Ring-ring isomerization in the series of N-(carbamoyl)-1-aryl-2,3,4,5,6,7-hexahydro-3-hydroxy-6,6-dimethyl-2,4-dioxo-1H-indole-3-carboxamides

Article abstract of DOI:10.1007/s11172-015-0915-5

N-(Carbamoyl)-1-aryl-2,3,4,5,6,7-hexahydro-3-hydroxy-6,6-dimethyl-2,4-dioxo-1H-indole-3-carboxamides upon dissolution in DMSO or DMF undergo a reversible isomerization to 5-(2-arylamino-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-5-hydroxypyrimidine-2,4,6(1H,3H

Full text of DOI:10.1007/s11172-015-0915-5

Russian Chemical Bulletin, International Edition, Vol. 64, No. 3, pp. 664—667, March, 2015
664
Ringꢀring isomerization in the series
of Nꢀ(carbamoyl)ꢀ1ꢀarylꢀ2,3,4,5,6,7ꢀhexahydroꢀ3ꢀhydroxyꢀ
6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamides*
G. S. Borodkin, S. B. Zaichenko, I. G. Borodkina, L. V. Belousova, and L. Yu. Ukhin
Research Institute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 Rostov on Don, Russian Federation.
Fax: +7 (863) 243 4700. Eꢀmail: may@ipoc.sfedu.ru
Nꢀ(Carbamoyl)ꢀ1ꢀarylꢀ2,3,4,5,6,7ꢀhexahydroꢀ3ꢀhydroxyꢀ6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀinꢀ
doleꢀ3ꢀcarboxamides upon dissolution in DMSO or DMF undergo a reversible isomerizaꢀ
tion to 5ꢀ(2ꢀarylaminoꢀ4,4ꢀdimethylꢀ6ꢀoxocyclohexꢀ1ꢀenꢀ1ꢀyl)ꢀ5ꢀhydroxypyrimidineꢀ2,4,6ꢀ
(1H,3H,5H)ꢀtriones.
Key words: anilines, dimedone, Nꢀarylenaminones, Nꢀ(carbamoyl)ꢀ1ꢀarylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ3ꢀhydroxyꢀ6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamides, 5ꢀ(2ꢀarylaminoꢀ
4,4ꢀdimethylꢀ6ꢀoxocyclohexꢀ1ꢀenꢀ1ꢀyl)ꢀ5ꢀhydroxypyrimidineꢀ2,4,6(1H,3H,5H)ꢀtriones, dimꢀ
ethyl sulfoxide, ringꢀring isomerization.
Scheme 1
The ringꢀring isomerization processes, in contrast to
the ringꢀchain ones, are much rarer phenomena,1—15 the
more interesting is every new example.
Recently, it was reported that alloxane reacted with
Nꢀarylꢀsubstituted enaminones, the condensation prodꢀ
ucts of anilines with dimedone, to give polyfunctional inꢀ
dole derivatives.16 We reacted alloxane 1 with 3ꢀ(2ꢀ
aminophenyl)aminoꢀ5,5ꢀdimethylcyclohexꢀ2ꢀenꢀ1ꢀone
(2), the condensation product of oꢀphenylenediamine with
dimedone, to obtain one of such derivatives: Nꢀ(carbaꢀ
moyl)ꢀ1ꢀ(2ꢀaminophenyl)ꢀ2,3,4,5,6,7ꢀhexahydroꢀ3ꢀhyꢀ
droxyꢀ6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamide
(3). The structure of compound 3 was confirmed by Xꢀray
diffraction studies.17
The presence of the free amino group at oꢀposition of
the phenyl substituent makes compound 3 capable of the
reactions, which are impossible for its analogs described
in the work.16 Thus, upon heating in CF3COOH it underꢀ
goes recyclization to a spiro compound with the dibenzoꢀ
diazepine and barbituric acid fragments.17 Compound 3
was also found to undergo the ringꢀring isomerization. In
DMSO and DMF, it reversibly isomerizes to 5ꢀ[2ꢀ(2ꢀ
aminophenyl)aminoꢀ4,4ꢀdimethylꢀ6ꢀoxocyclohexꢀ1ꢀenꢀ
1ꢀyl]ꢀ5ꢀhydroxypyrimidineꢀ2,4,6(1H,3H,6H)ꢀtrione (4),
which was isolated as a solvate with DMSO.17 The recrysꢀ
tallization of solvate 4 from CH3CN led to the recovery of
compound 3 (see Ref. 17).
It seemed interesting to find out whether the ability to
undergo the ringꢀring isomerization is typical of only comꢀ
pound 3 or is a general property caracteristic of such group
of indole derivatives.
* Dedicated to Academician of the Russian Academy of Sciences
V. I. Minkin on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0664—0667, March, 2015.
1066ꢀ5285/15/6403ꢀ0664 © 2015 Springer Science+Business Media, Inc.

