324 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
S.-J. Tu, G. Li et al.
The reaction afforded 2-thioxo-1,3-thiazolidin-4-ones in
good yields at room temperature.
Anderluh et al. presented a fast and straightforward
three-component synthesis of 2-amino-5-alkylidene-thiazol-
4-ones 28 (Scheme 23).[46] In this synthesis, aromatic alde-
Scheme 23.
hydes were subjected to the reaction with rhodanine and
primary or secondary amines under solvent-free conditions
to produce excellent yields of the desired products. Since
the reaction was performed under microwave irradiation,
the reaction time was substantially shortened and the
workup was much easier.
Heterocycles with Three and Four Heteroatoms
The synthesis of triazoles and tetrazoles has been receiving
considerable attention for the past several decades.[47] The
importance of these heterocycles has been addressed in sev-
eral fields, such as material science, chemical biology, and
medicinal chemistry. A three-component Pd-catalyzed syn-
thesis of 2-allyl-1,2,3-triazoles has been reported recently.[48]
Ackermann et al. developed an elegant modular synthesis of
fully substituted 1,2,3-triazoles 29 through a chemo- and re-
gioselective one-pot, four-component coupling of alkynes
with sodium azide (Scheme 24).[49] This protocol is anticipat-
ed to find extensive applications as it allows for the use of
alkyl- and aryl-substituted alkynes.
Scheme 24.
The three-component copper(I)-catalyzed cycloaddition
of alkynes with sodium azide and formaldehyde to yield 2-
hydroxymethyl-2H-1,2,3-triazoles 30 was reported by Fokin
and co-workers (Scheme 25).[50] The hydroxymethyl triazoles
Scheme 25.
Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles

are versatile synthetic precursors that allow an easy access

to a wide variety of triazole derivatives.
For the multicomponent production of tetrazoles, Srihari
et al. recently demonstrated the synthesis of 1,5-disubstitut-
ed tetrazole 31 (17 examples) by the use of Baylis–Hillman
acetates, TMS azide, and arylnitrile (Scheme 26).[51] Excel-

Scheme 27.

Scheme 26.

lent yields were achieved by performing the reaction at

70 8C under solvent-free conditions in the presence of tetra-
butylammonium fluoride (TBAF) as the catalyst. Interest-
ingly, some resulting tetrazoles have been found to be a
TNF-a inhibitor candidate.

Construction of Six-Membered Heterocycles
Heterocycles with One Heteroatom
Six-membered N-heterocycles are of immense interest as
building blocks in organic and medicinal chemistry.[2]
Among them, pyridines are the most basic structural motifs;
they are found in numerous natural products and biological-
ly active compounds.[3] Many synthetic methodologies for
the synthesis of pyridines have been reported, which include
the condensation of a,b-unsaturated ketones with malononi-
trile in the presence of ammonium acetate[52] and [4+2] or
[3+3]-type ring forming reactions.[53] Despite the numerous
synthetic methodologies available in the literature, new effi-
cient methods for pyridine synthesis are still in demand. Re-
cently, Huangs group has developed a new multicomponent
reaction of arynes with isocyanides and terminal alkynes to
afford good to high yields and selectivity of products.[54] Dif-
ferent reaction pathways were suggested, which depend on
the appropriate reaction conditions; these include the ratio
of the reagent and solvents. It should be noted that this one-
pot multicomponent regioselective synthesis of polysubsti-
tuted pyridines 32 and isoquinolines 33 is difficult to achieve
through conventional methods (Scheme 27).
Tu et al. described an efficient reagent-controlled regio-
specific synthesis of 2,2’-bipyridine and unsymmetrical 2,4,6-
triarylpyridine derivatives 34 at high temperature by micro-
wave-assisted aqueous multicomponent reactions of aromat-
ic aldehydes, 3-aryl-3-oxopropanenitrile, 2-acetylpyridine, or
aromatic ketones and ammonium acetate.[55] The reaction of
aromatic aldehydes with 1,2-diphenylethanone resulted in
structurally complex penta-arylpyridines 35. This serves as
an efficient general approach to diversity-oriented polyaryl
pyridine skeletons (Scheme 28).
Scheme 28.
Tus group also developed the multicomponent reaction
of aldehydes, 1,3-dicarbonyl compounds, and various amines
for the construction of different heterocyclic skeletons con-
taining a pyridine unit 36 (Scheme 29),[56] including pyrido-
ACHTUNGRE[2,3-d]pyrimidine, benzo[b]ACHTUNGRE[4,7]phenanthroline, chromeno-
ACHTUNGRE[3,4-b]ACHTUNGRE[4,7]phenanthroline, furoACHTUNGRE[3,4-b]ACHTUNGRE[4,7]phenanthroline,
furoACHTUNGRE[3,4-e]pyrazoloACHTUNGRE[3,4-b]pyridine, pyrazolo[4’,3’:5,6]pyrido-
ACHTUNGRE[2,3-d]pyrimidine, naphthoACHTUNGRE[2,3-f]quinoline, pyrim-idoACHTUNGRE[5,4-b]-
ACHTUNGRE[4,7]phenanthroline, isoxazoloACHTUNGRE[5,4-b]pyridines, and furoACHTUNGRE[3,4-
b]indenoACHTUNGRE[2,1-e]pyridine.
Scheme 29.
The multicomponent cyclocondensations of 5-aminopyra-
zoles, barbituric acids, and aromatic aldehydes under con-
ventional heating, microwave irradiation, or ultrasonic irra-
diation were studied by Chebanov et al.[57] At high tempera-
tures, the starting materials react in two different manners
and yield pyrazolo[4’,3’:5,6]pyridoACHTUNGRE[2,3-d]pyrimidines 37 or
their dihydro analogues 38 depending on the nature of the
N-substituent on 5-aminopyrazole. The reaction at room
temperature in DMF smoothly resulted in 4,6-diarylspiro-
ACHTUNGRE[pyrazoloACHTUNGRE[3,4-b]pyridine-5,5c- pyrimidine] 39 (Scheme 30).

