Palladium-catalyzed C-H activation of simple arenes and cascade reaction with nitriles: access to 2,4,5-trisubstituted oxazoles

Article abstract of DOI:10.1039/d0cc07547g

An efficient and straightforward protocol for the assembly of the pharmaceutically and biologically valuable oxazole skeleton is achieved for the first time from readily available simple arenes and functionalized aliphatic nitriles. This transformation in

Full text of DOI:10.1039/d0cc07547g

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DOI: 10.1039/D0CC07547G
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Palladium-catalyzed C-H activation of simple arenes and cascade
reaction with nitriles: access to 2,4,5-trisubstituted oxazoles
Ling Dai,a Shuling Yu,a Yinlin Shao,a Renhao Li,b Zhongyan Chen,a Ningning Lv*a and Jiuxi Chen*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
confined to using preactivated organoboron reagent as the coupling
partner, leading to multistep synthetic procedures and undesirable
waste.
An efficient and straightforward protocol for the assembly of
pharmaceutically and biologically valuable oxazole skeleton is
achieved for the first time from readily available simple arenes
and functionalized aliphatic nitriles. This transformation
involves palladium-catalyzed C-H activation, carbopalladation
and tandem annulation sequence in one pot. Notably, the
reaction proceeds efficiently under redox-neutral conditions,
and exhibits high atom-economy. Deuterium-labeling
experiments suggested that C-H bond cleavage of the simple
arenes might be the rate-determining step.
From the synthetic and environmental perspective, the use of
inert C-H bond instead of prefunctionalized arene building blocks
represents the most straightforward route of formation
organometallic species. There have recently been several examples
of electron-rich heteroarenes reacting with nitriles to produce
heterocycles.11 To the best of our knowledge, the example of simple
arenes reacting with functionalized nitriles has still remained rare,
owing to the low electron density of simple arenes.12 Stimulated by
our ongoing efforts and interests in the nitrile chemistry, we herein
reported the first example of synthesis trisubstituted oxazoles
through palladium-catalyzed direct C-H activation of simple arenes,
followed by carbopalladation and tandem cyclization with
functionalized nitriles (Scheme 1, eq c). This transformation features
excellent reactivity and high atom-economy. Additionally, this
conversion could be easily scaled-up with excellent yield. Deuterium-
labeling experiments suggested that C-H activation process might be
the rate-determining step. It should be noted that 2,4,5-
trisubstituted oxazoles is an important class of five-membered
nitrogen/oxygen-containing heterocyclic framework that occur in a
broad library of natural products and synthetic bioactive
molecules.13
Nitrile is a highly privileged skeleton that has found widely
applications in synthetic chemistry and pharmaceutical fileds.1 In the
pioneering work, Larock exploited the nucleophilic addition strategy
of arylpalladium species to the cyano group, giving the
corresponding ketones and imines (Scheme 1, eq a).2 Afterwards,
transition-metal-catalyzed functionalization of nitriles reacting with
various coupling partners3-8 has aroused much attention owing to its
efficency. However, most of examples exclusively deliver simple
ketones, rendering the waste of nitrogen atom and lowering the
complexity of the target molecules.
Over the past few decades, cascade cyclization reactions have
become a powerful protocol for the synthesis of complicated
heterocycles and carbocycles through the introduction of multiple
functional groups on the substrates. By the employment of this
methodology, functionalized nitriles have been successfully
Scheme 1 Nucleophilic addition of arylpalladium species with
nitriles.
