5,5-Dimethyl-1,4,2-dioxazoles as versatile aprotic hydroxamic acid protecting groups

Article abstract of DOI:10.1021/jo0256890

5,5-Dimethyl-1,4,2-dioxazoles are readily installed by transketalization of 2,2-diethoxypropane, where both the NH and OH moieties are protected in a nonprotic form. The dioxazoles are stable to a wide variety of reaction conditions and readily revert back to the hydroxamic acid by treatment with Nafion-H in 2-propanol. The method is applicable to primary, secondary, tertiary, and aromatic hydroxamic acids, and the acidity of the protons adjacent to the dioxazole allows α-functionalization.

Full text of DOI:10.1021/jo0256890

5,5-Dim eth yl-1,4,2-d ioxa zoles a s Ver sa tile Ap r otic Hyd r oxa m ic
Acid P r otectin g Gr ou p s
Michel Couturier,* J ohn L. Tucker, Caroline Proulx, Ghislain Boucher, Pascal Dube´,
Brian M. Andresen, and Arun Ghosh
Process Research and Development, Pfizer Global Research and Development, Eastern Point Road, P.O.
Box 8013, Groton, Connecticut 06340-8013
michel_a_couturier@groton.pfizer.com
Received March 6, 2002
5,5-Dimethyl-1,4,2-dioxazoles are readily installed by transketalization of 2,2-diethoxypropane,
where both the NH and OH moieties are protected in a nonprotic form. The dioxazoles are stable
to a wide variety of reaction conditions and readily revert back to the hydroxamic acid by treatment
with Nafion-H in 2-propanol. The method is applicable to primary, secondary, tertiary, and aromatic
hydroxamic acids, and the acidity of the protons adjacent to the dioxazole allows R-functionalization.
In tr od u ction
(BOC),12 N-BOC-O-THP, and N-BOC-O-TBS.13 In the
course of developing a drug candidate, we investigated
the possibility of using a dioxazole as an aprotic hydrox-
amic acid protective group. In this context, the masked
hydroxamic acid could be introduced earlier in the
synthesis and could perhaps be released in a single
operation at the end of the sequence.
Dioxazolines are generally produced from the 1,3-
cycloaddition reaction of nitrile N-oxides14 with aldehydes
and ketones via the corresponding oximes,15 imidoyl
chlorides,16 nitro-17 and furoxanes.18 They can also be
Matrix metalloproteinases (MMPs) are a family of zinc
metalloenzymes that mediate the degradation of connec-
tive tissues and have become targets for therapeutic
inhibitors in several inflammatory, malignant, and de-
generative diseases.1 Considerable efforts in the pharma-
ceutical industry have been devoted toward perturbing
the endogenous zinc metal that is vital to the enzymatic
activity. In this context, the ability of hydroxamic acids
to act as bidentate ligands has made this functional group
a key component in the design of most MMP inhibitors.
The associated metal chelation and acquisition properties
of hydroxamic acids have also attracted much attention
in a broad range of disciplines.2
Due to its labile and diprotic nature, the hydroxamate
is typically installed in its protected form at the end of
the synthetic sequence.3 In general, only the alcohol
proton is derivatized, and examples include O-Bn,4 O-t-
Bu,5 O-Bz,6 O-TMS,7 O-TBS,8 O-TBDPS,9 O-Tr,10 and
O-SEM.11 In rare occasions, both differentially protected
devices can be cleaved in a single operation: N,O-bis-
(8) Hajduk, P. J .; Sheppard, G.; Nettesheim, D. G.; Olejniczak, E.
T.; Shuker, S. B.; Meadows, R. P.; Steinman, D. H.; Carrera, G. M.;
Marcotte, P. A.; Severin, J .; Walter, K.; Smith, H.; Gubbins, E.;
Simmer, R.; Holzman, T. F.; Morgan, D. W.; Davidsen, S. K.; Summers,
J . B.; fesik, S. W. J . Am. Chem. Soc. 1997, 119, 5818.
(9) Ma, C.; Miller, M. J . Tetrahedron Lett. 1991, 32, 2577.
(10) J ung, M.; Brosch, G.; Kolle, D.; Scherf, H.; Gerhauser, C.; Loidl,
P. J . Med. Chem. 1999, 42, 4669.
(11) Sakamoto, T.; Kikugawa, Y. J . Org. Chem. 1994, 59, 929.
(12) Staszak, M. A.; Doecke, C. W. Tetrahedron Lett. 1994, 35, 6021.
(13) Altenburger, J . M.; Mioskowski, C.; d’Orchymont, H.; Schirlin,
D.; Schalk, C.; Tarnus, C. Tetrahedron Lett. 1992, 33, 5055
(14) (a) Nair, V.; Radhakrishnan, K. V.; Sheela, K. C.; Rath, N.
P. Tetrahedron 1999, 55, 14199. (b) Coutouli-Argyropoulou, E.;
Thessalonikeos, E. J . Heterocycl. Chem. 1991, 28, 429. (c) Koumbis,
A. E.; Stephanidou-Stephanatou, J .; Alexandrou, N. E. J . Heterocycl.
Chem. 1991, 28, 605. (d) Hayakawa, T.; Araki, K.; Shiraishi, S. Bull.
Chem. Soc. J pn. 1984, 57, 1643. (e) Shiraishi, S.; Holla, B. S.; Imamura,
K. Bull. Chem. Soc. J pn. 1983, 56, 3457. (f) Argyropoulos, N. G.;
Alexandrou, N. E.; Nicolaides, D. N. Tetrahedron Lett. 1976, 83. (g)
Awad, W. I.; Abdel, S. M.; Omran, R.; Sobhy, M. J . Org. Chem. 1966,
31, 331.
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Rev. 1999, 99, 2735.
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derivatives, see: (a) Miller, M. J . Chem. Rev. 1989, 89, 1563. (b) Miller,
M. J .; Malouin, F. Acc. Chem. Res. 1993, 26, 241. (c) Roosenberg, J .
M., II.; Lin, Y.-M.; Lu, Y.; Miller, M. J . Curr. Med. Chem. 2000, 7,
159. (d) Bodwin, J . J .; Cutland, A. D.; Malkani, R. G.; Pecoraro, V. L.
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Morrocchi, S.; Ricca, A.; Velo, L. Tetrahedron Lett. 1967, 8, 331. (c)
Lee, G. A. Synthesis 1982, 508. (d) Grundmann, C.; Datta, S. K. J .
Org. Chem. 1969, 34, 2016.
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1989; Vol. III, pp 482-522.
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C. Liebigs Ann. Chem. 1986, 5, 938. (c) Lefkaditis, D. A.; Argyropoulos,
N. G.; Nicolaides, D. N. Liebigs Ann. Chem. 1986, 11, 1863. (d) Paton,
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Trans. 1 1985, 1517. (e) L’abbe, G.; Mathys, G. J . Org. Chem. 1974,
39, 1221.
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10.1021/jo0256890 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002
J . Org. Chem. 2002, 67, 4833-4838
4833

Couturier et al.
SCHEME 1
prepared by photolysis of acyl azides in the presence of
ketones,19 addition of hydroxamic acids onto acetylenic
esters20 and furans,21 and observed in the rearrangement
of N-acyloxaziridines.22 In the study of the thermal
decomposition of dioxazoles to isocyanates and ketones,
Mukaiyama has reported the preparation of aryl deriva-
tives through trans-acetalization.23 In this paper, the
examples were limited to aryl derivatives with variable
yields (%) ranging from mid 20’s to low 70’s. Cyclization
of N-acylated O-(2-methoxypropyl)hydroxylamine, a likely
intermediate in the previous reaction, has also been
shown to produce dioxazolines.24 With the exception of a
few isolated examples,25 a general deprotection procedure
of dioxazolines back to hydroxamic acids is not prece-
dented in the literature. Hence, we wish to demonstrate
herein the generality of the protection by broadening the
scope to include aliphatic systems, assess whether the
dioxazoles can be cleaved without alcoholysis to the
corresponding ester, and evaluate the dioxazoline stabil-
ity under various reaction conditions. We also wish to
further broaden the scope of dioxazolines through R-depro-
tonation and functionalization of the resulting carbanion.
known O-benzoylacetoneoxime (3),26 bis(hydroxamic acid)-
isopropylidene ketal (4),27 N-acylated O-(2-methoxypro-
pyl)hydroxyl-amine (5), N,O-dibenzoylhydroxylamine (6),28
and the corresponding ethyl ester 7a (Scheme 1).
Application of the Mukaiyama procedure to the ali-
phatic hydroxamic acid 1e was even more problematic
since it provided only 4% of dioxazoline 2e along with
the ethyl ester 7e and the rearranged acylated acetone-
oxime 8 in 43% yield each (Scheme 2).
