5-Pyrrolidin-2-yltetrazole-promoted one-pot hantzsch polyhydroquinoline synthesis using NH4HCO3 as nitrogen source

Article abstract of DOI:10.1071/CH08197

A straightforward and green synthesis of polyhydroquinoline derivatives was reported via a four-component coupling reaction of aldehydes, dimedone, active methylene compounds, and ammonium bicarbonate in the presence of 5-pyrrolidin-2-yltetrazole under solvent-free conditions. The method offers several advantages including high yields, an environmental friendly procedure, a short reaction time, and easy isolation of products.

Full text of DOI:10.1071/CH08197

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 860–863
www.publish.csiro.au/journals/ajc
5-Pyrrolidin-2-yltetrazole-Promoted One-Pot Hantzsch
Polyhydroquinoline Synthesis Using NH4HCO3
as Nitrogen Source
Weike Su,A,B Jia Li,A and Jianjun LiA
AKey Laboratory of Pharmaceutical Engineering of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, China.
BCorresponding author. Email: suweike@zjut.edu.cn
A straightforward and green synthesis of polyhydroquinoline derivatives was reported via a four-component coupling
reactionofaldehydes, dimedone, activemethylenecompounds, andammoniumbicarbonateinthepresenceof5-pyrrolidin-
2-yltetrazole under solvent-free conditions. The method offers several advantages including high yields, an environmental
friendly procedure, a short reaction time, and easy isolation of products.
Manuscript received: 9 May 2008.
Final version: 10 September 2008.
Polyhydroquinoline derivatives are of considerable interest in
industry as well as in academia owing to their promising
biological activity as calcium channel blockers, vasodilators,
bronchodilators, andanti-atherosclerotic, geroprotective, hepato-
protective and antidiabetic agents.[1] Furthermore, recent studies
have revealed several other medicinal applications that indicate
neuroprotectant and platelet anti-aggregratory activity, cerebral
anti-ischemic activity in the treatment of Alzheimer’s disease,
andasachemosensitizerintumourtherapy.[2] Thus, thesynthesis
of this heterocyclic nucleus is of great interest.
1,4-Dihydropyridines (1,4-DHPs) were first synthesized
more than a century ago by heating a mixture of aldehyde, β-keto
ester, and ammonia in ethanol and refluxing for several hours.[3]
However, the method suffers from drawbacks such as long reac-
tion times, drastic reaction conditions, the use of a large quantity
of volatile organic solvents, and providing unsatisfactory yields.
Recently, many synthetic methods for preparing these com-
pounds have been reported, including classical conditions, with
microwave or ultrasound irradiation, using Lewis acids as well
as protic acid promoters such as: microwaves,[4] ionic liquid,[5]
high temperature under reflux conditions,[6] iodine,[7] metal
triflates,[8] HY-zeolite (acidic molecular sieve),[9] TMSCl–
NaI (chlorotrimethylsilane–NaI),[10] ceric ammonium nitrate
(CAN),[11] or l-Proline,[12] and a grinding technique.[13] But
some of the methods still have their own limitations in terms of
yields, the use of high temperatures, catalysts that are harmful
to the environment, etc.
less hazardous solvents or solventless catalytic reactions has
received tremendous attention in recent years in the area of
green synthesis,[16] in the present paper, aiming at environmen-
tally friendly methodologies for the preparation of 1,4-DHPs, we
present our findings about a 5-pyrrolidin-2-yltetrazole-catalyzed
four-component Hantzsch reaction without solvent at ambient
temperature.
Results and Discussion
First the mixture of benzaldehyde 1A, 5,5-dimethylcyclohexane-
1,3-dione 2, ethyl acetoacetate 3α, and ammonium bicarbonate
inethanolwerechosenasthemodelreaction(Scheme1)todetect
whether the use of catalyst 4 was efficient and to investigate the
optimal conditions. The results are summarized in Table 1.
As shown in Table 1, it was found that the conditions of no
catalyst had a poor effect on the yield of the expected prod-
uct 5Aα, indicating a catalyst would be needed for it. Then the
condensation reaction of these compounds was tested in the pres-
ence of different amounts of catalyst 4, i.e. 1, 2, 5, 10 mol-%
under similar conditions. Fortunately, a significant improvement
was observed and the yield of the product 5Aα was dramati-
cally increased to 56% after workup; also, the reaction time was
greatly shortened (Table 1, entry 2). As indicated in Table 1, use
of just 2 mol-% of catalyst 4 in ethanol is sufficient to push the
reaction forward (Table 1, entry 3). In view of environmentally
friendly methodologies, we have discovered that the Hantzsch
Recently, organocatalysis has become an increasingly well-
investigated area of organic chemistry, the primary advantage
of which is that it avoids the use of metals, which can be both
expensive and toxic. Also, organocatalysts can often be used
under aerobic conditions, are cheap to use, and in most cases
only a small molecule is required to effect a high yield.[14]
The proline-derived organocatalyst 5-pyrrolidin-2-yltetrazole 4,
which has been applied in a variety of reactions, displayed great
catalyticactivityandefficiency.[15] Asexperimentaldesignusing
N
N
N
PhCHO
O
O
Ph
O
N
H
N
H
1A
OEt
4
ꢀ
ꢀ
O
N
H
5Aα
NH4HCO3, r.t.
O
O
2
OEt
3α
Scheme 1.
© CSIRO 2008
10.1071/CH08197
0004-9425/08/110860

