Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of α-trifluoromethylsulfonamido furans

Article abstract of DOI:10.1021/jo0341970

The reaction of α-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf₂O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf₂O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocyclic systems.

Full text of DOI:10.1021/jo0341970

Tr iflic An h yd r id e Med ia ted Cycliza tion of 5-Hyd r oxy-Su bstitu ted
P yr r olid in on es for th e P r ep a r a tion of
r-Tr iflu or om eth ylsu lfon a m id o F u r a n s
Albert Padwa,* Paitoon Rashatasakhon, and Mickea Rose
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received February 13, 2003
The reaction of R-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-
5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions,
the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either
class of compound with triflic anhydride (Tf2O) in pyridine resulted in the formation of various
substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium
ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly
electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino
dihydrofuran intermediate. This species reacts further with another equivalent of Tf2O to give the
observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization
reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the
synthesis of indolines and related heterocyclic systems.
In tr od u ction
the intramolecular reaction of cyclic iminium ions bearing
endocyclic N-acyl groups and tethered nucleophiles has
been successfully employed in the preparation of many
nitrogen-containing natural products.14-18 The presence
of the electron-withdrawing acyl functionality on the
nitrogen atom results in a more reactive iminium ion,
and consequently, this species reacts with a wider range
of intramolecular nucleophiles.12 A variety of useful
functionalities for terminating cyclization reactions have
also been developed.19,20 The most powerful of these are
ones which both “control” the cyclization process so that
a single product is produced and leave the cyclization
product with useful functionality for further synthetic
manipulation.21
Nitrogen-containing heterocycles are abundant in na-
ture and exhibit diverse and important biological proper-
ties.1 Accordingly, novel strategies for the stereoselective
synthesis of azapolycyclic ring systems continue to
receive considerable attention in the field of synthetic
organic chemistry.2-8 The utility of N-acyliminium ions
in heterocyclic chemistry is now well documented.9 Cyclic
N-acyliminium ions with exo-cyclic N-acyl groups can
adopt the s-cis-conformation and react as a 4π-electron
system with olefins and acetylenes in a Diels-Alder
cycloaddition reaction with inverse electron demand.10
Alternatively, they may behave as dienophiles in reac-
tions with conjugated dienes.11 The R-amidoalkylation/
cyclization sequence of N-acyliminium ions is widely
regarded as a powerful method for the synthesis of many
nitrogenated heterocyclic compounds.12,13 In particular,
Cyclic R-alkoxy amides (2) are among the most popular
precursors for N-acyliminium ions.22 Typically, these
versatile systems are prepared by electrochemical oxida-
tion of amides23 or by treating cyclic imides with various
organometallic reagents.24 Subsequent N-acyliminium
(1) Strunz, G. M.; Findley, J . A. The Alkaloids; Academic Press: New
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Pelletier, S. W., Ed.; Wiley: New York, 1988; Vol. 6, p 227.
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41, 9709.
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193.
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Commun. 1976, 182.
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Verlag: Berlin, 1983. Colvin, E. Silicon in Organic Synthesis; Butter-
worth: London, 1983.
(21) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857
and references therein.
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2, pp 1047-1082.
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(11) Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16.
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10.1021/jo0341970 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/05/2003
J . Org. Chem. 2003, 68, 5139-5146
5139

Padwa et al.
SCHEME 1
SCHEME 2
SCHEME 3
ion formation (3) by Lewis or protic acids followed by
trapping with various tethered π-bonds returns the
amido-alkylation products (4) in good to excellent yields
(Scheme 1).25 Often, the judicious choice of a Lewis acid
can greatly influence the outcome of the cyclization
reaction.26 Our own interest in this area stems from an
earlier observation made in our laboratory wherein cyclic
carbinol amines were readily converted into R-trifluo-
romethylsulfonamido furans when treated with triflic
anhydride.27 Because initial studies into the cycloaddition
chemistry of these aza-substituted furans were promis-
ing,28 a more detailed investigation has been conducted.
The results of these inquiries are reported herein.
the N-allyl-substituted pyrrolidinone 7 was treated with
p-TsOH in benzene at 80 °C, dimer 18 was formed as
the major product. On the other hand, reaction of the
N-benzyl cyclic carbinol amide 8 with trifluoroacetic
anhydride (TFAA) furnished enamide 19 in 79% yield,
presumably by an elimination/acylation process. The
structure of 19 was unequivocally established by a single-
crystal X-ray analysis. The pathway suggested for the
formation of 19 was supported by the finding that the
reaction of 8 with acetic anhydride gave enamide 20
which, in turn, was converted to 19 upon treatment with
TFAA (Scheme 3).
It is particularly interesting to note that when the
γ-keto N-(3,4-dimethoxyphenethyl)amide 17 was treated
with 10% HCl in THF, isoquinoline 23 was formed as
the major product in 70% yield (Scheme 4). Under these
conditions, N-acyliminium ion 22, derived from the
initially formed cyclic carbinol amide 21, undergoes a
well-established electrophilic aromatic substitution reac-
tion with the tethered benzenoid ring. Since it is known
that the nature of the Lewis acid can often influence the
cyclization outcome,26 we opted to study the conversion
of 17 to 23 in greater detail using a variety of Lewis acids.
It was during the course of these studies that we
happened to discover that reaction of either the γ-keto
amido system (i.e., 12-17) or the isomeric cyclic carbinol
amides (i.e., 6-11) with triflic anhydride resulted in the
clean formation of R-trifluoromethylsulfonamido furans
(28-35). Sulfonamidofuran 35 was hydrolyzed to give the
crystalline carboxylic acid 36 whose structure was un-
equivocally established by an X-ray crystal structure
analysis. All of the other related sulfonamidofurans (i.e.,
28-34) showed comparable NMR signals (see Experi-
Resu lts a n d Discu ssion
Cyclic carbinol amides such as 6-11 were readily
prepared by either exposing the corresponding N-alkyl-
substituted succinimide to an organometallic reagent
such as methylmagnesium iodide or by treating R-an-
gelica lactone (5) with various alkylamines under aque-
ous conditions.29 Interestingly, when lactone 5 was
allowed to react with several primary amines under
anhydrous conditions (i.e., THF), only the corresponding
4-oxopentanoic acid amides (12-17) were obtained
(Scheme 2). Subjection of a typical γ-keto amide such as
12 to the aqueous acidic conditions resulted in the
complete formation of cyclic carbinol amide 8 in 84%
isolated yield. From these observations, it would seem
as though the specific experimental conditions used
control the equilibrium distribution of products. When
(23) Shono, T.; Matsumura, Y.; Tsubata, K. J . Am. Chem. Soc. 1981,
103, 1172. Shono, T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1985,
63, 206.
(24) Bailey, P. D.; Morgan, K. M.; Smith, D. I.; Vernon, J . M.
Tetrahedron Lett. 1994, 35, 7115. De Koning, H.; Speckamp, W. N. In
Houben-Weyl, Methods in Organic Chemistry; Helmchen, G., Hoffmann,
R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart, Germany,
1995; Vol. E21b, pp 1953-2009.
