New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicine

Article abstract of DOI:10.1021/jo0344337

Pyrazolium-3-carboxylates were examined as relatives of the betainic alkaloid Nigellicine and as new examples of the sparsely populated class 16 of heterocyclic pseudo-cross-conjugated mesomeric betaines (PCCMB). The title compounds were prepared in a 4-step procedure starting from β-diketo compounds 8 which were cyclized with substituted hydrazines. The resulting isomeric pyrazole esters 9 and 10 were separated and subsequently quaternized with dimethyl sulfate in the presence of nitrobenzene to pyrazolium esters 11 and 12. Saponification was best accomplished in diluted sulfuric acid, which resulted in the formation of the pseudo-cross-conjugated mesomeric betaines 13 and 14 in one step. Protonation to the corresponding carboxylic acids required the treatment of the betaines with tetrafluoroboric acid in dichloromethane. The effect of negative solvatochromism proves the charge separation in the ground state of the molecules. X-ray crystallographic analyses, semiempirical calculations, and ESI mass spectrometric measurements were performed to gain knowledge about the phenomenon of pseudo-cross-conjugation.

Full text of DOI:10.1021/jo0344337

New P yr a zoliu m -ca r boxyla tes a s Str u ctu r a l An a logu es of th e
P seu d o-Cr oss-Con ju ga ted Beta in ic Alk a loid Nigellicin e
†
‡
Andreas Schmidt,* Tobias Habeck, Markus Karl Kindermann, and Martin Nieger
Technical University of Clausthal, Institute of Organic Chemistry, Leibnizstrasse 6,
D-38678 Clausthal-Zellerfeld, Germany
schmidt@ioc.tu-clausthal.de
Received April 4, 2003
Pyrazolium-3-carboxylates were examined as relatives of the betainic alkaloid Nigellicine and as
new examples of the sparsely populated class 16 of heterocyclic pseudo-cross-conjugated mesomeric
betaines (PCCMB). The title compounds were prepared in a 4-step procedure starting from â-diketo
compounds 8 which were cyclized with substituted hydrazines. The resulting isomeric pyrazole
esters 9 and 10 were separated and subsequently quaternized with dimethyl sulfate in the presence
of nitrobenzene to pyrazolium esters 11 and 12. Saponification was best accomplished in diluted
sulfuric acid, which resulted in the formation of the pseudo-cross-conjugated mesomeric betaines
1
3 and 14 in one step. Protonation to the corresponding carboxylic acids required the treatment of
the betaines with tetrafluoroboric acid in dichloromethane. The effect of negative solvatochromism
proves the charge separation in the ground state of the molecules. X-ray crystallographic analyses,
semiempirical calculations, and ESI mass spectrometric measurements were performed to gain
knowledge about the phenomenon of pseudo-cross-conjugation.
In tr od u ction
positive charge can be realized by an inspection of the
canonical formulas. Examples are the well-known five-
Alkaloids, which belong to the class of heterocyclic
mesomeric betaines, form a relatively small group of
natural products with interesting biological and chemical
6
7
membered mesoions such as sydnones, m u¨ nchnones,
and derivatives, and six-membered systems such as
8
1
-alkyl-pyridinium-3-olates. Most synthetic or natural
1
properties between the large group of cationic alkaloids
heterocyclic mesomeric betaines known to date belong to
on one hand (e.g. pyridinium-, quinolinium-, and iso-
quinolinium-alkaloids) and the very small group of
anionic alkaloids on the other.2-4 Mesomeric alkaloid
betaines are dipolar molecules with opposite charges
delocalized within a common π-electron system. It has
been recognized that heterocyclic mesomeric betaines can
be divided into four major classes depending on their type
of conjugation, i.e. conjugated (CMB), cross-conjugated
1
9
this class of compounds, which are versatile 1,3-dipoles
and valuable starting materials for heterocyclic synthe-
sis.10 N-Ylides (best represented as 1,2-dipoles) form the
second class of heterocyclic mesomeric betaines. Several
alkaloids belonging to this class of compounds have been
1
isolated from natural sources. In molecules which belong
(
5) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
1, 2239.
6) (a) Eade, R. A.; Earl, J . C. J . Chem. Soc. 1946, 591. (b) Stewart,
F. H. C. Chem. Rev. 1964, 64, 129.
7) (a) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Sch a¨ fer, F. C.
Angew. Chem. 1964, 76, 185; Angew. Chem., Int. Ed. Engl. 1964, 3,
36. (b) Bayer, H. O.; Huisgen, R.; Knorr, R.; Sch a¨ fer, F. C. Chem.
Ber. 1970, 103, 2581.
8) E.g.: Ishag, C. Y.; Fisher, K. J .; Ibrahim, B. E.; Iskander, G.
