Quinoxalines. Part 12: Synthesis and structural study of 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines - The dehydrogenative cyclization with hydroxylamine hydrochloride

Article abstract of DOI:10.1016/S0040-4020(03)01024-X

Starting with 2-acetylquinoxaline a novel class of heterocyclic compounds, the 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines 4, were prepared by following two different synthetic procedures: 2-acetylquinoxaline reacted with thiosemicarbazide to the thiosemicarbazones 1a which was (i) cyclized with α-halogeno ketones to the thiazoles 3. These compounds were dehydrogenated in acidic medium to the title compounds 4. (ii) The thiosemicarbazone 1a could be also dehydrogenated using NH₂OH·HCl to the thioamide 5a and these, finally, were cyclized with α-halogeno ketones to the title compounds 4. Only thiazole 3a was isolated, the other thiazoles 3 were dehydrogenated in a one-pot procedure. From the thioamide 5a also both the compounds 9, by reacting with dibromodiacetyl, and 10, by treatment with dimethyl acetylenedicarboxylate, were obtained. The analysis of both the ¹H and ¹³C NMR spectra was not straightforward but could be attained finally by employing the whole arsenal of 1D and 2D NMR spectroscopy.

Full text of DOI:10.1016/S0040-4020(03)01024-X

Tetrahedron 59 (2003) 6311–6321
Quinoxalines. Part 12: Synthesis and structural study
of 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines—the
dehydrogenative cyclization with hydroxylamine hydrochlorideq
*
Gerhard Sarodnick, Matthias Heydenreich, Torsten Linker and Erich Kleinpeter
Department of Organic Chemistry and Structure Elucidation, University of Potsdam, P.O. Box 60 15 53, D-14415 Potsdam, Germany
Received 28 January 2003; revised 10 March 2003; accepted 20 June 2003
Abstract—Starting with 2-acetylquinoxaline a novel class of heterocyclic compounds, the 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines
4, were prepared by following two different synthetic procedures: 2-acetylquinoxaline reacted with thiosemicarbazide to the
thiosemicarbazones 1a which was (i) cyclized with a-halogeno ketones to the thiazoles 3. These compounds were dehydrogenated in
acidic medium to the title compounds 4. (ii) The thiosemicarbazone 1a could be also dehydrogenated using NH2OH·HCl to the thioamide 5a
and these, finally, were cyclized with a-halogeno ketones to the title compounds 4. Only thiazole 3a was isolated, the other thiazoles 3 were
dehydrogenated in a one-pot procedure. From the thioamide 5a also both the compounds 9, by reacting with dibromodiacetyl, and 10, by
treatment with dimethyl acetylenedicarboxylate, were obtained. The analysis of both the 1H and 13C NMR spectra was not straightforward
but could be attained finally by employing the whole arsenal of 1D and 2D NMR spectroscopy.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
the pyrazolo[3,4-b]quinoxalines (B) are substituted in
position 3 by another heteroaromatic moieties, they show
fungicidal activity.5
In consequence of their interesting biologically active
properties and synthetic utility, considerable interest has
been demonstrated towards 1H-pyrazolo[3,4-b]quinoxa-
lines; the parent compound was found in 1971 to be highly
tuberkulostatic.2 1-(4-Nitrophenyl)-1H-pyrazolo[3,4-b]quin-
oxaline-3-carbohydrazide A (cf. Scheme 1) proved to be of
highly anti-bacteriological activity vs. both gramopositive
and gramonegative bacteria;3 if the flavazole system in A is
replaced by the pyridazino[3,4-b]quinoxaline moiety, the
anti-bacteriological activity was lost.4 On the other hand, if
Pyrazolo[3,4-b]quinoxalines with similar heteroaromatic
substituents attached to position 1 (C) are still unknown
but heavily expected to be of similar biological activity.
In the present study the syntheses of several 1-(thiazol-2-
yl)-1H-pyrazolo[3,4-b]quinoxalines as representatives of
the 1-hetaryl-1H-pyrazolo[3,4-b]quinoxalines C are
reported.
Scheme 1.
q See Ref. 1.
Keywords: 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines; dehydrogenative cyclization; 2D NMR structure elucidation.
*
Corresponding author. Tel.: þ49-331-977-5210; fax: þ49-331-977-5064; e-mail: kp@chem.uni-potsdam.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01024-X

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G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
Scheme 2.
2. Results and discussion
In the retrosynthesis, given in Scheme 2, the reaction paths b
and c, known so far, are depicted: The hydrazone D is
obtained from the quinoxaline derivative and a thiazole
carrying the N–N sequence; the formation of the C–N bond
is crucial similarly to the N(2)–C(3) bond in the flavazole
analogue.
2.1. Syntheses
The crucial last step of the synthesis of the aromatically
substituted 1H-pyrazolo[3,4-b]quinoxalines of type A (cf.
Scheme 1) is the closure of the pyrazolo ring by
dehydrogenation,6 dehydration7 or dehydrohalogenation8
employing a useful arylhydrazone. These arylhydrazones D
(cf. Scheme 2) can be prepared from the corresponding
quinoxaline derivatives by addition of aromatic hydrazines6
or aromatic diazonium salts.8c,d So, we also expected to
receive the corresponding hydrazones of 3-methyl-1,2-
dihydroquinoxalin-2-one5a,8a and ethyl-2-oxo-1,2-dihydro-
quinoxalin-3-yl acetate,5b,8d respectively, by coupling with
the diazonium salt of 2-aminothiazole; further, the aryl-
hydrazones, thus obtained, should be chlorinated with
POCl3 and, finally, the heteroaromatic ring closed by
dehydrochlorination in the presence of strong bases.
However, we could not succeed in following this reaction
path.
In reaction path d (also given in Scheme 2), the much more
stable thiosemicarbazides were employed for the construc-
tion of the N–N sequence; the syntheses of the less stable
diazonium salts and the hydrazinothiazoles, respectively,
are unnecessary. In addition, the use of a protective group
(benzaldehyde, which has to be removed later),9b strongly
recommended for the preparation of the hydrazinothiazoles,
could be simplified and modified: the reaction partner itself
adopts the function of the protecting group and its removal
is not necessary.
As the first step of our synthetic path d (cf. Scheme 2) the
thiosemicarbazone 1a of 2-acetylquinoxaline was synthe-
sized in nearly quantitative yield through reaction of
2-acetylquinoxaline with thiosemicarbazide; the product
was clean enough to be further used without additional
purification.
It is very well known that hydrazinothiazoles are very
sensible to oxidation;9 especially in acidic media, giving
isomeric mixtures of the corresponding thiazoles, thiazo-
lines and 2-amino-1,3,4-thiadiazines.9 For these reasons
and in order to synthesize the first representative of the
1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines, unknown
so far, two new and independent synthetic routes will be
reported.
It should be mentioned that 1a was not giving a consistent
melting point due to its thermal decomposition near the
melting point to the thermally more stable and higher
melting 3-methyl-1H-pyrazolo[3,4-b]quinoxaline 2.6d,10
The thermal decomposition could be followed readily

G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
6313
Scheme 3.
with the microscope: Beginning at 1958C the crystals of 1a
decompose mainly by sublimation (dependent on the purity
of 1a and the heating velocity also more or less liquid
portions of 1a occur) to 2 which finally melts sharply at
224–2268C (2 can be also synthesized in a larger scale—cf.
Section 3).
with the FISCHER indole synthesis.11 The formation of the
1H-pyrazolo[3,4-b]quinoxalines 4 is preferred due to the
presence of the quinoxaline moiety in the molecule which
can be easily protonated; hereby, an electrophilic center in
position 3 is generated reacting readily under ring closure
with the spatially adjacent nucleophilic sp3-hybridized
nitrogen atom. In case of the phenyl hydrazone 6, where
the heterocyclic thiazole ring has been replaced by phenyl,
no indole derivatives could be obtained in the present
reaction. The pyrazole ring closure does not seem to be
limited to quinoxalines; Rykowski et al.12 published the
synthesis of pyrazolo[4,3-c][1,2,4]-triazines via the acid
promoted ring closure of the phenylhydrazones of 5-acyl-
1,2,4-triazines.
