Studies on the Carbon Zip Reaction of 2-Oxocycloalkane-1-carbonitriles

As a part of continuing interest in the zip reaction, we present the results on a carbon ring-enlargement reaction of activated ketones with a CN group as a charge stabilizer. Two series of (1-cyano-2-oxocy-cloalkyl)alkanoates were prepared from 8- and 12-membered cyano-ketones 1 and 2 , respectively, namely the propanoates 3 and 4 , the butanoates 6 , 8 and 9 as well as the pentanoates 12 and 15 . While treatment with t-BuOK of the former two homologous esters resulted in both ring enlargement and competitive transesterification, the pentanoates 12 and 15 afforded mostly the diastereoisomeric mixtures of bicyclic alcohols 20a – c and 31a , b , respectively, which remained intact on further exposure to base. It was shown that – apart from the base used (t-BuOK) vs. Li(i-Pr)₂N – the distribution of products was greatly influenced by the ring size of substrates. This is further illustrated by treatment of ketones 34 and 35 with t-BuOK. While the former rearranged smoothly to diketone 36 , no reaction at all took place with the latter. The behavior of the substrates is discussed in terms of steric and energetic reasons.     

Vinyl Ethers Containing an Epoxy Group: XXII. Synthesis and Base-Catalyzed Transformations of 1-(Allyloxy)- and 1-[2-(Vinyloxy)ethoxy]-3-(2-propynyloxy)propan-2-ols

Reactions of 2-(allyloxymethyl)- and 2-[2-(vinyloxy)ethoxy]methyloxiranes with 2-propynol (～3 wt % of t-BuOK, 75–85°C, 5–10 h) lead to formation of new 1-organyloxy-3-(2-propynyloxy)propan-2-ols (yield 65–95%). On heating to 45–100°C in the presence of bases (KOH, t-BuOK), 1-allyloxy- and 1-[2-(vinyloxy)ethoxy]-3-(2-propynyloxy)propan-2-ols are transformed into the corresponding 2-vinyl-1,3-dioxolane, 6-methyl-2,3-dihydro-1,4-dioxine, 6-methylene-1,4-dioxane, and 2,3-dihydro-5H-1,4-dioxepine derivatives, whose yield and ratio strongly depend on the solvent nature, catalyst, and substituent at the hydroxy group. 2-Vinyl-1,3-dioxolane and 6-methyl-2,3-dihydro-1,4-dioxine derivatives are formed as the major products (yield 70–99%) in the presence of t-BuOK in aprotic media (toluene, THF, DMSO) or in the absence of a solvent as a result of prototropic isomerization followed by intramolecular heterocyclization. Intramolecular nucleophilic cyclization of 3-(2-propynyloxy)propan-2-ols to 6-methylene-1,4-dioxane is the predominant process in water in the presence of KOH. In all cases, the fraction of 2,3-dihydro-5H-1,4-dioxepine derivatives among the cyclization products ranges from 0 to 5% (KOH) or to 14% (t-BuOK).     

On the amination of 1,2,4-triazines by potassium amide in liquid ammonia and by phenyl phosphorodiamidate. A 15n-study

The amination of 5-R- and 6-R-3-X-1,2,4-triazines (R = C₆H₅, t-C₄H₉, X = SCH₃, SO₂CH₃, N⁺ (CH₃)₃, Cl) by potassium amide in liquid ammonia has been studied. In all reactions the formation of the corresponding 3-amino-1,2,4-triazines takes place; in some reactions by-products were found: from 5-phenyl- and 5-t-butyl-3-(methylthio)-1,2,4-triazine a ring contracted product i.e. 5-phenyl and 5-t-butyl-3-(methylthio)-1,2,4-triazole, from 6-phenyl-3-(methylthio)-1,2,4-triazine the dimer 3,3′-bis-(methylthio)-6,6′-bisphenyl-5,5′-bi-1,2,4-triazine and from 5-t-butyl-3-(trimethylammonio)-1,2,4-triazine chloride compound bis-(5-t-butyl-1,2,4-triazin-3-yl)- amine. Furthermore the conversion of 5-phenyl- and 5-t-butyl-1,2,4-triazin-3-one into the corresponding 3-amino compound by treatment with phenyl phosphorodiamidate (PPDA) was studied. A ¹⁵N study of these aminations showed that nearly all compounds undergo substitution according to both S_N(AE) and S_N(ANRORC) processes. The contribution of each of the competitive mechanisms to the amination is strongly influenced by the character of the leaving group.     

Transformations of <Emphasis Type="Italic">N</Emphasis>-(2-acylaryl)benzamides and their analogs under the Camps cyclization conditions

N-(2-Acylaryl)benzamides and analogous N-substituted furan-2-, thiophene-2-, and cyclopropane-carboxamides in the systems EtONa–EtOH, EtONa–THF, and t-BuOK–t-BuOH undergo Camps cyclization to 2-aryl-, 2-hetaryl-, and 2-cyclopropylquinolin-4(1H)-ones with high yields. The same substrates in the system t-BuOK (5 equiv)–THF are converted mainly to the corresponding N-(2-hydroxyaryl) amides as a result of oxidative transformation of the acyl fragment into hydroxy group.     

Generation and Reactions of Lithiated tert-Butyl and 2,6-Di(tert-butyl)-4-methylphenyl Cyclopropanecarboxylates

tert-Butyl and 2,6-di(tert-butyl)-4-methylphenyl (BHT) cyclopropanecarboxylates ( 4 , 6 , 24 , 25 ) are lithiated with LiN(i-Pr)₂ and t-BuLi, respectively. Reactions with alkyl halides, aldehydes, acyl chlorides, and heteroelectrophiles give α-substituted BHT esters which can be cleaved (t-BuOK/H₂O/THF) to the corresponding carboxylic acids or reduced (LiAlH₄/THF) to the cyclopropanemethanols.     

Darzens reaction in the synthesis of 3-(α-chloroalkyl)quinoxalin-2(1H)-ones

A two-stage method was developed for the synthesis of 3-(α-chloroalkyl- and α-chlorophenylalkyl)-quinoxalin-2(1H)-ones proceeding from methyl chloroalkyl- and chlorophenylalkylpyruvates obtained by Darzens reaction from methyl dichloroacetate and appropriate aldehydes in the presence of t-BuOK.     

Generation and Trapping of Triafulvene

Substituted methylidenecyclopropanes 12a – d , being easily available from 1,1-dibromo-2-(phenylthio)-cyclopropane ( 9a ), are attractive precursors of triafulvene (2-methylidene-1-cyclopropene; 1 ). Both the sulfoxide 12b and the sulfone 12c react with an excess of alkoxides (t-BuOK and NaOMe) to give 12e and 12f , respectively, while the sulfinyl group of 12b may be replaced by the PhCH₂S substituent in the presence of PhCH₂SH/t-BuOK. These reactions (Scheme 4) may be explained by assuming 1 as a reactive intermediate, although an alternative sequence including carbene 20 (Scheme 6) is not completely ruled out. D -labelling experiments (Scheme 5) do not give conclusive evidence due to D scrambling, but deprotonation/methylation sequences show that H? C(2) of 12a – c is the most acidic proton. Final evidence for 1 results from the reaction of 12d with cyclopentadienide (Scheme 7): the reaction of 1 with cyclopentadiene produces the expected [4 + 2]-cycloaddition product 23 , while some mechanistic insight results from the sequence 12d → 24 → 25 .     

Reactivity of 1-phenylsulfinyl-2-phenylsulfanylethylene (SOSE) with O-nucleophiles generated by potassium tert-butoxide

E-1-Phenylsulfinyl-2-phenylsulfanylethylene (E-SOSE) reacts with O-nucleophiles generated by means of t-BuOK via an addition-elimination mechanism, thus affording the product of substitution of the phenylsulfanyl group in a stereo-conservative process. When used alone, the strongly basic and hindered tert-butoxide brings about elimination of either the phenylthiolate or phenylsulfinate groups. Z-SOSE is much more prone to elimination: either with t-BuOK alone or with other O-nucleophiles generated by t-BuOK, it always leads to products derived from elimination. Other alkaline tert-butoxides or other bases appear not as effective in generating species nucleophilic enough to react with E-SOSE.     

Regiospecific Functionalization of Dimetalated (1-Naphthyl)acetylene. Efficient Synthetic Procedures for Naphtho[2,1-b]chalcophenes

Treatment of (1-naphthyl)acetylene (1) with two mol equivalents of the BuLi-t-BuOK reagent in tetrahydrofuran/hexane, followed by successive addition of anhydrous lithium bromide, sulfur, selenium, or tellurium and t-butylalcohol gives naphtho[2,1-b]thiophene, -selenophene and -tellurophene in good yields. Reaction of dimetalated 1 with iodine or dimethyldisulfide afforded 2-iodo-, and 2-thiomethyl(1-ethylnyl)naphthalene.     

tert-BuOK-mediated carbanion-yne intramolecular cyclization: synthesis of 2-substituted 3-benzylbenzofurans

A mild, efficient, and regioselective carbanion-yne intramolecular cyclization mediated by t-BuOK for the synthesis of 2-substituted 3-benzylbenzofurans is developed. It was started from o-iodophenol (1), based on O-alkylation, and the Sonogashira reaction in sequence to produce 2-(2-phenylethynylphenoxy)-1-arylalkanones (5). An intramolecular carbanion-yne 5-exo-dig cyclization reaction of 5, which was mediated by t-BuOK, yielded title benzofurans in good yields.     

Alkoxide-Induced Reaction of 1-[(Trimethylsilyl)-Methyl]Azoles with Imines and Carbonyl Compounds

t-BuOK-induced reaction of 1-[(trimethylsilyl)methyl]-1,2,4-triazole with imines to yield (triazol-1- yl)ethylamines and (triazol-5-yl)methylamines was explored. Also, alkoxide-induced desilylation of 1-[(trimethylsilyl)methyl]azoles in the presence of carbonyl compounds was demonstrated, and (-BuOK and potassium trimethylsilanolate were found to be effective in this reaction.     

New Syntheses of Di-π-Substituted Heptalenes

To study the effect of double-bond shifts (DBS) in different type of heptalenes linked to extended π-systems, several di-π-substituted heptalenes were synthesized. 6-[(E)-Styryl]heptalene-dicarboxylate 4 was smoothly converted to 1-(chloromethyl)heptalene-dicarboxylate 5 by treatment with t-BuOK and C₂Cl₆ in THF at −78°. The one-pot reaction of 5 and P(OEt)₃ in the presence of NaI, followed by Wittig-Horner reaction, afforded the 1,6-di-π-substituted heptalene 6 . The reaction of 6-[(1E,3E)-4-phenylbuta-1,3-dienyl]heptalenes 7 or 15 with t-BuOK and benzaldehyde in THF led to the formation of the 1,6-di-π-substituted heptalenes 13 or 16 , together with transesterification products 14 or 17 . The transformation of the MeOCO group at C(4) of 6-[(E)-styryl]heptalene-dicarboxylate 4 to a phenylbuta-1,3-dienyl substituent afforded the 4,6-di-π-substituted heptalene 21a , which is in thermal equilibrium with its DBS isomer 21b in solution. Oxidation of heptalene 22 with SeO₂ in dioxane gave carbaldehyde 23 , which was then subjected to a Wittig reaction to give the 6,9-di-π-substituted heptalene-dicarboxylate 24 .     

Synthesis of chiral α-substituted N-[((2S)-2-hydroxy-2-phenyl)-ethyl]-2-phenylglycine derivatives by diastereocontrolled alkylation of (6 R)-2,3,5,6-tetrahydro-3,6-diaryl-N-[(2′R)-(2′-methyl)phenyl-methyl]-4H-1,4-oxazin-2-ones

The synthesis of α-substituted N-[((2S)-2-hydroxy-2-phenyl)-ethyl]-2-phenylglycine derivatives is reported. The key step of the sequence is the highly diastereoselective alkylation of (6R)-2,3,5,6-tetrahydro-3,6-diaryl-N-[(2′R)-(2′-methyl)phenylmethyl]-4H-1,4-oxazin-2-ones after deprotonation with t-BuOK. Opening of the resulting oxazinone with ethanolic KOH, followed by hydrogenolysis of the corresponding N-[(2R)-(2-methyl)phenylmethyl] compound to furnish the expected 2-phenylglycine derivative, is also described.     

Unnatural Amino Acids. 2. Simple Method of Obtaining Esters of Aziridine-2-carboxylic Acids by a Transesterification Reaction

A series of N-unsubstituted esters of aziridine-2-carboxylic acid has been obtained by transesterification in basic medium using primary, secondary, and tertiary alcohols. Methods of transesterification using various bases (K₂CO₃, ROLi, t-BuOK) have been compared. Transesterification with lithium alcoholates also affords the possibility of obtaining esters of N-substituted aziridine-2-carboxylic acids. Transesterification of chiral esters proceeds with retention of the configuration of the chiral center.     

Methylthiofurane: Herstellung und Reaktionen

Preparation and Reactions of Methylthiofurans By lithiation of 3,4-dimethoxyfuran, 2-methylfuran and furan, followed by reaction with dimethyldisulfide, the methylthiofurans 2, 8 , and 10 have been prepared. Reaction of 8 with maleic anhydride has yielded 6-methyl-3-(methylthio)phthalic anhydride ( 9 ), a yellow substance with a strong greenish fluorescence, obviously formed by elimination of H₂O from an unstable cycloadduct. An analgous reaction of 2 resulted in an unexpected mixture from which the following yellow compounds were isolated: 3-hydroxy-4,5-dimethoxy-6-(methylthio)phthalic anhydride ( 3 ), 4-hydroxy-5-methoxy-3,6-bis(methylthio)phthalic anhydride ( 4 ), and bis(S-methyl) (2Z,4E,6Z)-2,3,6,7-tetramethoxy-4,5-bis(methylthio)-2,4,6-octatrienethioate ( 5 ). Compound 5 is also formed on standing of 2 at RT. Mild acid hydrolysis of 2 results in ring-opening accompanied by an intramolecular oxido-reduction to yield S-methyl(3Z)-3-methoxy-4-(methylthio)-2-oxo-3-butenethioate ( 6a ). The structures of compounds 5 and 6a have been determined by X-ray analysis.     

Unusual Thermal Rearrangements of N-Cyclohexylidene-4-methyl-1-(methylthio)penta-1,3-dien-1-amine

We have observed unusual thermal rearrangements of N-cyclohexylidene-4-methyl-1-(methylthio)penta-1,3-dien-1-amine to 4,4-dimethyl-2-(methylthio)-3,3a,4,4a,5,6,7,8-octahydrobenzo[4,1]cyclobuta-[1,2-b]pyrrole and 1-cyclohexyl-5-methylpyridine-2(1H)-thione.     

Uncommon transformations of methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate initiated by bases

Methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate prepared in two stages from D-ribose acetonide underwent a series of uncommon transformations under the treatment with bases providing the following different products depending on the base applied: methyl 3-(5-acetyl-2,2-dimethyl-1,3-dioxol-4-yl)propionate (DBU), methyl 2,3-isopropylidenedioxy-7-oxabicyclo[2.2.1]heptane-6-carboxylate (t-BuOK), methyl {(5R)-2,2-dimethyl-5-[(2R)-oxiranyl]-1,3-dioxolan-4-ylidene}propionate and methyl-(E)-3-{(4S,5R)-2,2-dimethyl-5-[(1R)-(2-oxiranyl)]-1,3-dioxolan-4-yl}-2-propenoate (t-BuOK and LDA).     

Generation and Trapping of Cyclopropenes from 2-Alkoxy-1,1-dichlorocyclopropanes

In presence of crown ether, 2-alkoxy-1,1-dichlorocyclopropanes react with t-BuOK/THF preferentially via ring opening to 2-chloroalk-2-en-1-ones and alkynones or to chlorocyclopropenes. The latter may be intercepted with 1,3-diphenylisobenzofuran, but in the absence of trapping agent, the rearrangement to vinylcarbenes does not occur.     

Intramolecular Diels-Alder Reaction of Furans with Allenyl Ethers Followed by Phenylthio and Trialkylsilyl Groups Rearrangement

A new reaction involving an intramolecular Diels-Alder reaction of a furan diene with an allenyl ether dienophile followed by phenylthio group rearrangement was discovered. Treatment of the propargyl ethers 2a-c with t-BuOK in t-BuOH at 85 ° C gave the phenylthio group rearrangement products 5a-c and 6a-c . A reaction involving an intramolecular Diels-Alder reaction of a furan diene with an allenyl ether dienophile followed by trialkylsilyl group rearrangement is also demonstrated.     

Ruthenium(II) <Emphasis Type="Italic">N</Emphasis>-heterocyclic Carbene Complexes in the Transfer Hydrogenation of Ketones

Six ruthenium-N-heterocyclic carbene complexes (2–7) have been prepared and the new compounds characterized by C, H, N analyses, ¹H-n.m.r. and ¹³C-n.m.r. The reduction of ketones to alcohols via transfer hydrogenation was achieved with catalytic amounts of complexes (2–7) in the presence of t-BuOK.