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Recent advances in new multicomponent synthesis of structurally diversified
1,4-dihydropyridines
Jie-Ping Wan* and Yunyun Liu
Received 6th May 2012, Accepted 8th August 2012
DOI: 10.1039/c2ra21406g
1,4-Dihydropyridines (DHPs) are one of the most important classes of heterocyclic compounds as
privileged pharmacophores. They are therefore attractive synthetic targets of organic chemistry.
Multicomponent reactions (MCRs) are the most efficient strategies for the synthesis of 1,4-DHPs in
terms of providing both sufficient structural diversity and numbers for compound libraries.
Following the classical multicomponent synthesis of 1,4-DHPs by the Hantzsch reaction, chemists
have developed a large number of new MCRs to access 1,4-DHPs with significantly extended
structural diversity, which is pivotal for the process of discovering new lead compounds and drugs of
1,4-DHPs. The advances on the synthesis of structurally diversified 1,4-DHPs through new MCRs
beyond the classical Hantzsch reaction is reviewed.
1. Introduction
Among the known strategies of drug discovery, high throughput
screening is obviously the one that is serving most efficiently to
the pharmaceutical industry. To guarantee the success on
acquiring lead compounds via this kind of screening tactic,
sources of large amount of molecular libraries are important
preconditions.
1
To satisfy such requirements, new synthetic
strategies with robust efficiency in providing a massive amount
of structurally diverse organic products are the only solution.
MCRs which employ three or more reactants to furnish products
containing structure or substructure of all starting materials in
one-pot and one set of fixed reaction conditions are such
examples with powerful productivity.
2
The Hantzsch reaction
(Scheme 1) which provides 1,4-DHPs as products is one of the
earliest and most well-known MCRs owing to the excellent
pharmaceutical profile of 1,4-DHPs.
3
The most typical examples
of 1,4-DHPs pharmaceuticals are those broadly prescribed
calcium channel blockers, for example, Nifedipine (1),
Felodipine (2), Nicardipine (3) and Nimodipine (4), to name
but a few (Scheme 2). In addition, other versatile biological
profiles of 1,4-DHPs such as anticonvulsant activity,
4
selective
Key Laboratory of Functional Small Organic Molecules, Ministry of
Education and College of Chemistry and Chemical Engineering, Jiangxi
Normal University, Nanchang, 330022, P. R. China.
E-mail: wanjieping@gmail.com; Fax: +86 791 88120380
Dr Jie-Ping Wan obtained his
Bacholer’s degree by studying
chemistry in Nanchang University
in 2000–2004. He continued his
graduate study in Zhejiang
University in 2005–2010 in
Professor Yuanjiang Pan’s group
and obtained his Ph.D degree in
2010. In July, 2010, he joined
the College of Chemistry and
Chemical Engineering in Jiangxi
Normal University as an assistant
professor. In September 2011,
under the support of Chine-
sisch-Deutsche Zentrum fu¨r
Wissenschaftsfo¨rderung Dr Wan
joined Prof. Dieter Enders group in RWTH Aachen University as
a postdoctoral fellow working in organocatalysis. His present
research interest contains multicomponent reactions, organocata-
lysis and metal-catalyzed synthesis.
Dr Yunyun Liu was born in 1983 in
Shandong Province, China. She
obtained her Bachelor Degree in
Qufu Normal University in 2005.
She then moved to Zhejiang
University to continue her graduate
study in the Department of
Chemistry. Under the supervision
of Professor Weiliang Bao, she
worked in the field of copper-
catalyzed Ullmann coupling reaction
and related tandem reactions for her
doctorate study. She obtained her
doctorate degree in 2010 and pre-
sently is an assistant professor in
Jiangxi Normal University. She is
currently interested in the research
of metal-catalyzed organic synthesis
and the development of new cascade
organic reactions.
Jie-Ping Wan
Yunyun Liu
RSC Advances
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adenosine-A3 receptor antagonism,
5
radioprotective activity,
6
sirtuin activation and inhibition,
7
etc. have also been reported.
Therefore, it is not surprising that 1,4-DHPs receive daily
increasing interests as synthetic targets.
Conventionally, 1,4-DHPs could be accessed via the Hantzsch
reaction, reduction of pyridines, addition to pyridines or
cycloadditions etc.
8
As a facile and broadly tolerable protocol,
the Hantzsch reaction remains as a frequently employed tactic
for the synthesis of 1,4-DHPs in a large number of areas such as
stereoselective synthesis and green chemistry.
9
On the other
hand, following the rapid progress of chemical and pharmaceu-
tical industries, some limits have also been noticed on this
classical multicomponent synthetic route. A main limit of the
Hantzsch reaction is that the 1,4-DHPs provided by the reaction
are all symmetrical in the heterocyclic fragment since this unit
was constructed by employing two molecules of 1,3-dicarbonyl
compounds. Although Hantzsch reactions using two different
dicarbonyl compounds had been later achieved, the symmetrical
1,4-DHPs formed by the homo-condensation of same dicarbonyl
compound remained more or less as side products in these
entries. In terms of biological screening, acquiring diversified
derivatives of a known pharmacophore is a main and efficient
approach for discovering new biologically active lead com-
pounds.
