Oxygen Atom Transfer as Key to Reverse Regioselectivity in the Gold(I)-Catalyzed Generation of Aminooxazoles from Ynamides

Article abstract of DOI:10.1021/acs.joc.0c02584

We report on gold(I)-catalyzed oxidative annulation involving ynamides, nitriles, and 2,3-dichloropyridine N-oxide. The application of 2,3-dichloropyridine N-oxide as an oxygen atom transfer reagent reverses the regioselectivity to give 5-amino-1,3-oxazoles, in comparison with the previously reported syntheses of aminooxazoles based on gold-catalyzed nitrene transfers to ynamides to furnish 4-amino-1,3-oxazoles. The developed oxygen atom transfer approach allows the generation of 1,3-oxazoles containing a variety of sulfonyl-protected alkylamino groups in the fifth position of the oxazole ring (29 examples; up to 88% yields). In addition, the use of N-substituted nitriles, namely cyanamides, leads to the facile generation of difficult-to-obtain 2,5-diaminooxazoles. The process is feasible for wide ranges of ynamides or nitriles, and it can be conducted in gram scale.

Full text of DOI:10.1021/acs.joc.0c02584

pubs.acs.org/joc
Article
Oxygen Atom Transfer as Key To Reverse Regioselectivity in the
Gold(I)-Catalyzed Generation of Aminooxazoles from Ynamides
Dmitry P. Zimin, Dmitry V. Dar’in, Vadim Yu. Kukushkin,* and Alexey Yu. Dubovtsev*
Cite This: J. Org. Chem. 2021, 86, 1748−1757
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report on gold(I)-catalyzed oxidative annulation
involving ynamides, nitriles, and 2,3-dichloropyridine N-oxide. The
application of 2,3-dichloropyridine N-oxide as an oxygen atom transfer
reagent reverses the regioselectivity to give 5-amino-1,3-oxazoles, in
comparison with the previously reported syntheses of aminooxazoles
based on gold-catalyzed nitrene transfers to ynamides to furnish 4-
amino-1,3-oxazoles. The developed oxygen atom transfer approach
allows the generation of 1,3-oxazoles containing a variety of sulfonyl-
protected alkylamino groups in the fifth position of the oxazole ring (29
examples; up to 88% yields). In addition, the use of N-substituted
nitriles, namely cyanamides, leads to the facile generation of difficult-to-
obtain 2,5-diaminooxazoles. The process is feasible for wide ranges of ynamides or nitriles, and it can be conducted in gram scale.
mild reaction conditions with excellent functional group
compatibility and tolerance. Of particular interest are gold-
catalyzed oxygen atom33−38 and nitrene39−42 transfer reactions
of ynamides, which grant libraries of N-containing products
(Scheme 2). Usually these reactions proceed through the initial
INTRODUCTION
■
Since the beginning of this century, the chemistry of N-
substituted alkynes (or ynamides) has transformed from a
purely academic curiosity field into a well-developed approach
to the construction of molecular architectures.1,2 The unique
balance of stability and predictable reactivity of ynamides
determined their popularity as convenient building blocks for
the incorporation of nitrogen-based functionalities into target
molecules.3−10 Due to the presence of a nitrogen atom, the
ynamide triple bond is significantly polarized, whereas N-acyl
or N-sulfonyl moieties provide the stability of these
compounds and can also function as directing groups.11,12
Moreover, the electrophilic activation by Lewis acids
significantly expands the range of synthetic application of
ynamides and allows the fine selectivity control of their
transformations including, for example, nucleophilic addition
(Scheme 1).13−15
Scheme 2. Oxo and Imino Gold Carbenes from Ynamides
attack of the oxygen or nitrogen atom from the corresponding
nucleophiles on the gold-activated ynamides (Scheme 1; E =
Au). The resulting α-oxo- or α-imino carbenes can be further
involved in numerous intra- and intermolecular reactions such
as CH-insertions,43−45 cyclopropanations,46 carbene trans-
fers,47 hydride48,49 and acyl50 shifts, etc.
Scheme 1. Nucleophilic Addition to Electrophilically
Activated Ynamides
In the context of the studies focused on the transformations
of gold carbenes, a great deal of progress has been achieved in
the molecular design of amino-1,3-oxazoles, privileged
heterocyclic compounds contained in a variety of natural
Today, homogeneous gold-based catalysis is among the
most effective methods for the electrophilic activation of
alkynes.16−25 Its importance was proved by the discovery of
varieties of new synthetic methodologies.26−32 It is therefore
not surprising that the gold-catalyzed reactions of ynamides
exhibit impressive synergy: ynamides combine reactivity and
diverse substitution patterns, while Au-based catalysts provide
Received: October 30, 2020
Published: December 28, 2020
https://dx.doi.org/10.1021/acs.joc.0c02584
© 2020 American Chemical Society
J. Org. Chem. 2021, 86, 1748−1757
1748

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
products and valuable synthetic molecules.51−56 Recently, the
first Au-catalyzed synthesis of 4-amino-substituted oxazoles
that utilizes the formal [3 + 2] cycloaddition of N-ylides (as
nitrene transfer reagents) to ynamides was reported (Scheme
3, top panel).57,58 Next, some other effective nitrene
provide a facile access to 2,5-diamino-1,3-oxazoles. All our
results relevant to this novel synthetic method are
consequently disclosed in sections that follow.
RESULTS AND DISCUSSION
■
To evaluate our idea (Scheme 3, bottom panel), we attempted
the reaction between terminal ynamide 1a and pyridine N-
oxide (2a) in neat acetonitrile in the presence of the gold
NHC-based complex IPrAuNTf2,85 and target aminooxazole
3a was obtained in 49% yield (Table 1, entry 1). Inspired by
Scheme 3. Au-Catalyzed Syntheses of Aminooxazoles from
Ynamides
Table 1. Optimization of the Gold(I)-Catalyzed Synthesis of
a
5-Aminooxazoles
b
entry
N-oxide
catalyst
yield,%
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2d
2d
2d
2d
2d
2d
2d
2d
2d
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
Ph3PAuNTf2
L1AuCl/AgNTf2
L2AuCl/AgNTf2
PicAuCl2
49
37
71
83
27
12
53
59
61
46
56
65
45
−
equivalents were proposed for this reaction.59,60 In all these
cases,57−60 nitrene equivalents attack exclusively the sp-carbon
in the α-position of ynamides and, accordingly, the only
products of these transformations are oxazoles bearing amino
groups in the fourth position.
1,3-Oxazoles featuring a 5-amino group are also of
significant importance from viewpoints of medicinal chemistry
and drug discovery, functioning as antagonists of histamine61
or adenosine62 receptors, antibacterial agents,63 and remedies
for the treatment of prion diseases.64 2,5-Diamino-1,3-oxazole
(CP-810,123) has been identified as a potential treatment for
schizophrenia and Alzheimer’s disease.65 Despite all these, the
synthetic approaches toward these heterocyclic systems are
rather limited, and the known methods are based either on the
amination66,67 of preprepared oxazoles or on the assembly of
the 5-amino-1,3-oxazole68−73 or 2,5-diamino-1,3-oxazole74,75
framework. The main disadvantage of both routes is the usage
of complex and/or prefunctionalized substrates.
c
c
9
10
11
12
13
14
15
IPrAuCl/AgOTf
IPrAuCl/AgNTf2
IPrAuCl/AgSbF6
TfOH
d
IPrAuNTf2
16
a
All reactions were carried out on a 0.1 mmol scale (0.2 M).
Estimated by H NMR spectroscopy using durene as an internal
standard. L1 = JohnPhos, L2 = tBuXPhos. 10 equiv of MeCN in
PhCF3 were used.
b
1
c
d
The most appealing method for the construction of 1,3-
oxazole entities is based on intermolecular trapping of α-oxo
gold carbenes (generated from conventional terminal alkynes)
by nitriles proposed by Zhang.76 Recently, we successfully
extended this formal [2 + 2 + 1] Au-catalyzed oxidative
annulation to the synthesis of oxazoles from internal electron-
deficient alkynes, such as propiolate derivatives.77 Notably, the
generation of gold oxo-carbenes from electron-rich ynamides
(Scheme 2, X = O) occurs with a reverse regiochemistry as
compared with similar reactions of propiolates.78−84
this success, we tested a number of the oxygen sources (2b−f)
under the same reaction conditions, because it is known that
the choice of an oxidizing agent is a crucial factor in the gold-
based catalysis.86−89 The application of 2,3-dichloropyridine
N-oxide (2d, entry 4), previously proposed by us as an
effective oxidizing agent,90 led to the best results.
Next, we studied the effect of various catalysts, including the
phosphine gold complexes (entries 7−9), the gold(III)
complex PicAuCl2 (entry 10), and systems containing silver
salts (entries 11−13), but their application was not as efficient
as the initially used IPrAuNTf2. Triflic acid was completely
inactive with respect to the studied reaction (entry 14). When
PhCF3 was used as a solvent with 10 equiv of MeCN, the yield
of 3a dropped dramatically (entry 15). Finally, experiments to
In the framework of the Zhang chemistry,36,76 we assumed
that the intramolecular trapping by nitriles of α-oxo gold
carbenes generated from ynamides can be key to the
generation of oxazoles with a 5-amino-substitution pattern
(Scheme 3, bottom panel). Moreover, the use of amino-
functionalized nitriles, namely cyanamides, could potentially
1749
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
optimize the reaction temperature and time indicated that the
best yield of 3a was achieved at 60 °C for 3 h (entry 4).
