SODIUM AMALGAM 1
Sodium Amalgam Longer reaction times are required for nonconjugated enol
phosphates. Aromatic cis- and trans-enediol diesters are reported
to give the corresponding diaryl alkynes in modest yield by reduc-
Na(Hg)
tive elimination with the reagent (eq 4).9 This procedure has been
modified to provide for a one-pot operation in which 4 equiv of
[11110-52-4] Na (MW 22.99)
an aromatic acyl chloride is treated with an excess of the reagent
InChI = 1/Na in ether.9
InChIKey = KEAYESYHFKHZAL-UHFFFAOYAO
Na(Hg)
Ph OCOPh
(used in the preparation of alkenes and alkynes; to reductively Et2O
(4)
Ph Ph
cleave C S and N O bonds; for the reductive cleavage of qua-
50%
Ph OCOPh
ternary phosphonium and arsonium salts; selective dehalogena-
tion of aryl halides; also for the reduction of a variety of other
functional groups)
Alkene Synthesis. The preparation of trans-alkenes from the
Physical Data: the consistency and mp vary with the sodium
reaction of ²-alkoxy or acyloxy sulfones with sodium amalgam
content; 1.2% sodium is a semisolid at room temperature and
has been reported (eq 5).10 Trisubstituted and tetrasubstituted pre-
ć% ć%
melts completely at 50 C; 5.4% sodium melts above 360 C.
cursors generally give disappointing results. Stereoselective intro-
Solubility: sodium amalgams are decomposed by water but more
duction of the double bond in a total synthesis of diumycinol was
slowly than sodium.
accomplished with this method (eq 6).11 This protocol is effective
Form Supplied in: crushed solid; limited commercial availability.
when other standard conditions fail.
Analysis of Reagent Purity: the amalgam can be analyzed for
sodium by titration with 0.1 N sulfuric or hydrochloric acid.
Na(Hg)
SO2Ph
Preparative Methods: several procedures for the preparation of EtOH
(5)
sodium amalgam have been reported.1 4 Amalgams containing 79%
Bu
Bu OAc
2 6% sodium are the most commonly employed for synthetic
work. The safest and most convenient procedure for the prepa-
ration of 2% sodium amalgam is the addition of Mercury(0)
OBn 1. Na(Hg)
SO2Ph
to ribbons of Sodium metal.5,6 No external heating is required THF, MeOH
0 °C
with this protocol. The resulting solid can be crushed and stored
2. Na, NH3
indefinitely in a tightly stoppered container.
OBz
33%
Handling, Storage, and Precautions: moisture sensitive; keep
tightly closed. OH
(6)
Alkyne Synthesis. Reductive cleavage of the triflate salts of
vinyl phosphonium triflates with 2% sodium amalgam affords
pure alkynes in good to excellent yield (eqs 1 and 2).7 This repre-
sents a significant improvement in yield and purity over the method
Desulfurization.12 17 This reaction has perhaps found the
involving thermal cleavage of acyl ylides. The highest yields are
widest use of the reagent. The value of sulfides, sulfoxides, and sul-
obtained when one group is aryl (eq 2). Alkynes are also obtained
fones in organic synthesis is increased by the ease with which their
in respectable yields by the reductive elimination of enol phos-
removal is accomplished. For example, sulfones are conveniently
phates of ²-oxo sulfones with the reagent (6%) in DMSO THF
hydrogenolyzed with 6% reagent in boiling ethanol (eq 7).12 The
(eq 3).8
use of disodium hydrogen phosphate is recommended as a buffer
with the reagent in some applications with allylic sulfones and
2% Na(Hg)
Bu OSO2CF3 ²-keto sulfides (eqs 8 and 9).15
THF
(1)
Bu C6H13
+
52%
C6H13 PPh3  OSO2CF3
6% Na(Hg), EtOH
Bu Bu
reflux
SO2Ar (7)
Ph 92% Ph
2% Na(Hg)
Ar = p-ClC6H4
Ph OSO2CF3
THF
(2)
Ph
+
80%
PPh3  OSO2CF3
SO2-p-Tol
6% Na(Hg)
NC
MeOH, Na2HPO4
SO2Ph 6% Na(Hg) Ph
66%
DMSO THF
Ph
2 h
(3)
NC
O 72%
P(OEt)2
(8)
O
Avoid Skin Contact with All Reagents
2 SODIUM AMALGAM
PhS O O
6% Na(Hg) N O Bond Hydrogenolysis. Reductive cleavage of N O
MeOH, Na2HPO4
bonds is easily accomplished with the reagent (eqs 15 and 16).
