Nucleosides. Part LI The 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) and 2-(2,4-dinitrophenyl)ethoxycarbonyl (dnpeoc) groups for protection of hydroxy functions in ribonucleosides and 2′ -deoxyribonucleosides

The Common 2′ -deoxypyrimidine and -purine nucleosides, thymidine ( 4 ), O⁴-[2-(4-nitrophenyl)ethyl]-thymidine ( 17 ), 2′-deoxy-N⁴-[2-(4-nitrophenyl)ethoxycarbonyl]cytidine ( 26 ), 2′-deoxy-N⁶-[2-(4-nitrophenyl)-ethoxycarbonyl]adenosine- 39 , and 2′-deoxy-N²-[2-(4-nitrophenyl)(ethoxycarbonyl]-O⁶-[2–4-nitrophenyl)ethyl]-guanosine ( 52 ) were further protected by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) and the 2-(2,4-dinitrophenyl)ethoxycarbonyl (dnpeoc) group at the OH functions of the sugar moiety to form new partially and fully blocked intermediates for nucleoside and nucleotide syntheses. The corresponding 5′-O-monomethoxytrityl derivatives 5 , 18 , 30 , 40 , and 56 were also used as starting material to synthesize some other intermediates which were not obtained by direct acylations. In the ribonucleoside series, the 5′ -O-monomethoxytrityl derivatives 14 , 36 , 49 , and 63 reacted with 2-(4-nitrophenyl) ethyl chloroformate ( 1 ) to the corresponding 2′,3′-bis-carbonates 15 , 37 , 50 , and 64 which were either detriylated to 16 , 38 , 51 , and 65 , respectively, or converted by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) treatment to the 2′,3′-cyclic carbonates 66 – 69 . The newly synthesized compounds were characterized by elemental analyses and UV and ¹H-NMR spectra.     

Nucleotides. Part XXXI. Modified Oligomeric 2′–5′ A Analogues: Synthesis of 2′–5′ oligonucleotides with 9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine and 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)adenine as modified nucleosides

A series of new 2′–5′ oligonucleotides carrying the 9-(3′-azido-3′deoxy-β-D-xylofuranosyl)adenine moiety as a building block has been synthesized via the phosphotriester method. The use of the 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) blocking groups for phosphate, amino, and hydroxy protection guaranteed straightforward syntheses in high yields and easy deblocking lo form the 2′–5′ trimers 21 , 22 , and 25 and the tetramer 23 . Catalytic reduction of the azido groups in [9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine]2′-yl-[2′-(O^p-ammonio)→ 5′]-[9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenin]-2′-yl-[2′-(O^p-ammonio)→ 5′]-9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine ( 21 ) led to the corresponding 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)-adenine 2′–5′ trimer 26 in which the two internucleotidic linkages are formally neutralized by intramolecular betaine formation.     

Nucleotides,Part LXIII,New 2-(4-Nitrophenyl)ethyl(Npe)- and 2-(4-Nitrophenyl)ethoxycarbonyl(Npeoc)-Protected 2′-Deoxyribonucleosides and Their 3′-Phosphoramidites – Versatile Building Blocks for Oligonucleotide Synthesis

A series of new base-protected and 5′-O-(4-monomethoxytrityl)- or 5′-O-(4,4′-dimethoxytrityl)-substituted 3′-(2-cyanoethyl diisopropylphosphoramidites) and 3′-[2-(4-nitrophenyl)ethyl diisopropylphosphoramidites] 52 – 66 and 67 – 82 , respectively, are prepared as potential building blocks for oligonucleotide synthesis (see Scheme). Thus, 3′,5′-di-O-acyl- and N ²,3′-O,5′-O-triacyl-2′-deoxyguanosines can easily be converted into the corresponding O⁶-alkyl derivatives 6 , 8 , 10 , 12 , 14 , and 16 by a Mitsunobu reaction using the appropriate alcohol. Mild hydrolysis removes the acyl groups from the sugar moiety (→ 9 , 11 , 13 , 15 , and 19 (via 18 ), resp.) which can then be tritylated (→ 38 – 42 ) and phosphitylated (→ 57 – 61 ) in the usual manner. N ²-[2-(4-nitrophenyl)ethoxycarbonyl]-substituted and N ²-[2-(4-nitrophenyl)ethoxycarbonyl]-O⁶-[2-(4-nitrophenyl)ethyl]-substituted 2′-deoxyguanosines 5 and 7 , respectively, are synthesized as new starting materials for tritylation (→ 28 , 35 , and 37 ) and phosphitylation (→ 54 , 56 , 70 , and 78 ). Various O⁴-alkylthymidines (see 20 – 24 ) are also converted to their 5′-O-dimethoxytrityl derivatives (see 43 – 47) and the corresponding phosphoramidites (see 62 – 66 and 79 – 82 ).     

Nucleotides,Part LX,Synthesis and Characterization of New 2′-O-Methylriboside 3′-O-Phosphoramidites Useful for the Solid-Phase Synthesis of 2′-O-Methyloligoribonucleotides

A series of new 2′-O-methylribonucleoside 3′-O-[2-(4-nitrophenyl)ethyl dialkylphosphoramidites] 27 – 31 , 33 – 38 , 40 – 44 , and 45 – 50 were synthesized and their stability and reactivity compared in automated oligonucleotide synthesis with the standard 2′-O-methylribonucleoside 3′-O-(β-cyanoethyl diisopropylphosphoramidites) 32 , 39 , 45 , and 51 , respectively. The 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) groups were used for the protection of the base moieties.     

Nucleosides. Part LIX. The 2-(4-nitrophenyl)ethylsulfonyl (Npes) Group: A New Type of Protection in Nucleoside Chemistry

The 2-(4-nitrophenyl)ethylsulfonyl (npes) group is developed as a new sugar OH-blocking group in the ribonucleoside series. Its cleavage can be performed in a β-eliminating process under aprotic conditions using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the most effective base. Since sulfonates do not show acyl migration, partial protection of 1,2-cis-diol moieties is possible leading to new types of oligonucleotide building blocks. A series of Markiewicz-protected ribonucleosides 1–10 is converted into their 2′-O-[2-(4-nitrophenyl)ethylsulfonyl] derivatives 29–38 in which the 5′-O? Si bond can be cleaved by acid hydrolysis forming 39–45 . Subsequent monomethoxytritylation leads to 46–50 , and desilylation affords the 5′-O-(monomethoxytrityl)-2′-O-[2-(4-nitrophenyl)ethylsulfonyl]ribonucleosides 51–55 . Acid treatment to remove trityl groups do also not harm the npes group (→ 56–58 ). Unambiguous syntheses of fully blocked 2′-O-[2-(4-nitrophenyl)ethylsulfonyl]ribonucleosides 96–102 are achieved from the corresponding 3′-O-(tert-butyl)dimethylsilyl derivatives. Furthermore, various base-protected 5′-O-(monomethoxytrityl)- and 5′-O-(dimethoxytrityl)ribonucleosides, i.e. 59–77 , are treated directly with 2-(4-nitrophenyl)ethylsulfonyl chloride forming in all cases a mixture of the 2′,3′-di-O- and the two possible 2′- and 3′-O-monosulfonates 107–148 which can be separated into the pure components by chromatographic methods. The npes group is more labile towards DBU cleavage than the corresponding base-protecting 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) groups allowing selective deblocking which is of great synthetic potential.     

Synthesis of polyesters by the polyaddition of bis(oxetane)s with active di(ester)s

The polyaddition of bis(oxetane)s 1,4‐bis[(3‐ethyl‐3‐oxetanylmethoxymethyl)]benzene (BEOB), 4,4′‐bis[(3‐ethyl‐3‐oxetanyl)methoxy]benzene (4,4′‐BEOBP), 1,4‐bis[(3‐ethy‐3‐oxetanyl)methoxy] ‐benzene (1,4‐BEOMB), 1,2‐bis[(3‐ethyl‐3‐oxetanyl)methoxy]benzene (1,2‐BEOMB), 4,4‐bis[(3‐ethyl‐3‐oxetanyl)methoxy]biphenyl (4,4′‐BEOMB), 3,3′,5,5′‐tetramethyl‐[4,4′‐bis(3‐ethyl‐3‐oxetanyl)methoxy]biphenyl (TM‐BEOBP) with active diesters di‐s‐phenylthioterephthalate (PTTP), di‐s‐phenylthioisoterephthalate (PTIP), 4,4′‐di(p‐nitrophenyl)terephthalate (NPTP), 4,4′‐di(p‐nitrophenyl)isoterephthalate (NPIP) were carried out in the presence of tetraphenylphosphonium chloride (TPPC) as a catalyst in NMP for 24 h, affording corresponding polyesters with M_n's in the range 2200–18,200 in 41–98% yields. The obtained polymers would soluble in common organic solvents and had high thermal stabilities. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 1528–1536, 2004     

Azoles and Azines: CXIX. Alkylation of 5,5'-(4-Nitrobenzylidene)bis(2-thiobarbituric) Acid and 5-(4-Nitrophenyl)-2,8-dithioxo-5,7,8,9-tetrahydro-2H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H)-dione with Haloacetic Acids and Their Esters

5,5'-(4-Nitrobenzylidene)bis(2-thiobarbituric) acid and 5-(4-nitrophenyl)-2,8-dithioxo-5,7,8,9-tetrahydro-2H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H)-dione, similar to unsubstituted 2-thiobarbituric acid, readily react with haloacetic acids and their esters to form regioselectively the S-alkylation products. The alternative routes fo 5,5'-(4-nitrobenzylidene)bis[(4-hydroxy-6-oxo-1,6-dihydropyrimidine-5,2-diyl)sulfanyl]diacetic acids, based on condensation of 4,6-dihydroxypyrimidin-2-ylthioacetic acid with carbonyl compounds followed by cyclodehydration to [(5-(4-nitrophenyl)-4,6-dioxo-3,5,6,7-tetrahydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-2,8-diyl)di(sulfanyl)]diacetic acid derivatives, are less efficient. Alkylation of 2-thiobarbituric acid with ethyl bromoacetate in ethanol in the presence of alkali yields 5-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-2-thiobarbituric acid.     

Nucleosides. Part LXI. A Simple Procedure for the Monomethylation of Protected and Unprotected Ribonucleosides in the 2′-O- and 3′-O-Position Using Diazomethane and the Catalyst Stannous Chloride

Intensive studies on the diazomethane methylation of the common ribonucleosides uridine, cytidine, adenosine, and guanosine and its derivatives were performed to obtain preferentially the 2′-O-methyl isomers. Methylation of 5′-O-(monomethoxytrityl)-N²-(4-nitrophenyl)ethoxycarbonyl-O⁶-[2-(4-nitrophenyl)ethyl]-guanosine ( 1 ) with diazomethane resulted in an almost quantitative yield of the 2′- and 3′-O-methyl isomers which could be separated by simple silica-gel flash chromatography (Scheme 1). Adenosine, cytidine, and uridine were methylated with diazomethane with and without protection of the 5′ -O-position by a mono- or dimethoxytrityl group and the aglycone moiety of adenosine and cytidine by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group (Schemes 2–4). Attempts to increase the formation of the 2′-O-methyl isomer as much as possible were based upon various solvents, temperatures, catalysts, and concentration of the catalysts during the methylation reaction.     

Nucleotides. Part XLVI. The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology

The application of the improved phosphoramidite strategy for the synthese of oligonucleotides using β-eliminating protecting groups to phospholipid chemistry offers the possibility to synthesize phospholipid conjugates of AZT ( 6 ) and cordycepin. The synthesis of 3′-azido-3′-deoxythymidine ( 6 ) was achieved by a new isolation procedure without chromatographic purification steps in an overall yield of 50%. Protected cordycepin ( = 3′-de-oxyadenosine) derivatives, the N⁶,2′-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin ( 12 ) and the N⁶,5′-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin ( 13 ) wre prepared by known methods and direct acylation of N⁶-[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin ( 9 ), respectively. These protected nucleosides and the 3′-azido-3′-de-oxythymidine ( 6 ) reacted with newly synthesized and properly characterized lipid-phosphoramidites 21–25 , catalyzed by 1H-tetrazole, to the corresponding nucleoside-phospholipid conjugates 26–38 in high yield. The deprotection was accomplished via β-elimination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in aprotic solvents to give analytically pure nucleoside-phospholipid diesters 39–51 as triethylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and UV and ¹H-NMR spectra.     

