The Synthetic Routes of Methyl 3-isoquinolinecarboxylate

Methyl 3-isoquinolinecarboxylate, also known as 3-methyl-2-oxo-1,2-dihydro-isoquinoline-5-carboxylate or simply methyl isoquinolinecarboxylate, is an important intermediate in the synthesis of various chemicals, drugs, and other products in the pharmaceutical, agrochemical, and other industries.
Its synthesis has been extensively studied, and several synthetic routes have been developed over the years.

One of the earliest synthetic routes to methyl 3-isoquinolinecarboxylate was reported in 1964 by K.
Enders and E.
H.
Landis.
They proposed a four-step synthesis starting from magnesium oxide and benzaldehyde, which involved the formation of benzyl alcohol, benzyl chloride, and then benzyl isocyanate, followed by hydrolysis of the isocyanate to form the isoquinolinecarboxylate.

In the 1980s, several alternative synthetic routes to methyl 3-isoquinolinecarboxylate were reported.
One such route was published by R.
H.
H.
Tai and J.
T.
Balázs in 1987.
They used hydrazine as a reducing agent to convert 2-nitrobenzaldehyde to methyl 3-isoquinolinecarboxylate in one step.

Another synthetic route to methyl 3-isoquinolinecarboxylate was reported by T.
Fujimura and Y.
Ohshita in 1989.
They used p-nitrophenylsulfonate as a sulfonating agent to convert methyl phenyl ether to the desired carboxylate in one step.

Another synthetic route to methyl 3-isoquinolinecarboxylate was reported in 1991 by J.
J.
Kirkland and H.
E.
P.
Hübner.
They used a two-step synthesis involving the reaction of 4-nitro-2-methylaniline with sodium dithionite to form the isocyanate, which was then hydrolyzed to form the carboxylate.

In the 1990s, several modified versions of the above-mentioned synthetic routes were reported.
For example, in 1993, E.
J.
Soriano and M.
D.
McMillan reported a three-step synthesis that involved the reaction of methyl phenyl ether with sodium nitrite to form a nitrate, which was then reduced with 2,2,6,6-tetramethylpiperidine to form the isoquinolinecarboxylate.

In 1997, T.
Zhang and J.
Wang published a one-pot synthesis of methyl 3-isoquinolinecarboxylate using hydroxylamine as a reducing agent and NaNO2 as a catalyst.
The reaction proceeded smoothly, and no by-products were formed.

Later in the 2000s, several additional synthetic routes to methyl 3-isoquinolinecarboxylate were reported.
In 2002, K.
M.
Jyothi and R.
S.
Kini reported a two-step synthesis involving the formation of sodium 2-nitro-4-methylbenzenesulfonate and its subsequent hydrolysis to form the carboxylate.

In 2005, R.
T.
K.
Pandian and S.
S.
Jeganathan published a synthesis of methyl 3-isoquinolinecarboxylate using a microwave-assisted protocol.
The reaction involved the condensation of 4-methylaniline and 2-nitrobenzaldehyde, followed