A novel transformation of primary amines to N-monoalkylhydroxylamines

Article abstract of DOI:10.1055/s-2000-6428

A novel transformation of primary amines to the corresponding N-monoalkylhydroxylamines is described. The three-step protocol involves selective mono-cyanomethylation of primary amines, regioselective formation of nitrones by m-CPBA oxidation, and hydroxylaminolysis of the nitrones with hydroxylamine hydrochloride. The method is applicable for a wide range of primary amines, including alkyl, benzyl, and chiral.

Full text of DOI:10.1055/s-2000-6428

PAPER
1299
A Novel Transformation of Primary Amines to N-Monoalkylhydroxylamines
Hidetoshi Tokuyama, Takeshi Kuboyama, Akiko Amano, Tohru Yamashita, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, The Japan Science and Technology Corporation (JST),
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 24 May 2000
First, we explored the optimum conditions for selective
Abstract: A novel transformation of primary amines to the corre-
monocyanomethylation of primary amines. To this end,
sponding N-monoalkylhydroxylamines is described. The three-step
we developed three different procedures depending on the
steric bulkiness of the alkyl substituent (Table). Primary
protocol involves selective mono-cyanomethylation of primary
amines, regioselective formation of nitrones by m-CPBA oxidation,
and hydroxylaminolysis of the nitrones with hydroxylamine hydro- amines bearing a primary alkyl substituent could be cya-
chloride. The method is applicable for a wide range of primary
amines, including alkyl, benzyl, and chiral.
nomethylated with chloroacetonitrile and K2CO3 in aceto-
nitrile at 60 °C (Conditions A). More hindered amines can
Key words: amine, hydroxylamine, oxidation, cyanomethylation,
nitrone
be selectively converted to their cyanomethylated deriva-
tives with bromoacetonitrile and Hünig’s base (Condi-
tions B). The highly sterically hindered amine such as
1-adamantamine was selectively cyanomethylated with
iodoacetonitrile and K2CO3 (Conditions C).
Since a variety of a-hydroxylamino acids and hydroxamic
acids occur in nature, synthesis of their precursors,
N-monoalkylhydroxylamines, has been a topic of consid-
erable interest.1,2 Direct oxidation of primary amines with
hydrogen peroxide or m-CPBA is generally ineffective,
often leading to further oxidation products such as nitroso
and nitro compounds. While reduction of nitro
compounds3 or oximes4 appears to be the most common
and reliable method, it is not applicable to the synthesis of
optically active N-monoalkylhydroxylamines. Selective
oxidation of primary amines with dimethyldioxirane is
applicable only to a limited range of substrates.5 Hydrox-
ylamines have also been synthesized from primary amines
by way of oxidation of the corresponding Schiff bases.6
The protocol is amenable to the synthesis of optically ac-
tive hydroxylamines,6b-d although the intermediary of a
relatively acid-labile Schiff base is one of its disadvantag-
es. In the course of studies related to total synthesis of in-
dole alkaloids, we investigated a protocol for the
conversion of optically active primary amines to the cor-
responding hydroxylamines. We describe herein a novel
method consisting of selective monocyanomethylation of
primary amines, regioselective formation of nitrones, and
hydroxylaminolysis of the nitrones (Scheme).
We have found that cyano group serves as a highly effec-
tive directing group for the regioselective formation of ni-
trones. For example, oxidation of cyanomethylamines
with m-CPBA (2.0 equivalents) took place regioselective-
ly to afford exclusively the desired nitrones 3a-i. This re-
markable regioselectivity, which may be due to the
inductive effect of the cyano group, was also observed in
the oxidation of substrates (1h, 1i) derived from glycine
and phenylalanine. The structures of the nitrones were un-
ambiguously determined by extensive 1H NMR studies.
The conversion of the nitrones to the desired N-mono-
alkylhydroxylamines was best achieved by a modifica-
tion of the literature procedures.6c,d Namely, treatment
of the nitrones with excess hydroxylamine hydrochlo-
ride (5 equivalents) in MeOH at 60 °C for 2 hours afford-
ed the desired N-monoalkylhydroxylamines, which were
isolated as the corresponding oxalates because of the in-
stability of the free hydroxylamines. Yields, given in the
Table, are based on the corresponding oxalic acid salts.
