Synthesis of 3-Arylpyridines via Palladium/Copper-Catalyzed Annulation of Allylamine/1,3-Propanediamine and Aldehydes

Article abstract of DOI:10.1002/adsc.201500685

A novel and efficient method for the synthesis of 3-arylpyridines from allylamine/propanediamine and aldehydes by palladium/copper-catalyzed oxidative tandem cyclization has been developed. With this reaction, a series of desired 3-arylpyridines was synthesized in moderate yields via C-C/C-N bond formation and 6-endo/exo-trig cyclization.

Full text of DOI:10.1002/adsc.201500685

UPDATES
DOI: 10.1002/adsc.201500685
Synthesis of 3-Arylpyridines via Palladium/Copper-Catalyzed
Annulation of Allylamine/1,3-Propanediamine and Aldehydes
Xiaodong Yang,a Shenghua Yang,a Likui Xiang,a Xiaobo Pang,a Baohua Chen,a
Guosheng Huang,a and Rulong Yana,*
a
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, Department of Chemistry, Lanzhou University, Lanzhou, Gansu 730000, Peopleꢀs Republic
of China
Fax: (+86)-0931-891-2596; e-mail: yanrl@lzu.edu.cn
Received: July 17, 2015; Revised: August 27, 2015; Published online: October 27, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500685.
Abstract: A novel and efficient method for the syn-
thesis of 3-arylpyridines from allylamine/propanedi-
amine and aldehydes by palladium/copper-catalyzed
oxidative tandem cyclization has been developed.
With this reaction, a series of desired 3-arylpyri-
prompted to consider a simple and facile Heck-type
cyclization method for the synthesis of 3-arylpyridines
from readily available substrates.
As an ideal oxidant, O2 has emerged for the synthe-
sis of heterocycles in a step- and atom-economical
fashion due to its abundance and environmental
friendly nature in organic chemistry.[7] Moreover,
simple amines and aldehydes have received great at-
tention for the synthesis of heterocyclic compounds.[8]
À
dines was synthesized in moderate yields via C C/
À
C N bond formation and 6-endo/exo-trig cycliza-
tion.
Keywords: allylamine/propanediamine; 3-arylpyri-
dines; copper; palladium
As one of the most important heterocyclic com-
pounds, substituted pyridine and its derivatives are
present in various natural products and pharmaceuti-
cals.[1] Besides the medicinal interests, these com-
pounds have been widely used in the synthesis of
functional materials.[2] A number of approaches to
synthesize aryl-substituted pyridines has been devel-
oped. Among them, the synthesis 3-arylpyridines has
relied on the use of cross-coupling reactions, such as
the Suzuki–Miyaura reaction, the Stille reaction and
the Negishi reaction.[3] These reactions, however, have
drawbacks in substrate synthesis and usually have to
be operated under harsh conditions. Compared to the
progress on the synthesis of 3-arylpyridines by cross-
coupling reactions, the use of cyclization methods is
more challenging and less well studied.[4] The Heck-
type cyclization (Scheme 1), which was reported by
Narasaka, Faulkner, Guan et al., has emerged as an
efficient approach to the synthesis of heterocyclic
compounds in the past years.[5] Recently, the Glorius
group reported an elegant Heck-type cyclization to
synthesize polysubstituted pyrroles from imines.[6] In
Scheme 1. Methods for the synthesis of aryl-substituted pyri-
view of the importance of arylpyridines, we are dines.
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Synthesis of 3-Arylpyridines via Palladium/Copper-Catalyzed Annulation
In the past years, our group has developed several 10). Among the solvents examined, the highest yield
methods for the synthesis of substituted pyridines, was obtained in DMSO at 1008C (Table 1, entries 11–
quinolones and pyrroles from amines and aldehydes.[9] 15). In this transformation, the use of NaOAc slightly
Herein, we wish to report a synthetic route to 3-aryl- improved the yield of the desired product (Table 1,
pyridines by the annulation of allylamine/propanedi- entry 15). The reaction did not work in the absence of
amine with aldehydes via 6-endo/exo-trig cyclization.
catalyst or O2 (Table 1, entries 16 and 17). After
The initial study began with the treatment of 2-phe- screening other parameters, such as the Pd salts, the
nylacetaldehyde (1a) and allylamine (2a) with reaction temperature and the equivalents of sub-
Pd(OAc)2 in DMSO at 1008C. The desired product, strates, the optimized reaction conditions were estab-
3-phenylpyridine (3aa), was isolated in 33% yield lished as shown in Table 1 entry 15.
after 6 h. In order to improve the yield of 3aa, we
With the optimized conditions in hand, the reaction
studied the effect of various phosphorus ligands and scope of aldehydes was examined and the results are
the PCy3 proved to be an efficient ligand for this reac- illustrated in Table 2. It was gratifying to find that
tion (Table 1, entry 6). Then various oxidants were a variety of substituted aldehydes reacted with allyl-
also evaluated for this process and O2 showed the amine to give the desired products in moderate yields.
highest activity for this reaction (Table 1, entries 6– As shown in Table 2, substituted aldehydes with both
Table 2. The reaction of substituted aldehydes and allyl-
Table 1. Optimization of the reaction conditions.[a]
amine.
Entry Catalyst
(0.1 equiv.)
Oxidant Ligand
(mol%)
Solvent Yield
[%][b]
1[c]
2[c]
3[c]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
O2
O2
O2
DMSO 33
PPh3 (10) DMSO 52
Xantphos DMSO 43
(10)
4[c]
Pd(OAc)2
O2
BINAP
(10)
DMSO 41
5[c]
6[c]
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
O2
O2
TBHP
TBP
PCy3 (10) DMSO 67
PCy3 (20) DMSO 71
PCy3 (10) DMSO 12
PCy3 (10) DMSO 18
TEMPO PCy3 (10) DMSO 16
10
air
O2
O2
O2
O2
O2
O2
N2
PCy3 (20) DMSO 40
PCy3 (20) NMP 37
PCy3 (20) MeCN 25
PCy3 (20) toluene 22
11[c]
12[c]
13[c]
14[c]
PCy3 (20) DMF
48
15[d] Pd(OAc)2
PCy3 (20) DMSO 73
16
17
–
PCy3(20) DMSO
PCy3(20) DMSO
–
–
Pd(OAc)2
[a]
Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), sol-
vent (2 mL), 1008C.
Yields of isolated products.
[b]
[c]
[d]
The reaction was carried out under O2 (balloon).
The reaction was carried out with NaOAc (1.0 equiv.).
The entry in bold highlights the optimized reaction con-
ditions, and the reaction time was monitored by TLC.
Xantphos=9,9-dimethyl-4,5-bis(diphenylphosphino)xan-
thene, BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaph-
thalene, PCy3 =tricyclohexylphosphine, TBHP=tert-
butyl hydroperoxide (5.0–6.0M in decane), TBP=di-tert-
butyl peroxide. TEMPO=2,2,6,6-tetramethyl-1-piperidi-
nyloxy, DMF=N,N-dimethylformamide, DMSO=di-
methyl sulfoxide, NMP=N-methylpyrrolidone.
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Xiaodong Yang et al.
Table 3. The reaction between substituted aldehydes and
1,3-propanediamine.
electron-withdrawing and electron-donating groups,
such as alkyl, methoxy, and fluoro groups, were toler-
ated in this procedure. Obviously, the nature of the
substituents on the aldehydes had no significant effect
on the yields of the desired products. The reaction of
the aldehyde with but-3-en-2-amine 2b also proceed-
ed smoothly and gave the product 3ab in 70% yield.
Unfortunately, when aliphatic aldehydes and allyl-
amine were subjected to the standard conditions, no
desired product was detected.
In order to enlarge the scope of this transformation
and test the 6-endo-trig cyclization, the more interest-
ing substrate 1,3-propanediamine, was employed for
this reaction. Fortunately, the desired product, 3-phe-
nylpyridine, was isolated in 22% yield when the reac-
tion was performed in the presence of Cu(OAc)2 and
O2 in PhCl. Inspired by this result, we extensively
screened the catalysts, solvents, ligands, oxidants and
other factors under oxygen atmosphere. The results
are summarized in Table S1 in the Supporting Infor-
mation. The highest yield of 5a was achieved when
the reaction was carried out with 1a and
4
(2.5 equiv.), Cu(OAc)2 (10 mol%) as the catalyst and
AcOH (0.6 equiv.) in PhCl at 1108C under O2 (Sup-
porting Information, Table S1, entry 2). Under these
optimized reaction conditions, we explored the sub-
strate scope of this reaction, and the results are illus-
trated in Table 3. Generally, the reactions of substitut-
ed aldehydes and 1,3-propanediamine proceeded
smoothly and afforded the corresponding substituted
pyridines in moderate yields (Table 3). Similar to the
reaction with allylamine, the substituents of the alde-
hyde did not significantly affect the yields of the prod-
ucts. Particularly, phenylpropyl aldehyde 4l could
react with 1,3-propanediamine to give 5l in 42%
yield.
On the basis of the results described above, a plausi- of desired 3-arylpyridines was efficiently synthesized
ble mechanism is proposed in Scheme 2. The transfor- in moderate yields. The procedure, using oxygen as
mation of substrates 1a and 2a/4 occurs in different oxidant, provides a simple and practical approach to
À
À
pathways. In the reaction of 1a and 2a, firstly, the sub- synthesis 3-arylpyridines via C C/C N bond forma-
strate 1a reacts with 2a to produce the imine A. The tion and 6-endo/exo-trig cyclization.
palladium complex B is generated from A which is ac-
tivated by Pd(OAc)2. Then, intermediate C, formed
via the intramolecular nucleophilic addition of B, gen-
erates D through the b-H elimination Finally, the de-
sired product 3aa is afforded by an oxidation reaction.
Experimental Section
Similar to the transformation of 1a and 2a, substrate
1a reacts with 4 to produce imine I firstly. The impor-
General Procedure for Synthesis of Substituted 3-
Arylpyridines from Allylamine and Aldehydes
tant diimine II, formed from I via oxidation, gener-
The 2-phenylacetaldehyde (1a, 0.5 mmol), allylamine (2a,
ates the intermediate III through hydrolysis. Subse-
1.25 mmol), Pd(OAc)2 (0.05 mmol), PCy3 (0.1 mmol) and
NaOAc (0.5 mmol) were mixed in DMSO (2 mL) and this
mixture was heated under O2 (balloon) at 1008C for 5 h.
The reaction mixture was cooled to room temperature and
quenched with water. Then it was extracted with ethyl ace-
tate (15 mL”3). The combined organic phase was dried
over anhydrous Na2SO4. The solvent was evaporated under
quently, intermediate IV is afforded by intramolecular
nucleophilic attack of III. Finally, the desired product
5a is synthesized by oxidation.
In summary, we have successfully developed a palla-
dium/copper-catalyzed oxidative cyclization method
for the synthesis of 3-arylpyridines by the reaction of
allylamine/propanediamine with aldehydes. A series vacuum and the crude product was purified by column chro-
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Synthesis of 3-Arylpyridines via Palladium/Copper-Catalyzed Annulation
Scheme 2. Proposed mechanism.
matography, eluting with petroleum ether/EtOAc (10:1) to References
afford the desired pyridine (3aa).
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Acknowledgements
This work was supported by National Natural Science Foun-
dation of China (21202067) and the Fundamental Research
Funds for the Central Universities (lzujbky-2014-71).
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