Synthesis of Isoxazolines from Nitroalkanes via a [4+1]-Annulation Strategy

Article abstract of DOI:10.1002/adsc.201901000

A novel access to isoxazolines was developed using the [4+1]-annulation of α-keto-stabilized sulfur ylides with N,N-bis(siloxy)enamines derived from aliphatic nitro compounds. The resulting 5-keto-substituted isoxazolines were shown to be convenient precursors of polysubstituted 3-hydroxypyrrolidines via the one-pot catalytic N?O hydrogenolysis/intramolecular reductive amination sequence. Application of this approach to the formal synthesis of Merck's potent NK₁ receptor antagonist was demonstrated. (Figure presented.).

Full text of DOI:10.1002/adsc.201901000

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DOI: 10.1002/adsc.201901000
Synthesis of Isoxazolines from Nitroalkanes via a [4+1]-
Annulation Strategy
Pavel Yu. Ushakov,a, b Elizaveta A. Khatuntseva,a Yulia V. Nelyubina,c
Andrey A. Tabolin,a Sema L. Ioffe,a and Alexey Yu. Sukhorukova, d, e,
*
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Leninsky prospect, 47, Moscow, Russian
Federation
Fax: +7 499 1355328
Tel: +7 499 1355329
E-mail: sukhorukov@ioc.ac.ru
b
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991, Leninskie gory, 1, str. 3, Moscow, Russian
Federation
A. N. Nesmeyanov Institute of Organoelement Compounds, 119991, Vavilov str. 28, Moscow, Russian Federation
D. Mendeleev University of Chemical Technology of Russia, 125047, Miusskaya sq., 9, Moscow, Russian Federation
Plekhanov Russian University of Economics, 117997, Stremyanny per. 36, Moscow, Russian Federation
c
d
e
Manuscript received: August 11, 2019; Revised manuscript received: October 2, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201901000
on a [4+1]-annulation reaction of N,N-bis(siloxy)-
Abstract: A novel access to isoxazolines was
enamines
2 (prepared by double silylation of
developed using the [4+1]-annulation of α-keto-
stabilized sulfur ylides with N,N-bis(siloxy)enam-
ines derived from aliphatic nitro compounds. The
resulting 5-keto-substituted isoxazolines were
shown to be convenient precursors of polysubsti-
tuted 3-hydroxypyrrolidines via the one-pot cata-
lytic NÀ O hydrogenolysis/intramolecular reductive
amination sequence. Application of this approach to
the formal synthesis of Merck’s potent NK1 receptor
antagonist was demonstrated.
nitroalkanes[7]) and α-keto-stabilized sulfur ylides 3
(Scheme 1).[8] Also, synthetic utility of the resulting
isoxazolines using a novel reductive recyclization to
valuable 3-hydroxypyrrolidines was demonstrated.
In our initial experiments, model N,N-bis(siloxy)-
enamine 2a (prepared by a double silylation of 2-
nitropropane) was reacted with an excess of acetophe-
none-derived sulfur ylide 3a (Table 1). In CH2Cl2,
slow conversion of starting material was observed, and
about 60% of the desired isoxazoline 1a was isolated
after 48 h at rt (entry 1, Table 1). Screening of solvents
revealed that MeCN was beneficial (entries 2–5 in
Table 1), the use of which under same conditions
resulted in 85% yield of product 1a (entry 5). Since
the conversion was slow at rt (entries 6–8 in Table 1),
°
Keywords: nitrogen heterocycles; ylides; annulation;
isoxazolines; enamines
Isoxazolines 1 are privileged heterocycles, which are reaction at higher temperature (50 C) was checked
highly useful both as intermediates in organic (entry 9, Table 1). Indeed, full consumption of starting
synthesis[1] and scaffolds for medicinal chemistry.[1c,2] material and 98% yield of isoxazoline 1a (based on
Among numerous synthetic strategies towards isoxazo- 2a) was achieved within 2 h. Finally, the effect of
lines methods based on [3+2]-cycloaddition reactions enamine 2a/ylide 3a ratio on the yield of isoxazoline
of nitroalkane-derived 1,3-dipoles (nitrile oxides[1f,g,i,3] 1a was studied (entries 9–12 in Table 1) showing that
and silyl nitronates[1i,3c,4]) to alkenes are probably the a 1.2-fold excess of ylide 3a was optimal for keeping
most commonly used ones (Scheme 1). These ap- high efficiency of the [4+1]-annulation reaction
proaches, however, have some drawbacks associated (entry 11).
with the instability of nitrile oxides[3a] and low hydro-
With these optimized conditions in hand, substrate
lytic stability of silyl nitronates,[4a] as well as regiose- scope studies were performed (Scheme 2). N,N-Bis-
lectivity issues[5] in Mukaiyama’s method.[6] Here, we (siloxy)enamines 2a–f derived from readily available
describe a conceptually different strategy towards the nitro compounds bearing alkyl, aryl and functionalized
assembly of isoxazoline ring from nitroalkanes based alkyl groups successfully entered the [4+1]-process
Adv. Synth. Catal. 2019, 361, 1–7
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Scheme 1. Conventional and proposed approaches to isoxazo-
lines 1 from aliphatic nitro compounds.
Table 1. Reaction of N,N-bis(siloxy)enamine 2a with ylide 3a:
an optimization study.
°
Entry ratio 2a:3a solvent T, C time, h Yield, %
1
1:1.5
1:2
CH2Cl2 rt
48
48
48
48
48
2
60[a]
47[b]
60[b]
59[b]
85[b]
31[b]
53[b]
84[b]
98[b]
98[b]
90[a]
68[b]
2
THF
rt
3
1:2
DMF
rt
4
5
6
7
8
9
10
11
12
1:2
1:1.5
1:2
1:2
1:2
PhMe
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
rt
rt
rt
rt
rt
50
50
6
24
2
2
2
1:2
Scheme 2. Synthesis of racemic isoxazolines 1a–s by [4+1]-
annulation of N,N-bis(oxy)enamines 2 and sulfur ylides 3:
substrate scope study.
1:1.3
1:1.2
1:1
MeCN 50
MeCN
50
2
[a] Isolated yield.
1
[b] Yield determined by H NMR with internal standard
ring fragmentation to β-hydroxy nitriles[9a] during
column chromatography (see Supporting information).
It is noteworthy, that isoxazolines of this type cannot
(CHCl=CCl2).
with ylide 3a producing corresponding racemic iso- be prepared by Mukaiyama method because of the
xazolines 1a–f in good to high yields. The reaction high instability of hydrogen cyanide N-oxide.
could be scaled up to 10 mmol without a significant
Enamine 2g with an internal double bond afforded
decrease of the yield as demonstrated by the synthesis a mixture of diastereomeric isoxazolines 1g/1g’ in
of isoxazoline 1b on a gram scale. Generally, some- 5.5:1 ratio in favor of the trans-isomer (Scheme 2). In
what lower yields were observed for isoxazolines a similar fashion, 3,4,5-trisubstituted isoxazolines 1h/
possessing hydrogen or aryl groups at the C-3 atom. In 1h’ were prepared in 5:1 ratio. Moderate yield in this
the case of 3-unsubstituted isoxazolines (e.g. 1b, 1g) case might be attributed to a low thermal stability of
reduction of the yield can be explained by the partial trisubstituted enamines of type 2h.[7]
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In the reaction with the model enamine 2a, α-keto- ine 2a[7c] is faster than the [4+1] reaction under these
stabilized ylides 3 with various substituents in the aryl conditions. Decrease of the temperature did not result
ring delivered corresponding isoxazolines 1i–s in in any improvement of the yield of isoxazoline 1n
moderate to good yields (Scheme 2). However, ylides (Scheme 2). 2-Furyl- and 2-thienyl-groups in ylides 3
3 bearing highly electronwithdrawing trifluoromethyl were tolerated in the [4+1] reaction with N,N-bis
and nitro groups produced isoxazolines 1n,o in poor (siloxy)enamine 2a (products 1r and 1s in Scheme 2).
yields. It is likely, that these ylides are less reactive, However, product 1r with furyl group was obtained
and therefore, decomposition of N,N-bis(siloxy)enam- only in moderate yield.
The synthesis of a fused isoxazoline 1t was also
attempted starting from a cyclic N,N-bis(siloxy)enam-
ine 2i derived from nitrocyclopentane (Scheme 3). In
this experiment, in addition to the desired stereo-
isomeric products 1t/1t’, an acyclic diketonitrile 4 was
obtained. The latter arises from an interesting base-
promoted fragmentation of isoxazoline ring.[9b,c]
A plausible mechanism of the developed [4+1]-
annulation reaction is depicted in Scheme 4.
Due to the presence of a weak NÀ O bond, N,N-
bis(siloxy)enamines exhibit umpolung reactivity at the
β-carbon atom as compared to normal enamines.[10]
Hence, the nucleophilic addition of the ylide to the β-
position of enamine 2 can take place leading to the
anion A, which cyclizes to isoxazoline 1 with the loss
Scheme 3. Synthesis and fragmentation of bicyclic isoxazolines of Me2S. Alternatively, decomposition of enamine 2 to
form elusive nitrosoalkene intermediate B[10a,d] and
1t/1t’.
subsequent Michael reaction with ylide 3 can also lead
to anion A. Interestingly, in reactions with ylides
bearing electron-rich aryl group (R2 =4-MeOC6H4 and
2-thienyl), the formation of enol ethers 5 as side-
products was observed. The latter likely originate from
the [2,3]-rearrangement[11] of intermediate C formed by
a reversible deprotonation of the methyl group A
(Scheme 4).
2-Keto-substituted isoxazolines 1 accessible using
our strategy can be viewed as useful precursors of
nitrogen-containing heterocycles. Thus, we discovered
that upon the catalytic hydrogenation over Raney
nickel isoxazolines 1 undergo recyclization to racemic
polysubstituted pyrrolidines 6 (Scheme 5). This trans-
formation involves reductive cleavage of the isoxazo-
line ring followed by the intramolecular reductive
amination reaction. Exceptional 2,3-cis-stereoselectiv-
ity was observed in the formation of C-2 stereocenter
in all examples. The stereogenic center at C-5 was
formed with less stereoselectivity (d.r. up to 3:1), yet
the diastereomers were separable by column chroma-
tography. The use of other hydrogenation catalysts
such as PdÀ C and PtO2 did not result in any improve-
ment of the stereoselectivity or yield of target
pyrrolidines.
The stereochemistry of pyrrolidines 6 was con-
firmed by 2D NOESY, as well as by the single-crystal
X-Ray diffraction analysis of product 6g (Scheme 5).
The 2-aryl-3-oxy-substituted pyrrolidine motif is
Scheme 4. Plausible mechanism for the formation of isoxazo-
common in numerous pharmaceutically relevant com-
pounds and natural products, including NK1 receptor
À
lines 1. 5j, R=Me, R1 =H, R2 =4-MeOC6H4 ; 5s, R=Me,
R1 =H, R2 =2-thienyl.
antagonists,[12]
hRIP1
inhibitors,[13]
CFTR
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Furthermore, pyrrolidine 6b was successfully trans-
formed into a potent NK1 receptor antagonist 10[12a]
(analogue of L-733,060[17]) by benzylation with mesy-
late 8 and subsequent deprotection of Boc-group in the
intermediate 9 (Scheme 7). Thus, racemic synthesis of
target compound 10 was accomplished in only 5 steps
from nitroethane. Previous synthesis of 10 from N-
Boc-phenylglycine reported by Merck consisted of 7
steps and was not stereoselective.[12a]
In conclusion, we developed a novel strategy for
the assembly of isoxazolines from aliphatic nitro
compounds, which is alternative to well-established
[3+2] cycloadditions with nitrile oxides (Mukaiya-
ma’s reaction) or silyl nitronates. The suggested
sequence involves double silylation of the nitro
compound followed by the [4+1]-annulation of the
resulting N,N-bis(siloxy)enamine with α-keto-stabi-
lized sulfur ylide. Synthetic utility of the resulting 5-
keto-substituted isoxazolines was demonstrated by
their reductive recyclization into valuable 3-hydrox-
ypyrrolidines bearing up to three contiguous stereo-
genic centers.
Experimental Section
General procedure for the synthesis of isoxazolines 1: a stock
1 M solution of N,N-bis(siloxy)enamine 2 in CH2Cl2 (1 mL,
1 mmol, 1 equiv.) was placed in Schlenk tube and solvent was
evaporated in vacuum. To the residue, a solution of sulfonium
ylide 3 (1.2 mmol, 1.2 equiv.) in MeCN (2 mL) was added at rt
under argon atmosphere and the mixture was stirred for 2 h at
Scheme 5. Reductive recyclization of 2-keto-substituted isoxa-
zolines 1 to 3-hydroxy-substituted pyrrolidines 6.
°
50 C. Then the mixture was concentrated under reduced
pressure. The crude product was purified by flash column
modulators,[14]
analogues
of
natural
1,4-
iminocyclitols[15] and aza-C-nucleosides.[16] Pyrrolidine
7, which is structurally related to fucosidase inhibitors
from Codonopsinine family,[15] was prepared in diaster-
eomerically pure form by deprotection of the Boc-
derivative 6a (Scheme 6).
Scheme 7. Synthesis of NK1 receptor antagonist rac-10 from
Boc-pyrrolidine 6b.
Scheme 6. Deprotection of pyrrolidine 6a.
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chromatography to give pure isoxazoline 1. All products were
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General procedure for the reduction of isoxazolines 1to
pyrrolidines 6: Raney nickel (ca. 50 mg, aqueous slurry
washed with methanol) was added to a solution of isoxazoline 1
(1 equiv.) and Boc2O (3 equiv.) in methanol (3 mL). The vial
(equipped with a magnetic stirring bar) was placed in a steel
autoclave, which was then flushed and filled with H2 to a
pressure of 10 bar. After stirring the mixture for 3 h at rt, the
autoclave was slowly depressurized. The solution was filtered
and concentrated in vacuum. The residue was subjected to a
column chromatography on silica gel to give pure Boc-
pyrrolidine 6. All products were racemates.
CCDC-1942275 contains the supplementary crystallographic
data for 6g. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Acknowledgements
This work was supported by Russian Foundation for Basic
Research (grant 17-03-01079). X-ray diffraction data were
collected with the financial support from Ministry of Science
and Higher Education of the Russian Federation using the
equipment of Center for molecular composition studies of
INEOS RAS.
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COMMUNICATIONS
Synthesis of Isoxazolines from Nitroalkanes via a [4+1]-An-
nulation Strategy
Adv. Synth. Catal. 2019, 361, 1–7
P. Y. Ushakov, E. A. Khatuntseva, Y. V. Nelyubina, A. A.
Tabolin, S. L. Ioffe, A. Y. Sukhorukov*