Copper-catalyzed C–N cross-coupling of arylboronic acids with N-acylpyrazoles

Article abstract of DOI:10.1016/j.tetlet.2016.06.044

A copper-catalyzed C–N bond forming reaction of arylboronic acids and N-acylpyrazoles was developed. This procedure used N-acetyl protected pyrazoles as starting material instead of free pyrazoles (NH). The reaction worked under neutral conditions and did not require any base or ligand. The reaction showed good functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2016.06.044

Accepted Manuscript
Copper-Catalyzed C–N Cross-Coupling of Arylboronic Acids with N-Acylpyr-
azoles
Jin Zhang, Run-Ping Jia, Dong-Hui Wang
PII:
S0040-4039(16)30713-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.044
TETL 47771
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 April 2016
8 June 2016
12 June 2016
Please cite this article as: Zhang, J., Jia, R-P., Wang, D-H., Copper-Catalyzed C–N Cross-Coupling of Arylboronic
Acids with N-Acylpyrazoles, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.044
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Copper-Catalyzed C–N Cross-Coupling of
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Arylboronic Acids with N-Acylpyrazoles
Jin Zhang,a Run-Ping Jia,a and Dong-Hui Wangb*
HO
OH
O
B
10 mol% Cu(OAc)2
N
N
N
N
MeOH, O2 (1 atm)
80oC, 20h
R
R
23 Samples

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper-Catalyzed C–N Cross-Coupling of Arylboronic Acids with
N-Acylpyrazoles
Jin Zhang,a Run-Ping Jia,a Dong-Hui Wang b*
a School of Materials Science and Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Fengxian District, Shanghai 201418, China.
b Laboratory of Synthetic & Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A copper-catalyzed C–N bond forming reaction of arylboronic acids and N-acylpyrazoles was
developed. This procedure used N-acetyl protected pyrazoles as starting material instead of
free pyrazoles (NH). The reaction worked under neutral conditions and did not require any
base or ligand. The reaction showed good functional group tolerance.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper-Catalyzed,
N-acylpyrazoles
Arylboronic acids
C–N aerobic oxidative Couping
Pyrazole derivatives exist mostly in man-made functional
molecules,1 such as industrial intermediates, dye,2 and
biologically active compounds for the agrochemical and
pharmaceutical industries.3 For example, tebufenpyrad is a
world-widely used insecticide in the green house (Figure 1);
celecoxib is a NSAID medicine to treatment of human's pain and
inflammation; mavacoxib is a veterinary drug for dogs in
were used as either electrphile or nucleophile in the Suzuki, Stille,
Sonogashira, Negishi and Heck reactions, by means of halide
substituted pyrazoles or pyrazole-metal reagents, respectively.
Recent research on C–H activation demonstrated that pyrazoles
could be used directly as starting materials and thus provided a
straight forward modification for pyrazoles.11 For the C–N bond
forming reactions of pyrazole substrates, the palladium- or
copper-catalyzed Buchwald-Hartwig type and Chan-Lam type
reactions played important role to decorate the nitrogen
component, which used free pyrazole (NH) as starting
materials.12
treatment
of
degenerative
joint
disease;
pyrazolo[5,1-c]-1,2,4-triazole is the backbone for photographic
dye couplers and pigment in color ink. However, pyrazole
structure is a rare feature in the natural resource,4 majority
pyrazole containing natural products are found in cultivated
plants, for example: 1-α-amino-β-(pyrazolyl-N)-propanoic acid
(Figure 2),5 withasomnine and derivetives,6 pyrazofurin and
formycin.7 So, methods and procedures to the synthesis of
pyrazole and its derivatives are very attractive in organic
chemistry.8
The efforts to the synthesis of pyrazole derivatives included
the creating of substituted 5-membered pyrazole rings and
modification of the existing pyrazole rings. The construction of
pyrazole rings included but not limited to: the cyclo-condensation
of hydrazine with 1,3-dicarbonyl compounds or surrogates; the
1,3-dipolar (3+2) cycloadditions of alkenes or alkynes with
Figure 1. Some man-made functional molecules contain pyrazole
moiety.
HO2C
H
N
N
R
N
N
H2N
diazonium or imine compounds; and the
intramolecular
R = H,
withasomnine
1- -amino- -(pyrazolyl-N)-propanoic acid
R = OH, 4-hydroxywithasomnine
R = OMe, 4-methoxywithasomnine
nitrogen (most are substituted hydrazine) addition to alkynes.
These synthesis methods inevitably afforded the isomers or
limited the diversity of substituted groups.9 The further
modification on the existing pyrazole rings were mostly achieved
by the transition-metal catalyzed C–C and C–N cross-coupling
reactions,10 and thus greatly expended the pyrazole products
versatility. For the C–C bond forming reactions, pyrazole motif
HN
N
O
O
HN N
O
H2N
OH
H2N
OH
OH
HO
N
OH
N
HO
OH
pyrazofurin
formycin

