One-pot synthesis of hexahydroquinolines via Hantzsch four-component reaction catalyzed by a cheap amino alcohol

Article abstract of DOI:10.1080/00397910903370626

An economic, efficient access to hexahydroquinolines was found. In the presence of threo-(1S,2S)-2-amino-1-(4'-nitrophenyl)-1,3-propanediol, a waste product formed in the production of chloromycetin, a one-pot, four-component Hantzsch reaction of dimedone

Full text of DOI:10.1080/00397910903370626

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One-Pot Synthesis of
Hexahydroquinolines via Hantzsch Four-
Component Reaction Catalyzed by a
Cheap Amino Alcohol
Shao-Jun Song a , Zi-Xing Shan a & Yong Jin a
a Department of Chemistry, Wuhan University, Wuhan, Hubei, China
Version of record first published: 13 Sep 2010.
To cite this article: Shao-Jun Song , Zi-Xing Shan & Yong Jin (2010): One-Pot Synthesis of
Hexahydroquinolines via Hantzsch Four-Component Reaction Catalyzed by a Cheap Amino Alcohol,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:20, 3067-3077
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Synthetic Communications1, 40: 3067–3077, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903370626
ONE-POT SYNTHESIS OF HEXAHYDROQUINOLINES
VIA HANTZSCH FOUR-COMPONENT REACTION
CATALYZED BY A CHEAP AMINO ALCOHOL
Shao-Jun Song, Zi-Xing Shan, and Yong Jin
Department of Chemistry, Wuhan University, Wuhan, Hubei, China
An economic, efficient access to hexahydroquinolines was found. In the presence of threo-
(1S,2S)-2-amino-1-(40-nitrophenyl)-1,3-propanediol, a waste product formed in the production
of chloromycetin, a one-pot, four-component Hantzsch reaction of dimedone, aldehydes,
ethyl acetoacetate, and ammonium acetate at room temperature furnished hexahydroquinoline
derivatives in excellent yield. A possible catalytic mechanism was also suggested.
Keywords: Amino alcohol; Hantzsch reaction; hexahydroquinolines; one-pot synthesis
INTRODUCTION
Hexahydroquinoline derivatives possess a variety of biological activities, such
as vasodilatory, bronchodilatory, antiatherosclerotic, antitumor, geroprotective,
hepatoprotective, and antidiabetic activity,[1] and some of them have been used as
calcium channel modulators and curatives for cardiovascular diseases.[2] For
example, dihydropyridyl compounds nifedipine, nicardipine, amlodipine, and other
related derivatives are effective in the treatment of hypertension.[3] In past years,
their uses as neuroprotectants, platelet anti-aggregatory agents, and cerebral
anti-ischemic agents in the treatment of Alzheimer’s disease and as chemosensitizers
in tumor therapy have been also reported.[4] They clearly show the remarkable
potential of novel dihydropyridine derivatives as sources of valuable drug
candidates.
Hexahydroquinolines generally are synthesized by condensation of aldehydes,
ethyl acetoacetate, and ammonia either in acetic acid or by refluxing in alcohol.[5]
This method, however, requires long reaction times, harsh reaction conditions,
and large quantities of volatile organic solvents and commonly gives poor yields.
In the past several years, some Lewis acids,[6,9] bases,[10,11] and salts[12,14] have been
examined as catalysts for the preparation of hexahydroquinolines, and microwave
irradiation,[15] ionic liquids,[16] and solvent-free reactions[17] have been utilized in
their preparation. Although some of these are successful to a certain degree, they
are not perfect for reasons such as utilization of expensive reagents or poor yield.
Received April 14, 2009.
Address correspondence to Zi-Xing Shan, Department of Chemistry, Wuhan University, Wuhan
430072, Hubei, China. E-mail: zxshan@whu.edu.cn
3067

3068
S.-J. SONG, Z.-X. SHAN, AND Y. JIN
Therefore, development of convenient, economic, high-yielding preparative
procedure for hexahydroquinolines is of much practical importance.