Tautomerism of 1ꢀHꢀindoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
665
To obtain an unambiguous answer to this question, we
had to have a full set of 1H, 13C, and 15N NMR spectra for
several analogs of compound 3. For this purpose, we used
our procedure described earlier17 to synthesize four analogs
of compound 3 from compound 5: with phenyl (6a), pꢀfluꢀ
oroꢀ (6b), pꢀchloroꢀ (6c), and pꢀbromophenyl (6d) substitꢀ
uents (Scheme 2). The compounds obtained by this proꢀ
cedure do not require further purification, since they crysꢀ
tallize from the reaction mixture in the spectrally pure form.
a correlation sequence COSY, for the 13C NMR spectra —
HMBC and HSQC, for the 15N NMR spectra — HMBC.
The unambiguous choice in favor of structures 7a—d
was made based on the correlation (HMBC) 1H—15N
NMR spectra. They showed that upon dissolution of comꢀ
pounds 6a—d in DMSO, the atom N(1) acquires a proꢀ
ton, that can be explained by the rearrangement to the
structures 7a—d (see Scheme 2).
The structures 7a—d explain the inconsistency in the
number of signals in the 13C NMR spectra and the numꢀ
ber of carbon atoms in the compounds: in the symmetric
pyrimidinetrione ring atoms C(4) and C(6) are characterꢀ
ized by the same chemical shifts.
1
The H and 13C NMR spectra of all four compounds reꢀ
corded in DMSOꢀd6 completely agree with the spectra
given in the literature.16 Like in the case of compound 3, the
number of signals in the 13C NMR spectra of compounds
6a—d was one signal short than the expected number for
this structure. To make a full assignment of signals in the
1H NMR spectra of the described compounds, we used
1
Figure 1 shows a correlation H—15N HMBC NMR
spectrum of compound 7d, which exhibits a number of
crossꢀpeaks for the signals of nitrogen nuclei N(7´)
Scheme 2
X = H (a), F (b), Cl (c), Br (d)

90
100
110
120
130
140
150
160
170
11
10
9
8
7
6
5
4
3
2
1

Fig. 1. 1H—15N HMBC correlation spectrum of compound 7d (DMSOꢀd6).

