Copper- or Nickel-Enabled Oxidative Cross-Coupling of Unreactive C(sp3)-H Bonds with Azole C(sp2)-H Bonds: Rapid Access to β-Azolyl Propanoic Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b02265

β-Azolyl propanoic acid derivatives are frequently found in biologically active molecules and pharmaceuticals. Here, we report the oxidative heteroarylation of unactivated C(sp³)-H bonds with azole C(sp²)-H bonds via copper or nickel catalysis with the aid of removable bidentate auxiliary, which provides a rapid pathway to β-azolyl propanoic acid derivatives. A variety of azoles such as oxazole, benzoxazole, thiazole, benzothiazoles, benzimidazole, purine, and even [1,2,4]triazolo[1,5-a]pyrimidine could be engaged in this protocol.

Full text of DOI:10.1021/acs.orglett.7b02265

Letter
pubs.acs.org/OrgLett
Copper- or Nickel-Enabled Oxidative Cross-Coupling of Unreactive
3
2
C(sp )−H Bonds with Azole C(sp )−H Bonds: Rapid Access to β‑Azolyl
Propanoic Acid Derivatives
Guangying Tan, Luoqiang Zhang, Xingrong Liao, Yang Shi, Yimin Wu, Yudong Yang,
†
†
and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University,
2
9 Wangjiang Road, Chengdu 610064, China
*
S Supporting Information
ABSTRACT: β-Azolyl propanoic acid derivatives are fre-
quently found in biologically active molecules and pharma-
ceuticals. Here, we report the oxidative heteroarylation of
3
2
unactivated C(sp )−H bonds with azole C(sp )−H bonds via
copper or nickel catalysis with the aid of removable bidentate
auxiliary, which provides a rapid pathway to β-azolyl propanoic acid derivatives. A variety of azoles such as oxazole, benzoxazole,
thiazole, benzothiazoles, benzimidazole, purine, and even [1,2,4]triazolo[1,5-a]pyrimidine could be engaged in this protocol.
3
−7
β-Azolyl propanoic acid derivatives are frequently found in
biologically active molecules and pharmaceuticals (Scheme 1).
well-demonstrated. However, the oxidative heteroarylation of
1
,2
3
unreactive C(sp )−H bonds remains under-represented because
3
of the high bond strengths of inert C(sp )−H bonds and low
8
Scheme 1. Pharmaceutical and Biologically Active Molecules
Containing β-Azolyl Propanoic Acid Derivatives
reactivity of metal−C(alkyl) species. In 2015, Ge reported
8-aminoquinoline-assisted copper-promoted oxidative hetero-
3
arylation of unactivated C(sp )−H bonds with acidic poly-
fluoroarenes. Very recently, Yin realized the nickel-catalyzed
oxidative cross-coupling of unactivated C(sp )−H bonds with
electron-rich heteroarenes such as thiophen and furan.
9
3
1
0
Recently, the Muria group and our group have individually
demonstrated the copper-, cobalt-, or nickel-promoted/catalyzed
2
heteroarylation of C(sp )−H bonds of (hetero)arene acid deriv-
2
atives with azole C(sp )−H bonds with the help of 8-amino-
5c,6,7
quinoline auxiliary as a bidentate directing group (Scheme 2a).
We envisaged that the bidentate-assisted strategy could enable the
first row transition-metal-catalyzed oxidative cross-coupling of
3
2
unactivated C(sp )−H bonds with azole C(sp )−H bonds. Herein,
we reported the copper- or nickel-promoted/catalyzed oxidative
3
cross-coupling of unreactive C(sp )−H bonds with azole
2
C(sp )−H bonds, offering a rapid gateway to β-azolyl propanoic
acid derivatives (Scheme 2b).
Our investigation commenced with the reaction between
2
-pivalamidopyridine 1-oxide 1a and benzoxazole 2a (for
detailed optimization, see Table S1). By employing 2.0 equiv
of Cu(OAc) ·H O as the promoter and 0.5 equiv of PivOH as
the additive in o-xylene at 140 °C under a N atmosphere for
Traditional approaches to β-azolyl propanoic acid derivatives
generally require multiple-step sequences and harsh reaction
conditions. Thus, it would be highly desirable to develop an
2
2
2
2
innovative strategy for the synthesis of these structural motifs.