RESULTS AND DISCUSSION
Threo-(1S,2S)-2-amino-1-(40-nitrophenyl)-1,3-propanediol [ANP],
a waste
product in the production of chloromycetin, is one of the cheapest amino alcohols
available. Previously, Jiang et al. utilized ANP and its derivatives to catalyze alkyny-
lation of aldehydes or a-keto esters[18] to excellent effect. Our group is also interested
in ANP chemistry and has revealed some novel chemistry of it and its derivatives,
including selective oxazolidination of ANP,[19] selective oxidation formylation of
the N,N-dimethyl derivative of ANP,[20] resolution of racemic 1,10-bi-2-naphthol[21]
using ANP derivatives, and asymmetric Henry reaction catalyzed by ANP
derivatives.[22] As a part of our interest, the catalytic activity of ANP toward a
four-component synthesis of hexahydroquinolines was examined (Scheme 1).
In an initial experiment, dimedone was allowed to react directly with benzal-
dehyde, acetoacetate, ester and ammonium acetate in ethanol for 4 h, and the
product 6a was obtained in only 10% yield. By extending the reaction time to
24 h, the yield was upgraded to 35%. However, when the reaction was performed
for 4 h in the presence of 5 mol% ANP, the yield of 6a was heightened to 71% (entry
3 in Table 1). It can be seen in Table 1 that 10% of ANP loading afforded the best
result (entry 4).
Catalytic activities of ANP (5a) derivatives, threo-(1S,2S)-2-dimethylamino-1-
(40-nitrophenyl)-1,3-propanediol (DMANP, 5b), and threo-(1S,2S)-3-triphenylmethoxy-
2-amino-1-(40-nitrophenol)propanol (TPANP, 5c) (Fig. 1) toward the reaction were
compared. It was found that the modification of ANP could not improve the 6a yield
(Table 2).
In view of these results, ANP was used as catalyst for Hantzsch synthesis of
hexahydroquinolines. A wide range of aromatic, heteroaromatic, and aliphatic alde-
hydes were subjected to this procedure. The results are shown in Table 3. All the pro-
1
ducts were characterized by infrared (IR), H NMR, and 13C NMR spectra, and 6b
was authorized by the single-crystal x-ray diffraction analysis (Fig. 2). It can be seen
in Table 3 that under ANP catalysis, all the reactions furnished hexahydroquinolines
in good yield; however, the attribute of aldehyde, the position and the electronic
property of the substituent in the aromatic aldehydes, as well as the alkyl group
of acetoacetic esters influence the selectivity of the reaction. In general, the aliphatic
aldehyde (entry 14) and the a,b-unsaturated aldehyde (entry 13) furnished less of
the desired products than the aromatic or heteroaromatic aldehydes; for the substi-
tuted benzaldehydes, the yields of the desired products from the reactions of the
Scheme 1. Synthesis of hexahydroquinolines through the Hantzsch reaction catalyzed by ANP.

HANTZSCH FOUR-COMPONENT REACTION
3069
Table 1. Dependence of Hantzsch synthesis of 1,4-dihydropyridines on ANP
Entry
Amount of ANP (mol %)
Time (h)
Yielda (%)
1
2
3
4
5
0
0
4
24
4
10
35
71
88
85
5
10
30
4
4
aRefers to isolated yield.
Figure 1. Catalysts used for Hantzsch reaction.
Table 2. Effect of the composition of catalyst on the yield of 1,4-dihydropyridine 6a
Entry
Catalyst
Time
Yielda
2
3
4
5a
5b
5c
4
4
4
88
85
80
aRefers to isolated yield.
