Sulfoxide-directed metal-free ortho-propargylation of aromatics and heteroaromatics

Article abstract of DOI:10.1002/chem.201406424

Abstract A sulfoxide-directed, metal-free ortho-propargylation of aromatics and heteroaromatics exploits intermolecular delivery of a propargyl nucleophile to sulfur followed by an intramolecular relay to carbon. The operationally simple cross-coupling procedure is general, regiospecific with regard to the propargyl nucleophile, and shows complete selectivity for products of ortho-propargylation over allenylation. The use of secondary propargyl silanes allows metal-free ortho-coupling to form carbon-carbon bonds between aromatic and heteroaromatic rings and secondary propargylic centres. The 'safety-catch' nature of the sulfoxide directing group is illustrated in a selective, iterative double cross-coupling process. The products of propargylation are versatile intermediates and they have been readily converted into substituted benzothiophenes. A sulfoxide-directed, metal-free ortho-propargylation of aromatics and heteroaromatics exploits intermolecular delivery of a propargyl nucleophile to sulfur followed by an intramolecular relay to carbon (see scheme). The process allows metal-free ortho-coupling to form carbon-carbon bonds between aromatic and heteroaromatic rings and propargylic centres.

Full text of DOI:10.1002/chem.201406424

DOI: 10.1002/chem.201406424
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Cross-Coupling |Hot Paper|
Sulfoxide-Directed Metal-Free ortho-Propargylation of Aromatics
and Heteroaromatics
Andrew J. Eberhart, Harry J. Shrives, Estela ꢀlvarez, Amandine Carrꢁr, Yuntong Zhang, and
David J. Procter*[a]
Abstract: A sulfoxide-directed, metal-free ortho-propargyla-
tion of aromatics and heteroaromatics exploits intermolecu-
lar delivery of a propargyl nucleophile to sulfur followed by
an intramolecular relay to carbon. The operationally simple
cross-coupling procedure is general, regiospecific with
regard to the propargyl nucleophile, and shows complete
selectivity for products of ortho-propargylation over allenyla-
tion. The use of secondary propargyl silanes allows metal-
free ortho-coupling to form carbon–carbon bonds between
aromatic and heteroaromatic rings and secondary propargyl-
ic centres. The ‘safety-catch’ nature of the sulfoxide directing
group is illustrated in a selective, iterative double cross-cou-
pling process. The products of propargylation are versatile
intermediates and they have been readily converted into
substituted benzothiophenes.
su[6a–e] and Maulide[6f–i] have recently employed Pummerer reac-
tions in approaches to targets such as benzofurans and a-aryl-
b-ketoesters/a-arylamides, and we have described the use of
an interrupted Pummerer approach for the allylation of aro-
matic and heteroaromatic rings.[7]
Introduction
Selective carbon–carbon bond formation to aromatic and het-
eroaromatic systems is an important synthetic objective be-
cause the resulting structural motifs are found in many phar-
maceuticals, agrochemicals and functional materials. Such
transformations are currently achieved by using late-transition-
metal-mediated couplings, however, issues with the cost and
future supply of such metals and the metal contamination of
products makes the development of metal-free coupling pro-
cesses of great importance.
Herein, we report in full our development of a sulfoxide-di-
rected ortho-propargylation of aromatics and heteroaromatics
that proceeds by a new interrupted Pummerer-allenyl thio-
Claisen rearrangement[8] sequence involving allenyl sulfonium
salts 4 (Scheme 1).[8j] The operationally simple, metal-free pro-
cedure is general, regiospecific with regard to the propargyl
nucleophile, and shows complete selectivity for products of
propargylation over allenylation.[9]
In particular, coupling products arising from the propargyla-
tion[1] of aromatic and heteroaromatic systems are of high
value because they are versatile synthetic intermediates of
relevance to the synthesis of carbo- and heterocycles.[1] Un-
fortunately, the direct propargylation of aromatics is often chal-
lenging and can lead to mixtures of propargyl and allenyl
products. Although metal-catalysed couplings are possible,[2]
many methods rely on electrophilic Friedel–Crafts-type pro-
cesses that can require stoichiometric metal reagents.[3] In
recent years, a new strategy has emerged in which sulfoxide
substituents have been exploited as activating groups in nucle-
ophilic alkylations of electron-rich heteroaromatics[4] that pro-
ceed through Pummerer-type reactions.[5] In particular, Yorimit-
Scheme 1. Sulfoxide-directed, metal-free ortho-propargylation of aromatic
and heteroaromatics. TMS=trimethylsilyl, Tf=1,1,1-trifluoromethylsulfonyl.
