Bischler-napieralski cyclization-N/C-alkylation sequences for the construction of isoquinoline alkaloids. Synthesis of protoberberines and benzo[c]phenanthridines via C -2′-functionalized 3-arylisoquinolines

Article abstract of DOI:10.1021/jo960007s

Efficient synthetic routes to isoquinoline alkaloids of the protoberberine and benzo[c]phenanthridine classes are reported. The key transformations are derived from the intramolecular cyclization of C-2'-functionalized N-(1,2-diarylethyl)amides or enamides via 3-arylisoquinoline derivatives. Thus, under Bischler-Napieralski reaction conditions (PCl₅, nitrile as solvent, room temperature) N-(1,2-diarylethyl)amides 12 regioselectively yielded 2,3-disubstituted 13,14-dihydroprotoberberinium salts 20, a scarcely studied oxidation state in this class of alkaloids. Subsequent reduction of the iminium bond gave the known coralydine (21a) and O-methylcorytenchirine (21b) and their 8-phenyl analogue 21c. The one-pot preparation of these dihydroprotoberberinium salts 20 is shown to proceed with cleavage of the silyl ether and immediate halogenation of the resulting hydroxyl group, followed by cyclization of the obtained AT-(1,2-diarylethyl)amide 18 to a 3,4-dihydroisoquinoline derivative 19 and subsequent intramolecular in situ N-alkylation of the latter imine. Ready access to planar 8,9-dialkoxylated benzo[c]phenanthridinium salts is also described. Condensation of ketoester 23 with benzylamine in the presence of titanium(IV) chloride, followed by acetylation, afforded a mixture of naphthylamide 24 and (E)-enamide 25. Both enamides were efficiently cyclized by POCI₃. While the planar benzo[c]phenanthridinium salt 26 was directly produced from 24, the (E)-enamide 25 gave the 3-arylisoquinolinium salt 27, which was reduced and intramolecularly C-alkylated to yield the tetracyclic nucleus of these alkaloids.

Full text of DOI:10.1021/jo960007s

4062
J . Org. Chem. 1996, 61, 4062-4072
Bisch ler -Na p ier a lsk i Cycliza tion -N/C-Alk yla tion Sequ en ces for
th e Con str u ction of Isoqu in olin e Alk a loid s. Syn th esis of
P r otober ber in es a n d Ben zo[c]p h en a n th r id in es via
C-2′-F u n ction a lized 3-Ar ylisoqu in olin es1
Nuria Sotomayor, Esther Dom´ınguez, and Esther Lete*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco,
Apdo. 644, 48080 Bilbao, Spain
Received J anuary 2, 1996X
Efficient synthetic routes to isoquinoline alkaloids of the protoberberine and benzo[c]phenanthridine
classes are reported. The key transformations are derived from the intramolecular cyclization of
C-2′-functionalized N-(1,2-diarylethyl)amides or enamides via 3-arylisoquinoline derivatives. Thus,
under Bischler-Napieralski reaction conditions (PCl5, nitrile as solvent, room temperature) N-(1,2-
diarylethyl)amides 12 regioselectively yielded 2,3-disubstituted 13,14-dihydroprotoberberinium salts
20, a scarcely studied oxidation state in this class of alkaloids. Subsequent reduction of the iminium
bond gave the known coralydine (21a ) and O-methylcorytenchirine (21b) and their 8-phenyl
analogue 21c. The one-pot preparation of these dihydroprotoberberinium salts 20 is shown to
proceed with cleavage of the silyl ether and immediate halogenation of the resulting hydroxyl group,
followed by cyclization of the obtained N-(1,2-diarylethyl)amide 18 to a 3,4-dihydroisoquinoline
derivative 19 and subsequent intramolecular in situ N-alkylation of the latter imine. Ready access
to planar 8,9-dialkoxylated benzo[c]phenanthridinium salts is also described. Condensation of
ketoester 23 with benzylamine in the presence of titanium(IV) chloride, followed by acetylation,
afforded a mixture of naphthylamide 24 and (E)-enamide 25. Both enamides were efficiently cyclized
by POCl3. While the planar benzo[c]phenanthridinium salt 26 was directly produced from 24, the
(E)-enamide 25 gave the 3-arylisoquinolinium salt 27, which was reduced and intramolecularly
C-alkylated to yield the tetracyclic nucleus of these alkaloids.
In tr od u ction
methods of these compounds, in order to study structure-
activity relationships.7
Benzo[c]phenanthridine and protoberberine alkaloids
have represented continuing challenge for organic syn-
thesis due to their widespread occurrence in nature and
broad range of biological activities.2,3 Protoberberines
have been found to exert physiological activities of diverse
nature (antimicrobial, antitumor, antineoplastic, etc....).
Much interest has been focused on their effectiveness as
antileukemic agents, and research in this area has
revealed that the intercalation of coralyne and berberine
with DNA may play a critical role in their antileukemic
action.4 Recently, benzo[c]phenanthridines have at-
tracted considerable attention because nitidine and other
8,9-disubstituted planar benzophenanthridinium salts
such as fagaronine have been shown to have antitumor
activity in animal tumor models, an activity which could
be related to inhibition of DNA topoisomerase.5 Interest-
ingly, 7,8-disubstituted benzophenanthridine alkaloids
such as chelerythrine have not generally been found to
have antitumor activity.6 However, the toxicological
problems associated with the most active members of
these groups have led to development of new synthetic
Although a wide variety of methods have been utilized
for the synthesis of these classes of natural products,8
especially attractive are those in which the key step for
the construction of the protoberberine or benzo[c]phenan-
thridine skeleton is the annelation of an isoquinoline
derivative.9 However, only a few examples have been
reported on the preparation and synthetic applications
of C-2′-functionalized 3-arylisoquinolines. Onda10 and
Hanaoka11 have developed a biomimetic approach in
which 2′-vinyl-3-aryl-1-isoquinolones are obtained by
Hofmann degradation of protoberberinium salts and
further cyclized to the benzo[c]phenanthridine skeleton
photochemically or by derivatization of the vinyl group,
respectively. Other approaches rely on the ammonolysis
of benzopyrylium salts,12 SRN1 reaction of iodobenzamides
(6) Ishii, H.; Ichikawa, Y.-K.; Kawanabe, E.; Ishikawa, M.; Ishikawa,
T.; Kuretani, K.; Inomata, M.; Hoshi, A. Chem. Pharm. Bull. 1985,
33, 4139.
(7) Mart´ın, G.; Guitia´n, E.; Castedo, L. J . Org. Chem. 1992, 57, 5907.
(8) (a) For a review on benzo[c]phenanthridine synthesis, see ref 2,
p 209. (b) For a review on protoberberine synthesis, see ref 3, p 134.
(9) For a few representative examples, see the following. Protober-
berine synthesis from (a) 1-benzylisoquinolines: Suau, R.; Valpuesta,
M. Tetrahedron 1990, 46, 4421. (b) N-Phenethyl-1,4-dihydroisoquino-
linium salts: Dean, R. T.; Rapoport, H. J . Org. Chem. 1978, 43, 2115;
J . Org. Chem. 1978, 43, 4183. (c) N-acylalkylidenetetrahydroiso-
quinolines: Naito, T.; Katsumi, K.; Toda, Y.; Ninumiya, I. Heterocycles
1983, 20, 775. Lenz, G. R. J . Org. Chem. 1977 42, 1117. (d) N-
functionalized 3-arylisoquinolines: Dyke, S. F.; Brown, D. W.; Sains-
bury, M.; Hardy, G. Tetrahedron 1971, 27, 3495. Benzo[c]phenanthri-
dine synthesis from (e) 4-phenylacetylisoquinolones: Onda, M.; Harigaya,
Y.; Suzuki, T. Chem. Pharm. Bull. 1977, 23B, 79. (f) C-4-functionalized
isoquinolines: Sainsbury, M.; Dyke, S. F.; Moon, B. J . J . Chem. Soc.,
Chem. Commun. 1970, 1797. (g) C-4-functionalized isoquinolones:
Cushman, M; Abbaspour, A.; Gupta, Y. P. J . Am. Chem. Soc. 1983,
105, 2873.
* To whom corresondence should be addressed. Phone: 34-4-
4647700, ext. 2623. FAX: 34-4-4648500. E-mail: qopleexe@lg.ehu.es.
X Abstract published in Advance ACS Abstracts, May 15, 1996.
(1) For preliminary communications: Sotomayor, N.; Dom´ınguez,
E.; Lete, E. Synlett 1993, 431. Sotomayor, N.; Dom´ınguez, E.; Lete, E.
Tetrahedron Lett. 1994, 35, 2973.
(2) Sima´nek, V.: Benzophenanthridine Alkaloids. In The Alkaloids.
Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press, Inc.:
Orlando, 1985; Vol. 26; p 229.
(3) Bhakuni, D. S.; J ain, S.: Protobeberine Alkaloids. In The
Alkaloids. Chemistry and Pharmacology; Brossi, A., Ed.; Academic
Press, Inc.: Orlando, 1986; Vol. 28; p 169.
(4) Taira, Z.; Matsumoto, M.; Ishida, S.; Icikawa, T.; Sakiya, Y.
Chem. Pharm. Bull. 1994, 42, 1556.
(10) Onda, M.; Yamaguchi, I. Chem. Pharm. Bull. 1979, 27, 2076.
(11) Hanaoka, M.; Kobayashi, N.; Mukai, C. Heterocycles 1987, 26,
1499.
(5) Fang, S.-D.; Wang, L.-K.; Hetch, S. M. J . Org. Chem. 1993, 58,
5025.
S0022-3263(96)00007-2 CCC: $12.00 © 1996 American Chemical Society

Construction of Isoquinoline Alkaloids
J . Org. Chem., Vol. 61, No. 12, 1996 4063
Sch em e 1
Sch em e 2a
with 2-acetylhomoveratric acid enolates,13 cycloaddition
of lithiated toluamides and benzaldimines,14 or cycload-
dition of N-(2-ethenylbenzoyl)-N,2-dimethylbenzamide
derivatives.15
In formulating a general strategy for the synthesis of
benzo[c]phenanthridines 1 and protoberberines 2, we
recognized the potential of the Bischler-Napieralski
cyclization reaction to generate these alkaloids via a
common and versatile synthetic intermediate: a C-2′-
functionalized 3-arylisoquinoline derivative (Scheme 1).
On the basis of previous methodological studies, we
anticipated that 13,14-dihydroprotoberberines (7,8-de-
hydroberbines), a scarcely studied oxidation stage in the
chemistry of protoberberines, could arise from intramo-
lecular N-alkylation of C-2′-functionalized 3-aryl-3,4-
dihydroisoquinolines (imines), whereas benzo[c]phenan-
thridines could be obtained by C-alkylation or acylation
of N-substituted 3-aryl-1,2-dihydroisoquinolines (enam-
ines). Two different methods were studied for the
synthesis of the key C-2′-functionalized 3-arylisoquino-
lines. The first relied on assembling the isoquinoline
nucleus via Bischler-Napieralski cyclization of N-(1,2-
diarylethyl)amides16 or enamides17 5. The second ap-
proach was the joining of the pertinent deoxybenzoin 4
and nitrile units via a Ritter-type reaction.18 We now
wish to present the findings from our investigations of
the Bischler-Napieralski cyclization-N/C-alkylation se-
quences for the construction of protoberberine and benzo-
[c]phenanthridine skeletons. A retrosynthetic analysis
for these alkaloids is depicted in Scheme 1.
a
Reagents: (a) NaBH4, TiCl4, DME (81%); (b) t-BuPh2SiCl,
imidazole, DMF (94%); (c) PCC, CH2Cl2 (88%); (d) NH2OH‚HCl,
pyridine (89%, anti-10a /syn-10b 1.2/1.0); (e) NaBH4, TiCl4, DME
(60%); (f) Et3N, DMAP, R3COCl, CH2Cl2, 12a (85%) and 12b (89%);
12c: HCONH2, (85%); (g) Bu3P, PhSSPh; then NaBH3CN, AcOH,
then Ac2O, 12a (45%); (h) MeI, KOH, DMSO (60%).
the 2-[(3,4-dimethoxyphenyl)acetyl]-4,5-dimethoxyphe-
nylacetic acid (6)19 to the corresponding dialcohol 7 has
been reported20 to proceed in moderate yield (65%), other
reduction agents were tried. Best results (81%) were
obtained with NaBH4-TiCl4 in DME,21 while NaBH4-
22
AlCl3 gave only a low yield of 7 (40%). In the latter
case, competitive lactone formation was an important
side reaction, affording isochromanone 13 as a byproduct
(31%) (Figure 1). Attempts for selective reduction of the
carboxyl group via boranes23 were unsuccessful: only
small quantities of the dialcohol 7 were obtained by using
BH3-DMS (35%). Selective protection of the primary
hydroxyl group with tert-butyldiphenylchlorosilane24 (94%),
followed by PCC oxidation,25 afforded the deoxybenzoin
9 (88%). PDC26 or Swern27 oxidation gave lower yields
Resu lts a n d Discu ssion
Preparation of the requisite 1,2-diarylethylamines and
amides is outlined in Scheme 2. Since LAH reduction of
(12) Carty, A.; Elliot, I. W.; Lenior, G. L. Can. J . Chem. 1984, 62,
2435.
