Stannyl radical addition-cyclization of oxime ethers connected with olefins

Article abstract of DOI:10.1248/cpb.52.74

Stannyl radical addition-cyclization of oxime ethers connected with olefin moieties was studied. The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process.

Full text of DOI:10.1248/cpb.52.74

74
Chem. Pharm. Bull. 52(1) 74—78 (2004)
Vol. 52, No. 1
Stannyl Radical Addition-Cyclization of Oxime Ethers Connected with
Olefins
Hideto MIYABE,1) Hirotaka TANAKA, and Takeaki NAITO*
Kobe Pharmaceutical University; Motoyamakita, Higashinada-ku, Kobe 658–8558, Japan.
Received September 4, 2003; accepted October 24, 2003
Stannyl radical addition-cyclization of oxime ethers connected with olefin moieties was studied. The radical
reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized
pyrrolidines via a carbon–carbon bond-forming process.
Key words radical reaction; stannyl radical; oxime ether; cyclization; triethylborane
Free radical-mediated cyclization has developed as a pow- stirred in boiling benzene for 2 h (entry 2). The reaction
erful method for preparing various types of cyclic com- using 0.4 eq of AIBN also proceeded smoothly to give the
pounds via carbon–carbon bond-forming processes.2—5) Al- cyclic product 4 in 81% yield (entry 3). The reaction path-
though a number of extensive investigations into radical reac- way is that the stannyl radical initially reacted with olefin
tions were reported in recent years, the majority of them em- moiety of 1 to form intermediate alkyl radical which attacked
ploy methods utilizing typical radical precursors such as intramolecularly the oxime ether group as in 5-exo-trig radi-
halides, selenides, and xanthates.2—5) One drawback in tradi- cal cyclization (Chart 4).
tional procedures using such radical precursors is loss of the
We next examined the stannyl radical addition-cyclization
inherent functional groups.6,7) Our laboratory is interested in reaction of oxime ether 1 by using triethylborane as a radical
developing the effective and convenient methods for the syn- initiator. In contrast to the reaction using AIBN, the reaction
thesis of highly functionalized cyclic compounds.8—21) Par- using triethylborane (2.5 eq) proceeded smoothly to give the
ticularly, strategies involving the radical addition-cyclization
reactions offer the advantage of the formation of multiple
carbon–carbon and carbon–heteroatom bonds in a single op-
eration. We recently reported the carbon tandem radical addi-
tion-cyclization of oxime ethers connected with the a,b-un-
saturated carbonyl group.22—24) As a part of our program di-
rected toward the development of radical addition-cyclization
Chart 1
reactions, we now describe full details of the heteroatom rad-
ical addition-cyclization reaction of substrates having two
different radical acceptors such as olefin and oxime ether
moieties (Chart 1).25) This investigation is the first example
of the stannyl radical-mediated reaction between oxime
ethers connected with olefin moieties.
Chart 2
Results and Discussion
We first investigated the reaction of oxime ether 1, which
was prepared as shown in Chart 2. a-Chloroacetaldoxime
ether 2 was prepared from chloroacetaldehyde and O-benzyl-
hydroxyamine hydrochloride.26) The reaction of 2 with allyl-
amine gave the secondary amine 3 in 76% yield. The amine
3 was protected as the N-Boc derivative 1 in quantitative
yield as an E/Z mixture in a 3 : 2 ratio. In our recent studies
Chart 3
on the radical reaction of oxime ethers, we have observed no
remarkable effect of the geometry of the starting oxime ether
Table 1. Stannyl Radical Addition-Cyclization of Oxime Ether 1a)
group on either the chemical yield or stereoselectivity by em-
ploying geometrically pure E and Z-isomers.10) Thus, oxime
ether 1 was subjected to the following radical reactions with-
out the separation of E/Z-isomers.
At first, we examined the stannyl radical addition-cycliza-
tion reaction of oxime ether 1 (Chart 3). Treatment of 1 with
Bu3SnH in the presence of AIBN (1.0 eq) in boiling benzene
for 15 min gave the cyclic product 427) in 31% yield accom-
panied with 65% yield of the starting material 1 (Table 1,
entry 1). The reaction using AIBN as a radical initiator pro-
ceeded slowly to give the product 4 in 84% yield, after being
Entry
Initiator
T (°C)
Time (min)
Yield (%)b)
1
2
3
4
5
6
7
8
AIBN (1.0 eq)
AIBN (1.0 eq)
AIBN (0.4 eq)
Et3B (2.5 eq)
Et3B (0.2 eq)
Et3B (5.0 eq)
Et2Zn (2.5 eq)
9-BBN (2.5 eq)
reflux
reflux
reflux
reflux
reflux
20
15
120
120
15
15
120
15
31 (65)
84
81
82
27 (61)
37 (57)
73
reflux
reflux
15
trace
a) Reactions were carried out with Bu3SnH in benzene. b) Yields of isolated prod-
uct; yields in parentheses are for the recovered starting material 1.
