Nucleophilic carbenes and pseudo-cross-conjugated mesomeric betaines of indazole starting from analogues of the alkaloid-betaine nigellicine

Article abstract of DOI:10.1002/ejoc.200500032

The alkaloid Nigellicine possesses the indazolium-3-carboxylate ring system as electronically relevant partial structure which represents a member of the class of pseudo-cross-conjugated mesomeric betaines. Indazolium-3-carboxylate, prepared starting from indazole-3-carboxylic acid by an esterification- methylation-saponification sequence, can be converted into the isoconjugated phenyl- and 4-(nitrophenyl)-amidates and the thiocarboxylate as additional examples of pseudo-cross-conjugated systems. In accordance with results of ab initio calculations decarboxylation of indazolium-3-carboxylate with formation of the nucleophilic carbene indazol3-ylidene begins at approximately 40°C as evidenced by temperature-dependent NMR spectroscopy. The carbene can be trapped with protons as indazolium salts, and carbon dioxide which reconstitutes the pseudo-cross-conjugated mesomeric betaine. According to the calculations, the carbene adopts a singlet ground state. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200500032

FULL PAPER
Nucleophilic Carbenes and Pseudo-Cross-Conjugated Mesomeric Betaines of
Indazole Starting from Analogues of the Alkaloid-Betaine Nigellicine
[a]
[a]
[b]
Andreas Schmidt,* Lars Merkel, and Wolfgang Eisfeld
Keywords: Betaines / Nitrogen heterocycles / Carbenes / Insertion / Indazolium salts
The alkaloid Nigellicine possesses the indazolium-3-carbox-
boxylate with formation of the nucleophilic carbene indazol-
ylate ring system as electronically relevant partial structure 3-ylidene begins at approximately 40 °C as evidenced by
which represents a member of the class of pseudo-cross-con-
jugated mesomeric betaines. Indazolium-3-carboxylate, pre-
pared starting from indazole-3-carboxylic acid by an esterifi-
cation–methylation–saponification sequence, can be con-
verted into the isoconjugated phenyl- and 4-(nitrophenyl)-
amidates and the thiocarboxylate as additional examples of
pseudo-cross-conjugated systems. In accordance with results
temperature-dependent NMR spectroscopy. The carbene can
be trapped with protons as indazolium salts, and carbon di-
oxide which reconstitutes the pseudo-cross-conjugated
mesomeric betaine. According to the calculations, the car-
bene adopts a singlet ground state.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
of ab initio calculations decarboxylation of indazolium-3-car- Germany, 2005)
Introduction
enables the prediction of physical and chemical properties
[
5]
of a given betaine. However, whereas CMB are well docu-
mented and widely applied in 1,3-dipolar cycloaddition re-
The class of alkaloids contains a surprisingly large
number of heterocyclic mesomeric betaines which recently
have been surveyed and classified in a first review article.
[
4]
actions, less is known about CCMB, and information
about chemical, physical, and biological properties of
pseudo-cross-conjugated mesomeric betaines (PCCMB) are
[
1]
Mesomeric betaines are neutral aromatic compounds which
can exclusively be represented by an even number of posi-
tive and negative charges within a common π-electron sys-
[
1,5]
very scarce.
a relatively broad variety of representatives of this class of
It is apparent, however, that nature produces
[
2]
tem. This feature obviously contradicts one of the most
fundamental rules for the formulation of canonical formu-
lae, i.e. “stability is decreased by an increase in charge sepa-
ration”. In the history of heterocyclic mesomeric betaines
this fact induced controversal discussions about the correct
structures and their adequate representation.[ Mesoions
such as sydnones and münchnones are five-membered
mesomeric betaines[ and have been used in numerous ele-
gant syntheses of alkaloids.[ According to a classification
first proposed by Ollis, Stanforth, and Ramsden in 1985, all
mesomeric betaines can be divided into four major classes,
conjugated (CMB), cross-conjugated (CCMB), and pseudo-
[
1]
compounds. Homarine (found in numerous marine or-
ganisms such as Arca noae, Arbatia, Cnidaria, Porifera, Ar-
[
6]
thropoda, Echinodermata), 1-methylisoquinolinium 2-car-
[
7]
boxylate (Photuris versicolor), Shihunine (Dendrobium
[
8]
[9]
sp.), Flavocarpine (Pleiocarpa mutica), Aeroginosine A
1]
[
10]
and B (Pseudomonas aeruginosa),
as well as Vincarpine
and its dihydro derivative (Vinca major elegantissima)[ are
examples for PCCMB isolated from natural sources. Some
scattered reports provide evidence for the assumption that
pseudo-cross-conjugated mesomeric betaines can be con-
verted into nucleophilic carbenes by decarboxylation.[
Interestingly, the reverse process was also realized by trap-
ping experiments of imidazol-2-ylidenes with carbon diox-
11]
3]
4]
12]
cross-conjugated
heterocyclic
mesomeric
betaines
[
2]
(PCCMB) as well as N-ylides which are related to CMBs.
[
13]
ide.
The type of conjugation considerably influences the chemis-
try and properties of those systems so that its recognition
We focussed our interest on analogues of the betaine-
[
14]
alkaloid Nigellicine (1)
which was isolated from the
widely distributed herbaceous plant Nigella sativa L. (black
cummin) (Scheme 1). The seeds of this plant have been used
for thousands of years as a spice and for the treatment of
[
[
a] Clausthal University of Technology, Institute of Organic Chem-
istry,
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
Fax: +49-5323-723861
[
15]
E-mail: schmidt@ioc.tu-clausthal.de
b] Technical University Munich, Chair of Theoretical Chemistry,
Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49-89-28913622
various diseases.
