An improved procedure to prepare 3-methyl-4-nitroalkylenethylisoxazoles and their reaction under catalytic enantioselective Michael addition with nitromethane

Article abstract of DOI:10.1039/c4ob02109f

Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding γ-nitroacids. This journal is

Full text of DOI:10.1039/c4ob02109f

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An improved procedure to prepare 3-methyl-
4-nitroalkylenethylisoxazoles and their reaction
under catalytic enantioselective Michael addition
with nitromethane†
Cite this: DOI: 10.1039/c4ob02109f
Maria Moccia,* Robert J. Wells and Mauro. F. A. Adamo*
Received 3rd October 2014,
Accepted 2nd December 2014
Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as
Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to
provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding
γ-nitroacids.
DOI: 10.1039/c4ob02109f
www.rsc.org/obc
Introduction
The isoxazole nucleus is an important pharmacophore in
medicinal chemistry, due to its isosterism with an ester.1 In
addition isoxazoles could be employed as precursors to
notable organic compounds such as 1,3-dicarbonyls,2 hydroxy-
ketones,3 azirines,4 enamines and β-hydroxynitriles.5 In the
recent past, we have developed several synthetic routes starting
from aromatic styrylisoxazoles 2 (Scheme 1).6–11 In compounds 2,
the 4-nitroisoxazole core activates the exocyclic alkene to react
with soft nucleophiles. The 4-nitroisoxazole could be converted
to a carboxylate via basic,12 oxidative13 and acidic14 procedures
which justified the definition of compounds 2 as a synthetic
equivalent to cinnamates 1.
Scheme 2 Condensation of 3 and aliphatic aldehydes in [bmIm]-OH.
reported a highly enantioselective thiolate addition to com-
pounds 2 catalysed by bifunctional organocatalysts;14 Rui
Wang reported a highly enantioselective addition of unsatu-
rated lactams to 2 catalysed by quinine-based thioureas.16
The preparation of aromatic compounds 2 proceeded via
condensation of commercially available 3,5-dimethyl-4-nitro-
isoxazole 3 and aromatic or heteroaromatic aldehydes 4.17
However, the same procedure failed when aliphatic alde-
hydes were employed.6,18 Considering the growing interest in
reagents 2, we have recently reported a method to prepare ali-
phatic 5-ethenyl-4-nitroisoxazoles.18 The synthesis involved
four steps and allowed obtaining compounds 7 (Scheme 2) in
high yields and exclusively as E stereoisomers.18
Following our reports, the synthetic relevance of com-
pounds 2 has been recognized by other groups: Shibata
reported the synthesis of trifluoromethylisoxazolines via
addition of CF3 nucleophiles to compounds 2;15 Yuan
−
Scheme 1 Retrosynthetic analysis of 3-methyl-4-nitro-5-styrilisoxa-
zoles 2.
Results and discussion
With the intention of streamlining the preparation of com-
pounds 7, we reconsidered the condensation of commercially
available 3 and aliphatic aldehydes 5a–i under a new set of
hitherto unexplored conditions. This study identified a two-
step procedure that allowed condensation of commercially
available 3,5-dimethyl-4-nitroisoxazole 3 and aliphatic alde-
hydes 5a–i to alkylethenylisoxazole 7a–i (Scheme 2). The
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical
and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen’s
Green, Dublin 2, Ireland. E-mail: madamo@rcsi.ie, mariamoccia@rcsi.ie;
Fax: (+353) 1 4022168
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, and spectra of new compounds. See DOI:
10.1039/c4ob02109f
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synthetic relevance of compounds 7a–i was then demonstrated of THF as a co-solvent to favor the formation of a homo-
by their reaction with nitromethane under phase transfer cata- geneous phase.
lysis (PTC).19 This reaction provided pharmaceutically relevant
Delightfully, under this set of optimized conditions, the
adducts 9a–i in high enantiomeric excesses (Table 4).
reaction of 3 and aldehydes 5a–i proceeded to completion and
During our studies on the preparation of compounds 7, alcohols 6a–i were obtained in high isolated yields (Table 1).
Reddy reported a fast preparation of 2 (yields of 85–92% in Compounds 6a–i were then treated with a small excess of
10–15 minutes) that occurred at room temperature. The new methane sulfonyl chloride (1.2 equiv.) and an excess of tri-
procedure involved the use of 1-butyl-3-methylimidazolium ethylamine (2 equiv.), providing the corresponding alkenes
hydroxide [bmIm]-OH as the media.20 The fast rates described 7a–i in good to excellent yields (Table 2). Significantly, only the
by Reddy prompted us to react 3 and 5d (Scheme 2) in E-alkene was observed.
