Gold(I)-Catalyzed Synthesis of Highly Substituted 1,4-Dicarbonyl Derivatives via Sulfonium [3,3]-Sigmatropic Rearrangement

Article abstract of DOI:10.1021/acs.orglett.0c04023

An efficient and straightforward gold-catalyzed protocol for the synthesis of 2-substituted 4-oxo-4-arylbutanal derivatives from commercially available or easily accessible alkynes and vinylsulfoxide substrates has been developed. Extension of the methodology to the use of 1-cycloalkenyl sulfoxides allowed the facile synthesis of five-, six-, and seven-membered-ring cycloalkyl-1-one backbone. Subsequently, the tetrahydrocycloalkyl[b]pyrrole derivatives, which are found in many active pharmaceutical ingredients, were isolated in good yields. Mechanistic investigation highlighted a [3,3]-sigmatropic rearrangement of a sulfonium intermediate in this process.

Full text of DOI:10.1021/acs.orglett.0c04023

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Letter
Gold(I)-Catalyzed Synthesis of Highly Substituted 1,4-Dicarbonyl
Derivatives via Sulfonium [3,3]-Sigmatropic Rearrangement
Weiping Zhou and Arnaud Voituriez*
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ABSTRACT: An efficient and straightforward gold-catalyzed protocol for the synthesis of 2-substituted 4-oxo-4-arylbutanal
derivatives from commercially available or easily accessible alkynes and vinylsulfoxide substrates has been developed. Extension of
the methodology to the use of 1-cycloalkenyl sulfoxides allowed the facile synthesis of five-, six-, and seven-membered-ring
cycloalkyl-1-one backbone. Subsequently, the tetrahydrocycloalkyl[b]pyrrole derivatives, which are found in many active
pharmaceutical ingredients, were isolated in good yields. Mechanistic investigation highlighted a [3,3]-sigmatropic rearrangement
of a sulfonium intermediate in this process.
acids, other strategies have emerged with the development of
interrupted Pummerer reaction/sigmatropic rearrangements
using charge-accelerated [3,3]-rearrangement.6,8,9 In this
context, in 2018 Maulide developed a powerful methodology
for the synthesis of functionalized 1,4-dicarbonyl compounds
(Scheme 1c).9e In the presence of triflimide, the ynamide
derivative is protonated to form a highly electrophilic
keteniminium intermediate, which can undergo addition of
the sulfoxide. The resulting key intermediate (III) could then
perform a rearrangement to deliver after hydrolysis the
corresponding γ-keto amide. Furthermore, starting with
enantiopure sulfoxides led to enantioenriched products with a
good chirality transfer. While ingenious, this methodology has
some perfectible features, namely, (1) the use of ynamides as
starting materials, whose syntheses can sometimes be challeng-
ing or are commercially very expensive; (2) the use of a strong
Brønsted acid, which must be handled carefully; and (3) the use
of mainly vinyl sulfoxides without aryl groups (R3, R4 ≠ Ar). To
overcome these limitations, we hypothesized that cationic
gold(I) complexes could activate simple alkynes 1 via formation
of π complexes and allow the regioselective addition of the
1,4-Dicarbonyl derivatives are widely present as structural motifs
in natural products and bioactive molecules.1 These compounds
are also useful building blocks and starting materials for different
reactions such as the Paal−Knorr synthesis, to easily prepare
heterocycles (furan, thiophene, pyrrole, etc.) from the same key
intermediate.2 Many different strategies have been described for
the synthesis of these valuable scaffolds, such as oxidative
couplings3 or umpolung processes,4a−e including enolate4f−i and
radical-based transformations,4j−o and others.5 However, each
of these approaches is necessarily limited to specific substrates,
and several methods failed to construct quaternary centers or to
use easy-to-handle reagents. In the framework of this study, we
proposed to develop a gold(I)-catalyzed sulfonium [3,3]-
sigmatropic rearrangement for the synthesis of highly function-
alized 1,4-dicarbonyls.
Indeed, in recent years cascade reactions, including [3,3]-
sigmatropic rearrangement of sulfur-containing substrates, have
emerged as powerful strategies for the synthesis of molecules of
interest.6,7 In 2007, Toste7a and Zhang7b independently
described the intramolecular gold-catalyzed alkynyl arylsulf-
oxide transformation to furnish the seven-membered thiepinone
ring (Scheme 1a). Initially it was proposed that the reaction
intermediate was an α-oxo gold carbene, but it was
demonstrated later that the reaction most certainly proceeded
through a [3,3]-sigmatropic rearrangement via intermediate
(I).7c The intermolecular version of this reaction was then
exemplified with aryl sulfoxide substrates (Scheme 1b).7d In
addition to these processes catalyzed by organometallic Lewis
Received: December 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c04023
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Scheme 1. Sigmatropic Rearrangement of Sulfonium
Intermediates for the Synthesis of Carbonyl-Containing
Compounds
Table 1. Optimization of the Reaction Conditions
a
a
entry
[Au]
AuCl
IPrAuCl
additive Conv. (%) (3a/3′a) yield of 3a (%)
1
2
3
4
5
6
−
−
−
−
−
−
−
H2O
H2O
H2O
90 (1/1.1)
90 (1/1)
>98 (1/1)
90 (1.1/1)
83 (1.8/1)
>98 (1/1)
<5
>98 (7/1)
50 (1/1)
>98 (10/1)
37
43
50
47
53
48
nd
72
25
(PhO)3PAuCl
b
L1AuCl
L2AuCl
c
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
−
d
7
e
e
e
8
9
f
g
10
Ph3PAuNTf2
76 (74 )
a
Conversions, 3a/3′a ratios, and yields of 3a were determined by 1H
NMR analysis of the crude reaction mixtures with an internal
standard. L1 = di-1-adamantyl-2-morpholinophenylphosphine. L2 =
tris(4-methoxyphenyl)phosphine. No silver salt was added. 3.0
b
c
d
e
f
equiv of H2O was added. Only the silver salt AgNTf2 was used.
g
Isolated yield.
necessary to form the cationic gold catalyst (entry 7), we added
some water to the reaction mixture to facilitate the hydrolysis of
the thionium ion and to favor the formation of 3a (entry 8). The
expected effect was verified, as the yield of 3a increased from 48
to 72%. Silver salt alone did not efficiently catalyze the reaction
(entry 9). It is noteworthy that the use of HNTf2 as the catalyst
gave the same disappointing results (38% yield). Among all of
the different solvents and counteranion tested, AgNTf2 proved
to be the best silver salt and DCE the best solvent (see Table
S1). Finally, the optimal result was obtained with the use of
preformed Ph3PAuNTf2 complex (10 mol %) in the presence of
water at room temperature for 14 h (entry 10). The desired
compound 3a was isolated in pure form in 74% yield.
Under the optimized reaction conditions, we next examined
the substrate scope, and the results are summarized in Scheme 2.
We started our study with the use of various substrates 2a−e (R1
= alkyl, R2 = H) (Scheme 2a). The products 3a−3e were isolated
in 44−74% yield. Product 3f, with a cyclohexyl group, was
isolated in 64% yield. Interestingly, the methodology could be
efficiently extended to the 2-arylvinyl sulfoxide substrates 2g−i
(R1 = aryl, R2 = H). 4-(4-Methoxyphenyl)-4-oxo-2-phenyl-
butanal (3g) was synthesized in 77% yield on a 1 mmol scale.
Regardless of the electron-donating p-methoxy and electro-
negative p-fluoro substituents, the corresponding products 3h
and 3i were obtained in 67−70% yield. A heteroaryl substituent
such as a thiophene group was also well-tolerated (compound 3j,
65% yield). The second step was then to expand the substrate
scope to various aryl alkynes 1b−h (Scheme 2b). Seven different
aryl-substituted alkynes reacted with vinyl sulfoxide 2a. Indeed,
1,2-dimethoxybenzene, 6-methoxynaphthalene, and ferrocene
alkynes reacted smoothly to give compounds 3k−m in up to
73% yield. Substrates possessing hydroxyl groups exhibited
moderate yields in this transformation because of the instability
of both the alkyne substrates and the compounds 3n and 3p
under air atmosphere. The use of a TBS protecting group
oxygen atom of the sulfoxide partner 27h (Scheme 1d).