(9)
90%
Keck reported the facile hydrogenolysis of the intramolecular
Diels Alder acyl-nitroso cycloadduct with excess reagent in a
buffered alcoholic medium to yield a hydroxy lactam (eq 15).21
Desulfonylation of unsaturated Ä…,²-unsaturated acetals with the
Similarly, Jager subjected dihydroisoxazoles to hydrogenolysis
reagent in buffered methanolic medium gives the reduced prod-
with 6% sodium amalgam to afford the corresponding 1,3-amino
ucts as a mixture of isomers (eq 10).17 Hydrolysis of the mixture
alcohols (eq 16).22 The syn and anti stereoselectivity is reported
affords the desired Ä…,²-unsaturated ketone as the major product.
to be lower with this reagent than with Lithium Aluminum
²-Hydroxynitriles have been prepared in good yield and with
Hydride. This method of N O bond reduction is less common
retention of stereochemistry by the action of the 2% reagent in
than those using either Aluminum Amalgam or LAH.
wet THF on sulfonylisoxazolines (eqs 11 and 12).18 The addi-
tion of aqueous phosphate buffer is sometimes required to prevent
TBDMSO TBDMSO
further hydrogenolysis (eq 12).
H H
6% Na(Hg)
O O
EtOH, Na2HPO4
N N
(15)
H
O 82%
6% Na(Hg)
O O O O O O
OH
MeOH, Na2HPO4
TsOH, EtOH
+
89% 74%
SO2Ph
6% Na(Hg)
59:41
C14H29
EtOH, Na2HPO4
O O
O N
C14H29 C14H29
+ (10) + (16)
OH NH2 OH NH2
88:12
80:20
Reductive Cleavage of Quaternary Phosphonium and
2% Na(Hg)
HO
O
wet THF Arsonium Salts. Reductive cleavage of achiral and optically
N (11)
89% active quaternary and phosphonium salts with the reagent affords
NC
tertiary phosphines and arsines in high yields and with retention
PhO2S
of configuration (eq 17).23
2% Na(Hg)
Na(Hg)
+
O
HO Ph
CH2Cl2
Ph (S)-(+)-PhCH2PMePhPr Br (S)-(+)-PMePhPr (17)
N
Na2HPO4, NaH2PO4
(12)
88%
NC Ph
PhO2S Ph
Selective reductive cleavage of the t-butyl group occurs in sub-
strates containing both the t-butyl and benzyl substituents. The
Enantiomerically pure 4,5-dihydroisoxazoles are available by
present method is reported to be superior to the conventional ca-
selective desulfurization of 3-p-tolylsulfinylmethyl-4,5-dihydro-
thodic cleavage. Emde degradation of the quaternary ammonium
isoxazoles with the reagent in a buffered medium (eq 13).19
chloride succeeds where the Hofmann method is unsuccessful
Further treatment of the products with Raney Nickel affords
(eq 18).24 In a similar fashion, hemimellitene was prepared by
the corresponding amino alcohols. Selective desulfurization of
treating an aqueous suspension of the benzyltrimethylammonium
methyl 3,4,6-tri-O-benzyl-2-O-(methylsulfonyl)-Ä…-D-mannopy-
iodide with a large excess of the reagent (eq 19).3
ranoside derivatives was accomplished with 6 7% reagent in 2-
propanol and ether (eq 14).20 Treatment with Nickel in ethanol,
Na(Hg)
(18)
Sodium Naphthalenide in THF, or Sodium Ammonia resulted
+
CH2NMe3 Cl
in removal of the benzyl groups as well.
