Alkynyl Thioethers in Gold-Catalyzed Annulations To Form Oxazoles

Article abstract of DOI:10.1002/anie.201706850

Non-oxidative, regioselective, and convergent access to densely functionalized oxazoles is realized in a functional-group tolerant manner using alkynyl thioethers. Sulfur-terminated alkynes provide access to reactivity previously requiring strong donor-substituted alkynes such as ynamides. Sulfur does not act in an analogous donor fashion in this gold-catalyzed reaction, thus leading to complementary regioselective outcomes and addressing the limitations of using ynamides.

Full text of DOI:10.1002/anie.201706850

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Title: Alkynyl thioethers in gold-catalysed annulations to form oxazoles
Authors: Raju Jannapu Reddy, Matthew P Ball-Jones, and Paul
William Davies
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Alkynyl thioethers in gold-catalyzed annulations to form oxazoles
Raju Jannapu Reddy, Matthew P. Ball-Jones and Paul W. Davies*
Abstract: Non-oxidative, regioselective and convergent access into
densely-functionalized oxazoles is realized in a functional-group
tolerant manner using alkynyl thioethers. Sulfur terminated alkynes
provide access to reactivity previously requiring strong donor-
substituted alkynes such as ynamides. Sulfur does not act in an
analogous donor-fashion in this gold-catalyzed reaction, leading to
complementary regioselective outcomes while limitations from the
use of ynamides are overcome by the synthetically useful thioether
substituent.
Compared to other heteroatom-substituted alkynes, alkynyl
thioethers are remarkably little explored in intermolecular late
transition metal-catalysis despite being readily accessed and
robust.[1-2] Ynamides, in contrast, are privileged substrates: In π-
acid catalysis their donor nature aids metal-alkyne coordination
and affords highly-polarized electrophiles, providing the high
chemo- and regioselectivity required for the discovery of efficient
intermolecular reactions (Scheme 1a).[3-4] As the resulting
inclusion of a donor-nitrogen limits the utility of the products,
retaining the reactivity profile of these transformations whilst
accessing more flexible and readily-elaborated substitution
patterns would be desirable. The value of sulfur-substituted
compounds[5] coupled with progress in C-C and C-heteroatom
Scheme 1. Donor substituent dictated reactivity and regioselectivity in π-acid
catalysis, and its application in enabling new cycloaddition reactions.
bond-formation from C-S bonds,[6] renders alkynyl thioethers
appealing alternatives to ynamides. Indeed the ketenethionium
pathway (Scheme 1a) from alkynyl thioethers has recently been
Following our interest in the use of gold catalysis with
invoked in proton-catalyzed reactions with nitriles[2g,h] and gold-
sulfides[17] we report here on the reactivity of alkynyl thioethers
catalyzed reactions with sulfides.[2i]
with nucleophilic nitrenoids to prepare oxazoles. Importantly, the
regioselectivity is not consistent with a controlling ketenethionium
species. The sulfur group plays an alternative role in enabling
reactivity, proving complementary to donor-enabled approaches.
Ynamides enabled the discovery of formal [3+2]-dipolar
cycloadditions
with
nucleophilic
nitrenoids[7]
allowing
intermolecular access to α-imino gold carbene-type reactivity for
heterocycle synthesis (Scheme 1b).[8-9] Such reactions that do not
depend on ynamides are scarce.[8b,h] A strong donor alkyne
substituent proved critical in the formation of oxazoles using N-
acyl pyridinium N-aminides as even electron-rich alkynes such as
anisole-derivatives did not react (Scheme 1b, inset).[8a,b] Oxazoles
are valuable synthetic intermediates[10-11] and structural
components in bioactive natural products,[12] agrochemicals,[13]
ligands,[14] and functional materials.[15] Despite recent advances,
a single modular and convergent route into trisubstituted oxazoles
that provides the structural and functional group diversity needed
across the 2-, 4-, and 5-positions remains unrealised.[16]
The reaction of alkynyl thioether 1a and aminide 2a showed
that conversion into oxazole 3 was possible at 125 C in
1,2-dichlorobenzene (1,2-DCB) (see Supporting Information for a
survey of reaction conditions and pyridine-modified aminides). No
reaction was seen without catalyst, with dichloro(pyridine-2-
carboxylato)gold superior to other metal salts including cationic
gold and Ir(cod)Cl2.[1c] 5-Methylthio-oxazole 3aa was favored over
4-methylthio-oxazole 3aa’ in all cases,[18] contradicting the
predicted outcome if sulfur were acting as π-donor substituent.
