Using Morita-Baylis-Hillman acetates of 2-azidobenzaldehydes for the synthesis of 2-alkoxy-3-cyanomethylquinolines and alkyl quinoline-3-carboxylates

Article abstract of DOI:10.1002/jhet.667

Figure represented. A simple method for the synthesis of several 2-alkoxy-3-cyanomethylquinolines and alkyl quinoline-3-carboxylates using iminophosphorane-mediated cyclization reactions of 3-(2-azidophenyl)-2- cyanomethylpropenoates and 3-(2-azidophenyl)-2-nitromethylpropenoates has been developed. These compounds were readily obtained from the Morita-Baylis-Hillman acetates of 2-azidobenzaldehydes using potassium cyanide or sodium nitrite, respectively. J. Heterocyclic Chem., (2011)

Full text of DOI:10.1002/jhet.667

July 2011
Using Morita–Baylis–Hillman Acetates of 2-Azidobenzaldehydes
for the Synthesis of 2-Alkoxy-3-Cyanomethylquinolines and
Alkyl Quinoline-3-Carboxylates
965
Hea Jung Kim, Eun Mi Jeong, and Kee-Jung Lee*
Organic Synthesis Laboratory, Department of Chemical Engineering, Hanyang University,
Seoul 133-791, Korea
*E-mail: leekj@hanyang.ac.kr
Received July 2, 2010
DOI 10.1002/jhet.667
Published online 19 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
A simple method for the synthesis of several 2-alkoxy-3-cyanomethylquinolines and alkyl quinoline-
3-carboxylates using iminophosphorane-mediated cyclization reactions of 3-(2-azidophenyl)-2-cyanome-
thylpropenoates and 3-(2-azidophenyl)-2-nitromethylpropenoates has been developed. These compounds
were readily obtained from the Morita–Baylis–Hillman acetates of 2-azidobenzaldehydes using potas-
sium cyanide or sodium nitrite, respectively.
J. Heterocyclic Chem., 48, 965 (2011).
INTRODUCTION
the corresponding 2-alkoxyquinoline derivatives involv-
ing an intramolecular aza–Wittig ring closure process
between an ester carbonyl and an iminophosphorane.
Herein, we describe the syntheses of 2-alkoxy-3-cyano-
methylquinolines from 3-(2-azidophenyl)-2-cyanome-
thylpropenoates and the unexpected quinoline-3-carbox-
ylic acid alkyl esters from 3-(2-azidophenyl)-2-
nitromethylpropenoates.
The Morita–Baylis–Hillman reaction [1] has attracted
the attention of organic chemists in recent years. This
reaction provides useful multifunctional molecules that
have been successfully used in the synthesis of various
heterocyclic compounds including quinolines [1(h)].
Quinolines and their derivatives occur in numerous natu-
ral products [2] show interesting physiological activities
and have attractive applications as pharmaceuticals and
agrochemicals [3]. Many methods for the synthesis of
quinolines have been developed [4]; however, the devel-
opment of new synthetic methods remains an active
research area.
RESULTS AND DISCUSSION
We initiated our studies by preparing the key interme-
diate 3-(2-azidophenyl)-2-cyanomethylpropenoates
2
Recently, we reported [5] the synthesis of 2-alkoxy-3-
arylsulfinylmethylquinolines using an intramolecular
aza–Wittig type reaction of (Z)-3-(2-azidophenyl)-2-
(arylsulfinylmethyl)propenoates, which were readily
obtained from the Morita–Baylis–Hillman acetates of 2-
azidobenzaldehydes, with triphenylphosphine via E/Z
isomerization, as shown in Scheme 1. To continue our
work on the Morita–Baylis–Hillman reaction [6], we
wanted to incorporate a cyano or nitro group in the al-
lylic position of 3-(2-azidophenyl)propenoates and
aimed to examine the feasibility of their conversions to
from known Morita–Baylis–Hillman acetates of 2-azido-
benzaldehydes previously reported in the literature [7].
The SN2’ displacement reaction of the acetates 1 with
potassium cyanide in aqueous dimethyl sulfoxide at
room temperature afforded 3-(2-azidophenyl)-2-cyano-
methylpropenoates 2 with (E)-stereoselectivity as the
sole product in good to excellent yields (Table 1 and
Scheme 2). The stereochemistry of product 2 was deter-
1
mined by comparing the H-NMR values of the olefinic
proton (d ¼ 7.84–8.01) with published values for similar
compounds [7]. The reaction of azide 2a with
C
V
2011 HeteroCorporation

966
H. J. Kim, E. M. Jeong, and K.-J. Lee
Vol 48
Scheme 1
Table 1
2-Cyanomethylpropenoates 2 and 2-alkoxy-3-cyanomethyl-
quinolines 5.
