The reaction of cyclic carbinol amides with triflic anhydride as a method to prepare α-trifluoromethyl-sulfonamido furans

Article abstract of DOI:10.1021/ol0272388

(Matrix presented) A novel synthesis of α -trifluoromethyl-sulfonamido furans via the reaction of cyclic carbinol amides with triflic anhydride has been developed. The reaction proceeds under very mild conditions with a wide set of representative lactams to provide the α-trifluoromethyl-sulfonamido-substituted furan in high yield. Rapid access to a 5-substituted indoline can be achieved by thermolysis of the N-but-3-enyl-substituted sulfonamido furan.

Full text of DOI:10.1021/ol0272388

ORGANIC
LETTERS
2003
Vol. 5, No. 2
189-191
The Reaction of Cyclic Carbinol Amides
with Triflic Anhydride as a Method to
Prepare r-Trifluoromethyl-Sulfonamido
Furans
Paitoon Rashatasakhon and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received November 5, 2002
ABSTRACT
A novel synthesis of r-trifluoromethyl-sulfonamido furans via the reaction of cyclic carbinol amides with triflic anhydride has been developed.
The reaction proceeds under very mild conditions with a wide set of representative lactams to provide the r-trifluoromethyl-sulfonamido-
substituted furan in high yield. Rapid access to a 5-substituted indoline can be achieved by thermolysis of the N-but-3-enyl-substituted sulfonamido
furan.
The R-amidoalkylation/cyclization sequence involving N-
acyliminium ions is widely regarded as a powerful method
for the synthesis of nitrogenated heterocyclic compounds.1,2
Cyclic R-alkoxy amides are among the most popular precur-
sors for N-acyliminium ions.3 Typically, these versatile
systems (e.g. 2a-c) are prepared by electrochemical oxida-
tion of amides4 or by treating cyclic imides (i.e. 1) with
various organometallic reagents.5 Subsequent N-acyliminium
formation (3) by Lewis or protic acids followed by trapping
with various tethered π-bonds returns the amido-alkylation
Scheme 1
(1) For reviews see: Speckamp. W. N. Recl. TraV. Chim. Pays-Bas 1981,
100, 345. Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
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B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 2, pp
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products (4) in good to excellent yields (Scheme 1).6 Often
the judicious choice of a Lewis acid can greatly influence
(6) Santos, L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 6999. Pilli, R.
A.; Zanotto, P. A.; Bo¨ckelmann, M. A. Tetrahedron Lett. 2001, 42, 7003.
10.1021/ol0272388 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003

the outcome of the cyclization reaction.7 Herein, we report
on the reaction of cyclic carbinol amides with triflic
anhydride as a method to prepare various R-trifluoromethyl-
sulfonamido furans, some of which can be further utilized
for cycloaddition chemistry.
Scheme 3
Recent work in our laboratory has shown that the reaction
of R-angelica lactone (5) with various alkylamines under
aqueous conditions afforded 5-hydroxy-5-methylpyrrolidi-
nones (6, 7) in high yield (Scheme 2).8 When 6 was treated
Scheme 2
furan also took place when trifluoroacetic anhydride was used
as the acylating agent. Both 16 and the related cyclic keto
amide 19 underwent smooth cyclization with TFAA to
furnish furans 18 and 20 in high yield. Attempts to remove
the trifluoroacetyl group of 20 under basic conditions with
K2CO3/MeOH resulted in an oxidative rearrangement giving
carbinol amide 21 in modest yield.
Recently, Charette and co-workers have demonstrated that
secondary and tertiary amides can be activated with triflic
anhydride to generate the corresponding iminium salts which
can react further with various nucleophiles.11 Iminium
triflates were originally used by Ghosez as precursors of
ketiminium cations which can function as electrophilic
substrates in [2+2]-cycloadditions.12 It would seem that when
a hydroxy pyrrolidinone such as 7 is used as the tertiary
amide, the resulting iminium ion (i.e., 22) derived from the
reaction of 7 with triflic anhydride undergoes a facile ring
opening as a consequence of the adjacent hydroxyl group to
produce imino triflate 23 (Scheme 4). Subsequent cyclization
of this highly electrophilic imine13 with the oxygen atom of
the adjacent carbonyl group results in the formation of imino
dihydrofuran 24. This transient species reacts further with
another equivalent of triflic anhydride to give the observed
furan. By using only 1 equiv of triflic anhydride and then
adding a second equivalent of acetyl chloride, acetylation
of 24 occurred in modest yield leading to the related N-acetyl
furan 25 (R ) CH2Ph).
with p-TsOH in benzene at 100 °C, dimer 8 was formed as
the major product. On the other hand, the reaction of 7 with
trifluoroacetic anhydride (TFAA) furnished enamide 9 in
79% yield, presumably by an elimination/acylation process.
The structure of 9 was unequivocally established by a single-
crystal X-ray analysis. The pathway suggested for the
formation of 9 was supported by the finding that the reaction
of 7 with acetic anhydride gave enamide 10 which, in turn,
was converted to 9 upon treatment with TFAA. Most
interestingly, when a sample of 7 was allowed to stir with 2
equiv of triflic anhydride9 and pyridine in CH2Cl2, R-trif-
luoromethyl-sulfonamido furan 11 was formed in 79% yield.
This reaction was quite general affording related sulfonamido
furans with a broad range of alkylamines (i.e., 12-15). The
same reaction occurred in good yield when cyclic carbinol
amides 2a-c were treated with triflic anhydride in CH2Cl2.
Cyclization to the sulfonamido furan also came about with
the isomeric γ-keto amide system 16,10 giving rise to furan
17 in excellent yield (Scheme 3). In fact, cyclization to the
The indoline nucleus is a key structural feature found in
a large number of alkaloids and related compounds, many
of which exhibit potent pharmacological activity.14 It is not
surprising that numerous routes have been devised over the
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1982, 85. Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S.
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Angew. Chem., Int. Ed. Engl. 1981, 20, 879. Barbaro, G.; Battaglia, A.;
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Org. Chem. 1997, 62, 2080.
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190
Org. Lett., Vol. 5, No. 2, 2003

Scheme 4
Scheme 5
years to construct this important heterocyclic system.15 New
procedures that can selectively generate indolines with
substituent groups in the aromatic ring would be of use to
the medicinal community. During the course of our studies
with these novel 2-sulfonamido furans, we found that rapid
access to 5-substituted indolines could easily be achieved
from thermolysis of the N-but-3-enyl furan 17 (or 18).
Previously we had prepared 2-amido furans from either
the N-alkylation of carbamates or the copper-catalyzed
amidations of 2-bromo furans16 and have shown that these
heteroaromatic systems are useful substrates for [4+2]-
cycloaddition chemistry.17 We have extended our earlier
studies to include the IMDAF (intramolecular Diels-Alder
of furans)18 reaction of furans 17 and 18 which are easily
prepared from R-angelica lactone 5. Thermolysis of furan
17 in toluene at 130 °C for 4 h furnished indoline 27 in
96% yield. More than likely the reaction proceeds through
the [4+2]-cycloadduct 26, which readily loses water to
produce 27 (Scheme 5). Reduction of 27 with LiAlH4
furnished indoline 28 in 90% yield. A related set of reactions
also occurred with the N-trifluoroacetyl furan 18 leading to
indoline 30 via cycloadduct 29. The cycloaddition of furan
17 is about three times faster than that of 18 and is probably
related to HOMO-LUMO considerations. It would seem as
though the π-electron-withdrawing trifluoroacetyl group
diminishes the ability of the electron pair on nitrogen to
interact with the adjacent π-array of the heteroaromatic ring
thereby decreasing the overall rate of the HOMO-controlled
reaction.
The [4+2]-cycloaddition was also carried out with tethered
alkenes that possess a substituent on the 3-position of the
π-bond and, in this case, cycloadduct 32 could be isolated
in 85% yield. The formation of a single diastereomer where
the oxygen bridge and methyl groups are anti to each other
is perfectly consistent with other reports in the literature for
related furanyl systems possessing short tethers.19 The Diels-
Alder prefers to occur where the sidearm of the tethered
alkenyl group is oriented syn (exo) with respect to the oxygen
bridge. This result is not so surprising since, in these mobile
cycloaddition equilibria, the exo-adducts are expected to be
thermodynamically more favored.
In summary, an efficient method for the conversion of
cyclic carbinol amides into R-trifluoromethyl-sulfonamido
furans has been uncovered. The procedure takes place under
very mild conditions with a wide set of representative
hydroxy lactams. In certain cases the resulting sulfonamido
furans have been utilized as substrates for the synthesis of
indolines and related heterocyclic systems. We are further
evaluating their cycloaddition behavior for alkaloid synthesis
and results along these lines will be disclosed in due course.
Acknowledgment. This research was supported by the
National Institutes of Health (GM 59384 and GM 60003).
We thank our colleague, Dr. Kenneth Hardcastle, for his
assistance with the X-ray crystallographic studies together
with grants SF CHE-9974864 and NIH S10-RR13673.
Supporting Information Available: Complete descrip-
tion of the synthesis and characterization of all compounds
prepared in this study and an Ortep drawing for compound
9. This material is available free of charge via the Internet
at http://pubs.acs.org.
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OL0272388
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