Synthesis of 4-Acylpyrazoles from Saturated Ketones and Hydrazones Featured with Multiple C(sp3)-H Bond Functionalization and C-C Bond Cleavage and Reorganization

Article abstract of DOI:10.1021/acs.joc.7b01013

In this paper, an efficient and convenient one-pot synthesis of diversely substituted 4-acylpyrazole derivatives via copper-catalyzed one-pot cascade reactions of saturated ketones with hydrazones is reported. Mechanistically, the formation of the title compounds involves the in situ formation of an enone intermediate through the dehydrogenation of a saturated ketone and the [2 + 3] cyclization of the enone with hydrazone followed by an aromatization-driven C-C bond cleavage and reorganization. To our knowledge, this is the first example in which the biologically and pharmaceutically important yet otherwise difficult-to-obtain 4-acylpyrazole derivatives are directly prepared from saturated ketones and hydrazones featured with multiple aliphatic C-H bond functionalization and C-C bond cleavage and reorganization. Compared with literature methods, this novel process has advantages such as simple and economical starting materials, a sustainable oxidant, excellent regioselectivity, and good efficiency.

Full text of DOI:10.1021/acs.joc.7b01013

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Article
Synthesis of 4-acylpyrazoles from saturated ketones
and hydrazones featured with multiple C(sp3)–H bond
functionalization, C–C bond cleavage and re-organization
Miaomiao Tian, Xiaonan Shi, Xinying Zhang, and Xuesen Fan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2017
Downloaded from http://pubs.acs.org on June 23, 2017
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Synthesis of 4-acylpyrazoles from saturated ketones and hydrazones featured with multiple
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C(sp3)–H bond functionalization, C–C bond cleavage and re-organization
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Miaomiao Tian, Xiaonan Shi, Xinying Zhang,* and Xuesen Fan*
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School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic
Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China
E-mail: xuesen.fan@htu.cn; xinyingzhang@htu.cn
Abstract: In this paper, an efficient and convenient one-pot synthesis of diversely substituted 4-
acylpyrazole derivatives via copper-catalyzed one pot cascade reactions of saturated ketones with
hydrazones is reported. Mechanistically, the formation of the title compounds involves the in situ
formation of an enone intermediate through the dehydrogenation of saturated ketone, and the
[2+3] cyclization of enone with hydrazone followed by an aromatization-driven C–C bond
cleavage and re-organization. To our knowledge, this should be the first example in which the
biologically and pharmaceutically important yet otherwise difficult-to-obtain 4-acylpyrazole
derivatives were directly prepared from saturated ketones and hydrazones featured with multiple
aliphatic C–H bond functionalization, C–C bond cleavage and re-organization. Compared with
literature methods, this novel process has advantages such as simple and economical starting
materials, sustainable oxidant, excellent regioselectivity and good efficiency.
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INTRODUCTION
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The pyrazole unit is an essential building block embedded in compounds routinely used as
pharmaceuticals, agrochemicals and functional materials, etc.1-4 Due to its importance, numerous
methods for the construction of the pyrazole scaffold have been developed.1-8 While these
literature protocols are generally reliable, some of them still suffer from limitations such as the
difficulty in obtaining the pre-functionalized substrates, poor regioselectivity and harsh reaction
conditions. Therefore, the development of more selective and general method to prepare
pyrazoles with diverse substitution patterns starting from simple and/or easily obtainable
substrates remains a highly desirable yet still challenging topic.
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In recent years, direct functionalization of the inert C(sp3)–H bonds has attracted much
attention. Among various versions of C(sp3)–H bond functionalization, the oxidative
dehydrogenation of saturated ketones without pre-activation affording the corresponding enone
derivatives is of significant importance as enones are highly valuable in organic synthesis.9-10
Moreover, some elegantly designed one-pot cascade reactions combining the oxidative
dehydrogenation of saturated ketones with other kinds of transformations leading to the formation
of advanced molecular scaffolds have also been successfully realized.11-15 Inspired by those
pioneering studies and as a continuation of our own interest in this aspect,16 we have designed an
alternative synthesis of 1,5-disubstituted pyrazoles from the reaction of saturated ketones with
hydrazine by taking advantages of the C(sp3)–H bond functionalization strategy. During our
study on this proposal, we serendipitously found a novel synthesis of the otherwise difficult-to-
obtain 1,3,4-trisubstituted pyrazoles with an acyl unit attached on the 4-position of the pyrazole
scaffold. Herein, we report the results we obtained in this regard.
RESULTS AND DISCUSSION
Our study was commenced by treating propiophenone (1a, 0.6 mmol) with phenyl hydrazine (I,
0.5 mmol) in the presence of Cu(OAc)2 (0.1 mmol), TEMPO (2,2,6,6-tetramethyl piperidine-N-
oxyl, 0.5 mmol) and bpy (2,2'-bipyridine, 0.05 mmol) in toluene at 120 °C for 10 h under N2.16
From this reaction, the proposed 1,5-diphenylpyrazole (II) was not obtained. An unexpected
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product, 1,3-diphenyl-4-benzoylpyrazole (3a), was isolated in a yield of 15% (Scheme 1).
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Scheme 1. Unexpected formation of 3a from the reaction of 1a with I
Notwithstanding the proposed 1,5-diphenylpyrazole (II) was not obtained, it occurred to us
that the unexpected formation of 3a might be more interesting owing to the following reasons: 1)
4-acyl substituted pyrazole derivatives are well known for their biological activities and rich
reactivity;17 2) in spite of their importance, synthetic methods for the preparation of 4-acyl
pyrazoles are only scarcely available.17-18 Based on these facts, we decided to have a thorough
study of this newly found reaction with the aim to establish it into a novel and practical synthesis
of 4-acyl pyrazole derivatives.
First of all, we need to clarify how 3a is formed from the reaction of 1a with I. Based on the
structure of 3a, we postulate that 1a should firstly condense with I to give hydrazone 2a.
Meanwhile, an oxidative dehydrogenation occurs with 1a to give enone A,10 which then
undergoes a conjugate addition with 2a to afford adduct B. Next, an intramolecular nucleophilic
addition occurs with B to afford tetrahydropyrazole C. Through an oxidative dehydrogenation of
C, dihydropyrazole D is formed. Finally, an aromatization-driven C–C bond cleavage occurs with
D to afford 3a as the final product (Scheme 2).
Scheme 2. Plausible reaction pathway accounting for the formation of 3a
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To verify the reaction mechanism as shown in Scheme 2, some control experiments were
carried out. Firstly, the proposed enone A10 and hydrazone 2a were synthesized separately from
1a and I. Then, 0.5 mmol of A was treated with 0.5 mmol of 2a in the presence of Cu(OAc)2 (0.1
mmol), TEMPO (0.5 mmol), and bpy (0.05 mmol). From this reaction, 3a was obtained in a yield
of 62% (Scheme 3, (1)). This result indicated that A and 2a should be the key intermediates in the
formation of 3a. Another control experiment showed that in the absence of any oxidant, 3a was
formed only in trace amount (Scheme 3, (2)). When it was carried out under air, 3a was obtained
in a yield of 27% (Scheme 3, (3)). In the presence of 0.2 equiv of Cu(OAc)2 under air, on the
other hand, the yield of 3a increased to 75% (Scheme 3, (4)). These results revealed that an
oxidant is indispensable for the formation of 3a from the reaction of A with 2a, and a
combination of Cu(II) with air can act as an efficient oxidant for this transformation.
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Scheme 3. Control experiments (I)
Moreover, it should be noted herein that violent gas bubbling was observed in the initial stage
of the reaction shown in Scheme 1, most likely due to the generation of nitrogen through the
oxidation and decomposition of I under the promotion of Cu(OAc)2 and TEMPO.19 In other
words, when the mixture of 1a and I was directly treated with Cu(OAc)2 and TEMPO, I could be
consumed by the oxidant, and decomposed rapidly before it had the chance to react with 1a to
afford 2a. That is why the yield of 3a was only 15% in that case.
