Cooperative C(sp3)-H and C(sp2)-H Activation of 2-Ethylpyridines by Copper and Rhodium: A Route toward Quinolizinium Salts

Article abstract of DOI:10.1021/acscatal.5b01244

A method for the synthesis of substituted quinolizinium salts from 2-ethylpyridines and alkynes is demonstrated. The transformation is conveniently achieved using 1 mol % of a Rh(III) catalyst along with an excess amount of copper(II) salt. The reaction gives high product yields with broad substrate scope and functional group tolerance. Detailed mechanistic studies suggest that 2-vinylpyridine is formed in situ from 2-ethylpyridine by a copper-promoted C(sp³)-H hydroxylation, followed by dehydration. Later, a Rh(III)-catalyzed pyridine-directed vinylic C(sp²)-H activation and annulation with alkynes provided the final product. (Chemical Equation Presented).

Full text of DOI:10.1021/acscatal.5b01244

Letter
pubs.acs.org/acscatalysis
Cooperative C(sp3)−H and C(sp2)−H Activation of 2‑Ethylpyridines by
Copper and Rhodium: A Route toward Quinolizinium Salts
Ching-Zong Luo, Parthasarathy Gandeepan, Yun-Ching Wu, Chia-Hung Tsai, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
S
* Supporting Information
ABSTRACT: A method for the synthesis of substituted quinolizinium salts
from 2-ethylpyridines and alkynes is demonstrated. The transformation is
conveniently achieved using 1 mol % of a Rh(III) catalyst along with an excess
amount of copper(II) salt. The reaction gives high product yields with broad
substrate scope and functional group tolerance. Detailed mechanistic studies
suggest that 2-vinylpyridine is formed in situ from 2-ethylpyridine by a copper-
promoted C(sp3)−H hydroxylation, followed by dehydration. Later, a Rh(III)-catalyzed pyridine-directed vinylic C(sp2)−H
activation and annulation with alkynes provided the final product.
KEYWORDS: rhodium, copper, C−H activation, dehydrogenation, quinolizinium salts, alkynes
ynthesis of heterocyclic and carbocyclic compounds via
transition-metal-catalyzed C−H activation has become an
presence of 1 mol % [RhCl2Cp*]2, Cu(OAc)2 (2.24 mmol),
acetic acid (5.60 mmol), and NaBF4 (0.28 mmol) in DMAc (3
mL) at 150 °C for 24 h to give quinolizinium salt 3a in 89%
isolated yield. The compound was thoroughly characterized by
1H, 13C, 19F and 11B NMR, HRMS, and X-ray data.11 In this
catalytic reaction, the choice of oxidant, solvent, and acid is
crucial. In the absence of rhodium(III) or copper(II), no
product 3a was observed. Moreover, a decrease in the amount
of Cu(OAc)2 lowers the product yields (See Table S3 for the
detailed optimization studies). It might be due to the reduction
of CuII to CuI by DMAc under the reaction conditions.12
Among the various copper salts tested, Cu(OAc)2·H2O,
Cu(BF4)2·6H2O, and Cu(OTf)2 afforded product 3a in 82%,
45%, and 30% yields, respectively. The catalytic reaction is less
effective with the other solvents tested. Notably, o-xylene, 2-
ethoxyethanol, dimethylformamide, and dimethyl sulfoxide
(DMSO) offered 3a in 35, 57, 44, and 27% yields, respectively.
S
important tool in organic synthesis because the reactions use
less-functionalized starting compounds, tolerate a wide range of
functional groups, and are generally more step- and atom-
economical.1 Over the past three decades, great advances have
been made in the area of C(sp2)−H functionalization and are
widely used in organic synthesis.2 In particular, Rh(III)-
catalyzed C(sp2)−H activation and annulation reactions have
become a powerful tool for the synthesis of heterocyclic
compounds.3 Similar annulation reactions via C(sp3)−H
activations are rare,4,5 but recently, the dehydrogenative
functionalization of aliphatic compounds into unsaturated or
aromatic compounds has gradually emerged as a new strategy
in organic synthesis.6 It is attractive because of the in situ
formation of unstable, unsaturated species from the stable and
readily available starting compounds.
