Chapter 1: Oxygen-Directed Hydroboration 1.1 The Versatility of Organoboranes Organoboron species are among the most versatile functionalities in synthetic chemistry. Aliphatic and alkenyl boranes can be oxidized to alcohols and carbonyl groups, respectively.1 Aliphatic boranes can also be converted to amines2 and are well known for undergoing one-carbon homologation chemistry, allowing for installation of formyl groups, esters, and nitriles.3-5 Transition metal catalysis greatly expands the utiltity of organoboron chemistry. Palladium catalysis enables Suzuki cross-coupling reactions with both aryl/vinyl6 and alkyl7,8 coupling partners as well as with carbon monoxide,9,10 while rhodium catalyzes addition of vinyl boranes to aldehydes.11-13 Trifuoroborate salts are more robust than other organoboron species, as they resist oxidation upon exposure to air and even by dimethyldioxirane (DMDO), enabling Scheme 1A: The Synthetic Transformations of Organoborons OH O BX NHBn n R 1A1 B R R 1A8 C 1A2 l 3 , NaOOH O B D n M N D 3 H BX LiCCl OMe N ClCH2CN n 2 O R R 1A7 R 1A3 O 0 H 0 Pd , CO, 'C Pd , R 0 , ROH h X R R' CO R OH 2 R R 1A6 1A4 R 1A5 1 oxidation of olefins in the presence of boron.14 What makes all of these boron species even more attractive as synthetic intermediates is that they are all conveniently accessible by hydroboration. 1.2 The Limitation of Steric and Electronic Influence on Intermolecular Hydroboration Regioselectivity Hydroboration is crucial for the synthesis of organoboranes, and involves the syn-addition of a boron-hydrogen bond across a carbon-carbon multiple bond in a four- membered transition state such as 1B2b.15 Intermolecular hydroboration of simple olefins is controlled by the steric environment of the olefin in concert with its electronic properties to provide anti-Markovnikov selectivity. The steric component of regioselectivity reflects the smaller bulk of hydride compared to a BR2 moiety (R= alkyl or H). Therefore, a borane (HBR2) preferentially approaches an olefin with boron at the 2 less hindered carbon. Electronic effects supplement the steric preference. The dipole of a borane B-H bond provides the hydrogen with negative character and the boron with positive character. The four-membered transition state features the hydride of the borane forming a bond with the more substituted carbon, which favors having partial positive character relative to the less substituted carbon.16 (Scheme 1B). The combination of steric and electronic effects leads to excellent selectivity (19:1) with terminal olefins even when R=H. Good selectivity is also achieved with trisubstituted olefins (98:2) and 2,2-disubstituted olefins (99:1). However, achieving regioselective hydroboration of a 1,2-disubstituted olefin remains an unresolved issue in the hydroboration literature. The following chapter presents the reports in the literature that discuss the possibility of affecting regio- and stereoselectivity by directing hydroboration with oxygen-containing functionalities. 1.3 Mechanistic Proposals of Brown (Dissociative) and Pasto (Associative) It has been proposed that intermolecular hydroboration can occur via either a dissociative pathway or an associative pathway. The work of H. C. Brown et al. supports a mechanism requiring that an uncomplexed trivalent borane be generated via dissociation from either its dimer 1C1 or a Lewis-base complex 1C2, in order to react with an olefin (Scheme 1C).17-20 There are several kinetic studies that report the observation of first order (in dimer) and three-halves order (1/2 order in dimer) kinetics for reactions of 9-BBN dimer with fast reacting and slow reacting olefins, respectively.17-19 Another study using disiamylborane provides similar kinetic evidence that dialkylboranes participate in hydroborations via a dissociative pathway.20 3 Scheme 1C: Brown's Dissociation Pathway for Hydroboration17-20 R H R BR2 B B R H R 1C5 1C1 R H BR BR2 LB H B 2 R 1C3 1C4 1C5 H R BR2 B THF LB R 1C5 1C2 Compared to monoborane (BH3), dialkylboranes are much easier reagents with which to conduct kinetic studies. This is due to the fact that BH3 reacts with alkenes to form multiple alkylborane species RXBH(3-X), rendering kinetic data unclear. Despite this setback, Brown initiated Lewis base concentration studies involving dimethylsulfide- 21 borane (Me2S·BH3; BMS) and triethylamine-borane (Et3N·BH3). A qualitative rate reduction was observed upon increasing the concentration of excess Me2S and Et3N in the reactions of their corresponding borane complex with 1-octene. This led Brown to propose a dissociative mechanism for BH3, as a rate reduction under such conditions would not be expected if an associative mechanism were in effect. Pasto has published an alternative associative hydroboration mechanism, proposing that THF remains complexed to boron while an olefin complexes to the boron 22, 23 atom of THF·BH3 1D1 and undergoes hydroboration (Scheme 1D). This mechanism is supported by kinetic studies conducted with 2-methyl-2-butene and 1D1. In addition to the observation of second order kinetics, first order in both olefin and borane, Pasto also reports an entropy value of -27 ± 1 eu.22 The kinetic data support a mechanistic pathway in which 1D1 is directly attacked by an olefin and the entropy value indicates that this attack does not result in the displacement of THF. The mechanism has been supported by 4 several theoretical studies,24,25 including work by Schleyer, which supports ethylene 26 complexation to R2O·BH3 occurring in a SN2-like fashion. Scheme 1D: Pasto's Associative Mechanism for Hydroboration22,23 H H H H H H O B H O B O B O B H H H H 1D1 1D2 1D3 1D4 1.4 Defining Oxygen-Directed Hydroboration In order to discuss oxygen-directed hydroboration (ODHB), one must first establish what is meant by „directed reaction‟. Whenever the incorporation of an oxygen atom into a substrate affects the reactivity or selectivity of a transformation, one can argue that the change is due to some form of oxygen direction. This is regardless of whether the effect is due to the steric environment of oxygen or to an inductive or resonance polarization effect the oxygen might impose upon the substrate. For example, Brown refers to “directive effects in the hydroboration of substituted styrenes” in a study reporting the effects of a methoxy group on regioselectivity (Equation 1).27 Due to the planar structure of the fully conjugated system that separates oxygen from the alkene-borane complex in the transition state with five bonds, these 5 results are due to the electronic perturbation placed on the substrate by remote oxygen. “Directive Effects” is also the terminology used by Brown to describe the inductive effects that chloride and tosylate groups have on the regioselectivity of a proximal terminal alkene (Equation 2).28 For the purposes of providing a perspective on literature accounts of ODHB in the following chapter, the definition of a directed reaction to be used will be that of Hoveyda, Evans, and Fu:29 “Preassociation of the reacting partners either through hydrogen bonding, covalent, or Lewis acid-base union is followed by the maintenance of this interaction during the ensuing chemical transformation.” This is not to indicate that all reports of ODHB to be discussed share(d) the same definition, but to establish a point of reference for the discussion herein. 1.5 Oxygen Directed Hydroboration in the Literature 1.5i Ether Directed Hydroboration Narutis et al. have recognized contrasting results in hydroboration studies conducted by Gassman and Brown.30 Brown has reported that norbornene 1E5 provides >99:1 exo-selectivity upon hydroboration/oxidation, while increasing steric bulk at C-7 via incorporation of a methyl group syn to the alkene (1E6) leads to 22:78 exo:endo selectivity (Scheme 1E).31 However, Gassman has reported that 7,7-dimethoxy- norbornene 1E1 undergoes hydroboration with THF·BH3 to provide a 78:22 exo/endo mixture of alcohol 1E2 upon oxidative workup.32 This selectivity does not correspond with Brown‟s steric argument. Narutis attributes the contrast of the 7,7-dimethoxy- norbornene result to the formation of ether-borane complex 1E3 but a proposed mechanistic pathway is not specified.30 6 Methyl ethers have also been reported as affecting the regioselectivity of the hydroboration of E- and Z-methoxy-ene-ynes.33 Zweifel et al. have reported that treating Z-methoxy-ene-ynes 1F1 and 1F5 with dicyclohexylborane (chex2BH) in THF leads to preferential delivery of the boron to the alkyne carbon proximal to the methoxy group. On the other hand, treating the corresponding E-substrates 1F4 and 1F8 under the same conditions results in an increased preference for boron delivery to the distal alkyne carbon. The authors rationalize the change in regioselectivities by invoking a transition state 1F9, which illustrates the Z-methyl ether maintaining an interaction with chex2BH while the B-H bond is added across the carbon-carbon triple bond (Scheme 1F). It should be noted that the olefin geometry equilibrates to trans under the oxidation conditions, after the hydroboration events. 7 Scheme 1F: Anomalous Hydroboration Results on Methoxy Ene-Ynes H H H O MeO O MeO H 1.chex2BH OMe THF H H 2. NaOOH 1F1 1F2 1F3 96 : 4 H H O H 1.chex2BH MeO O MeO MeO THF H H H 2. NaOOH 1F4 1F2 1F3 65 : 35 H H H O H 1.chex BH MeO O MeO 2 Si OMe Si THF H H 2. NaOOH Si 1F5 1F6 1F7 56 : 44 H H H O MeO 1.chex2BH MeO O MeO Si H Si THF H 2. NaOOH Si H 1F8 1F6 1F7 1 : 99 H H MeO B R H R' R' 1F9 Results reported by Suzuki serve as evidence against ether complexation to a hindered dialkylborane in an intramolecular hydroboration.