Lithium Aluminum Hydride: A Powerful Reducing Agent

Biographical Sketches

Srinivasarao Yaragorla was born in Sattupally, Andhra Pradesh, India in 1981, and received his Masters degree in 2003 from the University of Hyderabad. After qualifying in a CSIR-JRF exam in 2003, he started his Ph.D. studies under the supervision of Dr. S. Chandrasekhar, Deputy Director, Indian Institute of Chemical Technology, India. His research interests include asymmetric total synthesis of bioactive natural products, and medicinal chemistry.

Introduction

Lithium aluminum hydride (LiAlH₄) is a powerful reducing agent used in organic synthesis [¹] and is commonly abbreviated as LAH. It is more powerful than the related reagent sodium borohydride because of the relatively weaker Al-H bond compared to the B-H bond. It reduces a vast number of functional groups. For example, it converts esters, [²a] [b] carboxylic acids [²c] and carbonyl compounds [²d] into the corresponding alcohols; α,β-unsaturated ketones are reduced to allylic alcohols. [²e] When epoxides are reduced using LAH, the reagent attacks the less hindered end of the epoxide, usually producing a secondary or tertiary alcohol. Epoxycyclohexanes are reduced to give axial alcohols preferentially. [²f] Using LAH, amines can be prepared by the reduction of amides, [²g] [h] oximes, [²i] nitriles, nitro compounds or alkyl azides. LAH does not reduce simple alkenes, arenes, or alkynes; but alkynes can be reduced if an alcohol group is nearby. [²j]

Figure 1

Preparation

Treatment of lithium hydride with an ethereal solution of AlCl₃ produces the new ether-soluble compound, LAH. [³] Addition of further quantities of AlCl₃ yields a mild reducing agent, aluminum hydride (AlH₃). [4]

Figure 2

Abstracts

(A) Stereoselective reduction Various syn-1,3-diols were prepared convienently by reduction of β-alkoxy ketones with LiI and LAH (syn/anti selectivity up to >99:1). Here the coordination of LiI gives rise to a syn-selective reducing agent as a consequence of the intervention of a Li+-containing six-membered chelation. [5]
(B) Reductive removal of a tosylated hydroxy group/epoxide formation/epoxide opening LAH is also employed in a highly chemo- and regioselective reduction of 2-tosyloxy esters, followed by epoxide formation via an SN2 mechanism and reductive opening of the epoxide. [6]
(C) Enantioselective reduction of ketones by modified LAH Highly enantioselective reduction of ketones by chiral-diol modified LAH was successfully demonstrated, with good yields and high ee. [7]
(D) Synthesis of amines LAH is a powerful reducing agent, it reduces azide and nitro functionalities into the corresponding amines in a one-pot process. [8]
(E) Reduction of amides LAH reduces both cyclic and acyclic amides to the corresponding amines. [9]
(F) Epoxide ring opening LAH attacks the epoxide at the less hindered side and produces the alcohols. [¹0]
(G) Reduction of lactones LAH reduces lactones to the corresponding diols. [¹¹]
(H) Formation of cyclopropane derivatives A homoallylic mesylate, when subjected to LAH, provided the cyclopropane derivative through homoallylic π-participation. [¹²]

References

• 1 Brown HC. Org. React.  1951,  6:  469 
• 2a Reetz MT. Drewes MW. Schwickardi R. Org. Synth., Coll. Vol. X  2004,  256 
• 2b Oi R. Sharpless KB. Org. Synth., Coll. Vol. IX  1998,  251 
• 2c Oi R. Sharpless KB. Org. Synth.  1996,  73:  1 
• 2d Koppenhoefer B. Schurig V. Org. Synth., Coll. Vol. VIII  1993,  434 
• 2e Barnier JP. Champion J. Conia JM. Org. Synth., Coll. Vol. VII  1990,  129 
• 2f Elphimoff-Felkin I. Sarda P. Org. Synth., Coll. Vol. VI  1988,  769 
• 2g Rickborn B. Quartucci J. J. Org. Chem.  1984,  29:  3185 
• 2h Seebach D. Kalinowski H.-O. Langer W. Crass G. Wilka E.-M. Org. Synth., Coll. Vol. VII  1990,  41 
• 2i Park CH. Simmons HE. Org. Synth., Coll. Vol. VI  1988,  382 
• 2j Chen YK. Jeon S.-J. Walsh PJ. Nugent WA. Org. Synth.  2005,  82:  87 
• 2k Wender PA. Holt DA. Sieburth SMcN. Org. Synth., Coll. Vol. VII  1990,  456 
• 3 Finholt AE. Bond AC. Schlesinger HI. J. Am. Chem. Soc.  1947,  69:  1199 
• 4 Lopinti K. Synlett  2005,  2265; Spotlight No. 134 
• 5 Ghosh AK. Lei H. J. Org. Chem.  2002,  67:  8783 
• 6 Chandrasekhar S. Rambabu C. Prakash SJ. Tetrahedron Lett.  2006,  46:  1213 
• 7 Ren Y. Tian X. Sun K. Xu J. Xu X. Lu S. Tetrahedron Lett.  2006,  47:  463 
• 8 Chandrasekhar S. Reddy NR. Rao YS. Tetrahedron  2006,  62:  12098 
• 9 Kouklovsky C. Hoang CT. Nguyen VH. Alezra V. J. Org. Chem.  2008,  73:  1162 
• 10 Chapelon AS. Moraleda D. Rodriguez R. Ollivier C. Santelli M. Tetrahedron  2007,  63:  11511 
• 11 Grieco PA. Takigawa T. Schillinger WJ. J. Org. Chem.  1980,  45:  2247 
• 12 Pan L.-R. Tokoroyama T. Tetrahedron Lett.  1992,  33:  1473