To whom correspondence should be addressed. e-mail: taknaito@kobepharma-u.ac.jp
© 2004 Pharmaceutical Society of Japan

January 2004
75
Table 2. 1H-NMR Data for Oxime Ether 1 in C6D6
Et3B (none)
Et3B (0.2 eq)
3.69
Et3B (0.4 eq)
3.71
Et3B (0.6 eq)
3.72
BCH2CH3 of Et3B
Benzylic H of (E)-1
Benzylic H of (Z)-1
Imino H of (E)-1
5.02 (2H, s)
5.06 (2H, s)
7.34 (1H, s)
5.00 (2H, s)
5.04 (2H, s)
7.31 (1H, s)
4.99 (2H, s)
5.03 (2H, s)
7.29 (1H, s)
4.98 (2H, s)
5.02 (2H, s)
Imino H of (Z)-1
6.66 (1H, s)
6.61 (1H, s)
6.59 (1H, s)
6.58 (1H, s)
Methylene H of (E,Z)-1
–CHϭCH2 of (E,Z)-1
–CHϭCH2 of (E,Z)-1
Aromatic H of (E,Z)-1
3.4—4.3 (4H, m)
4.8—5.0 (2H, m)
5.53 (1H, m)
7.0—7.3 (5H, m)
3.4—4.3 (4H, m)
4.8—5.0 (2H, m)
5.53 (1H, m)
7.0—7.3 (5H, m)
3.4—4.3 (4H, m)
4.8—5.0 (2H, m)
5.53 (1H, m)
7.0—7.3 (5H, m)
3.4—4.3 (4H, m)
4.8—5.0 (2H, m)
5.53 (1H, m)
7.0—7.3 (5H, m)
Chart 4
Chart 5
cyclic product 4 in 82% yield, after being stirred in boiling
benzene for only 15 min (entry 4). However, the use of a cat-
alytic amount of triethylborane (0.2 eq) was less effective for
the radical cyclization (entry 5). The reaction using triethyl-
borane (5.0 eq) proceeded moderately even at 20 °C (entry 6).
These results indicate that triethylborane exhibits an excel-
lent reactivity as a radical initiator and triethylborane acts as
not only a radical initiator but also a Lewis acid and a radical
terminator. Thus, the rationale of the major reaction pathway
is that the stannyl radical adds to the olefin moiety of 1 to
form intermediate alkyl radical A, which attacked intramole-
cularly the triethylborane-activated oxime ether group to
form the benzyloxyaminyl radical B (Chart 5). The benzyl-
oxyaminyl radical B would be trapped by triethylborane as a
radical terminator to give the product C and an ethyl radical
(path a); therefore, more than a stoichiometric amount of tri-
ethylborane is required.28—30) Alternative catalytic reaction
pathway involving stannyl radical as a chain carrier (path b)
would be less important for this reaction, because of the high
reactivity of triethylborane as a trapping reagent toward a key
intermediate aminyl radical B. Recently, Ryu and Komatsu
reported that diethylzinc-air system can serve as an initiator
of tin hydride-mediated radical reaction as well as triethylbo-
rane.31) In order to test the viability of diethylzinc, we also in-
vestigated the reaction of oxime ether 1 using a commer-
cially available 1.0 M solution of diethylzinc. Diethylzinc also
Chart 6
Table 3. Heteroatom Radical Addition-Cyclization of Oxime Ether 1a)
Time
(min)
Entry
Initiator
XH
Product
Yield (%)b)
1
2
3
4
5
6
Et3B (2.5 eq) Ph3SnH
Et3B (2.5 eq) PhSH
AIBN (1.0 eq) PhSH
Et3B (2.5 eq) Ph2PH
Et3B (2.5 eq) Et3SiH
Et3B (2.5 eq) (TMS)3SiH
15
15
180
15
15
15
5a
5b
5b
81
24 (54)
76
Complex mixture
32 (39)
79
6
5c
a) Reactions were carried out in boiling benzene. b) Yields of isolated product;
yields in parentheses are for the recovered starting material 1.
worked well as an effective radical initiator at high tempera- results suggest that triethylborane was captured by the oxime
ture to give the product 4 in 73% yield, after being stirred in ether group of 1.
boiling benzene for 15 min (entry 7). The use of 9-BBN32) as
To survey the scope and limitations of the triethylborane-
a radical initiator was less effective for the reaction of 1 promoted radical addition-cyclization of oxime ether 1, we
(entry 8). next investigated the reaction using different radical precur-
1
The H-NMR spectra data of the E/Z-mixture of oxime sors (Chart 6). High chemical yield was also observed in the
ether 1 obtained in the presence of triethylborane are shown addition-cyclization of oxime ether 1 using triphenyltin hy-
in Table 2. The upper field shift of the chemical shifts for the dride to give the cyclic product 5a in 81% yield (Table 3,
hydrogens of the oxime ether moiety (benzylic H and imino entry 1). The combination of triethylborane and thiophenol
H) and the downfield shifts of the chemical shift for the hy- was less effective for the sulfanyl radical addition-cyclization
drogens of triethylborane (BCH2CH3) were observed. These reaction, presumably due to the formation of an unidentified

76
Vol. 52, No. 1
Chart 7
Chart 8
complex from triethylborane and thiophenol (entry 2). Thus,
the cyclic product 5b was obtained in only 24% yield accom-
panied with 54% yield of the starting material 1. In contrast,
the reaction of 1 with thiophenol is known to proceed slowly
by using AIBN as a radical initiator to give the product 5b in
76% yield, after being stirred in boiling benzene for 3 h
Chart 9
(entry 3).33) The combination of triethylborane and diphenyl- lation, leading to product 15 in 91% yield. The reaction
phosphine also did not give the good result (entry 4). The use using tris(trimethylsilyl)silane proceeded smoothly to give
of the less reactive triethylsilane led to the predominant for- the cyclic product 16 in 63% yield, although the reaction
mation of the ethylated product 6 as a result of the competi- using triethylsilane led to the predominant ethylation. We fi-
tive intermolecular addition of an ethyl radical, generated nally examined the reaction of oxime ether 9 having an elec-
from triethylborane, to oxime ether group (entry 5). In con- tron-deficient carbon–carbon double bond. Treatment of 9
trast to triethylsilane, the reaction using the more reactive with triethylborane in the presence of Bu3SnH gave the
tris(trimethylsilyl)silane proceeded smoothly to give the cyclic product 17 in 82% yield, after being stirred in boiling
cyclic product 5c in 79% yield (entry 6).