Effective reaction was seen with alkyl and aryl substitution at
sulfur (Entries 1-5). Smaller S-substituents gave improved
conversion and higher regioselectivity. Conjugating the alkyne
with a strongly electron-withdrawing group shut down the reaction
while an electron-donating substituent saw smooth reactions and
excellent regioselectivities across the S-alkyl and S-aryl series
(Entries 6-10). The sulfur substituent is critical; internal alkynes
4a/b did not react (Entries 11-12).
[a]
Dr Raju Jannapu Reddy, Matthew P. Ball-Jones and Dr. P. W.
Davies
School of Chemistry,
University of Birmingham, Birmingham, UK
E-mail: p.w.davies@bham.ac.uk
Supporting information for this article is given via a link at the end of
the document
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Entry
1
R
R1
Time /h
3
Yield / %
(3:3’)
1
1a
1b
1c
1d
1e
1f
SMe
SEt
SiPr
SPh
SBn
SMe
SEt
SEt
SPh
SMe
Ph
H
24
24
24
24
24
48
36
24
24
24
48
48
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ga
3ha
3ia
-
72% (8.4:1)
70% (6.5:1)
65% (4.5:1)
61% (4.8:1)
51% (6.3:1)
-
2
H
3
H
4
H
5
H
6[b]
7
CO2Et
OMe
OMe
OMe
OMe
OMe
OMe
1g
1g
1h
1i
64% (>20:1)
78% (>20:1)
67% (15:1)
73% (>20:1)
-
8[b]
9
10
11
12
4a
4b
Me
-
-
[a] Reactions performed using alkynyl thioether (0.2 mmol) and PicAuCl2
(5 mol%), unless otherwise stated. Isolated yields of regioisomers with the ratio
determined by 1H NMR analysis. [b] PicAuCl2 (10 mol%).
Site-specific Ni-catalyzed cross-coupling with MeMgBr saw
conversion of thio-oxazoles 3/3’ into the known and separable
methyl oxazoles 5a/5a’ or 5b confirming preferential formation of
5-thio-oxazoles in the annulation (Scheme 2).[19-20] X-Ray
diffraction subsequently confirmed the structures of 3aa and 3ga
(see the Supporting Information).[21] These first nickel-mediated
Kumada-type couplings with 5-thioether oxazoles[22] demonstrate
the value of the thioether handle, here in preparing substitution
patterns that are not directly accessible from the annulation (cf.
4b, Table 1).
Scheme 3. Intermolecular formal [3+2]-dipolar cycloaddition of alkynyl
thioethers with N-acyl pyridinium N-aminides.[a] [a] PicAuCl2 (5 mol%) unless
otherwise mentioned. Isolated yields of regioisomers with the ratio determined
by 1H NMR analysis. [b] PicAuCl2 (10 mol%). [c] 2.0 eq. of 2. [d] Reaction carried
out on 0.4 mmol scale. [e] 0.5 mmol scale. [f] 3.0 eq. of 2.
Scheme 2. Nickel-catalyzed Kumada cross-coupling of thioether substituted
oxazoles. dppp = 1,3-Bis(diphenylphosphino)propane
-rich and -poor (hetero)aromatics, alkyl chains, acetals, aryl
halides, Lewis bases, carbamates, aromatic and aliphatic amines,
aromatic or enolisable carboxylic esters, and even a benzylic
tertiary alcohol (Scheme 3, 0.2 to 3.0 mmol scale).
The reactivity of alkynyl thioethers was evaluated across
functionalized N-acyl aminides 2 (accessible from carboxylic
acids or esters in one-step[23]). Broad functional group and
structural tolerance was seen, with incorporation of electron-
Motifs found in bioactive compounds and natural products,
such as peptidic oxazoles (3gh-3kj)[24] and (3-indolyl)oxazoles
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(3na-3nn),[12] are readily prepared. Alkynyl thioether 1j gave 5-
thioethers 3ja/c as the major isomers, providing 4-alkyl oxazoles.
Sterically-congested bi-(hetero)aryl linkages may also be formed
as single regioisomers (3lc).[21]
The favored addition of the nitrenoid -to the sulfur (an
inversion of regioselectivity compared to ynamides) is rationalized
by a stabilizing Au–S interaction in the development of vinyl gold
carbenoid D2, maintained to aurated heterocycle E2 (Scheme 4).
Three-membered metal-C-S dative interactions are known,[2c,d]
while stabilizing hyperconjugative C–Au to *C–S interactions (D2
inset) could also be invoked.[25] Sulfur-gold coordination (B) may
aid formation of a π-activated complex in the presence of other
effective ligands to the metal. Ground state perturbation of the
alkyne-gold complex with slippage of gold toward sulfur (extreme
form C2) is reinforced by more electron-donating groups at R1.
The aminide nitrogen reconfigures as the nucleofuge is extruded
with cyclisation requiring the acyl group to move up toward the
aurated carbon. The lower regioselectivities seen with larger acyl-
(3gc vs 3gd, Scheme 3) or sulfur-substituents are consistent with
the conformations imposed in D2. To maintain the S-Au
interactions the sulfur substituent is positioned toward the
approaching aminide, causing repulsive interactions.[26]
Scheme 5. Regiodivergent synthesis of thio-oxazoles using gold or protic
catalysis. [a] Isolated yield of pure material after column chromatography, with
further 3aa’ contaminated with dioxalane 7.
In summary, broad functional group and structural tolerance
allows for convergent and regioselective access into densely
substituted oxazoles in the first example of gold catalyzed group-
transfer reactions onto alkynyl thioethers. Such alkynes are
complementary to strong π-donor substituted-alkynes, the sulfur
is required for reactivity but gives inverted regioselectivity relative
to the heteroatom, indicating that (metal)ketenethionium-directed
pathways invoked in other annulation processes do not apply here.
Limitations from forming a donor-atom substituted product are
addressed by this approach, as demonstrated by the Kumada
coupling with 5-thioether-oxazoles.
Acknowledgements
We thank the EC for a Marie-Curie IIF SYNHET (RJR) and the
EPSRC and University of Birmingham (UoB) for a studentship
(MPBJ). Thomas E. Baker (UoB) is acknowledged for preliminary
investigations into the cycloaddition reactions of alkynyl thioethers.
We thank the Centre for Chemical and Materials Analysis in the
School of Chemistry, and Dr Louise Male (UoB) for X-ray
crystallography.
Keywords: cycloaddition • gold • heterocycles • regioselectivity •
sulfur
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Entry for the Table of Contents (Please choose one layout)
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Raju Jannapu Reddy, Matthew P. Ball-
Jones and Paul W. Davies*
Page No. – Page No.
Alkynyl thioethers in gold-catalysed
annulations to form oxazoles
The first gold catalysed annulations with alkynyl thioethers are reported. This
transformation provides ready and convergent access into densely-functionalised
1,3-oxazole motifs. The sulfur substituent is integral to access the desired reactivity
and provides a useful synthetic handle for later elaboration. In contrast with recent
reports, the reaction is not directed through a ketenethionium pathway.
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