Cyclization of 1-benzyl-1,2-dihydro-2-(substituted methylene)quinolines to pyrrolo[1,2-a]quinoline derivatives

Article abstract of DOI:10.1248/cpb.54.334

1-Alkyl-2-alkylthioquinolinium salts were prepared from 1-alkyl-2(1H)-quinolones via 1-alkyl-2(1H)-thioquinolones in two steps. Under mild conditions, the reaction of 1-alkyl-2-alkylthioquinolinium iodides with active methylene compounds in the presence o

Full text of DOI:10.1248/cpb.54.334

334
Chem. Pharm. Bull. 54(3) 334—337 (2006)
Vol. 54, No. 3
Cyclization of 1-Benzyl-1,2-dihydro-2-(substituted methylene)quinolines
to Pyrrolo[1,2-a]quinoline Derivatives
Reiko FUJITA,* Masato HOSHINO, and Hiroshi TOMISAWA
Tohoku Pharmaceutical University; Komatsushima, Aoba-ku, Sendai 981–8558, Japan.
Received September 27, 2005; accepted November 21, 2005
1-Alkyl-2-alkylthioquinolinium salts were prepared from 1-alkyl-2(1H)-quinolones via 1-alkyl-2(1H)-thio-
quinolones in two steps. Under mild conditions, the reaction of 1-alkyl-2-alkylthioquinolinium iodides with active
methylene compounds in the presence of sodium hydride afforded 1-alkyl-1,2-dihydro-2-(substituted methyl-
ene)quinolines in good yields. The cyclization of 1-benzylquinolines using acetic anhydride produced the corre-
sponding pyrrolo[1,2-a]quinoline derivatives.
Key words 1-benzyl-2(1H)-thioquinolone; dimethyl malonate; cyclization; pyrrolo[1,2-a]quinoline; 2-methylthioquinolinium
iodide
Previously we reported a new method for the formation of of 3 with methyl iodide (4a) afforded 1-benzyl-2-methylthio-
a carbon–carbon bond at the 2-position of a quinoline ring quinolinium iodide (5) in 72% yield. The reaction of quino-
using the reaction of 1-methyl-2-methylthioquinolinium io- linium iodide (5) with active methylene compounds (6a—e)
dide with active methylene compounds.1) Excellent yields in the presence of sodium hydride at room temperature for
were obtained as shown in Chart 1. Various methods for the 2 h in tetrahydrofuran (THF) afforded 2-(substituted methyl-
synthesis of the pyrrolo[1,2-a]quinoline skeleton have also ene)quinolines (7a, 91%; 7b, 97%; 7c, 76%; 7d, 63%; 7e,
been reported.2—7) The conventional methods for preparing 62%; entries 1—5, respectively), as listed in Table 1. Fur-
the substituted pyrrolo[1,2-a]quinoline derivatives typically thermore, studies using cyclic active methylene compounds
involve reactions of 2-substituted quinolines having a have shown that the reaction between 6f and 5 at room tem-
phenacyl group with acetic anhydride.5,7) Recently, Komatsu
and co-workers reported synthesis of the pyrrolo[1,2-
a]quinoline by cycloaddition of quinolinium methylide at
180 °C for 6 h in 84% yield.8) Further, Weaver et al. reported
synthesis of indolizines and pyrrolo[2,1-a]-isoquinolines
using cycloaddition of pyridinium-1- and isoquinolinium-2-
yl-methylene compounds with 1,1-diiodo-2,2-dinitroethylene
in 17—43% yields. But, they did not report synthesis of
pyrrolo[1,2-a]quinolines.9) Therefore, 2-substituted quino-
lines having a benzyl group would be extremely useful as an
intermediate for the synthesis of the pyrrolo-fused heterocy-
cles. Herein, we report a new method for the synthesis of a
pyrrolo[1,2-a]quinoline skeleton using the cyclization of 1-
benzyl-1,2-dihydro-2-(substituted methylene)quinolines,
which were easily prepared from the reaction of 1-benzyl-2-
methylthio-quinolinium iodides with active methylene com-
pounds, and the reaction of 1-methyl-2-alkylthioquinolinium
salts with cyclic active methylene compounds.
Reaction of 2-Alkylthioquinolinium Salts with Active
Methylene Compounds First, the reaction of 1-benzyl-
quinolinium iodide (5) having a methylthio group as a leav-
Chart 2
ing group at the 2-position with active methylene compounds
(6a—g) was examined under mild conditions in the presence
Table 1. Reactions of 5 with 6a—g
of sodium hydride (Chart 2, Table 1). 1-Benzyl-2(1H)-thio-
quinolone (3) was readily prepared from 2(1H)-quinolone (1)
via 1-benzyl-2(1H)-quinolone (2) in two steps. The reaction
Temp.
(°C)
Time
(h)
Product Yield
Entry
6
Solvent
7
(%)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
f
f
g
a
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
90
90
90
2
2
2
2
2
2
2
6
6
6
THF
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
a
b
c
d
e
f
f
f
g
a
91
97
76
63
62
22
26
75
73
86
10
Chart 1
∗ To whom correspondence should be addressed. e-mail: refujita@tohoku-pharm.ac.jp
© 2006 Pharmaceutical Society of Japan

March 2006
335
perature for 2 h in either THF or DMF gives 2-(substituted 10g (82%) and 10h (17%). However, the reactions of 9b and
methylene)quinoline (7f) in poor yields (entries 6, 7). In con- 9c with 6g at room temperature and at 90 °C afforded only
trast, the reaction of 6f with 5 at 90 °C for 6 h in DMF gave the 2-(substituted methylene)quinoline (10g) (entries 13, 14,
7f in 75% yield (entry 8). Interestingly, the reaction of 6g 16, 17). These results indicate that at room temperature, a
with 5 at 90 °C for 6 h in DMF resulted in two products bulky group on the sulfur atom interfere the interaction be-
(entry 9): 2-(substituted methylene)quinoline (7g, 73%) and tween the carbanion arised from 6a, f, g and the carbocation
4-(substituted methylene)quinoline (7h, 18%). However, the on the 2-position of the quinolines ring and tends to reduce
reaction of 6a with 5 at 90 °C for 6 h afforded only one prod- the yields of product (Table 2, entries 6—8, 12—14). In ad-
uct: 2-(substituted methylene)quinoline (7a, entry 10).
dition, a bulky substituent on the nitrogen atom can affect the
To investigate the influence of steric or ionic effect, reac- reaction of 5 with 6f at room temperature, while at 90 °C it
tions of 1-methylquinolinium salts (9a—c) bearing methyl- can not affect the reaction (Table 1, entries 6—8). Further the
thio, ethylthio, or isopropylthio group at the 2-position with steric interaction between hydrogens on the 4- and 5-posi-
6a, f, g were carried out (Chart 3, Table 2). The reaction of 1- tions of quinoline ring is known. It can be presumed that as
methyl-2(1H)-thioquinolone (8)1) with alkyl iodides (4a—c) 6g is smoller size than 6f, the carbanion arising from 6g can
proceeded smoothly to produce the corresponding 1-methyl- reacted with the carbocation on the 4-position of 5 and 9a.
2-alkylthioquinolinium iodides (9a—c) in high yields (Chart On the other hand, as the carbanion arising from 6g would be
3). The reactions of 9a—c with 6a at room temperature for a soft base (Lewis base) than the carbanion arising from 6a,
0.5 h gave 2-(substituted methylene)quinoline (10a)1) in 95%, it can be assumed that the carbanion arising from 6g reacted
82%, and 66% yields, respectively (entries 1—3). Similar re- with the soft acid (Lewis acid) on the 4-position.
actions of 9b, c for 1.5 h afforded 10a in 79% and 78% yields
The structures of 2-(substituted methylene)quinolines
(entries 4, 5). The reactions of 9a—c with 6f in DMF gave 2- (7a—g, 10a, f, g) and 4-substituted quinolines (7h, 10h) were
(substituted methylene)quinoline (10f)1) in 81%, 28% and determined from 1H-NMR spectra studies as follows. For the
24% yields at room temperature for 2 h (entries 6—8), and 2-(substituted methylene)quinolines, the signals due to the
85%, 75% and 76% at 90 °C for 6 h (entries 9—11), respec- alkylthio group disappeared with replacement of the
tively. The reaction of 9a with 6g gave two products: 2- and alkylthio group by the active methylene compounds. In con-
4-(substituted methylene)quinolines (10g, 10h). Reaction at trast, for 4-(substituted methylene)quinolines (7h, 10h), a
room temperature (entry 12) afforded products (10g, 40%; signal due to the methylthio group at 2.83 ppm and a singlet
10h, 15%), whereas reaction at 90 °C (entry 15) resulted in signal due to H-3 at 8.40 ppm were observed.
Spectroscopic studies of compounds (7c, d) showed nu-
clear Overhauser and exchange spectroscopy (NOE) correla-
tions between the methyl of the ester (3.80, 3.69 ppm) and
the proton (8.28, 8.06 ppm) at the 3-position, and therefore
those configuration are suggested to be cis. The reaction de-
scribed herein can be regarded as a promising method for
carbon–carbon bond formation at the 2- and 4-positions in
the quinoline ring.
Cyclizations of 1-Benzylquinoline Compounds in
Acetic Anhydride Next, we attempted the cyclizations of
1-benzylquinoline compounds (7a, d, e) in acetic anhydride
to provide the corresponding functionalized pyrrolo[1,2-
Chart 3
Table 2. Reactions of 9a—c with 6a, f, g
Yield (%)
Entry
9
6
Temp. (°C)
Time (h)
Solvent
2-Position
10a1)
10a
10a
10a
10a
10f1)
10f
10f
10f
10f
10f
10g
10g
10g
10g
10g
10g
4-Position
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
a
b
c
b
c
a
b
c
a
b
c
a
b
c
a
b
c
a
a
a
a
a
f
f
f
f
f
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
90
90
90
r.t.
r.t.
r.t.