transformed into
a range of high-valued nitrogen-containing
a) Pd-catalyzed nucleophilic addition of arenes or organoboron reagent with nitriles
heterocyclic compounds (Scheme 1, eq b).9 Among them, our group
has realized the construction of practical utility N-heterocycle
frameworks, including isoquinolines, isoquinolones, quinazolines,
ArH/hetero Ar-H
O/NH
N
RC
electropalladation
transmetalation
or
+
Pd(II)
Ar[Pd]
carbopalladation
Ar
R
ArB(OH)2
ketone or imine
pyrroles,
pyridines,
dibenzo[c,e]azepines
and
benzofuro[2,3-c]pyridines etc.10 Nevertheless, such reactions are still
b) Pd-catalyzed annulation of organoboron reagents with functionalized nitriles
Ar
N
C
R
R
N
FG
carbopalladation/cyclization
transmetalation
Xn = (OH)2, F3K
ArBXn
+
Pd(II)
Ar[Pd]
a. College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou
325035, China E-mail: ningninglv@wzu.edu.cn; jiuxichen@wzu.edu.cn.
b. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
325035, P. R. China
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
c) Pd-catalyzed annualtion of simple arenes with functionalized nitriles for oxazoles synthesis
R1
O
R1
R2
C
O
N
electropalladation
O
ArH
+
Pd(II)
Ar[Pd]
Ar
R2
carbopalladation/cyclization
N
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Table 1 Optimization of reaction conditionsa
yields. Notably, this methodology could be successfully extended to
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heterocyclic-substituted substrates, leadinDgOtIo: 10th.1e03c9o/Drr0eCsCp0o7n5d4i7nGg
oxazole products (3p-3r). With respect to alkyl-substituted
substrates, the reaction underwent smoothly to give the 2-
alkylsubstituted oxazoles in good yields (3s-3t). The exact structure
of 3a was identified by X-ray diffraction.15
Pd(acac)2 (10 mol %)
DMSO (2 equiv)
O
H
O
+
TFA (1 mL), 100 oC, 6 h, air
O
N
C
N
1a
2a
3a
entry deviation from“standard conditions”
yield(%)b
Table 2 Scope of functionalized nitrilesa
1
none
95
nr
R1
Pd(acac)2 (10 mol %)
O
R1
H
+
O
R2
O
DMSO (2 equiv)
TFA (1 mL)
2
no Pd(acac)2
N
C
N
R2
1
2a
3
3
mesitylene as solvent without TFA
Pd(TFA)2 instead of Pd(acac)2
Pd(OAc)2 instead of Pd(acac)2
no DMSO
trace
78
72
25
82
88
91
85
40
60
X
4
O
O
N
5
O
O
N
N
N
6
3d,
3e,
3f,
X = F, 90%
X =Cl, 89%
X = Br, 80%
3a,
3b,
3c,
91%
95%
90%
7
0.2 equiv. DMSO was used
0.5 equiv. DMSO was used
1 equiv. DMSO was used
DMF instead of DMSO
2,2'-bipyridine instead of DMSO
1,10-phenanthroline instead of DMSO
8
O
R1
O
O
O
9
N
N
N
10
11c
12c
3i,
R
1 = propyl, 88%
1 = cyclohexyl, 90%
3a CCDC: 2032715
3g,
3h,
85%
88%
3j,
R
3k,
R
1 = phenethyl, 80%
3l,
X = OMe, 85%
3m,
3n,
3o,
X = Cl, 81%
X = Br, 82%
X = CF3, 91%
O
N
O
aConditions: 1a (0.3 mmol), 2a (7 equiv), Pd-catalyst (10 mol %), DMSO (2
O
N
N
equiv), TFA (1 mL), 100 oC, 6 h, air. bIsolated yield. c20 mol % ligand was used.
S
X
3p,
%
3q,
85%
90
We commenced our investigations by screening the reaction
conditions of the model reaction of cyano(phenyl)methyl benzoate
1a with mesitylene 2a (Table 1). Optimal conditions were obtained
by using catalyst derived from Pd(acac)2 and additive DMSO in
solution of TFA at 100 oC for 6 h, generating target oxazole 3a in 95%
yield (Table 1, entry 1). Control experiments indicated that Pd-
catalyst and TFA were essential to this transformation (Table 1,
entries 2-3). Using Pd(TFA)2 or Pd(OAc)2 instead of Pd(acac)2, the
decreased yield of product 3a was observed (Table 1, entries 4-5). It
was found that DMSO, which is known to be a unique ligand in many
O
N
O
O
N
N
N
3r,
3s,
3t,
90%
45%
71%
aConditions: 1 (0.3 mmol), 2a (7 equiv), Pd(acac)2 (10 mol %), DMSO (2 equiv),
TFA (1 mL), 100 oC, 6 h, air. bIsolated yield.
