An expeditious synthesis of [1,2]isoxazolidin-5-ones and [1,2]oxazin-6-ones from functional allyl bromide derivatives

Article abstract of DOI:10.3390/molecules15064094

Reaction of allyl bromide (Z)-1 and (Z)-2 with N-substituted hydroxylamine hydrochlorides in presence of tert-butoxide in tert-butanol at reflux provides a short and effective route to [1,2]isoxazolidin-5-ones 3 and [1,2]oxazin-6-ones 4.

Full text of DOI:10.3390/molecules15064094

Molecules 2010, 15, 4094-4101; doi:10.3390/molecules15064094
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molecules
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Article
An Expeditious Synthesis of [1,2]Isoxazolidin-5-ones and
[1,2]Oxazin-6-ones from Functional Allyl Bromide Derivatives
Imen Beltaïef, Aïcha Arfaoui and Hassen Amri *
Laboratoire de Chimie Organique et Organométallique, Université de Tunis El Manar, Faculté des
Sciences, Campus Universitaire 2092-Tunis, Tunisia
* Author to whom correspondence should be addressed; E-Mail: hassen.amri@fst.rnu.tn;
Tel.: +216 71 872 020; Fax: +216 71 871 666.
Received: 26 April 2010; in revised form: 14 May 2010 / Accepted: 24 May 2010 /
Published: 7 June 2010
Abstract: Reaction of allyl bromide (Z)-1 and (Z)-2 with N-substituted hydroxylamine
hydrochlorides in presence of tert-butoxide in tert-butanol at reflux provides a short and
effective route to [1,2]isoxazolidin-5-ones 3 and [1,2]oxazin-6-ones 4.
Keywords: functional allyl bromides; conjugate addition; N-substituted hydroxylamines;
isoxazolidin-5-ones; oxazin-6-ones
1. Introduction
Acrylic compounds have become highly attractive and building blocks for the synthesis of several
biologically active molecules such as α-methylene-γ-butyrolactones [1–5] and γ-butyrolactams [6–9].
Several studies have proposed methods for the preparation of compounds bearing a α-bromomethyl
moiety [10–14] commonly called Baylis-Hillman bromides [15–19]. In an ongoing project aimed at
further illustrating the potential of readily prepared α-bromomethylated esters analogs 2 [9,20], we
have shown the importance of functional allylic bromide 2 as an electrophilic reagent for access to
pyrrolidin-2-ones [9], α-alkyl-β-carbomethoxy-γ-butyrolactams [21,22], (E,Z)-α-alkylidene-γ-butyro-
lactones [23] and 4-methoxycarbonyl-1-N-alkyl-∆2-pyrrolidin-2-ones. In order to explore the potential
of hydroxylamines in organic synthesis, we have been examining their nucleophilic reactivity as an
N,O-centered tandem nucleophile. We report here a direct synthesis of isoxazolidin-5-ones 3 and

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oxazin-6-ones 4 via Michael addition then intramolecular cyclization of N-substituted hydroxylamines
to functional allyl bromides (Z)-1 and (Z)-2 (Scheme 1).
Scheme 1. Synthesis of [1,2]oxazin-6-ones and [1,2]isoxazolidin-5-ones from allyl
bromides 1-Z and 2-Z.
O
R2
R1
Br
R1
O
MeO2C
Br
N
O
N
R
CO2Et
3-E
2-Z
CO2Me
1-Z
4
O
MeO2C
2. Results and Discussion
Despite the interesting potential synthetic and pharmacological value of the isoxazolidin-5-ones 3,
there are only a few works in the literature reporting their synthesis [24,25]. The majority of the
recorded examples have been prepared by condensation of ester enolates and their equivalents [26–29]
or pyrazolidinone acrylamides [30] with N-substituted hydroxylamines. More recently, α,β-sugar
lactones [31–33] were used as good starting Michael acceptors to produce the isoxazolidin-5-one ring
system, thus providing an effective route for the selective formation of substituted azetidin-2-ones
[34,35] or β-substituted-β-amino acids [36]. In order to examine the feasibility of the route outlined in
Scheme 2, available allyl bromides (Z)-1 were prepared. Then, their condensation with a variety of N-
substituted hydroxylamine hydrochlorides in the presence of potassium tert-butoxide in tert-butanol at
reflux was carried out, which results in the formation of isoxazolidin-5-ones 3 in good yields, as
shown in Table 1.
Scheme 2. Synthesis of (E)-4-alkylidene-2-alkylisoxazolidin-5-ones 3 from allyl bromide (Z)-1.
Table 1. (E)-4-Alkylidene-2-alkylisoxazolidin-5-ones 3a-e prepared.
Product
3a
R1
R2
Yielda (%)
nC3H7
C6H5
nC3H7
C6H5
nC5H11
tC4H9
tC4H9
cC6H11
cC6H11
cC6H11
60
83
48
61
56
3b
3c
3d
3e
a Isolated yield after chromatography.
The initial reaction was considered to be, as described before in our previous work [37], a
conjugated addition of the hydroxylamine amino group to the allyl bromide (Z)-1 leaving an
ammonium intermediate which reacted with second hydroxylamine equivalent leading to an expected