benzene for 15 min. This observation indicates that the stan-
We next investigated the reaction of different types of nyl radical adds to electron-deficient carbon–carbon double
oxime ethers 7—9 (Chart 7). Preparation of oxime ethers 7— bonds as well as isolated carbon–carbon double bonds when
9 is shown in Chart 8. Ketoxime ether 10 was prepared from triethylborane was used as a radical initiator.
chloroacetone and O-benzylhydroxyamine hydrochloride.
In conclusion, we have demonstrated the radical addition-
The reaction of 10 with allylamine gave the secondary amine cyclization of oxime ethers connected with olefin moieties.
11 in 74% yield. The amine 11 was protected as the N-Boc The reaction of oxime ethers with stannyl radical proceeded
derivative 7 in 97% yield. Treatment of a-chloroacetal- smoothly by the use of triethylborane as a radical initiator to
doxime ether 2 with propargylamine gave the secondary provide the functionalized pyrrolidines.
amine 12, which was protected as the N-Boc derivative 8.
Experimental
The reaction of 2 with 2-aminoethanol gave the secondary
1
General Melting point is uncorrected. H- and 13C-NMR spectra were
recorded at 200, 300, or 500 MHz and at 50 or 125 MHz, respectively. IR
spectra were recorded using FTIR apparatus. Mass spectra were obtained by
amine 13 in 88% yield. Treatment of amine 13 with acryloyl
chloride in the presence of Na2CO3 in acetone–H2O gave
oxime ether 9 in 87% yield.
EI or CI methods. Preparative TLC separations were carried out on pre-
coated silica gel plates (E. Merck 60F254). Flash column chromatography
was performed using E. Merck Kieselgel 60 (230—400 mesh).
At first, we examined the stannyl radical addition-cycliza-
tion of ketoxime ether 7 by using triethylborane as a radical
initiator. However, ketoxime ethers (E)-7 and (Z)-7 did not
work under similar reaction conditions (Chart 9). We next
examined the reaction of oxime ether 8 having the propargyl
group.34—36) Treatment of an E/Z mixture of 8 with triethyl-
borane in the presence of Bu3SnH gave the cyclic product 14
in 61% yield, after being stirred in boiling benzene for
15 min. Additionally, the reaction of the cyclic product 14
N-(2-Propenyl)aminoethanal O-Benzyloxime (3) To allylamine (16.6
g, 290 mmol) was added chloroacetaldehyde O-benzyloxime (2) (17.8 g,
96.3 mmol) under a nitrogen atmosphere at 0 °C. After being stirred at room
temperature for 20 h, the reaction mixture was added to saturated aqueous
NaHCO3 and AcOEt. The layers were separated, and the aqueous phase was
extracted with AcOEt. The combined organic phase was dried over Na2SO4
and concentrated at reduced pressure. Purification of the residue by flash
chromatography (CHCl3/MeOH 30 : 1) afforded 3 (14.9 g, 76%) as a yellow
oil and a 3 : 2 mixture of E/Z-oxime. IR (CHCl3) cmϪ1: 1644, 1496. 1H-
with hydrogen chloride in ethanol resulted in protodestanny- NMR (CDCl3) d: 7.49 (3/5H, t, Jϭ5.3 Hz), 7.38—7.24 (5H, m), 6.79 (2/5H,

January 2004
77
12 in 90% yield as a colorless oil and a 3 : 2 mixture of E/Z-oxime. IR
(CHCl3) cmϪ1: 1690. 1H-NMR (CDCl3) d: 7.41 (3/5H, t, Jϭ5.6 Hz), 7.36—
7.26 (5H, m), 6.80 (2/5H, br t, Jϭ4.4 Hz), 5.13 (4/5H, s), 5.08 (6/5H, s),
4.27—3.88 (4H, m), 2.21 (2/5H, t, Jϭ2.5 Hz), 2.18 (3/5H, t, Jϭ2.4 Hz),
1.45 (9H, s). 13C-NMR (CDCl3) d: 154.5, 154.4, 149.7 (br), 146.3, 137.5,
137.3, 128.2 (2C), 128.1, 127.8 (2C), 127.7. 80.9, 80.8, 79.0, 78.7, 76.0,
75.8, 72.1, 71.7, 45.0, 42.9, 36.9, 35.9, 28.1 (2C). HR-MS m/z: 303.1712
(Calcd for C17H23N2O3 (MϩHϩ): 303.1707).
N-(2-Hydroxyethyl)aminoethanal O-Benzyloxime (13) To 2-amino-
ethanol (10 ml, 166 mmol) was added chloroacetaldehyde O-benzyloxime
(2) (10.0 g, 54.5 mmol) under a nitrogen atmosphere at 0 °C. After being
stirred at room temperature for 12 h, the reaction mixture was added to satu-
rated aqueous NaHCO3 and CH2Cl2. The layers were separated and the
aqueous phase was extracted with CH2Cl2. The combined organic phase was
washed with brine, dried over Na2SO4 and concentrated at reduced pressure.