Given that both propanoic acid derivatives and azoles are among
the most prevalent scaffolds, we surmised that transition-metal-
catalyzed oxidative C−H/C−H cross-coupling of propanoic acid
derivatives with azoles would be a distinct, straightforward
gateway to β-azolyl propanoic acid derivatives.
2
4 h, a deoxygenated product 3a could be obtained in 36% yield
(
Table 1, entry 1). The addition of 2.0 equiv of K CO improved
2
3
the yield of 3a to 56% (Table 1, entries 2−4). Other copper salts
such as Cu(OAc) , CuCl , and Cu(OTf) were less effective for
2
2
2
the process (Table 1, entries 7−9). After the solvents were
2
In recent years, transition-metal-catalyzed oxidative C(sp )−
2
H/C(sp )−H cross-coupling reactions between a directing-
Received: July 23, 2017
group-containing (hetero)arene and a heteroarene have been
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02265
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. First Row Transition-Metal-Catalyzed C−H
progressively diminished along with the decrease of Cu(OAc)2·
2
Heteroarylation Assisted by Bidentate Auxiliary
H O, suggesting that the N−O bond might not act as a co-
(
DG: Directing Group)
oxidant. In addition, only a trace amount of deoxidized
byproduct 1aa (N-(pyridin-2-yl)pivalamide) was observed in
the absence of benzoxazole 2a, implying that the deoxygenation
of pyrinde N-oxide might mainly occur along with the formation
of 3a (for details, see Table S2, entries 1−3).
With the optimized conditions in hand, we explored the scope
of propanoic acid derivatives and azoles. As shown in Scheme 3,
Scheme 3. Scope of Copper-Promoted Heteroarylation of
3
,
a b
Unreactive C(sp )−H Bonds with Azoles
Table 1. Optimization of the Reaction Conditions ,
a b
entry
copper salt
additive
PivOH
Na CO /PivOH
solvent
3a (%)
1
Cu(OAc) ·H O
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
toluene
DCE
36
2
2
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
Cu(OAc) ·H O
41
2
2
2
3
Cu(OAc) ·H O
K CO /PivOH
56
2
2
2
3
Cu(OAc) ·H O
K HPO /PivOH
27
2
2
2
4
K CO /PivOH
nr
2
3
Cu(OAc) ·H O
K CO
2
26
2
2
3
Cu(OAc)2
K CO /PivOH
53
2
3
CuCl2
K CO /PivOH
49
2
3
Cu(OTf)2
K CO /PivOH
trace
47
2
3
0
1
2
3
4
Cu(OAc) ·H O
K CO /PivOH
2 3
2
2
Cu(OAc) ·H O
K CO /PivOH
20
2
2
2
3
Cu(OAc) ·H O
K CO /PivOH
DMSO
o-xylene
o-xylene
o-xylene
o-xylene
trace
trace
62
2
2
2
3
a
Reactions were performed with 1 (0.2 mmol) and 2 (0.4 mmol) in
Cu(OAc) ·H O
K CO /AcOH
2 3
2
2
b
c
c
1.0 mL of o-xylene at 140 °C for 24 h under N . Yields of isolated
products. 67% yield was obtained from a 1.0 mmol scale reaction.
Cu(OAc) ·H O
K CO /PivOH
2
2
2
2
3
c
,
d
5
cde
, ,
Cu(OAc) ·H O
K CO /PivOH
67
2
2
2
3
6
Cu(OAc) ·H O
K CO /PivOH
34
2
2
2
3
a
a series of 2,2-disubstituted propanamides bearing linear chains
could react with benzoxazole 2a, delivering the corresponding
deoxygenated products in moderate to good yields (Scheme 3,
3a−3h). Isobutyric acid and n-propanoic acid derivatives did not
undergo this transformation. Moreover, benzoxazoles with
methyl and tert-butyl and 5-phenyloxazole could be engaged in
this reaction (Scheme 3, 3i−3k). Phenylthiazoles and thiazoles
were also compatible with this protocol (Scheme 3, 3l−3q).
