Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro5-styrylisoxazoles

Article abstract of DOI:10.1002/anie.200905018

(Chemical equation presented) Nitro versus nitro: 4-Nitro-5- styrylisoxazoles were used as masked α,β-unsaturated carboxylic acids in the titled catalytic asymmetric transformation. The 4-nitroisoxazole core acts as an activator of the conjugated alkene and a latent carboxylate functionality. The reaction proceeded with 5 mol% of a readily prepared phasetransfer catalyst at room temperature with remarkable diastereo- and enantioselectivity (see scheme).

Full text of DOI:10.1002/anie.200905018

Communications
DOI: 10.1002/anie.200905018
Organocatalysis
Catalytic Asymmetric Conjugate Addition of Nitroalkanes to 4-Nitro-
5-styrylisoxazoles**
Andrea Baschieri, Luca Bernardi,* Alfredo Ricci, Surisetti Suresh, and Mauro F. A. Adamo*
Herein, we describe the development of an organocatalytic
enantioselective conjugate addition (Michael reaction) of
nitroalkanes to 3-methyl-4-nitro-5-styrylisoxazoles 1 and the
use of the resulting adducts 2 for the preparation of
enantiomerically enriched compounds of pharmaceutical
philic nature of cinnamates, which is not well-matched with
soft nitroalkane nucleophiles. Additionally, since the carbonyl
group of cinnamates does not establish well-defined inter-
actions with commonly used catalysts (e.g. amines or chiral
Lewis acid complexes), an efficient transfer of chirality from
the catalyst to the substrate is problematic. To overcome these
problems, various a,b-unsaturated carbonyl compounds have
been used in catalytic enantioselective Michael reactions[3–7]
to give products in which the desired carboxylates could be
unveiled in a subsequent step. Notable examples of such
compounds include chalcones,[3] enals,[4] a’-hydroxyenones,[5]
alkylidene malonates,[6] and alkenoyl pyrazoles and pyr-
roles.[7]
interest, such as g-nitroesters
3 and g-amino acids 4
(Scheme 1).
We have developed styrylisoxazoles 1 as cinnamate
equivalents that show high reactivity towards stabilized
(soft) nucleophiles. Compounds 1 are stable solids that can
be obtained in large quantities (10–100 mmol) as single
E isomers through the reaction of commercially available 3,5-
dimethyl-4-nitroisoxazole with an aromatic or heteroaromatic
aldehyde.[8] We previously described efficient Michael addi-
tion reactions of compounds 1 with soft nucleophiles, such as
enolates,[9] nitroalkanes,[10] and indoles.[11] The 4-nitroisoxa-
zol-5-yl core present in adducts 2 (Scheme 1) could be opened
to display a carboxylic acid by a reaction described by Sarti-
Fantoni and co-workers: an operationally simple procedure
involving the treatment of 4-nitroisoxazoles with excess
aqueous NaOH.[12]
Therefore, compounds 1 constitute a valuable synthetic
alternative to cinnamic esters in procedures that require
tuning of the acceptor electrophilicity. We now report the use
of compounds 1 in catalytic asymmetric settings in combina-
tion with phase-transfer catalysis (PTC)[13] and the use of the
resulting adducts 2 for the preparation of g-nitroesters 3 and
g-amino acids 4. The high enantioselectivity observed when
the reactions were carried out at room temperature with a low
catalyst loading (2–5 mol%), the compatibility of nitrome-
thane as well as secondary and tertiary nitroalkanes with the
reaction conditions, and the unusual diastereocontrol when
secondary nitroalkanes were used, are advantages of this
process over many other procedures in which a,b-unsaturated
carboxylic acid analogues are used.[3–7] As the substrate and
catalyst could be prepared in one step from inexpensive
starting materials, the procedure is also practical to execute.
We initially treated the styrylisoxazole 1a with nitro-
methane (5 equiv) in the presence of various inorganic bases
in suitable organic solvents. This study identified solid K2CO3
and toluene as the most suitable combination of a base and a
solvent. Having identified suitable reaction conditions, we
tested a range of quaternary ammonium salts derived from
cinchona alkaloids as catalysts (Table 1).[14] Use of the
Scheme 1. Catalytic asymmetric conjugate addition of nitroalkanes to
4-nitro-5-styrylisoxazoles 1 and synthetic applications of Michael
adducts 2.
