LITHIUM CHLORIDE

1

Lithium Chloride

LiCl

[7447-41-8]

ClLi

(MW 42.39)

InChI = 1/ClH.Li/h1H;/q;+1/p-1/fCl.Li/h1h;/q-1;m
InChIKey = KWGKDLIKAYFUFQ-HPRMROJMCO

(source of Cl

−

as nucleophile and ligand; weak Lewis acid that

modifies the reactivity of enolates, lithium dialkylamides, and

other Lewis bases)

Physical Data:

mp 605

◦

C; bp 1325–1360

◦

C; d 2.068 g cm

−

3

.

Solubility:

very sol H

2

O; sol methanol, ethanol, acetone, acetoni-

trile, THF, DMF, DMSO, HMPA.

Form Supplied in:

white solid, widely available.

Drying:

deliquescent; for most applications, drying at 150

◦

C

for 3 h is sufficient; for higher purity, recrystallization from
methanol, followed by drying at 140

◦

C/0.5 mmHg overnight,

is recommended.

Handling, Storage, and Precautions:

of low toxicity; take

directly from the oven when dryness is required.

Original Commentary

James S. Nowick
University of California, Irvine, CA, USA
Guido Lutterbach
Johannes Gutenberg University, Mainz, Germany

Source of Chloride Nucleophile. The solubility of LiCl in

many organic dipolar solvents renders it an effective source of
nucleophilic chloride anion. Lithium chloride converts alcohols
to alkyl chlorides.

1

under Mitsunobu conditions,

2

or by way of

the corresponding sulfonates

3

or other leaving groups.

4

This salt

cleanly and regioselectively opens epoxides to chlorohydrins in
the presence of acids and Lewis acids such as Acetic Acid,

5

Amberlyst 15 resin,

6

and Titanium(IV) Chloride

7

In the presence

of acetic acid, LiCl regio- and stereoselectively hydrochlorinates
2-propynoic acid and its derivatives to form the corresponding
derivatives of (Z)-3-chloropropenoic acid.

8

Oxidative decarboxy-

lation of carboxylic acids by Lead(IV) Acetate in the presence of
1 equiv of LiCl generates the corresponding chlorides.

9

In wet DMSO, LiCl dealkoxycarbonylates various activated

esters (eq 1).

10,11

If the reaction is performed in anhyd solvent

the reaction generates a carbanion intermediate, which can
undergo inter- or intramolecular alkylation or elimination. Other
inorganic salts (NaCN, NaCl, Lithium Iodide) and other dipolar
aprotic solvents (HMPA, DMF) can also be employed. Under
similar conditions, lithium chloride cleaves alkyl aryl ethers
having electron-withdrawing substituents at the ortho or para
positions.

12

X

R

1

R

2

CO

2

R

3

X

R

1

R

2

H

LiCl

wet DMSO

(1)

X = CO

2

R, COR, CN, SO

2

R; R

3

= Me, Et

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-
catalyzed coupling and carbonylative coupling reactions of
organostannanes and vinyl triflates.

13,14

Lithium chloride has a

dramatic effect on the stereochemical course of palladium-cata-
lyzed 1,4-additions to 1,3-dienes.

15

Treatment of 1,3-cyclohexa-

diene with Palladium(II) Acetate and LiOAc and the oxidiz-
ing agents 1,4-Benzoquinone and Manganese Dioxide affords 1,
4-trans-diacetoxy-2-cyclohexene (eq 2). In the presence of a cat-
alytic quantity of LiCl, the cis isomer is formed (eq 3). If 2
equiv LiCl are added, the cis-acetoxychloro compound forms
(eq 4). These methods are general for both cyclic and acyclic
dienes, and have recently been extended to the stereospecific
formation of fused heterocycles.

16

Lithium chloride is also used in

the preparation of Dilithium Tetrachloropalladate(II)

17

and zinc

organocuprate reagents.

18

(2)

OAc

AcO

Pd(OAc)

2

, LiOAc

no added LiCl

1,4-benzoquinone, MnO

2

93%

>91% trans

(3)

OAc

AcO

Pd(OAc)

2

, LiOAc

0.2 equiv LiCl

1,4-benzoquinone, MnO

2

85%

>96% cis

(4)

OAc

Cl

Pd(OAc)

2

, LiOAc

2 equiv LiCl

1,4-benzoquinone, MnO

2

89%

>98% cis

Weak Lewis Acid.

Lithium chloride is a weak Lewis

acid that forms mixed aggregates with lithium dialkylamides,
enolates, alkoxides, peptides, and related ‘hard’ Lewis bases.

19

Thus LiCl often has a dramatic effect on reactions involving
these species. In the deprotonation of 3-pentanone by Lithium
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

Enhancement in the enantioselectivity of deprotonation of pro-
chiral ketones by a chiral lithium amide has also been reported.

21

Lithium chloride stabilizes anions derived from α-phosphono-
acetates, permitting amine and amidine bases to be used to
perform Horner–Wadsworth–Emmons reactions on base-sensitive
aldehydes under exceptionally mild conditions.

22

Lithium

chloride and other lithium salts disrupt peptide aggregation and
increase the solubilities of peptides in THF and other ethereal sol-
vents, often by 100-fold or greater.

23

These effects render LiCl a

useful additive in the chemical modification of peptides (e.g. by the
formation and alkylation of peptide enolates).

19,24

Lithium chlo-

ride has also shown promise as an additive in solid-phase peptide
synthesis, increasing resin swelling and improving the efficiencies
of difficult coupling steps.

25

(5)

O

OTMS

OTMS

1. LiTMP (LiCl)

2. TMSCl, THF

+

0.0 equiv LiCl
0.3 equiv LiCl

9:1

52:1

Avoid Skin Contact with All Reagents

2

LITHIUM CHLORIDE

First Update

J. Kent Barbay & Wei He
Johnson & Johnson Pharmaceutical Research & Development,
Spring House, PA, USA

Source of Chloride Nucleophile. Cyclic sulfites react with

LiCl to produce chlorohydrins upon hydrolytic work-up. This
transformation was employed in the regioselective conversion of
a 1,2-diol to a chlorohydrin intermediate for the preparation of the

HIV protease inhibitor Nelfinavir

R

(eq 6).

26

PhS

NHCbz

O S

O

O

PhS

OH

OH

NHCbz

CH

2

Cl

2

PhS

NHCbz

Cl

OH

SOCl

2

, Et

3

N

1. LiCl, DMF
80

°C

70%

(6)

2. aq HCl

2,3-Epoxy alcohols, readily available from allylic alcohols

by the Katsuki-Sharpless procedure, preferentially yield chloro-
hydrins derived from substitution at C

2

upon treatment with LiCl

in the presence of trimethyl borate and acetic acid (eq 7); C

2

/C

3

selectivities are further enhanced by the use of sodium iodide as
halide source under the same conditions.

27

O

OH

BnO

BnO

OH

O

Cl

BnO

OH

Cl

OH

LiCl, B(OMe)

3

AcOH, acetone

88%

3

2

+

3

2

(7)

85:15 ratio of 2-chloro:3-chloro product

Lithium halides open epoxides to the corresponding β-halohyd-

rins under solvent-free conditions in the presence of silica gel.
The reactivity decreases in the order lithium iodide > lithium
bromide > LiCl. The addition of an equivalent amount of water
dramatically increases the reactivity of LiCl.

28

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-
nesium bromide, copper(II) bromide, lithium iodide) are also
suitable halogen sources.

29

Oxidative halodecarboxylation of α,β-

unsaturated acids to vinyl chlorides occurs upon treatment with
LiCl and cerium(IV) ammonium nitrate.

30

A combination of LiCl

and sodium periodate in acidic media converts olefins to chloro-
hydrins regioselectively (eq 8).

31

Ph

Ph

Cl

OH

LiCl, NaIO

4

aq H

2

SO

4

, CH

3

CN

81%

(8)

Source of Chloride Ligand.

LiCl and lithium bromide

increase the reducing power of samarium(II) iodide and influence
the selectivity of this reagent in the reductive coupling of alkyl
halides and ketones.

32

Weak Lewis Acid. Lithium chloride is employed for the cleav-

age of protecting groups under mild conditions. At elevated tem-
peratures (90–130

◦

C), LiCl in wet DMSO converts acetals and

ketals to the corresponding carbonyl compounds. Aryl and α,β-
unsaturated acetals and ketals are more readily cleaved under these
conditions than are their saturated counterparts.