Table 3. ANP-catalyzed Hantzsch synthesis of 1,4-dihydropyridines
Mp (ꢀC)
Entry
R1
R2
Time (h)
Product
Yield (%)a
Observed
Reported
1
2
C6H5
4-ClC6H4
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OBun
4
4
4
4
4
4
5
4
4
5
4
4
5
5
4
5
6a
6b
6c
6k
6f
88
88
92
83
86
95
75
82
87
78
83
85
77
75
85
76
203–205
243–245
255–257
235–237
263–265
242–244
177–179
261–263
257–259
194–196
233–234
229–231
205–206
147–148
247–249
223–224
202–204[7]
245–246[8]
253–255[7]
234–236[6]
—
241–244[7]
177–178[8]
260–261[7]
257–259[7]
193–195[7]
232–234[7]
229–231[7]
204–206[7]
147–148[7]
246–248[7]
222–223[8]
3
4-BrC6H4
3-BrC6H4
4
5
2,6-Cl2C6H3
2,4-Cl2C6H4
3-NO2C6H4
4-CH3C6H4
4-CH3OC6H4
2-CH3OC6H4
4-OHC6H4
4-(CH3)2NC6H4
6
6l
7
6g
6h
6i
8
9
10
11
12
13
14
15
16
6j
6d
6e
6m
6n
6o
6p
=
C6H5CH CH
CH3CH2CH2
Fur-2-yl
C6H5
aRefers to isolated yield.

3070
S.-J. SONG, Z.-X. SHAN, AND Y. JIN
Figure 2. Showing the ORTEP diagram of 6b.
4-substituted aromatic aldehydes are greater by nearly 10% than those of the 2- or
3-substituted ones (entries 3 and 4, 9 and 10, 5 and 6), and the longer chain alkyl
group of acetoacetic ester is not beneficial for the reaction (entries 1 and 16).
Scheme 2. Possible mechanism for the formation of hexahydroquinolines in the presence of ANP.

HANTZSCH FOUR-COMPONENT REACTION
3071
A possible mechanism for ANP-catalyzed synthesis of hexahydroquinolines
has been suggested (Scheme 2). ANP is a 1,3-dihydroxyl primary amine. The basic
property of ANP determines that it is easy to accept the a acidic proton of dimedone
and alkyl acetoacetates to form a carbon negative ion; on the other hand, it is also
possible that the hydroxyl groups of ANP activated the carbonyls of dimedone and
alkyl acetoacetates via the formation of H bonding. Namely, the existence of ANP
strengthens the activity of dimedone and alkyl acetoacetates and lays a foundation
for their reaction with other components. Furthermore, ANP can promote liberation
of ammonia from NH4OAc. Thus, in the presence of ANP, dimedone readily under-
goes condensation with aldehyde to generate an alkylidenedimedone 1, and the prob-
ability of the formation of amination product 2 of alkyl acetoacetates is increased.
Under the experiment conditions, 1,4-addition of the b-imino ester 2 to the alkylide-
nedimedone 1 took place, forming intermediate 3, which further dehydrated and
cyclized into the desired hexahydroquinoline derivatives. The crystallographic analy-
sis has shown that the hexahydroquinoline derivative 5 is the most stable form of the
four-component Hantzsch reaction product.
In conclusion, we have successfully developed a convenient, efficient method
for the synthesis of hexahydroquinolines via a one-pot, four-component reaction
of dimedone, aldehydes, ethyl acetoacetate, and ammonium acetate in the presence
of ANP. The major advantages of this method include mild conditions, simple
experimental procedure, low cost, and excellent yield.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Testscan Shimadzu Fourier transform
(FT)–IR 8000 in KBr. 1H and 13C NMR spectra were performed on a Varian
Mercury VS 300, with d values (ppm) relative to Me4Si. Melting points were determ-
ined on a VEB Wagetechnik Rapio PHMK05 instrument and are uncorrected.
Typical Procedure
Aldehyde (2 mmol) and ammonium acetate (2 mmol) were added to a stirred
mixture of dimedone (2 mmol), ethyl acetoacetate (2 mmol), and compound 5a
(0.042 g, 10 mol%) in ethanol (4 mL). The reaction mixture was stirred at room tem-
perature for 4–5 h. The resulting yellow solid was filtered and treated by reflux in
ethanol to give the pure hexahydroquinoline derivatives.
