Copper-catalyzed three-component cyanotrifluoromethylation/ azidotrifluoromethylation and carbocyclization of 1,6-enynes

Article abstract of DOI:10.1021/ol501574f

A novel three-component strategy for the cyanotrifluoromethylation/ azidotrifluoromethylation and carbocyclization of 1,6-enynes is developed. The reaction proceeds smoothly under a moderate temperature by using a copper catalyst, which provides a rapid a

Full text of DOI:10.1021/ol501574f

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Three-Component Cyanotrifluoromethylation/
Azidotrifluoromethylation and Carbocyclization of 1,6-Enynes
Yu-Tao He,† Lian-Hua Li,† Zhao-Zhao Zhou,† Hui-Liang Hua,† Yi-Feng Qiu,† Xue-Yuan Liu,†
and Yong-Min Liang*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
‡State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou, 730000, P.
R. China
S
* Supporting Information
ABSTRACT: A novel three-component strategy for the
cyanotrifluoromethylation/azidotrifluoromethylation and car-
bocyclization of 1,6-enynes is developed. The reaction
proceeds smoothly under a moderate temperature by using a
copper catalyst, which provides a rapid and concise access to
addition−carbocyclization products. Furthermore, the prod-
ucts obtained can be useful building blocks in discoveries of lead compounds and other biologically active CF3-containing
heterocycles.
he cyclization of 1,6-enynes has attracted ever-increasing
synthetic intermediates for the reaction of a cyano group.
Tinterest in the field of organic chemistry because of their Encouraged by this result and on account of our research in the
exploration of novel fluorine-containing pharmaceutical candi-
dates, we envisioned that the cyano group and trifluoromethyl
group could be achieved concurrently by catalytic addition−
carbocyclization of 1,6-enynes (Scheme 1). Herein, we report a
synthetic utility for accessing complicated carbocyclic and
heterocyclic frameworks.1 Strategies for 1,6-enynes cyclization
can be classified into two types, that is, transition-metal-
catalyzed cyclization and radical cyclization.2,3 Such cyclization
processes are inherently atom economical in the assembly
synthetically versatile compounds, which give an impetus to
synthetic chemists to design and develop new synthetic
protocols. Important examples of metal-catalyzed reactions
include Au-,4 Ru-,5 Rh-,6 Pd-,7 and Ni-catalyzed8 cyclization of
1,6-enynes. Although related reactions have been extensively
and repeatedly investigated, the metal-catalyzed cyclization
reactions of 1,6-enynes are ultimately impeded by the limitation
of simple addition−carbocyclization and many of them require
a relatively high reaction temperature. Thus, seeking novel
linkers, especially for the introduction of two important
functional groups into 1,6-enynes in one step, is highly
desirable.
Compounds bearing a trifluoromethyl group (CF3),
especially heterocycles, play an important role as pharmaceut-
icals and functional materials due to their potential improve-
ment in lipophilicity, membrane permeability, and bioactiv-
ity.9,10 Therefore, much attention has been focused on the
introduction of the CF3 group into organic compounds and
tremendous progress in the transition-metal-catalyzed trifluor-
omethylation has been achieved,11,12 in particular the reactions
based on the difunctionalization strategy, such as hydro-
trifluoromethylation,13 carbotrifluoromethylation,14 oxytri-
fluoromethylation,15 and aminotrifluoromethylation.16 Re-
cently, we reported a new type of copper-catalyzed
intermolecular cyanotrifluoromethylation of alkenes to con-
struct two vicinal chemical bonds.17 The produced cyano-
trifluoromethylation products could be used as versatile
Scheme 1. Cyanotrifluoromethylation and Carbocyclization
of 1,6-Enynes
novel three-component cyanotrifluoromethylation/carbocycli-
zation of 1,6-enynes with Togni’s reagent (2a)18 and
trimethylsilyl cyanide (TMSCN) by copper catalysis at room
temperature (rt). This methodology allows a broad substrate
scope to access cycloaddition products, and the efficiently
constructed cyanotrifluoromethylation/carbocyclization prod-
ucts show great potential in subsequent transformations in
organic chemistry.
To probe the feasibility of our envisioned strategy, the
commercially available TMSCN was chosen as the CN source.
We initially selected 1,6-enyne 1a as the starting material to
react with Togni’s reagent 2a and 1,10-phenanthroline L1 in
the presence of 10 mol % Cu(OTf)2 at rt. Unfortunately, only a
Received: June 1, 2014
Published: July 16, 2014
© 2014 American Chemical Society
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Letter
trace amount of the cyanotrifluoromethylation and carbocyc-
lization product 3a was obtained in DMF (Table 1, entry 1).
Scheme 2. Substrate Scope of the Cyanotrifluoromethylation
and Carbocyclization of 1,6-Enynes
a
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ligand
solvent
DMF
t (h) yield (%)
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
CuF2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1

