Gold-catalyzed multicomponent reaction: Facile strategy for the synthesis of N-substituted 1,4-dihydropyridines by using activated alkynes, aldehydes, and methanamine

Article abstract of DOI:10.1002/ejoc.201301203

A convenient and efficient gold-catalyzed multicomponent reaction was developed for the synthesis of a wide range of N-substituted 1,4-dihydropyridines, which are found in a variety of bioactive compounds. This process proceeds smoothly under mild conditions with the use of commercially available substrates and affords the desired products in good to excellent yields. This method provides a highly efficient synthetic route to N-substituted 1,4-dihydropyridines from activated alkynes, aldehydes, and methanamine for which catalytic approaches are scarce. A facile gold-catalyzed strategy for the synthesis of N-substituted 1,4-dihydropyridines is developed through the multicomponent reaction of activated alkynes, aldehydes, and methanamine. The reaction is conducted under convenient conditions and affords the desired compounds in good to excellent yields. Copyright

Full text of DOI:10.1002/ejoc.201301203

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301203
Gold-Catalyzed Multicomponent Reaction: Facile Strategy for the Synthesis of
N-Substituted 1,4-Dihydropyridines by Using Activated Alkynes, Aldehydes,
and Methanamine
Shaohua Wang,[a] Huoji Chen,[b] Hong Zhao,[a] Hua Cao,*[a] Yongjian Li,[a] and
Qiang Liu*[b]
Keywords: Multicomponent reactions / Nitrogen heterocycles / Aldehydes / Alkynes / Gold
A convenient and efficient gold-catalyzed multicomponent
reaction was developed for the synthesis of a wide range of
N-substituted 1,4-dihydropyridines, which are found in a
variety of bioactive compounds. This process proceeds
smoothly under mild conditions with the use of commercially
available substrates and affords the desired products in good
to excellent yields. This method provides a highly efficient
synthetic route to N-substituted 1,4-dihydropyridines from
activated alkynes, aldehydes, and methanamine for which
catalytic approaches are scarce.
Scheme 1), nimodipine (II), cinildipine (III), arandipine, ler-
candipine, watanidipine hydrochloride, efonidipine hydro-
chloride ethanol, palonidipine hydrochloride, and elgodip-
ine hydrochloride.
Introduction
Multicomponent reactions (MCRs) have evolved as
powerful tools in synthesis that push the limits of synthetic
efficiency by using more than two reactants to create novel
products with an optimal number of new bonds and func-
tionalities.[1] At the forefront of these chemical methodolo-
gies, the MCR strategy has been developed to enable the
construction of complex and diverse structures from readily
available starting materials in one single operation under
mild conditions.[2]
Rapid synthesis of elaborated and diverse 1,4-DHPs (1,4-
dihydropyridines) has been recognized as a very important
issue, owing to their significant biochemistry and biological
activity.[3] 1,4-DHPs exhibit a wide range of pharmacologi-
cal activities such as acting as calcium channel blockers,[4]
HIV protease inhibitors,[5] multidrug-resistance (MDR) re-
versing agents,[6] radioprotection agents,[7] cocaine depend-
ent regulators,[8] vasodilators,[9] and antitumor agents, and
they additionally show hepatoprotective activity.[10] Since
the first report of the Hantzsch synthesis of 1,4-DHPs, a
number of strategies have been developed for their synthe-
sis,[11] because 1,4-DHPs are well-known Ca2+ channel
blockers, and they have emerged as one of the most impor-
tant classes of drugs for the treatment of cardiovascular dis-
eases. Examples included well-known nifedipine (I,
Scheme 1. Important 1,4-dihydropyridines derivatives.