(13) Beugelmans, R.; Bois-Choussy, M. Tetrahedron 1992, 48, 8285.
(14) Clark, R. D.; J ahangir J . Org. Chem. 1989, 54, 117.
(15) Couture, A.; Cornet, H.; Grandclaudon, P. Tetrahedron Lett.
1993, 34, 8097.
(16) Dom´ınguez, E.; Lete, E. Heterocycles 1983, 20, 1247.
(17) Sotomayor, N.; Vicente, T.; Dom´ınguez, E.; Lete, E.; Villa, M.
J . Tetrahedron 1994, 50, 2207.
(18) Garc´ıa, A.; Lete, E.; Villa, M. J .; Dom´ınguez, E.; Bad´ıa, D.
Tetrahedron 1988, 48, 6681.
(19) Elliot, I. W. J . Heterocycl. Chem. 1972, 9, 853.
(20) Dom´ınguez, E.; Iriondo, C.; Laborra, C.; Linaza, A.; Mart´ınez,
J . Bull. Soc. Chim. Belg. 1989, 98, 133.
(21) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S. Synthesis 1980,
695.
(22) Brown, H. C.; Rao, B. C. S. J . Am. Chem. Soc. 1956, 78, 2582.
(23) Lane, C. Chem. Rev. 1976, 76, 774.
(24) Hanessian, S.; Lavalle, P. Can. J . Chem. 1975, 53, 2975.
(25) Corey, E. J .; Suggs, W. Tetrahedron Lett. 1975, 2647.
(26) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(27) Omura, A.; Swern, D. Tetrahedron 1978, 34, 1651.

4064 J . Org. Chem., Vol. 61, No. 12, 1996
Sotomayor et al.
Sch em e 4
F igu r e 1.
Sch em e 3a
(1.2:1 ratio). Since hydrogenation in the presence of Pd/
charcoal in EtOH/HCl has been shown to be a mild high-
yielding procedure for the reduction of oximes,30 this
method was applied to the oximes 10. However, the
isochroman 16 was obtained in high yield (75%) instead
of the desired amine (Scheme 4). Formation of this cyclic
ether 16 could be explained by hydrolysis of the oxime
moiety, followed by reduction of the resulting ketone, and
subsequent intramolecular cyclization of the obtained
dialcohol. Attempts to perform the catalytic hydrogena-
tion under neutral conditions31 were unsuccessful: start-
ing material was recovered even at high pressures of H2
(30 atm). In view of the failure of oximes 10 to undergo
catalytic hydrogenation, we next considered the reduction
with hydrides, although it was anticipated that this
might be problematic. For example, it has been reported
that LAH reduction of benzyl ketone oximes yielded
aziridines,32 while the use of DIBALH promoted Beck-
man-type rearrangement.33 In our case, after consider-
able optimization, we found that the oximes 10 could be
reduced selectively with the pair NaBH4-TiCl4 to give
the amine 11 in a moderate yield (60%). It is worth
mentioning that attempts to convert the alcohol 8 to the
amine 11 by activation and displacement of the secondary
hydroxyl group failed. Thus, when 8 was treated with
NaH/sulfamoyl chloride,34 â-elimination was the main
reaction and the stilbene 14 was obtained as the major
product (83%). The alcohol-to-amine Mitsunobu reaction
(PPh3, DEAD, phthalimide)35 gave a similar result.
a
Reagents: (a) NH2OH‚HCl, pyridine (89%, 10a :10b 1.2:1); (b)
Ac2O, py (96%, 15a :15b 1.2:1).
(67 and 51%, respectively). During the latter reduction,
a side product, the (E)-stilbene 14, was also isolated (10%)
(Figure 1).
Reductive amination of the ketone 9 was carried out
via oximes. Thus, treatment of 9 with hydroxylamine
hydrochloride afforded the oxime 10 as a mixture of the
anti (10a ) and syn (10b) isomers in a 1.2:1 anti/ syn ratio.
The similar size of both oxime carbon substituents could
explain this product distribution. The pure diastereo-
mers were obtained by careful column chromatography
and unambiguously identified by NMR spectroscopy. The
differences among the chemical shift values of the R-me-
thylene protons and the R-carbons in the NMR spectra
of both isomers were used to assign the stereochemistry.
It has been observed that these protons experience a
downfield shift for the isomer in which they are in a cis
disposition to the hydroxyl group (anti isomer in this
case) relative to the other isomer (trans disposition),28
while the corresponding R-carbon is shifted upfield. We
observed similar trends for our oximes: the R-methylene
protons resonated at δ 3.67-3.74 and 3.84 ppm for the
syn (10b) and anti (10a ) isomers, respectively (Scheme
3). In addition, a difference of around 6 ppm was
observed in the R-carbon chemical shift values, which
appeared at 42.41 (syn) and 36.19 (anti) ppm, respec-
tively. Since the oxime esters can be reduced to amines
under milder conditions than the oximes themselves,23
the oxime acetates 15a (anti) and 15b (syn) were quan-
titatively prepared (Ac2O, pyridine) (Scheme 3) and their
stereochemistry assigned using the same criteria as
described above for the oximes 10.
Smooth reductive amidation of the ketone 9 was
observed upon conversion to the oxime 10, followed by
reduction and acylation (Scheme 2). Thus, treatment of
this oxime with Bu3P-PhSSPh,36 operating under strictly
anhydrous conditions at room temperature, led to an
intermediate imine. Subsequent reduction with NaBH3-
CN and acetic acid, followed by in situ acetylation of the
so-obtained amine with Ac2O, generated the acetamide
12a in a moderate yield (45%). Alternatively, acylation
of the amine 11 with acetyl and benzoyl chloride37
afforded 85-90% isolated yields of 12a and 12b, respec-
tively. Formylation of 11 was accomplished with HCONH2
at 150 °C to give the formamide 12c in good yield (85%).
Methylation of acetamide 12a (MeI, KOH, DMSO)38
afforded the N-methyl derivative 12d . It should be noted
that, due to restricted rotation about the CO-N bond,
the amides 12c and 12d were obtained as mixtures of
the cis and trans rotamers in a 2.5:1 ratio. Their ratio
(30) Vicente, T. Ph.D. Thesis, Universidad del Pa´ıs Vasco, 1995.
(31) Harlung, W. H.; Breaujon, J . H.; Cocolas, G. Organic Syntheses;
Wiley: New York, 1973; Collect. Vol. V, p 376.
Several procedures for the reduction of the oximes 10
and their acetates 15 to the corresponding amine 11 were
examined. Reduction of 15a with BH3-THF in diglyme
at 110 °C29 resulted in isomerization of the starting
material to a mixture of oxime acetates 15a and 15b
(32) Ferrero, L.; Rouillard, M.; Couzon, M. D.; Azzaro, M. Tetrahe-
dron Lett. 1974, 131.
(33) Sasatami, S.; Miyazaki, T.; Maruoka, K.; Yamamoto, H. Tet-
rahedron Lett. 1983, 24, 4711.
(34) White, E. H.; Ellinger, C. A. J . Am. Chem. Soc. 1965, 87, 5261.
(35) Mitsunobu, O. Synthesis 1981, 1.
(36) Barton, D. H. R.; Motherwell, W.; Simon, E. S.; Zard, S. Z. J .
Chem. Soc., Perkin Trans. 1 1986, 2243.
(28) Karabastos, G. S.; Hsi, N. Tetrahedron 1967, 23, 1079.
(29) Feuer, H.; Braunstein, D. M. J . Org. Chem. 1969, 34, 1817.
(37) Djuri, S. W. J . Org. Chem. 1984, 49, 1331.
(38) J ohnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169.

Construction of Isoquinoline Alkaloids
J . Org. Chem., Vol. 61, No. 12, 1996 4065
Sch em e 5
Sch em e 6
and stereochemistry were established by NMR.39 Thus,
1
though in the H NMR spectrum of formamide 12c most
of the signals for both rotamers were overlapped, sepa-
rate 13C NMR resonances could be observed for both
rotamers. For instance, the carbonyl carbon signal
appears at higher field for the cis rotamer (160.18 ppm)
than for the trans isomer (164.20 ppm). The cis/ trans
rotamers of the N-methylacetamide 12d could be easily
detected by both 1H and 13C NMR.40 In this case, for
example, the methinic proton signal is shifted downfield
in the cis isomer (6.18 ppm) relative to the trans isomer
(5.08 ppm). Acetamide 12a and benzamide 12b were
obtained as single rotamers, presumably the more stable
cis isomer.40
Sch em e 7
P r otober ber in e Syn th esis. With amine 11 and
amides 12 in hand, we investigated the synthesis of the
target protoberberine derivatives. We have recently
reported41 the preparation of several C-2′-functionalized
3-aryl-1,2,3,4-tetrahydroisoquinolines 3 (Scheme 1) by
TiCl4-induced cyclization of bis(methoxymethyl)amines
under mild conditions (TiCl4, -78 °C). However, at-
tempts to obtain the tetrahydroprotoberberine skeleton
via intramolecular N-alkylation reactions of these tet-
rahydroisoquinoline derivatives were unsuccessful.42
A
anticipate any difficulty in the analogous transformation
here, since elimination of the amide group as a nitrile
via a retro-Ritter reaction could be avoided by using PCl5
as condensing agent and the “appropriate” nitrile as
solvent.16 Although it was expected that the silyl ether
would be stable under the reaction conditions,43 when
amides 12a and 12b were treated with PCl5 at room
temperature for 14 h, the C-8-substituted 2,3,10,11-
tetramethoxy-13,14-dihydroprotoberberinium chlorides
20a (67%) and 20b (54%) were obtained, respectively, in
a one-pot procedure (Scheme 6). An explanation for the
latter results involves initial cleavage of the silyl ether
and halogenation, followed by Bischler-Napieralski cy-
clization of the resulting 1,2-diarylethylamide to a 3-aryl-
3,4-dihydroisoquinoline derivative and subsequent in situ
intramolecular N-alkylation of the imine. In order to
establish that we were correct in assuming this pathway,
modification of the reaction conditions was undertaken
to isolate the proposed intermediates. Thus, we were
able to obtain C-2′-chloroethyl-substituted amide 18 and
3-aryl-3,4-dihydroisoquinoline 19a , after workup, from
amide 12a by varying the reaction time and PCl5/amide
ratio (Scheme 7). Nevertheless, under the same reaction
conditions, the formamide 12c afforded a mixture of
products, from which only the 3,4-dihydroisoquinoline
19b could be isolated (28%) (Scheme 8). We suspected
that the failure of this reaction was due to the presence
of the highly electrophilic unsubstituted C-1 carbon atom,
which could suffer from nucleophilic attack and/or sub-
sequent oxidation. Therefore, this procedure affords the
quinolizidine nucleus of the protoberberine alkaloids in
one pot, starting from N-(1,2-diarylethyl)amides.
direct and efficient approach to 3-arylisoquinolines is the
condensation of deoxybenzoins with nitriles promoted by
P2O5, a procedure based on a Ritter-type reaction,
reported earlier from our laboratory.18 However, treat-
ment of the deoxybenzoin 9 with acetonitrile in the
presence of P2O5 resulted in isolation of isochroman 17
as the major product (75%) (Scheme 5). Presumably,
deprotection of the hydroxyl group occurred in the
reaction medium, despite the reported stability of the
TBDPS protecting group under acidic conditions.43 Sub-
sequent intramolecular nucleophilic attack of the result-
ing hydroxyl group to the carbonyl group, followed by
dehydration, afforded the cyclic ether 17.
Our next approach to the isoquinoline nucleus of the
C-2′-functionalized 3-arylisoquinolines was the Bischler-
Napieralski reaction of amides 12. From our experience
in the Bischler-Napieralski cyclization applied to the
synthesis of 3-aryl-3,4-dihydroisoquinolines, we did not
(39) Arrieta, J . M.; Dom´ınguez, E.; Lete, E.; Villa, M. J . Acta
Crystallogr. 1990, C47, 2115.
(40) Pretsch, E.; Clerc, T.; Seibl, J .; Simon, W. Tables of Spectral
Data for Structure Determination of Organic Compounds, 2nd ed.;
Springer-Verlag: New York, 1989.
(41) Sotomayor, N.; Dom´ınguez, E.; Lete, E. Tetrahedron 1995, 51,
12159.
(42) Treatment of 3-[2-(2-hydroxyethyl)-4,5-dimethoxyphenyl]-6,7-
dimethoxytetrahydroisoquinoline (ref 41) with PCC in CH2Cl2, PCl5
in acetonitrile, SOCl2 in benzene, or PBr3 in pyridine gave only complex
mixtures of products. No formation of the desired tetrahydroprotober-
berine could be detected.
(43) The TBDPS group has been reported to be stable under the
acidic conditions that may cause the removal of other silicon protecting
groups (Greene, T. W. Protective Groups in Organic Synthesis; J ohn
Wiley & Sons: New York, 1981; pp 47). However, in order to test its
stability under the reaction conditions that were going to be used, 2-[2-
[(tert-butyldiphenylsilyl)oxy]ethyl]benzene was prepared from 2-phe-
nylethanol [tert-BuPh2SiCl, imidazole, DMF, rt, 1.5 h (95%)] and used
as a model compound. This silyl ether was stable when treated with
P2O5, PCl5, or POCl3 under the conditions used later on.
To further extend the synthetic utility of the dihydro-
protoberberine synthesis, these compounds were trans-
formed into berbines (tetrahydroprotoberberines) very

4066 J . Org. Chem., Vol. 61, No. 12, 1996
Sotomayor et al.
Sch em e 8
Sch em e 9
F igu r e 2.
F igu r e 3. NOE enhancements observed for 21c.
efficiently. Thus, reduction of the dehydroberbines 20a
and 20b with NaBH4 in THF provided tetrahydroproto-
berberines 21a and 21b (as a 4:1 ratio of R/â C-8
diastereomers) and 21c (as a single C-8 diastereomer),
respectively (Scheme 9). As frequently happens,44 in the
reduction of imine 20a , the amines 21a and 21b were
isolated as very stable borane adducts. This is reflected
in the presence of three bands in the IR spectrum in
CHCl3 (νmax ) 2300-2400 cm-1, BH) and a downfield
by nuclear Overhauser effect difference spectroscopy
1
and H-1H decoupling experiments. Berbine 21c dem-
onstrated an H-8 hydrogen signal enhancement upon
irradiation of H-14 methine hydrogen, and vice versa,
which confirms that they are in a cis disposition. On the
other hand, the NOE observed between axial H-6 and
H-8 and the absence of NOE between H-13 and H-6
indicate a trans B/C ring junction48 (Figure 3). The rest
of the NOE experiments carried out are consistent
with the proposed stereochemistry and have allowed
us to unequivocally assign the chemical shifts of all
protons.
1
shift for most of the H NMR signals relative to the free
amine; i.e., the resonances of the H-14 proton appeared
at δ 4.05 and δ 4.34-4.41 ppm for the adducts of 21a
and 21b, respectively, and at δ 3.71 and 4.24 ppm for
the free bases. Hydrolysis (3 M HCl, methanol, rt,
overnight) of the borane-amine complexes gave the
known natural alkaloids coralydine (21a ) and O-meth-
ylcorytenchirine (21b), whose data are identical to those
reported,45 and their 8-phenyl-substituted analogue 21c.
The stereochemistry of coralydine and O-methylcory-
tenchirine has been previously determined by NMR45 and
X-ray crystallography.46 Thus, coralydine (21a ) presents
a trans-fused B/C ring system in chairlike arrangements
with the C-8 substituent in a pseudoequatorial disposi-
tion. This is associated with high-field chemical shifts
for H-14 and H-8 in the 1H NMR spectrum (3.71 and 3.72
ppm, respectively) and Bohlman bands in the IR spec-
trum. However, O-methylcorytenchirine (21b) was re-
ported to adopt a cis form at the B/C ring junction with
the C-8-Me in pseudoaxial disposition, which is reflected
in the absence of Bohlman bands and lower field shifts
for H-14 and H-8 (4.24 and 4.10 ppm, respectively)
(Figure 2). The most likely stereochemistry for the single
diastereomer 21c, obtained from the NaBH4 reduction
of 20b, would be that resulting from hydride attack on
the re face, leaving the phenyl group in a pseudoequa-
Ben zo[c]p h en a n th r id in e Syn th esis. Our next con-
cern was the preparation of the planar benzo[c]phenan-
thridinium salts. The key step for the cyclization to the
benzo[c]phenanthridine skeleton would be the C-4 alky-
lation of C-2′ functionalized 1,2-dihydroisoquinolines
(enamines). These compounds can be readily prepared
by reduction of the iminium bond of N-alkylisoquino-
linium salts by classical procedures.49 However, because
of the instability of these enamines, which easily undergo
oxidation or disproportionation reactions, they are usu-
ally generated in situ and immediately alkylated. Sev-
eral approaches to the synthesis of isoquinolinium salts
were investigated. First, we reasoned that the Bischler-
Napieralski reaction of N-substituted amides would
afford N-protected 3,4-dihydroisoquinolines, thus pre-
venting cyclization of the C-2′ side chain to the proto-
berberine skeleton. However, the reactions of the N-me-
thylacetamide 12d under the previously tested conditions
(PCl5 or POCl3, CH3CN) gave mixtures of products, and
the desired dihydroisoquinoline could not even be de-
tected (1H NMR). Next, we tried the reduction-alkyla-
tion sequence on 3-arylisoquinolinium salts, previously
prepared by oxidation of the corresponding C-2′-func-
tionalized 3-aryl-1,2,3,4-tetrahydroisoquinolines.50 Un-
fortunately, all attempts to perform the intramolecular
cyclization on these substrates were unsuccessful: the
intermediate 1,2-dihydroisoquinoline was detected by 1H
NMR, but no alkylation was observed.51
1
torial disposition. Thus, the H NMR chemical shift of
H-8 (4.49 ppm) and the presence of Bohlman bands in
the IR spectrum (2740 cm-1) were consistent with a trans
B/C ring junction, with the C-8-Ph in a pseudoequatorial
disposition, in accordance with the data reported for other
8-phenyltetrahydroprotoberberines.47 Besides compara-
tive criteria, the stereochemistry of 21c was confirmed
In view of these results, we planned a route to the
benzo[c]phenanthridine skeleton on the basis of our
earlier report of the synthesis 3-arylisoquinolinium salts
(44) Pelter, A.; Smith, K.: Boron-Hydrogen Compounds. In Com-
prehensive Organic Chemistry; Barton, D., Ollis, W. D., Eds.; Pergamon
Press: Oxford, 1979; Vol. 3; p 766.
(48) Bad´ıa, D.; Dom´ınguez, E.; Lete, E.; Villa, M.-J .; Castedo, L.;
(45) Kametani, T.; Ohtsuka, C.; Nemoto, H.; Fukumoto, K. Chem.
Pharm. Bull. 1976, 24, 2525.
(46) Bruderer, H.; Metzger, J .; Brossi, A.; Daly, J . J . Helv. Chim.
Acta 1976, 59, 2793.
Dom´ınguez, D. Heterocycles 1988, 27, 687.
(49) Gensler, W. J .; Shanasundar, K. T. J . Org. Chem. 1975, 40,
123.
(50) Sotomayor, N.; Dom´ınguez, E.; Lete, E. Tetrahedron 1995, 51,
(47) Mali, R. S.; Patil, S. D.; Patil, S. L. Tetrahedron 1986, 42, 2075.
12721.

Construction of Isoquinoline Alkaloids
J . Org. Chem., Vol. 61, No. 12, 1996 4067
Sch em e 10
Sch em e 12
nitrilium salts, proposed intermediates in the Bischler-
Napieralski cyclization.52 Consequently, the presence of
the N-benzyl group would avoid the retro-Ritter reaction.
On the other hand, isomerization of the (E)-enamide to
the synthetically useful (Z)-enamide could take place
under the reaction conditions as we have observed for
related systems.17 Preliminary experiments which em-
ployed PCl5 as condensing agent revealed that these
enamides could not be cyclized under several different
conditions. However, treatment of 24 with POCl3 in
acetonitrile under reflux provided the benzophenanthri-
dinium salt 26 in high yield (80%) (Scheme 12). Although
the use of naphthylamides in the synthesis of benzo[c]-
phenanthridines is well precedented,8a their preparation
usually involves lengthy synthetic sequences. For in-
stance, the synthesis of sanguilutine of Ishii53 requires
the preparation of a naphthylamide from a 2-aryltetral-
one (four steps), which was obtained by the Robinson
method54 (five steps). Ishikawa55 has recently reported
a novel synthesis of macarpina whose last step is a
Bischler-Napieralski cyclization of a naphthylforma-
mide. The latter amide was prepared from a deoxyben-
zoin by a sequence that involved, as key steps, a
Reformatsky reaction, intramolecular acylation, and
aromatic nitrosation (11 steps). Furthermore, Bisagni
and J anin have also reported56 new access to ben-
zophenanthridines through thermal cyclization of ethyl
carbamates of 2-aryl-1-naphthylamines. The requisite
urethanes for the key cyclization step were prepared from
2-aryltetralones. Our methodology considerably reduces
the number of steps and therefore simplifies the synthesis
of this type of alkaloid.
On the other hand, under the same cyclization condi-
tions the (E)-enamide 25 was isomerized to the Z dias-
tereomer (1H NMR monitoring), which is readily cyclized
to the 3-arylisoquinolinium salt 27. Because of its
instability, 27 was transformed into the dihydroben-
zophenanthridine 28 without further purification. Thus,
reduction of 27 with NaBH4 in THF at room temperature,
followed by intramolecular acylation (HCl/MeOH)12 of the
resulting 1,2-dihydroisoquinoline, led to 28 (overall yield
35%, from enamide 25). Since this phenolic benzophenan-
thridine also decomposed rapidly, it was O-acetylated
(Ac2O/pyridine) to give quantitatively 29 (Scheme 13).
Fortunately, we discovered that treatment of the
mixture of naphthylamide 24 and (E)-enamide 25 with
POCl3 in acetonitrile under reflux gave a mixture of the
benzophenanthridine 26 and the 3-arylisoquinoline 27,
which was subjected to the above-described synthetic
sequence to afford 29: (a) reduction (NaBH4, THF), (b)
intramolecular acylation (HCl/MeOH), and (c) acylation
of the phenolic hydroxyl group (Ac2O, pyridine). This
considerably improved the overall yield of the process
(60% vs 35%).
Sch em e 11
via enamides.17 The overall strategy involved the syn-
thesis and Bischler-Napieralski cyclization of appropri-
ately functionalized N-1,2-diarylethylenamides. This
may offer a rapid entry into the benzo[c]phenanthridine
skeleton, and we were interested in trying this methodol-
ogy to simplify the synthesis of planar 8,9-disubstituted
benzophenanthridinium salts. Since treatment of the
enamide 22, derived from deoxybenzoin 9, has been
shown17 to produce the isochroman 17, instead of the
expected isoquinoline (Scheme 10), we decided to test the
above-mentioned strategy on the keto ester 23.
The starting keto ester 23 was prepared by esterifica-
tion of keto acid 6 with methyl iodide in acetone using
potassium carbonate. Treatment of 23 with benzylamine
in the presence of triethylamine and titanium tetrachlo-
ride in dimethoxyethane at -83 °C under strictly anhy-
drous conditions led to an intermediate imine, which was
in situ acetylated with acetyl chloride to afford a 1:1.1
mixture of naphthylamide 24 and the (E)-enamide 25
(overall yield 60%). These products were separated by
HPLC and the stereochemistry of 25 assigned on the
basis of NOE difference experiments. Thus, the large
NOE from the enamidic proton to the methyl protons of
the acetyl group, and vice versa, is only compatible with
an E configuration for this compound. Presumably, 24
is formed by intramolecular acylation of the initially
formed Z-isomer of 25 to give the corresponding naphthol,
which is in situ acetylated to afford 24 (Scheme 11).
Both products, the naphthylamide 24 and the (E)-
enamide 25, proved to be useful precursors of benzo[c]-
phenanthridines. Since 24 and 25 are N,N-disubstituted
amides, we thought that cyclization must proceed through
an intermediate chloriminium salt, a highly electrophilic
species, because of the impossibility of formation of
(51) The 3-[2-(2-hydroxyethyl)-4,5-dimethoxyphenyl]-6,7-dimethoxy-
N-methylisoquinolinium chloride 31 was prepared by deprotection of
3-[2-[2-[(tert-butyldiphenylsilyl)oxy]ethyl]-4,5-dimethoxyphenyl]-6,7-
dimethoxy-N-methylisoquinolinium iodide 30 with methanolic HCl (see
the supporting information for data). Treatment of 31 with NaBH4
afforded the corresponding 1,2-dihydroisoquinoline, which could be
detected (1H NMR) but was too labile to be fully characterized.
Treatment of the crude product with PCC or PBr3, under previously
described conditions for similar substrates (ref 13), gave only mixtures
of products.
(52) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
(53) Ishii, H.; Ishikawa, T.; Watanabe, T.; Ishikawa, Y. I.; Kawanabe,
E. J . Chem. Soc., Perkin Trans. 1 1984, 2283.
(54) Richardson, T.; Robinson, R. J . Chem. Soc. 1937, 855.
(55) Ishikawa, T.; Saito, T.; Ishii, H. Tetrahedron 1995, 51, 8447.
(56) J anin, Y. L.; Bisagni, E. Tetrahedron 1993, 49, 10305.

4068 J . Org. Chem., Vol. 61, No. 12, 1996
Sotomayor et al.
Sch em e 13a
stirred at rt for 2 h. After this period, the reaction was
quenched with MeOH (0.5 mL), the solvent was removed in
vacuo, and the reaction mixture was dissolved in CH2Cl2 (20
mL). The solution was washed with brine (2 × 10 mL), dried
(Na2SO4), and concentrated in vacuo. Flash column chroma-
tography (silica gel, 9:1 hexane/ethyl acetate) afforded the
alcohol 7 (70 mg, 35%) as a white solid which was recrystal-
lized from ethyl acetate: mp 135-136 °C (lit.20 mp 139-141
°C).
Meth od B. Keto acid 6 (500 mg, 1.3 mmol) was added in
portions to a mixture of NaBH4 (223 mg, 51.5 mmol) and AlCl3
(193 mg, 1.5 mmol) in diglyme (10 mL) at 0 °C. The reaction
mixture was stirred at rt for 14 h and then poured into an ice
(5 g)-12 M HCl (1 mL) mixture and extracted with CH2Cl2 (3
× 5 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, 2:8 hexane/ethyl acetate)
to afford two fractions:
a
F r a ction 1: 1-(3,4-d im eth oxyben zyl)-6,7-d im eth oxy-3-
isoch r om a n on e (13): 146 mg, 31%; mp (MeOH) 174-175
°C (lit.20 mp 173-175 °C).
Reagents: (a) POCl3, CH3CN; (b) (1) NaBH4, THF, (2) 12 M
HCl, MeOH; (c) (AcO)2O, pyridine.
F r a ction 2: a lcoh ol 7: 200 mg, 40%; mp (EtOAc) 135-
Con clu sion s
136 °C (lit.20 mp 139-141 °C).
Convenient approaches to the target protoberberine
and benzo[c]phenanthridine derivatives via Bischler-
Napieralski cyclization-N/C-alkylation sequences have
been developed. It has been demonstrated that reactions
of C-2′-functionalized 1,2-diarylethylamides under Bis-
chler-Napieralski cyclization conditions allow the one-
pot preparation of 2,3-disubstituted 13,14-dihydroproto-
berberines, which could not be synthesized by direct
oxidation of the corresponding tetrahydroprotoberberines,57
and represent additional examples of this novel oxidation
stage in the chemistry of protoberberine alkaloids. In
addition, the Bischler-Napieralski reaction of C-2′-
functionalized 1,2-diarylethylenamides constitutes a very
direct route into planar 8,9-dialkoxylated benzo[c]phenan-
thridinium salts in a reduced number of steps (three to
four steps from keto acid 4, one more from commercial
homoveratric acid), with comparatively high overall
yields.
Meth od C. Keto acid 6 (16.30 g, 43.5 mmol) was added in
portions to a mixture of NaBH4 (7.27 g, 0.2 mol) and TiCl4
(4.7 mL, 47.8 mmol) in dry DME (300 mL) at 0 °C, under argon
atmosphere. The reaction mixture was stirred at rt for 16 h,
and then the reaction was quenched with water (150 mL) and
the solution was extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were washed with brine, dried (Na2-
SO4), and concentrated in vacuo. The residue was recrystal-
lized from ethyl acetate to afford 7 (13.18 g, 81%) as a white
solid: mp 135-136 °C (lit.20 mp 139-141 °C).
1-[2-[2-[(t er t -B u t y ld i p h e n y ls i ly l)o x y ]e t h y l]-4,5-
d im eth oxyp h en yl]-2-(3,4-d im eth oxyp h en yl)eth a n ol (8).
To a stirred solution of the alcohol 7 (1.00 g, 2.7 mmol) and
imidazole (413 mg, 6.1 mmol) in dry DMF (15 mL) was added
dropwise tert-butyldiphenylchlorosilane (0.79 mL, 3.0 mmol)
at rt under argon atmosphere. After 1.5 h, water (5 mL) was
added, and the resulting mixture was extracted with CH2Cl2
(3 × 15 mL). The combined organic extracts were washed with
brine (2 × 10 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
(silica gel, 50% hexane/ethyl acetate) to afford 8 (1.55 g, 94%)
as a white solid which was recrystallized from hexane: mp
1
89-90 °C; IR (KBr) 3600, 1100 cm-1; H NMR (CDCl3) 1.01
Exp er im en ta l Section
(s, 9H), 2.00 (broad s, 1H), 2.76 (t, J ) 6.7 Hz, 2H), 2.86 (m,
2H), 3.77 (t, J ) 6.7 Hz, 2H), 3.78 (s, 6H), 3.87 (s, 3H), 3.88 (s,
3H), 4.92 (t, J ) 7.4 Hz, 1H), 6.54 (s, 1H), 6.59 (d, J ) 1.9 Hz,
1H), 6.66 (dd, J ) 8.1, 1.9 Hz, 1H), 6.76 (d, J ) 8.1 Hz), 6.94
(s, 1H), 7.25-7.60 (m, 10H); 13C NMR (CDCl3) 19.11, 26.73,
34.88, 44.77, 55.62, 55.66, 55.78, 55.84, 65.00, 71.37, 109.02,
111.04, 112.67, 113.06, 121.34, 127.52, 127.94, 129.54, 130.76,
133.28, 133.35, 134.19, 135.43, 135.45, 147.54, 147.77, 148.56;
MS (EI) m/z (rel intensity) 582 (29, M+ - 18), 449 (24), 199
(59), 194 (28), 193 (100), 165 (20), 152 (65), 151 (51). Anal.
Calcd for C36H44O6Si : C, 71.96; H, 7.39. Found: C, 71.98; H,
7.44.
2-[2-[(ter t-Bu t yld ip h en ylsilyl)oxy]et h yl]-4,5-d im et h -
oxyp h en yl 3,4-Dim eth oxyben zyl Keton e (9). Meth od A.
A solution of DMSO (0.26 mL, 3.8 mmol) in CH2Cl2 (0.5 mL)
was added dropwise to a stirred solution of oxalyl chloride (0.14
mL, 1.8 mmol) in CH2Cl2 (5 mL) at -83 °C under argon
atmosphere. After 10 min, a solution of the alcohol 8 (984 mg,
1.6 mmol) in CH2Cl2 (4 mL) was added, and the reaction
mixture was stirred at -83 °C for 20 min. Triethylamine (1.1
mL, 8.2 mmol) was added, and the resulting solution was
allowed to warm to rt (1 h). Water (12 mL) was added, the
mixture was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic extracts were washed with HCl (5 mL, 1%
aqueous), water (5 mL), Na2CO3 (5 mL, 5% aqueous), and
water (5 mL). The organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, 7:3 hexane/ethyl acetate)
to afford two fractions:
Gen er a l P r oced u r es. Melting points were determined in
unsealed capillary tubes and are uncorrected. IR spectra were
obtained on KBr pellets (solids) or CHCl3 solution (oils). NMR
spectra were recorded at 20-25 °C, running at 250 MHz for
1H and 62.8 MHz for 13C in CDCl3 solutions, unless otherwise
stated. 1H-{1H} NOE experiments were carried out in the
difference mode by irradiation of all the lines of a multiplet.58
Assignment of individual 13C resonances are supported by
DEPT experiments. Mass spectra were recorded by the
Universities of La Laguna and Santiago de Compostela. TLC
was carried out with 0.2 mm thick silica gel plates (Merck
Kiesegel GF254). Visualization was accomplished by UV light
or by spraying with Dragendorff’s reagent.59 Flash column
chromatography60 on silica gel was performed with Merck
Kiesegel 60 (230-400 mesh). HPLC was performed using a
LiChrosorb Si60 (7 µm) column. All solvents used in the
reactions were anhydrous and purified according to standard
procedures.61
2-(3,4-Dim e t h oxyp h e n yl)-1-[2-(2-h yd r oxye t h yl)-4,5-
d im eth oxyp h en yl]eth a n ol (7). Meth od A. BH3-DMS (0.3
mL of a 2 M solution in THF, 0.6 mmol) was added dropwise
to a solution of the keto acid 6 (200 mg, 0.5 mmol) in THF (10
mL) at rt, under argon atmosphere. The reaction mixture was
(57) Suau, R.; Silva, M. V.; Valpuesta, M. Tetrahedron 1991, 47,
5841.
(58) Kinss, M.; Sanders, J . K. M. J . Magn. Reson. 1984, 56, 518.
(59) Stahl, E. Thin-Layer Chromatography, 2nd ed.; Springer-
Verlag: Berlin, 1969.
(60) Still, W. C.; Kann, H.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(61) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Berlin, 1988.
F r a ction 1: (E)-1-[2-[2-[(ter t-bu tyld ip h en ylsilyl)oxy]-
et h yl]-4,5-d im et h oxyp h en yl]-2-(3,4-d im et h oxyp h en yl)-
eth en e (14): 95 mg, 10%; colorless oil; IR (CHCl3) 1610, 1520

Construction of Isoquinoline Alkaloids
J . Org. Chem., Vol. 61, No. 12, 1996 4069
1
cm-1; H NMR (CDCl3) 1.01 (s, 9H), 2.98 (t, J ) 6.7 Hz, 2H),
mixture of the oximes 10a and 10b (613 mg, 1mmol) and acetic
anhydride (2.7 mL, 30 mmol) in dry pyridine (15 mL) was
stirred at rt for 4 h. The reaction mixture was poured into
water (10 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were washed with water (2 × 5 mL),
dried (Na2SO4), and concentrated in vacuo. Column chroma-
tography (silica gel, 7:3 hexane/ethyl acetate) afforded the
oxime acetate 15 in 96% overall yield (628 mg) as a separable
anti/ syn 1.2:1 mixture of diastereomers. An ti d ia ster eom er
3.81 (s, 3H), 3.85 (t, J ) 6.7 Hz, 2H), 3.89 (s, 3H), 3.90 (s, 3H),
3.93 (s, 3H), 6.61 (s, 1H), 6.78 (d, J ) 16.0 Hz, 1H), 6.85 (d, J
) 8.2 Hz, 1H), 6.99-7.07 (m, 2H), 7.07 (s, 1H), 7.18 (d, J )
16.0 Hz, 1H), 7.23-7.58 (m, 10H); 13C NMR (CDCl3) 19.07,
26.76, 35.97, 55.73, 55.79, 55.89, 64.76, 108.37, 109.15, 111.25,
113.46, 119.26, 124.45, 127.50, 128.30, 129.45, 129.05, 129.48,
130.98, 133.59, 135.46, 147.60, 148.35, 148.61, 149.00; MS (EI)-
m/z (rel intensity) 582 (M+, 71), 525 (29), 477 (81), 199 (49),
151 (85), 135 (100), 43 (81). Anal. Calcd for C36H42O5Si : C,
74.19; H, 7.27. Found: C, 74.35; H, 7.15.
15a : colorless oil; IR (CHCl3) 1610, 1770 cm-1 1H NMR
;
(CDCl3) 1.03 (s, 9H), 2.20 (s, 3H), 2.78 (t, J ) 6.6 Hz, 2H),
3.68 (s, 3H), 3.71 (s, 3H), 3.75 (s, 3H), 3.80 (s, 3H)*, 3.77-
3.82 (m, 2H)*, 3.92 (s, 2H), 6.46 (s, 1H), 6.55-6.71 (m, 4H),
7.30-7.43 (m, 6H), 7.56-7.64 (m, 4H) (*: partially overlapped
signals); 13C NMR (CDCl3) 19.13, 26.83, 36.07, 37.64, 55.71,
55.77, 55.85, 65.17, 111.09, 111.91, 112.34, 113.31, 121.48,
126.38, 126.85, 127.56, 129.54, 130.34, 133.70, 133.47, 146.82,
147.96, 148.80, 149.26, 165.52, 169.04; MS (EI) m/z (rel
intensity) 596 (M+ - 59, <1), 199 (48), 151 (100), 135 (33), 77
(17), 43 (13). Anal. Calcd for C38H45NO7Si: C, 69.59; H, 6.92;
N, 2.14. Found: C, 69.61; H, 6.87; N, 2.23. Syn d ia ster e-
om er 15b: colorless oil; IR (CHCl3) 1610, 1770 cm-1; 1H NMR
(CDCl3) 1.05 (s, 9H), 2.03 (s, 3H), 2.50 (t, J ) 6.6 Hz, 2H),
3.61 (s, 3H), 3.75 (s, 3H)*, 3.78 (s, 3H)*, 3.80 (s, 3H)*, 3.75-
3.82 (m, 4H)*, 6.41 (s, 1H), 6.53-6.72 (m, 4H), 7.31-7.41 (m,
6H), 7.56-7.62 (m, 4H) (*: partially overlapped signals); 13C
NMR (CDCl3) 19.89, 26.83, 36.07, 42.43, 55.63, 55.71, 55.78,
55.84, 65.35, 109.19, 110.56, 110.94, 112.51, 121.98, 125.09,
126.97, 127.64, 128.36, 129.64, 133.54, 135.48, 146.65, 148.11,
148.74, 148.85, 166.33, 168.48. Anal. Calcd for C38H45NO7-
Si: C, 69.59; H, 6.92; N, 2.14. Found: C, 69.72; H, 6.74; N,
2.24.
1-(3,4-Dim eth oxyben zyl)-6,7-dim eth oxyisoch r om an (16).
To a solution of a 1.2:1 mixture of the oximes 10a and 10b
(200 mg, 0.3 mmol) and 12 M HCl (2 mL) in methanol (8 mL)
was added 10% Pd/C (40 mg). The resulting suspension was
stirred under H2 atmosphere (2 atm) at rt for 6 h. The catalyst
was filtered off and the filtrate basified with NaOH (40%
aqueous). The aqueous layer was extracted with CH2Cl2 (3 ×
15 mL). The combined organic extracts were washed with
brine (2 × 5 mL), dried (Na2SO4), and evaporated to dryness
in vacuo. The residue was purified by flash chromatography
(silica gel, 6:4 hexane/ethyl acetate) to afford 16 (69 mg, 75%)
as a white solid which was recrystallized from methanol: mp
70-71 °C (lit.20 mp 69-71 °C).
1-[2-[2-[(t er t -B u t y ld i p h e n y ls i ly l)o x y ]e t h y l]-4,5-
d im eth oxyp h en yl]-2-(3,4-d im eth oxyp h en yl)eth yla m in e
(11). A solution of a 1.2:1 mixture of the oximes 10a and 10b
(613 mg, 1 mmol) in DME (3 mL) was added dropwise to a
stirred mixture of NaBH4 (160 mg, 4.2 mmol) and TiCl4 (0.2
mL, 2.1 mmol) in dry DME (10 mL) at 0 °C, under argon
atmosphere. The reaction mixture was stirred at rt for 14 h,
water (10 mL) was added, and the mixture was basified with
NaOH (40% aqueous). The aqueous layer was extracted with
CH2Cl2 (3 × 100 mL), and the combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo.
Column chromatography (silica gel, 9.8:0.2 CH2Cl2/MeOH)
afforded the amine 11 (359 mg, 60%) as a yellowish oil: IR
(CHCl3) 3360 cm-1; 1H NMR (CDCl3) 0.95 (s, 9H), 1.29 (broad
s, 2H), 2.52-2.80 (m, 4H), 3.66-3.71 (m, 2H)*, 3.68 (s, 3H)*,
3.70 (s, 3H)*, 3.77 (s, 3H), 3.82 (s, 3H), 4.16 (dd, J ) 8.4, 4.9
Hz, 1H), 6.47 (s, 1H), 6.48 (d, J ) 1.8 Hz, 1H), 6.57 (dd, J )
8.1, 1.8 Hz, 1H), 6.67 (d, J ) 8.1 Hz, 1H), 6.99 (s, 1H), 7.19-
7.34 (m, 6H), 7.46-7.51 (m, 4H) (*: partially overlapped
signals); 13C NMR (CDCl3) 19.01, 26.73, 35.27, 45.37, 52.09,
55.56, 55.61, 55.73, 55.86, 65.00, 108.90, 111.06, 112.37,
113.17, 121.03, 127.48, 127.78, 129.47, 131.55, 133.42, 133.49,
135.43, 147.19, 147.41, 147.57, 148.51. Anal. Calcd for
C36H45NO5Si: C, 72.08; H, 7.56; N, 2.34. Found: C, 72.14; H,
7.50; N,.2.27.
F r a ction 2: k eton e 9: 500 mg, 51%; colorless oil; IR
(CHCl3) 1680 cm-1; 1H NMR (CDCl3) 1.00 (s, 9H), 3.08 (t, J )
6.1 Hz, 2H), 3.77 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H)*, 3.87 (s,
3H)*, 3.83-3.87 (m, 2H)*, 4.04 (s, 2H), 6.67-6.79 (m, 4H),
7.24-7.37 (m, 7H), 7.50-7.54 (m, 4H) (*: partially overlapped
signals); 13C NMR (CDCl3) 19.18, 26.87, 37.27, 44.91, 55.76,
55.84, 56.13, 64.87, 111.27, 112.32, 112.74, 115.47, 121.45,
127.50, 129.11, 129.43, 133.86, 135.14, 135.53, 146.46, 147.91,
148.98, 151.07, 199.43; MS (EI) m/z (rel intensity) 598 (M+,
<1), 541 (35), 447 (29), 199 (58), 197 (41), 151 (83), 135 (100).
Anal. Calcd for C36H42O6Si: C, 72.21; H, 7.07; Found: C,
72.30; H, 6.86.
Meth od B. A solution of the alcohol 8 (600 mg, 1 mmol) in
CH2Cl2 (8 mL) was added to a suspension of PCC (323 mg,
1.5 mmol) in CH2Cl2 (2 mL), and the reaction mixture was
stirred at rt for 2 h. The resulting solution was diluted with
Et2O and filtered through a short pad of silica gel. The filtrate
was evaporated to dryness in vacuo, and the residue was
purified by flash column chromatography (silica gel, 7:3
hexane/ethyl acetate) to afford the ketone 9 (526 mg, 88%) as
a colorless oil, identical with a sample prepared as in method
A.
Meth od C. According to the procedure described in method
B, alcohol 8 (210 mg, 0.4 mmol) was treated with PDC (129
mg, 0.4 mmol) for 16 h. Workup and column chromatography
afforded the ketone 9 (176 mg, 67%) as a colorless oil, identical
with a sample prepared as in method A.
a n ti- a n d syn -r-(3,4-Dim eth oxyben zyl)-2-[2-[(ter t-bu -
t yld ip h en ylsilyl)oxy]et h yl]-4,5-d im et h oxyp h en yl 3,4-
d im eth oxyben za ld eh yd e Oxim e (10a ) a n d (10b). A solu-
tion of the ketone 9 (598 mg, 1 mmol) and hydroxylamine
hydrochloride (417 mg, 6 mmol) in dry pyridine (10 mL) was
refluxed for 1.5 h. The reaction mixture was allowed to cool
to rt and evaporated to dryness in vacuo, and the residue was
partitioned between water (15 mL) and CH2Cl2 (40 mL). The
organic extracts were dried (Na2SO4) and concentrated in
vacuo. Flash chromatography (silica gel, 6:4 hexane/ethyl
acetate) gave the oxime 10 in 89% overall yield (545 mg) as a
separable anti/ syn 1.2:1 mixture of diastereomers. a n ti-
Oxim e 10a : white solid; mp 129-131 °C (MeOH); IR (KBr)
1
1605, 3260 cm-1; H NMR (CDCl3) 1.02 (s, 9H), 2.73 (t, J )
7.1 Hz, 2H), 3.64 (s, 3H), 3.69 (s, 3H), 3.73 (s, 3H)*, 3.77 (s,
3H)*, 3.73-3.77 (m, 2H)*, 3.84 (s, 2H), 6.41 (s, 1H), 6.61-
6.62 (m, 4H), 7.23-7.38 (m, 6H), 7.58-7.62 (m, 4H), 7.84
(broad s, 1H) (*: partially overlapped signals); 13C NMR
(CDCl3) 19.14, 26.87, 35.32, 36.19, 55.70, 55.78, 65.42, 110.93,
111.75, 112.49, 113.32, 121.46, 127.57, 128.16, 128.52, 129.53,
129.90, 133.87, 135.58, 146.75, 147.53, 148.60, 148.89, 158.75;
MS (EI) m/z (rel intensity) 613 (8, M+), 556 (44), 388 (97), 199
(47), 151 (100). Anal. Calcd for C36H43NO6Si: C, 70.44; H,
7.06; N, 2.28. Found: C, 70.39; H, 7.06; N, 2.45. syn -Oxim e
10b: colorless oil; IR (CHCl3) 1605, 3450 cm-1 1H NMR
;
(CDCl3) 1.03 (s, 9H), 2.59 (t, J ) 6.9 Hz, 2H), 3.60 (s, 3H),
3.71 (s, 3H)*, 3.72 (s, 3H)*, 3.77 (s, 3H), 3.67-3.74 (m, 4H)*,
6.09 (s, 1H), 6.56-6.69 (m, 4H), 7.03-7.39 (m, 6H), 7.57-7.61
(m, 4H) (*: partially overlapped signals); 13C NMR (CDCl3)
19.14, 26.87, 36.06, 42.41, 55.67, 55.78, 55.81, 64.61, 109.81,
110.96, 112.48, 112.53, 121.71, 125.41, 127.61, 128.45, 128.76,
129.58, 133.76, 135.56, 146.91, 147.88, 148.62, 148.77, 158.90
; MS (EI) m/z (rel intensity) 614 (MH+), 199 (15), 152 (13),
N -[1-[2-[2-[(t er t -Bu t yld ip h e n ylsilyl)oxy]e t h yl]-4,5-
d im eth oxyp h en yl]-2-(3,4-d im eth oxyp h en yl)eth yl]a ceta -
m id e (12a ). Meth od A. Bu3P (1.1 mL, 4.4 mmol) was added
to a stirred solution of a 1.2:1 mixture of the oximes 10 (1 g,
1.6 mmol) and diphenyl disulfide (391 mg, 1.8 mmol) in THF
(6 mL) at rt, under argon atmosphere. After 2 h, NaBH3CN
(307 mg, 4.7 mmol) was added, followed by glacial AcOH (1.15
151 (100), 107 (12), 91 (10), 77 (13). Anal. Calcd for C36H43
-
NO6Si: C, 70.44; H, 7.06; N, 2.28; Found: C, 70.63; H, 7.43;
N, 2.58.
a n ti- a n d syn -O-Acetyl r-(3,4-Dim eth oxyben zyl)2-[2-
[(t er t -b u t y ld ip h e n y ls ily l)o x y ]e t h y l]-4,5-d im e t h o x y -
ben za ld eh yd e Oxim es (15a ) a n d (15b). A solution of a 1.2:1

4070 J . Org. Chem., Vol. 61, No. 12, 1996
Sotomayor et al.
mL), and the reaction mixture was stirred for 2 h. After this
period, Ac2O (1.15 mL) was added, and the mixture was stirred
for a further 62 h. The reaction was quenched with K2CO3 (5
mL, 5% aqueous) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo, and the residue was purified by flash chro-
matography (silica gel, 5:5 hexane/ethyl acetate) to obtain the
acetamide 12a (470 mg, 45%) as a colorless oil: IR (CHCl3)
(s, 3H, both rotamers)*, 3.79-3.89 (m, 2H, both rotamers)*,
5.19-5.27 (m, 1H, both rotamers), 6.08 (d, J ) 6.4 Hz , 1H,
both rotamers), 6.39-6.69 (m, 5H, both rotamers), 7.30-7.40
(m, 5H, both rotamers), 7.48-7.57 (m, 5H, both rotamers), 7.94
(s, 1H, both rotamers) (*: partially overlapped signals); 13C
NMR (CDCl3) 19.05, 26.78 (both rotamers), 35.24 (major
rotamer), 35.32 (minor rotamer), 41.57 (major rotamer), 43.74
(minor rotamer), 50.49 (major rotamer), 53.62 (minor rotamer),
55.59, 55.65, 55.70, 55.76, 55.93, 55.98, 64.65 (both rotamers),
109.03 (minor rotamer), 109.91 (major rotamer), 110.81 (major
rotamer), 111.13 (minor rotamer), 112.44 (major rotamer),
112.65 (minor rotamer), 113.39 (minor rotamer), 113.72 (major
rotamer), 121.38 (major rotamer), 121.54 (minor rotamer),
127.50, 127.55, 127.64, 129.51, 129.70 (both rotamers), 129.63
(major rotamer), 130.72 (major rotamer), 131.44 (minor rota-
mer), 133.26 (minor rotamer), 133.39 (minor rotamer), 133.43
(major rotamer), 135.45 (major rotamer), 147.35 (major rota-
mer), 147.53 (major rotamer), 147.85 (major rotamer), 147.91
(minor rotamer), 147.94 (minor rotamer), 148.40 (major rota-
mer), 148.68 (minor rotamer), 160.18 (major rotamer), 164.20
(minor rotamer); MS (EI) m/z (rel intensity) 583 (M+-44, <1)
199 (53), 197 (31), 165 (23), 151 (60), 135 (100), 105 (80), 91
(13), 77 (13), 57 (13), 44 (3). Anal. Calcd for C37H45NO6Si: C,
70.78; H, 7.23; N, 2.23. Found: C, 70.92; H, 7.18; N, 2.20.
1
1650, 1520 cm-1; H NMR (CDCl3) 1.01 (s, 9H), 1.81 (s, 3H),
2.68-2.89 (m, 3H), 3.09 (dd, J ) 13.4, 5.7 Hz, 1H), 3.67 (s,
3H)*, 3.73 (s, 3H), 3.77 (s, 3H), 3.83 (s, 3H), 3.62-3.71 (m,
2H)*, 5.22 (ddd, J ) 8.0, 6.8, 5.7 Hz, 1H), 5.57 (d, J ) 6.8 Hz,
1H), 6.43 (d, J ) 1.8 Hz, 1H), 6.49 (dd, J ) 8.1, 1.8 Hz, 1H),
6.57 (s, 1H), 6.62 (d, J ) 8.1 Hz, 1H), 6.67 (s, 1H), 7.26-7.38
(m, 6H), 7.40-7.57 (m, 4H) (*: partially overlapped signals);
13C NMR (CDCl3) 19.08, 23.27, 26.80, 35.41, 41.48, 50.90,
55.63, 55.67, 56.14, 64.52, 109.58, 110.82, 112.46, 113.91,
121.41, 127.57, 129.50, 129.93, 131.12, 133.69, 133.78, 135.52,
147.49, 147.80, 148.44, 168.90; MS (EI) m/z (rel intensity) 584
(M+-57, 1), 490 (21), 431 (21), 311 (21), 240 (15), 199 (54), 197
(24), 192 (22), 151 (72), 135 (100), 120 (75), 107 (75), 107 (21),
91 (21), 77 (21), 75 (24), 57 (25), 43 (60). Anal. Calcd for
C38H47NO6Si: C, 71.10; H, 7.39; N, 2.18. Found: C, 71.20; H,
7.43; N, 2.16.
Meth od B. Acetyl chloride (0.15 mL, 2.1 mmol) was added
dropwise to a solution of the amine 11 (1 g, 1.6 mmol),
triethylamine (0.31 mL, 2.5 mmol), and DMAP (24 mg, 0.2
mmol) in CH2Cl2 (50 mL) at 0 °C, under argon atmosphere.
The reaction mixture was stirred at rt for 4 h and then poured
into ice (25 g) and extracted with CH2Cl2 (3 × 30 mL). The
combined organic extracts were washed with brine (2 × 25
mL) and dried (Na2SO4), and the solvent was removed in
vacuo. Flash chromatography (silica gel, ethyl acetate) yielded
the acetamide 12a (910 mg, 85%), identical with a sample as
prepared in method A.
N-Meth yl-N-[1-[2-[2-[(ter t-bu tyldiph en ylsilyl)oxy]eth yl]-
4,5-(d im et h oxyp h en yl)-2-(3,4-d im et h oxyp h en yl)et h yl]-
a ceta m id e (12d ). A suspension of KOH (224 mg, 4 mmol) in
DMSO (2 mL) was stirred at rt for 5 min. Acetamide 12a (600
mg, 1 mmol) and MeI (2 mmol, 0.12 mL) were added, and the
reaction mixture was stirred at rt until no further evolution
of the starting material was observed (TLC monitoring, 16 h).
Water (5 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 15 mL). The combined organic extracts were
washed with brine (2 × 5 mL) and dried (Na2SO4), and the
solvent was evaporated to dryness in vacuo. The residue was
purified by flash chromatography (silica gel, 3:7 hexane/ethyl
acetate) to obtain recovered starting material (155 mg, 26%)
and the acetamide 12d (370 mg, 60%) as a mixture of rotamers
in a 2.5:1 major/ minor ratio: IR (CHCl3) 1740, 1640 cm-1; 1H
NMR (CDCl3) 1.01 (s, 9H, both rotamers), 1.55 (s, 3H, minor
rotamer), 1.83 (s, 3H, major rotamer), 2.58 (s, 3H, major
rotamer), 2.66 (s, 3H, minor rotamer), 2.70-3.22 (m, 4H, both
rotamers), 3.60-3.67 (m, 2H, both rotamers) , 3.73 (s, 3H,
major rotamer), 3.74 (s, 3H, major rotamer), 3.75 (s, 3H, minor
rotamer), 3.78 (s, 3H, both rotamers), 3.84 (s, 3H, minor
rotamer), 3.89 (s, 3H, major rotamer), 3.92 (s, 3H, minor
rotamer), 5.08 (dd, J ) 10.3, 2.8 Hz, 1H, minor rotamer), 6.18
(t, J ) 7.9 Hz, 1H, major rotamer), 6.52-6.58 (m, 4H, both
rotamers), 6.94-6.97 (m, 1H, both rotamers), 7.29-7.43 (m,
6H, both rotamers), 7.51-7.54 (m, 4H, both rotamers); 13C
NMR (CDCl3) 19.13 (both rotamers), 20.58 (minor rotamer),
22.21 (major rotamer), 26.82 (both rotamers), 27.92 (minor
rotamer), 30.75 (major rotamer), 34.88, 36.88 (both rotamers),
37.42 (minor rotamer), 55.57, 55.67, (both rotamers), 55.77
(major rotamer), 56.84, 56.28 (both rotamers), 59.24 (minor
rotamer), 64.55, (both rotamers) 110.80 (major rotamer),
111.04 (minor rotamer), 111.40 (minor rotamer), 111.85 (major
rotamer), 112.09 (major rotamer), 112.36 (minor rotamer),
114.01 (minor rotamer), 114.67 (major rotamer), 120.99 (major
rotamer), 121.37 (minor rotamer), 128.32 (major rotamer),
129.65 (major rotamer), 130.39 (major rotamer), 131.09 (minor
rotamer), 132.64 (major rotamer), 133.34 (minor rotamer),
133.64 (minor rotamer), 133.71 (minor rotamer), 127.55,
129.46, 135.50 (both rotamers), 146.59 (major rotamer), 147.10
(minor rotamer), 147.39 (major rotamer), 147.84 (minor rota-
mer), 148.04 (minor rotamer), 148.33 (minor rotamer), 148.59,
(major rotamer) 149.06 (major rotamer), 169.50 (major rota-
mer), 170.92 (minor rotamer). Anal. Calcd for C39H49NO6Si:
C, 71.41; H, 7.53; N, 2.14. Found: C, 71.32; H, 7.62; N, 2.16.
N -[1-[2-[2-[(t er t -Bu t yld ip h e n ylsilyl)oxy]e t h yl]-4,5-
d im eth oxyp h en yl]-2-(3,4-d im eth oxyp h en yl)eth yl]ben za -
m id e (12b). According to the procedure described in method
B for the synthesis of 12a , a solution of the amine 11 (680
mg, 1.1 mmol), triethylamine (0.22 mL, 1.7 mmol), and DMAP
(24 mg, 0.2 mmol) in CH2Cl2 (50 mL) was treated with benzoyl
chloride (0.16 mL, 1.4 mmol). After workup and column
chromatography (silica gel, 6:4 hexane/ethyl acetate), benza-
mide 12b was obtained (707 mg, 89%) as a white solid which
was recrystallized from methanol: mp 129-130 °C; IR (KBr)
1
1640 cm-1; H NMR (CDCl3) 1.00 (s, 9H), 2.75-2.90 (m, 2H),
3.02 (dd, J ) 13.6, 7.7 Hz, 1H), 3.19 (dd, J ) 13.6, 5.8 Hz,
1H), 3.67 (s, 3H), 3.74 (s, 3H)*, 3.79 (s, 3H)*, 3.82 (s, 3H)*,
3.72-3.82 (m, 2H)*, 5.44 (ddd, J ) 7.7, 6.8, 5.8 Hz, 1H), 6.32
(d, J ) 6.8 Hz, 1H), 6.51 (d, J ) 1.8 Hz , 1H), 6.56 (dd, J )
8.1, 1.8 Hz, 1H), 6.59 (s, 1H), 6.66 (d, J ) 8.1 Hz, 1H), 6.73 (s,
1H), 7.26-7.39 (m, 8H), 7.43-7.62 (m, 7H) (*: partially
overlapped signals); 13C NMR (CDCl3) 18.77, 26.21, 35.17,
41.27, 50.86, 55.24, 55.34, 56.73, 64.28, 109.49, 111.67, 112.24,
113.67, 121.17, 126.51, 127.26, 128.09, 129.20, 129.57, 129.65,
130.98, 135.19, 131.09, 133.32, 133.42, 134.17, 147.21, 147.28,
147.52, 148.23, 166.22; MS (EI) m/z (rel intensity) 552 (M+
-
151, 3), 199 (19), 151 (30), 135 (36), 105 (100), 77 (41). Anal.
Calcd for C43H49NO6Si: C, 73.36; H, 7.02; N, 1.99. Found: C,
73.42; H, 7.12; N, 2.04.
N -[1-[2-[2-[(t er t -Bu t yld ip h e n ylsilyl)oxy]e t h yl]-4,5-
d im eth oxyp h en yl]-2-(3,4-d im eth oxyp h en yl)eth yl]for m a -
m id e (12c). A solution of the amine 11 (1 g, 1.6 mmol) in
formamide (20 mL) was stirred at 150 °C for 15 min and then
allowed to cool to rt. The reaction mixture was diluted with
water (10 mL) and extracted with CH2Cl2 (3 × 25 mL). The
organic extracts were washed with brine (2 × 20 mL), dried
(Na2SO4), and concentrated to in vacuo. Flash chromatogra-
phy (silica gel, 3:7 hexane/ethyl acetate) gave 12c (890 mg,
85%) as a white solid which was recrystallized from hexane/
ethyl acetate. The formamide 12c was isolated as a mixture
of cis and trans rotamers in a 2.5:1 ratio: mp 50-52 °C; IR
1-(3,4-Dim eth oxyben zylid en e)-6,7-d im eth oxyisoch r o-
m a n (17). To a solution of the ketone 9 (100 mg, 0.17 mmol)
in acetonitrile (10 mL) was added P2O5 (97 mg, 0.68 mmol) in
portions at rt, under strictly anhydrous conditions. The
reaction mixture was stirred at rt for 20 h, the solvent was
removed in vacuo, and water (5 mL) was added. The resulting
solution was basified with NaOH (10% aqueous) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts were
1
(KBr) 1665, 1680 cm-1; H NMR (CDCl3) 1.00 (s, 9H, major
rotamer), 1.04 (s, 9H, minor rotamer), 2.68-2.78 (m, 2H, both
rotamers), 2.86-2.90 (m, 1H, both rotamers), 3.12 (dd, J )
13.5, 5.7 Hz, 1H, both rotamers), 3.66 (s, 3H, both rotamers),
3.73 (s, 3H, both rotamers), 3.76 (s, 3H, both rotamers), 3.79

Construction of Isoquinoline Alkaloids
J . Org. Chem., Vol. 61, No. 12, 1996 4071
washed with brine (2 × 5 mL), dried (Na2SO4), and concen-
trated in vacuo to afford 17 as a yellow solid which was
recrystallized from methanol (36 mg, 75%): mp 169-170 °C
(lit.20 mp 173-175 °C).
2,3,10,11-Tetr a m eth oxy-8-p h en yl-13,14-d ih yd r op r oto-
ber ber in iu m Ch lor id e (20b). According to the one-pot
procedure described for 20a , a solution of benzamide 12b (288
mg, 0.4 mmol) in benzonitrile (10 mL) was treated with PCl5
(666 mg, 3.2 mmol) and the resulting mixture stirred at rt for
14 h. After workup, the crude reaction mixture was purified
by column chromatography (silica gel, 9.9:0.1 to 9.7:0.3 CH2-
Cl2/MeOH) to afford the protoberberinium chloride 20b (100
mg, 54%) as a yellow solid, which was recrystallized from ethyl
2,3,10,11-Tetr a m eth oxy-8-m eth yl-13,14-d ih yd r op r oto-
ber ber in iu m Ch lor id e (20a ). On e-P ot P r oced u r e. To a
solution of the acetamide 12a (256 mg, 0.4 mmol) in dry CH3-
CN (10 mL) was added PCl5 (666 mg, 3.2 mmol) in portions (6
× 111 mg) at 0 °C during 30 min, operating under strictly
anhydrous conditions. The reaction mixture was allowed to
warm to rt and stirred for 14 h. After this period, the solvent
was evaporated in vacuo, HCl (10 mL, 10% aqueous) was
added, and the mixture was extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were washed with brine
(2 × 10 mL) and dried (Na2SO4), and the solvent was removed
in vacuo. Column chromatography (silica gel, 9.95:0.05 to 9.7:
0.3 CH2Cl2/MeOH) afforded the dihydroprotoberberinium chlo-
ride 20a (108 mg, 67%) as a yellow solid, which was recrys-
tallized from ethyl acetate: mp 212-213 °C dec; IR (KBr) 1610
1
acetate: mp 234-235 °C dec; IR (KBr) 1610, 1730 cm-1; H
NMR (CDCl3) 2.79-2.86 (m, 1H), 2.99-3.12 (m, 1H), 3.26 (dd,
J ) 17.6, 16.7 Hz, 1H), 3.59 (s, 3H), 3.67 (dd, J ) 17.6, 4.7 Hz,
1H), 3.86 (s, 3H), 3.91 (s, 3H), 4.02 (s, 3H), 4.22-4.25 (m, 2H),
6.16 (dd, J ) 16.7, 4.7 Hz, 1H), 6.38 (s, 1H), 6.64 (s, 1H), 7.03
(s, 1H), 7.07 (s, 1H), 7.27-7.31 (m, 1H), 7.56-7.75 (m, 3H),
8.3-8.41 (m, 1H); 13C NMR (CDCl3) 29.00, 36.09, 52.12, 56.02,
56.40, 56.89, 60.33, 109.56, 110.81, 116.01, 120.25, 124.25,
124.96, 125.40, 130.68, 128.48, 128.89, 132.08, 135.58, 148.47,
148.61, 148.92, 157.07, 174.04; MS (EI) m/z (rel intensity) 430
(M+, 10), 429 (33), 353 (26), 352 (100), 336 (16), 214 (6), 176
(8), 77 (2). Anal. Calcd for C27H28ClNO4: C, 69.65; H, 6.06;
N, 3.01. Found: C, 69.36; H, 6.20; N, 3.11.
3-[2-(2-H yd r oxye t h yl)-4,5-d im e t h oxyp h e n yl]-6,7-d i-
m eth oxy-3,4-dih ydr oisoqu in olin iu m Hydr och lor ide (19b).
According to the one-pot procedure described for 20a , a
solution of formamide 12c (300 mg, 0.4 mmol) in CH2Cl2 (10
mL) was treated with PCl5 (666 mg, 3.2 mmol), and the
resulting mixture was stirred at rt for 16 h. After workup,
the crude reaction mixture was column chromatographed
(silica gel, 9.9:0.1 to 9.7:0.3 CH2Cl2/MeOH) to afford the
dihydroisoquinolinium chlorhydrate 19b (45 mg, 28%): IR
(CHCl3) 1610, 3300 cm-1; 1H NMR (CDCl3) 2.81-2.99 (m, 4H),
3.76 (s, 3H), 3.72-3.77 (m, 2H)*, 3.82 (s, 3H), 3.86 (s, 3H),
3.87 (s, 3H), 4.76 (ddd, J ) 13.8, 6.9, 2.8 Hz, 1H), 6.65 (s, 1H),
6.71 (s, 1H), 6.80 (s, 1H), 6.82 (s, 1H), 8.21 (d, J ) 2.8 Hz, 1H)
(*: partially overlapped signals); 13C NMR (CDCl3) 32.46,
35.87, 55.81, 56.09, 58.43, 63.82, 110.08, 111.10, 111.19,
113.31, 121.22, 129.31, 129.62, 134.09, 148.10, 148.82, 149.03,
153.20. Anal. Calcd for C21H25NO5‚HCl: C, 61.83; H, 6.42;
N, 3.42. Found: C, 62.10; H, 6.45; N,.3.66.
2,3,10,11-Tetr a m eth oxy-8-p h en yl-7,8,13,14-tetr a h yd r o-
p r otober ber in e (21c). NaBH4 (8 mg, 0.21 mmol) was added
to a suspension of dihydroprotoberberine 20b (100 mg, 0.21
mmol) in THF (10 mL) at 0 °C. The mixture was stirred for
15 min, going into solution. Water (5 mL) was added, and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The organic
extracts were washed with brine (2 × 5 mL) and dried (Na2-
SO4), and the solvent was removed in vacuo to afford the
protoberberine 21c as a yellow solid, which was recrystallized
from hexane/ethyl acetate (86 mg, 95%): mp 160-162 °C; IR
(CHCl3) 2740 cm-1 (trans-quinolizidine); 1H NMR (CDCl3)
2.29-2.38 (m, 1H), 2.43-2.50 (m, 1H), 2.81-2.87 (m, 1H),
2.94-3.05 (m, 1H), 2.99-3.10 (m, 1H), 3.28 (dd, J ) 15.3, 2.8
Hz, 1H), 3.57 (s, 3H), 3.83-3.87 (m, 1H)*, 3.86 (s, 3H)*, 3.87
(s, 3H)*, 3.91 (s, 3H), 4.49 (s, 1H), 6.13 (s, 1H), 6.58 (s, 1H),
6.67 (s, 1H), 6.82 (s, 1H), 7.27-7.41 (m, 5H) (*: partially
overlapped signals); 13C NMR (CDCl3) 29.42, 37.24, 48.44,
55.76, 55.81, 56.06, 59.27, 71.76, 108.74, 110.65, 111.20,
111.37, 126.52, 127.30, 127.45, 130.11, 130.62, 128.37, 129.36,
144.87, 147.13, 147.36; MS (EI) m/z (rel intensity) 431 (M+,
39), 354 (17), 241 (25), 240 (100), 239 (45), 225 (10), 210 (11),
209 (63), 192 (15), 191 (10), 176 (9), 165 (13), 91 (14), 77 (11).
Anal. Calcd for C27H29NO4: C, 75.15; H, 6.77; N, 3.24.
Found: C, 75.22; H, 6.92; N, 3.14.
Cor a lyd in e (21a ) a n d O-Meth ylcor yten ch ir in e (21b).
According to the procedure described for 21c, dihydroproto-
berberine (20a ) (100 mg, 0.25 mmol) was treated with NaBH4
(10 mg, 0.25 mmol) in THF (10 mL). After workup, a mixture
of coralydine (21a ) and O-methylcorytenchirine (21b) was
obtained quantitatively, in a 4:1 ratio, as boron complexes: IR
(CHCl3) 2300-2400 cm-1 (3 bands, BH); 1H NMR (CDCl3) 1.84
(d, J ) 6.5 Hz, 3H, 21a ), 1.97 (d, J ) 6.8 Hz, 3H, 21b), 2.63-
3.02 (m, 4H, 21b and 4H, 21a ), 3.10-3.30 (m, 1H, 21b), 3.31
(dd, J ) 16.6, 3.5 Hz, 1H, 21a ), 3.54 (dd, J ) 16.6, 11.5Hz,
1H, 21a ), 3.58-3.71(m, 1H, 21b), 3.81 (s, 6H, 21b), 3.84 (s,
6H, 21b), 3.88 (s, 6H, 21a ), 3.9 (s, 6H, 21a ), 3.96-3.98 (m,
1H, 21a ), 4.05 (dd, J ) 11.5, 3.5 Hz, 1H, 21a ), 4.34-4.41 (m,
1
cm-1; H NMR (CDCl3) 3.00 (s, 3H), 3.07-3.24 (m, 4H), 3.39
(dd, J ) 16.9, 4.5 Hz, 1H), 3.87 (s, 6H), 3.94 (s, 3H), 3.99 (s,
3H), 4.65 (broad d, J ) 13.2 Hz, 1H), 5.15 (broad d, J ) 14.8
Hz, 1H), 6.72 (s, 1H), 6.80 (s, 1H), 6.91 (s, 1H), 7.30 (s, 1H);
13C NMR (CDCl3) 19.72, 28.44, 35.48, 50.20, 55.99, 56.19,
56.38, 56.66, 59.41, 108.79, 110.18, 111.03, 112.55, 119.71,
123.62, 125.40, 133.88, 148.79, 148.91, 149.24, 157.01, 175.00;
MS (EI) m/z (rel intensity) 368 (M+, 3), 366 (24), 365 (100),
364 (71), 352 (20), 351 (12), 350 (47), 348 (13). Anal. Calcd
for C22H26ClNO4: C, 65.42; H, 6.48; N, 3.47. Found: C, 65.63;
H, 6.90; N, 3.45.
Bisch ler -Na p ier a lsk i Cycliza tion of Aceta m id e 22.
Isola tion of In ter m ed ia tes: (a ) N-[1-(2-Ch lor oeth yl-4,5-
d im et h oxyp h en yl)-2-(3,4-d im et h oxyp h en yl)et h yl]a cet -
a m id e (18). To a solution of the acetamide 22 (189 mg, 0.29
mmol) in dry CH3CN (7 mL) was added PCl5 (242 mg, 1.16
mmol) in portions at 0 °C, operating under strictly anhydrous
conditions. The reaction mixture was allowed to warm to rt
and then stirred for 2.5 h. The solvent was evaporated in
vacuo, the residue was dissolved in HCl (7 mL; 10% aqueous),
and the solution was extracted with CH2Cl2 (3 × 15 mL). The
organic extracts were washed with brine (2 × 5 mL), dried
(Na2SO4), and concentrated in vacuo. Column chromatography
(silica gel, 3:7 hexane/ethyl acetate) afforded the chloroaceta-
mide 18 (43 mg, 35%) as a colorless oil: IR (CHCl3) 1660 cm-1
;
1H NMR (CDCl3) 1.72 (s, 3H), 2.87 (t, J ) 7.0 Hz, 2H), 2.75-
2.94 (m, 1H), 3.08-3.020 (m, 1H), 3.64 (t, J ) 7.0 Hz, 2H),
3.68 (s, 3H)*, 3.78 (s, 6H), 3.84 (s, 3H)*, 3.77-3.84 (m, 1H),
4.32 (ddd, J ) 13.0, 9.1, 5.4 Hz, 1H), 6.20 (s, 1H), 6.63-6.70
(m, 3H), 6.74 (s, 1H) (*: partially overlapped signals); 13C NMR
(CDCl3) 22.53, 33.19, 33.36, 43.45, 51.16, 55.83, 56.00, 111.17,
112.78, 120.78, 127.37, 131.38, 134.65, 147.52, 148.23, 148.78,
148.88, 171.10; MS (EI) m/z (rel intensity) 423 (M+ + 2, <1),
421 (M+ < 1), 259 (14), 257 (43), 221 (15), 192 (10), 178 (32),
164 (15), 161 (12), 151 (24), 107 (15), 91 (15), 77 (17), 65 (11),
43 (100). Anal. Calcd for C22H28ClNO5: C, 62.68; H, 6.70; N,
3.32. Found: C, 62.59; H, 6.72; N, 3.30.
(b ) 3-[2-(2-Ch lor oet h yl)-4,5-d im et h oxyp h en yl]-6,7-d i-
m et h oxy-1-m et h yl-3,4-d ih yd r oisoq u in olin iu m H yd r o-
ch lor id e (19a ). To a solution of the acetamide 12a (140 mg,
0.22 mmol) in dry CH3CN (2 mL) was added PCl5 (366 mg,
1.76 mmol) in portions at 0 °C, very slowly (time, 2 h; PCl5/
amide ratio, 2/1; time, 6 h; PCl5/amide ratio, 4/1; time, 16 h;
PCl5/amide ratio, 8/1), operating under strictly anhydrous
conditions. The solvent was evaporated in vacuo, the residue
was dissolved in HCl (2 mL, 10% aqueous), and the solution
was extracted with CH2Cl2 (3 × 10 mL). The organic extracts
were washed with brine (2 × 5 mL), dried (Na2SO4), and
concentrated in vacuo. Column chromatography (silica gel,
9.5:0.5 CH2Cl2/MeOH) gave the isoquinolinium hydrochloride
1
19a (52 mg, 54%): IR (CHCl3) 1610 cm-1; H NMR (CDCl3)
2.71 (s, 3H), 2.82-2.99 (m, 2H), 3.17-3.31 (m, 2H), 3.71-3.76
(m, 2H), 3.87 (s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H),
4.58-4.69 (m, 1H), 6.75 (s, 1H), 6.80 (s, 1H), 7.35 (s, 1H), 8.12
(s, 1H); 13C NMR (CDCl3) 21.18, 26.42, 33.19, 43.82, 56.23,
56.60, 56.69, 57.48, 109.80, 110.51, 111.24, 113.26, 119.81,
123.01, 133.16, 134.47, 148.93, 149.77, 150.47, 157.17, 177.68.

4072 J . Org. Chem., Vol. 61, No. 12, 1996
Sotomayor et al.
1H, 21b), 4.52 (q, J ) 6.8 Hz, 1H, 21b), 6.50 (s, 1H, 21b), 6.54
(s, 1H, 21b), 6.8 (s, 1H, 21b), 6.54 (s, 1H, 21a ), 6.72 (s, 2H,
21a ), 6.74 (s, 1H, 21b), 6.76 (s, 1H, 21a ); 13C NMR (CDCl3)
(21a ) 15.43, 25.80, 31.09, 55.87, 56.13, 56.19, 57.59, 66.00,
68.44, 108.23, 109.17, 110.81, 125.50, 125.90, 126.06, 127.67,
147.67, 147.90, 148.11.
Treatment of these complexes with methanolic 3 M HCl at
rt for 16 h afforded coralydine (21a ) and O-methylcorytenchir-
ine (21b) quantitatively, whose physical data are identical to
those previously reported.45,46
with CH2Cl2 (3 × 15 mL). The combined organic extracts were
washed with brine (2 × 5 mL), dried (Na2SO4), and concen-
trated in vacuo. The residue was column chromatographed
(silica gel, 9.9:0.1 to 9.5:0.5 CH2Cl2/MeOH) to obtain the benzo-
[c]phenanthridinium chloride 26 as a yellow solid, which was
recrystallized from ethyl acetate/methanol (116 mg, 80%): mp
>380 °C dec; IR (KBr) 1610, 1770 cm-1 1H NMR (CDCl3
; +
d1-TFA) 2.71 (s, 3H), 3.31 (s, 3H), 4.04 (s, 3H), 4.10 (s, 3H),
4.14 (s, 3H), 4.27 (s, 3H), 6.27 (broad s, 2H), 7.16-7.18 (m,
3H), 7.25 (s, 1H), 7.43-7.46 (m, 3H), 7.80 (s, 1H), 8.33 (s, 1H),
8.73 (s, 1H); 13C NMR (CDCl3 + d1-TFA) 19.51, 21.40, 56.15,
56.34, 56.43, 56.79, 57.25, 98.56, 106.13, 106.95, 109.15,
114.26, 121.16, 123.60, 125.18, 129.17, 130.00, 130.53, 130.97,
131.57, 142.46, 150.87, 152.77, 153.11, 158.02, 169.47; MS-
(CI) m/z (rel intensity) 511(M+ - 1, 86), 454 (21), 378 (47),
304 (6), 234 (6), 165 (9), 91 (100), 43 (60). Anal. Calcd for
Meth yl 2-[(3,4-Dim eth oxyph en yl)acetyl)-4,5-dim eth oxy-
p h en yla ceta te (23). To a stirred mixture of the acid 6 (1.00
g, 2.7 mmol) and K2CO3 (1.51 g, 10.8 mmol) in acetone (50
mL) was added methyl iodide (1.7 mL, 27.0 mmol), and stirring
was continued for 1 h at 40-50 °C. The mixture was filtered,
the filtrate was evaporated to dryness, and the residue was
chromatographed (silica gel, 6:4 hexane/ethyl acetate) to obtain
23 (953 mg, 91%) as a yellowish solid, which was recrystallized
C
31H30ClNO6: C, 67.94; H, 5.52; N, 2.55. Found: C, 67.66; H,
5.50; N, 2.53.
1
from MeOH: mp 130-132 °C; IR (KBr) 1680, 1740 cm-1; H
11-Acetoxy-5-ben zyl-2,3,8,9-tetr a m eth oxy-6-m eth yl-5,6-
d ih yd r oben zo[c]p h en a n th r id in e (29). (a ) N-Ben zyl-11-
h yd r oxy-2,3,8,9-tetr a m eth oxy-6-m eth ylben zo[c]p h en a n -
th r id in e (28). According to the procedure described for 26,
a solution of the enamide 25 (200 mg, 0.38 mmol) and POCl3
(0.23 mL, 3.42 mmol) in dry acetonitrile (10 mL) was refluxed
for 3 h. After workup, the crude reaction mixture, without
further purification, was dried under high vacuum and dis-
solved in THF (10 mL). NaBH4 (20 mg, 0.4 mmol) was added
at 0 °C, and the solution was stirred for 45 min. After this
period, HCl (2 mL, 50% methanolic) was added, and the
resulting mixture was refluxed for 2 h. The reaction mixture
was basified with NaOH (40% aqueous), extracted with CH2-
Cl2 (3 × 15 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was chromatographed (silica gel, 5:5 hexane/ethyl
acetate) to obtain the benzo[c]phenanthridine 28 (63 mg,
NMR (CDCl3) 3.63 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 3.84 (s,
3H), 3.85 (s, 2H), 3.87 (s, 3H), 4.12 (s, 2H), 6.67 (s, 1H), 6.72
(broad s, 1H), 6.65-6.67 (m, 2H), 7.36 (s, 1H); 13C NMR
(CDCl3) 40.01, 47.27, 51.77, 55.74, 55.79, 55.91, 56.03, 111.25,
112.30, 113.42, 115.29, 121.36, 127.43, 128.51, 129.63, 147.17,
147.88, 148.98, 151.61, 172.05, 198.98; MS (EI) m/z (rel
intensity) 389 (MH+, 42), 388 (M+, 15), 357 (22), 237 (52), 209
(84), 179 (23), 151 (100). Anal. Calcd for C21H24O7: C, 64.92;
H, 6.23. Found: C, 64.65; H, 6.32.
N -[3-Ace t oxy-2-(3,4-d im e t h oxyp h e n yl)-6,7-d im e t h -
oxyn a p h th yl]-N-ben zyla ceta m id e (24) a n d Meth yl (E)-
2-[1-(N-Ben zyla ceta m id o)-2-(3,4-d im eth oxyp h en yl)eth e-
n yl]-4,5-d im eth oxyp h en yla ceta te (25). TiCl4 (1 mL of a 1
M solution in CH2Cl2, 1 mmol) was added dropwise to a solu-
tion of keto ester 23 (390 mg, 1 mmol), benzylamine (0.10 mL,
1 mmol), and triethylamine (0.42 mL, 3 mmol) in dry DME
(7 mL) at -83 °C, under argon atmosphere. The mixture was
allowed to warm to rt and stirred for 30 min. Acetyl chloride
(0.21 mL, 3 mmol) and TiCl4 (1 mL of a 1 M solution in CH2-
Cl2, 1 mmol) were added, and the resulting mixture was stirred
at rt for 2 h. After this period, K2CO3 (5 mL; saturated
aqueous) was added, and the mixture was extracted with CH2-
Cl2 (3 × 15 mL). The combined organic extracts were washed
with brine (3 × 10 mL), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, 4.5:5.5 hexane/ethyl acetate) to give a mixture
of the naphthylamide 24 and the enamide 25 in a 1:1.1 ratio
(315 mg, 60% overall). Analytical samples of both products
could be obtained by HPLC (5:5 hexane/ethyl acetate). 24: mp
186-188 °C; IR (KBr) 1655, 1770 cm-1; 1H NMR (CDCl3) 1.99
(s, 3H), 2.09 (s, 3H), 3.58 (d, J ) 14.5 Hz , 1H), 3.86 (s, 3H),
3.94 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 5.27 (d, J ) 14.5 Hz,
1H), 6.78-6.83 (m, 2H), 6.92-6.99 (m, 3H), 7.08 (s, 1H), 7.14-
7.23 (m, 5H); 13C NMR (CDCl3) 20.38, 22.81, 51.74, 55.63,
55.74, 55.79, 99.86, 106.19, 110.92, 112.56, 121.86, 122.31,
125.10, 126.10, 127.03, 128.07, 128.69, 128.81, 137.09, 137.16,
144.32, 148.48, 150.49, 150.20, 168.76, 170.51; MS(CI) m/z (rel
intensity) 529 (M+, 57), 488 (43), 446 (42), 445 (32), 444 (33),
396 (19), 395 (19), 355 (37), 354 (19), 323 (25), 322 (22), 91
(72), 57 (10), 43 (69). Anal. Calcd for C31H31NO7: C, 70.29;
H, 5.90; N, 2.65. Found: C, 70.06; H, 5.86; N, 2.71.
1
35%): IR (CHCl3) 3500 cm-1; H NMR (CDCl3) 1.17 (d, J )
6.5 Hz, 3H), 3.86 (s, 3H), 3.99 (s, 6H), 4.05 (s, 3H), 4.35 (q, J
) 6.5 Hz, 1H), 5.01 (d, J ) 15.6 Hz, 1H), 5.19 (d, J ) 15.6 Hz,
1H), 5.30 (s, 1H), 6.40 (s, 1H), 7.28-7.33 (m, 5H), 7.46 (s, 1H),
7.64 (s, 1H), 8.1 (s, 1H).
(b) 28 turned out to be unstable so, in successive experi-
ments, the crude reaction mixture described in (a), without
further purification, was dissolved in pyridine (3 mL) and
treated with Ac2O (0.2 mL) at 60-70 °C for 1 h. Water (3 mL)
was added, and the mixture was extracted with CH2Cl2 (3 ×
10 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was chromatographed (silica gel, 6:4 hexane/ethyl
acetate) to obtain the dihydrobenzo[c]phenanthridine 29 (68
mg, 35% overall from 25): IR (CHCl3) 1770 cm-1 1H NMR
;
(CDCl3) 1.15 (d, J ) 6.5 Hz, 3H), 2.40 (s, 3H), 3.88 (s, 3H),
3.96 (s, 3H), 3.96 (s, 6H), 4.21 (q, J ) 6.5 Hz, 1H), 4.35 (d, J
) 15.0 Hz, 1H), 4.74 (d, J ) 15.0 Hz, 1H), 6.58 (s, 1H), 6.81 (s,
1H), 6.90 (s, 1H), 6.99 (s, 1H), 7.29-7.41 (m, 5H), 7.78 (s, 1H);
13C NMR (CDCl3) 16.73, 21.29, 53.68, 55.82, 56.04, 57.58,
100.30, 105.50, 106.80, 108.23, 110.11, 127.13, 127.56, 128.60,
116.39, 116.95, 121.07, 130.23, 134.75, 137.97, 141.74, 142.10,
147.68, 147.90, 148.43, 150.17, 168.57; MS(CI) m/z (rel inten-
sity) 513 (M+, 12), 498 (47), 456 (18), 365 (42), 364 (24), 91
(100), 65 (12), 57 (18), 43 (91), 32 (37). Anal. Calcd for C31H31
-
NO6: C, 72.49; H, 6.09; N, 2.73. Found: C, 72.36; H, 6.19; N,
2.88.
1
25: IR (CHCl3) 1650, 1740 cm-1; H NMR (CDCl3) 2.41 (s,
3H), 3.25 (broad s, 2H), 3.49 (s, 3H), 3.51 (s, 3H), 3.70 (s, 3H),
3.81 (s, 3H), 3.89 (s, 3H), 4.53 (broad s, 2H), 6.32 (s, 1H), 6.37
(s, 1H), 6.53-6.55 (m, 2H), 6.65 (d, J ) 8.3, 1H), 6.81 (s, 1H),
7.18-7.28 (m, 5H); 13C NMR (CDCl3) 22.54, 36.94, 48.44, 51.82,
55.31, 55.77, 55.97, 110.76, 111.08, 112.54, 113.52, 122.35,
126.36, 127.06, 127.59, 128.24, 129.67, 135.76, 137.80, 148.63,
149.55, 171.03, 171.70; MS(CI) m/z (rel intensity) 520 (MH+,
100), 446 (4), 406 (10), 371 (4), 355 (4), 167 (33), 153 (13). Anal.
Calcd for C30H33NO7: C, 69.33; H, 6.40; N, 2.70. Found: C,
69.45; H, 6.36; N, 2.69.
11-Acet oxy-N-b en zyl-6-m et h yl-2,3,8,9-t et r a m et h oxy-
ben zo[c]p h en a n th r id in iu m Ch lor id e (26). POCl3 (0.23
mL, 3.42 mmol) was added to a solution of naphthylamide 24
in dry acetonitrile (10 mL), and the resulting solution was
refluxed for 3 h. The solvent was removed in vacuo, HCl (10
mL; 10% aqueous) was added, and the solution was extracted
Ack n ow led gm en t . Financial support from the
Basque Government (Project PI9370) and the University
of the Basque Country (Project 170.310-EA107/92) is
gratefully acknowledged. We also thank the Ministerio
de Educacio´n y Ciencia for a fellowship to N.S.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for new compounds described, assigned NMR data for
protoberberine 20c, and experimental procedure for isoquino-
line 31 (26 pages). This material is contained in libraries on
microfiche, immediately follows this article in microfilm ver-
sion of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O960007S