[a] Dr. A. J. Eberhart, H. J. Shrives, E. ꢀlvarez, Dr. A. Carrꢁr, Y. Zhang,
Prof. Dr. D. J. Procter
School of Chemistry
University of Manchester
Results and Discussion
Realising the value of a cross-coupling process that would
allow propargyl groups to be selectively introduced to aromat-
ic and heteroaromatic rings under metal-free coupling condi-
tions, we sought to develop such a process by exploiting
a strategy in which intermolecular delivery of a carbon nucleo-
phile to sulfur would be followed by an intramolecular relay to
Oxford Road
Manchester M13 9PL (UK)
Fax: (+44)161-275-4939
E-mail: david.j.procter@manchester.ac.uk
Homepage: http://people.man.ac.uk/~mbdssdp2/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406424.
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cally hindered ortho-substituted substrates underwent propar-
gylation to give 3l and 3t in 85 and 96% yield, respectively.
The reaction exhibits excellent functional group tolerance:
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. Importantly, a substrate known to undergo classi-
cal Pummerer chemistry,[14] gave 3aa in 89% yield when ex-
posed to Tf2O in the presence of 2a (see below).
Pleasingly, the ortho-propargylation reaction also works well
with some readily available heteroaryl sulfoxides 1ab–ak
(Table 3). Thiophene and furan substrates underwent smooth
metal-free coupling provided that milder activation conditions
employing trifluoroacetic anhydride (TFAA) and lower tempera-
tures were employed for the more reactive heteroaryl sulfox-
ides (cf. arylsulfoxides; see Table 2). The optimal temperature
in each case depended on the nature and position of the sulf-
oxide directing group (from À788C to RT). The propargylation
was found to tolerate the presence of organylsulfanyl groups
(3ak and 3ah) and halogens (3ag), thus suggesting further
Table 1. Optimization of the sulfoxide-directed, metal-free ortho-propar-
gylation[a]
Entry
Solvent
[h]
[8C]
Base
Yield 3 [%]
1
2
3
4
5
6
7[b]
8[b]
9[b]
CH2Cl2
CHCl3
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[c]
99
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
pyridine
2,6-lutidine
2,6-DTBP
[a] Yield determined by 1H NMR spectroscopic analysis. [b] Base
(2.5 equiv) added; [c] Isolated yield; 2,6-DTBP=2,6-di-tert-butylpyridine
carbon (Scheme 1). We began by investigating the re-
action of diphenyl sulfoxide 1a with propargyl silane
2a (Table 1). The use of Tf2O (trifluoromethanesulfon-
Table 2. Sulfoxide-directed metal-free cross-couplings of aromatic substrates.
ic anhydride) as an electrophilic activating agent de-
livered propargylation product 3a, albeit in low yield
(entry 1). We next varied the reaction solvent and ob-
tained the best result by using MeCN (entry 4).[10] The
reaction was found to proceed readily at room tem-
perature in 36 h (entry 5) or in 1 h when the reaction
temperature was increased to 608C (entry 6). Addi-
tion of base led to a significant improvement in yield,
and 3a was isolated in 99% yield (entry 8). The base
prevents products of propargylation from undergo-
ing acid-mediated cyclisation.