Molecules 2010, 15
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SN2 product followed by a reasonable transesterification (5-exo-trig process) to give (E)-4-alkylidene-2-
alkylisoxazolidin-5-ones 3 as only isolated products in fair to good yields (48–83%) and with total (E)-
stereoselectivity (Scheme 2, Table 1).
Although this route in fact proved a successful strategy to access to the five-membered ring
heterocyclic system of [1,2]isoxazolidin-5-ones 3, we considered the possibility of a more efficient and
shorter sequence to generate uncommon six member structures bearing the N-O linkage, in particular
[1,2]oxazin-6-ones 4. Since the [1,2]oxazine and [1,2]oxazinone skeletons have recently been found to
be the central features in antitumor and antibiotic products [38–40], synthetic methods providing
access to these skeletons have gained considerable attention [41–44]. To the best of our knowledge,
there are only a few literature reports on this topic [45–47]. As shown in Scheme 3, we found that the
conjugate addition of N-substituted hydroxylamine hydrochlorides (3 equiv.) to dimethyl (Z)-2-
(bromomethyl) fumarate (2) afforded pure [1,2]oxazin-6-ones 4 in fair to good yields.
Scheme 3. 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 prepared.
Product
4a
R
Yielda (%)
iC3H7
79
76
58
35
6
4b
tC4H9
4c
cC6H11
4d
C6H5
4e
CH2C6H5
a Isolated yield after chromatography.
The synthetic approach proceeds through a two-step sequence as expected: allylic substitution
(SN2’) of allyl bromide 2 by the N,O-binucleophilic reagent providing a zwitterion cyclobutane
intermediate whose opening leads to the most stable (E) enaminic structure, then a spontaneous 6-exo-
trig [48] cyclization process, leading to the formation of 4. Additional proof of the enaminic system in
[1,2]oxazin-6-one 4a came from the 1H- and 13C-NMR data, which unequivocally showed the high and
low values of the shifts of the vinylic proton at 8.04 ppm and both allylic carbon atom at 27.1 ppm,
respectively. Surprisingly, the chemical yields were notably lower when N-substituted hydroxylamine

