Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol- 4(1H)-ones

Article abstract of DOI:10.1016/j.jfluchem.2010.07.007

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c] pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′, 3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.

Full text of DOI:10.1016/j.jfluchem.2010.07.007

Journal of Fluorine Chemistry 131 (2010) 1013–1024
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Novel fluoro-substituted benzo- and benzothieno fused
pyrano[2,3-c]pyrazol-4(1H)-ones
*
Wolfgang Holzer , Angelika Ebner, Karin Schalle, Gyselle Batezila, Gernot A. Eller
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
A R T I C L E I N F O
A B S T R A C T
straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]
Article history:
A
benzothieno[20,30:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of
1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides
or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing
1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused
ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the
1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochro-
meno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as
2-methyl-7-phenyl-2,7-dihydropyrazolo[40,30:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscop-
ic investigations (1H, 13C, 15N, 19F) with the obtained compounds were undertaken.
Received 9 June 2010
Received in revised form 8 July 2010
Accepted 9 July 2010
Available online 16 July 2010
Keywords:
Pyrazolones
Acylation
Ring closure
Chromeno[2,3-c]pyrazol-4(1H)-one
NMR (1H, 13C, 15N, 19F)
ß 2010 Elsevier B.V. All rights reserved.
1. Introduction
chromeno[2,3-c]pyrazol-4(1H)-ones (H = benzene) are already
known and have been primarily described by Sarenko et al. [13].
The important role of fluorine in medicinal and pharmaceutical
chemistry is indisputable and well reflected by a large number of
recent publications, including some excellent reviews [1–4].
Introduction of fluorine into a biologically active molecule often
enhances the metabolic stability and modulates physicochemical
properties such as basicity or lipophilicity [1,2]. Moreover, the
presence of fluorine can enhance the binding affinity of drug
molecules to the target protein [1,2]. Considering these facts there
is an ongoing interest in the synthesis of fluorinated heterocyclic
compounds, which may serve as building blocks or precursors of
biologically active fluorine-containing molecules.
Type A compounds are interesting for medicinal chemists, as an
example the A2-subtype specific adenosine receptor antagonist B –
containing a substituted pyrazole system – may serve (Fig. 1) [14].
Hence, in this paper we want to present the synthesis of fluoro-
substituted compounds of type A, with the H-ring consisting of
benzene or a benzothiophene system. Moreover, extensive NMR
spectroscopic studies (1H, 13C, 15N, 19F) with the title compounds
are showcased as well as their potential to act as precursors for the
synthesis of higher condensed systems of biological interest.
2. Results and discussion
In the course of a program aimed to the synthesis of new
heterocyclic scaffolds we recently presented a short and generally
applicable synthetic approach to various fused pyrano[2,3-
c]pyrazol-4(1H)-ones of type A, which can be considered as
heterocyclic analogues of xanthone (Fig. 1) [5–11]—the latter
representing the core of several biologically active molecules [12].
In compounds A one benzene system of the parent xanthone is
replaced by a pyrazole system whereas ring H is a heteroaromatic
moiety or a benzene ring. Some representatives of the latter
2.1. Chemistry
The synthesis of target compounds of type A was accomplished
according to the general approach described in Refs. [5–11]. Hence,
pyrazolones 1 were reacted with fluoro-substituted 2-fluoroben-
zoyl chlorides 2–7 under the conditions described by Jensen to
achieve selective C-4 acylation of pyrazolones (calcium hydroxide,
dioxane, reflux) [15] (Scheme 1). Cyclization of the thus obtained
4-aroylpyrazol-5-ols 8–13 by treatment with sodium hydride in
dry DMF or by K2CO3 in MeCN afforded the fluorinated pyrano[2,3-
c]pyrazol-4(1H)-ones 14–19 (Scheme 1). In this manner, all ring-H
monofluoro products were obtained (compounds 14–17, F in
* Corresponding author. Tel.: +43 1 4277 55623; fax: +43 1 4277 9556.
E-mail address: wolfgang.holzer@univie.ac.at (W. Holzer).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.07.007

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W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
Fig. 1. Xanthone and pyrazole analogues thereof.
position 5, 6, 7 and 8 at the tricyclic system). Moreover, two
difluoro congeners (18a, 19a) were prepared.
boiling temperature, leading to the liberation of dimethylamine
[16]. The latter process can even occur at lower temperatures and
to a higher degree when catalyzed by basic or acidic materials [16].
Thus, in the case of 13a cyclization using the system K2CO3/MeCN
turned out to be advantageous as here 19a resulted as the only
isolated reaction product (Scheme 3). In principle, also compounds
14 and 18 carry an activated fluoro substituent in position 5 of the
tricyclic system. Indeed, during the synthesis of 14b upon forced
reaction conditions and prolonged heating, formation of some 5-
dimethylamino substitution product was observed. Nevertheless,
cyclization of 8b in the system NaH/DMF led to higher yields of 14b
compared to the usage of K2CO3/MeCN.
Furthermore, the N-unsubstituted 5-fluorochromeno[2,3-
c]pyrazol-4(1H)-one 14x was prepared from 14c via removal of
the PMB protecting group [17] upon heating with trifluoroacetic
acid (Scheme 3) [5–7].
Similarly as described for the synthesis of chromeno[2,3-
c]pyrazol-4(1H)-ones 14–19 we also obtained the fluorinated
tetracycle 25 (Scheme 4). Reaction of 3-methyl-1-phenyl-2-
pyrazolin-5-one (1a) with 3-chloro-6-fluoro-1-benzothiophene-2-
The ring closure reaction of the 4-(2,3,6-trifluorobenzoyl)pyr-
azol-5-ol 12a theoretically may lead to two different cyclization
products, namely the 5,8-difluoro compound 18a or the isomeric
5,6-difluoro congener C (Scheme 2). Nevertheless, only a single
product was isolated upontreatment of12a withNaH/DMF towhich
structure 18a was unequivocally assigned considering the NMR
spectra (Scheme 2). Obviously, in the course of the intramolecular
nucleophilic substitution reaction the fluoro atom in position 2 of
the benzene system of 12a is more reactive than that in 6-position.
An interesting phenomenon was observed upon the cyclization
of the trifluorobenzoylpyrazolol 13a: conducting the ring closure
reaction in the usual way by treatment of 13a with NaH/DMF led to
a mixture of two reaction products (Scheme 3). Besides the desired
5,7-difluorinated tricycle 19a a second compound was formed in
considerable amount which turned out to be the 5-dimethylamino
congener 19y. The formation of 19y via nucleophilic displacement
of the activated fluorine substituent in position 5 can be explained
considering the tendency of DMF to slow decomposition at its
Scheme 1.
Scheme 2.

W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
1015
Scheme 3.
Scheme 4.
carbonyl chloride (23) afforded the aroylation product 24 which
was consecutively cyclized into the annelation product 25 with
NaH/DMF.
construction of higher anellated systems. This is demonstrated by
means of reaction of 14a or 14b, respectively, with methylhydrazine
leading to tetracycles 28a,b—the latter containing two different
condensed pyrazole moieties (Scheme 6). The structure of
compounds 28 (methyl group attached to N-2) was explicitly
confirmed by NMR experiments (Fig. 4). Compounds structurally
related to 28 have been found to exhibit interesting antiproliferative
and cytotoxic activity as well as ability to overcome multi-drug
resistance [18–21]. In contrast, reaction of 14a with hydrazine
hydrate afforded the hydrazine 29, which did not cyclize into the
corresponding tetracycle even at elevated temperature. However,
the formation of 29 demonstrates that in the reaction of 14 with
hydrazines the nucleophilic substitution of the fluoro atom –
expectedly – proceeds a lot easier than the condensation reaction of
The presented approach also permitted access to products of
type 22, carrying a 4-substituted phenyl ring at position 1 of the
chromeno[2,3-c]pyrazol-4(1H)-one system (Scheme 5). The N-
fluorophenyl congener 22d resulted from reaction of pyrazolone
1d with 2-chlorobenzoyl chloride (20) and subsequent cyclization
of the aroylpyrazolol 21d. For comparison purposes, also the
corresponding chloro compound 22e was prepared in a similar
way starting from pyrazolone 1e (Scheme 5).
Type 14 compounds can be regarded as 1,3-dielectrophiles as
they feature an activated fluoro atom and a carbonyl group in 1,3-
position. Due to this fact they can act as precursors for the
Scheme 5.

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W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
Scheme 6.
hydrazine with the pyranone C55O group. The strong intramolecular
hydrogen bond between hydrazine NH and C55O in compound 29
(Scheme 6, Fig. 4), which prevents attack of the terminal NH2 group
at the carbonyl C-atom, may serve as a possible explanation why 29
resists cyclization. NMR experiments showed that this hydrogen
bond is even fully intact in the strong acceptor solvent (CD3)2SO, in
which such hydrogen bonds are usually broken. From numerous
examples it is known that in SNAr reactions with methylhydrazine
the N-atom attached to the methyl group is more nucleophilic than
NH2 [22–24]. Consecutively,theprimarysubstitutionproductsupon
reaction of 14a or 14b with methylhydrazine are intermediates 29x
(Scheme 6), the latter having no possibility for the formation of such
a strong intramolecular hydrogen bond comparable to that in 29. As
a consequence, compounds 29x readily cyclize into the correspond-
ing tetracycles 28a and 28b, respectively.
Finally,itshouldbementionedthattheaccesstofused systemsof
type 28 was not possible upon replacement of 2,6-difluorobenzoyl
chloride (2) by 2,6-dichlorobenzoyl chloride (30) (Scheme 7). Thus,
treatment of 1a with 30 under Jensen-conditions did not afford the
desired 4-aroylpyrazol-5-ol D. Instead, from the complex reaction
mixture the isomeric O-aroyl compound 26 was isolated as the main
component by column chromatography. Besides, the N-substitution
product 27 was obtained in traces (Scheme 7).
decoupled 19F NMR spectra, APT, HMQC, gs-HSQC, gs-HMBC, COSY,
TOCSY, NOESY and NOE-difference spectroscopy. Moreover,
experiments with selective excitation (DANTE) of certain 1H-
resonances were performed, such as long-range INEPT [26] and
2D(d,J) long-range INEPT [27]. The latter experiments were
indispensable for the unambiguous mapping of some long-range
13C,1H coupling constants. The complete analysis of 1H,1H and
19F,1H-spin coupling constants was performed as far as possible,
however, due to overlapping of signals and the presence of higher
order spin systems this task was unfeasible in some cases. In the
numerous compounds carrying a phenyl substituent attached at
pyrazole N-1 the phenyl protons establish an AA0BB0C spin systems
which cannot be analyzed according to the first order. Neverthe-
less, assignment of the corresponding resonances is easy as the
signals due to Ph H-3,5 and Ph H-4 resemble a triplet, whereas
those of Ph H-2,6 have more ‘dublet’-character. Even so, these
signals are always designated as multiplets (m) in Section 4.
2.2.1. 4-Aroylpyrazol-5-ols (compounds 8–13, 21, 24)
In principle, these compounds are capable of prototropic
tautomerism and can exist in several isomeric forms [28–31]
(Fig. 2). However, 13C and particularly 15N NMR data reveal them to
exist as hydroxypyrazoles B0 in CDCl3 solution. Thus, for instance,
pyrazole N-1 and pyrazole N-2 exhibit large differences regarding
their 15N NMR chemical shifts (8a–11a: N1 ꢀ ꢁ190 ppm,
N2 ꢀ ꢁ100 ppm) what excludes the existence of larger amounts
of NH-form C in the overall tautomeric composition. The CH-form
A can be ruled out owing to the lack of a pyrazole H-4 signal and the
fact that C-4 shows to be a quaternary C-atom in the 13C NMR
2.2. NMR spectroscopic investigations
Full and unambiguous assignment of all 1H, 13C, 15N and 19F
NMR resonances was achieved by combining standard NMR
techniques [25], such as fully 1H-coupled 13C NMR spectra, 1H-
Scheme 7.

