Novel synthesis of pyrrolo[2,1-a]-isoquinoline using the reaction of isoquinolinium salts with active methylene compounds

Article abstract of DOI:10.3987/COM-00-9115

2-Alkyl-1-methylthioisoquinolinium salts were easily prepared from 2-alkyl-1(2H)-isoquinolones via 2-alkyl-1(2H)-thioisoquinolones in two steps. Under mild conditions, the reaction of 2-alkyl-1-methylthioisoquinolinium salts with active methylene compounds in the presence of sodium hydride afforded 2-alkyl-1-(substituted methylene)isoquinolines in good yields. The cyclizationof 2-benzylisoquinolines using acetic anhydride produced the pyrrolo[2,1-a]isoquinolines. Further, the reaction of 1-chloro-2-phenacylisoquinolinium salt with active methylene compounds afforded the pyrrolo[2,1-a]isoquinolines in one pot.

Full text of DOI:10.3987/COM-00-9115

HETEROCYCLES, Vol. 55, No. 3, 2001, pp. 435 - 438, Received, 20th November, 2000
NOVEL SYNTHESIS OF PYRROLO[2,1-a]-
ISOQUINOLINE USING THE REACTION OF
ISOQUINOLINIUM SALTS WITH ACTIVE
METHYLENE COMPOUNDS
Reiko Fujita,* Noriyuki Watanabe, and Hiroshi Tomisawa
Tohoku Pharmaceutical University, 4-4-1, Aoba-ku, Komatsushima,
981-8558, Sendai, Japan
Abstract
2-Alkyl-1-methylthioisoquinolinium salts were easily
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-methylthioisoquin-
olinium salts with active methylene compounds in the presence of sodium hydride
afforded 2-alkyl-1-(substituted methylene)isoquinolines in good yields. The cycli-
zationof 2-benzylisoquinolines using acetic anhydride produced the pyrrolo[2,1-a]-
isoquinolines. Further, the reaction of 1-chloro-2-phenacylisoquinolinium salt with
active methylene compounds afforded the pyrrolo[2,1-a]isoquinolines in one pot.
Various methods for the synthesis of indolizine derivatives have been reported.1 Recently, Iwao et al.
reported the novel total synthesis of the marine alkaloid lamellarins containing the pyrrolo[2,1-a]iso-
quinoline skeleton (Scheme 1).2 Therefore, the functionalized pyrrolo[2,1-a]isoquinolines are very useful
synthetic intermediate for them. The conventional methods for preparing the substituted pyrrolo[2,1-a]
isoquinoline derivatives are a) Michael condensation of Reissert compounds,3 and b) 1,3- and 1,5-dipolar
cycloaddition reactions.4,5 In this communication, we report a novel method for the synthesis of a
pyrrolo[2,1-a]isoquinoline skeleton using the cyclization of 2-alkyl-1-(substituted methylene)isoquinolines,
which were easily prepared from the reaction of 2-alkyl-1-methylthioisoquinolinium iodides with active

