Nucleophilic vinylic substitution (SNV) of activated alkoxymethylene derivatives with 6-aminoquinoxaline

Article abstract of DOI:10.1002/ejoc.200500298

Treatment of 6-aminoquinoxaline with β,β-diactivated alkoxymethylene derivatives gave the corresponding N-(quinoxalin-6-yl)enamines. A variant of the S_NV reaction mechanism was proposed for substitution of the alkoxymethylene compounds, on the basis of the structures of the precursor enol ether and the vinylic substitution product and on computations. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500298

FULL PAPER
Nucleophilic Vinylic Substitution (S V) of Activated Alkoxymethylene
N
Derivatives with 6-Aminoquinoxaline
[
a]
[a]
[b]
[c]
[c][†]
Jozef Salo nˇ , Viktor Milata,* Anton Gatial, Nade zˇ da Prónayová, Ján Le sˇ ko,
ˇ
[a]
[d]
[e]
[e]
Petra Cernuchová, Zvi Rappoport, Giang Vo-Thanh, and André Loupy
Dedicated to Prof. D. Bellu sˇ on the occasion of his 65th birthday
Keywords: Nucleophilic vinylic substitution (S V) mechanism / Enol ethers / Alkoxymethylene compounds / Quinoxalines /
N
Molecular calculations
Treatment of 6-aminoquinoxaline with β,β-diactivated alk-
oxymethylene derivatives gave the corresponding N-(quin-
enol ether and the vinylic substitution product and on com-
putations.
N
oxalin-6-yl)enamines. A variant of the S V reaction mecha-
nism was proposed for substitution of the alkoxymethylene
compounds, on the basis of the structures of the precursor
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
despite the importance of this reaction, which is the first
step of the tandem Gould–Jacobs reaction often exploited
for preparation of compounds containing the condensed
pyridone nucleus of antibacterial compounds of the nali-
Quinoxalines and many of their condensed derivatives
have been prepared in studies designed to produce biolo-
gically active materials:[1] imidazoquinoxalines, for example,
have been found to be strong carcinogens in food.[ In con-
tinuation of our work on the synthesis of polyheterocyclic
fused systems containing the quinoxaline moiety we report
here the synthesis and spectral properties of new quinox-
aline derivatives, each substituted at C-6 with a substituted
vinylamino group, which serve as precursors for fused quin-
oxalines. The mechanism and stereochemistry of nucleo-
philic substitution of alkoxy groups in alkoxymethylene de-
rivatives of propanedioic acid, 3-oxobutanoic acid and cya-
noacetic esters with amines have not been reported so far,
[3]
dixic acid type.
2]
Even though these compounds have very often been ex-
[4]
ploited in the preparation of nalidixic acid analogues,
[5,6]
only a few reviews about them
(i.e., on diethyl ethoxy-
ethoxymethylenemalononitrile or
[3,7]
[8]
methylenemalonate,
[9]
aminomethylenemalonates ) have been published.
Results and Discussion
Addition of amines to activated carbon–carbon double
[
10]
[11]
bonds is a variant of the Michael addition. In the case
of primary amines in acidic media, the monoaddition prod-
[
a] Department of Organic Chemistry, Faculty of Chemical and
[
11]
[12]
uct affords, without catalysis, the bis(adduct). Several
reactions have been reviewed
reaction has been studied over the past few decades and
Food Technology, Slovak University of Technology,
[
13]
8
1237 Bratislava, Slovak Republic
and the mechanism of the
E-mail: viktor.milata@stuba.sk
[14]
salon@angelfire.com
[
15]
[
[
[
b] Department of Physical Chemistry, Faculty of Chemical and also very recently.
Treatment of a nucleophile with an
Food Technology, Slovak University of Technology,
activated α,β-unsaturated system containing a β-leaving
8
1237 Bratislava, Slovak Republic
group (nucleofuge) results in nucleophilic vinylic substitu-
E-mail: anton.gatial@stuba.sk
[
16]
c] Central Laboratory of Chemical Technique, Faculty of Chemi- tion (S V) of the nucleofuge,
and different reaction
N
cal and Food Technology, Slovak University of Technology,
[16,17]
mechanisms for the S V route have been reviewed.
N
8
1237 Bratislava, Slovak Republic
α-Alkoxymethylene compounds 1 substituted with two
E-mail: nadezda.pronayova@stuba.sk
d] Department of Organic Chemistry and the Minerva Center for electron-withdrawing groups at C are typical push-pull sys-
β
Computational Quantum Chemistry, The Hebrew University,
tems. In such enol ethers or trifunctional electrocyclo-
Jerusalem 91904, Israel
[
7]
E-mail: ZR@vms.huji.ac.il
philes the nucleophilic replacement of the alkoxy group is
[
e] Laboratory of Selective Reactions on Supports, Institute of
Molecular Chemistry, University Paris-South,
Orsay Cedex, 91405 France
[18]
the predominant reaction,
as demonstrated in Scheme 1
for the reaction with 6-aminoquinoxaline (2), which gives
the enamines 3.
[
†] Deceased
4870
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500298
Eur. J. Org. Chem. 2005, 4870–4878

N
S V of Activated Alkoxymethylene Derivatives with 6-Aminoquinoxaline
FULL PAPER
Scheme 1. Substituents for 1 and 3 (stereochemistry is discussed below).