With optimal conditions in hand, the oxidative annulation
scope was then examined. We explored different nitriles with
ynamide 1a taken as the alkyne component (Table 2). Various
Scheme 4. Gram-Scale Synthesis of 3v
a
Table 2. Scope for the Synthesis of 5-Aminooxazoles
o-nosyl group from 3v, but the isolation of the corresponding
deprotected oxazole or its derivatives failed. This is probably
because of the instability of oxazoles containing NH in the fifth
position.
The 5-amino substitution pattern of oxazoles 3 was
unambiguously confirmed by X-ray diffraction of oxazole 3o
(Figure 1).94
Figure 1. Molecular structure of 3o (50% probability amplitude
displacement ellipsoids).
We tested internal ynamides in our heterocyclization;
however, they are not suitable substrates for the reported
transformation, as the only products formed are α-ketoamides
that result from gold-catalyzed overoxidation of the CC
triple bonds.90,95 Notably, terminal ynamides also undergo
competitive overoxidation. A mixture of oxazole 3w and
glyoxamide 3w′ was isolated when ynamide 1w was used as
starting material (Scheme 5, NMR yield, the products exhibit
a
All reactions were carried out on a 0.2 mmol scale (0.2 M). Isolated
yields are reported.
Scheme 5. Annulation and Overoxidation of 1w
aliphatic (primary, secondary, tertiary, and cyclic) heteroar-
omatic (α-furyl, α-thienyl) and aromatic nitriles reacted to
grant corresponding oxazoles 3a−j in 57−83% yields.
Saturated nitriles with functional substituents (MeO, Cl)
gave, however, moderate yields of target products 3k,l. A range
of terminal ynamides was then tested using acetonitrile as the
reaction partner. The reaction proceeded smoothly with
various functionalities at the N-sulfonyl substituent including
electron-donating, electron-withdrawing, and bulky substitu-
ents in various positions of the aromatic ring (3m−r).
Oxazoles 3s,t, bearing an easily cleavable o- or p-nosyl
protective group, were obtained in 72−88% yields. The
ynamide featuring a primary butyl group also delivered the
corresponding oxazole 3u.
When ynamides with other NR-substituents (R = Ph, Bn,
allyl) were employed, we observed the generation of complex
product mixtures. In these cases, intramolecular reactions of
gold oxo-carbenes (e.g., CH-insertions91,92 and cyclopropana-
tions93) with the involvement of NR-substituents are
prevailing. The developed oxidative annulation can be readily
performed in gram scale (Scheme 4). We tried to remove the
the same polarity). A plausible related mechanism for the
formation of oxazoles and the dicarbonyl byproducts from
propiolates has been discussed in our recent works.77,88
After the successful synthesis of 2-amino-1,3-oxazoles, our
idea was to demonstrate the utility of our synthetic approach
to construct the 2,5-diamino-substituted heterocycles (Table
3) starting from cyanamides 4 as amino-functionalized building
blocks. According to our expectations, application of both
N,N-dimethyl- and N,N-diethylcyanamides led to good yields
of corresponding oxazoles 5a,b. The reaction conditions were
satisfactory for introducing a diversity of amino functionalities
(such as pyrrolidine, piperidine, morpholine, and isoquinoline
heterocyclic fragments 5c−f) into the fifth position of the
oxazole core. Unfortunately, when the unsubstituted cyana-
mide NH2CN was employed as a reactant, complex mixtures of
1750
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
activated 4 Å molecular sieves before use. Other reagents were
purchased from commercial vendors and were used as received.
General Procedure for the Gold(I)-Catalyzed Synthesis of
Aminooxazoles 3 and 5. IPrAuNTf2 (8.7 mg, 10.0 μmol, 5 mol %)
was added to a solution of ynamide (1, 0.2 mmol) and 2,3-
dichloropyridine N-oxide 2d (36.1 mg, 0.22 mmol, 1.1 equiv) in
nitriles 3 (0.5 mL). The resulting solution was stirred at 60 °C in an
oil bath for 3 h. After completion, all volatile components were
removed in vacuo, and the residue was purified by silica gel
chromatography, eluting with hexane/EtOAc to afford oxazoles 3 and
5.
Table 3. Scope for the Synthesis of 2,5-Diaminooxazoles
N,4-Dimethyl-N-(2-methyloxazol-5-yl)benzenesulfonamide (3a).
Colorless solid (44.2 mg, 83%); mp 108.0−109.0 °C (hexane/
1
EtOAc); Rf 0.45 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl3)
δ 7.62 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.66 (s, 1H), 3.12
(s, 3H), 2.43 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 159.5, 146.1, 144.6, 134.2, 129.8, 127.9, 121.0, 37.7, 21.7,
14.4; HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O3S+:
267.0798; found: 267.0799.
N-(2-Ethyloxazol-5-yl)-N,4-dimethylbenzenesulfonamide (3b).
Colorless solid (43.2 mg, 77%); mp 106.0−107.0 °C (hexane/
1
EtOAc); Rf 0.40 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl3)
a
δ 7.62 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 6.70 (s, 1H), 3.14
(s, 3H), 2.67 (q, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.25 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.9, 145.9, 144.6, 134.2,
129.9, 127.9, 121.0, 37.7, 22.1, 21.7, 11.0; HRMS (ESI): m/z [M +
H]+ calcd for C13H17N2O3S+: 281.0954; found: 281.0955.
All reactions were carried out on a 0.2 mmol scale (0.2 M). Isolated
yields are reported.
products were detected, probably because of competing gold-
catalyzed hydroamination of the starting ynamides.96
N-(2-Isopropyloxazol-5-yl)-N,4-dimethylbenzenesulfonamide
1
(3c). Colorless oil (37.7 mg, 64%); Rf 0.40 (hexane/EtOAc 2:1); H
NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0
Hz, 2H), 6.72 (s, 1H), 3.14 (s, 3H), 2.94 (hept, J = 7.0 Hz, 1H), 2.43
(s, 3H), 1.25 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 167.0, 145.7, 144.5, 134.3, 129.8, 127.9, 121.0, 37.6, 28.8, 21.7, 20.2;
HRMS (ESI): m/z [M + H]+ calcd for C14H19N2O3S+: 295.1111;
found: 295.1109.
CONCLUSIONS
■
Summarizing, we developed a facile gold-catalyzed method,
based on the integration of ynamides and nitriles, for the
construction of 1,3-oxazoles featuring an amino group in the
fifth position. The proposed approach involves oxygen atom
transfer, as the key step, to give gold α-oxocarbenes followed
by their trapping by nitriles. In contrast to the previously
described methods for the synthesis of 4-amino-1,3-oxazoles
through the reactions of gold α-iminocarbenes, our annulation
demonstrates completely reverse regioselectivity. Probably, the
reason for the observed regioselectivity is the higher rate of
nucleophilic addition of N-oxides to gold-activated ynamides
in comparison with nitriles, as well as the reversibility of the
addition of the nitriles. The main advantage of the proposed
methodology over other routes to 5-amino-oxazoles is the
ability to use simple and easily accessible building blocks. The
optimized reaction conditions are easily scalable and
demonstrate a high functional group tolerance. In addition,
the use of cyanamides, as a nitrile component, grant valuable
2,5-diamino-substituted heterocycles.
N-(2-(tert-Butyl)oxazol-5-yl)-N,4-dimethylbenzenesulfonamide
1
(3d). Colorless oil (41.3 mg, 67%); Rf 0.45 (hexane/EtOAc 2:1); H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.9
Hz, 2H), 6.73 (s, 1H), 3.14 (s, 3H), 2.43 (s, 3H), 1.26 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 145.6, 144.5, 134.3,
129.8, 127.9, 121.0, 37.5, 34.0, 28.3, 21.7; HRMS (ESI): m/z [M +
H]+ calcd for C15H21N2O3S+: 309.1267; found: 309.1270.
N-(2-Cyclopropyloxazol-5-yl)-N,4-dimethylbenzenesulfonamide
(3e). Colorless solid (41.5 mg, 71%); mp 69.0−71.0 °C (hexane/
1
EtOAc); Rf 0.50 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl3)
δ 7.62 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 6.65 (s, 1H), 3.12
(s, 3H), 2.45 (s, 3H), 1.97−1.90 (m, 1H), 1.00−0.90 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.2, 145.1, 144.5, 134.3,
129.8, 128.0, 121.4, 37.8, 21.7, 9.3, 8.3; HRMS (ESI): m/z [M + H]+
calcd for C14H17N2O3S+: 293.0954; found: 293.0958.
N-(2-(Furan-2-yl)oxazol-5-yl)-N,4-dimethylbenzenesulfonamide
1
(3f). Colorless oil (45.2 mg, 71%); Rf 0.30 (hexane/EtOAc 2:1); H
NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H),
7.32 (d, J = 7.9 Hz, 2H), 6.95−6.94 (m, 2H), 6.52−6.51 (m, 1H),
3.21 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
152.1, 146.0, 144.9, 144.8, 142.4, 134.1, 130.0, 128.0, 121.7, 112.2,
112.1, 37.6, 21.8; HRMS (ESI): m/z [M + H]+ calcd for
C15H15N2O4S+: 319.0747; found: 319.0751.
N , 4 - D i m e t h y l - N - ( 2 - ( t h i o p h e n - 2 - y l ) o x a z o l - 5 - y l ) -
benzenesulfonamide (3g). Colorless oil (43.4 mg, 65%); Rf 0.35
(hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.4
Hz, 2H), 7.55−7.54 (m, 1H), 7.43−7.41 (m, 1H), 7.33 (d, J = 8.0 Hz,
2H), 7.10−7.07 (m, 1H), 6.90 (s, 1H), 3.21 (s, 3H), 2.45 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 155.7, 145.9, 144.8, 134.2,
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded at ambient
temperature with a Bruker Avance III 400 instrument at 400.13 MHz
(1H NMR) and 100.61 MHz (13C NMR) in CDCl3 or DMSO-d6.
