SODIUM ETHOXIDE 1
Condensations of esters with the enolate of acetone can be
Sodium Ethoxide1
effected using sodium ethoxide as a base to yield products such
as acetylacetone.2a and the precursor to chelidonic acid depicted
NaOEt
in eq 22b The corresponding enolates of methyl aryl ketones can
similarly be utilized.2c,1f
[141-52-6] C2H5NaO (MW 68.06)
O
InChI = 1/C2H5O.Na/c1-2-3;/h2H2,1H3;/q-1;+1 O
O
H2O
NaOEt
InChIKey = QDRKDTQENPPHOJ-UHFFFAOYAQ EtO
+
OEt
EtOH HCl
O
(used as a base for the Ä…-deprotonation of carbonyl- EtO2C O O CO2Et
containing compounds for subsequent intermolecular2 or
O
intramolecular1f condensations, displacements,3 or skele-
(2)
tal rearrangements,1d,4 arylacetonitriles,5 nitro-containing
aliphatic compounds,6 sulfonium salts,3j,7 for the dehydra-
HO2C O CO2H
tion of carbinolamines8 and for dehydrohalogenation,1b,9
76 79%
for the N-deprotonation of amides,10a d tosylamines,10e
amine hydrochlorides1c or toluenesulfonates,10f cyanamide,10g
Condensation of the sodium ethoxide-generated enolate of
and the S-deprotonations of sulfides,1c,11 often followed
cyclohexanone with ethyl formate yields 2-hydroxymethylene-
by cyclizations;1c,10b,10g,11 can be used as a nucleophile
cyclohexanone which, upon treatment with hydrazine
in ipso substitution reactions of vinyl sulfides,12a aromatic
monohydrate, forms indazole in excellent yield (eq 3).2d
halides,12b i sometimes catalyzed by copper12c or palladium,12h,i
aryl sulfones,12j and aromatic nitro compounds,12k in the CHOH
NaOEt, EtOH N2H4" H2O
Williamson ether synthesis,13a c in displacements of halo,13d h
+ HCO2Et
0 °C to rt
nitro,13e thiooxy,13g,h and phenoxy13g groups from dichloro- O
O
methane and chloroform analogs, in a novel transesterification
conjugate addition protocol of acrylic esters,14 with Ä…-nitro
N (3)
epoxides to form Ä…-ethoxy ketones,15 in the nucleophilic attack N
H
on nitriles1e,16 and polyhaloalkenes,17 in reaction with chloro-
95 98%
diphenylphosphine to form Arbuzov precursors,18 and with
Grignard reagents to form organomagnesium ethoxides19)
Sodium ethoxide is often the base of choice in the Ä…-
ć%
Physical Data: mp >300 C.
acylation2e i and alkylation3h of esters. Interesting intramolec-
Solubility: sol ethanol, diethyl ether.
ular cyclizations sometimes follow in good yield (eq 4).
Form Supplied in: white or yellowish powder or as 21 wt %
O
O
solution in ethanol; widely available.
NaOEt, EtOH
EtO
+
Preparative Methods: it is often necessary to prepare sodium
OEt
OEt
Et2O
ethoxide immediately prior to its use. Preparation of a 6 10%
Ph
O
solution in ethanol: to commercial absolute ethanol is added the
O
O
required amount of Sodium in lumps or slices with or without
stirring and with or without a nitrogen atmosphere and the solu- OEt
(4)
O
tion is cooled or heated as required until the metal is dissolved. Ph OEt
O
The evolved hydrogen should be vented into a hood. Addition
O
O
of ethanol to sodium is also reported. Alcohol-free reagent can
73 81%
also be prepared.1a
Handling, Storage, and Precautions: is a hygroscopic, flamma-
Alkylation of malonate esters through the intermediacy of eno-
ble, corrosive, and toxic solid which will decompose upon
lates generated using sodium ethoxide is quite common.3 Sub-
exposure to air. The solid or solution reagent should be tightly
sequent decarboxylation to the carboxylic acid can then be
sealed under an inert atmosphere in a dark bottle.
