A Bronsted acid catalyzed redox arylation

Article abstract of DOI:10.1002/anie.201310865

A Bronsted acid catalyzed redox arylation of ynamides that employs aryl sulfoxides as the arylating agents is reported. This metal-free transformation proceeds at room temperature and efficiently affords α-arylated oxazolidinones in a redox-neutral, atom-

Full text of DOI:10.1002/anie.201310865

Angewandte
Chemie
DOI: 10.1002/anie.201310865
Redox Catalysis
Hot Paper
A Brønsted Acid Catalyzed Redox Arylation**
Bo Peng, Xueliang Huang, Lan-Gui Xie, and Nuno Maulide*
Dedicated to the centennial of the MPI fꢀr Kohlenforschung
Abstract: A Brønsted acid catalyzed redox arylation of
ynamides that employs aryl sulfoxides as the arylating agents
is reported. This metal-free transformation proceeds at room
temperature and efficiently affords a-arylated oxazolidinones
in a redox-neutral, atom-economic fashion.
R
edox-neutral reactions have recently emerged as concep-
tually appealing transformations in synthesis. The current
interest in redox and atom economy as well as the continued
advancement of green chemistry further stimulate the devel-
opment of such reactions.[1,2] These processes, which do not
always rely on transition-metal catalysis, often allow the
À
functionalization of C H bonds in organic molecules through
mechanistically novel pathways.[1]
On the other hand, there has recently been considerable
synthetic exploration of the electronic properties of yna-
mides.[3] Owing to their uniquely polarized triple bond,
several exciting reactions were discovered; most of them
involve one of the multiple modes of cycloaddition and rely
on soft, alkynophilic transition-metal catalysts or promoters.
Herein, we report a metal-free Brønsted acid catalyzed redox
arylation reaction of ynamides through a [3,3]-sigmatropic
rearrangement.
Our group has recently developed an a-arylative lactoni-
zation reaction by the electrophilic activation of amide
substrates (Scheme 1a).[4] The treatment of amide 1 with
triflic anhydride and 2,4,6-collidine generates ketenimi-
nium A in situ, its intramolecular nucleophilic capture leads
to intermediate B. Claisen rearrangement and hydrolysis
eventually afford the a-arylated lactone 3. In practice, how-
ever, this transformation proceeded in modest to good yields
and had a relatively narrow scope.[4a] These shortcomings
were ascribed to the rather high energy penalty that is
associated with the inevitable transient loss of aromaticity
during the [3,3]-sigmatropic rearrangement step.
Scheme 1. Intramolecular a-arylation and intermolecular redox aryla-
tion.[8]
Inspired by this intramolecular a-arylation reaction,[5] we
became curious whether an intermolecular version would be
possible (Scheme 1b). Aware of the probable, deleterious
competitive reaction of any added nucleophile with the Tf2O
activator (Tf = trifluoromethylsulfonyl), we sought to employ
an ynamide such as 4a[3] to generate the pivotal ketenimi-
nium C through protonation. Benzyl alcohol was the obvious
choice of nucleophile, as we hoped that intermediate D would
be formed to give arylated product 6a. However, even though
allylic and propargylic alcohols have been successfully
employed in similar transformations before, no reaction was
observed.[6] This failure of benzyl alcohol to serve as the aryl
donor might again be attributed to the challenging transient
loss of aromaticity upon [3,3]-sigmatropic rearrangement of D.
In contrast, the use of diphenyl sulfoxide 5a[7] under
otherwise identical conditions led to smooth conversion of the
starting material. Strikingly, the desired a-arylated amide 7a
was generated in excellent yield at room temperature within
only five minutes (Scheme 1b).[8]
[*] Dr. B. Peng,[+] Dr. X. Huang[+]
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim (Germany)
Dr. L.-G. Xie, Prof. Dr. N. Maulide
University of Vienna, Faculty of Chemistry
Institute of Organic Chemistry
Wꢁhringer Straße 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[+] These authors contributed equally to this work.
[**] We are grateful to the Max-Planck-Society and the University of
Vienna for support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310865.
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Encouraged by this exciting preliminary result, we
proceeded to further optimize the reaction conditions
(Table 1). The use of two equivalents of the sulfoxide reagent
was required for complete conversion (entry 4). Pleasingly,
a catalytic amount of HOTf (10 mol%) was sufficient to
promote the reaction under these conditions within a very
short reaction time (entry 6).
Table 1: Optimization of the Brønsted acid catalyzed redox arylation.[a]
Entry
Acid (equiv)
Amount of
5a [equiv]
Solvent
Yield[b] [%]
89
1
2
3
4
5
6
HOTf (1.0)
TFA (1.0)
HOTf (0.2)
HOTf (1.0)
HOTf (1.0)
HOTf (0.1)
1.0
1.0
1.0
2.0
1.0
2.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
[c]
–
90
>95
74
>95
[a] Unless otherwise noted, all reactions were performed under argon
