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Novel synthetic route for phosphanylidene-benzothiophenethione, benzothiaphosphinine-4-thione, triphenylphosphoranylidenecyclobutane and benzodithiolylidenephosphonate derivatives has been proposed...

The reactions of bis(diphenylphosphino)alkanes with benzophenone, bis(piperidinocarbonyl)diazene, isatin, and quinoxaline1,4-di- N-oxide have been studied and the products characterised by elemental analysis and spectroscopic measurements.

Phosphazine and phosphazide derivatives are described herein as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and β-amyloid aggregation inhibitors. Phosphazines (5–7) were synthesized smoothly via a redox-condensation reaction of 1,2-bis(diphenylphosphino)ethane with different amines derivatives in the presence of dialkyl azodicarboxylate (Staudinger reaction) while phosphazides (8) via electrophilic attack of azido derivatives. Structures of the synthesized compounds were justified on the basis of compatible elementary and spectroscopic analyses. All the compounds were evaluated for their acetylcholinesterase inhibitory activity. The most three potent compounds (5b-c and 8b) showing AChE IC50 values (29.85–34.96 nM) comparable to that of donepezil (34.42 nM) were subjected to further investigation by testing their butyrylcholinesterase, MMP-2 and self-induced Aβ aggregation inhibition activity. Especially, the coumarin phosphazide derivative (8b) presented the best AChE inhibition selectivity index (IC50 = 34.96 nM, AChE/BuChE; 3.81) together with good inhibition ability against MMP-2 (IC50 = 441.33 nM) and self-induced Aβ1-42 aggregation (IC50 = 337.77 nM). In addition, the inhibition of metal-induced Aβ aggregation by 8b was confirmed by thioflavine T fluorescence. The most potent effect of 8b was observed on the Zn2+-induced Aβ42 aggregation. Kinetic study of compound 8b suggested it to be a competitive AChE inhibitor. Also, it specifically chelates metal and is predicted to be permeable to BBB. It also possesses low toxicity on SH-SY5Y neuroblastoma cells with a safety index of 15.37. In addition, it was demonstrated that compound 8b can improve the cognitive impairment of scopolamine-induced model in mice with % alternations and transfer latency time comparable to that of donepezil. Also, a docking study was carried out and it was in accordance with the in vitro results. These promising in vitro and in vivo findings highlight compound 8b as a possible drug candidate in searching for new multifunctional AD drugs.

The reaction of 1,1-bis(diphenylphosphino)methane with substituted o-quinones afforded the novel 6-[bis(diphenylphosphoryl)methyl]-, and 6-bis(diphenyl phosphoryl)methylidene derivatives. Moreover, 1,1-bis(diphenylphosphino)methane reacts with 3,4,5,6-tetrabromo-o-benzoquinone to give only the new 6-[bis(diphenylphosphoryl)methyl] derivative. Mechanisms accounting for the formation of the new products are discussed. The antimicrobial activity of some of the newly synthesized compounds was also examined.

The reactions are reported of 4-(furan-3-ylcarbonyl)-1,5-diphenylpyrrolidine-2,3-dione with six classes of organophosphorus reagents: carboalkoxymethylene triphenylphosphoranes, triphenyl (phenylimino)-λ5-phosphane, trialkylphosphonoacetates, trialkylphosphites, tris (dialkylamino)phosphines, and Lawesson's reagent. Several of the products showed antitumour activity.

The reaction of 5(4H)-pyrazolone with phosphorus ylides afforded new triphenylphosphanylidene alkanone derivatives. Moreover, its benzylidene derivative reacted with Wittig–Horner reagents to give the corresponding dialkoxyphosphoryl, alkyl phosphonate, and heterocyclic products. Treatment of pyrazole-4-carbaldehyde with Wittig–Horner reagents and trialkyl phosphites gave the respective alkyl phosphonate adducts. Mechanisms accounting for the formation of the new products are discussed. The biological activity of some of the newly synthesized compounds was also examined.

