Enantioselective functionalization of radical intermediates in redox catalysis: Copper-catalyzed asymmetric oxytrifluoromethylation of alkenes

Article abstract of DOI:10.1002/anie.201307790

Something radical: An efficient enantioselective oxytrifluoromethylation of alkenes has been developed using a copper catalyst system. Mechanistic studies are consistent with a metal-catalyzed redox radical addition mechanism in which a C-O bond is formed by the copper-mediated enantioselective trapping of a prochiral alkyl radical intermediate derived from the initial trifluoromethyl radical addition. Copyright

Full text of DOI:10.1002/anie.201307790

Angewandte
Chemie
DOI: 10.1002/anie.201307790
Synthetic Methods Very Important Paper
Enantioselective Functionalization of Radical Intermediates in Redox
Catalysis: Copper-Catalyzed Asymmetric Oxytrifluoromethylation of
Alkenes**
Rong Zhu and Stephen L. Buchwald*
Transition-metal-catalyzed alkene difunctionalization repre-
sents a versatile and step-economical strategy for the
enhancement of molecular complexity, as it accesses multiple
carbon–carbon/carbon–heteroatom bonds and stereogenic
centers in a single step from simple precursors.[1,2] One of
the most synthetically important transformations of this class
is the radical addition of alkenes catalyzed by a transition-
metal redox system.[3] In a typical catalytic cycle (Scheme 1a),
on reactions that afford racemic products, catalyst-controlled
enantioselective functionalizations of A, interesting and
potentially useful processes, have been rarely explored. The
only disclosure is by Sonoda and co-workers and Kamigata
and co-workers who reported the use of chiral rhodium and
ruthenium complexes as catalysts for the atom-transfer
radical addition involving carbon–halogen bond formation
to afford products with 16% ee and 10–40% ee, respectively.[5]
Our interest in developing a transition-metal-catalyzed asym-
metric radical addition reaction by the enantioselective
trapping of A originated from our recent study on the
copper-catalyzed ligand-assisted oxytrifluoromethylation of
alkenes.[6] This method provides efficient access to a variety of
CF3-containing building blocks such as lactones, cyclic ethers,
and epoxides. A redox radical addition mechanism was
À
proposed for this transformation, in which a C O bond was
formed by the copper-mediated trapping of the a-CF3-alkyl
radical species C, which is derived from the addition of CF3
radical (Scheme 1b).[7]
During the course of our study, the use of a bidentate
À
pyridine-based ligand was found to facilitate the C O bond-
formation step. This ligand effect prompted us to explore the
possibility of achieving asymmetric catalysis in this system by
means of enantioselectively trapping the putative intermedi-
ate C. This strategy represents a mechanistically unique
À
approach to enantioselective C O bond formation via
a radical intermediate. Given the wide range of difunction-
alization reactions such radical intermediates can participate
in and the lack of methods for exploiting their reactivity in
enantioselective transformations, we believed that the study
of this transformation could have a significant impact in the
broader context of transition-metal redox catalysis.
Herein, we disclose the realization of this strategy in the
copper-catalyzed enantioselective oxytrifluoromethylation of
alkenes (Scheme 1c). Mechanistic investigations are consis-
tent with a metal-catalyzed redox radical addition mecha-
nism, featuring the enantioselective functionalization of an
alkyl radical intermediate.
Scheme 1. Background of the methodology development.
