One-pot synthesis of [1,2]isoxazolidin-5-ones and [1,2]oxazin-6-ones

Article abstract of DOI:10.1080/00397911.2010.487292

Michael tandem addition-cyclization of N-substituted hydroxylamine hydrochloride in the presence of tBuOK in tBuOH at reflux to allyl bromides (Z)-1 and (Z)-2 provides an effective alternative to access to [1,2]isoxazolidin-5-ones 3 and functional 2,5-dih

Full text of DOI:10.1080/00397911.2010.487292

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One-Pot Synthesis of [1,2]Isoxazolidin-5-
ones and [1,2]Oxazin-6-ones
Aïcha Arfaoui a , Imen Beltaïef a & Hassen Amri a
a Laboratory of Organic and Organometallic Chemistry, Faculty of
Science, Tunis El Manar University , Tunis , Tunisia
Published online: 30 Mar 2011.
To cite this article: Aïcha Arfaoui , Imen Beltaïef & Hassen Amri (2011) One-Pot Synthesis of
[1,2]Isoxazolidin-5-ones and [1,2]Oxazin-6-ones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:10, 1536-1543, DOI:
10.1080/00397911.2010.487292
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Synthetic Communications1, 41: 1536–1543, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.487292
ONE-POT SYNTHESIS OF [1,2]ISOXAZOLIDIN-5-ONES
AND [1,2]OXAZIN-6-ONES
A¨ıcha Arfaoui, Imen Belta¨ıef, and Hassen Amri
Laboratory of Organic and Organometallic Chemistry, Faculty of Science,
Tunis El Manar University, Tunis, Tunisia
GRAPHICAL ABSTRACT
Abstract Michael tandem addition–cyclization of N-substituted hydroxylamine hydro-
t
t
chloride in the presence of BuOK in BuOH at reflux to allyl bromides (Z)-1 and (Z)-2
provides an effective alternative to access to [1,2]isoxazolidin-5-ones 3 and functional
2,5-dihydro[1,2]oxazin-6-ones 4 in fair to good yields and total stereoselectivity.
Keywords Allyl bromides; 2,5-dihydro[1,2]oxazin-6-ones; [1,2]isoxazolidin-5-ones;
Michael reaction; N-substituted hydroxylamine
INTRODUCTION
The Michael reaction is considered today as one of the most important organic
reactions, being the highlight of the development methodology leading to the cre-
ation of a new carbon–carbon bond-forming reaction from activated olefins. These
Michael acceptor types of molecules are known for their great ability to react as
good electrophiles toward miscellaneous nucleophiles. The homologous gem-bifunc-
tionalized acceptors like allyl bromides (Z)-1[1,2] and (Z)-2[3–6] revealed a range of
very popular products in organic synthesis and are considered as powerful intermedi-
ates endowed with important biological activities[7] such as pyrrolin-2-ones deriva-
tives,[6] c-butyrolactones,[8] and c-butyrolactams[9,10] (Scheme 1).
Because of the importance of some N,O-heterocycles as synthetic intermediates
in medicinal chemistry and their usefulness as pharmacological molecules, much
attention has been focused on their synthesis, particularly [1,2]isoxazolidin-5-
ones[11–15] 3 and [1,2]oxazin-6-ones[16,17] 4 (Scheme 2). We report here a new alterna-
tive to prepare these uncommon hetreocycles 3 and 4 through a Michael tandem
Received February 5, 2010.
Address correspondence to Hassen Amri, Laboratory of Organic and Organometallic Chemistry,
Faculty of Science, Tunis El Manar University, 2092 Tunis, Tunisia. E-mail: hassen.amri@fst.rnu.tn
1536

[1,2]ISOXAZOLIDIN-5-ONES
1537
Scheme 1. Allyl bromide derivatives (Z)-1,2.
Scheme 2. (E)-Alkylidene-2-alkylisoxazolidin-5-ones 3 and [1,2]oxazin-6-ones 4.
addition–cyclization reaction of N-substituted hydroxylamine to functional allyl
bromides (Z)-1 and (Z)-2.
RESULTS AND DISCUSSION
N-Substituted hydroxylamines are excellent nucleophiles in conjugate addition
to a,b-unsaturated enoates and their equivalent[18,19] or to pyrazolidinone acryla-
mides.[20] More recently, a,b-sugar lactones[21] could be used as good starting
Michael acceptors to produce the isoxazolidin-5-one ring, providing an effective
route to the selective formation of substituted azetidin-2-ones[22] or b-substituted-
b-amino acids.[23]
To examine the feasibility of the first route outlined in Scheme 2, using allyl
bromide (Z)-1, we demonstrate that its condensation with N-substituted hydroxyla-
mine hydrochloride in the presence of potassium tert-butoxide in tert-butanol at
reflux resulted in the formation of isoxazolidin-5-ones 3. What took place initially
was considered to be an addition of hydroxylamine to the allyl bromide (Z)-1 by
the amino group, leading to an expected SN2 product, followed by an intramolecular
transesterification (5-exotrig process)[24] to give (E)-4-alkylidene-2-alkylisoxazolidin-
5-ones 3 as the only isolated product in good yields (48–83%) and in total
(E)-stereoselectivity[25] (Scheme 3, Table 1).
During the course of our studies concerning the preparation and the evaluation
of the synthesis of unsaturated cyclic compounds containing two heteroatoms,[26,27]
the possibility of generating structures containing a nitrogen–oxygen linkage and in
particular [1,2]oxazines has been envisaged. There are few reports concerning N,O-
cleavage, which has received substantial attention because it might lead to antitumor
Scheme 3. General procedure for the synthesis of (E)-4-alkylidene-2-alkylisoxazolidin-5-ones 3 from ally
bromide (Z)-1.

¨
A. ARFAOUI, I. BELTAIEF, AND H. AMRI
1538
Table 1. (E)-4-Alkylidene-2-alkylisoxazolidin-5-ones 3a–e prepared
Product
R1
R2
Yielda (%)
3a
3b
3c
3d
3e
nC3H7
C6H5
tC4H9
tC4H9
cC6H11
cC6H11
cC6H11
60
83
48
61
56
nC3H7
C6H5
nC5H11
aIsolated yield after chromatography.
and antibiotic products.[16,17] However, the synthetic methods of oxazin-6-ones are
limited in literature.[28–30] These structures could be efficiently reduced to create
uncommon heterocycles compounds such as [1,2]oxazines for which utility has
alreadybeendemonstratedasnaturalantibioticsandtheirsyntheticderivatives.[16,17,31]
On the basis of this result, we found that Michael addition of N-substituted
hydroxylamine hydrochloride (3 equiv.) to dimethyl (Z)-2-(bromomethyl) fumarate
2 afforded pure [1,2]oxazin-6-ones 4 in moderate to good yields. The synthetic
approach proceeded through a two-step sequence as expected: allylic substitution
(SN20) of allyl bromide 2 by the N,O-binucleophilic reagent, providing a zwitterion
cyclobutane intermediate and then spontaneous 6-exotrig[32] cyclization process,
leading to the formation of 4 (Scheme 4, Table 2). Additional proof of enaminic sys-
1
tem in [1,2]oxazin-6-ones 4a, as an example, came from the H and 13C NMR data,
Scheme 4. N-Substituted hydroxylamine addition to dimethyl (Z)-2-(bromomethyl) fumarate 2.
Table 2. Methyl 2-alkyl-6-oxo-5,6-dihydro-2H-
1,2-oxazine-4-carboxylate 4a–e
Product
R
Yielda (%)
4a
4b
4c
4d
4e
iC3H7
tC4H9
cC6H11
C6H5
CH2C6H5
79
76
58
35
6
aIsolated yield after chromatography.

