Comparison of different reducing systems in the synthesis of functionally substituted benzylamines from alkyl aryl ketones and aromatic aldehydes

Article abstract of DOI:10.1134/S1070428010070110

Different synthetic approaches to functionally substituted benzylamines were examined: reductive amination of alkyl aryl ketones and reduction of aromatic aldehyde oximes. The most efficient procedures were used to prepare a series of previously unknown h

Full text of DOI:10.1134/S1070428010070110

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 1021–1028. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © D.M. Musatov, E.V. Starodubtseva, O.V. Turova, D.V. Kurilov, M.G. Vinogradov, A.K. Rakishev, M.I. Struchkova, 2010, published
in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 7, pp. 1023–1029.
Comparison of Different Reducing Systems
in the Synthesis of Functionally Substituted Benzylamines
from Alkyl Aryl Ketones and Aromatic Aldehydes
D. M. Musatov, E. V. Starodubtseva, O. V. Turova, D. V. Kurilov, M. G. Vinogradov,
A. K. Rakishev, and M. I. Struchkova
Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia
e-mail: turova@ioc.ac.ru
Received July 27, 2009
Abstract—Different synthetic approaches to functionally substituted benzylamines were examined: reductive
amination of alkyl aryl ketones and reduction of aromatic aldehyde oximes. The most efficient procedures were
used to prepare a series of previously unknown hydroxy-, alkoxy-, and halogen-substituted benzylamines.
DOI: 10.1134/S1070428010070110
Benzylamines are widely used in the synthesis of
enzyme inhibitors [1–5] and compounds exhibiting
analgesic [3], antithrombotic [2], antibacterial [6],
fungicidal [7], and other kinds of biological activity.
Benzylamines are usually prepared by reductive
amination of carbonyl compounds [8–12] and reduc-
tion of the corresponding oximes, nitriles, or azines.
Oximes can be reduced with sodium amalgam [13],
metallic sodium in liquid ammonia [14, 15], Mg–
HCOONH4–MeOH [16], Raney nickel–EtOH–base
[17–19], LiAlH4 [10], NaBH4–TiCl4 [20], and NaBH4–
LiCl–Amberlyst [21]. Oxime ethers, nitriles, and azines
were also reduced in the presence of Pd/C [19, 22, 23].
However, despite diversity of methods for the prepara-
tion of benzylamines, there are very limited published
data on the synthesis of benzylamines with hydroxy and
alkoxy groups in the aromatic ring [11, 13, 16–18, 21].
model substrates we used acetophenone oxime and its
O-methyl ether. Both these substrates were completely
reduced in boiling THF in 3 h, but the reactions were
not selective: apart from the target 1-phenylethan-
amine, secondary N-ethylaniline was formed as a result
of side Beckmann rearrangement followed by reduc-
tion of intermediate acetanilide. In the reaction with
acetophenone oxime the ratio 1-phenylethanamine–
N-ethylaniline was 1:1.5, and in the reduction of
acetophenone O-methyloxime both products were
formed in equimolar amounts. The reduction of aceto-
phenone oxime with the system LiAlH4–Me3SiCl was
more selective, and the ratio of 1-phenylethanamine
and N-ethylaniline was 3:1. With a view to obtain
functionally substituted benzylamine, 1-(4-hydroxy-
phenyl)ethanamine, the corresponding oxime was
reduced with sodium in liquid ammonia. This reaction
was not accompanied by side Beckmann rearrange-
ment, and the target product was formed in high yield.
As far as we known, we were the first to apply this
procedure for the reduction of an aromatic ketone
oxime having a hydroxy group in the aromatic ring.
However, the use of sodium in liquid ammonia for the
reduction of ketone oximes is strongly limited. For
example, alkoxy-substituted benzylamines cannot be
obtained in such a way, for alkoxy group is readily
converted to hydroxy by the action of sodium.
In the present work we examined different synthetic
approaches to functionally substituted benzylamines,
primarily to those containing hydroxy and alkoxy
substituents. In particular, such standard procedures as
hydride reduction of aldehyde and ketone oximes with
LiAlH4, reduction of ketone oximes with sodium in
liquid ammonia, and reductive amination of ketones
according to Leuckart–Wallach were studied.
In the first step of our study we examined the
possibility for synthesizing functionally substituted
1-phenylalkan-1-amines by reduction of the corre-
sponding aromatic ketone oximes with LiAlH4; as
Our further study showed that, unlike reduction of
ketone oximes, reductive amination of ketones with
1021

MUSATOV et al.
1022
Scheme 1.
R2
O
R2
R1
R2
R1
(1) KOH, H2O–EtOH
(2) HCl, dioxane
CHO
R1
N
NH2
HCONH2, HCOOH
·HCl
H
R3
R3
R3
Ia–Ij
IIa–IIj
IIIa–IIIj
For substituents R1–R3, see Table 1.
formamide in the presence of formic acid (Leuckart–
Wallach) provides the most convenient and universal
method for the synthesis of various functionally substi-
tuted benzylamines (Scheme 1). Under the optimal
conditions (130°C, reaction time 20 h for ketones Ia–
Ig and 50 h for hydroxyphenyl ketones Ih–Ij), we
synthesized a series of alkoxy-, hydroxy-, and halogen-
substituted benzylamines with different numbers and
positions of the substituents. As follows from the data
in Table 1, the nature of substituents in the benzene
ring affects the yield of the resulting benzylamines.
The highest yield (64%) was obtained for 1-(2,4-di-
fluorophenyl)ethanamine. Hydroxy-substituted deriva-
tives require longer reaction time, and their yields are
lower (40–45%). The final products were isolated as
with an acceptable yield. Amine VIIn was synthesized
in 47% yield by reductive amination.
Thus our results showed that the most effective
procedure for the synthesis of hydroxy-, alkoxy-, and
halogen-substituted benzylamines from the corre-
sponding alkyl aryl ketones is reductive amination
according to Leuckart–Wallach and that reduction of
aldehyde oximes with LiAlH4 is most appropriate for
the preparation of functionally substituted benzyl-
amines from aromatic aldehydes.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
Avance II 300 spectrometer. The melting points were
determined on a Boetius melting point apparatus and
were not corrected. The mass spectra (electron impact,
70 eV) were obtained on a Kratos MS-30 instrument.
1
hydrochlorides which were characterized by H NMR
and mass spectra and elemental analyses.
The yields of benzylamines in the reductive amina-
tion of aromatic aldehydes IV were somewhat lower,
and the reaction time was considerably longer. How-
ever, unlike the examined ketone oximes, aldehyde
oximes V with various substituents in the aromatic ring
are selectively reduced with LiAlH4 in high yield at
room temperature in 4–5 h (Scheme 2, Table 2).
An exception was aldehyde oxime Vn. We failed to
reduce it do 2-hydroxy-3-methoxybenzylamine (VIIn)
Reduction of 4-hydroxyacetophenone oxime with
sodium in liquid ammonia. Ammonia, 100 ml, was
distilled into a flask equipped with a stirrer and
a reflux condenser and cooled with dry ice, 10.9 g
(0.072 mol) of 4-hydroxyacetophenone oxime [11] and
29 ml of methanol were added, and 7.1 g (0.31 mol) of
metallic sodium was added in portions over a period of
2.5–3 h. The mixture was stirred for 2 h and left to
Scheme 2.
R1
R1
R1
R2
R3
CHO
R2
R3
OH
R2
R3
NH2OH ·HCl, EtOH–H2O
LiAlH4, THF
N
NH2
R4
R4
Va–Vf
R4
IVa–IVf
VIa, VIc, VIf
R1
R2
R3
HCl, dioxane
NH2
· HCl
R4
VIIb, VIId, VIIe, VIIg–VIIq
For substituents R1–R4, see Table 2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

COMPARISON OF DIFFERENT REDUCING SYSTEMS
1023
Table 1. Synthesis of benzylamines IIIa–IIIj by reductive amination of functionally substituted alkyl aryl ketones Ia–Ij
Product
R1
Et
R2
R3
Yield of hydrochloride III,a %
mp, °C
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
H
H
59
56
53
63
60
59
64
40
45
43
182–183
148–150
153–154
157–158
Me
Me
Me
Et
EtO
PrO
H
H
H
PrO
EtO
PrO
F
H
209–211 (decomp.)
163–164
Et
H
Me
Me
Me
Et
F
154–155
OH
H
H
150–152
OH
OH
185–186
IIIj
H
200–202
a
Calculated on the initial ketone.
Table 2. Synthesis of benzylamines VIa, VIc, and VIf and hydrochlorides VIIb, VIId, VIIe, and VIIg–VIIq by reduction of
aromatic aldehyde oximes V with LiAlH4
Product
R1
R2
R3
R4
Yield, %
mp, ºC
VIa
PrO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
77
67
82
70
62
79
67
72
65
72
75
69
69
47
72
72
71
a131–132a
141–142
a125–126a
188–190
96–97
VIIb
VIc
PrO
i-PrO
H
H
VIId
VIIe
VIf
H
i-PrO
H
s-BuO
H
H
s-BuO
H
H
a128–130a
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
VIIm
VIInb
VIIo
VIIp
VIIq
H
s-BuO
H
EtO
PrO
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
187–188
105–106
H
PrO
i-PrO
BuO
i-AmO
H
186–187 (decomp.)
195–200
H
H
180–185 (decomp.)
199–200
H
OH
PrO
i-PrO
Cl
194–196
H
154–156
H
H
147–149
H
Cl
188 decomp.)
a
Boiling point (5 mm).
Obtained by reductive amination.
b
stand for 24 h at room temperature until complete
evaporation of ammonia. The white precipitate was
dissolved in 200 ml of water, the mixture was acidified
with 4.5 N hydrochloric acid to pH 3–4 and then made
alkaline by adding aqueous ammonia to pH 8–9. The
aqueous phase was washed with diethyl ether, and
water was distilled off. The residue was dissolved in
ethanol, the undissolved material was filtered off, the
filtrate was acidified to pH 1–2, and the precipitate of
1-(4-hydroxyphenyl)ethanamine hydrochloride (IIIi)
was filtered off, washed with diethyl ether, and dried
under reduced pressure. Yield 10.5 g (75%).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

MUSATOV et al.
1024
1-(2-Propoxyphenyl)ethanamine hydrochloride
(IIIc). H NMR spectrum (DMSO-d6), δ, ppm: 1.08 t
Reductive amination of ketones Ia–Ig (general
1
procedure). A mixture of 1 mol of ketone I, 465 ml of
formamide, and 310 ml of formic acid was heated for
30 h under reflux (130°C). The mixture was then
poured into ice water and extracted with ethyl acetate.
The organic phase was washed with water, a saturated
aqueous solution of NaHCO3, and a saturated solution
of NaCl and dried over MgSO4. The solution was
filtered through a layer of silica gel, the solvent was
distilled off on a rotary evaporator, and the solid
residue was recrystallized from ethyl acetate–hexane
(2 :1). Formamide derivative II thus obtained was
dissolved in 1 l of ethanol, 0.5 l of water and 200 g of
potassium hydroxide were added, and the mixture was
heated for 20 h under reflux. The mixture was then
poured into 1 l of methylene chloride, the organic
phase was separated, washed with water and a saturat-
ed solution of NaCl, and dried over MgSO4, the sol-
vent was removed, and the residue was distilled under
reduced pressure. The resulting amine was dissolved in
ethyl acetate, a 6 N solution of HCl in dioxane was
added, and the precipitate was filtered off, washed with
diethyl ether, and dried under reduced pressure. The
yields of compounds IIIa–IIIg are given in Table 1.
(3H, CH2CH3), 1.59 d (3H, CHCH3), 1.87 m (2H,
OCH2CH2), 3.99 m (2H, OCH2), 4.63 m (1H, CH),
6.89 d (1H, Harom), 6.98 t (1H, Harom), 7.25 t (1H,
Harom), 7.58 d (1H, Harom), 8.72 br.s (3H, NH3+). Mass
spectrum, m/z (Irel, %): 179 (3) [M]+·, 164 (100), 147
(7), 136 (24), 122 (92), 104 (14), 95 (58), 77 (16), 65
(11), 59 (18). Found, %: C 61.42; H 8.45; Cl 16.55;
N 6.20. C11H17NO · HCl. Calculated, %: C 61.25;
H 8.41; Cl 16.43; N 6.49. M 179 (free amine).
1-(4-Propoxyphenyl)ethanamine hydrochloride
1
(IIId). H NMR spectrum (DMSO-d6), δ, ppm: 1.02 t
(3H, CH2CH3), 1.60 d (3H, CHCH3), 1.80 m (2H,
OCH2CH2), 3.88 m (2H, OCH2), 4.25 m (1H, CH),
6.84 d (2H, Harom), 7.44 d (2H, Harom), 8.75 br.s (3H,
NH3+). Mass spectrum, m/z (Irel, %): 179 (23) [M]+·, 164
(70), 136 (32), 122 (64), 107 (14), 95 (65), 77 (100),
65 (41). Found, %: C 61.40; H 8.47; Cl 16.55; N 6.18.
C11H17NO·HCl. Calculated, %: C 61.25; H 8.41;
Cl 16.43; N 6.49. M 179 (free amine).
1-(4-Ethoxyphenyl)propan-1-amine hydro-
1
chloride (IIIe). H NMR spectrum (DMSO-d6), δ,
ppm: 0.80 t (3H, OCH2CH3), 1.39 t (3H, CHCH2CH3),
1.91 m (1H, CHCH2CH3), 2.15 m (1H, CHCH2CH3),
3.99 m (3H, CH, OCH2), 6.84 d (2H, Harom), 7.40 d
(2H, Harom), 8.73 br.s (3H, NH3+). Mass spectrum, m/z
(Irel, %): 178 (1) [M – 1]+·, 163 (3), 150 (89), 133 (8),
122 (100), 106 (10), 95 (53), 76 (40), 59 (24). Found,
%: C 61.39; H 8.44; Cl 16.53; N 6.22. C11H17NO·HCl.
Calculated, %: C 61.25; H 8.41; Cl 16.43; N 6.49.
M 179 (free amine).
N-(1-Phenylpropyl)formamide (IIa) was obtained
from 148 g of ethyl phenyl ketone (Ia). Yield 130 g
(80%). 1H NMR spectrum (DMSO-d6), δ, ppm: 0.81 m
(3H, CH3), 1.70 m (2H, CH2), 4.79 m (1H, CH), 7.31 m
(5H, Harom), 8.10 s (1H, CHO), 8.43 d (1H, NH).
1-Phenylpropan-1-amine hydrochloride (IIIa).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.82 t (3H,
CH3), 1.93 m (1H, CH2), 2.18 m (1H, CH2), 4.01 m
(1H, CH), 7.33 m (3H, Harom), 7.49 d (2H, Harom),
8.85 br.s (3H, NH3+). Mass spectrum, m/z (Irel, %): 135
(2) [M]+·, 118 (4), 106 (100), 91 (5), 78 (30), 63 (5).
Found, %: C 63.24; H 8.28; Cl 20.83; N 7.65.
C9H13N · HCl. Calculated, %: C 62.97; H 8.22;
Cl 20.65; N 8.16. M 135 (free amine).
1-(4-Propoxyphenyl)propan-1-amine hydro-
1
chloride (IIIf). H NMR spectrum (DMSO-d6), δ,
ppm: 0.74 t (3H, OCH2CH2CH3), 0.95 t (3H, CHCH2-
CH3), 1.75 m (3H, CHCH2CH3, OCH2CH2CH3),
1.99 m (1H, CHCH2CH3), 3.91 t (2H, OCH2), 4.01 m
(1H, CH), 6.96 d (2H, Harom), 7.41 d (2H, Harom),
8.59 br.s (3H, NH3+). Mass spectrum, m/z (Irel, %): 193
(6) [M]+·, 177 (40), 164 (100), 150 (17), 133 (16), 122
(75), 107 (63), 95 (77), 76 (80). Found, %: C 62.87;
H 8.82; Cl 15.56; N 5.84. C12H19NO·HCl. Calculated,
%: C 62.73; H 8.77; Cl 15.43; N 6.10. M 193
(free amine).
1-(2-Ethoxyphenyl)ethanamine hydrochloride
1
(IIIb). H NMR spectrum (DMSO-d6), δ, ppm: 1.48 t
(3H, CH2CH3), 1.59 d (3H, CHCH3), 4.11 m (2H,
OCH2), 4.63 m (1H, CH), 6.87 d (1H, Harom), 6.93 t
(1H, Harom), 7.21 t (1H, Harom), 7.57 d (1H, Harom),
8.72 br.s (3H, NH3+). Mass spectrum, m/z (Irel, %): 165
[M]+· (8), 150 (100), 136 (5), 133 (22), 122 (27), 105
(22), 95 (31), 91 (24), 77 (43), 65 (12). Found, %:
C 59.70; H 8.08; Cl 17.68; N 6.71. C10H15NO·HCl.
Calculated, %: C 59.55; H 8.00; Cl 17.58; N 6.94.
M 165 (free amine).
1-(2,4-Difluorophenyl)ethanamine hydrochloride
1
(IIIg). H NMR spectrum (DMSO-d6), δ, ppm: 1.60 d
(3H, CHCH3), 4.59 m (1H, CH), 6.88 t (1H, Harom),
7.01 m (1H, Harom), 7.90 m (1H, Harom), 9.01 br.s (3H,
+
NH3 ). Mass spectrum, m/z (Irel, %): 157 (3) [M]+·, 156
(17), 142 (100), 121 (27), 115 (73), 101 (50), 95 (57),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

COMPARISON OF DIFFERENT REDUCING SYSTEMS
1025
75 (19), 63 (25). Found, %: C 49.74; H 5.23; Cl 18.45;
F 19.83; N 6.75. C8H9F2N · HCl. Calculated, %:
C 49.63; H 5.21; Cl 18.31; F 19.62; N 7.23. M 157
(free amine).
(1.2 mol) of sodium hydroxide in 0.5 l of water was
added to a solution of 1 mol of aldehyde IV in 0.5 l of
methanol, and the mixture was heated under reflux for
8 h. The mixture was poured into cold water, and the
product was extracted into methylene chloride. The
extract was washed with water, a saturated solution of
NaHCO3, and a saturated solution of NaCl and dried
over MgSO4, and the solvent was distilled off. The
residue (oxime V) was subjected to reduction without
additional purification; it was added in portion to
a suspension of 38.7 g (1.02 mol) of LiAlH4 in 1 l of
THF at such a rate that the mixture weakly boiled.
When the entire amount of oxime V was added, the
mixture was stirred for 3 h at room temperature and
heated for 1 h under reflux. Excess reducing agent was
quenched by treatment with ~100 ml of 40% aqueous
sodium hydroxide, the solution was separated by
decanting, and the precipitate was treated with THF on
heating under reflux over a period of 1 h. The solution
was filtered, the organic phases were combined, the
solvent was removed, and the residue (amine VI) was
distilled under reduced pressure. Hydrochlorides VII
were obtained as described above. The yields are given
in Table 2.
Reductive amination of ketones Ih–Ij (general
procedure). A mixture of 1 mol of ketone Ih–Ij,
465 ml of formamide, and 310 ml of formic acid was
heated for 30 h under reflux (130°C). Excess form-
amide and formic acid were distilled off from the
mixture at a residual pressure of 20 mm on heating on
a water bath, and the residue was subjected to alkaline
hydrolysis. The resulting amines was treated with
~450 ml of concentrated hydrochloric acid which was
added in portions until pH 2–3. The salt was filtered
off, and the mother liquor was evaporated. The solid
residue was dissolved in propan-2-ol, and the undis-
solved material was filtered off. After removal of the
solvent, benzylamine hydrochloride IIIh–IIIj was
recrystallized from propan-2-ol–diethyl ether (1:1).
The yields are given in Table 1.
1-(2-Hydroxyphenyl)ethanamine hydrochloride
1
(IIIh). H NMR spectrum (DMSO-d6), δ, ppm: 1.45 d
(3H, CHCH3), 4.51 m (1H, CH), 6.81 t (1H, Harom),
6.96 d (1H, Harom), 7.15 t (1H, Harom), 7.39 d (1H,
Harom), 8.38 br.s (3H, NH3+), 10.01 br.s (1H, OH).
Found, %: C 55.52; H 7.03; Cl 20.57; N 7.82.
C8H11NO · HCl. Calculated, %: C 55.34; H 6.97;
Cl 20.42; N 8.07.
2-Propoxyphenylmethanamine (VIa). bp 131–
1
132°C (5 mm). H NMR spectrum (CDCl3), δ, ppm:
1.09 t (3H, CH3), 1.82 m (4H, CH3CH2, NH2CH2),
3.98 t (2H, OCH2), 4.83 s (2H, NH2CH2), 6.90 m (2H,
H
arom), 7.22 m (2H, Harom). Mass spectrum, m/z
1-(4-Hydroxyphenyl)ethanamine hydrochloride
(IIIi). H NMR spectrum (DMSO-d6), δ, ppm: 1.47 d
(Irel, %): 165 (35) [M]+·, 148 (44), 133 (38), 122 (100),
106 (94), 95 (54), 77 (44), 69 (17), 57 (22). Found, %:
C 72.83; H 9.21; N 8.21. C10H15NO. Calculated, %:
C 72.69; H 9.15; N 8.48. M 165.
1
(3H, CHCH3), 4.24 m (1H, CH), 6.79 d (2H, Harom),
+
7.31 d (2H, Harom), 8.43 br.s (3H, NH3 ), 9.67 br.s (1H,
OH). Mass spectrum, m/z (Irel, %): 137 (34) [M]+·, 122
(100), 95 (77), 91 (24), 76 (44), 65 (54). Found, %:
C 55.57; H 7.03; Cl 20.56; N 7.84. C8H11NO·HCl.
Calculated, %: C 55.34; H 6.97; Cl 20.42; N 8.07.
3-Propoxyphenylmethanamine hydrochloride
1
(VIIb). H NMR spectrum (DMSO-d6), δ, ppm: 0.97 t
(3H, CH3), 3.95 m (4H, OCH2, NCH2), 1.41 m (3H,
CH3CH2CH2), 1.72 m (2H, CH3CH2), 6.90 d (1H,
Harom), 7.03 d (1H, Harom), 7.16 s (1H, Harom), 7.39 t
(1H, Harom), 8.61 br.s (3H, NH3+). Mass spectrum, m/z
(Irel, %): 165 (62) [M]+·, 148 (79), 136 (12), 133 (18),
122 (67), 106 (80), 95 (55), 77 (100), 66 (33). Found,
%: C 59.71; H 8.10; Cl 18.01; N 6.58. C10H15NO·HCl.
Calculated, %: C 59.55; H 8.00; Cl 17.58; N 6.94.
M 165 (free amine).
1-(4-Hydroxyphenyl)propan-1-amine hydro-
1
chloride (IIIj). H NMR spectrum (DMSO-d6), δ,
ppm: 1.23 t (3H, CH2CH3), 1.76 m (1H, CHCH2CH3),
1.98 m (1H, CHCH2CH3), 3.95 m (1H, CH), 6.81 d
(2H, Harom), 7.29 d (2H, Harom), 8.51 br.s (3H, NH3+),
9.71 br.s (1H, OH). Mass spectrum, m/z (Irel, %): 151
(5) [M]+·, 133 (32), 133 (22), 122 (73), 105 (27), 95
(78), 76 (100), 65 (30). Found, %: C 57.85; H 7.60;
Cl 19.01; N 7.08. C9H13NO · HCl. Calculated, %:
C 57.60; H 7.52; Cl 18.89; N 7.46. M 151 (free amine).
3-Isopropoxyphenylmethanamine (VIc). bp 125–
1
126°C (5 mm). H NMR spectrum (CDCl3), δ, ppm:
Reduction of aldehyde oximes IVa–IVq with
LiAlH4 (general procedure). A solution of 77.4 g
(1.2 mol) of hydroxylamine hydrochloride and 48 g
1.32 d [6H, (CH3)2CH], 1.43 br.s (2H, NCH2), 3.83 s
(2H, NH2), 4.59 m (1H, OCH), 6.87 m (3H, Harom),
7.22 m (1H, Harom). Mass spectrum, m/z (Irel, %): 165
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

MUSATOV et al.
1026
[M]+· (81), 149 (78), 133 (21), 122 (67), 107 (100), 95
(62), 77 (69), 69 (55), 56 (32). Found, %: C 72.84;
H 9.20; N 8.11. C10H15NO. Calculated, %: C 72.69;
H 9.15; N 8.48. M 165.
NH3+). Mass spectrum, m/z (Irel, %): 181 (28) [M]+·, 164
(20), 152 (100), 133 (40), 121 (11), 107 (32), 93 (37),
76 (27), 65 (34). Found, %: C 55.27; H 7.46; Cl 16.45;
N 6.07. C10H15NO2 ·HCl. Calculated, %: C 55.17;
H 7.41; Cl 16.29; N 6.43. M 181 (free amine).
4-Isopropoxyphenylmethanamine hydrochloride
(VIId). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.29 d
[6H, CH(CH3)2], 3.91 m (2H, NCH2), 4.55 m (1H,
OCH), 6.82 d (2H, Harom), 7.43 d (2H, Harom), 8.70 br.s
(3H, NH3+). Mass spectrum, m/z (Irel, %): 165 (48)
[M]+·, 149 (21), 122 (68), 107 (100), 95 (63), 76 (56),
65 (11). Found, %: C 59.72; H 8.08; Cl 17.72; N 6.69.
C10H15NO · HCl. Calculated, %: C 59.55; H 8.00;
Cl 17.58; N 6.94. M 165 (free amine).
3-Methoxy-2-propoxyphenylmethanamine
hydrochloride (VIIi). 1H NMR spectrum (DMSO-d6),
δ, ppm: 0.98 t (3H, CH3CH2), 1.71 m (2H, CH3CH2),
3.80 s (3H, OCH3), 3.97 m (4H, OCH2, NCH2), 7.08 m
(3H, Harom), 8.49 br.s (3H, NH3+). Mass spectrum, m/z
(Irel, %): 195 (38) [M]+·, 180 (5), 178 (29), 164 (13),
152 (75), 136 (100), 122 (26), 106 (81), 93 (54), 77
(24), 65 (38). Found, %: C 57.17; H 7.86; Cl 15.46;
N 5.78. C11H17NO2 ·HCl. Calculated, %: C 57.02;
H 7.83; Cl 15.30; N 6.04. M 195 (free amine).
2-(1-Methylpropyloxy)phenylmethanamine
hydrochloride (VIIe). 1H NMR spectrum (DMSO-d6),
δ, ppm: 1.01 t (3H, CH3CH2), 1.34 d (3H, CHCH3),
1.69 m (1H, CH3CH2), 1.82 m (1H, CH3CH2), 3.38 m
(1H, OCH), 3.98 m (2H, NCH2), 6.89 m (2H, Harom),
7.24 t (1H, Harom), 7.59 d (1H, Harom), 8.65 br.s (3H,
NH3+). Mass spectrum, m/z (Irel, %): 179 (19) [M]+·, 162
(27), 146 (73), 133 (60), 122 (62), 107 (100), 95 (70),
77 (87), 57 (71). Found, %: C 61.41; H 8.45; Cl 16.58;
N 6.01. C11H17NO·HCl. Calculated, %: C 61.25;
H 8.41; Cl 16.43; N 6.49. M 179 (free amine).
3-Methoxy-4-propoxyphenylmethanamine
hydrochloride (VIIj). 1H NMR spectrum (DMSO-d6),
δ, ppm: 0.94 t (3H, CH3), 1.70 m (2H, CH3CH2),
3.78 s (3H, OCH3), 3.89 m (4H, OCH2, NCH2), 6.96 m
(2H, Harom), 7.28 s (1H, Harom), 8.60 br.s (3H, NH3+).
Mass spectrum, m/z (Irel, %): 195 (75) [M]+·, 180 (6),
164 (46), 152 (100), 136 (70), 122 (62), 109 (24), 93
(37), 77 (22), 65 (38). Found, %: C 57.20; H 7.88;
Cl 15.46; N 5.78. C11H17NO2·HCl. Calculated, %:
C 57.02; H 7.83; Cl 15.30; N 6.04. M 195 (free amine).
3-(1-Methylpropyloxy)phenylmethanamine
1
(VIf). bp 128–130°C (5 mm). H NMR spectrum
4-Isopropoxy-3-methoxybenzaldehyde oxime
1
(CDCl3), δ, ppm: 1.00 t (3H, CH3CH2), 1.40 br.s (2H,
NH2), 1.59 d (3H, CHCH3), 1.70 m (2H, CH3CH2),
3.65 s (2H, NCH2), 4.62 m (1H, OCH), 6.63 m (3H,
Harom), 7.43 t (1H, Harom). Mass spectrum, m/z (Irel, %):
179 [M]+· (29), 163 (32), 148 (5), 133 (6), 122 (85),
107 (100), 94 (23), 78 (45), 69 (17), 56 (21). Found,
%: C 73.84; H 9.59; N 7.53. C11H17NO. Calculated, %:
C 73.70; H 9.56; N 7.81. M 179.
(Vk). H NMR spectrum (CDCl3), δ, ppm: 1.23 d
[6H, CH(CH3)2], 3.71 s (3H, OCH3), 4.54 m [1H,
CH(CH3)2], 6.71 d (1H, Harom), 7.01 d (1H, Harom), 7.48 s
(1H, Harom), 8.19 s (1H, CH=N), 9.59 br.s (1H, OH).
4-Isopropoxy-3-methoxyphenylmethanamine hy-
1
drochloride (VIIk). H NMR spectrum (DMSO-d6),
δ, ppm: 1.23 d [6H, CH(CH3)2], 3.77 s (3H, OCH3),
3.90 m (2H, NCH2), 4.52 m (1H, OCH), 6.96 m (2H,
Harom), 7.28 s (1H, Harom), 8.53 br.s (3H, NH3+). Mass
spectrum, m/z (Irel, %): 195 (78) [M]+·, 180 (3), 164
(15), 152 (100), 136 (58), 124 (90), 110 (31), 105 (13),
93 (27), 77 (29), 65 (27), 59 (13). Found, %: C 57.18;
H 7.88; Cl 15.45; N 5.77. C11H17NO2·HCl. Calculated,
%: C 57.02; H 7.83; Cl 15.30; N 6.04. M 195
(free amine).
4-(1-Methylpropyloxy)phenylmethanamine
hydrochloride (VIIg). 1H NMR spectrum (DMSO-d6),
δ, ppm: 0.92 t (3H, CH3CH2), 1.21 d (3H, CHCH3),
1.60 m (2H, CH3CH2), 3.91 br.s (2H, NCH2), 4.40 m
(1H, OCH), 6.92 d (2H, Harom), 7.42 d (2H, Harom),
8.55 br.s (3H, NH3+). Mass spectrum, m/z (Irel, %): 179
(46) [M]+·, 162 (12), 150 (11), 133 (9), 123 (89), 107
(100), 95 (35), 89 (35), 76 (80), 65 (23). Found, %:
C 61.38; H 8.46; Cl 16.57; N 6.02. C11H17NO·HCl.
Calculated, %: C 61.25; H 8.41; Cl 16.43; N 6.49.
M 179 (free amine).
4-Butoxy-3-methoxyphenylmethanamine hydro-
1
chloride (VIIl). H NMR spectrum (DMSO-d6), δ,
ppm: 0.90 t (3H, CH3), 1.41 m (2H, CH3CH2CH2),
1.67 m (2H, CH3CH2CH2), 3.67 s (3H, OCH3), 3.89 s
(2H, NCH2), 3.92 m (2H, OCH2), 6.95 m (2H, Harom),
7.27 s (1H, Harom), 8.58 br.s (3H, NH3+). Mass spec-
trum, m/z (Irel, %): 209 (72) [M]+·, 178 (10), 152 (100),
136 (62), 122 (28), 109 (34), 93 (13), 83 (15), 65 (21),
2-Ethoxy-3-methoxyphenylmethanamine hy-
drochloride (VIIh). 1H NMR spectrum (DMSO-d6), δ,
ppm: 1.30 t (3H, CH3CH2), 3.82 s (3H, OCH3), 4.03 m
(4H, OCH2, NCH2), 7.21 m (3H, Harom), 8.50 br.s (3H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

COMPARISON OF DIFFERENT REDUCING SYSTEMS
1027
59 (75). Found, %: C 58.90; H 8.22; Cl 14.60; N 5.43.
C12H19NO2 ·HCl. Calculated, %: C 58.65; H 8.20;
Cl 14.43; N 5.70. M 209 (free amine).
(21) [M]+·, 161 (10), 140 (100), 123 (9), 110 (15), 75
(17), 59 (24). Found, %: C 39.78; H 3.83; Cl 50.26;
N 6.13. C7H7Cl2N · HCl. Calculated, %: C 39.56;
H 3.79; Cl 50.05; N 6.59. M 176 (free amine).
3-Methoxy-4-(3-methylbutoxy)phenylmethan-
1
amine hydrochloride (VIIm). H NMR spectrum
REFERENCES
(DMSO-d6), δ, ppm: 0.89 d [6H, CH(CH3)2], 1.58 m
(2H, CHCH2CH2), 1.75 m [1H, CH(CH3)2], 3.77 s
(3H, CH3O), 3.90 s (2H, NCH2), 3.94 m (2H, OCH2),
6.95 m (2H, Harom), 7.28 s (1H, Harom), 8.57 br.s (3H,
NH3+). Mass spectrum, m/z (Irel, %): 223 (68) [M]+·, 193
(16), 167 (6), 152 (100), 136 (77), 122 (65), 109 (17),
92 (10), 80 (11), 65 (10), 59 (19). Found, %: C 60.27;
H 8.59; Cl 13.81; N 5.01. C13H21NO2·HCl. Calculated,
%: C 60.11; H 8.54; Cl 13.65; N 5.39. M 223
(free amine).
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2-Hydroxy-3-methoxyphenylmethanamine hy-
drochloride (VIIn). 1H NMR spectrum (DMSO-d6), δ,
ppm: 3.81 s (3H, OCH3), 3.93 m (2H, NCH2), 6.81 m
(1H, Harom), 6.99 d (2H, Harom), 8.41 br.s (3H, NH3+),
9.18 br.s (1H, OH). Mass spectrum, m/z (Irel, %): 153
(35) [M]+·, 136 (100), 122 (72), 106 (64), 95 (26), 79
(28), 65 (43). Found, %: C 50.81; H 6.44; Cl 18.84;
N 7.01. C8H11NO2 · HCl. Calculated, %: C 50.67;
H 6.38; Cl 18.69; N 7.39. M 153 (free amine).
5-Chloro-2-propoxyphenylmethanamine hydro-
1
chloride (VIIo). H NMR spectrum (DMSO-d6), δ,
ppm: 0.96 t (3H, CH3), 1.77 m (2H, CH3CH2), 3.96 m
(4H, NCH2, OCH2), 7.07 d (1H, Harom), 7.38 m (1H,
H
arom), 7.55 s (1H, Harom), 8.59 br.s (3H, NH3+). Mass
spectrum, m/z (Irel, %): 201/199 (15/45) [M]+·, 182
(39), 164 (45), 156 (100), 140 (90), 129 (36), 122 (80),
112 (78), 106 (40), 93 (15), 77 (40), 65 (40). Found,
%: C 51.03; H 6.47; Cl 30.20; N 5.55. C10H14ClNO·
HCl. Calculated, %: C 50.86; H 6.40; Cl 30.03;
N 5.93. M 200 (free amine).
7. Yamanaka, Y., Moritomo, M., Fujii, K., Tanaka, T.,
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Soc., 1948, vol. 70, p. 1315.
5-Chloro-2-isopropoxyphenylmethanamine hy-
1
drochloride (VIIp). H NMR spectrum (DMSO-d6),
δ, ppm: 1.28 d [6H, CH(CH3)2], 3.91 s (2H, NCH2),
4.63 m (1H, OCH), 7.08 d (1H, Harom), 7.33 d (1H,
H
arom), 7.56 s (1H, Harom), 8.51 br.s (3H, NH3+). Mass
spectrum, m/z (Irel, %): 201/199 (10/30) [M]+·, 182
(41), 164 (17), 156 (81), 140 (100), 129 (22), 122 (70),
112 (70), 106 (40), 93 (15), 77 (39), 65 (26). Found,
%: C 51.09; H 6.43; Cl 30.20; N 5.58. C10H14ClNO·
HCl. Calculated, %: C 50.86; H 6.40; Cl 30.03;
N 5.93. M 200.
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1983, vol. 38, p. 310.
2,4-Dichlorophenylmethanamine hydrochloride
(VIIq). 1H NMR spectrum (DMSO-d6), δ, ppm: 4.07 s
(2H, CH2), 7.51 d (1H, Harom), 7.70 m (2H, Harom),
8.84 br.s (3H, NH3+). Mass spectrum, m/z (Irel, %): 176
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vol. 34, p. 599.
17. Staskun, B. and van Es, T., J. Chem. Soc. C, 1966,
p. 531.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010