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Scheme 30.
Jis group reported the one-pot multicomponent reaction
of aldehydes and 3-cyanoacetyl indoles with 5-aminopyrazol
under microwave irradiation, yielding polysubstituted (3’-
indolyl)pyrazoloACHTUNGRE[3,4-b]pyridines 40 in good chemical
yields.[58] Aromatic aldehydes bearing either electron-with-
drawing functional groups or -donating ones, as well as het-
erocyclic aldehydes, can be employed for this synthesis. Par-
ticularly, valuable features of this method include a broad
substrate scope, a shortened reaction time, and a convenient
and straightforward synthetic route. 3-(Cyanoacetyl)indoles
can also be reacted with aldehydes and heterocyclic ketones
in the presence of ammonium acetate in butan-1-ol at
100 8C to produce a series of new 4-aryl-6-(1H-indol-3-yl)-
2,2’-bipyridines 41 (Scheme 31).[59]
Scheme 31.
Li and co-workers have reported the synthesis of dihydro-
pyridinones 42 through the aza-Diels–Alder reaction of N-
benzyl- and N-aryl-protected imines with 4-iodo-2-trimethyl-
silyloxy-butadiene, which was generated by treating 3-butyn-
2-one with TMSI (Scheme 32).[60]
Diastereoselective synthesis of chiral dihydropyridinones
43 has also been developed by Li and co-workers by react-
ing chiral imines derived from (S)-a-methylbenzyl amine
2326 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
S.-J. Tu, G. Li et al.
Scheme 32.
and 4-iodo-2-trimethylsilyloxy-butadiene with 4-iodo-2-tri-
methylsilyloxy-butadiene (Scheme 33). Modest to good dia-
stereoselectivities were observed in this asymmetric aza-
Diels–Alder reaction.
Scheme 33.
A convenient and environmentally friendly solvent-free
procedure has been developed by Rong et al. for the synthe-
sis of polysubsituted pyridine derivatives 44 and 45 by the
multicomponent reaction of aromatic aldehydes with 2,3-di-
hydroinden-1-one (or cyclopentanone) and NH4OAc
(Scheme 34).[61] As anticipated, this new MCR method has
Scheme 34.
the advantage over traditional systems in regard to chemical
yield, easy workup, and milder reaction conditions. Subse-
quently, the same group also synthesized indenoACHTUNGRE[1,2-b]pyri-
dine-3-carbonitrile and benzo[h]quinoline-3-carbonitrile de-
rivatives 46 through the three-component condensation of
aromatic aldehydes, malononitrile, and the 2,3-dihydroin-
den-1-one or 3,4-dihydronaphthalen-1(2H)one in the pres-
ence of sodium hydroxide under similar conditions
(Scheme 35).[62]
Shi et al. synthesized new 3,3’-benzylidenebis(4-hydroxy-
6-methylpyridin-2(1H)one) derivatives 47 in 69–95 % yields
by a three-component reaction of an aldehyde, an amine,
and 6-methyl-4-hydroxypyran-2-one in an ionic liquid at
95 8C (Scheme 35).[63] The resulting heterocyclic products
Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles
Scheme 35.
can be conveniently separated from the reaction mixture
without the use of any volatile organic solvents, and the
ionic liquid cab be readily reused without losing efficiency
after simple treatment (Scheme 36).
Scheme 36.
Recently, Tus group reported a highly stereoselective
four-component domino reaction of 2,6-diaminopyrimidine-
4-one with structurally diverse aryl aldehydes and various
barbituric acids to give 6-spirosubstituted pyridoACHTUNGRE[2,3-d]pyri-
midines 48 with high diastereoselectivities (up to 99:1).
They found that major diastereomeric products bear a cis
relationship between substituents at the five- and seven-po-
sitions (Scheme 37). These reactions take the advantage of
Scheme 37.
microwave heating and the use of water as an environmen-
tally benign medium. The reaction can be completed in 7–
9 min at 100 8C. The mechanism for its diastereoselectivity
has been studied by DFT (B3LYP)-based computation.[64]
Jiang and co-workers synthesized polysubstituted 1,2,3,4-
tetrahydropyridines 49 through hydroalkylation of electron-
deficient alkynes, followed by two Mannich addition reac-
tions (Scheme 38). Eleven examples were investigated under
mild conditions; atom efficiency and good substrate scope
was seen to show moderate to good yields.[65]
