Unexpectedly Simple Synthesis of Benzazoles by tBuONa-Catalyzed Direct Aerobic Oxidative Cyclocondensation of o-Thio/Hydroxy/Aminoanilines with Alcohols under Air

Article abstract of DOI:10.1002/chem.201501184

tBuONa-catalyzed direct aerobic oxidative cyclocondensation reactions of readily available alcohols and o-thio/hydroxy/aminoanilines under air have been developed and provide an efficient, practical, and green method for the synthesis of benzazoles. Mechanistic studies revealed that o-substituted anilines promote the initial aerobic alcohol-oxidation step, which explains the high reactivity and success of this unexpectedly simple and practical cyclocondensation method. Simple and straight: tBuONa-catalyzed direct aerobic oxidative cyclocondensation reactions of readily available alcohols and o-thio/hydroxy/aminoanilines under air provide an efficient, practical, and green method for the synthesis of benzazole heterocycles (see scheme). Mechanistic studies revealed that o-substituted anilines promote the initial aerobic alcohol-oxidation step.

Full text of DOI:10.1002/chem.201501184

DOI: 10.1002/chem.201501184
Communication
&
Synthetic Methods
Unexpectedly Simple Synthesis of Benzazoles by tBuONa-
Catalyzed Direct Aerobic Oxidative Cyclocondensation of o-Thio/
Hydroxy/Aminoanilines with Alcohols under Air
Xinkang Shi, Junmei Guo, Jianping Liu, Mingde Ye, and Qing Xu*[a]
Abstract: tBuONa-catalyzed direct aerobic oxidative cyclo-
condensation reactions of readily available alcohols and o-
thio/hydroxy/aminoanilines under air have been devel-
oped and provide an efficient, practical, and green
method for the synthesis of benzazoles. Mechanistic stud-
ies revealed that o-substituted anilines promote the initial
aerobic alcohol-oxidation step, which explains the high re-
activity and success of this unexpectedly simple and prac-
tical cyclocondensation method.
Developing efficient methods that use greener, cheaper, and
more-readily available substrates and catalysts and avoid muta-
genic and waste-producing reagents, unnecessary steps, and
energy waste has been a major target in modern sustainable
chemistry.[1] For example, constantly improving methods have
been developed for the synthesis of benzazoles (benzothia-
zoles, benzoxazoles, and benzimidazoles),[2–8] which are impor-
tant building blocks for pharmaceutical agents, bioactive mole-
cules, natural products, agrochemical compounds, and organic
materials.[2] Benzazoles are traditionally prepared by condensa-
tion of carboxylic acid derivatives (acids, acyl chlorides, esters,
nitriles, amides, etc.) with o-thio/hydroxy/aminoanilines
(Scheme 1a), but harsh conditions, such as high temperatures
and strong dehydrating reagents, are generally required.[2,3] Re-
actions with alkyl polyhalides,[4] oxidative condensation with al-
dehydes (Scheme 1a),[5] and intramolecular coupling reactions
(Scheme 1b)[6] were developed later, but these methods have
inherent drawbacks such as the utilization of reactive and toxic
reagents, less-common substrates, transition-metal (TM) cata-
lysts and ligands, and formation of undesired waste products.
Because alcohols are readily available chemical feedstock, fre-
quently used for the preparation of organohalides, aldehydes,
and acid derivatives,[9] recently TM-catalyzed anaerobic dehy-
drogenation methods have also been developed recently
(Scheme 1c).[7] Despite the improvement by using alcohol sub-
Scheme 1. Methods for the synthesis of benzazoles.
strates, this method still requires high temperatures and ex-
pensive TM complexes and ligands because the dehydrogena-
tive process with hydrogen extrusion is a thermodynamically
unfavorable process.[9f] More recently, Nguyen and co-workers
reported an advantageous redox-neutral Fe/S-catalyzed cyclo-
condensation of more-readily available heteroarylmethanes
and 2-amino/hydroxy nitrobenzenes (Scheme 1d).[8] This
method is incompatible with methylarenes and thionitroben-
zenes and is limited to the reactions of heteroarylmethanes to
give benzoxazoles and benzimidazoles. Therefore, research
into general methods for the efficient and sustainable synthe-
sis of benzazoles, especially benzothiazoles, is still highly desir-
able. Herein, we report an unexpectedly simple and practical
tBuONa-catalyzed[10] direct aerobic oxidative cyclocondensation
reaction of alcohols and o-thio/hydroxy/aminoanilines that
uses air as the sole oxidant (Scheme 1e). This reaction provides
an efficient, practical, and green method for the synthesis of
a diverse range of benzazoles.