The reaction of 1,2-bis(diphenylphosphino)ethane with substituted o-benzo-quinones afforded new bis(6-hydroxycyclohexa-2,4-dienone) derivatives. Treatment of the same reagent with o-naphthoquinone, phenanthrenequinone, and acenaphthenequinone gave the respective bis(diphenylphosphoryl)ethylidenes or diacenaphthylenone derivatives. On the other hand, p-quinones react with 1,2-bis(diphenylphosphino)methane to yield the corresponding 4-hydroxycyclohexa-2,5-dien-1-ones. Possible reaction mechanisms are considered and the structural assignments are based on compatible analytical and spectroscopic data.

3-(Hydroxyimino)pentane-2,4-dione reacts with phosphonium ylides, Wittig–Horner reagents, trialkyl phosphites, and Lawesson's reagents to give the olefinic and cyclic products, the phosphonate adducts, the dialkyl phosphate products, the phosphinodithioic acid, and 2,4-dithione products, respectively. Furthermore, the reaction of 3-(phenylimino)pentane-2,4-dione with Wittig, Wittig–Horner reagents and trialkyl phosphite resulted in the formation of 2,5-diendioate, diethoxy phosphoryl hexanoate and the phosphate products. Possible reaction mechanisms are considered and the structural assignments are based on analytical and spectroscopic results. The antibacterial and antifungal activities for some of the new compounds are also reported.

2-Arylidenebenzosuberones react with a Wittig-Horner reagent in the presence of sodium hydride as a base to give the novel dimethyl (4-(4-methoxyphenyl)-2-oxa-2,3,4,5,6,7-hexahydrobenzo- [6,7]cyclohepta[1,2-b]pyran-3-yl)phosphonate. On the other hand, 6,7-dihydrobenzo[6,7]cyclohepta- [1,2-b]pyran-2(5H)-ones were isolated from the reaction of 2-arylidenebenzosuberones withWittig- Horner reagents using alcoholic sodium alkoxide. The reaction of 2-arylidenebenzosuberones with trialkyl phosphites affords the alkyl phosphonate derivatives. Tris(dialkylamino)phosphines react with 2-arylidenebenzosuberones to give the oxaphospholanoxide products. 2-Arylidenebenzosuberones react with Lawesson’s reagent to yield the corresponding dimers. Some of the prepared products were screened for antitumor activity

1,1′-(Azodicarbonyl)dipiperidine reacts with tris(dimethylamino)phosphine, trialkyl phosphites, phosphorus ylides, and Lawesson's reagents to give the phosphorodihydrazidic amide, oxadiazole, dihydropyridazine, ethylenic, and thicarbonyl products, respectively. The antibacterial and antifungal activities for the new compounds are reported. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: Biological Evaluation.

The reaction of 5(4H)-oxazolones with tetraethyl methanediylbis(phosphonate) afforded new 1,1-bisphosphonate and 1,1-bisphosphonic acid derivatives. Moreover, 5(4H)-oxazolones reacted with Wittig reagents to give the corresponding heterocyclic products. Treatment of 5(4H)-oxazolones with trisdialkylaminophosphanes gave the corresponding N-(1-dialkylcarbamoyl)-2-phenylvinylbenzamides. Mechanisms accounting for the formation of the new products are discussed. The biological activity of the newly synthesized compounds was also examined.

1,3,2,4-Dithiadiphosphetane-2,4-disulfide and its p-phenoxy derivatives react with 2-indanone-, 1-indanone-oxime, and tetralone oxime at different reaction temperatures to give 1,3,2-dithiaphosphetane-2-sulfide, dimeric compounds, 1-thioxo-1H-inden- phosphinodithioic acid, and 1,3,5,2-trithiaphosphorine. Compatible analytical and spectroscopic results were obtained for all the new compounds.

The reaction of 2,6-bis(benzylidene)cyclohexanones with dialkylphosphonates and tris(dialkylamino)phosphines afforded the new benzoxaphosphole derivatives (5a–5d) and (9a–9f). The biological activity of the newly synthesized compounds was also examined. Possible reaction mechanisms are considered, and the structural assignments are based on analytical and spectroscopic results. The structure of the new benzoxaphosphole 5a was confirmed by a single crystal X-ray determination.

