A novel approach for the synthesis of highly fluorescent pyrrolo[1,2-b]pyridazines

Article abstract of DOI:10.1055/s-2008-1042929

Pyrrolo[1,2-b]pyridazine derivatives were synthesized for the first time by 1,3-dipolar cycloaddition reaction between mesoionic 1,3-oxazolo[3,2-b] pyridazinium-2-oxides and acetylenic dipolarophiles. The isolation and characterization of the stable mesoionic oxazolo[3,2-b]pyridazines are also presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042929

LETTER
813
A Novel Approach for the Synthesis of Highly Fluorescent Pyrrolo[1,2-
b]pyridazines
A
N
ew Synthe
l
sis of
P
o
yrrolo[1,2-
b
r
]
pyridaz
e
a
Centre of Organic Chemistry ‘C. D. Nenitzescu’, Romanian Academy, Spl. Independentei 202B, 060023 Bucharest, Romania
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax +27(21)6897499; E-mail: Mino.Caira@uct.ac.za
b
Received 26 June 2007
N
N
Abstract: Pyrrolo[1,2-b]pyridazine derivatives were synthesized
for the first time by 1,3-dipolar cycloaddition reaction between me-
soionic 1,3-oxazolo[3,2-b]pyridazinium-2-oxides and acetylenic
dipolarophiles. The isolation and characterization of the stable me-
soionic oxazolo[3,2-b]pyridazines are also presented.
1
Figure 1 Unsubstituted pyrrolo[1,2-b]pyridazine
Key words: 1,3-dipolar cycloaddition, mesoionic oxazolopyr-
idazine, pyrrolo[1,2-b]pyridazines, Michael addition, hydrogena-
tion
mostly generated in situ in the presence of the dipolaro-
phile. The traditional Huisgen synthesis of münch-
nones,22a,b involving cyclodehydration of N-acylamino
acids, usually with acetic anhydride or other acid anhy-
drides, is still the method of choice due to its simplicity,
although other synthetic methods have since been discov-
ered.21a,b
Pyrrolopyridazine derivatives have various biological ap-
plications,1-6 and their fluorescent properties have been
investigated for potential uses in sensors, lasers, and semi-
conductor devices.7-11
The synthesis and properties of pyrrolo[1,2-b]pyridazine
derivatives were reviewed in 1977 by Kuhla and Lombar-
dino.12 Subsequently, new methods for the synthesis of
these compounds were described, which can be classified
into two main approaches. The first comprises condensa-
tion reactions, such as the condensation of oxazolo[3,2-
b]pyridazinium perchlorates with malonitrile, ethyl cyano
acetate and ethyl malonate in the presence of sodium
ethoxide,13 the condensation of 1,4,7-triketones with hy-
drazine followed by dehydrogenation,14 the condensation
of cyanacetic acid hydrazide with 3-bromo-1,1,3-tricy-
ano-2-phenylpropene,15 and the reaction between 3-chlo-
ropyridazines with propargylic alcohol in the presence of
a Pd(PPh3)2Cl2-CuI with diethylamine as the reaction
medium.16 The second path is based on cycloaddition re-
actions, such as the cycloaddition of dimethyl acetylene-
dicarboxylate to the Reissert compound of pyridazine,17
the 1,3-dipolar cycloaddition of pyridazinium dichloro-
methylide generated by the carbene method,18 and the cy-
cloaddition of alkylidene cyclopropane derivatives to
pyridazine in the presence of Pd(PPh3)4.19 Unsubstituted
pyrrolo[1,2-b]pyridazine 1 was obtained by Flitsch and
Kramer (Figure 1).20
A survey of the literature indicated that mesoionic oxazo-
lo[3,2-b]pyridazin-2-ones and their reactions leading to
pyrrolo[1,2-b]pyridazines have not been reported to date.
