An Efficient One–pot Procedure for the Direct Preparation of 4,5-Dihydroisoxazoles from Amides

Article abstract of DOI:10.1002/adsc.201700154

A Mo(CO)₆ (molybdenumhexacarbonyl) catalyzed reductive functionalization of amides to afford 5-amino substituted 4,5-dihydroisoxazoles is presented. The reduction of amides generates reactive enamines, which upon the addition of hydroximinoyl chlorides and base undergoes a 1,3-dipolar cycloaddition reaction that gives access to the desired heterocyclic compounds. The transformation of amides is highly chemoselective and tolerates functional groups such as nitro, nitriles, esters, and ketones. Furthermore, a versatile scope of 4,5-dihydroisoxazoles derived from a variety of hydroximinoyl chlorides and amides is demonstrated. (Figure presented.).

Full text of DOI:10.1002/adsc.201700154

Title: An Efficient One-pot Procedure for the Direct Preparation of 4,5-
Dihydroisoxazoles from Amides
Authors: Tove Slagbrand, Gabriella Kervefors, Fredrik Tinnis, and
Hans Adolfsson
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10.1002/adsc.201700154
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Efficient One-pot Procedure for the Direct Preparation of
4,5-Dihydroisoxazoles from Amides
Tove Slagbrand,[a] Gabriella Kervefors,[a] Fredrik Tinnis*[a] and Hans Adolfsson[a,b]*
a
Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden. +46(0)8-162486, fredrik.tinnis@su.se
Department of Chemistry, Umeå University, Umeå University, SE-901 87 Umeå, Sweden, +46 (0)90-786 53 30,
b
hans.adolfsson@umu.se
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
extensive during the last decade and the
catalyzed reductive functionalization of amides to afford 5- transformation of amides into amines, aldehydes,
Abstract.
A
Mo(CO)6 (molybdenumhexacarbonyl)
amino substituted 4,5-dihydroisoxazoles is presented. The
reduction of amides generates reactive enamines, which
upon the addition of hydroximinoyl chlorides and base
undergoes a 1,3-dipolar cycloaddition reaction that gives
access to the desired heterocyclic compounds. The
transformation of amides is highly chemoselective and
tolerates functional groups such as nitro, nitriles, esters, and
imines and enamines can today be performed in the
presence of other reducible functional groups such as
esters, ketones, aldehydes and imines.[5],[11]
Consequently, reductive functionalization of amides
has recently emerged as a new field in organic
chemistry. The strategy is based on the possibility of
trapping the intermediate (iminum ion) formed during
the amide reduction and has been used for
nucleophilic addition to tertiary, secondary and N-
methoxy amides and for the preparation of
nitrones.[12] The amide functionalization methods
described above are based on the induced
amplification of the amide electrophilicity. However,
there are also mild and chemoselective protocols for
the transformation of amides into nucleophilic species,
namely enamines.[12e],[13] This type of reductive amide
functionalization was recently exploited at late stages
in the total synthesis of alkaloids,[14] (+)-neostenine[15]
and turkiyenine.[16]
ketones. Furthermore,
a
versatile scope of 4,5-
dihydroisoxazoles derived from a variety of hydroximinoyl
chlorides and amides is demonstrated.
Keywords: 4,5-dihydroisoxazole; Amides; Reductive
functionalization; Chemoselectivity; Enamines
The amide group is an essential functionality in nature
that constitutes the backbone of proteins and enzymes.
