The Journal of Organic Chemistry
Article
N-Hydroxybenzamides 1H−3H were prepared by N-benzoylation
of (R)-N-(phenylethyl)hydroxylamine (1H) or methyl (S)-2-hydroxyl-
amino-3-phenylpropanoate (2H−3H) synthesized following a general
procedure reported in the literature.10
Methyl (S)-2-Benzoylhydroxylamino-3-phenylpropanoate
(2H) and Methyl (S)-2-(4-Cyanobenzoyl)hydroxylamino-3-
phenylpropanoate (3H). 2H and 3H were prepared by reacting
methyl (S)-2-hydroxylamino-3-phenylpropanoate with benzoyl chlor-
ide and 4-cyanobenzoyl chloride, respectively. The latter compound
was prepared according to the procedure reported above starting from
L-phenylalanine methyl ester with some modification for the last step
of hydrolysis of methyl (S)-2-cyanomethylenamino-3-phenyl-
propanoate N-oxide.26
L-Phenylalanine Methyl Ester. Thionyl chloride (4.8 mL, 66 mmol)
was added over 10 min in a 100 mL two-neck round-bottom flask
containing a stirred solution of L-Phe (10 g, 60 mmol) in MeOH (50
mL) at 0 °C. During the addition, a rapid formation of a white
precipitate was observed. After being stirred at 70 °C for 2 h, a clear
yellow solution was obtained that was concentrated under reduced
pressure to give a white precipitate that was filtered affording methyl
(S)-2-amino-3-phenylpropanoate hydrochloride (12.8 g, 60 mmol,
98%): 1H NMR (D2O) δ 7.17−7.32 (m, 5H), 4.30−4.35 (dd, 1H, J1 =
6.5 Hz, J2 = 8.5 Hz), 3.72 (s, 3H), 3.08−3.28 (m, 2H).
The precipitate was diluted in saturated NaHCO3 (200 mL) and
extracted with diethyl ether. The organic phase was dried over
anhydrous Na2SO4 and the solvent removed by rotary evaporator to
yield 10.4 g (59.0 mmol, 95%) of methyl (S)-2-amino-3-phenyl-
propanoate as a white solid: 1H NMR (CDCl 3) δ 7.17−7.41 (m, 5H),
3.73−3.78 (m, 1H), 3.74 (s, 3H), 2.81−3.15 (m, 2H).
Methyl (S)-2-Cyanomethylamino-3-phenylpropanoate. 2-Bromo-
acetonitrile (4,4 mL, 64 mmol) was added, over a period of 2 h, to a
stirred solution of methyl (S)-2-amino-3-phenylpropanoate (10.4 g, 59
mmol) and N,N-diisopropylethylamine (11 mL, 64 mmol) in ethyl
acetate (50 mL) at 40 °C. The mixture was then stirred for 3 h at 40
°C, cooled to room temperature, washed with water, and dried over
anhydrous Na2SO4, affording an ethyl acetate solution of methyl (S)-2-
cyanomethylamino-3-phenylpropanoate: 1H NMR (CDCl3) δ 7.4−7.2
(m, 5H), 3.76 (s, 3H), 3.69−3.73 (dd, 1H, J1 = 6 Hz, J2 = 8 Hz), 3.55
(d, 2H, J = 2 Hz), 2.90−3.15 (m, 2H); 13C NMR δ 172.9, 135.8, 129.2,
128.8, 128.3, 126.8, 116.9, 60.6, 51.8, 38.7, 35.6.