In this report, we disclose an interesting cooperative CuII-
mediated C(sp3)−H and a RhIII-catalyzed C(sp2)−H activation
and annulation reaction for the synthesis of quinolizinium salts
from 2-ethylpyridines and alkynes (Scheme 1).7 Quinolizinium
cation is an important core found in many natural and bioactive
compounds8 and materials.9 They are also potential inter-
mediates for the synthesis of heterocyclic compounds.10 After a
great effort to optimize the catalytic reaction (see Supporting
Information), we found that diphenylacetylene (1a) (0.28
mmol) reacted with 2-ethylpyridine (2a) (0.56 mmol) in the
The reaction also proceeded well with different anion sources.
−1
Quinolizinium salt 3a containing different anions SbF6
,
OSO2CF3−1, or PF6 was isolated in 84%, 84%, and 76%
yields, respectively.11 Because of the lower cost and higher
solubility of NaBF4 relative to other anion sources, NaBF4 was
selected for all other studies. An acid additive is also crucial for
a high product yield, and AcOH appears more appropriate in
terms of the yield of 3a than the other acids tested (see
Supporting Information for the detailed optimization studies).
To understand the scope of the reaction, we examined the
reaction of various symmetrical and unsymmetrical alkynes with
2-ethylpyridine (2a) under the optimized reaction conditions.
The results are presented in Table 1. Thus, p-Me- and p-OMe-
substituted diphenyl acetylenes (1b−c) reacted smoothly with
2a to afford quinolizinium salts 3b and 3c in 83 and 81% yields,
−1
Scheme 1. Quinolizinium Salt Formation via C−H
Activation
Received: June 15, 2015
Revised: July 14, 2015
© XXXX American Chemical Society
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the respective salts 3d and 3e in good yields (entries 4 and 5).
Thiophene-substituted alkyne 1f is also compatible under the
reaction conditions to afford the expected quinolizinium salt 3f
in 69% yield. Unsymmetrical alkynes were also successfully
employed in this bimetal mediated C(sp3)−H and C(sp2)−H
activation to form the corresponding quinolizinium salts in high
regioselectivity. Thus, the reaction of 1-phenyl-1-propyne (1g)
and 1-phenyl-1-butyne (1h) with 2a effectively afforded the
expected products 3g and 3h in high yields. Unfortunately,
terminal alkynes and dialkyl alkyne failed to give the
corresponding quinolizinium salt under the standard reaction
conditions.
Table 1. Scope of Alkynes in the Formation of
Quinolizinium Salts
a
To further extend the scope of the present reaction, we
examine the reaction of diphenylacetylene with different 2-alkyl
substituted pyridines under the optimized reaction conditions
(Table 2). First, we probed the effect of substituent at carbon-1
of the ethyl group in 2a on the product yield by carrying out
the reaction of 2-(hexan-2-yl)pyridine (2b), 2-(1- phenyl-
propan-2-yl)pyridine (2c), and 2-isopropylpyridine (2d) with
1a. All three substrates gave the expected substituted
quinolizinium salts 3i−3k in moderate to good yields (entries
1−3). The reactions show excellent chemoselectivity; only the
methyl group in the alkyl substituent is involved in the C−H
bond activation to give the final products. The n-propyl group
in 2b and the phenyl group in 2c likely prevent the C−H bond
activation reaction from occurring at the attached methylene
carbon (carbon-2) as a result of the very large steric effect of
these moieties compared with a hydrogen.
Next, we investigated the effect of the substituent at carbon-2
on the ethyl group of 2. 2-(n-Pentyl)pyridine (2e) reacted
smoothly with 1a to give product 3l in 75% yield, implying that
a long alkyl chain is compatible with the present catalytic
reaction. Similarly, treatment of 2-phenethylpyridine (2f) with
1a afforded the desired C−H bond activation product 3m in
moderate yields. Furthermore, 5-methyl-substituted 2-aryle-
thylpyridines 2g and 2h also reacted with 1a efficiently to
furnish quinolizinium salts 3n and 3o, respectively, in good
yields. Interestingly, 2-ethylbenzimidazole derivative 2i also
successfully underwent dehydrogenative C−H activation to
give respective quinolizinium salt product 3p (entry 8), but
under the reaction conditions, 2-(t-butyl)-5-methylpyridine
(2j) did not offer any C−H activation product (entry 9).
To understand the nature of the present catalytic trans-
formation, we examined the reactions of diphenylacetylene
(1a) with 2-vinylpyridine (2A) and 2-styrylpyridine (2F) under
the reaction conditions similar to those shown in Tables 1 and
2. The reactions afforded products 3a and 3m in 91% and 65%
yields, respectively (Scheme 2a). In the absence of Rh catalyst,
no products were obtained for Scheme 2a. Next, we treated 2g
under the standard reaction conditions, but in the absence of
acetylene 1a. The reaction afforded dehydrogenation product
2G in 33% yield along with unreacted 2g in 50%. We then
carried out the above reaction in the absence of [RhCp*Cl2]2.
