N-Bromosuccinimide as an oxidant for the transition-metal-free synthesis of 2-aminobenzoxazoles from benzoxazoles and secondary amines

Article abstract of DOI:10.1039/c4ob00386a

A facile and transition-metal-free method was developed through merging the ring opening of benzoxazoles with secondary amines and N-bromosuccinimide (NBS) mediated oxidative cyclization toward the synthesis of 2-aminobenzoxazoles. NBS was selected as a powerful oxidant in the oxidative cyclization of ring-opening amidines to provide the desirable 2-aminobenzoxazoles in excellent yields (up to 94%).

Full text of DOI:10.1039/c4ob00386a

Organic &
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N-Bromosuccinimide as an oxidant for the
transition-metal-free synthesis of
2-aminobenzoxazoles from benzoxazoles and
secondary amines†
Cite this: Org. Biomol. Chem., 2014,
12, 3108
Xiaoe Wang,a,b Daqian Xu,a Chengxia Miao,a Qiaohong Zhanga and Wei Sun*a
Received 19th February 2014,
Accepted 7th March 2014
A facile and transition-metal-free method was developed through merging the ring opening of benzoxa-
zoles with secondary amines and N-bromosuccinimide (NBS) mediated oxidative cyclization toward the
synthesis of 2-aminobenzoxazoles. NBS was selected as a powerful oxidant in the oxidative cyclization of
ring-opening amidines to provide the desirable 2-aminobenzoxazoles in excellent yields (up to 94%).
DOI: 10.1039/c4ob00386a
www.rsc.org/obc
conomic effects. Hence, the development of environmentally
benign procedures based on transition-metal-free catalysis to
Introduction
2-Aminooxazoles are very important structural units in many synthesize such compounds is highly desirable.
natural products and widely employed in biological, pharma-
Recently, Chang et al. developed a new metal-free system
ceutical and materials science, such as small-molecule using iodobenzene diacetate as the oxidant for the amination
somatostatin receptor subtype 5 (SST5R) antagonists (Fig. 1).1 of azoles with amines through a unique ring-opening and sub-
So, the synthesis of 2-aminooxazoles has received more and sequent ring-closing strategy, performing in a one-pot process
more attention in recent years. Conventionally, 2-amino- without isolation of the amidine intermediate (Scheme 1, (i)).9
benzoxazole derivatives are generally synthesized by transition- Studer and co-workers also reported a highly efficient system
metal-catalyzed amination of compounds with pre-installation including catalytic amounts of triflic acid and a readily recycl-
of reactive functional groups along with N-chloroamines, able N-oxoammonium salt as an organic oxidant for direct
amines, and amides or O-acylated hydroxylamines at high amination of nonactivated benzoxazoles and 1,3,4-oxadiazoles
temperatures.2,3 As a complementary methodology of the with good to excellent yields (Scheme 1, (ii)).10 And several other
above methods, transition metal, including Mn, Co, Ag, Fe, metal-free systems, such as catalytic iodine or tetrabutylammo-
Cu, and Ni, catalyzed C–H direct amination has become the niumiodide in combination with tert-butyl hydroperoxide
main strategy to construct 2-aminooxazoles.3–8 Although sig- (TBHP) or H2O2 as the oxidant appeared nearly at the same
nificant advances have been achieved, still there are some dis- time for amination of benzoxazoles through activation of C–H
advantages associated with the method, such as high bonds.11 Recently, an environmentally friendly method was
temperature, long reaction time, poisonous ligands, and none- developed by our group through merging the ring opening of
benzoxazoles with secondary amines and iron-catalyzed oxi-
dative cyclization with H2O2 as the oxidant (Scheme 1, (iii)).12
Attracted by the two-step strategy for amination of benzoxazoles
under metal-free conditions reported by Chang et al. and conti-
nuing our research on the use of NBS for oxidation,13 we herein
wish to report an efficient and transition-metal-free system for
the synthesis of 2-aminooxazoles, employing cheap and easily
available NBS as a powerful organic oxidant for oxidative cycliza-
tion of ring-opening amidines in a biphasic system.
Fig. 1 Somatostatin receptor subtype 5 antagonists.
aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
Results and discussion
E-mail: wsun@licp.cas.cn; Fax: +86 931 827 7088
bUniversity of Chinese Academy of Sciences, Beijing, 100049, P. R. China
†Electronic supplementary information (ESI) available: The copies of NMR
Our initial optimization of the model reaction between benzox-
spectra. See DOI: 10.1039/c4ob00386a
azole (1a) and piperidine (2a) is summarized in Table 1. There
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Scheme 1 Indirect method for the amination of benzoxazoles.
entry 5). Additionally, the amount of NBS and KOAc was also
investigated. The results indicated that 0.9 mmol KOAc and
0.75 mmol NBS were the optimized conditions (Table 1,
entries 6–9). Furthermore, various organic solvents were sub-
jected to the biphasic system, and dioxane/H2O proved to be
the best choice as it resulted in the desirable 2-aminooxazole
4aa in a 94% yield (Table 1, entries 11–13).
Table 1 Optimization of the oxidative cyclization reaction conditions
with NBS as an oxidanta
NBS
KOAc
(mmol)
Temp.
(°C)
Yieldb
Various amines were explored to study the substrate scope
of this reaction under optimized reaction conditions for the
two-step oxidative amination between different types of cyclic/
acyclic aliphatic secondary amines with benzoxazole. The
results are summarized in Table 2. Cyclic aliphatic secondary
amines such as piperidine and its derivatives, pyrrolidine,
morpholine and piperazine derivatives all smoothly underwent
the ring opening reaction with 1a to provide amidine adducts
3 in excellent yields. And the subsequent cyclization of the
amidines performed well at 0 °C for 5 min, leading to the
corresponding compounds 4 in excellent yields (Table 2,
entries 1–7). Interestingly, employing equimolar substrates of
1a and 2h or 2i could directly give the desired product in
about 90% yields without isolating the amidine adducts 3
(Table 2, entries 8 and 9). Additionally, the reactivities of
acyclic aliphatic secondary amines were also tested. The ring
opening step could occur through elevating the temperature to
80 °C and prolonging the reaction time to 8 or 10 h, and the
corresponding 2-aminooxazoles 4 could be afforded in about
90% yields (Table 2, entries 10 and 11). In addition, linear ali-
phatic amines were also transformed into the desired 2-amino-
benzoxazoles in good yields, but Sc(OTf)3 should be used as
the catalyst in the ring opening step according to the Studer
process (Table 2, entries 12, 13).10
These promising results prompted us to investigate our novel
method toward amination of a variety of substituted benzoxa-
zoles with pyrrolidine. Intriguingly, nearly quantitative yields of
3 and above 90% yields of 4 were acquired employing benzoxa-
zoles and their derivatives with substituents such as CH3,
OMe or Cl as the substrates (Table 3, entries 1–5). The oxidative
cyclization of amidine 3 proceeded uneventfully to provide the
2-aminooxazoles 4 in excellent yields with NBS as the oxidant.