M.; Katritzky, A. R. J . Chem. Soc., Perkin Trans. 1 1988, 917.
9) Gribble, G. W. In The Chemistry of Heterocyclic Compounds; Vol.
(CCMB), pseudo-cross-conjugated (PCCMB) heterocyclic
4
mesomeric betaines, and heterocyclic N-ylides which are
related to CMB. A subdivision on the basis of the
isoconjugate equivalents led to 4 subclasses, respectively,
i.e. to at least 16 distinct structural classes of heterocyclic
mesomeric betaines. The charges in CMB are in mutual
conjugation and common atoms for the negative and the
(
(
1
5
(
(
†
Present address: Ernst-Moritz-Arndt-Universit a¨ t Greifswald, In-
59: Synthetic applications of 1,3-dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W.
H., Eds.; Wiley: New York, 2002;, p 681.
stitut f u¨ r Chemie und Biochemie, Soldmannstrasse 16, D-17487
Greifswald.
‡
Present address: Rheinische Friedrich-Wilhelms-Universit a¨ t Bonn,
(10) (a) Straub, C. S.; Padwa, A. Org. Lett. 1999, 1, 83. (b) Padwa,
A.; Sheehan, S. M.; Straub, C. S. J . Org. Chem. 1999, 64, 8648. (c)
Padwa, A.; Heidelbaugh, T. M.; Kuethe, J . T. J . Org. Chem. 2000, 65,
2368. (d) Padwa, A.; Beall, L. S.; Heidelbaugh, T. M.; Liu, B.; Sheehan,
S. M. J . Org. Chem. 2000, 65, 2684. (e) Katritzky, A. R.; Belyakov, S.
A.; Fang, Y.; Kiely, J . S. Tetrahedron Lett. 1998, 39, 8051. (f) Sung,
M. J .; Lee, H. I.; Chong, Y.; Cha, J . K. Org. Lett. 1999, 1, 2017. (g)
Pham, V. C.; Charlton, J . L. J . Org. Chem. 1995, 60, 8051. (h)
Katritzky, A. R.; Dennis, N.; Dowlatshahi, A. J . Chem. Soc., Perkin
Trans. 1 1980, 331. (i) Katritzky, A. R.; Cutler, A. T.; Dennis, N.;
Sabonji, G. J .; Rahimi-Rastgoo, S.; Fisher, G. W.; Flechter, I. J . J .
Chem. Soc., Perkin Trans. 1 1980, 1176. (j) Padwa, A.; Brodney, M.
A.; Marino, J . P., J r.; Sheehan, S. M. J . Org. Chem. 1997, 62, 78.
Institut f u¨ r Anorganische Chemie, Gerhard-Domagk-Strasse 1, D-53121
Bonn, Germany.
(
1) Schmidt, A. Adv. Heterocycl. Chem. 2003, in print.
(2) E.g., Clathridine (Clathrina clathrus): Ciminiello, P.; Fattorusso,
E.; Mangoni, A.; Di Blasio, B.; Pavone, V. Tetrahedron 1990, 46, 4387.
3) Bis(isonaamidinato) A zinc(II) (Leucetta sp.): Mancini, I.; Guella,
G.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1995, 78, 1178.
4) Magnesidine (Pseudomonas magnesiorubra, Vibrio gazogenes):
a) Kohl, H.; Bhat, S. V.; Patell, J . R.; Gandhi, N. M.; Nazareth, J .;
(
(
(
Divekar, P. V.; De Souza, N. J .; Berscheid, H. G.; Fehlhaber, H. W.
Tetrahedron Lett. 1974, 12, 983. (b) Imamura, N.; Adachi, K.; Sano,
H. J . Antibiot. 1994, 47, 257.
1
0.1021/jo0344337 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/26/2003
J . Org. Chem. 2003, 68, 5977-5982
5977

Schmidt et al.
