Reaction of 1-alkylthioisoquinolinium salts with active methylene compounds

Article abstract of DOI:10.1248/cpb.50.225

2-Alkyl-1-alkylthioisoquinolinium salts were readily prepared from 2-alkyl-1(2H)-isoquinolones via 2-alkyl-1(2H)-thioisoquinolones in two steps. Under mild conditions, the reaction of 2-alkyl-l-alkylthioisoquinolinium salts with active methylene compounds in the presence of sodium hydride afforded 2-alkyl-1-(substituted methylene) iso-quinolines in good yields. Pyrrolo[2,1-a]isoquinolines were synthesized by the cyclization of 2-benzyl-1-(substituted methylene)isoquinolines using acetic anhydride.

Full text of DOI:10.1248/cpb.50.225

February 2002
Chem. Pharm. Bull. 50(2) 225—228 (2002)
225
Reaction of 1-Alkylthioisoquinolinium Salts with Active Methylene
Compounds
Reiko FUJITA,* Noriyuki WATANABE, and Hiroshi TOMISAWA
Tohoku Pharmaceutical University, 4–4–1 Komatsushima, Aoba-ku, Sendai 981–8558, Japan.
Received September 10, 2001; accepted October 23, 2001
2-Alkyl-1-alkylthioisoquinolinium salts were readily prepared from 2-alkyl-1(2H)-isoquinolones via 2-alkyl-
1(2H)-thioisoquinolones in two steps. Under mild conditions, the reaction of 2-alkyl-l-alkylthioisoquinolinium
salts with active methylene compounds in the presence of sodium hydride afforded 2-alkyl-1-(substituted methyl-
ene)iso-quinolines in good yields. Pyrrolo[2,1-a]isoquinolines were synthesized by the cyclization of 2-benzyl-1-
(substituted methylene)isoquinolines using acetic anhydride.
Key words cyclization; pyrrolo[2,1-a]isoquinoline; dimethyl malonate; methylthioisoquinolinium salt; active methylene com-
pound
We have previously reported on the reaction of 2- the alkylthio group at the 1-position, the experiments were
methylthioquinolinium salts with active methylene com- repeated using other alkyl iodides. In comparison to methyl
pounds for the formation of a carbon–carbon bond.1) Addi- iodide, the reaction of 3 with ethyl iodide (5b) and isopropyl
tionally, various methods for the synthesis of indolizine iodide (5c) afforded low yields of the corresponding 1-
derivatives have been reported.2) In view of the recent report alkylthioisoquinolinium salts (6b, 75%; 6c, 52%). Further-
by Iwao and Kuraishi.2) on the novel total synthesis of the more, the reactions of 6b, c with 8a and with 8g gave prod-
marine alkaloid lamellarins, which contain the pyrrolo[2,1- ucts [9a ( 65%, 65%); 9g (42%, 40%)] in lower yields than
a]isoquinoline skeleton (Chart 1),3) functionalized pyrrolo- that of 6a with 8a, g (Table 1). These results can be explained
[2,1-a]isoquinolines would function as very useful synthetic by assuming that the enol form arising from the active meth-
intermediates toward their syntheses. The conventional meth- ylenes (8d—f) would be more stable than the corresponding
ods for preparing the substituted pyrrolo[2,1-a]isoquinoline keto form, and would tend to lower the yields. The reactions
derivatives are either via Michael condensation of Reissert of 7 with bulky methylene compounds (8f—h) did not give
compounds,4) or via 1,3- and 1,5-dipolar cycloaddition reac- the desired products (10f—h), whereas reactions of 6a bear-
tions.5,6) In this paper, we report a novel method for the syn- ing a smaller methyl group at the 2-position proceeded with
thesis of a pyrrolo[2,1-a]isoquinoline skeleton using the cy- 8f—h; hence it can be implied that steric hindrance between
clization of 2-benzyl-1-(substituted methylene) isoquino- two bulky groups, specifically, 2-benzyl and phenyl in 8f or
lines, which are readily prepared by the reaction of 2-benzyl- alicyclic rings (8g, h) was a main factor in reducing the yield.
1-alkylthioisoquinolinium iodides with active methylene Spectroscopic studies of compound 10b showed nuclear
compounds.
Overhauser and exchange spectroscopy (NOE) correlations
Reaction of 1-Alkylthioisoquinolinium Iodides with Ac- between the methyl of the ester and the 2-methylene groups,
tive Methylene Compounds Initially, the reaction of active and therefore their configuration is suggested to be the Z-
methylene compounds with isoquinolinium salts that have a form. Unfortunately, similar NOE correlations were not ob-
methylthio group as a leaving group at the 1-position was served between the ester and the 2-substituent groups of
examined under mild conditions in the presence of sodium 9b, d, and 10d. In summary, this type of reaction is a promis-
hydride (Chart 2, Table 1). 2-Methyl- and 2-benzyl-1(2H)- ing method to form a carbon-carbon bond at the 1-position of
thioisoquinolones (3,7) 4) were prepared from 2-methyl- and an isoquinoline ring.