Entry
2 [Yield (%)/time (h)]
5 [Yield (%)/time (h)]
1
2
3
4
5
2a (88/1)
2b (74/5)
2c (92/1)
2d (87/3)
2e (63/6)
5a (87/30)
5b (83/25)
5c (75/20)
5d (95/48)
5e (87/28)
triphenylphosphine in anhydrous toluene at room tem-
perature for 4 h gave the iminophosphorane 3a in a
98% yield. Treatment of 3a in toluene at reflux tempera-
ture for 30 h produced, after column chromatography,
an 89% yield of 3-cyanomethyl-2-methoxyquinoline
(5a) with triphenylphosphine oxide (90%). In situ gener-
ation of iminophosphoranes 3 and subsequent aza–Wit-
tig ring closure of other 3-(2-azidophenyl)-2-cyanome-
thylpropenoates 2 were very successful, resulting in the
corresponding 2-alkoxy-3-cyanomethylquinoline deriva-
tives 5 in 75–95% yields (Table 1 and Scheme 2).
A possible mechanism for the transformation of 3
into 5 is shown in Scheme 3 based on our previous
study [5]. The mechanistic sequence involves an
abstraction of the acidic a-hydrogen of nitrile by the
nitrogen anion of (E)-iminophosphorane 3 to give sev-
eral zwitterionic intermediates (3A–3D). The formula
3B, corresponding to a negative charge located on C-3,
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Using Morita–Baylis–Hillman Acetates of 2-Azidobenzaldehydes for the
Synthesis of 2-Alkoxy-3-Cyanomethylquinolines and Alkyl Quinoline-3-Carboxylates
967
Scheme 3
enabled rotation about the C-2–C-3 bond, and subse-
quent proton migration through the zwitterionic inter-
mediates gave (Z)-iminophosphorane 4, followed by an
aza–Wittig reaction at the ester carbonyl group to pro-
duce quinoline 5.
quent ring closure were successful, producing the corre-
sponding quinoline-3-carboxylic acid alkyl esters 10 in
40–49% yields. A plausible mechanism for the forma-
tion of the quinoline derivative 10 involved initial
migration of the acidic a-hydrogen of the nitro group
with the assistance of the iminophosphorane 7 nitrogen
anion to form the nitronic acid 8. Nucleophilic attack by
the nitrogen anion on the nitronic acid 8, followed by a
loss of triphenylphosphine oxide and an unstable hypo-
nitrous acid (HNO) [9] through the cyclic intermediate
9, resulted in the quinoline 10 [10].
Encouraged by these results, we used the same
method for the synthesis of 2-alkoxy-3-nitromethylqui-
nolines from the substrate afforded by the SN2’ reaction
of the acetates 1 with nitrite ions [8]. The acetates 1
were treated with sodium nitrite in dimethylformamide
at room temperature to give the corresponding 3-(2-azi-
dophenyl)-2-nitromethylpropenoates 6 with (E)-stereose-
lectivity as the sole product in moderate yields (Scheme
4 and Table 2). The stereochemistry of product 6 was
determined by comparing the 1H-NMR values of the
olefinic proton (d ¼ 8.04–8.16) with the values of simi-
lar compounds published in ref. 8. Again, the reaction
of 6a with triphenylphosphine in toluene at room tem-
perature for 30 min gave the iminophosphorane 7a
(91%). Treatment of 7a in toluene at reflux temperature
resulted in the formation of an unexpected quinoline-3-
carboxylic acid methyl ester 10a (54%) along with tri-
phenylphosphine oxide (63%), whereas the expected 2-
methoxy-3-nitromethylquinoline was not produced at all.
In situ generation of iminophosphoranes 7 and subse-
CONCLUSIONS
In summary, we prepared several 2-alkoxy-3-cyano-
methylquinolines and quinoline-3-carboxylic acid alkyl
esters from the reaction of 3-(2-azidophenyl)-2-cyano-
methylpropenoates and 3-(2-azidophenyl)-2-nitromethyl-
propenoates, respectively, which were readily obtained
from the Morita–Baylis–Hillman acetates of 2-azidoben-
zaldehydes, using triphenylphosphine at reflux tempera-
ture in toluene. In particular, we discovered an unusual
behavior of the nitro group when it acted as a leaving
group after nucleophilic attack of the iminophosphorane.
Journal of Heterocyclic Chemistry
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H. J. Kim, E. M. Jeong, and K.-J. Lee
Vol 48
Scheme 4
EXPERIMENTAL
The known Morita–Baylis–Hillman acetates, methyl 3-ace-
toxy-3-(2-azidophenyl)-2-methylenepropanoates 1a–c [7,11],
ethyl 3-acetoxy-3-(2-azidophenyl)-2-methylenepropanoate (1d)
[7], and butyl 3-acetoxy-3-(2-azidophenyl)-2-methylenepropa-
noate (1e) [5] were prepared according to published
procedures.
