Metal-Free sp3 C-H Functionalization: PABS/I2-Promoted Synthesis of Polysubstituted Oxazole Derivatives from Arylethanones and 2-Amino-2-alkyl/arylacetic Acid

Article abstract of DOI:10.1055/s-0035-1560660

A nonmetal-catalyzed process for the synthesis of polysubstituted oxazoles from inexpensive and readily available α-amino acids and methyl ketones is established. This reaction is proposed to achieve oxidative cleavage of C(sp³)-H bonds, followed by decarboxylation and annulation. The mild reaction conditions employed in both cases enable the tolerance of a wide range of functional groups as well as high reaction efficiency.

Full text of DOI:10.1055/s-0035-1560660

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2866–2869
letter
2866
T. Hu et al.
Letter
Synlett
Metal-Free sp3 C–H Functionalization: PABS/I2-Promoted Synthe-
sis of Polysubstituted Oxazole Derivatives from Arylethanones
and 2-Amino-2-alkyl/arylacetic Acid
Ting Hua
I2 (2.0 equiv)
Hao Yanb
COOH
NH2
PABS (0.5 equiv)
DMSO, air, 100 °C
O
N
Xingxing Liua
Chaoyang Wua
Yuxing Fana
Jing Huangc
Guosheng Huang*a
R2
+
R1
R2
R1
2–5 h
O
R1 = aryl, alkyl, aryl halide, nitrophenyl
R2 = aryl, alkyl
26 examples
up to 99% yield
CO2, H2O
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. of China
hgs@lzu.edu.cn
b College of Pharmacy, Shaanxi University of Chinese Medicine, Shaanxi
Province, 712046, P. R. of China
c Department of Chemistry, and Macromolecules and Interfaces Institute,
Virginia Tech, Blacksburg, VA 24061, USA
Received: 21.07.2015
Accepted after revision: 13.09.2015
Published online: 14.10.2015
sive, environmentally friendly, and highly atom-efficient
starting materials have attracted the attention of many
chemists. The exploitation of the cyclization reaction that
enables the realization of transformation in good yields and
mild-condition manner still remains challenging. We found
a kind of additive (p-aminobenzenesulfonic acid) to greatly
increase the efficiency of a similar reaction in the product.
Herein, we report a facile synthesis of 2,5-disubstituted ox-
azoles from α-amino acids via PABS/I2-promoted oxidative
cyclization of ketone C(sp3)–N bonds (resulting in C–N bond
formation). This nonmetal-catalyzed reaction with easily
available starting material and high yields can potentially
serve as a new practical route to the synthesis of oxazole
derivatives.
DOI: 10.1055/s-0035-1560660; Art ID: st-2015-w0563-l
Abstract A nonmetal-catalyzed process for the synthesis of polysub-
stituted oxazoles from inexpensive and readily available α-amino acids
and methyl ketones is established. This reaction is proposed to achieve
oxidative cleavage of C(sp3)–H bonds, followed by decarboxylation and
annulation. The mild reaction conditions employed in both cases en-
able the tolerance of a wide range of functional groups as well as high
reaction efficiency.
Key words nonmetal-catalyzed, oxazoles, sp3 C–H functionalization,
high yield, amino acids
Oxazoles represent an important class of five-mem-
bered N-heterocyclic aromatic compounds.1–3 They have at-
tracted remarkable attention not only because they serve
as one of the key building blocks in various natural prod-
ucts, pharmaceuticals, and synthetic intermediates, but
also due to their biological activities such as bacteriostatic
and fungistatic activities, fluorescent whitening activities,
and scintillator properties.4–19 In addition, oxazole deriva-
tives are also employed as corrosion inhibitors20,21 and in
photography.15 A wide variety of synthetic routes have been
developed for oxazole derivatives.22–29 Classical synthesis of
oxazole derivatives includes the Robinson–Gabriel synthe-
sis, the Fischer synthesis, and the Van Leusen reaction.30 In
2010, an elegant work for the synthesis of polysubstituted
oxazoles using copper salts were reported by Wang and co-
workers.23 And then, the excellent preparations of substi-
tuted oxazoles from benzylamines were consecutively re-
ported.24–27 More recently, amino acids as a sort of inexpen-
Initial experiments were carried out using acetophe-
none (1a) and phenylglycine (2a) as model substrates. The
mixture was stirred without any protection gas. A range of
oxidants, such as I2 (1.0 and 2.0 equiv), CuI (1.0 equiv), and
NIS (1.0 equiv) were examined, and I2 (2.0 equiv) showed
the best capability to promote the reaction and gave the de-
sired 2,5-diphenyloxazole in 66% yield (Table 1, entries 1–
4). Unexpectedly, the yield decreased when using more
than 2.5 equivalents of I2 as oxidant (Table 1, entry 5). In the
optimization of the reaction temperature, it was found that
the reaction has the best yield at 100 °C (Table 1, entries 4, 6
and 7). After that, we examined three different solvents (Ta-
ble 1, entries 8 and 9), interestingly, none of the other
aprotic polar solvents afforded the product except DMSO.
Since acid can promote the formation of intermediate D, in-
cluding PivOH (1.0 equiv), TsOH (1.0 equiv), AcOH (1.0
equiv), and PABS (1.0 equiv), were tested to improve the
yield. The reaction with PABS (0.5 equiv) produced 2,5-di-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2866–2869

