A novel route to 5-substituted 3-isoxazolols. Cyclization of N,O-diBoc β-keto hydroxamic acids synthesized via acyl Meldrum's acids

Article abstract of DOI:10.1021/jo991409d

3-Isoxazolols are most often synthesized from a β-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N,O-diBoc-protected β- keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3- isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N,O-bis(tert- butoxycarbonyl)hydroxylamine, lead to the N,O-diBoc-protected β-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3- isoxazolols.

Full text of DOI:10.1021/jo991409d

J . Org. Chem. 2000, 65, 1003-1007
1003
A Novel Rou te to 5-Su bstitu ted 3-Isoxa zolols. Cycliza tion of
N,O-DiBoc â-Keto Hyd r oxa m ic Acid s Syn th esized via Acyl
Meld r u m ’s Acid s
Ulrik S. Sørensen, Erik Falch, and Povl Krogsgaard-Larsen*
NeuroScience PharmaBiotec Research Centre, Department of Medicinal Chemistry, The Royal Danish
School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark
Received September 7, 1999
3-Isoxazolols are most often synthesized from a â-keto ester and hydroxylamine. This cyclization
typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that
N,O-diBoc-protected â-keto hydroxamic acids can be synthesized and cyclized to 5-substituted
3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step
procedure in which carboxylic acid derivatives are converted into acyl Meldrum’s acids which, upon
aminolysis with N,O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N,O-diBoc-protected â-keto
hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric
acid, cyclized to the corresponding 5-substituted 3-isoxazolols.
In tr od u ction
The 3-isoxazolol moiety is a constituent of a number
of biologically active compounds (Figure 1). Muscimol (1)
and ibotenic acid (2) are compounds isolated from the
mushroom Amanita muscaria.1 Muscimol (1), which is
a nonselective GABAA receptor agonist,2 has been used
as a lead for the synthesis of THIP (3) a specific3 and
clinically active4 GABAA agonist and THPO (4) a specific
inhibitor of GABA uptake.5 Whereas ibotenic acid (2)
interacts nonselectively with all types of (S)-glutamate
receptors,6 the analogues (S)-AMPA (5)7 and (S)-homo-
AMPA (6)8 are specific agonists at subtypes of ionotropic
and metabotropic (S)-glutamate receptors, respectively.
Other examples of biologically active 3-isoxazolols are
5-methyl-3-isoxazolol (Tachigaren, 7) and the phospho-
rothioate Karphos (8), which are used as a soil fungicide
and a broad-spectrum insecticide, respectively.9
Incorporation of the 3-isoxazolol moiety into com-
pounds with potential biological activity normally re-
quires multistep and low-yield reaction sequences, and
there is a need for efficient and versatile synthetic
methods. The most common route to 3-isoxazolols has
been cyclization of â-keto esters with hydroxylamine
(Scheme 1). This method does, however, in addition to
F igu r e 1.
3-isoxazolol 9, lead to the undesired 5-isoxazolone 10, due
to the several possible ways of attack by hydroxylamine
on the â-keto ester.10 The amount of this byproduct is
most often substantial leading to low yields of the desired
isoxazolol.
The effects of temperature and pH on the relative
amounts of cyclization products have been studied,9-11
but attempts to optimize these parameters in order to
maximize the yield of the 3-isoxazolol and, thus, elimi-
nate the formation of 5-isoxazolone 10 have not been
successful. Another solution could be a temporary protec-
tion of the â-carbonyl as an acetal. This has in fact been
* To whom correspondence should be sent. E-mail: ano@
dfh.dk. Fax: (+45) 35306040.
(1) Eugster, C. H. Fortschr. Chem. Org. Naturst. 1969, 27, 261.
(2) Krogsgaard-Larsen, P.; Hjeds, H.; Curtis, D. R.; Lodge, D.;
J ohnston, G. A. R. J . Neurochem. 1979, 32, 1717.
(3) Krogsgaard-Larsen, P.; J ohnston, G. A. R.; Lodge, D.; Curtis, D.
R. Nature (London) 1977, 268, 53.
(4) Krogsgaard-Larsen, P.; Falch, E.; Christensen, A. V. Drugs Fut.
1984, 9, 597.
(5) Krogsgaard-Larsen, P.; J ohnston, G. A. R. J . Neurochem. 1975,
25, 797.
(6) Krogsgaard-Larsen, P.; Ebert, B.; Lund, T. M.; Bra¨uner-Osborne,
H.; Sløk, F. A.; J ohansen, T. N.; Brehm, L.; Madsen, U. Eur. J . Med.
Chem. 1996, 31, 515.
(7) Krogsgaard-Larsen, P.; Honore´, T.; Hansen, J . J .; Curtis, D. R.;
Lodge, D. Nature (London) 1980, 284, 64.
(8) Ahmadian, H.; Nielsen, B.; Bra¨uner-Osborne, H.; J ohansen, T.