The pseudo-cross-conjugated meso-
meric betaine Nigellicine and the closely related zwitterion
[
16]
Nigellidine (2)
belong to the seldom class of indazole
E-mail: wolfgang.eisfeld@ch.tum.de
alkaloids.
2124
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500032
Eur. J. Org. Chem. 2005, 2124–2130

Pseudo-Cross-Conjugated Mesomeric Betaines
FULL PAPER
Scheme 1. Nigellicine 1 and Nigellidine 2 from Nigella sativa L.
In continuation of our interest in heterocyclic mesomeric
[
17]
[18]
[19]
betaines including alkaloids, nucleobases, and beta-
[
20]
ines of pyrazole we report here the syntheses of Nigellic-
ine analogues possessing the indazole nucleus and their
conversion into amidates and thiocarboxylates as ad-
ditional new representatives of the class of pseudo-cross-
conjugated mesomeric betaines. We examined the decarbox-
ylation of indazolium-3-carboxylate to indazol-3-ylidene,
and report trapping experiments of this new nucleophilic
carbene, as well as results of spectroscopic examinations
and ab initio calculations.
Scheme 2. Synthesis of indazolium-3-carboxylate 5 as model com-
pound for the pseudo-cross-conjugated mesomeric betaine alkaloid
Nigellicine.
from ν˜ = 1657 cm–1 to ν˜ = 1740 cm–1 in the IR spectra in
the solid state.
Several canonical formulae of the mesomeric betaine 5
can be drawn. Two of them possess electron-sextet struc-
tures without internal octet stabilisation (one of which is
Results and Discussion
The synthesis of the target 1,2-dimethyl-1H-indazolium- shown in Scheme 3) which are characteristic for pseudo-
[
1,2,5]
3-carboxylate (5) starts with the esterification of indazole- cross-conjugated mesomeric betaines.
Although these
3-carboxylic acid (3) which proved to be insensitive towards formulae have only a small contribution, if at all, to the
the conditions necessary for the subsequent alkylation. overall-electronic structure of the molecule, the charges are
Two-fold methylation of the nitrogen atoms of 3 to the salt effectively, but obviously not exclusively delocalised in sepa-
4
was accomplished in one step by reaction with dimethyl rated parts of the common π-electron system. The second
sulfate in the presence of catalytic amounts of nitrobenzene characteristic feature of PCCMB is the masked 2-oxyallyl
Scheme 2). Without this catalyst, no reaction took place, 1,3-dipole II which can be dissected from the canonical for-
(
regardless of the methylating agent applied. Saponification mulae. As 5 is isoconjugate to the 3-isopropenyl-1H-indene
of 4 was best achieved with aqueous sulfuric acid and sub- dianion I it represents at the same time a member of class
[
2]
sequent neutralization, which resulted in the straightfor- 16 of heterocyclic mesomeric betaines which was un-
[
1]
ward formation of the target pseudo-cross-conjugated known before Nigellicine was isolated. As an additional
mesomeric betaine, the indazolium-3-carboxylate 5, in good characteristic feature of PCCMB[1,2,5] the negative partial
yields.
structure of the pyrazolium-carboxylate is isoconjugate
1,2-Dimethyl-1H-indazolium-3-carboxylate (5) was iso- with an odd alternant hydrocarbon anion, the propenyl
lated as a slightly yellow solid which decomposed at tem- anion (cf. I). It is joined by a union bond through an un-
peratures above 120 °C in the solid state with loss of carbon starred, i.e. even-numbered atom, to the cationic structure
dioxide (vide infra). It is stable in water and acids and can element. The results of our ab initio calculations are dis-
be recovered quantitatively even after prolonged heating cussed below.
times in these solvents. As described below, in non-polar
Before we focussed our interest on decarboxylation reac-
solvents decomposition of the betaine 5 occurs. Evidenced tions to nucleophilic carbenes, we studied the properties of
1
13
1
13
by ( H, C)-HSQC- and ( H, C)-HMBC-measurements, the carboxylate group of 5 and intended to prepare ad-
2
the methyl groups appear at δ = 4.21 ppm (N –Me) and ditional representatives of the class of pseudo-cross-conju-
1
1
3
.90 ppm (N –Me) in H NMR spectroscopy. The nitrogen gated mesomeric betaines. Thus, the acid chloride 7 is avail-
atoms show two resonance frequencies at δ = –180.2 ppm able as a stable compound starting from the betaine 5 on
N2) and –211.1 ppm (N1) which were assigned by means reaction with thionyl chloride in dichloromethane in the
(
1
15
of ( H, N)-HMBC spectra. Protonation of the betaine 5 presence of pyridine. When the hot solution is treated with
to the indazolium salt 6 was accomplished by HBF in aniline and 4-nitroaniline, respectively, followed by the ad-
4
dichloromethane at low temperatures in quantitative yield. dition of HBF , the amides 8a and 8b were isolated in good
4
On protonation, the resonance frequency of the carbonyl yields (Scheme 4). The corresponding pseudo-cross-conju-
1
3
atom shifts from δ = 157.1 ppm to 160.4 ppm in C NMR gated mesomeric betaines, the indazolium-3-amidates 9a
spectroscopy; the corresponding absorption band shifts and 9b, were prepared by deprotonation with Amberlite
Eur. J. Org. Chem. 2005, 2124–2130
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2125

A. Schmidt, L. Merkel, W. Eisfeld
FULL PAPER
Scheme 5. Synthesis of new PCCMBs: thiocarboxylates.