Chem. Asian J. 2010, 5, 2318 – 2335  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 38.
Condensation of 3-aminocoumarin with 4-nitrobenzalde-
hyde afforded 2-azadienes, which were then reacted with
various electron-rich alkenes (10 examples) in the presence
of YbACHTUNGRE(OTf)3 to afford 1,2,3,4-tetrahydropyridoACHTUNGRE[2,3-c]cou-
marins 50 as reported by Bodwell et al.[66] Some of these
products have been converted into the corresponding
pyridoACHTUNGRE[2,3-c]coumarins 51 upon treatment with various oxi-
dants, such as Br2 and NaIO4 and nitrous gases (Scheme 39).
Scheme 39.
Wang et al. described the iodine-catalyzed three-component
reaction of an aromatic aldehyde, naphthalen-2-amycliine,
and a cyclic ketone in THF, providing a small library of ben-
zo[a]phenanthridine derivatives 52 in good yields.[67] The
process works for both electron-donating and -withdrawing-
substituted benzaldehyde substrates (Scheme 40).
Scheme 40.
Polyfunctionalized 4H-pyrans belong to a privileged het-
erocyclic ring system. The synthesis of more complex het-
erocycles containing a pyran nucleus, such as pyranoACHTUNGRE[2,3-d]-
pyridoACHTUNGRE[2,3-d]pyrimidines and pyranoACHTUNGRE[3,2-c]benzopyran, has
recently attracted attention as well.
Saikia et al. presented a diastereoselective three-compo-
nent Prins–Friedel–Crafts reaction for the synthesis of 4-ar-
yltetrahydropyran derivatives 53 from the condensation of
carbonyl compounds (aldehydes and ketones) with homoal-
lylic alcohols and arenes promoted by boron trifluoride
etherate (Scheme 41).[68] Aromatic aldehydes containing
electron-withdrawing groups and simple benzaldehyde af-
forded better yields relative to electron-donating groups. Sa-
turated aliphatic aldehydes are found to be better substrates
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FOCUS REVIEWS
Scheme 41.
than the conjugated aliphatic aldehydes. In addition, the re-
action can be extended to cyclic and symmetrical acyclic ke-
tones.
Jiangs group reported the multicomponent synthesis of
5,6-dihydro(2H)pyran-2-ones 54 initiated by hydroalkylation
of alkynoates with activated methylenes (Scheme 42).[69]
Scheme 42.
Under the optimized conditions (20 mol % NaOH and diox-
ane, at room temperature), the desired products were ob-
tained in 47–92 % yields of isolated product through the re-
action of electron-deficient alkynoates with activated meth-
ylenes and formaldehyde. The reaction offers a convenient
entry into several important heterocyclic structures.
Reddy et al. reported a four-component reaction between
an aromatic aldehyde, hydrazine hydrate, ethyl acetoacetate,
and malononitrile to produce substituted pyranopyrazoles
55 in good yields under solvent-free conditions. The pres-
ence of an electron-releasing group in the para position of
aromatic aldehydes can increase the yield and shorten the
reaction period (Scheme 43),[70] but an aldehyde with a
strong electron-withdrawing group leads to lower yields.
Scheme 43.
Cyanoacetic acid derivatives were found to react with a
wide variety of substituted isatins and carbonyl compounds
or phenols to give 2-amino-spiroACHTUNGRE[(3’H)indol-3’,4-(4H)pyrans]
56 through a three-component condensation (Scheme 44) as
reported by Shestopalov et al.[71] The reaction proceeds
under mild conditions and results in a small library of 40
new spiropyrans in modest to excellent yields.
Shaabanis group developed the three-component reaction
of dialkyl acetylenedicarboxylate, isocyanides, and 2,5-dihy-
2328 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
S.-J. Tu, G. Li et al.
Scheme 44.
droxycyclohexa-2,5-diene-1,4-dione or 2-hydroxynaphtha-
lene-1,4-dione under mild conditions (Scheme 45).[72] The re-
action proceeded smoothly to afford the corresponding
polyfunctionalized bis(4H-chromene)- and 4H-benzo[g]chro-
Scheme 45.
mene-3,4-dicarboxylate derivatives 57 and 58 without the
use of any catalyst. The same group reported the synthesis
of fully substituted pyranoACHTUNGRE[2,3-c]pyrazole derivatives 59 in
58–79 % yields by a similar reaction process (Scheme 46).[73]
Scheme 46.
