Convenient synthesis of benzoxazolone derivatives by cross-coupling of benzoxazolone boronates with aryl halides

Article abstract of DOI:10.1055/s-0033-1339799

Benzoxazolone derivatives with various substituents at the C-5 position were synthesized efficiently via benzoxazolone boronates as the key intermediate. The target compounds were also synthesized from (het)aryl halides in a one-pot process. These methods permitted efficient exploratory syntheses of a series of benzoxazolone derivatives. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339799

PAPER
▌3269
paper
Convenient Synthesis of Benzoxazolone Derivatives by Cross-Coupling of
Benzoxazolone Boronates with Aryl Halides
Convenient Synthesis of Benzoxazolone Derivatives
Takayuki Fukaya,* Shuji Masumoto
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki, Suita, Osaka 564-0053, Japan
Fax +81(6)63376010; E-mail: takayuki-fukaya@ds-pharma.co.jp
Received: 15.07.2013; Accepted after revision: 18.08.2013
H2, 5% Rh/C
THF, r.t.
CDI
THF, r.t.
Br
NH2
OH
Br
NO2
OH
Abstract: Benzoxazolone derivatives with various substituents at
the C-5 position were synthesized efficiently via benzoxazolone bo-
ronates as the key intermediate. The target compounds were also
synthesized from (het)aryl halides in a one-pot process. These
methods permitted efficient exploratory syntheses of a series of
benzoxazolone derivatives.
1
2
O
t-BuO2CCH2Br
K2CO3
Ot-Bu
H
N
Key words: heterocycles, boron, cross-coupling, biaryls, catalysis,
arylations
Br
Br
N
DMF, r.t.
O
O
O
O
3
4
The benzoxazolone scaffold is an important structural
motif in a range of medicines.1–3 We recently reported that
benzoxazolone derivatives act as selective ligands for 18-
kDa translocator protein (TSPO).2 Our exploratory stud-
ies on benzoxazolone derivatives identified important
rules that link substitution at the C-5 position with the
pharmacokinetic profiles of these compounds, especially
their metabolic stability.2b As a result, we needed conve-
nient methods to prepare benzoxazolone derivatives with
various substituents in the C-5 position. Although many
arylboronate reagents are commercially available, we
needed to synthesize (het)arylboronate reagents with mul-
tiple substituents or unique substituents as intermediates
for a diversity of compounds for bioassay studies. To pre-
pare benzoxazolone derivatives with various substituents
at the C-5 position effectively, we needed to synthesize
the corresponding benzoxazolone boronates. Although
syntheses and applications of benzoxazolone boronates
have been described in several patents,3 no detailed inves-
tigation on these compounds has been reported. Here, we
present a convenient method for the synthesis of benzox-
azolone derivatives with various substituents at the C-5
position via benzoxazolone boronates as key intermedi-
ates. The method permits the preparation of several potent
TSPO ligands, including a promising compound 8j with a
high TSPO affinity and acceptable metabolic stability (see
Table S1 in the Supporting Information).
amine
O
O
HCl, 1,4-dioxane
AcOH, 50 °C
EDCI or BOPCl
DMF, r.t.
Me
N
R
O
OH
Br
Br
N
O
N
O
O
5
6a R = Ph
6b R = 4-F3CC6H4
Scheme 1 Synthesis of amides 6a and 6b
which was condensed with N-methylaniline or N-methyl-
4-(trifluoromethyl)aniline in the presence of 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDCI), 1-hydroxybenzotriazole (HOBt), or bis(2-oxo-3-
oxazolidinyl)phosphinic chloride (BOPCl) to afford the
corresponding amide derivatives 6a2a,b and 6b.
Bromobenzoxazolones 4, 6a, and 6b were cross-coupled
with bis(pinacolato)diboron under the conditions reported
by Miyaura and co-workers6 to give the corresponding
benzoxazolone boronates 7a–c in moderate yield (Table
1). Amide 6a required a slightly longer reaction time than
did ester 4 or amide 6b (entry 2).
Next, we examined the Suzuki–Miyaura reaction7 of 7a–
c with various (het)aryl bromides in refluxing 1,4-dioxane
containing 5 mol% of tetrakis(triphenylphosphine)palla-
dium as a catalyst and potassium carbonate as a base (Ta-
ble 2). The coupling reaction of amide 7b2a with aryl
bromides containing alcohol or amine groups gave mod-
erate yields of the corresponding N-aryl derivatives 8a–f2a
(entries 1–6). Whereas the cross-coupling of amine 6a
with 2-pyridineboronic acid8 under the above conditions
was unsuccessful, the reaction of amide 7b with 2-bro-
mopyridine gave the desired compound 8g2a,b in 70%
yield. A variety of pyridyl bromides containing electron-
donating or electron-withdrawing substituents underwent
Suzuki–Miyaura coupling (entries 8–12). Products 8h–j
have been reported in our patent.2a
First, we synthesized a series of 5-bromobenzoxazolone
derivatives (Scheme 1). The nitro group in the phenol 1
was reduced chemoselectively by hydrogenation over
rhodium on carbon in tetrahydrofuran4 to give the amine
2.5 Carbonylation of 2 with 1,1'-carbonyldiimidazole
(CDI) followed by N-alkylation gave the N-acetate 4.2a,b
Deprotection of 4 with hydrochloric acid gave acid 5,2a,b
SYNTHESIS 2013, 45, 3269–3275
Advanced online publication: 24.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339799; Art ID: SS-2013-F0488-OP
© Georg Thieme Verlag Stuttgart · New York

3270
T. Fukaya, S. Masumoto
PAPER
Table 1 Synthesis of Pinacol Arylboronates
R
R
O
B
Pd2(dba)3 (5 mol%)
Br
O
O
O
O
N
O
N
O
Cy3P (25 mol%), KOAc
O
+
B
B
O
O
1,4-dioxane, reflux
7a–c
Entry
R
Substrate
Product
Time (h)
Yielda (%)
1
2
3
CO2t-Bu
4
7a
7b
7c
15
28
12
78
83
76
C(O)N(Me)Ph
6a
6b
C(O)N(Me)-4-F3CC6H4
a Isolated yield.
