New synthesis of 2-alkyl-4,4-dimethyl-5-halomethylisoxazolidin-3-ones via intramolecular halocyclization of N-alkyl-2,2-dimethyl-3-butenohydroxamic acids

Article abstract of DOI:10.1055/s-1998-1782

N-Alkyl-2,2-dimethyl-3-butenohydroxamic acids and their cyclic derivatives were halocyclized by iodine monochloride, N-bromosuccinimide, or N-chlorosuccinimide to afford the corresponding 2-alkyl-4,4-dimethyl-5-halomethylisoxazolidinones and 5-membered ring fused isoxazolidinones in excellent yields.

Full text of DOI:10.1055/s-1998-1782

July 1998
SYNLETT
789
New Synthesis of 2-Alkyl-4,4-dimethyl-5-halomethylisoxazolidin-3-ones via Intramolecular
Halocyclization of N-Alkyl-2,2-dimethyl-3-butenohydroxamic Acids
Hyoung Rae Kim,* Seung Il Shin, Hyun Ju Park, Dong Ju Jeon, and Eung K. Ryu
Bioorganic Science Division, Korea Research Institute of Chemical Technology, P. O. Box 107, Yusong, Taejon 305-606, Korea
Fax + 82 42 861 0307 ; E-mail hyungrk@pado.krict.re.kr
Received 21 April 1998
Abstract: N-Alkyl-2,2-dimethyl-3-butenohydroxamic acids and their
cyclic derivatives were halocyclized by iodine monochloride, N-
bromosuccinimide, or N-chlorosuccinimide to afford the corresponding
2-alkyl-4,4-dimethyl-5-halomethylisoxazolidinones and 5-membered
ring fused isoxazolidinones in excellent yields.
1,2
2-(2-Chlorobenzyl)-4,4-dimethylisoxazolidin-3-one (command)
is
one of the most useful herbicidal compounds, and many modifications
of this compound have been performed in order to introduce better
herbicidal activity or better tolerance in crops, which contain an
isoxazolidine ring as a key structure of this herbicide. Isoxazolidines
3
occur in a variety of natural products as a key moiety, and one of the
synthetic routes toward obtaining the substituted isoxazolidines involves
4
halocyclization of N-alkenylhydroxylamines. However, there appears
to be no precedential reports of the halocyclizations of
alkenohydroxamic acids in the synthesis of isoxazolidin-3-ones. In the
course of modifying command, we synthesized new 2-alkyl-4,4-
dimethyl-5-halomethylisoxazolidin-3-ones via halocyclization of N-
alkyl-2,2-dimethyl-3-butenohydroxamic acid.
The
preparation
of
N-(2-chlorobenzyl)-2,2-dimethyl-3-
butenohydroxamic acid (7) as a starting material was summarized in
Scheme 1. Methyl acetoacetate (1) was dimethylated and reduced by
sodium borohydride or methyl magnesium chloride to afford the
corresponding β-hydroxy compounds 3 and 4, respectively. The
Scheme 1
5
compounds 3 and 4 were dehydrated by phosphorous pentoxide and the
resulting esters were hydrolyzed by lithium hydroxide in methanol-
water to afford the acid 6. The compound 6 (R=H) was also prepared
from 3-butenoic acid 5 by treatment of LDA and iodomethane. The acid
6 was converted to acid chloride by thionyl chloride and reacted with N-
(2-chlorobenzyl)-O-trimethylsilylhydroxylamine which was prepared in
situ from N-benzylhydroxylamine with chlorotrimethylsilane to afford
2
the
compound
7.
