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The pK a values of the freely water-soluble opened form of a thieno-1,2,4-triazolo-1,4-diazepine, namely 2-(3-amino- methyl-5-methyl-1,2,4-triazolo)-3-(2-chlorobenzoyl)- [2,3-c]thienopiperidine, were determined. pH measurements were made in the range 1 < pH < 10. Two of the three pK a values found in this range significantly overlapped; they quantify the ionization of both the aminomethyl residue and the piperidino moiety of the molecule. The third corresponds exclusively to the ionization of the triazolo nucleus. The pK a value of the thienophenone was obtained by UV spectrophotometry using acidity functions. All results were extracted from experimental data by a curve-fitting method.

Properties of three derivatives of trifluoacetophenone [4-(n-butyl)-1-trifluoroacetylbenzene (BTFAB), 4-(n-hexadecyl)-1-trifluoroacetylbenzene (HDTFAB), p-dodecyloxytrifluoroacetylbenzene (DDTFAB)] as neutral carriers for carbonate were examined. The best electrode characteristic (slope, S= 29 mV decade–1, lowest detection limit) was for HDTFAB. The sensitivity towards carbonates was for DDTFAB pH dependent. This eliminates DDTFAB from practical applications. A theoretical treatment concerning carbonate and hydrogencarbonate selectivity under investigated conditions has been performed. Preliminary determination of carbonate in bovine serum was made using electrodes with HDTFAB.

Flash vacuum pyrolysis of the ester 1,3,4,5,6,7,8-heptafluoro-2-naphthyl propynoate (6) at 550 °C/0.01 mmHg gave three products: 3 and 4 by an overall decarbonylation reaction, and 5 by a further decarbonylation of 3 and/or 4. Isomerisation of 6 to 2-fluoropropynyl 2-naphthoate 8 by a Diels–Alder/retro-Diels-Alder sequence followed by decarbonylation and a series of 1,2-fluorine shifts offers a rationalisation for the formation of the products.

Tin enolates 1 reacted with α-halogeno ketones 2 and esters 10 to give a variety of 1,4-diketones 3 and γ-keto esters 11, respectively, in the presence of appropriate additives such as hexamethylphosphoric triamide (HMPT), tributylphosphine oxide and tetrabutylammonium bromide, while complexation of these additives with tributyltin bromide allowed catalytic production of β-keto oxiranes 4 instead of 3. The reaction mechanism for the preparation of 1,4-diketone 3 is discussed.

Ambident anions [CH2COC(X)Me2]–, on collisional activation in the gas phase, could, in principle, undergo cyclisations through (i) C– to form a Favorskii cyclopropanone ion complex, or (ii) O– to form an allene oxide ion complex. No Favorskii intermediates are detected, but allene oxide ion complexes are formed when X = OMe or SMe. These cyclisation reactions are endothermic and would not be expected to occur should lower energy reaction channels be available. Such a scenario pertains when X = OH, i.e. no internal cyclisation occurs for ambident enolate [CH2COC(OH)Me2]– following collisional activation. Instead, proton transfer produces the alkoxide [MeCOC(O–)Me2] which undergoes the acyloin rearrangement (to equilibrate the three methyl groups by 1,2-methyl anion migration) prior to decomposition.

The highly oxygenated α-tropolone antibiotic 3,4-dimethoxy-α-tropolone 3 has been synthesized in a fully regiocontrolled manner from commercially available cis-1,2-dihydrocatechol 5. Demethylation of 3,4-dimethoxy-α-tropolone 3 produced the potent antitumour agent 3,4-dihydroxy-α-tropolone 4.

A convenient method for the unambiguous preparation of α,α′-dihalogeno ketones 3 from in situ generated chloromethyllithium and α-chloro or α-bromo carboxylic acid esters 1 at –78 °C, is described. The unambiguous preparation of α,α-dihalogeno ketones 7 by using in situ-generated dihalogenomethyllithium and carboxylic acid esters 5 at –78 °C is also reported.

(±)-Estrone is synthesised via Torgov's compound by an AB→ABC→ABCD route. The C-ring is constructed by a new Diels–Alder methodology and the D-ring by a novel cyclopentane annulation reaction from a cyclopropanol precursor.

Optically active diazoketones derived from N-protected amino acids and (S)-2-chloropropionic acid have been used as homochiral group transfer reagents in the synthesis of various optically active α-functionalised ketones and related compounds.

The addition of dibromodifluoromethane to electron-deficient alkenes proceeds smoothly in the presence of a CrCl3/Fe bimetal redox system, giving various β-bromodifluoromethyl-functionalized esters, nitriles and ketones in good yields.

An intramolecular coupling of 1,6-bis(5-oxohepta-1,3-dien-6-ynyl)cyclohepta-1,3,5-triene under Glaser conditions affords 12,15-dichloro-13,14-didehydro-1,6-methano[20]annulene-11,16-dione, which exhibits strong diatropicity in D2SO4, suggesting the formation of the highly delocalized dicationic species.

A novel one-pot generation of perfluoroalkylated enolates by the reaction of PhMgBr with fluorinated β-ketophosphonium salts and its application to the synthesis of perfluoroalkylated vinyl ethers, β-hydroxy ketones, ketones and vinyl ethers are described.

A convenient method has been developed for the synthesis of substituted cyclopentadienes, starting from allylidene triphenylphosphoranes and α-halocarbonyl compounds, via a [3 + 2] annulation process.

Various α-halogeno ketones undergo reductive dehalogenation to the corresponding ketones almost quantitatively with sodium dithionite using viologen as an electron-transfer catalyst in organic solvent–water two-phase systems.

Amino acid recovery of dipeptidyl chloromethyl ketones is remarkably low owing to the formation of 2-hydroxy-3, 6-dialkyl-5-methylpyrazine during acid hydrolysis.

Photocaging of the known Diels–Alder dimer of 2,3-dichlorocyclopentadienone, compound 1, followed by alkali-induced double ring-cleavage of the resulting caged diketone rac-2 or its dihydrate rac-3, led to the title tetrachloro dicarboxylic acid rac-5, thus affording a novel entry into the inherently chiral tricyclo[4.2.0.03,8]octane (C2-bissecocubane) system. Electrolysis of the disodium salt of rac-5 gave the tetrachloro alkene rac-14, from which other derivatives were obtained by standard methods.

2, 2-Dichlorocyclobut-3-enones undergo VO(OEt)Cl2-induced ring-opening oxidation in ethanol to give ethyl 2,4,4-trichlorobut-3-enoates regioselectively.

Bisethynylation of the vinylogous dialdehydes of cyclohepta-1,3,5-triene-1,6-dicarbaldehyde with ethynylmagnesium bromide followed by oxidation of the resulted diols afforded the diacetylenic diketones. Intramolecular oxidative coupling of these diketones under the Glaser conditions unexpectedly afforded three annulenediones with a 1,4-dichlorobutatriene moiety. The unusual structures were confirmed by X-ray crystallographic analysis of 10,13-dichloro-11,12-didehydro-1,6-methano[16]annulene-9,14-dione. These annulenediones exhibited strong diatropicity in D2SO4 due to the dicationic 14π-, 18π- and 22π-electron species and their diatropicities were shown to increase with increasing ring size.

Photolytic ethylene addition to 3-methoxychromones 3a–cfurnished the 3-hydroxyoxetanes4a–c; reduction to the diols 5a–c followed by acid-catalysed rearrangement afforded the benzooxabicyclo[3.2.1]octanones 6a–cand bromination of 6c furnished7, which has previously been converted to filiformin 2.

Anodic oxidation of 3,5-dibromo-4-methoxyphenylalanine methyl ester 3, led to cavernicolin [3,3a,7,7a-tetrahydro-3a-hydroxyindole-2,6(1H)-dione] model compounds although equilibration to all four possible stereoisomers 4α, 4β, 5α and 5β was a special characteristic of the model compounds only. This may constitute a new model for the biogenesis of the cavernicolins as an alternative to a spirolactone route from oxidation of amino-protected tyrosines. Chemical oxidation gave poor results.

A convenient method for the synthesis of substituted cyclopentadienes has been developed using allylidene(triphenyl)phosphoranes. (3-Ethoxycarbonyl-2-substituted-2-propenylidene)triphenylphosphoranes 1 reacted with α-halogenoketones under very mild reaction conditions to undergo a [3 + 2]-annulation leading to the regioselective formation of tri- or tetra-substituted cyclopentadienes in good to excellent yields. Allylidenephosphoranes 1 also reacted with S-ethyl bromoethanethioate to yield 4-ethylthiocyclopentadienes, which was readily converted into a cyclopentenone.

2,3,5,6-Tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone in acetone solution nitrates 4-methoxyphenol by a radical mechanism, but acts mainly as a brominating agent towards phenol, after rearrangement.

Phenylsulphonyloxiranes can be lithiated with butyllithium α to the phenylsulphonyl group at low temperature. The anions formed are unstable, but sufficiently reactive to allow the isolation of adducts in good yield following treatment with a variety of electrophiles. Reaction of functionalised phenylsulphonyloxiranes with magnesium bromide–diethyl ether at room temperature allows the preparation of synthetically useful α-bromo ketones with complete regiocontrol.

The hetero Diels–Alder reaction of trifluoromethyl ketones and 1-benzyloxy-3- trimethylsilyloxybutadiene is developed as a route to 4-hydroxytetrahydropyranyl acetal derivatives. Several 6,6-disubstituted tetrahydropyran-2,4-diols have been prepared, and their anomeric equilibria measured by 1H NMR spectroscopy. Attempted cyclodehydration to 2,6-dioxabicyclo[3.1.1]heptanes (thromboxane A2 analogues) failed under various conditions.

The reactions of 2-halogenotropones (3a–c) with hydride reagents giving 2-halogenocycloheptadienone enolates (4a–c) have been studied to provide a reverse polarity (umpolung) of tropone. The structures of 2-chlorocycloheptadienone enolate (4a) and 2-chloro-7-deuteriocycloheptadienone enolate (4D) were confirmed by 1H NMR spectral studies. The enolates were easily reacted with tropylium and substituted tropylium cations to give 2-(2,4,6-cycloheptatrienyl)tropone (8) and its derivatives, (13b–d) and (14b–d) in good yields. The other cationic electrophiles, such as benzo- and dibenzotropylium cations, di- and triphenylcyclopropenylium cations as well as tricarbonyl(cyclopentadienylium)iron and tricarbonyl(cyclohexadienylium)iron, were also reacted with the enolate to give the corresponding 2-substituted tropones (21–27) in good to modest yields. In a similar fashion, 2-halogeno-7-substituted cycloheptadienone enolates (28a–e) were generated through the reaction of 2-chlorotropone (3a) with Grignard and organolithium reagents as well as the reaction of 2-bromo-7-methoxytropone (3d) and 2,7-dibromotropone (3e) with hydride reagent. They reacted also with tropylium cation to give 2,7-disubstituted tropones (29a–e).

The reaction of α-chloro or α-bromo carboxylic acid esters (1) with in situ-generated chloromethyllithium (1 : 1.5 molar ratio) at –78 °C in the presence of lithium bromide leads, after hydrolysis, to the corresponding α,α′-dichloro or α-chloro-α′-bromo ketones (2), respectively.

A highly convergent and efficient synthesis of methylenomycin B has been achieved by the reaction of the lithium enolate of 4-chloro-4,5-dimethyl-5-hexen-3-one with phenylselenenyl bromide followed by selenoxide elimination.

Sodium selenite catalyses, under mild conditions, the reductive debromination of vic-dibromides [e.g., meso- or (±)-1,2-dibromo-1,2-diphenylethane, trans-10,11-dibromodibenzosuberone, 2,3-dibromo-1,3-Biphenyl-1-propanone, α,β-dibromobenzenepropanoic acid, and cholesterol dibromide] to alkenes in the presence of the thiols cysteine or glutathione.

A Barbier procedure, under moderate pressure, was used for the trifluoromethylation of various carbonyl compounds, starting from trifluoromethyl bromide and zinc in pyridine. Trifluoromethyl methanols were obtained from aldehydes and trifluoromethyl ketones from activated esters. Ethyl benzoate, or acetone, induced the formation of the solvated trifluoromethylzinc derivatives which did not react with carbonyl compounds. Consequently, the Barbier condensation in that case was considered to involve nascent organometallics reacting near the zinc surface. The reaction with sulphur dioxide, leading to trifluoromethanesulphinate, showed striking differences from that of carbonyl compounds. It was shown that the main pathway occurred in solution. This condensation was interpreted by the initial formation of sulphur dioxide radical anion, which reacts with trifluoromethyl bromide by a single-electron-transfer process. Attempts to condense iminium salts failed when a hydrogen atom was lacking in the α position. When the iminium ion can be transformed in situ to an enamine, a reaction occurred, leading to α-trifluoromethyl ketones. This condensation was interpreted by a chain mechanism involving trifluoromethyl radicals.

New α-amino ketones (5) derived from leucine have been synthesized by reaction of organometallics on N-methoxy-N-methylamide (4). The stereoselectivity of reduction of the α-amino ketones (5) was studied. The stereochemistry of the resulting α-amino alcohols (6) was established by transforming them into the oxazolidinones (8) by means of a new procedure.

We report that, on treatment with phenyl-lithium, followed by triethyloxonium tetrafluoroborate in diethyl ether at –78°C, (i) 2-chloro- and 2-bromo-tropone give the corresponding 1-ethoxy-2-halogeno-7-phenylcycloheptatriene; (ii) 2-fluorotropone gives 2-ethoxy-3,7-diphenylcycloheptatriene; and (iii) tropone affords 1-ethoxy-2-phenylcycloheptatriene. Conceivably, in case (i) the tropone undergoes phenyl-lithium attack at C-7, followed by O-alkylation of the enolate, while in case (iii) the intermediate enolate suffers base-catalysed rearrangement and, finally, in case (iii) nucleophilic replacement of fluorine by phenyl-lithium from the tropone precedes phenyl-lithium attack at C-7 of the resulting 2-phenyl-tropone. This gives a better synthesis, than those available so far, of 2-chloro-7-aryltropones; in addition, a 1-alkoxy-2-chloro-7-phenylcycloheptatriene undergoes selenium dioxide oxidation to 2-chloro-7-phenyltropone.

α-Halogeno ketones have been dehalogenated with a combination of aluminium chloride and ethanethiol. The mechanism involved in deiodination and debromination differs from that of dechlorination and defluorination. A hard-hard interaction between carbonyl oxygen and aluminium chloride and a soft-soft interaction between iodine or bromine and thiol are the dominant factors for direct deiodination and debromination. In dechlorination and defluorination there is initial formation of the corresponding dithioacetal, whereby hard carbonyl oxygen is replaced by the soft sulphur atom. α-Chloro- and α-fluoro-dithioacetals then undergo dehalogenation to afford vinyl sulphide as a result both of a favourable soft-soft interaction between the sulphur atoms in the dithioacetal entity and thiol, and also a favourable hard-hard interaction between the nucleophilic chlorine or fluorine and aluminium chloride. α-Chloro- and α-fluoro-benzyl benzyl ketones afforded the dehalogenated product with concomitant 1,2-transposition of the carbonyl group. This suggests that there is an indirect path which operates competitively via a 1,2-dithio-olefin from α-halogenodithioacetals to vinyl sulphide. Addition of thiol to vinyl sulphide leads to the final product. A concept of hard-soft affinity inversion is proposed.

The polymer-supported chiral amino alcohol (3) has been prepared by the reaction of chloromethylated polystyrene resin and (S)-(–)-2-amino-3-(p-hydroxy)phenyl-1,1-diphenylpropan-1-ol (2); the chiral polymeric reagent has been prepared from (3) and borane. The asymmetric reductions of ketones and oxime ethers with the polymeric reagent have been shown to give optically active alcohols (up to 97% optical purity) and amines (up to 67% optical purity), respectively. The results are compared with those obtained with (S)-(–)-2-amino-1,1,3-triphenylpropan-1-ol (4) or (S)-(–)-2-amino-3-(p-benzyl-oxyphenyl)-1,1 -diphenylpropan-1-ol (5) which are soluble model reagents.

Known methods were developed to give convenient general procedures for preparing N-acyl-N′-mono and -N′,N′-disubstituted thioureas from acid chlorides, and related N-imidoyl thioureas from imidoyl chlorides. In the products from three acid chlorides and ammonium thiocyanate the acyl isothiocyanates did not appear to be accompanied by the isomeric thiocyanates.Treatment of N-(anilino)benzylidene-N′,N′-disubstituted thioureas with chloroacetone in the presence of triethylamine leads to 5-acetyl-4-phenyl -2-(N,N-disubstituted amino)thiazoles. In contrast, the corresponding N-benzoyl thioureas form only small amounts of these compounds; the main products are the 5-benzoyl-4-methyl isomers, and this unexpected outcome requires a revision of the literature. It is thought that formation of the 5-benzoyl-4-methylthiazoles involves N–C(4) fission of a cyclic intermediate to give an open-chain intermediate in which nucleophilic attack can occur at either the acetyl or the benzoyl group. One of the latter intermediates was generated directly from 2-acetyl-2-bromoacetophenone and N-methyl-N-phenylthiourea, and found to give the 5-benzoyl-4-methyl - and 5-acetyl-4-phenyl-thiazoles as the major and minor products, respectively.

Benzeneselenenyl derivatives, PhSe-X (X = Cl, Br, OCOCH3, and SCN) react readily with α-diazo ketones, RCOC(N2)R1(R1= H or alkyl), with loss of nitrogen, furnishing αα-adducts of the type RCOCR1(X)SePh. The α-chloro and α-bromo adducts can be converted into α-methoxy adducts in methanol–sodium hydrogen carbonate. The utility of these adducts in synthesis is illustrated by their conversion (where structural considerations permit)via selenoxide fragmentation into α- heterosubstituted αβ-unsaturated ketones. Treatment of the series RCOCR1(X)SePh (R1= alkyl; X = Cl, Br, OCOCH3, and OCH3) with hydrogen peroxide–pyridine produces α-chloro-, α-bromo-, α-acetoxy-, and α-methoxy-αβ–unsaturated ketones, whereas treatment of the series RCOCR1(X)SePh (R1= alkyl; X = Cl and Br) with lithium carbonate in dimethylformamide produces α-phenylseleno-αβ-unsaturated ketones. Several α-substituted cyclopentenones, cyclohexenones, and cycloheptenones have been synthesised in this way and acyclic examples are illustrated by the synthesis of 3-chloro-, 3-bromo-, 3-acetoxy-, 3-methoxy-, and 3-phenylselenobut-3-en-2-one from 3-diazobutan-2-one.

Reaction of α-halogeno ketones with aldehydes in the presence of CeI3 in tetrahydrofuran is found to give α,β-unsaturated ketones in excellent yields under mild conditions. In contrast, treatment of α-halogeno ketones and carbonyl compounds with CeCl3–NaI or CeCl3–SnCl2 affords β-hydroxy ketones in good yields. It is assumed that these reactions proceed via cerium enolates. The combined reagents, however, cannot be applied to a Reformatsky-type reaction. Regiospecific and aldehyde chemoselective aldol synthesis are also described.

α,α,α′-Dibromochlorocycloalkanones of medium ring size have been prepared by treatment of chlorocycloalkanones with bromine and were separated by chromatorgraphy and then submitted to Favorskii reaction. The stereoisomeric reaction products have in each case been evaluated by gas chromatography and the selectivity of bromide elimination deduced.

The initial reaction of 4-substituted 2′-halogenoacetophenones with an excess of methyl Grignard reagent is shown to be an attack at the 1′-carbonyl to form a halohydrin salt. The various reactions which then follow are substituent dependent. In the 4-hydroxy case [(12) and (16)] the only product is 1-(4-hydroxyphenyl)-2-methylpropan-2-ol (13) which arises via a [1,2]-aryl shift with simultaneous elimination of magnesium halide. When the substituent is 4-methoxy, a second pathway becomes important involving epoxide formation and a subsequent [1,2]-hydride migration to the benzylic position, or attack of the Grignard reagent at the benzylic carbon of the epoxide, When the substituent is 4-bromo, the reaction proceeds exclusively via the epoxide and, following a [1, 2]-hydride shift, leads to the isomeric butanols (33) and (34). The reasons underlying such diversity of reactivity are discussed.

The valence-bond configuration mixing model (VBCM) is applied to the nucleophilic substitution reactions of α-carbonyl derivatives. The model appears to resolve satisfactorily a number of features of these reactions that current mechanisms have not dealt with. These include: (i) the dependence of the rate-enhancing efect of the carbonyl upon the nucleophilic strength of the entering group, (ii) the unusually large Hammett ρ value for the reaction of PhCOCH2Br with substituted pyridines, and (iii) the mechanism by which the rate-enhancing effect of the carbonyl group is transmitted to the reaction centre.

A stereoselective synthesis of a morphinan ring system has been achieved by employing an intramolecular Diels–Alder reaction of a benzocyclobutene derivative (3) to provide a tricyclic compound (4) having a B/Ccis ring junction. After manipulation of a cyano group, the resulting amine (13) was converted into a morphinan derivative (16) by cyclization of an aminylium ion.

1,4-Addition of MeMgl on D-homo-18-norandrost-13(17a)-en-17-one (3) yields stereospecifically D-homo-13α-androstan-17-one (4). Ring-D contraction leads to a compound having a 13α-androstane skeleton: the Favorskii rearrangement of bromo ketone (9) yields 13α-androstane-16α- and 16β-carboxylic acids (8) and (14). Ketone (4) is oxidized by TlIII to (8). The transformation of these carboxylic acids into methyl ketones, alcohols, and, finally, 13α-androstan-16-one is described.

Enantioselective Darzens condensation has been achieved from optically active 2-methylbenzaldehyde(tricarbonyl)chromium;enantiomeric excesses are in the range 40-88%.

β-Acetylenic radicals, e.g., (6b) and (12), generated in three steps from epoxides or in two steps from α-halogenoketones, respectively, react with electron-deficient olefins to produce five-membered carbocycles by a process of conjugate addition and 5-exo-digonal closure.

2,4,4,6-Tetrabromocyclohexa-2-4-dienone, usually used as a mild and selective brominating agent, acts as an electron acceptor in the sensitized photo-oxygenation of several unsaturated substrates; a mechanism is proposed.

Diazotization and Sandmeyer reactions of representative arylamines (la–h) proceed smoothly in PEG–CH2Cl2 and were found to be effective for the preparations of halogenoarenes (X = Cl, Br, and I) and cyanoarenes (X = CN).

2,2-Dialkylcyclopropylamines have been prepared by a new synthetic method involving cyclopropanation of α-chloro imines and reductive demethoxylation of the resulting 1-methoxycyclopropylamines.

γ-Iodoketones, prepared by ene–halogenocyclization of α-haloketones with Pd(PPh3)4, on treatment with diazabicyclo[5.4.0]undec-7-ene afford three-membered ring compounds in good yield via syn-1,3-elimination, presumably via W-shaped transition states.

The title compound (9) has been synthesised in seven steps from inexpensive, commercially available starting materials using, as a key step, the bicyclo[3.2.0]heptenone (A)→ tricyclo[4.3.0.03.7]nonenone (B) transformation.

The first synthesis of the iridoid monoterpene lactone boonein (1) has been achieved, in seven steps, from the bicyclo-octenone (5).

Reaction of 2′-bromodeoxybenzoins with copper powder in refluxing dimethylacetamide gives the corresponding 2-phenylfuran in good yields.