Transition-Metal-Free Selective Iodoarylation of Pyrazoles via Heterocyclic Aryliodonium Ylides

Article abstract of DOI:10.1002/ejoc.201800416

A one-pot transition-metal-free selective iodoarylation of pyrazoles with aryliodine diacetates has been developed. The reaction proceeds via the generation of NH-pyrazole-iodonium salts in situ, followed by sequential phen/K₂CO₃-mediated intermolecular arylation. When the iodonium ylide was directly used as substrate, the difunctionalization products could be prepared in high yield under base- and metal-free conditions. This transformation provides an efficient route to high-value multisubstituted pyrazole derivatives from simple and readily available substrates.

Full text of DOI:10.1002/ejoc.201800416

A Journal of
Accepted Article
Title: Transition-metal Free Selective Iodoarylation of Pyrazoles via the
Heterocyclic Aryliodonium Ylides
Authors: Nannan Lu, Liangsen Huang, Lili Xie, and Jiajia Cheng
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10.1002/ejoc.201800416
European Journal of Organic Chemistry
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Transition-metal Free Selective Iodoarylation of Pyrazoles via the
Heterocyclic Aryliodonium Ylides
Nannan Lu,†[a] Liangsen Huang,†[a] Lili Xie,*[a] and Jiajia Cheng*[a,b]
Dedication ((optional))
Abstract: A one-pot transition-metal free selective iodoarylation of
pyrazoles with aryliodine diacetates is developed. The reaction
proceeds via the in-situ generation of NH-pyrazole-iodonium salts
followed by sequential phen/K2CO3-mediated intermolecular
arylation. When iodonium ylide was directly used as substrate, the
difunctionalization products could be prepared in high yield under
base- and metal-free conditions. The transformation provides an
efficient route to high-value multi-substituted pyrazole derivatives
from simple and readily available substrates.
Introduction
Pyrazoles are important structural motifs of numerous
biologically relevant molecules that found extensive applications
in pharmaceutical, agrochemistry and biological science. For
example, Celecoxib, the widely prescribed cyclooxygenase-2
inhibitor, is a non-steroidal drug containing a pyrazole core for
the treatment of rheumatoid arthritis and osteoarthritis (Scheme
1a, compound A).[1a] Similar structure also forms the key scaffold
of the anti-inflammatory and anti-hyperglycemic drug, Lonazolac
(Scheme 1a, compound B).[1b] The multi-substituted pyrazole,
halosulfuron methyl also exhibited high herbicidal activity and
excellent crop safety (Scheme 1a, compound C).[1c] Traditionally,
the pyrazole derivatives could be synthesized through the
cyclocondensation of 1,3-diketones with hydrazines. However,
the limited number and explosive nature of hydrazines have
restricted its development so far. For this reason, the synthesis
of pyrazole derivatives through the selective functionalization of
pyrazole is still in high demand.[2] To date, there have been
substantial efforts on the N1-functionalization of pyrazoles, but
the construction of the 1,4-disubstituted pyrazoles through the
selective difunctionalization of the heterocyclic core in a single
step was still a challenge. Especially, serious side reactions
would take place with transition-metal catalysis if one iodide
group was attached to the pyrazole ring.[3] Hypervalent iodonium
species have found wide synthetic applications as versatile and
sustainable reagents.[4] In this context, heterocyclic 3-iodanes,
Scheme 1. Transition-metal free selective iodoarylation of pyrazoles.
especially NH-heterocyclic 3-iodanes[5] are receiving increasing
attention due to their promise in heterocycle functionalizations.[6]
In 1973, Neiland et al. first reported the preparation of
phenyliodonium derivatives of pyrazoles through the reaction of
pyrazole with phenyliodine diacetate (PIDA).[7] In 2013, Suna et
al. reported a method for intermolecular C-H amination of
pyrazoles through the in situ formation of pyrazole-3-iodanes,
while NH-pyrazoles was not applicable and Cu salt was
needed.[8] Later, Novák et al. developed one transition-metal
free synthetic method for the N-arylation of pyrazoles with
diaryliodonium salts.[9] Despite these undisputed advances,
selective difunctionalization via NH-pyrazoles in a single step
continue to face challenges. Since the pioneering work of
Neiland et al. in the 1960s,[10] aryliodonium ylides have been
known for their ability of concurrent difunctionalization of inert
arenes through intramolecular rearrangement.[11] Recently,
Shafir et al. reported a family of imidazolyl aryliodonium ylide,
which could be converted to N1-aryl-5-iodoimidazoles by a
copper-catalyzed aryl migration.[12] Nonetheless, pyrazole-
derived iodonium ylide exhibited poor performance in their report.
In continuation of our research on the use of iodonium ylide in
heterocycle synthesis,[13] we herein present a novel method for
the production of 1,4-disubstituted pyrazoles under transition-
metal-free conditions (Scheme 1b).[14] The one-pot, two-step
approach starts first by the oxidation of NH-pyrazoles 1 with
PIDA 2 to give pyrazole-4-phenyliodonium tosylates 4 in the
presence of TsOH•H2O. Due to the increased acidity of pyrazole
[a]
N, Lu; L, Huang; L, Xie; J. Cheng
State Key Laboratory of Photocatalysis on Energy and Environment,
College of Chemistry, Fuzhou University, Fuzhou 350116, P. R.