Having optimised the reaction conditions, we next
investigated the scope of the process with regard to
the aromatic sulfoxide. Pleasingly, the ortho-propar-
gylation reaction worked well with readily available,
simple alkyl aryl sulfoxides 1b–1aa to give the corre-
sponding products 3b–3aa, containing pharmaceuti-
cally relevant alkylsulfanyl groups (Table 2). Methyl
phenyl sulfoxide was easily converted into 3b in ex-
cellent yield on a 1 gram scale. Surprisingly, the for-
mation of classical Pummerer products was not ob-
served, even in substrates containing electron-with-
drawing alkyl chains on sulfur (e.g., formation of 3d,
3e, 3 f and 3aa; see below). Attractively, the proce-
dure also tolerates the synthetically important per-
fluorinated alkyl chain[11] in 3 f and the medicinally
relevant trifluoromethyl sulfide group in 3g.[12] The
reaction also shows excellent generality with respect
to ring substituents: neutral, electron-rich and elec-
tron-deficient benzene rings are propargylated in
high yields (3h–z) with no significant changes in the
overall reaction efficiency observed when substitu-
tion position was varied (3h–p; 71–93%). Even steri-
[a] 2,6-DTBP was used as base; [b] No base.
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directing group: Only upon oxidation to the sulfoxide is the
substrate receptive to metal-free cross-coupling. Thus, a sulfide
substituent can be carried through a synthesis before selective
sulfur oxidation delivers the directing group effect precisely
when and where it is required. Furthermore, over-alkylation to
give mixtures is impossible because the directing group is
‘switched off’ during the metal-free coupling. Reoxidation of
sulfur reactivates the directing group (releases the safety-
catch) and a controlled second coupling using a different
carbon nucleophile is then possible. This approach is illustrated
in Scheme 2 for the selective synthesis of 3bb by using two
metal-free cross-couplings.
Table 3. Sulfoxide-directed metal-free cross-couplings of heteroaromatics
After electrophilic activation of the sulfoxide with Tf2O/
TFAA,[15] the nucleophile reacts at sulfur in an interrupted Pum-
merer-type reaction,[7] followed by rearrangement during
which the incoming group is passed to the aromatic ring. An
alternative mechanism in which the nucleophile attacks direct-
ly at the aromatic ring with concomitant triflate expulsion fol-
lowed by rearomatisation[4a,b] can be ruled out because regioi-
someric products of ortho and para allenylation would result:
our process provides products of propargylation, with no alle-
nylation, with complete ortho-selectivity, clearly suggesting
that the interrupted Pummerer pathway is operational. Fur-
thermore, allenyl sulfonium salt 4 (Scheme 1), formed by nucle-
ophilic addition to sulfur, can be observed when reactions are
[a] À408C to RT, 18 h; [b] RT, 1 h; [c] À788C, 2 h; [d] À208C to RT, 2 h.
elaboration of the products by a second metal-free propargyla-
tion (after a selective oxidation of SPh; see below) or by more
conventional metal-mediated couplings exploiting the carbon–
halogen bond. Finally, two-directional coupling of a thiophene
bearing two sulfoxide directing groups gave 3ak in good yield
(Table 3).
1
monitored by H and 13C NMR spectroscopy.[16,17] The formation
of 4 is surprisingly fast and outcompetes classical thionium ion
formation and the Pummerer reaction. The choice of the elec-
trophilic activator is key to the success of the interrupted Pum-
merer-type process. For example, in the reaction of sulfoxide
1b with nucleophile 2a, only activation with Tf2O leads to effi-
cient formation of the allenylsulfonium salt intermediate 4b
and thus to high yields of 3b. The use of TFAA as an activator
leads to significant amounts of classical Pummerer product 5b,
whereas the use of Ac2O results in no reaction (Scheme 3a).
