One-pot synthesis of alkoxyamine derivatives by reductive alkoxyamination with a 2-picoline-borane complex

Article abstract of DOI:10.3987/COM-08-11532

Reduction of oxime ethers with a 2-picoline-borane complex was examined to give alkoxyamine derivatives. The reduction was found to proceed in the presence of aqueous HCl in MeOH-AcOH. The method was extended to one-pot synthesis of alkoxyamine derivative

Full text of DOI:10.3987/COM-08-11532

HETEROCYCLES, Vol. 78, No. 2, 2009
463
HETEROCYCLES, Vol. 78, No. 2, 2009, pp. 463 - 470. © The Japan Institute of Heterocyclic Chemistry
Received, 20th August, 2008, Accepted, 6th October, 2008, Published online, 9th October, 2008.
DOI: 10.3987/COM-08-11532
ONE-POT SYNTHESIS OF ALKOXYAMINE DERIVATIVES BY
REDUCTIVE ALKOXYAMINATION WITH A 2-PICOLINE-BORANE
COMPLEX
Yasushi Kawase,a Takehiro Yamagishi,a Teruo Kutsuma,a Kimio Ueda,b
Takeo Iwakuma,b Tadashi Nakata,c and Tsutomu Yokomatsu a*
a School of Pharmacy, Tokyo University of Pharmacy & Life Sciences 1432-1
Horinouchi,
Hachioji,
Tokyo
192-0392,
Japan
(e-mail:
b
yokomatu@ps.toyaku.ac.jp) Development Laboratory, Junsei Chemical Co.,
c
LTD, 6, 1-Chome, Ohmano-Cho, Koshigaya, Saitama 343-0844, Japan
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3,
Kagurazaka, Shinjuku-ku Tokyo 162-8601, Japan
Abstract – Reduction of oxime ethers with a 2-picoline-borane complex was
examined to give alkoxyamine derivatives. The reduction was found to proceed
in the presence of aqueous HCl in MeOH–AcOH. The method was extended to
one-pot synthesis of alkoxyamine derivatives from aldehydes and ketones. The
reaction of carbonyl compounds with alkoxyamines in MeOH–AcOH (10:1),
followed by sequential treatment with 2-picoline-borane and 3M HCl afforded
alkoxyamine derivatives in good yields. This procedure can be applied to the
synthesis of various alkoxyamine derivatives from aliphatic/aromatic aldehydes
and ketones.
INTRODUCTION
Reductive amination is one of the most effective methods for the introduction of an amino functionality
into a molecule.1 Various kinds of reducing agents for reductive amination have been developed. For
example, sodium cyanoborohydride (NaBH3CN),2 sodium triacetoxyborohydride (NaBH(OAc)3),3
5
Zn(BH4)2-silica gel,4 and NaBH4-Ti(Oi-Pr)4 are widely used for reductive amination. However, these
reducing agents have some disadvantages from the viewpoint of process chemistry. The use of
NaBH3CN on large scale should be achieved with great care due to its high toxicity. NaBH(OAc)3 has
been developed as an alternative reagent of NaBH3CN. The reaction with NaBH(OAc)3, however, has to

