OrganometallicOrganometallic Chemistry Chemistry Worawan Bhanthumnavin Department of Chemistry Chulalongkorn University Bangkok 10330, Thailand Given as part of the 6th semester organic chemistry course at the University of Regensburg (May 2008) Under the ASEM-DUO Thailand 2007 exchange program organoboron, organosilicon Organoboron compounds • Revise: what organoboron have you seen before? boranes Organoboron compounds • vast array of C-C-forming reactions involving organoborons • Here: focus on transfer reactions of C moieties from boron to an adjacent C. Examples: transfer of CO, CN, carbanions derived from dichloromethyl methyl ether and dichloromethane, and allyl groups in reactions of allylic boranes with aldehydes. Preparations Reaction of Organoborons Carbonylation • reaction of organoboranes with carbon monoxide [(–):C≡O:(+) ], which is an ylide, gives rise to 3 possible rearrangements. • Depending on reaction conditions, single, double, and triple migrations of groups may occur leading, after appropriate workup, to a variety of aldehydes and ketones as well as primary, secondary, and tertiary alcohols. Reaction of Organoborons Carbonylation Synthesis of Aldehydes and Primary Alcohols • Addition of CO to trialkylboranes leads to the formation of an ate-complex (structure A). Subsequent migration of an R group to the CO ligand yields intermediate B. In the presence of a mild reducing agent, such as lithium trimethoxyaluminum hydride or potassium triisopropoxyborohydride, B is converted to the mono-migration product C. Reaction of Organoborons Carbonylation Synthesis of Aldehydes and Primary Alcohols • Oxidation (H2O2) of C furnishes the corresponding aldehyde. On the other hand, treatment of C with LiAlH4 followed by oxidative workup produces the primary alcohol. Reaction of Organoborons Carbonylation Synthesis of Aldehydes and Primary Alcohols • To maximize utilization of valuable alkyl groups, alkenes used for the transfer reaction are hydroborated with 9-BBN. The resultant alkyl-9-BBN derivatives undergo selective migration of the alkyl group when treated with CO in the presence of a reducing agent. •Ex.applying this sequence to 2-methylcyclopentene produces trans-2-methylcyclopentane carboxaldehyde, with retention of configuration of the migrating group. Reaction of Organoborons Carbonylation Synthesis of Ketones • If the carbonylation reaction is done in the presence of a small amount of water at 100 °C, a second alkyl group migrates from B to the adjacent carbon to furnish, after oxidative workup, the corresponding ketone. Reaction of Organoborons Carbonylation Synthesis of Ketones • The use of thexylborane (1,1,2-trimethylpropylborane) as the hydroborating agent permits – (a) the synthesis of mixed trialkyboranes, and – (b) cyclic hydroboration of dienes. Reaction of Organoborons Carbonylation Synthesis of Ketones • When followed by carbonylation, these hydroboration- carbonylation sequences generate a variety of unsymmetrically substituted ketones and cyclic ketones, respectively. Since thexyl moiety exhibits low migratory aptitude in carbonylation, it serves as an anchor group. Reaction of Organoborons Carbonylation Synthesis of Ketones Reaction of Organoborons Carbonylation Synthesis of tertiary alcohol • Carbonylation of trialkylboranes in the presence of ethylene glycol results in migration of a second and a third alkyl group to give, after oxidation, the corresponding tert-alcohols. • Hydroboration of polyenes followed by carbonylation and oxidation provides access to carbocyclic systems. Reaction of Organoborons Cyanidation • A useful alternative to carbonylation route to ketones and trialkylmethanols from alkylboranes • nitrile anion [(–):C≡N:] is isoelectronic with CO and also reacts with R3B. However, the cyanoborate salts are thermally stable and therefore require an electrophile such as benzoyl chloride or trifluoroacetic anhydride (TFAA) to induce 1,2-migration. Reaction of Organoborons Cyanidation Reaction of Organoborons Cyanidation • formation of ketones and trialkylmethanols occurs under milder conditions than when using CO. thexyl group = anchor group in the preparation of ketones. • NaCN must be dry. • excess of TFAA results in a third migration, after oxidation, trialkylmethanols Reaction of Organoborons Dichloromethyl Methyl Ether Reaction • reaction of organoboranes with nucleophiles containing more than one leaving group results in multiple migrations. • Thus, on treatment of R3B with α,α-dichloromethyl methyl ether (DCME) in the presence of a sterically hindered base, such as Li-triethylmethoxide (LiOCEt3), all three groups are transferred, and oxidation of the product affords the corresponding tertiary alcohol. • LiCCl2OMe is generated in situ from dichloromethyl methyl