SCHEME 1. Alk a loid s th a t Belon g to th e Cla ss of
P seu d o-Cr oss-Con ju ga ted Heter ocyclic Mesom er ic
Beta in es
SCHEME 2. Nigellicin e 6 a n d
P yr a zoliu m -3-ca r boxyla tes 7 a s Its Electr on ica lly
Releva n t P a r tia l Str u ctu r e: Isocon ju ga te
Rela tion sh ip s
to the third class, i.e. cross-conjugated mesomeric be-
taines (CCMB), the positive and negative charges are
alkaloid Nigellicine, isolated from the widely distributed
herbaceous plant Nigella sativa L. (black cumin, “love
in the mist”), which is used as a spice and for the
treatment of various diseases.20 Nigellicine belongs to the
extremely rare class of indazole alkaloids. As it is
isoconjugate to the 3-isopropenyl-1H-indene dianion it
represents at the same time a member of class 16 of
heterocyclic mesomeric betaines from which to the best
of our knowledge only very few stable representatives
have been described to date.21
The parent heterocyclic ring system of Nigellicine 6 is
the pyrazolium-3-carboxylate, from which several canoni-
cal formulas can be drawn. Two of them possess electron-
sextet structures without internal octet stabilization,
which is characteristic for pseudo-cross-conjugated me-
someric betaines. Although these formulas have only a
small contribution, if at all, to the overall electronic
structure of the molecule, the charges are effectively, but
obviously not exclusively delocalized in separated parts
of the common π-electron system. The second character-
istic feature of PCCMB is the masked 2-oxyallyl 1,3-
dipole, which can be dissected from the canonical formu-
las.11 Third, the negative partial structure of the
pyrazolium-carboxylate is isoconjugate with an odd al-
ternant hydrocarbon anion, the propenyl anion. It is
typically joined by a union bond through the unstarred,
i.e. even-numbered atom, to the cationic structure ele-
ment.
delocalized in separated parts of the common π-electron
system.11 Very little information is available to date
concerning stability as well as physical, biological, and
chemical properties of pseudo-cross-conjugated systems
(
PCCMB) which form the fourth class of heterocyclic
1
1
mesomeric betaines. Nonetheless, the biological role of
betainic alkaloids possessing this type of conjugation is
apparent. The alkaloid Homarine 1 has been isolated
1
,12
from numerous marine organisms
and its biological
role has been discussed intensively.13 1-Methylquino-
linium-2-carboxylate (2), which belongs to the very rare
class 13 of heterocyclic mesomeric betaines, has recently
been identified as defense betaine from the fireflies
Photuris versicolor.14 Flavocarpine 3 (Pleiocarpa mutica)
15
and the closely related structures Vincarpine and Dihy-
drovincarpine (Vinca major elegantissima),16 as well as
Aeruginosine A 4 and B 5 (Pseudomonas aeruginosa),17
are known pseudo-cross-conjugated betainic alkaloids.
On continuation of our work on heterocyclic mesomeric
betaines,18 including alkaloids and nucleobases,19 we
became interested in model compounds of the PCCMB-
(
11) (a) Potts, K. T.; Murphy, P. M.; Kuehnling, W. R. J . Org. Chem.
988, 53, 2889. (b) Potts, K. T.; Murphy, P. M.; DeLuca, M. R.;
Kuehnling, W. R. J . Org. Chem. 1988, 53, 2898.
12) (a) Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A.-L.; Tille-
quin, F.; Vardala-Theodorou, E.; Tsarbopoulos, A. Nat. Prod. Lett. 2001,
5 (6), 411. (b) He, H. M.; Wenig, Z. Y. Yaoxue Xuebo 1989, 24, 302
Chem. Abstr. 1989, 111, 108492].
13) (a) Berking, S. Development 1987, 99, 211. (b) Gasteiger, E. L.;
1
(
1
[
(
Haake, P. C.; Gergen, J . A. Ann. New York Acd. Sci. 1960, 90, 622. (c)
Nishitani, H.; Kikushi, S.; Okumura, K.; Taguchi, H. Arch. Biochim.
Biophys. 1995, 322, 327. (d) Netherton, J . C.; Gurin, S. J . Biol. Chem.
We present here our results on syntheses and studies
of pseudo-cross-conjugated pyrazolium-carboxylates as
the electronically relevant partial structure of Nigellicine,
structure elucidations by means of X-ray analyses,
NOESY-NMR spectroscopy, and the results of semiem-
pirical calculations.
1
982, 257, 11971.
14) Gonz a´ les, A.; Schroeder, F.; Meinwald, J .; Eisner, T. J . Nat.
Prod. 1999, 62, 378.
15) (a) B u¨ chi, G.; Manning, R. E.; Hochstein, F. A. J . Am. Chem.
(
(
Soc. 1962, 84, 3393. (b) Gribble, G. W.; J ohnson, D. A. Tetrahedron
Lett. 1987, 5259.
(
(
16) Ali, E.; Giri, V. S.; Pakrashi, S. C. Tetrahedron Lett. 1976, 4887.
17) (a) Holliman, F. G. J . Chem. Soc. (C) 1969, 2514. (b) Herbert,
Resu lts a n d Discu ssion
R. B.; Holliman, F. G. South Afr. Ind. Chem. 1961, 15, 233.
18) (a) Schmidt, A.; Mordhorst, T.; Habeck, T. Org. Lett. 2002, 4,
375. (b) Schmidt, A.; Vainiotalo, P.; Kindermann, M. K.; Nieger, M.
