New synthesis of isoquinoline derivatives by reactions of 2-(2-methoxyethenyl)benzonitriles with organolithiums and lithium dialkylamides

Article abstract of DOI:10.1246/cl.2004.236

A simple and efficient synthesis of 1-alkyl(or aryl)isoquinoline and isoquinolin-1-amine derivatives based on intramolecular cyclization of 2-(2-methoxyethenyl)benzonitriles initiated by the addition of alkyl(or aryl)lithiums and lithium dialkylamides to the nitrile carbons, respectively, is described.

Full text of DOI:10.1246/cl.2004.236

2
36
Chemistry Letters Vol.33, No.3 (2004)
New Synthesis of Isoquinoline Derivatives by Reactions of 2-(2-Methoxyethenyl)benzonitriles
with Organolithiums and Lithium Dialkylamides
Ã
Kazuhiro Kobayashi, Taiyo Shiokawa, Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552
(Received November 17, 2003; CL-031110)
A simple and efficient synthesis of 1-alkyl(or aryl)isoquino-
line and isoquinolin-1-amine derivatives based on intramolecu-
lar cyclization of 2-(2-methoxyethenyl)benzonitriles initiated
by the addition of alkyl(or aryl)lithiums and lithium dialkyl-
amides to the nitrile carbons, respectively, is described.
Recently, we have described a new and efficient synthesis of
,4-disubstituted quinolines via a sequence of addition and intra-
2
molecular ring closure between o-isocyano-ꢀ-methoxystyrene
derivatives and organolithiums. In this paper, we wish to de-
1
Scheme 1.
scribe the results of our extensive investigation of this quinoline
synthesis, which provide a convenient method to prepare 1-
alkyl(or aryl)isoquinoline 2 and isoquinolin-1-amine derivatives
3
by reactions of 2-(2-methoxyethenyl)benzonitriles (o-cyano-
-methoxystyrenes) 1 with alkyl(or aryl)lithiums and lithium di-
alkylamides. Over recent years, development of new methods
ꢀ
2
for the preparation of isoquinolines, including isoquinolin-1-
3
amines, has attracted much attention due to their biological ac-
tivities.4
Scheme 2.
Scheme 3.
The starting nitriles 1 were readily prepared by treatment of
the respective 2-acylbenzonitriles, which were commercially
5
–8
available or readily available by the literature methods, with
(methoxymethylene)triphenylphosphoran in 1,2-dimethoxy-
ꢀ
ethane (DME) at 0 C.
We first investigated reactions of 2-(2-methoxy-1-phenyl-
ethenyl)benzonitrile (1a) (a mixture of E and Z isomers; ca.
1:1) with alkyl(or aryl)lithiums, and found that these reactions
resulted in the formation of 1-alkyl(or aryl)-4-phenylisoquino-
lines 2a–2e in good yields, as shown in Scheme 1. Thus, 2 equiv.
9
of the organolithiums were added to a solution of 1a in DME at
ꢀ
À78 C. After 10 min the mixture was warmed to room temper-
ature and stirring was continued for an additional 1 h at the same
temperature. The attack of organolithiums on the nitrile carbon
of 1a followed by ring closure proceeded smoothly. After usual
aqueous workup and purification using preparative TLC on silica
gel the desired isoquinolines were obtained. A similar sequence
between 4-methoxy-2-(2-methoxy-1-phenylethenyl)benzonitrile
Scheme 4.
(
1b) (a mixture of E and Z isomers; ca. 2:1) and phenyllithium
molecular ring closure sequence could be carried out using lithi-
um dialkylamides in the place of alkyl(or aryl)lithiums to afford
N,N-diakylisoquinolin-1-amines 3. Thus, according to the proce-
dure mentioned above for the preparation of 1-alkyl(or aryl)iso-
quinolines 2, 2-(2-methoxy-1-phenylethenyl)benzonitriles 1a
and 1b were allowed to react with lithium dialkylamides in
THF (instead of DME) to afford 3 in fair yields generally, as il-
lustrated in Scheme 4. The reaction using 4-methoxy-2-(2-me-
thoxy-1-phenylethenyl)benzonitrile (1b) also proved to give a
rather diminished yield of the desired product 3g. It should be
noted that attempts to obtain the expected isoquinolineamines
from the reactions of 1c and 1d with lithium piperidide were un-
also proceed and the desired isoquinoline derivative 2f could
be obtained but in rather diminished yield.
Conducting reactions of 2-(2-methoxyethenyl)benzonitrile
(E-1c) and 2-(2-methoxy-1-methylethenyl)benzonitrile (E-1d)
with phenyllithium, 1-phenylisoquinoline (2g) and 4-methyl-1-
phenylisoquinoline (2h) could be prepared in moderate to fair
yields, as shown in Scheme 2. The corresponding Z-isomers of
these starting nitriles proved to be less reactive to phenyllithium
in the present sequence giving poorer results than those using E-
isomers, as shown in Scheme 3.
Subsequently, we discovered that the same addition/intra-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.3 (2004)
237
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Scheme 5.
successful; an intractable mixture of products was obtained in
each case.
The pathway to isoquinoline derivatives 2 and 3 is outlined
in Scheme 5. Thus, the addition of a nucleophile to the nitrile
ꢀ
carbon of 1 at À78 C results in the formation of the nitrogen
3
anion intermediate 4. When the reaction temperature is raised
to room temperature, the attack of this anion at the ꢁ-carbon
atom of the methoxyvinyl moiety occurs to give the benzyl anion
5
. Subsequent loss of methoxide gives rise to the isoquinoline
derivatives 2 and 3. It is reasonable that the poorer results were
obtained in the cases of using 1b as the lower stability of the cor-
responding intermediate benzyl anions due to the methoxy sub-
stituent at the benzene nucleus is taken into consideration.
In summary, an efficient procedure for the preparation of
isoquinoline derivatives has been developed. It may offer the
4
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5
6
7
2
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9
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10 All new compounds gave satisfactory apectral and analytical
data. Physical data for compounds 2 and 3 follow. 2a: mp
ꢀ
11
ꢀ
141 C (lit., 131 C); 2b: Rf 0.54 (CH2Cl2); 2c: Rf 0.58 (5:1
ꢀ
(
3
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hexane-AcOEt); 2d: Rf 0.68 (CH2Cl2); 2e: mp 204–205 C;
ꢀ
ꢀ
ꢀ
12
2f: mp 108 C; 2g: mp 100–101 C; 2h: mp 77–78 C (lit.
ꢀ
mp 75–76 C); 3a: Rf 0.63 (2:1 hexane-AcOEt); 3b: Rf 0.71
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ꢀ
ꢀ
ꢀ
mp 133–134 C; 3f: mp 151–152 C; 3g: mp 136–137 C.
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Published on the web (Advance View) January 26, 2004; DOI 10.1246/cl.2004.236