Reactions of N-benzyloxycarbamate derivatives with stabilized carbon nucleophiles: A new synthetic approach to polyhydroxamic acids and other hydroxamate-containing mixed ligand systems

Article abstract of DOI:10.1021/jo802410u

Hydroxamic acids are an important class of chelators of hard metal ions such as Fe(III), which have found applications in therapeutic, diagnostic, and separation chemistry. Hence, methods for their preparation and incorporation into various matrices are i

Full text of DOI:10.1021/jo802410u

Reactions of N-Benzyloxycarbamate Derivatives with Stabilized
Carbon Nucleophiles: A New Synthetic Approach to
Polyhydroxamic Acids and Other Hydroxamate-Containing Mixed
Ligand Systems†
Yuan Liu, Hollie K. Jacobs, and Aravamudan S. Gopalan*
Department of Chemistry and Biochemistry, MSC 3C, New Mexico State UniVersity,
Las Cruces, New Mexico 88003-8001
agopalan@nmsu.edu
ReceiVed October 29, 2008
Hydroxamic acids are an important class of chelators of hard metal ions such as Fe(III), which have
found applications in therapeutic, diagnostic, and separation chemistry. Hence, methods for their preparation
and incorporation into various matrices are important. A new strategy for the preparation of hydroxamic
acids that uses readily available N-benzyloxy carbamic acid ethyl ester, 1, has been developed. N-Alkylation
of 1 occurs readily to give N-alkyl-N-benzyloxy carbamates, 2, which react with a variety of stabilized
carbon nucleophiles to give functionalized protected hydroxamic acids, 3, in good to excellent yields.
The O-protected hydroxamate intermediates 3 can be further alkylated with halides to access a variety of
potential metal binding hosts. The usefulness of this methodology has been demonstrated by the synthesis
of a novel trihydroxamic acid 6, mixed ligand systems 9 and 12, and the macrocyclic dihydroxamic acid
16.
Introduction
In addition to their role as iron chelators, hydroxamic acids
exhibit varied biological activity including antibacterial, anti-
fungal, anti-inflammatory, and antitumor properties, which are
due to their ability to inhibit a variety of enzymes.5 There has
been a recent surge in the interest of hydroxamic acids as
inhibitors of histone deacetylases, resulting in the recent approval
of suberoylanilide hydroxamic acid (SAHA) for the treatment
of cutaneous T-cell lymphoma.6 It is also noteworthy that many
hydroxamic acid containing molecules are potent inhibitors of
matrix metalloproteinases, which have been implicated in a
number of pathological conditions.7 Given the incredible
pharmaceutical relevance of hydroxamic acids,8 it is essential
Hydroxamic acids are well-known chelators of hard metal
ions such as Fe(III) and the actinide(IV) ions. Many bacterial
and fungal siderophores rely on the hydroxamate functionality
to complex and transport the ferric ion.1 Desferrioxamine, a
trihydroxamate siderophore, is used for the treatment of iron
overload in patients with ꢀ-thalassemia.2 Recently, hydroxamic
acid iron chelators have been examined as potential cancer
chemotherapeutic agents.3 Another potential application of iron
chelators is in the development of novel antibacterial agents.4
† Portions of this work were presented at the 232nd American Chemical
Society National Meeting, San Francisco, CA, September 10-14, 2006, ORGN
534.
(1) (a) Renshaw, J. C.; Robson, G. D.; Trinci, A. P. J.; Wiebe, M. G.; Livens,
F. R.; Collison, D.; Taylor, R. J. Mycol. Res. 2002, 106/10, 1123–1142. (b)
Dhungana, S.; Miller, M. J.; Dong, L.; Ratledge, C.; Crumbliss, A. L. J. Am.
Chem. Soc. 2003, 125, 7654–7663. (c) Dhungana, S.; Ratledge, C.; Crumbliss,
A. L. Inorg. Chem. 2004, 43, 6274–6183.
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1021. (b) Lovejoy, D. B.; Richardson, D. R. Curr. Med. Chem. 2003, 10, 1035.
(c) Weinberg, E. D. AdV. Appl. Microbiol. 2003, 52, 187–204. (d) Richardson,
D. R. Crit. ReV. Oncol. Hematol. 2002, 42, 267–281. (e) Richardson, D. R. Curr.
Med. Chem. 2005, 12, 2711. (f) Weinberg, E. D. Hemoglobin 2008, 32, 117.
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782 J. Org. Chem. 2009, 74, 782–788
10.1021/jo802410u CCC: $40.75 2009 American Chemical Society
Published on Web 12/08/2008

Synthesis of Hydroxamic Acids and Mixed Ligand Systems
to develop new methods for their incorporation into a variety
of complex structures.
As part of a program for the design and synthesis of
chelators for the specific binding of ferric ion, we have been
interested in developing methods for the preparation of a
variety of hydroxamic acids including polyhydroxamic acids.9
The conventional method for the preparation of hydroxamic
acids usually involves coupling of acid derivatives with
hydroxylamines.10,11 Recently, there has been considerable
interest in parallel methods for the synthesis of hydroxamic
acids both in solution and on solid support.12 The microwave-
assisted conversion of esters into hydroxamic acids was
recently reported.13 However, the limited availability of
substituted hydroxylamines places limits on the traditional
coupling method, in particular in terms of the diversity of
polyhydroxamates and mixed hydroxamate ligand systems
that can be readily accessed.
The direct reaction of N-benzyloxy carbamates, such as 2,
with carbon nucleophiles is an attractive alternate approach for
the synthesis of hydroxamic acids (Figure 1). There may be a
couple of reasons why this strategy has not been explored.
Carbamates are usually viewed as useful amine protecting
groups and not as efficient electrophiles. Only recently it was
reported that simple carbamates can act as electrophiles when
reacted with the dianion of methyl phenyl sulfone to give
FIGURE 1. Strategy for the synthesis of hydroxamic acids.
(5) TACE inhibition: (a) Lu, Z.; Ott, G. R.; Anand, R.; Liu, R.-Q.; Covington,
M. B.; Vaddi, K.; Qian, M.; Newton, R. C.; Christ, D. D.; Trzaskos, J.; Duan,
J. J.-W. Bioorg. Med. Chem. Lett. 2008, 18, 1958–1962. (b) Ott, G. R.; Azakawa,
N.; Lu, Z.; Liu, R.-Q.; Covington, M. B.; Vaddi, K.; Qian, M.; Newton, R. C.;
Christ, D. D.; Trzaskos, J. M.; Decicco, C. P.; Duan, J. J.-W. Bioorg. Med.
Chem. Lett. 2008, 18, 694–699. Bacterial peptide deformylase inhibition: (c)
Jain, R.; Chen, D.; White, R. J.; Patel, D. V.; Yuan, Z. Curr. Med. Chem. 2005,
12, 1607–1621. PDE4 inhibition: (d) Ochiai, H.; Ohtani, T.; Ishida, A.; Kusumi,
K.; Kato, M.; Kohno, H.; Odagaki, Y.; Kishikawa, K.; Yamamoto, S.; Takeda,
H.; Obata, T.; Nakai, H.; Toda, M. Bioorg. Med. Chem. 2004, 12, 4645–4665.
Carbonic anhydrase inhibition: (e) Ilies, M. A. ; Banciu, M. D. In Carbonic
Anhydrase Its Inhibitors and ActiVators; CRC Press: Boca Raton, FL, 2004;
Chapter 7.
(6) For recent reviews on histone deacetylase inhibitors, see: (a) Jones, P.;
Steinku¨hler, C. Curr. Pharm. Design 2008, 14, 545. (b) Dokmanovic, M.; Clarke,
C.; Marks, P. A. Mol. Cancer Res. 2007, 5 (10), 981. (c) Marks, P. A.; Breslow,
R. Nat. Biotechnol. 2007, 25, 84. (d) Xu, W. S.; Parmigiani, R. B.; Marks, P. A.
Oncogene 2007, 26, 5541. (e) Monneret, C. Eur. J. Med. Chem. 2005, 40, 1.
(7) (a) Hanessian, S.; Moitessier, N.; Gauchet, C.; Viau, M. J. Med. Chem.
2001, 44, 3066. (b) Woessner, J. F.; Nagase, H. Matrix Metalloproteinases and
TIMPs; Oxford University Press: New York, 2000; pp 109-125. (c) Brown, P.
In Matrix Metalloproteinases; Parks, W. C., Mecham, R. P., Eds.; Academic
Press: San Diego, 1998; pp 243-262. (d) Kumaran, S.; Gupta, S. P. J. Enzyme
Inhib. Med. Chem. 2007, 22 (1), 23. (e) Skotnicki, J. S.; DiGrandi, M. J.; Levin,
J. I. Curr. Opin. Drug DiscoVery DeV. 2003, 6/5, 742–759. (f) Park, S.-K.; Han,
S. B.; Lee, K.; Lee, H. J.; Kho, Y. H.; Chun, H.; Choi, Y.; Yang, J. Y.; Yoon,
Y. D.; Lee, C.-W.; Kim, H. M.; Choi, H.-M.; Tae, H. S.; Lee, H.-Y.; Nam,
K.-Y.; Han, G. Biochem. Biophys. Res. Commun. 2006, 341, 627–634.
(8) For reviews on the use of hydroxamic acids as pharmacological agents,
see: (a) Muri, E. M. F.; Nieto, M. J.; Sindelar, R. D.; Williamson, J. S. Curr.
Med. Chem. 2002, 9, 1631–1653. (b) Muri, E. M. F.; Nieto, M. J.; Williamson,
J. S. Med. Chem. ReV. 2004, 1, 385–394.
amidosulfones.14 It has also been shown that R-sulfonyl
carbanions undergo intramolecular cyclization with carbamates
to yield lactams.15
Another reason carbamates, such as 2, have not been thought
to be good synthons for the preparation of hydroxamic acids
may be a perceived similarity to the well-known Weinreb amide
chemistry. Reaction of 2 with a strongly basic nucleophile such
as n-butyl lithium would be expected to give an intermediate
Weinreb-like amide, I, that would react further to give the
corresponding ketone (Figure 1). As predicted, when 2 was
treated with n-butyllithium (2 equiv), 5-nonanone was obtained
in high yield.16
However, we postulated that reaction of an N-benzyloxy
carbamate, such as 2, with stabilized carbanions should cir-
cumvent this reaction pathway and lead to the desired hydrox-
amate product 3 (Figure 1). Intermediate II, obtained by the
reaction of 2 when a stabilized carbanion serves as the
nucleophile, has an acidic proton and will be expected to
undergo immediate deprotonation to give a stable carbanion III,
incapable of functioning as an electrophile. Here we report a
novel preparation of hydroxamic acids based on our hypothesis
that allows us to access a variety of hydroxamic acids and mixed
ligand chelators.
(9) (a) Koshti, N.; Gantla, V. R.; Jacobs, H. K.; Gopalan, A. S. Synth.
Commun. 2002, 32/24, 3779–3790. (b) Bisset, W.; Jacobs, H.; Koshti, N.; Stark,
P.; Gopalan, A. React. Funct. Polym. 2003, 55/2, 109–119. (c) Koshti, N. M.;
Jacobs, H. K.; Martin, P. A.; Smith, P. H.; Gopalan, A. S. Tetrahedron Lett.
1994, 5157–5160.
Results and Discussion
The N-benzyloxycarbamate 1 was prepared by the reaction
of O-benzylhydroxylamine hydrochloride with ethyl chlorofor-
mate in pyridine at room temperature in excellent yield (Scheme
1). It is important to point out that the use of triethylamine or
4-methylmorpholine instead of pyridine in this reaction gave
(10) Sandler, S. R.; Karo,W. Organic Functional Group Preparations, 2nd
ed.; Academic Press: San Diego, 1989; Vol. 3, pp482-522.
(11) For some syntheses of hydroxamic acids, see: (a) Sibi, M. P.; Hasegawa,
H.; Ghorpade, S. R. Org. Lett. 2002, 4, 3343–3346. (b) Sibi, M. P.; Hasegawa,
H. Org. Lett. 2002, 4, 3347–3349. (c) Hu, J.; Miller, M. J. J. Org. Chem. 1994,
59, 4858–4861.
(12) For a review, see: (a) Yang, K.; Lou, B. Mini ReV. Med. Chem. 2003,
3, 349–360. (b) Volonterio, A.; Bravo, P.; Zanda, M. Tetrahedron Lett. 2001,
42, 3141–3144. (c) Krchna´k, V.; Slough, G. A. Tetrahedron Lett. 2004, 45, 4649–
4652. (d) Yin, Z.; Low, K.; Lye, P. Synth. Commun. 2005, 35, 2945–2950. (e)
Porcheddu, A.; Giacomelli, G. J. Org. Chem. 2006, 71, 7057–59.
(13) Massaro, A.; Mordini, A.; Reginato, G.; Russo, F.; Taddei, M. Synthesis
2007, 3201.
(14) White, J. D.; Blakemore, P. R.; Milicevic, S.; Choudhry, S. C.; Cupano,
J.; Serico, L. Org. Lett. 2002, 4, 1803–1806.
(15) Hernandez, N. M.; Sedano, M. J.; Jacobs, H. K.; Gopalan, A. S.
Tetrahedron Lett. 2003, 44, 4035–4039.
(16) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
J. Org. Chem. Vol. 74, No. 2, 2009 783

Liu et al.
TABLE 1. Results for the Acylation of 2a-d with Carbon
SCHEME 1
Nucleophilesa
mixtures of the desired product 1 along with major quantities
of the corresponding N,N-diacylated product.
A number of N-alkylcarbamates were readily prepared by
alkylation of 1 using one of two conditions (Scheme 1). For
example, treatment of 1 with NaH in DMF followed by addition
of methyl iodide (1.1 equiv) gave 2a in 81% yield. N-Benzyl
carbamate, 2c, potentially a convenient synthon for the synthesis
of primary hydroxamic acids, was prepared using a similar
procedure. The dicarbamate 2d could be prepared in excellent
yields by alkylation of 1 with dibromopentane (0.5 equiv) in
the presence of K2CO3 in refluxing acetonitrile.
With the N-benzyloxycarbamates 2 in hand, their reactions
with stabilized carbon nucleophiles were then examined. The
carbamate 2a served as the model in our initial studies.
Treatment of methyl phenyl sulfone (1 equiv) with LHMDS (2
equiv) in THF at -78 °C followed by addition of N-benzy-
loxycarbamate 2a (1 equiv) gave the corresponding protected
hydroxamic acid 3a in 72% yield after workup and chromato-
graphic purification. It was gratifying to note that our key
postulate in the development of this methodology proved to be
right. The presence of the electron-withdrawing sulfone group
on the carbon nucleophile clearly suppresses the undesired
Weinreb chemistry of the initial intermediate II and promotes
rapid proton abstraction of the intermediate to give an enolate
III as illustrated in Figure 1.
The coupling reaction proved to be quite general, and a variety
of stabilized carbon nucleophiles could be coupled with 2a and
its analogs to give the corresponding functionalized protected
hydroxamic acids, 3, in good to excellent yield (Table 1). In
most cases, efficient coupling of 2 to give 3 could be achieved
by use of only 1 equiv of the carbon nucleophile and 2 equiv
of LHMDS. Carbon nucleophiles carrying sulfoxide, phospho-
nate, sulfonamide, ester, and nitrile moieties all reacted suc-
cessfully with 2 to give the corresponding product 3 in good to
excellent yields. When the enolate of tert-butyl acetate was used
in the reaction with 2 under the standard conditions, the yields
were somewhat lower as a result of competing self-condensation
of the ester.17 Hence, 2 equiv of the ester enolate were initially
generated with LHMDS and subsequent coupling with 2 gave
good yields of the desired product. The anions of ethyl phenyl
sulfone and allyl phenyl sulfone reacted cleanly with 2a to give
the desired products 3g and 3h in 92% and 79% yields,
respectively. Further, it was possible to acylate the dicarbamate
a Conditions: (a) Carbamate (1 equiv), RCH2EWG (1-1.1 equiv),
LHMDS (2 equiv), THF, -78°C to rt. (b) Carbamate (1 equiv),
RCH2EWG (2 equiv), LHMDS (2 equiv), THF, -78°C to rt. (c)
Carbamate (1 equiv), RCH2EWG (4 equiv), LHMDS (4 equiv), THF,
-78°C to rt. (d) Carbamate (1 equiv), RCH2EWG (2.2 equiv), LHMDS
(4 equiv), THF, -78°C to rt.
2d with carbon nucleophiles of interest to give products 3k-3m
in good yields. One reaction that did fail was the attempted
acylation of the enolate of tert-butyl propionate with carbamate
2a presumably as a result of unfavorable steric factors and
competing side reactions.
The presence of electron-withdrawing groups on the N-
benzyloxy hydroxamates 3 allows further synthetic manipula-
tions to obtain other polydentate chelators. The synthetic utility
of these intermediates has been demonstrated by the synthesis
of a number of potential metal ion binding hosts.
(17) Lithium tert-butyl acetate was generated by slow addition of tert-butyl
acetate to a solution of LHMDS in THF at-78°C to avoid or reduce the self-
condensation of tert-butyl acetate.
The first target to be synthesized was the trihydroxamic acid
6, a potential iron chelator (Scheme 2). Treatment of 1,3,5-
784 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Hydroxamic Acids and Mixed Ligand Systems
SCHEME 2
SCHEME 4
Treatment of disulfone 3l with 2.3 equiv of 1-iodo-2-(2-
methoxyethoxy)ethane and potassium carbonate in refluxing
acetonitrile gave the dialkylated product 7 in 82% yield after
purification (Scheme 3). Subsequent desulfonylation using 6%
Na/Hg amalgam followed by removal of the benzyl protecting
groups by hydrogenolysis gave the desired dihydroxamic acid
9. The presence of two hydroxamic acids as well as two
polyether arms makes 9 a unique metal ion binding ligand.
Two important classes of chelators for hard trivalent and
tetravalent cations contain the bidentate hydroxamic acids or
hydroxypyridinone ligands in their backbones. We have used
the disulfone 3l to construct a unique mixed ligand chelator 12
having both 3,2-hydroxypyridinone (HOPO) and hydroxamic
acid ligands (Scheme 4). Alkylation of 3l with 2.4 equiv of the
hydroxypyridinone iodide 1319 using potassium carbonate in
refluxing acetonitrile gave the desired product 10 in 89% yield
after purification. Reductive removal of the sulfone followed
by benzyl deprotection by hydrogenolysis gave the dihydrox-
amic acid/diHOPO ligand 12. This interesting ligand may be
well-suited to bind hard cations such as Pu(IV) and Th(IV) that
have larger coordination number than Fe(III).20
The diene intermediate 3m provides a pathway to access
macrocyclic dihydroxamic acids by RCM exemplified by our
synthesis of 16. When the diene 3m was treated with 5 mol %
Grubbs’ II catalyst in refluxing dichloromethane, the cyclic
product 14 was obtained in 85% yield after purification (Scheme
5). The macrocycle 14 was obtained as a diastereomeric mixture
as determined by 1H NMR. The sulfone groups were removed
using 6% Na/Hg amalgam. Finally, hydrogenolysis of the benzyl
protecting groups with concomitant reduction of the double bond
gave the desired dihydroxamic acid 16. Macrocyclic dihydrox-
amic acids, such as the siderophores bisucaberin and alcaligin,
have been shown to bind Fe(III) strongly. Macrocyclic hydrox-
amic acids have also been shown to be inhibitors of MMPs21
and TACE.22
SCHEME 3
tris(bromomethyl)benzene with 3 equiv of 3e in the presence
of potassium carbonate in refluxing acetonitrile gave the desired
product of trialkylation, 4, in 72% yield after chromatographic
purification. Hydrolysis of the tert-butyl esters by treatment with
trifluoroacetic acid in dichloromethane and subsequent decar-
boxylation of the intermediate acid in refluxing toluene gave 5.
The benzyl protecting groups of 5 were removed using 10%
Pd/ C to give the trihydroxamic acid 6 in 71% yield.18 It is
interesting to note that the trihydroxamic acid 6 is not only
soluble in organic solvents but also in water.
It was felt that the dihydroxamato tert-butyl ester 3k and the
dihydroxamato sulfone 3l were both good platforms that would
allow the introduction of a variety of other ligands to obtain
novel classes of metal ion chelators. To demonstrate this
possibility, we embarked on the synthesis of dihydroxamic acid
polyether 9 (Scheme 3) from the tert-butyl ester 3k. When 3k
was treated with allyl bromide (6 equiv) in the presence of
potassium carbonate in refluxing acetonitrile, the corresponding
diallyl dihydroxamic acid could be isolated in 80% yield.
Unfortunately, our attempts to introduce a polyether side chain
by alkylation of 3k with the less reactive 1-iodo-2-(2-methoxy-
ethoxy)-ethane failed and only unreacted starting materials were
recovered. This forced us to examine the use of the disulfone
3l in this synthesis.
In summary, N-benzyloxycarbamic acid ethyl ester, 1, is a
useful starting material for the preparation of N-alkyl carbamates
2 that serve as synthons for the preparation of hydroxamic acids.
(19) Lambert, T. N.; Dasaradhi, L.; Huber, V. J.; Gopalan, A. S. J. Org.
Chem. 1999, 64, 6097.
(20) Gorden, A. E. V.; Xu, J.; Raymond, K. N. Chem. ReV. 2003, 103, 4207–
4282.
(21) Steinman, D. H.; Curtin, M. L.; Garland, R. B.; Davidsen, S. K.;
Heyman, H. R.; Holms, J. H.; Albert, D. H.; Magoc, T. J.; Nagy, I. B.; Marcotte,
P. A.; Li, J.; Morgan, D. W.; Hutchins, C.; Summers, J. B. Bioorg. Med. Chem.
Lett. 1998, 8, 2087–2092.
(18) Our preliminary binding studies show that when trihydroxamate 6 is
mixed with an equimolar quantity of Fe(III) in PIPES buffer at pH 7.4, a
trishydroxamato 6-Fe(III) complex (λmax ) 430 nm) is formed.
J. Org. Chem. Vol. 74, No. 2, 2009 785

Liu et al.
SCHEME 5
80.6%) as a colorless oil: 1H NMR (200 MHz, CDCl3) δ
7.52-7.29(m, 5H), 4.86(s, 1H), 4.21(q, J ) 7.0 Hz, 1H), 3.08(s,
3H), 1.31(t, 2H), 1.32-1.25(t, J ) 7.0 Hz, 3H).
N-Benzyloxy-[5-(benzyloxyethoxycarbonylamino)pentyl]car-
bamic Acid Ethyl Ester (2d). Potassium carbonate (0.863 g, 6.25
mmol) was added to a solution of 1 (0.229 g, 1.25 mmol) and 1,5-
dibromopentane (0.07 mL, 0.5 mmol) in dry acetonitrile (5 mL) at
room temperature, and the mixture was heated at reflux for 2 days.
The reaction mixture was cooled, poured into water (50 mL), and
extracted with CH2Cl2 (3 × 20 mL). The combined organic layer
was dried (Na2SO4), and the solvent was removed in vacuo. The
crude product was purified by radial chromatography (EtOAc/
hexanes) followed by a second purification by radial chromatog-
raphy (CH2Cl2) to give 2c (0.265 g, 89.5%) as a colorless oil: IR
(neat) 2981, 2938, 1704 cm-1; 1H NMR (200 MHz) δ 7.48-7.28(m,
10H), 4.83(s, 4H), 4.20(q, J ) 7.0 Hz, 4H), 3.41(t, J ) 7.0 Hz,
4H), 1.71-1.48(m, 4H), 1.38-1.22(m, 2H), 1.30(t, J ) 7.0 Hz,
6H); 13C NMR (50 MHz) δ 157.4, 135.6, 129.3, 128.5, 128.4, 77.1,
62.0, 49.6, 26.8, 23.9, 14.6. Anal. Calcd for C25H34N2O6: C, 65.48;
H, 7.47; N, 6.11. Found: C, 65.29; H, 7.63; N, 5.87.
We have demonstrated that carbon nucleophiles stabilized by a
variety of electron-withdrawing groups react with carbamates
2 to give functionalized protected hydroxamic acids 3. As
hypothesized, the use of stabilized carbon nucleophiles in the
reaction with 2 yields the enolate of the initially formed coupled
product, suppressing the Weinreb chemistry. The intermediates
3 obtained in this study can be elaborated by subsequent
reactions to incorporate other desirable ligand moieties or can
be easily incorporated into diverse spacer groups. Finally, we
have demonstrated that this new methodology can be used to
prepare a variety of polyhydroxamic acids including mixed
ligand HOPO-hydroxamate ligand systems and cyclic dihy-
droxamic acids. We are confident that the electrophilic chemistry
of N-benzyloxy carbamates will lead to a range of new
interesting applications.
Representative Procedure for the Intermolecular Acylation of
2a-c. Synthesis of 2-Benzenesulfonyl-N-benzyloxy-N-methyl Ac-
etamide (3a). A solution of LHMDS (1.24 mL, 1.24 mmol) was
added to a solution of methyl phenyl sulfone (0.097 g, 0.62 mmol)
in anhydrous THF (2.5 mL) at -78 °C under N2, and the mixture
was stirred at -78 °C for 30 min. A solution of 2a (0.130 g, 0.62
mmol) in anhydrous THF (2.5 mL) was added, and the reaction
mixture was stirred at -78 °C for 30 min and then at room
temperature for 16 h. The reaction was quenched with 10% aqueous
AcOH solution (5 mL), and the solvent was removed in vacuo.
The residue was diluted with EtOAc (50 mL), washed with saturated
NaHCO3 (2 × 10 mL) and brine (10 mL), and dried (Na2SO4).
The solvent was removed in vacuo. The crude product was purified
by radial chromatography to give 3a (0.144 g, 72.7%) as a colorless
1
oil: IR (neat) 3065, 3032, 2929, 1668 cm-1; H NMR (200 MHz)
Experimental Section
δ 8.04-7.85(m, 2H), 7.75-7.48(m, 3H), 7.48-7.30(m, 5H), 4.94(s,
2H), 4.22(s, 2H), 3.19(s, 3H); 13C NMR (100 MHz) δ 162.9, 139.3,
134.0, 133.8, 129.6, 129.3, 129.0, 128.9, 128.6, 76.8, 58.1, 33.6.
Anal. Calcd for C16H17NO4S: C, 60.17; H, 5.37; N, 4.39. Found:
C, 60.37; H, 5.39; N, 4.43.
N-Benzyloxycarbamic Acid Ethyl Ester (1). A mixture of
O-benzylhydroxylamine hydrochloride (1.59 g, 10 mmol) and
pyridine (5 mL) was stirred at room temperature under N2 for 2 h.
The mixture was then cooled to 0 °C, ethyl chloroformate (0.96
mL, 10 mmol) was added, and the mixture was stirred at room
temperature for 16 h. The reaction mixture was diluted with EtOAc
(100 mL), washed with 2 N HCl (3 × 30 mL) and saturated
NaHCO3 (3 × 30 mL), and dried (Na2SO4). The solvent was
removed in vacuo. The carbamate 1 (1.84 g, 94.6%) was obtained
as a colorless oil which was homogeneous by TLC and was used
in the next step without purification: IR (neat) 3277, 2983, 1724
N-Benzyloxy-N-methylmalonamic Acid tert-Butyl Ester (3e). A
solution of tert-butyl acetate (0.216 g, 1.86 mmol) in anhydrous
THF (2 mL) was added to a solution of LHMDS (1.86 mL, 1.86
mmol) in anhydrous THF (2 mL) at -78 °C under nitrogen, and
the solution was stirred at -78 °C for 30 min. A solution of 2a
(0.195 g, 0.93 mmol) in anhydrous THF (2 mL) was then added,
and the reaction mixture was stirred at -78 °C for 4 h and then at
room temperature for 16 h. The reaction workup followed the
representative procedure. The product 3e (0.195 g, 75.3%) was
cm-1
;
1H NMR (400 MHz) δ 7.91(s, 1H), 7.37-7.29(m, 5H),
4.81(s, 2H), 4.14(q, J ) 7.2 Hz, 2H), 1.22(t, J ) 7.2 Hz, 3H); 13
C
obtained as a colorless oil. IR (neat) 2934, 2979, 1732, 1668 cm-1
;
NMR(100 MHz) δ 157.8, 135.6, 129.1, 128.5, 128.4, 78.5, 61.8,
14.4. Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found:
C, 61.20; H, 6.63; N, 7.24.
1H NMR (200 MHz) δ 7.49-7.30(m, 5H), 4.86(s, 2H), 3.35(s, 2H),
3.23(s, 3H), 1.43 (s, 9H); 13C NMR (50 MHz) δ 168.6, 166.4, 134.3,
129.3, 129.0, 128.7, 81.6, 76.4, 41.8, 33.7, 27.9. Anal. Calcd for
C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.63; H, 7.50;
N, 4.63.
N-Benzyloxy-N-methylcarbamic Acid Ethyl Ester (2a). Sodium
hydride (60% mineral oil dispersion, 0.408 g, 10.2 mmol) was added
to a solution of 1 (1.80 g, 9.2 3mmol) in dry DMF (10 mL) at
room temperature. After 30 min, iodomethane (0.65 mL, 10.2mmol)
was added, and the mixture was stirred at room temperature for
6 h. The reaction mixture was poured into water (150 mL), and
the product was extracted into hexane (3 × 50 mL). The combined
organic layer was dried (Na2SO4) and the solvent was removed in
vacuo. Purification by flash chromatography gave 2a23 (1.55 g,
2-Benzenesulfonyl-N-[5-(benzenesulfonylacetylbenzyloxyamino]-
pentyl-N-benzyloxy Acetamide (3l). Following the representative
procedure using 2d (0.229 g, 0.5 mmol), methyl phenylsulfone
(0.172 g, 1.1 mmol), and LHMDS (2.0 mL, 2.0 mmol), the product
3l (0.262 g, 77.3%) was obtained as a white solid. Mp 197.0-198.0
1
°C; IR (KBr) 3009, 2930, 2877, 1659 cm-1; H NMR (200 MHz)
δ 7.92-7.90(m, 4H), 7.64-7.51(m, 6H), 7.39(s, 10H), 4.90(s, 4H),
4.19(s, 4H), 3.60(t, J ) 7.0 Hz, 4H), 1.60-1.52(m, 4H), 1.26-1.22
(m, 2H); 13C NMR (50 MHz) δ 162.6, 139.6, 133.9, 129.5, 129.3,
129.0, 128.9, 128.6, 76.8, 58.3, 45.3, 26.2, 23.6. Anal. Calcd for
C35H38N2O8S2: C, 61.93; H, 5.64; N, 4.13. Found: C, 61.58; H,
5.39; N, 3.87.
(22) Xue, C.-B.; Voss, M. E.; Nelson, D. J.; Duan, J. J.-W.; Cherney, R. J.;
Jacobson, I. C.; He, X.; Roderick, J.; Chen, L.; Corbett, R. L.; Wang, L.; Meyer,
D. T.; Kennedy, K.; DeGrado, W. F.; Hardman, K. D.; Teleha, C. A.; Jaffee,
B. D.; Liu, R.-Q.; Copeland, R. A.; Covington, M. B.; Christ, D. D.; Trzaskos,
J. M.; Newton, R. C.; Magolda, R. L.; Wexler, R. R.; Decicco, C. P. J. Med.
Chem. 2001, 44, 2636–2660.
2-Benzenesulfonylpent-4-enoic Acid {5-[(2-Benzenesulfonylpent-
4-enoyl)benzyloxyamino]pentyl}benzyloxy Amide (3m). Following
(23) Inglesi, M.; Nicola, M.; Magnetti, S. Farmaco 1990, 45 (12), 1327–
1340.
786 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Hydroxamic Acids and Mixed Ligand Systems
the representative procedure using 2d (0.345 g, 0.75 mmol), (but-
3-enylsulfonyl)benzene (0.323 g, 1.65 mmol), and LHMDS (3.3
mL, 3.3 mmol) in THF (10 mL), the product 3m (0.380 g, 66.8%)
was obtained as a pale yellow oil. IR (neat) 3066, 3033, 2945, 2871,
7.70-7.45(m, 6H), 7.45-7.27(m, 20H), 6.69-6.53(m, 4H),
5.86-5.77(m,2H),5.12-4.97(m,4H),4.97-4.80(m,4H),4.25-4.12(m,
2H), 4.07-3.92(m, 2H), 3.84-3.70(m, 2H), 3.68-3.48(m, 8H),
3.44-3.29(m, 2H), 3.24-3.11(m, 2H), 2.27-1.18(m, 10H); 13C
NMR (100 MHz) δ 165.7, 158.0, 148.7, 137.1, 136.4, 134.0, 130.2,
129.8, 129.6, 129.3, 128.9, 128.7, 128.5, 127.9, 127.3, 115.8, 104.0,
77.2, 70.7, 68.5, 67.3, 62.8, 49.5, 45.8, 45.0, 28.5, 26.3, 23.8.
N-Benzyloxy-N-[5-(benzyloxy-4-[2-(3-benzyloxy-2-oxo-2H-pyri-
din-1-yl)ethoxy]butyryl}benzyloxyamino)pentyl]-4-[2-(3-benzyloxy-
2-oxo-2H-pyridin-1-yl)-ethoxy] Butyramide (11). To a solution of
10 (0.122 g, 0.1 mmol) in MeOH (2 mL) at 0 °C were added
Na2HPO4 (0.114 g, 0.8 mmol) and 10% Na/Hg amalgam (0.56 g,
2.4 mmol). The mixture was stirred at 0 °C for 5 h and then at
room temperature for 16 h. The reaction mixture was vacuum
filtered through a short silica gel column and rinsed with MeOH
(50 mL). The solvent was removed in vacuo. The residue was
diluted with EtOAc (50 mL), washed with saturated NaHCO3 (3
× 10 mL), and dried (Na2SO4). The solvent was removed in vacuo.
Purification by radial chromatography gave the protected hydrox-
amic acid 11 (0.072 g, 76.6%) as a colorless oil. IR (neat) 3064,
1661, 1652 cm-1 1H NMR (400 MHz) δ 7.87-7.84(m, 4H),
;
7.66-7.62(m, 6H), 7.49-7.38(m, 10H), 5.56-5.48(m, 2H),
5.07-4.98(m,6H),4.87-4.76(m,4H),3.74-3.67(m,2H),3.51-3.45(m,
2H), 2.70-2.66(m, 2H), 2.57-2.49(m, 2H), 1.53-1.47(m, 4H),
1.27-1.20(m, 2H); 13C NMR (100 MHz) δ 165.4, 136.8, 134.1,
133.9, 131.8, 129.9, 129.3, 129.1, 128.8, 128.7, 119.0, 77.4, 64.7,
45.5, 32.4, 26.0, 23.6. Anal. Calcd for C41H46N2O8S2: C, 64.88; H,
6.11; N, 3.69. Found: C, 64.66; H, 6.19; N, 3.68.
N-Benzyloxy-2-{3,5-bis[2-benzyloxymethylcarbamoyl)-2-tert-bu-
toxycarbonylethyl]benzyl}-N-methylmalonamic Acid tert-Butyl Es-
ter (4). Potassium carbonate (0.690 g, 5.0 mmol) was added to a
solution of 3e (0.279 g, 1.01 mmol) and 1,3,5-tris(bromomethyl)-
benzene (0.120 g, 0.34mmol) in dry acetonitrile (10 mL) at room
temperature, and the mixture was heated at reflux for 2 days. After
cooling, the reaction mixture was poured into water (50 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic layer
was dried (Na2SO4), and the solvent was removed in vacuo. The
crude product was purified by radial chromatography to give 4
(0.232 g, 71.8%) as a colorless oil: IR (neat) 2979, 2933, 1732,
3033, 3937, 2868, 1652, 1602 cm-1 1H NMR (400 MHz) δ
;
7.45-7.27(m, 20H), 6.94(dd, J ) 6.8, 1.6 Hz, 2H), 6.59(dd, J )
7.4, 1.6 Hz, 2H), 5.89(t, J ) 7.2 Hz, 2H), 5.07(s, 4H), 4.75(s, 4H),
4.11(t, J ) 4.9 Hz, 4H), 3.70(t, J ) 5.1 Hz, 4H), 3.64-3.55(m,
4H), 3.39(t, J ) 6.2 Hz, 4H), 2.41(t, J ) 7.2 Hz, 4H), 1.81(quintet,
J ) 6.4 Hz, 4H), 1.62(quin, J ) 7.6 Hz, 4H), 1.31-1.21(m, 2H);
13C NMR (100 MHz) δ 174.0, 158.1, 148.7, 136.4, 134.6, 130.5,
129.0, 128.9, 128.7, 128.5, 127.9, 127.3, 115.7, 103.9, 76.3, 70.7,
70.4, 68.5, 49.7, 45.4, 28.9, 26.6, 24.6, 24.0. Anal. Calcd for
C55H64N4O10: C, 70.19; H, 6.85; N, 5.95. Found: C, 70.33; H, 6.55;
N, 6.12.
1
1668 cm-1; H NMR (200 MHz) δ 7.45-7.15(m, 15H), 6.88(d, J
) 2.9 Hz, 3H), 4.67-4.58(m, 6H), 3.93-3.70(m, 3H), 3.11-3.00(m,
15H), 1.34(s, 27H); 13C NMR (50 MHz) δ 170.8, 168.4, 139.0,
134.5, 129.2, 128.8, 128.6, 127.9, 81.5, 76.5, 51.4, 34.5, 34.3, 27.9.
Anal. Calcd for C54H69N3O12 ·3H2O: C, 64.46; H, 7.51; N, 4.18.
Found: C, 64.23; H, 7.17; N, 4.12.
N-Benzyloxy-3-{3,5-bis[2-benzyloxymethylcarbamoyl)eth-
yl]phenyl}-N-methyl Propionamide (5). Trifluoroacetic acid (0.08
mL, 0.92 mmol) was added to a solution of 4 (0.146 g, 0.15 mmol)
in CH2Cl2 (1 mL) at 0 °C, and the mixture was stirred at room
temperature for 2 h. Solvent and the excess trifluoroacetic acid were
removed in vacuo. The crude tricarboxylic acid was dissolved in
toluene (5 mL), and the solution was heated at reflux for 2 d. The
solvent was removed in vacuo. The crude product was purified by
radial chromatography to give 5 (0.084 g, 85.7%) as a colorless
N-Hydroxy-N-[5-(hydroxy-4-[2-(3-hydroxy-2-oxo-2H-pyridin-1-
yl)ethoxy]butyryl}benzyloxyamino)pentyl]-4-[2-(3-hydroxy-2-oxo-
2H-pyridin-1-yl)ethoxy] Butyramide (12). Palladium on carbon
(10%, 10 mg) was added to a solution of 11 (54 mg, 0.057 mmol)
in MeOH (2 mL), and the mixture was stirred at room temperature
under H2 atmosphere for 16 h. The catalyst was removed by
centrifugation followed by filtration. The solvent was removed in
vacuo. The dihydroxamic acid/dihydroxypyridinone 12 (30 mg,
90.9%) was obtained as a reddish oil. IR (neat) 3207(br), 2931,
2869, 1652, 1601 cm-1; 1H NMR (300 MHz, CD3OD) δ 7.10(d, J
) 6.7 Hz, 2H), 6.82(d, J ) 7.4 Hz, 2H), 6.20(t, J ) 7.2 Hz, 2H),
4.17(t, J ) 5.0 Hz, 4H), 3.70(t, J ) 5.1 Hz, 4H), 3.72(t, J ) 4.7
Hz, 4H), 3.56(t, J ) 6.8 Hz, 4H), 3.45(t, J ) 6.2 Hz, 4H), 2.48(t,
J ) 7.3 Hz, 4H), 1.79(quintet, J ) 6.2 Hz, 4H), 1.64(quintet, J )
6.5 Hz, 4H), 1.29(t, J ) 6.8 Hz, 2H); 13C NMR (100 MHz, CD3OD)
δ 175.6, 160.0, 148.1, 130.4, 117.1, 107.6, 71.5, 69.4, 50.8, 48.7,
34.7, 30.0, 27.3, 26.0, 24.6. Anal. Calcd for C27H40N4O10 ·H2O: C,
54.17; H, 7.07; N, 9.36. Found: C, 53.95; H, 6.98; N, 9.04.
9,14-Bis-benzenesulfonyl-1,7-bis-benzyloxy-1,7-diazacyclopenta-
dec-11-ene-8,15-dione (14). To a solution of Grubbs’ catalyst
(second generation, 15 mg, 5% mmol) in CH2Cl2 (30 mL) at room
temperature under N2 was added a solution of 3m (0.268 g, 0.35
mmol), and the mixture was heated at reflux for 20 h. The solvent
was removed in vacuo. The crude product was purified by radial
chromatography (EtOAc/hexane ) 1:4-1:1) to give 14 as yellowish
oil (0.217 g, 84.7%, mixture of diastereomers) Anal. Calcd for
C39H42N2O8S2: C, 64.09; H, 5.79; N, 3.83. Found: C, 64.06; H,
5.61; N, 3.52. In order to characterize and simplify the NMR
spectra, 14 was purified by a second careful chromatography to
give less polar isomer and more polar isomer. Less polar isomer:
1
oil: IR (neat) 3031, 2931, 1661 cm-1; H NMR (200 MHz) δ
7.38-7.26(m, 15H), 6.81(s, 3H), 4.73(s, 6H), 3.18(s, 9H),
2.96-2.73(m, 6H), 2.73-2.51(m, 6H); 13C NMR (50 MHz) δ
174.3, 141.6, 134.6, 129.2, 129.0, 128.7, 126.3, 76.3, 34.1, 33.8,
30.6. Anal. Calcd for C39H45N3O6: C, 71.87; H, 6.96; N, 6.45.
Found: C, 71.82; H, 7.09; N, 6.55.
3-{3,5-Bis[2-hydroxymethylcarbamoyl)ethyl]phenyl}-N-hydroxyl-
N-methyl Propionamide (6). Palladium on carbon (10%, 16 mg)
was added to a solution of 5 (0.083 g, 0.127 mmol) in MeOH (4
mL), and the mixture was stirred at room temperature under H2
atmosphere for 6 h. The catalyst was removed by centrifugation
followed by filtration. After drying under high vacuum, the
trihydroxamic acid 6 (0.034 g, 70.8%) was obtained as a pale yellow
oil: IR (neat) 3412, 2930, 1605 cm-1; 1H NMR (200 MHz, CD3OD)
δ 6.92(s, 3H), 3.19(s, 9H), 2.84-2.73(m, 12H); 13C NMR (50 MHz,
CD3OD) δ 173.6, 141.5, 125.8, 36.6, 32.7, 29.2. Anal. Calcd for
C18H27N3O6 ·H2O: C, 54.12; H, 7.32; N, 10.52. Found: C, 54.36;
H, 7.27; N, 10.43.
2-Benzenesulfonyl-N-[5-({2-benzenesulfonyl-4-[2-(3-benzyloxy-
2-oxo-2H-pyridin-1-yl)ethoxy]butyryl}benzyloxyamino)pentyl]-N-
benzyloxy-4-[2-(3-benzyloxy-2-oxo-2H-pyridin-1-yl)-ethoxy] Bu-
tyramide (10). To a solution of 3l (123 mg, 0.18 mmol) in dry
acetonitrile (5 mL) at room temperature were added K2CO3 (248
mg, 1.8 mmol) and 3-(benzyloxy)-1-(2-(2-iodoethoxy)ethyl)pyridin-
2(1H)-one, 1319 (176 mg, 0.44 mmol), and the mixture was heated
at reflux for 2 d. After cooling, the reaction mixture was poured
into water (50 mL) and extracted with ethyl acetate (100 mL). The
organic layer was dried (Na2SO4), and the solvent was removed in
vacuo. Purification by radial chromatography gave 10 (0.195 g,
88.6%) as a viscous yellow oil. IR (neat) 3065, 3031, 2871, 2931,
1660, 1652, 1606 cm-1; 1H NMR (400 MHz) δ 7.94-7.78(m, 4H),
1
IR (neat) 3065, 2944, 1661, 1652 cm-1; H NMR (200 MHz) δ
7.89-7.74(m,4H),7.72-7.59(m,2H),7.59-7.44(m,4H),7.44-7.29(m,
10H), 5.14(t, J ) 3.0 Hz, 2H), 5.09(d, J ) 10.3 Hz, 2H), 4.89(d,
J ) 10.2 Hz, 2H), 4.70(dd, J ) 11.8, 1.4 Hz, 2H), 4.19(ddd, J )
14.6, 11.0, 3.6 Hz, 2H), 3.22(dt, J ) 14.6, 3.6 Hz, 2H), 2.59(d, J
)13.2Hz,2H),2.42-2.33(m,2H),1.81-1.74(m,2H),1.46-1.39(m,
2H), 1.14(quin, J ) 7.4 Hz, 2H); 13C NMR (50 MHz) δ 165.2,
136.9, 134.2, 134.0, 130.1, 129.0, 128.9, 128.8, 128.7, 127.8, 76.6,
J. Org. Chem. Vol. 74, No. 2, 2009 787

Liu et al.
64.9, 45.5, 31.2, 26.5, 23.6. More polar isomer: IR (neat) 3065,
2945, 1668 cm-1 1H NMR (200 MHz) δ 7.91-7.74(m, 4H),
1,7-Dihydroxy-1,7-diazacyclopentadecane-8,15-dione (16). Pal-
ladium on carbon (10%, 26 mg) was added to a solution of 15
(0.139 g, 0.31 mmol) in MeOH (6 mL), and the mixture was stirred
at room temperature under H2 atmosphere for 18 h. The catalyst
was removed by centrifugation followed by filtration. The solvent
was removed in vacuo. The macrocyclic dihydroxamic acid 16
(0.081 g, 96.4%) was obtained as a light pink solid, which was
homogeneous on the basis of 1H NMR and TLC. Mp 195.0-196.0
;
7.73-7.59(m, 2H), 7.58-7.44(m, 4H), 7.44-7.29(m, 10H), 5.19(d,
J ) 5.9 Hz, 2H), 4.91(d, J ) 11.0 Hz, 2H), 4.88(d, J ) 10.2 Hz,
2H), 4.72(dd, J ) 9.5, 3.7 Hz, 2H), 4.16(ddd, J ) 14.6, 11.7, 2.2
Hz, 2H), 3.14(dt, J ) 14.6, 3.7 Hz, 2H), 2.52-2.41(m, 4H),
1.65-1.54(m, 2H), 1.34-1.25(m, 2H), 1.12-1.03(m, 2H); 13C
NMR (50 MHz) δ 165.3, 136.8, 134.0, 133.9, 130.1, 129.2, 129.1,
128.9, 128.7, 127.5, 76.6, 65.6, 44.5, 27.6, 27.1, 24.6.
1
°C; IR (KBr) 3195(br), 2941, 2864, 1587 cm-1; H NMR (200
1,7-Bis-benzyloxy-1,7-diazacyclopentadec-11-ene-8,15-dione (15).
To a solution of 14 (0.539 g, 0.74 mmol) in MeOH (15 mL) at 0
°C were added Na2HPO4 (0.838 g, 5.9 mmol) and 10% Na/Hg
amalgam (4.15 g, 17.7 mmol), and the mixture was stirred at 0 °C
for 4 h and at room temperature overnight. The reaction mixture
was vacuum filtered through a short silica gel column rinsing with
MeOH (50 mL). The solvent was removed in vacuo. The residue
was diluted with EtOAc (50 mL), washed with saturated NaHCO3
(3 × 10 mL), and dried (Na2SO4). The solvent was removed in
vacuo. Purification by radial chromatography gave 15 (0.235 g,
70.8%) as a yellowish oil. IR (neat) 3064, 3032, 2932, 2860, 1661,
1652cm-1;1HNMR(200MHz)δ7.49-7.21(m,10H),5.61-5.35(m,
2H), 4.88-4.63(m, 4H), 3.89-3.52(m, 4H), 2.63-2.17(m, 8H),
1.75-1.42(m, 4H), 1.39-1.08(m, 2H); 13C NMR (50 MHz) δ
173.5, 134.9, 129.5, 129.0, 128.9, 128.6, 75.9, 75.8, 44.1, 32.4,
30.9, 26.9, 26.2, 23.6, 23.5. Anal. Calcd for C27H34N2O4: C, 71.97;
H, 7.61; N, 6.22. Found: C, 71.88; H, 7.72; N, 6.19.
MHz,CD3OD)δ3.87-3.44(m,4H),2.72-2.16(m,4H),1.91-1.46(m,
8H), 1.46-1.02(m, 6H); 13C NMR (50 MHz, CD3OD) δ 176.3,
47.9, 31.9, 29.1, 26.8, 25.2, 23.7. Anal. Calcd for
C13H24N2O4 ·0.25H2O: C, 56.40; H, 8.92; N, 10.12. Found: C, 56.14;
H, 9.05; N, 10.13.
Acknowledgment. This research was supported by grants
from the National Institutes of Health under PHS Grants S06
GM08136 and 1SC3GM084809-01.
Supporting Information Available: Synthetic details for all
1
compounds and H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802410U
788 J. Org. Chem. Vol. 74, No. 2, 2009