Herein we report a new method for the synthesis of highly
fluorescent pyrrolo[1,2-b]pyridazines, namely 1,3-dipolar
cycloaddition between mesoionic oxazolo[3,2-b]pyr-
idazine-2-ones and dimethyl acetylenedicarboxylate
(DMAD) as dipolarophile.
The starting materials for the synthesis of pyrrolo[1,2-
b]pyridazine derivatives were 3(2H)-pyridazinone acetic
acids 2a-d and propanoic acids 6a-d, respectively
(structures in Scheme 1). The compounds 2 and 6 were
easily prepared by a documented procedure23a-f consisting
of an N-alkylation of 3(2H)-pyridazinones24a-d with esters
of bromoacetic and bromopropanoic acid followed by al-
kaline hydrolysis.
The synthesis of pyrrolopyridazines was performed by
treatment of acids 2a-d with DMAD in acetic anhydride
at 90 °C for three hours. By this method the new com-
pounds 5a-d were obtained in good yield (53-60%) as
yellow crystals which showed high fluorescence both in
solution and in the solid state (Scheme 1). The mechanism
involves the generation in the first step of the previously
unknown mesoionic structures 3 by cyclodehydration of
acids 2 through the action of acetic anhydride. Under re-
action conditions the intermediate adducts 4, resulting
from mesoionic 1,3-dipole and dipolarophile (DMAD),
lose carbon dioxide giving fused pyrroles 5. The elemen-
tal analysis and NMR spectroscopy confirmed the struc-
ture of the compounds 5.25
One of the most versatile synthetic routes for obtaining
pyrroles, fused pyrroles, and derived ring systems is via
1,3-dipolar cycloaddition reactions between acetylenic di-
polarophiles and mesoionic oxazolones, so called münch-
nones.21a-g Due to their usually low stability, they are
SYNLETT 2008, No. 6, pp 0813–0816
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042929; Art ID: D19107ST
© Georg Thieme Verlag Stuttgart · New York

814
F. Dumitraşcu et al.
LETTER
It is interesting to note that under similar reaction condi- of 6.5 Hz. These values for 3JC–H provide strong evidence
tions and in the absence of DMAD from the acetic acid an- for a trans configuration of the alkene moiety. The corre-
hydride medium, the mesoionic compounds 3b and 3d, lation method between the values of 3JC–H and configura-
were isolated as yellow precipitates. The mesoionic struc- tion was successfully applied in the case of trisubstituted
ture was assigned on the basis of NMR spectroscopy.26 alkenes and buten-2-ene-1,4-dioates substituted in the 2-
1
Thus, in the H NMR spectra, the presence of a methyl position with an aryl or pyrrole ring.28g,29a-c
group grafted to the 3-position of the oxazole ring is evi-
denced by a singlet and the two protons of the pyridazine
It must be mentioned that the mesoionic compounds 8a-
d are more stable in protic solvents (e.g., water or metha-
moiety by two doublets. The most characteristic feature in
nol) than their analogues containing a methyl group in the
the 13C NMR spectra for the mesoionic structure is the
oxazole moiety (3b and 3d). The optical properties of me-
strongly shielded signal for methyl groups (d = 6.9 ppm
and 7.0 ppm), as well as the presence of the deshielded (to
ca. d = 160 ppm) signals attributed to the mesoionic car-
bonyl group. The values of chemical shifts for the methyl
groups in the 13C NMR spectra of compounds 3b and 3d
are close to those from pyrrolopyridazine 5. This repre-
sents good evidence that the methyl radical is grafted to
the C-3 carbon atom of the five-membered heteroaromatic
ring.
soionic oxazolones 8 were recently reported.30a,b
The chemical properties of pyrrolopyridazines include the
transformation of the functional groups substitution and
oxidation reactions.12,28c Herein we report their selective
hydrogenation (Scheme 2). The reduction was performed
with Zn in AcOH under reflux to give 3,4-dihydroderiva-
tives 9a-c.31
R1
R1
The münchnones generated from 2-[2(3H)pyridazin-1-
yl]acetic acids 6a-d, under similar reaction conditions,
reacted with DMAD via two parallel routes (Scheme 1).