methylene compounds such as dimethyl malonate, malononitrile, methyl cyanoacetate, and 1,3-cyclo-
hexanedione, and the cyclization of 1-chloro-2-phenacylisoquinolinium salt with active methylene
compounds using sodium hydride as a base.
RO
O
N
HO
O
RO
HO
R = Me lamellarin D
R = H
lamellarin H
OH
OR
Scheme 1
Reaction of 1-Methylthioisoquinolinium Salts with Active Methylene Compounds
First, the reaction of active methylene compounds with isoquinolinium salts having a methylthio group as a
leaving group at position-1 was examined under milder conditions in the presence of sodium hydride
(Scheme 2 and Table 1). 2-Methyl- and 2-benzyl-1(2H)-thioisoquinolone (3 and 4) were prepared from
2-methyl- and 2-benzyl-1(2H)-isoquinolones (1 and 2) in excellent yields. The reaction of thioisoquinolone
(3 and 4) with methyl iodide afforded 2-methyl- and 2-benzyl-1-methylthioisoquinolinium iodides (5 and
6) in 99 and 91% yields, respectively. The reaction of 2-methylisoquinolinium iodide (5) with straight-
chain active methylene compounds (7a-c) in the presence of sodium hydride for 1.5 h at room temperature
afforded 2-methyl-1-(substituted methylene)isoquinolines [8a (88%), 8b (81%), and 8c (85%)]. Further,
the reaction of 5 with cyclic active methylene compound (7d) at 90 ℃ for 6 h gave 2-methyl-1-(substituted
methylene)isoquinoline (8d) in 92% yield. Similarly, the reaction of 2-benzylisoquinolinium iodide with
7a-d produced 2-benzyl-1-(substituted methylene)isoquinolines [9a (95%), 9b (98%), 9c (99%), and 9d
(96%)]. Nuclear Overhauser and exchange spectroscopies of 8b and 9b showed that the methyl group
in the ester group correlated to the N-methyl or N-methylene group. Thus, the stereochemistries between
the ester and the N-substituted groups in 8b and 9b were suggested to be Z-form. This type of reaction
is regarded as a promising method for the carbon-carbon bond forming reaction at position-1 in the
P2S5
MeI, Acetone
reflux
N R
N R
N R
Pyridine
O
S
SMe I
3 : quant.
4 : 97%
5 : quant.
6 : 91%
1,2
X
CH2
( 7a-d )
Y
1 ; 3 ; 5 ; 8a-d : R = Me
2 ; 4 ; 6 ; 9a-d : R = CH Ph
2
N R
X
NaH
7a ; 8a ; 9a
7b ; 8b ; 9b
7c ; 8c ; 9c
7d ; 8d ; 9d
;
: X = COOMe
Y = COOMe
Y = CN
Y = CN
;
;
X = COOMe
:
Y
X = CN
:
8a-d,9a-d
X = COCH CH CH CO =Y
:
2
2
2
Scheme 2

Table 1. Reaction of Isoquinolinium Salt with Active Methylene Compounds
Entry
Temp.
Time
(h)
Solvent
X
Y
Product
Yield
(%)
(℃)
COOMe
CN
COOMe
COOMe
CN
1
2
3
4
5
6
7
8
rt
rt
1.5
1.5
1.5
6
THF
THF
THF
DMF
THF
THF
THF
DMF
8a
8b
8c
8d
9a
9b
9c
9d
88
81
85
92
rt
90
rt
CN
COCH2 CH2CH2CO
2
COOMe
CN
COOMe
COOMe
95
98
99
96
rt
2
rt
rt
2
2
CN
CN
COCH2 CH2CH2CO
isoquinoline ring. Next, we attempted cyclization of 2-benzyl compounds (9a-d) in acetic anhydride to
provide the pyrrolo[2,1-a]isoquinoline derivatives functionalized (Scheme 3). Heating of 9a-c in acetic
anhydride at 130 ℃ for 4 h afforded the corresponding pyrrolo[2,1-a]isoquinolines [10a (91%), 10b
(98%), and 10c (12%)]. Unfortunately, cyclization of 9d did not give pyrrolo[2,1-a]isoquinoline with
decomposition of 9d. Cyclization of 9a,b having the ester group smoothly proceeded to afford 10a,b.
Ac O
2
1
2
9a-c
N
;
;
;
R = COOMe 91%
10a : R = OCOMe
reflux
1
2
;
10b : R = OCOMe
R = CN
98%
12%
1
2
2
1
10c : R = NH
; R = COOH
;
2
R
R
10a-c
Scheme 3
Cyclization of 1-Chloroisoquinolinium Salt with Active Methylene Compounds
Moreover, cyclization of 2-phenacylisoquinolinium bromide (1 1) bearing the chloro group as a leaving
group at position-1 was examined (Scheme 4). Isoquinolinium salt (1 1) was easily prepared from
1-chloroisoquinoline with phenacyl bromide in the presence of potassium carbonate as a base in 70% yield.
The THF suspensions of isoquinolinium salt (1 1) and 7a-c in the presence of sodium hydride (2 eq)
refluxed for 5 h to give successfully the corresponding pyrrolo[2,1-a]isoquinolines functionalized [12a
(53%), 12b (51%), and 12c (50%)] in one step. The structures of all new compounds (5,6,8a-d,9a-d,
1
10a-c, and 12a-c) were confirmed by IR, H-NMR and MS spectral analyses.6)
In conclusion, a novel reaction of active methylene compounds with isoquinolinium salts having a
methylthio group as a leaving group at position-1 gave the 2-alkyl-1-(substituted methylene)isoquinolines
under mild condition in fairly good yields. Cyclization of 2-benzyl compounds having the ester group in
acetic anhydride produced the pyrrolo[2,1-a]isoquinolines in excellent yields. Moreover, reaction of 1-
chloro-2-phenacylisoquinolinium salt with active methylene compounds successfully afforded the pyrrolo-

