Synthesis of 2,4,5-Trisubstituted Oxazoles via Pd-Catalyzed C-H Addition to Nitriles/Cyclization Sequences

Article abstract of DOI:10.1021/acs.orglett.9b00700

A practical and flexible intermolecular protocol for the diverse synthesis of trisubstituted oxazole derivatives via a Pd-catalyzed direct C-H addition of electronic-rich heteroarenes to O-acyl cyanohydrins bearing an α-hydrogen/cyclization sequence is described. A wide range of trisubstituted oxazoles can be prepared from readily available starting materials in good to high yields with high efficiency under redox neutral reaction conditions.

Full text of DOI:10.1021/acs.orglett.9b00700

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2,4,5-Trisubstituted Oxazoles via Pd-Catalyzed C−H
Addition to Nitriles/Cyclization Sequences
Di Zhang, Hao Song, Na Cheng, and Wei-Wei Liao*
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
S
* Supporting Information
ABSTRACT: A practical and flexible intermolecular protocol
for the diverse synthesis of trisubstituted oxazole derivatives
via a Pd-catalyzed direct C−H addition of electronic-rich
heteroarenes to O-acyl cyanohydrins bearing an α-hydrogen/
cyclization sequence is described. A wide range of
trisubstituted oxazoles can be prepared from readily available starting materials in good to high yields with high efficiency
under redox neutral reaction conditions.
xazoles represent one of the most important five-
membered nitrogen-/oxygen-containing heterocyclic
heterocyclic compounds, but regioselectivity issues and
inevitable multistep processes can limit such methods.6
Moreover, transition-metal-catalyzed transformations7 and
iodine-mediated cyclization reactions8 have been developed
to construct these synthetic scaffolds via the direct cyclization
of alkyne, enamide, or other precursors. However, most of
them suffer from insufficiency such as utilization of
stoichiometric amounts of Lewis acids, additional oxidants,
and a limited substrate scope or inaccessible starting materials.
Thus, it is still desirable to develop a practical and atom-
economic approach to assemble a broad variety of trisub-
stituted oxazole derivatives, in which the substituents can be
readily assembled from available starting materials with high
tunability.
O
compounds and were frequently found in biologically active
compounds and natural products.1,2 In particular, 2,4,5-
trisubstituted oxazoles have attracted considerable attention
because of their various promising biologically activities such as
antidiabetic,3a antibacterial,3b and anti-inflammatory3c,d activ-
ities (Figure 1). For example, siphonazole is a structurally
Recently, transition-metal-catalyzed C−H bond additions to
nitriles have experienced remarkable advances.9 In most cases,
nitriles can serve as C building blocks and provide acyclic aryl
ketone products. Very recently, this strategy has been found to
be applicable to the assembly of azaheterocyclic skeletons in an
atom-economic fashion, in which nitriles serve as C−N
building blocks. For example, we have recently developed an
intramolecular and intermolecular cyclization approach to
prepare indole and thiophene fused polycyclic derivatives via
Pd-catalyzed direct C−H bond addition to nitriles.10 Given the
importance of the trisubstituted oxazoles-containing molecules
in medicinal chemistry and our ongoing interest in the
development of efficient catalytic processes to prepare diverse
heterocyclic frameworks, we envision that a practical, modular,
and flexible intermolecular method for the efficient assembly of
diverse trisubstituted oxazole derivatives would be feasible, in
which Pd-catalyzed direct C−H addition of various electronic-
rich heteroarenes to the cyano group of O-acyl cyanohydrins
bearing an α-hydrogen under redox neutral reaction con-
ditions, could lead to ketoimine intermediates, and subsequent
cyclization would furnish functionalized targeted products in
Figure 1. Examples of oxazole containing natural products and
biological relevant compounds.
novel natural product isolated from a Gram-negative
filamentous gliding bacterium of the Herpetosiphon genus3e
and aleglitazar is a dual agonist of PPAR-α/PPAR-γ for the
treatment of type 2 diabetes.3f Moreover, substituted oxazoles
can be utilized in fluorescent dyes,4a polymers,4b and also as
ligands for transition-metal catalysis.4c,d Consequently, sig-
nificant effort has been devoted to the development of efficient
methodologies for the construction of this privileged
heterocyclic motif.