Table 2 Suzuki–Miyaura Coupling of Benzoxazolone Boronates with Substituted (Het)aryl Bromides
R
R
O
O
O
B
N
N
Me
Pd(PPh3)4 (3 mol%)
1 M K2CO3 (aq)
Me
Ar
N
O
N
O
O
ArX
O
+
O
1,4-dioxane, reflux, 2 h
Entry
Ar
Amide
Product
Yielda (%)
1
2
3
2-
3-
4-
7b
7b
7b
8a
8b
8c
75
72
54
O
Br
HO
4
5
6
2-
3-
4-
7b
7b
7b
8d
8e
8f
43
89
70
Me2N
Br
N
7
8
7b
7b
8g
8h
70
64
Br
Br
Br
NH2
N
OMe
N
9
7b
7b
8i
8j
68
75
N
10
NC
Br
N
7b
7c
8k
8l
11
12
59
62
Br
a Isolated yield.
Finally, we examined a one-pot synthesis of the substitut- solution (entry 2). The addition of tetrakis(triphenylphos-
ed benzoxazolone 92 from ester 4 (Table 3). Benzoxazo- phine)palladium in the second coupling reaction was not
lone 9 was obtained by cross-coupling of 4 with advantageous (entry 3). Furthermore, the desired com-
bis(pinacolato)diboron, followed by coupling with bro- pound 7a2a was not obtained when the cross-coupling re-
mobenzene in the presence of potassium carbonate action of bromo compound 4 with bis(pinacolato)diboron
Synthesis 2013, 45, 3269–3275
© Georg Thieme Verlag Stuttgart · New York

PAPER
Convenient Synthesis of Benzoxazolone Derivatives
3271
Table 3 One-Pot Synthesis of Benzoxazolone 9
O
Ot-Bu
Br
N
O
O
O
O
O
B
Ot-Bu
Ot-Bu
Pd2(dba)3 (5 mol%)
PhBr
4
N
O
N
O
Pd catalyst, base
PCy (25 mol%), KOAc
O
O
O
+
reflux, 5.5 h
1,4-dioxane, reflux, 15 h
7a
O
O
O
O
9
B
B
Entry
Catalyst
Base
–
Yielda (%)
1
2
3
–
0
–
aq K2CO3
aq K2CO3
26
30
Pd(PPh3)4 (5 mol%)
a Isolated yield.
1H NMR (400 MHz, DMSO-d6): δ = 9.29 (s, 1 H), 6.72 (d, J = 2.4
Hz, 1 H), 6.56 (d, J = 8.3 Hz, 1 H), 6.50 (dd, J = 8.3, 2.4 Hz, 1 H),
4.91 (br s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 143.3, 138.6, 118.2, 116.1,
115.6, 110.6.
was conducted in the presence of potassium carbonate in-
stead of potassium acetate, as the use of the former base
resulted in recovery of the starting material. We are con-
ducting further optimization studies in attempts to im-
prove the yield of this one-pot process.
HRMS (ESI): m/z [M + H]+ calcd for C6H7BrNO: 187.9706; found:
In conclusion, we have developed a convenient method
for the synthesis of benzoxazolone derivatives with vari-
ous substituents at the C-5 position by using benzoxazo-
lone boronates as key intermediates. Furthermore, we
have developed a one-pot synthesis of the target com-
pounds from the corresponding aryl halides. These meth-
ods will permit efficient exploratory syntheses of a series
of benzoxazolone derivatives.
187.9704.
5-Bromo-1,3-benzoxazol-2(3H)-one (3)
1,1′-Carbonyldiimidazole (46.5 g, 287 mmol) was added to a solu-
tion of bromophenol 2 (49.0 g, 261 mmol) in THF (300 mL) at r.t.,
and the mixture was stirred at r.t. for 2 h. The reaction was then
quenched with 2 M aq HCl (700 mL), and the mixture was extracted
with EtOAc (2 × 500 mL). The organic layers were combined,
washed with brine (500 mL), dried (NaSO4), filtered, and concen-
trated in vacuo to give a brown solid; yield: 53.2 g (95%); mp 206–
208 °C.
Melting points were determined on a Stanford Research Systems
OptiMelt MPA100 and are uncorrected. NMR spectra were record-
ed at r.t. on a JEOL JNM-AL400 FT NMR spectrometer. Chemical
shifts are expressed in δ values (ppm) relative to TMS as an internal
standard. IR spectra were recorded on a JEOL JIR-SPX60 spec-
trometer in the ATR mode. High-resolution mass spectra were re-
corded on Thermo Fisher Scientific LTQ orbitrap Discovery MS
equipment. Elemental analyses were performed on a CE Instrument
EA1110 and a Yokokawa analytical system IC7000. In general, re-
agents and solvents were used as received from commercial suppli-
ers without further purification. The progress of reactions was
monitored by TLC on Merck silica gel 60 F254 coated glass plates,
with visualization by UV radiation (254 nm) or I2. Flash column
chromatography was performed on Merck silica gel 60 (70–230
mesh). All reactions were carried out under N2 unless otherwise
stated.