The reaction of 3-amino-2-phenyl-4(3H)-quinazolinone with oxovinylidenetriphenylphosphorane afforded 5-phenylpyrazolo[1,5-c] quinazoline-2(3H)-one and triphenylphosphine oxide. On the other hand, when quinazolinone reacts with phosphorus ylides, the corresponding phosphorane adducts were obtained. Moreover, quinazolinone reacts with trisdialkylaminophosphines to give the new (dialkylamino)oxophosphonium dipolar products. Possible reaction mechanisms are considered and the structural assignments are based on analytical and spectroscopic results.

The reaction of dibenzoyldiazine with phosphorus ylides afforded the new 2-[(benzoylhydrazono)phenylalkyl]but-2-enedioic acid dialkylesters. Moreover, ethyl-2(triphenylphosphoranylidene)propionate reacts with dibenzoyldiazine to give the olefinic compound and triphenylphosphine oxide. On the other hand, oxovinylidene-triphenylphosphorane reacts with dibenzoyldiazine to give a new phosphorane adduct. Trialkyl phosphites react with dibenzoyldiazine to yield the dialkyl phosphonate products. The reaction of dibenzoylhydrazide with Wittig reagents gave rise to the new 3,7-diphenylpyrazolo[1,2-α]pyrazole-1,5-diones. Possible reaction mechanisms are considered, and the structural assignments are based on analytical and spectroscopic results.

1,2,3,4-tetrahydro-1-naphthylidene-malononitrile (1) reacts with carbethoxymethylene and carbmethoxymethylene- triphenylphosphoranes (2a, 2b) to give the new phospho-ranylidenecyclopentaylidene products (4a, 4b, and 5), respectively. The treatment of (1) with phosphorus ylide 2c afforded the new phosphonium ylide 6. Moreover, the application of reagent (2d) on (1) renders compound 7. On the other hand, when N-phenyliminotriphenylphosphorane (3) reacts with (1), the corresponding adduct (8) was obtained together with triphenylphosphine. Mechanisms accounting for the formation of new products are discussed, and probable structures of products are presented based on analytical and spectroscopic data.

Thiohydantoin 1 reacts with 2-oxovinylidenetriphenylphosphorane (2) to give 1-methyl-2-thioxo-6-(triphenyl-λ5-phosphoranylidene)-hexahydro-furo[2,3-d]imidazol-5-one (5). On the other hand, when 1 reacts with phosphorus ylides 3a–d, the respective olefinic adducts 6a, 6b, 8, and the dimeric product 7 were obtained together with triphenyl-phosphine oxide. Moreover, the application of reagent 4 on 1 renders the new product 4-methyl-2,3-diphenyl-2,3,4,6-tetrahydro-1-oxa-1,3,4,6-tetra-azapentalene-5-thione. Mechanisms accounting for the formation of the products are presented based on analytical and spectroscopic data.

3,4-Diphenyl-5-cyanopyridazine-6-thione (1) reacts with carbethoxy-methylene and carbmethoxymethylene-triphenylphosphoranes (2a,b) to give both the olefinic compounds (3a,b) and 3,4-diphenyl-6-alkoxyfuro-[3,2-c]-pyridazines (4a,b) respectively. Treatment of 1 with phosphorus ylide (2c) afforded only the new furopyridazine (4c). On the other hand, when (1) reacts with diphenylmethylenetriphenylphosphorane (2d), adduct (5) was obtained together with triphenylphosphine. Moreover, application of reagent (2e) on (1) renders the new product 3,4-diphenyl-6-(phenylimino)-5-cyanopyridazine (6). Mechanisms accounting for the formation of the new products are discussed and the probable structures of the products are presented based on analytical and spectroscopic data.

