Base-mediated reactions of N-alkyl-O-acyl hydroxamic acids: Synthesis of 3-oxo-2,3-dihydro-4-isoxazole carboxylic ester derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.08.098

Treatment of malonyl derived O-acyl hydroxamic acid derivatives 10a-h with the phosphazene super base P-2-t-Bu 7 gives 2,3-dihydro-4-isoxazole carboxylic ester derivatives 11a-h. The rate and yield of the reaction is dependent upon the O-acyl substituent.

Full text of DOI:10.1016/j.tetlet.2003.08.098

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7763–7765
Base-mediated reactions of N-alkyl-O-acyl hydroxamic acids:
synthesis of 3-oxo-2,3-dihydro-4-isoxazole carboxylic
ester derivatives
Andrew J. Clark,a,* Divya Patela and Michael J. Broadhurstb
aDepartment of Chemistry, University of Warwick, Coventry, CV4 7AL, UK
bFormerly of Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire, AL7 3AY, UK
Received 21 July 2003; revised 12 August 2003; accepted 21 August 2003
Abstract—Treatment of malonyl derived O-acyl hydroxamic acid derivatives 10a–h with the phosphazene super base P-2-t-Bu 7
gives 2,3-dihydro-4-isoxazole carboxylic ester derivatives 11a–h. The rate and yield of the reaction is dependent upon the O-acyl
substituent.
© 2003 Published by Elsevier Ltd.
Hydroxamic acids have been studied for over 100
years.1 However, the reactivity and chemistry of
tion of the O-acyl group in 4 gives rise to 2-hydroxy-
amides 5 which are versatile synthetic intermediates.4b
The rearrangement (1 to 4, Scheme 1) was found to be
heavily dependent upon the nature of the group R1.
Thus, when R1 was an aryl or alkenyl group the
reactions were easy occurring with Et3N at room tem-
perature, but when R1 was an alkyl group, harsher
conditions using strong phosphazene bases5 were
required (Scheme 1). Thus, the ease of the reactions was
linked to the acidity of the protons adjacent to the
O-acylated hydroxamic acids
1 have been little
explored.2–4
Recent studies have included the cleavage of the weak
NꢀO bond to generate amidyl radicals 2,2 the base-
mediated [3,3]-sigmatropic reactions of their corre-
sponding bis-enolates 3,3 and their base-catalysed
rearrangement to give 2-acyloxyamides 4.4 Deprotec-
Scheme 1.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.08.098

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A. J. Clark et al. / Tetrahedron Letters 44 (2003) 7763–7765
at reflux for 2 days). This was surprising as previous
work suggested that the presence of any activating
group (e.g. 1, R1=CO2R) would facilitate the rear-
rangement reaction.4a,b Thus, we next tried the harsher
conditions reported for deactivated substrates4c and
heated 10a–d with one equivalent of the phosphazene
base 7 in toluene at reflux for 3 h. However, under
these conditions, instead of the desired rearranged com-
pounds 4 we isolated the 2,3-dihydro-2,5-dimethyl-3-
oxo-4-isoxazole carboxylic ester derivatives 11a–c (note:
reaction of 10d only gave recovered starting material
even after 2 days). The structures of these heterocycles7
are interesting as they are tautomeric to isoxazol-3-ols
12 which have been studied in detail as conformation-
ally restricted analogues of GABA and glutamic acid
(Scheme 3).8
amide carbonyl group. As part of a programme
towards the synthesis of 2-acyloxy malonamide deriva-
tives (e.g. 6) we decided to investigate the base-medi-
ated rearrangement of the malonate derived
hydroxamic acid derivatives 1, R1=CO2Et. We antici-
pated that rearrangement would be easy due to the
activating effect of the ester group.
Initial work focussed upon the preparation and rear-
rangement of four N-alkyl-O-acyl hydroxamate deriva-
tives 10a–d (Table 1). Thus, to
a solution of
N-methylhydroxylamine hydrochloride in MeOH at
0°C was added potassium hydroxide and a THF solu-
tion of the corresponding acid chloride 8a–d (prepared
by treatment of the corresponding acid with oxalyl
chloride). Reaction of the intermediate hydroxamic
acids 9a–d with acetyl chloride and Et3N in CH2Cl2 at
0°C produced the desired precursors 10a–d (Table 1,
Scheme 2).6
Presumably our isoxazole derivatives 11a–c are
obtained by direct attack of the malonate derived anion
onto the ester group of the O-acyl substituent followed
by elimination of water. Having observed that this
reaction did not occur for the phenyl substituted mal-
onate derivative 10d we briefly investigated the chem-
istry of a range of other derivatives where we varied the
nature of the O-acyl substituent 10e–h to determine the
scope and limitation of the reaction (Scheme 4).
With the precursors 10a–d in hand, attention now
turned to investigating their rearrangement reactions.
However, treating 10a–d with either a catalytic (10
mol%) or stoichiometric amount of Et3N in CH2Cl2 at
room temperature or at reflux led only to recovered
starting materials (as did heating in toluene with Et3N
Table 1.
Changing the nature of the O-acyl substituent from an
alkyl group (10a–c,e) to an aryl group (10f, 10h)
severely retarded the rate and yield of the cyclisation.
Thus, while 10e underwent cyclisation in 68% yield in
only 3 h, the phenyl substituted precursor 10f only gave
11f in 47% yield after 27 h. The presence of the strongly
electron-withdrawing p-nitrophenyl group 10h also low-
ered the yield substantially (13%). The rest of the mass
Substrate
R1
R2 Yield 9 (%)
Yield 10 (%)
a
b
c
Et
PhCH2
t-Bu
H
H
H
52
52
51
53
82
97
95
71
d
PhCH2 Ph
Scheme 2.
Scheme 3.
Scheme 4.

A. J. Clark et al. / Tetrahedron Letters 44 (2003) 7763–7765
7765
balance in both these reactions was unreacted starting
material. No reaction occurred when a bulky t-butoxy
group was present with starting material 10g being
recovered, even after 72 h.
J. L.; Thomas, G. H. Tetrahedron Lett. 1998, 39, 1269–
1272; (b) Clark, A. J.; Al-Faiyz, Y. S. S.; Broadhurst, M.
J.; Patel, D.; Peacock, J. L. J. Chem. Soc., Perkin Trans. 1
2000, 1117–1127; (c) Clark, A. J.; Al-Faiyz, Y. S. S.; Patel,
D.; Broadhurst, M. J. Tetrahedron Lett. 2001, 42, 2007–
2010.
In conclusion we have reported an easy synthesis of
2,3-dihydro-2,5-dialkyl-4-isoxazole carboxylic ester
derivatives by reaction of O-acylated malonate derived
hydroxamic acid derivatives with the strong phos-
phazene base 7. The nature of the O-acyl substituent
affected the reactions, with aromatic or bulky groups
retarding the rate of cyclisation.
5. Verkade, J. G. Topics Curr. Chem. 2003, 223, 1–44.
6. All new compounds exhibited satisfactory spectroscopic
and analytical data. Typical data N-acetoxy-N-methyl
malonamic acid tert-butyl ester 10c: Yield 95%; yellow oil;
Rf (hexane (60–80°C)–ethyl acetate: 1:2): 0.50; (found: C,
51.7; H, 7.4; N, 6.0%; MH+(CI), 232.1188. C10H17NO5
requires C, 51.9; H, 7.4; N, 6.0%; M+H, 232.1107); wmax
(neat)/cm−1 2938, 1802, 1745, 1694; lH (300 MHz; CDCl3)
1.44 (9H, s), 2.17 (3H, s), 3.24 (2H, s), 3.29 (3H, s); lC
(100.6 MHz; CDCl3) 18.8 (q), 28.3 (3×q), 35.9 (q), 42.8 (t),
82.6 (s), 165.9 (2×s), 168.3 (s); m/z (CI) 232 (MH+, 24%),
193 (100), 176 (94), 135 (72), 118 (67), 91 (17), 74 (51).
7. Compound 11a has been previously reported: Schlewer,
G.; Krogsgaard-Larsen, P. Acta. Chem. Scand. Ser. B.
1984, 38, 815. General procedure for cyclisation: To a
solution of the substrate hydroxamic acid derivatives 10a–
c (0.50 mmol) in toluene (5 mL) was added the phos-
phazene base-P2-t-Bu (184 mL, 0.50 mmol). The mixture
was heated for 3 h at 110°C. The mixture was then washed
with dilute HCl (15 mL) and dried over MgSO4. Evapora-
tion of the solvent gave the crude product, which was
purified by chromatography (hexane (60–80°C)-ethyl ace-
tate 1:2). 2,5-Dimethyl-3-oxo-2,3-dihydro-isoxazole-4-car-
boxylic acid tert-butyl ester 11c: Yield 57%; yellow oil; Rf
(hexane (60–80°C)–ethyl acetate 1:2): 0.18; (found: M+
(EI), 213.0996. C10H15NO4 requires M, 213.1001); wmax
(neat)/cm−1 2987, 2926, 1739, 1703, 1617; lH (300 MHz;
CDCl3) 1.59 (9H, s), 2.54 (3H, s), 3.51 (3H, s); lC (75.5
MHz; CDCl3) 14.6 (q), 28.6 (3×q), 33.3 (q), 82.2 (s), 104.9
(s), 161.1 (s), 165.0 (s), 175.4 (s); m/z (EI) 213 (M+, 18%),
158 (63), 140 (100), 113 (47), 57 (34), and 43 (29).
8. (a) Krogsgaardlarsen, P. Med. Res. Rev. 1988, 8, 27–56;
(b) Hansen, J. J.; Krogsgaardlarsen, P. Med. Res. Rev.
1990, 10, 55–94.
Acknowledgements
We wish to acknowledge the EPSRC and Roche Dis-
covery Welwyn for funding (CASE award for D.P.).
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