China.
E-mail: jjcheng@fzu.edu.cn, E-mail: xielili@fzu.edu.cn
http://chem.fzu.edu.cn
[b]
J. Cheng
State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, Fujian 350002, P. R. China.
†Authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800416
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moiety of 4, facile deprotonation took place to afford the
zwitterionic
iodonium
ylide
5.
Phen/K2CO3-mediated
Table 1. Screening of the optimal reaction conditions.[a]
intermolecular N-arylation and selective C-I cleavge finally
afforded the desired 1,4-disubstituted pyrazoles 3 with good
yield and excellent regioselectivity. Control reactions showed
that phen may directly worked as a base or coordinate with the
counterions of the added bases to increase their alkalinity.
Furthermore, starting with isolated iodonium ylide 5, the target
compound could be efficiently afforded under base- and metal-
free conditions.
Entry
Catalyst
Ligand
Base
Solvent
Yield
(%)[b]
1[c]
2
CuBr
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
CH2Cl2
MeOH
toluene
THF
18
45
40
50
61
73
55
51
42
57
64
62
73
35
ND
69
37
47
55
52
Results and Discussion
CuBr
-
3
CuBr
-
To begin our study, the commercially available 3,5-diethyl-
1H-pyrazole 1a and phenyliodine diacetate 2a were chosen
as the model substrates. TsOH•H2O (1 equiv.) was added to
improve the reactivity of 3 iodanes.[15] The reaction mixture
was stirred in CH2Cl2 at rt untill the full conversion of 1a was
achieved. Inspired by the development on transition-metal-
catalyzed C-N coupling reactions, we first decided to test the
reaction under the Cu-catalysis. Without isolation, the solvent
was removed and CuBr (10 mol-%), K2CO3 (4 equiv.) were
added to the remaining mixture, which was stirred in CH2Cl2
at rt under N2 atmosphere for 24 h. Gratifyingly, the expected
4
CuBr
-
5
CuBr
-
CH3CN
CH3CN
CH3CN
CH3CN
HFIP
6
CuBr
1,10-phen
2,2’-bpy
IMes•HCl
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
-
7
CuBr
8
CuBr
9
CuBr
10
11
12
13
14
15
16[d]
17
18
19
20
Cu(OTf)2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CuI
1-phenyl-4-iodo-pyrazole 3a was formed in
a low but
encouraging 18% yield (Table 1, entry 1). In this process, 4
equiv. of base was added due to the fact that 1 equiv. of
TsOH•H2O and 2 equiv. of AcOH need to be neutralized.
Switch to other solvent with a higher boiling point, the
reaction yield could be significantly improved (entries 2-4).
The best result was obtained by using CH3CN as the solvent,
which afforded the desired product in 61% yield (entry 5).
Adding 1,10-phenanthroline (1,10-phen) as ligand to the
reaction was benifical for the reaction (entry 6). However, the
similar effect was not observed when utilize 2,2’-bpy or IMes
as the ligand (entries 7 and 8). Reaction conducted in HFIP
gave lower yield (entry 9).[12] A variety of Cu catalysts were
then tested and we were quite surprised that the reaction
worked well with all the copper salts (entries 10-12). Several
control experiments were then conducted. The results
showed that although K2CO3 and phen were indispensable
for the reaction, the reaction efficiently proceeded to afford
the target compound in the absence of transition-metal
catalysts (entries 13-15). To exclude the possibility of trace
amount of Cu salt presented in the reagent, extra pure phen
and K2CO3 was used to afford the target compound in 69%
yield (entry 16). K2CO3 was the most suitable base, other
bases such as Cs2CO3, Na2CO3 or tBuOK led to diminished
yield (entries 17-19). Novák’s conditions was also not
appropriate for this one-pot reaction (entry 20).[9a] Finally, we
could reduce the amount of phen to only 5 mol-%, and the
1,4-disubstituted pyrazole 3a was obtained in the best 74%
yield (entries 21-22).
Cu
-
-
-
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
-
-
K2CO3
Cs2CO3
Na2CO3
tBuOK
-
-
-
NH3 (aq.)/Toluene 1:1
-
21[e]
-
-
1,10-phen
1,10-phen
K2CO3
K2CO3
CH3CN
CH3CN
74
54
22[e,f]
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), TsOH•H2O (0.5 mmol),
CH2Cl2 (3 mL) at r.t. for 8 h, after removing CH2Cl2, 1,10-phen (5 mol-%), K2CO3
(4 equiv.), CH3CN (5 mL) was added and the reaction mixture was stirred at 70
oC for 24 h. [b] Isolated yield. [c] The reaction was stirred at room temperature.
[d] Extra pure phen (>99% purity) and K2CO3 (99.997% purity) was used. [e] 5
mol-% of ligand was added. [f] 3 equiv. of K2CO3 was used.
