Synthesis of phthalideisoquinoline and protoberberine alkaloids and indolo[2,1-α]isoquinolines in a divergent route involving palladium(0)- catalyzed carbonylation

Article abstract of DOI:10.1021/jo982451w

6,7,3',4'-Alkoxy-substituted 1-(2'-bromobenzoyl)-3,4-dihydroisoquinoline methiodides 17 were treated with sodium borohydride in methanol or acetic acid to give erythro-1-(2'-bromo-α-hydroxybenzyl)-2-methyl-1,2,3,4- tetrahydroisoquinolines 19. Treatment of 17 with lithium aluminum hydride in tetrahydrofuran gave the threo-isomer 20 in preference to the erythro 19. On the basis of studies on palladium(0)-catalyzed carbonylation of 2-bromo-3,4- dimethoxybenzyl alcohol to 6,7-dimethoxyphthalide, amino alcohol 19 or 20 was treated with a catalytic amount of palladium(II) acetate and triphenylphosphine in an atmosphere of carbon monoxide in the presence of chlorotrimethylsilane and potassium carbonate in boiling toluene to give the corresponding erythro- or threo-types of phthalideisoquinoline alkaloids 1 or 2, respectively. One-pot cyclization of the erythro-amino alcohols 19 was achieved by heating in N,N-dimethylformamide containing potassium carbonate to give 2,3,8,9- or 2,3,9,10-alkoxy-substituted 5,6-dihydroindolo[2,1- α]isoquinolines 3, which have a unique tetracyclic skeleton characteristic of dibenzopyrrocoline alkaloids. Similarly, palladium-(0)-catalyzed carbonylation of 1-(2'-bromobenzyl)tetrahydroisoquinolines 21 in the presence of excess potassium carbonate was found to give 8-oxoberbines 22, which on reduction with lithium aluminum hydride can be converted to protoberberine alkaloids 4.

Full text of DOI:10.1021/jo982451w

J . Org. Chem. 1999, 64, 6583-6596
6583
Syn th esis of P h th a lid eisoqu in olin e a n d P r otober ber in e Alk a loid s
a n d In d olo[2,1-a ]isoqu in olin es in a Diver gen t Rou te In volvin g
P a lla d iu m (0)-Ca ta lyzed Ca r bon yla tion 1
Kazuhiko Orito,* Mamoru Miyazawa, Ryo Kanbayashi, Masao Tokuda, and Hiroshi Suginome
Laboratory of Organic Synthesis, Division of Molecular Chemistry, Graduate School of Engineering,
Hokkaido University, Sapporo 060-8628, J apan
Received December 16, 1998
6,7,3′,4′-Alkoxy-substituted 1-(2′-bromobenzoyl)-3,4-dihydroisoquinoline methiodides 17 were treated
with sodium borohydride in methanol or acetic acid to give erythro-1-(2′-bromo-R-hydroxybenzyl)-
2-methyl-1,2,3,4-tetrahydroisoquinolines 19. Treatment of 17 with lithium aluminum hydride in
tetrahydrofuran gave the threo-isomer 20 in preference to the erythro 19. On the basis of studies
on palladium(0)-catalyzed carbonylation of 2-bromo-3,4-dimethoxybenzyl alcohol to 6,7-dimethoxy-
phthalide, amino alcohol 19 or 20 was treated with a catalytic amount of palladium(II) acetate
and triphenylphosphine in an atmosphere of carbon monoxide in the presence of chlorotrimethyl-
silane and potassium carbonate in boiling toluene to give the corresponding erythro- or threo-types
of phthalideisoquinoline alkaloids 1 or 2, respectively. One-pot cyclization of the erythro-amino
alcohols 19 was achieved by heating in N,N-dimethylformamide containing potassium carbonate
to give 2,3,8,9- or 2,3,9,10-alkoxy-substituted 5,6-dihydroindolo[2,1-a]isoquinolines 3, which have
a unique tetracyclic skeleton characteristic of dibenzopyrrocoline alkaloids. Similarly, palladium-
(0)-catalyzed carbonylation of 1-(2′-bromobenzyl)tetrahydroisoquinolines 21 in the presence of excess
potassium carbonate was found to give 8-oxoberbines 22, which on reduction with lithium aluminum
hydride can be converted to protoberberine alkaloids 4.
