Synthesis and structural Studies of phosphonothioamidates

Article abstract of DOI:10.1080/10426507.2015.1024783

The reaction of isothiocyanates with dialkylphosphites in the presence of strong base yielded the phosphonothioamides 2. Treatment of 2 with methyl iodide afforded the corresponding thioimidates 3 with high yields. All compounds were characterized on the

Full text of DOI:10.1080/10426507.2015.1024783

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis and structural studies of
phosphonothioamidates
R. Omrania, F. Ben Amorb, M. Bahric, M. L. Efrita & A. Ben Akachaa
a Department of Chemistry, Faculty of Science, Laboratory of Heterocyclic and Organic
Synthesis, El Manar, 2092 Tunisia
b Department of Chemistry, Faculty of Science, Laboratory of Materials and Crystalloid
Chemistry, El Manar, 2092 Tunisia
c Department of Physics, Faculty of Science, Laboratory of Atomic Spectroscopic, Molecular
and Applications, El Manar, 2092 Tunisia
Accepted author version posted online: 18 Mar 2015.
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To cite this article: R. Omrani, F. Ben Amor, M. Bahri, M. L. Efrit & A. Ben Akacha (2015): Synthesis and structural studies of
phosphonothioamidates, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2015.1024783
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Synthesis and structural studies of phosphonothioamidates
R.Omrania, F. Ben Amorb, M.Bahric, M. L.Efrita, A. Ben Akachaa*
aDepartment of Chemistry, Faculty of Science, Laboratory of Heterocyclic and Organic
Synthesis, El Manar, 2092 Tunisia
bDepartment of Chemistry, Faculty of Science, Laboratory of Materials and Crystalloid
Chemistry, El Manar, 2092 Tunisia
c
Department of Physics, Faculty of Science, Laboratory of Atomic Spectroscopic, Molecular
and Applications, El Manar, 2092 Tunisia
*e-mail: azaiezbenakacha@yahoo.fr
Abstract
The reaction of isothiocyanates with dialkylphosphites in the presence of strong base yielded the
phosphonothioamides 2. Treatment of 2 with methyl iodide afforded the corresponding
thioimidates 3 with high yields.All compounds were characterized on the basis of their IR, NMR
Spectroscopy (1H, 13C, 19F and 31P) and in some cases by elemental analysis, HRMS data and
calculations using Density Functional Theory (DFT)-B3LYP//6-311G** and evolution study by
31P-NMR in an external lock with D2O. The conformational molecular structure of compounds
2d and 2f were determined by single-crystal X-ray diffraction analysis.
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O
P
O
P
O
K+
RO
RO
RO
RO
RO
N-
1/ t-BuO- K+ / THF (r.t)
NR1
P
H
R1
2/ R1-N=C=S
RO
K+
S-
S
1
3/ H2O / H+
3/ MeI
4/ H2O / H+
O
H
N
O
P
RO
P
RO
RO
N
RO
R1
R1
S
S
2
3
Keywords
phosphonothioamidates, phosphonatesthioimidates, X-ray, DFT
2
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1. Introduction
Thioamides are commonly known for their biological activity [1] as antifungal and anticancer
[2] agents, are used in the development of peptide [3] and protein chemistry [3]. Many studies
describe the preparation of thioamide derivatives[1],[2],[5-12], as the best known methods of adding
isothiocyanates to secondary amines[1], or the thionation of amides[2],[4],[5]; by the reaction of
dialkylphosphite with isothiocyanate which gave reasonable yields of phosphothioamidates[11]-
[12]. Furthermore They were a preparation of triethylphosphite-pyridinium iodide and
isothiocyanates[13]. The synthesis of thioimidates derivatives has been the prominent research
discussed in different academic studies [14-16].In the present work, we report on the synthesis of a
series of phosphonothioamidates2and the corresponding methyl alkylated thioimidates 3.
2. Results and discussion
2.1. Synthesis
2.1.1 Preparation of phosphonothioamidates2a-h
A general strategy based on the reaction of isothiocyanates with dialkylphosphites1 in the
presence of potassium tert-butoxide in anhydrous THF, followed by acid hydrolysis at room
temperature is a useful method to prepare the thioamide derivatives2a-h. The synthetic
approach to obtain thioamides followed the reactions shown in Table 1. The thioamide
derivatives 2a-h were obtained in high yields in s-Cis conformation, which is the most
favored major product in general [17]. It is worth noting that, as far as we are aware, these
[11]
compounds are all new except product 2h which was previously described by Tashma
using NaH as the base.