Surprisingly, the dehydrogenation product 2G was obtained in
35% yield with 38% unreacted 2g recovered. Interestingly,
treatment of 2g under the standard catalytic conditions but in
the absence of Cu(OAc)2, 99% of 2g was recovered and no
dehydrogenation product 2G was detected. Furthermore, when
2g was treated with a stoichiometric amount of [RhCp*Cl2]2 in
the absence of Cu(OAc)2, a quantitative amount of unreacted
2g was recovered (Scheme 2b). The results suggest that the
Cu(OAc)2 plays the key role in the dehydrogenation of 2-
ethylpyridine to 2-vinylpyridine.
a
All reactions were carried out using alkyne 1 (0.28 mmol), 2-
ethylpyridine 2a (0.56 mmol), [Cp*RhCl2]2 (1.0 mol %), Cu(OAc)2
(2.24 mmol), AcOH (5.60 mmol), and NaBF4 (0.28 mmol) in DMAc
(3.0 mL) at 150 °C for 24 h. Isolated yield. The ratios of
regioisomers are given in parentheses and were determined by H
b
c
1
NMR analysis; the major isomers are shown.
respectively (Table 1, entries 2 and 3). Similarly, electron-
withdrawing 4-fluorophenyl- and 4-trifluoromethylphenyl-
group-substituted alkynes 1d and 1e reacted with 2a to give
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Table 2. Scope of 2-Alkylpyridines in the Catalytic Synthesis
of Quinolizinium Salts
Scheme 2. Mechanistic Studies
a
dehydration; however, our attempt to isolate the hydroxyla-
tion/acetoxylation product from 2-ethylpyridine failed. The
reaction of 2-(pyridin-2-yl)ethanol (4) with 1a under the
standard reaction conditions for 12 h afforded product 3a in
44% and the intermediate product vinylpyridine (2A) in 40%
yields. As the reaction time increased, the yield of 3a increased
along with the decrease of 2A, and no salt product was formed
in the absence of RhIII (Scheme 2c).
We also tested several reaction conditions for the
dehydration of 2-(pyridin-2-yl)ethanol (4) and found that no
rhodium or copper is necessary for the dehydration (Scheme
2d). Interestingly, the reaction of 2-(1-hydroxyethyl)pyridine
(5) with 2a under the standard reaction conditions did not give
either 2A or 3a at the end of the reaction (Scheme 2e). An
alternative pathway for the in situ generation of vinylpyridine
from 2-ethylpyridine through Cu-mediated C(sp3)−H activa-
tion followed by β-hydride elimination cannot be ruled out.
On the basis of the results of the present catalytic reaction
and the above mechanistic studies, a possible catalytic cycle is
a
All reactions were carried out using diphenylacetylene 1a (0.28
mmol), 2-alkylpyridine 2 (0.56 mmol), [Cp*RhCl2]2 (1.0 mol %),
Cu(OAc)2 (2.24 mmol), AcOH (5.60 mmol), and NaBF4 (0.28
mmol) in DMAc (3.0 mL) at 150 °C for 24 h. Isolated yield.
b
[RhCp*Cl2]2 clearly is not involved in the dehydrogenation
reaction to form intermediate 2A from 2a. The in situ-formed
2-vinylpyridine (2A) undergoes Rh(III)-catalyzed C−H
activation and annulation with alkynes to give product 3a.
The formation of 2-vinylpyridine from 2-ethylpyridine probably
occurs through a copper-mediated hydroxylation,13 followed by
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Notes
proposed, as shown in Scheme 3. The catalytic cycle is initiated
by the dehydrogenation of 2-ethylpyridine by copper(II)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 3. Plausible Catalytic Cycle
■
We thank the Ministry of Science and Technology of the
Republic of China (MOST-103-2633-M-007-001) for support
of this research.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b01244.
■
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and 1H and 13C NMR spectra of new compounds (PDF)
Supplementary crystallographic data (C21H16BF4N)
(CIF)
Supplementary crystallographic data (C22H16F3NO3S)
(CIF)
Supplementary crystallographic data (C21H16F6NSb)
(CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: chcheng@mx.nthu.edu.tw.
■
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