Melting points were measured using an electrothermal melt-
ing point apparatus and were uncorrected. TLC analyses were
conducted on Merck silica gel 60F254, and spots were visual-
ized under UV light. Chromatography on the silica gel was
conducted on Merck silica (70–230 mesh ASTM), and IR
spectra were determined using a Nicolet Magna 550 FTIR
spectrometer with KBr discs. The 1H-NMR spectra were
recorded using a Varian 300 spectrometer in CDCl3 at 300
MHz, and all chemical shifts are given in parts per million
(ppm) using dH Me4Si ¼ 0 ppm as reference and the coupling
constants (J) are given in Hertz. The Varian spectrophotometer
was used to measure both 13C-NMR spectra, at 75.4 MHz
using the solvent peak as an internal reference, and 31P-NMR
spectra at 121 MHz using (PhO)3PO ¼ 0 as the reference.
Low-resolution mass spectra were recorded using a Thermo-
Quest Polaris Q mass spectrometer operating at 70 eV. Ele-
mental analyses were conducted on a Thermo Electron Corpo-
ration Flash EA 1112 instrument.
Table 2
2-Nitromethylpropenoates 6 and alkyl quinoline-3-carboxylates 10.
Entry
6 [Yield (%)/time (h)]
10 [Yield (%)/time (h)]
1
2
3
4
5
6a (74/1)
10a (48/22)
10b (49/27)
10c (41/8)
10d (42/12)
10e (40/20)
6b (76/40 min)
6c (66/100 min)
6d (67/3)
6e (82/2)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Using Morita–Baylis–Hillman Acetates of 2-Azidobenzaldehydes for the
Synthesis of 2-Alkoxy-3-Cyanomethylquinolines and Alkyl Quinoline-3-Carboxylates
969
NMR (deuteriochloform) d 13.7, 17.2, 19.2, 30.6, 65.8, 117.2,
118.6, 123.6, 125.0, 125.3, 129.8, 131.0, 139.1, 139.5, 165.3;
ms: m/z (%) 256 (20) [Mþ–N2], 199 (100), 183 (33), 155 (20),
128 (18). Anal. Calcd. for C15H16N4O2: C, 63.37; H, 5.67; N,
19.71. Found: C, 63.21; H, 5.40; N, 19.58.
General procedure for the synthesis of (E)-alkyl 3-(2-azi-
dophenyl)-2-cyanomethylpropenoates 2. Potassium cyanide
(6 mmole) was added to a stirred solution of Morita–Baylis–
Hillman acetates 1 (4 mmole) in 20 mL of dimethyl sulfoxide
and 10 mL of water at room temperature. After stirring for 1–
6 h, the mixture was extracted with diethyl ether (3 ꢀ 20 mL).
The combined organic layers were dried over anhydrous mag-
nesium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified via column chromatography
with silica gel by elution with hexane and ethyl acetate (3:1)
to produce 2.
Two-step synthesis of 3-cyanomethyl-2-methoxyquinoline
(5a). (Z)-Methyl 2-cyanomethyl-3-[2-N-(triphenylphosphor-
anylidene)phenyl]- propenoate (3a). A mixture of 2-cyanome-
thylazide 2a (0.97 g, 4 mmole) and Ph3P (1.15 g, 4.4 mmole)
in 10 mL of anhydrous toluene was stirred at room tempera-
ture for 4 h. The mixture was concentrated under reduced pres-
sure, and the residue was purified using column chromatogra-
phy with silica gel and eluted with hexane and ethyl acetate
(3:1) providing 1.87 g (98%) of 3a as a yellow solid: mp 165–
166ꢁC (hexane–EtOAc); IR (potassium bromide) 2248, 1704,
(E)-Methyl
(2a). Reaction time: 1 h; yield: 88%; yellow solid: mp 66–
3-(2-azidophenyl)-2-cyanomethylpropenoate
67ꢁC (hexane–EtOAc); IR (potassium bromide) 2250, 2128,
2088, 1716 cmꢂ1 1H-NMR (deuteriochloform) d 3.42 (s, 2H,
;
1589, 1470 cmꢂ1 1H-NMR (deuteriochloform) d 3.53 (s, 2H,
;
CH2), 3.91 (s, 3H, CH3), 7.24–7.27 (m, 2H, aromatic), 7.33–
7.35 (m, 1H, aromatic), 7.45–7.48 (m, 1H, aromatic), 7.95 (s,
1H, CH); 13C-NMR (deuteriochloform) d 17.2, 52.8, 117.2,
118.7, 123.3, 125.0, 125.2, 129.8, 131.1, 139.1, 139.7, 165.8
[7].
(E)-Methyl 3-(2-azido-5-chlorophenyl)-2-cyanomethylpro-
penoate (2b). Reaction time: 5 h; yield: 74%; brown solid: mp
101–102ꢁC (hexane–EtOAc); IR (potassium bromide) 2252,
2135, 2098, 1699 cmꢂ1 1H-NMR (deuteriochloform) d 3.41
;
(s, 2H, CH2), 3.91 (s, 3H,CH3), 7.19 (d, J ¼ 8.5 Hz, 1H, aro-
matic), 7.28 (d, J ¼ 2.5 Hz, 1H, aromatic), 7.44 (dd, J ¼ 8.5
and 2.5 Hz, 1H, aromatic), 7.84 (s, 1H, CH); 13C-NMR (deu-
teriochloform) d 17.1, 52.9, 116.6, 119.9, 124.5, 126.5, 129.4,
130.4, 130.9, 137.6, 138.3, 165.4; ms: m/z (%) 250 (19),
248 (55) [Mþ–N2], 235 (34), 233 (100), 218 (26), 216 (60),
188 (34), 164 (10), 162 (29). Anal. Calcd. for C12H9ClN4O2:
C, 52.09; H, 3.28; N, 20.25. Found: C, 51.87; H, 3.12; N,
20.04.