Heterocycles 2002, 57, 615. (c) Schmidt, A. J . Heterocyl. Chem. 2002,
(
The synthesis of the target compounds starts from 2,4-
1
1
dioxo-pentanoic acid ethyl ester 8 (R ) Me) or the 2,4-
1
dioxo-4-phenyl-butyric acid ethyl ester 8 (R ) Ph) which
3
1
6
9, 949. (d) Schmidt, A.; Nieger, M. J . Chem. Soc., Perkin Trans. 1
999, 10, 1325. (e) Schmidt, A.; Kindermann, M. K. J . Org. Chem. 1998,
3, 4636. (f) Schmidt, A.; Nieger, M. Heterocycles 1999, 51, 2119.
are readily available by Claisen-condensation of oxalic
acid diethyl ester and 1-phenyl-ethanone or acetone,
(19) (a) Schmidt, A.; Kobakhidze, N.; Kindermann, M. K. J . Chem.
(20) Atta-ur-Rahman, Malik, S.; Cun-heng, H.; Clardy, J . Tetrahe-
dron Lett. 1985, 26, 2759.
(21) When the comprehensive classification system was developed
by Ollis, Stanforth, and Ramsden in 1985 this class was unknown.
For known representatives today, cf. ref 11.
5
978 J . Org. Chem., Vol. 68, No. 15, 2003

New Pyrazolium-carboxylates
SCHEME 3. Ca n on ica l F or m u la s, Ch a r ge
Distr ibu tion Accor d in g to th e VB Meth od , a n d
Ma sk ed 1,3-Dip ole of P yr a zoliu m -2-ca r boxyla tes a s
Ch a r a cter istic F ea tu r es of
SCHEME 4. Syn th esis of Su bstitu ted P yr a zole
Ester s
a
P seu d o-Cr oss-Con ju ga tion
SCHEME 5. Qu a ter n iza tion a n d Sa p on ifica tion to
th e Ta r get Beta in es
a
An unstarred position of the isoconjugate equivalent of the
anionic segment forms a union bond to the cationic partial
structure
respectively.22 These â-diketo compounds undergo reac-
tions with methyl and phenyl hydrazine, yielding a 2:1
to 1:2 mixture of the two isomeric disubstituted pyrazole-
fonate (“magic methyl”), and trioxonium tetrafluoroborate
failed even when vigorous reaction conditions were
applied. The quaternization was finally successful with
dimethyl sulfate in the presence of nitrobenzene. After
heating samples 9b,c and 10b in a 2:1 mixture of
o-xylene and nitrobenzene to 140 °C, addition of dimethyl
sulfate to the warm solution, and additional heating for
3
-carboxylic acid ethyl esters 9 and 10, respectively.
These are readily separable by column chromatography
on silica gel. For unambiguous structure elucidation we
performed a single-crystal X-ray analysis of 9a , which
allowed us to differentiate between the isomers by means
1
of H NMR spectroscopy. The ORTEP plot, given in the
Supporting Information, shows an essentially planar
2
h, the new pyrazolium esters 11b,c and 12b were
molecule. Pyrazol ester 9a was obtained as an oil that
1
obtained in high yields as brownish oils and could be used
after aqueous workup without further purification. The
phenyl derivatives 9d and 10d , however, did not react
under these conditions, which is presumably due to steric
reasons. They were recovered quantitatively. The pyra-
zole esters 9a and 10a decomposed to a black tar from
which no identifiable compounds could be extracted.
Saponification of the pyrazolium esters was best ac-
complished on heating 11b,c an 12b in 50% aqueous
sulfuric acid and gave the target compounds in 32-80%
yield for the two steps. The betaines could be extracted
with nonpolar solvents such as dichloromethane or
chloroform. Surprisingly, the betainic structures formed
without deprotonation. In neither case were pyrazolium
carboxylic acids obtained as hydrogensulfates or sulfates.
No saponification could be observed in basic media.
The new pseudo-cross-conjugated mesomeric betaines
are stable, brownish to gray compounds at room temper-
ature. Derivative 14b, which forms a monohydrate on
crystallized slowly. In H NMR spectroscopy, the N-
methyl group appears at δ 4.11 ppm. Its isomer 10a is a
pale yellow solid, the N-methyl group of which is detect-
able at δ 3.85 ppm. The esters 9b and 10b were obtained
as brownish solids. Whereas the N-phenyl group of 9b
gives resonance frequencies at δ 7.34-7.50 ppm, the
corresponding signals of 10b were found at δ 7.36-7.45
ppm. Isomer 9c is a yellow oil [δ(N-Me) 3.95 ppm],
whereas 10c forms a colorless solid [δ(N-Me) 4.23 ppm].
The two phenyl-substituted esters 9d and 10d , obtained
as brownish solids, displayed no significant differences
1
in the H NMR spectra. All structure elucidations were
later confirmed by NOESY spectroscopy performed on the
target betaines (vide infra).