Chemical shifts (δ) are given in ppm relative to resonances of the
solvents (1H: δ = 7.26 for residual CHCl3 peak, δ = 2.50 for residual
DMSO peak; 13C: δ = 77.2 for CDCl3, δ = 39.5 for DMSO-d6). Mass
spectra were recorded on Bruker MicroTOF (ESI) and Bruker maXis
HRMS-ESI-QTOF instruments. Chromatographic separation was
carried out on Macherey−Nagel silica gel 60 M (0.04−0.063 mm).
Analytical TLC was performed on unmodified Merck ready-to-use
plates (TLC silica gel 60 F254); detection was achieved with a UV
lamp. Melting points were measured with Stuart smp30 apparatus.
Gold complexes (IPrAuNTf2,85 Ph3PAuNTf2,97 PicAuCl298) were
synthesized according to the published protocols. Known ynamides
112,99 and N-oxides 290 were prepared by the literature procedures.
The solvents were purified using standard techniques and stored over
130.0, 129.8, 128.9, 128.1, 128.1, 128.0, 122.2, 37.8, 21.8; HRMS
+
(ESI): m/z [M + H]+ calcd for C15H15N2O3S2 : 335.0519; found:
335.0527.
N,4-Dimethyl-N-(2-phenyloxazol-5-yl)benzenesulfonamide (3h).
Yellowish oil (48.6 mg, 74%); Rf 0.50 (hexane/EtOAc 2:1); 1H NMR
(400 MHz, CDCl3) δ 7.89−7.87 (m, 2H), 7.68 (d, J = 8.3 Hz, 2H),
1751
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
7.45−7.40 (m, 3H), 7.32 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 3.24 (s,
3H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.3, 146.3,
144.7, 134.2, 130.7, 130.0, 128.9, 128.0, 127.3, 126.3, 122.2, 37.7,
21.8; HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O3S+:
329.0954; found: 329.0966.
NMR (400 MHz, CDCl3) δ 6.95 (s, 2H), 6.53 (s, 1H), 3.21 (s, 3H),
2.53 (s, 6H), 2.42 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 160.1, 146.1, 143.7, 140.8, 132.2, 131.4, 120.0, 36.5, 22.9,
21.1, 14.3; HRMS (ESI): m/z [M + H]+ calcd for C14H19N2O3S+:
295.1111; found: 295.1106.
N,4-Dimethyl-N-(2-(o-tolyl)oxazol-5-yl)benzenesulfonamide (3i).
Colorless oil (39.0 mg, 57%); Rf 0.35 (hexane/EtOAc 4:1); 1H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 8.3 Hz,
2H), 7.34−7.31 (m, 3H), 7.26−7.22 (m, 2H), 7.01 (s, 1H), 3.24 (s,
3H), 2.53 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
159.8 (br.), 146.1 (br.), 144.8, 137.6, 134.1, 131.8, 130.5, 130.0,
128.9, 127.9, 126.2, 125.9, 121.3, 37.5, 21.9, 21.7; HRMS (ESI): m/z
[M + H]+ calcd for C18H19N2O3S+: 343.1111; found: 343.1108.
N,4-Dimethyl-N-(2-(m-tolyl)oxazol-5-yl)benzenesulfonamide
(3g). Colorless solid (52.7 mg, 74%); mp 59.0−60.0 °C (hexane/
EtOAc); Rf 0.30 (hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3)
δ 7.77−7.66 (m, 4H), 7.36−7.24 (m, 4H), 6.94 (s, 1H), 3.23 (s, 3H),
2.44 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
159.5, 146.3, 144.7, 138.7, 134.2, 131.6, 129.9, 128.8, 128.0, 127.0,
126.9, 123.4, 121.9, 37.7, 21.7, 21.4; HRMS (ESI): m/z [M + H]+
calcd for C18H19N2O3S+: 343.1111; found: 343.1104.
N-Methyl-N-(2-methyloxazol-5-yl)naphthalene-2-sulfonamide
1
(3r). Brownish oil (48.4 mg, 80%); Rf 0.30 (hexane/EtOAc 1:1); H
NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H),
7.94 (d, J = 8.2 Hz, 1H), 7.71−7.62 (m, 3H), 6.73 (s, 1H), 3.20 (s,
3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 146.0,
135.3, 134.2, 132.2, 129.6, 129.58, 129.5, 129.4, 128.1, 127.9, 122.8,
121.3, 37.9, 14.5; HRMS (ESI): m/z [M + Na]+ calcd for
C15H14N2NaO3S+: 325.0617; found: 325.0609.
N-Methyl-N-(2-methyloxazol-5-yl)-4-nitrobenzenesulfonamide
(3s). Yellow solid (52.3 mg, 88%); mp 113.0−115.0 °C (hexane/
1
EtOAc); Rf 0.30 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl3)
δ 8.38 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 6.78 (s, 1H), 3.21
(s, 3H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1,
150.7, 144.9, 143.1, 129.1, 124.6, 121.9, 38.0, 14.5; HRMS (ESI): m/z
[M + H]+ calcd for C11H12N3O5S+: 298.0492; found: 298.0488.
N-Methyl-N-(2-methyloxazol-5-yl)-2-nitrobenzenesulfonamide
(3t). Yellow solid (42.8 mg, 72%); mp 44.5−46.0 °C (hexane/
N-(2-(3-Chloropropyl)oxazol-5-yl)-N,4-dimethylbenzenesulfona-
1
EtOAc); Rf 0.40 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl3)
mide (3k). Colorless oil (37.5 mg, 57%); Rf 0.50 (hexane/EtOAc
1
δ 7.91 (d, J = 8.1 Hz, 1H), 7.78−7.75 (m, 1H), 7.70−7.66 (m, 2H),
6.77 (s, 1H), 3.36 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 160.5, 148.3, 144.7, 134.7, 131.9, 131.7, 131.2, 124.6, 121.6,
38.5, 14.4.; HRMS (ESI): m/z [M + H]+ calcd for C11H12N3O5S+:
298.0492; found: 298.0481.
1:1); H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.32
(d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 3.57 (t, J = 6.4 Hz, 2H), 3.14 (s,
3H), 2.83 (t, J = 7.3 Hz, 2H), 2.44 (s, 3H), 2.15 (p, J = 6.8 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 161.4, 146.2, 144.7, 134.2,
129.9, 127.9, 121.0, 43.7, 37.6, 29.4, 25.7, 21.7; HRMS (ESI): m/z
[M + H]+ calcd for C14H18ClN2O3S+: 329.0721; found: 329.0718.
N-(2-(2-Methoxyethyl)oxazol-5-yl)-N,4-dimethylbenzenesulfo-
namide (3l). Yellowish oil (30.4 mg, 49%); Rf 0.30 (hexane/EtOAc
N-Butyl-4-methyl-N-(2-methyloxazol-5-yl)benzenesulfonamide
1
(3u). Colorless oil (30.8 mg, 50%); Rf 0.40 (hexane/EtOAc 2:1); H
NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0
Hz, 2H), 6.68 (s, 1H), 3.43 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.37 (s,
3H), 1.49−1.42 (m, 2H), 1.36−1.29 (m, 2H), 0.88 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 144.5, 144.3, 135.7,
129.8, 127.8, 123.4, 50.4, 30.5, 21.7, 19.6, 14.6, 13.7; HRMS (ESI):
m/z [M + H]+ calcd for C15H21N2O3S+: 309.1267; found: 309.1273.
N-Ethyl-4-methyl-N-(2-methyloxazol-5-yl)benzenesulfonamide
(3w) and N-Ethyl-2-oxo-N-tosylacetamide (3w′). Brownish oil (49.0
1
1:1); H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.31
(d, J = 7.6 Hz, 2H), 6.73 (s, 1H), 3.69 (t, J = 6.6 Hz, 2H), 3.34 (s,
3H), 3.13 (s, 3H), 2.92 (t, J = 6.6 Hz, 2H), 2.44 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 160.3, 146.2, 144.6, 134.2, 129.9, 128.0,
121.1, 69.1, 58.9, 37.6, 29.3, 21.7; HRMS (ESI): m/z [M + H]+ calcd
for C14H19N2O4S+: 311.1060; found: 311.1067.
N-Methyl-N-(2-methyloxazol-5-yl)benzenesulfonamide (3m).
Colorless oil (38.9 mg, 77%); Rf 0.30 (hexane/EtOAc 1:1); 1H
NMR (400 MHz, CDCl3) δ 7.77−7.75 (m, 2H), 7.64 (t, J = 7.5 Hz,
1H), 7.53 (t, J = 7.7 Hz, 2H), 6.69 (s, 1H), 3.16 (s, 3H), 2.35 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.6, 145.9, 137.3, 133.6, 129.3,
1
mg, 58% (3w), 31% (3w′)); Rf 0.60 (hexane/ethyl acetate 1:1); H
NMR for 3w (400 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H), 7.31 (d, J
= 8.0 Hz, 2H), 6.74 (s, 1H), 3.52 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H),
1
2.43 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H); H NMR for 3w′ (400 MHz,
127.9, 121.2, 37.8, 14.4; HRMS (ESI): m/z [M + H]+ calcd for
CDCl3) δ 9.66 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.2 Hz,
2H), 3.63 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.17−1.14 (m, 3H);
13C{1H} NMR for 3w and 3w′ (100 MHz, CDCl3) δ 184.3, 166.1,
C11H13N2O3S+: 253.0641; found: 253.0645.