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HETEROCYCLES, Vol. 78, No. 2, 2009
be carried out in aprotic polar solvents or halogenated hydrocarbon solvents, which have environmental
problems, due to their inducing high chemo-selectivity of the reduction and the instability of the reagent
in protic solvents.3 In addition, reduction with this reagent is somewhat inefficient because it possesses
only one hydrogen atom for reduction in a molecule. Some of the heterocyclic compound-borane
complexes, which overcome these problems mentioned above,6b,c are also effective reducing agents for
reductive amination. For example, successful reductive aminations with pyridine-borane (Pyr-BH3) have
been developed and applied to the organic syntheses.6 However, it has been reported that thermally
unstable Pyr-BH3 decomposes above 54 oC and explodes under thermal condition.7 Furthermore, its shelf
life is relatively short (6 months). On the other hand, 2-picoline-borane (2-Pic-BH3) had much attention
paid to it as a new type of the reducing reagent for reductive amination, because it is a thermally stable
crystalline powder and can be stored for a long period. Kikugawa et al. reported the reductive amination
of carbonyl compounds with 2-Pic-BH3,8 although the scope and limitation of these reactions with this
reagent have not been studied in details. Very recently, Burlhardt et al. reported the reductive amination
with 5-ethyl-2-methylpyridine-borane complex as a replacement for Pyr-BH3 or 2-Pic-BH3.9
Alkoxyamine derivatives, which can be synthesized by reductive alkoxyamination of carbonyl
compounds, are efficient tools for the synthesis of amine-contained compounds on solid support, because
amino-functionalized materials can be readily released by cleavage of the N-O bond under mild
conditions.10c Thus, the development of new simple methods for the synthesis of alkoxyamines is required
in the field of combinatorial chemistry.
In this paper we wish to report on the reduction of oxime ethers with 2-Pic-BH3, along with the one-pot
synthesis of alkoxyamine derivatives 2 through reductive alkoxyamination from carbonyl compounds 1
with 2-Pic-BH3 (Scheme 1).10, 11
OR3
R3O NH2
O
R1 R2
1
1)
2)
HN
R1 R2
BH3
2
N
Me
(2-Pic-BH3)
Scheme 1. Synthesis of alkoxyamines by reductive alkoxyamination via oxime ethers
RESULTS AND DISCUSSION
First, we studied the reduction of oxime ether 3a (X=H, R=H), derived from benzaldehyde and
methoxyamine, with 2-Pic-BH3 (Table 1). Kikugawa et al. carried out the reductive amination of carbonyl
compounds with 2-Pic-BH3 in MeOH–AcOH (10:1).8 For our preliminary study, we examined the
reduction of the oxime ether under Kikugawa’s conditions. However, no reduction took place on

HETEROCYCLES, Vol. 78, No. 2, 2009
465
treatment of the oxime ether with 1.5eq of 2-Pic-BH3 even in refluxing MeOH–AcOH. We were pleased
to find that the reduction began to proceed upon addition of 3M HCl (1 equiv.) to the mixture. Under the
conditions, methoxyamine derivative 2a was produced in 41% yield along with 37% yield of recovered
corresponding oxime ether after 0.5 h (entry 1). This observation means that aqueous HCl is crucial to
this reaction. To optimize the reaction condition, we investigated the effect of amounts of 3M-HCl on the
reduction of two varieties of the substrates derived from benzaldehyde and 2-bromobenzaldehyde which
differ in the electronic nature of aromatic rings. The results are summarized in Table 1.
R
X
R
OMe
2-Pic-BH3 (1.5eq.)
OMe
N
N
H
MeOH-AcOH 10:1
3M HCl
X
rt, 30min
2a-c
3a-c
Table 1. Reduction of oxime ethers 3 to alkoxyamines 2
Entry
X
H
R
H
3M HCl (equiv.)
Yield of 2a (%)
Recovered 3b (%)
1
2
3
4
5
6
7
1
2
3
5
3
5
5
2a (41)
37
6c
1
H
H
2a (71)
H
H
2a (76)
H
H
2a (75)
0
Br
Br
H
H
2b (76)
15
10
13
H
2b (85)
Me
2c (78)
a Isolated yields. b Isolated yields unless noted. c Determined by 1H-NMR of crude product.
In the reduction of oxime ether 3a (X=H, R=H) derived from benzaldehyde, more than 2eq of 3M HCl
was required for the smooth reaction (entry 1 vs. entries 2-4) and we found that using 3–5eq of 3M HCl
gave a maximum yield (entries 3 and 4). As for the reduction of oxime ether 3b (X=Br, R=H) derived
from 2-bromobenzaldehyde, 5 eq of 3M HCl obviously gave the better yield than 3eq of 3M HCl (entry 5
vs. entry 6). Therefore, we concluded that the reaction with 1.5eq of 2-Pic-BH3 in MeOH-AcOH (10:1),
followed by the addition of 5 eq of 3M HCl was the optimal condition for the reduction of general oxime
ethers.11 The reduction of oxime ether 3c (X=H, R=Me) derived from an aromatic ketone also gave the
corresponding alkoxyamine 2c in good yield under this condition (entry 7).
Based on above results, we next studied the one-pot synthesis of alkoxyamine derivatives through
2-Pic-BH3-mediated reductive alkoxyamination of carbonyl compounds (Table 2). Benzaldehyde (1a:
R1=Ph, R2=H) was treated with methoxyamine (4: R3=Me) in MeOH-AcOH (10:1) at room temperature
for 2h, followed by the addition of 1.5eq of 2-Pic-BH3 in the presence of 5eq of 3M HCl at room
temperature (entry 1). After being stirred for 0.5h, methoxyamine derivative 2a was isolated in 79% yield