Table 3 Scope of simple arenesa
Ph
Pd(II) transformations,2,14 has
a significant effect on this
O
Ph
O
Pd(acac)2 (10 mol %)
transformation. The addition of 0.2 equiv DMSO into the reaction,
the yield was drastically increased to 82%. Subsequently, the yield
was increased by margin when DMSO was increased to 2 equivalents
(Table 1, entries 6-9). Additionally, DMSO showed better reactivity
than other ligands, including DMF, 2,2'-bipyridine and
phenanthroline. (Table 1, entries 10-12). Further screening revealed
that the optimal dosage of the simple arene is 7 equivalents (see the
ESI† for details, Table S1)
O
N
R3
+
C
R3
N
DMSO (2 equiv)
TFA (1 mL)
1a
2
4
O
O
O
Me
Me
N
N
N
Me
4a,
4b,
4c,
65% (o:m = 1:1.9)
32%
51% (o:m:p = 1.97:1:2.34 )
With the optimal reaction conditions in hand, the generality by
varying the substituents on the cyanomethyl carboxylates was
demonstrated in Table 2. In general, this transformation exhibits a
broad substrate scope. Substrates of para-tolyl and ortho-tolyl
attached to α-position of the cyano group give the corresponding
oxazoles in 90% and 91% yield, respectively (3b-3c), suggesting that
the steric hindrance has a negligible impact on the reaction. Halogen
substituents attached to the benzene ring of α-position of the cyano
group could be tolerated well, affording the target products in
excellent yields (3d-3f), which allows the as-prepared oxazoles for
late-stage elaborations. Substrates with diverse R1 substituents, such
as furyl, hydrogen atom, propyl, cyclohexyl and phenethyl groups,
are also amenable to this transformation and exhibit excellent
reactivity (3g-3k). In addition, the cyano(phenyl)methyl benzoates
with -OMe, -Cl, -Br and -CF3 groups on the aryl ring participate in this
transformation smoothly, giving the desired products 3l-3o in 81-91%
O
N
3
O
N
O
N
2
Me
1
Me
4d,
75%
4e,
4f,
50%
65%
(C3:C2:C1 = 6.5:29.1:1)
OMe
OMe
X
O
O
O
OMe
N
N
N
MeO
MeO
4h,
4i,
4j
X= F, 78%
, X=Br, 77%
4g,
36%
51%
aConditions: 1a (0.3 mmol), 2 (7 equiv), Pd(acac)2 (10 mol %), DMSO (2 equiv),
TFA (1 mL), 100 oC, 6 h, air. Isolated yield. cThe value given in parentheses
b
denotes the relative ratio of regioisomers detected by GC-MS.
2 | J. Name., 2012, 00, 1-3
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Scheme 2 Synthetic applications
Scheme 3 Mechanistic investigations
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(a) scaled-up reaction
DOI: 10.1039/D0CC07547G
control experiments:
Ph
O
O
O
Ph
O
Standard conditions
O
H
Standard conditions
N
O
+
O
N
C
(a)
(b)
+
Ph
O
N
C
N
O
3a
1a
5a,
5b,
not detected
not detected
Ph
1a,
2a,
7 equiv
5 mmol, 1.18 g
yield 91%, 1.54 g
(b) late-stage derivatization
O
Ph
OMe
O
Standard conditions
H2O (1 mL)
H
Ph
3a
O
N
+
C
O
Ph
B(OH)2
+
Br
Pd(OAc)2 (5 mol %)
PPh3 (10 mol %)
O
O
N
+
90%
5c,
not detected
O
N
1a
2a
K3PO4 (2 equiv)
Ph
1,4-dioxane, 120 o
C
OMe
O
Ph
O
4j,
6a,
91%
0.3 mmol
2 equiv
Standard conditions
N
O
(c)
CF3COONH4 (20 equiv)
without Pd-catalyst
O
After examining the compatibility of the various cyanomethyl
carboxylates, we next investigated the substrate scope of simple
arenes (Table 3). It should be noted that the reaction system
displayed good tolerance toward bare benzene substrate (4a),
indicating that large steric effect of the simple arene is not essential
to this conversion. Toluene, o-xylene and m-xylene substrates, each
of which possesses two or three potential reaction sites, generated
the corresponding mixtures of oxazoles in good yields (4b-4d). With
respect to p-xylene and 1,2,4,5-tetramethylbenzene, the reaction
proceeded well to provide the desired products in 65% and 50% yield,
respectively (4e-4f). Methoxyl-substituted benzenes were also
compatible in this reaction to produce the target products (4g-4h).
The transformation was further extended to 2-fluoro-1,3,5-
trimethylbenzene and 2-bromo-1,3,5-trimethylbenzene, delivering
the target oxazoles in excellent yields (4i-4j). However, no reaction
occurred with respect to the electron-deficient arenes, such as
benzonitrile, (trifluoromethyl)benzene, methyl benzoate and
pentafluorobenzene, owing to the key arylpalladium species was
formed via the electrophilic palladation between the palladium
catalyst with the simple arenes.
5c
3a,
85%
competitive experiment:
Ph
Ph
O
O
H
Standard conditions
O
N
C
(d)
N
+
F3C/MeO
1l : 1o =
F3C/MeO
2a
3l : 3o
= 1:1
1:1
deuterium-labeling experiment:
D
Ph
Ph
1a
(0.3 mmol)
D
D
D5
Standard conditions
O
O
(e)
or
or
D
D
from 0.5 h to 2.5 h
parallel KIE
N
N
Ph
Ph
= 2.84
D
2a'
D6-2a'
D5-4a
4a
Scheme 4 Proposed reaction mechanism
R1
Pd(acac)2
O
R1
N
HN
Ar
O
Ar
tautomerization
TFA/DMSO
Hacac
O
R2
annulation/dehydration
R2
Ar-H
2
E
3
4
or
[Pd](II)
A
protonation
electrophilic palladation
TFA
Gratifyingly, this transformation could be easily scaled-up to 5
mmol scale, producing the target oxazloe 3a in 91% yield (Scheme 2,
eq a). Moreover, the as-prepared oxazole 4j could be further
transformed into more complicated molecules through cross-
coupling reaction (Scheme 2, eq b). These results further highlight
the robustness and practical potential of this protocol.
TFA
R1
O
N
[Pd]
O
Ar[Pd]
O
R2
Ar
R2
B
D
R1
O
1
C
N
coordination
R1
carbopalladation
Preliminary experiments were performed under standard
conditions for the better understanding of the reaction mechanism
as depicted in Scheme 3. First, the reaction was carried out in the
absence of simple arenes, the corresponding cyclized products 2,5-
diphenyloxazole (5a) and 3-phenylisochromane-1,4-dione (5b) were
not detected. These results implicated that this transformation was
initiated by the carbopalladation between the arylpalladium species
with nitrile substrate. The arylpalladium species was generated from
the electropalladation of palladium catalyst with the simple arenes
(Scheme 3, eq a). When the model reaction of 1a with 2a was treated
with 1 mL water, no 2-oxo-1,2-diphenylethyl benzoate (5c) was
obtained, indicating that the ketimine intermediate is more prone to
undergo domino cyclization reaction compared with the hydrolysis
process (Scheme 3, eq b). In addition, we synthesized the compound
5c according to the literature,16 then the target oxazole 3a was
obtained when it reacted with 20 equiv ammonium trifluoroacetate
in the absence of palladium catalyst, further underscoring the
ketimine was the indeed intermediate of this transformation
(Scheme 3, eq c). An intermolecular competition experiment of 1l
and 1o with mesitylene 2a was performed (Scheme 3, eq d), and the
result revealed that the electronic effect of the benzene ring of the
benzoate had little impact on this conversion. Subsequently, the
parallel kinetic isotope reactions of 2a’ or D6-2a’ with 1a were
conducted from 0.5 h to 2.5 h separately (Scheme 3, eq e, see the
O
O
N
C
Ar[Pd]
R2
C
ESI† for details). Then, the primary kinetic isotope effect of 2.84 was
observed, revealing that the C-H activation process might be the rate
determining step.17
On basis of the aforementioned experiment results and previous
reports,2,18 we propose a plausible mechanism for the synthesis of
trisubstituted oxazole as demonstrated in Scheme 4. Initially, an
activated palladium catalyst A is formed from Pd(acac)2 catalyst in
the presence of TFA and DMSO.2,14 The subsequent
electropalladation between the species A and the simple arene 2
furnishes the key arylpalladium species B,2,18 followed by
coordination with the nitrile substrate gives the intermediate C. The
carbopalladation of species C generates imine-Pd complex D, which
undergoes protonation process to form the ketimine intermediate E
and release the activated palladium catalyst A to fulfil the catalytic
cycle.
