Site selectivity in the synthesis of O-methylated hydroxamic acids with diazomethane

Article abstract of DOI:10.1021/jo0012391

In this paper we report the results obtained by treating some selected hydroxamic acids with diazomethane in ethereal media. The multitask reagent diazomethane was used either as a base to induce deprotonation of the chosen hydroxamic acids or as conjugated acid which undergoes one-pot methylation processes of the generated anions. Product distributions clearly showed that a high site selectivity is expressed by the different deprotonated species in the alkylation processes. Under the adopted conditions, the prevalent site of methylation is in all the cases the oxygen of the hydroxamic acid. While in aliphatic hydroxamic acids only O-alkylation is observed, in the aromatic substrates, the NH group competes with the OH function as the nucleophilic site, although the OH reactivity still dominates.

Full text of DOI:10.1021/jo0012391

2246
J . Org. Chem. 2001, 66, 2246-2250
Site Selectivity in th e Syn th esis of O-Meth yla ted Hyd r oxa m ic
Acid s w ith Dia zom eth a n e
Antonella Leggio, Angelo Liguori,* Anna Napoli, Carlo Siciliano, and Giovanni Sindona
Dipartimento di Chimica, Universita` della Calabria, Via Ponte P. Bucci, Cubo 15/ C,
I-87030 Arcavacata di Rende (CS), Italy
A.Liguori@unical.it
Received August 14, 2000
In this paper we report the results obtained by treating some selected hydroxamic acids with
diazomethane in ethereal media. The multitask reagent diazomethane was used either as a base
to induce deprotonation of the chosen hydroxamic acids or as conjugated acid which undergoes
one-pot methylation processes of the generated anions. Product distributions clearly showed that
a high site selectivity is expressed by the different deprotonated species in the alkylation processes.
Under the adopted conditions, the prevalent site of methylation is in all the cases the oxygen of
the hydroxamic acid. While in aliphatic hydroxamic acids only O-alkylation is observed, in the
aromatic substrates, the NH group competes with the OH function as the nucleophilic site, although
the OH reactivity still dominates.
In tr od u ction
deprotonation sites has not yet been clearly performed
either in solution or in the gas phase. Past and recent
reports have shown that both OH and NH groups are
possible ionization sites in solution.8
Hydroxamic acids belong to an important class of
reagents in organic and inorganic chemistry,1 also being
valuable intermediates in pharmaceutical applications.2
In fact, they are used as siderophores, antibiotics, power-
ful chelating agents, and protease inhibitors.3 In this
context, methylated derivatives of hydroxamic acids are
active inhibitors of cyclooxygenase- and lypooxygenase-
mediated processes.4 More recently, great interest has
been addressed by theoretical studies dealing with the
determination of the proton affinities and the gas-phase
basicities of simple hydroxamic acids in order to elucidate
the solution behavior of more complex similar systems
having biological applications.5
The structure-function relationships of hydroxamic
acids still present some unresolved questions6 related to
the understanding of their exceptionally low pKa values,
if compared with structurally similar amide derivatives,
and to the evaluation of the structural features of their
conjugated bases.7 In fact, the identification of the
A study of the oxidation potentials9 and cation com-
plexation experiments in alkaline media10 of the hydrox-
amate ions have proposed the NH group to be the
preferred ionization site in polar solvents, such as di-
methyl sulfoxide, whereas the hydroxylic function acts
as proton donor in protic solvents.11 On the other hand,
the NH moiety seems to be able to furnish predominant
deprotonation with respect to the OH group under gas-
phase conditions.12 Moreover, extended spectroscopic
experiments (14N, 15N, and 17O heteronuclear NMR
relaxation with the aid of NOE evaluation)6,13 and
theoretical calculations (ab initio methods)14 have dem-
onstrated that the acidity of both NH and OH functions
(7) (a) Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13,
376. (b) Poth Brink, C.; Crumbliss, A. L. J . Org. Chem. 1982, 47, 1171.
(8) See: (a) Plapinger, R. E. J . Org. Chem. 1959, 24, 802. (b)
Steiberg, G. M.; Swidler, R. J . Org. Chem. 1965, 30, 2362. (c) Reichardt,
C. Angew. Chem., Int. Ed. Engl. 1965, 4, 29. (d) Gerstein, J .; J encks,
W. P. J . Am. Chem. Soc. 1967, 86, 4655. (e) Dessolin, M.; Laloi-Diard,
M.; Vilkas, M. Bull. Soc. Chim. Fr. 1970, 2573. (f) Reichardt, C. Angew.
Chem., Int. Ed. Engl. 1979, 18, 98. (g) Glover, S. A.; Goosen, A.;
McLelland, C. W.; Schoonraad, J . L. Tetrahedron 1987, 43, 2577. (h)
Exner, O.; Hradil, M.; Mollin, J . Collect. Czech. Chem. Commun. 1993,
58, 1109.
(9) Bordwell, F. G.; Harrelson, J . A., J r.; Linch, T.-Y. J . Org. Chem.
1990, 55, 3337.
(10) (a) Chatterjee, B. Coord. Chem. Rev. 1978, 26, 281. (b) Chang,
C. A.; Sekhar, V. C.; Garg, B. S.; Guziec, F. S.; Carrera Russo, T. Inorg.
Chim. Acta 1987, 135, 11.
(11) (a) Exner, O.; Holubek, J .Collect. Czech. Chem. Commun. 1965,
30, 940. (b) Exner, O.; Simon, W. Collect. Czech. Chem. Commun. 1965,
30, 4078.
(12) Decouzon, M.; Exner, O.; Gal, J .-F.; Maria, P.-C. J . Org. Chem.
1990, 55, 3980.
(13) (a) Lipczynska-Kochany, E.; Iwamura, H. J . Org. Chem. 1982,
47, 5277. (b) Brown, D. A.; Glass, W. K.; Mageswaran, R.; Mohammed,
S. A. Magn. Res. Chem. 1991, 29, 40.
(14) (a) Fitzpatrick, N. J .; Mageswaran, R. Polyhedron 1989, 8, 2255.
(b) Turi, L.; Dannenberg, J . J .; Rama, J . B.; Ventura, O. N. J . Phys.
Chem. 1992, 96, 3709. (c) Renko, M.; Mach, P.; Schleyer, P. v. R.; Exner,
O. J . Mol. Struct. (THEOCHEM) 1993, 279, 139. (d) Ventura, O. N.;
Rama, J . B.; Turi, L.; Dannenberg, J . J . J . Am. Chem. Soc. 1993, 115,
5754.
(1) Munson, J . W. Hydroxamic Acids In The Chemistry of Acid
Derivatives; Patai, S., Ed.; J . Wiley and Sons: New York, 1992; Suppl.
B, Vol. 2, p 849.
(2) (a) Summers, J . B.; Mazdiyasni, H.; Holm, J . H.; Ratajczyk, J .
D.; Dyer, R. D.; Carter, G. W. J . Med. Chem. 1987, 30, 574. (b) Kurzak,
B.; Kozlowski, H.; Farkas, E. Coord. Chem. Rev. 1992, 114, 169. (c)
Kazmiersky, W. M.; Wolberg, G.; Wilson, J . G.; Smith, S. R.; Williams,
D. S.; Thorp, H. H.; Molina, L. Proc. Natl. Acad. Sci. U.S.A. 1996, 93
(N17), 9138.
(3) (a) Arnold, M.; Brown, D. A.; Deeg, O.; Errington, W.; Haase,
W.; Herlihy, K.; Kemp, T. J .; Nimir, H.; Werner, R. Inorg, Chem. 1998,
37, 2920. (b) Inaoka, Y.; Takahashi, S.; Kinoshita, T. J . Antibiot. 1986,
39, 1378. (c) Brown, D. A.; Cuffe, L. P.; Deeg, O.; Errington, W.;
Fitzpatrick, N. J .; Glass, W. K.; Herlihy, K.; Kemp, T. J .; Nimir, H.
Chem. Commun. 1998, 2433. (d) Dobosz, A.; Fritsky, O.; Karaczyn,
A.; Kozlowski, H.; Sliva, T. Y.; Swiatek-Kozlowska, J . J . Chem. Soc.,
Dalton Trans. 1998, 1089.
(4) Musser, J . H.; Kreft, A. F.; Bender, R. H. W.; Kubrak, D. M.;
Grimes, D.; Carlson, R. P.; Hand, T. M.; Chang, J . J . Med. Chem. 1990,
33, 240.
(5) Mun˜oz-Caro, C.; Nin˜o, A.; Senent, M. L.; Leal, J . M.; Ibeas, S. J .
Org. Chem. 2000, 65, 405.
(6) For a recent and comprehensive report, see also: Bagno, A.;
Comuzzi, C.; Scorrano, G. J . Am. Chem. Soc. 1994, 116, 916 and
references therein.
10.1021/jo0012391 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/07/2001

Synthesis of O-Methylated Hydroxamic Acids
J . Org. Chem., Vol. 66, No. 7, 2001 2247
Sch em e 1. Meth yla tion of Hyd r oxa m ic Acid s 1a -e
Sch em e 2. Equ ilibr ia a n d Rea ction P a th w a ys in
th e Meth yla tion of Hyd r oxa m ic Acid s 1a -e
Ta ble 1. P r od u ct Distr ibu tion s Obta in ed in th e
Meth yla tion of Hyd r oxa m ic Acid s 1a -e
entry
hydroxamic acid
products
yields (%)
1
2
3
4
5
1a
1b
1c
1d
1e
2a , 5a , 6a
2b, 3b, 5b, 6b
2c, 5c, 6c
2d , 3d , 4d
2e, 3e, 4e
70, 3, 22
72, 5, 8, 10
69, 9, 18
85, 10, 3
81, 8, 5
isomerization at 150 °C into methyl (E)-O-methylbenzo-
1
hydroximate 3a . The latter provided H NMR data which
fully correlate with those reported in the literature17 for
is strongly affected by the structural characteristics of
the substrate, also depending on the solvent used in the
experimental investigations.15
the same compound. The two isomers 2a and 3a mainly
1
differ for their H NMR spectroscopic properties, showing
well distinguishable frequencies for both N- and C-
Resu lts a n d Discu ssion
methoxy substituents. The electron impact mass spec-
trum and the H NMR analysis of the side product 5a
1
To achieve the aim of a more profound evaluation
either of the acidic properties or the nucleophilic reac-
tivities of both NH and OH functions, we now propose a
novel tool based on the use of diazomethane. This
multitask reagent behaves as a base,16 generating the
methyldiazonium ion which can perform a selective
alkylation of the hydroxamate ions produced in an
ethereal solvent. Diazomethane might also prove useful
to open short and convenient synthetic routes to meth-
ylated derivatives of structurally complex hydroxamic
acids having biological importance. Finally, the avail-
ability of a one-pot selective methylation of hydroxamic
acid models might represent a remarkable tool to improve
the understanding of the structures and the reactivity
of their charged conjugated bases.
To evaluate the reaction with diazomethane, benzo-
hydroxamic acid 1a was chosen as a model compound for
its well-known ability to stabilize the negative charge on
the nitrogen atom of the corresponding hydroxamate ion.
Compound 1a reacts with 3 equiv of diazomethane in a
1:3 (v/v) tetrahydrofuran/diethyl ether solution to afford
methyl (Z)-O-methylbenzohydroximate 2a , methyl N-
methylbenzohydroxamate 5a , and methyl (Z)-benzohy-
droximate 6a (Scheme 1), whose respective overall yields
are reported in Table 1.
were found to be identical to those obtained from an
authentic sample of methyl N-methylbenzohydroxamate
synthesized by treatment of N,O-dimethylhydroxylamine
with benzoyl chloride. In the reaction of 1a with diazo-
methane, the product distribution appears to be related
to the hydrogen abstraction affording the charged species
I and II, and more closely to the proton-transfer equi-
libria which could allow the interconversion between the
same anions through an intramolecular hydrogen bond
(Scheme 2). The formation of dimethylated oximes of the
type 2 could be attributed to the reaction of the charged
intermediates II and III which are preliminary meth-
ylated at the anionic site to generate 4. Subsequent
alkylation of the O-methyl derivative 4 gives the final
dimethylated product 2. Instead, the hydroxamic acid
anion I, formally originated from a deprotonation process
occurring at the NH site, is believed to be responsible
for the formation of the monoalkylated oxime derivatives
6.
When 6a was treated with diazomethane, no reaction
was observed, and the monomethylated oxime precursor
was quantitatively recovered unchanged. The unsuccess-
ful alkylation of 6a to give the corresponding dimeth-
ylated product excludes the formation of 2a by the
intermediates involved in the path A. Furthermore, the
hypothesis that the conversion of 1a into 2a could occur
through the mechanism depicted in the path B is sup-
ported by the evidence that the methyl benzohydrox-
The correct configuration of the oxime ether 2a , the
major product reaction, was assigned after its thermal
(15) Lindberg, B.; Berndtsson, A.; Nilsson, R.; Nyholm, R.; Exner,
O. Acta Chem. Scand. A 1978, 32, 353.
(16) Zollinger, H. Diazo Chemistry II. Aliphatic, Inorganic and
Organometallic Compounds; VCH Publishers: New York, 1995; p 147.
(17) J ohnson, J . E.; Nalley, E. A.; Kunz, Y. K.; Springfield, J . R. J .
Org. Chem. 1976, 41, 252.

2248 J . Org. Chem., Vol. 66, No. 7, 2001
Leggio et al.
amate 4a is a real reaction intermediate, the existence
of which was confirmed by performing GC/MS analysis
of the crude mixture. The collected data clearly show that
paths A and B are competitively active in the reaction of
1a with diazomethane. The observed product distribution
could thus be explained on the basis of a comparable
reactivity of the anions I and II, determined by the
presence of a charge delocalization involving the nitrogen
atom in the former species and the phenyl group in the
latter charged structure.
The reaction of 1a with diazomethane also showed total
stereoselection. The exclusive formation of the (Z) oxime
6a can be attributed to its higher stability with respect
to the (E) isomer. This difference is probably due to a
minimization of the steric hindrance between the phenyl
substituent and the OH group in the (E) oxime and to
the possible formation of an intramolecular hydrogen
bond involving the oxygenated parts in the same isomer.
Finally, despite the previously reported procedure,18
methylation of benzohydroxamic acid 1a did not afford
other side products. In fact, the literature method gave
methyl O-methylbenzohydroximate, as a mixture of 2a
and 3a (45% total yield), 3,4-diphenyl-1,3,5-oxadiazolin-
2-one (42%), and traces of methyl benzoate, the last ones
probably arising from thermal degradation processes
operating when the reaction crude mixture is submitted
to distillation. The thermal effects on the stability of
mono- and dimethylated products were confirmed by
warming a crude mixture of 2a , 5a , and 6a in a screw-
capped vial at 150 °C for 24 h. Under the adopted
conditions, the formation of 3,4-diphenyl-1,3,5-oxadiazo-
lin-2-one and methyl benzoate was observed as detected
by GC/MS analysis.
The introduction of a substituent on the aromatic ring
of the hydroxamic acid structure does not alter the course
of the methylation. p-Butoxyphenylhydroxamic acid 1b
showed the same general behavior of 1a . In this case,
the electron-releasing group placed on the aryl moiety
introduces only a slight change in the product distribu-
tion with respect to that obtained from the treatment of
1a with the methylating agent. In fact, when 1b was
allowed to react with diazomethane under the usual
conditions (Scheme 1), methyl (Z)-O-methyl-p-butoxyphe-
nylhydroximate 2b was recovered as the prevalent
product in 72% total yield (Table 1). Only traces of the
(E) isomer 3b were also isolated (5%), whereas the side
products 5b and 6b were obtained in scarce overall yields
(8 and 10%, respectively). Moreover, alkylation of p-
chlorophenylhydroxamic acid 1c gave a product distribu-
tion analogous to that observed in the case of benzohy-
droxamic acid 1a . In fact, methyl (Z)-O-methyl-p-
chlorophenylhydroximate 2c, N-methyl-p-chlorophenyl-
hydroxamate 5c, and methyl (Z)-p-chlorophenylhydroxi-
mate 6c were recovered by chromatographic purification
in 69, 9, and 18% overall yields, respectively. Thus, the
product distributions observed in the treatment of aryl
hydroxamic acids 1a , 1b, and 1c with diazomethane do
not closely depend on the electronic effects exerted by the
substituent present on the aromatic ring of the hydrox-
amic acid.
droxamic acids (1d and 1e, respectively; Scheme 1) were
chosen as suitable models for the fulfillment of our
purpose. When 1d and 1e were allowed to react under
the experimental conditions adopted to carry out the
methylation, methyl O-methylphenylaceto- and methyl
O-methylpalmitohydroximate were obtained, each one as
a mixture of the corresponding (Z) and (E) isomers (2d ,
3d and 2e, 3e, respectively; Scheme 1), in appreciable to
good total yields (Table 1). In this case also, all the
examined reactions showed a preference toward the
formation of the oxime derivative having the (Z) config-
uration. Moreover, the observed results are consistent
with the assumption that the reactivity of the alkyl-
oxyanion III, in which the negative charge is localized
on the hydroximate oxygen, is remarkably increased with
respect to the corresponding aryl analogue, stabilized by
a charge conjugation involving the substituent group.
Hence the formation of the recovered products could be
exclusively rationalized on the basis of the path B
(Scheme 2), as also confirmed by the isolation and fully
characterization of the respective reaction intermediates
of the type 4.
Treatment of alkyl hydroxamic acids 1d and 1e with
diazomethane did not afford the corresponding N,O-
dimethylhydroxamates. The ambident nucleophile I is
probably the reactive species involved in the formation
of the dimethylated products 5a , 5b, and 5c. The nit-
ranion I, in fact, initially reacts with the methyldiazo-
nium ion to give the N-methylated intermediates which,
in turn, are subjected to a second alkylation step afford-
ing the N,O-dimethylhydroxamates. When the substitu-
ent R on the hydroxamic acid structure is an aryl group
(as in 1a , 1b, and 1c), the nitranion I also generate (O)-
methylhydroximates 6a , 6b, and 6c, which are preva-
lently obtained respect to the N,O-dimethylated deriva-
tives 5a , 5b, and 5c. This preferred O-methylation (path
A, Scheme 2), could be justified by a fast hard-hard
reaction driven by the presence of a preformed positive
charge on the methyldiazonium ion.
In all the examined cases the reaction between hy-
droxamic acids and diazomethane results in prevalent
formation of methyl O-methyl hydroxymates through a
process characterized by high site selectivity. The studied
methylations appear also to be stereocontrolled since the
Z isomer of each generated hydroxymate is recovered as
the major product of any process. Under the adopted
conditions, the conjugated acid methyldiazonium ion was
able to react with the obtained N- or O-hydroxamates
leading to processes whose reaction rates are determined
by the peculiar reactivity of each hydroxamic acid anion.
Proton abstraction and transfer equilibria generating
the anions from the respective hydroxamic acid are not
directly implicated in the control of the product distribu-
tions observed in the methylation processes. If the N2 loss
from methyldiazonium ion (paths A and B; Scheme 2)
was not considered as the rate-determining step of the
entire methylation processes, the charged electrophile
would be able to quench the conjugated bases derived
from the hydroxamic acids. Consequently, the observed
site selectivity in the product distributions should be
considered a valuable evidence of only the different acidic
properties of both NH and OH functionalities. On the
contrary, as reported for some model compounds in a
considerable study,19 the rate-determining step of the
To explain the role played by the substituent R on the
competitive alkylation of both NH and OH functionalities,
the behavior of some alkyl hydroxamic acids was finally
investigated. In particular, phenylaceto- and palmitohy-
(18) Arndt, F.; Scholtz, H. Annalen 1934, 510, 62.
(19) More O’Ferrall, R. A. Adv. Phys. Org. Chem. 1967, 5, 331.

Synthesis of O-Methylated Hydroxamic Acids
J . Org. Chem., Vol. 66, No. 7, 2001 2249
2a . IR (film): ν 3066 cm-1, 2939, 1613, 1573, 1320, 1054,
alkylation of the generated ions is considered to be the
reactive event occurring between the methyldiazonium
ion and the different nucleophiles involved in the above-
mentioned equilibria. Previous reports have been focused
on the possibility either of N or O deprotonation; however,
the relative reactivity of each conjugated base seems to
drive the product distribution in the methylation, rather
than the preferred H-extraction. In fact, all the hydrox-
amic acid anions react in a competitive manner with the
charged methyldiazonium ion, leading to a significant
shift of the ionization equilibria which, in turn, move to
the formation of the most reactive nucleophiles, affording
the prevalent reaction products.
1
773, 649. H NMR: δ 3.91 ppm (s, 3 H, OCH3), 3.92 (s, 3 H,
OCH3), 7.35-7.49 (m, 3 H, ArH), 7.60-7.72 (m, 2 H, ArH).
GC/MS: m/z, (%) 165 (57) [M+], 164 (67), 119 (39), 104 (100),
91 (38), 77 (62). Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.35; H, 6.70; N, 8.50. 5a . IR (film): ν
3060 cm-1, 2964, 1640, 1448, 1380, 786, 706. 1H NMR: δ 3.35
ppm (s, 3 H, NCH3), 3.53 (s, 3 H, OCH3), 7.35-7.48 (m, 3 H,
ArH), 7.61-7.71 (m, 2 H, ArH). GC/MS: m/z, (%) 165 (2) [M+],
105 (100), 77 (51). Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.40; H, 6.72; N, 8.49. 6a . IR (film): ν
3321 cm-1, 3070, 2948, 1638, 1325, 982, 773, 695. 1H NMR: δ
3.97 ppm (s, 3 H, OCH3), 7.36-7.49 (m, 3 H, ArH), 7.61-7.73
(m, 2 H, ArH), 8.70 (s, 1 H, OH). GC/MS: m/z, (%) 151 (14)
[M+], 150 (19), 134 (22), 119 (11), 103 (100), 91 (10), 77 (31).
Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00; N, 9.27. Found:
C, 63.60; H, 5.98; N, 9.28.
Isom er iza tion of Meth yl (Z)-O-Meth ylben zoh yd r oxi-
m a te (2a ). Pure 2a (0.5 g, 3.03 mmol) was warmed at 150 °C
in a tightly sealed screw-capped vial. After 48 h GC/MS
analysis of the recovered residue showed the presence of two
products corresponding to the isomers methyl (Z)-O-methyl-
benzohydroximate 2a (56%) and methyl (E)-O-methylbenzo-
hydroximate 3a (44%). The obtained isomers were then
separated by SCFC using light petroleum (bp 40-60 °C)/
diethyl ether (9:1, v/v) as eluent.
Exp er im en ta l Section
Commercially available reagents were purchased from
Aldrich Chemical Co. and used as supplied unless stated
otherwise. Solvents were purified and dried by the standard
1
procedures and distilled prior to use. H NMR were recorded
at 300 MHz using diluted solutions of each compound in CDCl3
as solvent and tetramethylsilane as internal standard. GC/
MS analyses were carried out using a 30 m HP-5MS capillary
column with a 0.25 mm internal diameter and a 0.25 µm film
thickness, purchased from Hewlett-Packard. Gas chromato-
graphic conditions for the analyses were as follows: the initial
oven temperature was 60 °C for 2 min and then programmed
to 280 °C at a rate of 8 °C/min with a 10 min final hold time;
the injection port temperature was set at 250 °C, and the
carrier gas (He) was maintained at a flow rate of 1.2 mL/min.
The mass detector was held at 280 °C and was operated in
the electron impact ionization mode (EIMS) at an electron
energy of 70 eV. Reaction mixtures were monitored by TLC
using Merck silica gel 60-F254 precoated glass plates. Short-
column flash chromatography (SCFC) was performed on Merck
Kieselgel 60H without gypsum. Elemental analysis were
performed on a Perkin-Elmer Elemental Analyzer. Hydrox-
amic acids 1a -e were prepared by treating the corresponding
ethyl ester with hydroxylamine hydrochloride in a methanolic
potassium hydroxide solution, as described in the literature.20
The diethyl ether solution of diazomethane was prepared from
N-methyl-N-nitrosourea using a classical procedure.21 The
concentration of the diazomethane solution (0.66 M) was
obtained by a back-titration performed with a standard benzoic
acid solution. Caution: diazomethane is highly toxic. Hence,
this reagent must carefully be handled.21 Diethyl ether solu-
tions of diazomethane are stable also for long periods if stored
on KOH pellets at -20 °C. All reactions were carried out under
inert atmosphere (N2).
3a . Colorless oil (0.2 g, 40% recovered yield). IR (film): ν
1
3056 cm-1, 2962, 1630, 1592, 1262, 1101, 798, 700. H NMR:
δ 3.80 ppm (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 7.37-7.43 (m,
3 H, ArH), 7.68-7.73 (m, 2 H, ArH). GC/MS: m/z, (%) 165
(68) [M+], 164 (61), 119 (36), 104 (100), 91 (33), 77 (58). Anal.
Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C,
65.46; H, 6.67; N, 8.50.
Syn th esis of 5a . Benzoyl chloride (0.281 g, 2 mmol) and
N,O-dimethylhydroxylamine hydrochloride (0.214 g, 2.2 mmol)
was dissolved in ethanol free chloroform (20 mL). The resulting
mixture was cooled to 0 °C, and dry triethylamine (0.31 mL,
2.2 mmol) was added. The homogeneous solution was stirred
at room temperature until complete conversion of the starting
chloride. Saturated aqueous NaHCO3 (10 mL) and brine (10
mL) were then added, and the mixture was extracted twice
with diethyl ether. The organic layer was dried (Na2SO4) and
evaporated to dryness to afford crude 5a which was purified
by SCFC using light petroleum (bp 40-60 °C)/diethyl ether
(7:3, v/v) as eluent (0.297 g, 90%).
IR (film): ν 3060 cm-1, 2964, 1640, 1448, 1380, 786, 706.
1H NMR: δ 3.35 ppm (s, 3 H, NCH3), 3.53 (s, 3 H, OCH3),
7.41 (m, 3 H, ArH), 7.68 (m, 2 H, ArH). GC/MS: m/z, (%) 165
(12) [M+], 134 (18), 105 (100), 77 (51). Anal. Calcd for C9H11
-
NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.49; H, 6.67; N,
8.52.
Tr ea tm en t of 6a w ith Dia zom eth a n e. A solution of 6a
(0.305 g, 2 mmol) in dry tetrahydrofuran (1.1 mL) was allowed
to react with a diethyl ether solution of diazomethane (3.3 mL,
2.2 mmol) at room temperature for 24 h. After evaporation of
the volatiles, unreacted 6a was quantitatively recovered.
Th er m a l Degr a d a tion of 2a , 5a , a n d 6a . A 0.5 g amount
of a crude mixture obtained from the reaction of 1a with
diazomethane was warmed at 150 °C for 24 h in a tightly
sealed screw-capped vial. The mixture was then cooled at room
temperature and fractionated by SCFC using light petroleum
(bp 40-60 °C)/diethyl ether (9:1, v/v) as eluent. Purification
afforded the two isomers 2a and 3a , and methyl benzoate, in
18, 30, and 36% yield, respectively. GC-MS analysis performed
on the crude mixture also revealed the presence of 3,4-
diphenyl-1,3,5-oxadiazolin-2-one. GC/MS: m/z, (%) 238 (8)
[M+], 194 (10), 119 (35), 103 (100), 91 (18), 76 (33).
Meth yla tion of p-Bu toxyp h en ylh yd r oxa m ic Acid (1b).
A solution of 1b (0.5 g, 2.39 mmol) in dry tetrahydrofuran (5
mL) was allowed to react with a diethyl ether solution of
diazomethane (11 mL; 7.26 mmol) to give a crude oil (0.55 g)
which was fractioned by SCFC using chloroform/methanol (9:
1, v/v) as eluent. Chromatographic purification afforded 2b
(0.41 g, 72%), 3b (28 mg, 5%), 5b (46 mg, 8%), and 6b (54 mg;
10%), each compound as a colorless oil.
Meth yla tion of Hyd r oxa m ic Acid s 1a -e. General Pro-
cedure. A 0.66 M solution of diazomethane in diethyl ether (3
mmol) was added to a solution of the appropriate hydroxamic
acid 1a -e (1 mmol) in dry tetrahydrofuran. The reaction
mixture was stirred for 24 h at room temperature. After this
time, TLC analysis showed complete conversion of the precur-
sor. Evaporation of the solvent under reduced pressure gave
crude product which was chromatographed to afford a mixture
of the corresponding methyl (Z)-O-methylhydroximate 2,
methyl (E)-O-methylhydroximate 3, methyl hydroxamate 4,
methyl N-methylhydroxamate 5, and methyl (Z)-hydroximate
6.
Meth yla tion of Ben zoh yd r oxa m ic Acid (1a ). A solution
of 1a (2.0 g, 14.6 mmol) in dry tetrahydrofuran (20 mL) was
allowed to react with a diethyl ether solution of diazomethane
(66.3 mL, 43.8 mmol) to give a crude oil (2.4 g). SCFC of the
recovered material using light petroleum (bp 40-60 °C)/diethyl
ether (7:3, v/v) as eluent afforded 2a (1.69 g, 70%), 5a (73 mg,
3%), and 6a (0.49 g, 22%), each one as colorless oil.
(20) Liguori, A.; Sindona, G.; Romeo, G.; Uccella, N. Synthesis 1987,
168.
(21) Arndt, F. Org. Synth. 1934, 2, 165.

2250 J . Org. Chem., Vol. 66, No. 7, 2001
Leggio et al.
2b. IR (film): ν 3062 cm-1, 2961, 1613, 1560, 1320, 1250,
773. 1H NMR: δ 0.97 ppm (t, J ) 7.3 Hz, 3 H, OCH2CH2-
CH2CH3), 1.48 (m, 2 H, OCH2CH2CH2CH3), 1.75 (m, 2 H,
OCH2CH2CH2CH3), 3.89 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3),
3.95 (t, J ) 6.5 Hz, 2 H, OCH2CH2CH2CH3), 6.87 (d, J ) 9.0
Hz, 2 H, ArH), 7.75 (d, J ) 9.0 Hz, 2 H, ArH). GC/MS: m/z,
(%) 237 (77) [M+], 180 (100), 150 (11), 135 (47), 120 (95), 107
(21). Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90.
(23), 90 (11), 75 (28). Anal. Calcd for C8H8ClNO2: C, 51.77; H,
4.34; Cl, 19.10; N, 7.55. Found: C, 51.76; H, 4.35; Cl, 19.08;
N, 7.55.
Meth yla tion of P h en yla cetoh yd r oxa m ic Acid (1d ). A
solution of 1d (2 g, 13.2 mmol) in dry tetrahydrofuran (18 mL)
was allowed to react with a diethyl ether solution of diazo-
methane (60 mL, 39.6 mmol) to give a crude oil (2.35 g). The
recovered material was fractioned by SCFC performed using
light petroleum (bp 40-60 °C)/diethyl ether (1:1, v/v) as eluent
to afford 2d (2.0 g, 85%), 3d (0.24 g, 10%), and 4d (67 mg,
3%), each compound as a colorless oil.
Found: C, 65.75; H, 8.09; N, 5.91. 3b. IR (film): ν 3062 cm-1
,
1
2961, 1607, 1510, 1320, 1259, 773. H NMR: δ 0.99 ppm (t, J
) 7.4 Hz, 3 H, OCH2CH2CH2CH3), 1.50 (m, 2 H, OCH2CH2CH2-
CH3), 1.76 (m, 2 H, OCH2CH2CH2CH3), 3.80 (s, 3 H, OCH3),
3.81 (s, 3 H, OCH3), 3.97 (t, J ) 6.6 Hz, 2 H, OCH2CH2CH2-
CH3), 6.87 (d, J ) 9.0 Hz, 2 H, ArH), 7.75 (d, J ) 9.0 Hz, 2H,
ArH). GC/MS: m/z, (%) 237 (79) [M+], 180 (100), 150 (12), 135
(47), 120 (90), 107 (21). Anal. Calcd for C13H19NO3: C, 65.80;
H, 8.07; N, 5.90. Found: C, 65.77; H, 8.06; N, 5.89. 5b. IR
(film): ν 3024 cm-1, 2956, 1718, 1606, 1560, 1435, 1250, 790.
1H NMR: δ 0.96 ppm (t, J ) 7.3, 3 H, OCH2CH2CH2CH3), 1.48
(m, 2 H, OCH2CH2CH2CH3), 1.76 (m, 2 H, OCH2CH2CH2CH3),
3.33 (s, 3 H, NCH3), 3.54 (s, 3 H, OCH3), 3.98 (t, J ) 6.5 Hz,
2 H, OCH2CH2CH2CH3), 6.87 (d, J ) 8.9 Hz, 2 H, ArH), 7.69
(d, J ) 8.9 Hz, 2 H, ArH). GC/MS: m/z, (%) ) 237 (77) [M+],
177 (95), 150 (5), 121 (100), 93 (9), 65 (7). Anal. Calcd for
2d . IR (film): ν 3030 cm-1, 2946, 1638, 1495, 1310, 1259,
1
1088, 701. H NMR: δ 3.30 ppm (s, 2H, CH2Ph), 3.58 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 7.20-7.38 (m, 5H, ArH). GC/MS:
m/z, (%) 179 (24) [M+], 148 (13), 132 (100), 105 (16), 91 (68),
77 (18). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.98; H, 7.29; N, 7.84. 3d . IR (film): ν 3020 cm-1
,
2950, 1628, 1450, 1315, 1260, 1060, 705. 1H NMR: δ 3.30 ppm
(s, 2 H, CH2Ph), 3.34 (s, 3 H, OCH3), 3.41 (s, 3 H, OCH3), 7.22-
7.41 (m, 5 H, ArH). GC/MS: m/z, (%) 179 (34) [M+], 148 (12),
132 (100), 105 (16), 91 (70), 77 (18). Anal. Calcd for C10H13
-
NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.05; H, 7.33; N,
7.80. 4d . IR (film): ν 3356 cm-1, 3029, 2952, 2361, 1663, 1602,
720. 1H NMR: δ 3.20 ppm (s, 2 H, CH2Ph), 3.62 (s, 3 H, OCH3),
5.54 (s, 1 H, NH), 7.21-7.43 (m, 5 H, ArH). GC/MS: m/z, (%)
165 (27) [M+], 148 (18), 118 (37), 91 (100), 77 (38). Anal. Calcd
for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.43; H,
6.69; N, 8.41.
Meth yla tion of P a lm itoh yd r oxa m ic Acid (1e). A solu-
tion of 1e (0.8 g, 2.95 mmol) in dry tetrahydrofuran (18 mL)
was allowed to react with a diethyl ether solution of diazo-
methane (14 mL, 9.24 mmol) to give a crude oil (0.8 g). The
recovered material was fractioned by SCFC performed using
chloroform/methanol (1:1, v/v) as eluent to afford 2e (0.72 g,
81%), 3e (70 mg, 8%), and 4e (42 mg, 5%), each compound as
a colorless oil.
C
13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.78; H,
8.07; N, 5.88. 6b. IR (film): ν 3330 cm-1, 3060, 2950, 1620,
1350, 987, 773. 1H NMR: δ 0.96 ppm (t, J ) 7.4 Hz, 3 H, OCH2-
CH2CH2CH3), 1.47 (m, 2 H, OCH2CH2CH2CH3), 1.74 (m, 2 H,
OCH2CH2CH2CH3), 3.87 (s, 3 H, OCH3), 3.98 (t, J ) 6.6 Hz, 2
H, OCH2CH2CH2CH3), 7.55 (d, J ) 8.8 Hz, 2 H, ArH), 7.98 (d,
J ) 8.8 Hz, 2 H, ArH), 8.30 (s, 1 H, OH). GC/MS: m/z, (%)
223 (33) [M+], 191 (3), 175 (15), 166 (55), 150 (25), 119 (100).
Anal. Calcd for C12H17NO3: C, 64.56; H, 7.67; N, 6.27. Found:
C, 64.52; H, 7.69; N, 6.29.
Meth yla tion of p-Ch lor op h en ylh yd r oxa m ic Acid (1c).
A solution of 1c (0.8 g, 4.7 mmol) in dry tetrahydrofuran (7
mL) was allowed to react with a diethyl ether solution of
diazomethane (21.3 mL, 14.1 mmol) to give a crude oil (0.92
g). The recovered material was fractioned by SCFC performed
using light petroleum (bp 40-60 °C)/diethyl ether (1:1, v/v)
as eluent to afford 2c (0.65 g, 69%), 5c (84.4 mg, 9%), and 6c
(0.16 g, 18%), each compound as colorless oil.
2e. IR (film): ν 2924 cm-1, 2853, 1640, 1465, 1310, 1064.
1H NMR: δ 0.88 ppm [t, J ) 6.5 Hz, 3 H, CH2(CH2)13CH3],
1.05-1.28 [m, 26 H, CH2(CH2)13CH3], 2.22 [t, J ) 6.6 Hz, 2 H,
CH2(CH2)13CH3], 3.75 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3). GC/
MS: m/z, (%) 268 (1), 253 (68), 130 (7), 116 (24), 103 (100), 43
(77). Anal. Calcd for C18H37NO2: C, 72.19; H, 12.45; N, 4.68.
2c. IR (film): ν 3063 cm-1, 2942, 1612, 1568, 1320, 1094,
773. 1H NMR: δ 3.92 ppm (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3),
7.33 (d, J ) 9.1 Hz, 2 H, ArH), 7.58 (d, J ) 9.1 Hz, 2 H, ArH).
GC/MS: m/z, (%) 201 (21), 200 (24), 199 (64) [M+], 198 (75),
153 (47), 140 (30), 138 (100), 125 (27), 111 (29), 75 (19). Anal.
Calcd for C9H10ClNO2: C, 54.15; H, 5.05; Cl, 17.76; N, 7.02.
Found: C, 54.18; H, 5.03; Cl, 17.75; N, 7.02. 5c. IR (film): ν
3072 cm-1, 2970, 1645, 1440, 1360, 1096, 780. 1H NMR: δ 3.48
ppm (s, 3 H, NCH3), 3.51 (s, 3 H, OCH3), 7.38 (d, J ) 8.8 Hz,
2 H, ArH), 7.65 (d, J ) 8.8 Hz, 2 H, ArH). GC/MS: m/z, (%) )
201 (1), 199 (4) [M+], 141 (42), 139 (100), 113 (35), 111 (37),
75 (16). Anal. Calcd for C9H10ClNO2: C, 54.15; H, 5.05; Cl,
17.76; N, 7.02. Found: C, 54.15; H, 5.06; Cl, 17.74; N, 7.01.
6c. IR (film): ν 3325 cm-1, 3072, 2945, 1648, 1332, 1094, 980,
773. 1H NMR: δ 4.00 ppm (s, 3 H, OCH3), 7.32 (d, J ) 10.0
Hz, 2 H, ArH), 7.60 (d, J ) 10.0 Hz, 2 H, ArH), 8.27 (s, 1 H,
OH). GC/MS: m/z, (%) 189 (5), 187 (17) [M+], 186 (22), 185
(56), 184 (72), 168 (20), 155 (13), 153 (56), 141 (11), 140 (34),
139 (56), 138 (100), 137 (52), 125 (20), 113 (11), 111 (36), 102
Found: C, 72.22; H, 12.48; N, 4.67. 3e. IR (film): ν 2930 cm-1
,
2845, 1636, 1450, 1320, 1060. 1H NMR: δ 0.88 ppm [t, J )
6.5 Hz, 3 H, CH2(CH2)13CH3], 1.04-1.27 [m, 26 H, CH2(CH2)13-
CH3], 2.32 [t, J ) 6.5 Hz, 2 H, CH2(CH2)13CH3], 3.64 (s, 3 H,
OCH3), 3.71 (s, 3 H, OCH3). GC/MS: m/z, (%) 268 (1), 253 (81),
130 (7), 116 (24), 103 (100), 43 (64). Anal. Calcd for C18H37
-
NO2: C, 72.19; H, 12.45; N, 4.68. Found: C, 72.21; H, 12.47;
N, 4.67. 4e. IR (film): ν 3310 cm-1, 2920, 2852, 1672, 1467,
984. 1H NMR: δ 0.88 ppm [t, J ) 6.0 Hz, 3 H, CH2(CH2)13CH3],
1.10-1.28 [m, 26 H, CH2(CH2)13CH3], 2.42 [t, J ) 6.6 Hz, 2 H,
CH2(CH2)13CH3], 3.65 (s, 3 H, OCH3), 5.62 (s, 1 H, NH). GC/
MS: m/z, (%) 239 (100), 103 (28), 85 (36), 71 (56), 57 (84), 43
(76). Anal. Calcd for C17H35NO2: C, 71.52; H, 12.36; N, 4.91.
Found: C, 71.48; H, 12.37; N, 4.92.
Ack n ow led gm en t. This work was supported by
MURST grants.
J O0012391