Synthesis of Hydroxamic Esters via Alkoxyaminocarbonylation of β-Dicarbonyl Compounds

Article abstract of DOI:10.1021/jo990353k

N-t-Butoxycarbonyl-O-sulfonyl-substituted hydroxylamines react with soft enolates to yield O-t-butoxycarbonylamino derivatives rather than the expected Boc-protected amino acids. The reaction is limited to enolates of β-dicarbonyl compounds. Decarboxylation of the resultant tricarbonyl compound affords malonyl α-alkyl O-t-butoxycarbonylamino derivatives.

Full text of DOI:10.1021/jo990353k

5896
J . Org. Chem. 1999, 64, 5896-5903
Syn th esis of Hyd r oxa m ic Ester s via Alk oxya m in oca r bon yla tion of
â-Dica r bon yl Com p ou n d s
Stephen Hanessian* and Shawn J ohnstone
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale, Centre-ville,
Montre´al, QC H3C 3J 7, Canada
Received February 26, 1999
N-t-Butoxycarbonyl-O-sulfonyl-substituted hydroxylamines react with soft enolates to yield O-t-
butoxycarbonylamino derivatives rather than the expected Boc-protected amino acids. The reaction
is limited to enolates of â-dicarbonyl compounds. Decarboxylation of the resultant tricarbonyl
compound affords malonyl R-alkyl O-t-butoxycarbonylamino derivatives.
Sch em e 1
In tr od u ction
Hydroxamic acids have long been associated with
diverse biological activities including antiinflammatory,
antibacterial, antifungal, and antitumor profiles that are
becoming increasingly important in medicinal chemistry.1
As shown by elegant X-ray crystallographic studies,2
these compounds are known to inhibit matrix metallo-
proteases (MMPs), a class of enzymes implicated in
several diseases, by virtue of their ability to form a
bidentate chelate with an active site zinc atom.3 The more
potent inhibitors for some MMPs, such as thermolysin,
collagenase, elastase, neutral endopeptidase, and endo-
thelin converting enzyme, are hydroxamic acid analogues
of malonic esters.4
Hydroxamic acids are usually prepared by reacting
hydroxylamine with an activated carboxylic derivative.5
In a number of cases, side reactions such as nitrogen and
oxygen acylations decrease the yields and make purifica-
tion difficult.6 Moreover, aliphatic acid chlorides are
known to decompose in the presence of hydroxylamine,
which is also prone to be explosive under certain condi-
tions making scale-up operations hazardous. To circum-
vent these problems, many substituted hydroxylamine
derivatives have been prepared, but they can be difficult
to handle, deprotect, and prepare.7
Previous publications from this laboratory have shown
that 2-alkylpyridyl sulfonates are excellent leaving groups
that can be displaced by halide ion even at 0 °C to give
the corresponding alkyl halide. These reagents were
based on a design element that capitalized on internal
activation (Scheme 1). The enhanced reactivity of this
leaving group was attributed8 to a pre-coordination of a
divalent metal salt to the pyridyl nitrogen, thus promot-
ing nucleophilic displacement with release of an intra-
molecularly coordinated 2-pyridylsulfonate. The analo-
gous reactions with p-tolylsulfonates were more sluggish.
Based on the same notion, we anticipated that N-bu-
toxycarbonyl(2-pyridylsulfonyl)hydroxylamine (1a ) would
act as an electrophilic NHBoc transfer agent when
reacted with enolates (Scheme 2). Electrophilic amina-
tions with “activated amines” are well-known, although
successful applications have been limited.9 Activation has
been achieved through the use of suitable leaving groups.
For example, reagents of the type p-MeC6H6-SO2ONHBoc
have been shown to transfer NHBoc to carbanions, albeit
in modest yields.10 It is interesting to point out that it is
(1) (a) Onishi, H. R.; Pelak, B. A.; Gerckens, L. S.; Lilver, L. L.;
Fredrick, M. K.; Chen, M.; Patchet, A. A.; Galloway, S. M.; Hyland, S.
A.; Anderson, M. S.; Raetz, C. R. H. Science 1996, 274, 980-982. (b)
Gearing, A. J . H.; Beckett, P.; Christodoulou, M.; Churchill, M.;
Clements, J .; Davidson, A. H.; Drummond, A. H.; Galloway, W. A.;
Gilbert, R.; Gordon, J . L.; Leber, T. M.; Mangan, M.; Miller, K.; Nayee,
P.; Owen, K.; Patel, S.; Thomas, W.; Wells, G.; Wood, L. M.; Woolley,
K. Nature 1994, 370, 555-557. (c) Patel, D. V.; Young, M. G.; Robinson,
S. P.; Hunihan, L.; Dean, B. J .; Gordon, E. M. J . Med. Chem. 1996,
39, 4197-4210. (d) Kleinman, E. F.; Campbell, E.; Giordano, L. A.;
Cohan, V. L.; J enkinson, T. H.; Cheng, J . B.; Shirley, J . T.; Pettipher,
E. R.; Salter, E. D.; Hibbs, T. A.; DiCapua, F. M.; Bordner, J . J . Med.
Chem. 1998, 41, 266-270. (e) Powers, J . C.; Harper, J . W. In Proteinase
Inhibitors; Barret, A. J ., Salvesen, G., Eds.; Elsevier: Amsterdam,
1986; pp 244-298.
(2) Holmes, M. A.; Matthews, B. W. Biochemistry 1981, 20, 6912-
6920.
(3) (a) Levy, D. E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.;
Li, X.; Grobelny, D.; Casabonne, M.; Tyrrel, D.; Holme, K.; Nadzan,
A.; Galardy, R. E. J . Med. Chem. 1998, 41, 199-223. (b) MacPherson,
L. H.; Bayburt, E. K.; Capparelli, M. P.; Carroll, B. J .; Goldstein, R.;
J ustice, M. R.; Zhu, L.; Hu, S.; Melton, R. A.; Fryer, L.; Goldberg, R.
L.; Doughty, J . R.; Spirito, S.; Blancuzzi, V.; Wilson, D.; O’Byrne, E.
M.; Ganu, V.; Parker, D. T. J . Med. Chem. 1997, 40, 2525-253.
(4) (a) Bihovsky, R.; Levinson, B. L.; Loewi, R. C.; Erhardt, P. W.;
Polokoff, M. A. J . Med. Chem. 1995, 38, 2119-2129. (b) von Roedern,
E. G.; Grams, F.; Brandstetter, H.; Moroder, L. J . Med. Chem. 1998,
41, 339-345. (c) Nishino, N.; Powers, J . C. Biochemistry 1978, 17,
2846-2850. (d) Che´rot, P.; Devin, J .; Fournie´-Zaluski, M. C.; Roques,
B. P. Mol. Pharm. 1986, 30, 338-344.
(6) Side reactions include diacylation on nitrogen, nitrogen, and
oxygen acylation and triacylation. See, for example, ref 5a,b as well
as: J ohnson, J . E.; Springfield, J . R.; Hwang, J . S.; Hayes, L. J .;
Cunningham, W. C.; McClaugherty, D. L. J . Org. Chem. 1971, 36, 284-
294.
(7) Romine, J . Org. Prep. Proc. Int. 1996, 251-288.
(8) Hanessian, S.; Kagotani, M.; Komaglou, K. Heterocycles 1989,
28, 2, 1115-1120.
(9) For reviews, see: Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947-
1980. Greck, C. G.; Genet, J . P. Synlett 1997, 741-748. Mulzer, J .;
Altenbach, H. J .; Braun, M.; Krohn, K.; Reissig, H. U. Organic
Synthesis Highlights; VCH Publishers: Weinheim, 1991; pp 45-53.
(10) (a) Genet, J . P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron
Lett. 1991, 32, 2359-2362. (b) Zheng, N.; Armstrong, J . D.; McWill-
iams, C.; Volante, R. P. Tetrahedron Lett. 1997, 38, 2817-2820.
(5) For reviews, see: (a) Sandler, S. R.; Karo, W. In Organic
Functional Group Preparations; Wasserman, H. H., Ed.; Academic
Press: San Diego, 1989; Vol. 3, pp 482-522. (b) Bauer, L.; Exner, O.;
Angew. Chem., Int. Ed. Engl. 1974, 13, 376-384.
10.1021/jo990353k CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

Synthesis of Hydroxamic Esters
J . Org. Chem., Vol. 64, No. 16, 1999 5897
Ta ble 1. O-Bu toxya m in oca r bon yla tion of En ola tes
Sch em e 2
Sch em e 3
a
b
Yield of isolated pure product, LiBr (4 equiv) was added to
enolate; in the absence of LiBr, the yield was 35%.
