Enantioselective and Regiodivergent Copper-Catalyzed Electrophilic Arylation of Allylic Amides with Diaryliodonium Salts

Article abstract of DOI:10.1021/jacs.5b03937

A catalytic enantioselective and regiodivergent arylation of alkenes is described. Chiral copper(II)bisoxazoline complexes catalyze the addition of diaryliodonium salts to allylic amides in excellent ee. Moreover, the arylation can be controlled by the el

Full text of DOI:10.1021/jacs.5b03937

Communication
pubs.acs.org/JACS
Enantioselective and Regiodivergent Copper-Catalyzed Electrophilic
Arylation of Allylic Amides with Diaryliodonium Salts
Elise Cahard, Henry P. J. Male, Matthieu Tissot, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
*
S Supporting Information
ABSTRACT: A catalytic enantioselective and regiodiver-
gent arylation of alkenes is described. Chiral copper(II)-
bisoxazoline complexes catalyze the addition of diary-
liodonium salts to allylic amides in excellent ee. Moreover,
the arylation can be controlled by the electronic nature of
the diaryliodonium salt enabling the preparation of
nonracemic diaryloxazines or β,β′-diaryl enamides.
he catalytic asymmetric addition of carbon electrophiles to
alkenes represents a strategically important bond-forming
T
process. Successful examples of this have arisen from variations of
1
the venerable Heck reaction, with Sigman’s enantioselective
palladium-catalyzed addition of aryl diazonium salts and
2
arylboronic acids to alkenols most notable. Despite this
remarkable transformation, catalytic enantioselective variants
3
remain underdeveloped and are in contrast to the burgeoning
4
area of catalytic enantioselective halogenation. Therefore, the
identification of distinct strategies for the catalytic enantiose-
lective addition of carbon electrophiles to unactivated alkenes
remains an important challenge.
Over the last 7 years our laboratory has explored the novel
reactivity of a putative copper(III)-aryl species as an aromatic
5
−7
electrophile equivalent.
These high oxidation state organo-
metallics can be catalytically generated by the combination of
simple copper complexes and diaryliodonium salts, and we have
shown that a range of latent nucleophiles undergo site-selective
arylation reactions to form synthetically versatile products. An
important facet of many of these reactions is the presence of a
proximal carbonyl group that steers reaction of the substrate. In
6d
addition to these studies, our group, as well as that of
7
b,c
MacMillan,
has also shown that copper−bisoxazoline
complexes can function as excellent catalysts for enantioselective
arylation reactions between electron-rich alkenes and diary-
liodonium salts (eq 1). A proposed pathway for these reactions
involves the electrophilic Cu(III)-aryl center engaging the
carbon−carbon double bond through a two-point binding
mode with a proximal carbonyl group, organizing the substrate
for selective insertion to the Cu(III)−aryl bond. In light of these
advances, we questioned whether these enantioselective
arylation tactics could be merged with a carbonyl-directed oxy-
to the carbonyl, to form 1,3-oxazines. During our studies, we also
discovered a remarkable electronic effect that enabled
enantioselective arylation at the other position on the double
bond leading to a β,β′-diaryl enamide. Together, this represents
an electronically controllable regiodivergent enantioselective
alkene arylation which forms synthetically versatile nonracemic
8
,9
products from a single starting material.
6f
At the outset of our studies, we focused on creating a catalytic
enantioselective variant of an endo selective oxy-arylation of
allylic amides, that we had recently published using CuTC as the
arylation of alkenes (eq 2).
Here we report the successful realization of this idea through a
copper-catalyzed enantioselective arylation of allylic amides with
diaryliodonium salts (eq 3). Chiral copper(II)bisoxazoline
catalysts impart high enantioselectivity in an oxy-arylation
process wherein arylation takes place at alkene position proximal
Received: April 16, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b03937
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
6
f
catalyst (eq 2). Treatment of alkene 1a with the diaryliodonium
salt 2a in the presence of copper(II) bisoxazoline catalyst 3 at
products but a loss in regioselectivity and reactivity (entries 2−
5), and so dichloromethane was retained as the optimum
reaction medium. Use of the symmetrical diphenyliodonium
hexafluorophosphate salt did not significantly change the
regioselectivity, but the ee of the enamide was lower (entry 6).
However, when we changed the electronic nature of the
transferring aryl group from phenyl to 4-methoxyphenyl (2d),
we were surprised to find that the 1,3-oxazine was formed
exclusively in 93% assay yield and in 95% ee (Scheme 2a). This
6d
room temperature, conditions similar to our enantioselective
arylation of enol silanes, disappointingly returned only starting
material. Pleasingly, reaction at 50 °C afforded a 70% yield (by
H NMR) of the desired 1,3-oxazine product 4a but with only a
% enantiomeric excess (Scheme 1). The reaction of diary-
1
6
Scheme 1. Discovery of Regiodivergent Arylation
Scheme 2. Electronically Controlled Regiodivergent
Arylation
selectivity was further exemplified when we reversed the electron
nature of the aryl group; the electron-deficient diaryliodonium
salt 2e gave exclusively the β,β′-diaryl enamide product in 78%
liodonium triflates in such a reaction is accompanied by the
formation of trifluoromethanesulfonic acid, which we speculated
might lead to decomposition of the chiral catalyst ultimately
leading to a racemic reaction. To counter this, we added 2 equiv
of the hindered base, 2,6-ditertbutylpyridine (DTBP), to the
reaction. Although we were pleased to observe the formation of
the oxazine 4a, this time with 45% ee, we were surprised to find
that the reaction also produced a second product determined to
be β,β′-diarylenamide 5a in 21% yield and 48% ee. While 1,3-
oxazine 4a is constructed via arylation at the alkene carbon atom
proximal to the amide motif and is accompanied by concomitant
carbon−oxygen bond formation, β,β′-diaryl enamide 5a is the
result of arylation at the other end of the double bond,
accompanied by alkene transposition into conjugation with the
amide group.
11
assay yield and 95% ee (Scheme 2b).
Encouraged by these results, we next explored the
regiodivergency of the arylation process using a single,
electronically unbiased alkene. Focusing initially on the oxy-
arylation of alkenes to form 1,3-oxazines, we found that a
selection of electron-rich aryl groups could be transferred from
the corresponding unsymmetrical aryl(mesityl)diaryliodonium
hexafluorophosphate salts (Table 2a). In most cases the yields of
the oxy-arylation process were good and accompanied by
excellent enantioselectivities in the products (4b−f); only the
Table 2a. Enantioselective Aryl Transfer to Form Oxazines
In order to further investigate this unusal regioselective
arylation, we varied the counteranion of the diaryliodonium
10
reagent and found changing from the OTf to the PF salt
6
resulted in a small increase in the regioselectivity but huge
improvement in enantioselectivity for both the oxazine (to 98%)
and enamide (to 94%) products (Table 1, entries 1 and 2). A
brief survey of solvents revealed consistently high ee for both
Table 1. Optimization of Regiodivergent Arylation
a
b
yield %
ee %
entry
[Ar−I−Ar′]X (2)
solvent
4a:5a
4a, 5a
1
2
3
4
5
6
[Mes−I−Ph]OTf
[Mes−I−Ph]PF6
[Mes−I−Ph]PF6
[Mes−I−Ph]PF6
[Mes−I−Ph]PF6
[Ph−I−Ph]PF6
CH Cl
40:21
65:26
5:0
45, 48
98, 94
90, −
95, 94
93, 93
96, 88
2
2
2
CH Cl
2
1,4 dioxane
1,2-DCE
PhMe
34:25
27:33
70:26
CH Cl
2
2
a
b
Yield measured by 1H NMR against an internal standard. Measured
by chiral HPLC.
a
b
15 mol % 3 employed. 28% diphenyl enamide is isolated.
B
DOI: 10.1021/jacs.5b03937
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Journal of the American Chemical Society
Communication
Table 2b. Enantioselective Aryl Transfer to β,β′-Diaryl
Table 3a. Alkene Scope in the Enantioselective Oxy-Arylation
Enamides
a
4−8% (by NMR) of the corresponding oxazine product is observed.
a
1
5 mol % 3 employed.
oxazine product was observed. Although the transfer of a
thiophene group proceeded in lower yield the ee was high (4g).
