Synthesis and reactions of 2-substituted ethyl N-alkylmalonylhydroxamic acids

Article abstract of DOI:10.1021/jo0300690

Alkylation of O-silylated N-alkylmalonylhydroxamic acids provides a method for the synthesis of 2-substituted N-alkylmalonyl hydroxamic acids. The substituent at C-2 does not materially change the chemistry of the α-lactam intermediates produced from them. They can be converted to unsymmetric ureas and hydantoins in high yields. The addition of unsaturated substituents at C-2 is used to produce cyclic ureas containing medium rings via RCM reactions.

Full text of DOI:10.1021/jo0300690

Syn th esis a n d Rea ction s of 2-Su bstitu ted Eth yl
N-Alk ylm a lon ylh yd r oxa m ic Acid s
Robert V. Hoffman* and Sachin Madan
Department of Chemistry and Biochemistry, New Mexico State University, North Horseshoe Drive,
Las Cruces, New Mexico 88003-8001
rhoffman@nmsu.edu
Received February 24, 2003
Alkylation of O-silylated N-alkylmalonylhydroxamic acids provides a method for the synthesis of
2-substituted N-alkylmalonyl hydroxamic acids. The substituent at C-2 does not materially change
the chemistry of the R-lactam intermediates produced from them. They can be converted to
unsymmetric ureas and hydantoins in high yields. The addition of unsaturated substituents at
C-2 is used to produce cyclic ureas containing medium rings via RCM reactions.
SCHEME 1
We have found that N-alkylated hydroxamic acids are
convenient sources of R-lactams when converted to the
N-mesyloxy derivative and treated with base.1 Particular
interest developed in ethyl N-alkylmalonylhydroxamic
acids 1, which proved to be versatile synthetic intermedi-
ates for the synthesis of unsymmetric ureas, N-amino-
hydantoins, and 1,2,4-triazolin-3,6-diones via R-lactams.2-4
In all cases studied thus far, the 2-position has been
unsubstituted (1, R ) H). Substitutents at the 2-position
could be useful as elements of diversity as well as for
the incorporation of additional functionality that could
be manipulated in the products. Moreover, the ability of
electron-withdrawing groups to control the regiochemis-
try of nucleophilic addition to the intermediate R-lac-
tam1,2 suggests other electron-withdrawing groups such
as an acyl group (e.g., 2) would also lead to potentially
new and interesting chemistry.
knowledge, bis-anions of hydroxamic acids have not been
reported previously in the literature.
Resu lts a n d Discu ssion
A. Syn th esis. When hydroxamic acid 3a was treated
with 2.2 equiv of LDA at 0 °C for 1 h and then prenyl
bromide 7a was added, prenylated adduct 4a a could be
isolated in yields of 50-55%. In addition to 4a a , bis-
alkylated product 5 (19%) as well as unsaturated amide
6 (10-12%) could be isolated from the reaction mixture
(eq 1).
In considering ways to prepare 1 and 2, it occurred to
us that if hydroxamic acids could be converted to their
bis-anions (in analogy to carboxylic acid bis-anions5), they
could be carboxylated or acylated to give 1 and 2 (Scheme
1). This would provide a novel and potentially general
way to prepare such materials from readily available
starting materials without having to deal with unstable
â-keto acid or malonic half ester intermediates. To our
(1) Hoffman, R. V.; Nayyar, N. K.; Chen, W. J . Am. Chem. Soc. 1993,
115, 5031.
(2) Hoffman, R. V.; Reddy, M. M.; Cervantes-Lee, F. J . Org. Chem.
2000, 65, 2591-2595.
(3) Hoffman, R. V.; Reddy, M. M.; Klumas, C. M.; Cervantes-Lee,
F. J . Org. Chem. 1998, 63, 9128-9130.
(4) Hoffman, R. V.; Nayyar, N. K. J . Org. Chem. 1995, 60, 5992-
5994.
Similar results were obtained if the same sequence was
carried out at -20 °C. Lower yields of monoalkylated
(5) Thompson, C. M. Dianion Chemistry in Organic Synthesis; CRC
Press: Boca Raton, FL, 1994.
10.1021/jo0300690 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003
4876
J . Org. Chem. 2003, 68, 4876-4885

2-Substituted Ethyl N-Alkylmalonylhydroxamic Acids
TABLE 1. Alk yla tion of N-Alk ylh yd r oxa m ic Acid
Bis-a n ion s
product from 3a and presumably other hydroxamic acids
as well.
Several attempts to circumvent the decomposition of
8a -2 were made. O-Silylation with tert-butyldimethylsilyl
chloride or tert-butyldiphenylsilyl chloride gave TBDMS
derivative 9 and TBDPS derivative 10, respectively.
Treatment of either 9 or 10 with LDA (1 equiv) and then
prenyl bromide gave no alkylated product. In each case,
the starting material was recovered in 50% yield along
with the corresponding silanol. For comparison pur-
poses, the Weinreb amide was prepared from 3a . Treat-
ment with LDA and then prenyl bromide led to com-
plete decomposition. This is consistent with observations
showing that Weinreb amides are quite unstable to either
strong7 or weak8 bases. Thus, silylation of the oxygen of
a hydroxamic acid does not prevent decomposition of the
enolate and appears to retard the alkylation of the
R-position.
starting
material
alkylating
agent
temp
(°C)
yield
entry
producta
4 (%)b
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3c
3e
3f
7a
7a
7b
7c
7d
7b
7a
7c
7a
4a a
4a a
4a b
4a c
4a d
4bb
4ca
4ec
4fa
0
-20
0
55
52
47
40
39
45
26
38
42
-20
0
-20
-20
0
0
a
Product structures are indicated by the reaction of starting
material 3x with alkylating agent 7y to give product 4xy. Yields
b
are for isolated yields of purified products.
product 4a a were obtained at -78 °C (35%). A lower yield
of 4a a was observed if the reaction time for bis-anion
formation at 0 °C was decreased from 1 h to 30 min (21%
4a a but 48% of unreacted 3a ) due to incomplete reaction.
A lower yield of 4a a was also observed if the reaction
time for bis-anion formation was increased to 2 h (29%
4a a and 32% 5). These results define the best conditions
for the sequence, namely, bis-anion formation at either
0 or -20 °C for 1 h followed by addition of an alkylating
agent 7 at the same temperature. A series of N-alkylhy-
droxamic acids was alkylated using these conditions, and
the results are presented in Table 1.
The importance of lithium ions in the decomposition
of 8a -2 was easily shown. When potassium hexamethyl-
disilylamide was used in place of LDA for enolate
formation with 3a , the yield of alkylation product 4a a
decreased significantly (due to increased decomposition),
yet no 6 was formed. This suggests that lithium ions
stabilize 8a -2, presumably by stabilization of the oxy-
anions in 8a -2
.
The yields of monoalkylated products were only fair
to moderate. It became pertinent to ask (a) if the bis-
anion was, in fact, being generated in the reaction mix-
ture and (b) if the bis-anion is stable under the reac-
tion conditions. Treatment of 3a with 1 equiv of LDA at
0 °C for 1 h followed by aqueous workup led to near
quantitative recovery of 3a ; thus, the hydroxamate
monoanion 8a - is stable to the reaction conditions.
Treatment of 3a with 2.2 equiv of LDA for 1 h at 0 °C
followed by an aqueous quench led to only 50% recovery
of the starting material and 7% of 6. Finally, treatment
of 3a with 2.2 equiv of LDA for 1 h at 0 °C followed by a
D2O quench gave 51.5% recovered starting material that
had a single deuterium at the R-position as well as 10%
of 6.
These experiments demonstrate that bis-anion 8a -2 is
formed from 3a under the reaction conditions but that
it is unstable and begins to decompose at 0 °C prior to
the addition of the alkylating agent. This accounts for
the modest yields of monoalkylated products. Further-
more, decomposition of the bis-anion would lead to an
excess of prenyl bromide, relative to the bis-anion,
which accounts for the dialkylated product (eq 1).6
Thus, decomposition of the bis-anion 8a -2 appears to
be a limiting factor in production of monoalkylated
The formation of 6 is quite interesting since nitrogen
is reduced and the R- and â-carbons are oxidized relative
to the starting material. Moreover, formation of 6 pro-
ceeds by cleavage of the N-O bond of 8-2, in which the
oxygen bears a negative charge yet functions as a leaving
group!
Hydroxamic acids 3a -f were treated with 3 equiv of
LDA at 0 °C and then allowed to stir at room tempera-
ture until the starting material was consumed (TLC). The
unsaturated amides 6a -c,f were isolated from the
dark red reaction mixtures. The results are presented in
Table 2.
The results suggest that the â-proton must be activated
by conjugation in order to form 6 (cf. entries 1-4 and 5,
6), and an electron-donating substituent on the aromatic
(6) Treatment of 4a with 1 equiv of LDA and then 1 equiv of prenyl
bromide at 0 °C gives 5 in high yield.
(7) Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31, 6269.
(8) Keck, G. E.; McHardy, S. F.; Murry, J . A. Tetrahedron Lett. 1993,
34, 6215.
J . Org. Chem, Vol. 68, No. 12, 2003 4877

Hoffman and Madan
TABLE 2. Con ver sion of Hyd r oxa m ic Acid s to
r,â-Un sa tu r a ted Am id es
SCHEME 3
entry
hydroxamic acid
product
yield (%)a
1.
2.
3.
4.
5.
6.
