Carbamoyl and thiocarbamoyl derivatives of N-benzyl-aminomethyl-dimethyl- phosphine oxide

Article abstract of DOI:10.1080/10426500490466364

A series of thirteen new carbamoyl and thiocarbamoyl derivatives of N-benzyl-aminomethyl-dimethyl-phosphine oxide have been synthesized and characterized. The compounds were prepared via interaction of N-benzyl-aminomethyl-dimethyl-phosphine oxide with th

Full text of DOI:10.1080/10426500490466364

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Phosphorus, Sulfur, and Silicon and the Related
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CARBAMOYL AND THIOCARBAMOYL DERIVATIVES OF N-
BENZYL-AMINOMETHYL-DIMETHYL-PHOSPHINE OXIDE
Emil Tashev a , Viktoria Lachkova b , Helmut Keck c , Stoycho Shenkov a , Wolfgang Kläui c
Sabi Varbanov a
&
a Institute of Polymers, Bulgarian Academy of Sciences , Sofia, Bulgaria
b Department of Ecology , Sofia, Bulgaria
c Department of Inorganic Chemistry and Structural Chemistry , Düsseldorf, Germany
Published online: 16 Aug 2010.
To cite this article: Emil Tashev , Viktoria Lachkova , Helmut Keck , Stoycho Shenkov , Wolfgang Kläui & Sabi Varbanov (2004)
CARBAMOYL AND THIOCARBAMOYL DERIVATIVES OF N-BENZYL-AMINOMETHYL-DIMETHYL-PHOSPHINE OXIDE, Phosphorus, Sulfur,
and Silicon and the Related Elements, 179:9, 1757-1767, DOI: 10.1080/10426500490466364
To link to this article: http://dx.doi.org/10.1080/10426500490466364
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Phosphorus, Sulfur, and Silicon, 179:1757–1767, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490466364
CARBAMOYL AND THIOCARBAMOYL DERIVATIVES
OF N-BENZYL-AMINOMETHYL-DIMETHYL-
PHOSPHINE OXIDE
Emil Tashev,a Viktoria Lachkova,b Helmut Keck,c
Stoycho Shenkov,a Wolfgang Kla¨ui,c and Sabi Varbanova
Institute of Polymers, Bulgarian Academy of Sciences, Sofia,
Bulgaria;a Department of Ecology, Forestry University, Sofia,
Bulgaria;b and Department of Inorganic Chemistry and
Structural Chemistry, Heinrich-Heine University—Du¨sseldorf,
Du¨sseldorf, Germanyc
(Received December 30, 2003; accepted January 8, 2004)
A series of thirteen new carbamoyl and thiocarbamoyl derivatives of
N-benzyl-aminomethyl-dimethyl-phosphine oxide have been synthe-
sized and characterized. The compounds were prepared via inter-
action of N-benzyl-aminomethyl-dimethyl-phosphine oxide with the
corresponding isocyanates or isothiocyanates. The composition of the
synthesized novel compounds was proved by elemental analysis for ni-
trogen and the structures were confirmed by IR,1H-, 31P- 31P{1H} NMR
spectroscopy and by mass spectrometry.
Keywords: N-Benzyl-aminomethyl-dimethyl-phosphine oxide; N-
substituted-carbamoyl-(or thiocarbamoyl-)-N-benzyl-aminomethyl-
dimethyl-phosphine oxides; phosphorus-containing ureas and thio-
ureas; tertiary phosphine oxides
INTRODUCTION
Tertiary phosphine oxides functionalized with primary or secondary
amino groups and diesters of aminophosphonic acids are very inter-
esting as starting reagents for preparation of new organophosphorus
compounds.1−4 The highly reactive amino groups included in such com-
pounds allow the preparation of a great number of derivatives, such as
ureas, nitrosoureas, thioureas, Shiff bases, adducts with oxyranes and
bisoxyranes, and coordination compounds with metal ions.4−10 Some
The paper is dedicated to the memory of Professor Gueorgui Borissov.
Address correspondence to S. Varbanov, Institute of Polymers, Bulgarian Academy of
Sciences, BG-1113 Sofia, Bulgaria. E-mail: varbanov@polymer.bas.bg
1757

