Ring-closing metathesis as a key step to construct the 2, 6-dihydropyrano[2, 3-c]pyrazole ring system

Article abstract of DOI:10.24820/ark.5550190.p010.407

A simple and efficient synthetic route to the 2, 6-dihydropyrano[2, 3-c]pyrazole ring system was developed by employing ring-closing metathesis (RCM) as a key step. The required diene substrate for the RCM reaction was prepared by a three-step procedure s

Full text of DOI:10.24820/ark.5550190.p010.407

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Ring-closing metathesis as a key step to construct the 2,6-dihydropyrano[2,3-
c]pyrazole ring system
Aurimas Bieliauskas,a,b Sonata Krikštolaitytė,b Wolfgang Holzer,c and Algirdas Šačkusa,b*
aInstitute of Synthetic Chemistry, Kaunas University of Technology, K. Baršausko g. 59, Kaunas LT-51423,
Lithuania
b Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254,
Lithuania
c Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Viena 1090, Austria
Email: algirdas.sackus@ktu.lt
Received 11-25-2017
Accepted 02-17-2018
Published on line 07-07-2018
Abstract
A simple and efficient synthetic route to the 2,6-dihydropyrano[2,3-c]pyrazole ring system was developed by
employing ring-closing metathesis (RCM) as a key step. The required diene substrate for the RCM reaction was
prepared by a three-step procedure starting form 1-phenyl-1H-pyrazol-3-ol. Treatment of the obtained 4-
ethenyl-1-phenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole with Grubbs‘ first-generation catalyst afforded the
target 2-phenyl-2,6-dihydropyrano[2,3-c]pyrazole. 2-(4-Fluorophenyl)- and 2-(4-bromophenyl)-2,6-
dihydropyrano[2,3-c]pyrazole were synthesized by an analogous way. The structures of the obtained
1
heterocyclic products were unequivocally confirmed by detailed H, 13C, 15N and 19F NMR spectroscopic
experiments and HRMS measurements. The optical properties of 2-phenyl-2,6-dihydropyrano[2,3-c]pyrazole
were studied by UV–Vis and fluorescence spectroscopy.
Keywords: 1-Phenylpyrazol-3-ol, Wittig olefination, Ring-closing metathesis, 2,6-Dihydropyrano[2,3-c]pyrazole
DOI: https://doi.org/10.24820/ark.5550190.p010.407
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Introduction
The pyrano[2,3-c]pyrazole ring system (Fig. 1, A) is present in a wide variety of biologically active compounds.1
In recent years, there has been increasing interest in the chemistry of its dihydro analogues. The 1,4- and 2,4-
dihydropyrano[2,3-c]pyrazole ring systems, which correspond to tautomeric forms B and C (Fig. 1), often
appear as the main structural motifs of anticancer,2-5 anti-inflammatory,6 and anti-diabetic agents.7 The known
numerous methods for the preparation of these compounds are generally based on a multicomponent
reaction of an aromatic aldehyde, 3-oxobutanoate, hydrazine hydrate, and malononitrile in the presence of a
suitable catalyst.8 However, access to derivatives of 1,6- and 2,6-dihydropyrano[2,3-c]pyrazole isomers D and
E (Fig. 1) is very limited, and their chemistry and biological properties remain largely unexplored. Derivatives
of pyrano[2,3-c]pyrazol-6(1H)-one9 (Fig. 1, F) are structurally similar and are known as analgesic, anti-
inflammatory10 and antiviral agents.11
Figure 1. Pyrano[2,3-c]pyrazole and its hydro derivatives.
In the present work, we describe a method for the construction of the 2,6-dihydropyrano[2,3-c]pyrazole
ring system (Fig. 1, E) via a ring-closing metathesis (RCM) reaction. RCM reactions catalyzed by ruthenium
alkylidene complexes12,13 have proven to be one of the most powerful tools for the construction of non-
aromatic (hetero)carbocyclic compounds14-16, in particular, oxygen heterocycles.17-19 For example, treatment
of 2-allyloxy-1-ethenylbenzene with Grubb’s first-generation catalyst, [Cl2(PCy3)2Ru=CHPh],20 afforded 2H-1-
benzopyran in 95% yield.21
Results and Discussion
The synthetic strategy designed to construct the 2,6-dihydropyrano[2,3-c]pyrazole ring system employs a
diene substrate that contains an ethene unit attached to an allyloxy unit onto the pyrazole core, which can
participate in the RCM reaction (Scheme 1). As a starting material, we used 1-phenylpyrazol-3-ol (1a), which is
readily accessible from the oxidation of 1-phenyl-3-pyrazolidinone.22-24 Recently, we applied this scaffold to
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obtain the novel pyrazolo[4,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepine and pyrazolo[4’,3’:3,4]pyrido[1,2-
a]benzimidazole ring systems25,26 and to prepare building blocks for the preparation of optoelectronic
materials and fluorescent organic nanoparticles.27-30
The O-allylation of 1a with allyl bromide in the presence of NaH gave O-allylated pyrazole 2a.31 To
introduce a formyl group at the 4-position of the pyrazole ring, we employed a previously reported procedure
based on the Vilsmeier-Haack reaction.32 Heating compound 2a with POCl3 in N,N-dimethylformamide (DMF)
at 60 °C resulted in the formation of the desired pyrazole-4-carbaldehyde 3a in 91% yield (Scheme 1). The
1
characteristic signals of aldehyde 3a in the H NMR spectrum were the singlets at 8.25 (5-H) and 9.88 ppm
(CHO). The 13C NMR spectrum contained the signal of a formyl carbon at 183.4 ppm.