Sensitive functional groups such as fluoro, acetyl, nitro, cyano,
alkoxy, and even acetoxyl were well-tolerated under the opti-
mized conditions. Other electron-deficient heteroarenes such as
benzimidazole, purine, and [1,2,4]triazolo[1,5-a]pyrimidine
could also couple with 1a to give the desired products in
satisfactory yields (Scheme 3, 3r−3t).
Reaction conditions: 2-pivalamidopyridine 1-oxide 1a (0.2 mmol),
benzoxazole 2a (0.4 mmol), Cu(OAc) ·H O (2.0 equiv), base
2
2
(
2.0 equiv), additive (50 mol %), and solvent (1.0 mL) at 140 °C
b c
under an N atmosphere for 24 h. Yields of isolated products. 2.2
2
d
e
equiv of K CO was used. 1.5 equiv of Cu(OAc) ·H O was used. At
1
2
3
2
2
20 °C; nr: no reaction.
examined, o-xylene proved to be superior to toluene, DCE, and
DMSO (Table 1, entries 3 and 10−12). Either removal or
replacement of PivOH with AcOH led to a reduced yield
(Table 1, entries 6 and 13). Further optimization of the reaction
parameters, such as the amounts of Cu(OAc) ·H O and K CO ,
and reaction temperature, improved the yield of 3a to 67% yield
2
2
2
3
(
Table 1, entries 14−16). Notably, the diarylated product was
not detected. To clarify whether the N−O bond plays a role of
co-oxidant together with the Cu(II) oxidant, a control experi-
ment for the dosage of Cu(OAc) ·H O was performed. As
Inspired by our previous nickel-catalyzed oxidative C−H/C−H
cross-coupling between two heteroarenes with the aid of 8-amino-
7
quinoline, we investigated the reactivity of nickel in the hetero-
2
2
3
shown in Table S1 (entries 31−36), the yields of 3a were
arylation of C(sp )−H by replacing 2-aminopyridine 1-oxide with
B
DOI: 10.1021/acs.orglett.7b02265
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
-aminoquinoline as a bidentate directing group. After nickel salts,
Letter
8
Scheme 5. Removal of the Directing Groups of 3r and 5a
oxidants, ligands, additives, and solvents were screened, the best
result was observed under a catalytic system comprising Ni(OAc)2·
4
H O (20 mol %), Ag CO (2.0 equiv), 1-AdCO H (60 mol %),
2 2 3 2
and PPh (40 mol %) in chlorobenzene at 160 °C for 24 h (for
3
detailed optimization, see Table S3). Given that PPh could
3
remarkably enhance the yield of 5a (Table S3, entries 2 and 9),
7
we speculated that PPh might act as an efficient ligand. As
3
Scheme 4. Scope of Nickel-Catalyzed Heteroarylation of
3
,
a b
Unreactive C(sp )−H Bonds with Azoles
Scheme 6. Deuterium Labeling
respectively, implying that the cleavage of the C2−H bond of
2
a could be a reversible process (Scheme 6b,c).
Treatment of 1a with 1.0 equiv of Cu(OAc) in dioxane at
2
II
8
0 °C led to Cu complex 6 and its structure was established by
X-ray crystallographic analysis (Scheme 7a). The in situ formed
a
Reactions were performed with 4 (0.2 mmol) and 2 (0.4 mmol) in
b
Scheme 7. Preparation and Reactivity of Complex 6
0
.5 mL of chlorobenzene (MCB) at 160 °C for 24 h under N . Yields
2
c
of isolated products. Azole 2 (0.6 mmol) was used.
summarized in Scheme 4, various 2,2-disubstituted propanamides
bearing a linear or cyclic chain could smoothly react with benzo-
thiazole 2n, giving the β-azolyl propanamides 5 (Scheme 4,
5a−5i). Isobutyric acid and n-propanoic acid derivatives could not
be compatible with this protocol. Substrates with functional groups
such as (hetero)aryl and alkoxy on the alkane skeletons were
compatible with this reaction (Scheme 4, 5j−5m). Benzothiazole
with the electron-withdrawing (Br) or electron-donating
(
methoxy) groups underwent this coupling process in a moderate
yield (Scheme 4, 5n−5o). Note that the diarylated products were
not observed.
complex 6 could react with benzoxazole 2a, giving 3a in 42%
yield (Scheme 7b). This result suggested that a ligand exchange
of 2-pivalamidopyridine 1-oxide 1a with Cu(OAc) ·H O might
occur initially in the mechanistic pathway, forming the inter-
mediate 6.
To further highlight the synthetic utility of our strategy, the
hydrolysis of 3r and the esterlysis and hydrolysis of 5a were
performed to remove the directing group, affording 3rr, 5aa, and
2
2
11,12
5ab in 86, 83, and 92% yields, respectively (Scheme 5a,b).
To gain some insights into the reaction mechanism,
Based on the above results and previous copper-promoted
2
5
hydrogen/deuterium exchange experiments were performed
for both coupling partners. Under the standard conditions, the
reaction of 2-(2-methyl-2-phenylbutanamido)pyridine 1-oxide
C(sp )−H heteroarylation, a plausible mechanistic pathway is
proposed in Scheme 8. First, a ligand exchange of 2-pivalamidopyr-
idine 1-oxide 1a with Cu(OAc) ·H O forms the complex 6. Next,
2
2
(
1h) with 20 equiv of CD OD in the absence or presence of
the complex 6 reacts with benzoxazole 2a to produce the inter-
3
3
benzoxazole (2a) for 1 h did not lead to any deuterated [D ]-1h
mediate IM1. Then, the C−H cupration of primary C(sp )−H
n
3
III
(
Scheme 6a,c), suggesting that the primary C(sp )−H bond
bond forms the Cu complex IM3 with the help of an additional
5
c,13
cleavage could be an irreversible process. Whereas 2a reacted
Cu(OAc) (disproportionation).
Subsequently, IM3 under-
2
14
with CD OD in the absence or presence of 1h, the H/D
goes a reductive elimination to give a Cu(I)-coordinated
3
exchange ratios of 2a were approximately 60 and 62%,
intermediate IM4. Finally, the N−O bond of IM4 is fractured
C
DOI: 10.1021/acs.orglett.7b02265
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
3) For selected examples of chelation-assisted rhodium-catalyzed
Scheme 8. Plausible Mechanistic Pathway
2
heteroarylation of (hetero)arene C(sp )−H bonds, see: (a) Wencel-
Delord, J.; Nimphius, C.; Wang, H.; Glorius, F. Angew. Chem., Int. Ed.
2
012, 51, 13001. (b) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.; Lan,
J.; You, J. Angew. Chem., Int. Ed. 2013, 52, 580. (c) Huang, Y.; Wu, D.;
Huang, J.; Guo, Q.; Li, J.; You, J. Angew. Chem., Int. Ed. 2014, 53, 12158.
(
(
d) Shang, Y.; Jie, X.; Zhao, H.; Hu, P.; Su, W. Org. Lett. 2014, 16, 416.
e) Qin, X.; Li, X.; Huang, Q.; Liu, H.; Wu, D.; Guo, Q.; Lan, J.; Wang,
R.; You, J. Angew. Chem., Int. Ed. 2015, 54, 7167. (f) Qin, D.; Wang, J.;
Qin, X.; Wang, C.; Gao, G.; You, J. Chem. Commun. 2015, 51, 6190.
(
g) Deng, H.; Li, H.; Wang, L. Org. Lett. 2016, 18, 3110. (h) Hu, J.; Li,
G.; Yuan, C.; Huang, Z.-B.; Shi, D.-Q.; Zhao, Y. Org. Lett. 2016, 18, 5998.
4) For chelation-assisted palladium-catalyzed heteroarylation of
(
2
(
hetero)arene C(sp )−H bonds, see: Gao, D.-W.; Gu, Q.; You, S.-L.
J. Am. Chem. Soc. 2016, 138, 2544.
5) For chelation-assisted copper-catalyzed/mediated heteroarylation
with the aid of reductive Cu(I) along with the release of 3a and
CuO (observed in the reaction mixture and tube wall). The
formation of inert CuO also explains why a superstoichiometric
(
2
of (hetero)arene C(sp )−H bonds, see: (a) Kitahara, M.; Umeda, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2011, 133, 2160.