90
90
90
0.5
0.5
0.5
1.5
1.5
2.0
2.0
2.0
6.0
6.0
6.0
2.0
2.0
2.0
6.0
6.0
6.0
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
95
82
66
79
78
81
28
24
85
75
76
40
25
20
82
69
67
—
—
—
—
—
—
—
—
—
—
—
15
—
—
17
—
—
f
g
g
g
g
g
g
10h
10h

336
Vol. 54, No. 3
4a (1.42 g, 10 mmol) was gently refluxed for 6 h. The resulting yellow pre-
cipitate was collected by filtration then recrystallized from methanol to give
1-benzyl-2-methylthioquinolinium iodide (5, 0.57 g, 72%). Reactions of 8
with 4b, c were carried out under similar conditions to give 2-ethylthio-1-
methylquinolinium iodide (9b, 100%) and 1-methyl-2-isopropylthioquino-
linium iodide (9c, 80%), respectively.
5: Yellow crystalline powder (methanol), mp 109—110 °C. IR (CHCl3)
cmꢀ1: 1597, 770, 753. 1H-NMR (DMSO-d6) d: 3.03 (3H, s, SMe), 6.28 (2H,
s, CH2), 7.23 (2H, m, H-Ph), 7.36—7.42 (3H, m, H-Ph), 7.92 (1H, ddd,
Jꢁ0.6, 7.8, 8.4 Hz, H-aromatic), 8.11 (1H, ddd, Jꢁ1.5, 7.8, 9.1 Hz, H-aro-
matic), 8.20 (1H, d, Jꢁ9.0 Hz, H-3), 8.30 (1H, dd, Jꢁ0.6, 9.1 Hz, H-aro-
matic), 8.42 (1H, dd, Jꢁ1.5, 8.4 Hz, H-aromatic), 9.10 (1H, d, Jꢁ9.0 Hz, H-
4). 13C-NMR (CDCl3) d: 15.88, 54.55, 117.68, 120.10, 125.70 (C2), 127.67,
128.05, 128.57 (C2), 130.21, 131.65, 134.98, 139.45 (C2), 143.25, 167.08.
Anal. Calcd for C17H16NIS: C, 51.91; H, 4.10; N, 3.56. Found: C, 51.76; H,
3.83; N, 3.59.
Chart 4
a]quinoline derivatives (Chart 4). Refluxing of 7a, e in acetic
anhydride for 4 h afforded the corresponding pyrrolo[1,2-
a]quinolines (11a, 65% and 11e, 86%, respectively). The cy-
clization of 7d, which has an ester and acetyl groups, pro-
ceeded smoothly to afford 11d (75%) and 12d (21%). Unfor-
tunately, the cyclization of 7b and 7c was unsuccessful with
the recovery of the starting materials. The structures of
11a, d, e and 12d were determined from the 1H-NMR spectra
for 11a, d, e and 12d, which showed that the signals (5.50—
5.92 ppm) due to the methylene proton of benzyl groups in
11a, d, e and 12d disappeared by dehydration and condensa-
tion.
9b: Yellow needles (methanol), mp 104 °C. IR (KBr) cmꢀ1: 1594, 1319,
1142, 769, 743. 1H-NMR (DMSO-d6) d: 1.47 (3H, t, Jꢁ7.5 Hz, CMe), 3.63
(2H, q, Jꢁ7.5 Hz, SCH2), 4.40 (3H, s, NMe), 7.92 (1H, dd, Jꢁ0.7, 8.0 Hz,
H-aromatic), 8.13—8.20 (2H, m, H-aromatic), 8.37 (1H, dd, Jꢁ0.7, 8.0 Hz,
H-aromatic), 8.47 (1H, d, Jꢁ9.3 Hz, H-3), 8.96 (1H, d, Jꢁ9.3 Hz, H-4). 13C-
NMR (DMSO-d6) d: 13.18, 27.53, 40.36, 118.23, 120.12, 125.78, 128.31,
130.28, 134.87, 140.26, 142.85, 165.39. Anal. Calcd for C12H14NIS: C,
43.52; H, 4.26; N, 4.23. Found: C, 43.03; H, 4.03; N, 4.20.
9c: Yellow needles (methanol), mp 139—140 °C. IR (KBr) cmꢀ1: 1614,
1597, 1321, 1144, 819, 766. 1H-NMR (DMSO-d6) d: 1.53 (6H, d, Jꢁ6.6 Hz,
CMeꢃ2), 4.36 (1H, m, Jꢁ6.6 Hz, SCH), 4.39 (3H, s, NMe), 7.92 (1H, ddd,
Jꢁ0.6, 7.6, 8.4 Hz, H-aromatic), 8.14 (1H, dd, Jꢁ1.7, 7.6 Hz, H-aromatic),
In conclusion, we have developed a methodology for the
pyrrolo-fused heterocycles. Thus, the reactions between ac-
tive methylene compounds and quinolinium salts having an
alkylthio group as a leaving group at the 2-position to give 1- 8.19 (1H, ddd, Jꢁ1.7, 7.1, 8.4 Hz, H-aromatic), 8.37 (1H, dd, Jꢁ0.6, 7.1 Hz,
H-aromatic), 8.46 (1H, d, Jꢁ9.3 Hz, H-3), 8.97 (1H, d, Jꢁ9.3 Hz, H-4). 13C-
NMR (CDCl3) d: 22.18 (C2), 39.24, 39.98, 118.37, 120.82, 125.87, 128.40,
130.26, 134.89, 140.36, 143.00, 164.68. Anal. Calcd for C13H16NIS: C,
alkyl-2- or 4-(substituted methylene)quinolines under mild
conditions in high yields were described. The cyclizations in
the acetic anhydride of 1-benzylquinolines having an ester or
acetyl group produced pyrrolo[1,2-a]quinolines in good
45.23; H, 4.67; N, 4.06. Found: C, 45.05; H, 4.37; N, 3.99.
General Procedure for the Reactions of Quinolinium Salts (5, 9a—c)
with Active Methylene Compounds (6a—g) To a suspension of NaH
(15 mg, 0.6 mmol) in THF (5 ml) was added dimethyl malonate (6a, 79 mg,
0.6 mmol) at 0 °C under N2. The mixture was stirred for 10 min at rt, fol-
lowed by the addition of 5 (197 mg, 0.5 mmol). The reaction mixture was
stirred for 2 h at rt, quenched with H2O (5 ml), and treated with saturated
Na2S2O3 solution (3 ml). The reaction mixture was extracted with CHCl3.
The CHCl3 layer was dried over MgSO4, and concentrated in vacuo to give
1-benzyl-1,2-dihydro-2-[bis-(methoxycarbonyl)methylene]quinoline (7a,
159 mg, 91%). Reactions of 5 with 6b—g and 9a—c with 6a, f, g were car-
ried out by similar procedures (specific conditions are listed in Tables 1 and
2 to give 1-benzyl-2-[bis(cyano)methylene]-1,2-dihydroquinoline (7b), 1-
benzyl-2-[cyano(methoxycarbonyl)methylene]-1,2-dihydroquinoline (7c), 2-
[acetyl(methoxycarbonyl)methylene]-1-benzyl-1,2-dihydroquinoline (7d),
2-[bis(acetyl)methylene]-1-benzyl-1,2-di-hydroquinoline (6e), 1-benzyl-1,2-
dihydro-2-(2,6-dioxocyclohexylidene)quinoline (7f), 1-benzyl-1,2-dihy
dro-2-(2,5-dioxocyclopentylidene)quinoline (7g), 1-benzyl-1,4-dihydro-2-
methylthio-4-(2,5-dioxocyclopentylidene)quinoline (7h), 1-methyl-1,2-dihy-
dro-2-[bis(methoxycarbonyl)methylene]quinoline (10a),1) 1,2-dihydro-1-
methyl-2-(2,6-dioxocyclohexylidene)quinoline (10f),1) 1,2-dihydro-1-
methyl-2-(2,5-dioxocyclopentylidene)quinoline (10g), and 1,4-dihydro-1-
methyl-2-methylthio-4-(2,5-dioxocyclopentylidene)quinoline (10h). The
yields are listed in Tables 1 and 2.
yields.
Experimental
General The following instruments were used to obtain physical data:
Melting points, Yanaco micromelting point apparatus (values are uncor-
rected); IR spectra, Perkin Elmer FT-IR1725X spectrophotometer; MS spec-
tra, JEOL JMN-DX 303/JMA-DA 5000 spectrometer; NMR spectra, JNM-
GSX 400 (1H-NMR, 400 MHz; 13C-NMR, 100 MHz), JNM-EX270 (1H-
NMR, 270 Hz; 13C-NMR, 67.8 MHz), JEOL JNM-PMX 60SI spectrometers
with tetramethylsilane (TMS) as an internal standard, and elemental analy-
ses, Perkin Elmer 2400 CHN Elemental Analyzer. The following experimen-
tal conditions were used for chromatography: column chromatography,
Merck Kieselgel silica gel 60 (230—400 mesh); TLC, precoated TLC plates
with 60F254 (2 mm, Merck).
Synthesis of 2 An ethanol solution (10 ml) of KOH (0.59 g, 10.5 mmol),
quinolone (1: 1.45 g, 10 mmol), and benzyl chloride (1.35 g, 10.5 mmol) was
heated at 100 °C for 10 h in a sealed tube and then removed the solvent by
evaporation in vacuo. The residue was washed with hexane and recrystal-
lized from isopropyl ether to give 2 as colorless needles (1.27 g, 54%): mp
70 °C. IR (KBr) cmꢀ1: 1651, 1591, 831, 765, 734. 1H-NMR (CDCl3) d: 5.56
(2H, s, CH2), 6.80 (1H, d, Jꢁ9.4 Hz, H-3), 7.17 (7H, m, H-aromatic), 7.41
(1H, dd, Jꢁ1.5, 8.1 Hz, H-aromatic), 7.75 (1H, dd, Jꢁ1.5, 7.7 Hz, H-aro-
matic), 7.73 (1H, d, Jꢁ9.4 Hz, H-4). 13C-NMR (CDCl3) d: 45.89, 115.01,
120.92, 121.67, 122.15, 126.56 (C2), 127.22, 128.75 (C2), 128.79, 130.57,
136.33, 139.49, 139.51, 162.45. MS m/z: 235 (Mꢂ), 129, 91. HR-MS Calcd
for C16H13NO, 235.0997. Found: 235.1045.
