Reactions of alkyl radicals with oxime ether: One-pot synthesis of α- amino acids

Article abstract of DOI:10.1016/S0040-4020(00)00119-8

The addition of water-resistant carbon radicals to glyoxylic oxime ether provided a new method for the one-pot synthesis of α-amino acids via a carbon-carbon bond formation. The reaction of 2-hydroxy-2-methoxyacetic acid methyl ester with benzyloxyamine a

Full text of DOI:10.1016/S0040-4020(00)00119-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2413–2420
Reactions of Alkyl Radicals with Oxime Ether:
One-Pot Synthesis of a-Amino Acids
*
Hideto Miyabe, Masafumi Ueda, Naoko Yoshioka, Kumiko Yamakawa and Takeaki Naito
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 19 January 2000; accepted 9 February 2000
Abstract—The addition of water-resistant carbon radicals to glyoxylic oxime ether provided a new method for the one-pot synthesis of
a-amino acids via a carbon–carbon bond formation. The reaction of 2-hydroxy-2-methoxyacetic acid methyl ester with benzyloxyamine and
an alkyl radical gave the protected a-amino acids via the stannyl radical-mediated reaction. In the absence of Bu3SnH, the predominant
formation of the desired alkylated products was also observed by using RI and Et3B in boiling toluene. Et2Zn could serve as an initiator of
these radical reactions as well as Et3B. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
from 2-hydroxy-2-methoxyacetic acid methyl ester and
benzyloxyamine.6,7
Integration of multi-step chemical reactions into a one-pot
reaction is of great significance from both economical and
ecological points of view. Moreover, multi-component reac-
tions facilitate the rapid construction of compound libraries
from simple building blocks, as exemplified by the recent
progress in the field of combinatorial chemistry.1
Results and Discussion
One-pot synthesis of a-amino acids
In recent years, much attention has been paid to the
development of concise and flexible synthetic approaches
to a-amino acids, allowing facile incorporation of
functional groups and structural variability. Multi-step
synthetic routes to a-amino acids are available;8 however,
the development of one-pot procedures remains a challenge
in organic synthesis.9 We have recently reported the
first asymmetric synthesis of a-amino acids based on a
diastereoselective carbon radical addition to glyoxylic
oxime ether.10 This reaction is particularly useful because
there currently exists no general synthetic method for the
construction of a wide range of aliphatic a-amino acids
using glyoxylic imines as the starting material.11 We next
started synthetic studies on a novel one-pot approach to
a-amino acids via the condensation of an a-keto acid
derivative with alkoxyamine, followed by the addition of
an alkyl radical to the resulting oxime ether.
The reaction of imines with C-nucleophiles provides a
useful route for preparing a variety of amines.2 The reac-
tions are generally carried out by using moisture-sensitive
organometallic reagents, except for a few outstanding
examples.3 These methods necessitate strictly anhydrous
reaction conditions and additional protection-deprotection
steps. The imine derivative has emerged as a radical
acceptor, and thus numerous synthetically useful reactions
are available.4 However, the radical reactions of water-
sensitive imines have generally been performed under
anhydrous reaction conditions. In principle, the reactions
of strictly neutral species such as uncharged free radicals
are not affected by the presence of water.5 Therefore,
employment of a moisture-resistant radical species would
eliminate the cumbersome operations involved in con-
ventional ionic reactions and successfully integrate a
multi-step reaction into a one-pot reaction. In this paper,
we describe full details of the one-pot synthesis of
a-amino acid derivatives based on a moisture-resistant
carbon radical addition to glyoxylic oxime ether generated
We first investigated the one-pot reaction using com-
mercially available 2-hydroxy-2-methoxyacetic acid methyl
ester 1, benzyloxyamine 2 and triethylborane as an ethyl
radical source in CH2Cl2 (Scheme 1). Condensation of
2-hydroxy-2-methoxyacetic acid methyl ester 1 with
benzyloxyamine 2 proceeded smoothly in the presence of
MgSO4 to give the glyoxylic oxime ether 6 after being
stirred at 25ЊC for 24 h. To the reaction vessel was added
Et3B and then the reaction mixture was stirred at 25ЊC for
Keywords: radical addition; oxime ether; atom-transfer; one-pot; a-amino
acids.
* Corresponding author. Tel.: ϩ81-78-441-7554; fax: ϩ81-78-441-7556;
e-mail: taknaito@kobepharma-u.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00119-8

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H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
Scheme 1.