IR (ATR): 2359, 1751, 1622, 1473, 1254 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 11.99 (s, 1 H), 7.27–7.26 (m,
3 H).
13C NMR (100 MHz, DMSO-d6): δ = 154.0, 142.5, 132.0, 124.3,
115.3, 112.4, 111.3.
HRMS (ESI): m/z [M – H]– calcd for C7H3BrNO2: 211.9353; found:
211.9350.
tert-Butyl [5-Bromo-2-oxo-1,3-benzoxazol-3(2H)-yl]acetate (4)
t-BuO2CCH2Br (38.4 mL, 260 mmol) was added to a suspension of
benzoxazolone 3 (53.0 g, 248 mmol) and K2CO3 (51.3 g, 371 mmol)
in DMF (500 mL) cooled in an ice bath. The mixture was warmed
to r.t. and stirred for 3 h. H2O (1000 mL) was added, and the mixture
was extracted with 1:1 toluene– EtOAc (2 × 500 mL). The organic
layer was separated, washed with H2O (2 × 500 mL) and brine (500
mL), dried (NaSO4), filtered, and concentrated in vacuo. The resi-
due was triturated with hexane (200 mL) to give a solid that was re-
covered by filtration and washed with hexane (100 mL) to give a
beige solid; yield: 75.2 g (92%); 144–145 °C.
2-Amino-4-bromophenol (2)
5% Rh/C (5.00 g) was added to a solution of 4-bromo-2-nitrophenol
(1; 50.7 g, 233 mmol) in THF (500 mL), and the mixture was stirred
at r.t. for 11 h under H2. The mixture was then filtered through
Celite, and the filtrate was concentrated to give a brown solid; yield:
43.3 g (99%); mp 133–135 °C.
IR (ATR): 1781, 1736, 1608, 1485, 1387 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.26 (dd, J = 8.5, 1.9 Hz, 1 H),
7.10 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 1.9 Hz, 1 H), 4.43 (s, 2 H),
1.48 (s, 9 H).
IR (ATR): 3062, 1497, 1444, 1437, 1279 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3269–3275

3272
T. Fukaya, S. Masumoto
PAPER
13C NMR (100 MHz, CDCl3): δ = 165.3, 154.0, 141.6, 132.1, 125.6,
116.5, 111.7, 111.5, 83.8, 43.9, 28.0.
HRMS (ESI): m/z [M + H]+ calcd for C13H15BrNO4: 328.0179;
found: 328.0181.
13C NMR (100 MHz, CDCl3): δ = 164.6, 154.1, 145.0, 141.6, 132.4,
127.8 (m), 127.7 (m), 125.6, 124.8, 122.1, 116.5, 112.0, 111.5, 43.9,
37.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H13BrF3N2O3: 429.0056;
found: 429.0054.
Anal. Calcd for C13H14BrNO4: C, 47.58; H, 4.30; N, 4.27; Br, 24.35.
Found: C, 47.72; H, 4.30; N, 4.32; Br, 24.04.
Anal. Calcd for C17H12BrF3N2O3: C, 47.57; H, 2.82; N, 6.53; Br,
18.62; F, 13.28. Found: C, 47.58; H, 2.84; N, 6.54; Br, 18.68; F,
13.22.
[5-Bromo-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic Acid (5)
4 M HCl in 1,4-dioxane (0.518 mL) was added to a solution of ester
4 (170 mg, 0.518 mmol) in AcOH (1.0 mL). The mixture was stirred
at 50 °C for 6.5 h then cooled to r.t. The solvent was removed in
vacuo, and the resulting solid was triturated with Et2O (2.0 mL) to
give a white solid; yield: 132 mg (94%); mp 204–206 °C.
IR (ATR): 2953, 1736, 2701, 1483, 1227 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 13.42 (br s, 1 H), 7.68 (d, J =
Pinacol Aryboronates 7a–c; General Procedure
Bis(pinacolato)diboron (1.1 equiv), Pd2(dba)3 (5 mol%), PCy3 (25
mol%), and KOAc (1.5 equiv) were added to a suspension of the ap-
propriate 5-bromo-1,3-benzoxazol-2-one in 1,4-dioxane (0.20 M)
at r.t. The mixture was stirred at reflux for the appropriate time then
cooled to r.t. H2O was added, and the mixture was extracted with
EtOAc. The organic layers were combined, washed with brine,
dried (NaSO4), filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel; hexane–EtOAc).
1.7 Hz, 1 H), 7.37–7.33 (m, 2 H), 4.66 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.6, 153.6, 141.1, 132.7,
125.0, 115.8, 112.6, 111.6, 43.1.
HRMS (ESI): m/z [M – H]– calcd for C9H5BrNO4: 269.9407; found:
269.9406.
tert-Butyl [2-Oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1,3-benzoxazol-3(2H)-yl]acetate (7a)
Prepared from ester 4 (5.00 g, 15.2 mmol) as a white solid; yield:
4.46 g (78%); mp 176–178 °C.
2-[5-Bromo-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phen-
ylacetamide (6a)
IR (ATR): 1768, 1745, 1458, 1342, 1238 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 1 H), 7.31 (s,
1 H), 7.22 (d, J = 8.0 Hz, 1 H), 4.46 (s, 2 H), 1.47 (s, 9 H), 1.35 (s,
12 H).
13C NMR (100 MHz, CDCl3): δ = 165.6, 154.4, 145.0, 130.5, 130.1,
113.9, 109.6, 84.1, 83.4, 43.8, 27.9, 24.8.
