Quinoxalines XIV. Synthesis, 1H, 13C,15N NMR spectroscopic, and quantum chemical study of 1H-pyrazolo[3,4-b]quinoxalines (flavazoles)

Article abstract of DOI:10.1016/j.tet.2005.01.013

The synthesis of a series of 1H-pyrazolo[3,4-b]quinoxalines (flavazoles) by acylation, alkylation, halogenation, and aminomethylation of the parent compound is reported and their structure is investigated by ¹H, ¹³C, and ¹⁵

Full text of DOI:10.1016/j.tet.2005.01.013

Tetrahedron 61 (2005) 2373–2385
†
1
13
15
Quinoxalines XIV. Synthesis, H, C, N NMR spectroscopic,
and quantum chemical study of
1H-pyrazolo[3,4-b]quinoxalines (flavazoles)
*
Matthias Heydenreich, Andreas Koch, Gerhard Sarodnick and Erich Kleinpeter
Department of Chemistry, University of Potsdam, PO Box 69 15 53, D-14415 Potsdam, Germany
Received 25 October 2004; revised 15 December 2004; accepted 7 January 2005
Available online 27 January 2005
Abstract—The synthesis of a series of 1H-pyrazolo[3,4-b]quinoxalines (flavazoles) by acylation, alkylation, halogenation, and
aminomethylation of the parent compound is reported and their structure is investigated by H, C, and N NMR spectroscopy. The
1
13
15
restricted rotation about the partial C, N double bond of the N-acyl derivatives 7–10 is studied by dynamic NMR spectroscopy and the
barriers to rotation are determined. In order to assign unequivocally the N chemical shifts of N-4 and N-9, in case of 3-substituted
1
5
1
13
15
flavazoles, exemplary the H, C, and N NMR chemical shifts of 34, 35, and 39 are also theoretically calculated by quantum chemical
methods [ab initio at different levels of theory (HF/6-31G* and B3LYP/6-31G*)].
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
by employing the whole arsenal of 1D and 2D NMR
spectroscopy and also theoretical methods. The restricted
rotation about the exocyclic partial C, N double bond in the
N-acyl compounds 7, 8, 9, and 10, respectively, was studied
by dynamic NMR.
Previously, we reported a new and convenient synthesis of
H-pyrazolo[3,4-b]quinoxalines (flavazoles) by reacting
quinoxaline-2-aldoximes and -ketoximes with hydrazine,
alkylhydrazines or arylhydrazines under acidic conditions to
afford unsubstituted, 1- and/or 3-substituted flavazoles;
various other substituents could be introduced by acylation
1
2. Results and discussion
2
and alkylation of the 1-unsubstituted compounds.
2.1. Syntheses
It is the major objective of the present paper to continue
these studies and to further investigate substitution
possibilities by acylation, alkylation, halogenation, and
Mannich reaction. Beside synthesis, NMR spectroscopic
properties of the flavazoles (cf. Fig. 1) were studied in detail
1H-Pyrazolo[3,4-b]quinoxalines were acylated only in
position 1 by applying aroyl chlorides in the presence of
2
pyridine. When employing acetic anhydride instead, also
the nonsubstituted flavazole (1), the 3-methyl substituted
analogue 2, and the 3-chloro- and 3-bromo-substituted
compounds (5 and 6), could be acylated. If acetic anhydride
is applied in 25-fold excess and as solvent too, 7–10 could
be also obtained (cf. Scheme 1).
1
H-Pyrazolo[3,4-b]quinoxaline (1) can be readily halo-
genated, but the reaction product proved to be dependent on
the substituent pattern: nonsubstituted flavazole is halo-
genated in position 3, thus, with trichloroisocyanuric acid
Figure 1. Investigated 1H-pyrazolo[3,4-b]quinoxalines (flavazoles) (1–48),
R and R are given in Schemes 1–4.
(
obtained which is described as cytotoxic and was already
TCC) 3-chloro-1H-pyrazolo[3,4-b]quinoxaline (5) was
1
3
3
synthesized from 3-amino-1H-pyrazolo[3,4-b]quinoxaline.
The reaction of 1 with N-bromosuccinimide yielded
3-bromo-1H-pyrazolo[3,4-b]quinoxaline (6).
Keywords: 1H-Pyrazolo[3,4-b]quinoxalines; Flavazoles; Restricted
rotation; Dynamic NMR; Theoretical calculations.
†
See Ref. 1.
Corresponding author. Tel.: C49 331 9775210; fax: C49 331 9775064;
e-mail: kp@chem.uni-potsdam.de
*
The 3-halogeno substituted reaction products 5 and 6 can be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.013

2374
M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
Scheme 1.
further acylated and alkylated in position 1; thus, the
reaction of 5 with methyl iodide yielded 3-chloro-1-methyl-
alkylation reaction of 5. Similarly, halogenation of 1-tert-
butyl-1H-pyrazolo[3,4-b]quinoxaline (4) with NBS led to
3-bromo-1-tert-butyl-1H-pyrazolo[3,4-b]quinoxaline (14).
1H-pyrazolo[3,4-b]quinoxaline (11), with ethyl iodide
-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoxaline (12) was
3
obtained and with 1-bromo-1-phenylethane the correspond-
ing 3-chloro-1-(1-phenylethyl-1H-pyrazolo[3,4-b]quinoxa-
line (13) was synthesized (cf. Scheme 1).
The halogenation of 3-methylflavazole (2) and 1,3-
dimethylflavazole (33) under the same conditions was
useless, the unsuccessful bromination of 15 (cf. Scheme 2)
4
was already reported previously. However, if elemental
As seen in Scheme 1 there is a second path of reaction from
the nonsubstituted flavazole (1) to the 1-alkyl-3-halogeno-
bromine in glacial acetic acid at room temperature is used,
the p-substituted product 16 could be isolated. The
corresponding chloro compound 17 could be synthesized
with TCC. 17 was already obtained from the reaction of
1
H-pyrazolo[3,4-b]quinoxalines via the alkyl substituted
derivatives (e.g., 3, 4): first, 1 is alkylated to 3 and, then,
chlorinated employing TCC. Along this path, the methyl
group remains in the molecule and the reaction product 11
obtained proved to be identical to the reaction product of the
2
2-acetylquinoxaline oxime with 4-chlorophenylhydrazine.
Generally, the chemical reactivity of the methyl group in
position 3 of the 1H-pyrazolo[3,4-b]quinoxalines proved to
be very weak. Experiments to oxidize 15 by KMnO , CrO ,
4
3
4
SeO , and CrO Cl were unsuccessful. Otherwise, El-
2
2
2
Maghraby et al. report the oxidation of 15 with SeO in
2
5
ethanol to the corresponding aldehyde. This procedure
could not be reproduced in our investigations, even when
replacing ethanol by other solvents as dioxane/water,
toluene, xylene, mesitylene, diethyleneglycol diethylether,
or at their reflux temperature. On the other hand, 1-phenyl-
1
6
H-pyrazolo[3,4-b]quinoxalin-3-carbaldehyde (19) can be
synthesized by oxidation of 1-phenyl-3-(D-erythro-tri-
hydroxypropyl)-1H-pyrazolo[3,4-b]quinoxaline (18) with
potassium periodate.
7
The aldehyde 19 reacted with p-toluenesulfonyl hydrazide
giving the corresponding tosylhydrazone 20.
Also the Mannich reaction of 3-methyl flavazoles was
studied: the electron withdrawing effect of the nitrogen
atoms in the 1H-pyrazolo[3,4-b]quinoxaline ring system
should accelerate the elimination of the proton and, thus,
from 3-methyl-1H-pyrazolo[3,4-b]quinoxaline (2) with
Scheme 2.

M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
2375
Scheme 3.
8
range and J-HMBC-1 experiments for J(C,H) and
J-HMBC-2 experiments for J(N,H) were proceeded
exemplary at compound 4. The corresponding values thus
obtained are given in Table 1.
9
n
formaldehyde and a number of different secondary amines
the corresponding Mannich bases (21–29) were synthesized
in mostly good or very good yields (cf. Scheme 3).
9
n
2.2. General assignment of the chemical shifts and
coupling constants
2
The difference in the value of J(C-3a, H-3) between the two
experiments may be due to a relatively bad digital resolution
of about 3.6 Hz in the J-HMBC-1 experiment. Recently it
For NMR analysis additional compounds (30–48) were
taken into account for which the syntheses were already
1
0
was shown that both experiments agree well.
2
described in a previous paper. Their substitution pattern is
given in Scheme 4.
3
In cases where R ZCH or CHO, long-range connectivities
3
from the corresponding substituent protons to C-3a, N-2,
and N-1, respectively, were used to assign unequivocally the
latter chemical shifts. The chemical shift of C-9a was then
assigned by long-range connectivities to substituent protons
The unequivocal assignment of the chemical shifts of both
proton and carbon atoms of the pyrazole ring of the
compounds 1–4, 7, and 30–32 proved unequivocal. The
3
1
HMQC and HMBC experiments (starting from R ZH)
in R , or, if this was not possible, using the rule that this
carbon is the only one in the whole molecule who gives no
HMBC signals to any of the hydrogen atoms. To know
show all connectivities which are needed to assign also
nitrogen chemical shifts. To get an impression about the
value of the long-range coupling constants selective long-
n
something about the long-range coupling constants J(C, H)
Scheme 4.

2376
M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
Table 1. Long-range coupling constants in compound 4 (Hz); signs not estimated
n
J(X,H) N-1,
t-Bu
N-1,
H-3
N-4,
H-3
N-4,
H-5
N-9,
H-8
C-3a,
H-3
C-4a,
H-6
C-4a,
H-8
C-5,
H-7
C-6,
H-8
C-7,
H-5
C-8,
H-5
C-8,
H-6
C-8a,
H-5
C-8a,
H-7
C-9a,
H-3
a
Sellr
HMBC 2.4
10.0
13.4
9.5
9.4
1.8
z0
5.5
5.1
3.7
3.4
b
6.6
13.4
1.1
1.2
9.9
5.1
7.4
9.4
7.5
9.9
a
Selective long-range experiment according to Ref. 8. Not all possible long-range couplings were determined; only two hydrogens (H-3 and H-5) were
selected for irradiation.
J-HMBC experiments according to Ref. 9.
b
1
2.2.1. H NMR chemical shifts. The experimentally
in these compounds exemplary a J-HMBC-2 experiment on
compound 40 was carried out. The detected coupling
constants are given in Table 2.
1
detected H NMR chemical shifts of the investigated
compounds are given in Table 3.
The compounds 9–14 contain no protons in position 3,
therefore, the corresponding long-range couplings cannot be
taken to assign unequivocally C-3a. Here, the assignments
given in Table 3 are in analogy with the other compounds
studied.
In the compounds 1, 3, 4, 7, and 30–32 (cf. Tables 3 and 4)
position 3 is nonsubstituted: the H-3 protons were found to
be in the range of 8.40–8.79 ppm. All attempts to correlate
their chemical shifts with electronic substituent parameters
3
(s , s , s , and s , respectively) failed. In cases of R ZMe
m
p
I
R
the range of the chemical shifts of the methyl protons was
determined to be even more narrow (2.66–2.89 ppm). An
The chemical shifts of N-4 and N-9 were assigned by
HMBC measurements corroborated by theoretical calcu-
lations (vide infra). Each of them were found for the
compounds studied in a relatively narrow range (K67 to
K57 ppm for N-4, and K116.6 to K97.5 ppm for N-9).
These two absorption ranges are considered to be large
1
influence of the different substituents in R is again not
perceptible.
The ranges of the chemical shifts of the phenylene protons
are as follows: 8.03–8.35 ppm for H-5, 7.52–7.91 ppm for
H-6, 7.60–7.98 ppm for H-7, and 7.92–8.35 ppm for H-8,
respectively. In all compounds having no carbonyl
function directly bound to positions 1 or 3, H-5 is always
downfield with respect to H-8, and H-6 is upfield
with respect to H-7 (with the exception of 31: here is
d[H-6]zd[H-7]). Introducing an aldehyde group into
position 3 (19) reverses this rule. Carbonyl functions at
position 1 reduce at least the difference between H-5 and
H-8 (47) up to zero (9, 10) or even below zero (7, 8, 46, 48).
As to H-6 and H-7 of the carbonyl containing compounds,
however, they follow (with the exception of 19) the rule
given above.
1
5
enough to assign the two N chemical shifts unequivocally.
These different chemical shifts of the nitrogen atoms N-4
and N-9 are thus the key to assign the chemical shifts of the
phenylene ring atoms. The long-range connectivities in the
H,N-HMBC from H-5 to N-4 and H-8 to N-9 are marking
the beginning and the end of the four-spin system H-5–H-8,
which can be assigned unequivocally furthermore by H,H-
COSY experiments. Direct C–H correlation NMR exper-
1
3
iments (HMQC) yield the C chemical shifts of C-5–C-8,
and the corresponding values of C-4a and C-8a are
accessible via long-range connectivities from the H,C-
HMBC spectra.
Table 2. Long-range C,H coupling constants as determined in compound 40 (Hz); sign not estimated
CH
3
–CH
2
CH
2
–CH
3
CH
2
–OCO
CH
3
–C-3a
CH
3
–C-3
CH
2
–C-9a
2
CH –CO
n
J(C,H)
4.2
2.1
2.6
2.7
7.2
2.1
5.4
1
Table 3. H NMR chemical shifts (ppm) and H,H-coupling constants (Hz) of some selected compounds studied
1
R
3
Compound
R
5
6
7
8
1
2
3
4
7
9
14.15 (br)
11.23 (br)
4.18 (s)
1.92 (s)
2.94 (s)
2.93 (s)
8.79 (s)
2.85 (s)
8.40 (s)
8.43 (s)
8.56 (s)
–
8.27 (d, 8.0)
8.32 (d, 8.6)
8.13 (d, 8.5)
8.15 (d, 8.3)
8.17 (d, 8.4)
8.35 (d, 8.5)
8.03 (d, 8.5)
8.05 (d, 8.7)
8.12 (d, 8.3)
8.04 (d, 8.6)
8.12 (d, 8.6)
8.23 (d, 8.5)
8.26 (d, 8.1)
7.86 (t, 8.3)
7.76 (t, 8.3)
7.63 (t, 8.3)
7.63 (t, 8.2)
7.80 (t, 8.3)
7.91 (t, 8.2)
7.52 (t, 8.3)
7.81 (t, 8.3)
7.63 (t, 8.5)
7.54 (t, 7.7)
7.58 (t, 8.0)
7.67 (t, 8.3)
7.83 (t, 8.2)
7.95 (t, 8.3)
7.87 (t, 8.3)
7.73 (t, 8.5)
7.70 (t, 8.5)
7.88 (t, 8.4)
7.98 (t, 8.4)
7.60 (t, 8.5)
7.75 (t, 8.3)
7.71 (t, 8.3)
7.64 (t, 8.0)
7.68 (t, 8.3)
7.76 (t, 8.4)
7.89 (t, 8.3)
8.18 (d, 8.5)
8.19 (d, 8.5)
8.01 (d, 8.6)
8.09 (d, 8.5)
8.25 (d, 8.7)
8.35 (d, 8.5)
7.92 (d, 8.5)
8.35 (m)
8.06 (d, 8.7)
7.89 (d, 8.6)
7.98 (d, 8.5)
8.06 (d, 8.7)
8.25 (d, 8.1)
15
19
30
33
34
40
47
o: 8.30 (d, 8.3); m: 7.44 (t, 8.6); p: 7.20 (t, 8.3) 2.72 (s)
o: 8.35 (m); m: 7.53 (t, 7.4); p: 7.36 (t, 7.4) 10.38 (s)
o: 8.37 (d, 8.7); m: 7.50 (t, 8.5); p: 7.27 (t, 7.4) 8.54 (s)
4.01 (s)
4.53 (q, 7.3); 1.56 (t, 7.3)
5.30 (s); 4.22 (q, 7.2); 1.23 (t, 7.2)
2.66 (s)
2.75 (s)
2.80 (s)
0
0
0
0
4 , 5 : 7.50 (m); 6 : 7.44 (m); 7 : 7.64 (d, 7.0) 2.74 (s)
A complete table containing data of all measured compounds is included in the Supplementary material.

