Chemistry of phosphorus ylides: Part 45 synthesis of phosphoranylidene, thietane, azetidine and thiazinane derivatives as potent chemo preventative agents

Article abstract of DOI:10.1080/10426507.2017.1370467

Reactions of nucleophilic active phosphacumulenes with iso(thio)cyanate compounds were performed. The reaction products depend on the nature of the reagent, substrate and the condition of the reaction used. New heterocyclic 4-membered or 6-membered sulfur

Full text of DOI:10.1080/10426507.2017.1370467

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Chemistry of Phosphorus Ylides: Part 45 Synthesis
of Phosphoranylidene Thietane, Azetidine
and Thiazinane Derivatives as Potent Chemo
Preventative Agents
Ahmed I. Hashem, Marwa El-Hussieny , Mansoura A. Abd-El-Maksoud, Soher
S. Maigali, Shaimaa T. Mansour & Fouad M. Soliman
To cite this article: Ahmed I. Hashem, Marwa El-Hussieny , Mansoura A. Abd-El-Maksoud, Soher
S. Maigali, Shaimaa T. Mansour & Fouad M. Soliman (2017): Chemistry of Phosphorus Ylides:
Part 45 Synthesis of Phosphoranylidene Thietane, Azetidine and Thiazinane Derivatives as Potent
Chemo Preventative Agents, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2017.1370467
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1370467
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Chemistry of Phosphorus Ylides: Part 45 Synthesis of Phosphoranylidene Thietane,
Azetidine and Thiazinane Derivatives as Potent Chemo Preventative Agents
Ahmed I. Hashem1,Marwa El-Hussieny2,Mansoura A. Abd-El-Maksoud2, Soher S. Maigali2,
Shaimaa T. Mansour2, Fouad M. Soliman2,*
1Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo, Egypt,
11566.
2Department of Organometallic and Organometalloid Chemistry, National Research Centre, 33-
El-Behouth St.,12622, Dokki, Giza, Egypt
Corresponding author: Fouad M. Soliman. E-mail: solimanfma2@yahoo.com
Abstract
Reactions of nucleophilic active phosphacumulenes with iso(thio)cyanate compounds were
performed. The reaction products depend on the nature of the reagent, substrate and the condition
of the reaction used. New heterocyclic 4-membered or 6-membered sulfur and nitrogen
compounds such as phosphoranylidene thietane, azetidine and thiazinane were obtained. On the
other hand, the stable phosphonium ylides with the iso(thio)cyanate afforded phosphoranylidene
thiocarbamoyl derivatives. Possible reaction mechanisms are considered and the structural
assignments are based on compatible analytical and spectroscopic data.
Keywords
1
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Isothiocyanates; isocyanate; ylides; phosphoranylidene; thietane; azetidine; thiazinane;
thiocarbamoyls
2
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Introduction
Naturally occurring isothiocyanates are effective chemo protective agents against chemical
carcinogenesis in experimental animals.1-5 These compounds inhibit rat lung, esophagus,
mammary gland, liver, small intestine, colon and bladder tumorigeneses.5,6 They also reduce risk
for prostate cancer.7-9 Moreover, studies have demonstrated that several isothiocyanates inhibit
cell growth by inducing apoptosis which is suggested to be potentially involved in the
anticarcinogenic action of isothiocyanates.10-12 On the other hand, methyl isocyanate is an
intermediate chemical in the production of carbamate pesticides,13-15 such as carbaryl,
carbofuran, methomyl and aldicarb. It has also been used in the production of rubber coatings
and adhesive.16-18 In summary, isocyanates are very useful and versatile compounds in organic
and polymer chemistry and their applications are focused on the production of polyurethanes.19
The isocyanate group contains cumulated double bond sequence, which in its reactivity is
governed by the positive character of the carbon atom, which is susceptible to attack by
nucleophiles and oxygen and nitrogen by electrophiles. On the other hand, phosphacumulenes
and stabilized phosphonium ylides have numerous industerial applications20,21. Moreover, their
different pharmacological applications22 are well known.
Results and Discussion
In our continuing studies on the reactions of active and stabilized phosphonium ylides we have
described the isolation and identification of different homocyclic and heterocyclic compounds
bearing phosphorus moieties, which have antimutagenic effects.23-28
In the present study, we describe the reactions of the active nucleophilic reagents and stabilized
phosphonium ylides with isocyanate and isothiocyanate compounds to prepare heterocyclic
phosphorus compounds of biological interest.
Phosphacumulene ylides can be represented by the resonance structures 2A and 2B. They react
with some unsaturated compounds according to the resonance structure 2A and with carbonyl
compounds according to the resonance structure 2B (Wittig reaction). Thus, the reaction of 4-
methoxyphenylisothiocyanate (1) with (2-oxovinylidene)-triphenylphosphorane (2a) in THF,
3
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afforded firstly the dipolar intermediate 3.29 2,2-Cyclization in the intermediate occurs via the
sulfur atom, which is more nucleophilic than the nitrogen atom to give the four-membered
heterocyclic thiocarbomyl compounds, 4-((4-methoxyphenyl)imino)-3-(triphenylphosphoranyli-
dene)thietan-2-one (4a). The most important features in the spectroscopic data of 4a are the
13
disappearance of thiocarbonyl group in their C NMR and IR spectra and the appearance of the
carbonyl group at  = 189.5 and at  = 1731 cm1, respectively. In the 31P NMR spectrum of 4a a
signal is observed at  = 10.0, which supports the presence of phosphorus in the four membered
ring.30 Moreover, the proposed structure of 4a was further unequivocally confirmed by X-ray
crystallography (Figure 1).