a metal-generated radical adds across the alkene to give the
nascent carbon radical intermediate A. Subsequent function-
alization of A gives rise to B while regenerating the metal
catalyst. Depending on the nature of the functional group
À
À
À
À
used for trapping, a C X (X = halogen), C O, C N, or C C
bond can be incorporated.[4] In contrast to numerous reports
[*] R. Zhu, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
We began our study by examining the reaction of 4-
phenyl-4-pentenoic acid (2a) with Togniꢀs reagent (1)[8] in the
presence of a catalytic amount of [Cu(MeCN)4]PF6 combined
with a series of chiral ligands. The combination of [Cu-
(MeCN)4]PF6 and (S,S)-tBuBox (L1) in methyl tert-butyl
ether (MTBE) at room temperature furnished the oxytri-
fluoromethylation product 3a in 85% yield and 81% ee
(Table 1, entry 1). The enantioselectivity showed a significant
dependence on the solvent, following the trend: ethereal
solvents > ethyl acetate > chloroalkane solvents > alcohol
E-mail: sbuchwal@mit.edu
[**] Research reported in this publication was supported by the National
Institutes of Health under award number GM46059. The content is
solely the responsibility of the authors and does not necessarily
represent the offical views of the National Institutes of Health.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307790.
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Table 1: Effect of reaction parameters on the copper-catalyzed enantio-
Table 2: Copper-Catalyzed enantioselective oxytrifluoromethylation.[a]
selective oxytrifluoromethylation.
Entry
Substrate
Product
Yield [%][b]
ee [%][c]
Entry
Change from standard conditions
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
none
L2 instead of L1
L3 instead of L1
85
<2
<2
82
84
57
80
<2
66
<2
<2
<2
81
n.d.
n.d.
71
62
36
1
2
3
4
5
2a
2b
2c
2d
2e
R=H
3a
3b
3c
3d
3e
88
78
81
80
74
82
83
81
75
81
EtOAc instead of MTBE
CH2Cl2 instead of MTBE
MeOH instead of MTBE
CH3CN instead of MTBE
CuI instead of [Cu(MeCN)4]PF6
CuCl instead of [Cu(MeCN)4]PF6
Cu(OTf)2 instead of [Cu(MeCN)4]PF6
Zn(OTf)2 instead of [Cu(MeCN)4]PF6
Sc(OTf)3 instead of [Cu(MeCN)4]PF6
R=Br
R=Cl
R=F
4
R=CF3
n.d.
À21
n.d.
n.d.
n.d.
9
10
11
12
6
2 f
3 f
78
83
[a] Determined by 19F NMR spectroscopy using PhCF3 as an internal
standard. [b] Determined by HPLC analysis using a chiral stationary
phase. Tf=trifluoromethanesulfonyl.
(70)[d]
(98)[d]
7
8
2g
2h
3g
3h
44
87
81
74
solvents > acetonitrile (entries 4–7). Next, the use of a cationic
copper(I) precatalyst was found necessary for the desired
reaction to take place. Copper(I) iodide was incapable of
catalyzing the desired transformation, while the use of
copper(I) chloride provided a substantial amount of 3a with
slight selectivity for the opposite enantiomer (entries 8 and
9).[9] The reaction could not be catalyzed by a cationic
copper(II) salt (entry 10).[10] In addition, two Lewis acids were
tested and 3a was detected in neither of these cases
(entries 11 and 12). This result suggested the activation of
1 as an electrophile by means of Lewis acid coordination is
not likely involved in the productive pathway.[11]
We next explored the scope of the transformation and
representative examples are shown in Table 2. An array of
unsaturated carboxylic acids bearing different aryl groups
were found to undergo the desired transformation to give the
corresponding trifluoromethylated lactones in good yields
and useful enantiomeric excesses. The mild reaction con-
ditions were compatible with a number of functional groups
including aryl halides (Table 2, entries 2–4) and ketones
(entry 6). An electron-deficient aryl substituent (entry 5)
and a 3-thiophenyl substituent (entry 8) on the alkene were
also tolerated. The incorporation of a geminal dimethyl group
showed little effect on the yield or enantiomeric excess
realized (entries 9 and 11). Incomplete conversion of the
starting material and a diminished yield of product was
observed when the sterically demanding 1-naphthyl substitu-
ent was present, even though a good level of enantiomeric
excess was still observed (entry 7). It was found that both g-
and d-lactones (entries 10 and 11) were accessible under the
standard reaction conditions.[12]
9
2i
2j
3i
3j
72
85
80
81
10
11
2k
3k
85
83
[a] Reaction conditions: [Cu(MeCN)4]PF6 (7.5 mol%), L1 (7.5 mol%),
1 (1.0 equiv), 2 (0.50 mmol, 1.0 equiv) in 10 mL MTBE at 258C for 16 h.
