Trimethyl Borate-Catalyzed, Solvent-Free Reductive Amination

Article abstract of DOI:10.1021/acs.joc.0c02143

Solvent-free reductive amination of aldehydes and ketones with aliphatic and aromatic amines in high-to-excellent yields has been achieved with sub-stoichiometric trimethyl borate as promoter and ammonia borane as reductant.

Full text of DOI:10.1021/acs.joc.0c02143

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Trimethyl Borate-Catalyzed, Solvent-Free Reductive Amination
P. Veeraraghavan Ramachandran,* Shivani Choudhary, and Aman Singh
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ABSTRACT: Solvent-free reductive amination of aldehydes and
ketones with aliphatic and aromatic amines in high-to-excellent
yields has been achieved with sub-stoichiometric trimethyl borate as
promoter and ammonia borane as reductant.
Scheme 1
eductive amination of carbonyls (reductive alkylation of
Ramines), the one-pot reaction of aldehydes or ketones
with amines in the presence of a reducing agent, is one of the
key reactions in organic chemistry with myriad applications for
the synthesis of simple and complex bioactive molecules.1
Several borohydrides, such as sodium,2 zinc,3 or lithium
borohydride,4 tetrabutylammonium5 or sodium cyanoborohy-
dride (NaBH3CN),6,7 and sodium triacetoxyborohydride
(NaBH(OAc)3),8 as well as catalytic hydrogenation9 have
been utilized for the reduction step. However, most of these
procedures suffer from drawbacks. For example, NaBH3CN
produces toxic and volatile hydrogen cyanide byproducts,
NaBH(OAc)3 fails to aminate aromatic ketones,10 and
hydrogenation is not chemoselective.
Another class of reducing agents that is routinely utilized for
reductive amination is amine boranes, such as pyridine-
borane,11−13 2-picoline-borane,14,15 dimethylamine-borane,16
N-isopropyl-N-methyl-tert-butylamine-borane,17 5-ethyl-2-
methylpyridine-borane,18 and benzylamine-borane.19 With
these reagents, an equivalent of the amine from the reductant
remains in the product mixture, necessitating their difficult
separation from the desired product amine. This inconven-
ience was overcome using a protocol involving ammonia
borane (AB, 1) as the reductant, with ammonia as the
byproduct, achieving the synthesis of primary-, secondary-, and
tertiary-amines.20 Nevertheless, the use of an equivalent of
toxic, air- and moisture-sensitive titanium isopropoxide (Ti(O-
i-Pr)4)21 as the Lewis acid made the process still unfavorable.
Aiming for a greener protocol, the project was revisited, which
resulted in a solvent-free, catalytic, green reductive amination
with 1 (Scheme 1). The details follow.
the reductant.22 Other Lewis acids employed to promote
imination include Ti(OiPr)4,2,23 Mg(ClO4)2,24 ZnCl2,25
LiClO4,16,26 TiCl4,27 Bu2SnCl2,28 etc.
Optimization trials (for summary: see Table S1, Supporting
Information) were begun by examining acetic acid and boric
acid for the reductive amination of benzaldehyde (2a) with
benzylamine (3a) using 1 in methanol, the common solvent
for such reductive aminations.18 The reaction, monitored by
thin layer chromatography (TLC) for the disappearance of 3a,
was complete in 4 h, and the product dibenzylamine (4aa)29
was obtained in 49% (AcOH) and 59% (B(OH)3) yields,
respectively. Following the literature,14 water or a mixture of
methanol−water was also verified as solvents. However,
A successful reductive amination relies on a rapid imine
formation and selective reduction. Recent reductive amination
literature contains numerous protocols examining various
Lewis/Bronsted acids for the initial “carbonyl imination”
step. For example, acetic acid has been used as the promoter
when 2-picoline-borane was used as the reductant22 and boric
acid has been utilized when sodium borohydride was used as
Received: September 4, 2020
Published: February 19, 2021
https://dx.doi.org/10.1021/acs.joc.0c02143
© 2021 American Chemical Society
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contrary to high yields from a similar solvent system for 2-
picoline-borane as the reductant, very low yields (16−39%)
were noticed.14 On the basis of a recent reductive amination
using borane and borohydride reagents in “greener” solvents,30
ethyl acetate was examined, which resulted in no product
formation. Having failed to improve the yields, we decided to
examine trimethyl borate as a promoter due to its ease of
handling compared to boric acid, which has to be ground with
the aldehyde.28 Thus, a reductive amination of 2a with 3a was
carried out, under neat conditions, with an equivalent each of
trimethyl borate and 1, when 4aa was obtained in 65% yield.
Cognizant of the fact that water generated during the imine
formation could hydrolyze trimethyl borate to boric acid and
methanol, the above reaction was performed in methanol and a
similar yield (65%) of 4aa was obtained. Consequently, the
role of trimethyl borate on the reaction was scrutinized under
neat conditions. Increasing the measure of trimethyl borate to
2 equiv provided a modest increase in the yield to 68%, and
decreasing it to 0.5 equiv provided 73% of 4aa. A further
decrease to 0.2 equiv also gave the increased yield (73%).
However, difficulty in stirring of this mixture necessitated the
addition of methanol as solvent.
In all of the above reactions, a nontrivial amount (∼10%) of
benzyl alcohol was formed as a side product from the
competitive reduction of 2a by 1. The addition of a slight
excess (10%) of 3a suppressed the carbinol formation and gave
the best yield (85%) for 4aa with negligible reduction product.
Under the optimized, solvent-free, reductive amination
protocol, 3a (1.1 mmol) was added to 2a (1 mmol), at
room temperature (RT), followed by the addition of trimethyl
borate (0.5 mmol) and 1 (1 mmol). The reaction was stirred
to completion (TLC, 4 h) and worked up with dil. HCl,
followed by treatment of the aqueous layer with NaOH.
Next, the solvent-free reductive amination was evaluated
with other amine-boranes that are commonly used for
reductive amination, such as pyridine-borane (5), 2-picoline-
borane (6), and t-butylamine-borane (7) as well as several in-
house synthesized31 amine-boranes, such as triethylamine-
borane (8), piperidine-borane (9), morpholine-borane (10),
benzylamine-borane (11), and cyclohexylamine-borane (12).
The results summarized in Table 1 reveal very unsatisfactory
yields with 2-picoline-borane (entry 3) and t-butylamine-
borane (entry 4). Triethylamine-borane (entry 5), pyridine-
borane (entry 2), piperidine-borane (entry 6), morpholine-
borane (entry 7), and benzylamine-borane (entry 8) also gave
subpar yields. Only cyclohexylamine-borane (entry 9) gave
yields comparable to 1. Given the benefits, such as low
molecular weight, remarkable thermal and hydrolytic stability,
convenient handling, and no contamination with byproducts, 1
was adopted as the preferred reductant.
The scope of the trimethyl borate-catalyzed reductive
amination with 1 was further demonstrated for aldehydes
and amines with variable steric and electronic environments as
illustrated in Table 2. The effect of amines was examined first
by maintaining 2a as the aldehyde. Electron-rich 4-methox-
ybenzylamine (3b, entry 2) and deactivated 4-chlorobenzyl-
amine (3c, entry 3) yielded the corresponding dibenzylamines,
4ab and 4ac in 94% and 96% yields, respectively.
Reaction with aniline (3d, entry 4) and electron-rich
anilines, such as 4-methoxyaniline (3e, entry 5) and 2-
methoxyaniline (3f, entry 6), proceeded without difficulty to
produce the corresponding N-benzylanilines in 79−85% yields.
However, electron deficient 4-nitroaniline (3g) gave relatively
poor yield (64%, entry 7). In the case of aliphatic 1°- and 2°-
alkylamines, this protocol yielded the corresponding N-
alkylated benzylamines contaminated with a substantial
amount of 1°-alcohol from the reduction of the aldehyde. To
avoid this undesired product, we modified our protocol with a
stepwise reductive amination. Accordingly, the aldehyde or
ketone was stirred, at RT, with the amine until complete
conversion to the corresponding imine (TLC, ∼4−36 h),
followed by the addition of 1 and stirring until the
disappearance of the imine (TLC, ∼4 h). This procedural
change resulted in a significant decrease of the undesired
alcohol and improved amination of 2a. 1°-Amines, 1-
propanamine (3h) and 2-propanamine (3i) (entries 8 and
9), and a 2°-amine, piperidine (3j, entry 10), were benzylated
in 62%, 75%, and 71% yields, respectively.
Attention was now turned to the effect of substitution on the
aldehydes. Thus, the reaction of activated 4-hydroxybenzalde-
hyde (2b, entry 11) and deactivated 4-nitrobenzaldehyde (2c,
entry 12) with 3c proceeded smoothly in 77% and 85% yields,
respectively. An aliphatic aldehyde, cyclohexanecarbaldehyde
(2d), reacted with 3a, 3c, and 3d to produce the
corresponding secondary amines in 78−87% yields (entries
13−15). Reductive amination of heteroaraldehydes, such as 1-
methylpyrrole-2-carbaldehyde (2e, entry 16) and furfural (2f,
entry 17) with 3b and 3c, respectively, gave the appropriate
products in excellent yields (97% and 90%, respectively).
Given the facility of the reaction with various aldehydes, the
protocol was extended to ketones, which required the two-step
protocol for an efficient reaction. Thus, cyclohexanone (2g,
entry 18), cyclopentanone (2h, entry 19) with 3c, and 3-
pentanone (2i, entry 20) provided the corresponding amines
in yields ranging from 73% to 80%. Similarly, the reaction of
acetophenone (2j, entry 21) with 4-methoxybenzylamine (3b)
gave a very good yield (85%) for 4jb. Indanone (2k) reacted
with 4-methoxybenzylamine (3b, entry 22) and allylamine (3k,
entry 23) to provide the corresponding secondary amines in
98% and 93% yields, respectively.
Table 1. Examination of Amine-Boranes for Reductive
Amination of Benzaldehyde with Benzylamine Using
Trimethyl Borate Catalyst
entry
amine-borane
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
ammonia-borane (1)
pyridine-borane (5)
4
7
7
7
12
5
5.5
5
4
85
50
21
22
40
53
58
62
79
2-picoline-borane (6)
t-butylamine-borane (7)
triethylamine-borane (8)
piperidine-borane (9)
morpholine-borane (10)
benzylamine-borane (11)
cyclohexylamine-borane (12)
The utility of our protocol was demonstrated by isolating
4aa in comparable yield from a mole-scale reaction of 2a with
3a. Further, this (MeO)3B-catalyzed protocol was applied for
the preparation of racemic Rasagiline32 (4kl) in 92% yield
(Scheme 2). The R-isomer of this molecule is an irreversible
monoamine oxidase-B inhibitor used to treat symptoms in
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Table 2. Trimethyl Borate-Promoted Reductive Amination of Aldehydes and Ketones with Primary and Secondary Amines
a
b
c
One-pot direct amination protocol has been followed. Indirect reductive amination protocol has been followed. The reactions were carried out
using 1:1.1 equiv of benzaldehyde and benzylamine. The yields reported are for isolated product.
early Parkinson’s disease or as an adjunct therapy in more
advanced cases.33
The pharmaceutical industry selected, mass-based green
matrix value [Process Mass Intensity (PMI)]34 for this
protocol was computed35 to be 43.7. In comparison, the
PMI for our earlier Ti(O-i-Pr)4-catalyzed procedure20 is 60.77,
highlighting the low environmental impact of the new
reductive amination protocol. This favorably compares with
other frequently utilized procedures, such as NaBH(OAc)3-
and pyridine-borane-mediated reductive aminations.
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after purification via column chromatography on silica gel using
hexane/EtOAc (95:5) as an eluent. The spectral data matched with
those reported in the literature.37 1H NMR (300 MHz, Chloroform-
d) δ 7.37−7.25 (m, 10H), 3.79 (dd, J = 5.4, 0.9 Hz, 4H), 1.90 (s, 1H).
13C{1H} NMR (75 MHz, CDCl3) δ 139.8, 138.5, 132.6, 129.5, 128.4,
128.4, 128.1, 127.0, 53.1, 52.4.
Scheme 2
N-Benzylaniline (4ad). The product was isolated in 85% yield
(0.777 g, 4.25 mmol) as a colorless liquid after purification via column
chromatography on silica gel using hexane/EtOAc (95:5) as an
eluent. The spectral data matched with those reported in the
literature.37 1H NMR (300 MHz, Chloroform-d) δ 7.42−7.14 (m,
8H), 6.81−6.66 (m, 2H), 4.34 (s, 2H). 13C{1H} NMR (75 MHz,
CDCl3) δ 146.9, 129.2, 128.6, 127.7, 127.3, 118.4, 113.7, 49.0.
N-Benzyl-4-nitroaniline (4ag). The product was isolated in 64%
yield (0.729 g, 3.2 mmol) as an orange solid after purification via
column chromatography on silica gel using hexane/EtOAc (9:1) as an
eluent. The spectral data matched with those reported in the
literature.37 1H NMR (300 MHz, Chloroform-d) δ 8.13−8.06 (m,
2H), 7.43−7.29 (m, 5H), 6.63 (d, J = 9.1 Hz, 2H), 4.44 (s, 2H).
13C{1H} NMR (75 MHz, CDCl3) δ 152.9, 138.2, 137.3, 128.9, 127.8,
127.3, 126.3, 111.29, 47.7.
N-Benzyl-4-methoxyaniline (4ae). The product was isolated in
84% yield (0.894 g, 4.2 mmol) as a pale yellow solid after purification
via column chromatography on silica gel using hexane/EtOAc (95:5)
as an eluent. The spectral data matched with those reported in the
literature.37 1H NMR (300 MHz, Chloroform-d) δ 7.40−7.25 (m,
5H), 6.83−6.75 (m, 2H), 6.71−6.64 (m, 2H), 4.29 (s, 2H), 3.75 (s,
3H). 13C{1H} NMR (75 MHz, CDCl3) δ 152.2, 142.6, 139.9, 128.7,
127.6, 127.2, 115.0, 114.2, 55.9, 49.3.
N-Benzyl-2-methoxyaniline (4af). The product was isolated in
79% yield (0.841 g, 3.95 mmol) as a yellow solid after purification via
column chromatography on silica gel using hexane/EtOAc (95:5) as
an eluent. The spectral data matched with those reported in the
literature.38 1H NMR (300 MHz, Chloroform-d) δ 7.42−7.26 (m,
5H), 6.88−6.62 (m, 4H), 4.37 (s, 2H), 3.86 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 146.7, 139.4, 128.5, 127.5, 127.1, 121.2, 116.7,
110.2, 109.3, 55.5, 48.1.
N-Benzylpropan-1-amine (4ah). The product was isolated in 62%
yield (0.461 g, 3.1 mmol) as a yellow liquid after purification via
column chromatography on silica gel using hexane/EtOAc (95:5) as
an eluent. The spectral data matched with those reported in the
literature.39 1H NMR (300 MHz, Chloroform-d) δ 7.50 (d, J = 6.6
Hz, 2H), 7.43−7.40 (m, 2H), 7.36−7.32 (m, 1H), 3.67 (s, 2H),
2.68−2.34 (m, 2H), 1.87−1.42 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 140.1, 128.8, 128.2, 126.7, 58.5,
55.6, 20.4, 12.1.
N-Benzylpropan-2-amine (4ai). The product was isolated in 75%
yield (0.558 g, 3.75 mmol) as a yellow liquid after purification via
column chromatography on silica gel using hexane as an eluent. The
spectral data matched with those reported in the literature.40 1H
NMR (300 MHz, Chloroform-d) δ 7.38−7.20 (m, 5H), 3.79 (s, 2H),
2.86 (p, J = 6.2 Hz, 1H), 1.69 (s, 1H), 1.11 (d, J = 6.2 Hz, 6H).
13C{1H} NMR (75 MHz, CDCl3) δ 134.9, 129.3, 128.6, 128.0, 49.3,
48.1, 20.6.
Benzylpiperidine (4aj). The product was isolated in 71% yield
(0.621 g, 3.55 mmol) as a clear yellow liquid after purification via
column chromatography on silica gel using hexane/EtOAc (95:5) as
an eluent. The spectral data matched with those reported in the
literature.41 1H NMR (300 MHz, Chloroform-d) δ 7.40−7.23 (m,
5H), 3.51 (s, 2H), 2.42 (t, J = 5.3 Hz, 4H), 1.71−1.58 (m, 4H), 1.48
(td, J = 6.1, 3.2 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.6,
129.2, 128.0, 126.8, 64.0, 54.6, 26.2, 24.6.
(((4-Chlorobenzyl)amino)methyl)phenol (4bc). The product was
isolated in 77% yield (0.950 g, 3.85 mmol) as a yellow oil after
purification via column chromatography on silica gel using hexane/
EtOAc (95:5) as an eluent. HRMS (CI) m/z: [M + H]+ calcd for
C14H15ClNO 248.0842, found 248.0840. 1H NMR (300 MHz,
Chloroform-d) δ 7.41−7.22 (m, 4H), 7.22−7.03 (m, 2H), 6.83−6.47
(m, 2H), 3.74 (d, J = 23.6 Hz, 4H). 13C{1H} NMR (75 MHz,
In conclusion, we have herein reported a facile reductive
amination procedure involving trimethyl borate as a catalyst
and readily available and inexpensive ammonia borane as
reductant, providing 2°- and 3°-amines in good to excellent
yields. This convenient, solvent-free, and environmentally
benign protocol has a low PMI. The protocol has been
applied for a mole-scale reaction and utilized to synthesize
Rasagiline in excellent yield.
EXPERIMENTAL SECTION
General Information. All reactions were performed open to air.
■
All chemicals were purchased from Sigma-Aldrich and used without
further purification, unless otherwise noted. H (300 MHz) and 13C
1
(75 MHz) spectra were recorded in CDCl3 on a Varian Gemini-300
spectrometer with a Nalorac-Quad probe, and chemical shifts (δ) are
given in ppm relative to TMS. Flash chromatography was performed
using 40−63 μm, 60 Å silica gel.
General Experimental Procedure. One-pot direct reductive
amination of carbonyls: To the carbonyl compound (5 mmol, 1
equiv) was added the amine (5.5 mmol), followed by the addition of
(MeO)3B 2.5 mmol) and ammonia borane (5 mmol). The reaction
mixture was stirred for about 4 h at RT. Upon completion of the
reaction, as revealed by TLC, the resulting mixture was treated with
HCl (15 mL, 6 M), diluted with water (30 mL), and extracted with
diethyl ether (3 × 15 mL). The aqueous layer was then treated with
NaOH (6 M) until pH 10−12 and extracted with diethyl ether (3 ×
15 mL). The combined organic extracts were washed with brine (1 ×
45 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to
obtain the crude product, which was purified by silica gel flash
chromatography to obtain the desired product.
Indirect reductive amination of carbonyls: To the solution of the
carbonyl (5 mmol), the amine (5.5 mmol) was added (MeO)3B (2.5
mmol) and stirred at RT, followed by TLC until complete conversion
to the corresponding imine. Subsequently, ammonia borane (5 mmol)
was added and further stirred at the same temperature until the
disappearance of the imine. The resulting mixture was treated with
HCl (15 mL, 6 M), diluted with water (30 mL), and extracted with
diethyl ether (3 × 15 mL). The aqueous layer was then treated with
NaOH (6 M) until pH 10−12 and extracted with diethyl ether (3 ×
15 mL). The combined organic extracts were washed with brine (1 ×
45 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to
obtain the crude product, which was purified by silica gel flash
chromatography to obtain the desired product.
Dibenzyl Amine (4aa). The product was isolated in 84% yield
(0.828 g, 4.2 mmol) as a colorless liquid after purification via column
chromatography on silica gel using hexane/EtOAc (95:5) as an
eluent. The spectral data matched with those reported in the
literature.36 1H NMR (300 MHz, Chloroform-d) δ 7.42−7.25 (m,
10H), 3.85 (s, 4H), 2.09 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ
140.0, 128.4, 128.2, 127.0, 53.1.
N-Benzyl-1-(4-methoxyphenyl)methanamine (4ab). The product
was isolated in 94% yield (1.067 g, 4.7 mmol) as a pale yellow liquid
after purification via column chromatography on silica gel using
hexane/EtOAc (95:5) as an eluent. The spectral data matched with
those reported in the literature.37 1H NMR (300 MHz, Chloroform-
d) δ 7.36−7.27 (m, 8H), 6.89 (d, J = 8.6 Hz, 2H), 3.81 (s, 4H), 3.76
(s, 3H) 2.29 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) 158.7, 139.2,
131.2, 129.6, 128.4, 128.3, 127.1, 113.8, 55.3, 52.6, 52.2.
N-Benzyl-1-(4-cholorophenyl)methanamine (4ac). The product
was isolated in 96% yield (1.108 g, 4.8 mmol) as a colorless liquid
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CDCl3) δ 156.0, 138.6, 132.1, 130.3, 129.4, 129.2, 128.2, 115.3, 52.4,
52.0.
literature.43 1H NMR (300 MHz, Chloroform-d) δ 7.25 (d, J = 8.9
Hz, 5H), 3.72 (d, J = 9.4 Hz, 2H), 3.06 (p, J = 6.6 Hz, 1H), 1.95−
1.20 (m, 8H). 13C{1H} NMR (75 MHz, CDCl3) δ 140.3, 128.3,
128.2, 126.8, 59.1, 52.7, 33.2, 24.2.
N-(4-Methoxybenzyl)pentan-3-amine (4ib). The product was
isolated in 73% yield (0.755 g, 3.65 mmol) as a yellow liquid after
purification via column chromatography on silica gel using hexane/
EtOAc (9:1) as an eluent. HRMS (CI) m/z: [M + H]+ calcd for
C13H22NO 208.1696; found 208.1701. 1H NMR (300 MHz,
Chloroform-d) δ 7.34−7.17 (m, 2H), 6.91−6.73 (m, 2H), 3.79 (s,
3H), 3.69 (s, 2H), 2.43 (p, J = 5.9 Hz, 1H), 1.46 (qdd, J = 7.3, 5.9, 1.8
Hz, 4H), 1.25 (d, J = 13.0 Hz, 1H), 0.89 (t, J = 7.5 Hz, 6H). 13C{1H}
NMR (75 MHz, CDCl3) δ 158.4, 133.2, 113.6, 59.2, 55.2, 50.5, 25.7,
9.8.
N-(4-Methoxybenzyl)-1-phenylethan-1-amine (4jb). The product
was isolated in 85% yield (1.024 g, 4.25 mmol) as a light yellow liquid
after purification via column chromatography on silica gel using
hexane/EtOAc (95:5) as an eluent. HRMS (CI) m/z: [M + H]+ calcd
for C16H20NO 242.1545; found 242.1541. 1H NMR (300 MHz,
Chloroform-d) δ 7.53−7.07 (m, 7H), 7.01−6.75 (m, 2H), 3.82 (d, J =
8.1 Hz, 5H), 3.59 (d, J = 8.2 Hz, 1H), 1.61 (s, 1H), 1.39 (d, J = 6.6
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 145.5, 132.7,
129.2, 128.4, 126.6, 113.7, 57.4, 55.3, 51.1, 24.6.
N-(4-Chlorobenzyl)-1-(4-nitrophenyl)methanamine (4cc). The
product was isolated in 85% yield (1.176 g, 4.25 mmol) as a pale
yellow solid after purification via column chromatography on silica gel
using hexane/EtOAc (95:5) as an eluent. Mp. (92−93 °C). HRMS
(CI) m/z: [M + H]+ calcd for C14H14ClN2O2 277.0744; found
277.0740. 1H NMR (300 MHz, Chloroform-d) δ 8.26−8.10 (m, 2H),
7.60−7.49 (m, 2H), 7.40−7.18 (m, 4H), 3.84 (d, J = 33.7 Hz, 4H),
2.26 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 152.0, 142.3, 139.5,
128.5, 127.4, 127.1, 114.8, 114.0, 55.8, 49.3.
N-(4-Chlorobenzyl)-1-cyclohexylmethanamine (4dc). The prod-
uct was isolated in 87% yield (1.030 g, 4.35 mmol) as a yellow oil after
purification via column chromatography on silica gel using hexane/
EtOAc (95:5) as an eluent. HRMS (CI) m/z: [M + H]+ calcd for
C14H21ClN 238.1362; found 238.1356. 1H NMR (300 MHz,
Chloroform-d) δ 7.19 (m, J = 4.8 Hz, 4H), 3.65 (d, J = 5.2 Hz,
2H), 2.37 (dd, J = 6.7, 4.3 Hz, 2H), 1.68 (dt, J = 13.6, 6.8 Hz, 4H),
1.41 (ddd, J = 11.0, 7.1, 3.6 Hz, 1H), 1.16 (dq, J = 14.3, 10.9, 10.5 Hz,
4H), 1.00−0.67 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 139.2,
132.2, 129.2, 128.2, 56.2, 53.4, 38.2, 31.6, 26.8, 26.2.
N-(Cyclohexylmethyl)aniline (4dd). The product was isolated in
78% yield (0.621 g, 3.55 mmol) as a clear yellow liquid after
purification via column chromatography on silica gel using hexane as
an eluent. The spectral data matched with those reported in the
literature.41 1H NMR (300 MHz, Chloroform-d) δ 7.22−7.09 (m,
2H), 6.76−6.63 (m, 3H), 3.11 (s, 2H), 1.71−1.45 (m, 9H), 1.40−
1.26 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 148.7, 129.2,
117.6, 113.2, 71.5, 54.3, 35.9, 26.0, 22.1.
N-Benzyl-1-cyclohexylmethanamine (4da). The product was
isolated in 83% yield (0.791 g, 3.9 mmol) as a pale yellow liquid
after purification via column chromatography on silica gel using
hexane as an eluent. The spectral data matched with those reported in
the literature.42 1H NMR (300 MHz, Chloroform-d) δ 7.31 (dd, J =
23.7, 4.5 Hz, 5H), 3.80 (s, 2H), 2.50 (d, J = 6.7 Hz, 2H), 1.89−1.63
(m, 4H), 1.62−1.46 (m, 1H), 1.42−1.09 (m, 4H), 0.97 (td, J = 11.7,
2.9 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 140.6, 128.3, 128.1,
128.0, 126.8, 56.3, 54.3, 38.1, 31.9, 31.6, 26.9, 26.3.
N-(4-Methoxybenzyl)-1-(1-methyl-1H-pyrrol-2-yl)methanamine
(4eb). The product was isolated in 97% yield (1.115 g, 4.85 mmol) as
a dark brown liquid after purification via column chromatography on
silica gel using hexane/EtOAc (95:5) as an eluent. HRMS (CI) m/z:
[M + H]+ calcd for C14H19N2O 231.1497; found 231.1493. 1H NMR
(300 MHz, Chloroform-d) δ 7.28 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.5
Hz, 2H), 6.60 (t, J = 2.1 Hz, 1H), 6.06 (d, J = 2.6 Hz, 2H), 3.89−3.70
(m, 7H), 3.64 (s, 3H), 1.94 (s, 1H). 13C{1H} NMR (75 MHz,
CDCl3) δ 158.6, 132.6, 131.1, 129.3, 122.4, 113.8, 108.0, 106.5, 1,
55.3, 52.8, 44.9.
N-(4-Chlorobenzyl)-1-(furan-2-yl)methanamine (4fc). The prod-
uct was isolated in 90% yield (0.994 g, 4.50 mmol) as a brown oil after
purification via column chromatography on silica gel using hexane/
EtOAc (95:5) as an eluent. HRMS (CI) m/z: [M + H]+ calcd for
C12H13ClNO 222.0685; found 222.0682. 1H NMR (300 MHz,
Chloroform-d) δ 7.50−7.05 (m, 5H), 6.31 (dd, J = 3.2, 1.9 Hz, 1H),
6.17 (d, J = 3.2 Hz, 1H), 3.74 (d, J = 6.5 Hz, 4H), 1.98−1.70 (m,
1H). 13C{1H} NMR (75 MHz, CDCl3) δ 153.4, 141.8, 138.2, 132.6,
129.5, 129.5, 110.1, 107.2, 52.0, 45.3.
N-(4-Methoxybenzyl)-2,3-dihydro-1H-inden-1-amine (4kb). The
product was isolated in 98% yield (1.239 g, 4.90 mmol) as a dark
brown liquid after purification via column chromatography on silica
gel using hexane/EtOAc (95:5) as an eluent. HRMS (CI) m/z: [M +
1
H]+ calcd for C17H20NO 254.1545; found 254.1544. H NMR (300
MHz, Chloroform-d) δ 7.49−7.13 (m, 6H), 6.87 (d, J = 8.7 Hz, 2H),
4.30 (t, J = 6.5 Hz, 1H), 3.81 (d, J = 15.4 Hz, 5H), 3.12−2.95 (m,
1H), 2.82 (dt, J = 15.8, 7.6 Hz, 1H), 2.52−2.32 (m, 1H), 2.03−1.82
(m, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 145.2, 143.5,
132.6, 129.2, 127.3, 126.1, 124.6, 124.0, 113.7, 62.6, 55.3, 50.8, 33.7,
30.5.
N-Allyl-2,3-dihydro-1H-inden-1-amine (4kk). The product was
isolated in 93% yield (0.804 g, 4.65 mmol) as a brown oil after
purification via column chromatography on silica gel using hexane/
EtOAc (95:5) as an eluent. HRMS (CI) m/z: [M + H]+ calcd for
1
C12H16N 174.1282; found 174.1280. H NMR (300 MHz, Chloro-
form-d) δ 7.45−7.33 (m, 1H), 7.22 (dd, J = 8.6, 3.1 Hz, 3H), 6.09−
5.92 (m, 1H), 5.31−5.09 (m, 2H), 4.32−4.25 (m, 1H), 3.39 (ddd, J =
6.1, 3.3, 1.5 Hz, 2H), 3.03 (ddd, J = 13.6, 8.5, 5.0 Hz, 1H), 2.83 (dt, J
= 15.6, 7.6 Hz, 1H), 2.43 (dddd, J = 12.0, 8.2, 6.5, 5.0 Hz, 1H), 1.74
(m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 145.0, 143.6, 136.9,
127.4, 126.2, 124.7, 124.1, 115.9, 62.7, 50.0, 33.7, 30.5.
Rasagiline (4kl). The product was isolated in 92% yield (0.786 g,
4.6 mmol) as a solid, mp = 148 °C, after purification via column
chromatography on silica gel using hexane/EtOAc (95:5) as an
eluent. The spectral data matched with those reported in the
literature.44 1H NMR (300 MHz, Chloroform-d) δ 7.47−7.10 (m,
4H), 4.43 (dd, J = 6.8, 5.3 Hz, 1H), 3.53 (dd, J = 2.5, 1.5 Hz, 2H),
3.07 (ddd, J = 16.1, 8.3, 5.7 Hz, 1H), 2.84 (ddd, J = 15.3, 8.3, 6.2 Hz,
1H), 2.41 (ddddd, J = 12.6, 8.0, 6.8, 5.7, 1.0 Hz, 2H), 1.97−1.78 (m,
1H). 13C{1H} NMR (75 MHz, CDCl3) δ 144.4, 143.7, 127.5, 126.2,
124.8, 124.2, 82.6, 71.6, 61.9, 36.2, 33.5, 30.6
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02143.
■
N-(4-Chlorobenzyl)cyclohexanamine (4gc). The product was
isolated in 80% yield (0.892 g, 4.00 mmol) as a yellow liquid after
purification via column chromatography on silica gel using hexane as
an eluent. HRMS (CI) m/z: [M + H]+ calcd for C13H19ClN
sı
1
Optimization summary, PMI calculation, and copies of
PMR and CMR spectra (PDF)
224.1206; found 224.1203. H NMR (300 MHz, Chloroform-d) δ
7.52−7.09 (m, 4H), 3.77 (s, 2H), 2.45 (tt, J = 10.1, 3.7 Hz, 1H), 1.89
(dd, J = 11.8, 3.8 Hz, 2H), 1.81−1.69 (m, 2H), 1.66−1.54 (m, 1H),
1.38−0.87 (m, 5H). 13C{1H} NMR (75 MHz, CDCl3) δ 139.4,
132.3, 129.3, 128.3, 56.1, 50.3, 33.6, 26.2, 25.1.
N-Benzylcyclopentanamine (4ha). The product was isolated in
75% yield (0.791 g, 3.9 mmol) as a yellow oil after purification via
column chromatography on silica gel using hexane/EtOAc (9:1) as an
eluent. The spectral data matched with those reported in the
AUTHOR INFORMATION
Corresponding Author
■
P. Veeraraghavan Ramachandran − Department of
Chemistry, Purdue University, West Lafayette, Indiana
47907-2084, United States; orcid.org/0000-0002-5240-
4278
https://dx.doi.org/10.1021/acs.joc.0c02143
J. Org. Chem. 2021, 86, 4274−4280

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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reductive amination of aldehydes and ketones with α-picoline-borane
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3018; Phone: 765 494 5303; Email: chandran@
purdue.edu; Fax: 765 494 0239
Authors
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N. A general one-pot, three-component mono N-alkylation of amines
and amine derivatives in lithium perchlorate/diethyl ether solution.
Synthesis 2005, 2005 (4), 627−633.
Shivani Choudhary − Department of Chemistry, Purdue
University, West Lafayette, Indiana 47907-2084, United
States
Aman Singh − Department of Chemistry, Purdue University,
West Lafayette, Indiana 47907-2084, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02143
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank the Herbert C. Brown Center
for Borane Research for financial assistance.
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