B(C6F5)3-catalyzed tandem protonation/deuteration and reduction of: In situ -formed enamines

Article abstract of DOI:10.1039/d1ob00316j

A highly efficient B(C6F5)3-catalyzed tandem protonation/deuteration and reduction of in situ-formed enamines in the presence of water and pinacolborane was developed. Regioselective β-deuteration of tertiary amines was achieved with high chemo- and regioselectivity. D2O was used as a readily available and cheap source of deuterium. Mechanistic studies indicated that B(C6F5)3 could activate water to promote the protonation and reduction of enamines. This journal is

Full text of DOI:10.1039/d1ob00316j

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B(C6F5)3-catalyzed tandem protonation/deutera-
tion and reduction of in situ-formed enamines†
Cite this: Org. Biomol. Chem., 2021,
19, 4032
Rongpei Wu and Ke Gao
*
Received 20th February 2021,
Accepted 13th April 2021
DOI: 10.1039/d1ob00316j
rsc.li/obc
A highly efficient B(C6F5)3-catalyzed tandem protonation/deutera- used for target-labelling pharmaceutical compounds.8 Beyond
tion and reduction of in situ-formed enamines in the presence of the transition-metal-catalysed β-deuteration of amines,9 Wasa
water and pinacolborane was developed. Regioselective has reported that B(C6F5) exhibits comparable reactivity to
β-deuteration of tertiary amines was achieved with high chemo- transition-metals in the β-amino deuteration of amines.
and regioselectivity. D2O was used as a readily available and cheap Acetone-d6 was used both as the deuterium source and the
source of deuterium. Mechanistic studies indicated that B(C6F5)3 solvent (Scheme 1b).10 However, the use of expensive deuter-
could activate water to promote the protonation and reduction of ium sources and harsh reaction conditions (150 °C) limits the
enamines.
practical application of this method.
To address these problems, we aimed to use tandem proto-
nation (deuteration) and reduction processes in the presence
of enamine to efficiently synthesize various tertiary amines or
β-deuterated tertiary amines. To realize this, B(C6F5)3 was
chosen as the catalyst as it can activate H2O/D2O11 to generate
acidic H/D+ and borenium anions, respectively (Scheme 1c).
The activation of the moieties is followed by protonation/deu-
teration of enamine to form borenium activated iminium,3f
which accelerated the reduction with pinacolborane to afford
The bulky Lewis acid B(C6F5)3 usually forms the acidic com-
ponent of a Frustrated Lewis Pair (FLP). It has been used as a
versatile catalyst for various metal-free reduction reactions,1
such as the reduction of carbonyl groups,2 imines,3 pyridines4
and enamines.5 Among them, the reduction of enamines pro-
vides an efficient method to synthesize various tertiary
amines, which are predominantly found in pharmaceuticals
and natural products.6 Erker and Repo have developed various
phosphine/borane (P/B) or amine/borane (N/B) intramolecular
FLP catalysts for the hydrogenation of enamine using H2 as
the reducing agent (Scheme 1a).5 However, the complexity of
the catalyst and the high pressure of hydrogen (2.5–60 bar)
required for the effective reduction of enamine limit the appli-
cation of the process. Reports on the use of commercially avail-
able B(C6F5)3 as the catalyst for the reduction of enamine are
scarce. To the best of our knowledge, only a few examples of
B(C6F5)3-catalyzed enamine reduction reactions have been
reported in the presence of diphenylsilane (an expensive
reagent) or diisopropylamine (used in an excess amount) as
reducing agents (Scheme 1a).7 Therefore, there are still chal-
lenges and there is room for a comprehensive study of
B(C6F5)3-catalyzed reduction of enamines.
Recently, regioselective deuteration of N-alkyl amines has
gained immense attention as the products can be potentially
College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei, P.R. China. E-mail: gaoke0001@mail.ccnu.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00316j
Scheme 1 Synthesis of tertiary amines using B(C6F5)3 as a catalyst.
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Table 2 Scope of the reaction: study of aminesa
the corresponding tertiary amines or β-deuterated amines.
Herein, we report the development of a simple and efficient
method for the reduction of enamines for the synthesis of
various tertiary amines using B(C6F5)3 as the catalyst under
mild conditions. Furthermore, the present protocol can be
potentially used to achieve regioselective β-deuteration of
amines in the presence of D2O, which is a readily available
and cheap deuterium source.
We initially chose phenylacetaldehyde 1a and pyrrolidine
2a as the model substrates. The corresponding enamine was
generated in situ and used in the next step without further
purification (reaction conditions: 4 Å molecular sieves (MS) in
CHCl3 for 5 h). The reduction reaction proceeded in the pres-
ence of B(C6F5)3 (5 mol%) and pinacolborane (2 equiv.) in
non-purified 1,2-dichloroethane (DCE) at 80 °C to afford the
reduced product phenylethylpyrrolidine 3aa in 89% yield
(Table 1, entry 1). Following this, various solvents were
screened to study the influence of solvents (entries 2–4). It was
observed that B(C6F5)3 exhibited better catalytic efficiency in
nonpolar solvents (hexane and toluene). Subsequently, we
studied various reducing agents for the reduction reaction.
