Synthesis of 2-aminomethoxy-1-benzylsulfanylpentanes

Article abstract of DOI:10.1134/S1070428011060029

Mannich condensation of 1-benzylsulfanylpentane with equimolar amounts of formaldehyde and secondary amine gave in 3-4 h at 45-50°C the corresponding 2-aminomethoxy-1-benzylsulfanylpentanes in 72-76% yield. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011060029

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 6, pp. 842–844. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © E.G. Mamedbeili, I.A. Dzhafarov, K.A. Kochetkov, T.G. Kyazimova, Kh.I. Gasanov, S.T. Alieva, 2011, published in Zhurnal
Organicheskoi Khimii, 2011, Vol. 47, No. 6, pp. 830–832.
Synthesis of 2-Aminomethoxy-1-benzylsulfanylpentanes
E. G. Mamedbeilia, I. A. Dzhafarovb, K. A. Kochetkovc, T. G. Kyazimovaa,
Kh. I. Gasanovb, and S. T. Alievaa
a Mamedaliev Institute of Petrochemical Processes, National Academy of Sciences of Azerbaijan,
pr. Khodzhaly 30, Baku, Az 1025, Azerbaijan
e-mail: eldar_mamedbeyli@mail.ru
b Azerbaijan Pedagogical University, Baku, Azerbaijan
c Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
Received February 23, 2010
Abstract—Mannich condensation of 1-benzylsulfanylpentane with equimolar amounts of formaldehyde and
secondary amine gave in 3–4 h at 45–50°C the corresponding 2-aminomethoxy-1-benzylsulfanylpentanes in
72–76% yield.
DOI: 10.1134/S1070428011060029
Organic compounds containing both nitrogen and
sulfur atoms exhibit strong and diverse biological
activity. Effective antiviral, antitumor, neurotropic, and
antibacterial agents were found among such com-
pounds [1]. Some nitrogen-and-sulfur-containing
derivatives are used as antioxidant, anticorrosion, and
antimicrobial dopes to fuels and oils [2]. An important
problem is search for new N,S-containing compounds
and improvement of general procedures for their
synthesis [3].
phenylmethanethiol (I) with an equimolar amount of
1-bromopentan-2-ol (II) in alkaline medium (40% aq.
sodium hydroxide, 50–60°C, 3–4 h; Scheme 1). Alco-
hol III was then brought into Mannich condensation
with formaldehyde and secondary amines IVa–IVe
taken at an equimolar ratio. The Mannich reactions
were carried out at 45–50°C (reaction time 3–4 h), and
the products were new 2-aminomethoxy-1-benzylsul-
fanylpentanes Va–Ve (Scheme 2).
Scheme 2.
Mannich reaction is widely used in the synthesis of
organic compounds containing nitrogen and sulfur
atoms [4]. While continuing our studies on the
chemistry of dialkylamino derivatives of aryl(alkyl)-
sulfanylalkanes [5], in the present work we synthesized
aminomethoxy derivatives of 1-benzylsulfanylpentane
and examined their antimicrobial activity. In the first
step of our study we synthesized previously unknown
1-benzylsulfanylpentan-2-ol (III) by reaction of
Me
NR2
45–50°C
–H2O
Ph
S
III + CH2O + HNR2
IVa–IVe
O
Va–Ve
R = Et (a), Bu (b); R2N = piperidino (c), morpholino (d),
azepan-1-yl (e).
Alcohol III and amines Va–Ve were isolated as
colorless liquids with a sharp odor. Compounds Va–Ve
are insoluble in water but are readily soluble in organic
solvents (ethanol, acetone, benzene, CHCl3, CCl4,
etc.). Their structure was determined on the basis of
Scheme 1.
Me
Br
PhCH2SH +
1
their elemental compositions and IR, H NMR, and
OH
mass spectra. The purity of the initial compounds and
products and composition of the reaction mixtures
were monitored by gas–liquid chromatography.
