Synthesis of (E)-1-Propenyl Ketones from Carboxylic Esters and Carboxamides by Use of Mixed Organolithium-Magnesium Reagents. Synthesis of α-Damascone, β-Damascone,and β-Damascenone

The novel reagents formed by combination of allylmagnesium chloride and a strong non-nucleophilic lithium base (LiNR₂) convert non- or slowly enolizable carboxylic esters or carboxamides into 2-propenyl ketones which are protected from further reaction by their in situ conversion into enolates. This modified Grignard reaction is applied to efficient syntheses of α-damascone, β-damascone, β-damascenone, and various other (E)-1-propenyl ketones.     

Angular Alkylation of cis-Decalin Epoxides with C-nucleophiles: Mechanism,scope, and limitations of a novel bridgehead functionalisation

The angular alkylation of cis-decalin epoxides like 5 or 7 can be achieved at C(8a)

1 For convenience, the arbitrary numbering given for 5 (Scheme I) is used throughout the General Part; for systematic names, see Exper. Part.

in good yield by using CuI and a large excess of Grignard reagents without an sp³ centre at C(2). The reaction proceeds via a carbenium-ion intermediate which is stabilised by homoconjugative interaction with the adjacent double bond. Due to 1,3-diaxial strain in the alkoxides resulting from alkylation or reduction at C(4a) of the epoxides 5 or 7 , the nucleophile is delivered selectively to C(8a). Grignard reagents possessing H-atoms at C(β), transfer a hydride to the epoxide yielding the trans-decalol 11 (Grignard reduction). The angular alkylation of 5 with allylic and benzylic Grignard reagents proceeds with good yield.     

Preparation and Application of Solid,Salt‐Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

The treatment of various N‐morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t _1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd‐ and Cu‐catalyzed cross‐couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N‐morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti‐breast‐cancer drug candidate in six steps and 23 % overall yield.     

Non-destructive Removal of the Bornanesultam Auxiliary in α-Substituted N-Acylbornane-10,2-sultanis under Mild Conditions: An efficient synthesis of enantiomerically pure ketones and aldehydes

α-Substituted N-acylbornane-10, 2 -sultams 6, 9 , and 10 can be converted into enantiomerically pure ketones 5. 13 , and 14 , respectively, via a two-step procedure involving a known mercaptolysis reaction followed by an [Fe(acac)₃]-mediated coupling of the resulting S-benzyl thioesters with Grignard reagents. Furthermore, enantiomerically pure aldehydes 23 can be obtained from α-substituted N-acylbornane-10,2-sultams 6 via a one-step reduction with (i-Bu)₂AIH. No epimerization at the α-chiral center is observed during the cleavage reaction whereby the chiral auxiliary, bornane-10,2-sultam 1 or ent- l , was recovered. By using this methodology, several natural products or precursors thereof can be prepared.     

New Addition Reactions of Organometal Compounds with 4,4-Dimethyl-1,3-thiazole-5(4H)-thiones

Addition reactions of organometallic reagents with 4,4-disubstituted 1,3-thiazole-5(4H)-thiones were studied. Whereas the reactions with alkyllithium and alkyl Grignard reagents occurred in the thiophilic manner, the carbophilic addition was observed with allyllithium and allyl Grignard reagents. A radical reaction mechanism is proposed for rationalizing these observations (Scheme 5). A radical cyclization of the prepared 5-allyl-4,5-dihydro-1,3-thiazole-5-thiol derivatives yielded 1,6-dithia-3-azaspiro[4.4]non-2-enes (Table 4).     

Asymmetric Induction on Copper(I) Chloride catalyzed 1,4-addition of alkylmagnesium chlorides to α, β-disubstituted (E)-enoylsultams and subsequent protonation

Successive treatment of conjugated N-enoylsultams 2 with alkyl Grignard reagents/CuCl and aq. NH₄Cl solution generated selectively two stereogenic centers at C(α) and C(β) providing, after flash chromatography and crystallization, acylsultams 5 in high purity. Mild cleavage afforded the recovered sultam auxiliary 1 and enantiomerically pure carboxylic acids 7 .     

Utilisation d'ylides du phosphore en chimie des sucres VII. Synthèse de sucres ramifiés des types «streptose» et «apiose». Communication préliminaire

A new high-yielding route to branched-chain sugars of the streptose or the apiose type having at the branching point a configuration epimeric with that which would be obtained by the classical synthesis using Grignard reagents is described. The main steps are the preparation of branched-chain unsaturated cyano sugars by reaction of cyanomethylene triphenylphosphorane with keto sugars and the cis-dihydroxylation (KMnO₄) of the so obtained cyano sugars. The cis and the trans isomers of a series of cyanovinylidenic sugars have been separated and the stereodependence of the long-range coupling constants in this class of compounds has been examined.     

Organic phosphorus compounds 53 preparation and properties of bis-(chloromethyl)-phosphinic and -thiophosphinic acid derivatives as well as tertiary phosphine oxides and sulfides containing two ClCH2 groups [1]

Bis-chloromethyl-phosphinates, -thiophophinates, and -phosphinic amides are formed in fair yield by treating either bis-chloromethyl-phosphinic or-thiophosphinic chloride with alcohols, thiols, or amines in the presence of equivalent amounts of acid binding agents. Unexpectedly, the thiophosphinates show no insecticidal activity and only the β-cumaryl derivative exhibits a low herbicidal activity. Reduction of bis-chloromethyl-thiophosphinic chloride to bis-chloromethyl-phosphinous chloride is effected with (PhO)₃P at 170°. Interaction of this chloride, (ClCH₂₎₂PCl, with Grignard reagents yields tertiary phosphines, which at slightly above room temperature are unstable, but which may be characterized as oxides or sulfides.     

Nukleophile Alkylierung aromatischer Nitroverbindungen

Nucleophilic alkylation of aromatic nitro compounds Aromatic nitro compounds may be alkylated in o- or p-position by treatment with alkyl lithium or alkyl Grignard reagents.     

Grignard-Addition an Pyridin-N-oxid

Addition of phenyl-, alkyl-, alkenyl- and alkinyl-Grignard reagents to pyridine-N-oxide in THF leads to 5-substituted (2Z, 4E)-pentadien-aldoximes 6 having (E) (syn)-configuration of the C, N-double bond. The unsaturated oximes are shown to arise through an electrocyclic ring opening reaction from the primary Grignard adducts 5 . These can be trapped by protonation at low temperature.     

Synthesis and Addition Reactions of 1,3-Thiazole-5(4H)-thione Oxides

1,3-Thiazole-5(4H)-thione oxides 2 were prepared by oxidation of the corresponding 1,3-thiazole-5(4H)-thiones 1 with m-chloroperbenzoic acid (Table 1). Addition reactions of 2 with organolithium and Grignard reagents yielded 4,5-dihydro-4,4-dimethyl-1,3-thiazol-5-yl methyl sulfoxides of type 4 via thiophilic attack (Table 2). Whereas the reaction with the organolithium compounds proceeded with fair-to-excellent yields, the Grignard reagents reacted only very sluggishly. The sulfoxides 4 could also be prepared via oxidation of 4,5-dihydro-4,4-dimethyl-5-(methylthio)-1,3-thiazoles of type 3 with m-chloroperbenzoic acid, together with the corresponding sulfones 5 (Scheme 1).     

Umsetzungen von 1,3-Thiazol-5(4H)-thionen mit Grignard- und Organolithium-Verbindungen: Carbophile und Thiophile Additionen

Reactions of 1,3-Thiazole-5(4H)-thiones with Grignard- and Organolithium Compounds: Carbophilic and Thiophilic Additions Organolithium compounds and 1,3-thiazole-5(4H)-thiones 9 reacted via thiophilic addition on the exocyclic S-atom. The intermediate anion E has been trapped by protonation to give 12 and by alkylation to yield 16 , respectively (Schemes 5 and 6). In competition with protonation of E , a fragmentation to benzonitrile and a dithioester 14 was observed (Scheme 5). In some cases, the alkylation of E led to the formation of dithioacetals 17 instead of 16 (Scheme 6). Methyl, ethyl, and isopropyl Grignard reagents and 9 in THF underwent again a thiophilic addition yielding 4,5-dihydro-1,3-thiazoles of type 12 (Scheme 3). In contrast to this result, MeMgI reacted with 9a in Et₂O via carbophilic addition to 11 . Again a carbophilic attack at C(5) of 9 was observed with allylmagnesium and 2-propynylmagnesium bromide, respectively, in Et₂O.     