Strong reducing agents such as the borane–trimethylamine
complex and NaBH4 promoted the reduction reaction to afford
3aa in lower yields (entries 5 and 6). In sharp contrast, in the
presence of diphenylsilane, 3aa was produced in significantly
low yield under the reaction conditions reported herein (entry
7).7a Various boron catalysts, such as BF3·OEt2 and BH3·SMe2
exhibited low catalytic efficiencies during the reduction reac-
tions (entries 8 and 9). The reaction could proceed in the
absence of B(C6F5)3, albeit in low yield (entry 10).
a Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), 4 Å MS (135 mg),
CHCl3 (0.4 mL), 5 h; HBpin (0.4 mmol), B(C6F5)3 (5 mol%), DCE
(0.8 mL), 80 °C, 6 h. b 8 mmol scale.
After optimizing the reaction conditions, we examined the
substrate scope of the amines. As shown in Table 2, cyclic
amines, such as pyrrolidine, piperidine, morpholine, and
indoline, reacted with 1a to afford the corresponding tertiary amines in good yields (3aa–3af). It is noteworthy that the reac-
tion with 1,2,3,4-tetrahydroquinoline could be performed on
multigram scale to afford 3ae in 77% yield. The reactions of
acyclic amines also proceeded efficiently to afford various ter-
tiary amines in good yields (3ag–3ar). Anilines bearing both
electron-donating and electron-withdrawing groups did not
Table 1 Optimization of B(C6F5)3-catalyzed reduction of in situ-formed
enaminea
significantly influence the reaction efficiency (3aj–3ao, 3ar).
Various functional groups, such as pyridyl (3ai), methoxy (3aj),
and halides (3al–3ao) were tolerated under the optimized reac-
tion conditions.
We next examined the substrate scope of the reaction using
various aldehydes (Table 3). Sterically hindered aldehydes,
such as 2-(o-tolyl)acetaldehyde and 2-mesitylacetaldehyde,
reacted with morpholine to afford 3bc and 3ic in 68% and
61% yields, respectively. The reaction of aldehydes with elec-
tron-donating groups afforded the corresponding products
with higher efficiency than did those bearing electron-with-
drawing groups (3dc–3hc). Functional groups such as methoxy
(3fc), bromo (3gc), and hydroxyl (3hc) groups were tolerated
under the optimized conditions. Notably, the reducible olefin
group also could be tolerated (3kc and 3mh). Aldehydes
bearing long chains underwent the reduction reaction,
affording 3lc and 3mh in 51% and 91% yields, respectively.
Entry
Catalyst
Reducing agent
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
BF3·OEt2
BH3·SMe2
—
HBpin
HBpin
HBpin
HBpin
BH3·NMe3
NaBH4
Ph2SiH2
HBpin
HBpin
HBpin
DCE
89
53
80
83
46
40
15
56
18
32
MeCN
Hexane
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
10
a Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), 4 Å MS (135 mg),
CHCl3 (0.4 mL), 5 h; HBpin (pinacolborane) (0.4 mmol), catalyst
(5 mol%), solvents (0.4 M), 80 °C, 6 h. b Determined by NMR using
1,1,2,2-tetrachloroethane as an internal standard.
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Table 3 Scope of the reaction: study of aldehydesa
C–H bonds. Aldehydes such as 2-mesitylacetaldehyde and
1-naphthylacetaldehyde could be efficiently deuterated at the
β-amino position (3ic-d and 3jc-d). Notably, this highly syn-
thetically relevant transformation could be used for regio-
selective deuterium-labelling of drug derivatives. For example,
the chlorcyclizine derivative 3at-d was synthesized in good
yield from 1-(4-chlorobenzhydryl)piperazine with phenylacetal-
dehyde 1a. Good deuterium incorporation was achieved at the
benzylic position. The reduction of a ranolazine based com-
pound with 1a afforded the deuterated compound 3au-d in
good yield. The percentage of deuterium incorporation was
determined to be 82%. The late-stage modification of paroxe-
tine afforded the deuterium-labelled product 3av-d in good
yield.
Table 4 β-Deuteration of aminesa
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), 4 Å MS (135 mg),
CHCl3 (0.4 mL), 0.5 h; HBpin (0.4 mmol), B(C6F5)3 (5 mol%), DCE
(0.8 mL), 80 °C, 10 h. b Enamine formation reaction was carried out at
r.t. for 5 h, and then 6 h for B(C6F5)3-catalyzed reduction.
2-Phenylpropionaldehyde
and
2,2-diphenylacetaldehyde
reacted with N-methylaniline to afford 3ns and 3os, respect-
ively, in good yields. An indole-based aldehyde was well toler-
ated to produce 3pc in 76% yield.