In tr od u ction
exchange followed by treatment of the resulting lithium
salts with CO2 gas.5 In this paper, we report a new
method involving palladium(0)-catalyzed carbonylation
for the preparation of 5,6-dialkoxy-substituted phthalides
from 3,4-dialkoxy-substituted 2-bromobenzyl alcohols and
its application to the synthesis of phthalideisoquinoline
alkaloids.6
Palladium-catalyzed carbonylation leading to the for-
mation of benzolactams and benzolactones has recently
been studied extensively.2 These techniques have been
applied to the preparation of heterocyclic compounds and
some biologically active alkaloids.3,4 We have also been
interested in aromatic metalations, especially followed
by carboxylation and carbonylation, to use them as
synthetic tools for the construction of heterocyclic com-
pounds. We have reported a method for the preparation
of alkoxy-substituted benzolactones via halogen-lithium
Phthalideisoquinoline alkaloids are known to possess
a variety of physiological activities, including the inter-
esting roles of noscapine as a nonnarcotic cough cure and
(+)-bicuculline 1d as an effective antagonist of an inhibi-
tory neurotransmitter, γ-aminobutyric acid (GABA).7 The
alkaloids comprise a 6,7- or 6,7,8-alkoxy-substituted
1,2,3,4-tetrahydroisoquinoline and a 6′,7′-alkoxy-substi-
tuted phthalide ring; these two units are linked together
at their C-1 and C-3′ carbons to form either erythro- or
threo-isomers in Berberidaceae, Fumariaceae, Papaver-
aceae, and Ranunculaceae plants.8
Among many approaches,7,9,10 some methods for the
selective synthesis of the erythro-form of these alkaloids,
such as (()-â-hydrastine (1c),10c,11 (+)- and (-)-bicuculline
(1d ), (+)- and (-)-corytensine,10g,h or (+)-corlumine,10d,h
have been reported. In contrast, the methods devised for
synthesis of the threo-alkaloids have been based only on
the inversion of the erythro-form.12 We previously ob-
(1) This paper is subtitled “Benzolactams III”.
(2) For general reviews on carbonylation, see (a) Heck, R. F.
Palladium Reagents in Organic Syntheses; Academic Press: Orlando,
1985; pp 341-400. (b) Colquhoun, H. M.; Thompson, D. J .; Twigg, M.
V. In Carbonylation, Direct Synthesis of Carbonyl Compounds, Plenum
Press: New York, 1991. (c) Tsuji, J . In Palladium Reagents and
Catalysts, Innovation in Organic Synthesis; J ohn Wiley & Sons: New
York, 1995.
(3) For preparation of benzolactams, see: (a) Mori, M.; Chiba, K.;
Ban, Y. J . Org. Chem. 1978, 43, 1684-1687. (b) Ishikura, M.; Mori,
M.; Terashima, M.; Ban, Y. Chem. Commun. 1982, 741-742. (c) Mori,
M.; Ishikura, M.; Ikeda, T.; Ban, Y. Heterocycles 1981, 16, 1491-1494.
(d) Ishikura, M.; Mori, M.; Ikeda, T.; Terashima, M.; Ban, Y. J . Org.
Chem. 1982, 47, 2456-2461. (e) Mori, M.; Ishikura, M.; Ikeda, T.; Ban,
Y. Heterocycles 1984, 22, 253-256. (f) Mori, M.; Purvaneckas, G.-E.;
Ishikura, M.; Ban, Y. Chem. Pharm. Bull. 1984, 32, 3840-3847. (g)
Mori, M.; Uozumi, Y.; Kimura, M.; Ban, Y. Tetrahedron 1986, 42,
3793-3806. (h) Y. Uozumi, Y.; Kawasaki, N.; Mori, E.; Shibasaki, M.
