A novel oxidation-ring-contraction of Hantzsch 1,4-dihydropyridines to polysubstituted furans

Article abstract of DOI:10.1016/j.tetlet.2007.05.071

A novel oxidation-ring-contraction reaction took place when 4-substituted Hantzsch 1,4-dihydropyridines were treated with Oxone. This reaction pattern provided a convenient method for the synthesis of polysubstituted furans.

Full text of DOI:10.1016/j.tetlet.2007.05.071

Tetrahedron Letters 48 (2007) 5321–5324
A novel oxidation–ring-contraction of Hantzsch
1,4-dihydropyridines to polysubstituted furans
Zhengang Liu, Wei Yu,* Li Yang* and Zhong-Li Liu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, PR China
Received 17 January 2007; revised 13 May 2007; accepted 14 May 2007
Available online 18 May 2007
Abstract—A novel oxidation–ring-contraction reaction took place when 4-substituted Hantzsch 1,4-dihydropyridines were treated
with Oxone. This reaction pattern provided a convenient method for the synthesis of polysubstituted furans.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The oxidation of Hantzsch 1,4-dihydropyridines
(DHPs), a class of model compounds of NADH co-
enzyme,1 has attracted continuing interest of organic
chemists over the years. A plethora of protocols has
been developed for such a purpose.2–10 On continuance
of our interest in the DHP based chemistry, we have also
studied the oxidation of DHPs under different condi-
tions.11 With all the reported methods, DHPs are invari-
ably transformed to pyridine derivatives via oxidative
aromatization. Recently, we applied Oxone to the oxida-
tion of DHPs, and found, unexpectedly, a novel oxida-
tion–ring-contraction reaction took place, leading to
the formation of polysubstituted furans. Herein we
report this result.
obtained in the yield of 11%, was characterized to be
the four substituted furan 3b (Scheme 1). This result
was totally unexpected, as no similar result was
reported before using other oxidants so far to our
knowledge.
Polysubstituted furans are present as key structural
units in many natural products and pharmaceuticals.13
They are also used as versatile synthetic intermediates
for the preparation of a variety of heterocyclic and
acyclic organic compounds.14 Consequently, many
efforts have been devoted to the development of efficient
methodology for the construction of polysubstituted
furan rings.15,16 We assumed that the oxidation of
4-substituted DHPs by Oxone might provide a conve-
nient approach for the preparation of polysubstituted
furans from the easily available 4-substituted
dihydropyridines.
Oxone, a commercially available triple salt of 2KHSO5Æ
KHSO4ÆK2SO4, is an efficient and mild oxidant widely
used for the epoxidation of olefins, and the oxidation
of boron-, nitrogen-, phosphorus-, and sulfur-contain-
ing compounds.12 In the initial part of this study,
HEH (1a) was treated with 2 equiv of Oxone in CH3CN
at room temperature, and the aromatization product
2a was generated as expected in 64%. However, when
4-phenyl DHP (1b) was treated with Oxone under the
same condition, two products were isolated from the
reaction mixture. One is the normal pyridine derivative
2b, which was obtained in 28%. The other product,
In light of this goal, the reaction condition was opti-
mized to raise the yield of 3b. Various solvent systems
were tested, and the representative results are listed in
Table 1. It turned out that nonpolar solvents such as
toluene and CH2Cl2 were unfavorable for the formation
of 3b, even in the presence of phase transfer reagent
n-Bu4NHSO4. Polar solvents such as CH3CN, CH3OH,
and C2H5OH were better solvents to effect the reaction,
especially in the presence of H2O (entries 10–14). But no
furan product was generated in DMF (entry 9). The best
result was obtained when an aqueous solution of
1.5 equiv of Oxone (3 equiv of KHSO5) was added drop-
wise to a stirred solution of 1b in MeCN at refluxing
temperature,17 from which 3b was obtained in 44%
Keywords: Hantzsch 1,4-dihydropyridines; Oxone; Polysubstituted
furans.
*
Corresponding authors. Fax: +86 931 8625657; e-mail addresses:
yuwei@lzu.edu.cn; yangl@lzu.edu.cn
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.071

