The preparation of 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles

Article abstract of DOI:10.1016/j.tetlet.2013.11.099

We report the first synthetic route to prepare 3-methyl-4-nitro-5-(2- alkylethenyl)isoxazoles in high yields and exclusively as E-diastereoisomers.

Full text of DOI:10.1016/j.tetlet.2013.11.099

Accepted Manuscript
The preparation of 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles
Robert Wells, Maria Moccia, Mauro F.A. Adamo
PII:
S0040-4039(13)02056-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.099
TETL 43895
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2013
1 November 2013
26 November 2013
Please cite this article as: Wells, R., Moccia, M., Adamo, M.F.A., The preparation of 3-methyl-4-nitro-5-(2-
alkylethenyl)isoxazoles, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.11.099
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The preparation of 3-methyl-4-nitro-5-(2-
alkylethenyl)isoxazoles
Robert Wells, Maria Moccia, Mauro F. A. Adamo*
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The
Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Dublin, Ireland.
Abstract: We report the first synthetic route to prepare 3-methyl-4-nitro-5-(2-
alkylethenyl)isoxazoles in high yield and exclusively as E-diastereoisomers.
Keywords: Michael addition, 4-nitroisoxazoles, polyfunctional scaffolds,
organocatalysis.
The isoxazole nucleus has been recognized as an important heterocycle in medicinal
chemistry. Several reports have appeared describing the biological activity of
isoxazoles as GABAA antagonists,1 analgesics,2 anti-inflammatory,3 antimicrobial,3
antifungal,4 and anticancer agents,5 as well as selective agonists of dopamine D4
receptors.6 For this reason the synthesis of novel compounds containing the isoxazole
core is of interest for both the academic and industrial communities. The isoxazole
nucleus is only poorly aromatic as it contains a weak nitrogen-oxygen bond, which is
a potential site for ring cleavage. The limited aromaticity makes isoxazoles useful
intermediates since they can be easily manipulated to obtain functionally complex
derivatives, namely 1,3-dicarbonyls,7 hydroxyketones,8 azirines,9 enamines and β-
hydroxynitriles.10 Moreover 4-nitroisoxazoles have been shown to undergo hydrolysis
when treated with metal hydroxides, and for this reason, they can be considered as
carboxylic acid equivalents.11,12
*Corresponding author: tel ++353-1-4022208; fax ++353-1-4022168; e-mail: madamo@rcsi.ie.
1

Scheme 1. 3-Methyl-4-nitro-5-styrylisoxazole (1) as a cinnamate equivalent
Our group has developed the synthesis of 3-methyl-4-nitro-5-styrylisoxazoles 1 and
reported some of their synthetic applications (Scheme 1). Compounds 1 contain two
electrophilic centres, each of which can selectively react. It has been shown that soft
+
nucleophiles, such as enolates, are selective for the soft electrophilic centre E1 ,
whereas hard nucleophiles such as OH– react exclusively at the hard electrophilic
+ 12-14
centre E2 .
We have shown that when reacted with an excess of NaOH, the 4-
nitroisoxazol-5-yl core revealed a carboxylic acid,12,13 for which reason compounds 1
should be considered as synthetic equivalents to cinnamate esters 2 (Scheme 1). The
synthetic applications of 5-(2-arylethenyl)-4-nitroisoxazoles have been studied
extensively in our laboratory.16 It is noteworthy that the synthetic relevance of
compounds 1 has been recognized by at least three other groups worldwide.14,17,18
–
Shibata reported that the addition of CF3 nucleophiles to 1 occurred selectively at E2
(Scheme 1), thus allowing an easy and efficient entry to important classes of
trifluoromethylisoxazolines.15 Yuan et al. have reported a highly enantioselective
thiolate addition to compounds 1 that proceeded via bifunctional organocatalysis.17
Also, Rui Wang reported a highly enantioselective addition of unsaturated lactams to
1 catalysed by quinine-based thioureas.18
The preparation of aromatic compounds 1 proceeded via the condensation of
commercially available 3,5-dimethyl-4-nitroisoxazole (3) and aromatic aldehydes 4.19
Compound 3 underwent efficient condensation with aromatic aldehydes 3, but not
with aliphatic aldehydes, 16f,19 for which reason the preparation of 5-(2-alkyethenyl)-4-
nitroisoxazoles has not been reported. In view of the growing interest on reagents 1, it
would be desirable to provide a method to access the aliphatic series. Herein, we
report the first synthesis of 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles 6a-d which
complement compound 1 (Scheme 1). It was also decided to investigate strategies
alternative to the condensation of 3 and an aliphatic aldehyde, since these are known
to be restricted to aromatic aldehydes, α,β-unsaturated aldehydes19 and
cyclopropylcarboxaldehyde.18 It is known that 3,5-dimethylisoxazole (10) (Scheme 2)
2

can be selectively deprotonated,20 and its anion used as a nucleophile in reactions with
classic electrophiles such as alkyl halides21 and carbonyl compounds.22 Butyllithium,
or NaNH2/NH3 were equally good bases affording 5-methyl metallated 10.23 In this
context, the aldol reaction of 10 and aldehydes 11 was identified as the C-C bond-
forming step required to access products 6. A retrosynthetic analysis identified
mesylate 7 as a suitable starting material to prepare compounds 6. In turn, compound
7 could be obtained from parent alcohol 9, available via aldol reaction of 10 and 11
(Scheme 2).
Scheme 2. Retrosynthetic analysis of compounds 6
Compound 10 could be easily prepared by condensation of acetylacetone and
hydroxylamine.19 The first step of this synthesis involved deprotonation of 10 to
generate a C-5-methyl anion and its subsequent addition to aldehydes 11a-d (Table
1). Aldehydes 11a-d were selected for this study as representative examples of cyclic,
acyclic and branched compounds. It was decided to employ lithium diisopropylamide
(LDA) as the base and THF as the solvent. THF was a remarkably good solvent for 5-
metallated 10, which tended to crystallise out when generated in alkanes or in ethers.
Compound 10 was treated with one equivalent of LDA to give a deep yellow solution,
the colour of which was dissipated upon addition of one equivalent of aldehyde 11a-
d. At room temperature, this reaction gave the products 9a-d in moderate yields, but
contaminated by several side products, presumably arising from self-aldol
condensation of 11a-d. However, when the addition of the aldehyde to metallated 10
was carried out dropwise over the course of one hour at -78 oC, compounds 9a-d were
obtained in high isolated yields after column chromatography (Table 1).
3

Table 1. Synthesis of hydroxy isoxazoles 9a-d
Entry Aldehyde R
Product Yield (%)a
1
2
3
cyclohexyl
74
55
70
64
11a
11b
11c
11d
9a
9b
9c
9d
CH(CH2CH3)CH2CH2CH2CH3
CH2CH(CH3)2
4
CH2CH2CH2CH2CH2CH3
a
Isolated yields after flash chromatography eluting with 10% EtOAc in petroleum ether, followed by 20% EtOAc
in petroleum ether.
Nitration at this stage might have induced dehydration19 or formation of a nitrate
ester, so it was decided to protect the alcohol as a mesylate, which would also allow
elimination at a subsequent stage. Mesylation of 9a-d was achieved by treating
alcohols 9a-d in CH2Cl2 with an excess (5 equivalents) of mesyl chloride and
o
triethylamine at 0 C. Under these conditions, compounds 9a-d were completely
converted in less than two hours, and the products 8a-d were obtained in high yields
(Table 2). Attempts were made to employ lower amounts of mesyl chloride and
triethylamine, however these reactions gave incomplete conversions.
Having optimised the procedure to prepare compounds 8a-d, we proceeded to study
the aromatic nitration step. The classic method, involving treating 8a-d with a mixture
of concentrated sulfuric and nitric acids, was not attempted as it was anticipated that
the strong acidity of this medium might promote a subsequent uncontrolled
elimination leading to formation of 6 as an E/Z mixture. To avoid this potential risk, it
was decided to perform the nitration using tetramethylammonium nitrate and
trifluoromethanesulfonic (triflic) anhydride, which are mild and well known
conditions employed to install an aromatic nitro group.
4

