Reactions of Benzylboronate Nucleophiles

Abstract

This short review summarizes our laboratory’s development of benzylboronic esters as nucleophiles. Activation of the benzylboronic ester is achieved by irreversible coordination of an alkyllithium Lewis base to form a nucleophilic benzylboronate. This boronate was found to react with aldehydes, imines, ketones and alkyl bromides. A copper catalyst was employed in reactions of the boronate with epoxides and aziridines.

Graphical Abstract

1. Introduction

Organoboranes have found great utility in organic synthesis.^1-3 Transition metal cross-coupling reactions with arylboronic acids and esters have been used extensively in natural product synthesis and drug discovery.¹ Allylboron reagents have similarly played an important role in the allylation of carbonyl and imine electrophiles with and without transition metal catalysts.⁴ More recently, reactions with other alkylboron reagents have been developed, and this area has been a field of great interest to the synthetic community.^3,5-6 This short review details our laboratory’s examination of reactions using benzylboronic acid pinacol ester and secondary and tertiary benzylboronic esters as nucleophiles.

Benzylboronic esters are not as commonly used as arylboronic acids and not as reactive as allylboron reagents. Benzylboronic acid pinacol ester (BnBpin) has been synthesized from the corresponding Grignard reagent and in transition metal-catalyzed reactions and is commercially available.^7,8 There have been reports of the use of secondary and tertiary benzylic boronic esters for stereospecific transformations, leading to the synthesis of tertiary alcohols, amines, and other compounds (Scheme 1).^5,9

Scheme 1.

Stereospecific transformation of secondary benzylboronates^{9b, 5c}

Prior to our work, primary benzylboronic esters had been examined less with reported reactions limited to Pd- and Cu-catalyzed cross-couplings and oxidations to the corresponding alcohol, iodide and amine compounds.^10,9b The primary BnBpin has been shown to be less reactive than substituted benzylboronic esters.¹¹ Our research group sought to activate BnBpin by using a Lewis base to generate a boronate, making it a more reactive nucleophile (Equation 1). It was anticipated that a transition metal catalyst would not be required for reactions of these preformed boronates to react with electrophiles, making these reactions attractive methods for C-C bond formation.

Equation 1 Lewis Base Activation of BnBpin

2. 1,2-Additions

Initially, aldehydes were examined as electrophiles.¹² Use of common activating Lewis bases such as metal alkoxides did not afford any desired product using benzylboronic acid pinacol ester (BnBpin) in a reaction with benzaldehyde. The Lewis base activator was then switched to alkyllithium reagents in order to irreversibly form the desired benzylboronate nucleophile.^5,13-14 s-Butyllithium and n-butyllithium were found to be an effective Lewis bases for this transformation with much lower yields being observed with phenyllithium, methyllithium and methylmagnesium bromide as the Lewis base activator. A variety of aldehydes were shown to react under these conditions (Scheme 2). Aromatic aldehydes with electron-donating and electron-withdrawing substituents were found to be good substrates for this reaction. Examples of heteroaromatic aldehydes also provided good yields of the corresponding alcohol products 7 and 8.

Scheme 2.

Reactions with Aldehydes

¹¹B NMR experiments performed were consistent with the formation of a bisalkylboronate intermediate that directly reacted with benzaldehyde (Scheme 3). Addition of s-BuLi to BnBpin was found to result in a shift in the ¹¹B NMR from 33 ppm to 8 ppm. Introduction of benzaldehyde at −78 °C, resulted in the appearance of a new ¹¹B NMR shift at 34.5 ppm, consistent with the formation of s-BuBpin.¹⁵

Scheme 3.

Following Reaction of BnBpin with Benzaldehyde by ¹¹B NMR Spectroscopy

The conditions were examined with branched benzylboronic ester reagents as well. Use of a secondary branched boronate nucleophile afforded the desired product 10 in a 79% yield as a 1:1 mixture of diastereomers (Scheme 4). The sterically hindered tertiary benzylboronate nucleophile also reacted with benzaldehyde providing alcohol 11 in a 69% yield.¹⁶

Scheme 4.

Reactions of Branched Boronates with Aldehydes

Imines were the next class of electrophiles that were examined with the Lewis base-activated boronate.¹⁷ Previous examples of alkylboron additions to imines include a Rh-catalyzed addition of secondary benzylic trifluoroborates and photochemical induced additions of alkyltrifluoroborates.^18,19 Both N-tosyl imines and N-tert-butanesulfinyl imines were found to react with the activated boronate in good yields (Scheme 5). Electron-donating groups and electron-withdrawing groups were tolerated on the imines with both protecting groups. Attempts to use BnBF₃K instead of BnBpin did not provide any desired product. Reactions with the N-tert-butanesulfinyl imines gave the corresponding amine products in diastereoselectivity similar to that previously observed with benzylzinc additions to N-tert-butanesulfinyl imines.²⁰ Previously reported data of the products helped establish the absolute configuration of the products.²⁰ The reaction is believed to proceed through an open transition state due to the observed stereochemistry of the products, consistent with the proposed tetracoordinate boronate nucleophile (Scheme 6).

Scheme 5.

Reactions with Imines

Scheme 6.

Proposed Open Transition State in Addition to N-tert-butanesulfinyl imines

It was also found that secondary benzylboronic ester reagents could react with imines in modest yield (Scheme 7). A 2:1 mixture of diastereomers was observed in the amine product 21. A similar diastereomeric mixture was reported in the previously mentioned Rh-catalyzed addition of secondary benzyltrifluoroborate salts; however, the major diastereomer was different due to the reactions going through open vs closed transition states.¹⁸

Scheme 7.

Comparison of Reactions using Branched Boron Nucleophiles with an N-Tosyl Imine^17,18

Further studies employed activated ketones as electrophiles.²¹ 1,4-Diazabicyclo[2.2.2]octane (DABCO) was found to be a beneficial additive that increased the rate of reaction and yield of the alcohol products (Scheme 8). It was hypothesized that DABCO coordinates the Li counterions, creating a more reactive dialkylboronate.²² Trifluoromethyl ketones and other activated ketones were found to be good substrates in the reaction. Specifically, substrates containing esters and amides α to the ketone were found to be compatible under these reaction conditions with no reaction being observed at the ester or amide carbonyl carbon (25 and 26). A reaction with acetophenone provided the alcohol product 27 in a lower yield than the activated ketones.

Scheme 8.

Reactions with Ketones

Two competition experiments were conducted to study the relative electrophilicity of carbonyl compounds including those compounds with α-fluorine substituents (Scheme 9). The first experiment revealed that 2,2,2-trifluoroacetophenone was more reactive than benzaldehyde with an observed 68:32 ratio of tertiary alcohol 22 to secondary alcohol 1. In a second experiment it was concluded that 2,2,2-trifluoromethylacetophenone was less reactive than 2,2-difluoroacetophenone with a 37:63 ratio of alcohol products 22 and 28 obtained. The relative reactivity order was found to be CHF₂ ketone > CF₃ ketone > aldehyde under these conditions, with electronic activation being the controlling factor in the competition between the CF₃ ketone and aldehyde. There are two possible factors that could be considered for the observed difference in reactivity between the CF₃ and CHF₂ ketone: steric considerations or avoidance of dipole repulsions in the transition state. In a previously disclosed Rh-catalyzed arylation reaction of carbonyls with arylboronic acids, competition experiments revealed a relative reactivity order of aldehyde > CHF₂ ketone > CF₃ ketone.²³ Steric differences were proposed to account for the relative reactivity trend in the Rh-catalyzed system. Mechanistic differences can help rationalize the reactivity differences in the two systems. The Rh-catalyzed reaction has a proposed closed transition state with precoordination of the Rh to the carbonyl, making that reaction more sensitive to steric considerations. The benzylboronate addition proceeds through an open transition state, making it less sensitive to steric considerations.

Scheme 9.

Competition Experiments

3. Additions to sp³ Electrophiles

With initial success in these nucleophilic addition reactions to carbonyls and imines, the expansion to alkyl halides as electrophiles provided the opportunity to examine reactions at sp³ electrophilic centers.²⁴ Previously, transition metal catalysts had been used to cross-couple alkylboron reagents with alkyl halide electrophiles in enantioconvergent reactions.²⁵ There are also several examples of Pd-catalyzed stereospecific cross-couplings with sp² electrophiles.²⁶ Alkoxide-promoted reactions between secondary and tertiary benzylic boronic esters with alkyl halides have been reported that proceed through stabilized benzylic carbanion intermediates.²⁷ Benzylboronic acid pinacol ester activation with sec-butyllithium was followed by reaction with various alkyl electrophiles. Alkyl bromides and alkyl iodides were found to be effective substrates, while reactions with alkyl chlorides and alkyl tosylates did not provide the desired product. In the reaction with an alkyl tosylate electrophile, the unprotected alcohol was the only observed product, suggesting the benzylboronate was reacting at the electrophilic sulfur of the tosylate rather than at the carbon of the polarized C-O bond. The reaction conditions tolerated the presence of the triisopropylsilyl-protected (TIPS) alcohol in product 32 (Scheme 10). It was found that less bulky silyl protecting groups such as the tert-butyldimethylsilyl were not stable under the reaction conditions. The reaction was effective with activated secondary bromides to yield products 31 and 33 in good yield. Reactions with unactivated secondary bromides such as 2-bromopropane and bromocyclohexane were less effective.

Scheme 10.

Reactions with Alkyl Bromides

To highlight the chemoselectivity present in this reaction, 1-bromo-5-chloropentane and an epoxyalkyl bromide were examined under the reaction conditions (Scheme 11). In both cases, the reaction was selective for the bromide, providing the resulting products 35 and 36 in good yield with no evidence of the reaction of the alkyl chloride or addition to the epoxide being observed.

Scheme 11.

Chemoselectivity of Reactions with Dielectrophiles

Additional experiments showed this reaction was effective with both secondary and tertiary benzyl boronate nucleophiles (Scheme 12). The secondary benzylboronate nucleophile provided a 84% yield of 37 in a reaction with 1-bromopentane. The tertiary benzylboronate provided a 91% yield of 38 when reacted with 1-bromoheptane.

Scheme 12.

Reactions of Secondary and Tertiary Benzylboronates with Alkyl Bromides

Examination of an enantioenriched secondary boronic ester would help distinguish if this reaction proceeds through a stereospecific inversion of configuration at the carbon-boron center or a free radical mechanism.^14a The reaction with an enantioenriched secondary boronic ester with 1-bromopentane provided a good yield, but product 37 was found to be racemic (Scheme 13).²⁸ An additional experiment using TEMPO as an additive revealed that TEMPO inhibited the reaction with the TEMPO benzyl adduct 39 also observed, suggesting radical intermediates were present under the reaction conditions.²⁹ These results suggest the boronate forms a radical benzyl intermediate before reacting with the alkyl bromide. The high yield and selectivity for the addition with the tertiary benzyl boronate would also support that a radical mechanism is operative.

Scheme 13.

Mechanistic Experiments

Epoxides were the next electrophile examined in reactions with dialkylboronates.³⁰ In dialkylboronate reactions with alkyl bromides, epoxides were found to be an unreactive, compatible functional group under the reaction conditions. Previously, Pd, Ni, and Cu catalysts have been used to couple arylboronic acids and epoxides.³¹ Cu had also been used to couple gem-diborylmethane (pinBCH₂Bpin) and epoxides.³² To promote a reaction between an epoxide and the benzylboronate nucleophile, a copper catalyst was required. It was found that CuI was an effective catalyst for this reaction and good yields of the alcohol products were observed as seen in representative examples in Scheme 14.^32,33 The reaction tolerated various substitution on the epoxide with regioselective addition to the less substituted side of the epoxide being observed. 1,1-Disubstituted and 1,2-disubstituted epoxides were capable substrates, yielding alcohol products 42 and 46. As seen in reactions with the alkyl bromides, a TIPS-protected alcohol was well tolerated as seen in product 45 while less bulky silyl protecting groups such as the tert-butyldimethylsilyl were unstable under the reaction conditions. Use of other alkylboronic esters such as cyclopropylBpin and hexylBpin under the standard reaction conditions yielded no desired product.

Scheme 14.

Reactions with Epoxides

The stereospecificity of the Cu-catalyzed reactions was examined with both respect to the epoxide and the benzylboronic ester (Scheme 15). When using enantioenriched (S)-propylene oxide, the desired product 47 was obtained as a single enantiomer as determined by Mosher ester analysis, so the reaction is stereospecific with respect to the epoxide.³⁴ The reaction with enantioenriched alpha-methylbenzylboronic acid pinacol ester resulted in a 56:44 diastereomeric mixture of alcohol products 48, the same diastereomeric mixture as was observed using racemic alkylboronic ester. The conclusion of these results is that the reaction is not stereospecific with respect to the boronate under these reaction conditions as was previously observed in a reaction with an alkyl bromide. These results are consistent with a single electron transfer (SET) alkyl transfer between the boronate and Cu catalyst, resulting in racemization of the stereocenter.⁵ A reasonable mechanism would include homolytic cleavage of the boronate to generate a racemic benzylic radical. The addition of two of these radicals to CuI could form an active dibenzylcuprate nucleophile that reacts with the epoxide.

Scheme 15.

Stereospecificity of Reactions with Epoxides

The last class of electrophile examined with benzylboronic ester nucleophiles was aziridines.³⁵ The N-tosyl-protected aziridines were easily accessed either through the use of chloramine-T and phenyltrimethylammonium tribromide with the corresponding alkene or the reaction of excess tosyl chloride with the 1,2-aminoalcohols.^36,37 Upon optimization it was found that reactions with aziridines required the use of a Lewis acid catalyst. After examining numerous metal triflates and Cu salts as catalysts, CuBr₂ was found to be the most effective catalyst.³⁸

Examination of the substrate scope was performed on a series of aziridines providing varying yields of the amine product (Scheme 16). Monosubstituted aziridines were the best substrates in this reaction. An example of a 1,1-disubstituted aziridine gave a comparable yield of amine 54, but when examining the 1,2-substituted aziridine prepared from cyclohexene, the yield of the product 56 was only 29%. Substrates with an aryl chloride (54) and a TIPS-protected alcohol (55) demonstrate some of the functional groups compatible with these reaction conditions.

Scheme 16.

Reactions with Aziridines

Of interesting note was the reaction of the styryl aziridine that provided a 55:45 mixture of regioisomers 53 with the major isomer coming from addition to the more substituted side of the aziridine. This result is in contrast to the regioselectivity in a reaction with styrene epoxide where an 80:20 mixture of regioisomers 40 was observed, with the addition to the less substituted side of the epoxide as the major product. The role of CuBr₂ in the mechanism is not fully understood at this time. Cu(II) can be reduced to Cu(I) to create dibenzylcuprate nucleophiles proposed to be the active nucleophile in the Cu(I)-catalyzed benzyl addition to epoxides. Additionally, it is hypothesized that some of the CuBr₂ catalyst could remain as Cu(II) and function as a Lewis acid in these reactions. In the context of the reaction with styryl aziridine, a Lewis acid coordinating to the N-tosyl group would make the benzylic carbon of the aziridine more electrophilic, consistent with the nominal regioselectivity observed. With the 1,1-disubstituted stryl aziridine as a substrate, addition to the less substituted side of the aziridine resulted in the major regioisomer 54 along with a small amount of the regioisomer that was the result of addition to the more substituted side of the aziridine.

An example was also shown with allylboronic acid pinacol ester as the nucleophilic boronate formed upon complexation with sec-butyllithium, resulting in formation of the amine product 57 in 76% yield (Equation 2). In the case with aldehydes, imines and ketones, allylation with allylboron reagents are well established.⁴ More recently, the stereospecific allylation reactions with a wide range of electrophiles has been demonstrated that proceed through an allylarylboronate intermediate.³⁹ There are no previously reported allylations of aziridine with allylboronic esters to the best of our knowledge.

Equation 2 Reaction of Allylboronate with an Aziridine

4. Conclusion and Outlook

In summary, we have performed a comprehensive study of the reactivity of benzylboronic ester nucleophiles after activation with s-butyllithium. A wide variety of electrophiles have been found to participate in reactions with this class of nucleophiles with only epoxides and aziridines requiring a transition metal catalyst. Mechanistic experiments are consistent with the formation of benzylic radical intermediates through a SET mechanism precluded a stereospecific C-C bond-forming reaction using an enantioenriched benylboronic ester under the reaction conditions described in this review. Under our conditions, the expansion of this Lewis base activation methodology to other non-benzylic and non-allylic alkylboronic esters remained elusive; however, a recently published report found success using t-butyllithium activation of the alkylboronic ester in the presence of a copper catalyst promotes a stereospecific cross-coupling of non-benzylic primary and secondary alkylboronic esters with a number of electrophile classes.⁴⁰ The combination of the steric bulk and electron-rich nature of the t-butyl activated boronate are thought to be key to the success of this type of Lewis base activation and provide valuable insight for the potential development of additional stereospecific cross-coupling reactions of secondary alkylboronates.