On the basis of all the results described above and the pre-
vious report,9 a possible mechanism for the oxidative cycliza-
tion of amidines was proposed (Scheme 2). NBS may react with
imine to form a 1 : 1 electron-donor–acceptor complex I via the
Entry
Solvent (mL)
(mmol)
1c
2
3
4
5
6
7
8
9
10
11
12
13
CH2Cl2(2)
CH2Cl2(2)
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.65
0.85
0.75
0.75
0.75
0.75
No
No
No
0.8
0.8
0.9
0.7
0.9
0.9
0.9
0.9
0.9
0.9
20
20
20
20
0
0
0
0
0
0
0
—
45d
47d
75
83
87
75
55
79
43
92
94
68
CH2Cl2/H2O(1/1)
CH2Cl2/H2O(1/1)
CH2Cl2/H2O(1/1)
CH2Cl2/H2O(1/1)
CH2Cl2/H2O(1/1)
CH2Cl2/H2O(1/1)
CH2Cl2/H2O(1/1)
Toluene/H2O(1/1)
THF/H2O(1/1)
Dioxane/H2O(1/1)
MeCN/H2O(1/1)
0
0
a Oxidative cyclization step: 3aa (0.5 mmol), KOAc (0–0.9 mmol) in a
biphasic system, and the NBS were added to the mixture and stirred at
the specified temperature for 5 min. b Isolated yield. c 0.5 mmol 1a,
1.0 mmol 2a and 0.75 mmol NBS were added to 2.0 mL of CH2Cl2 at
the same time. d The brominated product was observed.
was nearly no product detected, when 1.5 equiv. of NBS along
with 0.5 mmol benzoxazole and 1 mmol piperidine was added
into a reaction tube at the same time using CH2Cl2 as a
solvent (Table 1, entry 1). To our delight, a 45% yield was
observed when NBS was added after the reaction of benzoxa-
zole and piperidine under neat conditions for 30 min (entries
2, 3). It indicates that the present system should involve the
amidine intermediate. Then, NBS serves as an oxidant to
mediate the resulting oxidative cyclization.9 However, a bromi-
nated product was always generated under the above con-
ditions. During the study on the oxidative kinetic resolution of
secondary alcohols with NBS as an oxidant, potassium acetate
can be used to neutralize HBr in the enantioselective oxi-
dation.13 As expected, the addition of potassium acetate
(KOAc, 0.8 mmol) in this reaction could not only inhibit the
generation of the brominated product but also improve the
yield (Table 1, entry 4 vs. 3). Besides, the yield would be
further improved by lowering the temperature to 0 °C (Table 1,
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Table 2 Scope of the oxidative C–H amination of benzoxazoles with
various aminesa
Table 3 Scope of the benzoxazole derivativesa
Entry
Benzoxazoles (R)
Yield of 3b [%]
Yield of 4c [%]
Entry
1
Amine 2
Yield of 3b [%]
Yield of 4c [%]
93(4aa)
1
2
3
4
5
H, 1a
99
99
99
99
99
93(4ab)
92(4bb)
93(4cb)
91(4db)
90(4eb)
99
5-Me, 1b
6-Me, 1c
5-OMe, 1d
5-Cl, 1e
2
3
99
99
92(4ab)
92(4ac)
a Ring-opening step: benzoxazoles
1 (0.5 mmol) and pyrrolidine
(1 mmol) were stirred at rt for 30 min; Ring-closing step: NBS
(0.75 mmol, 1.5 equiv.) and KOAc (0.9 mmol, 1.8 equiv.) were added to
the solution of 3 (0.5 mmol) in 1 mL of H2O and 1 mL of dioxane, and
then the mixture was stirred at 0 °C for 5 min. b Isolated yield.
c Isolated yield based on the two steps.
4
99
93(4ad)
5
99
99
99
—
92(4ae)
91(4af)
90(4ag)
91(4ah)
6
7
8d
9d
—
91(4ai)
10d
11
—
89(4aj)
86(4ak)
95
90e
89 f
83(4al)
Scheme 2 Proposed mechanism for the oxidative cyclization of
amidines.