4-Fluoro-N-methyl-N-(2-methyloxazol-5-yl)benzenesulfonamide
(3n). Colorless solid (36.8 mg, 68%); mp 95.0−97.0 °C (hexane/
EtOAc); Rf 0.35 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3)
δ 7.74−7.79 (m, 2H), 7.17−7.23 (m, 2H), 6.70 (s, 1H), 3.15 (s, 3H),
2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.7 (d, JF =
256.2 Hz), 159.7, 145.7, 133.3 (d, JF = 3.4 Hz), 130.6 (d, JF = 9.4 Hz),
121.4, 116.6 (d, JF = 22.7 Hz), 37.8, 14.4; HRMS (ESI): m/z [M +
H]+ calcd for C11H12FN2O3S+: 271.0547; found: 271.0545.
4-Bromo-N-methyl-N-(2-methyloxazol-5-yl)benzenesulfonamide
(3o). Yellow solid (47.0 mg, 71%); mp 96.0−98.0 °C (hexane/
EtOAc); Rf 0.40 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3)
δ 7.70−7.66 (m, 2H), 7.63−7.60 (m, 2H), 6.72 (s, 1H), 3.16 (s, 3H),
2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.9, 145.6,
136.2, 132.6, 129.3, 128.9, 121.2, 37.8, 14.4; HRMS (ESI): m/z [M +
Na]+ calcd for C11H11BrN2NaO3S+: 352.9566; found: 352.9561.
4 - M e t h o x y - N - m e t h y l - N - ( 2 - m e t h y l o x a z o l - 5 - y l ) -
benzenesulfonamide (3p). Colorless oil (35.6 mg, 63%, 91% purity
form NMR assay); Rf 0.40 (hexane/EtOAc 1:1); 1H NMR (400
MHz, CDCl3) δ 7.68 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H),
6.67 (s, 1H,), 3.88 (s, 3H), 3.13 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 163.7, 159.5, 146.3, 130.1, 128.7, 121.0, 114.4,
55.8, 37.7, 14.5; HRMS (ESI): m/z [M + H]+ calcd for
C12H15N2O4S+: 283.0747; found: 283.0753.
160.7, 151.0, 146.2, 144.5, 135.6, 134.4, 130.4, 129.9, 128.2, 127.8,
122.6, 45.8, 40.9, 21.8, 21.7, 14.5, 14.1, 13.6; HRMS (ESI) for 3w: m/
z [M + H]+ calcd for C13H17N2O3S+: 281.0954; found: 281.0944;
HRMS (ESI) for 3w′: m/z [M + Na]+ calcd for C10H11NNaO4S+:
264.0301; found: 264.0305.
N-(2-(Dimethylamino)oxazol-5-yl)-N,4-dimethylbenzenesulfo-
namide (5a). Brown oil (43.7 mg, 74%); Rf 0.30 (hexane/EtOAc
1
1:1); H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.31
(d, J = 8.1 Hz, 2H), 6.46 (s, 1H), 3.11 (s, 3H), 2.95 (s, 6H), 2.44 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 144.2, 139.9, 134.7,
129.7, 128.1, 123.1, 38.6, 37.4, 21.7; HRMS (ESI): m/z [M + H]+
calcd for C13H18N3O3S+: 296.1063; found: 296.1071.
N-(2-(Diethylamino)oxazol-5-yl)-N,4-dimethylbenzenesulfona-
mide (5b). Browm oil (50.5 mg, 78%); Rf 0.50 (hexane/EtOAc 1:1);
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.30 (d, J =
8.1 Hz, 2H), 6.49 (s, 1H), 3.34 (q, J = 7.1 Hz, 4H), 3.13 (s, 3H), 2.43
(s, 3H), 1.13 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.1, 144.1, 139.3, 134.9, 129.7, 128.0, 123.0, 42.5, 38.5, 21.7, 13.4;
HRMS (ESI): m/z [M + H]+ calcd for C15H22N3O3S+: 324.1376;
found: 324.1387.
N, 4-Dimethyl-N-(2-(pyrrolidin-1-yl)oxazol-5-yl)-
benzenesulfonamide (5c). Yellowish oil (42.4 mg, 66%); Rf 0.50
(hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3
Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 6.45 (s, 1H), 3.40−3.37 (m, 4H),
3.10 (s, 3H), 2.43 (s, 3H), 1.97−1.91 (m, 4H); 13C{1H} NMR (100
N , 2 , 4 , 6 - T e t r a m e t h y l - N - ( 2 - m e t h y l o x a z o l - 5 - y l ) -
benzenesulfonamide (3q). Colorless solid (38.9 mg, 66%); mp
85.0−87.0 °C (hexane/EtOAc); Rf 0.30 (hexane/EtOAc 2:1); 1H
1752
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
MHz, CDCl3) δ 158.3, 144.2, 139.7, 134.7, 129.7, 128.1, 123.0, 47.1,
38.6, 25.6, 21.7; HRMS (ESI): m/z [M + H]+ calcd for
C15H20N3O3S+: 322.1220; found: 322.1224.
(E)-N-(1,2-Dichlorovinyl)-N-ethyl-4-methylbenzenesulfonamide
(1w′). Colorless solid (1.35 g, 92%); mp 56.0−58.0 °C (hexane/
1
EtOAc); Rf 0.50 (hexane/EtOAc 4:1); H NMR (400 MHz, CDCl3)
δ 7.78 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.51 (s, 1H), 3.30
(br. s, 2H), 2.41 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C{H} NMR (100
MHz, CDCl3) δ 144.5, 135.2, 129.6, 129.4, 128.2, 121.5, 43.0, 21.5,
12.8; HRMS (ESI): m/z [M + Na]+ calcd for C11H13Cl2NNaO2S+:
315.9936; found: 315.9937.
N , 4 - D im e t h y l - N - ( 2 - ( p i p e r i d i n - 1 - y l ) o x a z o l - 5 - y l ) -
benzenesulfonamide (5d). Brown oil (44.3 mg, 66%); Rf 0.50
(hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3
Hz, 2H, Ar), 7.31 (d, J = 7.9 Hz, 2H, Ar), 6.47 (s, 1H, Ar), 3.36−3.34
(m, 4H, 2CH2), 3.11 (s, 3H, NMe), 2.44 (s, 3H, Me), 1.60−1.58 (m,
6H, 3CH2); 13C NMR (100 MHz, CDCl3) δ 159.6, 144.2, 139.7,
134.8, 129.7, 128.1, 122.8, 46.2, 38.6, 25.1, 24.1, 21.7; HRMS (ESI):
m/z [M + H]+ calcd for C16H22N3O3S+: 336.1376; found: 336.1380.
N,4-Dimethyl-N-(2-morpholinooxazol-5-yl)benzenesulfonamide
General Procedure for the Synthesis of Ynamides 1q,r,w
Using n-Butyllithium. A solution of 1,2-dichloroenamide (1q′, 1r′,
or 1w′, 1.0 mmol) in anhydrous THF (5 mL) was stirred under argon
atmosphere and cooled to −78 °C in an acetone/dry ice bath. A
solution of n-butyllithium (2.5 M in hexane, 1.4 mL, 3.5 equiv) was
then added dropwise over 10 min, such that the reaction did not
exceed −70 °C, and the resulting mixture was then stirred at −78 °C
for 30 min. Next, water (1 mL) was added at −78 °C and the stirred
mixture was allowed to warm to room temperature, diluted with water
(30 mL), and extracted with DCM (3 × 15 mL). The combined
organic extracts were dried over anhydrous Na2SO4. After filtration,
the solvent was removed in vacuo to afford pure terminal ynamides
1q, 1r, or 1w.
N-Ethynyl-N,2,4,6-tetramethylbenzenesulfonamide (1q). Brown
solid (225 mg, 95%); mp 65.0−67.0 °C (DCM); 1H NMR (400
MHz, CDCl3) δ 6.99 (s, 2H), 3.13 (s, 3H), 2.71 (s, 1H), 2.65 (s, 6H),
2.32 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 143.5, 141.1, 132.4,
132.1, 131.9, 118.7, 35.3, 23.4, 21.1.; HRMS (ESI): m/z [M + Na]+
calcd for C12H15NNO2S+: 260.0716; found: 260.0718.
1
(5e). Brown oil (41.8 mg, 62%); Rf 0.30 (hexane/EtOAc 1:1); H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0
Hz, 2H), 6.48 (s, 1H), 3.75−3.72 (m, 4H), 3.39−3.37 (m, 4H), 3.12
(s, 3H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.2,
144.4, 140.6, 134.7, 129.8, 128.1, 122.6, 66.2, 45.5, 38.6, 21.7; HRMS
(ESI): m/z [M + H]+ calcd for C15H20N3O4S+: 338.1169; found:
338.1171.
N-(2-(3,4-Dihydroisoquinolin-2(1H)-yl)oxazol-5-yl)-N,4-dime-
thylbenzenesulfonamide (5f). Brown oil (49.9 mg, 65%); Rf 0.30
(hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.4
Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.21−7.09 (m, 4H), 6.51 (s, 1H),
4.56 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.14 (s, 3H), 2.91 (t, J = 5.9 Hz,
2H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 144.3,
140.1, 134.7, 134.1, 132.5, 129.7, 128.9, 128.0, 126.8, 126.5, 126.4,
122.8, 46.8, 42.7, 38.6, 28.4, 21.7; HRMS (ESI): m/z [M + H]+ calcd
for C20H22N3O3S+: 384.1376; found: 384.1373.
Gram-Scale Synthesis of 3v. IPrAuNTf2 (218 mg, 0.25 mmol, 5
mol %) was added to a solution of N-ethynyl-N-methyl-2-nitro-
benzenesulfonamide (1t, 5.0 mmol, 1.20 g) and 2,3-dichloropyridine
N-oxide 2d (0.90 g, 5.50 mmol, 1.1 equiv) in benzonitrile (5.0 mL).
