New azabenzoquinones by ring-expansion reactions

Article abstract of DOI:10.1002/jhet.5570400108

Ozonolysis of the pyrrolidinediones 4 afforded the pyrrolidinetriones 5, which in the presence of Lewis acids were converted into maleimide 6. Analogously, ozonolysis of the pyrrolidinones 7 gave the pyrrolidinediones 8, which were converted into the pyridinetriones 11a, b via Lewis acid catalyzed isomerization to yield the trihydroxypyridones 10 and ensuing air oxidation. In solution two tautomeric forms of the pyridinetriones 11 may exist both of which represent hydroxy-azabenzoquinones. In two steps compounds 11 were transformed into the azaquinone derivatives 19. Representatives of another type of azaquinones are compounds 28a, b. These were generated in two steps from the pyridones 25. The azaquinone 28a reacted easily with acidic compounds yielding the adducts 26, 27 and 29 or with 2-butenal forming the cycloadduct 30.

Full text of DOI:10.1002/jhet.5570400108

Jan-Feb 2003
New Azabenzoquinones by Ring-expansion Reactions
61
H. Poschenrieder [a], H.-D. Stachel* [a], B. Wiesend [a] and K. Polborn [b]
[a] Department Pharmazie / Zentrum für Pharmaforschung, Universität München,
Butenandtstr. 7 – 13, D 81377 München, Germany
[b] Department Chemie, Universität München, Butenandtstr. 7 – 13, D 81377 München, Germany
Received April 25, 2002
Ozonolysis of the pyrrolidinediones 4 afforded the pyrrolidinetriones 5, which in the presence of Lewis
acids were converted into maleimide 6. Analogously, ozonolysis of the pyrrolidinones 7 gave the pyrrolidine-
diones 8, which were converted into the pyridinetriones 11a, b via Lewis acid catalyzed isomerization to yield
the trihydroxypyridones 10 and ensuing air oxidation. In solution two tautomeric forms of the pyridinetriones
11 may exist both of which represent hydroxy-azabenzoquinones. In two steps compounds 11 were trans-
formed into the azaquinone derivatives 19. Representatives of another type of azaquinones are compounds
28a, b. These were generated in two steps from the pyridones 25. The azaquinone 28a reacted easily with
acidic compounds yielding the adducts 26, 27 and 29 or with 2-butenal forming the cycloadduct 30.
J. Heterocyclic Chem., 40, 61 (2003).
Introduction.
difficulties also exist with the designation of quinones with
fused heterocycles as azaquinones [13].
Because of the structural resemblance with fungal pig-
ments named grevellins 1 [1-3] compounds of type 2, for
the sake of convenience, have been called azagrevellins
(Scheme 1). It has been claimed that some of the azagrev-
ellins exhibit physiological actions of potentially therapeu-
tic value [4,5]. Recently we have described two methods
for the synthesis of azagrevellins and structural isomers by
ring enlargement reactions of 2-pyrrolidone derivatives
[4,5]. Analogously, starting with 2,5-pyrrolidinediones the
synthesis of compounds of type 3a appeared feasible.
Tautomers of 3a can be regarded as hydroxy-azabenzo-
quinones (3b). Proof of a similar tautomerism was given
for dihydropyridones related to 3 [6,7].
The term azaquinones for compounds containing nitro-
gen atoms as members of the quinonoid ring was intro-
duced in the chemical literature by H. J. Boyer in 1957 [8].
A recent survey on the chemistry of mono- and diaza-
quinones was given by S. Radl [9]. The significance of
azaquinones and derivatives as bacterial pigments and
metabolites was summarized by H.-J. Knackmuss [7].
Later on a yellow fungal pigment called incaflavin was
recognized as an azaquinone [10,11]. Deviating from the
above definition the term azaquinone was sometimes used
for quinone imines in the literature [12]. Nomenclatory
Up to now, investigations concerning physiological
effects of azaquinones are lacking. It should be noted,
however, that a compound structurally related to 3 was rec-
ognized as an antibiotic [14]. But strictly speaking, this
substance named SEN-34 is not an azaquinone because of
it posesses a substituted nitrogen.
Chemistry.
The azagrevellins 2 were prepared from epoxides 4
(Scheme 2) in a ring enlargement reaction initiated by
alkylating agents especially triethyloxonium tetrafluorobo-
rate (Meerwein's reagent) [5]. The isomerization proceeds
by an anionotropic 1,2-shift of one of the two acyl groups
present after opening of the oxirane ring. Thereby usually
the oxo carbonyl group showed a higher migration apti-
tude than the lactam carbonyl group. It was our aim to
apply this ring-expansion reaction to the epoxides 5.
We planned to produce the unknown imides 5 by
ozonolysis from the benzylidene lactams 4 in stock assum-
ing that the oxirane would sustain the procedure [15]. The
ozonolysis indeed proceeded as expected. However, the
compounds 5 could not be purely obtained because of the
rapid hydrolytic cleavage of the oxirane and the ensuing
retro-aldol reaction. The maleimide 6 was isolated as final
product beside benzaldehyde or 4-chlorobenzaldehyde,
respectively. The yield of 6 was better than 50% so that
this new synthesis constitutes a convenient and inexpen-
sive alternative to the literature method [16].
The rapid degradation of epoxide 5 may be attributed to
an unfavorable molecular geometry enforced by the neigh-
boring carbonyl groups. In consequence, the partly satu-
rated epoxides 8 should be more stable and therefore rep-
resent suitable intermediates for the desired ring-expan-
sion. We have found indeed that the premature cleavage of
the oxirane can be avoided if the ozonolysis is carried out
with the benzylidene lactams 7. These compounds were
obtained by partial hydrogenation of the lactams 5 as

62
H. Poschenrieder, H.-D. Stachel, B. Wiesend and K. Polborn
Vol. 40
in the same region [6], which also showed up in the ir
spectrum of 12a. The strong absorptions at 1730 – 1700
-1
cm in the spectra of both 11a and 12a can be addressed as
13
imide carbonyl bands. Likewise the C nmr spectra of 11a
and 12 were essentially identical. From this it must be
concluded that the tautomeric equilibrium of compounds
11 is shifted to the trione system. Likewise other aza-
quinones capable of tautomerism appear to exist largely in
the imide form [7]. The only reference to partial enoliza-
tion of compounds 11 was found in their uv spectra. While
the uv spectrum of 11a showed two absorption maxima at
272 and 379 nm the long wave maximum was missing in
solutions of 12a. Therefore compounds 11 can be consid-
ered as azaquinonoids but are written here as pyridinetri-
ones (Scheme 2).
To further confirm the structure of compounds 11 we
have prepared a number of derivatives. Although the
reduction of compounds 11 can be carried out easily with
sodium dithionite we did not succeed in the isolation of the
corresponding azahydroquinones 10 in pure state.
Reduction of compound 11a with zinc and acetic anhy-
dride led to the tetraacetoxypyridines 13. The reactions of
compounds 11 with diazomethane proceeded in three
steps. First the enol ethers 14 were formed very rapidly.
These were then converted into the epoxides 16 and finally
into the N-methylated epoxides 17. From the reaction of
the trione 11a with the less reactive p-chlorophenyldia-
zomethane only the benzyl ether 15a was isolated which
formed crystals suitable for X-ray structure determination.
The single crystal diffraction analysis (Figure 1, Tables 1a,
1b) confirmed the structure of 15a and with it the struc-
tures of the progenitor 11a as well as of 11b by analogy.
mixtures of two stereoisomers. Therefore the ozonolysis
yielded the imides 8a, 8b as mixtures of two isomers each.
The separation of the stereoisomers proved unnecessary.
Addition of boron trifluoride to the solution of either epox-
ide initiated the ring enlargement reaction and finally the
formation of the pyridones 10. These compounds are best
formulated as endiols because they are easily oxidized by
air oxygen yielding the yellow pyridinetriones 11. In
between a transient red color appeared. The color might be
attributed to intermediate radicals or radical anions as it
was demonstrated to be the case during the oxidation of a
similar system [6,17].