[bmIm]-OH.
This two steps procedure was run under a milder set of con-
Hence, equimolar amounts of 3,5-dimethyl-4-nitroisoxazole ditions (NaOH in H2O/MeOH) compared to those previously
3 and isovaleraldehyde 5d were taken in IL [bmIm]-OH and reported (LDA in THF)18 and expanded significantly the scope
the reaction mixture was stirred at room temperature for 1 h. of alkenes 7 that could be prepared. The reactivity of com-
This reaction provided 20% of compound 7d and 32% of pounds 7a–i was then tested in the Michael reaction with
alcohol 6d. Increase of temperature, reaction time or reactant nitromethane. We initially treated a solution of 7d in toluene
concentration did not prove useful and 7d was obtained in (0.1 M) with nitromethane (5 equiv.), solid K2CO3 (5 equiv.), a
yields not greater than 20–25%.
suitable combination of bases and solvents already reported
The unprecedented reaction of 3 and aliphatic 5d in IL by us,6 with a range of cinchonidine-derived phase transfer cata-
[bmIm]-OH was explained considering quantitative formation lysts (Table 3).
of deprotonated 3 which is very stable in a polar solvent. The
The use of catalysts 8 and 8.2 at room temperature provided
high concentration of deprotonated 3 was responsible for the compound 9d in 86% ee (Table 3, entries 1 and 5). The reac-
generation of compounds 6d and 7d. In order to prove this, we tion carried out at lower temperature (−30 °C) afforded 9d in a
have designed a new protocol in which compound 3 was first decreased enantiomeric excess (Table 3, entry 3). The use of
reacted with 1 equiv. of NaOH in a mixture of 9 : 1 of ethanol– commercially available catalyst 8.3 provided the desired
water and then the resulting metallated-3 quenched with iso- product 9d in a lower 74% at 0 °C (Table 3, entry 7). Similarly,
valeraldehyde 5d.
catalysts 8.4 and 8.5 gave 9d in reduced enantioselectivity
This new protocol provided about 50% of compounds 6d (Table 3, entries 8 and 9). Final optimisation involved the use
and 7d in 1 : 1 ratio, proving therefore that the amount of of 10 mol% of catalyst and diluting the reaction from 0.1 M to
ionized 3 was crucial to ensure progress of the desired aldol 0.03 M, which enhanced the ee. Hence, the optimised set of
reaction.
conditions required the use of 10 mol% of catalyst 8 at 0 °C,
Further improvements were logically achieved by (a) solid K2CO3 as the base, a concentration of reagents of 0.03 M
reduction of NaOH base to 0.2 equiv., to decrease aldehyde (Table 3, entry 4). Importantly, the use of pseudoenantiomeric
self-condensation; (b) replacement of ethanol with methanol catalysts allowed obtaining ent-9d in similarly high ee (Table 3,
to increase the amount of isoxazole 3 in solution; (c) addition entries 2 and 6).
The scope of the reaction was shown by reacting alkylethe-
nylisoxazoles 7a–i with nitromethane under the catalysis of 8
Table 1 Synthesis of hydroxyl isoxazoles
Table 2 Synthesis of alkenethyl isoxazolesa
Entrya
Ald.
R group
T [h]
Prod.
Yieldsb [%] Entry
R
Prod.
Yieldb [%]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH2CH3
36
36
36
36
48
48
48
60
60
6a
6b
6c
6d
6e
6f
6g
6h
6i
90
88
88
92
87
88
85
84
84
1
2
3
4
5
6
7
8
9
CH2CH3
7a
7b
7c
7d
7e
7f
7g
7h
7i
98
96
97
95
96
94
90
88
88
CH2CH2CH3
(CH2)3CH3
CH2CH(CH3)2
(CH2)4CH3
(CH2)5CH3
(CH2)6CH3
(CH2)7CH3
(CH2)8CH3
CH2CH2CH3
(CH2)3CH3
CH2CH(CH3)2
(CH2)4CH3
(CH2)5CH3
(CH2)6CH3
(CH2)7CH3
(CH2)8CH3
a Reaction conditions: 3,5-dimethyl-4-nitroisoxazole 3 (5 mmol), H2O/ a Reaction conditions: 6a–i (1 mmol), CH2Cl2 (7mL), MsCl (1.2 mmol),
MeOH/THF, NaOH (0.2 mmol), aldehydes 5a–i (6 mmol), 18 °C. Et3N (2 mmol), 0 °C then 18 °C. b Isolated yields after flash column
b Isolated yields after flash column chromatography.
chromatography.