Based on the results as described above, we tried to realize the preparation of 3a in a more
efficient manner by directly using 1a and 2a, instead of 1a and I, as the substrates in order to
prevent the oxidation and decomposition of I. To be specific, 0.5 mmol of 1a was treated with 0.1
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mmol of Cu(OAc)2, 0.5 mmol of TEMPO, and 0.05 mmol of bpy in toluene at 120 °C under N2
for 10 h. The resulting mixture was then treated with 0.5 mmol of 2a at 120 °C under air for 4 h.
From this reaction, 3a was obtained in a yield of 60%. To further improve the yield of 3a, a series
of solvents, various temperatures and periods, different amounts of 1a, 2a and the oxidants were
screened. After some trials and errors, we found that a yield of 72% could be realized through
treatment of 0.6 mmol of 1a with 0.1 mmol of Cu(OAc)2, 0.5 mmol of TEMPO and 0.05 mmo1
of bpy in chlorobenzene (PhCl) under N2 at 120 oC for 10 h, and then with 0.5 mmol of 2a under
air at 120 oC for 4 h.
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With the optimized reaction conditions in hands, the scope and generality of this 4-
acylpyrazole forming reaction was studied, and the results were listed in Table 1. Firstly, a range
of ketones (1) were screened by using 2a as a model substrate. It turned out that propiophenones
with various substituents on the phenyl ring reacted with 2a smoothly to give 3a-3h in good
yields. Various functional groups, from the electron-donating methoxy to the electron-
withdrawing trifluoromethyl, were well compatible with the reaction conditions. Meanwhile, it
was also noted that the electronic nature of the phenyl unit of 1 has some effect on the outcome of
this reaction in that substrates bearing electron-withdrawing groups (EWG) on the phenyl ring
generally showed higher efficiency than those with electron-donating groups (EDG) (3b-3d, 3g
vs 3e-3f). Moreover, heteroaromatic ketones such as 2-propionylthiophene and 3-propionyl
pyridine took part in this cascade process to give 3i and 3j with equally good efficiency.
Interestingly, an aliphatic ketone, 1-cyclohexylpropan-1-one, was found to be also compatible
although the yield of the corresponding product (3k) was lower. Next, the scope of hydrazones (2)
was studied. It was firstly found that hydrazones derived from 4-chlorophenylhydrazine, 4-
methylphenylhydrazine, isopropylhydrazine, methylhydrazine, or benzylhydrazine could take
part in this cascade reaction as smoothly as 2a to give 3l−3p in moderate to good yields.
Promisingly, hydrazones (2) derived from diversely substituted propiophenones and 2-propionyl
thiophene were found to be also suitable substrates for this reaction to give 3q-3y in reasonably
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good yields.
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Table 1. Substrate scope for the preparation of 3 a, b
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3c, 75%
3a, 72%
3b, 76%
3f, 60%
3d, 85%
3e, 65%
3h, 62%
3k, 48%
3g, 80%
3j, 63%
3m, 70%
3g
3i, 82%
3l, 80%
3n, 72%
3r, 80%
3v, 70%
3o, 68%
3s, 78%
3w, 71%
3p, 70%
3t, 89%
3x, 79%
3q, 82%
3u, 83%
3y, 81%
a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), Cu(OAc)2 (0.1 mmol), TEMPO (0.5 mmol), bpy (0.05
mmol), PhCl (3 mL). b Isolated yields.
Next, the scope of the hydrazone substrates was extended from acyclic ketone hydrazones (2)
to cyclic ketone hydrazones (4). Thus, 1a was let to react with 1-cyclopentylidene-2-phenyl
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hydrazine (4a) following the procedure employed in the preparation of 3. To our surprise, the
expected (3-butyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (III) was not obtained from this
reaction. Instead, 7-(4-benzoyl-1-phenyl-1H-pyrazol-3-yl)-1-phenylheptan-1-one (5a) was
formed in a yield of 36% (Scheme 4).
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Scheme 4. Unexpected formation of 5a from the reaction of 1a and 4a
We realized that this should be a synthetically promising and mechanistically intriguing
transformation as it led to a novel pyrazole derivative (5a) with a considerable increase in its
molecular complexity compared with that of 3a. Meanwhile, the structure of 5a indicated that 2
equiv of 1a should have been involved by acting as the required enone intermediate, in situ
formed via the oxidative dehydrogenation. Under this circumstance, we tried to improve the yield
of 5a by increasing the amounts of 1a and the oxidants. Thus, 1.2 mmol of 1a was treated with
0.2 mmol of Cu(OAc)2, 1 mmol of TEMPO, and 0.1 mmo1 of bpy in PhCl at 120 oC under N2 for
10 h, and the resulting mixture was then treated with 0.5 mmol of 4a under air at 120 oC for 4 h.
From this one pot cascade process, 5a was obtained in a yield of 65% (Table 2).
To explore the substrate scope of this novel reaction, several cyclic ketone hydrazones (4) were
tried to react with propiophenone (R1 = Ph) or 1-(p-tolyl)propan-1-one (R1 = 4-CH3Ph). The
results listed in Table 2 showed that in addition to hydrazone derived from cyclopentanone, from
which 5a and 5b were obtained, those derived from cyclohexanone or cycloheptanone could also
take part in this reaction to afford 5c, 5d and 5e in good yields. Promisingly, the reactions of the
hydrazones derived from 2-methyl cyclohexanone not only took place smoothly but also showed
an excellent regioselectivity in that only the more substituted α-C–C bond of the hydrazone was
broken to afford 5f and 5g in 60% and 67% yields, respectively.20
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Next, the substrate scope was extended from hydrazones derived from simple cyclic ketones (4)
to those derived from 2,3-dihydro-1H-inden-1-one and 3,4-dihydronaphthalen-1(2H)-one (6). To
our pleasure, the corresponding reactions proceeded smoothly to give 4-acylpyrazole derivatives
with a phenyl group bearing an ortho-functionalized side chain attached on the 3-position of the
pyrazole scaffold in moderate to good yields (7a-7f, Table 3).
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Table 2. Substrate scope for the preparation of 5 a, b
5a, 65%
5e, 68%
5d, 75%
5b, 67%
5f, 60%
5c, 70%
5g, 67%
a Reaction conditions: 1 (1.2 mmol), 4 (0.5 mmol), Cu(OAc)2 (0.2 mmol),
TEMPO (1 mmol), bpy (0.1 mmol), PhCl (3 mL). b Isolated yields.
Table 3. Substrate scope for the preparation of 7 a, b
7a, 78%
7d, 72%
7b, 45%
7e, 70%
7c, 75%
7f, 75%
a
Reaction conditions: 1 (1.2 mmol), 6 (0.5 mmol), Cu(OAc)2 (0.2 mmol),
TEMPO (1 mmol), bpy (0.1 mmol), PhCl (3 mL). b Isolated yields.
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Based on the above results, a plausible mechanism for the formation of 8-(4-benzoyl-1-phenyl-
1H-pyrazol-3-yl)-1-phenyloctan-1-one (5c) from the reaction of 1a with 1-cyclohexylidene-2-
phenylhydrazine (4b) was proposed in Scheme 5. Initially, 1a is transformed into enone A
through an oxidative dehydrogenation. Next, conjugate addition of 4b onto A affords
intermediate E, which then undergoes an intramolecular nucleophilic addition to give a
spirocyclic tetrahydropyrazole (F). Through the dehydrogenation of F, dihydropyrazole G was
formed, which then undergoes an aromatization-driven ring opening through C–C bond cleavage
to form 4-acylpyrazole attached with an alkyl chain radical (H). The alkyl chain radical is then
trapped by enone A to afford a radical intermediate I. Finally, I couples with a hydrogen radical
to give the final product 5c.
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Scheme 5. Proposed mechanism accounting for the formation of 5c
To verify the reaction mechanism as described in Scheme 5, the following control experiments
were carried out. First, the pre-prepared enone A (1 mmol) was treated with 4b (0.5 mmol) in the
presence of Cu(OAc)2 (0.1 mmol) under air. From this reaction, 5c was obtained in a yield of
76%. When A (1 mmol) was treated with 4b (0.5 mmol) in the presence of Cu(OAc)2 (0.1 mmol)
and TEMPO (0.5 mmol) under air, phenyl(1-phenyl-3-(5-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)
pentyl)-1H-pyrazol-4-yl)methanone (8) was isolated in a yield of 77%, and the formation of 5c
was almost completely inhibited (Scheme 6). This study suggests that the formation of 5c should
involve a single electron transfer (SET) process, and the proposed C-radical H (Scheme 5) must
be a key intermediate leading to the formation of 5c.
