Organic Letters
Letter
electron-rich 2-(4-tert-butylphenyl)-N-tosylaziridine (1b) and
the 3-fluoro variant of the 2-aryl-N-tosylaziridine 1c were
reacted with 2a under the optimized DROC conditions for 2 h,
the corresponding quinoline derivates 4b and 4c, respectively,
were obtained in very good yields with high diastereoselectiv-
ity. It is noteworthy that various organic compounds and drug
molecules with fluorine substituents can exhibit special
Scheme 5. Synthesis of Hexahydroimidazo[1,2-a]quinolines
yn-1-yl)anilines
19
biological properties. For further functionalization of the
products, halo-aryl substituted aziridines were studied. When
2
-(3-chlorophenyl)-N-tosylaziridine (1d) and 2-(3-bromo-
phenyl)-N-tosylaziridine (1e) were reacted with 2a under the
optimized DROC conditions, the corresponding products 4d
and 4e were obtained in very good yields with excellent
diastereoselectivity (Scheme 3).
To study the electronic effect of the N-arylsulfonyl group,
several 2-phenyl-N-arylsulfonylaziridines were investigated as
substrates. When aziridines bearing aryl groups with + I effect
such as 4-tert-butylphenyl (1f) and mesityl (1g) on the N-
sulfonyl group or aziridine 1h with a 4-methoxyphenyl group
on the sulfonamide nitrogen exerting a strong + R effect were
used, the corresponding products 4f−h were obtained in high
yields with high diastereoselectivity (up to 91:9 dr). The
transformation also effectively worked with aziridine 1i bearing
an electron-withdrawing 4-fluorophenylsulfonyl group on the
nitrogen to furnish the corresponding hexahydroimidazo[1,2-
a]quinoline derivative 4i in good yield with excellent
diastereoselectivity (94:6 dr). All of the results are summarized
in Scheme 4.
In order to increase the available sites for substructural
variation of the products, 4-chloro-N-(prop-2-yn-1-yl)aniline
(2d) was used as the functionalized nucleophile for the DROC
with 1a, and the desired product 4m was obtained in 62% yield
with 87:13 dr. Electron-rich 2-(p-tolyl)-N-tosylaziridine (1j)
also performed well, and in 4 h, the corresponding quinoline
product 4n was obtained in good yield with high dr. When 2-
(2-chlorophenyl)-N-tosylaziridine (1m) was used as the
substrate with 2d, within just 1 h, 4o was formed in 60%
yield with high diastereoselectivity. When 4-bromo-N-(prop-2-
yn-1-yl)aniline (2e) was reacted with 1a and 2-(2-fluorophen-
yl)-N-tosylaziridine (1l) separately under the DROC con-
ditions, the respective quinolines 4p and 4q were obtained in
good yields with high diastereoselectivities (87:13 and 86:14
dr). The structure of compound 4 was confirmed by the single-
crystal X-ray analysis of 4q as a representative example. The
relative stereochemistry of the 2-fluorophenyl group at carbon
Scheme 4. Synthesis of N-Arylsulfonyl-Substituted
Hexahydroimidazo[1,2-a]quinolines from 2-Phenyl-N-
arysulfonylaziridines and N-Propargylaniline
1
and the hydrogen at 3a carbon were found to be syn to each
18
other.
Finally, the strategy was extended for the synthesis of
nonracemic hexahydroimidazo[1,2-a]quinolines starting from
enantiopure (R)-2-phenyl-N-tosylaziridine, (R)-1a (>99% ee).
When (R)-1a was reacted with 2a under the DROC
conditions, the corresponding nonracemic hexahydroimidazo-
[
1,2-a]quinoline derivative (1S,3aR)-4a was obtained with
poor enantioselectivity (25% ee). The reduced ee of (1S,3aR)-
a was probably due to the partial racemization of the
4
20
enantiopure starting material (R)-1a during the reaction. To
enhance the enantioselectivity of the reaction, the ring-opening
To extend the scope of the strategy further, a wide range of
step was carried out in the presence of 20 mol % Zn(OTf) in
2
2
-aryl-N-tosylaziridines and 4-substituted N-(prop-2-yn-1-yl)-
toluene at room temperature. Upon complete consumption of
the starting aziridine, the temperature of the reaction was
elevated to 110 °C and in 2 h, (1S,3aR)-4a was obtained with
54% enantiomeric excess. Next, a milder Lewis acid, Yb(OTf)3,
was used (10 mol %) to effect the initial ring-opening of (R)-
1a in toluene at 80 °C followed by treatment of the reaction
anilines were subjected to the optimized DROC conditions.
The results are shown in Scheme 5. When N-(prop-2-yn-1-
yl)aniline (2b) was used with aziridines 1d and 2-(4-
chlorophenyl)-N-tosylaziridine (1k) in two separate sets of
experiments, the respective quinolines 4j and 4k were obtained
in very good yields with high diastereoselectivities. Similar
DROC of 4-fluoro-N-(prop-2-yn-1-yl)aniline (2c) with 1e for
mixture with 20 mol % Zn(OTf) at 110 °C for 2.5 h to obtain
2
the corresponding cyclized product in 57% yield with very
poor enantioselectivity (19%). Gratifyingly, when (R)-1a was
subjected to the ring-opening with 2a in the presence of 10
3
h gives the corresponding quinoline derivative 4l in 55%
yield with high diastereoselectivity (Scheme 5).
C
Org. Lett. XXXX, XXX, XXX−XXX
Bhattacharyya, Aditya
