Oxidative C-H/C-H Annulation of Imidazopyridines and Indazoles through Rhodium-Catalyzed Vinylene Transfer

Article abstract of DOI:10.1021/acs.orglett.0c00975

Transition-metal-catalyzed C-H activation followed by oxidative annulation with alkynes has been an efficient synthetic tool for the assembly of various polyaromatic scaffolds. Despite the substantial progress in this field, it is still a significant chal

Full text of DOI:10.1021/acs.orglett.0c00975

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Letter
Oxidative C−H/C−H Annulation of Imidazopyridines and Indazoles
through Rhodium-Catalyzed Vinylene Transfer
Koushik Ghosh, Yuji Nishii,* and Masahiro Miura*
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sı Supporting Information
ABSTRACT: Transition-metal-catalyzed C−H activation fol-
lowed by oxidative annulation with alkynes has been an efficient
synthetic tool for the assembly of various polyaromatic scaffolds.
Despite the substantial progress in this field, it is still a significant
challenge to achieve the synthesis of nonsubstituted vinylene-fused
compounds. In this contribution, we report a Rh-catalyzed C−H/
C−H vinylene cyclization adopting vinylene carbonate as a “vinylene transfer” agent. This protocol achieves the direct annulative π-
extension of imidazole- and pyrazole-fused aromatics.
used polycyclic (hetero)aromatic scaffolds are fundamen-
tal components in a wide range of biologically active
π-extension method via the C−H/C−H oxidative vinylene
cyclization. To test the feasibility, we chose imidazole- and
pyrazole-fused aromatics as representative substrates, whose
enriched nucleophilicity of the C3 positions would facilitate
F
compounds and manufactured functional molecules, so that
there has been a great demand for the development of efficient
synthetic methodologies to assemble the π-extended mole-
6
,7
the carbocyclization. Considering the potential application
of the corresponding coupling products in biologically active
1
cules. Transition-metal-catalyzed C−H activation followed by
2
8
oxidative annulation with alkynes has been a straightforward
compounds (such as rifaximin derivatives ), fluorescence
9
,10
6f
and versatile tool for the construction of polyaromatic
skeletons; however, most of these reactions are only applicable
to internal alkynes. Accordingly, this method has found limited
materials,
photoredox catalysis, etc., the development of
a new vinylene annulation protocol would attract considerable
attention. In this manuscript, we report a direct assembly of
polyaromatic scaffolds by the Rh-catalyzed annulative coupling
of imidazopyridine and indazole derivatives with vinylene
carbonate (Scheme 1b). In addition, we conducted a
preliminary study on the optoelectronic properties of the
synthesized fused-aromatics.
3
practical application as the annulative π-extension protocol
due to the lack of structural diversity as well as the requisite
stoichiometric external oxidants.
We recently established a catalytic “vinylene transfer”
strategy adopting vinylene carbonate as an oxidizing acetylene
4
,5
equivalent. This reaction system offers an easy access to
First, we conducted an optimization study adopting 2-
phenylimidazo[1,2-a]pyridine (1a) as a model substrate for the
C−H/C−H oxidative annulation with vinylene carbonate 2
various nonsubstituted N-heteroaromatics through the Rh-
III)-catalyzed C−H/N−H oxidative annulation and, notably,
does not require any external oxidants or bases since the
vinylene carbonate itself fulfills both functions (Scheme 1a).
Upon our continuous research interest in this area, we
envisioned utilizing this reaction system as an unprecedented
(
(
Table 1). Under the standard reaction conditions using a
cationic [Cp*Rh(MeCN) ][SbF ] catalyst (5.0 mol %) in
3
6 2
DCE solvent at 120 °C, the target product 3a was obtained in
9% yield (entry 1). To our delight, neither external oxidants
6
nor bases were required to ensure the catalyst turnover.
Scheme 1. Rh-Catalyzed Vinylene Transfer Protocol for the
Construction of Polycyclic Scaffolds
Addition of Cu(OAc) ·H O oxidant resulted in a complex
2
2
outcome (entry 2). The Rh catalyst was essential to the present
transformation (entry 3), and an analogous neutral complex
[
Cp*RhCl ] was totally inactive (entry 4). The product yield
2 2
was somewhat decreased at a lower reaction temperature
Received: March 16, 2020
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00975
A
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a
Table 1. Optimization Study
substituted substrates 1h and 1i resulted in the selective
formation of 3h and 3i, respectively, where C−H bonds at the
sterically more accessible sites were activated. A similar trend
was observed for the reaction of 1j, giving an acene-fused
isomer 3j as a sole product in 61% yield. A thiophene ring (1k,
1
l) could participate in this reaction system, and the C3
b
Entry
Deviation from the standard conditions
Yield
position preferentially reacted for the 3-thienyl variant 1l.
Additionally, substituents at the pyridine ring did not interfere
the productivity to give 3m−3o in more than 80% yield. The
reaction of 1m could be conducted at 1.0 mmol scale (Scheme
3). A 2-aminobenzothiazole-derived compound 1p also
underwent the annulation smoothly to produce the pentacyclic
product 3p.