[b] Yields of isolated products are an average of two runs. [c] Determined
by HPLC analysis using a chiral stationary phase. [d] The product
crystallized from the crude reaction mixture after work-up. For details see
the Supporting Information.
radical clock (Æ)-4 was treated with 1 in the presence of the
catalyst system, the oxytrifluoromethylation product 5 was
not detected. Instead, a complex mixture of CF3-containing
products resulting from cyclopropane ring opening was
observed, the largest component of which was identified to
be 6. Further, the use of the diallyl malonate 7 as substrate
provided two 5-exo-cyclization products, 8 and 9.[13] These
observations are consistent with a mechanism involving an a-
CF3 alkyl radical intermediate (D; Scheme 1c). Next, the
reaction between 1 and the radical scavenger TEMPO
[(2,2,6,6-tetramethylpiperidin-1-yl)oxyl] in the presence of
the catalyst system afforded the trifluoromethyl-trapping
adduct 10 in 45% yield (Scheme 2b).[14]
A series of experiments was performed to test our
mechanistic hypothesis (Scheme 2a). When the cyclopropane
A study of the reaction of trisubstituted alkene substrates
provided further insight into the reaction mechanism. As
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formation process.[15] Next, from these results we were able to
calculate the ratio of the four stereoisomers 3l/ent-3l/3m/ent-
3m to be 36:1:50:13. In terms of the CF3-bearing stereogenic
center (C2’), the ratio between the products with a 2’R
configuration (3m and ent-3l) and those with a 2’S config-
uration (3l and ent-3m) were essentially 1:1. This observation
indicated a stepwise mechanism consisting of 1) a nonster-
À
eoselective C CF3 bond-forming step and 2) a diastereose-
À
lective C O bond-forming step, which explains the stereo-
isomer ratio obtained as illustrated below.
As shown in Scheme 3b, in the first radical addition step,
either (E)- or (Z)-2l reacts with a trifluoromethyl radical to
À
form a C CF3 bond in a nonstereoselective fashion, thus
furnishing a pair of enantiomeric a-CF3-alkyl radicals E and F
À
in a ratio close to 1:1. In the C O bond-forming step, both the
copper catalyst system and the already established stereo-
genic center at the 2’-position come into play, thus providing
matched/mismatched scenarios. For E, the catalyst-controlled
selectivity (6R over 6S) contradicts the substrate-controlled
selectivity (6S, 2’S over 6R, 2’S), therefore affording a dimin-
ished selectivity (36:13) for the catalyst-controlled product 3l.
For its enantiomer F, the catalyst-controlled selectivity (6R
over 6S) is reinforced by the substrate-controlled selectivity
(6R, 2’R over 6S, 2’R), thus leading to an enhanced selectivity
(50:1) for 3m.
Scheme 2. a) Radical clock experiments. b) TEMPO trapping experi-
ment.
shown in Scheme 3a, both geometric isomers of 5-phenyl-5-
heptenoic acid (2l) were synthesized and subjected to the
standard reaction conditions. It was found that, regardless of
the alkene geometry of the substrate, almost the same product
diastereomeric ratio (3l/3m = 1:1.7), and same enantiomeric
excess for each diastereomer (92 and 93% ee for 3l, 58 and
59% ee for 3m) were obtained. This observation excluded
A catalytic cycle consistent with the mechanistic study
discussed above is proposed (Scheme 4). A single-electron
transfer between 1 and the CuI catalyst generates a CF3
radical and a CuII complex. The CF3 radical then adds
À
a Wacker-like oxycupration mechanism for the C O bond-
across the alkene to give D, which undergoes enantioselective
II
À
C O bond formation mediated by the Cu species, thus
affording the lactone product while regenerating the CuI
catalyst.[16]
Scheme 4. Mechanistic proposal.