HRMS (ESI): m/z [M – H]– calcd for C19H25BNO6: 374.1780;
found: 374.1776.
PhNHMe (4.78 mL, 44.1 mmol), 1-hydroxybenzotriazole (4.97 g,
36.8 mmol), and EDCI·HCl (9.07 g, 47.3 mmol) were added to a so-
lution of acid 5 (10.0 g, 36.8 mmol) in DMF (100 mL) at r.t., and
the mixture was stirred at r.t. for 6 h. H2O (200 mL) was added and
the mixture was extracted with 1:1 toluene–EtOAc (2 × 200 mL).
The organic layer was separated, washed sequentially with H2O
(2 × 200 mL), 1 M aq HCl (200 mL), and brine (200 mL) then dried
(NaSO4) and filtered. The solvent was removed in vacuo, and the
residue was purified by column chromatography [silica gel, hex-
ane–EtOAc (1: 1)]. The solvent was again removed in vacuo, and
the resulting solid was crystallized (i-PrOH) to give a white solid;
yield: 7.16 g (54%); mp 122–124 °C (i-PrOH).
Anal. Calcd for C19H26BNO6: C, 60.82; H, 6.98; N, 3.73. Found: C,
60.81; H, 7.07; N, 3.73.
N-Methyl-2-[2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1,3-benzoxazol-3(2H)-yl]-N-phenylacetamide (7b)
Prepared from amide 6a (6.18 g, 17.1 mmol) as a white solid; yield:
5.81 g (83%); mp 163–164 °C.
IR (ATR): 1772, 1666, 1483, 1377, 1244 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 7.6, 7.6 Hz, 2 H),
7.45 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 2 H), 7.23 (dd, J = 8.3,
1.7 Hz, 1 H), 7.06 (d, J = 8.3 Hz, 1 H), 7.01 (d, J = 1.7 Hz, 1 H),
4.28 (s, 2 H), 3.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.7, 154.2, 141.8, 141.6, 132.6,
130.5, 129.0, 127.2, 125.4, 116.4, 112.0, 111.3, 43.9, 37.8.
IR (ATR): 1788, 1668, 1458, 1379, 1342 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 7.8, 1.0 Hz, 1 H),
7.52 (dd, J = 7.6, 7.6 Hz, 2 H), 7.44 (dd, J = 7.6, 7.6 Hz, 1 H), 7.37
(d, J = 7.6 Hz, 2 H), 7.28 (br s, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 4.32
(s, 2 H), 3.32 (s, 3 H), 1.36 (s, 12 H).
13C NMR (100 MHz, CDCl3): δ = 165.1, 154.5, 145.1, 141.9, 131.0,
130.4, 129.9, 128.8, 127.3, 114.0, 109.5, 84.0, 43.7, 37.7, 24.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H14BrN2O3: 361.0182;
found: 361.0177.
Anal. Calcd for C16H13BrN2O3: C, 53.21; H, 3.63; N, 7.76; Br,
22.12. Found: C, 53.15; H, 3.68; N, 7.84; Br, 21.90.
HRMS (ESI): m/z [M – H]– calcd for C22H24BN2O5: 407.1784;
found: 407.1775.
2-[5-Bromo-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-[4-
(trifluoromethyl)phenyl]acetamide (6b)
Anal. Calcd for C22H25BN2O5: C, 64.72; H, 6.17; N, 6.86. Found: C,
64.57; H, 6.28; N, 6.72.
N-methyl-4-(trifluoromethoxy)aniline (1.42 g, 8.11 mmol), BOPCl
(2.82 g, 11.1 mmol), and Et3N (3.10 mL, 22.2 mmol) were added to
a solution of acid 5 (2.01 g, 7.39 mmol) in DMF (10 mL) at r.t., and
the mixture was stirred at r.t. for 3 h. H2O (30 mL) was added, and
the mixture was extracted with 1:1 toluene–EtOAc (2 × 30 mL).
The organic layer was separated, washed sequentially with H2O
(2 × 30 mL) and brine (30 mL), dried (NaSO4), and filtered. The
solvent was removed in vacuo, and the residue was purified by col-
umn chromatography [silica gel, hexane–EtOAc (3: 1)] to give a
white solid; yield: 2.60 g (82%); mp 137–139 °C (i-PrOH).
N-Methyl-2-[2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1,3-benzoxazol-3(2H)-yl]-N-[4-(trifluoromethyl)phe-
nyl]acetamide (7c)
Prepared from amide 6b (2.46 g, 5.73 mmol) as a white solid; yield:
2.07 g (76%); mp 156–157 °C.
IR (ATR): 1792, 1655, 1464, 1344, 1321 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.0 Hz, 2 H), 7.61 (dd,
J = 8.0, 1.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.29 (br s, 1 H), 7.20
(d, J = 8.0 Hz, 1 H), 4.33 (s, 2 H), 3.35 (s, 3 H), 1.35 (s, 12 H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 154.4, 145.2, 145.1, 130.8,
130.1, 127.9 (m), 127.6 (m), 114.0, 109.6, 84.1, 43.8, 37.7.
HRMS (ESI): m/z [M – H]– calcd for C23H23BF3N2O5: 475.1658;
found: 475.1661.