1758
E. Tashev et al.
of these derivatives have shown physiological activity, even antitumor
activity.7,11−13 This article is a continuation of our investigations on
the preparation of carbamoyl and thiocarbamoyl derivatives based on
tertiary phosphine oxides, functionalized with primary or secondary
amino groups and diesters of aminophosphonic acids.4−6 We report
here the synthesis and characterization of N-substituted carbamoyl-
(or thiocarbamoyl)-N-benzyl-aminomethyl-dimethylphosphine oxides
1–13 (Table I), which are expected to exhibit biological activity and
complex formation properties with metal ions.
RESULTS AND DISCUSSIONS
The starting secondary phosphorus-containing monoamine N-benzyl-
amino-methyl-dimethyl-phosphine oxide (BAPO) was prepared via sub-
stitution of the chlorine atom in dimethyl-chloromethyl-phosphine ox-
ide according to Scheme 1.
SCHEME 1
The preparation of BAPO from the same starting compounds was
marked by Maier2 and Schmutzler and coworkers,14,15 and was used
for synthetic purposes, but the synthesis, identification, and charac-
terization of the compound was not described. The BAPO is a solid,
white crystal and a hygroscopic substance soluble in alcohols, di-
ethyl ether, tetrahydrofurane, ethylacetate, DMFA, DMSO, toluene,
dichloromethane, and chloroform, and insoluble in aliphatic hydrocar-
bons (hexane, heptane) and water. The nuclear magnetic resonance
(NMR) data in CDCl3 (presented in the experimental part) confirm the
structure of the compound.
The carbamoyl- and thiocarbamoyl derivatives 1–13 (Table I) were
synthesized by nucleophilic addition of BAPO to the corresponding iso-
cyanates and isothiocyanates according to Scheme 2.
The interaction between the reagents was realized as described
previously by us5,6 in dichloromethane solution at room tempera-
ture with molar ratio of the reagents of 1:1. The products were iso-
lated by filtration after crystallization from the reaction mixture and
washing with dry diethyl ether, and recrystallized from ethanol or
ethanol-ethylacetate mixture. All reported new carbamoyl and thio-
carbamoyl derivatives have been prepared with almost quantitative

Carbamoyl Derivatives of Phosphine Oxides
1759
SCHEME 2
yields (Table II). The interaction between the reagents proceeds with an
exothermal effect. These two facts indicate that N-benzyl-aminomethyl-
dimethyl-phosphine oxide is a strong nucleophilic agent, similar
to the primary phosphorus-containing monoamine, aminomethyl-
dimethyl-phosphine oxide,1 and the secondary phosphorus-containing
monoamine with two phosphine oxide groups in the molecule,
bis(dimethyl-phosphinyl-methyl)amine.3
Some preparative and analytical data for the compounds 1–13 are
shown in Table II. All compounds are white crystalline substances that
melt at high temperatures. They are soluble in DMSO and DMFA, less
soluble in dichloromethane, chloroform, acetone, and methanol, spar-
ingly soluble in diethyl ether, tetrahydrofuran, and dioxane, and insol-
uble in aliphatic and aromatic hydrocarbons. The composition of 1–13
was established by elemental analysis for nitrogen (Table II). Their
1
1
structures were confirmed by IR-, H-, 31P-, and 31P{ H}-NMR spec-
troscopy and mass spectrometry.
The infrared spectra of 1–13 (Table III) showed characteristic bands
assigned to the phosphoryl group (P O) at 1141–1178 cm−1, methyl
groups bonded to a phosphorus atom (CH3-P) at 1294–1331 cm−1
,
bands of the carbonyl groups (C O) involved in hydrogen bonds at
1634–1657 cm−1 (Amide I), and intensive bands of the thiocarbonyl
group (C S) at 933–939 cm−1 and at 1246–1295 cm−1 (corresponding
to Amide I). Bands for amide (NH C O) and thioamide (NH C S)
groups at 1528–1547 cm−1 (Amide II) and several bands for N H at
3025–3386 cm−1 are present as well. Characteristic bands for aromatic

1760
E. Tashev et al.
TABLE I Molecular Structure of Carbamoyl and Thiocarbamoyl
Derivatives 1–13 of N-benzyl-aminomethyl-dimethyl-phosphine Oxide
No.
Compounds
1
1-Phenyl-3-benzyl-3-dimethylphosphinylmethyl-urea
2
3
4
1-(3-Chlorophenyl)-3-benzyl-3-dimethylphosphinylmethyl-urea
1-(4-Chlorophenyl)-3-benzyl-3-dimethylphosphinylmethyl-urea
1-(1-Naphthyl)-3-benzyl-3-dimethylphosphinylmethyl-urea
1-Cyclohexyl-3-benzyl-3-dimethylphosphinylmethyl-urea
1-Phenyl-3-benzyl-3-dimethylphosphinylmethyl-thiourea
1-(4-Chlorophenyl)-3-benzyl-3-dimethylphosphinylmethyl-thiourea
1-(4-Methylphenyl)-3-benzyl-3-dimethylphosphinylmethyl-thiourea
1-(4-Methoxyphenyl)-3-benzyl-3-dimethylphosphinylmethyl-thiourea
1,3-Dibenzyl-3-dimethylphosphinylmethyl-thiourea
5
6
7
8
9
10
11
12
13
1-Cyclohexyl-3-benzyl-3-dimethylphosphinylmethyl-thiourea
1-Ethyl-3-benzyl-3-dimethylphosphinylmethyl-thiourea
1-n-Butyl-3-benzyl-3-dimethylphosphinylmethyl-thiourea