induced, as depicted in eq 5.3d
O
General Discussion. Kinetic studies of the proton trans-
Br Br O O
2 equiv NaOEt
OEt
fer reaction between bis(4-nitrophenyl)methane and alkoxide
+
EtO OEt EtOH OEt
base systems reveal that sodium ethoxide is a kinetically faster
(kH = 2.16 M-1 s-1) base than either sodium isopropoxide O
(kH = 0.280 M-1 s-1) or sodium t-butoxide (kH = 1.05 M-1 s-1)
O
(5)
(eq 1).20a Reaction between alkali alkoxides and p-nitrophenyl
OH
methanesulfonate have revealed the following order of reactivity:
18 21%
LiOEt< NaOEt < CsOEt H" KOEt H" KOEt + 18-crown-6 <
KOEt + [2.2.2]cryptand.20b
Sodium ethoxide and Sodium Hydroxide have both proven
Ar2CH2 + RONa Ar2CHNa + ROH (1)
effective in the cyclopropanation of various Å‚,´-epoxy ketones,
Avoid Skin Contact with All Reagents
2 SODIUM ETHOXIDE
O
as illustrated in eq 6. Adducts are generated in good to excellent
yields.4 H2, Raney Ni
NaOEt, EtOH
O
EtOH, rt reflux
N
O N
OH
H
m-CPBA, CH2Cl2
R
R
0 °C
O
70%
(10)
O
NaOEt, EtOH
OH
O
reflux, 15 min
R
O O (6)
>90%
65 67%
NaOEt, DMSO
80 °C
Ph3C Cl
Ph3C
(11)
Deprotonation Ä… to nitriles has been found to be strongly
90%
influenced by the purity of the sodium ethoxide used5a and can
be done selectively over Ä…-deprotonation of an ester.5b Reactions
Heteroatom deprotonations using sodium ethoxide as the base
with aromatic aldehydes lead to condensation adducts (eq 7).5c
are also quite common. Sodium ethoxide serves as an effective
base when the nitrogen of cyanoacetamide must be condensed
O on an ester. Subsequent intramolecular cyclization proceeding via
CN
NaOEt, EtOH
+ (7) Ä…-deprotonation to the nitrile leads to excellent yield of the di-
PhCH
Ph CN
Ph H 83 91%
Ph
cyanoglutarimide shown in eq 12.10a
Ph
1. NaOEt
O NC CN
Deprotonations Ä… to nitro functionalities have been found to Ph CN
2. HCl
+ NC (12)
proceed with greater ease using sodium ethoxide rather than
NH2
90 92%
CO2Et
O N O
Sodium Methoxide.6 The in situ generated anion of 2-nitro-
H
propane transforms a benzylic bromide to its aromatic aldehyde
derivative in good yield (eq 8).7a
Other N-deprotonations include that of urea,10b thiourea,10c
succinimide,10d tosylamines,10e cysteamine hydrochloride
(eq 13),1c ribofuranosylamine toluenesulfonate,10f and cyana-
 Br
NO2 NaOEt NO2
mide (eq 14).10g Similarly, S-deprotonations of sulfides
Na+
(eq 13)1c,11 have been reported. Often, adducts can be used in
EtOH rt, 4 h
subsequent cyclizations.1c,10b,g,
O
NaOEt
NH2" HCl NH2 xs. MeCN
HS HS
+ + NaBr (8) reflux reflux
NOH
S
68 73%
(13)
N
67 73%
Sodium ethoxide serves as a multipurpose base to generate both
1. HBr, H2O
the ylide of dimethyl-2-propynylsulfonium bromide and the anion
NC
NaOEt 2. NaOEt, EtOH
of acetylacetone in the synthesis of 3-acetyl-2,4-dimethylfuran NC OEt  NH
EtOH reflux
+ H2NCN
NC CN
illustrated in eq 9.3j The intermediacy of an allene has been
95% 65%
NC
Na+
suggested.7b
NC
N
(14)
O O
+
NaOEt, EtOH
Me2S
H2N N OEt
+
Br
reflux, 6 h
The synthesis of 6,6-dialkoxyfulvenes from 6,6-bis(methyl-
O
thio)fulvene has been reported in good yield via treatment with
+ Me2S (9)
sodium ethoxide or related nucleophiles, followed by thermolysis
(eq 15).12a
O
81%
C(OEt)3 C(OEt)3
10 equiv NaOEt
MeS
THF PhH
+
rt, 2.5 h reflux, 5 h
