An efficient synthesis of furyl sulfonamides from the reaction of furan with in situ generated N-tosyl imines

Article abstract of DOI:10.1016/S0040-4020(03)00766-X

Treatment of an aldehyde and furan with N-sulfinyl-p-toluenesulfonamide/zinc chloride leads to the formation of furyl sulfonamides via an in situ generated N-tosyl imine intermediate. In one case, a novel 4-tosylamino-5,6-dihydro-4H-3-oxa-benz[e]azulene w

Full text of DOI:10.1016/S0040-4020(03)00766-X

Tetrahedron 59 (2003) 4939–4944
An efficient synthesis of furyl sulfonamides from the reaction of
furan with in situ generated N-tosyl imines
†
*
Albert Padwa, Atsuhiku Zanka, Michael P. Cassidy and Joel M. Harris
Department of Chemistry, Emory University, 1515 Pierce Drive, Atlanta, GA 30322, USA
Received 17 March 2003; accepted 14 May 2003
Abstract—Treatment of an aldehyde and furan with N-sulfinyl-p-toluenesulfonamide/zinc chloride leads to the formation of furyl
sulfonamides via an in situ generated N-tosyl imine intermediate. In one case, a novel 4-tosylamino-5,6-dihydro-4H-3-oxa-benz[e]azulene
was obtained by intramolecular aromatic substitution of the activated imine at the 3-position of the furan ring. q 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
toluenesulfonamide in the presence of a Lewis acid and that
the in situ formed N-sulfonyl imines could be efficiently
trapped with several dienes in a [4þ2]-cycloaddition
reaction (Scheme 1).7 As part of our cycloaddition program,
we envisioned using the Kresze/Weinreb protocol to
generate various activated imines in the presence of furan
with the hope of inducing a Diels–Alder reaction across the
furan ring so as to ultimately generate 1,6-dihydro-2H-
pyridin-3-ones (8) via the rearrangement of the transient
[4þ2]-cycloadduct 7 (Scheme 2). A trial reaction of imine 6
(R¼iPr), generated by treating isobutyraldehyde with
N-sulfinyl-p-toluenesulfonamide14 and zinc chloride in
THF, with furan gave no signs of any product derived
from a [4þ2]-cycloaddition. However, the reaction proved
to be extremely efficient and gave rise to a single product in
83% isolated yield whose structure was established as
furanyl p-toluenesulfonamide 9 as evidenced from its
spectral properties (Scheme 3). The structure of 9 was
unequivocally established by an X-ray crystallographic
study. Presumably, the formation of 9 occurs by initial
activation of tosyl imine 6 with zinc chloride followed by
The imino Diels–Alder reaction has become a highly useful
tool for the construction of a variety of tetrahydropyridines.1
Both inter- and intramolecular versions of this cycloaddition
have been widely utilized in alkaloid synthesis.2 Imines,
however, are relatively unreactive dienophiles unless the
cycloaddition is catalyzed by protonation of the imine3 or
when the imine is complexed by a Lewis acid.4 A good
alternative for simple imines in the [4þ2]-cycloaddition is
to utilize the more reactive acyl imine (4)5 or sulfonyl imine
(5).6 Previous studies with these imines have demonstrated
that a variety of dienes can be used for the imino-Diels–
Alder reaction.7,8 Our ongoing efforts dealing with the
synthesis of biologically active alkaloids have been based,
in part, on the use of substituted amido furans for
intramolecular Diels–Alder cycloaddition chemistry.9
Although furans10 and isobenzofurans11 are frequently
employed as 4p-substrates, little is known about the imino
Diels–Alder reaction of furans with activated imines. As a
consequence of our ongoing efforts in this area, we thought
it might be possible to access a variety of alkaloid natural
products by employing an imino Diels–Alder cycloaddition
of furans with activated imines (i.e. Scheme 2).