15 min. This simple one-pot reaction would proceed as indi-
cated in Scheme 1 to afford the a-amino acid derivative 3a
in 90% yield. A similar result was obtained in the absence of
MgSO4 because triethylborane and the alkyl radical are
stable even in aqueous media.5 In this reaction, triethyl-
borane acts not only as a radical initiator but also a Lewis
acid and a radical terminator to trap the intermediate benzyl-
oxyaminyl radical; thus a radical reaction cycle proceeds
through the regeneration of the ethyl radical. It is also
important to note that the radical addition to glyoxylic
oxime ether takes place regioselectively at the imino carbon
atom on the oxime ether group to give C-ethylated product
3a, because the related addition of organometallic reagents
is frequently plagued by the Michael-type addition to give
N-alkylated products.
We then extended the radical reaction to the one-pot
synthesis of a-amino acids by using different radical pre-
cursors, allowing structural variety (Table 1). Reactions
were run both in the presence of Bu3SnH (method I) and
in the absence of Bu3SnH (method II). In the case of method
II, the radical reaction proceeded via a route involving the
iodine atom-transfer process between the alkyl iodide and
the ethyl radical generated from triethylborane. Both
Table 1. One-pot synthesis of a-amino acid derivatives 3b–h and 5 in CH2Cl2 (b: R ˆ i-Pr, c: R ˆ t-Bu, d: R ˆ i-Bu, e: R ˆ s-Bu, f: R ˆ c-Hexyl,
g: R ˆ Adamantyl, h: R ˆ ꢀCH2†4OAc, i: R ˆ ꢀCH2†3Cl†
Entry
RI
Methoda
Productb
Yield (%)c
1
2
3
4
5
6
7
8
i-PrI
i-PrI
t-BuI
t-BuI
i-BuI
s-BuI
s-BuI
c-Hexyl I
c-Hexyl I
Adamantyl I
AcO(CH2)4I
Cl(CH2)3I
I
II
I
II
I
I
II
I
II
II
I
3b
3b
3c
3c
3d
3e
3e
3f
74
52
86
85
49
71
64
72
60
73
57
46
9
3f
10
11
12
3g
3h
5
I
a Method I: Reaction was carried out with 2-hydroxy-2-methoxyacetic acid methyl ester (1 equiv.), BnONH2 (1 equiv.), RI (5 equiv.), Bu3SnH (2.5 equiv.),
and Et3B in hexane (2.5 equiv.) under N2 at 25ЊC.; Method II: Reaction was carried out with 2-hydroxy-2-methoxyacetic acid methyl ester (1 equiv.),
BnONH2 (1 equiv.), RI (10 equiv.), and Et3B in hexane (5 equiv.) under N2 at 25ЊC.
b A small amout of the ethylated product 3a was also obtained.
c Isolated yields.

H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
Table 2. Alkyl radical addition to 6 (a: RˆEt, b: Rˆi-Pr, c: Rˆt-Bu, d: Rˆi-Bu)
2415
Entry
Reagents (equiv.)
T (ЊC)
Solvent
Product (% yield)a
1
2
3
4
5
6
i-PrI (3.5), Bu3SnH (2.2), AIBN (0.2)
i-PrI (5.0), Bu3SnH (2.5), Et3B (0.2)
i-PrI (3.5), Bu3SnH (2.2), V-70 (0.5)
i-PrI (5.0), Et3B (5.0)
t-BuI (5.0), Et3B (5.0)
i-BuI (5.0), Et3B (5.0)
Reflux
25
25
25
25
Toluene
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
3b (39%)
3b (trace)ϩ3a (trace)
No Reaction
3b (65%)ϩ3a (17%)
3c (74%)ϩ3a (9%)
3d (6%)ϩ3a (69%)
25
a Yields of isolated product.
methods were effective for the one-pot reactions using
secondary and tertiary alkyl iodides, although the stannyl
radical-mediated reactions proceeded with slightly higher
efficiency (Table 1, entries 1–4 and 6–10). In contrast, the
use of Bu3SnH was essential for the successful one-pot
reaction with the unstable primary alkyl radicals (Table 1,
entries 5, 11 and 12). Expecting that the addition of func-
tionalized radicals would make the products more useful
building blocks, we investigated the reaction employing
bifunctional halides as an alkyl radical precursor. As was
expected from the nature of the radical reaction, alkyl
iodides containing an ester moiety or a chlorine atom under-
went smooth radical addition reactions to give the corre-
spondingly functionalized a-amino acid derivatives (Table
1, entries 11 and 12). In the case of 1-chloro-3-iodopropane
4i, the proline derivative 5 was obtained by the concomitant
intramolecular N-alkylation of 3i which was preformed by
the one-pot reaction of the chloropropyl radical. In all cases,
the competitive formation of the ethylated products 3a was
observed as a result of the addition of the ethyl radical
generated from triethylborane.
