Cross-Coupling of α-Carbonyl Sulfoxonium Ylides with C?H Bonds

Article abstract of DOI:10.1002/anie.201706804

The functionalization of carbon–hydrogen bonds in non-nucleophilic substrates using α-carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross-coupling reactions of sulfoxonium ylides with C(sp²)?H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C?H activation, migratory insertion of the ylide into the carbon–metal bond, and protodemetalation, the last step being turnover-limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium-catalyzed dehydrative cyclization.

Full text of DOI:10.1002/anie.201706804

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Accepted Article
Title: Cross-Coupling of α-carbonyl sulfoxonium ylides with C-H bonds
Authors: Manuel Barday, Christopher Janot, Nathan R Halcovitch,
James Muir, and Christophe Aissa
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706804
Angew. Chem. 10.1002/ange.201706804
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COMMUNICATION
Cross-Coupling of α-carbonyl sulfoxonium ylides with C–H bonds
[a]
[a]
[b]
[c]
[a]
Manuel Barday, Christopher Janot, Nathan R. Halcovitch, James Muir, and Christophe Aïssa*
Abstract: The functionalization of carbon-hydrogen bonds in non-
nucleophilic substrates using α-carbonyl sulfoxonium ylides has not
been so far investigated, despite the potential safety advantages that
those reagents would provide over diazo compounds or their in situ
precursors. We describe the cross-coupling reactions of sulfoxonium
address the potential safety issues of the recently reported group-
directed C–H functionalization reactions with diazo compounds[
and their in situ precursors such as triazoles[5] or hydrazones.[6]
Moreover, it would complement the scope of recently reported
rhodium-catalyzed annulation reactions with cyclopropenes[ and
enynes,[8] that also likely proceed by migratory insertion similar to
the postulated evolution of D into E. Finally, it would also expand
the scope of the well-established C–H insertion chemistry of
metal-carbenoids generated from diazo compounds.[
4]
7]
2
ylides with C(sp )–H bond of arenes and heteroarenes in the presence
of a rhodium catalyst. The reaction proceeds by a succession of C–H
activation, migratory insertion of the ylide into the carbon-metal bond
and protodemetalation, the last step being turnover-limiting. The
method is applied to the synthesis of benz[c]acridines when allied to
an iridium-catalyzed dehydrative cyclization.
9]
Herein, we show that α-carbonyl sulfoxonium ylides undergo
2
efficient cross-coupling reactions with C(sp )–H bond of arenes
and heteroarenes in the presence of a rhodium catalyst that do
not require a sacrificial oxidizing reagent. Data from control
experiment supports the sequence of steps depicted in Figure 1c.
Thus, the cross-coupling reaction described herein is strongly
distinct from the single previous example of C–H functionalization
by α-carbonyl sulfoxonium ylides,[ both in its scope and in terms
of mechanism.
Metal-catalyzed reactions of sulfoxonium ylides are rare and
underexploited.[1] Specifically, the iridium-catalyzed formation of
carbon-nitrogen and carbon-oxygen bonds from α-carbonyl
sulfoxonium ylides has been optimized in industry in an effort to
provide a safer alternative to the analogous diazo compounds,
and thus avoid the risk of potential exothermic reactions linked to
the release of nitrogen gas.[2] This issue is particularly relevant in
the context of relatively large scale applications at a late stage of
drug development, as illustrated in the multi-kilogram synthesis of
MK-7246, a drug candidate with potential application against
respiratory disease [Figure 1a].[2d] Iridium carbene A [Figure 1b]
is a likely intermediate of these reactions and was also postulated
to account for the iridium-catalyzed synthesis of pyrroles from α-
carbonyl sulfoxonium ylides.[3] In this case, the formation of a
carbon-carbon bond plausibly proceeds via electrophilic
substitution by the reactive α,β-unsaturated β-amino-esters
substrates.