MeS
Sodium ethoxide both dehydrates and nucleophilically assists
in the deacylation of the carbinolamine intermediate depicted
EtO
in eq 10.8 Furthermore, sodium ethoxide-mediated dehydrohalo- (15)
EtO
genation in DMSO solvent has been achieved in excellent yield
70%
(eq 11).1b,9
A list of General Abbreviations appears on the front Endpapers
SODIUM ETHOXIDE 3
Addition of a large excess of sodium ethoxide or methoxide to followed by chain transfer from the resulting p-ethoxybenzo-
11-chloro[5]metacyclophanes leads to good yields of ipso alkoxy- phenone radical, resulting in the adduct pictured in eq 20.12k
substituted adducts.12b Sodium ethoxide proves to be the fastest of
O
O
NaOEt, HMPA
a series of nucleophiles in ipso substitution reactions of aromatic
60 h
bromides employing a Copper(I) Bromide catalyst (eq 16). Once
Ph (20)
Ph
29%
again, purity of alkoxide seems to be important.12c Substitution
OEt
NO2
of aryl iodides is also known.12d
NaOEt, CuBr (cat)
Sodium ethoxide is frequently employed as the nucleophile in
EtOH
the Williamson ether synthesis,.13a c as illustrated in eq 21
Br (16)
OEt
NMe Furthermore, polydisplacements of halo,13d h nitro,13e
93%
thiooxy,13g,h and phenoxy13g groups of dichloromethane and
O
chloroform analogs have been realized by the use of sodium
ethoxide as the nucleophile. This methodology has been used
Ipso ethoxy substitutions of halo-pyrimidines,10g -purines
in the syntheses of ethyl orthocarbonate (eq 22) and ethyl
(eq 17),12e -thiophenes,12c,f -furans,12c and -triazines12g using
diethoxyacetate (eq 23) in moderate to good yields.
sodium ethoxide have also been reported in good yield.
O O
BzO N3 NaOEt, EtOH
NaOEt, EtOH
N
rt, 5 h
60 °C, 5 h
(21)
N
Cl
67%
84%
Ph O Ph O
O
N N
Br OEt
HO N3
N
4 equiv NaOEt NaOEt
N
(17)
EtO
Cl3C S Cl (EtO)3C S OEt
EtOH EtOH
O
N N
C(OEt)4 (22)
78%
Aryl iodides, vinyl bromides, and tricarbonyl(chloroarene)-
chromium complexes have been found to react under mild con-
1. 3 equiv NaOEt
ditions with sodium alkoxides in the presence of catalytic 2. HCl, EtOH
Cl2HC CO2H (EtO)2HC CO2Et (23)
dichlorobis(triphenylphosphine)palladium(II) (see Palladium(II)
45 50%
Chloride) to afford the corresponding benzoate esters as the major
products (eq 18).12h,i It has been rationalized that the higher base
Sodium ethoxide has been employed for a transesterification
strength of sodium ethoxide compared to that of sodium methox- conjugate addition protocol, which takes advantage of the syn-
ide allows the former to successfully decarbonylate ethyl formate,
selective addition of sodium alkoxides to acrylic esters such as
whereas the latter proves more sluggish, yielding poorer results.
the one depicted in eq 24.14
Cl OEt
NaOEt, HCO2Et NaOEt, EtOH
O O
 50 °C
0.55% PdCl2(PPh3)2
(24)
O CO2Me O CO2Et
>85%
Cr(CO)3
CO2Et CO2Et
syn:anti = 86:14
+ + (18)
An interesting synthesis of Ä…-ethoxy ketones employs nucle-
Cr(CO)3 Cr(CO)3 Cr(CO)3 ophilic reaction of sodium ethoxide with Ä…-nitro epoxides. The
20% 2%
66%
reaction appears to be quite general and a variety of nucleophiles
may be employed (eq 25).15
Ipso substitution of 2- and 4-pyridyl sulfones is also possi-
EtO
ble using a variety of nucleophiles, including sodium ethoxide.