W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
1017
Fig. 2. Possible tautomeric forms of 4-aroylpyrazolones and tautomeric behavior of 11a in CDCl3 and (CD3)2SO solution.
spectra. However, an interesting phenomenon in some of these
typical influences of the fluorine’s ꢁI and +M effect on 1H and 13
C
chemical shifts are present. A comparison of the 19F shifts in
isomeric compounds 14a–17a clearly exhibits the marked influ-
ence of the pyrane-ring O-atom, most notably in ortho (17a:
compounds was observed. For instance, in the 1H-broadband
decoupled 13C NMR spectrum of 11a in (CD3)2SO solution the
signal due to the methyl-C atom appears as a singlet (
whereas in CDCl3 solution the corresponding signal is split into a
dublet (
13.9 ppm, J = 2.0 Hz). In the 1H NMR spectrum of 11a, the
3-methyl signal appears as a singlet in (CD3)2SO ( 2.37 ppm) and
as a dublet in CDCl3 ( 2.01 ppm, J = 0.9 Hz). This can be explained
d 13.8 ppm),
d
F-8 = ꢁ133.6 ppm) and – weakened – in para position (15a:
6 = ꢁ115.4 ppm), whereas the shifts in 14a ( F-5 = ꢁ110.6 ppm)
and 16a (
d F-
d
d
d
d
F-7 = ꢁ102.8 ppm) are the least affected (meta-position
d
of O and F). The pyrane O-atom and the C55O function impair the
one-bond 19F,13C couplings as well, the latter ranging from
246.6 Hz (1J(C6,F6) in 15a) to 265.6 Hz (1J(C5,F5) in 14a).
by the presence of 11a (in CDCl3) in form B0, where the strong
intramolecular hydrogen bond fixes the benzoyl moiety and brings
the methyl group close to the fluoro atom F-2 (Fig. 2). In contrast, in
(CD3)2SO solution (a strong acceptor) the hydrogen bond is
obviously broken (predominance of form B) and the average
distance between methyl-group and fluoro substituent is now
much larger. Similar splittings due to 19F,13C and 19F,1H (through-
space) couplings in CDCl3 solution were found in the spectra of 8b,
8c, 9a and 10a. Moreover, the intramolecular hydrogen bond of 11a
in CDCl3 solution is evidenced by a significant downfield shift for
As described in the chemistry part, cyclization of 12a
exclusively leads to the 5,8-difluoro compound 18a and not to
the 5,6-difluoro isomer C (Scheme 2). Unequivocal assignment of
structure 18a and thus discrimination from C can be achieved
considering the 19F,13C coupling constants of C-5 (157.3 ppm) and
C-8 (147.2 ppm): apart from the large direct C,F couplings
(1J(C5,F5) = 262.4 Hz, 1J(C8,F8) = 249.4 Hz) the C-signals are addi-
tionally split by
a second, but small coupling, namely
the carbonyl C-atom (
corresponding value found in (CD3)2SO (
d
187.0 ppm, CDCl3) compared to the
183.7 ppm) (Fig. 4) [32].
4J(C5,F8) = 3.1 Hz and 4J(C8,F5) = 4.3 Hz. In structure C, where
the two fluoro atoms are in ortho-position at the benzene ring,
much larger long-range C,F couplings (3J(C,F) ꢀ 12–14 Hz, compare
corresponding couplings in 11a) have to be expected. Moreover,
many other 13C,19F couplings found do not fit for structure C. In
18a, also the F,F coupling of 17.7 Hz perfectly matches the 5J
coupling in 1,4-difluorobenzene (5J(F,F) = 17.6 Hz [35,36]), where-
upon 3J(F,F) as present in C should be larger (ꢀ21 Hz in 1,2-
difluorobenzene [35,36], 21.6 Hz in 11a). As a typical example,
some important chemical shift and coupling data are displayed for
14a in CDCl3 solution (Fig. 3).
d
With congener 8b, the C55O resonance is shifted from 179.2 ppm
(in (CD3)2SO) to 183.3 ppm upon switching to CDCl3 solution.
Similar phenomena have been described by us for 4-acyl-3-
trifluoromethylpyrazol-5-ols [33].
In the spectra of 8–13, 21a and 24 the typical influences of
fluoro substituents on 13C and 1H NMR chemical shifts could be
observed [32,34]. Thus, protons located in ortho-position to a
fluorine atom receive a significant upfield shift, which becomes
larger for protons between two F-atoms in ortho-position (10a:
CPh H-3 = 6.96 ppm, 13a:
d
d
CPh H-3,5 = 6.80 ppm). 13C NMR
signals of carbons being in ortho or para-position to a fluoro
substituent are significantly shifted to lower frequencies, whereas
ipso C-atoms are characterized by a marked downfield shift.
Compounds 8–13 feature a di- or trifluoro substituted benzene
ring. Here the 19F chemical shifts agree well with those found in
correspondingly substituted di- or trifluorobenzenes, this is also
the case for 19F,19F coupling constants [35–37]. The unambiguous
determination of 19F,19F couplings was facilitated by recording 1H-
decoupled 19F spectra, whereas the 19F,13C spin coupling constants
could be easily derived from the 1H-decoupled 13C NMR spectra.
2.2.2. Chromeno[2,3-c]pyrazol-4(1H)-ones 14–19
Tricycles 14–17 with one fluoro atom attached to the
condensed benzene ring exhibit complex splitting patterns in
the 1H and 19F NMR spectra, which in some cases could be
completely analyzed according to the first order. Again, here the
Fig. 3. 1H (in italics), 13C, 15N (in bold) and 19F NMR (in bold) chemical shifts (
and spin coupling constants (in parentheses, Hz) of 14a (in CDCl3).
d, ppm)

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W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
Fig. 4. 1H (in italics), 13C, and 15N NMR (in bold) chemical shifts (
d, ppm) of 28a and 29 (in CDCl3).
Tricycle 14x, carrying no substituent at pyrazole N-1 can be
present in three tautomeric forms (Scheme 3). Considering the
chemical shifts of C-3 ( 129.0 ppm) and C-9a ( 160.2 ppm), the
indicating its involvement into an intramolecular hydrogen bond
to the pyranone carbonyl O-atom (Fig. 4). In contrast, the terminal
d
d
NH2 protons exhibit a much smaller chemical shift (
d 4.01 ppm).
diagnostic coupling constant 2J(C3a,H3) = 8.3 Hz [31] as well as
the results of NOE-experiments (NOE on H-3 upon irradiation of
NH) it is assumed that 14x exists in an equilibrium of the 1H and
2H-form in (CD3)2SO solution (Scheme 3), as found with related
compounds [5–8].
The substitution pattern in the N,N-dimethlylamino product 19y
clearly results from an NOE-difference experiment: irradiation of the
NMe2 resonance (2.97 ppm) gives the H-6 signal an explicit NOE,
whereas the signal of H-8 remains unaffected (Scheme 3). This
unequivocally assigns the 5-NMe2-7-F substitution pattern of 19y. In
caseofa reverse5-F-7-NMe2 substitutionanNOEon bothH-6as well
as H-8 has to be expected after irradiation of the NMe2 transition.
Similar chemical shifts ( NH 9.91 ppm, NH2 4.46 ppm) were
d
d
found in (CD3)2SO solution. Moreover, it should be mentioned that
in both solvents a marked NOE between NH2 and H-6 (Fig. 4) and
no NOE between NH and H-6 was observed, providing an
additional hint for the strong fixation via the intramolecular
hydrogen bond.
3. Conclusions
In summary we have presented a simple and straightforward
synthesis of fluoro-substituted benzo- and benzothieno fused
pyrano[2,3-c]pyrazol-4(1H)-ones starting from commercially avail-
able or easily accessible pyrazolones and aroyl chlorides. It was
demonstrated that representatives of type 14 can be used as
precursors for further anellation reactions. Furthermore, we have
presented extensive NMR studies with all compounds obtained,
2.2.3. Other compounds
Products 26 and 27 resulting from reaction of 1a with 2,6-
dichlorobenzoyl chloride (Scheme 7) can be easily distinguished
on basis of their NMR data. The ester 26 exhibits a C–H moiety
incorporated in the pyrazole system which can be only attributed
to pyrazole C-4 with the H-4 singlet resonating at 6.34 ppm and C-
4 at 95.7 ppm (1J(C4,H4) = 181.7 Hz). Moreover, the small chemical
shift of pyrazole C-5 (143.6 ppm) is typical for such a structure
[38]. The large differences regarding the 15N chemical shifts of
providingfulland unambiguousassignmentof all1H, 13C, 15N and19
F
resonances as well as an ambitious analysis of homo- and hetero-
nuclear spin coupling constants. We continue to explore related
compounds with biologically relevant side-chains attached to the
tricyclic or tetracyclic cores—these results will be published
elsewhere.
pyrazole N-1 (ꢁ
d
183.1 ppm) and N-2 (
d
ꢁ95.1 ppm) hint to two
different types of N-atoms and thus to an ‘aromatic’ pyrazole
4. Experimental
system. In contrast, the N-benzoyl derivative 27 shows two much
more similar N-atoms (
reverse numbering of ring atoms compared to 26!) and a pyrazole
C-3 ( 168.0 ppm) typical for a pyrazolone structure.
d
N-1 = ꢁ190.7 ppm,
d
N-2 = ꢁ211.5 ppm;
4.1. General
d
Melting points were determined on a Reichert–Kofler hot-
stage microscope and are uncorrected. Mass spectra were
obtained on a Shimadzu QP 1000 instrument (EI, 70 eV) and on
a Finnigan MAT 8230 instrument (EI, 70 eV, HRMS). IR spectra
were recorded on a Perkin-Elmer FTIR 1605 spectrophotometer or
on a Perkin-Elmer FTIR spectrum 1000 spectrometer. Elemental
analyses (C, H, N) were performed at the Microanalytical
Laboratory, University of Vienna, and were in good agreement
Reaction of 14a,b with methyl hydrazine can principally lead to
two regioisomeric anellation products. Attachment of the methyl
group at N-2 (and hence presence of 28a,b) was confirmed by NOE-
difference experiments. Irradiation of the N-methyl resonance
(NMe) clearly enhanced the signal due to H-3 (6.69 ppm) (Fig. 4).
For a possible isomeric structure (methyl group attached to N-1) an
NOE to the signal of C-9-methyl has to be expected. In Fig. 4,
important chemical shifts (mainly assigned via HSQC and HMBC
experiments) and NOE correlations unequivocally confirming
structure 28 are given. According to its NMR spectra (1H NMR:
(
ꢂ0.4%) with the calculated values. 1H and 13C NMR spectra were
recorded on a Varian UnityPlus 300 spectrometer (299.95 MHz for
1H, 75.43 MHz for 13C) or on a Bruker Avance 500 spectrometer
(500.13 MHz for 1H, 125.77 MHz for 13C) at 25 8C. The centre of the
solvent signal was used as an internal standard which was related to
TMS with d 7.26 ppm (1H in CDCl3), d 2.49 ppm (1H in (CD3)2SO), d
77.0 ppm (13C in CDCl3), and d 39.5 ppm (13C in (CD3)2SO). 15N NMR
spectra (50.68 MHz, referenced against external nitromethane) and
19F NMR spectra (470.56 MHz, absolute referencing via Jratio) were
3 protons exchangeable with D2O; 13C NMR: signal at
d 178.1 ppm;
15N NMR: signals at ꢁ324.4 ppm and ꢁ288.7 ppm), MS, IR and
microanalytical data the reaction product of 14a with hydrazine
(compound 29) cannot be a tetracyclic system similar to 28 but
must be the substituted hydrazine 29. In CDCl3 solution the
hydrazine NH-proton has a marked downfield shift (d 10.15 ppm)