N.; Stensbøl, T. B.; Sløk, F. A.; Sekiyama, N.; Nakanishi, S.; Krogs-
gaard-Larsen, P.; Madsen, U. J . Med. Chem. 1997, 40, 3700.
(9) Sato, K.; Sugai, S.; Tomita, K. Agric. Biol. Chem. 1986, 50, 1831.
(10) Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf, T.
I. J . Org. Chem. 1986, 51, 4037.
(11) J acobsen, N.; Kolind-Andersen, H.; Christensen, J . Can. J .
Chem. 1984, 62, 1940.
10.1021/jo991409d CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/21/2000

1004 J . Org. Chem., Vol. 65, No. 4, 2000
Sørensen et al.
Sch em e 1
Sch em e 3
bis(trimethylsilyl)hydroxylamine to give compound 14,
which was cyclized to 5-methyl-3-isoxazolol (7) upon
treatment with methanolic HCl.14 This method is, how-
ever, not generally useful since the lack of analogues of
diketene (13) limits the method to the synthesis of
3-isoxazolol 7.
Sch em e 2
Our first attempt to synthesize a compound of the
general structure 11 was based on the conversion of
â-keto ester 15 into the corresponding â-keto carboxylic
acid 16. Formation of the acid chloride under standard
conditions and in situ reaction with N,O-bis(tert-butoxy-
carbonyl)hydroxylamine15 (N,O-diBoc hydroxylamine)
yielded â-keto hydroxamic acid 17. Treatment of 17 with
concentrated hydrochloric acid gave the expected 3-isox-
azolol derivative 18 in 82% yield and as the only product.
Our experiments aiming at generalizing this method
starting from ethyl acetoacetate or ethyl benzoyl acetate
were, unfortunately, not successful due to rapid decar-
boxylation of the formed â-keto carboxylic acid. In
comparison, â-keto carboxylic acid 16 underwent decar-
boxylation slower and could, therefore, when used with-
out delay, be converted into hydroxamic acid 17. Thus,
formation of 3-isoxazolol 18 from 17 had been successful,
but with the marked instability of the â-keto carboxylic
acids we had to search for other ways to synthesize the
protected â-keto hydroxamic acid 11.
It is well-known that 2,2-dimethyl-1,3-dioxane-4,6-
dione (19)16,17 (Meldrum’s acid) (Scheme 3) can be acy-
lated and that such acyl Meldrum’s acids can be con-
verted into â-keto esters by reaction with alcohols.16-20
In contrast, only few examples describe the formation
of â-keto amides from the reaction between acyl Mel-
drum’s acids and nitrogen-containing nucleophiles.21-23
Our approach was to perform an aminolysis of acyl
derivative 20a with N,O-diBoc-hydroxylamine, and we
found that this reaction gave the corresponding â-keto
hydroxamic acid 21a in good yield. The subsequent
treatment of 21a with concentrated hydrochloric acid
cleaved the Boc protecting groups and cleanly cyclized
the hydroxamic acid to give 7 in 92% yield. We were able
to reproduce these findings using a number of different
used in the synthesis of 5-methyl-3-isoxazolol (7),12 but
the method is unfortunately not generally feasible since
it seems to be highly dependent on the nature of the R-
and â-substituents of the â-keto ester.13
These synthetic problems prompted us to search for
an efficient synthetic route to 5-substituted 3-isoxazolols.
This paper presents a novel and generally applicable
method for introducing the 3-isoxazolol moiety starting
from a carboxylic acid derivative without formation of any
detectable 5-isoxazolone byproduct.
Resu lts a n d Discu ssion
(14) Oster, T. A.; Harris, T. M. J . Org. Chem. 1983, 48, 4307.
(15) Staszak, M. A.; Doecke, C. W. Tetrahedron Lett. 1993, 34, 7043.
(16) Chen, B.-C. Heterocycles 1991, 32, 529.
(17) McNab, H. Chem. Soc. Rev. 1978, 7, 345.
(18) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J . Org. Chem. 1978, 43,
2087.
The basis for the approach presented here was our
prediction that a â-keto hydroxamic acid of the general
type 11, with acid-labile protecting groups (PG’s), upon
treatment with acid would lead exclusively to the forma-
tion of the desired 5-substituted 3-isoxazolol 12 (Scheme
2). To our knowledge, only one related example has been
described, in which diketene (13) was reacted with N,O-
(19) Shinkai, I.; Liu, T.; Reamer, R. A.; Sletzinger, M. Tetrahedron
Lett. 1982, 23, 4899.
(20) Lermer, L.; Neeland, E. G.; Ounsworth, J . P.; Sims, R. J .;
Tischler, S. A.; Weiler, L. Can. J . Chem. 1992, 70, 1427.
(21) Pak, C. S.; Yang, H. C.; Choi, E. B. Synthesis 1992, 1213.
(22) Moya, P.; Cant´ın, AÄ .; Castillo, M.-A.; Primo, J .; Miranda, M.
A.; Primo-Yu´fera, E. J . Org. Chem. 1998, 63, 8530.