13
15
Table 4. C and N NMR chemical shifts (ppm) of some of the selected compounds studied
Compound
1
2
3
3a
4
4a
5
6
7
8
8a
9
9a
Others
1
1
K202.0 JN,H
06.7 Hz
:
:
K42.6
134.4
136.4
K62.9
140.6
129.9
127.8
130.8
128.4
141.0
K113.4
143.1
1
1
2
K209.5 JN,H
05.8 Hz
K51.8
144.7
136.6
K64.7
141.0
130.4
127.8
131.1
128.2
141.3
K114.5
144.0
CH
3
: 11.8
: 33.9
1
3
4
7
9
K210.2
K182.8
K167.2
K172.0
K198.8
K37.8
K39.7
K45.2
K60.7
K52.8
132.8
131.6
141.5
140.9
143.9
136.4
137.3
138.1
134.4
137.3
K63.0
K67.0
K60.0
K64.3
K63.5
140.8
140.4
141.5
142.1
140.2
129.9
129.7
129.8
130.4
129.8
127.3
127.2
129.3
130.4
127.5
130.3
129.8
131.5
132.7
130.4
128.3
128.9
129.3
129.7
128.7
141.2
140.6
141.3
142.5
141.0
K114.3
K106.7
K99.5
K97.9
K109.8
141.7
142.0
142.6
143.4
142.0
CH
3
a
a
t-Bu: 60.5; 28.8
C]O: 168.1; CH : 23.5
3
COCH
CH : 11.5; i: 129.2; o: 119.0;
3
: 167.6; 23.7
15
19
30
3
m: 128.8; p: 124.9
CHO: 184.3; i: 138.0; o: 120.
K185.8
K192.4
K29.4
K44.2
140.7
135.0
134.1
137.8
K59.0
K62.7
142.4
141.1
130.3
130.0
129.3
128.2
131.5
130.8
128.8
129.0
140.7
141.3
K103.7
K108.5
142.2
141.7
2
; m: 129.0; p: 127.0
i: 139.2; o: 119.7; m: 129.0;
p: 125.7
3
3
4
3
4
0
K217.9
K204.2
K217.2
K46.0
K48.7
K47.6
141.3
141.5
143.6
135.5
136.0
136.5
K63.7
K64.1
K62.3
139.8
140.2
140.8
129.8
129.9
130.2
126.5
126.6
127.3
129.9
130.0
130.6
127.9
128.1
128.3
140.9
141.1
141.5
K116.3
K116.6
K115.9
142.1
141.9
143.3
CH
CH
3
: 11.2; NCH
3
: 33.2
3
: 11.4; Et: 41.6; 14.5
0
0
CH : 11.6; 1 : 47.9; 2 : 167.9;
3
0
0
3
CH : 11.7; C]O: 164.6; 1 :
: 61.6; 4 : 14.0
0
4
7
K172.9
K53.8
149.8
138.6
K60.3
141.5
130.0
131.5
129.5
129.6
141.7
K98.1
143.8
3
0 0
0
1
4
34.4; 2 : 131.7; 3 : 129.5;
0
0
:131.6; 5 : 126.6; 6 : 129.3
A complete table containing data of all measured compounds is included in the Supplementary material.
a
Or reversed.

2378
M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
1
5
Table 5. Qualitative correlation between d N-1 and E
s
substitution in position 3 changes it to 132.2–136.2 ppm.
The influence of the character of the substituent R is not
significant.
1
1
R (compound)
15
d
N (ppm)
E
s
Me (33)
Et (34)
i-Pr (35)
t-Bu (38)
K217.9
K204.2
K194.3
K188.8
0
K0.07
K0.47
K1.54
Both the quarternary carbons of the phenylene moiety were
found to resonate in very narrow ranges: 139.8–142.4 ppm
for C-4a, and 140.6–142.5 ppm for C-8a. However, the
other carbons of this ring are more separated and resonate in
the ranges of 129.7–130.4 ppm for C-5, 126.5–130.4 ppm
for C-6, 129.8–132.7 ppm for C-7, and 127.3–129.9 ppm for
C-8, respectively. Interestingly, in all investigated com-
pounds the chemical shift of C-5 is downfield from C-8 and
that of C-6 is highfield shifted from C-7.
1
.2.2. C NMR chemical shifts. In general, the C NMR
chemical shifts of the carbon atoms of the flavazole ring
system are observed mostly in very narrow ranges for each
position. These values are listed in Table 4.
3
13
2
The widest range is shown by C-3. However, its chemical
shifts can be grouped in different sets depending on the
The chemical shifts of C-9a show only a small influence of
the substituents R and R , all signals are in the range 141.7–
3
nature of the substituents in positions 3 and 1. If R ZH, the
values were found between 131.6 and 135.7 ppm for 3, 4,
1
3
1
44.7 ppm.
1
and 30–32; introducing a carbonyl function into R (7)
increases the chemical shift to 141.5 ppm. Compounds with
3
1
15 15
2.2.3. N NMR chemical shifts. All measured N NMR
chemical shifts are given in Table 4.
R ZMe and no carbonyl function in R show values in the
range of 140.4–146.9 ppm; the carbonyl function in R
1
again increases the value to 148.5–149.8 ppm. If chlorine is
introduced into position 3, the chemical shifts of this carbon
atom were observed in the range of 132.4–133.0 ppm
Due to the varying substitution in position 1 the
chemical shift of N-1 shows the widest range (K222.2 to
K166.8 ppm). All available substituent constants were tried
to be correlated with the N-1 chemical shifts, however only
a qualitative correlation between the steric substituent
1
(
without a carbonyl containing substituent R ); the corre-
sponding carbonyl compound (9) shows again an increased
value of 140.9 ppm. The chemical shifts of C-3 in
compounds 10 and 19, having bromine and CHO at position
1
1
15
parameter E and d N in the series 33, 34, 35, and 38,
s
3
1
3
, respectively, were determined to be 130.4 and 140.7 ppm.
where R ZMe and R Z Me, Et, i-Pr, and t-Bu,
respectively, were found (Table 5).
The chemical shifts of the carbon atoms in position 3a are in
the range of 135.8–138.6 ppm for R ZH; halogen or CHO
3
15
The N chemical shifts of N-2 were found in the range of
1
13
15
Figure 2. Experimental (%) and calculated (HF/6-31G*: &; B3LYP/6-31G*: :) H, C, and N chemical shifts of 3.
1
13
15
Figure 3. Experimental (%) and calculated (HF/6-31G*: &; B3LYP/6-31G*: :) H, C, and N chemical shifts of 33.

