Copper-catalyzed difunctionalization of activated alkynes by radical oxidation-tandem cyclization/dearomatization to synthesize 3-trifluoromethyl spiro[4.5]trienones

Article abstract of DOI:10.1002/chem.201405672

A copper-catalyzed difunctionalizing trifluoromethylation of activated alkynes with the cheap reagent sodium trifluoromethanesulfinate (NaSO₂CF₃ or Langlois' reagent) has been developed incorporating a tandem cyclization/ dearomatiza

Full text of DOI:10.1002/chem.201405672

DOI: 10.1002/chem.201405672
Communication
&
Tandem Reactions
Copper-Catalyzed Difunctionalization of Activated Alkynes by
Radical Oxidation–Tandem Cyclization/Dearomatization to
Synthesize 3-Trifluoromethyl Spiro[4.5]trienones
Hui-Liang Hua, Yu-Tao He, Yi-Feng Qiu, Ying-Xiu Li, Bo Song, Pin Gao, Xian-Rong Song,
Dong-Hui Guo, Xue-Yuan Liu,* and Yong-Min Liang*[a]
Abstract: A copper-catalyzed difunctionalizing trifluoro-
methylation of activated alkynes with the cheap reagent
sodium trifluoromethanesulfinate (NaSO2CF3 or Langlois’
reagent) has been developed incorporating a tandem cyc-
lization/dearomatization process. This strategy affords
a straightforward route to synthesis of 3-(trifluoromethyl)-
spiro[4.5]trienones, and presents an example of difunc-
tionalization of alkynes for simultaneous formation of two
carbon–carbon single bonds and one carbon–oxygen
double bond.
The trifluoromethyl group is considered an important structur-
al motif in pharmaceuticals and agrochemicals owing to its ad-
vantageous properties such as lipophilicity, metabolic stability,
and bioavailability.[1] In the past few decades, a series of syn-
thetic methods have been reported for the introduction of CF3
into organic molecules.[2,3] In particular, transition-metal cata-
lyzed or -mediated trifluoromethylations of alkenes based on
difunctionalization strategies, such as hydrotrifluoromethyla-
tion,[4] oxytrifluoromethylation,[5] aminotrifluoromethylation,[6]
carbotrifluoromethylation[7] and halotrifluoromethylation,[8]
have undergone rapid development. Nevertheless, the trifluo-
romethylation of alkynes, especially those going through a di-
functionalization strategy, remains less explored.[9] In 2012,
copper-catalyzed oxytrifluoromethylation of terminal alkynes
was reported by the groups of Szabꢀ[9e] and Sodeoka[9f] inde-
Scheme 1. Transition-metal-catalyzed difunctionalization of alkenes or
pendently. Recently, Hu and co-workers described an iron-cata-
lyzed iodotrifluoromethylation of terminal alkynes using CF3I as
the CF3 source.[9i] Similarly, Cho and co-workers disclosed the
iodotrifluoromethylation of terminal alkynes by visible-light
photoredox catalysis.[9h] However, these transformations have
all involved either expensive electrophilic CF3 reagents or CF3I,
which is gaseous and difficult to handle. Therefore, a new and
alkynes.
economic method for difunctionalization of alkynes to con-
struct C(sp2)ÀCF3 bonds[10] warrants further investigation.
Among the various forms of alkene trifluoromethylation, the
formation of five- or six-membered rings has attracted much
interests (Scheme 1a,b).[11] In 2014, Wang and co-workers dem-
onstrated the trifluoromethylation of alkenes coupled with
dearomatization in the presence of Togni’s reagent
(Scheme 1c).[12] Very recently, we reported a copper-catalyzed
trifluoromethylation/aryl migration/carbonyl formation with
homopropargylic alcohols.[13] Inspired by these works, and
based on our ongoing interest in the development of alkyne
trifluoromethylation, we envisaged that a transition-metal-cata-
lyzed difunctionalization of alkynes to introduce a CF3 group
[a] Dr. H.-L. Hua, Y.-T. He, Y.-F. Qiu, Y.-X. Li, B. Song, P. Gao, X.-R. Song,
D.-H. Guo, Prof. Dr. X.-Y. Liu, Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (P. R. China)
Fax: (+86)931-891-2582
E-mail: liuxuey@lzu.edu.cn
liangym@lzu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405672.