8% Na(Hg) +
O
N O N O
CH2NMe3 I
MeOH, Na2HPO4
S+ Na(Hg)
(13)
p-Tol
98%
large excess
Ph Ph
(19)
85%
6% Na(Hg)
OMs
OH
Et2O, i-PrOH BnO
BnO
O O Dehalogenation of Aryl Halides. Selective dehalogenation
pH 7
BnO BnO
BnO BnO (14)
of aryl halides with the reagent in liquid ammonia has been found
98%
OMe OMe
(eqs 20 and 21).25
A list of General Abbreviations appears on the front Endpapers
:
SODIUM AMALGAM 3
Na(Hg)
2% Na(Hg), AcOH
Cl Cl
NH2 (27)
NOH
NH3 (l)
Cl
Cl
(20) 76%
O
O
80%
Br
O
2% Na(Hg)
HO
HO CHO
H2O, H2SO4
O
Cl
(28)
Na(Hg) 56%
HO
HO OH
NH3 (l)
(21)
OH
OH
100%
Other Applications. Several recent useful miscellaneous
Reduction of Miscellaneous Functional Groups. Many ad- applications have been reported. They include the use of the
3% reagent for the reduction of 1-ethyl-4-methoxycarbonyl-
ditional functional groups react readily with the reagent to afford,
pyridinium iodide in acetonitrile to produce a stable radical
in generally good yields, the corresponding reduced products. For
example, phthalic acid reacts with the 3% reagent to yield trans- (eq 29);29 the use of the reagent as a catalyst to initiate aromatic
radical nucleophilic substitution reactions;30 and the use of the
1,2-dihydrophthalic acid in good yield (eq 22).4 Ä…,²-Unsaturated
carboxylic acids are also readily reduced by the reagent. Thus cin- reagent for the preparation of novel titanium catalysts for the stere-
oselective cyclization of diynes to (E,E)-exocyclic dienes.31
namic acid is reduced to hydrocinnamic acid with 2.5% reagent
in aqueous base (eq 23).4
CO2Me
CO2Me
3% Na(Hg)
3% Na(Hg)
"
CO2H CO2H MeCN
H2O, AcOH
(29)
+
AcONa 10 30%
(22) N
N
CO2H 62% CO2H I
Et
Et
CO2H CO2H
2% Na(Hg)
1. Holleman, A. F., Org. Synth., Coll. Vol. 1941, 1, 554.
(23)
2. Renfrow, W. B., Jr.; Hauser, C. R., Org. Synth., Coll. Vol. 1943, 2, 607.
H2O, AcOH
Ph Ph
3. Brasen, W. R.; Hauser, C. R., Org. Synth., Coll. Vol. 1963, 4, 508.
4. McDonald, R. N.; Reineke, C. E., Org. Synth. 1970, 50, 50.
5. Fieser, L. F.; Fieser, M., Fieser & Fieser 1967, 1, 1030.
The product from the condensation of vanillin and creatinine
6. Blomquist, A. T.; Hiscock, B. F.; Harpp, D. N., J. Org. Chem. 1966, 31,
is reduced by 3% reagent in water (eq 24).26 Xanthone was re-
4121.
duced to xanthydrol with the reagent in ethanol (eq 25).1 Triph-
7. Bestmann, H. J.; Kumar, K.; Schaper W., Angew. Chem., Int. Ed. Engl.
enylchloromethane is converted to triphenylmethylsodium by ac-
1983, 22, 167.
tion of the 1% reagent (eq 26).2 Oximes are reduced to primary
amines with the 2.5% reagent with acetic acid in ethanol (eq 27).27 8. (a) Lythgoe, B.; Waterhouse, I., Tetrahedron Lett. 1978, 2625.