Synthesis of 3 A pyridine solution (8 ml) of 2 (1.18 g, 5 mmol) and
phosphorus pentasulfide (1.6 g, 1 mmol) was heated at 150 °C for 5 h. The
reaction mixture was diluted with water (10 ml), then extracted with CHCl3.
The CHCl3 layer was dried over MgSO4 and evaporated. The residue was re-
crystallized from acetone to give 3 as yellow needles (0.98 g, 78%): mp
109—110 °C. IR (KBr) cmꢀ1: 1649, 1614, 1136, 766, 712. 1H-NMR
(CDCl3) d: 6.31 (2H, s, CH2), 7.17—7.37 (6H, m, H-aromatic), 7.41—7.53
(3H, m, H-aromatic), 7.57—7.65 (1H, m, H-aromatic), 7.74 (1H, d,
Jꢁ9.0 Hz, H-4). 13C-NMR (CDCl3) d: 53.49, 116.56, 124.11, 124.53,
126.36 (C2), 127.32, 128.84, 128.87 (C2), 131.22, 132.12, 133.46, 134.99,
140.55, 185.43. MS m/z: 251 (Mꢂ), 218, 91. HR-MS Calcd for C16H13NS,
251.0769. Found: 251.0750.
7a: Yellow plates (methanol), mp 182—183 °C. IR (KBr) cmꢀ1: 1709,
1671, 1604, 827, 756, 713. 1H-NMR (CDCl3) d: 3.75 (6H, s, OMeꢃ2), 5.50
(2H, s, CH2), 6.95 (2H, d, Jꢁ7.0 Hz, H-aromatic), 7.15—7.20 (3H, m, H-
aromatic), 7.23—7.31 (1H, m, H-aromatic), 7.40 (1H, ddd, Jꢁ1.5, 7.0,
8.5 Hz, H-aromatic), 7.49 (1H, d, Jꢁ8.8 Hz, H-aromatic), 7.59 (1H, d,
Jꢁ8.5 Hz, H-aromatic), 7.82 (1H, d, Jꢁ9.5 Hz, H-3 or 4), 7.93 (1H, d,
Jꢁ9.5 Hz, H-3 or 4). 13C-NMR (CDCl3) d: 51.10 (C2), 58.22, 119.44,
125.00, 125.65, 126.45 (C2), 127.61, 127.03, 128.34, 128.76 (C2), 130.64,
135.04, 135.96 (C2), 138.92, 163.02, 168.04 (C2). MS m/z: 349 (Mꢂ), 230,
91. HR-MS Calcd for C21H19NO4, 349.1314. Found: 349.1327.
7b: Red needles (methanol), mp 232—234 °C. IR (KBr) cmꢀ1: 2198,
1
2179, 1628, 1568, 812, 765, 720. H-NMR (CDCl3) d: 5.84 (2H, s, CH2),
7.12 (2H, d, Jꢁ6.9 Hz, H-aromatic), 7.31—7.40 (4H, m, H-aromatic),
7.49—7.55 (2H, m, H-aromatic), 7.55—7.65 (2H, m, H-aromatic), 7.72 (1H,
d, Jꢁ9.5 Hz, H-3 or 4). 13C-NMR (CDCl3) d: 54.32, 116.10, 117.00, 118.00,
121.07, 123.62 (C2), 125.31, 125.55 (C2), 128.16, 129.12, 129.28 (C2),
132.33, 134.33, 137.06, 139.83, 159.91. MS m/z: 283 (Mꢂ), 91. HR-MS
Calcd for C19H13N3, 283.1109. Found: 283.1136.
General Procedure for the Syntheses of 1-Alkyl-2-alkylthioquinolin-
ium Iodides (5, 9b, c) A benzene solution (7 ml) of 3 (0.5 g, 2 mmol) and

March 2006
337
7c: Yellow plates (methanol), mp 171—172 °C. IR (KBr) cmꢀ1: 2187,
1681, 1624, 824, 750, 736. 1H-NMR (CDCl3) d: 3.80 (3H, s, OMe), 5.70
(2H, s, CH2), 6.94 (2H, d, Jꢁ6.6 Hz, H-aromatic), 7.19—7.32 (4H, m, H-
aromatic), 7.41—7.42 (2H, m, H-aromatic), 7.60 (1H, d, Jꢁ7.7 Hz, H-aro-
matic), 7.74 (1H, d, Jꢁ9.5 Hz, H-4), 8.28 (1H, d, Jꢁ9.5 Hz, H-3). 13C-NMR
(CDCl3) d: 51.69, 58.27, 118.69, 120.79, 123.53, 124.92, 124.95, 126.23,
127.78, 128.52, 128.84 (C2), 131.14, 135.73 (C2), 136.02, 139.51, 160.68
(C2), 166.72. MS m/z: 316 (Mꢂ), 257, 91. HR-MS Calcd for C20H16N2O2,
316.1212. Found: 316.1222.
8.40 (1H, s, H-3), 8.54 (1H, dd, Jꢁ1.5, 8.4 Hz, H-5). 13C-NMR (CDCl3) d:
16.43, 33.80 (C2), 37.17, 110.50, 114.35, 114.86, 123.46, 124.91, 132.76,
133.68, 140.69, 152.59, 159.01, 201.61 (C2). MS m/z: 285 (Mꢂ). HR-MS
Calcd for C16H15NO2S, 285.0823. Found: 285.0805.
General Procedure for the Cyclization Reactions of 7a, d, e with
Acetic Anhydride A mixture of 7a (0.349 g, 1.0 mmol) and acetic anhy-
dride (4 ml) was refluxed for 4 h and then concentrated in vacuo. The
residure was purified by silica gel column chromatography, in which the first
fraction eluted with hexane–ether (1 : 1) gave methyl 2-acetoxy-3-
phenylpyrrolo[1,2-a]quinolinyl-1-carboxylate (11a, 0.232 g, 65%). Reaction
of 7d with acetic anhydride was carried out similarly to give methyl 2-
methyl-3-phenylpyrrolo[1,2-a]quinolinyl-1-carboxylate (11d, 75%) and 2-
acetoxy-1-acetyl-3-phenylpyrrolo[1,2-a]quinoline (12d, 21%); reaction of
7e with acetic anhydride afforded 1-acetyl-2-methyl-3-phenylpyrrolo[1,2-
a]quinoline (11e, 86%).
7d: Yellow plates (methanol), mp 105—106 °C. IR (KBr) cmꢀ1: 1655,
1
1608, 1581, 825, 751, 716. H-NMR (CDCl3) d: 2.54 (3H, s, COMe), 3.69
(3H, s, OMe), 5.80 (2H, s, CH2), 6.98—7.00 (2H, m, H-Ph), 7.14—7.27
(3H, m, H-Ph), 7.46 (1H, ddd, Jꢁ1.0, 7.3, 7.3 Hz, H-aromatic), 7.56 (1H,
ddd, Jꢁ1.5, 7.3, 8.8 Hz, H-aromatic), 7.76—7.82 (2H, m, H-aromatic), 7.89
(1H, d, Jꢁ9.1 Hz, H-4), 8.06 (1H, d, Jꢁ9.1 Hz, H-3). 13C-NMR (CDCl3) d:
29.80, 50.28, 57.79, 98.75, 120.08, 126.37 (C2), 126.57 (C2), 126.94,
127.77, 128.90, 128.95, 129.80, 131.53, 135.88, 138.02, 138.31, 165.38,
168.38, 190.91. MS m/z: 333 (Mꢂ), 230, 91. HR-MS Calcd for C21H19NO3,
333.1365. Found: 333.1377.
11a: Yellow plates (acetone), mp 165—166 °C. IR (KBr) cmꢀ1: 1761,
1
1694, 1605, 791, 773, 761. H-NMR (CDCl3) d: 2.25 (3H, s, COMe), 3.95
(3H, s, OMe), 6.93 (1H, d, Jꢁ7.3 Hz, H-3), 7.45—7.63 (8H, m, H-aro-
matic), 7.83 (1H, d, Jꢁ7.3 Hz, H-4), 9.39 (1H, ddd, Jꢁ0.7, 1.4, 8.3 Hz, H-
aromatic). 13C-NMR (CDCl3) d: 20.64, 51.60, 101.44, 113.70, 119.17,
121.31, 125.38, 126.61, 126.91, 127.61, 127.65, 127.83, 128.82, 129.02,
129.13 (C2), 129.80, 130.06 (C2), 137.30, 164.77, 170.01. MS m/z: 359
(Mꢂ), 285. HR-MS Calcd for C22H17NO4, 359.1158. Found: 359.1172.
11d: The second fraction: Yellow needles (acetone), mp 185—186 °C. IR
(KBr) cmꢀ1: 1764, 1718, 1655, 1604. 1H-NMR (CDCl3) d: 2.15 (3H, s,
COMe), 2.51 (3H, s, OCOMe), 7.14 (1H, dd, Jꢁ1.6, 7.1 Hz, H-5 or 8),
7.16—7.36 (2H, m, H-6, 7), 7.40—7.54 (6H, m, H-Ph, 3), 7.71 (1H, dd,
Jꢁ1.5, 8.1 Hz, H-5 or 8), 8.50 (1H, d, Jꢁ9.4 Hz, H-4). 13C-NMR (CDCl3) d:
20.69, 30.00, 108.22, 117.76, 118.92, 121.10, 124.46, 125.49, 125.55,
127.76, 128.95, 129.01 (C2), 129.07, 130.5 (C2), 131.26, 132.75, 133.31,
138.47, 169.60, 192.12. MS m/z: 343 (Mꢂ), 301, 286. HR-MS Calcd for
C22H17NO3, 343.1208. Found: 343.1222.