Decarboxylation of the indazolium-3-carboxylate 5,
+
which appears as a peak at m/z = 213 [5·Na] in electro-
spray ionization mass spectrometry (ESI-MS), results in the
formation of the nucleophilic carbene 11 which can be de-
tected mass spectroscopically, whereas the extrusion of
phenyl isocyanate or 4-(nitrophenyl) isocyanate from 9a,b,
respectively, was not observed under the applied reaction or
measurement conditions. The carbene sodium adduct [11·
Na], the mass of which was calculated to be 169.07417
Scheme 3. Characteristic features of pseudo-cross-conjugation.
IRA-402 in its hydroxy form. These betaines were isolated
as stable solids which are greenish in color. On deproton-
ation, the absorption band of the NH band at ν˜ = 3338–
[
C H N Na ], causes
a
prominent peak at m/z
=
9
10
2
1
169.07376. In addition, characteristic peaks of the indazol-
ium cation 12 and a dimerized species such as 13 are ob-
servable at m/z = 147.09117 and m/z = 293.17669, respec-
tively [calculated masses: 147.09167 for C H N and
–
1
3
278 cm disappears in parallel to the resonance frequency
1
at δ = 12.00–11.40 ppm in the H NMR spectra. The amid-
ates 9a and 9b are formal isocyanate adducts of the nucleo-
philic carbene indazol-3-ylidene.
9
11
2
2
93.17662 for C H N ] (Scheme 6).
18 21 4
Scheme 6. Decarboxylation produces a nucleophilic carbene 11 and
characteristic trapping products.
Heating of the betaine 5 at reflux temperature in acetone
results in the formation of the (2,3-dihydroindazol-3-yl)pro-
pan-2-one 14 by deprotonation of the solvent by the nucleo-
Scheme 4. Synthesis of new PCCMBs: amidates.
Lawesson’s reagent, 2,4-bis(4-methoxyphenyl)-1,3-dithia- philic carbene 11, and subsequent addition of the resulting
,4-diphosphetane 2,4-disulfide, converted the betaine 5 acetone enolate to the iminium moiety of the indazolium
2
into the corresponding thiocarboxylate 10 (Scheme 5) cation. This reaction is reversible at room temperature on
which is an additional stable representative of the class of exposure to carbon dioxide. Thus, indazolidine 14, the
pseudo-cross-conjugated mesomeric betaines, albeit this re- structure of which was unambiguously elucidated by
action proceeds in low yields (Scheme 5). On thionation, HSQC, HMBC, and H,H-COSY experiments, reacts repro-
the carboxylate carbon atom shifts from 161.7 ppm (D O) ducibly within a couple of days at room temperature in the
2
1
3
to 194.7 ppm ([D ]DMSO) in the C NMR spectra.
presence of carbon dioxide to form the mesomeric betaine
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6
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 2124–2130

Pseudo-Cross-Conjugated Mesomeric Betaines
FULL PAPER
5
and acetone in addition to approximately 10% of yet un-
identified by-products (Scheme 7).
6
Figure 1. Decarboxylation of the mesomeric betaine 5 in [D ]-
DMSO with temperature: Integration of the signal of 4-H of the
resulting indazolium salt 12.
Scheme 7. Formal CH-insertion into the methyl group of acetone
by the nucleophilic carbene.
1
Table 1. Integration of the H NMR signal of indazolium salt 12 in
6
a [D ]DMSO solution of PCCMB 5 dependent on the temperature.
Spectra were taken after 10 minutes at the temperature indicated
We examined the decarboxylation of 5 by temperature in the table.
1
dependent H NMR spectroscopy, taking advantage of the
T [°C]
Integration of the signal at δ = 9.23 ppm [%]
equimolar amounts of water of crystallization present in the
crystals of 5. The temperature between 20 °C and 60 °C was
adjusted in the NMR spectrometer before a freshly dis-
solved sample of 10 mg of 5 in 0.6 mL of anhydrous [D ]- 50
2
3
4
0
0
0
3.3
4.8
14.5
34.0
50.0
57.6
62.4
6
1
55
DMSO was inserted. After 10 minutes, the H NMR spec-
6
6
0
tra were measured. The resonance frequency of 4-H of 5 at
δ = 8.41 ppm was taken as the reference signal to determine
the concentration of the iminium salt by integration of the
0 (1 h)
signal of 3-H of 12 which appears at δ = 9.23 ppm. The was calculated, necessary for the decarboxylation of 5 to
imininium salts formed by protonation of the in-situ gener- start under a pressure of 1 atm. This is in excellent agree-
ated nucleophilic carbene 11 by the water of crystallization. ment with the results of the temperature-dependent 1H-
Our results are presented in Figure 1 and Table 1. At 20 °C NMR measurements. The singlet ground state of the re-
and 30 °C, the concentration of the indazolium salt is less sulting nucleophilic carbene was calculated to be 45.2 kcal/
than 5%. The decarboxylation accelerates on warming to mol more stable than the triplet state. The N1–N2 bond
approximately 40 °C. Prolonged heating at 60 °C does not length increases from 138.8 to 144.6 pm on decarboxyl-
cause considerable changes, as the concentration of 12 in- ation, which reflects a conversion of a N–N bond with par-
creases from 57.6% to only 62.4% within 50 minutes. Un- tial double bond character to a N–N bond. The N2–C3
der analoguous reaction conditions, the amidates 9a,b as bond length is a shortened C–N single bond in the betaine
well as the thiocarboxylate 10 are stable up to 90 °C.
5 (133.9 pm) as well as in the carbene (132.9 pm). The dihe-
A mixture of indazolium salt 12, the dimeric species 13, dral angle C8–N1–N2–C9 is 20.6° in the betaine 5. On de-
and unchanged starting material is formed in 10 mg sam- carboxylation to the singlet carbene, this angle is widened
ples of 5 in 0.6 mL of [D ]DMSO solution after ultrasound to 43.4°, whereas the triplet carbene adopts an angle of
6
irradiation for 30 seconds. The dimeric species 13, which is 97.5° (Table 2).
red in color, can be assigned to the resonance frequencies
at δ = 2.75, 2.95, 6.80, 6.89, and 7.13 ppm in the H NMR culations. Table 3 lists the partial Mulliken charges of
spectra, which correspond well to calculated values, and, as groups and atoms for the betaine 5 and the carbenes 11.
The charge distribution is also obtained by the DFT cal-
1
already mentioned, the high resolution ESI-MS measure-
It is evident that the CO fragment of 5 carries a signifi-
2
ments. We were not able, however, to separate this species cant negative charge (–0.52 a.u.). Within the CO moiety
2
from the crude reaction mixture as it decomposes rapidely the negative charge is evenly distributed over both O atoms
on trying to chromatograph the crude mixture.
and thus completely delocalized. The adjacent carbon atom
Density functional theory (DFT) calculations at the (C3) compensates this charge only partially, corresponding
B3LYP/6-31G(d) level were carried out for compounds 5 to structure II in Scheme 3. Comparison with the carbenes
[
21,22]
and 11.
The Gibbs free energy difference for the decar- 11 shows that the positive charge of C3 is increased in 5,
boxylation of 5 under standard conditions (25 °C, 1 atm) is indeed. It is also observed that the negative charge of the
found to be 3.4 kcal/mol. A threshold temperature of 38 °C N1–CH group of 5 increases on decarboxylation while the
3
Eur. J. Org. Chem. 2005, 2124–2130
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2127

A. Schmidt, L. Merkel, W. Eisfeld
FULL PAPER
Table 2. Results of DFT B3LYP/6-31G(d) calculations of the
PCCMB 5 and the nucleophilic carbene 11 in the singlet and triplet
ground state. Bond lengths [pm], bond angles [°], and dihedral
angles [°]. Numberings.
using the following abbreviations: s = singlet, d = doublet, t =
triplet, m = multiplet, br = broad. Peak assignments were ac-
complished by results of HMBC-, HSQC-NMR and HH-COSY
measurements. FT-IR spectra were obtained on a Bruker Vektor
–
1
2
2 in the range of 400 to 4000 cm (2.5% pellets in KBr). The GC-
MS spectra (EI) were recorded either on a GC Hewlett–Packard
980, Serie II / MS Hewlett–Packard 5989 B, or on a Varian
5
GC3900 with SAT2100T. The ESI mass spectra were measured
with an Agilent LCMSD Series HP1100 with APIES. Samples were
sprayed from methanol at 0 V fragmentor voltage unless otherwise
noted. Melting points are not corrected.
Betaine 5
Carbene 11
Carbene 11
Ethyl Indazole-3-carboxylate: Indazole-3-carboxylic acid (10 g,
123 mmol) in 350 mL of ethanol and 40 mL of concentrated sulfu-
ric acid was heated at reflux temperature over a period of 5 h.
After cooling to room temp., the solution was neutralised with 2 n
NaOH, and extracted seven times with 100 mL of diethyl ether,
respectively. The combined organic extracts were dried over
Na SO and the solvents evaporated in vacuo to give 21.7 g
(singlet)
(triplet)
N1–N2
N2–C3
C3–C3a
C3a–C7a
C3a–C4
C4–C5
C5–C6
C6–C7
C7–C7a
C7a–N1
N1–C8
138.8
133.9
142.4
141.5
141.0
138.2
141.6
138.6
140.4
137.3
145.1
146.2
157.8
124.7
124.0
133.1
20.6
144.6
132.9
145.8
141.6
140.2
139.0
140.9
139.2
140.0
138.3
145.5
145.3
–
146.1
138.9
139.5
143.3
141.1
139.4
140.1
140.9
138.3
141.8
146.2
146.8
–
2
4
1
(
(
(
7
114 mmol) of the ester as a yellowish solid, m.p. 130 °C. H NMR
[D ]DMSO): δ = 13.94 (s, 1 H), 8.10 (d, J = 8.08 Hz, 1 H), 7.69
d, J = 8.34 Hz, 1 H), 7.47 (m, 1 H), 7.33 (m, 1 H), 4.41 (q, J =
6
1
3
6
.13 Hz, 2 H), 1.39 (t, J = 7.13 Hz, 3 H) ppm. C NMR ([D ]-
DMSO): δ = 163.6, 142.2, 136.5, 127.9, 124.1, 123.4, 122.3, 112.4,
–
1
6
1.6, 15.6 ppm. IR (KBr): ν˜ = 3297, 1718, 1480, 1233 cm . ESI-
N2–C9
+
+
C3–C10
C10–O11
C10–O12
O11–C10–O12
C8–N1–N2–C9
MS: m/z = 191.1 (6%) [M + H] , 213.1 (100%) [M + Na] .
