N-Heterocyclic Carbene (NHC)-Catalyzed One-Pot Aerobic Oxidative Synthesis of 2-Substituted Benzo[ d ]oxazoles, Benzo[ d ]thiazoles and 1,2-Disubstituted Benzo[ d ]imidazoles

Article abstract of DOI:10.1055/s-0036-1591524

N-Heterocyclic carbene (NHC), generated in situ from easily available N-heterocyclic imidazolium salt with air as terminal oxidant, has successfully been utilized as a cheap and efficient catalyst for one-pot aerobic oxidative synthesis of 2-arylbenzo[ d ]oxazoles, 2-substituted benzo[ d ]thiazoles, and 1,2-disubstituted benzo[ d ]imidazoles.

Full text of DOI:10.1055/s-0036-1591524

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
de
Q. Zhou et al.
Paper
Synthesis
N-Heterocyclic Carbene (NHC)-Catalyzed One-Pot Aerobic Oxida-
tive Synthesis of 2-Substituted Benzo[d]oxazoles, Benzo[d]thiazoles
and 1,2-Disubstituted Benzo[d]imidazoles
Quan Zhoua
Shu Liub
Ming Mab
He-Zhen Cuia
Xi Honga
Shuang Huanga
Jing-Fan Zhanga
Xiu-Feng Hou*a
Air
X
XH
R
R'
NHC
R
R'
O
N
NH2
X = O, S, NMe, NBu, NPh
R = aryl, styryl, alkyl
H2O
61 examples, up to 98% yield
green, easy-access catalyst
gram-scale
atom-economic
air as oxidant
0
0
0
0
0-
0
0
1
7-
5
1
3
4-
6
5
0
a Department of Chemistry, Fudan University, 220 Handan Rd.,
Shanghai 200433, P. R. of China
xfhou@fudan.edu.cn
b Technical Center for Industrial Product and Raw Material
Inspection and Testing, Shanghai Entry-Exit Inspection and
Quarantine Bureau, Shanghai 200135, P. R. of China
Received: 18.10.2017
Accepted after revision: 24.11.2017
Published online: 20.12.2017
N
nPr
N
N
DOI: 10.1055/s-0036-1591524; Art ID: ss-2017-h0674-op
N
HO
H
S
N
N
Abstract N-Heterocyclic carbene (NHC), generated in situ from easily
available N-heterocyclic imidazolium salt with air as terminal oxidant,
has successfully been utilized as a cheap and efficient catalyst for one-
pot aerobic oxidative synthesis of 2-arylbenzo[d]oxazoles, 2-substituted
benzo[d]thiazoles, and 1,2-disubstituted benzo[d]imidazoles.
11CH3
Pittsburgh compound B
COOH
Telmistartan
tBu
X
Key words N-heterocyclic carbene, organocatalysis, aerobic oxida-
tion, cyclization, benzazoles
N
Me
C
N
N
M
N
Five-membered heterocyclic rings, such as benzoxaz-
oles, benzothiazoles, and benzimidazoles are versatile
building blocks in biologically and therapeutically active
compounds, natural products, and functional materials,
etc.1 For example, telmisartan is a well-known angiotensin-
receptor blocker used for the treatment of essential hyper-
tension.2 Pittsburgh compound B is a positron emission to-
mography (PET) imaging agent for Alzheimers disease,3
which has entered the stages of clinical trials. In photore-
dox field, 2-arylbenzo[d]oxazole- or 2-aryl benzo[d]thi-
azole-fused iridium/rhodium complexes could function as
both the Lewis acid catalyst and the photocatalyst for asym-
metric transformations (Figure 1).4
Mainly, the synthetic protocol for benzo[d]oxazoles,
-thiazoles and -imidazoles could be classified into two
methods. First, various transition-metal-catalyzed cross-
coupling between benzo[d]oxazole, -thiazole, -imidazole
and expensive/toxic organometallic regents5 or intramolec-
ular ortho-arylation of o-haloanilides;6 second, ortho-amino-
phenol/benzenethiol/aniline coupling with aryl carboxylic
acid or analogues,7 aryl aldehydes,8 or benzyl alcohols.9 In
C
Me
M = Ir, Rh
X = O, S
tBu
X
Chiral Lewis acid catalyst
Figure 1 Molecules containing benzazole motif
the last few years, aerobic oxidative cyclization between
ortho-aminophenol/benzenethiol/aniline and aryl aldehydes
with the molecular oxygen/air as the terminal oxidant have
frequently been studied. Activated carbon,10 metal
nanoparticles,11 metal salts,12 aminoxyl radical 4-methoxy-
TEMPO,13 and cyanide14 could work as catalysts in the aero-
bic oxidative cyclization process. However, relatively high
catalyst loadings or toxic catalysts are required as well as
the scopes and types of substrates are limited in some case.
Recently, water as ‘ambiphilic catalyst’ was applied in the
process for the synthesis of various 2-arylbenzazoles;15
however, the substrates were limited to aromatic aldehydes.
