A Method to Access Symmetrical Tetrasubstituted Pyridines via Iodine and Ammonium Persulfate Mediated [2+2+1+1]-Cycloaddition Reaction

Article abstract of DOI:10.1002/adsc.201601225

A novel metal-free [2+2+1+1]-cycloaddition method for rapid and productive preparation of symmetrical 2,3,5,6-tetrasubstituted pyridines has been developed from α-substituted arones and N,N-dimethyl formamide (DMF) using iodine (I₂) and ammonium persulfate ((NH₄)₂S₂O₈) as mediators. In this process, both DMF and (NH₄)₂S₂O₈ play a dual role for the formation of pyridines. DMF acts as the reaction medium and the C4 source (the methyl group of DMF), while (NH₄)₂S₂O₈ serves as the oxidant and nitrogen resource. Notably, this transformation exhibited a broad substrate scope towards a wide variety of different arones to give the corresponding tetrasubstituted pyridines in moderate to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201601225

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A Method to Access Symmetrical Tetrasubstituted Pyridines via
Iodine and Ammonium Persulfate Mediated
[2+2+1+1]-Cycloaddition Reaction
Weibing Liu,a,* Hua Tan,a Cui Chen,a and Yupeng Panb
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a
College of Chemical Engineering, Guangdong University of Petrochemical Technology, 2 Guandu Road, Maoming
525000, People’s Republic of China
Fax: +86-668-2923575
Tel: +86-668-2923956; e-mail: lwb409@gdupt.edu.cn
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, Peopleꢀs Re-
public of China
b
E-mail: panyp@dicp.ac.cn
Received: November 4, 2016; Revised: January 17, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601225
Recently, Yuan et al. developed a facile NH4I-
promoted method to synthesize symmetrical 2,3,5,6-
tetrasubstituted pyridines from a-substituted ketones
and NH4OAc using DMSO as the source of methylene
Abstract: A novel metal-free [2+2+1+1]-cyclo-
addition method for rapid and productive prepara-
tion of symmetrical 2,3,5,6-tetrasubstituted pyri-
dines has been developed from a-substituted
units (Scheme 1, path a).[9] This method was the first
arones and N,N-dimethyl formamide (DMF) using
report for capturing in situ-generated methylene
iodine (I2) and ammonium persulfate ((NH4)2S2O8)
intermediates from DMSO. Based on this result, Wu
as mediators. In this process, both DMF and (NH4)2
et al. reported an improved approach to access the
S2O8 play a dual role for the formation of pyridines.
symmetrical 2,3,5,6-tetrasubstituted pyridines by using
DMF acts as the reaction medium and the C4
iodine and Cu(NO3)2·3H2O as the alternative pro-
source (the methyl group of DMF), while (NH4)2S2
moters (Scheme 1, path b).[10] Similar to DMSO, DMF
O8 serves as the oxidant and nitrogen resource.
Notably, this transformation exhibited a broad
substrate scope towards a wide variety of different
arones to give the corresponding tetrasubstituted
pyridines in moderate to excellent yields.
Keywords: Symmetrical tetrasubstituted pyridines;
[2+2+1]-cycloaddition; a-substituted arones; al-
kynes; N,N-dimethyl formamide (DMF)
45 Pyridines constitute privileged structures in natural
46 products,[1] functional materials,[2] pharmaceuticals and
47 agrochemicals,[3] as well as in biological[4] and synthetic
48 chemistry.[5] Starting with the seminal synthesis by the
49 greatest chemist William Ramsay, synthetic approach
50 to this class of compounds has received widespread
51 attention for more than 130 years,[6] and a wide range
52 of synthetic methods has became available.[7] Among
53 the numerous synthetic routes to pyridines, condensa-
54 tion of amines and carbonyl compounds, and transi-
55 tion-metal-catalyzed cross cyclization reactions are
56 considered to be the main available routes.[8]
Scheme 1. Different procedures for pyridine synthesis em-
ploying DMF and DMSO as the sources of carbon.
