A. Zervosen et al. / Bioorg. Med. Chem. 20 (2012) 3915–3924
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2.6 mL Diphenylphosphoryl azide (DPPA) (10 mmol) and 3.75 mL
di-isopropyl ethylamine (0.02 mol) were slowly added. After 4 h
at 0 °C the solution was stirred overnight at room temperature.
The reaction was followed by TLC (silica gel 60, ethyl acetate, RF
(product): 0.62). After the addition of 100 mL dichloromethane
the solution was washed first with 2 N HCl and then with NaHCO3
(5% w/v) and dried over Na2SO4. After filtration and the solvents re-
moval the product was solubilized in a small amount of dichloro-
methane and purified by filtration through silica gel using ethyl
acetate/petroleum ether 40–60, 4:1. After the elimination of the
solvent under vacuum a white solid (1.65 g, 0.0065 mol, yield:
65%) was obtained. The product was mixed with 2 equiv LiOH
solved in THF/water 1:1 v/v (20 mL). The pH of the solution was
adjusted to 1 with 6 N HCl. After the extraction of the product with
ethyl acetate the solution was washed with water and dried over
Na2SO4. After filtration the solvent was removed under vacuum
and a white solid (1.52 g, 6.4 mmol, yield: 98%) was obtained.
Mp: 110 °C. HPLC: Rt: 11.6 min (210 nm). 1H NMR was in agree-
ment with Chavez.31 13C NMR (100 MHz, DMSO): d (ppm) = 171.1
(COOH), 164.9 (CO), [156.9, 130.2, 116.4, 104.4 (Ar)], 55.8 (OCH3),
40.9 (CH2). MS (ESI, positive ion): m/z: [240 (100%), 241 (12%),
242 (2%)], (M+1). FT-MS: calculated (M+Na): 262.0691, observed:
262.0691.
CH2-B), 4.01 (s, 3H, OCH3), 7.18 (t, 3J = 7.6 Hz, 1H, Ar-H), 7.24 (d,
3J = 7.6 Hz, 1H, Ar-H), 7.69 (t, 3J = 7.2 Hz, 1H, Ar-H), 8.01 (d,
3J = 7.6 Hz, 1H, Ar-H). 13C NMR (62 MHz, D2O): d (ppm) = 28.8 (br,
CH2-B), 58.7 (OCH3), [114.9, 115.2, 123.7, 134.2, 139.1, 162.1
(Ar)], 172.7 (C@O). HPLC: Rt = 13.5 min (210 nm). MS (ESI, positive
ion) m/z: [191 (25%), 192 (100%), 193 (10%)] (MꢂH2O+H). FT-MS:
calculated (MꢂH2O+H): 192.0827, observed: 192.0826.
4.5.8. (2-Chlorobenzamido)methylboronic acid 11 (method A)
Two hundred and six milligrams (0.97 mmol) of a white solid
(yield: 44%) were obtained from 2-chlorobenzoyl chloride and 3
(2.2 mmol). 1H NMR (250 MHz, D2O): d (ppm) = 2.67 (s, 2H, CH2-
B), 7.36–7.52 (m, 4H, Ar-H). 13C NMR (62 MHz, D2O):
d
(ppm) = 33.5 (br, CH2-B), [130.1, 132.1, 133.0, 133.6, 134.2, 135.3
(Ar)], 173.8 (C@O). HPLC: Rt = 12 min (210 nm). MS (ESI, positive
ion) m/z: [195 (24%), 196 (100%), 197 (20%), 198 (34%)]
(MꢂH2O+H). FT-MS: calculated (MꢂH2O+H): 196.0331, observed:
196.0331.
4.5.9. (2-(2-Chlorophenyl)acetamido)methylboronic acid 12
(method B)
One hundred milligrams (0.44 mmol) of a white solid (yield:
26%) were obtained from 2-(2-chlorophenyl)acetyl chloride and 3
(1.7 mmol). 1H NMR (400 MHz, D2O): d (ppm) = 2.44 (s, 2H, CH2-
B), 3.88 (s, 2H, Ar-CH2), 7.35 (m, 3H, Ar-H), 7.48 (m, 1H, Ar-H).
