Selective Aerobic C-H Amination of Phenols with Primary Amines over Copper toward Benzoxazoles

Article abstract of DOI:10.1021/acs.orglett.7b01061

Using O₂ as the oxidant, the benzoxazole frameworks can be directly constructed from the readily available phenols and primary amines in the presence of NH₄PF₆ over copper under mild conditions. Mechanistic studies showed

Full text of DOI:10.1021/acs.orglett.7b01061

Letter
pubs.acs.org/OrgLett
Selective Aerobic C−H Amination of Phenols with Primary Amines
over Copper toward Benzoxazoles
Long Liu,† Liang-Wei Qian,† Shaofeng Wu,† Jianyu Dong,*,† Qing Xu,‡ Yongbo Zhou,*,†
and Shuang-Feng Yin†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, China
S
* Supporting Information
ABSTRACT: Using O2 as the oxidant, the benzoxazole
frameworks can be directly constructed from the readily
available phenols and primary amines in the presence of
NH4PF6 over copper under mild conditions. Mechanistic
studies showed that a novel mechanism involving biphenyl-
diols and o-quinones very possibly takes effect in the reaction,
because both can selectively give the benzoxazoles under the reaction conditions. An unprecedented unstrained Caryl−Caryl bond
cleavage takes place in the reaction.
ince benzoxazole skeletons are ubiquitous structures
occurring in numerous natural products, biologically active
prefunctionalized substrates, which are not easily available,
usually more expensive and consequently the reaction
procedures always suffer from low atom- and step-economy. In
comparison with above methods, using the abundant and easily
available phenols and primary amines instead of the function-
alized substrates should be a more straightforward approach for
benzoxazole framework construction. Yet, this ideal strategy has
not been realized so far.
S
compounds, and function-oriented materials,1 considerable
efforts have been paid to exploring new and efficient methods
to construct these motifs.2−6 Condensation of 2-aminophenols
with aldehydes, carboxylic acids, or benzylic compounds are
typical strategies (Scheme 1, a).2 Intermolecular coupling
Aerobic oxidation of phenols is a fascinating topic since it is
relevant to biosynthesis.7 Because of the facile oxidation of
phenols to structurally diverse compounds such as ortho-
oxidation products, coupling products, polymers and etc., their
selective transformation is thus very challenging and has fueled
much research.7,8 In recent years, great advancements have been
made in this field.8−10 For example, selective oxygenations of
phenols to para- or ortho-quinones have been well devel-
oped,9a−e and the cross-couplings of phenols with secondary
amines have also been achieved.10
Scheme 1. Strategies toward Benzoxazoles
Herein, we report an aerobic C−H amination and annulation
of phenols with primary amines over copper for the construction
of the benzoxazole skeletons. This selective transformation is
conducted under mild conditions, in which the diverse oxidation
products of phenols are converted into benzoxazoles. Interest-
ingly, the biphenyldiols could be transformed into benzoxazoles
via an unstrained Caryl−Caryl bond cleavage, which is not
recognized.11
We commenced our study by the reaction of 2,4-di-tert-
butylphenol (1a) and butan-1-amine (2a, 2.0 equiv) by the use of
CuPF6 (30 mol %) as catalyst in DCM at 30 °C under O2 for 24
h;9a−d the desired product 5,7-di-tert-butyl-2-propylbenzo[d]-
oxazole (3a) was obtained in 30% GC yield (Table 1, entry 1).
reactions of halogenated phenols with amidines, 1,2-dihalo-
genated aromatics with amides, as well as intramolecular
reactions of ortho-substituted acyl anilides are also developed
as alternative effective ways for benzoxazole construction
(Scheme 1, b−d).3−5 Despite these notable advances, one
common limitation is that they all require the use of
Received: April 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Information (SI), Table S1). The reaction could also proceed
under air, affording a 53% yield of 3a (Table 1, entry 23).