666
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
Borodkin et al.
Table 1. 1H, 13C, and 15N NMR chemical shifts for compounds 7a—d (DMSOꢀd6)
Atom
7a
7b
7c
7d
1H
13C/15
N
1H
13C/15
N
1H
13C/15
N
1H
13C/15
N
1(15N)
11.06
—
11.06
—
147.00
150.29
147.00
170.74
75.33
11.06
—
11.06
—
148.77
150.30
148.77
170.75
75.30
11.08
—
11.08
—
147.00
150.26
147.00
170.66
75.28
11.08
—
11.08
—
147.00
2
150.25
147.00
170.64
75.27
3(15N)
4
5
—
—
—
—
6
7
—
8.15
—
—
2.47
—
2.00
—
9.92
0.94
0.94
—
7.17
7.39
7.20
170.74
—
106.84
162.11
40.69
32.82
48.79
193.89
113.75
27.40
—
8.12
—
—
2.39
—
1.99
—
9.80
0.93
0.93
—
7.21
7.22
—
170.75
—
106.81
162.36
40.55
32.73
48.77
193.90
110.56
27.41
—
8.19
—
—
2.47
—
2.00
—
9.90
0.95
0.95
—
7.19
7.43
—
170.66
—
107.40
161.75
40.61
32.86
48.77
194.20
111.50
27.35
—
8.19
—
—
2.48
—
2.00
—
9.89
0.95
0.95
—
7.13
7.55
—
170.64
—
107.47
161.64
40.60
32.87
48.77
194.23
111.60
27.87
1´
2´
3´
4´
5´
6´
7´(15N)
8´
9´
1
2
3
4
27.40
27.4
27.35
27.87
138.08
124.52
129.29
125.20
134.45
127.05
115.97
159.70
137.12
126.13
129.13
129.20
137.54
126.41
132.05
117.31
( 111.50) with protons H(7´) (a doublet at  9.90,
1J = 90.4 Hz), besides, the nuclei N(7´) correlate with
protons H(3´) ( 2.47) and protons H(2) ( 7.19).
Atoms N(1) and N(3) ( 147.00) in the pyrimidine
fragment of the molecule correlate with the corresponding
protons H(1) and H(3) (a doublet at  11.08, 1J = 90.2 Hz).
The data of the described 1H—15N HMBC NMR specꢀ
trum unambiguously determine the environment of nitroꢀ
gen atoms N(7´), N(1), and N(3).
spectra of the colorless precipitates isolated from soluꢀ
tions of 6c and 6d in DMSO showed that they were not the
starting compounds. A shortꢀtime mild heating of these
precipitates in MeCOOH led to their quantitative transꢀ
formation to the starting compounds 6a and 6d, thus demꢀ
onstrating a reversibility of the isomerization taking place
in DMSO.
In the work,16 for all the obtained polyfunctional inꢀ
dole derivatives, the melting points are given within the
1—2 C range. An impression was formed that these comꢀ
pounds are stable, melting sharply virtually in one point.
In fact, all the colorless compounds 6a—d obtained in this
work are stable only until a certain temperature. Upon
heating, they first turn dark and then decompose with the
gas liberation and the formation of black melts. The 1—2 C
range means only the last step of decomposition, accomꢀ
panied by a vigorous gas evolution. In the case of comꢀ
pounds 6a and 6c, the melting—decomposition points
found by us are slightly higher than those indicated in the
work,16 whereas for 6b it is lower. The largest difference
(~30 C) was observed for compound 6d. We carried out
its elemental analysis, which confirmed the analytical
purity of this compound (see Experimental).
Similar patterns were found in the correlation 1H—15N
HMBC NMR spectra for all compounds 7a—d (Tables 1
and 2).
In conclusion, a combination of the NMR data (see
Tables 1 and 2) unambiguously indicates the isomerizaꢀ
tion of compounds 6a—d to compounds 7a—d upon disꢀ
solution in DMSO (see Scheme 2).
Attempted obtaining of complexes of compounds 6a—d
with DMSO (similar to 4) was unsuccessful. The IR
Table 2. Some spinꢀspin coupling constants (J/Hz)
for compounds 7a—d
Compound
1JN(1),H = 1JN(3),H
JN(7´),H
7a
7b
7c
7d
90.1
89.7
90.2
89.5
90.0
91.2
90.4
91.0
Experimental
Spectroscopic studies were carried out using facilities of the
Molecular Spectroscopy Multiꢀuser Center of the Southern Fedꢀ
eral University. NMR spectra were recorded on a Bruker
AVANCEꢀ600 spectrometer.
Note. For compound 7b 1JF,H(4) = 242.6 Hz, 2JF,H(3)
= 22.2 Hz, 3JF,H(2) = 8.4 Hz, 4JF,H(1) = 2.1 Hz.
=