W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
1019
obtained on a Bruker Avance 500 instrument with a ‘directly’
detecting broadband observe probe (BBFO). Digital resolutions were
0.2 Hz/data point in the 1H and 19F NMR spectra and 0.4 Hz/data
point in the 1H coupled 13C NMR spectra (gated decoupling).
Systematic names according to IUPAC recommendations were
generated with ACD/Name [39] and subsequently proved manually
to ensure correct nomenclature within this publication [40].
Pyrazolone 1c was prepared according to Ref. [17], all other starting
materials are commercially available.
(CD3)2SO):
NMR (470 MHz, CDCl3):
(CD3)2SO):
MS (m/z, %): 301 (M++1, 13), 300 (M+, 78), 186 (85), 141 (100), 113
d
ꢁ181.9 (pyraz N-1), pyraz N-2 was not found. 19F
d
ꢁ111.3 (CPh F-2,6). 19F NMR (470 MHz,
d
ꢁ114.4 (CPh F-2,6). IR (KBr):
n
(cmꢁ1) 1623.0 (C55O).
(22), 91 (22), 77 (63), 53 (20), 51 (31). Anal. Calcd for
C16H10F2N2O2: C, 64.00; H, 3.36; N, 9.33. Found: C, 63.99; H,
3.21; N, 9.49.
4.2.3. (2,6-Difluorophenyl)[5-hydroxy-1-(4-methoxybenzyl)-1H-
pyrazol-4-yl]methanone (8c)
4.2. General procedure for the 4-aroylation of pyrazolones 1:
synthesis of compounds 8–13, 21 and 24
Yield 62%; brownish crystals; mp 146–148 8C (EtOH–H2O). 1H
NMR (300 MHz, CDCl3): d 3.78 (3H, s, OMe), 5.11 (2H, s, NCH2), 6.88
(2H, m, CH2Ph H-3,5), 6.99 (m, CPh H-3,5), 7.30 (2H, m, CH2Ph H-
2,6), 7.41 (1H, m, CPh H-4), 7.43 (1H, t, pyraz H-3,
Under anhydrous conditions, to a suspension of pyrazolone 1a–
d and Ca(OH)2 (2 equiv) in dry 1,4-dioxane (2 mL per mmol of
pyrazolone) a solution/suspension of the corresponding acid
chloride 2–7, 20, 23 (1 equiv) in dry 1,4-dioxane (2 mL per mmol)
was added. The reaction mixture was heated at reflux for 3 h under
stirring. After cooling to room temperature, the mixture was
treated with 2 N HCl (4 mL per mmol), stirred for 15 min, and
poured into H2O (10 mL per mmol). After 30 min, the solid
products were filtered off, washed with H2O, and recrystallized
from the solvent given below.
J(H3,F2,6) = 1.6 = Hz), 9.50 (1H, OH). 13C NMR (75 MHz, CDCl3):
d
49.8 (NCH2, 1J = 140.6 Hz, 3J = 4.5 Hz), 55.2 (OMe, 1J = 143.9 Hz),
105.2 (pyraz C-4, 2J(C4,H3) = 10.5 Hz), 112.1 (m, CPh C-3,5), 114.1
(CH2Ph C-3,5), 115.9 (CPh C-1, 2J(C1,F2,6) = 20.0 Hz, 3J(C1,H-
3,5) = 4.6 Hz), 127.2 (CH2Ph C-1), 129.5 (CH2Ph C-2,6), 132.4
(CPh C-4, 1J = 164.7 Hz, 3J(C4,F2,6) = 10.1 Hz), 139.2 (pyraz C-3,
1J = 190.7 Hz, J(C3,F2,6) = 2.7 Hz), 157.6 (pyraz C-5), 159.5 (CH2Ph
C-4), 159.6 (CPh C-2,6, 1J(C,F) = 253.7 Hz, 3J(C,F) = 6.8 Hz), 183.0
(C55O). 15N NMR (50 MHz, CDCl3):
(pyraz N-2). 19F NMR (470 MHz, CDCl3):
(KBr):
(cmꢁ1) 1660.0 (C55O). MS (m/z, %): 344 (M+, 19), 141 (19),
d
ꢁ189.0 (pyraz N-1), ꢁ97.0
ꢁ111.5 (CPh F-2,6). IR
d
4.2.1. (2,6-Difluorophenyl)(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)methanone (8a)
n
121 (100). Anal. Calcd for C18H14F2N2O3: C, 62.79; H, 4.10; N, 8.14.
Found: C, 62.70; H, 4.08; N, 8.18.
Yield 81%; colorless solid; mp 176–180 8C (EtOH–H2O). 1H NMR
(300 MHz, CDCl3):
(1H, m, NPh H-4), 7.47(1H, m, CPh H-4), 7.48(2H, m, NPh H-3,5), 7.84
(2H, m, NPh H-2,6), 9.64 (1H, br s, OH). 13C NMR (75 MHz, CDCl3):
13.2 (3-Me, 1J = 128.9 Hz), 105.5 (pyraz C-4, 3J(C4,3Me) = 2.7 Hz),
112.0 (m, CPh C-3,5), 116.4 (CPh C-1, 2J(C1,F2,6) = 21.5 Hz), 121.1
(NPh C-2,6), 127.0 (NPh C-4), 129.1 (NPh C-3,5), 132.3 (CPh C-4,
1J = 164.7 Hz, 3J(C4,F2,6) = 9.7 Hz), 136.9 (NPhC-1), 148.3 (pyraz C-3,
2J(C3,3Me) = 6.9 Hz), 159.1 (CPh C-2,6, 1J(C,F) = 252.0 Hz,
3J(C,F) = 7.2 Hz), 159.7 (pyraz C-5), 183.6 (C55O). 15N NMR
d 1.98 (3H, s, 3-Me), 7.04 (2H, m, CPh H-3,5), 7.32
4.2.4. (2,5-Difluorophenyl)(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)methanone (9a)
Yield 55%; colorless solid; mp 168 8C (EtOH–H2O). 1H NMR
(300 MHz, CDCl3): 2.04 (3H, s, 3-Me), 7.17 (1H, m, CPh H-6), 7.19
(1H, m, CPh H-3), 7.20 (1H, m, CPh H-4), 7.33 (1H, m, NPh H-4), 7.48
(2H, m, NPh H-3,5), 7.84 (2H, m, NPh H-2,6), 6–9 (1H, very br s, OH).
d
13C NMR (75 MHz, CDCl3):
d
13.9 (3-Me, 1J = 128.9 Hz,
J(Me,F) = 2.6 Hz), 104.6 (pyraz C-4, 3J(C4,3Me) = 2.7 Hz), 115.5
(CPh C-6, 2J(C6,F5) = 25.4 Hz, 3J(C6,F2) = 3.5 Hz), 117.7 (CPh C-3,
(50 MHz, CDCl3):
NMR(470 MHz, CDCl3):
(C55O). MS (m/z, %): 314 (M+, 53), 200 (71), 141 (100), 132 (20), 113
d
ꢁ190.3 (pyraz N-1), ꢁ100.7 (pyraz N-2). 19F
d
ꢁ113.1 (CPhF-2,6). IR(KBr):
n
(cmꢁ1) 1628
2J(C3,F2) = 24.3 Hz,
3J(C3,F5) = 8.3 Hz),
119.3
(CPh
C-4,
2J(C4,F5) = 24.1 Hz, 3J(C4,F2) = 8.5 Hz), 121.0 (NPh C-2,6), 127.1
(NPh C-4), 127.8 (CPh C-1, 2J(C1,F2) = 19.1 Hz, 3J(C1,F5) = 7.1 Hz),
129.2 (NPh C-3,5), 136.9 (NPh C-1), 148.2 (pyraz C-3,
2J(C3,3Me) = 6.8 Hz), 154.5 (CPh C-5, 1J(C5,F5) = 246.3 Hz,
4J(C5,F2) = 2.6 Hz), 158.5 (CPh C-2, 1J(C2,F2) = 245.5 Hz,
4J(C2,F5) = 2.5 Hz), 160.0 (pyraz C-5), 186.9 (C55O). 15N NMR
(23), 91 (57), 77 (59), 67 (37), 51 (39), 63 (21). Anal. Calcd for
C
17H12F2N2O2ꢃ0.1 H2O: C, 64.60; H, 3.89; N, 8.86. Found: C, 64.51; H,
4.00; N, 8.84.
4.2.2. (2,6-Difluorophenyl)(5-hydroxy-1-phenyl-1H-pyrazol-4-
yl)methanone (8b)
(50 MHz, CDCl3):
NMR (470 MHz, CDCl3):
d
ꢁ190.3 (pyraz N-1), ꢁ100.6 (pyraz N-2). 19F
Yield 50%; yellowish solid; mp 140–144 8C (EtOH). 1H NMR
d
ꢁ120.6 (CPh F-5), ꢁ117.1 (CPh F-2). IR
(300 MHz, CDCl3):
d
7.03 (2H, m, CPh H-3,5), 7.34 (1H, m, NPh H-4),
(KBr): n
(cmꢁ1) 1628 (C55O). MS (m/z, %): 314 (M+, 37), 200 (33),
7.48 (3H, m, CPh H-4 and NPh H-3,5), 7.63 (1H, t, pyraz H-3,
J(H3,F2,6) = 1.6 Hz), 7.85 (2H, m, NPh H-2,6), 10.69 (1H, OH). 1H
141 (100), 113 (40), 91 (39), 77 (73), 67 (40), 63 (24), 51 (39). Anal.
Calcd for C17H12F2N2O2: C, 64.97; H, 3.85; N, 8.91. Found: C, 64.65;
H, 3.75; N, 8.75.
NMR (300 MHz, (CD3)2SO):
d 7.22 (2H, m, CPh H-3,5), 7.35 (1H, m,
NPh H-4), 7.49 (2H, m, NPh H-3,5), 7.58 (1H, m, CPh H-4), 7.69 (2H,
m, NPh H-2,6), 7.75 (1H, s, pyraz H-3), 7.98 (1H, br s OH). 13C NMR
(75 MHz, CDCl3):
(CPh C-3,5), 115.6 (CPh C-1, 2J(C1,F2,6) = 19.6 Hz), 121.2 (NPh C-
2,6), 127.3 (NPh C-4), 129.1 (NPh C-3,5), 132.8 (CPh C-4,
1J = 165.0 Hz, 3J(C4,F2,6) = 10.2 Hz), 137.0 (NPh C-1), 139.8 (pyraz
C-3, 1J = 191.2 Hz, J(C3,F2,6) = 2.9 Hz), 158.3 (pyraz C-5,
4.2.5. (2,4-Difluorophenyl)(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)methanone (10a)
d
106.0 (pyraz C-4, 2J(C4,H3) = 10.5 Hz), 112.2
Yield 71%; colorless solid; mp 145 8C (EtOH–H2O). 1H NMR
(300 MHz, CDCl3): d 2.04 (3H, d, 3-Me, J(Me,F) = 1.1 Hz), 6.96 (1H, m,
CPh H-3), 7.04 (1H, m, CPh H-5), 7.32 (1H, m, NPh H-4), 7.47 (2H, m,
NPhH-3,5), 7.49 (1H, m,CPhH-6),7.85(2H, m, NPhH-2,6), 9.92(1H, s,
3J(C5,H3) = 4.6 Hz),
159.7
(CPh
C-2,6,
1J(C,F) = 254.2 Hz,
OH). 13C NMR (75 MHz, CDCl3): 14.0 (3-Me, 1J = 128.8 Hz,
d
3J(C,F) = 6.8 Hz), 183.3 (C55O). 13C NMR (75 MHz, (CD3)2SO):
d
J(Me,F) = 2.7 Hz), 104.7 (CPh C-3, 1J(C3,H3) = 167.4 Hz, 2J(C3,F2) =
25.3 Hz, 2J(C3,F4) = 25.3 Hz, 3J(C3,H5) = 4.3 Hz, 4J(C3,H6) = 1.5 Hz),
104.8 (pyraz C-4, 3J(C4,3Me) = 2.8 Hz), 112.1 (CPh C-5,
106.8 (pyraz C-4, 2J(C4,H3) = 9.2 Hz), 112.1 (m, CPh C-3,5), 117.7 (t,
CPh C-1, 2J(C1,F2,6) = 22.6 Hz), 122.2 (NPh C-2,6), 127.0 (NPh C-4),
129.0 (NPh C-3,5), 132.1 (t, CPh C-4, 3J(C4,F2,6) = 10.1 Hz), 137.1
(NPh C-1), 141.2 (pyraz C-3, 1J = 189.3 Hz), 155.6 (pyraz C-5,
1J(C5,H5) = 167.5 Hz, 2J(C5,F4) = 21.7 Hz, 3J(C5,H3)
= 3.8 Hz,
4J(C5,F2) = 3.7 Hz), 121.0 (NPh C-2,6), 123.2 (CPh C-1, 2J(C1,F2) =
16.1 Hz, 3J(C1,H3) = 4.2 Hz, 3J(C1,H5) = 7.3 Hz, 4J(C1,F4) = 3.9 Hz),
126.9 (NPh C-4), 129.1 (NPh C-3,5), 130.6 (CPh C-6,
1J(C6,H6) = 165.5 Hz, 3J(C6,F2) = 4.6 Hz, 3J(C6,F4) = 10.0 Hz), 137.0
3J(C5,H3) = 4.9 Hz),
158.7
(CPh
C-2,6,
1J(C,F) = 248.0 Hz,
3J(C,F) = 8.1 Hz), 179.2 (C55O). 15N NMR (50 MHz, CDCl3):
d
ꢁ185.0 (pyraz N-1), ꢁ96.6 (pyraz N-2). 15N NMR (50 MHz,