3a
3b
3c
3f
3d
3e
6a
6b
6c
6f
6d
6e
40
42
42
15
0
SCHEME 4
0
a
Yield of pure material after column chromatography.
SCHEME 2
alkylate simple hydroxamic acids, led to complete de-
struction of the starting material! Of the two anionic sites
in 12-2, the resonance-delocalized malonyl anion should
be reasonably stable. Thus, blocking the hydroxamic acid
group by silylation should result in a more stable malonyl
monoanion. Treatment of 12 with 1 equiv of sodium
hydride and TBDMSCl or treatment with triethylamine
and TBDMSCl also led to decomposition of the starting
material. Clearly, the hydroxamate anion of 12 is un-
stable and does not survive long enough to be silylated.11
Since direct O-silylation of 12 could not be accom-
plished, N-methylhydroxylamine was O-silylated with
TBDPSCl to give 13.12 Slow addition of ethyl malonyl
chloride to a mixture of 13 and Et3N (1 equiv) gave
O-silylated hydroxamic acid 14 in good yield. Consistent
with prediction, the O-silylated hydroxamate 14 could be
alkylated with prenyl bromide to give 15a in very high
yields (Scheme 4).
Desilylation of 15a with TBAF in THF13 failed to
deliver the hydroxamic acid. Instead, a compound that
appeared to be the cyclized product 16 by IR and NMR
spectroscopy was isolated in 16% yield. Since 16 presum-
ably results from cyclization of the hydroxamate anion
of 15a , a process suspected earlier in the reaction of
hydroxamic acid 12 with bases, the use of fluoride to
desilylate 15 is not a good choice. We found, however,
that 1% methanesulfonic acid in absolute ethanol desi-
ring suppresses its formation (cf. entries 1-3 and 4).
Thus, proton removal from the â-position is required for
the formation of 6. LDA is not involved in its removal,
however, since doubling the concentration of LDA in the
reaction of 3a does not change the yield of 6a .9 Formation
of 6 appears to be a first-order reaction of bis-anion 8-2
characterized by an intramolecular proton rearrange-
ment to one of the anionic oxygens to give conjugated ion
11 (Scheme 2). Of the two likely pathways shown in
Scheme 2, path b is preferred due to the six-membered
ring transition state for proton loss. In either case, a third
equivalent of LDA is required to neutralize the ultimate
product of proton removal. The formation of 6 occurs upon
generation of bis-anion 8-2 even at -20 °C, so it is always
a part of the product mixture.
Attempts to acylate 8a -2 with ethyl chloroformate were
uniformly unsuccessful, as complete decomposition was
observed on addition of the acylating agent, even at -78
°C. While hydroxamic acid dianions can be alkylated with
modest success, they do not provide a viable route to 1.
In considering alternate synthetic approaches to 1, R
* Η, a straightforward strategy would be to simply
alkylate 12 (Scheme 3). We anticipated that the ester
group in the malonylhydroxamate bis-anion should sta-
bilize the negative charge of dianion 12-2 and hopefully
reduce the amount of competing decomposition.
(9) R-Lactams with â-hydrogens can react with bases to produce R,â-
unsaturated amides in a second-order reaction. (See for example:
Quast, H., Meichsner, G., Seiferling, B. Chem. Ber. 1987, 120, 217-
223.) This scenario predicts that the yield of 6 should increase as the
concentration of LDA is increased, contrary to observations. Thus, the
involvement of R-lactams in the formation of 6 is discounted.
(10) Hoffman, R. V.; Nayyar, N. K.; Chen, W. J . Org. Chem. 1995,
60, 4121-4125
(11) A product was isolated that lacked the ethoxy group and
appeared to be the result of intramolecular cyclization between the
hydroxamate oxyanion and the ester group to give an isoxazolidine
dione.
(12) Altenburger, J . M.; Mioskowski, C.; d’Orchymont, H.; Schirlin,
D.; Schalk, C.; Tarnus, C. Tetrahedron Lett. 1992, 33 5055-5058.
(13) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
Treatment of N-methylhydroxamate 1210 with 2 equiv
of LDA followed by prenyl bromide, conditions used to
4878 J . Org. Chem., Vol. 68, No. 12, 2003

2-Substituted Ethyl N-Alkylmalonylhydroxamic Acids
SCHEME 5
SCHEME 7
SCHEME 6
TABLE 3. P r ep a r a tion of Un sym m etr ic Ur ea s fr om th e
Rea ction of N-Mesyloxy Am id es w ith Am in e Nu cleop h iles
in Reflu xin g Dich lor om eth a n e
entry
mesylate
amine
producta
timeb
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
19a
19a
19b
19b
19b
19b
19c
19c
19d
19d
19e
19e
19e
20
22d
22e
22g
22h
22i
22j
22b
22c
22a
22f
22h
22i
22j
22h
21a d
21a e
21bg
21bh
21bi
21bj
21cb
21cc
21d a
21d f
21eh
21ei
21ej
23
4 h
4 h
2 h
15 h
2 h
4 h
2 h
2 h
7 h
5 h
24 h
2 h
5 h
5 h
86
81
79
76
93
87
92
91
81
77
74
90
88
82
lylated 15a smoothly to the hydroxamic acid in 70%
yield.14
A series of N-methyl ethyl malonylhydroxamates 15
was prepared by the alkylation and desilylation of 14
(Scheme 4). Activated alkyl bromides (allyl, prenyl,
benzyl) reacted smoothly at room temperature as did
methyl iodide. Unactivated primary bromides (4-butenyl
bromide and the acetal of 3-bromopropanal) required the
addition of 1 equiv of sodium iodide and overnight reflux
for efficient reaction. Nevertheless excellent yields of 15
were obtained. Desilylation gave the hydroxamic acids
1a -f in good yields.
N-Isopropyl analogue 17 was alkylated with prenyl
bromide and desilylated to give 18 in 70% overall yield
(Scheme 6), which suggests that it is possible to prepare
other N-substituted analogues as well.
The TBDPS protecting group was chosen so that the
intermediate alkylation products 15 could be isolated and
purified. In practice, however, the crude alkylation
product was quite pure and could be desilylated without
purification. Good results could also be obtained using
the TBDMS protecting group if the crude alkylation
product was carried on without purification.
a
Mesylate 19x reacting with amine 22y would give product
b
21xy. Time for complete disappearnace of starting material by
TLC. c Yields of pure product after column chromatography.
reaction with methanesulfonyl chloride and triethyl-
amine.10 Mesylates 19a -e and 20 were reacted with
amines to provide unsymmetric ureas in high yields
(Scheme 7). The results are shown in Table 3.
The data in Table 3 show that both primary and
secondary amines react effectively to give unsymmetric
ureas in high yields. Thus, a substituent at the 2-posi-
tion of the malonyl hydroxamate does not alter the course
of the reaction. It does, however, slow the rate of reac-
tion. It was reported that the reactions of amines (2.2
equiv) with ethyl N-methyl-N-mesyloxymalonamide (19,
R2 ) H) require 6-8 h at room temperature for comple-
tion.10 Similar reactions of 19a -f were very sluggish, and
it was necessary to use 5 equiv of amine and refluxing
dichloromethane to achieve complete reaction in compa-
rable times. We attribute this to a steric effect that
produces greater strain in the transition state for ring
closure to the R-lactam intermediate. Steric retardation
of ring closure to an R-lactam was previously observed
in the reactions of 2-substituted phenylacetohydroxam-
ates.15
B. Rea ction s. With a source of malonyl hydroxamic
acids 1 in hand, their chemistry could be investigated.
Hydroxamic acids 1a -e and 18 were converted to the
N-mesyloxy derivatives 19a -e and 20, respectively, by
Steric retardation is further exacerbated in substrate
20, which reacts with allylamine to give 23 (eq 2) nearly
(14) We have just recently learned that 0.5% methanesulfonic acid
in absolute ethanol gives even higher yields of desilylation (80-85%).
J . Org. Chem, Vol. 68, No. 12, 2003 4879

Hoffman and Madan
three times more slowly than N-methyl analogue 19b (cf.
entries 4 and 19, Table 3). Despite the reduced reactivity,
however, the reactions of 19a -f and 20 with amine
nucleophiles are quite clean and give generally high
yields. Moreover, the sequence 14 to 21 provides a way
to prepare complex ureas rapidly and easily.
yield (eq 3). The same reaction in benzene at 55 °C gave
a 34% yield.
The substituent on the external urea nitrogen exerts
a remarkable effect on the reaction. If there is no external
nitrogen substituent present as in 21bh , no RCM is
observed. A methyl substituent gives 34%. However,
when N-cyclohexyl analogue 21bj was treated with
Grubbs catalyst in benzene at 55 °C, cyclic urea 29 was
obtained in 86% yield (eq 4).
The use of sodium hydride as a consumable base
permitted a single equivalent of the amine to serve as
the capturing nucleophile.2 Under these conditions, how-
ever, the initial urea product underwent base-pro-
moted cyclization to a hydantoin (Scheme 8). Hydantoins
24-27 were prepared in good yields. Ultrasonic irradia-
tion gave comparable yields but a shorter reaction time.
It was reported earlier that unsubstituted 19 (R2 ) H)
reacts with primary amines in the presence of 1 equiv of
sodium hydride to give unsymmetric ureas.2 Addition of
a second equivalent of sodium hydride resulted in cy-
clization to the hydantoin. In the present case, slightly
more than 1 equiv of sodium hydride results in both
R-lactam formation and cyclization of the urea. This
suggests that ureas derived from 2-substituted malonyl-
hydroxamates 19 are more prone to cyclization than
unsubstituted analogues. Therefore, open chain ureas
must be prepared using primary amines in excess, not
using sodium hydride as a consumable base.
