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The first catalytic approach to the nucleophilic addition of silyl ketene acetals 2 to epoxides 1 is reported. The defined protocol is metal-free using tetrabutylammonioum fluoride as the catalyst. It works in a very efficient manner under solvent-free conditions (SolFC) allowing γ-lactones 3 to be directly obtained with high regioselectivities and yields.

This contribution reports the preparation and use of a new immobilized catalyst, PS-DABCOF (9), which has been specifically designed to access for the first time the efficient β-azidation of α,β-unsaturated carboxylic acids.

This report concerns Lewis acid catalyzed enantioselective sulfa-Michael addition in neutral water by using a very efficient Sc(OTf)(3)/bipyridine 1 catalytic system. It is noteworthy that the protocol presented employs water as a reaction medium and allows us to obtain very high stereoselectivity and satisfactory yields for β-keto sulphides deriving from aliphatic thiols. The recovery and reuse of both the aqueous medium and the catalytic system is also reported.

Diels-Alder cycloaddition reactions of 3-cyanocoumarin, hydroxy-substituted 3-cyanocoumarins and mesyl-substituted 3-cyano-coumarins with methyl-1,3-butadienes carried out under high pressure (11 kbar) are reported. Activation by high pressure allows these reactions to proceed satisfactorily under mild conditions to produce 6a-cyano-hydroxy- and 6a-cyano-mesyl-tetrahydro-6H-benzo[c]chromen-6-ones in moderate to excellent yield. The synthesis of cis-1-hydroxy-9-methyl-3-pentyl-6a,7,10,10a-tetrahydro-benzo[c]chromen-6-one as precursor of Delta(6)-3,4-cis-cannabidiol (Delta(6)-cis-CBD) and Delta(8)-cis-tetrahydrocannabinol (Delta(8)-cis-THC) is outlined.

Amberlite IRA900N3 is an excellent organocatalyst for the azidation of alpha,beta-unsaturated ketones with trimethylsilyl azide under solvent-free conditions. By avoiding the use of metallic species and of the organic reaction medium, the procedure is a green tool for the preparation of beta-azido ketones under mild conditions with yields from good to excellent. The catalyst can be recovered and re-used with no loss of its efficiency.

An innovative route to prepare a number of variously substituted new biphenyl derivatives is presented here. The protocol avoids the use of a catalyst, an organic solvent, and dry conditions. [reaction: see text]

[AlCl(3) + 2THF] is a new catalytic system for the Diels-Alder cycloaddition under SFC and air atmosphere. By using equimolar amounts of reactants, this catalyst prevents the polymerization of the diene and allows the corresponding adducts to be isolated with high regio- and stereocontrol and in excellent yields. [reaction: see text]

[reaction: see text] Diels-Alder reactions of 3-substituted coumarins 1a-g with methyl-1,3-butadienes 2a-c carried out in water alone and in CH2Cl2 under 9 kbar pressure are reported. In aqueous medium satisfactory results were obtained by operating at 150 degrees C, whereas under high pressure the cycloadditions were complete at 60-70 degrees C with excellent yields (85-95%). The reactions with isoprene (2b) always resulted in the exclusive formation of para cycloadducts, whereas with (E)-piperylene (2c) only ortho products were detected. The cycloaddition of 3-phenylsulfonylcoumarin (1a) with (E)-piperylene (2c) allowed the endo adduct to be obtained exclusively, whereas 3-carboxycoumarin (1b) reacted with 2c to give a mixture of the corresponding endo/exo adducts in a 58:42 ratio in water and in a 45:55 ratio under high-pressure condition.

[reaction: see text] The thiolysis of alpha,beta-epoxycarboxylic acids 1a-e by thiols 2a,b is more efficient in water than in dichloromethane or SFC. At pH 9.0 phenylthiolate generally attacks the C-alpha carbon while at pH 4.0, and in the presence of InCl3 (10 mol %), the thiolysis is exclusively C-beta regioselective. In all cases, the processes are completely anti-diasteroselective, and the corresponding products 3, 4, and 5 have been isolated in good yields. Both water and catalysts have been recovered and reused.

TBAF-catalyzed [3 + 2] cycloaddition reactions of 2-aryl-1-cyano- or 2-aryl-1-carbethoxy-1-nitroethenes 1 with TMSN3 under SFC allow the corresponding 4-aryl-5-cyano- or 4-aryl-5-carbethoxy-1H-1,2,3-triazoles 2 to be prepared under mild reaction conditions and with good to excellent yields (70-90%). The proposed protocol does not require dried glassware or inert atmosphere.