atmosphere at room temperature for 5 min. [b] Determined by NMR
spectroscopy using mesitylene as the internal standard. [c] No reaction
was observed. TFA=trifluoroacetic acid.
With suitable reaction conditions in hand, we examined
several ynamides 4a–m. The reaction is applicable to a broad
range of substrates, which generally afforded the a-arylated
acyl oxazolidinones 7a–m in good to excellent yields under
mild conditions (Scheme 2). Substitution at the a- or b-
position of the ynamide substrate (4d–h) does not have any
detrimental influence on the yield. Remarkably, ynamides 4k
and 4l, which bear functional groups, namely a nitrile and an
ester moiety, respectively, are also compatible with the
reaction conditions, thus allowing the a-arylation of
a formal acyl oxazolidinone in the presence of other
enolizable functional groups.
Subsequently, a broad range of aryl sulfoxides were
submitted to this redox arylation reaction (Scheme 3). Both
electron-donating and -withdrawing substituents were toler-
ated on the aryl ring. Importantly, the alkyl aryl sulfoxides
5 f–l also proved to be suitable reaction partners for this
transformation, leading to smooth aryl transfer in typically
excellent yields.
To gain more insight into the mechanism of this reaction,
we conducted various labelling experiments. The use of DOTf
as the acid catalyst led to the a-deuterated product [D1]-7a
(Scheme 4a). This supports the assumption that initial pro-
tonation of the ynamide triggers nucleophilic attack of the
sulfoxide to the keteniminium intermediate. Another infor-
mative labelling experiment involved the competitive reac-
tion of equimolar amounts of diphenyl sulfoxide (5a) and its
deuterated analogue ([D10]-5a; 80% deuteration; Sche-
me 4b). The reaction generated 7a and [D9]-7a in a 63:37
ratio.[9] Considering the degree of deuteration of [D10]-5a, it
Scheme 2. Variation of the ynamide component of the Brønsted acid
catalyzed redox arylation reaction.
A control experiment was also performed with equimolar
amounts of methylated sulfoxide 5b and the chlorinated
analogue 5c (Scheme 5a). In this experiment, 7ab and 7ac
were formed in a ratio of 72:28. Similarly, the use of
unsymmetric diaryl sulfoxide 5m led to the formation of
two regioisomers in a 66:34 ratio (Scheme 5b). The observed
clear preference for the more electron-rich aryl moiety during
À
the crucial C C bond forming event rules out an SN-type
mechanism at the ortho position of the sulfoxide.[7f,h]
The presence of an oxazolidinone in both the substrates
and the products renders the development of an asymmetric
variant of this transformation possible (Scheme 6).[10] After
a brief preliminary screen of chiral auxiliaries,[8] a promising
diastereoselectivity of 75:25 was obtained with a tert-butyl-
substituted oxazolidinone (Scheme 6), which demonstrated
the feasibility of an asymmetric redox-neutral arylation
reaction.
With this transformation, relevant heterocyclic cores may
be easily prepared. For example, the use of the cyclic
sulfoxide 5n led to the a-arylated product 7an in 72%
yield, thus opening a practical alternative for the synthesis of
functionalized dibenzothiophenes (Scheme 7).[11] Addition-
ally, the aryl sulfanyl moiety can be easily removed under
mild conditions to give the product of formal phenylation 10
in excellent yield.
À
can be concluded that C H bond cleavage or formation is not
involved in the rate-determining step of the overall process.
2
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Scheme 5. Control experiments with 5b, 5c, and 5m.
Scheme 3. Variation of the nucleophile of the Brønsted acid catalyzed
redox arylation reaction. [a] Reaction time: 30 min. Bn=benzyl.
Scheme 6. Asymmetric Brønsted acid catalyzed redox arylation.
In summary, we have developed a Brønsted acid catalyzed
redox arylation of ynamides. This simple reaction is compat-
ible with a broad range of functional groups and delivers a-
arylated oxazolidinones in good to excellent yields under mild
conditions. Further experiments focusing on asymmetric
redox arylation reactions that rely on the use of suitable
chiral auxiliaries or chiral counteranions are currently under-
way.[12]
Scheme 4. Selected labelling experiments. R=nC10H21.
Scheme 7. Synthesis of a dibenzothiophene and product elaboration.
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Received: December 15, 2013
Published online: && &&, &&&&
Keywords: Brønsted acid catalysis · oxazolidinones ·
.
redox reactions · sulfoxides · ynamides
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Redox Catalysis
B. Peng, X. Huang, L.-G. Xie,
N. Maulide*
&&&& — &&&&
A Brønsted Acid Catalyzed Redox
Arylation
Playing a neutral game: A Brønsted acid
catalyzed redox-neutral arylation of yna-
mides with aryl sulfoxides is described. A
broad range of ynamides were converted
into the corresponding a-arylated oxazo-
lidinones in good to excellent yields
under mild conditions and in an atom-
economic fashion. Tf=trifluoromethyl-
sulfonyl.
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