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without recovering the corresponding oxime ether. This method was applied to the alkoxyamination of
various carbonyl compounds. Representative results are summarized in Table 2.
1) MeOH-AcOH 10:1
OR3
O
rt, 2h
HN
R3O NH2
+
R1 R2
R1 R2
2) 2-Pic-BH3 (1.5eq)
3M HCl (5eq)
rt, 30min
1a-k
4
2a-k
Table 2. 2-Picoline borane-mediated reductive alkoxyamination of carbonyl compounds 1 with alkoxyamine 4
R1
C6H5
R2
H
R3
Me
Product
Yield %a
79
Entry
1
2a
2
2-Br-C6H4
C6H5
H
Me
H
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
2b
2c
2d
2e
2f
84 b
68c
81d
92
3
4
3-Br-C6H4
4-MeO-C6H4
cyclohexyl
n-pentyl
5
H
6
H
94
7
H
2g
2h
2i
88
8
n-pentyl
Me
n-Pr
Me
90
9
n-Pr
87
10
11
cyclohexyl
2j
98
–(CH2)2-O-(CH2)2–
Bn
2k
93
a
b
Isolated yields after purification by silica gel column chromatography. The corresponding oxime ether was recovered
(9%). c The corresponding oxime ether was recovered (13%). d The corresponding oxime ether was recovered (6%).
In this method, aromatic aldehydes bearing an electron-withdrawing group (entries 2 and 4) or an
electron-donating group (entry 5), and aliphatic aldehydes/ketones (entries 6-11) including a cyclic ketone
(entry 11) could be converted into the corresponding alkoxyamine derivatives 2b-k in good to excellent
yields. The one-pot reductive alkoxyamination of acetophenone with methoxyamine gave the
corresponding alkoxyamine 2c in 68% yield (entry 3), although the yield was somewhat lower compared
with that of the direct reduction of oxime ether 3c (see Table 1).
In conclusion, the synthesis of alkoxyamine derivatives via one-pot reductive alkoxyamination with
2-Pic-BH3 was achieved. Because of the simplicity and good yields, the method presented in this paper is
very useful for the synthesis of alkoxyamine derivatives. Further application of this method is now being
investigated in our laboratories.
EXPERIMENTAL
1H and 13C-NMR were taken at 400 MHz and 100 MHz, respectively. The chemical shifts were reported
1
in ppm relative to CHCl3 (7.26 ppm) for H-NMR and relative to the central resonance of CDCl3 (77.00

HETEROCYCLES, Vol. 78, No. 2, 2009
467
ppm) for 13C-NMR.
N-Benzyl-O-methylhydroxylamine (2a)
Et3N (0.26 mL,1.88 mmol) was added to a solution of methoxyamine hydrochloride (157 mg, 1.88 mmol)
in 2.5 mL of MeOH at 0 oC and the mixture was stirred for 10 min at the same temperature. A solution of
benzaldehyde (199.5 mg, 1.88 mmol) in 2.5 mL of MeOH and 0.5 mL of AcOH was added to the mixture
at 0 oC. After stirring for 2 h at rt, 2-Pic-BH3 (302 mg, 2.82 mmol) was added to the reaction mixture at 0
oC and the mixture was stirred for 5 min at the same temperature. After the addition of 3 M HCl (3.13 mL,
o
o
9.4mmol) at 0 C, the mixture was stirred for 0.5 h at ambient temperature. After cooling to 0 C,
aq.Na2CO3 (2.5 g/10 mL) was carefully added to the mixture at 0 oC and the mixture was extracted with
AcOEt(x3). The combined extracts were washed with brine and dried over MgSO4. After the removal of
MgSO4 by filtration, the solvent was evaporated in vacuo. The residue was purified by silica-gel column
chromatography (n-hexane:AcOEt=20:1) to give 202.9 mg of 2a (79 % yield) as a colorless oil. IR (neat)
3258, 2937, 1494, 1454 cm-1. 1H-NMR (400 MHz, CDCl3) δ 7.33–7.22 (5H, m), 5.71 (1H, br s), 3.99 (2H,
s), 3.47 (3H, s). 13C-NMR (100 MHz, CDCl3) δ 137.5, 128.6, 128.2, 127.2, 61.5, 55.9. MS (ESI) m/z: 138
[M+H]+. HRMS (ESI) m/z:138.0938 [M+H]+ Calcd for C8H12NO: 138.0919.
Alkoxyamines (2b-2k) were synthesized in a similar way as described for 2a.
N-(2-Bromobenzyl)-O-methylhydroxylamine (2b)
13C-NMR (100 MHz, CDCl3) δ 136.7, 132.8, 131.2, 129.1, 127.4, 124.1, 61.6, 55.8. Other spectral data
(1H-NMR and IR) were identical with the data on this compound in reference 10c.
O-Methyl-N-(1-phenylethyl)hydroxylamine (2c)
Colorless oil; IR (neat) 3247, 2976, 2937, 1493, 1453 cm–1. 1H-NMR (400 MHz, CDCl3) δ 7.36–7.28 (5H,
13
m), 4.14 (1H, q, J=6.7 Hz), 3.48 (3H, s), 1.37 (3H, d, J=6.7 Hz). C-NMR (100 MHz, CDCl3) δ 142.8,
128.4, 127.4, 127.0, 62.4, 60.4, 19.8. MS (ESI) m/z: 152 [M+H]+. HRMS (ESI) m/z:152.1082 [M+H]+
Calcd for C9H14NO: 152.1075.
N-(3-Bromobenzyl)-O-methylhydroxylamine (2d)
1
Colorless oil; IR (neat) 3257, 2937, 1471 cm–1. H-NMR (400 MHz, CDCl3) δ 7.53–7.18 (4H, m), 4.01
13
(2H, s), 3.50 (3H, s). C-NMR (100 MHz, CDCl3) δ 140.2, 131.7, 130.4, 129.9, 127.3, 122.4, 55.5. MS
(ESI) m/z: 216 [M+H]+. HRMS (ESI) m/z:216.0017 [M+H]+ Calcd for C9H14NO: 216.0024.

