Copper-catalyzed intramolecular electrophilic carbofunctionalization of allylic amides

Article abstract of DOI:10.1002/anie.201303724

An endo-selective copper-catalyzed oxyarylation and oxyvinylation of allylic amides was developed. The products are the six-membered ring oxazines and are formed exclusively as the antiisomers. A range of substituted allylic amides and a wide selection of diaryliodonium and vinyl(aryl)iodonium triflates are compatible with this transformation. Copyright

Full text of DOI:10.1002/anie.201303724

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Communications
Alkene Difunctionalization
E. Cahard, N. Bremeyer,
M. J. Gaunt*
&&&& — &&&&
Copper-Catalyzed Intramolecular
Electrophilic Carbofunctionalization of
Allylic Amides
An endo-selective copper-catalyzed oxy-
arylation and oxyvinylation of allylic
amides was developed. The products are
the six-membered ring oxazines and are
formed exclusively as the anti isomers. A
range of substituted allylic amides and
a wide selection of diaryliodonium and
vinyl(aryl)iodonium triflates are compat-
ible with this transformation.
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DOI: 10.1002/anie.201303724
Alkene Difunctionalization
Copper-Catalyzed Intramolecular Electrophilic Carbofunctionalization
of Allylic Amides**
Elise Cahard, Nadine Bremeyer, and Matthew J. Gaunt*
Allylic amides and their derivatives represent a versatile class
of nitrogen-containing building blocks, the bifunctional
nature of which has enabled a diverse array of transforma-
tions and established them as strategically important mole-
cules in chemical synthesis.[1,2] Particularly useful are reac-
tions where an electrophile activates the carbon–carbon
double bond towards attack of the pendant oxygen atom of
the amide carbonyl group to form either a five or six-
membered ring heterocycle, depending on the mode of
cyclization (Scheme 1a).[3] Most of these reactions are
triggered by heteroatom electrophiles, often activated by
a catalyst, and result in the formation of a carbon–oxygen and
a carbon–heteroatom bond. It is, however, surprising that the
related electrophilic carbofunctionalization process is rare.
One possible reason for this is the lack of suitable carbon
electrophiles that can activate the carbon–carbon double
bond of the allylic amide. The development of Pd-catalyzed
oxyarylation and aminoarylation reactions, in particular by
Wolfe and co-workers,[4] as well as related Pd,[5] Cu,[6] and Au-
catalyzed[7] processes have provided an alternative approach
to related alkene difunctionalization[8] and can be applied to
derivatives of the generic allylic amine framework. Despite
these advances, the development of novel methods that
catalytically generate carbon electrophiles capable of activat-
ing alkenes to nucleophilic attack remains a challenge; the
solution to this challenge would be of significant use in
complex molecule synthesis.
As part of an overarching program aimed at the exploi-
tation of high oxidation state metal species we,[9] and others,[10]
have established that the combination of copper catalysts and
diaryliodonium salts gives rise to a high oxidation state CuIII/
aryl[11] intermediate that displays reactivity of an aromatic
electrophile (Scheme 1b). We reasoned that this distinct
catalytic activation strategy could be used to generate the
aromatic electrophile equivalent that would be needed to
affect an intramolecular oxyarylation of allylic amides, thus
complementing the corresponding heteroatom electrophile
triggered cyclizations that have become a mainstay in syn-
thesis.
We selected aryl-substituted allylic amides with which to
test our copper-catalyzed oxyarylation strategy as the prod-
ucts would generate a broadly useful class of diarylated amino
alcohols. Furthermore, we noted that some aryl-substituted
allylic amides have been utilized in other electrophile
triggered cyclization reactions. For example, treatment with
acid induces an intramolecular hydration-type reaction to
form the 6-membered-ring oxazine product (Scheme 1c).[13]
Similarly, treatment with bromine gives rise to a bromocycli-
zation, again forming the oxazine product, although this is
dependent on the geometry of the starting alkene and the
electronic nature of the aromatic ring.[14,15] To the best of our
knowledge, there are no examples of such a catalytic electro-
philic carbofunctionalization of this class of molecules.