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Table 3 Representative results of the screening of cinchonidine-
derived catalysts 8–8.5
Table 5 Synthesis of aliphatic γ-nitro acidsa
Entry
R
Prod.
Yieldb [%]
1
2
3
4
5
6
CH2CH3
10a
10c
10d
10e
10f
10i
92
90
94
88
87
87
(CH2)3CH3
CH2CH(CH3)2
(CH2)4CH3
(CH2)5CH3
(CH2)8CH3
a Reaction conditions: compounds 9 (0.25 mmol), THF (0.5 mL),
aqueous NaOH (1.25 mmol), reflux. b Isolated yields after flash column
chromatography.
Entrya
Cat.
Temp [°C]
T [h]
Conv.b [%]
eec [%]
1
2
3
4
5
6
7
8
9
8
8
8
8.1
8.2
8.2
8.3
8.4
8.5
RT
0
−30
0
RT
0
0
0
0
1.5
3
98
98
87
98
92
92
98
98
98
86
87(72)d
82
18
18
0.25
1.5
18
48
24
73
86
86(85)d
74
78
53
Scheme 3 Preparation of enantioenriched (S)-Pregabalin 11.
a Reaction conditions: alkenethylisoxazole 7d (0.1 mmol), toluene
(1.0 mL), cat. 8–8.5 (10 mol%), nitromethane (0.5 mmol), K2CO3
(0.5 mmol). b Conversion was determined by 1H NMR analysis. c The
enantiomeric excess (ee) of the product was determined by chiral
stationary phase HPLC. d In parentheses the ee of ent-9d obtained
using the pseudoenantiomeric catalysts 8 and 8.2.
c,d,e,f,i could be obtained in a preparative scale (Table 4)
without loss of yield or enantioselectivity. The absolute con-
figuration of compounds 9a–i obtained was determined to be
R by comparison of optical rotation and HPLC data of com-
pounds 10d and ent-10d with published data.21
The carboxylic acid functionality was then unveiled from
Michael adducts 9a,b,d,e,f,i (Table 5) which were efficiently
converted into the corresponding γ-nitro acids 10a,b,d,e,f,i in
high yields (87%–94%).
(Table 4). The results collected pointed out: (a) compounds
containing either short (7a,7b) or long chains (7h,7i) were
equally good substrates and the corresponding compounds
9a,b and 9h,i were obtained in good yields and in up to 93%
ee; (b) importantly, it was verified that at least compounds 9a,
This transformation required treatment with 1 M aqueous
NaOH in THF. The ee reflected the values of the starting
materials thus demonstrating the stereochemical stability of
compounds under the conditions adopted.6 The γ-nitroacids
obtained are important intermediates as precursors of
γ-amino acids.5,7,16 This has been demonstrated by reducing
γ-nitroacid ent-10d to enantioenriched (S)-Pregabalin 11
(Scheme 3), using a literature procedure.22
Table 4 Enantioselective addition of nitromethane to alkenethenyl-
isoxazoles 7a–i under the catalysis of 8
Entrya
R
Prod.
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
9
CH2CH3
9ad
9bd
9c
91
91
90
90
91
90
99
89
89
93
87
88
89
88
86
83
87
85
CH2CH2CH3
(CH2)3CH3
CH2CH(CH3)2
(CH2)4CH3
(CH2)5CH3
(CH2)6CH3
(CH2)7CH3
(CH2)8CH3
Conclusions
9dd
9ed
9fd
9g
In conclusion, we have developed a new short synthesis of
E-alkenylethyl isoxazoles, the aliphatic version of a popular
class of Michael acceptors. Similarly to their aromatic ana-
logues 2, compounds 7 reacted promptly under phase transfer
catalysis providing highly enantioenriched nitromethane
adducts. This study delivers to the scientific community a
novel enantioselective strategy for the synthesis of aliphatic
γ-nitroacids and confirms 4-nitro-5-alkethenylisoxazoles as a
useful synthon for organic synthesis.
9h
9id
a Reaction condition: styrylisoxazoles 7a–i (0.2 mmol), toluene
(6.7 mL), cat. 8 (0.02 mmol), CH3NO2 (1 mmol), K2CO3 (1 mmol).
b Isolated yields after flash column chromatography. c The
enantiomeric excess (ee) of the product was determined by chiral
stationary phase HPLC. d Reaction performed on a 5.0 mmol scale.
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12 M. F. A. Adamo, P. Sarti-Fantoni, S. Chimichi and
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