One-Pot Hantzsch Polyhydroquinoline Synthesis
861
reaction proceeds very efficiently by stirring a mixture of neat
reactants at room temperature for only 15 min, under solvent-
free conditions, and produces polyhydroquinoline derivatives
5Aα in high yields (Table 1, entry 6). Here, we considered that
ammonium bicarbonate is a promising alternative to ammonium
acetate or ammonia as nitrogen source, because carbon dioxide
that is formed from the decomposition of ammonium bicarbon-
ate can be released directly. Actually, in order to examine effect
of acidity of AcOH from the cleavage of ammonium acetate
used in traditional method, AcOH was used as catalyst under
optimized conditions. In contrast to 4, the reaction gave a lower
yield (Table 1, entry 7).
aldehydes carrying either electron donating or withdrawing sub-
stituents worked well, giving excellent yields of products with
little difference in high purity. Aliphatic or heterocyclic aldehy-
des under similar conditions also gave medium to good yields
(Table 2, entries 11–14). Other active methylene compounds
such as methyl acetoacetate or pentane-2,4-dione under simi-
lar conditions gave the corresponding products in relative lower
yields (Table 2, entries 15–19).
Later, cyclohexane-1,3-dione 6 was used with similar suc-
cess to provide the corresponding 1,4-DHPs in order to check
the versatility of the procedure (Scheme 3). The results (Table 3)
also showed a series of aromatic and heterocyclic aldehydes
that underwent cyclocondensation to give good to high yields
(83–97%) of the products.
As 4 has a similar structure and properties to l-proline,[15a]
its mechanism as a catalyst for the unsymmetric Hantzsch reac-
tion under solvent-free conditions is proposed (Scheme 2). It
might catalyze the Knoevenagel-type coupling of aldehydes with
active methylene compounds and then the Michael-type addi-
tion of intermediates through either path A or path B to give the
1,4-DHPs.
With good results in hand, we then selected the optimized
reaction conditions to examine the universality of this cata-
lyst’s application (Scheme 3). As shown in Table 2, aromatic
Conclusions
In summary, we have developed a simple, efficient, and green
method for the synthesis of 4-substituted-1,4-dihydropyridines
with the aid of 5-pyrrolidin-2-yltetrazole at room temperature
without solvent.The method offers several advantages including
high yields, a short reaction time, and a simple experimen-
tal workup procedure, which makes it a useful process for the
synthesis of 1,4-dihydropyridines.
Table 1. Optimizing the reaction conditions
All reactions were carried out in ethanol at room temperature and the ratio
of 1A:2:3α:NH4HCO3 was 1:1:1:1.2
Experimental
Melting points were obtained with a capillary melting point
apparatus and are uncorrected. Infrared spectra were recorded on
a Thermo Nicolet Avatar 370 spectrophotometer. 1H NMR and
13C NMR spectra were recorded on a Varian-400 and Bruker
Entry
Catalyst [mol-%]
Time
Yield [%]A
1
2
3
4
5
6
7
None
1
2
24 h
4 h
2 h
2 h
2 h
12
56
88
85
85
98B
48
N
N
N
RꢂCHO
O
O
Rꢂ
O
5
N
H
N
H
1
R
4
10
2
20C
ꢀ
Rꢁ
Rꢁ
ꢀ
Rꢁ
Rꢁ
O
15 min
4 h
N
H
5 or 7
NH4HCO3, r.t.
O
O
2 or 6
R
AIsolated yields.
3
2 Rꢁ ꢃ Me
6 Rꢁ ꢃ H
5 Rꢁ ꢃ Me
7 Rꢁ ꢃ H
BReactions was carried out under solvent-free conditions at room
temperature.
CAcOH as catalyst.
Scheme 3.
NH4HCO3
H2O ꢀ CO2
Rꢁ
Rꢁ
O
O
O
R
NH3
O
Rꢁ
Rꢁ
Rꢁ
Rꢁ
Rꢁ
Rꢁ
NH2
O
O
Rꢂ
O
R
O
Rꢂ
O
ꢀ
H N
2OH
O
O
O
OH
H2N
or
B
R
NH2
R
Rꢂ
H O
ꢀ
Ar
Rꢁ
Rꢁ
Rꢁ
Rꢁ
N
H
Rꢂ
N
H
Rꢂ
Path B
O
HB
Path A
R
R2
O
O
R
O
O
H
R
R
B
O
N
N
RꢂCHO
HB
HB ꢃ
O
O
N
N
H
N
H
Rꢁ
Rꢁ
O
R
Scheme 2. Proposed mechanism for 5-pyrrolidin-2-yltetrazole-catalyzed polyhydroquinoline synthesis.