33

Lithium chlo-

ride and water cleave tert-butyldimethylsilyl (TBDMS) ethers of
primary and secondary alcohols upon heating in DMF.

34

The dehydrohalogenation of α-halocarbonyl compounds to

α

,β-unsaturated carbonyls occurs upon treatment with LiCl in

DMF, or with a combination of LiCl and lithium carbonate
under the same conditions. For example, (Z)-alkyl α-chloro-
α

,β-unsaturated esters were prepared stereoselectively by

dehydrobromination of α-bromo-α-chloro esters under the latter
conditions (eq 9).

35

Cl

CO

2

Et

Br

CO

2

Et

Cl

LiCl, Li

2

CO

3

DMF, 70

°C

94%

(Z):(E) = 24:1

(9)

N

-acyloxazolidones are prepared in high yields from mixed

anhydrides and oxazolidinones in the presence of 1 equiv of LiCl
using triethylamine as base. Other metal halides, such as mag-
nesium bromide, failed to promote this reaction.

36

The complex-

ation of N,N-dialkylhydrazines with 2 equiv of LiCl forms an
adduct which undergoes efficient N-arylation with aryl bromides
in the presence of palladium catalysts to afford N,N-dialkyl-N

′

-

arylhydrazines (eq 10).

37

N

NH

2

Br

2 LiCl

N

N
H

Pd

2

(dba)

3

, NaOt-Bu

Xantphos, toluene, 80

°C

82%

(10)

Related

Reagents. Lithium

Chloride–Diisopropylethyl-

amine; Lithium Chloride–Hexamethylphosphoric Triamide.

1.

Magid, R. M., Tetrahedron 1980, 36, 1901.

2.

Manna, S.; Falck, J. R.; Mioskowski, C., Synth. Commun. 1985, 15, 663.

3.

(a) Owen, L. N.; Robins, P. A., J. Chem. Soc. 1949, 320. (b) Owen, L.
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.,
J. Org. Chem. 1971

, 36, 3044. (e) Stork, G.; Grieco, P. A.; Gregson,

M., Tetrahedron Lett. 1969, 18, 1393.

4.

(a) Czernecki, S.; Georgoulis, C., Bull. Soc. Chem. Fr. 1975, 405.
(b) Camps, F.; Gasol, V.; Guerrero, A., Synthesis 1987, 511.

5.

Bajwa, J. S.; Anderson, R. C., Tetrahedron Lett. 1991, 32, 3021.

6.

Bonini, C.; Giuliano, C.; Righi, G.; Rossi, L., Synth. Commun. 1992,
22

, 1863.

A list of General Abbreviations appears on the front Endpapers

LITHIUM CHLORIDE

3

7.

Shimizu, M.; Yoshida, A.; Fujisawa, T., Synlett 1992, 204.

8.

(a) Ma, S.; Lu, X., Tetrahedron Lett. 1990, 31, 7653. (b) Ma, S.; Lu, X.;
Li, Z., J. Org. Chem. 1992, 57, 709.

9.

(a) Kochi, J. K., J. Am. Chem. Soc. 1965, 87, 2500. (b) Review: Sheldon,
R. A., Kochi, J. K., Org. React. 1972, 19, 279.

10.

Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E., Jr.;
Lovey, A. J.; Stephens, W. P., J. Org. Chem. 1978, 43, 138.

11.

Reviews: (a) Krapcho, A. P., Synthesis 1982, 805. (b) Krapcho, A. P.,
Synthesis 1982

, 893.

12.

Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A., Synthesis
1989, 287.

13.

(a) Scott, W. J.; Crisp, G. T.; Stille, J. K., J. Am. Chem. Soc. 1984, 106,
4630. (b) Crisp, G. T.; Scott, W. L.; Stille, J. K., J. Am. Chem. Soc.
1984, 106, 7500.

14.

Reviews: (a) Stille, J. K., Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(b) Scott, W. J.; McMurry, J. E., Acc. Chem. Res. 1988, 21, 47.

15.

