Acid-catalyzed cascade reactions of enaminones with aldehydes: C-H functionalization to afford 1, 4-dihydropyridines

Article abstract of DOI:10.1002/ejoc.201000607

An efficient acid-catalyzed approach to the synthesis of functional 1,4-dihydropyridines from the reaction of readily available enaminones with aldehydes has been developed. This methodology was realized by a cascade reaction involving first formation of divinylmethanes and subsequent intramolecular cyclization.

Full text of DOI:10.1002/ejoc.201000607

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000607
Acid-Catalyzed Cascade Reactions of Enaminones with Aldehydes:
C–H Functionalization To Afford 1,4-Dihydropyridines
Jingyu Yang,[a] Chengyu Wang,[a] Xin Xie,[a] Hongfeng Li,[a] and Yanzhong Li*[a]
Keywords: Nitrogen heterocycles / Cyclization / Lewis acids / C–H activation / Domino reactions
An efficient acid-catalyzed approach to the synthesis of func-
tional 1,4-dihydropyridines from the reaction of readily avail-
able enaminones with aldehydes has been developed. This
methodology was realized by a cascade reaction involving
first formation of divinylmethanes and subsequent intramo-
lecular cyclization.
though much progress has been made in recent years in
devising new processes, especially for the synthesis of
heterocycles, that involve the use of enaminones, direct
carbon–carbon bond-forming reactions with carbon elec-
trophiles is still quite limited.[8] Herein, we would like to
report the stereoselective synthesis of enaminones and its
cascade addition/cyclization reactions with aldehydes cata-
lyzed by Brønsted or Lewis acids, in which a C–C bond is
formed directly at the α-carbon of the enaminone
(Scheme 1). This reaction offers an efficient and straightfor-
ward route to 1,4-dihydropyridines.
Introduction
1,4-Dihydropyridines (1,4-DHPs) are very attractive
heterocycles in medicinal chemistry and pharmacology due
to their wide range of biological activities.[1] For example,
these compounds are known as calcium channel blocker
drugs,[2] and they have also been reported to be vasodilators
and bronchodilators. They also possess antiatherosclerotic,
antitumor, antidiabetic, or photosensitizing activities.[3]
Furthermore, they are useful and versatile synthetic inter-
mediates in organic chemistry.[4] As a result, much effort
has been paid to their preparation. The Hantzsch reaction,
the condensation of a β-keto ester or a 1,3-dicarbonyl com-
pound with an aldehyde and ammonia, is one of the most
well-documented methods for the formation of 1,4-DHPs,
and improved procedures for the synthesis of 1,4-DHPs
have been reported.[5] For example, it is known that 1,4-
DHPs can be constructed through the condensation of en-
aminones with α,β-unsaturated aldehydes.[5b,6f] The reaction
of amines and 3-(2-formylphenoxy)propenoates to 1,4-
DHPs is also reported.[6e] Although these procedures are
efficient for the synthesis of 1,4-DHPs, the C–H function-
alization of enaminones to 1,4-DHPs remains a challenging
task. In recent years, the direct conversion of C–H bonds
into C–C bonds has emerged as a rapidly growing area in
organic chemistry, as the process is atom economic and en-
vironmentally benign for the synthesis of useful synthetic
intermediates and materials.[7] In this regard, enaminone
derivatives are considered to serve as a viable C–H compo-
nent for direct functionalization. Enaminones are versatile
reagents that combine the ambident nucleophilicity of en-
amines with the ambident electrophilicity of enones. Al-
Scheme 1.
Results and Discussion
It is known that enaminones are prepared by direct con-
densation of 1,3-dicarbonyl compounds with amines in re-
fluxing aromatic hydrocarbons, or by the addition of
amines to alkynones.[9] In recent years, transition-metal-me-
diated approaches have also been reported.[10] However,
many of these processes suffer from limitations such as
drastic reaction conditions, low yields, or lack of stereose-
lectivity. Here we found that N-substituted enaminones 2
were readily prepared through conjugate addition of an-
ilines or aliphatic amines with terminal alkynones or ethyl
propiolate (Table 1). The reaction could be carried out con-
veniently at room temperature or at 80 °C in toluene, and
the corresponding enaminones were formed in good to high
yields. It is noteworthy that the stereoselectivity of this reac-
tion is high except for 2h, and the Z-isomer was observed
[a] Institute of Medicinal Chemistry, Department of Chemistry,
East China Normal University,
3663 North Zhongshan Road, Shanghai, 200062, People’s
Republic of China
Fax: +86-21-62233969
E-mail: yzli@chem.ecnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000607.