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T. Hu et al.
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phenyloxazole (3a) in high yield (90%, Table 1, entries 10–
15). Gas atmosphere, such as O2 and N2, was also tested but
neither gave better yields (Table 1, entries 16 and 17).
suitable substrates for this process, which produced the
corresponding compounds in excellent yields (3ja, 99%;
3ka, 93%). Besides, variation of the R1 substituent of 1
showed that 1-naphthyl and 2-naphthyl groups (3ra, 82%;
3sa, 92%) can also be converted into the corresponding 2,5-
diphenyloxazole through the same reaction conditions. No-
tably, the reaction with 4-methylpentan-2-one could also
proceed to furnish the desired product 3ta in 42% isolated
yield, thus indicating that alkyl methyl ketone could pro-
duce the corresponding products.
Table 1 Optimization of the Reaction Conditionsa
O
COOH
NH2
N
O
1a
Entry
2a
Additive
3aa
This oxidative decarboxylative annulation was further
expanded to a range of substituted α-amino acids 2 (Table 2).
The introduction of alkyl groups [R2 = n-Pr, i-Pr, and i-Bu] at
Oxidant
(equiv)
Solvent
Temp
(°C)
Yield
(%)b
(equiv)
1
2
I2 (1.0)
CuI (1.0)
NIS (1.0)
I2 (2.0)
I2 (2.5)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
80
10
9
Table 2 Reaction Scope of Methyl Ketones and Amino Acida
–
I2 (2.0 equiv)
PABS (0.5 equiv)
O
COOH
NH2
2
N
3
–
trace
4
–
66
R2
R1
R1
R2
+
O
DMSO (2 mL), air
5
–
63
1
3
6
–
23
Entry
R1
1a Ph
R2
Product
Yield (%)b
7
–
120
100
100
100
100
100
100
100
100
100
100
58
8
–
trace
trace
63
1
2
2a Ph
3aa
3ba
3ca
3da
3ea
3fa
90
95
84
87
94
99
93
95
91
99
93
85
97
98
90
88
89
82
92
42
75
70
39
58
82
48
9
–
DMA
1b 2-MeC6H4
1c 2-MeOC6H4
1d 2-ClC6H4
1e 3-MeC6H4
1f 3-MeOC6H4
1g 3-ClC6H4
1h 3-BrC6H4
1i 3-O2NC6H4
1j 3,4-(MeO)2C6H3
1k 3,4-Cl2C6H3
1l 4-MeOC6H4
1m 4-FC6H4
1n 4-ClC6H4
1o 4-O2NC6H4
1p 4-F3CC6H4
1q 4-PhC6H4
1r 1-naphthyl
1s 2-naphthyl
1t Me2C2H3
1a Ph
2a Ph
10
11
12
13c
14
15
16d
17e
PivOH (1.0)
TsOH (1.0)
AcOH (1.0)
PABS (1.0)
PABS (0.5)
PABS (0.3)
PABS (0.5)
PABS (0.5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
2a Ph
76
4
2a Ph
58
5
2a Ph
89
6
2a Ph
90
7
2a Ph
3ga
3ha
3ia
56
8
2a Ph
90
9
2a Ph
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2a Ph
3ja
a Reaction conditions: 1a (0.32 mmol), 2a (0.38 mmol), solvent (2 mL), 4 h.
b All yields are isolated products.
2a Ph
3ka
3la
c PABS = p-aminobenzenesulfonic acid.
2a Ph
d The reaction was carried out under a O2 atmosphere.
e The reaction was carried out under a N2 atmosphere; DMF = N,N-dimethyl-
formamide, DMSO = dimethylsulfoxide, DMA = N,N-dimethylacetamide.
2a Ph
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
3ab
3ac
3ad
3ae
3af
2a Ph
2a Ph
Using the molecular iodine/p-aminobenzenesulfonic
acid oxidant system in DMSO (Table 1, entry 14), we exam-
ined the substrates scope of this oxidative cyclization for
the synthesis of 2,5-diphenyloxazole, the results are shown
in Table 2. Generally, acetophenone and its derivatives with
either electron-withdrawing or electron-donating groups
on the aromatic rings could readily participate in the reac-
tions and result in high yields (3ba, 95%; 3ca, 84%; 3ea,
94%; 3fa, 99%; 3la, 85%; 3oa, 90%; 3pa, 88%). A halogen at
the 2-, 3- or 4-position imparted mild reactivity furnishing
the corresponding products in perfect yields (3da, 87%;
3ga, 93%; 3ha, 95%; 3ma, 97%; 3na, 98%) with decent recov-
ery of the unreactive precursors. A favorable yield was ob-
served in the case of 2-substituted phenyl (3qa, 89%),
which indicated that steric hindrance did not affect the re-
action efficiency. Likewise, 3,4-(MeO)2 and 3,4-Cl2 were
2a Ph
2a Ph
2a Ph
2a Ph
2a Ph
2b n-Pr
2c i-Pr
2d MeCH(OH)
2e MeSCH2CH2
2f i-Bu
2g Bn
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
3ag
a Reaction conditions: 1 (0.32 mmol), 2 (0.38 mmol), I2 (2.0 equiv), PABS (0.5
equiv), DMSO (2 mL), at 100 °C, under air 2–5 h.
b All yields are isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2866–2869

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NH2
R2
COOH
2
O
O
O
O
O
I2
DMSO
N
O
R1
S
OH
I
R1
R1
R1
R2
1
A
B
C
O
[1,5]-H
R2
H2N
OH
O
PABS
COOH
OH
NH
R1
+
D
CO2
O
R2
O
O
R2
R2
H
R2
I2
O
O
R1
R1
O
O
R1
R1
O
H
+
OH
OH
N
N
NH
NH
H+
I
HI
E
F
G
3
Scheme 1
the α-amino acids were well tolerated in the reaction (3ab,
75%; 3ac, 70%; 3af, 82%). Meanwhile, it was noteworthy
that an unprotected hydroxyl group could also undergo this
process, although in lower yield (3ad, 39%). Additionally,
yields of oxazoles 3ae (58%) and 3ag (48%) with MeSCH2CH2
and benzyl substituents were distinctly lower even under
different reaction conditions, which appear to be sensitive
to the transformation time.
tion’s utility of this protocol. Furthermore, the transforma-
tion proceeds with perfect yields to a variety of functional
groups.
Acknowledgment
The authors are grateful for financial support by the Fundamental Re-
search Funds for the Central Universities, P. R. of China.
On the basis of the previous reports,23–29 a plausible
mechanism was proposed in Scheme 1. It may undergo ac-
cording to the following procedures. Initially, the substrates
1 were converted into the intermediate α-iodo acetophe-
none A in the presence of I2. Subsequently, A was oxidized
by DMSO to B. Then, amino acids 2 reacted with B to afford
C, C isomerized to D via a [1,5]-H shift. p-Aminobenzene-
sulfonic acid (PABS) acts as acid that promoted the reaction
by increasing the electrophilicity of C-1 on D through coor-
dination with nitrogen, providing a good electrophilic sec-
tion for the nucleophilic hydroxyl group, which underwent
an intramolecular cyclization furnishing the intermediate
E. Consequently, E converted into F through deprotonation,
and an iodine-mediated oxidative decarboxylation of G
generated the desired product 3 through the release of CO2
and HI.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560660.
S
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p
p
ortiInfogrmoaitn
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References and Notes
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ole
A test tube was charged with 1a (0.32 mmol), 2a (0.38 mmol), I2
(2.0 equiv), and PABS (0.5 equiv). Then DMSO (2 mL) was added
to the reaction system. The reaction was stirred at 100 °C for 5
h. After cooling to r.t., the solvent diluted with EtOAc (10 mL)
and washed with brine (5 mL) and dried over anhydrous
Na2SO4. After the solvent was evaporated in vacuo, the residues
were purified by column chromatography, eluting with PE–
EtOAc to afford pure 3aa as a yellow solid (64 mg, 90%); mp 58–
60 °C. 1H NMR (400 MHz, CDCl3): δ = 8.11–8.08 (m, 2 H), 7.70–
7.68 (m, 2 H), 7.48–7.39 (m, 6 H), 7.30 (t, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.02, 151.14, 130.20, 128.81,
128.70, 128.31, 127.91, 127.37, 126.18, 124.08, 123.37. ESI-
HRMS: m/z calcd for C15H12NO [M + H]+: 222.0914; found:
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2866–2869