When the isothiocyanate 1 was allowed to react with (N-phenyliminovinylidene)-
triphenylphosphorane
(2b),
the
corresponding
4-methoxy-N-4-(phenylimino)-3-
(triphenylphosphoranylidene)thietan-2-ylidene)aniline (4b) was obtained (Scheme1).
We have found that the reaction of methylisothiocyanate (5) with the phosphacumulenes 2a or
2b proceeds in THF at room temperature to give the dipolar intermediates 6, which under our
experimental conditions react with another molecule of methyl isothiocyanate 5 to give the
corresponding six-membered compounds, namely 3-methyl-6-(methylimino)-2-thioxo-5-
(triphenylphosphoranylidene)-1,3-thiazinan-4-one (7a) and 3-methyl-6-(methylimino)-4-
(phenylimino)-5-(triphenyl-phosphoranylidene)-1,3-thiazinane-2-thione (7b), respectively. The
structure of the six-membered compounds 7a,b was confirmed by their spectroscopic data. In the
13C NMR spectrum of compound 7b the signal of the C = S carbon atom appeared at  = 191.3
and the in the 31P NMR spectrum a signal at  = 26.2 was observed, which supports the presence
of a phosphorus group in the six membered ring.31,32 In the mass spectrum the M+ peak appeared
at 523 (5%).
Moreover, the reaction of 1,2-dichloro-4-isocyanatobenzene (8) with the phospha-cumulene 2a
in THF afforded firstly the dipolar intermediate 9a. [2+2]-Cycloaddition through the carbon-
nitrogen bond, leads to the four-membered hetero iminocarbonyl compound, 1-(3,4-
dichlorophenyl)-3-(triphenyl-5-phosphanylidene)azetidine-2,4-dione (10a). The most important
31
features in the spectroscopic data of 10a are, that a signal at  = 19.0 was observed in the P
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13
NMR spectrum and that in its C NMR spectrum two signals were observed at  = 170.0 and
167.8, which are assigned to the two carbonyl groups.
Reaction of phosphacumulene 2b with the isocyanate 8 afforded 1-(3,4-dichloro-phenyl)-4-
phenylimino-3-(triphenyl-5-phosphanylidene)azetidin-2-one (10b) (Scheme 3).
The behavior of the stabilized phosphonium ylides 11a-c towards the isothiocyanates 1, 5 and
the isocyanate 8 was also studied in order to determine the site of attack. It was found that the
methylene triphenylphosphoranes 11a-c react with the isothio-cyanate 1 in THF to give the
intermediate betaines 12a-c, which produce the new ylides 13a-c. In case of using the
phosphorane 11c, adduct 13c was isolated together with 1,3-bis(4-methoxyphenyl)thiourea (14).
Formation of the thiourea derivative 14 is catalyzed by the phosphorane 11c.33,34 The elemental
1
analysis, IR, H-, 13C-, 31P NMR and MS data support the structures of the compounds. For
example compound 13a showed bands at 3445 (NH), 1643 C = O, and 1290 cm1 C = S in its IR
1
spectrum. In the H NMR spectrum of 13a, signals at  = 11.98 (NH, exchangeable with D2O),
7.50-7.73 (aromatic protons), 3.67 (phenyl OCH3) and 2.84 (ester OCH3) were observed. The 13C
NMR spectrum of 13a, showed signals at  = 189.5 (C = S), 168.1 (C = O), 133.1-113.9
31
(aromatic carbon atoms), 55.7 (phenyl OCH3) and 50.1 (ester OCH3). The P NMR chemical
shift observed for 13a was at  = 12.4.35,36 (Scheme 4).
In the same sense, methylisothiocyanate (5) and 3,4-dichlorophenylisocyanate (8) react with the
stabilized phosphonium ylides 11a-c to give the corresponding thiocarbamoylphosphanylidenes
15a-c (Scheme 5) and the phosphanylidenes 16a-c (Scheme 6), respectively. In case of using the
phosphorane 11c, the urea derivative 17 was also isolated. All the spectroscopic data of the
above mentioned new compounds are cited in the experimental section. The molecular structure
of compound 15a, determined by single crystal X-ray diffraction, is shown in Figure 2.
Experimental
Melting points were determined with an electrothermal digital melting point apparatus (Electro-
Thermal Engineering Ltd., Essex, United Kingdom). The IR spectra were recorded in KBr disks
with a Pye Unicam SP 3300 and a Shimadzu FT IR 8101 PC IR spectrophotometer (Pye Unicam
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1
13
Ltd, Cambridge, UK and Shimadzu, Tokyo, Japan, respectively). H and C NMR spectra were
obtained with a Jeol ECA 500 MHz NMR Spectrometer (Tokyo, Japan) using CDCl3 and d6-
DMSO as solvents and TMS as internal reference at 500 and 125 MHz, respectively. 31P NMR
spectra were obtained with a Jeol ECA 500 MHz NMR spectrometer operating at 200 MHz.
Mass spectra (EI-MS) were obtained with an ISQ (Single Quadrupole MS, Thermo Scientific)
instrument. Elemental analyses (C, H, N, S) were performed with an Elementar Vario EL
Analyzer; the phosphorus content was measured by spectrophotometric methods. X-ray
crystallography was carried out with a Kappa CCD Enraf Nonius FR 590 diffractometer,
National Research Centre, Dokki, Cairo, Egypt. The reported yields are of pure isolated
materials obtained by column chromatography using silica gel 60 (Merck) and TLC, which was
performed on Merck Kiesel gel F254 precoated plates (Merck, Darmstall, Germany). Solvents
were dried / purified according to literature procedures. The starting materials 1, 5 and 8 were
obtained from Fluka Chemicals.
Reaction of 4-Methoxyphenylisothiocyanate (1) with (2-Oxovinylidene)- triphenyl-
phosphorane (2a) and (N-phenyliminovinylidene)triphenylphosphorane (2b). General
Procedure
To a solution of 1 (0.165 g, 0.001 mol) in 20 mL of dry THF was added a solution of 2a37 (0.302
g, 0.001 mol), or 2b38 (0.377 g, 0.001 mol) in 30 mL of THF. The reaction mixture was stirred
for 8 h in case of 2a or 6 h in case of 2b; the progress of the reaction was monitored by TLC. The
solvent was distilled off under reduced pressure and the residue was crystallized to give 4a or 4b.
4-((4-Methoxyphenyl)imino)-3-(triphenylphosphoranylidene)thietan-2-one (4a)
The compound was obtained from petrol ether (60-80 °C) as yellow crystals, yield 85%; m.p.
171--173 °C. IR (KBr, cm1): ν = 1731 (C = O), 1644 (C = N). 1H NMR (500 MHz, d6- DMSO):
δ = 3.66 (s, 3H, OCH3), 7.51-7.61 (m, 19H, arom-H). 13C NMR (125 MHz, d6-DMSO): δ =
189.5 (C = O), 162.2 (C = N), 129.2, 129.3, 129.9, 130.0, 133.4, 134.0, 134.1, 134.7, 134.8,
31
135.1 (arom-C), 55.5 (OCH3). P NMR (200 MHz, d6-DMSO): δ = 10.0. MS (EI, 70 eV): m/z
6
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(%) 278 [(TPPO), 5], 262 [(TPP), 55]. Anal. Calcd. for C28H22NO2PS (467.52): C, 71.93; H,
4.74; N, 3.00; P, 6.63; S, 6.86. Found: C, 71.83; H, 4.60; N, 2.90; P, 6.54; S, 6.74%.
X-Ray crystallography of 4a
Single crystals of compound 4a were obtained by slow evaporation of the solvent. A suitable
crystal was selected, checked and mounted on top of a thin glass fiber. The X-ray single crystal
diffraction data were collected at room temperature (298 K) with an Enraf-Nonius 590
diffractometer with a Kappa CCD detector using graphite monochromated Mo-Kα (λ =
0.71073Å) radiation at the National Research Centre of Egypt.39,40 The structure was solved by
direct methods using SHELXS-9741 and SUPERFLIP42 implemented in the CRYSTALS
program suit.43 The refinement was carried out by the full-matrix least-squares method on the
positional and anisotropic temperature parameters of all non-hydrogen atoms based on F2 using
the CRYSTALS package. The general-purpose crystallographic tool PLATON44 was used for the
structure analysis and presentation of the results. Molecular graphics were generated using
ORTEP-3 for Windows45 and DIAMOND46 programs. Details of the data collection conditions
and the parameters of the refinement process are given in Table 1.
Crystallographic data (excluding structure factors) for the structure in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 1532652. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:+44(0)1223 336033 or E-mail:
deposit@ccdc.cam.ac.uk].
4-Methoxy-N-4-(phenylimino)-3-(triphenylphosphoranylidene)thietan-2-ylidene)aniline (4b)
Isolated from column chromatography using petrol ether (60-80 °C) ethyl acetate (80:20, v/v) as
an eluent, white crystals, yield 75%, m.p. 103--105 °C. IR (KBr, cm1): ν = 2928 (arom-CH),
1
1648, 1618 (2 C = N), 1439 (C = P). H NMR (500 MHz, d6-DMSO): δ = 3.72 (s, 3H, OCH3)
6.85-7.84 (m, 24H, arom-H).13C NMR (125 MHz, d6-DMSO): δ = 164.6 (C = N), 155.9 (C = P),
114.2, 114.4, 119.6, 121.2, 123.4, 126.7, 129.1, 129.2, 132.6, 140.0 (arom-C), 55.7 (OCH3). MS
(EI, 70 eV): m/z (%) 511 [(M+ -OCH3), 5], 294 [(TPPS), 100], 262 [(TPP), 10]. Anal. Calcd. for
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C34H27N2OPS (542.16): C, 75.26; H, 5.02; N, 5.16; P, 5.71; S, 5.91. Found: C, 75.16; H, 4.97; N,
5.10; P, 5.63; S, 5.82%.
