Supplementary materials
Acid
catalyzed
Direct-Amidation-Dehydrocyclization
of
2-hydroxy-
acetophenones to benzoxazoles by a one-pot sustainable synthesis
Elia Rancan, Fabio Aricò Giuseppe Quartarone, Lucio Ronchin and Andrea Vavasori
Materials details
All the solvent and products were employed as received without further purification. Acetophenone
≥ 98%, acetone ≥ 99.9%, 2-hydroxyacetophenone ≥ 98%, 4-methyl-2-hydroxyacetophenone ≥ 95%,
5-methyl-2-hydroxyacetophenone
≥
98%,
5-Br-2-hydroxyacetophenone
98%,
5-NO2-2-
hydroxyacetophenone 98%, trifluoroacetic acid 99%, hydroxylamine hydrochloride 99%,
hydroxylamine Sulfate 99%, hydroxylamine phosphate 99% and acetonitrile were all Aldrich
products. Deuterated chloroform and deuterated DMSO-d6 were EurisoTop products.
Instruments and Analysis details
Reaction products were analyzed by Gas Cromatograph (GC) Agilent model 7890 and Gas
Cromatograph coupled mass spectroscopy (GC-MS), using an Agilent model 5975C interfaced with
a GC Agilent model 7890 a HP5 capillary column was used in both cases (300 µm i.d. 30 m long,
95% methyl, 5% phenyl silicone phase).
The samples were also checked by high performance liquid chromatography (HPLC) the instrument
employed was a Perkin Elmer binary LC pump 250 with phenomenex Luna, 5 μm C18 100 Å, LC
Column 30 mm × 4.6 mm (detector: Perkin Elmer LC 235 C Diode Array, wavelengths: 255 nm and
220 nm; eluent: water-acetonitrile with a concentration gradient 60 % water (9 min), 50 % water (5
min) and 30 % water (1 min).
The 1H Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker AC 200
spectrometer operating at 200.13 MHz, the sample temperature was maintained at 298 K. All the
chemical shifts were referred to internal tetramethylsilane.
2-hydroxy ketones reactivity
All reaction were carried out in a 10 mL autoclave thermostated at various temperature by a solid,
aluminum block heated by resistance regulated with a temperature controller the system reach
thermal equilibration in about 3 minute.
In a typical experimental an autoclave equipped with magnetic bar was charge with 1.5 mmol of 2hyroxyacetophenone, 4.5 mmol of hydroxylamine hydrochloride, and 30 mmol of trifluoroacetic
acid as a solvent under inert atmosphere of nitrogen. The reaction time was computed after the
autoclave is insert in a preheated aluminum block at temperature comprise between 343 and 443K
for 1 or 16 h, then chilled in a ice bath and analyzed by GC and GC-MS. Products characterization
was carried out by NMR spectroscopy. Products with sufficient purity for obtaining precise NMR
spectra were obtained from the mixture of reaction by the following procedure: i) vacuum
distillation of TFA (at 40°C and 250 Pa of pressure in a rotary evaporator); ii) the oily phase was
washed with water and extracted with dichloromethane; iii) the extracted was dried with anhydrous
sodium sulfate and the solvent eliminated in a rotary evaporator; iv) the solid was purified by
column chromatography employing hexane/ethyl acetate 9:1 as elution mixture and the solvent is
eliminated in rotary evaporator. The solid is weighted and analyzed by NMR (isolated yield and
NMR spectra in supplementary materials).
NMR and Mass spectra of some reagents and products
1.
1
H NMR (CDCl3, 400 MHz),
13
C NMR (CDCl3, 400 MHz) and MS of 2-methyl-1,3-
benzoxazole
2.
1
H NMR (CDCl3, 400 MHz),
13
C NMR (CDCl3, 400 MHz) and MS of 2,5-dimethyl-1,3-
benzoxazole
3.
1
H NMR (CDCl3, 400 MHz),
13
C NMR (CDCl3, 400 MHz) and MS of 2,4-dimethyl-1,3-
benzoxazole
4.
1
H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 400 MHz) and MS of 5-bromo-2-methyl-1,3-
benzoxazole
5.