[1,2]ISOXAZOLIDIN-5-ONES
1539
which unequivocally justified respectively the high and low values of the shifts of the
vinylic proton at 8.04 ppm and allylic carbon atom at 27.1 ppm. Surprisingly, the
chemical yields decreased when the compounds had phenyl and benzyl groups at
the N-substituted hydroxylamine moieties.
In conclusion, simple and practical construction of highly functionalized het-
erocyclic systems, such as (E)-4-alkylidene-2-alkylisoxazolidin-5-ones 3 and methyl
2-alkyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate 4 from readily prepared
starting materials (Z)-1 and (Z)-2 is a great challenge and highly desirable.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography (TLC) on silica-gel
plates (Fluka Kieselgel 60 F254). For column chromatography, Fluka Kieselgel (70–
1
230 mesh) was used. H and 13C NMR spectra (fully decoupled) were recorded on
Bruker AMX 300 in CDCl3 as solvent and tetramethysilane (TMS) as the internal
standard. Infrared (IR) spectra were recorded with a Perkin-Elmer paragon 1000
Fourier transform (FT)–IR spectrophotometer. Mass spectrometry was performed
on an Autospec 200, Micromass (Waters) instrument.
Synthesis of (E)-4-Alkylidene-2-alkylisoxazolidin-5-ones 3a–e
Hydroxylamine chlorhydrate (R-NHOH, HCl) (30 mmol) and potassium tert-
butoxide (28 mmol) in tert-butanol (45 mL) were introduced into a 100-mL flask
under nitrogen atmosphere. The reaction mixture was stirred at reflux for 10 min,
and then allyl bromide 1 (10 mmol) was added. After filtration under reduced
pressure and evaporation of the solvent, the crude oil was purified by column chro-
matography on silica gel with CH2Cl2 as eluent to provide the pure 3a–e.
Selected Data 3a–e
(E)-2-tert-Butyl-4-butylideneisoxazolidin-5-one 3a. Yield: 1.97 g, 60% as
a viscous yellow oil; nmax (neat) 1760, 1645 cmꢀ1 1H NMR (CDCl3, d ppm, J
;
Hz): 6.68 (m, 1H), 4.00 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.17 (s, 9H), 0.97 (t,
13
=
=
=
3H, J ¼ 7.00); C NMR (CDCl3, d ppm): 168.9 (C O), 139.9 ( CH), 126.8 ( C),
59.9 [C(CH3)3], 49.7 (NCH2), 32.3 (CH2), 24.4 [C(CH3)3], 21.4 (CH2), 13.8 (CH3);
m=z (EI) 197 (Mþ, 11), 182 (28), 141 (43), 57 (100), 56 (40), 44 (3), 41 (47), 29
(25). HRMS calcd. for C11H19NO2: 197.1416; found: 197.1407.
(E)-4-Benzylidene-2-tert-butylisoxazolidin-5-one 3b. Yield: 2.31 g, 83%
1
as a viscous yellow oil; nmax (neat) 1730, 1595 cmꢀ1; H NMR (CDCl3, d ppm):
7.53 (m, 5H), 7.52 (s, 1H), 3.36 (s, 2H), 1.22 (s, 9H); 13C NMR (CDCl3, d ppm):
=
=
=
=
170.2 (C O), 140.3 ( CH), 135.4 (aromatic C), 130.1 (aromatic CH), 128.9 (aro-
=
=
=
matic CH), 128.1 ( C), 124.6 (aromatic CH), 60.4 [C(CH3)3], 40.2 (NCH2), 24.5
(CH3); m=z (EI) 231 (Mþ, 14), 216 (24), 175 (49), 130 (48), 115 (64), 57 (100), 56 (45),
44 (4), 41 (53). HRMS calcd. for C14H17NO2: 231.1259; found: 231.1270.
(E)-4-Butylidene-2-cyclohexylisoxazolidin-5-one 3c. Yield: 2.15 g, 48% as
1
a viscous yellow oil; nmax (neat) 1725, 1614 cmꢀ1; H NMR (CDCl3, d ppm, J Hz):