Purification of the residue by flash column chromatography (CHCl3/MeOH
30 : 1 to CHCl3/MeOH 15 : 1) afforded N-(2-hydroxyethyl)aminoethanal O-
benzyloxime (9.96 g, 88%) as colorless crystals and a 3 : 2 mixture of E/Z-
oxime: mp 58.5—60 °C (AcOEt/hexane). IR (CHCl3) cmϪ1: 3600—3300.
1H-NMR (CDCl3) d: 7.49 (3/5H, t, Jϭ5.2 Hz), 7.38—7.25 (5H, m), 6.79
(2/5H, t, Jϭ4.4 Hz), 5.10 (4/5H, s), 5.07 (6/5H, s), 3.65—3.57 (2H, m), 3.56
(4/5H, d, Jϭ4.4 Hz), 3.38 (6/5H, d, Jϭ5.2 Hz), 2.78—2.70 (2H, m). 13C-
NMR (CDCl3) d: 151.3, 149.0, 137.6, 137.4, 128.3, 128.2, 128.0, 127.8,
76.1, 75.8, 60.8, 60.7, 51.0, 50.6, 47.7, 44.4. Some carbon peaks were miss-
ing due to overlapping. HR-MS m/z: 209.1271 (Calcd for C11H17N2O2
(MϩHϩ): 209.1289). Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N,
13.45, Found: C, 63.43; H, 7.76; N, 13.50.
t, Jϭ4.4 Hz), 5.95—5.74 (1H, m), 5.22—5.10 (2H, m), 5.10 (4/5H, s), 5.07
(6/5H, s), 3.54 (4/5H, t, Jϭ4.4 Hz), 3.35 (6/5H, t, Jϭ5.3 Hz), 3.25—3.19
(2H, m). 13C-NMR (CDCl3) d: 151.5, 149.0, 137.6, 137.4, 136.0, 135.9,
128.2 (2C), 128.0 (2C), 127.7, 127.6, 116.2 (2C), 75.8, 75.6, 51.9, 51.5,
47.2, 44.0. HR-MS m/z: 205.1355 (Calcd for C12H17N2O (MϩHϩ):
205.1340).
N-(tert-Butoxycarbonyl)-N-(2-propenyl)aminoethanal O-Benzyloxime
(1) To a solution of 3 (4.83 g, 23.7 mmol) in acetone (100 ml) was added a
solution of Na2CO3 (4.27 g, 40.3 mmol) in H2O (15 ml) under a nitrogen at-
mosphere at room temperature. After di-tert-butyl dicarbonate (7.39 g,
35.5 mmol) was added dropwise at 0 °C, the reaction mixture was stirred at
room temperature for 20 h. After the reaction mixture was filtered through a
pad of Celite, the filtrate was concentrated at reduced pressure. The resulting
residue was diluted with water and then extracted with CH2Cl2. The organic
phase was washed with brine, dried over MgSO4, and concentrated at re-
duced pressure. Purification of the residue by flash column chromatography
(AcOEt/hexane 1 : 8) afforded 1 (7.20 g, quantitative yield) as a colorless oil
and a 3 : 2 mixture of E/Z-oxime. IR (CHCl3) cmϪ1: 1687. 1H-NMR (CDCl3)
d: 7.38—7.24 (3/5Hϩ5H, m), 6.69 (2/5H, br t, Jϭ4.4 Hz), 5.85—5.60 (1H,
m), 5.18—5.03 (2H, m), 5.10 (4/5H, s), 5.07 (6/5H, s), 4.13—3.70 (4H,
br m), 1.44 (9H, br s). 13C-NMR (CDCl3) d: 155.0 (2C), 150.2 (br), 146.7,
137.5, 137.3, 133.3, 133.2, 128.2, 128.1, 127.8, 127.7, 116.8 (br), 80.1, 80.0,
76.0, 75.7, 50.2, 49.0, 45.0, 41.6, 28.1, 27.2. Some carbon peaks were miss-
ing due to overlapping. HR-MS m/z: 305.1857 (Calcd for C17H25N2O3
(MϩHϩ): 305.1864).
Chloroacetone O-Benzyloxime (10) To a solution of chloroacetone
(10.0 g, 108 mmol) in H2O–MeOH (200 ml, 1 : 1, v/v) was added O-benzyl-
hydroxylamine hydrochloride (17.3 g, 108 mmol) under a nitrogen atmos-
phere at room temperature. After being stirred at room temperature for 30 h,
MeOH was evaporated at reduced pressure. The resulting residue was ex-
tracted with Et2O. The organic phase was dried over MgSO4 and concen-
trated at reduced pressure to afford 10 (20.3 g, 95%) as a yellow oil and an
8 : 1 mixture of E/Z-oxime. E-Isomer: IR (CHCl3) cmϪ1: 1644. 1H-NMR
(CDCl3) d: 7.38—7.25 (5H, m), 5.11 (2H, s), 4.05 (2H, s), 1.98 (3H, s). 13C-
NMR (CDCl3) d: 153.4, 137.5, 128.3, 127.9, 127.7, 75.9, 45.8, 12.4. HR-
MS m/z: 197.0621 (Calcd for C10H12ClNO (Mϩ): 197.0607).
