A direct and mild conversion of tertiary aryl amides to methyl esters using trimethyloxonium tetrafluoroborate: A very useful complement to directed metalation reactions

Article abstract of DOI:10.1016/S0040-4020(00)00969-8

The scope and generality of a direct process for the conversion of tertiary amides directly to methyl esters has been investigated. The process involves a two-step, one pot procedure in which a tertiary amide is first treated with trimethyloxonium tetrafluoroborate to generate an imidate intermediate which is then hydrolyzed, generally by the addition of saturated aqueous sodium bicarbonate solution. Although this process fails for aliphatic amides, very good yields are realized for a variety of amides derived from aromatic carboxylic acids. Steric hindrance at the N-alkyl group is well tolerated; thus N,N-dimethyl, -diethyl, and -diisopropyl amides can all be utilized successfully. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00969-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9875±9883
A Direct and Mild Conversion of Tertiary Aryl Amides to Methyl
Esters Using Trimethyloxonium Tetra¯uoroborate: A Very Useful
Complement to Directed Metalation Reactions
*
Gary E. Keck, Mark D. McLaws and Travis T. Wager
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA
Received 13 September 2000; accepted 13 October 2000
AbstractÐThe scope and generality of a direct process for the conversion of tertiary amides directly to methyl esters has been investigated.
The process involves a two-step, one pot procedure in which a tertiary amide is ®rst treated with trimethyloxonium tetra¯uoroborate to
generate an imidate intermediate which is then hydrolyzed, generally by the addition of saturated aqueous sodium bicarbonate solution.
Although this process fails for aliphatic amides, very good yields are realized for a variety of amides derived from aromatic carboxylic acids.
Steric hindrance at the N-alkyl group is well tolerated; thus N,N-dimethyl, -diethyl, and -diisopropyl amides can all be utilized successfully.
q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
philic additions. These include vigorous acid or base
hydrolysis,4 reduction to give an aldehyde,5 reduction to
give an amine,6 and reduction to give an alcohol.7 The
dif®culty of these transformations is a signi®cant limitation
in the use of directed metalation reactions. One recent
approach to this problem uses N-acyl hydrazides as
amide-like directing groups that are more easily converted
to the free acid or ester.8
Polyfunctional aromatic moieties are found in a variety of
important synthetic and naturally occurring products.
Because of their importance and widespread occurrence, a
number of methods have been developed to introduce
functionality onto an aromatic nucleus. Of these, directed
ortho lithiation reactions have proven to be one of the most
effective and generally useful methods for the regioselective
synthesis of 1,2-disubstituted aromatic compounds.1 The
success of these reactions is dependent upon the directing
ability of the substituent on the aromatic ring, and it has
been shown that tertiary amides serve well in this capacity.2
On the other hand, the very robust nature of these amides
can complicate further elaboration.
It was envisioned that the tertiary amide 3 could be reduced
to the aldehyde 5 and subsequently oxidized directly to the
methyl ester 6 using Corey±Gilman±Ganem conditions.9
However, it was found that reduction with Red-Al failed.
The use of LiH2Al(OEt)2 resulted in low yields of the
aldehyde accompanied by a product arising from reduction
of the aryl iodide. Attempts to oxidize the resulting
aldehyde as planned also failed with this substrate.
In studies toward the total synthesis of (1)-narciclasine,3 it
became necessary to perform two such directed ortho
lithiations as shown below to prepare the pentasubstituted
aromatic moiety found in this structure. It was found that
directed metalation reactions using the N,N-dimethyl amide
1 served admirably for the sequential introduction of oxygen
and iodide substituents; however, further progress required
the conversion of the tertiary amide 3 to the methyl ester 6
(Scheme 1).
In an effort to ®nd an alternative method for converting the
tertiary amide to the corresponding ester,10 we were led to
examine a procedure that involved treating amide 3 with
trimethyloxonium tetra¯uoroborate, followed by mild
basic hydrolysis to give the desired methyl ester 7 as
shown in Scheme 2. This proved to be a reliable and high
yielding transformation, which was easily amenable to
scale-up. Herein we report the results of a study in which
we explore the generality of this method.
Commonly used procedures for converting tertiary amides
to other functional groups usually involve harsh conditions
due to the very low reactivity of these amides in nucleo-
Previous Synthetic Work
Keywords: amides; esters; imidic acids and derivatives; ortho lithiation.
* Corresponding author. Fax: 11-801-581-7055;
e-mail: keck@chemistry.utah.edu
In 1967, Hanessian reported the successful N-deacetylation
of secondary amides in acetamido deoxy sugars using
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00969-8

9876
G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
Scheme 1. Synthetic studies directed towards (1)-narciclasine.
triethyloxonium tetra¯uoroborate.11 It was shown that treat-
ing N-acylated sugars with the alkyloxonium salt, followed
by hydrolysis resulted in the free amine and ethyl acetate.
Other reports of N-deacetylation using this approach soon
followed.12
hydrolysis of an imidate ester to the ethyl ester for charac-
terization purposes.16 More recently, enroute to a total
synthesis of (s)-zearalenone, Hegedus and coworkers were
able to effectively convert a tertiary aryl amide to the
corresponding methyl ester using this approach.17
The use of alkyloxonium tetra¯uoroborate salts has also
been investigated in the ring opening of lactams to give
amino esters.13 Thus, Smith and Menezes reported that treat-
ment of lactams with triethyloxonium tetra¯uoroborate and
subsequent hydrolysis in neutral water gave amino esters.13b
More recently, McClure and Kiessling showed that both
trimethyl- and triethyloxonium tetra¯uoroborate salts
worked well in the conversion of a variety of primary and
secondary amides to the corresponding methyl and ethyl
esters. However, tertiary amides were not examined as
substrates in either of these reports.14
Despite the existence of these three isolated examples, no
study has been reported wherein the general utility of
converting tertiary amides to esters using alkyloxonium
salts is explored. Indeed, in a recent report on the conversion
of amides to esters using an intermediate tri¯ate, the authors
seem to suggest that this reaction does not work.10c We
record herein the results of an extensive study of this
process, which we have found to provide a powerful
complement to directed metalation reactions of aromatic
amides.
Surprisingly, only a few isolated examples can be found
using tertiary amides, despite the potential utility of this
transformation as a very useful adjunct to directed metala-
tion reactions. In 1968, Borch reported a two step reduction
of both secondary and tertiary amides to give amines.15 By
treating an amide in dichloromethane with triethyloxonium
tetra¯uoroborate, the imidate ester was formed. After
removal of the solvent and subsequent reduction of the
residue with NaBH4 in ethanol, the amine was produced.