Then, treatment of the 2-acetylquinoxaline thiosemicarba-
zone 1a with a-halogeno ketones gave the thiazoles 3 along
the HANTZSCH thiazole synthesis. However, in the
reaction mixture not only 3 was obtained, but along a
redox process (caused by the formation of the corresponding
hydrogen halogenides) from the hydrazones 3 also the
1H-pyrazolo[3,4-b]quinoxalines 4 could be obtained
(cf. Scheme 3).
The present dehydrogenative cyclization proceeds already
under inert atmosphere when boiling the acidic solution;
yields around 50% were obtained. If oxidizing agents
(including air oxygen) are added, the yields improve
essentially, corroborating that addition of oxidizing agents
proves profitable and that both starting materials and
reaction products could be self-oxidizing.
Ethyl 3-bromopyruvate, as expected, proved to be highly
reactive to the nucleophilic thioamide 1a; the reaction was
strongly exothermic. Dependent on the solvent used, two
different reaction products were obtained: In 2-methoxy-
ethanol the final product was 4a, but in ethanol only the
hydrazone 3a was isolated, since due to its low solubility it
crystallized already from boiling ethanol. The solubility of
3a in 2-methoxyethanol, however, at 1008C is still good
enough to allow it to react further to 4a. The isolation of 3a
along the course of the present reaction is of two-fold
interest: First, it proves that this reaction proceeds via 3a,
and second, it offers the opportunity to study the synthesis of
4a separately from 3a and, hereby, to find out optimal
reaction conditions.
In part X of this series,6d we reported a convenient synthesis
of 1H-pyrazolo[3,4-b]-quinoxalines and interpreted the
formation of these compounds from the corresponding
oximes as a redox process in which hydroxylamine,
generated in situ, was reduced to water and ammonia by
absorbing both two electrons and two protons. Now, we
learned that hydroxylamine hydrochloride, as an oxidizing
agent in acidic media, can be also employed to proceed
with the ring closure of the corresponding hydrazones 3
The ring closure of the hydrazones 3 occurs in competition

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G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
Scheme 4.
(cf. Scheme 3). This is extremely useful in cases where a
necessary elongated boiling in acidic media decomposes the
molecules aimed at; with this procedure, 4a was formed
easily from the corresponding hydrazone 3a in 62% yield.
Through the same pathway, the corresponding carboxylic
acid 4b can be synthesized from bromopyruvic acid; instead
of the acid we used the ester 4a, hydrolyzed it with KOH
and, by acidifying the solution, prepared the free carboxylic
acid 4b.
pyrazolo[3,4-b]-quinoxalines 4, e.g. 1H-pyrazolo[3,4-b]-
quinoxaline-1-thiocarboxamide 5a could be obtained from
the thiosemicarbazone 1a. In 5a, a thioamide group is
attached directly to a ring nitrogen atom (a substituted
thiourea or thiosemicarbazide); thus, starting from 5a
the same compounds 4 (e.g. 4a and 4g) could be prepared
by reaction with halogeno ketones and dimethyl acetylene-
dicarboxylate (DMAD), respectively (cf. Schemes 2 and 5,
path e).
As further oxidizing agents, to be employed in the
dehydrogenative cyclization reaction, azobenzene, phenyl-
hydrazine and hydrazine itself have been found useful.6
Along our study, in addition, sulfur, nitrobenzene, p-chloro-
anil and hydroxylammoniumchloride, respectively, were
tested as oxidizing agents for the cyclization of the
phenylhydrazone of 2-acetylquinoxaline 6 to 3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]quinoxaline 7 (cf. Scheme 4);
the yields obtained—except for sulfur—were very close to
each other.
Not unexpected, the reaction of 5a with 1,4-dibromo-butan-
2,3-dione, in a molar ratio of 2:1, yielded 9 as the reaction
product because of the two halogeno ketone moieties in the
reagent. This compound was obtained from the solution of
the starting materials at 1008C as yellow crystals; it is
thermally very stable (not yet melting at 3608C), insoluble
in organic solvents, only a solid-state 13C NMR spectrum
could be obtained, however, both the IR and the mass
spectrum together with the elemental analysis proved the
structure unequivocally.
Hydroxylammoniumchloride, however, proved to be the
most useful reaction agent: The structure is optimal (with
the hydrogen atoms at periphery of the molecule and the
electronegative atoms in the centre) in both electronic and
steric respect, its solubility in water is unlimited, the
reaction proceeds sufficiently fast in boiling ethanol and the
products formed beside the product of ring closure, water
and ammonia, can be separated easily.
The reaction of 5a with DMAD, in a molar ratio of 1:1,
yielded a colourless product 10, melting at 298–3008C; it
could be concluded from the molecular ion in the mass
spectrum that the molar mass of the product is m(DMAD)þ
m(5a)2m(CH3OH). It should be mentioned that, prin-
cipally a 5-membered 1,3-thiazolin-4-one ring and/or a six-
membered 1,3-thiazin-4-one ring could be expected. It is
generally accepted that, as the first step of the reaction, the
tautomeric SH function of the thioamide group is added to
the triple bond of DMAD (caused by bonding of sulfur to
one of the former acetylenic carbon atoms of DMAD). As
the second step, the thioamide nitrogen in a nucleophilic
attack at one of the two ester carbonyl carbons forms the
heterocyclic ring system; in analogous reactions only the
formation of the 5-membered thiazolinone ring was
observed.13 For this reason, the 6-membered ring was
excluded and the structure given in Scheme 5 assigned to
product 10 (based on MS, IR and CP-MAS 13C NMR data).
The E/Z isomerism at the exo-cyclic CvC double bond
could not be determined from the NMR due to insolubility
in organic solvents.
Employing a concentrated aqueous solution of hydroxyl-
ammoniumchloride, the 1H-pyrazolo[3,4-b]quinoxalines
4a–i were synthesized from the hydrazone 1a with
chloroacetone, ethyl-2-chloro-acetoacetate, ethyl-4-chloro-
acetoacetate, chloro-oxaloacetate, phenacyl bromide,
4-chlorophenacyl bromide and 4-bromophenacyl bromide,
respectively, in a one-pot reaction without isolating the
intermediate products 3.
Finally, along the dehydrogenative cyclization reaction
with hydroxylamine hydrochloride as oxidizing agent,
we found a second path to the 1-(thiazol-2-yl)-1H-

G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
6315
Scheme 5.
Finally (cf. Scheme 5) the reactivity of heteroanalogous
compounds was studied: The reaction of 2-acetyl-quinoxa-
line with methyl dithiocarbazate yielded the dithiocarbazate
1b, with semicarbazide the semicarbazone 1c, with methyl
carbazate the carbazate 1d.
definition of the attachment with the heterocyclic quinoxa-
line ring system is the problem. In compounds 1, 3, and 6 a
long-range C–H correlation (3JC,H) between the hydrogen
nucleus at position 3 and the 4a-carbon atom was observed
and can be used for an unambiguous assignment of the
chemical shifts in the benzylidene ring moiety (cf. Scheme
6); the 13C chemical shift of carbon 4a can be employed as
From the dithiocarbazate 1b, the dithioester 5b could be
prepared by dehydrogenative cyclization employing
hydroxylamine hydrochloride as the oxidizing agent (cf.
Scheme 5); the yield of the crude product (mp 197–1998C)
was 80%, and of the clean product (mp 199–2008C) 74%.