L1
L1
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
5.0
4.0
4.0
4.0
4.0
trace
18
10
10
82
65
60
52
60
76
21
20
80
82
0
2
CH3CN
DCE
3
4
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
6
7
Cu(MeCN)4PF6
CuSO4
8
9
CuCl
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2

c
15
d
16
0
e
17
Cu(OAc)2
trace
a
Reaction conditions: 1a (0.2 mmol), Togni’s reagent (0.3 mmol),
a
TMSCN (0.4 mmol), copper catalyst (10 mol %), ligand (20 mol %),
Reaction conditions: 1 (0.2 mmol), Togni’s reagent (0.3 mmol),
b
solvent (2.0 mL), room temperature, under argon. Isolated yield.
TMSCN (0.4 mmol), Cu(OAc)2 (10 mol %), L1 (20 mol %), CH3CN
(2 mL), room temperature, 4 h, under argon, isolated yield.
c
d
e
Without ligand. Without copper catalyst. Umemoto’s reagent 2b
was used.
case of the p-methoxy gave the desired product 3d in 48% yield.
When o-substituted 1,6-enynes (3f, 3m) were used in our
reaction, two spatial configuration products could be detected
by NMR. The structure of compound 3i was identified
unambiguously by X-ray diffraction. It was worth noting that
the addition−carbocyclization was effective with a 2-thiophenyl
group (3n) attached to the triple bond as well as with
methacrylamide (3o). Enyne with a phenyl substituent
furnished the desired product 3q in 74% yield. After further
investigation of the scope of this reaction, we found that the
oxygen- and carbon-tethered 1,6-enynes also reacted well, with
the corresponding products obtained in 65% and 86% yield,
respectively. Eyne 1t was converted into the corresponding
product in 44% yield.
Encouraged by this successful cyanotrifluoromethylation/
carbocyclization reaction, we attempted to broaden this
addition−carbocyclization of 1,6-enynes to their azidotrifluoro-
methylation/carbocyclization reactions with Togni’s reagent
and TMSN3. During the process of our investigation, we were
pleased to find that the desired azidotrifluoromethylation and
carbocyclization product could be obtained in good yields. As
described in Scheme 3, in the presence of 20 mol % CuBr, the
reaction of 1,6-enyne (1a, 0.2 mmol) with Togni’s reagent (2a,
0.36 mmol) and TMSN3 (0.5 mmol) was carried out in
CH3CN (2 mL) at 40 °C for 5 h giving the azidotrifluoro-
methylation and carbocyclization product 4a in 75% yield.19
The substrates 1, bearing either an electron-donating or
-withdrawing group on the aromatic rings, were converted
into the corresponding products in moderate to good yields. In
contrast with the cyanotrifluoromethylation/carbocyclization,
the p-methoxy substituent of 1,6-enyne proceed smoothly
The screening of the solvents demonstrated that CH3CN was
effective for this transformation and the targeted product was
obtained in 18% yield (Table 1, entry 2). Encouraged by this
result, we varied the copper catalysts. Cu(OAc)2 was found to
be the most effective catalyst which can increase the yield to
82% (Table 1, entry 5), albeit some desired addition−
carbocyclization products were obtained by using CuF2,
Cu(MeCN)4PF6, CuSO4, and CuCl (Table 1, entries 6−9).
Compared to 1,10-phenanthroline L1, ligands L2−L4 were
found to be less efficient for this transformation (Table 1,
entries 10−12). Besides, the reaction time could be decreased
to 4 h without variation of the outcome (Table 1, entries 14).
The control experiments confirmed that no reaction occurred
in the absence of a ligand or copper catalyst (Table 1, entries
15−16). However, only a trace of 3a was observed when
Umemoto’s reagent 2b was used as the trifluoromethylation
reagent (Table 1, entry 17). Finally, the optimal reaction
conditions were established as Cu(OAc)2 (10 mol %), 1,10-
phenanthroline L1 (20 mol %) in CH3CN at rt under Ar.19
Under the optimal reaction conditions, the scope of 1,6-
enynes was investigated. As demonstrated in Scheme 2, in most
cases, the cyanotrifluoromethylation and carbocyclization
proceeded in moderate to good yields with a series of 1,6-
enynes, and the substrates bearing electron-withdrawing groups
work more efficiently than those bearing electron-donating