With the optimal reaction conditions (Table 1, entry 21) in
hand, we proceeded to explore the generality of the one-pot
methodology (Table 2). The reaction protocol was first
applied for the 1,4-difunctionalization of 3,5-diethyl-1H-
pyrazole 1a with a wide range of substituted phenyliodine
diacetate derivatives
2. It was observed that the reaction
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10.1002/ejoc.201800416
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1,4-difunctionalization smoothly (3b and 3c). Electron-
withdrawing group, such as fluorine, was well tolerated under
the reaction conditions (3d). Notably, 1-bromophenyl-4-iodo-
pyrazole was efficiently constructed, which could be derived
sequentially with transition-metal catalyzed cross-coupling
reaction to afford polyarene compounds (3e). We then found
that substrate attached a steric-demanding 2-Br group also
serve as suitable substrate and gave the expected product
efficiently (3f).
was not sensitive to the electronic or steric effect of the
substitute of PIDA. All of the substrates tested here afforded
the target compounds in high yield and excellent selectivity
(
3a-3f). PIDA containing an electron-donating group on the
para position of the phenyl moiety, which was not prone to
transfer the aryl group,[16] could undergo the
Table 2. Scope of the one-pot iodoarylation of pyrazole.[a,b]
We also investigated the difunctionalization of various
substituted
pyrazoles
with
phenyliodine
diacetate
derivatives to further expand the substrate scope (Table 2).
For example, with 3,5-dimethyl-1H-pyrazole as substrate,
PIDA that contain a range of functional groups on the
aromatic ring, such as CH3-, CH3O-, halogen, and
C2H5OCO-, underwent the intended transformation cleanly
to give the corresponding products (3g-3n). In particular,
the steric-encumbered 3,5-di-i-Pr substituted pyrazole did
not interfere with the reaction effciency, providing 3o in
good yield. Moreover, unsubstituted simple NH-pyrazole
could be readily converted into N-Ph-4-I-pyrazole 3p under
the reaction conditions. Finally, while utilizing the
unsymmetrical 3-methyl pyrazole 1q as the substrate, the
1,4-and 2,4-substituted regio-isomers 3q and 3q’ could be
isolated in approximately equal amounts separately.
To expand the substrate scope, with [PhI(pyrazole)][OTs]
salt 4r as substrate,[7] the desired 1,4-difunctionalization
product 3r could be afforded in 71% yield (Scheme 2a).
This result indicates that our method can be further applied
to
a big set of substrates. In addition, gram-scale
preparation of 3a in high yield further demonstrate the
synthetic value of the method (Scheme 2b).
Scheme 2. Reaction with 3,5-diphenyl pyrazole and scale-up experiment.
To shed some light on the mechanistic details of the one-
pot reaction, several control experiments were conducted
[a] Similar conditions as in Table 1, entry 19. [b] Isolated yield. [c] 1.2 equiv. of
2
trimethoxybenzene as an internal standard. [e] 5.0 equiv. of base was used.
was used. [d] Purity was determined by 1H NMR with 1,3,5-
(Scheme
3).
4.0
equiv
of
TEMPO
(2,2,6,6-
tetramethylpiperidinyloxy, radical scavenger) included with
the standard conditions had little impact on the reaction
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10.1002/ejoc.201800416
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Table 3. Study on the effect of 1,10-phen.[a]
outcome (Scheme 3a). Moreover, when the reaction was
conducted in the presence of air, the efficiency of the
transformation was preserved, implying that a radical
intermediate was not likely to be involved in the reaction
pathway (Scheme 3b). Thus, a mixture of iodonium salts 4b
and 4g were subjected to the standard conditions (Scheme
3c). The observation of the cross-over products 3a and 3h
by GC-MS and electrospray ionization mass spectrometry
(ESI-MS) indicated that the reaction involves an
intermolecular N-arylation process.[17]
Entry
Additive
Yield (%)[b]
1
2
3
4
5
6
7
Phen (5 mol-%)
Phen (10 mol-%)
Phen (20 mol-%)
Phen (50 mol-%)
Phen (100 mol-%)
Py (5 mol-%)
74
74
72
67
75
65
58
18-crown-6 (2 equiv.)
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), TsOH•H2O (0.5 mmol),
CH2Cl2 (3 mL) at rt for 8 h, after removing CH2Cl2, K2CO3 (4 equiv.), additive
and CH3CN (5 mL) was added and the reaction mixture was stirred at 70 oC for
24 h. [b] Isolated yield.
To study the property of iodonium ylide and the details of
the reaction process, iodonium ylide 5a was prepared by
base treatment of [PhI(pyrazole)][OTs] salt 4a and
subjected to the reaction conditions.[7] We are delighted to
find that the reaction proceeded smoothly under base- and
metal-free conditions to afford the iodoarylation product 3a
(Scheme 4).
[a] The yield was determined by GC-MS.
Scheme 3. Mechanism studies.
The facilitating effect of 1,10-phenanthroline on the
reaction was carefully studied (Table 3). The reaction with
varying amount of phen was first conducted (entries 1-5).
The result showed that the reaction yield has no
dependence on the amount of phen. With catalytic of
pyridine as additive, the difunctionalization product was
obtained in 65% yield (entry 6). Furthermore, 18-crown-6
was added to the reaction mixture instead of phen (entry 7).
In contrast with the low yield without phen (Table 1, entry
14), pyrazole underwent smooth transformation to give the
difunctionalization product with a 58% yield. With this
results, we proposed that by adding catalytic amount of
phen, the alkalinity of the system was significantly
enhanced. Phen may directly worked as a base to abstract
a proton or coordinate with the potassium ion of K2CO3 to
increase their basicity.