Instead, the expected carboxylic acid derivatives were not
obtained from the oxygen analogues 1c,d but the oxime of
2-acetylquinoxaline 8 was isolated and the structure
assigned unequivocally by mass spectrometry, IR and
NMR spectroscopy.6d However, this result is completely
in line with the behaviour of acylhydrazones, which,
opposite to alkyl- and aryl-hydrazones, could not be
cyclized in acidic media when employing the oximes as
starting material.6d
1
starting point for the assignment of the other H and 13C
chemical shifts using (i) the long-range C,H connectivities
1
(HMBC) to find the H chemical shifts of H-6 and H-8,
3
(ii) the JH,H connectivities (H,H-COSY) to determine the
1
1H chemical shifts of positions 5 and 7, (iii) the JC,H
connectivities (HMQC) to determine the 13C chemical shifts
of the carbons attached directly to the protons, and (iv) the
long-range connectivities (HMBC) of H-5 and 7-H to C-8a.
Unfortunately, in compounds 4 and 5 the corresponding
position is no longer hydrogen substituted since it is
involved in a further ring closure to yield the pyrazolo-
[3,4-b]quinoxalines. An assignment of the chemical shifts of
the benzylidene moiety in these compounds was therefore
done only by analogy to the known behaviour of these
substances, which is the topic of other investigations.14
2.2. Structure elucidation of the compounds
All synthesized compounds were investigated by 1D and 2D
NMR spectroscopic methods to elucidate their structures
unambiguously (4b and 10, caused by their insolubility in
common organic solvents, could be characterized solely
by 1D solid state 13C CP-MAS NMR spectra). Crucial for
the assignment of both the 1H and 13C NMR spectra proves
the benzylidene ring moiety: Within this ring the assign-
ment of the chemical shifts is readily available employing
H,H-COSY, HMQC and HMBC NMR experiments. The
Scheme 6.

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G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
2.3. Conclusions
(DMSO-d6): d 10.59 (s, 1H, NH), 9.95 (s, 1H, 3-H), 8.58 (s,
1H, NH2), 8.46 (s, 1H, NH2), 8.10–8.05 (m, 2H, H-5, H-8),
7.86–7.80 (m, 2H, H-6, H-7), 2.49 (s, 3H, CH3). 13C NMR
(DMSO-d6): d 179.3 (CvS), 149.5 (C-2), 146.5 (CvN),
144.5 (C-3), 141.3 (C-4a), 140.5 (C-8a), 130.3, 130.1 (C-6,
C-7), 129.1, 128.8 (C-5, C-8), 11.6 (CH3). Analysis:
calculated for C11H11N5S: C, 53.36; H, 4.52; N, 28.55; S,
13.07; found: C, 53.74; H, 4.57; N, 28.37; S, 12.92.
The synthesis of a new and biologically very interesting
class of compounds, the 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]-
quinoxalines 4, was reported. Starting from 2-acetyl-
quinoxaline, in three steps, (i) formation of the hydrazone,
(ii) closure of the thiazole ring, and (iii) final closure of the
pyrazol ring [steps (ii) and (iii) could be exchanged] this
new class of compounds could be readily obtained in good
yields. For the ring closure of step (iii) the dehydrogenative
cyclization with hydroxylamine hydrochloride proved very
useful.
3.1.2. Methyl 3-[1-(quinoxalin-2-yl)ethyliden]dithio-
carbazate (1b). The compound was obtained from methyl
dithiocarbazate15 (2.70 g) as pale yellow, nearly colorless
needles. The yield of 1b was 4.31 g (78%); mp 206–2088C
(recrystallised from 1,2-dichloroethane). MS: m/z (%) 228
(61) (M(CH3SH)þ, 200 (26) (M(CS2)þ, 199 (24), 167 (18),
156 (20), 149 (30), 130 (18), 129 (92), 102 (57), 97 (24), 85
(34), 83 (39), 71 (27), 69 (25). IR: 3203, 2916, 1598, 1547,
1486, 1463, 1419, 1368, 1335, 1269, 1232, 1146, 1111,
1064, 978, 958, 928, 882, 760, 744, 678, 635, 561, 541, 484,
3. Experimental
All melting points were determined on a Boetius micro
hotstage microscope (Fa. Analytik Dresden). The IR spectra
(potassium bromide) were recorded with a Perkin Elmer
FTIR 1600 spectrometer (cm21). The mass spectra were
obtained on a Finnigan-MAT SSQ 710 (70 eV). Elemental
analyses were performed on the autanalyser CHNS-932
(Fa. Leco Instruments GmbH); satisfactory microanalyses
were obtained for all substances (C, H, N, S ^0,4%). For
the NMR spectra the samples were dissolved in CDCl3 or
DMSO-d6 and the spectra acquired with Bruker NMR
spectrometers (ARX 300, Avance 300 and 500); the
chemical shifts are given in the d scale (ppm) downfield
from tetramethylsilane (TMS) as internal standard. Solid
state CP-MAS 13C NMR spectra were recorded on a
BRUKER DMX 400. All 1D and 2D NMR spectra were
acquired using the standard BRUKER software.
1
463, 413. H NMR (CDCl3): d 10.15 (s, 1H, NH), 9.71 (s,
1H, H-3), 8.14–8.08 (m, 2H, H-5, H-8), 7.81–7.76 (m, 2H,
H-6, H-7), 2.71 (s, 3H, S–CH3), 2.56 (s, 3H, C–CH3). 13
C
NMR (DMSO-d6): d 201.6 (CvS), 149.7, 149.1 (C-2,
CvN), 143.2 (C-3), 141.4, 140.6 (C-4a, C-8a), 130.6
(2C, C-6, C-7), 129.2, 128.8 (C-5, C-8), 17.2 (S–CH3), 12.3
(C–CH3). Analysis: calculated for C12H12N4S2: C, 52.15;
H, 4.38; N, 20.27; S, 23.20; found: C, 52.36; H, 4.45; N,
20.29; S, 22.90.
3.1.3. 2-Acetylquinoxaline semicarbazone (1c). The
compound was prepared from semicarbazide hydrochloride
(2.45 g, 22 mmol) and sodium acetate trihydrate (3.40 g,
25 mmol) both dissolved in water (20 ml). The crude yield
was 4.00 g (87%), recrystallization from DMF/Pyridin
(10:1) gave 3.30 g (72%) of 1c; mp 278–2828C. MS: m/z
(%) 229 (21) Mþ, 186 (19), 185 (80) (M2CONH2)þ, 171
(8) (M2NHCONH2)þ, 158 (12), 157 (100) (185(N2)þ, 156
(13), 155 (11), 130 (10), 129 (42) (quinoxalin-2-yl)þ, 118
(10), 102 (22) (1292HCN)þ, 76 (12), 75 (11). IR: 3478,
3196, 1707, 1585, 1550, 1484, 1431, 1405, 1375, 1346,
1320, 1239, 1207, 1144, 1097, 983, 958, 929, 887, 763, 731,
3.1. General procedure for the synthesis of 1a–d
A solution of 2-acetylquinoxaline (3.44 g, 20 mmol) in
ethanol (50–500 ml) and a solution of the hydrazino
compound (22 mmol) in ethanol or water were mixed and
heated under reflux for 5–60 min. When a solid product was
not obtained after 10–15 min, the mixture was acidified
weakly with acetic acid or hydrochloric acid and further
heated under reflux. The reaction mixture was allowed to
cool to room temperature and overnight in the refrigerator.
The crystals were filtered under suction and washed with a
small volume of ethanol. Normally, the products were
sufficiently pure for the subsequent syntheses; if not, they
were purified by recrystallisation from the given solvents.
1
626, 472, 413: H NMR (DMSO-d6): d 9.89 (s, 1H, H-3),
9.86 (s, 1H, NH), 8.11–8.06 (m, 2H, H-5, H-8), 7.88–7.80
(m, 2H, H-6, H-7), 6.88 (s, br, 2H, NH2), 2.39 (s, 3H, CH3).