The resulting solution was stirred at 60 °C in an oil bath for 3 h. After
completion, all volatile components were removed in vacuo and the
residue was purified by silica gel chromatography, eluting with
hexane/EtOAc to afford oxazole 3v.
N-Ethynyl-N-methylnaphthalene-2-sulfonamide (1r). Brown
solid (233 mg, 95%); mp 58.5−60.0 °C (DCM); 1H NMR (400
MHz, CDCl3) δ 8.49 (s, 1H), 8.03−8.01 (m, 2H), 7.96−7.90 (m,
2H), 7.71−7.63 (m, 2H), 3.13 (s, 3H), 2.71 (s, 1H); 13C{H} NMR
(100 MHz, CDCl3) δ 135.5, 133.4, 132.2, 129.71, 129.68, 129.63,
129.5, 128.1, 127.9, 122.7, 77.6, 57.8, 39.1; HRMS (ESI): m/z [M +
Na]+ calcd for C13H11NNaO2S+: 268.0403; found: 268.0405.
N-Ethyl-N-ethynyl-4-methylbenzenesulfonamide (1w). Yellowish
1
oil (226 mg, 97%); H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3
N-Methyl-2-nitro-N-(2-phenyloxazol-5-yl)benzenesulfonamide
(3v). Yellow oil (1.17 g, 65%); Rf 0.50 (hexane/EtOAc 1:1); 1H NMR
(400 MHz, CDCl3) 7.95−7.89 (m, 3H), 7.77−7.72 (m, 1H), 7.69−
7.64 (m, 2H), 7.45−7.39 (m, 3H), 7.00 (s, 1H), 3.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.9, 148.4, 144.8, 134.7, 131.9, 131.8,
131.3, 131.1, 129.0, 126.9, 126.4, 124.6, 123.0, 38.6; HRMS (ESI):
m/z [M + H]+ calcd for C16H14N3O5S+: 360.0649; found: 360.0635.
Synthesis of Starting Ynamides. General Procedure for the
Preparation of 1,2-Dichloroenamides 1q′,r′,w′. Trichloro-
ethylene (1.31 g, 10.0 mmol, 2.0 equiv) was added dropwise to a
stirred suspension of amide (5.0 mmol) and K2CO3 (2.07 g, 15.0
mmol, 3.0 equiv) in DMF (5.0 mL) at 70 °C in an oil bath under
argon atmosphere. The reaction mixture was stirred overnight, cooled
to rt, diluted with water (50 mL), and extracted with DCM (3 × 30
mL). The combined organic extracts were dried over anhydrous
Na2SO4. After filtration, the solvent was removed in vacuo and the
residue was purified by silica gel chromatography, eluting with
hexane/EtOAc to afford 1,2-dichloroenamides 1q′,r′,w′.
Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 3.37 (q, J = 7.2 Hz, 2H), 2.72 (s,
1H), 2.43 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 135.5, 133.4, 132.2, 129.71, 129.68, 129.63, 129.5, 128.1,
127.9, 122.7, 77.6, 57.8, 39.1; HRMS (ESI): m/z [M + Na + H2O]+
calcd for C11H15NNaO3S+: 264.0665; found: 264.0673.
Synthesis of Ynamide 1t. A mixture of N-methyl-2-nitro-
benzenesulfonamide (10 mmol, 2.16 g), K2CO3 (2.76 g, 20 mmol, 2
equiv), CuSO4·5H2O (250 mg, 1.0 mmol, 10 mol %), 1,10-
phenanthroline (360 mg, 2.0 mmol, 20 mol %), 1-bromo-2-
triisopropylsilylacetylene (2.86 mg, 11 mmol, 1.1 equiv), and toluene
(50 mL) was stirred at 70 °C under argon atmosphere in an oil bath
overnight After completion, the reaction mixture was cooled to rt,
diluted with DCM (150 mL), filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography, eluting with
hexane/EtOAc to afford the TIPS-protected ynamide, as a yellow
solid (1.82 g, Rf 0.40 (hexane/EtOAc 4:1)) that was used further
without additional purification. Next, a solution of TBAF (1 M in
THF, 0.12 mmol, 12 mL) was added dropwise to a stirred solution of
the TIPS-protected ynamide (1.82 g) in anhydrous THF (30 mL) at
0 °C in an ice bath. The resulting dark solution was stirred at 0 °C in
an ice bath for 1 h, allowed to warm to rt, diluted with water (70 mL),
and extracted with DCM (3 × 50 mL). The combined organic
extracts were dried over anhydrous Na2SO4. After filtration, the
solvent was removed in vacuo and the residue was purified by silica
gel chromatography, eluting with hexane/EtOAc to afford 1t.
(E)-N-(1,2-Dichlorovinyl)-N,2,4,6-tetramethylbenzenesulfona-
mide (1q′). Colorless solid (1.33 mg, 84%); mp 145.0−147.0 °C
(hexane/EtOAc); Rf 0.45 (hexane/EtOAc 8:1); 1H NMR (400 MHz,
CDCl3) δ 6.94 (s, 2H), 6.22 (s, 1H), 3.06 (s, 3H), 2.64 (s, 6H), 2.28
(s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 135.3, 134.5, 132.1,
131.5, 130.3, 129.5, 129.44, 129.38, 128.1, 127.8, 123.3, 120.0, 35.5;
HRMS (ESI): m/z [M + Na]+ calcd for C12H15Cl2NNaO2S+:
330.0093; found: 330.0099.
(E)-N-(1,2-Dichlorovinyl)-N-methylnaphthalene-2-sulfonamide
(1r′). Colorless solid (1.33 mg, 84%); mp 114.0−115.0 °C (hexane/
EtOAc); Rf 0.45 (hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3)
δ 8.49 (s, 1H,), 7.98 (d, J = 8.5 Hz, 2H), 7.93−7.90 (m, 2H), 7.69−
7.60 (m, 2H), 6.42 (s, 1H), 3.00 (s, 3H); 13C{H} NMR (100 MHz,
CDCl3) δ 135.3, 134.5, 132.1, 131.5, 130.3, 129.5, 129.44, 129.38,
128.1, 127.8, 123.3, 120.0, 35.5; HRMS (ESI): m/z [M + Na]+ calcd
for C13H11Cl2NNaO2S+: 337.9780; found: 337.9779.
N-Ethynyl-N-methyl-2-nitrobenzenesulfonamide (1t). Yellow
solid (1.88 g, 83% relative to starting sulfonamide); mp 100.0−
1
101.0 °C (hexane/EtOAc); Rf 0.35 (hexane/EtOAc 2:1); H NMR
(400 MHz, CDCl3) δ 8.17−8.15 (m, 2H), 7.82−7.72 (m, 2H), 3.32
(s, 3H), 2.76 (s, 1H); 13C{H} NMR (100 MHz, CDCl3) δ 148.1,
135.0, 132.1, 132.0, 130.1, 124.5, 77.2, 76.1, 59.0, 39.5; HRMS (ESI):
m/z [M + Na]+ calcd for C9H8N2NaO4S+: 263.0097; found:
263.0099.
1753
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(4) Pan, F.; Shu, C.; Ye, L.-W. Recent Progress towards Gold-
Catalyzed Synthesis of N-Containing Tricyclic Compounds Based on
Ynamides. Org. Biomol. Chem. 2016, 14 (40), 9456−9465.
(5) Zhou, B.; Tan, T.-D.; Zhu, X.-Q.; Shang, M.; Ye, L.-W. Reversal
of Regioselectivity in Ynamide Chemistry. ACS Catal. 2019, 9 (7),
6393−6406.
(6) Duret, G.; Le Fouler, V.; Bisseret, P.; Bizet, V.; Blanchard, N.
Diels−Alder and Formal Diels−Alder Cycloaddition Reactions of
Ynamines and Ynamides. Eur. J. Org. Chem. 2017, 2017 (46), 6816−
6830.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02584.
Copies of 1H and 13C{1H} NMR spectra and XRD data
(PDF)
FAIR data, including the primary NMR FID files, for all
compounds 1q, 1q′, 1r, 1r′, 1t, 1w, 1w′, 3a−w, and 5a−
f (ZIP)
(7) Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Gold-Catalyzed
Intermolecular [4 + 2] and [2 + 2+2] Cycloadditions of Ynamides
with Alkenes. Angew. Chem., Int. Ed. 2012, 51 (1), 113−117.
Accession Codes
́
(8) Xie, L.-G.; Niyomchon, S.; Mota, A. J.; Gonzalez, L.; Maulide, N.
CCDC 2035080 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Metal-Free Intermolecular Formal Cycloadditions Enable an
Orthogonal Access to Nitrogen Heterocycles. Nat. Commun. 2016,
7 (1), 10914.
(9) Xie, L.-G.; Shaaban, S.; Chen, X.; Maulide, N. Metal-Free
Synthesis of Highly Substituted Pyridines by Formal [2 + 2+2]
Cycloaddition under Mild Conditions. Angew. Chem., Int. Ed. 2016,
55 (41), 12864−12867.
(10) Dubovtsev, A. Y.; Shcherbakov, N. V.; Dar’in, D. V.;
Kukushkin, V. Y. The Dichotomy of Gold-Catalyzed Interplay
between Cyanamides and Ynamides: Controllable Switch from [2 +
2+2] to [4 + 2] Cycloaddition. Adv. Synth. Catal. 2020, 362 (13),
2672−2682.
(11) Evano, G.; Michelet, B.; Zhang, C. The Anionic Chemistry of
Ynamides: A Review. C. R. Chim. 2017, 20 (6), 648−664.
