Facile Gold-Catalyzed Heterocyclization of Terminal Alkynes and Cyanamides Leading to Substituted 2-Amino-1,3-Oxazoles

Article abstract of DOI:10.1021/acs.orglett.5b01592

Facile gold-catalyzed heterocyclization based upon intermolecular trapping of the generated α-oxo gold carbenes with various cyanamides R²R³NCN (R²/R³ = Alk/Alk, -(CH₂)₂O(CH₂)₂-, Ar/Ar, Ar/H) has been developed. In most cases, 2-amino-1,3-oxazoles functionalized at the nitrogen atom as well as at the fifth position of the heterocyclic ring (12 examples) were isolated in good to moderate yields.

Full text of DOI:10.1021/acs.orglett.5b01592

Letter
pubs.acs.org/OrgLett
Facile Gold-Catalyzed Heterocyclization of Terminal Alkynes and
Cyanamides Leading to Substituted 2‑Amino-1,3-Oxazoles
Valentin A. Rassadin,* Vadim P. Boyarskiy, and Vadim Yu. Kukushkin*
Institute of Chemistry, Saint Petersburg State University, Universitetskii Pr. 26, Stary Petergof, 198504 Saint Petersburg, Russia
S
* Supporting Information
ABSTRACT: Facile gold-catalyzed heterocyclization based upon intermolecular trapping of the generated α-oxo gold carbenes
with various cyanamides R2R3NCN (R2/R3 = Alk/Alk, −(CH2)2O(CH2)2−, Ar/Ar, Ar/H) has been developed. In most cases, 2-
amino-1,3-oxazoles functionalized at the nitrogen atom as well as at the fifth position of the heterocyclic ring (12 examples) were
isolated in good to moderate yields.
omogeneous gold catalysis is among innovative projects
with a nucleophile according to the SN2′ type reaction, is also
Hof modern organic chemistry. From its many versatile plausible (Scheme 1, route B).7h A full account study regarding
1
the role of the α-oxo gold carbenes in the oxidation reactions of
alkynes with pyridine oxide employing tandem mass spectrom-
etry, ion spectroscopy, and quantum-chemical calculations has
been recently published.8 It is pointed out that, first, I
undergoes rearrangement toward more stable intermediate
III, which serves as a synthetic equivalent of α-oxo gold
carbenes (Scheme 1, route C). Second, it is indicated that the
existence of naked α-oxo carbenes of type II are quite unlikely.
Therefore, the reaction might proceed via different routes
including several intermediates, and all these routes lead to the
same product.
aspects, the one including an oxidation of Au-activated alkyne is
particularly important as it provides a facile route to highly
reactive electrophilic gold species. The latter can be intra- or
intermolecular trapped by various nucleophiles, leading to
diverse types of important organic compounds (Scheme 1).2
Scheme 1. Generation and Trapping of the Highly Reactive
Electrophilic Gold Species
Herein, we report on the trapping of the electrophilic gold
species with cyanamides R2R3NCN, accomplishing the syn-
thesis of a series of substituted 2-amino-1,3-oxazoles. Hetero-
cycles bearing a 2-amino-1,3-oxazole moiety demonstrate a
wide spectrum of biological activity such as antiviral (HIV-1),9
enzyme (VEGFR2,10 inosine monophosphate dehydrogen-
ase11), and valosin-containing protein12 inhibition. They behave
as TRPV1 receptor antagonist13 and also as antihelminthic,
diuretic, and fungicidal active compounds.14 Synthetic
approaches toward substituted 2-amino-1,3-oxazoles are rather
limited.15,16
We checked the possibility of formation of the substituted 2-
amino-1,3-oxazole with readily available phenyl acetylene (1a)
and dimethylcyanamide (2a) (Table 1). Initial conditions were
chosen based on the previous works on gold-catalyzed organic
transformations,7 and the reaction was carried out in neat
Among many oxidants such as sulfoxides,3 epoxides,4
nitrones,5 or nitro compounds,6 pyridine N-oxides7 are the
most commonly applied to synthetic procedures as these N-
oxides are efficient in intermolecular oxygen transfer. It is
believed that the key intermediates are the highly reactive α-oxo
gold carbenes of type II, which are formed from initially
generated β-gold(I) (vinyloxy)pyridinium species I (Scheme 1,
route A). However, an alternative pathway, i.e., reaction of I
Received: June 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01592
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
transformations,7c−e gave excellent results, viz. 3.0 equiv of the
cyanamide and chlorobenzene as a bulk solvent gave the same
yield of the target product as for the neat cyanamide (Table 1,
entry 12). An unexpected result was obtained when the
reaction was carried out in DMF. In this case, 2-oxo-2-
phenylethyl formate was isolated (48%) as a major product
from the reaction mixture and its appearance is accounted for
by the reaction of electrophilic gold species with DMF (Table
1, entry 14). Finally, we tested different amounts of the oxidant
and found that when 1.0 equiv of 2-picoline oxide was used, the
yield of the target product was 17% (Table 1, entry 15). If a
large excess of 2-picoline oxide (4.0 equiv) was employed, a
significant amount of 1,1-dimethyl-3-(6-methylpyridin-2-yl)-
urea (7) was isolated from the reaction mixture (Table 1, entry
16). To summarize optimization of the reaction conditions, we
found that performance of the reaction in chlorobenzene with
3.0 equiv of cyanamide 2a, 2.0 equiv of 2-picoline oxide (5),
and 3 mol % of Ph3PAuNTf2 at 60 °C for 2 h leads to the best
synthetic results. To verify the scope and limitations of the
developed approach, several alkynes and cyanamides were
tested (Scheme 2).
First, we tested several cyanamides and observed no or
insignificant substitution effect on the reaction time and yield of
target 2-amino-1,3-oxazole 6. All employed cyanamides, viz.
dialkylcyanamides, diarylcyanamides, arylcyanamides, and even
4-morpholinecarbonitrile, gave corresponding products in good
to moderate yields (78−56%) (Scheme 2).
Second, we demonstrated that terminal aliphatic alkynes as
well as phenylacetylene derivatives also yielded 6 in good to
moderate yields. We did not observe any significant difference
between phenyl acetylenes and its derivatives substituted with
strong electron donating (4-MeOC6H4) or electron with-
drawing (2-FC6H4) groups. All our experiments indicate that
the α-oxo gold carbenoid species can be easily generated, and
they are extremely reactive independently on the substitution in
the reactants.
Table 1. Optimization of the Reaction Conditions
molar ratio of the reagents
a
2a
3
4
5
conditions (yield)
1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
3.0
3.0
2.0
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.10
0.03
0.01
0.03
0.03
0.03
0.05
0.05
1.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
4.0
60 °C, 3 h (59%)
60 °C, 3 h (7%)
60 °C, 1 h (48%)
60 °C, 2 h (75%)
60 °C, 4 h (61%)
60 °C, 6 h (46%)
23 °C, 3 h (10%)
80 °C, 3 h (64%)
60 °C, 2 h (74%)
2
3
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.5
4
5
6
7
8
9
10
11
12
13
14
15
16
60 °C, 2 h (71%)
60 °C, 2 h (26%)
60 °C, PhCl, 2 h (68%)
60 °C, C6H6, 2 h (35%)
60 °C, DMF, 2 h (48%)
60 °C, PhCl, 2 h (17%)
b
c
10
60 °C, PhCl, 2 h (38%)
a
b
Isolated yields. 2-Oxo-2-phenylethyl formate was isolated as the
c
main product. 1,1-Dimethyl-3-(6-methylpyridin-2-yl)urea (7) was
isolated in significant amount.
dimethylcyanamide (5.0 equiv) as a solvent by employing 2-
picoline oxide as an oxidant. From many suitable gold catalysts,
we choose Ph3PAuNTf2, which is air-stable and can be easily
prepared by metathesis reaction from the commercially
available Ph3PAuCl and AgNTf2.17 In the attempted reaction,
target N,N-dimethyl-5-phenyloxazol-2-amine (6aa) was isolated
in 59% yield (Table 1, entry 1).
When we replaced the terminal alkynes by diphenylacetylene
and checked the reactivity of the latter with dimethylcyanamide,
we were unable to isolate target N,N-dimethyl-4,5-diphenylox-
azol-2-amine. The conversion of diphenylacetylene was 48%
(respective amount of the starting material was recovered from
the reaction mixture after column chromatography), and 1,2-
diphenylethane-1,2-dione was isolated in 42% yield. However,
we detected target N,N-dimethyl-4,5-diphenyloxazol-2-amine in
trace amounts by TLC-HRMS (ESI) technique. The oxidation
of diaryl alkynes and ynamides with sulfoxide in the presence of
gold(I) salts leading to substituted 1,2-diaryl-1,2-diones was
earlier reported.3e Later, Hashmi and co-workers extended this
approach to a terminal alkyne, however, the reaction was less
selective.7i Hence, the formation of 1,2-diphenylethane-1,2-
dione is not unusual.
To demonstrate the possibility of the scale up synthesis of
the target oxazoles, we carried out the reaction starting from 5
mmol of 1a. In this case, the isolated yield of 6aa was 76%.
One should mention that a good number of various
cyanamides, whose intriguing chemistry is at the early stage
of development although they become increasingly popular in
recent years,18 are commercially available. Moreover, disub-
stituted cyanamides can be easily prepared from amines
R2R3NH and potassium or sodium cyanate followed by
dehydration in the presence of p-TsCl in pyridine.19
Monosubstituted cyanamides are generated from amidoximes
To optimize the reaction conditions, we tested different
reagent ratios, amount of the catalyst, solvents, temperature,
and reaction time. It is noteworthy that, under the same
conditions but in the absence of MeSO3H, oxazole 6aa was
isolated in 7% yield, probably due to deactivation of the catalyst
by 2-picoline formed upon the reduction (Table 1, entry 2). On
the next step, we modified the reaction time. The best-isolated
yield of 6aa was achieved after 2 h (Table 1, entry 4).
Moreover, we noticed that keeping the reaction mixture for
more than 2 h at 60 °C (Table 1, entries 5 and 6) did not
increase the yield of the target compound and, in addition,
resulted in partial decomposition of the product, and all these
led to the decreased yield of 6aa. The effect of temperature was
then studied. Reaction was quite slow at rt, and after 3 h
oxazole 6aa was isolated in 10% yield (Table 1, entry 7),
although at 80 °C the yield was 64% (Table 1, entry 8).
Employing 3 mol % of the catalyst was efficient, whereas when
1 mol % of Ph3PAuNTf2 was used, the yield of 6aa decreased
dramatically (Table 1, entries 9, 10, and 11, respectively).
Therefore, we continued our work employing 3 mol % of the
catalyst.
At the initial stage of the project, usage of rather expensive
cyanamide 2a as a solvent was a certain drawback of our
approach. To solve this problem, we tested several solvents and
tried to reduce amount of the cyanamide. Gratifyingly,
chlorobenzene, which was previously employed in a relevant
B
DOI: 10.1021/acs.orglett.5b01592
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Reaction Scope with Various Alkynes and
Cyanamides
Scheme 3. Synthesis of the 1,1-Dimethyl-3-(6-methylpyridin-
2-yl)urea (7)
To conclude, we developed a facile gold-catalyzed hetero-
cyclization based on intermolecular trapping of the in situ
generated α-oxo gold carbenes with various cyanamides
R2R3NCN (R2/R3 = Alk/Alk, −(CH2)2O(CH2)2−, Ar/Ar,
Ar/H) leading to 2-amino-1,3-oxazoles functionalized at the
nitrogen atom as well as at the fifth position of the heterocyclic
ring. Insofar as the starting materials are easily available, this
method can be used for the construction of the chemical
libraries containing a wide range of heterocycles bearing an
important 2-amino-1,3-oxazole moiety. Further development of
the observed gold-catalyzed reaction is underway in our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data of all compounds,
1
copy of the H, 13C{H}, 31P{H} NMR, and HRMS (ESI)
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01592.
AUTHOR INFORMATION
Corresponding Authors
■
*For V.A.R.: E-mail, v.rassadin@spbu.ru.
*For V.Yu.K.: phone, 78124286890; fax, 78124286939; E-mail:
kukushkin@vk2100.spb.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Saint Petersburg State University for financial
support (grants 12.38.225.2014 and 12.50.1190.2014). V.A.R.
gratefully acknowledges the support of the Scientific Council of
the President of the Russian Federation (grant MK-
3228.2015.3). We are much obliged to the Center for Magnetic
Resonance, Center for Chemical Analysis and Material
Research, and Educational Center of Chemistry (all belong to
Saint Petersburg State University) for physicochemical
measurements.
via Tiemann rearrangement in the presence of dehydrating
agents like p-TsCl in pyridine.20
Finally, one should comment on the generation of byproduct
7. Oxoarylation of nitriles with a pyridine oxide under gold-
catalyzed conditions leading to substituted 2-aminopyridines
has been recently reported.7j However, in our case, the skeleton
of the starting alkyne was not incorporated in final product 7.
To understand the role of the gold catalyst and alkyne in this
transformation, we modified the reaction conditions and found
that the reaction proceeds efficiently only with Me2NCN taken
alone under acid catalysis in the absence of the gold complex,
alkyne, or their mixtures. Thus, treatment of a mixture of 2-
picoline oxide (5) and dimethylcyanamide (2a) with
methanesulfonic acid at 60 °C gave 7 in 86% yield (Scheme 3).
In our opinion, the observed transformation can be quite
useful and we are going to provide a full account research on
this reaction in our further works.
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