Cycloaddition across the benzofuran ring as an approach to the morphine alkaloids

Article abstract of DOI:10.1021/jo8016956

(Chemical Equation Presented) The intramolecular Diels-Alder reaction of several amidofurans tethered onto a benzofuran ring was examined as a strategy for the synthesis of morphine. Bromo substitution on the furan ring did not provide sufficient activation to allow the cycloaddition to take place across the aromatic benzofuran. However, the presence of a large o-methyl-benzyl group on the amido nitrogen atom causes the reactive s-trans conformation of the amidofuran to be highly populated, thereby facilitating its Diels-Alder cycloaddition across a tethered benzofuran.

Full text of DOI:10.1021/jo8016956

lenging framework of morphine and its potent derivatives insures
that any novel method that can rapidly construct polyfunction-
alized analogues, particularly C-ring derivatives, would be
attractive for both synthetic and medicinal chemistry.
Cycloaddition Across the Benzofuran Ring as an
Approach to the Morphine Alkaloids
Stefan France,† Jutatip Boonsombat, Carolyn A. Leverett,
and Albert Padwa*
Department of Chemistry, Emory UniVersity,
Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed July 30, 2008
Our synthetic approach toward the morphinan alkaloids was
guided by a longstanding interest in developing new applications
of the intramolecular [4 + 2]-cycloaddition of furans (IMDAF)
toward the synthesis of complex natural products.8 The yields
of intramolecular Diels-Alder reactions involving furan are
known to be highly sensitive to both diene and dienophile
substitution, as well as to the nature and length of the tether.9
In particular, substitution on the furan ring greatly affects the
chemical reactivity of these reactions.10 Several years ago we
began a synthetic program to provide general access to a variety
of alkaloids by [4 + 2]-cycloaddition of substituted 2-amid-
ofurans.8 Our recently completed synthesis of (()-erysotrami-
dine11 and (()-lycoricidine12 nicely demonstrates the utility of
this process for the construction of various alkaloids. Most
noteworthy is that the key reaction employed in our synthesis
of (()-strychnine involved a novel cycloaddition of the furan
ring across the 2,3-double bond of the indole ring (7-9).13 The
reaction was remarkably efficient given that two heteroaromatic
systems are compromised in the cycloaddition (Scheme 1).
In the context of extending the IMDAF cycloaddition toward
a synthesis of morphine, we wondered whether the furan ring
might also undergo cycloaddition across a tethered benzofuran.
The intramolecular Diels-Alder reaction of several amid-
ofurans tethered onto a benzofuran ring was examined as a
strategy for the synthesis of morphine. Bromo substitution
on the furan ring did not provide sufficient activation to
allow the cycloaddition to take place across the aromatic
benzofuran. However, the presence of a large o-methyl-
benzyl group on the amido nitrogen atom causes the
reactive s-trans conformation of the amidofuran to be
highly populated, thereby facilitating its Diels-Alder
cycloaddition across a tethered benzofuran.
Morphinan alkaloids, of which morphine (1) is representative,
are particularly important to the medical community given their
longstanding prescription as analgesics in the management of
severe pain and as anesthetics.1 The downside of employing
opiads as analgesics is the potential for physical and psychologi-
cal dependence associated with long-term use. Small variations
of the substituents in the core pentacycle (i.e., 2-6), particularly
in the C-ring, have profound effects on the biological response.
For example, 14-hydroxymorphinans such as naloxone (4) and
naltrexone (5) behave as potent analgesics and narcotic antago-
nists.2 Most synthetic derivatives have been prepared by
functional group manipulation around the C-ring. Unfortunately,
the preparation of these semisynthetic derivatives usually
requires transformation of the natural alkaloid into a common
intermediate such as noroxymorphone (6).2 In view of the
relative scarcity of natural sources, many synthetic approaches
and several total syntheses of morphine (1) have been reported,3-6
often including the synthesis of other morphinans.7 The chal-
(3) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R.
Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amster-
dam, 1996; Vol. 18, p 43.
(4) Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr.
Org. Chem. 2000, 4, 343.
(5) (a) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449. (b) Trost,
B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785. (c) Trost,
B. M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542. (d) Taber, D. F.; Neubert,
T. D.; Rheingold, A. L. J. Am. Chem. Soc. 2002, 124, 12416. (e) Hong, C. Y.;
Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028. (f) Uchida, K.;
Yokoshima, S.; Kan, T.; Fukuyama, T. Org. Lett. 2006, 8, 5311.
(6) For an excellent review and other syntheses, see: Zezula, J.; Hudlicky,
T. Synlett 2005, 388.
(7) (a) White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64,
7871. (b) Blakemore, P. R.; White, J. D. Chem. Commun. 2002, 1159.
(8) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998, 63,
5304. (b) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515. (c) Lynch, S. M.;
Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643. (d) Wang, Q.; Padwa, A. Org.
Lett. 2004, 6, 2189. (e) Padwa, A.; Ginn, J. D. J. Org. Chem. 2005, 70, 5197.
(f) Padwa, A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833.
(9) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179.
(10) (a) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999, 55,
13521. (b) Lipshutz, B. H. Chem. ReV. 1986, 86, 795.
† Current address: Department of Chemistry, Georgia Institute of Technology,
901 Atlantic Drive, Atlanta, GA 30322-0400.
(1) Lednicer, D. Central Analgesics; Wiley: New York, 1982; pp 137-
213.
(2) Szantay, G.; Dornyei, G. In The Alkaloids; Cordell, G. A.; Brossi, A.,
Eds.; Academic Press: New York, 1994; Vol. 45, pp 127-232.
(11) Padwa, A.; Wang, Q. J. Org. Chem. 2006, 71, 7391.
(12) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247.
(13) (a) Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279. (b)
Boonsombat, J.; Zhang, H.; Chughtai, M.; Hartung, J.; Padwa, A. J. Org. Chem.
2008, 73, 3539.
8120 J. Org. Chem. 2008, 73, 8120–8123
10.1021/jo8016956 CCC: $40.75 2008 American Chemical Society
Published on Web 09/13/2008

SCHEME 1
SCHEME 3
SCHEME 2
Five-membered heteroaromatics such as benzothiophene or
benzofuran have, despite their aromaticity, frontier orbital
energies and shapes similar to those of cyclopentadiene.14 The
reactivity of the heteroaromatic dienophile is, however, sharply
decreased because of the loss of aromaticity in the cycloaddition
transition state. Nevertheless, the remarkable rate enhancement
observed by incorporating an sp2 center in the furanyl tether15
combined with our recent success with cycloadditions across
indolyl-substituted π-systems16 prompted us to examine possible
synthetic applications of this reaction.
Our projected approach toward morphine features an IMDAF
reaction of 2-amidofuran 10 across a substituted benzofuran ring
(Scheme 2). The close proximity of both heteroaromatic systems
and the high reactivity associated with the internal cycloaddition
should facilitate the proposed reaction. Although benzofurans
are rarely employed as 2π-partners in Diels-Alder chemistry,
there is a report published by Ciganek in 1981 describing an
intramolecular Diels-Alder reaction of a tethered diene deriva-
tive across the benzofuran ring.17 If successful, our intention
was to convert the oxabicyclic ring system found in the resulting
cycloadduct 11 to the corresponding ketal 12 and then close
the final B-ring of morphine from 12 making use of a procedure
reported by Rapoport18 and Evans.19 Accordingly, we decided
to study the facility of this process using some model substrates
prior to commencing with the synthesis of morphine.
cloaddition rate for 5-bromo-substituted furans was recently
investigated by Houk and Pieniazek using quantum mechanical
calculations.21 The increased rate of cycloaddition for 5-bromo-
substituted furans when compared to the unsubstituted examples
was attributed to an increase in reaction exothermicity.21 This
both decreased the activation enthalpy and increased the barrier
to retrocycloaddition. Bromine substitution on furan also
increased reactant energy and stabilized the product due to the
preference of the electronegative halogen atom to be attached
to a more highly alkylated and therefore more electropositive
framework. With this in mind, we decided to investigate the
IMDAF reaction of bromofuranyl amide 13. Unfortunately, all
of our attempts to effect the cycloaddition of 13 only resulted
in the removal of the labile t-butyl group to give 14. Thermal
conditions (heating at 180 °C in xylene), microwave assistance,
and the addition of several Lewis acids failed to promote the
desired cycloaddition. Similarly, our attempts to cycloadd across
the benzofuran ring using the related N-(2-methylbenzyl)imide
15 also failed to produce a cycloadduct (Scheme 3).
We also studied the thermolysis of the simpler benzofuranyl
amides 16 and 18, which are devoid of the bromo group, but
now have the nitrogen atom attached directly to the furan ring.
The only product isolated from heating a sample of the Boc
amidofuran 16 to 120 °C corresponded to the NH-amide 17.
However, the thermolysis of 18 in toluene at 120 °C gave the
rearranged cycloadduct 19 in 55% yield. It would seem as
The rate enhancement in the Diels-Alder reaction of furans
by incorporating a bromine or another halogen group at the
5-position of the heteroaromatic ring appears to be a general
phenomenon.20 The origin of the increased bimolecular cy-
(14) Del Bene, J.; Jaffe, H. H. J. Chem. Phys. 1968, 48, 4050.
(15) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(16) (a) Mej´ıa-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241. (b) Padwa,
A.; Lynch, S. M.; Mej´ıa-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70, 2206.
(17) Ciganek, E. J. Am. Chem. Soc. 1981, 103, 6261.
(18) Moos, W. H.; Gless, R. D.; Rapoport, H. J. Org. Chem. 1983, 48, 227.
(19) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285.
(20) (a) Klepo, Z.; Jakopcic, K. J. Heterocycl. Chem. 1987, 1787. (b)
Crawford, K. R.; Bur, S. K.; Straub, C. S.; Padwa, A. Org. Lett. 2003, 5, 3337.
(21) (a) Pieniazek, S. N.; Houk, K. N. Angew. Chem., Int. Ed. 2006, 45,
1442. (b) Padwa, A.; Crawford, K. R.; Straub, C. S.; Pieniazek, S. N.; Houk,
K. N. J. Org. Chem. 2006, 71, 5432.
J. Org. Chem. Vol. 73, No. 20, 2008 8121

N-(2-(Benzofuran-3-yl)acetyl)-5-bromo-N-(2-methylbenzyl)fu-
ran-2-carboxamide (15). To a stirred suspension containing 0.29 g
(1.5 mmol) of 5-bromo-2-furoic acid and 4 Å molecular sieves in
7 mL of CH2Cl2 were added 0.26 mL (3.0 mmol) of oxalyl chloride
and 2 drops of DMF. The reaction mixture was stirred at rt for
1.5 h, filtered over Celite, and concentrated under reduced pressure.
The residue was dissolved in 3 mL of THF, and the solution was
added to a stirred suspension containing 0.2 g (1.65 mmol) of
2-methylbenzylamine and 4 Å molecular sieves in 7 mL of THF.
The reaction mixture was stirred at rt for 1.5 h, filtered over Celite,
diluted with H2O, and extracted with EtOAc. The organic layer
was washed with a saturated aqueous NaHCO3 solution, dried
over MgSO4, filtered, and concentrated to provide 0.4 g (91%)
of 5-bromo-N-(2-methylbenzyl)furan-2-carboxamide as a yellow
solid: mp 86-88 °C; IR (thin film) 3287, 3125, 3064, 2925,
1646, 1597, 1530, 1471, 1306, 1125, 1012, 927, 798, and 740
though the presence of the large o-methylbenzyl group on the
amido nitrogen causes the reactive s-trans conformer to be
highly populated, thereby promoting the intramolecular cy-
cloaddition. Apparently, bromo substitution on the furan ring
is not important enough a factor to allow the [4 + 2]-cycload-
dition to occur with aromatic benzofurans of type 13 or 15.
In summary, the intramolecular [4 + 2]-cycloaddition reaction
of several amidofurans tethered onto a benzofuran ring was
examined as a strategy for the synthesis of morphine. Although
the cycloaddition failed using furanyl amides of type 13 and
15, the presence of a large o-methylbenzyl group on the amido
nitrogen atom of the related carboxamide 18 facilitates the
cycloaddition across the tethered benzofuran ring. Further
application and extension of the methodology is currently
ongoing in our laboratory and will be reported in due course.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H), 4.61 (d, 2H,
J ) 5.2 Hz), 6.39 (br s, 1H), 6.44 (dd, 1H, J ) 3.6 and 0.8 Hz),
7.10 (d, 1H, J ) 3.6 Hz), and 7.21-7.31 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 19.3, 41.6, 114.4, 117.0, 124.6, 126.5,
128.3, 129.1, 130.9, 135.5, 136.9, 150.0, and 157.1.
Experimental Section
5-Bromofuran-2-carboxylic acid (2-Benzofuran-3-yl-ethyl)-
tert-butylamide (13). To a solution of 2-benzofuran-3-yl-ethanol22
(6.2 g, 38 mmol) in CH2Cl2 (200 mL) at 0 °C were added Et3N
(8.0 mL, 57 mmol) and TsCl (8.4 g, 44 mmol). The resulting
solution was allowed to slowly warm to rt and was then stirred for
12 h. At the end of this time, the reaction mixture was washed
with H2O, dried over Na2SO4, and concentrated under reduced
pressure to give 10.1 g (84%) of the crude tosylate that was
immediately used in the next step. The crude tosylate was dissolved
in 160 mL of MeCN and was treated sequentially with NaHCO3
(8.1 g, 96 mmol) and tert-butylamine (8.4 mL, 80 mmol). The
resulting suspension was warmed to 55 °C for 2 h. The mixture
was then cooled to rt and was treated with additional NaHCO3 (8.1
g, 96 mmol) and tert-butylamine (8.4 mL, 80 mmol). After heating
for an additional 8 h at 55 °C, the suspension was cooled to rt,
filtered through a pad of Celite, and concentrated under reduced
pressure to leave behind a tan oil. The crude (2-benzofuran-3-yl-
ethyl) tert-butylamine solidified upon standing in the freezer (5.0
g, 72%) and was used directly in the next step without further
purification.
To a stirred solution containing 0.5 g (1.7 mmol) of the above
amide and 0.33 mL (2.3 mmol) of Et3N in 15 mL of THF was
added 0.45 g (2.3 mmol) of 2-(benzofuran-3-yl)acetyl chloride
dropwise. The mixture was heated at reflux for 18 h, cooled to rt,
concentrated under reduced pressure, and purified by silica gel
chromatography to give 0.13 g (20%) of carboxamide 15: 1H NMR
(CDCl3, 400 MHz) δ 2.26 (s, 3H), 4.08 (s, 2H), 5.05 (s, 2H), 6.39
(d, 1H, J ) 3.9 Hz), 6.95 (d, J ) 3.6 Hz, 1H), 6.98-7.04 (m, 2H),
7.11 (d, J ) 3.6 Hz, 2H), 7.21 (t, J ) 7.4 Hz, 1H), 7.28 (dt, J )
7.8 and 1.4 Hz, 1H), 7.44 (d, J ) 8.0 Hz, 1H), 7.49 (d, J ) 7.6 Hz,
1H), and 7.58 (s, 1H); HRMS calcd for C23H18NO4Br 451.0419,
found 451.0438.
tert-Butyl 2-(benzofuran-3-yl)acetyl(furan-2-yl)carbamate (16).
To a solution containing 0.4 g (2.2 mmol) of furan-2-yl carbamic
acid tert-butyl ester in 10 mL of THF at 0 °C was added dropwise
0.96 mL (2.4 mmol) of n-BuLi (2.5 M in hexane). The reaction
mixture was stirred at 0 °C for 20 min. In a separate flask, 0.38 g
(2.2 mmol) of benzofuran-3-acetic acid was dissolved in 15 mL of
THF and 0.24 mL (2.2 mmol) of 4-methylmorpholine at 0 °C, and
then 0.29 mL (2.2 mmol) of isobutyl chloroformate was added
dropwise. After stirring for 5 min, the white precipitate that
formed was removed by filtration and was washed with 10 mL
of THF. The filtrate was cooled to 0 °C, and the preformed
lithiate obtained from the above Boc carbamate was added
dropwise via syringe. After stirring at 0 °C for 20 min, the
reaction mixture was quenched with H2O and extracted with
EtOAc. The organic layer was washed with saturated aqueous
NaHCO3 solution, dried over MgSO4, and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography to afford 0.45 g (60%) of 16 as a white solid:
mp 72-74 °C; IR (film) 3125, 2980, 1787, 1747, 1257, 1152,
To a solution of the above amine (0.44 g, 2.0 mmol) and Et3N
(0.5 mL, 3.6 mmol) in 15 mL of CH2Cl2 at 0 °C was added a cooled
solution of 5-bromo-2-furoyl chloride (0.4 g, 2.0 mmol) in CH2Cl2
(5 mL) dropwise. After warming to rt over 1 h, the reaction mixture
was subjected to normal aqueous workup. The crude product was
purified by silica gel flash chromatography to give 13 (0.84 g, 73%)
as a pale yellow oil: IR (neat) 1639, 1476, 1452, 1012 and 744
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.61 (s, 9H), 3.07 (t, 2H, J
) 8.1 Hz), 3.83 (t, 2H, J ) 8.1 Hz), 6.32 (d, 1H, J ) 3.4 Hz), 6.86
(d, 1H, J ) 3.4 Hz), 7.17-7.34 (m, 2H), 7.40 (d, 1H, J ) 8.1 Hz),
7.46 (d, 1H, J ) 7.5 Hz), and 7.51 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 26.8, 28.7, 45.7, 58.2, 111.5, 113.2, 116.8, 118.0, 119.2,
122.4, 123.0, 124.3, 127.6, 141.8, 151.7, 155.2, and 160.7; HRMS
calcd for C19H20BrNO3 389.0627, found 389.0625.
1
1094, and 744 cm-1; H NMR (CDCl3, 400 MHz) δ 1.42 (s,
9H), 4.25 (d, 2H, J ) 0.8 Hz), 6.13 (dd, 1H, J ) 3.2 and 0.8
Hz), 6.41 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.22-7.33 (m, 3H),
7.46 (d, 1H, J ) 8.0 Hz), 7.57 (d, 1H, J ) 8.0 Hz), and 7.66 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 27.7, 32.6, 84.2, 106.0,
111.3, 111.4, 112.9, 119.8, 122.5, 124.3, 127.8, 140.6, 143.3,
143.5, 151.4, 155.6, and 171.9; HRMS calcd for C19H19NO5
341.1263, found 341.1257.
3-Bromofuran-2-carboxylic acid (2-Benzofuran-3-ylethyl) amide
(14). Heating a sample of the above amide 13 at 180 °C in xylene
for 12 h afforded the secondary amide 14 in 72% isolated yield as
a pale yellow oil: IR (film) 3298 (br), 1649, 1597, 1530, 1472,
1453, 1305, 1094, 1010, and 747 cm-1 1H NMR (600 MHz,
;
CDCl3) δ 3.00 (t, 2H, J ) 6.6 Hz), 3.75 (q, 2H, J ) 6.6 Hz), 6.42
(d, 1H, J ) 3.6 Hz), 6.48 (br s, 1H), 7.06 (d, 1H, J ) 3.6 Hz), 7.26
(t, 1H, J ) 7.2 Hz), 7.32 (t, 1H, J ) 7.2 Hz), 7.49 (d, 1H, J ) 7.8
Hz), 7.50 (s, 1H), and 7.60 (d, 1H, J ) 7.8 Hz); 13C NMR (150
MHz, CDCl3) δ 24.0, 38.7, 111.6, 114.1, 116.5, 117.1, 119.4, 122.6,
124.3, 124.5, 127.7, 141.8, 149.8, 155.4, and 157.3; HRMS calcd
for C15H12BrNO3 333.0001, found 333.0003.
2-(Benzofuran-3-yl)-N-furan-2-ylacetamide (17). To a solution
containing 0.44 g (1.3 mmol) of benzofuran 16 in 10 mL of CH3CN
was added 0.46 g (2.1 mmol) of magnesium perchlorate. The
solution was heated to 45 °C for 1.5 h, then cooled to room
temperature, and the solvent was removed under reduced pressure.
The residue was subjected to flash silica gel chromatography to
afford 0.11 g (34%) of 17 as a white solid: mp 104-106 °C; IR
(film) 3242, 3208, 3061, 1668, 1557, 1452, 1097, and 746 cm-1
;
(22) Albancz-Walker, J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 1999, 40, 4917.
1H NMR (CDCl3, 400 MHz) δ 3.78 (s, 2H), 6.31 (m, 2H), 6.97 (s,
8122 J. Org. Chem. Vol. 73, No. 20, 2008

1H), 7.26 (t, 1H, J ) 7.6 Hz), 7.33 (t, 1H, J ) 7.6 Hz), 7.50 (d,
1H, J ) 7.6 Hz), 7.55 (d, 1H, J ) 7.6 Hz), 7.64 (s, 1H), and 7.86
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 31.7, 95.8, 111.5, 111.8,
113.1, 119.5, 123.2, 125.1, 127.0, 135.5, 143.5, 144.7, 155.4, and
166.2; HRMS calcd for C14H11NO3 241.0739, found 241.0750.
2-(Benzofuran-3-yl)-N-furan-2-yl-N-(2-methylbenzyl)aceta-
mide (18). To a solution containing 0.1 g (0.42 mmol) of the above
primary amide 17 in 10 mL of DMF at 0 °C was added 0.017 g
(0.42 mmol) of NaH. The mixture was stirred for 2 h at 0 °C, and
then a solution of 0.12 g (0.5 mmol) of R-iodo o-xylene in 5 mL
of DMF at 0 °C was added by cannula. The reaction mixture was
stirred at 0 °C for 3 h, then quenched with water and extracted
with EtOAc. The combined organic layer was dried over Na2SO4,
and the solvent was removed under reduced pressure. The crude
residue was purified by flash silica gel column chromatography to
provide 0.073 g (51%) of the titled compound as a pale yellow oil:
IR (film) 3122, 3061, 2925, 1683, 1608, 1501, 1453, 1180, 1156,
1097, and 744 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.19 (s, 3H),
3.63 (s, 2H), 4.88 (s, 2H), 5.85 (d, 1H, J ) 3.2 Hz), 6.30 (dd, 1H,
J ) 3.2 and 1.6 Hz), 7.05-7.36 (m, 7H), 7.42-7.45 (m, 2H), and
7.52 (d, 1H, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 18.9,
29.6, 49.4, 105.6, 111.2, 111.3, 113.6, 119.8, 122.5, 124.3, 125.8,
127.5, 127.6, 129.1, 130.2, 134.4, 136.5, 140.2, 142.7, 147.6, 155.1,
and 170.8; HRMS calcd for C22H19NO3 345.1365, found 345.1361.
1-(2-Methylbenzyl)-8a,10-dihydrobenzofuro[3,2-d]indole-
2,9(1H,3H)-dione (19). A solution containing 0.073 g (0.21 mmol)
of furanyl amide 18 in 5 mL of toluene was heated at reflux for
18 h. After cooling to rt, the solution was concentrated under
reduced pressure. The resulting residue was purified by flash silica
gel chromatography to provide 0.04 g (55%) of the titled compound
19 as a yellow solid: mp 174-175 °C; IR (thin film) 3046, 2926,
1
1727, 1673, 1475, 1465, 1397, 1212, and 748 cm-1; H NMR
(CDCl3, 400 MHz) δ 2.40 (s, 3H), 2.77 (ddd, 1H, J ) 18.0, 7.2,
and 1.6 Hz), 2.89 (d, 1H, J ) 17.2 Hz), 2.94 (dd, 1H, J ) 18.0
and 2.8 Hz), 3.08 (d, 1H, J ) 17.2 Hz), 4.68 (d, 1H, J ) 16.0 Hz),
4.71 (d, 1H, J ) 1.6 Hz), 4.90 (d, 1H, J ) 16.0 Hz), 4.92 (dd, 1H,
J ) 7.2 and 2.8 Hz), 6.90 (t, 1H, J ) 8.0 Hz), 6.96 (t, 1H, J ) 7.2
Hz), 7.09 (d, 2H, J ) 7.2 Hz), 7.15-7.26 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 19.5, 35.2, 42.2, 45.8, 51.8, 86.3, 94.9, 110.7, 122.0,
123.0, 126.4, 126.7, 127.9, 130.3, 130.5, 130.9, 132.9, 135.7, 142.3,
158.2, 172.5, and 201.0; HRMS calcd for C22H19NO3 345.1365,
found 345.1368.
Acknowledgment. We appreciate the financial support pro-
vided by the National Science Foundation (CHE-0742663).
Supporting Information Available: 1H and 13C NMR data
of various key compounds lacking CHN analyses. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO8016956
J. Org. Chem. Vol. 73, No. 20, 2008 8123