Ethyl 2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate (6a)
1H NMR (300 MHz, CDCl3): d 7.06–7.31 (m, 5H), 6.14 (s, 1H), 5.05 (s, 1H),
4.05 (q, J ¼ 7.2 Hz, 2H), 2.35 (s, 3H), 2.22 (s, 2H), 2.17 (s, 2H), 1.12 (t, J ¼ 7.2 Hz,
3H), 1.06 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3): d 196.2, 167.8, 163.9,
150.0, 147.4, 144.3, 128.2, 128.1, 126.2, 111.8 106.0, 77.5, 77.3, 77.1, 60.0, 51.0,
40.8, 36.9, 36.8, 32.8, 29.7, 27.3, 19.3, 19.2, 14.4. IR (KBr): (3289, 1689, 1611,
1484, 1382, 1211 cmꢁ1
.

3072
S.-J. SONG, Z.-X. SHAN, AND Y. JIN
Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-chlorophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6b)
1H NMR (300 MHz, CDCl3): d 7.23 (d, J ¼ 9.0 Hz, 2H), 7.15 (d, J ¼ 8.1 Hz,
2H), 6.52 (s, 1H), 5.01 (s, 1H), 4.05 (q, J ¼ 7.2 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 2H),
2.20 (s, 2H), 1.18 (t, J ¼ 7.2 Hz, 3H), 1.05 (s, 3H), 0.91 (s, 3H);13C NMR (75 MHz,
CDCl3): d 195.7, 167.7, 148.1, 144.3, 135.6, 128.8, 128.1, 112.5, 106.4, 77.6, 77.2,
76.8, 60.0, 50.9, 41.3, 36.2, 32.9, 29.6, 27.4, 21.2, 19.6, 14.4. IR (KBr): (3274,
1706, 1605, 1496, 1382, 1214 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-bromophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6c)
1H NMR (300 MHz, CDCl3): d 7.30 (d, J ¼ 8.7 Hz, 2H), 7.17 (d, J ¼ 8.1 Hz,
2H), 5.95 (s, 1H), 5.00 (s, 1H), 4.05 (q, J ¼ 7.2 Hz, 2H), 2.36 (s, 3H), 2.19 (s, 2H),
2.15 (s, 2H), 1.18 (t, J ¼ 7.2 Hz, 3H), 1.06 (s, 3H), 0.91 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 195.9, 167.5, 148.9, 146.4, 144.1, 131.1, 130.1, 120.0, 111.8,
105.8, 60.1, 50.9, 41.1, 36.5, 32.9, 29.7, 27.3, 19.6, 14.4; IR (KBr): (3274, 1703,
1604, 1497, 1382, 1215 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-hydroxylphenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6d)
1H NMR (300 MHz, CDCl3): d 7.16 (d, J ¼ 8.1 Hz, 2H), 6.64 (d, J ¼ 8.7 Hz,
2H), 5.62 (s, 1H), 4.98 (s, 1H), 4.86 (s, 1H), 4.05 (q, J ¼ 7.2 Hz, 2H), 2.37 (s, 3H),
2.31 (s, 2H), 2.22 (s, 2H), 1.19 (t, J ¼ 7.2 Hz, 3H), 1.07 (s, 3H), 0.93 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 195.9, 167.5, 148.9, 145.9, 144.1, 131.8, 129.7, 128.2,
111.9, 105.9, 60.1, 50.9, 41.1, 36.5, 32.9, 29.7, 27.3, 19.6, 14.5; IR (KBr): (3417,
3382, 1686, 1613, 1485, 1383, 1221 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-dimethylaminophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6e)
1H NMR (300 MHz, CDCl3): d 7.15 (d, J ¼ 8.7 Hz, 2H), 6.59 (d, J ¼ 8.7 Hz,
