Lithium Hydroxide

LiOH

[1310-65-2]  · HLiO  · Lithium Hydroxide  · (MW 23.95) (.H2O)

[1310-66-3]  · H3LiO2  · Lithium Hydroxide  · (MW 41.97)

(very strong alkali; reacts readily with acids and is used as a base as well as a nucleophile in organic reactions, particularly in the hydrolysis of esters and amides)

Physical Data: d (anhyd.) 2.54 g cm-3; (monohyd.) 1.51 g cm-3; mp (anhyd.) 471 °C.

Solubility: sol water: (w/w) 10.7% at 0 °C, 10.9% at 20 °C, 14.8% at 100 °C; pH of 1.0 N soln. about 14; slightly sol ethanol.

Form Supplied in: the commercially available material is the monohydrate: small, white monoclinic crystals.

Handling, Storage, and Precautions: corrosive. Harmful if swallowed, inhaled, or absorbed through skin. Toxicity in rat: LD50 365 mg kg-1 (oral dose). Material is extremely destructive to tissue of the mucous membranes and upper respiratory tract, eyes, and skin. Inhalation may be fatal; do not breathe dust. Avoid contact with eyes, skin, and clothing. Incompatible with strong oxidizing agents and strong acids. Absorbs moisture and CO2 from air. Hygroscopic; store in a cool dry place. Wash thoroughly after handling.

Hydrolysis of Esters.

The methyl ester of the 9,11-azo analog of prostaglandin endoperoxide PGH2 (1) was hydrolyzed under mild conditions using 0.15 N LiOH in 2.5:1 THF-H2O at 0 °C for 2.5 h to give the 9,11-azo analog of PGH2 (2) in 99% isolated yield (eq 1).1

Hydrolysis of Urethanes to Alcohols.

The p-phenylphenylcarbamoyl group served as a protecting group for the C-11 alcohol and also as a directing group to control the stereochemistry of the carbonyl reduction at C-15 in the synthesis of the prostaglandin synthon (3). This protecting group was removed following the ketone reduction by treating (3) with 1 M aq LiOH at 120 °C for 72 h to afford (4) in >90% yield.2

Hydrolysis of Bile Acid Methyl Esters.

Bile acid methyl esters were hydrolyzed under mild conditions with LiOH in aq. methanol at 25 °C to the bile acids. This procedure gave higher yields (80-98%) compared to conventional Sodium Hydroxide or Potassium Hydroxide hydrolysis reactions (48-55%). The procedure caused no racemization or elimination side reactions, e.g. (23R)-methyl 3a,7a,23a-trihydroxy-5b-cholan-24-oate (5) gave the corresponding acid (6) in 96% isolated yield (eq 2).3

Hydrolysis of N-Boc Lactams and N-Boc Secondary Amides.

N-Boc derivatives of lactams were regioselectively hydrolyzed with LiOH in aq. THF to the corresponding o-amino acids. For example, N-Boc valerolactam was hydrolyzed with 3.0 equiv of LiOH in aq. THF at rt to give the N-Boc-d-aminovaleric acid in 90% yield (eq 3). The reaction conditions are very mild and provide the o-amino group in a protected form, thus permitting further elaboration of the carboxylic acid residue. The procedure was applied successfully to the hydrolysis of N-Boc secondary amides to the corresponding acids.4

Cleavage of 2-Oxazolidinone Chiral Auxiliaries.

The hydrolysis of the N-(a-azidoacyl)- and N-[a-((+)-MTPA-amino)acyl]-2-oxazolidinone derivatives (7) with LiOH (2 equiv) in THF-H2O (3:1) for 30 min at 0 °C afforded the corresponding a-amino acid synthons (8) in 95-100% yields (eq 4). No detectable racemization was observed when R = Bn and about 1% racemization occurred with the phenylglycine synthons (R = Ph).5

Regioselective Hydrolysis of Carboximide Derivatives.