12
13
82(4am)
halogen bond interaction, which will be further transformed
into a more electrophilic species II-1 and II-2.14,15 Then inter-
mediate III is generated via nucleophilic substitution of imine
by oxygen anions to achieve the ring-closing step. Finally, the
product will be formed through removing of HBr in the pres-
ence of KOAc as a base.
a Ring-opening step: benzoxazole (0.5 mmol) and secondary amine
(1 mmol) were stirred at rt for 30 min. Ring-closing step: NBS
(0.75 mmol, 1.5 equiv.) and KOAc (0.9 mmol, 1.8 equiv.) were added to
the solution of 3 (0.5 mmol) in 1 mL of H2O and 1 mL of dioxane, and
then the mixture was stirred at 0 °C for 5 min. b Isolated yield.
c Isolated yield based on the two steps. d Benzoxazole (0.5 mmol) and
piperidine (0.5 mmol) were stirred in 1 mL of dioxane for certain time
(2i: at rt for 2 h; 2j: at 80 °C for 10 h; 2k: at 80 °C for 8 h), the mixture
was cooled to 0 °C and NBS (0.75 mmol, 1.5 equiv.), KOAc (0.9 mmol,
1.8 equiv.) in 1 mL of H2O was stirred at 0 °C for 5 min. e Ring-opening
step was conducted according to the method reported by Studer:10
benzoxazole 1a (0.5 mmol), 2l (0.75 mmol) and 5.0 mol% of Sc(OTf)3
under an Ar atmosphere at 80 °C for 2 hours in MeCN (1.0 mL). f Ring-
opening step: benzoxazole 1a (0.5 mmol) and 2m (1.0 mmol) under an
Ar atmosphere at 80 °C for 12 hours in MeCN (1.0 mL).
Conclusions
In conclusion, a new transition-metal-free system for the amin-
ation of benzoxazoles with aliphatic secondary amines
through the ring-opening step and further oxidative cyclization
was developed. The ring-opening step executed well under
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neat conditions to give the amidine adducts. The subsequent
2-(Pyrrolidin-1-yl)benzoxazole (4ab).9 White solid; M.p.
1
ring-closing strategy was performed by oxidative cyclization of 60–62 °C; H NMR (400 MHz, CDCl3) δ = 7.37 (dd, J = 12.1, 4.8
the amidine adducts employing cheap and easily available Hz, 1H), 7.28–7.21 (m, 1H), 7.19–7.08 (m, 1H), 7.04–6.86 (m,
NBS as the powerful organic oxidant, which makes the proto- 1H), 3.79–3.51 (m, 4H), 2.11–1.93 (m, 4H). 13C NMR (100 MHz,
col more practical toward the synthesis of 2-aminooxazoles. CDCl3) δ = 161.0, 149.0, 143.6, 123.8, 120.0, 116.0, 108.6, 47.4,
Besides, an electron-donor–acceptor complex as the intermedi- 25.6. HRMS (ESI) calcd for C11H13N2O [M + H]+: 189.1022,
ate was proposed in the oxidative cyclization step. Efforts are found: 189.1017.
currently underway in our group to further expand the other
oxidant system for the reaction or synthetic application of the M.p. 64–67 °C; 1H NMR (400 MHz, CDCl3) δ = 7.27 (dd, J = 7.8,
2-(4-Methylpiperidin-1-yl)benzoxazole (4ac).11 White solid;
current system.
0.6 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.07 (td, J = 7.7, 1.1 Hz,
1H), 6.94–6.89 (m, 1H), 4.25–4.17 (m, 2H), 2.99 (td, J = 12.9,
2.8 Hz, 2H), 1.72–1.62 (m, 2H), 1.60–1.45 (m, 1H), 1.27–1.13
(m, 2H), 0.91 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ = 161.4, 147.7, 142.3, 122.8, 119.3, 115.0, 107.6, 45.1, 32.4,
29.6, 20.8. HRMS (ESI) calcd for C13H17N2O [M + H]+:
217.1335, found: 217.1353.
Experimental
General remarks
NMR spectra were recorded on a Bruker Avance III 400 MHz
spectrometer operating at 400 MHz for H NMR and 100 MHz
1
2-(3-Methylpiperidin-1-yl)benzoxazole (4ad). White solid;
M.p. 60–63 °C; 1H NMR (400 MHz, CDCl3) δ = 7.34 (dd, J = 7.8,
0.6 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.14 (td, J = 7.7, 1.1 Hz,
1H), 6.99 (td, J = 7.8, 1.2 Hz, 1H), 4.26–4.12 (m, 2H), 3.07–2.97
(m, 1H), 2.71 (dd, J = 12.9, 10.8 Hz, 1H), 1.91–1.83 (m, 1H),
1.81–1.69 (m, 2H), 1.68–1.55 (m, 1H), 1.27–1.08 (m, 1H), 0.97
(d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 162.3, 148.7,
143.3, 123.9, 120.3, 116.0, 108.6, 53.0, 46.0, 32.7, 30.7, 24.8,
18.9. HRMS (ESI) calcd for C13H17N2O [M + H]+: 217.1335,
found: 217.1341.
for 13C NMR in CDCl3. The chemical shifts (δ) are reported in
ppm and coupling constants (J) are reported in Hz. High
resolution mass spectra (HRMS) were recorded using a Bruker
micrOTOF-QII spectrometer (ESI). GC-MS was recorded using
an Agilent 7890A/5975C. Column chromatography was gener-
ally performed on silica gel (200–300 mesh) and TLC inspec-
tions were on silica gel GF254 plates. Unless otherwise stated,
solvents were purchased from commercial suppliers and used
without further purification. NBS, amines, benzoxazole and
potassium acetate were purchased from Aldrich and used as
received. Other substituted benzoxazoles were obtained
according to the reported procedures.6d
2-Morpholinobenzoxazole (4ae).9 Colorless solid; M.p.
1
90–93 °C; H NMR (400 MHz, CDCl3) δ = 7.41 (d, J = 1.8 Hz,
1H), 7.30 (dd, J = 8.3, 1.8 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.3
Hz, 1H), 3.83–3.81 (m, 4H), 3.69–3.67 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ = 162.0, 148.7, 142.7, 124.1, 121.0, 116.5,
108.8, 66.2, 45.7. HRMS (ESI) calcd for C11H13N2O2 [M + H]+:
205.0972, found: 205.0969.
General procedures of ring-opening
The ring-opening step was according to the Chang’s pro-
cedures: benzoxazole (0.5 mmol) and amine (1 mmol,
2 equiv.) were added to a tube and the mixture was stirred
under neat conditions at the specified temperature for certain
time. After the reaction detected by TLC was complete, the
desired product 3 was obtained by column chromatography to
give the amidines 3.9,10
2-(4-Methylpiperazin-1-yl)benzoxazole (4af).9 White solid;
M.p. 36–38 °C; 1H NMR (400 MHz, CDCl3) δ = 7.36 (d, J =
7.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.16 (td, J = 7.7, 1.0 Hz,
1H), 7.05–6.98 (m, 1H), 3.75–3.70 (m, 4H), 2.57–2.51 (m, 4H),
2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 162.2, 148.7,
143.0, 124.0, 120.8, 116.3, 108.8, 54.2, 46.2, 45.5. HRMS (ESI)
calcd for C12H16N3O [M + H]+: 218.1288, found: 218.1284.
General procedures for ring-closing steps
In a 10 mL tube, amidine 3 (0.5 mmol) was stirred in 1 mL of
2-(4-Ethylpiperazin-1-yl)benzoxazole (4ag). White solid; M.p.
1
H2O and 1 mL of dioxane at 0 °C. Then KOAc (0.9 mmol, 1.8 44–46 °C; H NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 7.8 Hz,
equiv.) and NBS (0.75 mmol, 1.5 equiv.) were added directly 1H), 7.25 (s, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.7 Hz,
and stirred for 5 min in air. The crude mixture was diluted 1H), 3.78–3.70 (m, 4H), 2.60–2.55 (m, 4H), 2.49 (q, J = 7.2 Hz,
with dichloromethane (10 mL), and washed with saturated 2H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
NaCl solution (3 × 15 mL). Then the organic layer was dried δ 162.2, 148.8, 143.1, 124.0, 120.7, 116.3, 108.7, 52.4, 52.0,
over MgSO4 and concentrated under reduced pressure. Finally, 45.5, 11.9. HRMS (ESI) calcd for C13H18N3O [M + H]+:
the desired product
chromatography.