J . Am. Chem. Soc. 1989, 111, 3725-3727. (i) Pandey, G. D.; Tiwari,
K. P. Synth. Commun. 1979, 9, 895-900. (j) Pandey, G. D.; Tiwari, K.
P. Tetrahedron 1981, 37, 1213-1214. (k) Cacchi, S.; Fabrizi, G.;
Malinelli, F. Synlett 1996, 997-998. (l) Cho, C. S.; Lee, J . W.; Lee, D.
U.; Shim, S. C.; Khim, T. J . Chem. Commun. 1996, 2115-2116.
(4) For preparation of benzolactones, see (a) Mori, M.; Chiba, K.;
Inotsume, N.; Ban, Y. Heterocycles 1979, 12, 921-924, and ref 3h. (b)
Coowel, A.; Stille, J . K. J . Am. Chem. Soc. 1980, 102, 4193-4198. (c)
Martin, L. D.; Stille, J . K.; J . Org. Chem. 1982, 47, 3630-3633. (c)
Larock, R. C.; Fellow, C. A. J . Am. Chem. Soc. 1982, 104, 1900-1907.
(d) Crisp, G. T.; Meyer, A. G. J . Org. Chem. 1992, 57, 6972-6975.
(5) Orito, K.; Miyazawa, M.; Suginome, H. Tetrahedron 1995, 51,
2489-2496.
(6) For a preliminary report, see Orito, K.; Miyazawa, M.; Suginome,
H. Synlett 1994, 245-246.
(7) For a review, see MacLean, D. B. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: Orlando, 1985; Vol. 24; pp 253-286.
(8) For a review, see Blasko, G.; Gula, D. J .; Shamma, M. J . Nat.
Products 1982, 45, 105-122.
(9) (a) Kametani, T. In The Total Synthesis of Natural Products;
ApSimon, J ., Ed.; J ohn Wiley and Sons: New York, 1977; Vol. 3, pp
1-272. (b) Rozwadowska, M. D. Heterocycles 1994, 39, 903-931.
10.1021/jo982451w CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/06/1999

6584 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
Sch em e 1
Ta ble 1. P d (0)-Ca ta lyzed Ca r bon yla tion of
2-Br om o-3,4-d im eth oxyben zyl Alcoh ol 5a a
products (%)
solvent time, h (5a ) 6a 7a 8a
entry
additivesb
K2CO3
Na2CO3
K2HPO4
K3PO4
K2CO3
20Na2CO3
20K3PO4
20K2CO3
K2CO3-2TMSCl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
benzene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
24
24
24
24
24
24
24
24
26
24
24
24
24
24
100
66
66
0
7
6
4
0
14
19
0
8
9
tained an initial idea for the selective formation of each
isomer from a common precursor13 and have also studied
some procedures for aromatic carboxylation and carbon-
ylation starting with aromatic metalations.5,6 In this
paper, we deal with the selective hydride reductions of
1-(2′-bromobenzoyl)-3,4-dihydroisoquinoline methiodides
17 and the palladium(0)-catalyzed carbonylation of the
resultant erythro- or threo-amino alcohols 19 or 20 in a
new route to the synthesis of phthalideisoquinoline
alkaloids. We also describe a similar carbonylation for
the preparation of 8-oxoberbines, synthetic precursors of
protoberberine alkaloids 4, and one-pot conversion of
erythro-amino alcohols 19 to an indolo[2,1-a]isoquinoline
skeleton 3, characteristic of dibenzopyrrocoline alkaloids.
46
30 20
56 27 15 25
49 13 27 11
21
35 21 35
30 40 21
18 13 66
0
59 20
9
9
4
2
4
3
0
5K2CO3-2TMSCl toluene
20K2CO3-2TMSCl toluene
0
90
95
94
23 75
Et3N
i-Pr2EtN
Bu3N
toluene
toluene
toluene
5
2
6
0
0
0
a
Reactions were carried out by heating a mixture of 5a (25 mg,
0.1 mmol), Pd(OAc)2 (4.4 mg, 0.02 mmol), PPh3 (10.6 mg, 0.04
mmol), and the appropriate additives in boiling solvent (2 mL) in
b
an atmosphere of CO gas. Arabic numerals in front of the bases
and TMSCl show their molar ratios to the substrate 5a .