(5 equiv.), Bu3SnH (2.5 equiv.), and triethylborane (5 equiv.)
proceeded smoothly in CH2Cl2 at 25ЊC to give the desired
isopropylated product 3b in 79% yield accompanied with
8% yield of the ethylated product 3a, which was formed by a
competitive reaction with the ethyl radical generated from
triethylborane. Although treatment of 6 with i-PrI and
Bu3SnH in the presence of AIBN (0.2 equiv.) in boiling
toluene gave the isopropylated product 3b in 39% yield,
the reaction using triethylborane (0.2 equiv.) or V-70
(0.5 equiv.) as a radical initiator did not take place at 25ЊC
(Table 2, entries 1–3).12 These results support the multiple
roles of triethylborane as a Lewis acid, a radical initiator,
and a terminator; therefore, more than a stoichiometric
amount of triethylborane is required.
Since the radical reactions including atom- and group-
transfer processes have been a subject of current interest
from the ecological point of view,13 the reactions involving
an iodine atom-transfer process using triethylborane
(5 equiv.) and alkyl iodides (5 equiv.) were also examined
in the absence of Bu3SnH. The isopropyl radical addition
reaction proceeded smoothly at 25ЊC to give a good yield of
alkylated products 3b and 3a with slightly low selectivity
compared with that obtained by the stannyl radical-induced
radical addition (Table 2, entry 4). Although the addition of
the most stable tertiary alkyl radical such as tert-butyl radi-
cal led to higher selectivity to give an excellent yield of 3c,
the reaction with the unstable primary isobutyl radical gave
Optimization of reaction conditions
To learn the reaction pathway, we first examined the iso-
propyl radical addition to glyoxylic oxime ether 6 under
several reaction conditions (Table 2). As shown in our
previous reports,6b,10b the reaction of
6 with i-PrI
Scheme 2.

2416
H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
Table 3. Effect of solvent and reaction temperature on the isopropyl radical addition to 6 (reaction was carried out with i-PrI (5 equiv.) and Et3B in hexane
(5 equiv.) under N2)
Entry
Solvent
T (ЊC)
Time (min)
15
Yield (%)a
3b
3a
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
CH2ClCH2Cl
MeCN
MeOH
MeOH
Toluene
Toluene
25
15
180
15
15
15
15
15
15
15
1
65
42
42
62
46
59
41
47
66
70
17
44
46
18
23
34
37
38
27
13
Ϫ78
Ϫ78
25
25
25
25
reflux
25
10
reflux
a Yields of isolated product.
significant amounts of the ethylated product 3a (Table 2,
entries 5 and 6). These observations suggest that the radical
reaction through a route involving the iodine atom-transfer
process is an effective method when the stable tertiary and
secondary alkyl radicals are employed (Scheme 2). This
reaction has a tremendous practical advantage over the
stannyl radical-induced reaction which requires tedious
work-up to remove the tin-residues from the reaction mixture.
not influence the degree of selectivity. The replacement of
CH2Cl2 with Et2O, CH2ClCH2Cl, MeCN, or MeOH as a
solvent led to low chemical yield of the isopropylated
product 3b (Table 3, entries 4–8). Effect of the reaction
temperature was observed in the reaction using toluene as
a solvent, and the best result was obtained in the reaction
carried out in boiling toluene (Table 3, entries 9 and 10).
These results indicate that the isopropyl radical addition
reaction proceeded effectively in boiling toluene via a
route involving the iodine atom-transfer process between
the isopropyl iodide and ethyl radical, and the predominant
addition of the more nucleophilic and stable isopropyl
radical was observed.
In order to optimize the reaction conditions of the radical
addition reaction via the iodine atom-transfer process, we
then investigated the reaction by varying the reaction
temperature, solvent, and the radical initiator. The isopropyl
radical addition reaction to glyoxylic oxime ether 6 was run
by using i-PrI (5 equiv.) and triethylborane (5 equiv.) to
give the alkylated products 3b and 3a (Table 3). The forma-
tion of the isopropylated product 3b in CH2Cl2 was shown to
be dependent on the reaction temperature; thus, changing
the temperature from 25 to Ϫ78ЊC led to a decrease in the
ratio of the isopropylated product 3b to the ethylated
product 3a (Table 3, entries 1–3). The reaction time did
We next investigated the isopropyl radical addition using
i-PrI and triethylborane or diethylzinc as a radical initiator
(Table 4). Recently, Ryu and Komatsu reported that a
diethylzinc-air system can serve as an initiator of tin
hydride-mediated radical reaction.14 Therefore, the iodine
atom-transfer reaction using diethylzinc in the absence of
Bu3SnH is a new subject of considerable interest. The
Table 4. Isopropyl radical addition to 6 using Et3B or Et2Zn (reaction was carried out with EtnM in hexane (2.5 equiv.) under N2)
Entry
EtnM
i-PrI (equiv.)
