2,3-Dichloro-5,6-Dicyano-1,4-Benzoquinone (DDQ)-Mediated Tandem Oxidative Coupling/Intramolecular Annulation/Dehydro-Aromatization for the Synthesis of Polysubstituted and Fused Pyridines

Article abstract of DOI:10.1002/adsc.201900956

A DDQ-mediated tandem reaction of 1,3-diarylpropenes and β-enaminoesters/4-aminocoumarins is disclosed. It involves oxidative coupling, intramolecular annulation and dehydro-aromatization reaction, which provides an efficient and mild method for the synthesis of polysubstituted and fused pyridines under metal-free conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201900956

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DOI: 10.1002/adsc.201900956
2,3-Dichloro-5,6-Dicyano-1,4-Benzoquinone (DDQ)-Mediated
Tandem Oxidative Coupling/Intramolecular Annulation/Dehydro-
Aromatization for the Synthesis of Polysubstituted and Fused
Pyridines
Dongping Cheng,a,* Zhiteng Deng,a Xianhang Yan,a Mingliang Wang,a
Xiaoliang Xu,b,* and Jizhong Yana,*
a
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
E-mail: chengdp@zjut.edu.cn; yjz@zjut.edu.cn
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
b
E-mail: xuxiaoliang@zjut.edu.cn
Manuscript received: July 31, 2019; Revised manuscript received: August 31, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900956
Abstract: A DDQ-mediated tandem reaction of 1,3-diarylpropenes and β-enaminoesters/4-aminocoumarins is
disclosed. It involves oxidative coupling, intramolecular annulation and dehydro-aromatization reaction, which
provides an efficient and mild method for the synthesis of polysubstituted and fused pyridines under metal-free
conditions.
Keywords: Annulation; DDQ; Oxidation; Pyridine; Tandem reaction
Introduction
a structure containing pyridine ring from readily
available reactants under mild reaction conditions.
Push-pull enamine is a class of versatile synthetic
Pyridine is the simplest and most fundamental N-
heterocycle which widely exists as moiety in natural building blocks and has been widely applied in the
products, pharmaceuticals, and functional materials.[1] synthesis of N-heterocycles such as pyridines, pyra-
It could be used as ancillary ligand and organo-catalyst zoles, and chromones.[12] Recently, by utilizing push-
in homogeneous reactions.[2] As a consequence, con- pull enamines as the substrates, our group has
siderable efforts have been devoted to developing developed some new methods for constructing diverse
efficient approaches for the preparation of pyridines. compounds via oxidative reaction in the presence of
The traditional methods include the Hantzsch DDQ or I2/benzoyl peroxide.[13] In aim of further
reaction,[3] Kröhnke pyridine synthesis,[4] Chichibabin expanding the application of enamines for the syn-
reaction,[5] and Bohlmann-Rahtz reaction.[6] During the thesis of N-heterocycles and our longstanding research
past few decades, a large number of alternative interest in the oxidative reaction of 1,3-
strategies for preparing pyridines have been success- diarylpropenes,[13a,c–d,14] herein we wish to report a
fully
established
such
as
metal-mediated tandem reaction of β-enaminoesters and 1,3-diary-
cycloaddition,[7] metal-free multicomponent reaction,[8] lpropenes mediated by DDQ via oxidative coupling/
transition-metal-catalyzed coupling of ketoxime intramolecular
annulation/dehydro-aromatization,
acetates,[9] ring-expansion reaction,[10] and so on.[11] which gives the polysubstituted pyridines under metal-
However, many of these reported methods suffer from free condition. Moreover, this process is also appli-
the disadvantages such as harsh reaction conditions, cable for 4-aminocoumarins, which generates the fused
functionalized starting materials, and use of transition- pyridocoumarins in moderate to good yields.
metal catalysts in the synthesis of polysubstituted
pyridines. Due to the compelling attractions of the
pyridine motif in several fields, it’s still desirable to
Results and Discussion
develop versatile and efficient synthetic routes for such Initially, β-enaminoester 1a and 1,3-diphenylpropene
2a were chosen as model substrates. The reaction was
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performed with 1.2 equiv. DDQ in ClCH2CH2Cl
(DCE) at room temperature. After 2 hours, extra
2.1 equiv. DDQ was added, and the reaction was
continuously stirred for another 0.5 hour. Delightfully,
the desired polysubstituted pyridine 3a was obtained,
although the yield was only 29% (Table 1, entry 1).
Table 2. The tandem reaction of β-enaminoesters and 1,3-
diarylpropenes.[a]
Table 1. Optimization of the tandem reaction conditions.[a]
Entry Ar1, R, 1
Ar2, Ar3, 2
3
Yield
(%)[b]
1
2
3
4
5
6
7
8
C6H5, OEt, 1a
C6H5, C6H5, 2a
3a 80
3b 73
3c 78
3d 76
3e 90
3f 71
3g 77
3h 83
3i 83
3j 60
3k 75
3l 93
3m 87
2-FC6H4, OEt, 1b
3-FC6H4, OEt, 1c
4-FC6H4, OEt, 1d
2-ClC6H4, OEt, 1e 2a
3-ClC6H4, OEt, 1f 2a
4-ClC6H4, OEt, 1g 2a
3-BrC6H4, OEt, 1h 2a
4-BrC6H4, OEt, 1i
4-IC6H4, OEt, 1j
2a
2a
2a
Entry
Solvent
DDQ (equiv)
Yield (%)[b]
1
2
3
4
5
6
7
8
DCE
1,4-dioxane
THF
CHCl3
CH2Cl2
CH3NO2
CH3CN
DMSO
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
1.2+2.1
3.3
29
80
58
40
43
53
36
34
56
63
38
70
79
9
2a
2a
10
11
12
13
2-CH3C6H4, OEt, 1k 2a
3-CH3C6H4, OEt, 1l 2a
4-CH3C6H4, OEt,
2a
1m
9[c]
10[d]
11
12
13
14
15
16
2-CH3OC6H4, OEt, 2a
1n
3-CH3OC6H4, OEt, 2a
1o
4-CH3OC6H4, OEt, 2a
1p
3n 70
3o 83
3p 76
1.2+2.0
1.2+2.2
[a] 2a (0.24 mmol) and DDQ (0.24 mmol) in solvent (3 mL)
were stirred for 10 mins at rt, 1a (0.2 mmol) was added and
stirred for 2 hrs, then DDQ (0.42 mmol) was added and
stirred for another 0.5 hr.
17
18
4-CF3C6H4, OEt, 1q 2a
3q 85
3r 85
3,5-Cl2C6H3, OEt,
2a
1r
19
20
21
22
23
24
25
26
27
28
29
30
3,4-F2C6H3, OEt, 1s 2a
1-naphthyl, OEt, 1t 2a
2-thienyl, OEt, 1u 2a
3s 75
3t 78
3u 83
3v 46
3w 83
3x 82
[b] Isolated yield.
[c]
°
At 10 C.
[d]
°
At 40 C.
2-furyl, OEt, 1v
C6H5, OCH3, 1w
C6H5, OBu-t, 1x
C6H5, OBn, 1y
CH3, OEt, 1z
2a
2a
2a
2a
2a
Then, various solvents such as 1,4-dioxane, THF,
CHCl3, CH2Cl2, CH3NO2, CH3CN, and DMSO were
conducted (entries 2–8). It showed that 1,4-dioxane
was the best option (entry 2). Increasing or decreasing
the reaction temperature made the yield lower than that
under best condition (entries 9–10). Finally, the dosage
of DDQ was examined (entries 11–13). 3.3 equiv.
DDQ was added in one portion to make the reaction
complex, and only 38% yield was given (entry 11).
Increasing the total dosage of DDQ to 3.4 equiv. could
not promote the reaction yield (entry 13).