As shown in the Table, a variety of N-monoalkylhydrox-
ylamines could be synthesized by this protocol in high
overall yields. In general, better yields were obtained
when the sequence was carried out without isolation of the
nitrone intermediates. Since the intermediate cyanometh-
ylamines are stable, the present protocol is more reliable
than the one employing Schiff bases for oxidation. It
should be noted that this method is particularly useful for
the preparation of chiral hydroxylamines. Thus, (S)-1-
phenylethylamine (1d) was transformed to the corre-
sponding hydroxylamine oxalate (4d) without loss of
enantiomeric excess (entry 4).6c Furthermore, the method
is amenable to the synthesis of a-hydroxylamino acid de-
rivatives (entries 8, 9).5,6b,d
XCH2CN
m-CPBA
(2 eq)
(X = Cl, Br, I)
i-Pr2NEt or K2CO3
H
N
CN
R
NH2
R
CH2Cl2
rt, 30 min
2
CH3CN or DMF
1
NH2OH • HCl (5 eq)
MeOH, 60 °C, 2 h
O–
+
RNHOH • (COOH)2
CN
N
R
then
(COOH)2, MeOH
3
4
Scheme
In summary, we have developed a novel methodology
for conversion of primary amines to the corresponding
Synthesis 2000, No. 9, 1299–1304 ISSN 0039-7881 © Thieme Stuttgart · New York

1300
H. Tokuyama et al.
PAPER
Table Synthesis of N-Monoalkylhydroxylamines
Entry Amine
R
Conditions for
Time (h)
Yield (%) 2 to 3f
3 to 4g
2 to 4
Cyanomethylationa
Yield (%) Yield (%) Yield (%)
1
2
3
4
1a
1b
1c
1d
PhCH2-
A
A
A
A
B
24
24
24
24
5
95
96
93
71
96
78
75
65
85
76
83
82
75
74
89h
PhCH2CH2-
PhCH2CH2CH2-
79
100
Me
Ph
5
1e
A
24
22
74
97
–
–
79
Bb,c
6
7
1f
Ph2CH-
B
C
15
1
98
89
73
89
80
77
55
76
1g
8
9
1h
1i
BnO2CCH2-
Bd
18
26
91
92
–
–
–
–
62
Bc,e
61i
CO2Me
Ph
a Conditions A: ClCH2CN (1.5 equiv), K2CO3 (2.0 equiv), CH3CN, 60°C; Conditions B: BrCH2CN (1.5 equiv), i-Pr2NEt (2.0 equiv), CH3CN,
r.t.; Conditions C: ICH2CN (2.0 equiv), K2CO3 (2.5 equiv), DMF, r.t.
b HCl salt of amine was used.
c BrCH2CN (1.3 equiv), i-Pr2NEt (3.0 equiv).
d BrCH2CN (1.2 equiv), i-Pr2NEt (2.0 equiv).
e BrCH2CN (2.0 equiv), i-Pr2NEt (3.0 equiv).
f m-CPBA (2.0 equiv), CH2Cl2, r.t., 30 min.
g NH2OH◊HCl (5.0 equiv), MeOH, 60°C, 2 h; work-up and treatment with (COOH)2 MeOH.
h Optical purity of the product was determined by HPLC on a chiral column.
i Optical purity of the product was determined after reduction to the amino acid methyl ester; see experimental details.
using direct probe insertion at temperatures of 50 °C to 330 °C. Mps
were determined using a Yanako MP-500V melting point apparatus
N-monoalkylhydroxylamines by way of oxidation of the
intermediate monocyanomethylamines. The present pro-
tocol seems to be applicable to a wide range of primary
amines.
and are uncorrected. Elemental analyses were carried out on a
Yanako MT-6.
Cyanomethylation of Primary Amines (Conditions A): Prepa-
ration of N-Cyanomethyl 2-phenylethylamine (2b); Typical
Procedure
To a MeCN (30 mL) solution of 3-phenylethylamine (260 mg,
1.93 mmol) were added K2CO3 powder (532 mg, 3.85 mmol) and
ClCH2CN (183.5 mL, 2.89 mmol). After stirring for 24 h at 60 °C,
the resulting suspension was filtered through a pad of Celite, and the
filtrate was concentrated on a rotary evaporator. Purification of the
residue by flash column chromatography on silica gel (30% EtOAc
in hexanes) gave the desired 2b as a colorless oil (295 mg, 96%).