Table 2. Synthesis of mesylated isoxazoles 8a-d
Entry
Alcohol
9a
R
Product
8a
Yield (%)a
1
2
3
cyclohexyl
82
88
85
90
CH(CH2CH3)CH2CH2CH2CH3
CH2CH(CH3)2
9b
8b
9c
8c
4
CH2CH2CH2CH2CH2CH3
9d
8d
a
Isolated yields after flash chromatography eluting with 2% MeOH in CH2Cl2.
Pleasingly, compounds 9a-d underwent nitration at C-4 efficiently. Initial attempts
were conducted using 1.05 equivalents of tetramethylammonium nitrate and triflic
anhydride, however this only led to 50% conversion of the starting materials. This
problem was overcome by using two equivalents of nitronium triflate which resulted
in full conversions.
Table 3. Synthesis of 4-nitroisoxazoles 7a-d
Entry
Mesylate
R
Product
7a
Yield (%)a
1
2
3
cyclohexyl
79
75
70
80
8a
8b
8c
8d
CH(CH2CH3)CH2CH2CH2CH3
CH2CH(CH3)2
7b
7c
4
CH2CH2CH2CH2CH2CH3
7d
a
Isolated yields after flash chromatography eluting with 10% EtOAc in petroleum ether, followed by 20% EtOAc in petroleum
ether.
The addition of compounds 8a-d to a premixed solution of tetramethylammonium
nitrate and trifluoromethanesulfonic anhydride was carried out at -78 oC, the resulting
5

solution was left to warm to room temperature and then stirred for a further five
hours. This procedure gave the desired 4-nitroisoxazoles 7a-d in high isolated yields
(Table 3). It was noted that when the additions were carried out at higher temperatures
the yields decreased.
The final step involved a base-catalysed elimination to install the 5-ethenyl moiety.
This step was realized by submitting compounds 7a-d to mild basic conditions. The
desired compounds 6a-d were obtained by treating a solution of 7a-d in CH2Cl2 with
2.5 equivalents of triethylamine (Table 4). These conditions ensured rapid
conversions. Typically, the reactions were complete after one hour and the desired
compounds 6a-d were obtained as single E-diastereoisomers.
Table 4: Synthesis of aliphatic nitroisoxazoles 6a-d
Entry
Substrate
R
Product
6a
Yield (%)a
1
2
3
cyclohexyl
82
88
92
89
7a
7b
7c
7d
CH(CH2CH3)CH2CH2CH2CH3
CH2CH(CH3)2
6b
6c
4
CH2CH2CH2CH2CH2CH3
6d
a
Isolated yields after flash chromatography eluting with CH2Cl2.
In conclusion, we have developed the first route to prepare 4-nitro-5-
ethenylisoxazoles of the aliphatic series 6a-d (Scheme 3). The synthesis started from
the nucleophilic addition of 5-methyl metallated 10 to an aldehyde 11a-d, which
constitutes the key C-C bond forming reaction. Elaboration of the resulting alcohols
9a-d through mesylation, subsequent nitration and base-promoted elimination gave
the desired products 6a-d in high isolated yields and exclusively as the E-
diastereoisomers. Considering the demonstrated synthetic advantage of using 4-nitro-
5-(2-alkylethenyl)isoxazoles as Michael acceptors,12-16 and the growing interest of
other research groups on reagents 1, we believe this study will be of interest to those
involved in the preparation of compounds for medicinal chemistry screening and in
the development of novel organocatalytic enantioselective procedures.
6

Scheme 3. Synthetic route to aliphatic 4-nitro-5-alkylethenylisoxazoles 6a-d
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Graphical abstract
The preparation of 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles
Robert Wells, Maria Moccia, Mauro F. A. Adamo
10