The regioselective hydrolysis of the carboximide derivative (9) was achieved with excess 2 N aq LiOH in dioxane at rt overnight to give the desired b-hydroxy-a-amino acid (10) and a byproduct (11) (eq 5) in isolated yields of 83% and 17% respectively (a 5:1 ratio). The products (10) and (11) are the result of endocyclic and exocyclic carbonyl attack by the hydroxide ion, respectively. The success of this procedure was based on the selection of the sterically demanding N-protecting Boc group, which largely directed the regioselectivity of the attack by the hydroxide ion to the less hindered oxazolidinone carbonyl.6

If, on the other hand, the hydrolysis was to be directed towards the exocyclic carbonyl of a highly branched N-acyl oxazolidinone derivative, a complementary procedure was developed employing lithium hydroperoxide to achieve that regioselectivity.7

Hydrolysis of N-Monosubstituted Amides via Acetoxypivalimides.

Hydrolysis of N-monosubstituted amides under mild conditions without epimerization at the a-position was accomplished in two steps. The amides (12) were first converted into the N-acetoxypivaloyl derivatives (13) (eq 6). These derivatives were then treated with LiOH in THF to give the carboxylic acids (15) in good yields. The procedure takes advantage of the easier hydrolysis of imides than amides and the intramolecular nucleophilic attack by the acetoxy oxygen on the imide carbonyl (eq 7) causing an N-O acyl migration to form the intermediate acyloxypivalamide (14). Further hydrolysis of (14) gave the desired carboxylic acids (15) and N-alkylhydroxypivalamides (16).8

The method is mild enough to use with N-butyl-(2S,3S)-dimethyl-4-pentenamide to give (2S,3S)-dimethyl-4-pentenoic acid in 76% yield with practically no epimerization (eq 8).8

Selective O-Acetyl Hydrolysis of N,O-Diacetylhydroxamates.

Treatment of N-acetoxy-N-{1-[4-(phenylmethoxy)phenyl]ethyl}acetamide (17) with LiOH in 2:1 i-PrOH-H2O selectively hydrolyzed the O-acetyl to give the hydroxamic acid (18) (eq 9). The procedure was described as part of a two-step conversion of hydroxylamines into hydroxamic acids.9

Selective O-Deacetylation in Carbohydrates.

The O-acetyl groups in the penta-O-acetyl tri-N-acyl disaccharide (19) (eq 10) were selectively hydrolyzed with 0.6 M LiOH for 1 h at rt to give, after purification and recrystallization, the pentahydroxy tri-N-acyl disaccharide (20) in 92% yield.10

Dihydroquinoxalones from Ethyl Alkylglycidates.

The reactions of o-phenylenediamine with ethyl 2,3-epoxycrotonate (21a), ethyl 2,3-epoxypentenoate (21b), or ethyl 2,3-epoxy-3,3-dimethylacrylate (21c) were catalyzed by LiOH and gave the dihydroquinoxalones (22a-c) (eq 11). The initial nucleophilic attack occurred on the a-carbon of (21) followed by intramolecular aminolysis to give the cyclized product. When unsubstituted epoxyacrylates and cinnamates were used, the initial attack occurred on the b-carbon and gave the uncyclized hydroxyamino esters.11

Synthesis of 3-Hydroxybenzo[b]thiophene-2-carboxylates.

Substituted methyl 3-hydroxybenzo[b]thiophene-2-carboxylates (24) were prepared in yields ranging from 50 to 85% by the LiOH-catalyzed reaction of substituted methyl o-nitrobenzoates (23) and methyl thioglycolate in dry DMF (eq 12). Under the reaction conditions the activated nitro group was displaced by the thiolate anion, followed by cyclization.12

Stereochemical Control in Conversion of Diols to Epoxides.

The intermediate 22-tosyloxy-23-pivaloxy steroid (25) was prepared from the corresponding diol and then treated with LiOH in dioxane-H2O at rt for 8 h to give the 22,23-epoxy steroid (26) in 92% yield (eq 13).13

Oxetane Formation from 3,4-Epoxy Alcohols.