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J. Yang, C. Wang, X. Xie, H. Li, Y. Li
SHORT COMMUNICATION
as the major isomer, possibly due to the tendency to form idene)benzenamine byproduct was observed in these experi-
an intramolecular hydrogen bond. In the case of 2h, the ments. The Lewis acid FeCl3·6H2O afforded a moderate
ratio of Z/E changed greatly, as observed in the crude reac- yield (48%) of 3a (Table 2, Entry 8). In the absence of a
tion mixture and the isolated materials (Table 1, Entry 9). catalyst, no reaction occurred (Table 2, Entry 9). It is wor-
When a less nucleophilic amine such as 4-chlorobenzen- thy to note that the general and efficient approaches to 1,4-
amine was used, the addition of FeCl3 as a catalyst ac- DHPs without substituents in the 2- and 6-positions are
celerated the reaction, and desired 2b was obtained in 85% still limited,[5d,6] and most of the methods suffer from harsh
yield within 1 h. Without this catalyst, a longer reaction reaction conditions and relatively low yields of the prod-
time was required (Table 1, Entries 2 and 3). We can see ucts, or are specific to substituted substrates. It is reported
from Table 1 that the desired enaminones were obtained in that 1,4-DHPs without substitutes in the 2- and 6-positions
high yields and with excellent stereoselectivity within short exhibit important pharmaceutical activities; for example,
reaction time.
dimers of these compounds are potential inhibitors of HIV-
1 protease and possess anticancer activity.[11]
Table 1. Stereoselective formation of enaminones.
Table 2. Optimization studies for the formation of 1,4-dihydropyr-
idines.
[a] Isolated yields. Unless noted, all the reactions were carried out
for 0.5–1 h. The ratio of the Z/E isomers in the crude reaction
mixture is given in parentheses. [b] Reaction time was 5 h. [c] Reac-
tion time was 23 h. [d] Reaction time was 6 h. [e] The ratio is 100:23
in the isolated product. [f] Under solvent-free conditions.
[a] Isolated yields. [b] NR = no reaction.
With the optimized reaction conditions in hand, we next
We started our investigation with (Z)-3-(4-methoxyphen- examined the substrate scope of this catalytic method for
ylamino)-1-phenylprop-2-en-1-one (2a). The reaction of 2a the synthesis of 1,4-DHPs by using a variety of enaminones
with 4-nitrobenzaldehyde was selected as the prototypical 2 and aldehydes (Table 3). We first investigated the elec-
case to screen the experimental conditions (Table 2). To our tronic effects of the aromatic substituents on the aldehydes.
delight, it was found that in the presence of a catalytic It was found that an electron-withdrawing (-Cl) aryl group
amount of TsOH·H2O, TFA, or NaAuCl4·2H2O, 2a was afforded the corresponding product 3b in 78% yield
smoothly transformed into desired 1,4-DHP 3a in 75–79% (Table 3, Entry 1). Benzaldehyde also gave good yield of 3c
yield (Table 2, Entries 2–4). It is noteworthy that increasing (Table 3, Entry 2). However, an electron-donating (-Me)
the amount of aldehyde from 0.75 to 1.0 equiv. not only aryl group resulted in a longer reaction time of 4 d with
lessened the reaction time, but also enhanced the product 80% yield of 3d as a result of the lower reactivity of this
yield (Table 2, Entry 2 vs. 6). The best yields were achieved aldehyde (Table 3, Entry 3). The use of NaAuCl4·2H2O as
by employing TsOH·H2O as the catalyst (85–87%; Table 2, catalyst reduced the reaction time dramatically to 16 h, and
Entries 6 and 7). The results indicated that the use of an dihydropyridine 3d was formed in 83% yield (Table 3, En-
excess amount of aldehyde ensured efficient elimination of try 4). A heteroaryl aldehyde such as 2-thienylaldehyde was
amine. Actually, the imine 4-methoxy-N-(4-nitrobenzyl- also compatible under the reaction conditions, furnishing
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C–H Functionalization To Afford 1,4-Dihydropyridines
3f, 3g, and 3l in yields of 76–90% (Table 3, Entries 6–8, 13). through the reaction with p-nitrobenzaldehyde (Table 3, En-
The reaction also proceeded smoothly with N-alkyl-substi- try 14). However, the use of paraformaldehyde resulted in a
tuted enaminones 2d–f to produce desired 1,4-DHPs 3i–k complicated reaction mixture (Table 3, Entry 15). The
in yields of 48–81% (Table 3, Entries 10–12). Enaminone 2g structure of 1,4-DHP was further confirmed by X-ray crys-
with an alkyl substituent on the carbonyl carbon led to the tallographic analysis of 3c.[12]
formation of 3l in 90% yield (Table 3, Entry 13). The cycli-
To understand the reaction mechanism, we carried out
zation was also successfully extended to enaminoester 2h, the reaction of 2a with p-nitrobenzaldehyde at room tem-
and 77% yield of 3m bearing two ester groups was obtained perature. It was found that divinylmethane intermediate 4a
Table 3. Synthesis of various substituted 1,4-dihydropyridines.
[a] Conditions A: TsOH·H2O (10 mol-%), 80 °C in DCE. Conditions B: NaAuCl4·2H2O (10 mol-%), 80 °C in DCE. [b] Isolated yields.
[c] The reaction was not clean.
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J. Yang, C. Wang, X. Xie, H. Li, Y. Li
SHORT COMMUNICATION
was isolated in 53% yield along with 35% of desired 3a (Z)-4. Isomerization of (Z)-4 into (E)-4 followed by nucleo-
(Scheme 2). When TFA (20 mol-%) was used as the catalyst, philic attack of the amino group to the enone moiety leads
4a was obtained in a higher yield of 70% at room tempera- to cyclized product 3.
ture. Isolated 4a was subjected to standard conditions by
To make this overall approach more convenient, a one-
using p-nitrobenzaldehyde (1 equiv.) to afford 3a in 92% pot process proceeding through sequential reactions was
yield. Without p-nitrobenzaldehyde, 3a could also be also checked. Typically, alkynone 1a (1 equiv.) was first
formed in 73% yield; however, a longer reaction time of treated with furan-2-ylmethanamine (1 equiv.) in DCE for
19 h was required. The results indicated that an excess 0.5 h to form compound 2 in situ, and TsOH·H2O (10 mol-
amount of aldehyde could accelerate the reaction process %) was then added. The mixture was stirred at 80 °C for
by trapping the released amine. The formation of divin- 10 h to give 1,4-DHP 3i in 60% yield (Scheme 4).
ylmethane 4a might be the key step in this cascade reac-
tion. Interestingly, during the reaction, the double bond
configuration of the enaminone changed from the Z form
in 2a to exclusively the E form in 4a, which was verified by
its NOESY spectra. In addition, the reaction of 2a with
paraformaldehyde afforded divinylmethane 4b with the E
form in 81% yield; the structure of 4b was confirmed by X-
ray crystallography[12] (Scheme 2).
Scheme 4.
Conclusions
In conclusion, we have successfully developed an efficient
method for the synthesis of 1,4-DHPs without substituents
at the C-2 and C-6 positions through an acid-catalyzed vi-
nylation/cyclization cascade reaction, in which direct con-
version of the C–H bonds of enaminones to C–C bonds
was achieved. The 1,4-DHP products can also be con-
structed from alkynones, amines, and aldehydes by a se-
quential process that omits the isolation of the enaminone
intermediates. Further application of this novel acid-cata-
lyzed procedure and endeavors to extend the scope of the
reaction such as for the synthesis of unsymmetrical substi-
tuted 1,4-DHPs are under progress in our group.
Scheme 2.
On the basis of the above observations, a possible reac-
tion mechanism is proposed in Scheme 3. First, nucleophilic
addition of enaminone 2 to the carbonyl group of the alde-
hyde occurs to form 6. This process is different from the
Hantzsch reaction, which includes a Michael addition of
the enamine to the α,β-unsaturated carbonyl compound.
Compound 6 reacts with another enaminone molecule
through benzylic substitution to generate divinylmethane
Experimental Section
Typical Procedure for the TsOH·H2O- or NaAuCl4·2H2O-Catalyzed
Synthesis of 1,4-Dihydropyridines 3 from (Z)-Enaminones 2 and Al-
dehydes: To a solution of (Z)-enaminone 2 (0.4 mmol) and aldehyde
(0.4 mmol) in DCE (2 mL) was added TsOH·H2O (3.8 mg, 10 mol-
%) or NaAuCl4·2H2O (8.0 mg, 10 mol-%). The resulting solution
was stirred at 80 °C until the reaction was complete, as monitored
by thin-layer chromatography. The solvent was evaporated in
vacuo, and the residue was purified by chromatography on silica
gel to afford 1,4-dihydropyridine derivatives 3.
[1-(4-Methoxyphenyl)-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-diyl]-
bis(phenylmethanone) (3a): Yield: 88 mg (85%); yellow solid, m.p.
225–226 °C. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 3.78 (s, 3 H,
OCH3), 5.78 (s, 1 H, 4-H), 6.89–6.93 (m, 2 H), 7.11–7.15 (m, 2 H),
7.30 (s, 2 H, 2-H), 7.36–7.40 (m, 4 H), 7.44–7.48 (m, 2 H), 7.51–
7.53 (m, 4 H), 7.70–7.73 (m, 2 H), 8.12–8.16 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3, Me4Si): δ = 37.08, 55.52, 115.16, 118.67,
123.07, 123.56, 128.25, 128.32, 129.04, 131.23, 135.92, 138.51,
140.79, 146.37, 152.84, 158.68, 193.94 ppm. HRMS: calcd. for
C32H24N2O5 516.1685; found 516.1696.
Scheme 3.
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C–H Functionalization To Afford 1,4-Dihydropyridines
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20572025 and 20872037) for financial support. We also
thank the Laboratory of Organic Functional Molecules, Sino-
French Institute of ECNU, for support.
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Received: May 2, 2010
Published Online: June 15, 2010
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