Scheme 4. Preparation of iodonium ylide and conversion to the products.
The thermal stability of iodonium ylide 5a was
investigated by monitoring the reaction process with real-
time 1H NMR experiments. CDCl3 was chosen as the
solvent due to the poor solubility of 5a in CD3CN. As can be
o
seen in Scheme 5, the ylide 5a was very stable at 0 C and
no product was formed even after 24 h. When the reaction
o
o
was conducted at 10 C or 25 C, 5a slowly decomposed
and the conversion was moderate after 24 h. However, if
o
o
the reaction was heated at 50 C or 60 C, the reaction rate
of the iodonium ylide consumption is very fast and about
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10.1002/ejoc.201800416
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strategy to find wide application in heterocycle synthesis. Further
exploration on the synthetic applications based on this novel
synthetic methodology are currently under way in our laboratory.
80% of 5a reacted at the first 3 h. Then the reaction
became very slowly and about 10% of 5a was still left
unreacted in the reaction mixture after 24 h.
Experimental Section
General Information: Commercially available materials purchased from
Alfa Aesar or Aldrich was used as received. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on AscendTM 400 (400 MHz)
spectrometer. Chemical shifts were recorded in parts per million (ppm, δ)
relative to tetramethylsilane (δ 0.00) or appropriate solvent (CHCl3, δ
7.26) as internal standard. 1H NMR splitting patterns are designated as
singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets); m
(multiplets), and etc. All first-order splitting patterns were assigned on the
basis of the appearance of the multiplet. Splitting patterns that could not
be easily interpreted are designated as multiplet (m) or broad (br).
Carbon nuclear magnetic resonance (13C NMR) spectra were recorded
on AscendTM 400 (100 MHz) spectrometer. Mass spectral analysis (ESI-
MS) was performed on ThermoScientificLCQ Fleet mass spectrometer.
Analytical thin-layer chromatography (TLC) was carried out on Merck 60
F254 pre-coated silica gel plate (0.2 mm thickness). Visualization was
performed using a UV lamp.
Scheme 5. The thermal stability study of iodonium ylide 5a with real-time 1H
NMR experiments.
Typical Procedure for the Reaction of 3: To a dry Schlenk tube
equipped with a magnetic stir bar, was added 3,5-diethyl-1H-pyrazole 1a
(0.5 mmol), phenyliodine diacetate 2a (0.5 mmol), TsOH•H2O (0.5 mmol)
and dichloromethane (3 mL). The tube was closed with a septum, stirred
at room temperature for 8 hours till 1a was completely consumed
(monitored by TLC). The solvent was then removed by evaporation,
K2CO3 (4.0 equiv.), 1,10-phen (5 mol-%), MeCN (5 mL) was then added
to the resulting mixture and filled with nitrogen. The reaction mixture was
then stirred at 70 oC for about 24 hours and the resulting crude residue
was purified via column chromatography on silica gel (30:1
hexane/EtOAc) to afford the desired product 3a.
Transformations of the 1,4-substituted pyrazole 3a into
valuable derivatives were also achieved (Scheme 6). Pd-
catalyzed Suzuki reaction between 3a and PhB(OH)2
performed efficiently to afford the cross-coupling product 7a
in 88% yield under mild conditions. Additionally, conversion
of 3a to 4-alkynyl pyrazole 9a was readily achieved by the
Pd-catalyzed coupling with phenylacetylene.
3,5-Diethyl-4-iodo-1-phenyl-1H-pyrazole (3a): Yellow liquid, yield:
120.7 mg (74%); 1H NMR (400 MHz, CDCl3) δ 7.48-7.41 (m, 2H), 7.40-
7.34 (m, 3H), 2.80-2.60 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H), 1.09 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 155.2, 145.8, 139.9, 129.0, 128.0,
125.2, 62.6, 21.8, 19.8, 13.2, 13.1; HRMS (ESI): calculated for C13H16IN2
[M+H]+:327.0353, found: 327.0359.
3,5-Diethyl-4-iodo-1-(p-tolyl)-1H-pyrazole (3b): Yellow liquid, yield:
110.0 mg (65%); 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 4H), 2.73-2.57 (m,
4H), 2.40 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H), 1.09 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 155.0, 145.9, 138.1, 137.5, 129.6, 125.2, 62.2,
21.8, 21.1, 19.9, 13.3, 13.2; HRMS (ESI): calculated for C14H18IN2
[M+H]+:341.0509, found: 341.0518.
Scheme 6. Synthetic utilities of the products.
3,5-Diethyl-4-iodo-1-(4-methoxyphenyl)-1H-pyrazole (3c): Yellow
liquid, yield: 103.0 mg (58%); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J =
8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 2.71-2.58 (m, 4H),
1.28 (t, J = 7.5 Hz, 3H), 1.07 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.3, 154.9, 146.1, 133.0, 126.9, 114.2, 61.8, 55.5, 21.8, 19.8,
13.3, 13.2; HRMS (ESI): calculated for C14H18IN2O [M+H]+:357.0458,
found:357.0453.