The known configurations of the precursor alkoxymethy- (3JH–CN = 10.0 Hz) could be attributable to either isomer,
lene derivatives 1 and the products 3 suggest an S V reac- as it is in the borderline region for values of either cis or
N
tion mechanism. These conclusions can be extended for re- trans coupling constants. However, the spectrum of the
actions of (E)/(Z) mixtures of compounds 1 in which one crude reaction mixture also shows ca. 10% of the other iso-
isomer predominates.[
19]
mer, with a lower J value ( J
3
= 5.2 Hz), thus establish-
H–CN
To provide evidence for S V mechanisms for the dis- ing an (E) configuration for the major isomer (Tables 1 and
N
placement by amines of the alkoxy group in 1 and those in 2). The same conclusion also applies in the case of enol
related alkoxy ethers activated by two electron-withdrawing ether 1g, whilst a similar situation exists for the cyanoacetic
groups (EWGs) it is first necessary to establish the configu- acid derivatives, in which the (E)/(Z) ratios for 1h and 1i
ration of the enol ether. If the β-EWGs are identical, as in are also close to 10:1 (Scheme 2), according to the similar
derivatives of propanedioic or Meldrum’s acids and pen- coupling constants. This is consistent with the much smaller
tane-2,4-dione, only one product is formed; thus, such de- bulk of the linear cyano group in relation to the ester or
rivatives give no stereochemical information. With 3-oxobu- the acetyl groups, which makes the (E) isomers (with the
tanoic and cyanoacetic acid derivatives, however, the rela- alkoxy group and the bulkier alkoxycarbonyl group trans)
tionship between the configurations of the enol ether pre- thermodynamically more stable, and thus predominant in
cursors and the enamine products can serve as a mechan- both 1g and 1k. In contrast, due to the much closer sizes of
istic probe. Enol ethers 1e–1i are available at present as (E)/ the acetyl and alkoxycarbonyl groups, the alkoxymethylene
(Z) mixtures and have not yet been separated into their (E) derivatives of 3-oxobutanoic esters 1e and 1f exist as ca. 1:1
and (Z) isomers. In the previously described syntheses of
methoxy- or ethoxymethylene-3-oxobutanenitrile only the
E) isomers were obtained.[
20]
(
This is shown by the NMR spectrum of the enol ether
1k. In the isolated product the low value of the observed
vicinal coupling constant of the olefinic proton with the
1
3
cyano carbon atom in the C NMR spectrum of 1k Scheme 2. (E)/(Z) ratios for 1e–1i and 1k.
Table 1. 13C NMR spectroscopic data (δ in ppm) for 1k and 1g.
Compound
CH
3
CH
2
CH
3
CO–
ϾC=
–CH=
CN
CO
3JH–CN [Hz]
1
k
g
(E)-
Z)-
(E)-
Z)-
64.32
62.87
74.19
66.40
–
–
27.80
25.32
28.28
24.76
94.90
91.96
94.61
92.65
173.26
169.45
172.06
167.69
114.05
115.63
114.53
115.50
191.32
185.21
191.78
184.99
10.0
5.2
10.8
5.6
(
1
15.27
18.42
(
1
Table 2. H NMR spectroscopic data (δ in ppm) for the isomers of 1k and 1g.
Compound
1k
1g
% (E) isomer[a]
% (E) isomer[a]
(E)-
(Z)-
(E)-
(Z)-
1k
1g
CH
CH
CH
3
2
3
4.18
–
2.37
7.99
3.85
–
2.41
8.68
1.46
4.38
2.38
8.03
1.24
3.71
2.43
8.73
93
–
83
89
95
98
86
89
CO–
–CH=
[a] Estimated from corresponding signal.
Eur. J. Org. Chem. 2005, 4870–4878
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Milata et al.
FULL PAPER
(
E)/(Z) mixtures (based on the 3JH,C coupling constants has a major effect on the formation of the thermodynami-
and integration of the relevant signals). cally more stable product (e.g., the intramolecular hydrogen
Michael addition reactions are routinely used in many bond with the carbonyl group of the acetyl group is
[
25]
syntheses involving alkoxymethylenepropanedioic acid de- stronger than that to the ester group).
rivatives,
Both effects are
and the mechanism of substitution of an alk- important in the case of 3g, as is corroborated by the fact
oxy group attached to a double bond has been investigated that the (Z) isomer content prevails in the cyanoacetic es-
[
7,8]
[21]
in detail by Bernasconi et al.
and by Rappoport et al. ters 3h/3i, whereas the (E)/(Z) ratio in 3g is close to equi-
for amino nucleophiles.[ Only in recent years have works molar. The change of the solvent from CDCl to DMSO
22]
3
studying nucleophilic vinylic substitution with inversion of does not have any significant influence on the isomer ra-
configuration appeared.[
23]
tios.
[25c]
We prepared the products of reactions between 6-amino-
quinoxaline (2) and ten different enol ethers 1. The reac-
tions were carried out by mixing the components in ethanol
at room temperature and monitoring the disappearance of
Computations
Stabilities of the Isomers/Conformers of 1k and Its Product
with Methylamine
2
by TLC [R (amine) Ϸ 0 in CHCl /MeOH, 10:1]. The reac-
f
3
tion times were between 2 and 30 h. The reaction mixtures
were then concentrated to dryness at a temperature Ͻ40 °C,
For computational modelling of the reaction pathway be-
and the crude reaction mixtures were analysed by NMR in tween the studied β,β-diactivated alkoxymethylene com-
CDCl for 3e, 3f and 3i, or in DMSO (due to their low pounds and 6-aminoquinoxaline we chose the reaction be-
3
solubilities) for 3c and 3f–3i. The (E)/(Z) ratios are given in tween 1k and methylamine, as the simplest alkylamine rep-
Table 3 (in the row “before heating”). All products were resenting 6-aminoquinoxaline. The reactant 1k [Me–O–
then recrystallized from appropriate solvents and dried, and CH=C(CN)COCH ] and the Me–NH–CH=C(CN)COCH
3
3
the (E)/(Z) ratios of 3e–3i after crystallization were again product (4) can exist in several geometric and conforma-
determined and are given in Table 3 (row “after heating”). tional forms [the structures for the (Z) isomers are given in
Assignment of the structures of the isomers was based on Scheme 3].
3
the J
coupling constants, and the isomer ratios were
H,C
determined from the integrated intensities of corresponding
signals of both isomers, mainly in the aliphatic region. The
NMR spectroscopic data are given in the Exp. Sect.
Table 3. (E)/(Z) ratios of the products 3e–3i formed by the reactions
between 1e–1i and 6-aminoquinoxaline (2).
Scheme 3. Conformers of the (Z) isomers of 1k and 4.