The N-methylation of the pyrazole esters proved to be
difficult, as dimethyl sulfate, methyl trifluoromethylsul-
(22) Herold, P.; Indolese, A. F.; Studer, M.; J alett, H. P.; Siegrist,
U.; Blaser, H. U. Tetrahedron 2000, 56, 6497.
J . Org. Chem, Vol. 68, No. 15, 2003 5979

Schmidt et al.
F IGURE 1. Results of the X-ray analysis on PCCMB 13b.
SCHEME 6. P r oton a tion a n d Meth yla tion of th e
P CCMB
F IGURE 2. Effect of negative solvatochromism of the PCC-
MBs 13b,c and 14b.
drying in vacuo, is hygroscopic and rapidly picks up water
in moist air. For structure elucidation we performed
NOESY-NMR spectroscopy, which unambiguously shows
interactions between the two methyl groups in 14b. The
phenyl ring interacts with the N-methyl group, but not
with the 5-methyl group. In contrast, in 13b interactions
of the phenyl group to either methyl group are detectable
which are not influencing themselves.
For the sake of a NMR spectroscopic comparison
between the betainic and cationic species, we tried
protonations and methylations on a representative ex-
ample, respectively. Conversion of the PCCMB 13b into
the corresponding acids in hydrochloric acid, sulfuric acid,
and acetic acid failed. Reaction with tetrafluoroboric acid
in dichloromethane, however, gave the 2,5-dimethyl-1-
phenyl-pyrazolium-3-carboxylic acid 15 in good yield. The
spectroscopic properties of the betaine and its protonated
derivative differ significantly (cf. Experimental Section).
Thus, the N-methyl groups of 13b shift from δ 1.72 and
F IGURE 3. Semiempirically calculated dipole moments of the
PCCMB 14b.
tochromism. Indeed, with increasing solvent polarity the
UV-vis absorption maxima of these compounds shift in
a linear free enthalpy relationship to shorter wave-
lengths. This is mainly due to the decreasing permanent
dipole moment on electronic excitation. The dipolar
ground state is obviously better stabilized by polar than
by nonpolar solvents, so that the absorption maxima of
the compounds show a blue shift on changing polar
solvents to nonpolar solvents. The dependence of the π
3
.41 ppm to δ 2.39 and 4.20 ppm on protonation.
Treatment of the betaine 13b with a 5-fold excess of
methyl iodide gave the ester 16 as a yellow crystalline
solid in almost quantitative yield.
N
T
N
f π* transitions on the solvent polarity E between ET
)
We were able to obtain single crystals of the PCCMB
N
0.259 (chloroform) and ET ) 1.000 (water) is pre-
1
3b and performed an X-ray analysis (Figure 1). The
sented in Figure 2. The absorption maxima were found
between 277 and 245 nm depending on the solvent
polarity. In agreement with this observation, the semiem-
pirically calculated permanent dipole moment in the
ground state is considerably larger than in the first
excited state [∆µ(PM3) ) 4.7 D] (Figure 3).
Electrospray-ionization mass spectrometry (ESI-MS)
proved to be a valuable tool to determine the betainic
structures. The spectra were taken on spraying metha-
nolic solutions of the betaines 13b,c and 14b from
methanol.23 As examples, the ESI mass spectra at 0 V
fragmentor voltage display the peaks of the protonated
betaine, i.e. the pyrazolium-3-carboxylic acid at m/z 217.0
amu (18%). The betaine gives a peak as sodium adduct
at m/z 239 amu (82%). An additional prominent peak is
betaine crystallizes with one molecule of water of crystal-
lization, which forms a hydrogen bond of 192.2(13) pm
length to the carboxylate oxygen atom. The pyrazole ring
is essentially planar [τmin ) 0.17°, τmax ) 0.68°] and the
methyl groups are located in the plane. In contrast to
this, the carboxylate function is twisted about a torsion
angle of τ ) 167.57° [C(4)-C(5)-C(6)-O(2), crystal-
lographic numbering] from the plane of the pyrazole. The
bond length of the union bond predicted by the specific
architecture of PCCMB (Scheme 3) between the positive
and negative partial structures is 152.43(15) pm and is
considerably longer than the corresponding bond in ester
9
a [147.46(17) pm]. In addition, due to steric hindrance
to the methyl groups the phenyl ring is twisted by τ )
7
3.84° from planarity [N(1)-N(2)-C(9)-C(10)] and obvi-
ously is not involved in conjugation.
(23) The samples were dissolved in anhydrous MeOH and sprayed
To prove the charge separation in the ground state of
the molecules we examined the effect of negative solva-
from MeOH. Capillary voltage 3000 V; drying gas temperature 300°C;
35 psig drying gas pressure; 0 V fragmentor voltage; direct injection.
