A novel three-component reaction involving quinoline, dimethyl acetylenedicarboxylate, and C-H acids leading to the synthesis of pyrroloquinoline derivatives

Article abstract of DOI:10.1055/s-2008-1032128

The zwitterion derived from quinoline and dimethyl acetylenedicarboxylate on reaction with C-H acids afforded pyrroloquinoline derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032128

PAPER
1065
A Novel Three-Component Reaction Involving Quinoline, Dimethyl
Acetylenedicarboxylate, and C-H Acids Leading to the Synthesis of
Pyrroloquinoline Derivatives
S
ynthesis of Pyrro
i
loquino
j
line
D
e
a
rivatives y Nair,*a Satheesh Devipriya,a Eringathodi Sureshb
a
Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (Formerly Regional Research Laboratory),
CSIR, Trivandrum 695 019, India
Fax +91(471)2491712; E-mail: vijaynair_2001@yahoo.com
Analytical Science Discipline, Central Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India
b
Received 2 February 2007
O
O
CO2Me
CO2Me
Abstract: The zwitterion derived from quinoline and dimethyl
acetylenedicarboxylate on reaction with C-H acids afforded pyr-
roloquinoline derivatives.
+
+
N
Key words: zwitterion, quinoline, pyrroloquinoline, Michael addi-
1
2
3
tion
DME, r.t.
O
H
Ar, 10 h, 44%
Arguably, the Huisgen 1,3-dipolar cycloaddition reac-
tions constitute the most general and efficient protocol for
the construction of a wide variety of five-membered het-
erocycles.1,2 Less well known, however, is Huisgen’s
work on 1,4-dipolar cycloadditions resulting in the syn-
thesis of six-membered heterocycles. Trapping of the
zwitterion (1,4-dipole), formed by the addition of isoquin-
oline to dimethyl acetylenedicarboxylate with phenyl
isocyanate, diethyl mesoxylate, or dimethyl azodicarbox-
ylate can be regarded as laying the foundation for 1,4-di-
polar cycloaddition reactions.3 Recently, we have
succeeded in trapping this zwitterion with N-tosylimines,4
quinones,5 and electrophilic styrenes.6 In this context, and
in view of our long-standing interest in the chemistry of
zwitterions,7 it was of interest to examine the reactivity of
the zwitterion derived from quinoline and dimethyl acety-
lenedicarboxylate. Although this species is known from
the work of Acheson,8 its chemistry has not been investi-
gated in detail.9 In this paper we describe the preliminary
results of our investigations on the reaction of the quino-
line–dimethyl acetylenedicarboxylate zwitterion towards
C-H acids, constituting a novel pyrroloquinoline synthe-
sis.
5
N1
4
2
3
MeO2C
MeO2C
O
4
Scheme 1 Reaction of the quinoline–dimethyl acetylenedicarbox-
ylate zwitterion with indane-1,3-dione
The structure elucidation of 4 was accomplished by spec-
troscopic analysis. In the H NMR spectrum, the signals
1
due to the two methoxycarbonyl groups were observed at
d = 3.51 and 3.89 as two singlets, supporting the IR ab-
sorption at 1744 cm–1. The resonance signal due to the C2
proton appeared as a doublet at d = 4.99 (J = 7.8 Hz) and
the C5 proton displayed its signal as a multiplet in the
range d = 4.84–4.88. The C3 proton signal was discernible
as a doublet at d = 4.17 (J = 7.8 Hz). The alkene protons
of the dihydroquinoline moiety were discernible as a mul-
tiplet in the range d = 5.29–5.31 and as a doublet at d =
6.19 (J = 9 Hz). In the 13C NMR spectrum, the two meth-
oxycarbonyl groups were seen at d = 162.5 and 163.4. The
structure and stereochemistry of the compound 4 was un-
ambiguously established by single crystal X-ray analysis
(Figure 1).10
The present studies were initiated by treating indane-1,3-
dione (3) with quinoline and dimethyl acetylenedicarbox-
ylate in anhydrous 1,2-dimethoxyethane at room temper-
ature under an argon atmosphere. The reaction afforded
the pyrrolo[1,2-a]quinoline derivative 4 in 44% yield as a
yellow crystalline solid (Scheme 1). A trace amount of the
1:2 adduct of quinoline and dimethyl acetylenedicarbox-
ylate was also isolated from the reaction mixture.
Figure 1 Single crystal X-ray structure of compound 4
SYNTHESIS 2008, No. 7, pp 1065–1068
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032128; Art ID: Z02907SS
© Georg Thieme Verlag Stuttgart · New York

1066
V. Nair et al.
PAPER
A mechanism postulated for the reaction is shown in
Scheme 2. The zwitterion 5 formed from quinoline (1)
and dimethyl acetylenedicarboxylate (2) was quenched by
the C-H acidic compound 6 to afford the cation 7 and the
enolate 8. The enolate then underwent Michael addition to
7 to furnish the zwitterion 9, which was transformed into
another enolate 10 by an intramolecular deprotonation.
The cyclization of the enolate 10 then afforded the pyr-
roloquinoline 11.
Table 1 Reaction of Quinoline-Dimethyl Acetylenedicarboxylate
Zwitterion with C-H Acidsa
Entry Substrate
Time Product
Yield
(%)
O
O
O
O
N
1
10
46
35
48
44
MeO2C
O
O
O
O
MeO2C
12
CO2Me
18
19
20
O
O
+
+
O
N
R
R
N
N
CO2Me
2
12
12
10
H
MeO2C
MeO2C
O
CO2Me
MeO2C
1
2
5
6
13
OH
O
O
+
N
H
COR
OR
N
N
R
R
3
O
O
N
H
MeO2C
MeO2C
MeO2C
O
O
MeO2C
MeO2C
O
CO2Me
14
15
7
8
9
O
OH
N
4
5
6
COR
COR
N
N
COR
OR
MeO2C
MeO2C
O
O
O
MeO2C
MeO2C
MeO2C
CO2Me
21
O
OH
O
10
11
N
Scheme 2
12
11
32
50
N
O
MeO2C
Me
O
MeO2C
Me
As shown in Table 1, the reaction was found to be appli-
cable to a variety of C-H acids 12–17 resulting in pyrrolo-
quinolines 18–23 in moderate yields.
16
22
COPh
COPh
CO2Me
O
O
Under similar conditions, the reaction of quinoline–
dimethyl acetylenedicarboxylate dipole with ethyl ben-
zoylacetate (24a) led to pyrroloquinoline derivative 25a
and the fumarate derivative 26a; a similar result was ob-
tained with ethyl acetoacetate (Scheme 3).
N
Ph
Ph
MeO2C
17
23
a Reactions conditions: DME, argon, r.t., 10–12 h.
CO2Me
O
O
+
+
Melting points were recorded on a Büchi melting point apparatus
and are uncorrected. NMR spectra were recorded at 300 MHz (1H)
and 75 MHz (13C) on a Brüker Avance DPX-300 MHz NMR spec-
trometer, in CDCl3. Chemical shifts (d) are reported relative to TMS
(1H) and CDCl3 (13C) as the internal standards. Coupling constants
(J) are reported in Hertz (Hz). High-resolution mass spectra were
recorded under EI/HRMS (at 5000 resolution) or FAB+/HRMS us-
ing JEOL JMS 600H mass spectrometer. IR spectra were recorded
on Nicolet Impact 400D FT-IR spectrophotometer. Commercial-
grade solvents were distilled prior to use.
OEt
R
N
CO2Me
1
2
24a R = Ph
24b R = Me
OH
O
COR
R
OEt
CO2Me
DME, r.t
Ar, 8 h
N
+
CO2Et
MeO2C
CO2Me
CO2Me
Pyrroloquinoline Derivatives; General Procedure
25a 55%
25b 51%
26a 19%
26b 23%
To a solution of quinoline (68.45 mg, 0.53 mmol) and dimethyl
acetylenedicarboxylate (75.26 mg, 0.53 mmol) in anhyd DME (5
mL), the appropriate 1,3-dione (0.53 mmol) was added and the re-
action mixture was stirred at r.t. under argon for 10–12 h. The sol-
Scheme 3
Synthesis 2008, No. 7, 1065–1068 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrroloquinoline Derivatives
1067
vent was then evaporated under reduced pressure and the residue
was purified by silica gel column chromatography using hexane–
EtOAc (90:10).
HRMS (EI): m/z [M] calcd for C21H19NO7: 397.1162; found:
397.1165.
Dimethyl 2,4-Dioxo-1¢,2¢-dihydro-3a¢H,4H-spiro[chromene-
3,3¢-pyrrolo[1,2-a]quinoline]-1¢,2¢-dicarboxylate (21)
Yellow crystalline solid; mp 176–178 °C; yield: 190 mg (44%).
Dimethyl (1¢R,2¢R,3a¢R)-1,3-Dioxo-1,1¢,2¢,3-tetrahydro-3a¢H-
spiro[indene-2,3¢-pyrrolo[1,2-a]quinoline]-1¢,2¢-dicarboxylate
(4)
IR (KBr): 2512, 1740, 1735, 1511, 1444, 1402, 1278, 1214, 1195,
1127 cm–1.
Yellow crystalline solid; mp 144–146 °C; yield: 97 mg (44%).
IR (KBr): 2955, 1744, 1711, 1595, 1505, 1458, 1398, 1265, 1204,
1159 cm–1.
1H NMR: d = 8.08–7.96 (m, 1 H), 7.92–7.83 (m, 3 H), 7.12–7.06 (m,
1 H), 6.74–6.71 (m, 1 H), 6.63–6.59 (m, 2 H), 6.19 (d, J = 9.0 Hz, 1
H), 5.31–5.29 (m, 1 H),4.99 (d, J = 7.8 Hz, 1 H), 4.88–4.84 (m, 1
H), 4.17 (d, J = 7.8 Hz, 1 H), 3.89 (s, 3 H), 3.51 (s, 3 H).
13C NMR: d = 208.2, 207.5, 172.5, 163.4, 162.5, 142.9, 142.5,
135.9, 135.3, 130.4, 129.8, 127.7, 123.4, 118.5, 115.6, 110.4, 69.0,
67.5, 64.0, 52.9, 52.7, 51.2.
1H NMR: d = 7.94–7.91 (m, 1 H), 7.63–7.59 (m, 3 H), 7.32–7.26 (m,
2 H), 7.02–6.86 (m, 4 H), 4.91 (d, J = 7.8 Hz, 1 H), 4.75–4.72 (m, 1
H), 4.47 (d, J = 7.8 Hz, 1 H), 3.77 (s, 3 H), 3.69 (s, 3 H).
13C NMR: d = 190.3, 171.4, 166.8, 164.2, 149.2, 143.8, 133.2,
130.0, 129.2, 128.4, 127.7, 121.9, 119.7, 117.9, 115.6, 112.9, 66.1,
65.7, 61.8, 52.9, 51.3, 51.0.
HRMS (EI): m/z [M] calcd for C24H19NO7 433.1162; found
433.1155.
HRMS (EI): m/z calcd for C24H19NO6: 417.1212; found: 417.1216.
Dimethyl 1¢-Methyl-2¢,4¢-dioxo-1,1¢,2,4¢-tetrahydro-2¢H,3aH-
spiro[pyrrolo[1,2-a]quinoline-3,3¢-quinoline]-1,2-dicarbox-
ylate (22)
Dimethyl 2,6-Dioxo-1¢,2¢-dihydro-3a¢H-spiro[cyclohexane-1,3¢-
pyrrolo[1,2-a]quinoline]-1¢,2¢-dicarboxylate (18)
Colorless crystalline solid; mp 112–114 °C; yield: 176 mg (46%).
Colorless solid; mp 160–162 °C; yield: 143 mg (32%).
IR (KBr): 2603, 1699, 1643, 1480, 1423, 1362, 1256, 1234, 1105,
1075 cm–1.
1H NMR: d = 7.88–7.80 (m, 2 H), 7.61–7.58 (m, 2 H), 7.32–7.28 (m,
1 H), 7.14–7.09 (m, 2 H), 7.0–6.89 (m, 3 H), 5.09 (d, J = 5.6 Hz, 1
H), 4.58 (d, J = 6.9 Hz, 1 H), 4.12 (d, J = 3.8 Hz, 1 H), 3.73 (s, 3 H),
3.60 (s, 3 H), 3.48 (s, 3 H).
13C NMR: d = 193.4, 172.9, 169.4, 165.6, 144.6, 141.8, 132.5,
129.4, 128.5, 127.6, 126.8, 123.6, 123.5, 111.6, 66.4, 64.9, 57.1,
51.3, 51.1, 44.7, 29.7.
IR (KBr): 2949, 1741, 1710, 1602, 1514, 1401, 1399, 1244, 1189,
1139, 1127 cm–1.
1H NMR: d = 7.22–7.19 (m, 1 H), 7.01–6.99 (m, 2 H), 6.90–6.81 (m,
1 H), 6.72–6.68 (m, 1 H), 6.09 (d, J = 9.0 Hz, 1 H), 4.61 (d, J = 7.8
Hz, 1 H), 4.55–4.52 (m, 1 H), 4.32 (d, J = 7.8 Hz, 1 H), 3.72 (s, 3
H), 3.61 (s, 3 H), 2.79–2.65 (m, 4 H), 1.74–1.62 (m, 2 H).
13C NMR: d = 205.1, 205.0, 171.9, 168.7, 142.9, 127.9, 127.8,
127.6, 126.4, 119.6, 118.1, 113.0, 111.7, 78.6, 66.5, 61.5, 52.4,
51.3, 40.9, 39.4, 16.8.
HRMS (EI): m/z [M] calcd for C25H22N2O6: 446.1478; found:
HRMS (EI): m/z [M] calcd for C21H21NO6: 383.1369; found:
446.1483.
383.1361.
Dimethyl 3,3-Bis(phenylcarbonyl)-1,2,3,3a-tetrahydropyrro-
lo[1,2-a]quinoline-1,2-dicarboxylate (23)
Colorless solid; mp 132–134 °C; yield: 248 mg (50%).
Dimethyl 4,4-Dimethyl-2,6-dioxo-1¢,2¢-dihydro-3a¢H-spiro[cy-
clohexane-1,3¢-pyrrolo[1,2-a]quinoline]-1¢,2¢-dicarboxylate (19)
Colorless solid; mp 120–122 °C; yield: 114 mg (35%).
IR (KBr): 2487, 1755, 1696, 1501, 1484, 1411, 1277, 1205, 1176,
1023 cm–1.
1H NMR: d = 7.66–7.62 (m, 5 H), 7.61–7.58 (m, 5 H), 7.10–6.98 (m,
4 H), 6.22 (d, J = 8.6 Hz, 2 H), 4.96 (d, J = 7.4 Hz, 1 H), 4.86–4.84
(m, 1 H), 4.59 (d, J = 7.4 Hz, 1 H), 3.82 (s, 3 H), 3.69 (s, 3 H).
13C NMR: d = 195.8, 194.9, 169.9, 166.8, 144.5, 131.8, 131.0,
130.0, 129.8, 129.7, 128.8, 127.2, 127.0, 125.3, 125.0, 126.3, 126.1,
124.4, 122.1, 119.7, 117.1, 114.7, 112.1, 79.7, 65.7, 62.8, 56.8,
51.3.
IR (KBr): 2944, 1745, 1698, 1600, 1514, 1399, 1334, 1088, 1039,
1112 cm–1.
1H NMR: d = 7.26–7.20 (m, 1 H), 6.78–6.74 (m, 2 H), 6.72–6.63 (m,
2 H), 6.57–6.53 (m, 1 H), 4.63 (d, J = 7.6 Hz, 1 H), 4.49–4.45 (m, 1
H), 4.19 (d, J = 7.6 Hz, 1 H), 3.81 (s, 3 H), 3.69 (s, 3 H), 2.65–2.61
(m, 4 H), 1.05 (s, 3 H), 0.95 (s, 3 H).
13C NMR: d = 201.3, 198.8, 169.9, 168.7, 155.6, 130.7, 129.6,
129.0, 127.8, 126.9, 124.2, 116.4, 114.2, 76.9, 65.4, 59.9, 53.2,
52.7, 52.1, 49.8, 30.7, 29.5, 28.3.
HRMS (EI): m/z [M] calcd for C30H25NO6: 495.1682; found:
HRMS (EI): m/z [M] calcd for C23H25NO6: 411.1682; found:
495.1687.
411.1686.
3-Ethyl 1,2-Dimethyl 3-(Phenylcarbonyl)-1,2,3,3a-tetrahydro-
pyrrolo[1,2-a]quinoline-1,2,3-tricarboxylate (25a)
Pale yellow viscous liquid; yield: 255 mg (55%).
IR (film): 3011, 1752, 1684, 1521, 1425, 1295, 999 cm–1.
Dimethyl 6-Methyl-2,4-dioxo-1¢,2¢-dihydro-3a¢H,4H-spiro[pyr-
an-3,3¢-pyrrolo[1,2-a]quinoline]-1¢,2¢-dicarboxylate (20)
Yellow crystalline solid; mp 148–150 °C; yield: 191 mg (48%).
IR (KBr): 2300, 1744, 1723, 1577, 1515, 1402, 1300, 1213, 1188,
1139 cm–1.
1H NMR: d = 7.49–7.46 (m, 1 H), 7.11–7.02 (m, 2 H), 7.00–6.90 (m,
1 H), 6.l0 (s, 1 H), 5.88 (bs, 1 H), 5.83 (bs, 1 H), 4.11 (d, J = 7.1 Hz,
1 H), 4.03–3.96 (m, 1 H), 3.95 (d, J = 7.1 Hz, 1 H), 3.80 (s, 3 H),
3.75 (s, 3 H), 2.17 (s, 3 H).
13C NMR: d = 192.3, 172.4, 170.1, 167.0, 166.9, 145.3, 128.3,
127.8, 127.6, 124.9, 119.6, 118.4, 113.4, 108.0, 71.2, 65.5, 61.2,
51.4, 51.2, 51.0, 20.3.
1H NMR: d = 7.88–7.82 (m, 4 H), 7.80–6.92 (m, 3 H), 6.77–6.69 (m,
4 H), 4.90 (d, J = 5.9 Hz, 1 H), 4.64 (d, J = 5.1 Hz, 1 H), 4.10 (q, J =
4.4 Hz, 2 H), 3.71 (s, 3 H), 3.62 (s, 3 H), 3.60 (d, J = 5.1 Hz, 1 H),
1.20 (t, J = 4.3 Hz, 3 H).
13C NMR: d = 190.8, 170.7, 169.6, 166.9, 144.6, 130.6, 130.4,
129.5, 128.2, 127.5, 127.0, 126.4, 71.9, 67.7, 65.4, 62.3, 51.2, 43.8,
13.8.
HRMS (EI): m/z [M] calcd for C26H25NO7: 463.1631; found:
463.1628.
Synthesis 2008, No. 7, 1065–1068 © Thieme Stuttgart · New York

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V. Nair et al.
PAPER
3-Ethyl 1,2-Dimethyl 3-Acetyl-1,2,3,3a-tetrahydropyrrolo[1,2-
a]quinoline-1,2,3-tricarboxylate (25b)
Yellow viscous liquid; yield: 205 mg (51%).
IR (film): 2999, 1749, 1677, 1620, 1433, 1214, 1010 cm–1.
1H NMR: d = 7.09–6.97 (m, 3 H), 6.89–6.77 (m, 3 H), 4.91 (d, J =
5.9 Hz, 1 H), 4.50 (d, J = 5.8 Hz, 1 H), 4.0 (q, J = 4.5 Hz, 2 H), 3.73
(s, 4 H), 3.63 (s, 3 H), 2.22 (s, 3 H), 1.24 (t, J = 4.5 Hz, 3 H).
13C NMR: d = 199.5, 170.7, 170.3, 166.9, 145.4, 127.3, 126.4,
122.6, 119.2, 112.8, 73.2, 67.8, 61.2, 56.8, 52.8, 51.5, 42.9, 14.0.
References
(1) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(b) Huisgen, R. Z. Chem. 1968, 8, 290.
(2) (a) 1,3-Dipolar Cycloaddition Chemistry, Vols. I and II;
Padwa, A., Ed.; Wiley-Interscience: New York, 1984.
(b) Huisgen, R. In Topics in Heterocyclic Chemistry; Castle,
R., Ed.; John Wiley & Sons: New York, 1969, Chap. 8, 223.
(3) Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem.
Ber. 1967, 100, 1094.
(4) Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M. M.;
HRMS (FAB+): m/z [M] calcd for C21H23NO7: 401.1475; found:
401.1080.
Gonnade, R. C. Org. Lett. 2002, 4, 3575.
(5) Nair, V.; Sreekanth, A. R.; Biju, A. T.; Rath, N. P.
Tetrahedron Lett. 2003, 44, 729.
(6) Nair, V.; Remadevi, B.; Varma, L. R. Tetrahedron Lett.
2005, 46, 5333.
(7) (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth,
A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899. (b) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash,
N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520.
(8) Acheson, R. M.; Elmore, N. F. Adv. Heterocycl. Chem.
1978, 23, 263.
3-Ethyl 1,2-Dimethyl 4-Hydroxy-4-phenylbuta-1,3-diene-1,2,3-
tricarboxylate (26a)
Yellow viscous liquid; yield: 34 mg (19%).
1H NMR: d = 1.10 (t, J = 7 Hz, 3 H), 3.52 (s, 3 H), 3.78 (s, 3 H), 4.14
(q, J = 7 Hz, 2 H), 7.45–7.50 (m, 5 H), 7.9 (s, 1 H), 13.43 (s, 1 H).
HRMS (FAB+): m/z [M] calcd for C17H18O7: 334.1053; found:
334.3290.
(9) While this work was under completion, we came across an
isolated report in a paper mentioning the reaction of
quinoline and DMAD with ethyl bromopyruvate leading to
the synthesis of a pyrroloquinoline derivative: Yawari, I.;
Hossaini, Z.; Sabbaghan, M. Tetrahedron Lett. 2006, 47,
6037.
(10) Single crystal X-ray data for 4 has been deposited at the
Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 627201.
Acknowledgment
Financial assistance from the Council of Scientific and Industrial
Research (CSIR), Government of India, is acknowledged. The au-
thors also thank Mrs. Saumini Mathew for recording NMR spectra
and Mrs. S. Viji for mass spectral analysis.
Synthesis 2008, No. 7, 1065–1068 © Thieme Stuttgart · New York