Heterocycles of thiopyran derivatives are another series
of versatile building blocks for organic and medicinal
chemistry.[2] Recently, Muller et al. synthesized 4H-thiochro-
men-4-one 60 and 4H-thiopyranoACHTUNGRE[2,3-b]pyridine-4-ones in
good yields by a consecutive one-pot, three-component cou-
pling–addition–SNAr (CASNAR) sequence by starting from
aroyl chlorides, alkynes, and sodium sulfide nonahydrate
(Scheme 47).[74] An efficient pathway for the synthesis of thi-
opyran derivatives 61 was performed by Fan et al.; they de-
scribe a multicomponent reaction of aldehydes, cyanothio-
acetamide, and malononitrile promoted by ionic liquids.
Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles
Scheme 47.
Without the use of any catalysts, both aromatic and aliphatic
aldehydes participated in this reaction smoothly
(Scheme 48).[75]
Scheme 48.
Heterocycles with Two and Three Heteroatoms
The pyrimidine nucleus is commonly found in biologically
active natural products and has served as a central and pre-
cious unit in drug discovery. A copper-catalyzed multicom-
ponent reaction of sulfonyl azides, terminal alkynes, and
a,b-unsaturated imines was developed by Wangs group
(Scheme 49)[76] furnishing a new class of pyrimidine deriva-
Scheme 49.
tive, N-sulfonyl-2-alkylidene-1,2,3,4-tetrahydro-pyrimidines.
In all reported cases, the three-component reaction afforded
pyrimidines 62 as the major or sole product. In several
cases, the minor products azetidin-2-imines 63 were also iso-
lated with high trans selectivity. Both aryl and aliphatic al-
kynes can be employed to afford good to excellent yields
(60–96 %).
Konakahara et al. described a ZnCl2-catalyzed three-com-
ponent reaction involving structurally diverse enamines,
triethyl orthoformate, and ammonium acetate that lead to
the formation of 4,5-disubstituted pyrimidine derivatives 64
(15 examples) with 24–99 % yields in a single operation
(Scheme 50).[77] This procedure can also be successfully ap-
Scheme 50.
Chem. Asian J. 2010, 5, 2318 – 2335  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
plied to the synthesis of mono and disubstituted pyrimidine
derivatives, in 54–86 % yields, by using methyl ketones in-
stead of enamines.
Jiangs group presented two synthetic routes to polysub-
stituted pyrimidine derivatives 65 and 66 based on the reac-
tivity of various substrates (Scheme 51).[78] This synthesis in-
Scheme 51.
cludes a catalyst-free multicomponent reaction of electron-
deficient alkynes, aliphatic amines, and formaldehyde to
produce 65 and a AgI-catalyzed synthesis of pyrimidines 66
from electron-deficient alkynes, anilines, and formaldehyde.
High regioselectivities and good to excellent yields (73–
93 %) were achieved for the above synthesis. DFT (B3LYP)
computational studies were carried out to elucidate the
mechanism of the catalyst-free carboamination process.
A facile route to a series of new dihydropyrimidinones 67
through SnCl2-catalyzed cyclocondensation of b-oxodi-
thioesters with a variety of readily accessible aldehydes and
urea (Scheme 52) has been reported by Singh et al.[79] This
Scheme 52.
methodology involves the three-component Biginelli reac-
tion to afford 13 desired products in 70–82 % yields. In addi-
tion, substituted salicylaldehyde was reacted with b-oxodi-
thioesters under the same conditions to afford the substitut-
ed 2H-chromene-2-thiones in high yields.
1,2-Dihydro-pyrimidoACHTUNGRE[1,2-a]benzimidazole-3-carbonitrile
derivatives 68 were synthesized by Tu and co-workers by the
three-component reaction of aldehyde, malonodinitrile, and
2-aminobenzimidazole in water under microwave irradiation
(Scheme 53).[80] The protocol has the advantages of excellent
yields, reduced waste generation, wide substrate scope, and
convenient procedure and workup. A series of benzo-
ACHTUNGRE[4,5]imidazoACHTUNGRE[1,2-a]pyrimidine derivatives 69 were also syn-
thesized by the same group. In this synthesis, polyethylene
glycol (PEG) was utilized as a nontoxic and recyclable reac-
tion medium in the presence of K2CO3 (Scheme 54).[81]
www.chemasianj.org 2329
 S.-J. Tu, G. Li et al.
FOCUS REVIEWS

