LITHIUM CHLORIDE 1
Lithium Chloride Source of Chloride Ligand. In palladium-catalyzed reac-
tions, LiCl is often the reagent of choice as a source of chloride
ligand. Lithium chloride is a necessary component in palladium-
LiCl
catalyzed coupling and carbonylative coupling reactions of
organostannanes and vinyl triflates.13,14 Lithium chloride has a
[7447-41-8] ClLi (MW 42.39)
dramatic effect on the stereochemical course of palladium-cata-
InChI = 1/ClH.Li/h1H;/q;+1/p-1/fCl.Li/h1h;/q-1;m
lyzed 1,4-additions to 1,3-dienes.15 Treatment of 1,3-cyclohexa-
InChIKey = KWGKDLIKAYFUFQ-HPRMROJMCO
diene with Palladium(II) Acetate and LiOAc and the oxidiz-
ing agents 1,4-Benzoquinone and Manganese Dioxide affords 1,
(source of Cl- as nucleophile and ligand; weak Lewis acid that
4-trans-diacetoxy-2-cyclohexene (eq 2). In the presence of a cat-
modifies the reactivity of enolates, lithium dialkylamides, and
alytic quantity of LiCl, the cis isomer is formed (eq 3). If 2
other Lewis bases)
equiv LiCl are added, the cis-acetoxychloro compound forms
ć% ć%
Physical Data: mp 605 C; bp 1325 1360 C; d 2.068 g cm-3.
(eq 4). These methods are general for both cyclic and acyclic
Solubility: very sol H2O; sol methanol, ethanol, acetone, acetoni-
dienes, and have recently been extended to the stereospecific
trile, THF, DMF, DMSO, HMPA.
formation of fused heterocycles.16 Lithium chloride is also used in
Form Supplied in: white solid, widely available.
the preparation of Dilithium Tetrachloropalladate(II)17 and zinc
ć%
Drying: deliquescent; for most applications, drying at 150 C
organocuprate reagents.18
for 3 h is sufficient; for higher purity, recrystallization from
ć%
methanol, followed by drying at 140 C/0.5 mmHg overnight,
Pd(OAc)2, LiOAc
no added LiCl
is recommended.
(2)
AcO OAc
Handling, Storage, and Precautions: of low toxicity; take
1,4-benzoquinone, MnO2
93%
directly from the oven when dryness is required.
>91% trans
Pd(OAc)2, LiOAc
0.2 equiv LiCl
(3)
AcO OAc
1,4-benzoquinone, MnO2
85%
Original Commentary
>96% cis
Pd(OAc)2, LiOAc
James S. Nowick
2 equiv LiCl
University of California, Irvine, CA, USA
(4)
Cl OAc
Guido Lutterbach 1,4-benzoquinone, MnO2
89%
Johannes Gutenberg University, Mainz, Germany
>98% cis
Source of Chloride Nucleophile. The solubility of LiCl in
Weak Lewis Acid. Lithium chloride is a weak Lewis
many organic dipolar solvents renders it an effective source of
acid that forms mixed aggregates with lithium dialkylamides,
nucleophilic chloride anion. Lithium chloride converts alcohols
enolates, alkoxides, peptides, and related  hard Lewis bases.19
to alkyl chlorides.1 under Mitsunobu conditions,2 or by way of
Thus LiCl often has a dramatic effect on reactions involving
the corresponding sulfonates3 or other leaving groups.4 This salt
these species. In the deprotonation of 3-pentanone by Lithium
cleanly and regioselectively opens epoxides to chlorohydrins in
the presence of acids and Lewis acids such as Acetic Acid,5 2,2,6,6-Tetramethylpiperidide (LTMP), addition of 0.3 equiv LiCl
increases the (E)/(Z) selectivity from 9:1 to 52:1 (eq 5).20
Amberlyst 15 resin,6 and Titanium(IV) Chloride7 In the presence
Enhancement in the enantioselectivity of deprotonation of pro-
