557

Sandmeyer Isatin Synthesis

(Sandmeyer Synthesis)

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Sandmeyer in 1919.1 It is a synthesis of isatin deriva-
tive involving the condensation of chloral (i.e., trichloroacetaldehyde), hydroxylamine, and
a primary aryl amine to an α-isonitrosoacetanilide and subsequent electrophilic cyclization
of the latter in the presence of a strong acid such as concentrated sulfuric acid.2 Therefore,
this reaction is generally known as the Sandmeyer isatin synthesis2a,3 or the Sandmeyer
synthesis.4 During this reaction, the oximino intermediate can be isolated by extraction
with warm 2 N NaOH followed by the precipitation with a 2 N HCl solution and purified
by recrystallization in ethanol.5 The isatin derivatives from this reaction have been used as
the starting material for quinolines, acridines, and indophenazines.3c It is possible that the
oximino intermediate from the meta-substituted aryl amine may form two stereoisomers
during electrophilic cyclization (i.e., the 4- and 6-substituted isatins), which cannot be sepa-
rated completely by fractional crystallization.6 It is interesting that these two stereoisomers
could be completely and rapidly isolated by precipitation of 4-isomer (usually red nee-
dles) with acetic acid followed by the precipitation of 6-isomer (usually yellow plates) by
concentrated HCl.6 However, this reaction fails to convert the oximino intermediates aris-
ing from nitroanilines,7 2-fluoroanilines, and 2,4-difluoroanilines3c into the corresponding
isatin derivatives.

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

2467
2468 SANDMEYER ISATIN SYNTHESIS

B. GENERAL REACTION SCHEME

NOH
conc. H2SO4
X + Cl3CCHO + NH2OH X
NH2 N O
H O
(X = 3- or 4-F, Br, Me, etc.)
X O
N
H

C. PROPOSED MECHANISMS

It is assumed that hydroxylamine condenses with chloral to give oxime, which then
undergoes the nucleophilic substitution with aniline, and hydrolyzes to give oximino inter-
mediate under basic conditions. In the presence of a strong acid, such as concentrated
sulfuric acid, the oximino compound cyclizes via nucleophilic addition of aromatic ring to
C=N double bond. An illustrative mechanism is provided below.

D. MODIFICATION

The oximino intermediate has been cyclized with PPA as the dehydrating reagent.3a

E. APPLICATIONS

This reaction has a general application in the synthesis of isatin derivatives, which could
be used as the starting materials for quinolines, acridines and indophenazines etc.

F. RELATED REACTIONS

N/A
 CITED EXPERIMENTAL EXAMPLES 2469

G. CITED EXPERIMENTAL EXAMPLES

CO2Me O
HCl/Na2SO4 conc. H2SO4
+ Cl3CCHO + NH2OH
H2O, ∆ ∆ O
H2N CO2Me N
H
34%
Reference 4a.

A mixture of 13.6 g methyl 3-aminobenzoate (0.09 mol), 16.1 g chloral hydrate

(0.09 mol), 234.4 g Na2 SO4 , 19.8 g hydroxylamine hydrochloride (0.29 mol), 145 mL
water, and 8 mL concentrated HCl was refluxed for 2 h and then kept at room temperature
overnight. The cream color isonitroso intermediate was filtered off, washed with water, and
dried to give 16.0 g intermediate, in a yield of 80%. This compound in a total of 16.0 g
(0.07 mol), was added in portions to 70 mL conc. H2 SO4 maintained at 70–75◦ C over a
period of 30 min under stirring. The resulting mixture was then heated at 80◦ C until the
reaction was complete, as monitored by TLC (CHCl3 /EtOH, 8:2). After being cooled to
room temperature, the mixture was slowly poured onto ice. The aqueous phase was extracted
with EtOAc; the combined organic layers were dried over MgSO4 , filtered, and evaporated.
The resulting orange solid was purified by gradient flash column chromatography on silica
gel, eluting with CHCl3 /EtOH (8:2) to give 5.0 g methyl 4-isatincarboxylate, in a yield of
34%, m.p. 215–217◦ C.

O
Me Cl3CCH(OH)2 Me NOH Me
NH2OH · HCl O
MeO NH2 Na2SO4/H2O MeO N O PPA, ∆ MeO N
H H
OMe ∆ OMe OMe
70%
Reference 3a.

After a mixture of 1.68 g chloral hydrate (10.2 mmol), 2.03 g hydroxylamine hydro-
chloride (29.2 mmol), 13.4 g anhydrous Na2 SO4 , and 45 mL water was stirred at 45–50◦ C
for 15 min, a 7.0 mL solution prepared from 1.517 g aniline, 0.75 mL conc. HCl, and water
was added. The resulting mixture was heated for 1 h each at 45–50◦ C, 55–60◦ C and 65–
70◦ C. An additional 0.45 g chloral hydrate and 4.1 g hydroxylamine hydrochloride were
added, and the reaction mixture was heated at 75–80◦ C for another hour. When the mixture
was cooled in ice water, a light brown precipitate formed, which was filtered to afford 1.58 g
N-(2,3-dimethoxy-4-methylphenyl)-2-(hydroxyimino)-acetamide of sufficient purity, in a
yield of 73%. To 20 mL polyphosphoric acid at 100◦ C was added 2.0 g N-(2,3-dimethoxy-
4-methylphenyl)-2-(hydroxyimino)-acetamide (8.39 mmol) over a period of 5 min. After
20 min, the reaction mixture was cooled, and 40 mL water was carefully added to yield an
orange precipitate, which was filtered to give 1.30 g 6,7-dimethoxy-5-methyl-1H-indole-
2,3-dione, in a yield of 70%. This compound could be further purified by recrystallization
in methanol, m.p. 180.5–181.5◦ C.

Other references related to the Sandmeyer isatin synthesis are cited in the literature.8
2470 SANDMEYER ISATIN SYNTHESIS

H. REFERENCES

1. Sandmeyer, T., Helv. Chim. Acta, 1919, 2, 234.

2. (a) Gribble, G. W., J. Chem. Soc., Perkin Trans. I, 2000, 1045. (b) Gassman, P. G.; Cue, B. W.
and Luh, T.-Y., J. Org. Chem., 1977, 42, 1344. (c) Sumpter, W. C., Chem. Rev., 1944, 34, 393.
3. (a) Gainor, J. A. and Weinreb, S. M., J. Org. Chem., 1982, 47, 2833. (b) Ermili, A. and Giuliano, R.,
Gazz. Chim. Ital., 1959, 89, 517. (c) Yen, V. Q.; Buu-Hoı̈, N. P. and Xuong, N. D., J. Org. Chem.,
1958, 23, 1858. (d) Piozzi, F., Atti Accad. Nazl. Lincei, Rend., Classe Sci. Fis., Mat. Nat., 1957,
22, 629. (e) Sheibley, F. E. and McNulty, J. S., J. Org. Chem., 1956, 21, 171. (f) Favini, G. and
Piozzi, F., Atti Accad. Nazl. Lincei, Rend., Classe Sci. Fis., Mat. Nat., 1955, 19, 44. (g) Piozzi, F.
and Favini, G., Atti Accad. Nazl. Lincei, Rend., Classe Sci. Fis., Mat. Nat., 1955, 18, 647.
4. (a) Braña, M. F.; Gradillas, A.; Gómez, A.; Acero, N.; Llinares, F.; Muñoz-Mingarro, D.; Abradelo,
C.; Rey-Stolle, F.; Yuste, M.; Campos, J.; Gallo, M. A. and Espinosa, A., J. Med. Chem., 2004,
47, 2236. (b) Senear, A. E.; Sargent, H.; Mead, J. F. and Koepfli, J. B., J. Am. Chem. Soc., 1946,
68, 2695.
5. Sadler, P. W. and Warren, R. L., J. Am. Chem. Soc., 1956, 78, 1251.
6. Sadler, P. W., J. Org. Chem., 1956, 21, 169.
7. (a) Rupe, H. and Kersten, L., Helv. Chim. Acta, 1926, 9, 578. (b) Borsche, W.; Weussmann, H.
and Fritzsche, A., Ber., 1924, 57, 1149.
8. (a) Pirrung, M. C.; Pansare, S. V.; Sarma, K. D.; Keith, K. A. and Kern, E. R., J. Med. Chem., 2005,
48, 3045. (b) Da Silva, F.; Garden, S. and Pinto, A., J. Braz. Chem. Soc., 2001, 12, 273. (c) Garden,
S. J., Torres, J. C.; Ferreira, A. A.; Silva, R. B. and Pinto, A. C., Tetrahedron Lett., 1997, 38, 1501.
(d) Taylor, A., J. Chem. Res. Miniprint, 1980, 10, 4154. (e) Popp, F. D., Adv. Heterocycl. Chem.,
1975, 18, 1. (f) Yoda, N. and Kurihara, M., J. Poly. Sci.: Marcomol. Rev., 1971, 5, 109. (g) Bartlett,
M. F.; Dickel, D. F. and Taylor, W. I., J. Am. Chem. Soc., 1958, 80, 126. (h) Astill, B. D. and
Boekelheide, V., J. Am. Chem. Soc., 1955, 77, 4079. (i) Baker, B. R.; Schaub, R. E.; Joseph, J.
P.; McEvoy, F. J. and Williams, J. H., J. Org. Chem., 1952, 17, 164. (j) Marvel, C. S. and Hiers,
G. S., Org. Synth. Coll., 1943, 1, 327. (k) Martinet, J. and Cousset, P., Compt. Rend., 1921, 172,
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