3]
In contrast to the transformation depicted in Figure 1b, the
cross-coupling of sulfoxonium ylides with organometallic
intermediates generated by activation of C–H bonds in less
nucleophilic substrates has not yet been investigated. We
hypothesized that after group-directed cyclometallation involving
metal-catalyzed C-H bond cleavage, B thus formed would
undergo migratory insertion of α-carbonyl sulfoxonium ylides via
intermediates C and/or D to give E. This intermediate would then
liberate the cross-coupling products upon protodemetallation
[
Figure 1c]. Significantly, the realization of this design would
[
a]
M. Barday, C. Janot, Dr. Christophe Aïssa
Department of Chemistry, University of Liverpool
Crown Street, L69 7ZD (UK)
E-mail: aissa@liverpool.ac.uk
Dr N. R. Halcovitch
Department of Chemistry, Lancaster University
Bailrigg, Lancaster, LA1 4YB (UK)
Dr J. Muir
Pharmaceutical Technology and Development, AstraZeneca R&D,
Silk Road Business Park, Charter Way, Macclesfield, Cheshire
SK10 2NA (UK)
Figure 1. a) Iridium-catalyzed carbon-nitrogen bond formation from α-carbonyl
sulfoxonium ylides. b) Postulated iridium-carbene intermediates from α-
carbonyl sulfoxonium ylides during pyrrole synthesis. c) Hypothetical cross-
coupling of α-carbonyl sulfoxonium ylides with C–H bonds (this work).
[
[
b]
c]
We were mindful that the envisioned migratory insertion from
B to E was not known for α-carbonyl sulfoxonium ylides. Thus, we
initially focused our attention on known rhodium complex 1[ (Cp*
10]
=
1,2,3,4,5-pentamethylcyclopentadienyl) and observed its
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
reaction with ylide 2a to give a diastereomeric mixture of migratory
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COMMUNICATION
insertion complexes 3 and 4 in good yield [Eq. (1)]. The ratio of 3
and 4 varied from 2.8:1 to 5:1, depending on the duration of the
purification by flash chromatography. Compounds 3 and 4 are
configurationally stable in the solid state and in solution at room
temperature. Their structure was confirmed by X-ray
crystallography.[11]
pyrazole, pyrimidine and methyloxime could also act as
[
12]
competent directing group although the reaction of 13–16 was
more sluggish. Thus, it was necessary to increase the
temperature to 90 °C in order to obtain 6s in 84% yield. On the
other hand, 6t and 6v were obtained in good yield after incomplete
conversion, whereas 6u was obtained in 93% yield. Replacing the
rhodium and silver catalysts with the cationic rhodium complex
[
3 6 2
Cp*Rh(MeCN) ][SbF ] (8 mol%) was also necessary in order to
isolate 6w in 90% yield. It is noteworthy that the primary alkylation
products 6a–6w are obtained directly without requiring
decarboxylation, in contrast to previous group-directed Rh(III)-
catalyzed C-H functionalization reactions with diazo
derivatives.[4c,13]
Having established the crucial organometallic basis for the
development of the catalytic reaction, we then observed that HFIP
(
1,1,1,3,3,3-hexafluoro-2-propanol) was essential for the efficient
protodemetallation leading to catalyst turnover and product
formation [Eq. (2) and Tables S1–S3]. The reaction could proceed
without added base, but its presence enabled to reach full
conversion and led to higher yield of isolated products. Another
important factor was the amount of ylide. Thus, the yield of 6b
was quantitative when a 1.7 equiv of 2b was used (Cy =
cyclohexyl), whereas using 2 equiv of bulkier 2a was necessary
to reach full conversion and obtain 6a in 77% yield. The reaction
did not proceed at all without [Cp*RhCl
2
]
2
, but the conversion into
6b could reach 81% in the presence of this catalyst and in the
absence of AgSbF
6
. Attempts to replace the rhodium catalyst with
, [Cp*Co(CO)I ] or [Ru(p-cymene)Cl were
[
Cp*IrCl
2
]
2
, [Cp*CoI
2
]
2
2
2 2
]
unsuccessful.
Using ylides 2c–2k with 5 revealed that aryl ketones 6c and
d were obtained in excellent yields, whereas ylides with less
6
electron-rich substituents led to slightly (6e) or more markedly (6f)
decreased yields of products [Figure 2]. Heteroaryl ketones 6g
and 6h could also be obtained in excellent yields after a more
prolonged reaction. Furthermore, ylides 2i–2k with
a
cyclopropane, protected piperidine or adamantyl R group all gave
excellent yields of the desired products 6i, 6j, and 6k, respectively.
Electronic effects have a great influence on the rate of the reaction,
whereby both electron-donating and electron-withdrawing groups
in para position to the cleaved C–H bond in 7 and 8[12] led to lower
yields of 6l and 6m, as compared to 6b. The yield of 6l was not
further optimized. However, the yield of 6m could be improved to
Figure 2. Rhodium-catalyzed cross-coupling of α-carbonyl oxosulfonium ylides
with C(sp )–H bonds. All yields given are for isolated products after 17 h from
2
0.34 mmol of 2 (1.7 equiv) except otherwise noted. [a] No NaOAc. [b] 2.0 equiv
of 2. [c] After 48 h. [d] After 24 h. [e] Ratio of regioisomers. [f] At 90 °C. [g] Yield
of isolated product doubly substituted at positions 2 and 5. [h] Yield of recovered
1
1. [i] [Cp*Rh(OAc)
AgSbF . [j] Yield of recovered 15. [k] [Cp*Rh(MeCN)
used as rhodium catalyst without AgSbF . [l] Trans and cis methyl oximes (3.5:1).
2
•H
2
O] (8 mol%) was used as rhodium catalyst without
6
3
][SbF (8 mol%) was
6 2
]
6
73% by performing the reaction at 90 °C. In addition, besides
benzenic C–H bonds, the reaction was also amenable to the
functionalization of heteroaromatic C–H bonds in 9–12.[12] Thus,
indole 6n was obtained in very good yield, whereas mono-
substituted pyrrole 6o was obtained in 75% yield. Bis-substitution
at positions 2 and 5 was noticeable for 6p. Remarkably, furyl 6q
was obtained in 63% yield as single regioisomer and without
formation of doubly substituted product, whereas pyridin-2-one 6r
was obtained in 71% yield under modified conditions. Finally,
The effect of substitution at the ylide carbon atom was
investigated with compound 17. After 48 h at 90 °C, 85%
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COMMUNICATION
conversion was reached and 18 was isolated alongside
unidentified impurities in 50% NMR yield [Eq. (3)]. This decreased
reactivity could be explained by the increased bulkiness of 17.
Importantly, the C–H cross-coupling of sulfoxonium ylides
described herein enables the rapid synthesis of valuable
heterocycles. Thus, slightly modify conditions deliver 3-
monosubstituted N-methoxylactam 20 after reaction of 19 and 2b
Eq. (4)].[
14]
Alternatively, the pyrimidine directing group that
[
Figure 3. a) Deuterium-labelling experiment. b) Reversibility of C–H cleavage.
c) Kinetic isotope effect under catalytic conditions. d) Kinetic isotope effect in
the protodemetalation of complex 3. Yields of isolated products. [a] After 1 h. [b]
After 2 h.
enabled the formation of 6u can be cleaved to give 21 [Eq (5)].
Moreover, quinoline 23a was obtained in 77% yield by cross
coupling of 22 and 2b and was then converted into
benz[c]acridine 24a in one step and 60% yield, after treatment
2 2
with a catalytic amount of [{Cp*IrCl } ] in a mixture of isopropanol
First, we established that the C–H cleavage step is reversible.
Thus, the reaction of 5 and 2b under the optimized conditions but
in a mixture of 1,2-dichlorobenzene (1,2-DCB) and HFIP-D
and water (Scheme 1). This iridium-catalyzed dehydrative
cyclization was discovered whilst attempting the transfer
[
15]
hydrogenation of the quinoline moiety and likely proceeds via
,4-dihydroquinoline F, followed by attack of the enamine
(
(CF
3
)
2
CHOD), led to an extensive incorporation of deuterium in
and 6b-D at the positions indicated in Figure 3a.
1
recovered 5-D
n
n
fragment on the ketone and rearomatization. Although
serenditipitous, this two-step sequence was also amenable to the
synthesis of 24b and 24c in good overall yields. Significantly, this
approach offers an attractive alternative to the drastic conditions
typically used for the synthesis of benz[c]acridines,[16] a motif
frequently explored in drug discovery.[17]
Moreover, control experiments using 6b as substrate revealed
that i) the incorporation of deuterium at position β in 3a-Dn can
occur under the reaction conditions, and that ii) stirring 6b in 1,2-
DCB/ HFIP-D at 60 °C for 16 h in the absence of any other reagent
or catalyst is sufficient to enable deuterium incorporation in 6b at
the enolizable positions. Furthermore, when treating 5-D
under the optimized conditions for 1–2 h, we observed an
important loss of deuterium in recovered 5-D , even at low
conversion, whereas isolated 6b did not contain deuterium
Figure 3b]. This result suggests that the C–H cleavage is not only
reversible but also faster than the overall reaction leading to 6b.