NaOEt, EtOH
O
rt, 2 min
The sulfone moiety is preferentially displaced over a chlorine
O (25)
O2N 64%
substituent also present on the aromatic ring (eq 19). The same
reaction utilizing sulfoxides gives mixed results, while sulfides
fail to react.12j
Nucleophilic attack of sodium ethoxide on 3,4- or 2,3-
cyanomethyl cyanopyridines followed by cyclization provides
NaOEt, EtOH
access to amino alkoxy naphthyridines (eq 26).1e,16 The reaction
SO2Me (19)
OEt
50 °C, 1 h
N is believed to proceed through an imidate intermediate.16a Unfor-
N
84%
Cl
Cl
tunately, treatment of the analogous carbocyclic 2-cyanobenzyl
cyanides under similar conditions leads to dimerization of start-
It has been suggested that displacement of the nitro group of ing material, and cyclization must be achieved under acidic
the radical anion of p-nitrobenzophenone by sodium ethoxide is conditions.16b
Avoid Skin Contact with All Reagents
4 SODIUM ETHOXIDE
NH2
4. (a) Gaoni, J., Tetrahedron 1972, 28, 5525. (b) Gaoni, J., Tetrahedron
NaOEt, EtOH
CN
1972, 28, 5533.
reflux to rt N
(26)
5. (a) Horning, E. C.; Finell, A. F., Org. Synth., Coll. Vol. 1963, 4, 461.
N
N CN 72%
OEt
(b) Coan, S. B.; Becker, E. I., Org. Synth., Coll. Vol. 1963, 4, 174.
(c) Womack, E. B.; McWhirter, J., Org. Synth., Coll. Vol. 1955, 3, 714.
Sodium ethoxide is also known to nucleophilically add to
6. Dauben, Jr., H. J.; Ringold, H. J.; Wade, R. H.; Pearson, D. L.; Anderson,
polyhaloalkenes with preferential attack on the methylene with
Jr.; A. G., Org. Synth., Coll. Vol. 1963, 4, 221.
the highest degree of fluorine substitution (eqs 27 and 28).17
7. (a) Hass, W. B.; Bender, M. L., Org. Synth., Coll. Vol. 1963, 4, 932.
Excess nucleophile unveils an ethyl ester (eq 28).
(b) Batty, J. W.; Howes, P. D.; Stirling, C. J. M., J. Chem. Soc., Perkin
F F F F
Trans. 1 1973, 65.
NaOEt, EtOH
Cl F (27)
8. McMurry, J. E., Org. Synth., Coll. Vol. 1988, 6, 781.
92 97%
Cl F H OEt
9. Norman, R. O. C.; Thomas, C. B., J. Chem. Soc. (C) 1967, 1115.
1 equiv NaOEt
10. (a) McElvain, S. M.; Clemens, D. H., Org. Synth., Coll. Vol. 1963, 4,
Br Br Br OEt
3 equiv NaOEt
EtOH
662. (b) Sherman, W. R.; Taylor, Jr., E. C., Org. Synth., Coll. Vol. 1963,
80 °C, 40 h
4, 247. (c) Ulbricht, T. L. V.; Okuda, J.; Price, C. C., Org. Synth., Coll.
Br F Br F
Vol. 1963, 4, 566. (d) Crockett, G. C.; Koch, T. D., Org. Synth., Coll.
Br O
Vol. 1988, 6, 226. (e) Atkins, T. J.; Richman, J. E.; Oettle, W. F., Org.
Br (28)
Synth., Coll. Vol. 1988, 6, 652. (f) Espie, J. C.; Lhomme, M. F.; Morat,
H OEt
J.; Lhomme, J., Tetrahedron Lett. 1990, 31, 1423. (g) Schmidt, J.-W.;
80 85%
Koitz, J.; Junek, J., J. Heterocycl. Chem. 1987, 24, 1305.
11. Gillis, R. G.; Lacey, A. B., Org. Synth., Coll. Vol. 1963, 4, 396.
Reaction of sodium ethoxide with chlorodiphenylphosphine
12. (a) Gupta, J.; Yates, J., Synth. Commun. 1982, 12, 1007. (b) Kraakman, P.
provides access to Arbuzov precursors, which can be further
A.; Valk, J.-M.; Niederländer, H. A. G.; Brouwer, D. B. E.; Bickelhaupt,
reacted with suitable electrophiles to form phosphine oxides
F. M.; de Wolf, W. H.; Bickelhaupt, J.; Stam, C. H., J. Am. Chem.
(eq 29).18
Soc. 1990, 112, 6638. (c) Keegstra, M. A.; Peters, T. H. A.; Brandsma,
NaOEt
J., Tetrahedron 1992, 48, 3633. (d) Somei, J.; Yamada, J.; Kunimoto,
Cl
EtOH, Et2O
J.; Kaneko, J., Heterocycles 1984, 22, 797. (e) Carret, J.; Grouiller,
0 °C, 0.5 h
Cl
J.; Chabannes, J.; Pacheco, J., Nucleosides Nucleotides 1986, 3, 331.
Ph2P Cl Ph2P OEt
96% DMF, reflux, 15 h
(f) Puschmann, J.; Erker, J., Heterocycles 1993, 36, 1323. (g) Konno, J.;
82%
Ohba, J.; Agata, J.; Aizawa, J.; Sagi, J.; Yamanaka, J., Heterocycles 1987,
26, 3259. (h) Carpentier, J.-F.; Castanet, J.; Brocard, J.; Mortreux, J.;
O
Petit, J., Tetrahedron Lett. 1991, 32, 4705. (i) Carpentier, J.-F.; Castanet,
P Ph2
J.; Brocard, J.; Mortreux, J.; Petit, J., Tetrahedron Lett. 1992, 33, 2001.
(29)
(j) Furukawa, J.; Ogawa, J.; Kawai, J., J. Chem. Soc., Perkin Trans. 1
Ph2 P
1984, 1839. (k) Denney, D. B.; Denney, D. Z.; Perez, A. J., Tetrahedron
O
1993, 49, 4463.
Treatment of Grignard reagents (RMgBr) with sodium
13. (a) Slomkowski, J.; Winnik, M. A.; Furlong, J.; Reynolds, W. F.,
ethoxide offers a synthetic route to organomagnesium ethoxides
Macromolecules 1989, 22, 503. (b) Marei, M. G.; Mishrikey, M. M.;
(RMgOEt).19 No yields are reported for this reaction.
El-Kholy, I. El-S., Acta Chim. Hung. 1987, 124, 733. (c) Marei, M. G.;
Mishrikey, M. M.; El-Kholy, I. El-S., Indian J. Chem., Sect. B 1987, 26B,
163. (d) Moffett, R. B., Org. Synth., Coll. Vol. 1963, 4, 427. (e) Roberts, J.
Related Reagents. Potassium t-Butoxide; Potassium
D.; McMahon, R. E., Org. Synth., Coll. Vol. 1963, 4, 457. (f) Kaufmann,
2-Methyl-2-butoxide; Sodium Hydroxide; Sodium Methoxide.
W. E.; Dreger, E. E., Org. Synth., Coll. Vol. 1941, 1, 253. (g) Connolly,
J. M.; Dyson, G. M., J. Chem. Soc 1936, 827. (h) Tieckelmann, J.; Post,
H. W., J. Org. Chem. 1948, 13, 265.
1. (a) Fieser & Fieser 1967, 1, 1065. (b) Fieser & Fieser 1969, 2, 157.
14. Mulzer, J.; Kappert, J.; Huttner, J.; Jibril, J., Angew. Chem., Int. Ed. Engl.
(c) Fieser & Fieser 1972, 3, 265. (d) Fieser & Fieser 1974, 4, 451.
1984, 23, 704.
(e) Fieser & Fieser 1977, 6, 540. (f) Fieser & Fieser 1986, 12, 402.
15. Vankar, Y. B.; Shah, J.; Bawa, J.; Singh, S. P., Tetrahedron 1991, 47,
2. (a) Denoon, Jr., C. E., Org. Synth., Coll. Vol. 1955, 3, 16. (b) Riegel, E.
8883.
R.; Zwilgmeyer, J., Org. Synth., Coll. Vol. 1943, 2, 126. (c) Magnani,
J.; McElvain, S. M., Org. Synth., Coll. Vol. 1955, 3, 251. (d) Tishler, J.; 16. (a) Alhaique, J.; Riccieri, F. M.; Santucci, J., Tetrahedron Lett. 1975,
Gal, J.; Stein, G. A., Org. Synth., Coll. Vol. 1963, 4, 536. (e) Briese, R. 173. (b) Johnson, J.; Nasutavicus, W. W., J. Org. Chem. 1962, 27, 3953.
R.; McElvain, S. M., J. Am. Chem. Soc. 1933, 55, 1697. (f) Hershberg,
17. (a) Shainyan, B. A.; Rappoport, J., J. Org. Chem. 1993, 58, 3421.
E. B.; Fieser, L. F., Org. Synth., Coll. Vol. 1943, 2, 194. (g) Floyd, D.
(b) Englund, J., Org. Synth., Coll. Vol. 1963, 4, 184.
E.; Miller, S. E., Org. Synth., Coll. Vol. 1963, 4, 141. (h) Holmes, H.
18. Yang, J.; Geise, H. J.; Nouwen, J.; Adriaensens, J.; Franco, J.;
L.; Trevoy, L. W., Org. Synth., Coll. Vol. 1955, 3, 301. (i) Friedman, J.;
Vanderzande, J.; Martens, J.; Gelan, J.; Mehbod, J., Synth. Met. 1992,
Kosower, J., Org. Synth., Coll. Vol. 1955, 3, 510.
47, 111.
3. (a) Allen, J.; Kalm, M. J., Org. Synth., Coll. Vol. 1963, 4, 616. (b) Adams,
19. Gupta, J.; Sharma, J.; Narula, A. K., J. Organomet. Chem. 1993, 452, 1.
J.; Kamm, R. M., Org. Synth., Coll. Vol. 1941, 1, 245. (c) Cox, R. F. B.;
20. (a) Schroeder, J., React. Kinet. Catal. Lett. 1992, 46, 51. (b) Pregel, M.
McElvain, S. M., Org. Synth., Coll. Vol. 1943, 2, 279. (d) Callen, J. E.;
J.; Buncel, J., J. Am. Chem. Soc. 1993, 115, 10.
Dornfield, C. A.; Coleman, G. H., Org. Synth., Coll. Vol. 1955, 3, 212.
(e) Moffett, R. B., Org. Synth., Coll. Vol. 1963, 4, 291. (f) Mariella, R. P.;
Raube, J., Org. Synth., Coll. Vol. 1963, 4, 288. (g) Andruzzi, J.; Hvilsted,
K. Sinclair Whitaker
J., Polymer 1991, 32, 2294. (h) Marvel, C. S.; King, W. B., Org. Synth.,
Wayne State University, Detroit, MI, USA
Coll. Vol. 1941, 1, 246. (i) Shriner, R. L.; Todd, H. R., Org. Synth., Coll.
D. Todd Whitaker
Vol. 1943, 2, 200. (j) Howes, P. D.; Stirling, C. J. M., Org. Synth., Coll.
Vol. 1988, 6, 31. Detroit Country Day School, Beverly Hills, MI, USA
A list of General Abbreviations appears on the front Endpapers