T (ЊC)
Time (min)
Yield (%) of 3ba
Ratio (3b/3a)b
1
2
3
4
5
6
7
8
9
10
Et3B
Et3B
Et3B
Et3B
5
5
10
20
30
5
Reflux
Reflux
Reflux
Reflux
Reflux
25
25
25
25
25
1
30
1
1
1
1
30
1
1
1
78
75
85
88
87
52
51
58
67
68
7.6
7.0
10.6
14.4
32.1
3.1
4.5
6.8
12.4
19.0
Et3B
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
5
10
20
30
a Yields of isolated product.
1
b Based on H NMR.

H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
2417
Table 5. One-pot synthesis of a-amino acid derivatives in boiling toluene (reaction was carried out with 2-hydroxy-2-methoxyacetic acid methyl ester
(1 equiv.), BnONH2 (1 equiv.), RI (30 equiv.), and Et3B in hexane (2.5 equiv.) under N2. b: Rˆi-Pr, d: Rˆi-Bu, e: Rˆs-Bu, f: Rˆc-Hexyl, j: Rˆc-Pentyl)
Entry
RI
Product
Yield (%) of 3b–ka
Ratio (3b–k/3a)b
1
2
3
4
5
i-PrI
i-BuI
s-BuI
c-Hexyl I
c-Pentyl I
3b
3d
3e
3f
88
Ͼ10
1
Ͼ10
Ͼ10
Ͼ10
29 (ϩ30% yield of 3a)
94
83
76
3j
a Yields of isolated product.
b Based on 1H NMR.
reactions using triethylborane were run in boiling toluene
(Table 4, entries 1–5). The ratio of 3b to 3a was dependent
on the equivalent of i-PrI; thus, the best selectivity was
obtained when 30 equiv. of i-PrI were employed. A similar
trend was observed in the isopropyl radical addition using
i-PrI and diethylzinc as a radical initiator (Table 4, entries
6–10). In the case of diethylzinc, the reaction carried out in
boiling toluene gave a mixture of C- and N-alkylated
products as a result of the competitive Michael-type
addition of diethylzinc; thus, the reaction was carried out
in toluene at 25ЊC. Although chemical yields and selec-
tivities were slightly lower than that obtained by using
triethylborane, diethylzinc was found to serve as an initiator
of these radical reactions as well as triethylborane.
CDCl3. Chemical shifts (d scale) are relative to TMS as
internal reference. IR spectra were measured with a
Perkin–Elmer 1600 FTIR machine and mass spectra were
taken by Hitachi M-4100 spectrometer. For flash column
chromatography, E. Merck Kieselgel 60 (230–400 mesh)
was used. Preparative TLC separations were carried out
on precoated silica gel plates (E. Merck 60F254). Triethyl-
borane proved to be an effective radical initiator in the
presence of trace amount of oxygen.5
The one-pot synthesis of methyl 2-(benzyloxyamino)-
butanate (3a)15 (Scheme 1)
To a solution of 2-hydroxy-2-methoxyacetic acid methyl
ester 1 (80 mg, 0.67 mmol) in CH2Cl2 (1 mL) were added
benzyloxyamine
2 (82.4 mg, 0.67 mmol) in CH2Cl2
Based on these results, we finally examined the one-pot
synthesis of a-amino acids via a route involving the iodine
atom-transfer process (Table 5). The radical reactions were
run in toluene at reflux by using excessive amount of alkyl
iodide and triethylborane. As expected, the one-pot reaction
proceeded smoothly to give a good yield of alkylated
products 3b, 3f, 3g, and 3k with excellent selectivities,
when secondary alkyl iodides were employed (Table 5,
entries 1 and 3–5). The reaction using primary alkyl iodides
was less effective because of a competitive reaction with the
ethyl radical generated from triethylborane (Table 5, entry
2).