13C NMR (CDCl3): d 156.8 (CvO), 150.0 (CvN), 144.4
(C-3), 143.7 (C-2), 141.1 (C-4a), 140.7 (C-8a), 130.4 (C-7),
130.0 (C-6), 129.1, 128.9 (C-5 and C-8), 11.1 (CH3).
Analysis: calculated for C11H11N5O: C, 57.64; H, 4.84; N,
30.55; found: C, 57.71; H, 5.08; N, 30.20.
3.1.1. 2-Acetylquinoxaline thiosemicarbazone (1a). The
compound was prepared from thio-semicarbazide (2.00 g),
dissolved in water (25 ml), at 758C. The yield of 1a was
4.71 g (96%). Recrystallized from 2-ethoxy-ethanol, diox-
ane or pyridine, pale yellow needles, which convert into
prisms at ca. 196–1998C, were obtained; mp 224–2268C.
MS: m/z (%) 246 (29) (Mþ1)þ, 245 (100) Mþ, 244 (34)
(M21)þ, 232 (12), 203 (25), 200 (14), 185 (33)
(M2CSNH2)þ 184 (16), 171 (15), 158 (14), 157 (94)
(1852N2)þ, 156 (29), 155 (20), 130 (26), 129 (86)
(quinoxalin-2-yl)þ, 118 (19), 116 (72), 103 (21), 102 (63),
77 (18), 76 (26), 75 (23), 60 (28), 51 (18), 50 (15), 43 (14).
IR: 3394, 3265, 3144, 3054, 1619, 1546, 1491, 1456, 1417,
1370, 1323, 1275, 1209, 1127, 1093, 1051, 977, 952, 907,
3.1.4. Methyl 3-[1-(quinoxalin-2-yl)ethyliden]carbazate
(1d). The compound was obtained from methyl carbazate
(2.00 g) dissolved in EtOH (10 ml) as colorless needles;
yield 3.76 g (77%); mp 244–2468C (from toluene). MS: m/z
(%) 245 (16), 244 (36) Mþ, 185 (40) (M2COOCH3)þ, 158
(13), 157 (100) (185(N2)þ, 156 (16), 155 (11), 130 (11), 129
(57) (quinoxalin-2-yl)þ, 102 (28), 77 (11), 76 (15). IR:
2959, 1703, 1610, 1553, 1493, 1450, 1378, 1350, 1313,
1277, 1239, 1190, 1151, 1130, 1092, 1062, 962, 937, 879,
1
764, 687, 611, 490, 415. H NMR (DMSO-d6): d 10.73 (s,
1H, NH), 9.51 (s, 1H, H-3), 8.13–8.08 (m, 2H, H-5, H-8),
7.89–7.85 (m, 2H, H-6, H-7), 3.80 (s, 3H, OCH3), 2.42 (s,
3H, C–CH3). 13C NMR (DMSO-d6): d 154.5 (CvO),
1
888, 835, 760, 711, 682, 634, 580, 483, 407. H NMR

G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
6317
149.9, 148.0 (C-2, CvN), 143.4 (C-3), 141.2, 140.6 (C-4a
and C-8a), 130.7, 130.4 (C-7 and C-6), 129.2, 128.9 (C-5 and
C-8), 52.5 (O–CH3), 11.6 (C–CH3). Analysis: calculated
for C12H12N4O2: C, 59.01; H, 4.95; N, 22.94; found: C,
59.31; H, 5.27; N, 22.73.
under stirring. The reaction mixture was hold at this
temperature for 30 min and then concentrated in vacuo.
The solid residue was separated by suction, washed with
water and recrystallized from toluene; yield 2.10 g (62%)
yellow needles; mp 206–2088C. (ii) Ethyl 3-bromopyruvate
(1.95 g, 10 mmol), under stirring, was poured into the
solution of 1a (2.45 g, 10 mmol) in 2-methoxy-ethanol
(100 ml) at ca. 1058C. The mixture was hold at this
temperature for 30 min, cooled to room temperature and
kept overnight in the refrigerator. The crystals were
separated by suction, washed with ethanol; 1.68 g (50%)
yellow needles, after recrystallization from toluene 1.40 g
(41%) of 4a could be isolated. (iii) Compound 5a (2.43 g,
10 mmol) was solved in boiling 2-methoxy-ethanol
(150 ml), the solution filtered and ethyl 3-bromopyruvate
(2.15 g, 11 mmol) added. The reaction mixture was heated
for 30 min at 1158C; along this time the colour changes from
black dark to light dark near the end of the reaction. After
cooling to room temperature the reaction mixture was stored
overnight in the refrigerator. The precipitate was separated
by suction filtration, washed first with NaHCO3 solution,
later with water. After recrystallisation from toluene 1.56 g
(46%) 4a was obtained as yellow needles. MS: m/z (%) 340
(38) (Mþ1)þ, 339 (46) Mþ, 294 (11) (M2CH3CH2O)þ, 267
(33) (Mþ2COOC2H3)þ, 227 (33), 226 (12), 209 (11), 195
(10), 186 (66), 184 (12), 154 (17), 128 (10), 103 (17), 102
(100) (C6H4CN)þ, 101 (12), 90 (15), 76 (32), 75 (37), 71
(13), 67 (40), 58 (16), 57 (13), 51 (24), 50 (13), 45 (34). IR:
3112, 2980, 2930, 1711, 1539, 1474, 1440, 1379, 1331,
1237, 1204, 1129, 1095, 1027, 960, 872, 827, 768, 649, 603,
546, 457, 418. 1H NMR (CDCl3): d 8.29–8.23 (m, 2H, H-5,
H-8), 8.07 (s, 1H, thiazol), 7.91–7.79 (m, 2H, H-6, H-7),
4.48 (q, J¼7.1 Hz, 2H, CH2), 2.87 (s, 3H, 3-CH3), 1.47 (t,
J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3): d 161.1 (CvO),
157.7 (C-20), 148.2 (C-3), 144.3 (C-4), 141.5, 141.3,
141.2 (C-4a, C-8a, C-9a), 137.8 (C-3a), 131.7 (C-7), 130.1
(C-5), 129.1 (C-8), 128.9 (C-6), 122.9 (C-50), 61.4 (CH2),
14.2 (CH3), 11.6 (3-CH3). Analysis: calculated for
C16H13N5O2S: C, 56.63; H, 3.86; N, 20.64; S, 9.45;
found: C, 56.95; H, 3.90; N, 20.90; S, 9.29.
3.1.5. 3-Methyl-1H-pyrazolo[3,4-b]quinoxaline (2). A
suspension of 1a (2.45 g, 10 mmol) in light petroleum
(12 ml) was stirred vigorously and gently heated to 2208C;
at ca. 1908C the ring closure reaction started, indicated
readily by foaming of the suspension. The suspension was
cooled down to ca. 1108C and the crude product boiled two
times with 80 ml of toluene. The extracts, still boiling, were
filtered, the filtrates combined, cooled to room temperature
and, overnight, in the refrigerator. Compound 2 crystallized
from the solution as golden-bright plates; the crystals were
separated, washed with hexane and dried. The yield of the
pure 2; mp 222–2248C (from dioxane), was 0.98 g (53%).
MS: m/z (%) 185 (28) (Mþ1)þ, 184 (100) Mþ, 183 (42)
(M21)þ, 144 (12), 143 (80) (M2CH3CN)þ, 116 (41)
1
(1432HCN)þ, 102 (12), 90 (13), 89 (10). IR: H and 13C
NMR data, cf. Ref. 6d. Analysis: calculated for C10H8N4:
C, 65.21; H, 4.38; N, 30.42; found: C, 65.46; H, 4.68; N,
30.70.
3.1.6. Ethyl 2-[1-(quinoxalin-2-yl)ethylidenhydrazino]-
thiazol-4-carboxylate (3a). The solution of thiosemicarba-
zide (4.55 g, 50 mmol) in water (50 ml) was added to
the solution of 2-acetylquinoxaline (8.61 g, 50 mmol) in
ethanol (600 ml) and the mixture stirred at 508C. After
addition of acetic acid (6 g, 100 mmol) the reaction mixture
was heated under reflux for 30 min, then, ethyl 3-bromo-
pyruvate (9.75 g, 50 mmol) was added into the hot reaction
mixture with further stirring. After a few minutes yellow
crystals precipitated from the dark solution. The reaction
mixture was cooled in the refrigerator overnight; the
precipitate was collected by suction filtration (10.0 g,
59%). Recrystallization from pyridine afforded 3a as pale
yellow needles; mp 267–2688C. MS: m/z (%) 341 (5) Mþ,
238 (4), (M2C6H4NCH)þ, 212 (28) (M2quinoxalinyl)þ,
184 (10), 171 (7), 159 (11), 158 (100), 157 (44, 156 (27),
155 (10), 143 (8), 130 (14), 129 (24), 116 (11), 115, (39),
114 (18), 113 (15), 102 (43), 89 (19), 76 (17), 75 (10). IR:
3255, 3057, 2974, 1690, 1614, 1567, 1549, 1504, 1492,
1465, 1438, 1410, 1372, 1331, 1293, 1246, 1234, 1153,
1102, 1018, 957, 940, 930, 878, 855, 814, 770, 746, 624,
3.1.8. 2-(3-Methyl-1H-pyrazolo[3,4-b]quinoxalin-1-yl)-
thiazol-4-carboxylic acid (4b). The reaction mixture was
prepared from the ester 4a (1.70 g, 5 mmol) in boiling
ethanol and ethanolic KOH (0.56 g, 10 mmol KOH in 30 ml
EtOH). The potassium salt, thus obtained, was suction
filtrated, washed with ethanol and solved in heated water.
The hot solution was filtered and acidified with acetic acid.
The carboxylic acid 4b precipitated and was recrystallised
from 2-methoxy-ethanol; 0.55 g (35%) of 4b as a yellow
powder; mp 2568C. Even if the compound was stored in the
desiccator with calcium chloride for several days under
vacuum, the carboxylic acid bound 2 mole water per mole
acid. MS: m/z (%) 312 (16) (Mþ1)þ, 311 (100) Mþ, 267
(24) (M2CO2)þ, 227 (16), 226 (16) (2672CH3CN)þ, 187
(10), 186 (80) (2272CH3CN)þ, 170 (14), 142 (11), 102
(36). IR: 3439, 3075, 1705, 1597, 1582, 1539, 1500, 1477,
1446, 1383, 1352, 1314, 1282, 1241, 1200, 1118, 1069,
1003, 952, 910, 866, 828, 764, 729, 695, 647, 614, 602, 552,
458, 420. CP-MAS (solid state) 13C NMR: d 114, broad
(aromatic carbons), 13.1 (CH3). Analysis: calculated for
C14H9N5O2S.2H2O: C, 48.41; H, 3.77; N, 20.16; S, 10.30;
found: C, 48.03; H, 3.26; N, 20.17.
1
607, 569, 534, 481, 410. H NMR (DMSO-d6): d 12.16 (s,
1H, NH), 9.52 (s, 1H, H-3), 8.10–7.80 (m, 4H, aromatic),
7.85 (s, 1H, H-5), 4.26 (q, J¼7.1 Hz, 2H, CH2), 2.48 (s, 3H,
CH3–Cv), 1.30 (t, J¼7.1 Hz, 3H, CH3). 13C NMR
(DMSO-d6): d 168.9 (C-20), 161.0 (CvO), 149.4, 146.0
(C-2, CvN), 143.1 (C-3), 143.0, (C-40), 141.0 (C-8a), 140.7
(C-4a), 130.6 (C-7), 130.1 (C-6), 129.1 (C-5), 128.8 (C-8),
120.3 (C-50), 60.5 (CH2), 14.2 (CH3), 11.7 (CH3–Cv).
Analysis: calculated for C16H15N5O2S: C, 56.29; H, 4.43;
N, 20.51; S, 9.39; found: C, 56.17; H, 4.42; N, 20.31; S,
9.19.
3.1.7. Ethyl 2-(3-methyl-1H-pyrazolo[3,4-b]quinoxalin-
1-yl)thiazol-4-carboxylate (4a). (i) To the solution of 3a
(3.41 g, 10 mmol) in boiling 2-methoxy-ethanol (400 ml) at
ca. 1058C the solution of hydroxylamine hydrochloride
(1.39 g, 20 mmol) in 2N HCl (5 ml, 10 mmol) was poured

6318
G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
3.2. General procedure for the synthesis of 4c–i
m/z (%) 355 (20) (Mþ2)þ, 354 (73) (Mþ1)þ, 353 (100) Mþ,
325 (11), 308 (42) (M2C2H5O)þ, 284 (11), 281 (40)
(3082HCN)þ/(M2CO2C2H4)þ, 280 (11), 240 (12), 239
(18), 236 (12), 195 (40), 186 (10), 169 (19), 154 (12), 102
(18), 71 (17), 70 (17). IR: 2976, 2929, 1700, 1583, 1564,
1534, 1502, 1475, 1444, 1368, 1348, 1321, 1271, 1204,
1173, 1134, 1114, 1092, 1024, 827, 777, 760, 728, 658, 601,
544, 462, 417. 1H NMR (CDCl3): d 8.17–8.14 (m, 2H, H-5,
H-8), 7.79–7.71 (m, 2H, H-6, H-7), 4.33 (q, J¼7.0 Hz, 2H,
CH2), 2.80 (s, 3H, 3-CH3), 2.75 (s, 3H, 40-CH3), 1.38 (t,
J¼7.0, 3H, CH3). 13C NMR (CDCl3): d 162.2 (CvO), 158.2
(C-40), 157.6 (C-20), 148.8 (C-3), 141.4, 141.3, 141.0 (C-4a,
C-8a, C-9a), 137.9 (C-3a), 131.7 (C-7), 130.2 (C-5), 129.0
(C-8), 128.9 (C-6), 117.5 (C-50), 61.0 (CH2), 17.6
(40-CH3), 14.3 (CH3), 11.7 (3-CH3). Analysis: calculated
for C17H15N5O2S: C, 57.78; H, 4.28; N, 19.82 S, 9.27;
found: C, 57.73; H, 4.20; N, 20.24; S, 8.84.
The solution of the a-halogeno ketone in a useful solvent
(10–20 ml of 2-methoxyethanol, 2-ethoxyethanol or 1,4-di-
oxane, respectively) was poured into the solution of 1a
(10 mmol, 2.45 g) in 150 ml of hot 2-methoxyethanol. The
reaction mixtures were stirred at 100–1108C, and, after
5 min, the solution of hydroxylammonium chloride
(10 mmol, 0.70 g) in a few ml water slowly added dropwise.
Then, the mixture was stirred for 2–4 h at 100–1108C,
concentrated in vacuo, neutralized with NaHCO3, and
crystallised in the refrigerator. The precipitated yellow
crystals were suction filtrated, washed first with water, later
with ethanol and recrystallized from the given solvent.