3e
3f
3g
3h
3i
Before heating
After heating
53:47
85:15
49:51
87:13
7:93
45:55
12:88
67:33
9:91
81:19
Since all four substituents at the double bond differ, both
compounds can exist as two isomers, with the methoxy or
methylamino group trans or cis to the acetyl group. This
By comparison of the pairs of results it could be con- relationship is represented in the designator by the first let-
cluded that the reaction proceeds under kinetic conditions ter (E or Z). Each isomer has conformers obtained by rota-
with inversion of configuration, in contrast to almost all tion of the acetyl group, in which the carbonyl oxygen atom
[22]
known observed and deduced nucleophilic vinylic substi- may be oriented away from or towards the C=C double
[
17]
tutions,
but in agreement with the results obtained for bond (anti or syn position represented by the second letter
the reaction between methoxymethylene-substituted Meld- E or Z). Rotation of the methoxy or methylamino group
rum’s acid (in relation to thermodynamic vs. kinetic prod- can similarly orient their methyl group with reference to the
uct) and o-aminothiophenol[ and the computational re- C=C double bond (the anti or syn position is represented
24]
sults below.
by the third letter E or Z). Quantum chemical calculations
After heating of the reaction mixtures at reflux and/or of the energies of all four possible conformers of both iso-
recrystallization (heating at reflux in an appropriate mers of 1k, as well as for both isomers of the product based
crystallization solvent while dissolving), thermal isomeriza- on the AM1, PM3 and ab initio method using 6-31G and
tion takes place and the isomer ratios indicate higher per- 6-31G** basis sets, are given in Table 4.
centages of the (E) isomers (cf. Table 3), due to relatively
From Table 4 it is clear that the (EZE) conformer is the
low isomerization barriers between the isomers (83.3– most stable conformer for MeO–CH=C(CN)COMe ac-
–
1 [25]
1
00.9 kJmol )
and the formation of the sterically fav- cording to ab initio (AI) and PM3 calculations, but accord-
oured isomers with the bulkier substituents and the alk- ing to AM1 calculations it is the (EZZ) form. It is known
ylamino groups in 3h/3i in trans relationships. If the effec- that the AM1 method overestimates hydrogen–electronega-
tive bulks of the two groups are comparable (e.g., for 3e tive atom interactions when the hydrogen atom is bonded
and 3f), the formation of an intramolecular hydrogen bond to a carbon atom, and this is perhaps the reason why the
4872
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4870–4878

N
S V of Activated Alkoxymethylene Derivatives with 6-Aminoquinoxaline
FULL PAPER
–1
Table 4. Calculated relative energies [kJmol ] for the conformers of Me–O–CH=C(CN)(COMe) and Me–NH–CH=C(CN)(COMe).
Conformer Me–O–CH=C(CN)(COMe) Me–NH–CH=C(CN)(COMe)
MP2+HF+ZPE
HF
6-31G
AM1
PM3
MP2+HF+ZPE
6-31G**
HF
6-31G
AM1
PM3
6-31G**
(EZE)
(EZZ)
(EEE)
(EEZ)
(ZZE)
(ZZZ)
(ZEE)
(ZEZ)
0.0
1.8
0.0
2.9
5.3
0.0
0.0
1.7
13.0
12.1
7.9
12.5
-
15.5
22.8
30.1
40.3
0.0
44.1
53.0
–
11.2
22.0
36.9
50.2
0.0
49.7
61.7
–
5.9
14.6
24.0
33.9
0.0
28.5
34.6
–
1.2
16.4
9.2
23.2
0.0
23.3
16.9
–
14.9
14.7
16.7
23.0
15.2
–
24.8
21.9
30.5
24.4
22.6
–
22.7
15.0
18.5
14.3
20.9
–
–
is shown in Figure 1, together with the calculated structures
of the reactants, intermediates, transition states and prod-
ucts. Similar plots based on the semiempirical AM1 and
PM3 methods are given in Figure 2. The atom numbering
values differ from those obtained by the ab initio method.
However, the tendency to prefer the (E) isomer with the (Z)
conformation of the acetyl group over other isomers and
conformations is evident, supporting the conclusions drawn
from the NMR measurements. For the unsymmetric enol
ethers, the presence of the conformers was evident (in the
for all structures is given in Figure 3.
The reaction proceeds through two reaction intermedi-
1
3
ates and two transition states. Initially, in a slightly exother-
C NMR spectrum of 1e, for example, four signals with
mic process, the reactants 1k and MeNH create a reaction
2
one dominating were detected for the methyl part of the
acetyl group, together with four signals for the methyl and
the carbonyl carbon atoms of the methoxycarbonyl group).
For the product Me–NH–CH=C(CN)COMe, the (ZZE)
conformer is the most stable conformer according to all
three methods. This reflects the effect of the intramolecular
hydrogen bond between the amino hydrogen atom and the
carbonyl oxygen atom. These results are confirmed by
ab initio calculations at the MP2 level with full optimization
of geometry and inclusion of zero point energy (ZPE) for
all reactant and product conformers in the larger 6-31G**
basis set.
complex INT1 with a distance of approximately 3.4–4.0 Å
between the H N nitrogen atom and C , in which the amino
2
1
hydrogen atoms H17 are H23 are oriented toward the car-
bonyl oxygen atom O . The nitrogen atom of methylamine
4
is thus approaching with its lone electron pair oriented to-
ward the olefinic hydrogen atom H and therefore not from
9
the π-direction or from the in-plane backside of the σ-or-
bital of the C–OR bond. This orientation is supported by
the negative charge on the carbonyl oxygen atom O and
4
the positive charge on the olefinic carbon atom C and the
1
olefinic hydrogen atom H . The reactants then pass through
9
the first transition state TS1, 70 kJmol–1 above INT1, to
the second intermediate complex INT2. During this step
the distance between the amino nitrogen atom and C is
shortened to 1.9–2.0 Å in TS1 and 1.5–1.6 Å in INT2.
1
The Reaction Pathway
We performed calculations on the reaction pathways Simultaneously, the bond between the methoxy oxygen
from the (EZE) conformer of 1k by the ab initio and PM3 atom O18 and C is elongated to 1.4 Å. Because of the
1
methods and from the (EZZ) conformer of 1k by the AM1 changes in the bonding character of the C carbon atom
1
method. The calculated energies, relative energies and se- the C=C bond length increases. Simultaneously, one of the
veral isomeric parameters for reactants, intermediates amino hydrogen atoms (H ) is oriented towards the car-
17
(
INT), transitions states (TS) and products are given in bonyl oxygen atom O , forming an intramolecular hydrogen
4
Tables 5 and 6. The computed ab initio reaction path profile bond, whereas the second hydrogen atom H23 is orientated
Table 5. Calculated energies and relative energies (right-hand column) for the reactants, intermediates, transition states and products of
the reaction Me–O–CH=C(CN)(COMe) + MeNH
2
Ǟ Me–NH–CH=C(CN)(COMe) + MeOH.
HF/6-31G
a.u.
AM1
kJmol
PM3
kJmol
kJmol–1
–1
kJmol–1
–1
kJmol–1
Reactants:
(EZE)
EZZ)
–435.226701
–133.518
(
–153.425
–30.903
–184.328
–198.442
–125.053
–137.155
18.930
–13.222
–238.764
–251.986
MeNH
both
2
–95.170903
–530.397604
–530.409947
–530.380657
–530.395612
–530.340055
–415.439177
–114.988166
–530.427343
–21.710
–155.231
–168.279
–105.171
–121.588
25.992
7.573
–217.200
–209.627
0.0
–32.4
44.5
5.2
0.0
–14.1
59.2
47.1
203.1
0.0
–13.0
50.0
33.6
181.1
INT1
TS1
INT2
TS2
151.1
Products:
(ZZE)
CH OH
both
3
–78.1
–67.6
–54.4
Eur. J. Org. Chem. 2005, 4870–4878
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Milata et al.
FULL PAPER
Table 6. Calculated structural parameters for the reactants, intermediates, transitions states and products of the reaction Me–O–
CH=C(CN)(COMe) + MeNH Ǟ Me–NH–CH=C(CN)(COMe) + MeOH.
2
r
C–N
r
C–O
r
C=C
r
N–H17
r
N–H23
r
O–H17
r
O–H23
r
=O–H17
r
=O–H23
AI
AM1
PM3
1.331
1.349
1.358
1.341
1.361
1.359
0.994
1.000
0.999
0.994
1.000
0.999
Reactants
INT1
AI
AM1
PM3
3.386
3.771
3.955
1.327
1.348
1.357
1.347
1.363
1.359
1.000
1.002
1.000
0.998
1.002
0.998
4.221
4.542
4.333
4.639
4.589
5.596
2.259
2.448
3.161
3.766
2.474
4.713
AI
AM1
PM3
1.904
1.871
1.996
1.351
1.372
1.354
1.432
1.413
1.396
1.008
1.012
1.018
1.001
1.005
0.999
3.283
3.334
3.370
2.896
2.824
2.972
2.060
2.296
1.908
3.388
3.619
3.305
TS1
AI
AM1
PM3
1.518
1.588
1.568
1.403
1.400
1.416
1.498
1.459
1.475
1.039
1.033
1.042
1.006
1.018
1.004
3.143
3.253
3.192
2.458
2.710
2.483
1.698
2.054
1.749
3.117
3.359
3.132
INT2
AI
AM1
PM3
1.451
1.477
1.499
1.899
1.527
1.530
1.391
1.449
1.448
1.014
1.015
1.027
1.187
1.393
1.414
2.841
2.771
2.763
1.293
1.280
1.275
1.827
2.086
1.766
3.139
3.147
3.224
TS2
AI
AM1
PM3
1.322
1.349
1.378
1.378
1.384
1.375
1.000
1.002
1.014
0.950
0.964
0.949
1.941
2.122
1.854
Products
δ
O=C–C=C
δ
O–C=C–C
δ
N–C=C–C
δ
H–C=C–C
δ
C–O–C=C
δ
C–N–C=C
AI
AM1
PM3
0.0
0.0
0.0
180.0
180.0
180.0
0.0
0.0
0.0
180.0
0.0
180.0
Reactants
INT1
AI
AM1
PM3
–0.3
–0.2
10.8
179.6
180.0
–178.9
–0.1
0.0
0.7
177.1
0.0
–179.1
–105.6
AI
AM1
PM3
10.3
14.6
32.6
174.4
169.0
176.2
–66.1
–74.4
32.1
26.7
29.9
35.6
26.8
26.8
175.8
174.2
TS1
AI
AM1
PM3
7.4
15.3
17.6
–171.2
169.8
–167.6
–54.8
–66.5
–54.4
59.7
45.5
62.4
–83.2
40.4
–87.7
171.4
176.9
168.5
INT2
AI
AM1
PM3
–4.1
2.6
–1.6
–83.7
–75.6
–86.8
12.0
28.2
14.0
166.6
165.8
152.8
–20.5
5.4
–9.5
130.6
125.3
126.3
TS2
AI
AM1
PM3
0.0
0.1
2.5
0.0
–0.4
–7.8
180.0
179.8
175.7
180.0
179.0
162.6
Products
towards the methoxy oxygen atom. Because of bonding of amino nitrogen atom N12 at C are already turned close
1
the methylamino group at carbon atom C there is a ten- toward the (E) (anti) and (Z) (syn) positions, respectively.
1
dency towards deviation of the olefinic hydrogen atom H9 This causes inversion of configuration at the olefinic carbon
from the (Z) (syn) position and also towards rotation of the atom C . Figure 4 presents the ab initio energy profiles
1
methoxy group towards the (Z) (syn) position. In the last along the intrinsic reaction coordinates (IRCs) for the last
part of the reaction pathway, methanol is split off via the part of the reaction pathway from intermediate INT2 to the
four-centred transition state (C –O –H –N ) TS2, in products via transition state TS2. The IRCs were traced
1
18
23
12
which H23 is shifted from the amino nitrogen atom to the from TS2 (s = 0), which has an imaginary vibrational mode
–
1
methoxy oxygen atom O , and which is ca. 145– of 1521i cm , towards both intermediate INT2 (s Ͻ 0) and
1
1
8
–
1
50 kJmol above INT2. The geometric parameters of TS2 products (s Ͼ 0) directions. The energy and geometric pa-
calculated by the three methods are quite similar, except rameters are approaching those for the intermediate INT2
that the ab initio method gave longer and shorter C –O and and products for s Ͻ 0 and s Ͼ 0, respectively, as can be
1
N–H23 bond lengths, respectively, than the semiempirical seen from Figure 5 for the C –O and C –N bond
1
18
1
12
methods. In TS2 the olefinic hydrogen atom H and the lengths.
9
4874
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4870–4878

N
S V of Activated Alkoxymethylene Derivatives with 6-Aminoquinoxaline
FULL PAPER
Figure 4. Plot of the potential energy (a.u.) along the minimum-
energy pathway between the intermediate complex and the prod-
ucts.
Figure 1. Potential energy profile (a.u.) for the MeOCH=C(CN)
COMe + MeNH reaction obtained by use of ab initio 6-31G ener-
gies at the HF level.
2
–1
Figure 2. Potential energy profile [kJmol ] for the Me-
OCH=C(CN)COMe + MeNH reaction obtained by use of semi-
empirical AM1 and PM3 energies.
Figure 5. Distances [Å] between the amino nitrogen atom and the
2
methoxy oxygen atom and the doubly bonded carbon atom C
1
along the minimum-energy pathway between the intermediate com-
plex and the products.
Conclusions
Two effects – the bulk of the EWG and hydrogen bond-
ing – influence the configurations of the S V products.
N
(i) The stereochemistry in the proposed nucleophilic vi-
nylic substitution mechanism based on the quantum chemi-
cal calculations is in good agreement with the observed re-
sults under kinetic control: inversion of configuration on
the olefinic carbon atom takes place during nucleophilic vi-
nylic substitution in this type of compounds.
Figure 3. Schematic drawing and numbering of the atoms.
(
ii) A cyano group is much smaller than an acetyl or
alkoxycarbonyl group and the isomers with the cis-substi-
From Figure 5 we see that, from the almost identical val- tuted amino and cyano groups are sterically preferred.
ues of the C –O and C –N bond lengths in ITN2, the (iii) When the bulks of two groups are nearly equal (e.g.,
C –N bond length decreases towards the value in the acetyl and alkoxycarbonyl) the preferred configuration is
1
18
1
12
1
12
product whereas the C –O18 bond length increases due to that involving the stronger intramolecular hydrogen
1
[
25]
the expulsion of methanol.
bond.
Eur. J. Org. Chem. 2005, 4870–4878
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4875

V. Milata et al.
FULL PAPER
Aminomethylene-quinoxaline Derivatives 3: The 6-aminoquinox-
aline filtrate, prepared as described above, was treated with solu-
tions of 1a–1j (10 mmol) in ethanol (20 mL). The reaction mixtures
were stirred at room temperature until the amine had disappeared
Experimental Section
General Methods: H, 13C and 15N NMR spectra of 6-aminoquin-
1
oxalines were recorded with a Bruker DPX 400 spectrometer at
400, 100.61 and 40.56 MHz, respectively. Other spectra were re-
(TLC monitoring, eluent CHCl /MeOH, 10:1). The resulting mix-
3
corded with a Varian VXR-300 at 300 and 75.45 MHz, respectively.
ture was then analysed by NMR (CDCl ) for the ratio of isomers
(for 3e–3i). After concentration of the reaction mixtures to dryness,
the residue was recrystallized from the appropriate solvent.
3
1
5
Chemical shifts (ppm) are relative to TMS or nitromethane ( N)
in [D ]DMSO; coupling constants are in Hz. Data measured in
CDCl (due to the better solubility) are given. The EI MS were
measured with an MS 902S (AEI Kratos) instrument at 70 eV and
00 μA current trap. IR (0.5 mg of substance per 300 mg of KBr)
and UV spectra (in MeOH) were recorded with FTIR PU 9802
Philips) and Specord (Zeiss, Jena) spectrophotometers. Elemental
6
3
Dimethyl 2-(Quinoxalin-6-ylaminomethylene)propanedioate (3a):
1
M.p. 177–178 °C (EtOH). Yield 0.90 g (52%). H NMR (300 MHz,
1
CDCl
3
): δ = 3.83, 3.90 (2×s, 2×3 H), 7.58 (dd, J = 9.1, J7,5
.5 Hz, 1 H), 7.81 (d, J = 2.5 Hz, 1 H), 8.12 (d, J = 9.1 Hz, 1 H),
.68 (d, J = 13.3 Hz, 1 H), 8.78, 8.83 (2×d, J = 1.8 Hz, 2×1 H),
=
2
8
1
=
1
(
analyses were performed with an EA-1108 (Carlo Erba) apparatus.
Melting points (uncorrected) were measured with a Kofler micro
hot-stage.
1
3
1.27 (d, J = 13.3 Hz, 1 H) ppm. C NMR (75 MHz, CDCl
51.7, 51.9, 95.3, 113.4, 121.7, 131.5, 140.2, 140.6, 143.8, 144.1,
46.0, 151.1, 165.4, 169.1 ppm. IR (KBr): ν˜ max = 1692, 1607,
3
): δ
–
1
1229 cm . UV/Vis (MeOH): λmax (log ε) = 225 (3.46), 259 (3.40),
Computational Methods and Details: Quantum mechanical calcula-
+
·
tions were carried out with the Gaussian 94[
26]
[27]
305 (3.26), 333 (2.98), 374 (2.99) nm. EI MS: m/z (%) = 287 [M]
and MOPAC6
(
(
100), 255 (75), 227 (38), 196 (100), 169 (25), 129 (38). C14
287.28): calcd. C 58.53, H 4.56, N 14.63; found C 58.59, H 4.42,
13 3 4
H N O
program packages. Traditional Hartree–Fock (HF) ab initio meth-
ods with the simple 6-31G basis set and semiempirical AM1 and
PM3 methods for calculation of the reaction pathway were used.
The geometries of all reactants, intermediates, transitions states
and products were optimized at the levels of theory mentioned
above without imposition of any symmetry constraints. Vibrational
analysis was systematically carried out in order to ensure that all
optimized geometries corresponded to a local minimum with no
imaginary frequency mode or a transition state with only one imag-
inary frequency mode. For all transition states the intrinsic reaction
coordinate (IRC) analysis in mass-weighted Cartesian coordinates
with gradient step size of 0.08 bohramu½ were carried out in order
to confirm that the transition structure connected the desired reac-
tants and products. The reaction coordinate s is defined as the dis-
tance from the transition state, with s Ͼ 0 referring to the product
side. In order to confirm the conformational stability of the reac-
tant and product, ab initio calculations of the energy at the MP2
level with full geometry optimization and including zero point en-
ergy (ZPE) by use of the 6-31G** basis set were also conducted.
N 14.51.