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Scheme 6. Control experiments (II)
Furthermore, it is reasonable to deduce that the formation of 3a from the reaction of 1a with 2a
might involve an elimination of an ethyl radical (Et·) from the in situ formed dihydropyrazole
intermediate (D) as shown in Scheme 2. To verify this proposal, A was treated with 2a in the
presence of Cu(OAc)2 and TEMPO. From this reaction, 1-ethoxy-2,2,6,6-tetramethylpiperidine,
the proposed radical trapping product, was identified by a GC-MS study (Scheme 7).
Scheme 7. Control experiments (III)
Finally, to showcase the utility of this new synthetic method, we have tried to prepare 3a in a 5
mmol scale. As a result, 3a was obtained in a total yield of 61%. Moreover, we have also tried to
prepare 5a in an enlarged scale of 5 mmol, and 5a was obtained in a yield of 55% (Scheme 8).
Scheme 8. Gram-scale synthesis of 3a and 5a
In summary, we have developed a novel and efficient one-pot synthesis of diversely substituted
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4-acylpyrazole derivatives directly from saturated ketones and hydrazones through multiple
aliphatic C–H bond functionalization, C–C bond cleavage and re-organization. With advantages
such as simple and economical starting materials, sustainable oxidant, excellent regio-selectivity
and high efficiency, this new synthetic strategy is expected to find wide applications in both
heterocyclic and medicinal chemistry.
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EXPERIMENTAL SECTION
I. General methods. Commercial reagents were used without further purification, and solvents
were dried before using. Melting points were recorded with a micro melting point apparatus and
uncorrected. The 1H NMR spectra were recorded at 400 MHz or 600 MHz. The 13C NMR spectra
were recorded at 100 MHz or 150 MHz. Chemical shifts were expressed in parts per million (δ)
downfield from the internal standard tetramethylsilane, and were reported as s (singlet), d
(doublet), t (triplet), dd (doublet of doublet), dt (doublet of triplet), m (multiplet), br s (broad
singlet), etc. The coupling constants J were given in Hz. High resolution mass spectra (HRMS)
were obtained via ESI mode by using a MicrOTOF mass spectrometer. The conversion of starting
materials was monitored by thin layer chromatography (TLC) using silica gel plates (silica gel 60
F254 0.25 mm), and components were visualized by observation under UV light (254 and 365
nm).
II. Experimental Procedures
1. Typical Procedure for the Synthesis of 3a
To a reaction tube equipped with a stir bar were added propiophenone (1a, 81 mg, 0.6 mmol),
PhCl (3 mL), Cu(OAc)2 (18 mg, 0.1 mmol), bpy (8 mg, 0.05 mmol) and TEMPO (78 mg, 0.5
mmol). The mixture was stirred at 120 °C under N2 for 10 h. In another reaction tube,
propiophenone (67 mg, 0.5 mmol) was treated with phenyl hydrazine (54 mg, 0.5 mmol) in
ethanol (2 mL) at ambient temperature for 0.5 h to give 1-phenyl-2-(1-phenylpropylidene)
hydrazine (2a), which was then transferred into the first reaction tube after the mixture had been
concentrated under reduced pressure to remove ethanol and diluted with PhCl. The resulting
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mixture was then stirred under air at 120 C for 4 h. Upon completion, it was diluted with DCM
(15 mL), and washed with water (10 mL) and brine (10 mL). The organic layer was dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to give 3a.
3b-3w were obtained in a similar manner.
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(1,3-Diphenyl-1H-pyrazol-4-yl)(phenyl)methanone (3a): Eluent: petroleum ether/ethyl acetate
(20:1). White solid (117 mg, 72%), mp: 143-145 °C (lit.18b 138-141 °C). H NMR (400 MHz,
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CDCl3) δ: 7.32-7.42 (m, 6H), 7.47-7.54 (m, 3H), 7.72-7.74 (m, 2H), 7.79 (d, J = 8.0 Hz, 2H),
7.84 (d, J = 7.6 Hz, 2H), 8.28 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 119.6, 121.2, 127.6, 128.2,
128.4, 128.6, 128.9, 129.5, 129.7, 132.1, 132.3, 132.6, 138.9, 139.3, 154.0, 190.1. HRMS: calcd
for C22H16N2ONa: 347.1155 [M+Na]+, found: 347.1157.
(1,3-Diphenyl-1H-pyrazol-4-yl)(4-fluorophenyl)methanone (3b): Eluent: petroleum ether/
ethyl acetate (20:1). White solid (130 mg, 76%), mp: 146-147 °C. 1H NMR (600 MHz, CDCl3) δ:
7.03 (t, J = 8.4 Hz, 2H), 7.30-7.32 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H),
7.66-7.68 (m, 2H), 7.77-7.80 (m, 2H), 7.82-7.84 (m, 2H), 8.27 (s, 1H). 13C NMR (150 MHz,
CDCl3) δ: 115.5 (d, 2JC-F = 21.9 Hz), 119.6, 121.1, 127.6, 128.2, 128.7, 128.9, 129.7, 132.0, 132.1
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(d, JC-F = 9.9 Hz), 135.0 (d, JC-F = 3.3 Hz), 139.2, 153.8, 165.5 (d, JC-F = 252.6 Hz), 188.6.
HRMS: calcd for C22H15FN2ONa: 365.1061 [M+Na]+, found: 365.1031.
(4-Bromophenyl)(1,3-diphenyl-1H-pyrazol-4-yl)methanone (3c). Eluent: petroleum ether/
ethyl acetate (20:1). White solid (150 mg, 75%), mp: 153-155 °C. 1H NMR (400 MHz, CDCl3) δ:
7.33-7.34 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H), 7.48-7.53 (m, 4H), 7.67-7.70 (m, 4H), 7.78 (dd, J1 =
8.8 Hz, J2 = 1.2 Hz, 2H), 8.28 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 119.6, 121.0, 127.6, 127.7,
128.2, 128.8, 128.9, 129.7, 131.0, 131.6, 131.9, 132.2, 137.6, 139.2, 153.9, 188.9. HRMS: calcd
for C22H16BrN2O: 403.0441 [M+H]+, found: 403.0452.
(1,3-Diphenyl-1H-pyrazol-4-yl)(4-(trifluoromethyl)phenyl)methanone (3d): Eluent: petroleum
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ether/ethyl acetate (20:1). White solid (167 mg, 85%), mp: 163-165 °C. H NMR (400 MHz,
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CDCl3) δ: 7.31-7.38 (m, 4H), 7.46-7.50 (m, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.66-7.69 (m, 2H),
7.76-7.78 (m, 2H), 7.87 (d, J = 8.0 Hz, 2H), 8.29 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 119.6,
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120.9, 123.6 (q, JC-F = 271.3 Hz), 125.4 (q, JC-F = 3.7 Hz), 127.8, 128.2, 128.8, 129.0, 129.6,
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129.7, 131.8, 132.6, 133.8 (q, JC-F = 32.8 Hz), 139.1, 141.9, 154.2, 188.8. HRMS: calcd for
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C23H16F3N2O: 393.1209 [M+H]+, found: 393.1210.
(1,3-Diphenyl-1H-pyrazol-4-yl)(p-tolyl)methanone (3e): Eluent: petroleum ether/ ethyl acetate
(20:1). White solid (110 mg, 65%), mp: 159-161 °C (lit.18b 151-155 °C). H NMR (400 MHz,
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CDCl3) δ: 2.38 (s, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.32-7.35 (m, 4H), 7.47 (t, J = 8.0 Hz, 2H),
7.74-7.78 (m, 6H), 8.24 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 21.7, 119.5, 121.4, 127.4, 128.2,
128.6, 128.9, 129.1, 129.6, 129.7, 132.0, 132.2, 136.3, 139.3, 143.5, 153.8, 189.8. HRMS: calcd
for C23H19N2O: 339.1492 [M+H]+, found: 339.1474.
(1,3-Diphenyl-1H-pyrazol-4-yl)(4-methoxyphenyl)methanone (3f): Eluent: petroleum ether/
ethyl acetate (10:1). White solid (106 mg, 60%), mp: 132-134 °C. 1H NMR (400 MHz, CDCl3) δ:
3.85 (s, 3H), 6.87 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 2H), 7.32-7.34 (m, 3H), 7.37 (d, J = 7.2 Hz, 1H),
7.50 (t, J = 8.0 Hz, 2H), 7.71-7.73 (m, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.85 (dd, J1 = 6.8 Hz, J2 =
2.0 Hz, 2H), 8.26 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 55.5, 113.6, 119.5, 121.5, 127.4, 128.2,
128.5, 128.8, 129.6, 131.4, 131.6, 132.0, 132.2, 139.4, 153.6, 163.4, 188.9. HRMS: calcd for
C23H18N2O2Na: 377.1260 [M+Na]+, found: 377.1228.
(3-Chlorophenyl)(1,3-diphenyl-1H-pyrazol-4-yl)methanone (3g): Eluent: petroleum ether/ethyl
acetate (20:1). White solid (143 mg, 80%), mp: 154-156 °C. 1H NMR (600 MHz, CDCl3) δ: 7.31
(t, J = 7.8 Hz, 1H), 7.33-7.35 (m, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.47 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz,
1H), 7.50 (t, J = 7.8 Hz, 2H), 7.66-7.69 (m, 3H), 7.78-7.80 (m, 3H), 8.31 (s, 1H). 13C NMR (150
MHz, CDCl3) δ: 119.7, 120.9, 127.6, 127.7, 128.2, 128.8, 129.0, 129.4, 129.6, 129.7, 131.9,
132.3, 132.5, 134.6, 139.2, 140.4, 154.1, 188.6. HRMS: calcd for C22H15ClN2ONa: 381.0765
[M+Na]+, found: 381.0769.
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(1,3-Diphenyl-1H-pyrazol-4-yl)(3-methoxyphenyl)methanone (3h): Eluent: petroleum ether/
ethyl acetate (10:1). White solid (110 mg, 62%), mp: 131-133 °C. 1H NMR (400 MHz, CDCl3) δ:
3.66 (s, 3H), 6.94-6.97 (m, 1H), 7.16-7.27 (m, 6H), 7.31 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 8.0 Hz,
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2H), 7.62-7.68 (m, 4H), 8.18 (s, 1H). C NMR (150 MHz, CDCl3) δ: 55.4, 113.7, 119.3, 119.6,
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121.2, 122.3, 127.6, 128.2, 128.7, 128.9, 129.4, 129.7, 132.2, 132.4, 139.3, 140.2, 154.0, 159.7,
189.7. HRMS: calcd for C23H19N2O2: 355.1441 [M+H]+, found: 355.1434.
(1,3-Diphenyl-1H-pyrazol-4-yl)(thiophen-2-yl)methanone (3i): Eluent: petroleum ether/ethyl
acetate (20:1). White solid (135 mg, 82%), mp: 154-155 °C. 1H NMR (400 MHz, CDCl3) δ: 7.06-
7.09 (m, 1H), 7.35-7.40 (m, 4H), 7.52 (t, J = 8.0 Hz, 2H), 7.62 (dd, J1 = 4.0 Hz, J2 = 0.8 Hz, 1H),
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7.66 (dd, J1 = 4.8 Hz, J2 = 0.8 Hz, 1H), 7.78-7.82 (m, 4H), 8.40 (s, 1H). C NMR (150 MHz,
CDCl3) δ: 119.6, 121.1, 127.6, 128.0, 128.3, 128.7, 128.8, 129.7, 131.2, 132.0, 133.9, 134.0,
139.3, 145.0, 153.4, 181.4. HRMS: calcd for C20H14N2OSNa: 353.0719 [M+Na]+, found:
353.0707.
(1,3-Diphenyl-1H-pyrazol-4-yl)(pyridin-3-yl)methanone (3j). Eluent: dichloromethane/
1
methanol (20:1). White solid (102 mg, 63%), mp: 130-132 °C. H NMR (400 MHz, CDCl3) δ:
7.31-7.38 (m, 5H), 7.48 (t, J = 8.0 Hz, 2H), 7.67-7.69 (m, 2H), 7.78 (d, J = 8.0 Hz, 2H), 8.05 (d, J
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= 7.6 Hz, 1H), 8.35 (s, 1H), 8.71 (s, 1H), 9.02 (s, 1H). C NMR (100 MHz, CDCl3) δ: 119.6,
120.9, 123.4, 127.8, 128.3, 128.9, 129.1, 129.7, 131.8, 132.5, 134.4, 136.6, 139.1, 150.3, 152.8,
154.1, 188.1. HRMS: calcd for C21H16N3O: 326.1288 [M+H]+, found: 326.1276.
Cyclohexyl(1,3-diphenyl-1H-pyrazol-4-yl)methanone (3k): petroleum ether/ethyl acetate
(20:1). White solid (79 mg, 48%), mp: 113-114 °C. 1H NMR (600 MHz, CDCl3) δ: 1.13-1.24 (m,
3H), 1.45-1.51 (m, 2H), 1.64-1.66 (m, 1H), 1.76-1.79 (m, 2H), 1.83-1.85 (m, 2H), 2.78-2.82 (m,
1H), 7.36 (t, J = 7.8 Hz, 1H), 7.42-7.46 (m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.73 (dd, J1 = 7.8 Hz, J2
= 1.2 Hz, 2H), 7.78 (d, J = 7.2 Hz, 2H), 8.42 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 25.7, 25.8,
29.4, 48.9, 119.7, 121.7, 127.6, 128.1, 128.8, 129.3, 129.6, 130.9, 132.7, 139.3, 153.9, 199.0.
HRMS: calcd for C22H23N2O: 331.1805 [M+H]+, found: 331.1789.
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(1-(4-Chlorophenyl)-3-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3l): Eluent: petroleum
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ether/ethyl acetate (20:1). White solid (143 mg, 80%), mp: 165-167 °C (lit.18b 171-172 °C). H
NMR (600 MHz, CDCl3) δ: 7.32-7.34 (m, 3H), 7.39 (t, J = 7.2 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H),
7.52 (t, J = 6.6 Hz, 1H), 7.70-7.74 (m, 4H), 7.82 (d, J = 7.2 Hz, 2H), 8.25 (s, 1H). 13C NMR (150
MHz, CDCl3) δ: 120.7, 121.6, 128.2, 128.4, 128.7, 128.9, 129.5, 129.8, 131.9, 132.1, 132.7,
133.1, 137.8, 138.7, 154.2, 189.9. HRMS: calcd for C22H15ClN2ONa: 381.0765 [M+Na]+, found:
381.0747.
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Phenyl(3-phenyl-1-(p-tolyl)-1H-pyrazol-4-yl)methanone (3m): Eluent: petroleum ether/ethyl
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acetate (20:1). White solid (118 mg, 70%), mp: 148-150 °C (lit.18b 149-151 °C). H NMR (600
MHz, CDCl3) δ: 2.41 (s, 3H), 7.29 (d, J = 7.8 Hz, 2H), 7.32-7.34 (m, 3H), 7.40 (t, J = 7.2 Hz,
2H), 7.52 (t, J = 7.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.83 (d, J = 7.2
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Hz, 2H), 8.24 (s, 1H). C NMR (150 MHz, CDCl3) δ: 21.0, 119.5, 121.0, 128.1, 128.3, 128.5,
128.9, 129.5, 130.1, 132.2, 132.3, 132.6, 137.0, 137.5, 139.0, 153.8, 190.1. HRMS: calcd for
C23H19N2O: 339.1492 [M+H]+, found: 339.1475.
(1-Isopropyl-3-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3n): Eluent: petroleum ether/ethyl
acetate (20:1). White solid (104 mg, 72%), mp: 98-99 °C. 1H NMR (600 MHz, CDCl3) δ: 1.51 (d,
J = 6.6 Hz, 6H), 4.48-4.50 (m, 1H), 7.19-7.21 (m, 3H), 7.28 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 6.6
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Hz, 1H), 7.55 (d, J = 6.6 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H), 7.74 (s, 1H). C NMR (150 MHz,
CDCl3) δ: 21.8, 53.4, 118.0, 127.0, 127.1, 127.2, 127.9, 128.3, 131.2, 131.5, 131.7, 138.2, 151.6,
189.2. HRMS: calcd for C19H19N2O: 291.1492 [M+H]+, found: 291.1468.
(1-Methyl-3-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3o): Eluent: petroleum ether/ethyl
acetate (20:1). White solid (89 mg, 68%), mp: 88-90 °C. 1H NMR (600 MHz, CDCl3) δ: 3.95 (s,
3H), 7.28-7.37 (m, 5H), 7.47 (t, J = 7.2 Hz, 1H), 7.62-7.64 (m, 2H), 7.73-7.76 (m, 3H). 13C NMR
(150 MHz, CDCl3) δ: 39.3, 119.5, 128.1, 128.2, 128.3, 128.8, 129.4, 132.3, 132.4, 136.2, 139.2,
153.2, 189.9. HRMS: calcd for C17H14N2NaO: 285.0998 [M+Na]+, found: 285.0999.
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(1-Benzyl-3-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3p): Eluent: petroleum ether/ethyl
acetate (20:1). White solid (118 mg, 70%), mp: 102-103 °C. 1H NMR (600 MHz, CDCl3) δ: 5.34
(s, 2H), 7.27-7.37 (m, 10H), 7.44 (t, J = 7.2 Hz, 1H), 7.63-7.65 (m, 2H), 7.73 (d, J = 8.0 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ: 56.5, 119.9, 128.0, 128.1, 128.2, 128.3, 128.6, 128.9, 129.1,
129.4, 132.3, 132.4, 135.3, 135.4, 139.1, 153.2, 190.0. HRMS: calcd for C23H19N2O: 339.1492
[M+H]+, found: 339.1498.
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(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3q): Eluent: petroleum
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ether/ethyl acetate (20:1). White solid (140 mg, 82%), mp: 135-136 °C. H NMR (400 MHz,
CDCl3) δ: 7.00-7.06 (m, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.46-7.50 (m, 2H),
7.52-7.56 (m, 1H), 7.74-7.79 (m, 4H), 7.82-7.84 (m, 2H), 8.25 (s, 1H). 13C NMR (150 MHz,
CDCl3) δ: 115.2 (d, 2JC-F = 21.9 Hz), 119.6, 121.0, 127.7, 128.3 (d, 4JC-F = 3.3 Hz), 128.5, 129.4,
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129.7, 130.8 (d, JC-F = 8.7 Hz), 132.6, 132.7, 139.0, 139.2, 153.1, 163.1 (d, JC-F = 246.0 Hz),
189.9. HRMS: calcd for C22H16FN2O: 343.1241 [M+H]+, found: 343.1214.
(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3r): Eluent: petroleum
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ether/ethyl acetate (20:1). White solid (161 mg, 80%), mp: 159-161 °C. H NMR (600 MHz,
CDCl3) δ: 7.34 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.45-7.48 (m, 4H), 7.54 (t, J = 7.2 Hz,
1H), 7.66 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 2H), 8.23 (s, 1H). 13C
NMR (150 MHz, CDCl3) δ: 119.6, 121.1, 123.0, 127.7, 128.5, 129.5, 129.7, 130.5, 131.1, 131.3,
132.6, 132.8, 138.9, 139.1, 152.9, 189.7. HRMS: calcd for C22H16BrN2O: 403.0441 [M+H]+,
found: 403.0464.
(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3s): Eluent: petroleum
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ether/ethyl acetate (20:1). White solid (140 mg, 78%), mp: 147-149 °C (lit.18c 142-145 °C). H
NMR (600 MHz, CDCl3) δ: 7.31 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz,
2H), 7.47 (t, J = 7.8 Hz, 2H), 7.54 (d, J = 7.2 Hz, 1H), 7.72-7.75 (m, 4H), 7.83 (d, J = 7.2 Hz,
2H), 8.24 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 119.6, 121.1, 127.7, 128.4, 128.5, 129.5, 129.7,
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130.3, 130.7, 132.6, 132.8, 134.7, 138.9, 139.1, 152.9, 189.8. HRMS: calcd for C22H16ClN2O:
359.0946 [M+H]+, found: 359.0924.
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(3t):
Eluent:
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petroleum ether/ethyl acetate (20:1). White solid (174 mg, 89%), mp: 141-143 °C. 1H NMR (600
MHz, CDCl3) δ: 7.38 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.57 (t,
J = 7.2 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 7.8 Hz, 2H), 7.91
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(d, J = 7.8 Hz, 2H), 8.28 (s, 1H). C NMR (100 MHz, CDCl3) δ: 119.6, 121.3, 124.2 (q, JC-F
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270.6 Hz), 125.1 (q, JC-F = 4.4 Hz), 127.9, 128.6, 129.2, 129.4, 129.7, 130.4 (q, JC-F = 32 Hz),
132.7, 132.9, 135.7 (q, 4JC-F = 1.5 Hz), 138.8, 139.1, 152.6, 189.6. HRMS: calcd for C23H16F3N2O:
393.1209 [M+H]+, found: 393.1218.
Phenyl(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)methanone (3u): Eluent: petroleum ether/ethyl
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acetate (20:1). White solid (140 mg, 83%), mp: 146-148 °C (lit.18c 137-140 °C). H NMR (400
MHz, CDCl3) δ: 2.34 (s, 3H), 7.14 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.8
Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.76 (d, J =
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7.8 Hz, 2H), 7.84 (d, J = 7.2 Hz, 2H), 8.23 (s, 1H). C NMR (150 MHz, CDCl3) δ: 21.4, 119.6,
121.1, 127.4, 128.4, 128.8, 128.9, 129.2, 129.5, 129.6, 132.3, 132.6, 138.5, 139.1, 139.3, 154.1,
190.0. HRMS: calcd for C23H19N2O: 339.1492 [M+H]+, found: 339.1506.
(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3v): Eluent: petroleum
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ether/ethyl acetate (10:1). White solid (124 mg, 70%), mp: 132-134 °C. H NMR (400 MHz,
CDCl3) δ: 3.81 (s, 3H), 6.88 (d, J = 9.2 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H),
7.48 (t, J = 8.0 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 7.6 Hz,
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2H), 7.84 (d, J = 7.2 Hz, 2H), 8.24 (s, 1H). C NMR (150 MHz, CDCl3) δ: 55.3, 113.6, 119.5,
120.9, 124.6, 127.4, 128.4, 129.5, 129.6, 130.3, 132.4, 132.6, 139.1, 139.3, 153.8, 160.0, 190.1.
HRMS: calcd for C23H19N2O2: 355.1441 [M+H]+, found: 355.1442.
(3-(3-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3w): Eluent: petroleum
1
ether/ethyl acetate (20:1). White solid (121 mg, 71%), mp: 129-131 °C. H NMR (600 MHz,
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CDCl3) δ: 6.90-6.94 (m, 1H), 7.17-7.20 (m, 1H), 7.25 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H),
7.38 (t, J = 7.8 Hz, 2H), 7.43-7.45 (m, 3H), 7.66 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H),
8.16 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 115.5 (d, 2JC-F = 20.7 Hz), 115.8 (d, 2JC-F = 23.0 Hz),
119.6, 121.2, 124.8 (d, 4JC-F = 3.3 Hz), 127.7, 128.5, 129.5, 129.6 (d, 3JC-F = 8.7 Hz), 129.7, 132.5,
132.8, 134.3 (d, 3JC-F = 8.7 Hz), 138.9, 139.1, 152.7 (d, 4JC-F = 2.2 Hz), 162.6 (d, 1JC-F = 242.7 Hz),
189.8. HRMS: calcd for C22H16FN2O: 343.1241 [M+H]+, found: 343.1242.
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(3-(3-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone (3x): Eluent: petroleum
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ether/ethyl acetate (20:1). White solid (159 mg, 79%), mp: 145-147 °C. H NMR (600 MHz,
CDCl3) δ: 7.20 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.40-7.46 (m, 3H), 7.50 (t, J = 7.2 Hz,
2H), 7.55 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 7.8
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Hz, 2H), 7.96 (s, 1H), 8.27 (s, 1H). C NMR (150 MHz, CDCl3) δ: 119.6, 121.3, 122.2, 127.7,
127.8, 128.5, 129.4, 129.6, 129.7, 131.6, 131.7, 132.6, 132.8, 134.1, 138.9, 139.1, 152.5, 189.8.
