Angewandte
Communications
Chemie
could set up the addition–rearrangement sequence for biaryl
[
11]
synthesis. If this concept could be demonstrated for ground
state molecules such as alkynes, it would offer a one-step
route into enamine chemistry using a novel and versatile
2
2
source of amine component. Notably for an sp –sp bond
forming reaction, the transformation would have no require-
ment for transition metal catalysis.
To begin, we trialed the addition of p-nitrobenzenesul-
[
12]
fonamide 4a to various electron-deficient alkynes (2), and
were delighted to find that straightforward reaction condi-
tions of K CO in DMF at 708C were sufficient to form the
2
3
desired enaminoates 3 (Scheme 2). While the Smiles rear-
Scheme 3. Scope of the sulfonamide. Reaction conditions: 1.0 equiv
alkyne (0.4 mmol), 3.0 equiv sulfonamide, 3.0 equiv K CO , 708C for
2
3
1
1
6 h. The yields of isolated products are given. [a] Reaction run at
008C. [b] Obtained as an inseparable mixture of Michael addition and
Smiles rearrangement products in a 1:3 ratio. [c] Reaction was
conducted on a 4.4 mmol scale.
intermediate (6 in Scheme 1) and enable successful Smiles
[
14]
rearrangement. We were pleased, therefore, to find that
while activation of the sulfonamide was necessary, it could be
achieved using a variety of functional groups. Switching the
nitro group to the ortho-position was effective, and the
electron withdrawal could also be attenuated by a methoxy
group without problem (3q). Compounds with moderately
electron-deficient groups such as para-acetyl and cyano were
good substrates, as was the triply chlorinated sulfonamide
which gave enaminoate 3n in an excellent 89% yield. Most
importantly, the reaction could be extended to heteroaryl
sulfonamides, which enabled access to novel enaminoates
having pyridyl, benzothiazyl, and benzimidazyl substitution
without recourse to transition metal cross-coupling. Finally,
we observed that secondary N-alkyl sulfonamides presented
a similar reactivity to primary sulfonamides, producing
alkylated enaminoates 3u, 3w, and 3x in good yield.
Secondary N-aryl sulfonamides were not as successful,
producing low yields (3v) presumably because the substan-
tially attenuated nucleophilicity prevents effective conjugate
addition. Tertiary sulfonamides were unreactive.
Scheme 2. Scope of the alkyne. Reaction conditions: 1.0 equiv alkyne
(
0.4 mmol), 3.0 equiv sulfonamide, 3.0 equiv K CO , 708C for 16 h.
2 3
The yields of isolated products are given.
rangement must occur initially to give E-isomers as shown in
[
13]
Scheme 1C, X-ray crystal structures of 3d and 3g estab-
lished Z-geometry indicating isomerization in situ to struc-
tures stabilized by an internal hydrogen bond (d (NH)
H
ꢀ
10 ppm).
Despite the weak nucleophilicity of sulfonamide 4a, the
alkyne scope proved to be very broad with a variety of
primary and secondary alkyl-, aryl-, and heteroaryl-substi-
tuted alkynes producing enaminoates in good to excellent
yields (Scheme 3). Electron-rich and electron-poor aryl sub-
stitution was well tolerated, although some sensitivity to steric
hindrance in the ortho-position was noted (3 f).
The enaminoate products can be easily transformed into
diverse building blocks for biologically active molecules, with
a selection of examples shown in Scheme 4. Oxidation though
a choice of hypervalent iodine(III) reagents under conditions
developed by Zhao et al. enables a two-step production of
indoles 7 or azirines 8, respectively, from simple sulfonamide
Interestingly, the reaction was successful for methyl
ethoxypropiolate, producing the mixed N,O-ketene acetal
3
j. Ketones could also be used to activate the alkyne,
affording the enaminone 3l in good yield. The principle
limitation in terms of alkyne structure was the nonproductiv-
ity of terminal alkynes in the reaction.
[15]
and alkyne starting materials. We could successfully reduce
Turning to the sulfonamide component, we were cogni-
zant that Smiles rearrangements frequently require strongly
electron-withdrawing groups to stabilize the Meisenheimer
enaminoate 3u to the b-amino acid derivative 9 through
hydrogenation over Adams catalyst (stereochemistry es-
tablished through X-ray structure analysis of an amide
[16]
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!
Rabet, Pauline T. G.