M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
2379
Table 6. Calculated and experimental chemical shifts of compounds 34, 35
and 39, respectively (ppm)
Table 6 (continued)
Atom
Exp.
HF/6-31G*
B3LYP/6-31G*
Atom
Exp.
HF/6-31G*
B3LYP/6-31G*
N-4
N-9
K63.3
K115.5
K77.05
K171.60
K54.48
K115.44
Compound 34
H-5
H-6
H-7
H-8
8.12
7.58
7.68
7.98
4.53
1.56
2.75
8.66
7.79
8.05
8.41
4.18
1.85
2.72
7.88
7.36
7.46
7.74
4.13
1.52
2.36
K60.7 to K37.1 ppm, whereby the compounds with
3
R Z H are situated at the lowfield end, the compounds with
CH
CH
CH
2
3
3
3
3
-1
-3
R Z Me more in the middle, and the compounds with R Z
halogen at the highfield end of this absorption range. Only
1
C-3
141.5
139.82
135.62
136.16
130.20
121.88
129.11
125.76
141.48
142.13
37.80
12.77
14.33
K283.56
K88.00
K77.94
K167.52
130.27
125.71
129.67
120.17
114.58
117.83
117.83
129.48
129.48
37.06
6.93
8.34
K198.21
K46.08
K54.91
K112.03
3
9 with R ZCHO is highfield shifted to K29.4 ppm.
C-3a
C-4a
C-5
C-6
C-7
C-8
C-8a
C-9a
136.0
140.2
129.9
126.6
130.0
128.1
141.1
141.9
41.6
14.5
11.4
K204.2
K48.7
K64.1
K116.6
Successful correlation with common substituent parameters
was not observed.
Both, the chemical shifts of N-1 and N-2 are in a
comparable range as those found for (substituted)
indazoles.
1
2
CH
CH
CH
2
3
3
-1
-3
The chemical shifts of N-4 and N-9 show two well separated
ranges, which can be used successfully for the unambiguous
assignment of the proton and carbon chemical shifts of the
phenylene moiety. These ranges are K67.0 to K59.0 ppm
for N-4 and K116.6 to K97.9 ppm for N-9. However, an ab
initio assignment was only possible for compounds with
N-1
N-2
N-4
N-9
Compound 35
H-5
H-6
H-7
H-8
CH
8.18
8.64
7.77
8.04
8.37
5.00
1.56
2.74
7.87
7.35
7.43
7.70
5.04
1.30
2.38
3
R ZH, using the long-range connectivity from H-3 to N-4
7.60
7.71
8.05
5.32
1.65
2.81
from the HMBC experiments. This was corroborated by
quantum chemical calculations (see below), which gave also
different well separated ranges of the chemical shifts of N-4
and N-9, respectively. Accordingly, it was concluded that
CH
CH
3
-1
-3
3
3
where R is other than hydrogen, the chemical shift ranges
of N-4 and N-9 do not overlap (Fig. 1).
C-3
141.5
141.21
134.76
135.92
130.30
121.61
129.28
125.53
141.44
141.49
41.63
21.92
14.49
K273.16
K90.19
K77.23
K171.25
131.37
124.89
129.79
120.16
114.36
117.91
117.61
129.52
128.57
60.10
34.94
26.05
K188.53
K48.39
K54.85
K115.02
C-3a
C-4a
C-5
C-6
C-7
136.4
140.5
130.1
126.8
130.1
128.3
141.3
141.9
48.4
21.7
11.6
K194.3
K52.1
K64.1
K115.7
2.2.4. Quantum chemical calculations. For some of the
1
13
15
compounds the H, C and N chemical shifts were
calculated theoretically at different levels of theory (HF/6-
C-8
C-8a
C-9a
CH
3
1G* and B3LYP/6-31G*). From Figures 2 and 3 and
1
Table 6 it can be concluded that for the H NMR chemical
shifts neither of these methods gave significantly better
results. In contrast, in case of the C NMR chemical shifts
the HF/6-31G* method and in case of the N NMR
chemical shifts the B3LYP/6-31G* method supplied the
best results.
CH
CH
3
-1
-3
1
3
3
N-1
N-2
N-4
N-9
15
Compound 39
1
The H NMR chemical shifts, especially for the protons of
H-5
H-6
H-7
H-8
8.19
8.65
7.79
8.06
8.38
4.82
6.16
5.52
2.70
141.68
135.22
135.87
130.30
121.79
129.37
125.50
141.32
142.04
45.25
7.88
7.35
7.46
7.70
4.70
5.75
5.08
2.34
132.07
125.07
129.58
120.22
114.52
118.04
117.55
129.49
129.21
44.27
7.63
7.74
8.05
5.14
6.12
5.27
2.78
the phenylene moiety, should be influenced by the
aromaticity of the flavazole ring system. Therefore, the
aromaticity of the different rings were calculated
exemplarily for compounds 3, 4, 7–10, 19, and 33–36.
However, the aromaticity (Table 7) as judged from the
–
–
CH
2
–
CH]
]
CH
CH
C-3
2
3
-3
˚
calculated chemical shielding of a ghost atom situated 2 A
142.5
above the corresponding ring did not show significant
differences for the phenyl ring and for the six-membered
heterocyclic ring system in the centre of the compounds.
The only remarkable deviation was found for the five-
membered pyrazole ring system. In this case, the chemical
shielding (which was used as an indication of aromaticity) is
lowered due to the acetyl group in position 3. However, no
significant correlation with the experimental data could be
obtained.
C-3a
C-4a
C-5
C-6
C-7
C-8
C-8a
C-9a
136.2
140.5
130.1
127.0
130.3
128.3
141.4
142.4
49.1
–
–
]
CH
2
–
CH]
CH
CH -3
132.6
118.0
11.5
131.48
116.23
14.35
122.77
107.62
8.32
2
3
N-1
N-2
K208.6
K48.0
K282.80
K83.49
K198.62
K40.21
Decisive for the unambiguous assignment of the chemical
shifts of the phenylene ring nuclei is the unequivocal

2380
M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
knowledge of the chemical shifts of N-4 and N-9. As
already mentioned they could be determined experimentally
3
only for compounds with R ZH. Therefore, special
attention was paid to the exact calculation of these chemical
1
5
shifts. The N chemical shifts, thus calculated for 34, 35,
and 39 (as examples for the whole variety), proved to be
different sufficiently to distinguish unequivocally the two
nitrogen atoms in the compounds studied. This is surprising
because they seem to be very similar. This is why an natural
1
3
chemical shift (NCS) analysis was carried out for one case
35) which gives the different partitions to the shielding
(
constants from the different chemical bonds, lone pairs, and
core electrons. Contributions to the shielding of N-4 and
N-9 of major importance are given in Table 8.
Table 8. Most important partitions to the isotropic chemical shielding
(ppm) of the nitrogen atoms N-4 and N-9 of 35 as calculated by the NCS
analysis
Bond/electron
N-4
239.66
Bond/electron
N-9
239.62
Core
Core
Lone pair N-4
N-4–C-3a
N-4–C-4a
C-3a–C-3
C-3a–C-9a
C-4a–C-5
C-4a–C-8a
K184.14
K60.2
K50.2
K3.05
K3.46
K2.34
K0.1
Lone pair N-9
N-9–C-9a
N-9–C-8a
C-9a–N-1
C-9a–C-3a
C-8a–C-8
C-8a–C-4a
K130.2
K54.66
K48.22
K2.65
K2.74
K1.48
K0.35
a
a
Total
K62.96
Total
K2.79
Lewis and non-Lewis contributions are added.
a
Total means of the sum of all partitions to the chemical shieldings of N-4
and N-9, respectively.
As a whole it is found that N-4 is less shielded by about
6
0 ppm as compared with N-9. This is in good agreement
with the experimentally determined values of compound 35
ca. 52 ppm). From Table 8 it can be seen that the reason for
(
the different chemical shifts of the two nitrogen atoms are
the very different contributions of their corresponding
N-lone pairs to the shieldings; the other contributions are
much more the same.
2
.2.5. Restricted rotation about the amide bond. The
1
compounds with R Z COMe show a splitting of the COMe
proton signal at low temperature. This is due to the restricted
rotation of the amide bond. Calculated and experimentally
detected values of the free energy difference of the rotamers
#
DG8) and the free energy of activation (DG ) are given in
(
Table 9. The calculated and experimentally determined
#
values of DG agree very well; small differences may be due
to the inaccuracy of the calculation method. These
inaccuracies are probably also the reason for the differences
in DG8 values, which are, however, in this case of higher
significance because of their much smaller values compared
#
to DG of the rotational isomers.
#
The rotational barriers (DG ) for 7–10 are located at the
lower end of the range of the free energy of rotation of the
amide bond in common amides. Lowering of the barrier in
these cases can be caused by a weak basic character of N-1
1
4
and by a steric hindrance of the annelated ring system. The
theoretical calculations showed that in all cases the (Z)-
configuration is more stable than the (E)-analogue. The
strong steric hindrance in this part of the molecule should