A butenyl substituent at C-2 provides an opportunity
to prepare nine-membered ring products. However N-
methyl urea 21ei gave no cyclic products but instead
yielded dimers from intermolecular metathesis. In con-
trast, N-cyclohexyl analogue 21ej gave the nine-mem-
bered RCM product 30 in 61% yield (eq 5).
The use of unsaturated substituents at C-2 of malo-
nylhydroxamates 19 and an allylamine as the trapping
nucleophile provides a potential route to medium-ring
ureas. When urea 21bi was added to a solution of Grubbs
catalyst in refluxing dichloromethane and stirred for 24
h, eight-membered cyclic urea 28 was obtained in 41%
These results suggest that bulkier substituents on the
external nitrogen provide a conformational bias around
the urea linkage, which causes the olefinic bonds to be
in closer proximity to each other, thus providing an
entropic advantage for cyclization.16 Without such con-
formational control, the formation of medium (8-11-
membered) rings by RCM is not usually successful. By
imposing conformational bias either by structural con-
straints16 or by hydrogen bonding17 it is possible to
successfully construct medium rings by RCM. Moreover,
it appears that an amide group, probably due to restricted
rotation, is a common feature of successful medium-ring
RCM processes.16,18 In the present study, the urea group
is sufficiently rigid that conformational preferences
dictated by substituents on the external nitrogen signifi-
cantly influence the proximity of the olefin groups.
These are the first examples of cyclic ureas to be
produced by RCM and the first examples of medium-ring
cyclic ureas. Moreover, many structural variations can
SCHEME 8
(15) Hoffman, R. V.; Nayyar, N. K.; Chen, W. J . Am. Chem Soc.
1993, 115, 5031.
(16) Miller, S. J .; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J . Am.
Chem. Soc. 1995, 117, 2108.
(17) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606.
(18) Chacun-Lefe`vre, L.; Be´ne´teau, V.; J oseph, B.; Me´rour, J .-Y.
Tetrahedron 2002, 58, 10181.
4880 J . Org. Chem., Vol. 68, No. 12, 2003

2-Substituted Ethyl N-Alkylmalonylhydroxamic Acids
3H), 1.62-1.66 (m, 7H), 2.75-2.77 (m, 1H), 2.92-2.94 (m, 1H),
3.47-3.51 (m, 1H), 6.61 (br s, 1H), 7.17-7.26 (m, 5H); 13C NMR
δ 18.4, 25.1, 25.7, 29.9, 30.6, 37.7, 40.7, 58.2, 126.6, 128.7,
be incorporated into the basic synthetic scheme so that
ring size and substitution pattern can be modified easily.
This approach should provide a rich source of cyclic ureas.
In summary, the addition of substituents to the 2-posi-
tion of malonyl hydroxamates does not materially change
the chemistry of the R-lactams produced from them. Such
additions do, however, reduce the rate of 1,3-elimination
that produces the R-lactam. The addition of unsaturated
substituents at C-2 offers the opportunity to further
manipulate the unsymmetric urea products via RCM
reactions to produce cyclic ureas containing medium
rings.
129.0, 139.6, 168.6; IR 3169, 1603 cm-1
.
N-(ter t-Bu t yl)-N-h yd r oxy-2-p r en yl-3-p h en ylp r op ion -
a m id e (4ca ) was prepared from 3c and 7a in 26% yield as an
oil after flash chromatography (ethyl acetate/hexane, 1:5): 1H
NMR (CDCl3) δ 1.29 (s, 9H), 1.66 (d, 6H, J ) 16.0 Hz), 2.27-
2.29 (m, 2H), 2.80-2.82 (m, 2H), 3.26-3.28 (m, 1H), 5.15 (t,
1H), 7.19-7.27 (m, 5H); 13C NMR δ 18.0, 25.5, 25.9, 28.2, 29.0,
35.2, 41.4, 117.8, 126.3, 129.1, 129.7, 133.8, 140.2, 175.0; IR
3411, 1670, 1605 cm-1
.
N-(Meth yl)-N-h yd r oxy-2-p r en yl-3-(p-m eth oxyp h en yl)-
p r op ion a m id e (4fa ) was prepared from 3f and 7a in 42%
yield as an oil after flash chromatography (ethyl acetate/
hexane, 1:4): 1H NMR δ 1.65 (d, 6H, J ) 16.0 Hz), 2.30-2.34
(m, 2H), 2.77-2.79 (m, 3H), 2.93 (s, 3H), 3.77 (s, 3H), 5.07 (t,
1H), 6.80 (d, 2H), 7.04 (d, 2H), 8.66 (br s, 1H); 13C NMR δ 17.9,
25.9, 31.4, 35.4, 37.9, 44.2, 55.3, 114.0, 120.8, 129.9, 131.5,
Exp er im en ta l Section
Hydroxamic acids were prepared by reported procedures.19
N-Mesyloxyamides were prepared as reported earlier.10 N-
Methyl-O-TBDPS hydroxylamine and N-isopropyl-O-TBDPS
hydroxylamine were prepared from their corresponding hy-
drochloride salts.12
134.6, 158.3, 169.0; IR 3186, 1612 cm-1
.
N-(Meth yl)-N-h yd r oxy-2-ben zylh exa n a m id e (4ec) was
prepared from 3e and 7c in 38% yield as an oil after flash
chromatography (ethyl acetate/hexane, 1:3): 1H NMR δ 0.88
(t, 3H), 1.23-1.27 (m, 4H), 1.72-1.74 (m, 1H), 2.74 (d, 1H),
2.88 (s, 3H), 3.15 (d, 1H), 7.14-7.27 (m, 5H), 8.68 (br s, 1H);
13C NMR δ 14.1, 20.7, 35.2, 39.3, 43.6, 126.3, 128.5, 128.9,
Syn th esis of N-Alk yl-N-h yd r oxy-2-a lk ylca r boxa m id es
4: Gen er a l P r oced u r e. To a 0 °C solution of LDA prepared
from diisopropylamine (0.26 mL, 1.87 mmol) and n-BuLi (0.75
mL, 2.5 M solution in hexanes, 1.87 mmol) in dry THF (2.5
mL) was added dropwise a solution of hydroxamic acid 3 (0.85
mmol) in dry THF (2.5 mL), and the mixture was stirred for
1 h at 0 °C. An alkyl halide 7 (0.85 mmol) was added very
slowly, and the reaction mixture was stirred for another 1 h.
The reaction mixture was diluted with water, acidified (pH )
6) with 1 N HCl, and extracted with methylene chloride (3 ×
20 mL). The combined organic extracts were washed with brine
(10 mL) and then dried (MgSO4). After rotary evaporation, the
crude product was purified by flash chromatography.
N -M e t h y l-N -h y d r o x y -2-p r e n y l-3-p h e n y lp r o p i o n -
a m id e (4a a ) was prepared from 3a and 7a in 55% yield as a
colorless oil after flash chromatography (ethyl acetate/hexane,
1:3): 1H NMR δ 1.65 (d, 6H, J ) 16.0 Hz), 2.30-2.38 (m, 2H),
2.91 (s, 3H), 5.08 (t, 1H), 7.16-7.32 (m, 5H); 13C NMR δ 17.6,
25.5, 31.1, 35.2, 38.4, 43.7, 120.5, 126.2, 128.2, 128.7, 134.2,
139.2, 168.7; IR 3171, 1608 cm-1. Anal. Calcd for C15H21NO2:
C, 72.89; H, 8.49; N, 5.66. Found: C, 72.73; H, 8.39; N, 5.45.
When the same reaction was carried out at -20 °C, 3a a was
obtained in 52% yield.
139.5, 169.3; IR 3186, 1615 cm-1
.
P r ep a r a tion of N-Alk yl-r,â-u n sa tu r a ted Ca r boxa m -
id es 6: Gen er a l P r oced u r e. To a 0 °C solution of LDA (2.5
mmol) in dry THF (2.5 mL) was added dropwise a solution of
hydroxamic acid 3 (0.83 mmol) in dry THF (2.5 mL). The
reaction was allowed to warm to room temperature and stirred
for 4 h. It was diluted with water, acidified (pH ) 6) with 1 N
HCl, and extracted with methylene chloride (3 × 20 mL). The
combined organic extracts were washed with brine (10 mL)
and then dried (MgSO4). After rotary evaporation, the crude
product was purified by flash chromatography.
N-Meth yl-3-p h en yl-2-p r op en a m id e (6a ) was prepared
from 3a in 40% yield as a light yellow solid after flash
chromatography (ethyl acetate/hexane, 1:1): mp 84-88 °C; 1H
NMR δ 2.94 (d, 3H, J ) 6.0 Hz), 6.31 (br s, 1H), 6.47 (d, 1H,
J ) 16.0 Hz), 7.31-7.50 (m, 5H), 7.62 (d, 1H, J ) 16.0 Hz);
13C NMR δ 26.7 and 31.4 (rotamers), 120.7, 126.5, 128.0, 128.6,
128.76, 129.0, 129.9, 135.1, 141.2, 167.0; IR 3284, 1657 cm-1
.
N-Cycloh exyl-3-p h en yl-2-p r op en a m id e (6b) was pre-
pared from 3b in 42% yield as a white solid after flash
chromatography (ethyl acetate/hexane, 1:3): mp 152-156°C;
1H NMR δ 1.17-1.21 (m, 3H), 1.36-1.38 (m, 2H), 1.65-1.69
(m, 3H), 1.97 (d, 2H), 3.90-3.92 (m, 1H), 5.45 (br s, 1H), 6.34
(d, 1H, J ) 16.0 Hz), 7.32-7.51 (m, 5H), 7.59 (d, 1H, J ) 16.0
Hz); 13C NMR δ 25.0, 25.7, 33.3, 48.6, 121.4, 127.9, 128.9,
129.6, 135.1, 140.7, 165.2; IR 3272, 1656 cm-1. This compound
has been reported in the literature, but no data was given.20
N -Me t h y l-N -h y d r o x y -2-m e t h y l-3-p h e n y lp r o p io n -
a m id e (4a b) was prepared from 3a and 7b in 47% yield as
an oil after flash chromatography (ethyl acetate/hexane, 4:6):
1H NMR δ 1.12 (d, 3H), 2.68-2.78 (m, 2H), 2.99 (s, 3H), 3.40-
3.46 (m, 1H), 7.12-7.22 (m, 5H), 8.22 (br s, 1H); 13C NMR δ
17.5, 35.81, 37.5, 40.3, 126.6, 128.6, 129.1, 139.6, 170.1; IR
3174, 1608 cm-1
.
N -M e t h y l-N -h y d r o x y -2-b e n z y l-3-p h e n y lp r o p i o n -
a m id e (4a c) was prepared from 3a and 7c in 40% yield as a
light yellow solid after flash chromatography (ethyl acetate/
hexane, 1:3): mp 79-81 °C; 1H NMR δ 2.56 (s, 3H), 2.82-
3.05 (m, 5H), 7.13-7.30 (m, 10H); 13C NMR δ 35.0, 37.8, 39.1,
46.2, 126.3, 126.7, 128.6, 128.9, 139.1, 140.0, 168.1; IR 3172,
N-(ter t-Bu tyl)-3-p h en yl-2-p r op en a m id e (6c) was pre-
pared from 3c in 42% yield (after stirring overnight) as a white
solid after flash chromatography (ethyl acetate/hexane, 1:4):
1
mp 130-134 °C; H NMR δ 1.43 (s, 9H), 5.61 (br s, 1H), 6.35
1613 cm-1
.
(d, 1H, J ) 16.0 Hz), 7.32-7.46 (m, 5H), 7.57 (d, 1H, J ) 16.0
Hz); 13C NMR δ 26.7 & 31.4 (for rotamers), 120.7, 126.5, 128.0,
128.6, 128.7, 129.0, 129.9, 135.1, 141.2, 167.0; IR 3294, 1657
cm-1. This compound has been reported in the literature, but
no data were given.19
N-Met h yl-N-h yd r oxy-2-et h yl-3-p h en ylp r op ion a m id e
(4a d ) was prepared from 3a and 7d in 39% yield as a colorless
oil after flash chromatography (ethyl acetate/hexane, 1:3): 1H
NMR δ 0.89 (t, 3H), 1.61-1.67 (m, 2H), 2.63-2.67 (m, 2H),
2.91 (s, 3H), 3.18-3.20 (m, 1H), 7.11-7.29 (m, 5H), 8.45 (br s,
1H); 13C NMR δ 12.0, 26.0, 35.4, 39.2, 45.5, 126.7, 128.6, 128.9,
N-Meth yl-3-(p-m eth oxyph en yl)-2-pr open am ide (6f) was
prepared from 3f in 15% yield (after stirring the reaction for
2 days) as a white solid after flash chromatography (ethyl
acetate/hexane, 1:1): mp 118-120 °C; 1H NMR δ 2.92 (d, 3H),
3.77 (s, 3H), 5.81 (br s, 1H), 6.31 (d, 1H, J ) 16.0 Hz), 6.87 (d,
3H, J ) 8.0 Hz), 7.43 (d, 2H, J ) 8.0 Hz), 7.57 (d, 1H, J )
139.4, 169.1; IR 3196, 1618 cm-1
.
N-Cycloh exyl-N-h yd r oxy-2-m et h yl-3-p h en ylp r op ion -
a m id e (4bb) was prepared from 3b and 7b in 45% yield as a
white solid after flash chromatography (ethyl acetate/hexane,
1
1:5): mp 115-117 °C; H NMR δ 1.10-1.16 (m, 4H), 1.24 (d,
(20) Sugihara, T.; Okada, Y.; Yamaguchi, M.; Nishigawa, M. Synlett
1999, 768.
(19) Hoffman, R. V.; Nayyar, N. K. J . Org. Chem. 1994, 59, 3530.
J . Org. Chem, Vol. 68, No. 12, 2003 4881

Hoffman and Madan
16.0 Hz); 13C NMR δ 26.6, 55.3, 14.2, 118.5, 127.6, 129.5, 140.0,
160.8, 167.5; IR 3280, 1658 cm-1
Reaction of 3d and 3e under the same conditions led to the
3H), 3.62 (t, 1H), 4.12 (q, 2H), 4.90-4.93 (m, 2H), 5.61-5.65
(m 1H), 7.38-7.46 (m, 6H), 7.65-7.75 (m, 4H); IR 1737, 1677
.
cm-1
.
N-(OTBDP S)-N-Meth yl-2-ca r beth oxy-2-(2-eth yl-1,3-d i-
oxa n e)a ceta m id e (15f) was prepared from 14, 2-(2-bromo-
ethyl)-1,3-dioxane, and NaI (4.4 mmol) after refluxing over-
night in 81% yield as a colorless oil after flash chromatography
(EtOAc/hexane, 1:4): 1H NMR δ 1.14 (s, 9H), 1.24 (t, 3H),
1.66-1.68 (m, 2H), 1.80-1.83 (m, 4H), 3.08 (s, 3H), 3.69 (t,
3H), 4.10-4.12 (m, 4H), 4.42 (t, 1H), 7.38-7.47 (m, 6H), 7.66-
quantitative recovery of starting material.
P r ep a r a tion of N-(Silyloxy)-N-a lk yl-2-ca r beth oxy
Aceta m id es, 14 a n d 17: Gen er a l P r oced u r e. To a well-
stirred solution of O-(tert-butyldiphenylsilyl)-N-alkylhydroxy-
lamine (5.2 mmol) and triethylamine (5.72 mmol) in dry
methylene chloride (100 mL) at 0 °C was added dropwise a
solution of ethylmalonyl chloride (5.72 mmol) in dry methylene
chloride (30 mL). The reaction mixture was warmed to room
temperature and allowed to stir for 2 h. It was diluted with
water (100 mL), and the organic layer was washed with 1 N
HCl (2 × 20 mL) and brine, dried (MgSO4), and concentrated
under reduced pressure. The crude product was then purified
by flash chromatography.
7.74 (m, 4H); IR 1737, 1676 cm-1
.
N-(OTBDP S)-N-Isop r op yl-2-ca r beth oxy-2-p r en yla cet-
a m id e was prepared from 17 and prenyl bromide in 98% yield
as a colorless oil: 1H NMR δ 1.08-1.25 (m, 18H), 1.50-1.62
(d, 6H), 1.59 (d, 6H, J ) 12.0 Hz), 2.43 (t, 2H), 3.20-3.24 (m,
1H), 3.74 (t, 1H), 4.11 (q, 2H), 4.82-4.85 (m, 1H), 7.39-7.41
(m, 6H), 7.68-7.73 (m, 4H); IR 1743, 1667 cm-1
.
N-(OTBDP S)-N-Meth yl-2-car beth oxyacetam ide (14) was
prepared in 76% yield as a colorless oil after flash chroma-
tography (EtOAc/hexane, 1:10): 1H NMR δ 1.14 (s, 9H), 1.26
(t, 3H), 3.12 (s, 3H), 3.31 (s, 2H), 4.16 (q, 2H), 7.41-7.71 (m,
P r ep a r a t ion of N-H yd r oxy-N-a lk yl-2-ca r b et h oxy-2-
a lk yl Aceta m id es, 1: Gen er a l P r oced u r e. To the N-(sily-
loxy)-N-alkyl-2-carbethoxy-2-alkyl acetamide 15 or 18 (2 mmol)
was added a solution of methanesulfonic acid (1% solution in
ethanol, 100 mL), and the reaction mixture was stirred at room
temperature for 1 h. The solvent was reduced to one half of
its volume under reduced pressure and the reaction mixture
extracted with methylene chloride (4 × 100 mL). The organic
extracts were washed with water (2 × 50 mL) and brine and
dried (MgSO4). Removal of solvent under reduced pressure
gave the crude product that was purified by flash chromatog-
raphy (EtOAc/hexane, 4:6).
N -H y d r o x y -N -m e t h y l-2-c a r b e t h o x y -2-p r e n y la c e t -
a m id e (1a ) was prepared in 65% yield after flash chromatog-
raphy (ethyl acetate/hexane, 4:6) as a colorless oil: 1H NMR
δ 1.26 (t, 3H), 1.66 (d, 6H, J ) 8.0 Hz), 2.60 (t, 2H), 3.28 (s,
3H), 3.87 (t, 1H), 4.18 (q, 2H), 5.09 (t, 1H), 7.93 (br s, 1H); IR
3199, 1738, 1626 cm-1; m/z 229 (M+), 230 (M + 1)+.
10H); IR 1746, 1677 cm-1
.
N-(OTBDP S)-N-Isop r op yl-2-ca r beth oxya ceta m id e (17)
was prepared in 42% yield as an oil after flash chromatography
(EtOAc/hexane, 1:15): 1H NMR δ 1.11 (s, 9H), 1.20-1.22 (m,
9H), 3.27 (s, 2H), 3.81-3.83 (m, 1H), 4.13 (q, 2H), 7.38-7.73
(m, 10H); IR 1742, 1672 cm-1
.
P r ep a r a tion of N-(Silyloxy)-N-a lk yl-2-ca r beth oxy-2-
a lk yl Aceta m id es 15: Gen er a l P r oced u r e. To a solution
of 14 (or 17) (4.0 mmol) in dry THF (100 mL) was added NaH
(4.0 mmol, 60% dispersion in mineral oil) at room temperature.
After the reaction was stirred for 15 min, the alkylating agent
(4.4 mmol) was added over a period of 5 min. Progress of the
reaction was monitored by TLC. The reaction mixture was
evaporated under reduced pressure, and the residue was
triturated with methylene chloride (3 × 100 mL). The organic
extracts were washed with water (2 × 50 mL) and brine (2 ×
50 mL) and dried over anhydrous MgSO4. The solvent was
removed by rotary evaporation to give the crude product in
almost quantitative yield that was sufficiently pure, in most
cases, for the next reaction.
N-H yd r oxy-N-m et h yl-2-ca r b et h oxy-2-a llyla cet a m id e
(1b) was prepared in 67% yield after flash chromatography
(ethyl acetate/hexane, 1:1) as an oil: 1H NMR δ 1.28 (t, 3H),
2.66 (t, 2H), 3.29 (s, 3H), 3.99 (t, 1H), 4.19 (q, 2H), 5.06-5.10
(m, 2H), 5.77-5.81 (m 1H), 7.94 (br s, 1H); IR 3195, 1739, 1678,
+
1627 cm-1; m/z 202 (M + 1) +, 203 (M + 2)
.
N -(OTBDP S)-N -Me t h yl-2-ca r b e t h oxy-2-p r e n yla ce t -
a m id e (15a ) was prepared from 14 and prenyl bromide. After
a reaction time of 5-6 h, 15a was obtained in 95% yield as a
colorless oil: 1H NMR δ 1.14 (s, 9H), 1.26 (t, 3H), 1.59 (d, 6H,
J ) 12.0 Hz), 2.42 (t, 2H), 3.08 (s, 3H), 4.11-4.15 (m, 3H),
4.79 (t, 1H), 7.39-7.46 (m, 6H), 7.66-7.74 (m, 4H); IR 1739,
N -H y d r o x y -N -m e t h y l-2-c a r b e t h o x y -2-b e n zy la c e t -
a m id e (1c) was prepared in 68% yield after flash chromatog-
raphy (ethyl acetate/hexane, 1:3) as an oil: 1H NMR δ 1.23 (t,
3H), 3.15 (d, 2H), 3.22 (s, 3H), 3.69 (t, 1H), 4.17 (q, 2H), 7.16-
7.25 (m, 5H); IR 3190, 1733, 1626 cm-1; m/z 253 (M + 2)+.
N -H y d r o x y -N -m e t h y l-2-c a r b e t h o x y -2-m e t h y la c e t -
a m id e (1d ) was prepared in 70% yield after flash chroma-
tography (ethyl acetate/hexane, 1:1) as an oil: 1H NMR δ 1.26
(t, 3H), 1.36 (d, 3H, J ) 8.0 Hz), 3.26 (s, 3H), 3.92 (q, 1H),
4.17 (q, 2H), 9.06 (br s, 1H); IR 3187, 1739, 1639 cm-1; m/z
175 (M+), 176 (M + 1)+.
N-H yd r oxy-N-m et h yl-2-ca r b et h oxy-2-(1-b u t -3-en yl)-
a ceta m id e (1e) was prepared in 78% yield after flash chro-
matography (ethyl acetate/hexane, 1:1) as an oil: 1H NMR δ
1.28 (t, 3H), 2.08-2.12 (m, 4H), 3.29 (s, 3H), 3.92-3.94 (m,
1H), 4.19 (q, 2H), 5.02-5.06 (m, 2H), 5.78-5.82 (m 1H); IR
3182, 1738, 1626 cm-1; m/z 215 (M+), 216 (M + 1)+.
N-H yd r oxy-N-m et h yl-2-ca r b et h oxy-2-(2-et h yl-1,3-d i-
oxa n e)a ceta m id e (1f) was prepared in 51% yield after flash
chromatography (Rf ) 0.2; ethyl acetate/hexane, 6:4) as an
oil: 1H NMR δ 1.23-1.29 (m, 8H), 1.60-1.64 (m, 3H), 2.01-
2.05 (m, 6H), 3.28 (s, 3H), 3.42 (s, 3H), 3.75-3.77 (m, 4H), 3.97
(t, 1H), 4.08-4.10 (m, 4H), 4.18 (q, 4H), 4.54-3.58 (m, 1H),
8.04 (s, 1H); IR 3202, 1738, 1627 cm-1; m/z 229 (M - 46). In
addition to 1f, a product of trans acetalization was isolated in
which the cyclic 1,3-propanedioxy acetal was exchanged to the
diethyl acetal. N-Hydroxy-N-methyl-2-carbethoxy-2-(3,3-di-
ethoxy-1-propyl)acetamide was isolated in 22% yield after flash
chromatography (Rf ) 0.3; ethyl acetate/hexane, 6:4) as an
oil: 1H NMR δ 1.21-1.27 (m, 13H), 1.64-1.68 (m, 3H), 1.93-
1.97 (m, 3H), 3.27 (s, 3H), 3.48-3.54 (m, 4H), 3.61-3.67 (m,
1682 cm-1
.
N -(O T B D P S )-N -Me t h y l-2-c a r b e t h o x y -2-a lly la c e t -
a m id e (15b) was prepared from 14 and allyl bromide. After
a reaction time of 6 h, 15b was obtained in 96% yield as an
oil: 1H NMR δ 1.15 (s, 9H), 1.24 (t, 3H), 2.43 (t, 2H), 3.11 (s,
3H), 3.75 (t, 1H), 4.13 (q, 2H), 4.93-4.97 (m, 2H), 5.47-5.49
(m 1H), 7.39-7.47 (m, 6H), 7.67-7.74 (m, 4H); IR 1739, 1678,
1644 cm-1
.
N -(OTBDP S)-N -Me t h yl-2-ca r b e t h oxy-2-b e n zyla ce t -
a m id e (15c) was prepared from 14 and benzyl bromide. After
a reaction time of 4 h, 15c was obtained in 97% yield as an
oil: 1H NMR δ 1.14 (s, 9H), 1.26 (t, 3H), 3.14 (s, 3H), 3.23 (d,
2H), 4.13-4.17 (m, 3H), 6.97-7.04 (m, 2H), 7.17-7.20 (m, 3H),
7.28-7.45 (m, 6H), 7.56-7.59 (m, 4H); IR 1738, 1676 cm-1
.
N -(OTBDP S)-N -Me t h yl-2-ca r b e t h oxy-2-m e t h yla ce t -
a m id e (15d ) was prepared from 1 and methyl iodide. After a
reaction time of 6 h, 15d was obtained in 96% yield as a
colorless oil: 1H NMR δ 1.12 (d, 3H, J ) 7.0 Hz), 1.15 (s, 9H),
1.24 (t, 3H), 3.13 (s, 3H), 3.70 (q, 1H), 4.15 (q, 2H), 7.40-7.47
(m, 6H), 7.67-7.73 (m, 4H); IR 1741, 1675 cm-1
.
N-(OTBDP S)-N-Meth yl-2-ca r beth oxy-2-(1-bu t-3-en yl)-
a ceta m id e (15e) was prepared from 14, 4-bromo-1-butene,
and NaI (4.4 mmol) after refluxing overnight in 75% yield as
an oil after flash chromatography (EtOAc/hexane, 1:10): 1H
NMR δ 1.15 (s, 9H), 1.25 (t, 3H), 1.77-1.79 (m, 4H), 3.11 (s,
4882 J . Org. Chem., Vol. 68, No. 12, 2003

2-Substituted Ethyl N-Alkylmalonylhydroxamic Acids
1
4H), 3.91 (t, 1H), 4.16 (q, 2H), 4.51 (t, 1H), 8.43 (s, 1H); IR
3204, 1739, 1627 cm-1; m/z 246 (M - 45).
64-66 °C; H NMR δ 1.26 (t, 3H), 1.35 (s, 9H), 1.65 (d, 6H, J
) 10.0 Hz), 2.50-2.52 (m, 2H), 2.77 (s, 3H), 4.17 (q, 2H), 4.43
(br s, 1H), 4.84 (dd, 1H), 5.05 (t, 1H); 13C NMR δ 14.2, 17.9,
25.8, 28.4, 29.4, 30.9, 50.8, 57.4, 60.9, 119.7, 134.2, 157.6, 172.4;
IR 3364, 1738, 1641 cm-1. Anal. Calcd for C15H28N2O3: C,
63.35; H, 9.92; N, 9.85. Found: C, 63.60; H, 9.75; N, 9.68.
Ur ea 21a e was prepared from 19a (110 mg, 0.35 mmol) and
morpholine 22e (0.15 mL, 1.75 mmol). After a reaction time
of 4 h, 21a e was obtained as a colorless oil in 81% yield after
flash chromatography (ethyl acetate/hexane, 1:4): 1H NMR δ
1.27 (t, 3H), 1.66 (d, 6H, J ) 7.0 Hz), 2.52-2.58 (m, 2H), 2.88
(s, 3H), 3.19-3.23 (m, 4H), 3.65-3.71 (m, 4H), 4.19 (q, 2H),
4.38 (dd, 1H), 5.03 (t, 1H); 13C NMR δ 14.2, 17.9, 25.7, 27.8,
33.6, 47.2, 59.5, 60.8, 66.5, 119.6, 134.2, 164.5, 171.9; IR 1739,
1651 cm-1. Anal. Calcd for C15H26N2O4: C, 60.38; H, 8.78; N,
9.39. Found: C, 60.11; H, 8.69; N, 9.35.
N-H yd r oxy-N-isop r op yl-2-ca r b et h oxy-2-p r en yla cet -
a m id e (18) was prepared in 72% yield after flash chromatog-
raphy (ethyl acetate/hexane, 1:3) as a colorless oil: 1H NMR
δ 1.21-1.25 (m, 9H), 1.66 (d, 6H, J ) 8.0 Hz), 2.60 (t, 2H),
3.81-3.85 (m, 1H), 4.18 (q, 2H), 4.68-3.70 (m, 1H), 5.06-5.10
(m, 1H), 6.85 (br s, 1H); IR 3201, 1740, 1667, 1620 cm-1; m/z
256 (M - 1)+.
P r ep a r a tion of N-(Mesyloxy)-N-a lk yl-2-ca r beth oxy-2-
a lk yl Aceta m id es, 19 a n d 20: Gen er a l P r oced u r e. To a
solution of N-hydroxy-N-alkyl-2-carbethoxy-2-alkylacetamide
1 or 18 (2 mmol) in CH2Cl2 (30 mL) at 0 °C was added
triethylamine (2 mmol). The mixture was stirred for 10 min,
and methanesulfonyl chloride (2.2 mmol) was added dropwise.
The reaction mixture was stirred at 0 °C for 1 h, allowed to
warm to room temperature, and stirred for another 2 h. The
reaction mixture was washed with water (2 × 20 mL), 1 N
HCl (2 × 10 mL), and brine (20 mL) and dried over anhydrous
MgSO4. After rotary evaporation, the crude product obtained
that was purified by flash chromatography (EtOAc/hexane).
Mesylates 19 and 20 should be stored in the refrigerator. Due
to slow decomposition, accurate elemental analyses could not
be obtained.
Ur ea 21bg was prepared from 19b (70 mg, 0.25 mmol) and
cyclohexylamine 22g (0.14 mL, 1.25 mmol). After a reaction
time of 2 h, 21bg was obtained in 79% yield as a white solid
after flash chromatography (ethyl acetate/hexane, 1:4): mp
1
68-70 °C; H NMR δ 1.10-1.17 (m, 3H), 1.26 (t, 3H), 1.37-
1.41 (m, 2H), 1.63-1.69 (m, 3H), 1.93-1.97 (m, 2H), 2.46-
2.50 (m, 1H), 2.6-2.70 (m, 1H), 2.79 (s, 3H), 3.64-3.68 (m,
1H), 4.16 (q, 2H), 4.35 (d, 1H), 5.05-5.09 (m, 3H), 5.73-5.77
(m, 1H); 13C NMR δ 14.3, 25.2, 25.8, 30.5, 34.1, 49.7, 57.1, 61.1,
117.6, 134.3, 157.8, 172.1; IR 3348, 1739, 1627 cm-1. Anal.
Calcd for C15H26N2O3: C, 63.80; H, 9.28; N, 9.92. Found: C,
63.76; H, 9.43; N, 9.70.
N-(Me syloxy)-N-m e t h yl-2-ca r b e t h oxy-2-p r e n yla ce t -
a m id e (19a ) was prepared from 1a in 88% yield after flash
chromatography (ethyl acetate/hexane, 1:5) as a colorless oil:
1H NMR δ 1.27 (t, 3H), 1.66 (d, 6H, J ) 8.0 Hz), 2.64 (t, 2H),
3.18 (s, 3H), 3.49 (s, 3H), 3.68 (t, 1H), 4.19 (q, 2H), 5.08 (t,
Ur ea 21bh was prepared from 19b (170 mg, 0.61 mmol)
and allylamine 22h (0.14 mL, 1.83 mmol). After the mixture
was refluxed overnight, 21bh was obtained as a colorless oil
in 76% yield after flash chromatography (ethyl acetate/hexane,
1:4): 1H NMR δ 1.26 (t, 3H), 2.46-2.50 (m, 1H), 2.70-2.72
(m, 1H), 2.83 (s, 3H), 3.88 (t, 2H), 4.19 (q, 2H), 4.61 (t, 1H),
5.13-5.15 (m, 5H), 5.83-5.87 (m, 2H); 13C NMR δ 14.1, 30.3,
33.7, 43.3, 57.1, 60.9, 115.3, 117.4, 134.0, 135.6, 158.2, 171.7;
1H); IR 1740, 1705 cm-1
.
N -(Me s y lo x y )-N -m e t h y l-2-c a r b e t h o x y -2-a lly la c e t -
a m id e (19b) was prepared from 1b in 95% yield after flash
chromatography (ethyl acetate/hexane, 1:4) as an oil: 1H NMR
δ 1.27 (t, 3H), 2.67-2.69 (m, 2H), 3.19 (s, 3H), 3.49 (s, 3H),
3.76 (t, 1H), 4.20 (q, 2H), 5.08-5.12 (m, 2H), 5.76-5.78 (m
1H); IR 1737, 1708 cm-1
.
IR 3348, 1738, 1635 cm-1
.
N-(Me syloxy)-N-m e t h yl-2-ca r b e t h oxy-2-b e n zyla ce t -
a m id e (19c) was prepared from 1c in 83% yield after flash
chromatography (ethyl acetate/hexane, 1:5) as an oil: 1H NMR
δ 1.23 (t, 3H), 2.95 (s, 3H), 3.26 (d, 2H), 3.38 (s, 3H), 3.96 (t,
Ur ea 21bi was prepared from 19b (200 mg, 0.7 mmol) and
N-methylallylamine 22i (0.33 mL, 3.5 mmol). After a reaction
time of 2 h, 21bi was obtained as an oil in 93% yield after
flash chromatography (ethyl acetate/hexane, 4:6): 1H NMR δ
1.27 (t, 3H), 2.50-2.54 (m, 1H), 2.73 (s, 3H), 2.74-2.78 (m,
1H), 2.88 (s, 3H), 3.71 (d, 2H), 4.19 (q, 2H), 4.44 (dd, 1H), 5.14-
5.20 (m, 4H), 5.80-5.83 (m, 2H); 13C NMR δ 13.9, 33.2, 33.7,
35.5, 53.1, 59.1, 60.6, 116.8, 117.1, 133.8, 134.2, 164.8, 171.72;
IR 1739, 1639 cm-1. Anal. Calcd for C13H22N2O3: C, 61.39; H,
8.72; N, 11.01. Found: C, 60.97; H, 8.65; N, 10.82.
Ur ea 21bj was prepared from 19b (200 mg, 0.7 mmol) and
N-allylcyclohexylamine 22j (0.52 mL, 3.5 mmol). After a
reaction time of 4 h, 21bj was obtained in 87% yield as an oil
after flash chromatography (ethyl acetate/hexane, 1:10): 1H
NMR δ 1.09-1.12 (m, 3H), 1.26 (t, 3H), 1.53-1.57 (m, 4H),
1.73-1.77 (m, 4H), 2.53-2.57 (m, 1H), 2.65-2.70 (m, 1H), 2.88
(s, 3H), 3.30 (t, 1H), 3.74-3.78 (m, 2H), 4.17 (q, 2H), 4.40-
4.43 (m, 1H), 5.03-5.07 (m, 4H), 5.78-5.82 (m, 2H); 13C NMR
δ 14.1, 25.6, 26.2, 26.2, 30.9, 30.9, 33.5, 33.7, 46.2, 58.7, 59.6,
60.7, 114.91, 117.1, 134.5, 136.6, 164.8, 171.8; IR 1740, 1651
1H), 4.18 (q, 2H), 7.19-7.28 (m, 5H); IR 1739, 1703 cm-1
.
N-(Mesyloxy)-N-m et h yl-2-ca r b et h oxy-2-m et h yla cet -
a m id e (19d ) was prepared from 1d in 86% yield after flash
chromatography (ethyl acetate/hexane, 1:3) as an oil: 1H NMR
δ 1.26 (t, 3H), 1.44 (d, 3H, J ) 8.0 Hz), 3.20 (s, 3H), 3.49 (s,
3H), 3.77 (q, 1H), 4.21 (q, 2H); IR 1738, 1708 cm-1
.
N-(Mesyloxy)-N-m eth yl-2-ca r beth oxy-2-(1-bu t-3-en yl)-
a ceta m id e (19e) was prepared from 1e in 93% yield after
flash chromatography (ethyl acetate/hexane, 1:4) as an oil: 1H
NMR δ 1.28 (t, 3H), 2.08-2.14 (m, 4H), 3.21 (s, 3H), 3.49 (s,
3H), 3.68 (t, 1H), 4.20 (q, 2H), 5.0-5.02 (m, 2H), 5.74-5.78
(m 1H); IR 1739, 1706 cm-1
.
N -(Me syloxy)-N -iso p r o p yl-2-c a r b e t h ox y-2-p r e n yl-
a ceta m id e (20) was prepared from 18 in 87% yield after flash
chromatography (ethyl acetate/hexane, 1:5) as a colorless oil:
1H NMR δ 1.30-1.32 (m, 9H), 1.66 (d, 6H, J ) 10.0 Hz), 2.62
(t, 2H), 3.29 (s, 3H), 3.58 (t, 1H), 4.18 (q, 2H), 4.48-4.52 (m,
cm-1
.
1H), 5.08 (t, 1H); IR 1739, 1693 cm-1
.
Ur ea 21cb was prepared from 19c (120 mg, 0.36 mmol) and
N-ethylisopropylamine 22b (0.22 mL, 1.8 mmol). After a
reaction time of 2 h, 21cb was obtained as a colorless oil in
92% yield after flash chromatography (ethyl acetate/hexane,
1:3): 1H NMR δ 0.92 (t, 6H), 1.05 (d, 3H), 1.25 (t, 3H), 3.02-
3.06 (m, 2H), 3.30-3.36 (m, 2H), 4.19 (q, 2H), 4.64 (dd, 1H),
7.17-7.31 (m, 5H); 13C NMR δ 14.3, 15.0, 20.4, 34.3, 35.3, 36.2,
49.9, 60.9, 61.2, 126.5, 128.4, 128.8, 138.1, 164.8, 172.1; IR
1739, 1636 cm-1. Anal. Calcd for C18H28N2O3: C, 67.47; H, 8.81;
N, 8.74. Found: C, 67.60; H, 8.64; N, 8.97.
Rea ction of N-Mesyloxy-2-a lk yl Ma lon a m id es w ith
Nu cleop h iles: Gen er a l P r oced u r e. A solution of N-mesyl-
oxy-2-alkyl malonamide 19 or 20 (1 equiv) and the correspond-
ing nucleophile (5 equiv) in methylene chloride (30 mL) was
refluxed. After completion of the reaction (TLC), the reaction
mixture was diluted with water and extracted with methylene
chloride (2 × 20 mL). The organic extracts were washed with
1 N HCl (2 × 10 mL) and brine and then dried (MgSO4). The
solvent was removed under vacuum, and the product was
purified by flash chromatography.
Ur ea 21a d was prepared from 19a (110 mg, 0.35 mmol)
and tert-butylamine 22d (0.18 mL, 1.75 mmol). After a reaction
time of 4 h, 21a d was obtained as a white solid in 86% yield
after flash chromatography (ethyl acetate/hexane, 1:5): mp
Ur ea 21cc was prepared from 19c (120 mg, 0.36 mmol) and
pyrrolidine 22c (0.15 mL, 1.8 mmol). After a reaction time of
2 h, 21cc was obtained as an oil in 91% yield after flash
chromatography (ethyl acetate/hexane, 1:3): 1H NMR δ 1.25
J . Org. Chem, Vol. 68, No. 12, 2003 4883

Hoffman and Madan
(t, 3H), 1.65-1.77 (m, 4H), 2.82 (s, 3H), 3.01-3.07 (m, 3H),
3.25-3.31 (m, 3H), 4.17 (q, 2H), 4.67 (dd, 1H), 7.18-7.26 (m,
5H); 13C NMR δ 14.2, 25.5, 34.4, 35.3, 48.1, 60.9, 126.5, 128.3,
128.9, 138.1, 162.9, 172.2; IR 1738, 1636 cm-1. Anal. Calcd
for C17H24N2O3: C, 67.08; H, 7.95; N, 9.20. Found: C, 66.86;
H, 7.63; N, 9.22.
1H), 7.15-7.29 (m, 5H); 1H NMR for the second diastereomer
δ 1.24 (d, 3H), 2.85 (s, 3H), 3.50 (d, 2H), 3.72 (q, 1H), 3.78 (s,
3H), 4.95 (t, 1H), 7.15-7.29 (m, 5H); 13C NMR δ 14.9, 27.5,
34.3, 53.0, 56.8, 27.1, 128.6, 129.2, 136.7, 155.1, 169.3, 173.7;
IR 1775, 1747, 1714 cm-1. Anal. Calcd for C15H18N2O4: C,
62.06; H, 6.25; N, 9.65. Found: C, 62.20; H, 6.28; N, 9.90.
Ur ea 21d a was prepared from 19d (160 mg, 0.6 mmol) and
benzylamine 22a (0.34 mL, 5 mmol). After a reaction time of
7 h, 21d a was obtained as an oil in 81% yield after flash
chromatography (ethyl acetate/hexane, 4:6): 1H NMR δ 1.26
(t, 3H), 1.41 (d, 3H), 2.83 (s, 3H), 4.18 (q, 2H), 4.46 (d, 2H),
4.83 (t, 1H), 5.13 (q, 1H), 7.25-7.32 (m, 5H); 13C NMR δ 14.2,
15.2, 30.1, 44.9, 53.1, 61.0, 127.2, 127.5, 128.5, 139.6, 158.2,
172.8; IR 3352, 1734, 1635 cm-1. Anal. Calcd for C14H20N2O3:
C, 63.62; H, 7.63; N, 10.59. Found: C, 62.89; H, 7.24; N, 11.06.
Ur ea 21d f was prepared from 19d (110 mg, 0.4 mmol) and
methyl phenylalanate 22f (230 mg, 1.2 mmol). After a reaction
time of 5 h, 21d f was obtained as an oil in 77% yield after
flash chromatography (ethyl acetate/hexane, 1:3): 1H NMR δ
1.26 (t, 3H), 1.41 (d, 3H), 2.76 (s, 3H), 3.14 (d, 2H), 3.72 (s,
3H), 4.16 (q, 2H), 4.80-4.83 (m, 1H), 4.97-5.03 (m, 2H), 7.08-
7.33 (m, 5H); 13C NMR δ 14.3, 15.2, 30.0, 38.3, 52.3, 53.0, 54.6,
61.2, 127.2, 128.6, 129.5, 136.3, 157.3, 172.7, 173.0; IR 3354,
1739, 1644 cm-1. Anal. Calcd for C17H24N2O5: C, 60.70; H, 7.09;
N, 8.33; Found C, 60.81; H, 6.95; N, 8.24.
Im id a zolid in ed ion e 25 was prepared from 19d (110 mg,
0.4 mmol), NaH (35 mg, 0.8 mmol), and L-leucine methyl ester
(45 mg, 0.4 mmol) in dry THF (30 mL). The reaction mixture
was irradiated with ultrasound for 6 h. After the completion
of reaction (TLC), 25 was obtained as a colorless oil in 84%
yield after flash chromatography (ethyl acetate/hexane, 1:3):
1H NMR δ 0.93 (d, 6H, J ) 6.6 Hz), 1.45 (d, 3H, J ) 6.6 Hz),
1.84-1.88 (m, 1H), 2.25-2.29 (m, 1H), 2.97 (s, 3H), 3.73 (s,
3H), 3.91 (q, 1H), 4.72 (dd, 1H); 13C NMR δ 15.3, 21.2, 23.3,
25.3, 27.6, 36.9, 51.5, 52.9, 57.1, 155.5, 170.3, 173.4; IR 1777,
1747, 1713 cm-1
.
Im id a zolid in ed ion e 26 was prepared from 19e (60 mg,
0.2 mmol), NaH (8 mg, 0.2 mmol), and l-methionine methyl
ester (50 mg, 0.3 mmol) in dry THF (20 mL) after stirring
overnight. After the completion of reaction (TLC), 26 was
obtained as a colorless oil in 75% yield after flash chromatog-
raphy (ethyl acetate/hexane, 1:4): 1H NMR δ 2.06-2.12 (m,
7H), 2.44-2.50 (m, 4H), 2.97 (s, 3H), 3.74 (s, 3H), 3.95-4.00
(m, 1H), 4.87 (t, 1H), 5.04-5.08 (m, 2H), 5.76-5.80 (m, 1H);
13C NMR δ 15.5, 27.5, 27.8, 28.0, 29.9, 31.0, 51.8, 52.9, 60.7,
Ur ea 21eh was prepared from 19e (140 mg, 0.47 mmol) and
allylamine 22h (0.11 mL, 1.41 mmol). After a reaction time of
24 h, 21eh was obtained in 74% yield as an oil after flash
chromatography (ethyl acetate/hexane, 1:3): 1H NMR δ 1.26
(t, 3H), 1.76-1.82 (m, 1H), 2.03-2.09 (m, 3H), 2.84 (s, 3H),
3.88 (t, 2H), 4.15 (q, 2H), 4.82 (t, 1H), 5.03-5.10(m, 5H), 5.83-
5.89 (m, 2H); 13C NMR δ 14.25, 28.58, 30.24, 30.39, 43.48,
57.03, 61.01, 115.51, 115.55, 135.66, 137.29, 158.36, 172.34;
116.2, 136.7, 155.8, 169.5, 172.5; IR 1773, 1744, 1718 cm-1
.
1,5-Dim e t h yl-3-(2,5-d ich lor oa n ilin o)-2,4-im id a zoli-
d in ed ion e 27 was prepared from 19d (85 mg, 0.33 mmol),
NaH (12 mg, 0.3 mmol), and 2,5-dichlorophenyl hydrazine (60
mg, 0.33 mmol). After a reaction time of 22 h at room
temperature, 27 was obtained as pale yellow oil in 62% yield
after flash chromatography (ethyl acetate/hexane, 1:3): 1H
NMR δ 1.53 (d, 3H, J ) 6.0 Hz), 3.01 (s, 3H), 4.06 (q, 1H),
IR 3352, 1738, 1634 cm-1
.
6.55-6.60 (m, 2H), 6.83-6.89 (m, 1H), 7.24-7.26 (m, 1H); 13
C
Ur ea 21ei was prepared from 19e (200 mg, 0.68 mmol) and
N-allylmethylamine 22i (0.32 mL, 3.4 mmol). After a reaction
time of 2 h, 21ei was obtained in 90% yield as an oil after
flash chromatography (ethyl acetate/hexane, 1:5): 1H NMR δ
1.27 (t, 3H), 2.0-2.02 (m, 4H), 2.76 (s, 3H), 2.88 (s, 3H), 3.73
(d, 2H), 4.17 (q, 2H), 4.28-4.32 (m, 1H), 5.14-5.20 (m, 4H),
5.80-5.86 (m, 2H); 13C NMR δ 13.9, 28.0, 30.3, 33.3, 35.6, 53.1,
58.8, 60.4, 115.3, 116.8, 133.7, 136.9, 164.9, 172.2; IR 1739,
NMR δ 15.2, 28.0, 56.2, 113.6, 118.2, 122.4, 130.7, 133.8, 142.7,
153.8, 171.2; IR 1789, 1733 cm-1
.
1,3-Dim eth yl-4-eth oxyca r bon yl-(6H)1,3-d ia zocin e (28).
To a refluxing solution of Grubb’s catalyst (PCy3)2Cl2Ru
benzylidene (41 mg, 0.05 mmol, 10 mol %) in dry CH2Cl2 (300
mL, 0.001 M) was added a solution of 21b i (130 mg, 0.5
mmol) in dry CH2Cl2 (10 mL). The reaction mixture was
refluxed for 24 h. The reaction mixture was then exposed to
air, and the solvent was removed under reduced pressure to
afford a black residue. Flash chromatography (EtOAc/hexane,
4:6) afforded 28 (48 mg, 41%) as an oil: 1H NMR δ 1.27 (t,
3H), 2.73 (s, 3H), 2.77-2.81 (m, 2H), 2.87 (s, 3H), 3.46-3.52
(m, 1H), 4.16-4.22 (m, 3H), 4.32-4.38 (m, 1H), 5.70-5.75 (m,
2H); 13C NMR δ 14.4, 28.4, 36.2, 37.3, 49.5, 61.3, 65.5, 128.1,
129.7, 163.2, 171.3; IR 1741, 1646 cm-1. Anal. Calcd for
1651 cm-1
.
Ur ea 21ej was prepared from 19e (200 mg, 0.68 mmol) and
N-allylcyclohexylamine 22j (0.5 mL, 3.4 mmol). After a reac-
tion time of 5 h, 21ej was obtained in 88% yield as an oil after
flash chromatography (ethyl acetate/hexane, 1:8): 1H NMR δ
1.08-1.12 (m, 3H), 1.26 (t, 3H), 1.52-1.58 (m, 4H), 1.80-1.84
(m, 4H), 2.05-2.07 (m, 3H), 2.88 (s, 3H), 3.35 (t, 1H), 3.70-
3.76 (m, 2H), 4.17 (q, 2H), 4.27-4.31 (m, 1H), 5.00-5.04 (m,
4H), 5.80-5.84 (m, 2H); 13C NMR δ 14.0, 25.4, 26.0, 28.2, 30.4,
30.6, 30.8, 33.4, 46.0, 58.5, 59.1, 60.4, 114.8, 115.3, 136.5, 137.0,
C
11H18N2O3: C, 58.39; H, 8.02; N, 12.38. Found: C, 58.93; H,
7.87; N, 12.47.
164.7, 172.3; IR 1739, 1646 cm-1
.
When the same reaction was carried out in dry benzene
(0.005 M) at 55 °C for 3 days using 10 mol % Grubb’s catalyst
and 21bi, cyclized product 28 was obtained in 34% yield after
flash chromatography.
Ur ea 23 was prepared from 20 (160 mg, 0.48 mmol) and
22h (0.18 mL, 2.4 mmol). After a reaction time of 6 h, 23 was
obtained as an oil in 82% yield after flash chromatography
(ethyl acetate/hexane, 1:3): 1H NMR δ 1.17 (dd, 6H), 1.25 (t,
3H), 1.66 (d, 6H, J ) 8.0 Hz), 2.50-2.53 (m, 1H), 2.84-2.90
(m, 1H), 3.79-3.83 (m, 3H), 4.16-4.22 (m, 3H), 5.11-5.15 (m,
3H), 5.47 (t, 1H), 5.86-5.92 (m, 1H); 13C NMR δ 14.2, 20.2,
21.3, 25.9, 29.7, 43.4, 47.6, 56.3, 61.4, 115.4, 120.4, 134.8, 136.9,
157.6, 173.4; IR 3359, 1738, 1627 cm-1. Anal. Calcd for
1-Cycloh exyl-3-m et h yl-4-et h oxyca r b on yl-(6H )1,3-d i-
a zocin e, 29. To a well-stirred solution of Grubb’s catalyst
(PCy3)2Cl2Ru benzylidene (25 mg, 0.03 mmol, 10 mol %) in dry
benzene (50 mL, 0.005 M) at 55 °C was added dropwise a
solution of 21bj (97 mg, 0.3 mmol) in dry benzene (10 mL).
The reaction mixture was stirred at 55 °C for 36 h. The
reaction mixture was then exposed to air, and the solvent was
removed under reduced pressure to afford a black residue.
Flash chromatography (EtOAc/hexane, 1:5) afforded 29 (74 mg,
86%) as an oil: 1H NMR δ 1.26 (t, 3H), 1.30-1.34 (m, 6H),
1.73-1.79 (m, 6H), 2.71 (s, 3H), 2.76-2.81 (m, 2H), 3.54-3.57
(m, 1H), 3.85 (t, 1H), 4.17-4.22 (m, 4H), 5.67-5.73 (m, 2H);
13C NMR δ 14.1, 25.5, 25.6, 26.0, 27.9, 29.3, 31.7, 37.0, 42.5,
C
16H28N2O3: C, 64.33; H, 9.72; N, 9.45. Found: C, 63.82; H,
9.87; N, 9.42.
Im id a zolid in ed ion e 24 was prepared from 19d (110 mg,
0.4 mmol), NaH (35 mg, 0.8 mmol), and L-Phe-Me ester HCl
salt (94 mg, 0.4 mmol) in dry THF (30 mL). The reaction
mixture was irradiated with ultrasound for 2 h. After the
completion of reaction (TLC), 24 was obtained as a colorless
oil in 68% yield after flash chromatography (ethyl acetate/
hexane, 1:3): 1H NMR for one diastereomer δ 1.11 (d, 3H),
2.83 (s, 3H), 3.48 (d, 2H), 3.72 (q, 1H), 3.78 (s, 3H), 4.94 (t,
56.4, 60.9, 65.4, 128.9, 130.0, 162.6, 171.1; IR 1746, 1635 cm-1
.
Anal. Calcd for C16H26N2O3: C, 65.28; H, 8.75; N, 9.51.
Found: C, 65.45; H, 8.75; N, 9.50.
4884 J . Org. Chem., Vol. 68, No. 12, 2003

2-Substituted Ethyl N-Alkylmalonylhydroxamic Acids
1-Cycloh exyl-3-m et h yl-4-et h oxyca r b on yl-(6H )1,3-d i-
a zon in e, 30. To a well-stirred solution of Grubb’s catalyst
(PCy3)2Cl2Ru benzylidene (25 mg, 0.03 mmol, 10 mol %) in dry
benzene (50 mL, 0.005M) at 55 °C was added dropwise a
solution of 21ej (100 mg, 0.3 mmol) in dry benzene (10 mL).
The reaction mixture was stirred at 55 °C for 40 h. The
reaction mixture was then exposed to air, and the solvent was
removed under reduced pressure to afford a black residue.
Flash chromatography (EtOAc/hexane, 1:5) afforded 30 (55 mg,
61%) as an oil: 1H NMR δ 1.10-1.17 (m, 1H), 1.25 (t, 3H),
1.40-1.44 (m, 3H), 1.75-1.83 (m, 3H), 1.96-2.03 (m, 2H),
2.05-2.10 (m, 1H), 2.49 (s, 3H), 2.55-2.60 (m, 1H), 3.35-3.39
(m, 2H), 3.90-3.94 (m, 1H), 4.14-4.20 (m, 2H), 4.48 (d, 1H),
5.75-5.80 (m, 2H); 13C NMR δ 14.3, 21.7, 25.3, 25.5, 26.0, 26.2,
29.2, 29.9, 32.5, 42.7, 57.1, 60.9, 61.5, 130.0, 131.8, 168.3, 171.8;
IR 1736, 1657 cm-1. Anal. Calcd for C17H28N2O3: C, 66.20; H,
9.36; N, 9.03. Found: C, 66.28; H, 9.36; N, 8.97.
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE 9900402).
Su p p or tin g In for m a tion Ava ila ble: 1H or 13C NMR
spectra are provided for 4a b, 4a c, 4a d , 4bb, 4ca , 4ec, 4fa ,
6a -c,f, 14, 17, 19a -e, 20, 21bh , 21bj, 21eh , 21ei, 21ej, and
25-27. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0300690
J . Org. Chem, Vol. 68, No. 12, 2003 4885