Among them, the intramolecular cyclization of acyclic
oxazole precursors such as Robinson−Gabriel synthesis
represents an attractive and effective strategy for the
preparation of substituted oxazoles, but it is challenging due
to the cumbersome preparation of the acyclic precursors.5
Functionalization of pre-existing oxazole skeletons is another
important strategy to access these highly functionalized
Received: February 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
an atom-economic fashion (Scheme 1). Heteroarenes are
common feedstock chemicals, while O-acyl cyanohydrins
Table 1. Selected Optimization of Reaction Conditions
Scheme 1. Working Plan
yield
b
entry
[Pd]
ligand
solvent
t (h)
(%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Pd(TFA)2
Pd(TFA)2
−
Pd(TFA)2
Pd(TFA)2
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
L1
NMA/HOAc = 3/1
NMA
HOAc
DMA/HOAc = 3/1
PhCH3/HOAc = 3/1
NMA/TFA = 3/1
NMA/TFA
NMA/HOAc
NMA/TFA
NMA/TFA
NMA/TFA
NMA/TFA
NMA/TFA
12
12
12
12
12
9
9
12
9
9
9
9
9
50
8
2
3
4
5
6
7
8
9
12
40
20
21
68
22
69
74
74
70
64
<1
<1
83
c
c
bearing α-hydrogen, which have demonstrated considerable
synthetic potential as useful building blocks,11 are readily
prepared from aldehydes and acylcyanides or from cyanohy-
drins and carboxylic derivatives (Scheme 1). The readily
availability and manipulation of reaction partners would enable
this transformation to streamline the assembly of diverse
trisubstituted oxazoles with high tunability under redox neutral
and catalytic reaction conditions. Herein, we report this
preliminary work.
d
d
10
11
12
13
14
15
16
de
,
d
d
d
d
L2
−
−
bpy
NMA/TFA
NMA/TFA
NMA/TFA
12
12
4
dfg
, ,
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (10
We commenced our investigations by studying the reaction
of N-methyl-indole 1a with O-benzoyl cyanohydrin 2a as a
model reaction. To our delight, the expected C−H addition/
cyclization sequence occurred by using Pd(OAc)2 (10 mol %)
and 2,2′-bipyridine (bpy) (12 mol %) at 120 °C and NMA/
HOAc (3/1) as the mixed solvent, affording the desired 4-(1-
methyl-1H-indol-3-yl)-2,5-diphenyloxazole 3aa, but in low
yield (Table 1, entry 1). The notably diminished yield was
observed when either NMA or HOAc was employed as a sole
solvent (Table 1, entries 2−3). Further investigation on
solvents revealed that the combination of less polar solvents
such as toluene with HOAc provided inferior results to those
of polar solvents such as DMA, while NMA was more
promising (Table 1, entries 4−5, and Table S1 of the
Supporting Information). The influence of the nature and
loading of acids on the reaction outcome was subsequently
probed. It turned out that the reduced loading of acids such as
TFA gave improved yields in the presence of NMA as a
solvent, while HOAc gave a deteriorated yield (Table 1, entries
6−8, and Table S1 of the Supporting Information). Notably,
the desired C−H addition/cyclization sequence proceeded
well with TFA (20 mol %) and gave product 3aa in 69% yield
(Table 1, entry 9; for details, see Table SI-1 of the Supporting
Information (SI)). The screening of Pd(II) catalysts and
ligands revealed that both catalyst and ligand are essential for
this transformation, and either Pd(TFA)2 or cationic Pd(II)
intermediate, in situ generated from PdCl2 (10 mol %) and
AgSbF6 (20 mol %), afforded a superior result by using 2,2′-
bipyridine (bpy) as a ligand (Table 1, entries 10−15). Further
survey on other reaction parameters such as the loading of the
catalyst, reaction temperature, and ratio of 1a and 2a (1a/2a =
2.5/1) enabled this transformation to provide the product 3aa
in high yield in the presence of Pd(TFA)2 (5 mol %), bpy (6
mol %), and TFA (20 mol %) in NMA at 120 °C (Table 1,
entry 16), establishing the optimized reaction conditions (for
details see the SI).