1020
W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
(NPh C-1), 148.2 (pyraz C-3, 2J(C3,3Me) = 6.9 Hz), 159.6 (CPh C-2*,
1J(C2,F2) = 253.7 Hz, 3J(C2,F4) = 12.4 Hz), 160.2 (pyraz C-5), 164.6
4J(F2,H4) = 8.6 Hz, 5J(F2,H5) = 1.8 Hz), ꢁ118.3 (m, CPh F-6,
5J(F6;F3) = 15.5 Hz, 3J(F6,H5) = 7.9 Hz, 4J(F6,H4) = 5.0 Hz). IR
(CPhC-4*,1J(C4,F4) = 254.5 Hz, 3J(C4,F2) = 11.6 Hz),187.1(C55O).15
N
F
(KBr): n
(cmꢁ1) 1635 (C55O). MS (m/z, %): 333 (M++1, 19), 332
NMR (50 MHz, CDCl3):
NMR (470 MHz, CDCl3):
(KBr):
d
ꢁ190.5 (pyraz N-1), ꢁ100.7 (pyraz N-2). 19
(M+, 100), 313 (33), 201 (19), 200 (57), 159 (49), 91 (47), 77 (59), 67
(26). Anal. Calcd for C17H11F3N2O2ꢃ0.2 H2O: C, 60.79; H, 3.42; N,
8.34. Found: C, 60.74; H, 3.19; N, 8.34.
d
ꢁ109.9 (CPh F-2), ꢁ104.0 (CPh F-4). IR
n
(cmꢁ1) 1637 (C55O). MS (m/z, %): 314 (M+, 26), 200 (55), 141
(100),113(32),91(41),67(26),51(37).Anal.CalcdforC17H12F2N2O2:
C, 64.97; H, 3.85; N, 8.91. Found: C, 64.80; H, 3.89; N, 8.77.
4.2.8. (5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(2,4,6-
trifluorophenyl)methanone (13a)
4.2.6. (2,3-Difluorophenyl)(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)methanone (11a)
Yield 71%; colorless solid; mp 160 8C (EtOH–H2O). 1H NMR
(300 MHz, CDCl3):
d 2.01 (3H, s, 3-Me), 6.80 (2H, m, CPh H-3,5,
Yield 56%; colorless solid; mp 110 8C (EtOH–H2O). 1H NMR
3J(H3,F2) = 7.5 Hz, 3J(H3,F4) = 8.5 Hz), 7.32 (1H, m, NPh H-4), 7.47
(2H, m, NPh H-3,5), 7.82 (2H, m, NPh H-2,6), 10.05 (1H, br s, OH).
(300 MHz, CDCl3):
d 2.01 (3H, d, 3-Me, J(Me,F) = 0.9 Hz), 7.22 (1H,
m, CPh H-6), 7.24 (1H, m, CPh H-5), 7.33 (1H, m, NPh H-4), 7.36 (1H,
m, CPh H-4), 7.48 (2H, m, NPh H-3,5), 7.84 (2H, m, NPh H-2,6),
10.50 (1H, br s, OH). 1H NMR (300 MHz, (CD3)2SO):
d 2.37 (3H, s, 3-
13C NMR (75 MHz, CDCl3): 13.3 (3-Me, 1J = 128.7 Hz), 101.1 (CPh
d
C-3,5, 2J(C,F) = 26.0 Hz, 4J(C,F) = 3.8 Hz), 105.5 (pyraz C-4,
3J(C4,3Me) = 2.7 Hz), 113.2 (CPh C-1, 2J(C1,F2,6) = 22.1 Hz,
4J(C1,F4) = 4.4 Hz), 121.1 (NPh C-2,6), 127.2 (NPh C-4), 129.2
Me), 7.24 (1H, m, CPh H-6), 7.25 (1H, m, CPh H-5), 7.28 (1H, m, NPh
H-4), 7.46 (2H, m, NPh H-3,5), 7.52 (1H, m, CPh H-4), 7.61
(NPh
C-3,5),
136.8
(NPh
C-1),
148.1
(pyraz
C-3,
(2H, m, NPh H-2,6), 6-10 (1H, br s, OH). 13C NMR (75 MHz, CDCl3):
d
2J(C3,3Me) = 6.9 Hz), 159.6 (pyraz C-5), 159.7 (CPh C-2,6
1J(C,F) = 253.1 Hz, 3J(C,F) = 14.9 and 10.0 Hz), 163.9 (CPh C-4,
1J(C4,F4) = 254.2 Hz, 3J(C4,F2,6) = 14.9 Hz), 182.6 (C55O). 15N
13.9 (3-Me, 1J = 128.9 Hz, J(Me,F) = 2.0 Hz), 104.6 (pyraz C-4,
3J(C4,3Me) = 2.7 Hz), 119.7 (CPh C-4, 2J(C4,F3) = 17.3 Hz), 121.0
(NPh C-2,6), 123.6 (CPh C-6, J(C6,F) = 3.9 and 1.7 Hz), 124.9 (CPh C-
5, J(C5,F) = 6.5 and 4.6 Hz), 127.1 (NPh C-4), 128.8 (CPh C-1,
2J(C1,F2) = 12.9 Hz), 129.2 (NPh C-3,5), 136.9 (NPh C-1), 147.1
(CPh C-2, 1J(C2,F2) = 253.0 Hz, 2J(C2,F3) = 14.0 Hz), 148.2
(pyraz C-3, 2J(C3,3Me) = 7.0 Hz), 150.4 (CPh C-3, 1J(C3,F3) =
251.1 Hz, 2J(C3,F2) = 12.5 Hz), 159.9 (pyraz C-5), 187.0 (C55O,
NMR (50 MHz, CDCl3):
d
ꢁ190.2 (pyraz N-1), ꢁ100.5 (pyraz N-
2). 19F NMR (470 MHz, CDCl3):
d
ꢁ109.7 (m, CPh F-2,6,
3J(F2,H3) = 7.5 Hz, 4J(F2/6,F4) = 7.5 Hz,), ꢁ102.8 (m, CPh F-4,
3J(F4,H3/5) = 8.5 Hz, 4J(F4,F2/6) = 7.5 Hz). IR (KBr):
n
(cmꢁ1) 1640
(C55O). MS (m/z, %): 333 (M++1, 11), 332 (M+, 56), 201 (16), 200
(99), 159 (100), 132 (47), 131 (27), 91 (78), 77 (63), 67 (32), 51 (41).
Anal. Calcd for C17H11F3N2O2ꢃ0.1 H2O: C, 61.12; H, 3.38; N, 8.39.
Found: C, 60.96; H, 3.12; N, 8.46.
3J(CO,F2) = 2.7 Hz). 13C NMR (75 MHz, (CD3)2SO):
d 13.8 (3-Me,
1J = 129.9 Hz), 104.6 (pyraz C-4, 3J(C4,3Me) = 2.4 Hz), 118.7 (CPh C-
4, 2J(C4,F3) = 17.1 Hz), 121.1 (NPh C-2,6), 124.4 (CPh C-6), 124.7
(CPh C-5, J(C5,F) = 6.7 and 4.3 Hz), 126.2 (NPh C-4), 129.0 (NPh C-
3,5), 131.2 (CPh C-1, 2J(C1,F2) = 12.9 Hz), 136.2 (NPh C-1), 147.0
(CPh C-2, 1J(C2,F2) = 249.0 Hz, 2J(C2,F3) = 13.4 Hz), 149.3 (CPh C-3,
1J(C3,F3) = 245.7 Hz, 2J(C3,F2) = 13.1 Hz), 150.6 (pyraz C-3), 158.4
(pyraz C-5), 183.7 (C55O, 3J(CO,F2) = 2.5 Hz) 15N NMR (50 MHz,
4.2.9. (2-Chlorophenyl)[1-(4-fluorophenyl)-5-hydroxy-3-methyl-
1H-pyrazol-4-yl]methanone (21d)
Yield 60%; colorless solid; mp 122–124 8C (EtOH–H2O). 1H NMR
(300 MHz, CDCl3):
d 1.84 (3H, s, 3-Me), 7.16 (2H, m, NPh H-3,5),
7.36 (1H, m, CPh H-6), 7.41 (1H, m, CPh H-5), 7.46 (1H, m, CPh H-4),
7.49 (1H, m, CPh H-3), 7.83 (2H, m, NPh H-2,6), 8.78 (1H, br s, OH).
d
13C NMR (75 MHz, CDCl3): 13.7 (3-Me, 1J = 129.0 Hz), 104.4
CDCl3):
(50 MHz, (CD3)2SO):
d
ꢁ190.1 (pyraz N-1), ꢁ100.5 (pyraz N-2). 15N NMR
d
pyraz N-1 not found, ꢁ93.3 (pyraz N-2). 19
F
NMR (470 MHz, CDCl3):
d
ꢁ139.8 (m, CPh F-2), ꢁ136.1 (m, CPh F-
(pyraz C-4, 3J(C4,3Me) = 2.7 Hz), 116.0 (NPh C-3,5, 2J(C,F4) =
23.0 Hz), 122.7 (NPh C-2,6, 3J(C,F4) = 8.4 Hz), 127.1 (CPh C-5),
127.8 (CPh C-6), 130.0 (CPh C-3), 130.4 (CPh C-2), 131.4 (CPh C-4),
133.2 (NPh C-1, 4J(C1,F4) = 3.0 Hz), 137.6 (CPh C-1), 148.6 (pyraz C-
3, 2J(C3,3Me) = 6.9 Hz), 159.9 (pyraz C-5), 161.1 (NPh C-4,
3), 3J(F2,F3) = 21.6 Hz. 19F NMR (470 MHz, (CD3)2SO):
d
ꢁ142.3 (m,
CPh F-3*), ꢁ139.3 (m, CPh F-2*), 3J(F2,F3) = 22.6 Hz. IR (KBr):
n
(cmꢁ1) 1628 (C55O). MS (m/z, %): 315 (M++1, 18), 314 (M+, 83), 295
(25), 200 (40), 141 (100), 113 (49), 91 (65), 77 (92), 69 (45), 67 (80),
63 (33), 51 (58). Anal. Calcd for C17H12F2N2O2: C, 64.97; H, 3.85; N,
8.91. Found: C, 64.67; H, 3.60; N, 8.84.
1J(C4,F4) = 247.2 Hz), 190.5 (C55O). 15N NMR (50 MHz, CDCl3):
d
ꢁ192.1 (pyraz N-1), ꢁ101.1 (pyraz N-2). 19F NMR (470 MHz,
CDCl3):
(KBr): n
d
ꢁ114.6 (F-4, 3J(F4,H3,5) = 8.2 Hz, 4J(F4,H2,6) = 4.8 Hz). IR
4.2.7. (5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(2,3,6-
trifluorophenyl)methanone (12a)
(cmꢁ1) 1624 (C55O). MS (m/z, %): 330/332 (M+, 45/16), 296
(20), 295 (M+ꢁCl, 100), 218 (32), 139/141 (2-chlorobenzoyl, 70/
Yield 71%; colorless solid; mp 157–158 8C (EtOH–H2O). 1H NMR
27), 95 (FC6H4, 64), 82 (48), 75 (65), 66 (78). Anal. Calcd for
(300 MHz, CDCl3):
3J(H5,H4) = 9.3 Hz,
d
2.00 (3H, s, 3-Me), 7.00 (1H, m, CPh H-5,
3J(H5,F6) = 7.9 Hz, 4J(H5,F3) = 3.4 Hz,
C17H12ClFN2O2: C, 61.73; H, 3.66; N, 8.47. Found: C, 61.71; H, 3.47;
N, 8.46.
5J(H5,F2) = 2.0 Hz), 7.31 (1H, m, CPh H-4, 3J(H4,F3) = 9.4 Hz,
3J(H4,H5) = 9.3 Hz, 4J(H4,F2) = 8.6 Hz, 4J(H4,F6) = 5.0 Hz), 7.34
(1H, m, NPh H-4), 7.49 (2H, m, NPh H-3,5), 7.83 (2H, m, NPh H-
4.2.10. (2-Chlorophenyl)[1-(4-chlorophenyl)-5-hydroxy-3-methyl-
1H-pyrazol-4-yl]methanone (21e)
2,6), 9.57 (1H, br s, OH). 13C NMR (75 MHz, CDCl3):
d
13.3 (3-Me,
ield 88%; colorless solid; mp 141–142 8C (EtOH–H2O). 1H NMR
1J = 129.0 Hz), 105.3 (pyraz C-4, 3J(C4,3Me) = 2.7 Hz), 111.8 (CPh C-
5, 2J(C5,F6) = 23.8 Hz, 3J(C5,F3) = 6.1 Hz*, 4J(C5,F2) = 4.2 Hz*), 118.0
(CPh C-1, 2J(C1,F) = 23.9 and 17.8 Hz), 119.1 (CPh C-4), 121.2 (NPh
C-2,6), 127.3 (NPh C-4), 129.2 (NPh C-3,5), 136.7 (NPh C-1), 146.9
(CPh C-2, 1J(C2,F2) = 254.5 Hz, 2J(C2,F3) = 15.7 Hz, 3J(C2,F6) =
8.1 Hz), 147.1 (CPh C-3, 1J(C3,F3) = 248.3 Hz, 2J(C3,F2) = 12.5 Hz,
4J(C3,F6) = 4.0 Hz), 148.1 (pyraz C-3, 2J(C3,3Me) = 6.9 Hz), 154.1
(300 MHz, CDCl3): d 1.84 (3H, s, 3-Me), 7.36 (1H, m, CPh H-6), 7.41
(1H, m, CPh H-5), 7.43 (2H, m, NPh H-3,5), 7.46 (1H, m, CPh H-4),
7.50 (1H, m, CPh H-3), 7.83 (2H, m, NPh H-2,6), 9.22 (1H, br s, OH).
13C NMR (75 MHz, CDCl3):
d
13.8 (3-Me, 1J = 129.0 Hz), 104.6
(pyraz C-4, 3J(C4,3Me) = 2.7 Hz), 121.8 (NPh C-2,6), 127.1 (CPh C-
5), 127.9 (CPh C-6), 129.3 (NPh C-3,5), 130.1 (CPh C-3), 130.5 (CPh
C-2), 131.4 (CPh C-4), 132.3 (NPh C-4), 135.7 (NPh C-1), 137.3 (CPh
C-1), 148.7 (pyraz C-3, 2J(C3,3Me) = 6.9 Hz), 160.4 (pyraz C-5),
(CPh C-6, 1J(C6,F6) = 248.7 Hz), 159.5 (pyraz C-5), 182.4 (C55O). 15
NMR (50 MHz, CDCl3):
ꢁ190.0 (pyraz N-1), ꢁ100.3 (pyraz N-2).
19F NMR (470 MHz, CDCl3):
ꢁ140.4 (m, CPh F-3,
3J(F3,F2) = 21.7 Hz, 3J(F3,H4) = 9.4 Hz,
N
d
190.2 (C55O). 15N NMR (50 MHz, CDCl3):
d
ꢁ192.1 (pyraz N-1),
d
ꢁ101.3 (pyraz N-2). IR (KBr):
n
(cmꢁ1) 1625 (C55O). MS (m/z, %):
5J(F3,F6) = 15.5 Hz,
346/348/350 (M+, 28/20/3), 311/313 (M+ꢁCl, 100/35), 139/141 (2-
4J(F3,H5) = 3.4 Hz), ꢁ136.0 (m, CPh F-2, 3J(F2,F3) = 21.7 Hz,
chlorobenzoyl, 77/29), 111/113 (ClC6H4, 64/25). Anal. Calcd for

