Formation of 1,2-dihydroquinoline-3-carboxylic acid derivatives from methyl 3-(arylamino)acrylates with hydrogen iodide

Article abstract of DOI:10.1055/s-0030-1258229

The reaction of methyl 3-(arylamino)acrylates with hydrogen iodide gave 1,2-dihydroquinoline-3-carboxylic acid derivatives at room temperature. This reaction proceeds efficiently in alcoholic solvent; bulky tert-butyl alcohol is the best solvent to give t

Full text of DOI:10.1055/s-0030-1258229

PAPER
3615
Formation of 1,2-Dihydroquinoline-3-carboxylic Acid Derivatives from
Methyl 3-(Arylamino)acrylates with Hydrogen Iodide
Formation of
1
h
,2-Dihydroq
o
uinoline-3-c
j
arboxy
i
A
cid
D
eriv
M
atives atsumoto,* Takahiro Mori, Motohiro Akazome
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoicho, Inageku,
Chiba 263-8522, Japan
Fax +81(43)2903401; E-mail: smatsumo@faculty.chiba-u.jp
Received 28 June 2010; revised 29 July 2010
hydroquinoline structure 3. Regarding the resonance
structure A¢, structure A has a good charge distribution to
promote the cyclization reaction based on the electron-do-
nating nitrogen atom and the electron-accepting tosyl
Abstract: The reaction of methyl 3-(arylamino)acrylates with hy-
drogen iodide gave 1,2-dihydroquinoline-3-carboxylic acid deriva-
tives at room temperature. This reaction proceeds efficiently in
alcoholic solvent; bulky tert-butyl alcohol is the best solvent to give
the 1,2-dihydroquinoline derivatives. It is particularly interesting group. When a carboxyl group is introduced instead of the
that hydrogen iodide is the most efficient acid to achieve this reac-
tion in tert-butyl alcohol. Various substituents at the phenyl ring are
tosyl group such as in 4, the charge distribution will be re-
tained and the reaction will yield 1,2-dihydroquinoline-3-
applicable. Compounds bearing meta-substituted phenyl ring with
carboxylic acid derivatives 5. Few reports in the relevant
electron-donating group led to the corresponding 1,2-dihydroquin-
literature describe the useful formation of 1,2-dihydro-
oline derivatives in good yields.
quinoline-3-carboxylic acid derivatives.6d,f–h,9 Herein, we
Key words: cyclization, hydrogen iodide, heterocycles, solvent ef-
report the reaction of 3-(arylamino)acrylic esters with
fects, substituent effects
protic acid to give 1,2-dihydroquinoline-3-carboxylic
acid derivatives at room temperature.
Quinolines and hydroquinolines are important organic
SMe
H
N
H
materials for synthesizing alkaloids, agrochemicals, dyes,
and pharmaceuticals. Various synthetic methods of the
1,2-dihydroquinolines have been reported.1–3 The reaction
of quinoline derivatives with alkylmetal reagents or with
reducing agents (NaBH4, LiAlH4, etc.) is an important
method to form 1,2-dihydroquinoline derivatives.4,5 How-
ever, it presents the limitation that quinoline derivatives
bearing the reactive substituent interact with alkyl anion
or hydride to give undesired products. To overcome this
limitation, condensation type reactions were sought,
which offer useful methods to produce 1,2-dihydroquino-
line derivatives.6 We reported earlier the formation of the
3-tosylquinoline derivatives 2 by the reaction of 2-(aryl-
amino)-1-(methylthio)-1-tosylethenes 1 with hydrogen
iodide in refluxing toluene.7 In that report, the formation
of 3-tosyl-1,2-dihydroquinoline derivatives 3 was de-
scribed. In the proposed mechanism, the in situ formed 2-
(arylamino)-1-tosylethene A was reacted bimolecularly
(Scheme 1). A similar type of the formation of 2-methyl-
1,2,3,4-tetrahydroquinolines from aniline and vinyl ethers
with cerium ammonium nitrate was reported by Menéndez
and co-workers.8 They extracted the dihydroquinoline
derivatives from the 4-alkoxy-2-methyl-1,2,3,4-tetrahyd-
roquinolines through an additional reaction with hydro-
chloric acid. Their result relies upon the lesser leaving
ability of the alkoxy group. In our system, the good aryl-
amino leaving group under acidic conditions is attached in
the cyclic system to effect the formation of the 1,2-di-
N
Ts
CO2R
4
1
HI, toluene
reflux
H+
r.t.
H
H
N
N
Ts
Ts
H
N
CO2R
CO2R
A
PhNH
Ts
5
H
N
A'
Ts
Ts
PhNH
H
N
N
[O]
Ts
Ts
Ts
Ts
2
3
Scheme 1 Quinoline formation from 1 with HI and the application
to 4
Methyl 3-(arylamino)acrylates 4 were prepared easily
from the reaction of methyl prop-2-ynoate and the corre-
sponding aniline derivatives using a procedure reported
by Isobe and co-workers.10 Although the reaction of 4a
with hydrogen iodide was examined under the same con-
ditions as for 1,7 it was not possible to initiate the reaction
SYNTHESIS 2010, No. 21, pp 3615–3622
x
x.
x
x
.