3.2.1. 3-Methyl-1-(4-methyl-thiazol-2-yl)-1H-pyrazolo-
[3,4-b]quinoxaline (4c). The compound was obtained
from chloroacetone (12.5 mmol, 1 ml) and 1a (10 mmol,
2.45 g) as yellow needles, 0.98 g (35%); mp 162–1638C
(from EtOH). MS: m/z (%) 282 (17) (Mþ1)þ, 281 (100)
Mþ, 248 (8) (M2HS)þ, 240 (10) (M2CH3CN)þ, 195 (15)
(M2CHS)þ, 169 (8) (1952HCN)þ, 126 (12), 102 (8), 71
(10), 55 (7). IR: 3087, 2972, 2919, 1583, 1568, 1535, 1509,
1475, 1440, 1380, 1348, 1320, 1253, 1197, 1141, 1123,
1067, 1036, 1015, 970, 912, 871, 824, 760, 728, 655, 604,
556, 536, 464, 420. 1H NMR (CDCl3): d 8.24–8.20 (m, 2H,
H-5, H-8), 7.84–7.74 (m, 2H, H-6, H-7), 6.74 (s, 1H, H-50),
2.87 (s, 3H, 3-CH3), 2.54 (s, 3H, 40-CH3). 13C NMR
(CDCl3): d 156.8 (C-20), 149.9 (C-40), 147.4 (C-3), 141.3,
141.2, 141.1 (C-9a, C-8a, C-4a), 137.8 (C-3a), 131.04,
128.5 (C-6, C-7), 130.1, 129.0 (C-5, C-8), 109.0 (C-5 ),
17.5 (40-CH3), 11.6 (3-CH3). Analysis: calculated for
C14H11N5S: C, 59.75; H, 3.94; N, 24.89; S, 11.40; found:
C, 59.90; H, 4.03; N, 25.07; S, 11.20.
3.2.4. Diethyl 2-(3-methyl-1H-pyrazolo[3,4-b]quinoxa-
lin-1-yl)thiazol-4,5-dicarboxylate (4f). The compound
was obtained from diethyl 3-chlorooxaloacetate (10.5 mmol,
2.34 g) and 1a (10 mmol, 2.45 g) as yellow needles, 1.16 g
(29%); mp 181–1838C (from EtOH). MS: m/z (%) 412 (13)
(Mþ1)þ, 411 (70) Mþ, 366 (9) (M2C2H5O)þ, 338 (8)
(M2C2H5OCO)þ, 294 (9), 268 (14), 267 (100) (M2
2C2H4–2CO2)þ, 227 (9), 186 (22), 170 (8), 110 (9), 102
(14). IR: 3370, 2983, 2938, 1744, 1719, 1588, 1567, 1506,
1474, 1446, 1390, 1370, 1348, 1329, 1285, 1209, 1140,
1131, 1112, 1094, 1020, 858, 827, 798, 770, 746, 728, 684,
1
668, 654, 602, 586, 554, 468, 418. H NMR (CDCl3): d
8.28–8.25 (m, 2H, H-5, H-8), 7.92–7.82 (m, 2H, H-6, H-7),
4.43 and 4.50 (2q, J¼7.2 Hz, 4H, 2CH2), 2.87 (s, 3H,
30-CH3), 1.44 and 1.47 (2t, J¼7.1 Hz, 6H, 2CH3). 13C NMR
(CDCl3): d 162.8, 160.2 (CvO), 158.6 (C-40), 149.6 (C-3),
148.0 (C-20), 141.5, 141.5, 141.0 (C-9a, C-4a, C-8a), 138.1
(C-3a), 132.1, 128.9 (C-6, C-7), 130.3, 129.3 (C-5, C-8),
123.4 (C-50), 62.3, 62.1, (2-CH2), 14.1, 14.0 (CH3), 11.7
(3-CH3). Analysis: calculated for C19H17N5O4S: C, 55.47;
H, 4.16; N, 17.02; S, 7.79; found: C, 55.54; H, 4.07; N,
17.32; S, 7.94.
3.2.2. Ethyl 2-(3-methyl-1H-pyrazolo[3,4-b]quinoxalin-
1-yl)thiazol-4-ylacetate (4d). The compound was obtained
from ethyl 4-chloroacetoacetate (10.5 mmol, 1.73 g) and 1a
(10 mmol, 2.45 g) as yellow needles, 1.34 g (38%) 4d; mp
1228C (from cyclohexane). MS: m/z (%) 355 (20) (Mþ2)þ,
354 (95) (Mþ1)þ, 353 (100) Mþ, 326 (6) (M2HCN)þ, 307
(7), 282 (16), 281 (70), 280 (94) (M2COOEt)þ, 279 (10),
248 (11), 239 (30) (2802CH3CN)þ, 236 (13), 195 (12), 169
(32) (952HCN)þ, 154 (10), 102 (24), 71 (28), 45 (44). IR:
3106, 2985, 1738, 1635, 1583, 1518, 1475, 1381, 1350,
1243, 1200, 1127, 1067, 1028, 980, 868, 824, 766, 729, 660,
604, 566, 536, 464, 420. 1H NMR (CDCl3): d 8.15–8.10 (m,
2H, H-5, H-8), 7.79–7.65 (m, 2H, H-6, H-7), 7.07 (s, 1H,
thiazol), 4.18 (q, J¼7.1 Hz, 2H, CH2), 3.91 (s, 2H, thiazol-
4-CH2), 2.80 (s, 3H, 3-CH3), 1.26 (t, J¼7.1 Hz, 3H, ester-
CH3): 13C NMR (CDCl3): d 170.1 (CvO), 156.4 (C-20),
147.4 (C-3), 145.6 (C-40), 141.0, 140.9, 140.9 (C-4a, C-8a,
C-9a), 137.4 (C-3a), 131.4 (C-7), 129.9 (C-5), 128.7 (C-8),
128.5 (C-6), 111.7 (C-50), 60.8 (O–CH2), 36.9 (40-CH2),
14.1 (CH3), 11.5 (3-CH3). Analysis: calculated for
C17H15N5O2S: C, 57.78; H, 4.28; N, 19.82; S, 9.07;
found: C, 57.72; H, 4.25; N, 20.10; S, 9.08.
3.2.5. 1-(4-Phenyl-thiazol-2-yl)-3-methyl-1H-pyrazolo-
[3,4-b]quinoxaline (4g). (i) The compound was obtained
from phenacyl bromide (10.5 mmol, 2.09 g) and 1a
(10 mmol, 2.45 g) as yellow needles, 2.03 g (59%); mp
183–1858C (from 2-methoxy-ethanol). MS: m/z (%) 344
(18) (Mþ1)þ, 343 (100) Mþ, 301 (20) (M2CH2CN)þ, 195
(9), 134 (15). IR: 3060, 2360, 2343, 1580, 1539, 1497, 1477,
1443, 1395, 1379, 1352, 1310, 1278, 1236, 1196, 1119,
1064, 1028, 1001, 964, 916, 868, 841, 819, 759, 711, 660,
1
616, 599, 560, 477, 457, 419. H NMR (CDCl3): d 8.18–
8.15 (m, 2H, H-5, H-8), 7.98 (d, J¼7.2, 2H, o-Ph), 7.80–
7.65 (m, 2H, H-6, H-7), 7.44–7.29 (m, 3H, m-Ph, p-Ph),
7.25 (s, 1H, H-50), 2.84 (s, 3H, 3-CH3). 13C NMR (CDCl3): d
157.1 (C-20), 152.2 (C-40), 147.5 (C-3), 141.4, 141.3, 141.1
(C-4a, C-8a, C-9a), 137.6 (C-3a), 133.9 (i-Ph), 131.3 (C-7),
130.1 (C-5), 129.0 (C-8), 128.5 (C-6), 128.4 (m-Ph), 128.0
(p-Ph), 126.3 (o-Ph), 108.2 (C-50), 11.7 (CH3). Analysis:
calculated for C19H13N5S: C, 66.45; H, 3.81; N, 20.39; S,
9.33; found: C, 66.53; H, 3.81; N, 20.39; S, 9.06. (ii) The
reaction mixture of 3-methyl-1H-pyrazolo[3,4-b]quinoxa-
line-1-thiocarboxamide (5a) (10 mmol, 2.43 g), phenacyl-
bromide (12.2 mmol, 2.43 g) and 2-methoxy-ethanol
3.2.3. Ethyl 2-(3-methyl-1H-pyrazolo[3,4-b]quinoxalin-
1-yl)-4-methyl-thiazol-5-yl-carboxylate (4e). The com-
pound was obtained from ethyl 2-chloroacetoacetate
(10.5 mmol, 1.73 g) and 1a (10 mmol, 2.45 g) as yellow
needles, 1.47 g (42%); mp 236–2388C (from DMF). MS:

G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
6319
(75 ml) was heated to 1008C for 2 h, concentrated in vacuo
and neutralized with NaHCO3. The precipitated product was
suction filtered, recrystallized from butanol and dried in the
air on filter paper; 1.89 g (55%) 4 g as yellow needles were
obtained; mp 183–1858C.