10
Even though many reported biologically active 1,4-
DHPs are symmetrical, this was not the requirement of
biological receptors, but the results of employing the Hantzsch
reaction for 1,4-DHPs synthesis in most cases. For the sake of
finding more 1,4-DHPs possessing new and improved biological
functions, the synthesis of structurally diverse 1,4-DHPs such as
unsymmetrical 1,4-DHPs is pivotal work. Therefore, new MCRs
that are capable of generating novel 1,4-DHPs have attracted
significant attention in recent years. Considering the merits of
1,4-DHPs for the development of chemical biology and
medicinal chemistry as well as the impressive progress being
made in this field, it is therefore necessary to summarize the
research advances on the multicomponent synthesis of 1,4-DHPs
with different new MCRs. We present herein the first review on
the advances of 1,4-DHPs synthesis with new MCRs beyond the
Hantzsch reaction. Based on the analysis of all known literature
on this topic, we classified these reactions into different sections
according to the amino sources employed for the construction of
the dihydropyridine ring. The main content of this review
covered the period from 2004 to 2012.
2. Multicomponent synthesis of 1,4-DHPs using amine
as amino source
Amines are obviously the most easily available and widely
utilized amino sources in organic synthesis. They have been
frequently employed as the amine component in the classical
Hantzsch reaction. Similarly, amines are also favorable amino
sources in the devisal of new multicomponent synthesis of 1,4-
DHPs. For example, employing a,b-unsaturated aldehydes, 1,3-
dicarbonyl compounds and amines has been found as a very
practical approach for the synthesis of unsymmetrical 1,4-DHPs.
During their work of synthesizing 1,4-DHPs 6 by two-
component condensation of b-enamino esters 5 and a,b-unsatu-
rated aldehydes, Renaud et al. conducted tentative investigations
on direct three-component reaction of 1,3-dicarbonyl com-
pounds, amines and a,b-unsaturated aldehydes to access 1,4-
DHPs with Lewis acid catalysis. Moderate to excellent yields
have been obtained by performing the reactions in a stepwise
manner (Scheme 3).
11
Later on, the one step, three-component
reaction of a 1,3-dicarbonyl compound, primary amine and
a,b-unsaturated aldehyde has been realized by Mene´ndez and
coworkers. Their method was established by employing cerium
ammonium nitrate (CAN) as a Lewis acid catalyst. This protocol
has been demonstrated with excellent substrate tolerance by
providing a sound number of 1,4-DHPs of type 6 with moderate
to good yields at room temperature. And a noteworthy feature of
this methodology was that b-ketothioesters could be efficiently
employed as the dicarbonyl component to correspondingly give
1,4-DHPs containing a reactive thioester group as shown by
typical results outlined in Scheme 4.
12
In addition, as a widely
employed catalysis tactic, organocatalysis had also turned out to
be practical for this kind of three-component 1,4-DHPs synthesis
Scheme 1 Classical Hantzsch reaction.
Scheme 2 1,4-DHPs used as clinical drugs.
Scheme 3 Three-component stepwise synthesis of 1,4-DHPs.
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according to the results presented by Kumar et al. While a series
of different organocatalysts such as (2)-cinchonidine, (2)-
ephedrine,
L-lysine, L-histidine, L-glutamic acid, L-asparatic
acid,
L-pipecolic acid and L-proline have been screened, L-
proline displayed the best activity as an organocatalyst. By
performing the reactions of different a,b-unsaturated aldehydes,
amines and dicarbonyl compounds at room temperature and
solvent free conditions, various 1,4-DHPs of type 6 have been
obtained with generally excellent yields. For example, the
reaction of cinnamaldehyde, aniline and 2-acetyl ethyl acetate
provided the corresponding 1,4-DHP in 90% yield.
13
Following
these results, some other different catalysts such as nano CuO,
14
silica-supported perchloric acid (HClO4?SiO
2
)
15
and InCl
3
16
were also discovered as practical catalysts for this three-
component 1,4-DHPs synthesis.
One of the most important properties of unsymmetrical 1,4-
DHPs is the chiral center embedded in the central heterocycle.
Therefore, performing this kind of multicomponent reactions in
an enantioselective manner is of great significance. Few methods
of asymmetric catalysis on 1,4-DHPs synthesis are currently
available. The representative results on this area was reported by
Gong and coworkers, in which a chiral phosphoric acid was used
as a Brønsted acid to catalyze the three-component reaction of
a,b-unsaturated aldehydes, amines and dicarbonyl compounds
giving (S)-6 with good to excellent enantioselectivity in general
(66–97% ee) and fair to good yields (31–93%). Some typical
results on the synthesized chiral 1,4-DHPs of type 6 are shown in
Scheme 5.