Some physical and chemical properties of compounds 11
are consistent with a tautomeric azaquinone structure. The
compounds prove to be relatively strong acids with pK val-
a
ues of 3.7 in aqueous dioxane. Owing to ionization the solu-
tions appear reddish in solvents containing water. Upon
addition of bases the color changes to the deep red of the
respective anions. The same behavior was reported as typi-
cal for hydroxyquinones [18]. On the other hand the com-
pounds 11 are weak bases and dissolve in concentrated sul-
furic acid with red color owing to the formation of N-proto-
nated azaquinones. Likewise the compounds 11 typically
exhibited a red color on silicagel during chromatography.
Some information on the tautomeric equilibrium of
compounds 11 can be drawn by comparison of their spec-
tra with those of the N-methylated pyridone 12a which
was prepared for this purpose from epoxide 9a. The ir
spectrum of 11a did not allow the clear identification of
NH-absorptions because of several OH-association bands
The pyridinetriones 11 reacted with o-phenylenediamine
in 3- and 4-position yielding the violet quinoxalines 18
(Scheme 3). By reaction of compound 18 with dia-
zomethane the azaquinone derivatives 19 were obtained.

Jan-Feb 2003
New Azabenzoquinones by Ring-expansion Reactions
63
Table 1b
Bond Lengths [Å] and Angles [°] for 15a
Cl(1)-C(10)
O(1)-C(3)
O(2)-C(4)
O(3)-C(5)
O(4)-C(1)
O(4)-C(6)
N(1)-C(4)
N(1)-C(3)
C(1)-C(2)
C(1)-C(5)
C(2)-C(13)
C(2)-C(3)
C(4)-C(5)
C(6)-C(7)
C(7)-C(12
C(7)-C(8)
C(8)-C(9)
C(9)-C(10)
C(10)-C(11)
C(11)-C(12)
C(13)-C(14)
C(13)-C(18)
C(14)-C(15)
(15)-C(16)
C(16)-C(17)
C(17)-C(18)
C(1)-O(4)-C(6)
C(4)-N(1)-C(3)
C(2)-C(1)-O(4)
C(2)-C(1)-C(5)
O(4)-C(1)-C(5)
1.736(4) C(1)-C(2)-C(13)
122.4(3)
1.211(4)
C(1)-C(2)-C(3)
118.8(3)
118.7(3)
118.9(3)
122.2(3)
118.9(3)
123.4(3)
121.3(3)
115.2(3)
123.1(3)
118.5(3)
118.4(3)
108.7(3)
118.3(3)
120.1(3)
121.6(3)
121.1(3)
119.4(4)
120.7(4)
119.8(3)
119.5(3)
119.7(4)
120.7(3)
118.9(3)
119.4(3)
120.2(3)
120.7(3)
119.7(3)
120.1(3)
120.4(3)
1.201(4) C(13)-C(2)-C(3)
1.207(3) O(1)-C(3)-N(1)
1.363(3) O(1)-C(3)-C(2)
1.452(4) N(1)-C(3)-C(2)
1.361(4) O(2)-C(4)-N(1)
1.381(4) O(2)-C(4)-C(5)
1.348(4) N(1)-C(4)-C(5)
1.460(4) O(3)-C(5)-C(1)
1.475(4) O(3)-C(5)-C(4)
1.486(4) C(1)-C(5)-C(4)
1.523(4) O(4)-C(6)-C(7)
1.497(4) C(12)-C(7)-C(8)
1.381(4) C(12)-C(7)-C(6)
1.383(4) C(8)-C(7)-C(6)
1.372(5) C(9)-C(8)-C(7)
1.371(5) C(8)-C(9)-C(10)
1.364(5) C(11)-C(10)-C(9)
1.379(5) C(11)-C(10)-Cl(1)
1.384(4) C(9)-C(10)-Cl(1)
1.391(4) C(10)-C(11)-C(12)
1.372(5) C(11)-C(12)-C(7)
1.374(5) C(14)-C(13)-C(18)
1.374(5) C(18)-C(13)-C(2)
1.376(5) C(15)-C(14)-C(13)
Figure 1. ORTEP plot of Azaquinone 15a.
Table 1a
Single Crystal X-Ray Crystallographic Analysis of 15a
A. Crystal Parameters
Formula
C H ClNO (341.74)
18 12 4
Temperature
Wavelength
293(2) K
0.71073 Å
115.7(2)
C(14)-C(15)-C(16)
Crystal system
Space group
Unit cell dimensions
orthorhombic
Pbca
126.2(3) C(17)-C(16)-C(15)
120.9(3) C(16)-C(17)-C(18)
121.9(3) C(17)-C(18)-C(13)
117.0(3)
a = 11.832(2) Å
b = 7.661(2) Å
c = 35.362(10) Å
3
Volume
3205.6(13) Å
of compound 24a, was formed analoguosly from enol
ether 14a.
Z
8
3
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
B. Refinement Parameters
Reflections collected
Independent reflections
Observed reflections [I>2σ(I)]
Absorption correction
Refinement method
Data / restraints / parameters
Goodness-of-fit on F
Final R indices [I>2σ(I)]
R indices (all data)
1.416 Mg/m
0.260 mm
1408
0.53 x 0.43 x 0.13 mm
2.30 to 22.97º
0<=h<=12, 0<=k<=8, -38<=l<=0
-1
Recently we have reported on the synthesis of the
hydroxypyridones 25a, b (Scheme 4) by a ring-expansion
reaction [19]. These compounds can be viewed as azahy-
droquinones and were easily oxidized to the corresponding
azaquinones by dichlorodicyanoquinone or silver nitrate.
The red solutions of the azaquinones went colorless upon
addition of protic solvents like water during work-up. In
the latter case, adducts 26 were obtained the structure of
which was secured by NOE and CH-COSY experiments.
Adducts 26 were converted upon heating with acetic anhy-
dride into the acetates 27. Solutions of 27a in dioxane
reversibly turned red on heating thus indicating a tempera-
ture dependent equilibrium of adduct 27a and its compo-
nents, the azaquinone 28a and acetic acid. The thermolysis
of both adducts 27 as solids under reduced pressure led to
the corresponding red azaquinones 28.
2226
2225 [R(int) = 0.0820]
1598
None
Full-matrix least-squares on F
2225 / 0 / 217
2
2
1.086
R1 = 0.0510, wR2 = 0.1098
R1 = 0.0775, wR2 = 0.1270
0.168 and -0.267 e.A
-3
Largest diff. peak and hole
The structure of 19b was secured by X-ray diffraction
analysis (Figure 2, Tables 2a, 2b). In the reaction of com-
pound 11a with excessive phenylhydrazine only the poorly
soluble monohydrazone 20 was formed. Compound 20
yielded the enol ether 21 upon reaction with diazomethane.
The oximes 22 and their derivatives 24 were all obtained
as mixtures of syn/anti isomers by reaction of the triones
11 and hydroxylamine hydrochloride or O-methylhydrox-
ylamine, respectively. The oxime 23a, a structural isomer
The high reactivity at the eletron-deficient imine double
bond is a characteristic of azaquinones [9]. Accordingly,
the azaquinone 28a reacted with dimethyl malonate in the
presence of pyridine to give the adduct 29. The reaction of
28a and the heterodiene 2-butenal yielding the cyclo-
adduct 30 was reversed upon heating under reduced pres-
1
sure. According to the H nmr spectrum compound 30 was

64
H. Poschenrieder, H.-D. Stachel, B. Wiesend and K. Polborn
Vol. 40
uniform and therefore evidently the product of a stereo-
selective Diels-Alder reaction. The configuration at C-4
bearing the methyl group is still to be determined.
Table 2a
Single Crystal X-Ray Crystallographic Analysis of 19b
A. Crystal Parameters
Formula
C H ClN O (351.78)
19 14 3 2
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
293(2) K
0.71073 Å
triclinic
P-1
a = 7.152(2) Å alpha = 92.96(3)°
b = 11.152(4) Å beta = 97.35(3)°
c = 10.759(3) Å gamma = 93.84(3) °
3
Volume
847.6(5) Å
Z
2
3
Density (calculated)
Absorption coefficient
F(000)
1.378 Mg/m
0.243 mm
364
-1
Crystal size
Theta range for data collection
Index
0.53 x 0.20 x 0.13 mm
2.57 to 23.98°
-8<=h<=0, -12<=k<=12, -12<=l<=12
B. Refinement Parameters
Reflections collected
Independent reflections
Observed reflections [I>2σ(I)]
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
2530
2345 [R(int) = 0.0133]
1696
Semi-empirical
0.9983 and 0.9448
Full-matrix least-squares on F
2345 / 0 / 228
2
2
Goodness-of-fit on F
1.007
Final R indices [I>2σ(I)]
R indices (all data)
Largest diff. peak and hole
R1 = 0.0581, wR2 = 0.1343
R1 = 0.0828, wR2 = 0.1511
0.190 and -0.210 e.A
-3
Table 2b
Bond Lengths [Å] and Angles [°] for 19b
Cl(1)-C(17)
O(1)-C(1)
O(1)-C(12)
O(2)-C(11)
O(2)-C(13)
N(1)-C(3)
N(1)-C(4)
N(2)-C(9)
N(2)-C(10)
N(3)-C(11)
N(3)-C(1)
C(1)-C(2)
1.716(4) C(11)-O(2)-C(13)
1.390(5) C(3)-N(1)-C(4)
1.414(4) C(9)-N(2)-C(10)
1.313(4) C(11)-N(3)-C(1)
1.428(5) N(3)-C(1)-C(2)
1.337(5) N(3)-C(1)-O(1)
1.375(5) C(2)-C(1)-O(1)
1.328(5) C(1)-C(2)-C(3)
1.363(5) C(1)-C(2)-C(14)
1.325(5) C(3)-C(2)-C(14)
1.334(5) N(1)-C(3)-C(10)
1.348(5) N(1)-C(3)-C(2)
1.460(5) C(10)-C(3)-C(2)
1.460(5) N(1)-C(4)-C(9)
1.395(5) N(1)-C(4)-C(5)
1.387(6) C(9)-C(4)-C(5)
1.415(6) C(6)-C(5)-C(4)
1.394(6) C(7)-C(6)-C(5)
1.377(7) C(8)-C(7)-C(6)
1.339(7) C(7)-C(8)-C(9)
1.458(6) N(2)-C(9)-C(4)
1.434(6) N(2)-C(9)-C(8)
1.340(6) C(4)-C(9)-C(8)
1.409(6) N(2)-C(10)-C(3)
1.361(6) N(2)-C(10)-C(11)
1.395(7) C(3)-C(10)-C(11)
1.325(6) O(2)-C(11)-N(3)
1.362(6) O(2)-C(11)-C(10)
114.8(4)
118.7(3)
118.0(3)
118.7(3)
123.3(4)
117.3(3)
119.4(3)
117.9(3)
120.4(4)
121.6(3)
117.1(4)
122.0(3)
120.8(4)
123.0(4)
121.1(4)
115.9(4)
122.1(5)
121.7(5)
118.0(5)
122.2(5)
118.7(4)
121.1(4)
120.2(4)
124.3(4)
122.3(4)
113.4(4)
121.9(4)
112.3(4)
119.2(4)
C(2)-C(3)
C(2)-C(14)
C(3)-C(10)
C(4)-C(9
C(4)-C(5)
C(5)-C(6)
C(6)-C(7)
C(7)-C(8)
C(8)-C(9)
C(10)-C(11)
C(14)-C(15)
C(14)-C(19)
C(15)-C(16)
C(16)-C(17)
C(17)-C(18)
C(18)-C(19)
Figure 2. ORTEP plot of Quinoxaline 19b.
The oximes 22 and 23a as well as the azaquinones 11
contain partial structures which are present in some sub-
stances with known antagonistic action at the physiologi-
cally important NMDA receptor [20] and played a role in
the development of a pharmacophor model [21].
Representative members of the compounds described here
are being tested pharmacologically.
C(1)-O(1)-C(12)
120.4(3) C(15)-C(14)-C(19)

Jan-Feb 2003
New Azabenzoquinones by Ring-expansion Reactions
65
Table 2b (Continued)
nmr: δ 10.85 (s, 0.45 H), 10.56 (s, 0.55 H), 7.54-7.34 (m, 9 H),
6.32 (d, J = 8 Hz, 0.45 H), 5.74 (s, 0.45 H), 5.66 (s, 0.55 H), 5.45
(d, J = 8 Hz, 0.55 H), 4.96 (d, J = 8 Hz, 0.45 H), 4.80 (d, J = 8 Hz,
C(15)-C(14)-C(2)
C(19)-C(14)-C(2)
C(14)-C(15)-C(16)
C(15)-C(16)-C(17)
C(18)-C(17)-C(16)
117.9(4)
123.0(4)
117.7(5)
121.7(4)
122.1(4)
C(18)-C(17)-Cl(1)
116.1(4)
121.8(4)
115.8(5)
123.5(4)
C(16)-C(17)-Cl(1)
C(17)-C(18)-C(19)
C(18)-C(19)-C(14)
+
0.55 H), 4.52 (s, 0.45 H), 4.44 (s, 0.55 H); ms: m/z 327 (M ).
Anal. Calcd. for C H ClNO (327.77): C, 65.96; H, 4.30; N,
18 14
3
4.27. Found: C, 65.73; H, 4.35; N, 4.17.
7-Hydroxy-2-phenyl-1-oxa-5-aza-spiro[2,4]heptane-4,6-dione
(8a).
EXPERIMENTAL
Ozone was passed through a solution of 1.0 g (3.4 mmol) of
compound 7a in dichloromethane (50 ml) and methanol (150 ml)
at -15° over a period of 4 minutes. The solvent was removed in
vacuo at a temperature not exceeding 10° (danger of explosive
decomposition of by-products) and the oily residue extracted
with petrol ether (30 ml). The solution was discarded and the
solid residue was crystallized from diethyl ether. Yield 0.52 g
(70%), colorless crystals (mixture of two stereoisomers), mp
Melting points were determined by using a Büchi Melting
Point B-540 apparatus and are uncorrected. Uv analysis was per-
formed in methanolic solution if not stated otherwise on UV/VIS
Spectrometer Lambda 20 (Perkin Elmer) or UV/VIS
Spectrophotometer Jasco V-530. Infrared spectra were measured
as potassium bromide plates by using a FT-IR-Spectrometer
1
PARAGON 1000 (Perkin Elmer). H nmr spectra (internal stan-
-1
161-163° (dec); ir: ν 3432, 3271, 1802, 1719 cm ; uv: λ max
dard tetramethylsilane) were recorded on FT NMR Spectrometer
Elipse 400 (JEOL) or FT NMR Spectrometer Elipse 500 (JEOL).
The solvent was hexadeuteriodimethylsulfoxide if not indicated
otherwise. Mass spectra were recorded with a Hewlett Packard
5989A Mass Spectrometer. Microanalyses were carried out with
an Analysator CHN-O-Rapid (Heraeus). CC: By flash column
250 ml (Baker) with silica gel 0.040 – 0.063 mm (Merck). Ozone
was generated by the Ozongenerator Fischer 502, capacity: 4.3 g
ozone/h at an oxygen flow rate 60 L/h.
1
(log ε) 220 nm (4.038); H nmr: δ 11.84 (s, 0.6 H), 11.52 (s, 0.4
H), 7.48-7.29 (m, 5 H), 6.48 d, J = 8 Hz, 0.4 H), 5.51 (d, J = 8 Hz,
0.6 H), 4.82 (d, J = 8 Hz, 0.4 H), 4.76 d, J = 8 Hz, 0.6 H), 4.51 (s,
+
0.4 H), 4.42 (s, 0.6 H); ms: m/z 219 (M ).
Anal. Calcd. for C H NO (219.20): C, 60.27; H, 4.14; N,
11
9
4
6.39. Found: C, 60.03; H, 4.21; N, 6.42.
2-(4-Chlorophenyl)-7-hydroxy-1-oxa-5-aza-spiro[2,4]heptane-
4,6-dione (8b).
3,4-Dihydroxy-pyrrole-2,5-dione (6).
This compound was prepared analogously to 8a from 1.0 g (3
mmol) of compound 7b. Yield 0.45 g (60%), colorless crystals
(mixture of two stereoisomers), mp 172-176° (diisopropyl
Ozone was passed through a solution of 1.0 g (3.4 mmol) of
compound 4a [4] in dichloromethane (50 ml) and methanol (150
ml) at –15° over a period of 4 minutes. The solvent was removed
in vacuo at a temperature not exceeding 10° (danger of explosive
decomposition of by-products). The residue was stirred with 1 ml
of trifluoroacetic acid. After a short time the product started to
crystallize. Yield 0.30 g (52%), light yellow crystals, mp >165°
(dec), ref. [16]: mp 180° (dec).
-1
ether/ethanol); ir: ν 3453, 3204, 1802, 1720 cm ; uv: λ max (log
1
ε) 229 nm (4.216); H nmr: δ 1.85 (s, 0.6 H), 11.53 (s, 0.4 H),
7.50-7.37 (m, 4 H), 6.44 d, J = 8 Hz, 0.4 H), 5.54 (d, J = 8 Hz, 0.6
H), 4.80 (d, J = 8 Hz, 0.4 H), 4.76 (d, J = 8 Hz, 0.6 H), 4.51 (s, 0.4
+
H), 4.45 (s, 0.6 H); ms: m/z 253 (M ).
Anal. Calcd. for C H ClNO (253.64): C, 52.09; H, 3.18; N,
11
8
4
5.52. Found: C, 52.19; H, 3.11; N, 5.62.
6-Benzylidene-7-hydroxy-2-phenyl-1-oxa-5-aza-spiro[2,4]hep-
tan-4-one (7a).
7-Hydroxy-5-methyl-2-phenyl-1-oxa-5-aza-spiro[2,4]heptane-
4,6-dione (9a).
To a stirred and cooled suspension of 2.90 g (10 mmol) of
compound 4a in aqueous methanol (1:2, 45 ml) were added 0.55
g (15 mmol) of sodium borohydride. After continued stirring for
one hour the mixture was acidified with diluted sulfuric acid and
the precipitate collected and washed with methanol. Yield 2.0 g
(68%), colorless crystals (mixture of two stereoisomers), mp
Compound 8a (1.10 g, 5 mmol) was added to an etheral solu-
tion of excessive diazomethane. After the evolution of nitrogen
had ceased the solution was evaporated to dryness and the
residue crystallized from diisopropyl ether/ethanol 1:1. Yield
0.45 g (38%), colorless crystals, mp 163°; ir: ν 3452, 1732, 1710
-1
1
-1
cm ; uv: λ max (log ε) 228 nm (4.097); H nmr: δ 7.37-7.30 (m,
200-203° (methanol); ir: ν 3477, 3231, 1728, 1685 cm ; uv: λ
max (log ε) 218 (4.365), 272 nm (4.348); H nmr: δ 10.84 (s, 0.6
1
5 H), 5.55 (d, 1 H, J = 8 Hz), 4.77 (d, 1 H, J = 8 Hz), 4.49 (s, 1 H),
+
2.95 (s, 3 H); ms: m/z 233 (M ).
H), 10.53 (s, 0.4 H), 7.44-7.29 (m, 10 H), 6.35 (d, J = 8 Hz, 0.4
H), 5.74 (s, 0.4 H), 5.68 (s, 0.6 H), 5.44 (d, J = 8 Hz, 0.6 H), 4.96
(d, J = 8 Hz, 0.4 H), 4.79 (d, J = 8 Hz, 0.6 H), 4.51 (s, 0.4 H), 4.42
Anal. Calcd. for C H NO (233.22): C, 61.80; H, 4.75; N,
12 11
4
6.00. Found: C, 61.13; H, 4.51; N, 5.87.
+
(s, 0.6 H); ms: m/z 293 (M ).
4-Hydroxy-5-phenyl-pyridine-2,3,6-trione (11a).
Anal. Calcd. for C H NO (293.32): C, 73.70; H, 5.15; N,
18 15
3
A solution of 1.10 g (5 mmol) of compound 7a and 1 ml of
boron trifluoride diethyl etherate in dioxane (50 ml) was heated
at reflux for one hour. The solution was concentrated to a volume
of 10 ml, poured into ice water (30 ml) and extracted twice with
ethyl acetate (70 ml). The combined organic layers were dried
with sodium sulfate. The solvent was removed in vacuo and the
residue crystallized from diisopropyl ether/ethanol 1:1. Yield
0.44 g (40%), yellow crystals, mp 230° (dec); ir: ν 3434, 3192,
4.77. Found: C, 74.00; H, 5.02; N, 4.82.
6-(4-Chloro-benzylidene)-7-hydroxy-2-phenyl-1-oxa-5-aza-
spiro[2,4]heptan-4-one (7b).
This compound was prepared analogously to 7a from 3.25 g
(10 mmol) of compound 4b and 0.55 g (15 mmol) of sodium
borohydride. Yield 2.80 g (85%), colorless crystals (mixture of
two stereoisomers), mp 170-173° (methanol); ir: ν 3470, 1730,
-1
1
-1
1685cm ; uv: λ max (log ε) 220 (4.364), 272 nm (4.347); H
1735, 1712, 1669 cm ; uv: λ max (log ε) 272 (3.761), 379 nm

66
H. Poschenrieder, H.-D. Stachel, B. Wiesend and K. Polborn
Vol. 40
13
5-(4-Chloro-phenyl)-4-methoxy-pyridine-2,3,6-trione (14b).
(3.372); C nmr: δ 173.4, 164.7, 155.6, 147.5, 130.9, 130.5,
+
127.8, 127.3, 117.7; ms: m/z 217 (M ).
Anal. Calcd. for C H NO (217.18): C, 60.83; H, 3.25; N,
6.45. Found: C, 60.83; H, 3.42; N, 6.30.
This compound was prepared analogously to 14a from 0.25 g (1
mmol) of compound 11b. Yield 0.10 g (40%), yellow crystals (diethyl
11
7
4
-1
ether), mp 167°; ir: ν 3229, 1762, 1686 cm ; uv: λ max (log ε) 224
1
(4.192), 276 nm (3.768); H nmr (CDCl ): δ 8.51 (s, 1 H), 7.45, 7.34
5-(4-Chlorophenyl)-4-hydroxy pyridine-2,3,6-trione (11b).
3
+
(2d, each, 2 H, J = 8.3 Hz), 4.01 (s, 3 H); ms: m/z 265 (M ).
This compound was prepared analogously to 11a from 1.0 g (4
mmol) of compound 8b and 1 ml of boron trifluoride diethyl
etherate. Yield 0.50 g (50%), yellow crystals (diisopropyl
ether/ethanol 1:1), mp 185° (dec); ir: ν 3471, 3183, 1752, 1703,
Anal. Calcd. for C H ClNO (265.65): C, 54.25; H, 3.03; N,
12
8
4
5.27. Found: C, 54.37; H, 3.14; N, 5.14.
4-(4-Chloro-benzyloxy)-5-phenyl-pyridine-2,3,6-trione (15a).
-1
1663 cm ; uv: λ max (log ε) 273 (3.829), 378 nm (3.342); ms:
A solution of 0.39 g (3 mmol) of 4-chlorophenyldiazomethane
[22] in hexane (10 ml) was added to a stirred solution of 0.43 g (2
mmol) of compound 11a in dioxane (50 ml). After one hour the
excess of 4-chlorophenyldiazomethane was destroyed by addi-
tion of acetic acid (0.2 ml). The volatile components were
removed in vacuo and the residue was crystallized from ethyl
acetate. Yield 0.13 g (20%), yellow crystals, mp 197°; ir: ν 3441,
+
m/z 251 (M ).
Anal. Calcd. for C H ClNO (251.62): C, 52.50; H, 2.40; N,
5.56. Found: C, 52.13; H, 2.51; N, 5.72.
11
6
4
4-Hydroxy-1-methyl-5-phenyl-pyridine-2,3,6-trione (12a).
This compound was prepared analogously to 11a from 0.46 g
(2 mmol) of compound 9a and 1 ml of boron trifluoride diethyl
etherate. Yield 0.16 g (35%), yellow crystals (diisopropyl
ether/ethanol 1:1), mp 155°; ir: ν 3543, 1701, 1647 cm ; uv: λ
max (log ε) 281 (3.863); H nmr: δ 11.32 (s, 1 H), 7.40-7.33 (m,
5 H), 3.14 (s, 3 H); C nmr: δ 172.5, 164.3, 155.9, 153.1, 130.4,
127.8, 127.4, 127.3, 118.3, 26.6; ms: m/z 231 (M ).
Anal. Calcd. for C H NO (231.21): C, 62.34; H, 3.92; N,
-1
1741, 1678 cm ; uv: λ max (log ε) 219 (4.446), 267 nm (3.891);
1
H nmr: δ (CDCl ): δ 11.97 (s, 1H), 7.38-7.19 (m, 9 H), 5.10 (s,
3
-1
+
2H); ms: m/z 341 (M ).
1
Anal. Calcd. for C H ClNO (341.75): C, 63.26; H, 3.53; N,
18 12
4
13
4.10. Found: C, 63.41; H, 3.72; N, 4.02.
+
X-ray Diffraction Analysis of 15a.
12
9
4
6.05. Found: C, 62.14; H, 4.02; N, 5.96.
Data collection: CAD4 Diffractometer, crystal mounted in a glass
capillary, cell constants from 25 centered reflections. Mo-K radia-
α
Acetic Acid 2,3,6-Triacetoxy-5-phenyl-pyridine-4-yl Ester (13a).
tion, λ = 0.71073 Å, graphite monochromator, ω-scan, maximum
measuring time 60 s, intensity of three standard reflections checked
every two hours. Structure solution by SHELXS-86 [23] and refine-
ment by SHELXL-93 [24], non-hydrogen atoms refined anisotropi-
A solution of 0.22 g (1 mmol) of compound 11a in acetic anhy-
dride (10 ml) was heated with powdered zinc (1.0 g) for 5 minutes
to 100°. After cooling the mixture was diluted with ethyl acetate
(50 ml) and filtered. From the solution obtained the solvent was
removed in vacuo and the residue crystallized from diisopropyl
ether/ethanol 1:1. Yield 0.15 g (40%), colorless crystals, mp 137°;
cally, hydrogens with U = 1.2 x U of the adjacent non-hydrogen
i
eq
2
atom. Full-matrix refinement against F . Weight: SHELXL-93.
Maximum and minimum of the final difference Fourier synthesis
-1
ir: ν 1784, 1760 cm ; uv: λ max (log ε) 240 (3.967), 269 nm
-3
0.168 and –0.267 e Å . The drawing (Figure 1) was made by
1
(3.883); H nmr (CDCl ): δ 7.41-7.39 (m, 2 H), 7.29-7.27 (m, 3 H),
3
ZORTEP [25]. Selected data are given in tables 1. The complete
data are available from the Cambridge Crystallographic Data
Centre [26]. The deposition number is CCDC 183746.
+
2.32 (s, 3 H), 2.30 (s, 3 H), 1.97 (s, 6 H); ms: m/z 387 (M ).
Anal. Calcd. for C H NO (387.34): C, 58.91; H, 4.42; N,
19 17
8
3.61. Found: C, 50.81; H, 3.63; N, 4.34.
8-Methoxy-7-phenyl-1-oxa-5-aza-spiro[2,5)oct-7-ene-4,6-dione
(16a).
Acetic Acid 5-(4-Chloro-phenyl)-2,3,6-triacetoxy-pyridine-4-yl
Ester (13b).
An ethereal solution of diazomethane was added in several
portions to a stirred solution of 0.22 g (1 mmol) of compound 11a
in methanol (25 ml) until the red color disappeared. After 5 min-
utes the volatile components were removed and the residue was
crystallized from diisopropyl ether/ethanol 1:1. Yield 0.05 g
(20%), light yellow crystals, mp 192°; ir: ν 3053, 1736, 1667,
This compound was prepared analogously to 13a from 0.25 g
(1 mmol) of compound 11b. Yield 0.12 g (30%), colorless crys-
tals (diisopropyl ether/ethanol 1:1), mp 151°; ir: ν 1790, 1765
-1
1
cm ; uv: λ max (log ε) 243 (4.076), 267 nm (3.975); H nmr
(CDCl ): δ 7.39, 7.23 (d, each, 2 H, J = 8.1 Hz), 2.32 (s, 3 H),
3
+
-1
1
2.30 (s, 3 H), 2.06 (s, 6 H); ms: m/z 421 (M ).
1624 cm ; uv: λ max (log ε) 217 (4.337), 275 nm (3.758); H
Anal. Calcd. for C H ClNO (421.79): C, 54.10; H, 3.82; N,
nmr (CDCl ): δ 8.22 (s, 1H), 7.43-7.31 (m, 5 H), 3.57 (d, J = 7.5
19 16
8
3
3.32. Found: C, 54.03; H, 3.85; N, 3.31.
Hz, 1 H), 3.53 (d, J = 7.5 Hz, 1 H), 3.37 (s, 3H); ms: m/z 245
+
(M ).
4-Methoxy-5-phenyl-pyridine-2,3,6-trione (14a).
Anal. Calcd. for C H NO (245.23): C, 63.67; H, 4.52; N,
13 11
4
An ethereal solution of diazomethane was added in several
portions to a solution of 0.22 g (1 mmol) of compound 11a in
methanol (25 ml) until the red color disappeared. The volatile
components were removed in vacuo and the residue was crystal-
lized from diethyl ether. Yield 0.10 g (45%), yellow crystals, mp
5.71. Found: C, 63.53; H, 4.58; N, 5.59.
8-Methoxy-5-methyl-7-phenyl-1-oxa-5-aza-spiro[2,5]oct-7-ene-
4,6-dione (17a).
An ethereal solution of excessive diazomethane was added to a
solution of 0.22 g (1 mmol) compound 11a in methanol (25 ml).
After one hour the solvent was removed in vacuo. The residue
was crystallized from diisopropyl ether/ethanol 1:1. Yield 0.065
g (25%), light yellow crystals, mp 86°; ir: ν 2952, 1707, 1661,
-1
153°; ir: ν 3233, 1761, 1686 cm ; uv: λ max (log ε) 275 (3.818),
1
385 nm (3.240); H nmr (CDCl ): δ 8.60 (s, 1 H), 7.46-7.39 (m, 5
3
+
H), 3.94 (s, 3 H); ms: m/z 231 (M ).
Anal. Calcd. for C H NO (231.21): C, 62.34; H, 3.92; N,
12
9
4
-1
1
6.05. Found: C, 61.82; H, 3.3.92; N, 5.96.
1639 cm ; uv: λ max (log ε) 225 (4.310), 277 nm (3.659); H

Jan-Feb 2003
New Azabenzoquinones by Ring-expansion Reactions
67
nmr (CDCl ): δ 7.41-7.31 (m, 5 H), 3.57 (d, J = 7.5 Hz, 1 H), 3.51
(d, J = 7.5 Hz, 1 H), 3.35 (s, 3 H) 3.31 (s, 3 H); ms: m/z 259 (M ).
X-ray Diffraction Analysis of 19b.
Data collection: CAD4 Diffractometer, crystal mounted in a
glass capillary, cell constants from 25 centered reflections. Mo-K
radiation, λ = 0.71073 Å, graphite monochromator, ω-scan, maxi-
mum measuring time 60 s, intensity of three standard reflections
checked every two hours. Structure solution by SHELXS-86 [23]
and refinement by SHELXL-93 [24], non-hydrogen atoms refined
3
+
Anal. Calcd. for C H NO (259.26): C, 64.86; H, 5.05; N,
14 13
4
α
5.40. Found: C, 64.55; H, 5.32; N, 5.07.
(4-Chlorophenyl)-8-methoxy-5-methyl-7-1-oxa-5-aza-spiro-
[2,5]oct-7-ene-4,6-dione (17b).
This compound was prepared analogously to 17a from 0.25 g
(1 mmol) of compound 11b. Yield 0.90 g (30%), light yellow
crystals (diisopropyl ether/ethanol 1:1), mp 126°; ir: ν 2953, 1711,
anisotropically, hydrogens with U = 1.2 x U of the adjacent car-
i
eq
2
bon atom. Full-matrix refinement against F . Weight: SHELXL-
93. Maximum and minimum of the final difference Fourier syn-
thesis 0.190 and –0.210 e Å . The drawing (Figure 2) was made
-1
1
1654 cm ; uv: λ max (log ε) 226 (4.388), 275 nm (3.700); H nmr
-3
(CDCl ): δ 7.41-7.27 (m, 4 H), 3.56 (d, J = 8 Hz, 1 H), 3.50 (d, J =
3
by ZORTEP [25]. Selected data are given in tables 1. The com-
plete data are available from the Cambridge Crystallographic Data
Centre [26]. The deposition number is CCDC 183747.
+
8 Hz, 1 H), 3.39 (s, 3 H), 3.31 (s, 3 H); ms: m/z 293 (M ).
Anal. Calcd. for C H ClNO (293.70): C, 57.25; H, 4.11; N,
14 12
4
4.76. Found: C, 56.80; H, 4.18; N, 4.67.
4-Hydroxy-5-phenyl-3-(phenylhydrazono)-3H-pyridine-2,6-
dione (20).
3-Hydroxy-4-phenyl-2H-pyrido[3,4-b]quinoxalin-1-one (18a).
A solution of 0.21 g (1 mmol) of compound 11a und 0.11 g (1
mmol) of 1,2-diamino benzene in methanol (10 ml) were heated
at reflux for 15 minutes. The product precipitated while cooling.
Yield 0.17 g (85 %); violet crystals (methanol), mp 270° (dec); ir:
A solution of 0.24 g (2.2 mmol) of phenylhydrazine in
methanol (5 ml) was added to a stirred solution of 0.43g (2
mmol) of compound 11a in methanol (25 ml). After 1 day the
precipitate was collected and recrystallized from methanol. Yield
0.37 g (60%), orange crystals, mp 252°; ir: ν 3010, 1648, 1597
-1
ν 3153, 2983, 1698, 1605 cm ; uv: λ max (log ε) 226 (4.334),
1
291 (4.443), 538 nm (3.784); H nmr: δ 11.30 (s, 1 H), 10.84 (s, 1
-1
1
cm ; uv: λ max (log ε) 260 (4.317), 431 nm (4.500); H nmr: δ
+
H), 7.48-7.33 (m, 9 H); ms: m/z 289 (M ).
14.24 (s, 1 H), 11.38 (s, 1 H), 10.12 (s, 1 H), 7.79-7.36 (m, 10 H);
Anal. Calcd. for C H N O (289.29): C, 70.58; H, 3.83; N,
+
17 11
3 2
ms: m/z 307 (M ).
14.52. Found: C, 69.59; H, 3.67; N, 14.44.
Anal. Calcd. for C H N O (307.31): C, 66.44; H, 4.26; N,
17 13
3 3
13.67. Found: C, 66.21; H, 4.19; N, 13.96.
4-(4-Chloro-phenyl-3-hydroxy 2H-pyrido[3,4-b]quinoxalin-1-
one (18b).
4-Methoxy-5-phenyl-3-(phenylhydrazono)-3H-pyridine-2,6-
dione (21).
This compound was prepared analogously to 18a from 0.25 g
(1 mmol) of compound 11b. Yield 0.26 g (80%), violet crystals
An ethereal solution of excessive diazomethane was added to a
solution of 0.31 g (1 mmol) of compound 21 in methanol (50 ml).
After vigorous evolution of nitrogen had ceased the solution was
evaporated to dryness and the residue crystallized from methanol.
Yield 0.27 g (90%), yellow crystals, mp 248°; ir: ν 3014, 1661,
-1
(methanol), mp > 280°; ir: ν 2976, 2836, 1703, 1603 cm ; uv: λ
1
max (log ε) 291 (4.447), 535 nm (3.769); H nmr: δ 11.34 (s, 1
+
H), 10.93 (s, 1 H), 7.78-7.25 (m, 8 H); ms: m/z 323 (M ).
Anal. Calcd. for C H ClN O (323.74): C, 63.07; H, 3.11;
17 10
3 2
-1
N, 12.98. Found: C, 62.13; H, 2.98; N, 12.01.
1643, 1589 cm ; uv: λ max (log ε) 259 (4.235), 427 nm (4.522);
1
H nmr: δ 14.27 (s, 1 H), 11.65 (s, 1 H), 7.54-7.30 (m, 10 H), 3.81
1,3-Dimethoxy-4-phenylpyrido[3,4-b]quinoxaline (19a).
+
(s, 3 H); ms: m/z 321 (M ).
An ethereal solution of excessive diazomethane was added to a
solution of 0.14 g (0.5 mmol) of compound 18a in acetone (25
ml) and methanol (25 ml). After 5 hours the solvent was evapo-
rated and the residue purified by column chromatography using
diethyl ether as eluent. Yield 0.11 g (70%), orange crystals (ethyl
Anal. Calcd. for C H N O (321.33): C, 67.28; H, 4.70; N,
13.07. Found: C, 67.34; H, 4.92; N, 12.97.
18 15
3 3
4-Hydroxy-5-phenylpyridine-2,3,6-trione-3-oxime (22a).
A solution of 0.22 g (1 mmol) of compound 11a and 0.21 g (3
mmol) of hydroxylamine hydrochloride in methanol (20 ml) was
heated at reflux for 30 minutes. The solvent was evaporated and
the residue extracted with acetone (20 ml). The solution obtained
was filtered and again freed of the solvent. The residue crystal-
lized from diisopropyl ether/ethanol 1:1. Yield 0.12 g (50%), yel-
-1
acetate); mp 249°; ir: ν 2944, 1618, 1587, 1521 cm ; uv: λ max
1
(log ε) 275 (4.610), 472 nm (3.647); H nmr (CDCl ): δ 8.29 (d,
3
1 H, J = 8.4 Hz), 8.05 (d, 1 H, J = 8.4 Hz), 7.64-7.43 (m, 7 H),
+
4.39 (s, 3 H), 4.10 (s, 3 H); ms: m/z 317 (M ).
Anal. Calcd. for C H N O (317.35): C, 71.91; H, 4.76; N,
19 15
3 2
-1
13.24. Found: C, 71.62; H, 4.70; N, 13.11.
low crystals, mp 191°; ir: ν 3171, 3028, 2844, 1662 cm ; uv: λ
1
max (log ε) 253 (4.121), 366 nm (3.606); H nmr: δ 11.51 (s, 1
4-(4-Chlorophenyl)-1,3-dimethoxypyrido[3,4-b]quinoxaline
(19b).
+
H), 10.61 (s, 1 H), 7.36-732 (m, 5 H); ms: m/z 232 (M ).
Anal. Calcd. for C H N O (232.19): C, 56.90; H, 3.47; N,
11
8 2 4
This compound was prepared analogously to 19a from 0.16 g
(0.5 mmol) of compound 18b. Yield 0.13 g (75%), orange crys-
tals (diisopropyl ether/ethanol 1:1), mp 248°; ir: ν 2938, 1618,
12.06. Found: C, 56.60; H, 3.89; N, 11.97.
5-(4-Chlorophenyl)-4-hydroxy pyridine-2,3,6-trione-3-oxime (22b).
-1
1586, 1518 cm ; uv: λ max (log ε) 272 (4.561), 470 nm
This compound was prepared analogously to 22a from 0.25 g
(1 mmol) of compound 11b. Yield 0.16 g (60%), yellow crystals
(diisopropyl ether/ethanol 1:1), mp 183°; ir: ν 3154, 3022,
1
(3.585); H nmr (CDCl ): δ 8.30 (d, 1 H, J = 8.5 Hz), 8.04 (d, 1
3
H, J = 8.5 Hz), 7.80-7.46 (m, 8 H), 4.39 (s, 3 H), 4.11 (s, 3 H);
+
-1
ms: m/z 351 (M ).
2841, 1680, 1660 cm ; uv: λ max (log ε) 255 (4.285), 368 nm
1
Anal. Calcd. for C H ClN O (351.79): C, 64.87 ; H, 4.01;
(3.634); H nmr: δ 11.52 (s, 1 H), 10.79 (s, 1 H), 7.40-7.35 (m,
19 14
3 2
+
N, 11.94. Found: C, 65.03; H, 3.98; N, 11.69.
4 H); ms: m/z 266 (M ).

68
H. Poschenrieder, H.-D. Stachel, B. Wiesend and K. Polborn
Vol. 40
Anal. Calcd. for C H ClN O (266.64): C, 49.55; H, 2.64; N,
6-Hydroxy-4-methoxy-6-phenyl-1,6-dihydropyridine-2,5-dione
11
7
2 4
(26b).
10.50. Found: C, 48.82; H, 2.94; N, 10.33.
This compound was prepared analogously to 26a from 0.39 g
(1.8 mmol) of compound 25b [19]. Eluent: chloroform/methanol
10:1. Yield 0.19 g (45%), colorless powder (diisopropyl
ether/methanol 1:1), mp 151°; ir: ν 3320, 3060, 1705, 1650, 1605
4-Methoxy-5-phenylpyridine-2,3,6-trione-3-oxime (23a).
This compound was prepared analogously to 22a from 0.24 g
(1 mmol) of compound 14a and 0.14 g (2 mmoles) of hydroxy-
lamine hydrochloride. Yield 0.10 g (40%), light yellow crystals
(diisopropyl ether/ethanol 1:1), mp 180° (dec); ir: ν 3038, 1668,
-1
1
cm ; uv: λ max (log ε) 208 (4.129), 258 nm (4.003); H nmr
(CDCl ): δ 8.83 (broad s, 1 H), 7.42 (s, 5 H), 7.30 (s, 1 H), 6.03
3
-1
1590 cm ; uv: λ max (log ε) 225 (4.082), 262 (4.083), 338 nm
+
(d, 1 H, J = 2 Hz), 3.73 (s, 3 H); ms: m/z 233 (M ).
1
(3.669); H nmr (CDCl ): δ 8.33 (s, 1 H), 7.50-7.30 (m, 5 H),
3
Anal. Calcd. for C H NO (233.23): C, 61.80; H, 4.75; N,
12 11
4
+
3.73 (s, 3 H); ms: m/z 246 (M ).
6.01. Found: C, 61.69; H, 4.85; N, 6.10.
Anal. Calcd. for C H N O (246.22): C, 58.54; H, 4.09; N,
12 11
2 4
6-Acetoxy-4-methoxy-2,5-dioxo-6-phenyl-1,2,5,6-tetrahydropy-
ridine-3-carboxylic Acid Methyl Ester (27a).
11.37. Found: C, 58.19; H, 3.99; N, 10.73.
4-Hydroxy-5-phenyl-pyridine-2,3,6-trione-3-(O-methyloxime)
(24a).
A solution of 0.30 g (1 mmol) of compound 26a and 0.12 g
(1.5 mmol) of pyridine in acetic anhydride (10 ml) was stirred at
room temperature for 1 hour. The solvent was removed com-
pletely in vacuo at 45° by repeating the evaporation several times
after addition of small amounts of benzene. The solution of the
reddish residue in diethyl ether (5 ml) containing two drops of
acetic acid was kept in the refrigerator for crystallization. Yield
0.25 g (73%), colorless crystals (diisopropyl ether/methanol 1:1),
mp 120° (dec, with red color); ir: ν 3180, 3060, 2930, 1745,
A solution of 0.22 g (1 mmol) of compound 11a and 0.25 g (3
mmol) of O-methylhydroxylamine hydrochloride in methanol
(20 ml) were heated at reflux for one hour. The solvent was evap-
orated, the residue extracted with ethyl acetate (20 ml) and the
solution obtained filtered. The product crystallized in the refrig-
erator as a mixture of syn/anti isomers. Yield 0.06g (25%), yel-
low crystals (ethyl acetate), mp 193-195°; ir: ν 3186, 1707, 1660,
-1
1
1572 cm ; uv: λ max (log ε) 262 (4.271), 365 nm (3.754); H
-1
1
1720, 1165 cm ; uv: λ max (log ε) 267 nm (4.218); H nmr
nmr (CDCl ): δ 9.05 (s, 0.75 H), 8.15 (s, 0.25 H), 7.42-7.37 (m,
3
(CDCl ): δ 9.00 (s, 1 H), 7.73-7.27 (m, 5 H), 3.90 (s, 6 H), 2.20
3
+
5H), 4.41 (s, 2.25 H), 4.37 (s, 0.75 H); ms: m/z 246 (M ).
+
(s, 3 H); ms: m/z 333 (M ).
Anal. Calcd. for C H N O (246.22): C, 58.54; H, 4.09; N,
12 10
2 4
Anal. Calcd. for C H NO (333.30): C, 57.66; H, 4.54; N,
16 15
7
11.37. Found: C, 58.37; H, 4.34; N, 11.30.
4.20. Found: C, 57.44; H, 4.67; N, 4.20.
5-(4-Chlorophenyl)-4-hydroxypyridine-2,3,6-trione-3-(O-
methyloxime) (24b).
Acetic Acid 4-Methoxy-3,6-dioxo-2-phenyl-1,2,3,6-tetrahy-
dropyridin-2-yl Ester (27b).
This compound was prepared analogously to 24a from 0.25 g
(1 mmol) of compound 11b. Yield 0.08 g (30%) as a mixture of
syn/anti isomers; the more soluble isomer was removed by
recrystallization from ethyl acetate.Yellow crystals, mp 220°
This compound was prepared analogously to 27a from 0.30 g
(1.3 mmol) of compound 26b. Yield 0.21 g (58 %), colorless
crystals (diisopropyl ether/methanol 1:1), mp 145° (dec, with red
-
color); ir: ν 3170, 3040, 2930, 2890, 1730, 1710, 1650, 1605 cm
-1
(dec); ir: ν 3353, 3191, 3083, 1724, 1698 cm ; uv: λ max (log ε)
1
1
; uv: λ max (log ε) 264 nm (4.216); H nmr (CDCl ): δ 8.50
3
1
259 (4.284), 3.66 nm (3.782); H nmr (CDCl ): δ (CDCl ): 9.12
3
3
(broad s, 1H), 7.83-730 (m, 5 H), 6.00 (d, 1 H, J = 2 Hz), 3.80 (s,
(s, 1 H), 8.11 (s, 1 H), 7.40-7.35 (m, 4 H), 4.42 (s, 3 H); ms: m/z
+
3 H), 2.20 (s, 3 H); ms: m/z 275 (M ).
+
280 (M ).
Anal. Calcd. for C H NO (275.26 ): C, 61.09; H, 4.76; N,
14 13
5
Anal. Calcd. for C H ClN O (280.67): C, 51.35; H, 3.23; N,
12
9
2 4
5.09. Found: C, 60.62; H, 4.81; N, 5.31.
9.98. Found: C, 51.86; H, 3.40; N, 10.07.
4-Methoxy-2,5-dioxo-6-phenyl-2,5-dihydropyridine-3-car-
boxylic Acid Methyl Ester (28a).
6-Hydroxy-4-methoxy-2,5-dioxo-6-phenyl-1,2,5,6-tetrahydropy-
ridine-3-carboxylic Acid Methyl Ester (26a).
Compound 27a (0.1 g, 0.4 mmol) was heated to 120° in vacuo
A solution of 0.50 g (1.8 mmol) of compound 25a [19] and
0.45 g (2 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in dioxane (20 ml) was heated at reflux for 10 minutes.
After 1 hour at room temperature the hydroquinone had separated
from the red solution. After filtration the solvent was evaporated
and the residue purified by column chromatography using diethyl
ether (containing water) as eluent. Yield 0.20 g (38%), light yel-
low crystals (diisopropyl ether/methanol 1:1); mp 155°; ir: ν
for 48 hours. Quantitative yield, light red powder, mp 149°; uv
(CH Cl ): λ max (log ε) 233 (4.188), 337 (3.971), 512 nm
2
2
1
(3.002); H nmr (CDCl ): δ 8.33–8.10 (m, 2 H), 7.76-7.30 (m, 3
3
H), 4.13 (s, 3 H), 3.98 (s, 3 H).
4-Methoxy-6-phenylpyridine-2,5-dione (28b).