MS of 5-nitro-2-methyl-1,3-benzoxazole
1
H NMR (CDCl3, 400 MHz) spectrum of 2-methyl-1,3-benzoxazole
13
C NMR (CDCl3, 400 MHz) spectrum of 2-methyl-1,3-benzoxazole
MS spectrum of 2-methyl-1,3-benzoxazole
A b u n d a n c e
S c a n
8 0 0 0 0 0 0
1 3 3 7 (1 0 .7 3 7
1 3 3 .1
m in ) : 4 E 3 0 . D \ d a t a . m s
7 5 0 0 0 0 0
7 0 0 0 0 0 0
6 5 0 0 0 0 0
6 0 0 0 0 0 0
5 5 0 0 0 0 0
5 0 0 0 0 0 0
4 5 0 0 0 0 0
4 0 0 0 0 0 0
3 5 0 0 0 0 0
3 0 0 0 0 0 0
2 5 0 0 0 0 0
6 3 .1
1 0 4 .1
2 0 0 0 0 0 0
1 5 0 0 0 0 0
1 0 0 0 0 0 0
5 0 0 0 0 0
8 7 .0
0
6 0
8 0
1 5 5 .0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0 .8
1 8 0
2 0 6 .9
2 0 0
2 3 4 .7
2 2 0
2 4 0
m / z -->
1
H NMR (CDCl3, 400 MHz) spectrum of 2,5-dimethyl-1,3-benzoxazole
2 5 3 .8
2 6 0
2 8 1 .0
2 8 0
13
C NMR (CDCl3, 400 MHz) spectrum of 2,5-dimethyl-1,3-benzoxazole
MS spectrum of 2,5-dimethyl-1,3-benzoxazole
Abundance
S c a n 1 6 6 0 (1 2 . 5 8 5 m in ): 4 E 4 4 . D \ d a t a . m s
1 4 7 .1
7000000
6000000
7 8 .1
5000000
4000000
3000000
2000000
1 0 6 .0
5 1 .1
1000000
2 0 7 .0
0
60
80
100
120
140
160
180
200
220
2 5 1 .8
240
260
2 8 0 .8
280
m / z -->
1
H NMR (CDCl3, 400 MHz) spectrum of 2,6-dimethyl-1,3-benzoxazole
3 4 4 .9
300
320
340
13
C NMR (CDCl3, 400 MHz) spectrum of 2,6-dimethyl-1,3-benzoxazole
MS spectrum of 2,6-dimethyl-1,3-benzoxazole
A b u n d a n c e
S c a n
2 1 8 2
8 0 0 0 0 0 0
(1 2 .6 3 0
1 4 7 .1
m in ) : 4 E 3 9 . D \ d a t a . m s
7 5 0 0 0 0 0
7 0 0 0 0 0 0
7 8 .1
6 5 0 0 0 0 0
6 0 0 0 0 0 0
5 5 0 0 0 0 0
5 0 0 0 0 0 0
4 5 0 0 0 0 0
4 0 0 0 0 0 0
3 5 0 0 0 0 0
3 0 0 0 0 0 0
1 0 6 .0
2 5 0 0 0 0 0
2 0 0 0 0 0 0
5 1 .1
1 5 0 0 0 0 0
1 0 0 0 0 0 0
5 0 0 0 0 0
1 3 0 .0
0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 8 .1 1 8 6 .9
1 6 0
1 8 0
2 3 4 .8 2 5 1 .8 2 6 9 .8
2 0 7 .1
2 0 0
2 2 0
2 4 0
2 6 0
m / z -->
1
H NMR (CDCl3, 400 MHz) spectrum of 5-bromo-2-methyl-1,3-benzoxazole
2 8 0
13
C NMR (CDCl3, 400 MHz) spectrum of 5-bromo-2-methyl-1,3-benzoxazole
MS spectrum of 5-bromo-2-methyl-1,3-benzoxazole
A bundanc e
S c a n 2 0 8 7 ( 1 5 . 0 2 9 m in ) : 4 E 3 3 . D \ d a t a . m s
2 1 1 .0
7000000
6000000
5000000
6 3 .1
4000000
3000000
1 0 4 .1
2000000
1 3 2 .0
1000000
1 6 9 .9
8 5 .0
0
60
2 3 4 .9
1 9 0 .8
80
100
120
140
160
180
200
220
3 1 3 .8
2 8 1 .9
240
260
280
300
320
m / z -->
MS spectrum of 5-nitro-2-methyl-1,3-benzoxazole
A
b
u
n
d
a
n
c
e
6
0
0
0
0
0
0
5
5
0
0
0
0
0
5
0
0
0
0
0
0
4
5
0
0
0
0
0
4
0
0
0
0
0
0
3
5
0
0
0
0
0
3
0
0
0
0
0
0
2
5
0
0
0
0
0
2
0
0
0
0
0
0
1
5
0
0
0
0
0
1
0
0
0
0
0
0
5
0
0
0
0
0
S
c
a
1
9
1
1
8
2 4
. 1
5
9
3
2
z - - >
2
0
0
. 1
5
7
m
in
) :
4
E
6
3
. D
\
d
a
t a
. m
s
. 1
2
5
/
7
. 1
0
m
( 1
. 0
1
5
n
7
0
1
0
0
1
5
0
1
8
. 9
2
2
5
5
3
0
. 8
3
3
1
0
0
2
. 9
3
3
5
5
0
9
. 9
4
0
4
1
0
. 0
0
4
4
5
0
7
5
. 0
Influence of temperature: complete data.
Table I. Influence of the temperature on the DAD of 2HAP. Run conditions: substrate 10 mmol,
NH2OH.HCl 30mmol, TFA 200 mmol.
Temperature
Time
Conversion
K
343
H
16
(%)
14
363
16
64
343
1
1
363
1
15
383
1
44
413
1
99
453
1
92
2MB
Selectivity
(%)
2HAA
other
90
91
81
85
8
6
11
10
2
3
8
5
Pale orange
Dark orange
Pale yellow
Pale yellow
88
97
92
9
1
2
3
2
6
Pale yellow
Pale yellow
Black
Notes