Synthesis of 2,5-disubstituted oxazoles: Via cobalt(III)-catalyzed cross-coupling of N -pivaloyloxyamides and alkynes

Article abstract of DOI:10.1039/c7cc08611c

An efficient synthesis of 2,5-disubstituted oxazoles via Co(iii) catalysis is described herein. The synthesis is achieved under mild conditions through [3+2] cycloaddition of N-pivaloyloxyamides and alkynes. The reaction operates through an internal oxidation pathway and features a very broad substrate scope. The one-step synthesis of natural products such as texamine and balsoxin has been demonstrated via this protocol.

Full text of DOI:10.1039/c7cc08611c

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Synthesis of 2,5-Disubstituted Oxazoles via Cobalt(III)-Catalyzed
Cross-Coupling of N-Pivaloyloxyamides and Alkynes
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaolong Yu, Kehao Chen, Qi Wang, Wenjing Zhang, and Jin Zhu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
available.5,7,9 Therefore, the development of more efficient
methods for the synthesis of oxazoles are highly desirable.
An efficient synthesis of 2,5-disubstituted oxazoles via Co(III)
catalysis is described herein. The synthesis is achieved under mild
condition through [3+2] cycloaddition of N-pivaloyloxylamides and
alkynes. The reaction operates through an internal oxidation
pathway and features a very broad substrate scope. One-step
synthesis of natural products texamine and balsoxin has been
demonstrated via this protocol.
Previous work
(a)
for the formation of 2,5-disubstituted oxazoles
O
N
O
I2, TBHP
[Au], [O]
+
(1)
(2)
Ar
R
NH2 HCl
Ar
Ph
R2
O
Ph
N
+
R
CN
R2
O
N
[Cu], O2
[Cu]
O
The oxazole ring is an important structural motif in compounds
with activities relevant to biology and medicinal chemistry.1
Especially, 2,5-disubstituted oxazoles are prevalent chemical
and pharmaceutical synthetic intermediates.2 Organic
chemists have developed many methods to synthesize
oxazoles over the past decades.3 A noteworthy example was
the construction of 2,5-diaryl substituted oxazoles via TBHP/I2-
mediated tandem oxidative cyclization (Scheme 1a, eq 1).4 In
2011, Zhang and coworkers developed a [2+2+1] annulation of
a terminal alkyne, a nitrile, and an oxygen atom (from
pyridine/quinoline N-oxides) through gold catalysis (Scheme
1a, eq 2).5 In 2012, the Jiao group described a copper-
catalyzed oxidative dehydrogenative annulation method
starting from aldehydes, amines, and molecular oxygen
(Scheme 1a, eq 3).6 The Pérez group demonstrated another
copper-catalyzed synthetic method for oxazoles through the
reaction of alkynes and aryl carbonyl azides (Scheme 1a, eq
4).7 Despite the tremendous progress witnessed in this field,
synthetic challenges remain because of the requirement of
stoichiometric amount of an external oxidant3b,c,e,g,h,4-6 or toxic
metal salts,8 limited substrate scope,4,6,7 and pre-installation of
multiple functionalities in a single substrate for intramolecular
cyclyzation reactions (potentially generating functionality
compatibility issue).2f,g In addition, azides and α-functionalized
ketones (e.g., α-diazoketones) used for the synthesis are
potentially explosive and generally not commercially
+
+
(3)
(4)
R
NH2
R
Ar
O
N
Ar
O
R2
Ar
R2
Ar
N3
O
This work
(b)
O
N
O
[Co]
R2
R
+
OPiv
R
N
R2
H
Notable synthetic features:
1) Earth-abundant transition metal as catalyst
2) Internal oxidation reaction pathway
3) Broad substrate scope, applicable to aryl- and alkyl-
substituted N-pivaloyloxyamides, aryl and alkyl alkynes
4) Low catalyst loading
5) N-pivaloyloxyamides as safe, easy-to-prepare, and stable reagents
Scheme 1. Previous work and this work for the formation of
2,5-disubstituted oxazoles
We have developed several Co(III)-catalyzed C-H activation
strategies for the construction of heterocycles in the past
years.10 In an attempt to expand the synthetic scope enabled
by this earth-abundant metal, we have uncovered a reactivity
pattern not previously identified. Herein, we discolse an
efficient [3+2] synthesis of 2,5-disubstituted oxazoles via
cobalt(III)-catalyzed cross-coupling of N-pivaloyloxyamides and
alkynes. Notable features associated with the protocol are
three-folds: 1) N-Pivaloyloxyamides are safe, easy to prepare,
and stable on storage;11 2) The reaction proceeds through an
internal oxidation pathway; and 3) The substrate scope is
broad, applicable to aryl- and alkyl-substituted N-
pivaloyloxyamides, aryl and alkyl alkynes.
We commenced our studies by investigating the reaction
between N-(pivaloyloxy)benzamide (1a) and ethynylbenzene
(
2a) (Table 1). Preliminary examination (entries 1−4) identified
[Cp*Co(MeCN)3(SbF6)2] as the effective catalyst, DCE as the
solvent of choice, 80 oC and 20 h as the ideal reaction
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temperature and reaction time, affording target product 2,5-
diphenyloxazole (3a) in 75% yield with 10 mol % Co(III) catalyst
compatible. Alkynes bearing thiophenyl and alkyl groups could
also react efficiently to afford the respective target products
(
2m-2t). Noteworthy was the ability to incorporate hydroxyl
Table 1. Optimization of reaction conditionsa,b
group (2t) into the product, providing a potential reaction site
for further manipulation. Internal alkynes were tested under
the conditions reported herein, and minimal reactivity was
observed at the current stage. The reaction conditions for
internal alkynes might be different from those for terminal
alkynes and need further fine tuning for the best outcome.
and 2 equiv 2a. No extra additive proved to be necessary for
effecting the transformation (entries 4, 6), and basic condition
was detrimental (entry 5). Further optimization indicated that
decrease of the amount of Co(III) catalyst to 5 mol % or even 3
mol % and the amount of 2a to 1.5 equiv did not affect the
yield (entries 6, 8, 9, 14). The reaction could proceed efficiently
in both air and nitrogen, rendering it unnecessary to exclude
air during the reaction (entries 6, 7). The switching of reaction
medium from DCE to other solvents (entries 8, 10−12) and
Scheme 2. Substrate scope for N-pivaloyloxyamidesa,b
o
decrease of the reaction temperature to 60 C diminished the
yield (entry 13). Taken together, 3 mol % or 5 mol %
o
[Cp*Co(MeCN)3(SbF6)2], 1.5 equiv alkyne, DCE, 80 C, and 20 h
were selected as the optimized reaction condition.
Using the acquired optimized reaction condition and with
2a as the coupling reagent, the scope of N-pivaloyloxyamides
was inspected (Scheme 2). Notably,
a variety of N-
pivaloyloxyamides, which bear both electron-donating (1b
,
Me) and electron-withdrawing (1c, F; 1d, Cl; 1e, CF3) groups at
the para position of aryl group, were compatible with the
trasformation. The reaction also proceeded effectively for
ortho- and meta-substituted substrates (1f, Me; 1g, F; 1h, Me;
1i
, F; 1j, Cl). In addition, N-(pivaloyloxy)thiophene-2-
carboxamide (1k) was a viable substrate. Further exploration
suggested the ability to extend substrate scope to alkyl-
substituted
N-pivaloyloxyamides
(
1l
-
1n).
N-
(methoxy)benzamide as a substrate was tested under the
optimized reaction condition, and no product was obtained
(Only the surplus of the starting material).
Scheme 3. Substrate scope for alkynesa,b
The optimized reaction condition was then challenged with
a diversity of alkynes to probe its scope, by taking 1a as the
reaction partner (Scheme 3). Satisfactorily, a diverse range of
The effectiveness of the reaction and broadness of the
substrate scope prompted the investigation of reaction
mechanism (Scheme 4). Two different reaction pathways could
be envisaged: one proceeds through the formation of a Co(III)–
acetylide species; the other proceeds through the formation of
a Co(III)-alkyne π-complex. In order to pinpoint the actual
pathway, several reactions were performed. A reaction
between 1a and 2c-d (94% D) under optimized reaction
functional groups on ethynylbenzene (2b
-2t), including both
electron-donating (2b, Me; 2c, OMe) and electron-
withdrawing (2d, F; 2e, Cl; 2f, Br) groups at the para position of
aryl group were tolerated. The ortho- and meta-substituted
substrates (2g, Me; 2h, F; 2i, Me; 2j, F; 2k, Cl; 2l, Br) were also
2 | J. Name., 2012, 00, 1-3
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With these experiments and literature precedents7b,10c,12 in
hand, a reaction pathway is proposed in Scheme 5. At first,
condition generates 4c-d (63% D) (Scheme 4, eq 1). Since the
catalysis results in the production of PivOH, the D/H
scrambling could come from the exchange between 2c-d and
PivOH. This was indeed the case and a reaction between 2c-d
and PivOH leads to a decrease of D percentage to 57%
(Scheme 4, eq 2). One formed, the product does undergo H/D
scrambling reaction (Scheme 4, eq 3). Further, no H/D
scrambling occurred between 2b and 2c-d (Scheme 4, eq 4)
under Co(III) catalysis, consistent with the absence of Co(III)–
chelation of 1a with Co(III) catalyst affords complex
I; and
then, 2a binds to the cobalt center and forms a π-complex II
;
this is followed by a concerted process, featuring cleavage of
weak N-O bond and formation of O-C bond, Co(V)-N bond,
Co(V)-C bond and yielding complex III; Subsequent reductive
elimination and C-N bond formation leads to the formation of
cyclized product 3a and regeneration of Co(III) catalyst.
acetylide species. A reaction comprising 1a, 2b, and 2c-d under
optimized reaction condition afforded strictly non-D-labeled
4b and D-labeled 4c-d (Scheme 4, eq 5), also supporting the
absence of a Co(III)–acetylide species. Taken together, the
To demonstrate the synthetic utility of the reaction
protocol developed herein, direct synthesis of natural products
was pursued (Scheme 6). It is noteworthy that natural
reaction proceeded through
formation pathway.
a
Co(III)-alkyne π-complex
13
14
products texamine (4u
)
and balsoxin (4v
)
could be
accessed through a straightforward one-step procedure. In
comparison, the synthesis of these natural products typically
required either high temperature15 or stoichiometric metal
complexes.16
D/H
D
O
N
[Cp*Co(MeCN)3(SbF6)2]
OPiv
+
(1)
(2)
N
OMe
DCE, 20 h, 80 o
C
O
H
MeO
D
1a
2c-d (94% D)
4c-d: 90% (63% D)
D
DCE, 20 h, 80 o
C
+
PivOH
MeO
MeO
2c-d (94% D)
2c-d (57% D)
37% scrambled
N
O
DCE, 20 h, 80 o
C
OMe
+
No scrambling
(3)
(4)
CD3COOD
D
4c
[Cp*Co(MeCN)3(SbF6)2]
+
No scrambling
DCE, 20 h, 80 o
C
Me
Scheme 6. One-step synthesis of natural products
MeO
2b
2c-d (94% D)
N
O
Me
In summary, an efficient [3+2] synthesis of 2,5-
disubstituted oxazoles via cobalt(III)-catalyzed cross-coupling
of N-pivaloyloxyamides and alkynes has been achieved. The
reaction operates through an internal oxidation pathway and
as such is compatible with a broad scope of substrates
(applicable to aryl- and alkyl-substituted N-pivaloyloxyamides,
aryl and alkyl alkynes). The synthetic protocol developed
herein has demonstrated its synthetic utility in the expedient
construction of natural products and is expected to play an
crucial role in future synthesis of complex and important
oxazole compounds.
4b
D
O
Me
+
[Cp*Co(MeCN)3(SbF6)2]
D
OPiv
2b
(5)
N
H
DCE, 20 h, 80 o
C
N
OMe
O
1a
MeO
2c d
-
(94% D)
4c-d
4b 4c-d
:
= 1:3.5
4b (0% D); 4c-d (68% D)
No scrambling
Scheme 4. Mechanistic studies for Co(III)-catalyzed coupling of
N-pivaloyloxyamides with alkynes
We gratefully acknowledge support from the National
Natural Science Foundation of China (21425415) and the
National Basic Research Program of China (2015CB856303).
Conflicts of interest
The authors declare no competing financial interest.
Notes and references
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An efficient synthesis of 2,5-disubstituted oxazoles via cobalt(III)-catalyzed cross-coupling of N-pivaloyloxyamides
and alkynes is described herein.
This journal is © The Royal Society of Chemistry 20xx
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