Facile synthesis of cyanofurans via Michael-addition/cyclization of ene-yne-ketones with trimethylsilyl cyanide

Article abstract of DOI:10.1039/C6CC08320J

We have developed a Michael-addition/cyclization procedure between ene-yne-ketones and TMSCN under metal-free conditions. A wide range of cyanofurans was delivered in high yields, which could be further transformed to a series of furo-furanimines, furo-pyridazines or carboxamido-furans. In addition, deuterium-labeling experiments have been conducted to clarify the reaction pathway.

Full text of DOI:10.1039/C6CC08320J

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DOI: 10.1039/C6CC08320J
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Facile Synthesis of Cyanofurans via Michael-Addition/Cyclization of
Ene-Yne-Ketones with Trimethylsilyl Cyanide
Yue Yu, Yang Chen, Wanqing Wu*, Huanfeng Jiang*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
We have developed a Michael-addition/cyclization procedure
between ene-yne-ketones and TMSCN under metal-free
conditions. A wide range of cyanofurans were delivered in
10 high yields, which could be further transformed to a series of
furo-furanimines, furo-pyridazines or carboxamido-furans.
In addition, deuterium-labeling experiments have been
conducted to clarify the reaction pathway.
Given their frequent appearance in many important
15 pharmaceuticals1, materials2 and natural products3, the efficient
construction of functionalized furans is a major challenge in
organic synthesis. Although many synthetic routes have been
well established,4 the development of new efficient ways to
valuable furan derivatives from widely available starting
20 materials still represents a continuing goal in the synthetic
community. In particular, cyanofurans are ideal synthetic
building blocks for the elaboration of more complex scaffolds,
owing to the versatile chemistry of the cyano group.5 However,
synthetic methods for the formation of cyanofurans have been
25 less explored until now.6
On the other hand, considerable studies have been reported for
the synthesis of functionalized furans through 5ꢀexoꢀdig
cyclization of eneꢀyneꢀketones in past years, in which eneꢀyneꢀ
ketone was mainly utilized as a carbene precursor under
30 transitionꢀmetalꢀcatalyzed conditions.7 For example, Vicente,
López and coꢀworkers demonstrated that a furyl Fischerꢀtype zinc
carbenoid intermediate obtained from eneꢀyneꢀketones underwent
XꢀH (X = O, Si, N, Csp2) insertions.8 Wang and coꢀworkers have
recently reported the Pdꢀ or Cuꢀcatalyzed crossꢀcoupling of
35 terminal alkynes with eneꢀyneꢀketones, affording conjugated
Scheme 1. Different strategies for the transformations of eneꢀyneꢀketones
Previously, our group developed a catalystꢀcontrolled strategy
50 for the synthesis of various phosphorylated furans via Cuꢀ
catalyzed Csp3ꢀP or base promoted Csp2ꢀP bond construction
between eneꢀyneꢀketones and Hꢀphosphonates.11 Encouraged by
this result, we herein disclose a straightforward approach for
utilizing eneꢀyneꢀketones as a Michaelꢀaddition acceptor to react
55 with TMSCN12, affording a series of cyanofurans. This reaction
was supposed to begin with the process of Michaelꢀaddition in
the presence of base and water, leading to intermediate A2 and
allenyl intermediate B2. Afterwards, a nucleophilic attack by the
carbonyl oxygen atom generated intermediate C2. Subsequent
60 protonation and aromatization afforded the final cyanofurans
(Scheme 1, b).
At the outset of this transformation, we treated eneꢀyneꢀketone
1a with trimethylsilyl cyanide (2) as the model substrates for
reaction development (Table 1). Initially, 3a was obtained in 74%
65 yield under simple conditions that KF was used as base and 5
equiv H2O (see Supporting Information for details) were added to
CH3CN in a test tube at room temperature for 6 h (entry 1).
Subsequent survey on a series of solvents including THF, DCE,
toluene, DMF, DMSO and dioxane revealed that DMF gave the
70 best result, affording 3a in 93% yield (entries 2ꢀ7). Screening of
other bases such as CsF or KOH did not improve the yield
enynes or allenes through
a carbene migratory insertion
pathway.9 In those transformations, the alkyne moiety was
activated by transition metal species at first, which then
underwent 5ꢀexoꢀdig cyclization to form zwitterionic
40 intermediate B1 or its resonance structure, furyl metalꢀcarbene
species C1. In the presence of nucleophiles, species C1 could
subsequently participate in a metal carbene migratory insertion
process to give the NuꢀH inserted products (Scheme 1, a). Despite
the impressive progress in this field, new strategies for the
45 transformations
underdeveloped.10
of
eneꢀyneꢀketones
have
remained
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(entries 8ꢀ9). Finally, when the amounts of trimethylsilyl cyanide
arenes (3t-3w). It is worth mentioning that 2ꢀbenzoylꢀ5ꢀ
and KF decreased to 1.5 equiv, the reaction rate and conversion 40 phenylpentꢀ2ꢀenꢀ4ꢀynenitrile (1x) could be converted into 3x as
rate were not affected and the target product 3a was obtained in
94% yield. Howerer, the yield would drop to 85% when the
amounts were further reduced to 1.2 equiv (entry 13).
well, albeit with relatively lower efficiency.
Table 2. Substrate scope for the synthesis of cyanofurans 3a
5
Table 1. Optimization of reaction conditionsa
entry
base
solvent
CH3CN
THF
yield of 3a (%)b
1
2
KF
KF
74
66
3
KF
KF
DCE
N.R
N.R
93
4
Toluene
DMF
5
KF
6
KF
DMSO
1,4ꢀDioxane
DMF
68
7
KF
71
8
CsF
KOH
89
9
DMF
76
10c
11d
KF
DMF
94
KF
DMF
85
a Reaction conditions: All reactions were performed with 1a (0.1 mmol), 2
(2.0 equiv), base (2.0 equiv), H2O (5.0 equiv), 1.0 mL solvent at room
a Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), KF (0.6 mmol) and
45 H2O (5 equiv) in 2 mL DMF at room temperature for 6 h unless otherwise
noted. b Determined by NMR.
c
10 temperature for 6 h unless otherwise noted. b Determined by GCꢀMS.
2
(1.5 equiv), base (1.5 equiv). d 2 (1.2 equiv), base (1.2 equiv).
We next moved toward synthetic applications of cyanofurans
to prepare three important intermediate scaffolds, namely, furoꢀ
furanimines5e, furoꢀpyridazines5f and carboxamidoꢀfurans5h,
50 which were found as scaffolds in biologically active molecules.
As shown in Scheme 2, for the synthesis of furoꢀfuranimine,
sodium borohydride was carefully added to a solution of 3ꢀacetylꢀ
4ꢀcyano furan 3a in MeOH, the target product 4 was formed in
69% yield (Scheme 2, Eqn. 1). On the other hand, the reaction of
55 3i with hydrazine hydrate could easily give furoꢀpyridazine 5
with the yield of 76% (Scheme 2, Eqn. 2), and the hydration of 3i
catalyzed by InCl3 led to carboxamidoꢀfuran 6 in 72% yield with
With the optimized reaction conditions in hand (Table 1, entry
10), we turned our attention to explore the scope of this
transformation (Table 2). The reaction proceeded smoothly under
15 the standard reaction conditions and afforded the products 3aꢀ3e
in 77ꢀ91% yields when R1 and R2 were alkyl or phenyl groups.
Notably, the mixture of (E)ꢀ and (Z)ꢀeneꢀyneꢀketones afforded the
single products, and only 5ꢀexoꢀdig cyclization occurred. Thus, to
examine the nucleophilicity of different ketone carbonyl oxygen
20 atoms, we synthesized 1c for this transformation and the desired
products 3c and 3c’ were obtained in a total yield of 84% with a
regioselectivity of 1: 1. We supposed that the steric hindrance of
phenyl group made negligible influence on the inserted cyanoꢀ
group in this case. To our delight, the reactions for
25 alkoxycarbonylꢀsubstituted eneꢀyneꢀketones showed high
functional group tolerance (such as R2 = OEt, R1 = Me, Et, nꢀPr,
cyclopropyl, substituted arenes, pyridyl or furyl; R1 = Me, R2 = tꢀ
Bu, benzyl or isopropyl), leading to the corresponding products
3f-3r in good to excellent yields. When R2 is ethyl, the reactions
30 with electronꢀwithdrawing groups on phenyl ring provided
similar yields to those with electronꢀdonating groups. In addition,
heterocyclic group such as pyridyl and furyl were also compatible
with the reaction conditions, affording the desired products 3n
and 3o in 68% and 76% yields, respectively. Carboxamidoꢀ
35 substituted eneꢀyneꢀketone was also a suitable substrate for this
cyclization, and the target product 3s was isolated in 61% yield.
Moreover, the reaction was found to tolerate a broad range of R3
groups on the alkyne terminus, including alkanes and substituted
Scheme 2. Further modification on cyanofurans
2
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DOI: 10.1039/C6CC08320J
Key Laboratory of Functional Molecular Engineering of Guangdong
Province, School of Chemistry and Chemical Engineering, South China
45 University of Technology, Guangzhou 510640, China. Fax: +86 20-
87112906; Tel: +86 20-87112906; E-mail: cewuwq@scut.edu.cn,
jianghf@scut.edu.cn
the aid of acetaldoxime (Scheme 2, Eqn. 3).
To gain more insight into the mechanism of this reaction,
several control experiments were performed (Scheme 3). Initially,
when benzylideneacetone (7) was used to replace eneꢀyneꢀ
† Electronic Supplementary Information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
50 spectra for selected compounds. See DOI: 10.1039/b000000x/
5
ketones under the standard conditions, a Michaelꢀaddition
product 8 was obtained in 84% yield, indicating that the
transformation could start with a Michaelꢀaddition pathway in
this situation (Scheme 3, Eqn. 1).13 The deuteriumꢀlabeling
experiments were next conducted. On one hand, the reaction of
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afforded [D1]ꢀ3a in 78% total yield with 85% D (Scheme 1, Eqn.
2). On the other hand, [D1]ꢀ3a was not detected by the treatment
of cyanofurans 3a in the same conditions (Scheme 3, Eqn. 3). The
15 structure of [D1]ꢀ3a shows that one of the hydrogen atom on the
methylene position comes from water. In consideration of the
result of the first reaction, the most possible way is that the
hydrogen atom of water inserts into the vinyl moiety of eneꢀyneꢀ
ketones with the CN anion via a Michaelꢀaddition and then
20 transfer to the methylene position through a hydrogen shift during
the process of aromatic isomerization (Scheme 1, b).
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85
90
Scheme 3. Control experiments
In conclusion, we have established a highly efficient protocol
25 for the synthesis of various cyanofurans via Michaelꢀ
addition/cyclization of eneꢀyneꢀketones with trimethylsilyl
cyanide. These valuable products could easily transfer to other
biologically active molecules such as furoꢀfuranimines, furoꢀ
pyridazines and carboxamidoꢀfurans. Furthermore, this method
30 features transitionꢀmetalꢀfree, broad substrate scope, high
efficiency and atom economy, which make it attractive and
practical. Deuteriumꢀlabeling experiments have been conducted
to clarify the reaction pathway. Further applications of this
reaction is currently underway in our laboratory.
95
100
105
110
35
The authors thank the National Key Research and Development
Program of China (2016YFA0602900), the National Natural
Science Foundation of China (21420102003 and 21490572),
40 Pearl River S&T Nova Program of Guangzhou (201610010160)
for financial support.
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