862
W. Su, J. Li, and J. Li
Avance DRX-500 using CDCl3 or [D6]DMSO as the solvent
with tetramethylsilane (TMS) as an internal standard at room
temperature. Chemical shifts (δ) are expressed in ppm and cou-
pling constants J are given in Hz. Mass spectra were obtained
on a Trace DSQ mass spectrometer. Elemental analysis was per-
formed on a VarioEL-3 instrument. 5-Pyrrolidin-2-yltetrazole
used in the current work was prepared according to previously
published work;[15i] [α]D25 −9.0 (c 0.65, MeOH). δH (400 MHz,
[D6]DMSO) 4.78 (m, 1H), 3.30 (m, 2H), 2.36 (m, 1H), 1.98–
2.20 (m, 3H). δC (100 MHz, [D6]DMSO) 157.74, 54.97, 44.64,
29.94, 23.17. m/z (%) 70 ([M+], 100), 139 (20).
Ethyl 4-(2,4-Dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5Cα
Mp 237−238◦C. Calc. for C23H29NO5: C 69.2, H 7.3, N 3.5.
Found: C 69.2, H 7.2, N 3.2%. νmax (KBr)/cm−1 3290, 3082,
2953, 2835, 1694, 1648, 1605. δH (400 MHz, CDCl3) 7.18 (t, J
4.0, 1H), 6.65 (s, 1H), 6.34 (m, 2H), 5.16 (s, 1H), 4.03 (q, J 8.0,
2H), 3.75 (s, 3H), 3.72 (s, 3H), 2.26–2.06 (m, 7H), 1.19 (t, J 8.0,
3H), 1.04 (s, 3H), 0.91 (s, 3H). δC (100 MHz, CDCl3) 195.6,
168.1, 159.1, 158.5, 149.1, 143.2, 131.6, 127.5, 110.7, 105.1,
103.9, 98.4, 59.5, 55.3, 55.2, 50.8, 41.0, 33.0, 32.5, 29.6, 26.8,
19.1, 14.2. m/z (%) 399.2 ([M+], 25), 398.1 ([M+ − 1], 100).
General Procedure for the Synthesis of Polyhydroquinoline
Derivatives under Solvent-Free Conditions
Accessory Publication
General experimental details and experimental characterization
data for compounds are available from the journal’s website.
To a mixture of aldehyde (2 mmol), dimedone (2 mmol),
β-keto ester (2 mmol) and ammonium bicarbonate (2.4 mmol),
5-pyrrolidin-2-yltetrazole (0.04 mmol) was added and the
mixture was stirred at room temperature for the given time,
monitoringthereactionbyTLC.Afterthecompletionofthereac-
tion, ethyl acetate (20 mL) was added, and the solution washed
with brine and dried over sodium sulfate. After concentration
under vacuum, a crude solid was obtained. The pure product
was obtained through crystallization from ethanol.
Table 3. 5-Pyrrolidin-2-yltetrazole-promoted one-pot Hantzsch poly-
hydroquinoline synthesis using NH4HCO3 as nitrogen source
The ratio of 1:6:3α:NH4HCO3 was 1:1:1:1.2. See Scheme 3 for compounds
Entry
1
Rꢀꢀ
Time
[min]