Compound 27b (0.1 g, 0.5 mmol) was heated to 140° in vacuo
for 5 hours and then held at 120° for 40 hours. Yield quantitative,
-1
3346, 3251, 1731, 1650, 1621 cm ; uv: λ max (log ε) 207
dark red powder, mp 146°; uv (CH Cl ): λ max (log ε) 232
2
2
1
1
(4.171), 260 nm (4.011); H nmr: δ 9.29 (s, 1 H), 7.50 (s, 1 H),
(4.206), 328 (3.982), 515 nm (2.968); H nmr (CDCl ): δ 8.21-
3
7.46-7.38 (m, 5 H), 3.80 (s, 3 H), 3.77 (s, 3 H); 13C nmr: 189.3
(C-5), 163.3, 160.5 (C-2), 151.0, 138.6 (C-1´), 128.6 (C-4´),
128.1 (C-3´), 126.3 (C-2´), 120.1 (C-3), 84.3 (C-6), 58.9, 52.6;
CH-COSY: H-1/C-3, H-1/C-5, H-2´/C-6; NOE: H-1/H-2'. ms:
7.97 (m, 2 H), 7.63-7.25 (m, 3 H), 6.27 (s, 1 H), 3.88 (s, 3 H).
(4-Methoxy-5-methoxycarbonyl-3,6-dioxo-2-phenyl-1,2,3,6-
tetrahydro-yridin-2-yl)-malonic Acid Dimethyl Ester (29).
+
m/z 291 (M , 1%), 105 (100).
A solution of 0.83 g (2.5 mmol) of compound 27a, 0.35 g (2.6
mmol) of dimethyl malonate and 0.5 ml of pyridine in toluene (10
ml) was heated to 80° for one hour. From the now colorless
Anal. Calcd. for C H NO (291.26): C, 57.73; H, 4.50; N,
14 13
6
4.81. Found: C, 57.43; H, 4.49; N, 4.58.

Jan-Feb 2003
New Azabenzoquinones by Ring-expansion Reactions
69
Ashworth, Tetrahedron, 32, 261 (1976).
[8] J. H. Boyer and S. Kruger, J. Am. Chem. Soc., 79, 3552
(1957).
[9] S. Radl, in: Advances in Heterocyclic Chemistry, Vol. 61,
ed. A. R. Katritzky, Academic Press, San Diego/ New York 1994, p
141.
[10] J. Backhaus, Ph. D. Dissertation, Universität Bonn,
Germany, 1979.
[11] M. Gill and, W. Steglich, in: Progress in the Chemistry of
Organic Natural Products, Vol. 51, W. Herz, H. Grisebach, G. W.
Kirby, C. Tamm, ed., Springer Verlag, Wien/ New York, 1987, p 231
– 235.
solution the volatile components were removed in vacuo and the
residue crystallized from diisopropyl ether/methanol 1:1. Yield
0.66 g (65%), colorless crystals, mp 110°; ir: ν 3360, 3010, 2960,
-1
1745, 1705, 1675, 1630 cm ; uv: λ max (log ε) 212 (3.861), 260
1
nm (3.874); H nmr (CDCl ): δ 7.43 (s, 5 H), 5.05 (s, 1 H), 3.97 (s,
3
+
3 H), 3.93 (s, 3 H), 3.83 (s, 3 H), 3.60 (s, 3 H); ms: m/z 405 (M ).
Anal. Calcd. for C H NO (405.36): C, 56.30; H, 4.72; N,
19 19
9
3.46. Found: C, 56.28; H, 4.83; N, 3.25.
8-Methoxy-4-methyl-6,9-dioxo-9a-phenyl-9,9a-dihydro-4H,6H-
pyrido[2,1-b][1,3]oxazine-7-carboxylic Acid Methyl Ester (30).
A solution of 0.41 g (1.5 mmol) of compound 28a (freshly pre-
pared by thermolysis of 0.5 g of compound 27a) and 0.14 g (0.2
mmol) of 2-butenal in toluene (5 ml) was heated to 80° under
nitrogen until the red colour disappeared. The volatile compo-
nents were removed in vacuo and the residue was purified by col-
umn chromatography using chloroform/ethyl acetate as eluent.
Yield 0.25 g (45%), yellow crystals (diisopropyl ether/methanol
1:1), mp 125-129° (dec, with red color); ir: ν 3100, 3060, 2980,
[12] K. C. Nicolaou, S. Sugita, P. S. Baran and Y.-L. Zhong,
Angew. Chem., Int. Ed. Engl., 40, 207 (2001); Nicolaou, Y.-L. Zhong,
P. S. Baran and K. Sugita, Angew. Chem., Int. Ed. Engl., 40, 2145
(2001).
[13] T. Billert, R. Beckert, P. Feeling, M. Döring and H. Görls,
Tetrahedron, 53, 5455 (1997).
[14] M. Ozaki, Y. Ezure, T. Okubo, K. Yamane and S.
Matsumura, Heterocycles 11, 191 (1978).
[15] P. S. Bailey and W. Trahanovsky, in: Organic Chemistry,
Vol. 39, ed. A. T. Blomquist, H. H. Wasserman, Academic Press,
New York 1978, p 197 – 219.
-1
1745, 1720, 1670, 1650, 1630 cm ; uv: λ max (log ε); 212
1
(3.794), 260 nm (3.880); H nmr (CDCl ): δ 7.40 (s, 5 H), 6.36
3
(d, 1 H, J = 8.1 Hz), 5.00 (dd, 1 H, J = 8.1 Hz, J = 2.4 Hz), 4.33
[16] H. Poschenrieder and H.-D. Stachel, Arch. Pharm.
(Weinheim, Germany), 322, 301 (1989).
[17] G. A. Swan, J. Chem. Soc. Perkin Trans. I, 1757 (1985); P.
Ashwood, Tetrahedron, 32, 261 (1976).
(mc, 1 H), 3.90 (s, 3 H), 3.80 (s, 3 H), 1.52 (d, 3 H, J = 6.1 Hz);
+
ms: m/z 243 (M ).
Anal. Calcd. for C H NO (343.33 ): C, 62.97; H, 4.99; N,
18 17
6
4.08. Found: C, 63.16; H, 5.20; N, 4.00.
[18] R. Kuhn, H. Bauer and H.-J. Knackmuss., Chem. Ber., 98,
2139 (1965); A. J. Shand and R. H. Thomson, Tetrahedron, 19, 1919
(1963).
[19] H.-D. Stachel, B. Wiesend and C. Kreiner, J. Heterocyclic
Chem., 22, 1413 (1985).
REFERENCES AND NOTES
[1] W. Steglich, H. Besl and A. Prax, Tetrahedron Letters, 13,
4895 (1972); H.-J Lohrisch, L. Kopanski, R. Herrmann, H. Schmidt
and W. Steglich, Liebigs Ann. Chem., 177 (1986).
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Chem., 43, 1497 (1990).
[20] H. Poschenrieder, G. Höfner and H.-D. Stachel, Arch.
Pharm. Pharm. Med. Chem., 332, 309 (1999).
[21] M. Mawr, J. J. Kulagowski, P. D. Leeson, S. Grimwood
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(1964).
[3] G. Pattenden, N. A. Pegg and R. W. Kenyon, Tetrahedron
Letters, 28, 4779 (1987); G. Pattenden, N. A. Pegg and R. W.
Kenyon, J. Chem. Soc., Perkin Trans. I, 2363 (1991).
[4] H. Poschenrieder, E. Eckl, H.-D. Stachel, A. Windt and K.
Polborn, J. Heterocyclic Chem., 37, 839 (2000).
[5] H. Poschenrieder, G. Höfner and H.-D. Stachel, Arch.
Pharm. Pharm. Med. Chem., 333, 211 (2000).
[6] H.-J. Knackmuss, Chem. Ber., 101, 1148 (1968); H.-J.
Knackmuss, Chem. Ber., 101, 2679 (1968).
[23] G. M. Sheldrick, SHELXS-86, Universität Göttingen,
Germany, 1990.
[24] G. M. Sheldrick, SHELXL-93, Universität Göttingen,
Germany, 1993.
[25] L. Zolnay, G. Huttner, XPMA, ZORTEP, Universität
Heidelberg, Germany, 1994.
[26] Copies of the data can be obtained free of charge on
request to The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, Great Britain [fax: (+44) 1223-336-033;
email: deposit@ccdc.cam.ac.uk].
[7] H.-J. Knackmuss, Angew. Chem., 95, 163 (1973); P.