Interestingly, Borch observed that while imidate esters of
secondary amides could be isolated by washing the
dichloromethane solution with cold sodium carbonate solu-
tion, imidate esters of tertiary amides underwent hydrolysis
to give ethyl esters.
Results and Discussion
The results obtained with a variety of amides are sum-
marized in Table 1. Since we were primarily interested in
this reaction process in the context of directed metalations,
our initial efforts focused on amides derived from aromatic
carboxylic acids. The ease with which the imidate ester
formed from the corresponding N,N-dimethyl- and N,N-
diethylamides varied little from substrate to substrate.
With these aryl substrates, formation of the imidate ester
intermediate 9 was usually complete after six hours under
the conditions utilized. However additional trimethyl-
oxonium tetra¯uoroborate was required to completely
consume the amides derived from p-methoxybenzoic acid
or from 2,4,6-trichlorobenzoic acid (entries 9, 10, 16 and
17).
Later, while studying cycloaddition reactions of acetylenic
iminium compounds, Baum and Viehe reported the
Hydrolysis of the imidate esters gave mixed results.
Although hydrolysis with saturated NaHCO3 generally
afforded the methyl ester, we were disappointed by the
complete failure to produce methyl esters using the aromatic
amides shown in entries 14±19. It can be seen that all of
these cases correspond to aryl substrates with o-o0 substitu-
tion. The imidate esters formed from the amides in these
cases hydrolyzed to give mainly recovered starting material.
Scheme 2. Direct conversion of an aryl amide to the methyl ester.

G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
Table 1. Results for the direct conversion of tertiary amides to methyl esters
9877
a
Values represent isolated yields.
b Only starting material was recovered.
Na2HPO4 was used instead of NaHCO3.
c
d Imidate ester formed, but major product resulted from N-dealkylation. Recovered only small amounts of starting material.
e
pHˆ10 phosphate buffer was used instead of NaHCO3.
It seems likely that this apparent hydrolysis actually occurs
by nucleophilic O-dealkylation due to severe steric
hindrance for nucleophilic addition to the iminium carbon
of the intermediate imidate in these cases (Fig. 1). In an
attempt to retard reaction via this pathway, we investigated
the use of triethyloxonium tertra¯uoroborate in two cases,
using substrates 8q and 8x. In neither case was a prepara-
tively useful result obtained, although a small amount of
ethyl ester was detectable in the crude reaction product in
the case of 8q. The imidate esters formed from the amides
derived from bromopiperonylic acid, and p-methoxy-
benzoic acid (entries 8±10) also suffered incomplete
hydrolysis using NaHCO3. Complete hydrolysis of these
imidate esters could be accomplished using a pHˆ10 phos-
phate buffer or a saturated solution of Na2HPO4, however.
methyl esters using this method. This contradicts the earlier
observation that compound 3 was ef®ciently converted to
the methyl ester 7 despite the presence of substituents in
both ortho positions. To better understand this apparent
contradiction, the reaction was carried out using both the
free hydroxyl substrate 4 and the O-methyl protected
derivative 11 corresponding to substrate 3 as shown in
Scheme 3. While compound 4 with an unprotected hydroxyl
substituent worked well, the methoxy substituted compound
11 gave only starting material as well as unhydrolyzed
imidate ester after several days. Since the TBS protected
compound 3 actually affords the free phenol as product, it
seems clear that the sequence of events in this case is initial
It is interesting to note that compounds with substitution in
both positions ortho to the amide group failed to produce
Figure 1. Pathways for imidate hydrolysis.
Scheme 3. Result for ortho±ortho0 disubstituted aryl amides.

9878
G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
Summary and Conclusions
A mild conversion of a variety of tertiary amides to methyl
esters using trimethyloxonium tetra¯uoroborate has been
documented. While most aryl amides were effectively
converted to methyl esters using the conditions described,
imidate esters of aliphatic amides and aryl amides with
ortho±ortho0 substitution hydrolyzed to give back the
amide. The sole exception to this generalization was the
case of aryl amides with ortho±ortho0 substitution where
one of the groups was hydroxyl, or a group which cleaves
under the reaction conditions to a free hydroxyl, such as
TBS. Since aryl tri¯ates (derived from such phenols) can
be elaborated in a number of useful ways, this observation
has clear impact on synthetic planning en route to densely
functionalized aromatic compounds using a directed meta-
lation strategy. The steric nature of the N-alkyl groups has
no appreciable affect on the success of the conversion. Thus,
N,N-dimethyl, N,N-diethyl, and N,N-diisopropyl aryl
amides were all cleanly converted to methyl esters using
this mild procedure.
Scheme 4. Result for sterically demanding aryl amides.
cleavage of the TBS ether, followed by imidate hydrolysis.
It is not clear in these cases whether the free hydroxyl
actually serves to assist imidate hydrolysis or simply
presents a sterically less demanding substituent than those
in the protected substrates.
The apparent lack of sensitivity to the steric environment
present at the nitrogen center prompted an examination of
the use of N,N-diisopropyl aryl amides. As shown in
Scheme 4 the direct conversion of N,N-diisopropyl aryl
amides to methyl esters using these conditions worked
well despite the extreme steric demand of the N-alkyl
substituents.
Experimental
All amides used are readily available from well-established
chemical transformations.19 Solvents were puri®ed accord-
ing to the guidelines in Puri®cation of Common Laboratory
Chemicals (Perrin, Armarego, and Perrin, Pergamon:
Oxford, U.K., 1966). All other reagents were purchased
and used without further puri®cation. Yields were calcu-
lated for material judged homogenous by thin-layer chro-
matography and NMR. Thin-layer chromatography was
performed on Merck Kieselgel 60 F254 plates eluting with
the solvents indicated, visualizing by a 254 nm UV lamp,
and stained with an ethanolic solution of 12-molybdophos-
phoric acid or p-anisaldehyde. Flash column chromato-
graphy was performed with Davisil 62 silica gel, slurry
packed with 5% EtOAc/hexanes or CHCl3 in glass columns,
and ¯ushed with hexanes or CHCl3 respectively. Chromato-
graphy was also carried out using a Chromatotron, using
glass plates coated with silica gel (P.F. 254 60) of 2 and
4 mm thickness (RPLC). Nuclear magnetic resonance
Given the success realized with a variety of aryl amides,
attention was then turned to an examination of simple
aliphatic amide derivatives. The a-b unsaturated dimethyl-
and diethyl amides derived from cinammic acid could be
successfully converted to methyl esters in good yield using
this approach provided that the hydrolysis was carried out
using pHˆ10 phosphate buffer. Also, in this case, the start-
ing amides were never completely converted to the imidate,
even when additional Meerwein's reagent was used.
However, saturated aliphatic amides (entries 22±25)
could not be converted to methyl esters via this protocol.
With these substrates, hydrolysis of the intermediate
imidates occurred to give back the starting amide, rather
than the desired methyl ester. This happened both with a
non-enolizable substrate (adamantyl), as well as with the
diethyl amide derived from cyclohexane carboxylic acid,
and the dimethyl and diethyl amides derived from 2-meth-
yl-3-phenylpropionic acid. Although a variety of conditions
were examined for these hydrolyses in addition to those
described previously (including the use of pHˆ4, 7, or 10
buffer solutions) no success was realized in these cases. The
pH dependence of this reaction type has been extensively
examined particularly as it relates to the mechanisms of
amide hydrolysis and ester aminolysis; in general, these
mechanisms are quite complex.18
1
spectra were acquired at 300 MHz for H, and 75 MHz for
13C. Chemical shifts for carbon nuclear magnetic resonance
(13C NMR) spectra are reported in parts per million relative
to the center line of the CDCl3 triplet at 77.0 ppm. The
abbreviations s, d, t, apt t, q, br s, dd, tt, Abq, and m stand
for the resonance multiplicity singlet, doublet, triplet,
apparent triplet, quartet, broad singlet, doublet of doublets,
triplet of triplets, AB quartet, and multiplet, respectively.
Melting points were obtained on an Electro thermal melting
point apparatus and are uncorrected. Analytical C and H
combustion analyses were performed by Atlantic Microlab,
Inc., Norcross, GA. Glassware for all reactions was oven
dried at 1058C and cooled in a dessicator prior to use.
This result stands in sharp contrast to those obtained by
Charette with aliphatic amides and his tri¯ate procedure,
where good yields were obtained.10c An inspection of the
available data suggests that Charette's procedure is far
superior to the one investigated herein for aliphatic amides,
but that the Meerwein method may give better yields with
aromatic amides. Thus it appears that these two procedures
may be complementary with respect to the scope of
substrates that can be employed.
Representative procedure for the direct conversion of
tertiary aryl amides to esters
Preparation of methyl naphthalene-2-carboxylate (10a).
To a stirring solution of N,N-dimethyl-2-naphthylcarboxa-
mide (100 mg, 0.50 mmol) in 2.5 mL of CH3CN at rt, was

G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
9879
added Na2HPO4 (107 mg, 0.75 mmol), followed by
(CH3)3OBF4 (223 mg, 1.5 mmol). After consumption of
the amide was complete, as indicated by TLC analysis
(ca. 18 h), a saturated solution of NaHCO3 (10 mL) was
slowly added, followed by solid NaHCO3 (100 mg). The
resulting mixture was stirred for 18 h then extracted with
EtOAc (3£50 mL). The combined organic layers were dried
over MgSO4, ®ltered through a pad of Celite (4 mm), and
concentrated under reduced pressure. Puri®cation of this
material was accomplished by RPLC using a 2 mm plate,
eluting with 50% ethyl acetate/hexanes, collecting 8 mL
fractions. The product containing fractions (6±7) were
combined and concentrated to give 10a (86 mg, 92%
yield) as a colorless crystalline solid. Ester 10a was also
obtained in 86 and 90% yields from the corresponding
N,N-diethyl and N,N-diisopropyl amides, respectively: mp
79±818C (lit.20 mp 78±798C); Rf 0.56 (50% EtOAc/
the corresponding N,N-dimethyl and N,N-diethyl amides,
respectively: Rf 0.50 (25% EtOAc/hexanes); 300 MHz H
1
NMR (CDCl3) d 7.99 (d, Jˆ9.0 Hz, 2H), 6.92 (d, Jˆ9.0 Hz,
2H), 3.88 (s, 3H), 3.86 (s, 3H); 75 MHz 13C NMR (CDCl3) d
166.8, 163.3, 131.5, 122.5, 113.5, 55.4, 51.8; IR (CHC13)
1712, 1606 cm21
.
Analytical data for methyl 3,4,5-trimethoxybenzoate
(10f). Obtained as a colorless crystalline solid in 87 and
95% yield from the corresponding N,N-dimethyl and N,N-
diethyl amides, respectively: mp 79±818C (lit.26 mp 82±
1
838C); Rf 0.56 (50% EtOAc/hexanes); 300 MHz H NMR
(CDCl3) d 7.31 (s, 2H), 3.91 (s, 9H), 3.91 (s, 3H); 75 MHz
13C NMR (CDCl3) d 166.6, 152.9, 142.1, 125.1, 106.7, 60.8,
56.1, 52.2; IR (CHCl3) 1715, 1592 cm21
.
Analytical data for methyl 2-benzoylbenzoate (10g).27
Obtained as a light yellow oil in 84% yield from the
corresponding N,N-diisopropyl amide: Rf 0.45 (25%
1
hexanes); 300 MHz H NMR (CDCl3) d 8.61 (s, 1H), 8.06
(d, Jˆ8.4 Hz, 1H), 7.95 (d, Jˆ7.2 Hz, 1H), 7.89 (d,
Jˆ9.0 Hz, 2H), 7.54±7.60 (m, 2H), 3.98 (s, 3H); 75 MHz
13C NMR (CDCl3) d 167.2, 135.5, 132.4, 131.0, 129.3,
128.2, 128.1, 127.7, 127.3, 126.6, 125.2, 52.2; IR (CHCl3)
1
EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 8.04±8.07
(m, 1H), 7.77±7.40 (m, 8H), 3.61 (s, 3H); 75 MHz 13C NMR
(CDCl3) d 197.1, 166.4, 141.6, 137.1, 133.1, 132.4, 130.1,
129.6, 129.2, 129.1, 128.5, 127.7, 52.2; IR (CHCl3) 1723,
1715 cm21
.
1671 cm21
.
Methyl (2E)-3-phenylprop-2-enoate (10k).21 Obtained as
a colorless crystalline solid in 77 and 72% yields from the
corresponding N,N-dimethyl and N,N-diethyl amides,
respectively: mp 31±31.58C; Rf 0.65 (50% EtOAc/hexanes);
Analytical data for methyl 4-hydroxy-6-iodo-2H-benzo-
[3,4-d]1,3-dioxolene-5-carboxylate (7).3 Obtained as a
light yellow solid in 88% yield from the corresponding
N,N-dimethyl amide: mp 155±1578C; Rf 0.18 (50%
1
300 MHz H NMR (CDCl3) d 7.70 (d, Jˆ15.9 Hz, 1H),
1
7.53±7.51 (m, 2H), 7.39±7.37 (m, 3H), 6.44 (d, Jˆ16.2,
1H), 3.81 (s, 3H); 75 MHz 13C NMR (CDCl3) d 167.4,
144.8, 134.3, 130.2, 128.8, 128.0, 117.7, 51.6; IR (CHCl3)
EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 11.00 (s,
1H), 7.20 (s, 1H), 6.08 (s, 2H), 3.97 (s, 3H); 75 MHz 13C
NMR (CDCl3) d 168.7, 152.6, 146.7, 135.6, 115.4, 112.4,
1711 cm21
.
102.9, 84.6, 51.9; IR (KBr) 1666 cm21
.
Analytical data for methyl 2-methylbenzoate (10b).22
Obtained as a light yellow oil in 94 and 87% yield from
the corresponding N,N-dimethyl and N,N-diethyl amides,
respectively: Rf 0.59 (40% Et2O/pentane); 300 MHz 1H
NMR (CDCl3) d 7.91 (d, Jˆ8.4 Hz, 1H), 7.39 (t,
Jˆ7.2 Hz, 1H), 7.26±7.21 (m, 2H), 3.89 (s, 3H), 2.60 (s,
3H); 75 MHz 13C NMR (CDCl3) d 168.0, 140.1, 131.9,
Representative procedure for the syntheses of tertiary
amides from the corresponding acid chloride
Preparation of N,N-dimethyl(2,4,6-trichlorophenyl)car-
boxamide (8p). To a stirring suspension of dimethyl amine
hydrochloride salt (0.67 mg, 8.2 mmol) and pyridine
(1.5 mL, 19.0 mmol) in 15 mL of CH2Cl2 at 08C was
added 2,4,6-trichlorobenzoyl chloride (1.0 g, 4.1 mmol)
dropwise via syringe. The resulting solution was stirred
18 h at rt, then 15 mL of CH2Cl2 was added, and the solution
was washed, alternating between saturated solutions of
CuSO4 (2£25 mL) and brine (2£25 mL). The combined
organic layers were dried over MgSO4, and concentrated
under reduced pressure. Puri®cation of this material was
accomplished by gravity chromatography, eluting with
200 mL of each of 20, 40 and 60% EtOAc/hexanes, collect-
ing 8 mL fractions. The product containing fractions were
combined and concentrated under reduced pressure to give
8p (1.0 g, quantitative) as a colorless crystalline solid: mp
131.6, 130.5, 129.5, 125.6, 51.7, 21.7; IR (neat) 1724 cm21
.
Analytical data for methyl 2-chlorobenzoate (10c).23
Obtained as a light yellow oil in 95 and 98% yield from
the corresponding N,N-dimethyl and N,N-diethyl amides,
respectively: Rf 0.58 (40% Et2O/pentane); 300 MHz 1H
NMR (CDCl3) d 7.82 (d, Jˆ6.9 Hz, 1H), 7.45±7.31 (m,
3H), 3.94 (s, 3H); 75 MHz 13C NMR (CDCl3) d 166.1,
133.6, 132.5, 131.3, 131.0, 130.0, 126.5, 52.3; IR (CHCl3)
1730 cm21
.
Analytical data for methyl 6-bromo-2H-benzo[3,4-d]1,3-
dioxolene-5-carboxylate (10d). Obtained as a colorless
crystalline solid in 88% yield from the corresponding
N,N-diethyl amide: mp 81±828C (lit.24 mp 84±858C); Rf
1
658C; Rf 0.48 (50% EtOAc/hexanes); 300 MHz H NMR
(CDCl3) d 7.36 (s, 2H), 3.16 (s, 3H), 2.87 (s, 3H);
75 MHz 13C NMR (CDCl3) d 164.5, 135.2, 134.1, 132.2,
1
128.0, 37.2, 34.4; IR (KBr) 1640 cm21
.
0.67 (50% EtOAc/hexanes); 300 MHz H NMR (CDCl3)
d 7.32 (s, 1H), 7.09 (s, 1H), 6.05 (s, 2H), 3.89 (s, 3H);
75 MHz 13C NMR (CDC13) d 165.7, 150.9, 147.1, 124.4,
Analytical data for N,N-diethyl(2,4,6-trichlorophenyl)-
carboxamide (8q). Obtained as a light yellow oil: Rf 0.58
(50% EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 7.35
114.9, 114.3, 111.0, 102.5, 52.3; IR (CHCl3) 1727 cm21
.
1
Analytical data for methyl 4-methoxybenzoate (10e).25
Obtained as a light yellow oil in 78 and 85% yield from
(s, 2H), 3.61 (q, Jˆ7.2 Hz, 2H), 3.15 (q, Jˆ7.2 Hz, 2H),
1.28 (t, Jˆ7.2 Hz, 3H), 1.14 (t, Jˆ7.2 Hz, 3H); 75 MHz

9880
G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
13C NMR (CDCl3) d 163.7, 135.0, 134.4, 132.4, 128.1, 42.7,
39.0, 13.7, 12.3; IR (CHCl3) 1637 cm21
(lit.30 mp 87±888C); Rf 0.12 (50% EtOAc/hexanes);
1
.
300 MHz H NMR (CDCl3) d 7.92±7.84 (m, 4H), 7.54±
7.50 (m, 3H), 3.16 (br s, 3H), 3.03 (br s, 3H); 75 MHz 13C
NMR (CDCl3) d 171.6, 133.6, 133.5, 132.6, 128.3, 128.1,
127.7, 126.9, 126.8, 126.5, 124.4, 39.6, 35.4; IR (KBr)
1619 cm21. Anal. Calcd for C9H8Cl3NO: C, 42.81; H,
3.19; N, 5.55. Found C, 42.74; H, 3.18; N, 5.44.
Analytical data for (2,6-dimethoxyphenyl)-N,N-di-
methylcarboxamide (8r). Obtained as a colorless crystal-
line solid: mp 105±1078C (lit.28 mp 105±1078C); Rf 0.13
1
(50% EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 7.26
(apt t, Jˆ8.4 Hz, 1H), 6.56 (d, Jˆ8.4 Hz, 2H), 3.81 (s, 6H),
3.13 (s, 3H), 2.83 (s, 3H); 75 MHz 13C NMR (CDCl3, -208C)
d 167.1, 156.5, 130.1, 115.0, 103.9, 55.8, 37.6, 34.4, 22.1;
Analytical data for N,N-diethyl-2-naphthylcarboxamide
(8b). Obtained as a colorless crystalline solid: mp 35±378C;
Rf 0.33 (50% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3)
d 7.88±7.84 (m, 4H), 7.53±7.45 (m, 3H), 3.59 (br s, 2H),
3.30 (br s, 2H), 1.28 (br s, 3H), 1.13 (br s, 3H); 75 MHz
13C NMR (CDCl3) d 171.2, 134.6, 133.3, 132.7, 128.2,
128.1, 127.7, 126.7, 126.5, 125.7, 123.9, 43.3, 39.3, 14.2,
12.9; IR (KBr) 1617 cm21. Anal. Calcd for C15H17NO:
C, 79.26; H, 7.54; N, 6.16. Found C, 79.04; H, 7.50;
N, 6.06.
IR (KBr) 1636 cm21
.
Analytical data for (2,6-dimethoxyphenyl)-N,N-diethyl-
carboxamide (8s). Obtained as a colorless crystalline solid:
mp 70±718C; Rf 0.13 (50% EtOAc/hexanes); 300 MHz H
1
NMR (CDCl3) d 7.24 (apt t, Jˆ8.4 Hz, 1H), 6.55 (d,
Jˆ8.4 Hz, 2H), 3.79 (s, 6H), 3.59 (q, Jˆ7.2 Hz, 2H), 3.13
(q, Jˆ7.2 Hz, 2H), 1.24 (t, Jˆ7.2 Hz, 3H), 1.01 (t,
Jˆ7.2 Hz, 3H); 75 MHz 13C NMR (CDCl3) d 166.2,
156.5, 129.8, 115.6, 103.9, 55.7, 42.5, 38.6, 13.6, 12.8; IR
(KBr) 1632 cm21. Anal. Calcd for C13H19NO3: C, 65.80; H,
8.07; N, 5.90. Found C, 65.94; H, 8.06; N, 5.87.
Analytical data for (2E)-N,N-dimethyl-3-phenylprop-2-
enamide (8t). Obtained as a colorless crystalline solid: mp
93±958C (lit.31 mp 96±988C); Rf 0.12 (50% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3)
d 7.68 (d,
Analytical data for N,N-bis(methylethyl)[2-phenylcar-
bonyl)phenyl]carboxamide (8m).29 Obtained as a colorless
crystalline solid: mp 92±948C; Rf 0.25 (25% EtOAc/
Jˆ15.6 Hz, 1H), 7.55±7.52 (m, 2H), 7.38±7.36 (m, 3H),
6.90 (d, Jˆ15.6 Hz, 1H), 3.18 (s, 3H), 3.08 (s, 3H);
75 MHz 13C NMR (CDCl3) d 166.7, 142.3, 135.3, 129.5,
hexanes); 300 MHz 1H NMR (CDCl3)
d
7.81 (d,
128.8, 127.8, 117.4, 37.4, 35.9; IR (KBr) 1652 cm21
.
Jˆ7.5 Hz, 2H), 7.58±7.32 (m, 7H), 3.87±3.82 (m, 1H),
3.48±3.43 (m, 1H), 1.44 (d, Jˆ6.6 Hz, 6H), 1.20 (d,
Jˆ6.6 Hz, 6H); 75 MHz 13C NMR (CDCl3) d 196.7,
169.5, 139.8, 137.3, 136.7, 132.8, 130.7, 130.3, 129.9,
128.2, 127.5, 126.1, 51.3, 45.7, 20.4, 20.2; IR (KBr) 1661,
Analytical data for (2E)-N,N-diethyl-3-phenylprop-2-
enamide (8u). Obtained as a colorless crystalline solid:
mp 65±668C (lit.32 mp 678C); Rf 0.25 (50% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3)
d 7.71 (d,
1628 cm21
.
Jˆ15.4 Hz, 1H), 7.55±7.51 (m, 2H), 7.40±7.34 (m, 3H),
6.83 (d, Jˆ15.4 Hz, 1H), 3.49 (br d, 4H), 1.26±1.20 (m,
6H); 75 MHz 13C NMR (CDCl3) d 165.6, 142.2, 135.4,
129.4, 128.7, 127.7, 117.7, 42.2, 41.0, 15.0, 13.2; IR
Analytical data for adamantanyl-N,N-dimethylcarboxa-
mide (8y). Obtained as a colorless crystalline solid: mp 73±
748C; Rf 0.35 (50% EtOAc/hexanes); 300 MHz H NMR
1
(KBr) 1648 cm21
.
(CDCl3) d 3.07 (br s, 6H), 2.02 (br s, 9H), 1.72 (br s, 6H);
75 MHz 13C NMR (CDCl3) d 176.8, 41.8, 38.6, 38.4,
. Anal. Calcd for
C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found C, 75.37;
H, 10.13; N, 6.69.
Analytical data for N,N-dimethyl(2-methylphenyl)car-
boxamide (8d).33 Obtained as a light yellow oil: Rf 0.07
(40% Et2O/pentane); 300 MHz H NMR (CDCl3) d 7.29±
36.5, 28.4; IR (KBr) 1613 cm21
1
7.17 (m, 4H), 3.13 (s, 3H), 2.83 (s, 3H), 2.29 (s, 3H);
75 MHz 13C NMR (CDCl3) d 171.4, 136.6, 133.8, 130.2,
128.6, 125.8, 125.6, 38.2, 34.4; IR (neat) 1641 cm21
.
Representative procedure for the syntheses of tertiary
amides from the corresponding carboxylic acid
Analytical data for N,N-diethyl(2-methylphenyl)carbox-
amide (8e).2 Obtained as a light yellow oil: Rf 0.42 (50%
EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 7.28±7.14
Preparation of N,N-dimethyl-2-naphthylcarboxamide
(8a). To a stirring suspension of 2-naphthoic acid
(600 mg, 3.48 mmol) in 25 mL of CH2Cl2 was added the
minimum amount of DMF (5.00 mL) to dissolve the acid.
Oxalyl chloride (460 mL, 5.25 mmol) was added dropwise
at rt. The solution was heated at re¯ux for 2 h, then cooled to
rt and transferred to a suspension of dimethyl amine hydro-
chloride salt (570 mg, 7.00 mmol), and pyridine (1.13 mL,
14.0 mmol) in 10 mL of CH2Cl2. After 20 h of stirring, the
solution was washed with 2% HCl (3£25 mL), dried over
MgSO4, ®ltered through a pad of Celite (4 mm), and
concentrated under reduced pressure. Puri®cation of this
material was accomplished by RPLC using a 4 mm plate,
eluting with 40% Et2O/pentane, collecting 8 mL fractions.
The product containing fractions were combined and
concentrated under reduced pressure to give 8a (572 mg,
82% yield) as a colorless crystalline solid: mp 83±848C
1
(m, 4H), 3.74 (br s, 1H), 3.37 (br s, 1H), 3.13 (q, Jˆ7.2 Hz,
2H), 2.29 (s, 3H), 1.26 (t, Jˆ7.2 Hz, 3H), 1.03 (t, Jˆ7.2 Hz,
3H); 75 MHz 13C NMR (CDCl3) d 170.8, 137.0, 133.8,
130.2, 128.5, 125.7, 125.4, 42.6, 38.6, 18.7, 13.9, 12.8; IR
(neat) 1634 cm21
.
Analytical data for (2-chlorophenyl)-N,N-dimethylcar-
boxamide (8f).34 Obtained as a light yellow oil: Rf 0.09
(40% Et2O/pentane); 300 MHz H NMR (CDCl3) d 7.41±
1
7.26 (m, 4H), 3.14 (s, 3H), 2.86 (s, 3H); 75 MHz 13C NMR
(CDCl3) d 168.2, 136.1, 130.0, 129.9, 129.3, 127.5, 127.0,
.
37.9, 34.4; IR (neat) 1639 cm21
Analytical data for (2-chlorophenyl)-N,N-diethylcarbox-
amide (8g).2 Obtained as a light yellow oil: Rf 0.39 (50%

G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
9881
1
EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 7.41±7.26
Representative procedure for the syntheses of tertiary
amides from the corresponding aldehyde via Gilman
oxidation19a
(m, 4H), 3.83±3.76 (m, 1H), 3.41±3.18 (m, 1H), 3.19±3.12
(m, 2H), 1.27 (t, Jˆ7.5 Hz, 3H), 1.06 (t, Jˆ6.9 Hz, 3H);
75 MHz 13C NMR (CDCl3) d 167.7, 136.6, 130.2, 129.7,
129.5, 127.4, 126.9, 42.6, 38.9, 13.9, 12.6; IR (neat)
Preparation of N,N-dimethyl(3,4,5-trimethoxyphenyl)-
carboxamide (8k). To a stirring solution of NaCN
(625 mg, 12.7 mmol) in 27 mL of i-PrOH was added a
2.0 M solution of dimethyl amine in CHCl3 (12.7 mL,
25.5 mmol), 3,4,5-trimethoxy benzaldehyde (500 mg,
2.55 mmol), and MnO2 (4.40 g, 51.0 mmol). After stirring
for 20 h at rt, the solution was ®ltered through a pad of
Celite (8 mm) and concentrated under reduced pressure to
give 8k (600 mg, 98% yield) as a light yellow oil: Rf 0.10
1638 cm21
.
Analytical data for N,N-diethyl(4-methoxyphenyl)car-
boxamide (8j).35 Obtained as a light yellow oil: Rf
0.34 (50% EtOAc/hexanes); 300 MHz 1H NMR
(CDCl3) d 7.35 (d, Jˆ9.0 Hz, 2H), 6.90 (d, Jˆ9.0 Hz,
2H), 3.83 (s, 3H), 3.42 (br s, 4H), 1.18 (br s, 6H);
75 MHz 13C NMR (CDCl3, -208C) d 171.1, 159.8, 128.9,
127.9, 113.3, 55.1, 43.2, 39.0, 14.1, 12.7; IR (neat)
1
(50% EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 6.64
1631 cm21
.
(s, 2H), 3.87 (s, 6H), 3.86 (s, 3H), 3.10 (br s, 3H), 3.02 (br s,
3H); 75 MHz 13C NMR (CDCl3, 2208C) d 171.2, 152.9,
138.0, 131.6, 103.4, 60.8, 55.9, 39.6, 35.2; IR (neat)
Analytical data for N,N-diethyl(3,4,5-trimethoxy-
phenyl)carboxamide (8l). Obtained as a light yellow oil:
Rf 0.16 (50% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3)
d 6.60 (s, 2H), 3.87 (s, 6H), 3.86 (s, 3H), 3.51 (br s, 2H),
3.32 (br s, 2H), 1.21 (br s, 6H); 75 MHz 13C NMR (CDCl3,
-208C) d 170.9, 153.8, 137.6, 132.6, 102.6, 60.9, 56.0, 43.2,
39.1, 14.3, 12.8; IR (CHCl3) 1618 cm21. Anal. Calcd for
C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found C, 62.82;
H, 8.00; N, 5.34.
1626 cm21
.
Analytical data for (6-bromo(2H-benzo[3,4-d]1,3-dioxo-
len-5-yl))-N,N-diethylcarbamide (8h). Obtained as a
colorless crystalline solid: mp 74±768C; Rf 0.39 (50%
1
EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 6.99 (s,
1H), 6.71(s, 1H), 6.00 (d, Jˆ6.0 Hz, 2H), 3.85±3.74 (m,
1H), 3.35±3.24 (m, 1H), 3.18 (q, Jˆ7.2 Hz, 2H), 1.25 (t,
Jˆ7.2 Hz, 3H), 1.08 (t, Jˆ7.2 Hz, 3H); 75 MHz 13C NMR
(CDCl3) d 168.0, 148.5, 147.4, 131.7, 112.8, 110.1, 107.4,
101.0, 42.7, 38.9, 13.9, 12.4; IR (KBr) 1626 cm21. Anal.
Calcd for C12H14BrNO3: C, 48.02; H, 4.70; N, 4.67.
Found C, 48.03; H, 4.63; N, 4.61.
Analytical data for (2,6-dimethylphenyl)-N,N-dimethyl-
carboxamide (8n). Obtained as a colorless crystalline solid:
mp 59±608C (lit.36 mp 62±638C); Rf 0.18 (50% EtOAc/
1
hexanes); 300 MHz H NMR (CDCl3) d 7.14 (dd, Jˆ6.9,
Jˆ8.4 Hz, 1H), 7.02 (d, Jˆ7.2 Hz, 2H), 3.15 (s, 3H), 2.79
(s, 3H), 2.23 (s, 6H); 75 MHz 13C NMR (CDCl3) d 171.2,
136.5, 133.3, 128.1, 127.3, 37.3, 34.0, 18.8; IR (KBr)
Analytical data for N,N-dimethyl(4-methoxyphenyl)car-
boxamide (8i).39 Obtained as a light yellow oil: Rf 0.13
(50% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) d
7.41 (d, Jˆ9.0 Hz, 2H), 6.90 (d, Jˆ8.7 Hz, 2H), 3.83 (s,
3H), 3.06 (br s, 6H); 75 MHz 13C NMR (CDCl3, 2208C)
d 171.3, 160.2, 129.0, 127.8, 113.2, 55.2, 39.7, 35.4; IR
1633 cm21
.
Analytical data for (2,6-dimethylphenyl)-N,N-diethyl-
carboxamide (8o).37 Obtained as a colorless crystalline
solid: mp 31±338C; Rf 0.38 (50% EtOAc/hexanes);
(neat) 1633 cm21
.
1
300 MHz H NMR (CDCl3) d 7.13 (dd, Jˆ6.9, Jˆ8.4 Hz,
2H), 7.01 (d, Jˆ7.2 Hz, 2H), 3.61 (q, Jˆ7.2 Hz, 2H), 3.11
(q, Jˆ7.2 Hz, 2H), 2.25 (s, 6H), 1.28 (t, Jˆ7.2 Hz, 3H), 1.03
(t, Jˆ7.2 Hz, 3H); 75 MHz 13C NMR (CDCl3) d 170.3,
136.8, 133.4, 128.0, 127.4, 42.2, 38.1, 19.0, 13.8, 12.7; IR
Representative procedure for the syntheses of tertiary
amides from the corresponding aldehyde via radical
oxidation19b
(KBr) 1625 cm21
.
Preparation of cyclohexyl-N,N-diethylcarboxamide (8x).40
To a stirring solution of cyclohexanecarboxaldehyde
(2.00 g, 1.80 mmol) in 50 mL of CCl4 at rt was added
AIBN (50.0 mg, 0.300 mmol), and NBS (4.13 g,
23.2 mmol). The ¯ask was then equipped with a re¯ux
condenser, placed in a pre-heated oil bath at 958C, and
stirred for 12 min. The reaction was then cooled to 08C,
and diethyl amine (2.80 mL, 27.0 mmol) was added drop-
wise via syringe. The solution was stirred for 10 min at rt,
then ®ltered to remove solid material, washing with 20 mL
of CCl4. The ®ltrate was washed with water (2£50 mL), the
layers were separated, dried over MgSO4, and concentrated
under reduced pressure. This material was puri®ed by RPLC
using a 4 mm plate, eluting with 40% EtOAc/hexanes,
collecting 8 mL fractions. The product containing fractions
were combined and concentrated under reduced pressure to
give 8x (1.96 g, 60% yield) as a light yellow oil: Rf 0.45
Analytical data for 2-methyl-N,N-dimethyl-3-phenyl-
propanamide (8v).38 Obtained as a light yellow oil: Rf
0.33 (50% EtOAc/hexanes); 300 MHz H NMR (CDCl3)
1
d 7.29±7.16 (m, 5H), 3.02±2.94 (m, 2H), 2.88 (s,
3H), 2.79 (s, 3H), 2.68±2.60 (m, 1H), 1.14 (d, Jˆ6.6 Hz,
3H); 75 MHz 13C NMR (CDCl3) d 175.8, 140.1, 128.9,
128.2, 126.1, 40.4, 37.8, 36.9, 35.5, 17.4; IR (neat)
1644 cm21
.
Analytical data for 2-methyl-N,N-diethyl-3-phenylpro-
panamide (8w). Obtained as a light yellow oil: Rf 0.15
(50% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) d
7.27±7.15 (m, 5H), 3.47±3.36 (m, 1H), 3.25±3.12 (m,
1H), 3.09±3.00 (m, 3H), 2.92±2.82 (m, 1H), 2.67±2.60
(m, 1H), 1.16 (d, Jˆ6.6 Hz, 3H), 1.02 (t, Jˆ7.2 Hz, 3H),
0.96 (t, Jˆ7.2 Hz, 3H); 75 MHz 13C NMR (CDCl3) d 175.1,
140.2, 129.0, 128.2, 126.0, 41.2, 40.7, 40.4, 38.1, 18.2, 14.5,
1
(50% EtOAc/hexanes); 300 MHz H NMR (CDCl3) d 3.36
(q, Jˆ7.0 Hz, 2H), 3.33(q, Jˆ7.2 Hz, 2H), 2.40 (tt, Jˆ3.5,
12.9; IR (neat) 1638 cm21
.
Jˆ11.4 Hz, 1H), 1.82±1.78 (m, 2H), 1.72±1.67 (m, 2H),

9882
G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
1.62±1.49 (m, 2H), 1.30±1.23 (m, 4H), 1.18 (t, Jˆ7.2 Hz,
3H), 1.09 (t, Jˆ7.2 Hz, 3H); 75 MHz 13C NMR (CDCl3) d
175.5, 41.6, 40.8, 29.6, 25.9, 25.8, 15.0, 13.1; IR (neat)
References
1. Snieckus, V. Chem. Rev. 1990, 90, 879.
1647 cm21
.
2. Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
3. Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc.
1999, 121, 5176.
Analytical data for N,N-bis(methylethyl)-2-naphthylcar-
boxamide (8c). Obtained as a colorless crystalline solid: mp
146±1488C (lit.41 mp 150±1528C); Rf 0.63 (50% EtOAc/
4. (a) Ben-Ishai, D.; Altman, J.; Peled, N. Tetrahedron 1977, 33,
2715. (b) Corey, E. J.; Balanson, R. D. J. Am. Chem. Soc. 1974, 96,
6516. (c) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J.
J. Am. Chem. Soc. 1976, 98, 1275. (d) Other hydrolysis methods:
1
hexanes); 300 MHz H NMR (CDCl3) d 7.87±7.80 (m,
4H), 7.52±7.49 (m, 2H), 7.43±7.26 (m, 1H); 3.75 (br s,
1H), 3.64 (br s, 1H), 1.50 (br s, 6H), 1.23 (br s, 6H);
75 MHz 13C NMR (CDCl3, 2208C) d 170.9, 136.0, 132.8,
132.7, 128.2, 128.1, 127.7, 126.5, 124.7, 123.2, 51.0, 45.8,
Ã
(i) Tsunoda, T.; Sasaki, O.; Ito, S. Tetrahedron Lett. 1990, 31, 731.
(ii) Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J. C.;
Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38, 4535.
5. Godjoian, G.; Singaram, B. Tetrahedron Lett. 1997, 38, 1717.
6. (a) Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron Lett. 1998,
39, 1017. (b) Salunkhe, A. M.; Burkhardt, E. R. Tetrahedron Lett.
1997, 38, 1519.
20.7, 20.5; IR (KBr) 1620 cm21
.
Representative procedure for the syntheses of tertiary
amides from the corresponding methyl ester19c
7. Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett.
1996, 37, 3623.
Preparation of (6-iodo-4-methoxy(2H-benzo[3,4-d]1,3-
dioxolen-5-yl))-N,N-dimethylcarboxamide (11). To a stir-
ring suspension of dimethyl amine hydrochloride salt
(206 mg, 2.6 mmol) in 20 mL of benzene at 08C was
added a 2.0 M solution of trimethyl aluminum in hexanes
(1.3 mL, 2.6 mmol) dropwise. The resulting mixture was
stirred for 2 h at rt, then transferred to a stirring solution
of methyl 6-iodo-4-methoxy-2H-benzo[3,4-d]1,3-dioxo-
lene-5-carboxylate (425 mg, 1.3 mmol) in 15 mL of
benzene. This mixture was heated at re¯ux for 72 h, then
cooled to rt and quenched by addition of 5% HCl solution.
The layers were separated and the aqueous layer was
extracted with EtOAc (2£25 mL). The organic layers
were combined, dried over MgSO4, and concentrated
under reduced pressure. The crude material was puri®ed
by ¯ash chromatography, eluting with 100 mL of each of
25, 50, 75 and 100% EtOAc/hexanes, collecting 8 mL frac-
tions. The product containing fractions were combined and
concentrated under reduced pressure to give 11 (93 mg,
21% yield) as a light yellow crystalline solid: Rf 0.18
(50% EtOAc/hexanes); mp 130±1328C; 300 MHz 1H
NMR (CDCl3) d 6.95 (s, 1H), 5.96 (Abq, Dnˆ5.6 Hz,
Jˆ1.2 Hz, 2H), 3.98 (s, 3H), 3.12 (s, 3H), 2.86 (s, 3H);
75 MHz 13C NMR (CDCl3) d 168.3,150.2, 140.2, 137.0,
129.0, 113.0, 101.6, 81.6, 60.2, 37.8, 34.7; IR (KBr)
8. (a) McCombie, S. W.; Lin, S.-I.; Vice, S. F. Tetrahedron Lett.
1999, 40, 8767. (b) Pratt, S. A.; Goble, M. P.; Mulvaney, M. J.;
Wuts, P. G. M. Tetrahedron Lett. 2000, 41, 3559.
9. Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem Soc.
1968, 90, 5616.
10. For other methods for converting an amide directly to an ester,
see: (a) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011. (b) Kende,
A. S.; Bentley, T. J.; Draper, R. W.; Jenkins, J. K.; Joyeux, M.;
Kubo, I. Tetrahedron Lett. 1973, 16, 1307. (c) Charette, A. B.;
Chua, P. Synth. Lett. 1998, 163.
11. Hanessian, S. Tetrahedron Lett. 1967, 16, 1549.
12. Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.;
Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc.
1972, 94, 9219.
13. (a) Sheehan, J. C.; Na®ssi, V. M. M. J. Org. Chem. 1970, 35,
4246. (b) Menezes, R.; Smith, M. B. Synth. Commun. 1988, 18,
1625.
14. Kiessling, A.; McClure, C. K. S. Synth. Commun. 1997, 27,
923.
15. Borch, R. F. Tetrahedron Lett. 1968, 1, 61.
16. Baum, J. S.; Viehe, H. G. J. Org. Chem. 1976, 41, 183.
17. Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem.
1991, 56, 2883.
18. (a) Satterthwait, A. C.; Jencks, W. P. J. Am. Chem. Soc. 1974,
96, 7031. (b) Brown, R. S.; Bennet, A. J.; Slebocka-Tilk, H. Acc.
Chem. Res. 1992, 25, 481.
1610 cm21
.
Â
19. (a) Gilman, N. W. Chem. Commun. 1971, 733. (b) Marko, I. E.;
Analytical data for (4-hydroxy-6-iodo(2H-benzo[3,4-
d]1,3-dioxolen-5-yl))-N,N-dimethylcarboxamide (4).
Obtained as a colorless crystalline solid: mp 217±
Mekhal®a, A. Tetrahedron Lett. 1990, 31, 7237. (c) Lipton, M. F.;
Basha, A.; Weinreb, S. M. Org. Synth. 1979, 49.
20. Bahl, A. K.; Kemp, W. J. Chem. Soc. C. 1971, 2268.
21. Zhou, Z.-L.; Huang, Y.-Z.; Shi, L.-L. Tetrahedron 1993, 49,
6821.
2198C (lit.3 mp 218±2208C) Rf 0.33 (100% EtOAc/
1
hexanes); 300 MHz H NMR (CDCl3) d 9.55 (br s, 1H),
6.73 (s, 1H), 5.92 (d, Jˆ19.7 Hz, 2H), 3.14 (s, 3H), 2.91
(s, 3H); 75 MHz 13C NMR (CDCl3) d 170.5, 149.8, 138.0,
137.1, 126.6, 110.8, 102.3, 80.6, 38.3, 35.0; IR (KBr)
22. Snider, B. B.; Roush, D. M.; Rodini, D. J.; Gonzalez, D.;
Spindell, D. J. Org. Chem. 1980, 49, 2773.
È
23. Honig, H. Magn. Reson. Chem. 1996, 34, 395.
1604 cm21
.
24. Swenton, J. S.; Carpenter, K.; Chen, Y.; Kerns, M. L.;
Morrow, G. W. J. Org. Chem. 1993, 58, 3308.
25. Logue, M. W.; Han, H. B. J. Org. Chem. 1981, 46, 1638.
26. Bachelor, F. W.; Loman, A. A.; Snowdon, L. R. Can. J. Chem.
1970, 48, 1554.
Acknowledgements
27. Wagner, P. J.; Siebert, E. J. J. Am. Chem. Soc. 1981, 103,
7329.
Financial assistance provided by the National Institutes of
Health (through grant GM-28961) and by P®zer, Inc. is
gratefully acknowledged.
Â
28. Holõk, M.; Mannschreck, A. Org. Magn. Reson. 1979, 12, 223.

G. E. Keck et al. / Tetrahedron 56 (2000) 9875±9883
29. Evans, P. A.; Nelson, J. D.; Stanley, A. L. J. Org. Chem. 1995, 35. Yuste, F.; Origel, A.; BrenÄa, L. Synthesis 1983, 109.
9883
60, 2298.
È
36. Lofgren, N.; Stoffel, W. Acta Chem. Scand. 1959, 13, 1585.
37. Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54,
4372.
30. Brown, H.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089.
31. Tsuge, O.; Sone, K.; Urano, S.; Matsuda, K. J. Org. Chem.
1982, 47, 5171.
38. Sucrow, W. Chem. Ber. 1968, 101, 4230.
Â
39. Perjessy, A. J. Org. Chem. 1983, 48, 1266.
32. Zheng, J.; Wang, Z.; Shen, Y. Synth. Commun. 1992, 22, 1611.
33. Campaigne, E.; Skowronski, G.; Forsch, R. A.; Beckman, J. C.
Synth. Commun. 1976, 6, 387.
40. Barton, D. H. R.; Ferreira, J. A. Tetrahedron 1996, 52, 9347.
41. Pagani, G.; Baruf®ni, A.; Borgna, P. Farmaco Ed. Sci. 1974,
29, 491.
34. Lewin, A. H.; Dinwoodie, A. H.; Cohen, T. Tetrahedron 1966,
22, 1527.