Herein, we report the successful realization of this electro-
philic carbofunctionalization hypothesis through the develop-
ment of a new intramolecular copper-catalyzed oxyarylation
and oxyvinylation of allylic amides that exclusively forms
highly functionalized oxazine heterocycles (Scheme 1d). The
new process is operationally simple, uses readily available
reagents and catalysts and works for a wide range of
substrates, and is complementary to existing methods for
Scheme 1.
[*] E. Cahard, Dr. N. Bremeyer, Prof. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: mjg32@cam.ac.uk
Homepage: http://www-gaunt.ch.cam.ac.uk/
[**] We acknowledge the EPRSC (Leadership Fellowship) and GSK for
funding. Mass spectrometry data was acquired at the EPSRC UK
National Mass Spectrometry Facility at Swansea University. We are
grateful to Dr. Luke Humphreys (GSK) and Dr. Anna Allen for useful
discussion and assistance in the preparation of this manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303724.
2
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intramolecular carbofunctionalization. The products are also
precursors to useful substituted 1,3-amino alcohols, a class of
molecule that displays versatile functionality and finds broad
application in chemical synthesis.[12]
At the outset of our investigations, we tested this
hypothesis on a simple cinnaminyl amide wherein the
pendant carbonyl is derived from the pivaloyl group. Accord-
ingly, allylic amide (Z)-1a was synthesized and treated with
10 mol% of copper (I) chloride and diphenyl iodonium
triflate 2a; after reaction for 2 h, the oxyarylation product 3a
1
was formed in 49% yield (determined by H NMR spectros-
copy; Table 1, entry 1). Not only does this reaction proceed
Table 1: Optimization of Cu-catalyzed endo-selective oxyarylation.
Entry
Catalyst
Solvent
Conc. [m]
Yield 3a [%][a]
1
2
3
4
5
6
7
8
9
10
CuCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
EtOAc
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane[c]
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.05
0.05
0.05
49
51
73
73
52
56
Cu(OTf)2
CuI/AgOTf
CuTC
CuTC
CuTC
CuTC
CuTC
None
None
81
94 (87)[b]
0
4
Scheme 2. Cu-catalyzed oxyarylation (a) and oxyvinylation (b) of allylic
amides. [a] Yield determined by 1H NMR spectroscopy with 1,3,5-
(MeO2C)3C6H3 as internal standard.
[a] Yield determined by 1H NMR spectroscopy with 1,3,5-(MeO2C)3C6H3
as internal standard. [b] Yield of isolated product. [c] Reaction at 908C for
24 h. TC=thiophenecarboxylate, Tf=trifluoromethanesulfonyl.
with exclusive endo regioselectivity, thus representing a rare
example of a metal-catalyzed endo-selective alkene carbo-
functionalization, it is also completely diastereoselective with
respect to the formation of carbon–carbon and carbon–
oxygen bonds within the newly formed oxazine product. A
brief survey of the reaction parameters revealed that optimal
conditions were 10 mol% of CuTC as catalyst, 2 equivalents
of 2a in a 0.05m solution of dioxane at 708C, and gave oxazine
3a in 87% yield upon isolation. At 708C, no reaction
occurred in the absence of copper catalysts. A small amount
of product (4%) was obtained when the control reaction was
conducted at 908C, although we cannot rule out that this
comes from a reaction catalyzed by trace copper impurities at
the higher temperature.
With optimal conditions established, we first examined
the scope of the new copper-catalyzed endo-selective oxy-
arylation process by assessing the capacity of the aryl-transfer
component (Scheme 2).[16] We were pleased to find that
a range of substituted diaryliodonium triflates worked well in
the reaction to provide access to aryl-substituted oxazines.
Aromatic groups displaying electron-donating substituents
(3a–d) are transferred in particularly good yields from the
corresponding diaryliodonium triflates. Useful halogenated
arenes are also accommodated (3e–g), thereby providing
possibilities for subsequent chemical transformations. Ortho-
substituted aryl groups could also be transferred through this
protocol although reduced yields were observed (3h), pre-
sumably as a result of increased steric hindrance attenuating
the reactivity of the di(o-tolyl)iodonium triflate. Also, diary-
liodonium triflates displaying electron-withdrawing groups
performed poorly in the reaction, and none of the desired
product was obtained. However, we were pleased that the
coupling of a heterocyclic thiophene motif was possible and
proceeded in excellent yield (3i), thus enhancing the scope of
our reaction. In all cases, only the anti-endo-oxyarylation
products were observed.
An important extension of this reaction was realized when
we tested the endo-selective carbofunctionalization with
vinyl(aryl)iodonium triflates[17] and found that the corre-
sponding oxyvinylation provides the respective vinyl-substi-
tuted products in excellent yield as a single diastereomer
(Scheme 2). Interestingly, the oxyvinylation operates at room
temperature in contrast to the reaction with diaryliodonium
triflates, which occurred at 708C, thus reflecting the increased
reactivity of this class of hypervalent iodine reagent. Styrenyl,
simple alkyl-substituted vinyl, alkyl-substituted vinyl motifs
displaying remote functionality, and allyl ethers can be
transferred. This simple extension in substrate scope signifi-
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cantly expands the synthetic versatility of the products
derived from the new copper-catalyzed reaction.
excellent yields (3p–r). When the aromatic group was
replaced with an alkyl chain the reactivity of the substrate
was greatly diminished, and gave a 1:1 mixture of endo and
exo isomers (3s). Despite this apparent limitation, the
reaction is not restricted to aromatic substituents; we were
delighted that dienyl substrates undergo the copper-catalyzed
oxyarylation in very good yield (see 3t), thus expanding the
scope of the reaction beyond the generic aryl-substituted
allylic amides. These results do, however, point to the
requirement for a group with an sp2-hybridized carbon atom
to be directly attached to the alkene in order for the reaction
to work well. Finally, the nature of the amide group can
also be varied in this protocol. Reaction of an allylic
benzamide produced the corresponding oxazine in high
yield, as a single regio- and diastereoisomer (3u). Unsur-
prisingly, the oxyvinylation process was also found to be
amenable to a broad range of allylic amides. Aryl
substitution, including electron-rich and electron-poor
groups, as well as the cyclohexene-substituted allylic
amide are all tolerated and their reactions provide only
the oxazine isomer.
Next, we turned our attention to the substituent on the
carbon–carbon double bond of the allylic amide (Scheme 3).
As well as the original phenyl substituent, a broad range of
aromatic groups were tolerated and endo-oxazine products
with electron-donating substituents (3j–k), halogens (3l), and
electron withdrawing-substituents (3m–o) on the aromatic
ring were produced in good yield as a single diastereoisomer.
We also found that ortho-substituents on the aromatic group
are also tolerated and produced the desired products in
Finally, we investigated the effect of a substituent at the
allylic position by replacing one of the hydrogen atoms
with an iso-propyl group (Scheme 4). Under standard
oxyvinylation reaction conditions, we found the reaction
Scheme 4. Diastereoselectivity in the Cu-catalyzed oxyvinylation.
produced a single isomer 7 in 73% yield. Interestingly, the
vinylation takes place from the same face as the iso-propyl
group to give the syn relationship, whereas the diastereo-
selectivity of the oxyvinylation remains anti. This reaction
affords a product that displays a high density of stereogenic
centers and functional groups and such a transformation
will likely find broad utility in synthesis applications given
the plethora of methods available to make chiral allylic
amides.
We conducted a number of simple experiments to
probe the mechanism of this reaction. Firstly, only copper
salts catalyze this reaction and use of other classical metal
and non-metal Lewis acids resulted in no reaction (Bi-
(OTf)3, Sc(OTf)3, Zn(OTf)2, BF3·OEt2). Given that the
Z alkene (Z)-1a produces the anti-substituted oxazine 3a,
we expected that the E alkene (E)-1a would form the
corresponding syn product. However, we were surprised to
find that (E)-1a formed the same product (3a), with
identical selectivity to that from the reaction of (Z)-1a
(Scheme 5a).
In a competition experiment, the allylic amide with the
electron-donating substituent reacted faster than that with
either neutral or electron-deficient aromatic substituents
(Scheme 5b). These results clearly demonstrate that the
Scheme 3. Scope of alkene substituent in oxyarylation (a) and oxyvinylation
(b).
4
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the formation of stereochemically complex oxazine products.
The heterocyclic products can be further manipulated into
1,3-amino alcohol derivatives that will find widespread use in
synthesis.[12,19]
Received: May 1, 2013
Published online: && &&, &&&&
Keywords: copper · cyclization · diaryliodonium salts ·
.
homogeneous catalysis · oxazine
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