Next, we investigated the conversion of aldehyde 3a into 4-ethenylpyrazole 4a. One of the most popular
methods for the synthesis of alkenes from aldehydes and ketones is the Wittig reaction, which is based on the
coupling of carbonyl compounds with single-substituted phosphonium ylides.33 To introduce a methylene
-
group, methylenetriphenylphosphorane (Ph3P=CH2
Ph3P+-CH2 ) generated by the addition of a base to a
solution of methyltriphenylphosphonium bromide or iodide is typically used as an ylide source.34,35 For
example, the Wittig reaction of benzaldehyde with methyltriphenylphosphonium iodide in the presence of
K2CO3 in DME provided styrene in 90% yield.35 In our case, the reaction of aldehyde 3a with
methyltriphenylphosphonium iodide in the presence of KOtBu in toluene resulted in the formation of 4-
ethenylpyrazole 4a in 89% yield. The 13C NMR spectrum of 4a exhibited the corresponding signals of the newly
formed vinyl carbon atoms at 113.4 and 125.1 ppm.
Scheme 1. Synthetic route to the 2,6-dihydropyrano[2,3-c]pyrazole ring system.
Having prepared the required diene 4a, we further investigated its RCM reaction in order to convert the
latter into the target compound 5a. When 4a was heated with Grubbs‘ first-generation catalyst in
dichloromethane, no RCM reaction occurred. However, the replacement of the solvent with THF gave the
desired 2-phenyl-2,6-dihydropyrano[2,3-c]pyrazole 5a in 42% yield. The application of microwave heating
allowed to shorten the RCM reaction time from 48 h to 3 h, but the isolated yield of 5a was only 34%.
The heterocyclic compounds of type 5 represent dihydropyrano[2,3-c]pyrazole substructures related to
important functional organic molecules with wide biomedical applications. Because popular NMR prediction
programs, such as ACD C+H predictor,36 depend on high-quality data with unambiguously assigned
resonances, we carried out NMR studies with compound 5a in an attempt to fully map all the NMR signals for
1H, 13C and 15N as accurately as possible (Fig. 1). The desired results were achieved through a combination of
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standard NMR techniques, such as DEPT, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY37, H2BC38 and 1,1-
ADEQUATE39 experiments. The broad-band decoupled 13C NMR spectrum of compound 5a showed resonances
for 10 carbon atoms. The DEPT-90 and 135 spectra indicated the presence of 1 methylene and 6 methine
carbon atoms. Comparison of the DEPT spectrum with the broad-band decoupled 13C NMR spectrum revealed
1
the presence of 3 quaternary carbons. The multiplicity-edited H-13C HSQC spectrum indicated that the
methylene protons H-6 have one-bond connectivity with the C-6 carbon at 68.8 ppm. Moreover, this also
revealed heteronuclear interactions between the protons of two pairs of chemically equivalent methine
groups (7.36-7.40 and 7.54-7.58 ppm), with their respective carbons, which resonated at 129.4 and 117.6,
1
respectively. The data from the H-13C HMBC spectrum revealed long-range correlations of the methylene
protons with the quaternary carbon C-7a (at 161.9 ppm) and protonated carbons C-5 (at 119.0 ppm) and C-4
(118.1 ppm). The aforementioned protonated carbon C-4 showed correlation with quaternary carbon C-3a in
the 1,1-ADEQUATE spectrum, which was also supported by the correlation of C-3 with C-3a. The 15N NMR data
were obtained via a 1H-15N HMBC experiment. Both nitrogen atoms showed appropriate couplings to H-3, and
in the case of N-2, it had strong coupling with the aromatic protons 2-H and 6-H. The TOCSY spectrum showed
1
that there were two distinct spin systems in the molecule. The H-1H connectivities within each spin system
were confirmed using the data from the COSY, TOCSY and NOESY spectra.
1
Figure 2. (a) 13C and 15N (in bold) NMR chemical shifts of compound 5a. (b) Characteristic H-13C HMBC, H2BC
1
and 1,1-ADEQUATE correlations are represented by arrows. (c) Characteristic H-1H NOESY correlations are
represented by arrows.
Compounds 5b,c were obtained analogously to compound 5a. Although the preparation of the starting
compound 1b was reported in a patent applications,40,41 neither a detailed synthesis description nor
spectroscopic data of the product were provided. The O-allylation of 1b and 1c42 and the subsequent
formylation of 2b,c produced aldehydes 3b,c which after conversion to the corresponding ethenyl derivatives
afforded the diene substrates 4b and 4c. Treatment of 4b,c with Grubbs‘ first-generation catalyst resulted in
the formation of the target compounds 5b and 5c in 56% and 39% yield, respectively.
The optical properties of compound 5a were investigated by UV–Vis spectroscopy and fluorometric
measurements. The electronic absorption spectra of compound 5a in THF did not show absorption bands in
the visible region of the electronic spectra, and it showed an absorption maximum at 310 nm (Fig. 3, a). Upon
excitation of compound 5a at 320 nm (in THF solution), the fluorescence spectrum exhibited three peaks at
360, 381 and 395 nm (Fig. 3, b). The fluorescence quantum yield (Φf) of the solution was estimated by the
integrating sphere method and gave a Φf value of ca. 1%.