4
was obtained by column 232.1444, found: 232.1440.
2-(4-Benzhydrylpiperazin-1-yl)benzoxazole
(4ah).11 White
2-(Piperidin-1-yl)benzoxazole (4aa).9 White solid; M.p. solid; M.p. 165–167 °C; 1H NMR (400 MHz, CDCl3) δ = 7.44 (d,
1
55–57 °C; H NMR (400 MHz, CDCl3) δ = 7.36 (dd, J = 10.3, 4.6 J = 7.5 Hz, 4H), 7.39–7.33 (m, 1H), 7.31 (t, J = 7.6 Hz, 4H),
Hz, 1H), 7.28–7.21 (m, 1H), 7.15 (dd, J = 15.7, 8.0 Hz, 1H), 6.99 7.25–7.18 (m, 3H), 7.18–7.11 (m, 1H), 7.05–6.98 (m, 1H), 4.30
(t, J = 7.8 Hz, 1H), 3.66 (s, 4H), 1.68 (s, 6H). 13C NMR (s, 1H), 3.79–3.55 (m, 4H), 2.63–2.31 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ 162.4, 148.7, 143.3, 123.9, 120.3, 116.0, (100 MHz, CDCl3) δ162.2, 148.7, 143.1, 142.1, 128.6, 127.9,
108.6, 46.6, 25.3, 24.1. HRMS (ESI) calcd for C12H15N2O [M + 127.2, 123.9, 120.6, 116.2, 108.7, 76.1, 51.1, 45.8. HRMS (ESI)
H]+: 203.1179, found: 203.1170.
calcd for C24H24N3O [M + H]+: 370.1914, found: 370.1911.
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2-(3,4-Dihydroisoquinolin-2(1H)-yl)benzoxazole
(4ai).11 106.4, 101.2, 55.9, 47.4, 25.6. HRMS (ESI) calcd for C12H15N2O2
White solid; M.p. 84–86 °C; 1H NMR (400 MHz, CDCl3) δ = [M + H]+: 219.1128, found: 219.1123.
7.32 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.18–7.07 (m,
5-Chloro-2-(pyrrolidin-1-yl)benzoxazole (4db).9 Brown solid;
5H), 6.96 (td, J = 7.8, 1.2 Hz, 1H), 4.80 (s, 2H), 3.90 (t, J = 5.9 M.p. 87–89 °C; 1H NMR (400 MHz, CDCl3) δ = 7.31 (d, J =
Hz, 2H), 2.95 (t, J = 5.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 1.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.96–6.91 (m, 1H),
162.0, 148.8, 143.0, 134.0, 132.3, 128.8, 126.9, 126.6, 126.4, 3.67–3.63 (m, 4H), 2.06–1.97 (m, 4H).13C NMR (100 MHz,
124.1, 120.6, 116.3, 108.8, 47.2, 43.1, 28.5. HRMS (ESI) calcd CDCl3) δ = 161.7, 147.6, 144.9, 129.2, 119.9, 116.0, 109.1, 47.5,
for C16H15N2O [M + H]+: 251.1179, found: 251.1175.
25.6. HRMS (ESI) calcd for C11H13ClN2O [M + H]+: 223.0633,
N-Benzyl-N-methylbenzoxazol-2-amine
(2aj).7 Colorless found: 223.0640.