2
0
1
0
Advanced online publication: 25.08.2010
DOI: 10.1055/s-0030-1258229; Art ID: F11110SS
© Georg Thieme Verlag Stuttgart · New York

3616
S. Matsumoto et al.
PAPER
because of the lower solubility of 4a in toluene. There- mer mixture of 4a revealed no influence of geometric
fore, a suitable solvent for the reaction was surveyed at isomerism (entry 11).
first and the results are presented in Table 1. To a solution
The reaction pathway depicted in Scheme 2 is inferred
of 4a was added 55% aqueous hydrogen iodide (1.0
based on the reaction of 1 with hydrogen iodide.7 Hydro-
equiv) under a nitrogen atmosphere. The reaction pro-
gen iodide combines with 4a to produce the cationic inter-
mediate I to promote the ring-closing reaction in
cooperation with the proper charge distribution B. Inter-
mediate I undergoes addition to another 4a to give the in-
termediate II. In methanol, the cationic carbon of II is
solvated to form the intermediate III; thereby, the reactiv-
ity of II will be decreased. Consequently, the intramolec-
ular nucleophilic substitution occurred efficiently using
ceeded even at room temperature affording two or three
products. Regarding the formation of dihydroquinoline
derivatives, results show that the most promising solvent
was a protic solvent such as methanol, which gave 21%
yield of 5a together with 33% yield of MeO-5a (Table 1,
entry 4). The effect of an acid in this reaction was also
studied. It was found that the reaction proceeded efficient-
ly with hydrogen iodide or p-toluenesulfonic acid as an
the aromatic electron at the ortho position of the nitrogen
acid (entries 4 and 7) affording both 5a and MeO-5a.11
atom to give the intermediate IV. The 1,2-dihydroquino-
Furthermore, the formation of undesired compounds such
line derivative 5a is formed by elimination of proton and
aniline with the recovery of hydrogen iodide. When the at-
as 6 and 7 was observed using other acids (entries 5–7).
An increase in the formation of 5a was attempted by tack from the phenyl ring occurs at the carbon of a-amino
changing the protic solvent from methanol to tert-butyl al- ether moiety in III, both 5a (path a) and MeO-5a (path b)
cohol to cease the formation of MeO-5a. The yield of 5a are obtained. Compared to the refluxing conditions in the
improved to 34% when the reaction was conducted with reaction of 1,7 milder conditions such as room tempera-
hydrogen iodide (entry 8). However, the reaction with p- ture will prevent oxidation to form the quinoline deriva-
toluenesulfonic acid was inhibited (entry 9), revealing the tives. However, in the case of the other solvents, the
importance of the counter anion as well as the solvent. intermediate III cannot form. Therefore, the elimination
The amount of hydrogen iodide was also controlled and will proceed to give 7 and its regioisomer 7¢. Subsequent-
found that it can be reduced to 0.6 equivalent to maintain ly, 7¢ can add a proton to undergo another cyclization re-
the yield of 5a, the slightly prolonged reaction time was action. The detailed mechanism for the formation of 6
necessary (entry 10). The reaction using a geometric iso- remains unclear. However, the regiospecific formation of
7 includes a hint; the proposed mechanism shown in
Table 1 Reaction of 4a with Acid in Various Solvents
H
CO2Me
H
N
N
CO2Me
CO2Me
CO2Me
CO2Me
acid
Ph
N
+
+
+
NH
CO2Me
CO2Me
solvent
r.t.
CO2Me
PhNH
CO2Me
OMe
4a
CO2Me
5a
7
MeO-5a
6
Yield (%)
Entry
Solvent
CHCl3
MeCN
THF
Acid (equiv)
Time (h)
5a
MeO-5a
6
7
1
2
55% aq HI (1.0)
55% aq HI (1.0)
55% aq HI (1.0)
55% aq HI (1.0)
concd HCl (1.0)
CF3CO2H (1.0)
2
12
9
–
52
43
32
0
0
0
2
–
3
1
0
–
44
0
4
MeOH
MeOH
MeOH
MeOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
1
21
10a
19
34
34b
8
33
10
30
21
–
5
1.5
39
26
14
0
8
6
24
6
7
TsOH·H2O (1.0)
55% aq HI (1.0)
TsOH·H2O (1.0)
55% aq HI (0.6)
55% aq HI (0.6)
1
3
4
4
4
10
3
8
9
–
25
0
35
18
19
10
11c
38
41
–
–
0
a Quinoline derivative formed in 11% yield.
b Quinoline derivative formed in 10% yield.
c A geometric isomer mixture of 4a (E/Z = 24:76) was used.
Synthesis 2010, No. 21, 3615–3622 © Thieme Stuttgart · New York

PAPER
Formation of 1,2-Dihydroquinoline-3-carboxylic Acid Derivatives
3617
Scheme 2 is plausible. Additionally, an iodide ion pos- and 5e, respectively, although it took a long period of the
sesses nucleophilicity.12 Therefore, decrease of the reac- reaction time (entries 3 and 4). Based on the schematic
tivity of II will be realized by the addition of the iodide proposal portrayed in Scheme 1, it would be reasonable to
ion to form V. The effect of the iodide ion worked also ef- require longer reaction times in the cases of 4d and 4e be-
ficiently in tert-butyl alcohol, although its ability is insuf- cause of the decreased nucleophilicity of the phenyl ring,
ficient to strictly inhibit the formation of the side product especially at the ortho position from nitrogen atom, in the
7. This could be the reason for the decrease in the yield of resonance structure C (Scheme 3). The influence of the
5a in the case of using p-toluenesulfonic acid in tert-butyl substituents in the phenyl ring at 2 and 3 positions was
alcohol (Table 1, entry 9).
also examined (entries 5 and 6). Consequently, 4f gave the
corresponding 1,2-dihydroquinolines 5f and 5f¢ in the
highest yield (totally 60%) between the methyl substituted
compounds (5b, 48%; 5g, 48%). A good explanation
might be that the cyclization reactions occurred at the
para or ortho position from the electron-donating methyl
group, which would enhance the nucleophilicity at the re-
action site (see D in Scheme 3).14 Based on these sugges-
tions, 5i was ultimately obtained in 71% yield by the
reaction of 4i that is doubly activated by two methoxy
groups at the meta position of the phenyl ring from the ni-
trogen atom. It is also noteworthy that the methyl ester
part and methoxy group are unchanged in these reaction
conditions, although hydrogen iodide is well known as a
demethylation reagent.15 This is true because the present
reaction conditions using 0.6 equivalent of hydrogen io-
dide at room temperature are too mild to cleave the O–Me
bond.