[a] X. Shi, J. Guo, Dr. J. Liu, Prof. M. Ye, Prof. Dr. Q. Xu
Zhejiang Key Laboratory of Carbon Materials
College of Chemistry and Materials Engineering
Wenzhou University
We recently reported the synthesis of amine, amide,[11] alco-
hol, ketone,[12] and imine[13] derivatives from alcohols in the
presence of air as a promoter or an oxidant. In a continuous
study, when benzyl alcohol (1a; 3 mmol) and 2-aminothiophe-
Wenzhou, Zhejiang 325035 (P. R. China)
E-mail: qing-xu@wzu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501184.
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nol (2a; 2 mmol) were heated under air with NaOH (50 mol%)
in a 20 mL tube (containing ꢀ0.20 mmol O2), cyclized 2-phenyl
benzothiazole (3a) was obtained in 7% isolated yield
(0.14 mmol, 70% yield based on O2).[14] According to the reac-
tion scheme (Table 1), this result signified a rather efficient oxi-
dation process in which 70% O2 uptake occurred from 20 mL
of air. Inspired by this result, we envisioned a direct and green
method for benzazole synthesis by aerobic oxidative cyclocon-
densation of alcohols and o-thio/hydroxy/aminoanilines, which,
if achieved, can overcome many drawbacks of the known
methods.[2–8] Next, the reaction of 1a and 2a was investigated
in the presence of greater amounts of air (Table 1). To our de-
light, the reaction in a 130 mL tube (ꢀ1.3 mmol O2) afforded
3a in 40% yield (Table 1, entry 1). Performing the reaction in
toluene further enhanced the yield of 3a to 54% (Table 1,
entry 2). Examination of the reaction temperature showed that
the reaction was also effective at 1008C (Table 1, entry 3). As
expected, running the reaction with an air balloon attached
further increased the yield of 3a (Table 1, entry 4). Various
bases (KOH, CsOH, and tBuOK) were screened:[14] tBuONa gave
the highest yield of 3a (82%; Table 1, entry 5). With tBuONa,
the base loading could even be reduced to 20 mol% without
erosion of the product yield (Table 1, entry 6). The reaction
conditions were further investigated by testing various sol-
vents, temperatures, and reaction times, but no better result
was obtained.[14]
Table 1. Optimization of the reaction conditions for benzothiazole syn-
thesis.[a]
Entry Base ([mol%])[b] Additive ([mol%]) Solvent ([mL]) T [oC] 3a [%][c]
1[d] NaOH (50)
2[d] NaOH (50)
3[d] NaOH (50)
–
–
–
–
–
–
–
–
150
150
100
100
100
100
100
100
100
100
100
100
100
100
40
54
53
58
82
82
76
82
37
55
toluene (1)
toluene (2)
toluene (2)
toluene (2)
toluene (2)
toluene (2)
toluene (2)
toluene (2)
4
5
6
NaOH (50)
tBuONa (50)
tBuONa (20)
7[e] tBuONa (20)
8
tBuONa (20)
Co(OAc)2 (5)
FeCl3 (5)
Cu(OAc)2·H2O (5) toluene (2)
9
tBuONa (20)
10
tBuONa (20)
11[f]
12[f]
13[f]
14[f]
–
–
–
–
–
toluene (2)
toluene (2)
toluene (2)
<5
<5
<5
<5
Co(OAc)2 (5)
FeCl3 (5)
Cu(OAc)2·H2O (5) toluene (2)
[a] Unless otherwise noted, 1a (3 mmol, 1.5 equiv), 2a (2 mmol,
1.0 equiv), and base in solvent in a 130 mL Schlenk tube adapted with an
air balloon was heated for 24 h, then monitored by TLC. [b] Unless other-
wise noted, tBuONa (ꢁ 98% purity) was used. [c] Isolated yields based on
2a. [d] Without air balloon. [e] Virgin glassware and stirrer bar, pure 1a
and 2a (100% purity, confirmed by GC), and tBuONa (ꢁ99.9% purity)[16]
were used. [f] 1a (100% purity) was used.