17
Notably, elegant results on the enantioselective
synthesis of 1,4-DHPs by the Hantzsch reaction has also recently
been accomplished by Gestwicki and co-workers employing
BINOL-phosphoric acid catalysis.
18
Alkynes were another type of frequently employed building
block in the multicomponent synthesis of 1,4-DHPs of both
symmetrical and unsymmetrical structures. For example, Wang,
et al. developed an interesting multicomponent synthesis of 1,4-
DHPs of type 7 via TFA-catalyzed assembly of 3 molecules of
E-3-(2-formylphenoxy)propenoates 8 and amines (Scheme 6).
Corresponding salicaldehydes were generated as side products
from 8 after incorporating amines and two ethyl propiolate
building blocks. The salicaldehydes were able to be regenerated
to 8 by incorporating ethyl propiolate. This transformation has
been found to be specifically applicable for the starting materials
of type 8 since no corresponding reactions were observed when
using either the para-substituted isomers of 8 to incorporate
amines or direct three-component reactions of salicaldehyde,
aniline and ethyl propiolate/ethyl 3-phenoxyacrylate under
standard reaction conditions.
19
However, it was later discovered
that the direct MCRs of ethyl propiolate, benzaldehyde and a
primary amine were capable of providing corresponding 1,4-
DHPs 9 by heating the starting materials in acetic acid. The
application scope of this protocol, however, was not defined, as
only 4 examples of 1,4-DHPs 9 were prepared for the sake of
biological research (Scheme 7).
7
Also employing propiolates as
building blocks for the dihydropyridine ring construction, Yan
et al. established a four-component synthesis of 1,4-DHPs 10
from methyl propiolate, aryl amines, aromatic aldehydes and
acetonitriles. With the catalysis of triethyl amine, the
Knoevenagel condensed intermediates 11 incorporated inter-
mediates 12 from an aza-Michael addition to provide inter-
mediates 13 which underwent subsequent intramolecular
cyclization and tautomerization to 1,4-DHPs 10 as final
products. On the other hand, when ethyl 2-cyanoacetate was
used as the starting material in the place of malonitrile/2-
cyanoacetamide, 2-pyridinones 15 were afforded as main or
single products in the corresponding entries (Scheme 8).
20
As
alkyne substrates with similar reactivity as alkyl propiolates,
dialkyl acetylenedicarboxylates were also found to be versatile
materials for the synthesis of novel functionalized 1,4-DHPs. For
example, under the catalysis of organocatalyst
L-proline,
acetylene-dicarboxylates 16 efficiently reacted with amines to
generate b-enamino esters of type 17. Based on this transforma-
tion, Jiang and coworkers designed an
L-proline catalyzed
multicomponent synthetic method starting from acetylenedicar-
boxylates (alkyl propiolates as well), amines, aldehydes and 1,3-
dicarbonyl compounds to synthesize 1,4-DHPs of type 21.As
shown in Scheme 9, active intermediates 17 generated from the
addition of amines to electron deficient alkynes were believed to
directly couple with Knoevenagel condensed intermediates 18 to
form 19/20, which were efficiently transformed to 1,4-DHPs 21
via further intramolecular condensation. Mild reaction condi-
tions and wide substrate tolerance on all starting materials were
advantages in this method.
21
Similar to acyclic 1,3-dicarbonyl
compounds, cyclic1,3-dicarbonyl compounds also reacted with
aromatic amines, aromatic aldehydes and dimethyl acetylenedi-
carboxylate to give corresponding 1,4-DHPs 22 in a fused
Scheme 4 Typical results on enal-based synthesis of unsymmetrical 1,4-
DHPs.
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structure by employing HOAc as solvent as well as acid catalyst
(Scheme 10).
22
Instead of enone intermediates 18, a,b-unsaturated aldehydes
could be directly employed as building blocks to prepare 1,4-
DHPs by reacting with acetylenedicarboxylates and primary
amines. In the presence of TFA or TfOH, 1,4-DHPs 23 were
easily afforded by the three-component reactions of dimethyl
acetylenedicarboxylate, amines and a,b-unsaturated aldehydes at
room temperature in THF. 1,2-DHPs 24 were formed as minor
side products in these reactions. Based on the proposed reaction
mechanism, the initial N-nucleophilic site in b-enamino esters
attack the different electrophilic sites in a,b-unsaturated
aldehydes was believed to determine the regioselectivity.
N-attacking led to the formation of 1,4-DHPs, while minor
1,2-DHPs products was proposed to be provided by the aza-
Michael addition of the N-nucleophilic site to enals
(Scheme 11).
23
Interestingly, the homo-condensation of acetyle-
nedicarboxylates with amines and aldehydes were also capable of
delivering 1,4-DHPs. Yan et al. discovered the synthesis of fully
substituted 1,4-DHPs 25 by directly reacting acetylenedicarbox-
ylates with aromatic amines and aromatic aldehydes in absolute
ethanol. When 95% EtOH was employed, 2-hydroxylhydropyr-
idines 26 were obtained diastereoselectively probably by the
addition of H
2
Oto25 (Scheme 12).
24
Scheme 5 Enal-based enantioselective synthesis of 1,4-DHPs.
Scheme 6 Three-component synthesis of 1,4-DHPs initiated by E-3-(2-
formylphenoxy)propenoates.
Scheme 7 Direct synthesis of symmetrical 1,4-DHPs from propiolate.
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Recently, Kumar et al. discovered that malonitrile or ethyl
cyanoacetate was able to efficiently react with diethyl acetylene-
dicarboxylate, aromatic amines and aromatic aldehydes to
provide 1,4-DHPs of type 27 by a solvent- and catalyst-free
grinding protocol. This clean synthetic method proceeded also
via enamino esters and Knoevenagel condensed intermediates
(Scheme 13).
25
Besides those aforementioned alkynes, alkenes have also been
found as applicable substrates in 1,4-DHPs synthesis. In 2011,
Jiang et al. reported an interesting multicomponent synthesis of
1,4-DHPs directly employing aldehydes, amines and electron
deficient alkenes 28 with palladium(
II) catalysis in O
2
atmo-
sphere. The 1,4-DHPs of type 29 were given in moderate to good
yields. Compared with benzaldehyde derivatives, heteroaromatic
aldehydes were not good reaction partners as lower yields of the
corresponding products were afforded (Scheme 14).
26
Another
multicomponent synthesis of 2,6-unsubstituted 1,4-DHPs of type
29 employing electron rich alkenes 30 as precursors of
enaminone intermediates 31 was reported recently. In the
presence of the Lewis acid Sc(OTf)
3
, corresponding 1,4-DHPs
were afforded in fair to good yields. However, 2–19 days of
Scheme 8 Four-component synthesis of 1,4-DHPs with aldehyde, amine, propiolate and nitrile.
Scheme 9 Synthesis of fused 1,4-DHPs using cyclic diketones.
Scheme 10 Synthesis of 1,4-DHPs using aldehyde, amine, a 1,3-
dicarbonyl compound and electron deficient alkynes.
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reaction time and the presence of side products 31 as well as
other types of side products in the reactions were the main
restrictions of this method (Scheme 15).
27
As reactants possessing analogous reactivity with 30, the
b-ester acetals 32 could also be employed as C-nucleophile
sources for 1,4-DHP synthesis by serving as the precursors of
b-enamino esters. The in situ generated b-enamino esters from
starting acetals and aromatic amines efficiently reacted with
aldehydes in the manner of homo-condensation to provide 1,4-
DHPs 33 by heating at 90 uC in dioxane in the presence of Lewis
acid Yb(OTf)
3
(Scheme 16).
28
In addition to the utility of new C-nucleophiles for devising
new MCRs assembling 1,4-DHPs, the employment of a new
electrophilic species to replace traditional aldehyde electrophiles
has also been recently developed as practical tactic. And some
well defined electrophilic species such as isatin and analogous
1,2-dicarbonyl compounds have been found particularly inter-
esting in this regard by affording spirocyclic 1,4-DHPs deriva-
tives through MCRs. For example, isatin 34 as well as analogous
dicarbonyl substrate 36 have been both successfully utilized to
react with cyclic 1,3-dicarbonyl compounds and aromatic
primary amines respectively to construct polycyclic 1,4-DHPs
35
29
and 37
30
which containing both spiro- and fused architec-
ture (Scheme 17). It should be noted that the essence of these
reactions is identical as that of the Hantzsch reaction.
Scheme 11 Regioselective three-component synthesis of 1,4-DHPs using dimethylacetylenedicarboxylate, enal and amine.
Scheme 12 Regioselective three-component synthesis of 1,4-DHPs and tetrahydropyridines.
Scheme 13 Solvent- and catalyst-free synthesis of 1,4-DHPs.
Scheme 14 Electron deficient alkene-based synthesis of 1,4-DHPs.
Scheme 15 Alkoxyl activated alkene initiated synthesis of 1,4-DHPs.
Scheme 16 b-Ester acetal initiated synthesis of 1,4-DHPs.
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Reasonably, following the consideration on designing new
MCRs for the synthesis of structurally diverse 1,4-DHPs
employing aldehydes as C-electrophiles, new types of MCRs
employing electrophilic isatins had also been developed for 1,4-
DHP library synthesis. Through an analogous route described in
Scheme 13, Perumal et al. performed MCRs for synthesis of
spiro-1,4-DHPs 40 wherein isatin took the place of the aldehyde
component in Scheme 13. With the catalysis of triethylamine,
key Knoevenagel condensed intermediates 38 and enamino
ethers 39 assembled to provide corresponding products in
generally good yields (Scheme 18).
31
On the other hand,
Alizadeh et al. employed diamines 41 and 1,1-bis(methylthio)-
2-nitroethylene 42 as precursors of enaminone intermediates 43,
which incorporated 38 to provide spiro- and fused 1,4-DHPs 44
under the promotion of piperidine (Scheme 18).
32
After their
synthesis of 1,4-DHPs 44, Alizadeh et al. later developed another
four-component reaction for 1,4-DHP synthesis. The protocol
employed Wittig reagent 45 to react with isatin to form an
electron deficient Wittig intermediate which was efficiently
captured by the enamino ester intermediates in situ generated
from ketoesters and amines to give 1,4-DHPs products 46 in
good to excellent yields (Scheme 19).
33
On the other hand,
Sambri and coworkers developed an unconventional multi-
component protocol for the synthesis of 1,4-DHPs 47 from ethyl
propiolate, two 1,3-dicarbonyl compounds and primary amines
wherein ethyl propiolate served as electrophile (Scheme 20).
34
3. Multicomponent synthesis of 1,4-DHPs using
ammonia as amino source
Ammonia was used as the amino source in the earliest version of
the Hantzsch 1,4-DHPs synthesis, the reactivity of ammonia was
identical as primary amines in most 1,4-DHPs synthesis, the
difference was that 1,4-DHPs containing a free NH-group in the
DHP ring were the products when ammonia was utilized as the
amino source. Similar to the cases of amine-based reactions,
novel MCRs have been known for the synthesis of new 1,4-
DHPs libraries bearing a free NH group in the central ring by
using ammonia as the amino source. For instance, starting
from aldehyde, alcohols, diketene 48 and ammonia acetate, an
alternative four-component protocol for synthesizing Hantzsch-
type 1,4-DHPs 50 in the presence of 10 mol% H
2
SO
4
had been
Scheme 17 Synthesis of spiro-1,4-DHPs with 1,2-dicarbonyl substrates.
Scheme 18 Multicomponent synthesis of spiro-1,4-DHPs using isatins as carbonyl electrophiles.
Scheme 19 Four-component synthesis of spiro-1,4-DHPs involving
Wittig reagent and isatin.
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achieved. The reactions proceeded via key intermediates 49
which were generated from 4-methyleneoxetan-2-one 48, alde-
hydes and alcohols (Scheme 21).
35
In another example, the
(2-aryl)methylene malononitriles 50 which were prepared from
aldehydes and malonitrile have been successfully employed to
react with ethyl acetoacetate and ammonia acetate to provide
1,4-DHPs 51 by grinding under solvent-free conditions
(Scheme 22).
36
Safari et al. developed a new three-component
synthesis of NH-free 1,4-DHPs of type 53 using chalcones 52,
ethyl acetoacetate and ammonia. Excellent yields of products
were obtained in refluxing water with the catalysis of cellulose
sulfuric acid (Scheme 23).
37
Ammonia acetate has also been used successfully as the
reaction partner of cyclic 1,3-diketone 54. Acylic 1,3-dicarbonyl
compounds and isatin for multicomponent synthesis of 1,4-
DHPs, unsymmetrical sipro- and fused cyclic scaffolds 55 were
provided in good to excellent yield by subjecting the four-
component reactions to refluxing toluene in the presence of 15
mol% pyridine (Scheme 24).
38
4. Multicomponent synthesis of 1,4-DHPs using
enaminone, b-enamino esters or enamines as amino
source
Enaminones, b-enamino esters and enamines are dinucleophilic
species which possess broad reactivity through employing both
the amino group and b-nucleophilic sp
2
carbon. These com-
pounds have been proved particularly useful for the synthesis of
various heterocyclic products. As introduced in the above
contents, b-enamino esters were key intermediates in many
amine-based MCRs synthesis of 1,4-DHPs, it is therefore not
surprising that b-enamino esters as well as analogous substrates
were also frequently employed as starting materials for 1,4-
DHPs synthesis directly. Actually, during chemists’ earliest
efforts in devising new synthesis of structurally unsymmetrical
1,4-DHPs, b-enamino esters were selected as ideal candidates as
starting building blocks. Usually, b-enamino esters are first
prepared by subjecting an amine to incorporate a 1,3-dicarbonyl
compound. The obtained b-enamino ester was then employed
with an aldehyde and a different 1,3-dicarbonyl compound to
provide unsymmetrical 1,4-DHPs in the manner of a three-
component reaction. This kind of strategy had been applied for
the synthesis of pyrazolyl functionalized 1,4-DHPs 57 by
Perumal and co-workers. As a result, acyclic 1,3-dicarbonyl
compounds, b-enamino ester 56 and pyrazolyl aldehydes were
successfully assembled to provide 57 in ionic liquid [bmim]Cl
in the presence of 3,4,5-trifluorobenzene boronic acid
(Scheme 25).
39
Wang et al. conducted a systematic investigation
on this kind of synthesis using cyclic diketone based b-enamino
esters 58, aromatic aldehydes and a different cyclic diketone.
These reactions were found practical in refluxing water or
solvent-free heating conditions to yield 1,4-DHPs 59
(Scheme 26).
40
An important feature of b-enamino ester/enaminone based
MCRs was that they are not only useful in the synthesis of 1,4-
DHPs with unsymmetrical structure, but also capable of serving
as building blocks in the synthesis of symmetrical 1,4-DHPs.
Dondoni et al. synthesized highly functionalized 1,4-DHPs 61
Scheme 20 Propiolate as electrophile in 1,4-DHPs synthesis.
Scheme 21 Synthesis of 1,4-DHPs involving 4-methyleneoxetan-2-one.
Scheme 22 Three-component synthesis of 1,4-DHPs using dienemalo-
nonitriles.
Scheme 23 Chalcone-based three-component 1,4-DHPs synthesis.
Scheme 24 Ammonia-based synthesis of fused spiro-1,4-DHPs.
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using b-keto esters and b-enamino esters prepared from identical
b-keto esters and ammonia to incorporate functionalized
aldehyde 60, the products were obtained as enantioenriched
compounds owing to the use of functional chiral aldehyde as
starting materials (Eq 1, Scheme 27).
41
Later on, the same group
developed an organocatalyzed three-component reaction of
sugar aldehydes 62, enaminones 63 and 1,3-dicarbonyl com-
pounds in the presence of
L-proline catalyst, 1,4-DHPs 64 were
furnished in excellent diastereoselectivity with the inducement of
chiral sugar aldehydes (Eq 2, Scheme 27).
42
Mirza-Aghayan et al.
developed a three-component synthesis of symmetrical 1,4-DHPs
65 by directly employing two molecules of identical b-enamino
esters and aldehydes (Eq 3, Scheme 27).
43
In addition, the free
NH group functionalized enaminones/b-enamino esters of 66
have also been discovered as practical materials for the synthesis
1,4-DHPs. Li and coworkers successfully performed the assem-
bly of 2 molecules of 66 and aldehydes to provide 2,6-
unsubstituted 1,4-DHPs 67 with the catalysis of TsOH?H
2
Oor
NaAuCl
4
?2H
2
O. Excellent tolerance had been demonstrated
with this protocol as R
2
and R
3
could both be alkyl or aryl
groups when incorporating aromatic aldehydes (Eq 4,
Scheme 27).
44
Interestingly, besides serving as dinucleophiles, b-enamino
esters could also act as electrophilic acceptors for multicompo-
nent 1,4-DHPs synthesis under proper conditions. Ajavakom
et al. discovered that the Lewis acid TiCl
4
catalyzes the assembly
of three molecules of b-enamino ester 68 to yield symmetrical
1,4-DHPs 72. This three-component process was initiated by a
Michael addition between 2 molecules of 66 affording inter-
mediates 69. Upon the elimination of one molecule of amine on
69, intermediates 70 were generated as new Michael acceptors.
The addition of one more 69 to 70 led to formation of
intermediates 71, and the intramolecular elimination cyclization
of 71 provided products 72 (Scheme 28).
45
Owing to the excellent reactivity and diverse availability of
enaminones, many diversity oriented, enaminone-based synthesis
of 1,4-DHPs have been reported by using either new 1,3-
dicarbonyl substrates or enaminones/b-enamino esters. For
example, enaminone 73 has been found as an ideal reaction
partner of isatin and cyclic 1,3-diketones to yield spiro-fused 1,4-
DHPs 74 in refluxing water with the catalysis of Brønsted acid
p-TSA (Eq 1 in Scheme 29),
46
while enaminone 75 with the
Scheme 25 Enaminone-based synthesis of pyrazolyl 1,4-DHPs.
Scheme 26 Enaminone-based synthesis of fused 1,4-DHPs.
Scheme 27 Various multicomponent synthesis of symmetrical 1,4-
DHPs.
Scheme 28 Assembly of 1,4-DHPs from three enaminones.
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coumarin backbone has been reported as practical precursor for
the synthesis of highly functionalized 1,4-DHPs 76 employing
(¡) lactic acid and ethyl lactate as catalyst and green solvent,
respectively (Eq 2 in Scheme 29).
47
Recently, the easily available
6-amino-1,3-dimethyl uracil 77, which was also formally an
enaminone building block, has been demonstrated as a useful
starting material in the three-component synthesis of 1,4-DHPs
78 by incorporating aromatic aldehydes and b-ketoesters in
water (50 uC) in the presence of thiourea dioxide (Eq 3 in
Scheme 29).
48
In the process of exploring new MCRs for heterocyclic
scaffold synthesis, Li et al. established the synthesis of fused
multicyclic 1,4-DHPs 81 from b-ketoester, aldehydes and ketene
aminal compounds (cyclic enaminones) 79. It was the 1,4-DHPs
80 that were first generated from a triethyl amine promoted
three-component assembly, as intermediate products, 80 under-
went efficient intramolecular coupling cyclization with K
2
CO
3
catalysis to produce the final products. On the other hand, fused
pyridine derivatives 83 were yielded when Meldrum’s acid 82 was
used as the dicarbonyl compound for the reaction under
standard reaction conditions (Scheme 30).
49
Similar to the cases of amine-based multicomponent synthesis
of 1,4-DHPs, substituted acetonitriles and enals were also
frequently employed reaction partners in enaminone/b-enamino
ester-based multicomponent synthesis of 1,4-DHPs, particularly
for the synthesis of unsymmetrical 1,4-DHPs. For example,
starting from enaminones 79, aldehydes and malonitrile, Li et al.
attained 1,4-DHPs 84 in refluxing MeCN in the presence of
Scheme 29 Various synthesis of spiro- or fused 1,4-DHPs with different enaminones.
Scheme 30 1,4-DHPs-based polycycles synthesis via enaminone-based three-component reaction.
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triethylamine, and further treatment with K
2
CO
3
in DMF on 84
led to the production of 85 (Scheme 31).
50
On the other hand,
interesting chemo-selective formation of 1,4-DHPs were dis-
covered in the three-component reactions of enaminones 86,
aldehydes and b-cyanoketones, wherein the selective condensa-
tion of the carbonyl instead of cyano group in the b-cyanoke-
tones allowed the production of 3-cyano functionalized 1,4-
DHPs 87,
51
and a similar transformation was also applied for the
synthesis of indolyl substituted 1,4-DHPs 88 by using corre-
sponding indolyl functionalized cyanoketones (Scheme 31).
52
More recently, malonitrile and ethyl 2-cyanoacetates were also
successfully subjected to incorporate aldehydes and nitro-
functionalized cyclic enaminones 89 for 1,4-DHP synthesis.
Unlike the reaction process involved in the MCRs using
b-cyanoketones, 2-amino functionalized fused 1,4-DHPs 90 were
afforded in the reactions via a nucleophilic addition transforma-
tion on the cyano group of the b-cyanoester (Scheme 31).
53
In
the area of multicomponent synthesis of 1,4-DHPs employing
enaminone as amino source, Pan and coworkers developed the
three-component regioselective synthesis of 1,4-DHPs of type 92
and isomeric 1,2-DHPs 93 using N,N9-dimethyl amino functio-
nalized enaminones 91, primary amines and enals. The designed
systematic experiments using primary amines of different
electronic and steric properties suggested that a strong electron
withdrawing group or bulky ortho-group tend to induce the
formation of 1,2-DHPs 93, combined with the observation of
compounds 94 in some entries, it was proposed that 94 were the
key intermediates of the reaction. The normal transformation of
the N-nucleophilic condensation with the formyl group in the
enal component led to the production of 1,4-DHPs 92, when a
strong electron withdrawing or bulky ortho-group was included
in the amine component, the nucleophilicity of the amino group
in 94 was significantly hindered, which allowed the nucleophilic
carbon atom in 94 to attack the enal formyl first and led to the
regioselective formation of 1,2-DHPs 93. This work was the first
example on the tunable selective synthesis of 1,4-DHPs and 1,2-
DHPs with three-component reactions (Scheme 32).
54
Although not frequently available, simple enamines have also
been reported to be capable of serving as dinucleophilic building
blocks for multicomponent synthesis of 1,4-DHPs by acting
similarly as enaminones and b-enamino esters. Quiroga et al.
reported the synthesis of elaborated polycyclic products 96 with
heteroaryl amines 95, isatin and various 1,3-dicarbonyl sub-
strates. Although 96 are formally fused aromatic heterocycles,
the central 1,4-DHP backbone was formed during the transfor-
mation via cross-condensed intermediates 97 (Scheme 33).
55
Scheme 31 Various synthesis of 1,4-DHPs-based heterocycle synthesis with different enaminones.
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Rather recently, a similar three-component transformation using
enamine 98, cyclic diketones and aromatic aldehydes have been
reported to provide multicyclic elaborated 1,4-DHPs 99
(Scheme 34).
56
5. Multicomponent synthesis of 1,4-DHPs using other
amino sources
According to related results in the known literature, amines,
ammonia and enaminone analogs were obviously the most
frequently and conventional amino sources used for the synthesis
of 1,4-DHPs, however, some other types of N-containing species
such as cyanides, imines etc. were also able to serve as the amino
sources for the synthesis of novel 1,4-DHPs via MCRs as
occasional cases. Depending on the properties of these amino
resources, both 1,4-DHPs with novel elaboration and 1,4-DHPs
with similar structure as those equivalents obtained from
conventional amino resources were possible.
5.1. Using cyanide as amino source
As reactive starting materials, cyanide derivatives such as
malonitrile were frequently utilized in the synthesis of 1,4-DHPs
in amine, ammonia or enaminone participated MCRs. In these
kinds of reactions, as introduced above, it was amine, enamione
or ammonia that served as the amino source to construct the
heterocyclic backbone while cyano groups were mainly involved
as the donor of electrophilic carbons in those MCRs.
Interestingly, in some reactions, it was also possible to directly
employ the N atom in the cyano group as the amino source of
1,4-DHPs. Fustero and coworkers developed the three-compo-
nent protocol involving fluorinated nitriles (cyanides) 100,alkyl
propiolates and chiral allyl p-tolyl sulfoxide 101 for the
synthesis of 1,4-DHPs 104. The reactions proceeded under the
promotion of KN(SiMe
3
)
2
via two steps of cascade transforma-
tions, the first nucleophilic addition of 101 to 100 under
catalysis of base gave intermediates 102, the second step
addition of 102 to propiolates led to the formation of
intermediates 103, and intramolecular Michael addition on
103 provided enantioenriched 1,4-DHPs 104 in generally
excellent diastereoselectivity, which was induced by the chiral
p-tolyl sulfoxide (Scheme 35).
57
Scheme 32 Enaminone initiated regioselective synthesis of 1,4- and 1,2-DHPs.
Scheme 33 Cyclic enamine-based three-component synthesis of highly
functionalized 1,4-DHPs.
Scheme 34 Multicyclic 1,4-DHPs synthesis using cyclic enamines.
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5.2. Using imine as amino source
Imines were usually the resulted products from the condensation
of amines and aldehydes. Direct employment of aldehydes,
amines and propiolates have been a well established protocol for
the synthesis of 1,4-DHPs. Interestingly, Fukuzawa et al.
developed a three-component reaction of imines 105 and two
molecules of propiolates to provide 1,4-DHPs of type 9 (see also
Scheme 7) in the presence of 10 mol% Lewis acid catalyst
Sc(OTf)
3
. In these reactions, one key step was the decomposition
of imines 105 to aldehydes and amines. Only low to moderate
yields of products were obtained by this methodology with
imines prepared from the condensation of aromatic aldehydes
with aromatic/aliphatic amines (Scheme 36).
58
5.3. Using thioamide as amino source
In devising the MCRs synthesis of structurally diverse 1,4-DHPs
employing new C-nucleophilic building blocks, b-arylthioamides
106 have been found as useful starting materials in the synthesis
of 1,4-DHPs 108 containing a thioester functional group. During
the reaction process, 106 tautomerized as 107 to incorporate
aldehydes in the presence of electron withdrawing group
functionalized acetonitriles and alkyl halide. Microwave irradia-
tion had been found to give superior results over traditional
heating conditions to this Et
3
N-catalyzed 1,4-DHPs synthetic
method (Scheme 37).
59
On the basis of this transformation, a
further devised cascade three-component protocol for the
synthesis of fused heterocyclic 1,4-DHPs 112 was reported by
employing 2-chlorophenyl functionalized thioamides 109, alde-
hydes and malonitrile. In the presence of KF/neutral Al
2
O
3
catalysts with PEG6000 and microwave irradiation, 112 were
efficiently provided through the intramolecular cyclization of
intermediates 110/111 (Scheme 38).
60
6. Conclusions
As a class of typical heterocyclic scaffolds with broad spectrum
of biological and pharmaceutical profiles, 1,4-DHPs have been
regarded as significant targets of organic synthesis. Following
the daily increasing requirement on molecular libraries during
the discovering process of new lead compounds and drugs,
urgent promotion was simultaneously brought to the chemistry
of 1,4-DHPs synthesis. Particularly, the synthesis of 1,4-DHPs
possessing novel and diverse elaboration consists of the main
effort in this field. With those various types of newly designed
MCRs, it is now possible to access highly functionalized 1,4-
DHPs with enormously expanded diversity on the basis of the
classical Hantzsch multicomponent synthesis. The breakthrough
in the field should be ascribed to those highly diversified and
reactive starting materials including amine resources, various
C-electrophiles such as aldehydes and isatins, bifunctional
building blocks such as enals, enones, 1,3-dicarbonyl compounds
Scheme 35 Diastereoselective synthesis of 1,4-DHPs using cyanide
amino source.
Scheme 36 Imine in three-component synthesis of 1,4-DHPs.
Scheme 37 Three-component synthesis of thioester functionalized 1,4-
DHPs.
Scheme 38 Cascade three-component synthesis of sulphur-containing
heterocycle fused 1,4-DHPs.
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as well as different alkynes/alkenes etc. In this regard, devising
more new MCRs for the synthesis of structurally novel 1,4-
DHPs relies on further endeavours in exploring more unconven-
tional building blocks.
In addition, in terms of sustainable synthesis, to develop 1,4-
DHPs synthesis with MCRs under milder, greener conditions is
also highly desirable in this field. More importantly, as most new
MCRs for 1,4-DHPs assembly provide products containing chiral
centers, methods of directly accessing enantiomerically pure 1,4-
DHPs with MCRs is in urgent requirement. Establishment of
efficient methodologies providing chiral 1,4-DHPs is highly
expectable to significantly enhance the progress of discovering
more medicinally valuable heterocyclic compounds.
Acknowledgements
The authors gratefully acknowledge the financial support from
the NSFC of China (21102059), the NSF of Jiangxi Province
(20114BAB213005) and a Sponsored Program for Cultivating
Youths of Outstanding Ability from Jiangxi Normal University.
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