2. Results and discussion
A number of years ago both Kresze12 and Weinreb13
showed that non-enolizable aldehydes could be converted to
the corresponding N-tosyl imines (i.e. 6) using N-sulfinyl-p-
Keywords: N-tosyl imine; furyl sulfonamide; dihydro-4H-3-oxa-
benz[e]azulene; furan; heteroaromatic; substitution.
*
Corresponding author. Tel.: þ1-404-727-0283; fax: þ1-404-727-6629;
e-mail: chemap@emory.edu
NIH Postdoctoral fellow, grant GM 64027-0.
†
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00766-X

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A. Padwa et al. / Tetrahedron 59 (2003) 4939–4944
Scheme 2.
Scheme 3.
electrophilic aromatic substitution on the heteroaromatic
framework of furan.15 The reaction proved to be quite
general and proceeded smoothly with a variety of aldehydes
to furnish p-toluenesulfonamides 10-16 in ca. 80% yield
(Table 1). Previous work by Ciufolini and Wood16 provides
good precedence for the observed reaction since these
workers demonstrated that the reaction of a-hydroxy
amides with furan afforded N-acyl 2-furylamines in good
yield. Similarly, imino acetates have been found to react
with furan under thermal conditions to furnish furfuryl
amines.17
Table 1.
Entry
Aldehyde
Product
Yield (%)
81
a
b
77
It was also possible to synthesize a related furyl sulfonamide
(e.g. 19) by condensation of furfural (17) with p-toluene-
sulfonamide using p-TsOH as the Lewis acid (Scheme 4).
Treatment of the resulting imine 18 with methyl magnesium
iodide produced 19 in 95% yield. Furyl sulfonamides such
as 10-16 (and 19) are useful substrates for alkaloid synthesis
as they readily undergo the aza-Achmatowicz reaction, a
process defined as the conversion of furyl amides into 1,6-
dihydro-2H-pyridin-3-ones.18 This novel rearrangement has
been used for the synthesis of azasaccharides,19 izidine
structures, b-lactam intermediates, trisubstituted piper-
idines20 and unusual amino acids. In fact, 6-methoxy-2-
methyl-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-
one (21) could be prepared from furyl sulfonamide 19 in 2
steps in 72% overall yield (Scheme 4). The stereochemical
assignment of 21 as the cis-isomer is based on NMR
spectroscopic analysis (1D NOE). The exclusive formation
of 21 can be rationalized by assuming the A1,3-strain
between the two substituents and the tosyl group forces the
methoxy and methyl groups to adopt a pseudoaxial
orientation.
c
80
73
d
e
f
82
81
g
81
In an attempt to enhance the desired [4þ2]-cycloaddition of
a tosyl imine across the furan ring, we attempted to carry out

A. Padwa et al. / Tetrahedron 59 (2003) 4939–4944
4941
Scheme 4.
Figure 1. Ortep drawing of N-(5,6-dihydro-4H-3-oxa-benzo[e]azulen-4-
yl)-4-methyl-benzenesulfonamide (26).
Scheme 5. Reagents: (a) CH2vCHCH2OH, DMF, C6H5CH2N(C2H5)3Cl, NaHCO3, Pd(OAc)2, 83%; (b) (EtO)3CH, NBS, EtOH, 92%; (c) 2-furanylB(OH)2,
Pd(PPh3)4, benzene, Na2CO3, 89%; (d) thiourea, EtOH, H2O, 50%; (e) TsNSO, ZnCl2, CH2Cl2, 97%.
an intramolecular Diels–Alder reaction (IMDAF).21 Not
only do IMDAF reactions allow for the preparation of
complex oxygenated polycyclic compounds, but they often
proceed at lower temperatures than their intermolecular
counterparts. With this in mind, we investigated the ZnCl2-
induced reaction of aldehyde 25 with N-sulfinyl-p-toluene-
sulfonamide with the hope of obtaining an IMDAF product.
Synthesis of the required aldehyde 25 was carried out in 5
steps from commercially available starting materials
(Scheme 5). Thus, treatment of 2-bromo-iodobenzene with
allyl alcohol, benzyltriethylammonium chloride and
palladium(II) acetate afforded 3-(2-bromophenylpropional-
dehyde (22) in 83% yield.22 Protection of 22 as the diethoxy
acetal 23 proceeded uneventfully in 92% yield. Coupling of
the furan segment to the aromatic ring was accomplished
using 2-furanboronic acid and palladium tetrakis(triphenyl-
phosphine) which afforded 3-(2-furan-2-ylphenyl)propion-
aldehyde (25) after hydrolysis of acetal 24. The reaction
of 25 with N-sulfinyl-p-toluenesulfonamide and zinc
chloride delivered a single product in 97% yield which
was assigned as the unusual fused furan 26 based upon
its spectroscopic properties. This structure was unequi-
vocally established by an X-ray crystallographic study (see
Fig. 1).
In conclusion, our attempts to carry out an imino
Diels–Alder reaction between a tosyl imine and a furan
remain elusive. We have, however, developed an efficient
synthesis of furyl sulfonamides from the reaction of
aldehydes with N-sulfinyl-p-toluenesulfonamide and furan.
The synthesis proved to be quite general with respect to the
starting aldehyde used. In one case, a novel 4-tosylamino-
5,6-dihydro-4H-3-oxabenz[e]azulene was obtained by intra-
molecular aromatic substitution of the activated imine at the
3-position of the furan ring. The scope and generality of this
cyclization will be the subject of future investigations.
3. Experimental
3.1. General
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise
noted, all reactions were performed in flame dried glassware
under an atmosphere of dry argon. Solutions were
evaporated under reduced pressure with a rotary evaporator
and the residue was chromatographed on a silica gel column
using an ethyl acetate/hexane mixture as the eluent unless

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A. Padwa et al. / Tetrahedron 59 (2003) 4939–4944
specified otherwise. All solids were recrystallized from
ethyl acetate/hexane for analytical data.
(m, 5H), and 7.57 (d, J¼8.1 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 21.8, 41.3, 53.2, 107.9, 110.4, 127.1, 127.2,
128.7, 129.6, 129.7, 136.4, 137.7, 142.1, 143.3, and 152.5.
Anal. calcd for C19H19NO3S: C, 66.84; H, 5.61; N, 4.10.
Found: C, 66.74; H, 5.63; N, 4.07.
3.1.1. N-(1-Furan-2-yl-2-methyl-propyl)-4-methyl-ben-
zenesulfonamide (9). To a solution containing 1.9 g
(9 mmol) of N-sulfinyl-p-toluenesulfonamide in 12 mL of
THF was added 0.6 mL (6 mmol) of isobutyraldehyde,
0.9 mL (12 mmol) of furan and 12 mL of ZnCl2 in THF
(0.5 M) at 08C. After stirring at 08C for 2 h and at 258C for
16 h, 24 mL of CH2Cl2 was added to the reaction mixture.
The solution was subjected to flash silica gel chromato-
graphy in order to remove the ZnCl2. The eluent was
concentrated under reduced pressure and the residue was
purified by flash silica gel chromatography to give 9 as a
white solid: mp 119–1208C; IR (KBr) 3266, 1437, 1322,
3.1.5. N-(1-Furan-2-yl-2-propyl)-4-methyl-benzenesul-
fonamide (13). The title compound was prepared in 73%
yield; mp 92–938C; IR (KBr) 3257, 1425, 1322, and
1161 cm21
;
1H NMR (CDCl3, 300 MHz) d 0.81 (t,
J¼7.2 Hz, 3H), 1.79 (dt, J¼7.5, 7.2 Hz, 2H), 2.36 (s, 3H),
4.31 (dd, J¼8.1, 7.5 Hz, 1H), 5.23 (d, J¼8.7 Hz, 1H), 5.90
(d, J¼3.3 Hz, 1H), 6.09 (dd, J¼3.3, 2.1 Hz, 1H), 7.11–7.12
(m, 1H), 7.17 (d, J¼8.1 Hz, 2H), and 7.62 (d, J¼8.1 Hz,
2H); 13C NMR (CDCl3, 75 MHz) d 10.3, 21.6, 28.2, 53.3,
107.0, 110.0, 127.1, 129.5, 137.9, 141.9, 143.1, and 153.1.