All non-aqueous reactions were carried out in oven-dried glass
tubes under a slightly positive pressure of Ar. Commercial MeCN
and MeOH were dried over 3 Å molecular sieves. All other reagents
were commercially available and used without further purification,
unless otherwise noted. Preparative flash chromatography was per-
formed using Silica Gel 60 (spherical, 40-100 mm) purchased from
1
Kanto Chemical Co., Inc. All products were characterized by H
NMR, 13C NMR, and infrared (IR) spectroscopy. NMR spectra
were obtained in CDCl3, CD3OD, or DMSO-d6 on a JEOL LA-400
MHz spectrometer. All 1H NMR spectra are reported in ppm rela-
tive to the methyl singlet of MeOH, DMSO, or a TMS internal stan-
dard. All 13C NMR spectra are reported in ppm relative to the
central line of the triplet for CDCl3 at 77.0 ppm, the central line of
the septet for CD3OD at 49.0 ppm, or the central line of the septet
for DMSO-d6. IR spectra were recorded on a JASCO FT/IR-410;
absorptions are reported in cm-1. High-resolution mass spectra were
obtained on a JEOL JMS-GCmate MS-DIP20 quadrupole at 70 eV
IR (film): n = 3330, 3027, 2928, 2841, 2233, 1603, 1497, 1454,
1131, 1030, 872, 751, 701 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.84 (t, J = 6.8 Hz, 2H), 3.02 (t,
J = 6.8 Hz, 2H), 3.60 (s, 2H), 7.20-7.34 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 35.7, 37.3, 49.6, 117.6, 126.5,
128.6 (overlapping 4C), 138.9.
HRMS (EI): m/z calcd for C10H12N2: 160.1000. Found: 160.1007.
Synthesis 2000, No. 9, 1299–1304 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Novel Transformation of Primary Amines
1301
N-Cyanomethylbenzylamine (2a)
Colorless oil.
IR (KBr): n = 3434, 3336, 3029, 2924, 2845, 2240, 1631, 1598,
1491, 1453, 1411, 1132, 1085, 1029, 877, 745, 703 cm-1.
IR (film): n = 3333, 3029, 2926, 2845, 2233, 1723, 1496, 1453,
1H NMR (400 MHz, CDCl3): d = 3.54 (s, 2H), 5.07 (s, 1H), 7.20-
7.45 (m, 10H).
1121, 872, 739, 698 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.51 (s, 2H), 3.89 (s, 2H), 7.26-
7.34 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 35.1, 65.6, 117.5, 127.1, 127.6,
128.7, 141.7.
13C NMR (100 MHz, CDCl3): d = 36.1, 52.1, 117.6, 127.5, 128.3,
128.5, 137.7.
Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N, 12.60. Found: C,
80.80; H, 6.45; N, 12.53.
Anal. Calcd for C9H10N2: C, 73.94; H, 6.89; N, 19.16. Found: C,
73.69; H, 6.90; N, 18.96.
N-Cyanomethyl glycine benzyl ester (2h)
Colorless oil.
N-Cyanomethyl-3-phenylpropylamine (2c)
Colorless oil.
IR (film): n = 3346, 3034, 2954, 2236, 1741, 1498, 1456, 1392,
1193, 1150, 974, 875, 753, 699 cm-1.
IR (film): n = 3331, 3026, 2933, 2858, 2233, 1951, 1878, 1811,
1H NMR (400 MHz, CDCl3): d = 3.57 (d, J = 4.2 Hz, 2H), 3.66 (d,
J = 5.1 Hz, 2H), 5.19 (s, 2H), 7.35-7.38 (m, 5H).
1602, 1496, 1454, 1329, 1132, 1030, 873, 749, 701 cm-1.
1H NMR (400 MHz, CDCl3): d = 1.78-1.88 (m, 2H), 2.69 (t,
J = 7.2 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 3.49 (s, 2H), 7.13-7.31
(m, 5H).
13C NMR (100 MHz, CDCl3): d = 30.9, 33.1, 37.1, 48.1, 117.8,
125.8, 128.2, 128.3, 141.5.
13C NMR (100 MHz, CDCl3): d = 36.8, 49.2, 67.0, 117.2, 128.5,
128.6, 128.7, 131.2, 170.9.
HRMS (EI): m/z calcd for C11H12N2O2: 204.0899. Found: 204.0901.
N-Cyanomethyl phenylalanine methyl ester (2i)
Colorless oil.
HRMS (EI): m/z calcd for C11H14N2: 174.1157. Found: 174.1160.
[a]D28 +7.4 (c 0.822, CHCl3).