CH2), 3.92 (s, 3H, CH3), 6.50–6.53 (m, 1H, aromatic), 6.70–
6.75 (m, 1H, aromatic), 6.93–6.98 (m, 1H, aromatic), 7.27–
7.76 (m, 16H, aromatic), 8.73 (s, 1H, CH); 13C-NMR (deuter-
iochloform) d 17.3, 52.3, 117.3, 117.9, 118.4, 127.0, 128.4,
128.5, 128.6, 128.7, 128.8, 129.3, 129.9, 130.4, 131.2, 131.8,
131.9, 132.0, 132.1, 132.4, 132.5, 145.5, 151.5, 167.2; 31P-
NMR [deuteriochloform/(PhO)3PO] d 20.57. ms: m/z (%) 277
(100), 201 (11), 199 (50). Anal. Calcd. for C30H25N2O2P: C,
75.62; H, 5.29; N, 5.88. Found: C, 75.40; H, 5.11; N, 5.62.
3-Cyanomethyl-2-methoxyquinoline (5a). Iminophosphorane
(0.95 g, 2 mmole) in 10 mL of anhydrous toluene was stirred
at reflux temperature for 26 h. The mixture was concentrated
under reduced pressure, and the residue was chromatographed
on silica gel and eluted with hexane and ethyl acetate (2:1)
providing 0.35 g (89%) of 5a and 0.50 g (90%) of triphenyl-
phosphine oxide in the order of elution: mp 103–104ꢁC (hex-
ane–EtOAc); IR (potassium bromide) 2243, 1629 cmꢂ1 1H-
;
NMR (deuteriochloform) d 3.80 (d, J ¼ 1.1 Hz, 2H, CH2),
4.12 (s, 3H, CH3), 7.39–7.44 (m, 1H, aromatic), 7.62–7.68 (m,
1H, aromatic), 7.73–7.76 (m, 1H, aromatic), 7.84–7.87 (m, 1H,
aromatic), 8.09 (s, 1H, aromatic); 13C-NMR (deuteriochloform)
d 19.1, 53.9, 114.8, 117.1, 124.6, 124.8, 127.0, 127.3, 129.9,
137.0, 146.1, 159.1; ms: m/z (%) 198 (86) [Mþ], 183 (19), 169
(27), 158 (100), 130 (26). Anal. Calcd. C12H10N2O: C, 72.71;
H, 5.08; N, 14.13. Found: C, 72.88; H, 4.82; N, 14.03.
General procedure for one-pot synthesis of 2-alkoxy-3-
cyanomethylquinoline 5. A mixture of 2-cyanomethylazide 2
(4 mmole) and Ph3P (1.15 g, 4.4 mmole) in 10 mL of toluene
was stirred at reflux temperature for 20–48 h. The mixture was
cooled to room temperature and concentrated under reduced
pressure. The resulting mixture was chromatographed on silica
gel and eluted with hexane and ethyl acetate (2:1) to produce
pure quinoline 5.
(E)-Methyl 3-(2-azido-5-methoxyphenyl)-2-cyanomethylpro-
penoate (2c). Reaction time: 1 h; yield: 92%; brown solid: mp
72–73ꢁC (hexane–EtOAc); IR (potassium bromide) 2251,
2126, 2100, 1713 cmꢂ1 1H-NMR (deuteriochloform) d 3.78
;
(s, 2H, CH2), 3.90 (s, 3H, CH3), 4.08 (s, 3H, CH3), 7.06 (d, J
¼ 3.0 Hz, 1H, aromatic), 7.30 (dd, J ¼ 9.1 and 2.8 Hz, 1H, ar-
omatic), 7.76 (d, J ¼ 9.1 Hz, 1H, aromatic), 8.01 (s, 1H, CH);
13C-NMR (deuteriochloform) d 17.3, 52.8, 55.7, 114.3, 117.2,
117.3, 119.8, 123.5, 126.0, 131.3, 139.9, 156.7, 165.7; ms: m/z
(%) 244 (89) [Mþ–N2], 229 (100), 212 (85), 201 (28), 184
(47). Anal. Calcd. for C13H12N4O3: C, 57.35; H, 4.44; N,
20.58. Found: C, 57.09; H, 4.67; N, 20.28.
(E)-Ethyl
(2d). Reaction time: 3 h; yield: 87%; yellow solid: mp 59–
3-(2-azidophenyl)-2-cyanomethylpropenoate
60ꢁC (hexane–EtOAc); IR (potassium bromide) 2251, 2129,
1
2094, 1709 cmꢂ1; H-NMR (deuteriochloform) d 1.40 (t, J ¼
3-Cyanomethyl-2-methoxyquinoline (5a). Reaction time: 30
h; yield: 87%; white solid: mp 103–104ꢁC (hexane–EtOAc).
