An improved synthesis of isonitrosoacetanilides

Article abstract of DOI:10.1016/j.tetlet.2005.10.046

A novel two-step synthesis of isonitrosoacetanilides [2-(hydroxyimino)-N- phenylacetamides] has been developed, involving the initial acylation of aniline derivatives with 2,2-diacetoxyacetyl chloride, followed by reaction with hydroxylamine hydrochloride. The method works equally well with a variety of different aniline derivatives, including those with poor aqueous solubility and those containing electron rich ortho-substituents, neither of which react well under traditional conditions.

Full text of DOI:10.1016/j.tetlet.2005.10.046

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8719–8721
An improved synthesis of isonitrosoacetanilides
Gordon W. Rewcastle,* Hamish S. Sutherland, Claudette A. Weir,
Adrian G. Blackburn and William A. Denny
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland,
Private Bag 92019, Auckland 1020, New Zealand
Received 26 August 2005; accepted 12 October 2005
Available online 27 October 2005
Abstract—A novel two-step synthesis of isonitrosoacetanilides [2-(hydroxyimino)-N-phenylacetamides] has been developed, involv-
ing the initial acylation of aniline derivatives with 2,2-diacetoxyacetyl chloride, followed by reaction with hydroxylamine hydrochlo-
ride. The method works equally well with a variety of different aniline derivatives, including those with poor aqueous solubility and
those containing electron rich ortho-substituents, neither of which react well under traditional conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
The Sandmeyer isonitrosoacetanilide method1,2 is the
most frequently used route to isatins 3 (Scheme 1) and
its use for this purpose has been well reviewed.3–6 Tradi-
tionally the method involves treating a substituted
aniline with chloral hydrate and hydroxylamine hydro-
chloride (or other hydroxylamine salt), in an aqueous
sodium sulfate medium.2 Recent modifications include
the use of ethanol as a co-solvent,7 microwave irradia-
tion,8 and the use of the ethyl hemiacetal of chloral,
2,2,2-trichloro-1-ethoxyethanol, as an alternative chlo-
ral source,9,10 although the other components remained
unchanged.
requires a five-step procedure, which involves the inter-
mediacy of nitrone intermediates.11
We have developed a two-step synthesis of isonitroso-
acetanilides 2 that involves the simple acylation of ani-
lines 1 with 2,2-diacetoxyacetyl chloride,13,14 followed
by reaction of the resulting 2,2-diacetoxyacetanilide 4
with hydroxylamine hydrochloride in refluxing aqueous
ethanol (Scheme 2).15 Hydrolysis of the diacetates 4 to
the aldehyde occurs in situ, eliminating the need to per-
form a separate hydrolysis step. A similar transforma-
tion has previously been reported using 2-chloro-2-
ethoxyacetyl chloride as the acylating species,16 but the
poor availability17,18 of this reagent compared to 2,2-
diacetoxyacetyl chloride makes the present procedure
much more viable for larger scale use. We also investi-
gated the use of 2,2-diethoxyacetanilides, 2,2-bis(4-chlo-
rophenoxy)acetanilides, and 2,2-dichloroacetanilides as
a source of the isonitrosoacetanilides 2, and although
successful reaction with hydroxylamine hydrochloride
The synthesis of isonitrosoacetanilides 2 by the Sand-
meyer method is less efficient with aniline derivatives
having poor solubility in the aqueous sodium sulfate
medium, but more importantly, it fails to work well with
anilines that contain electron rich ortho-substitu-
ents.11,12 In fact, the only currently viable route to iso-
nitrosoacetanilides with electron rich ortho-substituents
Scheme 1. Sandmeyer isatin synthesis.
Keywords: Aniline; Isatin; Isonitrosoacetanilide.
*
Corresponding author. Tel.: + 64 9 373 7599x86147; fax: + 64 9 373 7502; e-mail: g.rewcastle@auckland.ac.nz
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.046

8720
G. W. Rewcastle et al. / Tetrahedron Letters 46 (2005) 8719–8721
Scheme 2. Two-step synthesis of isonitrosoacetanilides.
Table 1. Synthesis of substituted isonitrosoacetanilides15
Scheme 3. Synthesis of 2,2-diacetoxyacetyl chloride (5).
did occur in the first case, we found the reaction involv-
ing the diacyloxy species 4 to be much more facile.
R
Yielda (%)
Lit. yieldb (%)
2,2-Diacetoxyacetyl chloride (5) is readily prepared by
the literature procedure,13 which involves acylation of
glyoxylic acid monohydrate with acetic anhydride, fol-
lowed by reaction with thionyl chloride (Scheme 3). In
addition, we found that 50% aqueous glyoxylic acid
could equally be used as the starting material,14 pro-
vided additional acetic anhydride was employed to neu-
tralize the extra water. Following removal of excess
thionyl chloride and other volatiles, clean acid chloride
5 was obtained by vacuum distillation.
a
b
c
d
e
f
H
87
8260.3
55
81
85
90
80
63
65
91
80
85
87
8288
83
84
73
90
80–912
c,11
2-OCH3
2-NO2
2-Cl
2-I
2-Ph
2-OPh
3-OMe
3-Cl
4-CH3
4-Br
47.820
85–89d,7
7621
4219
e
g
h
i
—
4222
4022
j
96–99d,7
9023
k
l
4-CO2Et
4-CN
4-NO2
8523
For the acylation reaction between the acid chloride 5
and aniline derivatives 1, we investigated a number of
different bases, but found that KHCO3 offered the best
compromise in terms of yield and ease of use.15 Simple
filtration to remove the inorganic base, followed by
removal of solvent, gave the crude diacetates 4, which
could be purified by recrystallization or chromatogra-
phy on silica, but normally were treated directly with
hydroxylamine hydrochloride in refluxing ethanol to
furnish the isonitrosoacetanilides 2. The products were
usually sufficiently pure for direct conversion to isatins,
but when further purification was required, this could be
achieved by extraction into 5–10% aqueous NaOH at
room temperature, filtration through Celite, and precip-
itation with acetic acid or dilute HCl. A number of
examples of isonitrosoacetanilides 2 prepared by this
two-step procedure are shown in Table 1.
e
m
n
o
p
q
r
—
f,
24
2,3-(CH3)2
2,3-Cl2
2-NO2-3-CH3
2-OCH3-5-Cl
2,4-(OCH3)2
2,4-Cl2
2,5-Cl2
2,5-(OCH3)2
2,5-(CH3)2
6424
6625
e
—
38.5c,11
g
s
60
87
87
90
—
g
t
—
u
v
w
6824
75.5c,11
7826
78
a Combined isolated yields for two steps.
b Sandmeyer method1,2 unless otherwise noted.
c Five-step nitrone method.
d Ethanol co-solvent.
e All new compounds gave satisfactory spectral and analytical data.27
f Microwave procedure.
g Lit. yield not given.28
The two-step route to isonitrosoacetanilides is compar-
able to the standard Sandmeyer method1,2 in a number
of cases, although in the case of anilines with electron
rich ortho-substituents (e.g., 1b,r,s,v) it is clearly superior
to both the Sandmeyer and alternative literature
routes.11 In addition, in the case of lipophilic and less
water soluble amines such as 2-aminobiphenyl (1f) the
product yield is significantly improved (90% vs 42%)
over that obtained by the traditional procedure.19
References and notes
1. Sandmeyer, T. Helv. Chim. Acta 1919, 2, 234–242.
2. Marvel, C. S.; Hiers, G. S. Org. Synth. 1941, 1, 327–330.
3. Sumpter, W. C. Chem. Rev. 1944, 34, 393–434.
4. Bayer, O.; Eckert, W. Methoden zur Herstellung und
Umwandlung von Isatinen. In Houben-Weyl, Methoden der
Org. Chemie; Thieme: Stuttgart, 1968; Bd. VII/4, pp 1–31.
5. Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1–58.
6. Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz.
Chem. Soc. 2001, 12, 273–324.
7. Garden, S. J.; Torres, J. C.; Ferreira, A. A.; Silva, R. B.;
Pinto, A. C. Tetrahedron Lett. 1997, 38, 1501–1504.
8. Jnaneshwara, G. K.; Bedekar, A. V.; Deshpande, V. H.
Synth. Commun. 1999, 29, 3627–3633.
In conclusion, we have developed a new route to isonitro-
soacetanilides that provides access to a wide variety of
isatin derivatives. The route offers two distinct advanta-
ges over literature methods in that it can be equally used
with aniline derivatives containing electron rich ortho-
substituents, and also with those having poor aqueous
solubility.
9. Kollmar, M.; Parlitz, R.; Oevers, S. R.; Helmchen, G.
Org. Synth. 2003, 79, 196–203.

G. W. Rewcastle et al. / Tetrahedron Letters 46 (2005) 8719–8721
8721
10. Krapcho, A. P.; Cadamuro, S. A. Org. Prep. Proced. Int.
2004, 36, 74–76.
11. Prinz, W.; Kayle, A.; Levy, P. R. J. Chem. Res. (M) 1978,
1347–1370.
12. Taylor, A. J. Chem. Res. (M) 1980, 4154–4171.
13. McCaully, R. J.; Conklin, G. L. U.S. Patent 3,663,605,
1972; Chem. Abstr. 1972, 77, 61616.
16. Petrov, A. S.; Somin, I. N.; Kuznetsov, S. G. Zh. Org.
Khim. 1965, 1, 1434–1437; J. Org. Chem. USSR (Engl.
Transl.) 1965, 1, 1454–1457.
17. (a) Baganz, H.; Domaschke, L. Chem. Ber. 1959, 92, 3170–
3174; (b) Baganz, H.; Domaschke, L.; Kruger, K. E.
Chem. Ber. 1959, 92, 3167–3170.
18. Bach, K. K.; El-Seedi, H. R.; Jensen, H. M.; Nielsen, H.
B.; Thomsen, I.; Torssell, K. B. G. Tetrahedron 1994, 50,
7543–7556.
19. Batt, D. G.; Jones, D. G.; La Greca, S. J. Org. Chem.
1991, 56, 6704–6708.
20. Buchman, E. R.; McCloskey, C. M.; Seneker, J. A. J. Am.
Chem. Soc. 1947, 69, 380–384.
21. Lisowski, V.; Robba, M.; Rault, S. J. Org. Chem. 2000,
65, 4193–4194.
22. Sadler, P. W. J. Org. Chem. 1956, 21, 169–170.
23. Varma, R. S.; Khan, I. A. Curr. Sci. 1978, 47, 114–115.
24. Baker, B. R.; Schaub, R. E.; Joseph, J. P.; McEvoy, F. J.;
Williams, J. H. J. Org. Chem. 1952, 17, 149–156.
25. Buscarons, F.; Sanchez Moreno, L. Analitica 1967, 21,
191–201.
14. Synthesis of 2,2-diacetoxyacetyl chloride (5): A mixture of
51.8 g (0.35 mol) of 50% w/w aqueous glyoxylic acid,
350 mL of acetic anhydride and 80 mL of glacial acetic
acid were heated under reflux for 2h, and the solvents
were removed on a rotary evaporator. After azeotropic
removal of remaining volatiles with toluene, the residual
oil was dissolved in a mixture of 175 mL of CH2Cl2 and
90 mL of SOCl2, and heated under gentle reflux for
30 min. The volatiles were removed under vacuum, an
additional 75 mL of CH2Cl2 was added, and the mixture
was re-evaporated to remove remaining volatiles. The
residue was then distilled under vacuum to give 45.5 g
(67% yield) of 5: bp 58–59 °C (0.5 mm Hg); 1H NMR
(CDCl3): d 6.92 (s, 1H, CH), 2.22 (s, 6H, CH3); 13C NMR:
d 168.0 (C), 167.4 (C), 87.9 (CH), 20.3 (CH3).
15. General procedure for the synthesis of isonitrosoacetan-
ilides: The aniline 1 (4 mmol) and potassium hydrogen-
carbonate (2.0 g, 20 mmol) in dichloromethane (10 mL)
were cooled to À10 °C. A solution of freshly distilled 2,2-
diacetoxyacetyl chloride11 (1.0 g, 5.2mmol) in dichloro-
methane (5 mL) was added dropwise. The mixture was
removed from the cooling bath and allowed to warm to
room temperature. When the complete consumption of
the aniline 1 was confirmed by TLC, the solid was
removed by filtration, washed well with dichloromethane,
and the filtrate was concentrated. Hydroxylamine hydro-
chloride (1.4 g, 20 mmol) was dissolved in a mixture of
ethanol (10 mL) and water (5 mL), and the solution was
then added to the crude diacetates 4. The mixture was
heated under reflux for 2h, cooled to room tempera-
ture, and concentrated on a rotary evaporator until
precipitation commenced. Water was then added to
precipitate further product. The solid isonitrosoacetanilide
2 was collected by filtration and washed with water.
Purification was by recrystallization or reprecipitation
from 5% aqueous NaOH solution with acetic acid.
26. Gronowitz, S.; Hansen, G. Ark. Kemi. 1967, 27, 145–151.
27. Compound 2g: mp 92–94 °C; 1H NMR (400 MHz,
CDCl3): d 8.93 (br s, 1H, exchangeable with D2O), 8.46
(dd, J = 8.1, 1.6 Hz, 1H), 8.02(br s, 1H, exchangeable
with D2O), 7.56 (s, 1H), 7.38–7.33 (m, 2H), 7.17–7.10 (m,
2H), 7.05–7.01 (m, 3H), 6.86 (dd, J = 8.1, 1.4 Hz, 1H).
Anal. Calcd for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93.
Found: C, 65.88; H, 4.62; N, 10.90. Compound 2m: mp
1
180–184 °C; H NMR (400 MHz, DMSO-d6): d 12.27 (br
s, 1H, exchangeable with D2O), 10.55 (br s, 1H, exchange-
able with D2O), 7.89 (d, J = 8.9 Hz, 2H), 7.79 (d,
J = 8.9 Hz, 2H), 7.66 (s, 1H). Anal. Calcd for
C9H7N3O2: C, 57.14; H, 3.73; N, 22.21. Found: C,
57.37; H, 3.83; N, 22.44. Compound 2q: mp 139–141 °C;
1H NMR (CDCl3): d 9.61 (br s, 1H, exchangeable with
D2O), 8.38 (br s, 1H, exchangeable with D2O), 8.23 (d,
J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.09
(d, J = 7.7 Hz, 1H), 2.44 (s, 3H). Anal. Calcd for
C9H9N3O4: C, 48.43; H, 4.06; N, 18.83. Found: C,
48.69; H, 4.15; N, 18.88.
28. Baruffini, A.; Borgna, P.; Pagani, G.; Ponci, R. Farmaco,
Ed. Sci. 1967, 22, 590–611.