Manganese-Promoted Oxidative Cyclization of Unsaturated Oximes Using Molecular Oxygen in Air under Ambient Conditions

Article abstract of DOI:10.1002/ejoc.201600998

A highly efficient manganese-promoted oxidative cyclization of unsaturated oximes to afford the corresponding 4,5-dihydroisoxazoline alcohols was developed. A very low loading (generally 0.1–0.2 mol-%) of Mn(acac)₃(acac = acetylacetonate) promoted the oxidative cyclization through the direct incorporation of molecular oxygen present in air (open flask) at room temperature.

Full text of DOI:10.1002/ejoc.201600998

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Accepted Article
Title: Manganese-promoted oxidative cyclisation of unsaturated oximes using mole-
cular oxygen in air under ambient conditions
Authors: Daisuke Yamamoto; Takuto Oguro; Yuuki Tashiro; Masayuki Soga; Kazu-
hito Miyashita; Yoshiaki Aso; Kazuishi Makino
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600998
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COMMUNICATION
Manganese-promoted oxidative cyclisation of unsaturated
oximes using molecular oxygen in air under ambient conditions
Daisuke Yamamoto,[a] Takuto Oguro,[a] Yuuki Tashiro,[a] Masayuki Soga,[a] Kazuhito Miyashita,[a]
Yoshiaki Aso,[a] and Kazuishi Makino*[a]
Abstract:
A
highly efficient manganese-promoted oxidative
4,5-dihydroisoxazolines using molecular oxygen present in air
(open flask) at room temperature.
cyclisation of unsaturated oximes to afford the corresponding 4,5-
dihydroisoxazoline alcohols was developed. A very low loading
(generally 0.1–0.2 mol%) of Mn(acac)3 promoted the oxidative
cyclisation through the direct incorporation of molecular oxygen
present in air (open flask) at room temperature.
a) Previous studies:
OH
R3
N O
N
R3
air or pure O2
OR
R1
R5
R1
Pd- or Co-catalyst
or TEMPO / photocatalyst
(10 mol%)
R5
R2 R4
R = H
2' R = Ac
R2 R4
1
Introduction
2
additives
Molecular oxygen is recognized as an ideal oxidant because
it is abundantly available, inexpensive and environmentally
benign.[1] In this context, transition metal-catalysed and metal-
free oxidative difunctionalisation of unactivated carbon–carbon
double bonds for directly incorporating molecular oxygen into
substrates has emerged as an attractive and powerful strategy
for efficient assembly of new bonds.[2-12] Recently, a few novel
approaches have been reported for the construction of the 4,5-
dihydroisoxazoline alcohols, which are an important class of
compounds found in several biologically active agents[13] and
versatile intermediates in organic synthesis,[14] by the oxidative
cyclisation of ,-unsaturated oximes using molecular oxygen
(Scheme 1). In 2010, Loh et al. demonstrated the use of 10
mol% palladium complex-promoted 4,5-dihydroisoxazoline
formation from ,-unsaturated oximes to yield a mixture of 4,5-
dihydroisoxazoline alcohol and its acetate ester in the presence
of acetic acid.[15] Yu et al. reported a 10 mol% cobalt (II) complex
in the presence of tert-butyl hydroperoxide acting as a catalyst to
afford 4,5-dihydroisoxazoline alcohols under a pure molecular
oxygen atmosphere.[16] Very recently, Chen et al. reported a
organophotocatalytic reaction to provide 4,5-dihydroisoxazoline
alcohols using 9-metsityl-10-methyl-acridinium perchlorate (5
mol%) and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 10
mol%) under O2 atmosphere.[17] While these pioneering works
provided new methods for the construction of 4,5-
dihydroisoxazolines from unsaturated oximes through the
incorporation an oxygen atom from gaseous dioxygen into
carbon–carbon double bonds, there still remain challenges in
terms of yield, substrate scope, functional group tolerance and
environmentally friendly conditions. In particular, highly active
and robust catalysts capable of directly incorporating molecular
oxygen present in air into organic substrates without cooling or
heating are in high demand. In the course of our studies on
manganese-promoted oxidative reactions using molecular
oxygen,[18] we report herein a highly efficient manganese-
promoted oxidative cyclisation of unsaturated oximes to provide
b) This study:
OH
R3
N O
N
R3
O2 in air
OH
R1
R5
R1
Mn(acac)3
(0.05 – 1 mol%)
then reductive work-up
flask open to air
R5
R2 R4
2
R2 R4
1
at room temperature
Scheme 1. Aerobic oxidative cyclisation of ,-unsaturated oximes
Results and Discussion
Our initial investigations began with the screening of various
metal complexes for the oxidative cyclisation reaction of ,-
unsaturated oxime 1a in MeOH in air. Among them, using 1
mol% of Mn(acac)3 provided the desired 4,5-dihydroisoxazoline
alcohol 2a incorporating an oxygen atom present in air in 80%
yield at room temperature after treatment with a saturated
aqueous sodium thiosulfate solution (Table 1, entry 1). The
corresponding peroxide derived from 1a was obtained without a
reductive work-up.[19] This result clearly indicates that this
manganese-promoted 4,5-dihydroisoxazoline formation does not
proceed through an epoxidation of carbon–carbon double bond.