W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
1021
C17H12Cl2N2O2: C, 58.81; H, 3.48; N, 8.07. Found: C, 58.80; H, 3.34;
N, 8.01.
4.3.2. 5-Fluoro-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one (14b)
Yield 64% (method a); colorless solid; mp 203–206 8C (EtOH).
1H NMR (300 MHz, CDCl3):
7.12 (1H, ddd, H-6,
d
4.2.11. (3-Chloro-6-fluoro-1-benzothiophen-2-yl)(5-hydroxy-3-
methyl-1-phenyl-1H-pyrazol-4-yl)methanone (24)
3J(H6,F5) = 10.7 Hz, 3J(H6,H7) = 8.2 Hz, 4J(H6,H8) = 1.0 Hz), 7.37
(1H, d0t0, H-8, 3J(H8,H7) = 8.6 Hz, 4J(H8,H6) = 1.0 Hz, 5J(H8,F5) =
1.3 Hz), 7.43 (1H, m, NPh H-4), 7.56 (2H, m, NPh H-3,5), 7.65 (1H,
Yield 53%; brownish solid; mp 199 8C (EtOH–H2O). 1H NMR
(300 MHz, CDCl3):
d
2.13 (3H, s, 3-Me), 7.30 (1H, dt, BTh H-5,
d0t0,
4J(H7,F5) = 5.4 Hz), 7.88 (2H, m, NPh H-2,6), 8.22 (1H, s, H-3).
13C NMR (75 MHz, CDCl3): 107.3 (C-3a, 2J(C3a,H3) = 10.0 Hz),
H-7,
3J(H7,H8) = 8.6 Hz,
3J(H7,H6) = 8.2 Hz,
3J(H5,H4) = 8.9 Hz, 3J(H5,F6) = 8.8 Hz, 4J(H5,H7) = 2.1 Hz), 7.34 (1H,
m, NPh H-4), 7.49 (2H, m, NPh H-3,5), 7.58 (1H, dd, BTh H-7,
3J(H7,F6) = 8.3 Hz, 4J(H7,H5) = 2.1 Hz), 7.87 (2H, m, NPh H-2,6), 7.90
(1H, dd, BTh H-4, 3J(H4,H5) = 8.9 Hz, 4J(H4,F6) = 5.0 Hz), 9.49 (1H, br
d
113.1 (C-6, 2J(C6,F5) = 21.4 Hz), 113.5 (C4a, 2J(C4a,F5) = 10.0 Hz),
113.7 (C8, 4J(C8,F5) = 4.5 Hz), 121.4 (NPh C-2,6), 127.9 (NPh C-4),
129.5 (NPh C-3,5), 133.9 (C-7, 3J(C7,F5) = 11.1 Hz), 136.8 (C-3,
s, OH). 13C NMR (75 MHz, CDCl3): 13.9 (3-Me, 1J = 129.0 Hz), 105.4
d
(pyraz C-4, 3J(C4,3Me) = 2.7 Hz), 109.1 (BTh C-7, 2J(C7,F6) = 26.0 Hz),
115.5 (BTh C-5, 2J(C5,F6) = 24.9 Hz), 120.8 (BTh C-3, 3J(C3,H4) =
.7 Hz), 121.0 (NPh C-2,6), 124.6 (BTh C-4, 3J(C4,F6) = 9.5 Hz), 127.1
(NPh C-4), 129.2 (NPh C-3,5), 131.8 (BTh C-2, 5J(C2,F6) = 3.8 Hz),
132.8 (BTh C-3a), 136.9 (NPh C-1), 138.9 (BTh C-7a, 3J(C7a,F6) =
10.6 Hz), 148.5 (pyraz C-3, 2J(C3,3Me) = 6.9 Hz), 159.9 (pyraz C-5),
162.1 (BTh C-6, 1J(C6,F6) = 249.5 Hz), 183.6 (C55O). 15N NMR
1J(C3,H3) =
3J(C9a,H3) = 4.8 Hz), 155.6 (C-8a, 3J(C8a,F5) = 3.9 Hz), 162.2 (C5,
195.0 Hz), 136.9 (NPh C-1), 152.0 (C-9a,
1J(C5,F5) = 266.1 Hz), 171.1 (C-4). 15N NMR (50 MHz, CDCl3):
d
ꢁ187.4 (N-1), ꢁ88.5 (N-2). 19F NMR (470 MHz, CDCl3):
d
ꢁ110.0
(F-5, 3J(F5,H6) = 10.7 Hz, 4J(F5,H7) = 5.4 Hz, 5J(F5,H8) = 1.3 Hz). IR
(KBr):
139 (100), 110 (20), 94 (21), 77 (94), 51 (50). Anal. Calcd for
C16H9FN2O2: C, 68.57; H, 3.24; N, 10.00. Found: C, 68.29; H, 3.08;
n
(cmꢁ1) 1672 (C55O). MS (m/z, %): 280 (M+, 41), 142 (31),
(50 MHz, CDCl3):
NMR (470 MHz, CDCl3):
d
ꢁ189.9 (pyraz N-1), ꢁ100.2 (pyraz N-2). 19F
d
ꢁ112.2 (F-6, ddd, 3J(F6,H5) = 8.8 Hz,
N, 9.94.
3J(F6,H7) = 8.3 Hz, 4J(F6,H4) = 5.0 Hz). IR(KBr): (cmꢁ1)1635(C55O).
n
MS (m/z, %): 386/388 (M+, 8/3), 351 (100), 352 (23), 200 (53), 91 (36),
67 (27), 51 (22). Anal. Calcd for C19H12ClFN2O2S: C, 58.99; H, 3.13; N,
7.24. Found: C, 58.81; H, 3.05; N, 7.13.
4.3.3. 5-Fluoro-1-(4-methoxybenzyl)chromeno[2,3-c]pyrazol-4(1H)-
one (14c)
Yield 54% (method a); beige solid; mp 168–171 8C (EtOH). 1
H
NMR (300 MHz, CDCl3):
d 3.78 (3H, s, OMe), 5.35 (2H, s, NCH2),
4.3. General procedure for the synthesis of anellated systems 17–19,
22 and 25
6.88 (2H, m, Ph H-3,5), 7.08 (1H, ddd, H-6, 3J(H6,F5) = 10.8 Hz,
3J(H6,H7) = 8.2 Hz, 4J(H6,H8) = 1.0 Hz), 7.29 (2H, m, Ph H-2,6),
7.31 (1H, d0t0, H-8, 3J(H8,H7) = 8.5 Hz, 4J(H8,H6) = 1.0 Hz,
5J(H8,F5) = 1.2 Hz), 7.61 (1H, d0t0, H-7, 3J(H7,H8) = 8.5 Hz,
3J(H7,H6) = 8.2 Hz, 4J(H7,F5) = 5.4 Hz), 8.04 (1H, s, H-3). 13C
Method a. Under anhydrous conditions, to a solution of the
corresponding 4-aroyl pyrazol-5-ol (8–13, 21, 24) (1 mmol) in
anhydrous DMF (5 mL) was added NaH (60% in mineral oil; 40 mg,
1 mmol). The reaction mixture was stirred at 150 8C overnight and
thenthe solventwasremovedunderreducedpressure. Water(5 mL)
was added to the residue and stirring was continued for 1 h further.
The precipitate formed was filtered off, washed with H2O and
petroleum ether and recrystallized from the solvent given below.
Method b. Under anhydrous conditions, to the corresponding 4-
aroylpyrazol-5-ol (1 mmol) in dry acetonitrile (5 mL) was added
K2CO3 (276 mg, 2 mmol) and the mixture was heated at reflux
overnight. Then the solvent was removed under reduced pressure,
H2O (5 mL) was added and the mixture was stirred for 1 h. The
precipitatewasfilteredoff, washedwithH2Oandrecrystallizedfrom
the solvent given below.
NMR (75 MHz, CDCl3):
d
51.1 (NCH2, 1J = 140.9 Hz, 3J(NCH2,Ph
H-2,6) = 4.5 Hz), 55.3 (OMe, 1J = 144.0 Hz), 106.1 (C-3a,
2J(C3a,H3) = 10.2 Hz), 112.8 (C-6, 2J(C6,F5) = 21.6 Hz), 113.5
(C4a, 2J(C4a,F5) = 9.7 Hz), 113.5 (C8, 4J(C8,F5) = 4.3 Hz), 114.3
(Ph C-3,5), 126.8 (Ph C-1), 129.4 (Ph C-2,6), 133.7 (C-7,
3J(C7,F5) = 11.1 Hz), 135.9 (C-3, 1J(C3,H3) = 194.2 Hz), 152.4 (C-
9a, 3J(C9a,H3) = 5.0 Hz, 3J(C9a,NCH2) = 2.5 Hz), 155.5 (C-8a,
3J(C8a,F5) = 3.8 Hz), 162.3 (C5, 1J(C5,F5) = 265.5 Hz), 159.7 (Ph
C-4), 171.1 (C-4). 15N NMR (50 MHz, CDCl3):
(N-2). 19F NMR (470 MHz, CDCl3):
d
ꢁ192.6 (N-1), ꢁ87.5
ꢁ110.2 (F-5,
d
3J(F5,H6) = 10.8 Hz, 4J(F5,H7) = 5.4 Hz, 5J(F5,H8) = 1.2 Hz). IR
(KBr):
n
(cmꢁ1) 1660 (C55O). MS (m/z, %): 324 (M+, 23), 121
(100). Anal. Calcd for C18H13FN2O3ꢃ0.4 H2O: C, 65.21; H, 4.20; N,
8.45. Found: C, 65.07; H, 3.93; N, 8.30.
4.3.1. 5-Fluoro-3-methyl-1-phenylchromeno[2,3-c]pyrazol-4(1H)-
one (14a)
4.3.4. 6-Fluoro-3-methyl-1-phenylchromeno[2,3-c]pyrazol-4(1H)-
one (15a)
Yield 83% (method a); colorless solid; mp 167–169 8C (EtOH).
1H NMR (300 MHz, CDCl3):
d
2.67 (3H, s, 3-Me), 7.10 (1H, ddd, H-6,
Yield 80% (method a); colorless solid; mp 163–169 8C. 1H
3J(H6,F5) = 10.7 Hz, 3J(H6,H7) = 8.2 Hz, 4J(H6,H8) = 1.1 Hz), 7.33
(1H, dt, H-8, 3J(H8,H7) = 8.5 Hz, 4J(H8,H6) = 1.1 Hz, 5J(H8;F5) =
1.2 Hz), 7.40 (1H, m, NPh H-4), 7.45 (2H, m, NPh H-3,5), 7.62 (1H,
d0t0, H-7, 3J(H7,H8) = 8.5 Hz, 3J(H7,H6) = 8.2 Hz, 4J(H7,F5) = 5.4 Hz),
NMR (300 MHz, CDCl3): d 2.69 (3H, s, 3-Me), 7.40 (3H, m, H-7
and Ph H-4), 7.52 (1H, dd, H-8, 3J(H8,H7) = 5.0 Hz,
4J(H8,F6) = 4.1 Hz), 7.55 (2H, m, Ph H-3,5), 7.86 (2H, m, Ph H-
2,6), 7.99 (1H, dd, H-5, 3J(H5,F6) = 8.3 Hz, 4J(H5,H7) = 3.1 Hz). 13
C
7.85 (2H, m, NPh H-2,6). 13C NMR (75 MHz, CDCl3):
d
14.0 (3-Me,
NMR (75 MHz, CDCl3): d
14.1 (3-Me, 1J = 129.3 Hz), 104.6 (C-3a,
1J = 129.4 Hz), 105.4 (C-3a, 3J(C3a,3Me) = 2.7 Hz), 113.0 (C-6,
2J(C6,F5) = 21.4 Hz), 113.6 (C8, 4J(C8,F5) = 4.3 Hz), 113.8 (C4a,
2J(C4a,F5) = 9.7 Hz), 121.3 (NPh C-2,6), 127.5 (NPh C-4), 129.4
(NPh C-3,5), 133.6 (C-7, 3J(C7,F5) = 11.1 Hz), 136.9 (NPh C-1), 148.4
(C-3, 2J(C3,3-Me) = 7.2 Hz), 152.1 (C-9a), 155.7 (C-8a, 3J(C8a,F5) =
3.8 Hz), 162.2 (C5, 1J(C5,F5) = 265.6 Hz), 172.1 (C-4). 15N NMR
3J(C3a,3Me) = 2.7 Hz), 112.2 (C-5, 2J(C5,F6) = 24.2 Hz), 119.4 (C-
8, 3J(C8,F6) = 7.8 Hz), 121.4 (Ph C-2,6), 121.4 (C-7,
2J(C7,F6) = 25.4 Hz), 124.9 (C-4a, 3J(C4a,F6) = 6.8 Hz), 127.5 (Ph
C-4), 129.4 (Ph C-3,5), 136.9 (Ph C-1), 148.1 (C-3, 2J(C3,3-
Me) = 7.1 Hz), 150.5 (C8a, 4J(C8a,F6) = 2.1 Hz), 153.1 (C-9a),
159.6 (C-6, 1J(C6,F6) = 246.6 Hz), 172.5 (C-4, 4J(C4,F6) = 1.9 Hz).
(50 MHz, CDCl3):
d
ꢁ193.6 (N-1), ꢁ95.5 (N-2). 19F NMR (470 MHz,
15N NMR (50 MHz, CDCl3):
(470 MHz, CDCl3):
d
ꢁ193.0 (N-1), ꢁ94.8 (N-2). 19F NMR
CDCl3):
d
ꢁ110.6 (F-5, 3J(F5,H6) = 10.7 Hz, 4J(F5,H7) = 5.4 Hz,
d
ꢁ115.4 (F-6, 3J(F6,H5) = 8.3 Hz,
5J(F5,H8) = 1.2 Hz). IR (KBr):
n
(cmꢁ1) 1672 (C55O). MS (m/z, %):
3J(F6,H7) = 7.3 Hz, 4J(F6,H8) = 4.1 Hz). IR (KBr): (cmꢁ1) 1662
n
295 (M++1, 16), 294 (M+, 100), 293 (M+ꢁ1, 60), 91 (35), 77 (74), 51
(40). Anal. Calcd for C17H11FN2O2ꢃ0.8 H2O: C, 66.14; H, 4.11; N,
9.07. Found: C, 66.00; H, 3.81; N, 9.00.
(C55O). MS (m/z, %): 295 (M++1, 16), 294 (M+, 100), 293 (M+ꢁ1,
77), 91 (20), 77 (57), 51 (30). Anal. Calcd for C17H11FN2O2: C,
69.38; H, 3.77; N, 9.52. Found: C, 69.48; H, 3.85; N, 9.32.

1022
W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
4.3.5. 7-Fluoro-3-methyl-1-phenylchromeno[2,3-c]pyrazol-4(1H)-
one (16a)
(C-8, 1J(C8,F8) = 249.4 Hz, 2J(C8,H7) = 5.9 Hz, 3J(C8,H6) = 11.2 Hz,
4J(C8,F5) = 4.3 Hz), 148.4 (C-3, 2J(C3,3-Me) = 7.2 Hz), 151.5 (C-9a),
157.3 (C-5, 1J(C5,F5) = 262.4 Hz, 2J(C5,H6) = 5.3 Hz, 3J(C5,H7) =
11.8 Hz, 4J(C5,F8) = 3.1 Hz), 171.2 (C-4). 15N NMR (50 MHz, CDCl3):
Yield 90% (method a); colorless solid; mp 165–169 8C. 1H NMR
(300 MHz, CDCl3):
d 2.69 (3H, s, 3-Me), 7.17 (1H, ddd, H-6,
3J(H6,H5) = 8.8 Hz, 3J(H6,F7) = 7.9 Hz, 4J(H6,H8) = 2.4 Hz), 7.23 (1H,
dd, H-8, 3J(H8,F7) = 8.9 Hz, 4J(H8,H6) = 2.4 Hz), 7.40 (1H, m, Ph H-4),
7.55 (2H, m, Ph H-3,5), 7.85 (2H, m, Ph H-2,6), 8.36 (1H, dd, H-5,
d
ꢁ192.7 (N-1), ꢁ94.9 (N-2). 19F NMR (470 MHz, CDCl3):
ꢁ136.7 (F-
d
8, 3J(F8,H7) = 9.5 Hz, 4J(F8,H6) = 3.7 Hz, 5J(F8,F5) = 17.7 Hz), ꢁ115.9
(F-5, 3J(F5,H6) = 10.2 Hz, 4J(F5,H7) = 4.3 Hz, 5J(F5,F8) = 17.7 Hz). IR
3J(H5,H6) = 8.8 Hz, 4J(H5,F7) = 6.3 Hz). 13C NMR (75 MHz, CDCl3):
d
(KBr): n
(cmꢁ1) 1679 (C55O). MS (m/z, %): 313 (M++1, 12), 312 (M+,
14.1 (3-Me, 1J = 129.3 Hz), 104.8 (C-8, 1J(C8,H8) = 167.0 Hz,
2J(C8,F7) = 26.2 Hz, 3J(C8,H6) = 4.1 Hz, 4J(C8,H5) = 1.4 Hz), 104.9
(C-3a, 3J(C3a,3Me) = 2.7 Hz), 113.6 (C-6, 1J(C6,H6) = 167.5 Hz,
2J(C6,F7) = 22.1 Hz, 3J(C6,H8) = 4.3 Hz), 120.2 (C-4a, 4J(C4a,F7) =
2.7 Hz), 121.4 (Ph C-2,6), 127.6 (Ph C-4), 129.1 (C-5,
1J(C5,H5) = 167.7 Hz, 3J(C5,F7) = 10.6 Hz), 129.5 (Ph C-3,5), 136.9
(Ph C-1), 148.2 (C-3, 2J(C3,3-Me) = 7.2 Hz), 153.0 (C-9a), 155.5 (C-8a,
68), 311 (M+ꢁ1, 41), 155 (37), 91 (40), 77 (100), 51 (54). Anal. Calcd
for C17H10F2N2O2: C, 65.39; H, 3.23; N, 8.97. Found: C, 65.01; H, 3.27;
N, 8.92.
4.3.8. Cyclization of 13a
4.3.8.1. 5,7-Difluoro-3-methyl-1-phenylchromeno[2,3-c]pyrazol-
4(1H)-one
2J(C8a,H8) = 5.0 Hz,
3J(C8a,F7) = 13.0 Hz,
3J(C8a,H5) = 10.7 Hz,
4J(C8a,H6) = 1.6 Hz), 165.6 (C-7, 1J(C7,F7) = 255.3 Hz), 172.6 (C-4).
(19a). Yield 81% (method b); colorless solid; mp 178–180 8C (EtOH–
H2O). 1H NMR (300 MHz, CDCl3):
d 2.66 (3H, s, 3-Me), 6.88 (1H, ddd,
15N NMR (50 MHz, CDCl3):
(470 MHz, CDCl3):
8.9 Hz, 4J(F7,H5) = 6.3 Hz). IR (KBr):
%): 295(M++1, 18), 294(M+, 100), 293(M+ꢁ1, 79), 91 (19), 77 (55), 51
(29). Anal. Calcd for C17H11FN2O2: C, 69.38;H, 3.77; N, 9.52. Found:C,
69.44; H, 3.89; N, 9.45.
d
ꢁ192.8 (N-1), ꢁ95.4 (N-2). 19F NMR
H-6, 3J(H6,F5) = 10.8 Hz, 3J(H6,F7) = 8.7 Hz, 4J(H6,H8) = 2.4 Hz), 7.07
(1H. ddd, H-8, 3J(H8,F7) = 8.7 Hz, 4J(H8,F6) = 2.4 Hz, 5J(H8,F5) =
1.8 Hz), 7.41 (1H, m, Ph H-4), 7.54 (2H, m, Ph H-3,5), 7.81 (2H, m, Ph
d
ꢁ102.8 (F-7, 3J(F7,H6) = 7.9 Hz, 3J(F7,H8) =
n
(cmꢁ1) 1660 (C55O). MS (m/z,
H-2,6). 13C NMR (75 MHz, CDCl3): 14.0 (3-Me, 1J = 129.4 Hz), 105.3
d
(C-3a, 3J(C3a,3Me) = 2.7 Hz), 101.4 (C-8, 1J(C8,H8) = 169.3 Hz,
2J(C8,F7) = 25.9 Hz, 3J(C8,H6) = 4.4 Hz, 4J(C8,F5) = 4.5 Hz), 102.4
(C-6, 1J(C6,H6) = 169.3 Hz, 2J(C6,F5) = 25.3 Hz, 2J(C6,F7) = 25.3 Hz,
3J(C6,H8) = 4.4 Hz), 110.9 (C-4a, 2J(C4a,F5) = 9.9 Hz, 3J(C4a,H6) =
4.4 Hz, 3J(C4a,H8) = 4.4 Hz, 4J(C4a,H7) = 3.7 Hz), 121.4 (Ph C-2,6),
127.7 (Ph C-4), 129.5 (Ph C-3,5), 136.7 (Ph C-1), 148.4 (C-3, 2J(C3,3-
Me) = 7.2 Hz), 152.0 (C-9a), 156.5 (C8a, 2J(C8a,H8) = 5.1 Hz,
3J(C8a,F5) = 6.1 Hz, 3J(C8a,F7) = 15.4 Hz), 163.1 (C-5, 1J(C5,F5) =
267.9 Hz, 2J(C5,H6) = 6.2 Hz, 3J(C5,F7) = 14.8 Hz), 164.6 (C-7,
4.3.6. 8-Fluoro-3-methyl-1-phenylchromeno[2,3-c]pyrazol-4(1H)-
one (17a)
Yield 64% (method a); colorless solid; mp 165–170 8C (EtOH). 1H
NMR (300 MHz, CDCl3):
d2.69 (3H, s, 3-Me), 7.37 (3H, m, Ph H-4 and
H-6, 3J(H6,H5) = 8.1 Hz, 3J(H6,H7) = 8.1 Hz, 4J(H6,F8) = 4.5 Hz), 7.48
(1H,
ddd,
H-7,
3J(H7,H6) = 8.1 Hz,
3J(H7,F8) = 10.2 Hz,
4J(H7,H5) = 1.5 Hz), 7.54 (2H, m, Ph H-3,5), 7.92 (2H, m, Ph H-2,6),
8.09 (1H, d0t0, H-5, 3J(H5,H6) = 8.1 Hz, 4J(H5,H7) = 1.5 Hz,
1J(C7,F7) = 255.7 Hz,
2J(C7,H6) = 6.0 Hz,
2J(C7,H8) = 6.0 Hz,
3J(C7,F5) = 15.1 Hz), 171.3 (C-4). 15N NMR (50 MHz, CDCl3):
d
5J(H5,F8) = 1.3 Hz). 13C NMR (75 MHz, CDCl3):
d
14.1 (3-Me,
1J = 129.3 Hz), 105.0 (C-3a, 3J(C3a,3Me) = 2.7 Hz), 119.9 (C-7,
1J(C7,H7) = 165.2 Hz, 2J(C7,F8) = 16.8 Hz, 2J(C7,H6) = 0.9 Hz,
ꢁ193.2 (N-1), ꢁ95.1 (N-2). 19F NMR (470 MHz, CDCl3):
ꢁ105.1 (F-
d
5, 3J(F5,H6) = 10.8 Hz, 4J(F5,F7) = 12.1 Hz, 5J(F5,H8) = 1.8 Hz),
ꢁ100.1 (F-7, 3J(F7,H6) = 8.7 Hz, 3J(F7,H8) = 8.7 Hz, 4J(F7,F5) =
3J(C7,H5) = 9.5 Hz), 120.7 (Ph C-2,6), 121.7 (C-5, 1J(C5,H5) =
167.5 Hz, 2J(C5,H6) = 1.3 Hz, 3J(C5,H7) = 8.5 Hz, 4J(C5,F8) = 3.8 Hz),
124.8 (C-6, 1J(C6,H6) = 166.3 Hz, 2J(C6,H5) = 1.1 Hz, 2J(C6,H7) =
12.1 Hz). IR (KBr):
n
(cmꢁ1) 1679 (C55O). MS (m/z, %): 313 (M++1,
20), 312 (M+, 100), 311 (M+ꢁ1, 68), 156 (15), 91 (19), 77 (31), 51
(15). Anal. Calcd for C17H10F2N2O2: C, 65.39; H, 3.23; N, 8.97. Found:
C, 65.11; H, 2.90; N, 8.89.
1.7 Hz,
3J(C6,F8) = 6.5 Hz),
125.5
(C-4a,
3J(C4a,H6) = 8.7,
3J(C4a,F8) = 0.6 Hz), 127.4 (Ph C-4), 129.5 (Ph C-3,5), 136.9 (Ph C-
1),
143.0
(C8a,
2J(C8a,F8) = 11.8 Hz,
3J(C8a,H5) = 7.5 Hz,
3J(C8a,H7) = 9.6 Hz, 4J(C8a,H6) = 1.7 Hz), 148.2 (C-3, 2J(C3,3-
Me) = 7.2 Hz), 150.9 (C-8, 1J(C8,F8) = 252.7 Hz), 152.2 (C-9a,
4.3.8.2. 5-(Dimethylamino)-7-fluoro-3-methyl-1-phenylchro-
meno[2,3-c]pyrazol-4(1H)-one (19y). Cyclization of 13a with NaH/
DMF (method a) gave 90% of a 2:1 mixture of 19a and 19y which
was separated by column chromatography (silica gel, eluent: light
petroleum–ethyl acetate, 2:1).
4J(C9a,F8) = 1,1 Hz),
172.5
(C-4,
3J(C4,H5) = 3.7 Hz,
4J(C4,F8) = 2.6 Hz). 15N NMR (50 MHz, CDCl3):
d
ꢁ192.3 (N-1),
ꢁ95.4 (N-2). 19F NMR (470 MHz, CDCl3):
d
ꢁ133.6 (F-8, 3J(F8,H7) =
Compound 19y: colorless solid, mp 184–186 8C. 1H NMR
10.2 Hz, 4J(F8,H6) = 4.5 Hz, 5J(F8,H5) = 1.3 Hz). IR (KBr):
n )
(cmꢁ1
1667 (C55O). MS (m/z, %): 295 (M++1, 18), 294 (M+, 100), 293 (M+ꢁ1,
80), 91 (37), 77 (94), 51 (60). Anal. Calcd for C17H11FN2O2ꢃ0.1 H2O: C,
68.96; H, 3.81; N, 9.46. Found: C, 68.99; H, 3.59; N, 9.36.
(300 MHz, CDCl3):
d 2.66 (3H, s, 3-Me), 2.97 (6H, s, NMe2), 6.58
(1H, dd, H-6, 3J(H6,F7) = 11.8 Hz, 4J(H6,H8) = 2.5 Hz), 6.65 (1H, dd,
H-8, 3J(H8,F7) = 8.7 Hz, 4J(H8,H6) = 2.5 Hz), 7.36 (1H, m, Ph H-4),
7.52 (2H, m, Ph H-3,5), 7.83 (2H, m, Ph H-2,6). 13C NMR (75 MHz,
CDCl3):
d
14.0 (3-Me, 1J = 129.1 Hz), 44.7 (NMe2, 1J = 136.8 Hz,
4.3.7. 5,8-Difluoro-3-methyl-1-phenylchromeno[2,3-c]pyrazol-
4(1H)-one (18a)
3J(CH3,CH3) = 4.1 Hz), 105.4 (C-3a, 3J(C3a,3Me) = 2.7 Hz), 95.9 (C-8,
2J(C8,F7) = 26.8 Hz), 100.6 (C-6, 2J(C6,F7) = 23.3 Hz), 110.9 (C-4a,
4J(C4a,F7) = 2.7 Hz), 120.9 (Ph C-2,6), 127.1 (Ph C-4), 129.4 (Ph C-
3,5), 137.1 (Ph C-1), 148.1 (C-3, 2J(C3,3-Me) = 7.1 Hz), 151.7 (C-9a),
156.2 (C-5, 3J(C5,F7) = 12.4 Hz), 159.2 (C8a, 3J(C8a,F7) = 16.4 Hz),
165.0 (C-7, 1J(C7,F7) = 251.2 Hz), 172.6 (C-4). MS (m/z, %): 337 (M+,
33), 91 (21), 77 (100), 69 (30), 51 (61). HRMS (ESI): Calcd for
Yield 87% (method a); colorless solid; mp 155–157 8C (EtOH). 1H
NMR (300 MHz, CDCl3):
d 2.67 (3H, s, 3-Me), 7.06 (1H, ddd, H-6,
3J(H6,F5) = 10.2 Hz, 3J(H6,H7) = 9.1 Hz, 4J(H6,F8) = 3.7 Hz), 7.39 (1H,
m, Ph H-4), 7.45 (1H, ddd, H-7, 3J(H7,H6) = 9.1 Hz, 3J(H7,F8) = 9.5 Hz,
4J(H7,F5) = 4.3 Hz), 7.54 (2H, m, Ph H-3,5), 7.90 (2H, m, Ph H-2,6). 13
C
NMR (75 MHz, CDCl3):
3J(C3a,3Me) = 2.8 Hz),
d
14.1 (3-Me, 1J = 129.5 Hz), 105.4 (C-3a,
112.1 (C-6,
1J(C6,H6) = 168.2 Hz,
C
19H17FN3O2 (MH+) 338.1305. Found: 338.1312.
2J(C6,F5) = 23.9 Hz, 2J(C6,H7) = 0.8 Hz, 3J(C6,F8) = 6.1 Hz), 114.9 (C-
4a, 2J(C4a,F5) = 11.3 Hz, 3J(C4a,F8) = 1.2 Hz, 3J(C4a,H6) = 5.3 Hz),
4.3.9. 1-(4-Fluorophenyl)-3-methylchromeno[2,3-c]pyrazol-4(1H)-
one (22d)
119.8
(C-7,
1J(C7,H7) = 167.1 Hz,
2J(C7,F8) = 19.0 Hz,
Yield 45% (method a); colorless solid; mp 182–184 8C (EtOH). 1H
3J(C7,F5) = 10.3 Hz), 120.7 (Ph C-2,6), 127.5 (Ph C-4), 129.5 (Ph C-
3,5), 136.8 (Ph C-1), 143.7 (C8a, 2J(C8a,F8) = 13.0 Hz,
3J(C8a,F5) = 4.3 Hz, 3J(C8a,H7) = 8.6 Hz, 4J(C8a,H6) = 1.6 Hz), 147.2
NMR (300 MHz, CDCl3):
d 2.69 (3H, s, 3-Me), 7.24 (2H, m, Ph H-3,5),
7.45(1H, m,H-6), 7.51(1H, m, H-8), 7.70(1H, m, H-7),7.85(2H, m,Ph