The synthetic utility of amides can be realized by the
frequent occurrence of this substrate class in
pharmaceuticals, agrochemicals and different organic
materials.[1] Whereas significant effort has been put
into the development of methods for the preparation
of amides,[2] the use of this functional group as
synthetic intermediate is less explored. The inherent
stability can nevertheless be of great value to the
synthetic chemist and due to several recent
discoveries the concept of mild activation and
functionalization of amides is expanding.[3]
Triflic anhydride (Tf2O) is a mild activation agent
that upon treatment of amides generates the highly
electrophilic species iminium triflate.[4] The activation
system based on a combination of Tf2O and halogen
substituted pyridines is particularly efficient and have
been exploited for a variety of transformations such as
chemoselective reduction of amides into amines,
imines and aldehydes,[5] chemoselective α-
arylation[6]/α-amination[7] of amides and for the
conversion of amides into ketones, aldehydes or
ketimines.[8] Among a variety of other applications[9]
this type of amide activation strategy has also been
employed in total synthesis.[10]
We have previously reported on
a highly
chemoselective Mo-catalyzed protocol for the
reduction of amides to yield either amines or
aldehydes.[11a] The Mo(CO)6-catalyzed system was
further investigated and it was found that amides also
can be transformed into reactive enamine
intermediates, which we used for the synthesis of
triazolines and triazoles.[13] Herein, we report a Mo-
catalyzed reductive functionalization of amides into
4,5-dihydroisoxazoles (2-isoxazolines).[17]
4,5-dihydroisoxazoles are frequently employed as
intermediates for the preparation of a wide variety of
important compounds such as β-amino ketones, β-
hydroxyketones, β-amino alcohols, β-amino acids,
oxazolines, pyrroles, acylaziridines,[18] and several
4,5-dihydroisoxazoles are also known to exhibit
biological activity.[19] The 1,3-dipolar cycloaddition
of nitrile oxides and olefins is the most common
approach to prepare these types of heterocyclic
compounds.[18a],[20] There are three main routes for the
in situ preparation of nitrile oxides; oxidative
dehydrogenation of aldoximes, dehydration of
primary nitro compounds and base promoted
The development of protocols for mild and
chemoselective reduction of amides have been
1
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10.1002/adsc.201700154
Advanced Synthesis & Catalysis
dehydrodehalogenation of hydroximinoyl halides with benzonitrile- and mesitonitrile oxide that
(Scheme 1, A-C). The approaches for nitrile oxide provided 2-isoxazolines in poor to good yields after a
preparation have all been employed in combination reaction time of two months.[24] Enamines are reactive
with olefins for the one-pot synthesis of 2- species that easily hydrolyze and can be difficult to
isoxazolines (Scheme 1.1).[21]
isolate in high yields. There are a few examples of
Although enamines have been employed in various 1,3-cycoaddition reaction where both nitrile oxides
1,3-dipolar cycloaddition reactions there are not many and enamines are generated in situ. Wang and Du
reports on the reaction of enamines and nitrile oxides recently reported on a protocol for the preparation of
for the preparation of 5-amino-4,5-dihydroisoxazoles.
a
variety
of
5-amino
substituted
4,5-
In 1964, Kuehne and co-workers reported on dihydroisoxazoles in which the enamines were
enamines as 1,3-dipolarophiles in the reaction with prepared in situ by treating aldehydes with amines
benzhydroxamoyl chlorides that afforded the amino (Scheme 1.3).[25] The reactions were performed under
substituted heterocycle (Scheme 1.2).[22] Similar mild conditions with short reactions times; however, a
protocols have later been published by Sasaki and large excess of aldehydes and amines were required.
Yoshioka and the group of Trimarco,[23] however, in The nitrile oxide 1,3-cycloaddition reaction with in
these protocols, the enamines were synthesized prior situ generated enamine from phenylacetone was also
to use which limits the overall yields.
applied in the synthesis of valdecoxib, a nonsteroidal
anti-inflammatory drug.[26]
The chemoselective Mo-catalyzed reduction of
amides into enamines is hereby demonstrated to be
suitable for the one-pot direct preparation of a large
variety of 3,4,5-trisubstituted-4,5-dihydroisoxazoles
(Scheme 1.4). Moreover, 3,4-disubstituted isoxazoles
are shown to be accessible from the obtained 4,5-
dihydroisoxazoles through base promoted elimination
of the amine moiety (vide infra).[27]
Initially, we performed an evaluation with amide
1a in order to form 3,4,5-trisubstituted-4,5-
dihydroisoxazole 4a. Amide 1a was reduced into the
corresponding enamine 2a using 2 mol% Mo(CO)6 in
combination
with
1,1,3,3-tetramethyldisiloxane
(TMDS, 1.5 equiv). 2a was then treated with 1.5
equivalents of hydroximinoyl chloride 3a in a one-pot
procedure. Some hydroxyimioyl chlorides are
commercially available; however, these compounds
can easily be prepared from the corresponding
aldehydes (see Supporting Information).
