Lithium bromide: an inexpensive and efficient catalyst for imine hydroboration with pinacolborane at room temperature

Article abstract of DOI:10.1039/d0ra06023b

An efficient protocol for the hydroboration of imines is reported. Lithium halide salts are effective catalysts to convert aldimines and ketimines to their corresponding amines. Here, we report excellent isolated yield of secondary amines (>95%) using 3 mol% lithium bromide in THF at room temperature. In addition, DFT calculations for a plausible reaction pathway are reported.

Full text of DOI:10.1039/d0ra06023b

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Lithium bromide: an inexpensive and efficient
catalyst for imine hydroboration with
pinacolborane at room temperature†
Cite this: RSC Adv., 2020, 10, 34421
*
Hanbi Kim, Hyun Tae Kim, Ji Hye Lee,
Hyonseok Hwang
and Duk Keun An
Received 10th July 2020
Accepted 7th September 2020
An efficient protocol for the hydroboration of imines is reported. Lithium halide salts are effective catalysts
to convert aldimines and ketimines to their corresponding amines. Here, we report excellent isolated yield
of secondary amines (>95%) using 3 mol% lithium bromide in THF at room temperature. In addition, DFT
calculations for a plausible reaction pathway are reported.
DOI: 10.1039/d0ra06023b
rsc.li/rsc-advances
or water. The method provided good yields for aliphatic imines,
while aniline derived imines (electron decient substituents)
Introduction
were highly ineffective. The dehydrocoupling of pinacolborane
with additives is the major issue in this protocol.12
Thus, methods that achieve efficient hydroboration using
sustainable protocols are necessitated.
The hydroboration reaction was rst reported in 1956 by H. C.
Brown and co-workers.1 Thereaer, numerous alcohols and
amines have been synthesized through hydroboration/
borohydride reduction of carbonyls, imines and unsaturated
hydrocarbons using boron hydride reagents such as NaBH4 and
LiBH4.2
Amines are ubiquitous functional groups; they are found in
many natural products and are used as building blocks for the
production of agrochemicals, pharmaceuticals, polymers, and
dyes.3 Therefore, the synthesis of amines and their derivatives
has gained signicant attention in chemistry and biology.
Catalytic hydroboration of imines is a simple and straight-
forward method for the preparation of amines, unlike conven-
tional hydrogenation reactions and stoichiometric reductions,
which are carried out at high pressure and temperature.4 Several
catalytic systems for imine hydroboration have been reported,
including the use of transition metals (e.g., Ti, Co, Ni, Ru),5 rare-
earth metal complexes (Er, Y, Dy, Gd),6 an actinide group metal
(Th),7 main group metals (Li, Na, Mg, Al, etc.),8 non-metals (P,
B),9 and frustrated Lewis pairs.10
Recently, the hydroboration of imines has also been realized
under catalyst-free conditions. In 2019, Pandey et al. reported
the catalyst-free, solvent-free hydroboration of imines using
pinacolborane (HBpin).11 However, although this method
provided amines from aldimines in good to reasonable yields,
the hydroboration of ketimines proceeded with lower yields,
even under high temperatures and prolonged reaction times.
Speed et al. reported hydroboration of ketimines promoted
by stoichiometric amounts of protic additives such as alcohols
Recently, our group reported that Li+ salts13 are superior and
effective catalysts for the hydroboration of carbonyl
compounds.14 Prompted by those results, we decided to extend
the methodology to the hydroboration of other functional
groups. Herein, we report an economical method for the
hydroboration of imines with pinacolborane and LiBr under
mild conditions to afford excellent yields of secondary amines
from both aldimines and ketimines (Scheme 1).
Results and discussion
First, we investigated the hydroboration of N-benzylideneani-
line with pinacolborane using various Li, Na, and K metal
halide salts in THF at room temperature (Table 1). The Li+
salts—LiCl, LiBr, and LiI showed superior catalytic activity aer
30 min reaction time (entries 2–4). Among these salts, LiBr was
chosen as the catalyst for further optimization because of its
easy availability and cost-effectiveness.
Moreover, further optimization of the reaction conditions
was conducted by adjusting the catalyst loading, pinacolborane
stoichiometry, type of solvent, and reaction time. The results are
summarized in Table 2. When hydroboration was carried out in
the absence of a catalyst, only 24% yield of the desired product
Department of Chemistry, Kangwon National University, Institute for Molecular
Science and Fusion Technology, Chunchon, 24341, Republic of Korea. E-mail:
dkan@kangwon.ac.kr
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra06023b
Scheme 1 Catalytic hydroboration of imines using LiBr as the catalyst.