M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
2381
#
), free energies (DG8), and free energies of activation (DG ) of the restricted rotation about the amide partial double bond
Table 9. Coalescence temperatures (T
kJ/mol)
c
(
#
DG (kJ/mol)
a
#
DG (kJ/mol)
b,c
a
b
Compound
T
c
(K)
DG8 (kJ/mol)
DG8 (kJ/mol)
7
8
9
235
250
240
240
54.6 and 50.7
52.9 and 50.0
48.9 and 46.5
51.0 and 47.7
46.2
48.4
47.5
47.3
3.43
2.34
3.16
3.52
4.26
3.76
3.85
3.97
1
0
Experimental DG8 was determined at TZ203 K.
Experimental.
a
b
2 2
Calculated with DFT (B3LYP/6-31G*) under consideration of solvent (CD Cl ).
Rotation from (E) to (Z).
c
also be the reason that no dynamic phenomena of other
amidic compounds with a (substituted) benzoyl group at R
3.1.1. General procedure for the synthesis of 3-halo-1H-
pyrazolo[3,4-b]quinoxalines (5–6). The N-Hal-compound
was added slowly to a solution of 1 (50 mmol, 8.50 g) in
N,N-dimethylformamide (300 mL) at room temperature
with stirring. The mixture was heated at 80 8C for 10 min
and then 220 mL of the solvent were removed in vacuo.
After cooling down to 15 8C the residue was treated with
water (100 mL) and kept overnight in the refrigerator. The
solid was collected by filtration, washed twice with
methanol and recrystallized from xylene or dioxane.
1
(
46, 47, and 48, respectively) could be observed. In these
cases, obviously one of the two ground states is energeti-
cally too unstable to be experimentally detected.
In contrast to the restricted rotation about the amide bond
the hindrance of the rotation of the C(O)–C-3 bond in
compound 19 could not be observed. The theoretical
#
calculations show a DG of 36.3 kJ/mol as barrier of this
rotation. Thus, it is much smaller than the energy barrier for
the restricted rotation about the amide bond.
3.1.1.1. 3-Chloro-1H-pyrazolo[3,4-b]quinoxaline (5).
From trichloroisocyanuric acid (TCC) (20 mmol, 4.65 g) in
72% yield as yellow prisms, mp 280–281 8C; ms: m/z (%)
2
.2.6. Conjugation within 1-phenyl substituted flava-
1
C
C
C
zoles. If R ZPh, delocalisation of the p electrons of this
phenyl ring at N-1 and the flavazole ring system can be
expected. As a measure for this conjugation the torsional
angle between the two planes of the both aromatic moieties
can be considered. For compound 19 it was found by the
theoretical calculations to be 0.9 and 2.18 for (E) and (Z),
207 (20) (MC3) , 206 (36) (MC2) , 205 (60) (MC1) ,
204 (100) M , 169 (10) (MKCl) , 143 (30) (169–CN) ,
C
C
C
C
116 (37) (143–HCN) , 102 (17), 90 (52), 75 (24), 63 (55);
IR: 3126, 3038, 2918, 2817, 1716, 1594, 1500, 1480, 1462,
1342, 1294, 1274, 1240, 1202, 1132, 1090, 1036, 968, 916,
852, 800, 768, 728, 606, 544, 460, 436, 420. Elemental
1
3
respectively; so it is more or less planar. The C NMR
chemical shifts of the o-carbons and the difference of
analysis (%) for C H ClN : calcd C 52.87, H 2.46, N 27.38;
9 5 4
1
3
C
found C 53.11, H 2.50, N 27.40. Because of its extremely
low solubility in common solvents no NMR spectra could be
taken.
NMR chemical shifts of the m- and o-carbons of the phenyl
moiety were used to assess this interannular conjugation.
For an unhindered conjugation in 1-phenyl pyrazoles d(o-C)
proved to be 118.5–118.8 and the d(m-C)–d(o-C)
3.1.1.2. 3-Bromo-1H-pyrazolo[3,4-b]quinoxaline (6).
From N-bromosuccinimide (NBS) (55 mmol, 9.75 g) in
83% yield as yellow as prisms, mp 283–284 8C; ms: m/z (%)
1
5
1
0.5 ppm. The detected values for compounds 15, 19,
and 30 [d(o-C) 119.0–120.2 and d(m-C)–d(o-C) 8.8–9.8] are
much closer to the values of 1-phenyl pyrazole than to
the given values obtained in cases of hindered conjugation
C
C
C
251 (11) (MC3) , 250 (83) (MC2) , 249 (12) (MC1) ,
248 (96) M , 169 (50) (MKBr) , 143 (14) (169–CN) ,
C
C
C
C
117 (32) (143–HCN) , 90 (100), 85 (16), 76 (14), 64 (31),
[
d(o-C) 124.6–125.4 and d(m-C)–d(o-C) 3.3–4.0]. Together
with the results of the theoretical calculation a non-hindered
63 (39); IR: 3112, 3022, 2896, 2776, 1716, 1622, 1582,
1500, 1478, 1458, 1424, 1346, 1288, 1270, 1206, 1134,
1086, 1016, 1000, 916, 784, 758, 732, 606, 594, 544, 516,
conjugation along the two aromatic moieties in 15, 19, and
3
0 can be concluded.
426. Elemental analysis (%) for C H BrN : calcd C 43.40,
9 5 4
H 2.02, N 22.50; found C 43.65, H 2.12, N 22.74. Because
of its extremely low solubility in common solvents no NMR
spectra could be taken.
3. Experimental
All melting points were determined on a Boetius micro
hotstage microscope (Fa. Analytik Dresden). The IR spectra
3.1.2. General procedure for the acetylation of
1-unsubstituted flavazoles (7–10). The mixture of the
appropriate 1-unsubstituted flavazole (10 mmol) and acetic
anhydride (25 mL, 265 mmol) was heated under reflux for
30 min and kept overnight in the refrigerator. The solid was
collected by filtration under suction, washed with 50%
aqueous ethanol and recrystallized.
(
potassium bromide) were recorded with a Perkin Elmer
K1
FTIR 1600 spectrometer (cm ). 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); reliable microanalyses were
obtained for all substances (C, H, N, S G0.3%).
3
.1. Syntheses
3.1.2.1. 1-Acetyl-1H-pyrazolo[3,4-b]quinoxaline (7).
From 1 in 45% yield as colourless needles (hexane), mp
162–164 8C; ms: m/z (%) 212 (22) M , 211 (100) (MK1) ,
C
C
Compounds 1–4, 15–17, and 30–48 were synthesized
according to literature.
2
C
C
210 (95) (MK2) , 169 (20), 168 (85) (MKCH CO, –H) ,
3