The resulting mixture consisted of the expected pyrrol-
opyridazine derivatives 7a-d along with variable
amounts of mesoionic oxazolo[3,2-b]pyridazin-2-ones
8a-d.27 The formation of these latter compounds could be
explained by the Michael addition of DMAD to the me-
soionic münchnone ring in the 3-position. The Michael
addition is well known in the series of pyrrole and con-
densed pyrrole derivatives,28a-g but to our knowledge
there are no such examples in the class of münchnones.
N
N
N
N
Zn, AcOH
R2
R2
MeO2C
MeO2C
CO2Me
CO2Me
9a–c
5a, 7b,c
a: R1 = R2 = Me; b: R1 = Ph, R2 = H; c: R1 = 4-MeC6H4, R2 = H
Scheme 2 Reductive hydrogenation of pyrrolo[1,2-b]pyridazines
The stereostructure for a representative compound in this
series (9b, R1 = Ph, R2 = H) was determined by X-ray
crystal structure analysis32 which showed that in the novel
6,5-bicyclic system present, the ring N1 → C6 has a con-
formation between that of a half-chair and a twist boat
(Figure 2). Endocyclic torsion angles (average e.s.d. 0.2°)
The assignment of the configuration of the Michael ad-
ducts 8 was deduced from the off-resonance spectrum of
compound 8a on the basis of the 3JC–H coupling constant.
3
The value of the J constant between H-10 and C-9 is
3
found to be 11.5 Hz, whereas JC-3–H-10 presented a value
R
R
R
R
R
N
N
N
N
N
Ac2O
90 °C
DMAD
N
N
N
N
_
+
Me
N
+
Me
Me
– CO2
Me
Me
COOH
O
O
O
O
_
MeO2C
MeO2C
O
O
CO2Me
O
CO2Me
2a–d
3A
3B
4
5a–d
R
R
R
_
R
R
Ac2O
90 °C
N
N
DMAD
N
N
7
N
N
N
N
N
H
COOMe
10
+
+
+
– CO2
N
9
H
8
H
H
H
3
COOH
H
O
O
O
O
1
2
_
COOMe
MeO2C
MeO2C
O
O
CO2Me
O
CO2Me
6a–d
7a–d
3
8a–d
4
a: R = Me; b: R = Ph; c: R = 4-MeC6H4; d: R = 4-ClC6H4
Scheme 1 Synthesis of pyrrolo[1,2-b]pyridazines
Synlett 2008, No. 6, 813–816 © Thieme Stuttgart · New York

LETTER
A New Synthesis of Pyrrolo[1,2-b]pyridazines
815
(8) Mitsumori, T.; Bednikov, M.; Sedo, J.; Wudl, F. Chem.
Mater. 2003, 15, 3759.
(9) Mitsumori, T.; Craig, I. M.; Martini, I. B.; Schwartz, B. J.;
Wudl, F. Macromolecules 2005, 38, 4698.
(10) Swamy, K. M. K.; Park, M. S.; Han, S. J.; Kim, S. K.; Kim,
J. H.; Lee, C.; Bang, H.; Kim, Y.; Kim, S.-J.; Yoon, J.
Tetrahedron 2005, 61, 10227.
(11) Zbancioc, G. N.; Mangalagiu, I. I. Synlett 2006, 804.
(12) Kuhla, D. E.; Lombardino, J. G. Adv. Heterocycl. Chem.
1977, 21, 50.
(13) Satoh, K.; Miyasaka, T.; Arakawa, K. Yakugaku Zasshi
1977, 97, 422.
(14) Stetter, H.; Landscheidt, A. J. Heterocycl. Chem. 1979, 16,
839.
(15) Abdelrazek, F. M. Synth. Commun. 2005, 35, 2251.
(16) (a) Ohsawa, A.; Abe, Y.; Igeta, H. Bull. Chem. Soc. Jpn.
1980, 53, 3273. (b) Ohsawa, A.; Abe, Y.; Igeta, H. Chem.
Pharm. Bull. 1980, 28, 3488.
(17) Khlebnikov, A. F.; Kostik, E. I.; Kostikov, R. R. Synthesis
1993, 568.
(18) Veeraraghavan, S.; Bhattacharjee, D.; Popp, F. D.
J. Heterocycl. Chem. 1981, 18, 443.
(19) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y. J. Org.
Chem. 2004, 69, 3202.
(20) Flitsch, W.; Kramer, U. Tetrahedron Lett. 1968, 12, 1479.
(21) For reviews on mesoionic compounds including
münchnones, see: (a) Palmer, D. C. In Oxazoles: Synthesis,
Reactions and Spectroscopy, Part A; John Wiley and Sons:
New Jersey, 2003, 473–576. (b) Gribble, G. W. In Synthetic
Applications of Dipolar Cycloaddition Chemistry towards
Heterocycles and Natural Product; Padwa, A.; Pearson, W.
H., Eds.; John Wiley and Sons: New York, 2002, 681–754.
(c) Potts, K. T. In 1,3-Dipolar Cycloaddition Chemistry,
Vol. 2; Padwa, A., Ed.; Wiley: New York, 1984, 1–81.
(d) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A.
Tetrahedron 1985, 41, 2239. (e) Ramsden, C. A.; Newton,
C. G. Tetrahedron 1982, 38, 2965. (f) Ramsden, C. A. In
Comprehensive Organic Chemistry, Vol. 4; Barton, D. H.
R.; Ollis, W. D., Eds.; Academic Press: New York, 1979,
1171–1228. (g) Ollis, W. D.; Ramsden, C. A. Adv.
Heterocycl. Chem. 1976, 19, 1.
Figure 2 X-ray crystal structure of 9b (R1 = Ph, R2 = H) with ther-
mal ellipsoids drawn at the 50% level
defining the exact conformation are included in Figure 2.
As found in 2-(4-chlorophenyl)-7-methyl-pyrrolo[1,2-
b]pyridazine,33 the phenyl group in 9 is not coplanar with
the pyrrolopyridazine moiety. Here, the angle between the
least-squares planes through the phenyl and pyrrole rings
is 27.3(1)°.
(22) (a) Huisgen, R.; Gotthardt, H.; Bayer, H. O. Angew. Chem.,
Int. Ed. Engl. 1964, 3, 135. (b) Huisgen, R.; Gotthardt, H.;
Bayer, H. O. Chem. Ber. 1970, 103, 2356.
Acknowledgment
(23) (a) King, J. A.; McMillan, F. H. J. Am. Chem. Soc. 1952, 74,
3222. (b) McMillan, F. H.; McMillan, G. B.; Kun, K. A.;
King, J. A. J. Am. Chem. Soc. 1956, 78, 407. (c) McMillan,
F. H.; McMillan, G. B.; Kun, K. A.; King, J. A. J. Am. Chem.
Soc. 1956, 78, 2642. (d) Sayed, A. A.; Jahine, H.; Zaher, H.-
A.; Sherif, O. Indian J. Chem. 1975, 13, 1142. (e) Ismail,
M. F.; Shams, N. A.; Abdel Rahman, S. E.; Fateen, A. K.
Rev. Roum. Chim. 1979, 24, 899. (f) Jahine, H.; Zaher, H.
A.; Akhnookh, Y.; El-Gendy, Z. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1978, 16, 1000.
(24) (a) Tišler, M.; Stanovnik, B. Adv. Heterocycl. Chem. 1968,
9, 211. (b) Tišler, M.; Stanovnik, B. Adv. Heterocycl. Chem.