IR (ATR): 1794, 1663, 1612, 1485, 1323 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 2 H), 7.50 (d,
J = 8.0 Hz, 2 H), 7.24 (dd, J = 8.5, 2.0 Hz, 1 H), 7.07 (d, J = 8.5 Hz,
1 H), 7.03 (s, 1 H), 4.29 (s, 2 H), 3.35 (s, 3 H).
Synthesis 2013, 45, 3269–3275
© Georg Thieme Verlag Stuttgart · New York

PAPER
Convenient Synthesis of Benzoxazolone Derivatives
3273
Anal. Calcd for C23H24BF3N2O5: C, 58.00; H, 5.08; N, 5.88. Found:
C, 58.06; H, 5.10; N, 5.93.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O5: 419.1601; found:
419.1596.
Anal. Calcd for C24H22N2O5·0.25 H2O: C, 68.15; H, 5.36; N, 6.62.
Found: C, 68.24; H, 5.35; N, 6.57.
Amides 8a–l; General Procedure
Pd(PPh3)4 (3 mol%) was added to a suspension of the appropriate
benzoxazole 7 and (het)aryl bromide (1 equiv) in 1 M aq K2CO3 (3
equiv) and 1,4-dioxane (0.15 M) at r.t. The mixture was stirred at
reflux for 2 h then cooled to r.t. H2O was added, and the mixture was
extracted with EtOAc. The organic layers were combined, washed
with brine, dried (NaSO4), filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
hexane–EtOAc or CHCl3–MeOH).
2-[5-{2-[(Dimethylamino)methyl]phenyl}-2-oxo-1,3-benzoxa-
zol-3(2H)-yl]-N-methyl-N-phenylacetamide (8d)
Prepared from 7b (150 mg, 367 μmol) and 2-BrC6H4NMe2 (78.7
mg, 367 μmol) as a brown solid; yield: 66.0 mg (43%); mp 106–
107 °C.
IR (ATR): 1782, 1697, 1684, 653, 1558 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.46 (m, 3 H), 7.43 (dd, J =
6.8, 6.8 Hz, 1 H), 7.38–7.29 (m, 4 H), 7.28–7.24 (m, 1 H), 7.21 (d,
J = 8.0 Hz, 1 H), 7.11 (dd, J = 8.0, 1.7 Hz, 1 H), 7.09–7.06 (m, 1 H),
4.32 (s, 2 H), 3.29 (s, 3 H), 3.27 (s, 2 H), 2.18 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.0, 154.9, 142.0, 141.8, 141.8,
137.5, 136.4, 130.9, 130.4, 130.4, 130.3, 128.8, 127.4, 127.3, 126.9,
124.0, 110.1, 109.4, 61.2, 45.3, 43.8, 37.8.
2-{5-[2-(2-Hydroxyethoxy)phenyl]-2-oxo-1,3-benzoxazol-
3(2H)-yl}-N-methyl-N-phenylacetamide (8a)
Prepared from amide 7b (55.0 mg, 135 μmol) and 2-(2-bromophe-
noxy)ethanol (29.3 mg, 135 μmol) as a white solid; yield: 42.6 mg
(75%); mp 158–160 °C (i-PrOH).
IR (ATR): 1780, 1653, 1485, 1385, 1255 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 7.3, 7.3 Hz, 2 H),
7.43 (dd, J = 7.3, 7.3 Hz, 1 H), 7.35–7.31 (m, 5 H), 7.23 (d, J = 8.3
Hz, 1 H), 7.15 (dd, J = 8.3, 1.7 Hz, 1 H), 7.07–7.03 (m, 1 H), 6.99
(d, J = 7.8 Hz, 1 H), 4.34 (s, 2 H), 4.06 (t, J = 4.1 Hz, 2 H), 3.91–
3.89 (br m, 2 H), 3.52–3.50 (br m, 1 H), 3.33 (s, 3 H).
HRMS (ESI): m/z calcd for C25H26N3O3: 416.1969; found:
416.1958.
Anal. Calcd for C25H25N3O3·0.25 H2O: C, 71.49; H, 6.12; N, 10.01.
Found: C, 71.64; H, 6.18; N, 10.26.
13C NMR (100 MHz, CDCl3): δ = 166.2, 155.7, 154.7, 141.9, 141.7,
134.5, 130.8, 130.7, 130.5, 130.2, 129.0, 128.9, 127.2, 123.5, 121.2,
112.4, 111.5, 109.7, 70.4, 61.3, 43.9, 37.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O5: 419.1601; found:
419.1594.
2-[5-{3-[(Dimethylamino)methyl]phenyl}-2-oxo-1,3-benzoxa-
zol-3(2H)-yl]-N-methyl-N-phenylacetamide (8e)
Prepared from 7b (150 mg, 367 μmol) and 3-BrC6H4NMe2 (78.7
mg, 367 μmol) as a white solid; yield: 136 mg (89%); mp 146–
148 °C.
IR (ATR): 1778, 1662, 1595, 1487, 1383 cm–1.
Anal. Calcd for C24H22N2O5: C, 68.89; H, 5.30; N, 6.69. Found: C,
68.55; H, 5.35; N, 6.85.
1H NMR (400 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.52 (dd, J = 7.5, 7.5
Hz, 2 H), 7.45 (dd, J = 7.5. 7.5 Hz, 2 H), 7.43–7.37 (m, 3 H), 7.33–
7.28 (m, 2 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.15 (s, 1 H), 4.37 (s, 2 H),
3.59 (s, 2 H), 3.32 (s, 3 H), 2.36 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.2, 154.8, 142.2, 142.0, 141.0,
137.6, 131.8, 130.4, 128.8, 128.3, 128.2, 127.3, 126.4, 121.8, 110.0,
107.7, 64.1, 45.1, 43.9, 37.8.
2-{5-[3-(2-Hydroxyethoxy)phenyl]-2-oxo-1,3-benzoxazol-
3(2H)-yl}-N-methyl-N-phenylacetamide (8b)
Prepared from amide 7b (55.0 mg, 135 μmol) and 2-(3-bromophe-
noxy)ethanol (29.3 mg, 135 μmol) as a white solid; yield: 40.8 mg
(72%); mp 145–147 °C (i-PrOH).
IR (ATR): 1782, 1662, 1597, 1587, 1485 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C25H26N3O3: 416.1969; found:
416.1959.
1H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 7.6, 7.6 Hz, 2 H),
7.44 (dd, J = 7.6, 7.6 Hz, 1 H), 7.37–7.35 (m, 3 H), 7.29 (dd, J = 8.3,
1.7 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.16–7.12 (m, 1 H), 7.11–
7.08 (m, 1 H), 7.03 (d, J = 1.7 Hz, 1 H), 6.92 (dd, J = 7.8, 2.2 Hz, 1
H), 4.35 (s, 2 H), 4.16 (t, J = 4.5 Hz, 2 H), 4.02–4.00 (m, 2 H), 3.32
(s, 3 H), 2.06 (t, J = 6.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 165.1, 159.0, 154.8, 142.5, 142.3,
142.0, 137.6, 131.7, 130.5, 129.9, 128.9, 127.3, 121.8, 120.3, 114.1,
113.2, 110.1, 107.6, 69.3, 61.5, 43.9, 37.8.
Anal. Calcd for C25H25N3O3·0.50 H2O: C, 70.74; H, 6.17; N, 9.90.
Found: C, 70.74; H, 6.04; N, 10.11.
2-[5-{4-[(Dimethylamino)methyl]phenyl}-2-oxo-1,3-benzoxa-
zol-3(2H)-yl]-N-methyl-N-phenylacetamide (8f)
Prepared from 7b (150 mg, 367 μmol) and 4-BrC6H4NMe2 (78.7
mg, 367 μmol) as a brown solid; yield: 107 mg (70%); mp 64–
66 °C.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O5: 419.1601; found:
419.1595.
IR (ATR): 1774, 1668, 1595, 1489, 1385 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.41 (m, 5 H), 7.40–7.32 (m,
4 H), 7.32–7.26 (m, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.04 (s, 1 H),
4.35 (s, 2 H), 3.48 (s, 2 H), 3.32 (s, 3 H), 2.28 (s, 6 H).
Anal. Calcd for C24H22N2O5: C, 68.89; H, 5.30; N, 6.69. Found: C,
68.51; H, 5.36; N, 6.71.
13C NMR (100 MHz, CDCl3): δ = 165.1, 154.8, 142.1, 142.0, 139.6,
138.1, 137.7, 131.7, 130.5, 129.6, 128.9, 127.2, 127.2, 121.7, 110.1,
107.4, 64.0, 45.4, 43.9, 37.8.
HRMS (ESI): m/z [M + H]+ calcd for C25H26N3O3: 416.1969; found:
416.1961.
2-{5-[4-(2-Hydroxyethoxy)phenyl]-2-oxo-1,3-benzoxazol-
3(2H)-yl}-N-methyl-N-phenylacetamide (8c)
Prepared from amide 7b (55.0 mg, 135 μmol) and 2-(4-bromophen-
oxy)ethanol (29.3 mg, 135 μmol) as a white solid; yield: 30.5 mg
(54%); mp 175–177 °C (i-PrOH).
IR (ATR): 1774, 1674, 1597, 1489, 1383 cm–1.
Anal. Calcd for C25H25N3O3·0.75 H2O: C, 69.99; H, 6.23; N, 9.79.
Found: C, 70.27; H, 6.16; N, 9.48.
1H NMR (400 MHz, CDCl3): δ = 7.51 (dd, J = 7.6, 7.6 Hz, 2 H),
7.48–7.42 (m, 3 H), 7.34 (d, J = 7.1 Hz, 2 H), 7.26–7.19 (m, 2 H),
7.02–6.97 (m, 3 H), 4.35 (s, 2 H), 4.14 (t, J = 4.5 Hz, 2 H), 4.04–
3.97 (m, 2 H), 3.32 (s, 3 H), 2.04 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 165.2, 158.3, 154.8, 142.0, 141.9,
137.5, 133.9, 131.7, 130.5, 128.9, 128.5, 127.2, 121.4, 114.9, 110.1,
107.2, 69.3, 61.5, 43.9, 37.8.
N-Methyl-2-[2-oxo-5-(pyridin-2-yl)-1,3-benzoxazol-3(2H)-yl]-
N-phenylacetamide (8g)
Compound 8g was prepared from 7b (150 mg, 367 μmol) and 2-bro-
mopyridine (35.0 μL, 367 μmol) as a beige solid; yield: 92.5 mg
(70%); mp 166–168 °C (i-PrOH).
IR (ATR): 1786, 1660, 1587, 1471, 1464 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3269–3275

3274
T. Fukaya, S. Masumoto
PAPER
1H NMR (400 MHz, CDCl3): δ = 8.68 (d, J = 4.9 Hz, 1 H), 7.79–
7.73 (m, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.53
(dd, J = 7.3, 7.3 Hz, 2 H), 7.45 (t, J = 7.3 Hz, 1 H), 7.37 (d, J = 7.3
Hz, 2 H), 7.29–7.23 (m, 2 H), 4.39 (s, 2 H), 3.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.1, 156.7, 154.7, 149.5, 143.4,
142.0, 136.9, 135.9, 132.0, 130.4, 128.9, 127.3, 122.2, 121.4, 120.6,
110.0, 107.4, 43.9, 37.8.