2
Figure 2. Natural products contain pyrazole motif.
Table1, entries 3-7). The yield dropped when shortened the
reaction time or decreased the temperature (28% and 30% yield,
respectively, Table1, entries 8-9). When further reduced the
catalyst loading to 10 mol%, similar yield was obtained. (Table1,
entry 10).
Another fact lies in the transition-metal catalyzed C–N
cross-coupling reactions is that the majority of these reactions
need free amines (NH) as the coupling partners, such as
ammonium, primary and secondary amines, anilines, amide,
imides, ureas, carbamates, sulfonamides, azides and
N-hetero-aromatics.13 While in the multi-step syntheses or in
complicated reaction conditions, protected procedures on free
amine motifs are widely employed during the chemistry
conversions, thus extra deprotecting step(s) must be consumed
for the coming consequence,14 which defects the synthetic
efficiency. To date, the uses of protected amines or pyrazoles as
the nitrogen resource for the C–N bond forming reactions are
rarely reported,15 only in the specific C–H activation16 and
several amidation reactions,17 while the generalizable process are
yet under investigation. Herein, we would like to report a C–N
bond forming reaction via copper-catalyzed aerobic oxidative
coupling of N-acetyl protected pyrazoles with arylboronic acids.
Considering the expense of staring materials, (for 500g scale
package from commercial resources, 3,5-dimethylpyrazole costs
$33/mol, and phenylboronic acid costs $105/mol), we choose the
phenylboronic acid as the limiting reagent. In this case, we
isolated 53% yield of desired product (Table1, entries 11-12).
When 1 atmosphere pressure O2 was employed as oxidant, we
obtained higher yield (58%, Table 1, entry 14). We further
examined the ligand effects for this C–N coupling, and found that
pyridine type ligands would hamper the conversion (Table1,
entries 15-16).
We next turned our attention to the efficiency of this
copper-catalyzed cross-coupling reactions, and examined the
substrate scope.18 Various N-acetylpyrazoles 1 reacted with
phenylboronic acid 2a smoothly and afforded the directed C–N
coupling products with reasonable to good yields (Table 2).
Though both the electron-donating and the electron-withdrawing
groups on the pyrazole rings were tolerated under this conditions,
the electron donating substitute groups (Table 2, 3b-3e) gave
much higher yield than those electron-withdrawing substituted
groups (Table 2, 3f and 3g). The bromo-containing substrates
could also afford desired product 3h in middle yield, which could
be easily converted to more complicated functional molecules.
1,3,5-triphenylpyrazole could also be prepare with this method
(Table 2, 3j).
Table 1. Cross-Coupling of N-acetylpyrazole and Phenylboronic
Acid.a
Entry
Cu(OAc)2
(x mol%)
Solvent
Modified Conditions
Yield (%)b
1
2
3
4
5
6
7
8
9
20%
----
DMF
----
----
----
----
----
----
----
15 h
15
0
DMF
Table 2. Scope of N-Acylpyrazoles. a,b
20%
20%
20%
20%
20%
20%
20%
DMA
16
Toluene
t-BuOH
EtOH
trace
24
29
MeOH
MeOH
MeOH
36
28
30
60℃
10
11
12
13
14
15
16
10%
10%
10%
10%
10%
10%
10%
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
----
34
51
53
35
58
56
39
1a:2a = 3:1
1a:2a = 4:1
1a:2a = 3:1, N2 (1 atm)
1a:2a = 3:1, O2 (1 atm)
1a:2a = 3:1, O2 (1 atm)
1a:2a = 3:1, O2 (1 atm)
aStandard reaction conditions: In a sealed tube, 1 (1.5 mmol),
phenylboronic acid 2 (0.5 mmol), Cu(OAc)2 (0.05 mmol, 10
mol%), MeOH (4 mL), 80 oC, under O2 atmosphere (balloon) for
20 hrs. bIsolated yield.
aReaction conditions: N-acetyl-3,5-dimethylpyrazole (1a, 0.5
mmol), phenylboronic acid (2a, 1 mmol), and Solvent (4 mL) at 80
oC at 1 atm air atmosphere for 20 h. Isolated yield. Pyridine (20
b
c
mol%) as additive. d2,2-Dipyridyl (20 mol%) as additive.
The activity of a variety of aryl boronic acids were also
tested under the optimized conditions. The results were
summarized in Table 3. Variety of substituted functional groups
on the phenyl ring of arylboronic acids, such as methyl, methoxy,
trifluoromethyl, fluoro, chloro, bromo and carbony groups were
compatible under this procedure. The substrates bearing
electron-donating groups (Table 3. 4a, 4b and 4c) usually gave
higher yield than those containing electron-withdrawing groups
(Table 3. 4e, 4g and 4k). The steric effect was observed on the
phenyl ring in this transformation. For example, para-methyl
Our initial studies were conducted under following conditions:
N-acetyl-3,5-dimethylpyrazole 1a (0.5mmol) and phenylboronic
acid 2a (1.0 mmol, 2 equiv) in the presence of Cu(OAc)2 (0.1
mmol, 20 mol%) in DMF (4 mL) under air (1 atm). The desired
C–N cross-coupling product 3a was obtained in 15% isolated
yield (Table1, entry 1). Control experiments showed no product
was observed in the absence of Cu(OAc)2 (Table1, entry 2).
Though this reaction could afforded the desired product in most
solvents, methanol was found the best (36% isolated yield,