Molecules 2010, 15
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moieties bearing phenyl and benzyl groups were used; this is probably due to the low solubility of the
intermediary imine in the tert-butanol solvent before cyclization.
3. Experimental
3.1. General
All reactions were monitored by TLC on silica gel plates (Fluka Kieselgel 60 F254). For column
1
chromatography, Fluka Kieselgel 70-230 mesh was used. H- and 13C-NMR spectra (fully decoupled)
were recorded on a Bruker AMX 300 instrument in CDCl3 as solvent and with TMS as the internal
standard. IR spectra were recorded with a Perkin-Elmer Paragon 1000 FT-IR spectrophotometer. Mass
spectrometry was performed on an Autospec 200 Micromass instrument (Waters). Most of the
reagents and solvents were obtained from commercial sources (Aldrich, Merck, Fluka) and used as
received. Except for the commercially available dimethyl itaconate, allyl bromides 1 and 2 were
prepared as described in references [16] and [8], respectively.
3.2. General procedure for the synthesis of (E)-4-alkylidene-2-alkylisoxazolidin-5-ones 3
N-Alkylhydroxylammonium chloride (30 mmol) and potassium tert-butoxide (28 mmol) in tert-
butanol (45 mL) were placed in a 100 mL flask under a nitrogen atmosphere. The reaction mixture was
stirred at reflux for 10 minutes then allyl bromide 1-Z (10 mmol) was added. After the disappearance
of the substrate (TLC), the mixture was filtered under reduced pressure, evaporated and purified by
chromatography on silica gel (CH2Cl2) to afford the pure 3.
(E)-2-N-tert-Butyl-4-butylidene isoxazolidin-5-one (3a): Yield: 60% as a viscous yellow oil; IR (neat)
1
1,760, 1,645 cm-1; H-NMR (δ ppm, J Hz): 6.68 (m, 1H), 4.00 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H),
13
1.17 (s, 9H), 0.97 (t, 3H, J = 7); C-NMR (δ ppm): 168.9 (C=O), 139.9 (=CH), 126.8 (=C), 59.9
(C(CH3)3), 49.7 (CH2-N), 32.3 (CH2), 24.4 (CH3), 21.4 (CH2), 13.8 (CH3); MS m/z (EI) 197 (M+., 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-N-tert-butylisoxazolidin-5-one (3b): Yield: 83% as a viscous yellow oil; IR (neat)
1,730, 1,595 cm-1; 1H-NMR (δ ppm): 7.53 (m, 5H), 7.52 (s, 1H), 3.36 (s, 2H), 1.22 (s, 9H); 13C-NMR
(δ ppm): 170.2 (C=O), 140.3 (=CH), 135.4 (aromatic =C), 130.1 (aromatic =CH), 128.9 (aromatic
=CH), 128.1 (=C), 124.6 (aromatic =CH), 60.4 (C(CH3)3), 40.2 (NCH2), 24.5 (CH3); MS m/z (EI) 231
(M+., 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-N-cyclohexylisoxazolidin-5-one (3c): Yield: 48% as a viscous yellow oil; IR (neat)
1
1,725, 1,614 cm-1; H-NMR (δ ppm, J Hz): 6.68 (m, 1H), 3.40 (s, 2H), 2.73 (m, 1H), 2.17 (m, 2H),
13
1.96 (m, 10H), 1.27 (m, 2H), 0.96 (t, 3H, J = 7.00); C-NMR (δ 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),

Molecules 2010, 15
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13.9 (CH3); MS 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.
3.3. General procedure for the synthesis of methyl 2-alkyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-
carboxylates 4
N-Alkylhydroxylammonium chloride (31 mmol) and potassium tert-butoxide (30 mmol) in tert-
butanol (45 mL) were placed in a 100 mL flask under a nitrogen atmosphere. The reaction mixture was
stirred at reflux for 10 minutes then was added 2-Z (10 mmol). After disappearance of the substrate
(TLC), the solution was filtered under reduced pressure, evaporated and purified by chromatography
on SiO2 with chloroform as an eluent to provide the pure 4.
Methyl 2-N-iso-propyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate (4a): Yield: 79% as a yellow
1
oil; IR (neat) 1,775, 1,730, 1,620 cm-1; H-NMR (δ ppm, J Hz): 8.04 (s, 1H), 4.01(m, 1H), 3.72 (s,
13
3H), 3.31 (s, 2H), 1.33 (d, 6H, J = 6.8); C-NMR (δ 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); MS m/z (EI) 199 (M+., 42), 168
(1), 157 (47), 125 (33), 98 (100); HRMS calcd. for C9H13NO4: 199.0845; found: 199.0855.
Methyl 2-N-tert-butyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate (4b): Yield: 76% as a pale
1
yellow oil; IR (neat) 1,778, 1,740, 1,660 cm-1; H-NMR (δ ppm): 7.90 (s, 1H), 3.54 (s, 3H), 3.13 (s,
2H), 1.22 (s, 9H); 13C-NMR (δ 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); MS m/z (EI) 213 (M+., 5), 198 (1), 182 (47), 154
(3), 98 (6), 57 (100); HRMS calcd. for C10H15NO4: 213.1001; found: 213.1012.
Methyl 2-N-cyclohexyl-6-oxo-5,6-dihydro-2H-1,2-oxazine-4-carboxylate (4c): Yield: 58% as a
colorless oil; IR (neat) 1,757, 1,735, 1,624 cm-1; 1H-NMR (δ ppm): 8.03 (s, 1H), 3.72 (s, 3H), 3.30 (s,
13
2H), 2.02 (m, H), 1.53 (m, 10H); C-NMR (δ 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); MS m/z (EI) 239
(M+., 21), 180 (11), 126 (17), 83 (74). HRMS calcd. for C12H17NO4: 239.1158; found: 239.1170.
4. Conclusions
We have developed a versatile synthetic approach to obtain [1,2]isoxazolidin-5-ones 3 in good
yields and with total stereoselectivity. In addition, the method was used in the preparation of
4-functional heterocyclic compounds 4 in good overall yields.
References
1. Mattes, H.; Benezra, C. Reformatsky-type reactions in aqueous media. Use of bronometryl-acrylic
acid for the synthesis of
α-methylene-γ-butyrolactones. Tetrahedron Lett. 1985, 26, 5697-5698.
2. Fürstner, A. Recent advancements in the Reformatsky reaction. Synthesis 1989, 571-590.
3. Hoffmann, H.M.R.; Rabe, J. Synthesis and biological activity of α-methylene-γ-butyrolactones.
Angew. Chem. Int. Ed. Engl. 1985, 24, 94-110.