Even sulfoxide 1aa, bearing acidic a-protons, underwent
smooth formation of allenylsulfonium salt 4aa upon activation
with Tf2O, thus delivering propargylation product 3aa in high
We next explored the scope of the metal-free process with
regard to the propargyl silane cross-coupling partner. Methyl
phenyl sulfoxide 1b and/or 3-methylsulfinyl thiophene 1ab
were exposed to propargyl silanes 2b–n under the described
conditions (Table 4). 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 (entries 3 and 6) produced products of se-
lective propargylation in high
yields. Sterically more demand-
ing silanes (entries 2, 7 and 8–
16) and functionalised silanes
(entries 4 and 5) were also effec-
tive coupling partners. Impor-
tantly, nucleophiles having sub-
stitution at both propargylic po-
sitions 2g–n also participated in
the metal-free cross-couplings to
deliver products 3as–ba, in
which
a new carbon–carbon
bond has been formed between
an ortho sp2 carbon on the aro-
matic/heteroaromatic ring and
a
secondary sp3 propargylic
centre (entries 8–16).
Crucially, the sulfoxide in our
approach acts as a ‘safety-catch’ Scheme 2. A safety-catch directing group for metal-free propargylation. DG=directing group.
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Table 4. Sulfoxide-directed metal-free cross-couplings: scope of propargyl nucleophile partner.[a]
Entry
1
Silane
Product
Yield [%]
96
Entry
9
Silane
Product
Yield [%]
64
61
52
61
2
3
4
72
10
11
12
92
88[b]
5
6
95[b]
13
14
60
63
64
7
8
71
15
16
50
45
64[b]
[a] Tf2O conditions used for propargylation of 1b; TFAA conditions used for propargylation of 1ab. [b] 2,6-DTBP was used as the base.
yield. Attempted activation with TFAA and Ac2O led to ineffi-
cient allenylsulfonium salt formation and significant amounts
of the classical Pummerer products 5e and 5 f (Scheme 3b).
The nature of substituents on the aryl ring, as well as their
positions, affect the rate of the rearrangement of allenylsulfoni-
um salts 4 to coupling products 3. For example, the location
of an electron-releasing ‘OMe’ substituent and an electron-
withdrawing ‘CF3’ substituent on the benzene ring in a series
of aryl sulfoxide substrates had a marked effect on the prelimi-
nary rate of conversion of allenylsulfonium salts 4 into propar-
gylated products 3.[18] This is particularly the case for meta-sub-
stitution: whereas electron-rich 4j underwent almost quantita-
tive conversion into 3j after 30 min, electron-deficient 4m un-
derwent only 10% conversion into 3m after the same period.
Interestingly, sterically hindered 4l also showed an increased
rate of rearrangement to 3l (Scheme 4).
In additional mechanistic investigations, labelled sulfoxide
1
[D3]1b (Scheme 5a) was propargylated with no H incorpora-
tion at the methyl group, further highlighting the rapid forma-
tion of allenylsulfonium salts 4 by attack at sulfur rather than
loss of a proton a- to sulfur. Furthermore, a competition ex-
periment involving a 1:1 mixture of 1b and its aryl-deuterium
labelled analogue [D5]1b (Scheme 5b) showed no kinetic iso-
tope effect, suggesting that rearomatisation is not the rate-de-
termining step.
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ment[8,19] and rearomatisation to
yield 3.[20] Substituent ‘X’ could
be triflates,[9] although MeCN,
sulfide or base cannot be ruled
out.
The products of metal-free
ortho-propargylation are rich in
synthetic potential because the
combination of the alkyne[1] and
organosulfanyl groups opens up
a wide range of bond-forming
possibilities. In particular, recent
developments have shown that
substrates bearing CÀS bonds
are of growing utility as partners
in
transition-metal-catalysed
cross-couplings to form CÀC
bonds.[6d,7a,21] Preliminary studies
show the potential of the dual
functionality in the products aris-
Scheme 3. The importance of efficient sulfoxide activation in the metal-free propargylation. a) Methyl phenyl sulf-
oxide; b) methyl 2-(phenylsulfinyl)acetate. Yields and conversions obtained by H NMR spectroscopic analysis.