13C NMR (62 MHz, D2O): d (ppm) = 34.8 (br, CH2-B), 37.3 (Ar-
CH2), [130.3, 132.4, 134.0, 134.8, 137.0 (Ar)], 178.3 (C@O). HPLC:
Rt = 14.5 min (210 nm). MS (ESI, positive ion) m/z = [209, 210
(64%), 211, 212] (MꢂH2O+H). FT-MS: calculated (MꢂH2O+H):
210.0488, observed: 210.0488.
4.5.4. (2,6-Difluorobenzamido)methylboronic acid 7 (method A)
One hundred and sixty-two milligrams (0.75 mmol) of a white
solid (yield: 34%) were obtained from 2,6-difluorobenzoyl chloride
and 3 (2.2 mmol). 1H NMR was in agreement with Inglis.32 13C
NMR (62 MHz, D2O):
d (ppm) = 31.6 (br, CH2-B), 113.9 (t,
4
2
2JCF = 18.6 Hz, C-1), 114.8 (dd, JCF = 3.2 Hz, JCF = 22 Hz, C-3 and
3
1
C-5), 136.0 (t, JCF = 10.7 Hz, C-4), 162.2 (dd, JFC = 247 Hz,
3JCF = 6.6 Hz, C-2 and C-6), 166.9 (C@O). HPLC: Rt = 9.9 min
(210 nm). MS (ESI, positive ion) m/z: [197 (25%), 198 (100%), 199
(10%)] (MꢂH2O+H). FT-MS: calculated (MꢂH2O+H): 198.0532, ob-
served: 198.0532.
4.5.10. (2-Fluorobenzylamido)methylboronic acid 13 (method
B)
One hundred and eighty milligrams (0.91 mmol) of a white so-
lid (yield: 54%) were obtained from 2-fluorobenzoyl chloride and 3
(1.7 mmol). 1H NMR (400 MHz, D2O): d (ppm) = 2.66 (s, 2H, CH2-B),
3
3
4.5.5. (2,4-Dimethoxybenzamido)methylboronic acid 8 (method
B)
7.29 (dd, JHH = 8.6 Hz, JHF = 11.8 Hz 1H, Ar-H), 7.35 (t,
3JHH = 7.6 Hz, 1H, Ar-H), 7.66 (m, 1H, Ar), 7.87 (td, JHH = 7.6 Hz,
3
Forty two milligrams (0.18 mmol) of a white solid (yield: 10%)
4JHF = 1.6 Hz, 1H, Ar-H). 13C NMR (62 MHz, D2O): d (ppm) = 36.1
2
2
were obtained from 2,4-dimethoxybenzoyl chloride and
3
(br, CH2-B), 119.2 (d, JCF = 12 Hz, Ar), 119.3 (d, JCF = 21.7 Hz, Ar),
(1.7 mmol). 1H NMR (250 MHz, D2O): d (ppm) = 2.52 (s, 2H, CH2-
B), 3.88 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6.6 (s, 1H, Ar-H), 6.68
(dd, 3J = 8.8 Hz, 4J = 2.3 Hz, 1H, Ar-H), 7.91 (d, 3J = 9 Hz, 1H, Ar-H).
13C NMR (62 MHz, D2O): d (ppm) = 39.0 (br, CH2-B), 58.5 (OCH3),
[100.7, 108.2, 109.4, 136.1, 164.0, 168.2 (Ar)], 172.2 (C@O). HPLC:
Rt = 18.5 min (210 nm). MS (ESI, positive ion) m/z: [221 (24%),
222 (100%), 223 (11%)] (MꢂH2O+H). FT-MS⁄: calculated (M+Na):
262.0868, observed: 262.0864.
127.7 (d, JCF = 3.2 Hz, Ar), 133.4 (d, JCF = 1.8 Hz, Ar), 138.1 (d,
4
3
3JCf = 9.3 Hz, Ar), 163.4(d, JCF = 249 Hz, Ar), 170.9 (d, JCF = 2.2 Hz,
C@O). HPLC: Rt = 12.0 min (210 nm). MS (ESI, positive ion) m/z:
[179 (25%), 180 (100%), 181 (14%)] (MꢂH2O+H). FT-MS: calculated
(MꢂH2O+1): 180.0627, observed: 180.0627.
1
3
4.5.11. (2-Nitrobenzamido)methylboronic acid 14 (method A)
Two hundred and twenty-one milligrams (0.099 mmol) of a
white solid (yield: 45%) were obtained from 2-nitrobenzoyl chlo-
ride and 3 (2.2 mmol). 1H NMR (250 MHz, D2O): d (ppm) = 2.77
(s, 2H, CH2-B), 7.52 (m, 1H, Ar-H), 7.62 (m, 1H, Ar-H), 7.72 (m,
4.5.6. (3,4-Dimethoxybenzamido)methylboronic acid 9 (method
A)
Two hundred and eighty-three milligrams (1.2 mmol) of a
white solid (yield: 54%) were obtained from 3,4-dimethoxybenzoyl
chloride and 3 (2.2 mmol). 1H NMR (400 MHz, D2O): d (ppm) = 2.54
(s, 2H, CH2-B), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 7.05 (d,
3J = 8.4 Hz, 1H, Ar-H), 7.37 (s, 1H, Ar-H), 7.51 (d, 3J = 8.4 Hz, 1H,
Ar-H). 13C NMR (62 MHz, D2O): d (ppm) = 37.8 (br, CH2-B), 58.5
(OCH3), 58.6 (OCH3), [113.3, 114.1, 121.9, 125.4, 150.8, 155.6
(Ar)], 174 (C@O). HPLC: Rt = 13.2 min (210 nm). MS (ESI, positive
ion) m/z: [221 (23%), 222 (100%), 223 (17%)] (MꢂH2O+H). FT-MS:
calculated (MꢂH2O+H): 222.0932, observed: 222.0932.
1H, Ar-H), 8.06 (m, 1H, Ar-H). 13C NMR (62 MHz, D2O):
d
(ppm) = 32.4 (br, CH2-B), [127.6, 131.7, 132.4, 134.3, 137.4, 148.3
(Ar)], 172.9 (C@O). HPLC: Rt = 9.4 min (210 nm). MS (ESI, positive
ion) m/z: [206 (25%), 207 (100%), 208 (17%)] (MꢂH2O+H). FT-MS:
calculated (MꢂH2O+H): 207.0571, observed: 207.0571.
4.5.12. (2-(2-Nitrophenyl)acetamido)methylboronic acid 15
(method B)
One hundred and seventy-five milligrams (0.74 mmol) of a
white solid (yield: 43%) were obtained from 2-(2-nitro-
phenyl)acetyl chloride and 3 (1.7 mmol). 1H NMR (250 MHz,
D2O): d (ppm) = 2.52 (s, 2H, CH2-B), 4.09 (s, 2H, Ar-CH2), 7.55 (dd,
3J = 7.5 Hz, 4J = 1.5 Hz, 1H, Ar-H), 7.63 (td, 3J = 7.5 Hz, 4J = 1.5 Hz,
1H, Ar-H), 7.77 (td, 3J = 7.5 Hz, 4J = 1.5 Hz, 1H, Ar-H), 8.2 (dd,
3J = 8.0 Hz, 4J = 1.5 Hz, 1H, Ar-H). 13C NMR (62 MHz, D2O): d
4.5.7. (2-Methoxybenzamido)methylboronic acid 10 (method A)
One hundred and sixty-one milligrams (0.77 mmol) of a white
solid (yield: 35%) were obtained from 2-methoxybenzoyl chloride
and 3 (2.2 mmol). 1H NMR (400 MHz, D2O): d (ppm) = 2.56 (s, 2H,