2-benzyl-1(2H)-isoquinolones (1,8) 2) in excellent yields, re-
Synthesis of Pyrrolo[2,1-a]isoquinolines Our next step
spectively. The reaction of thioisoquinolones (3, 4) with was cyclization of the 2-benzyl compounds (10a—e) in
methyl iodide (5a) afforded 2-methyl- and 2-benzyl-1- acetic anhydride to provide the functionalized pyrrolo[2,1-
methylthioisoquinolinium iodides (6a,9) 7) in 99 and 77% a]isoquinoline derivatives (Chart 3). Heating of 10a, d, e in
yields, respectively. The reactions of 6a with straight-chain acetic anhydride at 130 °C for 4 h afforded the corresponding
active methylene compounds (8a—c) in the presence of pyrrolo[2,1-a]isoquinolines (11a, 91%; 11b, 88%; 11c, 68%;
sodium hydride for 1.5 h at room temperature afforded 2- respectively). Unfortunately, cyclizations of 10b, c were un-
methyl-1-(substituted methylene)isoquinolines (9a, 88%; 9b, successful, although 10b, c were recovered. The structures of
1
81%; 9c, 85%, respectively) in high yields. However, reac- 11a—c were determined as follows. H-NMR spectra of
tions of 6a with straight-chain active methylene compounds 11a—c showed that the signals (5.55—5.94 ppm) due to
(8d—f) afforded 9d—f in moderate yields. Reactions of 6a
with cyclic active methylene compounds (8g, h) at 90 °C for
3 h gave 2-methyl-1-(substituted methylene)isoquinolines
(9g, h) in 92% and 61% yields, respectively. Similarly, the
reaction of 7 with 8a—e produced 2-benzyl-1-(substituted
methylene)-isoquinolines (10a, 95%; 10b, 98%; 10c, 99%;
10d, 88%; 10e, 53%, respectively). To examine the effects of
Chart 1
To whom correspondence should be addressed. e-mail: refujita@tohoku-pharm.ac.jp
© 2002 Pharmaceutical Society of Japan

226
Vol. 50, No. 2
Chart 2
Table 1. Reaction of Isoquinolinium Salts with Active Methylene Compounds
8a—h
Temp
(°C)
Time
(h)
Yield
(%)
Entry
Salt
Solvent
Product
X
Y
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
6a
6a
6a
6a
6a
6a
6a
6a
7
7
7
7
7
7
7
7
6b
6c
6b
6c
rta)
rt
rt
rt
rt
1.5
1.5
1.5
1.5
1.5
1.5
3
3
2
2
2
THF
THF
THF
THF
THF
THF
DMF
DMF
THF
THF
THF
THF
THF
THF
DMF
DMF
THF
THF
DMF
DMF
COOMe
CN
CN
COMe
COMe
PhCO
COCH2CH2CH2CO
COCH2CH2CO
COOMe
CN
CN
COMe
COMe
PhCO
COCH2CH2CH2CO
COCH2CH2CO
COOMe
COOMe
CN
COOMe
COMe
COOEt
9a
9b
9c
9d
9e
9f
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
9a
97
81
85
69
47
49
92
61
95
98
99
88
53
0
0
0
65
59
42
40
rt
90
90
rt
rt
rt
rt
rt
rt
90
90
rt
rt
90
90
COOMe
COOMe
CN
COOMe
COMe
COOEt
2
2
2
3
3
1.5
1.5
3
COOMe
COOMe
COOMe
COOMe
9a
9g
9g
COCH2CH2CH2CO
COCH2CH2CH2CO
3
a) Room temperature.
Chart 3
methylenes of benzyl groups in 10a, d, e disappeared by de- alkyl-1-(substituted methylene)isoquinolines under mild con-
hydration and condensation. dition in fairly good yields. Cyclization of 2-benzyl com-
In conclusion, we found that a novel reaction of active pounds having an ester or an acetyl group in acetic anhydride
methylene compounds with isoquinolinium salts having a produced the pyrrolo[2,1-a]isoquinolines in excellent yields.
methylthio group as a leaving group at the 1-position gave 2-

February 2002
227
Experimental
(15 mg, 0.6 mmol) in tetrahydrofuran (THF) (5 ml) was added dimethyl mal-
The following instruments were used to obtain physical data: Melting onate (79 mg, 0.6 mmol) at 0 °C under N2. The mixture was stirred for
points, Yanaco micromelting point apparatus (values are uncorrected); IR 10 min at room temperature followed by the addition of 6a (165 mg, 0.5
spectra, Perkin-Elmer ET-IR1725X spectrometer; MS, JEOL JMN-DX mmol). The reaction mixture was stirred for 1.5 h at room temperature, then
303/JMA-DA 5000 spectrometer; NMR spectra, JNM-GSX 400 (1H-NMR, quenched with water (5 ml) followed by saturated Na2S2O3 solution (3 ml).