Reaction of Methylisothiocyanate (5) with (2-Oxovinylidene)triphenylphosphorane (2a) and
(N-Phenyliminovinylidene)triphenylphosphorane (2b). General Procedure
To a solution of 5 (0.073 g, 0.001 mol) in 20 mL of dry THF, was added a solution of 2a (0.302
g, 0.001 mol) or 2b (0.377 g, 0.001 mol) in 30 mL of THF. The reaction mixture was stirred for
12 h in case of 2a or 10 h in case of 2b (TLC). The solvent was distilled off under reduced
pressure and the residue was crystallized, yielding 7a or 7b, respectively.
3-methyl-6-(methylimino)-2-thioxo-5-(triphenylphosphoranylidene)-1,3-thiazinan-4-one (7a)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (5:95, v/v) as
an eluent, white crystals, yield 65%, m.p. 114--115 °C.1H NMR (500 MHz, d6-DMSO): δ = 1.98
(s, 3H, N-CH3), 2.00 (s, 3H, N-CH3), 7.46-7.71 (m, 15H, arom-H), 13C NMR (125 MHz, d6-
DMSO): δ = 197.5 (C = S), 181.3 (C = O), 132.0, 130.8, 130.7, 129.2, 129.1 (arom-C), 16.7,
16.1 (CH3). 31P NMR (200 MHz, d6- DMSO): δ = 28.2. MS (EI, 70 eV): m/z (%) 433 [(M+ -
CH3), 19], 418 [(M+ -2CH3), 14], 294 [(TPPS), 15], 262 [(TPP), 13]. Anal. Calcd. for
C24H21N2OPS2 (448.08): C, 64.27; H, 4.72; N, 6.25; P, 6.91; S, 14.30. Found: C, 64.16; H, 4.60;
N, 6.14; P, 6.79; S, 14.18%.
3-methyl-6-(methylimino)-4-(phenylimino)-5-(triphenylphosphoranylidene)-1,3-thiazinane-2-
thione (7b)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (75: 25, v/v) as
an eluent, yellow crystals, yield 70%, m.p. 125--128 °C. IR (KBr, cm1): ν = 1640, 1620 (2 C =
1
N), 1560 (C = P), 1249 (C = S). H NMR (500 MHz, d6-DMSO): δ = 2.83 (s, 3H, N-CH3), 2.89
13
(s, 3H, N-CH3), 7.48-7.68 (m, 20H, arom-H), C NMR (125 MHz, d6-DMSO): δ = 191.3 (C =
S), 168.6, 168.4 (C = N), 143.5 (C = P), 129.0, 129.1, 133.0, 133.1 (arom-C), 30.0 (CH3).31P
NMR (200 MHz, d6-DMSO): δ = 26.2. MS (EI, 70 eV): m/z (%) 523 [(M+), 5], 294 [(TPPS),
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100] 262 [(TPP), 15], 262 [(M+-TPP) 5]. Anal. Calcd. for C30H26N3PS2 (523.13): C, 68.81; H,
5.00; N, 8.02; P, 5.91; S, 12.25. Found: C, 68.68; H, 3.99; N, 7.90; P, 5.88; S, 12.14%.
Reaction of 3,4 Dichlorophenyl Isocyanate (8) with (2-Oxovinylidene) Triphenylphosphorane
(2a) and (N-Phenyliminovinylidene)triphenylphosphorane (2b). General Procedure
To a solution of 8 (0.188 g, 0.001 mol) in 20 mL of dry THF was added a solution of 2a (0.302
g, 0.001 mol) or 2b (0.377 g, 0.001 mol) in 30 mL of THF. The reaction mixture was stirred for
30 min in case of 2a or 2 h in case of 2b. The solvent was distilled off under reduced pressure,
and the residue was crystallized to give 10a or 10b.
1-(3,4-Dichlorophenyl)-3-(triphenyl-5-phosphanylidene)azetidine-2,4-dione (10a)
Crystallized from petrol ether (60-80 °C) as pale yellow crystals, yield 85%, m.p. 102--105 °C.
1
IR (KBr, cm1): ν = 1692 (C = O, ylide), 1590 (C = O). H NMR (500 MHz, d6-DMSO): δ =
7.54-7.63 (18H, arom-H).13C NMR (125 MHz, d6-DMSO): δ = 170.0 (C = O, ylide), 167.8 (C =
O), 140.5 (C = P), 119.1, 120.1, 126.1, 126.2, 126.8, 129.4, 130.9, 132.6, 133.4 (arom-C). 31P
NMR (200 MHz, d6-DMSO): δ = 19.0. MS (EI, 70 eV): m/z (%) 278 [(TPPO), 20], 262 [(TPP),
5]. Anal. Calcd. for C27H18Cl2NO2P (490.32): C, 66.14; H, 3.70; Cl, 14.46; N, 2.86; P, 6.32.
Found: C, 66.03; H, 3.60; Cl, 14.35; N, 2.77; P, 6.21%.
1-(3,4-Dichlorophenyl)-4-phenylimino-3-(triphenyl-5-phosphanylidene)azetidin-2-one (10b)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (70:30 v/v) as
an eluent, white crystals, yield 75%, m.p. 175--177 °C. IR (KBr, cm1): ν = 1672 (C = O), 1645
1
(C = N), 1560 (C = P). H NMR (500 MHz, d6-DMSO): δ = 6.94-7.81 (23H, arom-H).13C NMR
(125 MHz, d6-DMSO): δ = 161.8 (C = N), 152.7 (C = O), 140.1 (C = P), 114.0, 114.1, 119.2,
31
120.1, 124.1, 131.0, 131.1, 131.6, 132.8, 132.9 (arom-C). P NMR (200 MHz, d6-DMSO): δ =
14.2. MS (EI, 70 eV): m/z (%) 565 [M+, 5], 278 [(TPPO), 10] 262 [(TPP), 5]. Anal. Calcd. for
C33H23Cl2N2OP (565.43): C, 70.10; H, 4.10; Cl, 12.54; N, 4.95; P, 5.48. Found: C, 69.99; H,
4.00; Cl, 12.43; N, 4.82; P, 5.39%.
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Reaction of 4-Methoxyphenyl isothiocyanate (1) with Methoxycarbonyl- (11a),
Ethoxycarbonyl- (11b) and Acetyl-methylenetriphenylphosphorane (11c). General Procedure
To a solution of 1 (0.33 g, 0.002 mol) in 20 mL of dry THF was added a solution of 11a-c,47,48
11a (1.002 g, 0.003 mol) or 11b (1.044 g, 0.003 mol) or 11c (0.954 g, 0.003 mol) in 30 mL of
dry THF. The reaction mixture was refluxed for 20 h in case of 11a or 11b and stirred for 6 h in
case of 11c. The solvent was distilled off under reduced pressure and the residue was crystallized
to give compounds 13a-c and 14.
(4-Methoxyphenylthiocarbamoyl)(triphenyl-5-phosphanylidene)acetic Acid Methyl Ester
(13a)
Crystallized from ethanol as white crystals, yield 75%, m.p. 170--172 °C. IR (KBr, cm1): ν =
1
3445 (NH), 1643 (C = O, ester), 1290 (C = S). H NMR (500 MHz, d6- DMSO): δ = 2.84 (s, 3H,
OCH3 ester), 3.67 (s, 3H, OCH3-phenyl), 7.50-7.73 (m, 19H, arom-H), 11.98 (s, NH,
13
exchangeable with D2O). C NMR (125 MHz, d6-DMSO): δ = 189.5 (C = S), 168.1 (C = O),
156.5 (C = P), 113.9, 125.6, 127.8, 128.5, 129.1, 129.2, 131.9, 132.3, 133.0, 133.1 (arom-C),
55.7 (OCH3-phenyl), 50.1 (OCH3, ester). 31P NMR (200 MHz, d6-DMSO): δ = 12.4. MS (EI, 70
eV): m/z (%) 333 [M+-(CSNHC6H4OOCH3), 28], 294 [(TPPS), 17], 278 [(TPPO), 32], 262
[(TPP), 10]. Anal. Calcd. for C29H26NO3PS (499.56): C, 69.72; H, 5.25; N, 2.80; P, 6.20; S, 6.42.
Found: C, 69.61; H, 5.13; N, 2.69; P, 6.11; S, 6.36%.
(4-Methoxyphenylthiocarbamoyl)-(triphenyl-5-phosphanylidene)acetic Acid Ethyl Ester (13b)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (80:20, v/v) as
an eluent, white crystals, yield 70%, m.p. 159--161 °C. IR (KBr, cm1): ν =3480 (NH), 1630 (C
1
= O, ester), 1242 (C = S). H NMR (500 MHz, d6-DMSO): δ = 0.38 (m, 3H, CH3-CH2), 3.66 (s,
3H, OCH3), 4.06 (m, 2H, CH3-CH2), 6.78-7.51 (19H, arom-H), 12.07 (s, 1H, NH, exchangeable
13
with D2O). C NMR (125 MHz, d6-DMSO): δ = 189.5 (C = S), 168.1 (C = O), 156.6 (C = P),
113.9, 125.6, 129.1, 129.2, 132.8, 132.9 (arom-C), 59.0 (CH3-CH2), 55.7 (OCH3), 13.7 (CH3-
CH2).31P NMR (200 MHz, d6-DMSO): δ = 11.8. MS (EI, 70 eV): m/z (%) 511 [M2, 5], 294
[(TPPS), 100], 278 [(TPPO), 10], 262 [(TPP), 20], 165 [M+-Ph3P = CHCOOC2H5, 45]. Anal.
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Calcd. for C30H28NO3PS (513.59): C, 70.16; H, 5.50; N, 2.73; P, 6.03; S, 6.24. Found: C, 70.05;
H, 5.40; N, 2.64; P, 5.97; S, 6.13%.
N-(4-Methoxyphenyl)-3-oxo-2-(triphenyl-5-phosphanylidene)thiobutyramide (13c)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (58:42, v/v) as
an eluent, white crystals, yield 75%, m.p. 140--142 °C. IR (KBr, cm1): ν =3480 (NH), 1638 (C
= O), 1248 (C = S). 1H NMR (500 MHz, d6-DMSO): δ = 1.38 (s, 3H, OCH3), 3.79 (s, 3H, OCH3-
Ph), 6.78-7.85 (19H, arom-H), 13.75 (s, 1H, NH, exchangeable with D2O). 13C NMR (125 MHz,
d6-DMSO): δ = 191.6 (C = S), 168.1 (C = O), 156.8 (C = P), 113.6, 128.9, 129.0, 131.7, 133.1,
133.2 (arom-C), 55.5 (OCH3-Ph), 31.0 (OCH3). MS (EI, 70 eV): m/z (%) 294 [(TPPS), 51], 278
[(TPPO), 41], 262 [(TPP), 8]. Anal. Calcd. for C29H26NO2PS (483.56): C, 72.03; H, 5.42; N,
2.90; P, 6.41; S, 6.63. Found: C, 71.94; H, 5.30; N, 2.81; P, 6.32; S, 6.53%.
Reaction of Methylisothiocyanate (5) with Methoxycarbonyl- (11a), Ethoxy-carbonyl-(11b)
and Acetyl-methylenetriphenylphosphorane (11c). General Procedure.
To a solution of 5 (0.146 g,0.002 mol) in 20 mL of dry THF was added a solution of 11a (1.002
g, 0.003 mol) or 11b (1.044 g, 0.03 mol) or 11c (0.954 g, 0.003 mol) in 30 mL of dry THF. The
reaction mixture was refluxed for 24 h in case of 11a or 11b and stirred for 6 h in case of 11c.
The solvent was distilled off under reduced pressure, and the residue was crystallized to give
15a, b and 15c, respectively.
Methyl Thiocarbamoyl)-(triphenyl-5-phosphanylidene)acetic Acid Methyl Ester (15a)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (85:15, v/v) as
an eluent, white crystals, yield 85%, m.p. 181--183 °C. IR (KBr, cm1): ν =3480 (NH), 1636 (C
1
= O, ester), 1294 (C = S). H NMR (500 MHz, d6-DMSO): δ = 2.59 (s, 3H, CH3), 3.67 (s, 3H,
OCH3), 7.25-8.55 (15H, arom-H),12.06 (s, 1H, NH, exchangeable with D2O). 13C NMR (125
MHz, d6-DMSO): δ = 191.5 (C = S), 169.3 (C = O), 128.3, 128.4, 133.0, 133.1 (arom-C), 49.5
31
(OCH3), 31.5 (CH3). P NMR (200 MHz, d6-DMSO): δ = 12.3. MS (EI, 70 eV): m/z (%) 407
[M+, 37], 374 [M2-(OCH3), 100], 348 [M2-COOCH3, 6], 294 [TPPS, 26], 262 [TPP, 22]. Anal.
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Calcd. for C23H22NO2PS (407.47): C, 67.80; H, 5.44; N, 3.44; P, 7.60; S, 7.87. Found: C, 67.71;
H, 5.32; N, 3.33; P, 7.51; S, 7.75%.
X-Ray crystallography analysis of 15a
Single crystals of compound 15a were grown by slow solvent evaporation of the solvent. A
suitable crystal was selected, checked and mounted on top of a thin glass fiber. The X-ray single
crystal diffraction data were collected at room temperature (298 K) with an Enraf-Nonius 590
diffractometer with a Kappa CCD detector using graphite monochromated Mo-Kα (λ =
0.71073Å) radiation, at the National Research Centre of Egypt (Table 2). Crystallographic data
(excluding structure factors) for the structure of 15a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC 1532653.
(Methythiocarbamoyl)-(triphenyl-5-phosphanylidene)acetic Acid Ethyl Ester (15b).
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (88:12, v/v) as
an eluent, white crystals, yield 60%, m.p. 159--161 °C. 1H NMR (500 MHz, d6-DMSO): δ = 1.16
(s, 3H, CH3), 2.59 (m, 3H, CH3-CH2), 4.10 (m, 2H, CH3-CH2), 7.60-8.47 (m, 15H, arom-
H),12.05 (s, 1H, NH, exchangeable with D2O). 13C NMR (125 MHz, d6-DMSO): δ = 191.6 (C =
S), 169.1 (C = O), 128.3, 128.4, 132.9, 133.0 (arom-C), 58.6 (CH3-CH2), 31.4 (CH3-CH2), 13.6
(CH3). MS (EI, 70 eV): m/z (%) 421 [M+, 45], 376 [M+-(OC2H5), 35], 294 [(TPPS), 20], 262
[(TPP), 11]. Anal. Calcd. for C24H24NO2PS (421.49): C, 68.39; H, 5.74; N, 3.32; P, 7.35; S, 7.61.
Found: C, 68.30; H, 5.65; N, 3.24; P, 7.26; S, 7.52%.
N-Methyl-3-oxo-2-(triphenyl-5-phosphanylidene)thiobutyramide (15c)
Isolated from column chromatography using petrol ether 60--80 °C/ethyl acetate (65:35, v/v) as
an eluent, yellow crystals, yield 75%, m.p. 40--42 °C. IR (KBr, cm1): ν =3480 (NH), 1670 (C =
1
O, ester). H NMR (500 MHz, d6-DMSO): δ = 1.27 (s, 3H, CH3), 2.80 (s, 3H, OCH3), 5.00 (s,
1H, NH, exchangeable with D2O), 7.41-7.61 (m, 15H, arom-H), 13C NMR (125 MHz, d6-
DMSO): δ = 174.0 (C = S), 167.9 (C = O), 128.6, 128.7, 132.1, 132.2 (arom-C), 38.8 (OCH3),
14.1 (CH3). MS (EI, 70 eV): m/z (%) 374 [M2-CH3, 13], 294 [(TPPS), 10], 278 [(TPPO), 100],
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262 [(TPP), 30]. Anal. Calcd. for C23H22NOPS (391.47): C, 70.57; H, 5.66; N, 3.58; P, 7.91; S,
8.19. Found: C, 70.46; H, 5.56; N, 3.50; P, 7.81; S, 8.10%.
Reaction of 3,4 Dichlorophenylisocyanate (8) with Methoxycarbonyl- (11a), Ethoxycarbonyl-
(11b), and Acetyl-methylenetriphenylphosphorane (11c). General Procedure
To a solution of 8 (0.73 g, 0.002 mol) in 20 mL of dry THF was added a solution of 11a (1.002
g, 0.003 mol) or 11b (1.044 g, 0.003 mol) or 11c (0.954 g, 0.003 mol) in 30 mL of dry THF. The
reaction mixture was refluxed for 9 h in case of 11a or 11b and for 20 h in case of 11c (TLC).
The solvent was distilled off under reduced pressure and the residue was crystallized to give
compounds 16a-c. In case of using the phosphorane 11c the urea derivative 17 was isolated
together with 16c (m.p. and mixed m.p. 277--279 °C).
N-(3,4-Dichlorophenyl)-2-(triphenyl-5-phosphanylidene)malonamic Acid Methyl Ester (16a)
Crystallized from petrol ether (60-80 °C), white crystals, yield 90%, m.p. 192--194 °C. IR (KBr,
1
cm1): ν = 3435 (NH), 1642 (C = O, ester), 1613 (C = O, amide). H NMR (500 MHz, d6-
DMSO): δ = 3.03 (s, 3H, OCH3), 7.47-7.76 (m, 18H, arom-H), 11.06 (s, 1H, NH, exchangeable
13
with D2O). C NMR (125 MHz, d6-DMSO): δ = 170.6 (C = O, ester), 168.1 (C = O, amide),
140.0 (C = P), 118.7, 120.8, 127.1, 128.6, 128.7, 130.0, 132.0, 132.2, 133.4, 133.5 (arom- C),
49.7 (CH3). MS (EI, 70 eV): m/z (%) 524 [M+2, 5], 278 [(TPPO), 40], 262 [(TPP), 15]. Anal.
Calcd. for C28H22Cl2NO3P (522.36): C, 64.38; H, 4.25; Cl, 13.57; N, 2.68; P, 5.93. Found: C,
64.30; H, 4.16; Cl, 13.50; N, 2.57; P, 5.83%.
N-(3,4-Dichlorophenyl)-2-(triphenyl-5-phosphanylidene)malonamic acid ethyl ester (16b)
Crystallized from petrol ether (60-80 °C), white crystals, yield 80%, m.p. 131--133 °C. IR (KBr,
1
cm1): ν = 3449 (NH), 1639 (C = O, ester), 1605 (C = O, amide). H NMR (500 MHz, d6-
DMSO): δ = 0.38 (m, 3H, CH3-CH2), 3.56 (m, 2H, CH3-CH2), 7.36-7.65 (m, 18H, arom-H),
11.13 (s, 1H, NH, exchangeable with D2O), 13C NMR (125 MHz, d6-DMSO): δ = 170.0 (C = O,
ester), 167.8 (C = O, amide), 140.5 (C = P), 119.1, 119.6, 120.1, 123.2, 126.4, 127.1, 128.5,
129.3, 130.9, 131.4, 132.0, 132.6, 133.4 (arom-C), 58.6 (CH3-CH2), 13.8 (CH3-CH2). MS (EI, 70
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eV): m/z (%) 538 [M+2, 5], 278 [(TPPO), 85], 262 [(TPP), 10]. Anal. Calcd. for C29H24Cl2NO3P
(536.39): C, 64.94; H, 4.51; Cl, 13.22; N, 2.61; P, 5.77. Found: C, 64.83; H, 4.42; Cl, 13.13; N,
2.50; P, 5.64%.
N-(3,4-Dichlorophenyl)-3-oxo-3-phenyl-2-(triphenyl-5-phosphanylidene) butyramide (16c)
Isolated from column chromatography using petrol ether (60-80 °C)/ethyl acetate (75:25, v/v) as
eluent, white crystals, yield 80%, m.p. 146--148 °C. 1H NMR (500 MHz, d6-DMSO): δ = 1.41 (s,
13
3H, OCH3),7.16-7.75 (m, 18H, arom-H), 12.65 (s, 1H, NH, exchangeable with D2O). C NMR
(125 MHz, d6-DMSO): δ = 192.1 (C = O, ester), 168.5 (C = O, amide), 140.0 (C = P), 129.0,
129.1, 129.2, 129.3, 132.1, 132.5, 133.4, 133.5, 133.6 (arom-C), 29.8 (CH3). MS (EI, 70 eV): m/z
(%) 504 [M2, 5], 278 [(TPPO), 85], 262 [(TPP), 5]. Anal. Calcd. for C28H22Cl2NO2P (506.36):
C, 66.42; H, 4.38; Cl, 14.00; N, 2.77; P, 6.12. Found: C, 66.31; H, 4.29; Cl, 13.91; N, 2.65; P,
6.00%.
Conclusion
The synthesis of new heterocyclic compounds containing sulfur, nitrogen and thiocarbamoyl
moieties exemplify an interesting method for the reaction of isothiocyanate and isocyanate
compounds with active phosphacumulenes and stable phosphonium ylides. In case of using
active phosphacumulenes cycloaddition reactions took place and the reaction products depend on
the type of the reagent, substrate and the conditions of the reaction used. If the reaction is
performed between the isothiocyanate 1 or isocyanate 8 and the phosphacumulenes 2a,b, then
1,4-cyclization of the intermediates 3,9 proceeds quickly with the formation of the four
membered ring compounds 4a,b and 10a,b respectively. On the other hand, the isothiocyanate 5
reacts with 2a,b to give the dipolar intermediates 6a,b and by [4+2]-cycloaddition with a second
molecule of the isothiocyanate 5 to form the six membered compounds 7a,b. Moreover, a
difference in the nucleophilic character of phosphorus reagents was observed: phosphacumulenes
> phosphonium ylides. While the phosphacumulenes react smoothly with the reactants, the stable
phosphonium ylides react less rapidly to give the phosphoranylidene thiocarbamoyl derivatives
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13, 15 and 16. This process can be considered as a simple and efficient route for the formation of
new phosphanylidene-thietane, -azetidine, -thiazinanes and thiocarbamoyl compounds.
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Table 1. Details of data collection and structure refinement of compound 4a.
Chemical formula
Molecular mass
Crystal system, space group
Temperature (K)
a, b, c (Å)
C28H22NO2PS
467.53
Monoclinic, P21/n
298
8.7939 (5), 15.0079 (9), 17.571 (2)
β (°)
93.709 (2)
2314.1 (3)
4
V (Å3)
Z
Radiation type
Mo-Kα
0.24
µ (mm−1)
Data collection
Diffractometer
Tmin, Tmax
Nonius Kappa CCD
0.824, 0.990
No. of measured, independent and observed
[I 2σ(I)] reflections
Rint
6691, 6472, 1200
0.183
0.704
(sin θ/λ)max (Å−1)
Refinement
R[F2> 2σ(F2)], wR(F2), S
No. of reflections
No. of parameters
Δρmax, Δρmin (e Å−3)
0.155, 0.396, 0.96
6472
298
1.03, −0.42
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Table 2. Details for data collection and structure refinement of compound 15a.
Chemical formula
Molecular mass
C46H44N2O4P2S2
814.95
Crystal system, space group
Triclinic, P
1
Temperature (K)
a, b, c (Å)
298
10.0747 (2), 12.6518 (2), 17.7068 (4)
α, β, γ (°)
106.0305 (10), 95.7145 (11),
101.8313 (7)
2093.65 (5)
2
V (Å3)
Z
Radiation type
Mo-Kα
0.25
µ (mm−1)
Data collection
Diffractometer
Tmin, Tmax
Nonius Kappa-CCD
1.00, 1.00
35969, 18117, 6678
No. of measured, independent and observed [I  2.0σ(I)]
reflections
Rint
0.065
0.807
(sin θ/λ)max (Å−1)
Refinement
R[F2 > 2σ(F2)], wR(F2), S
No. of reflections
No. of parameters
No. of restraints
Δρmax, Δρmin (e Å−3)
0.060, 0.115, 0.90
6678
511
6
0.51, −0.39
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Figure 1. ORTEP view of the molecular structure of 4a in the crystal showing the atom-
numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms
are shown as small spheres of arbitrary radii.
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Figure 2. ORTEP view of the molecular structure of 15a in the crystal, showing the atom
numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms
are shown as small spheres of arbitrary radii.
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Scheme 1. Synthesis of compounds 4.
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Scheme 2. Synthesis of compounds 7.
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Scheme 3. Synthesis of compounds 10.
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Scheme 4. Synthesis of compounds 13.
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Scheme 5. Synthesis of compounds 15.
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Scheme 6. Synthesis of compounds 16.
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