Molecules 2010, 15
4099
4. Petragnani, N.; Ferraz, H.M.C.; Silva, G.V.J. Advances in the synthesis of
α-methylenelactones
Synthesis 1986, 157-183.
5. Baldwin, J.E.; Adlington, R.M.; Sweeney, J.B. Improved synthesis of α-methylene-γ-lactones via
organotin reagents. Tetrahedron Lett. 1986, 27, 5423-5424.
6. El Alami, N.; Belaud, C.; Villiéras, J. Isolement du “reactif de Reformatsky” derive de l'α-
(bromomethyl) acrylate d'ethyle. Tetrahedron Lett. 1987, 28, 59-60.
7. El Alami, N.; Belaud, C.; Villiéras, J. La reaction de “Reformatsky” de l'α-(bromomethyl)
acrylate d'ethyle avec les chlorures d'acide et les nitriles. J. Organomet. Chem. 1987, 319,
303-309.
8. Besbes, R.; Villiéras, M.; Amri, H. Improved synthesis and reaction of dimethyl α-(bromomethyl)
fumarate with primary amines. Indian J. Chem. 1997, 36B, 5-8.
9. Basavaiah, D.; Rao, J.S. Applications of Baylis-Hillman acetates: one-pot, facile and convenient
synthesis of substituted -lactams. Tetrahedron Lett. 2004, 45, 1621-1625.
γ
10. Ferris, A.F. The action of mineral acid on diethyl bis(hydroxymethyl)malonate. J. Org. Chem.
1955, 20, 780-787.
11. Villiéras, J.; Rambaud, M. Ethyl
12. Villiéras, J.; Rambaud, M. Wittig-Horner reaction in heterogeneous media; 1. An easy synthesis
of ethyl -hydroxymethylacrylate and ethyl -halomethylacrylates using formaldehyde in water.
Synthesis 1982, 924-926.
13. Charlton, J.L.; Sayeed, V.A.; Lypka, G.N. Phase transfer catalysed synthesis of methyl
-bromomethylacrylate. Synth. Commun. 1981, 11, 931-934.
14. Holm, A.; Scheuer, P.J. Synthesis of -methylene- -alanine and one of its naturally occurring
-ketomides. Tetrahedron Lett. 1980, 21, 1125-1128.
α-(hydroxymethyl)acrylate. Org. Synth. 1988, 66, 220-224.
α
α
α
α
β
α
15. Arfaoui, A.; Amri, H. An effective new access to ethyl 2-[(alkylamino)(cyano)methyl] acrylates:
First synthesis of ethyl 3-cyano-2-(hydroxymethyl) acrylate. Tetrahedron 2009, 65, 4904-4907.
16. Beltaief, I.; Hbaïeb, S.; Besbes, R.; Villiéras, M.; Villiéras, J.; Amri, H. A new and efficient
method for the isomerization of secondary functional allylic alcohols into their primary isomers.
Synthesis 1998, 1765-1768.
17. Lee, M.J.; Kim, S.C.; Kim, J.N. The first synthesis of 3,5-dimethylene-4-phenylpiperidine-2,6-
dione from Baylis-Hillman adduct. Bull. Korean Chem. Soc. 2006, 27, 140-142.
18. Lee, K.Y.; Kim, S.C.; Kim, J.N. Regioselective synthesis of 1-arylnaphthalenes from
N-tosylaziridine derivatives. Tetrahedron Lett. 2006, 47, 977-980.
19. Lee, K.Y.; Seo, J.; Kim, J.N. Serendipitous synthesis of 2-amino-2,3-dihydrobenzofuran
derivatives starting from Baylis-Hillman adducts. Tetrahedron Lett. 2006, 47, 3913-3917.
20. Vaughan, W.R.; Milton, K.M.
Chem. Soc. 1951, 73, 5497-5498.
21. Beltaief, I.; Besbes, R.; Ben Amor, F.; Villiéras, M.; Villiéras, J.; Amri, H. (Z)-Dimethyl
-(bromomethyl) fumarate, an efficient intermediate for the selective synthesis of dimethyl 3-
alkyl itaconates and 2-alkyl 3-carbomethoxy- -lactams. Tetrahedron 1999, 55, 3949-3958.
α-Bromocitraconic anhydride and α-bromomesaconic acid. J. Am.
α
γ
22. Beji, F.; Lebreton, J.; Villiéras, J.; Amri, H. A total stereospecific route to α-alkylidene-γ- lactams.
Tetrahedron 2001, 57, 9959-9962.

