Copper-catalyzed oxytrifluoromethylation of unactivated alkenes

Article abstract of DOI:10.1021/ja305840g

A mild, versatile, and convenient method for the efficient oxytrifluoromethylation of unactivated alkenes based on a copper-catalyzed oxidative difunctionalization strategy has been developed. This methodology provides access to a variety of classes of sy

Full text of DOI:10.1021/ja305840g

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Communication
Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes
Rong Zhu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja305840g • Publication Date (Web): 17 Jul 2012
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Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes
Rong Zhu and Stephen L. Buchwald*
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Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
hypothesized that either a single electron oxidation of the radi-
cal intermediate followed by trapping the resulting carbocation
ABSTRACT: A mild, versatile and convenient method for the
efficient oxytrifluoromethylation of unactivated alkenes has
been developed based on a copper-catalyzed oxidative difunc-
(Path A) or copper-mediated C−Nu bond formation (Path B)
would lead to the desired difunctionalization product (III).8
tionalization strategy. This methodology provides access to a
The success of this strategy lies in the identification of a cata-
variety of classes of synthetically useful CF3-containing build-
ing blocks from simple starting materials.
lytic system efficient for both the C−CF3 bond formation and
the subsequent functionalization steps, as well as the ability to
inhibit the competitive elimination pathway. Herein we de-
scribe a copper(I)/2,2’-biquinoline catalytic system that incor-
porates these qualities with oxygen-based nucleophiles.
The incorporation of fluoroalkyl groups and particularly the
trifluoromethyl (CF3) group in pharmaceutical and agrochemi-
cal relevant molecules has a significant impact on their physi-
cal and biological properties, mainly because of the unique
We began our study by examining the reaction of 4-
pentenoic acid (2a) in the presence of Togni’s reagent 19 and a
catalytic amount of Cu(MeCN)4PF6 in methanol. Only allylic
trifluoromethylated product 4a was observed in this case, sug-
metabolic stability, lipophilicity and electron-withdrawing
nature of the trifluoromethyl substituent.1 The importance of
gesting elimination as the major pathway (Table 1, entry 1).
After examining the effects of solvents and additives, we
CF3-containing compounds provides a continuing driving
found that switching to acetonitrile, in the presence of a cata-
force for the development of more efficient and versatile tri-
fluoromethylation methods.2 Our research group has focused
lytic amount of 2,2’-bipyridyl (L1), the desired oxytrifluoro-
on the development of new fluorination3 and trifluoromethyla-
methylation product 3a was obtained in 10% yield (entry 3).
tion4 reactions using transition-metal catalysis. Herein we re-
Encouraged by this result, we evaluated a series of different
bidentate pyridine-based ligands, which finally led to the iden-
port a mild and versatile copper-catalyzed oxytrifluoromethyl-
ation reaction of unactivated alkenes that allows rapid access
to a variety of CF3-containing building blocks from simple
starting materials.
tification of di-2-pyridylketone (L4) and 2,2’-biquinoline (L5)
as being optimal (entry 6 and 7). A nearly 90 % yield of 3a
could be obtained in the presence of either L4 or L5, with only
trace of 4a observed. Both the copper salt and ligand proved to
Recently, our group, as well as that of Liu and Wang, inde-
be essential in order for the oxytrifluoromethylation reaction
pendently reported the copper-catalyzed allylic trifluorometh-
to take place as no 3a was observed in the absence of either of
these components (entry 2 and 8).
Table 1. Ligand effect.a
ylation of unactivated alkenes (Scheme 1).4d,5 During the
course of our studies, we proposed that this transformation
might involve either an α-CF3-alkyl radical (I) or α-CF3-
alkylcopper species (II), which subsequently undergoes elimi-
Cu(MeCN)4PF6 (10 mol%)
Ligand (20 mol%)
1 (1.1 equiv.)
nation to afford the allylic trifluoromethyl product. We be-
came interested in the possibility of intercepting this putative
intermediate (I or II), as a means for the synthesis of a number
of structurally diverse CF3-containing building blocks in a
step-economical fashion.
O
O
O
O
+
CF3
HO
CF3
HO
Solvent, 55 °C
2a
3a
4a
Yield (%)b
Entry
Solvent
Ligand
Scheme 1. Copper-catalyzed trifluoromethylation of unac-
tivated alkenes.
3a
4a
1
2
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
-
< 5
< 5
10
46
< 5
18
Possibly via:
Cu-catalyzed Allylic Trifluoromethylation:
-
O
(I)
R
CF3
CF3
Cu(MeCN)4PF6 (15 mol%)
MeOH, 0 °C to RT
3
L1
L2
L3
L4
L5
L5
O
+
R
or
R
CF3
I
4
12
11
[Cu]
CF3
(II)
1
R
5
11
< 5
5
Cu-catalyzed Difunctionalization:
Path A
6
86
NuH
- 1 e
NuH
CF3
CF3
7
8c
89
< 5
< 5
Nu
CF3
NuH
1
< 5
cat. Cu(I)/L
NuH
(III)
Path B
[Cu]
aReaction conditions: Cu(MeCN)4PF6 (10 mol%), ligand (20
CF3
This work: Nu = O
oxytrifluoromethylation
mol%), 2a (0.10 mmol, 1.0 equiv.), 1 (1.1 equiv.), solvent (1.0
b
mL), 55 °C, 16 h. Determined by 19F NMR spectroscopy using
We envisioned that the oxidative difunctionalization of un-
actived alkenes involving tandem C−CF3 and C−Nu bond
formation could be achieved based on this strategy.6,7 It was
PhCF3 as an internal standard. cWithout Cu(MeCN)4PF6.
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O
O
1
2
3
4
5
6
2f
3f
6
71
77
O
N
HO
N
N
N
N
N
N
O
O
N
CF3
O
O
O
N
N
2g
3g
7
OH
O
CF3
7
8
9
L1
L2
L3
L4
L5
O
CF3
O
8c
9
42e
73e
35
2h
2i
2j
3h
O
With an optimized protocol in hand, we next explored the
scope of this oxytrifluoromethylation reaction. Illustrative
examples are shown in Table 2. A series of unsaturated ali-
phatic and aromatic carboxylic acids were found to undergo
the desired transformation to give the corresponding trifluo-
romethylated lactones in good yields (entry 1-8). With regard
to the scope of alkene moiety, monosubstituted and geminal
disubstituted alkenes were excellent substrates for this reac-
tion.10 Alkyl and aryl substituents on the carbon−carbon dou-
ble bond were well tolerated. In terms of the size of the ring
formed, δ-, γ-, and even β-lactones proved to be accessible.
HO
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O
3i
HO
CF3
OH
CF3
O
10d
3j
OH
O
11c,f
12
50
2k
3k
Ph
CF3
Ph
(dr 10:1)
Next, we sought to expand the scope of the nucleophile to
include other common oxygen-based functional groups. It was
found that primary alcohols (Table 2, entry 9) and phenols
(entry 10) also served as viable nucleophiles for this reaction.11
OH
O
2l
3l
70
n-heptyl
CF3
n-heptyl
Br OH
(dr 4:1)
Allylic alcohols (Table 2, entry 11-13) are an especially
interesting class of substrates because their oxytrifluorometh-
ylation reactions give rise to 3-trifluoromethyl-1,2-epoxides,
which are highly versatile CF3-containing intermediates. It
was found that both aryl- (2k, 2m) and alkyl- (2l) substituted
allylic alcohols furnished the desired products in moderate to
good yields. When the enantiomerically enriched 2k was sub-
jected with the standard protocol, 3k was produced with no
erosion in enantiomeric excess (eq. 1).
Br
O
13c
64
CF3
2m
3m
O
O
(dr >20:1)
O
O
aReaction conditions: Cu(MeCN)4PF6 (10 mol%), 2,2’-
biquinoline (20 mol%), 2 (0.50 mmol, 1.0 equiv.), 1 (1.1 equiv.),
MeCN (4 mL), 55 °C, 16 h. bIsolated yields, average of two runs.
Diastereo ratio determined by 19F NMR and 1H NMR spectro-
scopic analysis. Structures of the major diastereomers are shown.
cCu(MeCN)4PF6 (20 mol%) and 2,2’-biquinoline (30 mol%) were
used. dCu(MeCN)4PF6 (20 mol%) and di-2-pyridyl ketone (30
Table 2. Copper-catalyzed oxytrifluoromethylation.a
1 (1.1 equiv.)
Cu(MeCN)4PF6 (10 mol%)
OH
mol%) were used. Determined by 19F NMR spectroscopy using
e
2,2'-biquinoline (20 mol%)
MeCN (4 mL), 55 °C, 16 h
O
CF3
f
PhCF3 as an internal standard. The reaction did not go to full
conversion.
2a-m
3a-m
OH
O
Yield (%)b
standard conditions
(1)
Entry
1
Substrate
Product
Ph
CF3
Ph
50%
(R)-2k
(2S,3S)-3k
O
O
O
O
O
O
O
2a
3a
94% ee
94% ee
76
81
CF3
HO
To further demonstrate the synthetic utility of the products
derived from this method, oxytrifluoromethylation product 3m
was shown to undergo epoxide opening in good yields in the
presence of a number of different nucleophiles including an
azide, a Grignard reagent, a thiol and fluoride (Scheme 2). A
series of highly functionalized CF3-containing building blocks
(5-8), which are otherwise difficult to access, could easily be
prepared from the simple allylic alcohol 2m in two steps.
O
Ph
2b
3b
2
3
HO
CF3
Ph
Me
Ph
O
Ph
2c
3c
CF3
94
HO
Me
(dr 2.2:1)
While the mechanistic details of this copper-catalyzed oxy-
trifluoromethylation reaction remain unclear at present, the use
of a copper(I)/bidentate pyridine-based ligand system is sug-
gestive of an atom transfer-type radical addition pathway.8b,12
Further, the oxytrifluoromethylation reaction was found to be
completely inhibited by addition of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO), a known radical scavenger.13
O
O
O
CF3
2d
3d
4
74
HO
BzHN
NHBz
(dr 2.8:1)
O
O
OH
5c
64
O
2e
3e
CF3
Scheme 2. Versatile transformations of the oxytrifluoro-
methylation product 3m.a
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N3
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Org. Lett. 2012, 14, 2882.
(6) For recent examples of transition-metal-catalyzed oxidative di-
functionalization of unactivated alkenes involving tandem C−O/C−C
bond formation: (a) Nicolai, S.; Erard, S.; González, D. F.; J. Waser,
Org. Lett. 2010, 12, 384; (b) Pathak, T. P.; Gligorich, K. M.; Welm,
B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 7870; (c)
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son, C. R. J. Org. Lett. 2011, 13, 6320; (d) Zhu, R.; Buchwald, S. L.
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10.1021/ja3034075.
(7) For halo-trifluoromethylation and -perfluoroalkylation of ole-
fins via atom transfer radical addition: (a) Kamigata, N.; Fukushima,
T.; Yoshida, M. J. Chem. Soc. Chem. Commum. 1989, 1559; (b)
Kamigata, N.; Fukushima, T.; Terakawa, Y.; Yoshida, M.; Sawada,
H. J. Chem. Soc. Perkin Trans. 1 1991, 627; (c) Zou, X.; Wu, F.;
Shen, Y.; Xu, S.; Huang, W. Tetrahedron 2003, 59, 2555; For trifluo-
romethylation of alkenes catalyzed by palladium: (d) Mu, X.; Wu, T.;
Wang, H.; Guo, L.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878; (e)
Fuchikami, T.; Shibata, Y.; Urata, H. Chem. Lett. 1987, 521.
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Stahl, S. S. Angew. Chem. Int. Ed. 2011, 50, 11062.
1
2
3
4
5
6
7
8
CF3
CF3
62%
91%
OH
OH
O
O
Br
O
O
O
5
6
CF3
Cl
O
3m
Br
O
F
Br
O
S
c
d
CF3
CF3
OH
OH
92%
79%
9
O
O
10
11
12
13
7
8
aReaction conditions: (a) NaN3 (3 equiv.), NH4Cl (2 equiv.),
H2O/MeOH, 80 °C, 3 h; (b) Allylmagnesium bromide (3 equiv.),
Et2O, RT, 2 h; (c) p-ClC6H4SH (2 equiv.), NaOH (2 equiv.), diox-
ane/H2O, 65 °C, 2 h; (d) BF3•Et2O (0.33 equiv.), DCM, -15 °C, 5
min.
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In conclusion, a mild, versatile and convenient method for
the efficient oxytrifluoromethylation of unactivated alkenes
has been developed based on a copper(I)/2,2’-biquinoline cata-
lytic system. Carboxylic acids, alcohols and phenols all serve
as suitable nucleophiles under the conditions developed. The
reaction conditions are compatible with a range of functional
groups including amides, β-lactones, epoxides and aryl bro-
mides. All the reactions were carried out using simple, user-
friendly bench-top set-up. This methodology allows rapid ac-
cess to a variety of synthetically useful building blocks such as
CF3-containing lactones, cyclic ethers, and epoxides from
simple starting materials. We are continuing work to gain in-
sight into the reaction mechanism and expand the scope of this
copper-catalyzed alkene difunctionalization strategy.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, characteriza-
tion and spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(9) Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12,
2579.
* sbuchwal@mit.edu
(10) Low yields were obtained with 1,2-disubstituted alkene sub-
strates. For instance, under the standard conditions, (E)-5-phenyl-4-
pentenoic acid furnished the expected oxytrifluoromethylation prod-
uct in only 11% yield as determined by 19F NMR spectroscopy.
(11) In preliminary experiments, the reactions of substrates con-
taining secondary amides or sulfonamides in place of carboxylic acids
gave little or no yield of the desired product.
(12) C−O bond formation was observed as a side reaction in a
photoredox-catalyzed atom transfer radical addition reaction: Nguyen,
J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. J.
Am. Chem. Soc. 2011, 133, 4160.
(13) However, neither of the TEMPO adducts derived from CF3•
or the proposed α-CF3-alkyl radical (I) was observed in the inhibition
experiment, preventing us from making further conclusions. See sup-
porting information for detail. For recent examples of arene trifluo-
romethylation involving a trifluoromethyl radical: (a) Nagib, D. A.;
MacMillan, D. W. C. Nature 2011, 480, 224; (b) Ji, Y.; Brueckl, T.;
Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.;
Baran, P. S. Proc. Natl. Acad. Sci. 2011, 108, 14411. (c) Ye, Y.; San-
ford, M. S. J. Am. Chem. Soc. 2012, 134, 9034.
ACKNOWLEDGMENT
We thank the National Institutes of Health for financial support of
this work (Grant GM46059). This activity is supported, in part, by
an educational donation provided by Amgen for which we are
grateful. We thank Dr. Thomas J. Maimone for helpful discus-
sions. The Varian 300 MHz and Bruker 400 MHz NMR spec-
trometers used in this work were purchased with funds from the
National Science Foundation (Grants CHE 9808061 and DBI
9729592) and the National Institutes of Health (1S10RR13886-
01), respectively.
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