(12) Chen, Y.-L.; Sharma, P.; Liu, R.-S. Sulfonamide-Directed Gold-
Catalyzed [2 + 2 + 2]-Cycloadditions of Nitriles with Two Discrete
Ynamides to Construct 2,4-Diaminopyridine Cores. Chem. Commun.
2016, 52 (15), 3187−3190.
(13) Evano, G.; Lecomte, M.; Thilmany, P.; Theunissen, C.
Keteniminium Ions: Unique and Versatile Reactive Intermediates
for Chemical Synthesis. Synthesis 2017, 49 (15), 3183−3214.
(14) Patil, D. V.; Shin, S. Organocatalytic Oxidative Functionaliza-
tions of Alkynes. Asian J. Org. Chem. 2019, 8 (1), 63−73.
(15) Jadhav, A. M.; Pagar, V. V.; Huple, D. B.; Liu, R.-S. Zinc(II)-
Catalyzed Intermolecular Hydrative Aldol Reactions of 2-En-1-
Ynamides with Aldehydes and Water to Form Branched Aldol
Products Regio- and Stereoselectively. Angew. Chem., Int. Ed. 2015, 54
(12), 3812−3816.
(16) Hashmi, A. S. K. Gold-Catalyzed Organic Reactions Gold-
Catalyzed Organic Reactions. Chem. Rev. 2007, 107, 3180−3211.
(17) Hashmi, A. S. K.; Hutchings, G. J. Gold Catalysis. Angew.
Chem., Int. Ed. 2006, 45 (47), 7896−7936.
(18) Hashmi, A. S. K. Dual Gold Catalysis. Acc. Chem. Res. 2014, 47
(3), 864−876.
(19) Alyabyev, S. B.; Beletskaya, I. P. Gold as a Catalyst. Part I.
Nucleophilic Addition to the Triple Bond. Russ. Chem. Rev. 2017, 86
(8), 689−749.
AUTHOR INFORMATION
■
Corresponding Authors
Vadim Yu. Kukushkin − Saint Petersburg State University,
199034 Saint Petersburg, Russian Federation; South Ural
State University, Chelyabinsk 454080, Russian Federation;
orcid.org/0000-0002-2253-085X; Email: v.kukushkin@
spbu.ru
Alexey Yu. Dubovtsev − Saint Petersburg State University,
199034 Saint Petersburg, Russian Federation; orcid.org/
0000-0001-6576-814X; Email: a.dubovtsev@spbu.ru
Authors
Dmitry P. Zimin − Saint Petersburg State University, 199034
Saint Petersburg, Russian Federation; orcid.org/0000-
0002-3191-8899
Dmitry V. Dar’in − Saint Petersburg State University, 199034
Saint Petersburg, Russian Federation
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02584
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.Yu.D. thanks the Russian Science Foundation for support of
these studies (grant 20-73-10022). We are much obliged to the
Center for Magnetic Resonance, Center for Chemical Analysis
and Material Research, Center for X-ray Diffraction Studies (all
belonging to Saint Petersburg State University) for phys-
icochemical measurements. V.Y.K. thanks South Ural State
University (Act 211 Government of the Russian Federation,
contract 02.A03.21.0011) for putting facilities at the author’s
disposal.
(20) Arcadi, A. Alternative Synthetic Methods through New
Developments in Catalysis by Gold Alternative Synthetic Methods
through New Developments in Catalysis by Gold. Chem. Rev. 2008,
108, 3266−3325.
(21) Yang, W.; Hashmi, A. S. K. Mechanistic Insights into the Gold
Chemistry of Allenes. Chem. Soc. Rev. 2014, 43 (9), 2941−2955.
(22) Wegner, H. A.; Auzias, M. Gold for C−C Coupling Reactions:
A Swiss-Army-Knife Catalyst? Angew. Chem., Int. Ed. 2011, 50 (36),
8236−8247.
REFERENCES
(23) Furstner, A.; Davies, P. W. Catalytic Carbophilic Activation:
̈
■
Catalysis by Platinum and Gold π Acids. Angew. Chem., Int. Ed. 2007,
46 (19), 3410−3449.
(1) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Ynamides: A Modern Functional Group for the New
Millennium. Chem. Rev. 2010, 110 (9), 5064−5106.
(2) Evano, G.; Coste, A.; Jouvin, K. Ynamides: Versatile Tools in
Organic Synthesis. Angew. Chem., Int. Ed. 2010, 49 (16), 2840−2859.
(3) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.;
Kedrowski, B. L.; Hsung, R. P. Ynamides in Ring Forming
Transformations. Acc. Chem. Res. 2014, 47 (2), 560−578.
(24) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of
Alkynes for the Construction of Molecular Complexity. Chem. Rev.
2015, 115 (17), 9028−9072.
(25) Praveen, C. Carbophilic Activation of π-Systems via Gold
Coordination: Towards Regioselective Access of Intermolecular
Addition Products. Coord. Chem. Rev. 2019, 392, 1−34.
1754
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
̈
(26) Pflasterer, D.; Hashmi, A. S. K. Gold Catalysis in Total
Synthesis − Recent Achievements. Chem. Soc. Rev. 2016, 45 (5),
1331−1367.
(47) Hsu, Y.-C.; Hsieh, S.-A.; Liu, R.-S. Gold-Catalyzed Annulations
of N-Propargyl Ynamides with Anthranils with Two Distinct
Chemoselectivities. Chem. - Eur. J. 2019, 25 (20), 5288−5297.
(48) Davies, P. W.; Cremonesi, A.; Martin, N. Site-Specific
Introduction of Gold-Carbenoids by Intermolecular Oxidation of
Ynamides or Ynol Ethers. Chem. Commun. 2011, 47 (1), 379−381.
(49) Jin, H.; Tian, B.; Song, X.; Xie, J.; Rudolph, M.; Rominger, F.;
Hashmi, A. S. K. Gold-Catalyzed Synthesis of Quinolines from
Propargyl Silyl Ethers and Anthranils through the Umpolung of a
Gold Carbene Carbon. Angew. Chem., Int. Ed. 2016, 55 (41), 12688−
12692.
(50) Tian, X.; Song, L.; Farshadfar, K.; Rudolph, M.; Rominger, F.;
Oeser, T.; Ariafard, A.; Hashmi, A. S. K. Acyl Migration versus
Epoxidation in Gold Catalysis: Facile, Switchable, and Atom-
Economic Synthesis of Acylindoles and Quinoline Derivatives.
Angew. Chem., Int. Ed. 2020, 59 (1), 471−478.
(51) Azzali, E.; Girardini, M.; Annunziato, G.; Pavone, M.;
Vacondio, F.; Mori, G.; Pasca, M. R.; Costantino, G.; Pieroni, M. 2-
Aminooxazole as a Novel Privileged Scaffold in Antitubercular
Medicinal Chemistry. ACS Med. Chem. Lett. 2020, 11 (7), 1435−
1441.
(52) Chen, P.; Norris, D.; Haslow, K. D.; Murali Dhar, T. G.; Pitts,
W. J.; Watterson, S. H.; Cheney, D. L.; Bassolino, D. A.; Fleener, C.
A.; Rouleau, K. A.; Hollenbaugh, D. L.; Townsend, R. M.; Barrish, J.
C.; Iwanowicz, E. J. Identification of Novel and Potent Isoquinoline
Aminooxazole-Based IMPDH Inhibitors. Bioorg. Med. Chem. Lett.
2003, 13 (7), 1345−1348.
(53) Huang, H.; La, D. S.; Cheng, A. C.; Whittington, D. A.; Patel,
V. F.; Chen, K.; Dineen, T. A.; Epstein, O.; Graceffa, R.; Hickman, D.;
Kiang, Y.-H.; Louie, S.; Luo, Y.; Wahl, R. C.; Wen, P. H.; Wood, S.;
Fremeau, R. T. Structure- and Property-Based Design of Amino-
oxazoline Xanthenes as Selective, Orally Efficacious, and CNS
Penetrable BACE Inhibitors for the Treatment of Alzheimer’s
Disease. J. Med. Chem. 2012, 55 (21), 9156−9169.
(54) Chen, J. J.; Liu, Q.; Yuan, C.; Gore, V.; Lopez, P.; Ma, V.;
Amegadzie, A.; Qian, W.; Judd, T. C.; Minatti, A. E.; Brown, J.;
Cheng, Y.; Xue, M.; Zhong, W.; Dineen, T. A.; Epstein, O.; Human,
J.; Kreiman, C.; Marx, I.; Weiss, M. M.; Hitchcock, S. A.; Powers, T.
S.; Chen, K.; Wen, P. H.; Whittington, D. A.; Cheng, A. C.;
Bartberger, M. D.; Hickman, D.; Werner, J. A.; Vargas, H. M.; Everds,
N. E.; Vonderfecht, S. L.; Dunn, R. T.; Wood, S.; Fremeau, R. T.;
White, R. D.; Patel, V. F. Development of 2-Aminooxazoline 3-
Azaxanthenes as Orally Efficacious β-Secretase Inhibitors for the
Potential Treatment of Alzheimer’s Disease. Bioorg. Med. Chem. Lett.
2015, 25 (4), 767−774.
(27) Rudolph, M.; Hashmi, A. S. K. Heterocycles from Gold
Catalysis. Chem. Commun. 2011, 47 (23), 6536−6544.
(28) Akram, M. O.; Banerjee, S.; Saswade, S. S.; Bedi, V.; Patil, N. T.
Oxidant-Free Oxidative Gold Catalysis: The New Paradigm in Cross-
Coupling Reactions. Chem. Commun. 2018, 54 (79), 11069−11083.