(b) Lythgoe, B.; Waterhouse, I., J. Chem. Soc., Perkin Trans. 1 1979,
One of the oldest applications of sodium amalgam involves the re-
2429.
duction of aldonolactones to aldoses (eq 28).28
9. Horner, L.; Dickerhof, K., Chem. Ber. 1983, 116, 1615.
10. Julia, M.; Paris, J.-M., Tetrahedron Lett. 1973, 4832.
H
H
11. Kocienski, P.; Todd, M., J. Chem. Soc., Chem. Commun. 1982, 1078.
O
N O
N
NH 12. Posner, G. H.; Brunelle, D. J., Tetrahedron Lett. 1973, 935.
NH
Na(Hg)
N
13. Dabby, R. E.; Kenyon, J.; Mason, R. F., J. Chem. Soc. 1952, 4881.
N
H2O
Me
Me
(24) 14. Julia, M.; Blasioli, C., Bull. Soc. Chem. Fr., Part 2 1976, 1941.
72%
15. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R., Tetrahedron
Lett. 1976, 3477.
OMe
OMe
16. Chang, Y.-H.; Pinnick, H. W., J. Org. Chem. 1978, 43, 373.
OH
OH
17. Paquette, L. A.; Kinney, W. A., Tetrahedron Lett. 1982, 23, 131.
18. Wade, P. A.; Bereznak, J. F., J. Org. Chem. 1987, 52, 2973.
19. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gilardi, A.; Restelli, A., J.
Na(Hg), EtOH
O O Chem. Soc., Perkin Trans. 1 1985, 2289. (b) Annunziata, R.; Cinquini,
60 70 °C
M.; Cozzi, F.; Restelli, A., J. Chem. Soc., Perkin Trans. 1 1985, 2293.
(25)
91%
20. Webster, K. T.; Eby, R.; Schuerch, C., Carbohydr. Res. 1983, 123, 335.
O OH 21. (a) Keck, G. E.; Fleming, S. A., Tetrahedron Lett. 1978, 4763. (b) Keck,
G. E., Tetrahedron Lett. 1978, 4767.
22. (a) Jager, V.; Buss, V., Liebigs Ann. Chem. 1980, 101. (b) Jager, V.; Buss,
V.; Schwab, W., Liebigs Ann. Chem. 1980, 122.
Na(Hg), Et2O

23. Horner, L.; Dickerhof, K., Phosphorus Sulfur Silicon 1983, 15, 213.
(26)
Ph3CCl Ph3C Na+
100%
24. Emde, H.; Kull, H., Arch. Pharm. (Weinheim, Ger.) 1936, 274, 173.
Avoid Skin Contact with All Reagents
4 SODIUM AMALGAM
25. Austin, E.; Alonso, R. A.; Rossi, R. A., J. Chem. Res. (S) 1990, 190. 30. Austin, E.; Alonso, R. A.; Rossi, R. A., J. Org. Chem. 1991, 56,
4486.
26. Deulofeu, V.; Guerrero, T. J., Org. Synth., Coll. Vol. 1955, 3, 586.
31. Nugent, W. A.; Calabrese, J. C., J. Am. Chem. Soc. 1984, 106, 6423.
27. Hochstein, F. A.; Wright, G. F., J. Am. Chem. Soc. 1949, 71, 2257.
28. Sperber, N.; Zaugg, H. E.; Sandstrom, W. M., J. Am. Chem. Soc. 1947,
69, 915. Keith R. Buszek
Kansas State University, Manhattan, KS, USA
29. Kosower, E. M.; Waits, H. P., Org. Prep. Proced. Int. 1971, 3, 261.
A list of General Abbreviations appears on the front Endpapers