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is also a popular, cheap and low-toxic polar solvent, absence of (NH4)2S2O8 or I2 (entries 4–5). Further-
and has been widely used in organic synthesis as a more, increasing the amount of (NH4)2S2O8 did not
reaction medium and a promising reactant for the enhance the yield of the product (entry 6), however
formation of ÀCHO,[11] ÀN(CH3)2,[12] ÀCN,[13] and decreasing it to 1.0 equivalent reduced the yield
ÀH.[14] Lately, Guan et al. and Deng et al. diclosed two considerably (entry 7). Likewise, increasing the load-
novel methods for synthesis of pyridines using DMF ing of I2 to 1.5 equivalent did not show any beneficial
as CH group (C4 or C6) source (Scheme 1, path c and effect (entry 8), and decreasing I2 to 0.5 equivalent
d).[15] To the best of our knowledge, employing DMF greatly reduced the product yield (entry 9). The
as a source of one carbon synthon to provide CH structure of compound 2 was unambiguously con-
10 group for cyclization reaction has rarely been re- firmed by 1H-NMR, 13C-NMR, HR-MS and X-ray
11 ported.[16]
crystallography (Figure 1).[17]
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Herein, we report another example using DMF as
13 C4 source to access symmetrical 2,3,5,6-tetrasubsti-
14 tuted pyridines. This approach is the first example of
15 iodine and ammonium persulfate-mediated [2+2+
16 1+1]-cycloaddition reaction for pyridines synthesis
17 from a-substituted arones involving the capture of
18 in situ generated ammonia and methylene group
19 (Scheme 1, path e).
20
Initial screening was performed to find the opti-
21 mum reaction conditions for preparation of 2a by
22 varying different parameters (Table 1). The product
23 2a was obtained with 81% yield when propiophenone
24 (1a, 0.25 mmol) was reacted with (NH4)2S2O8
25 (0.5 mmol) and DMF (2 mL) in the presence of I2
26 (0.25 mmol) at 1208C for 8 h (entry 1). After screen-
27 ing the reaction time (entried 1–3), we found that the
28 reaction was completed in 10 h and afforded the
29 desired product 2a with 86% yield (entry 2). Unfortu-
30 nately, this desired reaction did not occur in the
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Figure 1. X-Ray structure of 2,6-diphenyl-3,5-dibenzoylpyri-
dine 2l.
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Table 1. Optimization-synthesis of symmetrical 3,5-dimeth-
yl-2,6-diphenylpyridine[a].
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Based on the optimized conditions identified for
the [2+2+1+1]-cycloaddition reaction, we explored
the scope of a-substituted arones, the results are
summarized in Scheme 2. In general, a range of
electron-neutral (1a), electron-rich (1b–1d) and elec-
tron-deficient (1e–1g) propiophenones reacted with
ammonium persulfate and DMF with high yields (71-
À89%) under the stipulated conditions. However, it is
worth mentioning that propiophenones with strong
electron-donating groups (ÀOCH3) show lower reac-
tivity than those with electron-withdrawing groups
(ÀCl and ÀF). The scope of b-substituted arones, such
as 1-(4-chlorophenyl)butan-1-one (1h), 4-chloro-1-(4-
fluorophenyl)butan-1-one (1i) and 1-phenylpentan-1-
one (1j) were also investigated, The results showed
that all reactions exclusively produced the correspond-
ing 2,3,5,6-tetrasubstituted pyridines 2h–2i with ex-
cellent isolated yields. Meanwhile, we also performed
the conversion employing 1,2-diphenylethanone (1k)
and 1,3-diphenylpropane-1,3-dione (1l) as the partners
of propiophenone under the optimized conditions.
The results indicated that 1k and 1l were fully
converted, and afforded the corresponding products
with 78% and 84% isolated yield, respectively. To
Entry
I2 (equiv.)
Time(h)
Yield%[b]
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2
1.0
1.0
1.0
1.0
–
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1.0
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0.5
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[a] Unless otherwise specified, all the reactions were carried
out on 1a 0.25 mmol, DMF 2.0 mL, (NH4)2S2O8 2.0
equivalent.
[b] GC yield.
[c] Without (NH4)2S2O8
[d] (NH4)2S2O8 3.0 equivalent.
[e] (NH4)2S2O8 1.0 equivalent.
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further extend the adaptability of this transformation,
1-(4-fluorophenyl)propan-2-one and 1-(4-chlorophen-
yl)propan-2-one were employed as the partners of a-
substituted arones under the standard conditions. We
are pleased to find that these two reactions proceed
smoothly, and provide 2,6-bis(4-fluorophenyl)-3,5-di-
methylpyridine (2m) and 2,6-bis(4-chlorophenyl)-3,5-
dimethylpyridine (2n) with high regioselectivity. How-
ever, the acetophenone fails to go through this
10 conversion under the stipulated conditions, and af-
11 fords N, N-dimethyl-2-oxo-2-phenylacetamide as the
12 main product (2o).