Because TM impurities on glassware and stirrer
bars or in catalysts, additives, and substrates can in-
Table 2. Synthesis of benzothiazoles 3.[a]
fluence reactivity, determination of the active cata-
lytic species is a key concern for many TM-catalyzed
or TM-free reactions.[15] We investigated whether the
present reaction is TM free. Thus, a control reaction
with virgin glassware and stirrer bar, pure 1a and
2a, and tBuONa (ꢁ99.9% purity)[16] was performed.
The reaction readily afforded 76% yield of 3a under
the optimized conditions (Table 1, entry 7),[17] which
was equally as efficient as the standard reaction con-
ditions (Table 1, entry 6). On the other hand, when
the possible contaminant TMs Co, Fe, or Cu in
tBuONa[16] were added, a higher yield of 3a could
not be obtained (Table 1, entries 8–10). The reaction
with Co(OAc)2 gave the same result as the standard
reaction (Table 1, entry 8 versus 6), whereas the reac-
tions with FeCl3 and Cu(OAc)2 gave 3a in much
lower yields (Table 1, entries 9–10). Besides, addition-
al control reactions, including a blank reaction with-
out both the tBuONa and TM additives (Table 1,
entry 11) and reactions with only the TM additive
(Table 1, entries 12–14), were ineffective. These re-
sults suggest not only the crucial role of the base in
the reaction, but also that TMs do not catalyze the
reaction. Therefore, the possibility of TM catalysis in
the reaction due to TM contamination can be ex-
cluded, and the reaction is thus a true TM-free reac-
tion.
[a] Unless otherwise noted, see Table 1, entry 6 for conditions. Isolated yields based
on 2. [b] 1208C. [c] Xylene, 1358C. [d] tBuONa (50 mol%).
The optimized conditions were employed to syn-
thesize 2-substituted benzothiazoles (Table 2). Both
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electron-deficient (Table 2, entries 2–7) and electron-
rich (Table 2, entries 9–16) benzylic alcohols, includ-
ing substrates with increased steric bulk (Table 2, en-
tries 15 and 16) or ortho substituents (Table 2, en-
tries 5, 12–14), reacted efficiently with 2a to give the
target benzothiazoles 3 under similar conditions.
The target reaction did not occur with 4-nitrobenzyl
alcohol (Table 2, entry 8), most probably because of
the sensitive nitro group.[8,18] The reaction of 2-ami-
nobenzyl alcohol gave a low yield of 3m (Table 2,
entry 13), which may be due to the instability of the
2-aminobenzaldehyde intermediate. The use of
more tBuONa (50 mol%) enhanced the yield of 3m
to 43% (Table 2, entry 14). Heteroaryl methanols
were also found to be reactive: 3p–3t were ob-
tained in generally high yields (Table 2, entries 17–
21). The reactions of 4-chloro-2-aminothiophenol re-
quired a higher temperature of 1358C (Table 2, en-
tries 22–25), which may be attributed to lower sub-
strate reactivity due to the presence of an electron-
withdrawing 4-chloro group. Notably, the active hal-
ogen groups (F, Cl, Br) were tolerated in the base-
catalyzed reaction (Table 2, entries 2–7 and 22–25)
and they afforded useful halobenzothiazoles 3b–3g
and 3u–3x that may provide more synthetic possi-
bilities. We also investigated other types of alcohol
under similar conditions. Although we attempted
many times, the reactions of simple aliphatic alco-
hols and the even-more reactive substrate trifluoroe-
thanol were not successful at present. The reaction
of cinnamyl alcohol gave a low yield of the target 2-
alkenyl benzothiazole 3y (Table 2, entry 26). In addi-
tion, the reaction of 2a and 2-hydroxy-1-phenyletha-
none did not give the target 2-carbonyl product, but
rather 3a in a low yield (Table 2, entry 27), which
Table 3. Synthesis of benzimidazoles 5.[a]
[a] See Table 1 for similar and Supporting Information for detailed conditions. Isolated
yields based on 4. [b] tBuONa (30 mol%), 1508C. [c] tBuONa (20 mol%), 1508C.