3y 79
[c]
–
–
4-CH3C6H4, Ph, 1aa 2a
3z 30
[c]
C6H5, CH3, 1bb
1a
1a
2a
–
–
C6H5, 4-ClC6H4, 2b 3aa 74[d]
C6H5, 4-CH3OC6H4, 3bb 70[d]
2c
[a] 2 (0.24 mmol) and DDQ (0.24 mmol) in 1,4-dioxane (3 mL)
were stirred for 10 mins at rt, 1 (0.2 mmol) was added and
stirred for 2 hrs, then DDQ (0.42 mmol) was added and
stirred for another 0.5 hr.
With the optimal reaction conditions in hand, [b] Isolated yield.
[c] The desired product could not be obtained.
various β-enaminoesters were investigated by new
developed method (Table 2). β-Enaminoesters 1b–1s,
which contained electron-donating or electron-with-
drawing group on the benzene ring, could react with
1,3-diphenylpropene 2a smoothly (entries 2–19). The
corresponding polysubstituted pyridines 3b–3s were
[d] Both α- and γ- positional isomeric products were obtained.
According to the NMR, the ratios of isomers of 3aa and 3bb
are 9:11 and 3:2, respectively.
obtained in 60–90% yields. No evidence of electron experimental data, regardless of their distinctive elec-
effect or hindrance effect was observed from the tronic property or position. β-Enaminoesters with
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heteroaryl substituents 1u–1v were also suitable for
the reaction conditions (entries 21–22). β-Enaminoest-
ers with different alkoxylcarbonyl groups 1w–1y were
surveyed (entries 23–25). The expected products were
given in 79–83% yields, which indicated that the
property of the examined alkoxylcarbonyl groups had
no significant effect on the reaction. The desired
product was not obtained when β-enaminoester 1z was
used as the substrate (entry 26). β-Enaminone 1aa
could react with 1,3-diphenylpropene with only 30%
yield, while 1bb could not (entries 27–28). 1,3-Diary-
lpropenes 2b–2c with a mixture of α- and γ- isomers
were prepared and surveyed in the reaction (entries 29-
Table 3. The reaction of 4-aminocoumarins and 1,3-diphenyl-
propene.
Entry
R, 4
5,[a] Yield (%)[b]
6,[c] Yield (%)[b]
1
2
3
4
5
6
7
8
H, 4a
H, 4a
6-F, 4b
5a, 90
5a, 98
5b, 84
5c, 94
5d, 93
5e, 92
5f, 92
5g, 88
5h, 87
5i, 85
5j, 82
6a, 84[d]
6a, 90
6b, 71
6c, 76
6d, 85
6e, 85
6f, 70
6g, 79
6h, 72
6i, 70
1
30). According to the H NMR, the products obtained
were also a mixture of α- and γ- isomers. However, the
ratios between isomers were different from those of the
corresponding 1,3-diarylpropenes, which indicated that
the allylic radicals or cations generated in the reaction
process.
7-Cl, 4c
6-Br, 4d
7-Br, 4e
6-CH3, 4f
7-CH3, 4g
5-CH3O, 4h
6-CH3O, 4i
7-CH3O, 4j
In consideration of 4-aminocoumarins have similar
structure unit to β-enaminoesters, we turned our
attention to the reaction of 4-aminocoumarins and 1,3-
diphenylpropene for the construction of coumarins
fused with pyridines. Pyridocoumarins have become
the research focus in recent years because these
privileged scaffolds exhibit a broad spectrum of
pharmacological activities and remarkable photochem-
ical properties.[15] Based on the previous reaction
conditions, we found that DCE was the best solvent
instead of 1,4-dioxane (Table 3, entries 1–2). The
coupling product 5a could be obtained when the
dosage of DDQ was 1.2 equiv. The pyridocoumarin
product 6a was obtained when extra 2.1 equiv. DDQ
was added to the reaction mixture. 4-Aminocoumarins
9
10
11
6j, 60
[a] 2a (0.24 mmol) and DDQ (0.24 mmol) in DCE (3 mL) were
stirred for 10 mins at rt, 4 (0.2 mmol) was added and stirred
for 4 hrs.
[b] Isolated yield.
[c] 2a (0.24 mmol) and DDQ (0.24 mmol) in DCE (3 mL) were
stirred for 10 mins at rt, 4 (0.2 mmol) was added and stirred
for 4 hrs, then DDQ (0.42 mmol) was added and stirred for
another 2 hrs.