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To gain a deeper insight into the mechanism for
14 the formation of product 2, several parallel experi-
15 ments were conducted (Scheme 3). First, to determine
16 the C4 source, a deuterium labelled experiment was
17 carried out using N,N-dimethyl-d6-formamide (DMF-
18 d6) as the solvent. It is found that this transformation
19 become slightly slower, but affords 4-deuterated
20 pyridine 2a–d1 as the only product (Scheme 2, eq1).
21 This finding evidences that the C4 carbon unit of the
22 pyridine ring derives from the methyl group rather
23 than the aldehyde group of DMF. However, this
24 conversion is completely inhibited when the radical
25 scavenger TEMPO is used (Scheme 2, eq2), which
26 suggested that a radical pathway may involve in the
27 mechanism.
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Scheme 3. Investigation of the reaction mechanism.
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Scheme 2. Synthesis of symmetrical 2,3,5,6-tetrasubstituted
pyridines (2a–2n) from a-substituted arones, (NH4)2S2O8
and DMF (All reactions were carried out on 1a–1o
1.0 mmol scale, DMF 2.0 mL).
On the basis of the aforementioned results and the
44 previous literatures, a tentative mechanism for the
45 reaction is proposed in Scheme 4 and exemplified by
46 the formation of 2a. The process is commenced with
47 the formation of two key intermediates, a-iodo ammonium persulfate and intramolecular cyclization
48 propiophenone A and iminium B.[18] A is produced forms dihydropyridine intermediate F, this process is
49 from iodination propiophenone (1a) with iodine,[19] known in the literature.[15a] Next, F undergoes the
50 and B is generated from the oxidation of persulfate to process of aromatization giving the final pyridine
51 DMF via a radical mechanism.[20] The interaction of A product 2a.[21,10, 15] Alternatively, the resulting enolate
52 and B leads to the formation of C in the presence of intermediate G generated from C undergoes a CÀN
53 persulfate, which is then attacked by the ammonium bond cleavage to afford the unsaturated ketone
54 cation to form imine intermediate D.[10] The condensa- intermediate H.[19] Subsequently, the condensation of
55 tion of D with propiophenone (1a) gives intermediate ammonium cation with H and 1a leads to intermedi-
56 E.[15a] The subsequent nucleophilic substitution of E by ate I. Finally, I experience the sequential 6p electro-
57 NH4HSO4 which is generated in-situ from the
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Scheme 4. Proposed mechanism for the cycloaddition reaction.
27 cyclization and aromatization reactions to provide the Typical procedure: 3,5-dimethyl-2,6-diphenylpyridine
28 expected pyridine 2a.
(2a)
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In summary, a convenient and efficient [2+2+1+
A mixture of ethyl propiophenone (1a) (134 mg, 1.0 mmol),
(NH4)2S2O8 (228 mg, 2.0 mmol), iodine (254 mg, 1.0 mmol)
and DMF (2.0 mL) was added successively in a round-
bottom flask, and the resulting soln. stirred for 10 h at 1208C.
The mixture was purified by column chromatography on
silica gel to afford product 2a with hexanes/ethyl acetate as
30 1]-cycloaddition method has been developed for the
31 preparation of symmetrical 2,3,5,6-tetrasubstituted
32 pyridines via iodine and ammonium persulfate medi-
33 ated cyclization of a-substituted arones with DMF. In
34 this reaction system, both DMF and (NH4)2S2O8 play
35 an important dual role, DMF is used not only as an the eluent.
36 effective reaction medium, but also as the source of
37 C4 via the methyl group, while (NH4)2S2O8 serves as
Acknowledgements
38 an oxidant and nitrogen source for the formation of
39 pyridines. This reaction complements related transi-
40 tion-metal catalyses and broadens the synthetic possi-
41 bilities of metal-free methodology to employ DMF
42 (the methyl group) as the carbon source.
43
We thank the Guangdong Provincial Department of Science
and Technology (No. 916014) and the Department of Educa-
tion of Guangdong Province (No. 916021) for financial
support.
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A Method to Access Symmetrical Tetrasubstituted
Pyridines via Iodine and Ammonium Persulfate
Mediated [2+2+1+1]-Cycloaddition Reaction
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