(25) 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.
(26) Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419. Keum,
G.; Kim, G. Bull. Korean Chem. Soc. 1994, 15, 278. Martin, S. F.; Bur,
S. K. Tetrahedron Lett. 1997, 38, 7641.
(27) Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 189.
(28) Padwa, A.; Dimitroff, M.; Liu, B. Org. Lett. 2000, 2, 3233.
Padwa, A.; Brodney, M. A.; Lynch, S. M. J . Org. Chem. 2001, 66, 1716.
Ginn, J . D.; Padwa, A. Org. Lett. 2002, 4, 1515.
(29) For some related work, see: J ones, J . B.; Young, J . M. Can. J .
Chem. 1966, 44, 1059.
5140 J . Org. Chem., Vol. 68, No. 13, 2003

Preparation of R-Trifluoromethylsulfonamido Furans
SCHEME 4
SCHEME 6
SCHEME 5
SCHEME 7
mental Section) to those exhibited by 35. Cyclization to
the furanyl sulfonamide systems also occurred with
hydroxy pyrrolidinones 24-27 and Tf2O. These cyclic
carbinol amides afforded furans 37-40 wherein different
substituent groups were incorporated into the 5-position
of the heteroaromatic ring (Scheme 5).
Cyclization of γ-keto amide 1430 to the furanyl system
also took place when trifluoroacetic anhydride was used
as the acylating agent. Both 14 and the related cyclic keto
amides 42-45 underwent smooth cyclization with TFAA
(or TF2O) to furnish furans 41 and 46-53 in high yield
(Scheme 6). Attempts to remove the trifluoroacetyl group
of 47 under basic conditions with K2CO3/MeOH resulted
in an oxidative rearrangement giving rise to carbinol
amide 54 in modest yield.
We also attempted to prepare the trifluoroacetyl (47)
or sulfonamido-substituted furan 51 starting from the
isomeric cyclic carbinol amide 55 as was done with the
previously described γ-keto amide system. However, all
of our efforts to synthesize 55 from 43 only afforded a
2:1:4 mixture of hexahydroindolones 56-58 (Scheme 7),
presumably derived by facile dehydration of 55, and
consequently we abandoned further studies with this
system.
Trifluoromethanesulfonic (triflic) anhydride has been
extensively used in synthetic organic chemistry as a
reagent for the conversion of various compounds to the
triflate functionality.31 The reaction of secondary or
tertiary amides with triflic anhydride is known to give
rise to iminium and imino triflates, respectively. These
salts are versatile reagents that can react with various
N-, O-, and S-nucleophiles thereby transforming the
amide group into other functionalities.32 Iminium triflates
(31) For some reviews dealing with triflic anhydride, see: Ritter,
K. Synthesis 1993, 735. Stang, P. J .; Hanack, M.; Subramanian, L. R.
Synthesis 1982, 85. Braznenok, I. L.; Nenajjdenko, V. G.; Balenkova,
E. S. Tetrahedron 2000, 56, 3077.
(32) Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 1997.
Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499. Charette,
A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245 Charette, A. B.; Chua,
P. J . Org. Chem. 1998, 63, 908. Charette, A. B.; Chua, P. Synlett 1998,
163. Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677.
(30) Collado, M. I., Manteca, I.; Sotomayor, N.; Villa, M. J .; Lete,
E. J . Org. Chem. 1997, 62, 2080.
J . Org. Chem, Vol. 68, No. 13, 2003 5141

Padwa et al.
SCHEME 8
SCHEME 9
were originally used by Ghosez as precursors of ketimin-
ium cations which can function as electrophilic substrates
in [2 + 2]-cycloadditions.33 It would seem that when a
hydroxypyrrolidinone such as 8 is used as the tertiary
amide, the resulting iminium ion (i.e., 59) derived from
the reaction of 8 with triflic anhydride undergoes a facile
ring opening as a consequence of the adjacent hydroxyl
group to produce imino triflate 60 (Scheme 8). Subse-
quent cyclization of this highly electrophilic imine34 with
the oxygen atom of the adjacent carbonyl group would
result in the formation of imino dihydrofuran 61. This
transient species could react further with another equiva-
lent of triflic anhydride to give the observed furan 30.
By using only 1 equiv of triflic anhydride and then adding
a second equivalent of acetic anhydride, acetylation of
61 occurred in modest yield leading to the related
N-acetyl furan 62, thereby providing support for the
proposed mechanism..
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.35
It is not surprising that numerous routes have been
devised over the years to construct this important
heterocyclic system.36 New procedures that can selec-
tively generate indolines with substituent groups in the
aromatic ring would be of use to the medicinal com-
munity. 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 31 (or 41).
extend our earlier studies to include the IMDAF (in-
tramolecular Diels-Alder of furans)39 reaction of furans
31 and 41. Thermolysis of furan 31 in toluene at 130 °C
for 4 h furnished indoline 64 in 96% yield. More than
likely, the reaction proceeds through the [4 + 2]-cycload-
duct 63, which readily loses water to produce 64 (Scheme
9). Reduction of 64 with LiAlH4 furnished indoline 65 in
90% yield. A related set of reactions also occurred with
the N-trifluoroacetyl furan 41 leading to indoline 67 via
cycloadduct 66. In a similar fashion, heating a sample of
either 48 or 52 led to benzo[f]indoles 68 or 69 in 89%
and 98% yield, respectively. The cycloaddition of sulfon-
amidofurans 31 and 52 proceeded three times faster than
the corresponding trifluoroacetyl furans 41 and 48. This
is probably related to HOMO-LUMO considerations. It
would seem as though the π-electron-withdrawing tri-
fluoroacetyl 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 a
tethered alkene that possesses a substituent on the
π-bond, and in this case, cycloadduct 70 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.40 The Diels-Alder reaction 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 cycload-
dition equilibria, the exo adducts are expected to be
thermodynamically more favored.
Previously, we had prepared 2-amido furans from
either the N-alkylation of carbamates or the copper-
catalyzed amidations of 2-bromo furans37 and have shown
that these heteroaromatic systems are useful substrates
for [4 + 2]-cycloaddition chemistry.38 We decided to
(33) Falmagne, J . B.; Escudero, J .; Taleb-Saharaoui, S.; Ghosez, L.
Angew. Chem., Int. Ed. Engl. 1981, 20, 879. Barbaro, G.; Battaglia,
A.; Bruno, C.; Giorgiannni, P.; Guerrini, A. J . Org. Chem. 1996, 61,
8480.
(34) Sisti, N. J .; Fowler, F. W.; Grierson, D. S. Synlett 1991, 816.
Sisti, N. J .; Zeller, E.; Grierson, D. S.; Fowler, F. W. J . Org. Chem.
1997, 62, 2093. Thomas, E. W. Synthesis 1993, 767.
(35) Szantay, C. Pure Appl. Chem. 1990, 62, 1299. Hibino, S.;
Choshi, T. Nat. Prod. Rep. 2002, 19, 148 and earlier reviews in the
series.
(36) Alvarez, M.; Salas, M.; J oule, J . A. Heterocycles 1991, 32, 1391.
Black, D. S. C. Synlett 1993, 246. Hughes, D. L. Org. Prep. Proc. Int.
1993, 25, 607.
In summary, an efficient method for the conversion of
cyclic carbinol amides into R-trifluoromethylsulfonamido
(38) Padwa, A.; Ginn, J . D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M.
J . Org. Chem. 2002, 67, 3412.
(39) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997,
53, 14179. Sternbach, D. D.; Rossana, D. M.; Onon, K. D. J . Org. Chem.
1984, 49, 3427. J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1989, 111,
5469.
(37) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J . Org.
Chem. 1999, 64, 3595. Crawford, K. R.; Padwa, A. Tetrahedron Lett.
2002, 43, 7365.
5142 J . Org. Chem., Vol. 68, No. 13, 2003

Preparation of R-Trifluoromethylsulfonamido Furans
of diastereomers: IR (neat) 1684, 1675, 1431, 1401, 1329 cm-1
;
furans has been uncovered. The reaction takes place
under very mild conditions with a wide set of representa-
tive hydroxy lactams. In certain cases, the resulting
sulfonamidofurans have been utilized as substrates for
the synthesis of indolines and related heterocyclic sys-
tems.
1H NMR (400 MHz, CDCl3) δ 1.18 and 1.22 (d, 3H, J ) 7.0
Hz), 1.60 (s, 3H), 1.84-1.97 (m, 1H), 2.29-2.44 (m, 3H), 3.44-
3.67 (m, 2H), 3.87-4.17 (m, 2H), 4.34-4.42 (m, 1H), 5.03-
5.18 (m, 4H), 5.67-5.84 (m, 2H), and 6.58 and 6.55 (t, 1H, J
) 2.0 Hz); 13C NMR (100 MHz CDCl3) δ 16.8, 24.6, 24.7, 29.6,
29.7, 32.3, 32.4, 42.7, 43.2, 55.2, 62.9, 63.1, 116.6, 117.9, 133.6,
134.5, 140.6, 142.37, 142.41, 168.3, 168.4, 175.48, and 175.52;
HRMS calcd for C16H22N2O2 274.1681, found 274.1670.
1-Ben zyl-5-(3,3,3-tr iflu or o-2-oxopr opyliden e)pyr r olidin -
2-on e (19). To a solution of cyclic carbinol amide 8 (0.1 g, 0.5
mmol) in CH2Cl2 (5 mL) at -78 °C was added pyridine (0.4
mL, 4.9 mmol) followed by TFAA (0.15 mL, 1.1 mmol). The
mixture was allowed to warm to room temperature and was
stirred for 10 min. The reaction was quenched with water (10
mL), and the organic layer was separated. The aqueous was
extracted twice with CHCl3, and the combined organic phase
was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography on silica gel to give 19 (0.11 g, 79%) as a white solid:
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of Hyd r oxy
La cta m s. A solution of the appropriate amine (5.6 mmol) in
water (0.5 mL) was added to R-angelica lactone (5) (0.5 g, 5.1
mmol), and the mixture was stirred at room temperature for
1 h. The mixture was concentrated under reduced pressure,
and the resulting residue was purified by flash chromatogra-
phy on silica gel using 20% acetone/CHCl3 as the eluent.41
5-Hyd r oxy-1,5-d im eth ylp yr r olid in -2-on e (6) was pre-
pared in 92% yield from lactone 5 and a 30% aqueous solution
of methylamine: 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 3H),
1.94-2.52 (m, 4H), 2.72 (s, 3H), and 4.60 (s, 1H). The spectral
data of this compound is identical to that reported in the
literature.42
mp 81-82 °C; IR (KBr) 1754, 1692, 1569, 1417, and 1290 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.68-2.71 (m, 2H), 3.30-3.36
(m, 2H), 4.77 (s, 2H), 5.89 (s, 1H), 7.20-7.25 (m, 2H), and
7.29-7.36 (m, 3H); 13C NMR (100 MHz CDCl3) δ 26.9, 27.5,
44.8, 92.3, 116.5 (q, J ) 289.8 Hz), 127.6, 128.5, 129.2, 134.1,
168.1, 177.5, and 178.9 (q, J ) 33.3 Hz). Anal. Calcd for
1-Allyl-5-h ydr oxy-5-m eth ylpyr r olid in -2-on e (7) was pre-
pared in 81% yield from lactone 5 and allylamine: IR (neat)
1673, 1454, 1409, and 1102 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.47 (s, 3H), 2.07-2.12 (m, 2H), 2.25-2.36 (m, 1H), 2.46-
2.56 (m, 1H), 3.80-3.92 (m, 2H), 4.31 (s, 1H), 5.09 (dd, 1H, J
) 10.0, 1.6 Hz), 5.16 (dd, 1H, J ) 17.2, 1.6 Hz), and 5.80 (qt,
1H, J ) 10.0, 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 27.0, 29.2,
C
14H12F3NO2: C, 59.34; H, 4.27; N, 4.95. Found: C, 59.55; H,
4.26; N, 4.97.
N-Ben zyl-5-m eth ylen ep yr r olid in -2-on e (20). To a solu-
tion of hydroxy pyrrolidinone 8 (0.1 g, 0.5 mmol) in CH2Cl2 (5
mL) was added pyridine (0.4 mL, 4.9 mmol) followed by Ac2O
(0.1 mL, 1.1 mmol). The mixture was heated at reflux for 16
h, cooled to room temperature, diluted with CHCl3, and washed
with water. The organic layer was separated, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue showed the following spectral properties
which are identical to those reported in the literature:45 1H
NMR (400 MHz, CDCl3) δ 2.52-2.65 (m, 2H), 2.67-2.80 (m,
2H), 4.12 (d, 1H, J ) 1.8 Hz), 4.19 (d, 1H, J ) 1.8 Hz), 4.68 (s,
2H), and 7.20-7.39 (m, 5H). Treating a sample of 20 with
TFAA as described above produced 19 in 85% yield.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk en yl-
Su bstitu ted Su lfon a m id o F u r a n s. To a solution of either
the cyclic carbinol amide or the 4-oxopentanoic acid amide (5
mmol) in 5 mL of CH2Cl2 at -78 °C was added pyridine (25
mmol) followed by triflic anhydride (Tf2O) (10 mmol). The
reaction was allowed to warm to room temperature over 30
min and was stirred for 10 min. Water was added and the
organic layer was separated. The aqueous layer was extracted
with chloroform and the combined organic phase was washed
with water and brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was purified
by flash chromatography on silica gel using 20% ether/hexane
as the eluent.
35.0, 41.4, 90.5, 116.9, 134.6, and 174.9; HRMS calcd for C8H13
NO2 155.0946, found 155.0950.
-
Gen er a l P r oced u r e for th e P r ep a r a tion of 4-Oxop en -
ta n oic Acid Am id es. To a solution of lactone 5 (0.5 g, 5.1
mmol) in 10 mL of THF at 0 °C was added the appropriate
amine (5.6 mmol) dropwise. The reaction was allowed to warm
to room temperature and was stirred for 2 h. The solvent was
removed under reduced pressure, and the residue was purified
by flash chromatography on silica gel using 20% acetone/CHCl3
as the eluent.
