Preparation and reactivity of [2-(3-methyl-4-nitro-isoxazol-5-yl)-vinyl]-amines

Article abstract of DOI:10.1016/j.tetlet.2015.11.037

Herein, we report our investigation into the reactivity of 5-enamino-4-nitroisoxazoles. This study revealed that the title compounds, in spite of conjugation to the 4-nitroisoxazole, displayed similar reactivity to enamines, reacting with electrophiles to form new C-C, C-N, and C-Cl bonds.

Full text of DOI:10.1016/j.tetlet.2015.11.037

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation and reactivity of [2-(3-methyl-4-nitro-isoxazol-5-yl)-
vinyl]-amines
⇑
Ravindra Dere, Claudio Monasterolo, 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
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report our investigation into the reactivity of 5-enamino-4-nitroisoxazoles. This study
revealed that the title compounds, in spite of conjugation to the 4-nitroisoxazole, displayed similar
reactivity to enamines, reacting with electrophiles to form new C–C, C–N, and C–Cl bonds.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 30 September 2015
Revised 9 November 2015
Accepted 11 November 2015
Available online xxxx
Keywords:
Polyfunctional scaffolds
4-Nitroisoxazoles
Isoxazoles
Enamines
b-Enaminoesters 1 are a class of key intermediates in organic
synthesis,1 employed as starting materials for the preparation of
many types of heterocyclic moieties2 or as precursors for a variety
of biologically active compounds including antibacterial,3 anticon-
vulsant,4 anti-inflammatory,5 and antitumor agents (Fig. 1).6 Sev-
eral procedures have been described for their preparation: direct
condensation of amines and b-ketoesters followed by Lewis acid
catalysis,7 addition of amines to alkynes,8 addition of ester enolates
to nitriles,9 addition of ester enolates to tosyl imines,10 and the
in high enantiomeric excess. Recently, compounds
3
were
employed as a key synthon in the development of a novel process
to manufacture
c
-aminoacids17 and in particular the Active
Pharmaceutical Ingredient (S)-Pregabalin.18 Following our
reports,14–18 other groups have used compounds 3 to develop
organocatalytic asymmetric procedures confirming, therefore, the
high synthetic value of these reagents.19
Compound 2 bears a structural similarity to enamines 1 which
are known to behave as nucleophilic species. However, compound
2 also contains the 4-nitroisoxazole core which is known to render
conjugated alkenes highly electrophilic. Therefore, at least in prin-
ciple, compound 2 could be considered as either an electrophilic or
a nucleophilic synthon. In order to establish its chemical nature,
we have carried out a study in which compound 2 was reacted
with nucleophiles and electrophiles. This study showed that com-
pound 2 behaved exclusively as an activated enamine, in spite of
the counter effect exerted by the conjugated nitro group.
Reformatsky
reaction
of
zinc
ester
enolates
with
dialkylformamides.11
It has been shown that 3,5-dimethyl-4-nitroisoxazole 4 reacts
with dimethylformamide to give the expected condensation pro-
duct 2 as a single diastereoisomer (Fig. 2).12 This procedure has
allowed the preparation of compound 2 in high yields using an
operatively simple procedure. In addition, being a solid, compound
2 was obtained in pure form by crystallization.
Our group has developed the synthesis of 3-methyl-4-nitro-5-
styrylisoxazoles 3 and demonstrated this class of compounds to
be excellent Michael acceptors, capable of reacting with many soft
nucleophiles to provide the corresponding 1,6 addition products in
high yields.13 Crucial to the observed behavior is the conjugation of
the 5-ethenyl electrophile with the 4-nitro group. Compounds 3
were found to react under phase transfer catalysis providing the
corresponding nitroadducts,14 cyclopropanes,15 and pyrrolidines16
At the onset, we screened 2 against common nucleophiles
including soft enolizable nitroalkanes, alkylmalonates, indoles,
bisulfite, and S-nucleophiles. These reactions were carried out
under Lewis acid and basic catalysis. In all experiments, unreacted
compound 2 was recovered, even after prolonged heating. The
reaction of compound 2 with harder nucleophiles such as Grignard
reagents, nBuLi or copper organometal species furnished a complex
reaction mixture. This was explained by considering the elec-
trophilicity of the isoxazole C-5, which likely reacted with the
nucleophiles leading to formation of an unstable isoxazoline that
underwent uncontrolled fragmentation. Surprisingly, the reaction
⇑
Corresponding author. Tel.: +353 1 4022208; fax: +353 1 4022168.
E-mail address: madamo@rcsi.ie (M.F.A. Adamo).
http://dx.doi.org/10.1016/j.tetlet.2015.11.037
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dere, R.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.037