(a) Bäckvall, J. E.; Byström, S. E.; Nordberg, R. E., J. Org. Chem. 1984,
49

, 4619. (b) Bäckvall, J. E.; Nyström, J. E.; Nordberg, R. E., J. Am.

Chem. Soc. 1985

, 107, 3676.

16.

(a) Bäckvall, J. E.; Andersson, P. G., J. Am. Chem. Soc. 1992, 114,
6374. (b) Review: Bäckvall, J. E., Pure Appl. Chem. 1992, 64, 429.

17.

Lipshutz, B. H.; Sengupta, S., Org. React. 1992, 41, 135.

18.

(a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J., J. Org. Chem.
1988, 53, 2390. (b) Jubert, C.; Knochel, P., J. Org. Chem. 1992, 57,
5431. (c) Ibuka, T.; Yoshizawa, H.; Habashita, H.; Fujii, N.; Chounan,
Y.; Tanaka, M.; Yamamoto, Y., Tetrahedron Lett. 1992, 33, 3783.
(d) Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T., J. Org. Chem.
1992, 57, 1024. (e) Knochel, P.; Rozema, M. J.; Tucker, C. E.; Retherford,
C.; Furlong, M.; AchyuthaRao, S., Pure Appl. Chem. 1992, 64, 361.

19.

Seebach, D., Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.

20.

(a) Hall, P. L.; Gilchrist, J. H.; Collum, D. B., J. Am. Chem. Soc. 1991,
113

, 9571. (b) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.;

Collum, D. B., J. Am. Chem. Soc. 1991, 113, 9575.

21.

Bunn, B. J.; Simpkins, N. S., J. Org. Chem. 1993, 58, 533.

22.

(a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T., Tetrahedron Lett. 1984, 25,
2183. (b) Rathke, M. W.; Nowak, M., J. Org. Chem. 1985, 50, 2624.

23.

Seebach, D.; Thaler, A.; Beck, A. K., Helv. Chim. Acta 1989, 72, 857.

24.

Seebach, D.; Bossler, H.; Gründler, H.; Shoda, S.-i.; Wenger, R., Helv.
Chim. Acta 1991

, 74, 197.

25.

(a) Thaler, A.; Seebach, D.; Cardinaux, F., Helv. Chim. Acta 1991, 74,
617. (b) Thaler, A.; Seebach, D.; Cardinaux, F., Helv. Chim. Acta 1991,
74

, 628.

26.

Ikunaka, M.; Matsumoto, J.; Fujima, Y.; Hirayama, Y., Organic Process
Res. Dev. 2002

, 6, 49.

27.

Tomata, Y.; Sasaki, M.; Tanino, K.; Miyashita, M., Tetrahedron Lett.
2003, 44, 8975.

28.

Kotsuki, H.; Shimanouchi, T.; Ohshima, R.; Fujiwara, S., Tetrahedron
1998, 54, 2709.

29.

Inukai, N.; Iwamoto, H.; Tamura, T.; Yanagisawa, I.; Ishii, Y.;
Murakami, M., Chem. Pharm. Bull. 1976, 24, 820.

30.

Roy, S. C.; Guin, C.; Maiti, G., Tetrahedron Lett. 2001, 42, 9253.

31.

Dewkar, G. K.; Narina, S. V.; Sudalai, A., Org. Lett. 2003, 5, 4501.

32.

(a) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II,
Tetrahedron Lett. 1997

, 38, 8157. (b) Miller, R. S.; Sealy, J. M.;

Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II, J. Am.
Chem. Soc. 2000

, 122, 7718.

33.

Mandal, P. K.; Dutta, P.; Roy, S. C., Tetrahedron Lett. 1997, 38,
7271.

34.

Farras, J.; Serra, C.; Vilarrasa, J., Tetrahedron Lett. 1998, 39, 327.

35.

Forti, L.; Ghelfi, F.; Pagnoni, U. M., Tetrahedron Lett. 1995, 36,
3023.

36.

Ho, G.-J.; Mathre, D. J., J. Org. Chem. 1995, 60, 2271.

37.

Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Licandro, E.; Maiorana, S.;
Perdicchia, D., Org. Lett. 2005, 7, 1497.

Avoid Skin Contact with All Reagents