The Journal of Organic Chemistry
Article
consumption of 1, the reaction mixture was cooled to room
temperature and concentrated. The crude mixture was purified by
flash column chromatography on silica gel using a mixture of ethyl
acetate and hexanes (EtOAc:hexanes = 1:20) as an eluent.
Method B: A solution of arene boronic acid 1 (0.50 mmol; 1.0
equiv) and AcOH (0.050 mL; 2.5 mmol; 5.0 equiv) in 1,4-dioxane (10
mL) was allowed to stir at 100 °C in an open flask, and the reaction
mixture was monitored by TLC. Once 1 was completely consumed,
the reaction mixture was cooled to room temperature and
concentrated. The crude mixture was purified by flash column
chromatography on silica gel using a mixture of ethyl acetate and
hexanes (EtOAc:hexanes = 1:20) as an eluent.
solvent. The undissolved solid was collected by filtration to recover
MIDA. The filtrate was purified by flash column chromatography on
silica gel using acetone as an eluent to afford a white solid. Then, the
solid obtained was redissolved in a minimum of acetone to which Et O
2
was slowly added to promote crystallization. MIDA boronate 1a-
MIDA was collected by filtration as a white solid. Yield: 0.25 g (90%).
1
H NMR (300 MHz, DMSO-d , 2.50 ppm) δ 7.21 (d, J = 9.5 Hz, 2H),
6
6.69 (d, J = 8.5 Hz, 2H), 4.26 (d, J = 17.3 Hz, 2H), 4.02 (d, J = 17 Hz,
2H), 2.89 (s, 6H), 2.45 (s, 3H). 13C NMR (125 MHz, DMSO-d6,
ppm) δ 172.3, 170.2, 151.46, 133.9, 112.3, 62.1, 57.4, 48.0. HRMS
(EI) calcd for C H BN O 276.1281, found 276.1281.
13
17
2
4
ortho-Functionalization of Electron-Rich Arene Boronic
Acids Using a Boronic Acid Moiety as a Blocking Group in
EAS Reactions. Synthesis of 2-Bromo-N,N-dimethylaniline (4). A
solution of MIDA boronate 1a-MIDA (0.28 g; 1.0 mmol; 1.0 equiv)
and N-bromosuccinimide (NBS, 0.21 g; 1.2 mmol; 1.2 equiv) in a
Method C: To a solution of arene boronic acid 1 (0.10 mmol; 1.0
equiv) in DMSO (1.0 mL) was added K CO (0.069 g; 0.50 mmol; 5.0
2
3
equiv). The reaction mixture was heated 100 °C in an open flask and
monitored by TLC. On the complete consumption of 1, the reaction
mixture was cooled to room temperature. The crude mixture was
purified by flash column chromatography on silica gel using a mixture
of ethyl acetate and hexanes (EtOAc:hexanes = 1:20) as an eluent.
N,N-Dimethylaniline (2a). Compound 2a was obtained as a
colorless liquid. The spectroscopic data of 2a obtained were in good
mixture of DMF and CH Cl (1:1, 10 mL) was allowed to stir under
2 2
an argon atmosphere at room temperature, and the reaction was
monitored by TLC. On the complete consumption of 1a-MIDA, the
reaction mixture was concentrated under reduced pressure. The crude
mixture was redissolved in THF (10 mL), and 1.0 M NaOH (3.0 mL;
3.0 mmol; 3.0 equiv) was added to the solution. The resulting mixture
was stirred at room temperature and monitored by TLC. After
complete consumption of the resulting MIDA boronate, a saturated
aqueous solution of ammonium chloride (9.0 mL) was added, and
then the reaction was stirred vigorously for 5 min. The resulting
mixture was poured into a 100 mL separatory funnel and extracted
28
agreement with the literature. Yield: 0.011 g (94%, Method A);
1
0
.056 g (93%, Method B). H NMR (300 MHz, CDCl , 7.26 ppm) δ
3
7
.25 (t, J = 7.8 Hz, 2H), 6.76−6.70 (m, 3H), 2.94 (s, 6H).
Anisole (2d). Compound 2d was obtained as a colorless liquid. The
spectroscopic data of 2d obtained were in good agreement with a
29
1
commercially available sample. Yield: 0.050 g (92%, Method B). H
NMR (300 MHz, CDCl , 7.26 ppm) δ 7.32−7.27 (m, 2H), 6.98−6.90
with diethyl ether. The combined organic layer was dried over MgSO
4
3
(
m, 3H), 3.81 (s, 3H).
Boronic acid 1f also provided anisole 2d in 93% yield (0.050 g,
and concentrated under reduced pressure. The crude residue was
dissolved in 1,4-dioxane (10 mL) and AcOH (0.30 mL). The reaction
mixture was stirred at 100 °C and monitored by TLC. After complete
protodeboronation of the resulting boronic acid, the reaction mixture
was cooled to room temperature and concentrated. The crude residue
was further purified by flash chromatography on silica gel using a
mixture of ethyl acetate and hexanes (EtOAc:hexanes = 1:15) to afford
the compound as a light yellow oil. Yield: 0.12 g (60%) over three
steps. The spectroscopic data were in good agreement with the
Method B).
1
,3-Dimethoxybenzene (2g). Compound 2g was obtained as a
white solid. The spectroscopic data of 2g obtained were in good
30
1
agreement with the literature. Yield: 0.064 g (93%, Method B). H
NMR (300 MHz, CDCl , 7.26 ppm) δ 7.20 (t, J = 8.2 Hz, 1H), 6.54−
3
6
.48 (m, 3H), 3.81 (s, 6H).
Boronic acid 1h also provided anisole 2g in 91% yield (0.063 g,
19
1
Method B).
literature. H NMR (300 MHz, CDCl , 7.26 ppm) δ 7.57−7.54 (m,
3
1
,2-Dimethoxybenzene (2i). Compound 2i was obtained as a white
1H), 7.29−7.24 (m, 1H), 7.11−7.08 (m, 1H), 6.92−6.87 (m, 1H),
2.80 (s, 6H).
solid. The spectroscopic data of 2i obtained were in good agreement
31
1
with the literature. Yield: 0.067 g (97%, Method B). H NMR (300
Synthesis of 2-Bromoanisole (7). To a solution of 1d-pin (0.23 g;
1
.0 mmol, 1.0 equiv) in CH Cl was added a solution of bromine
MHz, CDCl , 7.26 ppm) δ 6.96−6.88 (m, 4H), 3.90 (s, 6H).
2 2
3
N-Phenylacetamide (2j). Compound 2j was obtained as a white
solid. The spectroscopic data of 2j obtained were in good agreement
(0.050 mL; 1.1 mmol; 1.1 equiv) in CH Cl (10 mL) under an argon
2 2
atmosphere. The resulting mixture was stirred at room temperature
and monitored by TLC. On the complete consumption of 1d-pin, the
reaction mixture was concentrated under reduced pressure. The crude
32
with the literature. Yield: 0.065 g (96%, Method B); 0.013 g (96%,
1
Method C). H NMR (300 MHz, DMSO, 2.5 ppm) δ 9.91 (s, 1H),
mixture was redissolved in CH Cl (10 mL), and 1.0 M BCl in
7
1
.55 (d, J = 7.7 Hz, 2H), 7.27 (t, J = 7.9 Hz, 2H), 7.00 (t, J = 7.6 Hz,
H), 2.02 (s, 3H).
2
2
3
CH Cl (2.0 mL; 2.0 mmol; 2.0 equiv) was added to the above
2
2
solution. The resulting mixture was stirred at room temperature for 30
min. After complete hydrolysis of the pinacol boronate, the reaction
mixture was concentrated under reduced pressure. To the crude
residue redissolved in 1,4-dioxane (10 mL) was added AcOH (0.30
mL), and the reaction mixture was stirred at 100 °C. After complete
consumption of the resulting boronic acid, the reaction mixture was
cooled to room temperature and concentrated. The crude residue was
further purified by flash chromatography on silica gel using a mixture
of ethyl acetate and hexanes (EtOAc:hexanes = 1:15) to afford the
compound as a light yellow oil. Yield: 0.10 g (55%) over three steps.
Synthesis of Stable Surrogates 1a-pin and 1a-MIDA for
Boronic Acid 1a. Synthesis of 1a-pin. To a round-bottom flask were
added 1a (0.17 g; 1.0 mmol; 1.0 equiv) and pinacol (0.12 g; 1.0 mmol;
1
.0 equiv) and toluene (10 mL). The reaction mixture was stirred
under an argon atmosphere at room temperature and monitored by
TLC. On the complete consumption of 1a, the reaction mixture was
extracted with EtOAc. The organic layer was combined, dried over
MgSO , and concentrated. The residue was purified by column
4
chromatography on silica gel using a mixture of ethyl acetate and
hexanes (EtOAc:hexanes = 1:5) to afford compound 1a-pin as a
colorless oil. The spectroscopic data were in good agreement with the
34
The spectroscopic data were in good agreement with the literature.
33
1
1
literature. Yield: 0.22 g (89%). H NMR (300 MHz, CDCl , 7.26
H NMR (300 MHz, CDCl , ppm) δ 7.56−7.53 (m, 1H), 7.31−7.26
3
3
ppm) δ 7.68 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 2.98 (s,
H), 1.32 (s, 12H).
Synthesis of 1a-MIDA. A mixture of 1a (0.17 g; 1.0 mmol; 1.0
equiv) and MIDA (0.44 g; 3.0 mmol; 3.0 equiv) and molecular sieves
0.36 g) was dissolved in DMF (10 mL). The reaction mixture was
(m, 1H), 6.92−6.81 (m, 2H), 3.90 (s, 3H).
6
Synthesis of 2-Nitro-N,N-dimethylaniline (9). To a round-bottom
flask were added MIDA boronate 1a-MIDA (0.055 g; 0.20 mmol; 1.0
equiv), N-bromosuccinimide (NBS, 0.036 g; 0.20 mmol; 1.0 equiv),
(
and silver nitrate (AgNO , 0.034 g; 0.20 mmol; 1.0 equiv). The flask
3
heated at 120 °C under an argon atmosphere and monitored by TLC.
On the complete formation of MIDA boronate from 1a, the reaction
mixture was cooled to room temperature and concentrated. The crude
mixture was redissolved in acetone. The resulting MIDA boronate is
soluble in acetone, whereas a reacting MIDA is not soluble in that
was sealed with a septum and charged under argon, and to it was
added EtCN (4 mL). The reaction mixture was stirred at reflux and
monitored by TLC. On the complete consumption of 1a-MIDA, the
reaction mixture was concentrated, and the crude mixture was directly
subjected to column chromatography over silica gel using EtOAc
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dx.doi.org/10.1021/jo500780b | J. Org. Chem. 2014, 79, 7277−7285