Chemistry Reference
In-Depth Information
based on direct C(sp
3
)-H bond activation adjacent to a nitrogen atom of
tetrahydroisoquinoline.
Three types of pronucleophiles were coupled with tetrahydroisoquinoline
in a stainless steel vial by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) as oxidant and silica gel as grinding auxiliary: (1) active methylene
(C(sp
3
)-C(sp
3
)), (2) terminal alkyne (C(sp
3
)-C(sp)), and (3) indole (C(sp
3
)-
aryl-C(sp
2
)). A series of tetrahydroisoquinoline derivatives were prepared
under ball milling conditions. In addition, milling frequency, milling time
and grinding auxiliaries were studied and the reaction results were com-
pared with the traditional solution-based reactions.
5.2.1 C(sp
3
)-C(sp
3
) Coupling Reaction
The work began with CDC reactions between tetrahydroisoquinolines and
nitroalkanes under ball milling conditions without additional metal catalyst.
Several 2-substituted tetrahydroisoquinolines and 6,7-dimethoxytetra-
hydroisoquinolines were tested, affording desired products with moderate to
good yields within 30 min (Table 5.1).
Comparative experiments were performed under stirring conditions by
using nitroalkanes as solvent - the corresponding reaction times were much
longer and most of the products yields were lower than that obtained under
milling condition. (Table 5.1, see in parentheses).
This method has been extended to the synthesis of 1-aminomethyl-tetra-
hydroquinoline, a key intermediate of the anti-schistosomiasis praziquantel,
14
by reduction and deprotection of the CDC product of 3d (Scheme 5.2). In
the classic E. Merck's synthetic process, this intermediate was synthesized
from isoquinoline using an excessive amount of highly toxic cyanide.
As a viable participant, malononitrile was reacted with 2-phenyltetrahydro-
isoquinoline, affording comparable yields under above solvent and metal-free
condition. When using N-acryloyl-6,7-dimethoxytetrahydroisoquinoline (1f)
as the pro-electrophile, DDQ should be added in portions and an extra
pause during the milling is needed to avoid side reactions induced by a high
concentration of the reactive iminiumion (Scheme 5.3).
Diethyl malonate was also available as pronucleophile to react with 1f under
intermittent milling conditions (Scheme 5.4). However, Cu(OAc)
2
or Cu(OTf)
2
should be used to promote the reaction, due to the relative lower reactivity of
malonates. Subsequent transformation by intramolecular Michael addition,
hydrolysis and decarboxylation gave 3m
00
as a member of the tetra-
hydrobenzo[a]quinolizidine system that can be found in various alkaloids.
15
5.2.2 C(sp
3
)-C(sp) Coupling Reaction
C(sp
3
)-H bond and C(sp)-H bond coupling reactions of tetra-
hydroisoquinolines and alkynes were performed under ball milling con-
ditions. Owing to the expected lower activity of terminal alkynes as
pronucleophiles, various catalytic amount of copper catalysts such as Cu(0),
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