Tetrahedron Letters 54 (2013) 1008–1011

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Synthesis of substituted isatins

Larry L. Klein ⇑, Michael D. Tufano
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, United States

a r t i c l e i n f o a b s t r a c t

Article history: Isatins are valuable intermediates for heterocyclic chemistry. Most of the common methods for their pro-
Received 16 November 2012 duction are less than adequate when the number and lipophilicity of substituents on the targeted isatin
Revised 10 December 2012 are increased. Our group desired such molecules and identified an alternative method for their
Accepted 12 December 2012
production.
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.

Keywords:
Isatin
Sandmeyer isatin synthesis
Oximinoacetanilides

Isatins (1H-indole-2,3-diones, 1) are valuable intermediates in loximinoacetic acid 6 (Fig. 2) and an aniline under standard amide-
the field of heterocyclic and pharmaceutical chemistry.1 Several forming conditions; however, though hydroxyiminoacetic acid (6a)
of these derivatives show activities of biological interest2 but most is known,7 reaction of this compound with anilines failed to pro-
serve as templates in the construction of pharmaceutically active vide product 5. Crystalline benzyloximinoacetic acid (6b) is avail-
agents. Recently, we required multiply substituted isatins as able in multi-gram quantities via an extractive work-up
intermediates and found the standard methods for their prepara- following combination of O-benzylhydroxylamine and glyoxylic
tion to be less than optimal on a gram scale.3 acid hydrate.8 Coupling of 6b to a variety of substituted anilines
The most common procedure for the synthesis of isatins is the led to good yields of the benzyloximinoacetanilides, 7 as shown
Sandmeyer process4 which utilizes a mixture of chloral hydrate, in Table 1. The corresponding benzyloximinoacetyl chloride (8) is
an aniline (or its hydrochloride salt), hydroxylamine, and hydro- also available via treatment of 6b with oxalyl chloride and serves
chloric acid in a heated sodium sulfate-saturated aqueous media equally well to produce substituted anilines 7 in the presence of
(Fig. 1). The molecular mechanism for this process is believed to bases such as triethylamine or diisopropylethylamine in common
proceed through an initial glyoxamide 4 which reacts, in turn, with organic solvents (e.g., dichloromethane, tetrahydrofuran).
hydroxylamine to form oximinoacetanilide, 5.5a,b Heating It has been suggested that the ring cyclization step in the Sand-
compound 5 to 90 °C in sulfuric acid affects the ring cyclization meyer process involves a dehydration of the oxime to form a-acyl-
to produce isatin, 1. nitrile (Fig. 1). In the case of the benzyl analog, rather than loss of
Although this process has worked for simple analogs (Fig. 1, 2a), water, the loss of benzyl alcohol would have to take place to form
as the substitution of the precursor anilines increases both in num- this same reactive intermediate. When 7a was treated in this man-
ber and lipophilicity, the facility of this classical reaction to form ner, the isatin product was formed in a similar yield as for the
the oximinoacetanilide intermediate 5 suffers. For example, when unsubstituted oximinoacetanilide, 5. Since no chemical trace of
4-n-hexylaniline (2b) was used as starting material, <5% yield of the benzyl residue was apparent from this modified reaction, it is
intermediate 5b could be isolated. Attempts to modify this process presumed that any such alkyl moiety can be used in this approach.
through the use of co-solvents such as ethanol6a or microwave This reaction sequence was carried out at a 10 g scale without
heating6b have helped obtain some products not otherwise avail- change in the yield of isatin 9 produced (Table 2, entry 1).
able, albeit in moderate yields. The fact that the key reagent, chlo- When oximinoacetanilide analogs of high lipophilicity (e.g., 7f–
ral hydrate, is a regulated substance also impacts the potential to h) were heated in sulfuric acid as per the classical Sandmeyer
perform large scale production of the isatins. route, cyclization was frequently incomplete due to the poor solu-
An alternative method for production of intermediate 5 or its bility under these conditions. Use of methanesulfonic acid9 as the
equivalent was envisioned involving a coupling reaction of an alky- media with these three oximinoacetanilides proved to be helpful
in circumventing the problems and served to provide the corre-
sponding isatin products even when little or no product was avail-
⇑ Corresponding author. Tel.: +1 312 413 9440; fax: +1 312 355 5539. able from the sulfuric acid method (Table 2). In general, yields of
E-mail address: llk@uic.edu (L.L. Klein).