HRMS: calcd for C22H16BrN2O: 403.0441 [M+H]+, found: 403.0440.
Phenyl(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)methanone (3y): Eluent: petroleum ether/
ethyl acetate (20:1). White solid (133 mg, 81%), mp: 137-139 °C. 1H NMR (600 MHz, CDCl3) δ:
7.04-7.05 (m, 1H), 7.33-7.34 (m, 2H), 7.45-7.47 (m, 4H), 7.57 (t, J = 7.2 Hz, 1H), 7.73 (d, J = 8.4
Hz, 2H), 7.85 (d, J = 7.8 Hz, 2H), 7.93-7.94 (m, 1H), 8.17 (s, 1H). 13C NMR (150 MHz, CDCl3)
δ: 119.6, 120.4, 126.8, 127.5, 127.7, 128.6, 128.9, 129.4, 129.7, 132.6, 132.9, 134.2, 139.0, 139.5,
148.3, 189.5. HRMS: calcd for C20H14N2OSNa: 353.0719 [M+Na]+, found: 353.0706.
2. Typical Procedure for the Synthesis of 5a
To a reaction tube equipped with a stir bar were added propiophenone (1a, 161 mg, 1.2 mmol),
PhCl (5 mL), Cu(OAc)2 (36 mg, 0.2 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol) and TEMPO (156
mg, 1 mmol). The mixture was stirred under N2 at 120 °C for 10 h. Afterwards, 1-
cyclopentylidene-2-phenylhydrazine (4a, 87 mg, 0.5 mmol) was added, and the resulting mixture
was stirred under air at 120 oC for 4 h. Upon completion, it was diluted with DCM (15 mL), and
washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous
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Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (10:1) as the eluent to give 5a.
5b-5g and 7a-7f were obtained in a similar manner.
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7-(4-Benzoyl-1-phenyl-1H-pyrazol-3-yl)-1-phenylheptan-1-one (5a): Eluent: petroleum ether/
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ethyl acetate (10:1). Syrup (141 mg, 65%). H NMR (400 MHz, CDCl3) δ: 1.42-1.52 (m, 4H),
1.72-1.84 (m, 4H), 2.96 (t, J = 7.6 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H),
7.41-7.59 (m, 8H), 7.67 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H),
8.11 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 24.4, 28.0, 28.8, 29.1, 29.4, 38.6, 119.6, 120.7,
127.3, 128.1, 128.5, 128.8, 129.6, 132.1, 132.2, 132.8, 137.1, 139.3, 140.1, 157.4, 190.0, 200.6.
HRMS: calcd for C29H29N2O2: 437.2224 [M+H]+, found: 437.2224.
7-(4-(4-Methylbenzoyl)-1-phenyl-1H-pyrazol-3-yl)-1-(p-tolyl)heptan-1-one (5b): Eluent:
petroleum ether/ethyl acetate (10:1). Syrup (155 mg, 67%). 1H NMR (600 MHz, CDCl3) δ: 1.42-
1.51 (m, 4H), 1.71-1.76 (m, 2H), 1.77-1.82 (m, 2H), 2.39 (s, 3H), 2.43 (s, 3H), 2.92 (t, J = 7.2 Hz,
2H), 3.03 (t, J = 7.2 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.25-7.32 (m, 3H), 7.44 (t, J = 7.8 Hz, 2H),
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7.68 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 8.11 (s, 1H). C
NMR (150 MHz, CDCl3) δ: 21.6, 24.5, 27.9, 28.9, 29.2, 29.4, 38.5, 119.5, 120.8, 127.2, 128.2,
129.0, 129.2, 129.3, 129.6, 131.9, 134.7, 137.4, 139.4, 142.8, 143.5, 157.3, 189.8, 200.3. HRMS:
calcd for C31H32N2O2Na: 487.2356 [M+Na]+, found: 487.2366.
8-(4-Benzoyl-1-phenyl-1H-pyrazol-3-yl)-1-phenyloctan-1-one (5c): Eluent: petroleum ether/
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ethyl acetate (10:1). Syrup (157 mg, 70%). H NMR (400 MHz, CDCl3) δ: 1.40-1.47 (m, 6H),
1.70-1.82 (m, 4H), 2.95 (t, J = 7.6 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H),
7.42-7.47 (m, 4H), 7.49-7.52 (m, 2H), 7.54-7.60 (m, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.83 (d, J =
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7.2 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H), 8.11 (s, 1H). C NMR (150 MHz, CDCl3) δ: 24.4, 28.0,
28.9, 29.2, 29.3, 29.5, 38.7, 119.6, 120.7, 127.3, 128.1, 128.5, 128.6, 128.8, 129.6, 132.1, 132.2,
132.8, 137.1, 139.4, 140.1, 157.5, 190.0, 200.7. HRMS: calcd for C30H30N2O2Na: 473.2199
[M+Na]+, found: 473.2179.
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ethyl acetate (10: 1). Syrup (174 mg, 75%). H NMR (400 MHz, CDCl3) δ: 1.36 (s, 6H), 1.42-
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1.46 (m, 2H), 1.68-1.81 (m, 4H), 2.94 (t, J = 7.6 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6
Hz, 1H), 7.42-7.51 (m, 6H), 7.53-7.59 (m, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 6.8 Hz, 2H),
7.95 (d, J = 7.6 Hz, 2H), 8.11 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 24.4, 28.0, 28.9, 29.2, 29.3,
29.4, 29.6, 38.7, 119.6, 120.7, 127.3, 128.1, 128.5, 128.6, 128.8, 129.6, 132.1, 132.2, 132.9,
137.1, 139.3, 140.1, 157.5, 190.0, 200.7. HRMS: calcd for C31H32N2O2Na: 487.2356 [M+Na]+,
found: 487.2330.
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9-(4-(4-Methylbenzoyl)-1-phenyl-1H-pyrazol-3-yl)-1-(p-tolyl)nonan-1-one
(5e):
Eluent:
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petroleum ether/ethyl acetate (10:1). White solid (167 mg, 68%), mp 94-95 °C. H NMR (400
MHz, CDCl3) δ: 1.35 (s, 6H), 1.40-1.45 (m, 2H), 1.68-1.72 (m, 2H), 1.73-1.81 (m, 2H), 2.38 (s,
3H), 2.42 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.27-
7.31 (m, 3H), 7.43 (t, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.83 (d,
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J = 8.0 Hz, 2H), 8.11 (s, 1H). C NMR (150 MHz, CDCl3) δ: 21.6, 24.5, 28.0, 29.0, 29.3, 29.4,
29.6, 38.5, 119.5, 120.8, 127.2, 128.2, 129.0, 129.2, 129.3, 129.6, 131.9, 134.7, 137.4, 139.4,
142.8, 143.5, 157.4, 189.7, 200.3. HRMS: calcd for C33H36N2O2Na: 515.2669 [M+Na]+, found:
515.2623.
8-(4-Benzoyl-1-phenyl-1H-pyrazol-3-yl)-4-methyl-1-phenyloctan-1-one
(5f):
Eluent:
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petroleum ether/ethyl acetate (10:1). Syrup (139 mg, 60%). H NMR (600 MHz, CDCl3) δ: 0.93
(d, J = 7.2 Hz, 3H), 1.22-1.27 (m, 1H), 1.41-1.47 (m, 2H), 1.49-1.59 (m, 3H), 1.72-1.82 (m, 3H),
2.94-2.98 (m, 2H), 3.04 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.43-7.46 (m, 4H), 7.49 (t, J
= 7.2 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.82 (d,
J = 7.8 Hz, 2H), 7.95 (d, J = 7.8 Hz, 2H), 8.11 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 19.3, 27.0,
28.0, 29.2, 31.5, 32.6, 36.4, 36.5, 119.6, 120.7, 127.3, 128.1, 128.5, 128.6, 128.8, 129.6, 132.1,
132.2, 132.8, 137.1, 139.3, 140.1, 157.4, 190.0, 200.9. HRMS: calcd for C31H32N2O2Na:
487.2356 [M+Na]+, found: 487.2347.
