Metal-free synthesis of substituted pyridines from aldehydes and NH4OAc under air

Article abstract of DOI:10.1039/c4ra10880a

A metal-free and efficient method for the synthesis of substituted pyridines with aldehydes and NH₄OAc under mild conditions using air as the oxidant was developed. This oxidative cyclization process involves direct C-H bond functionalization, C-C/C-N bond formation and C-C bond cleavage.

Full text of DOI:10.1039/c4ra10880a

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Metal-free synthesis of substituted pyridines from
aldehydes and NH4OAc under air†
Cite this: RSC Adv., 2014, 4, 50369
Rulong Yan, Xiaoqiang Zhou,a Ming Li,b Xiaoni Li,a Xing Kang,a Xingxing Liu,a
a
*
a
a
*
Xing Huo and Guosheng Huang
Received 12th June 2014
Accepted 30th September 2014
DOI: 10.1039/c4ra10880a
www.rsc.org/advances
A metal-free and efficient method for the synthesis of substituted generation heteroaromatic compounds.6 In view of green and
pyridines with aldehydes and NH4OAc under mild conditions using air sustainable chemistry, development of economical and envi-
as the oxidant was developed. This oxidative cyclization process ronmentally benign strategies for the construction of useful
involves direct C–H bond functionalization, C–C/C–N bond forma- heterocyclic skeletons with simple and readily accessible
tion and C–C bond cleavage.
substrates is an attractive goal in contemporary organic
synthesis. Particularly, air has emerged as an ideal oxidant for
the synthesis of heterocyclic compounds in a step and atom-
economical fashion for its abundance, environment-friendly
and numerous advantages in industry.7 During our investiga-
tion the synthesis of heterocyclic compounds using dioxygen as
the oxidant,8 we discovered a rather surprising formation of
substituted pyridines from 2-phenylacetaldehydes and ammo-
nium acetate under air.
In our initial experiments, 2-phenylacetaldehyde (1a) and
NH4OAc (2) were chosen as the model substrates for the reac-
tion, as shown in Table 1. Treating the substrate 1a and 2 in
DMSO at 120 ꢀC, to our delight, an interesting product 3,5-
diphenylpyridine (3a) was obtained in 72% yield, and we
conrmed the structure of 3a unambiguously through an X-ray
crystal analysis. Among the N-source we examined, NH4OAc was
found the best substrate for the reaction (Table 1, entries 1–6).
Further studies showed that NaHCO3 was the most efficient
additive for the reaction when DMSO was used as solvent,
affording the desired product in 76% yield (Table 1, entries
7–10). Aer screening on different parameters, the highest yield
Substituted pyridines as one of the most prevalent heterocyclic
compounds are important building blocks for many natural
products, bioactive molecules, and functional materials,1 For
example, many herbicides and fungicides as well as thousands
of drugs contain the skeleton of pyridines.2 Thus, they have
drawn considerable interest for synthetic chemists. Accord-
ingly, numerous of well-documented traditional and modern
methods have been developed for the construction of pyridines
and their derivatives, among which the tradition metal cata-
lyzed cycloaddition reactions represent as typical method for
pyridines synthesis.3 Especially, the group of Eliel had reported
the synthesis of substituted pyridines from aldehyde and
ammonia gas via abnormal Chichibabin reaction.4 Very
recently, Yoshikai group has developed syntheses of pyridines
from oximes and enals (Scheme 1).5 However, most of those
methods suffer from several disadvantages such as use of highly
toxic metal compounds, instability of the substrates, poor yields
and harsh reaction conditions. Therefore, the development of
an alternative metal-free approach for the synthesis of pyridines
under air remains highly desirable.
Recently, the C–H activation and C–C/C–N bond formation
have presented an attractive and powerful strategies for
aState Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou, P. R. China. E-mail: yanrl@lzu.edu.cn;
hgs@lzu.edu.cn; Fax: +86 931 8912596; Tel: +86 931 8912586
bJinchuan Group Co., Ltd., Jinchuan, P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic, analytical and X-ray data. CCDC 958750. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra10880a
Scheme 1 Aldehydes and anilines in the synthesis of pyridines.
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Table 1 Optimization of reaction conditiona
Table 2 Synthesis of pyridines by aldehydes and NH4OAca
Entry
N source
Additive
Solvent
Temp
Yieldb
1
2
3
4
5
6
7
8
NH4OAc
NH4HCO3
NH4Cl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PhMe
EtOH
1,4-Dioxane
1,4-Dioxane
H2O
120
120
120
120
120
120
120
120
120
120
120
100
70
72
68
42
75
66
0
72
76
69
44
75
58
67
80
63
21
NH3$H2O
(NH4)2C2O4
NH2OH$HCl
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
K2CO3
NaHCO3
NaOAc
9
10
11
12
13
14
15c
16
HOAc
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
90
90
90
a
Reaction conditions: 1a (0.3 mmol), 2 (0.9 mmol), additive (0.3 mmol),
b
c
solvent (1 mL), 5 h. Yields of isolated products. The reaction was
