Organic Letters
Letter
C−O bond forming reactions, hydrosilylation, glycosylation,
and peptide synthesis.10,11 In contrast to the mild Lewis acidic
properties of boronic acids, the ability of boronic acids as mild
hydrogen bond donors has received limited attention in the
literature (Scheme 2).12 Specifically, the dual roles of both
hydrogen bonding and Lewis acid properties in a single
organoboronic system remain underdeveloped.
Table 1. Optimization Studies for the Reduction-Reductive
N-Alkylation of Quinoline
a
Scheme 2. Role of Boronic Acid in Organocatalysis
Entry
Deviation from above
Yield (%)
1
2
3
4
5
6
7
8
none
93%
b
with H2O
at 45 °C
at 80 °C
no catalyst
4 Å M.S.
cat.1
[23%, (20% of 1a′)]
10%
60%
2%
As part of our continuous efforts on metal-free reduction of
quinolines,13 we envisaged that boronic acid, a mild Lewis acid,
can catalyze the tandem reaction in which the quinoline is first
hydrogenated to a THQ that is subsequently reductively
alkylated by the aldehyde to provide the N-alkylated product.
Our optimization studies commenced with quinoline (1a), 4-
trifluoromethylbenzaldehyde (2g), Hantzsch ester (HE) (3.5
equiv), and 25 mol % of PhB(OH)2 (cat.1) in DCE at 60 °C.
Gratifyingly, after 12 h, the desired N-alkylated product 3g was
obtained in 72% yield, along with 27% intermediate hydro-
genated product THQ (1a′, Table 1, entry 7). To improve the
yield of desired product 3g, arylboronic acids with different
substituents (cat.1−7)14 were examined (entries 8−12).
Boronic acids cat.2 and cat.7 with electron-withdrawing
−CF3 and −F respectively have been found to be the best
catalysts for the current transformation with the product 3g
obtained in 93% yield in both cases (Table 1, entries 1 and
12). The yield of 3g was very similar in the presence of
molecular sieves (entry 6), whereas a decrease in the yield has
been observed in the presence of water15 (Table 1, entry 2).
Then, this reaction was compared to different hydrogen-bond
donors and Brønsted acids (Table 1, entries 16−21). When
−CF3 functionalized thiourea (cat.15) and squaramide
(cat.16) were used as the H-bond donor catalysts, product
3g was obtained in 81% and 74% yields respectively (Table 1,
entries 17 and 18). Silanol cat.18 has failed to catalyze the
transformation (Table 1, entry 20). Pentafluorobenzoic acid
and oxalic acid provided moderate to low yields (Table 1, entry
21). Furthermore, the aldehyde conversion to the N-alkylated
product was studied under the optimized conditions at
different time intervals. As shown in Figure S1 in the
aldehyde 2g is rapid (∼70% conversion in the first 2 h) after
which it required reaction for another 10 h for the complete
conversion of 2g.
93%
[72%, (27% of 1a′)]
80%
cat.3
9
cat.4
cat.5
cat.6
cat.7
cat.8
cat.10
cat.12
cat.14
cat.15
cat.16
cat.17
cat.18
85%
85%
80%
93%
12%, 80% of 1a′
72%
61%, 63% , 58%
7%
81%
74%
51%
0%
10
11
12
13
14
15
16
17
18
19
20
21
b
c
d
e
f
g
h
Brønsted acid
28%, 10%, 31%, 64%, 57%
a
Reaction conditions: 1a (0.5 mmol), 2g (0.5 mmol), catalyst (25
mol %), HE (1.75 mmol) in DCE (2 mL) at 60 °C for 12 h under air,
isolated yields. 5 equiv of H2O. With 4 Å M.S. With p-TsOH.
b
c
d
e
f
g
h
With PhCO2H. With TfOH. With C6F5CO2H. With oxalic acid.
selectivity of the present reductive protocol. With hetero-
aromatic aldehydes 2r and 2s, the desired products 3r and 3s
were formed in excellent yields (86% and 85% respectively). 1-
Napthaldehyde and 1-pyrene aldehyde also led to the products
3t and 3u efficiently (Scheme 3). Interestingly, poly-N-
alkylated THQ was also readily obtained under the present
reaction conditions to give 3am in 67% yield. It is noteworthy
that reaction of aliphatic aldehydes proceeded smoothly to
provide desired products 3aa−ad, including biologically
relevant N-methyltetrahydroquinoline motif. Besides alde-
hydes, aliphatic cyclic ketone 2ad was also amenable to this
method. Unfortunately, aromatic ketones were incompatible
with this process. Intriguingly, when 1,4-benzenedialdehyde
was used as an alkylating agent the bistetrahydroquinoline 3an
was obtained in notable selectivity. The current reductive N-
alkylation approach was also successfully utilized to synthesize
a lipoprotein receptor3d 3v (Scheme 3). Variously substituted
quinolines (1b−l) and N-heteroarene are also best-suited as
substrates under the reaction conditions, giving the desired
products 3ae−3al efficiently. Since the N-alkylated THQ motif
is found in various biologically and pharmaceutically relevant
Cat.2 has been chosen as the optimized catalyst to study the
substrate scope for the current protocol. The reaction has been
studied with a variety of aldehydes 2a−z, 2aa−ac and different
quinolines 1a−m (Scheme 3). The reaction of quinoline 1a
with benzaldehyde 2a−q bearing both electron-donating and
electron-withdrawing groups at various positions was per-
formed to obtain the desired N-benzylated THQs (3a−q) in
85−88% yields and 82−96% yields, respectively. Notably, the
retention of reducible functional groups (4-Cl, 4-CN, 4-CF3, 4-
CO2Me, 4-CCPh, 4-O-allyl, 4-OBn, 4-SMe, 3-Br, 2-NO2, 3-
Br) in the final products showcases the excellent chemo-
2438
Org. Lett. 2021, 23, 2437−2442