[d] tBuONa (50 mol%), 1508C.
may be generated by CÀC cleavage of the reactive hydroxyl
carbonyl moiety of the substrate.
Next, substituted benzimidazoles were synthesized under
similar conditions. For other alcohols and substituted o-diami-
nobenzenes, the reactions were conducted at higher tempera-
tures than required for 5a (Table 3, entries 8–27). Thus, elec-
tron-deficient (Table 3, entries 8–13) and electron-rich (Table 3,
entries 14–19) benzylic alcohols reacted effectively with 4a to
give good-to-excellent yields of benzimadazoles 5 at 1408C.
Ortho-substituted alcohols gave slightly lower yields of 5 than
the corresponding para and meta isomers (Table 3, entries 11
versus 9–10, 17 versus 15–16, 18 versus 19) due to steric hin-
drance of the ortho groups. Reactions of heterobenzylic alco-
hols at 1408C gave low yields of the target benzimidazoles
5n–5p (Table 3, entries 20–22). However, the reactions were
optimized with tBuONa (20–50 mol%) at 1508C to give higher
yields of 5n–5p (Table 3, entries 23-25).[14] Moreover, both elec-
tron-deficient and electron-rich o-diaminobenzenes 4 generally
reacted efficiently with 1a to give good yields of 5q–5t
(Table 3, entries 26–29). In addition to the synthesis of benzimi-
dazoles, the reaction of 4a and 2-hydroxy-1-phenylethanone
efficiently afforded a good yield of six-membered 2-phenylqui-
noxaline 5u under the standard conditions (Table 3, entry 30),
which revealed the versatility of the method. However, the re-
The above method was applied to o-diaminobenzenes 4 for
the synthesis of benzimidazoles 5 (Table 3). Initially, a low yield
of 2-phenyl benzimidazole (5a) was obtained from the reac-
tion of 1a and o-diaminobenzene 4a (Table 3, entry 1). Further
examination of the base, base loading, solvent, and reaction
temperature[14] showed that slight modification of the reaction
conditions could ensure efficient synthesis of 5a (Table 3, en-
tries 2–6). Thus, the reaction of 1a and 4a with tBuONa
(5 mol%) afforded the highest yield of 5a (89%) when heated
in xylene at 1308C (Table 3, entry 6). Similar to the reaction of
1a and 2a (Table 1, entry 7), tBuONa of ꢁ99.9% purity was
also tested in the reaction of 1a and 4a, and 5a was obtained
in a comparable yield to that from the optimized reaction
(Table 3, entry 7 versus 6),[17] which suggests that this is also
a TM-free reaction. In the above reactions, 2-monosubstituted
5a was obtained as the sole product without detection of the
possible product 1,2-disubstituted benzimidazole 5a’,[5j] there-
fore this is a selective reaction that is complementary to
known methods to produce 1,2-disubstituted benzimidazo-
les.[5j]
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cohols to aldehydes under air, similar to previous reports on
aerobic oxidation of secondary alcohols.[20] However, no effec-
tive oxidation of 1a was observed under the standard condi-
tions in the absence of 2a; only a trace amount of PhCHO 8a
was detected (Figure 1).[14] As the loading of 2a increased, the
Scheme 2. Abnormal reaction of 4a and 1b.
action of 4a and 2-aminobenzyl alcohol 1b was abnormal
(Scheme 2). Target benzimidazole 5v was not obtained under
the standard conditions, rather 52% yield of double-cyclized
product 5v’, confirmed by NMR spectroscopic analysis[14] and
comparison to the spectrum of the known compound,[19] was
obtained (Scheme 2, conditions 1). Using pure O2 as the oxi-
dant to improve the reaction did not work (Scheme 2, condi-
tions 2), whereas higher loadings of 1b enhanced the yield of
5v’ to 67% (Scheme 2, conditions 3).[14] The target 5v could
only be obtained as the minor product in a low yield of 6% by
using an excess of 4a (Scheme 2, conditions 4).
