Benzhydrylamine: An effective aminating agent for the synthesis of primary amines

Article abstract of DOI:10.3184/174751918X15232662638058

Aldehydes, ketones, alkyl toluene-p-sulfonates and halides are converted into the corresponding primary amines with benzhydrylamine as a valuable ammonia synthon in moderate to excellent yields.

Full text of DOI:10.3184/174751918X15232662638058

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 APRIL, 181–183
RESEARCH PAPER 181
Benzhydrylamine: an effective aminating agent for the synthesis of primary
amines
Quan-Wei Sun, Jun-De Xing*, Yu-Hong Qin, Xu-Wen Yin and Yi Zhou
College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, P.R. China
Aldehydes, ketones, alkyl toluene-p-sulfonates and halides are converted into the corresponding primary amines with benzhydrylamine
as a valuable ammonia synthon in moderate to excellent yields.
Keywords: benzhydrylamine, synthesis of primary amines, hydrolysis
Many primary amines are biologically active compounds or
form their synthetic building blocks. Important methods for the
synthesis of primary amines include the alkylation of ammonia by
organic halides and alcohols,1–3 the reductive amination of carbonyl
compounds,4,5 the reduction of nitro compounds6,7 and nitriles,8,9 as
well as other methods.10–12 The synthesis of primary amines has been
reported13,14 from benzylamine and carbonyl compounds via the
[1,3]-prototropic isomerisation of an imine followed by a hydrolysis
step. This is a useful procedure for the preparation of primary
amines avoiding the formation of secondary and tertiary amines
as byproducts. However, benzylamine has a moderate reactivity
as an aminating agent in organic synthesis and its application is
limited. Triphenylmethylamine as an alternative reagent has been
applied for the conversion of alkyl halides and alkyl tosylates to the
corresponding primary amines but is restricted by its high cost.15
Consequently, it is still a challenge to develop new aminating agents
for a facile and effective synthetic method of primary amines.
We report a high-yielding, low-cost synthesis of primary amines
by the amination of aldehydes, ketones, and alkyl toluene-p-
sulfonates and halides using benzhydrylamine as an ammonia
synthon (Scheme 1).
3f. Then with DMSO as the solvent and potassium tert-butoxide
as the catalyst, 4a–f were obtained by isomerisation of the
double bond of 3a–f. Ethanolamine, tetrabutylammonium
bromide, sodium methylate, sodium acetate and sodium bydride
were used as catalysts to replace potassium tert-butoxide in
this experiment, but the results were not as good as those with
Table 1 Synthesis of primary amines 5a–f from aldehydes and ketones
Aldehydes and ketones
Primary amines
Yield (%)
H
O
NH2
O
86
O
2a
5a
O
NH2
81
H
2b
5b
NH2
69
64
O
2c
5c
5d
NH2
O
Results and discussion
The primary amines that were prepared from aldehydes and
ketones using benzhydrylamine as an aminating agent are
shown in Table 1. Furfural, benzaldehyde and n-butyraldehyde
reacted with benzhydrylamine in dichloromethane as a solvent
to afford 3a–c. However, benzhydrylamine did not react with
butanone, cyclohexanone and 1-phenylethanone in CH2Cl2.
The reactivity of aldehydes is higher than that of ketones as
the steric hindrance of an aldehyde group is less than that of
a ketone group. Butanone or cyclohexanone were used as
both the starting material and the solvent in the reaction with
benzhydrylamine to obtain 3d and 3e. Acetophenone with
toluene as the solvent reacted with benzhydrylamine to obtain
2d
NH2
O
67
72
2e
5e
5f
NH2
O
2f
′
R′
Ph
R
′
Ph
Ph
R
(1) H+
(2)OH-
t-BuOK
O
″
R
NH2
R″
N
Ph
R″
N
f
R′
R″
5a-5f
2
-
a
2
3a-3f
4a-4f
Ph
Ph
NH2
R
X
6
a
-
6
f
(1) H+
(2)OH-
Ph
Ph
Ph
Ph
H
N
DD
Q
1
R
R
N
R
NH2
7a-7f
9a-9f
8a-8f
R, R′, R″: aryl, alkyl, H; X: Cl, Br, OTs
Scheme 1 General scheme for preparation of a primary amine.
* Correspondent. E-mail: xingjunde@126.com

182 JOURNAL OF CHEMICAL RESEARCH 2018
Synthesis of benzhydrylamine19 (1)
Table 2 Synthesis of primary amines 9a–f from alkyl toluene-p-
sulfonates and halides
A mixture of benzophenone (1.37 mol), formamide (250 mL) and formic
acid (85%, 31.50 mL) was heated to 190 °C for 3 h. The reaction mixture
was cooled to 140 °C and poured into cold water (1.20 L). The resulting
precipitate was collected by filtration, to which concentrated aqueous
hydrochloric acid (230 mL) was added, and the reaction mixture was heated
under reflux with vigorous stirring. The hydrochloride salt was collected
by filtration and washed with diethyl ether. The white crystals were treated
with an aqueous solution of sodium hydroxide (2.80 M) and extracted
with diethyl ether. The organic layer was distilled under reduced pressure
to afford benzhydrylamine 1 as a white solid; yield 94%; m.p. 293–294 °C
(lit.20 294–296 °C); FTIR (KBr) (nmax cm−1): 2956, 2852 (NH3+); 1H NMR
(400 MHz, DMSO-d6): δ 9.34 (s, 3H), 7.60–7.58 (m, 4H), 7.42–7.38 (m,
4H), 7.35–7.31 (m, 2H), 5.61 (s, 1H).
RX
Primary amines
NH2
Yield (%)
91
T
O S
S
S
6a
9a
NH2
T
O S
93
6b
6c
9b
9c
NH2
88
85
79
T
O S
NH2
Cl
Synthesis of 5a and 5b; general procedure
The arylaldehyde 2a or 2b (0.50 mol) was added to a solution of
benzhydrylamine (0.50 mol) in CH2Cl2 (230 mL) at room temperature.
After completion of the reaction, (TLC), the solvent was removed under
reduced pressure. The residue was dissolved in DMSO (850 mL) and
heated to 40 °C and portions of potassium tert-butoxide (0.13 mol) were
added over 10 min with stirring. After 10 min, the reaction mixture was
heated to 55 °C for about 12 h, evaporated in vacuo and treated with H2SO4
(1.40 M, 885 mL) at room temperature. After completion of the hydrolysis
(TLC), the aqueous phase was extracted with CH2Cl2, and separated into
organic and aqueous layers. The aqueous phase was adjusted to a basic pH
by sodium hydroxide solution (40%), extracted with CH2Cl2 and then the
organic phase was distilled under reduced pressure to yield the expected
products 5a and 5b.
6d
6e
9d
9e
NH2
Br
NH2
Br
72
6f
9f
potassium tert-butoxide. The amines were 5a–f obtained by
acid hydrolysis of 4a–f.
Primary amines were synthesised by treating alkyl toluene-
p-sulfonates or halides with benzhydrylamine. The reactants
and the products are shown in Table 2. Compounds 7a–f were
obtained by the reaction of 6a–f with benzhydrylamine dissolved
in acetonitrile, using sodium carbonate to neutralise the acid.
The reaction of the bromo compounds with benzhydrylamine
was slow. Although there are many ways to break a C–N bond
in secondary amines, these particular bonds were difficult to
cleave. We used the literature methods16–18 with 7a–f, expecting
to obtain 9a–f, but the yields were almost zero. However,
compared with a C–N single bond, a C=N double bond can be
easily broken. Compounds 8a–f were easily obtained by the
reaction of 7a–f with DDQ. Finally, the corresponding primary
amines 9a–f were obtained by the hydrolysis of the C=N bond
in sulfuric acid (1.4 mol L−1).
In conclusion, we have shown that benzhydrylamine can
be used to convert aldehydes, ketones, and alkyl toluene-
p-sulfonates and halides to amines. Aryl aldehydes and
ketones gave higher yields than their alkyl counterparts
with the aldehydes giving better yields than the ketones.
Dehydrogenation of the secondary amine obtained from the
reaction of benzhydrylamine and an alkyl toluene-p-sulfonate or
halide to an imine provided a route to a primary amine that was
not contaminated by secondary or tertiary amine byproducts.
Benzhydrylamine was more reactive than benzylamine in this
context and is cheaper than tritylamine.
2-Furanmethanamine (5a): Colourless liquid; yield 86%; FTIR (KBr)
(nmax cm−1): 3365, 3274 (N–H); 1H NMR (600 MHz, CDCl3): δ 7.49 (s, 1H),
7.18 (d, J = 3.4 Hz, 1H), 6.54 (t, J = 1.8 Hz, 1H), 6.30 (s, 1H), 5.87 (s, 1H),
3.01 (s, 2H).
Benzylamine (5b) hydrochloride: White solid; yield 81%; m.p.
262–263 °C (lit.21 264–265 °C); FTIR (KBr) (nmax cm−1): 3004, 2969
(NH3+); 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 3H), 7.54–7.52 (m, 2H),
7.42–7.34 (m, 3H), 3.99 (s, 2H).
Synthesis of 1-butanamine (5c)
n-Butyraldehyde 2c (0.50 mol) was added to a mixture of benzhydrylamine
(0.50 mol) and Na2SO4 (0.25 mol) in CH2Cl2 (230 mL) at room temperature.
The flask was then heated to reflux. After completion of the reaction
(TLC), the mixture was cooled, filtered and evaporated in vacuo. The
residue was dissolved in DMSO (850 mL) and heated to 40 °C. Portions of
potassium tert-butoxide (0.13 mol) were added over 10 min with stirring.
After 10 min, the reaction mixture was heated to 55 °C for about 12 h,
evaporated in vacuo and treated with H2SO4 (1.40 M, 885 mL) at room
temperature. After completion of the hydrolysis (TLC), the aqueous
phase was extracted with CH2Cl2, followed by separation of the organic
and aqueous layers. The aqueous phase was adjusted to a basic pH by
sodium hydroxide solution (40%), extracted with CH2Cl2 and then the
organic phase distilled under reduced pressure to yield 1-butanamine 5c
as: Colourless liquid; yield 69%; FTIR (nmax cm−1): 3357, 3300 (N–H);
1H NMR (400 MHz, CDCl3): δ 2.54 (t, J = 6.9 Hz, 2H), 1.30–1.15 (m, 6H),
0.77 (t, J = 7.2 Hz, 3H).
Synthesis of 5d and 5e; exemplified by 2-butanamine (5d); general
procedure
Experimental
A mixture of benzhydrylamine (0.50 mol), butanone 2d (3.33 mol) and
Na2SO4 (0.25 mol) was heated at 70 °C. After completion of the reaction
(TLC), the mixture was cooled, filtered and evaporated in vacuo. The
residue was dissolved in DMSO (850 mL), heated to 40 °C and portions
of potassium tert-butoxide (0.13 mol) were added over 10 min with
stirring. After 10 min, the reaction mixture was heated to 55 °C for
about 12 h, evaporated in vacuo and treated with H2SO4 (1.40 M, 885
mL) at room temperature. After completion of the hydrolysis (TLC), the
aqueous phase was extracted with CH2Cl2, followed by separation of the
organic and aqueous layers. The aqueous phase was adjusted to a basic
pH by sodium hydroxide solution (40%), extracted with CH2Cl2 and
Chemicals of high purity were purchased from Sinopharm Chemical
Reagent Co. Ltd. and used without further purification. The reactions
were monitored by TLC, and all yields refer to isolated products.
1H NMR spectra were obtained on a Bruker 400 MHz spectrometer
or a Bruker 600 MHz spectrometer in CDCl3 or DMSO-d6 using
tetramethylsilane (TMS) as internal standard. Chemical shifts (δ) are
given in ppm and coupling constants (J) are in Hertz (Hz). Melting
points were obtained using an Electrothermal YRT-3 apparatus.
Infrared spectra were recorded on
a Shimadzu FTIR-8400S
spectrometer in KBr with absorption values given in cm−1.

JOURNAL OF CHEMICAL RESEARCH 2018 183
then the organic phase was distilled under reduced pressure to yield the
expected product 5d.
2-Butanamine (5d): Colourless liquid; yield 64%; FTIR (KBr) (nmax
cm−1): 3338, 3283 (N–H); 1H NMR (400 MHz, CDCl3): δ 2.69–2.61 (m,
1H), 1.24–1.16 (m, 2H), 1.13 (s, 2H), 0.91 (d, J = 6.4 Hz, 3H), 0.76 (t, J = 7.4
Hz, 3H).
was extracted with CH2Cl2, followed by separation of organic and aqueous
layers. The aqueous phase was adjusted to a basic pH by sodium hydroxide
solution (40%), extracted with CH2Cl2 and then organic phase was distilled
under reduced pressure to yield 1-butylamine (9e) as a colourless liquid;
1
yield 79%; FTIR (KBr) (nmax cm−1): 3357, 3300 (N–H); H NMR (400
MHz, CDCl3): δ 2.54 (t, J = 6.9 Hz, 2H), 1.30–1.15 (m, 6H), 0.77 (t, J = 7.2
Cyclohexanamine (5e): Colourless liquid; yield 67%; FTIR (KBr) (nmax
cm−1): 3351, 3277 (N–H); 1H NMR (400 MHz, CDCl3): δ 2.51–2.43 (m,
1H), 1.69–1.65 (m, 2H), 1.59–1.54 (m, 2H), 1.47–1.43 (m, 1H), 1.17–1.05
(m, 4H), 1.02–0.84 (m, 3H).
Hz, 3H).
Synthesis of aniline (9f)
A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), CuO
(0.16 mol), Na2CO3 (0.91 mmol) and bromobenzene 6f (0.50 mol) was
heated under reflux. After completion of the reaction (TLC), the reaction
mixture was cooled, filtered and evaporated in vacuo. The residue was
dissolved in benzene (1.03 L) and stirred at room temperature for 10 min,
under a stream of N2, and then portions of DDQ (1.09 mol) were added
over 10 min with stirring. The reaction mixture was heated under reflux
for 5 h, evaporated in vacuo and treated with H2SO4 (1.40 M, 885 mL) at
room temperature. After completion of the hydrolysis, the aqueous phase
was extracted with CH2Cl2, followed by separation of organic and aqueous
layers. The aqueous phase was adjusted to a basic pH by sodium hydroxide
solution (40%), extracted with CH2Cl2 and then organic phase was distilled
under reduced pressure to yield aniline (9f) as a colourless liquid; yield
Synthesis of 1-phenylethylamine (5f)
A mixture of benzhydrylamine (0.50 mol), acetophenone 2f (0.50 mol),
toluene (460 mL) and Na2SO4 (0.25 mol) was heated at 90 °C. After
completion of the reaction (TLC), the reaction mixture was cooled, filtered
and evaporated in vacuo. The residue was dissolved in DMSO (850 mL)
and heated to 40 °C. Portions of potassium tert-butoxide (0.13 mol) were
added over 10 min with stirring. After 10 min, the reaction mixture was
heated to 55 °C for about 12 h, and then evaporated in vacuo and treated
with H2SO4 (1.40 M, 885 mL) at room temperature. After completion of the
hydrolysis (TLC), the aqueous phase was extracted with CH2Cl2, followed
by separation of the organic and aqueous layers. The aqueous phase was
adjusted to a basic pH by sodium hydroxide solution (40%), extracted with
CH2Cl2 and then the organic phase was distilled under reduced pressure to
yield 1-phenylthylamine 5f as a colourless liquid; yield 72%; FTIR (KBr)
(nmax cm−1): 3365, 3282 (N–H); 1H NMR (400 MHz, CDCl3): δ 7.36–7.31
(m, 4H), 7.27–7.22 (m, 1H), 4.12–4.07 (q, J = 6.6 Hz, 1H), 1.70 (s, 2H), 1.39
(d, J = 6.7 Hz, 3H).
72%; FTIR (KBr) (nmax cm−1): 3431, 3354 (N–H); H NMR (400 MHz,
CDCl3): δ7.29–7.24 (m, 2H), 6.90–6.85 (m, 1H), 6.76 (m, 2H), 3.67 (s, 2H).
1
Electronic Supplementary Information
The ESI containing infrared and 1H NMR spectra is available
through:
Synthesis of 9a–9d; exemplified by 2-thiopheneethanamine (9a); general
http://ingentaconnect.com/content/stl/jcr/2018/00000042/00000003/art00002
procedure
A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), 2-(2-thienyl)
ethyl toluene-p-sulfonate 6a (0.50 mol) and Na2CO3 (0.91 mol) was heated
to 70 °C. After completion of the reaction, the reaction mixture was cooled,
filtered and evaporated in vacuo. The residue was dissolved in benzene
(1.03 L) and stirred at room temperature for 10 min, under a stream of N2,
and then portions of DDQ (1.09 mol) were added over 10 min with stirring.
The reaction mixture was heated under reflux for 5 h, evaporated in vacuo
and treated with H2SO4 (1.40 M, 885 mL) at room temperature. After
completion of the hydrolysis, the aqueous phase was extracted with CH2Cl2,
followed by separation of organic and aqueous layers. The aqueous phase
was adjusted to a basic pH by sodium hydroxide solution (40%), extracted
with CH2Cl2 and then the organic phase was distilled under reduced
pressure to yield the expected product 9a.
Received 6 February 2018; accepted 22 March 2018
Paper 1805245
https://doi.org/10.3184/174751918X15232662638058
Published online: 18 April 2018
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A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), KI
(0.56 mol), Na2CO3 (0.91 mol) and 1-bromobutane 6e (0.50 mmol) was
heated under reflux. After completion of the reaction (TLC), the reaction
mixture was cooled, filtered and evaporated in vacuo. The residue was
dissolved in benzene (1.03 L) and stirred at room temperature for 10 min,
under a stream of N2, and then portions of DDQ (1.09 mol) were added
over 10 min with stirring. The reaction mixture was heated under reflux
for 5 h, evaporated in vacuo and treated with H2SO4 (1.40 M, 885 mL) at
room temperature. After completion of the hydrolysis, the aqueous phase
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