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Table 1 Catalyst study for the hydroboration of N-benzylideneaniline
conducted hydroboration of imine in wet THF (trace amounts of
water/tBuOH with THF respectively under catalyst-free condi-
tion). A similar result (lower conversions) was observed from
aniline derived imines as suggested by Speed et al. Conse-
quently, the optimal reaction conditions for the hydroboration
of N-benzylideneaniline was determined to be 3.0 mol% of LiBr,
1.5 equiv. of HBpin in THF with a reaction time of 1 h (entry 6).
Furthermore, the substrate scope was extended to aldimines
1b–o (Table 3). We were pleased to observe that all aldimines
tested underwent smooth hydroboration to afford the corre-
sponding amines in excellent yield (2b–k). The reaction was
equally efficient with aldimines bearing electron-withdrawing
substituents (1d, and 1h–k) and electron-donating substitu-
ents (1b, 1c, and 1e–g). Furthermore, polyaromatic imines 1l
and 1m underwent hydroboration to afford the respective
amines 2l and 2m in excellent yield. Although pyrenyl imine 1m
required a 3 h reaction time for complete conversion, it afforded
amine 2m in 97% isolated yield. In addition, the hydroboration
of heteroaromatic imine 1n and aliphatic imine 1o proceeded
smoothly, affording the respective amines 2n and 2o in excel-
lent yield.
Entity
Cat
Time
Yielda (%) (imine/amine)
1
2
3
4
5
6
7
8
LiF
1 h
48/37 (15)
0/99
0/99
LiCl
LiBr
Lil
NaF
Nacl
NaBr
Nal
KF
30 min
30 min
30 min
1 h
1 h
1 h
1 h
1 h
1 h
1 h
0/99
51/45 (4)
52/39 (7)
66/30 (4)
4/96
47/38 (15)
55/28 (15)
77/18 (3)
33/50 (16)
9
10
11
12
KCl
KBr
Kl
1 h
a
Yields were determined by GC. The values in parenthesis belong to
those for aldehyde.
Next, the hydroboration of ketimines was investigated using
N-(1-phenylethylidene)aniline (Table 4). We observed that 20%
of the starting imine remained unreacted (entry 1, Table 4), and
increasing the reaction time from 1 to 3 h showed only
a marginal improvement in the conversion with 1.5 equiv. of
HBpin (entry 2). Finally, with 2.0 equiv. of HBpin and 3 mol%
LiBr, the ketimine underwent hydroboration smoothly to afford
the desired product in 99% yield over 30 min reaction time
(entry 4, Table 4).
Next, the substrate scope was extended to a range of keti-
mines (3b–l). Substrates bearing electron-withdrawing groups,
e.g. 4-bromo (3d and 3g) and 4-nitro (3h), and electron-donating
substitutions, e.g. 4-methyl (3b and 3e) and 4-methoxy (3c and
3f), afforded their corresponding amines in excellent yield,
(N-benzylaniline) was afforded aer 1 h (entry 1, Table 2). As
expected, a dramatic improvement was observed in the pres-
ence of LiBr (3.0 mol%), affording quantitative conversion to
the product (entry 6). Only moderate conversions were achieved
with a reduced catalyst loading (entry 2), lower stoichiometries
of pinacolborane (entries 3 and 4) and a shorter reaction time
(entry 5). Next, the reaction was optimized in various solvent
systems including n-hexane, toluene, diethyl ether, and
dichloromethane (entries 7–10). Both diethyl ether and
dichloromethane afforded yield comparable to THF, whereas
the reaction performed poorly in n-hexane and toluene. We also
Table 2 Reaction conditions for the hydroboration of aldimine with pinacolborane and LiBr
Entry
LiBr (mol%)
Pinacolborane (equiv.)
Solvent (0.5 ml)
Time
Yielda (%) (S. M/product)
1
2
3
4
5
6
7
8
9
10
none
1.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
1.5
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
THF
THF
THF
THF
THF
THF
Hexane
Toluene
Ether
MC
1 h
1 h
1 h
3 h
30 min
1 h
1 h
1 h
1 h
71/24 (2)
45/56 (2)
16/76 (8)
21/73 (4)
13/82 (2)
0/100
86/7 (4)
52/40 (4)
1/95
1 h
6/87 (1)
a
Yields were determined by GC. The values in parenthesis belong to those for aldehyde.
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Table 3 Substrate scope for the catalytic hydroboration of aldimines with pinacolborane and LiBra
a
Isolated yields aer column chromatography. b Reaction time: 3 h.
although the ketimines bearing a 4-methoxy substituent decomposition of HBpin to B2(pin)3 during the reduction (11B
required 3.0 equiv. of HBpin for complete conversion. Similarly, NMR of crude reaction, refer S62 in ESI†) which was observed
3.0 equiv. of HBpin was required to convert polyaromatic (3i) comparatively more in ketamine hydroboration.
and sterically hindered imines (3j–k) to the desired amines (4i–
Finally, we investigated the chemoselectivity of our protocol.
k) in high yield. However, dihydronaphthalene imine 3l Accordingly, N-benzylideneaniline was treated with 3.0 equiv. of
underwent smooth hydroboration to afford the corresponding HBpin and 3 mol% LiBr in the presence of other reducible
amine 4l in 97% yield with 2.0 equiv. of pinacolborane (Table 5). functional groups, such as esters and amides as well as nitrile,
The use of excess HBpin in the reaction is mainly due to the alkene, alkyne, alkyl halide, and epoxide moieties (Table 6). In
Table 4 Optimization of reaction conditions for ketamine hydroboration
Entry
LiBr (mol%)
Pinacolborane (equiv.)
Time
Yielda (%) (S. M/product)
1
2
3
4
3.0
3.0
3.0
3.0
1.5
2.0
1 h
3 h
10 min
30 min
20/79
14/83
18/82
0/99
a
Yields were determined by GC.
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Table 5 Catalytic hydroboration of ketimines with LiBra
a
b
Isolated yields aer silica column chromatography. HBpin: 3.0 equiv.
all cases, our protocol exhibited high chemoselectivity toward and ketamine (5b) proceeded selective hydroboration with
imine hydroboration and excellent yield. 3 mol% LiBr to afford desired amines 6a and 6b in 98% and
In addition, intramolecular hydroboration of imines was 97% yield, respectively, by leaving the ester group unreacted
analyzed in the presence of an ester group. Both aldimine (5a) (Scheme 3).
Table 6 Chemoselective catalytic hydroboration of imines over various functional groups
Yielda (%)
Entry
1
Imine
Substrate 1
Substrate 2
Imine (S. M/product)
Substrate 1 (S. M/product)
97/0
Substrate 2 (S. M/product)
98/0
0/98
2
0/99
96/0
95/0
3
4
0/99
0/99
99/0
99/0
99/0
97/0
5
5/92
99/0
95/0
a
Yields were determined by GC.
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Scheme 2 Free energy profile (in kcal molÀ1) for LiBr catalyzed hydroboration of aldimine (PhHCNPh).
Scheme
3 Chemoselective catalytic hydroboration from intra-
molecular compounds.
The reaction pathway for LiBr catalyzed hydroboration of
aldimine (PhHCNPh) was explored using density functional
theory (DFT) calculations at the M06-2X/6-31+G(d,p) level of
theory. The electronic energy prole for the reaction pathway is
illustrated in Scheme 2. The mechanism was predicted based
on recent work done by Thomas15 et al., Clark16 et al., and
Wuesthoff17 et al. Accordingly, HBpin undergoes reaction with
LiBr catalyst initially to produce the hydridoborate intermediate
INT1.15,16 The subsequent reaction of the INT1 with aldimine
generates the INT2 which turns into the INT3 through a hexag-
onal ring transition state TS1. INT3 then undergoes a unim-
Scheme 4 A plausible mechanism based on the energy profiles shown
in Scheme 2. Coordinates for the intermediate and transition state
structures are provided in ESI.†
Conclusions
olecular transformation into the INT4 through
a four-
We demonstrated that LiBr, an inexpensive, mild, and stable
reagent, efficiently catalyzes the hydroboration of imines at
room temperature. Various imines (aldimines and ketimines)
successfully underwent hydroboration with HBpin in the
membered ring transition state TS2. Upon the reaction of
INT4 with HBpin via ligand exchange, providing desired
substrate dioxolan amine with regeneration of INT1 for the next
catalytic cycle (Scheme 4).
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presence of 3 mol% LiBr to afford the desired amines in
excellent yield. Furthermore, we demonstrated the high che-
moselectivity of our protocol. DFT calculations for a plausible
reaction pathway are reported. The proposed method involving
the use of a very mild and easy-to-handle catalyst (LiBr) is
a potential, industrially viable protocol for the preparation of
secondary amines through the hydroboration of imines.
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There are no conicts to declare.
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Acknowledgements
This study was supported by the National Research Foundation
of Korea Grant funded by the Korean Government
(2017R1D1A1B03035412
for
D.
K.
An
and
2020R1I1A1A01073381 for J. H. Lee).
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