[d] 1,4-Dioxane as solvent.
4b–4j with halo, methyl or methoxyl substituent on TEMPO was added to the system. These results
the benzene ring could react with 1,3-phenylpropene indicated that a single-electron-transfer (SET) was
2a successfully to give the corresponding products involved in the reaction. Based on above experiment
5b–5j and 6b–6j under the different dosage of DDQ, results and the literature,[16] a possible mechanism was
respectively (entries 3–11).
proposed in Scheme 2. Initially, 1,3-diphenylpropene
To explore the tandem reaction mechanism, some 2a reacts with DDQ to give the ion pair I through
control experiments were surveyed (Scheme 1). The hydrogen abstraction after a single-electron-transfer
yield of coupling product 5a was decreased to 60% from allylic double bond to DDQ. Subsequently,
when 2 equiv. radical scavenger TEMPO was applied nucleophilic attack of 4a takes place to allylic cation
to the reaction mixture of 4 and 2a. The cyclization of of the ion pair I to give the intermediate 5a. Similarly,
coupling product 5a was examined in DCE in the 5a could react with DDQ to give the allylic cation,
presence of 2.2 equiv. DDQ, and the cyclization followed by the intramolecular nucleophilic attack of
product 6a was obtained in 93% yield within 1 hour. amino group and the dehydro-aromatization to produce
The yield was sharply decreased to 24% when 2 equiv. the final product 6a.
Conclusion
In conclusion, we have developed a tandem reaction of
1,3-diarylpropenes and β-enaminoesters/4-aminocou-
marins. The procedure involves oxidative coupling/
intramolecular annulation/dehydro-aromatization reac-
tion. It provides an efficient and mild method for the
Scheme 1. Control Experiments.
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General procedure for the synthesis of 5: To a solution of
1,3-diphenylpropene 2 (0.24 mmol, 0.047 g) in ClCH2CH2Cl
(3 mL), DDQ (0.24 mmol, 0.055 g) was added. The mixture
was stirred for 10 mins at room temperature, 4-aminocoumarin
4 (0.2 mmol) was added and stirred for 4 hrs. After the
completion of the reaction, the solvent was concentrated under
reduced pressure. Purification was done by column chromatog-
raphy on silica gel (200–300 mesh) with petroleum ether and
ethyl acetate (3:1–6:1) as the eluent to give the pure product 5.
General procedure for the synthesis of 6: To a solution of
1,3-diphenylpropene 2 (0.24 mmol, 0.047 g) in ClCH2CH2Cl
(3 mL), DDQ (0.24 mmol, 0.055 g) was added. The mixture
was stirred for 10 mins at room temperature, 4-aminocoumarin
4 (0.2 mmol) was added and stirred for 4 hrs. Then extra DDQ
(0.42 mmol, 0.095 g) was added and the mixture was stirred for
another 2 hrs. After the completion of the reaction, the solvent
was concentrated under reduced pressure. Purification was done
by column chromatography on silica gel (200–300 mesh) with
petroleum ether and ethyl acetate (10:1–20:1) as the eluent to
give the pure product 6.
Scheme 2. Possible Mechanism.
Acknowledgements
synthesis of polysubstituted and fused pyridines under
metal-free conditions.
This work was supported by the Natural Science Foundation of
China (21602197) and the Natural Science Foundation of
Zhejiang Province (LY18B020018).
Experimental Section
General information. Column chromatography was carried out
on silica gel (200–300 mesh). H NMR spectra were recorded
1
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Adv. Synth. Catal. 2019, 361, 1–6
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FULL PAPER
2,3-Dichloro-5,6-Dicyano-1,4-Benzoquinone (DDQ)-
Mediated Tandem Oxidative Coupling/Intramolecular Annu-
lation/Dehydro-Aromatization for the Synthesis of Polysub-
stituted and Fused Pyridines
Adv. Synth. Catal. 2019, 361, 1–6
D. Cheng*, Z. Deng, X. Yan, M. Wang, X. Xu*, J. Yan*