(29) Wei, Y.; Shi, M. Divergent Synthesis of Carbo- and
Heterocycles via Gold-Catalyzed Reactions. ACS Catal. 2016, 6 (4),
2515−2524.
(30) Li, Y.; Li, W.; Zhang, J. Gold-Catalyzed Enantioselective
Annulations. Chem. - Eur. J. 2017, 23 (3), 467−512.
(31) Quach, R.; Furkert, D. P.; Brimble, M. A. Gold Catalysis:
Synthesis of Spiro, Bridged, and Fused Ketal Natural Products. Org.
Biomol. Chem. 2017, 15 (15), 3098−3104.
(32) Zhang, M.; Zhu, C.; Ye, L. W. Recent Advances in Dual Visible
Light Photoredox and Gold-Catalyzed Reactions. Synthesis 2017, 49
(6), 1150−1157.
(33) Bhunia, S.; Ghosh, P.; Patra, S. R. Gold-Catalyzed Oxidative
Alkyne Functionalization by N-O/S-O/C-O Bond Oxidants. Adv.
Synth. Catal. 2020, 362 (18), 3664−3708.
(34) Yeom, H. S.; Shin, S. Catalytic Access to α-Oxo Gold Carbenes
by N-O Bond Oxidants. Acc. Chem. Res. 2014, 47 (3), 966−977.
(35) Huple, D. B.; Ghorpade, S.; Liu, R. S. Recent Advances in
Gold-Catalyzed N- and O-Functionalizations of Alkynes with
Nitrones, Nitroso, Nitro and Nitroxy Species. Adv. Synth. Catal.
2016, 358 (9), 1348−1367.
(36) Zhang, L. A Non-Diazo Approach to α-Oxo Gold Carbenes via
Gold-Catalyzed Alkyne Oxidation. Acc. Chem. Res. 2014, 47 (3), 877−
888.
(37) Xiao, J.; Li, X. Gold α-Oxo Carbenoids in Catalysis: Catalytic
Oxygen-Atom Transfer to Alkynes. Angew. Chem., Int. Ed. 2011, 50
(32), 7226−7236.
(38) Karad, S. N.; Bhunia, S.; Liu, R.-S. Retention of Stereo-
chemistry in Gold-Catalyzed Formal [4 + 3] Cycloaddition of
Epoxides with Arenynamides. Angew. Chem., Int. Ed. 2012, 51 (35),
8722−8726.
(39) Aguilar, E.; Santamaría, J. Gold-Catalyzed Heterocyclic
Syntheses through α-Imino Gold Carbene Complexes as Intermedi-
ates. Org. Chem. Front. 2019, 6 (9), 1513−1540.
(40) Zhao, X.; Rudolph, M.; Asiri, A. M.; Hashmi, A. S. K. Easy
Access to Pharmaceutically Relevant Heterocycles by Catalytic
Reactions Involving α-Imino Gold Carbene Intermediates. Front.
Chem. Sci. Eng. 2020, 14 (3), 317−349.
(41) Tian, X.; Song, L.; Hashmi, A. S. K. α-Imino Gold Carbene
Intermediates from Readily Accessible Sulfilimines: Intermolecular
Access to Structural Diversity. Chem. - Eur. J. 2020, 26 (15), 3197−
3204.
(42) Li, L.; Tan, T.-D.; Zhang, Y.-Q.; Liu, X.; Ye, L.-W. Recent
Advances in Transition-Metal-Catalyzed Reactions of Alkynes with
Isoxazoles. Org. Biomol. Chem. 2017, 15 (40), 8483−8492.
(43) Li, L.; Shu, C.; Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W.
Generation of Gold Carbenes in Water: Efficient Intermolecular
Trapping of the α-Oxo Gold Carbenoids by Indoles and Anilines.
Chem. Sci. 2014, 5 (10), 4057−4064.
(44) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi,
A. S. K. Gold-Catalyzed C−H Annulation of Anthranils with Alkynes:
A Facile, Flexible, and Atom-Economical Synthesis of Unprotected 7-
Acylindoles. Angew. Chem., Int. Ed. 2016, 55 (2), 794−797.
(45) Shu, C.; Wang, Y.-H.; Zhou, B.; Li, X.-L.; Ping, Y.-F.; Lu, X.;
Ye, L.-W. Generation of α-Imino Gold Carbenes through Gold-
Catalyzed Intermolecular Reaction of Azides with Ynamides. J. Am.
Chem. Soc. 2015, 137 (30), 9567−9570.
(55) Guo, M.; Zheng, Y.; Starks, R.; Opoku-Temeng, C.; Ma, X.;
Sintim, H. O. 3-Aminooxazolidinone AHL Analogs as Hydrolytically-
Stable Quorum Sensing Agonists in Gram-Negative Bacteria.
MedChemComm 2015, 6 (6), 1086−1092.
́
(56) Galley, G.; Beurier, A.; Decoret, G.; Goergler, A.; Hutter, R.;
̈
̈
Mohr, S.; Pahler, A.; Schmid, P.; Turck, D.; Unger, R.; Zbinden, K.
G.; Hoener, M. C.; Norcross, R. D. Discovery and Characterization of
2-Aminooxazolines as Highly Potent, Selective, and Orally Active
TAAR1 Agonists. ACS Med. Chem. Lett. 2016, 7 (2), 192−197.
(57) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Intermolecular
and Selective Synthesis of 2,4,5-Trisubstituted Oxazoles by a Gold-
Catalyzed Formal [3 + 2] Cycloaddition. Angew. Chem., Int. Ed. 2011,
50 (38), 8931−8935.
(58) Gillie, A. D.; Jannapu Reddy, R.; Davies, P. W. Efficient and
Flexible Synthesis of Highly Functionalised 4-Aminooxazoles by a
Gold-Catalysed Intermolecular Formal [3 + 2] Dipolar Cycloaddition.
Adv. Synth. Catal. 2016, 358 (2), 226−239.
(59) Chen, M.; Sun, N.; Chen, H.; Liu, Y. Dioxazoles, a New Mild
Nitrene Transfer Reagent in Gold Catalysis: Highly Efficient
Synthesis of Functionalized Oxazoles. Chem. Commun. 2016, 52
(37), 6324−6327.
(60) Tian, X.; Song, L.; Han, C.; Zhang, C.; Wu, Y.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. Gold(III)-Catalyzed Formal [3 + 2]
(46) Song, L.; Tian, X.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K.
Gold(III)-Catalyzed Chemoselective Annulations of Anthranils with
N-Allylynamides for the Synthesis of 3-Azabicyclo[3.1.0]Hexan-2-
Imines. Chem. Commun. 2019, 55 (61), 9007−9010.
1755
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Annulations of N-Acyl Sulfilimines with Ynamides for the Synthesis of
(77) Dubovtsev, A. Y.; Dar’in, D. V.; Kukushkin, V. Y. Three-
Component [2 + 2+1] Gold(I)-Catalyzed Oxidative Generation of
Fully Substituted 1,3-Oxazoles Involving Internal Alkynes. Adv. Synth.
Catal. 2019, 361 (12). 2926.
4-Aminooxazoles. Org. Lett. 2019, 21 (8), 2937−2940.
́
(61) Walczynski, K.; Zuiderveld, O. P.; Timmerman, H. Non-
Imidazole Histamine H3 Ligands. Part III. New 4-n-Propylpiperazines
as Non-Imidazole Histamine H3-Antagonists. Eur. J. Med. Chem.
2005, 40 (1), 15−23.
(78) Zheng, Z.; Wang, Y.; Ma, X.; Li, Y.; Zhang, L. Non-Diazo C−H
Insertion Approach to Cyclobutanones through Oxidative Gold
Catalysis. Angew. Chem., Int. Ed. 2020, 59 (40), 17398−17402.
(79) Kim, H.; Jang, J.; Shin, S. Gold-Catalyzed Asymmetric
Thioallylation of Propiolates via Charge-Induced Thio-Claisen
Rearrangement. J. Am. Chem. Soc. 2020, 142 (49), 20788.
(80) Kim, H.; Choi, S. Y.; Shin, S. Asymmetric Synthesis of
Dihydropyranones via Gold(I)-Catalyzed Intermolecular [4 + 2]
Annulation of Propiolates and Alkenes. Angew. Chem., Int. Ed. 2018,
57 (40), 13130−13134.
(81) Shin, S. The Effect of Acceptor-Substituted Alkynes in Gold-
Catalyzed Intermolecular Reactions. Pure Appl. Chem. 2014, 86 (3),
373−379. .
(82) Park, S. R.; Kim, C.; Kim, D.; Thrimurtulu, N.; Yeom, H.-S.;
Jun, J.; Shin, S.; Rhee, Y. H. Entry to β-Alkoxyacrylates via Gold-
Catalyzed Intermolecular Coupling of Alkynoates and Allylic Ethers.
Org. Lett. 2013, 15 (6), 1166−1169.
(83) Yeom, H.-S.; Shin, S. Au(I)-Catalyzed Intramolecular Oxidative
Cyclopropanation of 1,6-Enynes Derived from Propiolamides with
Diphenyl Sulfoxide. Org. Biomol. Chem. 2013, 11 (7), 1089−1092.
(84) Yeom, H.-S.; Koo, J.; Park, H.-S.; Wang, Y.; Liang, Y.; Yu, Z.-X.;
Shin, S. Gold-Catalyzed Intermolecular Reactions of Propiolic Acids
with Alkenes: [4 + 2] Annulation and Enyne Cross Metathesis. J. Am.
Chem. Soc. 2012, 134 (1), 208−211.