HRMS (ESI): m/z [M + H]+ calcd for C22H17N4O3: 385.1295; found:
385.1294.
Anal. Calcd for C22H16N4O3: C, 68.74; H, 4.20; N, 14.58. Found: C,
68.39; H, 4.10; N, 14.46.
N-Methyl-2-[5-(2-methylpyridin-3-yl)-2-oxo-1,3-benzoxazol-
3(2H)-yl]-N-phenylacetamide (8k)
Prepared from 7b (70.0 mg, 171 μmol) and 3-bromo-5-methylpyri-
dine (35.4 mg, 206 μmol) as a beige solid; yield: 37.4 mg (59%); mp
152–154 °C (i-PrOH).
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3O3: 360.1343; found:
360.1341.
IR (ATR): 1786, 1670, 1597, 1497, 1427 cm–1.
Anal. Calcd for C21H17N3O3: C, 70.18; H, 4.77; N, 11.69. Found: C,
70.05; H, 4.83; N, 11.67.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 4.9 Hz, 1 H), 7.54–
7.47 (m, 3 H), 7.44 (dd, J = 7.6, 7.6 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 2
H), 7.28–7.23 (m, 1 H), 7.23–7.17 (m, 1 H), 7.04 (dd, J = 8.2, 1.8
Hz, 1 H), 6.80 (s, 1 H), 4.33 (s, 2 H), 3.31 (s, 3 H), 2.49 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.0, 156.0, 154.7, 148.2, 142.1,
141.9, 137.4, 136.3, 136.0, 131.5, 130.5, 128.9, 127.2, 123.4, 121.0,
109.9, 109.3, 43.9, 37.8, 23.5.
2-[5-(6-Aminopyridin-2-yl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-
methyl-N-phenylacetamide (8h)
Prepared from 7b (100 mg, 245 μmol) and 6-bromopyridin-2-amine
(42.4 mg, 245 μmol) as a white solid; yield: 59.1 mg (64%); mp
214–216 °C (i-PrOH).
IR (ATR): 1782, 1662, 1593, 1462, 1441 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63 (dd, J = 8.3, 1.7 Hz, 1 H),
7.55–7.48 (m, 4 H), 7.44 (dd, J = 7.3, 7.3 Hz, 1 H), 7.36 (d, J = 7.3
Hz, 2 H), 7.22 (d, J = 8.3 Hz, 1 H), 7.05 (d, J = 7.3 Hz, 1 H), 6.48
(d, J = 7.3 Hz, 1 H), 4.55 (s, 2 H), 4.38 (s, 2 H), 3.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.2, 158.2, 155.3, 154.8, 143.1,
142.0, 138.5, 136.2, 131.6, 130.4, 128.8, 127.3, 121.4, 110.9, 109.8,
107.3, 107.2, 43.9, 37.8.
HRMS (ESI): m/z [M + H]+ calcd for C22H20N3O3: 374.1499; found:
374.1493.
Anal. Calcd for C22H19N3O3·0.25 H2O: C, 69.92; H, 5.20; N, 11.12.
Found: C, 70.23; H, 5.21; N, 10.78.
N-Methyl-2-[5-(2-methylpyridin-3-yl)-2-oxo-1,3-benzoxazol-
3(2H)-yl]-N-[4-(trifluoromethyl)phenyl]acetamide (8l)
Prepared from 7c (81.7 mg, 171 μmol) and 3-bromo-5-methylpyri-
dine (35.4 mg, 206 μmol) as a pale-yellow solid; yield: 46.8 mg
(62%); mp 167–169 °C (i-PrOH).
HRMS (ESI): m/z [M + H]+ calcd for C21H19N4O3: 375.1452; found:
375.1450.
IR (ATR): 1794, 1667, 1612, 1381, 1323 cm–1.
Anal. Calcd for C21H18N4O3·0.25 H2O: C, 66.57; H, 4.92; N, 14.79.
Found: C, 66.69; H, 4.74; N, 14.55.
1H NMR (400 MHz, CDCl3): δ = 8.53 (dd, J = 4.9, 1.7 Hz, 1 H),
7.79 (d, J = 7.8 Hz, 2 H), 7.54–7.46 (m, 3 H), 7.29–7.24 (m, 2 H),
7.20 (dd, J = 7.8, 4.9 Hz, 1 H), 7.05 (dd, J = 8.3, 1.7 Hz, 1 H), 6.83
(s, 1 H), 4.34 (s, 2 H), 3.34 (s, 3 H), 2.49 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.8, 156.0, 154.6, 148.3, 145.1,
142.1, 137.4, 136.3, 136.2, 136.1, 131.3, 127.8 (m), 127.7 (m),
127.6 (m), 123.6, 121.0, 110.1, 109.3, 43.9, 37.8, 23.5.
2-[5-(6-Methoxypyridin-2-yl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-
N-methyl-N-phenylacetamide (8i)
Prepared from 7b (55.0 mg, 135 μmol) and 2-bromo-6-meth-
oxypyridine (25.3 mg, 135 μmol) as a white solid; yield: 35.6 mg
(68%); mp 179–181 °C (i-PrOH).
