n-Butyllithium

Dedicated to my research supervisor Dr. Pinaki S. Bhadury

Introduction

n-Butyllithium (n-BuLi) is one of the most prominent organolithium reagents in the whole of synthetic chemistry,[1] [2] [3] and available as solutions in alkanes such as pentane, hexane, or heptane, which is usually encountered as a pale yellow solution. It is unstable towards air or moisture but stable in an atmosphere of nitrogen. It has been widely used in organic reactions, such as regioselective lithiation reaction,[ ⁴ ] reversible metathesis reaction,[ ⁵ ] Claisen rearrangement,[ ⁶ ] phospho-Fries rearrangement,[ ⁷ ] coupling reaction,[ ⁸ ] asymmetric deprotonation–electrophilic trapping reaction,[ ⁹ ] enantioselective hydroxyalkylation,[ ¹⁰ ] etc. In general, n-butyllithium is commercially available and can also be prepared readily by the reaction of 1-bromobutane or 1-chlorobutane with Li metal (Scheme [1]).[ ¹¹ ] An overview of the usage of n-BuLi in ­organic synthesis is presented below.

Scheme 1

(A) Fort and co-workers described an efficient method for the synthesis of polysubstituted furo[2,3-c]pyridines via successive regio­selective lithiations, using n-BuLi or [n-BuLi/LiDMAE] as base. For each step the products were obtained in moderate to excellent yields.[ 4 ]
(B) Bailey et al. reported mild and highly efficient experimental conditions for the reversible metathesis reaction known as the lithium–halogen exchange. The reaction products of 1-bromo-4-tert-butylbenzene with n-BuLi at 0 °C are obtained quantitative in heptane containing a small quantity of THF. Particularly, nettlesome side ­reactions, including coupling of aryllithium with the co-generated alkyl halide and formation of a benzyne intermediate via ortho-metalation of the aryl halide, are effectively avoided.[ 5 ]
(C) Upon treatment with n-BuLi, a variety of allyl 1,1-dichlorovinyl ethers undergo rearrangement to furnish high yields of γ,δ-unsaturated esters after alcohol addition. A potential advantage of this method over other variants of the Claisen rearrangement is the ability to add a variety of alcohol nucleophiles to the proposed ketene intermediate, allowing the one-pot preparation of diverse esters of γ,δ-unsaturated carboxylic acids with high stereoselectivity.[ 6 ]
(D) n-BuLi together with i-Pr2NH has been used in the preparation of bifunctional BINOL ligands bearing phosphine oxides [P(=O)R2], phosphonates [P(=O)(OR)2], or phosphoramides [P(=O)(NR2)2] at the 3,3′-positions via a phospho-Fries rearrangement as key step. This method has an advantage with regard to yield and purification in comparison with a coupling method that uses halide compounds, expensive diphenylphosphine oxide [Ph2P(=O)H], and palladium or nickel catalysts.[ 7 ]
(E) Tarselli and Micalizio described a successful procedure for the coupling of aliphatic imines with allylic and allenic alkoxides enabled by a unique reactivity profile of Ti(IV) isopropoxide/n-BuLi compared to well-known Ti(IV) isopropoxide/RMgX systems. This coupling proceeds with moderate to excellent yields.[ 8 ]
(F) An enantioselective hydroxyalkylation of o-tolualdehyde and 3-aminotetrahydrofurans (or 3-aminopyrrolidines, 3-aminotetrahydrothiophens) in the presence of n-BuLi and lithium amides gives the target product 1-o-tolylpentan-1-ol in good yield and moderate ee.[ 10 ]
(G) The highly pyramidalized alkene pentacyclo-[4.3.0.02,4.03,8.05,7]non-4-ene was successfully synthesized with n-BuLi via dehalogenation of vicinal dihalides. The method has proven to be reliable for the synthesis of a variety of strained alkenes.[ 12 ]
(H) Luliński et al. found that lithiated benzonitriles can be generated in high yields from reactions of bromobenzonitriles with n-BuLi in THF under standard cryogenic conditions (ca. –70 °C, even up to –60 °C). The reverse addition mode is employed to reduce significantly side reactions.[ 13 ]

• References

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• 11 Brandsma L, Verkruijsse HD. Preparative Polar Organometallic Chemistry I . Springer; Berlin, Heidelberg: 1987
• 12 Mark AForman M. A, Moran C, Herres JP, Stairs J, Chopko E, Pozzessere A, Kerrigan M, Kelly C, Lowchyj L, Salandria K, Gallo A, Loutzenhiser E. J. Org. Chem. 2007; 72: 2996
• 13 Luliński S, Zajac K. J. Org. Chem. 2008; 73: 7785