carried out under O2 (1 atm).
of 3a was achieved, when the reaction was carried out at 90 ꢀC in
1,4-dioxane (Table 1, entry 14).
a
All the reaction were carried out in the presence of 1 (0.3 mmol), 2 (0.9
mmol) and NaHCO3 (0.3 mmol) in 1 mL 1,4-dioxane at 90 ꢀC for 5 h.
With the optimized reaction conditions in hand, we explored
the substrate scope of this reaction, and the results are illus-
trated in Table 2. Generally, the reaction of substituted alde-
hydes and NH4OAc proceeded smoothly and afforded the
corresponding substituted pyridines with high efficiency
(Table 2). It is observed that the nature of the substituent on the
aromatic rings did not signicantly affect the efficiency on the
yields of the products. The ortho-, meta-, and para-substituted
alkyl groups, as well as the electron-donating and electron-
withdrawing groups were well tolerated, such as methyl,
methoxyl, uoro groups (3a–3n). The 3,5-di(naphthalen-1-yl)
pyridine 3m was obtained in 61% yield when 2-(naphthalen-2-
yl)acetaldehyde 1m was employed as the substrate. Moreover,
when 2-(furan-2-yl) acetaldehyde was subjected to the trans-
formation, the desired product also was obtained in 48%
yield (3o).
Scheme 2 Diversity of polysubstituted pyridines synthesis.
Moreover, different aldehydes also can work together under optimized conditions and give the desired products in
the optimized conditions, and the scope was further expanded moderate yields (4a–4g). However, the reaction did not work
(Scheme 2). The reaction of 1b with 1g afforded 3p in 34% yield, when the butyraldehyde were employed as the reaction
and 1b with 1i afforded 3q in 36% yield, respectively. Mean- substrates (4k).
while, the 3b, 3g and 3i were also detected in this
To probe the mechanism further, some experiments were
transformation.
investigated. Firstly, annulation of 1a and 2 were carried out
Further experiments were conducted for the reaction of under standard conditions, benzaldehyde was detected by GC-
substituted 3-phenylpropanal and NH4OAc under optimized MS in the reaction system. The radical trapping experiment was
conditions. As shown in Table 3, the nature of substituted also performed in the presence of 2,2,6,6-teramethylpiperidine
groups on 3-phenylpropanals can not signicantly affect this oxide (TEMPO). Indeed, the addition of 2.0 equiv. of TEMPO
transformation. The substrates with electron-donating and that led to the oxidative process was remarkly suppressed and
electron-drawing group all can proceed well under the no desired product and useful intermediate was isolated
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Table 3 Synthesis of 2,3,5-trisubstituted pyridines by substituted 3-
phenylpropanal and NH4OAc
Scheme 4 Proposed mechanism of the synthesis pyridines.
(Scheme 3, step 1). Fortunately, When 2.0 equiv. of TEMPO was
employed in this transformation via standard condition under
argon, an unexpected compound 2-benzyl-3,5-diphenylpyridine
(3aa) was detected (Scheme 3, step 2). The structure of product
3aa and 4 mean that the carbon atom of C-2 position in pyridine
ring comes from the carbonyl of aldehydes in this trans-
formation. Moreover, the product of 3aa indicates that 12 would
be the intermediate of the transformation.
On the basis of the results described above, a plausible
mechanism with two paths is proposed in Scheme 4. First, the
acetaldehyde 1 condenses with 2 to form imine 5, which would
proceed aldol condensation with 1 to afford 7. The intermediate
7 equilibrates to generate enamine 8 easily.9 Then, intermediate
12 is formed via intramolecular nucleophile addition from
imine 9, which is generated by the reaction of enamine 8 and 1
(Path A). Alternatively, the imine 5 also can equilibrate to
generate the enamine 6. Sequently, the intermediate 10 is
formed by the reaction of enamine 6 and 1. Intermolecular
nucleophile addition of 10 and 1 gives rise to 11 (Path B). Then,
12 is generated by the intramolecular nucleophile. Further-
more, when substituted 3-phenylpropanals were served as
substrates, the hydroperoxide 12 was converted to product 4 via
the hydride elimination directly. When substituted acetalde-
hyde were served as substrates, the hydroperoxide 13 is
provided by the combination of the intermediate 12 and O2.
Moreover, the radical 14 and hydroxide radical (cOH) are
generated by decomposition of the hydroperoxide 13. The single
electron transfer of 14 forms the radical 15 and aldehyde with
C–C cleavage. Finally, the pyridine 3 is afforded by the radical
hydride elimination of 15.
In conclusion, we have developed a simple and efficient
method for the synthesis of substituted pyridines. This method
constructs the skeleton of pyridine with aldehydes and NH4OAc
by direct C–H functionalization, C–C/C–N bond formation and
C–C bond cleavage under mild reaction conditions. The
procedure, using air as oxidative agent, is a very practical,
Scheme 3 Control experiments.
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50372 | RSC Adv., 2014, 4, 50369–50372
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