[2,1-a]isoquinolines in one pot. Further applications and modifications of the methodology are in progress.
PhCOCH2 Br, K2CO3
EtO H, reflux, 4 d
7a-c,
NaH ( 2 eq )
CO
N
N
THF, reflux, 2 h
Cl
Cl
Br
11 : 70%
N
CO
12a
; R2 = COOMe ; 53%
; 51%
50%
: R1 = OH
12b : R1 = OH ; R2 = CN
: R1 = NH2
;
;
12c
R2 = CN
R1
12a-c
R2
Scheme 4
REFERENCES AND NOTES
1. M. Iwao, and T. Kuraishi, Bull. Chem. Soc. Jpn., 1980, 5 3, 297 ; Review for synthesis of
pyrrolo[2,1-a]isoquinolines : T. Uchida, and K. Matsumoto, Synthesis, 1976, 209.
2. F. Ishibashi, Y. Miyazaki, and M. Iwao, Tetrahedron, 1997, 5 3, 5951; N. Lindquist, W. Fenical,
G. D. Van Duyne, and J. Clardy, J. Org. Chem., 1988, 5 3, 4570; A. R. Carroll, B. F. Bowden,
and J. C. Coll, Aust. J. Chem., 1993, 4 6, 489.
3. V. Boekelheide, and J. C. Godfrey, J. Am. Chem. Soc., 1953, 7 5, 3679
4. R. Husgen, R. Grashey, and E. Steingruber, Tetrahedron Lett., 1963, 1441; Y. Kobayashi,
I. Kumadaki, Y. Sekine, and T. Kutsuma, Chem. Pharm. Bull., 1973, 2 1, 1118; N. S. Basketter,
and A. O. Plunkett, J. Chem. Soc., Chem. Comm., 1973, 188.
5. F. Krohnke, and W. Zecher, Chem. Ber., 1962, 9 5, 1128.
6. Representative data for 8a : yellow crystalline powder, mp 237-239 °C; IR (Nujol): 1720, 1600 cm-1;
1H-NMR (CDCl3)δ 3.56 (s, 6H), 4.15 ( s, 3H), 7.50-8.00 ( m, 5H), 8.35-8.60 (m, 1H); MS m/z: 273
(M+); Anal. Calcd for C15H12NO4 : C; 65.92; N, 5.13; H, 5.53. Found: C, 65.66; N, 5.40; H, 5.27.
9a: red plates, mp 239 °C; IR (Nujol): 1701, 1595, 758; 1H-NMR (CDCl3)δ3.63 (s, 6H), 5.72 ( s, 2
H ), 7.25 (dd, J =2.0, 6.6 Hz, 2H), 7.23 (s, 5H), 7.32-7.39 (m, 3H), 7.58 (d, J =7.0 Hz, 1H), 7.72-
7.88 (m, 4H), 8.60 (d, J= 8.2 Hz, 1H); MS m/z: 349 (M+); Anal. Calcd for C21H19NO4 : C; 72.19; N,
4.01; H, 5.48. Found: C,72.49; N, 3.80; H, 5.61. 10a: yellow needles, mp 165-166 °C; 1H-NMR
(CDCl3)δ2.25 (s, 3H), 3.95 ( s, 3H), 6.93 (d, J =7.4 Hz, 1H), 7.45-7.60 (m, 8H); MS m/z: 359 (M+)
; Anal. Calcd for C22H17NO4 :359.1158. Found: 359.1187. 12b: yellow crystalline powder, mp 219-
222 °C; IR (Nujol): 3187, 3136, 2217, 1665, 1609 cm-1; 1H-NMR (CDCl3)δ 6.98 (d, J =7.3 Hz, 1H),
7.55-7.71 (m, 8H), 7.93 ( d, J =7.3 Hz, 1H), 8.92-8.94 (m, 1H); MS m/z: 312 (M+); Anal. Calcd for
C15H12NO4 : 312.0899. Found: 312.0862.