N-(2-Chlorobenzyl)-2,2-dimethyl-3-
butenohydroxamic acid (7) could be halocyclized by treatment with
various halogenating reagents, and the results were summarized in
Scheme 2. The halocyclization using N-bromosuccinimide or iodine
monochloride was achieved smoothly under mild conditions to afford
the corresponding isoxazolidinones (8b, 8c, 9b, and 9c) in excellent
yields. However, the chlorocyclization using N-chlorosuccinimide
needed an elevated temperature and longer reaction time but the yields
of isoxazolidinones (8a and 9a) were also excellent. The
Scheme 2
1
isoxazolidinones were easily identified by H NMR spectra. The
characteristic peaks for the double bond of 7 (R=H) at 5.2 and 6.0 ppm
disappeared and the halomethylene protons appeared at around 3.62
ppm (8a), 3.43 (8b), and 3.14 (8c) as a doublet, respectively. The singlet
at 4.98 ppm (benzylic protons of 7) also changed to two doublets at
around 4.9 ppm owing to the stereo-environments of the isoxazolidinone
ring. The compound
7
(R=H) could be cyclized to 5-
Scheme 3
hydroxymethylisoxazolidinone (10) via an epoxide intermediate
generated in situ using m-CPBA. Since the compound 7 is very labile to
the oxidants, first we should protect the hydroxyl group of 7 by
trimethylsilyl group, and then well-dried m-CPBA solution in methylene
chloride was added to the reaction mixture in order to form an epoxide
intermediate. After stirring 2 h at rt, the reaction mixture was poured
into
a
cold
1
N
HCl solution to afford the 5-hydroxy-
1
methylisoxazolidinone (10) in 48% yield. The H NMR spectra of
hydroxymethyl group of 10 showed up at 3.5 ppm with good
coincidences of other protons with those of halomethyl compounds (8).

790
LETTERS
SYNLETT
1
In order to generalize the halocyclization of butenohydroxamic acids,
we prepared N-methyl-2,2-dimethyl-3-butenohydroxamic acid (11) by
good spectrum in H NMR. The crude product was further purified by
silica gel column chromatography (EtOAc/n-hexane, 1/10) to afford 8b,
9b, 12b, or 14b, respectively.
the reaction of 2,2-dimethyl-3-butenoic acid chloride with N-
6
methylhydroxylamine using NaHCO in ether/H O (9/1) and 11 was
3
2
General procedure C: To a solution of hydroxamic acid (7, 11, or 13)
halocyclized to afford 5-halomethylisoxazolidinones 12 in good yields
under the same reaction conditions in Scheme 2 (Scheme 4). Similarly,
1-methyl-2-cyclopentene-1-carboxylic acid N-methylhydroxamic acid
(13) was prepared from ethyl 2-oxocyclopentanecarboxylate by the
same procedure described in Scheme 1. We found the halocyclizations
of 13 were performed in a diastereoselective manner and only single
diastereomers of 5-membered ring fused isoxazolidinones 14 were
obtained in good yields, and their stereochemistry were confirmed by
NOE studies. Interestingly, the proton in 6a position of 14 showed a
(1.0 mmol) in methylene chloride (10 ml) was added iodine
monochloride (1 M solution, 2.0 mmol) at -40 C. After stirring for 1 h,
o
the reaction mixture was poured into ice-water and extracted with
methylene chloride (50 ml x 2). The combined organic layers were
washed with 5% aquous sodium bisulfite and brine, dried over
magnesium sulfate, and concentrated to afford a crude product. The
1
crude product showed a good spectrum in H NMR. The crude product
was further purified by silica gel column chromatography (EtOAc/n-
hexane, 1/10) to afford 8c, 9c, 12c, or 14c, respectively.
1
singlet in H NMR spectrum due to the right angle with halomethyne
2-(2-Chlorobenzyl)-4,4-dimethyl-5-hydroxymethylisoxazolidin-3-
one (10): To a solution of hydroxamic acid (7, R=H) (1.0 mmol) in
methylene chloride (10 ml) was added chlorotrimethylsilane (1.1 mmol)
proton. Representative spectroscopic data of the compounds we
7
prepared were listed in the references and notes.
o
and triethylamine (1.0 mmol) at 0 C. After stirring for 20 min, a
solution of anhydrous m-chloroperbenzoic acid (ca 1.1 mmol, dissolved
in methylene chloride and dried over anhydrous MgSO ) was added to
4
the reaction mixture by a syringe. The reaction mixture was stirred for 2
o
h at 0 C, then poured into ice-water, and extracted with methylene
chloride (50 ml x 2). The combined organic layers were washed with 1
N HCl and brine, dried over magnesium sulfate, and concentrated to
afford a crude product. The crude product was purified by silica gel
column chromatography (EtOAc/n-hexane, 1/5) to afford 10.
Scheme 4
Acknowledgment: Financial supports from the Ministry of Science and
Technology, Republic of Korea is gratefully acknowledged.
References and Notes
(1) (a) Warfield, T. R.; Carlson, D. B.; Bellman, S. K.; Guscar, H. L.
Weed Sci. Abstr. 1985, 25, 105. (b) Warfield, T. R.; Halvorson, G.
C.; Dobbins, L. D.; Hopper, D. M. NCWCC Proceedings 1985, 40,
80.
(2) Baker, D. R.; Fenyes, W. K.; Morberg, W. K.; Cross, B., Ed.
Synthesis and Chemistry of Agrochemicals, American Chemical
Society, Washington, DC 1987, pp 10-23.
Scheme 5
(3) Tacheuchi, Y. Adv. Heterocycl. Chem. 1977, 21, 207-252.
In conclusion, intramolecular halocyclizations of hydroxamic acids
were first achieved in this study, and new types of isoxazolidinones
could be easily synthesized in good yields.
(4) (a) Fiumana, A.; Lombardo, M.; Trombini, C. J. Org. Chem. 1997,
62, 5623. (b) Mancini, F.; Piazza, M. G.; Trombini, C. J. Org.
Chem. 1991, 56, 4246. (c) Dhavale, D. D.; Gentilucci, L.; Piazza,
M. G.; Trombini, C. Liebigs Ann. Chem. 1992, (12), 1289.
Experimental Procedure:
(5) Schank, K.; Frisch, A.; Zwanenburg, B. J. Org. Chem. 1983, 48,
4580.
General procedure A: To a solution of hydroxamic acid (7, 11, or 13)
(1.0 mmol) in THF (10 ml) was added N-chlorosuccinimide (2.0 mmol)
at rt, and the reaction mixture was heated at 60 C. After stirring for 6 h,
(6) Santo, P. F.; Lobo, A. M.; Prabhakar, S. Synth. Commun. 1995, 25,
3509.
o
1
(7) 7: H NMR (CDCl ) δ 1.33 (s, 6H), 4.98 (s, 2H), 5.08-5.17 (m,
3
1
the reaction mixture was poured into ice-water and extracted with
methylene chloride (50 ml x 2). The combined organic layers were
washed with brine, dried over magnesium sulfate, and concentrated to
afford a crude product. The crude product showed a good spectrum in
2H), 5.92-6.07 (m, 1H), 7.22-7.37 (m, 4H). 8a: H NMR (CDCl )
3
δ 1.19 (s, 3H), 1.26 (s, 3H), 3.62 (d, J=8.0 Hz, 2H), 4.28 (t, J=8.0
Hz, 1H), 4.82 (d, J=18.0 Hz, 1H), 4.95 (d, J=18.0 Hz, 1H), 7.23-
13
7.41 (m, 4H); C NMR (CDCl ) δ 17.15, 22.57, 44.82, 46.55,
3
1
H NMR. The crude product was further purified by silica gel column
86.27, 126.94, 129.16, 129.35, 129.58, 132.53, 133.32, 173.52;
1
chromatography (EtOAc/n-hexane, 1/10) to afford 8a, 9a, 12a, or 14a,
respectively.
HRMS calcd. For C
H
NO Cl 287.048, found 287.048. 8b: H
13 15
2
2
NMR (CDCl ) δ 1.18 (s, 3H), 1.33 (s, 3H), 3.42 (d, J=6.0 Hz, 2H),
3
General procedure B: To a solution of hydroxamic acid (7, 11, or 13)
(1.0 mmol) in THF (10 ml) was added N-bromosuccinimide (2.0 mmol)
at 0 C. After stirring for 1 h, the reaction mixture was poured into ice-
4.32 (t, J=8.0 Hz, 1H), 4.82 (d, J=18.0 Hz, 1H), 4.97 (d, J=18.0
13
Hz, 1H), 7.22-7.41 (m, 4H); C NMR (CDCl ) δ 17.09, 22.58,
3
o
45.26, 46.52, 86.24, 126.94, 129.16, 129.36, 129.57, 132.52,
water and extracted with methylene chloride (50 ml x 2). The combined
organic layers were washed with brine, dried over magnesium sulfate,
and concentrated to afford a crude product. The crude product showed a