7e: Yellow plates (methanol), mp 166—167 °C. IR (KBr) cmꢀ1: 1681,
1615, 1608, 832, 760, 750. 1H-NMR (CDCl3) d: 2.43 (6H, s, COMeꢃ2),
5.92 (2H, s, CH2), 7.05 (2H, dd, Jꢁ1.6, 8.1 Hz, H-Ph), 7.16—7.28 (3H, m,
H-Ph), 7.56 (1H, ddd, Jꢁ1.0, 8.0, 9.0 Hz, H-aromatic), 7.64 (1H, ddd,
Jꢁ1.6, 7.1, 8.7 Hz, H-aromatic), 7.83—7.87 (2H, m, H-aromatic), 7.90 (1H,
d, Jꢁ8.8 Hz, H-4), 8.25 (1H, d, Jꢁ8.8 Hz, H-3). 13C-NMR (CDCl3) d: 25.48
(C2), 51.23, 119.65, 124.90, 125.68, 126.99 (C2), 127.51, 127.66, 128.76,
128.66 (C2), 130.34, 135.45, 135.76 (C2), 138.73, 163.52, 168.51 (C2). MS
m/z: 317 (Mꢂ), 274, 232, 91. HR-MS Calcd for C21H19NO2, 317.1416.
Found: 317.1422.
7f: Yellow needles (acetone), mp 270—275 °C. IR (KBr) cmꢀ1: 1620,
1566, 757, 751, 718. 1H-NMR (CDCl3) d: 1.97—2.16 (2H, m, CH2), 2.48—
2.57 (4H, m, COCH2ꢃ2), 5.89 (2H, s, NCH2), 7.00 (2H, dd, Jꢁ1.6, 8.3 Hz,
H-Ph), 7.08—7.27 (3H, m, H-Ph), 7.50 (1H, ddd, Jꢁ1.0, 7.1, 8.6 Hz, H-aro-
matic), 7.60 (1H, ddd, Jꢁ1.6, 7.1, 8.6 Hz, H-aromatic), 7.83 (1H, dd, Jꢁ1.6,
8.6 Hz, H-aromatic), 7.91 (1H, dd, Jꢁ1.0, 8.6 Hz, H-aromatic), 8.07 (1H, d,
Jꢁ8.9 Hz, H-4), 8.25 (1H, d, Jꢁ8.9 Hz, H-3). 13C-NMR (CDCl3) d: 21.40,
34.59 (C2), 56.89, 108.59, 119.55, 124.60, 125.44 (C2), 126.10, 126.58,
127.44, 128.32 (C2), 129.00, 132.06, 134.99, 136.89, 140.40, 158.58,
201.00 (C2). MS m/z: 329 (Mꢂ), 321, 91. HR-MS Calcd for C22H19NO2,
329.1416. Found: 329.1394.
12d: The first fraction: Yellow plates (acetone), mp 123 °C. IR (CHCl3)
cmꢀ1: 1718, 1700, 1605. 1H-NMR (CDCl3) d: 2.66 (3H, s, CMe), 3.56 (3H,
s, OMe), 7.14 (1H, ddd, Jꢁ1.6, 7.1, 8.7 Hz, H-aromatic), 7.21—7.39 (2H,
m, H-aromatic), 7.44 (1H, d, Jꢁ9.4 Hz, H-3), 7.53 (5H, s, H-Ph), 7.69 (1H,
dd, Jꢁ1.5, 7.7 Hz, H-aromatic), 8.51 (1H, d, Jꢁ9.4 Hz, H-4). 13C-NMR
(CDCl3) d: 20.64, 31.60, 101.44, 113.70, 119.17, 121.31, 125.38, 126.61,
126.91, 127.61, 127.65, 127.83, 128.82, 129.02, 129.13 (C2), 129.80,
130.06 (C2), 137.30, 170.01. MS m/z: 315 (Mꢂ), 300, 284. HR-MS Calcd
for C21H17NO2, 315.1259. Found: 315.1227.
7g: Yellow needles (acetone), mp 239—240 °C. IR (KBr) cmꢀ1: 1657,
1605, 836, 755, 718. 1H-NMR (CDCl3) d: 2.60 (4H, s, CH2ꢃ2), 5.99 (2H, s,
NCH2), 6.86 (2H, dd, Jꢁ1.5, 6.9 Hz, H-Ph), 7.13—7.23 (3H, m, H-Ph), 7.51
(1H, ddd, Jꢁ1.0, 7.0, 7.0 Hz, H-6 or 7), 7.62 (1H, ddd, Jꢁ1.5, 7.0, 8.5 Hz,
H-6 or 7), 7.82—7.87 (2H, m, H-5,8), 8.32 (1H, d, Jꢁ9.1 Hz, H-3 or 4),
8.40 (1H, d, Jꢁ9.1 Hz, H-3 or 4). 13C-NMR (CDCl3) d: 33.95 (C2), 57.89,
109.58, 119.64, 125.49, 125.99 (C2), 126.70, 126.88, 127.87, 128.98 (C2),
129.19, 132.06, 135.57, 138.79, 140.30, 157.68, 200.47 (C2). MS m/z: 315
(Mꢂ), 230, 181, 91. HR-MS Calcd for C21H17NO2, 315.1259. Found:
315.1278.
11e: Yellow needles (acetone), mp 110—111 °C. IR (KBr) cmꢀ1: 1693,
1
1642, 1601, 821, 805, 748. H-NMR (CDCl3) d: 2.30 (3H, s, COMe), 2.65
(3H, s, CMe), 7.09 (1H, ddd, Jꢁ1.6, 6.9, 8.5 Hz, H-aromatic), 7.15—7.29
(2H, m, H-aromatic), 7.35—7.40 (3H, m, H-3, aromatic), 7.42—7.60 (3H,
m, H-aromatic), 7.67 (1H, dd, Jꢁ1.5, 7.9 Hz, H-aromatic), 8.42 (1H, d,
Jꢁ9.4 Hz, H-4). 13C-NMR (CDCl3) d: 13.05, 31.68, 100.51, 115.92, 117.77,
118.91, 123.89, 123.95, 124.59, 125.45, 127.39, 128.51, 128.60, 128.63,
129.08 (C2), 131.24, 133.43, 134.41, 134.71, 195.04. MS m/z: 299 (Mꢂ),
284. HR-MS Calcd for C21H17NO, 299.1310. Found: 299.1321.
7h: Yellow needles (acetone), mp 220 °C. IR (KBr) cmꢀ1: 1681, 1651,
1547, 1174, 820, 752, 711. 1H-NMR (CDCl3) d: 2.64 (4H, s, CH2CH2), 2.82
(3H, s, SMe), 5.83 (2H, s, NCH2), 7.05 (2H, dd, Jꢁ2.6, 7.8 Hz, H-Ph),
7.31—7.40 (3H, m, H-Ph), 7.49—7.56 (2H, m, H-7, 8), 7.68 (1H, ddd,
Jꢁ1.5, 6.8, 8.3 Hz, H-6), 8.47 (1H, s, H-3), 8.58 (1H, dd, Jꢁ1.5, 8.3 Hz, H-
5). 13C-NMR (CDCl3) d: 16.42, 33.82 (C2), 53.48, 110.81, 114.51, 115.71,
123.64, 124.98, 125.70 (C2), 128.52, 129.40 (C2), 132.46, 132.69, 133.87,
140.59, 152.98, 159.26, 201.73 (C2). MS m/z: 361 (Mꢂ), 270, 91. HR-MS
Calcd for C22H19NO2S, 361.1137. Found: 361.1157.
References
1) Tomisawa H., Tanbara T., Kato H., Hongo H., Fujita R., Heterocycles,
15, 277—280 (1981).
2) Tominaga Y., Matsuda Y., J. Syn. Org. Chem. Jpn., 43, 669—679
(1985). References cited therein.
3) Roberts E. M., Gates M., Boekelheide V., J. Org. Chem., 20, 1443—
1447 (1955).
4) Hurst J., Melton T., Wibberley D. G., J. Chem. Soc., 1965, 2948—2955
(1965).
10g: Pale yellow columns (methanol), mp 236—238 °C. IR (KBr) cmꢀ1
:
1660, 830, 750. 1H-NMR (CDCl3) d: 2.63 (4H, s, CH2ꢃ2), 4.15 (3H, s,
NMe), 7.61 (1H, ddd, Jꢁ1.5, 7.4, 8.9 Hz, H-aromatic), 7.80—7.90 (2H, m,
H-aromatic), 7.96 (1H, dd, Jꢁ0.8, 9.4 Hz, H-5 or 8), 8.19 (1H, d, Jꢁ9.0 Hz,
H-4), 8.33 (1H, d, Jꢁ9.0 Hz, H-3). 13C-NMR (CDCl3) d: 34.08 (C2), 42.70,
108.99, 117.96, 125.18, 126.03, 126.80, 129.05, 132.47, 139.22, 139.85,
156.56, 200.57 (C2). MS m/z: 239 (Mꢂ). HR-MS Calcd for C15H13NO2,
239.0946. Found: 239.0949.
5) Melton T., Taylor J., Wibberley D. G., J. Chem. Soc. Chem. Commun.,
1965, 151—152 (1965).
6) Henrick C. A., Ritchie E., Taylor W. C., Aust. J. Chem., 20, 2467—
2477 (1967).
7) Irwin W. J., Wibberley D. G., J. Chem. Soc., Perkin Trans 1, 1974,
250—252 (1974).
8) Komatsu M., Kasano Y., Yamaoka S., Minakata S., Synthesis, 2003,
1398—1402 (2003).
10h: Pale yellow columns (methanol), mp ꢄ300 °C. IR (KBr) cmꢀ1
:
1600, 840, 750. 1H-NMR (CDCl3) d: 2.61 (4H, s, CH2ꢃ2), 2.83 (3H, s,
SMe), 4.13 (3H, s, NMe), 7.55 (1H, ddd, Jꢁ1.5, 6.9, 8.4 Hz, H-6 or 7), 7.69
(1H, dd, Jꢁ1.5, 8.4 Hz, H-8), 7.80 (1H, ddd, Jꢁ1.5, 6.9, 8.4 Hz, H-6 or 7),
9) Boultadakis E., Chung B., Elsegood M. R. J., Weaver G. W., Synlett,
2002, 1547—1549 (2002).