Tautomerism of 1ꢀHꢀindoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
667
Synthesis of compounds 3a—d (general procedure). Alloxane
(0.19 g, 1 mmol) was dissolved in EtOH (5 mL) upon reflux,
followed by addition of the corresponding compound 5a—d
(1 mmol) and heating until dissolution. Then, CF3COOH (1 drop)
was added to the mixture, which was brought to reflux and left to
cool down to room temperature, rubbing with a glass rod. In
many cases, crystallization began from a still warm solution. To
obtain the maximal yields, the reaction mixture was allowed to
stand for 12 h, a precipitate was filtered off, washed with cold
EtOH and light petroleum, and dried.
Nꢀ(Carbamoyl)ꢀ1ꢀphenylꢀ2,3,4,5,6,7ꢀhexahydroꢀ3ꢀhydroxyꢀ
6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamide (6a). After the
reaction was complete, the mixture was cooled to room temperꢀ
ature, rubbing with a rod, when crystallization began, the mixꢀ
ture was placed in ice. The yield was 0.19 g (53%). A colorless
compound, turns dark above 195 C, m.p. 203—205 C (deꢀ
comp.) (cf. data in Ref. 16: m.p. 195—196 C).
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USSR (Engl. Transl.), 1984, 20, 180 [Zh. Org. Khim., 1984,
20, 180].
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(Engl. Transl.), 1985, 835 [Khim. Geterotsikl. Soedin.,
1985, 1000].
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1992, 851].
Nꢀ(Carbamoyl)ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ2,3,4,5,6,7ꢀhexahydroꢀ
3ꢀhydroxyꢀ6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamide
(6b). Addition of a crystallization seed and rubbing with a rod
initiated the crystallization from a warm solution. After standing
of the mixture in ice for 1 h, the yield of the product was 0.16 g
(43%). After standing of the mixture for 16 h, the yield was 0.26 g
(59%). A colorless compound, turns dark above 175 C, m.p.
188—190 C (with decomp.) (cf. data in Ref. 16: m.p. 203—204 C).
Nꢀ(Carbamoyl)ꢀ1ꢀ(4ꢀchlorophenyl)ꢀ2,3,4,5,6,7ꢀhexahydroꢀ
3ꢀhydroxyꢀ6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamide
(6c). The crystallization was initiated from a hot solution by
rubbing with a rod, the reaction mixture rapidly grew dense. The
mixture was cooled to room temperature and then in ice for
15 min. The yield of the product was 0.22 g (56%). A colorless
compound, turns dark at 199—200 C, m.p. 203—205 C (with
decomp.) (cf. data in Ref. 16: m.p. 199—200 C).
Nꢀ(Carbamoyl)ꢀ1ꢀ(4ꢀbromophenyl)ꢀ2,3,4,5,6,7ꢀhexahydroꢀ
3ꢀhydroxyꢀ6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1Hꢀindoleꢀ3ꢀcarboxamide
(6d). The rubbing with a rod initiated rapid formation of a crysꢀ
talline precipitate from a hot solution. After cooling in ice for
1 h, the yield of the product was 0.25 g (57%). A colorless comꢀ
pound, turns dark above 200 C, m.p. 207—208 C (with deꢀ
comp.) (cf. data in Ref. 16: m.p. 235—237 C). Found (%):
C, 49.60; H, 3.88; Br, 17.88. C18H18N3O5. Calculated (%):
C, 49.55; H, 4.16; Br, 18.32.
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This work was financially supported by the Ministry of
Education and Science of the Russian Federation (the
Project Part of the State Assignment in Academic Area of
the Southern Federal University, Theme No. 4.967.2014/K).
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in revised form January 20, 2015