Reactivity of alkyl aryl selenides towards butyllithiums: synthesis and alkylation of aryllithiums; a new synthetic route to aryl alkanes

This paper reports original results concerning the Se/Li exchange reaction involving the cleavage of the C-Se bond of aryl alkyl selenides by butyllithiums. This reaction is one of the methods available to produce functionalized organolithium compounds.


Introduction
Organolithium compounds, the "Gilman reagents", have found wide application in organic synthesis.1a-g They are easily accessible, possess a wide range of reactivity which at several occasions surpass that of their organomagnesium competitors, the "Grignard reagents". 2They are more reactive, possess a greater aptitude (i) to perform metallation reactions (hydrogen/lithium exchange) (ii) to add to unactivated C,C double bonds and (iii) to add 1,2 to enones.1h The two former reactions proved to be extremely valuable for the synthesis of other organolithiums which can be also produced by halogen/lithium-, metalloid/lithium-and metal/lithium exchange reactions.1a-g Organolithium compounds are also valuable precursors of high order cuprates and lithium amides.1a-g Their synthesis from organic halides is however usually far less efficient than that of related Grignard reagents due to the inherent reactivity of lithium and the high propensity of alkyllithiums to metallate ethers in which they are usually prepared.1a-g We report in this paper our detailed work on the synthesis of aryllithium compounds from related selenides which involve the selenium/lithium (Se/ Li)-exchange reaction.

Scheme 2
Although limited to the cases reported above, the selenium/lithium exchange offers the advantage 6 (i) to take place in an homogeneous solution, (ii) to proceed faster in THF than in ether 4 (iii) to be highly chemoselective even with benzaldehyde selenoacetals which were expected to be more prone for competing metallation reaction, (iv) to generate the organometallic whose carbanion is expected to be the most stabilized, (v) to produce concomitantly a novel selenide (usually butyl selenide) which is inert towards any of the organolithiums 6 used or generated in the process.In many cases reported above, the selenium/lithium exchange proved to be the only method available to produce organolithiums and in the case of allyl-and benzyllithiums the method of choice for their synthesis.

Results and Discussion
We report some specific examples which delineate the scope and limitation of the seleniumlithium exchange reaction between alkyllithiums and a series of alkyl phenyl selenides, producing dialkyl selenides and aryllithiums.We have particularly compared the reactivity of a series of alkyl phenyl selenides and alkyllithiums whose tetragonal carbon attached to the selenium or/and the lithium atom is increasingly substituted by alkyl groups.We have also compared the aptitude of alkyllithiums to cleave chemoselectively the C-Se bond of a series of butyl aryl selenides whose phenyl group is substituted by electron withdrawing or releasing groups.

Effect of the solvent
In our earlier work, we described that methyl phenyl selenide, reacts faster with n-butyllithium when the reaction is conducted in THF rather than in ether. 4We have now confirmed this tendency on performing the reaction on n-butyl phenyl selenide using sec-butyllithium instead of n-butyllithium (Scheme 3).

Scheme 3
For that purpose, we have systematically reacted at -78 °C and at -25 °C, the two partners and have quenched, after one hour, the medium with precooled methanol.
The reaction proceeds quite efficiently in one hour at -78 °C in THF but does not reach completion.It is however completely achieved if instead performed at -25 °C in the same solvent (Scheme 3, entry a).We have also observed an important difference of reactivity between THF and ether since butyl phenyl selenide does not react in the later solvent at -78°C and is only partially cleaved when the reaction is carried out -25 °C (Scheme 3, compare entries a and b).Finally, we have not been able to cleave the C-Se bond using pentane as the solvent (Scheme 3, compare entry c to entries a,b).

Role of the organolithium reagents
We have observed that sec-butyllithium is the most reactive organolithium among the series (n-BuLi, sec-BuLi, tert-BuLi), towards alkyl phenyl selenides.For that purpose we have performed on three alkyl phenyl selenides, possessing a side chain of increasing length (Me, n-Bu, n-Dec), competing experiments involving a ten fold excess of an equimolar mixture of n-BuLi, sec-BuLi, tert-BuLi.We obtained, after methanolysis, benzene arising from the protonation of the first formed phenyllithium and a series of butyl selenides resulting from the phenyl/butyl exchange.In all the cases, the n-butyl selenide was missing whereas s-butyl selenide largely predominates over the tertiary one (Scheme 4).This can be rationalized taking into account a subtle balance between steric and electronic effects on the carbanionic center.It is interesting to notice that the lowest chemoselectivity is observed with the selenide possessing the smallest alkyl substituent (Scheme 4, entry a, compare to entries b,c; relative selectivity : Me/Bu/Dec: 22/73/76).
We have also checked the intrinsic reactivity of methyllithium and each of the isomers of butyllithiums used separately towards n-butyl phenyl selenide used as a model.Those organolithiums possess an increasing alkyl substitution at their carbonic center (Scheme 5, compare entries a,d,g).
Methyllithium is inert towards n-butyl phenyl selenide even when the reaction is performed at room temperature for one hour.
The whole family of butyllithiums however cleaves the C-Se bond of n-butyl phenyl selenide at 0 °C.We have confirmed that sec-BuLi is the most reactive since it is the only one able to react reasonably efficiently in 1 h at -78 °C with n-butyl phenyl selenide (Scheme 5, entry d, compare to entries a and g).We have also observed that the whole series of butyllithiums (n-, sec-, tert-Bu) poorly reacts with sec-butyl phenyl selenide (Scheme 5, entries b,e,h) and is inert towards tert-butyl phenyl selenide (Scheme 5, entries c, f, i).

About the structure of the aryl alkyl selenide a. Effect of the alkyl chain
We observed a very big difference of reactivity, towards n-butyllithium, of the members of the family of (n,s,t)-butyl phenyl selenides whose carbon atom directly attached to the selenium atom is differently alkyl substituted.
Increasing alkyl substitution dramatically lowers the aptitude of n-butyllithium to produce phenyllithium by C-Se bond cleavage (Scheme 5, compare entries a,b and c): Thus whereas nbutyl phenyl selenide is quantitatively cleaved at 0 °C in THF by n-butyllithium, to produce di n-butyl selenide in 88 % yield (1 h, Scheme 5, entry a) its s-butyl isomer is poorly reactive and leads to dibutyl selenide in 24 % yield (1 h, Scheme 5, entry b) and tert-butyl phenyl selenide is recovered unchanged under the same conditions (Scheme 5, entry c).

b. Effect of the aryl group
Last but not least, we have compared the reactivity towards n-butyllithium (THF, -78°C, 1h), of a series of aryl methyl selenides variously substituted on the aromatic ring.For that purpose, we have reacted at -78 °C in THF, n-butyllithium and a five fold excess of equimolar amounts of methyl phenyl and aryl methyl selenides.We have compared by gas chromatography the ratio of benzene and arene resulting from methanolysis of the corresponding organolithium intermediates (Scheme 6).We have at the same time secured that the aryllithium as well as n-butyl methyl selenide, formed concomitantly, are produced in at least 80 % yield.The presence of an electron-withdrawing substituent such as the trifluoromethyl group in para-position or to a lower extend a methoxy group in meta-position favors the formation of the corresponding aryllithiums (Scheme 6, entries e,b) whereas electron-donating substituents such as p-methoxy-or p-dimethylamino substituents disfavors the reaction (Scheme 6, entries c,d).In that context, the propensity of methyl o-methoxy-phenyl selenide to produce omethoxyphenyllithium, although it possesses an electron-donating group in ortho-position, might be attributed to its chelating properties of the ortho-methoxy group (Scheme 6, entry a).Related behavior named ortho-lithiation or directed metallation, has been already used to explain the selective metallation of methoxy benzene in ortho-position using n-butyllitium.3a,12,13 The reactions have been carried in THF on the corresponding aryl methyl selenides using a solution Page 57 © ARKAT of s-butyllithium in cyclohexane, thus as estimated from the above result in the best solvent, with the more reactive family of selenides and the most efficient organolithium (Scheme 7).The reaction efficiently occurs in all the cases in less than one hour at -78 °C and provides, in almost quantitative yields, the whole series of aryllithiums bearing electron-withdrawing as well as donating groups attached to the aromatic ring (Scheme 7).
Alkylation of those aryllithiums with decyl bromide only takes place around 0 °C and produces, except for p-trifluoromethyl-phenyllithium (Scheme 7, entry d), 1-aryl-decanes in 60-70 % yield (Scheme 7, entries a-c).We found that the alkylation of p-trifluoromethylphenyllithium can be achieved in much better yield in the presence of HMPA (Scheme 7, entry e; compare to entry d).
This synthesis of aryllithiums offers advantages over the related one involving the Chalogen bond cleavage of aryl halides by the same reagents. 13ndeed, these processes concomitantly generate respectively methyl butyl selenide or butyl halide as by-product but whereas the former is inert, the later is prone to react with aryllithiums, n-BuLi or sec-BuLi.Therefore, a mixture of aryl alkanes is produced after addition of a different alkyl halide to the reaction medium unless special tricks are used such as performing the halogen/metal exchange with 2 equivalent of tert-BuLi.13d In conclusion, alkyl aryl selenides produce aryllithiums when reacted with butyllithiums.The reaction is more efficient with methyl selenides and more difficult when the alkyl chain is longer or branched.s-Butyllithium proved to be the best reagent among the series of butyllithiums and THF the best solvent.Work is in progress to determine the scope of this reaction as well as that of the alkylation of the aryllithiums produced.