Subsequently, the sulfonium intermediate (IV) should perform
a [3,3]-sigmatropic rearrangement to deliver a thionium ion
(V). After hydrolysis, the corresponding 1,4-keto aldehydes 3
should be isolated.
In this paper, we report our efforts in this direction and the
extension of this methodology to the use of 1-cycloalkenyl
sulfoxides 5 as starting materials, whose potential has been
underexploited to date. The corresponding highly function-
alized cycloalkyl ketones 6 have also been used as key building
blocks for the rapid synthesis of five active pharmaceutical
ingredients (APIs).
Our study was initiated by reacting 1-ethynyl-4-methox-
ybenzene (1a) and sulfoxide 2a in the presence of a 10 mol %
loading of different gold(I) precatalysts in dichloroethane at
room temperature (Table 1). After activation with silver
bis(trifluoromethanesulfonyl)imide, the corresponding cationic
gold catalysts without ligand (entry 1) or coordinated with
structurally diverse ligands such as an N-heterocyclic carbene
(entry 2), triphenyl phosphite (entry 3), or phosphine ligands
(entries 4−6) furnished the desired 2-(2-aryl-2-oxoethyl)-
pentanal (3a) in moderate yields. The formation of the
bis(arylsulfane) byproduct 3′a was also observed. Slight
differences in both conversion and product selectivity (3a/
3′a) were ascertained depending on the catalyst used. We
decided to continue our study with commercially available
Ph3PAuCl as the catalyst (entry 6). After verifying that it was
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e
Scheme 2. Reaction Scope of the Catalytic Transformation for the Formation of 1,4-Dicarbonyl Derivatives 3
a
b
The presence of water was not required to improve the yield. After 14 h of reaction time, chloreal, AgNO3, and CdCO3 were added.
c
d
(Johnphos)AuCl/AgNTf2 catalyst, 60 h, rt. (Z)-1-((5-Ethylocta-1,4-dien-4-yl)sulfinyl)-4-methylbenzene was used as the sulfoxide substrate; a
e
mixture of two isomers of 3w was obtained in a 1/0.8 ratio. Isolated yields after purification by column chromatography on silica gel are shown.
NMR yields are given in parentheses.
increased the isolated yield to 60% (compound 3o). For the
alkyne partner, an electron-rich alkyne would appear to be
necessary, since the use of ethynylbenzene provided the
corresponding product 3q in only 20% yield. It is noteworthy
that with this substrate, the use of HNTf2 did not furnish any
conversion to the desired product. In a general way, with
substrates having various substituents and/or electronic effects,
the bis(arylthio)methyl derivatives 3′ were rarely obtained in
more than 10% yield and were easily separated from the target
products with a simple purification step. Finally, six compounds
possessing quaternary stereogenic centers (compounds 3r−w)
were isolated in 50−70% yield (Scheme 2c). These last examples
highlight the versatility of our methodology to access complex
molecules in a single step. These 1,4-dicarbonyl derivatives can
be transformed into various useful disubstituted heterocycles.
For example, product 3g was converted into pyrrole 4a, furan 4b,
and thiophene 4c through Paal−Knorr reactions (Scheme S2).2
Next, we considered 1-cycloalkenyl sulfoxides 5a−d10 as
potential substrates for this transformation (Scheme 3). These
substrates have been scarcely used in [3,3]-sigmatropic
rearrangements. Reaction of 5a−c with 1a in the presence of
Ph3PAuNTf2 (10 mol %) led to compounds 6a−c possessing
five-, six-, and seven-membered cycloalkyl-1-one backbones,
respectively, in 67−85% yield. These skeletons have already
been synthesized, but using less direct synthetic pathways and/
or more complex procedures.11 3,6-Dihydro-2H-thiopyran
sulfoxide 5d was also engaged in the same transformation, and
product 6d was isolated in 55% yield. Finally, the substrate scope
Scheme 3. Au-Catalyzed Rearrangement of 1-Cycloalkenyl
Sulfoxides 5a−d
was extended to the use of (4-ethynylphenyl)(methyl)sulfane,
producing compounds 6e and 6f in 52% yield.
We next envisioned the application of our methodology to the
synthesis of APIs (Scheme 4). The tetrahydrocyclopenta-
[b]pyrrole backbone is present in many bioactive molecules,12
as demonstrated by the known anti-inflammatory activity12a,b of
compound 7 and the inhibitory activity of compound 8 toward
cyclooxygenase 2 (COX-2).12b Using our methodology, we
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Scheme 4. Application of the Methodology to the Synthesis of
APIs
Scheme 5. Mechanistic Proposal and Control Experiments
easily prepared 7 in 40% yield from diketone 6a (R = OMe) and
8 in 66% yield from diketone 6e (R = SMe), which was first
oxidized to the corresponding sulfone. Starting from cyclo-
hexanone 6b (X = CH2), the Paal−Knorr reaction with
benzylamine gave access to the potent antihepatitis C virus
agent 9 in 75% yield.13 Finally, compounds 10 and 11 possess
interesting properties as phosphodiesterase (PDE7) inhibitors,
involved in inflammatory processes.13d They were synthesized in
56−65% yield using dimethylpropane-1,3-diamine and sub-
strates 6d and 6c, respectively.
sulfoxides. Furthermore, this gold-catalyzed sulfonium [3,3]-
sigmatropic rearrangement furnishes easy two-step access to
tetrahydrocycloalkyl[b]pyrroles, a pattern present in many
bioactive molecules. Efforts are ongoing to expand the synthetic
potential of this transformation, particularly in the total synthesis
of natural products.
Concerning the mechanism of this transformation, the
cationic Au(I) complex activates alkyne 1 toward the addition
of vinyl sulfoxide 2 to form intermediate (IV) (Scheme 5a).
Then sulfonium (IV) can perform a [3,3]-sigmatropic
rearrangement to deliver thionium ion (V) (path a). After
hydrolysis and a protodemetalation step, the corresponding 1,4-
dicarbonyls 3 are formed in the presence of 4-methylbenzene-
thiol (TolSH). If the hydrolysis of (V) is not fast enough, the
latter can do an addition on (V) to form dithioacetal 3′.
Different reaction conditions were screened to convert the small
amounts of 3′ into 3 in situ. The addition of chloreal, AgNO3,
and CdCO3 after 14 h of reaction time in some cases allowed the
yield of 3 to increase (see, e.g., compound 3l in Scheme 2). In a
next step, we excluded a mechanism involving the in situ
formation of α-oxo gold carbenes (VI)14 and in situ generation
of p-tolyl(vinyl)sulfane (VII) as potential nucleophile (path b,
shown in red and in Scheme 5 and in Scheme S3). Finally,
enantiopure sulfoxide (R)-2a was reacted with 1a under the
optimized reaction conditions, leading to product 3a in 73%
yield with 95% ee (Scheme 5b). Starting from (R)-2c, 3c was
isolated with 90% ee. Interestingly, this asymmetric trans-
formation can be extended to the synthesis of enantioenriched
products possessing quaternary stereogenic centers (product 3r,
96% ee). This excellent chirality transfer from sulfur to carbon
attests that the reaction mechanism evolves most probably via a
[3,3]-sigmatropic rearrangement.9e
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04023.
General information, experimental procedures, NMR
spectra (1H, and 13C NMR), and HPLC data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Arnaud Voituriez − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France; orcid.org/0000-0002-7330-0819;
Email: arnaud.voituriez@cnrs.fr
Author
Weiping Zhou − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France
In summary, we have developed an efficient synthesis of 1,4-
dicarbonyl derivatives using simple alkyne substrates and vinyl
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04023
D
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Orbital Activation: The Enantioselective α-Enolation of Aldehydes. J.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the China Scholarship Council for a Ph.D. grant to
W.Z. and the CNRS for financial support.
■
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