Directing/Protecting-Group-Free Synthesis of Tetraaryl-Substituted Pyrazoles through Four Direct Arylations on an Unsubstituted Pyrazole Scaffold

Article abstract of DOI:10.1002/chem.201502399

A directing/protecting-group-free synthesis of 1,3,4,5-tetraaryl-substituted pyrazoles was achieved through four transition metal-catalyzed direct arylations. Various pyrazoles with four different aryl rings were obtained using readily available reagents from an unsubstituted pyrazole. Two aryl-substituted pyrazoles showed intense violet fluorescence, high quantum yields (Φ_f=0.68, 0.64), and large Stokes shifts (19000, 15200cm^-1).

Full text of DOI:10.1002/chem.201502399

DOI: 10.1002/chem.201502399
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&
CÀH Activation |Hot Paper|
Directing/Protecting-Group-Free Synthesis of Tetraaryl-
Substituted Pyrazoles through Four Direct Arylations on an
Unsubstituted Pyrazole Scaffold
Shinichiro Fuse,*[a, b] Taiki Morita,[a] Kohei Johmoto,[c] Hidehiro Uekusa,[c] and Hiroshi Tanaka[a]
Abstract:
A
directing/protecting-group-free synthesis of
ily available reagents from an unsubstituted pyrazole. Two
aryl-substituted pyrazoles showed intense violet fluores-
cence, high quantum yields (Ff =0.68, 0.64), and large
Stokes shifts (19000, 15200 cmÀ1).
1,3,4,5-tetraaryl-substituted pyrazoles was achieved through
four transition metal-catalyzed direct arylations. Various pyra-
zoles with four different aryl rings were obtained using read-
Introduction
tions of unsubstituted 1,3-azoles without the use of a directing
or a protecting group. However, directing group/protecting-
group-free sequential direct arylation of unsubstituted 1,2-
azoles has not yet been achieved, probably due to the lower
reactivity of CÀH bonds as well as to the smaller reactivity dif-
ferences among the CÀH bonds in 1,2-azoles compared with
those of 1,3-azoles. For instance, three CÀH bonds in pyrazole
were less reactive compared with those of imidazole. More-
over, the reactivity differences among the CÀH bonds were
smaller compared with those of imidazole.[10]
Sequential diversification approaches that are based on hetero-
aromatic scaffolds with multiple reaction centers are valuable
for use in drug discovery and in materials development. These
approaches enable the rapid installation of various substitu-
ents without extra synthetic steps, such as protection/depro-
tection and the introduction of activating/directing groups,
which do not contribute to structural diversification. From this
point of view, a sequential CÀH direct arylation approach
based on readily available unsubstituted heteroaromatics is an
attractive choice. Nakamura[1] and Ohta[2] have conducted pio-
neering studies on the direct CÀH arylation of heteroaromatics,
Multiaryl-substituted pyrazoles make up an important class
of compounds, because they are frequently found in pharma-
ceutical drugs, agricultural chemicals, functional materials, and
ligands for transition-metal catalysts.[11] In addition, functional
1,3,4,5-tetraaryl-substituted pyrazoles, such as the ligand in the
cannabinoid (CB1) receptor 1,[12] antimicrobial agent 2,[13] p38
MAP kinase inhibitor 3,[14] and electroluminescent compound
4[15] have been reported (Figure 1). For these reasons, there is
a great deal of interest in their synthesis in the academic field
as well as in agrochemical, pharmaceutical, and chemical in-
dustries.[11] The most conventional approach[11] to the synthesis
of multiaryl-substituted pyrazoles—condensation of 1,3-dike-
tone or a,b-unsaturated carbonyl compounds with substituted
hydrazines—often suffers from insufficient regioselectivity and/
or availability of substrates.[16] Notwithstanding the importance
of multiaryl-substituted pyrazoles, direct CÀH arylation based
on pyrazoles has attracted somewhat less attention. Recently,
direct CÀH arylation at the C3-, C4-, and C5-positions of pyra-
zoles[8a,17] and at the C3-position of indazoles[18] have been re-
ported. In particular, Sames achieved a multiaryl-substituted
pyrazole synthesis starting from 4-bromopyrazole with the aid
of a 2-(trimethylsilyl)ethoxymethyl (SEM) group.[17c] We have
developed sequential diversification approaches using Pd-cata-
lyzed cross-coupling based on aromatic scaffolds for drug dis-
covery and materials development.[19] In addition, we recently
and numerous useful reactions have been reported since.[3]
A
decade ago, Miura demonstrated the installation of multiple
aryl substituents to a thiazole[4] and a thiophene[5] with the aid