0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.035
 L. L. Klein, M. D. Tufano / Tetrahedron Letters 54 (2013) 1008–1011 1009

O
HN CHO
NH 2 Cl NH 2 OH
+ Cl CHO
4
Cl H 2 O, HCl,
R Na 2 SO 4
2 3 R
a. R = H 90 °C
b. R = n -hexyl

O O
O
NH + N
HN HN H 2 SO 4 HN OH
O
90 °C 5

isatin 1 R

Figure 1. Sandmeyer isatin process.

O
H2SO 4 O
N or
HO2C N NH 2 HN OBn HN
HOBT, EDAC CH 3SO 3H
OR + Ar O
6a R = H
DIPEA, DCM Ar 90 °C
b R = Bn Ar
2a-p 25 °C 40-85%
c R = CH 3 7a-p
46-93%
(COCl)2 isatin
25 °C 2 9-14
TEA, DCM
ClOC N
OBn 69-89%
8

Figure 2. Synthesis of alkyloximinoacetanilides 7.

Table 1
Preparation of benzyloximinoacetanilides
N
O

Ar Ar 7
NH2 N O
H

Entry Product Compd # Methoda Yield (%) Entry Product Compd # Methoda Yield (%)

NOBn
CH3
O NOBn
1 N O 7a A 85 9 CH3 7i B 80
H
N O
H
CH3 NOBn
NOBn
2 N O 7b B 75 10 7j A 46
H
CH3 N O
H
CH3 NOBn PhO NOBn
3 7c B 69 11 7k A 60
N O N O
H H
CH3
NOBn N NOBn
4 7d A 79 12 7l B 79
N O N O
H H
CH3
CH3
NOBn O NOBn
5 7e B 87 13 7m B 89
CH3 N O N O
H H
CH3 NOBn
NOBn
H 3C
6 7f A 93 14 N O 7n B 61
N O H
H

(continued on next page)

1010 L. L. Klein, M. D. Tufano / Tetrahedron Letters 54 (2013) 1008–1011

Table 1 (continued)

Entry Product Compd # Methoda Yield (%) Entry Product Compd # Methoda Yield (%)

CH3
H3 C NOBn
NOBn
7
H 3C 7g B 88 15 7o B 71
N O
N O H
H
Ph
Ph
NOBn NOBn
Ph
8 7h B 89 16 7p B 87
N O N O
H H

a
Method A: ArNH2, 1 equiv HO2CCH@NOBn, 1.5 equiv EDAC, 1.5 equiv HOBt, 3 equiv DIPEA, THF, rt; or Method B: ArNH2, 1.05 equiv ClCOCH@NOBn, 1.15 equiv TEA, DCM, rt.

Table 2 isatins were similar or slightly improved when methanesulfonic

Preparation of isatins acid was used as the media.
In the case of the extremely insoluble aryl-containing examples
O such as 7p, although heating in methanesulfonic acid produced
isatins, uncharacterized impurities arising from the process were
H difficult to remove. The preparation of 5-tritylisatin (16) from 4-
N O Ar O
Ar N N tritylaniline was chosen as the most difficult example for method
H modification. In order to further increase solubility in the acidic
O
media and avoid these impurities, two modifications were em-
Entry Product Compd # Methoda Yield (%) ployed: (1) the corresponding methyloximinoacetanilide, 15, was
utilized which was, in turn, prepared from acid 6c10 (Fig. 3), and
O
(2) polyphosphoric acid (PPA) was used as the media. In this
CH3 way, 5-tritylisatin (16) was produced in 67% yield.
1 O 9 H2SO4 85
N The straightforward preparation of benzyl-, or in certain cases
H
methyloximinoacetanilides (such as 7a–p, 15) and the heating of
O
CH3 these intermediates in sulfuric acid, methanesulfonic acid, or, for
O poorly soluble analogs PPA, has been shown to afford substituted
2 10 H2SO4 60
N isatins. This modified aniline-to-isatin route circumvents many of
H
CH3 the problems present in the classical Sandmeyer isatin synthesis
CH3 and allows production of these substituted isatins in a reproducible
O
manner.
3 O 11 H2SO4 46
H3C N Supplementary data
H
CH3 O
Supplementary data associated with this article can be found,
H3C in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
4 O 12 CH3SO3H 40
N 12.035.
H
CH3 O
H3 C References and notes
H 3C
5 O 13 CH3SO3H 64
1. Shvekhgeimer, M. G. A. Chem. Heterocycl. Compd. 1996, 32, 249.
N
H 2. (a) McIntyre, I. M.; Norman, T. R. J. Neural Transm. 1990, 79, 35–40; (b)
Dharmarajan, S.; Perumal, Y.; Gayatri, G. Eur. J. Med. Chem. 2005, 40, 1373–
O 1376.
3. DaSilva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273–324.
6 O 14 CH3SO3H 60 4. Sandmeyer, T. Helv. Chim. Acta 1919, 2, 234.
N 5. (a) Marvel, C. S.; Hiers, G. S. Org. Synth. 1941, Coll. Vol. 1, 327; (b) Silva, B. V.;
H Violante, F. A.; Pinto, A. C.; Santos, L. S. Rapid Commun. Mass Spectrom. 2011, 25,
423–428.
a
Method A: H2SO4 at 50 °C, heat to 80 °C; add to ice; Method B: CH3SO3H at 6. (a) Garden, S. J.; Torres, J. C.; Ferriera, A. A.; Silva, R. B.; Pinto, A. C. Tetrahedron
50 °C, heat to 80 °C; add to ice. Lett. 1997, 38, 1501; (b) Jnaneshwara, G. K.; Bedekar, A. V.; Deshpande, V. H.

O
N O
NH 2
HN OCH3 PPA HN
HOBT, EDAC
HO2C N O
OCH3 + DIPEA, DCM 100 °C
6c 25 °C 67%
2p 83% 15 16
Ph Ph
Ph Ph Ph Ph Ph
Ph Ph

Figure 3. Synthesis of 5-tritylisatin (16).

 L. L. Klein, M. D. Tufano / Tetrahedron Letters 54 (2013) 1008–1011 1011

Synth. Commun. 1999, 29, 3627–3633; (c) Mamun, H. M.; Foysal, M. A.; 9. Rewcastle, G. W.; Atwell, G. J.; Zhuang, L.; Baguley, B. C.; Denny, W. A. J. Med.
Mahabub, M.; Al-Amin J. Sci. Res. 2010, 2, 322–329. Chem. 1991, 34, 217–222.
7. (a) Gutsche, C. D.; Lau, H.-P. J. Am. Chem. Soc. 1978, 100, 1857–1865; (b) Waters, 10. Lapucci, A.; Macchia, M.; Orlandini, E.; Romagnoli, F.; Rossello, A. Farmaco
K. L.; Hartung, W. H. J. Org. Chem. 1947, 12(469), 472; (c) Dong, W.-L.; Yao, H.- 1996, 51, 33–40.
W.; Li, Z.-M.; Zhao, W. G. J. Chem. Res., Synop. 2008, 3, 145–147; (d) Kalisiak, J.;
Ralph, E. C.; Cashman, J. R. J. Med. Chem. 2012, 55, 465–474.
8. (a) Herscheid, J. D. M.; Colstee, J. H.; Ottenheijm, H. C. J. J. Org. Chem. 1981, 46,
3346–3348; (b) Kulkarni, N. A.; Yao, C.-F.; Chen, K. Tetrahedron 2007, 63, 7816–
7822.