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using cheaper NaSO2CF3 as the CF3 source could be achieved
(Scheme 1d). Herein, we report a Cu-catalyzed difunctionaliz-
ing trifluoromethylation of activated alkynes in the synthesis of
3-trifluoromethyl spiro[4.5]trienones. This strategy involves
a connection of the CF3 group with the electron-deficient
carbon–carbon triple bond to generate the spiro[4.5]decane
skeleton via a tandem cyclization/dearomatization process.
Our investigation started by using N-methyl-N,3-diphenyl-
propiolamide 1a as the model substrate with sodium trifluoro-
methanesulfinate (NaSO2CF3 or Langlois’ reagent) in the pres-
ence of CuSO4 (10%) and tert-butyl hydroperoxide (TBHP) in
a 2:1 CH3CN/H2O solvent mixture at 608C under air atmos-
phere. Gratifyingly, the desired product 2a was obtained in
13% yield (Table 1, entry 1). When Na2CO3 was added as a base
could promote the yield slightly, of which MnO2 led to the
best yield of 53% (Table 1, entries 13–17). Finally, a yield of
58% was obtained after adjusting the amount of MnO2 to
3.0 equivalents. Other attempts to promote this transformation
proved to be ineffective (see the Supporting Information).
After the detailed investigation mentioned above, the opti-
mized conditions for this process were defined as the use of
1a (0.2 mmol) with NaSO2CF3 (2.5 equiv), TBHP (7.0 equiv, 70%
aqueous), NaOAc (2.0 equiv), and MnO2 (3.0 equiv) in CH3CN/
H2O (2:1, 1.5 mL) at 608C under air atmosphere for 10 h. The
structure of 2a was confirmed by X-ray crystal structure analy-
sis (see the Supporting Information).[14]
To explore the scope of this reaction, various substituted N-
arylpropiolamides were investigated under the optimized reac-
tion conditions (Table 2). Firstly, we investigated the effect of
the substituent at nitrogen (R1). Whereas substrate 1c (R1 =H)
only gave a trace amount of the desired product, substrate 1b
(R1 =ethyl) afforded the corresponding product 2b in 41%
yield. Secondly, the effect of substituent R2 was investigated.
Both electron-withdrawing and electron-donating groups at
the ortho and meta positions were well tolerated and afforded
the desired products 2d–h in moderate yields, which demon-
strated that the electronic effect of R2 had no significant influ-
ence on the reaction. Notably, the products 2 f and 2h, in
which R2 =Cl, could be obtained smoothly in satisfactory
yields, which could provide a potential opportunity for further
transformations through orthogonal cross-couplings. The sub-
strates with two substituents on the phenyl rings were also tol-
erated to give the corresponding products 2i–k, albeit in rela-
tively low yields, which indicated that steric effect made some
difference to the yield. By changing the phenyl group to
a naphthyl group in substrate 1l, the corresponding product
2l was obtained in 44% yield. Subsequently, the effect of R3
on the reaction was studied under the optimized conditions.
Substrates 1m–s, which bore electron-donating or electron-
withdrawing at the ortho, meta, or para position of the aryl
group, were efficiently transformed into the desired products
2m–2s in moderate yields. Notably, the reaction of substrate
1t, with two electron-withdrawing chloro groups, still proceed-
ed smoothly and afforded the corresponding product 2t in
44% yield. Interestingly, a biphenyl group (1u) or 2-thienyl
group (1v) on the terminal alkyne was compatible with this
process to afford the products 2u or 2v, albeit in low yields.
