Copper-catalyzed aerobic synthesis of 2-arylpyridines from acetophenones and 1,3-diaminopropane

Article abstract of DOI:10.1021/ol5023596

A copper-catalyzed reaction providing direct access to 2-arylpyridines from acetophenones and 1,3-diaminopropane is described. A range of electronically diverse acetophenones undergo this transformation, affording 2-arylpyridines in good yields. (Chemical Equation Presented).

Full text of DOI:10.1021/ol5023596

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Aerobic Synthesis of 2‑Arylpyridines from
Acetophenones and 1,3-Diaminopropane
Long-Yi Xi, Ruo-Yi Zhang, Shuai Liang, Shan-Yong Chen,* and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu,
Sichuan 610064, P. R. China
S
* Supporting Information
ABSTRACT: A copper-catalyzed reaction providing direct access to 2-
arylpyridines from acetophenones and 1,3-diaminopropane is described. A
range of electronically diverse acetophenones undergo this transformation,
affording 2-arylpyridines in good yields.
a
Table 1. Optimization of the Reaction Conditions
he pyridine-containing motif is present in many natural
products, pharmaceutical agents, and functionalized
T
materials.1 Consequently, the development of methods for
the synthesis of pyridine derivatives is important in medicinal
chemistry and represents a worthwhile goal for organic
synthesis. Traditional synthetic methods are based upon
condensation reactions of carbonyl compounds. Recently,
many new methods, including transition-metal-catalyzed
cross-coupling, ring-closing metathesis, cycloadditions, radical
reactions and microwave-assisted procedures, have also been
developed.2 In light of the importance of the pyridine moiety,
developing an operationally simple approach for the prepara-
tion of pyridine derivatives from readily available starting
materials remains in demand. Methyl ketones and their
corresponding imines are attractive starting materials for the
synthesis of azaheterocycles, not only because they are readily
available and widely used chemical precursors but also because
their C−H bonds can be directly functionalized to generate
new C−C and C−N bonds in a step- and atom-economical
fashion.3
b
entry
catalyst (equiv)
solvent
acid
none
yield (%)
1
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
Cu(OTf)2 (0.6)
CuI (0.6)
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
DCE
22
2
MSA
43
3
acetic acid
TfOH
48
4
44
5
benzoic acid
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
51
6
60
7
trace
13
8
NMP
9
CH3CN
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
hexanol
37
10
11
12
13
14
15
16
8
Cu(OAc)2 (0.6)
Cu(NO3)2 (0.6)
Cu(OTf)2 (0.1)
Cu(OTf)2 (0.02)
Cu(OTf)2 (0.1)
Cu(OTf)2 (0.1)
trace
trace
60
Transition-metal-catalyzed oxidative cleavage of C(sp3)−N
bonds is of significant synthetic interest because such bonds are
common in organic chemistry and are usually unreactive. Using
amines as the carbon source for the generation of C−C bonds
via the cleavage of C−N bonds has attracted considerable
attention.4 Primary alkyl amines represent the most simple and
common amines. The cleavage of the C−N bond of a primary
amine for the construction of azaheterocycles or drugs is
especially desirable. Herein, for the first time, we report the
copper-catalyzed C−N bond cleavage of a simple primary
amine for the generation of 2-arylpyridines. The present
protocol features advantages that include easily available
starting materials, favorable atom economy, and the use of an
environmentally friendly oxidant.5
Initially, we heated acetophenone 1a, 1,3-diaminopropane
2a, and Cu(OTf)2 in ethanol at 80 °C for 72 h under an oxygen
atmosphere (Table 1, entry 1). Fortunately, 2-phenylpyridine
was isolated in 22% yield. Because we thought that an imine
intermediate would be initially generated, we reasoned that an
acid might promote this transformation. We therefore tested
several acids as additives. All of the tested acids improved the
20
c
61
cde
, ,
64
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), solvent (0.5
mL), acid (0.8 equiv), O2 (balloon), 72 h. Isolated yields. 0.6 equiv
b
c
d
e
of acid. Temperature of 110 °C. 24 h.
yield of the product. p-Toluenesulfonic acid was the most
effective additive for this reaction (Table 1, entry 6 vs entries
2−5). After screening other solvents and copper catalysts, we
found that the use of other solvents and metal catalysts was
ineffective (Table 1, entries 7−12 vs entry 6). The amounts of
catalyst and additive were also optimized. The addition of 10
mol % of Cu(OTf)2 and 0.6 equiv of p-toluenesulfonic acid was
most effective (Table 1, entries 13−15). Nitrogen-containing
ligands and other oxidants were also tested. Unfortunately,
none of them was effective.6 When hexanol was used as the
Received: August 9, 2014
Published: October 6, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
solvent, the reaction temperature could be increased to 110 °C,
and the transformation was complete in 24 h, affording the
product in 64% yield (Table 1, entry 16).
(3w−3z, 3aa, and 3ab). In addition, this reaction was easily
scaled up to the gram scale (Scheme 2).
Having optimized the reaction conditions, we examined the
scope of the reaction.7 Acetophenones with an electron-
donating or weak electron-withdrawing group on the para-
position of the benzene ring afforded the desired products in
good yields (Scheme 1, 3a−3j). Strong electron-withdrawing
Scheme 2. Gram Scale Reaction
Scheme 1. Scope of Ketones
To elucidate the reaction mechanism, several control
experiments were prepared (Scheme 3).
Scheme 3. Control Experiments
The reaction of N-methylpropanediamine with acetophe-
none under standard conditions afforded 2-phenylpyridine in
38% yield (Scheme 3, eq a). Tetramethylpropanediamine did
not undergo this transformation. These results show that the
formation of an imine intermediate is necessary for this
transformation. Glorius et al.8 reported that 2-phenylpyridine
was generated as a side product, through 6-endo cyclization, in a
Pd-catalyzed cyclization of imine A (eq c, right). However, only
a trace amount of product 3a was observed when allylamine
was used in this reaction instead of propanediamine. Therefore,
it seems impossible that this reaction proceeds through an
allylamine intermediate. On the basis of these results and
literature reports, a plausible mechanistic proposal is outlined in
Scheme 4. The transformation begins with the condensation of
Scheme 4. Proposed Mechanism
groups showed an obvious negative effect on the yield (3k).
The reaction tolerates a range of functionalities, including
fluoro, chloro, bromo, trifluoromethyl, nitro, ether, and free
phenol moieties. It should be noted that a phenol group often
needs to be protected in an oxidative reaction. The product
yield is also affected by the position of substituents on the aryl
ring. Acetophenones bearing a meta or ortho substituent
afforded the pyridines in lower yields than those with a para
substituent (3l vs 3i, 3m vs 3g, 3n vs 3b). 1-(Naphthalen-2-yl)
ethanone also underwent this transformation, affording
naphthylpyridine 3o in 66% yield. Disubstituted acetophenones
were then examined. Most gave the desired products in
moderate yields (3p−3u). Interestingly, this reaction also
occurred with aryl ketones with long-chain alkyl group and
cyclic aliphatic ketones to afford 2,3-disubstituted pyridines
the acetophenone with propanediamine. The resulting imine 4
is oxidized to diimine 5 by the Cu/O2 system. Intermediate 5
undergoes hydrolysis, condensation, elimination, and oxidation
to afford the product 3a.
In summary, we report a novel method for the synthesis of 2-
arylpyridines from methyl ketones and 1,3-propanediamine
through copper-catalyzed oxidative cyclization in an O2
atmosphere. The reaction features cleavage of the C−N bond
and formation of the C−C bond in one pot. Considering the
readily available starting materials, the lack of an expensive
metal catalyst, and the operationally straightforward proce-
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Organic Letters
Letter
Lett. 2011, 13, 522. (h) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H.
Org. Lett. 2011, 13, 522. (i) Patil, R. D.; Adimurthy, S. Adv. Synth.
Catal. 2011, 353, 1695. (j) Gao, L.; Tang, H.; Wang, Z. Chem.
Commun. 2014, 50, 4085. (k) Ling, Z.; Yun, L.; Liu, L.; Wu, B.; Fu, X.
Chem. Commun. 2013, 49, 4214.
dures, the method is a valuable synthesis of the pyridine
skeleton.
ASSOCIATED CONTENT
* Supporting Information
■
S
(5) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3381.
General experimental procedures and spectroscopic data (1H
NMR and 13C NMR) for the corresponding products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(6) See the Supporting Information for additional data.
(7) Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), hexanol (0.5
mL), TsOH·H2O (0.6 equiv), O2 (balloon), 110 °C, 24 h.
(8) Shi, Z.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed. 2013, 125,
4992.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chensy@scu.edu.cn.
*E-mail: xqyu@scu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Program
on Key Basic Research Project of China (973 Program,
2013CB328900) and the National Science Foundation of
China (Grant Nos. 21202107 and 21321061).
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