N-[2-(Benzyloxyimino)ethyl]-N-(2-hydroxyethyl)-2-propenamide (9)
To a solution of 13 (5.00 g, 24.0 mmol) in acetone (100 ml) was added a so-
lution of Na2CO3 (5.09 g, 48.0 mmol) in H2O (20 ml) at 20 °C. After acryloyl
chloride (2.92 ml, 36.0 mmol) was added dropwise at 0 °C, the reaction mix-
ture was stirred at the same temperature for 90 min. After the solvent was
evaporated at reduced pressure, the resulting residue was diluted with water
and then extracted with CH2Cl2. The organic phase was dried over MgSO4
and concentrated at reduced pressure. Purification of the residue by flash
columun chromatography (hexane/AcOEt 1 : 3) afforded 9 (5.47 g, 87%) as a
colorless oil and a 3 : 1 mixture of E/Z-oxime. The presence of rotamers and
E/Z-isomers precluded a comprehensive assignment of all proton and carbon
N-(2-Propenyl)aminoacetone O-Benzyloxime (11) Following the same
procedure as for 3, compound 11 was obtained from 10 in 74% yield as a
1
resonances. IR (CHCl3) cmϪ1: 3600—3300, 1647, 1611. H-NMR (CDCl3)
yellow oil and an 8 : 1 mixture of E/Z-oxime. E-Isomer: IR (CHCl3) cmϪ1
:
1
d: 7.50 (1/4H, t, Jϭ5.1 Hz), 7.43 (1/4H, t, Jϭ4.8 Hz), 7.40—7.25 (5H, m),
6.80—6.25 (5/2H, m), 5.72—5.64 (1H, m), 5.12 (1H, br d, Jϭ7.2 Hz), 5.05
(1H, br d, Jϭ7.5 Hz), 4.31 (1H, dd, Jϭ6.0, 4.2 Hz), 4.12 (1H, br d,
Jϭ4.8 Hz), 3.80—3.40 (5H, m). 13C-NMR (CDCl3) d: 168.1, 167.7, 167.4,
167.2, 149.1, 148.4, 147.1, 145.7, 137.5, 137.1, 129.7, 129.3, 128.7, 128.6,
128.5, 128.43, 128.36, 128.33, 128.25, 128.1, 128.0, 127.7, 127.5, 127.3,
126.9, 76.7, 76.3, 76.2, 76.0, 61.2, 61.1, 60.2, 60.0, 51.0, 50.8, 50.5, 50.4,
48.4, 45.6, 45.4, 43.3. HR-MS m/z: 262.1318 (Calcd for C14H18N2O2 (Mϩ):
262.1317).
General Procedure for Radical Reaction Using AIBN To a boiling
solution of 1 (100 mg, 0.345 mmol) in benzene (5 ml) was added portion-
wise a solution of Bu3SnH or PhSH (0.380 mmol) and AIBN (0.345 mmol)
in benzene (2 ml) under a nitrogen atmosphere over 15 min. The reaction
mixture was heated at reflux for 2—3 h, and then the solvent was evaporated
at reduced pressure. The resulting residue was diluted with water and then
extracted with CH2Cl2. The organic phase was washed with brine, dried over
MgSO4, and concentrated at reduced pressure. Purification of the residue by
preparative TLC (AcOEt/hexane) afforded 4 or 5b as colorless oils.
3331. H-NMR (CDCl3) d: 7.38—7.26 (5H, m), 5.86 (1H, m), 5.22—5.02
(2H, m), 5.10 (2H, s), 3.29 (2H, s), 3.21 (1H, t, Jϭ1.4 Hz), 3.18 (1H, t,
Jϭ1.4 Hz), 1.90 (3H, s). 13C-NMR (CDCl3) d: 156.0, 138.1, 136.4, 128.1,
127.8, 127.5, 116.0, 75.4, 52.6, 51.5, 13.2. HR-MS m/z: 219.1497 (Calcd for
C13H19N2O (MϩHϩ): 219.1496).
N-(tert-Butoxycarbonyl)-N-(2-propenyl)aminoacetone O-Benzyloxime
(7) Following the same procedure as for 1, compounds E-7 and Z-7 were
obtained from 11 in 87% and 10% yields, respectively, both as colorless oils.
E-7: IR (CHCl3) cmϪ1: 1686. 1H-NMR (CDCl3) d: 7.38—7.26 (5H, m), 5.68
(1H, br m), 5.12—4.97 (2H, m), 5.09 (2H, s), 3.95—3.62 (4H, br m), 1.84
(3H, s), 1.46 (9H, s). 13C-NMR (CDCl3) d: 155.8, 154.9, 138.2, 133.2,
128.3, 127.9, 127.7, 116.7, 80.0, 75.6, 49.4, 48.5, 28.4, 12.4. HR-MS m/z:
319.2013 (Calcd for C18H27N2O3 (MϩHϩ): 319.2020). Z-7: IR (CHCl3)
cmϪ1: 1692. 1H-NMR (CDCl3) d: 7.37—7.26 (5H, m), 5.74 (1H, br m),
5.17—5.02 (2H, m), 5.05 (2H, s), 4.15 (2H, br m), 3.82—3.67 (2H, br m),
1.83 (3H, s), 1.45 (9H, s). 13C-NMR (CDCl3) d: 156.8, 155.3, 137.9, 133.1,
128.3, 127.9, 127.7, 117.5, 80.3, 75.7, 50.2, 44.5, 28.3, 17.1. HR-MS m/z:
319.2010 (Calcd for C18H27N2O3 (MϩHϩ): 319.2020).
General Procedure for Radical Reaction Using Et3B To a boiling so-
lution of 1, 7, 8, or 9 (0.345 mmol) and Bu3SnH, Ph3SnH, PhSH, Ph2PH,
Et3SiH or (TMS)3SiH (0.380 mmol) in benzene (7 ml) was added portion-
wise a 1 M solution of Et3B in hexane (0.862 ml, 0.862 mmol) under a nitro-
gen atmosphere over 15 min. The reaction mixture was diluted with aqueous
NaHCO3 and then extracted with CH2Cl2. The organic phase was washed
with brine, dried over MgSO4, and concentrated at reduced pressure. Purifi-
cation of the residue by preparative TLC (AcOEt/hexane) afforded 4—6 or
14—18 as colorless oils. The presence of rotamers and isomers precluded a
comprehensive assignment of all proton and carbon resonances.
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-(tributylstannyl-
methyl)pyrrolidine (4) As a colorless oil and a 1 : 1 mixture of isomers:
IR (CHCl3) cmϪ1: 1684. 1H-NMR (CDCl3) d: 7.35 (5H, br m), 5.59 (1H,
br s), 4.69 (2H, br s), 3.62—2.85 (5H, m), 2.38 (1/2H, br m), 2.19
(1/2H, br m), 1.60—1.38 (2H, m), 1.47 (9/2H, s), 1.46 (9/2H, s), 1.37—
1.22 (6H, m), 0.92—0.81 (21H, m). HR-MS m/z: 539.2283 (Calcd
for C25H43N2O3Sn120 (MϩϪt-Bu): 539.2293), 538.2296 (Calcd for
N-(2-Propynyl)aminoethanal O-Benzyloxime (12) To propargylamine
(9.00 g, 164 mmol) was added chloroacetaldehyde O-benzyloxime (2)
(10.0 g, 54.5 mmol) under a nitrogen atmosphere at 0 °C. After being stirred
at room temperature for 20 h, the reaction mixture was added to saturated
aqueous NaHCO3 and AcOEt. The layers were separated, and the aqueous
phase was extracted with AcOEt. The combined organic phase was dried
over Na2SO4 and concentrated at reduced pressure. Purification of the
residue by flash chromatography (CHCl3/MeOH 30 : 1) afforded 12 (8.46 g,
77%) as a yellow oil and a 3 : 2 mixture of E/Z-oxime. IR (CHCl3) cmϪ1
:
1
3307. H-NMR (CDCl3) d: 7.50 (3/5H, t, Jϭ5.3 Hz), 7.34—7.25 (5H, m),
6.80 (2/5H, t, Jϭ4.4 Hz), 5.11 (4/5H, s), 5.08 (6/5H, s), 3.63 (4/5H, d,
Jϭ4.4 Hz), 3.45 (6/5H, d, Jϭ5.3 Hz), 5.41 (2H, m), 2.23 (1H, br t,
Jϭ2.3 Hz). 13C-NMR (CDCl3) d: 150.9, 148.5, 137.6, 137.3, 128.3 (2C),
128.1 (1C), 127.8 (3C), 81.4, 81.3, 75.9, 75.7, 71.8 (2C), 46.7 (2C), 37.9,
37.4. HR-MS m/z: 203.1204 (Calcd for C12H15N2O (MϩHϩ): 203.1184).
N-(tert-Butoxycarbonyl)-N-(2-Propynyl)aminoethanal O-Benzyloxime
(8) Following the same procedure as for 1, compound 8 was obtained from

78
Vol. 52, No. 1
C25H43N2O3Sn119 (MϩϪt-Bu): 538.2305), and 537.2298 (Calcd for
C25H43N2O3Sn118 (MϩϪt-Bu): 537.2287).
(5H, m), 5.45 (1H, br s), 5.19 (1H, br s), 5.13 (1H, br s), 4.72 (2H, s), 4.17—
3.84 (3H, m), 3.63—3.48 (2H, m), 1.47 (9H, s). HR-MS m/z: 305.1867
(Calcd for C17H25N2O3 (MϩHϩ): 305.1864).
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-(triphenylstannyl-
methyl)pyrrolidine (5a) As a colorless oil and a 1 : 1 mixture of isomers:
IR (CHCl3) cmϪ1: 1684. 1H-NMR (CDCl3) d: 7.64—7.17 (20H, m), 5.48
(1H, br s), 4.60—4.48 (2H, br m), 3.68—2.91 (5H, m), 2.58 (1/2H, br m),
2.37 (1/2H, br m), 1.72—1.40 (2H, m), 1.43 (9/2H, s), 1.38 (9/2H, s). HR-
MS m/z: 656.2033 (Calcd for C35H40N2O3Sn120 (Mϩ): 656.2059) and
654.2038 (Calcd for C35H40N2O3Sn118 (Mϩ): 654.2053).
Acknowledgements We thank Grant-in-Aids for Scientific Research on
Priority Areas (A) (T.N.) and for Young Scientists (B) (H.M.) from the Min-
istry of Education, Culture, Sports, Science and Technology of Japan and the
Science Research Promotion Fund of the Japan Private School Promotion
Foundation for research grants.
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-(phenylthiomethyl)-
pyrrolidine (5b) As a colorless oil and a 1 : 2 mixture of isomers: IR
References and Notes
1
(CHCl3) cmϪ1: 1686. H-NMR (CDCl3) d: 7.40—7.15 (10H, m), 5.60 (1H,
1) Present address: Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606–8501, Japan.
2) Giese B., Kopping B., Göbel T., Dickhaut J., Thoma G., Kulicke K. J.,
Trach F., Org. React. (N.Y.), 48, 301—856 (1996).
3) Renaud P., Gerster M., Angew. Chem., Int. Ed., 37, 2562—2579
(1998).
4) Sibi M. P., Porter N. A., Acc. Chem. Res., 32, 163—171 (1999).
5) “Radicals in Organic Synthesis,” ed. by Renaud P., Sibi M. P., Wiley-
VCH, New York, 2001.
6) Fallis A. G., Brinza I. M., Tetrahedron, 53, 17543—17594 (1997).