Conclusions
In summary, we have developed an effcient selective io-
doarylation of pyrazoles with readily available aryliodine
diacetates under transition-metal free conditions. The key
feature is the in-situ formation of NH-pyrazole-iodonium salts
followed by sequential phen/K2CO3-mediated intermolecular
arylation. The proposed iodonium ylide intermediate could be
isolated and transformed to the target compound under base-
and metal-free conditions. Given the operational simplicity and
commendable functional group tolerance, we expect this
3,5-Diethyl-1-(4-fluorophenyl)-4-iodo-1H-pyrazole (3d): Yellow liquid,
yield: 120.7 mg (70%); 1H NMR (400 MHz, CDCl3) δ 7.40-7.33 (m, 2H),
7.15 (t, J = 8.4 Hz, 2H), 2.72-2.60 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H), 1.09
(t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.3 (d, J = 246.8 Hz),
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10.1002/ejoc.201800416
European Journal of Organic Chemistry
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160.9, 155.4, 146.1, 136.1 (d, J = 2.9 Hz), 127.3 (d, J = 8.7 Hz), 116.0 (d,
J = 23.0 Hz), 62.6, 21.8, 19.9, 13.2; 19F NMR (376 MHz, CDCl3) δ -112.9;
HRMS (ESI): calculated for C13H15FIN2 [M+H]+:345.0258, found:345.0253.
-113.3; HRMS (ESI): calculated for C11H11FIN2 [M+H]+: 316.9945, found:
316.9955.
Ethyl 4-(4-Iodo-3,5-dimethyl-1H-pyrazol-1-yl) Benzoate (3m): Yellow
liquid, yield: 122.1 mg (66%); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J =
8.5 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 2.39 (s,
3H), 2.32 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
165.7, 151.6, 143.3, 140.9, 130.6, 129.4, 123.8, 66.8, 61.2, 14.3, 14.1,
13.8; HRMS (ESI): calculated for C14H16IN2O2 [M+H]+: 371.0251, found:
371.0258.
1-(4-Bromophenyl)-3,5-diethyl-4-iodo-1H-pyrazole (3e): Yellow liquid,
132.7 mg, 66% yield, 95% purity (Purity was determined with 1H NMR
analysis by adding 9.3 mg 1,3,5-trimethoxybenzene as an internal
standard to 10.5 mg 3e); 1H NMR (400 MHz, CDCl3) δ 7.71-7.50 (d, J =
8.4 Hz, 2H), 7.41-7.19 (d, J = 9.2 Hz, 2H), 2.75-2.57 (m, 4H), 1.27 (t, J =
7.2 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 155.7,
145.9, 139.0, 132.3, 126.7, 121.8, 63.3, 21.8, 19.9, 13.2, 13.1; HRMS
(ESI): calculated for C13H1579BrIN2 [M+H]+:404.9458, found: 404.9466.
1-(2-Bromophenyl)-4-iodo-3,5-dimethyl-1H-pyrazole (3p): Yellow solid,
yield: 137.6 mg (73%), 95% purity (Purity was determined with 1H NMR
analysis by adding 16.8 mg 1,3,5-trimethoxybenzene as an internal
standard to 27.0 mg 3p); Mp 91.5-93.0 oC; 1H NMR (400 MHz, CDCl3) δ
7.69 (d, J = 8.0 Hz, 1H), 7.46-7.39 (m, 1H), 7.37-7.30 (m, 2H), 2.30 (s,
3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.9, 142.4, 139.0,
133.3, 130.7, 129.7, 128.2, 122.3, 63.7, 14.1, 12.4; HRMS (ESI):
calculated for C11H1179BrIN2 [M+H]+: 376.9145, found: 376.9153.
1-(2-Bromophenyl)-3,5-diethyl-4-iodo-1H-pyrazole (3f): Yellow liquid,
yield: 127.0 mg (63%); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz,
1H), 7.46-7.26 (m, 3H), 2.73-2.61 (m, 2H), 2.52 (br, 2H) 1.29 (t, J = 7.9
Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 155.5,
146.9, 139.1, 133.4, 130.7, 129.9, 128.0, 122.8, 61.4, 21.9, 19.8, 13.2,
12.9; HRMS (ESI): calculated for C13H1579BrIN2 [M+H]+:404.9458, found:
404.9466.
4-Iodo-3,5-diisopropyl-1-phenyl-1H-pyrazole (3o): Yellow liquid, yield:
117.5 mg (66%); 1H NMR (400 MHz, CDCl3) δ 7.52-7.37 (m, 3H), 7.33 (d,
J = 7.2 Hz, 2H), 3.20-2.92(m, 2H), 1.37-1.25 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 158.8, 147.2, 140.2, 129.0, 128.4, 126.7, 58.5, 27.9, 26.6,
21.8, 20.7; HRMS (ESI): calculated for C15H20IN2 [M+H]+:355.0666,
found: 355.0661.
4-Iodo-3,5-dimethyl-1-phenyl-1H-pyrazole (3g): Yellow liquid, yield:
116.3 mg (78%); 1H NMR (400 MHz, CDCl3) δ 7.49-7.42 (m, 2H), 7.41-
7.33 (m, 3H), 2.33 (d, J = 1.8 Hz, 3H), 2.30 (d, J = 1.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 150.7, 140.8, 139.9, 129.1, 127.8, 124.8, 65.2, 14.1,
13.4; HRMS (ESI): calculated for C11H12IN2 [M+H]+: 299.0040, found:
299.0046.
4-Iodo-1-phenyl-1H-pyrazole (3p): Yellow liquid, yield: 87.7 mg (65%);
1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.4
Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 145.9, 141.5, 131.3, 129.5, 127.1, 119.1, 58.8; HRMS
(ESI): calculated for C9H8IN2 [M+H]+:270.9727, found: 270.9722.
4-Iodo-3,5-dimethyl-1-(p-tolyl)-1H-pyrazole (3h): Yellow liquid, yield:
109.2 mg (70%); 1H NMR (400 MHz, CDCl3) δ 7.37-7.09 (m, 4H), 2.40 (s,
3H), 2.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.4, 140.8, 137.8,
137.4, 129.6, 124.7, 64.8, 21.1, 14.1, 13.3; HRMS (ESI): calculated for
C12H14IN2 [M+H]+: 313.0196, found: 313.0203.
4-Iodo-3-methyl-1-phenyl-1H-pyrazole (3q):[18] Yellow liquid, yield:
42.5 mg (30%); 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.54-7.45 (m,
2H), 7.44-7.37 (m, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4,
140.4, 139.8, 129.2, 128.2, 124.9, 61.5, 12.8; HRMS (ESI): calculated for
C10H10IN2 [M+H]+:284.9883, found: 284.9879.
4-Iodo-1-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole (3i): Yellow
liquid, yield: 95.1 mg (58%); 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 6.4
Hz, 2H), 6.96 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 2.43-2.27 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 158.7, 148.5, 139.4, 133.0, 126.3, 114.1,
106.2, 55.5, 13.5, 12.1; HRMS (ESI): calculated for C12H14IN2O [M+H]+:
329.0145, found: 329.0152.
4-iodo-5-methyl-1-phenyl-1H-pyrazole (3q’): Yellow liquid, yield: 46.1
mg (32%); 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.60 (d, J = 6.8 Hz,
2H), 7.43 (t, J = 7.9 Hz, 2H), 7.27 (d, J = 5.2 Hz 1H), 2.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 152.6, 139.6, 131.8, 129.5, 126.6, 118.7, 62.5,
13.7; HRMS (ESI): calculated for C10H10IN2 [M+H]+:284.9883, found:
284.9880.
1-(4-Chlorophenyl)-4-iodo-3,5-dimethyl-1H-pyrazole (3j): Yellow liquid,
yield: 131.3 mg (79%), 96% purity (Purity was determined with 1H NMR
analysis by adding 16.8 mg 1,3,5-trimethoxybenzene as an internal
standard to 33.3 mg 3j); 1H NMR (400 MHz, CDCl3) δ 7.48-7.40 (m, 2H),
7.39-7.30 (m, 2H), 2.33 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 151.1, 140.9, 138.4, 133.6, 129.3, 125.9, 65.8, 14.1, 13.5; HRMS (ESI):
calculated for C11H11ClIN2 [M+H]+: 332.9650, found: 332.9657.
Reaction with 3,5-Diphenyl Pyrazole: To a dry Schlenk tube equipped
with a magnetic stir bar, was added 4r (0.1 mmol), K2CO3 (2.0 equiv.),
1,10-phen (5 mol-%), and MeCN (4 mL) was then added to the resulting
mixture and filled with nitrogen. The reaction mixture was then stirred at
120 oC for about 24 hours and the resulting crude residue was purified
via column chromatography on silica gel (30:1 hexane/EtOAc) to afford
the desired product 3r (29.8 mg, yield 71%).
1-(4-Bromophenyl)-4-iodo-3,5-dimethyl-1H-pyrazole (3k): Yellow solid,
yield: 137.6 mg (73%), 99% purity (Purity was determined with 1H NMR
analysis by adding 16.8 mg 1,3,5-trimethoxybenzene as an internal
standard to 37.7 mg 3k); Mp 120.8-121.9 oC; 1H NMR (400 MHz, CDCl3)
δ 7.58 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 2.32 (s, 3H), 2.29 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 151.1, 140.7, 138.8, 132.2, 126.0,
121.4, 65.9, 14.0, 13.4; HRMS (ESI): calculated for C11H1179BrIN2 [M+H]+:
376.9145, found: 376.9157.
4-Iodo-1,3,5-triphenyl-1H-pyrazole (3r): Yellow solid; Mp 138.5-139.8
oC; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.2
Hz, 2H), 7.43-7.36 (m, 4H), 7.35-7.30 (m, 2H), 7.29-7.22 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 153.0, 145.4, 139.9, 132.8, 130.5, 130.2,
129.0, 128.8, 128.6, 128.5, 128.4, 128.2, 127.5, 124.7, 63.6; MS (ESI):
calculated for C21H16IN2 [M+H]+: 423.03, found: 423.19; HRMS (ESI):
calculated for C21H16IN2 [M+H]+: 423.0353, found: 423.0353.