1
2
3
4
5
6
7
−
69%
n.d.
n.d.
n.d.
39%
61%
with Cu(OAc) ·H O (1.0 equiv)
2
2
no Rh catalyst
[Cp*RhCl ] (2.5 mol %) as catalyst
2
2
at 100 °C
1.2 equiv of 2
6.0 mol % Rh catalyst
c
80%
a
Standard reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol),
Scheme 3. A Scale-up Reaction
b
[
Cp*Rh(MeCN) ][SbF ] (5.0 mol %), DCE (1.0 mL). Deter-
3 6 2
1
c
mined by H NMR analysis. Isolated yield at 0.3 mmol scale in 1.5
mL of DCE.
(
entry 5) or with 1.2 equiv of 2 (entry 6). After screening
several reaction parameters, an increased amount of the
catalyst (6.0 mol %) improved the productivity, furnishing 3a
in 80% isolated yield in 0.3 mmol scale (entry 7). The
structure of 3a was unambiguously determined by the single
crystal X-ray diffraction analysis. We also examined the
catalytic annulation using some substituted vinylene carbo-
nates in place of 2, but the starting materials were fully
recovered.
1
2
According to the literature, we propose a reaction
mechanism for the annulative coupling of 1a as illustrated in
Scheme 4. The nitrogen atom coordinates to a cationic
11
Scheme 4. Proposed Reaction Mechanism
Having established reliable catalytic conditions, we then
investigated the scope of imidazo[1,2-a]pyridines (Scheme 2).
Scheme 2. Substrate Scope for Imidazo[1,2-a]pyridines
Cp*Rh(III) species to form a rhodacycle complex A via the
cyclometalation at the proximal position. After the migratory
insertion of vinylene carbonate (2) into the Rh−C bond, the
intermediate B undergoes nitrogen decoordination and
1
3
“
rollover” C−H activation to generate a seven-membered
complex C, whose conformation configurationally restricts the
β-hydrogen elimination. Subsequent C−C reductive elimi-
nation and oxidative addition into the adjacent C−O bond
14
produce an intermediate D. Afterward, formal β-oxygen
elimination is affected to liberate the product 3a and the
catalytically active Cp*Rh(III) species, closing the catalytic
cycle. Alternatively, β-oxygen elimination, decarboxylation, and
protonation from the intermediate B or C might produce the
desired product via the aldehyde E. This pathway is less likely
because the reaction of 1a-Br under the conditions did not
produce the corresponding aldehyde (Scheme 5). Most of the
starting material was recovered (81% 1a-Br) along with the
annulated product 3a (16% yield) probably formed through
protodebromination (1a was detected).
A series of functional groups involving alkyl (1b), alkoxy (1c),
chloro (1d), bromo (1e), aryl (1f), and cyano (1g) were well
tolerated to afford the corresponding annulated products in
good yields. Especially, the halogen (3d, 3e) and the cyano
(3g) substituents would offer numerous possible postfunction-
alizations of the polyaromatic scaffold. The reaction of meta-
B
https://dx.doi.org/10.1021/acs.orglett.0c00975
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Scheme 5. A Control Experiment
We next examined the reaction of indazole and pyrazolo-
1,5-a]pyridine derivatives (4 and 5), isomeric analogs of 1,
[
under the standard conditions (Scheme 6). In all cases, the
Figure 1. Normalized absorption and fluorescence spectra of 3a, 6a,
−
5
and 7a in CHCl solutions (top, 1.0 × 10 M) and in the solid states
3
Scheme 6. Substrate Scope for Pyrazole-Fused Heterocycles
(bottom).
Table 2. Summary of the Florescence Properties
compd
solution λmax (λex)
solid λmax (λex)
Φsolution
Φsolid
3
6
7
a
a
a
422 nm (278 nm)
425 nm (285 nm)
441 nm (269 nm)
431 nm (365 nm)
451 nm (336 nm)
451 nm (371 nm)
0.50
0.47
0.13
0.11
0.26
0.07
16
packing modes. Weak π−π stacking (3.35−3.44 Å) and C−
H···N hydrogen bonding interactions are presumably respon-
sible for their packing structures. These characteristics unique
to the unsubstituted compounds may meet requirements in the
application to charge transporting materials. Further study on
the electrochemical properties of the coupling products is
currently underway in our group.
In conclusion, we have developed a Rh-catalyzed direct π-
extension method adopting vinylene carbonate as a vinylene
transfer reagent. Notable features of the present protocol are
that (1) the nonsubstituted vinylene-fused scaffold can be
assembled in one step via the C−H/C−H oxidative cyclization
and (2) any external oxidants as well as bases are not necessary
for the catalytic turnover. The obtained polyaromatic
compounds were considerably luminescent and exhibited
well-ordered packing structures in the solid states.
target products, indazolo[2,3-a]quinolines 6 and benzo[g]-
pyrido[1,2-b]indazoles 7, were obtained in moderate to high
yields. The structures of 6a and 7a were confirmed by the X-
11
ray crystallographic analysis. These polyaromatic compounds
have been synthesized by the [3 + 2] cycloaddition of
10b,15
pyridinium imides with arynes;
however, 7a was only
obtained as an inseparable mixture of isomers. The developed
catalytic system would selectively assemble the fused aromatic
scaffolds and, moreover, offer an easy access to various
functionalized compounds from readily available starting
materials. While the vinylene annulation for 1-phenyl-1H-
imidazole, 1-phenyl-1H-pyrazole, 3-phenyl-1H-pyrazole, and 2-
phenylpyridine derivatives was examined, the desired cyclized
products were not obtained.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00975.
Detailed experimental procedures, characterization data
for all compounds, crystal structure images, copy of
NMR spectra, and Cartesian coordinates of the
calculated structures (PDF)
With a series of nonsubstituted polyaromatic compounds in
hand, we systematically evaluated their optical characteristics.
The UV−vis absorption and fluorescence spectra of 3a, 6a, and
Accession Codes
CCDC 1990592−1990594 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
7
a were measured as diluted CHCl solutions and in the solid
3
states (Figure 1, Table 2). The spectral shapes of 3a and 6a
were similar to each other with substantial internal quantum
efficiencies (Φ = 0.50 for 3a, 0.47 for 6a) in CHCl . These
3
characteristics are similar to those of internal-alkyne-derived
6
c,h,i
tetracyclic compounds.
=
In contrast, 7a was less emissive (Φ
0.13) and exhibited a relatively large Stokes shift. The
AUTHOR INFORMATION
Corresponding Authors
HOMO levels of these compounds were estimated by a
■
computational method to be around −5.2 eV. The HOMO/
LUMO energy gaps (E ) calculated from the UV−vis spectra
Yuji Nishii − Frontier Research Base for Global Young
Researchers, Graduate School of Engineering, Osaka University,
Suita, Osaka 565-0871, Japan; orcid.org/0000-0002-
6824-0639; Email: y_nishii@chem.eng.osaka-u.ac.jp
g
fall within the range 3.08−3.23, which are relatively small for
tetracyclic molecules. All these compounds have planar
structures and crystallize into well-ordered herringbone-type
C
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Letter
Masahiro Miura − Department of Applied Chemistry, Graduate
2012007086A1, 2012. (c) Jung, S.-J.; Kim, K.-Y.; Hong, J.-M.; Eum,
S.-J.; Lee, J.-D.; Jung, J.-H.; Kim, M.-J.; No, Y.-S.; Chung, S.-S. WO
School of Engineering, Osaka University, Suita, Osaka 565-
2
(
015034140A1, 2015.
10) For recent examples on the helicene derivatives, see: (a) Otani,
0
871, Japan; orcid.org/0000-0001-8288-6439;
Email: miura@chem.eng.osaka-u.ac.jp
T.; Tsuyuki, A.; Iwachi, T.; Someya, S.; Tateno, K.; Kawai, H.; Saito,
T.; Kanyiva, K. S.; Shibata, T. Angew. Chem., Int. Ed. 2017, 56, 3906.
Author
(
b) Yen-Pon, E.; Champagne, P. A.; Plougastel, L.; Gabillet, S.;
Koushik Ghosh − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
Thuery, P.; Johnson, M.; Muller, G.; Pieters, G.; Taran, F.; Houk, K.
N.; Audisio, D. J. Am. Chem. Soc. 2019, 141, 1435.
́
0
871, Japan
(11) The CCDC numbers are 1990592 (3a), 1990593 (6a), and
1
(
2
(
990594 (7a).
12) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
011, 133, 6449.
13) For early examples, see: (a) Zucca, A.; Doppiu, A.; Cinellu, M.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00975
Notes
A.; Stoccoro, S.; Minghetti, G.; Manassero, M. Organometallics 2002,
21, 783. (b) Minghetti, G.; Stoccoro, S.; Cinellu, M. A.; Soro, B.;
Zucca, A. Organometallics 2003, 22, 4770. (c) Minghetti, G.;
Stoccoro, S.; Cinellu, M. A.; Petretto, G. L.; Zucca, A. Organometallics
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant No. JP
9K15586 (Grant-in-Aid for Young Scientists) to Y.N. and JP
7H06092 (Grant-in-Aid for Specially Promoted Research) to
■
1
1
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008, 27, 3415. (d) Butschke, B.; Schlangen, M.; Schroder, D.;
̈
Schwarz, H. Chem. - Eur. J. 2008, 14, 11050. (e) Katagiri, T.; Mukai,
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G. J. Organomet. Chem. 2010, 695, 256. (h) Butschke, B.; Schwarz, H.
Chem. Sci. 2012, 3, 308. (i) Kwak, J.; Ohk, Y.; Jung, Y.; Chang, S. J.
Am. Chem. Soc. 2012, 134, 17778.
M.M.
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