of a directing and sacrificial carboxanilide group. Fagnou[6] and
Itami[7] recently reported sequential CÀH direct arylation ap-
proaches based on heteroaromatic scaffolds with N-oxide and
methoxy groups, respectively, which played the role of direct-
ing or protecting groups. Although many sequential CÀH
direct arylation approaches have been reported, the number
of directing group/protecting-group-free approaches is surpris-
ingly limited. As far as we could ascertain, only Murai[8] and
Itami[9] have demonstrated beautiful sequential direct aryla-
[a] Dr. S. Fuse, T. Morita, Dr. H. Tanaka
Department of Applied Chemistry, Tokyo Institute of Technology
2-12-1, Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
[b] Dr. S. Fuse
Present address: Chemical Resources Laboratory
Tokyo Institute of Technology, 4259 Nagatsuta-cho
Midori-ku, Yokohama 226-8503 (Japan)
E-mail: sfuse@res.titech.ac.jp
[c] Dr. K. Johmoto, Dr. H. Uekusa
Department of Chemistry and Materials Science
Tokyo Institute of Technology, 2-12-1
Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
accomplished
a
tetraaryl-substituted pyrazole synthesis
through a sequence of SNAr reaction/Suzuki-Miyaura coupling/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502399.
CÀH direct arylations that was based on a 3-iodo-pyrazole scaf-
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Figure 2. Cu-catalyzed N-arylation of unsubstituted pyrazole (5). Ac: acetyl,
MW: microwave, DMF: N,N-dimethylformamide.
Figure 1. Structures of various useful 1,3,4,5-tetraaryl-substituted pyrazoles.
to sucess was how to regioselectively activate the C4- and C5-
positions without affecting the other reaction centers.
The first arylation at the N1-position was examined. A proce-
dure established by Li and Lang[22] (method A) afforded the de-
sired products 6a–6c in high yields, whereas it afforded com-
plex mixtures in the synthesis of 6d and 6e. Modifications of
a procedure established by You[23] (method B) were useful for
the synthesis of 6d and 6e (Figure 2). The desired products
were obtained in excellent yields.
fold.[20] However, the most ideal approach, namely, installation
of four different aryl substituents onto an unsubstituted pyra-
zole ring by means of four direct arylations, has not been dem-
onstrated.
Herein, we wish to report the four-step synthesis of tetraar-
yl-substituted pyrazoles based on an unsubstituted pyrazole
scaffold without using directing/protecting groups. In order to
enable the facile and rapid combinatorial synthesis of a pyra-
zole library in the future, we only examined readily available
reagents that could be handled without using glovebox tech-
niques. In addition, we also report our evaluation of the photo-
physical properties of synthesized 1,4,5-triaryl- and 1,3,4,5-tet-
raarylpyrazoles.
A regioselective CÀH direct arylation at the C5-position of 1-
arylpyrazole was examined.[24] Daugulis reported an intermo-
lecular CÀH direct phenylation at the C5-position of 1-phenyl-
pyrazole (CuI, 1,10-phenanthloline, tBuOLi, in N,N’-dimethylpro-
pyleneurea, 52% yield).[17b] However, many attempts to obtain
7c based on the Daugulis conditions resulted only in recovery
of the substrate. Greaney reported a CÀH direct arylation at
the C1-position of 2-phenyl indazole ([Pd(dppf)Cl2]·CH2Cl2,
PPh3, Ag2CO3 in H2O, yield: 49–96%). These conditions were
applied to the synthesis of 7c, and the desired product was
obtained in a moderate yield (36%). After optimizing the
combination of phosphine ligands (PPh3, [(Cy3)PH]BF4,
[(tBu3)PH]BF4,[25] cataCXiumA,[26] JohnPhos,[27] DavePhos,[28]
SPhos,[29] and XPhos[30]) and solvents (H2O, H2O/MeCN, H2O/1,4-
dioxane, H2O/DMF, and H2O/DMSO), we found that method D
(Figure 3) afforded 7c in a better yield (46%). However, meth-
od D was not effective in the synthesis of either 7 f or 7j (28
and 26% yields, respectively). Thus, we extensively reinvesti-
gated the reaction conditions using Pd(OAc)2, aryl halides (Ar-I
and Ar-Br), phosphine ligands (PPh3, [(Cy3)PH]BF4, [(tBu3)PH]BF4,
cataCXium A, and DavePhos), additives (CuI and CuCl), bases
(K2CO3, Cs2CO3, and Ag2CO3), solvents (DMA, 1,4-dioxane, and
1,4-dioxane/tBuOH), and PivOH. As a result, our originally de-
veloped method C afforded the best results. Various Ar2
groups including electron-donating, electron-withdrawing, and
heteroatom-containing aryls were introduced in moderate to
good yields (45–72%), as shown in Figure 3. The electronic
factor of the Ar1 group did not greatly influence the yields of
this coupling reaction at the C5-position.