2
R. Dere et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
NO2
NO2
O
Synthesis of 1-[2-(3-methyl-4-nitro-isoxazol-5-yl)-vinyl]-amines 5–14
N
N
R1O
O
O
R2
NO2
NO2
N
H
N
5 equiv.
N
R
N
N
R3
1
2
3
O
O
toluene
reflux, 5 h
Figure 1. b-Enaminoesters 1, dimethyl-[2-(3-methyl-4-nitro-isoxazol-5-yl)-vinyl]-
amine 2, and 3-methyl-4-nitro-5-styrylisoxazoles 3.
N
N
2
5-14
Entry
H
N
Product
Yield (%)
NO2
NO2
N
HN
HN
1
2
5
6
99
96
O
N
O
N
2
4
Figure 2. Retrosynthesis of dimethyl-[2-(3-methyl-4-nitro-isoxazol-5-yl)-vinyl]-
amine 2.
H
H
HN
3
4
7
8
98
92
of 2 with amine nucleophiles occurred easily, generating the corre-
sponding N-substituted products in high yields (Table 1). The reac-
tions were conducted by heating 2 in toluene at reflux for 5 h with
5 equiv of the cyclic amine. This procedure furnished the desired
enamines 5–14 in 76–99% yields as single (E)-isomers (Table 1).
The ease of purification of compounds 5–14, which only involved
evaporation of the reaction mixture under reduced pressure,
ensured that the desired compounds 5–14 were obtained in high
yields.
The reactivity of enamines selected from compounds 5–14 with
electrophiles was investigated (Table 2) by the reaction with N-
electrophiles diethyl azodicarboxylate (DEAD) and diisopropyl
azodicarboxylate (DIAD). Delightfully, these reactions progressed
to full conversion, providing the desired products in high isolated
yields and as a near 1:1 mixture of (E) and (Z) isomers. It was note-
worthy that an increase of the steric hindrance of the cyclic amine
lead to a small change in the E/Z ratio from 1:1 to 4:6, presumably
favouring the (Z) isomer (Table 2, entries 5, 7, and 8).
H
HN
H
HN
HN
HN
5
6
7
9
76
95
96
NH
10
11
O
OH
8
12
89
HN
HN
HN
9
13
14
93
86
10
OH
Table 2
Reaction of selected enamines with DEAD or DIAD
O
R
O
R
O
N
R
O
NO2
O
O
O
R
N
O
2.1 equiv.
N
N
O
O
O
O
N
N
N
R
N
R
O
N
H
O
N
H
O
MeCN, r.t., 4 h
O2N
O2N
N
N
15-22 Z
15-22 E
Entry
H
N
R
Product
15
Yield (%)
75
(E/Z) ratio
1:1
1
2
–NEt2
–Et
–Et
N
16
88
1:1
N
N
3
4
–Et
–Et
17
18
89
84
1:1
1:1
O
N
5
6
7
–Et
19
20
21
84
92
89
4:6
1:1
4:6
–NEt2
–iPr
–iPr
N
N
8
–iPr
22
79
4:6
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R. Dere et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Et
O
Et
O
Et
O
Et
O
O
O
O
O
N
N
N
N
O
O
O
O
O
O
O
O
N
N
Et
N
N
Et
N
Et
N
Et
N
H
O
N
H
O
N
H
O
N
H
O
O2N
O2N
O2N
O2N
N
N
(Z)-17
(Z)-17'
(E)-17'
(E)-17
Scheme 1. Inter-conversion of (Z)-17 to (E)-17 in solution.
NO2
O
N
O
O
N
4 equiv.
N
R
Cl
Et2O, reflux.
O
R
O2N
N
23
R= Me, 55%,
R= Et, 71%, 24
Scheme 2. Reaction of enamine 5 with acyl chlorides.
Compounds 15–22 (Table 2) could not be separated as single (E)
or (Z) diastereoisomers by column chromatography. However, it
was possible to crystallize compound (Z)-17 and obtain a single
crystal X-ray diffraction measurement thereby confirming its
structure (Fig. 3).20 Interestingly, a pure sample of (Z)-17 estab-
lished equilibrium with its (E) form, rapidly forming a 1:1 E/Z mix-
ture in solution. It is possible that the electron withdrawing
character of the hydrazine moiety in compound 17 favored reso-
nance structure (Z)-170, thereby allowing rotation along the enam-
ine bond and consequent (Z) to (E) inter-conversion (Scheme 1).
The reactivity of compound 5 was further investigated by its
reaction with acetyl chloride and propionyl chloride (Scheme 2).
Hence, a solution of compound 5 was treated with acyl chloride
and the resulting mixture heated at reflux for 4 h. These reactions
provided the corresponding ketones 23 and 24 in 55% and 71%
yields, respectively. Interestingly, compounds 22 and 23 were
solely obtained as the (E)-isomers, thus demonstrating the capabil-
ity of the 1-[2-(3-methyl-4-nitro-isoxazol-5-yl)-vinyl]-amines to