On the other hand, other metal acetylacetonate complexes such
as Co(acac)3, Fe(acac)3, Ti(acac)3, MoO2(acac)2, and Ni(acac)2,
were completely ineffective at 1 mol%, and 1 mol% of Cu(acac)2
gave poor yield in the same conditions (entries 2–7). The solvent
screening indicated that the use of alcohols such as MeOH and
EtOH were suitable for this reaction (entries 1 and 8), while C6H6,
CH2Cl2 and CH3CN furnished 4,5-dihydroisoxazoline 2a in poor
yield (entries 9–11). Encouraged by these initial findings, we
examined the possibility of further decreasing the loading of
Mn(acac)3 in air at room temperature. The yield was at a similar
level with 0.5 mol% of Mn(acac)3 (entry 12), whereas a
significant deterioration of yield was observed after reducing the
Mn(acac)3 loading to 0.1 mol% (entry 13). To our delight, we
found that higher substrate concentration improved the yield and
[a]
Dr. D. Yamamoto, T. Oguro, Y. Tashiro, M. Soga, K. Miyashita, Y.
Aso, Prof. Dr. K. Makino
Department of Pharmaceutical Sciences
Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641,
Japan
E-mail: makinok@pharm.kitasato-u.ac.jp
http://www.pharm.kitasato-u.ac.jp/medicinal/Welcome.html
reaction rate (entries 14–17). At
a
starting substrate
concentration of 2.0 M in MeOH, 0.1 mol% of Mn(acac)3 worked
effectively to afford 4,5-dihydroisoxazoline 2a in 87% yield (entry
15). This protocol could be applied to the gram-scale synthesis
of 4,5-dihydroisoxazoline 2a using a 0.1 mol% Mn(acac)3 in high
yield in air at room temperature (entry 16). Moreover, using only
0.05 mol% Mn(acac)3 promoted the oxidative cyclisation of
unsaturated oximes carried out at room temperature for 72 h
Supporting information for this article is available on the WWW under
http://
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European Journal of Organic Chemistry
10.1002/ejoc.201600998
COMMUNICATION
(61% yield) at a higher concentration (4.0 M in MeOH), directly
incorporating molecular oxygen present in air (entry 17).
Table 1. Optimisation of the transition metal-promoted 4,5-
dihydroisoxazoline formation through the incorporation of molecular oxygen
present in air[a]
oximes were also viable substrates for this reaction. The highly
hindered tert-butyl oximes 1q and 1r as well as the primary alkyl
oximes 1o and 1p afforded the corresponding 4,5-
dihydroisoxazoline 2o–2r in high yield. The tert-butyldimethylsilyl
and tert-butoxycarbonyl groups were tolerated under the
reaction conditions (2s and 2t).