3
phenylboronic acid provided much higher yield than that of
ortho-methyl substituted (64% vs 45%, Table 3, 4a and 4b). The
similar results was also seen from the methoxyl substituted
aStandard reaction conditions: N-acyl-3,5-dimethylpyrazole (1.5
mmol), phenylboronic acid (0.5 mmol), Cu(OAc)2 (0.05 mmol,
10 mol%), MeOH (4 mL), 80 oC, under O2 atmosphere for 20 hrs.
bIsolated yield.
phenylbornic acids,
para-methoxyl phenylboronic acid
provided 66% yield of 4c, while ortho-methoxyl phenylboronic
acid provided only 31% yield of 4d. It should be noted that
1-naphthylboronic acid and heteroarylboronic acids were also
compatible with this reaction conditions (4f, 4n-4o), which
provide bi-heteroaryl compounds.
In conclusion, the direct coupling of N-acetyl pyrazoles and
arylboronic acids to afford C–N bond forming products have
developed. Compare to the classic Chan-Lam reaction, this
procedure avoided the use of free pyrazoles, and use the
protected pyrazoles as strating materials directly, which could
shorten the synthetic route and enhanced the synthetic efficiency
for the multi-steps synthesis. This reaction worked in a neutral
condition and did not require bases or ligands. The process
showed good functional groups tolerance. The further work
including the mechanism studies were still under investment.
Table 3. Scope of Arylboronic Acids.a,b
Acknowledgments
This work was supported by "Thousand Talents Program"
Young Investigator Award and the Start Funding Program of
SIOC.
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(a).
mmol, 10 mol%), MeOH (4 mL), 80 C, under O2 atmosphere
(balloon) for 20 hrs. bIsolated yields.
We also examined the other widely used N-acyl protecting
groups. The results showed that n-propyl, tert-butyl and
benzoyl worked very well in this C–N coupling reactions, and
afforded as good yields as acetyl protecting group. (see Table 4).
From this aspect, our C–N bond forming conditions showed
universal tolerance.
Table 4. Scope of N-Acylpyrazoles.a
HO
OH
O
B
N
N
Cu(OAc)2 (10 mol%)
N
R1
N
Me
+
Me
MeOH
Me
Me
80°C, O2, 20h
3a
Entry
R1
Me
Et
Yield (%)b
10. For recent review, see: Bariwalab, J.; Van der Eycken, E. Chem. Soc.
Rev., 2013, 42, 9283.
1
2
3
4
53
41
45
47
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t-Bu
Ph

4
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18. Typical
procedure
for
C–N
coupling
of
3,5-dimethyl-N-acetylpyrazole (1a) and Phenylboronic Acid (2a). To
a Schlenk-type sealed-tube (with a Teflon high pressure valve and side
arm) equipped with a stir bar, was treated with 1a (207 mg, 1.5 mmol),
2a (61 mg, 0.5 mmol), Cu(OAc)2 (0.05 mmol, 10 mol%) and MeOH (4
mL). The tube was then evacuated and back-filled with O2 (3 times,
balloon). The cap was sealed.The reaction mixture was then heated in a
preheated oil-bath at 80 oC for 20 hrs. After cooled to room temperature,
the reaction mixture was quenched with 10 mL H2O and then extracted
with DCM (4 × 10 mL). The combined organic layers were washed with
water and brine, and dried over anhydrous Na2SO4. The solution was
filtered and concentrated under reduced presure. The subject crude
produt was purified on silica gel column chromatography (hexanes:ethyl
acetate = 10:1). The pure product was obtained as colorless oil. 3,
5-dimethyl-1-phenyl-1H-pyrazole (3a). 1H NMR (400 MHz, CDCl3): δ
7.46-7.41 (m, 4H), 7.36-7.31 (m, 1H), 5.99 (s, 1H), 2.30 (s, 3H), 2.29 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 148.9, 139.8, 139.3, 128.9, 127.2,
124.7, 106.8, 13.4, 12.3. IR (neat) ν 2921, 1598, 1556, 1503, 1416, 1381,
778, 754, 696, 678 cm –1; HRMS (EI): C11H12N2+, calcd. 172.1000, found
172.1001.
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Supplementary Material
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Z.-B.; Guo, C.-C.; Chen, Q.-Y. J. Org. Chem. 2009, 74, 3286.
Supplementary data associated with this article can be found,
in the online version, at
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(b) Kong, L.; Yu, S.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 588. (c)
Sharma, S.; Pathare, R. S.; Maurya, A. K.; Gopal, K.; Roy, T. K.; Sawant,
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*Highlights
 A copper-catalyzed direct C–N cross-coupling of acyl-protected
pyrazole and aryl boronic acid was developed.
 This transformation did not require the free pyrazoles as the starting
material.
 The neutral and mild conditions enabled good functional group
tolerance.
 This reaction worked in the absence of ligand and base.