5
980 J . Org. Chem., Vol. 68, No. 15, 2003

New Pyrazolium-carboxylates
F IGURE 5. Frontier orbital profile of PCCMB 14b.
F IGURE 4. Most stable conformation according to a semiem-
pirical calculation on the PCCMB 14b.
separation in the ground state was proved by the effect
of negative solvatochromism (Figure 2).
detectable at m/z 173 amu (62%), which corresponds to
the decarboxylated derivative, i.e. the 2,5-dimethyl-1-
phenyl-pyrazolium salt formed via an ylidic species. On
increasing the fragmentor voltage to 20 and 40 V, the
peak at 173 amu increases and forms the base peak of
the spectrum as can be expected, whereas the peaks at
m/z 217.0 and 239 decrease to the relative intensity of
Exp er im en ta l Section
Mod ified P r oced u r e for th e P r ep a r a tion of 2,4-Dioxo-
4-p h en yl-bu tyr ic Acid Eth yl Ester (8) (R ) P h ). A suspen-
sion of sodium (0.18 mol, 4.14 g) in 200 mL of anhydrous
toluene was heated to approximately 80 °C and stirred
vigorously, until the sodium was molten. After the mixture
was cooled to 50 °C anhydrous ethanol was added slowly until
all traces of sodium had reacted. The resulting emulsion, cooled
to room temperature, was first treated dropwise with oxalic
acid diethyl ester (0.15 mol, 20.3 mL) then with 1-phenyl-
ethanone (0,15 mol, 17.5 mL), whereupon the color changed
to brownish-red. The mixture was stirred overnight and then
treated with 100 mL of concentrated acetic acid and water,
respectively. The aqueous layer was extracted several times
with diethyl ether and the combined organic layers and the
etheral phases were concentrated in vacuo. On cooling to -20
7
% and 30%, respectively. A dimerized ylide (2 × 172
amu) can be detected as protonated species at m/z 345
amu.
The betaines can unambiguously be differentiated from
the corresponding protonated species 15. Independent of
the fragmentor voltage in the range between 0 and 40
V, the spectrum constists only of two peaks at m/z 217.1
(95%) and 433.1 amu (100%) which are due to the salt
or to its dimer (m/z ) 434/2 ) 217 amu). The semidepro-
tonated salt causes the second peak of the spectrum.
To gain additional insight into the electronic structure
°
C, the precipitated product was finally recrystallized from
methanol. The desired compound 8 (R ) Ph) (0.14 mol, 31.85
g) was obtained as a yellow solid in 96.4% yield; mp 39-41
1
of the PCCMB, we performed semiempirical calcula-
°C. H NMR (CDCl
3
) δ 7.99 (m, 2 H; Ar-H), 7.42-7.67 (m, 3
tions24 on the PCCMB 14b and found a most stable
H; Ar-H), 7.08 (s, 1 H; CH), 4.40 (q, 2 H, J ) 7.15 Hz; CH
2
),
) δ 190.7,
69.8, 162.2, 134.9, 133.8, 128.9, 127.9, 98.0, 62.6, 14.1 ppm.
1
1
.41 (t, 3 H, J ) 7.15 Hz; CH
3 3
) ppm; 13C NMR (CDCl
conformation with the phenyl group twisted by 143.2°
from planarity (∆H (PM3) ) 103.61 kJ /mol). The car-
f
2
2
The spectroscopic data are identical with the reported data.
boxyl group and the N-methyl group are twisted by 36.8°
and 30.4° from the plane of the pyrazolium ring, respec-
tively. Thus, the substituents do not adopt a propeller-
like conformation. On one hand, steric hindrance between
the N-methyl group and the phenyl ring causes the
twisted conformation. On the other hand, an attractive
interaction is observed between one carboxy oxygen and
the aromatic C(2)-H group of the phenyl ring, which
have a distance of 177.3 pm. The most stable conforma-
tion is presented in Figure 4.
As expected for a pseudo-cross-conjugated system, the
highest occupied molecular orbital (HOMO) and the
lowest unoccupied molecular orbital (LUMO) are es-
sentially located in separated parts of the π-electron
system (Figure 5). The anionic partial structure is joined
to the cationic through a nodal position of the HOMO,
which consists mainly of the lone pairs of the oxygen
atoms. Thus, the carboxy carbon atom serves as an
isolator, which prevents the charge neutralization in the
ground state of the molecule. The resulting charge
P r ep a r a tion of 5-Meth yl-1-p h en yl-p yr a zole-3-ca r boxy-
lic Acid Eth yl Ester (9b) a n d 5-Meth yl-2-p h en yl-p yr a -
zole-3-ca r boxylic Acid Eth yl Ester (10b). 2,4-Dioxo-4-
phenyl-butyric acid ethyl ester (1.0 mmol, 0.14 mL) in 10 mL
of ethanol was treated dropwise with phenyl hydrazine (1.2
mmol, 0.12 mL) and the resulting solution was heated at reflux
temperature over a period of 3 h. After the mixture was cooled
to room temperature, the solvent was distilled off in vacuo.