of acetic acid, LiCl regio- and stereoselectively hydrochlorinates
chiral ketones by a chiral lithium amide has also been reported.21
2-propynoic acid and its derivatives to form the corresponding
Lithium chloride stabilizes anions derived from Ä…-phosphono-
derivatives of (Z)-3-chloropropenoic acid.8 Oxidative decarboxy-
acetates, permitting amine and amidine bases to be used to
lation of carboxylic acids by Lead(IV) Acetate in the presence of
perform Horner Wadsworth Emmons reactions on base-sensitive
1 equiv of LiCl generates the corresponding chlorides.9
aldehydes under exceptionally mild conditions.22 Lithium
In wet DMSO, LiCl dealkoxycarbonylates various activated
chloride and other lithium salts disrupt peptide aggregation and
esters (eq 1).10,11 If the reaction is performed in anhyd solvent
increase the solubilities of peptides in THF and other ethereal sol-
the reaction generates a carbanion intermediate, which can
vents, often by 100-fold or greater.23 These effects render LiCl a
undergo inter- or intramolecular alkylation or elimination. Other
useful additive in the chemical modification of peptides (e.g. by the
inorganic salts (NaCN, NaCl, Lithium Iodide) and other dipolar
formation and alkylation of peptide enolates).19,24 Lithium chlo-
aprotic solvents (HMPA, DMF) can also be employed. Under
ride has also shown promise as an additive in solid-phase peptide
similar conditions, lithium chloride cleaves alkyl aryl ethers
synthesis, increasing resin swelling and improving the efficiencies
having electron-withdrawing substituents at the ortho or para
of difficult coupling steps.25
positions.12
OTMS
O 1. LiTMP (LiCl) OTMS
R1 R1 + (5)
LiCl
(1) 2. TMSCl, THF
X CO2R3 X H
wet DMSO
R2 R2
0.0 equiv LiCl 9:1
X = CO2R, COR, CN, SO2R; R3 = Me, Et 0.3 equiv LiCl 52:1
Avoid Skin Contact with All Reagents
2 LITHIUM CHLORIDE
First Update Source of Chloride Ligand. LiCl and lithium bromide
increase the reducing power of samarium(II) iodide and influence
J. Kent Barbay & Wei He
the selectivity of this reagent in the reductive coupling of alkyl
Johnson & Johnson Pharmaceutical Research & Development,
halides and ketones.32
Spring House, PA, USA
Weak Lewis Acid. Lithium chloride is employed for the cleav-
Source of Chloride Nucleophile. Cyclic sulfites react with
age of protecting groups under mild conditions. At elevated tem-
LiCl to produce chlorohydrins upon hydrolytic work-up. This ć%
peratures (90 130 C), LiCl in wet DMSO converts acetals and
transformation was employed in the regioselective conversion of
ketals to the corresponding carbonyl compounds. Aryl and Ä…,²-
a 1,2-diol to a chlorohydrin intermediate for the preparation of the
unsaturated acetals and ketals are more readily cleaved under these
R
HIV protease inhibitor Nelfinavir© (eq 6).26
conditions than are their saturated counterparts.33 Lithium chlo-
ride and water cleave tert-butyldimethylsilyl (TBDMS) ethers of
NHCbz
primary and secondary alcohols upon heating in DMF.34
SOCl2, Et3N
PhS
The dehydrohalogenation of Ä…-halocarbonyl compounds to
OH
CH2Cl2
Ä…,²-unsaturated carbonyls occurs upon treatment with LiCl in
OH
DMF, or with a combination of LiCl and lithium carbonate
under the same conditions. For example, (Z)-alkyl Ä…-chloro-
NHCbz
1. LiCl, DMF
NHCbz