The spectral data were the same as previously described.
6-Chloro-3-cyanomethyl-2-methoxyquinoline (5b). Reaction
time: 25 h; yield: 83%; white solid: mp 159–160ꢁC (hexane–
7.2 Hz, 3H, CH3), 3.41 (s, 2H, CH2), 4.36 (q, J ¼ 7.2 Hz, 2H,
CH2), 7.24–7.28 (m, 2H, aromatic), 7.32–7.35 (m, 1H, aro-
matic), 7.45–7.47 (m, 1H, aromatic), 7.94 (s, 1H, CH); 3C-
NMR (deuteriochloform) d 14.2, 17.2, 61.9, 117.2, 118.6,
123.6, 125.0, 125.3, 129.8, 131.0, 139.1, 139.4, 165.2 [7].
EtOAc); IR (potassium bromide) 2262, 1632 cmꢂ1 1H-NMR
;
(E)-Butyl
(2e). Reaction time: 6 h; yield: 63%; yellow oil; IR (neat)
2253, 2128, 2094, 1711 cmꢂ1 1H-NMR (deuteriochloform) d
3-(2-azidophenyl)-2-cyanomethylpropenoate
(deuteriochloform) d 3.80 (d, J ¼ 1.1 Hz 2H, CH2), 4.11 (s,
3H, CH3), 7.59 (dd, J ¼ 9.1 and 2.2 Hz, 1H, aromatic), 7.72
(d, J ¼ 2.2 Hz, 1H, aromatic), 7.79 (d, J ¼ 9.1 Hz, 1H, aro-
matic), 8.01 (s, 1H, aromatic); 13C-NMR (deuteriochloform) d
19.2, 54.1, 116.0, 116.7, 125.4, 126.1, 128.6, 130.0, 130.6,
136.0, 144.5, 159.3; ms: m/z (%) 234 (14), 232 (47) [Mþ], 194
;
0.98 (t, J ¼ 7.4 Hz, 3H, CH3), 1.42–1.54 (m, 2H, CH2), 1.71–
1.80 (m, 2H, CH2), 3.41 (s, 2H, CH2), 4.31 (t, J ¼ 6.6 Hz,
2H, CH2), 7.21–7.27 (m, 2H, aromatic), 7.33–7.35 (m, 1H, ar-
omatic), 7.45–7.50 (m, 1H, aromatic), 7.94 (s, 1H, CH); 13C-
Journal of Heterocyclic Chemistry
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H. J. Kim, E. M. Jeong, and K.-J. Lee
Vol 48
(31), 192 (100). Anal. Calcd. for C12H9ClN2O: C, 61.95; H,
3.90; N, 12.04. Found: C, 61.79; H, 3.73; N, 11.81.
3-Cyanomethyl-2,6-dimethoxyquinoline (5c). Reaction time:
20 h; yield: 75%; white solid: mp 119–120ꢁC (hexane–
EtOAc); IR (potassium bromide) 2261, 1619 cmꢂ1 1H-NMR
;
(E)-Methyl 3-(2-azido-5-chlorophenyl)-2-nitromethylprope-
noate (6b). Reaction time: 40 min; yield: 76%; yellow solid:
mp 94–95ꢁC (hexane–EtOAc); IR (potassium bromide) 2137,
2102, 1706, 1550, 1298 cmꢂ1 1H-NMR (deuteriochloform) d
;
3.88 (s, 3H, CH3), 5.24 (s, 2H, CH2), 7.18 (d, J ¼ 8.8 Hz, 1H,
aromatic), 7.22 (d, J ¼ 2.5 Hz, 1H, aromatic), 7.44 (dd, J ¼
8.8 and 2.5 Hz, 1H, aromatic), 8.04 (s, 1H, CH); 13C-NMR
(deuteriochloform) d 52.9, 71.6, 119.9, 124.2, 126.2, 129.2,
130.4, 131.2, 137.8, 141.8, 165.4; ms: m/z (%) 223 (25), 222
(12) [Mþ–N2–NO2], 221 (76), 192 (33), 190 (100), 164 (21),
162 (59). Anal. Calcd. for C11H9ClN4O4: C, 44.53; H, 3.06;
N, 18.89. Found: C, 44.37; H, 2.85; N, 18.67.
(E)-Methyl 3-(2-azido-5-methoxyphenyl)-2-nitromethylpro-
penoate (6c). Reaction time: 100 min; yield: 66%; yellow
solid: mp 95–96ꢁC (hexane–EtOAc); IR (potassium bromide)
2140, 2130, 1700, 1551, 1299 cmꢂ1 1H-NMR (deuteriochlo-
;
(deuteriochloform) d 3.78 (d, J ¼ 1.1 Hz, 2H, CH2), 3.90 (s,
3H, CH3), 4.08 (s, 3H, CH3), 7.06 (d, J ¼ 2.8 Hz, 1H, aro-
matic), 7.30 (dd, J ¼ 9.1 and 2.8 Hz, 1H, aromatic), 7.76 (d, J
¼ 9.1 Hz, 1H, aromatic), 8.01 (s, 1H, aromatic); 13C-NMR
(deuteriochloform) d 19.1, 53.7, 55.5, 105.9, 114.9, 117.1,
121.6, 125.4, 128.3, 136.0, 141.5, 156.4, 157.8; ms: m/z (%)
228 (93) [Mþ], 213 (30), 188 (100), 185 (29). Anal. Calcd. for
C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.20; H,
5.09; N, 12.41.
3-Cyanomethyl-2-ethoxyquinoline (5d). Reaction time: 48
h; yield: 95%; white solid: mp 79–80ꢁC (hexane–EtOAc); IR
;
(potassium bromide) 2259, 1628 cmꢂ1 1H-NMR (deuterio-
form) d 3.77 (s, 3H, CH3), 3.88 (s, 3H, CH3), 5.27 (s, 2H,
CH2), 6.76 (d, J ¼ 2.8 Hz, 1H, aromatic), 7.02 (dd, J ¼ 8.8
and 2.8 Hz, 1H, aromatic), 7.16 (d, J ¼ 9.1 Hz, 1H, aromatic),
8.12 (s, 1H, CH); 13C-NMR (deuteriochloform) d 52.8, 55.6,
71.9, 114.0, 117.4, 119.8, 123.3, 125.6, 131.5, 143.3, 156.7,
165.7; ms: m/z (%) 218 (15) [Mþ–N2–NO2], 217 (100), 186
(72), 158 (52). Anal. Calcd. for C12H12N4O5: C, 49.32; H,
4.14; N, 19.17. Found: C, 49.14; H, 3.98; N, 18.89.
chloform) d 1.46 (t, J ¼ 7.2 Hz, 3H, CH3), 3.80 (d, J ¼ 1.1
Hz, 2H, CH2), 4.57 (q, J ¼ 7.2 Hz, 2H, CH2), 7.38–7.43 (m,
1H, aromatic), 7.61–7.66 (m, 1H, aromatic), 7.72–7.75 (m, 1H,
aromatic), 7.81–7.84 (m, H, aromatic), 8.09 (s, 1H, aromatic);
13C-NMR (deuteriochloform) d 14.5, 19.2, 62.4, 114.8, 117.1,
124.5, 124.7, 127.0, 127.3, 129.8, 136.9, 146.2, 158.8; ms: m/z
(%) 212 (24) [Mþ], 197 (13), 184 (100), 166 (21), 158 (22).
Anal. Calcd. for C13H12N2O: C, 73.56; H, 5.70; N, 13.20.
Found: C, 73.40; H, 5.54; N, 13.07.
(E)-Ethyl 3-(2-azidophenyl)-2-nitromethylpropenoate (6d).
Reaction time: 3 h; yield: 67%; light yellow solid: mp 104ꢁC
(hexane–EtOAc); IR (potassium bromide) 2142, 2101, 1701,
2-Butoxy-3-cyanomethylquinoline (5e). Reaction time: 28
h; yield: 87%; white solid: mp 45–46ꢁC (hexane–EtOAc); IR
;
(potassium bromide) 2255, 1625 cmꢂ1 1H-NMR (deuterio-
1
1553, 1299 cmꢂ1; H-NMR (deuteriochloform) d 1.36 (t, J ¼
7.2 Hz, 3H, CH3), 4.33 (q, J ¼ 7.2 Hz, 2H, CH2), 5.25 (s, 3H,
CH3), 7.16–7.27 (m, 3H, aromatic), 7.45–7.51 (m, 1H, aro-
matic), 8.15 (s, 1H, CH); 13C-NMR (deuteriochloform) d 14.1,
61.9, 71.9, 118.7, 123.5, 125.0, 125.1, 129.5, 131.4, 139.3,
143.0, 165.2; ms: m/z (%) 202 (12) [Mþ–N2–NO2], 201 (77),
173 (92), 156 (100), 128 (80). Anal. Calcd. for C12H12N4O4:
C, 52.17; H, 4.38; N, 20.28. Found: C, 52.28; H, 4.31; N,
20.04.
chloform) d 1.01 (t, J ¼ 7.4 Hz, 3H, CH3), 1.47–1.59 (m, 2H,
CH2), 1.79–1.88 (m, 2H, CH2), 3.79 (d, J ¼ 1.1 Hz, 2H, CH2),
4.52 (t, J ¼ 6.6 Hz, 2H, CH2), 7.38–7.43 (m, 1H, aromatic),
7.61–7.66 (m, H, aromatic), 7.72–7.75 (m, 1H, aromatic),
7.82–7.85 (m, 1H, aromatic), 8.08 (s, 1H, aromatic); 13C-NMR
(deuteriochloform) d 13.9, 19.2, 19.4, 30.9, 66.3, 114.9, 117.1,
124.5, 124.7, 127.0, 127.3, 129.8, 136.9, 146.2, 159.0; ms: m/z
(%) 240 (2) [Mþ], 184 (100), 166 (18). Anal. Calcd. for
C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found: C, 74.78; H,
6.56; N, 11.38.