1-(4-Fluorophenyl)-4-iodo-3,5-dimethyl-1H-pyrazole (3l): Yellow liquid,
yield: 121.7 mg (77%); 1H NMR (400 MHz, CDCl3) δ 7.44-7.30 (m, 2H),
7.20-7.10 (m, 2H), 2.40-2.10 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
161.9 (d, J = 246.4 Hz), 150.8, 141.0, 136.0 (d, J = 3.2 Hz), 126.7 (d, J =
8.6 Hz), 116.0 (d, J = 22.8 Hz), 65.2, 14.0, 13.3; 19F (376 MHz, CDCl3) δ
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10.1002/ejoc.201800416
European Journal of Organic Chemistry
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Scale-up Experiment: To a dry Schlenk tube equipped with a magnetic
stir bar, was added 3,5-diethyl-1H-pyrazole 1a (1 g, 8.1 mmol),
phenyliodine diacetate 2a (2.6 g, 8.1 mmol), TsOH•H2O (1.53 g, 8.1
mmol) and dichloromethane (48 mL). The tube was closed with a septum,
stirred at room temperature for about 6 hours till 1a was completely
consumed (monitored by TLC). The solvent was then removed by
evaporation, then K2CO3 (4.0 equiv.), 1,10-phen (5 mol-%), MeCN (80
mL) was added to the resulting mixture and filled with nitrogen. The
reaction mixture was stirred at 70 oC for about 24 hours and the resulting
crude residue was purified via column chromatography on silica gel (30:1
hexane/EtOAc) to afford the desired product 3a (1.88 g, 72%).
5092; h) X. Wang, A. Studer, Acc. Chem. Res. 2017, 50, 1712-1724; i)
K. Aradi, B. L. Tóth, G. L. Tolnai, Z. Novák, Synlett 2016, 27, 1456-
1485.
[5]
[6]
a) C. R. Jamison, J. J. Badillo, J. M. Lipshultz, R. J. Comito, D. W. C.
MacMillan, Nat. Chem. 2017, 9, 1165-1169; b) K. Ishida, H. Togo, K.
Moriyama, Chem. Asian J. 2016, 11, 3583-3588.
a) Q. Y. Toh, A. McNally, S. Vera, N. Erdmann, M. J. Gaunt, J. Am.
Chem. Soc. 2013, 135, 3772-3775; b) Z. Yuan, R. Cheng, P. Chen, G.
Liu, S. H. Liang, Angew. Chem. Int. Ed, 2016, 55, 11882-11886; Angew.
Chem. 2009, 128, 12061-12065; c) K. Morimoto, Y. Ohnishi, D. Koseki,
A. Nakamura, T. Dohi, Y. Kita, Org. Biomol. Chem, 2016, 14, 8947-
8951; d) E. A. Veretennikov, A. E. Gavrilov, Chem. Heterocycl. Compd.
2007, 43, 1273-1274.
[7]
[8]
[9]
B. Y. Karele, S. V. Kalnin’, I. P. Grinberga, O. Y. Neiland, Chem.
Heterocycl. Compd. 1973, 9, 226-229.
Acknowledgements
I. Sokolovs, D. Lubriks, E. Suna, J. Am. Chem. Soc. 2014, 136, 6920-
6928.
We gratefully acknowledge the National Natural Science
Foundation of China (21502019, 21402027), the Science
Foundation of the Fujian Province, China (2015J05021,
2015J05046), the Education Foundation of Fujian Province,
China (JA15095), Open Project Program of the State Key
Laboratory of Photocatalysis on Energy and Environment
(SKLPEE-KF201816), Fuzhou University for financial support.
a) Z. Gonda, Z. Novák, Chem. Eur. J. 2015, 21, 16801-16806; b) T.
Bihari, B. Babinszki, Z. Gonda, S. Kovács, Z. Novák, A. Stirling, J. Org.
Chem. 2016, 81, 5417–5422.
[10] O. Neilands, Chem. Heterocycl. Compd. 2003, 39, 1555-1556.
[11] For reviews on hypervalent iodonium ylide chemistry, see: a) P. Müller,
Acc. Chem. Res, 2004, 37, 243-251; b) E. Malamidou-Xenikaki, S.
Spyroudis, Synlett 2008, 2008, 2725-2740; c) R. M. Moriarty, J. Org.
Chem. 2005, 70, 2893-2903; d) A. Yoshimura, M. S. Yusubov, V. V.
Zhdankin, Org. Biomol. Chem. 2016, 14, 4771-4781; For recent
examples, see: e) Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki,
M. Shiro, N. Shibata, J. Am. Chem. Soc. 2013, 135, 8782-8785. f) S.
Chelli, K. Troshin, P. Mayer, S. Lakhdar, A. R. Ofial, H. Mayr, J. Am.
Chem. Soc. 2016, 138, 10304-10313; g) M. Saito, Y. Kobayashi, S.
Tsuzuki, Y. Takemoto, Angew. Chem. Int. Ed, 2017, 56, 7653-7657;
Angew. Chem, 2017, 129, 7761-7765; h) B. Xu, U. K. Tambar, J. Am.
Chem. Soc. 2016, 138, 12073-12076; i) B. Xu, U. K. Tambar, Angew.
Chem. Int. Ed, 2017, 56, 9868-9871; Angew. Chem, 2017, 129, 10000-
10003.