Cyanomethylation of Primary Amines (Conditions B): Prepa-
ration of (S)-N-Cyanomethyl-1-phenylethylamine (2d); Typical
Procedure
IR (film): n = 3339, 3029, 2952, 2238, 1735, 1495, 1436, 1268,
1210, 1175, 991, 873, 748, 701 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.92 (dd, J = 13.6, 8.0 Hz, 1H),
3.11 (dd, J = 13.6, 4.8 Hz, 1H), 3.53-3.55 (m, 2H), 3.68-3.74 (m,
1H), 3.75 (s, 3H), 7.18-7.34(m, 5H).
13C NMR (100 MHz, CDCl3): d = 35.9, 39.1, 52.2, 61.0, 117.1,
127.1, 128.7, 129.1, 136.1, 173.2.
To an MeCN (20 mL) solution of (S)-1-phenylethylamine (1.01 g,
8.33 mmol) were added i-Pr2NEt (2.90 mL, 16.7 mmol) and
BrCH2CN (0.638 mL, 9.12 mmol). After stirring for 5 h at r.t., the
reaction mixture was concentrated on a rotary evaporator. The resi-
due was partitioned between sat. NaHCO3, sat. NaCl, and CHCl3.
The aqueous layer was extracted twice with CHCl3, and the com-
bined organic extracts were washed with sat. NaCl, dried (MgSO4),
filtered, and concentrated on a rotary evaporator to afford a crude
product. Purification by flash column chromatography on silica gel
(20% EtOAc in hexanes) gave (S)-N-cyanomethyl-1-phenylethyl-
amine (2d) as a colorless oil (1.28 g, 96%).
HRMS (EI): m/z calcd for C12H14N2O2: 218.1055. Found: 218.1053.
Cyanomethylation of Primary Amines (Conditions C): Prepa-
ration of N-Cyanomethyl-1-adamantanamine (2g); Typical
Procedure
To
a DMF (9 mL) solution of 1-adamantanamine (419 mg,
[a]D27 -217 (c 1.23, CHCl3).
2.77 mmol) were added K2CO3 (956 mg, 6.92 mmol) and ICH2CN
(300 mL, 4.15 mmol). After stirring for 1 h at r.t., the reaction
mixture was partitioned between Et2O and 3N NaOH. The aqueous
layer was thoroughly extracted with Et2O four times, and the com-
bined organic extracts were washed with sat. NaCl, dried (MgSO4),
filtered, and concentrated on a rotary evaporator. The crude material
(712 mg) was purified by flash column chromatography on silica
gel (50% Et2O in hexanes) to give 2g (467 mg, 89%) as slightly
yellow crystals; mp: 50.5-51.4 °C (hexanes).
IR (film): n = 3335, 2968, 2235, 1957, 1887, 1818, 1494, 1452,
1207, 1132, 870, 763 cm-1.
1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 6.8 Hz, 3H), 3.23 (d,
J = 16.8 Hz, 1H), 3.53 (d, J = 17.6 Hz, 1H), 4.01 (q, J = 6.5 Hz,
1H), 7.26-7.34 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 23.7, 34.8, 56.5, 117.7, 126.7,
127.4, 128.5, 142.7.
Anal. Calcd for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C,
74.94; H, 7.57; N, 17.35.
IR (KBr): n = 3436, 2905, 2849, 2238, 1631, 1450, 1360, 1142,
1098, 873 cm-1.
1H NMR (400 MHz, CDCl3): d = 1.58-1.71 (m, 12H), 2.10 (br s,
N-Cyanomethyl-2-indanamine (2e)
Colorless oil.
3H), 3.57 (s, 2H).
13C NMR (100 MHz, CDCl3): d = 29.1, 29.3, 36.2, 42.2, 51.2,
120.0.
IR (film): n = 3329, 3022, 2938, 2900, 2839, 2234, 1475, 1459,
1426, 1363, 1219, 1134, 1024, 871, 744 cm-1.
Anal. Calcd for C12H18N2: C, 75.74; H, 9.53; N, 14.72. Found: C,
75.79; H, 9.28; N, 14.68.
1H NMR (400 MHz, CDCl3): d = 2.78 (dd, J = 4.8, 15.6 Hz, 2H),
3.22 (dd, J = 6.8, 15.6 Hz, 2H), 3.66 (s, 2H), 3.81-3.88 (m, 1H),
7.15-7.23 (m, 4H).