react with carbon electrophiles in a stereoselective fashion. The
structure of compound 23 was confirmed by single crystal X-ray
diffraction (Fig. 4).21
Figure 4. X-ray diagram of compound 23.
NO2
NO2
NO2
NCS 1 equiv.
Cl
DCM, r.t., 2 h
+
N
N
N
O
N
O
O
N
Cl
5
25
26
1) NCS 1 equiv.
DCM, r.t., 2h
94% Yield
2) SiO2, HCl 1M
45 °C, 2 h
Scheme 3. Reaction of enamine 5 with N-chloro succinimide.
Once it was established that compound 5 reacted as an enam-
ine, we studied its reaction with the electrophilic halogenating
reagent N-chlorosuccinimide (NCS). Hence, compound
reacted with NCS in an attempt to prepare compound 25
5 was
(Schemes 3 and 4). Compound 5 was completely converted to
the desired compound 25, which, however, could not be purified
as it rapidly decomposed on silica gel to provide a mixture of 25
and 5-chloromethyl-4-nitroisoxazole 26. Evidence for the forma-
tion of compound 25 was obtained by 1H NMR analysis of the
crude reaction mixture. Inspired by this finding, we optimized a
procedure which allowed the conversion of compounds 5–26 in
high yield. Hence, 5 was first submitted to chlorination to give
25, followed by treatment of the reaction mixture with silica gel
and hydrochloric acid to provide 26 in 94% isolated yield. It should
be noted that attempts to prepare alkyl chloride 26 via the chlori-
nation of commercially available 3,5,dimethyl-4-nitroisoxazole 4
led to complex mixtures of mono-, di-, and tri-chloromethyl com-
pounds. Hence, the method described constitutes an excellent
method to prepare monochloride 26 in high yields.
Evidence for the formation of compounds 25 and 26 indicated a
mechanism in which compound 25 underwent acid mediated
hydrolysis, presumably to form aldehyde 27. This, in turn, under-
went acid catalyzed decarbonylation to provide compound 26. It
is likely that the ability of the 4-nitroisoxazole to stabilize carboan-
ions favored the observed decarbonylation. A similar behavior has
Figure 3. X-ray diagram of compound (Z)-17.
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4
R. Dere et al. / Tetrahedron Letters xxx (2015) xxx–xxx
NO2
NO2
NO2
NO2
Cl
Cl
N
N
N
N
O
O
O
O
N
N
CHO
Cl
5
25
27
26
Scheme 4. Proposed mechanism for the formation of compound 26.
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N
NO2
O
O
N
THF, HCl 1N
60 °C, 90 min
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N
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O2N
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28
29 71% yield
Scheme 5. Preparation of ketone 29.
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been observed for the acidic hydrolysis of compound 28 (Scheme 5)
which gave b-ketoester equivalent 29 in 71% yields.
In conclusion, we have studied the reactivity of compound 2.
This study has provided a general method for the preparation of
compound 2 congeners thus allowing the generation of a family
of related products 5–14. Selected compounds from 5 to 14 were
shown to react with -N and -C electrophiles generating aza-substi-
tuted enamines and ketones in high yields. It was also shown that
electrophilic chlorination of compound 5 provided an efficient
method to prepare monochloromethyl isoxazoles. This study will
be of interest for those involved in the preparation of chemical
libraries and for the preparation of natural products and drug
discovery.
Acknowledgements
We thank the Irish Research Council for a grant to C.M., Enter-
prise Ireland for a grant to R.D. and Fondazione CON IL SUD for a
grant to M.M.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.11.
037.
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Commun. 2012, 3863.
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Chem. 2015, 13, 10609.
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