Resu lts a n d Discu ssion
the present carbonylation-lactonization, as it gave the
desired benzolactone 6a in a relatively high yield (entries
5 and 8). Use of a large excess of these bases (20 mol
equiv) clearly accelerated the consumption rate of 5a , but
gave the undesired benzaldehyde 7a in a higher yield
than that of 6a , as shown in entries 6-8. Tertiary
amines, such as Et3N, i-Pr2EtN, and Bu3N, appeared to
be less effective (entries 12-14).15 Lack of selectivity in
these reactions has been observed in those of the analo-
gous bromides reported by the aforementioned
pioneers.4a,16
It has been reported that TMSCl accelerates the
copper-catalyzed conjugate addition of Grignard re-
agents17 and more recently some reactions involving other
metal reagents, such as Zn,18 Mg,19 Mn,20 [RhCl(C2H4)2]2,21
(CH3)2GaCl,22 NaH,23 and LiH.24 Assuming that TMSCl
may have a similar effect on the present reaction, it was
added into the system. In entry 9, a significant accelera-
tion effect of carbonylation was observed by the addition
of TMSCl. The dual addition of TMSCl and excess of K2-
P a lla d iu m (0)-Ca ta lyzed Ca r bon yla tion of o-Br o-
m oben zyl Alcoh ols. Carbonylative cyclization of 2-bro-
mobenzyl alcohol 5a to the corresponding phthalides 6a
was examined using Pd(OAc)2 and Ph3P for in situ
generation of the Pd(0) catalyst,14 on the basis of the Pd-
(0)-catalyzed carbonylation of ortho-bromobenzyl alcohols
reported previously by Mori and Ban.4a Treatment with
Pd(OAc)2-PPh3/CO gas in the presence of a powdered
alkali, Na2CO3, K2CO3, K2HPO4, or K3PO4, using dry
boiling toluene as a solvent caused the consumption of
bromobenzyl alcohol 5a (Scheme 1, Table 1). K3PO4 gave
aldehyde 7a in a higher yield than that of the desired
phthalide 6a , together with debromobenzyl alcohol 8a
(entry 4). K2CO3 may be a better base than K3PO4 for
(10) For selected articles published on and after 1985: (a) Narasim-
han, N. S.; J oshi, R. R.; Kusurkar, R. S. J . Chem. Soc., Chem. Commun.
1985, 177-178. (b) Seebach, D.; Huber, I. M. P. Chimia 1985, 39, 233-
234. (c) Seebach, D.; Huber, I. M. P.; Syfrig, M. A. Helv. Chim. Acta
1987, 70, 1357-1377. (d) Huber, T. M. P.; Seebach, D. Helv. Chim.
Acta 1987, 70, 1944-1954. (e) Rein, K. S.; Gawley, R. E. Tetrahedron
Lett. 1990, 31, 3711-3714. (f) Kessar, S. V.; Singh, P.; Vohra, R.; Kaur,
N. P.; Singh, K. N. J . Chem. Soc., Chem. Commun. 1991, 568-570.
(g) Rein, K. S.; Gawley, R. E. J . Org. Chem. 1991, 56, 1564-1573. (h)
Gawley, R. E.; Zhang, P. J . Org. Chem. 1996, 61, 8103-8112.
(11) (a) Moniot, J . L.; Shamma, M. J . Am. Chem. Soc. 1976, 98,
6714-6715; J . Org. Chem. 1979, 44, 4337-4342. (b) Moniot, J . L.; Abd
el Rahman, A. H.; Shamma, M. Tetrahedron Lett. 1977, 3787-3790.
(c) Shamma, M.; Hindenlang, D. M.; Wu, T.-T.; Moniot, J . L. Tetra-
hedron Lett. 1977, 49, 4285-4288.
(12) (a) Marshall, M. A.; Pyman, F. L.; Robinson, R. J . Chem. Soc.