Synthesis of 4-aminothieno[2,3-b] pyridine-5-carboxylie acids

2-Amino-3-cyanothiophenes were reacted with ethyl aminocrotonate in the presence of catalytic amounts of p-toluensulfonic acid. The intermediates 2-[N-(3′-ethoxycarbonyl-2′-propenylamino]-3-cyanothiophenes obtained were cyclized with sodium ethoxide to give the desired ethyl 4-aminothieno[2,3-b] pyridine-5-carboxylate. Hydrolysis of the latter aminoesters afforded 4-aminothieno[2,3-b]pyridine-5-carboxylic acid. The overall yields were about 80%.     

Nucleotides. Part L. Aglycone protection by the (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group a new variation in oligodeoxyribonucleotide synthesis

The (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group was employed for protection of the amino functions of the aglycone residues. The lactam function of 2′-deoxyguanosine was on the one hand unprotected and on the other hand alkylated at O⁶ of the aglycone with the 2-(4-nitrophenyl)ethyl (npe) and 2-(phenylsulfonyl)ethyl (pse) group, respectively. The syntheses of monomeric building blocks, both phosphoramidites and nucleoside- functionalized supports, are described for the three common 2′-deoxynucleosides (2′-deoxycytidine, 2′-deoxyadenosine, 2′-deoxyguanosine). As kinetic studies with the tritylated nucleosides showed, the dnseoc group is more labile towards DBU cleavage than the corresponding 2-(4-nitrophenyl)ethyl-(npe) and [2-(4-nitrophenyl)ethoxy]carbonyl(npeoc)-protected analogues (see Table 2). These results were confirmed by the very fast deprotection rate of the dnseoc groups at some oligonucleotides.     

A convenient synthesis for some new pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine derivatives with potential biological activity

Ready, convenient synthesis for 8-cyano-7-ethoxy-4-oxo-9-phenyl-2-substituted-1,2,3,-4-tetrahydropyrido-[3′,2′:,4,5]thieno[3,2-d]pyrimidines 5 , 8-cyano-7-ethoxy-4-oxo-9-phenyl-2-substituted-3,4-dihydropyrido[3′,2-: 4,5]thieno[3,2-d]pyrimidines 6 , 4-chloro-8-cyano-7-ethoxy-9-phenyl-2-substitutedpyrido[3′,2′:4,5]thieno[3,2-4 -pyrimidines 7 and 8-cyano-7-ethoxy-2-(2′-nitrophenyl)-9-phenyl-4-substitutedpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidines 8-18 from 2-chloro-3,5-dicyano-6-ethoxy-4-phenylpyridine 1 via 3,5-dicyano-6-ethoxy-2-mercapto-4-phenylpyridine 2 and aminocarboxamide 4 are reported. In addition, the reaction of hydrazino derivative 12 with reagents such as formic acid and triethyl orthoformate yielded the fused tetraheterocyclic 8-cyano-9- ethoxy-5-(2′-nitrophenyl)- 7-phenylpyrido[3′,2′:4,5]thieno[2,3-e]-1, 2,4-triazolo[4,3-c]pyrimidine system 19 .     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.     

Synthesis and Spectroscopic Characterization of Some Ferrocenyl Schiff Bases Containing Pyridine Moiety and Their Complexation with Cobalt,Nickel, Copper and Zinc

Three novel ferrocenyl Schiff base ligands containing pyridine moiety have been formed by 1:2 molar condensation of 1,1′‐diacetylferrocene with 2‐aminopyridine, 2‐amino‐5‐picoline or 2‐amino‐5‐chloropyridine, respectively. The ligands are 1,1′‐bis[1‐(pyridyl‐2‐imino)‐ethyl]ferrocene (L1); 1,1′‐bis[1‐(5‐methyl‐pyridyl‐2‐imino)ethyl]ferrocene (L2) and 1,1′‐bis[1‐(5‐chloropyridyl‐2‐imino)ethyl]ferrocene (L3). These ligands form 1:1 complexes with Co(II), Cu(II), Ni(II) and Zn(II) ions. The prepared ligands and their complexes have been characterized by IR, ¹H NMR, ¹³C NMR, UV/Vis spectra as well as elemental analysis. The spectral data of the ligands and their complexes are discussed in connection with the structural changes due to complexation.     

Charge-Transfer Salts of Ferrocene Derivatives with Bis(maleonitriledithiolato)metallate(III) Complexes ([M(mnt)2]−, M=Ni,Pt): A Ground-State High-Spin [(Ni(mnt)2)2]2− Dimer

New hexamethylated ferrocene derivatives containing thioether moieties (1,1′-bis[(tert-butyl)thio]-2,2′,3,3′,4,4′-hexamethylferrocene ( 3a , b )) or fused S-heteropolycyclic substituents (rac-1-[(1,3-benzodithiol- 2-yliden)methyl]-2,2′,3,3′,4,4′-hexamethylferrocene ( 5 ) and rac-1-[1,2-bis(1,3-benzodithiol-2-yliden)ethyl]-2,2′,3,3′,4,4′-hexamethylferrocene ( 14 )), as well as a series of ferrocene-substituted vinylogous tetrathiafulvalenes (1,1′-bis[1,2-bis(1,3-benzodithiol-2-yliden)ethyl]ferrocene ( 6a ), 1,1′-bis[1-(1,3-benzodithiol-2-yliden)-2-(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)ethyl]ferrocene ( 6b ), [1,2-bis(1,3-benzodithiol-2-yliden)ethyl]ferrocene ( 21a ), [1-(1,3-benzodithiol-2-yliden)-2-(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)ethyl]ferrocene ( 21b ), [1,2-bis(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)ethyl]ferrocene ( 21c ), [1-(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)-2-(1,3-benzodithiol-2-yliden)ethyl]ferrocene ( 21d )) were prepared and fully characterized. Their redox properties show that some of them are easily oxidized and undergo transformation to paramagnetic salts containing bis(maleonitriledithiolato)-metallate(III) anions [M(mnt)₂]⁻ (M=Ni, Pt; bis[2,3-dimercapto-κS)but-2-enedinitrilato(2⁻)]nickelate (1⁻) or -platinate (1⁻). The derivatives [ 3a ] [Ni(mnt)₂] ( 26 ), [ 3a ] [Pt(mnt)₂] ( 27 ), [Fe{(η⁵-C₅Me₄S)₂S}] [Ni(Mnt)₂] ( 28 ), [Fe{(η⁵-C₅Me₄S)₂S}] [Pt(mnt)₂] ( 29 ), [ 5 ] [Ni(mnt)₂]⋅ClCH₂CH₂Cl ( 30 ), [ 6a ] [Ni(mnt)₂] ( 31 ), [ 6a ] [Ni(mnt)₂]⋅ClCH₂CH₂Cl ( 31a ), [ 6a ] [Pt(mnt)₂] [ 32 ), and [ 6b ] [Ni(mnt)₂] ( 33 ) were prepared and fully characterized, including by SQUID (superconducting quantum interference device) susceptibility measurements. X-Ray crystal-structural studies of the neutral ferrocene derivatives 6a , b , 21c , d , and 1,1′-bis[1-(1,3-benzodithiol-2-yliden)-2-oxoethyl]ferrocene ( 23 ), as well as of the charge-transfer salts 26 – 28 , 30 , and 31a , are reported. The salts 28 and 30 display both a D⁺A⁻A⁻D⁺ structural motif, however, with a different relative arrangement of the [{Ni(mnt)₂}₂]²⁻ dimers, thus giving rise to different but strong antiferromagnetic couplings. Salt 26 exhibits isolated ferromagnetically coupled [{Ni(mnt)₂}₂]²⁻ dimers. Salt 27 displays a D⁺A⁻D⁺A⁻ structural motif in all three space dimensions, and a week ferromagnetic ordering at low temperature. Salt 31a , on the contrary, shows segregated stacks of cations and anions. The cations are connected with each other in two dimensions, and the anions are separated by a 1,2-dichloroethane molecule.     