Even a methyl group on the terminal alkyne did not affect the
desired reaction, giving 2w in 36% yield. Finally, we replaced
Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst ([mol%]) Base ([equiv]) Additive ([equiv])
Yield[b] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuI (10)
CuCl2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
CuCl (10)
–
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
–
–
–
–
–
–
–
–
–
–
–
–
–
13
30
26
24
28
38
37
42
36
31
45
trace
37
49
42
53
58(21[c])
Na2CO3 (2.0)
KOH (2.0)
K2HPO4 (2.0)
KF (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
NaOAc (2.0)
K2S2O8 (2.0)
KIO3 (2.0)
NaOAc (2.0) Ce(SO4)2·4H2O (2.0)
NaOAc (2.0)
NaOAc (2.0)
MnO2 (2.0)
MnO2 (3.0)
[a] Reaction conditions: 1a (0.2 mmol,1 equiv), NaSO2CF3 (2.5 equiv),
TBHP (7.0 equiv, 70% aqueous solution) in CH3CN/H2O (2:1, 1.5 mL) at
608C under air atmosphere for 10 h; [b] yield of isolated product; [c] the
amount of recovered starting material is given in parentheses.
to this system, the yield was increased to 30%. We considered
that the addition of base might accelerate trifluoromethylation,
as the slower trifluoromethylation of electron-deficient
carbon–carbon triple bond, which is disfavored in atom-trans-
fer radical addition reactions. Thus, a series of bases were
tested, including KOH, K2HPO4, KF, and NaOAc, of which
NaOAc led to the most marked improvement in the yield
(Table 1, entries 2–6). Subsequently, different copper catalysts,
such as CuI, CuCl2, Cu(OAc)2, Cu(OTf)2, and CuCl, were investi-
gated, of which CuCl was most beneficial (Table 1, entries 7–
11). A control experiment revealed that the copper catalyst
was essential for the reaction (Table 1, entry 12). A further
study on this reaction indicated that the addition of oxidants
Scheme 2. Trifluoromethylation of substrates with para substituents R2.
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moiety was also tolerated to
give the desired product 2x in
41% yield. We attribute these re-
sults to the addition of the tert-
butylperoxy radical (from TBHP)
to the para position of the
phenyl group, forming a CÀO
bond and leading to cleavage of
the CÀF, or CÀN(CH3)2, or CÀCl
bonds to yield HF, HN(CH3)2, or
HCl, respectively,[15] prior to final
elimination of tBuOH to afford
the desired products.
Table 2. Copper-catalyzed trifluoromethylation of N-arylpropiolamides with NaSO2CF3.[a,b]
To gain further understanding
about the reaction mechanism,
some control experiments were
carried out (Scheme 3). When
2.5 equivalents
of
TEMPO
(2,2,6,6-tetramethyl-1-piperidinyl-
oxy) were added into the reac-
tion system, the transformation
was found to be inhibited and
only trace amounts of the prod-
uct were detected [Scheme 3,
Equation (1)], which suggested
that the reaction proceeded may
via a radical trifluoromethylation
process. Then, 18O-labeling ex-
periments were performed to
explore the source of the
oxygen atom of the newly-
formed carbonyl. 15% 18O-la-
beled product was obtained
when H218O was added into the
reaction, meanwhile, the desired
product was afforded in 11%
yield under the 18O2 atmosphere
and only 10% ratio of the 18O-la-
beled product was observed
[Scheme 3, Equations (2) and
(3)]. In light of these results, we
propose that the oxygen atom
of the newly formed carbonyl
mainly comes from TBHP,[15a,16]
with
a small amount of ex-
change with the oxygen atom
generated from H2O (see the
Supporting Information, sec-
tion 6). In addition, the intermo-
lecular kinetic isotope effect (KIE)
experiment was observed with
[a] Reaction conditions: 1a (0.2 mmol, 1 equiv), NaSO2CF3 (2.5 equiv), TBHP (7.0 equiv, 70% aqueous), NaOAc
(2.0 equiv), MnO2 (3.0 equiv) in CH3CN/H2O (2:1, 1.5 mL) at 608C under air atmosphere for 10 h; [b] yield of iso-
lated product; [c] the amount of recovered starting material is given in parentheses.
the amide moiety by an ester moiety, and the corresponding
products 2x–bb were also obtained in comparable yields
Interestingly, substrates with a fluoro or N,N-dimethylamino
group at the para position of the N-phenyl moiety afforded
the spirocyclic compound 2a in moderate yields (Scheme 2).