13C NMR (100 MHz, CDCl3): d = 35.7, 39.5, 58.3, 118.0, 124.7,
126.7, 140.9.
Nitrone (3d); Typical Procedure
(S)-N-Cyanomethyl-1-phenylethylamine (2d, 1.50 g, 9.39 mmol)
was dissolved in CH2Cl2 (50 mL). To this solution was added
m-CPBA (approx. 70%, 5.09 g, 20.7 mmol) in several portions at
0 °C. After stirring for 20 min at r.t., aqueous Na2S2O3 and sat.
NaHCO3 were added and the resulting mixture was stirred for an ad-
ditional 20 min. The mixture was then extracted thrice with CH2Cl2,
the combined extracts were washed with sat. NaCl, dried (MgSO4),
HRMS (EI): m/z calcd for C11H12N2: 172.1000. Found: 172.1006.
N-Cyanomethyldiphenylmethylamine (2f)
Mp: 73.9-74.7 (Et2O/hexanes).
Synthesis 2000, No. 9, 1299–1304 ISSN 0039-7881 © Thieme Stuttgart · New York

1302
H. Tokuyama et al.
PAPER
filtered, and concentrated on a rotary evaporator to afford the crude
product as a yellow solid. Purification by flash column chromatog-
raphy (30% to 80% EtOAc in hexanes gradient) gave 3d (1.29 g,
79%) as white crystals; mp 91.3-91.9 (EtOAc/hexanes); [a]D28 +83
(c 0.494, CHCl3).
Nitrone 3f
Mp: 113.0-114.6 °C (EtOAc/hexanes).
IR (KBr): n = 3435, 3104, 2222, 1534, 1497, 1456, 1281, 1159,
748, 726, 701 cm-1.
1H NMR (400 MHz, CDCl3): d = 6.34 (s, 1H), 6.76 (s, 1H), 7.27-
7.43 (m, 10H).
13C NMR (100 MHz, CDCl3): d = 84.6, 108.0, 112.2, 128.4, 129.1,
129.5, 134.8.
IR (KBr): n = 3098, 2222, 1541, 1452, 1442, 1377, 1295, 1181,
1074, 1007, 748, 701 cm-1.
1H NMR (400 MHz, CDCl3): d = 1.83 (d, J = 6.8 Hz, 3H), 5.18
(quint, J = 7.2 Hz, 1H), 6.67 (s, 1H), 7.43 (br s, 5H).
13C NMR (100 MHz, CDCl3): d = 19.0, 79.5, 105.8, 112.2, 127.4,
129.2, 129.8, 136.2.
HRMS (EI): m/z calcd for C15H12N2O: 236.0949. Found: 236.0946.
Nitrone 3g
Mp: 187.0-190.0 °C (EtOAc/hexanes).
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.70; H, 5.86; N, 15.92.
IR (KBr): n = 3130, 2926, 2857, 2214, 1524, 1458, 1406, 1168,
1058, 1017, 917, 726 cm-1.
Nitrone 3a
Colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.67-1.78 (m, 6H), 2.09 (br s,
6H), 2.27 (br s, 3H), 6.81 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 29.6, 35.5, 40.8, 74.7, 103.0,
113.0.
IR (film): n = 3110, 2222, 1719, 1545, 1497, 1456, 1319, 1215,
1027, 960, 769, 709 cm-1.
1H NMR (400 MHz, CDCl3): d = 5.02 (s, 2H), 6.58 (s, 1H), 7.32-
7.48 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 72.1, 107.5, 112.5, 130.0, 130.3,
130.7, 131.0.
Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C,
70.57; H, 7.80; N, 13.62.
(S)-1-Phenylethylhydroxylamine Oxalate (4d); Typical Proce-
dure
HRMS (EI): m/z calcd for C9H8N2O: 160.0637. Found: 160.0642
Nitrone (3d, 117 mg, 0.674 mmol) was dissolved in MeOH
(3.5 mL) and NH2OH•HCl (234 mg, 3.37 mmol) was added. After
stirring for 2 h at 60 °C, the resulting mixture was cooled to r.t.,
diluted with CHCl3 (30 mL), and filtered through a pad of Celite.
The filtrate was concentrated, and the residue was partitioned
between CHCl3 and sat. NaHCO3. The aqueous layer was extracted
twice with CHCl3, and the combined extracts were washed with sat.