IR (ATR): 1778, 1668, 1597, 1576, 1497 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.77 (dd, J = 8.5, 1.7 Hz, 1 H),
7.64 (m, 1 H), 7.58 (d, J = 1.7 Hz, 1 H), 7.52 (dd, J = 7.6, 7.6 Hz, 2
H), 7.44 (dd, J = 7.6, 7.6 Hz, 1 H), 7.36–7.29 (m, 3 H), 7.24 (d, J =
8.5 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H), 4.39 (s, 2 H), 4.05 (s, 3 H),
3.33 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C23H19F3N3O3: 442.1373;
found: 442.1359.
Anal. Calcd for C23H18F3N3O3·0.25 H2O: C, 61.95; H, 4.18; N, 9.42;
F, 12.78. Found: C, 62.13; H, 4.19; N, 9.26; F, 12.63.
13C NMR (100 MHz, CDCl3): δ = 165.1, 163.7, 154.8, 153.9, 143.3,
142.1, 139.3, 135.6, 131.6, 130.4, 128.9, 127.2, 121.4, 112.9, 110.0,
109.2, 107.0, 53.3, 43.9, 37.8.
HRMS (ESI): m/z [M + H]+ calcd for C22H20N3O4: 390.1448; found:
390.1445.
tert-Butyl (2-Oxo-5-phenyl-1,3-benzoxazol-3(2H)-yl)acetate (9)
Bis(pinacolato)diboron (277 mg, 1.10 mmol), Pd2(dba)3 (45.8 mg,
50.0 μmol), PCy3 (33.7 mg, 120 μmol), and KOAc (147 mg, 1.50
mmol) were added to a suspension of ester 4 (328 mg, 1.00 mmol)
in 1,4-dioxane (6.0 mL) at r.t. The mixture was stirred at reflux for
15 h then cooled to r.t. PhBr (116 μL, 1.10 mmol) and 1 M aq
K2CO3 (3.0 mL) were added, and the mixture was refluxed with stir-
ring for a further 5.5 h then cooled to r.t. H2O (10 mL) was added,
and the mixture was extracted with EtOAc (2 × 15 mL). The organic
layer was separated, washed with brine (10 mL), dried (NaSO4), fil-
tered, and concentrated in vacuo. The residue was purified by col-
umn chromatography [silica gel, hexane–EtOAc (1:7)] to give a
yellow solid; yield: 84.6 mg (26%); mp 99–100 °C (MeOH).
Anal. Calcd for C22H19N3O4: C, 67.86; H, 4.92; N, 10.79. Found: C,
67.49; H, 4.83; N, 10.60.
2-[5-(5-Cyanopyridin-3-yl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-
methyl-N-phenylacetamide (8j)
Prepared from 7b (245 mg, 600 μmol) and 5-bromopyridine-3-car-
bonitrile (110 mg, 600 μmol) as a white solid; yield: 172 mg (75%);
mp 270–272 °C (MeOH).
IR (ATR): 1759, 1743, 1485, 1230, 1026 cm–1.
IR (ATR): 1778, 1657, 1595, 1385, 1246 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.50 (m, 2 H), 7.45 (dd, J =
7.4, 7.4 Hz, 2 H), 7.40–7.32 (m, 2 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.05
(d, J = 1.7 Hz, 1 H), 4.50 (s, 2 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 165.6, 154.7, 142.1, 140.6, 138.0,
131.3, 128.9, 127.5, 127.2, 122.0, 110.3, 107.2, 83.5, 43.9, 28.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO4: 326.1387; found:
326.1395.
1H NMR (400 MHz, CDCl3): δ = 9.00 (d, J = 2.2 Hz, 1 H), 8.87 (d,
J = 2.2 Hz, 1 H), 8.11 (dd, J = 2.2, 2.2 Hz, 1 H), 7.55 (dd, J = 7.6,
7.6 Hz, 2 H), 7.47 (dd, J = 7.6, 7.6 Hz, 1 H), 7.40–7.26 (m, 4 H),
7.04 (d, J = 1.5 Hz, 1 H), 4.38 (s, 2 H), 3.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 154.3, 151.6, 150.8, 143.4,
141.8, 137.4, 136.6, 132.6, 131.8, 130.6, 129.1, 127.3, 122.0, 116.5,
110.9, 110.1, 107.6, 44.0, 37.8.
Anal. Calcd for C19H19NO4·0.25 H2O: C, 69.18; H, 5.96; N, 4.25.
Found: C, 69.32; H, 5.85; N, 4.64.
Synthesis 2013, 45, 3269–3275
© Georg Thieme Verlag Stuttgart · New York

PAPER
Convenient Synthesis of Benzoxazolone Derivatives
3275
Papillion, J. WO 2010/130773, 2010; Chem. Abstr. 2010,
153, 643461. (c) Courtney, S. M.; Prime, M.; Mitchell, W.;
Brown, C. J.; De Aguiar Pena, P. C.; Johnson, P.;
Dominguez, C.; Toledo-Sherman, L. M.; Munoz, I. WO
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(4) Akao, A.; Sato, K.; Nonoyama, N.; Mase, T.; Yasuda, N.
Tetrahedron Lett. 2006, 47, 969.
Acknowledgment
We thank Ms. K. Bando for performing the elemental analysis, and
Mr. H. Toda and Ms. S. Takayama for recording the high-resolution
mass spectra.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
(5) von Wantoch Rekowski, M.; Pyriochou, A.;
nnfomartit
Papapetropoulos, N.; Stöβel, A.; Papapetropoulos, A.;
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(7) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3269–3275