(23) Mohri, K.; Oikawa, Y.; Hirao, K.-I.; Yonemitsu, O. Chem.
Pharm. Bull. 1982, 30, 3097.
(12) Go¨th, H.; Gagneux, A. R.; Eugster, C. H.; Schmid, H. Helv.
Chim. Acta 1967, 50, 137.
(13) J acquier, R.; Petrus, C.; Petrus, F.; Verducci, J . Bull. Soc. Chim.
Fr. 1970, 1978.

Route to 5-Substituted 3-Isoxazolols
J . Org. Chem., Vol. 65, No. 4, 2000 1005
Ta ble 1
a
b
Via diethyl cyanophosphonate coupling. From benzoic acid anhydride. c 4 M aqueous HCl in MeOH 16 h at rt.
acyl Meldrum’s acids (Table 1), showing that this is a
generally useful route to 5-substituted 3-isoxazolols.
Acylation of Meldrum’s acid (19) has been performed
by several different methods. Carboxylic acid chlo-
rides18,19,23 and anhydrides,24 acyl imidazolides,25 and
peptide coupling reagents such as DCC26 or diethyl
cyanophosphonate27,28 have all proved to be equally
useful, but in the literature we found remarkably few
examples of acylations using benzoic acid derivatives23,24,29
and none with other aromatic or heteroaromatic acid
derivatives. Our own experiments demonstrated the
difficulties in synthesizing such acylated Meldrum’s
acids. Thus, we were unable to acylate Meldrum’s acid
(19) with either furoyl chloride or nicotinoyl chloride.
Using the peptide-coupling reagent diethyl cyanophos-
phonate, we obtained the desired product 20e from
cyclohexylcarboxylic acid in 99% yield, whereas no acy-
lation product could be detected under the same condi-
tions using benzoic acid and 19. Only benzoic anhydride
was successfully reacted with the sodium salt of 19
yielding compound 20f in 74% yield. Reactions under the
same conditions using nicotinic anhydride30 or tert-
butanoic anhydride were, however, without result, and
the desired compound could not be detected among
several reaction products of unknown structure. Also,
lowering the temperature or changing the base to tri-
ethylamine or 4-(dimethylamino)pyridine had no improv-
ing effect.
The aminolyses of acyl Meldrum’s acids with N,O-
diBoc-protected hydroxylamine in toluene at 65 °C pro-
ceeded smoothly, and the bulk of the two Boc groups did
not seem to hinder attack by the nitrogen atom on the
carbonyl group to any significant extent. Furthermore,
we did not observe that varying the structure of the acyl
Meldrum’s acid had any large effect on reactivity, since
all products 21a -h were isolated in good yields after a
reaction time of typically 4-16 h.
The cyclizations of the â-keto hydroxamic acids were
carried out in hot concentrated hydrochloric acid, since
this is the typical condition used for the cyclization step
when â-keto esters are reacted with hydroxylamine.11,12
We later found that a mixture of methanol and 4 M
aqueous hydrochloric acid at room temperature worked
equally well, although with prolonged reaction time. To
compare the two methods, 22b was first prepared using
concentrated hydrochloric acid at 50 °C for 2 h, and next
the reaction was performed in a (3:2) mixture of 4 M
aqueous hydrochloric acid and methanol at room tem-
perature overnight. Both methods turned out to give 22b
in 85-88% yield. Thus, the latter milder cyclization
conditions give a further advantage compared to the
much harsher method commonly used.
In conclusion, we have in this paper presented a novel
and efficient three-step procedure for the synthesis of
5-substituted 3-isoxazolols without formation of the
undesired 5-isoxazolone byproduct. The method uses the
easily accessible starting materials Meldrum’s acid, N,O-
diBoc-hydroxylamine,15 and an activated carboxylic acid
derivative. Furthermore, the method gives easy access
to N,O-protected â-keto hydroxamic acids from the reac-
tion of an acyl Meldrum’s acid and N,O-protected hy-
droxylamine.
(24) Houghton, R. P.; Lapham, D. J . Synthesis 1982, 451.
(25) Alker, D.; Campbell, S. F.; Cross, P. E.; Burges, R. A.; Carter,
A. J .; Gardiner, D. G. J . Med. Chem. 1989, 32, 2381.
(26) Maibaum, J .; Rich, D. H. J . Med. Chem. 1989, 32, 1571.
(27) Rosowsky, A.; Forsch, R.; Uren, J .; Wick, M.; Kumar, A. A.;
Freisheim, J . H. J . Med. Chem. 1983, 26, 1719.
(28) Hamada, Y.; Kondo, Y.; Shibata, M.; Shioiri, T. J . Am. Chem.
Soc. 1989, 111, 669.
(29) Bernasconi, C. F.; Ketner, R. J .; Chen, X.; Rappoport, Z. J . Am.
Chem. Soc. 1998, 120, 7461.
(30) Schrecker, A. W.; Maury, P. B. J . Am. Chem. Soc. 1954, 76,
5803.
Exp er im en ta l Section
Gen er a l Meth od s. Solvents and reagents were purchased
from commercial sources and used without further purification

1006 J . Org. Chem., Vol. 65, No. 4, 2000
Sørensen et al.
unless otherwise stated. Meldrum’s acid was recrystallized
from acetone/hexane before use as previously described.31
Melting points were determined in open capillaries and are
uncorrected. Elemental analyses were performed by Analytical
Research Department, H. Lundbeck A/S, Denmark, or by J .
Theiner, Microanalytical Laboratory, Institute of Physical
Chemistry, University of Vienna, Austria. Column chroma-
tography (CC) was performed using silica gel 60 (0.063-0.200
mm) from Merck. Compounds were visualized on TLC (silica
gel 60 F254 plates; Merck) using UV light and an FeCl3 spraying
reagent.
4-Meth yl-5-(4-tolyl)-3-isoxa zolol (18). Method A: 76 mg,
82%; mp >210 °C dec; 1H NMR (CDCl3) δ 2.19 (s, 3H), 2.41 (s,
3H), 4.8 (br s, 1H), 7.22-7.68 (m, 4H); 13C NMR (CDCl3) δ
6.8, 21.5, 100.7, 126.6, 129.8, 130.2, 140.4, 165.0, 171.0; MS-
(FAB+) m/z 190 ([M + 1]+, 22). Anal. Calcd for C11H11NO2: C,
69.83; H, 5.86; N, 7.40. Found: C, 69.79; H, 6.01; N, 7.46.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acyl Mel-
d r u m ’s Acid s. Meth od B: Syn th esis of 5-(1-Hyd r oxyeth -
ylid en e)-2,2-d im eth yl-1,3-d ioxa n e-4,6-d ion e (20a ). A so-
lution of Meldrum’s acid (3.00 g, 20.8 mmol) in CH2Cl2 (25 mL)
was cooled to 0 °C, and pyridine (3.29 g, 41.6 mmol) was added.
After stirring 15 min, acetyl chloride (1.63 g, 20.8 mmol) was
added dropwise. The reaction mixture was stirred at 0 °C for
1.5 h followed by 1.5 h at room temperature. To this solution
was added 2 M aqueous HCl, and the reaction mixture was
then extracted with CH2Cl2. The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo. CC
(EtOAc/hexane 1:9, 1% AcOH) yielded 20a as a crystalline solid
(3.20 g, 83%): mp 83-84 °C (lit.20 mp 83.5-84.5 °C); 1H NMR
(CDCl3) δ 1.75 (s, 6H), 2.69 (s, 3H), 15.13 (s, 1H); 13C NMR
(CDCl3) δ 23.6, 26.9, 92.0, 105.1, 160.8, 170.5, 195.0. Anal.
Calcd for C8H10O5: C, 51.61; H, 5.41. Found: C, 51.83; H, 5.43.
5-(1-H yd r oxyp r op ylid en e)-2,2-d im et h yl-1,3-d ioxa n e-
4,6-d ion e (20b). Method B: 3.85 g, 92%; mp 48-49 °C (lit.18
mp 55 °C); 1H NMR (CDCl3) δ 1.23 (t, 3H, J ) 7.5 Hz), 1.70 (s,
6H), 3.08 (q, 2H, J ) 7.5 Hz), 15.39 (s, 1H); 13C NMR (CDCl3)
δ 9.4, 26.6, 29.3, 90.8, 104.7, 160.2, 170.6, 199.0; IR (KBr) 2990,
1740, 1660, 1550 cm-1. Anal. Calcd for C9H12O5: C, 54.04; H,
6.04. Found: C, 54.44; H, 5.96.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5-Su bsti-
tu ted 3-Isoxa zolols. Meth od A: Syn th esis of 5-Meth yl-
3-isoxa zolol (7). Compound 21a (450 mg, 1.42 mmol) dis-
solved in MeOH (3 mL) was added to concentrated HCl (10
mL) at 50 °C. The mixture was stirred for 1 h, cooled to room
temperature, and concentrated in vacuo. The residue was
dissolved in water (10 mL) and pH adjusted to 3-4 with 2 M
aqueous NaOH followed by extraction with EtOAc. The
combined organic phases were dried (MgSO4) and concentrated
in vacuo. CC (EtOAc/hexane 1:9, 1% AcOH) yielded 7 as a
crystalline solid (130 mg, 92%): mp 83-84 °C (lit.14 mp 84-
1
85 °C); H NMR (CDCl3) δ 2.33 (s, 3H), 5.69 (s, 1H), 11.34 (s,
1H); 13C NMR (CDCl3) δ 12.7, 93.9, 170.6, 171.3; MS(FAB+)
m/z 100 ([M + 1]+, 100). Anal. Calcd for C4H5NO2: C, 48.49;
H, 5.09; N, 14.14. Found: C, 48.62; H, 5.05; N, 14.03.
Meth yl 2-Meth yl-3-oxo-3-(4-tolyl)p r op ion a te (15). A
stirred solution of methyl 4-methylbenzoate (41.2 g, 271 mmol)
and NaH (60% in mineral oil, 16.2 g, 406 mmol) in dry DMF
(350 mL) was added methyl propionate (35.8 g, 406 mmol)
dropwise under N2. After being stirred at room temperature
for 16 h, the reaction mixture was concentrated in vacuo, and
to the residue was added saturated aqueous NaHCO3 followed
by extraction with EtOAc. The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo. CC (EtOAc/
hexane 1:9) yielded 15 as a colorless oil (49.3 g, 88%): 1H NMR
(CDCl3) δ 1.48 (d, 3H, J ) 7.2 Hz), 2.41 (s, 3H), 3.67 (s, 3H),
4.38 (q, 1H, J ) 7.2 Hz), 7.22-7.30 (m, 2H), 7.84-7.92 (m,
2H); 13C NMR (CDCl3) δ 13.9, 21.7, 48.0, 52.6, 129.0, 129.7,
133.4, 144.8, 171.8, 195.8.
2-Meth yl-3-oxo-3-(4-tolyl)p r op ion ic Acid (16). To a solu-
tion of 15 (3.90 g, 18.9 mmol) in EtOH (140 mL) was added
NaOH (832 mg, 20.8 mmol) and the mixture stirred 16 h at
room temperature. The reaction mixture was concentrated in
vacuo, H2O was added, and the mixture was washed with CH2-
Cl2. The pH was adjusted to 2-3 with 4 M HCl and the
aqueous phase extracted with CH2Cl2. The combined organic
phases were dried (MgSO4), filtered, and concentrated in
vacuo. CC (EtOAc/hexane 1:9, 1% AcOH) afforded 16 in 73%
yield (2.66 g): 1H NMR (CDCl3) δ 1.49 (d, 3H, J ) 7.2 Hz),
2.41 (s, 3H), 4.42 (q, 1H, J ) 7.2 Hz), 7.23-7.30 (m, 2H), 7.82-
7.93 (m, 2H), 10.4 (br s, 1H); 13C NMR (CDCl3) δ 14.1, 21.6,
47.3, 128.9, 129.6, 132.9, 145.0, 176.5, 195.9.
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
2-(4-m eth ylben zoyl)pr opion am ide (17). Compound 16 (0.50
g, 2.60 mmol) dissolved in SOCl2 (3.0 mL) was added 1 drop
of DMF, and the solution was stirred under N2 for 14 h at room
temperature. The reaction mixture was concentrated in vacuo
and the residue dissolved in dry CH2Cl2 (1.0 mL). This solution
was added dropwise to a mixture of N,O-diBoc-hydroxy-
lamine15 (607 mg, 2.60 mmol) and Et3N (263 mg, 2.60 mmol)
in dry CH2Cl2 (5.0 mL) and stirred at room temperature for
16 h (N2 atm). To the reaction mixture was added saturated
aqueous NaHCO3, and this mixture was extracted with CH2-
Cl2. The combined organic phases were dried (MgSO4), filtered,
and concentrated in vacuo.The residue was purified by CC
(EtOAc/hexane 1:9) affording 17 in 56% yield (590 mg): 1H
NMR (CDCl3) δ 1.44-1.53 (m, 21H), 2.41 (s, 3H), 5.18-5.30
(m, 1H), 7.26-7.28 (m, 2H), 7.84-7.86 (m, 2H). Anal. Calcd
for C21H29NO7: C, 61.90; H, 7.17; N, 3.44. Found: C, 62.16;
H, 7.21; N, 3.52.
5-(1-Hyd r oxy-2-m eth yl-p r op ylid en e)-2,2-d im eth yl-1,3-
d ioxa n e-4,6-d ion e (20c). Method B: 3.65 g, 82%; yellowish
1
oil; H NMR (CDCl3) δ 1.25 (d, 1H, J ) 6.9 Hz), 1.74 (s, 6H),
4.10 (septet, 6H, J ) 6.9 Hz), 15.50 (s, 1H); 13C NMR (CDCl3)
δ 18.9, 26.6, 32.8, 90.0, 104.6, 160.1, 171.0, 202.5.
5-(Cyclop r op ylh yd r oxym eth ylid en e)-2,2-d im eth yl-1,3-
d ioxa n e-4,6-d ion e (20d ). Method B: 4.54 g, quantitative
yield; yellowish oil; 1H NMR (CDCl3) δ 1.15-1.49 (m, 4H), 1.76
(s, 6H), 3.48-3.56 (m, 1H), 15.45 (s, 1H); 13C NMR (CDCl3) δ
13.9, 15.3, 26.4, 90.9, 104.5, 161.1, 170.5, 197.9.
5-(Cycloh exylh yd r oxym eth ylid en e)-2,2-d im eth yl-1,3-
d ioxa n e-4,6-d ion e (20e). Method B: 4.45 g, 84%; mp 76-78
°C; 1H NMR (CDCl3) δ 1.20-1.90 (m, 10H), 1.74 (s, 6H), 3.74-
3.85 (m, 1H), 15.51 (s, 1H); 13C NMR (CDCl3) δ 25.3, 25.4, 26.5,
29.0, 42.7, 90.1, 104.5, 160.1, 171.0, 201.5. Anal. Calcd for
C
13H18O5: C, 61.41; H, 7.13. Found: C, 61.14; H, 7.05.
Meth od C. Cyclohexanecarboxylic acid (615 mg, 4.80 mmol)
and Meldrum’s acid (692 mg, 4.80 mmol) dissolved in dry DMF
(10 mL) was cooled to 0 °C, and to this mixture were dropwise
added diethyl cyanophosphonate (862 mg, 5.28 mmol) and
Et3N (1.51 g, 14.9 mmol) (N2 atm). The reaction mixture was
stirred at 0 °C for 0.5 h followed by 16 h at room temperature.
The mixture was then concentrated in vacuo, 2 M aqueous HCl
was added, and the mixture extracted with CH2Cl2. The
combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo. CC (EtOAc/hexane 1:9, 1% AcOH)
afforded pure 20e in 99% yield (1.21 g).
5-(Hyd r oxyp h en ylm eth ylid en e)-2,2-d im eth yl-1,3-d iox-
a n e-4,6-d ion e (20f).24 A solution of the sodium salt of Mel-
drum’s acid (1.50 g, 9.03 mmol) in dry DMF (15 mL) was cooled
to 0 °C, and benzoic acid anhydride (2.04 g, 9.03 mmol)
dissolved in anhyd DMF (6 mL) was added dropwise. The
reaction mixture was stirred at 0 °C for 1 h followed by 16 h
at room temperature. The mixture was concentrated in vacuo,
and 2 M aqueous HCl was added. This solution was then
extracted with CH2Cl2. The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo. CC (EtOAc/
hexane 1:9, 1% AcOH) yielded 20f as a crystalline solid (1.62
1
g, 72%); mp 107-109 °C dec (lit.29 mp 114 °C dec); H NMR
(CDCl3) δ 1.83 (s, 6H), 7.42-7.70 (m, 5H), 15.47 (s, 1H); 13C
NMR (CDCl3) δ 26.6, 90.8, 104.9, 128.0, 129.4, 132.6, 133.3,
159.8, 171.0, 189.3. A sample was recrystallized (EtOAc/
hexane) for elemental analysis. Anal. Calcd for C13H12O5: C,
62.90; H, 4.87. Found: C, 62.65; H, 4.99.
5-(3,3-Dim et h yl-1-h yd r oxyb u t ylid en e)-2,2-d im et h yl-
1,3-d ioxa n e-4,6-d ion e (20g). Method B: 4.45 g, 87%; yel-
(31) Oikawa, Y.; Yoshioka, T.; Sugano, K.; Yonemitsu, O. Org. Synth.
1984, 62, 198.

Route to 5-Substituted 3-Isoxazolols
J . Org. Chem., Vol. 65, No. 4, 2000 1007
1
lowish oil; H NMR (CDCl3) δ 1.08 (s, 9H), 1.74 (s, 6H), 3.13
5-Eth yl-3-isoxa zolol (22b). Method A: 290 mg, 85%; mp
42-43 °C (lit.33 mp 45-46 °C); reaction time 2 h; 1H NMR
(CDCl3) δ 1.27 (t, 3H, J ) 7.7 Hz), 2.66 (q, 2H, J ) 7.7 Hz),
5.67 (s, 1H), 11.9 (s, 1H); 13C NMR (CDCl3) δ 11.1, 20.5, 92.4,
(s, 2H), 15.39 (s, 1H); 13C NMR (CDCl3) δ 26.6, 29.8, 33.8, 46.2,
92.9, 104.4, 160.6, 170.7, 197.0.
5-(1-Hyd r oxy-2-p h en yleth ylid en e)-2,2-d im eth yl-1,3-d i-
oxa n e-4,6-d ion e (20h ). Method B: 5.50 g, quantitative yield;
mp 94-96 °C dec (lit.32 mp 90-92 °C dec); 1H NMR (CDCl3) δ
171.2, 175.8. IR (KBr): 3000, 2650, 1620, 1530, 1320 cm-1
;
MS(FAB+) m/z 114 ([M + 1]+, 100). Anal. Calcd for C5H7NO2:
C, 53.09; H, 6.24; N, 12.38. Found: C, 53.36; H, 6.14; N, 12.46.
Meth od E. Compound 21b (750 mg, 2.26 mmol) dissolved
in MeOH (20 mL) and 4 M aqueous HCl (30 mL) was stirred
at room temperature overnight. The mixture was concentrated
in vacuo, H2O was added, and the mixture was extracted with
EtOAc. The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Column chromatography (EtOAc/hex-
ane 1:9, 1% AcOH) yielded pure 22b in 88% yield (225 mg).
5-Isop r op yl-3-isoxa zolol (22c). Method E: 265 mg, 76%;
mp 42-43 °C (lit.9 mp 41-42 °C); 1H NMR (CDCl3) δ 1.28 (d,
6H, J ) 6.9 Hz), 2.94 (d septet, 1H, J ) 6.9 and 0.9 Hz), 5.64
(d, 1H, J ) 0.9 Hz), 11.2 (br s, 1H); 13C NMR (CDCl3) δ 20.3,
27.4, 91.2, 171.1, 179.6; MS(FAB+) m/z 128 ([M + 1]+, 100).
Anal. Calcd for C6H9NO2: C, 56.68; H, 7.13; N, 11.02. Found:
C, 56.39; H, 6.91; N, 10.80.
1.72 (s, 6H), 4.43 (s, 2H), 7.21-7.40 (m, 5H), 15.33 (s, 1H); 13
C
NMR (CDCl3) δ 26.6, 40.6, 91.3, 104.9, 127.5, 128.6, 129.6,
134.0, 160.3, 170.5, 194.7. Anal. Calcd for C14H14O5: C, 64.12;
H, 5.38. Found: C, 64.20; H, 5.38.
Gen er a l P r oced u r e for th e P r ep a r a tion of â-Keto
Hyd r oxa m ic Acid s. Meth od D: Syn th esis of N-(ter t-
Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)a cetyla ce-
ta m id e (21a ). To 20a (1.50 g, 8.06 mmol) dissolved in toluene
(75 mL) was added N,O-diBoc hydroxylamine15 (1.88 g, 8.06
mmol). The stirred solution was heated to 65 °C for 4 h and
then cooled to room temperature. After concentration in vacuo,
the residue was purified by CC (EtOAc/hexane 1:19) to afford
compound 21a as a colorless oil (1.89 g, 74%): 1H NMR (CDCl3)
δ 1.51-1.56 (m, 18H), 2.27 (s, 3H), 3.87-4.09 (m, 2H). Anal.
Calcd for C14H23NO7‚0.15 C6H14: C, 54.19; H, 7.66; N, 4.24.
Found: C, 54.23; H, 7.81; N, 4.31.
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
p r op ion yla ceta m id e (21b). Method D: 4.70 g, 71%; colorless
oil; 1H NMR (CDCl3) δ 1.09 (t, 3H, J ) 7.4 Hz), 1.50-1.56 (m,
18H), 2.57 (q, 2H, J ) 7.4 Hz), 3.88-4.10 (m, 2H); IR (KBr)
3300, 2980, 2920, 1780, 1750, 1460 cm-1. Anal. Calcd for
5-Cyclop r op yl-3-isoxa zolol (22d ). Method A: 280 mg,
96%; mp 103-104 °C (lit.34 mp 103-105 °C); reaction time 2
1
h; H NMR (CDCl3) δ 0.92-0.99 (m, 4H), 1.89-1.99 (m, 1H),
5.59 (s, 1H), 11.5 (s, 1H); 13C NMR (CDCl3) δ 8.0, 8.3, 90.8,
171.3, 175.6; MS(FAB+) m/z 126 ([M + 1]+, 100). Anal. Calcd
for C6H7NO2: C, 57.59; H, 5.64; N, 11.19. Found: C, 57.32; H,
5.60; N, 10.95.
C
15H25NO7: C, 54.37; H, 7.60; N, 4.23. Found: C, 54.64; H,
5-Cycloh exyl-3-isoxa zolol (22e). Method A: 385 mg, 89%;
mp 120-121 °C (lit.13 mp 123 °C); reaction time 5 h; 1H NMR
(CDCl3) δ 1.20-2.05 (m, 10H), 2.59-2.68 (m, 1H), 5.62 (s, 1H),
11.5 (br s, 1H); 13C NMR (CDCl3) δ 25.4, 25.5, 30.5, 36.5, 91.3,
171.1, 178.7; MS(FAB+) m/z 168 ([M + 1]+, 100). Anal. Calcd
for C9H13NO2: C, 64.65; H, 7.84; N, 8.38. Found: C, 64.43; H,
7.74; N, 8.28.
7.42; N, 4.49.
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
isop r op ion yla ceta m id e (21c). Method D: 1.33 g, 82%;
colorless oil; reaction time 16 h; H NMR (CDCl3) δ 1.14 (d,
1
6H, J ) 7.2 Hz), 1.50-1.56 (m, 18H), 2.74 (septet, 1H, J ) 7.2
Hz), 3.94-4.20 (m, 2H). Anal. Calcd for C16H27NO7: C, 55.64;
H, 7.88; N, 4.06. Found: C, 55.39; H, 8.09; N, 4.29.
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
4-cyclop r op yl-3-oxop r op ion a m id e (21d ). Method D: 1.82
g, 53%; colorless oil; reaction time 16 h; 1H NMR (CDCl3) δ
1.08-1.27 (m, 4H), 1.50-1.55 (m, 18H), 1.96-2.05 (m, 1H),
4.04-4.23 (m, 2H).