(R)-N-Hydroxy-N-(1-phenylethyl)benzamide (1H). (R)-2-(1-
Phenylethylamino)acetonitrile. 2-Bromoacetonitrile (6.1 mL, 90
mmol) was added over 2 h in a 250 mL two-neck round-bottom
flask containing a stirred solution of (R)-1-phenylethylamine (10 mL,
77 mmol) and N,N-diisopropylethylamine (15.7 mL, 90 mmol) in
ethyl acetate (50 mL). The reaction was then stirred for 3 h at 40 °C
and, after addition of 5 mL of ethyl acetate, cooled to room
temperature, washed with water, and dried over anhydrous sodium
sulfate. After solvent removal by a rotary evaporator, 12 g of (R)-2-(1-
phenylethylamino)acetonitrile was obtained that was used in the
following step without further purification: 1H NMR (CDCl3) δ 7.25−
7.34 (m 5H), 4.02 (q 1H), 3.53−3.59 (d 2H, J = 17 Hz), 3.22−3.28 (d
2H, J = 17 Hz), 1.84 (s 1H), 1.38−1.40 (d 3H, J = 6.5 Hz).
(R)-N-(Cyanomethylene)-1-phenylethylamine-N-oxide. A solution
of m-chloroperbenzoic acid (27 g, 156 mmol) in ethyl acetate (25 mL)
was slowly added, over a period of 2 h, in a 250 mL two-neck round-
bottom flask containing a stirred solution of (R)-2-(1-phenylethyl-
amino)acetonitrile (12 g) in ethyl acetate (25 mL) at 0 °C. The
mixture was stirred to 0 °C for 24 h, equilibrated to room temperature
and then washed with saturated sodium bicarbonate and brine. The
solution was dried over anhydrous sodium sulfate, and after solvent
removal by rotary evaporator, 13.5 g of a pale yellow solid was
1
obtained. H NMR analysis of the product showed that the solid was
almost exclusively composed by (R)-N-(cyanomethylene)-1-phenyl-
ethylamine-N-oxide, which was used in the next step without further
1
purification: H NMR (CDCl3) δ 7.33−7.41 (m 5H), 6.71 (s 1H),
5.18 (q 1H), 1.80−1.82 (d, 3H, J = 8 Hz).
(R)-N-(Phenylethyl)hydroxylamine. 4-Toluenesulfonic acid (15 g,
87 mmol) in ethyl acetate (10 mL) was added in a 25 mL round-
bottom flask containing (R)-N-(cyanomethylene)-1-phenylethyl-
amine-N-oxide (13.5 g). The mixture was stirred for 3 h at 40 °C
and then cooled to room temperature. A 2 mL aliquot of the mixture
was then taken and the solvent removed by rotary evaporator. The
resulting solid was then added to the reaction mixture that was stirred
at 4 °C for 2 h and at −20 °C overnight. A precipitate was obtained
that was filtered and washed with cold ethyl acetate, affording 13.6 g of
(R)-N-(phenylethyl)hydroxylamonium 4-toluenesulfonate as a white
Methyl (S)-2-Cyanomethylenamino-3-phenylpropanoate-N-
oxide. Ethyl acetate solution of methyl (S)-2-cyanomethylamino-3-
phenylpropanoate obtained in the previous step was cooled at 0 °C in
an ice bath. Then m-CPBA (18 g, 108 mmol) in ethyl acetate (40 mL)
was added over a period of 2 h. The mixture was equilibrated to room
temperature and washed with NaHCO3 and brine. The organic phase
was then dried over anhydrous Na2SO4, filtered, and evaporated,
affording methyl (S)-2-cyanomethylenamino-3-phenylpropanoate N-
1
solid: H NMR (CD3OD) δ 7.69−7.72 (d 2H), 7.45−7.48 (m 5H),
7.22−7.25 (d 2H), 4.52 (q, 1H), 2.37 (s, 3H), 1.67−1.70 (d, 3H, J =
6.9 Hz).
1
oxide (13 g, 52 mmol, 87% overall yield): H NMR (CDCl3) δ 7.4−
The solid was then diluted in ethyl acetate (10 mL) and washed
with saturated NaHCO3 and then with water. The organic solution
was dried over anhydrous Na2SO4, affording, after solvent removal, 6.5
g of (R)-N-(phenylethyl)hydroxylamine pure enough (≥95%, 1H
NMR) to be used in the following step without purification: 1H NMR
(CD3OD) δ 7.30−7.33 (m 5H), 4.29 (q, 1H), 1.67−1.70 (d, 3H, J =
6.9).
7.6 (m, 5H), 6.44 (s, 1H), 4.72−4.80 (m, 1H), 3.86 (s, 3H), 3.32−
3.57 (m, 2H).
Methyl (S)-2-Hydroxylamino-3-phenylpropanoate.26 In a care-
fully dried three-neck round-bottom flask, a mixture of methyl (S)-2-
cyanomethylenamino-3-phenylpropanoate N-oxide (13 g, 52 mmol)
and NH2OH·HCl (19 g, 280 mmol) in anhydrous MeOH (450 mL)
was stirred overnight at 60 °C under argon. The mixture was then
cooled to room temperature, and CH2Cl2 (4.6 L) was added. The
white precipitate formed was filtered off. After solvent removal, the
yellow-orange oil obtained was dissolved in CH2Cl2 (150 mL) and the
solution washed with saturated NaHCO3. The water fractions were
then extracted with CH2Cl2 (two portions, 150 mL each). All the
organic phases were collected, dried over anhydrous Na2SO4, and
evaporated. The product was purified by silica gel chromatography
(CHCl3), affording methyl (S)-2-hydroxylamino-3-phenylpropanoate
(R)-N-Hydroxy-N-(1-phenylethyl)benzamide. Benzoyl chloride (1
mL, 8.7 mmol) was added, under an argon stream, in a dried two-neck
round-bottom flask containing (R)-N-(phenylethyl)hydroxylamine
(0.5 g, 3.6 mmol) and pyridine (2.5 mL). The mixture was stirred,
under argon at room temperature, for 20 min after which water (5
mL) was added. The mixture was then extracted with ethyl acetate.
The organic phases were collected and washed with 0.1 M HCl. The
aqueous phase was extracted with ethyl acetate. The organic phases
were collected, dried over anhydrous Na2SO4, and the solvent
removed by rotary evaporator. The (R)-N-hydroxy-N-(1-phenylethyl)-
benzamide was purified by silica gel chromatography (hexane/ethyl
acetate 3:1) followed by recrystallization from hexane affording 0.73 g
(3.0 mmol, 83% yield) of a white solid. The overall yield was 51%: 1H
NMR (CD3CN) δ 7.65 (br, 1H), 7.55−7.29 (m, 10H), 5.52 (q, 1H),
1.61 (d, 3H); 13C NMR (CDCl3) δ 166.5, 141.0, 133.1, 129.1, 128.4,
128.3, 128.1, 127.6, 126.9, 60.7, 19.5; HRMS ESI-TOF Na+ adduct,
[C15H15NO2Na] 264.0971 (calcd 264.1000); [α]D (CH3Cl) = +123.7
0.1.
1
(2.6 g, 13.4 mmol, 24%): H NMR (CDCl3) δ 7.17−7.30 (m, 5H),
3.88−3.93 (dd, 1H, J1 = 5.3 Hz, J2 = 9 Hz), 3.74 (s, 3H), 2.88−3.07
(m, 2H); 13C NMR (CDCl3) δ 173.0, 136.2, 129.0, 128.7, 127, 66.0,
52.1, 35.2.
Methyl (S)-2-Benzoylhydroxylamino-3-phenylpropanoate (2H).
Benzoyl chloride (0.31 mL, 2.7 mmol) was added to a solution of
methyl (S)-2-hydroxylamino-3-phenylpropanoate (0.53 g, 2.7 mmol)
in dry pyridine (1.2 mL) under argon. The mixture was stirred at room
temperature for 20 min. After addition of water (10 mL), the mixture
was extracted with ethyl acetate and the organic phase was washed
G
dx.doi.org/10.1021/jo500844c | J. Org. Chem. XXXX, XXX, XXX−XXX