(190.1): calcd. C 63.15, N 14.73, H 5.30; found: C
–
–
–
43.4
–
–
–
97.5
10 10 2 2
C H N O
62.95, N 14.65, H 5.33.
Ethyl 1,2-Dimethyl-1H-indazolium-3-carboxylate Hydrogen Sulfate
(
4): Ethyl indazol-3-carboxylate (3.8 g, 20 mmol) was suspended in
a mixture of 50 mL of xylene and 0.21 mL (2 mmol) of nitroben-
zene and heated for 30 min to 140 °C. The hot solution was then
treated with dimethyl sulfate (2.28 mL; 24 mmol) and heated for
an additional hour at that temperature whereupon a brown oil de-
veloped. After cooling the solution was concentrated in vacuo and
treated with 100 mL of acetone. After several days at 8 °C, 3.62 g
Table 3. Mulliken charges [a.u.] of groups and atoms from B3LYP/
-31G(d) calculations.
6
Group/atom
5
11
singlet)
11
(triplet)
(
CO
C3–CO
C3
phenyl
C7a
N1–CH
N2–CH
2
–0.520
–0.230
0.290
0.389
0.384
–0.125
–0.034
–
–
–
–
(
12.4 mmol, 62%) of 4 precipitated which was filtered off and
2
1
washed with cold acetone, m.p. 203 °C. H NMR ([D
=
1
6
]DMSO): δ
8.28 (d, J = 8.46 Hz, 1 H), 8.20 (d, J = 8.97 Hz, 1 H), 7.97 (m,
H), 7.70 (m, 1 H), 4.63 (s, 3 H), 4.58 (q, J = 7.13 Hz, 2 H), 4.44
0.009
0.187
0.340
–0.201
0.009
0.062
0.218
0.302
–0.198
–0.082
1
3
(s, 3 H), 1.48 (t, J = 7.13, 3 H) ppm. C NMR ([D
6
]DMSO): δ =
3
3
158.8, 140.5, 134.6, 130.9, 128.7, 124.1, 120.5, 113.2, 64.7, 38.5,
3
2
5.6, 15.2 ppm. IR (KBr): ν˜ = 3092, 2875, 1736. ESI-MS: m/z =
19.1 (100%) [M – HSO ] . C12H N O S (316.1): calcd. C 45.56,
4 16 2 6
+
charge of the N2–CH3 fragment remains essentially un- N 8.86, H 5.10, S 10.14; found: C 45.04, N 8.85, H 5.04, S 10.09.
changed. The compensation of the negative partial charge
1
,2-Dimethyl-1H-indazolium-3-carboxylate (5): A sample of the es-
is achieved not only by C3 but also by the phenyl ring which
shows an increased positive charge in comparison to 11.
Within the six membered ring C7a plays a particular role
as the main carrier of positive partial charge, not only in
ter 4 (10 g, 32 mmol) was dissolved in 20 mL of 50% sulfuric acid
and heated at reflux temperature for six hours. The solution was
then neutralized with dilute NaOH and the solvents evaporated to
dryness. The resulting precipitate was extracted with ethanol, the
the betaine but in the carbenes as well. In fact, the change solvent evaporated, and the residue subjected to column
in the group charge of the phenyl system is due to small chromatography (silica gel, methanol). The betaine 5 was isolated
1
increases on all carbon atoms of the ring. Thus, apparently as yellowish solid, dec. Ͼ145 °C, yield 4.6 g (24 mmol; 76%). H
2
NMR (D O): δ = 7.64 (d, J = 8.31 Hz, 1 H, C4-H), 7.43 (m, 1 H,
C6-H), 7.27 (d, J = 8.80 Hz, 1 H, C7-H), 7.11 (m, 1 H, C5-H),
the positive partial charge of 5 is strongly delocalized.
1
4
.21 (s, 3 H, N2-CH
DMSO): δ = 8.41 (d, J = 8.29 Hz, 1 H, C4-H), 7.92 (d, J = 7.78 Hz,
H, C6-H), 7.78 (d, J = 8.45 Hz, 1 H, C7-H), 7.44 (dd, J =
8.32 Hz, 1 H, C5-H), 4.65 (s, 3 H, N2-CH ), 4.22 (s, 3 H, N1-
O): δ = 161.7 (C10), 139.2 (C7a), 137.4
(C3), 133.1 (C6), 125.7 (C5), 123.1 (C4), 119.0 (C3a), 110.4 (C7),
3 3 6
), 3.90 (s, 3 H, N1-CH ) ppm. H NMR ([D ]
Experimental Section
1
General Remarks: The H and 13C NMR spectra were recorded on
1
3
1
3
Bruker ARX-400 and DPX-200 spectrometers and were taken in
3 2
CH ) ppm. C NMR (D
[D
6
]DMSO and D
2
O at 200 and 400 MHz. The chemical shifts are
1
5
reported in ppm relative to internal tetramethylsilane (δ =
35.8 (C9), 33.0 (C8) ppm. N NMR (D
2
O): –211.1 (N1), –180.2
(N2) ppm. IR (KBr): ν˜ = 1657, 1320, 760 cm . ESI-MS (25 V):
–
1
0
.00 ppm) or HDO (δ = 4.65 ppm). Multiplicities are described by
128
2
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2124–2130

Pseudo-Cross-Conjugated Mesomeric Betaines
FULL PAPER
+
+
–1
m/z = 147.1 (16%) [M – CO
·H
C 56.81, N 13.26, H 5.75.
2
+ H] , 213.0 (26%) [M + Na] . 35.3 ppm. IR (KBr): ν˜ = 3338, 1691, 1513, 1348 cm . ESI-MS: m/z
–
+
C
10
H
10
N
2
O
2
2
O (190.1): calcd. C 57.68, N 13.45, H 5.81; found:
= 311.08 (100%) [M – BF
4 15 4 3
] . HR-ESI-MS calcd. for C16H N O
311.1144; found: 311.1154.
1
(
,2-Dimethyl-1H-indazolium-3-carboxylic Acid Tetrafluoroborate
6): A sample of 5 (100 mg, 0.53 mmol) was suspended in 5 mL of
dichloromethane and treated whilst stirring with 50% HBF
1,2-Dimethyl-N-phenyl-1H-indazolium-3-amidate (9a): Amberlite
IRA-402 (100 mL) was filled into a small column and was sub-
sequently treated with 400 mL of water and 50 mL of 4% NaOH.
After 1 h the resin was first washed with water until the elute was
neutral, and then with ethanol/water (1:1). A sample of 8a (200 mg,
4
(0.2 mL; 2.8 mmol) at 0 °C. Stirring was continued for additional
3
0 min. The precipitate was then filtered off and dried in vacuo to
1
give 147 mg (0.53 mmol) of the salt 6 (100%), m.p. 168–172 °C. H 0.57 mmol) was dissolved in the same solvent mixture and was
NMR ([D
8
3
1
6
]DMSO): δ = 8.31 (d, J = 8.59 Hz, 1 H), 8.14 (d, J =
.84 Hz, 1 H), 7.95 (m, 1 H), 7.65 (m, 1 H), 4.62 (s, 3 H), 4.38 (s,
H) ppm. 13C NMR ([D
]DMSO): δ = 160.4, 140.6, 134.5, 132.7,
28.3, 124.5, 120.9, 113.0, 38.2, 35.3 ppm. IR (KBr): ν˜ = 3575,
given on the resin and eluted. Evaporation of the elute gave 9a as
a greenish solid in almost quantitative yield (99%, 148 mg,
1
6
0.56 mmol), dec. 128 °C. H NMR ([D ]DMSO): δ = 8.33 (d, J =
6
8.41 Hz, 1 H, C4-H), 8.06 (d, J = 8.80 Hz, 1 H, C7-H), 7.88 (m, 1
H, C6-H), 7.76 (d, J = 7.43 Hz, 2 H, C14-H and C18-H), 7.53 (m,
1 H, C5-H), 7.33 (m, 2 H, C15-H and C17-H), 7.07 (m, 1 H, C16-
–1
3
BF
C
574, 1740, 1625, 1432, 1286 cm . ESI-MS: m/z = 191 (55%) [M –
+
+
4
] , 381 (100%) [M + (M – H]] . HR-ESI-MS calcd. for
: 191.0821; found: 191.0827.
1
3
10
H
11
N
2
O
2
3 3
H), 4.61 (s, 3 H, C9-H ), 4.34 (s, 3 H, C8-H ) ppm. C NMR
(
1
[D
29.8 (C15/C17), 126.4 (C5), 125.1 (C4), 124.6 (C16), 123.4 (C14/
C18), 119.4 (C3a), 112.3 (C7), 37.8 (C9), 34.7 (C8) ppm, C13 was
6
]DMSO): δ = 156.9 (C10), 140.4 (C7a), 139.8 (C3), 134.1 (C6),
3
-Chlorocarbonyl-1,2-dimethyl-1H-indazolium Chloride (7): Under
an inert atmosphere, a sample of 570 mg (3 mmol) of 5 was sus-
pended in freshly distilled SOCl (20 mL, 275 mmol) and stirred
for 30 min at room temp. Then the SOCl was distilled off in vacuo.
2
1
5
not detectable. N NMR ([D
6
]DMSO): δ = –210.4 (N1), –176.8
2
(
N2) ppm, N12 was not detectable. IR (KBr): ν˜ = 3487, 3410, 1682,
The resulting residue was dissolved in 5 mL of diethyl ether, the
solvent evaporated and the dry residue treated with 10 mL of petro-
leum ether. The suspension was stirred at room temp. for 30 min
and then evaporated to dryness to give 628 mg (3 mmol, 100%) of
–
1
+
1
555, 758 cm . ESI-MS (0V): m/z = 266.1 (100%) [M + H ]. HR-
266.1293; found: 266.1288.
O (265.03): calcd. C 60.23, H 6.63, N 13.17; found:
C 59.87, H 5.52, N 12.50.