(0.5 mL) and MgSO4 (10 mg) under a nitrogen atmosphere
at 25ЊC. After being stirred at the same temperature for
1 day, Et3B (1.0 M in hexane, 1.68 mL, 1.68 mmol) was
added to the reaction mixture. After being stirred at the
same temperature for 15 min, the reaction mixture was
diluted with saturated aqueous NaHCO3 and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification of the
residue by preparative TLC (hexane/AcOEt 12:1) afforded
the a-amino acid derivatives 3a as a colorless oil. IR
(CHCl3) 2954, 1728, 1605, 1496, 1455 cmϪ1. H NMR
1
(CDCl3) d 7.37–7.25 (5H, m), 4.69 (2H, s), 3.74 (3H, s),
3.53 (1H, br t, Jˆ6.6 Hz), 1.53 (2H, m), 0.91 (3H, t,
Jˆ7.4 Hz). 13C NMR (CDCl3) d 174.4, 137.6, 128.3,
128.1, 127.6, 76.0, 64.9, 51.7, 22.7, 10.3. HRMS: Calcd
for C12H17NO3 (Mϩ): 223.1207, Found: 223.1227.
Conclusion
We have demonstrated that the use of a moisture-resistant
radical species provides direct access to various types of
a-amino acids from 2-hydroxy-2-methoxyacetic acid
methyl ester. The advantages of this procedure are that the
tedious isolation of the intermediate glyoxylic oxime ethers
is unnecessary and aliphatic alkyl iodides having functional
groups participate readily as reagents.
General procedure for the one-pot synthesis of a-amino
acids by using Bu3SnH (Method I in Table 1)
To a solution of 2-hydroxy-2-methoxyacetic acid methyl
ester 1 (80 mg, 0.67 mmol) in CH2Cl2 (1 mL) were added
benzyloxyamine
2 (82.4 mg, 0.67 mmol) in CH2Cl2
(0.5 mL) and MgSO4 (10 mg) under a nitrogen atmosphere
at 25ЊC. After being stirred at the same temperature for
1 day, RI 4 (3.35 mmol), Bu3SnH (0.45 mL, 1.68 mmol),
and Et3B (1.0 M in hexane, 1.68 mL, 1.68 mmol) were
added to the reaction mixture. After being stirred at the
same temperature for 15 min, the reaction mixture was
diluted with saturated aqueous NaHCO3 and then extracted
Experimental
General
1H and 13C NMR spectra were measured using Varian
Gemini-200 (200 and 50 MHz, respectively) instrument in

2418
H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification of the residue
by preparative TLC (hexane/AcOEt 15:1, 2-fold develop-
ment) followed by preparative TLC (chloroform) afforded
the a-amino acid derivatives 3.
extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. Selectivity
was determined by 1H NMR analysis of the crude products.
Purification of the residue by preparative TLC (hexane/
AcOEt 12:1) afforded the a-amino acid derivatives 3a and
3b.
General procedure for the one-pot synthesis of a-amino
acids in the absence of Bu3SnH (Method II in Table 1)
Isopropyl radical addition to glyoxylic oxime ether 6 by
using Et2Zn (Table 4, entries 6–10)
To a solution of 2-hydroxy-2-methoxyacetic acid methyl
ester 1 (80 mg, 0.67 mmol) in CH2Cl2 (1 mL) were added
To a solution of glyoxylic oxime ether 6 (100 mg,
0.52 mmol) in toluene (10 mL) were added i-PrI 4b (5,
10, 20, or 30 equiv.) and Et2Zn (1.0 M in hexane, 1.3 mL,
1.3 mmol) at 25ЊC. After the reaction mixture was stirred at
the same temperature for 1 or 30 min, the reaction mixture
was diluted with saturated aqueous NaHCO3 and then
extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. Selectivity
was determined by 1H NMR analysis of the crude products.
Purification of the residue by preparative TLC (hexane/
AcOEt 12:1) afforded the a-amino acid derivatives 3a and
3b.
benzyloxyamine
2 (82.4 mg, 0.67 mmol) in CH2Cl2
(0.5 mL) and MgSO4 (10 mg) under a nitrogen atmosphere
at 25ЊC. After the reaction mixture was stirred at the same
temperature for 1 day, RI 4 (6.7 mmol) and Et3B (1.0 M in
hexane, 3.35 mL, 3.35 mmol) were added. After being stir-
red at the same temperature for 15 min, the reaction mixture
was diluted with saturated aqueous NaHCO3 and then
extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. Purifica-
tion of the residue by preparative TLC (hexane/AcOEt 15:1)
afforded the a-amino acid derivatives 3.
Isopropyl radical addition to glyoxylic oxime ether 6 by
using AIBN (Table 2, entry 1)
General procedure for the one-pot synthesis of a-amino
acids by using Et3B in boiling toluene (Table 5)
To a solution of glyoxylic oxime ether 6 (100 mg,
0.52 mmol) in toluene (10 mL) were added i-PrI 4b
(0.18 mL, 1.8 mmol), Bu3SnH (0.31 mL, 1.14 mmol), and
AIBN (17 mg, 0.104 mmol) at reflux. After the reaction
mixture was stirred at the same temperature for 5 min, the
reaction mixture was diluted with H2O and then extracted
with AcOEt. The organic phase was dried over MgSO4 and
concentrated under reduced pressure. Purification of the
residue by preparative TLC (hexane/AcOEt 10:1, 2-fold
development) afforded the a-amino acid derivatives 3b
(48 mg, 39%).
