Regiodivergent Cross-Dehydrogenative Coupling of Pyridines and Benzoxazoles: Discovery of Organic Halides as Regio-Switching Oxidants

Article abstract of DOI:10.1021/acs.orglett.6b00932

Cross-dehydrogenative coupling (CDC) of two unfunctionalized heteroarenes has been recognized as an ideal transformation to synthesize privileged heterobiaryl scaffolds. However, regioselective activation and transformation of a specific set of two heterocyclic C-H bonds among other bonds have been extremely challenging. Thus, discovering a new controlling element to achieve regio-controlled and regio-divergent heterocyclic CDCs is considered crucial. In this Letter, the unprecedented use of organic halides as an oxidant to achieve the CDC reaction of pyridines and benzoxazoles with palladium catalyst is described. Moreover, the regioselectivity of the pyridine functionalization site can be controlled by the choice of organic halides.

Full text of DOI:10.1021/acs.orglett.6b00932

Letter
pubs.acs.org/OrgLett
Regiodivergent Cross-Dehydrogenative Coupling of Pyridines and
Benzoxazoles: Discovery of Organic Halides as Regio-Switching
Oxidants
†
†
,†,‡
Shuya Yamada, Kei Murakami, and Kenichiro Itami*
†Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya
64-8602, Japan
4
‡
JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan
S Supporting Information
*
ABSTRACT: Cross-dehydrogenative coupling (CDC) of two
unfunctionalized heteroarenes has been recognized as an ideal
transformation to synthesize privileged heterobiaryl scaffolds.
However, regioselective activation and transformation of a
specific set of two heterocyclic C−H bonds among other bonds
have been extremely challenging. Thus, discovering a new
controlling element to achieve regio-controlled and regio-
divergent heterocyclic CDCs is considered crucial. In this Letter, the unprecedented use of organic halides as an oxidant to
achieve the CDC reaction of pyridines and benzoxazoles with palladium catalyst is described. Moreover, the regioselectivity of
the pyridine functionalization site can be controlled by the choice of organic halides.
he development of efficient methods to construct a bond
between two heteroarenes has been a topic of high scientific
T
significance in chemical synthesis due to the extensive utility of
the resulting heterobiaryl derivatives in pharmaceuticals, agro-
chemicals, and optoelectronic materials. As a result of
comprehensive investigations in the past two decades, the direct
C−H arylation of heteroarenes with arylating reagents such as
aryl halides and arylboron compounds has become a new
standard for heterobiaryl synthesis with high practicality and
1
,2
predictability. On the continuum of C−H functionalization
logic in streamlined chemical synthesis, the cross-dehydrogen-
3
ative coupling (CDC) of two unfunctionalized heteroarenes is
one of the most ideal methods for heterobiaryl synthesis, where
prefunctionalization steps to prepare arylating reagents are
unnecessary (Figure 1a). However, such heterocyclic CDC lags
far behind other coupling techniques, because the regioselective
activation and transformation of a specific set of two heterocyclic
C−H bonds among other C−H bonds are extremely difficult to
achieve. Thus, the development of a regio-controlled and regio-
divergent heterocyclic CDC reaction by establishing a new
controlling element is considered to be crucial to expand this
field. In order to achieve the regiodivergent CDC of simple
Figure 1. (a) Heterocyclic CDC reactions. (b) Regiodivergent pyridine
CDC by organohalide oxidants.
of the pyridine arylation site can be switched by the choice of
organohalide oxidant (C3-position with aryl bromide and C2-
position with benzyl bromide).
4
pyridine substrates, which are the most important yet the most
After extensive screening of the reaction conditions along this
line, we found that the use of bulky aryl bromides facilitates the
palladium-catalyzed CDC reaction of pyridine and benzoxazole
difficult class of heterocycles due to its relatively lower
5
−7
reactivity,
we envisioned that organohalides may act as a
potential “functional” CDC oxidant. Although organohalides are
10,11
8
,9
at the C3-position.
For example, treatment of benzoxazole
rather underexplored as oxidants in coupling reactions, their
organic moieties could be tuned to enhance pyridine’s reactivity
and regioselectivity for CDC reactions. We herein introduce
organic halides as a new class of “functional” oxidant that enables
CDC between pyridines and benzoxazoles with a palladium
catalyst (Figure 1b). Moreover, we found that the regioselectivity
(
0.25 mmol) with pyridine (1.5 mL) in the presence of palladium
acetate (10 mol %), 2-bromo-1,3,5-triisopropylbenzene (TIPBr:
Received: April 1, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. (a) C3-selective pyridine CDC reaction with benzoxazole. (b)
a
1
Effect of parameters. Determined by H NMR analysis.
2
1
2
.0 equiv), and cesium pivalate (CsOPiv: 3.0 equiv) at 170 °C for
7 h afforded the target CDC product 1a in 59% yield (Figure
a). The reaction took place preferentially at the C3-position of
the pyridine core (C2/C3/C4 = 17:74:9). In this reaction, TIPBr
functioned as an oxidant and did not act as a coupling component
neither with pyridine nor with benzoxazole.
a
Figure 3. C3-selective CDC of pyridines with benzoxazoles. Isolated
b
12
yield of the mixture of regioisomers. The ratio of regioisomers was
1
c
determined by H NMR analysis. 5,5′-Dimethyl-2,2′-bipyridine was
Based on this discovery, we further examined the effect of
parameters, such as the oxidant and the ligand in this pyridine
CDC reaction system. Shown in Figure 2b are the results of
screening based on the early standard conditions found in Figure
added as a ligand.
methyl, phenyl, or tert-butyl groups with good C3-selectivity.
When chloro-substituted benzoxazole was employed as a
coupling partner, the chloro-moiety remained intact. The
reactions of substituted pyridines also showed C3-selectivity
regardless of steric or electronic factors. 4-Methyl- or 3-
methylpyridine afforded 1f and 1g in good yield with moderate
selectivity. For the coupling reaction generating 1f, the addition
of 5,5′-dimethyl-2,2′-bipyridine as a ligand was important to
achieve good regioselectivity. The C2/C3 ratio was almost 1:1
without the addition of the ligand. 3-Trifluoromethylpyridine
underwent CDC reactions with benzoxazoles at the C5-position
of the pyridine core to produce 1h and 1i. Sterically bulky 2,6-
dimethylpyridine generated 1j as the sole product, and no C4-
2a. As for the CDC oxidant, aryl bromides generally worked well.
Interestingly, both the yield of 1a and the C3-regioselectivity
increase as the steric bulk of the aryl bromides increase.
Employment of mesityl bromide (MesBr) resulted in the highest
yield of 68% with a C3-selectivity of 72% (1a). The much bulkier
2
-bromo-1,3,5-tri-(tert-butyl)benzene was not suitable for this
reaction, as the intramolecular C−H activation preferentially
proceeded to generate the corresponding benzocyclobutane as a
major byproduct. Other frequently used CDC oxidants such as
O , AgOAc, CuCl , 2,3-dichloro-5,6-dicyanobenzoquinone
2
2
(
DDQ), and N-fluorodibenzenesulfonimide (NFSI) were
ineffective for the present pyridine CDC reaction. It was also
found that the addition of representative ligands only had
detrimental effects (Figure 2b). Addition of 2,2′-bipyridine (bpy)
or 1,10-phenanthlorine (phen) diminished the reaction. Employ-
ment of a N-heterocyclic carbene precursor (IPr·HCl: IPr = 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene) or a bulky phos-
phine SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxy-
biphenyl) suppressed the reaction, and 2,4,6-triisopropylphenyl-
benz[d]oxazole was obtained as a side product from the reaction
between TIPBr and benzoxazole.
13
arylated product was observed.
During our study on the screening of oxidants, we
unexpectedly discovered that benzyl bromide worked as a C2-
14,15
selective oxidant (Scheme 1).