Hence, an efficient and versatile catalyst was still needed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
Q. Zhou et al.
Paper
Synthesis
N-Heterocyclic carbene (NHC) is an important class of
organocatalyst in the field of umpolung reaction towards
aromatic aldehydes,16 which has been discovered to be a
good alternative to the toxic cyanides and utilized in the
benzoin condensation. More recently, NHC organocatalyst
utilizing oxidant or even molecular oxygen have been ap-
plied in various cascade reactions starting with aryl alde-
hydes.17
as the NHC precursor for further reaction optimization. De-
creasing the amount of base to 25 mol% led to an increased
NMR yield of up to 95% (entry 12, 90% isolated yield), while
further reducing the base amount, no better conversion
was achieved even under prolonged reaction time (entries
Table 1 Optimization of Reaction Conditionsa
Inspired from our group’s previous studies on NHC18
and 2-arylbenzo[d]oxazoles,19 we speculated that NHC
could be utilized in the aerobic oxidative synthesis of 2-ar-
ylbenzo[d]oxazole from 2-aminophenol derivatives and
benzaldehydes. Herein, we report a one-pot aerobic oxida-
tive synthesis of 2-arylbenzo[d]oxazoles, 2-substituted
benzo[d]thiazoles, and 1,2-disubstituted benzo[d]imidaz-
oles with in situ generated NHC from easy-available N-het-
erocyclic imidazolium salts.
NHC precursor
OH
K2CO3
O
N
O
xylene, 120 °C
NH2
1a
2a
3aa
Entry
NHC Precursor Time (h)
Base (equiv)
Yield (%)b
1
2
A
B
C
D
E
16
16
16
10
10
10
10
10
6
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.1
0.25
0.15
0.15
0.5
0.5
–
trace
64
3
79 (75)c
73
To test our hypothesis, the aerobic oxidative cyclization
was attempted between 2-amino-4-methylphenol (1a) and
benzaldehyde (2a) catalyzed by in situ generated NHC from
imidazolium salts (10 mol%) with K2CO3 (50 mol%) (Table
1). Initially, three imidazolium salts with different steric
hindered substitutions (Figure 2, NHC precursors A, B, C)
were tested as catalysts. To our delight, B and C could
smoothly afford the desired products in 64% and 79% yield,
respectively, while A showed no catalytic activity for this
transformation (Table 1, entries 1–3), which could result
from its steric hindered substitution. To consolidate this hy-
pothesis and improve the product yield, N-heterocyclic im-
idazolium salts D–I bearing less steric substitutions were
utilized as catalysts (entries 4–9). All these imidazolium
salts could afford the product in moderate to good yields.
Imidazolium salts with different counter anions slightly af-
fected this catalytic process, and the decrease of the catalyt-
ic activity was observed in the series I– > PF6– > Br– > Cl– (en-
tries 5–8). Probably, it would result from the counter-anion
effect on the imidazolium salts’ stability and solubility.20
Additionally, two benzo[d]imidazolium salts J and K, whose
in situ generated carbene were more stable under basic
condition,21 were also tested as NHC precursor and moder-
ate NMR yields were obtained by using NaOH as a stronger
base (entries 10, 11). Although the reaction using I was
complete in 6 hours and high conversion and 83% yield
were obtained, considering that the preparation of I in-
volved the use of highly toxic iodomethane, G was chosen
4
5
61
6
F
73
7
G
H
I
82
8
78
9
83
10
11
12
13
14
15
16
17
18
19
20
J
10
10
10
12
24
12
24
12
12
12
12
63d
K
G
G
G
–
G
G
G
G
G
64d
95 (90)c
74
81
tracee
tracef
traceg
48h
0.25
0.25
0.25
20i
80j
iPr
iPr
X–
R
R1
X–
N
R2
N
X–
+
N
N
R
N
N
+
+
N
N
iPr
N
nBu
+
+
N
I–
iPr
Cl–
B: R1 = R2 = Cy; X = Br
C: R1 = Cy, R2 nBu; X = I F: X = Br
D: R1 = R2 nBu; X = Br
G: X = I
H: X = PF6
E: X = Cl
J: R = Me; X = I
K: R = Et; X = Br
I
A
=
=
a Unless otherwise noted, the reactions were carried on a 1 mmol scale be-
tween 2-amino-4-methylphenol and benzaldehyde in a 15 × 150 mm tube
in xylene (3 mL, mixture of o-, m-, and p-xylene) in the presence of NHC pre-
cursor (10 mol%) and K2CO3 at 120 °C.
b Yield observed by 1H NMR spectroscopy.
c Isolated yield.
iPr
iPr
X–
R
R1
X–
N
R2
N
X–
N
+
N
R
N
N
+
+
N
N
iPr
+
N
Bu
+
N
d NHC Precursor (5 mol%), 10 mol% NaOH as base, O2.
e Without G.
I–
iPr
Cl–
B: R1 = R2 = Cy; X = Br
C: R1 = Cy, R2 = Bu; X = I
D: R1 = R2 = Bu; X = Br
E: X = Cl
F: X = Br
G: X = I
J: R = Me; X = I
K: R = Et; X = Br
I
f Under N2 atomsphere.
A
g Without base.
h DMF as solvent.
H: X = PF6
i EtOH as solvent, 70 °C.
j Toluene as solvent.
Figure 2 NHC precursors
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
Q. Zhou et al.
Paper
Synthesis
13, 14). Control experiments show that N-heterocyclic im-
idazolium salt, air, and base were indispensable (entries
15–17). When DMF, ethanol, and toluene were used as sol-
vent instead of xylene, no better yield was noticed and non-
polar aromatic solvent toluene was found to be more effec-
tive than polar solvents (DMF or ethanol) under the same
reaction conditions (entries 18–20). Notably, no benzoin
condensation product was observed in the reaction.17,22
With the optimal conditions in hand (Table 1, entry 12),
the scope and limitation of the reaction were examined
(Scheme 1). First, a wide range of aromatic aldehydes with
2-amino-4-methylphenol (1a) were found to be compati-
ble, delivering the corresponding 2-substituted benzo[d]ox-
azoles in good to excellent yields. Aromatic aldehydes with
electron-withdrawing or -donating substituents at the or-
tho-position 3aj–ao generated the target products in good
to excellent yields, which may be due to the benefit of or-
tho-substituted group in this oxidative cyclization process.
With substituents at the para- or meta-position, the yields
decrease slightly. Second, aromatic aldehydes with hetero-
cyclic rings were also tested. To our delight, the reaction
showed good tolerance to thiophene-2-carbaldehyde and
furan-2-carbaldehyde affording 3ap and 3aq, respectively.
More importantly, aromatic aldehydes containing nitrogen
atoms, for example, pyrrolyl, pyridinyl, and quinolinyl could
also give the corresponding products 3ar–au in moderate
yields. Furthermore, among the different ortho-aminophe-
nol derivatives, chloro-substituted and unsubstituted or-
tho-aminophenols afforded the related products 3ba–bd
and 3ca–ce, respectively, in good yields; 4-nitro-2-amino-
phenol could also give the desired products 3da–dd. Under
the optimized conditions, the strategy was not feasible for
the synthesis of 2-alkylbenzoxazoles or 2-aryloxazolines
from the corresponding nonaromatic fragment. In addition,
we noticed that when 2-fluorobenzaldehyde was used,
small amount of dibenz[b,f]-1,4-oxazepines 3ak′, 3bc′, and
3cc′ were generated via intermolecular cyclization besides
the aerobic oxidative products (see Supporting Informa-
tion).23
After examining the scope of the synthesis of 2-substi-
tuted benzo[d]oxazoles, we turned our attention to apply
this catalytic system to construct 2-substituted ben-
zo[d]thiazoles (Scheme 2). Different aromatic aldehydes in-
cluding ortho-, para-, and meta-substituted aromatic alde-
hyde were successfully fused with the 2-aminobenzenethi-
ol affording the 2-arylbenzo[d]thiazoles. These results
suggest that electron-donating functional groups have a
positive effect on the reaction conversion, while electron-
withdrawing ones revealed a slight negative effect (5a–j).
Additionally, cinnamaldehyde could also successfully afford
5k in moderate yield under the optimized conditions. More
importantly, alkyl aldehydes demonstrated good compati-
bility in this catalytic system, which afforded the corre-
sponding 2-alkylbenzo[d]thiazoles 5l–n in excellent yields.
The apparent success with respect to 2-arylbenzo[d]oxaz-
G (10 mol%)
K2CO3 (25 mol%)
OH
O
O
R1
1a–d
Ar/Het
Ar/Het
R1
R2
N
NH2
xylene (3 mL), air
120 °C, 10 h
R2
2
3
O
N
O
R
N
O
N
R
3aa: R = H, 90%
3ab: R = Me, 63%
3ac: R = tBu, 90%
3ad: R = OMe, 80%
3ae: R = F, 64%
3af: R = Cl, 65%
3ag: R = Br, 45%
3aj: R = OMe, 92%
3ak: R = F, 71%a,b
3al: R = Cl, 98%
3am: R = Br, 90%a,b
3an: R = OH, 89%
3ao: R = Me, 76%
R
3ah: R = Br, 53%
3ai: R = F, 30%
O
N
O
O
N
X
N
3as, 42%
O
N
N
G (10 mol%)
K2CO3 (25 mol%)
SH
S
N
3ap: X = S, 98%
3aq: X = O, 90%
3ar: X = NH, 25%
R
R
N
N
3au, 47%
CHO
3at, 47%a
xylene, 120 °C
air, 10 h
NH2
O
4
R
2
5
O
R
N
NO2
R
3da: R = H, 30%a
3db: R = Me, 25%
3dc: R = F, 39%c
N
R
Cl
O
N
S
N
S
S
N
S
N
3ba: R = 2-OMe, 89%
3bb: R = 2-Me, 90%
3bc: R = 2-F, 80%
3bd: R = 3-Br, 63%
R
5i, 90%
Br
O
S
3ca: R = 2-OMe, 98%
3cb: R = 2-Me, 97%
3cc: R = 2-F, 65%a,b
3cd: R = 4-Br, 68%
S
5e: R = Me, 70%
5f: R = OMe, 46%
5g: R = Br, 75%a
5h: R = F, 43%
5a: R = OH, 88%
5b: R = Br, 57%
5c: R = Me, 80%
5d: R = OMe, 90%
N
5j, 57%
5k, 63%
NO2
N
S
3dd, 33%
O
N
S
N
S
S
N
3ce, 97%
N
N
5m, 45%
5l, 90%
5n, 75%
Scheme 1 Aerobic oxidative synthesis of 2-arylbenzo[d]oxazoles. Re-
agents and conditions: 1 (1 mmol), 2 (1 mmol), xylene (3 mL), K2CO3 (25
mol%), G (10 mol%), 120 °C, 10 h, air. Isolated yields are given. a 5 mmol
scale; b K (5 mol%), NaOH (10 mol%), O2; c 3 mmol scale.
