Copper-catalyzed one-pot trifluoromethylation/aryl migration/carbonyl formation with homopropargylic alcohols

Article abstract of DOI:10.1002/anie.201403383

A novel copper-catalyzed one-pot functionalization of homopropargylic alcohols that involves trifluoromethylation, aryl migration, and formation of a carbonyl moiety has been developed. This reaction constitutes the first direct conversion of homopropargy

Full text of DOI:10.1002/anie.201403383

Angewandte
Chemie
DOI: 10.1002/anie.201403383
Trifluoromethylation
Copper-Catalyzed One-Pot Trifluoromethylation/Aryl Migration/Car-
bonyl Formation with Homopropargylic Alcohols**
Pin Gao, Yong-Wen Shen, Ran Fang, Xin-Hua Hao, Zi-Hang Qiu, Fan Yang, Xiao-Biao Yan,
Qiang Wang, Xiang-Jun Gong, Xue-Yuan Liu,* and Yong-Min Liang*
Abstract: A novel copper-catalyzed one-pot functionalization
of homopropargylic alcohols that involves trifluoromethyla-
tion, aryl migration, and formation of a carbonyl moiety has
been developed. This reaction constitutes the first direct
conversion of homopropargylic alcohols into CF3-containing
3-butenal or 3-buten-1-one derivatives in a regioselective
manner. Mechanistic studies indicate that the 1,4-aryl migra-
tion proceeds through a radical pathway.
alkenes[13] and on the directing-group-assisted trifluorome-
thylation of alkenes.[14] Furthermore, new synthetic methods
for the difunctionalization of alkynes to construct olefinic
T
rifluoromethyl-containing compounds have gained much
attention because of their unique electronegativity, metabolic
stability, and lipophilicity, which improve the physical and
biological properties of pharmaceuticals, agrochemicals, and
materials.[1] As a consequence, numerous versatile and
efficient methods to incorporate the CF3 group into target
molecules have been reported.[2,3] Transition-metal-catalyzed
trifluoromethylation reactions have emerged as powerful
synthetic methods and feature high regioselectivity, mild
reaction conditions, and efficient conversion.[4–7] Copper and
palladium complexes were shown to be efficient in the
Scheme 1. Difunctionalization of alkynes to construct olefinic
2
À
construction of aryl–CF3 bonds from aryl halides and aryl
C(sp ) CF3 bonds.
3
boronic acids.[5] The formation of C(sp ) CF3 bonds has also
À
been realized from allyl halides, allylsilanes, and even
Table 1: Optimization of the reaction conditions.[a]
unactivated alkenes with copper as the catalyst.[6] Further-
more, difunctionalizing trifluoromethylation reactions of
3
À
alkenes have been developed to construct C(sp ) CF3 bonds
with concomitant formation of carbon–nucleophile bonds.[7]
Trifluoromethylated alkenes are commonly found in
biologically active compounds and are featured in pharma-
ceuticals and agrochemicals.[8] Commonly used strategies for
the formation of vinyl–CF3 bonds are based on transition-
metal-mediated or -catalyzed trifluoromethylation reactions
of vinylboronic acids,[9] vinyl sulfonates,[10] potassium vinyl-
trifluoroborates,[11] a,b-unsaturated acids,[12] or unactivated
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
[Cu(CH3CN)4]PF6
CuBr
CuCN
CuI
CuOAc
Cu(OTf)2
FeCl2
CuI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
34
36
46
51
39
38
33
0
[*] Dr. P. Gao, Y.-W. Shen, R. Fang, X.-H. Hao, Z.-H. Qiu, F. Yang,
X.-B. Yan, Q. Wang, X.-J. Gong, Prof. Dr. X.-Y. Liu,
Prof. Dr. Y.-M. Liang
9
CuI
CuI
CuI
CuI
CuI
CuI
none
MeCN
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
0
0
10
11
12[c]
13[d]
14[e]
15
State key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (China)
62 (21[f])
44
55
56
0
E-mail: liuxuey@lzu.edu.cn
liangym@lzu.edu.cn
[**] We thank the National Science Foundation (NSF21072081) and the
National Basic Research Program of China (973 Program; 2010CB8-
33203) for financial support. We also acknowledge support from the
“111” Project and the Program for Changjiang Scholars and
innovative Research Team in University (IRT1138).
