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Several Wittig olefinations between α-heterosubstituted acetones and a phosphorus ylide were investigated concerning the product stereoselectivity. Benzyloxyacetone and tetrahydropyranyloxyacetone furnished trisubstituted (Z)-olefins exclusively. The stereoselective preparation of oxygenated acyclic terpenoids was practical by use of the direct Wittig olefination toward α-alkoxy ketones, and it facilitated a total synthesis of plaunotol from geraniol derivatives in short steps with high stereoselectivity.

o-Quinonemethides were prepared by treating o-[1-(alkylthio)alkyl]phenols with a Lewis acid. The Diels–Alder reaction of the resulting o-quinonemethides was also catalyzed by the Lewis acid. Hexahydrocanna-binol was synthesized according to this method.

The [2,3]sigmatropic rearrangement of α-substituted N,N-dimethylmethallylamine N-oxides results in a highly stereoselective formation of trans olefins oxygenating at the allylic position, and provi...

The reaction of o-[1-(alkylthio)alkyl]phenols with silver(I) oxide at room temperature generated o-quinonemethides in good yields along with silver alkanethiolate. This mechanism, based upon one-electron oxidation, is excluded in view of several experimental facts. The resulting o-quinonemethides reacted efficiently with ethyl vinyl ether to afford cis-chromans as the result of endo cycloaddition between (E)-o-quinonemethides and the ether. Similarly, o-[1-(alkylthio)allyl]phenols were converted to cis-chromans via the corresponding (E)-o-quinonemethides (6-allylidenecyclohexadienone). In the absence of dienophiles, some chromenes were obtained from the allylphenols.

The treatment of o-(1-(alkylthio)alkyl)phenols with Lewis acid resulted in the formation of o-quinone methides by the novel 1,4-dethiolation process, which, being activated with Lewis acid, reacted in situ with various dienophiles in the manner of Diels–Alder reaction in high efficiency. o-Quinone allide, provided from o-(1-(alkylthio)allyl)phenol, also behaved as heterodienes.

o-Quinonemethides were prepared by treating o-[1-(alkylthio)alkyl]phenols with a Lewis acid. The Diels–Alder reaction of the resulting o-quinonemethides was also catalyzed by the Lewis acid. Hexahydrocanna-binol was synthesized according to this method.

Several Wittig olefinations between α-heterosubstituted acetones and a phosphorus ylide were investigated concerning the product stereoselectivity. Benzyloxyacetone and tetrahydropyranyloxyacetone furnished trisubstituted (Z)-olefins exclusively. The stereoselective preparation of oxygenated acyclic terpenoids was practical by use of the direct Wittig olefination toward α-alkoxy ketones, and it facilitated a total synthesis of plaunotol from geraniol derivatives in short steps with high stereoselectivity.

The [2,3]sigmatropic rearrangement of α-substituted N,N-dimethylmethallylamine N-oxides results in a highly stereoselective formation of trans olefins oxygenating at the allylic position, and provi...

A very facile and efficient synthesis of (−)-trans-hexahydrocannabinol was achieved through the intramolecular Diels-Alder reaction of an o-quinonemethide derived from 2-(1-hydroxycitronellyl)olivetol 1,3-bismethoxymethyl ether in methanol.

4-, 5-, 6-, and 7-Substituted N-tosylindoles are prepared from N-tosylanilides, carrying 2-acetoxy-1-(isopropylthio)ethyl group at the ortho position, which can be prepared from substituted anilines and dialkyl sulfide by [2,3] sigmatropic rearrangement

A simple and very efficient synthesis of N-tosylindole is described, based on the acid-catalysed cyclization of ortho-alkylated N-tosylanilides, which can be prepared from aniline and dialkyl sulfide by [2,3]sigmatropic rearrangements

Photosensitized oxygenation of 5,6-dihydro-4-methyl-2H-pyran (1) in methanol followed by reduction gave two kinds of allyl alcohols [(2) and (3)] together with the epoxy-ethers (4) and (5). When the reaction was carried out in solvents other than alcohols it gave (2) and (3) exclusively. Ozonization of 4-methylenepyrans (2) and (13) followed by reduction with zinc powder–acetic acid afforded 3-hydroxytetrahydropyrans (11) and (14). Bromination of (14) gave the dibromide (16), which yielded bromopyran (17) and 3-acetoxy-4H-pyran-4-one (18) on treatment with 1,8-diazabicyclo[5.4.0]undecene. However, the reaction of (16) with silver acetate in acetic acid predominantly afforded (17) in excellent yield. Other allied reactions and mechanisms of these reactions are described.

4-Propyl-3,5-nonanedione was selectively formed by the reaction of methyl N-phenylacrylimidate with ethylmagnesium bromide in 80% yield. Similar diketones were obtained from methyl N-phenylcrotonimidate and N-phenylcinnamimidate with the Grignard reagents. The coupling of N-magnesio α-methoxy enamine and ketenimine, both of which are formed through the initial 1,4-addition of the Grignard reagent to α,β-unsaturated imidate, is the most plausible pathway for the formation of the diketones.

Highly stereoselective total synthesis of plaunotol has been achieved by the application of the (Z)-stereoselective direct Wittig olefination to α-alkoxy ketones having geranyl-acetone skeleton.

Ethyl c-3-bromo-1-methyl-2-oxocyclohexane-r-1-carboxylate (1a) is oxidized by dimethyl sulphoxide to the 2,3-dione derivative (3), whereas the t-3-bromo-isomer (1b) is apparently dehydrogenated to give the bromocyclohexenone (4). The mechanism for the formation of the product (4) is discussed. Allied reactions are described.

Allylation of active methylene compounds catalyzed by a palladium(0)-phosphine system took place highly stereoselectively by employing allyl oxime carbonates as the allylating reagent.

A new π-allylnickel(II) complex, di-µ-bromo-bis(1–3-η-2-methyl-6-methyleneocta-2,7-dienyl)dinickel (5) was prepared by the reaction of bromomyrcene (7a) and (8a) with nickel tetracarbonyl in benzene. The reaction of the complex (5) with iodobenzene in dimethylformamide afforded 8-phenylmyrcene (10) in a high degree of stereoselectivity (E/Z= 85/15). The complex (5) reacted with the chloro-acetal (14), derived in three steps from isoprene, to give the acetal (15) which upon hydrolysis afforded β-sinensal (1) in high stereoselectivity (93%E).

A new synthesis of 2-hydroxy-3-methyl-2-cyclohexen-1-one (1) is described. The Mannich reaction of cyclohexane-1,2-dione (2) or 2-morpholino-2-cyclohexen-1-one (3) with morpholine and formalin gave a Mannich base (4), which was then hydrogenolized to afford 1. However, the Mannich reaction of 1 merely gave a bis-Mannich base (22), which was then similarly hydrogenolized to afford 3,6-dimethyl-2-hydroxy-2-cyclohexen-1-one (7) along with 3,6-dimethyl-2-hydroxy-6-morpholinomethyl-2-cyclohexen-1-one (26); 2-hydroxy-3,6,6-trimethyl-2-cyclohexen-1-one could not be obtained under these conditions. The Mannich reaction of other alicyclic α-diketones and the hydrogenolysis of their Mannich bases are also described.

A stereoselective synthesis of (Z,Z,Z)-12-benzyloxy-1-chloro-2,6,10-trimethyldodeca-2,6,10-triene (3) was achieved starting from (Z,Z)-farnesol. All the components of betulaprenols were synthesized using the C15 block 3 and its lower homologue (C10 block) as the key building blocks for the cisoid polyprenyl skeletone.

The Wittig reaction of benzyloxyacetone or tetrahydropyranyloxyacetone with 4-pentynylidenetriphenylphosphorane in salt-free conditions followed by removal of the protecting group afforded (Z)-2-methylhept-2-en-6-yn-1-ol in 95–96 % stereoselectivity. After conversion of the allylic alcohol to the corresponding bromide, the latter was coupled with prenyl or neryl p-tolyl sulfone, followed by reductive desulfonation and hydration of the acetylenic bond, to give nerylacetone and (Z,Z) -farnesylacetone, respectively.

Several new synthetic reactions have been established which are useful to the synthesis of certain important natural products : (1) stereoselective formation of trisubstituted (E) -olefins by means of, π-allylic nickel bromide complexes, (2) stereoselective formation of trisubstituted (E) -allylic alcohols via [2, 3] sigmatropic rearrangement of α-isopropenylamine N-oxides, (3) stereoselective formation of trisubstituted (Z) -allylic alcohols via the Wittig reaction of unstabilized ylids with alkoxyacetones, (4) stereoselective synthesis of trisubstituted (Z) -allylic alcohols via nucleophilic ring opening of erythro-α-methyl-α, β-epoxy alcohols followed by cis-elimination of the resulting 1, 2-glycols, (5) stereospecific coupling of (E) -and (Z) -polyprenyl aryl sulfones with trisubstituted (Z) -allylic chlorides in the presence of PTC and aq. sodium hydroxide, and (6) ortho-selective alkylation of phenols by means of [2, 3] sigmatropic rearrangement of phenoxyisopropylsulfonium alkylids. They provide promising tools to manipulate acyclic terpenoids at the head or terminal position stereoselectively by the aid of easily accessible reagents under mild reaction conditions. Thus the stereoselective synthesis of the following three kinds of natural isoprenoids, i.e., isoprenoid quinones such as coenzyme Q10 and vitamin K, natural polyprenols which include betulaprenol, bacterialprenol and (S) -dolichol, and natural d-α-tocopherol (vitamin E) has been achieved by the application of the above methodologies.

In the presence of a catalytic amount of Pd(0), active methylene compounds were allylated by allyl imidates under neutral conditions. In allylation with 3,3-disubstituted allyl imidates, e.g., geranyl and neryl imidate the effect of solvent and ligand to the E/Z ratio are investigated. The reaction in dimethyl sulfoxide by addition of diphosphine, e.g., 1,2-bis(diphenylphosphino)ethane, or large excess of triphenylphosphine as additive ligand gave best results. In these conditions, various active methylene compounds were allylated stereoselectively, especially complete retention of starting olefin geometry was achieved with neryl imidate.

A New synthesis of 2-hydroxy-3-methyl-2-cyclohexen-1-one (Ia), a flavor component of coffee aroma, is described. The selenium dioxide oxidation of ethyl 1-methyl-2-oxocyclohexanecarboxylate (IIa) gave α-diketone (IIIa), which was then hydrolyzed and decarboxylated to afford Ia. The treatment of IIa with cupric chloride in 50% acetic acid also yielded Ia. The dimethyl sulfoxide oxidation of ethyl 3-bromo-1-methyl-2-oxocyclohexanecarboxylate (IV) afforded IIIa, along with 3-bromo-6-ethoxycarbonyl-2-hydroxy-6-methyl-2-cyclohexen-1-one (V). The halogenation of IIa produced dihalogeno ketoesters (VIa) (VIIa), which also yielded Ia in a pure state by means of a direct acidic hydrolysis or by a two-step hydrolysis using morpholine. Other allied compounds are also described.

Highly regio- and stereo-selective oxidation sequences are described for the efficient conversion of the gem-dimethyl olefin terminus of acyclic terpenes to terminal trans-allylic alcohols and trans-α,β-unsaturated aldehydes.

π-アリル型ニッケル錯体はハロゲン化アリル類から容易に合成でき,非プロトン性強極性溶媒中でハロゲン化アルキルと反応してオレフィン類を収率よく与えることに着目し,この反応を分子内アルキル化に応用して大環状ラクトンを合成する方法について検討した。その結果,中牲かつ穏和な条件下に炭素一炭素結合を形成させ不飽和大環状ラクトンを得ることができた。この方法では立体選択的に,trans-形ラクトンが生成した。また,16～14員環ラクトンは良収率で得られたが, 13 および 12 員環ではやや収率が低く,副生成物として二量化ラクトンが生成した。さらに,このようにこして得られたラクトンから天然香気化合物である exaltolide と(Z)-9-ドデセン-12-オリドを合成した。また,このラクトン合成法を用いて,プロパルギルテトラヒドロピラニルエーテルを出発化合物として短行程で,天然マクロライドである recifeiolide を立体選択的に合成することができた。

o-(1-(Alkylthio)alkyl)phenols are converted into o-quinone methides in good yield by treatment with silver oxide under mild conditions. Since the methides tend to prefer (E) configuration, cis-4-alkyl-2-alkoxychromans are exclusively obtained as a result of endo [4+2] cycloaddition of the methides and vinyl ethers.

Reactions of αα′-dibromocycloalkanones [(1) and (2)] with various bases in several solvents have been studied. Treatment of 2,5-dibromocyclopentanone (1) with bases such as sodium hydrogen carbonate, sodium acetate, sodium phenoxide, and secondary amines afforded the corresponding 2-substituted cyclopent-2-enones [(3), (4), (5), and (8)]. Similar treatment of 2,6-dibromocyclohexanone (2) with weak nucleophilic bases gave 2-substituted cyclohex-2-enones (9) and (10), but reactions with secondary amines possessing both strong basicity and high nucleophilicity gave 2-aminocyclohex-2-enones (13a–c) and cyclopent-1-enecarboxamides (14a–c). The ratio of (13) to (14) is strikingly affected by the reaction solvent: (13) or (14) was obtained selectively when hexamethylphosphoramide or chloroform was used, respectively. Allied reactions are described and mechanisms are suggested.

The reaction of several aliphatic ketones with α-cyano-α, β-unsaturated acid derivatives has been studied. Ethylidenecyanoacetic acid reacted with a large excess of acetone in an autoclave at 150–160°C to give 3-methyl-5-oxohexanonitrile, which was considered to be produced by the decarboxylation of the Michael-type adduct of acetone onto the acid. Similar adducts were obtained by the reaction of the acid with methyl ethyl ketone, cyclohexanone, and ethyl laevulinate. The reaction of ketones with ethyl ethylidenecyanoacetate did not afford Knovenagel-type condensates, but Michael-type adducts in appreciable yields, for example, ethyl 2-cyano-3,4-dimethyl-5-oxohexanoate from methyl ethyl ketone. Diethyl ethylidenemalonate also gave Michael-type adducts. These results seem to suggest that the γ-methyl group of ethylidenecyanoacetic acid or its ester is not active enough to give Knovenagel-type condensates with aliphatic ketones, and that, therefore, the Knovenagel-type reaction is preceded by the Michael-ty...

The reactions of methyl vinyl ketone with isobutylmagnesium bromide and ethylmagnesium bromide have been studied. Methyl vinyl ketone reacts with isobutylmagnesium bromide to give methylheptanone and 3-iso-amyl-2-vinyl-2-pentanol-4-one as a result of 1,4-addition; the latter compound is formed from 2 mol. of ketone and one mole of the Grignard reagent. On the other hand, in the reaction of ethylmagnesium bromide with methyl vinyl ketone, both 1,2- and 1,4-addition take place, and 3-methyl-1-penten-3-ol and 3-propyl-2-vinyl-2-pentanol-4-one are obtained. These keto-alcohols have been decomposed to the corresponding ketones and methyl vinyl ketone by heating or by treatment with sulfuric acid.

The catalytic hydrogenation of salicyloyl chloride at a mild temperature gave a high yield of salicylaldehyde. A similar partial reduction of substituted salicyloyl chlorides provided the corresponding salicylaldehydes in appreciable yields. Attempts to prepare other isomeric hydroxybenzoyl chlorides were, however, unsuccessful. The relationship between the structure of salicyloyl chlorides and the ease of their conversion to salicylaldehydes is discussed. Moreover, the formylation of phenol with dichloromethyl methyl ether and the selective ortho-formylation are described.

The preparation of pent-2-en-4-ynylamine and pent-2-en-4-ynylthiol and their derivatives from 5-bromopent-3-en-1-yne was studied. Moreover, in connection with the preparation of the bromide, the rearrangement-bromination of vinylethynylcarbinol was found to give three isomeric bromides, 5-bromopent-trans-3-en-1-yne, 5-bromopent-cis-3-en-1-yne, and 3-bromopent-1-en-4-yne. Pent-2-en-4-ynylamine was obtained from 5-bromopent-3-en-1-yne by two methods, by the hydrolysis of the hexaminium salt and by the cleavage of N-(pent-2-en-4-ynyl)phthalimide. The reaction of 5-bromopent-3-en-1-yne with potassium hydrosulfide and the decomposition of ethyl pent-2-en-4-ynylxanthate by alcoholic ammonia gave pent-2-en-4-ynylthiol.

The aluminum chloride-catalyzed reaction of aromatic compounds, such as benzene and phenols, with β-chlorocarboxylic acids was investigated. Although the reactions of benzene, toluene, and chlorobenzene with β-chloropropionic acid were found to give the corresponding dihydrocinnamic acids in high yields, attempts to prepare dihydrocoumarin by a similar reaction of phenol were unsuccessful. Similarly, β-arylbutyric acids were obtained in good yields by means of the aluminum chloride-induced reaction of aromatic hydrocarbons with β-chlorobutyric acid (Ib). In contrast, phenols, such as phenol, o- and m-cresols, reacted with Ib under similar conditions to provide the corresponding β-(p-hydroxyphenyl)butyric acids in 22–60% yields, while a 51% yield of β-(5-hydroxy-2-methylphenyl) butyric acid was obtained upon a similar treatment of p-cresol with the acid Ib.

A new synthesis of vitamins K1(1), and K2(5n)(2) is described. Reaction of bis-(1–3-η-3-alkylbut-2-enyl)di-µ-bromodinickel complexes (8a–c) with 2-bromo-3-methylnaphthalene-1,4-diyl bis(methoxymethyl) ether (6a) or diacetate (6b) in a polar, co-ordinating solvent gave the corresponding vitamin K derivatives (9a–d) in high yield, which were converted into vitamin K analogues also in high yield. The stereoselectivity decreases as the donor strength of the solvent increases. All-trans-vitamin K2(45)(2b) was isolated from the trans–cis-mixture (70:30) prepared by this method.