(E)-Butyl 3-(2-azidophenyl)-2-nitromethylpropenoate (6e).
Reaction time: 2 h; yield: 82%; brown oil; IR (neat) 2129,
;
1713, 1558, 1294 cmꢂ1 1H-NMR (deuteriochloform) d 0.97
(t, J ¼ 7.2 Hz, 3H, CH3), 1.36–1.49 (m, 2H, CH2), 1.66–1.75
(m, 2H, CH2), 4.28 (t, J ¼ 6.6 Hz, 2H, CH2), 5.25 (s, 2H,
CH2), 7.16–7.26 (m, 3H, aromatic), 7.45–7.51 (m, 1H, aro-
matic), 8.15 (s, 1H, CH); 13C-NMR (deuteriochloform) d 13.7,
19.1, 30.5, 65.7, 71.9, 118.7, 123.5, 125.0, 125.1, 129.5, 131.4,
139.4, 143.0, 165.3; ms: m/z (%) 229 (10), 228 (22), 173
(100), 156 (40), 155 (51), 128 (39). Anal. Calcd. for
C14H16N4O4: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.02; H,
5.07; N, 18.26.
General procedure for the synthesis of (E)-methyl 3-(2-
azidophenyl)-2-nitromethylpropenoates 6. Sodium nitrite
(4.4 mmole) was added to a stirred solution of Morita–Baylis–
Hillman acetates 1 (4 mmole) in 15 mL of dimethyl formam-
ide at room temperature. After stirring for 40 min to 3 h, the
mixture was extracted with diethyl ether (3 ꢀ 20 mL). The
combined organic layers were dried over anhydrous magne-
sium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified using column chromatogra-
phy with silica gel and was eluted with hexane and ethyl ace-
tate (6:1) to produce 6.
Two-step synthesis of methyl quinoline-3-carboxylate
(10a). (Z)-Methyl 2-nitromethyl-3-[2-N-(triphenylphosphor-
anylidene)phenyl]-propenoate (7a). A mixture of 2-nitrome-
thylazide 6a (1.05 g, 4 mmole) and Ph3P (1.15 g, 4.4 mmole)
in 10 mL of anhydrous toluene was stirred at room tempera-
ture for 30 min. The mixture was concentrated under reduced
pressure, and the residue was purified using column chroma-
tography with silica gel and was eluted with hexane and ethyl
acetate (2:1) providing 1.81 g (91%) of 7a as a yellow solid:
mp 153ꢁC (hexane–EtOAc); IR (potassium bromide) 1707,
(E)-Methyl
3-(2-azidophenyl)-2-nitromethylpropenoate
(6a). Reaction time: 1 h; yield: 74%; light yellow solid: mp
101–102ꢁC (hexane–EtOAc); IR (potassium bromide) 2143,
2102, 1710, 1555, 1302 cmꢂ1 1H-NMR (deuteriochloform) d
;
3.88 (s, 3H, CH3), 5.26 (s, 2H, CH2), 7.16–7.27 (m, 3H, aro-
matic), 7.46–7.51 (m, 1H, aromatic), 8.16 (s, 1H, CH); 13C-
NMR (deuteriochloform) d 52.8, 71.8, 118.7, 123.1, 124.9,
125.1, 129.5, 131.5, 139.4, 143.3, 165.8; ms: m/z (%) 188
(100) [Mþ–N2–NO2], 156 (55), 128 (31). Anal. Calcd. for
C11H10N4O4: C, 50.38; H, 3.84; N, 21.37. Found: C, 50.07; H,
3.72; N, 21.16.
1553, 1469, 1436 cmꢂ1 1H-NMR (deuteriochloform) d 3.89
;
(s, 3H, CH3), 5.37 (s, 2H, CH2), 6.49–6.52 (m, 1H, aromatic),
6.63–6.68 (m, 1H, aromatic), 6.93–6.99 (m, 1H, aromatic),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Using Morita–Baylis–Hillman Acetates of 2-Azidobenzaldehydes for the
Synthesis of 2-Alkoxy-3-Cyanomethylquinolines and Alkyl Quinoline-3-Carboxylates
971
7.09–7.13 (m, 1H, aromatic), 7.43–7.59 (m, 9H, aromatic),
7.69–7.76 (m, 6H, aromatic), 8.95 (s, 1H, CH); 13C-NMR
(deuteriochloform) d 52.2, 72.9, 117.4, 118.0, 128.1, 128.4,
128.6, 128.8, 128.9, 129.8, 130.9, 131.1, 131.9, 132.0, 132.4,
132.5, 149.3, 151.8, 167.3; 31P-NMR [deuteriochloform/
(PhO)3PO] d 20.94. ms: m/z (%) 277 (100), 199 (45). Anal.
Calcd. for C29H25N2O4P: C, 70.15; H, 5.08; N, 5.64. Found:
C, 69.91; H, 4.79; N, 5.43.