1
solid; M.p. 55–56 °C; H NMR (400 MHz, CDCl3) δ = 7.35–7.15
(m, 6H), 7.10 (td, J = 7.7, 1.1 Hz, 1H), 6.95 (td, J = 7.8, 1.2 Hz,
1H), 4.69 (s, 2H), 3.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ =
161.9, 147.9, 142.4, 135.4, 127.7, 126.7, 126.7, 123.0, 119.4,
Acknowledgements
115.1, 107.7, 52.8, 34.2. HRMS (ESI) calcd for C15H15N2O This work was supported by the National Natural Science
[M + H]+: 239.1179, found: 239.1182.
Foundation of China (21103207, 21103206 and 21133011).
N-Cyclohexyl-N-methylbenzoxazol-2-amine (2ak).11 Colorless
oil; 1H NMR (400 MHz, CDCl3) δ = 7.35 (dd, J = 7.8, 0.4 Hz,
1H), 7.23 (d, J = 7.9 Hz, 1H), 7.13 (td, J = 7.7, 1.0 Hz, 1H), 6.97
(td, J = 7.8, 1.1 Hz, 1H), 4.12 (ddd, J = 11.6, 7.6, 3.6 Hz, 1H),
3.05 (s, 3H), 1.89–1.77 (m, 4H), 1.70 (d, J = 13.2 Hz, 1H),
1.57–1.35 (m, 4H), 1.16–1.04 (m, 1H). 13C NMR (100 MHz,
CDCl3) δ = 162.8, 148.7, 143.5, 123.8, 119.9, 115.8, 108.5, 56.8,
30.0, 29.5, 25.6, 25.5. HRMS (ESI) calcd for C14H19N2O
[M + H]+: 231.1492, found: 231.1486.
Notes and references
1 (a) R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284;
(b) Amino Group Chemistry, From Synthesis to the Life
Sciences, ed. A. Ricci, Wiley-VCH, Weinheim, 2007;
(c) I. V. Seregin and V. Gevorgan, Chem. Soc. Rev., 2007, 36,
1173; (d) R. E. Martin, L. G. Green, W. Guba, N. Kratochwil
and A. Christ, J. Med. Chem., 2007, 50, 6291.
N,N-Diethylbenzoxazol-2-amine
(2al).6d Colorless
oil;
1H NMR (400 MHz, CDCl3) δ = 7.35 (d, J = 7.3 Hz, 1H),
7.28–7.18 (m, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.02–6.91 (m, 1H),
3.58 (q, J = 7.1 Hz, 4H), 1.28 (t, J = 7.1 Hz, 6H). 13C NMR
(100 MHz, CDCl3) δ = 162.2, 148.8, 143.6, 123.7, 119.9, 115.8,
108.4, 42.9, 13.4. GC-MS (EI-MS) calcd for C11H14N2O:190.1,
found: 190.1.
2 (a) T. Kawano, K. Hirano, T. Satoh and M. Miura, J. Am.
Chem. Soc., 2010, 132, 6900; (b) D. Monguchi, T. Fujiwara,
H. Furukawa and A. Mori, Org. Lett., 2009, 11, 1607;
(c) Q. Wang and S. L. Schreiber, Org. Lett., 2009, 11, 5178;
(d) N. Matsuda, K. Hirano, T. Satoh and M. Miura, Org.
Lett., 2011, 13, 2860.
N,N-Diisopropylbenzoxazol-2-amine (2am).6d White solid;
M.p. 52–53 °C; 1H NMR (400 MHz, CDCl3) δ = 7.35 (d, J =
7.7 Hz, 1H), 7.25 (d, J = 6.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H),
6.98 (t, J = 7.7 Hz, 1H), 4.24 (dt, J = 13.4, 6.7 Hz, 2H), 1.38 (d,
J = 6.8 Hz, 12H). 13C NMR (100 MHz, CDCl3) δ = 148.5, 123.7,
119.8, 115.5, 108.4, 58.4, 47.7, 20.8, 18.4. GC-MS (EI-MS) calcd
for C13H18N2O: 218.1, found: 218.1.
