Rhodium(III)-catalyzed vinylic C-H activation: A direct route toward pyridinium salts

Article abstract of DOI:10.1021/acs.orglett.5b00028

A synthetic method for highly substituted pyridinium salts from the multicomponent reaction of vinyl ketones/aldehydes, amines, and alkynes using a rhodium catalyst is demonstrated. The catalytic reaction proceeds via an in situ generated imine-assisted Rh^III-catalyzed vinylic C-H activation.

Full text of DOI:10.1021/acs.orglett.5b00028

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Vinylic C−H Activation: A Direct Route
toward Pyridinium Salts
Ching-Zong Luo, Jayachandran Jayakumar, Parthasarathy Gandeepan, Yun-Ching Wu,
and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
*
S Supporting Information
ABSTRACT: A synthetic method for highly substituted pyridinium salts
from the multicomponent reaction of vinyl ketones/aldehydes, amines, and
alkynes using a rhodium catalyst is demonstrated. The catalytic reaction
III
proceeds via an in situ generated imine-assisted Rh -catalyzed vinylic C−
H activation.
yridinium cation is an important structural motif found in
1
P
many natural and bioactive compounds. They were
employed as intermediates in natural and heterocyclic
2
,3
compounds synthesis. In addition, pyridinium salts have
4
a
4b,c
been used as dyes, ionic liquids, nonlinear optical (NLO)
4
d
4e
4f
materials, phase transfer catalysts, acylating agents, and
surfactants. SN2 type reaction of pyridines with alkyl halides is
most commonly used to synthesize quaternary pyridinium
4
g
5
salts. However, this known method cannot be applied to the
synthesis of N-arylpyridinium salts. It is worth to mention that,
there is no direct route for the synthesis of highly substituted
pyridinium salts.
In recent years, transition metal catalyzed C−H activation
and annulation reactions were emerged as an important
strategy in the synthesis of heterocyclic and carbocyclic
Figure 1. Effect of solvent on the pyridinium salt formation.
6
7
compounds. In this context, our group and others have
developed the vinylic C−H activation of α,β-unsaturated
8
this reaction (Scheme 1). BF − and SbF − anions gave product
oxime/imine with alkyne to form pyridines. Recently, rhodium
4
6
and ruthenium catalyzed C−H activation reactions were9
4a in 98 and 95% yields, respectively, higher than the other
successfully applied to the synthesis of isoquinolinium,
10
11
12
,
a b
pyridoisoquinolinium, quinolizinium, and cinnolinium
Scheme 1. Effect of Anion Source
9
−12
salts. We have been fascinated by organic salt compounds
and wish to establish a straightforward synthetic route to
quaternary pyridinium salts. Herein, we report a convenient
synthesis of pyridinium salts from vinyl ketones/aldehydes,
amines, and alkynes by rhodium(III)-catalyzed vinylic C−H
activation and annulation.
Treatment of benzylideneacetone (1a), methylamine (2a),
and diphenylacetylene (3a) in the presence of 1.0 mol % of
[
RhCl Cp*] , 2.0 equiv of Cu(OAc) ·H O, and 1.10 equiv of
2 2 2 2
a
NaBF in MeOH at 80 °C for 24 h gave N-methylpyridinium
4
All reactions were carried out using vinyl ketone 1a (0.34 mmol),
methylamine 2a (0.28 mmol), diphenylacetylene 3a (0.34 mmol),
salt 4a in 96% isolated yield. The present C−H activation
reaction strongly relies on the choice of solvent, oxidant, and
additives. Among the various solvents tested, most alcohol
solvents afford product 4a in good yield, while other solvents
are less effective (Figure 1).
[Cp*RhCl
] (1.0 mol %), Cu(OAc) ·H O (0.56 mmol), anion source
2 2 2 2
b
(
0.31 mmol), and MeOH (2.0 mL) at 80 °C for 24 h. Yields were
1
determined by the H NMR integration method using mesitylene as
the internal standard; amine was used as a limiting reagent.
We have examined the effect of diverse oxidants for this
reaction and none of them were suitable other than Cu(OAc)2.