[a] Reaction conditions: 1a (0.2 mmol), Togni’s reagent (2; 0.4 mmol),
and the catalyst (0.04 mmol) in the specified solvent (1.5 mL) were
stirred at 308C for 24 h under argon. [b] Yield of isolated product. [c] CuI
(0.06 mmol). [d] CuI (0.02 mmol). [e] The reaction was performed at
508C. [f] The amount of recovered starting material is given in
parentheses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403383.
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[15]
À
C(sp ) CF3 bonds have recently been explored. In 2012,
revealed that the reaction was highly solvent-dependent:
The highest yields were obtained for reactions conducted in
CHCl3, whereas no desired product was detected in DMF,
MeCN, and toluene (entries 8–11). Changing the catalyst
loading[20] or increasing the reaction temperature did not
improve the yield further (entries 12–14). Other attempts to
promote this transformation proved to be ineffective (see the
Supporting Information). A control experiment revealed that
the copper catalyst was essential for the reaction (entry 15).
Consequently, the reaction proceeded efficiently in the
presence of CuI (20 mol%) in CHCl3 at 308C.
the groups of Szabꢀ[15a] and Sodeoka[15b] independently
studied the oxy-trifluoromethylation of alkynes for the
construction of C(sp ) CF3 bonds [Scheme 1, Eq. (1)]. Very
recently, Cho and co-workers successfully performed the
iodo-trifluoromethylation and hydro-trifluoromethylation of
alkynes using CF3I as the trifluoromethylating reagent, and
two different products could be isolated depending on the
choice of visible-light photoredox catalyst, base, and solvent
[Scheme 1, Eq. (2)].[15c] These trifluoromethylation reactions
of alkynes, however, are mainly limited to additions to
terminal alkynes. There are few
2
À
reports on constructing olefinic
Table 2: Copper-catalyzed trifluoromethylation and aryl migration of secondary homopropargylic
2
À
C(sp ) CF3 bonds through the addi-
tion of trifluoromethyl radicals to
internal alkynes,[16] in spite of the
fact that carbon–carbon triple
bonds can easily be converted into
multisubstituted alkenes by addi-
tion reactions. Therefore, an effi-
cient method for the catalytic tri-
alcohols.[a,b]
fluoromethylation
of
alkynyl
carbon atoms is highly desired.
Herein, we report an unprece-
dented and highly regioselective
route to CF3-containing tetrasubsti-
tuted 3-butenal and 3-buten-1-one
derivatives under copper catalysis,
which combines alkyne trifluoro-
methylation, 1,4-aryl migration,
and formation of
a
carbonyl
moiety in one-pot reaction.
a
Importantly, this reaction involves
an intramolecular 1,4-aryl migra-
tion,[17] which proceeds via a 5-ipso
cyclization
intermediate
[II;
Scheme 1, Eq. (3)].[18]
Our investigation commenced
with the reaction of 1,4-diphenyl-
but-3-yn-1-ol (1a) with Togniꢁs
reagent (2) and [Cu(CH3CN)4]PF6
(20 mol%) in CH2Cl2 at 308C under
argon atmosphere. The unexpected
trifluoromethylated 3-butenal 3a
was formed in 34% yield (Table 1,
entry 1). The structure of 3a was
determined by X-ray crystallo-
graphic analysis (see the Supporting
Information).[19] Encouraged by this
result, we then screened different
copper salts, including CuBr, CuCN,
Cu(OTf)2, CuOAc, and CuI, for this
trifluoromethylation/aryl migration
reaction (entries 2-6), and found
that CuI was slightly more effective,
increasing the yield to 51%. FeCl2
showed poor catalytic activity
[a] Reaction conditions: CuI (0.04 mmol, 20 mol%), 1 (0.2 mmol, 1.0 equiv), Togni’s reagent (2;
0.2 mmol, 2.0 equiv), CHCl3 (1.5 mL), 308C, 24 h, argon atmosphere. [b] Yields of isolated products, the
towards
this
transformation
(entry 7). Next, a solvent screen amount of recovered starting material is given in parentheses.
2
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Table 3: Copper-catalyzed trifluoromethylation/aryl migration of tertiary
ever, when 1ee was chosen as the substrate to investigate the
selectivity of the aryl migration, the two isomeric products
3ee and 3ee’ could be isolated in a ratio of 2.5:1.
homopropargylic alcohols.[a,b]
To gain insight into the reaction mechanism, we per-
formed a control experiment. First, the reaction was com-
pletely inhibited when 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), a radical scavenger, was added to the system
under the standard reaction conditions (Scheme 2); instead,
the TEMPO–CF3 adduct (4) was formed in 70% yield, as
estimated by 19F NMR spectroscopy. Furthermore, we tried to
capture some radical intermediates by electron spin reso-
nance (ESR) with the 2-methyl-2-nitrosopropane dimer
(MNP) as the radical trap (Figure 1). An ESR spectrum of
a typical reaction mixture with MNP displayed a signal with
six peaks, which confirmed the presence of a CF3 radical
(trace b).[21] These results indicate that the reaction was
initiated by the CF3 radical. When MNP was added to the
reaction mixture at a later stage, a different signal was
observed, which might be the radical intermediate A (trace c;
see also Scheme 3) caught by the MNP, which is in line with
the species detected by HRMS–ESI (for details see the
Supporting Information).
[a] Reaction conditions: CuI (0.04 mmol, 20 mol%), 1 (0.2 mmol,
1.0 equiv), Togni’s reagent (2; 0.2 mmol, 2.0 equiv), CHCl3 (1.5 mL),
308C, 24 h, argon atmosphere. [b] Yields of isolated products, the
amount of recovered starting material is given in parentheses.
With the optimized reaction conditions established, we
next set out to evaluate the scope of the trifluoromethylation/
aryl migration reaction with various secondary homopropar-
gylic alcohols 1b–1w. The results are summarized in Table 2.
The effects of the substitution pattern of the aryl ring that is
attached to the triple bond were not obvious. Alcohols with
both electron-rich (1b–1d) and electron-poor (1e–1g) aryl
substituents were found to undergo migration, affording the
corresponding products 3b–3g in moderate yields. Even ester
and trifluoromethyl groups were tolerated under the reaction
conditions (1h, 1i). It is noteworthy that a substrate with
5-methylthiophene attached to the triple bond (1j) success-
fully provided the desired product in 43% yield. Then,
a number of alcohols derived from substituted benzaldehydes
were tested. Substrates 1k–1o, which bear electron-donating
substituents in the ortho, meta, or para position of the aryl
group, were efficiently transformed into the b-trifluoro-
methyl-substituted 3-butenals 3k–3o in moderate yields.
With a fluorine substituent in the para position, the desired
product 3p was formed in 58% yield. However, for substrates
with chloro, bromo, or CF3 groups in the para position (1q–
1s), not only the expected products 3q–3s were obtained, but
also isomers with a six-membered ring (4q–4s), which were
isolated in 9%, 13%, and 32% yield, respectively. A hydroxy
group was also tolerated under the reaction conditions, and 3t
was isolated in moderate yield.[19] Substrates with two or three
identical substituents on the aryl ring provided the products
(3u, 3v) in moderate to good yields. Even a 5-methylfuran
derivative could undergo the migration to give 3w in 31%
yield.
Scheme 2. Control experiment for mechanistic insights. Yields deter-
mined by 19F NMR spectroscopy.
Figure 1. ESR studies. a) ESR spectrum of a solution of 2-methyl-2-
nitrosopropane (MNP; 5ꢀ10À2 molLÀ1) in CHCl3 stirred for 1 h.
b) ESR spectrum of a solution of 1a (5ꢀ10À2 molLÀ1, 0.2 mmol),
Next, various tertiary homopropargylic alcohols were
investigated (Table 3). Symmetric a,a-diaryl homopropar-
gylic alcohols with electron-deficient or electron-rich aryl
groups (1aa–1cc) afforded the desired b-vinyl b-trifluoro-
methyl ketone derivatives in moderate yields. The reaction of
unsymmetric substrate 1dd was highly chemoselective, with
only the product of phenyl migration being observed. How-
Togni’s reagent 2 (0.1 molLÀ1, 0.4 mmol), MNP (0.1 molLÀ1
,
0.4 mmol), and CuI (1ꢀ10À2 molLÀ1, 0.04 mmol) in CHCl3 (4 mL)
stirred for 1 h. c) A solution of 1a (5ꢀ10À2 molLÀ1, 0.2 mmol), Togni’s
reagent 2 (5ꢀ10À2 molLÀ1, 0.2 mmol), and CuI (1ꢀ10À2 molLÀ1
,
0.04 mmol) in CHCl3 (4 mL) was stirred for 8 h, then a solution of
MNP (0.2 mmol) was added; the spectrum was recorded 30 min later.
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Experimental Section
General procedure for the trifluoromethylation/aryl
migration of homopropargylic alcohol 1: In a glass tube,
Togniꢁs reagent 2 (126.0 mg, 0.4 mmol) and CuI (7.6 mg,
0.04 mmol) were successively added to a solution of
1 (0.2 mmol) in CHCl3 (1.5 mL). The reactor was flushed
with argon and sealed. The reaction mixture was stirring at
308C for 24 h; then, the reaction mixture was partitioned
between CH2Cl2 and
a saturated aqueous NaHCO3
solution (15 mL each). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 ꢂ
15 mL). The combined organic extracts were washed
with saturated aqueous NaHCO3 solution, dried over
Na2SO4, and concentrated. The residue was purified by
column chromatography on silica gel (n-hexane/ethyl
acetate) to afford 3.
Received: March 17, 2014
Revised: April 8, 2014
Published online: && &&, &&&&
Keywords: aryl migration · copper · radical reactions ·
.
Togni’s reagent · trifluoromethylation
Scheme 3. Proposed mechanism.
To gain further understanding of the reaction mechanism,
we conducted computational studies using 1a as a model
compound.[22] The calculation indicated that 1,4-aryl migra-
tion can proceed through a radical pathway. Single-electron
transfer (SET) between radical intermediate A and the CuII
species, which would lead to a cationic transition state during
the migration, was found to be unfavorable (for details, see
the Supporting Information).
Based on the above experiments and density functional
theory (DFT) studies, a possible reaction mechanism for the
trifluoromethylation and aromatization of alkynes was pro-
posed (Scheme 3). The CF3 radical, generated from Togniꢁs
reagent (2) and CuI, undergoes radical addition to alkyne 1 to
afford radical A. A 5-ipso cyclization occurs on the benzene
ring, leading to radical A1,[17] which then undergoes intra-
molecular 1,4-aryl migration to form a new C(sp3)-centered
radical intermediate A2.[18] Finally, oxidation of radical A2
with CuII gives the desired product 3 and releases the
copper(I) catalyst (Path A). The radical intermediate A1
can undergo 1,2-migration to afford the radical intermediate
A3 (Path B),[17a] which would give the side products 4 through
a SET process.
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In conclusion, we have developed an unprecedented one-
pot reaction of homopropargylic alcohols that involves
copper-catalyzed trifluoromethylation, 1,4-aryl migration,
and formation of a carbonyl group. A series of 3-butenal
= À
and 3-buten-1-one derivatives containing a C C CF3 subunit
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4
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[22] See the Supporting Information for details of the theoretical
study.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Trifluoromethylation
P. Gao, Y.-W. Shen, R. Fang, X.-H. Hao,
Z.-H. Qiu, F. Yang, X.-B. Yan, Q. Wang,
X.-J. Gong, X.-Y. Liu,*
Y.-M. Liang*
&&&& — &&&&
A copper-catalyzed one-pot reaction of
homopropargylic alcohols involves tri-
fluoromethylation, aryl migration, and
formation of a carbonyl group. A series of
3-butenal and 3-buten-1-one derivatives
with a trifluoromethyl-substituted olefin
were obtained in moderate to good yields
with high regioselectivity. The mechanism
is proposed to involve a 5-ipso cyclization.
Copper-Catalyzed One-Pot
Trifluoromethylation/Aryl Migration/
Carbonyl Formation with
Homopropargylic Alcohols
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!