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0,25
0,20
0,15
0,10
0,05
0,00
5a
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
5a
225
250
275
300
325
350
375
400
350 375 400 425 450 475 500 525 550 575 600 625
Wavelength, nm
Wavelength, nm
a)
b)
Figure 3. (a) Absorption spectrum of 5a in THF (0.1 mM, 298 K); (b) fluorescence emission spectrum of 5a in
THF ( ex = 320 nm).
Conclusions
In summary, an efficient route to access the 2,6-dihydropyrano[2,3-c]pyrazole ring system was developed by
employing ring-closing metathesis (RCM) as the key step. The structures of the synthesized 2-phenyl-, 2-(4-
1
bromophenyl)- and 2-(4-fluorophenyl)-2,6-dihydropyrano[2,3-c]pyrazoles were characterized by H, 13C, 15N
and 19F NMR spectroscopy, UV–Vis and fluorescence spectroscopy and HRMS measurements.
Experimental Section
General. Microwave reactions were conducted using a CEM Discovery Synthesis Unit (CEM Corp., Matthews,
NC). The machine consists of a continuous focused microwave power delivery system with operator-selectable
power output from 0 to 300 W. The reactions were performed in glass vessels (capacity 10 mL) sealed with
septum. In the case of an open vessel conditions the reactions were performed in a round bottom flask
(capacity 25 mL) connected to a reflux condenser. All experiments were performed using a stirring option. For
thin layer chromatography (TLC), Merck pre-coated TLC plates (Silica gel 60 F254) were employed. The
purification of the products was performed using flash chromatography on a glass column with silica gel (high
purity grade 9385, pore size 60 A, 230-400 mesh particle size). The melting points were determined in capillary
1
tubes, on a capillary melting point apparatus Büchi Melting Point M-565 and are uncorrected. The H, 13C and
1
15N NMR spectra were recorded in CDCl3 solutions at 25 °C on a Bruker Avance III 700 (700 MHz for H, 176
1
MHz for 13C, 71 MHz for 15N) spectrometer equipped with a 5 mm TCI H-13C/15N/D z-gradient cryoprobe. The
chemical shifts, expressed in ppm, were relative to tetramethylsilane (TMS). The 15N NMR spectra were
referenced to neat, external nitromethane (coaxial capillary). 19F NMR spectra (376.46 MHz, absolute
referencing via δ ratio) were obtained on a Bruker Avance III 400 instrument with a ‘directly’ detecting
1
broadband observe probe (BBO). The full and unambiguous assignments of the H, 13C, 15N and 19F NMR
resonances were achieved using standard Bruker software and a combination of standard NMR spectroscopic
techniques, such as DEPT, COSY, TOCSY, NOESY, gs-HSQC, gs-HMBC, H2BC and 1,1-ADEQUATE. The infrared
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spectra were recorded on a Bruker Vertex v70 FTIR spectrometer equipped with a diamond ATR accessory.
The UV-vis spectra were recorded using 0.1 mM solutions of the compounds in THF on a Shimadzu 2600
UV/Vis spectrometer. The fluorescence spectra were recorded on a FL920 fluorescence spectrometer from
Edinburgh Instruments. The PL quantum yields were measured from dilute solutions by an absolute method
using Edinburgh Instruments integrating sphere excited with a Xe lamp. Optical densities of the sample
solutions were ensured to be below 0.1 to avoid reabsorption effects. All optical measurements were
performed at rt under ambient conditions. HRMS spectra were recorded with a Bruker maXis or Bruker
micrOTOF-QIII spectrometers.
1-(4-Fluorophenyl)-1H-pyrazol-3-ol (1b). An intensively stirred suspension of 4-fluorophenylhydrazine
hydrochloride (8.13 g, 50 mmol) in dry toluene/methanol (1/1, 100 mL) was kept under inert atmosphere, and
the potassium tert-butoxide (16.83 g, 150 mmol) was added in one portion. The reaction mixture was stirred
at room temperature for 30 min. Then it was subsequently raised to 50°C and the ethyl acrylate (150 mmol,
16.36 mL) was added dropwise over the 15 min. The reaction mixture was stirred at 50°C for 24 h, diluted with
100 mL of water and the organic layer was separated. The aqueous phase was adjusted to a pH of
6 and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtrated, and
concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with
dichloromethane/methanol 100:3, v/v. To yield the 1-(4-fluorophenyl)pyrazolidin-3-one. Yield 6.31 g (70%),
white crystals, m.p. 109–111 °C. IR (neat, νmax, cm-1): 3135, 2918, 1601, 1500, 1356, 1221, 1118. 1H NMR (700
MHz, CDCl3): δ (ppm) 2.56 (t, J 8.0 Hz, 2H, 4-CH2), 3.86 (t, J 8.0 Hz, 2H, 5-CH2), 7.00 (d, J 6.4 Hz, 4H, Ph 2,3,5,6-
H), 9.14 (s, 1H, NH). 13C NMR (176 MHz, CDCl3): δ (ppm) 29.9 (C-4), 55.9 (C-5), 116.0 (d, 2JC,F 22.7 Hz, Ph C-3,5),
3
4
1
118.1 (d, JC,F 7.9 Hz, Ph C-2,6), 147.6 (d, JC,F 2.3 Hz, Ph C-1), 158.9 (d, JC,F 241.6 Hz, Ph C-4), 175.7 (C-3). 15N
NMR (71 MHz, CDCl3): δ (ppm) -278.3 (N-1), -230.2 (N-2). 19F NMR (376 MHz, CDCl3): δ (ppm) -120.8. HRMS
(ESI TOF): [M+H]+ found 181.0771. [C9H10FN2O]+ requires 181.0772.
The obtained 1-(4-fluorophenyl)pyrazolidin-3-one (6.13 g, 34 mmol) and FeCl3·6H2O (2.3 g, 8.5 mmol) were
o
dissolved in dimethylformamide (50 mL). The reaction mixture was heated to 80 C, and gassed with oxygen
o
for 2 h. After gassing was stopped, the mixture was stirred for further 10 h maintaining at 80 C. Then it was
poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined,
washed with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with hexane/ethylacetate 2:1, v/v, to yield the title
compound 1b. Yield 4.91 g (81%), bright orange crystals, m.p. 152–154 °C. IR (neat, νmax, cm-1): 3139, 2938,
1
1556, 1510, 1393, 1230, 1158. H NMR (700 MHz, CDCl3): δ (ppm) 5.88 (d, J 2.6 Hz, 1H, 4-H), 7.11 – 7.18 (m,
2H, Ph 3,5-H), 7.43 – 7.48 (m, 2H, Ph 2,6-H), 7.58 (d, J 2.6 Hz, 1H, 5-H). 13C NMR (176 MHz, CDCl3): δ (ppm) 94.4
(C-4), 116.6 (d, 2JC,F 23.0 Hz, Ph C-3,5), 120.8 (d, 3JC,F 8.3 Hz, Ph C-2,6), 129.5 (C-5), 136.0 (d, 4JC,F 2.8 Hz, Ph C-1),
1
160.9 (d, JC,F 245.8 Hz, Ph C-4), 164.1 (C-3). 15N NMR (71 MHz, CDCl3): δ (ppm) -191.8 (N-1), -135.2 (N-2). 19F
NMR (376 MHz, CDCl3): δ (ppm) -116.2. HRMS (ESI TOF): [M+H]+ found 179.0615. [C9H8FN2O]+ requires
179.0615.
General procedure for the allylation of 1H-pyrazol-3-oles giving 3-[(prop-2-en-1-yl)oxy]-1H-pyrazoles
(compounds 2a-c). The solution of 1a-c (10 mmol) in dry DMF (15 mL) was cooled to 0°C under inert
atmosphere and NaH (60% dispersion in mineral oil, 400 mg, 10 mmol) was added portionwise. After mixing
for 15 min at 0°C, the mixture was gradually warmed up to 40°C temperature and stirred for additional 15 min.
Then it was subsequently raised to 60°C and an allyl bromide (12 mmol, 1.0 mL) was added dropwise over the
10 min. The mixture was stirred at 60°C for 8 h, diluted with 60 ml of water and extracted with ethyl acetate.
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The organic layers were combined, washed with brine, dried over Na2SO4, filtrated, and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethylacetate
15:1, v/v. To yield compounds 2a-c.
1-Phenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole (2a). Yield 1.56 g (78%), yellow oil. IR (neat, νmax, cm-1): 3132,
2927, 1541, 1505, 1396, 1236, 985, 936. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.79 (dt, J 5.6, 1.4 Hz, 2H, O-CH2-
CH=CH2), 5.26 – 5.32 (m, 1H, O-CH2-CH=CH2), 5.42 – 5.48 (m, 1H, O-CH2-CH=CH2), 5.91 (d, J 2.6 Hz, 1H, 4-H),
6.09 – 6.17 (m, 1H, O-CH2-CH=CH2), 7.19 – 7.22 (m, 1H, Ph 4-H), 7.39 – 7.42 (m, 2H, Ph 3,5-H), 7.59 – 7.62 (m,
2H, Ph 2,6-H), 7.73 (d, J = 2.6 Hz, 1H, 5-H). 13C NMR (176 MHz, CDCl3): δ (ppm) 70.0 (O-CH2-CH=CH2), 94.1 (C-4),
117.9 (O-CH2-CH=CH2), 118.0 (Ph C-2,6), 125.4 (Ph C-4), 127.8 (C-5), 129.5 (Ph C-3,5), 133.4 (O-CH2-CH=CH2),
140.3 (Ph C-1), 164.3 (C-3). 15N NMR (71 MHz, CDCl3): δ (ppm) -186.0 (N-1), -119.3 (N-2).30
1-(4-Fluorophenyl)-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole (2b). Yield 1.05 g (48%), bright yellow oil. IR (neat,
νmax, cm-1): 3098, 2915, 1547, 1516, 1392, 1217, 1175, 991, 942. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.77 (dt, J
5.6, 1.3 Hz, 2H, O-CH2-CH=CH2), 5.26 – 5.31 (m, 1H, O-CH2-CH=CH2), 5.41 – 5.48 (m, 1H, O-CH2-CH=CH2), 5.90
(d, J 2.6 Hz, 1H, 4-H), 6.07 – 6.15 (m, 1H, O-CH2-CH=CH2), 7.07 – 7.11 (m, 2H, Ph 3,5-H), 7.52 – 7.56 (m, 2H, Ph
2
2,6-H), 7.65 (d, J 2.6 Hz, 1H, 5-H). 13C NMR (176 MHz, CDCl3): 69.9 (O-CH2-CH=CH2), 94.0 (C-4), 116.1 (d, JC,F
3
23.0 Hz, Ph C-3,5), 118.0 (O-CH2-CH=CH2), 119.6 (d, JC,F 8.2 Hz, Ph C-2,6), 127.9 (C-5), 133.3 (O-CH2-CH=CH2),
136.6 (d, 4JC,F 2.7 Hz, Ph C-1), 160.5 (d, 1JC,F 244.5 Hz, Ph C-4), 164.3 (C-3). 15N NMR (71 MHz, CDCl3): δ (ppm) -
187.8 (N-1), -118.7 (N-2). HRMS (ESI TOF): [M+Na]+ found 241.0748. [C12H11FN2NaO]+ requires 241.0748.