Encouraged by the above results, we next explored whether
the present protocol could be used for achieving regioselective
deuteration of amines. The standard reaction conditions were
modified to realize regioselective β-deuteration of amines in
the presence of 3 equiv. of D2O. Notably, a similar deuterium
incorporation ratio was obtained by using purified or in situ-
formed enamine 4. With the optimized reaction conditions in
hand, we explored the versatility of B(C6F5)3-catalyzed
β-deuteration reactions with a variety of aldehydes and amines
(Table 4). In particular, some commercially available drugs
were also suitable for regioselective β-deuteration. In most
cases, deuterium could be incorporated to good degrees
(70–87%). Both cyclic and acyclic amines reacted smoothly to
afford β-deuterated amines in good yields. Particularly, no aro-
matic C–H deuterium incorporation was observed (see 3aj-d
and 3ap-d), and only the β-deuteration on aliphatic C–H bonds
was achieved to a good degree. In contrast to Werner’s work on
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), 4 Å MS (135 mg),
CHCl3 (0.4 mL), 5 h; B(C6F5)3 (5 mol%), D2O (3 equiv.), DCE (0.8 mL)
for 20 min, HBpin (0.4 mmol), 80 °C, 3 h. The percentage of deutera-
tion is shown in parentheses. b 0.5 h for enamine formation at 0 °C.
To gain more insight into the reaction mechanism, we per-
B(C6F5)3-catalyzed deuteration on aromatic C–H bonds,11 our formed several control experiments (Scheme 2). The rate of
methods showed high regioselective deuteration on aliphatic reduction of enamine 4 decreased in the absence of water,
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Scheme 3 Proposed mechanism for B(C6F5)3-catalyzed β-deuteration
of amines.
pinacolborane) formed the di-deuterated iminium III. The
reduction of iminium III with HBpin with the aid of a base
and a borenium anion3f afforded the deuterated tertiary
amines and regenerated the catalyst.
Scheme 2 Mechanistic studies.
In summary, we have developed efficient B(C6F5)3-catalyzed
tandem protonation and reduction reactions of in situ-formed
enamines with water and pinacolborane under mild con-
ditions. The present protocol was applied to a wide variety of
amines and aldehydes to synthesize various tertiary amines. In
addition, the reaction also achieved β-deuteration of tertiary
amines with high regioselectivity and good degree of deuter-
ium incorporation with D2O, which is a readily available and
cheap source. This would provide an alternative protocol for
the synthesis of β-deuterated tertiary amines. Mechanistic
studies indicated that B(C6F5)3 could activate water to promote
the protonation and reduction of enamines.
affording 3aa in 33% yield (Scheme 2a). This result, coupled
with the results from β-deuteration experiments (Table 4), indi-
cates that water acts as the proton source. We also observed
that the rapid dehydrogenation of pinacolborane with water
afforded the boric acid pinacol ester. H2 was simultaneously
released during the process. These results prompted us to
investigate whether B(C6F5)3 could activate the boric acid
pinacol ester or H2 to promote the reduction reaction of
enamine.5 Thus, the reaction was performed in the presence
of the deuterated boric acid pinacol ester (DOBpin) under an
atmosphere of H2. However, the reaction did not proceed
under these reaction conditions (Scheme 2b). Thus, it was con-
firmed that H2 was not the reducing agent. Surprisingly, we
observed that H/D exchange could be achieved using DOBpin
as the proton source (Scheme 2c). This revealed that DOBpin
could potentially act as a proton source. We also observed
that 99% of the H/D exchange occurred at the α-position of
the amines in the presence of deuterated pinacolborane
(Scheme 2d). This indicated that the proton at the α-position
of the amine was derived from pinacolborane. In addition, no
deuterium incorporation was observed in the reaction of
3aa under the standard conditions. This result revealed
that the enamine unit is essential for the deuterium
incorporation.
Author contributions
R. W. performed the experiments and data analysis. K. G. con-
ceived the project and wrote the paper. R. W. and
K. G. contributed to the editing.
Conflicts of interest
There are no conflicts to declare.
Based on the above results, a putative mechanism was pro-
posed (Scheme 3). The equilibrium between B(C6F5)3 and D2O
resulted in the formation of the zwitterionic adduct I under
basic conditions (base = tertiary amines),12 initiating the cata-
Acknowledgements
lytic cycle. The nucleophilic attack by enamine on the acidic We thank the NNSFC (no. 21702071) and the Fundamental
D3O+ afforded the β-deuterated iminium II. The deuteroxide Research Funds for the Central Universities (no.
moiety assisted in deprotonating the substrate to afford the CCNU18QN012) for the financial support. The Program of
monodeuterated enamine. The secondary nucleophilic attack Introducing Talents of Discipline to Universities of China (111
of enamine on D3O+ or DOBpin (generated from D2O and program, B17019) is also acknowledged.
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