1
Scheme 4. The effect of substituents and their location on the rate of rear-
rangement in the metal-free propargylation. Yields and conversions ob-
tained by H NMR spectroscopic analysis.
1
Scheme 6. Proposed mechanism for the sulfoxide-directed, ortho-propargy-
lation.
Scheme 5. Mechanistic studies involving labelled substrates. Yields and con-
1
versions obtained by H NMR spectroscopic analysis.
Scheme 7. Manipulation of ortho-propargylation products.
A possible mechanism for the selective ortho-propargylation
is therefore summarised in Scheme 6. Interrupted Pummerer
reactions, in which sulfoxides 1 activated by Tf2O (or an alter-
native activator) undergo nucleophilic attack by the propargyl
ing from sulfoxide-directed metal-free propargylation. For ex-
ample, 3b was converted into benzothiophenes 7a and 7b by
treatment with TfOH/NaI and I2,[22] respectively (Scheme 7a).
Coupling products arising from the use of nucleophilic part-
ners having substitution at both propargylic positions also un-
dergo heterocyclisation upon exposure to I2; for example, cou-
1
silanes at sulfur, give allenylsulfonium salts 4 (observed by H
and 13C NMR spectroscopy). These intermediates may then
convert into ylides 6 prior to [3,3]-sigmatropic rearrange-
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Conclusions
In summary, readily available aryl and heteroaryl sulfoxides un-
dergo sulfoxide-directed ortho-selective propargylation under
metal-free conditions. The cross-coupling process involves
a new interrupted Pummerer/allenyl thio-Claisen rearrange-
ment sequence. The operationally simple procedure allows
propargylic carbon nucleophiles to be added ortho to sulfur on
an aromatic or heteroaromatic ring, regiospecifically with
regard to the propargyl nucleophile, and with complete selec-
tivity for products of propargylation over allenylation. The use
of coupling partners bearing substitution at both propargylic
positions allows carbon–carbon bonds between aryl sp2 and
secondary propargylic sp3 carbon centres to be constructed.
The ‘safety-catch’ nature of the sulfoxide directing group is il-
lustrated in a selective, iterative double cross-coupling process.
The organosulfanyl group and the alkyne motif in the coupling
products are versatile handles for further manipulation.
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Acknowledgement
We acknowledge the EPSRC (Established Career Fellowship to
D.J.P and Doctoral Prize to A.J.E.), Merck Sharp and Dohme,
Novartis, The Leverhulme Trust (Research Fellowship to D.J.P.),
University of Manchester, M.E.C. Spain and Universidad de
Burgos (Predoctoral Fellowship and Mobility Grant to E.A.) for
financial support.
Keywords: alkynes · cross-coupling · metal-free · Pummerer ·
sulfoxide
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[10] See the Supporting Information of ref. [9a] for a complete optimisation
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[16] The structure of 4 was also confirmed by HRMS. See the Supporting In-
formation of ref. [9a].
[17] As expected, the rate of formation of product 3a via ionic intermediate
4 is accelerated by more polar solvents. See the Supporting Information
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Received: December 10, 2014
Published online on && &&, 0000
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FULL PAPER
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Cross-Coupling
A. J. Eberhart, H. J. Shrives, E. ꢀlvarez,
A. Carrꢁr, Y. Zhang, D. J. Procter*
&& – &&
Sulfoxide-Directed Metal-Free ortho-
Propargylation of Aromatics and
Heteroaromatics
A sulfoxide-directed, metal-free ortho-
propargylation of aromatics and hetero-
aromatics exploits intermolecular deliv-
ery of a propargyl nucleophile to sulfur
followed by an intramolecular relay to
carbon (see scheme). The process
allows metal-free ortho-coupling to
form carbon–carbon bonds between ar-
omatic and heteroaromatic rings and
propargylic centres.
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ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!