Palladium-Catalyzed Chelation-Assisted Regioselective Oxidative Dehydrogenative Homocoupling/Ortho-Hydroxylation in N-Phenylpyrazoles

Article abstract of DOI:10.1021/acs.joc.5b00733

A palladium-catalyzed pyrazole-directed regioselective oxidative C(sp2)-H functionalization of the N-phenyl ring in N-phenylpyrazoles to afford either a biaryl bis-pyrazole (via dehydrogenative homocoupling) or N-(o-hydroxyphenyl)pyrazole (via C-H oxygena

Full text of DOI:10.1021/acs.joc.5b00733

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Article
Palladium-catalyzed chelation-assisted regioselective oxidative
dehydrogenative homocoupling/ortho-hydroxylation in N-phenylpyrazoles
Harikrishna Batchu, Soumya Bhattacharyya, Ruchir Kant, and Sanjay Batra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00733 • Publication Date (Web): 07 Jul 2015
Downloaded from http://pubs.acs.org on July 9, 2015
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The Journal of Organic Chemistry
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Palladium-catalyzed chelation-assisted regioselective
oxidative dehydrogenative homocoupling/ortho-
hydroxylation in N-phenylpyrazoles
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a,†
a,†
b
,a,c
Harikrishna Batchu, Soumya Bhattacharyya, Ruchir Kant, and Sanjay Batra*
a
b
Medicinal and Process Chemistry Division and Molecular and Structural Biology Division, CSIRꢀ
Central Drug Research Institute, BSꢀ10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow
26031, Uttar Pradesh, India
2
c
Academy of Scientific and Innovative Research, New Delhi 110025
batra_san@yahoo.co.uk, s_batra@cdri.res.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT.
A
Palladiumꢀcatalyzed pyrazoleꢀdirected regioselective oxidative C(sp2)ꢀHꢀ
functionalization of the Nꢀphenyl ring in Nꢀphenylpyrazoles to afford either a biaryl bisꢀpyrazole (via
dehydrogenative homocoupling) or Nꢀ(orthoꢀhydroxyphenyl)pyrazole (via CꢀH oxygenation) or their
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mixture is described. The substitutions on the Nꢀphenyl ring and the pyrazole ring and the dilution of the
reaction medium with respect to TFA:TFAA mixture (substrate concentration) have remarkable
influence on the outcome of the reaction. It was discovered that if the reactions were performed under
highly dilute conditions (ca 10 times), Nꢀ(orthoꢀhydroxyphenyl)pyrazoles were the major or the sole
products.
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KEYWORDS. Palladium, pyrazole, oxidative CꢀH functionalization, dehydrogenative homocoupling,
CꢀH oxygenation.
Introduction
The pyrazole nucleus, a privileged heteroarene, is encountered in several pharmaceutical agents
1
including Viagra, Crizotinib, Lexiscan, and Celebrex. In addition, many differently substituted pyrazole
2
derivatives are endowed with diverse pharmacological properties. Given such immense significance,
there is continuing interest in development of new or alternative synthetic approaches toward efficient
3
synthesis of substituted pyrazoles. We have an ongoing program for formulating general routes to
4
pyrazole derivatives of biological significance. During the course of this work we noticed that recently
several compounds bearing 1ꢀ(2ꢀhydroxyphenyl)ꢀpyrazole subunit were reported to be useful as
5
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antifungal agents I, antiꢀtrichophytic adhesive patch, treatment of dermatophytosis and Nꢀtype Caꢀ
7
8
9
channel blockers II, βꢀsecretase inhibitors III and Cu(II) complexing ligandoside in DNA IV (Fig. 1).
Established routes to their synthesis required starting reactants bearing the hydroxyl group which were
either used directly or in the protected form. In principle, the orthoꢀhydroxyl group in the phenyl ring of
1
ꢀphenylpyrazole could be readily installed via transition metalꢀcatalyzed ligand assisted orthoꢀdirected
oxidative C(sp2)ꢀH functionalization.
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Figure 1. A few recently reported 1ꢀ(2ꢀhydroxyphenyl)pyrazoleꢀbased bioactive compounds.
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During the last decade, transition metalꢀcatalyzed ligandꢀassisted orthoꢀdirected oxidative C–H bond
cleavage to accomplish regioselective functionalization of otherwise unreactive C–H bonds in aromatic
1
0ꢀ11
molecules has been of considerable interest to synthetic organic chemistry.
These transformations
are considered to be green, sustainable and efficient as they do not require preactivation of the substrate.
Often such transformations are catalyzed by rhodium, ruthenium, platinum, palladium, copper, nickel
and cobalt catalysts but palladiumꢀcatalysts are more widely investigated due to several advantages that
1
1
they offer. Among these reactions, metalꢀcatalyzed oxidative functionalization of C(sp2)ꢀH bond
proceed regioselectively with the assistance of many directing groups including pyridine, triazole and
several other azaꢀheterocycles, oxime, imine, amidine, ester, amide, ketone, phenol, and carboxylic acid.
The approach has been effectively exploited to install aryl, alkyl, alkenyl, benzyl, hydroxy, acetoxy,
alkoxy, amide, trifluoromethyl, azide, nitro, nitrile and halogen groups at proximal CꢀH bond to the
directing group. Amongst the azaꢀheterocycles, 1ꢀphenylpyrazole has been widely exemplified to
undergo ligandꢀassisted oxidative C(sp2)ꢀH functionalization for introducing some of the
1
2
aforementioned groups. Intriguingly, the transition metalꢀcatalyzed CꢀO bond formation in 1ꢀ
phenylpyrazoles is limited to acetoxy and alkoxy groups and the oxygenation reaction leading to 1ꢀ(2ꢀ
12a,c
hydroxyphenyl)pyrazole exclusively has yet not been demonstrated. Sanford et al.
in their
pioneering work on palladiumꢀcatalyzed ligand assisted acetoxylation disclosed orthoꢀacetoxylation of
the phenyl ring in 1ꢀphenylpyrazole. More recently, Kim et al. extended the palladiumꢀcatalyzed
12t
acetoxylation of the orthoꢀpositions of different phenyl rings present in the pyrazole derivative. They
summarized that the quantity of PhI(OAc) influenced the degree of acetoxylation in the products
2
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formed. During investigations of the scope of palladiumꢀcatalyzed orthoꢀalkoxylation of 2-arylꢀ1,2,3ꢀ
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triazoles, Shi and Kuang reported that 1ꢀphenylpyrazole resulted into the formation of 1ꢀ(2ꢀhydroxyꢀ6ꢀ
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methoxy)phenyl pyrazole in 42% yield. Hence we sought probing the palladiumꢀcatalyzed orthoꢀ
hydroxylation of the phenyl ring in substituted 1ꢀphenylpyrazoles and found that the success of reaction
in these substrates is remarkably influenced by the nature of substitutions present on the phenyl ring and
the pyrazole ring and the substrate concentration in TFA:TFAA (9:1) mixture under which the reaction
was performed. Herein we present the details of our study in this direction.
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Results and Discussion
The study commenced by probing a few reported methods for the palladiumꢀmediated hydroxylation
using 1ꢀphenylpyrazole 1a as the model substrate. Accordingly 1a (0.25 g, 1.74 mmol) was first treated
o
with Pd(OAc) (10 mol%), oxone (2.0 equiv), Cs CO (2.0 equiv), in DMF (5 mL) at 120 C for 24 h
2
2
3
14a
but the starting material was recovered unreacted (Scheme 1). Next, 1a was treated with Pd(OAc)2
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(
10 mol%), K S O (4.0 equiv), TFA (0.5 equiv) in dichloroethane but this reaction too failed.
2 2 8
However it was gratifying to note that when 1a was reacted with Pd(OAc) (5 mol%), K S O (2.0
2
2
2
8
o
equiv), TFA:TFAA (9:1, v/v) (2.5 mL) at 90 C for 12 h, a solid product in 68% yield was isolated after
1
5,14b
the work up.
Against our anticipation, the structure of the product was delineated as 2,2'ꢀdi(1Hꢀ
pyrazolꢀ1ꢀyl)biphenyl (3a) instead of 1ꢀ(2ꢀhydroxyphenyl)ꢀpyrazole 2a. The formation of 3a was
attributed to the oxidative dehydrogenative homocoupling by cleavage of the ortho CꢀH bond. Notably
such dehydrogenative homocoupling in 1ꢀphenylpyrazole was earlier reported in the presence of
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rhodium or ruthenium catalysts but was unprecedented for the palladium catalyst. Therefore we
considered optimizing the reaction with palladium catalyst and examine its scope. As a result several
combinations of Pd(OAc) and oxidants including Na S O , molecular oxygen, benzoylperoxide, and
2
2
2
8
TBHP were screened and the results are summarized in Table 1. It is evident from Table 1 that
Pd(OAc) in combination with K S O or oxone offer superior yields of 3a but the reaction in the
2
2
2
8
presence of K S O was relatively fast (entries 1ꢀ2). In contrast Na S O , benzoylperoxide, and TBHP
2
2
8
2
2
8
afforded 3a in low yield while reaction failed under molecular oxygen (entries 3ꢀ6). It is worth
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mentioning that during compilation of this work Sun et al. reported palladiumꢀcatalyzed aryl C(sp2)–H
bond hydroxylation of 2ꢀarylpyridine in dichloroethane using TBHP as the sole oxidant but this
condition did not work in our hand for transforming 1a to 2a or 3a (entry 10). Thus the condition that
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offered best yield of 3a was heating 1a (0.25 g at a concentration of 694 mmol/L), Pd(OAc) (5 mol%),
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K S O (2.0 equiv) in TFA:TFAA (9:1, v/v) at 90 C for 12 h.