(b) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed.
2012, 51, 6993. (c) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2013, 52, 4457. (d) Odani, R.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2014, 53, 10784. (e) Zhao, S.; Yuan, J.;
Li, Y.-C.; Shi, B.-F. Chem. Commun. 2015, 51, 12823.
Cu(OAc) ·H O is necessary for this transformation. Notably, at
2
2
the present stage, another possible azolylcopper species
generated from a ligand exchange of benzoxazole 2a with
5c
Cu(OAc) could not be excluded.
2
In summary, we have addressed a copper- or nickel-promoted/
3
catalyzed oxidative cross-coupling of unreactive C(sp )−H
2
(6) For chelation-assisted cobalt-catalyzed heteroarylation of (hetero)
bonds with azole C(sp )−H bonds. Azoles such as oxazole,
2
arene C(sp )−H bonds, see: Tan, G.; He, S.; Huang, X.; Liao, X.; Cheng,
benzoxazole, thiazole, benzothiazoles, benzimidazole, purine,
and even [1,2,4]triazolo[1,5-a]pyrimidine can be engaged in this
protocol. We believe that this method would provide a rapid
route to β-azolyl propanoic acid derivatives in medical chemistry.
Y.; You, J. Angew. Chem., Int. Ed. 2016, 55, 10414.
(
7) For chelation-assisted nickel-catalyzed heteroarylation of (hetero)
2
arene C(sp )−H bonds, see: Cheng, Y.; Wu, Y.; Tan, G.; You, J. Angew.
Chem., Int. Ed. 2016, 55, 12275.
(
8) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011,
ASSOCIATED CONTENT
1
33, 6541.
■
*
S
Supporting Information
(
(
9) Wu, X.; Zhao, Y.; Ge, H. Chem. Sci. 2015, 6, 5978.
10) During the preparation of this paper, Yin’s group reported the
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02265.
3
nickel-catalyzed oxidative cross-coupling of unactivated C(sp )−H
bonds with electron-rich thiophen and furan with the aid of 8-
aminoquinoline auxiliary. Notably, while the thiazole was employed as
heteroarene partner, the transformation occurred at the electron-rich
C5−H bond of thiazole. See: Wang, X.; Xie, P.; Qiu, R.; Zhu, L.; Liu, T.;
Li, Y.; Iwasaki, T.; Au, C.-T.; Xu, X.; Xia, Y.; Yin, S.-F.; Kambe, N. Chem.
Commun. 2017, 53, 8316.
Experimental procedures, characterization data, copies of
1
13
H and C NMR spectra of final products (PDF)
X-ray data for 6 (CIF)
AUTHOR INFORMATION
■
(11) Li, M.; Yang, Y.; Zhou, D.; Wan, D.; You, J. Org. Lett. 2015, 17,
2546.
Corresponding Author
(
12) Wang, X.; Qiu, R.; Yan, C.; Reddy, V. P.; Zhu, L.; Xu, X.; Yin, S.-F.
Org. Lett. 2015, 17, 1970.
13) Takamatsu, K.; Hirano, K.; Miura, M. Angew. Chem., Int. Ed. 2017,
6, 5353.
14) For the rapid reductive elimination reaction of some CuIII
intermediates, see: (a) Casitas, A.; Canta, M.; Sola, M.; Costas, M.;
*E-mail: jsyou@scu.edu.cn.
ORCID
(
5
(
Jingsong You: 0000-0002-0493-2388
Author Contributions
̀
†
G.T. and L.Z. contributed equally to this work.
Ribas, X. J. Am. Chem. Soc. 2011, 133, 19386. (b) Wu, X.; Zhao, Y.;
Zhang, G.; Ge, H. Angew. Chem., Int. Ed. 2014, 53, 3706.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the financial support from the National NSF of China
No 21432005).
■
(
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DOI: 10.1021/acs.orglett.7b02265
Org. Lett. XXXX, XXX, XXX−XXX