Keywords: Pyrazoles • Transition-metal free • Iodonium ylide •
Iodoarylation • One-pot reaction
[1]
a) T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W.
Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M.
Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G.
Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins,
K.Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C.Isakson, J. Med. Chem.
1997, 40, 1347-1365; b) G. R. Bebernitz, G. Argentieri, B. Battle, C.
Brennan, B. Balkan, B. F. Burkey, M. Eckhardt, J. Gao, P. Kapa, R. J.
Strohschein, H. F. Schuster, M. Wilson, D. D. Xu, J. Med. Chem. 2001,
44, 2601-2611; (c) K. Morimoto, T. Sato, S. Yamamoto, H. Takeuchi, J.
Heterocycl. Chem. 1997, 34, 537-540.
[12] Y. Wu, S. Izquierdo, P. Vidossich, A. Lledós, A. Shafir, Angew. Chem.
Int. Ed. 2016, 55, 7152-7156; Angew.Chem. 2016, 128, 7268-7272.
[13] a) F. Hong, N. Lu, B. Lu, J. Cheng, Adv. Synth. Catal. 2017, 359, 3299-
3303; b) F. Hong, Y. Chen, B. Lu, J. Cheng, Adv. Synth. Catal. 2016,
358, 353-357.
[2]
[3]
a) Y. L. Janin, Chem. Rev. 2012, 112, 3924-3958; b) X. Wang, Y. Hu, S.
Bonacorsi, Y. Hong, R. Burrell, J. Yu, J. Am. Chem. Soc. 2013, 135,
10326-10329; c) D. Chand, J. M. Shreeve, Chem. Commun. 2015, 51,
3438-3441.
[14] a) N. Jalalian, T. B. Petersen, B. Olofsson, Chem. Eur. J, 2012, 18,
14140-14149; b) F. Tinnis, E. Stridfeldt, H. Lundberg, H. Adolfsson, B.
Olofsson, Org. Lett. 2015, 17, 2688-2691; c) M. Reitti, P. Villo, B.
Olofsson, Angew. Chem. Int. Ed, 2016, 55, 8928-8932; Angew. Chem.
2016, 128, 9074-9078; d) A. H. Sandtorv, D. R. Stuart, Angew. Chem.
Int. Ed. 2016, 55, 15812-15815; Angew. Chem. 2016, 128, 16044-
16047; e) T. L. Seidl, D. R. Stuart, J. Org. Chem. 2017, 82, 11765-
11771.
a) E. Arbačiauskiene, G. Vilkauskaite, G. A. Eller, W. Holzer, A. Šačkus,
Tetrahedron, 2009, 65, 7817-7824; b) M. Calle, P. Cuadrado, A. M.
Gonzalez-Nogal, R. Valero, Synthesis 2001, 2001, 1949-1958; c) C.-P.
Zhang, Z.-L. Wang, Q.-Y. Chen, C.-T. Zhang, Y.-C. Gu, J.-C. Xiao,
Angew. Chem. Int. Ed, 2011, 50, 1896-1900; Angew.Chem, 2011, 123,
1936-1940; d) K. W. Anderson, R. E. Tundel, T. Ikawa, R. A. Altman, S.
L. Buchwald, Angew. Chem. Int. Ed, 2006, 45, 6523-6527; Angew.
Chem. 2006, 118, 6673-6677.
[15] S. Izquierdo, S. Essafi, I. del Rosal, P. Vidossich, R. Pleixats, A.
Vallribera, G. Ujaque, A. Lledósand A. Shafir, J. Am. Chem. Soc. 2016,
138, 12747-12750.
[4]
a) A. Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116, 3328-3435; b)
L. F. Silva, Jr, B. Olofsson, Nat. Prod. Rep. 2011, 28, 1722-1754; c) E.
Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48, 9052-9070;.
Angew. Chem. 2009, 121, 9214-9234; e) H. Wu, Q. Wang, J. Zhu,
Angew. Chem. Int. Ed. 2018, 57, 2721-2725; Angew. Chem. 2018, 130,
2751-2755; f) Q. Ding, X. Zhou, R. Fan, Org. Biomol. Chem. 2014, 12,
4807-4815; g) C. K. Cao, J. Sheng, C. Chen, Synthesis 2017, 49, 5081-
[16] D. R. Stuart, Chem. Eur. J. 2017, 23, 15852-15863.
[17] Please see the SI for the details.
[18] Kim, M. M.; Ruck, R. T.; Zhao, D.; Huffman, M. A. Tetrahedron Lett.
2008, 49, 4026.
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Entry for the Table of Contents (Please choose one layout)
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Iodonium Ylide*
Nannan Lu, Liangsen Huang, Lili Xie,*
Jiajia Cheng*
Page No. – Page No.
Transition-metal
Free
Selective
A one-pot transition-metal free selective iodoarylation of pyrazoles with aryliodine
diacetates is developed. The reaction proceeds via the in-situ generation of NH-
Iodoarylation of Pyrazoles via the
Heterocyclic Aryliodonium Ylides
pyrazole-iodonium
salts
followed
by
sequential
phen/K2CO3-mediated
intermolecular arylation. The proposed iodonium ylide intermediate could be
isolated and directly afford the difunctionalization products in high yield under base-
and metal-free conditions.
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