Tautomerism and stereodynamics of indophenols, amidines, their derivatives, and analogs: XIV. New methods of synthesis of spiro-fused quinoxalines

Article abstract of DOI:10.1023/A:1012399922502

A new procedure was proposed for synthesis of quinoxaline derivatives by N-alkylation of 2,6-ditert-butyl-4-(o-R-sulfonylaminophenylimino)-2,5-cyclohexadienones and subsequent intramolecular spirocyclization. A necessary condition for the reaction to occu

Full text of DOI:10.1023/A:1012399922502

Russian Journal of General Chemistry, Vol. 71, No. 6, 2001, pp. 950 955. Translated from Zhurnal Obshchei Khimii, Vol. 71, No. 6, 2001,
pp. 1012 1017.
Original Russian Text Copyright
2001 by Kurbatov, Vikrishchuk, Simakov, Kuznetsov, Zhdanov, Olekhnovich.
Tautomerism and Stereodynamics of Indophenols, Amidines,
Their Derivatives, and Analogs: XIV.1 New Methods
of Synthesis of Spiro-Fused Quinoxalines
S. V. Kurbatov, N. I. Vikrishchuk, V. I. Simakov, D. N. Kuznetsov,
Yu. A. Zhdanov, and L. P. Olekhnovich
Rostov State University, Rostov-on-Don, 344104 Russia
Received September 27, 1999
Abstract A new procedure was proposed for synthesis of quinoxaline derivatives by N-alkylation of 2,6-di-
tert-butyl-4-(o-R-sulfonylaminophenylimino)-2,5-cyclohexadienones and subsequent intramolecular spiro-
cyclization. A necessary condition for the reaction to occur is a high mobility of hydrogen in the N-methylene
group, which is activated by electron-acceptor aroyl or two ethoxycarbonyl groups.
In the previous communication of this series [1] we
described a new intramolecular rearrangement of
O-methylene derivatives of 2,6-di-tert-butyl-4-(o-hy-
droxyphenylimino)-2,5-cyclohexadienones as a pre-
parative route to spirocyclic benzoxazines. Presumab-
ly, an analogous transformation can lead to formation
of other heterocyclic systems, primarily of quinoxali-
nes which exhibit a broas-spectrum antibacterial and
cardioprotecting activity [2]. It is also known that
be obtained by alkylation of 4-(o-benzylsulfonylamino-
phenylimino)-2,6-di-tert-butyl-2,5-cyclohexadienone
(I) with phenacyl bromides in acetone in the presence
of anhydrous potassium carbonate or of its thallium
salt II in acetonitrile (pathways a and b in Scheme 2).
Both these methods gave similar results. We have
found no advantages of method b from the synthetic
viewpoint (such as readiness of the reaction and purity
of the products); therefore, most quinoxalines were
heterocycles containing a spirocyclohexadiene moiety synthesized according to pathway a.
are structural fragments of a number of biologically
active natural compounds [3] which are available
through a limited set of fairly rare reactions [4].
The reaction of compound I with p-nitrophenacyl
bromide resulted in formation of product IV contain-
ing a stereogenic carbon atom. Additional informa-
tion about possible enantiomerization of spiroquinoxa-
lines like IV, e.g., via enolization (Scheme 3), can
be derived from the 1H NMR spectra. The figure shows
The goal of the present work was to examine the
possibility for synthesizing difficultly accessible spi-
roquinoxalines like IV by intramolecular cyclization
of quinonimines III (Scheme 1). Quinoxalines IV can
1
the H NMR spectra of quinoxaline IV and primary
product XVII formed by reaction of I with p-nitro-
benzyl bromide. The following evidence of spirocycli-
zation can be noted: (1) signals from both tert-butyl
groups, as well as from protons in positions 2 and
6 of the cyclohexadiene ring become isochronous
Scheme 1.
O
N
O
t-Bu
Bu-t
H
t-Bu
H N
Bu-t
E
(
1.3 and 6.9 ppm, respectively); (2) the two-
proton signal at 4.6 ppm from the CH2CO group
is transformed into two one proton signals, NH
6.1 ppm) and CH ( 6.6 ppm); and (3) the
R
E
C
R
SO2R
N
N
SO2R
(
singlet from the CH2SO2 group is converted into
an AB quartet ( 4.8 ppm), indicating that molecule
IV is chiral and that no fast enantiomerization occurs.
III
IV
R = CH2Ph, 4-NO2C6H4, 4-CH3C6H4; R = COOEt, H;
E = C(O)Ar, Ar, HC=CH2, COOEt.
By alkylation of o-sulfonylamino derivatives VI
and VII with phenacyl bromides and diethyl bromo-
malonate we obtained spirocyclic compounds VIII
XIV (Scheme 4). As in the alkylation of 2,6-di-tert-
1
For communication XIII, see [1].
1070-3632/01/7106-0950$25.00 2001 MAIK Nauka/Interperiodica

TAUTOMERISM AND STEREODYNAMICS OF INDOPHENOLS, AMIDINES... : XIV.
951
Scheme 2.
Scheme 3.
butyl-4-(o-hydroxyphenylimino)-2,5-cyclohexadi-
enones [1], we failed to isolate even traces of primary
alkylation products III (Scheme 1): In all cases final
spiroquinoxalines VIII XIV were obtained.
O
t-Bu
Bu-t
H
CH2R
Unlike spirobenzoxazines [1], in the synthesis of
spiroquinoxalines more rigorous requirements are
imposed on the electronic nature of the substituent at
the N-methylene group. We failed to effect cyclization
of N-allyl and N-p-nitrobenzyl derivatives XV XVII
into the corresponding quinoxalines even by pro-
longed heating in boiling chloropentafluorobenzene or
o-dichlorobenzene.
N
N
SO2R
XV XVII
XV, XVI, R = 4-NO2C6H4; XVII, R = CH2Ph; XV, R =
CH=CH2; XVI, XVII, R = 4-NO2C6H4.
Our attempts to increase the mobility of methylene
protons by replacement of vinyl or p-nitrophenyl
group by the electron-acceptor oxadiazole fragment
were unsuccessful: Compounds XX and XXI did not
undergo cyclization into the corresponding spiro-
quinoxalines (Scheme 5).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 6 2001

952
KURBATOV et al.
(a)
8
7
6
5
4
3
2
1
, ppm
10.65
11.00
26.83 10.57 5.43
10.63
90.95
11.70 10.86 4.98
(b)
8
7
6
5
4
3
2
1
, ppm
9.44 36.08 10.15
10.46 10.45
10.67 10.56
1
H NMR spectra of (a) 3,5-di-tert-butyl-3 -(p-nitrobenzoyl)-4 -benzylsulfonylspiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -tetra-
hydroquinoxalin]-4-one (IV) and (b) N-[o-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylideneamino)phenyl]-N-(p-nitrobenzyl)-
phenylmethanesulfonamide (XVII) in acetone-d (Varian Unity-300, 300 MHz).
6
Scheme 4.
O
O
t-Bu
Bu-t
t-Bu
Bu-t
R
H
H
C
R
t-Bu
t-Bu
H
COOEt
COOEt
N
R
O
SO2
N
O
C
H
COOEt
N
N
Br CH
N
Br CH2
O
N
COOEt
SO2
SO2
R
VIII XII
VI, VII
R
XIII, XIV
VI, VIII XI, XIII, R = CH3; VII, XII, XIV, R = NO2; VIII, R = H; IX, XII, R = 4-Br; X, R = 3-NO2; XI, R = 3,4-Cl2.
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TAUTOMERISM AND STEREODYNAMICS OF INDOPHENOLS, AMIDINES... : XIV.
953
Scheme 5.
O
t-Bu
Bu-t
CH2
CH2Cl
N
N
OH
H
O
O
H
N
O
N
O
O
N
N
O
SO2R
NH C
CH2Cl
XVIII
XIX
XX, XXI
XX, R = 4-CH3C6H4; XXI, R = 4-NO2C6H4.
Thus we have revealed a synthetic potential of
the new route to quinoxaline derivatives via nonca-
talytic intramolecular rearrangement of N-alkyl-4-(o-R-
sulfonylaminophenylimino)-2,6-di-tert-butyl-2,5-
cyclohexadienones. The previously described syntheses
of structurally related heterocycles are limited to two
main methods illustrated by Scheme 6 (pathways 1
and 2). According to these methods, the heterocycliza-
tion occurs in the final stage through formation of
carbon heteroelement bonds [5]. The procedure pro-
posed in the present work may be illustrated by
pathway 3 according to which the heterocycle is
formed by carbon carbon bond closure.
Scheme 6.
A
+
N
X
Y
A
X
1
2
N
B
Y
A, B, X, Y = N, O, Hlg.
N
X
N=C
3
X C
X = O, N, S(?).
A, B, X, Y = N, O, Hlg.
EXPERIMENTAL
was heated to the boiling point. It was then cooled,
and the light gray precipitate was filtered off and
recrystallized from methanol. Colorless crystals, mp
166 C. Yield 5.11 g (65%).
1
The H NMR spectra were recorded on Bruker
DPX-250 (250 MHz) and Varian Unity-300 spectrom-
eters (300 MHz) at 25 C. The elemental compositions
of the newly synthesized compounds were consistent
with the calculated values.
o-(p-Nitrophenylsulfonylamino)aniline,
mp 160 C, yield 50%, and o-(p-tolylsulfonylamino)-
aniline, mp 134 C, yield 65%, were synthesized in
a similar way.
o-(Benzylsulfonylamino)aniline. To a solution of
3.2 g of o-phenylenediamine in 20 ml of THF we
added a solution of 5.7 g of phenylmethanesulfonyl
chloride and 2.4 ml (2.37 g) of pyridine in 10 ml of
THF. The mixture was stirred for 1 h at room tem-
perature, 150 ml of water was added, and the mixture
4-(2-(Benzylsulfonylaminophenylimino)-2,6-di-
tert-butyl-2,5-cyclohexadienone (I). A mixture of
3 g of o-(benzylsulfonylamino)aniline and 2.52 g of
2,6-di-tert-butyl-1,4-benzoquinone [6] in 50 ml of
2-propanol was refluxed for 8 h and left overnight.
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954
KURBATOV et al.
The precipitate was filtered off and passed through a
column of Al2O3 using ethyl acetate as eluent. The
tetrahydroquinoxalin]-4-one (IX). Yield 50%.
mp 155 C. 1H NMR spectrum (CDCl3), , ppm:
eluate was evaporated to dryness, and the residue was 1.29 s (18H), 2.35 s (3H), 4.10 s (1H), 6.37 s (1H),
recrystallized from isopentyl alcohol. Red crystals.
Yield 3.3 g (62%). mp 173 C. H NMR spectrum
6.48 s (2H), 6.55 d (1H), 6.78 d.d (1H), 6.98 d.d
(1H), 7.14 d (2H), 7.50 m (3H), 7.62 d (2H).
1
(acetone-d6), , ppm: 1.27 s (9H), 1.33 s (9H), 4.50 s
(2H), 6.94 d.d (1H), 7.02 d (1H), 7.12 d (1H),
7.22 d.d (1H), 7.27 7.38 m (5H), 7.67 d.d (1H),
7.74 s (1H).
3,5-Di-tert-butyl-3 -(m-nitrobenzoyl)-4 -(p-tolyl-
sulfonyl)spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -
tetrahydroquinoxalin]-4-one (X). Yield 40%. mp
1
164 C. H NMR spectrum (CDCl3), , ppm: 1.28 s
Compounds VI and VII were synthesized in
a similar way.
(18H), 2.35 s (3H), 5.06 s (1H), 6.39 s (1H), 6.53 m
(3H), 6.89 d.d (1H), 6.98 d.d (1H), 7.18 d (2H),
7.52 m (3H), 7.66 d.d (1H), 8.40 d (1H), 8.49 d (1H),
8.92 s (1H).
2,6-Di-tert-butyl-4-[2-(p-tolylsulfonylamino)-
phenylimino]-2,5-cyclohexadienone (VI). Orange
crystals (from 2-propanol). Yield 50%. mp 190 C [7].
3,5-Di-tert-butyl-3 -(m,p-dichlorobenzoyl)-4 -(p-
tolylsulfonyl)spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -
tetrahydroquinoxalin]-4-one (XI). Yield 40%.
2,6-Di-tert-butyl-4-[2-(p-nitrophenylsulfonyl-
amino)phenylimino]-2,5-cyclohexadienone (VII).
1
1
Yield 40%. Red crystals. mp 234 C. H NMR spec-
mp 171 C. H NMR spectrum (DMSO-d6), , ppm:
trum (CDCl3), , ppm: 1.16 s (9H), 1.34 s (9H),
6.63 d.d (1H), 6.70 d (1H), 6.85 d (1H), 7.08 d.d
(1H), 7.21 d.d (1H), 7.40 s (1H), 7.61 d (1H), 7.98 d
(2H), 8.19 d (2H).