n
and 2b
n
[
Second, a kinetic isotope effect (k /k ) was observed when
H
D
comparing the reactivity of a mixture of 5 and 2b in the presence
of HFIP or HFIP-D and a co-solvent (1,2-dichloroethane (1,2-
DCE)). Thus, 6b and 6b-D [
7
18]
were obtained after 2 h in 18% and
H D
% yield, respectively (k /k = 2.6 by initial conversion rates)
n
Scheme 1. Reagents and conditions: a) See Figure 2; b) [{Cp*IrCl
i-PrOH/H O (9.5:0.5), air, 90 °C.
2 2
} ] (4 mol%),
2
[
Figure 3c]. Similarly, in parallel experiments using complex 3, the
[
18]
yields of isolated 6a and 6a-D
n
were 19% in 10%, respectively,
H D
(k /k = 1.9 by initial conversion rates) [Figure 3d], which is in
good agreement with the value found under catalytic conditions.
In a preliminary study of the mechanism of the C–H cross-
coupling of sulfoxonium ylides, we could verify that using rhodium
complexes [{Cp*RhCl
2
}
2
] (2 mol%), 1 (4 mol%), or 3 (4 mol%) as
Third, we were able to mimic the last step of the postulated
catalytic cycle[19] and convert 3 into 6a and 1 in 83% and 70%
yield, respectively, by treating a solution of 3 in HFIP with 5 (5
equiv).
rhodium source under the optimized conditions led to similar
yields of 6a (17–20% after 1 h, 72–77% after 17 h), which
suggests that these rhodium complexes are all kinetically
competent pre-catalysts of the reaction. We then attempted to
garner further support for the catalytic cycle postulated in Figure
1c and made the following observations.
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Angewandte Chemie International Edition
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COMMUNICATION
Overall, these results are in support of the reaction sequence
postulated in Figure 1c, whereby the C–H cleavage would be
reversible and the protodemetalation turnover-limiting.
Satoh, M. Miura, Angew. Chem. Int. Ed. 2012, 51, 775; Angew. Chem.
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In conclusion, the cross-coupling described herein expands
the traditional chemistry of sulfoxonium ylides[20] and brings these
reagents into the realm of metal-catalyzed C–H activation.[21,22]
[8]
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S. Y. Hong, J. Jeong, S. Chang, Angew. Chem. Int. Ed. 2017, 56, 2408;
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1
[
11] CCDC 1557332 (3) and CCDC 1557333 (4) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
We are grateful to the University of Liverpool (studentships to M.
B. and C. J.) and AstraZeneca (CASE award to C. J.) for financial
support. We thank Umicore for the generous gift of rhodium salts.
[
12] 7: 2-(3-methoxyphenyl)pyridine; 8: ethyl 3-(pyridin-2-yl)benzoate; 9: 1-
(pyridin-2-yl)-1H-indole; 10: 2-(1H-pyrrol-1-yl)pyridine; 11: 2-(furan-3-
yl)pyridine; 12: 2H-[1,2'-bipyridin]-2-one; 13: 1-phenyl-1H-pyrazole; 14:
Keywords: Sulfoxonium • Ylide • C–H activation • rhodium •
homogeneous catalysis
1-(pyrimidin-2-yl)-1H-indole; 15: 2-(furan-3-yl)pyrimidine; 16: (E)-1-
phenylethan-1-one O-methyl oxime.
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[
22] A report on the C–H activation of sulfoxonium ylides appeared during the
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5
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Angewandte Chemie International Edition
10.1002/anie.201706804
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Manuel Barday, Christopher Janot,
Nathan R. Halcovitch, James Muir,
Christophe Aïssa*
Page 1. – Page 4.
Cross-Coupling of α-carbonyl
sulfoxonium ylides with C–H bonds
The rhodium-catalyzed cross-coupling of sulfoxonium ylides with carbon-hydrogen
bonds in hexafluoroisopropanol at 60–90 °C brings these reagents into the realm of
C–H activation. When allied to an iridium-catalyzed dehydrative cyclization, this
cross-coupling streamlines the synthesis of valuable heterocycles.
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