1-(4-Bromophenyl) 3-[(prop-2-en-1-yl)oxy]-1H-pyrazole (2c). Yield 1.45 g (52%), colorless oil. IR (neat, νmax
,
cm-1): 3154, 2916, 1547, 1498, 1385, 1236, 1179, 982, 932. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.77 (dt, J 5.6,
1.3 Hz, 2H, O-CH2-CH=CH2), 5.26 – 5.31 (m, 1H, O-CH2-CH=CH2), 5.42 – 5.46 (m, O-CH2-CH=CH2), 5.92 (d, J 2.6
Hz, 1H, 4-H), 6.06 – 6.15 (m, 1H, O-CH2-CH=CH2), 7.47 – 7.53 (m, 4H, Ph 2,3,5,6-H), 7.70 (d, J 2.6 Hz, 1H, 5-H).
13C NMR (176 MHz, CDCl3): δ (ppm) 70.0 (O-CH2-CH=CH2), 94.7 (C-4), 118.1 (O-CH2-CH=CH2), 118.3 (Ph C-4),
119.3 and 132.4 (Ph C-2,3,5,6), 127.8 (C-5), 133.3 (O-CH2-CH=CH2), 139.3 (Ph C-1), 164.4 (C-3). 15N NMR (71
MHz, CDCl3): δ (ppm) -188.1 (N-1), N-2 was not found. HRMS (ESI TOF): [M+Na]+ found 300.9947
[C12H1179BrN2NaO]+ requires 300.9947.
General procedure for the formylation of 3-[(prop-2-en-1-yl)oxy]-1H-pyrazoles giving 3-[(prop-2-en-1-
yl)oxy]-1H-pyrazole-4-carbaldehydes (compounds 3a-c). Phosphorus oxychloride (1.86 mL, 20 mmol) was
added dropwise to dry DMF (1.55 mL, 20 mmol) at -10°C and the resulting mixture was stirred at the same
temperature for 10-20 min until the Vilsmeier-Haack complex formed. Then, the appropriate 3-[(prop-2-en-1-
yl)oxy]-1H-pyrazole 2a-c (5 mmol) in DMF (15 mL) was added to the Vilsmeier-Haack complex and the
temperature was slowly raised to 70°C and maintained for 12 h. The reaction mixture was cooled in an ice
bath, cautiously quenched with ice-cold water (100 mL), and basified with 10% NaHCO3 solution. The
precipitate was filtered off. The filtrate was extracted with ethyl acetate which was washed with brine, dried
over anhydrous Na2SO4, filtrated and then concentrated. The residue was purified by column chromatography
on silica gel with hexane/ethylacetate 3:1, v/v. To yield compounds 3a-c.
1-Phenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole-4-carbaldehyde (3a). Yield 1.04 g (91%), bright yellow crystals,
1
m.p. 107–109 °C. IR (neat, νmax, cm-1): 3126, 2938, 1665, 1552, 1501, 1391, 1222, 1205, 993, 943. H NMR (700
MHz, CDCl3): δ (ppm) 4.92 (dt, J 5.7, 1.3 Hz, 2H, O-CH2-CH=CH2), 5.30 – 5.35 (m, 1H, O-CH2-CH=CH2), 5.45 –
5.50 (m, 1H, O-CH2-CH=CH2), 6.11 – 6.18 (m, 1H, O-CH2-CH=CH2), 7.32 (t, J 7.4 Hz, 1H, Ph 4-H), 7.44 – 7.49 (m,
2H, Ph 3,5-H), 7.62 – 7.66 (m, 2H, Ph 2,6-H), 8.25 (s, 1H, 5-H), 9.88 (s, 1H, CHO). 13C NMR (176 MHz, CDCl3): δ
(ppm) 70.2 (O-CH2-CH=CH2), 111.6 (C-4), 118.7 (O-CH2-CH=CH2), 118.9 (Ph C-2,6), 127.4 (Ph C-4), 129.5 (C-5),
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129.7 (Ph C-3,5), 132.6 (O-CH2-CH=CH2), 139.1 (Ph C-1), 163.6 (C-3), 183.4 (CHO). 15N NMR (71 MHz, CDCl3): δ
(ppm) -179.2 (N-1), -118.0 (N-2). HRMS (ESI TOF): [M+Na]+ found 229.0974. [C13H13N2O2]+ requires 229.0972.
1-(4-Fluorophenyl)-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole-4-carbaldehyde (3b). Yield 0.86 g (70%), bright brown
1
crystals, m.p. 134–136 °C. IR (neat, νmax, cm-1): 3126, 2946, 1669, 1564, 1502, 1390, 1224, 1209, 989, 941. H
NMR (700 MHz, CDCl3): δ (ppm) 4.89 (dt, J 5.7, 1.3 Hz, 2H, O-CH2-CH=CH2), 5.30 – 5.34 (m, 1H, O-CH2-CH=CH2),
5.44 – 5.48 (m, 1H, O-CH2-CH=CH2), 6.09 – 6.16 (m, 1H, O-CH2-CH=CH2), 7.12 – 7.17 (m, 2H, Ph 3,5-H), 7.57 –
7.64 (m, 2H, Ph 2,6-H), 8.19 (s, 1H, 5-H), 9.86 (s, 1H, CHO). 13C NMR (176 MHz, CDCl3): δ (ppm) 70.2 (O-CH2-
2
3
CH=CH2), 111.6 (C-4), 116.6 (d, JC,F 23.2 Hz, Ph C-3,5), 118.8 (O-CH2-CH=CH2), 120.7 (d, JC,F 8.4 Hz, Ph C-2,6),
4
1
129.6 (C-5), 132.5 (O-CH2-CH=CH2), 135.4 (d, JC,F 2.8 Hz, Ph C-1), 161.6 (d, JC,F 247.4 Hz, Ph C-4), 163.6 (C-3),
183.4 (CHO). 15N NMR (71 MHz, CDCl3): δ (ppm) -181.2 (N-1), -117.3 (N-2). HRMS (ESI TOF): [M+Na]+ found
269.0696. [C13H11FN2NaO2]+ requires 269.0697.
1-(4-Bromophenyl)-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole-4-carbaldehyde (3c). Yield 1.15 g (75%), bright
brown crystals, m.p. 125–127 °C. IR (neat, νmax, cm-1): 3124, 2923, 1665, 1554, 1496, 1418, 1221, 1207, 988,
939. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.90 (dt, J 5.8, 1.2 Hz, 2H, O-CH2-CH=CH2), 5.31 – 5.35 (m, 1H, O-CH2-
CH=CH2), 5.45 – 5.50 (m, 1H, O-CH2-CH=CH2), 6.10 – 6.17 (m, 1H, O-CH2-CH=CH2), 7.50 – 7.66 (m, 4H, Ph
2,3,5,6-H), 8.23 (s, 1H, 5-H), 9.87 (s, 1H, CHO). 13C NMR (176 MHz, CDCl3): δ (ppm) 70.3 (O-CH2-CH=CH2), 111.9
(C-4), 118.9 (O-CH2-CH=CH2), 120.3 and 132.8 (Ph C-2,3,5,6), 120.7 (Ph C-4), 129.5 (C-5), 132.4 (O-CH2-
CH=CH2), 138.1 (Ph C-1), 163.6 (C-3), 183.4 (CHO). 15N NMR (71 MHz, CDCl3): δ (ppm) -181.5 (N-1), -118.3 (N-
2). HRMS (ESI TOF): [M+Na]+ found 328.9897. [C13H1179BrN2NaO2]+ requires 328.9896.
General procedure for the Wittig olefination of 3-[(prop-2-en-1-yl)oxy]-1H-pyrazole-4-carbaldehydes giving
4-ethenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazoles (compounds 4a-c). To a suspension of methyltriphenyl-
phosphonium iodide (1.83 g, 4.5 mmol) in dry toluene (60 mL) under inert atmosphere, the potassium tert-
butoxide (1.01 g, 9 mmol) was added in one portion. The reaction mixture was stirred at room temperature
for 30 min and subsequently refluxed for another 30 min. Formation of the ylide can be visibly observed by its
persistent yellow color. After refluxing, the reaction mixture was allowed to come to room temperature and
kept in an ice bath, followed by dropwise addition of an appropriate aldehyde 3a-c (3 mmol) dissolved in dry
toluene (30 mL). Then the reaction was carried out in room temperature for 3-5 hours, and the progress was
monitored by TLC. Upon completion, the reaction was quenched by saturated solution of ammonium chloride
and the organic layer was extracted with ethyl acetate several times. The organic layers were combined, dried
over Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel with hexane/ethylacetate 15:1, v/v to yield compounds 4a-c.
4-Ethenyl-1-phenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole (4a). Yield 0.60 g (89%), colorless oil. IR (neat, νmax
,
cm-1): 3081, 2928, 1564, 1500, 1396, 1235, 1205, 989, 940. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.89 (dt, J 5.5,
1.5 Hz, 2H, O-CH2-CH=CH2), 5.18 (dd, J 11.3, 1.7 Hz, 1H, Pyr 4-CH=CH2), 5.28 – 5.31 (m, 1H, O-CH2-CH=CH2),
5.45 – 5.50 (m, 1H, O-CH2-CH=CH2), 5.74 (dd, J 17.7, 1.7 Hz, 1H, Pyr 4-CH=CH2), 6.12 – 6.20 (m, 1H, O-CH2-
CH=CH2), 6.55 (dd, J 17.7, 11.3 Hz, 1H, Pyr 4-CH=CH2), 7.18 – 7.22 (m, 1H, Ph 4-H), 7.39 – 7.43 (m, 2H, Ph 3,5-
H), 7.57 – 7.61 (m, 2H, Ph 2,6-H), 7.75 (s, 1H, 5-H). 13C NMR (176 MHz, CDCl3): δ (ppm) 69.7 (O-CH2-CH=CH2),
108.7 (C-4), 113.4 (Pyr 4-CH=CH2), 117.6 (O-CH2-CH=CH2), 117.7 (Ph C-2,6), 125.1 (Pyr 4-CH=CH2), 125.2 (C-5),
125.3 (Ph C-4), 129.5 (Ph C-3,5), 133.4 (O-CH2-CH=CH2), 140.0 (Ph C-1), 161.7 (C-3). 15N NMR (71 MHz, CDCl3):
δ (ppm) -189.4 (N-1), -119.6 (N-2). HRMS (ESI TOF): [M+Na]+ found 249.1000. [C14H14N2NaO]+ requires
249.0998.