b
mol %), and ligand (12 mol %) in solvent (c = 0.4 M). Isolated
yields. Acid (100 mol %). Acid (20 mol %). AgSbF6 (20 mol %)
was added. Pd(TFA)2 (5 mol %), ligand (6 mol %). 1a (0.5 mmol).
bpy: 2,2′-bipyridine. L1: 1,10-phenanthroline. L2: 5,5′-dimethyl-2,2′-
bipyridyl. NMA: N-methylacetamide. DMA: N,N-dimethylacetamide.
c
d
e
f
g
indolyl-trisubstituted oxazoles from a broad range of
substituted indoles and O-acyl cyanohydrins 2 was examined.
Besides N-methyl 3-substituted indole 1a, both N-benzyl
substituted indole 1b and N-unsubstituted indole 1c could also
react with 2a to provide the desired products 3ba and 3ca with
similar yields to that of substrate 1a, while the latter can be
easily manipulated by introducing different N-substituents at
the indolyl of trisubstituted oxazole derivatives. Various
substituted free (NH) indoles can react with α-cyanobenzyl
benzoate 2a to afford the desired products 3 in high yields, and
both the substitution pattern and electronic nature of
substitutions at the benzene ring of the indole core were
well tolerated (3ea−3ja). The readily availability and
manipulation of O-acyl cyanohydrins bearing α-hydrogen 2
also enabled this transformation to streamline the introduction
of diverse substituents at the 2- or 5-position of trisubstituted
oxazoles under the optimized reaction conditions. For
example, electron-rich or -poor aromatic groups, heteroar-
omatic groups, alkenyl, and alkyl were all well introduced at the
2- (3fm−3fy) or 5-position (3fb−3fl) from the readily
available starting materials. Notably, a chiral amine unit can
be easily incorporated into the oxazole core, which gave (R)-1-
indolyl-5-phenyloxazol-2-yl)-N,N,2-trimethylpropan-1-amine
3fz in 77% yield when 5-chloro-1H-indole 1f and O-acyl
cyanohydrin prepared from N,N-dimethyl-D-valine and 2-
hydroxy-2-phenylacetonitrile were employed. Biotin, known
as vitamin H featured with the fused bicyclic ring system
containing ureido and thiophene moieties, is involved in a wide
range of metabolic processes, both in humans and in other
organisms. By virtue of the facile preparation of biotin-based
O-acyl cyanohydrin, this key substructure unit can be readily
With the optimized conditions in hand, we explored the
scope of the reaction (Scheme 2). First, versatile synthesis of 4-
B
DOI: 10.1021/acs.orglett.9b00700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope with Respect to Indole
Derivatives 1 and O-Acyl Cyanohydrins 2
Scheme 3. Substrate Scope with Other Heteroarenes
a
a
Reaction conditions: 4 (0.5 mmol), 2a (0.2 mmol), Pd(TFA)2 (10
mol %), and bpy (12 mol %) in NMA (c = 0.4 M). Yields shown are
b
c
of isolated products. Pd(TFA)2 (5 mol %) and bpy (6 mol %). 4
(1.0 mmol).
with 2,5-bis(2,5-diphenyloxazol-4-yl)-pyrrole 6a or 6b. When
2-phenyl (NH) pyrrole and N-methyl-2-phenyl pyrrole were
employed, the reactions delivered the desired pyrrolyl
substituted oxazoles 5c and 5d in good yields. The reactivities
of thiophene and furan were also investigated, and the
reactions of 2-substituted thiophenes and furan with α-
cyanobenzyl benzoate 2a proceeded smoothly and gave the
desired products in reasonable yields (5f−5h), albeit with
prolonged reaction times. Unsubmitted thiophene afforded the
product 5e in low yield under the optimized reaction
conditions. However, treatment of benzo[b]thiophene or
benzofuran with 2a did not give any desired products.