1979, 24, 365. (c) Tišler, M.; Stanovnik, B. Adv. Heterocycl.
Chem. 1990, 49, 385. (d) Csende, F.; Szabo, Z.; Bérnath, G.;
Stáger, G. Synthesis 1995, 1240.
(25) General Procedure for the Synthesis of Compounds 5
3 (2H)-Pyridazinone acid 2 (5 mmol) were suspended with
stirring in Ac2O (5 mL) and then DMAD (5.5 mmol) was
added.The reaction mixture was kept at ca. 90 °C for 3-4 h.
The pyrrolopyridazine derivatives 5 were isolated by
filtration or by evaporation of the solvent. In the latter case,
the crude product was purified by recrystallization or by
column chromatography using CH2Cl2 as eluent.
M.R.C. thanks the University of Cape Town for research support.
References and Notes
(1) Ruxer, J. M.; Lachoux, C.; Ousset, J. B.; Torregrosa, J. L.;
Mattioda, G. J. J. Heterocycl. Chem. 1994, 31, 409.
(2) Ungureanu, M.; Mangalagiu, I.; Grosu, G.; Petrovanu, M.
Ann. Pharm. Fr. 1997, 55, 69.
(3) Nasir, A. I.; Gundersen, L.-L.; Rise, F.; Antonsen, Ø.;
Kristensen, T.; Langhelle, B.; Bast, A.; Custers, I.; Haenen,
G. R. M. M.; Wikström, H. Bioorg. Med. Chem. Lett. 1998,
8, 1829.
(4) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast,
A.; Haenen, G. R. M. M. Eur. J. Org. Chem. 2000, 3763.
(5) Østby, O. B.; Gundersen, L.-L.; Rise, F.; Antonsen, Ø.;
Fosnes, K.; Larsen, V.; Bast, A.; Custers, I.; Haenen, G. R.
M. M. Arch. Pharm. Pharm. Med. Chem. 2001, 334, 21.
(6) (a) Ohtani, M.; Fuji, M.; Fukui, Y.; Adachi, M. WO 059999,
1999. (b) Salvati, M. E.; Illig, C. R.; Wilson, K. J.; Chen, J.;
Meegalla, S. K.; Wall, M. J. US 7030112, 2006. (c) Fu, J.-
M. US 7074791, 2006.
(7) Cheng, Y.; Ma, B.; Wudl, F. J. Mater. Chem. 1999, 9, 2183.
Synlett 2008, No. 6, 813–816 © Thieme Stuttgart · New York

816
F. Dumitraşcu et al.
LETTER
Dimethyl 2,7-Dimethylpyrrolo[1,2-b]pyridazine-5,6-
dicarboxylate (5a)
113.1 (C-8), 121.5 (C-7), 135.6 (C-9), 140.8 (C-8a), 155.4
(C-6), 156.8 (2-CO), 166.1, 166.7 (2 COO). Off-resonance
NMR experiment: JC-3–H-10 = 6.3 Hz; J9-CO–H-10 = 11.5 Hz.
(28) (a) Pleininger, H.; Wild, D. Chem. Ber. 1966, 99, 3070.
(b) Fried, F.; Taylor, J. B.; Westwood, R. J. Chem. Soc.,
Chem. Commun. 1971, 226. (c) Kon Thoo Lin, P. V. S.;
Buchan, R.; Fraser, M.; McHattie, D. Heterocycles 1990, 31,
1459. (d) Tighineanu, E.; Răileanu, D. Rev. Roum. Chim.
1992, 37, 1307. (e) Tighineanu, E.; Răileanu, D.; Simonov,
Yu.; Bouroş, P. Tetrahedron 1996, 52, 12475. (f) Cavdar,
H.; Saracoglu, N. J. Org. Chem. 2006, 71, 7793. (g) Jones,
R. A.; Sepulveda Arques, J. Tetrahedron 1981, 37, 1597.
(29) (a) Vogeli, U.; von Philipsborn, W. Org. Magn. Reson. 1975,
7, 617. (b) Barillier, D.; Strobel, M. P.; Morin, L.; Paquer, D.
Tetrahedron 1983, 39, 767. (c) Gregory, B.; Hinz, W.;
Jones, R. A.; Sepulveda Arques, J. J. Chem. Res., Synop.
1984, 311.
Colorless crystals from EtOH with mp 135-136 °C; yield
60%. Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N,
10.68. Found: C, 59.87; H, 5.70; N, 10.93. 1H NMR (300
MHz, CDCl3): d = 2.52 (s, 3 H, 2-Me), 2.61 (s, 3 H, 7-Me),
3.89, 3.95 (2 s, 6 H, 2 MeO), 6.76 (d, 1 H, J = 9.3 Hz, H-3),
8.27 (d, 1 H, J = 9.3 Hz, H-4). 13C NMR (75 MHz, CDCl3):
d = 9.7 (7-Me), 21.8 (2-Me), 51.3, 52.2 (2 MeO), 101.6 (C-
5), 116.3 (C-3), 117.7, 127.6, 128.3 (C-4a, C-6, C-7), 127.5
(C-4), 152.4 (C-2), 163.8, 166.3 (2 COO).
(26) General Procedure for the Synthesis of Compounds 3
Acid 6b or 6d (1 g) in Ac2O (3 mL) was kept at ca. 90 °C for
3 h. The yellow precipitate was filtered and washed with
Ac2O and then with anhyd Et2O.
3-Methyl-6-phenyloxazolo[3,2-b]pyridazinium-2-oxide
(3b)
Yellow crystals from Ac2O with mp 199–202 °C; yield 72%.
Anal. Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38.
Found: C, 69.43; H, 4.78; N, 12.70. 1H NMR (300 MHz,
CDCl3): d = 2.36 (s, 3 H, 3-Me), 7.31, 7.36 (2 d, 2 H, J = 8.8
Hz, H-7, H-8), 7.48–7.53, 7.89–7.94 (2 m, 5 H, H-2¢, H-3¢,
H-4¢, H-5¢, H-6¢). 13C NMR (75 MHz, CDCl3): d = 6.9 (3-
Me), 94.7 (C-3), 110.0, 112.3 (C-7, C-8), 126.7, 129.0 (C-2¢,
C-3¢, C-5¢, C-6¢), 130.2 (C-4¢) 134.6 (C-1¢), 138.4 (C-8a),
153.9 (C-6), 160.4 (2-CO).
(30) (a) Vasilescu, M.; Dumitraşcu, F.; Lemmetyinen, H.;
Tkachenko, N. J. Fluoresc. 2004, 14, 443. (b) Vasilescu,
M.; Dumitraşcu, F.; Bandula, R.; Drăghici, C.;
Lemmetyinen, H. Rev. Roum. Chim. 2004, 49, 905.
(31) General Procedure for the Synthesis of Compounds 9
Esters 5 or 6 (2 mmol) were dissolved in AcOH (10 mL) and
under reflux was added Zn powder (3 mmol) over a period
of 3 h. The reaction was monitored by 1H NMR or TLC. In
the case when the reaction was found to be incomplete, Zn
(1 mmol) was added and refluxing was continued for ca. 2 h.
The hot reaction mixture was filtered and the precipitate was
washed with AcOH. The AcOH was removed and the
residue was purified by column chromatography.
(27) General Procedure for the Synthesis of 7 and 8
The experimental procedure for compounds 7 and 8 was
similar to those for pyrrolopyridazines 5. The two
compounds were isolated by column chromatography using
neutral alumina (Merck 200–20 mesh) and CH2Cl2 as eluent.
Dimethyl 2-Methylpyrrolo[1,2-b]pyridazine-5,6-
dicarboxylate (7a)
Dimethyl 2-Phenyl-3,4-dihydropyrrolo[1,2-b]pyri-
dazine-5,6-dicarboxylate (9b)
Colorless crystals from EtOH with mp 145–147 °C; yield
77%. Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N,
8.97. Found: C, 65.72; H, 5.33; N, 9.21. 1H NMR (300 MHz,
CDCl3): d = 2.92 (t, 2 H, J = 8.1, 8.0 Hz, 3-CH2), 3.26 (t, 2
H, J = 8.1, 8.0 Hz, 4-CH2), 3.84, 3.87 (2 s, 6 H, 2 MeO),
7.46-7.48 (m, 3 H, H-3¢, H-4¢, H-5¢), 7.54 (s, 1 H, H-7),
7.85–7.88 (m, 2 H, H-2¢, H-6¢). 13C NMR (75 MHz, CDCl3):
d = 17.5 (4-CH2), 21.2 (3-CH2), 51.4, 51.5 (2 MeO), 109.7,
113.9, 127.2 (C-4a, C-5, C-6), 125.5 (C-7), 126.4, 128.7 (C-
2¢, C-3¢, C-5¢, C-6¢), 131.0 (C-4¢), 135.2 (C-1¢), 160.0 (C-2),
164.0, 165.5 (2 COO).
Colorless crystals from EtOH with mp 89–91 °C; yield 22%.
Anal. Calcd for C12H12N2O4: C, 58.06; H, 4.87; N, 11.29.
Found: C, 59.34; H, 5.21; N, 10.50. 1H NMR (300 MHz,
CDCl3): d = 2.52 (s, 3 H, 2-Me), 3.91, 3.92 (2 s, 6 H, 2 MeO),
6.75 (d, 1 H, J = 9.3 Hz, H-3), 7.92 (s, 1 H, H-7), 8.26 (d, 1
H, J = 9.3 Hz, H-4). 13C NMR (75 MHz, CDCl3): d = 21.7
(2-Me), 51.4, 52.1 (2 MeO), 103.4 (C-5), 117.3 (C-3), 117.9,
128.7 (C-4a, C-6, C-7), 121.0 (C-7), 128.2 (C-4), 153.4 (C-
2), 163.7, 164.5 (2 COO).
Dimethyl 3-[(E)-(Buten-2-yl-1,4-dioate)]-6-
methyloxazolo[3,2-b]pyridazinium-2-oxide (8a)
Yellow crystals from MeCN with mp 180-183 °C; yield
39%. Anal. Calcd for C13H12N2O6: C, 53.43; H, 4.14; N,
9.59. Found: C, 53.59; H, 4.33; N, 9.74. 1H NMR (300 MHz,
CDCl3): d = 2.65 (s, 3 H, 6-Me), 3.76, 3.99 (2 s, 6 H, 2 MeO),
6.97 (s, 1 H, =CHCOO), 7.21 (d, 1 H, J = 8.8 Hz, H-7), 7.45
(d, 1 H, J = 9.3 Hz, H-8). 13C NMR (75 MHz, CDCl3): d =
21.6 (6-Me), 51.7, 52.9 (2 MeO), 94.2 (C-3), 109.5 (C-10),
(32) Crystal data for 9b (R1 = Ph, R2 = H): C17H16N2O4; colorless
plate; M = 312.32, orthorhombic, Pbca, a = 8.1844(2) Å,
b = 13.4925(3) Å, c = 27.0683(6) Å, V = 2989.1(1) Å3,
Z = 8, T = 113(2) K, F000 = 1312, R1 = 0.0440,
wR2 = 0.1089. The CCDC deposition number is 651836.
(33) Caira, M. R.; Dumitraşcu, F.; Drăghici, C.; Dumitrescu, D.;
Cristea, M. Molecules 2005, 10, 360.
Synlett 2008, No. 6, 813–816 © Thieme Stuttgart · New York