The residue was purified by means of column chromatography
(silica gel; petroleum ether:ethyl acetate 4:1). Ester 9b (140
mg, 0.61 mmol; 60.8%) was isolated as a pale brownish solid;
1
mp 37 °C. H NMR (CDCl
q, 1 H, J ) 0.65 Hz; CH), 4.41 (q, 2 H, J ) 7.13 Hz; CH
.32 (d, 3 H, J ) 0.65 Hz; CH ), 1.39 (t, 3 H, J ) 7.13 Hz;
CH ) δ 169.9, 144.1, 140.9, 139.5, 129.5,
) ppm; 13C NMR (CDCl
28.9, 125.8, 109.5, 61.2, 14.8, 12.7 ppm; IR (KBr) 1721, 1235
3
) δ 7.34-7.50 (m, 5 H; Ar-H), 6.73
(
2
2
),
3
3
3
1
-1
cm ; MS (70 eV) m/z 77 (26.2%), 158 (100%), 185 (67.2%), 230
50.8%). Anal. Calcd.: C, 67.81; N, 12.17; H, 6.13. Found: C,
(
67.87; N, 12.16; H, 6.10.
Ester 10b (82 mg; 0.36 mmol; 35.6% yield) was isolated as
1
a pale yellow solid; mp 39-40 °C; H NMR (CDCl
3
) δ 7.36-
7
2
.45 (m, 5 H; Ar-H), 6.81 (q, 1 H, J ) 0.42 Hz; CH), 4.21 (q,
H, J ) 7.13 Hz; CH ), 2.35 (d, 3 H, J ) 0.42 Hz; CH ), 1.41
) ppm; 13C NMR (CDCl
) δ 159.6,
49.3, 140.8, 134.3, 128.9, 128.8, 126.4, 112.5, 61.4, 14.4, 13.8
ppm; IR (KBr) 1732, 1286, 1234 cm ; EIMS (70 eV) m/z 77
(45.9%), 158 (47.5%), 185 (63.9%), 230 (100%). Anal. Calcd.:
C, 67.81; N, 12.17; H, 6.13. Found: C, 67.76; N, 12.22; H, 6.12.
P r epar ation of 3-Eth oxycar bon yl-1,5-dim eth yl-2-ph en -
yl-p yr a zoliu m Su lfa te (12b). Pyrazole ester 10b (2.24 g, 9.7
mmol) was dissolved in a mixture of 20 mL of o-xylene and 10
mL of nitrobenzene and heated at 140 °C over a period of 2 h.
2
3
(
1
t, 3 H, J ) 7.13 Hz; CH
3
3
(
24) Semiempirical calculations were carried out with MOPAC 6.025
on a IBM workstation RS/6000, AIX V 4.3 to perform the PM3
calculations.26 The structures were first optimized with the default
gradient requirements and subsequently refined with the options EF
-
1
-10
DMAX ) 0.01, GNORM ) 0.01, SCFCRT ) 1 × 10 . The absolute
minima were proved by a force calculation. The first exited state was
calculated with the ground-state geometry and the option EXITED.
(
25) Stewart, J . J . P. QPCE, No 455, Department of Chemistry,
Bloomington, IN, 1989.
26) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209.
(
J . Org. Chem, Vol. 68, No. 15, 2003 5981

Schmidt et al.
The reaction mixture was then treated with dimethyl sulfate
10 mL, 10.5 mmol), heated for an additional hour to 140 °C,
and stirred overnight at room temperature. The reaction
mixture was then treated with 40 mL of water and stirred for
(100 mg, 0.46 mmol) in dichloromethane was cooled to 0 °C
and then treated with tetrafluoroboric acid (40%, 1 mL). After
the mixture was stirred for 30 min at 0 °C the resulting
precipitate was filtered off and washed with dichloromethane.
(
3
0 min. The organic layer was separated and the aqueous layer
The carboxylic acid was obtained as a colorless solid (51 mg,
1
was extracted several times with 10 mL of diethyl ether,
respectively. The aqueous layer was then evaporated to
dryness to give a brown oil of pyrazolium sulfate 12b (2.05 g,
0.17 mmol, 37.0% yield); decomposition at 265-268 °C.