7) Naito T., Heterocycles, 50, 505—541 (1999).
8) Kiguchi T., Tajiri K., Ninomiya I., Naito T. Hiramatsu H., Tetrahedron
Lett., 36, 253—256 (1995).
9) Kiguchi T., Tajiri K., Ninomiya I., Naito T., Tetrahedron, 56, 5819—
5833 (2000).
br s), 4.68 (4/3H, s), 4.65 (2/3H, s), 3.70—2.80 (7H, m), 2.45 (2/3H, br m),
2.33 (1/3H, br m), 1.45 (9H, br s). 13C-NMR (CDCl3) d: 154.4 (2C), 137.3,
137.2, 135.6, 135.5, 129.7, 129.5, 128.9, 128.4, 128.3, 127.9, 126.4, 126.3,
79.4, 79.3, 76.7, 76.5, 60.6, 60.1, 49.8, 49.6, 49.4, 49.2, 41.2, 40.4, 36.2,
31.8, 31.7, 28.4. Some carbon peaks were missing due to overlapping. HR-
MS m/z: 414.1968 (Calcd for C23H30N2O3S (Mϩ): 414.1976).
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-[tris(trimethylsilyl)-
silylmethyl]pyrrolidine (5c) As a colorless oil and a 1 : 2 mixture of iso-
1
mers: IR (CHCl3) cmϪ1: 1686. H-NMR (CDCl3) d: 7.40—7.20 (5H, br m),
5.53 (1H, br s), 4.69 (2H, br s), 3.67—2.93 (5H, m), 2.27 (2/3H, br m), 2.16
(1/3H, br m), 1.46 (9H, s), 1.02 (1H, m), 0.70 (1H, m), 0.18 (27H, s). HR-
MS m/z: 552.3054 (Calcd for C26H52N2O3Si4 (Mϩ): 552.3053) and 553.3149
(Calcd for C26H53N2O3Si4 (MϩHϩ): 553.3130).
O-Benzyl-N-[1-[N؅-(tert-butoxycarbonyl)-N؅-(2-propenyl)]amino-2-
10) Miyabe H., Torieda M., Inoue K., Tajiri K., Kiguchi T., Naito T., J.
Org. Chem., 63, 4397—4407 (1998).
1
butyl]hydroxylamine (6) As a colorless oil: IR (CHCl3) cmϪ1: 1683. H-
NMR (CDCl3) d: 7.38—7.23 (5H, m), 5.76 (1H, br m), 5.12—5.01 (2H,
br m), 4.68 (2H, s), 4.00—3.74 (2H, br m), 3.32—3.12 (2H, br m), 2.94 (1H,
br m), 1.65—1.40 (2H, br m), 1.42 (9H, s), 0.95 (3H, t, Jϭ7.4 Hz). 13C-NMR
(CDCl3) d: 155.7, 137.9, 134.0, 128.2 (2C), 127.7, 116.2, 79.6, 76.5, 61.5,
50.5, 48.1, 28.3, 23.0, 10.4. HR-MS m/z: 334.2233 (Calcd for C19H30N2O3
(Mϩ): 334.2255).
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-(tributylstannylmeth-
ylene)pyrrolidine (14) As a colorless oil and a 1 : 1 E/Z mixture: IR
(CHCl3) cmϪ1: 1688. 1H-NMR (CDCl3) d: 7.38—7.26 (5H, m), 6.07
(1/2H, br m), 5.45 (1H, br t, Jϭ5.1 Hz), 5.49 (1/2H, br m), 4.72 (2H, s),
4.16—3.72 (3H, m), 3.66—3.48 (2H, m), 1.48 (9/2H, s), 1.47 (9/2H, s),
1.38—1.21 (6H, m), 0.98—0.83 (21H, m). HR-MS m/z: 594.2854 (Calcd
for C29H50N2O3Sn120 (Mϩ): 594.2841) and 592.2813 (Calcd for
C29H50N2O3Sn118 (Mϩ): 592.2835).
11) Miyabe H., Kanehira S., Kume K., Kandori H., Naito T., Tetrahedron,
54, 5883—5892 (1998).
12) Miyabe H., Nishiki A., Naito T., Chem. Pharm. Bull., 51, 100—103
(2003).
13) Naito T., Nakagawa K., Nakamura T., Kasei A., Ninomiya I., Kiguchi
T., J. Org. Chem., 64, 2003—2009 (1999).
14) Naito T., Tajiri K., Harimoto T., Ninomiya I., Kiguchi T., Tetrahedron
Lett., 35, 2205—2206 (1994).
15) Iserloh U., Curran D. P., J. Org. Chem., 63, 4711—4716 (1998).
16) Boiron A., Zillig P., Faber D., Giese B., J. Org. Chem., 63, 5877—
5882 (1998).
17) Marco-Contelles J., Gallego P., Rodríguez-Fernández M., Khiar N.,
Destabel C., Bernabé M., Martínez-Grau A., Chiara J. L., J. Org.
Chem., 62, 7397—7412 (1997).
18) Clive D. L. J., Zhang J., Chem. Commun., 1997, 549—550 (1997).
19) Keck G. E., Wager T. T., J. Org. Chem., 61, 8366—8367 (1996).
20) Hollingworth G. J., Pattenden G., Schulz D. J., Aust. J. Chem., 48,
381—399 (1995).