Subsequently,
the
tautomerization/nucleophilic
addition/dehydration of complex E deliver the target oxazole
products.
In summary, we have developed a new route to construct diverse
2,4,5-trisubstituted oxazoles via palladium-catalysed domino
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and J. Chen, Adv. Synth. Catal., 2020, 362, 1893−1898; (h) S.
reaction of readily accessible simple arenes with cyanomethyl
carboxylates. The transformation involves the direct cleavage of inert
C-H bond and formation of multiple bonds in one pot under redox-
neutral reaction condition. Moreover, this synthetic strategy is
distinguished by its excellent reactivity (up to 95% yield) and high
atom efficiency. Notably, this protocol is of practical utility could be
easily scaled-up reaction and for late-stage derivatization. Further
investigations on exploiting efficient pathway to access more
privileged heterocycles are underway in our laboratory.
Yu, L. Dai, Y. Shao, R. Li, Z. Chen, N. Lv and J. CheVnie,wOArrgti.clCe hOenlmine.
DOI: 10.1039/D0CC07547G
Front., 2020, 7, 3439−3445.
11 (a) D. Zhang, H. Song, N. Cheng and W.-W. Liao, Org.
Lett.,2019, 21, 2745−2749; (b) W. Xiong, Z. Chen, Y. Shao, R.
Li, K. Hu and J. Chen, Org. Chem. Front., 2020, 7, 756−762; (c)
L. Zhao and W.-W. Liao, Org. Chem. Front., 2018, 5, 801−805;
(d) T-T. Wang, D. Zhang and W.-W. Liao, Chem. Commun.,
2018, 54, 2048−2051; (e) T.-S. Jiang and G.-W. Wang, Org.
Lett., 2013, 15, 788−791; (f) T.-S. Jiang and G.-W. Wang, Adv.
Synth. Catal., 2014, 356, 369–373; (g) Y. Ma, J. You and F. Song,
Chem. Eur. J., 2013, 19, 1189–1193; (h) J. Rydfjord, B.
Skillinghaug, P. Brandt, L. R. Odell and M. Larhed, Org. Lett.,
2017, 19, 4066-4069.
We thank the National Natural Science Foundation of China (No.
21572162), the Natural Science Foundation of Zhejiang Province (No.
LY20B020015 and Q21B050002) for financial support.
12 (a) B. Zhou, Y. Hu and C. Wang, Angew. Chem. Int. Ed., 2015,
54, 13659−13663; (b) H. Takaya, M. Ito and S. Murahashi, J.
Am. Chem. Soc., 2009, 131, 10824–10825.
Conflicts of interest
There are no conflicts to declare.