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Z. Liu et al. / Tetrahedron Letters 48 (2007) 5321–5324
R
O
O
O
R
O
O
R
Oxone
O
OEt
EtO
OEt
+
EtO
EtO
N
H
N
O
OEt
1
2
3
a R = H
b R = Ph
Scheme 1.
Table 1. Effect of solvents on the oxidation of 1a and 1b by Oxonea
Entry
Substrate
Solvent
Reaction time
Conversionb (%)
Products
Yield (2a or 2b/3b, %)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
Toluened,e
CH2Cl2
DMFd
12 h
12 h
6 h
6 h
40 min
10 min
12 h
12 h
12 h
90
90
100
95
100
100
65
60
90
60
96
2a
2a
54
68
45
65
78
84
8/6
8/5
20/—
28/12
10/26
8/44
6/23
5/28
d,e
2a
2a
Anhydrous CH3CNd
CH3CN:H2O = 3:2f
CH3CN:H2O17
Toluened,e
2a
2a
2b/3b
2b/3b
2b/3b
2b/3b
2b/3b
2b/3b
2b/3b
2b/3b
d,e
CH2Cl2
DMFd
Anhydrous CH3CNd
CH3CN:H2O = 3:2f
CH3CN:H2O17
CH3OH:H2Of
C2H5OH:H2Of
2 h
40 min
10 min
20 min
20 min
100
100
100
a 1.5 equiv of Oxone was used.
b Determined based on the recovered starting material after chromatography.
c Isolated yields.
d The reaction was carried out at room temperature.
e 0.1 equiv of n-Bu4NHSO4 was added as catalyst.
f The reaction was carried out under refluxing.
(entry 12). Using more Oxone did not improve the yield.
Apart from 3b and 2b, no other products could be
isolated and identified. In the case of 1a, however, no
ring contraction product was detected whatever the con-
dition was used. Only 2a was isolated in moderate to
good yields (entries 1–6).
A possible mechanism for this ring contraction rear-
rangement was proposed as shown in Scheme 2. Com-
pound 1 was firstly oxidized by KHSO5 to epoxide 4,
which was then transformed to 5 via an epoxide ring
opening as facilitated by the adjacent N atom attack.
Further epoxidation of 5 by another KHSO5 molecule
would give rise to 6, from which 7 was generated by
the intramolecular hydroxyl attack on the newly formed
epoxide ring. Dehydration of 7, followed by the retro-
Diels–Alder type breakage of the oxygen-bridged ring,
would lead to the formation of ring contraction product
3. In the epoxidation of 5, the epoxide ring could also be
delivered cis to the OH group, but the thus formed iso-
mer of 6 might not be transformed to 3 as OH could not
attack the epoxide ring from the anti direction. In the
case of 1a, the dehydration of the intermediate 5a would
be a quite facile process due to the presence of an anti H
atom adjacent to the hydroxy group, so that the second
epoxidation giving 6a could not compete, and only 2a
was obtained.
The effect of pH value of the solvent was also investi-
gated in the hope of raising the yield of 3b. It was found
that acidic conditions were more favorable for the
formation of 3b than basic conditions, and above pH
5, the yield and conversion rate of 3b decreased with
the increase in pH value. One reason for this is probably
because Oxone is labile to decomposition under heating
at high pH values.18 However, despite the attempt we
made, the yield of 3b could not be raised further.
To examine the scope of the reaction, various 4-substi-
tuted DHPs were prepared and subjected to the opti-
mized reaction condition. As shown in Table 2, the
furan products 3b–j were generated in varying yields ex-
cept for 1k, along with a small amount of pyridine deriv-
atives. Though the yields were generally not satisfactory,
the fact that only one step was required to get access to
the 2,3,4,5-four substituted furan rings from easily pre-
pared 4-substituted dihydropyridines still makes this
method a promising candidate among diverse protocols
for furan synthesis.
In conclusion, a novel oxidation–ring-contraction reac-
tion taking place when 4-substituted Hantzsch 1,4-
dihydrpyridines were treated with Oxone. Further
studies on the mechanistic details of the reaction, and
efforts to explore new reaction conditions to improve
the yields of furan products are underway in this
laboratory.

Z. Liu et al. / Tetrahedron Letters 48 (2007) 5321–5324
Table 2. Oxidation of Hantzsch 1,4-dihydropyridines by Oxone17
5323
R
O
O
O
R
O
O
R
Oxone
O
OEt
EtO
OEt
EtO
+
EtO
N
H
N
O
OEt
1
2
3
Entry
R
Substrate
Products
Yielda (2/3, %)
1
2
3
4
5
6
7
8
9
H
Ph
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
84/—
8/44
5/32
5/40
6/40
4/28
5/28
4/34
5/18
5/30
C6H4-p-Cl
C6H4-p-CH3
C6H4-p-OCH3
C6H4-p-OH
2-Furyl
n-Propyl
Styryl
C6H4-m-NO2
C6H4-p-NO2
1g
1h
1i
2g
2h
2i
3g
3h
3i
10
11
1j
1k
2j
3j
Complex mixtures
a Isolated yields. Products 3b–j were characterized by 1H and 13C NMR, EI-MS, and HR-MS spectra data.
R
O
R
O
O
H
O
H
R
O
O
OEt
OEt
EtO
EtO
OEt
OH
EtO
O
O
O
O
N
H
N
S
N
H
O
O
5
H
K
4
1
H
H
R
R
O
O
O
O
O
KHSO5
-H2O
OEt
OH
OEt
EtO
O
EtO
HO
O
N
N
7
6
R
O
R
O
O
-MeCN
EtO
OEt
EtO
O
N
OEt
O
8
3
H
H
N
H
O
O
O
O
-H2O
OEt
OEt
EtO
EtO
OH
N
5a
2a
Scheme 2.
3. Pfister, J. R. Synthesis 1990, 689.
Acknowledgements
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We thank the National Natural Science Foundation of
China (No. 20372030) and the Natural Science Founda-
tion of Gansu Province (No. 3ZS061-A25-004) for
financial support.
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17. General Procedure: An aqueous solution of 3 mL Oxone
(1.5 mmol) was added dropwise to a stirred solution of 1
(1 mmol) in MeCN (4 mL) at reflux temperature in 5 min.
The reaction mixture was stirred under refluxing for
another 5 min, and was then cooled to room temperature.
The reaction mixture was quenched with 20 mL of H2O,
neutralized with saturated aqueous solution of NaHCO3,
and then extracted with ethyl acetate (3 · 10 mL). The
combined organic layer was dried over anhydrous sodium
sulfate, and concentrated under a reduced pressure.
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gel column chromatography (petroleum/acetone 15:1 to
10:1).
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