¨
A. ARFAOUI, I. BELTAIEF, AND H. AMRI
1540
6.68 (m, 1H), 3.40 (s, 2H), 2.73 (m, 1H), 2.17 (m, 2H), 1.96 (m, 10H), 1.27 (m, 2H),
13
=
=
0.96 (t, 3H, J ¼ 7.00); C NMR (CDCl3, d ppm): 168.9 (C O), 140.4 ( CH), 126.2
=
( C), 67.8 (NCH), 54.7 (NCH2), 31.4 (CH2), 30.8 (CH2), 27.8 (CH2), 25.8 (CH2),
24.2 (CH2), 13.9 (CH3); m=z (EI) 150 (69), 136 (100), 94 (29), 82 (40), 80 (45), 67
(33), 56 (39), 55 (71), 53 (34), 44 (6), 41 (71). HRMS calcd. for C13H21NO2:
223.1572; found: 223.1583.
(E)-4-Benzylidene-2-cyclohexylisoxazolidin-5-one 3d. Yield: 2.57 g, 61%
1
as a viscous yellow oil; nmax (neat) 1736, 1609 cmꢀ1; H NMR (CDCl3, d ppm):
7.52 (s, 1H), 7.40 (m, 5H), 3.37 (s, 2H), 2.80 (m, 1H), 1.62 (m, 10H); 13C NMR
=
=
=
(CDCl3, d ppm): 171.1 (C O), 136.1 ( CH), 134.1 (aromatic C), 130.2 (aromatic
=
=
CH), 129.9 (aromatic CH), 129.1 (aromatic CH), 124.2 ( C), 67.8 (NCH), 56.1
=
=
(NCH2), 29.3 (CH2), 25.8 (CH2), 24.3 (CH2); m=z (EI) 213 (82), 212 (56), 156 (49),
130 (71), 115 (100), 83 (6), 77 (19), 55 (47), 44 (4), 41 (47). HRMS calcd. for
C16H19NO2: 257.1416; found: 257.1403.
(E)-2-Cyclohexyl-4-hexylideneisoxazolidin-5-one 3e. Yield: 2.51 g, 56%
1
as a viscous yellow oil; nmax (neat) 1740, 1615 cmꢀ1; H NMR (CDCl3, d ppm):
6.70 (m, 1H), 3.34 (s, 2H), 2.61 (m, 1H), 2.15 (m, 2H), 1.80 (m, 9H), 0.87 (m,
13
=
=
=
10H); C NMR (CDCl3, d ppm): 168.9 (C O), 140.0 ( CH), 126.5 ( C), 67.8
(NCH), 54.7 (NCH2), 32.3 (CH), 29.3 (CH2), 25.8 (CH2), 25.2 (CH2), 24.9 (CH2),
24.7 (CH2), 22.4 (CH2), 13.9 (CH3); m=z (EI) 251 (Mþ, 22), 208 (58), 169 (33), 83
(29), 67 (38), 55 (100), 53 (28), 44 (7), 44 (74). HRMS calcd. for C15H25NO2:
251.1885; found: 251.1872.
Synthesis of Methyl 2-Alkyl-6-oxo-3,6-dihydro-2H-1,2-oxazine-4-
carboxylates 4a–h: General Protocol
Chlorhydrate of hydroxylamine (R-NHOH, HCl) (31 mmol) and potassium
tert-butoxide (30 mmol) in tert-butanol (45 mL) were introduced into a 100-mL flask
under a nitrogen atmosphere. The reaction mixture was stirred at reflux for 10 min,
and then allyl bromide 2 (10 mmol) was added. After filtration under reduced press-
ure and evaporation of the solvent, the crude oil was purified by column chromato-
graphy on silica gel with chloroform as an eluent to provide the pure 4a–e.
Selected Data 4a–e
Methyl
4a. Yield: 1.57 g, 79% as a yellow oil; nmax (neat) 1775, 1730, 1620 cmꢀ1
NMR (CDCl3, d ppm, J Hz): 8.04 (s, 1H), 4.01 (m, 1H), 3.72 (s, 3H), 3.31 (s,
2-isopropyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate
;
1H
13
=
=
2H), 1.33 (d, 6H, J ¼ 6.8); C NMR (CDCl3, d ppm): 171.1 (C O), 170.5 (C O),
=
=
149.0 ( C), 95.6 ( CH), 55.3 [CH(CH3)2], 51.8 (OCH3), 27.1 (NCH2), 19.4 (CH3);
m=z (EI) 199 (Mþ, 42), 168 (1), 157 (47), 125 (33), 98 (100). HRMS calcd. for
C9H13NO4: 199.0845; found: 199.0855.
Methyl
4b. Yield: 1.62 g, 76% as a pale yellow oil; nmax (neat) 1778, 1740, 1660 cmꢀ1; H
2-tert-butyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate
1
NMR (CDCl3, d ppm): 7.90 (s, 1H), 3.54 (s, 3H), 3.13 (s, 2H), 1.22 (s, 9H); 13C

[1,2]ISOXAZOLIDIN-5-ONES
1541
=
=
=
=
NMR (CDCl3, d ppm): 170.9 (C O), 170.5 (C O), 147.4 ( CH), 95.8 ( C), 61.2
[C(CH3)3], 51.7 (OCH3), 27.1 (NCH2), 26.0 (CH3); m=z (EI) 213 (Mþ, 5), 198 (1),
182 (47), 154 (3), 98 (6), 57 (100). HRMS calcd. for C10H15NO4: 213.1001; found:
213.1012.
Methyl 2-cyclohexyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate
1
4c. Yield: 1.39 g, 58% as a colorless oil; nmax (neat) 1757, 1735, 1624 cmꢀ1; H
NMR (CDCl3, d ppm): 8.03 (s, 1H), 3.72 (s, 3H), 3.30 (s, 2H), 2.02 (m, H), 1.53
13
=
=
=
(m, 10H); C NMR (CDCl3, d ppm): 170.9 (C O), 170.7 (C O), 148.2 ( CH),
=
94.4 ( C), 62.2 (NCH), 51.8 (OCH3), 29.7 (OCCH2), 27.2 (CH2), 24.8 (CH2), 24.2
(CH2); m=z (EI) 239 (Mþ, 21), 180 (11), 126 (17), 83 (74). HRMS calcd. for
C12H17NO4: 239.1158; found: 239.1170.
Methyl
4d. Yield: 0.81 g, 35% as a yellow oil; nmax (neat) 1768, 1728, 1630 cmꢀ1
6-oxo-2-phenyl-5,6-dihydro-2H-1,2-oxazine-4-carboxylate
1H
;
NMR (CDCl3, d ppm, J Hz): 7.75 (t, 1H, J ¼ 2.00), 7.44–7.27 (2 m, 5H), 3.79 (s,
13
=
3H), 3.51 (d, 2H, J ¼ 2.00); C NMR (CDCl3, d ppm): 174.2 (C O), 163.4
=
(C O), 142.5 ( CH), 135.7 (aromatic C), 129.3 (aromatic CH), 126.9 (aromatic
=
=
=
=
=
=
CH), 122.1 (aromatic CH), 109.6 ( C), 51.5 (OCH3), 37.1 (CH2); m=z (EI) 233
(Mþ, 1), 202 (8), 174 (37), 77 (78). HRMS calcd. for C12H11NO4: 233.0688; found:
233.0676.
Methyl
4e. Yield: 0.15 g, 6% as a colorless oil; nmax (neat) 1756, 1718, 1597 cmꢀ1
NMR (CDCl3, d ppm): 7.91 (s, 1H), 7.39 (m, 5H), 4.62 (s, 2H), 3.66 (s, 3H), 3.23
2-benzyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate
;
1H
13
=
(s, 2H); C NMR (CDCl3, d ppm): 171.0 (C O), 170.5 (C O), 151.1 ( CH),
=
=
=
=
=
134.2 (aromatic C), 128.9 (aromatic CH), 127.4 (aromatic CH), 126.9 (aromatic
=
þ
=
CH), 97.6 ( C), 57.2 (PhCH2), 52.0 (OCH3), 27.3 (CH2); m=z (EI) 247 (M , 100),
188 (45). HRMS calcd. for C13H13NO4: 247.0845; found: 247.0833.
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