Results and Discussion
We planned to introduce Ar1 at the N1-position based on
a Buchwald–Hartwig coupling reaction[21] for the first step
(Scheme 1). Sames reported a reactivity trend of three CÀH
bonds of pyrazole against CÀH direct arylation (C5>C4@
C3).[17c] In accordance with the reported trend, we decided to
introduce Ar2 at the C5-position, Ar3 at the C4-position, and Ar4
at the C5-position, in the order indicated in Scheme 1. The key
Scheme 1. Synthetic plan for tetraaryl-substituted pyrazoles via four direct
arylations.
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Figure 4. Products of the CÀH direct arylation at the C4-position of 1,5-
diarylpyrazoles 7. [a] The ratio of substrate 7 to Ar-I was 2:1. The yields were
calculated based on the Ar-I.
Figure 3. Products of the CÀH direct arylation at the C5-position of 1-aryl-
pyrazoles 6. dppf: 1,1’-bis(diphenylphosphino)ferrocene, Cy: cyclohexyl,
JohnPhos: 2-(di-tert-butylphosphino)biphenyl, DavePhos: 2-dicyclohexyl-
phosphino-2’-(N,N-dimethylamino)biphenyl, SPhos: 2-dicyclohexylphosphi-
no-2’,6’-dimethoxybiphenyl, XPhos: 2-dicyclohexylphosphino-2’,4’,6’-triiso-
propylbiphenyl, cataCXium A: di(1-adamantyl)-n-butylphosphine, DMA: N,N-
dimethylacetamide. [a] Overarylation at the C4-position was observed. The
ratio of 7c to the undesired 1,4,5-triaryl product was 7:1 (method C) and 7:2
of various Lewis acids (MX2; M=Fe, Co, Ni, Cu, Zn, Mn, X=Cl,
Br, I, OTf) to enhance the acidity of the proton at the C3-posi-
tion by metal coordination to the nitrogen atom. However, the
desired coupling product could not be obtained in a satisfacto-
ry yield. Yu conditions were then examined for the coupling re-
action (Figure 5).[17h] In the case of Ar2 and/or Ar3 as electron-
donating groups (methoxy phenyl group), the coupling yields
tended to decrease (9g: 62% yield vs. 9j: 35% yield, 9d: 68%
yield vs. 9k: 41% yield). In the case of Ar1 as an electron-with-
drawing group (fluorophenyl group), the coupling yields also
tended to decrease (9d: 68% yield vs. 9a: 51% yield, 9g: 62%
yield vs. 9b: 35% yield) probably due to the undesired CÀH
direct arylation reaction on the Ar1 ring. In other cases, various
Ar4 groups including electron-donating, electron-withdrawing,
and heteroatom-containing aryls were introduced in satisfacto-
ry to good yields (57–88%).
1
(method D). The ratio was determined by H NMR analysis. [b] The ratio of
substrate 6 to Ar-Br was 1.2:1. The yield was calculated based on the Ar-Br.
Regioselective CÀH direct arylation at the C4-position of 1,5-
diaryl-substituted pyrazole was examined (Figure 4). Method C
(Figure 3) was not effective for this coupling reaction, whereas
the modified Yu’s conditions reported for the CÀH direct aryla-
tion at the C-3 position of 1,4,5-triphenylpyrazole were use-
ful.[17h] Although the introduction of a strong electron-donating
Ar3 group (methoxyphenyl group) resulted in low yields (8c:
35% yield, 8i: 21% yield), weak electron-donating, electron-
withdrawing, and heteroatom-containing Ar3 groups were in-
troduced in moderate to good yields (43–76%). The electronic
factors of the Ar1 and Ar2 groups did not greatly influence the
yields of this coupling reaction at the C4-position.
The structure of tetraaryl-substituted pyrazole 9c was unam-
biguously determined by X-ray crystallographic analysis
(Figure 6). All of the four aryl groups were introduced to de-
sired positions. They were distorted from coplanarity by
42.32(9) (4-MePh), 25.58(7) (4-MeOPh), 55.74(10) (4-CF3Ph), and
A final CÀH direct arylation at the most unreactive C3-posi-
tion of 1,4,5-triarylpyrazoles was investigated based on the use
of method C (Figure 3). We extensively examined the addition
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Figure 6. X-ray crystallographic analysis of 9c. Hydrogen atoms are omitted
for clarity.
42.29(12)8 (4-NO2Ph) with respect to the central pyrazole ring,
probably due to the steric repulsion among the aryl rings.
There are previous reports detailing interesting photophysi-
cal properties (large Stokes shifts) of 3,4-diaryl-[31] and 3,5-
diaryl-substituted pyrazoles[32] (6100–13600 cmÀ1) and 1,3,5-[32a]
and 3,4,5-triaryl-substituted pyrazoles[31] (4200–15800 cmÀ1)
that make them potentially useful for functional fluorescent
dyes.[32b] Therefore, we were interested in the photophysical
properties of the synthesized 1,4,5-triaryl-substituted pyrazoles
8 and 1,3,4,5- tetraaryl-substituted pyrazoles 9, as shown in
Table 1 (for the absorption/emission spectra, see the Support-
ing Information).
Pyrazoles 8 and 9, with the exceptions of 8d–8g and 9c
that all had nitro groups,[33] exerted violet emissions and large
Stokes shifts (8: 11000–19000 cmÀ1; 9: 14100–17900 cmÀ1). In
particular, 1,3,5-triaryl-substituted pyrazole 8i and 1,3,4,5-tet-
raaryl-substituted pyrazole 9e showed near UV absorption (8i:
lmax,abs =237 nm, e=24100 LmolÀ1 cmÀ1; 9e: lmax,abs =263 nm,
Table 1. Photophysical properties of triaryl- and tetraaryl-substituted pyr-
azoles.
[a]
[c]
lmax,abs
e[b]
lmax,em
Stokes shift[d]
[cmÀ1
[nm]
[LmolÀ1 cmÀ1
]
[nm]
]
8a
8b
8c
8d
8e
8 f
8g
8h
8i
9a
9b
9c
9d
9e
9 f
9g
9h
9i
249
272
235
262
277
253
254
273
237
252
256
267
253
263
247
251
247
270
243
236
17300
18600
23200
23100
30000
18900
20600
20900
24100
21800
22500
22700
15400
24300
23000
21100
25500
11100
23200
15900
390
387
389
14600
11 000
16800
[e]
[e]
–
–
–
–
–
[e]
[e]
–
[e]
[e]
–
[e]
[e]
–
436
432
395
429
13700
19000
14300
15700
[e]
[e]
–
–
435
436
438
436
439
436
428
410
16500
15200
17700
16900
17700
14100
17900
17900
9j
9k
Figure 5. Products of the CÀH direct arylation at the C3-position of 1,4,5-tri-
arylpyrazoles 8. [a] The ratio of substrate 8 to Ar-I was 2:1. The yields were
calculated based on the Ar-I. [b] The ratio of substrate 8 to Ar-I was 1.5:1.
The yield was calculated based on the Ar-I.
[a] Absorption maxima in MeCN at c=10À4 m. [b] Emission maxima in
MeCN at c=10À5 m. [c] Molar absorption coefficients in MeCN.
[d] lmax,absÀlmax,em. [e] Fluorescence too weak to be determined.
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should be noted that the both compounds 8i and 9e exerted
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;
9e:
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Conclusion
In summary, we demonstrated the rapid and divergent synthe-
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tion-metal-catalyzed direct arylations. Various pyrazoles with
four different aryl rings were obtained using readily available
reagents that can be treated, without using glovebox tech-
niques, based on an unsubstituted pyrazole scaffold. This is
the first synthesis of fully substituted 1,2-azoles by menas of
sequential direct arylation reactions. In addition, the absorp-
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pyrazoles 8 and 1,3,4,5-tetraaryl-substituted pyrazoles 9 were
measured. Two aryl-substituted pyrazoles, 8i and 9e, showed
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Experimental Section
Experimental details are given in the Supporting Information.
These include synthetic procedures, full spectroscopic and analyti-
cal data for all new compounds.
Keywords: CÀH activation · cross-coupling · fluorescence ·
heterocycles · palladium
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Received: June 21, 2015
Published online on August 21, 2015
Chem. Eur. J. 2015, 21, 14370 – 14375
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14375
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim