The reaction of ketones with an excess of (CH,),TiCI, (6) leads to the replacement of the carbonyl oxygen atom by two methyl groups. This mild method of direct geminal dimethylation involves Grignard-type addition followed by formation of tertiary carbocations which are captured by methyltitanium species. Additional functional groups such as primary alkyl chlorides, thioethers, aromatics, ethers, and esters are tolerated, but not thioketals. The procedure has been applied to the synthesis of ( f )-cuparene (44). Similarly, carboxylic acid chlorides are converted to fert-butyl derivatives. The geminal dimethyl structural unit occurs frequently in terpenes, steroids and compounds of theoretical interest. Compounds containing these and other types of quarternary carbon atoms are generally prepared via multistep syntheses using a variety of techniques l). An attractive strategy calls for geminal dimethylation of ketones, i. e., the position specific replacement of the carbonyl oxygen by two methyl groups. This can be accomplished by a three step sequence 1 + 2 + 3 -+ 4 involving Wittig olefination, Simmons-Smith cyclopropanation and hydrogenolysisz). Although this sequence has been applied successfully in several instances z), we sought a direct method. Previously, it had been shown that certain ketones are geminal dimethylated by a 3 -4 fold excess of AI(CH,), in a closed vessel at 120 -180°C3). Direkte geminale Dimethylierung von

The conversion of classical carbanions such as RMgX, RLi, or deprotonated nitriles, sulfones, and carboxylic esters into titanium analogs results in reagents which add chemoselectively to carbonyl compounds in the presence of other functional groups. The standard titanating agent is chlorotriisopropoxytitanium (1). Grignard-type reactions and aldol additions are aldehydeselective in the presence of ketones. Other functional groups such as alkyl and aryl halides, esters, amides as well as nitro and cyano moieties are tolerated. Discrimination between two aldehydes or two ketones is also possible. Replacing alkoxy ligands by methyl groups at titanium increases reactivity dramatically, relative rates increasing in the series CH,Ti(OCHMe2), < (CH,),Ti-(OCHMe2), < (CH3),Ti. The latter reagent and its zirconium analog methylate sterically hindered and/or enolizable ketones which normally fail to undergo Grignard reactions. The ate complex H,C = CHCH,Ti(OCHMe$,MgCI (63) is aldehyde-selective, while the amino analog H,C = CHCH2Ti(NMe2)4MgC1 (64) adds selectively to ketones in the presence of aldehydes.Chemoselektive Addition von Organotitan-Agenzien an Carbonyl-Verbindungen Die Uberfuhrung von klassischen Carbanionen wie RMgX, RLi oder deprotonierten Nitrilen, Sulfonen oder Carbonsaureestern in Titan-Analoga ergibt Agenzien, die in Gegenwart von anderen funktionellen Gruppen chemoselektiv an Carbonylverbindungen addieren. Das StandardTitanierungsagens ist Chlortriisopropoxytitan (1). Grignard-artige Reaktionen sowie Aldoladditionen sind aldehyd-selektiv in Gegenwart von Ketonen. Andere funktionelle Gruppen wie Alkylund Arylhalogenide, Ester, Amide sowie Nitro-und Cyanreste werden toleriert. Die Unterscheidung zwischen zwei Aldehyden oder zwei Ketonen ist ebenfalls moglich. Der Ersatz von Alkoxyliganden durch Methylgruppen hat eine drastische Erhdhung der Reaktivitat zur Folge, d. h. die relativen Geschwindigkeiten nehmen in folgender Serie zu: CH,Ti(OCHMe,), < (CH3),Ti-(OCHMe2), < (CH,),Ti. Das letztere Agens sowie das Zirkon-Analogon methylieren sterisch gehinderte und/oder enolisierbare Ketone, die normalerweise keine Grignard-Reak tionen eingehen. Der At-Komplex H2C = CHCH2Ti(OCHMez),MgC1 (63) ist aldehyd-selektiv, wahrend die entsprechende Aminoverbindung H,C = CHCH2Ti(NMe2),MgC1 (64) selektiv mit Ketonen in Gegenwart von Aldehyden reagiert.Although carbanions play an important role in synthetic organic chemistry, lack of chemo-and stereoselectivity is frequently observed'). For example, phenylmagnesium bromide hardly discriminates between aldehydes and ketones2). Similar lack of chemoselectivity has been observed for other Grignard reagents and their lithium counterparts3) as well as for such resonance stabilized species as lithium ester enolates4), 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1985

Titanation of alkyllithium or -magnesium compounds using CITi(OR), results in reagents which show markedly increased diastereofacial selectivity (80 -90%) in reactions with a-chiral aldehydes or ketones. Titanation is also the method of choice in Grignard-type additions to substituted cyclohexanones; CH3Ti(OCHMe2)3 (6a) adds predominantly from the equatorial direction, while allyltitanium reagents 11 b and 12 show axial preference. Crotyltitanium compounds react with carbonyl compounds to afford primarily adducts having anti-configuration, a process which is of particular value in case of k e p e s (anfi/syn ratios up to 99: 1). Titanation of (trimethylsi1yl)allyllithium (48) with Ti(OCHMe2), reverses regioselectivity in reactions with aldehydes and ketones, P-hydroxy silanes 50 being the only observed products. These have anticonfiguration and can be converted either into Z-or E-dienes using the Peterson elimination under basic or acidic conditions, respectively.Stereoselektive Addition von Organotitan-Agenzien an Carbonyl-Verbindungen Titanierung von Alkyllithium-oder -magnesium-Verbindungen mittels ClTi(OR), ergibt Reagenzien, die eine deutlich erhohte Diastereoselektivitat (80 -90%) bei Reaktionen mit a-chiralen Aldehyden oder Ketonen zeigen. Titanierung ist auch die Methode der Wahl im Falle von Grignardartigen Additionen an substituierte Cyclohexanone; CH,Ti(OCHMe,), (6 a) greift bevorzugt von der aquatorialen Seite an, wahrend die Allyltitan-Reagenzien 11 b und 12 hauptsachlich axialen Angriff eingehen. Crotyltitan-Agenzien reagieren mit Carbonyl-Verbindungen unter bevorzugter Bildung von Addukten mit der anti-Konfiguration, eine besonders wertvolle Reaktion im Falle von Ketonen (anti/syn-Verhaltnisse bis zu 99 : 1). Titanierung von (Trimethylsily1)allyllithium (48) mit Ti(OCHMe& kehrt die Regioselektivitat bei Additionen an Aldehyde und Ketone um, denn die einzigen Produkte sind f3-Hydroxysilane 50. Sie haben die anti-Konfiguration und konnen mit Hilfe der Peterson-Eliminierung unter basischen bzw. sauren Bedingungen in Z-oder E-Diene iibergefiihrt werden.In the preceding paper') we showed that titanation of carbanions provides a simple means to increase chemoselectivity in reactions with carbonyl corn pound^^.^). T h e present communication deals with the control of stereoselectivity2). In particular, three types of diastereodifferentiation are considered: 1) Diastereofacial selectivity involving a-chiral carbonyl compounds (1,t-asymmetric induction

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We describe here their use for the geminal dialkylation of ketones. Reaction of tert-alkyl chlorides (21, which are readily accessible from the ketones (I), with methyltitanium trichloride (3) or dimethyltitanium dichloride (4) at -30°C to room temperature leads to replacement of chlorine by the methyl group with formation of the desired product (5) containing a quaternary C-atom.