Diethyl 2-(Quinoxalin-6-ylaminomethylene)propanedioate (3b): M.p.
1
1
12–115 °C (EtOH). Yield 1.04 g (55%). H NMR (300 MHz,
CDCl
3
): δ = 1.37, 1.41 (2×t, 2×3 H), 4.30, 4.36 (2×q, 2×2 H),
.58 (dd, J = 9.0, J7,5 = 2.4 Hz, 1 H), 7.80 (d, J7,5 = 2.4 Hz, 1 H),
.12 (d, J = 9.0 Hz, 1 H), 8.68 (d, J = 13.3 Hz, 1 H), 8.78, 8.83
7
8
(
13
2×d, J = 1.8 Hz, 2×1 H), 11.27 (d, J = 13.3 Hz, 1 H) ppm.
C
NMR (75 MHz, CDCl
3
): δ = 14.3, 14.5, 60.4, 60.8, 96.1, 113.1,
1
1
21.8, 131.5, 140.4, 140.6, 143.9, 143.9, 146.0, 150.7, 165.1,
68.8 ppm. IR (KBr): ν˜ max = 1694, 1645, 1615, 1260, 1240 cm .
–1
UV/Vis (MeOH): λmax (log ε) = 226 (3.16), 248 (2.90), 298 (3.32),
+·
3
(
(
16 (3.30), 362 (3.21) nm. EI MS: m/z (%) = 315 [M] (100), 269
85), 242 (20), 213 (65), 196 (80), 169 (50), 145 (25), 129 (38), 102
25). C16 (315.33): calcd. C 60.94, H 5,43, N 13.33; found
17 3 4
H N O
C 60.99, H 5.45, N 13.22.
2
-(Quinoxalin-6-ylaminomethylene)propanedinitrile (3c): M.p. 270–
1
6
272 °C (xylene). Yield 0.53 g (40%). H NMR (300 MHz, [D ]-
Solvents and Materials: The alkoxymethylene derivatives 1a, 1b and
DMSO): δ = 7.97 (dd, J = 9.2, J7,5 = 2.4 Hz, 1 H), 8.07 (d, J =
1
c are commercially available. 3-Ethoxymethylene-2,4-pentane- 9.2 Hz, 1 H), 8.09 (d, J5,7 = 2.4 Hz, 1 H), 8.78 (s, 1 H), 8.85, 8.90
1
3
dione (1d), methyl (1e) and ethyl (1f) 2-alkoxymethylene-3-oxobut-
anoic acids, and 3-alkoxy-2-cyanopropenoic acids 1h and 1i were
synthesized by condensation of methyl or ethyl orthoformate with
the corresponding methylene compound (pentane-2,4-dione,
(2×d, J = 1.9 Hz, 2×1 H), 11.46 (s, 1 H) ppm. C NMR (75 MHz,
[D ]DMSO): δ = 54.2, 113.9, 116.2, 115.0, 122.2, 130.5, 140.0,
140.4, 142.9, 144.9, 146.6, 156.1 ppm. IR (KBr): ν˜ max = 3209, 2226,
6
–
1
1649, 1514, 1329 cm . UV/Vis (MeOH, saturated solution): λmax
+
·
methyl or ethyl 3-oxobutanoate and methyl or ethyl cyanoace- = 226, 247, 297, 315, 355 nm. EI MS: m/z (%) = 221 [M] (100),
[
28]
tate).
used.
Improved methods for the preparation of 1g and 1j were
194 (56), 156 (27), 129 (38), 102 (27). C12
7 5
H N (221.22): calcd. C
[
29]
65.15, H 3.19, N 31.66; found C 65.24, H 3.07, N 31.52.
-Aminoquinoxaline (2): 6-Nitroquinoxaline[30] (440 mg, 2.5 mmol)
was dissolved in ethanol (50 mL), treated with Pd/C catalyst (3%,
0 mg) and hydrogenated with magnetic stirring and an overpres-
sure of H (20 kPa) until hydrogen consumption stopped (about
10 mL). The catalyst was filtered off, the filtrate was concentrated
3-(Quinoxalin-6-ylaminomethylene)pentane-2,4-dione (3d): M.p.
59–161 °C (EtOH). Yield 0.89 g (58%). H NMR (300 MHz,
CDCl ): δ = 2.46, 2.60 (2×s, 2×3 H), 7.61 (dd, J = 9.0, J7,5
.6 Hz, 1 H), 7.86 (d, J5,7 = 2.6 Hz, 1 H), 8.16 (d, J = 9.0 Hz, 1
H), 8.41 (d, J = 12.3 Hz, 1 H), 8.82, 8.86 (2×d, J = 1.8 Hz, 2×1
6
1
1
3
=
5
2
2
1
1
3
H) ppm. C NMR (75 MHz, CDCl
3
): δ = 27.4, 32.2, 113.9, 114.7,
to dryness, and the product was recrystallized from toluene. Yield
77 mg (76%). M.p. 164–165 °C (ref.[
28]
1
122.3, 131.7, 140.3, 141.0, 143.7, 144.4, 146.1, 150.6, 195.0,
2
m.p. 159–160 °C). H
–
1
3
201.8 ppm. IR (KBr): ν˜ max = 1632, 1611, 1582, 1312 cm . UV/Vis
(MeOH): λmax (log ε) = 253 (3.28), 300 (3.12), 329 (3.21), 367 (3.39)
nm. EI MS: m/z (%) = 255 [M]+ (91), 240 (41), 222 (32), 198 (100),
NMR (400 MHz, CDCl
3
): δ = 8.61 (d, J = 1.7 Hz, 1 H), 8.45 (d,
3
3
3
4
J = 1.7 Hz, 1 H), 7.74 (d, J = 9 Hz, 1 H), 7.25 (dd, J = 9, J =
·
4
13
2
.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 6.06 (br.s, 2 H) ppm.
C
2
170 (41), 144 (35), 129 (24), 112 (53). C14
13 3 2
H N O (255.28): calcd.
NMR (100 MHz, CDCl
3
): δ = 150.61 (d, J = 9.9 Hz), 145.07 (dd,
1
2
2
3
C 65.87, H 5.13, N 16.46; found C 65.78, H 5.04, N 16.32.