In addition, this approach is also applicable to the
introduction of another oxazole unit into heteroarenes via
the second C−H addition/cyclization sequence (Scheme 4),
a
Scheme 4. Substrate Scope
a
Reaction conditions: 1 (0.5 mmol), 2 (0.2 mmol), Pd(TFA)2 (5 mol
%) and bpy (6 mol %) in NMA (c = 0.4 M). Yields shown are of
isolated products. Pd(TFA)2 (10 mol %) and bpy (12 mol %).
b
a
Reaction conditions: Pd(TFA)2 (10 mol %) and bpy (12 mol %) in
NMA (c = 0.4 M); for substrates 5: 5a or 5e (0.2 mmol), 2a (0.3
mmol); for substrate 3aa: 3aa (0.5 mmol), 2a (0.2 mmol). Yields
shown are of isolated products.
assembled at the oxazole core with high efficiency (3fz′). In
addition, 3-substituted indole 3k was also a suitable substrate
which reacted with α-cyanobenzyl benzoate 2a to provide the
desired indol-2-yl oxazole 3ka in 72% yield. The structures of
4-indolyl-trisubstituted oxazoles were unambiguously con-
firmed by the exemplification of X-ray crystal structural
analysis of product 3fd. To evaluate the practicality of this
catalytic transformation, the reaction of 2a (1 mmol) with 1a
was carried out, which furnished the desired product 3aa in
84% yield.
We next explored different heteroarenes (Scheme 3) and
were pleased to find that either free (NH) pyrrole or N-
methylpyrrole can react with α-cyanobenzyl benzoate 2a to
afford the desired product 5a or 5b in moderate yield, along
which further extended this method to access multioxazolyl
substituted heteroarenes with high efficiency. For example,
treatment of mono-oxazolyl substituted pyrrole 5a with 2a can
furnish 2,5-bis(2,5-diphenyloxazol-4-yl)-1H-pyrrole 6a in 77%
yield, while the corresponding thiophene analogue 6c can be
obtained in 46% yield. Interestingly, employing a 3-oxazolyl
substituted indole 3aa as a substrate led to the formation of the
2,3-bis- oxazolyl substituted indole 6d in 45% yield.
Furthermore, by virtue of the iterative operation of this C−
H addition/cyclization sequence, N-methyl-2-phenyl pyrrole
4c can react respectively with 1,4-phenylenebis(cyano-
C
DOI: 10.1021/acs.orglett.9b00700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Accession Codes
methylene) dibenzoate 7a and bis(cyano(phenyl)methyl)
terephthalate 7b to give the bis-trisubstituted-oxazole deriva-
tives 8a and 8b in reasonable yields (Scheme 5).
CCDC 1898596 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.
Scheme 5. Iterative C−H Addition/Cyclization Sequences
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wliao@jlu.edu.cn.
ORCID
Wei-Wei Liao: 0000-0001-6225-4258
Notes
The authors declare no competing financial interest.
On the basis of our results and the precedent reports,9d,e,10a
a possible mechanism was proposed (Scheme 6). First, direct
ACKNOWLEDGMENTS
■
We thank NSFC (No. 21772063) and Open Project of State
Key Laboratory for Supramolecular Structure and Materials
(sklssm2019016) for financial support.
Scheme 6. Proposed Mechanism
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DOI: 10.1021/acs.orglett.9b00700
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