N-Phenyliminophosphorane (1) reacts with 9,10-phenanthrenequinone (2a) to give the new products 2-phenylphenanthro[9,10-d][1,3,2]dioxazole (4a) and (10Z)-10-(phenylimino)-9(10H) phenanthrenone (4b). The reaction of 1 with 1,2-naphthoquinone (2b) afforded both the dioxazole derivative 5a and the known 2-anilino-naphthoquinone-1,4-anil (5b). On the other hand, 2,6-di-tert-butyl-2,3-diphenyl-2,3-dihydro-1,2,3-benzoxadiazole (6) was obtained from the reaction of (2c) with phosphinimine (1). Application of reagent 1 on 2d and 2e renders (6E)-2,3,4,5-tetrahalogeno-6-(phenylimino)-2,4-cyclohexadien-1-one 7a and 7b, respectively. Moreover, p-quinones (3a–3c) react with phosphinimine (1) to yield products 8, 9 and 10, respectively. Mechanisms accounting for the formation of the new products are discussed and the probable structures of the products are presented based on analytical and spectroscopic data.

The reaction of 1,3-diphenyl-2-(phenylimino)-3-(ylidenemethyl-acetate)-1-propanone (5) with trisdialkylaminophosphines (6a,b) in refluxing toluene afforded the new oxazaphospholene products (7a–b). On the other hand, the cyclic azaphospholene adducts 8a–b were isolated from the reaction of 5 with 6a,b without solvent. Trialkyl phosphites 1b–c react with compound 5 to give the respective dialkyl phosphate products (9a,b). Moreover, trisdialkylaminophosphines (6a,b) react with 2a and 2b to give the dipolar adducts 10a,b and the phosphonate products 11a,b, respectively. Possible reaction mechanisms are considered, and the structural assignments are based on compatible analytical and spectroscopic results. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:511–517, 2001

5-{[(1E)-(4-methoxyphenyl)methylene]amino}-1,3,4-thiadiazole-2-thiol (1a) reacts with trialkyl phosphites (2a–c) to give the respective dialkyl phosphonate adducts (4a–c). On the other hand, the reactions of trisdialkylaminophosphines (3a,b) with 1a, 5-{[(1E)-(4-phenyl)methylene]amino}-1,3,4-thiadiazole-2-thiol (1b) yield the corresponding open dipolar structures 6a–c. In the case of the reaction of triethyl phosphite (2a) with 1b, both the dialkyl phosphonate adduct (7) and the dipolar product (8a) are obtained. Moreover, triisopropyl phosphite (2c) reacts with 1b to give both the S-alkyl and the N-alkyl phosphonate adducts (9a,b), respectively. Mechanisms are proposed to explain the formation of the new products, and their structures were confirmed on the basis of elemental analysis and spectral studies. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:594–601, 2001

1,3,2,4-Dithiadiphosphetane-2,4-disulfide 1 reacts with substituted 2-amino-1,4-naphthoquinons 2a–d to give 4,5,4′,5′-benzodiphenoquinone-bis-1,3,2-thiazaphospholine-2-sulfide derivatives of type 3. Compatible analytical and spectroscopic results were obtained for all the new compounds. A mechanism is proposed to explain the formation of compounds 3. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 488–491, 1999

The reaction of methoxycarbonylmethylene 2b- and ethoxycarbonylmethylene 2c-triphenylphosphoranes with substituted 2-amino-1,4-naphthoquinones 1a-c afforded the new pyrroline-ylidphosphoranes 3b-3g via 1,2- and 1,4-addition reactions. On the other hand, 2-dimethylamino-1,4-naphthoquinone 1d reacts with cyanomethylenetriphenylphosphorane 2d to give adduct 4. Mechanisms accounting for the formation of the new products are discussed.

Wittig-Homer reagent 1a reacts with 2-nitroso-1-naphthol 3 to give the olefinic adduct 5, the alkylated product 4 and the dimeric compound 6. When 2-nitroso-1-naphthol 3 reacts with Wittig- Homer reagents 1b,c. the corresponding phosphonate adducts 8a,b together with compounds 4 and 6 were obtained. Oxovinylidenetriphenylphosphorane 2 reacts with 3 to give the corresponding phosphoranylidenecyclobutylidene adduct 10 and triphenylphosphine oxide. The structural assignments of the new products are based on compatible analytical and spectroscopic results.

Compounds (IV) and (VI) possess promising inhibiting activity in cell proliferation of MCF 7 and HEPG2 cells.

The reactions of 2-aryl-5(4H)-oxazolones with phosphonates, phosphates, and tris(alkylamino)phosphines are studied and the underlying different reaction mechanisms are discussed.

Wittig reagents (1a–c) react with N-(phenylsulfonyl)-1,4-benzoquinone monoimine 2a to give adducts 3a, 4a, and 4b. On the other hand, the reactions of 2b with the same ylides (1a–c) yield the new products 3b, 6a, and 6b, respectively. Mechanisms accounting for the formation of the new products are discussed and the probable structures of the products are presented, based on compatible analytical and spectral data.

Wittig-Horner reagents (1a–c) react with o-quinone diimine (2a) to give the respective phosphonate adducts (3a–c) and the alkylated product 4. The reaction of p-quinone diimine (2b) with the same reagents yield adducts 5, 6 and 7, respectively. Structural reasoning for the new compounds was based on compatible analytical and spectral data. The mechanism that accounts for formation of adducts 3 is illustrated in Scheme 2.

2, 4-Bis-(4-methoxyphenyl)-1, 3, 2, 4-dithiadiphosphetane-2, 4-disulfide [Lawesson reagent (LR)] 1 reacts with p-quinone monoimine-2a to give the novel benzo-1,3,2-oxathiaphosphol-5-(methanesulfonamido)-2-(4-methoxyphenyl)-2-sulfide 4. On the other hand, the reaction of 2b and 3 with LR 1 leads to the formation of the benzo- and the naphtho-1,3,2-dithiaphosphol-5 -(benzenesulfonamido)- 2- (4-methoxyphenyl) -2-sulfide 5, 6. Thiation of 2a, 2b, and 3 with P4S10 yields phenoxathiin derivatives 8a, 8b, and 9, respectively. The identity of the new products is established from analytical and spectroscopic evidence.

Cyanomethylenetriphenylphosphorane (1) reacted with 1,4-naphthoquinone 1 to give the new ylid-phosphorane adduct 4 and the dimeric product 5. Reaction of acenaphthenequinone (2) with phosphorus ylide I afforded compounds 6 and 7. On the other hand, ylide I reacts with phenanthrenequinone (3) yielding adducts 8, 9 and 10, respectively. Structural reasoning for the new products was based on compatible analytical and spectral data (IR, 1H, 31P-NMR and MS). The mechanism that accounts for the formation of the new adducts is discussed.

Wittig-Horner reagents (2a-c) react with 5-(4-pyridyl)-2-thiono-1,3,4-oxadiazole (1) yielding the new adducts (3a-c). Structural reasoning for compounds 3 was based on compatible analytical and spectral data. The mechanism that accounts for the formation of 3 is discussed.

Naphthalenone 1 reacts with tris(dialkylamino)phosphines 3 in refluxing benzene to give the corresponding 1,2-dihydro-2-dialkylamino-1,1-diphenylnaphth[1,2-d-][1, 2]oxaphosphine-2-oxides (7a, b). Reaction of 1 with 3a in boiling methanol affords the oxaphosphole 8 and adduct 9. The oxaphosphine 11 is obtained upon reacting 1 with ethyldiphenylphosphinite (10). Naphthalenone 2 reacts with 3a to give triaminodioxyphosphorane 13. Pyrolysis of 13 yields 2 and aminophosphine 3a. Upon reacting 2 with 10, adduct 14 is obtained. Structural assignments are based on analytical, chemical and spectroscopic evidence.

Diethyl phosphite 2a reacts with N- (phenylsulfonyl) - 1,4 - benzoquinone monoimine 1a to give 1,4-diethyl [(2-hydroxy-5-[(phenylsulfonyl) amino ] phenyl] [sphosphonate 3a, diethyl (1-hydroxy -4- [ ( phenylsulfonyl ) imino ] -2,5-cyclohexadiene )] phosphonate 3b and amide 3c , respectively. When quinone monoimine 1a was reacted with dimethyl and diisopropyl phosphites (2b,c), the corresonding dialkyl phosphonate adducts (bd3e) and (bd3f) were obtained. Whereas quinone monoimine (bd1b) is reduced mainly to amide (bd4b) when treated with diethyl phosphite (bd2a) , it reacts with dimethyl phosphite (bd2b) to give the dialkyl phosphonate adduct (bd4a) together with amide (bd4b) . Possible reaction mechanism are considered and the structural assignments are based on compatible analytical and spectroscopic results.

Trimethyl phosphite (2a) reacts with N-(phenylsulfonyl)-1,4-benzoquinone monoimine (1a) to give the respective phosphonate 3c, phosphates 3d, 3e and the alkylated products 3a and 3b. The reaction of triethyl phosphite (2b) with the same quinone imine 1a yields only the phosphate adduct 3f and the amide 3g. Triisopropyl phosphite (2c) reacts with 1a to form the alkylated product 3h. Trimethyl phosphite (2a) gives the phosphate 4a on reaction with N-(methylsulfonyl)- 1,4-benzoquinone monoimine (1b). In case of the reaction of triethyl and triisopropyl phosphites (2b, c) with 1b only the respective alkylated products 4b–d are obtained. A mechanism is proposed to explain the formation of the new adducts.

Wittig reagents (1a,c) react with phthalimidobenzoic acid azide (2a) to give the new products 3a, 3b, 3c, and 5, respectively. On the other hand, methylenetriphenylphosphorane (1b) reacts with azides (2a,b) to afford the corresponding 1,5-disubstituted-1,2,3-triazoles (4,6). Structural reasoning for the new products was based on compatible analytical and spectral data.

Trimethyl phosphite (2a) reacts with N-(phenylsulfonyl)-1,4-benzoquinone monoimine (1a) to give the respective phosphonate 3c, phosphates 3d, 3e and the alkylated products 3a and 3b. The reaction of triethyl phosphite (2b) with the same quinone imine 1a yields only the phosphate adduct 3f and the amide 3g. Triisopropyl phosphite (2c) reacts with 1a to form the alkylated product 3h. Trimethyl phosphite (2a) gives the phosphate 4a on reaction with N-(methylsulfonyl)- 1,4-benzoquinone monoimine (1b). In case of the reaction of triethyl and triisopropyl phosphites (2b, c) with 1b only the respective alkylated products 4b–d are obtained. A mechanism is proposed to explain the formation of the new adducts.

Naphthalenone 1 reacts with tris(dialkylamino)phosphines 3 in refluxing benzene to give the corresponding 1,2-dihydro-2-dialkylamino-1,1-diphenylnaphth[1,2-d-][1, 2]oxaphosphine-2-oxides (7a, b). Reaction of 1 with 3a in boiling methanol affords the oxaphosphole 8 and adduct 9. The oxaphosphine 11 is obtained upon reacting 1 with ethyldiphenylphosphinite (10). Naphthalenone 2 reacts with 3a to give triaminodioxyphosphorane 13. Pyrolysis of 13 yields 2 and aminophosphine 3a. Upon reacting 2 with 10, adduct 14 is obtained. Structural assignments are based on analytical, chemical and spectroscopic evidence.

2, 4-Bis-(4-methoxyphenyl)-1, 3, 2, 4-dithiadiphosphetane-2, 4-disulfide [Lawesson reagent (LR)] 1 reacts with p-quinone monoimine-2a to give the novel benzo-1,3,2-oxathiaphosphol-5-(methanesulfonamido)-2-(4-methoxyphenyl)-2-sulfide 4. On the other hand, the reaction of 2b and 3 with LR 1 leads to the formation of the benzo- and the naphtho-1,3,2-dithiaphosphol-5 -(benzenesulfonamido)- 2- (4-methoxyphenyl) -2-sulfide 5, 6. Thiation of 2a, 2b, and 3 with P4S10 yields phenoxathiin derivatives 8a, 8b, and 9, respectively. The identity of the new products is established from analytical and spectroscopic evidence.