1.28 s (18H), 2.34 s (3H), 5.06 s (1H), 6.35 s (1H),
6.49 s (2H), 6.59 d (1H), 6.79 d.d (1H), 6.99 d.d (1H),
7.16 d (2H), 7.51 m (4H), 8.01 d (1H), 8.11 s (1H).
3 -(p-Bromobenzoyl)-3,5-di-tert-butyl-4 -(p-nitro-
phenylsulfonyl)spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,-
3 ,4 -tetrahydroquinoxalin]-4-one (XII). Yield 70%.
mp 165 C. 1H NMR spectrum (CDCl3), , ppm:
1.26 s (18H), 5.04 s (1H), 6.48 s (1H), 6.43 s (2H),
6.62 d (1H), 6.88 d.d (1H), 7.05 d.d (1H), 7.51 d
(1H), 7.62 d (2H), 7.74 d (1H), 8.02 d (2H), 8.16 d
(2H).
4 -Benzylsulfonyl-3,5-di-tert-butyl-3 -(p-nitro-
benzoyl)spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -
tetrahydroquinoxalin]-4-one (IV). a. To a solution
of 2.32 g of compound I in 20 ml of acetone we
added 2 g of freshly calcined potassium carbonate and
1.22 g of p-nitrophenacyl bromide. The mixture was
refluxed for 1 h, cooled, and filtered, the filtrate was
evaporated to dryness, and the residue was recrystal-
lized from isobutyl alcohol. Red crystals. Yield 1.76 g
Diethyl 3,5-di-tert-butyl-4-oxo-4 -(p-tolylsul-
fonyl)spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -tetra-
hydroquinoxaline]-3 ,3 -dicarboxylate (XIII). Yield
1
(56%). mp 172 C. The H NMR spectrum of IV is
given in the figure.
1
30%. mp 160 C. H NMR spectrum (CDCl3), , ppm:
b. A mixture of 0.2 g of 4-[o-(benzylsulfonyl-
amino)phenylimino]-2,6-di-tert-butyl-2,5-cyclohexadi-
enone thallium salt and 0.07 g of p-nitrophenacyl
bromide in 10 ml of acetonitrile was refluxed for
40 min. The precipitate of thallium chloride was
filtered off, and the filtrate was evaporated and
then treated as described above in a.
1.22 t (6H), 1.42 s (18H), 2.44 s (3H), 4.22 m (4H),
5.22 s (1H), 6.57 d (1H), 6.69 d.d (1H), 6.85 d.d (1H),
6.99 d (1H), 7.24 s (2H), 7.32 d (2H), 8.04 d (2H).
Diethyl 3,5-di-tert-butyl-4 -(p-nitrophenylsul-
fonyl)-4-oxospiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -
tetrahydroquinoxaline]-3 ,3 -dicarboxylate (XIV).
Yield 30%. mp 135 C. 1H NMR spectrum (CDCl3), ,
ppm: 1.18 t (6H), 1.49 s (18H), 4.19 m (4H), 5.21 s
(1H), 6.52 d (1H), 6.69 d.d (1H), 6.86 d.d (1H),
7.04 d (1H), 7.18 s (2H), 8.32 s (4H).
Compounds VIII XVII were synthesized in
a similar way (method a) from the corresponding
2,6-di-tert-butyl-4-(o-sulfonylaminophenylimino)-2,5-
cyclohexadienones and alkyl halides.
N-Allyl-N-[o-(3,5-di-tert-butyl-4-oxo-2,5-cyclo-
hexadienylideneamino)phenyl]-p-nitrobenzenesul-
fonamide (XV). Yield 50%. mp 120 C. H NMR
spectrum (CDCl3), , ppm: 1.18 s (9H), 1.24 s (9H),
4.78 s (2H), 5.05 s (2H), 5.77 m (1H), 6.45 d (1H),
6.50 d (1H), 6.58 d (1H), 7.25 m (3H), 7.87 d (2H),
8.18 d (2H).
3 -Benzoyl-3,5-di-tert-butyl-4 -(p-tolylsulfonyl)-
spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -tetrahydro-
quinoxalin]-4-one (VIII). Yield 65%. mp 188 C.
1H NMR spectrum (acetone-d6), , ppm: 1.30 s (18H),
2.39 s (3H), 6.04 s (1H), 6.91 s (1H), 6.62 m (3H),
6.84 d.d (1H), 7.04 d.d (1H), 7.30 d (2H), 7.60 m
(6H), 8.22 d (2H).
1
3 -(p-Bromobenzoyl)-3,5-di-tert-butyl-4 -(p-tolyl-
sulfonyl)spiro[2,5-cyclohexadiene-1,2 -1 ,2 ,3 ,4 -
N-[o-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadi-
enylideneamino)phenyl]-N-(p-nitrobenzyl)-p-nitro-
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TAUTOMERISM AND STEREODYNAMICS OF INDOPHENOLS, AMIDINES... : XIV.
955
benzenesulfonamide (XVI). Yield 80%. mp 178 C.
1H NMR spectrum (CDCl3), , ppm: 1.21 s (9H),
1.29 s (9H), 5.06 s (2H), 6.42 d (1H), 6.51 d (1H),
6.52 d (1H), 7.13 m (2H), 7.24 m (1H), 7.49 d (2H),
7.87 d (2H), 8.09 d (2H), 8.19 d (2H).
(1H), 6.88 d (1H), 7.05 m (2H), 7.40 m (8H). 7.70 d
(1H), 10.50 s (1H).
N-[o-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadi-
enylideneamino)phenyl]-N-[5-(o-hydroxyphenyl)-
1,2,4-oxadiazol-3-ylmethyl]-p-nitrobenzenesulfon-
amide (XXI) was synthesized in a similar way by
reaction of oxadiazole XIX with compound VII. Yield
N-[o-(3,5-Di-tert-butyl-4-oxo-2,5-cyclohexadi-
enylideneamino)phenyl]-N-(p-nitrobenzyl)phenyl-
methanesulfonamide (XVII). Yield 56%. mp 177 C.
The 1H NMR spectrum of XVII is shon in figure.
1
67%. mp 176 C. H NMR spectrum (DMSO-d6), ,
ppm: 1.17 s (18H), 5.27 s (2H), 6.43 s (2H), 6.72 d
(1H), 7.01 d.d (1H), 7.10 d (1H), 7.40 m (4H), 7.85 d
(1H), 8.11 d (2H), 8.24 d (2H), 10.60 s (1H).
N-(Chloroacetyl)salicylamide (XVIII). To a solu-
tion of 3.4 g of salicylamide in 80 ml of freshly dis-
tilled ethyl acetate we added dropwise while stirring
2 ml of chloroacetyl chloride. The mixture was re-
fluxed for 4 h and cooled, and the precipitate was
filtered off and washed with chloroform. Yield 3.8 g
ACKNOWLEDGMENTS
This study was financially supported by the Rus-
sian Foundation for Basic Research (project no. 98-03-
32903a) and by the Program Universities of Russia
Fundamental Research (project no. 5.3.1387).
1
(72%). Colorless crystals. mp 173 C. H NMR spec-
trum (DMSO-d6), , ppm: 4.67 s (2H), 6.23 6.60 m
(4H), 11.20 s (1H).
3-Chloromethyl-5-(o-hydroxyphenyl)-1,2,4-oxa-
diazole (XIX). A suspension of 0.85 g of sodium
acetate and 0.72 g of hydroxylamine hydrochloride in
6 ml of glacial acetic acid was refluxed for 10 min.
The mixture was cooled, 2.14 g of N-(chloroacetyl)-
salicylamide was added, and the mixture was refluxed
for 1 h, cooled, and diluted with 30 ml of water.
The crystals were filtered off. Yield 1.15 g (55%).
Colorless crystals. mp 78 C. 1H NMR spectrum
(DMSO-d6), , ppm: 4.62 s (2H), 5.88 m (2H),
6.27 m (1H), 6.60 d (1H), 10.63 s (1H).
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1,2,4-oxadiazol-3-ylmethyl]-p-toluenesulfonamide
(XX). A suspension of 6.21 g of oxadiazole XIX and
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1
Orange crystals. Yield 58%. mp 179 C. H NMR
spectrum (DMSO-d6), , ppm: 1.10 s (9H), 1.19 s
(3H), 1.30 s (9H), 5.20 s (2H), 6.45 s (1H), 6.55 s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 6 2001