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)- crotyldiisopino campheylboranes can be prepared at low temperature from (Z)- or (E)- crotylpotassium and B-methoxydiisopinocampheyl borane, respectively, after

treatment of the resultant ate-complexes with BF3•OEt2.

•The B-methoxydiisopinocampheylboranes are prepared by reacting (–)-diisopinocampheylborane, derived from (+)-α- pinene, or (+)-diisopinocampheylborane, derived from (–)-α- pinene, with methanol. Reaction of Organoborons ™Brown’s Asymmetric Crotylboration Reaction of Organoborons ™Brown’s Asymmetric Crotylboration • reaction of the (Z)-crotyldiisopinocampheylborane derived from (+)- α-pinene with aldehydes at –78 °C, followed by oxidative workup, furnishes the corresponding syn-β-methylhomoallyl alcohols.

•Use of (Z)-crotyldiisopinocampheylborane derived from (–)-α-pinene also produces syn-alcohols with 99% diastereoselectivity but with opposite enantioselectivity, an example of reagent control. Reaction of Organoborons ™Brown’s Asymmetric Crotylboration •(E)-crotyldiisopinocampheylborane, from (+)-α-pinene, + aldehyde gives anti-alcohol (95% enantioselectivity). •(E)-crotyldiisopinocampheylborane, from (–)-α-pinene, with aldehydes yields the enantiomeric anti-alcohols, also with 95% enantioselectivity. By this approach, using cis-and trans-2- butene and (+)-α-pinene and (–)-α-pinene, all four stereoisomeric homoallyl alcohols may be obtained. Additional References - organoboron

• Ramachandran, P. V.; Brown, H. C. “Organoboranes for syntheses Washington, D.C. : American Chemical Society, 2001. • Thomas, S. E. “Organic synthesis : the role of boron and silicon” Oxford: Oxford University Press, 1991. • Pelter, A.; Smith, K. “Borane reagents” London: Academic Press, 1988. • Smith, K. “Organometallic compounds of boron” New York: Chapman and Hall, 1985. •Mikhaĭlov, B. M.; Bubnov, U. N. “Organoboron compounds in organic synthesis” New York: Harwood Academic, 1984. • Brown, H. C. “Organic syntheses via boranes” New York: Wiley, 1975. • Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. • Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1989, 111, 1236.