NMR (DMSO-d
CH), 3.94 (s, 3 H; CH
(DMSO-d ) δ 158.6, 147.4, 138.4, 132.9, 130.7, 130.3, 128.6,
110.7, 37.0, 12.0 ppm; ESIMS m/z 217.1 (100%), 245.1 (68.7%),
H
6
) δ 7.92-7.60 (m, 5 H; Ar-H), 7.44 (s, 1 H;
13
3 3
), 2.26 (s, 3 H; CH ) ppm; C NMR
1
6
.0 mmol, 61.8%). H NMR (DMSO-d
6
) δ 7.83-7.64 (m, 5 H;
), 3.68
), 1.01 (t, 3 H, J ) 7.12 Hz;
) δ 155.9, 148.4, 136.7, 132.5,
32.3, 129.8, 128.7, 111.5, 62.5, 35.1, 13.4, 11.9 ppm; ESIMS
6
Ar-H), 7.54 (s, 1 H; CH), 4.18 (q, 2 H, J ) 7.12 Hz; CH
2
-
1
(s, 3 H; CH ), 2.60 (s, 3 H; CH
3
3
589.0 (39.0%) amu; IR (KBr) 2983, 1644, 1041 cm .
1
3
CH
1
3
) ppm; C NMR (DMSO-d
6
P r ep a r a t ion of 3-Met h oxyca r b on yl-2,5-d im et h yl-1-
p h en yl-p yr a zoliu m Iod id e (16). A solution of the betaine
13b (50 mg, 0.23 mmol) in dichloromethane was treated
dropwise with methyl iodide (5 equiv, 0.07 mL) and heated at
reflux temperature for 2 h. After evaporation to dryness the
ester was obtained as a yellow solid in quantitative yield (82
m/z 217.1 (25.7%), 231.1 (62.8%), 245.1 (100%) amu.
P r ep a r a tion of 1,5-Dim eth yl-2-p h en yl-p yr a zoliu m -3-
ca r boxyla te (14b). Pyrazolium ester 12b (2.05 g, 6.0 mmol)
was dissolved in a mixture of 20 mL of water and 30 mL of
concentrated sulfuric acid and heated at reflux temperature
over a period of 7 h. The mixture was then neutralized with
aqueous sodium hydroxide and then evaporated to dryness.
The betaine was extracted from the residue with dichlo-
romethane and chloroform and purified on silica gel (petroleum
ether:ethyl acetate 4:1) by means of column chromatography.
The betaine was obtained as a yellow solid (1.615 g, 5.8 mmol,
9
7
2
1
1
1
mg, 0.23 mmol); decomposition at 145-147 °C. H NMR
(CDCl
(s, 3 H; CH
NMR (CDCl
111.7, 54.0, 38.5, 13.3 ppm; ESIMS m/z 217.1 (97.3%), 433.1
3
) δ 7.84-7.60 (m, 5 H; Ar-H), 7.24 (s, 1 H; CH), 4.20
13
3
), 4.04 (s, 3 H; CH
3
), 2.39 (s, 3 H; CH
3
) ppm;
C
3
) δ 157.3, 148.4, 138.0, 133.4, 131.1, 130.2, 129.3,
-
1
(100%) amu; IR (KBr) 1741, 1495, 1252 cm . Anal. Calcd.:
C, 43.59; N, 7.82; H, 4.22. Found: C, 44.70; N, 7.94; H, 4.84.
6.7%); decomposition at 101-104 °C. 1H NMR (CDCl
.61-7.40 (m, 5 H; Ar-H), 6.74 (s, 1 H; CH), 3.60 (s, 3 H; CH
) δ
),
3 3
.52 (s, 3 H; CH ) ppm; C NMR (CDCl ) δ 158.1, 149.5, 146.7,
3
3
Ack n ow led gm en t . We thank the Deutsche For-
schungsgemeinschaft DFG and the Fonds der Chemis-
chen Industrie for financial support.
1
3
33.4, 131.5, 129.9, 128.5, 108.6, 34.2, 12.5 ppm; ESIMS m/z
73.1 (41.2%), 217.1 (100%), 239.1 (20.3%), 345.1 (14.2%), 389.1
(
1
10.57%), 433.1 (33.8%), 455.1 (28.4%) amu; IR (KBr) 3130,
631, 1238 cm . Anal. Calcd. for 1.5 mol of water of crystal-
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
-
1
tails, spectroscopic data, 1H NMR spectra of all new com-
lization: C, 59.24; N, 11.51; H, 6.21. Found: C, 58.65; N, 11.00;
H, 5.91.
P r ep a r a tion of 3-Ca r boxy-2,5-d im eth yl-1-p h en yl-p yr a -
zoliu m Tetr a flu or obor a te (15). A solution of betaine 13b
pounds. X-ray data, and ORTEP plots. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0344337
5
982 J . Org. Chem., Vol. 68, No. 15, 2003