However, enolates of dicarbonyl compounds or those
substituted with an electron-withdrawing group afforded
the corresponding O-t-butoxycarbonylamino analogues in
good to moderate yields (Scheme 3). Thus, malonates,
2-substituted malonates, acyclic and cyclic â-keto esters,
R-alkoxy carbonyl lactones, and â-keto sulfones proved
to be good substrates for this reaction as seen in Table
1. Yields for the unsubstituted and substituted malonates
varied with the nature of the ester and R-substituents.
The O-t-butoxyaminocarbonylation of â-dicarbonyl es-
ter enolates was optimized by a systematic study of the
nature of the hydroxylamine reagent. The 2-pyridylsul-
fonyl reagent 1a and the tosyl reagent 1b10a are crystal-
line solids that can be stored at 0 °C for many months
without decomposition. In general, the 2-pyridylsulfonyl
reagent 1a gave higher yields than the tosyl reagent 1b
(Table 2) and was consistently more efficient than the
nosyl and mesyl derivatives. Unlike the tosyl reagent 1b,
unreacted 2-pyridyl reagent 1a unfortunately cannot be
recovered after the reaction. Reagents with a Cbz group
in place of a Boc group and reagents where the O-
arylsulfonyl portion of the molecule was replaced by a
2-mercaptopyridine or a OTBDMS group were unreac-
tive. Replacement of the sulfonyl group with a carbonyl
or phosphoryl group resulted in reagents that were
unreactive. The O-t-butoxyaminocarbonylation reaction
was more efficient when the protonated form of 1a or 1b
was added to the reaction containing an excess of base
rather than adding the preformed metalated reagent (Li,
Na, Mg, Cu, or Zn salts), which is unstable even at 0 °C.
In the cases of less reactive â-dicarbonyl enolates
(Table 1), the modest yields could be attributed to
protonation of the enolate by the acidic reagent. With the
deuterated reagent, PyrSO2ONDBoc, deuterium transfer
the N-lithiated form11 of the reagent that is actually the
electrophilic species in these reactions.
Resu lts a n d Discu ssion
Based on the above precedents and our expectations
of internal assistance in SN2-displacement reactions,8 we
studied the reaction of the sulfonyl hydroxylamine de-
rivative 1a with ester enolates such as malonates and
alkyl carboxylates. To our surprise, reaction took place
to give O-t-butoxycarbonylamino derivatives 2, rather
than the expected NH-Boc R-amino acids 3 (Scheme 3).
Initially, we were misled into assuming that we had
indeed achieved electrophilic aminations with “designed”
reagents such as 1a , since the expected products were
isomeric with the hydroxamates (Scheme 3). Mass spec-
tral and NMR analyses were not immediately conclusive.
An X-ray crystal structure of compound 2 (R1 ) R2 ) Me)
revealed in fact the incorporation of the O-t-butoxycar-
bonylamino motif in the malonate.
A variety of ester and amide enolates (Ti, Cu, Li, Na,
K, Zn, Mg, and Ce) of alkyl carboxylic acids as well as
silyl enol ethers and enamines were found not to react
with reagent 1a or 1b and led to the recovery of the
respective carbonyl compounds. The only exception was
the successful O-butoxyaminocarbonylation of the Zn
enolate of phenyl acetic acid isopropyl ester with 1b .
(11) (a) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J . Am. Chem. Soc.
1986, 108, 6016-6023. (b) Boche, G.; Wagner, H. U. J . Chem. Soc.,
Chem. Commun. 1985, 1591-1592. (c) Armstrong, D. R.; Snaith, R.;
Walker, G. T. J . Chem. Soc., Chem. Commun. 1984, 789-791.

5898 J . Org. Chem., Vol. 64, No. 16, 1999
Hanessian and J ohnstone
Sch em e 4
Ta ble 2. Com p a r ison of Tolyl a n d P yr id yl Rea gen ts
Sch em e 5
a
Percent conversion to product with Na enolate unless noted
otherwise, b Percent conversion to product with Li enolate, c With
the deprotonated tosyl reagent, no reaction occurred. With 4-6
equiv of LiBr added to reaction.
d
was observed in reactions with diethyl malonate. No
reaction took place with the N-methyl analogue of the
reagent.
tert-butyl bond is lengthened by 5 pm relative to the
neutral reagent.16 A similar bond lengthening has been
observed with lithium enolates, and elimination of LiOR
to form ketenes has been postulated.17 A plausible
mechanism to explain the unprecedented formation of the
tricarbonyl hydroxamates of the type reported here is
shown in Scheme 4.
Base-induced deprotonation and concomitant migra-
tion of the O-t-butoxy group with departure of the
arylsulfonyloxy group generates a O-t-butoxy isocyanate
intermediate, which acylates the enolate. Although some
examples of alkoxy isocyanates are known, they are
reported to be unstable.18 When the reaction was done
with an ethoxycarbamate reagent, the product was the
corresponding N-ethoxy derivative of 2. As expected from
the postulated mechanism, no reaction occurred with the
N-methyl reagent. To give credence to the isocyanate
mechanism, we treated the reagent 1a with NaH and
benzylamine. Only the urea derivative 18 was found
rather than the hydrazide (Scheme 5). When the original
reaction was done in the presence of benzylamine and
sodium dimethyl malonate, the major product was the
urea resulting from the acylation of the more basic
nucleophile.
The nature of the solvent and additives such as lithium
chloride or lithium bromide were found to have signifi-
cant effects on the yields. THF, diethyl ether, ether/
hexanes, benzene, and toluene12 were found to be suitable
solvents. Polar solvents, such as HMPA, DME, TMEDA,
and MeOH, which are known to promote cation dissocia-
tion and increase nucleophilicity,13 impede the reaction.
Dichloromethane was not a suitable solvent.
Addition of lithium bromide to the reactions of sodium
diethyl malonate and reagent 1a was found to increase
the yield substantially.14 Surprisingly, yields of other
reactions in the presence of LiBr were diminished by as
much as 20%, and the reaction failed altogether with
diethyl benzyl malonate. These changes in reactivity may
be due to a change in enolate geometry, solvent polarity,
or aggregation state, which LiBr is known to cause,13 or
from a change in the counterion of the enolate. In fact,
lithium and potassium enolates were also found to be less
reactive than sodium enolates (Table 2). Changes in the
bulk of the ester moiety, which can also affect enolate
geometry, led to a decrease in yield (Table 1).
A Lossen-type rearrangement is a likely mechanistic
rational for the O-t-butoxyaminocarbonylation reaction,
since such rearrangements with O-sulfonyl-substituted
hydroxamic acids have been observed before.15 Boche and
co-workers have studied the Li salt of the tosyl reagent
1b by X-ray crystallography and found that the C-O-
The differences in reactivities between 1a and 1b are
possibly due to the better coordinating ability of 1a , thus
(16) Boche, G.; Boie, C.; Bosold, F.; Harms, K.; Marsch, M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 115-117.
(17) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer, B.; Dunitz, J .
D. J . Am. Chem. Soc. 1985, 107, 5403-5409.
(18) (a) Romine, J . L.; Martin, S. W.; Meanwell, N. A.; Epperson, J .
RR. Synthesis 1994, 846-850. (b) Sheludyakov, V. D.; Gusev, A. I.;
Dmitrieva, A. B.; Los’, M. G.; Kirilin, A. D. Zh. Obshch. Khim. 1984,
53, 2051-2054. (c) Maier, G.; Teles, J . H. Chem. Ber. 1989, 122, 745-
748. (d) Mormann, W.; Leukel, G. Synthesis 1988, 990-991.
(12) Insolublity problems with toluene lowered the yields.
(13) J ackman, L. M.; Lange, B. C. Tetrahedron 1977, 33, 2737-2769.
(14) Lithium halides are known to increase the yields of enolate
reactions. See, for example: Seebach, D. Angew. Chem., Int. Ed. Engl.
1988, 27, 1624-1654.
(15) Pihuleac J .; Bauer, L. Synthesis 1989, 61-64.

