A novel one-pot method for the synthesis of substituted furopyridines: Iodine-mediated oxidation of enaminones by tandem metal-free cyclization

Article abstract of DOI:10.1039/c4cc08834d

A novel iodine-mediated oxidative tandem cyclization reaction of simple enaminones has been developed for the synthesis of substituted furopyridines through C-C/C-N/C-O bond formation in a one-pot procedure. Substituted furopyridines are obtained in moder

Full text of DOI:10.1039/c4cc08834d

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A novel one-pot method for the synthesis of
substituted furopyridines: iodine-mediated
oxidation of enaminones by tandem metal-free
cyclization†
Cite this:DOI: 10.1039/c4cc08834d
Received 7th November 2014,
Accepted 5th December 2014
Rulong Yan,* Xiaoni Li, Xiaodong Yang, Xing Kang, Likui Xiang and
Guosheng Huang*
DOI: 10.1039/c4cc08834d
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8
A novel iodine-mediated oxidative tandem cyclization reaction with simple starting materials, however, we have unexpectedly found
of simple enaminones has been developed for the synthesis of that substituted furopyridines can be formed by the one-pot
substituted furopyridines through C–C/C–N/C–O bond formation I2-mediated reaction of enaminone amides, with formation of C–C,
in a one-pot procedure. Substituted furopyridines are obtained in C–N and C–O bonds.
moderate to good yield. In addition, I- and Br-substituted furopyridines
In our initial experiments, (Z)-3-amino-1-phenylbut-2-en-1-one
in
dimethyl sulfoxide (DMSO) at 100 1C in air. To our great satisfaction,
have been successfully produced by the electrophilic substitution of (1a) was chosen as the test substrate for cyclization, using I
N-iodo- or N-bromosuccinimide.
2
Tandem reactions have attracted considerable interest for simplifying
a
reaction steps, reducing waste, and maximizing atom economy, and Table 1 Optimization of reaction conditions
have been developed as powerful and eco-friendly strategies for the
1
synthesis of complex molecules from simple starting materials. With
the development of C–H bond activation, oxidative tandem reactions
have emerged as an attractive and challenging method for construct-
2
ing heterocyclic compounds. With increasing concern regarding
b
Additive/equiv.
Solvent
Temp.
Yield of 2a
environmental issues, metal-free oxidative tandem reactions have
been developed for a number of new routes for the synthesis of
heterocyclic compounds from simple starting materials.
The furopyridine nucleus has been employed as a key structural
unit in a variety of therapeutic areas, for example in HIV protease
inhibitors. A great deal of effort has therefore been directed to the
development of new methods of synthesis. Two strategies for the
synthesis of furopyridines have been followed, the formal insertion of
new functional groups into the of furopyridine scaffold (Scheme 1, 11
strategy A), and transition-metal catalyzed tandem cyclization of
1
2
3
4
5
6
7
8
9
1
I
I
2
(1.2)
(1.2)
DMSO
DMF
100
100
80
100
80
80
80
80
80
80
60
36
38
87
12
18
—
—
10
46
86
63
2
3
I2 (1.2)
(1.2)
MeCN
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
I
2
4
NIS (1.2)
PIDA (1.2)
TBAI (1.2)
5
I
2
I
2
I
2
(0.1)
(0.5)
(1.2)
c
0
I2 (1.2)
6
a
b
Reaction conditions: 1a (0.3 mmol), additive, solvent (2 mL). Yield of
isolated product. Reaction carried out under O (1 atm). The entry in bold
2
7
pyridinyl allyl ethers (Scheme 1, strategy B). Both processes have
c
disadvantages, such as the involvement of expensive metal com- indicates optimal reaction conditions, the reaction time being monitored
by TLC. DMSO: dimethyl sulfoxide, DMF: N,N-dimethylformamide.
pounds, complex substrates, or harsh reaction conditions. To the best
of our knowledge, there is no method for the direct synthesis of the
furopyridine scaffold from simple substrates by a one-step reaction.
Inspired by recent studies in synthesizing heterocyclic compounds
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, 730000 China. E-mail: yanrl@lzu.edu.cn,
hgs@lzu.edu.cn; Fax: +86-0931-8912596
†
Electronic supplementary information (ESI) available. CCDC 1012693 and
032635. For ESI and crystallographic data in CIF or other electronic format
1
see DOI: 10.1039/c4cc08834d
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Scheme 1 Two approaches to the synthesis of substituted furopyridines.
Scheme 2
2
I -involved oxidative tandem cyclization of enaminones for the synthesis of substituted furopyridines.
an unexpected product, 7-methyl-2,5-diphenylfuro[3,2-b]pyridine giving an 87% yield. After further examining the effects of
2a) was obtained in 36% yield, and its structure was confirmed temperature, the highest yield of 2a was achieved when the reaction
by X-ray crystal analysis. Alternative solvents such as DMF, MeCN, or at was conducted at 80 1C in MeCN with I (Table 1, entry 3).
(
2
toluene were evaluated, and MeCN was chosen for the reaction
Table 1, entries 1–6). In addition, when I was evaluated against choice of additive in this reaction, and the results are illustrated in
N-iodosuccinimide (NIS), iodosobenzene diacetate (PIDA), or tetra- Scheme 2. The transformation showedgoodfunctional grouptolerance,
With the optimal reaction conditions established, we explored the
(
2
butylammonium iodide (TBAI), I
2
showed the highest activity, and proved to be an efficient method for the preparation of substituted
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a
Table 2 The reaction of substituted furopyridines and NXS
b
R
X
Product
Yield
1
2
3
4
5
6
7
8
9
H
Me
OMe
3,4-DiMe
F
Br
Naphthyl
H
F
I
I
I
I
I
I
I
Br
Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
68
67
45
60
70
80
25
45
43
Scheme 3 The reaction of 1p and 1q.
furopyridines. Enaminones with methyl, methoxyl, fluoro, chloro, and
phenyl groups on the aryl rings all gave the desired furopyridines in
moderate to good yield. The nature of the substituent on the aromatic
rings did not significantly affect the yield of the product (2b–2l). For
example, the naphthyl-substituted enaminone was tolerated in this
transformation and produced 7-methyl-2,5-di(naphthalen-2-yl)furo[3,2-
b]pyridine (2m) in 80% yield. Moreover, the transformation can even be
performed using an enaminone containing alkyl groups, and the
desired product (2n) was obtained in 55% yield. It is worth mentioning
that when the more challenging substrate (Z)-4-amino-3-phenylpent-3-
en-2-one (1o) was employed in this transformation, the desired product,
a
Reaction conditions: 2a (0.3 mmol), NXS (0.6 mmol), acid (0.3 mmol),
b
solvent (2 mL), 120 1C. Yield of isolated products.
2,5,7-trimethyl-3,6-diphenylfuro[3,2-b]pyridine (2o) was isolated in 35%
yield. On the other hand, when ethyl (Z)-3-aminobut-2-enoate (1p) was
used under the standard conditions, none of the expected product
could be detected (Scheme 3, eqn (1)). This result was caused by the
weaker electrophilicity of the ester carbonyl in 1p. In addition, when 1q
was used under optimized conditions, the desired substituted furo-
pyridine was again not observed, but the unexpected product, 2q, was
isolated in 21% yield (Scheme 3, eqn (2)). The result produced by I-
substituted furanpyridine meant that the steric hindrance caused by the
methyl group was less than that of other substituents, and inspired us
to optimize the reaction conditions to provide a general protocol for the
synthesis of halide furopyridines.
(
Z)-3-amino-1-phenylpent-2-ene-1,4-dione (2t), was produced in 52%
yield. Even when this reaction was performed under argon protection,
t was similarly formed in 47% yield. This result means that the substrate
t was equilibrated to generate the intermediate A, which was then
attacked by H O. 2t was then formed by oxidation (Scheme 4, eqn (5)).
2
1
2
On the basis of the results described above, a plausible mechanism
is proposed in Scheme 5. The reaction starts from the combination of
two molecules of substrate 1 to generate imine 4, which equilibrates to
intermediate 5 under the reaction conditions. Subsequently, intra-
molecular cyclization of 4 leads to intermediate 6. In this transforma-
tion, 6 would transfer to 7 via rearrangement under optimized
Encouraged by the above results, the substituted furopyridine 2a
was chosen as a model substrate with which to optimize the reaction
conditions. After examining the effects of varying I , NIS, acids and
2
other different parameters, the highest yield of 3a, which was con-
firmed by X-ray crystal analysis, was achieved when the reaction was
carried out with NIS (2.0 equiv.), p-toluene sulfonic acid (1.0 equiv.) in
DMSO at 120 1C (see ESI†). We then investigated the substrate scope of
this electrophilic substitution reaction (Table 2). Diverse substrates
underwent this substituted reaction with NIS to give the corresponding
products in moderate to excellent yield. Similarly, the substituents on
the aromatic rings did not affect the yield of the product. Moreover, the
substrates with Br and F groups proceeded well under optimized
conditions and gave the corresponding products in good yields. Even
substituted furopyridines could be employed to react with N-bromo-
succinimide (NBS) under optimized reaction conditions, and the
products were isolated in moderate yield (Table 2, entries 8 and 9).
To probe the mechanism further, control experiments were con-
ducted. When (Z)-1-phenyl-3-(phenylamino)but-2-en-1-one (1r) and
(Z)-3-amino-1,3-diphenylprop-2-en-1-one (1s) were used under standard
conditions, none of the required product was obtained (Scheme 4,
eqn (3) and (4)). In order to clarify this, 1-phenylpent-2-en-1-one (1t) was
used according to the optimized mechanism of the transformation,
using the (Z)-3-amino-condition substrate, an unexpected product, Scheme 4 Control experiments.
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Scheme 5 Proposed mechanism.
conditions. The iodonium ion 8, which is generated by iodination of
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and the furan unit 10 is formed by elimination of the HI. Then,
intermediate 11 undergoes protonation of the primary amine and
elimination to give 12 via aromatization. The furopyridine 2 is
afforded by deprotonation of 12. Finally, the product 3 is achieved
via electrophilic substitution reaction.
4
5
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I -mediated strategy to synthesize substituted furopyridines via oxida-
2
tive tandem cyclization of simple enaminones. This transformation
constructs the skeleton of furopyridines through C–C/C–N/C–O
bond formation in a one-pot manner. Moreover, I/Br-substituted
furopyridines were afforded efficiently via an electrophilic substitu-
tion reaction of NIS/NBS.
This work was supported by the National Natural Science
Foundation of China (21202067) and the Fundamental
Research Funds for the Central Universities (lzujbky-2014-71).
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