Construction of bicyclic tetrahydroisoquinolinones by combination of an IMDAF-ring cleavage reaction of N-allyl-2-furan-2-yl-acetamides

Article abstract of DOI:10.1139/v99-234

The intramolecular Diels-Alder reaction of furanyl amides from 2-furylacetic acid has been examined. Substrates containing either an imide or tertiary amide linkage between the furan and the dienophile underwent smooth cycloaddition upon thermolysis. By v

Full text of DOI:10.1139/v99-234

749
Construction of bicyclic tetrahydroisoquinolinones
by combination of an IMDAF-ring cleavage
reaction of N-allyl-2-furan-2-yl-acetamides
Albert Padwa and Thomas S. Reger
Abstract: The intramolecular Diels–Alder reaction of furanyl amides derived from 2-furylacetic acid has been exam-
ined. Substrates containing either an imide or tertiary amide linkage between the furan and the dienophile underwent
smooth cycloaddition upon thermolysis. By varying the reaction conditions, either the primary cycloadduct or the ring-
opened and acetylated product could be isolated in excellent yield. The stereochemical outcome of the IMDAF
cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. Semi-
empirical AM1 calculations show that the exo-cycloadduct is 11 kcal lower in energy than the corresponding endo
adduct and, presumably, some of this energy difference is reflected in the transition state for the cycloaddition. The
IMDAF reaction of N-allyl-[2-(3,4-dimethoxyphenethyl)]-2-furanyl-2-yl-acetamide proceeded in 90% yield upon heating
in xylene. The 4+2-cycloadduct undergoes ring-opening on treatment with base and the resulting alcohol was converted
into the corresponding benzyl ether. Raney nickel reduction followed by Bischler–Napieralski cyclization furnished the
tetracyclic skeleton of the berberine alkaloids.
Key words: intramolecular, cycloaddition, Diels–Alder, furanylamide, heterocycle.
Résumé : On a étudié la réaction de Diels–Alder intramoléculaire de furanylamides (« IMDAF ») dérivés de l’acide
furyl-2-acétique. Par thermolyse, les substrats comportant soit une liaison imide ou amide tertiaire entre le furane et le
diénophile subissent une cycloaddition facile. En faisant varier les conditions réactionnelles, on peut isoler avec un ex-
cellent rendement soit le cycloadduit primaire ou le produit dérivant d’une ouverture de cycle et d’une acétylation.
D’un point de vue stéréochimique, la cycloaddition « IMDAF » conduit à un produit dans lequel la chaîne latérale du
groupe alcényle prend une orientation syn par rapport au pont oxygéné. Des calculs semi-empiriques AM1 montrent
que l’énergie du cycloadduit exo est inférieure de 11 kcal par rapport à celle de l’adduit endo correspondant; il est
vraisemblable qu’une partie de cette différence d’énergie se reflète dans l’état de transition de la cycloaddition. La
réaction « IMDAF » du N-allyl-[2-(3,4-diméthoxyphénéthyl)]-2-furanyl-2-yl-acétamide se produit avec un rendement de
90% par chauffage dans le xylène. Le cycloadduit 4+2 subit une ouverture de cycle par traitement avec une base et
l’alcool qui en résulte a été transformé en éther benzylique correspondant. Une réduction à l’aide de nickel de Raney,
suivie d’une cyclisation de Bischler–Napieralski, conduit au squelette tétracyclique des alcaloïdes de la berbérine.
Mots clés : intramoléculaire, cycloaddition, Diels–Alder, furanylamide, hétérocycle. Padwa and Reger 756
Introduction
valuable synthetic intermediates which have been further
elaborated to substituted arenes, carbohydrate derivatives,
and various natural products (8–17). A crucial synthetic
transformation employing these oxabicyclic compounds in-
volves cleavage of the oxygen bridge to produce
functionalized cyclohexene derivatives (18–23). The
intramolecular Diels–Alder reactions of furans, often desig-
nated as IMDAF, has proven to be an extremely valuable
method for the construction of more complex oxygenated,
bicyclic structures (7). The IMDAF generally proceeds at
lower temperature than its bimolecular counterpart and,
more importantly, often allows for the use of unactivated
alkenes as dienophiles (24). Recent work in our laboratory
has shown that the intramolecular Diels–Alder of 2-amido
substituted furans such as 1 represents an effective route to
indolines and tetrahydroquinolines (25). This methodology
has also been utilized for the synthesis of the
hexahydroindolinone skeleton found in numerous alkaloids
(26). Intramolecular cycloaddition of the 2-amidofuran fol-
lowed by ring opening gives a zwitterionic intermediate 3
that can be channeled to different products depending on the
Furans are common substructures found in numerous nat-
ural products and are also present in many commercial prod-
ucts, including pharmaceuticals, fragrances, and dyes (1–4).
Furans also play an important role as intermediates in many
synthetic pathways, primarily because they react as a special
class of vinyl ethers (5, 6) or as dienes in the Diels–Alder
reaction (7). The resultant 7-oxabicyclo-[2.2.1]heptanes are
Received June 22, 1999. Published on the NRC Research
Press website on June 7, 2000.
This paper is dedicated to Stephen Hanessian on the occasion
of his 65th birthday and for his many significant
contributions to the art of organic synthesis.
A. Padwa1 and T.S. Reger. Department of Chemistry,
Emory University, Atlanta, GA 30322, U.S.A.
1Author to whom correspondence may be addressed.
Telephone: (404) 727-0283. Fax: (404) 727-6629.
e-mail: chemap@emory.edu
Can. J. Chem. 78: 749–756 (2000)
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Can. J. Chem. Vol. 78, 2000
Scheme 1.
Scheme 3.
Scheme 2.
ring-opening as a consequence of the acidic nature of the
protons adjacent to the oxygen bridge (Scheme 2). To the
best of our knowledge, amides derived from 2-furylacetic
acid have not been utilized in Diels–Alder chemistry. A
study to examine the synthesis of furans such as 6 and their
subsequent cycloaddition and ring-opening chemistry was
initiated with the intention of using this method as an entry
into the berberine alkaloid family (30). The biological activ-
ity that these molecules display varies widely and includes
anti-inflammatory, antimicrobial and antileukemic, as well
as antitumor, properties (30). In the light of these properties
and due to the general challenge that the construction of
complex alkaloids offers, the development of new methods
for the stereoselective synthesis of these nitrogen
heterocycles is of considerable interest. In this paper we re-
port the results of our IMDAF studies dealing with N-allyl
2-furan-2-yl-acetamides.
Results and discussion
As an entry into furanyl amides such as 6, 2-furylacetic
acid (10) was required as the key starting material. In our
hands, the most reliable synthesis corresponds to the one-pot
reaction between 2-furaldehyde and potassium cyanide (31).
Reaction of these two reagents in the presence of sodium
carbonate and glyoxal (sodium bisulfite addition compound
hydrate) in a 20:1 water:dioxane solution reproducibly gave
10 in 55% yield. Carboxylic acid 10 was converted to the N-
allyl amide 11 in 90% yield by reaction with 1,1-carbonyl-
diimidazole (CDI) followed by quenching with allylamine
(Scheme 3). The attempted Diels–Alder cycloaddition of 11
in refluxing toluene or xylene led only to recovered starting
material. This result is perfectly consistent with the earlier
reports of Jung (27) and Parker (28) who found that related
furans containing secondary amide tethers failed to undergo
the Diels–Alder reaction. Cycloaddition could be effected,
however, by heating 11 in refluxing acetic anhydride.2 Under
these conditions, the initial formation of imide 13 presumably
nature of the substituent group attached to the π-bond
(i.e., R1) (Scheme 1).
One of the most attractive features of this reaction se-
quence is the propensity for nitrogen assisted ring-opening
and subsequent iminium ion formation of the oxabicyclic
cycloadducts (i.e., 2 → 3). The majority of work carried out
by other investigators on the IMDAF reaction utilizing nitro-
gen containing tethers was done with furfurylamine derived
substrates whose cycloadducts are not predisposed to sponta-
neous ring-opening (27–29). As an extension of our earlier
work in this area, we believed that related furanyl amides
such as
6 should also be excellent substrates for
intramolecular Diels–Alder cycloaddition and oxabicyclic
2 The role of acetic anhydride in this reaction is to promote the [4+2]-cycloaddition by acylation at nitrogen as well as to assist in the subse-
quent oxa-bridge cleavage.
© 2000 NRC Canada

Padwa and Reger
751
Scheme 4.
Scheme 6.
Scheme 5.
Scheme 7.
Structure 1.
facilitates the Diels–Alder reaction to give the oxabicyclic
intermediate 14. The cycloadduct was not isolated as it un-
dergoes spontaneous ring-opening and O-acetylation to fur-
nish 12 as a single diastereomer in 85% yield (Scheme 4).
The trans relationship between the acetate and the bridge-
head hydrogen is derived from the presumed cycloadduct 14
which results from exo orientation of the tether during the
cycloaddition. This mode of cyclization for the IMDAF re-
action of substrates containing nitrogen in the tether is anal-
ogous to that reported by others for related furanyl systems
possessing short tethers (32, 33). The ring-opened acetate 12
is thus derived from an IMDAF cycloaddition where the side
arm of the tethered alkenyl group is oriented syn (exo) with
respect to the oxygen bridge. Products resulting from an
endo side arm transition state were neither detected nor iso-
lated. This result is not so surprising since, in these mobile
cycloaddition equilibria, the exo adducts are expected to be
thermodynamically more favored. Indeed, semi-empirical
AM1 calculations show that the exo-cycloadduct is 11 kcal
lower in energy than the corresponding endo (with respect to
the tether) adduct and, presumably, some of this energy dif-
ference is reflected in the transition state for cycloaddition.
We next turned our attention to determining whether a ter-
tiary amide linkage between the furan and alkene would al-
low the cycloaddition to proceed. Amide 15 was prepared in
94% yield by reaction of carboxylic acid 10 with CDI fol-
lowed by quenching with N-methylallylamine. Upon
thermolysis of 15 in acetic anhydride, the expected ring-
opened and acetylated lactam 16 was isolated in 83% yield
as a single diastereomer. The formation of 16 proceeds by a
similar pathway to that described for 13. Interestingly, when
amide 15 was heated in refluxing toluene, the primary
cycloadduct 17 was obtained in 85% yield, also as a single
diastereomer, and could be quantitatively converted to 16 by
heating in acetic anhydride (Scheme 5).
To further examine the scope of this cycloaddition with
respect to the dienophile, furan 18 containing an alkyne
tether was prepared in 86% yield. Heating a sample of 18 in
acetic anhydride gave the isoquinoline derivative 19 in 69%
yield (Scheme 6).
We next turned our attention to substrates bearing both a
dienophile and an electron-rich aromatic group connected to
the amide nitrogen (i.e., 23). It was envisioned that a
Bischler–Napieralski type cyclization (vide infra) could be
effected on the Diels–Alder cycloaddition product. To this
end, amide 20 was prepared in 87% yield by the usual reac-
tion of 2-furylacetic acid with CDI and quenching with 3,4-
dimethoxyphenethylamine. Unfortunately, all of our at-
tempts to alkylate 20 with allyl bromide using a variety of
bases (Cs2CO3 (DMF); NaH (THF); NaOH, K2CO3,
Bu4NHSO4) failed to give any product. Imide formation with
acryloyl chloride at room temperature in the presence of 4 Å
molecular sieves did produce cycloadduct 21, but only in
35% yield (Scheme 7).
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Can. J. Chem. Vol. 78, 2000
Scheme 8.
As an alternative route to 23, the known secondary amine
allyl-[2-(3,4-dimethoxyphenethylamine)] (22) (34) was pre-
pared and used to generate the desired tertiary amide di-
rectly. Thus, the reaction of carboxylic acid 10 with CDI
followed by addition of amine 22 gave the desired
cyclization precursor 23 in 77% yield. Upon heating 23 in
refluxing xylene, cycloadduct 24 was isolated in 90% yield
as a single diastereomer. A variety of bases were examined
to induce ring-opening of 24 to the allylic alcohol 25.
Triethylamine, sodium hydride, and potassium tert-butoxide
were all successful, but the use of the sodium in ethanol
gave the highest yield (92%) and cleanest reaction. We then
attempted a Bischler–Napieralski cyclization of the aromatic
ring onto the amide carbonyl of 25 but this gave only a com-
plex mixture of unidentifiable products. Instead, the alcohol
was protected as its benzyl ether with sodium hydride and
benzyl bromide in 83% yield. Compound 26 was then re-
duced to the decahydroisoquinoline 27 with Raney nickel in
85% yield. This compound was formed as a single
diastereomer and there is literature precedence for a similar
transformation in which Raney nickel reduction occurs from
the exo face of a bicyclic structure to yield a cis ring junc-
tion (35). The Bischler–Napieralski cyclization of 27 was ef-
fected with POCl3 followed by NaBH4 and furnished 9 in
52% yield (Scheme 8). The appearance of two singlets in the
smoothly and in high yield. The cyclization precursors are
easily synthesized from readily available starting materials.
The cycloaddition can be carried out under a variety of con-
ditions to yield either the primary cycloadduct or the ring-
opened and acetylated product. Consistent with previous
studies, only compounds bearing imide or tertiary amide
linkages between the furan and tethered dienophile were
suitable substrates for cycloaddition. Overall, this methodol-
ogy represents an efficient route to functionalized members
of the tetrahydroisoquinolinone ring system in various oxi-
dation states which could serve as intermediates to members
of the berberine alkaloid family. Applications toward spe-
cific natural products and the further development of the
IMDAF are currently underway and will be reported in due
course.
Experimental section
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 evapo-
rated under reduced pressure with a rotary evaporator, and
the residue was chromatographed on a silica gel column us-
ing an ethyl acetate – hexane mixture as the eluent unless
specified otherwise.
1
aromatic region of the H-NMR spectrum of 9 was indica-
tive that the desired cyclization had taken place. This reac-
tion proved to be very sensitive to the experimental
conditions and, unfortunately, even the use of freshly dis-
tilled POCl3 offered no advantage in terms of reaction yield.
Nevertheless, the tetracyclic compound 9 containing the core
skeleton of the berberine alkaloids was readily accessible in
just five steps from relatively simple cyclization precursors.
N-Allyl-2-furan-2-yl-acetamide (11): To a solution contain-
ing 1.4 g (11 mmol) of furan-2-yl-acetic acid (10) (31) in
25 mL of CH2Cl2 was added 2.0 g (12.6 mmol) of 1,1′-
carbonyldiimidazole. After stirring at room temperature for
1.5 h, 1.3 g (22 mmol) of allylamine was added and the mix-
ture was stirred for an additional 1 h. The mixture was con-
centrated under reduced pressure and the crude product was
purified by silica gel chromatography to give 1.6 g (90%) of
In conclusion, the intramolecular Diels–Alder reaction of
furanyl amides derived from 2-furylacetic acid proceeds
© 2000 NRC Canada

Padwa and Reger
753
4-Methyl-11-oxa-4-aza-tricyclo[6.2.1.01,6]undec-9-en-3-one (17):
A solution containing 1.6 g (8.8 mmol) of furan 15 in 15 mL
of toluene was heated at reflux for 20 h. The solution was
concentrated under reduced pressure and the crude solid was
purified by silica gel chromatography to give 1.3 g (85%) of
17 as a white solid, mp 89–90°C; IR (neat) ν : 1646, 1495,
11 as a pale yellow liquid; IR (neat) ν : 3290, 1652, 1545,
1
1418, and 1246 cm–1; H-NMR (400 MHz, CDCl3) δ : 3.64
(2H, s), 3.85–3.89 (2H, m), 5.08–5.14 (2H, m), 5.75–5.85
(1H, m), 5.95 (1H, brs), 6.24 (1H, d, J = 3.2 Hz), 6.36 (1H,
dd, J = 3.2 and 1.6 Hz), and 7.39 (1H, d, J = 1.6 Hz) ppm;
13C-NMR (100 MHz, CDCl3) δ : 36.1, 41.8, 108.5, 110.7,
116.0, 133.8, 142.4, 148.6, and 168.4 ppm; HRMS calcd for
C9H11NO2: 165.0790; found: 165.0787.
1
1394, and 1315 cm–1; H-NMR (400 MHz, CDCl3) δ : 1.44–
1.51 (2H, m), 1.85–1.91 (1H, m), 2.94 (1H, d, J = 18.8 Hz),
3.00 (3H, s), 3.14 (1H, d, J = 18.8 Hz), 3.31–3.34 (2H, m),
4.94 (1H, dd, J = 4.0 and 1.6 Hz), 6.14 (1H, d, J = 6.0 Hz),
and 6.40 (1H, dd, J = 6.0 and 1.6 Hz) ppm; 13C-NMR
(100 MHz, CDCl3) δ : 30.6, 35.0, 35.2, 35.5, 52.9, 78.1,
85.6, 137.3, 137.4, and 168.4 ppm. Anal. calcd. for
C10H13NO2: C 67.02, H 7.31, N 7.82; found: C 66.75, H
7.24, N 7.73.
7-Acetoxy-2-acetyl-1,7,8,8a-tetrahydro-2H-isoquinoline-3-one
(12): A solution containing 0.3 g (1.7 mmol) of 11 in 10 mL
of acetic anhydride was heated at reflux for 20 h. The solu-
tion was concentrated under reduced pressure and the crude
product was purified by silica gel chromatography to give
0.36 g (85%) of 12 as a white solid, mp 160–161°C; IR
1
(neat): 1734, 1676, 1467, 1371, and 1289 cm–1; H-NMR
2-Furan-2-yl-N-prop-2-ynyl-acetamide (18): To a solution
containing 0.8 g (6.4 mmol) of furan-2-yl-acetic acid (10) in
25 mL of CH2Cl2 was added 1.4 g (8.6 mmol) of 1,1′-
carbonyldiimidazole. After stirring at room temperature for
1.5 h, 0.6 mL (8.7 mmol) of propargylamine was added and
the mixture was stirred for an additional 1 h. The solution
was concentrated under reduced pressure and the crude
product was purified by silica gel chromatography to give
0.9 g (86%) of 18 as a white solid, mp 75–76°C; IR (neat)
ν : 3286, 1648, 1552, 1424, and 1240 cm–1; 1H-NMR
(400 MHz, CDCl3) δ : 2.23 (1H, t, J = 2.4 Hz), 3.63 (2H, s),
4.02 (2H, dd, J = 2.8 and 2.4 Hz), 6.23 (1H, d, J = 2.8 Hz),
6.34–6.36 (1H, m), 6.50 (1H, brs), and 7.38 (1H, s) ppm;
13C-NMR (100 MHz, CDCl3) δ : 29.1, 35.7, 71.4, 79.2,
108.4, 110.6, 142.3, 148.2, and 168.4 ppm. Anal. calcd. for
C9H9NO2: C 66.25, H 5.56, N 8.58; found: C 66.16, H 5.49,
N 8.61.
(400 MHz, CDCl3) δ : 1.46 (1H, dd, J = 12.8 and 11.6 Hz),
2.11 (3H, s), 2.30–2.35 (1H, m), 2.56 (3H, s), 2.69–2.76
(1H, m), 2.99 (1H, t, J = 12.8 Hz), 4.75 (1H, dd, J = 12.8
and 4.8 Hz), 5.55–5.59 (1H, m), 5.83 (1H, d, J = 2.0 Hz),
6.20 (1H, d, J = 10.0 Hz), and 6.35 (1H, dd, J = 10.0 and
2.0 Hz) ppm; 13C-NMR (100 MHz, CDCl3) δ : 21.0, 27.2,
31.9, 45.8, 68.6, 120.0, 127.3, 138.6, 151.0, 165.9, 170.2,
and 172.8 ppm. Anal. calcd. for C13H15NO4: C 62.64, H
6.07, N 5.62; found: C 62.52, H 6.09, N 5.54.
N-Allyl-2-furan-2-yl-N-methyl-acetamide (15): To a solution
of 0.6 g (4.8 mmol) of furan-2-yl-acetic acid (10) in 20 mL
of CH2Cl2 was added 1.0 g (6.4 mmol) of 1,1′-carbonyl-
diimidazole. After stirring for 1 h at room temperature, 0.7 g
(9.6 mmol) of N-methylallylamine was added and the mix-
ture was stirred for an additional 1 h. The solution was con-
centrated under reduced pressure and the crude product was
purified by silica gel chromatography to yield 0.8 g (94%) of
15 as a pale yellow oil which contained a mixture of amide
rotamers in solution; IR (neat) ν: 1652, 1477, 1396, and
2-Acetyl-7-acetoxy-1,4-dihydro-2H-isoquinolin-3-one (19):
A solution containing 0.2 g (1.4 mmol) of furan 18 in 10 mL
of acetic anhydride was heated at reflux for 24 h. The solu-
tion was concentrated under reduced pressure and the crude
residue was purified by silica gel chromatography to give
0.24 g (69%) of 19 as a pale yellow oil; IR (neat) ν: 1760,
1705, 1498, 1367, and 1208 cm–1; 1H-NMR (300 MHz,
CDCl3) δ : 2.32 (3H, s), 2.58 (3H, s), 3.74 (2H, s), 4.92
(2H, s), 7.02–7.05 (1H, m), 7.05 (1H, s), and 7.22–7.26
(1H, m) ppm; 13C-NMR (75 MHz, CDCl3) δ : 21.0, 27.2,
40.8, 45.3, 119.2, 121.2, 127.5, 129.5, 133.5, 149.4, 169.2,
170.8, and 172.1 ppm; HRMS (FAB) calcd. for
C13H13NO4Li (M + Li): 254.1005; found: 254.1006.
1
1147 cm–1; H-NMR (400 MHz, CDCl3) δ : 2.94 (3H, s) and
3.00 (3H, s), 3.71 (2H, s) and 3.76 (2H, s), 3.97 (2H, m) and
4.01 (2H, m), 5.11–5.24 (2H, m), 5.68–5.79 (1H, m),
6.19–6.20 (1H, m), 6.31–6.33 (1H, m), and 7.34–7.35
(1H, m) ppm; 13C-NMR (100 MHz, CDCl3) δ : 33.5, 33.6,
34.0, 34.9, 50.0, 52.4, 107.4, 110.4, 116.7, 117.2, 132.2,
132.5, 141.5, 141.6, 148.6, 148.7, 168.3, and 168.7 ppm;
HRMS calcd. for C10H13NO2: 179.0946; found: 179.0939.
7-Acetoxy-2-methyl-1,7,8,8a-tetrahydro-2H-isoquinoline-3-one
(16): A solution containing 0.2 g (1.1 mmol) of furan 15 in
10 mL of acetic anhydride was heated at reflux for 20 h. The
solution was concentrated under reduced pressure and the
crude solid was purified by silica gel chromatography to
give 0.21 g (83%) of 16 as a white solid, mp 104–105 °C;
N-[2-(3,4-Dimethoxyphenethyl)]-2-furan-2-yl-acetamide (20):
To a solution containing 0.86 g (6.8 mmol) of furan-2-yl-
acetic acid (10) in 25 mL of CH2Cl2 was added 1.5 g
(9.0 mmol) of 1,1′-carbonyldiimidazole. After stirring for
1 h at room temperature, 1.9 g (10.3 mmol) of 3,4-
dimethoxyphenethylamine was added and the mixture was
stirred for an additional 1 h. The solution was concentrated
under reduced pressure and the crude product was purified
by silica gel chromatography to give 1.7 g (87%) of 20 as a
white solid, mp 78–79°C; IR (neat) ν : 3293, 1648, 1511,
1
IR (neat) ν : 1730, 1652, 1590, and 1232 cm–1; H-NMR
(400 MHz, CDCl3) δ : 1.38–1.47 (1H, m), 2.10 (3H, s),
2.24–2.30 (1H, m), 2.82–2.85 (1H, m), 3.01 (3H, s), 3.26–
3.36 (2H, m), 5.52–5.55 (1H, m), 5.77 (1H, d, J = 1.6 Hz),
6.02 (1H, d, J = 10.0 Hz), and 6.29 (1H, dd, J = 10.0 and
1.6 Hz) ppm; 13C-NMR (100 MHz, CDCl3) δ : 20.9, 31.2,
31.8, 34.2, 52.9, 68.6, 119.8, 127.9, 135.3, 145.4, 165.4, and
170.2 ppm. Anal. calcd. for C12H15NO3: C 65.14, H 6.83, N
6.33; found: C 65.38, H 6.91, N 6.47.
1
and 1258 cm–1; H-NMR (400 MHz, CDCl3) δ : 2.72 (3H, t,
J = 6.8 Hz), 3.46 (2H, dt, J = 6.8 and 6.0 Hz), 3.57 (2H, s),
3.84 (3H, s), 3.85 (3H, s), 5.85 (1H, brs), 6.15–6.16 (1H, m),
6.31–6.33 (1H, m), 6.63–6.67 (2H, m), 6.76–6.78 (1H, m),
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Can. J. Chem. Vol. 78, 2000
and 7.32–7.33 (1H, m) ppm; 13C-NMR (100 MHz, CDCl3)
δ : 34.9, 36.1, 40.7, 55.6, 55.7, 108.3, 110.6, 111.1, 111.7,
120.4, 131.0, 142.2, 147.4, 148.6, 148.8, and 168.3 ppm;
Anal. calcd. for C16H19NO4: C 66.42, H 6.62, N 4.84; found:
C 66.40, H 6.60, N 4.89.
3.66–3.73 (1H, m), 3.86 (3H, s), 3.88 (3H, s), 4.89 (1H, dd,
J = 4.0 and 1.6 Hz), 6.14 (1H, d, J = 5.6 Hz), 6.37 (1H, dd,
J = 5.6 and 1.6 Hz), and 6.75–6.81 (3H, m) ppm; 13C-NMR
(100 MHz, CDCl3) δ : 30.3, 33.5, 35.9, 36.0, 50.0, 51.6,
55.7, 55.8, 78.1, 85.6, 111.1, 111.8, 120.6, 131.4, 137.3,
137.4, 147.4, 148.7, and 168.6 ppm; Anal. calcd. for
C19H23NO4: C 69.28, H 7.04, N 4.25; found: C 69.11, H
7.09, N 4.21.
4-[2-(3,4-Dimethoxyphenethyl)]-11-oxa-4-aza-tricyclo[6.2.1.01,6]
undec-9-ene-3,5-dione (21): To a solution containing 0.5 g
(1.7 mmol) of amide 20 in 15 mL of CH2Cl2 was added
1.7 g of powdered molecular sieves (4 Å) followed by 0.46 g
(5.1 mmol) of acryloyl chloride and the mixture was stirred
at room temperature for 20 h. The solution was filtered
through a pad of celite and concentrated under reduced pres-
sure. The crude product was purified by silica gel chroma-
tography to give 0.2 g (35%) of 21 as a pale yellow solid,
mp 170–171°C; IR (neat) ν : 1730, 1680, 1515, and 1365 cm–1;
1H-NMR (400 MHz, CDCl3) δ : 1.74 (1H, dd, J = 12.0 and
4.8 Hz), 2.26–2.32 (1H, m), 2.75–2.78 (3H, m), 3.24 (1H, d,
J = 16.8 Hz), 3.46 (1H, d, J = 16.8 Hz), 3.86 (3H, s), 3.88
(3H, s), 3.91–4.06 (2H, m), 5.09 (1H, dd, J = 4.8 and
2.0 Hz), 5.78 (1H, d, J = 5.6 Hz), 6.56 (1H, d, J = 5.6 Hz),
and 6.75–6.81 (3H, m) ppm; 13C-NMR (100 MHz, CDCl3)
δ : 28.6, 33.4, 40.5, 41.5, 47.1, 55.7, 55.8, 80.3, 82.1, 111.0,
112.0, 120.9, 130.6, 131.6, 141.7, 147.6, 148.7, 170.0, and
171.0 ppm; Anal. calcd. for C19H21NO5: C 66.46, H 6.16, N
4.08; found: C 66.39, H 6.14, N 4.06.
2-[2-(3,4-Dimethoxyphenethyl)]-7-hydroxy-1,7a,8,8a-tetrahy-
dro-2H-isoquinoline-3-one (25): To a solution containing
0.24 g (10 mmol) of sodium metal in 25 mL of EtOH was
added 1.0 g (3.0 mmol) of cycloadduct 24 at 0 °C. After stir-
ring for 1 h at room temperature, 20 mL of water was added
and the solution was extracted with CH2Cl2. The organic
layer was dried over MgSO4, concentrated under reduced
pressure, and the crude product was purified by silica gel
chromatography to give 0.9 g (92%) of 25 as a white solid,
mp 137–139°C; IR (neat) ν : 3348, 1641, 1511, 1478, and
1244 cm–1; 1H-NMR (400 MHz, CDCl3) δ : 1.21–1.30
(1H, m), 1.91 (1H, d, J = 6.6 Hz, exchangeable with D2O),
2.08–2.13 (1H, m), 2.57–2.60 (1H, m), 2.80–2.85 (2H, m),
3.17 (1H, s), 3.20 (1H, d, J = 3.6 Hz), 3.51–3.73 (2H, m),
3.86 (3H, s), 3.87 (3H, s), 4.41 (1H, dd, J = 10.0 and
4.8 Hz), 5.71 (1H, d, J = 1.6 Hz), 6.17 (2H, dd, J = 18.8 and
10.0 Hz), and 6.76–6.83 (3H, m) ppm; 13C-NMR (100 MHz,
CDCl3) δ : 31.8, 33.5, 35.4, 49.0, 51.9, 55.6, 55.7, 65.9,
111.2, 111.9, 118.3, 120.6, 126.0, 131.3, 141.1, 147.4,
148.7, and 165.8 ppm; Anal. calcd. for C19H23NO4: C 69.28,
H 7.04, N 4.25; found: C 69.14, H 7.05, N 4.20.
N-Allyl-[2-(3,4-dimethoxyphenethyl)]-2-furan-2-yl-acetamide
(23): To a solution containing 0.2 g (1.7 mmol) of furan-2-
yl-acetic acid (10) in 8 mL of CH2Cl2 was added 0.4 g
(2.5 mmol) of 1,1′-carbonyldiimidazole. After stirring at
room temperature for 1 h, 0.5 g (2.4 mmol) of allyl-[2-(3,4-
dimethoxyphenethyl)]amine (22) (34) was added and the
mixture was stirred for an additional 2 h. The solution was
concentrated under reduced pressure and the crude product
was purified by silica gel chromatography to give 0.4 g
(77%) of 23 as a clear oil which contained a mixture of am-
ide rotamers in solution; IR (neat) ν : 1651, 1515, 1457, and
7-Benzyloxy-2-[2-(3,4-dimethoxyphenethyl)]-1,7a,8,8a-tetra-
hydro-2H-isoquinolin-3-one (26): To a 5 mL solution of
THF was added 0.04 g (1.0 mmol) of NaH (60% dispersion)
which had been rinsed with hexane. After cooling to 0°C,
0.13 g (0.4 mmol) of alcohol 25 in 10 mL of THF was
added and the mixture was warmed to room temperature.
After stirring for 2 h, 0.24 g of benzyl bromide was added
and the solution was heated at 60°C for 15 h. The reaction
was cooled to 0°C and 10 mL of water was added slowly.
The mixture was extracted with ethyl acetate and the organic
layer was dried over MgSO4 and concentrated under reduced
pressure. Purification of the crude mixture by silica gel chro-
matography gave 0.12 g (83%) of 26 as a white solid, mp
118–119°C; IR (neat) ν : 1647, 1510, 1453, and 1260 cm–1;
1H-NMR (400 MHz, CDCl3) δ : 1.25–1.38 (1H, m), 2.14–
2.19 (1H, m), 2.50–2.58 (1H, m), 2.81–2.85 (2H, m), 3.11–
3.21 (2H, m), 3.52–3.73 (2H, m), 3.85 (3H, s), 3.87 (3H, s),
4.21 (1H, dd, J = 10.4 and 5.2 Hz), 4.62 (2H, s), 5.74 (1H,
d, J = 2.4 Hz), 6.22 (2H, s), 6.75–6.81 (3H, m), and 7.30–
7.36 (5H, m) ppm; 13C-NMR (100 MHz, CDCl3) δ : 31.8,
32.7, 33.7, 49.0, 52.1, 55.7, 55.8, 70.5, 73.2, 111.1, 111.9,
119.4, 120.6, 126.9, 127.6, 127.8, 128.4, 131.6, 137.9,
146.6, 147.4, 148.8, and 165.2 ppm; Anal. calcd. for
C26H29NO4: C 74.44, H 6.97, N 3.34; found: C 74.28, H
6.90, N 3.31.
1
1260 cm–1; H-NMR (400 MHz, CDCl3) δ : 2.74 (2H, t, J =
7.2 Hz) and 2.82 (2H, t, J = 7.2 Hz), 3.51–3.56 (2H, m),
3.70 (1H, s), 3.82–3.83 (2H, m), 3.84 (3H, s) and 3.85
(3H, s), 3.86 (3H, s) and 3.87 (3H, s), 4.02 (1H, d, J =
6.0 Hz), 5.13–5.21 (2H, m), 5.71 (1H, m) and 5.81 (1H, m),
6.14–6.18 (1H, m), 6.31–6.34 (1H, m), 6.65–6.83 (3H, m),
and 7.33–7.36 (1H, m) ppm; 13C-NMR (100 MHz, CDCl3)
δ : 33.4, 33.5, 33.7, 34.5, 48.0, 48.6, 49.2, 51.1, 55.7, 55.8,
55.9, 107.4, 107.5, 110.4, 110.5, 111.1, 111.4, 111.8, 111.9,
116.6, 117.1, 120.6, 120.7, 130.5, 131.6, 132.7, 133.1,
141.6, 141.7, 147.4, 147.8, 148.7, 148.8, 168.3, and
168.7 ppm; Anal. calcd. for C19H23NO4: C 69.28, H 7.04, N
4.17; found: C 68.98, H 7.04, N 4.22.
4-[2-(3,4-Dimethoxyphenethyl)]-11-oxa-4-aza-tricyclo[6.2.1.01,6]
undec-9-en-3-one (24): A solution containing 0.17 g (5.2 mmol)
of furan 23 in 10 mL of xylene was heated at reflux for 20 h.
The solution was concentrated under reduced pressure and
the crude solid was purified by silica gel chromatography to
give 0.15 g (90%) of 24 as a white solid, mp 119–120°C; IR
(neat) ν : 1644, 1513, 1449, and 1154 cm–1; 1H-NMR
(400 MHz, CDCl3) δ : 1.39–1.44 (2H, m), 1.71–1.75
(1H, m), 2.79–2.83 (2H, m), 2.92 (1H, d, J = 18.8 Hz), 3.15
(1H, d, J = 18.8 Hz), 3.18–3.22 (2H, m), 3.51–3.58 (1H, m),
7-Benzyloxy-2-[2-(3,4-dimethoxyphenethyl)]-octahydroisoq-
uinolin-3-one (27): To a solution of 0.05 g (0.13 mmol) of
26 in 8 mL of EtOH was added a slight excess of Raney
nickel. After stirring at room temperature for 15 h, the
mixture was filtered through Celite with ethyl acetate. The
© 2000 NRC Canada

Padwa and Reger
755
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solution was concentrated under reduced pressure and the
crude product was purified by silica gel chromatography to
give 0.047 g (85%) of 27 as a clear oil; IR (neat) ν : 1636,
1511, 1452, and 1264 cm–1; H-NMR (400 MHz, CDCl3) δ :
1
1.49–1.69 (5H, m), 1.83–1.91 (2H, m), 2.07–2.11 (2H, m),
2.27–2.47 (2H, m), 2.76–2.85 (2H, m), 3.07 (1H, dd, J =
12.0 and 2.8 Hz), 3.33–3.43 (3H, m), 3.68–3.75 (1H, m),
3.84 (3H, s), 3.87 (3H, s), 4.54 (2H, d, J = 2.4 Hz), 6.73–
6.77 (3H, m), and 7.25–7.35 (5H, m) ppm; 13C-NMR
(100 MHz, CDCl3) δ : 26.3, 26.7, 30.8, 31.4, 32.3, 32.6,
33.1, 49.1, 52.9, 55.7, 55.8, 69.8, 76.1, 111.1, 112.0, 120.7,
127.3, 127.4, 128.3, 131.6, 138.7, 147.4, 148.8, and 168.9 ppm;
HRMS calcd. for C26H33NO4: 423.2410; found: 423.2397.
10-Benzyloxy-2,3-dimethoxy-5,8,8a,9,10,11,12,12a,13,13a-
decahydro-6H-isoquino[3,2-a]isoquinoline (9): To a solution
of 0.3 g (0.6 mmol) of 27 in 10 mL of benzene was added
0.2 g (1.3 mmol) of phosphorous oxychloride. After heating
at reflux for 2 h, the solvent was removed under reduced
pressure and the crude product was taken up in 10 mL of
methanol. To this solution was added 0.05 g (1.3 mmol) of
sodium borohydride and the mixture was stirred for an addi-
tional 2 h. The solvent was removed under reduced pressure
and the crude material was purified by silica gel chromatog-
raphy to give 0.15 g (52%) of 9 as a yellow foam; IR (neat)
ν : 1601, 1510, and 1270 cm–1; H-NMR (400 MHz, CDCl3)
1
δ : 1.32–1.45 (1H, m), 1.56–2.04 (9H, m), 2.39 (1H, dt, J =
11.6 Hz and 3.6 Hz), 2.50–2.57 (2H, m), 2.72 (1H, dd, J =
11.6 and 1.6 Hz), 2.81–2.85 (1H, m), 3.02–3.11 (2H, m),
3.34–3.42 (1H, m), 3.84 (3H, s), 3.85 (3H, s), 4.55 (2H, dd,
J = 23.6 and 12.4 Hz), 6.57 (1H, s), 6.68 (1H, s), and 7.24–
7.33 (5H, m) ppm; 13C-NMR (100 MHz, CDCl3) δ : 27.0,
29.4, 29.5, 32.0, 32.3, 34.3, 35.1, 52.6, 55.7, 55.9, 62.0,
63.3, 69.3, 78.0, 108.0, 111.3, 127.0, 127.1, 127.3, 128.2,
130.5, 139.3, 147.0, and 147.1 ppm; HRMS calcd. for
C26H33NO3: 408.2539; found: 408.2526.
20. (a) M.E. Jung and L. Street. J. Am. Chem. Soc. 106, 8327
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Acknowledgements
We gratefully acknowledge the National Science Founda-
tion (CHE-9806331) for generous support of this work. High-
field NMR spectrometers used in these studies were made
possible through equipment grants from the NIH and NSF.
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