One-step synthesis of O-benzyl hydroxamates from unactivated aliphatic and aromatic esters

Article abstract of DOI:10.1021/jo0509713

We have developed a simple and high yielding one-step method for the synthesis of hydroxamate derivatives directly from a broad range of unactivated esters and the anion of O-benzyl-hydroxylamine generated in situ. The reaction takes place in minutes at -

Full text of DOI:10.1021/jo0509713

A one-step conversion of esters into hydroxamates
should therefore save both the hydrolysis and the poten-
tially troublesome activation steps. In fact, esters have
been successfully reacted with O-Bn hydroxylamine. To
overcome the alleged poor electrophilicity of unactivated
aliphatic esters, AlMe3 is yet necessary, the reaction
usually being carried out in THF or chlorinated solvents.4
This method is quite limited in scope because of envi-
ronmental concerns and poor functional group tolerance
associated with the use of the hazardous and very
reactive AlMe3.
Within the frame of a research project dealing with the
synthesis of fluorinated matrix metalloproteinases in-
hibitors,5 we decided to explore the feasibility of a one-
step protocol for the synthesis of hydroxamates directly
from esters and O-Bn hydroxylamine. In this article we
show that readily available methyl or ethyl esters
themselves are excellent electrophiles in the reaction
with the anion of O-Bn-hydroxylamine in the absence of
any activator.6 The reaction is operatively simple, takes
place smoothly and efficiently at -78 °C in THF, and is
very broad in scope.
One-Step Synthesis of O-Benzyl
Hydroxamates from Unactivated Aliphatic
and Aromatic Esters
Arnaud Gissot,* Alessandro Volonterio, and
Matteo Zanda*
C.N.R.-I.C.R.M., sezione “A. Quilico” and Dipartimento
C.M.I.C. “G. Natta”, Politecnico di Milano, via Mancinelli 7,
I-20131 Milan, Italy
matteo.zanda@polimi.it
Received May 16, 2005
In a first set of experiments, different organic bases
were tested in the reaction of ethyl benzoate with O-Bn-
hydroxylamine (Table 1). Thus, a mixture of O-Bn-
hydroxylamine hydrochloride and ethyl benzoate (1
equiv) in dry THF was treated with the base (3.1 equiv).
In a control reaction with triethylamine as a base,
neutral O-Bn hydroxylamine proved unreactive at room
temperature (entry 1). Although no reaction was observed
at -78 °C in the presence of the stronger KH base (entry
2), the desired O-Bn hydroxamate 1a was obtained in a
satisfactory 76% yield at room temperature (entry 3). At
least 3 equiv of base are necessary for this transforma-
tion, the first to neutralize hydrochloric acid, the second
to form the nucleophilic N-centered anion, and the third
We have developed a simple and high yielding one-step
method for the synthesis of hydroxamate derivatives directly
from a broad range of unactivated esters and the anion of
O-benzyl-hydroxylamine generated in situ. The reaction
takes place in minutes at -78 °C. Very importantly, the
method was successfully employed with enolizable esters,
including chiral R-amino acid esters and peptides, with no
trace of racemization/epimerization at the R carbon detected.
Hydroxamic acids are of utmost importance in the field
of bioorganic and coordination chemistry. They indeed
feature excellent bioavailability and count among the best
ligands known for most biologically relevant metals. They
are for instance found in the structure of numerous drugs
that either trigger metal-dependent proteins or are
involved in the regulation of intracellular concentrations
of metals such as iron and others.1 Their biological
significance is further illustrated by the number of
methods that have been and still are developed for their
chemical synthesis.2 These methods overwhelmingly
make use of activated forms of carboxylic acids that are
reacted with O-Bn hydroxylamine to give O-Bn hydrox-
amates, a conveniently protected form of free hydroxamic
acids, each method differing in the activating group used.
Hydrolysis is thus a prerequisite if very common precur-
sors such as esters are to be converted into hydrox-
amates.3 Besides, many carboxylic acids proved reluctant
in the activation step resulting in poor yields in the
coupling reaction.
(3) (a) Moriyama, H.; Tsukida, T.; Inoue, Y.; Kondo, H.; Yoshino,
K.; Nishimura, S. I. Bioorg. Med. Chem. Lett. 2003, 13, 2737-2740.
(b) Cherney, R. J.; Duan, J. J. W.; Voss, M. E.; Chen, L.; Wang, L.;
Meyer, D. T.; Wasserman, Z. R.; Hardman, K. D.; Liu, R. O.; Covington,
M. B.; Qian, M.; Mandlekar, S.; Christ, D. D.; Trzaskos, J. M.; Newton,
R. C.; Magolda, R. L.; Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2003,
46, 1811-1823. (c) Fujisawa, T.; Igeta, K. Odake, S.; Morita, Y.;
Yasuda, J.; Morikawa, T. Bioorg. Med. Chem. 2002, 10, 2569-2581,
(d) Kamimura, A.; Morita, R.; Matsuura, K.; Omata, Y.; Shirai, M.
Tetrahedron Lett. 2002, 43, 6189-6191. (e) Durham, B. T.; Miller, M.
J. Org. Lett. 2002, 4, 135-138.
(4) See for instance: (a) Pirrung, M. C.; Chau, J. H. L. J. Org. Chem.
1995, 60, 8084-8085. (b) Durham, T. B.; Miller, M. J. J. Org. Chem.
2003, 68, 27-34. (c) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S.
J. Am. Chem. Soc. 2000, 122, 2995-3000. (d) Banfi, L.; Cascio, G.;
Guanti, G.; Manghisi, E.; Narisano, E.; Riva, R. Tetrahedron 1994,
50, 11967-11982.
(5) Zanda, M. New. J. Chem. 2004, 28, 1401-1411.
(6) A classical protocol for the synthesis of Weinreb amides consists
of the treatment of methyl or ethyl esters with the anion of N,O-
dimethyl hydroxylamine. This concept is thus not new, but as we shall
see later, the conditions employed for the synthesis of Weinreb amides
are not suitable for the synthesis of O-Bn hydroxamates. For examples
of synthesis of Weinreb amides directly from esters, see: (a) Davis, F.
A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855-3857 (b) Ducharme,
Y.; Friesen, R. W.; Blouin, M.; Coˆte´, B.; Dube´, D.; Ethier, D.; Frenette,
R.; Laliberte´, F.; Mancini, J. A.; Masson, P.; Styhler, A.; Young, R. N.;
Girard, Y. Bioorg. Med. Chem. Lett. 2003, 13, 1923-1926, (c) Papaio-
annou, N.; Blank, J. T.; Miller, S. J. J. Org. Chem. 2003, 68, 2728-
2734, (d) Miller, A. K.; Banghart, M. R.; Beaudry, C. M.; Suh, J. M.;
Trauner, D. Tetrahedron 2003, 59, 8919-8930, (e) Wender, P. A.;
Koehler, M. F. T.; Sendzik, M. Org. Lett. 2003, 5, 4549-4552.
(1) (a) Abbenante, G.; Fairlie, D. P. Med. Chem. 2005, 1, 71-104.
(b) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H. Chem.
Rev. 1999, 99, 2735-2776. (c) Muri, E. M. F.; Nieto, M. J.; Sindelar,
R. D.; Williamson, J. S. Curr. Med. Chem. 2002, 9, 1631-1653. (d)
Marmion, C. J.; Griffith, D.; Nola, K. B. Eur. J. Inorg. Chem. 2004,
3003-3016.
(2) For recent examples: (a) De Luca, L.; Giacomelli, G.; Taddei,
M. J. Org. Chem. 2001, 66, 2534-2537. (b) Sibi, M. P.; Hasegawa, H.;
Ghorpade, S. R. Org. Lett. 2002, 4, 3343-3346. (c) Giacomelli, G.;
Porcheddu, A.; Salaris, M. Org. Lett. 2003, 5, 2715-2717 and refer-
ences therein.
10.1021/jo0509713 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/13/2005
J. Org. Chem. 2005, 70, 6925-6928
6925

TABLE 1. Reaction of Ethyl Benzoate and
°C in THF, affording the hydroxamate 1h quantitatively.
Cyclic enolizable esters such as R-methyl â-lactone and
γ-lactone also reacted effectively affording the hydrox-
amates HOCH2CH(CH3)CONHOBn (1i) and HO(CH2)2-
CH(CH3)CONHOBn (1j). Interestingly, chiral O-Bn hy-
droxamate 1k was obtained in good yields without
noticeable epimerization of the R position (1H and 13C
NMR analysis).
Given the significance of amino acid and peptide
derived hydroxamates, the method was also probed with
such derivatives such as N-Boc-Ala, N-Cbz-Glu, and
N-Boc-Ser methyl esters.
O-Bn-Hydroxylamine with Different Bases
entry
base
T (°C)
time (min)
yield of 1a (%)
1
2
3
4
5
6
TEA
25
-78
25
-78
-78
-78
360
240
120
20
0
0
76
47 a
86
95
KH
KH
n-BuLi
NaHMDS
LiHMDS
20
10
These substrates proved very reactive at -78 °Csno
protection of the free hydroxyl and carboxylic positions
was required using an additional equivalent of bases
affording the corresponding O-Bn hydroxamates 1l, 1m,
and 1n, respectively, in good to excellent yields.10 Quite
surprisingly, and to our delight, the stereochemistry of
the R-amino acidic carbon was preserved.11 The preserva-
tion of the stereochemical purity and the fact that 4.1
equiv of LiHMDS (or 5.1 in the case of Glu and Ser, which
have two acidic protons) are sufficient to perform the
reaction strongly suggest that deprotonation at the
R-carbon does not take place.12 The method could be
extended to peptidic esters as well, as demonstrated by
the formation of the O-Bn hydroxamate Cbz-Phe-Ala-
NHOBn (1p) from the corresponding dipeptide methyl
ester. In this case too, no trace of epimerization was
a Valerophenone was also obtained (40% yield) together with a
minor uncharacterized impurity.
to deprotonate the acidic hydroxamate proton of the
product. Commercially available solutions of strong
organic bases were used in the following experiments
(entries 4-6). Slow addition of n-BuLi at -78 °C to the
mixture of ester and O-Bn hydroxylamine hydrochloride
did produce 1a, although in modest yield (entry 4). The
attack of n-BuLi directly onto the carbonyl competes with
the desired coupling reaction as evidenced by the forma-
tion of valerophenone in 40% yield.7 We nevertheless
found that side reactions are suppressed using sodium
and lithium hexamethyldisilazide instead. Both afforded
the desired 1a in minutes and in excellent yield at -78
°C in THF (entries 5 and 6). The lithium salt of O-Bn
hydroxylamine proved more reactive over the sodium
derivative, perhaps due to its higher solubility in THF
at low temperatures, and was therefore used to study the
scope of the reaction (Table 2).
Electron-rich (R1 ) OMe) or -poor (R1 ) F) aromatics
gave the desired products 1b and 1c, respectively, in good
yields. Surprisingly, the nitro-substituted 1d was ob-
tained in 37% yield only from the highly activated 4-nitro
methyl benzoate.8 Heteroaromatic furyl and nicotinic
esters gave 1e and 1f in very good yields. No aza-Michael
addition of the nucleophile was observed with methyl
cinnamate, the desired hydroxamate 1g being obtained
quantitatively. Quite surprisingly, enolizable substrates
were also found very reactive provided that an additional
equivalent of base and a different addition sequence were
used.9 For instance, ethyl hydrocinnamate reacted virtu-
ally instantaneously when added slowly to a mixture of
O-Bn hydroxylamine and 4.1 equiv of LiHMDS at -78
detected despite the use of 5.1 equiv of base (1H and 13
NMR analysis).
C
In conclusion, we have disclosed a simple, straight-
forward, and high yielding method for the one-step
synthesis of O-Bn hydroxamates from a broad range of
unactivated esters. Very importantly, enolizable esters,
R-amino acid esters, and peptide esters were also suc-
cessfully reacted with no trace of racemization at the R
carbon. In the optimized experimental protocol for non-
enolizable esters, a mixture of O-Bn-hydroxylamine
hydrochloride and ester in dry THF was treated at -78
°C with 3 equiv of LiHMDS delivering in few minutes
the desired O-Bn hydroxamate. With enolizable esters
or esters containing acidic protons (such as amino acid
esters and peptide esters), addition of the ester to the
mixture of O-Bn hydroxylamine hydrochloride and 3 +
n equivalents of base (n is the number of acidic protons
of the ester) in dry THF at -78 °C represents the
optimized protocol. Good to excellent yields of O-Bn
hydroxamates were generally obtained. Given its sim-
plicity and efficiency, we hope this will become the
method of choice for the preparation of hydroxamates and
hydroxamic acids.
(7) Since n-BuLi is always present in excess to deprotonate the final
hydroxamate, this side reaction is unavoidable even if the ester is
added last to the anion of O-Bn-hydroxylamine (result not shown). In
turn, this result shows that if the use of n-BuLi or Grignard reagents
to deprotonate N,O-dimethylhydroxylamine constitutes a powerful
method to synthesize Weinreb amides from esters, this strategy cannot
be utilized with O-Bn-hydroxylamine (which has an additional proton)
to form hydroxamic acid derivatives, as addition of the base to the ester
will always compete with deprotonation.
(8) An intense red color was observed upon addition of the ester to
the lithiated O-Bn hydroxylamine. This color might indicate the
formation of a charge-transfer complex that perturbs the reaction.
Unfortunately, an even poorer yield was obtained with KH at 20 °C
instead of LiHMDS and no reaction was observed with TEA (5 equiv)
in refluxing THF.
(10) As the hydroxamates are poorly soluble in many organic
solvents, the flash chromatography was done using a CHCl3/MeOH
mixture as eluent.
(11) To assess the enantiomeric purity, 1n was derivatized with (S)-
R-methylphenylacetic acid affording the corresponding ester in de >
98% (95% yield). The enantiomeric purity of 1l was assessed by
polarimetric analysis, which showed an [R]D identical to that reported
in the literature for the enantiopure compound (see Supporting
Information).
(9) Deprotonation R to the ester does take place as evidenced by
the formation of the Claisen condensation product from ethyl hydro-
cinnamate when LiHMDS was slowly added to the mixture of ester
and O-benzylhydroxylamine at -78 °C in THF (result not shown).
(12) Prior deprotonation of the NH-Cbz or NH-Boc groups may
prevent the amino acid from undergoing additional deprotonation at
the stereogenic center.
6926 J. Org. Chem., Vol. 70, No. 17, 2005

TABLE 2. Reaction of O-Bn-Hydroxylamine with Different Esters under Optimized Conditions
a
Isolated yield of pure product. All reactions carried out on a 1 mmol scale. b Enantiomerically pure product. c Diastereomerically
pure product.
General Procedure with Enolizable Esters, Amino Acid,
and Peptide-Derived Esters Containing n Acidic Protons
(1h-p). A stirred suspension of O-Bn-hydroxylamine hydro-
chloride (1 equiv) in dry THF (10 mL) at -78 °C and under
nitrogen atmosphere was treated with a 1 M solution of LiHMDS
(3.1 + n equiv). After 10 min a solution of the ester (1 equiv) in
a minimum amount of dry THF was added. After the total
consumption of the starting material (TLC) the reaction was
quenched with a saturated aqueous solution of NH4Cl, warmed
to room temperature, and extracted with AcOEt. The collected
organic layers were dried (NaSO4), filtered, and concentrated
under reduced pressure, and the crude purified by flash chro-
matography.
Experimental Section
General Procedure with Nonenolizable Esters (1a-g).
A stirred suspension of O-Bn-hydroxylamine hydrochloride (1
equiv) and ester (1 equiv) in dry THF (10 mL) at -78 °C and
under nitrogen atmosphere was treated with a 1 M solution of
LiHMDS (3.1 equiv). After less than 10 min the reaction was
quenched with a saturated aqueous solution of NH4Cl, warmed
to room temperature, and extracted with AcOEt. The collected
organic layers were dried (NaSO4), filtered, and concentrated
under reduced pressure, and the crude purified by flash chro-
matography.
J. Org. Chem, Vol. 70, No. 17, 2005 6927

As the hydroxamates are often poorly soluble in many organic
solvents, the FC was done using a CHCl3/MeOH mixture as
eluent.
Bioattivi e Nanostrutturati”), Politecnico di Milano, and
C.N.R. for economic support.
Supporting Information Available: Spectroscopic char-
acterization and copies of the NMR spectra of the hydroxam-
ates 1a-p. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the European Com-
mission (IHP Network grant “FLUOR MMPI” HPRN-
CT-2002-00181), MIUR (Cofin 2004, Project “Polipeptidi
JO0509713
6928 J. Org. Chem., Vol. 70, No. 17, 2005