4-ethenyl-1-(4-fluorophenyl)-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole (4b). Yield 0.29 g (39%), colorless oil. IR
(neat, νmax, cm-1): 3086, 2929, 1564, 1511, 1396, 1226, 1205, 989, 941. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.86
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(dt, J 5.4, 1.4 Hz, 2H, O-CH2-CH=CH2), 5.17 (dd, J 11.3, 1.7 Hz, 1H, Pyr 4-CH=CH2), 5.27 – 5.31 (m, 1H, O-CH2-
CH=CH2), 5.43 – 5.49 (m, 1H, O-CH2-CH=CH2), 5.72 (dd, J 17.7, 1.7 Hz, 1H, Pyr 4-CH=CH2), 6.11 – 6.18 (m, 1H, O-
CH2-CH=CH2), 6.52 (dd, J 17.7, 11.3 Hz, 1H, Pyr 4-CH=CH2), 7.07 – 7.12 (m, 2H, Ph 3,5-H), 7.51 – 7.55 (m, 2H, Ph
2,6-H), 7.66 (s, 1H, 5-H). 13C NMR (176 MHz, CDCl3): δ (ppm) 69.7 (O-CH2-CH=CH2), 108.8 (C-4), 113.5 (Pyr 4-
CH=CH2), 116.2 (d, 2JC,F 22.9 Hz, Ph C-3,5), 117.6 (O-CH2-CH=CH2), 119.4 (d, 3JC,F 8.1 Hz, Ph C-2,6), 125.0 (Pyr 4-
4
1
CH=CH2), 125.3 (C-5), 133.4 (O-CH2-CH=CH2), 136.4 (d, JC,F 2.6 Hz, Ph C-1), 160.5 (d, JC,F 244.5 Hz, Ph C-4),
161.8 (C-3). 15N NMR (71 MHz, CDCl3): δ (ppm) -191.2 (N-1), -119.0 (N-2). HRMS (ESI TOF): [M+Na]+ found
267.0906. [C14H13FN2NaO]+ requires 267.0904.
1-(4-Bromophenyl)-4-ethenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole (4c). Yield 0.42 g (46%), colorless oil. IR
(neat, νmax, cm-1): 3083, 2925, 1563, 1493, 1392, 1231, 1181, 989, 937. 1H NMR (700 MHz, CDCl3): δ (ppm) 4.86
(dt, J 5.5, 1.4 Hz, 2H, O-CH2-CH=CH2), 5.18 (dd, J 11.3, 1.7 Hz, 1H, Pyr 4-CH=CH2), 5.27 – 5.31 (m, 1H, O-CH2-
CH=CH2), 5.43 – 5.48 (m, 1H, O-CH2-CH=CH2), 5.73 (dd, J 17.7, 1.7 Hz, 1H, Pyr 4-CH=CH2), 6.10 – 6.17 (m, 1H, O-
CH2-CH=CH2), 6.51 (dd, J 17.7, 11.3 Hz, 1H, Pyr 4-CH=CH2), 7.43 – 7.53 (m, 4H, Ph 2,3,5,6-H), 7.71 (s, 1H, 5-H).
13C NMR (176 MHz, CDCl3): δ (ppm) 69.8 (O-CH2-CH=CH2), 109.3 (C-4), 113.9 (Pyr 4-CH=CH2), 117.7 (O-CH2-
CH=CH2), 118.2 (Ph C-4), 119.0 and 132.4 (Ph C-2,3,5,6), 124.9 (Pyr 4-CH=CH2), 125.1 (C-5), 133.3 (O-CH2-
CH=CH2), 139.1 (Ph C-1), 161.9 (C-3). 15N NMR (71 MHz, CDCl3): δ (ppm) -191.5 (N-1), -119.9 (N-2). HRMS (ESI
TOF): [M+Na]+ found 327.0104. [C14H1379BrN2NaO]+ requires 327.0103.
General procedure for the ring-closing metathesis of 4-ethenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazoles giving
2,6-dihydropyrano[2,3-c]pyrazoles (compounds 5a-c)
Method A. Bis(tricyclohexylphosphine)benzylidene ruthenium dichloride (41 mg, 0.05 mmol) was added to a
solution of an appropriate diene 4a-c (1.0 mmol) in dry degassed tetrahydrofuran (10 mL). The reaction
mixture was refluxed under argon atmosphere for 24 h. Since the reaction was incomplete, and the catalyst
had become deactivated, another portion of it (41 mg, 0.05 mmol) was added (total catalyst loading 10 mol
%). The reaction mixture was refluxed for another 24 h. Subsequently the solvent was removed under vacuum
and the residue was purified by column chromatography on silica gel with hexane/ethylacetate 6:1, v/v. The
yields of compounds 5a (83 mg, 42%), 5b (121 mg, 56%) and 5c (108 mg, 39%).
