Cyanide as a powerful catalyst for facile preparation of 2-substituted benzoxazoles via aerobic oxidation

Article abstract of DOI:10.1002/adsc.201200684

A cyanide-catalyzed synthesis of 2-substituted benzoxazoles from Schiff bases via aerobic oxidation has been developed. The products from various Schiff bases were obtained in high yields in an open flask under ambient conditions without other external oxidants. We have also developed a simple one-step protocol for the synthesis of benzoxazoles from aminophenol and the corresponding aldehydes in the presence of cyanide without isolation of imine intermediates. Copyright

Full text of DOI:10.1002/adsc.201200684

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DOI: 10.1002/adsc.201200684
Cyanide as a Powerful Catalyst for Facile Preparation of
2-Substituted Benzoxazoles via Aerobic Oxidation
Yeon Ho Cho,a Chun-Young Lee,a Deok-Chan Ha,a and Cheol-Hong Cheona,*
a
Department of Chemistry, Korea University, Anam-ro, Seongbuk-gu, Seoul 136701, Republic of Korea
Fax : (+82)-2-3290-3121; phone: (+82)-2-3290-3147; e-mail: cheon@korea.ac.kr
Received: August 2, 2012; Revised: August 20, 2012; Published online: October 30, 2012
Dedicated to Professor Jung-Il Jin, Seoul, Republic of Korea, former President of IUPAC, on the occasion of
his 70th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200684.
Abstract: A cyanide-catalyzed synthesis of 2-substi-
tuted benzoxazoles from Schiff bases via aerobic
oxidation has been developed. The products from
various Schiff bases were obtained in high yields in
an open flask under ambient conditions without
other external oxidants. We have also developed
a simple one-step protocol for the synthesis of benz-
ACHTUNGTRENNUNGoxazoles from aminophenol and the corresponding
aldehydes in the presence of cyanide without isola-
tion of imine intermediates.
dations have been reported with catalytic amounts of
copper(II) chloride,[5] iron(III) chloride,[6] palladi-
AHCTUNGTRENNUNG
um(II) acetate,[7] TEMPO,[8] activated carbon,[9] and
AHCTUNGTRENNUNG
copper[10] and platinum[11] nanoparticles. However, in
most cases, relatively high catalyst loadings and/or
excess amounts of bases are generally required, and
long reaction times and/or high temperatures are
needed to get the desired products in reasonable
yields. Thus, the development of a more efficient
method for the synthesis of benzoxazoles[12] via aero-
bic oxidation under mild conditions is highly desired.
The formation of benzoxazole 5 from phenolic
Schiff base 3 is generally believed to proceed in
a two-step sequence (Scheme 1):[4] The first step is an
equilibrium step between Schiff base 3 and benzoxa-
zoline intermediate 4. Benzoxazoline 4 undergoes
subsequent oxidation to afford the benzoxazole 5. We
Keywords: aerobic oxidation; benzothiazoles; ben-
zoxazoles; cyanide; one-pot protocol
Benzoxazoles are common building blocks in biologi- hypothesized that in the aerobic oxidative cyclization
cally and therapeutically active compounds, natural of phenolic Schiff base 3, the first equilibrium step
products, and functional materials.[1] Consequently, might be the rate-determining step for the overall
great efforts have been made to develop efficient process. In this scenario, if the rate of the first step
methods for the preparation of benzoxazoles. Al- were accelerated, the overall reaction rate for the syn-
though several methods for the preparation of 2-sub- thesis of benzoxazole could increase. One way to fa-
stituted benzoxazoles using transition metal catalysts
have been developed recently,[2,3] conventional meth-
ods are still widely used for the preparation of 2-sub-
stituted benzoxazoles. One of the popular convention-
al methods for the preparation of these important
compounds is oxidative cyclization of phenolic Schiff
bases derived from ortho-aminophenol with aldehydes
in the presence of strong oxidants. However, this
method needs to use stoichiometric or excess amounts
of strong oxidants relative to the respective sub-
strates.[4]
Recently, oxidative cyclizations using oxygen as the
ultimate oxidant have attracted much attention from
the synthetic community. In this regard, several exam-
ples of the synthesis of benzoxazoles via aerobic oxi- Scheme 1. Working hypothesis.