In view of the importance of 1,4-DHPs, although some
procedures catalyzed by I2,[12] Yb(OTf)3,[13] 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU),[14] Et3N,[15] l-proline,[16]
AcOH,[17] and others have been reported in this area,[18]
only a few of these report the hydroamination of activated
alkynes with amines to form new carbon–heteroatom bonds
for the construction of 1,4-DHPs. Moreover, the biological
[a] School of Chemistry and Chemical Engineering, Guangdong
Pharmaceutical University,
Guangzhou 510006, P. R. of China
E-mail: caohua@gdput.edu.cn
[b] School of Traditional Chinese Medicine, Southern Medical
University,
Guangzhou, 510515, P. R. of China
E-mail: gzlq2002@163.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301203
Scheme 2. Important N-substituted 1,4-dihydropyridines deriva-
tives.
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Gold-Catalyzed Multicomponent Reaction
activity of N-substituted DHPs has started to attract in- used (Table 1, entries 3 and 4). Stimulated by these results,
creasing attention (Scheme 2).[19]
we attempted to examine Au(PPh3)Cl by using a silver salt
In earlier work, we developed efficient approaches to as the catalyst in the reaction (Table 1, entries 9–11). Excit-
synthesize heterocyclic compounds from activated alk- ingly, desired product 4aa was produced in 59% yield in
ynes.[20] In this context, we report herein our studies focused the presence of Au(PPh3)Cl with AgOTf as the co-catalyst
on preparing N-substituted DHPs from activated alkynes.
(Table 1, entry 11). To improve the process under the cataly-
sis of Au(PPh3)Cl with AgOTf as the co-catalyst, we at-
tempted to employ a variety of bases in the reaction system
(Table 1, entries 13–15). KHCO3 was the most helpful
(Table 1, entry 13). Subsequently, with regard to the sol-
vent, DMF, DMSO, 1,4-dioxane, and toluene all proved to
be suitable in the presence of Au(PPh3)Cl with AgOTf, and
3aa was given in 74–79% yield, whereas toluene (Table 1,
entry 19) led to a lower yield. Finally, different temperatures
and times were also tested (Table 1, entries 20–23), but
negative results were found related to that foregoing.
Results and Discussion
The MCRs of methyl but-2-ynoate (1a), methanamine
(2a), benzaldehyde (3a) did not proceed under catalyst-free
conditions at 100 °C over 6 h. Considering that the hydro-
amination was the triggering sequence, we then focused our
efforts on the search for a catalyst to promote the hydro-
amination to complete the transformation.
At the outset of our studies, we focused on identifying
the catalytic system and reaction conditions for the MCRs.
With the optimized conditions in hand (Table 1, entry 4),
Our studies began with optimizing the reaction conditions we next turned our attention to the scope of the multicom-
by choosing methyl but-2-ynoate (1a), methanamine (2a), ponent reaction, and the results are summarized in Table 2.
and benzaldehyde (3a) as model substrates. Initially, nine We used 1a as a fixed substrate to examine the reactions
different commonly used metal salts (Table 1, entries 1–6), with various types of aldehydes. Compounds 1a and 2a and
including AgBF4, AgSbF6, PdCl2, Pd(OAc)2, Pd(SbF6)2, aldehydes 3 were suitable partners in this process, and the
Pd(OTf)2, AuCl3, and Au(PPh3)Cl, were used as the catalyst products were obtained in similar yields. First, aromatic al-
to conduct this reaction at 100 °C over 8 h in CH3CN. To dehydes were treated with 1a and 2a under the optimized
our delight, we found that AgSbF6, Au(PPh3)Cl, and AuCl3 reaction conditions, and the corresponding N-substituted
afforded corresponding product 4aa (Table 1, entries 2, 5, DHPs were generated in moderate to excellent yields
6). The reaction did not proceed if palladium species were (Table 2, entries 1–11). Interestingly, the MCRs proceeded
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Base
Solvent
T [°C]
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
AgBF4
AgSbF6
PdCl2
Pd(OAc)2
Pd(SbF6)2
Pd(OTf)2
AuCl3
Au(PPh3)Cl
Au(PPh3)Cl/AgSbF6
Au(PPh3)Cl/AgBF4
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
Au(PPh3)Cl/AgOTf
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMSO
1,4-dioxane
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
80
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
12
5
trace
Ͻ5
–
–
–
–
11
18
49
42
58
trace
71
4
66
83
80
85
67
78
69
86
64
9[c]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
KHCO3
KH2PO4
KOAc
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
100
100
[a] Reaction conditions: 1a (1.2 mmol), 2a (0.5 mmol), 3a (0.8 mmol), catalyst (5 mol-%), base (0.7 mmol), solvent (3.0 mL). [b] Yield was
determined by GC. [c] Au(PPh3)Cl (5 mol-%), silver salt (5 mol-%).
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S. Wang, H. Chen, H. Zhao, H. Cao, Y. Li, Q. Liu
SHORT COMMUNICATION
Table 2. Au-catalyzed synthesis of 1,4-dihydropyridines.[a]
[a] Yield of isolated product.
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Gold-Catalyzed Multicomponent Reaction
Scheme 3. Proposed mechanism.
smoothly and generated the corresponding N-substituted dition with 1a to afford adduct A. Meanwhile, 1a is acti-
DHPs in good yields regardless of whether an electron- vated by [Au(PPh3)OTf] to give AuI–alkyne complex B,
withdrawing or an electron-donating group was introduced which would coordinate with adduct A to produce interme-
on the phenyl ring. Substituents at the para, meta, and ortho diate C. The coordination of the gold salt to 1a lowers the
positions of the arene ring did not affect the efficiencies. We electron density of the CϵC bond, which makes nucleo-
were next interested in evaluating the scope of this gold- philic attack of adduct A towards AuI–alkyne complex B
catalyzed MCR by using commercially available aliphatic easier and smoother. Intermediate C further undergoes C–
aldehydes as substrates. It was pleasing to find that a variety N bond formation to generate polarized intermediate D
of aliphatic aldehydes 3l–q reacted well under the optimized prior to the formation of intermediate E, and then interme-
conditions to afford the corresponding products in good diate E isomerizes to iminium intermediate EЈ, which at-
yields. All of these results indicated that both aromatic and tacks the carbonyl carbon atom of the aldehyde; de-
aliphatic aldehydes were suitable partners in this process hydration gives rise to intermediate F. Finally, intermediate
and that the catalytic system was applicable to the prepara- F evolves through 6π electrocyclization followed by depro-
tion of N-substituted DHPs. Finally, the desired product tonation to desired product 4aa.
was formed upon using 1,3-diphenylprop-2-yn-1-one (1b) as
the substrate (Table 2, entry 19), and the molecular struc-
Conclusions
ture of representative product 4ba was confirmed by an X-
ray diffraction analysis (Figure 1). Unfortunately, aniline
was ineffective in this reaction.
In summary, we have described the gold-catalyzed MCRs
of activated alkynes, methanamine, and aldehydes for syn-
thesis of N-substituted DHPs in one-pot fashion. The reac-
tion provided a convergent approach to generate a C–C and
a C–N bond for synthesis of N-substituted DHPs deriva-
tives in moderate to good yields. Further studies will focus
on utilizing this catalytic system in organic synthesis and
applications of this methodology are underway and will be
reported in future publications.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
pounds 4aa–ba.
Acknowledgments
Figure 1. X-ray structures of 4ba.
The work was financially Supported by the Foundation for Distin-
guished Young Talents in Higher Education of Guangdong, China
(LYM11083, 2012LYM_0086) and the National Natural Science
Foundation of China (NSFC) (grant numbers 21272044,
On the basis of the experimental results, a tentative
mechanistic interpretation of the preceding observations is
proposed in Scheme 3. First, 2a undergoes nucleophilic ad- 21302023).
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Received: August 9, 2013
Published Online: October 16, 2013
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