2H), 6.01 (s, 1H), 4.93 (s, 1H), 4.05 (q, J ¼ 7.2 Hz, 2H), 2.85 (s, 6H), 2.34 (s, 3H),
2.14–2.19 (s, 4H), 1.21 (t, J ¼ 7.2 Hz, 3H), 1.05 (s, 3H), 0.94 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 191.7, 163.4, 145.6, 144.4, 139.3, 131.6, 124.1, 107.7, 107.1,
101.7, 55.2, 46.4, 36.1, 35.8, 30.9, 28.0, 25.1, 22.6, 14.5, 9.8; IR (KBr): (3206,
2956, 1701, 1606, 1489, 1381, 1221 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(2,6-dichlorophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6f)
1H NMR (300 MHz, CDCl3): d 7.20 (m, 2H), 6.96 (t, J ¼ 8.1 Hz, 1H), 5.91 (s,
13
1H), 5.86 (s, 1H), 4.02 (q, J ¼ 7.2 Hz, 2H), 2.24 (s, 3H), 2.14 (s, 2H), 2.11 (s, 2H),
1.07–1.10 (m, 3H), 1.07 (s, 3H), 0.99 (s, 3H); C NMR (75 MHz, CDCl3): d 195.9,
167.7, 151.0, 145.6, 139.5, 138.2, 136.2, 130.0, 128.4, 127.4, 109.0, 102.5, 59.9,

HANTZSCH FOUR-COMPONENT REACTION
3073
51.1, 41.0, 35.8, 32.4, 29.4, 27.7, 19.4, 144.4; IR (KBr): (3288, 1702, 1600, 1493, 1383,
1221 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(3-nitrophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6g)
1H NMR (300 MHz, CDCl3): d 8.12 (s, 1H), 7.98 (d, J ¼ 8.1 Hz, 1H), 7.73 (d,
J ¼ 7.2 Hz, 1H), 7.38 (t, J ¼ 7.2 Hz, 1H), 6.55 (s, 1H), 5.16 (s, 1H), 4.06 (q, J ¼ 7.2 Hz,
2H), 2.39 (s, 3H), 2.28 (s, 2H), 2.17 (s, 2H), 1.17 (t, J ¼ 7.2 Hz, 3H), 1.09 (s, 3H), 0.93
(s, 3H); 13C NMR (75 MHz, CDCl3): d 195.7, 167.2, 149.5, 149.2, 148.5, 144.8, 135.0,
128.8, 123.1, 121.5, 111.4, 105.3, 60.3, 50.8, 41.1, 37.2, 32.9, 31.2, 29.6, 27.3, 19.6,
14.4; IR (KBr): (3285, 1705, 1606, 1486, 1382, 1211 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-methylphenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6h)
1H NMR (300 MHz, CDCl3): d 7.20 (d, J ¼ 7.5 Hz, 2H), 7.01 (d, J ¼ 7.5 Hz,
13
2H), 6.12 (s, 1H), 5.01 (s, 1H), 4.06 (q, J ¼ 7.2 Hz, 2H), 2.35 (s, 3H), 2.17–2.29 (m,
7H), 1.22 (t, J ¼ 7.2 Hz, 3H), 1.07 (s, 3H), 0.95 (s, 3H); C NMR (75 MHz, CDCl3):
d 196.3, 167.9, 158.0, 149.9, 144.1, 140.1, 129.1, 113.5, 111.9, 106.3, 60.0, 55.3, 51.1,
45.8, 40.8, 36.0, 32.8, 29.7, 27.3, 19.3, 14.5; IR (KBr): (3275, 1702, 1605, 1496, 1383,
1216 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-methoxyphenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6i)
1H NMR (300 MHz, CDCl3): d 7.22 (d, J ¼ 2.1 Hz, 2H), 6.73 (d, J ¼ 8.7 Hz,
2H), 6.40 (d, J ¼ 10.8 Hz, 1H), 4.99 (s, 1H), 4.06 (q, J ¼ 7.2 Hz, 2H), 3.73 (s, 3H),
2.35 (s, 3H), 2.20 (s, 2H), 2.18 (s, 2H), 1.21 (t, J ¼ 7.2 Hz, 3H), 1.06 (s, 3H), 0.93
