One disadvantage of using lithium triethylcarboxide (2.1) as the base in the reaction is that the protonated base (3-ethyl-3-pentanol) has to be separated from the desired product following work-up (which is often non-trivial as the products from the DCME-oxidation
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reaction are also tertiary alcohols). Therefore, it was decided to complete a few test reactions to check both that all was well with the reagents/procedures and to search for an alternative hindered base that might be easier to separate from the reaction products.
Two trialkylboranes were chosen for the small study – tricyclopentylborane and tri-n- octylborane, along with three hindered bases – lithium tetramethylpiperidide (LiTMP), lithium tert-butoxide and the regular base lithium triethylcarboxide (2.1).
Tricyclopentylborane and tri-n-octylborane were prepared by literature procedures4,5 by the reaction of the corresponding alkenes with borane·THF, while the bases were prepared by the addition of n-BuLi to TMP and 3-ethyl-3-pentanol (in the case of lithium tert-butoxide a solution in dry THF was purchased). The reaction of the trialkylboranes with
DCME/hindered base, followed by oxidation gave the corresponding tertiary alcohols, which were purified by column chromatography on neutral alumina (Scheme 2.4). The products of these reactions are known,6,7 but their structures were confirmed by full characterisation (E.S. 2.32a, 2.32b). Once a pure sample of the product was obtained, so that its GC response factor with respect to a hydrocarbon standard (tetradecane) could be determined, the reaction was followed by GC analysis thereafter.
Scheme 2.4 Synthesis and reaction of tricyclopentylborane under DCME conditions to give tricyclopentylmethanol (2.2)
Lithium triethylcarboxide (2.1) performed well in the DCME reaction of both
tricyclopentylborane and tri-n-octylborane, although the yields were lower than those for the same/closely related examples in the literature (97% by GC for tricyclopentylborane and 94% by GC for tri-n-butylborane2) (Table 2.1). It is probable that a portion of the lowering in yield compared to the literature is due to the fact that these reactions were completed on a 5 mmol scale, while those reported in the literature were completed on a 50 mmol scale. It is also possible that a lowering in the concentration of the borane.THF complex or n-BuLi used could account for some of this lowering in yield.
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LiTMP gave lower yields for both trialkylboranes relative to lithium triethylcarboxide, although the base could be separated from the product without the need for column chromatography by acidification of the aqueous phase during extraction. The use of two equivalents of LiTMP and DCME did improve matters for tri-n-octylborane, and so this stoichiometry was used for the subsequent reactions presented in Table 1. This increase in yield when a larger amount of LiTMP/DCME is used could be due to a number of factors -
e.g. the concentration of n-BuLi was lower than estimated or that the base is used up in a
process other than its role in the DCME reaction.
Lithium tert-butoxide gave slightly lower yields relative to lithium triethylcarboxide (even though two equivalents of both base and DCME were used), which is consistent with reactions reported in the literature.2
The importance of having a sterically hindered base was demonstrated by carrying out a reaction where lithium triethylcarboxide was added to tri-n-octylborane, followed by DCME. The yield of tri-n-octylmethanol (2.3) for this reaction dropped to 35% (as compared to 72%), indicating that even the highly hindered base triethylcarboxide (2.1) will complex to
trialkylboranes with detrimental results to the DCME reaction.
Table 2.1 DCME reaction of tricyclopentylborane and tri-n-octylborane with various hindered bases
Product Base/DCMEa
equivalents used
LiTMPb LitBuO LiOC(Et)3
tri-n-octylmethanol (2.3) 1.0 30% (isolated) - 72% by GC 2.0 66% (isolated) 59% by GC - tricyclopentylmethanol (2.2) 1.0 - - 72% by GC 2.0 48% by GC 57% by GC - a
α,α-Dichloromethyl methyl ether. b Lithium tetramethylpiperidide.
Two final reactions were carried out in an attempt to generate the DCME anion ex-situ before the addition of the trialkylborane. If successful, this would negate the need to use such
sterically hindered bases and perhaps make LiTMP or some other lithium amide the base of choice. However, both attempts (one at 0 ºC, and one at -78 ºC) failed to give any product
30
whatsoever, highlighting the unstable nature of the anion of DCME. The decision was therefore taken to use lithium triethylcarboxide (2.1) in all further DCME reactions.
2.22 Synthesis of a model chiral tertiary alcohol
To ascertain whether any future chiral DCME reactions work, a suitable model tertiary alcohol would need to be prepared from a mixed trialkylborane. Such mixed trialkylboranes are most easily synthesised by controlled sequential hydroborations of three different alkenes of decreasing steric bulk.
The controlled, sequential hydroboration of 2,3-dimethyl-2-butene, cyclopentene and 1- octene, followed by reaction with DCME/triethylcarboxide (100% excess) and finally
ethylene glycol followed by oxidation, gave the novel racemic tertiary alcohol cyclopentyl(n- octyl)(thexyl)methanol (2.4) in 57% GC yield. Compound 2.4 was fully characterised, with the data in accordance with the proposed structure (E.S. 2.32c)
The yield was a little lower than that reported for a closely-related example in the literature- (cyclopentyl)(n-pentyl)(thexyl)methanol (75% by GC).3 This result confirmed that the sequential hydroboration had been successful; however the lack of aromaticity in the
compound would make it a difficult compound to be observed by the HPLC UV detector. For this reason, the reaction was repeated, except 4-methoxystyrene was used in place of 1-octene to give the novel racemic tertiary alcohol cyclopentyl(2-(4-
methoxyphenyl)ethyl)(thexyl)methanol (2.5) in 55% GC yield (Scheme 2.5). Compound 2.5 was fully characterised, with the data in accordance with the proposed structure (E.S. 2.32d).
Scheme 2.5 Synthesis of cyclopentyl(2-(4-methoxyphenyl)ethyl)(thexyl)methanol (2.5) by the