Moreover, the substrate with a chloro group para to an ester
kH/kD =7.0, which indicated that the CarylÀH bond cleavage is
involved in the rate-determining step of this procedure (see
the Supporting Information, section 7).
On the basis of this study and previous reports,[15a,16,17]
a plausible mechanism was proposed (Scheme 4). Firstly, the
interaction of NaSO2CF3 with TBHP or MnO2 generates the ·CF3
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C,[18] the tert-butylperoxy radical
having been generated by the
reaction of TBHP with the tert-
butoxy radical or the CuII com-
plex (through a single-electron
transfer process from CuCl and
hydroxyl radical).[15a] Finally,
C
undergoes deprotonation and
the elimination of tBuOH in the
rate-limiting step to afford 2a.
Due to the significant intermo-
lecular KIE, we propose that the
intermediate C is likely unstable
and may regenerate the tert-bu-
tylperoxy radical and B, which
could undergo ring-opening to
regenerate radical A in a reversi-
ble process.[15a]
In summary, we have devel-
oped a novel Cu-catalyzed di-
functionalizing trifluoromethyla-
tion of activated alkynes with
NaSO2CF3 and TBHP via radical
oxidation–tandem
cyclization/
dearomatization process, to syn-
thesize a series of 3-trifluoro-
methyl spiro[4.5]trienones, incor-
porating a spirocycle unit that is
a common structural motif in
many natural products and phar-
maceuticals. This process is an
example of an electron-deficient
carbon–carbon triple bond react-
ing with NaSO2CF3 to form CÀ
CF3 bonds[19] and involves the si-
multaneous formation of two
carbon–carbon bonds and one
carbon–oxygen double bond,
providing a practical strategy for
the difunctionalization of alkynes
by a radical process.
Scheme 3. Mechanistic studies.
Experimental Section
General procedure for carbotri-
fluoromethylation/dearomati-
zation of N-arylpropiolamides 1
In
a
glass tube, substrate
1
(0.2 mmol, 1.0 equiv), Langlois
reagent (0.5 mmol, 78.0 mg), CuCl
(0.02 mmol, 2.0 mg), NaOAc
Scheme 4. Proposed mechanism.
(0.4 mmol, 32.8 mg), and MnO2
(0.6 mmol, 52.2 mg) were added.
CH3CN (1.0 mL), H2O (0.5 mL), and TBHP (1.4 mmol) were then
added to the mixture under air atmosphere. The mixture was
stirred for 10 h at 608C. The resulting reaction mixture was concen-
trated under reduced pressure and the residue was purified by
radical.[10l] Subsequently, the addition of the ·CF3 radical to the
a-position of the C=O bond of 1a generates vinyl radical A,
which undergoes an intramolecular radical cyclization to give
B. B is then trapped by the tert-butylperoxy radical to afford
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Acknowledgements
We thank the National Science Foundation (NSF21072080,
21302076, 21472074) for financial support. We also acknowl-
edge support from the “111” Project and Program for Chang-
jiang Scholars and Innovative Research Team in University
(IRT1138).
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Keywords: copper · cyclization · radical reactions · tandem
reactions · trifluoromethylation
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Communication
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Received: October 16, 2014
Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Tandem Reactions
H.-L. Hua, Y.-T. He, Y.-F. Qiu, Y.-X. Li,
B. Song, P. Gao, X.-R. Song, D.-H. Guo,
X.-Y. Liu,* Y.-M. Liang*
&& – &&
Copper-Catalyzed Difunctionalization
of Activated Alkynes by Radical
Oxidation–Tandem Cyclization/
Dearomatization to Synthesize 3-
Trifluoromethyl Spiro[4.5]trienones
Spiro mania: A copper-catalyzed di-
functionalizing trifluoromethylation of
activated alkynes with the cheap re-
agent NaSO2CF3 has been reported, af-
fording a series of 3-trifluoromethyl spi-
ro[4.5]trienones through a tandem cycli-
zation/dearomatization process. In this
alkyne difunctionalization process, two
carbon–carbon bonds and one carbon–
oxygen double bond are simultaneously
formed.
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