Method B. Bis(tricyclohexylphosphine)benzylidene ruthenium dichloride (41 mg, 0.05 mmol) was added to a
solution of diene 4a (99 mg, 0.5 mmol) in dry degassed tetrahydrofuran (5 mL). The reaction mixture was
heated in a microwave reactor (150 W) to 65 °C for 3 h. Standard workup and purification according to the
Method A yielded compound 5a (23 mg, 23%).
Method C. Bis(tricyclohexylphosphine)benzylidene ruthenium dichloride (82 mg, 0.1 mmol) was added to a
solution of diene 4a (198 mg, 1.0 mmol) in dry degassed tetrahydrofuran (10 mL). The reaction mixture was
refluxed in a microwave reactor (150 W) for 3 h, under open vessel conditions with an inert gas sparging. Glass
capillary for Ar purging were immersed through the reflux condenser into the solution maintaining the inert
gas introduction. The solvent was kept at the constant volume. Standard workup and purification according to
the Method A yielded compound 5a (67 mg, 34%).
2-Phenyl-2,6-dihydropyrano[2,3-c]pyrazole (5a). Pale crystals, m.p. 88–90 °C. IR (neat, νmax, cm-1): 3116, 2927,
1581, 1502, 1406, 1202. 1H NMR (700 MHz, CDCl3): δ (ppm) 5.03 (dd, J 3.3, 2.0 Hz, 2H, 6-H), 5.56 (dt, J 9.8, 3.4
Hz, 1H, 5-H), 6.47 (dt, J 9.8, 1.9 Hz, 1H, 4-H), 7.18 (t, J 7.4 Hz, 1H, Ph 4-H), 7.37 – 7.41 (m, 2H, Ph 3,5-H), 7.53 (s,
1H, 3-H), 7.55 – 7.58 (m, 2H, Ph 2,6-H). 13C NMR (176 MHz, CDCl3): δ (ppm) 68.8 (C-6), 104.8 (C-3a), 117.6 (Ph
C-2,6), 118.2 (C-4), 119.1 (C-5), 121.1 (C-3), 125.3 (Ph C-4), 129.4 (Ph C-3,5), 140.1 (Ph C-1), 161.9 (C-7a). 15N
NMR (71 MHz, CDCl3): δ (ppm) -188.7 (N-2), -120.2 (N-1). HRMS (ESI TOF): [M+H]+ found 199.0864.
[C12H11N2O]+ requires 199.0866.
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2-(4-Fluorophenyl)-2,6-dihydropyrano[2,3-c]pyrazole (5b). Pale crystals, m.p. 104–107 °C. IR (neat, νmax, cm-
1
1): 3133, 2927, 1590, 1510, 1399, 1206. H NMR (700 MHz, CDCl3): δ (ppm) 5.01 (dd, J 3.2, 1.7 Hz, 2H, 6-H),
5.54 (dt, J 9.8, 3.4 Hz, 1H, 5-H), 6.44 (dt, J 9.8, 1.5 Hz, 1H, 4-H), 7.04 – 7.09 (m, 2H, Ph 3,5-H), 7.44 (s, 1H, 3-H),
2
7.48 – 7.52 (m, 2H, Ph 2,6-H). 13C NMR (176 MHz, CDCl3): δ (ppm) 68.8 (C-6), 104.9 (C-3a), 116.2 (d, JC,F 22.9
Hz, Ph C-3,5), 118.0 (C-4), 119.1 (C-5), 119.3 (d, 3JC,F 8.2 Hz, Ph C-2,6), 121.2 (C-3), 136.4 (d, 4JC,F 2.6 Hz, Ph C-1),
160.4 (d, 1JC,F 244.4 Hz, Ph C-4), 161.9 (C-7a). 15N NMR (71 MHz, CDCl3): δ (ppm) -190.6 (N-2), -119.7 (N-1). 19F
NMR (376 MHz, CDCl3): δ (ppm) -117.7. HRMS (ESI TOF): [M+Na]+ found 239.0591. [C12H9FN2NaO]+ requires
239.0591.
2-(4-Bromophenyl)-2,6-dihydropyrano[2,3-c]pyrazole (5c). White crystals, m.p. 133–135 °C. IR (neat, νmax, cm-
1
1): 3134, 2927, 1592, 1495, 1398, 1207. H NMR (700 MHz, CDCl3): δ (ppm) 5.03 (dd, J 3.3, 2.0 Hz, 2H, 6-H),
5.57 (dt, J 9.8, 3.4 Hz, 1H, 5-H), 6.45 (dt, J 9.8, 1.9 Hz, 1H, 4-H), 7.42 – 7.50 (m, 5H, 3-H and Ph-2,3,5,6). 13C
NMR (176 MHz, CDCl3): δ (ppm) 68.9 (C-6), 105.3 (C-3a), 117.9 (C-4), 118.1 (Ph C-4), 119.0 and 132.4 (Ph C-
2,3,5,6), 119.6 (C-5), 120.9 (C-3), 139.1 (Ph C-1), 162.0 (C-7a). 15N NMR (71 MHz, CDCl3): δ (ppm) -190.8 (N-2), -
120.5 (N-1). HRMS (ESI TOF): [M+H]+ found 276.9973. [C12H1079BrN2O]+ requires 276.9971.
Supplementary Material
NMR spectra (1H, 13C, DEPT-135 13C, 1H-15N HMBC, 1H-13C, gs-HSQC, and 60 Hz 1,1- ADEQUATE) of compound
5a are available in the Supplementary material file.
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