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Scheme 1. Results of initial reactions explored for oxidative C(sp2)ꢀH hydroxylation in the phenyl ring
in 1ꢀphenylpyrazole (1a)
a
Table 1. Optimization of the palladiumꢀcatalyzed oxidative dehydrogenative homocoupling with 1ꢀ
phenylpyrazole 1a leading to biaryl bisꢀpyrazole 3a
entry catalyst
mol%)
oxidant
(equiv)
yield
3a (%)
solvent
time (h)
b
(
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Pd(OAc) (5) TFA:TFAA (9:1) oxone (2.0)
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68
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2
Pd(OAc) (5) TFA:TFAA (9:1) K S O (2.0)
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Pd(OAc) (5) TFA:TFAA (9:1) Na S O (2.0) 24
2
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Pd(OAc) (5) TFA:TFAA (9:1) O (balloon)
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2
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benzoyl
peroxide (2.0)
Pd(OAc) (5) TFA:TFAA (9:1)
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Pd(OAc) (5) TFA
K S O (2.0)
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Pd(OAc) (5) TFAA
K S O (2.0)
trace
trace
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Pd(OAc) (5) DCE
TBHP (6.0)
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a
All reactions were performed using 0.25 g of pyrazole 1a at a concentration of 694 mmol/L of
b
solvent, Yields of chromatographically pure product.
With optimized conditions in hand, we set out to test the scope of the methodology for a variety of 1ꢀ
(substitutedphenyl)pyrazoles (1b-1q) and the results are presented in Scheme 2. It was observed that in
all cases except for 1l and 1q, the corresponding biaryl bisꢀpyrazoles were isolated. Whereas the
substrates carrying orthoꢀ and paraꢀsubstitution on the phenyl ring (1b-e, 1h-k, 1m-n) produced the
corresponding products 3b-e, 3h-k, 3m-n in good yields, the ones with metaꢀsubstitutions (1f and 1g)
furnished the respective products 3f and 3g in moderate yields only. Further, pyrazoles 1o and 1p
bearing dimethylꢀsubstituted phenyl ring also furnished 3o and 3p, respectively in good yields. The
structure of the biaryl bisꢀpyrazole was unambiguously secured by the Xꢀray crystallographic analysis
of crystal of 3p obtained from hexanes: EtOAc (see Supporting Information). It is speculated that failure
of reaction in pyrazole 1l could be due to the electron donating character of the methoxy group whereas
failure of reaction in pyrazole 1q bearing Nꢀnaphthꢀ2ꢀyl group may be because of steric constraint
towards the formation of 3q. In order to ascertain the limitation of scope for substrates bearing electron
rich phenyl ring, we examined the reaction of 1ꢀ(3ꢀmethoxyphenyl)pyrazole (1r) and found that this
substrate too failed to react under the optimized conditions. The formation of 3 can be readily explained
on the basis of mechanism involving Pd (IV) species as proposed by Sanford et al. (vide infra). The
scope of the protocol was also tested with 1ꢀbenzylpyrazole (4) but this substrate failed to react under
the standardized conditions (Scheme 3).
Scheme 2. Scope of ligandꢀassisted palladiumꢀcatalyzed oxidative dehydrogenative homocoupling to
a,b
produce biaryl bisꢀpyrazoles in 1ꢀ(substituted phenyl)pyrazoles
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a
Reactions were performed with 0.5ꢀ0.77 g of pyrazoles (1a-r) at a substrate concentration of 694
b
mmol/L of solvent. Yields after column chromatography.
a
Scheme 3. Result of the reaction of 1ꢀbenzylpyrazole under the optimized condition
a
Reaction was performed with 0.55 g of pyrazole (4) at a substrate concentration of 694 mmol/L.
After studying the scope of the protocol with unsubstituted pyrazole derivatives, we turned our
attention to a variety of substituted 1ꢀphenylpyrazoles. Initially in a pilot experiment ethyl 1,5ꢀdiphenylꢀ
1
2
Hꢀpyrazoleꢀ3ꢀcarboxylate (5a) (0.25 g) was subjected to reaction with Pd(OAc) in TFA:TFAA (9:1,
2
.5 mL) under the optimized conditions which upon workup and purification resulted into isolation of
the major product in 76% and minor product in 3% yield only. We were pleased to discover that the
major product was spectroscopically characterized as ethyl 1ꢀ(2ꢀhydroxyphenyl)ꢀ5ꢀphenylꢀ1Hꢀpyrazoleꢀ
3
ꢀcarboxylate (6a) whereas the minor product was identified to be the biaryl bisꢀpyrazole 7a. However,
it was realized that in this pilot reaction, the substrate concentration of 5a was 342 mmol/L instead of
94 mmol/L optimized for the unsubstituted pyrazoles 1. As a consequence, the reaction was repeated
6
with 5a (0.5 g) at a substrate concentration of 685 mmol/L. Although presence of lower amount of
solvent made the reaction too cumbersome to perform, we could isolate the 6a in 44% and 7a in 10%
yields besides unreacted 5a and a mixture of unidentified products. Perhaps the presence of substitutions
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at 3ꢀ and 5ꢀpositions in pyrazole 5a may have induced certain steric constraint thereby favoring the
orthoꢀhydroxylation of phenyl ring rather than dehydrogenative homocoupling. In view of our interest
to synthesize substituted 1ꢀ(2ꢀhydroxyphenyl)pyrazoles exclusively coupled with ease of performing the
reaction with optimal solvent amount, we decided performing the reactions of substituted pyrazoles at a
substrate concentration of 342 mmol/L. In order to examine the possibility of improving the yields of
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a, we screened the reaction of 5a with respect to different palladium sources, oxidants and solvents and
the results are summarized in Table 2. Amongst several oxidants evaluated, K S O gave the best result
2
2
8
whereas oxone and PhI(OAc) gave 6a in slightly lower yields (compare entry 1 with entries 2, 3). In
2
contrast, the yield of 6a in the presence of all other oxidants screened for the reaction was found to be
inferior (entries 4ꢀ7). Reducing the amount of K S O from 2.0 equiv to 1.5 equiv reduced the yield of
2
2
8
6a appreciably (entry 8). Performing the reaction in the presence of TFA or TFAA individually or any
other organic solvent did not afford the required product 6a in better yields (entries 9ꢀ12). Altering the
palladium source revealed that Pd(TFA) was as effective as Pd(OAc) to afford 6a in 75% yield
2
2
whereas Pd(PPh ) Cl failed to yield any product (entries 13ꢀ14). However even in Pd(TFA) mediated
3
2
2
2
reaction, the presence of 7a was detected. Therefore it was concluded to continue to investigate the
scope further with the optimized conditions using substrate concentration of 342 mmol/L.
Table 2. Results of the study to examine the effect of different palladium source, oxidants and solvents
a
on the formation of 6a from 5a
CO Et
2
CO Et
2
CO Et
2
N
[
Pd] source, oxidant,
Ph
N
Ph
N
N
N
solvent, time
Ph
N
+
H
o
9
0 C
OH
N
Ph
N
5a
6a
7a EtO C
2
entry catalyst
(mol%)
oxidant
(equiv)
time
(h)
yield
6a (%)
solvent
c
d
1
2
Pd(OAc) (5) TFA:TFAA (9:1) K S O (2.0)
12
12
76
2
2
2
8
b
d
Pd(OAc) (5) TFA:TFAA (9:1) oxone (2.0)
72
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PhI(OAc)
2.0)
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Pd(OAc) (5) TFA:TFAA (9:1)
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24
24
70
10
ꢀ
(
4
Pd(OAc) (5) TFA:TFAA (9:1) TBHP (2.0)
2
5
benzoyl
peroxide (2.0)
Pd(OAc) (5) TFA:TFAA (9:1)
2
6
Pd(OAc) (5) TFA:TFAA (9:1) Na S O (2.0) 24
30
ꢀ
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
Pd(OAc) (5) TFA:TFAA (9:1) O (ballon)
24
24
24
24
24
72
2
2
d
d
8
Pd(OAc) (5) TFA:TFAA (9:1) K S O (1.5)
40
42
ꢀ
2
2
2
8
9
Pd(OAc) (5) TFA
K S O (2.0)
2 2 8
2
10
11
12
Pd(OAc) (5) TFAA
K S O (2.0)
2 2 8
2
Pd(OAc) (5) IPA
K S O (2.0)
ꢀ
2
2
2
8
Pd(OAc) (5) DCE
K S O (2.0)
20
2
2
2
8
1
3
Pd(PPh
5)
) Cl
3 2 2
TFA:TFAA (9:1) K S O (2.0)
12
ꢀ
2
2
8
(
d
1
4
Pd(TFA) (5) TFA:TFAA (9:1) K S O (2.0)
12 h
75
2
2
2
8
a
Except for entry 2, all reactions were performed using 0.1 g of pyrazole (5a) at a concentration of 342
mmol/L of solvent, Reaction in entry 2 was performed with 0.25 g of 5a at identical substrate
concentration; Yields of chromatographically pure products. 2ꢀ3% of 7a was isolated
b
c
d
In next stage of the study, we examined the scope of the reaction with several differently substituted
pyrazoles. In the first set, reactions of various ethyl 1,5ꢀdiphenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates (5b-g)
carrying differently substituted 5ꢀphenyl ring were probed as outlined in Scheme 4. It was observed that
in each case substituted 1ꢀ(2ꢀhydroxyphenyl)pyrazole 6b-d,f-g and biaryl bisꢀpyrazole 7b-d,f-g were
isolated in variable ratio but for the compound 5e bearing 4ꢀmethyl substituent, 1ꢀ(2ꢀ
hydroxyphenyl)pyrazole derivative 6e was isolated as the major product. Further substrate 5h bearing
3,4ꢀdimethyl group too furnished the product as isolable mixture of 6h and 7h, but the 3,4,5ꢀtrimethoxy
phenyl ring bearing substrate 5i afforded 6i exclusively. In the next stage we focused on substrateꢀset
bearing different substitutions in the Nꢀphenyl ring and unsubstituted 5ꢀphenyl ring as presented in
Scheme 5. Accordingly pyrazoles 5j-p were subjected to the palladiumꢀcatalyzed reaction and it was
found that all substrates (5k-n,p), except for 5j, 5o with orthoꢀsubstituted Nꢀphenyl ring, furnished a
mixture of substituted 1ꢀ(2ꢀhydroxyphenyl)pyrazoles 6k-n,p and biaryl bisꢀpyrazoles 7k-n,p. It seems
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that the presence of orthoꢀsubstituent in 5j and 5o offered resistance to chelation leading to the failure of
reaction. The structures for 1ꢀ(2ꢀhydroxyphenyl)pyrazoles 6 and biaryl bisꢀpyrazoles 7 were secured by
performing the Xꢀray crystallographic analysis of representative compounds 6l (hexanes: EtOAc) and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
b (CHCl : MeOH) (See Supporting Information).
3
Scheme 4. Results of the study of scope of the protocol for Cꢀhydroxylation with substituted 5ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a,b
substitutedphenylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates (5a-5i)
a
Reactions were performed with 0.5ꢀ0.65 g of pyrazoles (5a-i) at a substrate concentration of 342
b
mmol/L of solvent. Yields after column chromatography.
Scheme 5. Results of the study of scope of the protocol for Cꢀhydroxylation with substituted 5ꢀphenylꢀ
a,b
1ꢀsubstituted phenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates (5j-5p)
CO Et
2
CO2Et
Pd(OAc)2 (5 mol%),
CO Et
2
N
N
Ph
Ph
N
N
N
K2S2O8 (2.0 equiv),
Ph
R
N
+
H
OH
TFA/TFAA: (9:1,
R
R
N
R
Ph
o
5
mL), 90 C, 12 h
N
EtO C
2
5j R = 2-Cl
6j R = 2-Cl (0%)
7
j
R = 2-Cl (0%)
7k R = 3-Cl (10%)
5
5
5
5
5
5
k
l
R = 3-Cl
R = 4-F
6k R = 3-Cl (78%)
6l R = 4-F (41%)
6m R = 4-Cl (48%)
6n R = 4-Br (40%)
6o R = 2,5-Me2 (0%)
6p R = 3,4-Me2 (38%)
7l
R = 4-F (24%)
m R = 4-Cl
7
m R = 4-Cl (22%)
n
o
p
R = 4-Br
R = 2,5-Me2
R = 3,4-Me2
7n R = 4-Br (22%)
7o R = 2,5-Me2 (0%)
7p
R = 3,4-Me2 (20%)
a
Reactions were performed with 0.53ꢀ0.63 g of pyrazoles (5j-p) at a substrate concentration of 342
b
mmol/L. Yields after column chromatography.
Following these results, we considered investigating the protocol using ethyl 1ꢀsubstituted phenylꢀ5ꢀ
alkylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates 8a-g as the starting substrates (Scheme 6). In the first set the reactions
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The Journal of Organic Chemistry
of 1ꢀsubstituted phenylꢀ5ꢀmethylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates 8a-e were examined which under the
standardized conditions produced the corresponding 1ꢀ(2ꢀhydroxyphenyl)pyrazoles 9a-e only with no
trace of biaryl bisꢀpyrazoles 10a-e. Replacing the methyl group with propyl or isopropyl groups (8f-g),
however resulted in the formation of a mixture of 1ꢀ(2ꢀhydroxyphenyl)pyrazoles 9f-g and biaryl bisꢀ
pyrazoles 10f-g in approximately 2:1 ratio. Further, we discovered that if the 5ꢀposition in pyrazole ring
was left unsubstituted as in 8h then only the biaryl product 10h was isolated with no trace of 9h.
Scheme 6. Results of the study of scope of the protocol for Cꢀhydroxylation with ethyl 1ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a,b
substitutedphenylꢀ5ꢀalkylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates (8a-g)
a
Reactions were performed with 0.37ꢀ0.53 g of pyrazoles (8a-h) at a substrate concentration of 342
b
mmol/L. Yields after column chromatography.
Subsequently, we examined the scope of the methodology with substituted pyrazoles (11a-c and 14a-
d) bearing carboxylate group at Cꢀ5 and Cꢀ4 position, respectively. It was observed in the first subset
1
1a-c, whereas 11a-b afforded the biaryl bisꢀpyrazoles 13a-b exclusively in 70ꢀ72% yields, 11c was
recovered unreacted under the optimized conditions (Scheme 7). In lieu of these results, it was
speculated that the presence of phenyl ring at 3ꢀposition as in 11c interfered with the stabilization of the
palladium complex. Likewise for ethyl 5ꢀmethylꢀ1ꢀsubstituted phenylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylates 14a-
d, it was found that whereas 14a and 14b furnished 16a and 16b, respectively, 14c-d failed to react due
to the presence of orthoꢀsubstituted Nꢀphenyl ring (Scheme 8).
Scheme 7. Results of the study of scope of the protocol for Cꢀhydroxylation with ethyl 1ꢀ
a,b
(substituted)phenylꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate (11a-c)
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reactions were performed with 0.37ꢀ0.5 g of pyrazoles (11a-c) at a substrate concentration of 342
b
mmol/L. Yields after column chromatography.
Scheme 8. Results of the study of scope of the protocol for Cꢀhydroxylation with ethyl 5ꢀmethylꢀ1ꢀ
a,b
(substituted)phenylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylate (14a-d)
a
Reactions were performed with 0.39ꢀ0.52 g of pyrazoles (14a-d) at a substrate concentration of 342
b
mmol/L. Yields after column chromatography.
Finally we investigated the protocol with 3ꢀmethylꢀ1,5ꢀdiphenylꢀ1Hꢀpyrazole 17 and found that this
substrate resulted in a complex mixture of products from which we could isolate the 1ꢀ(2ꢀ
hydroxyphenyl)pyrazole (18) product in 7% yield only (Scheme 9). In addition 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ
pyrazolꢀ5(4H)ꢀone (20) was also investigated but this substrate failed to react under the optimized
conditions (Scheme 10).
a,b
Scheme 9. Reaction of 3ꢀmethylꢀ1,5ꢀdiphenylꢀ1Hꢀpyrazole
a
b
Reaction was performed with 0.4 g of pyrazole (17). Yield after column chromatography.
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The Journal of Organic Chemistry
Scheme 10. Reaction of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5(4H)ꢀone
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Reaction was performed with 0.3 g of pyrazole 20 at a substrate concentration of 342 mmol/L.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The plausible mechanism for the reaction with 5a as the model substrate is delineated in Scheme 11.
As proposed by Sanford et al. the first CꢀH activation event in 5a takes place at the Pd (II) stage leading
to the formation of a five membered cycloꢀpalladium (II) dimeric intermediate I which under the
reaction conditions, gets oxidized to Pd(IV) intermediate II. A second CꢀH activation event at the Pd
(IV) stage would result into the formation of intermediate III which on reductive elimination, gives
biaryl bisꢀpyrazole 7a. In contrast, if the second molecule of the 5a is not activated to attack the
intermediate II, then there is a likelihood that reductive elimination may occur to afford the intermediate
IV that during aqueous workup furnish the substituted orthoꢀhydroxyphenyl pyrazole 6a.
Scheme 11. Plausible mechanism
Based on the proposed mechanism and our initial optimization study with pyrazole 5a, we were
prompted to map product formation at different substrate concentration in TFA:TFAA mixture. It was
presumed that under dilute conditions the transformation of II to III may get suppressed driving the
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reaction to IV thereby producing orthoꢀhydroxylphenyl pyrazole exclusively. In this context, pyrazole
b which was known to afford both the products (6b and 7b) in 5:3 ratio was selected as representative
compound for the study. Accordingly, 5b (0.11 g) was treated with Pd(OAc) and K S O under the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
2
2
2
8
optimized conditions at varying substrate to solvent (TFA:TFAA) concentration of 685 mmol/L to 34.2
mmol/L and the product distribution of the resulting crude mixture of products was monitored via
HPLC (see Supporting Information). We were delighted to discover that when the reaction was
performed with 5b at a substrate concentration of 34.2 mmol/L then 6b was isolated in 68% yield while
7b was limited to 3% yield (Table 3, entry 1). Encouraged with the success, we tested 5d and 5m too
under the identical reaction conditions (ca 10ꢀfolds dilution) and found that these substrates afforded
respective 6d and 6m as the major products (entries 2, 3). Inspired by this success, we were prompted to
examine the substrates from all other series including 8, 11, 14, 17 and 1. Therefore, first 8h was
subjected to the reaction under dilute conditions and we were pleased to discover that the ethyl 1ꢀ(2,6ꢀ
dihydroxyphenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 21 was isolated in 55% yield beside the biaryl bisꢀ
pyrazole 10h in 20% yield (entry 4). However, when the carboxylate group was present at 5ꢀposition in
pyrazole as represented by series 11 we found that whereas 11a-b afforded the biaryl bisꢀpyrazole
exclusively, compound 11c gave the hydroxy derivative 12c in trace which could not be isolated but
was evident upon detailed LCꢀMS investigations (entries 5ꢀ7). Likewise, for the set of pyrazole bearing
carboxylate group at 4ꢀposition as represented by 14 we could not detect the presence of corresponding
hydroxyphenyl pyrazole product irrespective of dilution (entries 8ꢀ11). In contrast for substituted
pyrazole 17 we observed that under dilute reaction condition the yield of 1ꢀ(2ꢀhydroxyphenyl)pyrazole
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(18) improved to 60% (entry 12). Finally 1a-b, 1e, 1j as representatives from series 1 which furnished
the biaryl bisꢀpyrazoles (3) exclusively were investigated under the altered conditions and it was
gratifying to discover that all substrates gave 1ꢀ(2ꢀhydroxyphenyl) pyrazoles at a substrate concentration
of 69.4 mmol/L. Whereas compound 1b and 1e afforded 2b and 2e, pyrazoles 1a and 1j furnished 2ꢀ
(1Hꢀpyrazolꢀ1ꢀyl)benzeneꢀ1,3ꢀdiol 22a and 22j as the major products in good yields, respectively
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The Journal of Organic Chemistry
(
entries 13ꢀ16). These results clearly surmised that orthoꢀhydroxylation in the phenyl ring in Nꢀphenyl
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pyrazoles is favoured when the reaction is performed under excess of TFA:TFA (9:1) mixture.
Table 3. Results of the study towards scope of the protocol for C(sp2)ꢀhydroxylation under dilute
conditions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
reactant
major product minor product (yield
b
b
(
yield %)
%)
a
1
5
b
6b (71)
7b (3)
a
2
6d (66)
5d
7d (2)
a
3
5m
6m (70)
7m (2)
a
4
8h
21 (55)
10h (20)
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a
5
6
N
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EtO2C
N
N
CO2Et
N
1
1
1a
1b
12a (0)
13a (70)
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12b (0)
13b (65)
a
7
8
11c
12c (trace)
1
1
1
1
3c (0)
a
14a
15a (0)
6a (75)
6b (76)
6c (0)
a
EtO C
2
9
N
Me
N
Br
14b
15b (0)
15c (0)
a
10
14c
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The Journal of Organic Chemistry
a
1
1
2
1
2
3
4
5
6
7
8
9
1
1
4d
15d (0)
1
6d (0)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
1
7
18 (60)
19 (0)
3a (3)
3b (3)
3e (2)
b
b
b
b
1
1
1
1
3
4
5
6
1
a
22a (60)
1b
2b
(67)
1e
2e(64)
1j
22b (62)
3
j (3)
a
Reactions were performed with 0.079ꢀ0.112 g of pyrazoles 5, 8, 14, 11 or 17 at a substrate
concentration of 34.3 mmol/L. Reactions were performed with 0.1ꢀ0.15 g of pyrazoles 1 at a substrate
concentration of 69.4 mmol/L. Yields after column chromatography.
b
c
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Conclusions
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, we have demonstrated the ligand assisted palladiumꢀcatalyzed regioselective oxidative
C(sp2)ꢀH activation for dehydrogenative homocoupling and CꢀH oxygenation reactions in the phenyl
ring of substituted 1ꢀphenylpyrazoles. The scope has been explicitly investigated to demonstrate the
effect of different substitutions on the outcome of the reaction. It was shown that the set of compounds
wherein the pyrazole ring does not bear any substitution under low quantity of TFA:TFAA (9:1, v/v)
mixture (higher substrate concentration), afforded the biaryl bisꢀpyrazoles via dehydrogenative
homocoupling exclusively. But the same substrates resulted into the orthoꢀhydroxyphenyl pyrazoles as
the major products when the identical reaction was performed in the presence of increased quantity of
TFA:TFAA (9:1, v/v) mixture (low substrate concentration). Further in this set of pyrazoles if the
phenyl ring carried an orthoꢀsubstituent then monoꢀhydroxylation took place but if both the orthoꢀ
positions were free then bisꢀhydroxylation prevailed under the conditions. Unlike, in the set of
compounds where the pyrazole ring carried carboxylate group at the 3ꢀposition in most of the cases a
mixture of biaryl bisꢀpyrazoles and orthoꢀhydroxyphenyl pyrazoles were formed under higher substrate
concentration but orthoꢀhydroxyphenyl pyrazoles were isolated in superior yields when the
concentration of the starting material was low. In addition for these starting substrates, the protocol
worked only when both orthoꢀpositions of the phenyl ring were free since all compounds bearing orthoꢀ
substituted phenyl ring failed to yield any product. Unlike for the pyrazole substrates bearing
carboxylate group at the Cꢀ5 or Cꢀ4 position, mostly biaryl bisꢀpyrazoles were isolated. Interestingly,
for the pyrazoles bearing phenyl group at Cꢀ3 position in the place of carboxylate group at lower
substrate concentration we could isolate only the orthoꢀhydroxyphenyl pyrazole with no trace of biaryl
bisꢀpyrazoles. Further work to investigate the ligandꢀassisted Cꢀoxygenation in the phenyl ring in other
heterocyclic substrates is underway and would be reported in due course.
0
1
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0
Experimental Section
General. All experiments were monitored by analytical thin layer chromatography (TLC) performed
on preꢀcoated silica gel plates. After elution, plate was visualized under UV illumination at 254 nm for
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UV active materials. Further visualization was achieved by staining with KMnO and charring on a hot
4
1
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8
9
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
2
2
2
2
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5
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5
5
5
5
5
6
plate. Column chromatography was performed on silica gel (230ꢀ400 mesh) by standard techniques
1
eluting with solvents as indicated. IR spectra were recorded using a FTIR spectrophotometer. H NMR
13
and C NMR spectra were recorded on 400 MHz spectrometer using TMS as an internal standard
0
1
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(chemical shifts in δ). Peak multiplicities of NMR signals were designated as s (singlet), bs (broad
singlet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet) etc. The ESIꢀMS were recorded on
Ion Trap Mass spectrometer and the HRMS spectra were recorded as ESIꢀHRMS on a QꢀTOF LCꢀ
MS/MS mass spectrometer. Commercial grade reagents and solvents were used without further
purification. As 12c was formed in traces and mapped by LCꢀMS there is no physical or spectroscopic data
(except ESMS) is provided.
The syntheses of different 1ꢀ(substitutedphenyl)pyrazoles were carried out according to the literature
procedures.
18
1
-Phenyl-1H-pyrazole (1a).
19
1
-(2-Chlorophenyl)-1H-pyrazole (1b).
19
1
-(2-Methylphenyl)-1H-pyrazole (1c).
20
1
-(2-(Trifluoromethyl)phenyl)-1H-pyrazole (1d).
2
1
Ethyl 2-(1H-pyrazol-1-yl)benzoate (1e).
22
1-(3-Fluorophenyl)-1H-pyrazole (1f).
2
3
1
1
1
-(3-Chlorophenyl)-1H-pyrazole (1g).
23
-(4-Fluorophenyl)-1H-pyrazole (1h).
2
3
3
2
-(4-Chlorophenyl)-1H-pyrazole (1i).
2
1-(4-Bromophenyl)-1H-pyrazole (1j).
4
1
-(4-Methylphenyl)-1H-pyrazole (1k).
24
1
-(4-Methoxyphenyl)-1H-pyrazole (1l).
-(4-(Trifluoromethyl)phenyl)-1H-pyrazole (1m).
24
1
25
Ethyl 4-(1H-pyrazol-1-yl)benzoate (1n).
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Page 20 of 48
2
5
1
1
-(2,4-Dimethylphenyl)-1H-pyrazole (1o).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-(3,4-Dimethylphenyl)-1H-pyrazole (1p). Yield: 85 % (1.0 g from 1.5 g); a brown oil; R = 0.68
f
1
(hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ = 2.28 (s, 3H), 2.32 (s, 3H), 6.43 (t, J = 2.2
3
Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.37 (dd, J = 8.1 Hz, J = 2.3 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.69 (d,
1
2
13
J = 1.4 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H). C NMR (100 MHz, CDCl ): 19.4, 20.0, 107.3, 116.7, 120.8,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
26.8, 130.5, 135.1, 138.4, 140.8. Mass (ESI+) m/z = 173.2. ESIꢀHRMS calcd. for C H N (M +H):
1
1
13
2
173.1079, found: 173.1074.
2
6
1
1
1
-(Naphthalen-2-yl)-1H-pyrazole (1q).
27
-(3-Methoxyphenyl)-1H-pyrazole (1r).
2
8
-Benzyl-1H-pyrazole (4).
General procedure for oxidative dehydrogenative homocoupling of N-aryl pyrazoles (1a-r) as
exemplified for 3a.
A 50 mL sealedꢀtube charged with 1a (0.5 g, 3.47 mmol), K S O (1.87 g, 6.94 mmol), Pd(OAc)
2
2
2
8
o
(
0.04 g, 0.017 mmol), TFA (4.5 mL) and TFAA (0.5 mL) was heated at 90 C for 12 h. After
completion as monitored by the TLC, the reaction mixture was evaporated to obtain a residue which
was dissolved in EtOAc (25 mL) and washed with saturated aqueous NaHCO solution (50 mL). The
3
mixture was partitioned in a separating funnel, the organic layer separated and the aqueous layer was
further extracted with EtOAc (2 x 25 mL). The organic extracts were pooled, dried over anhyd. Na SO
2
4
and evaporated in vacuum to afford the crude product which was purified by column chromatography
(
silica gel, 20% EtOAc in hexanes) to afford the pure 3a (0.34 g, 68%) as a white solid.
o
1
2
,2'-Di(1H-pyrazol-1-yl)biphenyl (3a). Mp 107ꢀ109 C; R = 0.26 (hexanes: EtOAc, 80:20, v/v). H
f
NMR (400 MHz, CDCl ): δ = 6.17 (s, 2H), 7.19ꢀ7.26 (m, 4H), 7.32 (t, J = 6.9 Hz, 2H), 7.40ꢀ7.44 (m,
3
13
2
1
2
H), 7.48ꢀ7.52 (m, 4H). C NMR (100 MHz, CDCl ):106.6, 125.7, 127.9, 128.9, 130.4, 131.2, 133.5,
3
+
39.0, 140.5. Mass (ESI+) m/z = 287.0. ESIꢀHRMS calcd. for C H N (M +H): 287.1297, found:
18 15
4
87.1293.
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1
,1'-(3,3'-Dichlorobiphenyl-2,2'-diyl)bis(1H-pyrazole) (3b). Yield: 83 % (0.51 g from 0.62 g); a
1
2
o
1
white solid; mp 112ꢀ114 C; R = 0.30 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ =
f
3
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6.26 (s, 2H), 6.92 (d, J = 7.1 Hz, 2H), 7.12 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 7.7 Hz, 2H), 7.55 (brs, 2H),
13
7
.71 (brs, 2H). C NMR (100 MHz, CDCl ): 106.5, 128.4, 129.3, 130.0, 132.7, 137.1, 138.2, 140.6.
3
+
Mass (ESI+) m/z = 354.8. ESIꢀHRMS calcd. for C H Cl N (M +H): 355.0517, found: 355.0522.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
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4
5
6
7
8
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4
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6
7
8
9
0
18 13
2
4
1
,1'-(3,3'-Dimethylbiphenyl-2,2'-diyl)bis(1H-pyrazole) (3c). Yield: 80 % (0.44 g from 0.55 g); a
o
1
white solid; mp 144ꢀ146 C; R = 0.38 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ =
f
3
2.07 (s, 6H), 6.20 (t, J = 2.0 Hz, 2H), 6.84 (d, J = 7.6 Hz, 2H), 7.08 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 7.5
1
3
Hz, 2H), 7.53ꢀ7.59 (m, 4H). C NMR (100 MHz, CDCl ): 17.8, 105.8, 127.7, 128.0, 130.1, 136.2,
3
+
1
36.8, 138.5, 139.8. Mass (ESI+) m/z = 315.0. ESIꢀHRMS calcd. for C H N (M +H): 315.1610,
20
19
4
found: 315.1612.
1
,1'-(3,3'-Bis(trifluoromethyl)biphenyl-2,2'-diyl)bis(1H-pyrazole) (3d). Yield: 74 % (0.54 g from
o
1
0
.74 g); a white solid; mp 147ꢀ149 C; R = 0.20 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz,
f
CDCl ): δ = 6.14 (s, 2H), 7.15ꢀ7.19 (m, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.42 (s, 2H), 7.62ꢀ7.63 (m, 4H).
3
13
C NMR (100 MHz, CDCl ): 106.6, 121.6, 124.3, 127.0, 128.6, 133.4, 137.2, 138.1, 140.5. Mass
3
+
(
ESI+) m/z = 423.0. ESIꢀHRMS calcd. for C H F N (M +H): 423.1044, found: 423.1040.
20 13
6
4
Diethyl 2,2'-di(1H-pyrazol-1-yl)biphenyl-3,3'-dicarboxylate (3e) Yield: 60 % (0.45 g from 0.75 g);
ꢀ1
1
a brown oil; R = 0.30 (hexanes: EtOAc, 80:20, v/v). IR (Neat) ν : 1717 (CO Et) cm . H NMR (400
f
max
2
MHz, CDCl ): δ = 1.03 (t, J = 7.1 Hz, 6H), 4.01ꢀ4.06 (m, 4H), 6.14 (t, J = 2.1 Hz, 2H), 7.08 (dd, J =
3
1
7
7
.7 Hz, J = 1.2 Hz, 2H), 7.22 (t, J = 7.7 Hz, 2H), 7.44 (d, J = 1.1 Hz, 2H), 7.51 (d, J = 2.0 Hz, 2H),
2
1
3
.74 (dd, J = 7.7 Hz, J = 1.2 Hz, 2H). C NMR (100 MHz, CDCl ): 14.1, 61.7, 106.5, 128.2, 130.5,
1
2
3
130.6, 132.5, 133.4, 136.3, 138.2, 140.3, 166.1. Mass (ESI+) m/z = 431.1. ESIꢀHRMS calcd. for
+
C H N O (M +H): 431.1719, found: 431.1716.
24
23
4
4
1
,1'-(4,4'-Difluorobiphenyl-2,2'-diyl)bis(1H-pyrazole) (3f). Yield: 45 % (0.25 g from 0.56 g); a
o
1
yellow solid; mp 120ꢀ122 C; R = 0.32 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ =
f
3
6
.14 (t, J = 2.1 Hz, 2H), 6.97 (td, J = 8.4 Hz, J = 2.6 Hz, 2H), 7.06ꢀ7.09 (m, 2H), 7.15 (d, J = 2.3 Hz,
1
2
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The Journal of Organic Chemistry
Page 22 of 48
1
3
2
2
H), 7.18ꢀ7.21 (m, 2H), 7.42 (d, J = 1.3 Hz, 2H). C NMR (100 MHz, CDCl ): 107.2, 113.1 (d, J =
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.2 Hz), 115.1 (d, J = 21.1 Hz), 128.5, 130.2, 132.6 (d, J = 8.6 Hz), 140.2 (d, J = 10.0 Hz), 141.0,
+
162.5 (d, J = 247.8 Hz,). Mass (ESI+) m/z = 323.0. ESIꢀHRMS calcd. for C H F N (M +H):
1
8
13
2
4
3
23.1108, found: 323.1105.
1
,1'-(4,4'-Dichlorobiphenyl-2,2'-diyl)bis(1H-pyrazole) (3g). Yield: 48 % (0.30 g from 0.62 g); a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yellow oil; R = 0.31 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ = 6.16 (t, J = 2.1
f
3
Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 7.18ꢀ7.19 (m, 2H), 7.23 (dd, J = 8.3 Hz, J = 2.1 Hz, 2H), 7.44 (d, J
1
2
1
3
= 2.1 Hz, 4H). C NMR (100 MHz, CDCl ): 107.3, 125.9, 130.3, 131.0, 132.1, 134.9, 139.6, 141.0.
3
+
Mass (ESI+) m/z = 354.9. ESIꢀHRMS calcd. for C H Cl N (M +H): 355.0517, found: 355.0513.
1
8
13
2
4
1
,1'-(5,5'-Difluorobiphenyl-2,2'-diyl)bis(1H-pyrazole) (3h). Yield: 78 % (0.44 g from 0.56 g); an
o
1
off white solid; mp 144ꢀ146 C; R = 0.22 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ
f
3
=
6.16 (t, J = 2.2 Hz, 2H), 6.79 (dd, J = 8.7 Hz, J = 2.8 Hz, 2H), 7.02ꢀ7.07 (m, 2H), 7.23 (d, J = 2.4
1 2
1
3
Hz, 2H), 7.38 (dd, J = 8.8 Hz, J = 5.2 Hz, 2H), 7.42 (d, J = 1.6 Hz, 2H). C NMR (100 MHz,
1
2
CDCl ): 106.9, 116.2 (d, J = 22.3 Hz), 117.4 (d, J = 23.4 Hz), 127.7 (d, J = 8.8 Hz), 130.6, 134.8 (d, J
3
=
5.7 Hz), 135.3, 140.8, 161.6 (d, J = 247.7 Hz). Mass (ESI+) m/z = 323.0. ESIꢀHRMS calcd. for
+
C H F N (M +H): 323.1108, found: 323.1104.
18 13
2
4
1
,1'-(5,5'-Dichlorobiphenyl-2,2'-diyl)bis(1H-pyrazole) (3i). Yield: 75 % (0.46 g from 0.62 g); a
o
1
white solid; mp 160ꢀ162 C; R = 0.22 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ =
f
3
13
6.21 (brs, 2H), 7.23ꢀ7.26 (m, 4H), 7.41 (brs, 4H), 7.48 (brs, 2H). C NMR (100 MHz, CDCl ): 107.3,
3
1
27.0, 129.6, 130.2, 130.9, 133.7, 133.9, 137.6, 141.1. Mass (ESI+) m/z = 354.9. ESIꢀHRMS calcd. for
+
C H Cl N (M +H): 355.0517, found: 355.0520.
18
13
2
4
1,1'-(5,5'-Dibromobiphenyl-2,2'-diyl)bis(1H-pyrazole) (3j). Yield: 70 % (0.54 g from 0.77 g); a
o
1
white solid; mp 112ꢀ114 C; R = 0.30 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ =
f
3
1
3
6
.21 (s, 2H), 7.18ꢀ7.26 (m, 3H), 7.34ꢀ7.40 (m, 3H), 7.48 (s, 2H), 7.56 (d, J = 7.9 Hz, 2H). C NMR
(
100 MHz, CDCl ): 107.3, 121.4, 127.1, 130.1, 132.5, 133.8, 133.9, 138.0, 141.0. Mass (ESI+) m/z =
3
+
4
42.9. ESIꢀHRMS calcd. for C H Br N (M +H): 442.9507, found: 442.9510.
1
8
13
2
4
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Page 23 of 48
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1
,1'-(5,5'-Dimethylbiphenyl-2,2'-diyl)bis(1H-pyrazole) (3k). Yield: 72 % (0.39 g from 0.55 g); an
1
2
o
1
off white solid; mp 94ꢀ96 C; R = 0.28 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ): δ =
f
3
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2.27 (s, 6H), 6.08 (t, J = 2.1 Hz, 2H), 6.98 (d, J = 1.2 Hz, 2H), 7.06 (d, J = 2.3 Hz, 2H), 7.13 (dd, J =
1
13
8
.0 Hz, J = 1.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 1.4 Hz, 2H). C NMR (100 MHz,
2
CDCl ): 21.1, 106.3, 125.5, 129.5, 130.3, 131.6, 133.2, 136.7, 137.8, 140.1. Mass (ESI+) m/z = 315.0.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
+
ESIꢀHRMS calcd. for C H N (M +H): 315.1610, found: 315.1610.
2
0
19
4
1
,1'-(5,5'-Bis(trifluoromethyl)biphenyl-2,2'-diyl)bis(1H-pyrazole) (3m). Yield: 74 % (0.55 g from
o
1
0.74 g); an off white solid; mp 83ꢀ85 C; R = 0.40 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz,
f
CDCl ): δ = 6.17ꢀ6.18 (m, 2H), 7.20 (d, J = 2.16 Hz, 2H), 7.38 (d, J = 0.8 Hz, 2H), 7.43 (d, J = 1.3 Hz,
3
1
3
2
H), 7.58 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 8.4 Hz, J = 1.4 Hz, 2H). C NMR (100 MHz, CDCl ):
1 2 3
107.7, 123.6 (q, J = 272.6 Hz), 126.1, 126.5 (q, J = 3.6 Hz), 128.3 (q, J = 3.7 Hz), 130.1, 130.2 (q, J =
+
3
3.2 Hz), 132.9, 141.5, 141.6. Mass (ESI+) m/z = 423.0. ESIꢀHRMS calcd. for C H F N (M +H):
2
0
13
6
4
4
23.1044, found: 423.1044.
Diethyl 6,6'-di(1H-pyrazol-1-yl)biphenyl-3,3'-dicarboxylate (3n) Yield: 72 % (0.54 g from 0.75 g);
o
an off white solid; mp 99ꢀ101 C; R = 0.16 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν : 1716 (CO Et)
f
max
2
ꢀ1 1
cm . H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 6H), 4.33 (q, J = 7.1 Hz, 4H), 6.10 (t, J = 1.9
3
Hz, 2H), 7.02 (d, J = 2.4 Hz, 2H), 7.39 (d, J = 1.2 Hz, 2H), 7.50 (d, J = 1.7 Hz, 2H), 8.00 (d, J = 1.9 Hz,
13
2
H), 8.07 (dd, J = 8.5 Hz, J = 1.9 Hz, 2H). C NMR (100 MHz, CDCl ): 14.5, 61.6, 107.5, 125.2,
1
2
3
129.9, 130.0, 130.7, 132.2, 133.0, 141.2, 142.1, 165.6. Mass (ESI+) m/z = 431.1. ESIꢀHRMS calcd. for
+
C H N O (M +H): 431.1719, found: 431.1724.
24
23
4
4
1
,1'-(3,3',5,5'-Tetramethylbiphenyl-2,2'-diyl)bis(1H-pyrazole) (3o). Yield: 74 % (0.44 g from 0.6
o
1
g); a white solid; mp 127ꢀ128 C; R = 0.55 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ):
f
3
13
δ = 1.95 (s, 6H), 2.09 (s, 6H), 6.12 (t, J = 2.1 Hz, 2H), 6.57 (s, 2H), 6.88 (s, 2H), 7.44ꢀ7.46 (m, 4H). C
NMR (100 MHz, CDCl ): 17.7, 21.0, 105.6, 128.3, 130.7, 132.2, 135.7, 135.9, 136.5, 137.8, 139.6.
3
+
Mass (ESI+) m/z = 343.1. ESIꢀHRMS calcd. for C H N (M +H): 343.1923, found: 343.1925.
2
2
23
4
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1
,1'-(4,4',5,5'-Tetramethylbiphenyl-2,2'-diyl)bis(1H-pyrazole) (3p). Yield: 70 % (0.42 g from 0.6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
g); a white solid; mp 132ꢀ134 C; R = 0.25 (hexanes: EtOAc, 80:20, v/v). H NMR (400 MHz, CDCl ):
f
3
δ = 2.17 (s, 6H), 2.21 (s, 6H), 6.06 (t, J = 2.2 Hz, 2H), 6.93 (s, 2H), 7.09 (d, J = 6.6 Hz, 2H), 7.18ꢀ7.20
13
(
m, 2H), 7.38 (d, J = 1.3 Hz, 2H). C NMR (100 MHz, CDCl ): 19.6, 19.7, 106.4, 126.7, 130.3, 132.4,
3
+
1
36.5, 136.8, 137.6, 140.1. Mass (ESI+) m/z = 343.1. ESIꢀHRMS calcd. for C H N (M +H):
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22 23
4
3
43.1923, found: 343.1928.
General procedure for oxidative ortho-hydroxylation in N-aryl pyrazoles 1a, 1b, 1e and 1j for
the synthesis of 2b, 2e and 22a-b as exemplified for the synthesis of 2b.
A 50 mL sealedꢀtube charged with 1b (0.12 g, 0.69 mmol), K S O (0.375 g, 1.38 mmol), Pd(OAc)
2
2
2
8
o
(
0.008 g, 0.034 mmol), TFA (9.0 mL) and TFAA (1.0 mL) was heated at 90 C for 12 h. Following
similar experimental procedure as reported for 3a, a crude product was obtained which was purified by
column chromatography (silica gel, 20% EtOAc in hexanes) to afford the pure 2b (0.087 g, 67 %) as a
brown oil and 3b (0.003 g, 3%) as a white solid.
3-Chloro-2-(1H-pyrazol-1-yl)phenol (2b). R = 0.22 (hexanes: EtOAc, 80:20, v/v). IR (Neat) ν
f
max
ꢀ1
1
3
368 (OH) cm . H NMR (400 MHz, CDCl ): δ = 6.54 (s, 1H), 7.03 (t, J = 7.6 Hz, 2H), 7.17 (t, J = 6.9
3
1
3
Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 9.42 (s, 1H). C NMR (100 MHz, CDCl ):
3
1
06.9, 117.1, 122.1, 124.8, 126.5, 129.1, 133.2, 141.1, 152.5. Mass (ESI+) m/z = 194.8. ESIꢀHRMS
+
calcd. for C H ClN O (M +H): 195.0325, found: 195.0330.
9
8
2
Ethyl 3-hydroxy-2-(1H-pyrazol-1-yl)benzoate (2e) Yield: 64 % (0.103 g from 0.15 g); a pale yellow
o
solid; mp 125ꢀ127 C; R = 0.18 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν : 1718 (CO Et), 3390 (OH)
f
max
2
ꢀ
1 1
cm . H NMR (400 MHz, CDCl ): δ = 1.11 (t, J = 7.1 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 6.42 (m, 1H),
3
1
3
7.15ꢀ7.18 (m, 1H), 7.21ꢀ7.29 (m, 2H), 7.50 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H). C NMR (100
MHz, CDCl ): 14.1, 61.7, 107.1, 121.4, 122.0, 125.1, 126.8, 132.6, 141.2, 151.6, 166.8. Mass (ESI+)
3
+
m/z = 232.9. ESIꢀHRMS calcd. for C H N O (M +H): 233.0926, found: 233.0925.2-(1H-Pyrazol-1-
12 13
2
3
yl)benzene-1,3-diol (22a). Yield: 60 % (0.073 g from 0.1 g); a brown oil; R = 0.22 (hexanes: EtOAc,
f
ꢀ1
1
8
0:20, v/v). IR (Neat) νmax 3399 (OH) cm . H NMR (400 MHz, CDCl ): δ = 6.49 (t, J = 2.2 Hz, 1H),
3
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6
.57 (d, J = 8.2 Hz, 2H), 7.01 (t, J = 8.2 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 8.19 (brs, 2H), 8.36 (d, J =
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
2
.4 Hz, 1H). C NMR (100 MHz, CDCl ): 106.1, 109.4, 127.7, 132.8, 138.6, 149.6. Mass (ESI+) m/z =
3
+
176.8. ESIꢀHRMS calcd. for C H N O (M +H): 177.0664, found: 177.0665.
9
9
2
2
5
-Bromo-2-(1H-pyrazol-1-yl)benzene-1,3-diol (22b). Yield: 62 % (0.109 g from 0.154 g); a brown
ꢀ1
1
oil; R = 0.22 (hexanes: EtOAc, 80:20, v/v). IR (Neat) ν 3399 (OH) cm . H NMR (400 MHz,
max
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
1
3
CDCl ): δ = 6.50 (s, 1H), 6.77 (s, 2H), 7.75 (s, 1H), 8.38 (s, 1H), 8.97 (brs, 2H). C NMR (100 MHz,
3
CDCl ): 106.3, 112.7, 114.5, 119.8, 132.8, 138.6, 150.2. Mass (ESI+) m/z = 254.8. ESIꢀHRMS calcd.
3
+
for C H BrN O (M +H): 254.9769, found: 254.9765.
9
8
2
2
The syntheses of starting 5ꢀsubstitutedphenylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates or 5ꢀphenylꢀ1ꢀ
substitutedphenylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates were carried out via the reported methods.
2
9
Ethyl 1,5-diphenyl-1H-pyrazole-3-carboxylate (5a).
Ethyl 5-(2-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (5b). Yield: 85 % (1.1 g from 1.0
o
ꢀ
g); a white solid; mp 65ꢀ67 C; R = 0.47 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν 1722 (CO Et) cm
f
max
2
1
1
. H NMR (400 MHz, CDCl ): δ = 1.43 (t, J = 7.1 Hz, 3H), 4.46 (q, J = 7.1 Hz, 2H), 7.05 (s, 1H),
3
13
7
.23ꢀ7.24 (m, 2H), 7.28 (brs, 4H), 7.30ꢀ7.34 (m, 2H), 7.38ꢀ7.40 (m, 1H). C NMR (100 MHz, CDCl ):
3
1
4.6, 61.3, 111.9, 124.8, 127.0, 128.3, 129.0, 129.4, 130.2, 130.8, 132.2, 139.6, 142.5, 144.3, 162.5.
+
Mass (ESI+) m/z = 327.1. ESIꢀHRMS calcd. for C H ClN O (M +H): 327.0900, found: 327.0897.
1
8
16
2
2
Ethyl 5-(4-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (5c). Yield: 90 % (1.2 g from 1.0
o
g); a white solid; mp 113ꢀ115 C; R = 0.46 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν 1721 (CO Et)
f
max
2
ꢀ1 1
cm . H NMR (400 MHz, CDCl ): δ = 1.42 (t, J = 7.1 Hz, 3H), 4.46 (q, J = 7.1 Hz, 2H), 6.98ꢀ7.03 (m,
3
1
3
3
H), 7.17ꢀ7.21 (m, 2H), 7.29ꢀ7.33 (m, 2H), 7.35ꢀ7.37 (m, 3H). C NMR (100 MHz, CDCl ): 14.6, 61.3,
3
110.0, 115.9 (d, J = 21.7 Hz), 125.9, 128.6, 129.2, 130.8 (d, J = 8.2 Hz), 139.5, 143.8, 144.5, 162.5,
+
1
3
62.9 (d, J = 248.1 Hz). Mass (ESI+) m/z = 311.2. ESIꢀHRMS calcd. for C H FN O (M +H):
1
8
16
2
2
11.1196, found: 311.1191.
3
0
Ethyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (5d).
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Ethyl 1-phenyl-5-p-tolyl-1H-pyrazole-3-carboxylate (5e). Yield: 88 % (1.1 g from 1.0 g); a white
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
ꢀ1 1
solid; mp 84ꢀ86 C; R = 0.5 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν 1721 (CO Et) cm . H NMR
f
max
2
(400 MHz, CDCl ): δ = 1.43 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 4.45 (q, J = 7.0 Hz, 2H), 7.01 (s, 1H),
3
13
7
1
3
.34 (m, 5H) . C NMR (100 MHz, CDCl ): 14.6, 21.4, 61.2, 109.8, 125.9, 126.8, 138.9, 139.8, 144.4,
3
+
44.9, 162.7. Mass (ESI+) m/z = 307.2. ESIꢀHRMS calcd. for C H N O (M +H): 307.1447, found:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19 19
2
2
07.1449.
Ethyl 5-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-carboxylate (5f).
31
Ethyl 5-(4-nitrophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (5g). Yield: 80 % (1.0 g from 1.0 g);
o
ꢀ1
a white solid; mp 128ꢀ130 C; R = 0.2 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν 1721 (CO Et) cm .
f
max
2
1
H NMR (400 MHz, CDCl ): δ = 1.36 (t, J = 7.1 Hz, 3H), 4.39 (q, J = 7.1 Hz, 2H), 7.10 (s, 1H), 7.23ꢀ
3
1
3
7.26 (m, 2H), 7.30ꢀ7.35 (m, 5H), 8.09 (d, J = 8.8 Hz, 2H). C NMR (100 MHz, CDCl ): 14.5, 61.5,
3
1
11.1, 124.0, 126.0, 129.2, 129.6, 135.8, 139.1, 142.4, 144.9, 147.8, 162.1. Mass (ESI+) m/z = 338.2.
+
ESIꢀHRMS calcd. for C H N O (M +H): 338.1141, found: 338.1145.
18 16
3
4
Ethyl 5-(2,4-dimethylphenyl)-1-phenyl-1H-pyrazole-3-carboxylate (5h). Yield: 72 % (0.375 g
ꢀ1
1
from 0.5 g); a brown oil; R = 0.56 (hexanes: EtOAc, 80:20, v/v). IR (Neat) ν 1721 (CO Et) cm . H
f
max
2
NMR (400 MHz, CDCl ): δ = 1.43 (t, J = 7.1 Hz, 3H), 1.96 (s, 3H), 2.32 (s, 3H), 4.46 (q, J = 7.1 Hz,
3
1
3
2
H), 6.91 (s, 1H), 697ꢀ6.99 (m, 2H), 7.05ꢀ7.07 (m, 1H), 7.24ꢀ7.28 (m, 5H) . C NMR (100 MHz,
CDCl ): 14.6, 19.9, 21.3, 61.2, 111.1, 124.5, 126.8, 127.9, 128.9, 130.6, 131.3, 137.0, 139.4, 139.8,
3
+
144.1, 144.2, 162.7. Mass (ESI+) m/z = 321.2. ESIꢀHRMS calcd. for C H N O (M +H): 321.1603,
2
0
21
2
2
found: 321.1601.
Ethyl 1-phenyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole-3-carboxylate (5i). Yield: 88 % (1.1 g
o
from 1.0 g); a white solid; mp 147ꢀ149 C; R = 0.28 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν 1717
f
max
ꢀ1
1
(
CO Et) cm . H NMR (400 MHz, CDCl ): δ = 1.43 (t, J = 7.1 Hz, 3H), 3.64 (s, 6H), 3.85 (s, 3H), 4.46
2 3
1
3
(
q, J = 7.1 Hz, 2H), 6.39 (s, 2H), 7.35ꢀ7.38 (m, 5H). C NMR (100 MHz, CDCl ): 14.5, 56.1, 61.0,
3
6
1.3, 106.2, 109.4, 124.7, 126.1, 128.6, 129.1, 138.5, 139.8, 144.4, 144.7, 153.3, 162.5. Mass (ESI+)
+
m/z = 383.2. ESIꢀHRMS calcd. for C H N O (M +H): 383.1607, found: 383.1602.
2
1
23
2
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3
2
Ethyl 1-(2-chlorophenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5j).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
3
Ethyl 1-(3-chlorophenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5k).
3
4
Ethyl 1-(4-fluorophenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5l).
34
Ethyl 1-(4-chlorophenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5m).
Ethyl 1-(4-bromophenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5n).
3
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl 1-(2,5-dimethylphenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5o). Yield: 88 % (1.3 g from
o
1
.0 g); an off white solid; mp 98ꢀ100 C; R = 0.53 (hexanes: EtOAc, 80:20, v/v). IR (KBr) ν 1721
f
max
ꢀ1 1
(CO Et) cm . H NMR (400 MHz, CDCl ): δ = 1.42 (t, J = 7.1 Hz, 3H), 1.82 (s, 3H), 2.32 (s, 3H), 4.45
2
3
1
3
(
q, J = 7.1 Hz, 2H), 7.05ꢀ7.12 (m, 3H), 7.17ꢀ7.20 (m, 3H), 7.23ꢀ7.26 (m, 3H). C NMR (100 MHz,
CDCl ): 14.6, 17.1, 20.9, 61.2, 108.4, 127.9, 128.6, 128.7, 129.5, 130.4, 130.8, 132.1, 136.7, 138.9,
3
+
144.3, 145.7, 162.7. Mass (ESI+) m/z = 321.2. ESIꢀHRMS calcd. for C H N O (M +H): 321.1603,
2
0
21
2
2
found: 321.1607.
Ethyl 1-(3,4-dimethylphenyl)-5-phenyl-1H-pyrazole-3-carboxylate (5p).
3
5
The ethyl 5ꢀ(alkyl)ꢀ1ꢀ(substitutedphenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylates were prepared according to the
35
literature procedure.
3
6
Ethyl 5-methyl-1-phenyl-1H-pyrazole-3-carboxylate (8a).
Ethyl 1-(3-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxylate (8b).
3
7
38
Ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-3-carboxylate (8c).
3
6
Ethyl 1-(4-bromophenyl)-5-methyl-1H-pyrazole-3-carboxylate (8d).
3
6
Ethyl 5-methyl-1-p-tolyl-1H-pyrazole-3-carboxylate (8e).
3
9
Ethyl 1-phenyl-5-propyl-1H-pyrazole-3-carboxylate (8f).
Ethyl 5-isopropyl-1-phenyl-1H-pyrazole-3-carboxylate (8g). Yield: 85 % (1.2 g from 1.5 g); a
ꢀ1
1
brown oil; R = 0.56 (hexanes: EtOAc, 80:20, v/v). IR (Neat) ν
1721 (CO Et) cm . H NMR (400
2
f
max
MHz, CDCl ): δ = 1.11 (d, J = 6.9 Hz, 6H), 1.32 (t, J = 7.1 Hz, 3H), 2.88ꢀ2.97 (m, 1H), 4.34 (q, J = 7.1
3
1
3
Hz, 6H), 6.69 (d, J = 0.4 Hz, 1H), 7.34ꢀ7.47 (m, 5H). C NMR (100 MHz, CDCl ): 14.6, 22.9, 25.7,
3
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6
1.1, 105.7, 126.5, 129.1, 129.3, 139.5, 144.0, 152.3, 162.9. Mass (ESI+) m/z = 259.2. ESIꢀHRMS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
calcd. for C H N O (M +H): 259.1447, found: 259.1450.
1
5
19
2
2
4
0
Ethyl 1-phenyl-1H-pyrazole-3-carboxylate (8h).
41
Ethyl 1-phenyl-1H-pyrazole-5-carboxylate (11a).
Ethyl 1-(4-bromophenyl)-1H-pyrazole-5-carboxylate (11b).
4
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
9
Ethyl 1,3-diphenyl-1H-pyrazole-5-carboxylate (11c).
The ethyl 5ꢀmethylꢀ1ꢀ(substitutedphenyl)ꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylates were prepared according to the
3
6
literature procedure.
Ethyl 5-methyl-1ꢀphenylꢀ1H-pyrazole-4-carboxylate (14a).
Ethyl 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylate (14b).
Ethyl 5-methyl-1-o-tolyl-1H-pyrazole-4-carboxylate (14c). Yield: 86 % (1.3 g from 1.0 g); a brown
4
3
3
6
ꢀ1
1
oil; R = 0.5 (hexanes: EtOAc, 80:20, v/v). IR (Neat) ν
1721 (CO Et) cm . H NMR (400 MHz,
2
f
max
CDCl ): δ = 1.31 (t, J = 7.2 Hz, 3H), 1.96 (s, 3H), 2.27 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 7.13 (dd, J =
3
1
13
6.9 Hz, J = 0.7 Hz, 1H), 7.22ꢀ7.28 (m, 2H), 7.32 (td, J = 7.5 Hz, J = 1.2 Hz, 1H), 7.97 (s, 1H) . C
2
1
2
NMR (100 MHz, CDCl ): 11.3, 14.6, 17.3, 60.1, 112.1, 126.9, 127.7, 129.9, 131.3, 136.1, 137.8, 141.8,
3
+
1
44.5, 164.0. Mass (ESI+) m/z = 245.3. ESIꢀHRMS calcd. for C H N O (M +H): 245.1290, found:
14 17
2
2
2
45.1295.
Ethyl 1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (14d).
36
4
4
3-Methyl-1,5-diphenyl-1H-pyrazole (17).
-Methyl-1-phenyl-1H-pyrazol-5(4H)-one (21).
General procedure for oxidative C(sp2)-H functionalization in substituted N-aryl pyrazoles 5a-
4
5
3
p, 8a-h, 11a-c, 14a-d, 17 esters as exemplified for 5a.
To a 50 mL sealedꢀtube were added 5a (0.5 g, 1.7 mmol), K S O (0.925 g, 3.42 mmol), Pd(OAc)
2
2
2
8
o
(0.019 g, 0.08 mmol), TFA (4.5 mL) and TFAA (0.5 mL) and the mixture was heated at 90 C for 12 h.
Similar expertimental procedure as described for 3a afforded the crude product which was purified by
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The Journal of Organic Chemistry
column chromatography (silica gel, 20% EtOAc in hexanes) to obtain pure 6a (0.4 g, 76%) as a white
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solid and 7a (0.015 g, 3%) also as a white solid.
o
Ethyl 1-(2-hydroxyphenyl)-5-phenyl-1H-pyrazole-3-carboxylate (6a). Mp 145ꢀ147 C; R = 0.41
f
ꢀ1
1
(
hexanes: EtOAc, 80:20, v/v). IR (KBr) νmax 1721 (CO Et), 3423 (OH) cm . H NMR (400 MHz,
2
DMSOꢀd ): δ = 1.32 (t, J = 7.0 Hz, 3H), 4.32 (q, J = 7.0 Hz, 2H), 6.89ꢀ6.95 (m, 2H), 7.10 (s, 1H), 7.30ꢀ
0
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0
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0
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0
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0
1
2
3
4
5
6
7
8
9
0
6
1
3
7
1
.35 (m, 7H), 9.99 (s, 1H). C NMR (100 MHz, CDCl ): 14.2, 60.3, 107.8, 116.6, 119.1, 127.1, 127.4,
3
28.3, 128.4, 128.8, 129.3, 130.8, 143.1, 145.6, 152.7, 161.7. Mass (ESI+) m/z = 309.0. ESIꢀHRMS
+
calcd. for C H N O (M +H): 309.1239, found: 309.1242.
1
8
17
2
3
o
Diethyl 1,1'-(biphenyl-2,2'-diyl)bis(5-phenyl-1H-pyrazole-3-carboxylate) (7a). Mp 137ꢀ139 C; R
f
ꢀ1 1
=
0.27 (hexanes: EtOAc, 80:20, v/v). IR (KBr) νmax 1728 (CO Et) cm . H NMR (400 MHz, CDCl ): δ
2 3
= 1.39 (t, J = 7.1 Hz, 6H), 4.38ꢀ4.39 (m, 4H), 6.09ꢀ6.10 (m, 2H), 6.55 (d, J = 7.4 Hz, 4H), 6.74 (s, 2H),
6
.89 (s, 2H), 7.00 (t, J = 7.4 Hz, 4H), 7.14 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 6.4 Hz, 2H), 7.43ꢀ7.45 (m,
1
3
2
H). C NMR (100 MHz, CDCl ): 14.5, 60.7, 109.8, 127.7, 127.8, 128.0, 128.3, 128.5, 128.8, 130.0,
3
131.8, 134.1, 137.0, 144.4, 144.8, 162.1. Mass (ESI+) m/z = 583.2. ESIꢀHRMS calcd. for C H N O
4
3
6
31
4
+
(
M +H): 583.2345, found: 583.2340.
Ethyl 5-(2-chlorophenyl)-1-(2-hydroxyphenyl)-1H-pyrazole-3-carboxylate (6b). Yield: 45 %
o
(
0.25 g from 0.55 g); a white solid; mp 112ꢀ114 C; R = 0.62 (hexanes: EtOAc, 80:20, v/v). IR (KBr)
f
ꢀ1
1
νmax 1719 (CO Et), 3428 (OH) cm . H NMR (400 MHz, CDCl ): δ = 1.43 (t, J = 6.7 Hz, 3H), 4.44ꢀ
2
3
4.58 (m, 2H), 6.59ꢀ6.62 (m, 2H), 7.08ꢀ7.16 (m, 3H), 7.26ꢀ7.30 (m, 2H), 7.38ꢀ7.43 (m, 2H), 8.83 (s, 1H).
1
3
C NMR (100 MHz, CDCl ): 14.5, 61.6, 112.0, 118.8, 119.6, 123.7, 125.6, 127.2, 129.0, 129.6, 130.4,
3
1
31.1, 132.0, 134.2, 142.4, 144.0, 150.5, 161.7. Mass (ESI+) m/z = 342.9. ESIꢀHRMS calcd. for
+
C H ClN O (M +H): 343.0849, found: 343.0854.
18
16
2
3
Diethyl 1,1'-(biphenyl-2,2'-diyl)bis(5-(2-chlorophenyl)-1H-pyrazole-3-carboxylate) (7b). Yield:
o
2
9 % (0.16 g from 0.55 g); a white solid; mp 210ꢀ212 C; R = 0.37 (hexanes: EtOAc, 80:20, v/v). IR
f
ꢀ
1 1
(
KBr) νmax 1724 (CO Et) cm . H NMR (400 MHz, CDCl ): δ = 1.39 (t, J = 6.3 Hz, 6H), 4.37ꢀ4.39 (m,
2
3
4
H), 6.24 (brs, 2H), 6.41 (d, J = 6.8 Hz, 2H), 6.83ꢀ6.85 (m, 4H), 7.00 (s, 2H), 7.09ꢀ7.10 (m, 4H), 7.31ꢀ
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