I
II
Me
NaOH, 50–60°C
Ph
S
+ NaBr + H2O
OH
III
The IR spectrum of III contained a broad absorp-
tion band in the region of 3625 cm–1, which is typical
842

SYNTHESIS OF 2-AMINOMETHOXY-1-BENZYLSULFANYLPENTANES
843
of stretching vibrations of hydroxy group (νOH) in
secondary alcohols; no such band was present in the
IR spectra of Va–Ve. Compounds III and Va–Ve dis-
played in the IR spectra absorption bands at 2910–
2895 and 2850–2830 cm–1 due to vibrations of C–H
bonds in CH3 and CH2 groups, respectively. Stretching
vibrations of aromatic C–C bonds in Va–Ve gave
medium-intensity absorption bands at 1600–1585 and
1500–1400 cm–1. Medium-intensity bands at 3100–
3050 cm–1 belong to stretching vibrations of C–H
bonds in the benzene ring. The IR spectra of III and
Va–Ve also contained strong absorption bands in the
region 700–650 cm–1 due to out-of-plane bending vi-
brations of C–H bonds (δC–H). Stretching vibrations of
the C–O bonds appeared as a strong band at 1100–
1050 cm–1, and C–N vibrations gave rise to a medium-
intensity band at 1250–1200 cm–1. In the IR spectra of
Va–Ve we also observed absorption bands in the
region 735–730 cm–1, which are typical of C–S stretch-
ing vibrations.
washed with water until neutral washings and dried
over MgSO4. The solvent was distilled off, and the
residue was distilled under reduced pressure. Yield
73.6 g (70%), bp 146–148°C (1 mm), nD20 = 1.5476,
d240 = 1.0528; MRD = 63.42, calcd. 63.76. IR spectrum,
ν, cm–1: 3625 (OH), 2910 (CH3), 2850 (CH2), 3070
(C–Harom), 1590 (C=Carom), 1050 (C–O), 730 (C–S).
1H NMR spectrum, δ, ppm: 0.9 t (3H, CH3), 1.5 m
(4H, CH2), 2.5 t (2H, CH2S), 2.8 m (OH), 3.5 t (OCH),
3.8 s (2H, PhCH2), 7.30 m (1H, p-H), 7.34 m (2H,
m-H), 7.36 m (2H, o-H). Mass spectrum, m/z (Irel, %):
210 (10) [M]+, 193 (100) [M – OH]+, 179 (8) [M –
OH – CH2]+, 138 (72) [C8H10S]+, 135 (19) [M –
C11H9 – H2O]+, 122 (6) [C7H6S]+, 95 (50) [PhCH2]+.
Found, %: C 68.34; H 8.56; S 15.12. C12H18OS. Cal-
culated, %: C 68.54; H 8.62; S 15.24. M 210.34.
2-Aminomethoxy-1-benzylsulfanylpentanes Va–
Ve (general procedure). Freshly distilled amine IVa–
IVe, 0.03 mol, was added dropwise to a solution of
0.03 mol of alcohol III and 0.03 mol of formaldehyde
(generated from paraformaldehyde during the process)
in 30 ml of anhydrous benzene under stirring at 20–
22°C. The mixture was stirred for 1 h at that tempera-
ture and for 3–4 h at 45–50°C. The solvent was dis-
tilled off, and the residue was distilled under reduced
pressure.
1
The H NMR spectra of III and Va–Ve were con-
sistent with the assumed structures. Compounds III
and Va–Ve displayed in the mass spectra the corre-
sponding molecular ion peaks and fragment ion peaks.
EXPERIMENTAL
N-[1-(Benzylsulfanyl)pentan-2-yloxymethyl]-
N-ethylethanamine (Va) was synthesized from 6.3 g
(0.03 mol) of compound III, 0.9 g (0.03 mol) of para-
formaldehyde, and 2.19 g (0.03 mol) of diethylamine
(IVa). Yield 6.4 g (72%), bp 152–153°C (1 mm), nD20 =
1.5148, d240 = 0.9776; MRD = 91.09, calcd. 91.01. IR
spectrum, ν, cm–1: 3070 (C–Harom), 2900 (CH3), 2840
(CH2), 1600 (C=Carom), 1200 (C–N), 1100 (C–O), 735
The IR spectra were recorded on a UR-20 spec-
trometer. The H NMR spectra were measured on
1
a Bruker WP-400 spectrometer (400 MHz) from solu-
tions in CDCl3 using tetramethylsilane as internal
reference. The mass spectra (electron impact, 70 eV)
were obtained on a VG-7070E mass spectrometer. The
densities d420 (g/cm3) were determined by weighing
precisely measured volumes, and the refractive indices
n2D0 were measured using an IRF-22 refractometer.