4-Oxop en ta n oic a cid ben zyl a m id e (12) was prepared
in 74% yield from lactone 5 and benzylamine: 1H NMR (400
MHz, CDCl3) δ 2.10 (s, 3H), 2.45 (t, 2H, J ) 5.5 Hz), 2.82 (t,
2H, J ) 5.5 Hz), 4.40 (d, 2H, J ) 6.0 Hz), 6.10 (brs, 1H), and
7.20-7.35 (m, 5H). The spectral data of this compound is
identical to that reported in the literature.43
4-Oxop en ta n oic a cid a llyl a m id e (13) was prepared in
89% yield from lactone 5 and allylamine: 1H NMR (400 MHz,
CDCl3) δ 2.19 (s, 3H), 2.45 (t, 2H, J ) 6.4 Hz), 2.82 (t, 2H, J
) 6.4 Hz), 3.84-3.88 (m, 2H), 5.12 (dd, 1H, J ) 10.2, 1.4 Hz),
5.18 (dd, 1H, J ) 17.2, 1.4 Hz), 5.82 (ddt, 1H, J ) 17.2, 10.2,
,5.5 Hz), and 5.93 (brs, 1H). The spectral data of this compound
is identical to that reported in the literature.44
1,1′-Dia llyl-2,2′-d im et h yl-1,2,3,4,1′,2′-h exa h yd r o[2,3′]-
bip yr r olyl-5,5′-d ion e (18). To a solution of N-allyl pyrroli-
dinone 7 (0.05 g, 0.3 mmol) in benzene (2 mL) was added 0.006
g (0.03 mmol) of p-TsOH. The mixture was heated at reflux
for 5 h, allowed to cool, and concentrated under reduced
pressure. After purification by flash chromatography on silica
gel using 25% acetone/CHCl3 as the eluent, 0.014 g of 18 (33%
yield) was obtained as a yellow oil which consisted of a mixture
C,C,C-Tr iflu or o-N-m eth yl-N-(5-m eth yl-fu r an -2-yl)m eth -
a n esu lfon a m id e (28) was prepared in 60% yield from cyclic
carbinol amide 6: IR (neat) 1619, 1593, 1400, 1231, 1196, and
1128 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 3.40 (s,
3H), 5.97 (dd, 1H, J ) 3.2 and 1.0 Hz), and 6.18 (d, 1H, J )
3.2 Hz); 13C NMR (100 MHz CDCl3) δ 13.9, 40.1, 107.4, 107.6,
120.2 (q, J ) 322.4 Hz), 142.0, and 151.5; HRMS calcd for
C7H8F3NO3S 243.0177, found 243.0179.
(40) Woo, S.; Keay, B. Tetrahedron: Asymmetry 1994, 5, 1411.
Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477. Rogers, C.;
Keay, B. A. Can. J . Chem. 1992, 70, 2929. De Clercq, P. J .; Van Royen,
L. A. Synth. Commun. 1979, 9, 771. Fischer, K.; Hunig, S. J . Org.
Chem. 1987, 52, 564.
(41) For the preparation of compounds 8 and 17, see: Padwa, A.;
Crawford, K. R.; Rashatasakhon, P.; Rose, M. J . Org. Chem. 2003, 68,
2609.
N-Allyl-C,C,C-tr iflu or o-N-(5-m eth ylfu r an -2-yl)m eth an e-
su lfon a m id e (29) was prepared in 83% yield from 7 (or in
81% yield from 13): IR (neat) 1616, 1559, 1400, 1228, 1199,
1133, and 1055 cm-1 1H NMR (400 MHz, CDCl3) δ 2.26 (s,
;
3H), 4.27 (d, 2H, J ) 6.7), 5.19-5.23 (m, 1H), 5.24-5.26 (m,
1H), 5.83 (qt, 1H, J ) 10.2, 6.7 Hz), 5.97 (dd, 1H, J ) 3.2, 1.0
Hz), and 6.17 (d, 1H, J ) 3.2 Hz); 13C NMR (100 MHz, CDCl3)
(42) Wedler, C.; Costisella, B.; Schick, H. J . Prakt. Chem. 1990, 332,
557.
(43) Bryan J ones, J .; Young, J . M. Can. J . Chem. 1966, 44, 1059.
(44) Hilgenkamp, R.; Zercher, C. K. Tetrahedron, 2001, 57, 8793.
(45) J acobi, P. A.; Brielmann, H. L.; Hauck, S. I. J . Org. Chem. 1996,
61, 5013.
J . Org. Chem, Vol. 68, No. 13, 2003 5143

Padwa et al.
1
δ 13.9, 55.5, 107.4, 109.7, 120.1 (q, J ) 321.7 Hz), 120.9, 131.2,
140.1, and 151.9; HRMS calcd for C9H10F3NO3S 269.0333,
found 269.0338.
1694, 1637, 1547, 1453, and 1413 cm-1; H NMR (400 MHz,
CDCl3) δ 1.29 (qd, 1H, J ) 9.7, 3.8 Hz), 1.60-1.46 (m, 1H),
1.65 (qt, 1H, J ) 13.0, 9.7 Hz). 1.75-1.84 (m, 1H), 2.01 (dd,
1H, J ) 14.6, 5.4 Hz), 2.14-2.05 (m, 2H), 2.31 (d, 1H, J ) 5.7
Hz), 2.21-2.34 (m, 1H), 2.58 (dd, 1H, J ) 14.6, 7.3 Hz), 2.82-
2.92 (m 1H), 4.27-4.39 (m, 2H), 6.53 (brs, 1H), and 7.16-7.30
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 25.3, 28.0, 34.4, 36.6,
42.0, 43.4, 47.7, 127.3, 127.6, 128.6, 138.5, 171.9, and 212.6.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found:
C, 73.41; H, 7.85; N, 5.71.