123.2, 126.8, 127.4, 129.1, 129.4, 131.7, 138.6, 149.8, 150.0,
165.3 [13].
Butyl quinoline-3-carboxylate (10e). Reaction time: 20 h;
yield: 40%; yellow oil; IR (neat) 1720 cmꢂ1 1H-NMR (deu-
;
teriochloform) d 1.02 (t, J ¼ 7.4 Hz, 3H, CH3), 1.47–1.59 (m,
2H, CH2), 1.78–1.88 (m, 2H, CH2), 4.43 (t, J ¼ 6.6 Hz, 2H,
CH2), 7.61–7.66 (m, 1H, aromatic), 7.82–7.87 (m, 1H, aro-
matic), 7.96 (d, J ¼ 8.0 Hz, 1H, aromatic), 8.18 (d, J ¼ 8.5
Hz, 1H, aromatic), 8.85 (d, J ¼ 2.2 Hz, 1H, aromatic), 9.46
(d, J ¼ 2.2 Hz, 1H, aromatic); 13C-NMR (deuteriochloform) d
13.8, 19.2, 30.7, 65.4, 122.3, 126.8, 127.4, 129.1, 129.4, 131.8,
138.7, 149.8, 150.1, 165.4; ms: m/z (%) 229 (8) [Mþ], 228
(13), 173 (100), 155 (47), 128 (32). Anal. Calcd. for
C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.21; H,
6.38; N, 6.03.
Methyl quinoline-3-carboxylate (10a). Iminophosphorane
7a (0.98 g, 2 mmole) in 5 mL of anhydrous toluene was
stirred at reflux temperature for 22 h. The mixture was concen-
trated under reduced pressure, and the residue was chromato-
graphed on silica gel and was eluted with hexane and ethyl
acetate (2:1) providing 0.20 g (54%) of 10a as a white solid
and 0.35 g (63%) of triphenylphosphine oxide in the order of
elution: mp 76–77ꢁC (hexane–EtOAc); IR (potassium bromide)
1
1723 cmꢂ1; H-NMR (deuteriochloform) d 4.02 (s, 3H, CH3),
Acknowledgment. This work was supported in part by the Brain
Korea 21 program, Republic of Korea.
7.60–7.65 (m, 1H, aromatic), 7.81–7.87 (m, 1H, aromatic), 7.93
(d, J ¼ 8.0 Hz, 1H, aromatic), 8.17 (d, J ¼ 8.5 Hz, 1H, aro-
matic), 8.85 (d, J ¼ 1.7 Hz, 1H, aromatic), 9.45 (d, J ¼ 2.2 Hz,
1H, aromatic); 13C-NMR (deuteriochloform) d 52.5, 122.9,
126.7, 127.4, 129.1, 129.4, 131.8, 138.7, 149.7, 149.9, 165.8;
ms: m/z (%) 187 (52) [Mþ], 156 (80), 128 (100) [5,12].
General procedure for one-pot synthesis of alkyl quino-
line-3-carboxylates 10. A mixture of 2-nitromethylazide 6 (4
mmole) and Ph3P (1.15 g, 4.4 mmole) in 10 mL of toluene
was stirred at reflux temperature for 8–50 h. The mixture was
cooled to room temperature and concentrated under reduced
pressure. The resulting mixture was chromatographed on silica
gel and was eluted with hexane and ethyl acetate (2:1) to pro-
duce pure quinoline 10.
Methyl quinoline-3-carboxylate (10a). Reaction time: 22 h;
yield: 48%; white solid: mp 76–77ꢁC (hexane–EtOAc). The
spectral data were the same as previously described.
Methyl 6-chloroquinoline-3-carboxylate (10b). Reaction
time: 27 h; yield: 49%; white solid: mp 169–170ꢁC (hexane–
;
EtOAc); IR (potassium bromide) 1723 cmꢂ1 1H-NMR (deu-
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Methyl 6-methoxyquinoline-3-carboxylate (10c). Reaction
time: 8 h; yield: 41%; light yellow solid: mp 119–120ꢁC (hex-
ane–EtOAc); IR (potassium bromide) 1710 cmꢂ1 1H-NMR
;
(deuteriochloform) d 3.95 (s, 3H, CH3), 4.01 (s, 3H, CH3),
7.15 (d, J ¼ 2.8 Hz, 1H, aromatic), 7.47 (dd, J ¼ 9.3 and 2.8
Hz, 1H, aromatic), 8.04 (d, J ¼ 9.3 Hz, 1H, aromatic), 8.72
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;
1.47 (t, J ¼ 7.2 Hz, 3H, CH3), 4.49 (q, J ¼ 7.2 Hz, 2H, CH2),
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aromatic), 8.85 (d, J ¼ 1.9 Hz, 1H, aromatic), 9.46 (d, J ¼ 2.2
Hz, 1H, aromatic); 13C-NMR (deuteriochloform) d 14.3, 61.5,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

972
H. J. Kim, E. M. Jeong, and K.-J. Lee
Vol 48
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet