P. Bachu et al. / Tetrahedron Letters 54 (2013) 3977–3981
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Table 3
Molecular iodine catalyzed reduction of ketiminesa,b
2 (1.2 equiv)
I2 (10 mol%)
R''
R''
N
HN
CH2Cl2, rt, 24 h
R'
R'
9
10
OMe
OMe
HN
HN
HN
87%
82%
85%
Entry 2: 10b
Entry 3: 10c
Entry 1: 10a
OMe
OMe
OMe
HN
HN
HN
MeO
OMe
Cl
F
87%
81%
84%
Entry 6: 10f
Entry 5: 10e
Entry 4: 10d
OMe
OMe
HN
HN
HN
MeO
MeO
77%
87%
84%
Entry 7: 10g
Entry 8: 10h
Entry 9: 10i
a
All the reactions were performed using ketimine (0.10 mmol), Hantzsch ester (0.12 mmol) and
iodine (0.005 mmol) in solvent C = 0.1 M.
b
Isolated yield.
to yield the desired products in high yields (entries 3–7). Gratify-
ingly, ketimines bearing a relatively bulky R group, such as naph-
thyl and indanyl groups, were well tolerated (entries 8 and 9).
An aldimine derived from acetophenone and benzylamine did
not give the reduction product. Hence, use of N-aryl imine is
essential.11
method to prepare these biologically important compounds.5d
We therefore evaluated the utility of the iodine-catalyzed transfer
hydrogenation of quinoline 13, in view of the possibility of extend-
ing this method to the synthesis of tetrahydroquinolines. To our
delight, desired tetrahydroquinoline 14 was obtained in 97% yield
using 10 mol % of iodine and 2.1 equiv of Hantzsch ester 2 as the
hydrogen source after 24 h at room temperature (Scheme 2).
To further demonstrate the applicability and chemoselectivity
of this iodine catalyzed transfer hydrogenation method, we next
It should be noted that the present reduction of ketimines,
a-
investigated the reduction of
underwent reduction under the influence of 5% of I2 in the coexis-
tence of 1.2 equiv of Hantzsch ester at room temperature in dichlo-
a
-imino esters.
a
-Imino ester 15
imino esters, and quinoline proceeded smoothly at room tempera-
ture, in contrast to some of the previous reported reactions that re-
quired a higher temperature.6
romethane for 24 h to give corresponding
a
-amino ester 12b in
In order to exclude the possibility that the present reaction was
87% yield. A range of substituted imino esters were successfully re-
duced with remarkably high yields (Table 4). Aryl substrates next
to the imine carbon, having either electron-withdrawing or elec-
tron-donating functional group, were competent substrates (en-
tries 5, 7–10). On the other hand, replacing the PMP group on
the imine nitrogen with phenyl or other substituted arenes has
rather less significant impact on the yields of the products (entries
3 and 4). In the presence of aliphatic substituent, the reaction rate
was slightly reduced although the desired product was also ob-
tained in good isolated yields (entry 11).
catalyzed by HI generated in situ, a-imino ester 15 was treated
with iodine (5 mol %), sodium hydrogen carbonate (20 mol %),
and Hantzsch ester 2 (1.2 equiv) in dichloromethane at room tem-
perature under the optimized conditions. The reaction afforded a-
amino ester 12b in 76% yield, as expected (Scheme 3). This reaction
further underscored the potential of the proposed activation of
imine in the presence of molecular iodine as a mild Lewis acid, fol-
lowed by hydrogen transfer from Hantzsch ester 2 to result in de-
sired amine 12b.
In conclusion, we have developed an efficient and practical pro-
1,2,3,4-Tetrahydroquinolines are of great synthetic importance
in pharmaceuticals, agrochemicals, and natural products, particu-
larly in alkaloids as key structures.1d The regioselective reduction
of readily available quinoline derivatives is the most sought after
tocol for the reduction of aldimines, ketimines, and a-imino esters
in the presence of the catalytic amount of molecular iodine using
transfer hydrogenation at room temperature. This method is
equally effective for both cyclic and acyclic substrates. The simple