ESI-MS: calcd. for
O·3H
16 15 3
C H N O
C
16
H
15
N
3
2
1
the chloride 7 as a colorless solid, m.p. 159 °C (dec.). H NMR
(
[D
6
]DMSO): δ = 8.31 (d, J = 8.46 Hz, 1 H), 8.17 (d, J = 8.97 Hz,
1
,2-Dimethyl-N-(4-nitrophenyl)-1H-indazolium-3-amidate (9b): Am-
1
H), 7.94 (m, 1 H), 7.64 (m, 1 H), 4.64 (s, 3 H), 4.41 (s, 3 H) ppm.
C NMR ([D
berlite IRA-402 (100 mL) was filled into a small column and was
subsequently treated with 400 mL of water and 50 mL of 4%
NaOH. After 1 h the resin was first washed with water until the
elute was neutral, and then with ethanol/water (1:1). A sample of
1
3
6
]DMSO): δ = 160.1, 140.5, 134.3, 133.0, 128.1,
1
1
24.5, 120.8, 112.9, 38.1, 35.3 ppm. IR (KBr): ν˜ = 3169, 1707, 1623,
231 cm . C10H10Cl N O (244.0): calcd. C 49.00; H 4.11, N 11.43;
2 2
–1
found: C 48.90, H 5.46, N 11.24.
8b (200 mg, 0.50 mmol) was dissolved in the same solvent mixture
and was given on the resin and eluted. Evaporation of the elute
1
,2-Dimethyl-3-(N-phenylcarbamoyl)-1H-indazolium Tetrafluorobo-
gave 9b as a yellow solid in almost quantitative yield (99%, 199 mg,
rate (8a) and 1,2-Dimethyl-3-[N-(4-nitrophenyl)carbamoyl]-1H-ind-
azolium Tetrafluoroborate (8b): Samples of 570 mg (3 mmol) of 5
in 15 mL of dichloromethane were suspended under nitrogen atmo-
1
0
.50 mmol), m.p. 110–111 °C. H NMR ([D
6
]DMSO): δ = 8.64 (d,
J = 8.33 Hz, 1 H), 8.11 (d, J = 8.87, 2 H), 7.99 (m, 1 H), 7.85 (m,
H), 7.79 (d, J = 8.57 Hz, 2 H), 7.51 (m, 1 H), 4.74 (s, 3 H), 4.29
1
2
spheres with 1.3 mL of freshly distilled SOCl (9 mmol) and pyri-
1
3
(
s, 3 H) ppm. C NMR ([D
24.2, 123.2, 110.4, 35.6, 32.8 ppm, C
ficient solubility. IR (KBr): ν˜ = 1599.2, 1583.3, 1541.9, 1511.8,
6
]DMSO): δ = 132.2, 125.1, 124.5,
dine (0.16 mL; 2 mmol). The mixtures were then heated at reflux
temperature for 15 min. Freshly distilled aniline (0.82 mL; 9 mmol)
or 4-nitroaniline (414 mg; 9 mmol) were then added to the hot solu-
tions which were heated for additional 2 h at that temperature.
Evaporation to dryness in vacuo gave residues which were treated
with water and evaporated again. The resulting brown oils were
dissolved in 15 mL of methanol and treated with 2 mL of 50%
1
q
not detectable due to insuf-
–
1
1493.3, 1103.8 cm . ESI-MS (0V): m/z
=
311.08 (100%)
+
[M + H] . HR-ESI-MS: calcd. for C16H N O 311.1144; found:
15 4 3
311.1154.
1,2-Dimethyl-1H-indazolium-3-thiocarboxylate (10): Compound 5
HBF
colorless solids. 540 mg of 8a (1.53 mmol; 51%) and 884 mg
2.2 mmol; 74%) of 8b were obtained, respectively.
4
at 0 °C. After stirring for 30 min the amides were isolated as
(
950 mg, 5 mmol) was suspended in toluene (100 mL) and treated
with LawessonЈs reagent (2 g, 5 mmol). Then, the mixture was
heated at 90 °C and stirred at that temperature over a period of 2 h.
The solvent was then distilled off in vacuo and purified by column
chromatography (silica gel; petroleum ether ether/ethyl acetate,
(
1,2-Dimethyl-3-(N-phenylcarbamoyl)-1H-indazolium Tetrafluorobo-
1
rate (8a): M.p. 159 °C, H NMR ([D
6
]DMSO): δ = 11.40 (s, 1 H),
.15 (m, 2 H), 7.98 (m, 1 H), 7.81 (d, J = 7.71 Hz, 2 H), 7.65 (m,
H), 7.47 (m, 2 H), 7.26 (m, 1 H), 4.50 (s, 3 H), 4.42 (s, 3 H) ppm.
8
1
2:1). The thiocarboxylate was isolated in low yield (77 mg;
1
0.37 mmol, 7%), dec. 130 °C. H NMR ([D
6
]DMSO): δ = 8.34 (d,
13
C NMR ([D
6
]DMSO): δ = 156.0, 140.5, 138.8, 136.6, 134.8,
J = 8.34 Hz, 1 H), 7.90 (d, J = 8.72 Hz, 1 H), 7.78 (m, 1 H), 7.44
1
3
130.4, 127.3, 126.8, 123.9, 122.2, 118.7, 112.7, 38.2, 35.2 ppm. IR
6
(m, 1 H), 4.35 (s, 3 H), 4.20 (s, 3 H) ppm. C NMR ([D ]DMSO):
–1
(KBr): ν˜ = 3278, 1661, 1552 cm . ESI-MS: m/z = 266 (100%) [M –
δ = 194.7, 145.0, 140.4, 133.6, 125.7, 125.6, 118.4, 111.8, 36.5,
+
–1
BF
66.1284. C16
B 3.06; found: C 53.91, N 11.73, H 4.46, B 2.97.