(s, 3H); 13C NMR (75 MHz, CDCl3): d 190.8, 152.8, 143.3, 138.3, 134.7, 124.0,
108.3, 107.3, 101.3, 54.8, 50.1, 45.8, 36.0, 30.7, 27.7, 26.0, 24.5, 22.2, 14.4, 9.3; IR
(KBr): (3276, 1702, 1605, 1497, 1382, 1215 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(2-methoxyphenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6j)
1H NMR (300 MHz, CDCl3): d 7.28 (m, 2H), 7.08 (s, 1H), 6.80 (m, 2H), 6.04 (s,
1H), 5.26 (m, 2H), 4.01 (m, 2H), 3.80 (s, 3H), 2.29 (s, 3H), 2.12–2.16 (m, 4H), 1.18
(m, 3H), 1.06 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3): d 194.0, 167.0, 156.5,
149.1, 149.1, 143.5, 134.3, 130.1, 126.0, 118.8, 109.9, 108.9, 102.9, 58.2, 54.4, 49.9,
33.0, 31.9, 28.7, 25.7, 17.65, 13.3; IR (KBr): (3284, 1689, 1487, 1215 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(3-bromophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6k)
1H NMR (300 MHz, CDCl3): d 7.42 (s, 1H), 7.21–7.27 (m, 2H), 7.04–7.09 (m,
1H), 6.96 (s, 1H), 5.02 (s, 1H), 4.06–4.10 (m, 2H), 2.33 (m, 3H), 2.13–2.28 (m, 4H),

3074
S.-J. SONG, Z.-X. SHAN, AND Y. JIN
13
1.19–1.24 (m, 3H), 1.06 (s, 3H), 0.95 (s, 3H); C NMR (75 MHz, CDCl3): d 196.0,
167.5, 149.7, 149.6, 144.5, 131.3, 129.7, 129.4, 127.1, 122.3, 111.5, 105.6, 60.2,
51.0, 41.0, 36.9, 32.9, 29.7, 27.4, 19.5, 14.4; IR (KBr): (3273, 1702, 1604, 1489,
1211 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(2-chlorophenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6l)
1H NMR (300 MHz, CDCl3): d 7.32 (d, J ¼ 8.7 Hz, 1H), 7.24 (s, 1H), 7.09 (d,
J ¼ 8.7 Hz, 1H), 5.33 (s, 1H), 4.01–4.05 (m, 2H), 2.11–2.30 (m, 7H), 1.14–1.19 (3 m,
H), 1.04 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): d 195.8, 167.5, 149.5,
144.4, 143.0, 134.1, 133.1, 132.3, 129.5, 126.8, 110.9, 104.9, 60.1, 50.9, 41.1, 36.0,
32.7, 29.6, 27.4, 19.5, 14.5; IR (KBr): (3283, 1706, 1609, 1495, 1381, 1213 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-styryl-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (6m)
1H NMR (300 MHz, CDCl3): d 7.13–7.28 (m, 5H), 7.02 (s, 1H), 6.20–6.22 (m,
2H), 4.69 (d, J ¼ 3.9 Hz, 1H), 4.16 (q, J ¼ 7.2 Hz, 2H), 2.35 (s, 3H), 2.19–2.28 (m,
13
4H), 1.24–1.29 (m, 3H), 1.04 (m, 6H); C NMR (75 MHz, CDCl3): d 167.5, 150.0,
144.8, 137.7, 132.0, 128.6, 128.3, 126.8, 126.1, 109.5, 103.5, 59.8, 50.8, 40.8, 33.2,
32.6, 29.3, 27.4, 19.2, 14.4; IR (KBr): (3438, 3292, 2188, 1674, 1635 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-propyl-1,4,5,6,7,8-
hexahydro-quinoline-3-carboxylate (6n)