W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
1023
H-2,6), 8.35 (1H, m, H-5). 13C NMR (75 MHz, CDCl3):
d
14.1 (3-Me,
NPh H-3,5), 7.58 (2H, m, NPh H-2,6). 13C NMR (75 MHz, CDCl3):
d
14.4 (3-Me, 1J = 127.8 Hz), 95.7 (pyraz C-4, 1J(C4,H4) = 181.7 Hz,
3J(C4,3Me) = 3.5 Hz), 123.6 (NPh C-2,6), 127.3 (NPh C-4), 128.0 (CPh
C-3,5), 128.9 (NPh C-3,5), 131.5 (CPh C-1), 131.8 (CPh C-4), 132.1
(CPh C-2,6), 137.6 (NPh C-1), 143.6 (pyraz C-5, 2J(C5,H4) = 4.6 Hz),
148.9 (pyraz C-3, 2J(C3,3Me) = 6.7 Hz, 2J(C3,H4) = 4.0 Hz), 160.0
1J = 129.3 Hz), 104.9 (C-3a, 3J(C3a,3Me) = 2.7 Hz), 116.3 (Ph C-3,5,
2J(C3,F4) = 23.0 Hz), 117.6 (C-8), 123.2 (Ph C-2,6, 3J(C2,F4) = 8.5 Hz),
123.4 (C-4a), 125.3 (C-6), 126.9 (C-5), 133.2 (Ph C-1,
4J(C1,F4) = 2.8 Hz), 133.8 (C-7), 148.3 (C-3, 2J(C3,3-Me) = 7.1 Hz),
152.9 (C-9a), 154.4(C-8a), 161.4 (Ph F-4, 1J(C4,F4) = 247.9 Hz), 173.5
(C-4, 3J(C4,H5) = 4.0 Hz, 4J(C4,H8) = 1.5 Hz). 15N NMR (50 MHz,
(C55O). 15N NMR (50 MHz, CDCl3):
(pyraz N-2). IR (KBr):
(cmꢁ1) 1775 (C55O). MS (m/z, %): 346/348/
d
ꢁ183.1 (pyraz N-1), ꢁ95.1
CDCl3):
d
ꢁ195.1 (N-1), ꢁ96.0 (N-2). 19F NMR (470 MHz, CDCl3):
n
d
ꢁ113.7 (Ph F-4). IR (KBr):
n
(cmꢁ1) 1672 (C55O). MS (m/z, %): 294
350 (M+, 2.7/1.9/0.3), 173/175/177 (2,6-dichlorobenzoyl, 100/73/
11), 77 (39). Anal. Calcd for C17H12Cl2N2O2: C, 58.81; H, 3.48; N, 8.07.
Found: C, 58.72; H, 3.36; N, 8.07.
(M+, 40), 293 (M+ꢁ1, 23), 120 (27), 109 (31), 95 (99), 74 (97), 69
(100). Anal. Calcd forC17H11FN2O2ꢃ0.2H2O:C, 68.54;H, 3.86; N, 9.40.
Found: C, 68.61; H, 3.57; N, 9.39.
4.4.2. 1-(2,6-Dichlorobenzoyl)-5-methyl-2-phenyl-1,2-dihydro-3H-
4.3.10. 1-(4-Chlorophenyl)-3-methylchromeno[2,3-c]pyrazol-4(1H)-
one (22e)
pyrazol-3-one (27)
1H NMR (300 MHz, CDCl3):
d 2.71 (3H, s, 5-Me), 5.65 (1H, s, pyraz
Yield 77% (method b) or 33% (method a);colorless solid; mp202–
H-4), 6.90 (2H, m, NPh H-2,6), 7.04 (2H, m, COPh H-3,5), 7.07 (1H, m,
COPh H-4), 7.13 (1H, m, NPh H-4), 7.14 (2H, m, NPh H-3,5). 13C NMR
205 8C (EtOH–H2O). 1H NMR (300 MHz, CDCl3):
d 2.69 (3H, s, 3-Me),
7.46 (1H, m, H-6), 7.51 (2H, m, Ph H-3,5), 7.52 (1H, m, H-8), 7.71 (1H,
m, H-7), 7.86 (2H, m, Ph H-2,6), 8.36 (1H, m, H-5). 13C NMR (75 MHz,
(75 MHz, CDCl3): d
16.3 (5-Me, 1J = 131.5 Hz, 3J(5Me,H4) = 2.2 Hz),
103.3 (pyraz C-4, 1J(C4,H4) = 182.8 Hz, 3J(C4,5Me) = 4.5 Hz), 124.3
(NPh C-2,6), 127.6 (NPh C-4), 127.8 (COPh C-3,5), 128.8 (NPh C-3,5),
131.6 (COPh C-4), 133.0 (COPh C-2,6), 133.3 (COPh C-1), 137.4 (NPh
C-1), 156.3(pyraz C-5, 2J(C5,5Me) = 6.8 Hz, 2J(C5,H4) = 8.1 Hz), 163.2
(N1-CO), 168.0 (pyraz C-3, 2J(C3,H4) = 4.9 Hz). 15N NMR (50 MHz,
CDCl3):
d
14.1
(3-Me,
1J = 129.3 Hz),
105.1
(C-3a,
3J(C3a,3Me) = 2.7 Hz), 117.6 (C-8), 122.2 (Ph C-2,6), 123.4 (C-4a),
125.4 (C-6), 126.9 (C-5), 129.6 (Ph C-3,5), 132.9 (Ph C-4), 133.9 (C-7),
135.6 (Ph C-1), 148.5 (C-3, 2J(C3,3-Me) = 7.1 Hz), 153.0 (C-9a), 154.5
(C-8a), 173.5(C-4). 15N NMR (50 MHz, CDCl3):
(N-2). IR (KBr):
(cmꢁ1) 1670 (C55O). MS (m/z, %): 310/312 (M+, 3/1),
d
ꢁ194.9(N-1), ꢁ96.8
CDCl3):
d
ꢁ211.5 (pyraz N-2), ꢁ190.7 (pyraz N-1). IR (KBr):
n )
(cmꢁ1
n
1691 (C55O). MS (m/z, %): 346/348/350 (M+, 2.1/1.4/0.3), 173/175/
177 (2,6-dichlorobenzoyl, 100/71/11), 145 (16), 77 (36). Anal. Calcd
for C17H12Cl2N2O2: C, 58.81; H, 3.48;N, 8.07. Found:C, 58.83;H,3.52;
N, 8.09.
243(17),141(27),69(99), 43(100).Anal. CalcdforC17H11ClN2O2ꢃ0.4
H2O: C, 64.22; H, 3.74; N, 8.81. Found: C, 64.29; H, 3.38; N, 8.85.
4.3.11. 7-Fluoro-3-methyl-1-phenyl[1]benzothieno[20,30:5,6]pyrano
[2,3-c]pyrazol-4(1H)-one (25)
4.5. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one (14x)
Yield 97% (method a); yellowish solid; mp 228–231 8C. 1H NMR
(300 MHz, CDCl3):
d
2.69 (3H, s, 3-Me), 7.28 (1H, ddd, H-8,
Under anhydrous conditions, a solution of the PMB-substi-
tuted tricycle 14c (324 mg, 1 mmol) and trifluoroacetic acid
(TFA, 5 mL) was stirred overnight at 70 8C. After removal of
excess TFA under reduced pressure, the residue was dried over
solid KOH for 1 h. Then 5 mL of ice-cold diethyl ether–acetone
(2:1) was added and the resulting suspension was filtered
off and washed with cold diethyl ether to give 81 mg (79%) of
the N-unsubstituted compound 14x as colorless solid, mp
>295 8C (dec.).
3J(H8,F7) = 8.6 Hz, 3J(H8,H9) = 8.9 Hz, 4J(H8,H6) = 2.2 Hz), 7.44 (1H,
m, Ph H-4), 7.57 (1H, dd, H-6, 3J(H6,F7) = 8.6 Hz, 4J(H6,H8) = 2.2 Hz),
7.59 (2H, m, Ph H-3,5), 7.91 (2H, m, Ph H-2,6), 8.00 (1H, dd, H-9,
3J(H9,H8) = 8.9 Hz, 4J(H9,F7) = 5.0 Hz). 13C NMR (75 MHz, CDCl3):
14.0 (3-Me, 1J = 129.4 Hz), 106.3 (C-3a, 3J(C3a,3Me) = 2.7 Hz), 110.3
(C-6, 2J(C6,F7) = 25.8 Hz), 114.9 (C-8, 2J(C8,F7) = 25.0 Hz), 121.2 (Ph
d
C-2,6),
123.1
(C-9,
3J(C9,F7) =
9.7 Hz),
123.7
(C4a,
5J(C4a,F7) = 3.3 Hz), 124.9 (C-9a, 4J(C9a,F7) = 1.6 Hz), 127.7 (Ph C-
4), 129.6(Ph C-3,5), 137.0 (Ph C-1), 140.8 (C-5a, 3J(C5a,F7) = 10.5 Hz),
147.3 (C-3, 2J(C3,3-Me) = 7.2 Hz), 149.3 (C-9b, 3J(C9b,H9) = 3.3 Hz),
153.3(C-10a),162.8(C-7, 1J(C7,F7) = 251.8 Hz), 170.3(C-4). 15NNMR
1H NMR (300 MHz, CDCl3):
3J(H6,F5) = 11.5 Hz, 3J(H6,H7) = 8.3 Hz, 4J(H6,H8) = 1.1 Hz), 7.45
d
7.18 (1H, ddd, H-6,
(1H,
d0t0,
H-8,
3J(H8,H7) = 8.5 Hz,
4J(H8,H6) = 1.1 Hz,
(50 MHz, CDCl3):
d
ꢁ192.9 (N-1), ꢁ93.4 (N-2). 19F NMR (470 MHz,
5J(H8;F5) = 0.9 Hz), 7.75 (1H, d0t0, H-7, 3J(H7,H8) = 8.5 Hz,
3J(H7,H6) = 8.3 Hz, 4J(H7,F5) = 5.8 Hz), 8.58 (1H, s, H-3), 13.78 (1H,
CDCl3):
d
ꢁ109.3 (F-7, 3J(F7,H6) = 8.6 Hz, 3J(F7,H8) = 8.6 Hz,
4J(F7,H9) = 5.0 Hz). IR (KBr):
n
(cmꢁ1) 1664 (C55O). MS (m/z, %):
br s, NH). 13C NMR (75 MHz, CDCl3): 106.0 (C-3a, 2J(C3a,H3) =
d
351(M++17),350(M+,76), 349(M+ꢁ1, 30),155(22), 138(25),94(26),
77 (100), 51 (44). Anal. Calcd for C19H11FN2O2S: C, 65.13; H, 3.16; N,
8.00. Found: C, 65.12; H, 3.22; N, 7.92.
8.3 Hz), 111.4 (C-6, 1J(C6,H6) = 167.0 Hz, 2J(C6,F5) = 21.2 Hz,
3J(C6,H8) = 8.1 Hz), 112.1 (C4a, 2J(C4a,F5) = 9.8 Hz), 114.2 (C8,
4J(C8,F5) = 4.0 Hz), 129.0 (C-3, broad), 134.8 (C-7, 1J(C7,H7) =
165.5 Hz, 3J(C7,F5) = 11.5 Hz), 156.5 (C-8a, 3J(C8a,F5) = 3.9 Hz),
160.2 (C-9a, broad), 161.2 (C5, 1J(C5,F5) = 261.9 Hz), 172.4 (C-4).
4.4. Reaction of pyrazolone 1a with 2,6-dichlorobenzoyl chloride
19F NMR (470 MHz, CDCl3):
d
ꢁ112.2 (F-5, 3J(F5,H6) = 11.5 Hz,
Pyrazolone 1a (1.74 g, 10 mmol), Ca(OH)2 (1.48 g, 20 mmol)
and 2,6-dichlorobenzoyl chloride (2.09 g, 10 mmol) were reacted
as described in the general procedure for the synthesis of 8–13, 21,
24. After addition of 2 N HCl (40 mL) and H2O (100 mL) the mixture
was exhaustively extracted with ethyl acetate. The combined
organic phases were washed with H2O, dried (Na2SO4) and
evaporated under reduced pressure. The residue was subjected
to column chromatography (silica gel, ethyl acetate) to afford
2.25 g (65%) of 26 as a brownish solid with mp 105–107 8C and
278 mg (8%) of 27 as a brownish solid with mp 175–183 8C.
4J(F5,H7) = 5.8 Hz, 5J(F5,H8) = 0.9 Hz). IR(KBr): (cmꢁ1)1652(C55O),
n
3169 (NH). MS (m/z, %): 205 (M++1, 12), 204 (M+, 100), 121 (29), 94
(21), 53 (24). HRMS (EI): Calcd for C10H5FN2O2 (M+): 204.0335.
Found: 204.0341.
4.6. Reaction of 14a and 14b with methylhydrazine—formation of
tetracycles 28a and 28b
A mixture of 14a (294 mg, 1 mmol) or 14b (280 mg, 1 mmol)
and methylhydrazine (46 mg, 1 mmol) in 1,4-dioxane (8 mL) was
stirred at reflux overnight. After removal of the solvent under
reduced pressure, the residue was digested with H2O. The
remaining solid was filtered off, washed with H2O and recrys-
tallized from EtOH.
4.4.1. 3-Methyl-1-phenyl-1H-pyrazol-5-yl 2,6-dichlorobenzoate (26)
1H NMR (300 MHz, CDCl3):
d
2.37 (3H, s, 3-Me), 6.34 (1H, s, pyraz
H-4), 7.29 (1H, m, NPh H-4), 7.33 (3H, m, CPh H-3,4,5), 7.40 (2H, m,