2382
M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
C
41 (20) (MKCH CON ) , 115 (31) (141–CHCH), 74 (6),
2 (8); IR: 3082, 1738, 1577, 1501, 1406, 1380, 1350, 1298,
256, 1213, 1176, 1134, 1084, 1024, 969, 939, 907, 881,
40, 808, 763, 733, 738, 610, 584, 419. Elemental analysis
1
6
1
8
calcd C 54.94, H 3.22, N 25.63; found C 54.93, H 3.19, N
25.81.
3
2
3.1.3.2. 3-Chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoxa-
line (12). From 5 (2.04 g) and ethyl iodide (2.33 g) in 56%
yield as yellow prisms (hexane), mp 97–99 8C; ms: m/z (%)
(
C 62.45, H 3.82, N 26.52.
%) for C H N O: calcd C 62.26, H 3.80, N, 26.40; found
1
1 8 4
C
34 (30) (MC2) , 233 (25) (MC1) , 232 (100) M , 219
C
C
2
C
23), 217 (70) (MKCH ) , 206 (14), 204 (38) (MK
(
CH ]CH ) , 154 (8), 129 (35), 102 (23), 90 (14); IR:
3.1.2.2. 1-Acetyl-3-methyl-1H-pyrazolo[3,4-b]quin-
oxaline (8). From 2 in 88% yield as colorless needles
3
C
2
2
C
2
1
1
4
5
986, 2942, 1716, 1652, 1574, 1486, 1460, 1436, 1402,
378, 1352, 1296, 1238, 1224, 1194, 1166, 1116, 1086,
046, 982, 928, 882, 846, 794, 764, 724, 650, 618, 602, 554,
(
(
toluene), mp 191–193 8C; ms: m/z (%) 226 (9) M , 185
10), 184 (78) (MKCH CO), 183 (13), 155 (10) (184–HN ),
2
2
1
2
1
1
6
43 (54), 116 (18), 102 (17), 90 (10), 76 (11); IR: 3016,
928, 1846, 1722, 1618, 1580, 1542, 1500, 1446, 1418,
364, 1312, 1290, 1260, 1246, 1232, 1202, 1148, 1122,
096, 1038, 1010, 978., 924, 892, 834, 772, 730, 678, 634,
02, 578, 462, 420. Elemental analysis (%) for C H N O:
88, 424. Elemental analysis (%) for C H ClN : calcd C
4
11
9
6.78, H 3.90, N 24.08; found C 56.77, H 4.06, N 24.30.
3.1.3.3. 3-Chloro-1-(1-phenylethyl)-1H-pyrazolo[3,4-
b]-quinoxaline (13). From 5 (2.04 g) and (1-bromoethyl)-
1
2 10 4
calcd C 63.71, H 4.46, N 24.77; found C 63.56, H 4.48, N
4.56.
benzene (2.78 g) in 89% yield as yellow prisms (heptane),
mp 128–130 8C; ms: m/z (%) 310 (9) (MC2) , 309 (5)
2
C
C C
MC1) , 308 (19) M , 293 (8) (MKCH ), 207 (5), 206
(
(
(
3
3.1.2.3. 1-Acetyl-3-chloro-1H-pyrazolo[3,4-b]quin-
oxaline (9). From 5 in 62% yield as light brown needles
ethanol), mp 220.5–221.5 8C; ms: m/z (%) 248 (8) (MC
C
28), 205 (19), 204 (100) (MKC H CHCH ) , 177 (8), 175
6
5
2
C
10) (MKC H CHCH N ) , 169 (12) (204–Cl) , 154 (10)
C
6
C
5
2 2
(
C
C
C
) , 247 (7) (MC1) , 246 (16) M , 206 (32), 205 (12),
(169–NH) , 143 (22), 129 (16), 116 (23); IR: 3060, 2976,
2930, 2870, 1962, 1716, 1618, 1570, 1496, 1480, 1442,
2
2
1
1
1
8
C C
04 (100) (MKCH CO) , 169 (17) (204–Cl) , 143 (34),
2
1
1
7
404, 1378, 1350, 1298, 1228, 1206, 1176, 1144, 1132,
118, 1080, 1056, 1030, 1004, 982, 956, 934, 884, 850, 774,
58, 728, 716, 700, 624, 616, 602, 556, 546, 534, 490, 422.
16 (17), 102 (8), 90 (17), 76 (11), 63 (11); IR: 3062, 2888,
852, 1747, 1619, 1572, 1498, 1468, 1408, 1374, 1351,
301, 1281, 1250, 1222, 1188, 1151, 1131, 1066, 969, 918,
73, 836, 775, 725, 663, 630, 602, 571, 547, 420. Elemental
Elemental analysis (%) for C H ClN : calcd C 66.13, H
1
7
13
4
4
.24, N 18.15; found C 66.30, H 4.51, N 18.38.
analysis (%) for C H ClN O: calcd C 53.56, H 2.86, N
7
1
1
4
2
2.72; found C 53.61, H 2.86, N 23.01.
3
1
.1.4. General procedure of halogenation of substituted
H-pyrazolo[3,4-b]quinoxalines (11, 14, 16, 17). The
3.1.2.4. 1-Acetyl-3-bromo-1H-pyrazolo[3,4-b]quin-
oxaline (10). From 6 in 69% yield as light brown needles
N-Hal-compound was added slowly to a solution of the
substituted 1H-pyrazolo [3,4-b]-quinoxaline (3 mmol) in
N,N-dimethylformamide (5 mL) at room temperature with
stirring. The mixture was heated up to 80 8C and stirred at
this temperature for 10 min. After cooling the mixture was
diluted with water (5–20 mL). The solid was collected by
filtration, washed with a little amount of cold methanol and
recrystallized.
C
ethanol), mp 220–221 8C; ms: m/z (%) 293 (8) (MC3) ,
(
C
92 (21) (MC2) , 291 (8) (MC1) , 290 (21) M , 251 (9),
C
C
2
2
1
1
1
7
C
50 (100), 248 (84) (MKCH CO), 169 (42) (248–Br) ,
2
C
43 (12), 117 (12) (143–CN) , 90 (22); IR: 3063, 2934,
978, 1744, 1565, 1496, 1459, 1409, 1372, 1351, 1296,
276, 1250, 1216, 1190, 1128, 1058, 964, 916, 858, 835,
61, 727, 627, 573, 520, 419. Elemental analysis (%) for
C H BrN O: calcd C 45.38, H 2.43, N 19.25. Found C
1
1
7
4
3
.1.4.1. 3-Chloro-1-methyl-1H-pyrazolo[3,4-b]quin-
4
5.62, H 2.45, N 19.35.
oxaline (11). From TCC (1 mmol, 0.23 g) and 3 (0.55 g)
in 53% yield as yellow prisms (dioxane), mp 200–201 8C,
IR to be identical to the product 11 obtained from 3-
chloroflavazole.
3
.1.3. General procedure of alkylation of 3-halo-1H-
pyrazolo[3,4-b]quinoxalines (11–13). To a solution of
-halo-1H-pyrazolo[3,4-b]quinoxaline (10 mmol) in N,N-
dimethylformamide (30 mL) the alkylating agent
3
3
.1.4.2. 3-Bromo-1-tert-butyl-1H-pyrazolo[3,4-b]-
quinoxaline (14). From NBS (3.4 mmol, 0.60 g) and 4
0.68 g) in 48% yield as yellow needles (ethanol), mp 192–
(
(
15 mmol) and powdered anhydrous potassium carbonate
20 mmol, 2.76 g) were added. The mixture was stirred over
(
1
2
(
(
C
2
4 h at 50 8C and then diluted with water (50 mL). The
93.5 8C; ms: m/z (%) 307 (30) (MC3) , 306 (100) (MC
) , 305 (30) (MC1) , 304 (100) M , 291 (15), 289 (15)
C
C
C
precipitate was collected by filtration, treated with cold 2 N
NaOH, washed with water until neutral and dried.
C
C
MKCH ) , 250 (50), 248 (48) (MKC H ) , 169 (30)
3 4 8
C
248–Br) , 143 (20), 102 (22), 90 (25); IR: 3068, 2975,
3
.1.3.1. 3-Chloro-1-methyl-1H-pyrazolo[3,4-b]quin-
2933, 2683, 1967, 1715, 1622, 1565, 1494, 1477, 1436,
1414, 1388, 1368, 1348, 1292, 1258, 1233, 1198, 1148,
1122, 1068, 1025, 928, 871, 803, 759, 728, 606, 589, 496,
425. Elemental analysis (%) for C13H13BrN : calcd C 51.16,
4
H 4.29, N 18.36; found C 50.93, H 4.41, N 18.65.
oxaline (11). From 5 (2.04 g) and methyl iodide (2.13 g)
in 57% yield as yellow prisms (dioxane), mp 200–201 8C;
ms: m/z 220 (26) (MC2) , 219 (16) (MC1) , 218 (76)
C
C
C
C
C
M , 217 (19) (MK1) , 183 (15) (MKCl) , 129 (33), 102
18), 90 (14), 76 (11), 63 (11); IR: 3047, 2940, 1978, 1732,
(
1
1
5
574, 1488, 1462, 1400, 1352, 1302, 1242, 1208, 1166,
116, 1022, 940, 892, 846, 818, 768, 722, 658, 626, 602,
52, 528, 488, 424. Elemental analysis (%) for C H ClN :
3.1.4.3. 1-(4-Bromophenyl)-3-methyl-1H-pyrazolo-
[3,4-b]quinoxaline (16). Solutions of 15 (2.60 g,
10 mmol) in acetic acid (400 mL) and bromine (1.76 g,
1
0
7
4