1H NMR (300 MHz, CDCl3): d 7.36 (s, 1H), 4.16–4.17 (m, 2H), 4.02 (s, 1H),
2.32–2.34 (m, 5H), 2.25 (s, 2H), 1.26–1.31 (m, 4H), 1.09 (s, 6H), 0.83 (t, J ¼ 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 196.6, 168.4, 151.3, 145.1, 111.0, 105.3, 59.8,
51.2, 41.0, 39.1, 32.7, 30.1, 30.0, 27.3, 19.2, 18.5, 14.6; IR (KBr): (3293, 2962,
1699, 1604, 1487, 1216 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-(furan-2-yl)-1,4,5,6,7,8-
hexahydro-quinoline-3-carboxylate (6o)
1H NMR (300 MHz, CDCl3): d 7.18 (s, 1H), 6.20 (d, J ¼ 2.1 Hz, 1H), 6.01 (m,
13
2H), 5.25 (s, 1H), 4.15 (m, 2H), 2.36 (s, 3H), 2.26 (s, 2H), 1.62 (s, 2H), 1.26 (s, 3H),
1.10 (s, 3H), 1.02 (s, 3H); C NMR (75 MHz, CDCl3): d 200.2, 172.4, 163.8, 155.8,
150.8, 145.3, 115.1, 113.6, 109.3, 101.8, 64.4, 55.8, 37.4, 35.0, 34.6, 31.8, 23.7, 19.4;
IR (KBr): (3285, 3220, 1676, 1606, 1220 cmꢁ1
.
Ethyl 2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3- Carboxylate (6p)
1H NMR (300 MHz, CDCl3): d 7.08–7.31 (m, 5H), 6.93 (s, 1H), 5.04 (s, 1H),
3.99–4.05 (m, 2H), 2.10–2.32 (m, 7H), 1.52–1.57 (m, 2H), 1.18–1.30 (m, 2H), 1.05
(s, 3H), 0.91 (s, 3H), 0.84–0.89 (m, 3H); 13C NMR (75 MHz, CDCl3): d 196.1,

HANTZSCH FOUR-COMPONENT REACTION
3075
167.9, 149.2, 147.4, 144.2, 128.2, 128.1, 126.2, 112.1, 106.1, 64.0, 51.0, 41.0, 36.8,
32.9, 30.9, 29.6, 27.3, 19.4, 13.9.
Crystallography of Ethyl 2,7,7-Trimethyl-5-oxo-4-(4-chlorophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (6b)
Procedure. Compound 6b was dissolved in hot ethanol and then cooled
slowly to furnish a crystal suitable for crystallographic analysis, 0.42 mm ꢂ
0.33 mm ꢂ 0.31 mm.
Crystallographic data. C21H24ClNO3, M 373.86, orthorhombic, space
group Pbcn, a 18.1554 (12) ?, b 15.5900 (10) ?, c 14.2034 (9) ?, V ¼ 4020.2(4) ?3, Z
8, m(Mo Ka) 0.71073 mmꢁ1, absorption coefficient (m), 0.209 mmꢁ1; index ranges:
ꢁ22 < h < 21, ꢁ18 < k < 19, ꢁ17 < l < 17; F(000) 1584, GOF 0.993, T 273(2) K,
´
23080 reflections, 4164 independent (Rint ¼ 0.0223), R1 0.0746 (I > 2o(I)) and wR2
(all data) 0.1973.
Supplementary data. Final atomic coordinates of the crystal, along with
lists of anisotropic thermal parameters, hydrogen coordinates, bond lengths, and
bond angles, have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. 693368. The crystallographic information file can
be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: 44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Nos. 20672083
and 20872115) for financial support.
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