Treatment of benzoxazole
(0.25 mmol) with palladium acetate (10 mol %) and CsOPiv (3.0
equiv) in pyridine (1.5 mL) at 170 °C for 17 h afforded C2-
arylated pyridine 2a in 45% yield with very high regioselectivity
16
(C2/C3/C4 = 98:1:1). Although the reason for the regio-
switching was unclear at this stage, we performed several control
experiments to confirm whether the labile benzyl bromide
remained intact under the basic reaction conditions and worked
as the oxidant (Scheme 2). Benzyl bromide may react with
pyridine or cesium pivalate to form the pyridinium salt or benzyl
pivalate, respectively in situ, which may act as a substrate or an
oxidant. In order to test this possibility, we conducted the CDC
reaction in the presence of benzylpyridinium bromide or benzyl
Under the established conditions [Pd(OAc) , MesBr or
2
TIPBr, CsOPiv, 170 °C, 17 h], the CDC reaction took place
with a range of pyridines and benzoxazoles (Figure 3). The best
oxidant was dependent on the substrate, with TIPBr providing
better results than MesBr in terms of the yield with almost the
same regioselectivity except for 1b. A variety of substituents on
benzoxazole were compatible to the reaction conditions such as
B
DOI: 10.1021/acs.orglett.6b00932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Discovery of Benzyl Bromide as a C2-Selective
(Regio-switching) Oxidant
Scheme 2. Addition of Possible in Situ Forming Oxidant
a
Figure 4. C2-selective CDC of pyridines with benzoxazoles. The
b
reaction with 0.75 mL of 4-trifluoromethylpyridine. The reaction was
performed at 150 °C.
type reaction, which occurs at the most hindered position (i.e., 2-
position of 3-methylpyridine).
pivalate. No coupling product was observed when pyridinium
bromide was used. Although benzyl pivalate worked as an
oxidant, the yield was not as good as the reaction with benzyl
bromide. It is noteworthy that the reaction did not proceed in the
absence of an oxidant.
In summary, we have uncovered an unprecedented utility of an
organic halide as an oxidant for Pd-catalyzed CDC reactions.
This new class of oxidant enables the otherwise difficult CDC of
pyridines and provides a new convergent synthetic strategy, as
20
Pd-catalyzed heterocyclic CDC reactions have been known,
but the previous examples were mainly focused on inorganic
well as divergent access to various heterobiaryl structures.
Moreover, the regioselectivity of the pyridine functionalization
site can be controlled by the choice of organic halides. The CDC
reactions of pyridines with benzoxazoles took place at the C3-
position of pyridine cores with aryl bromides, while the use of
benzyl bromide completely switched the regiochemical outcome
to the C2-selective CDC pathway. Although the detailed
mechanism is still unclear at the moment, the successful
regiodivergent CDC reactions bode well for the potential of
organohalide control in many molecular transformations.
17,18
oxidants with five-membered heteroarenes.
As for the
regiodivergent CDC where the regioselectivity can be switched
17a
17b
by the reaction conditions, DeBoef and Fagnou have found
that the choice of metal-based oxidants in the CDC of indoles
with arenes can switch the reaction site of the indole core (C3-
position with copper acetate and C2-position with silver acetate).
These pioneering works and our present findings clearly show
that the CDC oxidant can be a regio-controlling factor whereas
19
the mechanism of regiodivergency is yet to be identified.
Further optimization of the C2-selective reaction was then
performed (see the Supporting Information for details). After a
screening of ligands, IMes (1,3-bis(2,4,6-trimethylphenyl)-
imidazol-2-ylidene), an N-heterocyclic carbene ligand, was
found to be the best ligand that afforded 54% of 2a with
exclusive formation of the C2-product (>99% C2-regioselectiv-
ity). Further screening of the catalyst precursor identified
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00932.
Detailed experimental procedures and spectral data for all
compounds, including scanned image of H, C NMR
spectra (PDF)
1
13
Pd(OPiv) as the best palladium source to provide 2a in 74%
2
yield. The high C2-selectivity was observed for the CDC of
pyridines with various benzoxazoles (Figure 4). Benzoxazoles
having the phenyl, tert-butyl, or methoxy group were applicable
to the C2-selective pyridine CDC producing 2b−2d in moderate
to good yields. Unfortunately, the reaction with electron-
deficient benzoxazoles such as 5-trifluoromethylbenz[d]oxazole
only led to trace amounts of the desired product. While the yields
were not high, substituted pyridines were applicable to our
reaction conditions and afforded C2-arylated products. The
reaction of 4-trifluoromethylpyridine generated 2e in 22% yield.
When 3-methylpyridine was used as a substrate, the reactions
took place at the 6-position to produce 2f or 2g in moderate
yields. The regioselectivity was different from the Chichibabin-
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: itami@chem.nagoya-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the ERATO program from JST
(K.I.) and a Grant-in-Aid from JSPS (15K17821 to K.M.). We
thank Dr. Ayako Miyazaki (ITbM, Nagoya University) for critical
comments and Dr. Keiko Kuwata (ITbM, Nagoya University)
C
DOI: 10.1021/acs.orglett.6b00932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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