Angewandte
Communications
Chemie
of [{Rh(cod)Cl}2](2.5 mol%), AgBF4 (10 mol%), (R)-
BINAP (L1; 7 mol%), and Cs2CO3 (1.5 equiv), reaction
of 1a with phenylboronic acid (2a) in tetrahydrofuran
(THF) at an ambient temperature for 12 hours pro-
ceeded smoothly to give the dearomative arylation
product (S)-3aa in 49% yield and 93% ee (entry 1).
From the screening of added inorganic bases, it was
found that K3PO4·3H2O delivered the best result in
terms of enantioselectivity and yield (entry 3). Organic
bases such as NEt3 also gave good ee values for 3aa
(entry 5). Subsequent assessment of the solvent revealed
that the transformation was very sensitive to the reaction
medium. Toluene (entry 6) gave a slightly higher yield of
3aa with the same ee value compared to those obtained
in THF. Raising the reaction temperature has a strong
effect on the yield of 3aa, but with almost no effect on the
enantioselectivity. Performing the reaction at 458C afforded
3aa in 79% yield with 95% ee (entry 10). Further exploration
of other commercially available bis(phosphine) ligands
showed that, compared to the ee value of 3aa using (R)-
BINAP (L1) as the ligand, (S)-SegPhos (L2) also gave
a similar result (entry 12), while (R)-3,5-xylyl-BINAP (L3)
delivered a slightly lower ee value (entry 13). Recently,
palladium(II)-catalyzed additions of arylboronic acids to
imines have been achieved with great progress.[18] Hence,
[Pd(PhCN)2Cl2] (5 mol%), AgBF4 (10 mol%), and L1
(7 mol%) as the chiral catalytic system was also tried in the
nucleophilic addition of 1a to 2a, but only trace amounts of
3aa were obtained.
Scheme 1. Enantioselective nucleophilic addition to quinolinium salts.
challenge and in pursuit of asymmetric transformations of
organic boronic acids,[16] herein, we report a highly enantio-
selective rhodium-catalyzed nucleophilic addition of aryl and
alkenyl boronic acids to quinolinium salts, and its application
in the formal asymmetric synthesis of bioactive tetrahydro-
quinoline and in the total synthesis of the naturally occurring
tetrahydroquinolines.
To initiate the study, N-ethyl quinolinium iodide (1a) was
chosen as a model substrate for the rhodium-catalyzed
asymmetric nucleophilic addition[17] (Table 1). In the presence
Table 1: Optimization of reaction conditions.[a]
With these optimized reaction conditions in hand, we
turned our attention to the investigation of the scope with
respect to substituted quinolinium salts from easily available
quinolines, and the results are summarized in Table 2.
Generally speaking, the quinolinium salts 1, bearing various
substituent groups at different positions of the quinoline ring,
performed quite well in the reaction, thus affording the
desired products in high enantiomeric excess. It is noteworthy
that under the standard reaction conditions, the reaction of
the 2-substituted quinolinium salt 1b with 2a proceeded
smoothly to give the dihydroquinoline 3ba, having a chiral
tetrasubstituted carbon center, in 98% ee and 38% yield
(entry 1). A methyl group at the 2-, 3-, 4-, 6-, and 7-positions
in the quinoline ring had an effect on the ee value and yield of
corresponding dihydroquinoline for this rhodium(I)-cata-
lyzed nucleophilic addition (entries 1–3, 8 and 9). It seems
that a methyl group situated nearer to the reacting carbon
center led to the corresponding product in lower yield,
probably because of the suppression of nucleophilic addition
by steric hindrance. Given the easy deprotection of the N-
substituted group, the quinolinium salt 1k, prepared from the
reaction of quinoline and BnBr, was tested in this reaction to
afford the desired product 3ka in 69% yield and 85% ee.
Subsequently, various substituted arylboronic acids (2)
were also tested to demonstrate the generality of the
dearomative arylation. The results are summarized in
Table 3. Arylboronic acids bearing either an electron-donat-
ing or electron-withdrawing group led to the corresponding
dihydroquinolines in moderate to good yields and excellent
ee values. To further explore the scope of organic boronic
Entry Solvent
Base
T [8C] Ligand Yield [%][b] ee [%][c]
1
2
THF
THF
Cs2CO3
K2CO3
K3PO4·3H2O RT
KOtBu
NEt3
K3PO4·3H2O RT
K3PO4·3H2O RT
K3PO4·3H2O RT
RT
RT
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
49
45
54
50
51
56
44
47
54
79
60
78
67
93
40
3
THF
93
4
THF
RT
RT
90
86
5
THF
6
7
8
toluene
EtOH
DCM
93
69
55
73
95
94
9
1,4-dioxane K3PO4·3H2O RT
10
11
12
13
toluene
toluene
toluene
toluene
K3PO4·3H2O 45
K3PO4·3H2O 80
K3PO4·3H2O 45
K3PO4·3H2O 45
À95
88
[a] Reaction conditions: 1 (0.1 mmol), [{Rh(cod)Cl}2] (2.5 mol%), ligand
(7 mol%), AgBF4 (10 mol%), base (1.5 equiv), solvent (3 mL), 12 h.
[b] Yield of isolated product. [c] Determined by chiral-phase HPLC.
cod=1,5-cyclooctadiene, DCM=dichloromethane, THF=tetrahydro-
furan.
Angew. Chem. Int. Ed. 2016, 55, 3776 –3780
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3777