133.32, 173.52; HRMS calcd. For C
H
NO ClBr 330.997,
13 15
2
1
found 330.998. 8c: H NMR (CDCl ) δ 1.09 (s, 3H), 1.27 (s, 3H),
3
3.13 (d, J=6.0 Hz, 2H), 4.24 (t, J=8.0 Hz, 1H), 4.75 (d, J=16.0 Hz,

July 1998
SYNLETT
791
13
1H), 4.87 (d, J=16.0 Hz, 1H), 7.16-7.33 (m, 4H); C NMR
132.49, 133.24, 173.47; HRMS calcd. For C
H
NO Cl 269.082,
13 16
3
1
(CDCl ) δ 16.98, 22.66, 45.63, 46.51, 86.93, 126.96, 129.19,
found 269.082. 12a: H NMR (CDCl ) δ 1.13 (s, 3H), 1.29 (s,
3
3
129.49, 129.61, 132.62, 133.40, 173.73; HRMS calcd. For
3H), 3.19 (s, 3H), 3.64 (d, J=5.70 Hz, 1H), 3.65 (d, J=5.70 Hz,
1H), 4.26 (d, J=6.92 Hz, 1H), 4.28 (d, J=6.92 Hz, 1H); C NMR
1
13
C
H
NO ClI 378.983, found 378.985. 9a: H NMR (CDCl ) δ
13 15
2
3
1.21 (s, 3H), 1.26 (s, 3H), 1.37 (s, 3H), 3.50 (d, J=8.0 Hz, 1H),
(CDCl ) δ 17.11, 22.37, 27.86, 31.85, 44.81, 86.12, 173.23;
3
1
3.65 (d, J=8.0 Hz, 1H), 4.81 (d, J=18 Hz, 1H), 4.93 (d, J=18 Hz,
HRMS calcd. For C H NO Cl 177.056, found 177.056. 12b: H
7
12
2
13
1H), 7.25-7.41 (m, 4H); C NMR (CDCl ) δ 17.04, 18.09, 20.52,
NMR (CDCl ) δ 1.12 (s, 3H), 1.29 (s, 3H), 3.20 (s, 3H), 3.34-3.51
3
3
1
29.55, 46.72, 47.81, 86.74, 126.92, 129.20, 129.56, 129.81,
(m, 2H), 4.30 (d, J=5.90 Hz, 1H), 4.34 (d, J=5.90 Hz, 1H). 12c: H
132.61, 133.40, 173.55; HRMS calcd. For
C
H
NO Cl
NMR (CDCl ) δ 1.05 (s, 3H), 1.23 (s, 3H), 3.13-3.22 (m, 2H),
14 17
2
2
3
1
301.064, found 301.064. 9b: H NMR (CDCl ) δ 1.18 (s, 3H),
3.15 (s, 3H), 4.23 (d, J=7.33 Hz, 1H), 4.27 (d, J=7.33 Hz, 1H).
3
1
1.24 (s, 3H), 1.47 (s, 3H), 3.43 (d, J=8.0 Hz, 1H), 3.54 (d, J=8.0
14a: H NMR (CDCl ) δ 1.50 (s, 3H), 2.05-2.37 (m, 4H), 3.14 (s,
3
13
Hz, 1H), 4.78 (d, J=16 Hz, 1H), 4.92 (d, J=16 Hz, 1H), 7.25-7.39
3H), 4.36 (s, 1H), 4.58 (s, 1H); C NMR (CDCl ) δ 22.57, 31.51,
3
1
(m, 4H). 9c: H NMR (CDCl ) δ 1.18 (s, 3H), 1.23 (s, 3H), 1.47
34.13, 35.88, 53.28, 63.60, 93.06, 171.64; MS (70 eV) m/z (rel.
intensity) 190 (0.94), 189 (1.84), 143 (2.41), 115 (12.19), 86
3
(s, 3H), 3.59 (d, J=11.0 Hz, 1H), 3.70 (d, J=11.0 Hz, 1H), 4.70 (d,
J=14 Hz, 1H), 4.82 (d, J=14 Hz, 1H), 7.05-7.34 (m, 4H). 10: H
1
(64.45), 84 (100); HRMS calcd. For C H NO Cl 189.055, found
8 12 2
1
NMR (CDCl ) δ 1.11 (s, 3H), 1.27 (s, 3H), 3.53 (d, J=6.26 Hz,
189.056. 14b: H NMR (CDCl ) δ 1.52 (s, 3H), 2.09-2.19 (m,
3
3
1
2H), 4.21 (t, J=6.43 Hz, 1H), 4.73 (d, J=16.32 Hz, 1H), 4.86 (d,
4H), 3.13 (s, 3H), 4.36 (s, 1H), 4.72 (s, 1H). 14c: H NMR
13
J=16.32 Hz, 1H), 7.16-7.33 (m, 4H); C NMR (CDCl ) δ 17.10,
(CDCl ) δ 1.56 (s, 3H), 2.07-2.28 (m, 4H), 3.13 (s, 3H), 4.38 (s,
3
3
22.51, 40.14, 44.76, 46.49, 86.21, 126.89, 129.11, 129.28, 129.52,
1H), 4.87 (s, 1H).