3 J. Y. Kim, S. H. Cho, J. Joseph and S. Chang, Angew. Chem.,
Int. Ed., 2010, 49, 9899.
4 S. H. Cho, J. Y. Kim, S. Y. Lee and S. Chang, Angew. Chem.,
Int. Ed., 2009, 48, 9127.
5 J. Wang, J. T. Hou, J. Wen, J. Zhang and X. Q. Yu, Chem.
Commun., 2011, 47, 3652.
6 (a) D. Monguchi, T. Fujiwara, H. Furukawa and A. Mori,
Org. Lett., 2009, 11, 1607; (b) Q. Wang and S. L. Schreiber,
Org. Lett., 2009, 11, 5178; (c) T. Kawano, K. Hirano, T. Satoh
and M. Miura, J. Am. Chem. Soc., 2010, 132, 6900;
(d) S. M. Guo, B. Qian, Y. J. Xie, C. G. Xia and H. M. Huang,
Org. Lett., 2011, 13, 522; (e) N. Matsuda, K. Hirano, T. Satoh
and M. Miura, Org. Lett., 2011, 13, 2860; (f) Y. Li, Y. Xie,
R. Zhang, K. Jin, X. Wang and C. Duan, J. Org. Chem., 2011,
76, 5444.
7 Y. M. Li, J. Liu, Y. S. Xie, R. Zhang, K. Jin, X. N. Wang and
C. Y. Duan, Org. Biomol. Chem., 2012, 10, 3715.
8 S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev.,
2011, 40, 5068.
5-Methyl-2-(pyrrolidin-1-yl)benzoxazole (4bb).9 Brown solid;
1
M.p. 100–102 °C; H NMR (400 MHz, CDCl3) δ = 7.16 (s, 1H),
7.11 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 8.1, 0.9 Hz, 1H), 3.64 (t, J =
6.7 Hz, 4H), 2.38 (s, 3H), 2.07–1.96 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ = 161.13, 147.13, 143.59, 133.47, 120.72,
116.37, 107.93, 47.40, 25.60, 21.55. HRMS (ESI) calcd for
C12H16N2O [M + H]+: 203.1179, found: 203.1175.
6-Methyl-2-(pyrrolidin-1-yl)benzoxazole (4cb).9 White solid;
M.p 94–96 °C; 1H NMR (400 MHz, CDCl3) δ = 7.23 (d, J =
7.9 Hz, 1H), 7.07 (s, 1H), 6.95 (d, J = 7.7 Hz, 1H), 3.63 (s, 4H),
2.39 (s, 3H), 2.02 (s, 4H). 13C NMR (100 MHz, CDCl3) δ = 160.8,
149.2, 141.2, 130.0, 124.5, 115.4, 109.2, 47.4, 25.6, 21.5. HRMS
(ESI) calcd for C12H16N2O [M + H]+: 203.1179, found: 203.1182.
9 J. Joseph, J. Y. Kim and S. Chang, Chem.–Eur. J., 2011, 17,
8294.
5-Methoxy-2-(pyrrolidin-1-yl)benzoxazole
(4db).9 White
solid; M.p. 72–74 °C; 1H NMR (400 MHz, CDCl3) δ = 7.12 (d, J = 10 S. Wertz, S. Kodama and A. Studer, Angew. Chem., Int. Ed.,
8.7 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.55 (dd, J = 8.7, 2.6 Hz,
2011, 50, 11511.
1H), 3.80 (s, 3H), 3.67–3.55 (m, 4H), 2.08–1.96 (m, 4H). 13C 11 (a) M. Lamani and K. R. Prabhu, J. Org. Chem., 2011, 76,
NMR (100 MHz, CDCl3) δ = 161.7, 157.0, 144.4, 143.5, 108.4,
3112 | Org. Biomol. Chem., 2014, 12, 3108–3113
7938; (b) T. Froehr, C. P. Sindlinger, U. Kloeckner,
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