N-Ben zyl-C,C,C-tr iflu or o-N-(5-m eth ylfu r a n -2-yl)m eth -
a n esu lfon a m id e (30) was prepared in 60% yield from 8 (or
in 79% yield from 12): IR (neat) 1619, 1497, 1404, 1209, 1141,
and 1027 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.21 (s, 3H), 4.82
(s, 2H), 5.85 (dd, 1H, J ) 3.2, 1.0 Hz), 5.91 (d, 1H, J ) 3.2
Hz), 7.20-7.27 (m, 2H), and 7.29-7.33 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 13.9, 56.5, 107.4, 110.2, 120.2 (q, J ) 321.1
Hz), 128.8, 129.1, 134.3, 139.7, and 151.8. Anal. Calcd for
N-(4-Meth oxyben zyl)-2-(2-oxocycloh exyl)acetam ide (43)
was obtained as a pale yellow solid in 86% yield: mp 114-
116 °C; IR (KBr) 1708, 1693, 1637, 1512, 1248, 1175, and 1036
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.40 (dq, 1H, J ) 12.7 and
3.8 Hz), 1.55-1.92 (m, 3H), 2.07 (dd, 1H, J ) 14.4, 4.8 Hz),
2.09-2.23 (m, 2H), 2.30-2.45 (m, 2H), 2.62 (dd, 1H, J ) 14.4,
7.7 Hz), 2.89-3.01 (m, 1H), 3.79 (s, 3H), 4.35 (qd, 2H, J )
10.6, 5.3 Hz), 6.03 (brs, 1H), 6.82-6.90 (m, 2H), and 7.17-
7.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.4, 28.2, 34.7,
36.9, 42.2, 43.2, 47.9, 55.4, 114.2, 129.2, 130.6, 159.1, 171.8,
and 212.7. Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N,
5.09. Found: C, 69.74; H, 7.67; N, 5.07.
N-Bu t-3-en yl-2-(2-oxocycloh exyl)a ceta m id e (44) was
obtained as a colorless oil in 45% yield: IR (neat) 1705, 1697,
1627, 1510, and 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.36
(qd, 1H, J ) 12.7, 3.8 Hz), 1.51-1.90 (m, 4H), 2.01 (dd, 1H, J
) 14.4, 5.0 Hz), 2.06-2.40 (m, 5H), 2.58 (dd, 1H, J ) 14.4, 7.7
Hz), 2.82-2.94 (m, 1H), 3.28 (q, 2H, J ) 6.5 Hz), 5.03-5.12
(m, 2H), 5.67-5.81 (m, 1H), and 5.90 (brs, 1H); 13C NMR (100
MHz, CDCl3) δ 25.5, 28.2, 33.9, 34.7, 37.0, 38.6, 42.3, 48.1,
117.3, 135.5, 171.9, and 212.8; HRMS calcd for C12H19NO2 [M
+ H]+ 210.1494, found 210.1497.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk yltet-
r a h yd r oben zofu r a n yltr iflu or oa ceta m id es. To a solution
of the appropriate ketoamide (1.2 mmol) in freshly distilled
CH2Cl2 (12.0 mL) was added pyridine (12.0 mmol) followed
by TFAA (2.5 mmol). The reaction mixture was stirred at room
temperature for 6 h. The solution was quenched by the
addition of water, and the organic layer was separated. The
aqueous layer was extracted with chloroform, and the com-
bined organic phase was washed with water and brine, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
on silica gel using 20% ether/hexane as the eluent.
C
13H12F3NO3S: C, 48.90; H, 3.79; N, 4.39. Found: C, 49.12;
H, 3.85; N, 4.42.
N-Bu t -3-en yl-C,C,C-t r iflu or o-N-(5-m et h ylfu r a n -2-yl)-
m eth a n esu lfon a m id e (31) was prepared in 75% yield from
14: IR (neat) 1619, 1558, 1402, 1230, 1196, 1131, and 1071
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 2.32 (q, 2H,
J ) 7.0 Hz), 3.74 (t, 2H, J ) 7.0 Hz), 5.07-5.09 (m, 1H), 5.10-
5.12 (m, 1H), 5.65-5.76 (m, 1H), 5.98 (dd, 1H, J ) 2.8, 0.8
Hz), and 6.19 (d, 1H, J ) 2.8 Hz); 13C NMR (100 MHz, CDCl3)
δ 13.9, 32.9, 52.1, 107.5, 109.9, 118.3, 120.1 (q, J ) 321.7),
133.3, 139.9, and 152.0. Anal. Calcd for C10H12F3NO3S: C,
42.40; H, 4.27; N, 4.94. Found: C, 42.41; H, 4.33; N, 4.89.
N-(3-Met h ylb u t -3-en yl)-C,C,C-t r iflu or o-N-(5-m et h yl-
fu r a n -2-yl)m eth a n esu lfon a m id e (32) was prepared in 62%
yield from 15: IR (neat) 1619, 1559, 1401, 1232, 1196, 1144,
and 1023 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 2.27
(d, 3H, J ) 1.0 Hz), 2.28 (t, 2H, J ) 7.4 Hz), 3.80 (dd, 2H, J )
7.4, 7.4 Hz), 4.71 (s, 1H), 4.83 (s, 1H), 5.99 (dd, 1H, J ) 3.1,
1.0 Hz), and 6.21 (d, 1H, J ) 3.1 Hz); 13C NMR (100 MHz,
CDCl3) δ 13.9, 22.4, 36.8, 51.1, 107.5, 109.9, 113.2, 120.2 (q, J
) 322.2 Hz), 140.0, 141.0, and 151.9. Anal. Calcd for C11H14F3-
NO3S: C, 44.44; H, 4.75; N, 4.71. Found: C, 44.16; H, 4.69;
N, 4.76.
N-Bu t-3-en yl-2,2,2-tr iflu or o-N-(5-m eth ylfu r a n -2-yl)a c-
eta m id e (41). To a cooled solution of 14 (0.1 g, 0.6 mmol) at
-78 °C in freshly distilled CH2Cl2 (5 mL) was added pyridine
(0.5 mL, 5.9 mmol) followed by TFAA (0.18 mL, 1.3 mmol).
The mixture was allowed to warm to room temperature over
30 min and was stirred for an additional 10 min. Water was
added, and the organic layer was separated. The aqueous layer
was extracted with chloroform, and the combined organic
phase was washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel
using 20% ether/hexane as the eluent. Furan 41 was obtained
in 76% yield (0.11 g) as a colorless oil: IR (neat) 1722, 1622,
1415, 1212, 1158, and 1023 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.25 (s, 3H), 2.29-2.38 (m, 2H), 3.72 (dd, 2H, J ) 7.6, 7.6
Hz), 5.02-5.12 (m, 2H), 5.66-5.79 (m, 1H), 5.96 (dd, 1H, J )
3.2, 1.2 Hz), and 6.08 (d, 1H, J ) 3.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 13.8, 31.8, 49.3, 107.1, 108.1, 116.2 (q, J ) 286.8 Hz),
117.7, 134.2, 142.0, 151.2, and 158.0 (q, J ) 35.1). Anal. Calcd
for C11H12F3NO2: C, 53.44; H, 4.89; N, 5.67. Found: C, 53.16;
H, 4.84; N, 5.62.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk yl-2-
(2-oxocycloh exyl)a ceta m id es. To a solution of 2-(2-oxocy-
clohexyl)acetic acid46 (1.0 g, 6.4 mmol) and the appropriate
amine (7.0 mmol) in CH2Cl2 (15 mL) was added EDCI (1.4 g,
7.0 mmol) in one portion, followed by DMAP (0.05 g). The
mixture was stirred at room temperature for 2 h and was
diluted with water. The organic phase was separated, and the
aqueous phase was extracted with CHCl3. The combined
organic phase was washed with 1 N HCl and brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica
gel (10% acetone/CHCl3).
2,2,2-Tr iflu or o-N-ben zyl-N-(4,5,6,7-tetr a h yd r oben zofu -
r a n -2-yl)a ceta m id e (46) was obtained in 77% yield as a
colorless oil: IR (neat) 1716, 1577, 1210, and 1161 cm-1; H
1
NMR (400 MHz, CDCl3) δ 1.66-1.90 (m, 4H), 2.30-2.39 (m,
2H), 2.49-2.58 (m, 2H), 4.83 (s, 2H), 5.81 (s, 1H), and 7.24-
7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.9, 23.0,
54.0, 108.2, 116.3 (q, J ) 286.8 Hz), 118.2, 128.2, 128.7, 128.9,
135.4, 141.4, 149.8, and 157.9 (q, J ) 35.5 Hz); HRMS calcd
for C17H16F3NO2 323.1133, found 323.1138.
2,2,2-Tr iflu or o-N-(4-m eth oxyben zyl)-N-(4,5,6,7-tetr a h y-
d r oben zofu r a n -2-yl)a ceta m id e (47) was obtained in 79%
yield as a colorless oil: IR (neat) 1716, 1513, 1251, 1209, and
1166 cm-1; H NMR (400 MHz, CDCl3) δ 1.66-1.75 (m, 2H),
1
1.78-1.87 (m, 2H), 2.30-2.37 (m, 2H), 2.48-2.55 (m, 2H), 3.78
(s, 3H), 4.73 (s, 2H), 5.76 (s, 1H), 6.80-6.86 (m, 2H), and 7.15-
7.22 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.9, 23.0,
53.5, 55.4, 108.2, 114.0, 116.2 (q, J ) 288.4 Hz), 118.1, 127.6,
130.5, 141.4, 149.7, 157.8 (q, J ) 35.1 Hz), and 159.6. Anal.
Calcd. for C18H18F3NO3: C, 61.19; H, 5.13; N, 3.96. Found: C,
61.35; H, 5.28; N, 4.04.
2,2,2-Tr iflu or o-N-(bu t-3-en yl)-N-(4,5,6,7-tetr ah ydr oben -
zofu r a n -2-yl)a ceta m id e (48) was obtained in 75% yield as
a colorless oil: IR (neat) 1713, 1577, 1205, and 1158 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.68-1.88 (m, 4H), 2.31-2.42 (m,
4H), 2.53 (t, 2H, J ) 6.0 Hz), 3.71 (t, 2H, J ) 7.3 Hz), 5.03-
5.13 (m, 2H), 5.50-5.68 (m, 1H), and 5.99 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 22.0, 22.9, 23.0, 23.1, 31.8, 49.3, 108.0,
116.2 (q, J ) 288.4 Hz), 117.6, 118.2, 134.2, 141.5, 149.8, and
N-Ben zyl-2-(2-oxocycloh exyl)a ceta m id e (42) was ob-
tained as a white solid in 80% yield: mp 110-112 °C; IR (KBr)
(46) Muthusamy, S.; Arulananda Babu, S.; Gunanathan, C.; Suresh,
E.; Dastidar, P.; Vir J asra, R. Tetrahedron 2000, 56, 6307.
5144 J . Org. Chem., Vol. 68, No. 13, 2003

Preparation of R-Trifluoromethylsulfonamido Furans
157.8 (q, J ) 35.9 Hz). Anal. Calcd for C14H16F3NO2: C, 58.53;
1401, 1322, 1245, and 1176 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.26-1.38 (m, 1H), 1.44-1.58 (m, 1H) 1.80-1.90 (m, 1H),
1.99-2.14 (m, 3H), 2.17 (dd, 1H, J ) 15.9, 9.8 Hz), 2.60 (dd,
1H, J ) 15.9, 8.9 Hz), 2.62-2.74 (m, 1H), 3.77 (s, 3H), 4.40 (d,
1H, J ) 15.2 Hz), 4.69 (d, 1H, J ) 15.2 Hz), 4.78 (q, 1H, J )
3.2 Hz), 6.80-6.85 (m, 2H), and 7.14-7.19 (m, 2H);13C NMR
(100 MHz, CDCl3) δ 22.5, 23.3, 28.1, 34.9, 37.0, 42.9, 55.4, 98.0,
114.0, 128.9, 129.0, 142.0, 159.0, and 174.8.
H, 5.61; N, 4.88. Found: C, 58.42; H, 5.63; N, 4.93.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk yltet-
r a h yd r oben zofu r a n yltr iflu or om eth a n esu lfon a m id es. To
a solution of the appropriate keto amide (0.8 mmol) in freshly
distilled CH2Cl2 (10 mL) was added pyridine (8.2 mmol)
followed by Tf2O (1.7 mmol). The reaction mixture was stirred
at room temperature for 6 h and was then quenched by the
addition of water. The organic layer was separated, and the
aqueous layer was extracted with chloroform. The organic
phase was washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel
using 20% ether/hexane as the eluent.
The second fraction (0.12 g, 12%) obtained from the column
was a pale yellow oil whose structure was assigned as 1-(4-
methoxybenzyl)-1,3,4,5,6,7-hexahydroindol-2-one (57): IR (neat)
1
1700, 1673, 1512, 1398, and 1248 cm-1; H NMR (400 MHz,
CDCl3) δ 1.56-1.70 (m, 4H), 1.98-2.10 (m, 4H), 2.92-3.00 (m,
2H), 3.76 (s, 3H), 4.54 (s, 2H), 6.79-6.85 (m, 2H), and 7.12-
7.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.5, 22.7,
23.5, 39.8, 42.8, 55.4, 111.1, 114.1, 128.7, 130.3, 137.5, 158.9,
and 177.2.
The third fraction (0.4 g, 40%) isolated from the column was
a colorless oil whose structure was assigned as 1-(4-methoxy-
benzyl)-1,4,5,6-tetrahydroindol-2-one (58): IR (neat) 1685,
1611, 1512, 1444, and 1247 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.88-0.98 (m, 1H), 1.14-1.31 (m, 2H) 1.66-1.78 (m, 1H),
1.84-1.94 (m, 1H), 2.01-2.12 (m, 1H), 2.20-2.30 (m, 1H),
2.60-2.68 (m, 1H), 3.49 (dd, 1H, J ) 11.4 and 6.0 Hz), 3.71 (s,
3H), 4.05 (d, 1H, J ) 15.2 Hz), 4.85 (d, 1H, J ) 15.2 Hz), 5.70
(s, 1H), 6.74-6.80 (m, 2H), and 7.07-7.13 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 23.0, 27.5, 28.4, 33.3, 42.9, 55.2, 61.2,
113.9, 118.0, 129.1, 130.0, 158.9, 162.4, and 171.4.
N-Ben zyl-C,C,C-tr iflu or o-N-(4,5,6,7-tetr a h yd r oben zo-
fu r a n -2-yl)m eth a n esu lfon a m id e (50) was obtained in 93%
yield as a colorless oil: IR (neat) 1570, 1406, 1221, 1145, and
1
1029 cm-1; H NMR (400 MHz, CDCl3) δ 1.58-1.65 (m, 2H),
1.70-1.77 (m, 2H), 2.21-2.26 (m, 2H), 2.41-2.46 (m, 2H), 4.77
(s, 2H), 5.79 (s, 1H), and 7.18-7.30 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 21.9, 22.8, 23.0, 56.4, 109.9, 118.5, 120.2 (q, J
) 323.6 Hz), 128.7, 128.8, 129.0, 134.5, 139.3, and 150.5;
HRMS calcd for C16H16F3NO3S 359.0803, found 359.0793.
N-(4-Meth oxyben zyl)-C,C,C-tr iflu or o-N-(4,5,6,7-tetr ah y-
d r oben zofu r a n -2-yl)m eth a n esu lfon a m id e (51) was ob-
tained in 81% yield as a colorless oil: IR (neat) 1614, 1398,
1224, 1139, and 1030 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.60-
1.70 (m, 2H), 1.76-1.84 (m, 2H), 2.26-2.34 (m, 2H), 2.46-
2.55 (m, 2H), 3.78 (s, 3H), 4.77 (s, 2H), 5.84 (s, 1H), 6.81-6.87
(m, 2H), and 7.13-7.19 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 21.9, 22.8, 23.0, 55.3, 56.1, 110.0, 114.1, 118.4, 120.2 (q, J )
323.5 Hz), 126.5, 130.5, 139.2, 150.4, and 159.9; HRMS calcd
for C17H18F3NO4S: 389.0909, found 389.0913.
N-Ben zyl-N-(5-m eth ylfu r a n -2-yl)a ceta m id e (62). A mix-
ture of cyclic carbinol 8 (0.1 g, 0.5 mmol) and pyridine (0.4
mL, 5.0 mmol) in CH2Cl2 (5.0 mL) was cooled at -78 °C. To
this solution was added Tf2O (0.07 mL, 0.53 mmol), the
mixture was allowed to stir for 30 min, and then Ac2O (0.07
mL, 0.75 mmol) was added. The reaction mixture was stirred
at room temperature overnight. The mixture was partitioned
between water and CHCl3. The organic phase was separated,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel using 25% ether/hexane as the eluent.
Furan 62 (0.027 g, 25%) was obtained as a colorless oil: IR
N-Bu t-3-en yl-C,C,C-tr iflu or o-N-(4,5,6,7-tetr a h yd r oben -
zofu r a n -2-yl)m eth a n esu lfon a m id e (52) was obtained in
80% yield as a colorless oil: IR (neat) 1570, 1403, 1224, 1196,
1
and 1133 cm-1; H NMR (400 MHz, CDCl3) δ 1.69-1.77 (m,
2H), 1.80-1.87 (m, 2H), 2.31-2.43 (m, 4H), 2.54 (t, 2H, J )
6.0 Hz), 3.74 (t, 2H, J ) 7.3 Hz), 5.08-5.16 (m, 2H), 5.66-
5.79 (m, 1H), and 6.11 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
22.0, 22.8, 22.9, 23.1, 33.0, 52.1, 109.8, 118.2, 118.6, 120.2 (q,
1
(neat) 1681, 1618 1571, 1380, 1289, 1208, and 1195 cm-1; H
NMR (400 MHz, CDCl3) δ 1.98 (s, 3H), 2.22 (d, 3H, J ) 1.0
Hz), 4.75 (s, 2H), 5.70 (d, 1H, J ) 1.0 Hz), 5.87 (dd, 1H, J )
3.2 and 1.0 Hz), and 7.20-7.29 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 13.8, 22.1, 51.6, 105.8, 106.9, 127.5, 128.5, 128.6,
137.5, 146.9, 149.8, and 171.9.
J
C
) 323.5 Hz), 133.4, 139.4, and 150.6. Anal. Calcd for
13H16F3NO3S: C, 48.29; H, 4.99; N, 4.33. Found: C, 48.51;
H, 4.96; N, 4.30.
7a -Hyd r oxy-1-(4-m eth oxyben zyl)-1,4,5,6,7,7a -h exa h y-
d r oin d ol-2-on e (54). To a solution of furan 47 (0.28 g, 0.8
mmol) in MeOH (5 mL) was added a solution of K2CO3 (0.55
g, 3.96 mmol) in 5 mL of water. The mixture was heated at
reflux for 2 h, cooled to room temperature, diluted with water,
and extracted with CHCl3. The combined organic phase was
washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was purified
by recrystallization from ether/hexane to give 54 (0.04 g, 19%)
as a white solid: mp 156-157 °C; IR (KBr) 1670, 1512, and
5-Meth yl-1-tr iflu or om eth a n esu lfon yl-2,3-d ih yd r o-1H-
in d ole (64). A solution of furan 31 (0.27 g, 0.95 mmol) in
toluene (5 mL) was heated in a sealed tube at 130 °C for 4 h.
The mixture was allowed to cool to room temperature and the
solvent was removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel to
give 64 (0.26 g, 96%) as a colorless oil: IR (neat) 1487, 1402,
1228, 1189, 1148, and 1059 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.32 (s, 3H), 3.17 (t, 2H, J ) 8.3 Hz), 4.20 (t, 2H, J ) 8.3
Hz), 7.01 (dd, 1H, J ) 8.3 and 1.0 Hz), 7.05 (d, 1H, J ) 0.6
Hz), and 7.30 (d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3)
δ 21.0, 28.2, 51.6, 114.4, 120.5 (q, J ) 323.2 Hz), 126.3, 128.7,
131.5, 135.1, and 137.5. Anal. Calcd for C10H10F3NO2S: C,
45.28; H, 3.80; N, 5.28. Found: C, 45.52; H, 3.90; N, 5.32.
5-Meth yl-2,3-d ih yd r o-1H-in d ole (65). To a solution of the
above dihydroindole 64 (0.2 g, 0.75 mmol) in ether (7.0 mL)
was added LiAlH4 (0.09 g, 2.26 mmol) in one portion. The
reaction was heated at reflux for 6 h, allowed to cool to 25 °C,
and slowly quenched by the addition of Na2SO4‚10H2O until
a white precipitate appeared. The mixture was filtered, and
the precipitate was washed with ether. The combined filtrate
was concentrated under reduced pressure, and the residue was
purified by flash chromatography on silica gel to give indoline
64 as a pale yellow oil in 90% yield: 1H NMR (400 MHz,
CDCl3) δ 2.23 (s, 3H), 3.01 (t, 2H, J ) 8.3 Hz), 3.56 (t, 2H, J
) 8.3 Hz), 4.34 (s, 1H), 6.65 (d, 1H, J ) 7.8 Hz), 6.86 (d, 1H,
1245 cm-1; H NMR (400 MHz, CDCl3) δ 0.91-1.06 (m, 1H),
1
1.12-1.30 (m, 1H), 1.50-1.75 (m, 2H), 1.87-2.00 (m, 1H),
2.01-2.12 (m, 1H), 2.41 (tdd, 1H, J ) 13.4, 5.5, 2.2 Hz), 2.55-
2.65 (m, 1H), 3.76 (s, 3H), 3.79 (brs, 1H), 4.24 (d, 1H, J ) 15.1
Hz), 4.64 (d, 1H, J ) 15.1 Hz), 5.61 (d, 1H, J ) 1.9 Hz), 6.76-
6.83 (m, 2H), and 7.20-7.28 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 21.5, 26.6, 27.7, 38.5, 41.2, 55.4, 89.3, 113.9, 117.4,
129.6, 131.4, 158.9, 163.9, and 170.4. Anal. Calcd for C16H19
NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 69.96; H, 7.31; N,
4.95.
-
1-(4-Me t h oxyb e n zyl)-1,3,3a ,4,5,6-h e xa h yd r oin d ol-2-
on e (56). A solution of γ-keto amide 43 (1.0 g, 3.9 mmol) in
xylene (2.0 mL) with a trace of p-TsOH was heated at 180 °C
for 2 h in a sealed tube. The reaction was allowed to cool to
room temperature and the mixture was subjected to a flash
chromatography on silica gel using 50% ether/hexane as the
eluent. The first fraction obtained from the column contained
0.25 g (25%) of 56 as a yellow oil: IR (neat) 1719, 1680, 1513,
J . Org. Chem, Vol. 68, No. 13, 2003 5145

Padwa et al.
J
) 7.8 Hz), and 6.97 (s, 1H). The spectral data of this
gel to give 69 (0.19 g, 98% yield) as a white solid: mp 82-83
°C; IR (KBr) 1495, 1390, 1253, 1195, 1148, and 1062 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.77-1.82 (m, 4H), 2.74 (brd, 4H, J
) 17.6 Hz), 3.15 (t, 2H, J ) 8.1 Hz), 4.18 (t, 2H, J ) 8.1 Hz),
6.96 (s, 1H), and 7.15 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
23.2, 23.3, 27.9, 29.3, 29.9, 51.7, 114.8, 120.5 (q, J ) 324.0
Hz), 126.1, 128.7, 134.3, 137.2, and 137.5. Anal. Calcd for
compound is identical to that reported in the literature.47
2,2,2-Tr iflu or o-1-(5-m eth yl-2,3-d ih yd r oin d ol-1-yl)eth a -
n on e (67). A solution of furan 41 (0.12 g, 0.95 mmol) in toluene
(2 mL) was heated in a sealed tube at 130 °C for 20 h. The
mixture was allowed to cool to room temperature, and the
solvent was removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel to
give 67 (0.11 g, 91%) as a white solid: mp 85-86 °C; IR (KBr)
C
13H14F3NO2S: C, 51.14; H, 4.62; N, 4.59. Found: C, 51.20;
H, 4.61; N, 4.63.
1686, 1487, 1442, 1252, 1203, 1141, and 1071 cm-1; H NMR
1
5,7-Dim eth yl-2-tr iflu or om eth a n esu lfon yl-10-oxa -2-a za -
tr icyclo[5.2.1.01,5]d ec-8-en e (70). A solution of furan 32 (0.13
g, 0.44 mmol) in toluene (4 mL) was heated in a sealed tube
at 130 °C for 36 h. The mixture was allowed to cool to room
temperature, and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel to give 70 (0.06 g, 46%) as a white solid:
mp 100-102 °C; IR (KBr) 1398, 1248, 1183, 1146, and 1107
(400 MHz, CDCl3) δ 2.34 (s, 2H), 3.21 (t, 2H, J ) 8.3 Hz), 4.22-
4.29 (m, 2H), 7.04-7.09 (m, 2H), and 8.07 (d, 1H, J ) 8.9 Hz);
13C NMR (100 MHz, CDCl3) δ 21.3, 28.5, 48.1, 116.0 (q, J )
288.1 Hz), 117.8, 125.7, 128.5, 131.9, 136.0, 139.5, and 154.0
(q, J ) 35.4 Hz). Anal. Calcd for C11H10F3NO: C, 57.64; H,
4.40; N, 6.11. Found: C, 57.61; H, 4.29; N, 5.99.
2,2,2-Tr iflu or o-1-(2,3,5,6,7,8-h exa h yd r ob en zo[f]in d ol-
1-yl)eth a n on e (68). A solution of furan 48 (0.2 g, 0.7 mmol)
in toluene (7.0 mL) was heated in a sealed tube at 130 °C for
12 h. The mixture was allowed to cool to room temperature,
and the solvent was removed under reduced pressure. The
crude residue was purified by flash chromatography on silica
gel to give 0.17 g (89%) of 68 as a white solid: mp 117-118
°C; IR (KBr) 1684, 1487, 1441, 1251, 1192, and 1137 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.75-1.84 (m, 4H), 2.76 (brd, 4H, J
) 16.2 Hz), 3.17 (t, 2H, J ) 8.3 Hz), 4.22 (dt, 2H, J ) 8.3, 1.0
Hz), 6.96 (s, 1H), and 7.92 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 23.3, 28.1, 29.5, 29.9, 48.1, 116.3 (q, J ) 287.6 Hz), 118.3,
125.3, 129.1, 135.0, 136.8, 139.4, and 153.9 (q, J ) 37.4 Hz).
Anal. Calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20.
Found: C, 62.46; H, 5.36; N, 5.27.
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.96 (s, 3H), 1.31 (d, 1 H,
J ) 11.4 Hz), 1.54 (s, 3H), 1.83 (d, 1H, J ) 11.4 Hz), 1.94 (ddd,
1H, J ) 12.4, 7.0, 1.2 Hz), 2.21 (q, 1H, J ) 11.4 Hz), 3.86-
4.00 (m, 2H), 6.24 (d, 1H, J ) 5.7 Hz), and 6.48 (d, 1H, J )
5.7 Hz); 13C NMR (100 MHz, CDCl3) δ 19.8, 21.7, 36.3, 47.8,
52.0, 52.6, 85.4, 105.7, 120.0 (q J ) 322.7 Hz), 132.3, and 139.0.
Anal. Calcd for C11H14F3NO3S: C, 44.44; H, 4.75; N, 4.71.
Found: C, 44.32; H, 4.76; N, 4.67.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (Grant No. CHE-
0132651). We thank our colleague, Dr. Kennneth Hard-
castle, for his assistance with the X-ray crystallographic
studies together with grants NSF CHE-9974864 and
NIH S10-RR13673.
1-Tr iflu or om eth a n esu lfon yl-2,3,5,6,7,8-h exa h yd r o-1H-
ben zo[f]in d ole (69). A solution of furan 52 (0.2 g, 0.6 mmol)
in toluene (6.0 mL) was heated in a sealed tube at 130 °C for
12 h. The mixture was allowed to cool to room temperature,
and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography on silica
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses to-
gether with an ORTEP drawing for compounds 19 and 36.
Preparation and characterization of compounds 9-11, 14-16,
33, 35-40, 45, 49, and 53. This material is available free of
charge via the Internet at http://pubs.acs.org.
(47) Nishiyama, T.; Suzuki, T.; Hashiguchi, Y.; Shiotsu, S.; Fujioka,
M. Polym. Degrad. Stab. 2002, 75, 549.
J O0341970
5146 J . Org. Chem., Vol. 68, No. 13, 2003