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4-Methyl-8-(4-(4-methylbenzoyl)-1-phenyl-1H-pyrazol-3-yl)-1-(p-tolyl)octan-1-one
(5g):
Eluent: petroleum ether/ethyl acetate (10:1). Syrup (164 mg, 67%). 1H NMR (400 MHz, CDCl3)
δ: 0.92 (d, J = 6.0 Hz, 3H), 1.21-1.28 (m, 1H), 1.39-1.45 (m, 2H), 1.47-1.57 (m, 3H), 1.71-1.78
(m, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.90-2.96 (m, 2H), 3.02 (t, J = 7.6 Hz, 2H), 7.23-7.34 (m, 5H),
7.46 (t, J = 8.0 Hz, 2H), 7.68 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.85 (d,
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J = 8.4 Hz, 2H), 8.12 (s, 1H). C NMR (150 MHz, CDCl3) δ: 19.6, 21.6, 27.0, 28.0, 29.3, 31.6,
32.6, 36.3, 36.5, 119.5, 120.8, 127.2, 128.2, 129.0, 129.1, 129.2, 129.6, 131.9, 134.7, 137.4,
139.4, 142.8, 143.5, 157.3, 189.8, 200.6. HRMS: calcd for C33H36N2O2Na: 515.2669 [M+Na]+,
found: 515.2652.
5-(2-(4-Benzoyl-1-phenyl-1H-pyrazol-3-yl)phenyl)-1-phenylpentan-1-one
(7a):
Eluent:
petroleum ether/ethyl acetate (10:1). White solid (188 mg, 78%), mp: 116-118 °C. 1H NMR (400
MHz, CDCl3) δ: 1.65-1.70 (m, 4H), 2.69 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 7.14-7.18
(m, 1H), 7.24-7.31 (m, 2H), 7.33-7.38 (m, 6H), 7.45-7.49 (m, 4H), 7.75-7.78 (m, 4H), 7.82 (d, J
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= 7.6 Hz, 2H), 8.34 (s, 1H). C NMR (100 MHz, CDCl3) δ: 24.1, 30.7, 33.4, 38.3, 119.4, 122.3,
125.6, 127.5, 128.0, 128.3, 128.5, 128.7, 129.1, 129.2, 129.7, 130.8, 131.3, 132.4, 132.8, 137.0,
138.8, 139.3, 141.1, 154.3, 189.3, 200.3. HRMS: calcd for C33H29N2O2: 485.2224 [M+H]+, found:
485.2224.
5-(2-(4-(4-Fluorobenzoyl)-1-phenyl-1H-pyrazol-3-yl)phenyl)-1-(4-fluorophenyl)pentan-1-one
(7b): Eluent: petroleum ether/ethyl acetate (10:1). White solid (117 mg, 45%), mp: 109-111 °C.
1H NMR (600 MHz, CDCl3) δ: 1.63-1.69 (m, 4H), 2.67 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz,
2H), 7.00-7.04 (m, 4H), 7.16 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.26-7.29 (m, 2H), 7.37
(t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.75-7.79 (m, 4H), 7.83-7.85 (m, 2H), 8.37 (s, 1H).
13C NMR (150 MHz, CDCl3) δ: 24.0, 30.6, 33.3, 38.1, 115.3 (d, 2JC-F = 21.9 Hz), 115.5 (d, 2JC-F
21.8 Hz), 119.4, 122.3, 125.7, 127.6, 128.8, 129.2, 129.7, 130.6 (d, 3JC-F = 8.7 Hz), 130.8, 130.9,
=
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131.1, 131.7 (d, JC-F = 8.7 Hz), 133.4 (d, JC-F = 2.3 Hz), 134.9 (d, JC-F = 3.3 Hz), 139.2, 141.0,
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154.0, 165.3 (d, JC-F = 252.8 Hz), 165.6 (d, JC-F = 252.6 Hz), 188.0, 198.6. HRMS: calcd for
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C33H26 F2N2O2Na: 543.1855 [M+Na]+, found: 543.1825.
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5-(2-(4-(4-Methylbenzoyl)-1-phenyl-1H-pyrazol-3-yl)phenyl)-1-(p-tolyl)pentan-1-one
(7c):
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Eluent: petroleum ether/ethyl acetate (10:1). White solid (192 mg, 75%), mp: 114-116 °C. H
NMR (400 MHz, CDCl3) δ: 1.63-1.69 (m, 4H), 2.35 (s, 3H), 2.36 (s, 3H), 2.71 (t, J = 7.2 Hz, 2H),
2.79 (t, J = 7.2 Hz, 2H), 7.16 (t, J = 7.6 Hz, 5H), 7.22-7.27 (m, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.47
(t, J = 8.0 Hz, 2H), 7.68-7.73 (m, 4H), 7.77 (d, J = 7.6 Hz, 2H), 8.32 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ: 21.6, 24.3, 30.7, 33.4, 38.2, 119.4, 122.5, 125.6, 127.4, 128.1, 128.6, 129.0, 129.2,
129.4, 129.6, 130.8, 131.0, 131.9, 134.6, 136.2, 139.3, 141.1, 143.2, 143.5, 154.2, 189.0, 200.0.
HRMS: calcd for C35H32N2O2Na: 535.2356 [M+Na]+, found: 535.2317.
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1-one (7d): Eluent: petroleum ether/ethyl acetate (5:1). White solid (195 mg, 72%), mp: 127-
1
129 °C. H NMR (600 MHz, CDCl3) δ: 1.64-1.68 (m, 4H), 2.69 (t, J = 7.2 Hz, 2H), 2.77 (t, J =
7.2 Hz, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.84 (d, J = 8.4 Hz, 4H), 7.16 (t, J = 7.2 Hz, 1H), 7.23-
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7.27 (m, 2H), 7.32-7.36 (m, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.77-7.81 (m, 6H), 8.33 (s, 1H). C
NMR (150 MHz, CDCl3) δ: 24.4, 30.7, 33.4, 37.9, 55.4, 55.5, 113.5, 113.6, 119.4, 122.6, 125.6,
127.3, 128.6, 129.2, 129.6, 130.1, 130.2, 130.7, 130.8, 131.4, 131.6, 131.9, 139.4, 141.1, 154.0,
163.1, 163.2, 188.1, 198.9. HRMS: calcd for C35H33N2O4: 545.2435 [M+H]+, found: 545.2397.
6-(2-(4-Benzoyl-1-phenyl-1H-pyrazol-3-yl)phenyl)-1-phenylhexan-1-one
(7e):
Eluent:
petroleum ether/ethyl acetate (10:1). White solid (174 mg, 70%), mp: 129-130 °C. 1H NMR (400
MHz, CDCl3) δ: 1.30-1.34 (m, 2H), 1.59-1.66 (m, 4H), 2.65 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 7.2
Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.21-7.27 (m, 2H), 7.31-7.42 (m, 6H), 7.44-7.53 (m, 4H), 7.77
(d, J = 8.0 Hz, 4H), 7.86 (d, J = 7.6 Hz, 2H), 8.35 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 24.0,
29.1, 30.9, 33.3, 38.4, 119.5, 122.3, 125.5, 127.5, 128.0, 128.3, 128.5, 128.7, 129.1, 129.2, 129.6,
130.7, 131.3, 131.8, 132.3, 132.8, 137.0, 138.8, 139.3, 141.4, 154.4, 189.3, 200.4. HRMS: calcd
for C34H31N2O2: 499.2380 [M+H]+, found: 499.2340.