Under solvent-free conditions, thiosalicylic acid (2) efficiently self-promotes the thiolysis of 1,2-epoxides 1, anti-stereoselectively and generally totally beta-regioselectively. The resulting beta-hydroxysulfide products 3 have been obtained in very good yields. Benzo[e]1,4-oxathiepin-5-ones 4 have been easily prepared in a regio- and diasteroselective manner and in satisfactory yields under SFC by a one-pot protocol including nucleophilic ring opening of 1,2-epoxides 1 by thiosalicylic acid (2) and thermally induced lactonization of beta-hydroxy arylsulfides 3. Solvent-free condition and the absence of any catalyst make this procedure atom-economical and environmentally friendly.

Beta-Amino alcohols N-2'-pyridylmethyl substituted 3 have been prepared in excellent yields under mild conditions by the first Lewis acid-catalyzed aminolysis of 1,2-epoxides 1 with the bihaptic amine 2-picolylamine (2) with use of 5 mol % of Al(OTf)(3) under solvent-free conditions. As a representative of a new class of ionic liquids, cis-5-[(4'-methylphenyl)sulfonyl]-1,2,3,4,4a,5,6,11a-octahydropyrido[1,2-a]quinoxalin-11-ium methanesulfonate (6) and its chloride derivative 7 have been synthesized under environmentally friendly conditions by the one-pot aminolysis of cyclohexene oxide (1a) with 2 and intramolecular cyclization of the resulting 2-[(pyridin-2'-yl)methylamino]cyclohexanol (3a).

Tetrabutylammonium fluoride (TBAF) is an efficient catalyst in the [3 + 2] cycloaddition reaction of organic nitriles 1 with trimethylsilyl azide (TMSN(3)) in solventless conditions. The corresponding 5-substituted 1H-tetrazoles 2 were obtained under mild conditions and in 80-97% yields.

NaOH (0.02-0.3 molar equiv) is an efficient catalyst for the thiolysis reactions of alpha,beta-epoxy ketones with alkyl and aryl thiols in water. Thiolysis of 3,4-epoxyheptan-2-one (1) with thiols 2a-d has been accomplished in mild conditions (30 degrees C and pH 6 or 9) with complete C-alpha-regioselectivity and anti-stereoselectivity, and the corresponding anti-beta-carbonyl-beta-hydroxysulfides 3a-d have been prepared in excellent yields (95-98%). Compounds 3a-d, depending on their nature and pH conditions, have undergone dehydration, C-3 epimerization reaction, and retroaldol condensation. Dehydration of anti-3a-d has been chemoselectively carried out by in situ acidic treatment at 70 degrees C, giving stereoselectively the related (Z)-vinyl sulfides 4 in 89-94% overall yields. Under NaOH-catalyzed thiolysis conditions, cyclic alpha,beta-epoxyketones 6-9 have shown C-alpha attack only and spontaneously dehydrated to furnish the corresponding vinyl sulfides in high yields (90-96%). The reactions of calchone oxide (10) with thiols 2b-d have exclusively resulted in the formation of beta-carbonylsulfides 10b-d (82-93% yield), coming from the nucleophilic attack at the alpha-position and retroaldol condensation. To highlight the synthetic utility of this procedure, one-pot multisteps preparation of vinyl sulfides 7b and 7c, vinyl sulfoxides 12 and 13, and 1,5,6,7-tetrahydro-4H-1,2,3-benzotriazol-4-one (14) starting from 2-cyclohexen-1-one (11) have also been reported.

The [4 + 2] cycloadditions of 3-nitrocoumarin (1a), 6-chloro-3-nitrocoumarin (1b), and 6-, 7-, and 8-hydroxy-3-nitrocoumarins (1c, 5, and 6) with (E)-piperylene (7), isoprene (8), 2,3-dimethyl-1,3-butadiene (9), 2-methoxy-1,3-butadiene (10), 2,3-dimethoxy-1,3-butadiene (11), and cyclopentadiene (12) were investigated in aqueous medium, in organic solvent and under solventless conditions. The reactions performed in water occurred in heterogeneous phase but were faster than those executed in toluene or dichloroethane (DCE). 1a-c, 5, and 6 behaved as 2pi components in the Diels-Alder cycloadditions with 7-10 and 12, and exo adducts were preferentially or exclusively produced. Surprisingly 1a, behaved as a 4pi component in the cycloaddition in water with 11 and 4-substituted 3-nitrochromanones 20 and 21 were isolated. The cycloadditions of hydroxy-3-nitrocoumarins 1c, 5, and 6 with 1,3-diene 9 did not work in water or in organic solvent, but did work under solventless conditions. Nitrotetrahydrobenzo[c]chromenones 13-16, 24, and 25, originating from the normal electron-demand Diels-Alder reactions, were converted into dihydrodibenzo[b,d]furans 27-31 in water, via one-pot Nef-cyclodehydration reactions.

Thiolysis of a variety of 1,2-epoxides in water at 30 degrees C and pH 7.0 is strongly accelerated by ZnCl(2) (10 mol %) except when amino- and carboxythiophenol are used. The aqueous medium and the catalyst were recovered and reused in various runs without affecting the efficiency of the process.

Alpha-hydroxy-beta-amino acids were synthesized with excellent yields for the first time in water and by a simple procedure based on a copper catalytic cycle, which included the recovery and reuse of the catalyst and is possible to realize by using only water as reaction medium.

The [4 + 2] cycloadditions of 3-nitrocoumarins 5 with electron-rich dienophiles (ethyl vinyl ether (8), 2,3-dihydrofuran (9), and 3,4-dihydro-2H-pyran (10)) were investigated in water, in neat conditions, and in organic solvents. The cycloadditions do not require the use of catalysts and are highly endo diastereoselective, and in water the cyclic nitronates 13, 18, and 23 are converted into chromene derivatives via hydrolysis, decarboxylation, and acetalation reactions. A one-pot procedure based on consecutive reactions in neat/water conditions allows 3-nitrocoumarins 5 to be used as building blocks for the synthesis of chromanols and tetrahydrofuro- and tetrahydropyranochromenes. For the first time, the hydrolysis of cyclic nitronates having the C-O bond of 1,2-oxazine ring as a part of an acetal was investigated.

(+)-(R)-[2.2]Paracyclophane[4,5-d]-1,3-oxazol-2(3H)-one exhibiting planar chirality has been used as a chiral auxiliary in asymmetric Diels-Alder, Michael, and aldol reactions of alpha,beta-unsaturated carboxy and enolate imides, respectively. The endo-exo- and face-diastereoselectivity is good and is controlled by the spatial relationship between the prochiral center and the C9-C10 ethylene bridge of the [2.2]paracyclophane moiety. The chiral auxiliary is easily removed and quantitatively recovered.

A very efficient procedure for the trimethylsilylation of a wide variety of alcohols, including primary, allylic, benzylic, secondary, hindered secondary, tertiary, and phenols is reported. The reactions were carried out under neat conditions with trimethylsilyl azide (TMSN(3)) and, when necessary, in the presence of a catalytic amount (20 mol %) of tetrabutylammonium bromide (TBABr) at 30 or 70 degrees C. Under catalytic conditions, the yields of the corresponding trimethylsilyl ethers were greater than 91%. This procedure also allows the selective protection of primary and secondary alcohols in the presence of tertiary ones.

The [4 + 2] cycloadditions of (E)-2-aryl-1-cyano-1-nitroalkenes 1 with achiral and enantiopure vinyl ethers 2 and 3 carried out in sole water are reported. These reactions occur in a heterogeneous phase under mild conditions and are fast and highly stereoselective. By using (-)-N,N-dicyclohexyl-(1S)-isoborneol-10-sulfonamide as a chiral auxiliary, the cycloadditions are totally asymmetric. The face selectivity is discussed in terms of the shape of the chiral auxiliary and the reactive conformation of vinyl ether.

The ring opening of alpha,beta-epoxycarboxylic acids by bromide and iodide ions has been efficiently carried out in water in high regio- and stereoselective fashion. The iodolysis of trans-beta-monoalkylated epoxycarboxylic acids at pH 4.0 was completely alpha-regioselective and anti diastereoselective. The InCl(3)-catalyzed iodolysis of a variety of alpha,beta-epoxycarboxylic acids at pH 1.5 gave the corresponding anti beta-iodohydrins in 88-95% yields. The one-pot synthesis of the alpha- and beta-hydroxyhexanoic acids, starting from the corresponding alpha,beta-epoxycarboxylic acid 1a by iodolysis followed by reduction of the resulting iodohydrins 4a and 4b by NaBH(4)-InCl(3) in water, has been performed.

Classical Lewis acids such as AlCl(3), TiCl(4), and SnCl(4), believed to be unusable as catalysts in aqueous medium, efficiently catalyzed regio- and stereoselective azidolysis and iodolysis of alpha,beta-epoxycarboxylic acids in water at pH 4.0 and 1.5, respectively. The concept of water-tolerant metal-salt is reexamined in direct relationship to the aqua ion hydrolysis constant.

The catalytic efficiency of InCl(3), Yb(OTf)(3), and Sc(OTf)(3) in the azidolysis of alpha,beta-epoxycarboxylic acids has been studied in water and in organic solvents, for comparison using NaN(3) and Me(3)SiN(3) as the source of the azido group. In water, the catalytic effectiveness of these metal salts strongly depends on the pH of the aqueous medium and on the type of Lewis acid catalyst. In water their catalytic activity is mostly due to the corresponding aqua ion species, the concentration of which becomes significant when the pH of the aqueous medium is below the corresponding pK(1,1) hydrolysis constant. The process is more efficient in water than in organic solvents. At pH 4.0, InCl(3) is a far better catalyst than Yb(OTf)(3) or Sc(OTf)(3) and allows the highly regio- and diasteroselective preparation of beta-azido-alpha-hydroxycarboxylic acids, which can be isolated in pure form in very high yields.