Chemoselective intermolecular α-arylation of amides

Article abstract of DOI:10.1002/anie.201402229

A new approach for the fully chemoselective α-arylation of amides is presented. By means of electrophilic amide activation, aryl groups can be regioselectively introduced α- to amides, even in the presence of esters and alkyl ketones. Mechanistic studies reveal key reaction intermediates and emphasize a remarkably subtle base effect in this transformation. Arylating me softly: A new approach for the fully chemoselective α-arylation of amides has been developed. When electrophilic amide activation is employed, aryl groups can be regioselectively introduced in the position α to the amide, and that even in the presence of esters or alkyl ketones. Mechanistic studies emphasize a remarkably subtle base effect in this transformation.

Full text of DOI:10.1002/anie.201402229

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Chemie
DOI: 10.1002/anie.201402229
Amide Activation Very Important Paper
Chemoselective Intermolecular a-Arylation of Amides**
Bo Peng, Danny Geerdink, Christophe Farꢀs, and Nuno Maulide*
Abstract: A new approach for the fully chemo-
selective a-arylation of amides is presented. By
means of electrophilic amide activation, aryl groups
can be regioselectively introduced a- to amides, even
in the presence of esters and alkyl ketones. Mecha-
nistic studies reveal key reaction intermediates and
emphasize a remarkably subtle base effect in this
transformation.
Scheme 1. Electrophilic amide activation used for the a-arylation of amides.
T
he a-arylation of carbonyl compounds continues to receive
hypothesized that the bond reorganization of intermediate A
considerable attention from the synthetic community.[1] Most
advances in this field rely on the transition-metal-catalyzed
coupling of enolates (or their equivalents) with aryl halides,
pseudohalides, or more reactive reagents.[2] Noble-metal-free
processes developed include nucleophilic addition to elec-
tron-deficient arenes,[3a,b] nucleophilic substitution of aryl
halides,[3c,d] arylation of enolate anions (or equivalents) with
the highly reactive electrophilic aromatic species of BiV,[4]
PbIV,[5] and IIII,[6] and benzynes,[7] and organocatalytic trans-
formations.[8] However, arylation at the a-position of simple
amides[9] remains a sizeable synthetic challenge.[10] To the best
of our knowledge, all existing intermolecular approaches rely
on the strong-base-promoted a-arylation of amides via the
corresponding enolate.[10a,11–14] Given that a-protons of esters
and ketones have a lower pKA than those of the correspond-
ing amides, the presence of those functional groups limits the
use of strong-base-dependant procedures. Though intramo-
lecular a-arylations have been extensively studied, especially
in oxindole synthesis,[12a–i] intermolecular approaches are
scarce.[12j–q] Herein, a novel mechanism-based approach for
the intermolecular a-arylation of amides, as well as a mech-
anistic study of the reaction, is presented. The mild conditions
of this method allow the exclusive a-arylation of amides over
esters and ketones.
en route to the product, involving the cleavage of a weak S O
À
bond along with the simultaneous formation of the strong
amide carbonyl, might counterbalance the transient loss of
aromaticity predicated by the rearrangement itself.[16a,e,18]
In first attempts, amide 1a was treated with Tf2O, which
was used to activate the amide, and Ph2SO in the presence of
the mild base 2-fluoropyridine (Scheme 2a).[16e] Unfortu-
Scheme 2. Initial results indicating a crucial addition protocol.
nately, no desired product could be detected. This was
ascribed to the competitive activation of amide and Ph2SO
by the strongly electrophilic Tf2O, highlighting the challenge
of this transformation. After further experimentation it was
found that pre-activating the amide, followed by addition of
Ph2SO, afforded the desired 2a in 25% yield (Scheme 2b).
Encouraged by this preliminary result, we further opti-
mized the reaction using amide 1a as a model substrate
(Table 1).[19] Notably, the time and temperature of the pre-
activation appear to have a strong impact on this trans-
formation (entries 1–5). Furthermore, 2-iodopyridine is
a superior base for this intermolecular amide a-arylation
(entry 6). The use of either pyridine or 2,4,6-collidine
completely shut down the reactivity (entries 8 and 9, vide
infra). Changing to 4-iodopyridine afforded the product in
only 30% yield.
Our initial design (Scheme 1) hinges on the formation of
pivotal intermediate A,[15,16] which should undergo a [3,3]-
sigmatropic rearrangement forming the Ca–Caryl bond.[17] We
[*] Dr. B. Peng, Dr. C. Farꢀs
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
Dr. D. Geerdink, Prof. Dr. N. Maulide
Faculty of Chemistry, Institute of Organic Chemistry
University of Vienna, Wꢂhringerstrasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[**] Support from the Max-Planck-Institut fꢁr Kohlenforschung, the
University of Vienna, and the Deutsche Forschungsgemeinschaft
(Heinz-Maier Leibniz Preis to N.M.) is greatly acknowledged. Z.
Zhang (MPI, Mꢁlheim) is acknowledged for assistance with in situ
IR measurements and P. Philips (MPI, Mꢁlheim) is acknowledged
for skillful NMR measurements and analysis.
This sensitivity of the reaction towards specific parame-
ters employed prompted us to study the reaction mechanism
in more detail. In particular, we sought to elucidate the nature
of the “activated amide” species whose preformation is
crucial for the success of this procedure. A combination of IR
and in situ NMR[19] analysis made it possible to observe an
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402229.
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Table 1: Optimization of reaction conditions.[a]
dine as the base, the presence of B2 was again confirmed. The
more nucleophilic and basic pyridine led, however, to the
complete consumption of C1 and afforded B2 as the only
intermediate, but as a mixture of Z- (major) and E-isomers.
As in the in situ IR experiment, the addition of Ph2SO to B2
resulted in no apparent change.[19]
Based upon these results we propose the mechanism
depicted in Scheme 3. After initial formation of C1 through
activation of the amide with Tf2O, it is likely converted to the
high-energy intermediates iminium dication D1 or ketenimi-
nium triflate D2, although neither was ever directly observed
by Charette and Grenon or by us when tertiary amides
bearing a-protons were employed.[15e] A second equivalent of
base then leads to B1. We believe that both the stability and
the reactivity of this intermediate are crucial for the fate of
the reaction. With pyridine, the strongest nucleophile in our
series, the biased equilibrium between B2 and keteniminium
D2 lies completely on the side of B2. This not only explains
Entry
Base
T [8C]
t [min]
Yield [%][b] of 2a
1
2
3
4
5
6
7
8
9
2-fluoropyridine
2-fluoropyridine
2-fluoropyridine
2-fluoropyridine
2-fluoropyridine
2-iodopyridine
4-iodopyridine
pyridine
RT
RT
À78
0
0
0
0
0
0
5
60
60
<1
15
15
15
15
15
25
0
0
12
75
93
30
0
2,4,6-collidine
0
[a] A mixture of amide (0.1 mmol) and base (3.0 equiv) in CH2Cl2 (1 mL)
was treated with Tf2O (1.0 equiv). The mixture was stirred at the
indicated temperature for the indicated time, then diphenyl sulfoxide
(2.0 equiv) was added at 08C. [b] Yield determined by NMR analysis with
mesitylene as the internal standard.
enamine-like intermediate characterized
as B1 (characteristic stretch at n =
1673 cmÀ1), formed as soon as Tf2O was
added to a mixture of 1a and 2-iodo-
pyridine (Figure 1a).[19] An enamine
related to B1 has been previously char-
acterized by NMR spectroscopy and
reported by Charette and Grenon when
they employed pyridine as base.[15e] We
have prepared and characterized (in situ
IR and NMR spectroscopy) such an
enamine B2 from amide 1a by addition
of triflic anhydride to a solution of 1a
and pyridine (Figure 1b). Remarkably,
this enamine B2 (with a stretching fre-
quency virtually identical to that of B1)
does not react upon subsequent addition
of diphenylsulfoxide and no further
reaction was observed. This highlights
the crucial role played by the base in this
arylation reaction.
Besides the in situ IR measurements,
NMR studies were also conducted.
Admixing 1a and 2-iodopyridine led to
no reaction (Figure 2, spectrum A); how-
ever, after addition of Tf2O, an immedi-
ate change was observed. The obtained
mixture (Figure 2, spectrum B) displays
the presence of two intermediates which
were characterized as B1 (major), solely
as its Z-isomer, and the presumed imi-
nium triflate C1 (minor) (2D-NMR;
Scheme 3).[19] As already confirmed by
IR spectroscopy, upon addition of
Ph2SO, B1 is completely converted into
2a within 2–3 h (spectrum C). When the
same reaction was conducted with pyri- Figure 1. IR studies on the reaction mechanism and the crucial role played by the base.
2
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treatment with strong base), even simple acetamide 1 f could
be used for this transformation. Remarkably, the chemo-
selectivity of this transformation means that, for the first time,
an amide can be directly a-arylated in the presence of an
enolizable ester (2k,l) or even an alkyl ketone with two
enolizable a-carbons (2j). In addition, the presence of
a pyrrolidine moiety is not a necessity, as evidenced by the
successful arylations of 1i and 1l.
Further, the transformations of substrates 1m and 1n,
both bearing an allyl ether moiety, are worthy of notice
(Scheme 5). These and related compounds have been pre-
viously shown by us to readily undergo deallylative lactone
formation at low temperatures in the absence of external
nucleophiles (Scheme 5a).[16b] However, the intermolecular
arylation remarkably overrides the intramolecular reaction,
allowing access to the arylated amides 2m and 2n
(Scheme 5b).
Figure 2. 1H NMR studies on the reaction mechanism.
Different aryl sulfoxides (3b–f)
were then employed as nucleophiles,
as shown in Scheme 6. Both electron-
rich and electron-poor aryl moieties
could be transferred to the a-position
of amide 1a. The products 4ad, 4ae,
and 4af further attest to the viability
of using monoarylsulfoxides carrying
either alkyl or benzyl residues on
sulfur.[20]
By performing
a competition
experiment using equimolar amounts
of diarylsulfoxides 3b and 3c in the
presence of pre-activated amide 1a
(Scheme 7), we observed a remark-
able difference in reaction rate for
the two sulfoxides. In the event, the
reaction exclusively produced the
arylated amide 4ab, resulting from
selective reaction with the most elec-
tron-rich diarylsulfoxide 3b. This
underscores the crucial role played
by electronics in this reaction, as the
most nucleophilic sulfoxide com-
pletely outperforms its electron-
poor counterpart in competition for
intermediate B1.
Scheme 3. Proposed reaction mechanism for the formation of 2a.
In summary, a novel approach for
the direct a-arylation of unactivated,
simple amides was developed relying
the complete inertia of B2 towards Ph2SO, but in addition the
observed complete consumption of C1. With 2-fluoropyri-
dine, a weaker nucleophile than 2-iodopyridine, C1 (and thus
its corresponding intermediate B) was only consumed to
a small extent. The optimal base is therefore a species not
only nucleophilic and/or basic enough to convert C1 to
enamine B, but one which is also a good enough leaving group
to be displaced by Ph2SO and produce enamine A.
With the optimized conditions in hand, we examined the
reaction of various amides (Scheme 4). Among the (halo)-
alkyl- and aryl-substituted substrates 1b–h tolerated (of
which 1h would likely have undergone cyclization upon
on an electrophilic rearrangement strategy. Remarkably,
through this approach it is possible for the first time to
arylate amides in the presence of enolizable esters and even
alkyl ketones. Mechanistic studies revealed the intermediacy
of enamine-like intermediates B1 and B2, whose reactivity is
dramatically affected by subtle changes of the base used.
Further mechanistic study of this a-arylation reaction,
exploration of the untapped reactivity of intermediates such
as B, and broadening of the strategies presented herein are
currently in progress and will be reported in due course.
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Scheme 6. Scope of sulfoxides for the a-arylation of amide 1a.[19]
Scheme 7. Competition experiment for the arylation of amide 1a.
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Received: February 11, 2014
Published online: && &&, &&&&
Keywords: amides · arylation · chemoselectivity ·
.
keteniminium ions · sulfoxides
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Communications
Amide Activation
B. Peng, D. Geerdink, C. Farꢁs,
N. Maulide*
&&&& — &&&&
Chemoselective Intermolecular a-
Arylation of Amides
Arylating me softly: A new approach for
the fully chemoselective a-arylation of
amides has been developed. When elec-
trophilic amide activation is employed,
aryl groups can be regioselectively intro-
duced in the position a- to the amide, and
that even in the presence of esters or alkyl
ketones. Mechanistic studies emphasize
a remarkably subtle base effect in this
transformation.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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