Figure 1. tBuONa-catalyzed oxidation of benzyl alcohol by air, promoted by
2a.[21]
The synthesis of benzoxazoles was also attempted starting
from 2-aminophenol 6 (Table 4).[14] Initially, no reaction was ob-
conversion of 1a (to trace 8a and good yields of 3a) increased
proportionately with values close to the yields of 3a. Interest-
ingly, these results clearly suggested that the substrate (e.g.,
2a) can promote the tBuONa-catalyzed aerobic oxidation of al-
cohols by air,[21] and also explains the reason why benzazoles
can be obtained effectively by such a simple, green, and practi-
cal method without using any complex catalyst systems.
Table 4. Synthesis of benzoxazoles 7.[a]
The oxidative cyclocondensation step was also investigated.
The reaction of 2a and 8a in the presence of tBuONa gave
only a low yield of 3a (Scheme 3, conditions 1). This is due to
Scheme 3. Mechanistic investigations for the oxidative cyclocondensation
step.
[a] See Table 1 for similar and Supporting Information for detailed condi-
tions. Isolated yields based on 6.
disproportionation reactions of 8a under basic conditions: 1a
and benzyl benzoate, products of the Cannizarro and Tishchen-
ko reactions, were observed in control reactions.[14] In contrast,
control reactions of 2a and 8a without tBuONa were very effi-
cient under either air or N2 (Scheme 3, conditions 2 and 3),
which suggested that the reactions of o-thio/hydroxy/amino-
anilines and aldehydes[5] can also be accessed under catalyst-
free conditions.[5i] Additionally, these results suggested that al-
dehydes generated in situ are more reactive in the cyclocon-
densation reaction, perhaps by interaction with the substrates
during the substrate-promoted alcohol oxidation step. Besides,
the benzothiazoline intermediate 9a, even under the anaero-
bic reaction (Scheme 3, conditions 3), was not detected, which
can be attributed to its instability.[5] This may also suggest that
served under the conditions similar to those reported in
Table 1 (Table 4, entry 1). Optimization showed that higher
loadings of tBuONa afforded higher yields of the target ben-
zoxazole 7a if the reaction was performed in toluene at 1208C
(Table 4, entries 2–4). Further examination of the base loading
(Table 4, entries 5–6) and other variables[14] showed that
tBuONa (1.7 equiv) gave the highest yield of 7a (52%; Table 4,
entry 4). The optimized conditions were employed to prepare
substituted benzoxazoles 7b–7e in moderate yields (Table 4,
entries 7–10).
With regards to the mechanism of these aerobic oxidative
cyclocondensation reactions, we initially considered that
tBuONa could effectively catalyze the oxidation of primary al-
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when exposed to air during workup. For this reason, air is a re-
active enough oxidant and the use of the more-powerful oxi-
dant pure O2 is not necessary in this method.
A possible reaction route for these cyclocondensation reac-
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with 2, 4, or 6 to give imine intermediates 10, then the cy-
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Conclusion
We have developed a simple and practical tBuONa-catalyzed
direct aerobic oxidative cyclocondensation for efficient and
green synthesis of benzazole heterocycles. In these reactions,
o-substituted anilines were found to promote the aerobic alco-
hol-oxidation step, which explains the unexpectedly high reac-
tivity and success of the present method. Investigations to ach-
ieve deeper mechanistic insights and further extensions of the
method are underway.
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Acknowledgements
We thank ZJNSF for Distinguished Young Scholars
(R14B020009), NNSFC (20902070), 580 Oversea Talents Program
of Wenzhou City, and Undergraduate Training Program for In-
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novation
and
Pioneering
of
Wenzhou
University
(JWDC2013043 and JW2015130) for financial support. We also
thank Prof. Shannon Stahl (University of Wisconsin-Madison),
Prof. Shuli You (Shanghai Institute of Organic Chemistry, Chi-
nese Academy of Sciences), and Prof. Chao-Jun Li (McGill Uni-
versity) for helpful discussions.
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Keywords: aerobic oxidation · alcohols · cyclocondensation ·
green chemistry · nitrogen heterocycles
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[16] According to a purity report, tBuONa of ꢁ99.9% purity contains TMs
such as Co, Fe, and Cu, but no Pd. See the Supporting Information for
details of the TM impurities.
Received: March 25, 2015
Published online on June 5, 2015
Chem. Eur. J. 2015, 21, 9988 – 9993
www.chemeurj.org
9993
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim