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RSC Advances
Page 3 of 5
DOI: 10.1039/C5RA21304E
Journal Name
COMMUNICATION
100 oC. bIsolated yield. cHCHO is formaldehyde solution. dNR: no
various substrates (1a-1t) were employed in the reaction. Electron-
withdrawing substituents such as 7-chloro (3a), 5-chloro (3b), 8-
chloro (3c), 7-fluoro (3d), 4-chloro-7-fluoro (3e), 6-bromo (3f), 8-
bromo (3g), and electron-donating substituents such as 6-methoxy
(3i), 8-methoxy (3j) were all well tolerated in the present reaction
condition to afford the desired 2-vinylquinolines. Among them, the
isolated yield of 8-bromo (3g) was the lowest which is 65%, but was
still quite acceptable. When both position 6 or position 8 and
position 2 were modified with methyl group, the methylene was
only introduced to the methyl group at position 2 to produce 3k
and 3i. The regioselectivity reminds us the importance of the
inductive effect of nitrogen atom. Besides, when 3-methylquinoline,
4-methylquinoline and 7-methylquinoline were used as substrates,
no desired products (3n-3p) were detected. However, their reaction
results were different that no reaction happened when either 3-
methyl or 7-methyl was used, but product of Mannich reaction
could be isolated when 4-methylquinoline was used. In contrast,
when 1-methylisoquinoline whose methyl group and nitrogen atom
have switched place was used in the reaction, the desired product
3q was still obtained in high isolated yield. These results indicate
that the relationship between the relative positions of methyl group
and nitrogen atom could affect the inducing effect of nitrogen
atom. Interestingly, different from other substitutes at position 8, 8-
hydroxyl failed to undergo the deamination reaction, which may be
owing to the interference from the hydroxyl to the electron transfer
of the adjacent nitrogen atom by hydrogen-bonding interaction. In
order to further extend the scope of the deamination reaction, 2-
methylquinoxaline, 2-methylbenzothiazole, and 2-ethylquinoline
were also evaluated as substrates, and they all provided their
corresponding products under the optimized condition in
acceptable yields (3r-3t).
desired products isolated. eMB: Only Mannich reaction happened.
In order to investigate the precise mechanism for the direct
deamination reaction happening instead of common Mannich
reaction, control experiments were performed. When the substrate
are 1-acetonaphthone and acetophenone, whose structures are
similar as 2-methyquinoline, the major products become Mannich
base 4u and 4v and only 15% and 13% vinyl products were obtained
respectively under the optimized condition (Scheme 2). The
reaction difference between 1-acetonaphthone, acetophenone and
2-methylquinoline reflects the substrate selectivity of the direct
deamination reaction and provides important clues for the
mechanism study. It indicated that not all the Mannich base was
able to be directly converted to the product of deamination
reaction in such a high yield and high rate, as mentioned in previous
reports.8 The participation of neighbouring nitrogen atom was
important for the direct deamination reaction.
Scheme 2. Reactions between 2-acetonaphthone, formaldehyde
solution and diethylamine hydrochloride
Based on the experimental results above, we proposed that the
Table 3. Substrate Scope of 1a
deamination reaction occurs through
a six-membered ring
intermediate 7 as shown in Scheme 3. First, Mannich base 4 was
formed through Mannich reaction among the enamine tautomer 5
of 2-methylquinoline 1, formaldehyde solution and diethylamine
hydrochloride. Then, unprotonated form of intermediate 6, which is
isomer of Mannich base 4, was generated after the addition of
base, followed by instantaneous hydrogen transfer to finally
produce the stable 2-vinylquinoline 3. Because the hydrogen
transfer provides an extra conjugated double bond to stabilize the
structure, the equilibrium tends to the direction of deamination
instead of providing Mannich base. And according to the
mechanism we proposed, protonated nitrogen atom is unable to
interact with the hydrogen atom of the enamine, therefore only
Mannich base was obtained when acid was added (Table 1, entries
20, 21) and significantly lower yield was obtained when no base was
added (Table 1, entry 1).
In conclusion, we have developed a simple catalyst-free method
for the synthesis of 2-vinylquinolines via direct deamination
reaction during Mannich synthesis. Although the procedure of this
one-pot synthesis is analogous to the classical Mannich reaction, by
suitable choice of substrates and optimization of reaction
conditions, the vinyl product instead of Mannich base is the direct
product isolated from the process. The substrate scope is pretty
wide that a series of 2-vinylquinolines could be obtained from
aReaction conditions: 1a-1t (0.5 mmol), HCHO (0.65 mmol),
diethylamine hydrochloride (0.65 mmol) react in dioxane (1 ml) at
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