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6-(2-(4-(4-Methylbenzoyl)-1-phenyl-1H-pyrazol-3-yl)phenyl)-1-(p-tolyl)hexan-1-one
(7f):
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Eluent: petroleum ether/ethyl acetate (10:1). White solid (197 mg, 75%), mp: 125-127 °C. H
NMR (600 MHz, CDCl3) δ: 1.29-1.33 (m, 2H), 1.57-1.63 (m, 4H), 2.36 (s, 3H), 2.37 (s, 3H),
2.65 (t, J = 7.8 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 7.17 (t, J = 9.0 Hz, 5H), 7.23 (t, J = 7.2 Hz, 1H),
7.27 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H),
7.76 (d, J = 7.2 Hz, 4H), 8.31 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 21.6, 24.2, 29.1, 30.9, 33.4,
38.3, 119.4, 122.4, 125.5, 127.4, 128.2, 128.6, 129.0, 129.1, 129.2, 129.4, 129.6, 130.7, 131.1,
131.9, 134.6, 136.2, 139.3, 141.4, 143.1, 143.5, 154.3, 188.9, 200.1. HRMS: calcd for
C36H35N2O2: 527.2693 [M+H]+, found: 527.2670.
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3. Control Experiments (I)
3.1. To a reaction tube equipped with a stir bar were added A (66 mg, 0.5 mmol), 2a (in situ
formed from the reaction of 0.5 mmol of propiophenone with 0.5 mmol of phenyl hydrazine),
toluene (3 mL), Cu(OAc)2 (18 mg, 0.1 mmol), bpy (8 mg, 0.05 mmol) and TEMPO (78 mg, 0.5
o
mmol). The resulting mixture was stirred at 120 C under N2 for 4 h. Then, it was diluted with
DCM (15 mL), and washed with water (10 mL). The organic layer was dried over anhydrous
Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to give 3a in
a yield of 62%.
3.2. To a reaction tube equipped with a stir bar were added A (66 mg, 0.5 mmol), 2a (in situ
formed from the reaction of 0.5 mmol of propiophenone with 0.5 mmol of phenyl hydrazine), and
toluene (3 mL). The resulting mixture was stirred at 120 oC under N2 for 4 h to give 3a in a trace
amount.
3.3. To a reaction tube equipped with a stir bar were added A (66 mg, 0.5 mmol), 2a (in situ
formed from the reaction of 0.5 mmol of propiophenone with 0.5 mmol of phenyl hydrazine), and
toluene (3 mL). The resulting mixture was stirred at 120 °C under air for 4 h. Then, it was diluted
with DCM (15 mL), and washed with water (10 mL). The organic layer was dried over anhydrous
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Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to give 3a in
a yield of 27%.
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3.4. To a reaction tube equipped with a stir bar were added A (66 mg, 0.5 mmol), 2a (in situ
formed from the reaction of 0.5 mmol of propiophenone with 0.5 mmol of phenyl hydrazine),
toluene (3 mL) and Cu(OAc)2 (18 mg, 0.1 mmol) with stirring. The resulting mixture was stirred
at 120 °C under air for 4 h. Then, it was diluted with DCM (15 mL), and washed with water (10
mL). The organic layer was dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on silica gel with petroleum
ether/ethyl acetate (20:1) as the eluent to give 3a in a yield of 75%.
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4. Control Experiments (II)
4.1. To a reaction tube equipped with a stir bar were added A (132 mg, 1.0 mmol), 4b (94 mg,
0.5 mmol), PhCl (5 mL) and Cu(OAc)2 (18 mg, 0.1 mmol) with stirring. The resulting mixture
was stirred at 120 oC under air for 4 h. Then, it was diluted with DCM (15 mL), and washed with
water (10 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The residue was purified by column chromatography on silica gel with
petroleum ether/ethyl acetate (10:1) as the eluent to give 5c in a yield of 76%.
4.2. To a reaction tube equipped with a stir bar were added A (132 mg, 1 mmol), 4b (94 mg,
0.5 mmol), PhCl (5 mL), Cu(OAc)2 (18 mg, 0.1 mmol) and TEMPO (78 mg, 0.5 mmol) with
o
stirring. The resulting mixture was stirred at 120 C under air for 4 h. Then, it was diluted with
DCM (15 mL), and washed with water (10 mL). The organic layer was dried over anhydrous
Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (10:1) as the eluent to give 8.
Phenyl(1-phenyl-3-(5-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pentyl)-1H-pyrazol-4-yl)metha-
none (8): Eluent: petroleum ether/ethyl acetate (10:1). Syrup (182 mg, 77%). 1H NMR (600 MHz,
CDCl3) δ: 0.99 (s, 6H), 1.06 (s, 6H), 1.17-1.23 (m, 1H), 1.33-1.34 (m, 4H), 1.42-1.54 (m, 5H),
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1.68-1.76 (m, 2H), 2.97 (t, J = 7.6 Hz, 2H), 3.66 (t, J = 6.4 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H),
7.35-7.43 (m, 4H), 7.50 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.73-7.75 (m, 2H), 8.03 (s,
1H). 13C NMR (100 MHz, CDCl3) δ: 17.2, 20.1, 26.5, 28.0, 28.6, 29.1, 33.1, 39.6, 59.6, 76.8,
119.6, 120.6, 127.3, 128.5, 128.8, 129.6, 132.1, 132.2, 139.3, 140.1, 157.4, 190.0. HRMS: calcd
for C30H40N3O2: 474.3115 [M+H]+, found: 474.3091.
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5. Control Experiments (III)
To a reaction tube equipped with a stir bar were added A (66 mg, 0.5 mmol), 2a (112 mg, 0.5
mmol), PhCl (5 mL), Cu(OAc)2 (18 mg, 0.1 mmol) and TEMPO (78 mg, 0.5 mmol) with stirring.
o
The resulting mixture was stirred at 120 C under air for 4 h. Afterwards, it was cooled to room
temperature, and filtered. A GC-MS study of the resulting mixture thus obtained showed that 1-
ethoxy-2,2,6,6-tetramethylpiperidine was formed.
6. Scale-up Synthesis of 3a and 5a.
To a reaction tube equipped with a stir bar were added propiophenone (1a, 0.67 g, 5 mmol),
PhCl (20 mL), Cu(OAc)2 (181 mg, 1 mmol), bpy (78 mg, 0.5 mmol) and TEMPO (781 mg, 5
mmol). The mixture was stirred at 120 °C under N2 for 10 h. In another reaction tube,
propiophenone (670 mg, 5 mmol) was treated with phenylhydrazine (540 mg, 5 mmol) in ethanol
(10 mL) at ambient temperature for 0.5 h to give 1-phenyl-2-(1-phenylpropylidene)hydrazine
(2a), which was then transferred into the first reaction tube after the mixture had been
concentrated under reduced pressure to remove ethanol and diluted with PhCl. The resulting
o
mixture was then stirred under air at 120 C for 4 h. Upon completion, it was diluted with DCM
(80 mL), and washed with water (30 mL) and brine (30 mL). The organic layer was dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (20:1) as the eluent to give 3a
(0.99 g, 61%).
To a reaction tube equipped with a stir bar were added propiophenone (1a, 1.34 g, 10 mmol),
PhCl (30 mL), Cu(OAc)2 (362 mg, 2 mmol), 2,2'-bipyridine (156 mg, 1 mmol) and TEMPO (1.56
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g, 10 mmol). The mixture was stirred under N2 at 120 °C for 10 h. Afterwards, 1-cyclopentyl
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idene-2-phenylhydrazine (4a, 870 mg, 5 mmol) was added, and the resulting mixture was stirred
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under air at 120 C for 4 h. Upon completion, it was diluted with DCM (100 mL), and washed
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with water (40 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, and
evaporated under reduced pressure. The residue was purified by column chromatography on
silica gel with petroleum ether/ethyl acetate (10:1) as the eluent to give 5a (1.20 g, 55%).
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Acknowledgments. We are grateful to the National Natural Science Foundation of China (NSFC)
(Grant No. 21572047), Program for Innovative Research Team in Science and Technology in
Universities of Henan Province (15IRTSTHN003), and Program for Science and Technology
Innovation Talents in Universities of Henan Province (15HASTIT005) for financial support.
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Supporting Information. Copies of H and C NMR spectra of all products, the X-ray crystal
structure and data of 3g, and the H-H COSY 2D NMR spectrum of 5f. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Supporting Information section for the details).
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