Chlorodifluoromethyl aryl ketones and sulfones as difluorocarbene reagents: The substituent effect

We have investigated the different chlorodifluoromethyl aryl ketones 1a-1g and sulfones 2a-2h as difluorocarbene reagents for O- and N-difluoromethylations. It was found that the sulfone reagents 2 were generally more efficient in difluoromethylation than the ketone reagents 1. Furthermore, while the different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethylation reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we found that p-chlorophenyl chlorodifluoromethyl sulfone 2d and p-nitrophenyl chlorodifluoromethyl sulfone 2h were among the most powerful difluorocarbene reagents in this category for O-difluoromethylations.     

Regioselective addition of Grignard reagents to 2,6-dicyanoanilines and cyclization to new quinazoline derivatives under thermal/microwave irradiation conditions

Two strategies have been developed for the synthesis of novel quinazoline derivatives. 2,6-Dicyanoanilines were reacted with Grignard reagents followed by cyclization to give two quinazoline regioisomers 2 and 3. Alternately 2,6-dicyanoanilines on reaction with Grignard reagents gave imine regioisomers 4 and 5. Each imine regioisomer was separated and independently cyclized to give new quinazoline derivatives 6, 7 and 8, 9, respectively, under different microwave irradiation conditions.     

Synthesis of naturally occurring bioactive butyrolactones: maculalactones A-C and nostoclide I

Starting from citraconic anhydride (13), a simple multistep (9-10 steps) synthesis of naturally occurring butyrolactones maculalactone A (3), maculalactone B (1), maculalactone C (2) and nostoclide I (4) have been described with good overall yields via dibenzylmaleic anhydride (20) and benzylisopropylmaleic anhydride (27). The two anhydrides 20 and 27 were prepared by S_N2′ coupling reactions of appropriate Grignard reagents with dimethyl bromomethylfumarate (14), LiOH-induced hydrolysis of esters to acids, bromination of carbon-carbon double bond, in situ dehydration followed by dehydrobromination and chemoselective allylic substitution of bromoatom in disubstituted anhydrides 19 and 26 with appropriate Grignard reagents. The NaBH₄ reduction of these anhydrides 20 and 27 furnished the desired lactones 21 and 29, respectively. The lactone 21 on Knoevenagel condensation with benzaldehyde, furnished maculalactone B (1), which on isomerization gave maculalactone C (2). Selective catalytic hydrogenation of 1 gave maculalactone A (3). The conversion of lactone 29 to nostoclide I (4) is known.     

Ring-opening reactions of cyclic ethers with diiodo- and dibromodimethylsilane equivalents

Ring-opening halosilation of cyclic ethers with reagents of (Me₂N)₂SiMe₂/4MeI (1a) and (Me₂N)₂SiMe₂/4allylBr (1b) was studied. Tetrahydrofuran and cyclohexene oxide reacted with 1a and 1b to give ring-opened di(haloalkoxy)dimethylsilanes in good yield. With less strained tetrahydropyran, however, only reagent 1a gave the ring-opened product. Reactions of reagents 1a and 1b with propylene oxide also proceeded smoothly, although the regioselectivity was rather low. When similar reactions were carried out with (Me₂N)₂SiMe₂/2MeI (2a) and (Me₂N)₂SiMe₂/2allylBr (2b) in a ratio of cyclic ethers/2a or 2b = 1/1, the corresponding 1:1 adducts were obtained.     

A convenient synthesis of di- and trisubstituted 2-aminoimidazoles from 1-amidino-3-trityl-thioureas

Convenient synthesis of 2-amino-1,5-disubstituted and 2-amino-1,4,5-trisubstituted imidazoles has been reported using readily available starting materials and simple reagents under mild conditions. Guanylation of 1-amidino-3-trityl-thioureas 1 and 7 using mercury(II) chloride (Caution) as a thiophile resulted in corresponding guanidines 2 and 8 which on reaction with α-bromo ketones yielded 2-tritylaminoimidazoles. Deprotection of 2-tritylaminoimidazoles using trifluoroacetic acid at room temperature furnished desired 2-aminoimidazoles 4 and 10 in good to moderate yields.     

1,2,5-Thiadiazole 2-oxides: selective synthesis,structural characterization,and electrochemical properties

A new general procedure for the selective synthesis of 1,2,5-thiadiazole 2-oxides (including fused derivatives) 8a,b,c,g,h from the reaction of vic-glyoximes with S₂Cl₂ and pyridine in acetonitrile was elaborated together with general procedure for the synthesis of 1,2,5-thiadiazoles 7a–i, 10, 12, and 14 from the same starting materials and reagents. Molecular structures of 3,4-dimethyl-1,2,5-thiadiazole 2-oxide 8a and [1,2,5]thiadiazolo[3,4-b]quinoxaline 10 were confirmed by single-crystal X-ray diffraction. Electrochemical properties of 1,2,5-thiadiazole 2-oxides 8 were studied by cyclic voltammetry and different behavior was observed for monocyclic and benzo-fused derivatives. With compounds 8g and 17, previously unknown deoxygenation of 2,1,3-benzothiadiazole 1-oxides was discovered by electrochemical reduction, and resulted 2,1,3-benzothiadiazoles 7g and 19 were detected in the forms of their radical anions by EPR spectroscopy combined with DFT calculations.     

The iron(III) chloride-mediated 1,4-addition of mercaptans to α,β-unsaturated ketones and esters under solvent free conditions

The 1,4-addition of various thiols to α,β-unsaturated ketones was completed rapidly in the presence of a catalytic amount (2-3 mol %) of anhydrous iron(III) chloride under solvent free conditions and an air atmosphere. Anhydrous iron(III) chloride is more active than that of other ferric salts. With more reactive and/or less steric reagents (1a-c and/or 2a-2c), expeditious conditions (short reaction times at room temperature) could be employed. With less reactive and/or steric reagents (1d-g and/or 2d-e), a slight increase in reaction time was required, but high yields were obtained. The FeCl₃ catalyst causes preferential interactions with α,β-unsaturated ketones present in the reaction.     

A quantum chemical study on the reaction of 1-aryl-1,2-dihydrophosphinine oxides with dimethyl acetylenedicarboxylate

A β-oxophosphorane/ylide (2a) and an oxaphosphete (3a), the product and the possible intermediate of an inverse Wittig type reaction of 1-(2,4,6-triisopropylphenyl-)1,2-dihydrophosphinine oxide with dimethyl acetylenedicarboxylate were studied by quantum chemical calculations. The reaction of the title reagents following either a traditional [4 + 2] cycloaddition protocol to afford phosphabicyclo[2.2.2]octadiene 5 or a novel route yielding eventually β-oxophosphorane/ylide 2 was evaluated by energy calculations. The mechanism for the formation of intermediate 3a₂ was refined by HF/6-31G* transition state calculations. Analysis of the HOMO-LUMO orbitals of the reagents justified the reactivity experienced.     

Cycloadditions of NS functions to cyclopentadienones

Cyclopentadienones react with EtO₂CNSO and related NS reagents to provide ready syntheses of 1,2,5-thiadiazolidines (8, 12, 17), diaminosulfanes (11, 13), an aminocyclopentenone (10) and the first unoxidised 1,2,3-oxathiazolidine (16), all in a mechanistically rational manner.     

A direct synthesis of α-(hydroxymethyl) and α-alkyl-vinyl alkyl ketones

Reaction of 2,4-diketoesters 3a-c with aqueous formaldehyde using potassium carbonate solution as base affords the corresponding α-methylene-β-hydroxyalkanones 4a-c which provide a route to α,β-unsaturated alkyl ketones 6a-e via coupling of α-acetoxymethyl alkyl vinyl ketone 5a with Grignard reagents in the presence of a catalytic amount of LiCuBr₂ at low temperature.     

Synthetic application of fluorinated vinamidinium salts: Synthesis of fluorinated 1,3-butadienylphosphonates by the reaction with Horner-Wadsworth-Emmons reagents

The reaction of β-fluoro vinamidinium salt 1 with Horner-Wadsworth-Emmons reagents (HWE) such as diethyl(ethoxycarbonyl)methylphosphonate (2a), diethyl(methoxycarbonyl)methylphosphonate (2b), diethyl-2-oxopropylphosphonate (2c), diethyl benzylphosphonate (2d), tetraethyl methylenediphosphonate (2e) and diethyl cyanomethylphosphonate (2f) under basic conditions gave the fluorinated 1,3-butadienylphosphonates 3 in moderate to good yields. The phosphonates 3 could be hydrolyzed with a 10% HCl aqueous solution to afford the corresponding γ-(diethylphosphono)-α-fluoro-α,β-unsaturated aldehydes 7 in good yields. The treatment of the phosphonate 3c with an NH₃ aqueous solution at 70 °C produced the pyridine derivative 8 in 60% yield.     

Enhancing the solubility for hypervalent ortho-sulfonyl iodine compounds

The synthesis and characterization of new hypervalent iodine reagents ArINTs (2a), ArIO (3a), and ArIO₂ (4a) (Ar=2-tert-butylsulfonyl-5-tert-butylphenyl) are described. These reagents are compared to previously reported analogous set of reagents Ar=2-tert-butylsulfonylphenyl and found to have significantly enhanced solubility and similar chemical reactivity. The X-ray crystal structures of 4a and of ArI (1a) (Ar=2-tert-butylsulfonyl-5-tert-butylphenyl) are discussed and compared. These reagents find use in atom and group transfer reactions.     

Facile and sustainable synthesis of the natural antioxidant hydroxytyrosol

Hydroxytyrosol [1, 2-(3,4-dihydroxyphenyl)ethanol], an olive-derived potent natural antioxidant was conveniently prepared from the clove-derived and commercially available eugenol (8, 4-allyl-2-methoxyphenol) using inexpensive reagents in a two-pot four-step process, which successively encompasses a reductive ozonolysis into homovanillyl alcohol (4, 4-hydroxy-3-methoxyphenethanol) and a sodium periodate-mediated oxidative demethylation using a reductive workup.     

Practical method for the synthesis of (R)-homopipecolinic acid and (R)-homoproline esters from ω-chloroalkanoic acids and available chiral amines

A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing (i) a direct intramolecular cyclization of ω-chloro-β-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine and ω-chloro-β-keto esters 5 and 10, respectively and (ii) a highly diastereoselective NaBH₄ reduction followed by hydrogenolysis. The present method is a short-step process using inexpensive and readily available substrates and reagents with fewer wasted materials.     

Synthesis of exo enol ether-cyclic ketal isomers of substituted furanmethanol structures related to marine furanocembranoids

Oxidations of the 2-alkenylfurans 8a and 8b, using peroxy reagents, lead to the dienedione 9 and the furan epoxide 10, respectively. Treatment of the epoxide 10 with p-TSA in MeOH produces the enol ether cyclic ketal 12, which is rapidly isomerised to the furanmethanol ether 15, isolated in 80% yield. By contrast, when the propanol-substituted furan epoxide 23 was kept in CDCl₃ containing traces of HCl for 2 h, a 3:2 mixture of Z- and E-isomers of the enol ether spiro ketals 25a and 25b was produced in >92% yield; after 24 h this mixture of isomers underwent dehydration leading to the corresponding enol ether triene 26 (70%). When a solution of the dienedione 9 in H₂O-THF containing p-TSA was stirred at 25 °C for 20 h, the tertiary alcohol 27 was produced which, after a further 20 h was converted into the furan vicinal diol 29. Likewise, when the ‘cembranoid’ dienedione 31 was treated with p-TSA-H₂O, the hydroxymethyl-substituted furanobutenolide 33 was produced in 40% yield. It is probable that the enol ether cyclic hemiketals 28 and 32/34, which are related to 12 and 25, and also to the naturally occurring cembranoids 1 and 2 found in corals, are transient intermediates in the conversions leading to 29 and 33 from 9 and 31, respectively.     

Asymmetric Michael addition using N-cinnamoyl- and N-crotonyl-trans-hexahydrobenzoxazolidin-2-ones

Preparation of N-cinnamoyl- and N-crotonyl-oxazolidin-2-ones 2 and 3 or ent-2 and ent-3 from (4S,5S)- and (4R,5R)-trans-hexahydrobenzoxazolidin-2-ones 1 or ent-1 are reported. Stereoselective copper promoted conjugated additions of Grignard reagents to chiral N-enoyl amides 2 and 3 or ent-2 and ent-3 in the presence of Zn(II) salts afforded the 1,4-addition products 4-11 and the corresponding enantiomers.     

On the reactivity of some 2-methyleneindolines with β-nitroenamines, α-nitroalkenes, and 1,2-diaza-1,3-butadienes

A study of the behaviour of some electron-rich 2-methyleneindolines (1-3) with different electron-poor reagents (formation of new carbon-carbon and nitrogen-carbon bonds) has furnished interesting results from both synthetic and the mechanistic viewpoints. Enamines 1-3 have been reacted with the β-nitroenamines 4-7 (reaction CeCl₃·7H₂O promoted), giving the polymethine dyes 14-23. The same bases 1-3 have been nitroalkylated with the nitroolefins 8-10, furnishing the indolines 24-32, and the diastereoselectivity of the reaction has been thoroughly investigated. The most unexpected results derived from the first example of reaction of Fischer's bases with 1,2-diaza-1,3-butadienes. In fact, with 11-13, the ‘unknown’ indoline spirodihydropyrroles 33-40 were formed. Their structures were unambiguously assigned, and we determined, as an example, that of 33 by X-ray analysis.     

Nucleophilic substitution approach to 4′-substituted thymidines by employing 4′-benzenesulfonyl leaving group

Synthesis of 4′-substituted thymidines was investigated based on nucleophilic substitution using organosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the 4′-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-α-l-threo-pentofuranosyl]thymine (8α) and the 4′-(benzenesulfonyl)thymidine derivative (8β). The reaction of 8α with organosilicon reagents (Me₃SiCH₂CHCH₂ and Me₃SiN₃) in combination with SnCl₄ gave preferentially the 4′-substituted β-d-isomer: the 4′-allyl (12β) and 4′-azido (15β) derivatives, respectively. The reaction of 8α with AlMe₃, however, gave the 4′-methyl-α-l-isomer (16α) as the major product, presumably through an ion pair mechanism. By employing the substrate 8β in this reaction, the 4′-methylthymidine derivative (16β) was obtained exclusively in high yield. The 4′-ethyl (20β) and 4′-cyano (24β) derivatives were also synthesized by reacting 8β with the respective organoaluminum reagent.     

A convenient synthesis of 1′-H-spiro-(indoline-3,4′-piperidine) and its derivatives

A simple synthetic route has been developed to prepare 1′-H-spiro(indoline-3,4′-piperidine) (1d). Dialkylation of 2-fluorophenylacetonitrile with N-(tert-butyloxycarbonyl)-bis(2-chloroethyl)amine (5) gave 6. Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective Boc or Cbz protection of 1′-N gave 1a or 1b with 90 and 85% yield, respectively. Thus, in a five-step procedure, 1a and 1b were synthesized from commercially available reagents in over 50% overall yield. All 3 compounds (1a, 1b and 1d) can be utilized as templates to synthesize compounds for GPCR targets.     

Synthesis and characterization of coumarin and dimedone-derived diazabicycles

A series of diazabicyclic derivatives were prepared in three to four steps from p-anisidine and p-nitrobenzaldehyde. The key step of the synthesis involved the acid-catalyzed coupling of 4-aminocoumarin or dimedone derivatives with amino alcohols 3 or 7 to give the ring-opened forms 4, 10, 12 and the ring-closed diazabicycles 5, 6, 9, 11. When 4-alkylaminocoumarins were used as the coupling reagents, the major cyclized product was N-dealkylated diazabicycle 5, rather than the corresponding N-alkylated products. Alternatively, compound 4 was cyclized by DDQ oxidation to produce quinone imine 13. The molecular structures of the synthesized compounds were characterized by X-ray crystallography.