Nucleophilic ortho-propargylation of aryl sulfoxides: An interrupted pummerer/allenyl thio-Claisen rearrangement sequence

Article abstract of DOI:10.1002/anie.201300223

A new direction: The nucleophilic ortho-propargylation of aryl sulfoxides exploits intermolecular delivery of the nucleophile to sulfur followed by an intramolecular relay to carbon (see scheme). The simple, metal-free procedure is general, regiospecific with regard to the propargyl nucleophile, and completely selective for products of ortho-propargylation over allenylation.

Full text of DOI:10.1002/anie.201300223

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Angewandte
Communications
DOI: 10.1002/anie.201300223
Synthetic Methodology
Nucleophilic ortho-Propargylation of Aryl Sulfoxides: An Interrupted
Pummerer/Allenyl Thio-Claisen Rearrangement Sequence**
Andrew J. Eberhart and David J. Procter*
À
Selective C C bond formation to aromatic systems is one of
the most important synthetic objectives as the resulting motifs
form the core of many pharmaceuticals, agrochemicals, and
functional materials. In this regard, products of propargyla-
tion[1] are valuable synthetic intermediates as they are
established precursors to other functional groups, and to
carbo- and heterocycles.[1] Unfortunately, direct propargyla-
tion of aromatics is often difficult and can lead to mixtures of
propargyl and allenyl products. Although metal-catalyzed
couplings are possible,[2] many methods rely on Friedel–
Crafts-type processes that can require stoichiometric metal
reagents.[3] Using activating substituents to facilitate nucleo-
philic substitution in aromatic systems is a relatively under-
exploited approach. In recent years, activation by sulfoxide
substituents has been exploited in nucleophilic alkylations of
electron-rich heteroaromatics[4] that proceed through Pum-
merer-type reactions.[5] Furthermore, Yorimitsu and Oshi-
ma[6a–d] and Maulide[6e] recently employed interrupted Pum-
merer reactions in approaches to targets such as benzofurans
and a-aryl-b-ketoesters, while we have described an inter-
rupted Pummerer approach for the allylation of aromatic and
heteroaromatic rings.[7]
regard to the propargyl nucleophile, and shows complete
selectivity for products of propargylation over allenylation.
Realizing the value of a process that would allow
propargyl groups to be selectively introduced to aryl rings
under metal-free conditions, we sought to develop a reaction
in which intermolecular delivery of a nucleophile to sulfur is
followed by an intramolecular relay to carbon (Scheme 1).
We began by investigating the reaction of diphenyl sulfoxide
1a with propargyl silane 2a (Table 1). Using Tf2O as an
Table 1: Optimization of the ortho-propargylation.[a]
Entry
Solvent
t [h]
T [8C]
Base
Yield
3 [%]
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
18
18
18
18
36
1
18
18
18
50
50
50
50
RT
60
60
60
60
–
–
–
–
–
–
35
28
27
63
72
73
16
99[b]
99
Herein we report a nucleophilic ortho-propargylation of
aryl sulfoxides that proceeds by a new interrupted Pummerer-
allenyl thio-Claisen rearrangement[8] sequence involving
allenyl sulfonium salts 4 (Scheme 1).[9] The operationally
simple, metal-free procedure is general, regiospecific with
pyridine
2,6-lutidine
2,6-DTBP
[a] Yields determined by 1H NMR spectroscopy. Conditions: entries 7–9:
base (2.5 equiv). [b] Yield of isolated product; 2,6-DTBP=2,6-di-tert-
butylpyridine.
electrophilic activating agent, propargylation product 3a was
obtained in low yield (entry 1). We next compared the
reaction in various solvents and obtained the best result
using MeCN (entry 4).[10a] The reaction proceeded readily at
room temperature in 36 h (entry 5) and the reaction time
could be shortened to 1 h at 608C (entry 6). Addition of base
significantly enhanced the reaction to give 3a in an isolated
yield of 99% (entry 8).[10b]
Scheme 1. Nucleophilic ortho-propargylation of aryl sulfoxides.
TMS=trimethyl silyl, Tf=1,1,1-trifluoromethylsulfonyl.
Having identified optimized reaction conditions we next
investigated the substrate scope. Pleasingly the ortho-prop-
argylation reaction is not restricted to diaryl sulfoxides, but
works well with readily available, simple alkyl aryl sulfoxides
1b-aa to give the corresponding products 3b-aa, containing
alkylsulfanyl groups that are of pharamaceutical relevance
(Table 2). Methyl phenyl sulfoxide was easily converted to 3b
in excellent yield on a 1 gram scale. Surprisingly, the
formation of classical Pummerer products (e.g. phenylthio-
methyl trifluoromethanesulfonate from 1b) was not
observed, even in substrates containing electron-withdrawing
[*] A. J. Eberhart, Prof. D. J. Procter
School of Chemistry, University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
Homepage: http://people.man.ac.uk/~mbdssdp2/
[**] We thank Merck Sharp & Dohme (CASE award to A.E.) and the
EPSRC (CPhD award to A.E.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300223.
4008
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Table 2: Aryl sulfoxide substrate scope.
Table 3: Propargyl silane substrate scope.
Entry
Silane
Product
Yield
[%]
1
2
3
96
72
92
4
64[a]
5
6
88[a]
95[a]
[a] 2,6-DTBP was used as the base.
high yields. Sterically more demanding silanes (entries 2, 4),
including those with substitution at both propargylic posi-
tions, and functionalized silanes (entries 5, 6) were also
effective.
After activation of the sulfoxide with Tf2O,[15] two
mechanisms are possible: A nucleophile could directly
attack the aromatic ring with concomitant triflate expulsion
followed by rearomatization,[4a,b] or the nucleophile could
react at sulfur in an interrupted Pummerer-type reaction,[7]
followed by rearrangement. The former pathway would be
expected to deliver, ortho and para regioisomeric products of
allenylation. In contrast, our process provides products of
propargylation, with no allenylation and with complete ortho-
selectivity. This suggests that the interrupted Pummerer
pathway is operational. Indeed, allenyl sulfonium salt 4
(Scheme 1) formed by reaction at sulfur can be observed
[a] 2,6-DTBP was used as the base. [b] No base.
alkyl chains (e.g. formation of 3d, 3e, 3 f, and 3aa). Interest-
ingly, the procedure also tolerates the synthetically important
perfluorinated alkyl chain[11] in 3 f and the medicinally
relevant trifluoromethyl sulfide group in 3g.[12] The reaction
is also general with respect to ring substituents: neutral,
electron-rich and electron-deficient benzene rings are prop-
argylated in high yields (3h–z) with no significant changes in
overall reaction efficiency when substitution position was
varied (3h–p, 71–93%). Even sterically hindered ortho-
substituted substrates underwent propargylation to give 3l
and 3t in 85% and 96% yield. The reaction tolerates a wide
range of functional groups: Substrates containing halogens
(3n–r), nitriles (3u), nitro (3w), and protected amines (3v)[13]
were all readily propargylated in good to excellent yields.
Furthermore, substrates bearing ester, amide and acid groups
underwent successful propargylation to give 3x–z. Impor-
tantly, a substrate known to undergo classical Pummerer
chemistry,[14] gave 3aa in 89% yield when exposed to Tf2O in
the presence of 2a.
1
when reactions are monitored by H and 13C NMR spectros-
copy.[16,17] The formation of 4 is fast[18] and outcompetes
classical thionium ion formation and Pummerer reaction. This
conclusion is supported by the observation that 3aa under-
goes smooth propargylation despite the presence of acidic a-
protons. In an additional experiment, labeled sulfoxide
[D3]1b (Scheme 2A) was propargylated with no 1H incorpo-
ration, further highlighting the rapid formation of allenyl
sulfonium salts 4 rather than loss of a proton a to sulfur. The
nature of substituents on the aryl ring, as well as their
positions,[19] affect the rate of the rearrangement of 4 to
products 3 as shown by preliminary rate and Hammett
studies.[20] Furthermore, a competition experiment involving
a 1:1 mixture of 1b and its aryl-deuterium labeled analog
[D5]1b (Scheme 2B) showed no isotope effect, suggesting
that rearomatization is not the rate-determining step.
Methyl phenyl sulfoxide 1b was exposed to propargyl
silanes 2b–g under the described conditions (Table 3). In all
cases the expected products of propargylation were obtained
in good to excellent yields. For example, commonly used
silane 2b (entry 1) and the protected propargyl silane 2d
(entry 3) produced products of selective propargylation in
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Scheme 4. Manipulation of ortho-propargylation products.
Scheme 2. Labeling experiments (yields and conversions measured by
1H NMR spectroscopy).
the propargyl motif in the products are versatile handles for
further manipulation.
Received: January 10, 2013
Published online: February 27, 2013
A proposed mechanism for the selective ortho-propargy-
lation is shown in Scheme 3. Interrupted Pummerer reactions,
in which sulfoxides 1 activated by Tf2O undergo nucleophilic
attack by the propargyl silanes at sulfur give allenylsulfonium
salts 4 (Scheme 3). These intermediates may then convert to
Keywords: arylsulfoxide · propargylation · Pummerer reaction ·
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silane · thio-Claisen
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À
that the C S bond can be readily utilized in transition-metal-
[6d,7,24]
À
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In summary, readily available aryl sulfoxides undergo
ortho-selective propargylation by a new interrupted Pum-
merer/allenyl thio-Claisen rearrangement sequence. The
operationally simple, metal-free procedure allows propargylic
carbon nucleophiles to be added ortho to sulfur on a benzene
ring, regiospecifically with regard to the propargyl nucleo-
phile, and with complete selectivity for products of prop-
argylation over allenylation. The organosulfanyl group and
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[16] Structure of 4 also confirmed by HRMS. See Supporting
Information.
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intermediate 4 is accelerated by more polar solvents. See
Supporting Information for an additional solvent study.
[18] See Supporting Information for a study of allenyl sulfonium salt
formation using Tf2O, TFAA and Ac2O as activating agents.
[19] Electron-donating substituents at the meta-position on the
benzene ring accelerate the rearrangement from 4 to 3. See
Supporting Information for further details.
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