400 MHz; 13C-NMR, 100 MHz), JNM-EX270 (1H-NMR, 270 MHz; 13C- The reaction mixture was extracted with CHCl3 and dried over MgSO4. The
NMR, 67.8 MHz), JEOL JNM- PMX 60SI spectrometer with tetramethylsi- organic layer was concentrated in vacuo to give 1,2-dihydro-1-[bis(methoxy-
lane (TMS) as an internal standard; elemental analyses, Perkin-Elmer 2400 carbonyl)methylene]-2-methylisoquinoline [9a (166 mg, 97%)]. Reactions
CHN Elemental Analyzer. The following experimental conditions were used of 1-ethylthio-, 1-isopropylthio-2-methylisoquinoline (6b, c) and 7 with di-
for chromatography; column chromatography, Merck Kieselgel silica gel 60 methyl malonate (8a), methyl cyanoacetate (8b), malononitrile (8c), methyl
(230—400 mesh); TLC, pre-coated TLC plates with 60F254 (2 mm, Merck).
acetoacetate (8d), acetylacetone (8e), ethyl benzoacetate (8f), 1,3-dioxocy-
Synthesis of 2 An ethanol solution (20 ml) of KOH (0.59 g, 10.5 mmol), clohexane (8g), and 1,3-dioxocyclopentane (8h) were carried out under
isoquinolone (1.45 g, 10 mmol), and benzyl chloride (1.35 g, 10.5 mmol) was the conditions shown in Table 1 and were similarly treated to give 1-
heated at 100 °C for 10 h in a sealed tube. After removing the solvent in
[cyano(methoxycarbonyl)methylene]-1,2-dihydro-2-methyl-isoquinoline
vacuo, the residue was washed with hexane and was recrystallized from iso- (9b), 1-[bis(cyano)methylene]-1,2-dihydro-2-methylisoquinoline (9c), 1-
propyl ether to afford 2 as colorless needles (2.33 g, 99%): mp 70 °C (iso- [acetyl(methoxy-carbonyl)methylene]-1,2-dihydro-2-methylisoquinoline
propyl ether). IR (CHCl3) cmϪ1: 1650, 1599, 741, 692. 1H-NMR (CDCl3) d:
(9d), 1-[bis(acetyl)methylene]-1,2-dihydro-2-methylisoquinoline (9e), 1-
5.22 (2H, s, CH2), 6.47 (1H, d, Jϭ7.4 Hz, H-4), 7.08 (1H, d, Jϭ7.4 Hz, H-3), [benzoyl(ethoxycarbonyl)methylene]-1,2-dihydro-2-methylisoquinoline (9f),
7.24—7.39 (5H, m, H–Ph), 7.46—7.65 (3H, br m, H-5, 6, 7), 8.46 (1H, dd,
1,2-dihydro-2-methyl-1-(2,6-dioxocyclohexylidene)isoquinoline (9g), 1,2-
Jϭ1.2, 7.2 Hz, H-8). 13C-NMR (CDCl3) d: 51.65, 106.38, 125.89, 126.32, dihydro-2-methyl-1-(2,5-dioxocyclopentylidene)isoquinoline (9h), 2-benzyl-
126.87, 127.79 (C2), 127.94, 128.06, 128.78 (C2), 131.27, 132.19, 136.90, 1,2-dihydro-1-[bis(methoxycarbonyl)methylene]isoquinoline (10a), 2-ben-
136.97, 162.24. MS m/z: 235 (Mϩ). High resolution (HR)-MS m/z: Calcd for zyl-1,2-dihydro-1-[cyano(methoxycarbonyl)methylene]isoquinoline (10b),
C16H13NO, 235.0997. Found: 235.0985.
2-benzyl-1,2-dihydro-1-[bis(cyano)methylene]isoquinoline (10c), 1-[acetyl-
Synthesis of 4 A solution of 2 (0.47 g, 2 mmol) and phosphorus penta- (methoxycarbonyl)methylene]-2-benzyl-1,2-dihydroisoquinoline (10d), and
sulfide (0.467 g, 2.1 mmol) in pyridine (6 ml) was heated at 150 °C for 5 h. 1-[bis(acetyl)methylene]-2-benzyl-1,2-dihydroisoquinoline (10e). Yields are
The reaction mixture was mixed with water (10 ml) and the resulting solu- listed in Table 1.