Interestingly, the limit of the electronic control of the
diaryliodonium salt extended to the transfer of a phenyl moiety;
here, we observed the formation of the oxazine product in high ee
and 53% yield (4h), but the reaction was accompanied by the
formation of 32% of the corresponding achiral β,β′-diphenyl
enamide (product not shown). Oxazine 4h was crystalline,
enabling identification of the absolute configuration by single
common 1,3-benzodioxozole and 3-indole motifs also worked
well to generate potentially interesting diarylated scaffolds in
high ee (4l−o). Alkenes substituted with alkyl groups did not
react in the oxy-arylation process (4p).
Using electron-deficient diaryliodonium salt 2e, a similar set of
allylic amides underwent arylation to β,β′-diaryl enamides (Table
3
b). Here we observed that the allylic amide needed an electron-
donating alkene substituent to impart sufficient reactivity.
Despite this, a number of alkenes performed well in the reaction
to form the β,β′-diaryl enamides with high enantioselectivity.
β,β′-Diaryl enamide 5l was crystalline, enabling identification of
12
crystal X-ray diffraction.
When we examined the transfer of electron-deficient aryl
groups to alkene 1b, we found that the enamide was usually the
exclusive product (Table 2b). Aryl groups displaying ester,
halogens, and trifluoromethyl groups in the para and meta
positions all worked well to produce the expected enamide
products (5b−i). Small amounts of the corresponding oxazine
12
the absolute configuration by single crystal X-ray diffraction.
Table 3b. Enantioselective Arylation to β,β′-Diarylaldehydes
(
4−8%) were observed in the reactions transfering of p-
Cl(C H ) and p-Br(C H ) groups. o-Fluoroaryl groups could
6
5
6
5
also be accommodated and proceeded with moderate yield but
excellent ee to form 5j. Interestingly, transfer of the electron-
donating o-tolyl group also formed the enamide product in high
ee (5k). This result is in contrast to other electron-rich salts that
generate the oxazine products and suggests there may be a subtle
steric effect involved in determining the reaction selectivity.
We next investigated the scope of the alkene substrate in this
process with a range of aryl-substituted allylic amides and either
an electron-rich or electron-deficient aryl(mesityl)iodonium
hexafluorophosphate. In general, substrates with electron-
donating or neutral substituents on the aryl group of the alkene
were highly reactive toward the 4-methoxyphenyl(mesityl)-
iodonium salt (2d) and gave oxazine products in high yields and
enantioselectivities (Table 3a). Synthetically versatile methoxy
and halogen substituents can be positioned at various points on
the aryl motif to afford oxazines in high yield and enantiomeric
excess (4a, 4i−k). 2-naphthyl, o-tolyl, and the pharmaceutically
C
DOI: 10.1021/jacs.5b03937
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
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*
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Supporting Information
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11) Reaction using Cu(I)OTf·bisoxazoline catalysts gave comparable
Experimental procedures and spectral data. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b03937.
́
(
yield and ee (5h, 58% yield and 93% ee)
AUTHOR INFORMATION
Corresponding Author
mjg32@cam.ac.uk
Notes
■
(12) Interestingly, the products 4h and 5l appear arise from arylation
on different faces of the alkene using the same chiral catalyst. This
suggests distinct regio- and enantiocontrol elements could be operating
for each arylation pathway.
*
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The authors declare no competing financial interest.
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Soc. 2002, 124, 7894. (c) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc.
ACKNOWLEDGMENTS
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We are grateful to EPSRC, GSK, and the University of
Cambridge (E.C., H.P.J.M., and M.T.) and the ERC and
EPSRC for fellowships (M.J.G.). Mass spectrometry data were
acquired at the EPSRC UK National Mass Spectrometry Facility
at Swansea University. We are grateful to Dr. Luke Humphries
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DOI: 10.1021/jacs.5b03937
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX