An Iridium-Catalyzed Reductive Approach to Nitrones from N-Hydroxyamides

Article abstract of DOI:10.1021/jacs.6b02324

An Ir-catalyzed reductive formation of functionalized nitrones from N-hydroxyamides was reported. The reaction took place through two types of iridium-catalyzed reactions including dehydrosilylation and hydrosilylation. The method showed high chemoselectivity in the presence of sensitive functional groups, such as methyl esters, and was successfully applied to the synthesis of cyclic and macrocyclic nitrones, which are known to be challenging compounds to access by conventional methods. ¹H NMR studies strongly supported generation of an N-siloxyamide and an N,O-acetal as the actual intermediates.

Full text of DOI:10.1021/jacs.6b02324

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Communication
An Iridium-Catalyzed Reductive Approach to Nitrones from N-Hydroxyamides
Seiya Katahara, Shoichiro Kobayashi, Kanami Fujita, Tsutomu Matsumoto, Takaaki Sato, and Noritaka Chida
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02324 • Publication Date (Web): 13 Apr 2016
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An Iridium-Catalyzed Reductive Approach to Nitrones from N-
Hydroxyamides
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Seiya Katahara, Shoichiro Kobayashi,† Kanami Fujita,† Tsutomu Matsumoto, Takaaki Sato,* Noritaka
Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yoko-
hama 223-8522, Japan
Supporting Information Placeholder
Scheme 1. Plan for Iridium-Catalyzed Reductive Formation
of Nitrones from N-Hydroxyamides
ABSTRACT: An iridium-catalyzed reductive formation of func-
tionalized nitrones from N-hydroxyamides was reported. The reac-
tion took place through two types of iridium-catalyzed reactions
including dehydrosilylation and hydrosilylation. The method
showed high chemoselectivity in the presence of sensitive func-
tional groups such as methyl esters, and was successfully applied
to the synthesis of cyclic and macrocyclic nitrones, which are
known to be challenging compounds to access by conventional
methods. 1H NMR studies strongly supported generation of an N-
siloxyamide and an N,O-acetel as the actual intermediates.
The development of useful methods to provide nitrones has been
extensively investigated, and is still an important topic in organic
chemistry.1 Nitrones can undergo a variety of reactions such as 1,3-
dipolar cycloadditions, and are recognized as promising key inter-
mediates for the synthesis of biologically active alkaloids and phar-
maceuticals. In this paper, we report an iridium-catalyzed reductive
formation of nitrones from N-hydroxyamides. The reaction 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.
Table 1. Scope of Iridium-Catalyzed Reductive Formation
of Nitrones from N-Hydroxyamides a,b
Nucleophilic addition to amide carbonyl groups has received
much attention in recent years due to the availability of the amides
themselves and a quick supply of multi-substituted amines.2-4 Dur-
ing our pursuit of practical transformations of amide groups, we
envisioned that reduction of N-hydroxyamides could be a straight-
forward method to access functionalized nitrones (Scheme 1).5
First, N-hydroxyamide 1 would be converted to N-siloxyamide 2
by dehydrosilylation6 with a catalytic amount of the Vaska complex
[IrCl(CO)(PPh3)2] and (Me2HSi)2O.7,8 The resulting N-siloxyamide
2 would subsequently undergo the hydrosilylation of the amide car-
bonyl group.9 If two different types of iridium-catalyzed reactions
(dehydrosilylation and hydrosilylation) were achieved under the
single catalytic system, N-hydroxyamide 1 could be directly con-
verted to N,O-acetal 3. Finally, addition of an acid or a fluoride
reagent to 3 would afford nitrone 4 through the elimination of the
hydroxy group, along with the cleavage of the silyl groups, in a
one-pot process. While a number of oxidative approaches to
nitrones from secondary amines have been reported,10 catalytic re-
ductive synthesis of nitrones from amides is unprecedented to the
best of our knowlege.11 Considering that formation of amides is
well established, our method will become a promising synthetic
tool to provide functionalized nitrones.
a
1 (1 equiv), [IrCl(CO)(PPh3)2] (1 mol %), (Me2HSi)2O (2.5
equiv), toluene (0.2 M), rt, 30 min; then <method A> PPTS (1
equiv), rt, 5 min; or <method B> TBAF (1 equiv), rt, 5 min. b Yield
of isolated product after purification by column chromatography.
with (Me2HSi)2O (2.5 equiv) and the Vaska complex
[IrCl(CO)(PPh3)2] (1 mol %) at room temperature, followed by ad-
dition of PPTS (method A), provided nitrone 4a in 96% isolated
yield. One of the salient features in this reaction is its high
chemoselectivity. The reductive formation of the nitrone took
place without reducing a methyl ester, which is generally more
electrophilic than an amide carbonyl group (4b: 88%). Competing
To test our hypothesis, we investigated the reaction of N-hydrox-
yamide 1a (Table 1). Gratifyingly, treatment of a solution of 1a
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hydrosilylation of a terminal olefin was not observed (4c
:
80%). A sulfonamide with an acidic proton did not disturb the
reaction (4d: 81%). Addition of TBAF instead of PPTS was an
alternative choice in the elimination step for N-hydroxyamide 1
known as the Shiina reagent for macrolactonization,17 proved to be
the most effective, giving 15-membered N-siloxylactam 16 in 84%
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yield (2 steps).18 As we expected, macrocyclic nitrone 17 was effi-
ciently formed under the developed conditions, and then underwent
[3+2] cycloaddition with methyl acrylate at 80 °C to give bicyclic
isoxazolidines 18 and 19 in 79% combined yield (18:19 = 2.2:1). It
is noteworthy that oxidation of the corresponding macrocyclic sec-
ondary amine would form the nitrone at the benzylic position.
However, our reductive method generated less accessible macrocy-
clic nitrone 17.
with acid-sensitive functional groups such as a THP group (4e:
86%). Moreover, when N-hydroxyamides had electron withdraw-
ing groups on aromatic groups, addition of TBAF resulted in better
yields than use of PPTS, probably due to the slow elimination step
(4f: 80%; 4g: 85%; 4h: 88%). The high chemoselectivity was also
observed with nitro, aromatic ester and aryl bromide moieties
under the developed reaction conditions.
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Scheme 3. Formation and Application of Cyclic and Macro-
cyclic Nitrones
Scheme 2. Issues in Synthesis of Cyclic Nitrones
A
lthough a number of studies related to nitrones have been
documented, efficient synthesis of cyclic nitrones still remains a
challenging task (Scheme 2).1a,f Condensation of a carbonyl group
with a hydroxyamine has been utilized as the most promising
method for the synthesis of acyclic nitrones. However, there are
few examples of cyclic nitrones (6→7) due to the tedious prepara-
tion of the substrate 6 itself.12 Synthesis of 6 requires extra steps in
order to differentiate the two carbonyl groups in 5, one of which is
used for the installation of NH2OH. The most promising methods
for synthesis of cyclic nitrones is the oxidation of secondary amines
(8→7).10 The oxidative approach is known to afford more substi-
tuted nitrone 7 as the major product versus -substituted nitrone
9.13,14
We considered that our reductive method could be complemen-
tary to the oxidative approach, and a successful example is shown
in Scheme 3A. Reductive amination of commercially available 5-
ketoacid 10 and concomitant cyclization gave six-membered N-hy-
droxylactam 11 in 66% yield. The iridium-catalyzed reduction of
11, followed by addition of TFA gave cyclic nitrone 12. The result-
ing solution of 12 was then heated with ethyl vinyl ether at 40 °C
in a one-pot sequence, promoting the [3+2] cycloaddition to give
bicyclic isoxazolidines 13 and 14 in 93% combined yield (13:14 =
1.4:1). This example demonstrated a number of synthetic ad-
vantages using our reductive method. First, N-hydroxylactam 11
was prepared in just one step from the commercially available com-
pound 10. Second, the reaction provided less accessible -substi-
tuted nitrone 12. Third, the one-pot [3+2] cycloaddition was possi-
ble without isolation of the cyclic nitrone, which is generally
known to be an unstable compound.
To elucidate the actual intermediates in the iridium-catalyzed re-
duction, 1H NMR experiments with N-hydroxyamide 1a were per-
formed (Figure 1). Treatment of a solution of 1a, which existed as
a 4:1 mixture of rotamers in d8-toluene, with (Me2HSi)2O (2.5
equiv) in the absence of the Vaska complex did not promote the
reaction (Spectra A and B). However, treatment of 1a with
(Me2HSi)2O (1.2 equiv) in the presence of the Vaska complex (1
mol %) resulted in the disappearance of the broad singlet peak at 
9.08 ppm from the N-hydroxy group to suggest the formation of N-
siloxyamide 2a (Spectrum C). In contrast, use of (Me2HSi)2O (2.5
equiv) and the Vaska complex (1 mol %) dramatically changed the
1H NMR spectrum, which indicated the formation of N,O-acetal 3a
(Spectrum D). Spectrum D shows the disappearance of the broad
singlet peak at  9.08 ppm from the N-hydroxy group, and contains
a doublet of doublets at  4.96 ppm (J = 7.8, 5.0 Hz) for the C8
methine. Two doublet peaks at  3.96 ppm (J = 13.5 Hz) and  3.91
ppm (J = 13.5 Hz) rather than a singlet indicates the presence of
two diastereotopic protons corresponding to the C9 benzylic meth-
ylene group. Generation of two resonances at  5.05 ppm (sep, J =
2.8 Hz, 1H, Si-H) and 4.88 ppm (sep, J = 2.8 Hz, 1H, Si-H), and
eight methyl signals clearly suggests that intermediate 3a possesses
A conspicuous example of our reductive method is its applica-
tion to macrocyclic nitrones (Scheme 3B). Although macrocyclic
nitrones have been desired over the years as key intermediates for
the synthesis of biologically active natural products such as man-
zamine alkaloids,15 development of methods to access macrocyclic
nitrones remains one of the most challenging topics.12b,16 However,
we envisioned that this task could be achieved by combination of a
reliable macrolactamization with our reductive approach. After hy-
drolysis of methyl ester 15 with TMSOK, macrolactamization of
the resulting N-siloxyamino acid was then investigated. Interest-
ingly, MNBA (2-methyl-6-nitrobenzoic anhydride), which is
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Figure 1. 1H NMR spectra (400 MHz) in the iridium-catalyzed reductive formation of N-hydroxyamide 1a. (A) N-hydroxyamide 1a in d8-
toluene; (B) N-hydroxyamide 1a and (Me2HSi)2O (2.5 equiv) in d8-toluene; (C) N-hydroxyamide 1a, (Me2HSi)2O (1.2 equiv) and
[IrCl(CO)(PPh3)2] (1 mol %) in d8-toluene, 30 min; (D) N-hydroxyamide 1a, (Me2HSi)2O (2.5 equiv) and [IrCl(CO)(PPh3)2] (1 mol %) in
d8-toluene, 30 min. d8-toluene, 30 min
two silyl groups. N,O-Acetal 3a was found to be a relatively stable
compound. When the reaction was quenched without addition of
PPTS, the 1H NMR spectrum of the crude sample was identical to
that of N,O-acetal 3a, although purification by silica gel column
chromatography resulted in degradation to nitrone 4a. Formation
of N,O-acetal 3a was also confirmed by the ESI-MS spectrum (M
+ H+: 516.2820). Thus, as hypothesized in Scheme 1B, we con-
cluded that the reaction of N-hydroxyamide 1a took place through
the initial dehydrogenative silylation of 1a, followed by hydrosi-
lylation of amide carbonyl 2a, giving the corresponding N,O-acetal
3a.
AUTHOR INFORMATION
Corresponding Author
*E-mail: takaakis@applc.keio.ac.jp; chida@applc.keio.ac.jp
Notes
The authors declare no competing financial interests.
† These authors contributed equally.
ACKNOWLEDGMENT
This research was supported by a Grant-in-Aid for Scientific Re-
search (C) from MEXT (15K05436). Synthetic assistance from Ms.
Shona Banjo is gratefully acknowledged.
In summary, we have developed an unprecedented reductive ap-
proach to nitrones from N-hydroxyamides. The reaction proceeded
via two different types of iridium-catalyzed reactions involving de-
hydrosilylation of the N-hydroxy group, and hydrosilylation of the
amide carbonyl under the single catalytic system using the Vaska
complex [IrCl(CO)(PPh3)2] and (Me2HSi)2O. 1H NMR studies
clearly suggested that the N-siloxyamide and the N,O-acetal were
the actual intermediates in this catalytic reaction. The method
showed high chemoselectivity in the presence of a variety of func-
tional groups such as a methyl ester. The clear utility of our meth-
odology was demonstrated in the synthesis and application of func-
tionalized cyclic and macrocyclic nitrones.
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hydroxyamides requires temporarily masking silyl groups.
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(18) The macrolactamization required the protection of the N-hydroxy
group as a TBS ether.
(8) Curtis reported synthesis of siloxane oligomer using (Me2HSi)2O and a
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