O2 in air
metal salt
OH
CH3
N O
N
CH3
OH
solvent, rt
then
Table 2. Substrate scope of the manganese-promoted 4,5-
dihydroisoxazoline formation through the incorporation of molecular oxygen
present in air
sat. Na2S2O3 aq
1a
2a
Entry
Metal salt (mol%)
Solvent (M)
Time (h)
Yield (%)
O2 in air
Mn(acac)3 (0.2 mol%)
OH
R2
N
R2
N O
1
2
Mn(acac)3 (1)
Co(acac)3 (1)
Fe(acac)3 (1)
Ti(acac)3 (1)
MeOH (0.1)
MeOH (0.1)
MeOH (0.1)
MeOH (0.1)
MeOH (0.1)
MeOH (0.1)
MeOH (0.1)
EtOH (0.1)
C6H6 (0.1)
0.25
24
24
24
24
24
24
0.25
4
80
N.R.[b]
N.R.[b]
N.R.[b]
N.R.[b]
N.R.[b]
< 10
73
OH
R2
R1
R1
MeOH (0.5 M), rt
then
sat. Na2S2O3 aq
1a - 1t
2a - 2t
3
R2
N O
N O
OH
OH
4
MeO
5
MoO2(acac)2 (1)
Ni(acac)2 (1)
2a R2 = CH3 4 h, 81%
2b R2 = H
4 h, 93%
2c R2 = CH3 24 h, 80%
2d R2 = H
5 h, 82%
6
R2
R2
N O
N O
7
Cu(acac)2 (1)
Mn(acac)3 (1)
Mn(acac)3 (1)
Mn(acac)3 (1)
Mn(acac)3 (1)
Mn(acac)3 (0.5)
Mn(acac)3 (0.1)
Mn(acac)3 (0.2)
Mn(acac)3 (0.1)
Mn(acac)3 (0.1)
Mn(acac)3 (0.05)
OH
OH
8
NC
2e R2 = CH3 24 h, 88%
2f R2 = H
5 h, 80%
2g R2 = CH3 24 h, 82%
9
34
2h R2 = H
4 h, 81%
10
11
12
13
14
15
16[c]
17
CH2Cl2 (0.1)
CH3CN (0.1)
MeOH (0.1)
MeOH (0.1)
MeOH (0.5)
MeOH (2.0)
MeOH (2.0)
MeOH (4.0)
24
2
33
R2
N O
R2
N O
OH
42
OH
S
0.25
24
4
73
2k R2 = CH3 6 h, 89%
2i R2 = CH3 28 h, 71%
2l R2 = H
2 h, 92%
2j R2 = H
48 h, 82%
Trace
81
R2
N O
R2
N O
OH
OH
O
24
24
72
87
2m R2 = CH3 48 h, 44%
2o R2 = CH3 24 h, 82%
2p R2 = H
28 h, 82%
2n R2 = H
48 h, 59%
(Recovered 1n: 13%)
81
61
R2
N O
R2
N O
OH
[a] Reaction conditions: 1a (0.300 mmol), metal salt (0.05 – 1 mol%), O2
(flask open to air), rt. [b] N.R. = no reaction. [c] The reaction was carried out
using 1a (1.00 g, 5.71 mmol).
OH
TBSO
2s R2 = CH3 6 h, 60%
2q R2 = CH3 2 h, 88%
2r R2 = H 24 h, 74%
R2
N O
With the optimal reaction conditions, we explored the scope
of this manganese-promoted reaction to various unsaturated
oximes (Table 2). Considering the solubility of each solid oxime,
the reaction was carried out in 0.5 M MeOH solution using 0.2
mol% of Mn(acac)3. Generally, the reactions of oximes with 1,1-
disubstituted and monosubstituted alkenes proceed effectively to
afford the oxygenated products 2a and 2b in 81% and 93% yield,
respectively. The oximes bearing electron-donating (p-OMe) or
electron-withdrawing (p-CN) substituents on the aryl ring
furnished the desired 4,5-dihydroisoxazoline (2c–2f) in high yield.
Additionally, more hindered substrates, - and -naphthyl
oximes, also reacted with molecular oxygen in air at room
temperature to afford the corresponding products (2g–2j) in
71%–82% yield. Heteroaromatic substrates such as the 2-thienyl
oximes 1k and 1l were suitable for the oxidative cyclisation. On
the other hand, the oxidative cyclisation of 2-furanyl oximes 1m
and 1n proceeded in good to moderate yield. Alkyl-substituted
BocHN
OH
2t R2 = CH3 8 h, 75%
Subsequently, to assess the potential for diastereocontrol in
the aerobic cyclisation process, we examined a number of
different substrates (Table 3). The oxime 1u with the
cyclopentenyl group and 1v with the cyclohexenyl group
afforded cis-fused products as a 2:1 diastereomeric mixture
(entries 1 and 2).[20] The ,-unsaturated substrate 1w was also
viable for the aerobic cyclisation. The addition of molecular
oxygen exclusively occurred from the opposite direction of the
phenyl group via a 5-endo-trig cyclisation to afford a single
diastereomer 2w in 57% yield.
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European Journal of Organic Chemistry
10.1002/ejoc.201600998
COMMUNICATION
alcohols. All manipulations in this reaction could be carried out in
air without cooling, heating or high pressure conditions. Notably,
a very low loading of Mn(acac)3 promoted the oxidative
cyclisation through the direct incorporation of molecular oxygen
from air (pure oxygen is not required) without any other additives.
In addition of the conventional 4,5-dihydroisoxazolines synthesis
by nitrile oxide cycloaddition,[14] this highly efficient manganese-
promoted oxidative cyclisation reaction utilizing molecular
oxygen in air as a sole oxidant provides another approach to
produce 4,5-dihydroisoxazolines in terms of the desirable
features such as simple operation, a wide substrate scope,
functional tolerance, and mild and environmentally benign
conditions. Further mechanistic investigations of the
manganese-promoted unactivated alkene difunctionalisation
reactions incorporating molecular oxygen and development of
an asymmetric version is currently ongoing in our laboratory.
Table 3. Manganese-promoted diastereoselective oxidative cyclisation of
unsaturated oximes through the incorporation of molecular oxygen from air
Entry
1[a]
Oxime
Products
OH
N
N O
N O
OH
OH
OH
Ph
Ph
Ph
Ph
Ph
Ph
a -2u 51%
b-2u 25%
1u
OH
N
N O
N O
OH
2[a]
a -2v 54%
b-2v 26%
1v
N O
OH
Experimental Section
N
Ph
Ph
3[b]
Ph
Ph
OH
2w 57% (single diastereomer)
Gram-scale synthesis of 4,5-dihydroisoxazoline alcohol 2a using
manganese-promoted oxidative cyclisation
1w
[a] Mn(acac)3 (0.2 mol%), O2 (flask open to air), MeOH (0.5 M), rt, 2 h. [b]
Mn(acac)3 (0.5 mol%), O2 (flask open to air), MeOH (1.0 M), rt, 24 h.
To a stirred solution of ,-unsaturated oxime 1a (1.00 g, 5.71
mmol) in MeOH (2.9 mL) at room temperature was added
Mn(acac)3 (2.0 mg, 5.7 mol, 0.10 mol%) and the mixture was
stirred for 24 h at room temperature under air (open flask). The
reaction was quenched by addition of saturated aqueous
Na2S2O3 (3.0 mL) and the mixture was stirred for 30 min at room
temperature. The resulting mixture was extracted with EtOAc (3
x 3.0 mL). The combined organic layers were washed with brine
(1 x 3.0 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The obtained crude material was
purified by column chromatography (silica gel, hexane : ethyl
acetate = 2 : 1 to 1 : 1) to give 2a (889.0 mg, 4.65 mmol, 81%).
To demonstrate the utility of this manganese-promoted
aerobic cyclisation, we applied our method to the synthesis of
the hydroxamic acid 3, which is a promising antitrypanosomal
agent for the management of Chagas disease (Scheme 2).[13d]
The ,-unsaturated oxime 4 was treated with 0.2 mol%
Mn(acac)3 in MeOH (0.5 M) in air to afford 4,5-dihydroisoxazline
alcohol 5 in 76% yield. The transformation to the methyl ester 6
was attained in 78% yield by oxidation with sodium
hypochlorite–sodium chlorite in the presence of TEMPO[21]
followed by esterification with trimethylsilyl diazomethane.
Finally, the desired hydroxamic acid 3 was obtained in 54% yield
by a reaction with hydroxyl amine.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
JP15K18837 to D.Y. and a Kitasato University Research Grant
for Young Researchers. We thank Dr K. Nagai and Ms M. Sato
of Kitasato University for instrumental analyses.
OH
O2 in air
Mn(acac)3 (0.2 mol%)
N
N O
H
OH
MeOH (0.5 M)
rt, 3 h
then
BnO
Keywords: dihydroisoxazoline
•
manganese
•
aerobic
BnO
5
4
cyclisation • molecular oxygen • environmentally benign
sat. Na2S2O3 aq
76%
1. TEMPO, NaClO2
NaOCl2, CH3CN
phsphate buffer
35 ˚C, 24 h
[1]
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rt, 1 h
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O
6
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H
O
NHOH
BnO
3
Scheme 2. Synthesis of the antitrypanosomal agent 3
In conclusion, we have developed a manganese-promoted
oxidative cyclisation reaction to provide 4,5-dihydroisoxazoline
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European Journal of Organic Chemistry
10.1002/ejoc.201600998
COMMUNICATION
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European Journal of Organic Chemistry
10.1002/ejoc.201600998
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
OH
R3
O
Daisuke Yamamoto, Takuto Oguro,
N
N
R3
O2 in air
OH
R1
R5
Yuuki Tashiro, Masayuki Soga, Kazuhito
Miyashita, Yoshiaki Aso, Kazuishi
Makino*
R1
Mn(acac)3
(0.05 – 1 mol%)
then reductive work-up
R5
R2 R4
R2 R4
flask open to air
at room temperature
Page No. – Page No.
Manganese-promoted oxidative
cyclisation of unsaturated oximes
using molecular oxygen in air under
ambient conditions
A very low loading of Mn(acac)3 promoted the oxidative cyclisation of ,-
unsaturated oximes through the direct incorporation of molecular oxygen present in
air (open flask) at room temperature.
This article is protected by copyright. All rights reserved