Scheme 2 Aerobic oxidative synthesis of 2-substituted benzo[d]thi-
azoles. Reactions conditions given in Table1 entry 12 were used. a NHC I
instead of G was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
Q. Zhou et al.
Paper
Synthesis
oles may benefit from the sulfur atom possessing more
electrons, and thus a stronger driving force for dehydroge-
native aromatization.24
were introduced into the catalytic system, 1,2-disubstituted
benzo[d]imidazoles 7ca–cf were successfully obtained in a
one-pot three-component synthesis approach (Scheme 3).
Furthermore, to demonstrate the practicability of this
method, the preparation of 2-arylbenzo[d]oxazoles 3ad,
3ac, 3am, and 2-arylbenzo[d]thiazole (5i) were tried on a
gram-scale (Figure 3). The desired aerobic oxidative synthe-
sis was proved to be effective with elongated time and/or
changing to oxygen atmosphere.
After the successful scope of constructing 2-arylben-
zo[d]oxazoles and 2-substituted benzo[d]thiazoles, we
tried to expand the catalytic system to the oxidative syn-
thesis of 2-substituted benzo[d]imidazoles.25 However, un-
der the optimized conditions, attempts to synthesize 2-ar-
ylbenzo[d]imidazoles from o-phenylenediamine with aryl
aldehydes were unsuccessful. According to previous re-
ports, one molecule of o-phenylenediamine was prone to
condense with two molecules of benzaldehyde, then isom-
erized to N-benzyl-2-arylimidazo[d]imidazoles.26 Thus, we
speculated that monoalkylated o-phenylenediamine in-
stead of o-phenylenediamine might promote the one-pot
synthesis of 1,2-disubstituted benzo[d]imidazoles (Scheme
3), which own broad-spectrum biological activities and
synthesis challenge.27 Two commercial N1-substituted o-di-
aminobenzenes [N1-methylbenzene-1,2-diamine (6a);
N1-phenylbenzene-1,2-diamine, (6b)] were then tried as
starting materials. To our delight, aerobic oxidative prod-
ucts 7aa–ae, ba, bb were formed in good isolated yields. Af-
ter these successes, we wondered whether the in situ al-
kylation of o-diaminobenzene could furnish the target aer-
obic oxidative products, so we tried 1-iodobutane as
alkylation reagent.28 When 1.5 equivalents of 1-iodobutane
O
O
O
N
N
3ac, 2.2 g (84%)a
3ad, 1.8 g (78%)
O
S
N
S
N
Br
5i, 1.5 g (70%)c
3am, 2.2 g (75%)b
Figure 3 Gram-scale reactions. Reactions were conducted in a 50 mL
tube on a 10 mmol scale, xylene (30 mL), K2CO3 (25 mol%), G (10
mol%), 120 °C, 48 h, air; isolated yield are shown. a Under O2 atmo-
sphere, 6 h; b K (5 mol%), NaOH (10 mol%), O2; c NHC I was used instead
of G.
Several experiments were carried out to have an insight
into the reaction mechanism (Scheme 4). We found that the
condensation product 3aa′ between 1a and benzaldehyde
was smoothly converted into 3aa in quantitative yield
(Scheme 4, A), which demonstrated the Schiff base phenol
might be one intermediate in the catalytic cycle. Addition-
ally, the aerobic oxidative process from imine 3aa′ to target
product 3aa was thought to involve free radical species.13a,29
To test the presence of a radical intermediate, two radical-
trapping experiments were performed. Both 2,6-di-tert-bu-
tyl-4-methylphenol (BHT) and 1,1-diphenylethene were
employed in the optimal conditions and the desired prod-
ucts were obtained in 70% and 77% yield (Scheme 4, B, C),
which indicated that this transformation is unlikely to in-
volve a radical intermediate.30
R'
O
R'
N
G (10 mol%)
NH
R
N
K2CO3 (25 mol%)
xylene, 120 °C
air, 10 h
NH2
7aa–ae, R = Me
7ba–bb, R = Ph
R
6a, R' = Me
6b, R' = Ph
2
Me
N
Me
N
Ph
N
R
N
N
N
R
R
7aa: R = Me, 50%
7ab: R = OMe 60%
7ba: R = 2-Br, 41%
7bb: R = 4-OMe, 51%
7ac: R = F, 87%
7ad: R = Br, 49%
7ae: R = tBu, 64%
OH
G (10 mol%)
K2CO3 (25 mol%)
(i) G (10 mol%)
K2CO3 (25 mol%)
OH
NH2
NH2
O
xylene
120 °C
N
Ar/Het
3aa
(A)
O
Ar/Het
xylene, 120 °C
air, 10 h
N
(ii) BuI (1.5 equiv)
xylene, 120 °C
air, 10 h
R
80%
NH2
N
R
(isolated yield)
3aa'
(monitored by TLC)
2
6c
7ca–cf
G (10 mol%)
K2CO3 (25 mol%)
BHT (100 mol%)
OH
N
O
N
N
S
N
N
3aa
(B)
(C)
R
xylene, 120 °C
air, 10 h
70%
(NMR yield)
NH2
N
H3C
7cc: R = OMe, 72%
7cd: R = F, 65%
7ce: R = Cl, 32%
7cf : R = Br, 27%
7ca, 69%
7cb, 74%
G (10 mol%)
OH
K2CO3 (25 mol%)
O
3aa
Scheme 3 Aerobic oxidative synthesis of N-substituted-2-arylben-
zo[d]imidazoles. Reactions were carried out on a 1 mmol scale; isolated
1,1-diphenylethene (300 mol%)
xylene, 120 °C, air, 10 h
77%
(NMR yield)
NH2
yields are shown.
Scheme 4 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
Q. Zhou et al.
Paper
Synthesis
Finally, on the basis of the above results and related
NHC-catalyzed aerobic reaction,17 a tentative mechanism is
proposed for 2-arylbenzo[d]oxazoles as shown in Scheme
5. N-Heterocyclic carbene i is first generated in situ by
deprotonation of the N-heterocyclic imidazolium salt in the
presence of K2CO3, which plays a role of cyanide, and under-
goes a nucleophilic addition to imine C=N bond,14 forming
the intermediate ii. Then the aldehyde proton (red font) is
transferred to molecular oxygen,22 which forms the inter-
mediate iii and HOO–. HOO– decomposes to hydroxide ion
and O2 under basic solution. Driven by the aromatization
force and the deprotonation of HX, nucleophilic attack from
the anion X– forms the aerobic oxidative product with con-
comitant regeneration of the NHC catalyst.17o Meanwhile,
hydroxide ion traps the proton, forming the by-product,
water.31
The experimental section has no title; please leave this line here.
All commercially available compounds were purchased and used
without purification. Reaction temperatures are reported as the tem-
perature of the bath surrounding the reaction vessel, unless other-
wise stated. Toluene, xylenes (mixture of o-, m-, and p-xylene), DMF,
CH2Cl2, and EtOH were purchased from commercial vendors and used
without purification.
Analytical TLC was performed on GF 254 plates. Flash chromatogra-
phy was performed on silica gel (200–300 mesh) by standard techni-
cal eluting with solvents as indicated. 1H and 13C NMR spectra were
recorded at 295 K in CDCl3 or DMSO-d6. The residual solvent signals
were used as references and the chemical shifts converted to the TMS
scale (CDCl3: δH = 7.26, δC = 77.16; CD3OD: δH = 3.31, δC = 49.00;
DMSO-d6: δH = 2.50, δC = 39.52). For 19F NMR, chemical shifts refer to
an external calibration using CFCl3 (δ = 0.00). Data for 1H NMR are re-
ported as follows: chemical shift, multiplicity (standard abbrevia-
tions), coupling constants (J) in Hz, and integration. Mass spectromet-
ric data were obtained using ESI (electrospray ionization, Q-Tof, posi-
tive ion) mode, and GC-MS (electron impact ionization). All FT-IR
spectra of solids were recorded as KBr pellets. Melting points of the
reported values are tested in capillary auxiliary.
R1
R2
N
N
X
H2O
K2CO3
– HX
R2
X
N
2-Arylbenzo[d]oxazoles 3 and 2-Substituted Benzo[d]thiazoles 5;
General Procedure A
NH2
O
R
R1
N
N
N
X
H
X
H
R
A 15 × 150 mm glass tube was charged with o-aminophenol (1)/ben-
zenethiol (4) (1 mmol) and the corresponding aldehyde (1 mmol), xy-
lenes (3 mL), K2CO3 (34 mg, 0.25 mmol), and NHC precursor G (26 mg,
0.1 mmol). The glass tube containing the mixture was lowered into a
pre-heated oil bath, and the mixture was stirred vigorously for 10 h
under air atmosphere. After completion of the reaction, the mixture
was diluted with EtOAc, and filtered. The organic solution was con-
centrated under vacuum, and the residue was purified by silica gel
column chromatography, which afforded the corresponding oxidative
cyclization product.
H
H
R
i
air
H2O
R2
N
R2
N
N
N
X
X
H
H
N
R1
H
H
R
N
R1
O
R
N-Substituted 2-Arylbenzo[d]imidazoles 7; General Procedures B
iii
ii
and C
OH–
–OOH
Procedure B (for 7aa–ae): A 15 × 150 mm glass tube was charged with
6a (195 mg, 1 mmol; salts with two molecules of HCl) and Et3N (212
mg, 2.1 mmol). The mixture was stirred at 120 °C by immersing the
glass tube in a preheated oil-bath for 0.5 h, then the corresponding
aromatic aldehyde (1 mmol), NHC precursor G (10 mol%), and K2CO3
(25 mol%) were added sequentially. The resulting mixture was stirred
at 120 °C using a preheated oil bath for an additional 10 h. After com-
pletion of the reaction, the solution was transferred into a 25 mL
round-bottomed flask, and concentrated under reduced pressure. The
residue was purified by flash silica column chromatography, which
afforded the targeted product.
OH– + 1/2 O2
Scheme 5 Proposed mechanism for 2-arylbenzo[d]oxazoles
In summary, N-heterocyclic carbene, generated in situ
from an easily available N-heterocyclic imidazolium salt
was discovered to be an efficient catalyst for one-pot aero-
bic oxidative synthesis of 2-arylbenzo[d]oxazoles, 2-substi-
tuted benzo[d]thiazoles as well as 1,2-disubstituted ben-
zo[d]imidazoles. The strategy presents high efficiency,
atom economy, and good tolerance over broad scopes of
substrates. Both catalyst and oxidant are environment-
friendly and easily accessible. The gram-scale preparation
demonstrates that this method is practical. Initial mecha-
nistic studies demonstrated that the process does not in-
volve free radicals. Meanwhile, the extension of this cata-
lytic system for the preparation of other useful heterocyclic
compounds is in progress in our laboratory.
Procedure C (for 7ba–bb): A 15 × 150 mm tube was charged with 6b
(184 mg, 1 mmol), the corresponding aromatic aldehyde (1 mmol),
NHC precursor G (10 mol%), and K2CO3 (25 mol%). The mixture was
stirred at 120 °C by immersing the glass tube in a preheated oil bath
for 10 h. After completion of the reaction, the solution was trans-
ferred into a 25 mL round-bottomed flask, and concentrated under
reduced pressure. The residue was purified by flash silica column
chromatography, which afforded the targeted product.
Details of all imidazolium salts and products are given in the Sup-
porting Information. Analytical and spectroscopic data for some se-
lected compounds are given below.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
Q. Zhou et al.
Paper
Synthesis
2-(3-Fluorophenyl)-5-methylbenzo[d]oxazole (3ai)32a
13C NMR (101 MHz, CDCl3): δ = 177.5, 153.1, 134.5, 125.8, 124.5,
122.5, 121.5, 43.4, 33.4, 26.0, 25.8.
Following general procedure A on a 1 mmol scale, 3ai was obtained as
a white solid; yield: 154 mg (30%); mp 83–85 °C; Rf = 0.3 (PE/EtOAc
50:1).
MS: m/z (%) = 217 (12), 162 (100), 149 (95).
FT-IR (KBr): 3074, 3016, 2968, 2930, 1559, 1469, 1264, 1210, 874, 806
2-Isopropylbenzo[d]thiazole (5m)32d
cm–1
.
Following general procedure A on a 1 mmol scale, 5m was obtained
as a colorless oil; yield: 80 mg (45%); Rf = 0.3 (PE/EtOAc 100:1).
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.7 Hz, 1 H), 7.94 (d, J = 9.4
Hz, 1 H), 7.57 (s, 1 H), 7.54–7.41 (m, 2 H), 7.31–7.15 (m, 2 H), 2.50 (s, 3
H).
FT-IR (neat): 3436, 2966, 2936, 2869, 1518, 1456, 1437, 1094, 1037,
1013, 758, 729 cm–1
.
13C NMR (101 MHz, CDCl3): δ = 162.8 (d, J = 246.8 Hz), 161.8, 149.0,
142.1, 134.6, 130.5 (d, J = 8.1 Hz), 129.3 (d, J = 8.6 Hz), 126.6, 123.2 (d,
J = 2.6 Hz), 120.1, 118.3 (d, J = 21.3 Hz), 114.4 (d, J = 24.0 Hz), 110.0,
21.5.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.9 Hz, 1 H), 7.84 (dd, J = 8.0,
0.5 Hz, 1 H), 7.49–7.38 (m, 1 H), 7.38–7.29 (m, 1 H), 3.43 (hept, J = 6.9
Hz, 1 H), 1.49 (d, J = 6.9 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 178.6, 153.1, 134.7, 125.8, 124.5,
122.6, 121.5, 34.1, 22.9
19F NMR (376 MHz, CDCl3): δ = –111.90 (td, J = 8.9, 5.8 Hz).
MS: m/z (%) = 227 (100), 226 (38), 78 (38).
MS: m/z (%) = 177 (32), 162 (100).
2-Ethylbenzo[d]thiazole (5n)32d
5-Methyl-2-(quinolin-2-yl)benzo[d]oxazole (3au)
Following general procedure A on a 1 mmol scale, 3au was obtained
as a grey solid; yield: 101 mg (47%); mp 141–143 °C; Rf = 0.3 (PE/EtO-
Ac 15:1).
Following general procedure A on a 1 mmol scale, 5n was obtained as
a colorless oil; yield: 123 mg (75%); Rf = 0.2 (PE/EtOAc 100:1).
FT-IR (neat): 3443, 2973, 2934, 2879, 1522, 1455, 1436, 1310, 1066,
947, 759, 729 cm–1
.
FT-IR (KBr): 3443, 3051, 2920, 2856, 1594, 1542, 1503, 1350, 1339,
1314, 1075, 959, 835, 796, 762, 594 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 8.0 Hz, 1 H), 7.83 (dd, J = 8.0,
0.5 Hz, 1 H), 7.44 (ddd, J = 8.2, 7.3, 1.2 Hz, 1 H), 7.37–7.29 (m, 1 H),
3.19–3.06 (m, 2 H), 1.47 (dd, J = 9.9, 5.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.5, 153.2, 135.0, 125.8, 124.6,
122.5, 121.5, 27.8, 13.8.
1H NMR (400 MHz, CDCl3): δ = 8.42 (t, J = 11.7 Hz, 1 H), 8.34 (t, J = 6.8
Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 7.85 (t, J = 9.5 Hz, 1 H), 7.79 (t, J = 7.6
Hz, 1 H), 7.69–7.52 (m, 3 H), 7.24 (d, J = 8.3 Hz, 1 H), 2.50 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 161.6, 149.5, 148.0, 146.0, 142.0,
137.1, 134.9, 130.3, 130.2, 128.6, 128.0, 127.6, 127.5, 120.5, 120.2,
110.8, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C9H10NS: 164.0534; found:
164.0528.
HRMS (ESI): m/z [M + H]+ calcd for C17H13N2O: 261.1028; found:
261.1022.
2-[4-(tert-Butyl)phenyl]-1-methyl-1H-benzo[d]imidazole (7ae)32e
Following general procedure B, 7ae was obtained as a white solid;
yield: 170 mg (64%); Rf = 0.3 (PE/EtOAc 10:1); mp 152–154 °C.
5-Nitro-2-(thiophen-2-yl)benzo[d]oxazole (3dd)32b
Following general procedure A on a 1 mmol scale, after completion of
the reaction finished, the solution was concentrated under reduced
pressure, and the residue was recrystallized from PE/EtOAc (10:1),
which afforded 3dd as a red colored solid; yield: 81 mg (33%); mp
182–183 °C; Rf = 0.4 (PE/EtOAc 10:1).
FT-IR (KBr): 3051, 2965, 2943, 2901, 2862, 1610, 1485, 1472, 1460,
1434, 1386, 1328, 835, 733, 604 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 3.2 Hz, 1 H), 7.72 (d, J = 6.8
Hz, 2 H), 7.53 (t, J = 15.2 Hz, 2 H), 7.35 (d, J = 21.4 Hz, 3 H), 3.92–3.70
(m, 3 H), 1.40 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 153.9, 152.9, 142.9, 136.6, 129.1,
127.2, 125.6, 122.6, 122.3, 119.7, 109.5, 34.8, 31.6, 31.2.
FT-IR (KBr): 3109, 3080, 1620, 1527, 1348, 1264, 995, 809, 745, 720,
691 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.56 (d, J = 1.8 Hz, 1 H), 8.29 (dd, J =
8.9, 2.0 Hz, 1 H), 8.04 (dd, J = 10.3, 4.0 Hz, 2 H), 7.98 (d, J = 8.9 Hz, 1 H),
7.33 (t, J = 4.3 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2: 265.1705; found:
265.1699.
13C NMR (101 MHz, DMSO-d6): δ = 161.7, 154.1, 145.5, 142.3, 133.9,
132.4, 129.6, 127.8, 121.7, 115.7, 111.9.
2-(2-Bromophenyl)-1-phenyl-1H-benzo[d]imidazole (7ba)32f
Following general procedure C, 7ba was obtained as a yellow solid;
yield: 145 mg (41%); mp 178–180 °C; mp 178–180 °C; Rf = 0.2
(PE/EtOAc 10:1).
HRMS (ESI): m/z [M + H]+ calcd for C11H7N2O3S: 247.0177; found:
247.0172.
FT-IR (KBr): 3064, 3013, 1597, 1495, 1452, 1426, 1383, 1323, 771,
2-Cyclohexylbenzo[d]thiazole (5l)32c
758, 741, 728, 697 cm–1
.
Following general procedure A on a 1 mmol scale, 5l was obtained as
a colorless oil; yield: 160 mg (90%); Rf = 0.35 (PE/EtOAc 100:1).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.6 Hz, 1 H), 7.55 (d, J = 7.9
Hz, 1 H), 7.47 (d, J = 6.7 Hz, 1 H), 7.43–7.22 (m, 11 H).
13C NMR (101 MHz, CDCl3): δ = 151.6, 142.8, 135.9, 135.7, 132.8,
132.5, 132.4, 131.1, 129.4, 128.1, 127.0, 126.7, 123.7, 123.6, 123.0,
120.3, 110.6.
FT-IR (neat): 3429, 3071, 2926, 2851, 1514, 1448, 1436, 1313, 1244,
1146, 1124, 1094, 1014, 992, 757, 728 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.0 Hz, 1 H), 7.81 (dd, J = 7.9,
0.4 Hz, 1 H), 7.48–7.36 (m, 1 H), 7.29 (dt, J = 12.5, 2.7 Hz, 1 H), 3.08 (tt,
J = 11.7, 3.6 Hz, 1 H), 2.19 (dd, J = 13.3, 2.1 Hz, 2 H), 1.93–1.80 (m, 2 H),
1.79–1.70 (m, 1 H), 1.62 (qt, J = 12.2, 6.1 Hz, 2 H), 1.51–1.35 (m, 2 H),
1.35–1.23 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H14BrN2: 349.0340 (100.0%),
351.0320 (97.3%); found: 349.0335 (100.0%), 351.0315 (97.3%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
Q. Zhou et al.
Paper
Synthesis
2-(4-Methoxyphenyl)-1-phenyl-1H-benzo[d]imidazole (7bb)
Lan, J.; Wu, D.; You, J. Angew. Chem. Int. Ed. 2015, 54, 14008.
(m) Ackermann, L.; Barfüsser, S.; Pospech, J. Org. Lett. 2010, 12,
724.
Following general procedure C, 7bb was obtained as a white solid;
yield: 154 mg (51%); mp 136–138 °C; Rf = 0.3 (PE/EtOAc 10:2).
(6) Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73,
3452; and references cited therein.
FT-IR (KBr): 3055, 3039, 2991, 2939, 2834, 1609, 1494, 14833, 1451,
1381, 1324, 1250, 1172, 1062, 831, 749, 699, 604 cm–1
.
(7) (a) Terashima, M.; Ishii, M.; Kanaoka, Y. Synthesis 1982, 484.
(b) Bourgrin, K.; Loupy, A.; Soufiaoui, M. Tetrahedron 1998, 54,
8055. (c) Pottorf, R. S.; Chadha, N. K.; Katkevics, M.; Ozola, V.;
Suna, E.; Ghane, H.; Regberg, T.; Player, M. R. Tetrahedron Lett.
2003, 44, 175.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.0 Hz, 1 H), 7.57–7.46 (m, 5
H), 7.33 (d, J = 7.5 Hz, 3 H), 7.28–7.22 (m, 2 H), 6.83 (d, J = 8.8 Hz, 2 H),
3.81 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.5, 152.4, 143.0, 137.2, 130.9,
(8) For oxidative cyclization synthesis, see: (a) Chang, J.; Zhao, K.;
Pan, S. Tetrahedron Lett. 2002, 43, 951. (b) Varma, R. S.; Saini, R.
K.; Prakash, O. Tetrahedron Lett. 1997, 38, 2621. (c) Praveen, C.;
Kumar, K. H.; Muralidharan, D.; Perumal, P. T. Tetrahedron 2008,
64, 2369. (d) Srivastava, R. G.; Venkataramani, P. S. Synth.
Commun. 1988, 18, 1537. (e) Bardajee, G. R.; Mohammadi, M.;
Kakavand, N. Appl. Organomet. Chem. 2016, 30, 51.
129.8, 128.5, 127.5, 123.0, 122.8, 122.3, 119.5, 113.7, 110.2, 55.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2O: 301.1341; found:
301.1348.
Funding Information
(9) For dehydrogenative coupling reaction of benzyl alcohols with
2-aminophenol or derivatives, see: (a) Shi, X.; Guo, J.; Liu, J.; Ye,
M.; Xu, Q. Chem. Eur. J. 2015, 21, 9988. (b) Khalafi-Nezhad, A.;
Panahi, F. ACS Catal. 2014, 4, 1686. (c) Shiraishi, Y.; Sugano, Y.;
Tanaka, S.; Hirai, T. Angew. Chem. Int. Ed. 2010, 49, 1656.
(d) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi,
O.; Williams, J. M. J. Org. Lett. 2009, 11, 2039.
We are grateful for the financial support by the National Science
Foundation of China (Grant No. 21271047), General Administration of
Quality Supervision, Inspection and Quarantine of China (No.
2015IK217, 2016IK225), and ShanXi Science and Technology Depart-
ment, China (Project No. MH2014-07).
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Lett. 2003, 5, 3713.
Supporting Information
(11) (a) Kidwai, M.; Bansal, V.; Saxena, A.; Aerryb, S.; Mozumdar, S.
Tetrahedron Lett. 2006, 47, 8049. (b) Maleki, B.; Baghayeri, M.;
Vahdat, S. M.; Mohammadzadeh, A.; Akhoondi, S. RSC Adv. 2015,
5, 46545. (c) Khalafi-Nezhad, A.; Panahi, F.; Yousefi, R. J. Iran.
Chem. Soc. 2014, 11, 1311. (d) Tang, L.; Guo, X.; Yang, Y.; Zha, Z.;
Wang, Z. Chem. Commun. 2014, 50, 6145. (e) Banerjee, S.; Payra,
S.; Saha, A.; Sereda, G. Tetrahedron Lett. 2014, 55, 5515.
(f) Sharma, H.; Singh, N.; Jang, D. O. Green Chem. 2014, 16, 4922.
(g) Yang, D.; Zhu, X.; Wei, W.; Sun, N.; Yuan, L.; Jiang, M.; You, J.;
Wang, H. RSC Adv. 2014, 4, 17832. (h) Brahmachari, G.; Laskar,
S.; Barik, P. RSC Adv. 2013, 3, 14245. (i) Yang, D.; Liu, P.; Zhang,
N.; Wei, W.; Yue, M.; You, J.; Wang, H. ChemCatChem 2014, 6,
3434.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591524.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H