Products Yield [%]A
1
2
3
4
5
6
7
8
1A
1B
1C
1D
1E
1F
1G
1H
1I
C6H5
15
20
20
15
20
15
15
15
15
20
30
7Aα
7Bα
7Cα
7Dα
7Eα
7Fα
7Gα
7Hα
7Iα
95
90
93
93
93
96
97
93
90
92
83
Spectroscopic Data for Selected Products
2-F-6-Cl-C6H3
2,4-(OCH3)2-C6H3
3-Cl-C6H4
3-NO2-C6H4
4-OCH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-F-C6H4
3-F-C6H4
4-Methylthiazol-5-yl
Ethyl 4-(2-Chloro-6-fluorophenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 5Bα
Mp 250–253◦C. Calc. for C21H23NO3: C 64.4, H 5.9, N 3.6.
Found: C 64.5, H 5.9, N 3.5%. νmax (KBr)/cm−1 3288, 3212,
3088, 2956, 1692, 1612. δH (400 MHz, CDCl3) 7.05 (m, 2H),
6.87 (t, 1H), 6.44 (s, 1H), 5.64 (s, 1H), 4.03 (q, J 7.2, 2H), 2.29–
2.08 (m, 7H), 1.14 (t, J 7.2, 3H), 1.06 (s, 3H), 0.96 (s, 3H).
δC (100 MHz, CDCl3) 195.6, 167.5, 150.2, 145.3, 135.3, 135.3,
130.9, 130.7, 127.5, 127.4, 125.7, 114.0, 113.7, 108.7, 102.1,
59.7, 50.6, 40.8, 32.3, 31.2, 29.6, 29.3, 27.1, 19.1, 14.3. m/z (%)
392.5 ([M+ + 1], 100), 394.5 ([M+ + 3], 37).
9
10
11B
1K
1L
7Kα
7Lβ
AIsolated yield.
B3β as active methylene compound.
Table 2. 5-Pyrrolidin-2-yltetrazole-promoted one-pot Hantzsch polyhydroquinoline synthesis using NH4HCO3 as nitrogen source
The ratio of 1:2:3:NH4HCO3 was 1:1:1:1.2
Entry
1
3
Rꢀꢀ
R
Time [min]
Products
Yield [%]A
1
2
3
4
5
6
7
8
1A
1B
1C
1D
1E
1F
1G
1H
1I
3α
3α
3α
3α
3α
3α
3α
3α
3α
3α
3α
3α
3α
3α
3β
3β
3β
3β
3γ
C6H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OCH3
15
20
20
15
20
15
15
15
15
30
35
35
40
45
15
20
15
15
20
5Aα
5Bα
5Cα
5Dα
5Eα
5Fα
5Gα
5Hα
5Iα
5Jα
5Nα
5Oα
5Pα
5Qα
5Aβ
5Fβ
5Gβ
5Iβ
98
92
96
93
93
98
98
92
92
90
88
86
82
80
92
88
91
96
85
2-F-6-Cl-C6H3
2,4-(OCH3)2-C6H3
3-Cl-C6H4
3-NO2-C6H4
4-OCH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-F-C6H4
3-OH-C6H4
Furan-2-yl
Thiophen-2-yl
Cyclohexyl
Ethyl
9
10
11
12
13
14
15
16
17
18
19
1J
1N
1O
1P
1Q
1A
1F
1G
1I
C6H5
4-OCH3-C6H4
4-CH3-C6H4
4-F-C6H4
OCH3
OCH3
OCH3
CH3
1A
C6H5
5Aγ
AIsolated yield.

One-Pot Hantzsch Polyhydroquinoline Synthesis
863
Acknowledgements
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We are grateful to the National Natural Science Foundation of China (Nos
20476098, 20806073) and the National Key Technology Reasearch and
Development Program (No. 2007 BAI34B00) for financial support.
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