Acylating and arylsulfonylating ability of O-derivatives of isatin 3-oximes

Article abstract of DOI:10.1007/s10593-005-0114-7

O-Acyl and O-arylsulfonyl derivatives of isatin 3-oximes have been synthesized and their interaction with alcohols and amines has been investigated. It was established that none of the esters of 1-substituted isatin 3-oximes reacted with the indicated nucleophiles. 1-Unsubstituted O-aryl and O-arylsulfonyl derivatives react with amines as acylating agents even at room temperature, but O-acetyl derivatives only on heating. Acylamides or arylsulfamides respectively are formed in this way. O-Acyl derivatives do not react with alcohols at room temperature. Only O-benzoyl derivatives form ethyl benzoate on heating in ethanol. A comparative analysis of mass spectrometric data on the processes of acylation and arylsulfonylation is given.

Full text of DOI:10.1007/s10593-005-0114-7

Chemistry of Heterocyclic Compounds, Vol. 41, No. 1, 2005
ACYLATING AND ARYLSULFONYLATING
ABILITY OF O-DERIVATIVES OF ISATIN 3-OXIMES
A. P. Stankevicius1, P. B. Terentiev2, L. N. Janushene1, and A. B. Savickas3
O-Acyl and O-arylsulfonyl derivatives of isatin 3-oximes have been synthesized and their interaction
with alcohols and amines has been investigated. It was established that none of the esters of
1-substituted isatin 3-oximes reacted with the indicated nucleophiles. 1-Unsubstituted O-aryl and
O-arylsulfonyl derivatives react with amines as acylating agents even at room temperature, but O-acetyl
derivatives only on heating. Acylamides or arylsulfamides respectively are formed in this way. O-Acyl
derivatives do not react with alcohols at room temperature. Only O-benzoyl derivatives form ethyl
benzoate on heating in ethanol. A comparative analysis of mass spectrometric data on the processes of
acylation and arylsulfonylation is given.
Keywords: O-acetates, O-benzoates, and O-arylsulfonates of 2,3-indoledione 3-oximes, acylation and
arylsulfonation, mass spectrometry.
We recently reported [1] that, on heating O-acetyl derivatives of 1-unsubstituted isatin 3-oximes with
alcohols in the presence of triethylamine, N-(2-cyanoaryl)carbamates are formed in good yield as a result of
fission of the C(2)-C(3) bond of the heterocycle. O-Aroyl- and O-arylsulfonyl-substituted isatin 3-oximes are more
reactive than the corresponding O-acetates.
Investigation of the analogous reaction with aliphatic and aromatic amines showed that only heating of
the latter with O-arylsulphonates of isatin 3-oxime leads to fission of the intercarbonyl bond and the
corresponding N-(2-cyanoaryl)carbamates are obtained in high yield [2]. O-Acetyl derivatives did not display
such reactivity, but 1-methyl-substituted derivatives generally did not react.
In this connection we decided to investigate in more detail the interaction of a series of O-acyl-
substituted isatin 3-oximes, where the acyl fragment is aliphatic, aromatic, or arylsulfonic acid residue, with
alcohols and amines under various conditions (Schemes 1 and 2).
On adding aniline to a solution of O-acetates 1a or 1e in acetonitrile at room temperature no reaction was
observed during 15 min, according to TLC data. However boiling these solutions for 20 min led to the
disappearance of even traces of the initial esters, and acetanilide and O-unsubstituted oximes 2a and 2c
respectively were isolated in good yield from the reaction mixture. However the O-benzoate 1b reacted
completely with aniline even under mild conditions (20°C, 15 h) with the formation of oxime 2a and benzanilide
3b.
We have established that the oxime O-acetate 1a did not react with ethanol either under mild (20°C,
15 h) or under more rigid conditions (boiling in alcohol for 30 min). Each time it was isolated in unchanged form
from the reaction mixture. The O-benzoate 1e also did not react with ethanol at room temperature, however
__________________________________________________________________________________________
1
Institute of Cardiology, Kaunas Medical University, Kaunas 50009, Lithuania; e-mail:
2
carsynt@kmu.lt.
petr@ms-bioorg.chem.msu.ru.
M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail:
3
Kaunas Medical University, Kaunas 44307, Lithuania; e-mail:
farmkurs@kmu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 113-119, January,
2005. Original article submitted June 29, 2004.
98
0009-3122/05/4101-0098©2005 Springer Science+Business Media, Inc.

Scheme 1
R2
C
R1
N
O
O
O
N
R
1a–e
EtOH
PhNH2
R1
R2COOEt
N
O
H
O
2a,b
+
4
PhNHCOR2
+
3a,b
N
R
2a–c
1 а, b, e R = H, c, d R = Me, a-d R1 = H, e R1 = Br; a, c, e R2 = Me, b, d R2 = Ph; 2 a,
c R = H, b R = Me, a, b R1 = H, c R1 = Br; 3 a R2 = Me, b R2 = Ph; 4 R2 = Ph
after boiling a solution in ethanol for 30 min the crystalline oxime 2c was isolated from the reaction mixture in
62% yield, and the filtrate had the odor of ethyl benzoate. Crystals of benzamide (34% yield) were obtained by
treating the filtrate with 25% ammonia solution. It must be stressed that oxime acetate 1c and oxime benzoate 1d
did not react under any conditions with amines or with alcohols, and were isolated from the medium in
unchanged form. Traces of oxime 2b were successfully detected in the filtrate only by TLC.
Finally, the isatin 3-oxime O-arylsulfonates 5a,c,d reacted smoothly with an excess of morpholine or
piperidine in dioxane at room temperature with the formation in high yield of oximes 2a,c,d and
N-arylsulfonamides 6a,b. The presence of substituents in the benzene ring had essentially no influence on the
course of the indicated reactions.
Scheme 2
O
Ar
O
N
O
S
X
HN
O
O
O
R1
X
Ar
S
N
2a–d
+
N
R
5a–d
6a,b
5 a,c,d R = H, b R = Me, a,b R1 = H, c R1 = 5-Br, d R1 = 5-Me, a, c, d Ar = C6H4NO2-2,
b Ar = C6H4Me-4; 2 a, c, d R = H, b R = Me, a, b R1 = H, c R1 = 5-Br, d R1 = 5-Me; 6 a X = O,
b X = CH2, a, b Ar = C6H4NO2-2
In the reaction of the 1-substituted derivative 5b, 1-methyl-2,3-indoledione 3-oxime was detected only
by chromatography, and a resinous substance was formed on heating on a water bath for 30 min. Such a clear
difference in reactivity of the 3-oxime O-esters of isatin and 1-methylisatin is probably linked with the different
lability of the C(2)–C(3) bond of the heterocycle and also with the possibility in the case of the 1-unsubstituted
compounds (and the impossibility for 1-substituted compounds) of tautomeric conversion into a 2-hydroxy form
(Scheme 3).
99

Scheme 3
.
+
+
–OH
N
.
R1OH
R1
A9
+
.
+
R1
N
O
R1
N
O
A4
O
N
N
OH
R = H
.
+
R
+
C
.
M
– R1OH
O
.
+
N
C
– (R1–H)
R = MeCO
OH
N
A3
N
R
O
–CO
A1
.
+
N
C7H4N2
+
N
O
C
– R1O
–R
O
A6
A3
C
+
–HCN
N
N
A2
R
R
C6H3N
–CO
A8
+
+
–HCN
C7H4RN2
C6H3RN
A7
A5

Such a form facilitates elimination of a molecule of acid (which is aided by base catalysis) with the
formation of the reactive 2-cyanophenyl isocyanate molecule, interaction of which with nucleophiles, alcohols
[1], amines [2], and hydrazines [3] , leads to the formation of urethanes, carbamides, and cyclization products of
semicarbazides respectively.
In a less polar medium in the absence of base, attack of the nucleophile is directed to the electrophilic
ester carbonyl-carbon (or sulfonyl-sulfur) atom with the formation of esters or amides and O-unsubstituted
oximes.
The hypotheses expressed above are confirmed in our opinion by data of a comparative analysis of the
mass spectra of the 1-methyl-substituted O-acetates 1a and 1c, O-benzoates 1b and 1d, and also the O-tosylate
5b and the O-tosylate of 2,3-indole-2,3-dione 3-oxime (5e, R = H, Ar = C6H4Me-4). The synthesis and mass
spectra of compounds 1a,c and 5b,e are given in [1], and the mass spectra of benzoates 1b,d are given in
Experimental.
It follows from the data of Table 1, that the stability (WM) of the molecular ions of the 1-unsubstituted
compounds is 1-2 orders of magnitude less than that of 1-methyl-substituted compounds, which is probably
linked with the inability of the latter to tautomerize in the gas phase.
The primary decomposition of the molecular ions of O-acetates 1a,b is linked first of all with loss of a
molecule of ketene (Scheme 3) and with the formation of the odd-electron ion Φ1, which then gives up a
hydroxyl group (the sequence of these processes was confirmed by the corresponding metastable ions). In the
case of the other unsubstituted O-esters the ion Φ1 is formed directly from the molecular ion by fission of the
N–O bond. The stability of this ion (fraction of the whole ion current) is significantly greater when R = Me. In
all probability this ion is isomerized into 2-cyanophenyl isocyanate, since it then eliminates molecules of CO and
HCN sequentially (ions Φ5 and Φ7).
The second breakdown path of the molecular ions of the 1-unsubstituted compounds is linked with
cleavage of a molecule (or cation radical) of acid R2OH by a McLafferty rearrangement (ortho-effect) with the
formation of pseudomolecular ions of acid Φ4 and 2-cyanophenyl isocyanate Φ3. Such a process in fact models
the reaction described by us previously of O-esters of isatin 3-monooximes with nucleophilic reagents [1-3].
Further decomposition of Φ3 ions is linked with loss of molecules of CO and HCN.
Summarizing the dissociative ionization of these compounds we may note that the 1-unsubstituted
compounds (1a,b, 5e) are characterized by low intensities for the molecular ion peaks and by intense peaks for
the Φ3, Φ4, and Φ6 ions.
The mass spectra of 1-substituted esters (1c,d, 5b) on the other hand are characterized by intense peaks
for the molecular ions and the even-electron fragments Φ2. However rearranged ions Φ3 are completely absent
from the mass spectra of these compounds. It may also be noted that the decrease in the stability of M+· ions in
TABLE 1. Peak Intensities of Characteristic Ions in the Mass Spectra of
Compounds 1a-d, 5b,e (ΣI, %)
Com-
pound
WM
Φ1
Φ2
Φ3
Φ4
Φ5
Φ6
Φ7
Φ8
Φ9
ΣΦ1-Φ9
1a
1c
1b
1d
5e
5b
1.3
9.8
7.7
5.2
—
—
—
—
4.4
16.9
0.2
35.2
—
4.2
—
1.1
6.3
0.5
2.9
1.3
2.8
7.0
0.7
9.8
0.4
7.7
0.5
1.4
2.2
0.3
0.7
1.9
2.5
3.9
1.3
2.4
0.3
8.5
1.9
7.4
8.6
72.3
41.2
0.1
4.7
25.4
—
17.5
—
17.8
52.0
3.7
85.8*
68.3*
47.5*2
71.9*2
6.8
0.05
5.9
3.1
10.3
—
1.2
—
15.5
8.6
_______
+
* Including ions С6Н5 (77): 1b [11.6]; 1d [4.7].
*2 Including ions С7Н7 (91): 2e [9.8]; 2b [34.4].
+
101

the series R1 = MeCO > PhCO > Tos is not in agreement with their reactivity in the acylation of nucleophilic
compounds (alcohols and amines), which may be used for mild selective acylation and arylsulfonation of
polyfunctional organic compounds.
EXPERIMENTAL
The mass spectra of compounds were obtained on a Varian MAT-212 mass spectrometer with direct
insertion of samples into the ion source. The energy of the ionizing electrons was 70 eV. Monitoring of the
progress of reactions and the purity of the compounds obtained was effected by TLC on Silufol UV 254 plates in
the systems: a) chloroform–acetone, 9:1, b) acetone–chloroform, 4:1, c) benzene–dioxane, 2:1, d) ethyl acetate–
carbon tetrachloride, 1:1. Spots were detected with iodine vapor.
2,3-Indoledione 3-Oxime O-Acetate (1a) was obtained by the procedure of [1]; mp 130°C
(chloroform). Mass spectrum, m/z (I, %): 204 (3) [M]+, 162 (20), 144 (100), 116 (20), 91 (3), 90 (4), 89 (11),
65 (4), 63 (5), 62 (65), 60 (12).
2,3-Indoledione 3-Oxime O-Benzoate (1b). A solution of NaOH (2.4 g, 60 mmol) in water (20 ml) was
added dropwise to a mixture of compound 2a (8.1 g, 0.05 mol), benzoic anhydride (12.43 g, 55 mmol), and
dilute (2:1) aqueous acetone (90 ml) with stirring and cooling to -5°C. The mixture was stirred for some time,
diluted with water (100 ml), the solid filtered off, and dried. After recrystallization from chloroform, compound
1b (11.3 g, 85%) was obtained; mp 135°C, Rf 0.17 (a). Found, %: N 10.36. C15H10N2O3. Calculated, %: N 10.52.
Mass spectrum, m/z (I, %): 266 (0.4) [M]+·, 145 (11), 144 (100), 122 (68), 116 (20), 105 (4), 89 (10), 77 (45), 51
(18), 50 (10).
1-Methyl-2,3-indoledione 3-Oxime O-Acetate (1c) was obtained by the procedure of [1]; mp 154°C
(chloroform), Rf 0.38 (a). Mass spectrum, m/z (I, %): 218 (19) [M]+, 176 (100) [M-CH2CO]+, 159 (25)
[M-CH3CO2]+, 144 (3), 131 (6), 117 (3), 104 (3), 102 (3), 90 (4), 76 (4), 43 (47) [CH3CO]+.
1-Methyl-2,3-indoledione 3-Oxime O-Benzoate (1d) was obtained analogously to compound 1b from
1-methyl-2,3-indoledione 3-oxime (2b) (1.76 g, 10 mmol), benzoic anhydride (2.44 g, 11 mmol), aqueous
acetone (1:2) (70 ml), and NaOH (0.48 g, 12 mmol) in water (5 ml). Yield 2.4 g (86%); mp 178°C (chloroform),
Rf 0.54 (a). Mass spectrum, m/z (I, %): 280 (8) [M]+, 160 (6), 132 (3), 131 (6), 105 (100), 104 (3), 78 (2), 77 (9),
76 (2), 51 (5), 50 (2).
5-Bromo-2,3-indoledione 3-Oxime O-Acetate (1e) was obtained analogously to the previous
experiment from 5-bromo-2,3-indoledione 3-oxime (2c) (2.41 g, 10 mmol), acetic anhydride (1.12 g, 11 mmol),
acetone (30 ml), and NaOH (0.48 g, 12 mmol) in water (5 ml). Yield 2.7 g (95%); mp 146-147°C (DMF–
chloroform, 1:3), Rf 0.28 (b). Found, %: Br 28.16; N 9.72. C10H7BrN2O3. Calculated, %: Br 28.27; N 9.89.
2,3-Indoledione 3-Oxime O-(2-Nitrobenzene)sulfonate (5a) was obtained analogously from
compound 2a (1.62 g, 10 mmol), 2-nitrobenzenesulfonyl chloride (2.44 g, 11 mmol), acetone (30 ml), and
NaOH (0.48 g, 12 mmol) in water (5 ml). Yield 2.3 g (66%); mp 197-198°C (DMF–chloroform, 1:2), Rf 0.65 (c).
Found, %: N 12.02; S 9.09. C14H9N3O6S. Calculated, %: N 12.10; S 9.22.
1-Methyl-2,3-indoledione 3-Oxime O-Tosylate (5b) was obtained by the procedure of [1];
mp 177-178°C (ethyl acetate). Mass spectrum, m/z (I, %): 330 (19) [M]+, 159 (45) [M-TosO]+, 155 (25) [Tos]+,
144 (11) [M-TosO-CH3]+, 133 (20) [M-TosO-CN]+, 131 (15) [M-TosO-CO]+, 103 (5), 102 (8), 91 (100), 76 (5),
65 (19).
5-Bromo-2,3-indoledione 3-Oxime O-(2-Nitrobenzene)sulfonate (5c) was obtained analogously from
5-bromo-2,3-indoledione 3-oxime (2c) (2.41 g, 10 mmol), 2-nitrobenzenesulfonyl chloride (2.44 g, 11 mmol),
acetone (20 ml), and NaOH (0.48 g, 12 mmol) in water (5 ml). Yield 3.44 g, 81%); mp >250°C (DMF–
chloroform, 1:1). Found, %: N 9.69; S 7.62. C14H8BrN3O6S. Calculated, %: N 9.85; S 7.51.
102

5-Methyl-2,3-indoledione 3-Oxime O-(2-Nitrobenzene)sulfonate (5d) was obtained analogously to
benzoate 1b from 5-methyl-2,3-indoledione 3-oxime (2d) (1.76 g, 10 mmol), 2-nitrobenzenesulfonyl chloride
(2.44 g, 11 mmol), acetone (20 ml), and NaOH (0.48 g, 12 mmol) in water (5 ml). Yield 2.54 g (70%);
mp 199°C (DMF–chloroform, 1:3). Found, %: N 11.52; S 8.74. C15H11N3O6S. Calculated, %: N 11.63; S 8.86.
2,3-Indoledione 3-Oxime O-Tosylate (5e) was obtained by the procedure of [1]; mp 210-211°C
(chloroform). Mass spectrum, m/z (I, %): 316 [missing M]+, 145 (18) [M-TosO]+, 144 (100) [M-TosOH]+, 118
(14) [M-TosOH-CN]+, 116 (40) [M-TosOH-CO]+, 102 (2) [C6H4CN]+, 91 (8) [C7H7]+, 89 (23), 76 (7), 64 (15)
[SO2]+, 62 (18).
Interaction of 2,3-Indoledione 3-Oxime O-Acetate (1a) with Aniline. A mixture of compound 1a
(2.04 g, 10 mmol), aniline (1.86 g, 20 mmol), and acetonitrile (15 ml) was boiled for 20 min and cooled to room
temperature. The solid, consisting of 2,3-indoledione 3-oxime (2a), was filtered off. Yield 1.1 g (68%);
mp 234-235°C (ethanol) (mp 234-236°C [4]). The filtrate was diluted with water (80 ml), the precipitated solid
was filtered off, washed with water, dried, then recrystallized from benzene (with addition of activated carbon).
Acetanilide 3a (0.98 g, 72%) was obtained having mp 114°C, which corresponds to [5], Rf 0.25 (d).
Analogously from O-acetate 1c only traces were obtained of the corresponding oxime 2b, Rf 0.2 (b) and
the initial 1c.
Compound 2c (1.2 g, 50%) was obtained analogously from 1e (2.83 g, 10 mmol); mp 249-250°C
(mp 250-251°C [6]). Acetanilide 3a (0.92 g, 47%) of mp 114°C was also obtained.
Interaction of 2,3-Indoledione 3-Oxime O-Benzoate (1b) with Aniline. A mixture of aniline (3 ml,
excess) and compound 1b (2.66 g, 10 mmol) was stirred for several minutes and left at room temperature for
15 h. Acetone (10 ml) was added, the mixture stirred, the solid was filtered off, washed with acetone (5 ml), and
recrystallized from ethanol. 2,3-Indoledione 3-oxime (2a) (1 g, 62%) was obtained; mp 233-234°C
(mp 234-236°C [4]). The acetone filtrate was diluted with water (70 ml), acidified with dilute HCl to a weakly
acid reaction, the solid was filtered off, and washed with water. After recrystallization from aqueous acetone
(1:1) with activated carbon, benzanilide 3b (1.2 g, 60.9%) was obtained of mp 162°C, which corresponds with
the data of [5], Rf 0.25 (ethyl acetate–carbon tetrachloride, 1:1).
On carrying out the reaction in acetic acid (15 ml) the same result was obtained.
Interaction of 2,3-Indoledione 3-Oxime O-Benzoate (1b) with Ethanol. A mixture of compound 1b
(2.66 g, 10 mmol) and ethanol (15 ml) was heated on a water bath until complete solution and the heating
continued for 30 min. The mixture was cooled, water (10 ml) added, the mixture stirred, the solid was filtered
off, and washed with water (10 ml). After recrystallization compound 2a (1.1 g, 68%) was obtained having
mp 233-234°C (ethanol). A 25% aqueous ammonia solution (25 ml) was added to the filtrate with an odor of
ethyl benzoate (4), the mixture was stopped, and shaked for 10-12 h. The solid was filtered off and washed with
water. After recrystallization from water, benzamide (0.4 g) was obtained having mp 128-129°C (mp 129°C
[5]).
Analogously from compound 1d only traces of oxime 2b were obtained in addition to the initial 1d.
2-Nitrobenzenesulfomorpholide (6a). Analogously to the previous experiment compound 5a (3.47 g,
10 mmol), dioxane (10 ml), and morpholine (1.7 g, 20 mmol) were stored for 15 h at room temperature. After
separating oxime 2a (60% yield); mp 234°C (234-236°C [4]), and diluting with water, the solid was filtered off,
and recrystallized from ethanol with activated carbon to give compound 6a (1.11 g, 40%) of mp 181°C. Rf 0.28
(ethyl acetate–carbon tetrachloride, 1:1). Found, %: N 10.34; S 11.68. C10H12N2O5S. Calculated, %: N 10.29;
S 11.76.
Compound 6a (37%) of mp 180-181°C, and compound 2d (64%) of mp 202-204°C (ethanol)
(mp 203-206°C [4]), were obtained analogously from compound 5d.
2-Nitrobenzenesulfopiperidide (6b). Piperidide 6b (1.4 g, 52%) of mp 95°C (ethanol) was obtained
analogously to the previous experiment from compound 5a (3.47 g, 10 mmol), dioxane (10 ml), and piperidine
(1.7 g, 20 mmol) after separating oxime 2a (40% yield). Found, %: N 10.24; S 11.93. C11H14N2O4S.
Calculated, %: N 10.37; S 11.85.
103

Compound 6b (1.5 g, 55%) of mp 95°C, and compound 2c (1.51 g, 62%) of mp 249-251°C
(mp 250-251°C [6]), were obtained analogously from 5c (3.81 g, 10 mmol).
On carrying out the analogous reaction from compound 2b (3.3 g, 10 mmol) no actual substances were
successfully isolated from the resulting resinous mixture. Only traces of oxime 2b were detected
chromatographically (a) with the aid of a reference spot.
REFERENCES
1.
2.
3.
A. P. Stankevicius, P. B. Terentiev, L. N. Janushene, and P. V. Vainauskas, Khim. Geterotsikl. Soedin.,
1729 (2003).
A. P. Stankevicius, P. B. Terentiev, L. N. Janushene, and P. V. Vainauskas, Khim. Geterotsikl. Soedin.,
1868 (2003).
A. P. Stankevicius, P. B. Terentiev, L. N. Janushene, and A. A. Zhevzhikovene, Khim. Geterotsikl.
Soedin., 1731 (2003).
4.
5.
6.
G. I. Zhungietu and M. A. Rekhter, Isatin and Its Derivatives, Shtiintsa, Kishinev (1977).
A. N. Kost (editor), Handbook of Organic Chemistry [Russian translation], Mir, Moscow (1965).
B. S. Jensen, T. D. Jorgensen, P. K. Ahring, P. Christophersen, D. Strobaek, L. Teuber, and S. P. Olesen,
PCT Int. Appl. WO00/33834 (2000); Chem. Abstr., 133 , 43434 (2000).
104