Table 1. Optimiaztion of the reaction conditions for
4,5-dihydroisoxazole formation.a)
Entry 3a
(equiv)
1.5
Temp.
(°C)
Additive
(equiv)
4a
(%)b)
1
2
3
4
5
6
7
r.t
65
r.t
r.t
r.t
r.t
r.t
r.t
-
-
-
-
1.5
1.5
1.5
1.5
1.5
1.1
1.5
NaOH (1.5)
Na2CO3 (1.5)
Et3N (1.5)
Et3N (1.1)
Et3N (1.5)
Et3N (1.25)
74
48
>95
89
76
93
Scheme 1. A-C; In situ preparation of nitrile oxide. 4,5-
dihydroisoxazoles synthesis from 1) alkenes 2) enamines 3)
enamines prepared in situ 4) This work; reductive
functionalization of amides into 4,5-dihydroisoxazoles (2-
isoxazoline).
8
a)
Hydroximinoyl chloride 3a was added after the catalytic
reduction of amide 1a into enamine 2a was complete.b)
Determined by 1H NMR spectroscopy using 1,3,5-
trimethoxy benzene as internal standard.
Furthermore, Caramella and Albini evaluated a
variety of indoles in the 1,3-cycloaddition reaction
2
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10.1002/adsc.201700154
Advanced Synthesis & Catalysis
The first attempts employing 3a failed to give the enamine was readily formed in the reduction after 3 h
1
desired product (Table 1, Entries 1-2). Sasaki and at 65 °C (88% H NMR yield). Unfortunately, a
Yoshioka did not report any use of base in their mixture of products was observed in the reaction with
protocol for the preparation of 4,5-dihydroisoxazole, nitrile oxide which most likely is related to the allyl
although, in this case the enamine was used in groups reactivity towards 1,3-cycloaddition.
excess.[23a] Wang, Du and co-workers employed Et3N
There are only a handful of protocols available for
in their protocol,[25] most likely to promote the in situ the reduction of amides into enamines[11e],[28] and we
dehydrodehalogenation of the hydroximinoyl chloride have recently showed that the Mo(CO)6-catalyzed
into nitrile oxide. Thus, we investigated the addition protocol is highly chemoselective.13 Enamines
of base and found that 4,5-dihydroisoxazole indeed containing nitro, cyano, ester and even ketone
was formed in the presence of NaOH, Na2CO3 and functionalities were readily formed under our
Et3N (Table 1, Entries 3-5). The use of triethylamine conditions, ultimately giving access to 4,5-
gave the best result and a >95% yield of 4a was dihydroisoxazoles substituted with these functional
1
observed as determined by H NMR spectroscopy. groups in good to high yields (Figure 2, 4o-4r).
Further optimization showed that 1.5 equivalents of
A selection of different hydroximinoyl chlorides
hydroximinoyl chloride and base were required to were then evaluated (Figure 2). In the above substrate
reach full conversion into 4a (Table 1, Entries 6-8). screening (Figure 1) the p-methoxy substituted
With the o conditions at hand we performed a hydroximinoyl chloride 3a was used; however,
substrate evaluation. The Mo(CO)6-catalyzed amide employing the corresponding p-nitro substituted
reduction generates the enamines in high yields, as compound gave 4,5-dihydroisoxazole 4s in a slightly
1
determined by H NMR, and they readily react with better yield (89%, compare compounds 4a and 4s).
nitrile oxide at ambient temperature to form the
desired 5-amino-4,5-dihydroisoxazoles. Initially we
screened amides with a variation of the amine part
and
4,5-dihydroisoxazoles
substituted
with
pyrrolidine, piperidine, sterically hindered 2,6-
dimethyl piperidine, morpholine, N,N-dimethyl, N,N-
dibutyl, N-methyl-N-phenyl, N,N-dibenzyl, and
indoline were obtained in good to high isolated yields
(Figure 1, 4a-4i).
Figure 1. Scope of 4,5-dihydroisoxazoles formed from
amides derived from different amines.
Next, we investigated a variety of amides derived
from different acids (Figure 2) and p-bromo or p-iodo
substituted amides did not undergo dehalogenation
during the amide reduction. The corresponding 4,5-
dihydroisoxazoles 4j and 4k were obtained in 93%
and 80% yields, respectively. Bis p-methoxy 4,5-
dihydroisoxazole 4l and thiophene substituted product
4m were isolated in 91% and 80% yields, respectively.
The reduction of aliphatic amide 1n was not selective
and a mixture of amine and enamine was observed.
Thus, only a moderate yield of compound 4n could be
obtained. We also evaluated a N,N-diallyl substituted
amide (N,N-diallyl-2-phenylacetamide) and the
Figure 2. Evaluation of the chemoselectivity and scope of
hydroximinoyl chlorides.
Thus, the electronic effect of the hydroxyiminoyl
chloride seems to have small influence on the
outcome of the reaction and compounds 4t-4v were
obtained in similar yields. Styryl substituted 4,5-
dihydroisoxazole 4w was isolated in 80% yield and
aliphatic hydroximinoyl chlorides also underwent 1,3-
dipolar cycloaddition to give access to compounds 4x
3
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10.1002/adsc.201700154
Advanced Synthesis & Catalysis
and 4y in good yields. The 1,3-dipolar cycloaddition catalytic hydrosilylation of the amides proceeds with
of olefins and nitrile oxides can give rise to two high chemoselectivity and functional groups such as
regioisomers (Scheme 2a, 5 and 6).[18a] Wang, Du and nitro, nitrile, ester and ketones were tolerated. The
co-workers reported that only one of the possible reported one-pot reductive amide functionalization is
regioisomers, namely 5-amino-4,5-dihydroisoxazole, a facile strategy to access a wide variety of 5-amino-
was formed in their reactions with the in situ prepared 4,5-dihydroisoxazoles.
enamine from aldehyde and amine. This result is also
in line with a computational study that showed that
olefins with electron donating substituents such as
Experimental Section
vinyl amine give rise to isomer 5 in the cycloaddition
reaction with nitrile oxide.[29] We did not observe any
Amide (1.0 mmol, 1.0 equiv) and Mo(CO)6 (0.0054 g, 0.02
mmol, 2 mol%) were added to an oven dried 10 mL vial
mixtures of isomers during the scope evaluation;
that was capped and the atmosphere was exchanged to N2.
Dried ethyl acetate (0.50 mL) was added and the reaction
nevertheless, we attempted to determine which
regioisomer that was formed using 1D NOE mixture was heated at 80 °C for 10 min in order to activate
the catalyst. The vial was flushed with N2 and then heated
experiments. Unfortunately, this investigation failed
to 65 °C followed by the addition of TMDS (0.26 mL, 1.5
mmol, 1.5 equiv). The reaction was stirred until full
1
to give any conclusive results. The H NMR shifts of
the protons on the ring should differ between the two
possible isomers (5 and 6) but we could not find any
spectroscopic data of 4-amino-4,5-dihydroisoxazoles
in the literature.
conversion into the corresponding enamine was obtained
(see Supporting Information). Et3N (0.21 mL, 1.5 mmol,
1.5 equiv) and hydroximinoyl chloride 3 (1.5 mmol, 1.5
equiv) dissolved in dried ethyl acetate (1.25 M) was added.
The reaction was then stirred at r.t. for 1 h and the crude
was purified by flash column chromatography.
Acknowledgements
The authors acknowledge the K. & A. Wallenberg Foundation
and the Swedish Research Council for financial support. The
reviewers are acknowledged for valuable comments that
ultimately improved the manuscript.
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Advanced Synthesis & Catalysis
UPDATE
An Efficient One-pot Procedure for the Direct
Preparation of 4,5-Dihydroisoxazoles from Amides
Adv. Synth. Catal. Year, Volume, Page – Page
Tove Slagbrand, Gabriella Kervefors, Fredrik
Tinnis* and Hans Adolfsson*
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