Treatment of the 3,4-epoxy alcohol (27) with LiOH, NaOH, or KOH in aq DMSO at 140-150 °C gave a mixture of the oxetane (28) in 49% yield and the 1,2,4-triol (29) in 32% yield (eq 14). Reaction times were 15, 45, and 90 min for LiOH, NaOH, and KOH, respectively. The procedure was presented as a nonphotochemical synthesis of oxetanes.14

Formation of trans-Hydrindanones.

Treatment of 8-oxo-2-methyl-6-nonenal (30) with LiOH in MeOH gave a 4:1 mixture of trans- and cis-hydroxyhydrindanones (32). The reaction proceeded via consecutive intramolecular Michael and aldol addition reactions. The stereochemical control was greatly improved by using the better chelating ZrIV n-propoxide in benzene to effect the initial Michael addition, yielding the monocyclic ketoaldehyde (31), and then adding LiOH/MeOH to effect the aldol addition step (eq 15). This modification gave the desired hydroxyhydrindanone (32) in 90% yield as a 40:1 mixture of the trans and cis isomers.15

Synthesis of 1-Deoxy-D-erythro-2-pentulose.

Treatment of a solution of methyl 4,6-O-benzylidene-2-deoxy-a-D-erythro-hexopyranosid-3-ulose (33) in ether with an aq. soln. of LiOH and vigorously stirring the two-phase system at 20 °C for 16 h gave 3,5-O-benzylidene-1-deoxyketo-D-erythro-2-pentulose (34) in 55% isolated yield (eq 16).16

Conversion of Mixed Phosphoric Acid Triesters to Mixed Phosphoric Acid Diesters.

In a three-step sequence for the conversion of bis(p-nitrophenyl) hydrogen phosphate to dialkyl phosphates (36), the intermediate dialkyl p-nitrophenyl phosphates (35) were selectively hydrolyzed with 1N LiOH in acetonitrile at rt to give the desired dialkyl phosphates under mild conditions (eq 17). Various mixed dialkyl phosphates were prepared in good overall yields without isolation of any synthetic intermediate.17


1. Corey, E. J.; Narasaka, K.; Shibasaki, M. JACS 1976, 98, 6417.
2. Corey, E. J.; Becker, K. B.; Varma, R. K. JACS 1972, 94, 8616.
3. Dayal, B.; Salen, G.; Toome, B.; Tint, G. S.; Shefer, S.; Padia, J. Steroids 1990, 55, 233.
4. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. JOC 1983, 48, 2424.
5. Evans, D. A.; Ellman, J. A.; Dorow, R. L. TL 1987, 28, 1123.
6. Evans, D. A.; Weber, A. E. JACS 1987, 109, 7151.
7. Evans, D. A.; Britton, T. C.; Ellman, J. A. TL 1987, 28, 6141.
8. Tsunoda, T.; Sasaki, O.; Ito, S. TL 1990, 31, 731.
9. Summers, J. B.; Gunn, B. P.; Martin, J. G.; Martin, M. B.; Mazdiyasni, H.; Stewart, A. O.; Young, P. R.; Bouska, J. B.; Goetze, A. M.; Dyer, R. D.; Brooks, D. W.; Carter, G. W. JMC 1988, 31, 1960.
10. Spinola, M.; Jeanloz, R. W. JBC 1970, 245, 4158.
11. Murata, S.; Sugimoto, T.; Matsuura, S. H 1987, 26, 883.
12. Beck, J. R. JOC 1973, 38, 4086.
13. Koreeda, M.; Ricca, D. J. JOC 1986, 51, 4090.
14. Murai, A.; Ono, M.; Masamune, T. CC 1976, 864.
15. Stork, G.; Shiner, C. S.; Winkler, J. D. JACS 1982, 104, 310.
16. Fischer, J.-C; Horton, D.; Weckerle, W. CJC 1977, 55, 4078.
17. Mukaiyama, T.; Morito, N.; Watanabe, Y. CL 1979, 531.

Ahmed F. Abdel-Magid

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA



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