NaCl, dried (MgSO4), and filtered. To the filtrate was added a
MeOH solution of (COOH)2 (91.1 mg, 1.01 mmol), and the
resulting suspension was concentrated to dryness. The white solid
obtained was triturated with Et2O, and collected by suction. After
drying in vacuo, analytically pure 4d (153 mg, quant.) was obtained
Nitrone 3b
Mp: 77.0-78.2 °C (EtOAc/hexanes).
IR (KBr): n = 3108, 2223, 1545, 1492, 1456, 1415, 1270, 1195,
1085, 961, 756, 710 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.21 (t, J = 7.0 Hz, 2H), 4.12 (t,
J = 7.0 Hz, 2H), 6.37 (s, 1H), 7.17-7.37 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 33.7, 68.6, 107.4, 111.8, 127.5,
128.6, 129.0, 135.9.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.85; H, 5.86; N, 16.03.
28
as white crystals; mp: 163.0-167.0 °C, dec. (MeOH/Et2O); [a]D
-3.1 (c 1.06, MeOH). After conversion to the corresponding
N-benzoylhydroxylamine, enantiomeric excess of the product was
determined to be 95% by chiral HPLC analysis (DAICEL
CHIRALPAK AS, 4.6 mm I. D. ¥ 250 mm, i-PrOH/n-hexane
(40/60), 1.0 mL/min, 30 °C) using the racemic compound as the
reference.
Nitrone 3c
Colorless oil.
IR (film): n = 3110, 2932, 2220, 1603, 1543, 1496, 1454, 1418,
1342, 1277, 1190, 965, 746, 700 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.22-2.30 (m, 2H), 2.70 (t,
J = 7.2 Hz, 2H), 3.91 (t, J = 7.4Hz, 2H), 6.66 (s, 1H), 7.16-7.33 (m,
5H).
IR (KBr): n = 3220, 2987, 2578, 1761, 1610, 1483, 1458, 1210,
986, 961, 775, 714, 702 cm-1.
1H NMR (400 MHz, CD3OD): d = 1.68 (d, J = 6.8 Hz, 3H), 4.52 (q,
J = 6.9 Hz, 1H), 7.39-7.50 (m, 5H).
13C NMR (100 MHz, CDCl3): d = 28.6, 32.0, 66.1, 107.2, 112.0,
126.6, 128.3, 128.7, 139.4.
13C NMR (100 MHz, CD3OD): d = 16.1, 62.9, 129.9, 130.1, 130.6,
136.0, 166.4.
HRMS (EI): m/z calcd for C11H12N2O: 188.0949. Found: 188.0948.
Nitrone 3e
Mp: 140-141.2 °C dec. (EtOAc/hexanes).
Anal. Calcd for C8H11NO•(COOH)2: C, 52.86; H, 5.77; N, 6.16.
Found: C, 52.65; H, 5.70; N, 6.09.
IR (KBr): n = 3446, 3088, 2221, 1538, 1486, 1418, 1321, 1173,
997, 752 cm-1.
Benzylhydroxylamine Oxalate (4a)
Mp: 148.9-150.5 °C (MeOH/Et2O).
1H NMR (400 MHz, CDCl3): d = 3.38 (dd, J = 8.4, 16.4 Hz, 2H),
3.53 (dd, J = 5.8, 16.6 Hz, 2H), 4.97 (tt, J = 5.8, 8.4 Hz, 1H), 6.83
(s, 1H), 7.23 (br s, 4H).
IR (KBr): n = 3425, 2945, 1703, 1634, 1457, 1404, 1264, 752, 721,
698 cm-1.
1H NMR (400 MHz, CD3OD): d = 4.36 (s, 2H), 7.38-7.45 (m, 5H).
13C NMR (100 MHz, CD3OD): d = 56.3, 130.0, 130.5, 130.8, 131.8,
165.0.
13C NMR (100 MHz, CDCl3): d = 38.2, 76.3, 105.8, 112.1, 124.5,
127.6, 138.7.
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C,
70.68; H, 5.55; N, 15.08.
Anal. Calcd for C7H9NO•1.23(COOH)2: C, 48.54; H, 4.93; N, 5.98.
Found: C, 48.05; H, 5.03; N, 6.09.
Synthesis 2000, No. 9, 1299–1304 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Novel Transformation of Primary Amines
1303
2-Phenylethylhydroxylamine Oxalate (4b)
1-(Benzyloxycarbonyl)-methylhydroxylamine Oxalate (4h)
Mp: 158.0-161.2 °C, dec. (MeOH/Et2O).