Anal. calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01.
Found: C, 60.17; H, 6.11; N, 4.95.
1
and 1164 cm21; H NMR (CDCl3, 300 MHz) d 0.78 (d,
J¼6.6 Hz, 3H), 0.93 (d, J¼6.6 Hz, 3H), 2.02 (dd, J¼6.9,
6.6 Hz, 1H), 2.39 (s, 3H), 4.13 (dd, J¼9.6, 7.2 Hz, 1H), 5.36
(d, J¼9.3 Hz, 1H), 5.79 (d, J¼3.0 Hz, 1H), 6.03 (dd, J¼3.0,
1.8 Hz, 1H), 7.09–7.12 (m, 1H), 7.13 (d, J¼7.8 Hz, 2H),
and 7.58 (d, J¼8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d
19.0, 19.1, 21.7, 33.2, 57.9, 107.5, 110.1, 127.2, 129.5,
137.9, 141.7, 143.1, and 152.7. Anal. calcd for
C15H18NO3S: C, 61.41; H, 6.53; N, 4.77. Found: C, 61.42;
H, 6.51; N, 4.73.
3.1.6. N-(1-Furan-2-yl-2,2-dimethyl-propyl)-4-methyl-
benzenesulfonamide (14). The title compound was pre-
pared in 42% yield; mp 179–1818C; IR (KBr) 3260, 1433,
1
1324, and 1163 cm21; H NMR (CDCl3, 300 MHz) d 0.91
(s, 9H), 2.31 (s, 3H), 4.04 (d, J¼10.2 Hz, 1H), 5.49 (d,
J¼10.2 Hz, 1H), 5.72 (d, J¼3.3 Hz, 1H), 5.98 (dd, J¼3.0,
1.2 Hz, 1H), 7.05 (d, J¼1.2 Hz, 1H), 7.07 (d, J¼8.1 Hz,
2H), and 7.51 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 21.7, 26.8, 35.8, 61.0, 108.1, 110.0, 127.1, 129.4,
137.5, 141.4, 143.0, and 152.1. Anal. calcd for
C16H21NO3S: C, 62.51; H, 6.89; N, 4.56. Found: C, 62.45;
H, 6.85; N, 4.65.
3.1.2. N-(1-Furan-2-yl-3-phenylpropyl)-4-methyl-
benzenesulfonamide (10). The title compound was pre-
pared in 81% yield; mp 93–948C; IR (KBr) 3303, 1454,
1
1314, and 1156 cm21; H NMR (CDCl3, 300 MHz) d 2.10
(dd, J¼7.8, 7.5 Hz, 2H), 2.38 (s, 3H), 2.54–2.61 (m, 2H),
4.43 (dd, J¼8.4, 7.2 Hz, 1H), 5.42 (d, J¼8.7 Hz, 1H), 5.93
(d, J¼3.0 Hz, 1H), 6.12 (dd, J¼3.0, 1.8 Hz, 1H), 7.09 (d,
J¼6.9 Hz, 2H), 7.14–7.28 (m, 4H), 7.17 (d, J¼8.1 Hz, 2H),
and 7.63 (d, J¼8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d
21.7, 32.1, 36.7, 51.5, 107.3, 110.2, 126.3, 127.2, 128.7,
129.6, 137.9, 141.1, 142.1, 143.3, 153.0. Anal. calcd for
C15H18NO3S: C, 67.58; H, 5.95; N, 3.94. Found: C, 67.49;
H, 6.02; N, 4.04.
3.1.7. N-(1-Furan-2-yl-2-methyl-butyl)-4-methyl-
benzenesulfonamide (15). The title compound was
prepared in 81% yield; mp 75–768C; IR (KBr) 3270,
1436, 1324, and 1162 cm21; 1H NMR (CDCl3, 300 MHz) d
0.73–0.92 (m, 6H), 1.01–1.14 (m, 1H), 1.29–1.54 (m, 1H),
1.75–1.81 (m, 1H), 2.34 (s, 3H), 4.19–4.29 (m, 1H), 5.29 (t,
J¼9.6 Hz, 1H), 5.78 (d, J¼3.3 Hz, 1H), 6.03–6.05 (m, 1H),
7.09 (d, J¼1.5 Hz, 1H), 7.13 (dd, J¼8.4, 1.5 Hz, 2H), and
7.57 (dd, J¼8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d
11.4, 11.6, 15.3, 15.5, 21.7, 25.7, 26.0, 39.7, 56.4, 76.9,
107.3, 107.6, 110.0, 110.1, 127.1, 129.5, 137.9, 141.7,
143.1, 152.5, and 153.0. Anal. calcd for C16H21NO3S: C,
62.51; H, 6.89; N, 4.56. Found: C, 62.32; H, 6.79; N, 4.74.
3.1.3. N-[3-(2-Bromophenyl)-1-furan-2-yl-propyl]-4-
methyl-benzenesulfonamide (11). The title compound
was prepared in 77% yield; mp 78–798C; IR (KBr) 3250,
1470, 1320, and 1160 cm21; 1H NMR (CDCl3, 300 MHz) d
2.07 (dd, J¼7.2, 1.8 Hz, 2H), 2.37 (s, 3H), 2.58–2.80 (m,
2H), 4.46 (dt, J¼9.0, 6.9 Hz, 1H), 5.27 (d, J¼9.0 Hz, 1H),
5.97 (d, J¼3.0 Hz, 1H), 6.12 (dd, J¼3.3, 1.8 Hz, 1H), 7.04
(dt, J¼7.8, 2.1 Hz, 1H), 7.14–7.19 (m, 3H), 7.18 (d,
J¼8.1 Hz, 2H), 7.48 (dd, J¼7.8, 0.9 Hz, 1H), and 7.63 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.8, 32.7,
35.1, 51.6, 107.4, 110.3, 124.6, 127.3, 127.8, 128.2, 129.7,
130.8, 133.1, 137.9, 140.5, 142.2, 143.4, and 152.9. Anal.
calcd for C20H20BrNO3S: C, 55.30; H, 4.64; N, 3.22. Found:
C, 55.09; H, 4.56; N, 3.08.
3.1.8. N-(1-Cyclohex-3-enyl-1-furan-2-yl-methyl)-4-
methyl-benzenesulfonamide (16). The title compound
was prepared in 81% yield; mp 86–888C; IR (KBr) 3281,
1437, 1331, and 1159 cm21; 1H NMR (CDCl3, 300 MHz) d
1.13–1.48 (m, 1H), 1.69–2.22 (m, 6H), 2.34 (s, 3H), 4.17–
4.24 (m, 1H), 5.41 (dt, J¼7.2, 2.7 Hz, 1H), 5.52 (d,
J¼9.6 Hz, 1H), 5.61 (s, 1H), 5.78 (dd, J¼10.8, 3.3 Hz, 2H),
6.01–6.04 (m, 1H), 7.09 (dd, J¼1.8, 0.6 Hz, 1H), 7.12 (dd,
J¼8.1, 1.5 Hz, 2H), and 7.56 (dd, J¼8.1, 2.1 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 21.7, 25.0, 25.2, 25.4, 28.4, 28.5,
38.4, 38.5, 56.1, 56.4, 107.7, 107.8, 110.0, 125.6, 125.9,
127.0, 127.1, 127.3, 130.0, 137.9, 141.9, 143.1, and 152.3.
Anal. calcd for C18H21NO3S: C, 65.23; H, 6.39; N, 4.23.
Found: C, 65.08; H, 6.41; N, 4.32.
3.1.4. N-(1-Furan-2-yl-2-phenylethyl)-4-methyl-
benzenesulfonamide (12). The title compound was pre-
pared in 80% yield; mp 110–1118C; IR (KBr) 3261, 1423,
1
1320, and 1155 cm21; H NMR (CDCl3, 300 MHz) d 2.38
(s, 3H), 3.08 (dd, J¼7.2, 3.0 Hz, 1H), 4.66 (dt, J¼7.8,
7.2 Hz, 1H), 5.14 (d, J¼8.1 Hz, 1H), 5.86 (d, J¼3.6 Hz,
1H), 6.11 (dd, J¼3.3, 1.8 Hz, 1H), 6.92 (dd, J¼5.7, 2.4 Hz,
1H), 7.14–7.19 (m, 3H), 7.15 (d, J¼5.7 Hz, 2H), 7.17–7.21
3.1.9. N-(1-Furan-2-yl-ethyl)-4-methyl-benzenesulfona-
mide (19). A 28.1 g (292 mmol) sample of furfural (17),

A. Padwa et al. / Tetrahedron 59 (2003) 4939–4944
4943
300 mL of toluene, p-toluenesulfonamide (40 g, 234 mmol)
and p-toluenesulfonic acid (0.5 g, 2.9 mmol) were placed in
a round bottom flask with a Dean Stark trap and heated at
reflux for 10 h. The reaction turned a deep brown color.
After 10 h, charcoal was added to the hot solution and the
mixture was stirred for 1 h and filtered. The solvent was
removed under reduced pressure to give N-furan-2-
aqueous NaHCO3 solution (25 mL) and 40 mL of ether was
added. The solution was extracted with ether, the layers
were separated, and the organic layer was dried (MgSO4).
Concentration under reduced pressure and purification by
silica gel chromatography gave 0.89 g (3.0 mmol, 85%) of
6-methoxy-2-methyl-1-(toluene-4-sulfonyl)-1,6-dihydro-
2H-pyridin-3-one (21); mp 113–1158C; IR (thin film) 1692,
1
ylmethylene-4-methyl-benzenesulfonamide (18) as
a
1597, 1453, 1340, 1168, 1080, and 1014 cm21; H NMR
brown solid. Recrystallization from benzene gave pure
brown crystals of 18 in 85% yield (62 g, 248 mmol); mp
100–1018C; IR (thin film) 1605, 1542, 1467, 1319, 1289,
(400 MHz, CDCl3) d 1.56 (d, 3H, J¼7.6 Hz), 2.38 (s, 3H),
3.57 (s, 3H), 4.30 (q, 1H, J¼7.6 Hz), 5.58 (dd, 1H, J¼4.8,
0.8 Hz), 5.82 (dd, 1H, J¼10.4, 0.8 Hz), 6.82 (dd, 1H,
J¼10.4, 4.8 Hz), 7.24 (dd, 2H, J¼8.0, 1.2 Hz), and 7.56
(dd, 2H, J¼8.0, 1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 20.8, 21.5, 56.0, 57.2, 80.7, 126.6, 126.8, 130.0, 136.1,
142.5, 144.1, and 195.5. Anal. calcd for C14H17NO4S:
C, 56.93; H, 5.81; N, 4.75. Found: C, 56.81; H, 5.69; N,
4.70.
1
1089, and 1023 cm21; H NMR (400 MHz, CDCl3) d 2.41
(s, 3H), 6.63 (dd, 1H, J¼2.8, 1.6 Hz), 7.33 (m, 3H), 7.73 (d,
1H, J¼1.6 Hz), 7.86 (dd, 2H, J¼6.8, 2.8 Hz) and 8.80 (s,
1H); 13C NMR (100 MHz, CDCl3) d 21.5, 113.7, 124.7,
128.0, 128.2, 129.7, 135.1, 144.5, 149.7, and 155.6.
The above compound (1.0 g, 4.0 mmol) was dissolved in
15 mL of THF and cooled to 08C and methyl magnesium
bromide (2.7 mL of a 3.0 M solution (8.0 mmol)) was added
to the solution. The reaction was quenched with a saturated
aqueous NaHCO3 solution (30 mL) and 30 mL of ether was
added. The solution was extracted with ether, the layers
were separated, and the organic layer was dried (MgSO4).
Concentration under reduced pressure and purification by
silica gel chromatography gave 1.0 g (3.8 mmol, 95%) of N-
(1-furan-2-yl-ethyl)-4-methyl-benzenesulfonamide (19):
mp 72–738C (lit.23 mp 72–72.38C); IR (thin film) 1599,
3.1.11. 3-(2-Bromophenyl)propionaldehyde (22).
A
solution containing 14.2 g (50 mmol) of 2-bromo-iodo-
benzene, 8.7 g (150 mmol) of allyl alcohol, 10.5 g
(125 mmol) of sodium hydrogencarbonate, 11.4 g
(50 mmol) of benzyltriethylammonium chloride and
0.24 g (1 mmol) of palladium (II) acetate in 50 mL of
DMF was stirred at 458C for 20 h. The reaction mixture was
cooled to room temperature and the precipitate was
removed by filtration, followed by addition of 250 mL of
CH2Cl2 and 100 mL of water. The layers were separated and
the aqueous layer was extracted with 100 mL of CH2Cl2.
The combined organic layers were washed several times
with water and brine, and concentrated under reduced
pressure. The residue was subjected to flash silica gel
chromatography to afford 8.8 g (83%) of 22 as a
colorless oil: 1H NMR (CDCl3, 300 MHz) d 2.80 (dt,
J¼7.5, 1.2 Hz, 2H), 3.07 (t, J¼7.5 Hz, 2H), 7.06–7.12 (m,
1H), 7.24–7.27 (m, 2H), 7.55 (d, J¼7.5 Hz, 1H), and 9.84
(t, J¼1.2 Hz, 1H).
1
1427, 1333, 1152, and 1093 cm21; H NMR (400 MHz,
CDCl3) d 1.41 (d, 3H, J¼7.2 Hz), 2.37 (s, 3H), 4.52 (ddd,
1H, J¼14.8, 7.2, 7.2 Hz), 5.37 (d, 1H, J¼8.4 Hz), 5.97 (dd,
1H, J¼3.2, 0.8 Hz), 6.12 (dd, 1H, J¼3.2, 1.6 Hz), 7.14 (dd,
1H, J¼1.6, 0.8 Hz), 7.21 (d, 2H, J¼8.4 Hz), and 7.68 (d,
2H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3) d 20.7, 21.4,
47.2, 106.0, 109.9, 126.9, 129.3, 137.5, 143.0, 141.7, and
154.0.
3.1.10. 6-Methoxy-2-methyl-1-(toluene-4-sulfonyl)-1,6-
dihydro-2H-pyridin-3-one (21). A 0.39 g (1.1 mmol)
sample of sulfonamide 19, 4 mL of CH2Cl2, and m-CPBA
(0.39 g, 2.3 mmol) were placed in a round bottom flask and
the mixture was stirred for 2 h. The reaction was quenched
with a saturated aqueous NaHCO3 solution (15 mL) and
15 mL of ether was added. The solution was extracted with
ether, the layers were separated, and the organic layer was
dried (MgSO4). Concentration under reduced pressure and
purification by silica gel chromatography gave 0.27 g
(0.96 mmol, 85%) of 6-hydroxy-2-methyl-1-(toluene-4-
sulfonyl)-1,6-dihydro-2H-pyridin-3-one (20); IR (thin
film) 1686, 1597, 1449, 1332, 1165, 1110, and
3.1.12. 1-Bromo-2-(3,3-diethoxypropyl)benzene (23). A
solution containing 6.4 g (30 mmol) of aldehyde 22,
10.0 mL of triethyl orthoformate (60 mmol) and 0.11 g of
N-bromosuccinimide (0.6 mmol) in 90 mL of ethanol was
stirred at room temperature for 1 h. After removal of the
solvent under reduced pressure, 100 mL of ether and 50 mL
of 10% of NaOH in water were added to the residue. The
layers were separated and the aqueous layer was extracted
with 50 mL of ether. The combined organic layers were
washed with 50 mL of brine. After removal of the solvent
under reduced pressure, the residue was subjected to flash
silica gel chromatography to give 7.9 g (92%) of 23 as a
yellow oil: IR (neat) 2974, 2877, 1471, and 1128 cm21; 1H
NMR (CDCl3, 300 MHz) d 1.23 (t, J¼7.2 Hz, 6H),
1.92–1.99 (m, 2H), 2.79–2.84 (m, 2H), 3.45–3.58 (m,
2H), 3.61–3.73 (m, 2H), 4.54 (t, J¼5.4 Hz, 1H), 7.03–7.08
(m, 1H), 7.22–7.24 (m, 2H), and 7.53 (d, J¼7.8 Hz, 1H);
13C NMR (CDCl3, 75 MHz) d 15.6, 31.7, 33.7, 61.3, 66.1,
102.4, 124.7, 127.7, 127.9, 130.7, 133.1, and 141.3; MS (EI)
m/z 286 (M)þ, 241, 197, 195, 171, 169, 103.
1006 cm21
;
1H NMR (400 MHz, CDCl3) d 1.59 (d,
J¼7.2 Hz, 3H), 2.38 (s, 3H), 3.82 (bs, 1H), 4.36 (q, 1H,
J¼7.2 Hz), 5.90 (dd, 1H, J¼4.8, 1.2 Hz), 5.96 (dd, 1H,
J¼10.0, 1.2 Hz), 6.86 (dd, 1H, J¼10.4, 4.8 Hz), 7.25 (d, 2H,
J¼8.4 Hz), and 7.62 (d, 2H, J¼8.4 Hz); 13C NMR
(100 MHz, CDCl3) d 21.5, 22.1, 57.0, 73.3, 126.2, 126.7,
130.0, 136.5, 143.5, 144.3, and 195.3.
A 1.0 g (3.5 mmol) sample of 6-hydroxy-2H-pyridin-3-one
(20) was dissolved in 20 mL of CH2Cl2 and trimethyl
orthoformate (777 mL, 7.1 mmol) and BF3·OEt2 (45 mL,
0.36 mmol) were added to the solution. The solution was
stirred for 3 h at 08C and was quenched with a saturated
3.1.13. 2-[2-(3,3-Diethoxypropyl)phenyl]furan (24). To a
solution containing 7.2 g (25 mmol) of acetal 23, 3.4 g
(26 mmol) of 2-furanboronic acid and 0.6 g (0.25 mmol) of
tetrakis(triphenylphosphine) palladium (0) was added

4944
A. Padwa et al. / Tetrahedron 59 (2003) 4939–4944
dropwise 32 mL (125 mmol, 2 M) of sodium carbonate in
water. The reaction mixture was heated to 1008C for 2 h and
then cooled to room temperature. The precipitate was
removed by filtration and the product was extracted with
ether and washed with water. The aqueous layer was
extracted several times with ether. The combined organic
layers were washed several times with 10% of brine and
saturated brine and then concentrated under reduced
pressure. The residue was subjected to flash silica gel
chromatography to give 6.1 g (89%) of 24 as a yellow oil:
Acknowledgements
We gratefully acknowledge support of this work by the
National Science Foundation (CHE-0132651). We thank
our colleague, Dr Kennneth Hardcastle, for his assistance
with the X-ray crystallographic studies together with grants
NSF CHE-9974864 and NIH S10-RR13673.
IR (neat) 2974, 2879, 1484, and 1157 cm21 1H NMR
;
References
(CDCl3, 300 MHz) d 1.22 (t, J¼7.2 Hz, 6H), 1.89–1.97 (m,
2H), 2.89–2.95 (m, 2H), 3.44–3.54 (m, 2H), 3.61–3.66 (m,
2H), 4.53 (t, J¼5.7 Hz, 1H), 6.49 (dd, J¼3.3, 2.1 Hz, 1H),
6.61 (d, J¼3.3 Hz, 1H), 7.23–7.30 (m, 3H), 7.50 (d,
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126.4, 128.1, 128.5, 128.6, 130.3, 130.5, 139.2, 142.1, and
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