J = 180.8, J = 11.3 Hz), 144.96 (dd, J = 10.9, J = 5.3 Hz),
1
2
2
3
1
5
6
39.78 (dd, J = 182.7, J = 11.0 Hz), 136.60 (td, J = 10.0, J = Methyl (E)-3-Oxo-2-(quinoxalin-6-ylaminomethylene)butanoate
1
1
2
1
.3 Hz), 129.73 (d, J = 162.1 Hz), 122.48 (dd, J = 159.65, J = (3e): M.p. 150–151 °C (EtOH). Yield 1.01 g (62%). H NMR
.6 Hz), 105.08 (dd, 1J = 159.5, 3J = 4.8 Hz) ppm. N NMR
15
3
(300 MHz, CDCl ): δ = 2.60 (s, 3 H), 3.85 (s, 3 H), 7.62 (dd, J =
(40 MHz, CDCl
3
): δ = –49.9 (N-1), –58.1 (N-4), –309.1 (NH ) ppm. 9.3, J7,5 = 2.4 Hz, 1 H), 7.87 (d, J5,7 = 2.4 Hz, 1 H), 8.13 (d, J =
2
4876
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4870–4878

N
S V of Activated Alkoxymethylene Derivatives with 6-Aminoquinoxaline
FULL PAPER
9
(
.3 Hz, 1 H), 8.67 (d, J = 12.3 Hz, 1 H), 8.82 (2×s, 2×1 H), 12.96
(75 MHz, CDCl
3
+ [D
6
]DMSO): (E) isomer: δ = 14.3, 60.7, 76.8,
d, J = 12.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 31.2,
114.7, 115.6, 122.2, 130.5, 140.0, 140.9, 142.9, 144.6, 146.4, 152.3,
164.3 ppm; JH,C=C–CN = 9.9 Hz; (Z) isomer: δ = 14.1, 60.7, 76.1,
114.5, 117.5, 122.0, 130.6, 139.8, 140.2, 143.2, 144.3, 146.0, 153.1,
3
5
1
1
3
1.4, 104.0, 114.2, 121.9, 131.5, 140.2, 140.9, 143.7, 144.1, 146.0,
51.0, 166.8, 200.7 ppm. IR (KBr): ν˜ max = 2942, 1698, 1638,
312 cm . UV/Vis (MeOH): λmax (log ε) = 244 (3.27), 301 (3.14), 166.2 ppm; JH,C=C–CN = 5.2 Hz. IR (KBr): ν˜ max = 3217, 2215, 1674,
30 (3.26), 367 (3.42) nm. EI MS: m/z (%) = 271 [M] (100), 256
–1
+
·
–1
1636, 1248 cm . UV/Vis (MeOH, saturated solution): λmax = 245,
298, 316, 359 nm. EI MS: m/z (%) = 268 [M]+ (80), 222 (60), 195
·
(
C
6
17), 239 (24), 224 (26), 211 (87), 196 (57), 169 (26), 129 (22).
(271.28): calcd. C 61.99, H 4.83, N 15.49; found C
2.21, H 4.61, N 15.47.
14
H
13
N
3
O
3
(100), 156 (40), 129 (35), 91 (35). C14
62.68, H 4.51, N 20.88; found C 62.92, H 4.34, N 20.65.
,2-Dimethyl-5-(quinoxalin-6-ylaminomethylene)[1,3]dioxane-4,6-di-
12 4 2
H N O (268.28): calcd. C
2
Ethyl (E)-3-Oxo-2-(quinoxalin-6-ylaminomethylene)butanoate (3f):
M.p. 116–117 °C (EtOH). Yield 1.11 g (65%). H NMR (300 MHz,
CDCl
1
8
1
1
one (3j): M.p. 204–205 °C (xylene). Yield 1.44 g (80%). H NMR
300 MHz, CDCl ): δ = 1.79 (s, 6 H), 7.74 (dd, J = 9.1, J7,5
.4 Hz, 1 H), 7.98 (d, J5,7 = 2.4 Hz, 1 H), 8.21 (d, J = 9.1 Hz, 1
H), 8.86 (d, J = 14.0 Hz, 1 H), 8.88 (2×s, 2×1 H), 11.51 (d, J =
(
2
3
=
3
): δ = 1.36 (t, 3 H), 2.50 (s, 3 H), 4.25 (q, 2 H), 7.9–8.0 (m,
H, 1 H), 8.12 (d, J = 9.1 Hz, 1 H), 8.65 (d, J = 13.1 Hz, 1 H),
.87 (2×s, 2×1 H), 12.76 (d, J = 13.1 Hz, 1 H) ppm. 1 C NMR
+ [D ]DMSO): δ = 14.5, 31.3, 60.3, 104.4, 114.1,
22.1, 131.5, 140.3, 140.9, 143.7, 144.1, 146.0, 150.9, 166.5,
3
1
3
1
1
4.0 Hz, 1 H) ppm. C NMR (75 MHz, CDCl
05.5, 116.0, 121.3, 131.9, 138.8, 141.3, 143.6, 144.9, 146.4, 152.4,
= 1731, 1680, 1618, 1273,
3
): δ = 27.2, 89.0,
(75 MHz, CDCl
3
6
1
2
–
1
163.1, 165.4 ppm. IR (KBr): ν˜
00.9 ppm. IR (KBr): ν˜ max = 2982, 1713, 1640, 1620, 1250 cm .
max
–
1
1223 cm . UV/Vis(MeOH, saturated solution): λmax = 224, 244,
UV/Vis (MeOH): λmax (log ε) = 244 (3.12), 300 (2.98), 326 (3.09),
+
·
67 (3.27) nm. EI MS: m/z (%) = 285 [M]+· (75), 270 (17), 239 (33),
299, 323, 347 nm. EI MS: m/z (%) = 299 [M]
(18), 241 (38), 196
(299.29): calcd.C
0.20, H 4.38; N 14.04; found C 60.03, H 4.52, N 14.28.
3
2
(
6
13 3 4
100), 169 (50), 142 (15), 115 (35). C15H N O
24 (21), 211 (100), 196 (83), 169 (29), 142 (29), 115 (25).
15 15 3 3
C H N O (285.31): calcd. C 63.15, H 5.30, N 14.73; found C
63.02, H 5.16, N 14.55.
Acknowledgments
3
-Oxo-2-(quinoxalin-6-ylaminomethylene)butanenitrile (3g): M.p.
1
226–228 °C (xylene). Yield 1.06 g (74%). H NMR (300 MHz, [D
6
]-
The authors thank Mrs. O. Lakato sˇ ová for the measurement of
the UV and IR spectra, Mrs. M. Ondrejkovi cˇ ová for the elemental
analyses and Dr. L. Laryna (Irkutsk Institute of Chemistry, Sibe-
rian Branch, Russian Academy of Sciences, Irkutsk, Russia) for the
NMR spectra of 6-aminoquinoxaline. The Slovakian authors thank
the Slovak grant agency VEGA for financial support (grants No.
DMSO): (E) isomer: δ = 2.37 (s, 3 H), 8.05 (m, 1 H), 8.08 (d, J =
.0 Hz, 1 H), 8.13 (d, J5,7 = 2.4 Hz, 1 H), 8.59 (s, 1 H), 8.85, 8.90
2×d, J = 2.0 Hz, 2×1 H), 11.02 (s, 1 H) ppm; (Z) isomer: δ =
.34 (s, 3 H), 8.05 (m, 1 H), 8.08 (d, J = 9.0 Hz, 1 H), 8.20 (d, J5,7
2.4 Hz, 1 H), 8.67 (d, J = 13.2 Hz, 1 H), 8.87, 8.90 (2×d, J =
9
(
2
=
.9 Hz, 2×1 H), 12.20 (d, J = 13.2 Hz, 1 H) ppm. 1 C NMR
75 MHz, [D ]DMSO): (E) isomer: δ = 26.5, 88.7, 115.0, 116.5,
22.7, 130.5, 139.9, 141.0, 143.0, 144.7, 146.5, 152.5, 192.2 ppm;
3
1
1/0058/03, 1/0052/03 and 1/2448/05), the Science and Technology
(
6
Assistance Agency APVT (APVT-20-00734) and the French Em-
bassy in Bratislava. Z. R. thanks the United States–Israel Bi-
national Science Foundation (BSF) for support.
1
(Z) isomer: δ = 28.5, 85.4, 115.4, 120.0, 122.6, 130.6, 139.8, 140.3,
1
1
2
42.9, 145.0, 146.7, 153.0, 196.1 ppm. IR (KBr): ν˜ max = 2207, 1657,
–1
617, 1312 cm . UV/Vis (MeOH, saturated solution): λmax = 251,
+
·
99, 333, 367 nm. EI MS: m/z (%) = 238 [M] (93), 195 (100), 168
O (238.25): calcd. C 65.54, H
.23, N 23.52; found C 65.32, H 4.14, N 23.44.
[1] A. R. Katritzky, A. J. Boulton, Advances in Heterocyclic Chem-
istry (Ed.: A. R. Katritzky), Academic Press, San Diego, USA,
10 4
(29), 141 (29), 102 (20). C13H N
1
978, vol. 22, p. 368.
4
[
2] a) M. Nagao, M. Honda, Y. Seino, T. Yahagi, T. Sugimura,
Cancer Lett. 1977, 2, 221–239; b) K. Wakabayashi, M. Nagao,
H. Esumi, T. Sugimura, Cancer Res. (Suppl) 1992, 52, 2092–
Methyl 2-Cyano-3-(quinoxalin-6-ylamino)propenoate (3h): M.p.
1
2
38–240 °C (xylene). Yield 0.84 g (55%). H NMR (300 MHz, [D
DMSO): (E) isomer: δ = 3.76 (s, 3 H), 7.98 (m, 1 H), 8.06 (d, J5,7
2.4 Hz, 1 H), 8.08 (d, J = 9.0 Hz, 1 H), 8.73 (d, J = 13.8 Hz, 1
6
]-
2098; c) Food Borne Carcinogens (Eds.: M. Nagao, T. Sugi-
mura), Wiley, Chichester, 2000; d) V. Milata, Advances in Het-
erocyclic Chemistry (Ed.: A. R. Katritzky), Academic Press,
San Diego, 2001, vol. 78, p. 189; e) F. T. Hatch, M. E. Colvin,
E. T. Seidl, Environ. Mol. Mutagen. 1996, 27, 314–330.
3] V. Milata, Aldrichim. Acta 2001, 34, 20–27.
=
H), 8.85, 8.91 (2×d, J = 2.1 Hz, 2×1 H), 10.94 (d, J = 13.8 Hz, 1
H) ppm; (Z) isomer: δ = 3.80 (s, 3 H), 8.05 (m, 1 H), 8.10 (d, J =
9
.0 Hz, 1 H), 8.19 (d, J5,7 = 2.4 Hz, 1 H), 8.55 (d, J = 11.4 Hz, 1
H), 8.85, 8.91 (2×d, J = 2.1 Hz, 2×1 H), 11.14 (d, J = 11.4 Hz, 1
H) ppm. 13C NMR (75 MHz, [D
]DMSO): (E) isomer: δ = 52.0,
6.4, 114.7, 115.5, 122.2, 130.5, 139.8, 140.8, 142.9, 144.6, 146.4,
[
[
4] G. Y. Lesher, E. J. Froehlich, M. D. Gruett, J. H. Bailey, R. P.
Brundage, J. Med. Pharm. Chem. 1962, 1063–1064.
6
7
1
1
1
1
2
1
[5] V. D. Dyachenko, R. P. Tkachev, Russ. J. Org. Chem. 2003, 39,
52.5, 164.7 ppm; JH,C=C–CN = 10.3 Hz; (Z) isomer: δ = 51.9, 75.4,
14.8, 117.8, 122.5, 130.4, 140.0, 140.0, 142.9, 144.7, 146.4, 153.5,
66.2 ppm; JH,C=C–CN = 5.7 Hz. IR (KBr): ν˜ max = 3216, 2211, 1684,
757–793.
[
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634, 1250 cm . UV/Vis (MeOH, saturated solution): λmax = 226,
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·
47, 298, 317, 358 nm. EI MS: m/z (%) = 254 [M] (100), 222 (72),
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.15 (m, 3 H) 8.51 (s, 1 H), 8.85 (dd, J = 1.9 Hz, 2×1 H), 11.10 (s,
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[
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4878
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Eur. J. Org. Chem. 2005, 4870–4878