Tandem asymmetric conjugate addition-enolacetates formation of enantiomerically enriched zinc and aluminium enolates

The metal enolates, resulting from the copper-catalyzed enantioselective conjugate addition of organometallic reagents (Et₂Zn or R₃Al) to cyclic and acyclic enones are quantitatively trapped as enolacetates with acetic anhydride.     

Chirale Alkoxytitan(IV)-Komplexe für enantioselektive nucleophile Additionen an Aldehyde und als Lewis-Säuren in Diels-Alder-Reaktionen

Chiral Alkoxytitanium(iv) Complexes for Enantioselective Nucleophilic Additions to Aldehydes and as Lewis Acids in Diels-Alder Reactions A Number of chiral 1,2-1,3 and 1,4-diols were prepared and used as alkoxy ligands on Ti for enantioselective nucleophilic transfer of methyl, butyl, cyclopropyl, allyl, alkinyl, and phenyl groups to aromatic aldehydes, as well as for the enantioselective[4+2]cycloaddition of acrylate to cyclopentadiene. The 1,2-diols were pinane diol 7 and 1,2:5.6-diacetonide-protected mannitol 9 (Scheme 3) and tartrates. The 1,3-diols were obtained from the yeast-reduction products of 2-oxocyclopentane- and 2-oxocyclohexanecarboxylates and excess MeLi, BuLi, or PhLi (or the corresponding Grignard reagents; see 4–6 .) As 1,4-diols, we used the products 2 and 3 from tartrate acetals and methyl or Pheny1 Grignard reagents, the bis(benzaldehyde) acetal 8 of d-mannitol and o,o'-binaphthol (22). These diols were attached to the Ti-atom by azeotropic removal of i-PrOH from a mixture with [TiCi(i-PrO)₃]. Addition of various organometallic reagents R-metal (metal = Li, BR₃, MgX, MnC1, CuLiR) was followed by combination with aldehydes at – 75^., a warm up period, quenching with aqueous KF solution, and workup (for results see Tables 1–6 and Formulae 17–20 ). The enantiomeric excess of the secondary alcohols obtained varies greatly, certain combinations of chiral ligands, nucleophilic groups, and aldehyde substrates give rise to values as high as 90% ee; see e.g. Table 4. The Ti-complexes of the general formula [Ti(R*O)₂Ci₂] or [Ti(R*O)₂(i-PrO)CI] induced the Diels-Alder addition of methyl acrylate to cyclopentadience to take place at –30^.. The best enantioselectivity (50% ee) was observed with the binaphthol derivative (Table 7). The structures of the complexes involved in these reactions are unknown. The substitution on C(2) of the dioxolanes 2 and 3 (derived from tartaric acid) has a pronounced effect on the selectivities of both reactions studied here (Tables 2, 3, and 7). This remote effect (1,6-distance between the stereogenic acetal-C-atom and the Ti-centers) must be caused by conformational changes in the vicinity of the reactive site, i.e. the Ti? C bond in the nucleophilic addition reactions and the Ti-acrylate-oxygen complexation in the Diels-Alder reaction.     

Diisophorone and related compounds. Part 15 2,7-Epoxydiisophoranes: Oxirane cleavage byGrignard reagents

Grignard reagents cleave the oxirane ring of 2,7-epoxydiisophoran-1-ol producing diisophor-7-ene-1,2-diol, the formulation of which is in accord with its¹³C-nmr spectrum, and its further reactions. It yields a 1,2-cyclic sulphite ester, a 7,8-epoxide, and is converted into 1-acetoxydiisophora-2,7-diene by acetic anhydride, and into diisophor-2(7)-en-1-ol by successive dehydration and hydrogenation. Its allylic hydroxylation by selenium dioxide is attended by dehydration, producing moderate yields of diisophora-2,7-diene-1,6-diol.

---

Diisophoron und verwandte Verbindungen. 15. Mitt. 2,7-Epoxydiisophorane: Oxiranspaltung mittelsGrignard-Verbindungen

Zusammenfassung 2,7-Epoxydiisophoran-1-ol wird vonGrignard-Verbindungen unter Spaltung des Oxiranringes in Diisophor-7-en-1,2-diol umgewandelt, dessen Struktur durch sein¹³C-Kernresonanz-Spektrum und seine weiteren Umsetzungen bewiesen wird: Es bildet einen cyklischen 1,2-Sulphit-Ester, ein 7,8-Epoxyd, und wird von Essigsäureanhydrid in 1-Acetoxydiisophora-2,7-dien sowie durch aufeinanderfolgende Wasserabspaltung und katalytische Hydrierung in Diisophor-2(7)-en-1-ol umgewandelt. Hydroxylierung in Allyl-Stellung durch Selendioxyd ergibt unter gleichzeitiger Wasserabspaltung geringe Ausbeuten von Diisophora-2,7-dien-1,6-diol.

     

Etudes sur les composés organométalliques. XI [1]. Action du tétrabutoxytitane sur des solutions de Grignard

The reaction of titanium tetra-n-butoxide with phenylmagnesium bromide inether has been investigated. The species (C₆H₅)₂Mg in the Grignard reagent leads to (C₆H₅)₄Ti, whereas the dimeric species (C₆H₅)₂Mg · MgBr₂ produces an insoluble complex mTi(OBu)₄ · n[(C₆H₅)₂Mg · MgBr₂]. Applied to other Grignard reagents, the use of R₂Mg allowed the preparation of tetrabenzyltitanium, tetracyclohexyltitanium and tetramethyltitanium. Cristalline (C₆H₅)₄Ti and (C₆H₅CH₂)₄ Ti have been isolated.     

Synthesis of 2,3‐Diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ol Derivatives by the Reaction of Aryl(3‐isocyanopyridin‐4‐yl)methanones with Aryl Grignard Reagents

The reaction of aryl(3‐isocyanopyridin‐4‐yl)methanones 1 , easily prepared from commercially available pyridin‐3‐amine, with aryl Grignard reagents gave, after aqueous workup, 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ols 2 . These rather unstable alcohols were O‐acylated with Ac₂O in pyridine in the presence of a catalytic amount of 4‐(dimethylamino)pyridine (DMAP) to afford the corresponding 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐yl acetates 3 in relatively good yields.     

Dérivés de désoxy-hydroxylamino-sucres et radicaux libres diglycosylnitroxydes correspondants. Communication préliminaire

Deoxy-hydroxylamino-sugar Derivatives and Corresponding Diglycosylnitroxides Radicals A number of sugar aldonitrones, including C,N-diglycosylnitrones, and ketonitrones have been treated with Grignard reagents or cyanide anion leading to the corresponding deoxy-hydroxylamino-sugars. On oxidation (air, H₅IO₆ or PbO₂), these compounds gave the corresponding nitroxide radicals whose ESR. spectra are reported. Analogues of disaccharides, in which the interglycosidic O-bridge is replaced by a hydroxyimino group, have been obtained by reacting a partially blocked sugar bearing a free hemiacetal group either with a deoxy-hydroxylaminosugar or with hydroxylamine, followed by reaction with an aldehydosugar and a reducing agent (NaBH₄). These reactions represents the key synthetic steps for the oligosaccharide-type synthesis of deoxy-hydroxyimino-oligosaccharides. Their oxidation yielded the corresponding nitroxide radicals whose ESR. spectra gave information on the conformation about the ‘interglycosidic’ bridge. This type of compounds should constitute useful spin markers for biological studies.     

Nickel-catalyzed Asymmetric Alkylation of Some Chiral and Achiral Allylic Alcohols. Preliminary communication

[(?) (R)-1,2-bis (Diphenylphosphino)-1-phenylethane]nickel (II) chloride was found to catalyze the asymmetric alkylation of some chiral and achiral allylic alcohols with Grignard reagents, leading to the formation of optically active olefins. Enantiomer discrimination of the substrate takes place in the alkylation of chiral allylic alcohols.     

Phenylselenoacetaldehyde,a Useful Reagent for the Homologative Conversion of Halides to Phenylselenomethyl Ketones

The conversion of primary, secondary and vinylic halides to the two C-atoms homologated phenylselenomethyl ketones 8 is described. The method involves addition of the readily available phenylselenoacetaldehyde 5 to the Grignard reagents 9 and oxidation of the resulting β-hydroxy-selenides 10 (Scheme 3).