In conclusion, we have developed a simple and mild
method for the efficient enantioselective oxytrifluoromethy-
lation of alkenes using a copper-based catalyst system. This
method delivers a set of enantioenriched CF3-containing
lactones with good functional-group compatibility. Evidence
was found in support of a redox radical addition mechanism,
À
in which a C O bond is enantioselectively formed via
a carbon radical intermediate. This method provides a novel
À
approach to enantioselective C O bond formation which can
Scheme 3. a) Trisubstituted alkenes as mechanistic probes.[a] Reaction
conditions: 1.2 equiv 1, 10 mol% [Cu(MeCN)4]PF6, 10 mol% L1,
MTBE, RT, 22 h. [a] Determined by 19F NMR analysis of the crude
reaction mixture. [b] Determined by HPLC analysis. b) Rationale for the
product distribution observed.
potentially be applied to a range of transition-metal-catalyzed
radical difunctionalization reactions. We are continuing work
to expand the scope of this copper-catalyzed enantioselective
difunctionalization strategy.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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bis[(4S)-4-tert-butyl-2-oxazoline] (11 mg, 0.0375 mmol, 0.075 equiv),
À
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1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one
1 (Togniꢀs reagent,
158 mg, 0.50 mmol, 1.0 equiv), and an unsaturated carboxylic acid
(0.50 mmol, 1.0 equiv). The tube was sealed with a Teflon screw-cap-
septum. The vessel was then briefly evacuated and backfilled with
argon (this sequence was repeated a total of three times). Anhydrous
methyl tert-butyl ether (10 mL) was added to the tube by syringe to
afford a blue mixture. The reaction mixture was stirred at room
temperature (258C) for 16 h. The reaction mixture was then washed
with saturated aqueous sodium bicarbonate solution (12 mL). The
aqueous layer was separated and extracted with diethyl ether (4 mL ꢁ
3). The combined organic layers were concentrated in vacuo. The
residue was purified by silica gel flash column chromatography
(EtOAc/hexanes or Et2O/hexanes) to afford the oxytrifluoromethy-
lation product.
Received: September 4, 2013
Published online: && &&, &&&&
Keywords: asymmetric catalysis · copper · enantioselectivity ·
.
radicals · synthetic methods
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relative air- and moisture-insensitivity which allows for easy
bench-top set-up.
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the carboxylic acid group did not undergo the similar oxy-
trifluoromethylation reaction; c) In preliminary experiments,
the intermolecular oxytrifluoromethylation of simple styrene
derivatives gave low ee values (around 10%).
[13] See the supporting Information for details.
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À
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[16] The details of this enantioselective C O bond-formation step
are unclear at this point. Three possible scenarios have been
proposed: a) single-electron oxidation of C to the corresponding
carbocation by the CuII complex, followed by nucleophilic
trapping; b) single-electron oxidation of C by the CuII complex
and nucleophilic trapping occurring simultaneously in a con-
certed transition state; c) recombination of C and the CuII
complex to afford an alkyl CuIII complex, which reductive
À
eliminates to give the C O bond.
4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Chemie
Communications
Synthetic Methods
Something radical: An efficient enantio-
selective oxytrifluoromethylation of
alkenes has been developed using
a copper catalyst system. Mechanistic
studies are consistent with a metal-cata-
lyzed redox radical addition mechanism
R. Zhu, S. L. Buchwald*
&&&& — &&&&
Enantioselective Functionalization of
Radical Intermediates in Redox Catalysis:
Copper-Catalyzed Asymmetric
À
in which a C O bond is formed by the
Oxytrifluoromethylation of Alkenes
copper-mediated enantioselective trap-
ping of a prochiral alkyl radical inter-
mediate derived from the initial trifluoro-
methyl radical addition.
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