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Adv. Synth. Catal. 2012, 354, 2992 – 2996

Cyanide as a Powerful Catalyst for Facile Preparation of 2-Substituted Benzoxazoles
cilitate the rate of the first step might be addition of might be ascribed to the poor solubility of NaCN in
a nucleophile. The higher nucleophilicity of the nucle- toluene,[16] we carried out the same reaction using dif-
ophile could lead to addition to the imine in Schiff ferent solvents. Interestingly, the choice of solvent
base 3 with ease to afford intermediate 6, and the re- had a significant effect on the reaction rate (entries 2–
sulting intermediate 6 could easily undergo a subse- 8). Etherated solvents provided a trace amount of the
quent ring closing reaction to generate benzoxazoline product (entries 3 and 4), while several polar solvents
4 due to the better leaving ability of the nucleophile. gave the desired product in high to excellent yield
Overall, the nucleophile was expected to decrease the (entries 5–8). Among the solvents tested, DMF and
activation energy for the first equilibrium step, which DMSO turned out to be the choice of solvent (en-
eventually facilitates the formation of benzoxazole 5. tries 7 and 8). It should be noted that CNÀ significant-
In this communication, we would like to present an ly increases the reaction rate and the desired benzox-
efficient synthetic protocol for the cyanide-catalyzed azole could be obtained in excellent yield under ex-
preparation of 2-substituted benzoxazoles from the tremely mild reaction conditions; benzoxazole forma-
corresponding Schiff bases under ambient conditions tion was completed at room temperature using air as
using air as the terminal oxidant without any bases the sole oxidant without any base and co-oxidant in
and co-oxidants. Moreover, we have also developed 1 hour. Based on our initial hypothesis, this reaction
a one-step procedure for the synthesis of 2-substituted should intrinsically proceed even with a catalytic
benzoxazoles from aldehydes and 2-aminophenol amount of CNÀ anion. Thus, the possibility of the
without isolation of the corresponding imines in the preparation of benzoxazoles with a catalytic amount
presence of cyanide anion under aerobic oxidation of CNÀ was tested (entries 9–11). To our delight, the
conditions. We further extended this method to the reaction proceeded with a catalytic amount of CNÀ
preparation of benzothioazoles.
anion and the catalyst loading could be lowered to
To test our hypothesis, we commenced with a study 1 mol% without any significant loss of catalytic effi-
to find out a suitable nucleophile to promote this re- ciency.
action under ambient conditions using air as an oxi-
With the optimized reaction conditions in hand, the
dant[13] (Table 1). Screening several nucleophiles re- scope of the reaction with respect to Schiff bases 3 de-
vealed that NaCN significantly facilitated the forma- rived from various aldehydes with ortho-aminophenol
tion of benzoxazole 5a.[14,15] In the absence of a nucleo- was investigated in the presence of a catalytic amount
phile, the oxidative cyclization reaction did not pro- of NaCN (Table 2). The desired benzoxazoles were
ceed at all even after 4 days (entry 1), while NaCN
would provide the desired product in 80% yield at
room temperature in an open flask although the reac-
tion was slow (entry 2). Since this slow reaction rate
Table 2. Substrate scope.[a]
Table 1. Optimization of reaction conditions.
Entry
Benzoxazoles 5
Yield[b,c] [%]
R1
R2
1[d]
2
3
4
5
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
5a: C5H5
93 (92)
76 (78)
76 (84)
78 (77)
81 (88)
80 (87)
80 (87)
82 (84)
82 (91)
81 (84)
81 (82)
80 (79)
84 (91)
5b: 4-(MeO2C)C6H4
5c: 4-ClC6H4
5d: 4-(t-Bu)C6H4
5e: 4-(Me)C6H4
5f: 4-(MeO)C6H4
5g: 2-(Me)C6H4
5h: 2-(MeO)C6H4
5i: 2-(HO)C6H4
5j: 2-naphthyl
5k: 1-naphthyl
5l: Ph
Entry
Nu (mol%)
Solvent
Time [h]
Yield[a] [%]
1
2
3
4
5
6
7
–
toluene
toluene
THF
dioxane
CH3CN
EtOH
96
96
24
24
24
24
1
1
8
48
96
N.R.[b]
80
trace
trace
70
NaCN (100)
NaCN (100)
NaCN (100)
NaCN (100)
NaCN (100)
NaCN (100)
NaCN (100)
NaCN (10)
NaCN (5)
NaCN (1)
6
7[e]
8[e]
9
75
91
10
11[e]
12
13
DMF
8[c]
9[c]
10[c]
11[c]
DMSO
DMSO
DMSO
DMSO
92 (99)[d]
93 (99)[d]
90 (97)[d]
74 (90)[d]
5m: Ph
[a]
For detailed reaction conditions: see Experimental Sec-
tion.
Isolated yields.
The values in parentheses are yields obtained with a stoi-
chiometric amount of NaCN.
DMSO-d6 was used.
[a]
[b]
[c]
Isolated yields.
N.R. means no reaction.
DMSO-d6 was used.
[b]
[c]
[d]
[d]
[e]
The values in parentheses were yields obtained by
1H NMR analysis of the crude mixture.
20 mol% of NaCN were used.
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Table 3. One-pot protocol for the synthesis of benzox-
obtained in high to excellent yields. The electronic
properties of aldehydes (R2 moieties in Schiff bases 3)
slightly affected the formation of benzoxazole and the
desired products were obtained in high yields regard-
less of the electronic properties of the aryl groups
(entries 1–6). However, the steric bulk of aldehydes
had a slightly deleterious effect on the formation of
benzoxazoles. Schiff bases from ortho-substituted al-
dehydes underwent the cyclization reaction a little bit
more slowly and 20 mol% of NaCN was needed to
get high yields (entries 7, 8, and 11). It is noteworthy
to mention that several functional groups, such as
ester, ether, and hydroxy groups, were well tolerated
under the reaction conditions. The electronic property
of ortho-aminophenol ring (R1 in Schiff bases) had
a minimal effect on the formation of benzoxazoles
(entries 12 and 13). Imines derived from aminophe-
nols bearing either electron-donating or electron-
withdrawing substituents provided the desired prod-
ucts in good to high yields. More importantly, all the
reactions with catalytic amounts of CNÀ provided
benzoxazoles in comparable yields as for the reactions
with stoichiometric amounts of NaCN.
AHCTUNGTRENNUNG
azoles.[a]
Entry
5
R1
R2
Time [h]
Yield[b] [%]
1[c]
2
5a
5a
5a
5c
5e
5l
5m
5n
5o
5p
5q
5r
H
H
H
H
H
Me
Cl
H
H
H
H
H
Ph
Ph
Ph
4-ClC6H4
4-MeC6H4
Ph
24
4
24
4
7
6
trace
78
74
86
80
76
71
71
70
81
80
76
3[d]
4
5
6
7
8
Ph
4
2-furyl
2-thienyl
t-butyl
c-hexyl
n-hexyl
10
10
10
10
10
9
10
11
12
[a]
For detailed reaction conditions: see Experimental Sec-
tion.
Isolated yields.
Reaction was carried out at room temperature.
10 mol% of NaCN were used.
[b]
[c]
[d]
One of the most significant drawbacks for the syn-
thesis of benzoxazoles via oxidative cyclization of
Schiff bases is that the imines have to be prepared
prior to the oxidative cyclization reaction.[17] We envi- was challenging in the oxidative cyclization method
sioned that as long as cyanide would not interfere in with Schiff bases not only because of the instability of
the imine formation reaction, benzoxazoles could be imines from aliphatic aldehydes but also unwanted
directly prepared from ortho-aminophenol and alde- side reactions[21] (entries 10–12).
hydes without isolation of imines. To test this idea, 2-
To demonstrate the practicability of this method,
aminophenol, benzaldehyde, and NaCN were dis- we carried out the preparation of benzoxazole from
solved in DMF and the reaction mixture was moni- the corresponding phenolic Schiff base in the pres-
tored at room temperature in an open flask (Table 3, ence of NaCN in a gram scale (Scheme 2). To our de-
entry 1). However, only a trace amount of benzoxa- light, the desired benzoxazole 5a was obtained in
zole was observed at room temperature even after 10 mmol scale without any significant loss of its effi-
a long reaction time. Since this low yield was presum- ciency. Furthermore, the one-pot protocol for the syn-
ably due to the inefficient formation of imines,[18] we thesis of benzoxazole 5a could be performed in
carried out the same reaction at 808C in the presence a gram scale.
of a molecular sieve. Delightfully, the desired product
Having successfully developed the cyanide-cata-
was obtained in high yield in 4 h (entry 2). Further- lyzed one-pot protocol for the synthesis of benzoxa-
more, the catalytic amount of NaCN was enough to zoles, we attempted to further apply this protocol to
promote this reaction although a longer reaction time the preparation of benzothiozaole with ortho-amino-
was needed (entry 3).
thiophenol.[22] To our satisfaction, benzothiazole 8 was
Under these conditions, various aromatic aldehydes
were applied to the benzoxazole formation reaction
and the desired products were obtained in good to
high yields, although the yields from this one-pot pro-
tocol were slightly lower than those from Schiff bases
(entries 3–5).[19] The electronic properties of alde-
hydes and/or ortho-aminophenol had little effect on
the formation of benzoxazoles (entries 2, 4–7). This
method could be extended to the preparation of ben-
zoxazoles from heteroaromatic aldehydes (entries 8
and 9). More importantly, the method could be ap-
plied to the preparation of 2-alkylbenzoxazoles with
aliphatic aldehydes bearing acidic a-protons,[20] which Scheme 2. Large-scale synthesis of benzoxazole 5a.
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Cyanide as a Powerful Catalyst for Facile Preparation of 2-Substituted Benzoxazoles
808C under air atmosphere and monitored by TLC. After
completion of the reaction, the reaction mixture was diluted
with H2O, and extracted with ether. The organic layer was
collected, dried over MgSO4, and concentrated under re-
duced pressure. The crude product was purified by column
chromatography on silica to give the corresponding benzox-
azole.
Scheme 3. Synthesis of benzothiazole 8.
obtained in good yields in the presence of CNÀ in an
open flask. Interestingly, the formation of benzothia-
zole proceeded even at room temperature presumably
due to the higher nucleophilicity of ortho-aminothio-
Acknowledgements
This work was supported by the nuclear research and devel-
opment program through the National Research Foundation
of Korea funded by the Ministry of Education, Science and
Technology. We also thank Korea University for the generous
support to this research.
phenol
as
compared
to
ortho-aminophenol
(Scheme 3).
In conclusion, we have developed the cyanide-cata-
lyzed synthesis of 2-substituted benzoxazoles from
Schiff bases of 2-aminophenol with aldehydes. The
desired 2-substituted benzoxazoles were obtained in
high yields under ambient conditions using air as the
only oxidant. We have also developed a simple one-
step protocol for the synthesis of benzoxazoles from
2-aminophenol and aldehydes in the presence of cya-
nide without isolation of Schiff base intermediates.
Furthermore, this method was extended to a one-pot
synthesis of benzothiazole from the corresponding
substrates. Although the exact role of cyanide needs
to be clarified, at this time the high reactivity en-
hancement might have been due to easy formation of
benzoxazoline 4 assisted by CNÀ. Further applications
of this method and investigation of the exact role of
CNÀ are underway in our laboratory.
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Experimental Section
General Experimental Procedure for the Aerobic
Oxidation of Phenolic Schiff Bases (Table 2)
In an open test tube were added a phenolic imine 3
(0.50 mmol, 1.0 equiv.) and NaCN (2.5 mg, 0.050 mmol,
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General Experimental Procedure for the One-Pot
Protocol (Table 3)
In an open test tube were added an aldehyde (0.50 mmol,
1.0 equiv.), an ortho-aminophenol (0.50 mmol, 1.0 equiv.),
NaCN (24.5 mg, 0.50 mmol, 1.0 equiv.) and molecular sieve
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Yeon Ho Cho et al.
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[18] 1H NMR analysis of the crude mixture revealed that 2-
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[19] The yields from one-pot protocol (Table 3) were slight-
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(Table 2). Although the 1:1 ratio of benzaldehyde 2a
and 2-aminophenol 1 was used, 1 remained even after
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under the reaction conditions, which might be responsi-
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ACHTUNGTRENNUNGoxazoles using air as an oxidant, although the reaction
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