With the optimized conditions in hand, the scope and
generality of this reaction were investigated next. The reaction of
2,4-di-tert-butylphenol 1a and 2.0 equiv of butan-1-amine 2a
gave 3a in 65% isolated yield (Table 2, entry 1). Long-chain
Table 1. Optimization of the Reaction Conditions
b
entry
[Cu]
additive
solvent
yield (%)
1
CuPF6
Cu
none
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
30
a b
,
Table 2. Substrate Scope
2
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
none
26
3
CuCl
Cul
11
4
24
5
Cu2O
CuCl2
Cu(OAc)2
CuO
none
Cu
22
6
trace
trace
trace
nd
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
trace
trace
trace
trace
11
Cu
KPF6
Cu
NaPF6
Cu
NH4I
Cu
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
Cu
CHCl3
CH3CN
toluene
DMSO
DCM
DCM
DCM
DCM
DCM
9
Cu
trace
trace
trace
37
Cu
Cu
c
Cu
d
Cu
10
ce
,
Cu
45
cef
, ,
Cu
69
cefg
, , ,
Cu
53
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), [Cu] (30 mol
%), and additive (30 mol %) in the solvent (2 mL) at 30 °C under O2
b
for 24 h. GC yield using dodecane as an internal standard.
c
d
e
Anhydrous CaSO4 (200 mg). 4 Å molecular sieves (200 mg). 23
f
g
°C. Cu 60 mol %, NH4PF6 45 mol %. Under air.
Due to the concern for the high cost of CuPF6, we envisioned
utilizing much cheaper copper sources, and the hexafluoro-
−
phosphate anion (PF6 ) could generate CuPF6 in situ, which
might promote this transformation. Based on this hypothesis, a
series of copper sources with NH4PF6 were screened. Copper
powder is superior to the Cu(I) and Cu(II) complexes, including
CuCl, CuI, Cu2O, CuCl2, Cu(OAc)2, and CuO, and 3a was
obtained in 26% yield (Table 1, entries 2−8). No desired product
was observed in the absence of a copper salt (Table 1, entry 9).
NH4PF6 was essential for the reaction, and only a trace of 3a was
detected in the absence of it (Table 1, entry 10). However, the
reaction was restrained by replacement of NH4PF6 with KPF6 or
NaPF6, probably due to their poor solubility in the solvent (Table
1, entries 11 and 12). The addition of NH4I resulted in a trace of
a
Reaction conditions:1 (0.2 mmol), amine compounds 2 (2.0 equiv),
Cu (60 mol %), NH4PF6 (45 mol %), anhydrous CaSO4 (200 mg) in
DCM (2 mL) at 23 °C under O2 for 24 h. Isolated yields.
b
amines such as hexan-1-amine and dodecan-1-amine were
suitable for the reaction, giving the corresponding products in
64% and 58% yields, respectively (Table 2, entries 2 and 3).
Propan-1-amine gave a relatively lower yield (45%, Table 2, entry
4), probably because of its strong volatility. When 3-
methylbutan-1-amine was employed as the substrate, the desired
product was obtained in a much lower yield (40%), probably due
to the steric effect (Table 2, entry 5). 2-(Cyclohex-1-en-1-
yl)ethan-1-amine was tolerated in this transformation, forming
the corresponding products in 30% yield (Table 2, entry 6). For
phenyl substituted amines, benzylamine could not be trans-
formed into the corresponding benzoaxzole (Table 2, entry 7).
Whereas, by extension of the carbon chain, a good yield (61%)
could be obtained (Table 2, entries 8−10). Our effort toward an
electron-poor amine exemplified by 2,2,2-trifluoro ethan-1-
amine failed (Table 2, entry 11). Next, a range of substituted
phenols were examined by the reactions with butan-1-amine. It
was found that strong electron-donating substituents on phenols
were beneficial for the reaction. For example, cumenyl and tert-
amyl groups on the para-position gave the corresponding
+
3a, illustrating that the NH4 cation did not contribute to this
transformation (Table 1, entry 13). For solvents, DCM was
identified as being optimal (Table 1, entries 14−18). Notably,
when anhydrous CaSO4 (200 mg) was added to remove the
water that was generated during the reaction, the yield of 3a was
improved to 37% (Table 1, entry 19). Whereas, when 4 Å
molecular sieves (200 mg) were used, 3a was only obtained in
10% yield (Table 1, entry 20). The reaction was sensitive to the
temperature, as a decrease in the reaction temperature to 23 °C
gave a higher yield of 3a (45% Table 1, entry 21). A significant
improvement was achieved by tuning the loading of the copper
powder and NH4PF6, and a good yield (69%) of 3a was gained in
the presence of 60 mol % of copper powder and 45 mol % of
NH4PF6 (Table 1, entry 22; for details, see Supporting
B
DOI: 10.1021/acs.orglett.7b01061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
products in 68% and 67% yields, respectively (Table 2, entries 12
and 13). While 2-(tert-butyl)-4-isopropylphenol was used, the
yield decreased to 43% (Table 2, entry 14). Other electron-rich
phenols were also determined to be suitable for this trans-
formation with satisfactory yields (60−61%, Table 2, entries 15−
17). However, by the reaction of 2,4-di-tert-butyl-5-methylphe-
nol, having greater electron density, no desired product was
observed, which is probably attributed to its strong steric
hindrance (Table 2, entry 18).
Given that phenols could be easily oxidized to ortho-quinones
and homocoupling products under aerobic oxidative conditions
over cooper,7−9 control experiments involving these side
products were performed to gain mechanistic details of this
reaction. First, 3,5-di-tert-o-quinone 1A was reacted with 2a
under the optimized conditions, affording 3a in 88% isolated
yield (Scheme 2, eq 1). When the homocoupling product
cleavage. Other than aromatic ring-opening reactions,9a,12,13
until now, this type of unstrained Caryl−Caryl bond cleavage has
not been reported. In addition, an adduct (D1) of 1AA with an
amine that was the probable intermediate was trapped by GC-
MS (Scheme 2, eq 4; see SI for details). Unfortunately, the
attempt failed to isolate pure D1, which was easily transformed
into 3a, with concomitant release of unknown side products.
Although the specific mechanism remains unclear, tentative
pathways were proposed based on the above results and
literature reports.6f,9a,12,14,15 First, CuPF6 is formed in situ from
the Cu powder and NH4PF6 under O2 (Scheme 3. eq I). Phenol 1
Scheme 3. Possible Reaction Mechanism
Scheme 2. Control Experiments
is oxidized to biphenyldiol A in the present of O2, copper, and
amine.9a Biphenyldiol A is oxidized by O2 over copper salt to
generate diphenoquinone B.12 Diphenoquinone B16 undergoes
an addition reaction with amine 2 leading to an amino-
substituted intermediate C, and C is subsequently oxidized to
imine intermediate D.14 An oxidative C−C bond cleavage takes
place to give intermediate E. Finally, the desired product 3 is
produced via tautomerism of E and subsequent intramolecular
cyclization (Scheme 3, path a).6f On the other hand, phenol 1 is
oxidized to ortho-quinone F, and F is easily converted into 3 by a
nucleophilic addition of an amine and intramolecular cyclization
(Scheme 3, path b).15
In summary, we have developed a novel and direct synthesis
toward benzoxazole frameworks from readily available phenols
and primary amines over cooper under mild aerobic conditions.
Oxidation products of phenols such as biphenyldiols and ortho-
quinones could be selectively converted into the annulation
products, which might be the reaction intermediates. A unique
Caryl−Caryl bond cleavage is involved in the procedure, which
provides a new dimension of inert C−C bond activation. Further
investigation on the mechanism and the scope of the reaction is
currently underway in our laboratory.
biphenyldiol 1AA was employed as the substrate under similar
conditions, 3a could also be afforded in 73% GC yield (based on
0.1 mmol, Scheme 2, eq 2). Noting that a catalytic amount of Cu
resulted in only a trace of product, the loading of Cu was
increased to 1.4 equiv, affording 3a in 80% GC yield. These
results illustrated that both ortho-quinone and biphenyldiol
probably served as the intermediates in this annulation reaction,
and stoichiometric Cu was required for the transformation of
biphenyldiol to benzoxazoles. Indeed, the homocoupling
product 1AA could be observed in 56% yield in 10 min under
the optimized reaction conditions. After the reaction was
completed, a trace of 1AA remained, in which 1AA was
converted into 3a. Only a 51% yield of 1AA was observed in the
absence of 2a, showing that the amines could also act as a ligand
and accelerate the oxidative transformation of phenols (Scheme
2, eq 3). Notably, the path via 1AA that discarded half of 1a
lowered the total yield of the product 3a, which also suggested
that another reaction pathway should be involved for the
reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01061.
Experimental procedures, full spectroscopic data, copies of
1H and 13C NMR data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
It was particularly noted that the formation of benzoxazoles
from biphenyldiols proceeded via an intriguing Caryl−Caryl bond
*E-mail: djyustc@hotmail.com.
*E-mail: zhouyb@hnu.edu.cn.
C
DOI: 10.1021/acs.orglett.7b01061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(f) Rolff, M.; Schottenheim, J.; Decker, H.; Tuczek, F. Chem. Soc. Rev.
2011, 40, 4077.
Yongbo Zhou: 0000-0002-3540-8618
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the National NSF of China (Grant Nos.
21573065, 21172062, and 21273066) and the NSF of Hunan
Province (Grant No. 2016JJ1007) is appreciated.
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D
DOI: 10.1021/acs.orglett.7b01061
Org. Lett. XXXX, XXX, XXX−XXX