SCHEME 2
Resu lts a n d Discu ssion
Initial attempts to convert benzohydroxamic acid (1a )
to the dioxazole 2a under a wide variety of reaction
conditions, including the original Mukaiyama procedure,
generates a wide variety of byproducts identified as the
The structure of the latter was confirmed through
independent synthesis by coupling the acid chloride 9
with acetoneoxime in 59% yield (Scheme 3). The ethyl
ester is most likely formed via the oxime ester since these
have been utilized as coupling agents.29,30
(19) (a) Clauss, K.-U.; Buck, K.; Abraham, W. Tetrahedron 1995,
51, 7181. (b) Eibler, E.; Skura, J .; Sauer, J . Tetrahedron Lett. 1976,
48, 4325.
(20) (a) Heindel, N. D.; Fives, W. P.; Carrano, R. A. J . Pharm. Sci.
1977, 66, 772. (b) Chen, F. M. F.; Forrest, T. P. Can. J . Chem. 1973,
51, 1368.
SCHEME 3
(21) (a) Mackay, D.; Neeland, E. G.; Taylor, Nicholas, J . J . Org.
Chem. 1986, 51, 2351. (b) Mackay, D.; Dao, L. H.; Dust, J . M. J . Chem.
Soc., Perkin Trans. 1 1980, 2408.
(22) (a) Bulman Page, P. C.; Murrell, V. L.; Limousin, C.; Laffan,
D. D. P.; Bethell, D.; Slawin, A. M. Z.; Smith, T. A. D. J . Org. Chem.
2000, 65, 4204. (b) Komatsu, M.; Ohshiro, Y.; Hotta, H.; Sato, M.-a.;
Agawa, T. J . Org. Chem. 1974, 39, 948. (c) Schmitz, E.; Ohme, R.;
Schramm, S. Tetrahedron Lett. 1965, 23, 1857. (d) Schmitz, E.;
Schramm, S. Chem. Ber. 1967, 100, 2593.
The postulated mechanism for generation of this
impurity is similar to the one proposed by Geffken
(23) Nohira, H.; Inoue, K.; Hattori, H.; Okawa, T.; Mukaiyama, T.
Bull. Chem. Soc. J pn. 1967, 40, 664.
(24) Geffken, D.; Froboese, J . J . Prakt. Chem./ Chem.-Ztg. 1994, 336,
550.
(25) (a) Mukhacheva, O. A.; Shchelkunova, M. A.; Razumov, A. I.
Zh. Obshch. Khim. 1980, 50, 1014. (b) Eremeev, A. V.; El’kinson, R.
S.; Liepins, E.; Imuns, V. Khim. Geterotsikl. Soedin. 1981, 124. (c)
Schroth, W.; Peters, O. Z. Z. Chem. 1978, 18, 57. (d) Geffken, D. Arch.
Pharm. (Weinheim, Ger.) 1985, 318, 895.
(26) Nishiyama, K.; Miyata, I. Bull. Chem. Soc. J pn. 1985, 58, 2419.
(27) Mukaiyama, T.; Nohira, H.; Asano, S. Bull. Chem. Soc. J pn
1962, 35, 71.
(28) Freeman, J . P. J . Am. Chem. Soc. 1960, 82, 3869.
(29) Fernandez, S.; Menendez, E.; Gotor, V. Synthesis 1991, 713.
(30) Upon prolonged reaction times, increased ester 7e formation
was observed at the expense of the oxime 8.
4834 J . Org. Chem., Vol. 67, No. 14, 2002

5,5-Dimethyl-1,4,2-dioxazoles as Hydroxamic Acid Protecting Groups
(Scheme 4).31 To corroborate this mode of formation, the
acid chloride was allowed to react with dimethyloxaziri-
dine generated in situ, and this reaction also led to the
formation of O-acyl acetoneoxime 8 in 11% yield.
TABLE 1. P r otection of Selected Hyd r oxa m ic Acid s
SCHEME 4
By carefully considering the source of the various
impurities generated in the process, we reasoned that
employing higher dilution would minimize the formation
of dimers. Also, since initial screens revealed that a full
equivalent of acid was required to ensure reasonable rate,
it is preferable to utilize an anhydrous acid source. This
is especially important due to the fact that hydrolysis of
ketal produces ethanol, which eventually leads to in-
creased ethyl ester formation. With these considerations,
we sought to develop a general, high-yielding procedure
applicable for both aromatic and aliphatic systems.
Finding the right conditions to convert the primary
hydroxamic acid 1e to the corresponding dioxazoline 2e
would not prove to be an easy task. After screening a
wide variety of various acid/solvent combinations, we
found that the use of camphorsulfonic acid (CSA) in
methylene chloride offered the best reaction profile.
Gratifyingly, this procedure led to the desired protected
hydroxamic acid 2e in 73% yield admixed with only 11%
of the rearranged O-acyl acetoneoxime 8 (Table 1).32 It
is noteworthy that application of this procedure to all
other hydroxamic acids tested herein led to no observed
rearranged product. Furthermore, the amount of the
major ester byproduct was in the range of 3-6%. This
procedure was consistently high yielding for the aromatic
series as well as for the olefinic system.
to be resistant to those reaction conditions tested, except
in the cases of sodium hydroxide in methanol, which led
to the opened methyl ketal, and basic bleach, which
affected the deprotection of dioxazole 2e back to the
hydroxamic acid. However, these may be regarded as only
moderately reactive. Not unexpectedly, hydrogenation
conditions led the corresponding amides.
We further explored the versatility of dioxazolines
through R-functionalization. Gratifyingly, deprotonation
of 2e could be achieved using sec-butyllithium-TMEDA
in THF, and the resulting anion was reacted with methyl
iodide to produce the dioxazoline 2f in an unoptimized
yield of 68% (Scheme 5).
Deprotection was best performed in refluxing 2-pro-
panol, which minimized transesterification. Unfortu-
nately, the camphorsulfonic acid utilized in this process
could not be separated by extractive workup, or by
chromatography, and yields were rather low due to high
water solubility. This matter was easily resolved by
employing Nafion-H resin. The yields using this proce-
dure were consistently high, with trans-esterification
occurring in the range of 0-4% (Table 2).
SCHEME 5
To test the chemical compatibility of the dioxazoline
protective group with various reagents, the primary and
aromatic systems were subjected to a wide variety of
reaction conditions (Table 3) at room temperature for a
period of 24 h. In most cases, the dioxazolines were found
In summary, we have developed a general, high-
yielding procedure to protect hydroxamic acids as 5,5-
dimethyl-1,4,2-dioxazoles where both NH and OH are
derivatized in a nonprotic form. We further demonstrated
that they are stable to a wide variety of reaction condi-
tions and readily revert back to the hydroxamic acid by
Nafion-H in 2-propanol. The method is applicable to
primary, secondary, tertiary, and aromatic hydroxamic
acids, and the dioxazole provides a handle that allows
(31) Geffken, D.; Frobo¨se, J . J . Prakt. Chem. 1993, 335, 555.
(32) The reaction was performed on a 50 mmol scale. It was noted
that this reaction is scale-dependent as a smaller scale experiment on
5 mmol led to a lower yield of 53%. However, the yield on the latter
scale could be further increased to 74% by utilizing the diisopropyl
ketal.
J . Org. Chem, Vol. 67, No. 14, 2002 4835

Couturier et al.
TABLE 2. Dep r otection of Selected Hyd r oxa m ic Acid s
Exp er im en ta l Section
Gen er a l Meth od s. The 1H and 13C NMR spectra were
recorded on a 400 MHz spectrometer. Elemental analyses were
performed by Schwarzkopf Microanalytical Laboratory, Inc.
(Woodside, NY). Melting points were obtained from a capillary
apparatus and are uncorrected. Reactions were monitored by
TLC using ethyl acetate in hexanes as eluant, followed by
visualization with p-anisaldehyde stain (prepared from anis-
aldehyde (9.2 mL), acetic acid (3.75 mL), ethanol (338 mL,
95%), and sulfuric acid (12.5 mL)). Column chromatography
purifications were carried out on silica gel 40 µm flash
chromatography packing (60 Å pore diameter). Hydroxamic
acids 1a -f,h were prepared according to known literature
procedures.33
2,2-Dim eth yl-3-p h en ylp r op ion oh yd r oxa m ic Acid (1g).
To a solution of 2,2-dimethyl-3-phenylpropionic acid34 (1.00 g,
5.61 mmol) and N,N-dimethylformamide (500 µL) in dichloro-
methane (10 mL) was added oxalyl chloride (540 µL, 6.17
mmol) dropwise over 10 min. After additional stirring for 15
min, hydroxylamine hydrochloride (430 mg, 6.17 mmol) was
added, and the mixture was heated to reflux for 4 h. The
reaction mixture was cooled to room temperature and quenched
in saturated aqueous sodium bicarbonate. The organic layer
was separated, dried (Na2SO4), and concentrated. The residual
material was purified by recrystallization using dichloro-
methane/hexanes to provide the title compound (510 mg, 47%)
1
as a white solid: mp 127-130 °C; H NMR (400 MHz, CD3-
OD) δ 7.25-7.12 (m, 5H), 2.81 (s, 2H), 1.12 (s, 6H); 13C NMR
(100 MHz, CD3OD) δ 175.53, 138.03, 130.02, 127.85, 126.26,
46.23, 42.13, 23.96. Anal. Calcd for C11H15NO2: C, 68.37; H,
7.82; N, 7.25. Found: C, 68.51; H, 8.04, N, 7.23.
P r ep a r a tion of O-Hyd r ocin n a m oyl Aceton e Oxim e (8)
fr om Aceton e Oxim e. To an ice-cold solution of acetone
oxime (1.30 g, 17.79 mmol) and triethylamine (3.30 mL, 23.7
mmol) in dichloromethane (20.0 mL) was added hydrocin-
namoyl chloride (880 µL, 5.93 mmol). The resulting mixture
was heated to reflux for 5 h. The reaction was cooled to 0 °C
and quenched with water, and the organic layer was dried
(MgSO4), filtered, and concentrated. Flash chromatography of
the residual material using ethyl acetate/hexane (1:4) provided
the O-acylacetone oxime 8 (850 mg, 59%) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 3.02 (t, J )
7.5 Hz, 2H), 2.73 (t, J ) 7.5 Hz, 2H), 2.03 (s, 3H), 1.91 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.7, 164.2, 140.5, 128.8, 128.5,
126.6, 34.9, 31.2, 22.2, 17.1. Anal. Calcd for C12H15NO2: C,
70.22; H, 7.37; N, 6.82. Found: C, 70.32; H, 7.27, N, 6.62.
P r ep a r a tion of O-Hyd r ocin n a m oyl Aceton e Oxim e (8)
fr om 3,3-Dim eth yloxa zir id in e. To an ice-cold solution of
acetone (1.47 mL, 20.0 mmol) in diethyl ether (10 mL) was
added an aqueous solution of sodium hydroxide (2 M, 20 mL).
The resulting mixture was treated with an aqueous solution
of sodium hydroxide (2 M, 10 mL) and hydroxylamine-O-
sulfonic acid (2.30 g, 20.0 mmol) in water (20 mL) was added
to the above mixture, immediately followed by hydrocinnamoyl
chloride (3.37 g, 20.0 mmol). The temperature of the reaction
mixture was maintained below 10 °C by addition of crushed
ice. After 10 min, the mixture was washed with an aqueous
solution of hydroxylamine-O-sulfonic acid (1 g) in water (5 mL)
to remove unreacted acetone followed by another solution of
hydroxylamine-O-sulfonic acid (0.8 g) in aqueous sodium
carbonate (2 M, 8 mL) to remove residual acid chloride. The
organic layer was dried (MgSO4), filtered, and concentrated.
Flash chromatography of the residual material using ethyl
acetate/hexane (1:9) provided the O-acylacetone oxime 8 (451
mg, 11%) as colorless oil.
TABLE 3. Ch em ica l Sta bility of Dioxa zoles 2a a n d 2e
u n d er Va r iou s Rea ction Con d ition s
dioxazole/
dioxazole
reaction conditionsa
NaOH/H2O
byproduct
none
byproductb
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
2a
2e
none
NaOH/MeOH
NaOMe/THF
t-BuOK/THF
EtMgBr/THF
NaBH4/THF
BH3‚THF
ketal
hydroxamic acid
none
none
none
none
none
none
none
none
none
none
none
4.3:1
2.4:1
KMnO4/MeCN/H2O
none
NaOCl/1 M aq NaOH none
hydroxamic acid
none
8.6:1
MeI/THF
none
amide
amide
H2/Pd-C
<1:50
<1:50
a
Unless otherwise noted, all the experiments were performed
using equimolar amounts of reagents and dioxazoline at a con-
b
centration of 0.1 M for 24 h. Determined by 1H NMR.
(33) (a) Liguori, A.; Sindona, G.; Romeo, G.; Uccella, N. Synthesis
1987, 168. (b) Ngu, K.; Patel, D. V. J . Org. Chem. 1997, 62, 7088. (c)
Campbell, J . J .; Glover, S. A.; Hammond, G. P.; Rowbottom, C. A. J .
R-functionalization. Due to the wide use of hydroxamates
in the design of MMPs, this concept should be of utility
for preparing these inhibitors, in addition to other
hydroxamic acids of interest.
Chem Soc., Perkin Trrans.
2 1991, 2067. (d) Potapov, V. M.;
Dem’yanovich, V. M.; Khlebnikov, V. A. J . Org. Chem. USSR 1982,
1041.
(34) Creger, P. L. J . Am. Chem. Soc. 1967, 89, 2500.
4836 J . Org. Chem., Vol. 67, No. 14, 2002

5,5-Dimethyl-1,4,2-dioxazoles as Hydroxamic Acid Protecting Groups
1
Gen er a l P r otection P r oced u r e. To a solution of hydrox-
amic acid (5.0 mmol) and 2,2-diethoxypropane (15.0 mmol) in
dichloromethane (100 mL) was added camphorsulfonic acid
(5.0 mmol), and the resulting mixture was stirred at room
temperature. Upon reaction completion, the reaction was
quenched with a saturated aqueous solution of sodium bicar-
bonate (10 mL). The aqueous layer was repeatedly extracted
with diethyl ether, and the combined organic solutions were
dried (Na2SO4), filtered, and concentrated under vaccuo. The
residual material was purified by chromatography to yield the
5,5-dimethyl-1,4,2-dioxazole.
83 °C; H NMR (400 MHz, CDCl3) δ 7.47 (d, J ) 7.5 Hz, 2H),
7.40-7.34 (m, 3H), 7.17 (d, J ) 16.5 Hz, 1H), 6.60 (d, J ) 16.5
Hz, 1H), 1.65 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 158.739,
138.0, 135.2, 129.8, 129.1, 127.5, 115.7, 109.7, 25.1. Anal. Calcd
for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.95;
H, 6.62, N, 6.67.
Gen er a l Dep r otection P r oced u r e. To a solution of 5,5-
dimethyl-1,4,2-dioxazole (2.0 mmol) in isopropyl alcohol (11.0
mL) was added Nafion-H (400 mg), and the mixture was
heated to relux. Upon reaction completion, the Nafion-H beads
were removed and rinsed with 2-propanol (5.0 mL) followed
by methanol (5.0 mL). The combined organic solutions were
concentrated under vaccum, and the residual material was
purified by chromatography (1% methanol in dichloromethane,
then 10% methanol in dichloromethane) to yield the hydrox-
amic acid.
Ben zoyd r oxa m ic Acid (1a ). Reaction time: 30 h. Isolated
(274 mg, 98%) as a white crystalline solid: mp 128-130 °C;
1H NMR (400 MHz, CD3OD) δ 7.73 (d, J ) 7.0 Hz, 2H), 7.49
(t, J ) 7.0 Hz, 1H), 7.41 (t, J ) 7.0 Hz, 2H); 13C NMR (100
MHz, CD3OD) δ 167.22, 132.20, 131.78, 128.60, 127.04. Anal.
Calcd for C7H7NO2: C, 61.31; H, 5.14; N, 10.21. Found: C,
61.27; H, 5.29, N, 10.05.
5,5-Dim eth yl-3-p h en yl-1,4,2-d ioxa zole (2a ).23 Reaction
time: 3 h. Column chromatography (2% ether in pentane)
yielded 2a (789 mg, 89%) as an oil: 1H NMR (400 MHz, CDCl3)
δ 7.70 (d, J ) 8.5 Hz, 2H), 7.49-7.41 (m, 3H), 1.68 (s, 6H); 13
C
NMR (100 MHz, CDCl3) δ 158.5, 131.5, 128.9, 126.9, 123.9,
115.8, 25.1. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.55; H, 6.27, N, 7.68.
5,5-Dim eth yl-3-(p-m eth oxyph en yl)-1,4,2-dioxazole (2b).
Reaction time: 3 h. Column chromatography (5% ether in
pentane) yielded 2b (952 mg, 92%) as an oil: 1H NMR (400
MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2H), 6.91 (d, J ) 9.0 Hz,
2H), 3.84 (s, 3H), 1.66 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
162.2, 158.4, 128.6, 116.2, 115.3, 114.3, 55.6, 25.0. Anal. Calcd
for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.69;
H, 6.22, N, 6.73.
p-Meth oxyben zoh yd r oxa m ic Acid (1b). Reaction time:
6 h. Isolated (290 mg, 88%) as a white crystalline solid: mp
1
153-155 °C; H NMR (400 MHz, CD3OD) δ 7.71 (d, J ) 7.5
Hz, 2H), 6.95 (d, J ) 7.5 Hz, 2H), 3.81 (s, 3H); 13C NMR (100
MHz, CD3OD) δ 166.95, 162.78, 128.72, 124.28, 113.68, 54.73.
Anal. Calcd for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found:
C, 57.34; H, 5.58, N, 8.34.
5,5-Dim et h yl-3-(p -n it r op h en yl)-1,4,2-d ioxa zole (2c).23
Reaction time: 25 h. Column chromatography (10% ether in
pentane) yielded 2c (920 mg, 83%) as a white crystalline
1
solid: mp 146-149 °C; H NMR (400 MHz, CDCl3) δ 8.28 (d,
J ) 8.5 Hz, 2H), 7.95 (d, J ) 8.5 Hz, 2H), 1.71 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 157.0, 130.9, 129.8, 127.7, 124.1,
117.4, 25.2. Anal. Calcd for C10H10N2O4: C, 54.06; H, 4.54; N,
12.61. Found: C, 54.44; H, 4.72, N, 12.27.
p-Nitr oben zoh yd r oxa m ic Acid (1c). Reaction time: 20
h. Isolated (364 mg, 99%) as an off-white crystalline solid; 1H
NMR (400 MHz, CD3OD) δ 8.30 (d, J ) 8.0 Hz, 2H), 7.95 (d,
J ) 8.0 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 164.66, 149.89,
138.17, 128.34, 123.55.
p-P h en ylben zoh yd r oxa m ic Acid (1d ). Reaction time: 48
h. Isolated (413 mg, 97%) as a white crystalline solid: mp 103-
104 °C; 1H NMR (400 MHz, CD3OD) δ 7.82 (d, J ) 8.0 Hz,
2H), 7.70 (d, J ) 8.0 Hz, 2H), 7.66 (d, J ) 8.5 Hz, 2H), 7.47-
7.35 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 166.76, 144.60,
140.03, 128.87, 128.84, 127.93, 127.51, 126.94, 126.92. Anal.
Calcd for C13H11NO2: C, 73.23; H, 5.20; N, 6.57. Found: C,
73.36; H, 4.85, N, 6.38.
5,5-Dim eth yl-3-(p-bip h en yl)-1,4,2-d ioxa zole (2d ). Reac-
tion time: 4 h. Column chromatography (2% ether in pentane)
yielded 2d (1.15 g, 92%) as a white crystalline solid: mp 103-
104 °C; 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J ) 8.0 Hz,
2H), 7.71 (d, J ) 8.0 Hz, 2H), 7.65 (d, J ) 8.0 Hz, 2H), 7.47-
7.35 (m, 3H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 158.4,
144.4, 139.9, 128.9, 128.0, 127.17, 126.9, 126.8, 122.3, 115.9,
23.7. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53.
Found: C, 75.83; H, 6.05, N, 5.27.
3-P h en ylp r op ion oh yd r oxa m ic Acid (1e). Reaction time:
20 h. Isolated (280 mg, 85%) as a white crystalline solid: mp
5,5-Dim et h yl-3-(3-p h en ylp r op yl)-1,4,2-d ioxa zole (2e).
The reaction was performed on 50 mmol scale over 30 min.
Column chromatography (2% ether in pentane) yielded 2e
(7.49 g, 73%) as an oil: 1H NMR (400 MHz, CDCl3) δ
7.32-7.20 (m, 5H), 2.93 (t, J ) 8.0 Hz, 2H), 2.64 (t, J ) 8.0
Hz, 2H), 1.54 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.9,
139.9, 128.8, 128.6, 126.8, 114.9, 31.7, 25.9, 25.0. Anal. Calcd
for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.57; H,
7.44, N, 6.77.
5,5-Dim et h yl-3-(1-m et h yl-3-p h en ylp r op yl)-1,4,2-d iox-
a zole (2f). Reaction time: 2 h. Column chromatography (2%
ether in pentane) yielded 2f (854 mg, 78%) as an oil: 1H NMR
(400 MHz, CDCl3) δ 7.31-7.17 (m, 5H), 3.00 (dd, J ) 6.5, 13.0
Hz, 1H) 2.84 (m, 1H), 2.69 (dd, J ) 8.0, 13.0 Hz, 1H), 1.54 (s,
3H), 1.50 (s, 3H), 1.18 (d, J ) 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.2, 138.9, 129.3, 128.7, 126.7, 114.7, 39.7, 32.0,
24.9, 16.9. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N,
6.39. Found: C, 71.20; H, 7.83, N, 6.33.
1
79-80 °C; H NMR (400 MHz, CD3OD) δ 7.26-7.14 (m, 5H),
2.89 (t, J ) 8.0 Hz, 2H), 2.36 (t, J ) 8.0 Hz, 2H); 13C NMR
(100 MHz, CD3OD) δ 170.79, 140.72, 128.33, 128.22, 126.10,
34.55, 31.45. Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N,
8.48. Found: C, 65.48; H, 6.82, N, 8.39.
2-Meth yl-3-p h en ylp r op ion oh yd r oxa m ic a cId (1f). Re-
action time: 20 h. Isolated (358 mg, 99%) as a white crystalline
1
solid: mp 128-130 °C; H NMR (400 MHz, CD3OD) δ 7.26-
7.14 (m, 5H), 2.90 (dd, J ) 8.5, 13.5 Hz, 1H), 2.62 (dd, J )
7.5, 13.5 Hz, 1H), 2.46 (m, 1H), 1.13 (d, J ) 7.5 Hz, 3H); 13C
NMR (100 MHz, CD3OD) δ 174.17, 139.69, 128.82, 128.18,
126.12, 40.00, 39.66, 16.86. Anal. Calcd for C10H13NO2: C,
67.02; H, 7.31; N, 7.82. Found: C, 66.65; H, 7.10, N, 7.88.
2,2-Dim eth yl-3-p h en ylp r op ion oh yd r oxa m ic Acid (1g).
Reaction time: 48 h. Isolated (478 mg, 90%) as a white
crystalline solid: mp 127-130 °C.
5,5-Dim eth yl-3-(1,1-d im eth yl-3-p h en ylp r op yl)-1,4,2-d i-
oxa zole (2g). Reaction time: 3 h. Column chromatography
(5% ether in pentane) yielded 2g (1.07 g, 91%) as an oil; H
Cin n a m oh yd r oxa m ic Acid (1h ). Reaction time: 13 h.
Isolated (305 mg, 94%) as a white crystalline solid: 1H NMR
(400 MHz, CD3OD) δ 7.58-7.52 (m, 3H), 7.39-7.32 (m, 3H),
6.46 (d, J ) 12.0 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ
165.18, 140.52, 134.98, 129.72, 128.79, 127.60, 117.18.
P r ep a r a tion of 2f fr om 2e. To a solution of dioxazole 2e
(410 mg, 2.0 mmol) and TMEDA (0.60 mL, 4.0 mmol) in
anhydrous THF (40 mL) cooled at -100 °C, was added a
solution of sec-butyllithium (1.3 M in cyclohexane, 3.1 mL, 4
mmol) dropwise over 5 min. Immediately following this addi-
tion, methyl iodide (0.62 mL, 10 mmol) was quickly added, and
1
NMR (400 MHz, CDCl3) δ 7.29-7.14 (m, 5H), 2.83 (s, 2H), 1.58
(s, 6H), 1.20 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.6, 137.2,
130.6, 128.2, 126.9, 114.9, 45.7, 35.7, 25.2, 24.9. Anal. Calcd
for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.72;
H, 7.92, N, 6.00.
5,5-Dim eth yl-3-(cyn n a m yl)-1,4,2-d ioxa zole (2h ). Reac-
tion time: 1 h. Column chromatography (2% ether in pentane)
yielded 2h (765 mg, 75%) as a white crystalline solid: mp 81-
J . Org. Chem, Vol. 67, No. 14, 2002 4837

Couturier et al.
the reaction mixture was allowed to warm to room tempera-
ture. After 40 min, the reaction mixture was poured into a
saturated aqueous ammonium chloride solution (10 mL) and
extracted several times with ethyl acetate. The combined
organics were washed with brine, dried (MgSO4), filtered, and
concentrated. Flash chromatography of the residual material
using ethyl ether/pentane (1:19) provided the alkylated diox-
azole 2f (292 mg, 68%) as a colorless oil.
Ack n ow led gm en t . We thank Professors David
Collum (Cornell) and Steven Ley (Cambridge) for help-
ful discussions. We also thank Drs. Stephane Caron,
J ohn Ragan, and Keith DeVries for proofreading this
manuscript and insightful comments.
J O0256890
4838 J . Org. Chem., Vol. 67, No. 14, 2002