Transition Metal Free sp³-sp³ carbon-carbon coupling between Benzylboronic Esters and Alkyl Bromides

Abstract

A transition metal free coupling reaction of benzylboronic esters and alkyl halides has been developed. Both alkyl bromides and alkyl iodides were found to be competent substrates with the nucleophilic boronate intermediate generated from the combination of benzylboronic ester and an alkyllithium. Good chemoselectivity was observed in substrates with a second electrophile. Both secondary and tertiary benzylboronic esters were effective nucleophiles in the reaction with primary alkyl halides. Mechanistic observations are consistent with a radical mechanism.

Graphical Abstract

An sp³-sp³ transition metal free coupling between benzylic boronic esters and alkyl halides has been developed. The boronate nucleophile reacts selectively with alkyl bromides in the presence of alkyl chlorides and epoxides. The boronate can be attached to a primary, secondary and tertiary carbon center.

Introduction

Alkylboron compounds have proven to be effective nucleophiles in a myriad of transition metal catalyzed carbon-carbon bond forming reactions.^1-8 Alkylboronic esters are air and moisture stable, making them attractive compounds to develop new carbon-carbon bond forming methods. Additionally, enantioenriched alkylboronic acid derivatives have been used extensively in enantiospecific transition metal-catalyzed reactions.¹ Our laboratory has been pursuing Lewis base activation of alkylboronic esters to create alkylboronate nucleophiles. This approach is attractive in that it does not require the use of a transition metal eliminating the often toxic metal byproducts. We have demonstrated our dialkylboronate nucleophile reacts with aldehydes, aldimines and ketones.^9-11

There was an interest in expanding electrophiles compatible with our dialkylboronate intermediate in order to make sp³-sp³ carbon-carbon bonds. Alkyl halides were chosen as electrophiles to pursue this type of bond formation. Previous work in this area include numerous examples of transition metal-catalyzed reactions using alkylboron nucleophiles including several enantioconvergent strategies using a chiral metal catalyst.^12-23 Additionally, Schomaker and coworkers have developed a transition metal free method of creating stabilized secondary benzyl carbanions by addition of an alkoxide base to benzylboronic esters that react with heteroallene electrophiles and alkyl halides.²⁴ Examples provided feature extended conjugation or electron withdrawing groups attached to the aromatic ring that stabilize the carbanion intermediate. Formation of a benzylic anion intermediate precluded a sterespecific reaction between an enantioenriched benzylboronic ester and an electrophile. We sought to develop a complementary benzylic sp³-sp³ coupling with alkyl halides. This reaction would be a transition metal free sp³-sp³ cross-coupling reaction and allows for examination of the viability of an enantiospecific transformation using a chiral enantioenriched nucleophile.¹

Results and Discussion

This investigation began by activation of benzylboronic acid pinacol ester with sec-butyllithium to form a boronate intermediate which was then reacted with various alkyl halides. As seen in Table 1, alkyl bromides and alkyl iodides were competent substrates (entries 1 and 2) whereas alkyl chlorides (entry 3) and alkyl tosylates (entry 4) showed little to no reactivity. Generating two equivalents of active dialkylboronate nucleophile provided the best conversion of starting material with remaining 1-bromoheptane observed when using less active nucleophile (entry 5).

Table 1:

Optimization Studies

entry	electrophile	change from standard conditions	yield %a
1	1-bromoheptane	none	100
2	1-iodoheptane	none	85
3	1-chloroheptane	none	3
4	phenylethyl tosylate	none	0
5	1-bromoheptane	1.6 equiv BnBpin, 1.4 equiv s-BuLi	75

^aYields determined by NMR using an internal standard.

The substrate scope of this reaction was examined next. A variety of primary alkyl bromides were examined in this reaction, providing the desired product in good yields. Entries 3-5 provide examples of an indole, a protected alcohol and and an aryl bromide incorporated into the alkyl bromide substrates, introducing more complex substrates with similar yields. For compound 6, cinnamyl chloride was used as the substrate, which provided excellent regioselectivity of the conjugated product. Two examples of secondary bromides yielded products 7 and 8 in respectable yields. For secondary bromides, it was observed that the substrate needed to be activated with a conjugated pi bond for an efficient reaction to occur.

Next, the chemoselectivity of this reaction was established. Given the selectivity in the reaction between an alkyl bromide and alkyl chloride substrate during optimization, we examined 1-bromo-5-chloropentane as a substrate in the reaction and saw excellent chemoselectivity for coupling with the bromide, providing the product in 87% yield (Scheme 1). We also examined an epoxyalkyl bromide substrate and obtained an acceptable yield of the coupled product 10. Both reactions favored substitution at the alkyl bromide with no evidence of reaction with the alkyl chloride or epoxide observed.

Scheme 1:

Chemoselectivity with Dielectrophiles

Use of secondary and tertiary benzylboronic esters was also examined (Scheme 2). The secondary substrate when reacted with 1-bromopentane provided product 11 in an 84% yield. The tertiary substrate reacted with 1-bromoheptane in a 91% yield of product 12. Previously, tertiary nucleophiles had not been examined in our reaction development of nucleophilic benzyl additions to aldehydes, imines, and ketones.^9-11 The excellent yield obtained for product 12 makes this reaction an attractive method for forming bonds between a fully substituted benzylic nucleophile and primary electrophile.

Scheme 2:

Secondary and Tertiary Nucleophiles

There are two possible mechanisms for this reaction, a S_N2 type mechanism with inversion at the carbon-boron center or a free radical mechanism.²⁵ Enantioenriched secondary boronic ester was prepared and subjected to the reaction conditions to determine if the reaction was enantiospecific with respect to the nucleophile and also to provide insight into the mechanism of this transformation (Scheme 3). The yield of the reaction was consistent with the previous result in Scheme 2, but the isolated product was found to be racemic. This result suggests the boronate is going through a radical benzyl intermediate before adding to the alkyl bromide. Results from Table 1, including the lack of reactivity with the alkyl chloride and alkyl tosylate are also consistent with a radical mechanism. Similarly, the successful reactivity with the tertiary boronate in Scheme 2 is most consistent with a radical mechanism.

Scheme 3:

Mechanistic Studies

Summary

In conclusion, a sp³-sp³ carbon-carbon bond forming reaction has been developed between an activated benzylboronic ester nucleophiles and electrophilic alkyl bromides. A variety of functional groups were tolerated in this reaction, that showed good chemoselectivity towards alkyl bromide in the presence of other electrophiles including alkyl chlorides and epoxides. Secondary and tertiary boronic esters reacted with alkyl bromides in good yields. A mechanistic study using an enantioenriched nucleophile suggest the reaction proceeds through a radical mechanism.

Experimental Section

General procedure for benzyl addition to alkyl halides:

A round-bottom flask was charged with a magnetic stir bar, flame dried under vacuum, covered with a new septum, and sealed with Parafilm. The flask was cooled to room temperature while remaining under vacuum and was purged with argon. Under argon, to a solution of 5 mL of THF and benzylboronic acid pinacol ester (256 μL, 1.15 mmol) was added. The flask was cooled to −78 °C and sec-butyllithium (1.2 M, 1.0 mmol) was put into the solution. Next, alkyl halide (0.5 mmol) was added to the round-bottom flask. The reaction was removed from the ice bath after an additional 15 minutes of stirring, allowed to warm to room temperature and stirred for 3 more hours. The reaction was quenched with 0.3 mL of ammonium chloride. The organic layer was concentrated by rotary evaporation under reduced pressure and purified by column chromatography.

Table 2:

Substrate Scope

^aThe alkyl chloride was the substrate.