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5153
acid present, entry 4, and the reductive amination of 2-pentanone
with weakly basic aniline, Entry 7.
R2
PEMB
O
O
R1
N
N
+
R2
R2
NH2
NH2
H
R1
R1
H
AcOH, RT
PEMB was very selective toward reductive amination over car-
bonyl reduction. Competitive reduction of the ketone or aldehyde
was not observed in any of the reactions except for entry 3 where
benzaldehyde reduction to benzyl alcohol was the sole product in
methanol. However, in the solvent-less reduction with PEMB, a
high yield (96%) of desired tertiary amine was produced. Using
PICB, Kikugawa et al. observed only a 48% yield of trialkylamine
in 24 h while using an excess of di-n-propylamine without solvent
and a 3% yield of amine and 77% benzyl alcohol with water as the
solvent.
The aldehyde reductive aminations using PEMB occurred quite
rapidly. For example, amination occurred in 2 h or less for benzal-
dehyde. For hexanal, the reductive amination without acetic acid
was complete within 5 min after the PEMB addition. Similar fast
reactions times have been observed with PICB and PYB in solvent.
The cyclohexanone aminations were typically complete at ambient
temperature within 1 h after the PEMB addition. For the reductive
aminations without solvent, PEMB performed considerably faster
than PICB. Kikugawa et al. reported reaction times of 3.5 and
15.5 h for entries 5 and 6, respectively. Presumably, the liquid state
of PEMB gives it a strong kinetic advantage over solid PICB in sol-
vent-less reductive aminations. Advantages of reductive amination
with neat PEMB are rapid reactions and high reactor utilization as
well as decreased amount of waste (solvent).
R3
R1
PEMB
R2
+
R3
AcOH, RT
H
Figure 1. Reductive amination of aldehydes and ketones.
(PYB) and 2-picoline borane (PICB) in reductive amination of alde-
hydes and ketones in methanol. DiMare et al. observed that reduc-
tive aminations with pyridine borane were significantly faster in
methanol than ethers or chlorinated hydrocarbon solvents. In addi-
tion, to support the ‘green chemistry mindset’,10 reductions were
conducted without solvent as a means to increase volume produc-
tivity and decrease solvent use. Previous reductive aminations
with PYB or STAB were conducted at 0.25–0.5 M concentration,
so a substantial increase in volume productivity can be achieved
by conducting reactions without solvent.11 The results of aldehyde
and ketone amination are listed in Table 1. Comparative literature
results for reductive amination with PICB8 and PYB12 are also
listed.
In the comparative literature examples using PICB and PYB, a
reagent ratio of 1:1:1 had been used for the carbonyl, amine, and
amine borane reagents. To further increase the economic advan-
tage of this process, the reagent ratio was aligned to use two of
the three hydrides available in PEMB, thus a 2:2:1 ratio for the car-
bonyl, amine and PEMB was successfully used in all examples. In
fact, in many reductions, 20–30% of the PEMB remained, which
would allow for a higher ratio of substrate to PEMB.
To demonstrate the scalability of using PEMB for reductive
aminations without solvent, we conducted 0.2 mol reductive ami-
nation of hexanal with aniline. A 93% yield of N-hexylaniline was
obtained after distillatitive removal of methyl borate and 5-
ethyl-2-methylpyridine.
Because acyclic and aromatic ketones, especially acetophenone,
only slowly undergo reductive amination, the reactions with 2-
pentanone and acetophenone were heated at 50 °C to increase
reaction rate. In contrast to PICB aminations of acetophenone with
benzyl amine, which took 72 h at ambient temperature (both neat
or in methanol), PEMB amination of acetophenone at 50 °C was
complete in 4 h (neat), and 62% complete in 1 h in methanol.
The reductive amination process generates water as a co-prod-
uct, therefore, the imine formation process could be inhibited in an
aqueous system, especially for ketones and amines with high water
solubility. In any event, reductive amination in water was demon-
strated by Kikugawa et al. using PICB, obtaining slightly lower
yields of amines from the aqueous system compared to reactions
Since carboxylic acid is beneficial for reductive amination, ace-
tic acid (2 equiv of acetic acid relative to the carbonyl compound)
was used in all reductions, except entry 4 with hexanal, which eas-
ily forms an imine. Most reactions were conducted at 20–25 °C by a
slow addition of PEMB to the stirred mixture of amine and car-
bonyl substrate under nitrogen. Several of the less reactive ketones
(entries 7, 8, and 9) were heated at 50 °C to increase reductive ami-
nation rate.
The reductive aminations with PEMB compare quite well with
the results of these other aromatic amine borane complexes. The
unoptimized yields were higher using PEMB than PYB in some
examples, notably, the neat reductive amination of benzaldehyde
with di-n-butylamine, entry 3, amination of hexanal without acetic
Table 1
Reductive amination of aldehydes and ketones; comparison of PEMB to 2-picoline borane and pyridine borane
Entry
Aldehyde or ketone/amine
pairs
Yielda w/ PEMB in MeOH
(%)
Yielda w/ PEMB neat
(%)
Yield w/ PICB in MeOH
(%)
Yield w/PICB neat
(%)
Yield w/ PYB in MeOH
(%)
1
2
3
Benzaldehyde/aniline
Benzaldehyde/benzylamine
Benzaldehyde/ di-n-
propylamine
72
87b
0d
80
95
76
NA
99
93c
96
92b
96
NA
48e
50f
4
5
6
Hexanal/aniline w/o AcOH
Cyclohexanone/aniline
Cyclohexanone/
92
94
82
95
73
77
94
78
91
92
93
71, 93c
96
83b
70b
benzylamine
7
8
9
2-Pentanone/aniline
2-Pentanone/benzylamine
Acetophenone/benzylamine
74
94
83
70
89
79
72
NA
63g
87
27
84
80
62h
10, 69c
a
GC yield.
b
c
d
e
f
Isolated as dialkylammonium acetate.
Ref. 4a, reaction in petroleum ether with acetic acid.
No reductive amination product, benzylalcohol generated.
24 h Reaction time with 3 equiv amine.
Di-n-butylamine.
Similar ketone.
Percent conversion in 1 h.
g
h