M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
2383
1
1 mmol) in acetic acid (30 mL) were mixed and kept in a
3.1.5. General procedure for aminomethylation of 1H-
pyrazolo[3,4-b]quinoxalines (21–29). To a suspension of 2
(10 mmol, 1.84 g) in ethanol (20 mL), an appropriate amine
(12 mmol) and finally formalin (1.2 mL, 16 mmol) [solution
closed bottle for 3 days at room temperature. Thereafter, the
mixture was diluted with water (700 mL) and kept in the
refrigerator for 24 h. The solid was collected by filtration,
washed with water and recrystallized twice from acetic acid.
The compound was obtained in 75% yield as yellow
needles, mp 241–2428, and found to be identical to the
product from 2-acetylquinoxaline oxime and 4-bromophe-
of 37% CH ]O in water] were added under stirring. The
2
reaction was weakly exothermic (the temperature increased
from 25 8C until 29 8C). The mixture was then heated under
reflux for 2–5 min till the product began to crystallize. The
mixture was kept overnight in the refrigerator. The solid was
collected by filtration, washed with cold 2 N NaOH (if not
esters), and with water or diluted ethanol. The products were
purified by recrystallization.
2
nylhydrazine. Because of its extreme bad solubility in
common solvents no NMR spectra could be recorded.
3.1.4.4. 1-(4-Chlorophenyl)-3-methyl-1H-pyrazolo-
3,4-b]quinoxaline (17). From TCC (1 mmol, 0.23 g) and
[
3
.1.5.1. 1-Diethylaminomethyl-3-methyl-1H-pyra-
15 (0.78 g) in 50% yield as yellow needles (toluene), mp
234–236 8C, IR is identically with the product from
2-acetylquinoxaline oxime and 4-chlorophenylhydrazine.
zolo[3,4-b]quinoxaline (21). From diethyl amine in 48%
yield as yellow needles (hexane), mp 75.5–76.5 8C; ms: m/z
2
C C
%) 270 (6) (MC1) , 269 (1.5) M , 213 (21), 212 (86)
(
Because of its extreme bad solubility in common solvents
no NMR spectra could be recorded.
C
C
(
MKC H –C H ) , 197 (29) (MKEt N) , 129 (30)
2 5 2 4 2
C
6 4 3 3 2 2
C
C H NC H ) , 102 (24), 87 (35), 86 (100) (Et NCH ) ,
(
5
1
1
8
8 (31); IR: 3066, 2964, 2926, 2822, 1958, 1576, 1498,
480, 1476, 1380, 1350, 1334, 1308, 1240, 1216, 1200,
172, 1134, 1118, 1090, 1062, 1022, 996, 978, 952, 898,
42, 802, 758, 730, 708, 640, 616, 602, 554, 424. Elemental
3.1.4.5. 1-Phenyl-1H-pyrazolo[3,4-b]quinoxalin-3-
carbaldehyde (19). A solution of 18 (10 mmol, 3.36 g)
in hot dioxane (200 mL) was slowly poured into a
suspension of KIO4 (25 mmol, 5.75 g) and NaHCO3
1
6
analysis (%) for C H N : calcd C 66.89, H 7.11, N 26.00;
1
found C 66.75, H 6.98, N 25.92.
5 19 5
(
30 mmol, 2.52 g) in 1 kg ice-water under vigorous stirring.
The mixture was allowed to warm up to room temperature
in 1 h and stirring was continued for 2–4 h. The mixture was
kept overnight in the refrigerator. The solid was collected by
filtration and washed with water. The crude product was
considerably pure. The yield was 2.60 g (95%) yellow–
brown prisms, mp 143.5–144.5 8C, after recrystallization
from ethanol 2.10 g (77%) golden prisms, mp 145–146 8C;
3
.1.5.2. 1-Diisobutylaminomethyl-3-methyl-1H-pyra-
zolo[3,4-b]quinoxaline (22). From diisobutyl amine in 75%
yield as yellow needles (heptane), mp 101.5–102.5 8C; ms:
m/z (%) 326 (5) (MC1) , 282 (21) (MKCH CHCH ), 241
20), 240 (82) (MKCH ]C–CH ), 198 (29), 197 (91), 143
2 3
55), 142 (100) (MKCH CN: 2ZC H N CC H N) ,
29 (70), 128 (23), 102 (31), 100 (20), 98 (19), 86 (37), 57
54) (CH CH(CH ) ) ; IR: 3040, 2964, 2866, 2826, 1946,
2 3 2
728, 1632, 1578, 1498, 1482, 1466, 1404, 1382, 1356,
352, 1308, 1282, 1244, 1204, 1170, 1120, 1078, 1018, 970,
54, 930, 900, 848, 822, 766, 726, 706, 646, 616, 602, 558,
24. Elemental analysis (%) for C H N : calcd C 70.12, H
C
3
3
(
(
1
(
1
1
9
4
8
C
C
C
3 8 4 3 9 20
ms: m/z (%) 276 (12) (MC2) , 275 (65) (MC1) , 274
(
C
100) M , 246 (14), 245 (64) (MKCHO), 219 (6), 218 (9)
C
C
245–HCN) , 77 (7) C H ; IR: 3043, 3063, 2867, 2829,
(
6
5
1
1
1
7
939, 1793, 1699, 1593, 1568, 1498, 1465, 1430, 1397,
375, 1359, 1331, 1322, 1292, 1237, 1205, 1149, 1069,
027, 1008, 996, 959, 934, 901, 891, 856, 847, 834, 802,
67, 743, 688, 669, 648, 614, 600, 536, 506, 481, 425.
1
9 27 5
.36, N 21.57; found C 70.05, H 8.30, N 21.44.
Elemental analysis (%) for C H N O: calcd C 70.06, H
6 10 4
1
3
.67, N 20.43; found C 70.22, H 3.59, N 20.27.
3
.1.5.3. 3-Methyl-1-pyrrolidinomethyl-1H-pyra-
zolo[3,4-b]quinoxaline (23). From pyrrolidine in 83%
yield as yellow needles (heptane), mp 137–139 8C; ms:
m/z (%) 268 (21) (MC1) , 267 (41) M , 199 (13), 198
3
carbaldehyde)-(p-tolylsulfonyl)hydrazone (20).
mixture of the carbaldehyde 19 (2.74 g, 10 mmol),
p-toluenesulfonyl hydrazide (2.05 g, 11 mmol) and ethanol
.1.4.6. (1-Phenyl-1H-pyrazolo[3,4-b]quinoxalin-3-
A
C
C
C
(71), 197 (22) (MKpyrrolidino) , 129 (23), 102 (19), 85
(32), 84 (100), 83 (18), 70 (47) pyrrolidino , 55 (27); IR:
C
(
300 mL) was heated under reflux for 30 min, in which time
3064, 2938, 2874, 2830, 1938, 1716, 1576, 1498, 1478,
1458, 1386, 1344, 1310, 1272, 1242, 1150, 1116, 1084,
1024, 980, 962, 900, 842, 754, 722, 648, 606, 588, 520, 420.
Elemental analysis (%) for C15H N : calcd C 67.39, H
17 5
6.41, N 26.20; found C 67.47, H 6.44, N 26.48.
the hydrazone began to crystallize. The product was allowed
to stand overnight in the refrigerator. The solid was
collected by suction filtration. The compound was obtained
in 56% yield after recrystallization as orange prisms
(
1
(
(
1-butanol), mp 205–207 8C (dec.); ms: m/z (%) 443 (MC
C
) , 287 (19) (MKCH C H SO ), 260 (20), 259 (100)
3.1.5.4. 3-Methyl-1-piperidinomethyl-1H-pyrazolo-
[3,4-b]quinoxaline (24). From piperidine in 87% yield as
yellow needles (heptane), mp 120–121 8C; ms: m/z (%) 282
3
6
4
2
C C
287–N ) , 258 (13), 156 (17) (MK287CH) , 139 (15)
2
C
156–OH) , 102 (12), 92 (17), 91 (31), 77 (36), 65 (18); IR:
C
C
3
1
1
7
4
6
442, 3190, 3046, 2923, 2860, 2794, 1936, 1597, 1567,
499, 1450, 1425, 1349, 1303, 1293, 1242, 1207, 1184,
165, 1092, 1078, 1041, 967, 920, 910, 885, 852, 818, 801,
84, 759, 706, 690, 673, 658, 595, 566, 546, 531, 498, 475,
21. Elemental analysis (%) for C H N O S: calcd C
(23) (MC1) , 281 (66) M , 198 (58), 197 (55) (MK
piperidino) , 185 (42), 155 (17), 143 (10), 129 (55), 128
C
C
(10), 102 (27), 98 (100) [CH N(CH ) ] , 96 (27), 84 (10)
2
2 5
C
piperidino , 55 (20); IR: 3040, 2936, 2852, 2810, 2762,
1618, 1580, 1558, 1514, 1498, 1480, 1452, 1404, 1386,
1348, 1328, 1310, 1285, 1248, 1170, 1136, 1118, 1062,
1022, 996, 978, 948, 902, 852, 842, 764, 728, 716, 648, 618,
604, 584, 552, 520, 482, 424. Elemental analysis (%) for
2
3 18 6 2
2.43, H 4.10, N 18.99; found C 62.25, H 4.01, N 19.18.
Because of its extremely low solubility in common solvents
no NMR spectra could be taken.

2384
M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
C H N : calcd C 68.30, H 6.81, N 24.89; found C 68.52, H
1
as yellow needles (ethanol), mp 113–115 8C; ms:m/z (%)
354 (1.9) (MC2) , 353 (4.2) (MC1) , 352 (3.8) M , 309
6 19 5
C
C
C
6
.93, N 25.12.
C
13), 199 (13), 198 (95) (MKCH NCHPyCl) , 197 (16),
(
3
3
7
C
3
.1.5.5. 3-Methyl-1-morpholinomethyl-1H-pyrazolo-
3,4-b]quinoxaline (25). From morpholine in 60% yield
as yellow needles (ethanol), mp 186.5–187.5 8C; ms: m/z
171 (90) (CH N(CH )CH Py Cl) , 169 (100) (CH -
3 2 2 3
N(CH )CH Py Cl) , 155 (13) (MK198) , 129 (25), 128
2 2
3
5
C
C
[
(65), 126 (95), 102 (24), 99 (11), 90 (20); IR: 3050, 2982,
2946, 2846, 2814, 1626, 1590, 1584, 1516, 1494, 1458,
1384, 1358, 1322, 1308, 1224, 1168, 1134, 1106, 1040,
1016, 974, 948, 916, 850, 816, 758, 720, 682, 640, 616, 602,
C
C
(
1
[
%) 284 (3.4) (MC1) , 283 (17) M ,199 (17), 198 (61),
C
97 (13) (MKmorpholino) , 129 (13), 101 (16), 100 (100)
CH N(C H ) O] , 86 (15) morpholino , 56 (34); IR:
2 2 4 2
C
C
3
1
1
1
6
062, 2968, 2938, 2914, 2853, 2826, 1918, 1806, 1700,
612, 1578, 1498, 1478, 1448, 1434, 1384, 1366, 1338,
310, 1264, 1240, 1208, 1170, 1150, 1138, 1116, 1100,
070, 1006, 976, 892, 862, 842, 798, 774, 754, 726, 650,
18, 608, 556, 528, 502, 424. Elemental analysis (%) for
5
calcd C 61.28, H 4.86, N 23.82; found C 61.42, H 5.08, N
58, 494, 452, 420. Elemental analysis (%) for C H ClN :
18 17 6
2
4.05.
3
.2. NMR measurements
C H N O: calcd C 63.59, H 6.05, N 24.72; found C 63.33,
1
5 17 5
H 6.16, N 24.17.
.1.5.6. Ethyl 1-(3-methyl-1H-pyrazolo[3,4-b]quinox-
alin-1-ylmethyl)piperidin-4-carboxylate (26). From ethyl
NMR spectra were recorded using Bruker Avance 500 or
Avance 300 spectrometers. For preparing the solutions 130–
3
1
0
60 mg (in case of good solubility) were dissolved in
.7 mL of chloroform-d. If the solubility was not good
piperidin-4-carboxylate in 91% yield as golden needles
(
C
heptane), mp 133–134 8C; ms: m/z (%) 354 (7) (MC1) ,
enough saturated solutions were used. Chemical shifts were
1
referenced to TMS (for H), to the solvent ( C), or to
13
C
C
3
(
53 (16) M , 308 (10) (MKC H O) , 198 (25), 197 (22)
2 5
1
5
C C
MK156) , 171 (31), 170 (100) (197–HCN) , 169 (10),
external CH NO (Z0 ppm for N). In some cases it was
3
2
C
57 (11), 156 (87) (MK197 or 170–CH or 197–CH CN) ,
15
not possible to get 1D N spectra, here the chemical shifts
1
1
9
1
1
9
2
3
1
15
42 (35) (170–CH N or 170–CH ]CH ), 129 (21), 99 (23),
2
were extracted from the 2D H, N-gs-HMBC spectra. All
1D and 2D COSY, HMQC, and HMBC experiments were
taken from the standard Bruker software. To measure
heteronuclear long-range J couplings pulse sequences
2
2
7 (12), 96 (20); IR: 2940, 2804, 2764, 1724, 1580, 1556,
510, 1496, 1480, 1444, 1402, 1370, 1348, 1326, 1308,
268, 1254, 1244, 1176, 1144, 1198, 1044, 1024, 998, 968,
52, 902, 864. 840, 766, 714, 648, 620, 602, 584, 552, 422.
8
,9
described in literature were used.
Elemental analysis (%) for C H N O : calcd C 64.57, H
1
9 23 5 2
1
Low-temperature H NMR measurements were done on
6
.56, N 19.82; found C 64.41, H 6.47, N 19.95.
solutions of ca. 20 mg in 0.7 mL of CD Cl . The free
2
2
#
energies of rotation (DG ) were calculated by the method of
Shanan-Atidi and Bar-Eli using the methyl signals of the
acetyl group.
3.1.5.7. 3-Methyl-1-(4-methylpiperazin-1-yl)methyl-
H-pyrazolo[3,4-b]quinoxaline (27). From 1-methyl-
1
7
1
piperazine in 62% yield as yellow needles (heptane), mp
1
1
(
C
43–144 8C; ms: m/z (%) 298 (6) (MC2) , 297 (20) (MC
C
) , 296 (13) M , 197 (18) (MKmethylpiperazine) , 129
C
C
C
3.3. Quantum chemical calculations
15), 114 (15), 113 (89) [CH N(C H ) NCH ] , 112 (36),
2 2 4 2 3
1
2
1
1
5
11 (100) (113–2H), 102 (16); IR: 3052, 2962, 2938, 2880,
828, 2794, 2764, 1580, 1514, 1500, 1450, 1406, 1386,
350, 1326, 1312, 1286, 1234, 1200, 1170, 1146, 1120,
072, 1052, 1010, 976, 902, 800, 768, 736, 724, 654, 618,
54, 526, 424. Elemental analysis (%) for C H N : calcd
1
8
The ab initio program package GAUSSIAN 98 was
used for all calculations which were carried out at
the Hartree-Fock and DFT-B3LYP level by means
1
9
2
0
of 6-31G* split-valence basis set.
The geometry
1
6 20 6
optimization of selected compounds was performed
without restrictions. The quantum-chemical calculations
were processed on SGI Octane and a Linux cluster at
Potsdam University.
C 64.84, H 6.80, N 28.36; found: C 64.71, H 6.53, N 28.18.
3.1.5.8. Ethyl 4-(3-methyl-1H-pyrazolo[3,4-b]quinox-
alin-1-ylmethyl)piperazin-1-carboxylate (28). From ethyl
piperazin-1-carboxylate in 81% yield as yellow needles
(
C
heptane), mp 165–166 8C; ms: m/z (%) 355 (3.9) (MC1) ,
The magnetic shieldings of all nuclei were calculated using
2
1
C
the GIAO method implemented in GAUSSIAN 98 at the
theory level mentioned above. The chemical shifts are
differences in magnetic shielding of atoms and references.
3
NCOOEt] , 172 (21), 171 (100) [CH N(C H ) N
54 (11) M , 199 (10), 198 (50), 197 (19) [MKN(C H ) -
2 4 2
C
2
2
4 2
C
COOEt] , 170 (11), 169 (32), 157 (39) (M-197), 143
28), 129 (40), 102 (24), 98 (14), 97 (29), 70 (28), 56 (41),
1
3
1
15
As references for C and H TMS, for N chemical shifts
nitromethane were employed.
(
5
1
1
1
5
6
5 (13); IR: 3060, 2978, 2952, 2832, 1682, 1580, 1516,
498, 1480, 1460, 1432, 1386, 1374, 1362, 1340, 1310,
282, 1244, 1211, 1176, 1156, 1118, 1100, 1080, 1028,
004, 962, 876, 842, 766, 732, 722, 654, 618, 602, 590, 554,
40, 422. Elemental analysis (%) for C H N O : calcd C
1
3
The NBO 5.0 was used to link the GAUSSIAN 98
program. The natural chemical shielding (NCS)-NBO
analysis partitions quantitatively the magnetic shielding of
a certain nucleus into magnetic contributions from core
orbitals (major), chemical bond and lone pair orbitals. The
shielding and deshielding contributions are divided into
Lewis and non-Lewis parts. Non-Lewis parts are connected
with electron density in antibonding orbitals.
1
8 22 6 2
1.00, H 6.26, N 23.71; found C 60.87, H 6.22, N 23.52.
3
.1.5.9. 1-[N-(2-Chlorpyrid-5-ylmethyl)-N-methyl-
amino]methyl-3-methyl-1H-pyrazolo-[3,4-b]-quinoxa-
line (29). From 2-chloro-5-(N-methylaminomethyl)pyridine

M. Heydenreich et al. / Tetrahedron 61 (2005) 2373–2385
2385
Supplementary data
M. L.; Elguero, J.; Fruchier, A. Magn. Reson. Chem. 1997, 35,
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3
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Theoretical Chemistry Institute, University of Wisconsin,
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J. Chem. Phys. 1997, 107, 1173–1184.
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