To a solution of 2-hydroxy-2-methoxyacetic acid methyl
ester 1 (80 mg, 0.67 mmol) in toluene (1 mL) were added
benzyloxyamine
2 (82.4 mg, 0.67 mmol) in toluene
(0.5 mL) and MgSO4 (10 mg) under a nitrogen atmosphere
at 25ЊC. After the reaction mixture was stirred at the same
temperature for 1 day, RI 4 (6.7 mmol) and Et3B (1.0 M in
hexane, 3.35 mL, 3.35 mmol) were added to the reaction
mixture at reflux. After being stirred at the same tempera-
ture for 1 min, the reaction mixture was diluted with
saturated aqueous NaHCO3 and then extracted with
CH2Cl2. The organic phase was dried over MgSO4 and
concentrated under reduced pressure. Purification of the
residue by preparative TLC (hexane/AcOEt 15:1) afforded
the a-amino acid derivatives 3.
Isopropyl radical addition to glyoxylic oxime ether 6 by
using Et3B (Table 3)
To a solution of glyoxylic oxime ether 6 (100 mg,
0.52 mmol) in CH2Cl2, Et2O, CH2ClCH2Cl, CH3CN,
MeOH, or toluene (10 mL) were added i-PrI 4b (0.26 mL,
2.6 mmol) and Et3B (1.0 M in hexane, 2.6 mL, 2.6 mmol) at
25ЊC, Ϫ78ЊC, or reflux. After the reaction mixture was stir-
red at the same temperature for 1, 15, or 180 min, the reac-
tion mixture was diluted with saturated aqueous NaHCO3
and then extracted with CH2Cl2. The organic phase was
dried over MgSO4 and concentrated under reduced pressure.
Purification of the residue by preparative TLC (hexane/
AcOEt 12:1, 2-fold development) afforded the a-amino
acid derivatives 3a and 3b.
Methyl 2-(benzyloxyamino)-3-methylbutanate (3b).
Colorless oil. IR (CHCl3) 2958, 1742, 1605, 1496,
1
1454 cmϪ. H NMR (CDCl3) d 7.35–7.26 (5H, m), 4.67
(1H, d, Jˆ12.5 Hz), 4.66 (1H, d, Jˆ12.5 Hz), 3.75 (3H,
s), 3.36 (1H, br m), 1.78 (1H, m), 0.91 (3H, d, Jˆ7.0 Hz),
0.89 (3H, d, Jˆ6.5 Hz). 13C NMR (CDCl3) d 174.5, 137.8,
128.6, 128.2, 127.7, 76.0, 69.6, 51.7, 29.2, 19.3, 19.3.
HRMS: Calcd for C13H19NO3 (Mϩ): 237.1363, Found:
237.1371.
Methyl 2-(benzyloxyamino)-3,3-dimethylbutanate (3c).
Colorless oil. IR (CHCl3) 2956, 1728, 1605, 1496,
1
1455 cmϪ1. H NMR (CDCl3) d 7.34–7.26 (5H, m), 4.65
Isopropyl radical addition to glyoxylic oxime ether 6 by
using Et3B (Table 4, entries 1–5)
(2H, s), 3.74 (3H, s), 3.31 (1H, br s), 0.90 (9H, s). 13C NMR
(CDCl3) d 174.5, 137.9, 128.7, 128.2, 127.7, 75.8, 72.1,
51.5, 33.1, 27.0. HRMS: Calcd for C14H21NO3 (Mϩ):
251.1521, Found: 251.1530.
To a solution of glyoxylic oxime ether 6 (100 mg,
0.52 mmol) in toluene (10 mL) were added i-PrI 4b (5,
10, 20, or 30 equiv.) and Et3B (1.0 M in hexane, 1.3 mL,
1.3 mmol) at reflux. After the reaction mixture was stirred at
the same temperature for 1 or 30 min, the reaction mixture
was diluted with saturated aqueous NaHCO3 and then
Methyl 2-(benzyloxyamino)-4-methylpentanate (3d).
Colorless oil. IR (CHCl3) 2959, 1736, 1603, 1496,
1
1455 cmϪ1. H NMR (CDCl3) d 7.34–7.27 (5H, m), 4.68
(2H, s), 3.74 (3H, s), 3.64 (1H, br t, Jˆ7.0 Hz), 1.65 (1H,

H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
2419
m), 1.33 (2H, m), 0.88 (3H, d, Jˆ6.5 Hz), 0.84 (3H, d,
Jˆ6.5 Hz). 13C NMR (CDCl3) d 175.2, 137.9, 128.5,
128.2, 127.8, 76.1, 62.2, 51.9, 38.6, 25.1, 22.7, 22.1.
HRMS: Calcd for C14H21NO3 (Mϩ): 251.1520, Found:
251.1529.
Japan Private School Promotion Foundation. Partial support
for this work was also provided (to H. Miyabe) by the
Nissan Chemical Industries Award in Synthetic Organic
Chemistry, Japan.
Methyl 2-(benzyloxyamino)-3-methylpentanate (3e).
References
Colorless oil. IR (CHCl3) 2967, 2935, 1733, 1496,
1
1455 cmϪ1. H NMR (CDCl3) d 7.37–7.25 (5H, m), 4.67
1. For reviews, see: (a) Brown, R. C. D. J. Chem. Soc., Perkin
Trans. 1 1998, 3293. (b) Chem. Rev. 1997, 97, whole issue of No.
2, pp 347–510. (c) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees,
D. C. Tetrahedron 1997, 53, 5643.
2. For reviews, see: (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b)
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(c) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996, 999.
(d) Risch, N.; Arend, N. In Stereoselective Synthesis; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme:
New York, 1996; Vol. 3; pp 1833–2009. (e) Volkmann, R. A. In
Comprehensive Organic Synthesis; Trost B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 1, pp 355–396.
3. For selected recent examples, see: (a) Akiyama, T.; Takaya, J.;
Kagoshima, H. Synlett 1999, 1426. (b) Petasis, N. A.; Zavialov,
I. A. J. Am. Chem. Soc. 1998, 120, 11798. (c) Petasis, N. A.;
Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. (d) Petasis,
N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53,
16463. (e) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem.
Commun. 1998, 19.
4. For reviews, see: (a) Naito, T. Heterocycles 1999, 50, 505. (b)
Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. Oxime
ethers are well known to be excellent radical acceptors. See: (c)
Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999, 64, 2174.
(d) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;
Naito, T. J. Org. Chem. 1998, 63, 4397. (e) Iserloh, U.; Curran,
D. P. J. Org. Chem. 1998, 63, 4711. (f) Boiron, A.; Zillig, P.; Faber,
D.; Giese, B. J. Org. Chem. 1998, 63, 5877. (g) Marco-Contelles,
J.; Balme, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C. D.;
Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997, 62, 1202. (h) Clive,
D. L. J.; Zhang, J. Chem. Commun. 1997, 549.
5. For radical reactions in aqueous media, see: (a) Yamazaki, O.;
Togo, H.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc. Jpn. 1997,
70, 2519. (b) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 1998, 63, 8604; (c) Nakamura, T.;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 1998, 1351.
(d) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron Lett. 1986,
27, 3149. (e) Giese, B.; Damm, W.; Roth, M.; Zehnder, M. Synlett
1992, 441. (f) Yorimitsu, H.; Wakabayashi, K.; Shinokubo, H.;
Oshima, K. Tetrahedron Lett. 1999, 40, 519.
6. (a) Miyabe, H.; Yoshioka, N.; Ueda, M.; Naito, T. J. Chem.
Soc., Perkin Trans. 1 1998, 3659. (b) Miyabe, H.; Ueda, M.;
Yoshioka, N.; Naito, T. Synlett 1999, 465.
7. Alkylative amination of aldehydes based on the radical reaction
of oxime ethers, see: Miyabe, H.; Yamakawa, K.; Yoshioka, N.;
Naito, T. Tetrahedron 1999, 55, 11209.
(1H, m), 4.66 (1H, m), 3.74 (3H, m), 3.48 (1H, m), 1.68–
1.05 (3H, m), 0.88–0.80 (6H, m). 13C NMR (CDCl3) d
174.6, 174.4, 137.8, 128.51, 128.45, 128.1, 127.6, 75.8,
68.0, 67.6, 51.6, 51.5, 35.7, 35.3, 26.2, 25.8, 15.4, 15.2,
11.2, 10.9. HRMS: Calcd for C14H21NO3 (Mϩ): 251.1521,
Found: 251.1544.
Methyl 2-(benzyloxyamino)-2-cyclohexylethanate (3f).
Colorless oil. IR (CHCl3) 2932, 1733, 1604, 1496,
1
1452 cmϪ1. H NMR (CDCl3) d 7.35–7.26 (5H, m), 4.66
(2H, s), 3.74 (3H, s), 3.40 (1H, br m), 1.81–0.88 (11H, m).
13C NMR (CDCl3) d 174.6, 137.9, 128.6, 128.2, 127.7, 75.9,
69.0, 51.7, 38.6, 29.8, 29.7, 26.1, 26.0, 25.9. HRMS: Calcd
for C16H23NO3 (Mϩ): 277.1676, Found: 277.1698.
Methyl 2-(benzyloxyamino)-2-(1-adamantyl)ethanate (3g).
Colorless oil. IR (CHCl3) 2909, 1731 cmϪ1 1H NMR
.
(CDCl3) d 7.34–7.28 (5H, m), 4.64 (2H, s), 3.74 (3H, s),
3.20 (1H, br m), 1.93–1.33 (15H, s). 13C NMR (CDCl3) d
173.9, 137.8, 128.5, 128.0, 127.5, 75.5, 72.9, 51.2, 39.0,
36.6, 35.0, 28.1. HRMS: Calcd for C20H27NO3 (Mϩ):
329.1989, Found: 329.2006.
Methyl 6-acetoxy-2-(benzyloxyamino)hexanate (3h).
Colorless oil. IR (CHCl3) 2956, 1734, 1496, 1454 cmϪ1
.
1H NMR (CDCl3) d 7.39–7.28 (5H, m), 4.68 (2H, s), 4.01
(2H, t, Jˆ6.3 Hz), 3.75 (3H, s), 3.56 (1H, br t, Jˆ6.4 Hz),
2.03 (3H, s), 1.74–1.23 (6H, m). 13C NMR (CDCl3) d 174.3,
170.9, 137.6, 128.4, 128.1, 127.7, 76.0, 63.9, 63.3, 51.8,
29.0, 28.0, 22.3, 20.3. HRMS: Calcd for C16H23NO5 (Mϩ):
309.1575, Found: 309.1588.
Methyl 2-(benzyloxyamino)-2-cyclopentylethanate (3j).
Colorless oil. IR (CHCl3) 2955, 1734, 1454 cmϪ1 1H
.
NMR (CDCl3) d 7.39–7.21 (5H, m), 4.66 (2H, s), 3.73
(3H, s), 3.39 (1H, br d, Jˆ8.8 Hz), 1.97–1.15 (9H, m).
13C NMR (CDCl3) d 174.5, 137.6, 128.4, 128.0, 127.5,
75.7, 68.1, 51.5, 39.7, 29.9, 28.9, 24.8, 24.7. HRMS:
Calcd for C15H21NO3 (Mϩ): 263.1521, Found: 263.1527.
N-Benzyloxyproline methyl ester (5). Colorless oil. IR
1
(CHCl3) 2955, 1740, 1496, 1454 cmϪ1. H NMR (CDCl3)
d 7.36–7.23 (5H, m), 4.82 (2H, s), 3.73 (3H, s), 3.72 (1H,
m), 3.32 (1H, m), 2.91 (1H, m), 2.15 (1H, m), 1.96–1.79
(3H, m). 13C NMR (CDCl3) d 173.0, 137.5, 128.5, 128.2,
127.7, 75.6, 68.8, 55.9, 51.8, 25.8, 20.9. HRMS: Calcd for
C13H17NO3 (Mϩ): 235.1208, Found: 235.1195.
8. (a) Williams, R. M. Synthesis of Optically Active a-Amino
Acids; Pergamon: Oxford; 1989. (b) Duthaler, R. O. Tetrahedron
1994, 50, 1539.
9. (a) Tempest, P. A.; Brown, S. D.; Armstrong, R. W. Angew.
Chem., Int. Ed. Engl. 1996, 35, 640. (b) Posner, G. H. Chem. Rev.
1986, 86, 831.
Acknowledgements
10. (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997,
1789. (b) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito,
T. J. Org. Chem. 2000, 65, 176. For related examples, high 1,3-
stereoinduction in radical additions to cyclic imines has recently
This work was supported by research grants from the
Ministry of Education, Science, Sports and Culture of
Japan and the Science Research Promotion Fund of the

2420
H. Miyabe et al. / Tetrahedron 56 (2000) 2413–2420
been reported. See: (c) Bertrand, M. P.; Feray, L.; Nouguier, R.;
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Int. Ed. Engl. 1998, 37, 2562. (b) Giese, B.; Kopping, B.; Gobel,
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12. V-70
(2,20-azobis-(2,4-dimethyl-4-methoxyvaleronitrile))
works well as a radical initiator at room temperature. See: (a)
Kita, Y.; Sato, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.; Matsugi,