Molecules 2010, 15
4100
23. Beji, F.; Besbes, R.; Amri, H. Synthesis of
α
-alkylidene-
β
-ethoxycarbonyl cyclopentanones and
-γ-butyrolactones. Synth. Commun. 2000, 30, 3947-3954.
24. Stamm, H.; Steudle, H. Nitrone-XI Isoxazolidin-verbindungen-VIII: N-substituierte 5-
isoxazolidinone durch reformatzky-reaktion mit nitronen. Tetrahedron 1979, 35, 647-650.
25. Lee, K.Y.; Lee, C.G.; Kim, T.H.; Kim, J.N. A facile synthesis of 4-arylidene-2-substituted
Isoxazolidin-5-ones from Baylis-Hillman acetates. Bull. Korean Chem. Soc. 2004, 25, 33-34.
26. Stamm, H.; Steudle, H. The mechanism of hydroxylamine addition to α,β-unsaturated esters.
Tetrahedron Lett. 1976, 17, 3607-3610.
27. Sibi, M.P.; Prabagaran, N.; Ghorpade, S.G.; Jasperse, C.P. Enantioselective synthesis of
α,β-disubstituted-β-amino acids. J. Am. Chem. Soc. 2003, 125, 11796-11797.
28. Sibi, M.P.; Liu, M. N-Benzylhydroxylamine addition to
β-aryl enoates. Enantioselective Synthesis
of β-aryl-β-amino acid precursors. Org. Lett. 2000, 2, 3393-3396.
29. Ishikawa, T.; Nagai, K.; Senzaki, M.; Tatsukawa, A.; Saito, S. Tetrahedron 1998, 54, 2433-2448.
30. Sibi, M.P.; Liu, M. Enantioselective conjugate addition of hydroxylamines to pyrazolidinone
acrylamides. Org. Lett. 2001, 3, 4181-4184.
31. Socha, D.; Jurczak, M.; Chmielewski, M. Synthesis of acosamine and daunosamine from sugar
δ-enelactones. Tetrahedron 1997, 53, 739-746.
32. Panfil, I.; Maciejewski, S; Bezecki, C.; Chmielewski, M. Synthesis of enantiomerically pure
2,3-disubstituted isoxazolidin-5-ones. Tetrahedron Lett. 1989, 30, 1527-1528.
33. Socha, D.; Jurczak, M.; Chmielewski, M. Stereocontrolled entry to Negamycin from D-Glucose.
Tetrahedron Lett. 1995, 36, 135-138.
34. Maciejewski, S; Panfil, I.; Bezecki, C.; Chmielewski, M. An approach to carbapenems from
α,β- unsaturated sugar lactones. Tetrahedron 1992, 48, 10363-10376.
35. Baldwin, S.W.; Aubé, J. Asymmetric synthesis with chiral hydroxylamines: Synthesis of optically
pure 4-substituted azetidinones. Tetrahedron Lett. 1987, 28, 179-182.
36. Merino, P.; Franco, S.; Merchan, F.L.; Tejero, T. Synthesis of isoxazolidin-5-ones via
stereocontrolled Michael additions of benzylhydroxylaminen to L-serine derived α,β-unsaturated
esters. Tetrahedron Asymmetry 1998, 9, 3945-3949.
37. Hbaieb, S.; Latiri, Z.; Amri, H. Stereoselective synthesis of 2-ethylidene-3-aminonitriles. Synth.
Commun. 1999, 29, 981-988.
38. Terano, H.; Takase, S.; Hosoda, J.; Kohsaka, M. A new antitumor antibiotic, FR-66979.
J. Antibiot. 1989, 42, 145-148.
39. Naoe, Y.; Inami, M.; Matsumoto, S.; Nishigaki, F.; Tsujimoto, S.; Kawamura, I.; Miyayasu, K.;
Manda, T.; Shimomura, K. FK317: A novel substituted dihydrobenzoxazine with potent
antitumor activity which does not induce vascular leak syndrome. Cancer Chemother. Pharmacol.
1998, 42, 31-36.
40. Inami, M.; Kawamura, I.; Tsujimoto, S.; Nishigaki, F.; Matsumoto, S.; Naoe, Y.; Sasakawa, Y.;
Matsuo, M.; Manda, T.; Goto, T. Effects of FK317, a novel anti-cancer agent, on survival of mice
bearing B16BL6 melanoma and Lewis lung carcinoma. Cancer Lett. 2002, 181, 39-45.
41. Miyata, O.; Namba, M.; Ueda, M.; Naito, T. A novel synthesis of amino-1,2-oxazinones as a
versatile synthon for β-amino acid derivatives. Org. Biomol. Chem. 2004, 2, 1274-1276.