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After following the steps for the preparation of compounds above, we have used 31P-NMR
spectroscopy for the detection of intermediate reaction in THF in an external lock with D2Oand
we give the case of 2f as example. From the 31P-NMR spectrum, the signal of diethylphosphite in
31
anhydrous THF appears at 7.1 ppm. By adding the t-BuOK, the P-NMR spectrum shows the
appearance of new signals between 154.7 and 145.1ppm corresponding to potassium diethyl
phosphate. The addition of Ph-N=C=S to potassium diethyl phosphate gives
potassium(diethoxyphosphoryl)-N-phenylmethanimidothioate and carbonothioyl (phenyl)amide.
This is confirmed by the presence in the NMR spectrum in THF in external lock with D2O of two
signals in the range 5.8 and 3.2ppm assignment to the two anions. After acid hydrolysis, a signal
appearing at -1.7ppm refers tothe compound 2f (Scheme 1).
All the compounds were characterized by their 31P-NMR and 19F-NMR spectra which
displayed one signal. For example, for 2 (entry d), we note the appearance of one signal at
0.1ppm in the 31P-NMR and -112.3ppm in the 19F-NMR spectra. The structures of the latter
products were confirmed by the presence of a characteristic signal due to the secondary amine
1
NHR1 proton at 8-11ppm in their H NMR spectra. The IR spectra of compounds 2a, c-f and h
displayed absorption bands in CHCl3 at 1520.0– 1650.0cm-1, 1240.1– 1250.5cm-1 and intense
absorption band at 3153.9-3249.1cm-1. These bands can be assigned to the stretching vibrations
of the υC=C, υPO and υNH, respectively. The 13C NMR spectra of the thioamides 2 shows a
doublet signal at 189.0-192.5ppm with a coupling constant of 183.0 Hz, which is typical for a
C=S group and at 115.0-134.0ppm, which is typical for a Carom fragment.
2.1.2. Preparation of phosphonothioamidates 3a-f
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The most convenient method was to generate the phosphonothioimidate 3a-f derivatives in-
situ by treating thioamides 2 with methyl iodide. In this way, dialkylphosphite (1.0 equiv),
therefore t-BuOK (1.5 equiv), R1NCS (1.0equiv), and methyl iodide (1.0 equiv) were mixed in a
suitable solvent at room temperature to give the desired phosphonothioimidates in good overall
yield (Table 2).
Taking the example of case of 3a, the signal of dimethylphosphite in anhydrous THF appears
at 10.3ppm. After addition of t-BuOK, the signal at 152.7ppm characterizing the potassium
dimethyl phosphate was observed. Adding phenyl isothiocyanate to the phosphonium potassium
salt produces the anion potassium sulfide and azide at 3.8-3.7ppm. After S-methylation followed
by acid hydrolysis, the appearance of signal at -3.5ppm, confirms the thioimidate structure with
Syn conformation (Scheme 2).
In the IR spectra in CHCl3 of the compounds 3a-f, the appearance of the absorption bands at
1645-1650 cm-1 and 1235 cm-1 corresponding to the stretching vibrations of the υC=C and υC=N
and υPO respectively. The 13C-NMR spectra in CDCl3of the compounds thioimidates shows a
doublet signal at 200 ppm with a coupling constant of 196 Hz, which is typical for a N=C-SMe
fragment and 10.3-16.3 ppm, which is typical for a S-CH3 fragment. The signal of S-Me in the
1H-NMR spectrum was observed at 2.1ppm with the absence of the secondary amine proton
31
signal. Only one signal was detected in the P-NMR spectra for all compounds confirming the
31
structure of 3a-f with a Syn conformation. For example, the P-NMR spectrum of 3ain CDCl3
shows one signal at -3.5ppm.
2.2. X-Rayanalysis
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The X-Ray analysis shows that the phosphonothioamidates2d and 2f adopt an s-Cis
conformation structure in the solid state (Figs.1and 2). The structure is built up from
C9H11FNO3PS and C11H16NO3PS molecules stabilized by N-H..O intermolecular hydrogen
bonds (Tables 5-6). The distances and the angles of the compounds 2d and 2f are summarized in
the table 3 and 4.