groups on the aromatic rings. Functionality with the curious
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Letter
Scheme 3. Substrate Scope of the Azidotrifluoromethylation
and Carbocyclization of 1,6-Enynes
Scheme 4. Trapping Experiments
a
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: 1a (0.2 mmol), Togni’s reagent (0.36 mmol),
TMSN3 (0.5 mmol), CuBr (20 mol %), CH3CN (2.0 mL), under
argon, isolated yield.
during this protocol. Furthermore, the product 4j was
unambiguously confirmed by X-ray crystallographic analysis.
It should be indicated that when 4a was dissolved in solvent for
several days, part of the product would convert into the spiro
compound 5a. As we know, organic azides were useful
nitrogen-containing building blocks, which were widely applied
in synthetic chemistry. Thus, this new protocol could hold great
potential applications in discoveries of lead compounds and
other biologically active CF3-containing heterocycles in organic
chemistry as well as biology.
afford the copper(III) cyanide complex D and nucleophilic
attack of the C−C triple bond affords Cu complex F. In path b,
the radical intermediate C attacks the C−C triple bond of 1,6-
enyne to give the radical intermediate E, which reacts with (2-
iodobenzoyloxy)copper(III) acetate (B) and TMSCN to
generate the copper(III) cyanide complex F. Subsequent
elimination of the copper(III) cyanide complex F would afford
the desired cyanotrifluoromethylation and carbocyclization
product 3.
In conclusion, we have finished the first copper-catalyzed
three-component cyanotrifluoromethylation/azidotrifluoro-
methylation accompanied by a carbocyclization reaction of
1,6-enynes. The reaction tolerates a broad substrate scope, and
it is a novel protocol for the synthesis of valuable CF3-
containing nitriles and azides, which would be an excellent
strategy in 1,6-enynes modification. Further investigations on
the scope and synthetic applications of this reaction are
currently underway in our group.
To elucidate the possible mechanism of the above two
reactions, a stoichiometric amount of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added as the radical inhibitor.
Significantly sluggish reactions were observed, and the
TEMPO−CF3 adducts were detected by GC-MS in 84% and
86% yield, respectively (Scheme 4). When 2,6-di-tert-butyl-4-
methyl-phenol (BHT) was added under the standard
conditions of the reaction, the desired product 3a was obtained
with a decreased yield (20%). The BHT−CF3 adduct was also
observed in 20% yield along with the recovery of 45% of enyne
1a. In addition, the reaction of N,N-diallyl-4-methylbenzene-
sulfonamide 1u, a radical clock, with Togni’s reagent 2a under
the standard reaction conditions resulted in cyclization of
cyanotrifluoromethylation product 3u in 64% yield (d.r. >
20:1). These experiments indicate that a radical pathway might
be included in the present reactions. On the basis of these facts
and previous studies,20 we propose a plausible mechanism as
depicted in Scheme 5. Togni’s reagent 2a is activated by copper
catalysis, leading to the CF3-containing radical species A. A CF3
radical, releasing from the decomposition of the CF3-containing
radical species A, reacts with 1,6-enyne 1a to give the radical
intermediate C. In path a, the radical intermediate C reacts with
(2-iodobenzoyloxy)copper(III) acetate (B) and TMSCN to
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, spectral data for all new
Compounds, crystallographic data, and CIF information for 3i
and 4j are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liangym@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation (NSF
21272101 and 201302076), the National Basic Research
Program of China (973 Program) 2010CB8-33203 for financial
support and the Fundamental Research Funds for the Central
Universities (lzujbky-2014-243 and lzujbky-2014-194) for
support as well. We also acknowledge support from the “111”
Project and Program for Changjiang Scholars and Innovative
Research Team in University (IRT1138).
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