Ä…,²-unsaturated esters were prepared stereoselectively by
80 °C
PhS
PhS
dehydrobromination of Ä…-bromo-Ä…-chloro esters under the latter
Cl (6)
O
2. aq HCl
conditions (eq 9).35
O 70%
S OH
O CO2Et
LiCl, Li2CO3
DMF, 70 °C
Cl
Br
2,3-Epoxy alcohols, readily available from allylic alcohols
94%
by the Katsuki-Sharpless procedure, preferentially yield chloro-
CO2Et
hydrins derived from substitution at C2 upon treatment with LiCl
(9)
in the presence of trimethyl borate and acetic acid (eq 7); C2/C3
Cl
selectivities are further enhanced by the use of sodium iodide as
(Z):(E) = 24:1
halide source under the same conditions.27
N-acyloxazolidones are prepared in high yields from mixed
LiCl, B(OMe)3
O
anhydrides and oxazolidinones in the presence of 1 equiv of LiCl
BnO
AcOH, acetone
OH
using triethylamine as base. Other metal halides, such as mag-
88%
nesium bromide, failed to promote this reaction.36 The complex-
Cl
O
ation of N,N-dialkylhydrazines with 2 equiv of LiCl forms an
+ BnO
2
BnO adduct which undergoes efficient N-arylation with aryl bromides
2
3 (7)
3
OH
OH
in the presence of palladium catalysts to afford N,N-dialkyl-N -
OH
Cl
arylhydrazines (eq 10).37
85:15 ratio of 2-chloro:3-chloro product
NH2
N
Lithium halides open epoxides to the corresponding ²-halohyd-
Br
(10)
rins under solvent-free conditions in the presence of silica gel.
Pd2(dba)3, NaOt-Bu N
N
The reactivity decreases in the order lithium iodide > lithium
Xantphos, toluene, 80 °C
2 LiCl
H
bromide > LiCl. The addition of an equivalent amount of water
82%
dramatically increases the reactivity of LiCl.28
Related Reagents. Lithium Chloride Diisopropylethyl-
amine; Lithium Chloride Hexamethylphosphoric Triamide.
Electrophilic Chlorination. In the presence of oxidants, LiCl
and other metal halides act as electrophilic halogenating reagents.
Chlorination of active methylene compounds has been reported
using LiCl and dibenzoyl peroxide; other metal halides (mag- 1. Magid, R. M., Tetrahedron 1980, 36, 1901.
nesium bromide, copper(II) bromide, lithium iodide) are also
2. Manna, S.; Falck, J. R.; Mioskowski, C., Synth. Commun. 1985, 15, 663.
suitable halogen sources.29 Oxidative halodecarboxylation of Ä…,²- 3. (a) Owen, L. N.; Robins, P. A., J. Chem. Soc. 1949, 320. (b) Owen, L.
unsaturated acids to vinyl chlorides occurs upon treatment with N.; Robins, P. A., J. Chem. Soc. 1949, 326. (c) Eglinton, G.; Whiting,
M. C., J. Chem. Soc. 1950, 3650. (d) Collington, E. W.; Meyers, A. I.,
LiCl and cerium(IV) ammonium nitrate.30 A combination of LiCl
J. Org. Chem. 1971, 36, 3044. (e) Stork, G.; Grieco, P. A.; Gregson,
and sodium periodate in acidic media converts olefins to chloro-
M., Tetrahedron Lett. 1969, 18, 1393.
hydrins regioselectively (eq 8).31
4. (a) Czernecki, S.; Georgoulis, C., Bull. Soc. Chem. Fr. 1975, 405.
(b) Camps, F.; Gasol, V.; Guerrero, A., Synthesis 1987, 511.
LiCl, NaIO4 OH
5. Bajwa, J. S.; Anderson, R. C., Tetrahedron Lett. 1991, 32, 3021.
(8)
Ph
Cl
aq H2SO4, CH3CN
6. Bonini, C.; Giuliano, C.; Righi, G.; Rossi, L., Synth. Commun. 1992,
Ph
81%
22, 1863.
A list of General Abbreviations appears on the front Endpapers
LITHIUM CHLORIDE 3
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Avoid Skin Contact with All Reagents