Molecules 2010, 15
4101
42. Le Flohic, A.; Meyer, C.; Cossy, J.; Desmurs, J.R. Synthesis of unsaturated [1,2]oxazines by
using sigmatropic rearrangements and the ring-closing metathesis reaction. Tetrahedron Lett.
2003, 44, 8577-8580.
43. Yang, Y.-K.; Tae, J. Ring-Closing Metathesis of enynes tethered by an N-O Bond: Synthesis of
1,2-oxaza polycycles by Diels-Alder reaction of the Ring-Closing Metathesis products. Synlett
2003, 2017-2020.
44. Koide, K.; Finkelstein, J.M.; Ball, Z.;Verdine, G.L. A synthetic library of cell-permeable
molecules. J. Am. Chem. Soc. 2001, 123, 398-408.
45. Reddy, V.K.; Miyabe, H.; Yamauchi, M.; Takemoto, Y. Enantioselective synthesis of
[1,2]-oxazinone scaffolds and [1,2]-oxazine core structures of FR900482. Tetrahedron 2008, 64,
1040-1048.
46. Patel, S.K.; Murat, K.; Py, S.; Vallée, Y. Asymmetric total synthesis and stereochemical
elucidation of the antitumor agent PM-94128. Org. Lett. 2003, 5, 4081-4084.
47. Le Flohic, A.; Meyer, C.; Cossy, J.; Desmurs, J.R. Synthesis of unsaturated [1,2]oxazines by
using sigmatropic rearrangements and the ring-closing metathesis reaction. Tetrahedron Lett.
2003, 44, 8577-8580.
48. Baldwin, J.E.; Cutting, J.; Dupont, J.; Kruse, L.; Silberman, L.; Thomas, R.C. 5-Endo-trigonal
reactions: A disfavoured ring closure. J. Chem. Soc. Chem. Commun. 1976, 736-738.
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