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-[tris(trimethylsilyl)-
silylmethylene]pyrrolidine (16) As a colorless oil and a single isomer: IR
1
(CHCl3) cmϪ1: 1688. H-NMR (CDCl3) d: 7.38—7.25 (5H, m), 5.76 (1H,
br s), 5.37 (1H, br s), 4.71 (2H, s), 4.12—3.82 (3H, m), 3.63—3.47 (2H, m),
1.47 (9H, s), 0.20 (27H, s). 13C-NMR (CDCl3) d: 154.5, 137.5, 128.5, 128.3,
127.9, 118.5, 79.4, 76.9, 65.4, 51.6, 49.6, 28.5, 1.1. One carbon peak was
missing due to overlapping. HR-MS m/z: 550.2888 (Calcd for C26H50N2O3Si
(Mϩ): 550.2896).
21) Parker K. A., Fokas D., J. Org. Chem., 59, 3927—3932 (1994).
22) Miyabe H., Fujii K., Goto T., Naito T., Org. Lett., 2, 4071—4074
(2000).
23) Miyabe H., Fujii K., Tanaka H., Naito T., Chem. Commun., 2001,
831—832 (2001).
4-(Benzyloxyamino)-3-(tributylstannylmethyl)-N-(2-hydroxyethyl)-2-
pyrrolidinone (17) Major isomer (58% yield): as a colorless oil: IR
24) Miyabe H., Ueda M., Fujii K., Nishimura A., Naito T., J. Org. Chem.,
68, 5618—5626 (2003).
25) Miyabe H., Tanaka H., Naito T., Tetrahedron Lett., 40, 8387—8390
(1999).
26) Stach L. J., U.S. Patent, 3920772 (1975) [Chem. Abstr., 84, 89603d
(1976)].
27) Although the cyclic product 4 was obtained as a cis/trans mixture in
1 : 1 ratio, the relative stereochemistry of two isomers was not deter-
mined.
28) Miyabe H., Ueda M., Yoshioka N., Naito T., Synlett, 1999, 465—467
(1999).
29) Miyabe H., Yamakawa K., Yoshioka N., Naito T., Tetrahedron, 55,
11209—11218 (1999).
30) Miyabe H., Ushiro C., Ueda M., Yamakawa K., Naito T., J. Org.
Chem., 65, 176—185 (2000).
31) Ryu I., Araki F., Minakata S., Komatsu M., Tetrahedron Lett., 39,
6335—6336 (1998).
1
(CHCl3) cmϪ1: 3368, 1674. H-NMR (CDCl3) d: 7.40—7.25 (5H, m), 4.70
(2H, s), 3.72 (2H, t, Jϭ5.1 Hz), 3.55 (1H, m), 3.46—3.26 (4H, m), 2.43 (1H,
dt, Jϭ5.7, 8.1 Hz), 1.52—1.41 (4H, m), 1.36—1.22 (6H, m), 0.92—0.81
(21H, m). 13C-NMR (CDCl3) d: 177.4, 137.2, 128.4, 128.3, 128.0, 76.5,
63.5, 60.6, 50.9, 46.1, 43.9, 29.0, 27.3, 13.6, 9.7. One carbon peak was miss-
ing due to overlapping. HR-MS m/z: 554.2548 (Calcd for C26H46N2O3Sn120
(Mϩ): 554.2528). Minor isomer (24% yield): as a colorless oil: IR (CHCl3)
1
cmϪ1: 3368, 1675. H-NMR (CDCl3) d: 7.40—7.25 (5H, m), 4.70 (2H, s),
3.72 (2H, t, Jϭ5.4 Hz), 3.64 (1H, m), 3.51—3.26 (4H, m), 2.69 (1H, dt,
Jϭ7.5, 9.3 Hz), 1.55—1.40 (4H, m), 1.38—1.21 (6H, m), 0.92—0.81 (21H,
m). 13C-NMR (CDCl3) d: 177.1, 137.1, 128.5, 128.4, 128.0, 76.4, 60.6, 58.0,
51.0, 46.2, 43.2, 29.1, 27.3, 13.6, 9.9. One carbon peak was missing due to
overlapping. HR-MS m/z: 554.2540 (Calcd for C26H46N2O3Sn120 (Mϩ):
554.2528).
3-(Benzyloxyamino)-N-(tert-butoxycarbonyl)-4-methylenepyrrolidine
(15) To a solution of 14 (20 mg, 0.034 mmol) in EtOH (1 ml) was added
conc. HCl (0.1 ml) at room temperature. After being stirred at room temper-
ature for 15 min, the reaction mixture was added to saturated aqueous
NaHCO3 and CH2Cl2. The layers were separated and the aqueous phase was
extracted with CH2Cl2. The combined organic phase was washed with brine,
dried over Na2SO4 and concentrated at reduced pressure. Purification of the
32) Perchyonok V. T., Schiesser C. H., Tetrahedron Lett., 39, 5437—5438
(1998).
33) Miyata O., Muroya K., Kobayashi T., Yamanaka R., Kajisa S., Koide
J., Naito T., Tetrahedron, 58, 4459—4479 (2002).
34) Marco-Contelles J., Destabel C., Chiara J. L., Bernabé M., Tetrahe-
dron: Asymmetry, 6, 1547—1550 (1995).
35) Pattenden G., Schulz D. J., Tetrahedron Lett., 34, 6787—6790 (1993).
residue by preparative TLC (AcOEt/hexane 1 : 5) afforded 15 (9.3 mg, 91%) 36) Enholm E. J., Burroff J. A., Jaramillo, L. M. Tetrahedron Lett., 31,
1
as a colorless oil. IR (CHCl3) cmϪ1: 1689. H-NMR (CDCl3) d: 7.38—7.29
3727—3730 (1990).