Carbamoyl Derivatives of Phosphine Oxides
1761
TABLE II Preparative and Analytical Data of Carbamoyl and Thiocarbamoyl
Derivatives 1–13 of N-benzyl-aminomethyl-dimethyl-phosphine Oxide
Nitrogen, %
No
Yield, %
Melting point,◦C
General formula, mol. mass
C17H21N2O2P, 316,34
Found
Calcd.
1
2
3
4
5
6
7
8
9
10
11
12
13
96
98
99
92
97.7
96
98
97
99
96
94
99
98
176–177
148–149.5
188–189
222–224
163–165
169–170
167–168
159–161
164–165
144–145
173–174
173.5–174.5
124–124.5
8.95
7.82
7.81
7.52
8.54
8.58
7.79
7.95
7.64
7.96
7.15
9.76
8.85
8.86
7.99
7.99
7.65
8.69
8.43
7.64
8.09
7.73
8.09
7.21
9.85
8.97
C
17H20ClN2O2P, 350,78
C17H20ClN2O2P, 350,78
C21H23N2O2P, 366,40
C17H27N2O2P, 322,39
C
17H21N2OPS, 332,40
C17H20ClN2OPS, 367,85
C18H23N2OPS, 346,43
C18H23N2O2PS, 362,43
C18H23N2OPS, 346,43
C
17H27N2OPS, 338,45
C13H21N2OPS, 284,36
15H25N2OPS, 312,41
C
rings were at 1490–1503 cm−1 and 1588–1602 cm−1. The bands of
the phosphoryl groups (P O) of 1–13 are shifted with 30–50 cm−1 to
the lower frequencies when compared to nonsubstituted tertiary phos-
phine oxides, which is due to their association with N H amide and
thioamide protons via hydrogen bonds.16 Some of the compounds 1–13
show two bands for the phosphoryl group. This phenomenon could be
ascribed to different spatial isomers or two kinds of phosphoryl groups:
the first one bonded with hydrogen bond, while the second one did not
bond.16
The bands of CH2 groups in the cyclohexane ring are at 883, 2850,
and 2933 cm−1 for the compound 5 and at 877, 2859, and 2924 cm−1
for the compound 12. The bands for monosubstituted Ar-rings in 8 and
9 are at 742 cm−1 and 735 cm−1, respectively.
The NMR data correspond to the structure of the prepared com-
1
pounds (Table IV). The H-NMR study of 1–13 showed resonance sig-
2
nals as doublets for CH3 P O at 1.30–1.51 ppm and JHP = 12.6–
13.2 Hz. The resonance signals of the methylene protons CH2-P O
were registered as broad singlets for thiocarbamoyl compounds 6–13 at
4.00–4.24 ppm and as doublets for 1–5 carbamoyl compounds at 3.58–
3.82 ppm with 2JHP = 3.1–5.4 Hz. The resonance signals for Ar CH2
N
protons were singlets at 4.58–5.24 ppm. The resonances for NH C(X)
amide or thioamide protons were broad singlets at a wide region from
5.37 ppm for 5 to 9.91 ppm for 7. These signals disappear or their in-
tegral intensity is significantly reduced after deuterium exchange with
CD3OD, which is a relatively slow process at room temperature even

1762

1763

1764
E. Tashev et al.
in homogenous solution of CDCl3 and CD3OD. The resonances of
both kinds of the aryl protons were observed as multiplets at range
6.78–7.74 ppm.
The resonances of methyl (CH3-P), methylene (CH2-P), and
(Ar CH2 N) protons of the carbamoyl derivatives 1–5 are in stronger
field than the resonances of the same proton of thiocarbamoyl deriva-
tives 6–13.
1
The 31P{ H}-NMR and 31P-NMR spectra of the carbamoyl and thio-
carbamoyl derivatives 1–13 represent singlet or multiplet resonance
signals in the range from +45.29 to +46.68 ppm, respectively, which is
typical for tertiary phosphine oxides containing one methylene and two
methyl groups at the phosphorus atom.17
Mass spectrometric data (EI: 70 eV) that confirm the proposed
structures and elemental compositions of the compounds, are pre-
sented in Table V. In all mass spectra, signals due to molecular
ions can be found. The fragmentations of [M]+· can easily been
understood. The N C(X) bond seems to be very labile, and the
main fragmentation pathway is loss of C(X)NHR under formation of
[(CH3)2P(O)CH2NCH2C6H5]+ m/z 196. Peaks due to fragmentation
within the substituents R are of no importance. All spectra show abun-
dant signals for [CH2NH(CH2C6H5]+ (m/z 120) that has been formed
by elimination of CH3(CH2)PO (−76u) and [NH(CH2C6H5]+ (m/z 106),
which is generated by elimination of CH3(CH2)PO(CH2) (−90u) from
the ion m/z 196 and H-migration to the nitrogen atom.The base peak in
all spectra is m/z 91. It belongs to [C7H7]+—a typical fragment in mass
spectra of compounds containing a C6H5 CH2 substituent.
EXPERIMENTAL
Starting Materials
The used isocyanates and isothiocyanates were commercially available
products from Fluka (Switzerland) and Merck (Germany), while
chloromethyl-dimethyl-phosphine oxide was purchased from Hoechst
AG (Germany). The solvents were dried by standard procedures before
use.
Characterization of the Prepared Compounds 1–13
The elemental analysis for nitrogen content was performed according to
the method of Dumas. The melting points were measured on a Boetzius
microheating plate PHMK05 (Germany) and were uncorrected.
The infrared spectra (400–4000 cm−1) were recorded on a Bruker
Vector-22 infrared (IR) spectrometer as KBr pellets.

1765

1766
E. Tashev et al.
The 1H-NMR spectra were taken on a Bruker Advance DRX 500 spec-
trometer at 500.13 MHz in CDCl3. The chemical shifts are given rel-
1
ative to internal TMS (tetramethylsilane). The 31P and 31P{ H} NMR
spectra were registered in the same solvent on the same instrument
at 202.45 MHz. The chemical shifts are given relative to external 85%
aqueous H3PO4.
EI-mass spectra [EI-MS] were measured at 70 eV, source tempera-
ture 200◦C, using the direct inlet system on a Finnigan MAT 8200 mass
spectrometer.
Procedure for the Preparation of N-Benzyl-aminomethyl-
dimethyl-phosphine Oxide
A mixture of dimethyl-chloromethyl phosphine oxide (12.7 g, 0.10 mol)
benzylamine (24.5 g, 0.23 mol), and xylene (150 ml) was refluxed for
12 h in argon atmosphere. The formed benzylamine-hydrochloride was
removed by filtration, and the xylene was evaporated at reduced pres-
sure. The crude yellowish oil was dissolved in 150 ml chloroform, and
after filtration the solution was washed twice with water. After drying
with Na2SO4, the solvent was evaporated and the product distilled at
152–154◦C/0.3 Torr. Yield 86% (17.1 g). The product melts at 30–35◦C.
1H-NMR: δ = 7.24–7.33 (m, 5H, Ar H), δ = 3.86 (s, 2H, CH2-N, δ = 2.86
2
(d, 2H, CH2-P, JHP = 7,3 Hz), δ = 2.21 (s, 1H, NH), δ = 1.49 (d, 6H,
1
(CH3)2-P, 2JHP = 12.6 Hz). 31P{ H}-NMR: δ = +43.53 (s).
General Procedure for the Preparation of Carbamoyl
and Thiocarbamoyl Derivatives 1–13
A solution of isocyanate or isothiocyanate (4.0 mmol) in dichloro-
methane (1.0 ml) was added dropwise to a stirred solution of N-benzyl-
aminomethyl-dimethyl-phosphine oxide (4.0 mmol) in dry dichloro-
methane (3.0 ml) at room temperature. An exothermal reaction was
observed, and the reaction mixture was stirred at room temperature
until a solid product was obtained, which was then allowed to stay for
2 h. In some cases the reaction mixture was stirred at 30–40◦C for
15 min and approximately 1 ml of hexane or diethylether added and
cooled. The crude products were separated by filtration, washed with
diethyl ether, and recrystallized from ethanol or ethanol-ethylacetate
mixture to a constant melting point. The preparative and analytical
data of 1–13 are presented in Table II.
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Carbamoyl Derivatives of Phosphine Oxides
1767
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