Synthesis of Hydroxamic Esters
J . Org. Chem., Vol. 64, No. 16, 1999 5899
Ta ble 3. Alk yla tion of O-t-Bu toxyca r bon yla m in o
Ta ble 4. P d -Ca ta lyzed Deca r boxyla tion of
Ma lon a tes
O-t-Bu toxyca r bon yla m in o Ma lon a tes
a
b
Yield of isolated pure product. Alkylated with alkyl iodide.
a
c With K2CO3, yields ranged from 24 to 37%. Alkylated with alkyl
d
Yield of isolated pure product.
bromide, e K2CO3 was used as a base.
amino derivatives either by hydrogenation/decarboxyla-
tion of the benzyl ester or by palladium-catalyzed cleav-
age/decarboxylation of the allyl ester under mild condi-
tions (Table 4).20
enhancing the leaving group character of the 2-pyridyl-
sulfonyloxy group compared to the tosyloxy group. As
previously mentioned, it is also of interest to note that
the reactions were less efficient when the preformed
lithium salts of 1a and 1b were used instead of the
neutral reagents.
To our surprise, the O-t-butoxycarbonylamino malonic
acid derivatives were found to be difficult to cleave. For
example, cleavage of O-t-butoxycarbonylamino com-
pounds has been reported to occur with hydrogen bromide
only at elevated temperatures.21 Our substrates were
inert to acidic and SN2-type conditions and underwent
decomposition and decarboxylation at elevated temper-
atures. After several acids and conditions (anhyd HBr
in AcOH, aqueous HBr, HCl in dioxane, aqueous HCl,
H2SO4 in dioxane, bromocatecholborane, B(OCOCF3)3,
BCl3, TiCl4, and TMS-I with and without tert-butyl
scavengers) were screened, it was found that dichlo-
romethane solutions of trifluoroacetic acid from freshly
opened bottles were effective to cleave the O-tert-butyl
group without decarboxylation (Figure 1). Older batches
of TFA or TFA that was distilled over P2O5 were not
effective.22 Freshly opened bottles of TFA maintained
under a N2 atmosphere could be used for a period of 1
week before reactions became sluggish.
Having demonstrated the viability of generating alkyl
malonic acid O-t-butoxycarbonylamino derivatives from
substituted enolates, we turned our attention to an
alternate method where the malonic acid is first con-
verted to the O-t-butoxycarbonylamino derivative and
then alkylated. Decarboxylation of these tricarbonyl
compounds would afford the corresponding malonyl O-t-
butoxycarbonylamino derivatives. Alkylations of hydrox-
amic acids are well-known to produce unpredictable
mixtures of compounds due to multiple nucleophilic
sites.6 Since our substrates have an acidic proton on the
central malonyl carbon atom, alkylation was potentially
even more problematic.19 However, treatment of the
tricarbonyl substrate with 1 equiv of Cs2CO3 and alkyl
halides led to the desired R-alkylated derivatives (Table
3). Mixtures of N- and C-alkylated products were ob-
tained in the case of dicarbonyl substrates with excess
Cs2CO3 or with other bases (NaH, KH, t-BuOK, etc.).
These products were easily transformed in one step to
the corresponding malonic ester O-t-butoxycarbonyl-
Con clu sion s
Hydroxamic acids of vicinal tricarbonyl compounds can
be prepared in one step from N-sulfonylhydroxylamine
(19) Alkylation with 1 equiv of alkylating reagent and a variety of
lithium, sodium, and potassium bases as well as Cs2CO3 or K2CO3
resulted in either no reaction, dialkylation on carbon, monoalkylation
on nitrogen, or mixtures of carbon and nitrogen alkylation. Knoev-
enegal strategies were also unsuccessful.
(20) For decarboxylation of a â-keto ester substrate, see: Aboulhoda,
S. J .; Henin, F.; Muzart, J .; Thorey, C. Tetrahedron: Asymmetry 1994,
5, 1321-1326. Tsuji, J .; Minami, I. Acc. Chem. Res. 1987, 20, 140-
145.
(21) Kolasa, T.; Chimiak, A. Tetrahedron 1974, 30, 3591-3595.

5900 J . Org. Chem., Vol. 64, No. 16, 1999
Hanessian and J ohnstone
g,19.87 mmol) and Et3N (2.011 g, 19.87 mmol) were dissolved
in benzene (140 mL) and cooled to 0 °C. After 10 min, N-tert-
butoxylcarbonyl hydroxylamine (2.646 g, 19.87 mmol) was
added as a solution in benzene (50 mL). The mixture stirred
for 30 min at 0 °C and was quenched with a saturated solution
of NH4Cl. The aqueous phase was extracted three times with
Et2O, and the combined organic fractions were washed with
brine and dried with Na2SO4. The mixture was filtered,
concentrated, and purified by recrystallization in EtOAc and
hexanes or by flash chromatography on silica gel (hexanes/
EtOAc 9:1, 2:1) to yield 1a as a white solid (3.2293 g, 11.73
mmol, 59%): Rf ) 0.37 on silica gel (2:1 hexanes/ethyl acetate);
mp 58-59 °C; IR (KBr pellet) 3450, 3140, 3020, 1750 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 8.79-8.77 (m, 1H), 8.12-8.09
(m, 1H), 8.00-7.96 (m, 1H), 7.84 (s, 1H), 7.63-7.59 (m, 1H),
1.36 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 154.3, 152.5, 150.3,
138.2, 128.2, 124.9, 83.9, 27.7; HRMS calcd for C10H15N2SO6
275.0701, found 275.0707. Anal. Calcd for C10H14N2SO6: C,
43.7; H, 5.1; N, 10.2; S, 11.6. Found: C. 43.9; H, 5.1; N, 10.2;
S, 11.6.
F igu r e 1. Deprotection of O-t-butoxycarbonylamino mal-
onates.
Gen er a l P r oced u r e for N-t-Bu toxyca r bon yla m in a tion
of En ola tes. NaH (60% dispersion in mineral oil, 1.5-2 equiv)
was weighed into a dry round-bottom flask equipped with a
stirring bar and capped with a rubber septum, and dry THF
was added. The slurry was adjusted to the required temper-
ature, and the malonate substrate (1 equiv) in dry THF was
transferred with a cannula to the slurry. The mixture stirred
for 10-60 min, and the O-t-butoxyaminocarbonylation reagent
(1 equiv) was added with a cannula as a solution in THF
dropwise over 20 min. The mixture was stirred at reduced
temperature and warmed to room temperature. After being
stirred for several h, the reaction was quenched with a
saturated solution of NH4Cl. The aqueous phase was extracted
four times with EtOAc, and the combined organic phases were
washed with brine and dried with Na2SO4. The solution was
filtered, and the filtrate was concentrated under reduced
pressure. The product was purified by flash chromatography
on silica gel eluting with mixtures of hexanes and ethyl
acetate.
2-ter t-Bu toxyca r ba m oylm a lon ic Acid Dim eth yl Ester
(5). According to the general procedure, dimethyl malonate
(57.8 mg, 0.437 mmol) was acylated with NaH (11 mg, 0.454
mmol) and 1a (125 mg, 0.454 mmol) in THF (4 mL) at - 78
°C (1 h) and then at room temperature (1.5 h). Flash chroma-
tography on silica gel, eluting with hexanes/ethyl acetate 4:1,
2:1, yielded 5 (81.3 mg, 0.33 mmol, 76%) as a white solid: Rf
) 0.53 on silica gel (2:1 hexanes/ethyl acetate); mp 88-90 °C;
IR (neat) 3222, 1759, 1675, cm-1; 1H NMR (300 MHz, CDCl3)
δ 9.27 (s, 1H), 4.42 (s, 1H), 3.82 (s, 6H), 1.29 s, 9H); 13C NMR
(75 MHz, CDCl3) δ 165.6, 160.4, 83.1, 58.1, 53.5, 26.1; HRMS
calcd for C10H18NO6 248.1126, found 248.1134.
2-ter t-Bu toxyca r ba m oyl-2-m eth ylm a lon ic Acid Dieth -
yl Ester (6). According to the general procedure, diethyl
ethylmalonate (38 mg, 0.218 mmol) was acylated with NaH
(8 mg, 0.33 mmol) and 1a (60 mg, 0.218 mmol) in THF (4 mL)
at - 40 °C (1 h) and then at room temperature (1.5 h). Flash
chromatography on silica gel, eluting with hexanes/ethyl
acetate 4:1-2:1, yielded 6 (32.3 mg, 0.11 mmol, 51%): Rf )
0.45 on silica gel (2:1 hexanes/ethyl acetate); IR (neat) 3438,
1756 (br), cm-1; 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 4.22
(q, 1H, J ) 9.3, 2.2 Hz), 1.65 (s, 3H,)1.26 (t, 6H, J ) 10.1, 7.1
Hz), 1.24 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 168.9, 159.3,
82.9, 72.5, 62.9, 27.3, 16.8, 13.9; HRMS calcd for C13H24NO6
290.1603, found 290.1595.
reagents. Normally, to synthesize such compounds re-
quires a three- or four-step sequence consisting of car-
boxylation of the enolate, activation of the carboxylate,
reaction with hydroxylamine, and finally protection of the
N-hydroxyl group. The pyridylsulfonyloxy reagent 1a , in
some cases, proved to be the most efficient reagent
examined compared to the N-tosyl reagent 1b. A series
of R-alkyl tricarbonyl and R-alkyl dicarbonyl O-tert-
butoxycarbonylamino derivatives were prepared, and a
new cleavage of O-tert-butoxycarbonylamino malonates
in this series was discovered. The products are closely
related to well-known hydroxamic acid derivatives of
malonates, which are inhibitors of MMPs. Previous
syntheses of these compounds by other methods were
complicated by side reactions, such as hydroxylamine
reacting with the coupling reagent and N-O bond
cleavage during deprotection.4a These problems are com-
pletely avoided with the 2-pyridylsulfonyloxy reagent.
Exp er im en ta l Section
1
Gen er a l Exp er im en ta l P r oced u r es. H and 13C spectra
were recorded at 300 and 400 MHz in CDCl3. IR spectra were
recorded as KBr pellets or neat. Mass spectra were obtained
at low and high resolution. Organic solvents were dried by
standard methods. All reactions were monitored by TLC with
Merck 60 F254 silica gel coated plates. Flash chromatography
was carried out using 230-400 mesh silica gel under pressure.
N-tert-Butoxycarbonylhydroxylamine was purchased from Lan-
caster and used without further purification and made by
reported procedures.23
2-P yr id ylsu lfon yl Ch lor id e. 2-Mercaptopyridine (20 g,
0.18 mol) was dissolved in concentrated HCl (160 mL), and
chlorine gas was bubbled through at 0 °C for 2 h. The mixture
was poured into ice-water (500 mL) and extracted three times
with dichloromethane. The combined organic fractions were
washed with brine and dried with Na2SO4. After filtering,
concentration under reduced pressure yielded a clear oil that
solidified to a white solid in the freezer. The reagent was pure
and could be used directly in the syntheses of the hydroxam-
ating reagents.
2-ter t-Bu toxyca r ba m oyl-2-eth ylm a lon ic Acid Dieth yl
Ester (7). According to the general procedure, diethyl ethyl
malonate (41 mg, 0.218 mmol) was acylated with NaH (13 mg,
0.33 mmol), LiBr (76 mg, 0.872 mmol), and 1a (60 mg, 0.218
mmol) in THF (4 mL) at -40 °C (3 h) and then at room
temperature (3 h). Flash chromatography on silica gel, eluting
with hexanes/ethyl acetate 5:1, yielded 7 (42 mg, 0.138 mmol,
64%): Rf ) 0.72 on silica gel (1:1 hexanes/ethyl acetate); IR
Gen er a l P r oced u r e for Syn th esis of Hyd r oxa m a tin g
R ea gen t s. N-(ter t-Bu t oxyca r b on yl)-O-(2-p yr id in ylsu l-
fon yl)h yd r oxyla m in e (1). 2-Pyridylsulfonyl chloride (3.529
(22) We thank one of the reviewers for suggesting the use of
triethylsilane in conjunction with TFA. This appeared to give less
colored solutions, but the yields were not improved.
(23) Baldwin, J . E.; Adlington, R. M.; Mellor, L. C. Tetrahedron 1994,
50, 5049-5066.
1
(neat) 3310, 1760, 1730 cm-1; H NMR (300 MHz, CDCl3) δ
10.20 (s, 1H), 4.20 (q, 4H, J ) 7.2, 6.5 Hz), 2.56 (q, 2H, J )
14.7, 7.7 Hz), 1.27 (s, 9H), 1.22 (t, 6H, J ) 13.6, 6.5 Hz), 0.87
(24) Falik, Z.; Plazek, E. Acta Pol. Pharm. 1955, 12, 5.

Synthesis of Hydroxamic Esters
J . Org. Chem., Vol. 64, No. 16, 1999 5901
(t, 3H,J ) 15.1, 7.6 Hz); 13C NMR (75 MHz, CDCl3) δ 168.5,
(s, 1H), 3.81 (s, 3H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3)
165.6, 164.8, 160.4, 130.6, 119.6, 83.1, 67.2, 58.4, 53.6, 26.2;
HRMS calcd for C12H20NO6 274.1290, found 274.1295.
164.6, 82.6, 65.5, 62.3, 27.6, 26.3, 13.9, 9.0; HRMS calcd for
C
14H26NO6 304.1749, found 304.1760.
2-ter t-Bu toxyca r ba m oyl-2-ben zylm a lon ic Acid Dieth yl
2-ter t-Bu toxyca r ba m oyl-2-m eth ylm a lon ic Acid Allyl
Ester ter t-Bu tyl Ester (13). According to the general proce-
dure, allyl tert-butyl methyl malonate (86 mg, 0.401 mmol) was
acylated with NaH (24.1 mg, 6.69 mmol) and 1a (1.223 g, 4.46
mmol) in THF (150 mL) at 0 °C (1 h) then at room temperature
(1 h). Flash chromatography on silica gel, eluting with hexanes/
ethyl acetate 9:1, yielded 13 (58.1 mg, 0.177 mmol, 44%): Rf
) 0.32 on silica gel (4:1 hexanes/ethyl acetate); IR (neat) 3321,
1756, 1728 (br) cm-1; 1H NMR (300 MHz, CDCl3) 9.70 (s, 9H),
5.89-5.75 (m, 1H), 5.25 (dd, 1H, J ) 17.2, 2.0 Hz), 5.17 (dd,
1H, J ) 10.4, 1.3 Hz), 4.59 (d, 2H, J ) 5.8 Hz), 1.63 (s, 3H),
1.37 (s, 9H), 1.20 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 169.0,
167.8, 166.0, 131.0, 119.3, 83.7, 82.6, 66.8, 61.1, 27.7, 26.2, 20.6.
2-ter t-Bu toxyca r ba m oyl-3-oxobu tyr ic Acid Eth yl Ester
(14). According to the general procedure, ethyl acetoacetate
(28.4 mg, 0.218 mmol) was acylated with NaH (7.9 mg, 0.33
mmol) and 1a (60 mg, 0.218 mmol) in THF (4 mL) at -40 °C
(2 h) and then at room temperature (3 h). Flash chromatog-
raphy on silica gel, eluting with hexanes/ethyl acetate 3:1,
yielded 14 (38 mg, 0.155 mmol, 71%): Rf ) 0.64 on silica gel
(2:1 hexanes/ethyl acetate); IR (neat) 3390, 3000, 1800, 1740
(br) cm-1; 1H NMR (300 MHz, CDCl3) δ 11.01 (s, 1H), 4.60 (s,
1H), 4.26 (dd, 2H, J ) 14.3, 7.2 Hz), 2.45 (s, 3H), 1.36 (dd, 3H,
J ) 14.3, 7.1 Hz), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
191.2, 171.4, 168.4, 93.7, 82.5, 60.8, 26.2, 25.9, 14.3; HRMS
calcd for C11H20NO5 246.1341, found 246.1330.
Ester (8). According to the general procedure, diethyl benzyl
malonate (55 mg, 0.219 mmol) was acylated with NaH (8 mg,
0.33 mmol) and 1a (60 mg, 0.219 mmol) in THF (4 mL) at 0
°C (45 min) and then at room temperature (3 h). Flash
chromatography on silica gel, eluting with hexanes/ethyl
acetate 6:1, yielded 8 (33.3 mg, 0.091 mmol, 42%): Rf ) 0.58
on silica gel (2:1 hexanes/ethyl acetate); IR (neat) 3940, 3327,
1
1761, 1729 cm-1; H NMR (300 MHz, CDCl3) δ 10.08 (s, 1H),
7.27-7.20 (m, 3H), 7.12-7.05 (m, 2H), 4.25 (q, 4H, J ) 7.1,
1.54 Hz), 3.63 (s, 1H), 1.28 (t, 6H, J ) 14.3, 7.1 Hz), 1.20 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 167.9, 163.8, 134.8, 129.6,
128.5, 127.4, 82.7, 62.5, 39.7, 28.0, 26.1, 13.9; HRMS calcd for
C
19H28NO6 366.1905, found 366.1916.
2-ter t-Bu toxyca r ba m oylm a lon ic Acid Ben zyl Ester
Meth yl Ester (9). According to the general procedure, benzyl
methyl malonate (189 mg, 0.911 mmol) was acylated with NaH
(55 mg, 1.37 mmol) and 1a (250 mg, 0.911 mmol) in THF (50
mL) at 0 °C (0.5 h) and then at room temperature (4 h). Flash
chromatography on silica gel, eluting with hexanes/ethyl
acetate 3:1, yielded 9 (140 mg, 0.433 mmol, 48%): Rf ) 0.32
on silica gel (2:1 hexanes/ethyl acetate); IR (neat) 3227, 1732
(br), 1682 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.25 (s, 1H), 7.32
(m, 5H), 5.20 (s, 2H), 4.42 (s, 1H), 3.74 (s, 3H), 1.21 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 165.5, 164.9, 160.4, 134.5, 128.6,
128.6, 128.4, 128.3, 83.0, 68.3, 50.3, 53.4, 26.1; HRMS calcd
for C16H22NO6 324.1454, found 324.1447.
2-ter t-Bu toxyca r ba m oyl-2-m eth ylm a lon ic Acid Ben zyl
Ester Meth yl Ester (10). According to the general procedure,
methyl benzyl methyl malonate (1 g, 0.446 mmol) was acylated
with NaH (268 mg, 6.69 mmol) and 1a (1.223 g, 4.46 mmol)
in THF (150 mL) at 0 °C (1 h) and then at room temperature
(1 h). Flash chromatography on silica gel, eluting with hexanes/
ethyl acetate 9:1, yielded 10 (822.8 mg, 2.44 mmol, 55%).
Alternatively, 10 was made according to the general procedure
for alkylation of O-t-butoxycarbonylamino derivatives (see
below) by mixing 9 (25 mg, 0.0773 mmol) with Cs2CO3 (23 mg,
0.0696 mmol) and iodomethane (13.2 mg, 0.0928 mmol) in
acetone (5 mL) at 40 °C for 4 h. Flash chromatography on silica
gel, eluting with hexanes/ethyl acetate 3:1, yielded 10 (13 mg,
0.039 mmol, 50%): Rf ) 0.36 on silica gel (2:1 hexanes/ethyl
acetate); IR (neat) 3325, 1733, 1697 cm-1; 1H NMR (300 MHz,
CDCl3) δ 9.63 (s, 1H), 7.40-7.24 (m, 5H), 5.21 (d, 2H, J ) 3.6
Hz), 3.71 (s, 3H), 1.77 (s, 1H), 1.24 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 169.3, 168.5, 165.2, 134.6, 128.5, 128.1, 126.8, 82.7,
1-ter t-Bu toxyca r ba m oyl-2-oxocyclop en ta n eca r boxyl-
ic Acid Eth yl Ester (15). According to the general procedure,
ethyl-2-oxocyclopentanecarboxylate (34 mg, 0.218 mmol) was
acylated with NaH (13 mg, 0.33 mmol) and 1a (60 mg, 0.218
mmol) in THF (4 mL) at -40 °C (1 h) and then at room
temperature (4 h). Flash chromatography on silica gel, eluting
with hexanes/ethyl acetate 3:1, yielded 15 (39 mg, 0.144 mmol,
66%) as a white solid: Rf ) 0.27 on silica gel (2:1 hexanes/
ethyl acetate); mp 57-59 °C; IR (neat) 3320, 1728 (br) cm-1
;
1H NMR (300 MHz, CDCl3) δ 9.12 (s, 1H), 4.23 (q, 2H, J )
7.2, 3.2 Hz), 2.90-2.78 (m, 1H), 2.63-2.53 (m, 1H), 2.53-2.35
(m, 2H), 2.08-1.95 (m, 2H), 1.30-1.21 (m, 12H); 13C NMR (75
MHz, CDCl3) δ 210.7, 167.4, 162.7, 82.8, 67.3, 62.7, 38.4, 31.5,
26.1, 19.8, 13.9; HRMS calcd for C13H22NO5 272.1498, found
272.1504.
3-ter t-Bu toxyca r ba m oyl-2-oxotetr a h yd r ofu r a n -3-ca r -
boxylic Acid Ben zyl Ester (16). According to the general
procedure, 2-oxotetrahydrofuran-3-carboxylic acid benzyl ester
(40 mg, 0.182 mmol) was acylated with NaH (11 mg, 0.273
mmol) and 1a (50 mg, 0.0.182 mmol) in THF (4 mL) at -40
°C (2 h) to -15 °C (2 h). Flash chromatography on silica gel,
eluting with hexanes/ethyl acetate 2:1, yielded 16 (26 mg,
0.078 mmol, 43%): Rf ) 0.29 on silica gel (2:1 hexanes/ethyl
acetate); IR (neat) 3329, 2928, 1767, 1744, 1720 cm-1; 1H NMR
(300 MHz, CDCl3) δ 9.29 (s, 1H), 7.38-7.30 (m, 5H), 5.24 (q,
2H, J ) 12.1, 8.5 Hz), 4.45 (dd, 2H, J ) 6.5, 5.4 Hz), 3.10-
2.98 (m, 1H), 2.80 (m, 1H), 1.19 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 171.6, 165.4, 161.1, 134.0, 129.0, 128.8, 128.5, 83.4,
68.0, 60.4, 53.2, 26.0, 20.3; HRMS calcd for
338.1618, found 338.1603.
C17H24NO6
2-ter t-Bu toxyca r ba m oylm a lon ic Acid Allyl Ester Eth yl
Ester (11). According to the general procedure, allyl ethyl
malonate (336 mg, 1.95 mmol) was acylated with NaH (130
mg, 3.25 mmol) and 1a (595 mg, 2.17 mmol) in THF (50 mL)
at 0 °C (1 h) and then at room temperature (4 h). Flash
chromatography on silica gel, eluting with hexanes/ethyl
acetate 5:1 then 3:1, yielded 11 (269 mg, 0.936 mmol, 48%) as
clear crystals: Rf ) 0.36 on silica gel (2:1 hexanes/ethyl
69.1, 67.6, 60.8, 30.2, 26.0; HRMS calcd for
336.1456, found 336.1447.
C17H22NO6
1
acetate); mp 39-41 °C; IR (neat) 3227, 1756, 1677 cm-1; H
NMR (300 MHz, CDCl3) δ 9.35 (s, 1H), 5.90-5.75 (m, 1H),
5.32-5.15 (m, 2H), 4.62 (q, 2H, J ) 5.9, 1.2 Hz), 4.37 (s, 1H),
4.18 (q, 2H, J ) 9.4, 2.2 Hz), 1.22 (s, 9H), 1.22 (t, 3H, J ) 5.1,
3.2 Hz); 13C NMR (75 MHz, CDCl3) δ 165.1, 164.9, 160.6, 130.7,
119.4, 83.0, 67.1, 62.9, 58.4, 26.1, 13.9; HRMS calcd for C13H22
NO6 288.1447, found 288.1440.
3-Ben zen esu lfon yl-N-ter t-bu toxy-3-oxo-3-p h en ylp r op i-
on a m id e (17). According to the general procedure, 2-(phen-
ylsulfonyl)acetophenone (47.4 mg, 0.182 mmol) was acylated
with NaH (11 mg, 0.273 mmol) and 1a (50 mg, 0.182 mmol)
in THF (4 mL) at 0 °C (0.5 h) and then at room temperature
(3 h). Flash chromatography on silica gel, eluting with hexanes/
ethyl acetate 2:1, yielded 17 (22 mg, 0.059 mmol, 32%): Rf )
0.14 on silica gel (2:1 hexanes/ethyl acetate); IR (neat) 3234,
-
2-ter t-Bu toxycar bam oylm alon ic Acid Allyl Ester Meth -
yl Ester (12). According to the general procedure, allyl methyl
malonate (620 mg, 0.392 mmol) was acylated with NaH (235
mg, 5.88 mmol) and 1a (1.075 g, 3.92 mmol) in THF (120 mL)
at 0 °C (1 h) and then at room temperature (3 h). Flash
chromatography on silica gel, eluting with hexanes/ethyl
acetate 3:1, yielded 12 (645 mg, 2.36 mmol, 60%): Rf ) 0.15
on silica gel (2:1 hexanes/ethyl acetate); IR (neat) 3213, 1760,
1
1698, 1672 cm-1; H NMR (300 MHz, CDCl3) δ 9.44 (s, 1H),
7.85 (dd, 4H, J ) 12.4, 7.3 Hz), 7.63-7.35 (m, 6H), 6.01 (s,
1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 187.6, 157.0,
137.3, 135.5, 134.9, 129.4, 129.2, 128.9, 83.8, 75.5, 26.2; HRMS
calcd for C19H22NSO5 376.1218, found 376.1227.
N-P h en ylm eth yl-N′-ter t-bu toxyu r ea (18). To a mixture
of 1a (66 mg, 0.24 mmol) and NaH (20 mg, 0.48 mmol) in 4
mL of THF was added benzylamine (26 mg, 0.24 mmol) at 0
1
1674 cm-1; H NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 5.95-
5.80 (m, 1H), 5.38-5.23 (m, 2H), 4.67 (d, 2H, J ) 5.8 Hz), 4.43

5902 J . Org. Chem., Vol. 64, No. 16, 1999
Hanessian and J ohnstone
°C (15 min) and then at room temperature (10 min). Flash
chromatography on silica gel, eluting with hexanes/ethyl
acetate 2:1, yielded 18 (39 mg, 0.175 mmol, 73%) as clear
crystals: Rf ) 0.44 on silica gel (1:1 hexanes/ethyl acetate);
mp 80-82 °C; IR (neat) 3439, 3205, 2931, 1668 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.39-7.24 (m, 5H), 6.82 (br s, 1H), 6.00
(br s, 1H), 4.48 (d, 2H, J ) 5.5 Hz), 1.24 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 160.9, 138.6, 128.6, 127.4, 127.3, 80.8, 43.5,
26.3; HRMS calcd for C12H19N2O2 223.1446, found 223.1453.
The same result was obtained in the presence of dimethyl
malonate.
Gen er a l P r oced u r e for Alk yla tion . Cs2CO3 or K2CO3
(0.9-0.95 equiv) was dried in an oven overnight and weighed
into a dry round-bottom flask equipped with a stir bar and
reflux condenser and capped with a rubber septum. Dry
acetone was added, followed by the O-t-butoxycarbonylamino
substrate (1 equiv). The mixture was stirred for 10 min, and
the alkylating reagent (1.2-2.0 equiv) was added. After being
heated at 40 °C for 2-17 h, the slurry was filtered and the
filtrate was concentrated under reduced pressure. The product
was purified on silica gel eluting with mixtures of hexanes and
ethyl acetate.
5.20 (m, 2H), 4.65-4.60 (m, 2H), 3.79 (s, 3H), 3.19 (d, 2H, J )
6.6 Hz), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 168.3, 167.6,
164.1, 136.6, 134.9, 130.8, 128.5, 127.7, 123.3, 119.4, 82.9, 67.0,
64.9, 53.4, 38.0, 26.2; HRMS calcd for C21H28NO6 390.1916,
found 390.1925.
1-ter t-Bu toxy-5-m eth oxyca r bon ylm eth yl-2-oxo-p yr r o-
lid in e-3,3-d ica r b oxylic Acid Allyl E st er Met h yl E st er
(23). According to the general procedure, 12 (59 mg, 0.216
mmol) was alkylated with Cs2CO3 (67 mg, 0.205 mmol) and
methyl-4-bromocrotonate (47 mg, 0.346 mmol) in acetone (5
mL) at 40 °C for 6 h. Flash chromatography on silica gel,
eluting with hexanes/ethyl acetate 4:1 and then 2:1, yielded
23 (60 mg, 0.16 mmol, 74%) as an inseparable 1.6:1 mixture
of diastereomers: Rf ) 0.38 on silica gel (2:1 hexanes/ethyl
1
acetate); IR (neat) 3456, 1732 (br) cm-1; H NMR (300 MHz,
CDCl3) δ 5.95-5.80 (m, 1H), 5.39-5.20 (m, 2H), 4.70-4.65 (m,
2H), 4.28-4.18 (m, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 2.96-2.73
(m, 2H), 2.68-2.55 (m, 1H), 2.40 (dd, 1H, J ) 16.4, 8.5 Hz),
1.29 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.1, 167.9, 167.3,
167.1, 166.6, 164.6, 130.9, 119.2, 85.2, 67.2, 67.0, 58.7, 58.7,
54.2, 53.7, 53.6, 51.9, 37.1, 37.1, 31.1, 31.1, 27.3; HRMS calcd
for C17H26NO8 372.1658, found 372.1649.
2-ter t-Bu toxyca r ba m oyl-2-ben zylm a lon ic Acid Ben zyl
Ester Meth yl Ester (19). According to the general procedure,
9 (38 mg, 0.117 mmol) was alkylated with K2CO3 (15 mg, 0.106
mmol) and BnBr (24.3 mg, 0.142 mmol) in acetone (4 mL) at
40 °C for 3 h. Flash chromatography on silica gel, eluting with
hexanes/ethyl acetate 4:1, yielded 19 (27 mg, 0.065 mmol,
52%): Rf ) 0.49 on silica gel (2:1 hexanes/ethyl acetate); IR
(neat) 3330, 1765, 1732, 1692 cm-1; 1H NMR (300 MHz, CDCl3)
δ 10.06 (s, 1H), 7.46-7.34 (m, 4H), 7.23-7.21 (m, 4H), 7.10-
7.02 (m, 2H), 5.29 (q, 2H, J ) 28.0, 12.0 Hz), 3.75 (s, 3H), 3.70
(s, 2H), 1.23 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 168.2, 167.5,
163.6, 134.6, 129.6, 128.7, 128.6, 128.5, 128.5, 127.5, 82.8, 68.1,
66.1, 53.2, 39.8, 26.1; HRMS calcd for C23H28NO6 414.1902,
found 414.1916.
2-Allyl-2-ter t-bu toxyca r ba m oylm a lon ic Acid Allyl Es-
ter Eth yl Ester (20). According to the general procedure, 11
(60 mg, 0.209 mmol) was alkylated with Cs2CO3 (61.2 mg,
0.188 mmol) and allyl iodide (42 mg, 0.251 mmol) in acetone
(5 mL) at 40 °C for 6 h. Flash chromatography on silica gel,
eluting with hexanes/ethyl acetate 4:1, yielded 20 (52 mg,
0.159 mmol, 76%): Rf ) 0.64 on silica gel (2:1 hexanes/ethyl
acetate); IR (neat) 3328, 1762, 1731, 1695 cm-1; 1H NMR (300
MHz, CDCl3) δ 10.10 (s, 1H), 5.90-5.75 (m, 1H), 5.75-5.55
(m, 1H), 5.38-5.09 (m, 4H), 4.64-4.61 (m, 2H), 4.23 (dd, 2H,
J ) 14.3, 7.1 Hz), 2.99 (dd, 2H, J ) 7.4, 0.9 Hz), 1.26 (s, 9H),
1.25 (t, 3H, J ) 8.8, 5.5); 13C NMR (75 MHz, CDCl3) δ 167.9,
167.6, 164.1, 131.2, 130.9, 120.1, 119.3, 82.8, 66.9, 64.6, 62.6,
38.6, 26.2, 13.9; HRMS calcd for C16H26NO6 328.1760, found
328.1771.
Gen er a l P r oced u r e for th e P d (OAc)2-Ca ta lyzed De-
ca r boxyla tion of Allyl Ester s. Pd(OAc)2 (0.1 equiv) and PPh3
(0.2 equiv) were weighed into a dry round-bottom flask
equipped with a stir bar and capped with a rubber septum.
MeCN was added, and the mixture stirred for 10 min. PhSiH3
(2-3 equiv) was added and the mixture stirred for 10 min. To
this dark brown mixture was added the allyl ester substrate
(1 equiv) in MeCN with a cannula. After the mixture stirred
at room temperature for 30-120 min, it was concentrated
under reduced pressure, applied to a column containg silica
gel, and eluted with a mixture of hexanes and EtOAc.
Gen er a l P r oced u r e for th e P d /C-Ca ta lyzed Deca r -
boxyla tion of Ben zyl Ester s. The benzyl ester substrate (1
equiv) and Pd/C (10%, 80 mg/mmol substrate) were weighed
into a dry round-bottom flask equipped with a stir bar and
capped with a rubber septum. MeCN was added, and a balloon
of H2 gas was attached. The reaction stirred a room temper-
ature for 20-120 min. The catalyst was removed by filtration
through a pad of Celite. After concentration under reduced
pressure, the product was purified by flash chromatography
on silica gel eluting with hexanes and EtOAc.
N-ter t-Bu toxy-2-m eth ylm alon am ic ter t-Bu tyl Ester (24).
According to the general procedure for decarboxylation with
Pd(OAc)2, 13 (50 mg, 0.152 mmol) was decarboxylated by
stirring for 1 h with Pd(OAc)2 (2 mg, 0.0076 mmol), PPh3 (4
mg, 0.0152 mmol), and PhSiH3 (49 mg, 0.456 mmol) in MeCN
(3 mL). The product was purified by flash chromatography on
silica gel eluting with hexanes/EtOAc 5:1 and then 1:1 to yield
24 (37 mg, 0.148 mmol, 98%): Rf ) 0.05 on silica gel (2:1
2-ter t-Bu toxyca r ba m oyl-2-ben zylm a lon ic Acid Allyl
Ester Meth yl Ester (21). According to the general procedure,
12 (89 mg, 0.326 mmol) was alkylated with Cs2CO3 (101 mg,
0.31 mmol) and benzyl bromide (84 mg, 0.49 mmol) in acetone
(3 mL) at 40 °C for 17 h. Flash chromatography on silica gel,
eluting with hexanes/ethyl acetate 4:1, yielded 21 (85 mg,
0.233 mmol, 72%): Rf ) 0.48 on silica gel (2:1 hexanes/ethyl
acetate); IR (neat) 3332, 1764, 1734, 1693 cm-1; 1H NMR (300
MHz, CDCl3) δ 10.01 (s, 1H), 7.27-7.18 (m, 3H), 7.10-7.05
(m, 2H), 5.93-5.78 (m, 1H), 5.36-5.26 (m, 2H), 4.65 (dd, 2H,
J ) 5.9, 1.4 Hz), 3.78 (s, 3H), 3.64 (d, 2H, J ) 2.5 Hz), 1.19 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 168.4, 167.4, 163.6, 134.6,
130.8, 129.6, 128.5, 127.5, 119.4, 82.8, 67.0, 66.0, 53.3, 39.8,
26.2; HRMS calcd for C19H26NO6 364.1760, found 364.1751.
2-ter t-Bu toxyca r ba m oyl-2-styr ylm a lon ic Acid Allyl Es-
ter Meth yl Ester (22). According to the general procedure,
12 (40 mg, 0.146 mmol) was alkylated with Cs2CO3 (43 mg,
0.132 mmol) and cinnamyl bromide (35 mg, 0.175 mmol) in
acetone (3 mL) at 40 °C for 7 h. Flash chromatography on silica
gel, eluting with hexanes/ethyl acetate 4:1, yielded 22 (24 mg,
0.062 mmol, 42%): Rf ) 0.52 on silica gel (2:1 hexanes/ethyl
acetate); IR (neat) 3329, 1762, 1762, 1695 cm-1; 1H NMR (300
MHz, CDCl3) δ 10.09 (s, 1H), 7.29-7.18 (m, 5H), 6.43 (d, 2H,
J ) 16.6 Hz), 6.09-5.98 (m, 1H), 5.90-5.78 (m, 1H), 5.32-
hexanes/ethyl acetate); IR (neat) 3198, 1740, 1667 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 3.17 (q, 1H, J ) 5.7,
4.9 Hz), 1.47 (s, 9H), 1.39 (d, 3H, J ) 5.4, 1.3 Hz), 1.28 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 170.8, 168.2, 82.5, 82.3, 46.4,
27.9, 26.2, 15.1; HRMS calcd for C12H24NO4 246.1697, found
246.1705.
2-ter t-Bu toxyca r ba m oylbu t-3-en oic Acid Eth yl Ester
(25). According to the general procedure for decarboxylation
with Pd(OAc)2, 20 (20 mg, 0.061 mmol) was decarboxylated
by stirring for 1 h with Pd(OAc)2 (1.4 mg, 0.0061 mmol), PPh3
(3.2 mg, 0.0122 mmol), and PhSiH3 (20 mg, 0.183 mmol) in
MeCN (3 mL). The product was purified by flash chromatog-
raphy on silica gel eluting with hexanes/EtOAc 3:1, 1:1, to yield
25 (16 mg, 0.59 mmol, 97%): Rf ) 0.26 on silica gel (3:1
hexanes/ethyl acetate); IR (neat) 3192, 1743, 1666 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 5.80-5.63 (m, 1H),
5.15-5.03 (m, 2H), 4.17 (q, 2H, J ) 14.2, 7.1 Hz), 3.26 (t, 1H,
J ) 14.4, 7.4 Hz), 2.67 (t, 2H, J ) 14.3, 7.2 Hz), 1.26 (s, 9H),
1.26 (t, 3H, J ) 14.3, 7.9 Hz); 13C NMR (75 MHz, CDCl3) δ
170.7, 166.6, 133.6, 118.2, 82.5, 61.8, 51.0, 34.2, 26.2, 14.1;
HRMS calcd for C12H23NO4 244.1548, found 244.1541.
N-ter t-Bu toxy-2-ben zylm a lon ic Acid Meth yl Ester (26).
According to the general procedure for decarboxylation with
Pd(OAc)2, 21 (13.5 mg, 0.037 mmol) was decarboxylated by

Synthesis of Hydroxamic Esters
J . Org. Chem., Vol. 64, No. 16, 1999 5903
1
stirring for 1 h with Pd(OAc)2 (1 mg, 0.0045 mmol), PPh3 (2.4
mg, 0.009 mmol), and PhSiH3 (12 mg, 0.111 mmol) in MeCN
(2 mL). The product was purified by flash chromatography on
silica gel eluting with hexanes/EtOAc 2:1, 1:1 to yield 26 (10
mg, 0.036 mmol, 98%). Alternatively, 26 was decarboxylated
with Pd/C (4 mg) and H2 to yield the same product (13 mg,
0.476 mmol, 98%): Rf ) 0.23 on silica gel (2:1 hexanes/ethyl
acetate); IR (neat) 3196, 1746, 1666 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.25 (s, 1H), 7.30-7.15 (m, 5H0, 3.68 (s, 3H), 3.42 (t,
1H, J ) 14.7, 7.5 Hz), 7.32-7.16 (m, 2H), 1.17 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 170.6, 166.4, 137.5, 128.9, 128.4, 126.9,
82.6, 53.0, 52.6, 35.4, 26.1; HRMS calcd for C15H22NO4
280.1548, found 280.1540.
IR (neat) 3457, 1726 (br) cm-1; H NMR (300 MHz, CDCl3) δ
4.26-4.16 (1H, m), 3.78 and 3.77 (s, 3H), 3.70 (s, 3H), 3.45-
3.36 (m, 1H), 2.99 and 2.84 (dd, 1H, J ) 20.8, 16.0 Hz), 2.70-
2.46 (m, 2H), 2.35 (dd, 1H, J ) 15.9, 8.1 Hz), 2.26-2.04 (m,
1H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.7, 171.0,
170.1, 168.2, 84.7, 84.5, 55.7, 55.3, 52.9, 51.9, 43.6, 43.4, 37.3,
36.2, 27.2, 25.4, 24.9; HRMS calcd for C13H22NO6 288.1447,
found 288.1437.
Gen er a l P r oced u r e for Acid Clea va ge of th e ter t-Bu tyl
Gr ou p fr om O-t-Bu toxyca r bon yla m in o Com p ou n d s. The
O-t-butoxycarbonylamino compound was dissolved in CH2Cl2,
and fresh trifluoroacetic acid (11 mL/mmol of substrate) was
added under a nitrogen atmosphere. The mixture was stirred
at room temperature for 48 h. The solvent was evaporated,
and the product was purified by flash chromatography on silica
gel eluting with mixtures of hexanes and EtOAc.
2-ter t-Bu toxyca r ba m oyl-4-p h en ylbu t-3-en oic
Acid
Meth yl Ester (27). According to the general procedure for
decarboxylation with Pd(OAc)2, 22 (18.3 mg, 0.047 mmol) was
decarboxylated by stirring for 2 h with Pd(OAc)2 (1.1 mg,
0.0047 mmol), PPh3 (2.5 mg, 0.0094 mmol), and PhSiH3 (15
mg, 0.141 mmol) in MeCN (2 mL). The product was purified
by flash chromatography on silica gel eluting with hexanes/
EtOAc 2:1 and then 1:1 to yield 27 (12 mg, 0.0393 mmol,
84%): Rf ) 0.23 on silica gel (2:1 hexanes/ethyl acetate); IR
2-Hydr oxycar bam oylm alon ic Acid Dim eth yl Ester (32).
According to the general procedure, 5 (23 mg, 0.093 mmol) was
stirred with TFA (1 mL) in CH2Cl2 (1.5 mL). The product was
purified by flash chromatography on silica gel eluting with
hexanes/ethyl acetate 1:1 to yield 32 (13.4 mg, 0.07 mmol,
75%): Rf ) 0.34 on silica gel (1:1 hexanes/ethyl acetate); IR
(neat) 3208, 1745, 1664 cm-1; H NMR (300 MHz, CDCl3) δ
(neat) 3457, 1726 (br) cm-1 1H NMR (300 MHz, CDCl3) δ
;
1
8.55 (s, 1H), 7.31-7.15 (m, 5H), 6.45 (d, 1H, J ) 15.8 Hz),
6.13-6.01 (m, 1H), 3.73 (s, 3H), 3.33 (t, 1H, 14.6, 7.2 Hz), 2.85-
2.75 (m, 2H), 1.24 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.0,
166.5, 136.8, 133.4, 128.5, 127.5, 126.2, 124.9, 82.6, 52.7, 51.2,
33.4, 26.2; HRMS calcd for C17H24NO4 306.1705, found 306.1696.
N-ter t-bu toxym a lon a m ic Acid Meth yl Ester (28). Ac-
cording to the general procedure for decarboxylation with Pd/
C, 9 (150 mg, 0.464 mmol) was decarboxylated by stirring
under H2 for 20 min with Pd/C (28 mg) in MeCN (5 mL). The
product was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc 3:1 and then 2:1 to yield 28 (81.2
mg, 0.43 mmol, 93%): Rf ) 0.09 on silica gel (2:1 hexanes/
ethyl acetate); IR (neat) 3208, 1748, 1668 cm-1; 1H NMR (300
MHz, CDCl3) δ 9.56 (s, 1H), 3.63 (s, 3H), 3.24 (s, 2H), 1.19 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 169.1, 163.7, 82.3, 52.5, 39.8,
26.1; HRMS calcd for C8H16NO4 190.1070, found 190.1079.
N-ter t-bu toxy-2-m eth ylm a lon a m ic Acid Meth yl Ester
(29). According to the general procedure for decarboxylation
with Pd/C, 10 (105 mg, 0.313 mmol) was decarboxylated by
stirring under H2 for 20 min with Pd/C (27 mg) in MeCN (5
mL). The product was purified by flash chromatography on
silica gel eluting with hexanes/EtOAc 5:1 and then 2:1 to yield
29 (63 mg, 0.31 mmol, 98%): Rf ) 0.11 on silica gel (2:1
4.26-4.16 (1H, m), 3.78 and 3.77 (s, 3H), 3.70 (s, 3H), 3.45-
3.36 (m, 1H), 2.99 and 2.84 (dd, 1H, J ) 20.8, 16.0 Hz), 2.70-
2.46 (m, 2H), 2.35 (dd, 1H, J ) 15.9, 8.1 Hz), 2.26-2.04 (m,
1H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.7, 171.0,
170.1, 168.2, 84.7, 84.5, 55.7, 55.3, 52.9, 51.9, 43.6, 43.4, 37.3,
36.2, 27.2, 25.4, 24.9; HRMS calcd for C6H10NO6 192.0508,
found 192.0502.
2-Hyd r oxyca r ba m oylm a lon ic Acid Allyl Ester Meth yl
Ester (33). According to the general procedure, 12 (23 mg,
0.093 mmol) was stirred with TFA (1 mL) in CH2Cl2 (1.5 mL)
for 48 h. The product was purified by flash chromatography
on silica gel eluting with hexanes/ethyl acetate 1:1 to yield 33
(15 mg, 0.07 mmol, 76%) as a white solid: Rf ) 0.15 on silica
gel (1:1 hexanes/ethyl acetate); mp 32-34 °C; IR (neat) 3307,
1
1742, 1678 (br) cm-1; H NMR (300 MHz, CDCl3) δ 9.8 (1H,
brs), 5.90-5.70 (1H, m), 5.30-5.15 (2H, m), 4.61 (2H, d, J )
5.9 Hz), 4.38 91H, s), 3.74 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 165.2, 164.4, 160.2, 130.6, 119.6, 67.4, 56.9, 53.8; HRMS calcd
for C8H12NO6 218.0664, found 218.0672.
2-Hyd r oxyca r ba m oyl-2-ben zylm a lon ic Acid Allyl Es-
ter Meth yl Ester (34). According to the general procedure,
26 (35 mg, 0.096 mmol) was stirred with TFA (1 mL) in CH2-
Cl2 (1.5 mL). The product was purified by flash chromatogra-
phy on silica gel eluting with hexanes/ethyl acetate 1:1 to yield
34 (20.0 mg, 0.065 mmol, 68%): Rf ) 0.42 on silica gel (1:1
hexanes/ethyl acetate); IR (neat) 3209, 1749, 1670 cm-1
NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 3.73 (s, 3H), 3.29 (dd,
1H, J ) 7.7, 7.2 Hz), 1.43d, 3H, J ) 7.7 Hz), 1.26 (s, 9H) ; 13
;
1H
hexanes/ethyl acetate); IR (neat) 3336, 1764, 1734, 1662 cm-1
;
C
1H NMR (300 MHz, CDCl3) δ 10.39 (1H, brs), 7.25-7.19 (3H,
m), 7.03-6.95 (2H, m), 5.90-5.75 (1H, m) 5.33-5.21 (2H, m),
4.64 (2H, d, J ) 5.6 Hz), 3.76 (3H, s), 3.60 (2H, s)); 13C NMR
(75 MHz, CDCl3) δ 167.6, 166.8, 162.3, 134.1, 130.6, 129.4,
128.6, 127.7, 119.5, 67.1, 64.1, 53.5, 40.1; HRMS calcd for
NMR (75 MHz, CDCl3) δ 172.1, 167.8, 82.4, 52.7, 44.9, 26.2,
14.7; HRMS calcd for C9H18NO4 204.1214, found 204.1235.
2-Oxocyclop en ta n eca r boxylic Acid ter t-Bu toxya m id e
(30). According to the general procedure for decarboxylation
with Pd/C, 1-tert-butoxycarbamoyl-2-oxocyclopentanecarboxy-
lic acid benzyl ester (39 mg, 0.117 mmol) was decarboxylated
by stirring under H2 for 2 h with Pd/C (9.5 mg) in MeCN (3
mL). The product was purified by flash chromatography on
silica gel eluting with hexanes/EtOAc 3:1 and then 2:1 to yield
30 (14 mg, 0.07 mmol, 61%): Rf ) 0.09 on silica gel (2:1
C
15H18NO6 308.1134, found 308.1124.
2-H yd r oxyca r b a m oyl-2-m et h ylm a lon ic Acid Diet h yl
Ester (35). According to the general procedure, 6 (40 mg, 0.138
mmol) was stirred with TFA (1.5 mL) in CH2Cl2 (1.5 mL). The
product was purified by flash chromatography on silica gel
eluting with hexanes/ethyl acetate 1:1 to yield 35 (21 mg, 0.09
mmol, 65%): Rf ) 0.34 on silica gel (1:1 hexanes/ethyl acetate);
hexanes/ethyl acetate); IR (neat) 3216, 1747, 1664 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 2.99 (t, 1H, J ) 17.7,
8.9 Hz), 2.42-2.19 (m, 4H), 2.13-2.05 (m, 1H), 1.92-1.78 (m,
1H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 215.7, 166.0,
82.1, 53.1, 38.6, 26.2, 25.5, 20.7; HRMS calcd for C10H18NO3
200.1286, found 200.1293.
1-ter t-Bu toxy-5-m eth oxyca r bon ylm eth yl-2-oxo-p yr r o-
lid in e-3-ca r boxylic Acid Meth yl Ester (31). According to
the general procedure for decarboxylation with Pd(OAc)2, 23
(55 mg, 0.148 mmol) was decarboxylated by stirring for 1 h
with Pd(OAc)2 (3.3 mg, 0.0148 mmol), PPh3 (8 mg, 0.0296
mmol), and PhSiH3 (34 mg, 0.311 mmol) in MeCN (5 mL). The
product was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc 2:1 and then 1:1 to yield 31 as
an inseparable 2.2:1 mixture of diastereomers (28.4 mg, 0.099
mmol, 67%): Rf ) 0.30 on silica gel (2:1 hexanes:ethyl acetate);
IR (neat) 3338, 25, 1733, 1670 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 10.18-10.0 (1H, brs), 4.10 (dd, J ) 14.2, 7.1 Hz, 4H),
1.72 (s, 3H), 1.25 (t, J ) 12.2, 7.1 Hz. 6H); 13C NMR (75 MHz,
CDCl3) δ 168.4, 164.8, 62.8, 29.7, 20.6, 13.8; HRMS calcd for
C9H16NO6 234.0977, found 234.0969.
Ack n ow led gm en t. S.J . thanks L.-D. Cantin for
helpful discussions and Biomega Boehringher-Ingelheim
(Canada) for a fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O990353K