tion was extracted with CHCl3. The CHCl3 layer was dried over MgSO4 and
evaporated. The residue was recrystallized from isopropyl ether to afford 4
as colorless needles (0.49 g, 97%): mp 95—97 °C. IR (CHCl3) cmϪ1: 1547,
1290, 773, 694. 1H-NMR (CDCl3) d: 6.01 (2H, s, CH2), 6.87 (1H, d,
9a: Yellow crystalline powder (acetone), mp 237—239 °C. IR (KBr)
1
cmϪ1: 1720, 1600. H-NMR (CDCl3) d: 3.62 (6H, s, OMeϫ2), 4.22 (3H, s,
NMe), 7.66 (1H, d, Jϭ7.0 Hz, H-4), 7.72 (1H, d, Jϭ2.0, 6.0, 8.0 Hz, H-7),
7.84—7.87 (2H, m, H-5, 6), 7.90 (1H, d, Jϭ7.0 Hz, H-3), 8.50 (1H, dd,
Jϭ7.1 Hz, H-4), 7.31—7.34 (5H, m, H–Ph), 7.40 (1H, d, Jϭ7.1 Hz, H-3), Jϭ1.5, 8.0 Hz, H-8). 13C-NMR (CDCl3) d: 45.00, 50.23 (C2), 121.07,
7.54—7.61 (2H, br m, H-5, 7), 7.67 (1H, ddd, Jϭ1.5, 7.5, 7.5 Hz, 6-H), 9.16
126.63, 129.69, 130.55, 131.40, 132.16, 133.54, 134.21, 136.31, 165.63,
(1H, dd, Jϭ1.5, 7.5 Hz, H-8). 13C-NMR (CDCl3) d: 59.26, 112.42, 126.67, 167.27 (C2). MS m/z: 273 (Mϩ). Anal. Calcd for C15H15N04: C, 65.92; H,
127.94 (C3), 127.97, 128.55, 128.85 (C2), 132.11, 132.41, 133.05 (C2),
135.76, 184.63. MS m/z: 251 (Mϩ). HR-MS m/z: Calcd for C16H13NS,
251.0769. Found: 251.0727.
5.53; N, 5.13. Found: C, 65.56; H, 5.07; N, 5.60.
9b: Yellow needles (benzene), mp 194—196 °C. IR (KBr) cmϪ1: 2200,
1660. 1H-NMR (CDCl3) d: 3.80 (3H, s, OMe), 4.06 (3H, s, NMe), 7.39 (1H,
General Procedure for Synthesis of 2-Alkyl-1-alkylthioisoquinolinium d, Jϭ7.1 Hz, H-4), 7.65 (1H, d, Jϭ7.1 Hz, H-3), 7.70—7.86 (3H, m, H-5, 6,
Iodides (6a—c, 7) A solution of 4 (0.5 g, 2 mmol), 5a (1.42 g, 10 mmol), 7), 8.93 (1H, dd, Jϭ1.0, 7.8 Hz, H-8). 13C-NMR (CDCl3) d: 47.22, 51.32,
and benzene (7 ml) was gently refluxed for 17 h. The resulting yellow precip-
118.61, 123.94, 126.97, 128.28, 129.33, 130.67, 133.96, 133.99, 135.59
itate was collected by filtration and was recrystallized from methanol to give (C2), 159.57, 167.77. MS m/z: 240 (Mϩ). Anal. Calcd for C14H12N202: C,
7 (0.6 g, 77%). Reactions of 3 with 5a—c were carried out under similar 69.99; H, 5.03; N, 11.66. Found: C, 69.77; H, 4.94; N, 11.65.
conditions to afford 6a, 1-ethylthio-(6b), and 1-isopropylthio-2-methyliso-
quinolinium iodide (6c). Yields are listed in Chart 2.
9c: Yellow needles (acetone–chloroform), mp 226—227 °C. IR (KBr)
cmϪ1: 2200, 1630. 1H-NMR (CF3COOD) d: 4.11 (3H, s, NMe), 7.10 (1H, d,
6a9): Yellow needles (methanol), mp 132—134 °C (mp 143—146 °C).9) Jϭ7.3 Hz, H-4), 7.32 (1H, d, Jϭ7.3 Hz, H-3), 7.65—7.84 (3H, m, H-5, 6, 7),
1H-NMR (DMSO-d6) d: 2.83 (3H, s, SMe), 4.66 (3H, s, NMe), 8.0—8.39 9.12 (1H, dd, Jϭ1.0, 8.1 Hz, H-8). 13C-NMR (CDCl3) d: 47.51, 116.00,
(3H, m, H-5, 6, 7), 8.75 (1H, d, Jϭ7.0 Hz, H-4), 8.85 (1H, dd, Jϭ2.0,
120.04 (C2), 125.91, 127.16, 128.53, 129.09, 133.89 (C2), 134.80 (C2),
6.0 Hz, H-8), 9.0 (1H, d, Jϭ7.0 Hz, H-3). 13C-NMR (CDCl3) d: 20.10, 158.17. MS: m/z: 207 (Mϩ). Anal. Calcd for C13H9N3: C, 75.34; H, 4.38; N,
48.77, 125.08, 128.17, 129.71, 130.10, 131.85, 136.00, 136.90, 138.22,
160.87.
20.28. Found: C, 75.28; H, 4.56; N, 20.31.
9d: Yellow crystalline powder (acetone), mp 224—225 °C. IR (KBr)
6b: Yellow needles (methanol), mp 104 °C. IR (CHCl3) cmϪ1: 1604, 773, cmϪ1: 1660, 1650. H-NMR (CDCl3) d: 2.62 (3H, s, COMe), 3.44 (3H, s,
1
755. 1H-NMR (DMSO-d6) d: 1.36 (3H, dd, Jϭ7.0, 7.0 Hz, CMe), 3.40 (2H,
ddd, Jϭ7.0, 7.0, 7.0 Hz, CH2), 4.96 (3H, s, NMe), 8.00—8.50 (3H, m, H-5,
6, 7), 8.54 (1H, d, Jϭ7.0 Hz, H-4), 8.87 (1H, br m, H-8), 9.21 (1H, d,
Jϭ7.0 Hz, H-3). 13C-NMR (CDCl3) d: 15.08, 32.64, 48.90, 125.30, 128.13,
NMe), 4.22 (3H, s, OMe), 7.69—7.78 (1H, br m, H-aromatic), 7.71 (1H, d,
Jϭ7.3 Hz, H-4), 7.84—7.92 (2H, m, H-aromatic), 7.95 (1H, d, Jϭ7.3 Hz, H-
3), 8.45 (1H, dd, Jϭ1.0, 8.6 Hz, H-8). 13C-NMR (CDCl3) d: 28.44, 45.83,
49.74, 118.55, 121.85, 126.66, 129.90, 131.00, 131.93, 133.65, 134.49,
129.92, 130.85, 131.91, 136.09, 136.94, 138.48, 159.29. Anal. Calcd for 136.47, 167.00, 167.66, 190.04. MS m/z: 257 (Mϩ). Anal. Calcd for
C12H14INS: C, 43.52; H, 4.26; N, 4.23. Found: C, 43.33; H, 4.20; N, 4.03.
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.90; H, 5.97; N, 5.50.
6c: Yellow needles (methanol), mp 139—140 °C. IR (CHCl3) cmϪ1: 1620,
9e: Yellow crystalline powder (acetone), mp 210—211 °C. IR (KBr)
785, 757. 1H-NMR (DMSO-d6) d: 1.35 (6H, d, Jϭ7.0 Hz, CMex2), 3.91 cmϪ1: 1670, 1640. H-NMR (CF3COOD) d: 1.95 (6H, s, COMeϫ2), 4.54
(1H, m, Jϭ7.0 Hz, CH), 4.76 (3H, s, NMe), 8.00—8.63 (3H, m, H-5, 6, 7),
1
(3H, s, NMe), 8.20 (1H, dd, Jϭ7.6, 7.6 Hz, H-6 or 7), 8.34—8.39 (3H, m,
8.73 (1H, d, Jϭ7.0 Hz, H-4), 9.00 (1H, br m, H-8), 9.09 (1H, d, Jϭ7.0 Hz, H-aromatic), 8.51 (1H, d, Jϭ6.8 Hz, H-3 or 4), 8.67 (1H, d, Jϭ6.8 Hz, H-3
H-3). 13C-NMR (CDCl3) d: 23.43 (C2), 44.83, 48.96, 125.57, 128.12, or 4). 13C-NMR (CF3COOD) d: 25.54 (C2), 48.81, 107.62, 130.12, 130.67,
130.08, 131.33, 132.02, 136.20, 137.06, 138.72, 158.20. Anal. Calcd for 131.18, 132.31, 136.36, 139.08, 140.78, 141.72, 157.94, 196.13 (C2). MS
C13H16INS: C, 45.23; H, 4.67; N, 4.06. Found: C, 45.05; H, 4.37; N, 3.99.
7: Yellow needles (methanol), mp 110 °C. IR (CHCl3) cmϪ1: 1618, 725,
696. 1H-NMR (CF3COOD) d: 2.67 (3H, s, SMe), 6.40 (2H, s, CH2), 7.32—
m/z: 241 (Mϩ). HR-MS m/z: Calcd for C15H15NO2, 241.1109. Found:
241.1111.
9f: Yellow crystalline powder (benzene), mp 175—178 °C. IR (KBr)
7.45 (5H, m, H–Ph), 8.17 (1H, ddd, Jϭ1.3, 7.1, 8.4 Hz, H-6), 8.30 (1H, ddd, cmϪ1: 1640, 1620. 1H-NMR (CDCl3) d: 0.85 (3H, dd, Jϭ8.0, 8.0 Hz, CMe),
Jϭ1.3, 7.1, 8.4 Hz, H-7), 8.45 (1H, dd, Jϭ1.3, 8.4 Hz, H-5), 8.74 (1H, d,
3.38 (2H, ddd, Jϭ8.0, 8.0, 8.0 Hz, COOCH2), 4.16 (3H, s, NMe), 7.16—
Jϭ6.8 Hz, H-4 ), 8.87 (1H, dd, Jϭ1.3, 8.4 Hz, H-8), 9.13 (1H, d, Jϭ6.8 Hz, 8.85 (10H, m, H-3, 4, 5, 6, 7, Ph), 8.32—8.60 (1H, m, H-8). 13C-NMR
H-3). 13C-NMR (CDCl3) d: 21.62, 63.24, 111.90, 126.05, 127.51 (C2),
(CDCl3) d: 14.06, 45.93, 58.52, 91.11, 121.18, 126.73, 127.40 (C2), 127.45
128.38, 128.46, 128.96 (C2), 132.19, 134.62, 136.50, 137.34, 137.33, (C2), 128.54, 129.71, 130.81, 131.81, 133.79, 134.21, 136.34, 144.35,
137.72, 161.43. Anal. Calcd for C17H16INS: C, 51.92; H, 4.10; N, 3.56. 166.04, 168.12, 188.91. MS m/z: : 333 (Mϩ). Anal. Calcd for C21H19NO3: C,
Found: C, 51.76; H, 3.83; N, 3.59.
75.65; H, 5.74; N, 4.20. Found: C, 75.61; H, 6.00; N, 4.17.
General Procedure for Reaction of Isoquinolinium Salts (6a—c, 7)
with Active Methylene Compounds (8a—h) To a suspension of NaH
9g: Pale yellow crystalline powder (benzene), mp 230—233 °C. IR (KBr)
cmϪ1: 1620, 1600, 820, 750. 1H-NMR (CDCl3) d: 2.00—2.40 (2H, m, CH2),

228
Vol. 50, No. 2
layer was dried over MgSO4, and concentrated in vacuo. The residue was pu-
rified using column chromatography on aluminum oxide (CHCl3–acetone,
2 : 1) to give 2-acetoxy-1-methoxycarbonyl-3-phenylpyrrolo[2-1-a]isoquino-
line [11a (0.357 g, 99%)]. Reactions of 10d, e with acetic anhydride were
similarly performed to give 2-acetoxy-1-acetyl-3-phenylpyrrolo[2-1-a]iso-
quinoline (11b), and 1-acetyl-2-methyl-3-phenylpyrrolo[2-1-a]isoquinoline
(11c). Yields are listed in Chart 3.
2.66—2.79 (4H, m, COCH2ϫ2), 4.23 (3H, s, NMe), 7.73 (1H, d, Jϭ7.0 Hz,
H-4), 7.72—8.00 (3H, m, H-5, 6, 7), 7.96 (1H, d, Jϭ7.0 Hz, H-3), 8.43 (1H,
br m, H-8). 13C-NMR (CDCl3) d: 21.52, 37.13 (C2), 46.09, 105.84, 122.62,
126.76, 129.89, 130.15, 132.35, 133.97, 134.95, 136.47, 165.31, 192.17
(C2). MS m/z: 253 (Mϩ). Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N,
5.53. Found: C, 75.44; H, 6.02; N, 5.44.
9h: Yellow needles (benzene), mp 291—293 °C. IR (KBr) cmϪ1: 1625,
11a: Yellow needles (Et2O), mp 165—166 °C. IR (CHCl3) cmϪ1: 1764,
1702, 1606. 1H-NMR (CDCl3) d: 2.25 (3H, s, COMe), 3.95 (3H, s,
COOMe), 6.93 (1H, d, Jϭ7.4 Hz, H-6), 7.45—7.60 (8H, m, H-7, 8, 9, Ph),
7.83 (1H, d, Jϭ7.4 Hz, H-5), 9.40 (1H, d, Jϭ8.0 Hz, H-10). 13C-NMR
(CDCl3) d: 20.64, 51.60, 101.45, 113.71, 119.18, 121.32, 125.40, 126.63,
126.92, 127.62, 127.65, 127.81, 127.84, 128.83, 129.03, 129.15, 129.23,
129.81, 130.08, 137.31, 164.77, 170.01. MS: m/z: 359 (Mϩ), 317, 285, 228.
HR-MS m/z: Calcd for C22H17NO4, 359.1158. Found: 359.1187.
1
1600, 810, 755. H-NMR (CDCl3) d: 2.73 (4H, s, COCH2ϫ2), 4.33 (3H, s,
NMe), 7.50—8.06 (5H, m, H-3, 4, 5, 6, 7), 8.43 (1H, m, H-8). 13C-NMR
(CDCl3) d: 34.48 (C2), 46.83, 106.45, 121.69, 126.68, 128.46, 129.82,
132.66, 134.21, 135.02, 136.31, 159.89, 199.66 (C2). MS m/z: 239 (Mϩ).
Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.87. Found: C, 75.03; H,
5.34; N, 5.87.
10a: Red plates (acetone), mp 239 °C. IR (KBr) cmϪ1: 1701, 1595, 758.
1H-NMR (CDCl3) d: 3.63 (6H, s, OMeϫ2), 5.76 (2H, s, CH2), 7.25 (2H, dd,
Jϭ2.0, 6.6 Hz, H–Ph), 7.32—7.39 (3H, m, H–Ph), 7.58 (1H, d, Jϭ7.0 Hz,
H-4), 7.72—7.88 (4H, m, H-3, 5, 6, 7), 8.60 (1H, d, Jϭ8.2 Hz, H-8). 13C-
NMR (CDCl3) d: 50.10 (C2), 60.49, 121.38, 126.63 (C2), 128.95, 129.04,
129.30 (C3), 129.81, 131.34, 132.26, 132.69, 134.54 (C2), 134.90, 136.33,
166.25, 167.24. MS m/z: 349 (Mϩ), 230. HR-MS m/z: Calcd for C21H19NO4,
349.1314. Found: 349.1283.
11b: Yellow plates (acetone), mp 145—146 °C. IR (CHCl3) cmϪ1: 1764,
1
1718, 1700, 1605. H-NMR (CDCl3) d: 2.22 (3H, s, COMe), 2.63 (3H, s,
OCOMe), 6.95 (1H, dd, Jϭ0.7, 7.3 Hz, H-6), 7.46—7.63 (8H, m, H-7, 8, 9,
Ph), 7.80 (1H, d, Jϭ7.3 Hz, H-5), 9.10 (1H, ddd, Jϭ0.7, 1.4, 6.4 Hz, H-10).
13C-NMR (CDCl3) d: 20.82, 31.10, 111.82, 114.10, 119.05, 121.16, 125.44,
126.18, 126.98, 127.59, 127.88, 127.91, 128.68, 128.94, 129.11, 129.23
(C2), 130.03 (C2), 136.88, 169.43, 194.95. MS: m/z: 343 (Mϩ), 301, 286.
HR-MS m/z: Calcd for C22H17NO4, 359.1158. Found: 359.1187.
10b: Red needles (acetone), mp 91—93 °C. IR (KBr) cmϪ1: 2172, 1713,
1643, 756. 1H-NMR (CDCl3) d: 3.81 (3H, s, OMe), 5.77 (2H, s, CH2),
7.17—7.24 (2H, m, H–Ph), 7.34—7.39 (4H, m, H-4, Ph), 7.50 (1H, d,
Jϭ7.2 Hz, H-3), 7.70—7.87 (3H, m, H-5, 6, 7), 9.09 (1H, d, Jϭ8.9 Hz, H-8).
13C-NMR (CDCl3) d: 51.29, 61.92, 118.47, 124.12, 127.02 (C2), 128.28,
128.50, 129.11 (C2), 129.42 (C2), 130.66, 132.56, 134.16, 135.08, 135.31
(C2), 139.87, 168.09. MS m/z: : 316 (Mϩ), 285, 257, 91. HR-MS m/z: Calcd
for C20H16N202, 316.1212. Found: 316.1248.
11c: Colorless oil. IR (CHCl3) cmϪ1: 1718, 1655, 1604. 1H-NMR (CDCl3)
d: 2.33 (3H, s, COMe), 2.71 (3H, s, Me), 6.78 (1H, dd, Jϭ0.8, 7.3 Hz, H-6),
7.39—7.56 (8H, m, H-7, 8, 9, Ph), 7.68 (1H, d, Jϭ7.3 Hz, H-5), 8.52 (1H,
dd, Jϭ0.8, 8.3 Hz, H-10). 13C-NMR (CDCl3) d: 12.11, 32.39, 112.42,
119.74, 120.89, 121.77, 125.04, 125.26, 126.21, 126.90, 126.93, 127.35,
128.41, 128.69, 128.85, 129.04 (C2), 130.53, 130.94 (C2), 200.30. MS: m/z:
299 (Mϩ), 284. HR-MS m/z: Calcd for C21H17NO, 299.1310. Found:
299.1311.
10c: Yellow needles (acetone), mp 215—216 °C. IR (KBr) cmϪ1: 2191,
2162, 1629, 732. 1H-NMR (CDCl3) d: 5.62 (2H, s, CH2), 7.00 (1H, d,
Jϭ7.0 Hz, H-4), 7,18—7.26 (3H, m, H-3, Ph), 7.38—7.44 (3H, m, H–Ph),
7.65—7.72 (2H, m, H-5, 6), 7.80 (1H, dd, Jϭ1.0, 7.6 Hz, H-7), 9.13 (1H, d,
Jϭ8.6 Hz, H-8). 13C-NMR (CDCl3) d: 61.42, 115.60, 119.98, 126.15,
127.13, 128.36, 128.53, 128.97, 129.11, 129.42, 132.83 (C5), 133.89,
134.00, 134.63, 158.54. MS: m/z: 283 (Mϩ). Anal. Calcd for C, 80.54; N,
14.83; H, 4.63. Found: C, 80.61; N, 14.75; H, 4.91.
References
1) Tomisawa H., Tanbara T., Kato H., Hongo H., Fujita R., Heterocycles,
15, 277—280 (1981).
2) Iwao M., Kuraishi T., Bull. Chem. Soc. Jpn., 53, 297—298 (1980); Re-
view of synthesis of pyrrolo[2,1-a]isoquinolines: Uchida T., Matsu-
moto K., Synthesis, 1976, 209—236.
3) Ishibashi F., Miyazaki Y., Iwao M., Tetrahedron, 53, 5951—5962
(1997); Lindquist N., Fenical W., Van Duyne G. D., Clardy J., J. Org.
Chem., 53, 4570—4574 (1988); Carroll A. R., Bowden B. F., Coll J.
C., Aust. J. Chem., 46, 489—501 (1993).
4) Boekelheide V., Godfrey J. C., J. Am. Chem. Soc., 75, 3679—3685
(1953).
5) Huisgen R., Grashey R., Steingruber E., Tetrahedron Lett., 1963,
1441—1445; Kobayashi Y., Kumadaki I., Sekine Y., Kutsuma T.,
Chem. Pharm. Bull., 21, 1118—1123 (1973); Basketter N. S., Plunkett
A. O., J. Chem. Soc., Chem. Comm., 1973, 188—189.
6) Krohnke F., Zecher W., Chem. Ber., 95, 1128—1137 (1962).
7) Tomisawa H., Wang C. H., Chem. Pharm. Bull., 21, 2607—2612
(1973).
8) Tomisawa H., Saito K., Hongo H., Fujita R., Chem. Pharm. Bull., 18,
937—940 (1970); Tomisawa H., Fujita R., ibid., 21, 2585—2589
(1973); Tomisawa H., Fujita R., Hongo H., Kato H., ibid., 22, 2091—
2096 (1974).
10d: Yellow plates (acetone), mp 250 °C. IR (KBr) cmϪ1: 1733, 1716,
1655, 772. 1H-NMR (CDCl3) d: 2.65 (3H, s, COMe), 3.43 (3H, s, OMe),
5.55 (1H, d, Jϭ15.0 Hz, CH–Ph), 5.94 (1H, d, Jϭ15.0 Hz, CH–Ph), 7.25
(5H, s, H–Ph), 7.66 (1H, d, Jϭ7.1 Hz, H-4), 7.72—7.92 (4H, m, H-3, 5, 6,
7), 8.53 (1H, d, Jϭ8.4 Hz, H-8). 13C-NMR (CDCl3) d: 28.37, 49.65, 60.52,
122.06, 126.72, 128.92 (C2), 129.11 (C2), 129.31, 130.02, 130.84 (C2),
132.42, 134.02 (C2), 130.84, 136.56 (C2), 167.60, 190.13. MS m/z: 333
(Mϩ), 274, 260, 91. HR-MS m/z: Calcd for C21H19NO3, 333.1365. Found:
333.1378.
10e: Yellow plates (acetone), mp 190 °C. IR (CHCl3) cmϪ1: 1735, 1718,
1699, 1629, 772, 686. 1H-NMR (CDCl3) d: 2.17 (6H, s, COMeϫ2), 5.74
(2H, s, CH2), 7.30—7.35 (2H, m, H–Ph), 7.36—7.41 (3H, m, H–Ph), 7.71—
7.82 (2H, m, H-aromatic), 7.86—7.94 (3H, m, H-aromatic), 8.57 (1H, d,
Jϭ8.6 Hz, H-8). 13C-NMR (CDCl3) d: 29.65, 30.88, 60.42, 122.27, 126.84,
129.16 (C2), 129.43 (C3), 129.46, 132.28 (C2), 132.47, 134.17, 135.20,
136.70 (C2), 169.98, 196.22 ( C2). MS m/z: 317 (Mϩ), 274, 260, 232. HR-
MS m/z: Calcd for C21H19NO2, 317.1416. Found: 317.1387.
General Procedure for Reaction of 10a, d, e with Acetic Anhydride
A mixture of 10a (0.349 g, 1.0 mmol) and acetic anhydride (4 ml) was re-
fluxed for 4 h and concentrated in vavuo. The residue was dissolved in water
(5 ml), and the resulting solution was extracted with CHCl3. The organic
9) Barlin G. B., Benbow J. A., J. Chem. Soc. Perkin Trans. II., 1975,
298—302.