Scheme 53.

Scheme 57.

Orru and co-workers have reported the one-pot multi-

component synthesis of triazinane diones 73, combining
phosphonates, nitriles, aldehydes, and isocyanates
(Scheme 58). The reaction is compatible with various inputs
Scheme 54.
including aldehydes with (hetero)aromatic and aliphatic sub-
stituents and isocyanate components with benzylic and aro-
Shaabani et al. synthesized a new class of highly substitut- matic substituents.[85]
ed 3,4-dihydroquinoxalin-2-amine derivatives 70, including
spirocyclic compounds from three-component condensation
of o-phenylenediamines, diverse carbonyl compounds, and
isocyanides in the presence of a catalytic amount of p-tolue-
nesulfonic acid (p-TsOH) in good to excellent yields (75–
95 %) at room temperature (Scheme 55).[82]

Scheme 58.

Construction of Seven-Membered Heterocycles

Scheme 55. The polysubstituted 1,4-benzodiazepin-3-ones 74 and 75

were synthesized by Andreana et al. by an isocyanide-based
multicomponent reaction (Scheme 59).[86] By using protic
Recently, the four-component condensation of alkynoates,
anilines, and formaldehyde was described by Jiangs group
(Scheme 56).[83] A series of 3,4,5-trisubstituted-3,6-dihydro-
2H-1,3-oxazines 71 were obtained in 71–84 % yields. The
six-membered N,O-heterocyclic skeleton was constructed by
HCl-promoted domino hydroamination/Prins reaction/cycli-
zation/dehydration reactions.

Scheme 56. Scheme 59.

The 1,4-dipolar cycloaddition reaction of benzofuran-2,3-
dione derivatives, dialkyl acetylenedicarboxylates (DAAD),
and isoquinoline was reported by Esmaeili and co-workers.
This reaction results in spiroACHTUNGRE[1,3]oxazinoACHTUNGRE[2,3-a]isoquinoline
derivatives 72 in good yields with 72’ obtained as the minor
product (Scheme 57).[84]
solvents, controlled microwave irradiation, and a reducing
agent, Fe0/NH4Cl, these derivatives can be prepared effi-
ciently through a one-pot, two-step process. Interestingly, o-
nitrobenzaldehyde and o-nitrobenyzlamine not only act as
bifunctional substrates, but also selectively direct a substitu-
tion pattern for benzodiazepin-3-ones of type 74 and 75.