13 For selected cases, see: (a) P. A. Searle and T. F. Molinski, J.
Am. Chem. Soc., 1995, 117, 8126−8131; (b) O. Banzragchgarav,
T. Murata, G. Odontuya, B. Buyankhishig, K. Suganuma, B.-O.
Davaapurev, N. Inoue, J. Batkhuu and K. Sasaki, J. Nat. Prod.,
2016, 79, 2933−2940; (c) B. Clapham, A. J. Richards, M. L.
Wood and A. J. Sutherland, Tetrahedron Lett., 1997, 38,
9061−9064; (d) P. A. Todd and R. N. Brogden, Drugs, 1986, 32,
291−312; (e) F. Akutsu, M. Inoki, K. Sunouchi, Y. Sugama, Y.
Kasashima, K. Naruchi and M. Miura, Polymer., 1998, 39,
1637−10641.
14 (a) D. Tanaka, S. P. Romeril and A. G. Myers, J. Am. Chem. Soc.,
2005, 127, 10323−10333; (b) R. I. McDonald and S. S. Stahl,
Angew. Chem., Int. Ed., 2010, 49, 5529−5532; (c) Z. Lu and S.
S. Stahl, Org. Lett., 2012, 14, 1234−1237; (d) C. Engelin, T.
Jensen, S. Rodriguez-Rodriguez and P. Fristrup, ACS Catal.,
2013, 3, 294−302; (e) K. J. Fraunhoffer, D. A. Bachovchin and
M. C. White, Org. Lett., 2005, 7, 223−226; (f) M. S. Chen, N.
Prabagaran, N. A. Labenz and M. C. White, J. Am. Chem. Soc.,
2005, 127, 6970−6971.
15 The structures of compounds 3a was determined by X-ray
crystallography (see the Supporting Information for full
details). CCDC 2032715 (3a) contain 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.
16 Y.-J. Kim, N. Y. Kim and C.-H. Cheon, Org. Lett., 2014, 16,
2514−2517.
17 (a) E. M. Simmons and J. F. Hartwig, Angew. Chem. Int. Ed.,
2012, 51, 3066−3072; (b) X. Wu, J. Fan, C. Fu and S. Ma, Chem.
Sci., 2019, 10, 6316−6321; (c) N. Lv, Y. Liu, C. Xiong, Z. Liu and
Y. Zhang, Org. Lett., 2017, 19, 4640−4643; (d) E. F. Flegeau, C.
Bruneau, P. H. Dixneuf and A. Jutand, J. Am. Chem. Soc., 2011,
133, 10161−10170; (e) C. S. Yi and S. Y. Yun, J. Am. Chem. Soc.,
2005, 127, 17000−17006.
Notes and references
1
(a) V. Y. Kukushkin and A. J. L. Pombeiro, Chem. Rev., 2002,
102, 1771−1802; (b) D. Enders and J. P. Shilvock, Chem. Soc.
Rev., 2000, 29, 359−373; For selected examples, see: (c) K.
Tokmic, B. J. Jackson, A. Salazar, T. J. Woods and A. R. Fout, J.
Am. Chem. Soc., 2017, 139, 13554−13561; (d) J. B. Geri and N.
K. Szymczak, J. Am. Chem. Soc., 2015, 137, 12808−12814; (e)
A. Mukherjee, D. Srimani, S. Chakraborty, Y. Ben-David and D.
Milstein, J. Am. Chem. Soc., 2015, 137, 8888−8891.
(a) C. Zhou and R. C. Larock, J. Am. Chem. Soc., 2004, 126,
2302−2303; (b) C. Zhou and R. C. Larock, J. Org. Chem., 2006,
71, 3551−3558.
2
3
4
(a) R. C. Larock, Q. Tian and A. A. Pletnev, J. Am. Chem. Soc.,
1999, 121, 3238−3239; (b) A. A. Pletnev, Q. Tian and R. C.
Larock, J. Org. Chem., 2002, 67, 9276−9287.
(a) K. Ueura, T. Satoh and M. Miura, Org. Lett., 2005, 7,
2229−2231; (b) B. Zha and X. Lu, Tetrahedron Lett., 2006, 47,
6765−6768; (c) H. Shimizu and M. Murakami, Chem. Commun.,
2007, 2855−2857; (d) Y.-C. Wong, K. Parthasarathy and C.-H.
Cheng, Org. Lett., 2010, 12, 1736−1739; (e) G. Tsui, Q.
Glenadel, C. Lau and M. Lautens, Org. Lett., 2011, 13, 208−211.
J. Lindh, P. Sjberg and M. Larhed, Angew. Chem., Int. Ed.,2010,
49, 7733−7737.
5
6
7
K. Cheng, G. Wang, M. Meng and C. Qi, Org. Chem. Front.,
2017, 4, 398−403.
(a) J. Liu, X. Zhou, H. Rao, F. Xiao, C. Li and G. Deng, Chem. –
Eur. J., 2011, 17, 7996−7999; (b) M. Behrends, J. Sämarker, P.
Sjöberg and M. Larhed, ACS Catal., 2011, 1, 1455−1459; (c) T.
Miao and G. Wang, Chem. Commun., 2011, 47, 9501−9503.
(a) J. Sheng, Y. Wang, X. Su, R. He and C. Chen, Angew. Chem.,
Int. Ed., 2017, 56, 4824−4828; (b) X. Su, C. Chen, Y. Wang, J.
Chen, Z. Lou and M. Li, Chem. Commun., 2013, 49, 6752−6754;
(c) X. Pang, C. Chen, X. Su, M. Li and L. Wen, Org. Lett., 2014,
16, 6228−6231.
8
9
18 (a) D. R.Stuart and K. Fagnou, Science., 2007, 316, 1172-1175;
(b) Y. Wei and W. Su, J. Am. Chem. Soc., 2010, 132,
16377−16379; (c) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39,
540–548; (d) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem.
Soc. Rev., 2011, 40, 5068–5083.
(a) H. Yu, L. Xiao, X. Yang and L. Shao, Chem. Commun., 2017,
53, 9745−9748; (b) M. Yousuf and S. Adhikari, Org. Lett., 2017,
19, 2214−2217; (c) H. Song, N. Cheng, L. She, Y. Wu and W.
Liao, RSC Adv., 2019, 9, 29424−29428.
10 (a) L. Qi, K. Hu, S. Yu, J. Zhu, T. Cheng, X. Wang, J. Chen and H.
Wu, Org. Lett., 2017, 19, 218−221; (b) K. Hu, Q. Zhen, J. Gong,
T. Cheng, L. Qi, Y. Shao and J. Chen, Org. Lett., 2018, 20,
3083−3087; (c) X. Yao, Y. Shao, M. Hu, Y. Xia, T. Cheng and J.
Chen, Org. Lett., 2019, 21, 7697−7701; (d) W. Xiong, K. Hu, Y.
Lei, Q. Zhen, Z. Zhao, Y. Shao, R. Li, Y. Zhang and J. Chen, Org.
Lett., 2020, 22, 1239−1243; (e) L. Chen, J. Gong, Y. Zhang, Y.
Shao, Z. Chen, R. Li and J. Chen, Org. Lett.,2020, 22,
6943−6947; (f) X. Yao, Y. Shao, M. Hu, M. Zhang, S. Li, Y. Xia,
T. Cheng and J. Chen, Adv. Synth. Catal., 2019, 361,
4707−4713; (g) L. Dai, S. Yu, W. Xiong, Z. Chen, T. Xu, Y. Shao
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC07547G
R1
[Pd]
DMSO
H
R3
O
R1
O
R3
+
R2
R2
O
N
C
N
R1 = Aryl, heteroaryl, alkyl, H
R2 = Aryl, heteroaryl, alkyl
up to 95% yield
30 examples
high atom-economy
redox-neutral reaction conditions
good functional group tolerance
An efficient and straightforward protocol for the assembly of pharmaceutically and biologically
valuable oxazole skeleton is achieved for the first time through palladium-catalyzed C-H
activation, carbopalladation and tandem annulation sequence from readily available simple
arenes and functionalized aliphatic nitriles.