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
4-cycloh exyl-3-oxop r op ion a m id e (21e). Method D: 2.08 g,
91%; colorless oil; 1H NMR (CDCl3) δ 1.15-1.95 (m, 10H),
1.50-1.56 (m, 18H), 2.42-2.53 (m, 1H), 3.91-4.19 (m, 2H).
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
ben zoyla ceta m id e (21f). Method D: 800 mg, 82%; mp 109-
111 °C; 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.56 (s, 9H), 4.44-
4.74 (m, 2H), 7.45-7.95 (m, 5H); 13C NMR (CDCl3) δ 27.3, 27.6,
48.5, 85.7, 86.1, 128.3, 128.7, 133.6, 136.0, 149.4, 150.9, 163.8,
192.2. Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64; N, 3.69.
Found: C, 60.09; H, 6.61; N, 3.69.
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
5,5-d im eth yl-3-oxoh exa n oa m id e (21 g). Method D: 2.60 g,
70%; colorless oil; reaction time 16 h; 1H NMR (CDCl3) δ 1.01-
1.08 (m, 9H), 1.50-1.56 (m, 18H), 2.45 (s, 2H), 3.85-4.07 (m,
2H). Anal. Calcd for C18H31NO7: C, 57.89; H, 8.37; N, 3.75.
Found: C, 58.11; H, 8.61; N, 3.59.
5-P h en yl-3-isoxa zolol (22f). Method A: 190 mg, 99%; mp
1
159-161 °C (lit.35 mp 162-163 °C); H NMR (CDCl3) δ 6.24
(s, 1H), 7.45-7.50 (m, 3H), 7.72-7.78 (m, 2H), 10.8 (br s, 1H);
13C NMR (CDCl3) δ 91.3, 125.7, 127.2, 129.0, 130.7, 170.2,
171.5; MS(FAB+) m/z 162 ([M + 1]+, 18). Anal. Calcd for C9H7-
NO2: C, 67.08; H, 4.38; N, 8.69. Found: C, 66.96; H, 4.37; N,
8.64.
5-Neop en tyl-3-isoxa zolol (22g). Method A: 375 mg, 90%;
1
mp 105-106 °C (lit.36 mp 102-103 °C); reaction time 8 h; H
NMR (CDCl3) δ 0.98 (s, 9H), 2.52 (s, 2H), 5.67 (s, 1H), 11.2 (br
s, 1H); 13C NMR (CDCl3) δ 29.2, 31.4, 41.2, 94.7, 171.1, 172.8;
MS(FAB+) m/z 156 ([M + 1]+, 65). Anal. Calcd for C8H13NO2:
C, 61.91; H, 8.44; N, 9.03. Found: C, 61.93; H, 8.57; N, 9.08.
5-Ben zyl-3-isoxa zolol (22h ). Method A: 410 mg, 99%; mp
93-94 °C (lit.37 mp 94-95 °C); 1H NMR (CDCl3) δ 3.95 (s, 2H),
5.62 (s, 1H), 7.22-7.46 (m, 5H), 11.5 (br s, 1H); 13C NMR
(CDCl3) δ 33.5, 94.2, 127.3, 128.8, 128.8, 135.3, 171.2, 172.9;
MS(FAB+) m/z 176 ([M + 1]+, 100). Anal. Calcd for C10H9NO2:
C, 68.56; H, 5.18; N, 8.00. Found: C, 68.33; H, 5.34; N, 7.96.
J O991409D
(33) Tomita, K.; Nagano, M.; Yanai, T.; Oka, H.; Murakami, T.;
Sampei, N. Sankyo Kenkyusho Nempo 1970, 22, 215; Chem. Abstr.
1971, 74, 125521e.
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Larsen, P. J . Chem. Soc., Perkin Trans. 1 1995, 221.
(35) Micetich, R. G.; Chin, C. G. Can. J . Chem. 1970, 48, 1371.
(36) Sløk, F. A.; Ebert, B.; Lang, Y.; Krogsgaard-Larsen, P.; Lenz,
S. M.; Madsen, U. Eur. J . Med. Chem. 1997, 32, 329.
(37) Sato, M.; Ogasawara, H.; Komatsu, S.; Kato, T. Chem. Pharm.
Bull. 1984, 32, 3848.
N-(ter t-Bu toxyca r bon yl)-N-(ter t-bu toxyca r bon yloxy)-
3-oxo-4-p h en ylbu tyr a m id e (21h ). Method D: 2.94 g, 75%;
colorless oil; reaction time 16 h; 1H NMR (CDCl3) δ 1.48-1.53
(m, 18H), 3.83 (s, 2H), 3.83-4.10 (m, 2H), 7.19-7.35 (m, 5H).
(32) House, H. O.; Outcalt, R. J .; Cliffton, M. D. J . Org. Chem. 1982,
47, 2413.