The reaction of the compounds having various substitu-
ents at the phenyl ring was examined to give the corre-
sponding 1,2-dihydroquinoline derivatives (Table 2)
under the efficient reaction conditions using tert-butyl al-
cohol as a solvent with 0.6 equivalent of hydrogen iodide
at room temperature. Introduction of the methyl group at
the 4 position of the phenyl ring gave 5b in 48% yield
(Table 2, entry 1). When a more electron-donating substit-
uent such as methoxy group was attached at that position,
the yield of 1,2-dihydroquinoline derivative was de-
creased (5%), although the oxidized quinoline derivative
of 5c was obtained in 25% yield (entry 2). The reason is
the substitution of the strong electron-donating group at
the 4 position of the phenyl ring enhanced the oxidation
ability of the formed 1,2-dihydroquinoline derivatives.13
The compounds bearing the electron-withdrawing substit-
uents at the 4 position of the phenyl ring, 4d and 4e, gave
the corresponding 1,2-dihydroquinoline derivatives 5d
H
I
H
I
H
H
N
N
HI
NH
4a
CO2Me
CO2Me
CO2Me
I
CH2O2Me
CO2Me
PhNH
PhNH
B
I
H
N
I
H
CO2Me
N
CO2Me
MeOH
CO2Me
CO2Me
7
+
– HI
– H2NPh
PhNH
CO2Me
b
HNPh
MeO
H
CO2Me
7'
a
PhNH
II
III
HI, 4a
b
a
CO2Me
H
I
I
H
N
MeO-5a
PhNH
CO2Me
CO2Me
CO2Me
CO2Me
H
N
PhNH
PhNH
CO2Me
IV
CO2Me
HNPh
I
CO2Me
CO2Me
I
– HI
– H2NPh
Ph NH
PhNH
V
5a
CO2Me
– HI
– H2NPh
6
Scheme 2 Proposed reaction mechanism for the formation of 5a, MeO-5a, and 6
Synthesis 2010, No. 21, 3615–3622 © Thieme Stuttgart · New York

3618
S. Matsumoto et al.
PAPER
Table 2 Reaction of 4b–i with HIa
Entry
1
Compound (E/Z)
Time (h)
2
Product
Yield (%)b
CO2Me
H
H
N
N
CO2Me
CO2Me
48 (10)
R
R
5b
4b (R = Me) (28:72)
4c (R = OMe) (27:73)
4d (R = CO2Me) (0:100)
4e (R = Br) (28:72)
2
3
4
2
48
72
5c
5d
5e
5 (25)
43
40
H
N
CO2Me
CO2Me
51 (13)
CO2Me
H
N
5f
5
2
H
N
CO2Me
CO2Me
4f (26:74)
9
5f¢
CO2Me
H
N
H
N
CO2Me
CO2Me
6
7
2
1
48
4g (0:100)
5g
CO2Me
H
N
H
N
CO2Me
CO2Me
66 (12)
71 (13)
5h
4h (5:95)
CO2Me
H
H
MeO
N
MeO
N
CO2Me
CO2Me
8
1
MeO
MeO
5i
4i (0:100)
a Reaction conditions: compound 4b–i (1.0 mmol) and 55% aq HI (0.6 equiv) in t-BuOH.
b Values in parentheses show the yield of quinoline derivative.
reduce the nucleophilicity of the aromatic ring
In summary, we have found that the reaction of methyl 3-
(arylamino)acrylates 4 with hydrogen iodide gave 1,2-di-
hydroquinoline-3-carboxylic acid derivatives 5. This re-
action is applicable to various substituents at the phenyl
ring. Furthermore, the results demonstrate that the addi-
tion of the electron-donating substituent(s) at the meta po-
sition of the phenyl ring from the nitrogen atom is an
efficient means to increase the yield of 5.
H
H
H
N
H
N
CO2Me
CO2Me
EWG
EWG
CO2Me
Me
CO2Me
ArNH
ArNH
C
H
H
N
CO2Me
CO2Me
Melting points were determined with Yanaco MP-J3 and values are
para position
from methyl group
1
uncorrected. H NMR measurement was performed on a Varian
GEMINI 2000 (300 MHz) spectrometer. Chemical shifts (d) of 1H
NMR were expressed in parts per million downfield from TMS as
an internal standard (d = 0 ppm). Multiplicities are indicated as s
ArNH
D
Scheme 3 Electronic effect of the substituents
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Formation of 1,2-Dihydroquinoline-3-carboxylic Acid Derivatives
3619
(singlet), br s (broadened singlet), d (doublet), t (triplet), m (multip-
let), br (broadened), and coupling constants (J) are reported in Hz.
IR spectra were recorded on a JASCO FT/IR-350 or a JASCO FT/
IR-460 plus spectrometers in KBr disk or on NaCl plates. Elemental
analyses (EA) were carried out on a PerkinElmer 2400CHN in An-
alytical Chemical Center of Chiba University. Mass spectra were
carried out on a JEOL JMS-AX500, a JMS-HX110, or a Thermo
Scientific Exactive in Analytical Chemical Center of Chiba Univer-
sity. Analytical TLC was performed on glass plates pre-coated with
silica gel (layer thickness 0.25 mm). Column chromatography was
performed on 70–230 mesh silica gel. Methyl prop-2-ynoate,
anilines, acids, and solvents were used as commercially available
(Aldrich Chemical Co., Tokyo Kasei Chemical Industry Co., Wako
Pure Chemical Co., Kanto Chemical Co., and Nacalai Tesque Inc.).
Anal. Calcd for C10H10BrNO2: C, 46.90; H, 3.94; N, 5.47. Found: C,
46.64; H, 3.70; N, 5.29.
E-Isomer: 1H NMR (300 MHz, CDCl3): d (selected data) = 5.23 (d,
J = 13.0 Hz, 1 H), 7.84 (t, J = 13.1 Hz, 1 H).
Methyl 3-(3-Tolylamino)acrylate (4f)
Reaction time: 48 h; yield: 98% (E/Z = 26:74).
Z-Isomer: colorless needles; mp 117.5–119.5 °C (hexane–EtOAc).
IR (KBr): 3290, 1698, 1619, 1586, 1275, 1141 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H), 3.73 (s, 3 H), 4.84
(d, J = 8.3 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 6.80 (s, 1 H), 6.82 (d,
J = 7.4 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H), 7.25 (dd, J = 8.4, 12.7 Hz,
1 H), 9.83 (br d, J = 12.5 Hz, 1 H).
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
68.88; H, 6.84; N, 7.21.
Methyl 3-(Arylamino)acrylates; (Z)-Methyl 3-(Phenylami-
no)acrylate (4a);10 Typical Procedure
To a solution of aniline (0.376 g, 4.04 mmol) in MeOH (8.4 mL)
was added methyl prop-2-ynoate (0.362 g, 4.31 mmol) at r.t. The
mixture was stirred for 48 h and was concentrated under reduced
pressure to give (E)- and (Z)-methyl 3-(phenylamino)acrylates
(24:76). The residue was subject to column chromatography on sil-
ica gel (CHCl3–EtOAc, 15:1) to give 4a; yield: 0.633 g (3.57 mmol,
88%); colorless solid; mp 155.0–156.3 °C (hexane–EtOAc) (Lit.10
mp 151–154 °C).
E-Isomer: 1H NMR (300 MHz, CDCl3): d (selected data) = 5.19 (d,
J = 13.1 Hz, 1 H), 7.93 (t, J = 13.3 Hz, 1 H).
(Z)-Methyl 3-(2-Tolylamino)acrylate (4g)
Reaction time: 54 h; yield: 85%; colorless needles; mp 64.4–
65.8 °C (hexane–EtOAc).
IR (KBr): 3297, 1674, 1632, 1600, 1461, 1246, 1215 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H), 3.74 (s, 3 H), 4.89
(d, J = 8.2 Hz, 1 H), 6.94 (t, J = 7.4 Hz, 1 H), 7.04 (d, J = 7.9 Hz, 1
H), 7.16–7.22 (m, 2 H), 7.33 (dd, J = 8.2, 12.5 Hz, 1 H), 10.20 (br
s, 1 H).
Methyl 3-(4-Tolylamino)acrylate (4b)16
Reaction time: 115 h; yield: 98% (E/Z = 28:72).
1H NMR (300 MHz, CDCl3): d (Z-isomer) = 2.30 (s, 3 H), 3.71 (s,
3 H), 4.81 (d, J = 8.3 Hz, 1 H), 6.83 (d, J = 9.0 Hz, 2 H), 7.10 (d,
J = 8.3 Hz, 2 H), 7.22 (dd, J = 8.3, 12.9 Hz, 1 H), 9.81 (br d,
J = 12.6 Hz, 1 H).
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
68.70; H, 6.83; N, 7.24.
1H NMR (300 MHz, CDCl3): d (E-isomer, selected data) = 5.17 (d,
J = 13.2 Hz, 1 H), 6.45 (br d, J = 12.7 Hz, 1 H), 7.89 (t, J = 13.2 Hz,
1 H).
Methyl 3-[(3,5-Dimethylphenyl)amino]acrylate (4h)
Reaction time: 120 h; yield: 99% (E/Z = 5:95).
Z-Isomer: brown oil.
IR (NaCl, neat): 3315, 2948, 1634, 1456, 1204, 1013, 909, 832, 789
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 6 H), 3.71 (s, 3 H), 4.81
(d, J = 8.3 Hz, 1 H), 6.60 (s, 2 H), 6.65 (s, 1 H), 7.24 (dd, J = 8.3,
12.8 Hz, 1 H), 9.75 (br d, J = 12.3 Hz, 1 H).
HRMS-ESI: m/z [M + Na]+ calcd for C12H15NO2 + Na: 228.0995;
found: 228.0995.
Methyl 3-[(4-Methoxyphenyl)amino]acrylate (4c)17
Reaction time: 48 h; yield: ~100% (E/Z = 27:73).
1H NMR (300 MHz, CDCl3): d (Z-isomer) = 3.71 (s, 3 H), 3.78 (s,
3 H), 4.79 (d, J = 8.4 Hz, 1 H), 6.84–6.93 (m, 4 H), 7.15 (dd, J = 8.3,
12.9 Hz, 1 H), 9.78 (br d, J = 12.7 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d (E-isomer, selected data) = 5.14 (d,
J = 13.0 Hz, 1 H), 7.82 (t, J = 12.9 Hz, 1 H).
E-Isomer: 1H NMR (300 MHz, CDCl3): d (selected data) = 5.17 (d,
J = 13.1 Hz, 1 H), 7.91 (t, J = 13.2 Hz, 1 H).
(Z)-Methyl 3-[(4-Methoxycarbonylphenyl)amino]acrylate (4d)
Reaction time: 125 h; yield: 23%; colorless solid; mp 128.7–
129.5 °C (hexane–EtOAc).
IR (KBr): 3300, 1712, 1669, 1634, 1432, 1286, 1202 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.74 (s, 3 H), 3.89 (s, 3 H), 4.96
(d, J = 8.4 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2 H), 7.28 (dd, J = 8.4, 12.5
Hz, 1 H), 7.98 (d, J = 8.8 Hz, 2 H), 10.06 (br d, J = 11.5 Hz, 1 H).
(Z)-Methyl 3-[(3,5-Dimethoxyphenyl)amino]acrylate (4i)
Reaction time: 144 h; yield: 90%; yellow solid; mp 99.5–101.7 °C
(hexane–CHCl3).
IR (KBr): 3142, 2992, 1688, 1627, 1590, 1539, 1267, 1204, 1155,
818 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.72 (s, 3 H), 3.78 (s, 6 H), 4.85
(d, J = 8.3 Hz, 1 H), 6.12 (s, 3 H), 7.21 (dd, J = 8.4, 12.7 Hz, 1 H),
9.84 (br d, J = 13.7 Hz, 1 H).
Anal. Calcd for C11H13NO2: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.32; H, 5.47; N, 5.86.
HRMS-ESI: m/z [M + Na]+ calcd for C12H15NO4 + Na: 260.0892;
found: 260.0893.
Methyl 3-[(4-Bromophenyl)amino]acrylate (4e)
Reaction time: 54 h; yield: 85% (E/Z = 28:72).
Z-Isomer: colorless solid; mp 155.2–156.7 °C (hexane–CHCl3).
1,2-Dihydroquinoline Derivatives; 3-(Methoxycarbonyl)-2-
[(methoxycarbonyl)methyl]-1,2-dihydroquinoline (5a); Typical
Procedure
IR (KBr): 3290, 1693, 1671, 1615, 1579, 1486, 1434, 1269, 1204,
1163, 1075, 973, 818 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.72 (s, 3 H), 4.88 (d, J = 8.3 Hz,
1 H), 6.84 (diffused d, J = 8.8 Hz, 2 H), 7.18 (dd, J = 8.4, 12.6 Hz,
1 H), 7.40 (diffused d, J = 8.8 Hz, 2 H), 9.88 (br d, J = 12.6 Hz, 1
H).
To a solution of methyl 3-(phenylamino)acrylate (4a; 0.177 g, 1.00
mmol) in t-BuOH (10 mL) was added aq 55% HI (0.136 g, 0.58
mmol) at r.t. and the mixture was stirred for 4 h. The mixture was
then poured into sat. aq Na2SO3 (10 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic layers were washed with H2O (5
Synthesis 2010, No. 21, 3615–3622 © Thieme Stuttgart · New York

3620
S. Matsumoto et al.
PAPER
mL) and dried (Na2SO4). After filtration and evaporation of the sol-
vent, the residue was subjected to column chromatography on silica
gel (CHCl3–EtOAc, 15: 1) to give 5a; yield: 53.0 mg (0.203 mmol,
41%); yellow needles; mp 61.4–63.4 °C (hexane–EtOAc).
Anal. Calcd for C14H14BrNO4: C, 49.43; H, 4.15; N, 4.12. Found: C,
49.31; H, 3.78; N, 4.07.
7-Methyl-3-(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-
1,2-dihydroquinoline (5f)
Yield: 51%; yellow needles; mp 80.1–82.0 °C (hexane–EtOAc).
IR (KBr): 3379, 2951, 1708, 1635, 1602, 1574, 1484, 1440, 1364,
1339, 1300, 1264, 1242, 987, 771, 743 cm–1.
IR (KBr): 3365, 2952, 1735, 1685, 1630, 1439, 1360, 1302, 1245,
1205 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.23 (s, 3 H), 2.41 (dd, J = 1.5,
16.3 Hz, 1 H), 2.77 (dd, J = 10.3, 16.7 Hz, 1 H), 3.69 (s, 3 H), 3.79
(s, 3 H), 4.90 (d, J = 11.1 Hz, 1 H), 4.94 (br s, 1 H), 6.35 (s, 1 H),
6.47 (d, J = 7.3 Hz, 1 H), 6.94 (d, J = 7.7 Hz, 1 H), 7.45 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.43 (dd, J = 2.1, 16.7 Hz, 1 H),
2.78 (dd, J = 10.2, 16.8 Hz, 1 H), 3.66 (s, 3 H), 3.80 (s, 3 H), 4.91
(dd, J = 2.2, 10.3 Hz, 1 H), 4.93 (br s, 1 H), 6.51 (d, J = 8.1 Hz, 1
H), 6.64 (t, J = 7.3 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 7.09 (t,
J = 8.1 Hz, 1 H), 7.46 (s, 1 H).
HRMS-ESI: m/z [M + Na]+ calcd for C14H15NO4 + Na: 284.0893;
found: 284.0891.
HRMS-ESI: m/z [M + Na]+ calcd for C15H17NO4 + Na: 298.1050;
found: 298.1049.
6-Methyl-3-(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-
1,2-dihydroquinoline (5b)
Yield: 48%; yellow needles; mp 99.0–101.3 °C (hexane–EtOAc).
5-Methyl-3-(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-
1,2-dihydroquinoline (5f¢)
1H NMR (300 MHz, CDCl3): d (selected data) = 2.16 (s, 3 H), 3.81
(s, 3 H), 6.38 (d, J = 8.1 Hz, 1 H), 6.49 (d, J = 7.7 Hz, 1 H), 6.98 (t,
J = 7.5 Hz, 1 H), 7.70 (s, 1 H).
IR (KBr): 3405, 2954, 1722, 1706, 1638, 1577, 1559, 1507, 1439,
1369, 1336, 1284, 1224, 1179, 1147, 808 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.02 (s, 3 H), 2.38 (dd, J = 1.7,
16.7 Hz, 1 H), 2.77 (dd, J = 10.2, 16.7 Hz, 1 H), 3.72 (s, 3 H), 3.80
(s, 3 H), 4.85 (br s, 1 H), 4.86 (dd, J = 2.2, 10.3 Hz, 1 H), 6.45 (d,
J = 8.2 Hz, 1 H), 6.86 (s, 1 H), 6.92 (d, J = 10.0 Hz, 1 H), 7.43 (s, 1
H).
HRMS-FAB: m/z [M]+ calcd for C15H17NO4: 275.1158; found:
275.1140.
8-Methyl-3-(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-
1,2-dihydroquinoline (5g)
Yield: 48%; yellow needles; mp 63.6–65.6 °C (hexane–EtOAc).
IR (KBr): 3409, 2955, 1725, 1706, 1441, 1360, 1249, 1217, 1173,
784, 745 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.09 (s, 3 H), 2.42 (dd, J = 2.2,
16.8 Hz, 1 H), 2.75 (dd, J = 10.1, 16.5 Hz, 1 H), 3.68 (s, 3 H), 3.80
(s, 3 H), 4.94 (br s, 1 H), 4.98 (br s, 1 H), 6.58 (t, J = 7.4 Hz, 1 H),
6.97 (d, J = 10.5 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.47 (s, 1 H).
6-Methoxy-3-(methoxycarbonyl)-2-[(methoxycarbonyl)meth-
yl]-1,2-dihydroquinoline (5c)
Yield: 5%; yellow needles; mp 115.1–116.3 °C (hexane–EtOAc).
HRMS-ESI: m/z [M + Na]+ calcd for C15H17NO4 + Na: 298.1050;
found: 298.1047.
IR (KBr): 3354, 2952, 1711, 1699, 1497, 1442, 1287, 1231, 1164,
1067, 1034, 822 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (dd, J = 2.3, 16.6 Hz, 1 H),
2.77 (dd, J = 10.5, 16.7 Hz, 1 H), 3.68 (s, 3 H), 3.74 (s, 3 H), 3.80
(s, 3 H), 4.74 (br s, 1 H), 4.84 (dd, J = 2.4, 10.1 Hz, 1 H), 6.49 (d,
J = 8.6 Hz, 1 H), 6.64 (d, J = 2.8 Hz, 1 H), 6.92 (dd, J = 2.8, 8.6 Hz,
1 H), 7.43 (s, 1 H).
HRMS-ESI: m/z [M + Na]+ calcd for C15H17NO5 + Na: 314.0999;
found: 314.0997.
5,7-Dimethyl-3-(methoxycarbonyl)-2-[(methoxycar-
bonyl)methyl]-1,2-dihydroquinoline (5h)
Yield: 66%; yellow needles; mp 89.5–91.4 °C (hexane–EtOAc).
IR (KBr): 3365, 2947, 1741, 1685, 1632, 1609, 1441, 1371, 1251,
1221, 1197, 1076, 825, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H), 2.29 (s, 3 H), 2.37
(dd, J = 2.4, 16.7 Hz, 1 H), 2.75 (dd, J = 10.2, 16.7 Hz, 1 H), 3.68
(s, 3 H), 3.79 (s, 3 H), 4.85 (dd, J = 2.3, 10.5 Hz, 1 H), 4.87 (br s, 1
H), 6.21 (s, 1 H), 6.33 (s, 1 H), 7.67 (s, 1 H).
3,6-Di(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-1,2-di-
hydroquinoline (5d)
Yield: 43%; yellow needles; mp 138.3–140.3 °C (hexane–EtOAc).
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C,
66.55; H, 6.48; N, 4.87.
IR (KBr): 3373, 2947, 1728, 1696, 1638, 1438, 1362, 1337, 1259,
1238, 1196, 1177, 881 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.55 (dd, J = 2.2, 17.1 Hz, 1 H),
2.76 (dd, J = 10.3, 17.0 Hz, 1 H), 3.70 (s, 3 H), 3.81 (s, 3 H), 3.85
(s, 3 H), 5.01 (d, J = 9.8 Hz, 1 H), 5.35 (s, 1 H), 6.47 (d, J = 8.4 Hz,
1 H), 7.46 (s, 1 H), 7.73–7.77 (m, 2 H).
5,7-Dimethoxy-3-(methoxycarbonyl)-2-[(methoxycar-
bonyl)methyl]-1,2-dihydroquinoline (5i)
Yield: 71%; yellow needles; mp 134.8–136.5 °C (hexane–EtOAc).
IR (KBr): 3384, 2949, 1718, 1692, 1628, 1577, 1514, 1439, 1319,
1245, 1221, 1171, 1145, 993 cm–1.
HRMS-FAB: m/z [M + H]+ calcd for C16H18NO6: 320.1134; found:
320.1121.
1H NMR (300 MHz, CDCl3): d = 2.39 (dd, J = 2.1, 16.8 Hz, 1 H),
2.76 (dd, J = 10.4, 16.9 Hz, 1 H), 3.69 (s, 3 H), 3.76 (s, 3 H), 3.77
(s, 3 H), 3.79 (s, 3 H), 4.85 (diffused d, J = 10.3 Hz, 1 H), 5.04 (br
s, 1 H), 5.69 (d, J = 1.8 Hz, 1 H), 5.76 (d, J = 2.0 Hz, 1 H), 7.79 (s,
1 H).
6-Bromo-3-(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-
1,2-dihydroquinoline (5e)
Yield: 40%; yellow needle crystals; mp 130.3–132.1 °C (hexane–
EtOAc).
Anal. Calcd for C16H19NO6: C, 59.81; H, 5.96; N, 4.36. Found: C,
59.76; H, 5.70; N, 4.28.
IR (KBr): 3373, 2947, 1728, 1696, 1638, 1438, 1362, 1337, 1259,
1238, 1196, 1177, 881 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.43 (dd, J = 2.1, 16.7 Hz, 1 H),
2.75 (dd, J = 10.4, 16.9 Hz, 1 H), 3.69 (s, 3 H), 3.80 (s, 3 H), 4.90
(d, J = 10.0 Hz, 1 H), 4.96 (br s, 1 H), 6.41 (d, J = 8.5 Hz, 1 H),
7.18–7.14 (m, 2 H), 7.38 (s, 1 H).
Reaction of Methyl 3-(Phenylamino)acrylate (4a) with
p-Toluenesulfonic Acid
To a solution of 4a (0.886 g, 0.500 mmol) in MeOH (5.0 mL) was
added p-toluenesulfonic acid monohydrate (94.9 mg, 0.499 mmol)
at r.t. and the mixture was stirred for 1 h. The mixture was poured
Synthesis 2010, No. 21, 3615–3622 © Thieme Stuttgart · New York

PAPER
Formation of 1,2-Dihydroquinoline-3-carboxylic Acid Derivatives
(2) (a) Martínez-Estíbalez, U.; Sotomayor, N.; Lete, E.
3621
into sat. aq NaHCO3 (2 × 5 mL ) and extracted with EtOAc (3 × 5
mL ). The combined organic layers were washed with H2O (5 mL),
and dried (Na2SO4). After filtration and evaporation, the residue
was subjected to column chromatography on SiO2 (hexane–
EtOAc, 5: 1) to give 5a (22.3 mg, 0.0854 mmol, 34%), 4-methoxy-
3-(methoxycarbonyl)-2-[(methoxycarbonyl)methyl]-1,2,3,4-tetra-
hydroquinoline (MeO-5a; 15.6 mg, 0.0854 mmol, 21%), 3,5-
di(methoxycarbonyl)-4-[(methoxycarbonyl)methyl]-1-phenyl-1,4-
dihydropyridine (6; 8.1 mg, 0.0235 mmol, 14%), and methyl
(2E,4Z)-4-(methoxycarbonyl)-5-(phenylamino)penta-2,4-dienoate
(7; 6.8 mg, 0.0260 mmol, 10%).
Tetrahedron Lett. 2007, 48, 2919. (b) Theeraladanon, C.;
Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron 2004,
60, 3017.
(3) (a) Migneault, D.; Bernstein, M. A.; Lau, C. K. Can. J.
Chem. 1995, 73, 1506. (b) Grignon-Dubois, M.; Diaba, F.;
Grellier-Marly, M.-C. Synthesis 1994, 800. (c) Qiang, L.
G.; Baine, N. H. J. Org. Chem. 1988, 53, 4218. (d)Arduini,
A.; Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G. Synthesis
1981, 975. (e) Dauphinee, G. A.; Forrest, T. P. Can. J.
Chem. 1978, 56, 632.
(4) (a) Voutchkova, A. M.; Gnanamgari, D.; Jakobsche, C. E.;
Butler, C.; Miller, S. J.; Parr, J.; Crabtree, R. H.
4-Methoxy-3-(methoxycarbonyl)-2-[(methoxycarbonyl)meth-
yl]-1,2,3,4-tetrahydroquinoline (MeO-5a)
Colorless solid; mp 72.5–74.4 °C (hexane–EtOAc).
J. Organomet. Chem. 2008, 693, 1815. (b) Fukuzumi, S.;
Fujita, M.; Noura, S.; Ohkubo, K.; Suenobu, T.; Araki, Y.;
Ito, O. J. Phys. Chem. A 2001, 105, 1857. (c) Zhu, D.;
Kochi, J. K. Organometallics 1999, 18, 161. (d) Fukuzumi,
S.; Kitano, T.; Ishikawa, K.; Tanaka, T. Chem. Lett. 1989,
1599.
IR (KBr): 3384, 2953, 1749, 1725, 1668, 1498, 1435, 1271, 1189,
1173, 1071, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.41 (dd, J = 9.6, 16.8 Hz, 1 H),
2.64 (dd, J = 2.9, 11.8 Hz, 1 H), 3.05 (dd, J = 2.4, 16.2 Hz, 1 H),
3.27 (s, 3 H), 3.73 (s, 3 H), 3.80 (s, 3 H), 4.17 (ddd, J = 2.4, 9.8, 11.9
Hz, 1 H), 4.49 (d, J = 3.0 Hz, 1 H), 4.93 (br s, 1 H), 6.59 (d, J = 8.1
Hz, 1 H), 6.64 (t, J = 7.4 Hz, 1 H), 7.08 (d, J = 7.5 Hz, 1 H), 7.13 (t,
J = 7.9 Hz, 1 H).
(5) (a) Amiot, F.; Cointeaux, L.; Silve, E. J.; Alexakis, A.
Tetrahedron 2004, 60, 8221. (b) Rezgui, F.; Mangeney, P.;
Alexakis, A. Tetrahedron Lett. 1999, 40, 6241. (c) Paris,
D.; Cottin, M.; Demonchaux, P.; Augert, G.; Dupassieux, P.;
Lenoir, P.; Peck, M. J.; Jasserand, D. J. Med. Chem. 1995,
38, 669. (d) Goldstein, S. W.; Dambek, P. J. Synthesis 1989,
221. (e) Ramadas, S. R.; Krishna, M. V. Curr. Sci. 1981, 50,
120. (f) Crawforth, C. E.; Meth-Cohn, O.; Russell, C. A.
J. Chem. Soc., Perkin Trans. 1 1972, 2807. (g) Elderfield,
R. C.; Wark, B. H. J. Org. Chem. 1962, 27, 543.
HRMS-ESI: m/z [M + Na]+ calcd for C15H19NO5 + Na: 316.1155;
found: 316.1151.
3,5-Di(methoxycarbonyl)-4-[(methoxycarbonyl)methyl]-1-phe-
nyl-1,4-dihydropyridine (6)
(6) (a) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jian, W.; Duesler, E. N.;
Wang, W. Org. Lett. 2007, 9, 965. (b) Ballini, R.; Bosica,
G.; Fiorini, D.; Palmieri, A. Green Chem. 2005, 7, 825.
(c) Yan, M.-C.; Tu, Z.; Lin, C.; Ko, S.; Hsu, J.; Yao, C.-F.
J. Org. Chem. 2004, 69, 1565. (d) Kobayashi, K.;
Nakahashi, R.; Mano, M.; Morikawa, O.; Konisi, H. Bull.
Chem. Soc. Jpn. 2003, 76, 1257. (e) Apple, I. A.; Meth-
Cohn, O. ARKIVOC 2002, (vi), 4. (f) Kobayashi, K.;
Nakahashi, R.; Shimizu, A.; Kitamura, T.; Morikawa, O.;
Konishi, H. J. Chem. Soc., Perkin Trans. 1 1999, 1547.
(g) Kobayashi, K.; Takabatake, H.; Kitamura, T.; Morikawa,
O.; Konishi, H. Bull. Chem. Soc. Jpn. 1999, 70, 1697.
(h) Yavari, I.; Esmaili, A. A.; Ramazani, A.; Bolbol-Amiri,
A. R. Monatsh. Chem. 1997, 128, 927.
Yellow oil.
IR (NaCl, neat): 2951, 1713, 1596, 1495, 1436, 1211, 1084, 755,
715, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.60 (d, J = 5.0 Hz, 2 H), 3.59 (s,
3 H), 3.77 (s, 6 H), 4.26 (t, J = 5.0 Hz, 1 H), 7.23 (d, J = 7.4 Hz, 2
H), 7.27 (t, J = 7.4 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 2 H), 7.59 (s, 2 H).
HRMS-ESI: m/z [M + Na]+ calcd for C18H19NO6 + Na: 368.1105;
found: 368.1101.
Methyl (2E,4Z)-4-(Methoxycarbonyl)-5-(phenylamino)penta-
2,4-dienoate (7)
Yellow solid; mp 117.1–118.5 °C (hexane–EtOAc) (Lit.18 mp
118.9 °C; Lit.19 mp 116.4–117.7 °C).
(7) Matsumoto, S.; Ogura, K. Tetrahedron Lett. 2007, 48, 1117.
(8) Sridharam, Y.; Avendaño, C.; Menéndez, C. Tetrahedron
2007, 63, 673.
Acknowledgment
(9) (a) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-
C. Angew. Chem. Int. Ed. 2009, 48, 5737. (b) Gusak, K. N.;
Kozlov, N. G. Russ. J. Org. Chem. 2007, 43, 706. (c) Lu,
G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 4701.
(d) Cheng, Y.; Yang, H.; Meth-Cohn, O. Org. Biomol.
Chem. 2003, 1, 3605. (e) Yamaguchi, R.; Tanaka, M.;
Matsuda, T.; Okano, T.; Nagura, T.; Fujita, K. Tetrahedron
Lett. 2002, 43, 8871. (f) Yamaguchi, R.; Nakayasu, T.;
Hatano, B.; Nagura, T.; Kozima, S.; Fujita, K. Tetrahedron
2001, 57, 109. (g) Yamaguchi, R.; Omoto, Y.; Miyake, M.;
Fujita, K. Chem. Lett. 1998, 547. (h) Sanechika, K.;
Kajigaeshi, S.; Kanemasa, S. Chem. Lett. 1977, 861.
(10) Mohri, K.; Kanie, A.; Horiguchi, Y.; Isobe, K. Heterocycles
1999, 51, 2377.
This work was supported by a Grant-in-Aid for Young Scientists
(B) (20750026) from the Japan Society for the Promotion of Sci-
ence.
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