2.3. DFT calculations
To study the relative stability of the different considered molecular species we have
performed DFT electronic structure calculations. All the minimum energy structures were
[17-[18]
determined by the B3LYP functional implemented in the Gaussian 03 series of programs
using the 6-311G** basis set. The optimization of each structure was considered as converging
with a maximum gradient less than 0.0001. No frozen coordinates and no symmetry restriction
were used. (Figure 3)
3. Conclusion
A new series of phosphonothioamidates 2a-h were synthesized with good yields. The methyl
alkylated analogs 3a-f were obtained in situ and isolated in good yields. The X-ray structures of
phosphonothioamidates2d and 2f were determined and showed that these compounds exist in the
the s-Cis form.
4. Experimentalsection
4.1. General
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1H, 13C, 19F and 31P NMR spectra were recorded at 300, 75, 282 and 121 MHz respectively on
a Bruker AC-300 with TMS as internal reference (for 1H and 13C), CHF3 (for 19F) and H3PO4 (for
31P) in CDCl3.
The melting point was determined by Büchi. Infrared spectra were recorded by using
Shimadzu FTIR 8400S.Mass spectra were accomplished with an HP 5889A quadripolar
spectrometer by electronic impact EI (70 eV) or chemical ionization CI (500 eV) with NH3 gas.
High-Resolution Mass Spectrometry (HRMS) analyses were performed at the “Centre Commun
de Spectrométrie de Masse” in Lyon (France), on a Micro-TOFOII Thermofischer Scientific for
electro-spray ionization (ESI) measurements. CHN elementary were performed at the INRAP
(National Institute of Physico-Chemical Analysis (INRAP) Bio-technopole Sidi Thabet, Tunisia)
Perkin Elmer Model: Analyzer 2400 series II CHN.
31
The study of the evolution of the reaction mixture was performed by P NMR using in an
31
19
external lock with D2O. The Supplemental Materials file presents sample 1H, P and F NMR
spectra of selected products (Figures S 1 – S 14)
4.2. Crystallographic information
CCDC-965890 and CCDC-1001884 of the compounds (2d) and (2f) contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
General procedure for the preparation of phosphonothioamidates (2a-h)
A solution composed by dialkylphosphite1 (0.02 mol, 1.0 equiv) in anhydrous THF (10 mL)
was added dropwise to a solution of potassium tert-butoxide (0.025 mol, 1.5 equiv) in anhydrous
THF (30 mL). Continuous stirring at room temperature and under a nitrogen atmosphere for 1 h.
Isothiocyanate (0.02 mol, 1.0 equiv) in dry THF (10 mL) was added to the reaction mixture.
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After 3h of stirring at room temperature, the hydrolysis was performed with an aqueous saturated
H2O/HCl solution. The aqueous layer was then extracted by CHCl3. After drying (MgSO4 or
Na2SO4), filtration and solvent evaporation, the residue obtained was recrystallized with
ethanol.The oily and viscous mixture residue was purified by column chromatography on Ether
to give pure product.
(2a). dimethyl phenylcarbamothioylphosphonate Yellow solid; yield= 92%; mp 102.3°C; 1H
NMR 8H (ppm): 3.94 ( d, J= 11.1 Hz, 6H, CH3), 7.25-7.51 ( m, 5H, Harom), 10.65 (d, J= 8.7 Hz,
1H, NH).13C NMR 8C (ppm): 189.0 (d, J= 183.7Hz, C=S), 137.9(d, J= 15.7Hz, Cipso), 122.1-
127.6 (Carom), 55.4 (s, MeO). 31P NMR 8H (ppm): (2a ) = 0.2. IR (CHCl3 , υ cm-1): NH= 3153.9,
(C=C)arom = 1601.6, PO = 1249.3. for m/z for C9H12NO3PS 245g.mol-1 found m/z: 244.95 (M+),
PO(OMe)2:109.90, S=C=NPh: 134.87.
(2b).dimethyl cyclohexylcarbamothioylphosphonate Yellow solid; yield= 80%; mp 108.8°C;
1H NMR 8H (ppm): 1.07– 2.27 ( m, 11H, Hcyclohexyl), 3.88 (d, J= 1.4 Hz, 6H, CH3), 4.26 – 4.63
(m, 1H, Hipso ), 8.89 (s, 1H, NH ).13C NMR 8C (ppm): 189.6 (d, 180.4Hz, C=S), 55.2 (s, Cipso),
53.8(d, 8Hz, MeO), 24.0-30.9 (Chexyl). 31P NMR 8P (ppm): (2b ) = 0.3. IR (CHCl3 , υ cm-1): NH=
3195.8, (C-C)hexyl= 1640.8, PO = 1246.6. m/z for C9H18NO3PS : 251g.mol-1 found m/z: 251.02
(M+), PO(OMe)2:109.90, NH(C6H11): 97.94.
1
(2c). dimethyl benzylcarbamothioylphosphonate Yellow viscous; yield= 70%; H NMR 8H
(ppm): 3.80 ( d, J= 11Hz, 6H, CH3),7.34-7.28 (m, 5H, Harom), 4.87 ( d, J= 1.8Hz, 2H, CH2), 8.89
(s, 1H, NH ).13C NMR 8C (ppm): 191.2(d, 182.9Hz, C=S), 55.1 (s, Cipso), 48.9(d, 9Hz, MeO),
128.3-134.4 (Carom). 31P NMR 8P (ppm): (2c ) = 0.1. IR (CHCl3 , υ cm-1): NH= 3217.9,
(C=C)arom= 1649.2, PO = 1249.1. Anal. Calc. for C10H14NO3PS (259g.mol-1): C, 46.33; H, 5.40;
N, 5.40; found C, 46.33; H, 5.41; N, 5.40%.
(2d).dimethyl (p-fluorophenyl)carbamothioylphosphonate Orange crystal; yield= 96%;
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mp118.6.°C; 1H NMR 8H (ppm): 3.92 ( d, J=11.1 Hz, 6H, CH3), 7.10-7.95 ( m, 4H, Harom), 10.82
(s, 1H , NH).13C NMR 8C (ppm): 189.3(d, 184.8Hz, C=S), 160.9 (d, 248.2Hz, C-F), 134.1(q,
31
12.82Hz, Cipso), 115.8-124.5 (Carom), 55. 1 (d, J= 7.54Hz, MeO). P NMR 8P (ppm): (2d)= 0.1.
19F NMR 8H (ppm): (2a)= -112.3. IR (CHCl3 , υ cm-1): NH= 3249.1, (C=C)arom = 1649.4, PO =
1250.1.Mr for C9H11FNO3PS: 263g.mol-1 found Mr=263.22g.mol-1. Anal. Calc. for
C9H11FNO3PS (263.22g.mol-1): C, 41.03; H, 4.17; N, 5.31; found C, 40.83; H, 5.28; N, 5.30%.
(2e). dimethyl (p-chlorophenyl)carbamothioylphosphonate Yellow solid; yield= 84%; mp
86.4°C; 1H NMR 8H (ppm): 3.90 ( d, J= 11.1 Hz, 6H, CH3), 7.10-7.98(m, 4H, Harom), 10.60 (s,
1H , NH).13C NMR 8C (ppm): 189.3 (d, 184.89Hz, C=S), 130.0 (s, C-Cl), 136.5(s, Cipso), 123.5-
132.9(Carom), 55. 5 (d, J= 6.7Hz, MeO). 31P NMR 8P (ppm): (2e)= 1.4. IR (CHCl3 , υ cm-1): NH=
3246.5, (C=C)arom= 1647.8, PO = 1249.5. Anal. Calc. for C9H11ClNO3PS (279g.mol-1): C, 38.70;
H, 3.94; N, 5.01; found C, 38.25; H, 3.82; N, 4.97 %.
1
(2f). diethyl phenylcarbamothioylphosphonate Yellow crystal; yield= 87%; mp 46.3°C; H
NMR 8H (ppm): 1.26 ( d, J= Hz, 6H, CH3), 4.25 (d, J= 14.3Hz, 4H, CH2 ), 6.84-8.68(m, 5H,
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Harom ), 11.38 (s, 1H, NH ). 13C NMR 8C (ppm): 190.5 (d, 183.3Hz, C=S), 65.3(d, 22.7Hz, CH2),
31
138.2(d, 15.7Hz, Cipso), 122.8-128.7(Carom), 15.4(d, 6.2Hz, Me). P NMR 8P (ppm): (2f) = -1.7,
IR (CHCl3 , υ cm-1): NH= 3201.9, (C=C)arom= 1601.2, PO= 1250.5. Mr for C11H16NO3PS:
273g.mol-1 found Mr=273.28g.mol-1.Anal. Calc. for C11H16NO3PS (273.28g.mol-1): C, 48.30; H,
5.85; N, 5.12; found C, 48.29; H, 5.85; N, 5.12%.
(2g). diethyl cyclohexylcarbamothioylphosphonate Yellow solid; yield= 80%; mp52°C;1H
NMR 8H (ppm): 0.21-0.98 ( m, 17H, CH3 , Hhexyl), 4.13-4.35 (m, 4H, CH2O), 9.03 (s, 1H,
NH)13C NMR 8C (ppm): 191.0 (d, 179.6Hz, C=S), 65.0 (d, 6.8Hz, CH2), 53.8(d, J= 7.5 Hz, Cipso),
24.6-30.8(Chexyl), 16.2 (d, 6.2Hz, Me). 31P NMR 8P (ppm): (2g) = -1.6. IR (CHCl3 , υ cm-1): NH=
3197.1, (C-C)hexyl = 1526.6, PO = 1240.1. Anal. Calc. for C11H22NO3PS (279g.mol-1): C, 47.31;
H, 7.88; N, 5.01; found C, 47.28; H, 7.65; N, 5.00%.
(2h). diethyl benzylcarbamothioylphosphonate Yellow solid; yield= 82%; mp 68°C; 1H NMR
8H (ppm): 1.33 ( d, J= 6.7Hz, 6H, CH3), 3.99 – 4.32 (m, 4H, CH2), 4.87 (d, J= 1.7Hz, 2H, CH2),
7.36-7.30 (m, 5H, Harom), 9.77 (s, 1H, NH ).13C NMR 8C (ppm): 192.6 (d, 181.5Hz, C=S), 135.
4(s, Cipso), 128.0-128.4(Carom), 65.1 (d, CH2), 49.0 (d, 8.9Hz, CH2)benzyl), 16.1(d, 65.1Hz, Me).31P
NMR 8P (ppm): (2h) = -1.9. IR (CHCl3 , υ cm-1): NH= 3229.3, (C=C)arom= 1521.1, PO = 1248.1.
Anal. Calc. for C12H18NO3PS (287g.mol-1): C, 50.17; H, 6.27; N, 4.87; found C, 49.87; H, 6.02;
N, 4.30%.
General procedure for the preparation of phosphonothioimidates (3a-f)
The same procedure applied for the preparation of phosphonoamidates, has been used to
prepare the phosphonothioimidates. Before the acid hydrolysis by H2O/HCl, we have to add
dropwise the methyl iodide MeI(0.02 mol, 1.0 equiv) in anhydrous THF (10 mL) during 1h. The
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aqueous layer was then extracted with CHCl3. After drying (MgSO4 or Na2SO4), filtration and
solvent evaporation, the residue obtained was recrystallized with ether and petroleum ether.
(3a).(Z)-methyl (dimethoxyphosphoryl)-N-phenylmethanimidothioate Pink solid; yield=
82%; mp 74°C; 1H NMR 8H (ppm): 2.16 (s, 3H , SMe), 3.54 (d, 10.80Hz, 6H, CH3), 7.07-7.57
(m, 5H, Harom). 13C NMR 8C (ppm): 204.2 (d, 196.1Hz, -C=N-), 131.2 (s, Cipso), 123.7-
31
129.3(Carom), 53.5 (d, 6.2Hz, MeO), 10.4 (s, SMe). P NMR 8P (ppm) (3a) = - 3.5. IR (CHCl3 ,
υ cm-1): (C=N)= 1646.0, (PO)= 1232.1. Anal. Calc. for C10H14NO3PS (259g.mol-1): C, 46.33;
H, 5.40; N, 5.40; found C, 46.32; H, 5.40; N, 5.40%.
(3b).(Z)-methyl (dimethoxyphosphoryl)-N-cyclohexylmethanimidothioate Yellow solid;
1
yield= 68%; mp 82°C; H NMR 8H (ppm): 1.05-2.17 (m, 10H, Hcyclohexyl), 2.35 (s, 3H, SMe),
3.47 (q, 7Hz, 1H, Hipso ), 3.67 (d, 10.8Hz, 6H, CH3).13C NMR 8C (ppm): 204.9 (d, 193.8Hz, -
C=N-), 65.8 (s, Cipso), 24.7-50.6(Chexyl), 53.6 (d, 4.2Hz, MeO), 10.5 (s, SMe).31P NMR 8P
(ppm)(3b) = - 4.4.IR (CHCl3 , υ cm-1): (C=N)= 1645.1, (PO)= 1233.2. Anal. Calc. for
C10H20NO3PS (265g.mol-1): C, 45.28; H, 7.57; N, 5.28; found C, 45.25; H, 7.55; N, 5.27%.
(3c).(Z)-methyl(dimethoxyphosphoryl)-N-benzylmethanimidothioate Yellow viscous; yield=
70%; 1H NMR 8H (ppm): 2.21 (s, 3H, SMe) , 3.40 ( d, 10.7Hz, 6H, CH3), 3.96 (s, 2H, CH2)benzyl
13
),7.52 (m, 5H, Harom). C NMR 8C (ppm): 205. 0 (d, 194.2Hz, -C=N-), 133. 4 (s, Cipso), 128.3-
31
129.1 (Carom), 53.3 (d, 6.10Hz, MeO), 43.3(s, CH2)benzyl), 10.3 (s, SMe). P NMR 8P (ppm) (3c)
= - 3.9. IR (CHCl3 , υ cm-1): (C=N)= 1648.8, (PO)= 1232.8.Anal. Calc. for C11H16NO3PS
(273g.mol-1): C, 48.35; H, 5.86; N, 5.12; found C, 48.18; H, 5.63; N, 5.09%.
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(3d).(Z)-methyl (diethoxyphosphoryl)-N-phenylmethanimidothioate Pink solid; yield= 85%;
1
mp: 108°C. H NMR 8H (ppm): 1.07 (d, 4Hz, 6H, CH3), 2.14 (s, 3H , SMe), 3.88 (t, 6.2Hz, 4H,
CH2), 7.41 ( m, 5H, Harom). 13C NMR 8C (ppm): 204.7 (d, 194.8Hz, -C=N-), 131. 4 (s, Cipso),
31
128.2-129.4(Carom), 62.8 (d, 6.10Hz, CH2O), 16.3 (d, 6.5Hz, SMe), 10.5 (s, Me). P NMR 8P
(ppm): (3d) = - 2.0. IR (CHCl3 , υ cm-1):(C=N)= 1646.6, (PO)= 1227.0. Anal. Calc. for
C12H18NO3PS (287g.mol-1): C, 50.17; H, 6.27; N, 4.87; found C, 50.17; H, 6.28; N, 4.87%.
(3e). (Z)-methyl (diethoxyphosphoryl)-N-cyclohexylmethanimidothioate Yellow solid;
yield= 59%; mp 72°C; 1H NMR 8H (ppm): 1.34 (d, 4.1Hz, 6H, CH3), 1.50 ( m, 10H, Hcyclohexyl),
2.31 (s, 3H, SMe) , 4.10 (t, 3.6Hz, 4H, CH2 ), 4.34( m, 1H, Hipso). 13C NMR 8C (ppm):205.7 (d,
192.3Hz, -C=N-), 64.7( d, 6.7Hz, Cipso), 24.7-50.6 (Chexyl), 62.5 (d, 6Hz, -CH2O), 16.6 (d, 6.5Hz,
31
Me), 10.5(s, SMe). P NMR 8P (ppm):(3e) = - 4.5. IR (CHCl3 , υ cm-1): (C=N)= 1648.6, PO=
1217.1. Anal. Calc. for C12H24NO3PS (293g.mol-1): C, 49.14; H, 8.19; N, 4.77; found C, 49.08;
H, 8.14; N, 4.75%.
(3f). (Z)-methyl (diethoxyphosphoryl)-N-benzylmethanimidothioate Yellow oil; yield= 72%;
1H NMR 8H (ppm): 1.12 ( d, 7.1H, CH3), 2.23 (s, 3H, SMe), 3.82 (s, 2H, CH2)benzyl), 3.85
13
(t,6.2Hz, 4H, CH2), 7.57(m, 5H, Harom). C NMR 8C (ppm): 205.2 (d, 194.10, -C=N-), 133.4 (s,
Cipso), 128.5-129.2(Carom), 62.6 (d, 6Hz, -CH2O), 43.3 (s, CH2)benzyl), 16.4 (d, 6.5Hz, Me), 10.53
(s, SMe). 31P NMR 8P (ppm)(3f) = - 4.8. IR (CHCl3 , υ cm-1):(C=N)= 1649.2, (PO)= 1230.9.
Anal. Calc. for C13H20NO3PS (301g.mol-1): C, 51.82; H, 6.64; N, 4.65; found C, 51.60; H, 6.60;
N, 4.58%.
X-ray structure analysis:
1. Structure ofC9H11FNO3PS
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The title compound crystallizes in the monoclinic system, space group P21/c. The parameters
of the unit cell are: a = 5.673(1) Å, b = 13.440(1) Å, c = 15.576(1) Å and β = 91.38(3)° (Table
7). The structure is built up from C9H11FNO3PS molecules stabilized by N-H...O intermolecular
hydrogen bonds (Table 5). The cell contains Z = 4 formula groups. The dihedral angle S1 - C3 -
N1 - H7 is 163(2)°. The atoms S1 and H7 deviate upon and under the plane formed by N1, C3
and P1 atoms (respectively 0.012(9) Å and -0.20(3) Å). Data collection is provided by Enraf-
Nonius CAD-4 diffractometer using molybdenum Kα radiation (Α = 0.71073 Å).
[21]
The structure was solved by SHELXS-97 program[20] and refined by SHELXL-97 program .
The final reliability factors are R1 = 0.0548 and wR2 = 0.1626, these values correspond to 1757
reflections and 175 parameters (intensity I > 2 σ(I)). Molecular graphics are provided by the
[22]
Diamond program .
The cif file is registered under CCDC 965890 number at Cambridge Crystallographic Data
Center.
2. Structure ofC11H16NO3PS
The title compound crystallizes in the orthorhombic system, space group P212121. The
parameters of the unit cell are a = 7.611(1) Å, b = 9.135(1) Å, c = 20.186(1) Å (Table 7). The
structure is built up from C11H16NO3PS molecules stabilized by N-H..O intermolecular hydrogen
bonds (Table 6).The cell contains Z = 4 formula groups. The structure was solved by SHELXS-
[21]
97 program [20]and refined by SHELXL-97 program . The final reliability factors are R1 =
0.0336 and wR2 = 0.0909, these values correspond to 2657 reflections and 211 parameters
(intensity I > 2 σ(I)). Molecular graphics are provided by Diamond program[22]. The cif file is
registered under CCDC 1001884 number at Cambridge Crystallographic Data Center.
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Acknowledgment
We thank Pr. Amel Belhaj for the reading the manuscript.
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References and notes.
1. Polshettiwar, V.; Kaushik, M. P.; Tetrahedron Lett. 2006, 47, 2315–2317.
2. Siemeling, U.; Rother, D.; J. Organomet. Chem. 2009, 694, 1055–1058.
3. Zabicky, J.; (dir.). The Chemistry of Amides, Interscience, John Wiley and Sons, New
York, Londres. 1970, 96.
4. Thanigaimalai, P.; Sharma, V. K.; Lee, K.; Yun, C. Y.; Kim, Y.; Jung, S. H.; J. Bioorg
Med. Chem. Lett. 2010, 20, 4771–4773.
5. Bose, D. S.; Idrees, M.; Todewale, I. K.; Jakka, N. M.; Venkateswara, R.; Eur. J. Med.
Chem. 2012, 50, 27-38.
6. Davies, C. D.; Elliotta, M. C.; Wood, J. L.; Tetrahedron. 2006, 62, 11158–11164.
7. Bondock, S.; Shymaa, A.; Etman, H. A.; Badria, F. A.; Eur. J. Med. Chem. 2012, 48,
192-199.
8. Trofimov, B. A.; Mal’kina, A. G.; Borisova, A. P.; Nosyreva, V. V.; Shemyakina, O. A.;
Kazheva, O. N.; Shilov.; G. V. Dyachenko, O. A.; Tetrahedron Lett. 2008, 49, 3104–
3107.
9. Dixon, S.; Whit, R. J.; Tetrahedron Lett. 2006, 47, 8147–8150.
10. Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S.; Tetrahedron Lett. 2012, 53, 7113-7116.
11. Zeev, T.; J.Org.Chem. 1982, 47, 3012- 3015.
12. Babak, K.; Hazegh, Z.; Heteroatom Chemistry. 2009, 20, 250-253.
13. Kolodyazhnaya, A. O.; Kolodyazhnaya, O. O.; Kolodyazhnyi, O. I.; Russian Journal of
General Chemistry (English). 2010, 80, 709–722.
14. Augustin, M.; Rudorf, W. D.; Schmidt. U, Tetrahedron. 1976, 32, 3055-3061.
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15. Karl Dieter, R.; Tetrahedron. 1986, 42, 3029-3096.
16. Rudorf, W. D.; Schierhorn, A.; Augustin, M.; Tetrahedron. 1979, 35, 551-556.
17. Rao, C. N. R.; Gurudath Rao, K.; Goel, A.; Balasubramanian, D.; J. Chem. Soc. A. Inorg.
Phys. Theor. 1971, 3077-3083.
18. Gaussian 03, Revision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant,
J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and
Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004.
19. SHELXS-97. G. M. Sheldrick. ActaCryst.1990, A46, 467.
20.SHELXL-97 - A program for crystal structure refinement. G. M. Sheldrick, University of
Gœttingen, Germany, 1997.
21. Diamond Version 2.1e, Klaus Brandenburg. Copyright © 1996-2001 Crystal Impact GbR.
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Table 1: Approach to the synthesis of thioamides
R
R1
Ph
a
b
Me
Me
Me
Me
c-C6H11
Bn
c
D
p-F-Ph
p-Cl-Ph
Ph
E
F
Me
Et
G
H
Et
c-C6H11
Bn
Et
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Table 2 : Preparation of Phosphonothioamidates
R
R1
Ph
a
b
c
d
e
f
Me
Me
Me
Et
c-C6H11
Bn
Ph
Et
c-C6H11
Bn
Et
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Table 3: Distances (A°) and Angles (°) of the compound 2d
Compound
P1-C3
2d
1.824(3)
1.453(2)
1.545(2)
1.565(2)
1.565(2)
1.652(3)
2.04
P1=O3
P1-O1
P1-O2
C3-N1
C3=S1
O3…H7
N1 C3P1
N1 C3 S1
C3 N1 C4
O3 P1 C3
113.1(2)
127.4(2)
126.4(2)
110.75(12)
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Table 4: Distances (A°) and Angles (°) of the compound 2f
Compound
P1-C5
2f
1.821(2)
P1=O3
1.4616(16)
1.5606(17)
1.5648(16)
1.327(3)
P1-O1
P1-O2
C5-N1
C5=S1
1.648(2)
O3…H1
N1 C5 P1
N1 C5 S1
C5 N1 C6
O3 P1 C5
2.09
115.39(16)
127.99(17)
127.53(19)
112.09(10)
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Table 5: Hydrogen bond of 2d
X-H..Y
N1-H7..O3i
H..O(Å)
2.04
N..O(Å)
2.789(3)
N-H-O(°)
159(2)°
i: 2-x, 1-y,1-z
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Table 6: Hydrogen bond of 2f
X-H..Y
N1-H1..O3i
H..O(Å)
2.09
N..O(Å)
2.819(3)
N-H-O(°)
152(2)°
i: 2-x, 1/(2+y),1/(2-z)
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Tables 7: Crystal Structure and Data Refinement Parameters of C9H11FNO3PS and
C11H16NO3PS
Compound
2d
C9H11FNO3PS
263.22 g.mol-1
Monoclinic / P21/c
5.673(1)
2f
C11H16NO3PS
273.28
Empirical Formula
Formula Weight
Crystal System / Space Group
Orthorhombic / P212121
7.611(1)
a / Å
b / Å
c / Å
13.440(1)
9.135(1)
15.576(1)
20.186(1)
90.00
90.00
/ °
β / °
91.38(1)
90.00
90.00
γ / °
90.00
V / Å3
1187.3(2)
4
1403.7(2)
4
Z
D calc (g/cm3)
μ (mm-1)
Crystal size (mm)
Color / Shape
Temp (K)
1.472
1.293
0.411
0.341
0.2 0.2 0.2
Yellow / Plate
298(2)
0.2 0.2 0.2
Yellow / Plate
298(2)
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Theta range for collection
2° - 26.98°
2.02° – 26.99°
3062
Reflections collected
3712
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
1757
2657
3712/0/175
1.043
3062/0/211
1.06
Final R indices [I > 2σ(I)]
R indices (all data)
0.0548
0.0864
0.401
0.0336
0.0425
0.242
Largest difference peak/hole
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H5
C2
H6
H11
C9
H10
C8
H4
S1
O2
H1
H3
P1
N1
C1
F1
H2
C3
C7
C6
H9
C4
O1
H7
O3
C5
H8
Figure 1: ORTEP representation of compound 2d.
(Displacement ellipsoids with 30 % of probability)
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Figure 2: Molecular representation of 2f.
(Displacement ellipsoïds are drawn at the 20% probability level)
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s-Cis1
s-Cis 2
s-Trans 1
E= -1469.6814047 u.a
E= -1469.6845694 u.a
E= -1469.6756842u.a
G= 2 kcal/mol
G= 0kcal/mol
G= 5.6 kcal/mol
s-Trans2
s-Trans 3
E= -1469.6701853 u.a
E= -1469.6725156 u.a
G= 9 kcal/mol
G= 7.6 kcal/mol
Figure 3: DFT calculations of the compound 2d
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Scheme 1: Proposed mechanism of the reaction
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Scheme 2: Proposed mechanism of the reactions
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