(85) Ricard, L.; Gagosz, F. Synthesis and Reactivity of Air-Stable N-
Heterocyclic Carbene Gold(I) Bis(Trifluoromethanesulfonyl)Imidate
Complexes. Organometallics 2007, 26 (19), 4704−4707.
(86) Schiessl, J.; Stein, P. M.; Stirn, J.; Emler, K.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. Strategic Approach on N-Oxides in
Gold Catalysis − A Case Study. Adv. Synth. Catal. 2019, 361, 725−
738.
(87) Dubovtsev, A. Y.; Dar’in, D. V.; Krasavin, M.; Kukushkin, V. Y.
Gold-Catalyzed Oxidation of Internal Alkynes into Benzils and Its
Application for One-Pot Synthesis of Five-, Six-, and Seven-
Membered Azaheterocycles. Eur. J. Org. Chem. 2019, 2019, 1856−
1864.
(88) Dubovtsev, A. Y.; Dar’in, D. V.; Kukushkin, V. Y. Gold(I)-
Catalyzed Oxidation of Acyl Acetylenes to Vicinal Tricarbonyls. Org.
Lett. 2019, 21 (11), 4116−4119.
(89) Karad, S. N.; Liu, R.-S. Gold-Catalyzed 1,2-Oxoarylations of
Nitriles with Pyridine-Derived Oxides. Angew. Chem., Int. Ed. 2014, 53
(21), 5444−5448.
(90) Dubovtsev, A. Y.; Shcherbakov, N. V.; Dar’in, D. V.;
Kukushkin, V. Y. Nature of the Nucleophilic Oxygenation Reagent
Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and
Internal Alkynes to 1,2-Dicarbonyls. J. Org. Chem. 2020, 85 (2), 745−
757.
(62) Holschbach, M. H.; Bier, D.; Stusgen, S.; Wutz, W.; Sihver, W.;
̈
Coenen, H. H.; Olsson, R. A. Synthesis and Evaluation of 7-Amino-2-
(2(3)-Furyl)-5-Phenylethylamino-Oxazolo[5,4-d]Pyrimidines as Po-
tential A2A Adenosine Receptor Antagonists for Positron Emission
Tomography (PET). Eur. J. Med. Chem. 2006, 41 (1), 7−15.
(63) Brown, P.; Davies, D. T.; O’Hanlo, P. J.; Wilson, J. M. The
Chemistry of Pseudomonic Acid. 15. Synthesis and Antibacterial
Activity of a Series of 5-Alkyl, 5-Alkenyl, and 5-Heterosubstituted
Oxazoles. J. Med. Chem. 1996, 39 (2), 446−457.
(64) Heal, W.; Thompson, M. J.; Mutter, R.; Cope, H.; Louth, J. C.;
Chen, B. Library Synthesis and Screening: 2,4-Diphenylthiazoles and
2,4-Diphenyloxazoles as Potential Novel Prion Disease Therapeutics.
J. Med. Chem. 2007, 50 (6), 1347−1353.
(65) O’Donnell, C. J.; Rogers, B. N.; Bronk, B. S.; Bryce, D. K.; Coe,
́
J. W.; Cook, K. K.; Duplantier, A. J.; Evrard, E.; Hajos, M.; Hoffmann,
W. E.; Hurst, R. S.; Maklad, N.; Mather, R. J.; McLean, S.; Nedza, F.
M.; O’Neill, B. T.; Peng, L.; Qian, W.; Rottas, M. M.; Sands, S. B.;
Schmidt, A. W.; Shrikhande, A. V.; Spracklin, D. K.; Wong, D. F.;
Zhang, A.; Zhang, L. Discovery of 4-(5-Methyloxazolo[4,5-b]pyridin-
2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a Novel A7
Nicotinic Acetylcholine Receptor Agonist for the Treatment of
Cognitive Disorders in Schizophrenia: Synthesis, SAR Development,
and in Vivo Efficacy. J. Med. Chem. 2010, 53 (3), 1222−1237.
(66) Wang, X.; Lei, B.; Ma, L.; Jiao, H.; Xing, W.; Chen, J.; Li, Z.
Iron-Catalyzed C(5)−H Imidation of Azole with N-Fluorobenzene-
sulfonimide. Adv. Synth. Catal. 2017, 359 (24), 4284−4288.
(67) Shibata, K.; Yoshida, M.; Doi, T.; Takahashi, T. Derivatization
of a Tris-Oxazole Using Pd-Catalyzed Coupling Reactions of a 5-
Bromooxazole Moiety. Tetrahedron Lett. 2010, 51 (13), 1674−1677.
(68) Wang, Q.; Xia, Q.; Ganem, B. A General Synthesis of 2-
Substituted-5-Aminooxazoles: Building Blocks for Multifunctional
Heterocycles. Tetrahedron Lett. 2003, 44 (36), 6825−6827.
(69) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J.
Brønsted Acid Catalyzed Enantioselective Three-Component Reac-
tion Involving the α Addition of Isocyanides to Imines. Angew. Chem.,
Int. Ed. 2009, 48 (36), 6717−6721.
(70) Luo, W.; Yuan, X.; Lin, L.; Zhou, P.; Liu, X.; Feng, X. A
N{,}N′-Dioxide/Mg(OTf)2 Complex Catalyzed Enantioselective α-
Addition of Isocyanides to Alkylidene Malonates. Chem. Sci. 2016, 7
(7), 4736−4740.
(71) Reddy, R. J.; Ball-Jones, M. P.; Davies, P. W. Alkynyl
Thioethers in Gold-Catalyzed Annulations To Form Oxazoles. Angew.
Chem., Int. Ed. 2017, 56 (43), 13310−13313.
(72) Han, X.-L.; Zhou, C.-J.; Liu, X.-G.; Zhang, S.-S.; Wang, H.; Li,
Q. Regioselective Synthesis of 5-Aminooxazoles via Cp*Co(III)-
Catalyzed Formal [3 + 2] Cycloaddition of N-(Pivaloyloxy)Amides
with Ynamides. Org. Lett. 2017, 19 (22), 6108−6111.
(91) Yang, L.-Q.; Wang, K.-B.; Li, C.-Y. Synthesis of Oxindoles
through the Gold-Catalyzed Oxidation of N-Arylynamides. Eur. J. Org.
Chem. 2013, 2013 (14), 2775−2779.
́
(73) Di Mauro, G.; Maryasin, B.; Kaiser, D.; Shaaban, S.; Gonzalez,
́
(92) Sanchez-Cantalejo, F.; Priest, J. D.; Davies, P. W. A Gold
L.; Maulide, N. Mechanistic Pathways in Amide Activation: Flexible
Synthesis of Oxazoles and Imidazoles. Org. Lett. 2017, 19 (14),
3815−3818.
Carbene Manifold to Prepare Fused γ-Lactams by Oxidative
Cyclisation of Ynamides. Chem. - Eur. J. 2018, 24 (65), 17215−17219.
(93) Wang, K.-B.; Ran, R.-Q.; Xiu, S.-D.; Li, C.-Y. Synthesis of 3-
Aza-Bicyclo[3.1.0]Hexan-2-One Derivatives via Gold-Catalyzed Ox-
idative Cyclopropanation of N-Allylynamides. Org. Lett. 2013, 15
(10), 2374−2377.
(74) Abdel Monaim, S. A. H.; Mhlongo, J. T.; Kumar, A.; El-Faham,
A.; Albericio, F.; de la Torre, B. G. Formation of Nα-Terminal 2-
Dialkyl Amino Oxazoles from Guanidinated Derivatives under Mild
Conditions. Org. Biomol. Chem. 2018, 16 (31), 5661−5666.
(75) Liu, J.; Dong, Y.; Li, G.; Min, X.; Hussain, M. Unexpected
Intramolecular Nucleophilic Cyclization of Ureidoacetamide: A Novel
Route towards the Synthesis of 2,4,5-Trisubsituted Oxazoles.
Tetrahedron Lett. 2019, 60 (26), 1691−1695.
(94) CCDC 2035080 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.
(95) Shi, S.; Wang, T.; Yang, W.; Rudolph, M.; Hashmi, A. S. K.
Gold-Catalyzed Synthesis of Glyoxals by Oxidation of Terminal
Alkynes: One-Pot Synthesis of Quinoxalines. Chem. - Eur. J. 2013, 19
(21), 6576−6580.
(76) He, W.; Li, C.; Zhang, L. An Efficient [2 + 2 + 1] Synthesis of
2,5-Disubstituted Oxazoles via Gold-Catalyzed Intermolecular Alkyne
Oxidation. J. Am. Chem. Soc. 2011, 133, 8482−8485.
1756
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
̈
(96) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottlander, M.;
Skrydstrup, T. Highly Regioselective Au(I)-Catalyzed Hydroamina-
tion of Ynamides and Propiolic Acid Derivatives with Anilines. Org.
Lett. 2009, 11 (18), 4208−4211.
(97) Rassadin, V. A.; Boyarskiy, V. P.; Kukushkin, V. Y. Facile Gold-
Catalyzed Heterocyclization of Terminal Alkynes and Cyanamides
Leading to Substituted 2-Amino-1,3-Oxazoles. Org. Lett. 2015, 17
(14), 3502−3505.
(98) Shapiro, N. D.; Toste, F. D. Synthesis of Azepines by a Gold-
Catalyzed Intermolecular [4 + 3]-Annulation. J. Am. Chem. Soc. 2008,
130 (29), 9244−9245.
(99) Mansfield, S. J.; Campbell, C. D.; Jones, M. W.; Anderson, E. A.
A Robust and Modular Synthesis of Ynamides. Chem. Commun. 2015,
51 (16), 3316−3319.
1757
https://dx.doi.org/10.1021/acs.joc.0c02584
J. Org. Chem. 2021, 86, 1748−1757