2330 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles
Shaabani et al. also described an isocyanide-based multi-
component reaction from readily available starting materi-
als, including 2,3-diaminomaleonitrile, a cyclic or acyclic
ketone, an isocyanide, and water (Scheme 60).[87] p-TsOH
was used as the catalyst in aqueous medium at ambient tem-
perature to provide 1,4-diazepine-5-carboxamide derivatives
76 in 80–92 % yields.
Scheme 60.
A highly efficient and chemoselective synthetic route to
the benzothiazepinones 77 and thiazolidinones 78 by a mi-
crowave-assisted three-component reaction of an aromatic
aldehyde, aniline, and mercaptoacetic acid was reported by
Tu et al. (Scheme 61).[88] The best results were obtained
Scheme 61.
when water was used as a solvent at 110 8C to produce 25
benzothiazepinones in 90–96 % yields. Tus group also stud-
ied the influence of electronic effects on the chemoselectivi-
ty of these reactions. The aromatic aldehydes bearing elec-
tron-donating groups (EDG), as well as heteroaromatic al-
dehydes, resulted in benzothiazepinones 77, whereas elec-
tron-withdrawing groups (EWG) on the phenyl ring led to
the formation of thiazolidinones 78. It is noteworthy that
when 3,4-(methylenedioxy)aniline was used as the substrate,
aromatic aldehydes bearing both EWG and EDG produced
benzothiazepinones.
One-Step Multicomponent Construction of New
Heterocyclic Scaffolds
As mentioned earlier, multicomponent domino reactions
can dramatically increase the molecular diversity and com-
plexity of target molecules and offer rapid and efficient pro-
cedures for the introduction of various functional groups
onto heterocyclic rings in concise manners, which is particu-
larly applicable to the synthesis of multiple cyclic com-
Chem. Asian J. 2010, 5, 2318 – 2335  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
pounds.[89] The design and development of new multicompo-
nent domino reactions that maximize efficiency is becoming
one of the major challenges in searching for a step-economic
synthesis. Recently, the Barluenga group developed a new
and simple synthetic protocol for the construction of spiro-
cyclic quinoline derivatives 78 (Scheme 62);[90] the reaction
Scheme 62.
involves a one-pot three-component coupling reaction of an
alkynol derivative, an aldehyde, and an aromatic amine. In
this Povarov synthesis, both reactive species, enol ether and
the N-arylaldimine, are catalytically preformed in situ prior
to the reaction. A remarkable aspect of the reaction is the
cooperative effect of the two catalysts: a platinum complex
and a Bronsted acid.
Tu and Li et al. recently developed a new four-component
domino reaction between simple aldehydes, cycloketones,
and cyanoamides to give a diverse set of quinazoline deriva-
tives 80 in 74–90 % yields, with remarkable chemo-, regio-,
and stereoselectivity (Scheme 63).[91] The reaction, which is
Scheme 63.
easily performed, is done by simply mixing four common re-
actants and K2CO3 in ethylene glycol under microwave irra-
diation; the reaction can be achieved within 10–24 min, leav-
ing water as the only byproduct, which makes the workup
convenient. This reaction demonstrates the efficiency of a
domino MCR with four stereogenic centers with one quater-
nary carbon–amino function with good control.
Later on, the same group found that when aromatic alde-
hydes were replaced by their aliphatic counterparts, the qui-
nazoline derivatives were not generated. Interestingly, the
reaction resulted in the formation of multifunctionalized tri-
cyclo[6.2.2.01,6]dodecanes 81. These novel scaffolds belong
to another very important class of compounds for organic
synthesis and drug design in pharmaceutical sciences
(Scheme 64).[92]
Tus group recently reported a three-component domino
reaction for the highly selective synthesis of tetracyclic cin-
nolino[5,4,3-cde]cinnolines 82 (Scheme 65).[93] In this reac-
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FOCUS REVIEWS
Scheme 64.
Scheme 65.
tion, anthenes with aliphatic groups (R1) were reacted with
hydrazine hydrate to yield 82, whereas anthenes with aryl
groups (R1) resulted in N-amino-1,8-dioxoacridines. The
same authors next presented an autocatalytic reaction of
imines with Meldrums acid leading to a series of polycyclic
spiroACHTUNGRE[5.5]undecane-1,5,9-trione and dispiro-
ACHTUNGRE[4.2.5.2]pentadecane-9,13-dione derivatives 83, with remark-
able diastereoselectivity, under acidic conditions
(Scheme 66).[94] The green chemoselective synthesis of
Scheme 66.
thiazoloACHTUNGRE[3,2-a]pyridine derivatives 84 and 85 was achieved
by the same group recently (Scheme 67).[95] The MCR of
malononitrile, aromatic aldehydes, and 2-mercaptoacetic
acid was preformed to produce two different products by
controlling the molar ratios of the starting materials. These
products have been screened for their antioxidant activity
Scheme 67.
2332 www.chemasianj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
S.-J. Tu, G. Li et al.
and cytotoxicity in carcinoma HCT-116 cells and mice lym-
phocytes. Nearly all of the tested compounds possessed
potent antioxidant activity.
Isoquinoline was found to react with dialkyl acetylenedi-
carboxylates and 1,3-dicarbonyl compounds in CH2Cl2 at
room temperature, providing functionalized hexacyclic de-
rivatives of isoquinoline 86 with high diastereoselectivity as
reported by Yavari and co-workers (Scheme 68).[96] This
multicomponent procedure has an attractive characteristic
of being performed under neutral conditions and without
the need of any prior activation of the reactant.
Scheme 68.
A new copper-catalyzed synthesis of 3-(aminomethyl)iso-
quinoline-fused polycyclic compounds 86, through four-com-
ponent coupling, cyclization, and oxidation, was described
by Fujii and Ohno (Scheme 69).[97] The Mannich-type reac-
Scheme 69.
tion of 2-ethynylbenzaldehyde with paraformaldehyde and a
secondary amine followed by the treatment with a diamine
component yielded tricyclic isoquinolines. In this reaction,
CuCl showed effective catalytic activity under an oxygen at-
mosphere to afford the desired products in moderate to
good yields.
The microwave-assisted Wolff rearrangement of cyclic 2-
diazo-1,3-diketones in the presence of aldehydes and pri-
mary amines was described by Coquerel and Rodriguez
et al. (Scheme 70).[98] The reaction provides a straightfor-
ward access to functionalized bi- and pentacyclic oxazinones
87 following an unprecedented three-component domino re-
Scheme 70.
Chem. Asian J. 2010, 5, 2318 – 2335
Multicomponent Reactions for the Synthesis of Heterocycles
action. This approach to 1,3-oxazin-4-ones is the first exam-
ple of the exploitation of the Wolff rearrangement in a mul-
ticomponent reaction.
Yan et al. synthesized polysubstituted pyridoACHTUNGRE[1,2-a]benzi-
midazole derivatives 88 in 25–51 % yields in a four-compo-
nent one-pot operation from pyridine or 3-picoline, chloroa-
cetonitrile, malononitrile, and an aromatic aldehyde in re-
fluxing acetonitrile (Scheme 71).[99] The mechanism was be-
lieved to involve the formation of polysubstituted benzenes
with subsequent substitution and annulation of pyridine.
Scheme 71.
Conclusions
MDRs have offered increasingly important opportunities for
synthesis of both chemically and medicinally useful com-
pounds because of their environmentally friendly character-
istics of atom-economy and green chemistry. These reactions
enable multistep processes to be achieved in a single step of
operation to produce a diverse variety of products that in-
clude useful heterocycles with structural complexity. As
compared with traditional multioperational synthesis, MDRs
can dramatically reduce the generation of chemical waste
and costs of starting materials. They can often shorten reac-
tion times and substantially save the use of energy and man-
power to give high overall chemical yields in a multistep
processes. As illustrated in this review, a wide variety of het-
erocycles of different sizes and ring systems can be readily
synthesized through MDR strategies that often result in a
broad scope of applications. More novel and efficient multi-
component domino reactions need to be developed for the
synthesis of leading structures, particularly, of those complex
products existing in nature. Solid-phase MDRs and enantio-
and diastereoselective MDRs have not been paid enough at-
tention and will be interesting and challenging topics in
modern organic chemistry.
Acknowledgements
We are grateful to financial support from the National Science Founda-
tion of China (20810102050 and 20928001), the Science Foundation in In-
terdisciplinary Major Research Project of Xuzhou Normal University
(no. 09XKXK01), the Qing Lan Project of Jiangsu Province (08QLT001),
the Robert A. Welch Foundation (D-1361), and the NIH (R03A026960)
for their generous support. We would like to thank A. Ballew and P.
McDowell for the refinement of our manuscript.
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Received: April 29, 2010
Published online: October 4, 2010
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