Facile synthesis and antifungal activity of 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

The reactions of the pyrazole-5-diazonium salt 3 with malononitrile and ethyl cyanoacetate gave 4-amino-3-cyano-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazine 7 and 4-amino-3,8-bisethoxycarbonylpyrazolo[5,1-c]-[1,2,4]triazine 8 , whose reactions with p-chloroaniline hydrochloride afforded 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)amidinopyrazolo[5,1-c][1,2,4]triazine 9 and 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)car-bamoylpyrazolo[5,1-c][1,2,4]triazine 10 , respectively. The reactions of 7 and 8 with o-phenylenediamine di-hydrochloride provided 9-ethoxycarbonyl-13H-spiro[benzimidazole-2′(3′H),6(5H)-pyrazolo[1,5′:3,4][1,2,4]tri-azino[5,6-b][1,5]benzodiazepine] hydrochloride 11a and 9-ethoxycarbonyl-6-oxo-13H-5,6-dihydropyrazolo-[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepine 12 , respectively. The antifungal activity of the above compounds was described.     

Synthesis of 5,5′[[[3-(dimethylamino)propyl]imino]]bis[3-(trichloromethyl)-1,2,4-thiadiazole] and related thiadiazoles as antimalarial agents

The condensation of 5-chloro-3-(trichloromethyl)-1,2,4-thiadiazole (VIII) with N,N-dimelhyl-1,3-propanediamine gave 5-¶ [3-(dimethylammo)propyl]amino¶-3-(trichloromethyl)-1,2,4-thia-diazole(5) and 5,5′-¶[3-(dimethylamino)propyl]imino)¶bis[3-(triehloromethyl)-1,2,4-tliiadiazole] (14), together with 5,5′-[(3-¶ methyl[ 3-(trichloromethyl)-1,2,4-thiadiazol-5-yl ]amino Jpropyl)-imino]bis[3-(trichloromethyl)-1,2,4-thiadiazole] ( 17 ) which was formed via an unusual displacement of the distal methyl group of 14. The remarkable antimalarial activity of 14 prompted the synthesis of an array of 5-amino-3-(trichloromethyl, methyl, and 3,4-dichlorophenyl)-1,2,4-thiadiazoles and 5,5′-¶[(dialkylamino)alkyl]imino¶bis[3-(trichloromethyl, methyl, and 3,4-dichlorophenyl)-1,2,4-thiadiazoles] from an amine and the requisite 5-chloro-3-substituted-1,2,4-thiadiazoles, which were prepared from the appropriate amidine and trichloromethylsull'enyl chloride. 5-¶3-[(Diethylamino)methyl]-p-anisidino ¶-3-(triehloromethyl)-1,2,4-thiadiazole ( 13 ) was active against a chloroquine-resistant line of Plasrnodium berghei in the mouse, and compound 14 , the most promising member of the series overall, was designated for expanded antimalarial and toxicological studies. Structure-activity relationships against P. berghei in mice and P. gallinaceum in chicks are discussed.     

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH₂, CH₂CH₂, or CH₂NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.     

Synthesis and properties of sulfonated polyimides from homologous sulfonated diamines bearing bis(aminophenoxyphenyl)sulfone

Three homologous sulfonated diamines bearing a bis(aminophenoxyphenyl)sulfone structure, namely, bis[4‐(4‐aminophenoxy)phenyl]sulfone‐3,3′‐disulfonic acid (pBAPPS‐3DS), bis[4‐(4‐aminophenoxy)phenyl]sulfone‐2,2′‐disulfonic acid (pBAPPS‐2DS), and bis[4‐(4‐aminophenoxy)‐2‐(3‐sulfobenzoyl)phenyl]sulfone (pBAPPS‐2DSB), were synthesized. A series of sulfonated polyimides (SPIs) were synthesized from 1,4,5,8‐naphthalene tetracarboxylic dianhydride, these sulfonated diamines, and nonsulfonated diamines, and their properties were investigated in comparison with those reported for the SPIs from another homologous diamine or bis[4‐(3‐aminophenoxy)phenyl]sulfone‐3,3′‐disulfonic acid (mBAPPS‐3DS). These SPIs were soluble in common aprotic solvents and showed reasonably high proton conductivity, except for pBAPPS‐2DS‐based SPIs, the conductivity of which was slightly lower because of the lower water uptake. The water stability of these SPIs considerably depended on the structure of the sulfonated diamines and was in the order of pBAPPS‐2DSB ≈ pBAPPS‐2DS > pBAPPS‐3DS ? mBAPPS‐3DS. Their water stability was much lower than that of the SPIs from 4,4′‐bis(4‐aminophenoxy)biphenyl‐3,3′‐disulfonic acid. The reason was discussed on the basis of the basicity of the sulfonated diamine and the solubility property of the SPIs. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2797–2811, 2007     

The Diels-Alder Reactivity of 2,2′-Ethylidenebis[3,5-dimethylfuran] and Exploratory Chemistry of the Mono-adducts

In the presence of Me₃Al, 1-cyanovinyl acetate added to 2,2′-ethylidenebis[3,5-dimethylfuran] ( 1 ) to give a 20:10:1:1 mixture of mono-adducts 4,5,6 , and 7 resulting from the same regiocontrol (‘para’ orienting effect of the 5-methyl substituent in 1 ). The additions of a second equiv. of dienophile to 4–7 were very slow reactions. The major mono-adducts 4 (solid) and 5 (liquid) have 2-exo-carbonitrile groups. The molecular structure of 4 (1RS,1′RS,2SR,4SR)-2-exo-cyano-4-[1-(3,5-dimethylfuran-2-yl)ethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate) was determined by X-ray single-crystal radiocrystallography. Mono-adducts 4 and 5 were saponified into the corresponding 7-oxanorbornenones 8 and 9 which were converted with high stereoselectivity into (1RS,1′SR,4RS,5RS,6RS)-4-[1-(3,5-dimethyl furan-2-yl)ethyl]-6-exo-methoxy-1,5-endo-dimethyl-7-oxabicyclo [2.2.1]heptan-2-one dimethyl acetal ( 12 ) and its (1′RS-stereoisomer 12a , respectively. Acetal hydrolysis of 12a followed by treatment with (t-Bu)Me₂SiOSO₂CF₃ led to silylation and pinacol rearrangement with the formation of (1RS,1′RS,5RS,6RS)-4-[(tert-butyl)dimethy lsilyloxy]-1-(3,5-dimethylfuran-2-yl)ethyl]-5-methoxy-6-methyl-3-methylidene- 2-oxabicyclo[2.2.1]heptane ( 16 ). In the presence of Me₃Al, dimethyl acetylenedicarboxylate added to 12 giving a major adduct 19 which was hydroborated and oxidized into (1RS,1′RS,2″RS,3″RS,4SR,4″RS,5 SR,6SR)-dimethyl 5-exo-hydroxy-4,6-endo-dimethyl-1-[1-(3-exo,5,5-trimeth oxy-2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-2-yl)ethyl]-7-oxabicyclo [2.2.1]hept-2-ene-2,3-dicarboxylate ( 20 ). Acetylation of alcohol 20 followed by C?C bond cleavage afforded (1′RS,1″SR,2RS,2′″SR,3RS, 3″SR,4RS,4″SR,5RS)-dimethyl {3-acetoxy-2,3,4,5-tetrahydro-2,4-dimethyl-5-[1-(3-exo,5,5-trimethoxy ?2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-1-yl)-ethyl]furan-2,5-diyl} bis[glyoxylate] ( 24 ).