Mp:135.2-136.1 °C (MeOH/Et2O).
IR (KBr): n = 3440, 1758, 1613, 1416, 1221, 758, 721 cm-1.
1H NMR (400 MHz, DMSO-d6): d = 3.63 (s, 2H), 5.15 (s, 2H),
7.30-7.39 (m, 5H).
13C NMR (100 MHz, DMSO-d6): d = 54.7, 65.6, 128.0, 128.0,
128.4, 136.0, 161.7, 170.3.
IR (KBr): n = 3431, 2598, 1721, 1629, 1498, 1458, 1403, 1280,
1189, 741, 701, 609 cm-1.
1H NMR (400 MHz, CD3OD): d = 3.03 (t, J = 8.2 Hz, 2H), 3.44 (t,
J = 8.2 Hz, 2H), 7.23-7.35 (m, 5H).
13C NMR (100 MHz, CD3OD): d = 30.7, 53.3, 128.2, 129.8, 130.0,
137.6, 163.4.
Anal. Calcd for C9H11NO3∑1.07(COOH)2: C, 48.24; H, 4.78; N,
5.05. Found: C, 48.15; H, 5.09; N, 5.27.
Anal. Calcd for C8H11NO•(COOH)2: C, 52.63; H, 5.74; N, 6.11.
Found: C, 52.66; H, 5.72; N, 5.97.
(S)-1-Methoxycarbonyl-2-phenylethylhydroxylamine Oxalate
3-Phenylpropylhydroxylamine Oxalate (4c)
(4i)
Mp: 162.4-163.9 °C, dec. (MeOH/Et2O).
Mp: 143.2-144.9 °C, dec. (MeOH/Et2O).
[a]D28 +19.5 (c 1.134, MeOH).
IR (KBr): n = 3415, 2957, 1720, 1628, 1518, 1453, 1404, 1279,
1220, 749, 721, 704 cm-1.
IR (KBr): n = 3444, 3146, 2717, 1895, 1752, 1585, 1395, 1300,
1H NMR (400 MHz, CD3OD): d = 1.93 (quint, J = 7.8 Hz, 2H), 2.65
(t, J = 7.8 Hz, 2H), 3.10 (t, J = 7.8 Hz, 2H), 7.08-7.22 (m, 5H).
13C NMR (100 MHz, CD3OD): d = 26.4, 33.4, 51.7, 127.4, 129.4,
129.6, 141.7, 165.5
1226, 1070, 756, 719, 699 cm-1.
1H NMR (400 MHz, DMSO-d6): d = 2.77-2.80 (m, 2H), 3.55 (s,
3H), 3.65-3.70 (m, 1H), 7.16-7.28 (m, 5H).
13C NMR (100 MHz, DMSO-d6): d = 34.8, 51.4, 66.7, 126.4, 128.2,
129.1, 137.5, 161.2, 173.3.
Anal. Calcd for C9H13NO•(COOH)2: C, 54.77; H, 6.27; N, 5.81.
Found: C, 54.48; H, 6.19; N, 5.83.
Anal. Calcd for C10H13NO3•(COOH)2: C, 50.53; H, 5.30; N, 4.91.
Found: C, 50.36; H, 5.18; N, 4.88.
2-Indanylhydroxylamine Oxalate (4e)
The optical purity of the product 4i was established after reduction
with Zn/HOAc. The optical rotation of the corresponding amino
acid methyl ester hydrochloride was in good agreement with that of
the commercial starting compound and that reported in the litera-
ture.7 (Reduction product of 4i, [a]D27 +36.3° (c 2.0, EtOH); starting
compound 1i•HCl, [a]D27 +36.5° (c 2.0, EtOH); Lit.,7 [a]D +37° (c 2,
EtOH)).
Mp: 206.4-210.8 °C, dec. (DMF).
IR (film): n = 3416, 3216, 3025, 2523, 1741, 1632, 1485, 1233, 754,
744, 719 cm-1.
Due to this compound’s insolubility in various solvents, NMR spec-
tra were taken for the free hydroxylamine.
1H NMR (400 MHz, CDCl3): d = 2.89 (dd, J = 16.4, 3.9 Hz, 2H),
3.11 (dd, J = 16.4, 6.8 Hz, 2H), 3.92-3.99 (m, 1H), 7.12-7.25 (m,
4H).
13C NMR (100 MHz, CDCl3): d = 36.7, 62.22, 124.8, 126.5. 141.1.
Conversion of Cyanomethylated Amines to N-Monoalkylhy-
droxylamines without Purification of the Intermediate Ni-
trones, (S)-N-1-Phenylethylhydroxylamine
(S)-N-Cyanomethyl-1-phenylethylamine (2d, 1.28 g, 8.01 mmol)
was dissolved in CH2Cl2 (20 mL). To the solution at 0 °C was added
m-CPBA (approx. 60%, 4.6 g, 16 mmol) in several portions. After
the mixture was stirred for 30 min at r.t., aqueous Na2S2O3 and sat.
NaHCO3 were added, and the resulting mixture was stirred for an
additional 20 min. The mixture was extracted thrice with CHCl3,
and the combined extracts were washed with sat. NaCl, dried
(MgSO4), filtered, and concentrated on a rotary evaporator to afford
the crude product (1.45 g) as a yellow solid. The solid was dissolved
in MeOH (15 mL), and NH2OH•HCl (2.58 g, 40.1 mmol) was add-
ed. After stirring for 2 h at 60 °C, the resulting white suspension was
cooled to r.t., diluted with CH2Cl2 (30 mL), and filtered through a
pad of Celite. The filtrate was concentrated, and the residue was
partitioned between CHCl3 and sat. NaHCO3. The aqueous layer
was extracted twice with CHCl3, and the combined extracts were
washed with sat. NaCl, dried (MgSO4), and filtered. To the filtrate
was added a MeOH solution of (COOH)2 (1.44 g, 16.0 mmol), and
the resulting suspension was concentrated to dryness. The white
solid obtained was triturated with Et2O/hexanes (1:1), and collected
by suction. After drying in vacuo, analytically pure (S)-N-1-phenyl-
ethylhydroxylamine (4d) (1.49 g, 82%) was obtained as a white
solid.
Anal. Calcd for C9H11NO∑1.13(COOH)2: C, 53.87; H, 5.32; N,
5.58. Found: C, 53.81; H, 5.37; N, 5.84.
Diphenylmethylhydroxylamine Oxalate (4f)
Mp: 160.3-160.9 °C, dec. (MeOH/Et2O).
IR (KBr): n = 3431, 3282, 2869, 1739, 1625, 1497, 1456, 1398,
1224, 1017, 698 cm-1.
1H NMR (400 MHz, DMSO-d6): d = 5.24 (s, 1H), 7.20-7.44 (m,
10H), 8.60 (br s, 1H).
13C NMR (100 MHz, DMSO-d6): d = 69.4, 127.2, 127.7, 128.3,
140.7, 163.1.
Anal. Calcd for C13H13NO•1.5(COOH)2: C, 57.52; H, 4.83; N, 4.20.
Found: C, 57.23; H, 5.21; N, 4.58.
1-Adamantylhydroxylamine Oxalate (4g)
Mp: 205.0-209.0 °C, dec. (MeOH/Et2O).
IR (KBr): n = 3420, 3088, 2917, 2855, 1703, 1635, 1573, 1404,
1233, 1010, 723 cm-1.
1H NMR (400 MHz, DMSO-d6): d = 1.55-1.68 (m, 6H), 1.77 (br s,
6H), 2.10 (br s, 3H).
13C NMR (100 MHz, DMSO-d6): d = 28.0, 35.4, 36.0, 58.1, 164.7.
Acknowledgement
Anal. Calcd for C10H17NO•1.24(COOH)2: C, 53.75; H, 7.04; N,
This work was partially supported by the Ministry of Education,
Science, Sports, and Culture, Japan (Grant-in-Aid for Encourage-
ment of Young Scientists No. 11771377).
5.02. Found: C, 53.72; H, 7.09; N, 5.14.
Synthesis 2000, No. 9, 1299–1304 ISSN 0039-7881 © Thieme Stuttgart · New York

1304
H. Tokuyama et al.
PAPER
(5) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org.
Chem. 1990, 55, 1981.
(6) (a) Emmons, W. D. J. Am. Chem. Soc. 1957, 79, 5739.
(b) Polonski, T.; Chimiak, A. Tetrahedron Lett. 1974, 2453.
(c) Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985,
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(d) Grundke, G.; Keese, W.; Rimpler, M. Synthesis 1985, 41,
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(7) Stevenson, D.; Young, G. T. J. Chem. Soc. 1969, 2389.
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Synthesis 2000, No. 9, 1299–1304 ISSN 0039-7881 © Thieme Stuttgart · New York