Synthesis and reactions of 2,2-[60]fullerenoalkanoyl chlorides

2,2-[60]Fullerenoalkanoyl chlorides (1a-d) were easily and securely prepared from the corresponding 2,2-[60]fullerenoalkanoic acids (2a-d) by the reaction with thionyl chloride in an unusual mixed solvent, CH2Cl2/dioxane. The characterization of 1a-d by 1H and 13C NMR, FT-IR, and MALDI-TOF-MASS was conducted for the first time. The 2,2-[60]fullerenoalkanoyl chlorides thus obtained were readily converted to the corresponding amides and esters in moderate to excellent yields by the condensation with amines and alcohols, respectively. Upon applying the condensation, [60]fullerene-biomolecule hybrids were easily prepared.     

Solid phase synthesis and application of trisubstituted thioureas

Resin-bound amines 1a-e condense with isothiocyanates to give thiourea resins 2a-i. Resins 2a-g subsequently react with iodomethane followed by cleavage affording S-methyl isothioureas 4a-g, and resins 2a-b,h-i react with acyl chlorides to afford N-acylated thioureas 6a-d. N-Acylthioureas 8a-f (R(2) = H) were prepared directly from resin-bound amines 1a-d with acyl isothiocyanates. N-Acylthioureas 8a-d,f(R(2) = H) were used for the preparation of S-methyl-N-acylisothioureas 10a-e. Alkylation was performed using methyl iodide. Resin-bound S-methyl-N-acylisothioureas 10a,b,d are converted by an action of hydrazines into 3-amino-1,2,4-triazoles 13a-d. Condensation of resins 8a-e (R(2) = H) with 2-bromoacetophenones in the presence of TEA affords thiazoles 15 a-e. All transformations proceeded in high yields and gave products of good purities.     

First Exclusive Regioselective Fragmentation of Primary Ozonides Controlled by Remote Carbonyl Groups and a New Method for Determining the Regiochemistry of Carbonyl Oxide Formation

The first exclusive regioselective fragmentation of primary ozonides controlled by remote carbonyl groups on ozonolysis of norbornene derivatives and reaction of final ozonides with triethylamine as a new probe for determining the regiochemistry of carbonyl oxide formation from primary ozonide fragmentation are reported. Ozonolysis of the endo adducts 3a-d and the deuterated compounds 8a and 8b in CDCl(3) at -78 degrees C gave the final ozonides 4a-d, 9a, and 9b as the sole products (>95%), respectively. No detectable amount of the isomeric final ozonides 5, 10, 11, and 12 was obtained. A mechanism is proposed to account for the exclusive regioselective fragmentation of the primary ozonides. Ozonolysis of 3a-d, 8a, and 8b in CH(2)Cl(2) at -78 degrees C followed by treatment with triethylamine exclusively gave the convex tetraquinane oxa cage compounds 16a-d, 19a, and 19b in 85-90% yields, respectively. No detectable amount of the other regioisomers 17a-d, 20a, and 20b was obtained. Ozonolysis of 3a-d, 8a, and 8b in CH(2)Cl(2) at -78 degrees C followed by reduction with dimethyl sulfide gave the tetraacetal tetraoxa cage compounds 21a-d, 23a, and 23b in 85% yields, respectively. The difference in function between triethylamine and dimethyl sulfide in reaction with final ozonide is demonstrated. Ozonolysis of the endo adducts 24a and 24b in CDCl(3) at -78 degrees C exclusively gave the final ozonides 27a and 27b, respectively. The order of the preference of various remote carbonyl groups to control the fragmentation of the primary ozonides formed by ozonolysis of norbornene derivatives is investigated. Ozonolysis of the endo esters 32a-c in CH(2)Cl(2) at -78 degrees C followed by reduction with dimethyl sulfide gave the new tetraacetal oxa cages 35a-c, with an alkoxyl group directly on the skeleton, and the novel triacetal oxa cages 36b and 36c, respectively. The structures of triacetal oxa cages are proven for the first time by X-ray analysis of the crystalline compound 36c.     

Intramolecular Diels-Alder reactions of brominated masked o-benzoquinones. A detour method to synthesize highly functionalized oxatricyclic [m.3.1.0] ring systems from 2-methoxyphenols

Intramolecular Diels-Alder (IMDA) reactions of masked o-benzoquinones (MOBs) 5a-d to 7a-d and 17a-d to 19a-d generated in situ from 2-methoxyphenols 2-4 and 14-16, respectively, in the presence of alkenols 1a-d, resulting in highly functionalized oxatricyclic [m.3.1.0] ring systems are described. The MOBs 5a-d to 7a-d underwent the IMDA reactions to furnish the adducts 8a-d, 10a-d, and 12a-d (direct method) in poor yields with the concomitant formation of considerable amounts of unexpected byproducts 9a-d, 11a-d, and 13a-d, respectively. To avoid the formation of byproducts and to improve the yields of the desired cycloadducts, a detour method comprising sequential bromination of 2-methoxyphenols 2-4, tandem oxidative acetalization-Diels-Alder reaction, and debromination has been developed. The oxidation of bromophenols 14-16 in the presence of alkenols 1a-d produced the corresponding MOBs 17a-d to 19a-d, which underwent cycloaddition to afford the cycloadducts 20a-d to 22a-d, respectively, as sole products in good to high yields in a highly regio- and stereoselective manner. Treatment of the bromoadducts 20a-d to 22a-d with tributylammonium formate-palladium reagent produced the corresponding debrominated products 8a-d, 10a-d, and 12a-d in high to excellent yields. In general, the latter oxatricycles were obtained in higher overall yields via the detour method than those via the direct method.     

Stereocontrolled IMDA reaction of styrene derivatives. A way to enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines

IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with high stereoselection and excellent chemical yields. After elimination of the chiral appendage, enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained when a methyl group was at C-2.     

The reducive amination of phthalaldehyde by tetracarbonylhydridoferrate : Synthesis of 2-arylisoindoles

Phthalaldehyde reacted with primary amines in the presence of tetracarbonylhydridoferrate under mild conditions to give 2-substituted isoindoles and/or isoindolines in good to excellent yields. Aliphatic amines gave selectively the isoindolines but aromatic amines had a great tendency to the isoindoles. 2-(2-Tolyl)-, 2-(4-tolyl)-, 2-(4-methoxyphenyl)-, 2-(3-chlorophenyl)-, 2-(4-chlorophenyl)- and 2-(3,4-dichlorophenyl)-isoindole were prepared by this method.     

Direct substitution of primary allylic amines with sulfinate salts

The NH(2) group in primary allylic amines was substituted directly by sulfinate salts with excellent regio- and stereoselectivities. In the presence of 0.1 mol % [Pd(allyl)Cl](2), 0.4 mol % 1,4-bis(diphenylphosphino)butane (dppb), and excess boric acid, a range of α-unbranched primary allylic amines were smoothly substituted with sodium sulfinates in an α-selective fashion to give structurally diverse allylic sulfones in good to excellent yields with exclusive E selectivity. Replacing dppb with 1,1'-bi-2-naphthol (BINOL) allowed unsymmetric α-chiral primary allylic amines to be transformed into the corresponding allylic sulfones in good to excellent yields with excellent retention of ee. Importantly, the reaction complements known asymmetric methods in substrate scope via its unique ability to provide α-chiral allylic sulfones with high optical purity starting from unsymmetric allylic electrophiles.     

Preparation of 1,5-disubstituted pyrrolidin-2-ones

1,5-Disubstituted pyrrolidin-2-ones 18a-g, 19a-h, and 20a-f were synthesized in good to excellent yields via the nucleophilic substitution of 5-(benzotriazol-1-yl)-1-substituted-pyrrolidin-2-ones 9 with allylsilanes, organozinc reagents, and phosphorus compounds. Compounds 9 and 5-(benzotriazol-2-yl)-1-substituted-pyrrolidin-2-one isomers 10 are readily prepared in total 70-84% yields from 2, 5-dimethoxy-2,5-dihydrofuran (7), primary amines 8, and benzotriazole; 9 and 10 react identically with nucleophiles.     

Synthesis of new visnagen and khellin furochromone pyrimidine derivatives and their anti-inflammatory and analgesic activity

6-[(4-Methoxy/4,9-dimethoxy)-7-methylfurochromen-5-ylideneamino]-2-thioxo-2,3-dihydropyrimidin-4-ones 1a,b were prepared by reaction of 6-amino-2-thiouracil with visnagen or khellin, respectively. Reaction of 1a,b with methyl iodide afforded furochromenylideneaminomethylsulfanylpyrimidin-4-ones 2a,b. Compounds 2a,b were reacted with secondary aliphatic amines to give the corresponding furochromen-ylideneamino-2-substituted pyrimidin-4-ones 3a-d. Reaction of 3a-d with phosphorus oxychloride yielded 6-chlorofurochromenylidenepyrimidinamines 4a-d, which were reacted with secondary amines to afford furochromenylideneamino-2,6-disubstituted pyrimidin-4-ones 5a-d. In addition, reaction of 5a-d with 3-chloropentane-2,4-dione gave 3-chloro-furochromenylpyrimidopyrimidines 6a-d. The latter were reacted with piperazine and morpholine to give 1-(furochromenyl)-pyrimidopyrimidine-3,6,8-triylpiperazines or -3,6,8-triylmorpholines 7a-d. The chemical structures of the newly synthesized compound ware characterized by IR, 1H-NMR, 13C-NMR and mass spectral analysis. These compounds were also screened for their analgesic and anti-inflammatory activities. Some of them, particularly 3-7, exhibited promising activities.     

Highly selective addition of chiral,sulfonimidoyl substituted bis(allyl)titanium complexes to N-sulfonyl alpha-imino esters: asymmetric synthesis of gamma,delta-unsaturated alpha-amino acids bearing a chiral,electron-withdrawing nucleofuge at the delta-position

Selective addition of the chiral, sulfonimidoyl substituted bis(allyl)titanium complexes 5a-d, which are configurationally labile in regard to the Calpha-atoms, to N-toluenesulfonyl (Ts)-, N-2-trimethylsilylethanesulfonyl (SES)-, and N-tert-butylsulfonyl (Bus) alpha-imino ester (9a-c) in the presence of Ti(OiPr)(4) and ClTi(OiPr)(3) afforded with high regio- and diastereoselectivities in good yields the (syn, E)-configured beta-alkyl-gamma,delta-unsaturated alpha-amino acid derivatives 2a-g, which carry a chiral, electron-withdrawing nucleofuge at the delta-position and a cyclohexyl, an isopropyl, a phenyl, and a methyl group at the beta-position. Addition of the cyclic bis(allyl)titanium complex 14 to N-Bus alpha-imino ester 9c afforded with similar high regio- and diastereoselectivities the (E)- and (Z)-configured amino acid derivatives (E)-8 and (Z)-8. Reaction of complexes 5a-d with alpha-imino esters 9a-c in the presence of Ti(OiPr)(4) occurs stepwise to give first the mono(allyl)titanium complexes containing 2a-g as ligands, which react in the presence of ClTi(OiPr)(3) with a second molecule of 9a-c with formation of two molecules of 2a-g. Formation of (S,R,E)-configured homoallylic amines 2a-g entails Si,Re,E processes of alpha-imino esters 9a-c with the (R,R)-configured bis(allyl)titanium complexes (R,R)-5a-d and (R)-configured mono(allyl)titanium complexes (R)-17a-d, both of which are most likely in rapid equilibrium with their (S,S)-diastereomers and (S)-diastereomers, respectively. Interestingly, in the reaction of 5a-d with aldehydes, the (S,S)-configured complexes (S,S)-5a-d are the ones which react faster. Reaction of the N-titanated amino acid derivatives Ti-2a and Ti-2b with N-Ts alpha-imino ester 9a led to the highly diastereoselective formation of imidazolidinones 15a and 15b, respectively. Cleavage of the sulfonamide group of the N-Bus amino acid derivative 2d with CF(3)SO(3)H gave quantitatively the sulfonimidoyl functionalized amino acid H-2d. A Ni-catalyzed cross-coupling reaction of the amino acid derivative 2e with ZnPh(2) led to a substitution of the sulfonimidoyl group by a phenyl group and furnished the enantiomerically pure protected alpha-amino acid Bus-1. Two new N-sulfonyl alpha-imino esters, the SES and the Bus alpha-imino esters 9b and 9c, respectively, have been synthesized from the corresponding sulfonamides by the Kresze method in medium to good yields. The N-SES alpha-imino ester 9b and the N-Bus alpha-imino ester 9c should find many synthetic applications, in particular, in cases where the N-Ts alpha-imino ester 9a had been used before.     

Diels-Alder reactions of 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienone. An expedient methodology for the synthesis of bicyclo[2.2.2]oct-5-en-2-ones and bicyclo[2.2.2]octa-5,7-dien-2-ones

The synthesis of 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienone (13), bicyclo[2.2.2]octenones 1a-j and 15a-j, and bicyclo[2.2.2]octadienones 2a-f, 6a-d, and 11a-f is described. The 2,4-cyclohexadienones 4 and 13 were used for the first time as nondimerizing and easily accessible alternatives to 2,6,6-trimethyl-2,4-cyclohexadienone 12 in Diels-Alder reactions with acetylene derivatives 5a-d to prepare the adducts 6a-d and 11a-e in excellent yields. Compounds 11a-d were initially prepared by the alcoholysis of 6a-d to afford bicyclo[2.2.2]octene-2,5-diones 7a-dfollowed by treatment of 7a-d with N-phenyltriflimide in the presence of LHMDS at -78 degrees C. Diels-Alder reaction of 13 with an acetylene equivalent, phenyl vinyl sulfoxide, was also studied. A detailed study of the Diels-Alder reactions of various olefinic dienophiles 14a-j with 13 has been carried out to furnish cycloadducts 15a-j in high yields. Reductive removal of triflyloxy group of vinyl triflates 11a-f and 15a-j was performed in the presence of [Pd(PPh(3))(2)Cl(2)-Bu(3)N-HCO(2)H] to obtain the desired bicyclo[2.2.2]octadienones 2a-f and bicyclo[2.2.2]octenones 1a-j, respectively, in good overall yields.     

6‐Nitro‐1,2,3,4‐tetrahydroquinolines by a tandem reductive amination‐SNAr reaction

A tandem reductive amination‐S_NAr reaction has been developed for the synthesis of 6‐nitro‐1,2,3,4‐tetrahydroquinolines. Treatment of 4‐(2‐fluoro‐5‐nitrophenyl)‐2‐butanone or 3‐(2‐fluoro‐5‐nitrophenyl)‐propanal with primary amines and sodium cyanoborohydride in methanol at room temperature provided good to excellent yields of the substituted tetrahydroquinolines. The reaction proceeded best with the ketone substrate using primary amines that were unbranched at the α‐carbon. The aldehyde also produced the target heterocycles, but these were accompanied by 10‐15% of the uncyclized side chain reductive amination products.     

A new route to the improved synthesis of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils

A new route to C-6-selenenyl analogs of compound 1a from 5-alkyl-6-chlorouracils 6a-b has been described. A mild and highly efficient synthesis of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils 8a-e has been accomplished from 6a-b in good yields using a two step procedure. Silylation of 5-alkyl-6-chlorouracils 6a-b using N,O-bis(trimethylsilyl)acetamide followed by regioselective alkylation of the silylated intermediate with ethyl or benzyl chloromethyl ether in dichloromethane afforded the desired 1-(alkoxymethyl)-5-alkyl-6-chlorouracils 7a-d in 88–94% yields. Compounds 7a-d readily underwent addition-elimination reaction with an appropriate arylselenol in the presence of ethanolic sodium hyroxide to produce the corresponding 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils 8a-e in excellent yields (94–99%).     

Lithiation of 1-chloromethylbenzotriazole: generation and elaboration of benzotriazolyloxiranes

1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a-g in good yields. The oxiranyllithiums 4a-d generated from 2a-d and n-BuLi at -78 degrees C were trapped by a variety of electrophiles to give oxiranyl derivatives 5a-j in good to excellent yields. Lewis-acid-promoted nucleophilic ring opening of benzotriazolyloxiranes 2a,f,g with allyltrimethylsilane gave the corresponding 1,7-octadien-4-ols 6a-c in 68-75% yield. Hydrolysis of alpha-acylbenzotriazolyloxiranes 5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.     

Synthesis of 2,5-disubstituted thienosultines and their thermal reactions with dienophiles and nucleophiles

The 2,5-disubstituted thienosultines (5,7-disubstituted 1,4-dihydro-1H-3lambda(4)-thieno[3,4-d][2,3]oxathiin-3-oxides) 5a-d were prepared from the corresponding dichlorides 4a-d with the commercially available Rongalite (sodium formaldehyde sulfoxylate) in 17-60% yields. When heated in the presence of electron-poor dienophiles, sultines 5a-d underwent elimination of SO(2), and the resulting non-Kekulé biradicals 7a-d were intercepted as the 1:1 adducts 8-12 in good to excellent yields. The pyrolysis of sultines and sulfolenes with different concentrations of dienophiles revealed that either a preequilibrium between starting reagents and biradical species or Diels-Alder and retro-Diels-Alder reaction mechanisms may be involved; however, more work is necessary to establish the proposed mechanisms. Reaction of sultine 5b with nBuLi was found to undergo a nucleophilic ring-opening reaction to give sulfinyl alcohol 17 after H(2)O workup. When sultine 5a was heated in benzene in a sealed tube in the presence of methanol, methanol-d(4), or 2-mercaptoethanol, the respective 1:1 trapping adducts 19-21 as well as the rearranged sulfolene 6a were isolated in similar amounts. The isolation of adducts 19-21 may be explained by the involvement of either biradical or ionic intermediates during the pyrolysis.     

Synthesis of α-Oxo and α-hydroxy-1-benzyl-1,4-dihydro-3(2H)-isoquinolinones

The reaction of some primary amines with the methyl 2-[(α-oxobenzyl)-(α-bromo)methyl]phenylacetate ( 5 ) afforded the isoquinolinones 7a-d , which in turn were hydrogenated to 10a-d . The synthesis of these compounds was designed on the basis of a potential depressant and antiinflammatory activity found in other structurally related compounds.     

Synthesis of 2,3-dihydroindoles, indoles, and anilines by transition metal-free amination of aryl chlorides

Aliphatic and aromatic amines react with 2- and 3-chlorostyrene in the presence of potassium tert-butoxide to give N-substituted 2,3-dihydroindoles in good yields. The combination of this domino-amination protocol with a suitable dehydrogenation reaction gives access to pharmacologically interesting indoles in a one-pot procedure. Overall product yields of N-substituted indoles >50% are obtained by this method starting from commercially available substrates. In addition to the intramolecular base-promoted amination of aromatic C-Cl bonds, metal-free intermolecular aminations of aryl chlorides with primary and secondary amines are described. The use of potassium tert-butoxide as base allows the synthesis of various anilines in good to excellent yields. Due to the formation of aryne intermediates, either N-substituted anilines or meta-substituted anilines are produced with excellent selectivities.     

Cyanomethyl anion/carbon dioxide system: an electrogenerated carboxylating reagent. Synthesis of carbamates under mild and safe conditions

A new carboxylating reagent ((-)CH(2)CN/CO(2)) was obtained by bubbling CO(2) in a CH(3)CN-TEAP (tetraethylammonium perchlorate) solution previously electrolyzed under galvanostatic control. Organic carbamates were isolated from these solutions after addition of amines and an alkylating agent. In this paper, we describe the optimized conditions for the electrochemical synthesis of carbamates from amines and CO(2), in mild and safe conditions, without any addition of bases, probases, or catalysts. Carbamates were isolated from primary and secondary aliphatic amines in high to excellent yields and from aromatic amines in moderate yields (dependent on the nucleophilicity of the nitrogen atom).     

First synthesis and isolation of the E- and Z-isomers of some new Schiff bases. Reactions of 6-azido-5-formyl-2-pyridone with aromatic amines

Some novel Schiff bases have been prepared by reacting 6-azido-5-formyl-2-pyridone 1 with a series of aromatic amines 2a-f. 5-Arylaminomethylene-6-(E)-aryl-iminopyridones 3a-e were obtained by reaction of 1 with 2a-e at room temperature, whereas with 2f, the 6-azido-5-naphthalen-2-yl-iminomethylpyridone derivative 4 was formed. On the other hand, heating 1 with 2a-d at 140-150 degrees C yielded two sets of isomeric products, (E)-3a-d and (Z)-5a-d. Refluxing compounds (Z)-3a,c with hydroxyl-amine in methanol gave the corresponding hydroxyliminopyridones 8a,c. Heating of (E)-3a-d with excess POCl3 at reflux did not give the expected tricyclic compound 9, but rather the isomeric products (Z)-5a-d were obtained. The structures of all these products have been characterized using IR and 1H- and 13C-NMR spectroscopy.     

A convenient synthesis of some α-oxoketene-N,S- and N,N-acetals

Some α-oxoketene-N,S- and N,N-acetals were selectively synthesized in good to excellent yields by the reaction of 1,1-dimethoxy-4,4-di(methylthio)-3-buten-2-one with primary and secondary amines under moderate conditions. Secondary amines in reaction with α-oxoketene dithioacetal yielded double-substitution products exclusively, whereas primary amines under the same conditions yielded the mono-substituted products as exclusive or main products.