The choice of the anion source also affects the product yield of
Received: January 5, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
anions. Because of the higher solubility of the product
containing BF4− anion, we choose this anion for all other
investigations. Other inorganic halide salts, such as NaI, NaBr,
NaCl, and NaF, as an anion source are less effective to afford
pyridinium salts.
Scheme 3. Scope of Amines in the Pyridinium Salts
a b
,
Formation
Having the optimized reaction conditions in hand, we next
investigated the scope of alkynes in the reaction with 1a and 2a
(Scheme 2). Various symmetrical diaryl- and dialkyl alkynes
Scheme 2. Scope of Alkynes in the Pyridinium Salts
,
a b
Synthesis
a
All reactions were carried out using vinyl ketone 1a (0.34 mmol),
amine 2 (0.28 mmol), diphenylacetylene 3a (0.34 mmol),
[
(
Cp*RhCl2]2 (1.0 mol %), Cu(OAc) ·H O (0.56 mmol), NaBF
2 2 4
b
0.31 mmol), and MeOH (2.0 mL) at 80 °C for 24 h. Isolated
yields calculated based on amines.
Scheme 4. Scope of Vinyl Ketones in the Pyridinium Salts
,
a b
Synthesis
a
All reactions were carried out using vinyl ketone 1a (0.34 mmol),
methylamine 2a (0.28 mmol), alkyne 3 (0.34 mmol), [Cp*RhCl2]2
(
1.0 mol %), Cu(OAc) ·H O (0.56 mmol), NaBF (0.31 mmol), and
2 2 4
b c
MeOH (2.0 mL) at 80 °C for 24 h. Isolated yields. Ratios of
regioisomers are given in parentheses and were determined by H
1
NMR analysis; the major isomers were shown.
reacted smoothly under the standard reaction conditions to
give corresponding pyridinium salts in good to excellent yields
(
Scheme 2, 4a−j). Unsymmetrical alkynes are also compatible
but give two regioisomeric products with moderate regiose-
lectivity. Thus, 1-phenyl-1-propyne and 1-phenyl-1-butyne gave
regioisomeric pyridinium salts 4k + 4k′ (62:38) and 4l + 4l′
(71:29) in 91% and 88% yields, respectively. Interestingly,
a
under similar reaction conditions, 3-(p-tolyl)prop-2-yn-1-ol
afforded single regioisomeric product 4m in 89% yield. While
the exact reason for the unique regioselectivity is not known,
the directing effect of the hydroxymethyl group attached to the
alkyne is likely involved in this alkyne insertion process.
We then examined the scope of amines in this catalytic
reaction, and the results are presented in Scheme 3. A variety of
alkyl amines including butylamine, 2-phenylethanamine, and 3-
aminopropan-1-ol underwent reaction with 1a and 3a to
furnish the desired pyridinium salts in excellent yields (Scheme
All reactions were carried out using vinyl ketone 1 (0.34 mmol),
methylamine 2a (0.28 mmol), diphenylacetylene 3a (0.34 mmol),
[Cp*RhCl ] (1.0 mol %), Cu(OAc) ·H O (0.56 mmol), NaBF (0.31
2
2
2
2
4
b
mmol), and MeOH (2.0 mL) at 80 °C for 24 h. Isolated yields
calculated based on amines.
the β-carbon of the vinyl group. In addition to the substituted
vinyl ketones, several heterocyclic methyl ketones were also
examined. Thus, 2-acetylfuran and 2-acetylthiophene reacted
with 2a and 3a to afford the expected pyridinium salts 4af and
4ag in good yields. Similarly, 2-acetylbenzofuran and 3-
acetylindole reacted smoothly to give the desired products
4ah and 4ai in 94% and 45% yields, respectively.
The present pyridinium salt synthesis can be further applied
to α,β-unsaturated aldehydes, but the reaction conditions are
modified. After detailed optimization studies, we found the
optimized reaction conditions consisting of amines 2 (0.30
mmol), alkynes 3 (0.30 mmol), unsaturated aldehydes 5 (0.360
mmol), [Cp*Rh(CH CN) ](SbF ) (2%, 0.0060 mmol),
3
). Further, substituted aryl amines were also studied under the
standard reaction conditions and most of them gave smoothly
the desired pyridinium salts in excellent yields (products 4q−
4
w) except o-toluidine. The large steric effect of o-toluidine
appears to inhibit substantially the formation of product 4w.
To understand the scope of vinyl ketones in the present
catalytic reaction, various substituted methyl vinyl ketones were
treated with 2a and 3a under the standard reaction conditions
to give the corresponding pyridinium salts 4aa−4ae in
moderate to excellent yields as shown in Scheme 4. It is
noteworthy that lower product yields were observed, if the
substituted methyl vinyl ketone does not have a substituent at
3
3
6 2
Cu(OAc) (0.30 mmol), and Cu(BF ) ·6H O (0.30 mmol)
in MeOH (3 mL) at 80 °C with a reaction time of 16 h. The
catalytic reactions gave the desired pyridinium salts in 76−88%
2
4 2
2
B
DOI: 10.1021/acs.orglett.5b00028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
isolated yields. By using these conditions, we examined α,β-
unsaturated aldehyde 5 with different amines and alkynes, and
their results are shown in Scheme 5. Both diaryl and dialkyl
Scheme 5. Synthesis of Pyridinium Salts from Unsaturated
,
ab
Aldehydes, Amines, and Alkynes
Scheme 7. Proposed Reaction Mechanism
a
Reaction conditions: amines 2 (0.30 mmol), alkynes 3 (0.30 mmol),
unsaturated aldehydes 5 (0.360 mmol), [Cp*Rh(CH CN) ](SbF )
3
3
6 2
(
0.0060 mmol), Cu(OAc) (0.30 mmol), and Cu(BF ) ·6H O (0.30
2 4 2 2
b
mmol) in MeOH (3 mL) at 80 °C for 16 h. Isolated yields based on
amines. Ratios of regioisomers are given in parentheses and were
determined by H NMR analysis; the major isomers are shown.
reaction is initiated by the coordination of α,β-unsaturated
c
III
imine I in situ formed from 1a and 2a to Rh -complex
1
followed by vinylic C−H cleavage to give a five-membered
rhodacycle II. Coordination of alkyne 3a to intermediate II and
consecutive regioselective insertion into carbon−rhodium bond
afford a seven-membered rhodacycle IV. Facile C−N bond
forming reductive elimination of intermediate IV affords
symmetrical alkynes react efficiently to afford the correspond-
ing pyridinium salts 6a−6e in good yields. Unsymmetrical
alkynes also underwent the [4 +2] cyclization to form
pyridinium salts in high yield with good regioselectivity
I
pyridinium salt 4a and Rh . The latter is oxidized by
III
(
Scheme 5, products 6f−6i).
Cu(OAc) ·H O salt to generate the active Rh -catalyst for
2
2
The N-methylpyridinium salts synthesized using the present
the next catalytic cycle.
method can be easily transformed into highly substituted
neutral pyridines by the treatment of the salts with pyridine at
In conclusion, we have developed an efficient method for the
synthesis of highly substituted pyridinium salts from vinyl
ketones/aldehydes, amines, and alkynes. The catalytic reaction
is proceeding through a Rh(III)-catalyzed alkenyl C−H bond
activation and annulations. Synthesis of highly substituted
pyridines from pyridinium salts also was demonstrated.
12
1
40 °C (Scheme 6). Similarly, condensation of α-methylpyr-
idinium salt (4a) with benzaldehyde in the presence of a base
afforded 2-styrylpyridinium salt 8a in 72% isolated yield (eq
1
3
1).
On the basis of the above results and the known literatures, a
plausible catalytic cycle for the rhodium(III) catalyzed
pyridinium salt synthesis is outlined in Scheme 7. The catalytic
ASSOCIATED CONTENT
Supporting Information
■
*
S
General experimental procedures, characterization details, and
H and C NMR spectra of new compounds. This material is
,
a b
Scheme 6. Synthesis of Pyridines from Pyridinium Salts
1
13
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: chcheng@mx.nthu.edu.tw. Web: http://mx.nthu.edu.
tw/~chcheng/.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China (MOST-103-2633-M-007-001) for support
of this research.
a
Reaction conditions: pyridinium salt 4 (0.240 mmol) and pyridine
b
(
2.4 mL). Isolated yields.
C
DOI: 10.1021/acs.orglett.5b00028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Org. Lett. XXXX, XXX, XXX−XXX