1024
W. Holzer et al. / Journal of Fluorine Chemistry 131 (2010) 1013–1024
4.6.1. 2,9-Dimethyl-7-phenyl-2,7-dihydropyrazolo[40,30:5,6]pyrano
[4,3,2-cd]indazole (28a)
NMR (50 MHz, CDCl3):
d
ꢁ324.4 (NH2), ꢁ288.7 (NH), ꢁ193.6 (N-1),
ꢁ97.9 (N-2). 15N NMR (50 MHz, (CD3)2SO):
d
ꢁ321.3 (NH2), ꢁ285.0
Yield 195 mg (65%) of a beige solid; mp 168–170 8C (EtOH). 1H
(NH), ꢁ193.6 (N-1), ꢁ95.9 (N-2). IR (KBr):
n
(cmꢁ1) 1631 (C55O). MS
NMR (300 MHz, CDCl3):
d
2.55 (3H, s, 9-Me), 3.85 (3H, s, 2-Me),
(m/z, %): 307 (M++1, 24), 306 (M+, 100), 289 (42), 275 (22), 91 (24), 77
(84), 69(38),51(45). Anal. CalcdforC17H14N4O2:C, 66.66;H,4.61;N,
18.29. Found: C, 66.69; H, 4.38; N, 18.18.
6.44 (1H, d, H-5, 3J(H5,H4) = 7.6 Hz), 6.69 (1H, d, H-3,
3J(H3,H4) = 8.2 Hz), 7.16 (1H, dd, H-4, 3J(H4,H3) = 8.2 Hz,
3J(H4,H5) = 7.6 Hz), 7.31 (1H, m, NPh H-4), 7.47 (2H, m, NPh H-
3,5), 7.80 (2H, m, NPh H-2,6). 13C NMR (75 MHz, CDCl3):
d 14.0 (9-
Acknowledgement
Me, 1J = 128.4 Hz), 35.5 (2-Me, 1J = 139.1 Hz), 98.1 (C-9a,
3J(C9a,9Me) = 3.4 Hz), 100.5 (C-5), 102.6 (C-3), 115.5 (C-9c),
121.3 (NPh C-2,6), 126.7 (NPh C-4), 129.0 (NPh C-3,5), 129.8
(C-4), 136.6 (C-9b), 137.7 (NPh C-1), 141.0 (C-2a), 143.5 (C-9,
The authors thank Mr. Ralf Dumler for experimental contribu-
tions.
2J(C9,9Me) = 6.9 Hz),
3J(C5a,H4) = 11.9 Hz, 4J(C5a,H3) = 1.7 Hz), 150.0 (C-6a). 15N NMR
(50 MHz, CDCl3):
148.9
(C-5a,
2J(C5a,H5) = 4.0 Hz,
References
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d
ꢁ213.2 (N-2), ꢁ189.4 (N-7), ꢁ103.5 (N-8),
ꢁ91.5 (N-1). MS (m/z, %): 302 (M+, 55), 158 (21), 77 (100), 51 (39).
Anal. Calcd for C18H14N4Oꢃ0.2 H2O: C, 70.67; H, 4.74; N, 18.31.
Found: C, 70.77; H, 4.44; N, 18.26.
[5] G.A. Eller, V. Wimmer, A.W. Haring, W. Holzer, Synthesis (2006) 4219–4229.
[6] G.A. Eller, A.W. Haring, B. Datterl, M. Zwettler, W. Holzer, Heterocycles 71 (2007)
87–104.
4.6.2. 2-Methyl-7-phenyl-2,7-dihydropyrazolo[40,30:5,6]pyrano[4,3,2
-cd]indazole (28b)
[7] G.A. Eller, W. Holzer, Molecules 12 (2007) 60–73.
Yield 230 mg (80%) of a yellowish solid, mp 156-158 8C (EtOH).
[8] G.A. Eller, B. Datterl, W. Holzer, J. Heterocycl. Chem. 44 (2007) 1139–1143.
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(Chem. Heterocycl. Comp. 44 (2008) 709–714).
1H NMR (300 MHz, CDCl3):
d 3.98 (3H, s, 2-Me), 6.60 (1H, d, H-5,
3J(H5,H4) = 7.7 Hz), 6.86 (1H, d, H-3, 3J(H3,H4) = 8.2 Hz), 7.31 (1H,
dd, H-4, 3J(H4,H3) = 8.2 Hz, 3J(H4,H5) = 7.7 Hz), 7.39 (1H, m, NPh H-
4), 7.54 (2H, m, NPh H-3,5), 7.87 (2H, m, NPh H-2,6), 7.96 (1H, s, H-9).
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521–526.
13C NMR (75 MHz, CDCl3):
d
35.8 (2-Me, 1J = 139.2 Hz), 98.9 (C-9a,
2J(C9a,H9) = 10.6 Hz), 100.9 (C-5, 1J(C5,H5) = 164.8 Hz, 2J(C5,H4) =
1.7 Hz, 3J(C5,H3) = 7.5 Hz), 103.1 (C-3, 1J(C3,H3) = 165.5 Hz,
2J(C3,H4) = 1.2 Hz, 3J(C3,H5) = 7.4 Hz), 115.8 (C-9c, 3J(C9c,H3) =
5.5 Hz, 3J(C9c,H5) = 5.5 Hz, 4J(C9c,H4) = 1.0 Hz), 121.9 (NPh C-2,6),
127.4 (NPh C-4), 129.3 (NPh C-3,5), 130.3 (C-4, 1J(C4,H4) = 158.9 Hz,
2J(C4,H3) = 1.2 Hz, 2J(C4,H5) = 1.2 Hz), 133.8 (C-9, 1J(C9,H9) =
191.4 Hz), 136.1 (C-9b), 137.8 (NPh C-1), 141.5 (C-2a), 149.1 (C-
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Kletsas, Bioorg. Med. Chem. Lett. 15 (2005) 5057–5060.
5a), 150.3 (C-6a). 15N NMR (50 MHz, CDCl3):
d
ꢁ213.0 (N-2), ꢁ184.3
(N-7), ꢁ97.9 (N-8), ꢁ90.7 (N-1). MS (m/z, %): 289 (M++1, 18), 288
(M+, 100), 157 (29), 77 (47), 51 (33). Anal. Calcd for C17H12N4O: C,
70.82; H, 4.20; N, 19.43. Found: C, 70.65; H, 3.98; N, 19.15.
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4.7. Reaction of 14a with hydrazine hydrate: formation of 5-
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hydrazino-3-methyl-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one (29)
A mixture of 14a (589 mg, 2 mmol) and hydrazine hydrate
(100 mg, 2 mmol) in EtOH (20 mL) was stirred at reflux overnight.
Afterremoval ofthe solventunderreducedpressure, theresiduewas
digested with H2O, filtered off, washed with EtOH and recrystallized
from CH2Cl2 to afford 372 mg (65%) of fine yellow fibers, mp 221–
222 8C (CH2Cl2). 1H NMR (500 MHz, CDCl3):
d2.65 (3H, s, 3-Me), 4.01
(2H, s, NH2), 6.66 (1H, dd, H-8, 3J(H8,H7) = 8.0 Hz,
4J(H8,H6) = 0.9 Hz), 7.16 (1H, dd, H-6, 3J(H6,H7) = 8.5 Hz,
4J(H6,H8) = 0.9 Hz), 7.37 (1H, m, NPh H-4), 7.45 (1H, m, H-7,
3J(H7,H6) = 8.5 Hz, 3J(H7,H8) = 8.0 Hz), 7.53 (2H, m, NPh H-3,5), 7.87
(2H, m, NPh H-2,6), 10.15 (1H, s, NH). 1H NMR (500 MHz, (CD3)2SO):
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d
2.50 (3H, s, 3-Me), 4.46 (2H, s, NH2), 6.65 (1H, dd, H-8,
´
[31] W. Holzer, C. Kautsch, C. Laggner, R.M. Claramunt, M. Perez-Torralba, I. Alkorta, J.
3J(H8,H7) = 8.1 Hz, 4J(H8,H6) = 1.0 Hz), 7.11 (1H, dd, H-6,
3J(H6,H7) = 8.6 Hz, 4J(H6,H8) = 1.0 Hz), 7.41 (1H, m, NPh H-4),
7.46 (1H, m, H-7, 3J(H7,H6) = 8.6 Hz, 3J(H7,H8) = 8.1 Hz), 7.58 (2H,
m, NPh H-3,5), 7.86 (2H, m, NPh H-2,6), 9.91 (1H, s, NH). 13C NMR
Elguero, Tetrahedron 60 (2004) 6791–6805.
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Verbindungen, 2nd ed., Springer, Berlin, 1981.
(125 MHz, CDCl3): d
14.1(3-Me, 1J = 129.1 Hz), 103.5(C-8), 104.6 (C-
[35] S. Berger, S. Braun, H.-O. Kalinowski, NMR-Spektroskopie von Nichtmetallen: 19F-
NMR-Spektroskopie, Thieme, Stuttgart/New York, 1994.
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[38] W. Holzer, C. Guo, K. Schalle, Molbank (2009) M603.
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Canada, 2006 http://www.acdlabs.com.
3a, 3J(C3a,3Me) = 2.7 Hz), 105.8 (C-6), 106.4 (C-4a), 121.0 (NPh C-
2,6), 127.1(NPhC-4), 129.4(NPhC-3,5), 134.5(C-7), 137.1(NPhC-1),
147.8 (C-3, 2J(C3,3-Me) = 7.2 Hz), 152.4 (C-9a), 154.9 (C-5), 156.7 (C-
8a), 178.1 (C-4). 13C NMR (125 MHz, (CD3)2SO):
d 13.8 (3-Me), 102.2
(C-8), 103.9 (C-3a), 105.0 (C-4a), 106.1 (C-6), 120.8 (NPh C-2,6),
127.3 (NPh C-4), 129.6 (NPh C-3,5), 134.6 (C-7), 136.7 (NPh C-1),
146.5 (C-3), 152.0 (C-9a), 154.9 (C-5), 156.3 (C-8a), 177.0 (C-4). 15
N
[40] G.A. Eller, Molecules 11 (2006) 915–928.