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N-(4-Methoxybenzyl)-O-methylhydroxylamine (2e)
1
Colorless oil; IR (neat) 3259, 2937, 1512, 1464 cm–1. H-NMR (400 MHz, CDCl3) δ 7.22 (2H, d, J=8.6
Hz), 6.83 (2H, d, J=8.6 Hz), 5.67 (1H, br s), 3.93 (2H, s), 3.60 (3H, s), 3.46 (3H, s). 13C-NMR (100 MHz,
CDCl3) δ 158.7, 129.8, 129.4, 113.5, 61.3, 55.2, 54.8. MS (ESI) m/z: 168 [M+H]+. HRMS (ESI)
m/z:168.1019 [M+H]+ Calcd for C9H14NO2: 168.1025.
O-Benzyl-N-cyclohexylhydroxylamine (2f)
1
Colorless oil; IR (neat) 3266, 2922, 2851, 1495, 1450 cm–1. H-NMR (400 MHz, CDCl3) δ 7.35–7.29
(5H,m), 5.60 (1H, br s), 4.69 (2H, s), 2.77 (2H, d, J=6.7Hz), 1.76-1.55 (6H, m), 1.26-0.88 (5H, m).
13C-NMR (100 MHz, CDCl3) δ 138.1, 128.34, 128.30, 127.7, 76.0, 58.7, 35.4, 31.4 (2 carbons), 26.6,
26.0 (2 carbons). MS (ESI) m/z: 220 [M+H]+. HRMS (ESI) m/z:220.1692 [M+H]+ Calcd for C14H22NO:
220.1701.
O-Benzyl-N-hexylhydroxylamine (2g)
Colorless oil; IR (neat) 3262, 2929, 2857, 1495, 1455 cm–1. 1H-NMR (400 MHz, CDCl3) δ 7.33–7.22 (5H,
m), 5.49 (1H, br s), 4.67 (2H, s), 2.87 (2H, t, J=7.1 Hz), 1.48–1.43 (2H, m), 1.32-1.23 (6H, m), 0.88 (3H,
13
t, J=6.4 Hz). C-NMR (100 MHz, CDCl3) δ 138.0, 128.04, 128.00, 127.4, 75.9, 51.9, 31.5, 27.1, 26.6,
22.3, 13.8. MS (ESI) m/z: 208 [M+H]+. HRMS (ESI) m/z:208.1697 [M+H]+ Calcd for C13H22NO:
208.1701
O-Benzyl-N-(1-methylhexyl)hydroxylamine (2h)
Colorless oil; IR (neat) 3251, 2957, 2929, 2857, 1495 cm–1. 1H-NMR (400 MHz, CDCl3) δ 7.35–7.24 (5H,
m), 5.37 (1H, br s), 4.69 (2H, s), 3.02-2.98 (1H, m), 1.50–1.23 (8H, m), 1.06 (3H, d, J=6.3 Hz), 0.88 (3H,
13
t, J=7.0 Hz). C-NMR (100 MHz, CDCl3) δ 138.0, 128.20, 128.18, 127.5, 76.6, 56.0, 33.9, 31.9, 25.5,
22.5, 18.1, 13.9. MS (ESI) m/z: 222 [M+H]+. HRMS (ESI) m/z:222.1845 [M+H]+ Calcd for C14H24NO:
222.1858.
O-Benzyl-N-(1-propylbutyl)hydroxylamine (2i)
Colorless oil; IR (neat) 3255, 2957, 2931, 2870, 1495 cm–1. 1H-NMR (400 MHz, CDCl3) δ 7.33–7.21 (5H,
m), 5.42 (1H, br s), 4.67 (2H, s), 2.86–2.82 (1H, m), 1.46-1.31 (8H, m), 0.89 (6H, t, J=7.1Hz). 13C-NMR
(100 MHz, CDCl3) δ 138.1, 128.12, 128.05, 127.4, 76.3, 59.9, 34.1 (2 carbons), 18.9 (2 carbons), 14.1 (2
carbons). MS (ESI) m/z: 222 [M+H]+. HRMS (ESI) m/z:222.1860 [M+H]+ Calcd for C14H24NO:
222.1858.

HETEROCYCLES, Vol. 78, No. 2, 2009
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O-Benzyl-N-(1-cyclohexylethyl)hydroxylamine (2j)
Colorless oil; IR (neat) 3244, 2924, 2852, 1495, 1450 cm–1. 1H-NMR (400 MHz, CDCl3) δ 7.33–7.19 (5H,
m), 5.43 (1H, br s), 4.68 (2H, s), 2.88-2.83 (1H, m), 1.85–1.67 (5H, m), 1.46-1.43 (1H, m), 1.25–1.10(3H,
m), 1.02–0.95 (5H, m). 13C-NMR (100 MHz, CDCl3) δ 138.1, 128.2, 128.1, 127.5, 76.4, 50.4, 40.1, 29.8,
27.9, 26.6, 26.4, 26.3, 14.5. MS (ESI) m/z: 234 [M+H]+. HRMS (ESI) m/z:234.1839 [M+H]+ Calcd for
C15H24NO: 234.1858.
O-Benzyl-N-tetrahydro-2H-pyran-4-ylhydroxylamine (2k)
Colorless oil; IR (neat) 3246, 2952, 2848, 1495, 1453 cm–1. 1H-NMR (400 MHz, CDCl3) δ 7.36–7.28 (5H,
m), 4.71 (2H, s), 3.97 (2H, ddd, J=3.6, 3.6, 11.2 Hz), 3.41 (2H, ddd, J=2.3, 11.2, 11.2 Hz), 3.15–3.09 (1H,
m), 1.84–1.80 (2H, m), 1.51–1.41 (2H, m). 13C-NMR (100 MHz, CDCl3) δ 137.8, 128.3 (4 carbons),
127.8, 76.8, 66.3 (2 carbons), 56.4, 30.8 (2 carbons). MS (ESI) m/z: 208 [M+H]+. HRMS (ESI)
m/z:208.1318 [M+H]+ Calcd for C12H18NO2: 208.1338.
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