of 5a is 3.98 g (66%); mp 222–2238C (from pyridine). MS:
m/z (%) 243 (10) Mþ, 185 (41), 184 (100) (M2HNCS)þ,
183 (52), 157 (13), 155 (15), 143 (83) (1842CH3CN)þ, 130
(10), 116 (56) (1432HCN)þ, 102 (20), 90 (18), 89 (14), 76
(13). IR: 3357, 3221, 3168, 1598, 1526, 1500, 1477, 1444,
1347, 1307, 1239, 1162, 1103, 1010, 969, 903, 853, 820,
1
3.2.6. 1-[4-(4-Chlorophenyl)thiazol-2-yl]-3-methyl-1H-
pyrazolo[3,4-b]quinoxaline (4h). The compound was
obtained from 4-chlorophenacyl bromide (10.5 mmol,
2.45 g) and 1a (10 mmol, 2.45 g) as yellow needles,
2.36 g (63%); mp 212.5–2138C (from 2-methoxy-ethanol).
MS: m/z (%) 380 (10) (Mþ3)þ, 379 (42) (Mþ2)þ, 378 (26)
(Mþ1)þ, 377 (100) Mþ, 335 (8), 195 (11), 168 (7). IR:
3033, 1638, 1586, 1570, 1530, 1501, 1474, 1443, 1402,
1377, 1355, 1320, 1290, 1258, 1198, 1142, 1132, 1121,
1100, 1090, 1056, 1014, 968, 928, 901, 870, 835, 820, 769,
737, 731, 702, 666, 612, 604, 566, 540, 488, 472, 441, 419.
1H NMR (CDCl3): d 8.33–8.29 (m, 2H, H-5, H-8), 7.97 (d,
2H, J¼8.7 Hz, H-200)0,0 7.96–7.82 (m, 2H, H-6, H-7), 7.41 (d,
2H, J¼8.7 Hz, H-3 ), 7.34 (s, 1H, H-500), 2.92 (s, 3H,
3-CH3). 13C NMR (CDCl3): d 157.7 (C-2 ), 151.4 (C-40),
148.0 (C-3), 141.9, 141.7, 141.5 (C-4a, C-8a, C-9a), 138.0
(C-3a), 134.0 (C-400), 132.6 (C-100), 131.7 (C-7), 130.4 (C-5),
129.3 (C-8), 128.9 (C-6), 128.8 (C-300), 127.7 (C-200), 108.7
(C-50), 11.8 (CH3). Analysis: calculated for C19H12ClN5S:
C, 60.39; H, 3.20; N, 18.53; S, 8.48; found: C, 60.70; H,
3.18; N, 18.45; S, 8.36.
762, 734, 681, 628, 604, 548, 416. H NMR (CDCl3): d
10.05, 9.88 (2 s, 2H, NH2), 8.34– 8.25 (m, 2H, H-5, H-8),
8.04–7.94 (m, 2H, H-6, H-7), 2.73 (s, 3H, CH3). 13C NMR
(CDCl3): d 177.5 (CvS), 147.7 (C-3), 142.5 (C-9a), 140.4,
139.6 (C-4a, C-8a), 139.1 (C-3a), 132.2 (C-7), 129.9 (C-5),
129.5 (C-6), 128.5 (C-8), 11.5 (CH3). Analysis: calculated
for C11H9N5S: C, 54.31; H, 3.73; N, 28.79; S, 13.18; found:
C, 54.10; H, 3.68; N, 29.11; S, 12.82.
3.2.9. Methyl 3-methyl-1H-pyrazolo[3,4-b]quinoxaline-
1-dithiocarboxylate (5b). Compound 1b (2.74 g, 10 mmol)
was dissolved in boiling 2-methoxy-ethanol (100 ml,
1208C); later, at 100–1108C, a solution of hydroxylamine
hydrochloride (1.40 g, 20 mmol) in 2N hydrochloric acid
(5 ml, 10 mmol) was added in portions within 10 min, with
vigorous stirring of the reaction mixture. After further
stirring for ca. 30 min at 95–1008C, 5b precipitated as
yellow needles. After cooling and storing in the refrigerator
overnight, the crystals were suction filtrated and washed
twice with ethanol. The raw material (yield 2.20 g, 80%)
was recrystallized from 2-methoxyethanol; finally 2.04 g
(74%) of 5b was obtained; mp 199–2008C. MS: m/z (%)
275 (12) (Mþ1)þ, 274 (98) Mþ, 228 (30), 227 (22)
(M2SCH3)þ, 198 (78) (M2CS2)þ, 197 (23), 188 (16), 187
(39), 186 (100) (M2SCH3–CH3CN)þ, 102 (43), 91 (63).
IR: 2988, 2913, 1578, 1570, 1546, 1497, 1443, 1417, 1356,
1344, 1317, 1286, 1250, 1239, 1228, 1196, 1156, 1133,
1120, 1026, 1010, 983, 902, 834, 775, 728, 665, 601, 446,
3.2.7. 1-[4-(4-Bromophenyl)thiazol-2-yl]-3-methyl-1H-
pyrazolo[3,4-b]quinoxaline (4i). The compound was
obtained from 4-bromophenacyl bromide (10.5 mmol,
2.92 g) and 1a (10 mmol, 2.45 g) as yellow needles,
2.41 g (57%); mp 232–2338C (from pyridine). MS: m/z
(%) 424 (15), 423 (100) (Mþ2)þ, 421 (85) Mþ, 381 (13),
379 (13), 214 (10), 212 (12), 195 (15), 151 (11), 133 (12),
102 (12), 89 (13). IR: 3098, 1734, 1586, 1570, 1530, 1501,
1472, 1443, 1397, 1376, 1356, 1320, 1290, 1260, 1198,
1142, 1132, 1122, 1070, 1056, 1010, 928, 901, 870, 832,
824, 771, 738, 730, 703, 668, 650, 614, 604, 566, 540, 502,
458, 441, 419. 1H NMR (CDCl3): d 8.32–8.29 (m, 2H, H-5,
H-8), 7.92 –7.79 (m, 4H, H-6, H-7, H-200), 7.57 (d,
J¼8.7 Hz, 2H, H-300), 7.35 (s, 1H, H-500), 2.91 (s, 3H,
CH3). 13C NMR (CDCl3): d 157.7 (C-2 ), 151.4 (C-40),
148.0 (C-3), 141.8,00141.7, 141.5 (C-4a, C-8a, C-9a), 138.0
(C-3a), 133.0 (C-1 ), 131.7 (C-7 and C-300), 130.4 (C-5),
129.3 (C-8), 128.9 (C-6), 128.0 (C-200), 122.2 (C-400), 108.8
(C-50), 11.8 (CH3). Analysis: calculated for C19H12BrN5S:
C, 54.04; H, 2.86; N, 16.58; S, 7.59; found: C, 54.43; H,
2.84; N, 16.88; S, 7.48.
1
419. H NMR (CDCl3): d 8.27–8.21 (m, 2H, H-5, H-8),
7.88–7.81 (m, 2H, H-6, H-7), 2.82 (s, 3H, S–CH3), 2.74 (s,
3H, 3-CH3). 13C NMR (CDCl3): d 196.4 (CvS), 148.4
(C-3), 144.2 (C-9a), 141.8, 141.5 (C-4a, C-8a), 139.1
(C-3a), 131.7 (C-7), 130.1 (C-5), 129.8 (C-8), 129.6 (C-6),
18.9 (3-CH3), 11.6 (S–CH3). Analysis: calculated for
C12H10N4S2: C, 52.54; H, 3.67; N, 20.42; S, 23.37; found:
C, 52.44; H, 3.76; N, 20.66; S, 23.14.
3.2.10. 2-Acetylquinoxaline phenylhydrazone (6). Freshly
distilled phenylhydrazine (27.5 mmol, 2.97 g) was added to
the solution of 2-acetylquinoxaline (25 mmol, 4.30 g) in
ethanol (250 ml). After 10 min the reaction mixture was
heated and refluxed for 5 min only. After cooling down to
room temperature and two days in the refrigerator, 6 was
obtained as yellow needles (6.03 g) in 92% yield; mp 227–
2288C (from ethanol)—2228C.16 MS: m/z (%) 264 (20)
(Mþ2)þ, 263 (95) (Mþ1)þ, 262 (100) Mþ, 261 (44)
(M21)þ, 247 (15), 246 (16), 245 (20) (M2NH3)þ, 220
(20), 157 (25) (M2C6H5N2)þ, 156 (17), 155 (11), 133 (11),
130 (10), 129 (36) (quinoxalin-2-yl)þ, 102 (11)
(1292HCN)þ, 77 (32), 76 (12), 65 (12). IR: 3260, 3057,
3026, 2936, 1700, 1647, 1600, 1564, 1545, 1494, 1405,
1365, 1304, 1256, 1236, 1167, 1128, 1084, 984, 952, 886,
3.2.8. 3-Methyl-1H-pyrazolo[3,4-b]quinoxaline-1-thio-
carboxamide (5a). Compound 1a (6.13 g, 25 mmol) was
dissolved in boiling 2-methoxy-ethanol (250 ml); at 100–
1108C a solution of hydroxylamine hydrochloride (5.21 g,
75 mmol) in some water (10 ml) was added in portions
within 10 min, with vigorous stirring of the reaction
mixture. After further stirring for ca. 20 min at 1108C, 5a
precipitated as yellow needles from the dark solution. After
cooling and storing in the refrigerator overnight, the crystals
were suction filtrated and washed with ethanol. After further
concentrating the reaction mixture, another fraction of 5a
could be isolated, washed with ethanol and water and
recrystallized from 2-methoxyethanol or pyridine; the yield
1
760, 725, 690, 624, 599, 411. H NMR (CDCl3): d 9.74 (s,
1H, H-3), 8.08–8.02 (m, 2H, H-6, H-7), 7.85 (s, 1H, NH),
7.73–7.67 (m, 2H, H-5, H-8), 7.35 (t, J¼7.0 Hz, 2H, m-Ph),
7.27 (d, J¼6.8 Hz, 2H, o-Ph), 6.98 (t, J¼7.2 Hz, 1H, p-Ph),
2.49 (s, 3H, CH3). 13C NMR (CDCl3): d 150.5 (CvN),

6320
G. Sarodnick et al. / Tetrahedron 59 (2003) 6311–6321
143.8, 143.7 (i-Ph and C-3), 141.6 (C-2), 140.9, 140.5
(C-4a, C-8a), 129.9 (C-6 or C-7), 129.5 (m-Ph), 129.1 (C-6
or C-7), 129.1, 128.9 (C-5, C-8), 121.5 (p-Ph), 113.6 (o-Ph),
9.0 (CH3). Analysis: calculated for C16H14N4: C, 73.26; H,
5.38; N, 21.36; found: C, 73.28; H, 5.49; N, 21.58.
tion of 5a (10 mmol, 2.43 g) in 1,4-dioxane (75 ml, 1008C)
was mixed with 1.56 g DMAD (11 mmol) and heated to
95–1008C for ca. 6 h. After cooling and storing the reaction
mixture overnight in the refrigerator, the precipitate was
suction filtered, washed with methanol and recrystallized
from DMF; 1.41 g (40%) of compound 10 as pink coloured
rods of mp 298–3008C were obtained. MS: m/z 354 (10)
(Mþ1)þ, 353 (45) Mþ, 312 (30) (M2CH3CN)þ, 294 (30)
(M2COOCH3)þ, 237 (18) (M(C6H4CN2)þ, 210 (14), 209
(22), 196 (14) (2372CH3CN)þ, 185 (10), 184 (72), 183
(14), 169 (14) (2092NCN)þ, 168 (56), 144 (34) (C3HOS2
COOCH3)þ, 143 (32) (M2C6H4CN–CH3CN)þ, 128 (16)
(quinoxalindiyl)þ, 116 (60), 102 (34), 85 (34). IR: 3036,
2956, 1725, 1700, 1588, 1548, 1527, 1501, 1476, 1432,
1381, 1361, 1328, 1192, 1128, 1099, 1055, 994, 896, 866,
819, 725, 704, 650, 626, 601, 513, 460, 417. CP-MAS (solid
state) 13C NMR: d 162.5 (CvO), 112 (aromatic carbons),
12.8 (CH3). Analysis: calculated for C16H11N5O3S: C,
54.39; H, 3.14; N, 19.82; S, 9.07; found: C, 54.80; H, 3.21;
N, 20.28; S, 9.07.
3.2.11. 3-Methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoxa-
line (7). (i) The mixture of 6 (2.62 g, 10 mmol) and sulfur
(0.40 g, 1.56 mmol S8) was heated to 220–2608C for 20 min
with stirring (CAUTION); along the reaction H2S was
prepared (fume hood!). The reaction mixture solidified upon
cooling, had to be reduced to smaller parts and, finally, was
stirred with 150 ml ethylacetate; insoluble residues were
removed by filtration. The solvent was removed in vacuo
and the residue recrystallized from ethanol. 1.10 g (42%) of
7 as yellow needles (mp 134–1358C) was obtained. (ii) The
mixture of 6 (2.62 g, 10 mmol) and nitrobenzene (25 ml)
was heated to 2108C for 5 h. Volatile components were
removed by water steam distillation, the residue dissolved in
chloroform, dried and purified by column chromatography.
2.26 g (87%) of raw product was obtained, after recrystalli-
zation from ethanol 1.70 g (65%) of 7. (iii) The reaction
mixture of 6 (2.62 g, 10 mmol), chloroanil (2.46 g,
10 mmol) and xylene (75 ml) was heated under reflux for
4 h. After cooling to room temperature, the reaction mixture
was extracted with diluted KOH, the xylene was removed in
vacuo and the residue, solved in CH2Cl2, purified by column
chromatography. 1.70 g (65%) of 7 recrystallized from
ethanol was obtained. (iv) To the golden yellow solution of
6 (2.62 g, 10 mmol) in boiling ethanol (300 ml) hydroxyl-
amine hydrochloride (1.39 g, 20 mmol) in 2N HCl (10 ml)
was added while stirring the reaction mixture. The dark
mixture, obtained hereby, was heated under reflux for
30 min and concentrated in vacuo. After one night in the
refrigerator, the yellow reaction product could be suction
filtered, chromatographed in CH2Cl2 on silicagel and
recrystallized from ethanol. 1.60 g (62%) of 7 was obtained.
Acknowledgements
The authors wish to thank Mr O. Niemeyer for recording the
13C CP-MAS NMR spectra.
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