The conjugate addition of nitroalkanes to activated
alkenes is a useful reaction[1] that involves the formation of
À
a new C C bond and the installation of an aliphatic nitro
group: a precursor of an amine, a ketone, or a carboxylate.[2]
Several catalytic asymmetric variants of this transformation
have been reported for alkenes that act as soft electro-
philes.[1a] However, reported methods are not suitable for a,b-
unsaturated esters or acids, such as cinnamates, which are
poor substrates in catalytic enantioselective Michael reac-
tions.[1b–d] This experimental finding is justified by the electro-
[*] A. Baschieri, Dr. L. Bernardi, Prof. A. Ricci
Dipartimento di Chimica Organica “A. Mangini”
Facoltꢀ di Chimica Industriale, Universitꢀ di Bologna
V. Risorgimento, 4, 40136 Bologna (Italy)
Fax: (+39)051-209-3654
E-mail: nacca@ms.fci.unibo.it
Dr. S. Suresh, Dr. M. F. A. Adamo
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)
Fax: (+353)1-402-2168
E-mail: madamo@rcsi.ie
[**] We acknowledge financial support from “Stereoselezione in Sintesi
Organica Metodologie e Applicazioni” 2007. Financial support by
the Merck-ADP grant 2007, the Health Research Board (HRB),
Science Foundation Ireland (SFI), and Enterprise Ireland is also
gratefully recognized.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905018.
9342
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Table 2: Catalytic asymmetric addition of nitromethane to styrylisoxa-
zoles 1a–k.[a]
commercially available quininium chloride 5a led to 89%
conversion of 1a into 2a with promising enantioselectivity
(78% ee; Table 1, entry 1). The reaction of 1a and nitro-
methane in the presence of other quinine-based catalysts 5b–f
furnished adduct 2a in variable yields and with ee values
Table 1: Representative results of the screening of cinchona-derived
catalysts 5 and 6.[a]
Entry
1
R
t [h]
2
Yield[b] [%]
ee[c] [%]
1[d]
2
1a
1b
1c
1d
1e
1 f
1g
1h
1i
C6H5
48
48
48
48
48
48
48
160
240
120
48
2a
2b
2c
2d
2e
2 f
2g
2h
2i
80 (78)
75
74 (62)
50
70
75
88 (75)
80
55
65
82
97[f] (90)
3-ClC6H4
4-ClC6H4
2,6-Cl2C6H3
3,5-Cl2C6H3
2,4-Cl2C6H3
4-MeOC6H4
1-pyranyl
3-indolyl
2-furyl
94
3[e]
4
91[f] (89)
77
5
6
7
8
9
10
11
93
87
96 (90)
98
88
Entry
Catalyst
Ar
Conversion[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5 f
6a
6b
6c
6c[d]
C6H5
2-MeOC6H4
2-FC6H4
4-MeOC6H4
4-CF3C6H4
2-naphthyl
C6H5
4-CF3C6H4
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
89
>95
57
91
78
78
76
78
69
83
81
90
93
97
97
1j
1k
2j
2k
97
96
2-pyridyl
78
[a] Reaction conditions: 1 (0.25 mmol), nitromethane (1.25 mmol), 6c
(0.0125 mmol), K2CO3 (1.25 mmol), toluene (2.5 mL), room temper-
ature. Results in brackets refer to the synthesis of the opposite
enantiomer through the use of 6’c as the catalyst. [b] Yield of the
isolated product after chromatography on silica gel. [c] The ee value was
determined by HPLC on a chiral stationary phase. [d] The reaction was
performed on a 1.0 mmol scale. [e] The reaction was performed on a
1.50 mmol scale. [f] The absolute configuration was determined to be S
by chemical correlation (see the Supporting Information).
>95
>95
>95
>95
10
[a] Reaction conditions: 1a (0.10 mmol), nitromethane (0.50 mmol), 5
or 6 (0.010 mmol), K2CO3 (0.50 mmol), toluene (1.0 mL), room temper-
ature, 48 h. [b] Conversion was determined by 1H NMR spectroscopy.
[c] The ee value was determined by HPLC on a chiral stationary phase.
[d] Catalyst: 0.0050 mmol (5.0 mol%).
98% ee. Compounds 1i–k containing aromatic heterocycles
were also excellent substrates; the products 2i–k were formed
with high enantioselectivity, although in the case of 2i and 2j
a prolonged reaction time was required (Table 2, entries 9–
11). The quasienantiomeric catalyst 6’c derived from cincho-
nine enabled the preparation of compounds ent-2 with
comparable high enantioselectivity (Table 2, entries 1, 3,
and 7, values in brackets).
Having established a highly enantioselective procedure
for the conjugate addition of nitromethane to styrylisoxazoles
1a–k, we tested other nitroalkanes as nucleophiles. The
reaction of styrylisoxazole 1a with 2-nitropropane proceeded
at 08C to give the expected adduct 2l in 75% yield with
81% ee (Scheme 2, top). A decrease in the catalyst loading to
2.0 mol% for this reaction was not detrimental to the yield or
enantioselectivity. Similarly, 1a reacted with nitroethane, 1-
nitropropane, and 2-phenylnitroethane to give products 2m–o
in high yield with high diastereo- and enantioselectivity
(Scheme 2, middle). In these experiments, which were carried
out at À308C, the kinetic product anti-2m–o prevailed. This
result could be rationalized on the basis of an acyclic,
extended transition state.[17] Importantly, the more thermo-
dynamically stable isomers syn-2m–o were obtained prefer-
entially by simply stirring the reaction mixture at room
temperature for 24 h after the catalytic Michael addition was
ranging from 69% for catalyst 5d to 83% for catalyst 5e
(Table 1, entries 2–6). A major improvement was observed
upon the replacement of the quinine catalysts 5 with
cinchonidine catalysts 6. The reaction of 1a and nitromethane
in the presence of catalyst 6a gave 2a with 90% ee (Table 1,
entry 7). On the basis of results collected for the quinine
series, we carried out a focused screening of cinchonidine
catalysts 6 (Table 1, entries 8 and 9). This study quickly
identified the 3,5-bis(trifluoromethyl)benzyl derivative 6c[15]
as the best catalyst. Catalyst 6c ensured complete conversion
of 1a and gave 2a with 97% ee. Importantly, the catalytic
loading of 6c could be limited to 5.0 mol% without a decrease
in the conversion and yield (Table 1, entry 10).[16]
We explored the scope of the reaction by treating
styrylisoxazoles 1b–k with nitromethane under the catalysis
of 6c (Table 2). We found that compounds containing
electron-withdrawing or electron-donating groups were
equally good substrates, with the exception of the sterically
demanding 2,6-dichloro derivative 1d (Table 2, entries 2–7).
Importantly, we verified that at least compounds 2a and 2c
could be obtained on a preparative scale (Table 2, entries 1
and 3) without a decrease in yield or enantioselectivity.
Styrylisoxazole 1h, which contains an extended aromatic
pyranyl system, was converted efficiently into 2h with
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Raney Ni catalyzed reduction of the resulting g-nitro acids 7c
and ent-7c gave the (S)- and (R)-baclofen hydrochlorides (+)-
4c·HCl and (À)-4c·HCl, respectively.[18]
Baclofen, a GABAB-receptor agonist used in the treat-
ment of spasticity, is currently commercialized as a racemate
(Lioresal, Baclon) although only the R enantiomer is
active.[19] g-Amino butyric acid (GABA) is the most abundant
neurotransmitter in the mammalian brain. Several disorders
are linked to the metabolism of GABA, and the study of such
disorders necessarily relies on straightforward, and possibly
enantioselective, syntheses of g-amino acid derivatives.[20]
In conclusion, we have described a highly enantioselective
addition of nitroalkanes to 5-styrylisoxazoles 1 under mild
PTC catalysis. This study has provided a family of novel
Michael acceptors to be used in asymmetric synthesis as well
as a procedure for the preparation of versatile enantiomer-
ically pure adducts 2.
Scheme 2. Catalytic asymmetric addition of secondary and tertiary
nitroalkanes to 5-styrylisoxazole 1a. Bn=benzyl.
Received: September 7, 2009
Published online: November 4, 2009
Keywords: asymmetric catalysis · isoxazoles · Michael addition ·
nitro compounds · phase-transfer catalysis
complete. The basic conditions and the higher temperature
enabled thermodynamic equilibration, which gave syn-2m–o
with moderate diastereoselectivity (Scheme 2, bottom).
The carboxylic acid functionality was then unveiled in
Michael adducts 2a, 2e, and 2g, which were converted
efficiently into the corresponding g-nitroesters 3a, 3e, and 3g
by treatment with 1m aqueous NaOH in THF and subsequent
formation of the methyl ester to facilitate their isolation by
chromatography on silica gel (Scheme 3). The ee values of g-
nitroesters 3a, 3e, and 3g reflected those observed for the
starting materials 2, which demonstrated the configurational
stability of these compounds under the conditions used.
.
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