4
] . HR-ESI-MS: calcd. for C16
H
16
N
3
O 266.1293; found:
34.1 ppm. IR (KBr): ν˜ = 1530, 1250, 1018 cm . ESI-MS: m/z =
+
+
2
H
16
N
3
OBF
4
(353.1): calcd. C 54.42, N 11.90, H 4.57, 229 (75%) [M + Na] , 435 (100%) [2 M + Na] . C10
10 2 2
H N OS·H O
(206.05): calcd. C 53.60, H 5.39, N 10.50; found: C 53.42, H 4.79,
N 10.55.
1
,2-Dimethyl-3-[N-(4-nitrophenyl)carbamoyl]-1H-indazolium Tetra-
1
fluoroborate (8b): M.p. 189 °C, H NMR ([D
6
]DMSO): δ = 12.00
1-(2,3-Dihydro-1,2-dimethyl-1H-indazol-3-yl)propan-2-one
(14):
(s, 1 H), 8.37 (d, J = 9.22 Hz, 2 H), 8.19 (m, 2 H), 8.08 (d, J =
Compound 5 (570 mg; 3 mmol) was suspended in 40 mL of acetone
9
3
1
.22 Hz, 2 H), 8.00 (m, 1 H), 7.66 (m, 1 H), 4.52 (s, 3 H), 4.44 (s,
H) ppm. 13C NMR ([D
and the mixture was refluxed for 1 h during which time the betaine
]DMSO): δ = 156.7, 145.0 (2 C), 140.5, was dissolved. After cooling, the solvent was distilled off and the
35.9, 134.8, 127.4, 126.3, 123.9, 122.2, 118.8, 112.8, 38.4, resulting residue was chromatographed (silica gel; ethyl acetate) to
6
Eur. J. Org. Chem. 2005, 2124–2130
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2129

A. Schmidt, L. Merkel, W. Eisfeld
FULL PAPER
1
give 14 as a yellow oil in 80% yield (489 mg, 2.4 mmol). H NMR
O): δ = 7.11 (t, J = 7.63 Hz, 1 H, C5-H), 6.91 (d, J = 7.43 Hz,
[11] E. Ali, V. S. Giri, S. C. Pakrashi, Tetrahedron Lett. 1976, 17,
4
887.
(D
2
[
[
[
12] A. R. Katritzky, H. M. Faid-Allah, Synthesis 1983, 149; A. R.
1
1
2
3
1
H, C4-H), 6.84 (t, J = 7.43 Hz, 1 H, C6-H), 6.67 (d, J = 8.02 Hz,
H, C7-H), 4.19 (t, J = 5.97 Hz, 1 H, C3-H), 2.88 (d, J = 6.06 Hz,
Katritzky, R. Awartani, R. C. Patel, J. Org. Chem. 1982, 47,
4
7
7
98; H. Quast, E. Schmitt, Justus Liebigs Ann. Chem. 1970,
32, 43; H. Quast, E. Schmitt, Justus Liebigs Ann. Chem. 1970,
32, 64.
H, C10-H
H, C12-H
30.7 (C3a), 129.2 (C5), 123.4 (C6)*, 123.2 (C7)*, 112.2 (C4), 65.7
2
), 2.69 (s, 3 H, C8-H
3 3
), 2.47 (s, 3 H, C9-H ), 2.07 (s,
O): δ = 212.5 (C11), 149.3 (C7a),
) ppm. 13C NMR (D
3
2
13] N. Kuhn, M. Steimann, G. Weyers, Z. Naturforsch. Teil B 1999,
(C3), 49.4 (C10), 42.5 (C9), 41.5 (C8), 30.3 (C12) ppm (* peak as-
5
4, 427; K. Ishiguro, K. Hirabayashi, T. Nojima, Y. Sawaki,
15
signments exchangeable). N NMR (40.5 MHz, D
N2), –255.9 (N1) ppm. ESI-MS: m/z
2
O): δ = –259.8
147 (43%)
Chem. Lett. 2002, 796; J. D. Holbrey, W. M. Reichert, I. Tkat-
chenko, E. Bouajila, O. Walter, I. Tommasi, R. D. Rogers,
Chem. Commun. 2003, 28.
(
=
+
+
2 3
[M – CH COCH ] , 203 (100%) [M – H] .
14] Atta-ur-Rahman, S. Malik, H. Cun-heng, J. Clardy, Tetrahe-
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[15] cf. Matthaeus, The Holy Bible, New Testament, Math. 23,23.
Acknowledgments
[
16] Atta-ur-Rahman, S. Malik, S. S. Hasan, M. I. Choudhary, C.-
We thank Prof. Dr. Pirjo Vainiotalo (University of Joensuu, Fin-
land) and Dr. Gerald Dräger (University of Hannover, Germany)
for performing the high-resolution electrospray ionization mass
spectra (HR-ESI-MS). Computer time at the Leibniz Rechenzen-
trum Munich is greatfully acknowledged. We thank the Deutsche
Forschungsgemeinschaft (DFG) for the financial support.
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[
2
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of theory as implemented [ in the Gaussian03 program,
22]
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energy at different temperatures for a standard pressure of 1
atm.
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Received: January 13, 2005
2130
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2124–2130