Chromatographic analysis of the reaction mixtures and
products was performed on an LKhM-8MD chroma-
tograph equipped with a thermal conductivity detector
and a 300 ×3-mm steel column packed with 5% of
polyethylene glycol succinate on Dinokhrom P; carrier
gas helium, flow rate 40 cm3/min; oven temperature
150°C, injector temperature 240°C.
1
(C–S). H NMR spectrum, δ, ppm: 1.0–1.18 m (9H,
CH3), 1.35 m (4H, CH2), 2.65–2.95 m (6H, NCH2,
SCH2), 7.36 m (2H, o-H), 3.40 t (OCH), 3.80 s (2H,
PhCH2), 4.20 d.d (2H, OCH2N), 7.34 m (2H, m-H),
7.30 m (1H, p-H). Mass spectrum, m/z (Irel, %): 295 (7)
[M]+, 223 (11) [M – C4H10N]+, 192 (9) [M – C5H11N –
H2O]+, 153 (72) [M – C8H10S]+, 122 (100) [C7H6S]+,
95 (36) [PhCH2]+, 72 (6) [C4H10N]+. Found, %:
C 68.88; H 9.82; N 4.70; S 10.75. C17H29NOS. Cal-
culated, %: C 69.10; H 9.89; N 4.74; S 10.85. M 295.5.
N-[1-(Benzylsulfanyl)pentan-2-yloxymethyl]-
N-butylbutanamine (Vb) was synthesized from 6.3 g
(0.03 mol) of compound III, 0.9 g (0.03 mol) of para-
formaldehyde, and 3.87 g (0.03 mol) of dibutylamine
(IVb). Yield 8.02 g (76%), bp 182–184°C (1 mm),
n2D0 = 1.5024, d420 = 0.9481; MRD = 109.5, calcd. 109.6.
IR spectrum, ν, cm–1: 3060 (C–Harom), 2910 (CH3),
1-(Benzylsulfanyl)pentan-2-ol (III). 1-Bromopen-
tan-2-ol (II), 83.5 g (0.5 mol), was added dropwise to
a mixture of 62 g (0.5 mol) of phenylmethanethiol (I)
and 20 g (0.5 mol) of sodium hydroxide in 30 ml of
water (a 40% solution) under vigorous stirring at 50°C.
The mixture was stirred for 3–4 h at 50–60°C and
cooled, 50 ml of benzene was added, the aqueous
phase was separated, and the organic phase was
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MAMEDBEILI et al.
844
2850 (CH2), 1585 (C=Carom), 1200 (C–N), 1050 (C–O),
735 (C–S). H NMR spectrum, δ, ppm: 0.95 t (9H,
alcohol III, 0.9 g (0.03 mol) of paraformaldehyde, and
2.97 g (0.03 mol) of hexamethyleneimine (IVe). Yield
7.33 g (76%), bp 180–182°C (1 mm), nD20 = 1.5268,
d240 = 1.0062; MRD = 98.21, calcd. 98.24. IR spectrum,
ν, cm–1: 3050 (C–Harom); 2895 (CH3); 2830 (CH2);
1600, 1500 (C=Carom); 1200 (C–N); 1050 (C–O); 735
1
CH3), 1.35–1.45 m (12H, CH2), 2.45–2.65 m (6H,
SCH2, NCH2), 3.40 t (OCH), 3.80 s (2H, PhCH2),
4.25 d.d (OCH2N), 7.35 m (5H, C6H5). Mass spectrum,
m/z (Irel, %); 352 (6) [M + H]+, 351 (27) [M]+, 333 (27)
[M – H2O]+, 193 (36) [M – C9H20NO]+, 122 (100)
[C7H6S]+. Found, %: C 71.58; H 10.53; N 3.94; S 9.03.
C21H37NOS. Calculated, %: C 71.74; H 10.60; N 3.98;
S 10.43. M 351.61.
1
(C–S). H NMR spectrum, δ, ppm: 0.95 t (3H, CH3),
1.35 m (4H, CH2), 1.62 t (8H, CH2), 2.60 m (4H,
NCH2), 3.35 t (OCH), 3.80 s (2H, PhCH2), 4.20 d.d
(2H, OCH2N), 7.30 m (5H, C6H5), Mass spectrum, m/z
(Irel, %): 321 (5) [M]+, 230 (5) [M – C6H5N]+, 213 (8)
[M – C6H6NO]+, 138 (27) [C8H10S]+, 91 (100)
[C6H5N]+. Found, %: C 70.75; H 9.66; N 4.33; S 9.89.
C19H31NOS. Calculated, %: C 70.98; H 9.72; N 4.36;
S 9.97. M 321.54.
N-[1-(Benzylsulfanyl)pentan-2-yloxymethyl]
piperidine (Vc) was synthesized from 6.3 g (0.03 mol)
of alcohol III, 0.9 g (0.03 mol) of paraformaldehyde,
and 2.55 g (0.03 mol) of piperidine (IVc). Yield 6.83 g
(74%), bp 176–178°C (1 mm), nD20 = 1.5282, d420
=
1.0094; MRD = 93.83, calcd. 93.60. IR spectrum, ν,
cm–1: 3050 (C–Harom), 2895 (CH3), 2850 (CH2), 1585
(C=Carom), 1250 (C–N), 1050 (C–O), 650 (C–S).
1H NMR spectrum, δ, ppm: 0.95 t (3H, CH3), 1.35 m
(4H, CH2), 1.63 m (6H, CH2), 2.40 m (2H, SCH2),
3.40 t (OCH), 3.80 s (2H, PhCH2), 4.25 d.d (2H,
OCH2N), 7.35 m (5H, C6H5). Mass spectrum, m/z
(Irel, %); 307 (6) [M]+, 289 (8) [M – H2O]+, 264 (5)
[M – C3H7]+, 204 (7) [M – C15H11N – H2O]+, 193 (5)
[C12H17S]+, 122 (100) [C7H6S]+, 91 (78) [PhCH2]+.
Found, %: C 70.16; H 9.43; N 4.51, S 10.34.
C18H28NOS. Calculated, %: C 70.31; H 9.51; N 4.55;
S 10.43. M 307.51.
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N-[1-(Benzylsulfanyl)pentan-2-yloxymethyl]-
morpholine (Vd) was synthesized from 6.3 g
(0.03 mol) of alcohol III, 0.9 g (0.03 mol) of para-
formaldehyde, and 2.61 g (0.03 mol) of morpholine
(IVd). Yield 6.96 g (75%), bp 182–184°C (2 mm),
n2D0 = 1.5278, d420 = 1.0456; MRD = 91.11, calcd. 90.72.
IR spectrum, ν, cm–1: 3060 (C–Harom); 2900 (CH3);
2840 (CH2); 1600, 1500 (C=Carom); 1250 (C–N); 1100
1
(C–O); 750 (C–S). H NMR spectrum, δ, ppm: 0.95 t
(3H, CH3), 1.35 m (4H, CH2), 2.60–2.80 m (10H,
OCH2, NCH2, SCH2), 3.20 quint (OCH), 3.80 s (2H,
PhCH2), 4.20 d.d (2H, OCH2N), 7.30 m (5H, C6H5).
Mass spectrum, m/z (Irel, %): 309 (6) [M]+, 291 (8)
[M – H2O]+, 225 (3) [M – C4H6NO]+, 210 (8) [M –
C5H9NO]+, 192 (5) [M – C5H11NO2]+, 99 (100)
[C5H9NO]+. Found, %: C 65.81; H 8.73; N 4.49;
S 10.28. C17H27NO2S. Calculated, %: C 65.98; H 8.79;
N 4.53; S 10.36. M 309.47.
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1-[1-(Benzylsulfanyl)pentan-2-yloxymethyl]az-
epane (Ve) was synthesized from 6.3 g (0.03 mol) of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011