Reductive approach to nitrones from N-Siloxyamides and N-Hydroxyamides

Article abstract of DOI:10.1246/bcsj.20170086

This article describes the full details of our reductive approach to nitrones from amides. Reduction of N-siloxyamides with the Schwartz reagent [Cp₂ZrHCl], followed by addition of an acid provided functionalized nitrones. The developed conditi

Full text of DOI:10.1246/bcsj.20170086

BCSJ Award Article
Reductive Approach to Nitrones from N-Siloxyamides
and N-Hydroxyamides
Seiya Katahara, Shoichiro Kobayashi, Kanami Fujita, Tsutomu Matsumoto,
Takaaki Sato,* and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522
E-mail: takaakis@applc.keio.ac.jp, chida@applc.keio.ac.jp
Received: March 10, 2017; Accepted: April 30, 2017; Web Released: May 9, 2017
Takaaki Sato
Takaaki Sato received his B.Sc. degree in 2001 from Tohoku University, and his Ph.D. degree in 2006 from
Tohoku University under the direction of Professor Masahiro Hirama. He spent two years in Professor Larry
E. Overman’s research group at the University of California, Irvine as a JSPS fellow. He joined the
Department of Applied Chemistry, Keio University as an assistant professor in 2008. He was promoted to
Associate Professor of Keio University in 2016. He was awarded Young Scientist’s Research Award in
Natural Product Chemistry in 2014, and Incentive Award in Synthetic Organic Chemistry, Japan in 2016.
Noritaka Chida
Noritaka Chida received his B.Sc. degree in 1979 from Keio University, and Ph.D. degree in 1984 from
Tohoku University under the direction of Professor Akira Yoshikoshi. From 1984 to 1987, he worked for
Mercian Co., Ltd., as a researcher. In 1987, he joined the Department of Applied Chemistry, Keio University
as a research assistant, and in 1988–1989, he spent one year as a postdoctoral researcher at the University
of Pennsylvania with Professor A. B. Smith, III. He was promoted to Professor of Keio University in 2003. In
2002, he was awarded the “BCSJ Award” from the Chemical Society of Japan.
Abstract
reaction, and are promising intermediates in the synthesis of
biologically active natural products.1 Therefore, developing
practical methods to synthesize functionalized nitrones has
been recognized as an important research topic in organic
chemistry. One of the most general approaches to nitrone 5 is
condensation of hydroxyamine 1 with aldehyde 2 (Scheme 1).
Oxidative methods have been extensively investigated because
they can provide quick access to nitrone 5 from easily available
secondary amine 3. On the contrary, reductive approaches have
been overlooked even in modern chemistry. In theory, reduc-
tion of N-hydroxyamide 4 and the subsequent elimination of
the hydroxy group would result in the direct formation of
This article describes the full details of our reductive
approach to nitrones from amides. Reduction of N-siloxyamides
with the Schwartz reagent [Cp2ZrHCl], followed by addition
of an acid provided functionalized nitrones. The developed
conditions were then extended to a catalytic version with the
Vaska complex [IrCl(CO)(PPh3)2] and (Me2HSi)2O starting
from N-hydroxyamides. 1H NMR studies of the Ir-catalyzed
reaction revealed that the developed conditions promoted two
different types of catalytic reactions including dehydrosilylation
of an N-hydroxyl group and subsequent hydrosilylation of an
amide carbonyl. A salient feature of our methods is their high
chemoselectivity in the presence of a variety of functional
groups. In addition, our reductive methods enabled concise
synthesis of cyclic and macrocyclic nitrones, which are known
to be challenging compounds to access by conventional
methods.
O
R
H 2
R'
HN
OH
condensation
H
O
reduction
1
R'
R'
R
N
O
R
N
this study
OH
5
4
R'
R
N
H
1. Introduction
oxidation
3
Nitrones have been utilized for a variety of transformations
such as [3+2] cycloaddition, Mannich reaction and Kinugasa
Scheme 1. Synthetic approach to nitrones.
Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan | 893

nitrone 5. However, this reduction is not trivial due to the
poor electrophilicity of amide carbonyl groups and the poten-
tial overreduction of subsequently generated nitrone 5 to pro-
vide N-hydroxyamine 3. In this paper, we report a reductive
approach to a variety of functionalized nitrones from N-
siloxyamides with the Schwartz reagent [Cp2ZrHCl]. The reac-
tion proved to be highly practical not only for the synthesis of
acyclic nitrones, but also for cyclic and macrocyclic nitrones,
which are known to be difficult to synthesize by conventional
methods. The reaction was ultimately extended to a catalytic
system starting from N-hydroxyamides in the presence of
Vaska complex [IrCl(CO)(PPh3)2] and (Me2HSi)2O.2 Although
a number of oxidative approaches to nitrones from secondary
amines have been reported,3 this is the first example of catalytic
reductive synthesis of nitrones from N-hydroxyamides.4
2918, 2851, 1595, 1458, 1426, 1174, 1123, 701 cm¹1; 1H NMR
(500 MHz, CDCl3) δ 7.41-7.38 (m, 5H), 6.62 (t, J = 5.8 Hz,
1H), 4.88 (s, 2H), 2.48 (td, J = 7.5, 5.8 Hz, 2H), 1.47 (tt,
J = 7.5, 7.5 Hz, 2H), 1.35-1.20 (m, 8H), 0.86 (t, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 139.9 (CH), 133.1 (C),
129.4 (CH), 129.1 (CH), 129.0 (CH), 69.3 (CH2), 31.8 (CH2),
29.5 (CH2), 29.0 (CH2), 26.9 (CH2), 25.7 (CH2), 22.7 (CH2),
14.2 (CH3); HRMS (ESI), calcd for C15H24NO+ (M+H)+
234.1858, found 234.1855.
N-Benzyl-5-methoxy-5-oxopentan-1-imine Oxide (5b):
Following the general procedure A, N-siloxyamide 10b (49.2
mg, 135 ¯mol) was converted to 25.2 mg of nitrone 5b (80%):
white crystals; mp 63.9-64.3 °C; IR (film) 2951, 1732, 1600,
1
1172, 1144, 705 cm¹1; H NMR (500 MHz, CDCl3) δ 7.40-
7.36 (m, 5H), 6.63 (t, J = 6.0 Hz, 1H), 4.87 (s, 2H), 3.64 (s,
3H), 2.51 (td, J = 7.5, 6.0 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H),
1.82 (tt, J = 7.5, 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 173.5 (C), 138.2 (CH), 132.8 (C), 129.5 (CH), 129.10 (CH),
129.08 (CH), 69.3 (CH2), 51.8 (CH3), 33.7 (CH2), 26.3 (CH2),
2. Experimental
General Details. Reactions were performed in oven-dried
glassware fitted with rubber septa under an argon atmosphere.
Toluene and (CH2Cl)2 were distilled from CaH2. DMF and
MeOH were distilled from CaSO4. Pyridine was distilled from
sodium hydroxide. All distilled solvents, MeCN, EtOH and
CH2Cl2, were dried over activated 3¡ molecular sieves. THF
(dehydrated, stabilizer free) Et2O (dehydrated, stabilizer free)
were purchased from KANTO CHEMICAL CO., INC. Other
commercial reagents were used without further purification.
Thin-layer chromatography was performed on Merck TLC
silica gel 60 F254, which were visualized by exposure to UV
(254 nm) or stained by submersion in ethanolic ninhydrin or
ethanolic phosphomolybdic acid solution followed by heating
on a hot plate. Flash column chromatography was performed
on silica gel (Silica Gel 60 N; 63-210 or 40-50 mesh, KANTO
CHEMICAL CO., INC.). Preparative layer chromatography
was performed on Merck PLC silica gel 60 F254. 1H NMR spec-
tra were recorded at 500 MHz with a JEOL ECA-500 spectrom-
eter or 400 MHz with JEOL ECS-400 spectrometer. 13C NMR
spectra were recorded at 125 MHz with a JEOL ECA-500
spectrometer or 100 MHz with JEOL ECS-400 spectrometer.
Chemical shifts are reported in ppm with reference to solvent
signals [1H NMR: CDCl3 (7.26), d8-toluene (2.08); 13C NMR:
CDCl3 (77.16)]. Signal patterns are indicated as brs, broad peak
signal; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
MPLC was performed on a Yamazen YFLC AI-580. Infrared
spectra were recorded using a BRUKER ALPHA FT-IR spec-
trometer. Mass spectra (ESI-TOF) were measured with a Waters
LCT Premier XE. Melting points were measured with a Yanaco
MODEL MP-S3.
+
21.0 (CH2); HRMS (ESI), calcd for C13H18NO3 (M+H)+
236.1287, found 236.1284.
N-Benzylundec-10-en-1-imine Oxide (5c): Following the
general procedure A, N-siloxyamide 10c (54.4 mg, 135 ¯mol)
was converted to 35.3 mg of nitrone 5c (96%): white crystals;
mp 85.0-86.0 °C; IR (film) 2918, 2850, 1593, 1458, 1427, 1114,
1
913, 763, 701 cm¹1; H NMR (500 MHz, CDCl3) δ 7.41-7.37
(m, 5H), 6.61 (t, J = 6.0 Hz, 1H), 5.81 (ddt, J = 17.2, 10.3,
6.6 Hz, 1H), 4.99 (ddt, J = 17.2, 2.3, 1.7 Hz, 1H), 4.78 (ddt,
J = 10.3, 2.3, 1.7 Hz, 1H), 4.88 (s, 2H), 2.48 (td, J = 7.5, 6.0
Hz, 2H), 2.03 (tddd, J = 6.6, 6.6, 1.7, 1.2 Hz, 2H), 1.47 (tt, J =
7.5, 7.5 Hz, 2H), 1.37 (tt, J = 7.7, 7.7 Hz, 2H), 1.32-1.23 (m,
8H); 13C NMR (125 MHz, CDCl3) δ 139.7 (CH), 139.3 (CH),
133.1 (C), 129.4 (CH), 129.03 (CH), 129.00 (CH), 114.3 (CH2),
69.3 (CH2), 33.9 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2),
29.1 (CH2), 29.0 (CH2), 26.9 (CH2), 25.6 (CH2); HRMS (ESI),
calcd for C18H28NO+ (M+H)+ 274.2171, found 274.2173.
N-Benzyl-7-((4-methylphenyl)sulfonamido)heptan-1-
imine Oxide (5d): Following the general procedure A, N-
siloxyamide 10d (68.8 mg, 133 ¯mol) was converted to 41.9
mg of nitrone 5d (81%): white crystals; mp 80.0-81.0 °C; IR
(film) 3065, 2930, 2858, 1599, 1455, 1324, 1157, 1093, 704,
1
551 cm¹1; H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz,
2H), 7.39 (m, 5H), 7.29 (d, J = 8.3 Hz, 2H), 6.63 (t, J = 6.0
Hz, 1H), 4.89 (s, 2H), 4.78 (brs, 1H), 2.89 (dt, J = 6.9, 6.3 Hz,
2H), 2.45 (td, J = 7.5, 6.0 Hz, 2H), 2.42 (s, 3H), 1.48-1.38 (m,
4H), 1.33-1.21 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 143.3
(C), 139.8 (CH), 137.3 (C), 133.0 (C), 129.7 (CH), 129.4 (CH),
129.0 (CH), 129.0 (CH), 127.2 (CH), 69.2 (CH2), 43.1 (CH2),
29.4 (CH2), 28.8 (CH2), 26.5 (CH2), 26.1 (CH2), 25.4 (CH2),
21.6 (CH3); HRMS (ESI), calcd for C21H29N2O3S+ (M+H)+
389.1899, found 389.1882.
General Procedure A: N-Benzyloctan-1-imine Oxide
(5a): Zirconocene chloride hydride (51.0 mg, 198 ¯mol, 1.5
equiv) was added to a solution of N-siloxyamide 10a (48.1 mg,
132 ¯mol) and (CH2Cl)2 (1.6 mL) at room temperature. After
stirring for 10 min, trifluoroacetic acid (9.8 ¯L, 130 ¯mol, 1.0
equiv) was added to the solution. After stirring for 1 h at room
temperature, the solution was quenched with saturated aque-
ous NaHCO3 (10 mL), and extracted with EtOAc (2 © 15 mL).
The combined organic extracts were dried over Na2SO4, and
concentrated. The residue was purified by silica gel column
chromatography (MeOH/CHCl3 1:170) to give 28.8 mg of
nitrone 5a (94%): white crystals; mp 88.5-89.5 °C; IR (film)
N-Benzyl-8-((tetrahydro-2H-pyran-2-yl)oxy)octan-1-imine
Oxide (5e):
Following the general procedure A, N-
siloxyamide 10e (60.7 mg, 129 ¯mol) was converted to 41.5
mg of nitrone 5e (96%): a colorless oil; IR (film) 2931, 2856,
1
1455, 1136, 1120, 1077, 1032, 703 cm¹1; H NMR (500 MHz,
CDCl3) δ 7.46-7.36 (m, 5H), 6.61 (t, J = 5.7 Hz, 1H), 4.88
(s, 2H), 4.56 (dd, J = 4.3, 2.6 Hz, 1H), 3.86 (ddd, J = 14.6,
7.2, 2.9 Hz, 1H), 3.71 (dt, J = 9.5, 6.6 Hz, 1H), 3.52-3.46 (m,
894 | Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan

1H), 3.36 (dt, J = 9.5, 6.6 Hz, 1H), 2.48 (td, J = 7.2, 5.7 Hz,
2H), 1.89-1.41 (m, 10H), 1.41-1.15 (m, 6H); 13C NMR (125
MHz, CDCl3) δ 139.6 (CH), 133.1 (C), 129.4 (CH), 129.05
(CH), 129.02 (CH), 99.0 (CH), 69.3 (CH2), 67.7 (CH2), 62.5
(CH2), 30.9 (CH2), 29.8 (CH2), 29.5 (CH2), 29.2 (CH2), 26.8
(CH2), 26.2 (CH2), 25.6 (CH2), 25.6 (CH2), 19.8 (CH2); HRMS
(ESI), calcd for C20H31NO3Na+ (M+Na)+ 356.2202, found
356.2201.
6.6 Hz, 1H), 2.34-2.27 (m, 1H), 1.97 (dddd, J = 13.8, 8.9,
6.0, 3.2 Hz, 1H), 1.87-1.79 (m, 1H), 1.78-1.70 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 165.6 (C), 139.8 (C), 128.8
(CH), 128.0 (CH), 126.2 (CH), 63.1 (CH), 32.9 (CH2), 30.9
(CH2), 18.1 (CH2); HRMS (ESI), calcd for C11H14NO2
(M+H)+ 192.1025, found 192.1026.
+
1-((tert-Butyldimethylsilyl)oxy)-6-phenylpiperidin-2-one
(24): Imidazole (34.4 mg, 505 ¯mol) and TBSCl (102 mg, 674
¯mol) was added to a solution of N-hydroxyamide 23 (64.4 mg,
337 ¯mol) and CH2Cl2 (6.7 mL) at room temperature. The
resulting white suspension was stirred at room temperature for
10 h, quenched with saturated aqueous NaHCO3 (6 mL), and
extracted with EtOAc (2 © 25 mL). The combined organic
extracts were washed with brine (6 mL), dried over Na2SO4,
and concentrated. The residue was purified by silica gel column
chromatography (EtOAc/hexane 1:10) to give 90.4 mg of 24
(88%): a colorless oil; IR (film) 2953, 2930, 2857, 1661, 1250,
N-(4-Nitrobenzyl)octan-1-imine Oxide (5f): Following
the general procedure A, N-siloxyamide 10f (53.8 mg, 132
¯mol) was converted to 33.4 mg of nitrone 5f (91%): white
crystals; mp 64.8-65.8 °C; IR (film) 2927, 2856, 1602, 1522,
1348, 713 cm¹1; 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 8.6
Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 6.83 (t, J = 5.8 Hz, 1H),
4.97 (s, 2H), 2.50 (td, J = 7.2, 5.8 Hz, 2H), 1.52 (tt, J = 7.2,
7.2 Hz, 2H), 1.37-1.21 (m, 8H), 0.86 (t, J = 6.6 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 148.2 (C), 140.8 (CH), 140.3
(C), 129.8 (CH), 124.1 (CH), 68.3 (CH2), 31.7 (CH2), 29.5
(CH2), 29.0 (CH2), 26.9 (CH2), 25.6 (CH2), 22.7 (CH2), 14.2
1
939, 832, 785 cm¹1; H NMR (500 MHz, CDCl3) δ 7.39-7.05
(m, 5H), 4.78 (dd, J = 5.4, 5.4 Hz, 1H), 2.59 (ddd, J = 17.2,
6.0, 6.0 Hz, 1H), 2.54 (ddd, J = 17.2, 8.3, 6.0 Hz, 1H), 2.26
(dddd, J = 13.5, 9.2, 5.4, 3.2 Hz, 1H), 1.99-1.93 (m, 1H),
1.79-1.71 (m, 1H), 1.69-1.62 (m, 1H), 0.73 (s, 9H), 0.20 (s,
3H), 0.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.6 (C),
140.7 (C), 128.5 (CH), 127.6 (CH), 126.7 (CH), 66.7 (CH),
33.2 (CH2), 33.1 (CH2), 25.8 (CH3), 18.5 (C), 17.8 (CH2), ¹4.2
(CH3), ¹4.9 (CH3); HRMS (ESI), calcd for C17H28NO2Si+
(M+H)+ 306.1889, found 306.1880.
+
(CH3); HRMS (ESI), calcd for C15H23N2O3 (M+H)+
279.1709, found 279.1702.
N-(4-Bromobenzyl)octan-1-imine Oxide (5g): Following
the general procedure A, N-siloxyamide 10g (59.5 mg, 135
¯mol) was converted to 34.4 mg of nitrone 5g (82%): white
crystals; mp 71.0-72.0 °C; IR (film) 2918, 2851, 1598, 1451,
1
1425, 1172, 806 cm¹1; H NMR (500 MHz, CDCl3) δ 7.52 (d,
J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 6.67 (t, J = 5.8 Hz,
1H), 4.82 (s, 2H), 2.48 (td, J = 7.5, 5.8 Hz, 2H), 1.49 (tt, J =
7.5, 7.5 Hz, 2H), 1.35-1.21 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 140.0 (CH), 132.19 (CH),
132.16 (C), 131.0 (CH), 123.3 (C), 68.6 (CH2), 31.8 (CH2),
29.6 (CH2), 29.0 (CH2), 26.9 (CH2), 25.6 (CH2), 22.7 (CH2),
14.2 (CH3); HRMS (ESI), calcd for C15H23NOBr+ (M+H)+
312.0963, found 312.0960.
2-Ethoxy-7-phenylhexahydro-2H-isoxazolo[2,3-a]pyri-
dines (26 and 27): Zirconocene chloride hydride (50.0 mg,
194 ¯mol) was added to a solution of N-siloxyamide 24 (38.0
mg, 124 ¯mol) and (CH2Cl)2 (1.6 mL) at room temperature.
After stirring for 10 min, trifluoroacetic acid (9.2 ¯L, 120 ¯mol)
was added to the solution. After stirring for 1 h at room tem-
perature, ethyl vinyl ether (stabilized with 0.1% KOH and
0.1% Et2NPh, 59 ¯L, 620 ¯mol) was added to the solution. This
solution was then heated to 40 °C, stirred for 27 h at 40 °C,
and cooled to room temperature. The resulting solution was
quenched with saturated aqueous NaHCO3 (2 mL), and extract-
ed with EtOAc (2 © 10 mL). The combined organic extracts
were dried over Na2SO4, and concentrated. The residue was
purified by silica gel column chromatography (EtOAc/hexane
1:10) to give 18.9 mg of isoxazolidine 26 (62%) and 9.9 mg of
isoxazolidine 27 (32%). Isoxazolidine 26: a colorless oil; IR
1-Hydroxy-6-phenylpiperidin-2-one (23): Preparation of
dry HCl in MeOH: Acetyl chloride (320 ¯L, 4.7 mmol) was
added dropwise to MeOH (2.0 mL) at 0 °C. The solution was
allowed to warm to room temperature, and stirred for 5 min.
Hydroxyamine hydrochloride (24.0 mg, 344 ¯mol) was
added to a solution of 4-benzoylbutyric acid 22 (60.0 mg,
312 ¯mol), pyridine (55 ¯L, 690 ¯mol) and MeOH (2.0 mL) at
room temperature. The solution was refluxed for 12 h to form
the oxime, and cooled to room temperature. The above HCl in
MeOH was added to a solution of the oxime at 0 °C. Sodium
cyanoborohydride (196 mg, 3.12 mmol) was then added to this
solution at 0 °C. The resulting mixture was allowed to warm to
room temperature, stirred for 15 h at room temperature, and
then heated to 40 °C. The mixture was stirred for 9 h at 40 °C,
cooled to room temperature, and quenched with saturated
aqueous NaHCO3 (4 mL). The resulting mixture was extracted
with EtOAc (2 © 10 mL). The combined organic extracts were
washed with brine (10 mL), dried over Na2SO4, and concen-
trated. The residue was purified by silica gel column chroma-
tography (EtOAc/hexane 1:1.5) to give 39.4 mg of 23 (66%):
white crystals; mp 109.1-109.5 °C; IR (film) 3248, 2951, 1635,
1
(film) 2934, 2865, 1447, 1117, 1088, 753, 700 cm¹1; H NMR
(500 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5,
7.5 Hz, 2H), 7.24 (t, J = 7.5, 7.5 Hz, 1H), 5.34 (d, J = 5.7 Hz,
1H), 3.95 (dddd, J = 12.6, 5.7, 5.7, 1.4 Hz, 1H), 3.70 (dq,
J = 9.5, 7.2 Hz, 1H), 3.59 (dd, J = 11.2, 3.2 Hz, 1H), 3.33 (dq,
J = 9.5, 7.2 Hz, 1H), 2.56 (ddd, J = 12.6, 12.6, 5.7 Hz, 1H),
2.17-2.09 (m, 1H), 2.04-1.98 (m, 1H), 2.00 (dd, J = 12.6,
5.7 Hz, 1H), 1.78-1.72 (m, 1H), 1.60-1.48 (m, 3H), 1.23 (dd,
J = 7.2, 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 144.1 (C),
128.4 (CH), 127.3 (CH), 127.0 (CH), 102.9 (CH), 66.4 (CH),
63.4 (CH2), 58.2 (CH), 37.0 (CH2), 34.9 (CH2), 25.2 (CH2),
+
19.2 (CH2), 15.2 (CH3); HRMS (ESI), calcd for C15H22NO2
1
1145, 936, 700 cm¹1; H NMR (500 MHz, CDCl3) δ 8.52 (brs,
(M+H)+ 248.1651, found 248.1652. Isoxazolidine 27: a color-
less oil; IR (film) 2929, 2858, 1091, 947, 700 cm¹1; H NMR
1
1H), 7.38 (t, J = 7.5, 7.5 Hz, 2H), 7.31 (t, J = 7.5, 7.5 Hz, 1H),
7.22 (d, J = 7.5 Hz, 2H), 4.91 (dd, J = 6.0, 6.0 Hz, 1H), 2.62
(ddd, J = 17.2, 6.6, 6.6 Hz, 1H), 2.58 (ddd, J = 17.2, 6.9,
(500 MHz, CDCl3) δ 7.40 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2,
7.2 Hz, 2H), 7.23 (t, J = 7.2, 7.2 Hz, 1H), 5.25 (dd, J = 5.4,
Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan | 895

5.4 Hz, 1H), 4.34 (dd, J = 12.0, 2.9 Hz, 1H), 3.74 (dddd,
J = 8.6, 8.6, 5.7, 1.2 Hz, 1H), 3.55 (dq, J = 9.5, 7.2 Hz, 1H),
3.31 (dq, J = 9.5, 7.2 Hz, 1H), 2.45-2.42 (m, 2H), 2.10 (dddd,
J = 14.5, 12.9, 5.7, 5.7 Hz, 1H), 1.99-1.93 (m, 1H), 1.80-1.74
(m, 1H), 1.71-1.47 (m, 3H), 1.15 (dd, J = 7.2, 7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 144.5 (C), 128.3 (CH), 127.4
(CH), 126.9 (CH), 106.7 (CH), 65.4 (CH), 64.4 (CH2), 60.7
(CH), 38.6 (CH2), 35.2 (CH2), 25.5 (CH2), 19.3 (CH2), 15.2
(CH3); HRMS (ESI), calcd for C15H21NO2Na+ (M+Na)+
270.1470, found 270.1469.
1-((tert-Butyldimethylsilyl)oxy)-5-vinylpyrrolidin-2-one
(31): A solution of N-siloxyamide 30 (330 mg, 1.04 mmol)
and CH2Cl2 (42 mL) was degassed using the freeze-pump-thaw
technique (3©). The solution was transferred to a flask charged
with Pd(PPh3)4 (24.0 mg, 20.8 ¯mol) at room temperature,
maintained for 9 h at room temperature, and concentrated. The
residue was purified by silica column chromatography (EtOAc/
hexane 1:8) to give 251 mg of N-siloxylactam 31 (100%): a
colorless oil; IR (film) 2956, 2931, 2859, 1728, 1250, 837,
1
786 cm¹1; H NMR (500 MHz, CDCl3) δ 5.76 (ddd, J = 17.2,
N-((tert-Butyldimethylsilyl)oxy)pent-4-enamide (29): N-
Methylmorpholine (720 ¯l, 6.5 mmol) was added to a solution
of carboxylic acid 28 (510 ¯L, 5.0 mmol) and Et2O (15 mL) at
0 °C. After cooling to 0 °C, ethyl chloroformate (570 ¯L, 6.0
mmol) was then added to the solution. The resulting sus-
pension was stirred for 1.5 h at 0 °C, added to a solution of
O-(tert-butyldimethylsilyl)hydroxylamine (1.10 g, 7.50 mmol)
and Et2O (7.0 mL) at 0 °C, and allowed to warm to room
temperature. After stirring for 4.5 h at room temperature, the
solution was concentrated. The residue was purified by silica
gel column chromatography (EtOAc/hexane 1:15 to 1:10) to
give 1.15 g of N-siloxyamide 29 (100%): white crystals; mp
57.1-58.0 °C; IR (film) 3159, 2961, 2859, 1655, 1259, 1247,
984, 834, 787 cm¹1; 1H NMR (500 MHz, CDCl3, 60 °C, a 5.5:1
mixture of two rotamers, Peaks of the major rotamer are report-
ed.) δ 7.42 (brs, 1H), 5.89-5.79 (m, 1H), 5.09 (d, J = 16.9 Hz,
1H), 5.03 (d, J = 10.6 Hz, 1H), 2.40 (td, J = 7.2, 7.2 Hz, 2H),
2.38-2.22 (m, 2H), 0.97 (s, 9H), 0.19 (s, 6H); 13C NMR (125
MHz, CDCl3, 60 °C, a mixture of two rotamers, Peaks of the
major rotamer were reported.) δ 161.9 (C), 137.0 (CH), 115.7
(CH2), 32.4 (CH2), 29.1 (CH2), 26.0 (CH3), 26.0 (CH3), 18.2
(C), ¹5.5 (CH3); HRMS (ESI), calcd for C11H24NO2Si+
(M+H)+ 230.1576, found 230.1570.
10.3, 8.0 Hz, 1H), 5.30 (ddd, J = 17.2, 0.9, 0.9 Hz, 1H), 5.24
(ddd, J = 10.3, 0.9, 0.9 Hz, 1H), 4.05 (ddddd, J = 8.0, 7.5, 6.3,
0.9, 0.9 Hz, 1H), 2.37 (ddd, J = 16.9, 9.7, 5.7 Hz, 1H), 2.29
(ddd, J = 16.9, 9.5, 6.3 Hz, 1H), 2.20 (dddd, J = 12.0, 9.5, 7.5,
5.7 Hz, 1H), 1.79 (dddd, J = 12.0, 9.7, 6.3, 6.3 Hz, 1H), 0.95
(s, 9H), 0.22 (s, 3H), 0.21 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 171.5 (C), 136.7 (CH), 118.9 (CH2), 63.3 (CH), 26.8 (CH2),
25.9 (CH3), 22.7 (CH2), 18.3 (C), ¹4.3 (CH3), ¹4.5 (CH3);
HRMS (ESI), calcd for C12H24NO2Si+ (M+H)+ 242.1576,
found 242.1579.
Dimethyl 6-vinylhexahydropyrrolo[1,2-b]isoxazole-2,3-
dicarboxylates (33 and 34): Zirconocene chloride hydride
(46.9 mg, 182 ¯mol) was added to a solution of N-siloxylactam
31 (29.1 mg, 121 ¯mol) and (CH2Cl)2 (1.5 mL) at room tem-
perature. After stirring for 1 h at room temperature, dimethyl
maleate (150 ¯L, 1.4 mmol) was added to the solution. This
solution was then heated to 40 °C, stirred for 5.5 h at 40 °C,
and cooled to room temperature. The resulting solution was
quenched with saturated aqueous NaHCO3 (2 mL), and extract-
ed with EtOAc (2 © 7 mL). The combined organic extracts were
dried over Na2SO4, and concentrated. The residue was purified
by silica gel column chromatography (EtOAc/hexane 1:1)
and subsequent preparative thin layer chromatography (EtOAc/
hexane 1:1) to give 19.8 mg of a mixture of isoxazolidines
33 and 34 (64%). For analytical samples, the diastereomeric
mixture was separated by HPLC (PEGASIL Silica 120-5, 250 ©
20 mm, Et2O/hexane 2.5:1, 10 mL/min, isoxazolidine 33: TR =
15.8 min, isoxazolidine 34: TR = 23.9 min). Isoxazolidine 33:
white crystals; mp 81.1-81.9 °C; IR (film) 2956, 2922, 1746,
1438, 1220 cm¹1; 1H NMR (500 MHz, CDCl3) δ 5.84 (ddd, J =
17.2, 10.3, 6.6 Hz, 1H), 5.23 (ddd, J = 17.2, 1.4, 1.4 Hz, 1H),
5.12 (ddd, J = 10.3, 1.4, 1.4 Hz, 1H), 4.91 (d, J = 7.7 Hz, 1H),
4.18 (ddd, J = 7.7, 7.7, 4.6 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H),
3.58 (ddddd, J = 6.9, 6.6, 6.3, 1.4, 1.4 Hz, 1H), 3.39 (dd, J =
7.7, 7.7 Hz, 1H), 2.20 (dddd, J = 12.0, 8.3, 8.3, 7.7 Hz, 1H),
2.07 (dddd, J = 11.5, 11.5, 8.3, 6.3 Hz, 1H), 1.79-1.69 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 169.9 (C), 169.5 (C), 137.9
(CH), 116.7 (CH2), 78.3 (CH), 69.6 (CH), 66.3 (CH), 57.1 (CH),
52.63 (CH3), 52.57 (CH3), 29.6 (CH2), 28.2 (CH2); HRMS
(E)-6-(((tert-Butyldimethylsilyl)oxy)amino)-6-oxohex-2-
en-1-yl Methyl Carbonate (30): A solution of (Z)-but-2-ene-
1,4-diyl dimethyl dicarbonate5 (2.3 mL) and CH2Cl2 (58 mL)
was refluxed for 2 h. N-Siloxyamide 29 (600 mg, 2.62 mmol)
and 2nd generation Hoveyda-Grubbs catalyst (32.7 mg, 52.4
¯mol) were added to the solution. This solution was heated to
reflux, and stirred for 18 h at that temperature. This solution
was quenched with a solution of potassium 2-isocyanoacetate6
(64.5 mg, 524 ¯mol) and MeOH (2 mL) at room temperature,
stirred for 30 min, and diluted with brine (20 mL). The mixture
was extracted with CH2Cl2 (2 © 20 mL). The combined organic
extracts were dried over Na2SO4, and concentrated. The residue
was purified by silica column chromatography (EtOAc/hexane
1:1) to give 759 mg of N-siloxyamide 30 (91%): a colorless oil;
IR (film) 3186, 2958, 2932, 2859, 1751, 1659, 1444, 1270,
1
836, 790 cm¹1; H NMR (500 MHz, CDCl3, 60 °C, a 6:1 mix-
+
ture of two rotamers, Peaks of the major rotamer are reported.)
δ 7.45 (brs, 1H), 5.83 (dt, J = 15.8, 6.9 Hz, 1H), 5.66 (dt, J =
15.8, 6.3 Hz, 1H), 4.57 (d, J = 6.3 Hz, 2 H), 3.78 (s, 3H), 2.42
(td, J = 6.9, 6.9 Hz, 2H), 2.32-2.18 (m, 2H), 0.98 (s, 9H), 0.19
(s, 6H); 13C NMR (125 MHz, CDCl3, 60 °C, a mixture of two
rotamers, Peaks of the major rotamer are reported.) δ 161.5 (C),
155.8 (C), 134.8 (CH), 124.9 (CH), 68.3 (CH2), 54.7 (CH3),
32.3 (CH2), 27.6 (CH2), 25.9 (CH3), 18.2 (C), ¹5.6 (CH3);
HRMS (ESI), calcd for C14H27NO5NaSi+ (M+Na)+ 340.1556,
found 340.1557.
(ESI), calcd for C12H18NO5 (M+H)+ 256.1185, found
256.1179. Isoxazolidine 34: a colorless oil; IR (film) 2954,
1
2924, 2852, 1741, 1438, 1207, 1177, 922, 733 cm¹1; H NMR
(500 MHz, CDCl3) δ 5.80 (ddd, J = 17.3, 10.5, 6.4 Hz, 1H),
5.25 (ddd, J = 17.3, 1.4, 1.4 Hz, 1H), 5.13 (ddd, J = 10.5, 1.4,
1.4 Hz, 1H), 4.72 (d, J = 8.2 Hz, 1H), 4.15 (ddddd, J = 9.5, 9.5,
6.4, 1.4, 1.4 Hz, 1H), 4.01 (ddd, J = 8.2, 8.2, 8.2 Hz, 1H), 3.95
(dd, J = 8.2, 8.2 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.27 (dddd,
J = 15.3, 9.5, 9.5, 6.2 Hz, 1H), 1.90-1.79 (m, 2H), 1.71 (dddd,
J = 15.3, 9.5, 9.5, 9.5, 1H); 13C NMR (125 MHz, CDCl3)
896 | Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan

1
δ 170.3 (C), 169.5 (C), 137.6 (CH), 116.3 (CH2), 77.5 (CH),
2930, 2857, 1740, 1456, 1207, 1032, 748 cm¹1; H NMR (500
69.3 (CH), 66.9 (CH), 53.5 (CH), 52.5 (CH3), 52.2 (CH3), 30.7
(CH2), 26.9 (CH2); HRMS (ESI), calcd for C12H18NO5
(M+H)+ 256.1185, found 256.1182.
MHz, CDCl3) δ 7.35 (d, J = 7.5 Hz, 1H), 7.23-7.11 (m, 3H),
4.55 (dd, J = 8.3, 7.7 Hz, 1H), 4.06 (d, J = 13.2 Hz, 1H), 3.93
(d, J = 13.2 Hz, 1H), 3.79 (s, 3H), 3.29 (brs, 1H), 2.86 (brs, 1H),
2.73 (ddd, J = 10.9, 7.7, 7.7 Hz, 1H), 2.61 (brs, 1H), 2.32 (ddd,
J = 10.9, 8.3, 4.0 Hz, 1H), 1.78-1.25 (m, 18H); 13C NMR (125
MHz, CDCl3) δ 173.3 (C), 142.4 (C), 135.1 (C), 131.5 (CH),
129.7 (CH), 127.8 (CH), 125.6 (CH), 76.6 (CH), 65.5 (CH),
60.8 (CH2), 52.5 (CH3), 38.6 (CH2), 33.3 (CH2), 33.0 (CH2),
29.6 (CH2), 27.4 (CH2), 26.9 (CH2), 26.24 (CH2), 26.21 (CH2),
25.1 (CH2), 24.8 (CH2), 24.5 (CH2); HRMS (ESI), calcd for
C22H34NO3+ (M+H)+ 360.2539, found 360.2541. Minor prod-
+
2-((tert-Butyldimethylsilyl)oxy)-1,2,4,5,6,7,8,9,10,11,12,13-
dodecahydro-3H-benzo[c][1]azacyclopentadecin-3-one (36):
Potassium trimethylsilanolate (303 mg, 2.36 mmol) was added
to a solution of N-siloxyamine 35 (256 mg, 588 ¯mol) and Et2O
(3.9 mL) at room temperature. The solution was maintained for
4 h at room temperature, neutralized with saturated aqueous
NH4Cl until pH = 7, and extracted with EtOAc (2 © 10 mL).
The combined organic extracts were washed with brine (5 mL),
dried over Na2SO4, and concentrated to give the crude N-
siloxyamino acid, which was directly used in the next reaction
without further purification.
uct 39: white crystals; mp 78.3-79.0 °C; IR (film) 2931, 2857,
¹1
1746, 1457, 1220, 749 cm
;
1H NMR (500 MHz, CDCl3)
δ 7.40-7.36 (m, 1H), 7.22-7.13 (m, 3H), 4.73 (dd, J = 9.7,
5.2 Hz, 1H), 3.98 (d, J = 13.8 Hz, 1H), 3.82 (d, J = 13.8 Hz,
1H), 3.76 (s, 3H), 3.13 (brs, 1H), 2.91 (ddd, J = 12.5, 9.7,
8.4 Hz, 1H), 2.82 (ddd, J = 13.2, 11.7, 4.9 Hz, 1H), 2.63-2.54
(m, 1H), 2.21 (ddd, J = 12.5, 5.2, 5.2 Hz, 1H), 1.74-1.21 (m,
18H); 13C NMR (125 MHz, CDCl3) δ 172.6 (C), 142.0 (C),
134.9 (C), 130.5 (CH), 129.7 (CH), 127.7 (CH), 125.8 (CH),
74.7 (CH), 65.7 (CH), 58.9 (CH2), 52.4 (CH3), 38.8 (CH2), 33.5
(CH2), 33.1 (CH2), 29.5 (CH2), 27.4 (CH2), 26.9 (CH2), 26.5
(CH2), 26.0 (CH2), 25.0 (CH2), 24.8 (CH2), 24.7 (CH2); HRMS
A solution of the crude N-siloxyamino acid and CH2Cl2
(15 mL) was added over 26 h using a syringe pump to a stirring
solution of DMAP (244 mg, 1.41 mmol), MNBA (244 mg, 707
¯mol) and CH2Cl2 (1.2 L) at room temperature. The solution
was maintained for an additional 1.5 d at room temperature,
and concentrated to a volume of ca 5 mL. Saturated aqueous
NaHCO3 (5 mL) was added to the solution at 0 °C. The mixture
was extracted with hexane (2 © 10 mL). The combined organic
extracts were washed with brine (5 mL), dried over Na2SO4,
and concentrated. The residue was purified by silica gel column
chromatography (EtOAc/hexane 1:50) to give 201 mg of N-
siloxylactam 36 (84% for 2 steps): white crystals; mp 73.5-
74.5 °C; IR (film) 2930, 2858, 1666, 1462, 1252, 838, 784
+
(ESI), calcd for C22H34NO3 (M+H)+ 360.2539, found
360.2538.
General Procedure B [Method A]: N-Benzyloctan-1-
imine Oxide (5a):
1,1,3,3-Tetramethyldisiloxane (61 ¯L,
1
cm¹1; H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 7.5 Hz, 1H),
345 ¯mol, 2.5 equiv) was added to a mixture of N-hydroxy-
amide 4a (34.5 mg, 138 ¯mol, 1.0 equiv), IrCl(CO)(PPh3)2 (1.1
mg, 1.4 ¯mol, 1 mol %) and toluene (690 ¯L) at room tem-
perature. After maintaining for 30 min at room temperature,
pyridinium p-toluenesulfonate (34.7 mg, 138 ¯mol, 1.0 equiv)
was added to the resulting solution at room temperature. The
solution was maintained for 5 min at room temperature,
quenched with triethylamine (20 ¯L, 1.1 equiv) and saturated
aqueous NaHCO3 (1.0 mL), and extracted with EtOAc (2 © 10
mL). The combined organic extracts were washed with brine
(1 mL), and dried over Na2SO4. Triethylamine (200 ¯L) was
added to the organic extracts. After concentration, the residue
was purified by silica gel column chromatography (MeOH/
CHCl3/Et3N 1:10:0.03) to give 30.9 mg of nitrone 5a (96%),
which was identical to the synthetic sample from N-siloxy-
amide 10a with the Schwartz reagent.
N-Benzyl-5-methoxy-5-oxopentan-1-imine Oxide (5b):
Following the general procedure B, N-hydroxyamide 4b (31.5
mg, 125 ¯mol) was converted to 26.0 mg of nitrone 5b (88%),
which was identical to the synthetic sample from N-siloxyamide
10b with the Schwartz reagent.
N-Benzylundec-10-en-1-imine Oxide (5c): Following the
general procedure B, N-hydroxyamide 4c (37.1 mg, 128 ¯mol)
was converted to 27.9 mg of nitrone 5c (80%), which was iden-
tical to the synthetic sample from N-siloxyamide 10c with the
Schwartz reagent.
7.25-7.14 (m, 3H), 4.84 (s, 2H), 2.60 (t, J = 7.7 Hz, 2H), 2.28
(brs, 2H), 1.66 (tt, J = 6.6, 6.6 Hz, 2H), 1.57 (tt, J = 7.7,
7.7 Hz, 2H), 1.46-1.16 (m, 12H), 0.85 (s, 9H), 0.16 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 172.9 (C), 140.2 (C), 133.7 (C),
129.4 (CH), 129.2 (CH), 127.7 (CH), 126.2 (CH), 53.7 (CH2),
33.2 (CH2), 32.1 (CH2), 28.6 (CH2), 26.6 (CH2), 26.6 (CH2),
25.9 (CH3), 26.0-25.5 (2 © CH2), 25.6 (CH2), 24.1 (CH2),
23.2 (CH2), 18.2 (C), ¹4.4 (CH3); HRMS (ESI), calcd for
C24H42NO2Si+ (M+H)+ 404.2985, found 404.2990.
Methyl 2,3,3a,4,5,6,7,8,9,10,11,12,13,18-tetradecahydro-
benzo[m]isoxazolo[2,3-a][1]azacyclopentadecine-2-carboxy-
lates (38 and 39): Zirconocene chloride hydride (19.3 mg,
74.8 ¯mol) was added to a solution of N-siloxylactam 36 (16.8
mg, 41.6 ¯mol) and (CH2Cl)2 (42 mL) at room temperature.
After stirring for 30 min, trifluoroacetic acid (1.3 M in (CH2Cl)2,
32 ¯L, 42 ¯mol) was added to the solution. After stirring for 1 h
at room temperature, methyl acrylate (150 ¯L, 1.7 mmol) was
added to the solution. This solution was then heated to 85 °C,
and stirred for 3 d at 85 °C. After cooling to room temperature,
the solution was quenched with saturated aqueous NaHCO3
(1 mL), and concentrated. The resulting aqueous solution was
extracted with EtOAc (2 © 5 mL). The combined organic
extracts were washed with brine (3 mL), dried over Na2SO4,
and concentrated. The residue was purified by silica gel column
chromatography (EtOAc/hexane 1:20 to 1:10) to give 9.6 mg
of isoxazolidines 38 and 39 (38:39 = 2:1, 64%). For analytical
samples, the diastereomeric mixture was separated by HPLC
(PEGASIL Silica 120E, 250 © 10 mm, EtOAc/hexane 1:12, 3.0
mL/min, major product 38: TR = 18.6 min, minor product 39:
TR = 21.5 min). Major product 38: a colorless oil; IR (film)
N-Benzyl-7-((4-methylphenyl)sulfonamido)heptan-1-
imine Oxide (5d): Following the general procedure B, N-
hydroxyamide 4d (51.4 mg, 127 ¯mol) was converted to 39.9
mg of nitrone 5d (81%), which was identical to the synthetic
sample from N-siloxyamide 10d with the Schwartz reagent.
Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan | 897

General Procedure C [Method B]: N-Benzyl-8-((tetra-
hydro-2H-pyran-2-yl)oxy)octan-1-imine Oxide (5e):
310 ¯mol) was added to the solution at room temperature. After
maintaining for 10 min at room temperature, TFA (1.3 M in
toluene, 24 ¯L, 31 ¯mol) was added to the solution. Then, Et3N
(9 ¯L, 65 ¯mol) and methyl acrylate (110 ¯L, 1.2 mmol) were
added to the resulting solution at room temperature. Mean-
while, a sealed tube with a rubber septa was charged with
toluene (18 mL). The solution containing the nitrone was then
transferred to the sealed tube via cannula at room temperature.
The rubber septa was replaced with a sealed vial stopper. The
solution in the sealed tube was then heated to 80 °C, stirred for
20 h at 80 °C, cooled to room temperature, and quenched with
saturated aqueous NaHCO3 (1 mL). The mixture was extracted
with hexane (2 © 10 mL). The combined organic extracts were
washed with brine (1 mL), dried over Na2SO4, and concentrat-
ed. The residue was purified by silica gel column chromatog-
raphy (EtOAc/hexane 1:20) to give 8.8 mg of isoxazolidines
38 and 39 (38:39 = 2.2:1, 79%), which were identical to the
synthetic samples from N-siloxyamide 36 with the Schwartz
reagent.
1,1,3,3-Tetramethyldisiloxane (57 ¯L, 320 ¯mol, 2.5 equiv)
was added to a mixture of N-hydroxyamide 4e (45.2 mg, 129
¯mol, 1.0 equiv), IrCl(CO)(PPh3)2 (1.0 mg, 1.3 ¯mol, 1 mol %)
and toluene (650 ¯L) at room temperature. After maintaining
for 30 min at room temperature, TBAF (1.0 M in THF, 130 ¯L,
130 ¯mol, 1.0 equiv) was added to the resulting solution at room
temperature. The solution was maintained for 5 min at room
temperature, quenched with H2O (1 mL), and extracted with
EtOAc (2 © 10 mL). The combined organic extracts were
washed with brine (1 mL), and dried over Na2SO4. Triethyl-
amine (200 ¯L) was added to the organic extracts. After con-
centration, the residue was purified by silica gel column chro-
matography (MeOH/CHCl3/Et3N 1:10:0.03) to give 36.9 mg of
nitrone 5e (86%), which was identical to the synthetic sample
from N-siloxyamide 10e with the Schwartz reagent.
N-(4-Nitrobenzyl)octan-1-imine Oxide (5f): Following
the general procedure C, N-hydroxyamide 4f (38.6 mg, 131
¯mol) was converted to 29.3 mg of nitrone 5f (80%), which
was identical to the synthetic sample from N-siloxyamide 10f
with the Schwartz reagent.
3. Results and Discussion
Our research group previously documented nucleophilic
addition to N-methoxyamides 6 (Scheme 2a).7-9 Treatment of
6 with the Schwartz reagent [Cp2ZrHCl]10 formed the five-
membered chelated intermediate 7.11 The subsequent addition
of an organometallic reagent and an acid provided multi-
substituted N-methoxyamine 8 via an iminium intermediate.
The reaction exhibited a wide substrate scope in high yields,
and was successfully applied to the concise total synthesis of
gephyrotoxin.8c,12 Taking promising results with N-methoxy-
amide 6, we next envisioned that the basic idea could be
extended to the reductive elimination of N-hydroxyamide 4 to
give nitrone 5 (Scheme 2b).13 N-Hydroxyamide 4 might be
converted to the chelated intermediate 9 upon treatment with
two equivalents of the Schwartz reagent. In contrast to N-
methoxy intermediate 7, addition of an acid to 9 would afford
nitrone 5 through the elimination of the hydroxy group.
Considering the fact that the formation of amide bonds is well
established, our method will become a promising synthetic tool
to provide functionalized nitrone 5.
N-(4-Bromobenzyl)octan-1-imine Oxide (5g): Following
the general procedure F, N-hydroxyamide 4g (42.4 mg, 129
¯mol) was converted to 35.4 mg of nitrone 5g (88%), which
was identical to the synthetic sample from N-siloxyamide 10g
with the Schwartz reagent.
2-Ethoxy-7-phenylhexahydro-2H-isoxazolo[2,3-a]pyri-
dines (26 and 27): A 10 mL flask containing N-hydroxyl-
actam 23 (1.10 g, 5.73 mmol, 1.0 equiv), IrCl(CO)(PPh3)2 (2.4
mg, 3.1 ¯mol, 0.05 mol %) and toluene (29 mL) was fitted with
a rubber septa. The solution was cooled to 0 °C. 1,1,3,3-
Tetramethyldisiloxane (2.3 mL, 13.0 mmol, 2.3 equiv) was
added dropwise over 5 min to the resulting solution at 0 °C.
The resulting solution was allowed to warm to room temper-
ature. After maintaining for 30 min at room temperature, MeCN
(3.0 mL) was added to the solution. The solution was then
cooled to 0 °C. Trifluoroacetic acid (520 ¯L, 6.9 mmol, 1.2
equiv) and ethyl vinyl ether (2.7 mL, 29 mmol, 5 equiv) were
added to the solution at 0 °C. The rubber septa was replaced
with a sealed vial stopper. The solution was then heated to
40 °C, stirred for 25 h at 40 °C, cooled to room temperature,
and quenched with saturated aqueous NaHCO3 (30 mL). The
mixture was extracted with EtOAc/hexane = 1:3 (2 © 30 mL).
The combined organic extracts were washed with brine (5 mL),
dried over Na2SO4, and concentrated. The residue was filtered
through a pad of silica gel, and purified by silica gel containing
10% KF column chromatography (EtOAc/hexane 7:1 to 5:1)
to give 697 mg of isoxazolidine 26 (49%) and 432 mg of
isoxazolidine 27 (31%), which were identical to the synthetic
samples from N-siloxyamide 24 with the Schwartz reagent.
Methyl 2,3,3a,4,5,6,7,8,9,10,11,12,13,18-tetradecahydro-
benzo[m]isoxazolo[2,3-a][1]azacyclopentadecine-2-carboxy-
lates (38 and 39): A 10 mL flask containing N-siloxylactam
36 (12.6 mg, 31.2 ¯mol), IrCl(CO)(PPh3)2 (1.2 mg, 1.5 ¯mol)
and toluene (160 ¯L) was fitted with a rubber septa. 1,1,3,3-
Tetramethyldisiloxane (17 ¯L, 96 ¯mol) was added to the
resulting solution at room temperature. The solution was main-
tained for 30 min at room temperature. Acetonitrile (16 ¯L,
Our hypothesis was first evaluated with N-benzyl-N-hydroxy-
octanamide (Table 1). A solution of N-hydroxyamide 4a in
(CH2Cl)2 was treated with the Schwartz reagent [Cp2ZrHCl]
(1.5 or 3.0 equiv) at room temperature, followed by addition of
trifluoroacetic acid (Table 1, Entries 1 and 2). However, nitrone
5a was not formed probably because it was inevitable for the
(a) Previous result: N-Methoxyamides
R1
H
[Zr]
O
Cp2ZrHCl
O
R1M, acid
R'
R'
OMe
R
N
H
R
R
N
N
OMe
OMe
R'
6
7
8
(b) This study: N-Hydroxyamides
[Zr]
O
H
Cp2ZrHCl
R'
O
acid
O
[Zr]
R'
N
R
N
H
R
N
R
OH
O
R'
4
9
5
Scheme 2. (a) Reductive nucleophilic addition to N-meth-
oxyamides. (b) Reductive formation of nitrones from N-
hydroxyamides.
898 | Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan

Table 1. Optimization of reductive formation of nitronesa)
Cp2ZrHCl
(CH2Cl)2, rt;
O
H
R'
R'
O
R
N
R
N
O
CF3CO2H, rt
Bn
OTBS
10
5
n-C7H15
N
4a: P = H, 10a: P = TBS
OP
11a: P = TBDPS, 12a: P = TIPS
H
H
H
ZrCp2Cl
H
Bn
Bn
MeO2C
Bn
Cp2ZrHCl
additive
O
N
O
n
-C7H15
N
N
O
OP
Bn
8
3
H
n-C7H15
N
O
N
O
(CH2Cl)2, rt
R
5a: 94%
5b: 80%
5c: 96%
Bn
5a
9a: P = ZrCp2Cl, 13a: P = TBS
14a: P = TBDPS, 15a: P = TIPS
H
H
THPO
Bn
TsHN
Bn
N
O
N
7
Yield of 5a [%]b)
6
Entry
Amide
Additive
O
1c)
2
3
4
5
6
7
4a
4a
CF3CO2H
CF3CO2H
CF3CO2H
TBAF
none
TBAF
0
0
5d: 81%
5e: 96%
H
H
10a
10a
10a
11a
12a
94
93
38
48
63
n
-C7H15
N
O
n-C7H15
N
O
NO2
Br
5f: 91%
5g: 82%
TBAF
Scheme 3. Scope of reductive formation of nitrones from
N-hydroxyamides. Reaction conditions: N-siloxyamides
10, Cp2ZrHCl (1.5 equiv), (CH2Cl)2 (0.08 M), rt, 10 min;
CF3CO2H (1.0 equiv), 1 h. Yields of isolated product after
purification by column chromatography are given.
a) N-Hydroxyamide derivatives 4a, 10a-12a, Cp2ZrHCl (1.5
equiv), (CH2Cl)2 (0.08 M), rt, 10 min; additive (1.0 equiv), 1 h.
b) Yields of isolated product after purification by column
chromatography are given. c) Cp2ZrHCl (3.0 equiv) was used.
(a)
protecting group
manipulations
reaction to proceed via an unstable dianionic intermediate 9a.
The corresponding N-siloxyamide 10a was then employed to
avoid the formation of dianionic intermediate 9a (Table 1,
Entry 3). Gratifyingly, the reduction of 10a with 1.5 equiv of the
Schwartz reagent afforded nitrone 5a in 94% yield through the
cleavage of the TBS group (Table 1, Entry 3).14 Of the additives
screened, trifluoroacetic acid and TBAF were found to be the
best additives (Table 1, Entries 3-5). The nature of the N-
siloxy group had a large effect on both the stability of the N-
siloxyamide and the reaction efficiency. While the N-siloxy-
amide with the TES group could not be isolated by column
chromatography due to the instability of the N-siloxyamide
itself, use of TBDPS and TIPS groups resulted in lower yields
than the TBS group probably due to the slow cleavage (Table 1,
Entries 6 and 7).
One of the salient features in our reductive methods is their
high chemoselectivity in the presence of a variety of functional
groups (Scheme 3).15 The reaction took place without affecting
the methyl ester group, which is in general more electrophilic
than the amide carbonyl group (5b: 80%). The competing
hydrozirconation was not observed even in the presence of a
terminal olefin (5c: 96%). Acidic protons derived from sul-
fone amides did not interfere with the reduction (5d: 81%).
Although the reaction requires addition of trifluoroacetic acid
in the elimination step, the THP group was not cleaved under
these acidic conditions (5e: 96%). A nitro group is generally
unstable under reductive conditions, but was well tolerated
under our developed conditions (5f: 91%). The reaction was
compatible with an aryl bromide, which was synthetically
useful upon further transformation using other transition-metal-
catalyzed reactions (5g: 82%).
OH
O
HN
O
R
N
O
O
redox reaction
R
R
16
17
18
H
(b)
(c)
O
R
O
R
Na2WO4, H2O2
NH
N
N
+
R
regioselectivity
19
18
20
(not obtained)
O
H
OTBS Cp2ZrHCl;
O
R
N
N
CF3CO2H
R
21
20
Scheme 4. (a) Issues in synthesis of cyclic nitrones.
(b) Oxidative approach to cyclic nitrone 18. (c) Reductive
approach to α-substituted cyclic nitrone 20.
(Scheme 4a). However, this useful method requires tedious
processes when applying it to the synthesis of cyclic nitrones
(17¼18).16 In general, the N-hydroxyamine group seen in 17
can be introduced to the reaction substrate through reductive
amination of a carbonyl group. Therefore, the two carbonyl
groups of 16 require prior differentiation through protecting
group manipulations or redox reactions. To avoid these tedious
processes, the oxidation of secondary amine has been utilized as
the most efficient method to give direct access to cyclic nitrones
(Scheme 4b, 19¼18).3 Although the oxidative approach pos-
sesses an inherent regioselectivity issue (18 versus 20), the
reaction gives a more substituted nitrone 18 as a major prod-
uct.17,18 On the contrary, our reductive method starting from 21
would be a complementary approach to provide α-substituted
nitrone 20 in a regiospecific manner (Scheme 4c).
While a number of studies involving synthesis of acyclic
nitrones have been documented, synthesis of cyclic nitrones
still remains an undeveloped research area.1 Condensation
between an N-hydroxyamine and a carbonyl group is considered
the most promising approach for synthesis of acyclic nitrones
Synthesis of α-substituted cyclic nitrone 25 commenced with
reductive amination of commercially available ketoacid 22,
followed by silylation of the resulting hydroxy group to pro-
Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan | 899

(a)
Condensation of 4-pentenoic acid 28 with commercially
available H2NOTBS, followed by cross metathesis with 2nd-
generation Hoveyda-Grubbs catalyst (HG-II)21 provided allylic
carbonate 30. Treatment of the resulting 30 with 2 mol % of
Pd(PPh3)4 at room temperature initiated the intramolecular
Tsuji-Trost cyclization to give five-membered N-siloxylactam
31 in 100% yield. The reductive formation of nitrone 32 from
N-siloxylactam 31, followed by [3+2] cycloaddition with
dimethyl maleate provided bicyclic isoxazolidines 33 and 34 in
64% combined yield.
Our reductive approach proved to be practical to give an
access to not only 5- and 6-membered cyclic nitrones, but
also more challenging macrocyclic nitrones in combination
with reliable macrolactamization (Scheme 5c).16b,22 Hydrolysis
of methyl ester 35 and macrolactamization with MNBA (2-
methyl-6-nitrobenzoic anhydride)23 provided 15-membered
macrolactam 36 in 84% yield over 2 steps.24 The subsequent
reduction of 36 under optimized conditions generated unstable
macrocyclic nitrone 37, which underwent [3+2] cycloaddition
with methyl acrylate at 85 °C in a one-pot process, affording 38
and 39 in 64% combined yield.
Although a practical reductive approach to give nitrones
from N-siloxyamides was successfully developed, we have to
point out two issues. Firstly, the method required the pre-
silylation step of N-hydroxyamides prior to the reduction as
shown in Table 1. Direct reduction of N-hydroxyamide 4a with
the Schwartz reagent [Cp2ZrHCl] did not provide the nitrone at
all. The other issue correlated with the Schwartz reagent itself.
This fine reagent displayed high chemoselectivity, but unfortu-
nately a stoichiometric amount of it was required. We therefore
decided to investigate catalytic conditions to overcome these
two issues. In 1980, Parish reported dehydrosilylation of alco-
hols in the presence of catalytic amount of the Vaska complex
[IrCl(CO)(PPh3)2] and HSi(OEt)3 (Scheme 6a).25,26 The group
of Nagashima then documented landmark hydrosilylation of
amide carbonyls using the Vaska complex and (Me2HSi)2O
(Scheme 6b).27-31 These two successful precedents indicated
that appropriate choice of silane reducing agent in combina-
tion with the Vaska complex could promote two different types
of iridium-catalyzed reactions under a single catalytic system,
enabling a direct access to the nitrones from the correspond-
ing N-hydroxyamides (Scheme 6c). First, N-hydroxyamide 4
would undergo dehydrosilylation with the silane reducing
agent and a catalytic amount of the Vaska complex. If the
generated N-siloxyamide 44 could be transformed to N,O-
acetal 45 under identical catalytic conditions, addition of an
acid or a fluoride reagent to N,O-acetal 45 would afford nitrone
5 through the elimination of the hydroxy group, and the
cleavage of silyl groups in a one-pot sequence.
NH2OH·HCl, Py
MeOH, reflux;
O
TBSCl
imidazole
HO2C
O
OH
Ph
N
NaBH3CN
AcCl, rt, 66%
CH2Cl2, rt
88%
Ph
22
23
R1
R2
O
N
Cp2ZrHCl
H
(CH2Cl)2, RT;
CH2=CHOEt
OTBS
Ph
O
H
N
O
N
CF3CO2H, rt
40 °C, 94%
26:27 = 1.9:1
Ph
Ph
24
25
: R1 = OEt, R2 = H
26
27: R1 = H, R2 = OEt
(b)
O
MeO2CO
OCO2Me
H2NOTBS
O
ClCO2Et, NMM
HG-II (2 mol %)
OTBS
OH
N
H
Et2O, 0 °C to rt
100%
CH2Cl2, 40 °C
91%
28
29
O
Pd(PPh3)4
(2 mol %)
O
H
Cp2ZrHCl
OTBS
OTBS
O
N
N
H
N
CH2Cl2, rt
100%
(CH2Cl)2, rt;
30
31
32
OCO2Me
R
2 R2
R1
R1
MeO2C
CO2Me
H
O
N
33: R1 = CO2Me, R2 = H
34: R1 = H, R2 = CO2Me
40 °C, 64%
33:34 = 5.6:1
(c)
O
MeO2C
1. TMSOK
Et2O, rt
TBSO
TBSO
N
NH
15
2. MNBA, DMAP
CH2Cl2, rt
84% (2 steps)
35
36
Cp2ZrHCl, (CH2Cl)2, rt;
CF3CO2H, rt
R2
R1
H
H
O
O
N
N
CO2Me
15
15
85 °C
64%, 38:39 = 2:1
38 (R1 = CO2Me, R2 = H)
39 (R1 = H, R2 = CO2Me)
37
Scheme 5. Synthesis and application of cyclic nitrones.
vide N-siloxylactam 24 (Scheme 5a). As we expected, cyclic
nitrone 25 was smoothly generated upon treatment of 24 with
the Schwartz reagent and subsequent addition of trifluoroacetic
acid. The resulting solution of 25 was then heated with ethyl
vinyl ether at 40 °C in a one-pot sequence, promoting the [3+2]
cycloaddition to give bicyclic isoxazolidines 26 and 27 in 94%
yield (dr = 1.9:1). It is noteworthy that our reductive method
actually solved the above two issues, which conventionally
involve the preparation of reaction substrates and regioselec-
tivity. Thus, N-siloxylactam 24 was prepared in just two steps
from the commercially available 22. The reaction provided α-
substituted cyclic nitrone 25, which was less obtainable by
conventional oxidative method. In addition, cyclic nitrones are
often known to be unstable, but the [3+2] cycloaddition was
feasible without the isolation of nitrone 25.
To test our hypothesis, we investigated the reaction of N-
hydroxyamide 4a using 1 mol % of the Vaska complex and the
silane reducing agent (Table 2). While use of Ph3SiH only
resulted in recovery of N-hydroxyamide 4a, the reaction with
Ph2SiH2 provided nitrone 5a in 5% yield after quenching with
TBAF (Table 2, Entries 1 and 2). The yield was slightly im-
proved with PhSiH3, giving nitrone 5a in 36% yield (Table 2,
Entry 3). The reaction with HSi(OEt)3, which was used in
Parish’s dehydrosilylation, was insufficient in our reaction
(Table 2, Entry 4). However, (Me2HSi)2O dramatically im-
Synthesis of N-siloxylactams allows us to use a variety of
methods including the Tsuji-Trost reaction (Scheme 5b).19,20
900 | Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan

(a) Dehydrogenative silylation of hydroxy groups by Parish (1980)
IrCl(CO)(PPh3)2 (1 mol %)
(Me2HSi)2O (2.5 equiv)
(a)
O
H
R'
R'
8 mol %
R
N
R
N
O
IrCl(CO)(PPh3)2
toluene (0.2 M), rt, 30 min
then PPTS (A) or TBAF (B), rt
EtOH
EtOSi(OEt)3
OH
4
5
HSi(OEt)3
40
41
H
H
H
(b) Hydrosilylation of amide carbonyls by Nagashima (2009)
0.05 mol %
Bn
MeO2C
Bn
Bn
n-C7H15
N
N
O
N
O
8
3
O
H
IrCl(CO)(PPh3)2
O
Ph
Ph
5a: 96% (A)
5b: 88% (A)
5c: 80% (A)
(Me2HSi)2O
97%
NEt2
NEt2
42
43
H
H
(c) Plan for an iridium-catalyzed approach to nitrones
cat. IrCl(CO)(PPh3)2
TsHN
Bn
THPO
Bn
N
N
O
7
6
O
O
O
[Si]-H
R'
R'
5d: 81% (A)
5e: 86% (B)
R
N
R
N
dehydrosilylation
O[Si]
H
OH
H
(–H2)
4
44
n-C7H15
N
O
n-C7H15
N
O
hydrosilylation
O[Si]
NO2
Br
H
H
H or F
5f: 80% (B)
5g: 88% (B)
R'
R'
R
N
R
N
O
(b)
desilylation
elimination
O[Si]
R1
R2
5
45
O
IrCl(CO)(PPh3)2 (0.05 mol %)
OH (Me2HSi)2O, toulene, rt;
H
O
Scheme 6. (a) Precedent for dehydrosilylation of alcohols.
(b) Precedent of hydrosilylation of amide carbonyls.
(c) Plan for an iridium-catalyzed reductive formation of
nitrones from N-hydroxyamides.
N
N
CF3CO2H, MeCN;
CH2=CHOEt, 40 ˚C
Ph
Ph
23
80%, 26:27 = 1.6:1
1.1 g scale
26: R1 = OEt, R2 = H
27: R1 = H, R2 = OEt
Table 2. Optimization of reductive formation of nitrones
from N-hydroxyamidesa)
(c)
R2
R1
O
IrCl(CO)(PPh3)2 (1 mol %)
(Me2HSi)2O, toluene, rt;
H
TBSO
N
IrCl(CO)(PPh3)2 (1 mol %)
[Si]-H
O
O
H
N
Bn
Bn
15
n-C7H15
N
n-C7H15
N
O
CF3CO2H, MeCN, rt; Et3N;
CH2=CHCO2Me, 80 °C
15
toluene (0.2 M), rt, 30 min
then additive, rt
OH
4a
5a
79%, 38:39 = 2.2:1
36
Yield of
5a [%]b)
38 (R1 = CO2Me, R2 = H)
39 (R1 = H, R2 = CO2Me)
Entry
[Si]-H
Additive
1
2
3
4
5
6
7
Ph3SiH (2.5 equiv)
Ph2SiH2 (2.5 equiv)
PhSiH3 (2.5 equiv)
(EtO)3SiH (2.5 equiv)
(Me2HSi)2O (2.5 equiv)
(Me2HSi)2O (1.2 equiv)
(Me2HSi)2O (2.5 equiv)
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
PPTS
0
5
Scheme 7. Scope of the iridium-catalyzed reductive forma-
tion of nitrones from N-hydroxyamides. (a) N-Hydroxy-
amide 4 (1equiv), [IrCl(CO)(PPh3)2] (1mol %), (Me2HSi)2O
(2.5 equiv), toluene (0.2 M), rt, 30 min; then <method A>
PPTS (1 equiv) or <method B> TBAF (1 equiv), rt, 5 min.
(b) Synthesis and application of six-membered cyclic
nitrone. (c) Synthesis and application of 15-membered
cyclic nitrone.
36
23
81
5
96c)
a) Amide 4a (1 equiv), [IrCl(CO)(PPh3)2] (1 mol %), [Si]-H,
toluene (0.2 M), rt, 30 min; then additive (1 equiv), rt, 5 min.
b) Yields were determined by 1H NMR using mesitylene as an
internal standard. c) Yield of isolated product after purification
by column chromatography is given.
The substrate scope of the iridium-catalyzed conditions was
then surveyed in the presence of a variety of functional groups
(Scheme 7a). While the reactions of N-hydroxyamides 4a-4d
provided nitornes in high yields with PPTS (method A), N-
hydroxyamides 4e-4g preferred TBAF (method B) for promot-
ing the desilylation and elimination steps because of the rela-
tively stable N,O-acetal intermediates. The iridium-catalyzed
reaction also showed high compatibility with a variety of func-
tional groups such as a methyl ester. The iridium-catalyzed
formation of nitrones was also applicable to a cyclic nitrone
(Scheme 7b). The iridium-catalyzed reaction of N-hydroxy-
lactam 23 formed the α-substituted cyclic nitrone, which
subsequently underwent [3+2] cycloaddition with ethyl vinyl
ether at 40 °C in a one-pot process. The reaction proceeded on
gram scale with 0.05 mol % of the Vaska complex. In the case
of the cyclic nitrones, better results were obtained with TFA
instead of TBAF and PPTS. It is noteworthy that functionalized
proved the reaction efficiency, giving nitrone 5a in 81%
yield (Table 2, Entry 5). The reaction of 4a with 1.2 equiv of
(Me2HSi)2O instead of 2.5 equiv generated some gas, but gave
the product 5a in only 5% yield, along with recovery of N-
hydroxyamide 4a in 87% yield after aqueous work-up (Table 2,
Entry 6). This result implied that the dehydrosilylation of the
N-hydroxy group might produce N-siloxyamide 44a with the
initial 1.0 equiv of (Me2HSi)2O, accompanied by the generation
of hydrogen gas. The best result was obtained in 96% yield
when using PPTS instead of TBAF for transformation of N,O-
acetal 45a to nitrone 5a (Table 2, Entry 7). Thus, we achieved
the development of catalytic conditions for the direct reductive
formation of nitrones from N-hydroxyamides.
Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan | 901

O
Vaska complex [IrCl(CO)(PPh3)2] and (Me2HSi)2O. The reac-
tion proceeded through the two different catalytic reactions
under the single catalytic system (dehydrosilylation and hydro-
silylation). Application to concise total syntheses of biolog-
ically active alkaloids is ongoing.
IrCl(CO)(PPh3)2
(1 mol %)
O
Bn
n-C7H15
N
O
Bn
n-C7H15
N
O
H
(Me2HSi)2O
d8-toluene, rt
Si
Si
OH
Me
Me
4a
Me Me
44a
with 1.2 equivalent of (Me2HSi)2O
detected by 1H NMR
This research was supported by a Grant-in-Aid for Scien-
tific Research (C) from MEXT (15K05436). Synthetic assis-
tance from Ms. Shona Banjo is gratefully acknowledged. S.
Kobayashi and K. Fujita contributed equally to this work.
Me Me
Me
O
Me
H
Si
Si
H
O
Bn
H
PPTS
Bn
n-C7H15
5a
N
O
n-C7H15
N
O
or TBAF
O
H
Si
Si
Me
Me
Me Me
Supporting Information
45a
with 2.5 equivalents of (Me2HSi)2O
detected by 1H NMR and ESI-MS (M+H+): 516.2820
This material is available on http://dx.doi.org/10.1246/bcsj.
20170086.
Scheme 8. Mechanistic investigation of the iridium-
catalyzed formation of nitrones from N-hydroxyamides.
References
1
For selected reviews on synthesis and transformations of
isoxazolidines 26 and 27 were obtained in just two steps from
commercially available ketoacid 22. The iridiuim-catalyzed
reaction of 15-membered macrolactam 36 efficiently formed
the macrocyclic nitrone, which was converted to tricyclic
isoxazolidines 38 and 39 in 79% combined yield (Scheme 7c).
The actual intermediates of the iridium-catalyzed reaction
nitrones, see: a) P. N. Confalone, E. M. Huie, in Organic
Reactions, ed. by A. S. Kende, Wiley, New York, NY, 1988,
Vol. 36, p. 1. b) K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998,
98, 863. c) P. de March, M. Figueredo, J. Font, Heterocycles 1999,
50, 1213. d) S. Kanemasa, Synlett 2002, 1371. e) M. Bonin, A.
Chauveau, L. Micouin, Synlett 2006, 2349. f) J. Revuelta, S.
Cicchi, A. Goti, A. Brandi, Synthesis 2007, 485. g) H. Pellissier,
Tetrahedron 2007, 63, 3235. h) V. Nair, T. D. Suja, Tetrahedron
2007, 63, 12247. i) L. M. Stanley, M. P. Sibi, Chem. Rev. 2008,
108, 2887. j) Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis: Novel Strategies in Synthesis, ed. by H. Feuer, John
1
were detected by H NMR experiments (Scheme 8). Treatment
of N-hydroxyamide 4a with (Me2HSi)2O (1.2 equiv) in the
presence of the Vaska complex (1 mol %) promoted only
dehydrosilylation of the hydroxy group. Although the resulting
N-siloxyamide 44a was too unstable to be isolated after aque-
ous work-up, the generation of 44a was detected by 1H NMR in
d8-toluene. On the contrary, use of (Me2HSi)2O (2.5 equiv)
promoted both dehydrosilylation and the hydrosilylation of the
amide carbonyl group, resulting in the generation of N,O-acetal
Wiley
& Sons, Inc, Hoboken, NJ, 2008. doi:10.1002/
9780470191552. k) Y. Ukaji, K. Inomata, Chem. Rec. 2010, 10,
173.
2
Part of this work was published as preliminary communi-
cations, see: S. Katahara, S. Kobayashi, K. Fujita, T. Matsumoto,
T. Sato, N. Chida, J. Am. Chem. Soc. 2016, 138, 5246.
1
45a, whose structure was confirmed by H NMR and ESI-MS
(M + H+: 516.2820). N,O-Acetal 45a was a relatively stable
compound. The crude sample after aqueous work-up without
addition of PPTS or TBAF suggested the presence of N,O-
acetal 45a, although purification by silica gel column chroma-
tography triggered degradation of N,O-acetal 45a. It is note-
worthy that the hydrosilylation of amide carbonyl 44a did not
form the seven-membered intermediate through the intramolec-
ular hydrosilylation with the second hydride derived from
(Me2HSi)2O. The intermolecular hydrosilylation took place
with another equivalent of (Me2HSi)2O. Thus, we concluded
that the iridium-catalyzed reaction of N-hydroxyamide 4a
proceeded through the dehydrosilylation (4a¼44a) and the
subsequent hydrosilylation (44a¼45a). Finally, N,O-acetal
45a underwent elimination and desilylation with PPTS or
TBAF to provide the corresponding nitrone 5a.
3
a) H. Mitsui, S. Zenki, T. Shiota, S. Murahashi, J. Chem.
Soc., Chem. Commun. 1984, 874. b) S. Murahashi, T. Shiota,
Tetrahedron Lett. 1987, 28, 2383. c) S. Murahashi, T. Oda, Y.
Masui, J. Am. Chem. Soc. 1989, 111, 5002. d) S. Murahashi, H.
Mitsui, T. Shiota, T. Tsuda, S. Watanabe, J. Org. Chem. 1990, 55,
1736. e) S. Sakaue, Y. Sakata, Y. Nishiyama, Y. Ishii, Chem. Lett.
1992, 289. f) F. P. Ballistreri, U. Chiacchio, A. Rescifina, G. A.
Tomaselli, R. M. Toscano, Tetrahedron 1992, 48, 8677. g) A. E.
McCaig, R. H. Wightman, Tetrahedron Lett. 1993, 34, 3939. h) R.
Joseph, A. Sudalai, T. Ravindranathan, Synlett 1995, 1177. i) E.
Marcantoni, M. Petrini, O. Polimanti, Tetrahedron Lett. 1995, 36,
3561. j) L. A. G. M. van den Broek, Tetrahedron 1996, 52, 4467.
k) A. Goti, L. Nannelli, Tetrahedron Lett. 1996, 37, 6025. l) R. W.
Murray, K. Iyanar, J. Chen, J. T. Wearing, J. Org. Chem. 1996, 61,
8099. m) S. Yamazaki, Bull. Chem. Soc. Jpn. 1997, 70, 877. n) M.
Forcato, W. A. Nugent, G. Licini, Tetrahedron Lett. 2003, 44, 49.
o) R. E. Looper, R. M. Williams, Angew. Chem., Int. Ed. 2004, 43,
2930. p) F. Sánchez-Izquierdo, P. Blanco, F. Busqué, R. Alibés, P.
de March, M. Figueredo, J. Font, T. Parella, Org. Lett. 2007, 9,
1769. q) M. Abrantes, I. S. Gonçalves, M. Pillinger, C. Vurchio,
F. M. Cordero, A. Brandi, Tetrahedron Lett. 2011, 52, 7079.
r) D.-V. Nguyen, P. Prakash, E. Gravel, E. Doris, RSC Adv. 2016,
6, 89238. s) P. Prakash, E. Gravel, D.-V. Nguyen, I. N. N.
Namboothiri, E. Doris, ChemCatChem 2017, 9, 2091.
4. Conclusion
We have developed a reductive approach to nitrones starting
from N-siloxyamides by taking advantage of the Schwartz
reagent [Cp2ZrHCl]. The reaction showed high chemoselec-
tivity in the presence of a variety of functional groups such as
a methyl ester. Conspicuous utility of our methodology was
demonstrated in the formation and application of functionalized
cyclic and macrocyclic nitrones due to the high accessibility of
the N-siloxylactams. Furthermore, the method was extended to
a catalytic protocol starting from N-hydroxyamides with the
4
Crist reported a pioneering work on synthesis and reactions
of acyclic α-alkoxynitrons from N-hydroxyamides, see: J. A.
Warshaw, D. E. Gallis, B. J. Acken, O. J. Gonzalez, D. R. Crist,
902 | Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan

J. Org. Chem. 1989, 54, 1736.
M. Morgen, S. Bretzke, P. Li, D. Menche, Org. Lett. 2010,
12, 4494.
Huang, Y.-H. Huang, H. Geng, J.-L. Ye, Sci. Rep. 2016, 6, 28801.
y) P.-Q. Huang, W. Ou, F. Han, Chem. Commun. 2016, 52, 11967.
z) P.-W. Tan, J. Seayad, D. J. Dixon, Angew. Chem., Int. Ed. 2016,
55, 13436. aa) Á. L. Fuentes de Arriba, E. Lenci, M. Sonawane, O.
Formery, D. J. Dixon, Angew. Chem., Int. Ed. 2017, 57, 3655. For
a complete list of references, see the supporting information.
10 a) P. C. Wailes, H. Weigold, J. Organomet. Chem. 1970, 24,
405. b) D. W. Hart, J. Schwartz, J. Am. Chem. Soc. 1974, 96, 8115.
11 a) D. J. A. Schedler, A. G. Godfrey, B. Ganem, Tetrahedron
Lett. 1993, 34, 5035. b) D. J. A. Schedler, J. Li, B. Ganem, J. Org.
Chem. 1996, 61, 4115. c) J. M. White, A. R. Tunoori, G. I. Georg,
J. Am. Chem. Soc. 2000, 122, 11995. d) J. T. Spletstoser, J. M.
White, A. R. Tunoori, G. I. Georg, J. Am. Chem. Soc. 2007, 129,
3408.
5
6
B. R. Galan, K. P. Kalbarczyk, S. Szczepankiewicz, J. B.
Keister, S. T. Diver, Org. Lett. 2007, 9, 1203.
7
For reviews and perspectives on nucleophilic addition to
amides, see: a) D. Seebach, Angew. Chem., Int. Ed. 2011, 50, 96.
b) T. Murai, Y. Mutoh, Chem. Lett. 2012, 41, 2. c) V. Pace, W.
Holzer, Aust. J. Chem. 2013, 66, 507. d) T. Sato, N. Chida, Org.
Biomol. Chem. 2014, 12, 3147. e) V. Pace, W. Holzer, B. Olofsson,
Adv. Synth. Catal. 2014, 356, 3697. f) A. Volkov, F. Tinnis, T.
Slagbrand, P. Trillo, H. Adolfsson, Chem. Soc. Rev. 2016, 45,
6685.
8
We reported nucleophilic addition to N-alkoxyamides, see:
a) K. Shirokane, Y. Kurosaki, T. Sato, N. Chida, Angew. Chem.,
Int. Ed. 2010, 49, 6369. b) Y. Yanagita, H. Nakamura, K.
Shirokane, Y. Kurosaki, T. Sato, N. Chida, Chem.®Eur. J. 2013,
19, 678. c) K. Shirokane, T. Wada, M. Yoritate, R. Minamikawa,
N. Takayama, T. Sato, N. Chida, Angew. Chem., Int. Ed. 2014, 53,
512. d) M. Yoritate, T. Meguro, N. Matsuo, K. Shirokane, T. Sato,
N. Chida, Chem.®Eur. J. 2014, 20, 8210. e) M. Nakajima, Y. Oda,
T. Wada, R. Minamikawa, K. Shirokane, T. Sato, N. Chida,
Chem.®Eur. J. 2014, 20, 17565. f) M. Nakajima, T. Sato, N.
Chida, Org. Lett. 2015, 17, 1696. g) Y. Fukami, T. Wada, T.
Meguro, N. Chida, T. Sato, Org. Biomol. Chem. 2016, 14, 5486.
For selected examples from other groups, see: h) H. Iida, Y.
Watanabe, C. Kibayashi, J. Am. Chem. Soc. 1985, 107, 5534. i) G.
Vincent, R. Guillot, C. Kouklovsky, Angew. Chem., Int. Ed. 2011,
50, 1350. j) G. Vincent, D. Karila, G. Khalil, P. Sancibrao, D. Gori,
C. Kouklovsky, Chem.®Eur. J. 2013, 19, 9358. k) M. Jäkel, J. Qu,
T. Schnitzer, G. Helmchen, Chem.®Eur. J. 2013, 19, 16746.
12 K. Shirokane, Y. Tanaka, M. Yoritate, N. Takayama, T.
Sato, N. Chida, Bull. Chem. Soc. Jpn. 2015, 88, 522.
13 Recently, Huang reported formation of azomethine ylides
from secondary amides, followed by 1,3-dipolar cycloaddition,
see: Ref. 9w.
14 Tanimoto reported synthesis of cyclic nitrones through
desilylation of N-siloxy-N-allenyl sulfonamide, see: H. Tanimoto,
T. Shitaoka, K. Yokoyama, T. Morimoto, Y. Nishiyama, K.
Kakiuchi, J. Org. Chem. 2016, 81, 8722.
15 For selected reviews on chemoselectivity, see: a) A.
Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem., Int.
Ed. 2000, 39, 4414. b) R. A. Shenvi, D. P. O’Malley, P. S. Baran,
Acc. Chem. Res. 2009, 42, 530. c) N. A. Afagh, A. K. Yudin,
Angew. Chem., Int. Ed. 2010, 49, 262.
16 For selected examples on practical synthesis of cyclic
nitrones through condensation, see: a) W. Oppolzer, O. Tamura, J.
Deerberg, Helv. Chim. Acta 1992, 75, 1965. b) T. Higo, T.
Ukegawa, S. Yokoshima, T. Fukuyama, Angew. Chem., Int. Ed.
2015, 54, 7367.
9
For recent selected examples on nucleophilic addition to
amides, see: a) Q. Xia, B. Ganem, Org. Lett. 2001, 3, 485. b) Y.-G.
Suh, D.-Y. Shin, J.-K. Jung, S.-H. Kim, Chem. Commun. 2002,
1064. c) T. Murai, Y. Mutoh, Y. Ohta, M. Murakami, J. Am. Chem.
Soc. 2004, 126, 5968. d) T. Murai, F. Asai, J. Am. Chem. Soc.
2007, 129, 780. e) O. Tomashenko, V. Sokolov, A. Tomashevskiy,
H. A. Buchholz, U. Welz-Biermann, V. Chaplinski, A. de Meijere,
Eur. J. Org. Chem. 2008, 5107. f) K.-J. Xiao, J.-M. Luo, K.-Y. Ye,
Y. Wang, P.-Q. Huang, Angew. Chem., Int. Ed. 2010, 49, 3037.
g) K.-J. Xiao, Y. Wang, K.-Y. Ye, P.-Q. Huang, Chem.®Eur. J.
2010, 16, 12792. h) G. Bélanger, G. O’Brien, R. Larouche-
Gauthier, Org. Lett. 2011, 13, 4268. i) W. S. Bechara, G. Pelletier,
A. B. Charette, Nat. Chem. 2012, 4, 228. j) K.-J. Xiao, A.-E.
Wang, Y.-H. Huang, P.-Q. Huang, Asian J. Org. Chem. 2012, 1,
130. k) Y. Oda, T. Sato, N. Chida, Org. Lett. 2012, 14, 950. l) J. W.
Medley, M. Movassaghi, Angew. Chem., Int. Ed. 2012, 51, 4572.
m) K.-J. Xiao, A.-E. Wang, P.-Q. Huang, Angew. Chem., Int. Ed.
2012, 51, 8314. n) Y. Inamoto, Y. Kaga, Y. Nishimoto, M. Yasuda,
A. Baba, Org. Lett. 2013, 15, 3452. o) Y. Gao, Z. Huang, R.
Zhuang, J. Xu, P. Zhang, G. Tang, Y. Zhao, Org. Lett. 2013, 15,
4214. p) S. Bonazzi, B. Cheng, J. S. Wzorek, D. A. Evans, J. Am.
Chem. Soc. 2013, 135, 9338. q) K.-J. Xiao, J.-M. Luo, X.-E. Xia,
Y. Wang, P.-Q. Huang, Chem.®Eur. J. 2013, 19, 13075. r) P.-Q.
Huang, W. Ou, K.-J. Xiao, A.-E. Wang, Chem. Commun. 2014, 50,
8761. s) A. W. Gregory, A. Chambers, A. Hawkins, P. Jakubec,
D. J. Dixon, Chem.®Eur. J. 2015, 21, 111. t) P.-Q. Huang, Q.-W.
Lang, A.-E. Wang, J.-F. Zheng, Chem. Commun. 2015, 51, 1096.
u) P.-Q. Huang, Y.-H. Huang, K.-J. Xiao, Y. Wang, X.-E. Xia,
J. Org. Chem. 2015, 80, 2861. v) P. Szcześniak, E. Maziarz, S.
Stecko, B. Furman, J. Org. Chem. 2015, 80, 3621. w) P.-Q. Huang,
Q.-W. Lang, X.-N. Hu, J. Org. Chem. 2016, 81, 10227. x) P.-Q.
17 Murahashi reported synthesis of α-substituted cyclic nitro-
nes through decarboxylative oxidation of N-alkyl-α-amino acids,
see: a) S.-I. Murahashi, Y. Imada, H. Ohtake, J. Org. Chem. 1994,
59, 6170. b) H. Ohtake, Y. Imada, S.-I. Murahashi, Bull. Chem.
Soc. Jpn. 1999, 72, 2737.
18 Strukul reported synthesis of α-substituted cyclic nitrones
through Pt(II)-catalyzed oxidation of secondary amines, see: M.
Colladon, A. Scarso, G. Strukul, Green Chem. 2008, 10, 793.
19 For an example on the Tsuji-Trost reaction of N-siloxy-
amides, see: M. J. Miller, G. Zhao, S. Vakulenko, S. Franzblau, U.
Möllmann, Org. Biomol. Chem. 2006, 4, 4178.
20 For selected examples on the Tsuji-Trost type reaction of N-
alkoxyamides, see: a) E. Öhler, S. Kanzler, Phosphorus, Sulfur
Silicon Relat. Elem. 1996, 112, 71. b) H. Miyabe, A. Matsumura,
K. Moriyama, Y. Takemoto, Org. Lett. 2004, 6, 4631. c) B. M.
Trost, G. Dong, J. Am. Chem. Soc. 2006, 128, 6054. d) X.-T. Sun,
A. Chen, Tetrahedron Lett. 2007, 48, 3459. e) S.-M. Yang, B.
Lagu, L. J. Wilson, J. Org. Chem. 2007, 72, 8123. f) B. M. Trost,
G. Dong, Chem. Eur. J. 2009, 15, 6910. g) H. Miyabe, K.
Moriyama, Y. Takemoto, Chem. Pharm. Bull. 2011, 59, 714. h) M.
Gärtner, M. Jäkel, M. Achatz, C. Sonnenschein, O. Tverskoy, G.
Helmchen, Org. Lett. 2011, 13, 2810. i) Ref. 8k.
21 a) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H.
Hoveyda, J. Am. Chem. Soc. 2000, 122, 8168. b) M. Morgen, S.
Bretzke, P. Li, D. Menche, Org. Lett. 2010, 12, 4494. For a
selected review on the cross metathesis, see: c) S. J. Connon, S.
Blechert, Angew. Chem. 2003, 115, 1944; S. J. Connon, S.
Blechert, Angew. Chem., Int. Ed. 2003, 42, 1900.
22 a) M. A. T. Rogers, Nature 1956, 177, 128. b) E. J. Alford,
Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan | 903

J. A. Hall, M. A. T. Rogers, J. Chem. Soc. C 1966, 1103. c) C. J.
Brown, J. Chem. Soc. C 1966, 1108. d) S. S. Al-Jaroudi, H. P.
Perzanowski, M. I. M. Wazeer, S. A. Ali, Tetrahedron 1997, 53,
5581. e) J. D. White, P. R. Blakemore, E. A. Korf, A. F. T.
Yokochi, Org. Lett. 2001, 3, 413. f) Y. Imada, C. Okita, H. Maeda,
M. Kishimoto, Y. Sugano, H. Kaneshiro, Y. Nishida, S.
Kawamorita, N. Komiya, T. Naota, Eur. J. Org. Chem. 2014, 5670.
23 a) I. Shiina, M. Kubota, R. Ibuka, Tetrahedron Lett. 2002,
43, 7535. b) I. Shiina, M. Kubota, H. Oshiumi, M. Hashizume,
J. Org. Chem. 2004, 69, 1822.
Mizuno, Adv. Synth. Catal. 2009, 351, 1405.
27 Curtis reported synthesis of siloxane oligomer using
(Me2HSi)2O and a catalytic amount of the Vaska complex
[IrCl(CO)(PPh3)2], see: J. Greene, M. D. Curtis, J. Am. Chem.
Soc. 1977, 99, 5176.
28 Nagashima reported a pioneering work using iridium-
catalyzed hydrosilylation of tertiary amides to give enamines, see:
a) Y. Motoyama, M. Aoki, N. Takaoka, R. Aoto, H. Nagashima,
Chem. Commun. 2009, 1574. b) A. Tahara, Y. Miyamoto, R. Aoto,
K. Shigeta, Y. Une, Y. Sunada, Y. Motoyama, H. Nagashima,
Organometallics 2015, 34, 4895. For a recent example of the
application, see c) H. Kobayashi, Y. Sasano, N. Kanoh, E. Kwon,
Y. Iwabuchi, Eur. J. Org. Chem. 2016, 270.
29 For examples on hydrosilylation of amides to give
enamines or imines, see: a) S. Bower, K. A. Kreutzer, S. L.
Buchwald, Angew. Chem., Int. Ed. Engl. 1996, 35, 1515. b) C.
Cheng, M. Brookhart, J. Am. Chem. Soc. 2012, 134, 11304. c) A.
Volkov, F. Tinnis, H. Adolfsson, Org. Lett. 2014, 16, 680. d) F.
Tinnis, A. Volkov, T. Slagbrand, H. Adolfsson, Angew. Chem., Int.
Ed. 2016, 55, 4562.
30 For examples on nucleophilic addition to amides by taking
advantage of Nagashima’s conditions, see Ref. 2, Ref. 8f, Ref. 9s,
Ref. 9y and Ref. 9z.
24 The macrolactamization required the protection of the N-
hydroxy group as a TBS ether.
25 For recent selected reviews on iridium-catalyzed reactions,
see: a) J. M. Ketcham, I. Shin, T. P. Montgomery, M. J. Krische,
Angew. Chem., Int. Ed. 2014, 53, 9142. b) A. Bartoszewicz, N.
Ahlsten, B. Martín-Matute, Chem.®Eur. J. 2013, 19, 7274. c) S.
Pan, T. Shibata, ACS Catal. 2013, 3, 704. d) J. F. Hartwig, Chem.
Soc. Rev. 2011, 40, 1992. e) J. Choi, A. H. R. MacArthur, M.
Brookhart, A. S. Goldman, Chem. Rev. 2011, 111, 1761. f) J. F.
Hartwig, L. M. Stanley, Acc. Chem. Res. 2010, 43, 1461. g) S. B.
Han, I. S. Kim, M. J. Krische, Chem. Commun. 2009, 7278.
26 For examples on iridium-catalyzed dehydrosilylation, see:
a) S. N. Blackburn, R. N. Haszeldine, R. V. Parish, J. H. Setchfield,
J. Organomet. Chem. 1980, 192, 329. b) J. Dwyer, H. S. Hilal,
R. V. Parish, J. Organomet. Chem. 1982, 228, 191. c) X.-L. Luo,
R. H. Crabtree, J. Am. Chem. Soc. 1989, 111, 2527. d) L. D. Field,
B. A. Messerle, M. Rehr, L. P. Soler, T. W. Hambley, Organo-
metallics 2003, 22, 2387. e) M.-K. Chung, M. Schlaf, J. Am.
Chem. Soc. 2005, 127, 18085. f) Y. Ojima, K. Yamaguchi, N.
31 Jeon reported a variety of reactions through hydrosilylation
of ester carbonyls, see a) Y. Hua, P. Asgari, U. S. Dakarapu, J.
Jeon, Chem. Commun. 2015, 51, 3778. b) U. S. Dakarapu, A.
Bokka, P. Asgari, G. Trog, Y. Hua, H. H. Nguyen, N. Rahman, J.
Jeon, Org. Lett. 2015, 17, 5792. c) Y. Hua, P. Asgari, T. Avullala, J.
Jeon, J. Am. Chem. Soc. 2016, 138, 7982.
904 | Bull. Chem. Soc. Jpn. 2017, 90, 893–904 | doi:10.1246/bcsj.20170086
© 2017 The Chemical Society of Japan