ether with lithium triethylmethoxide. Reaction of Organoborons Matteson’s boronic ester homologation • Homologation of chiral alkylboronic esters with dichloromethyl lithium introduces a chiral center while forming a C-C bond • The required boronic esters are readily accessible from Grignard reagents and trimethylborate or from lithium reagents and triisopropylborate. Hydrolysis of resultant alkylboronic esters gives (r)- or (s)-pinanediols furnish the stable (r)- or (s)- pinanediol alkylboronic esters. Reaction of Organoborons Matteson’s boronic ester homologation • The chiral directing groups are pinanediols derived from osmium tetroxide-catalyzed oxidation of (+)-α-pinene or (–)-α- pinene with trimethylamine oxide or with NMO • The (s) and (r) notations shown in the abbreviations refer to the configuration of the chiral center in the α-chloroboronic ester using the appropriate pinanediol. Reaction of Organoborons Matteson’s boronic ester homologation ZnCl2 catalyzes the rearrangement (s)-pinanediol rearr. upon giving improved diastereoselection boronic ester rapid warming borate complex (1S)-1-chloroalkylboronic ester secondary borate complex sec-alkylboronic ester alcohol in (>97% ee) • important feature of the boron ester homologation: the boronic ester E can itself be used as a starting boronic ester so that the cycle can be repeated to introduce a second chiral center. Reaction of Organoborons • Retrosynthetic analysis of homoallylic alcohol Brown’s Asymmetric Crotylboration • β-methyl homoallylic alcohol moiety of both anti- and syn- configurations is a characteristic structural element of a number of macrolides and polyether antibiotics. Reaction of Organoborons Brown’s Asymmetric Crotylboration • Reactions of crotylmetal (2-butenylmetal) reagents with carbonyl substrates provide access to acyclic stereo- and enantioselective syntheses of β-methyl homoallylic alcohols. • The alkene moiety can be further elaborated into aldehydes by oxidative cleavage of the double bond, leading to aldol-type products. Reaction of Organoborons Brown’s Asymmetric Crotylboration • Crotyl organometallics undergo 1,3-shifts of the metal at rt. • For the stereocontrolled use of allylic organometallic reagents in synthesis, it is important that the stereoisomeric reagents not equilibrate under the reaction conditions and add to C=O regioselectively and irreversibly. • Of the various allylic organometallic reagents, allylboronic esters and allyldialkylboranes are especially suited for acyclic stereoselective syntheses of homoallylic alcohols. Reaction of Organoborons Brown’s Asymmetric Crotylboration • rate of interconversion of crotyl boron reagents varies with the nature of the R groups on boron: crotyldialkylborane > crotylalkylborinate > crotylboronate crotyl-BR2 crotyl- BR(OR) crotyl-B(OR)2 Reaction of Organoborons Brown’s Asymmetric Crotylboration • Crotylboronic esters (2-butenylboronates) undergo nearly quantitative additions to aldehydes. • prepared by reaction of crotyl potassium reagents derived from cis-or trans-2-butene with n-butyllithium and potassium tert-butoxide followed by addition of the trialkyl borates thermally stable and isolable at room temp Reaction of Organoborons Brown’s Asymmetric Crotylboration • reactions of crotylboronic esters with RCHO is regioselective, generating 2 new stereochemical relationships and potentially 4 possible stereoisomeric products. Thus, there are 2 stereochemical aspects: enantioselection (Re- vs. Si-face addition) and diastereoselection (syn vs. anti). Reaction of Organoborons Brown’s Asymmetric Crotylboration • transfer of allylic moieties from B to C=O carbon proceeds via rearrangement to form intermediate boronic esters C and D • reaction is highly diastereoselective. •(E)-crotylboronate reacts to give the anti-homoallylic alcohol •(Z)-crotylboronate reacts to afford the syn-homoallylic alcohol. • This behavior has been interpreted in terms of the Zimmerman-Traxler chair-type transition state model. • Because of the double bond geometry, coordination of the (E)- crotylboronic ester places the Me preferentially equatorial, whereas coordination of the (Z)-crotylboronic ester places the Me axial, as illustrated in the cyclohexane chair-form transition state conformations A and B, respectively. In both cases, the R moiety of the aldehyde must occupy a pseudoequatorial position to avoid steric repulsion by one of the OR substituents on boron. Reaction of Organoborons Brown’s Asymmetric Crotylboration • Zimmerman-Traxler transition state model. Reaction of Organoborons Brown’s Asymmetric Crotylboration • The use of enantiopure allylic boranes in reactions with achiral aldehydes results not only in high diastereoselection, but also in high enantioselection. • Pure (Z)- and (E)-