1934, 1315-1320. (b) Gaa´l, G.; Kerekes, P.; Bogna´r, R. J . Prakt. Chem.
1971, 315, 935-939. (c) Gaa´l, G.; Kerekes, P.; Gorecki, P.; Bogna´r, R.
Magy. Ke´m. Foly. 1971, 77, 286-289; Chem. Abstr. 1971, 75, 98702b.
(d) Gaa´l, G.; Kerekes, P.; Bogna´r, R. Magy. Ke´m. Foly. 1971, 77, 533-
535; Chem. Abstr. 1972, 76, 25451e. (e) Teitel, S.; O’Brien, J .; Brossi,
A. J . Org. Chem. 1972, 37, 1879-1881.
(15) DBU, pyridine, 4-(dimethylamino)pyridine, and 2,2,6,6-tetra-
methylpiperidine were also ineffective.
(16) Other palladium catalysts were also examined. Under the
typical reaction conditions for carbonylation of o-iodobenzyl alcohols
[PdCl2(PPh3)2, Et3N, 1 atm of CO gas at 50-60 °C in DMF] reported
by Stille,4b,c 5a was unreactive. Treatments with PdCl2(PPh3)2 or Pd-
(PPh3)4 using K2CO3 as a base in boiling toluene consumed 5a slowly.
The main product was aldehyde 7a , accompanied with phthalide 6a
in 0-7% at most regardless of the presence or absence of TMSCl. Pd
black and Pd2(dba)3 did not work at all, and 5a was recovered
unchanged.
(17) (a) Chuit, C.; Foulon, J . P.; Normant, J . F. Tetrahedron Lett.
1980, 36, 2305-2310; 1981, 37, 1385-1389. (b) Bourgain-Commercon,
M.; Foulon, J . P.; Normant, J . F. J . Organomet. Chem. 1982, 228, 321-
326. (c) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015-
6018, 6019-6022. (d) Alexakis, A.; Berlan, J .; Besace, Y. Tetrahedron
Lett. 1986, 27, 1047-1050. (e) Horiguchi, Y.; Matsuzawa, S.; Naka-
mura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025-4028. (f)
Nakamura, E.; Matsuzawa, S.; Horiguchi, Y. Kuwajima, I. Tetrahedron
Lett. 1986, 27, 4029-4032.
(13) Orito, K.; Suginome, H.; De Silva, S. O.; Rodrigo, R. Heterocycles
1987, 26, 3077-3080.
(14) (a) Amatore, C.; J utand, A.; M’Barki, M. A. Organometallics
1992, 11, 3009-3013. (b) Amatore, C.; Carre´, E.; J utand, A.; M’Barki,
M. A. Organometallics 1995, 14, 1818-1826.

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids
J . Org. Chem., Vol. 64, No. 18, 1999 6585
Sch em e 2
CO3 induced faster consumption of 5a (entries 10 and
11), though the formation of benzaldehyde 7a again
became predominant. Although these results are not
satisfactory, it is notable that the aryl bromide (5a ) was
completely consumed within 24 h by the use of the
palladium(0) catalyst in the presence of TMSCl and a
large excess K2CO3 in refluxing toluene (entry 11).
Ster eoselective Red u ction of th e Im in iu m Sa lts
to Er yth r o- a n d Th r eo-Am in o Alcoh ols. Use of ami-
nobromobenzyl alcohols 19 and 20 carrying a tetrahy-
droisoquinoline ring as a key intermediate was planned
for the synthesis of phthalideisoquinoline alkaloids by the
carbonylative cyclization method. The isoquinoline sub-
stituent may act as an efficient internal trap of a
liberated HBr molecule25 and generate a steric repulsion
to the OH and Br (or Pd) groups, which provides a
favorable approach of both groups for the lactonization
of 19 (or 20) to a phthalideisoquinoline ring system. We
started to prepare bromobenzyl alcohol 19a as follows.
Acid chloride 12a was prepared from 2-bromo-3,4-
dimethoxybenzaldehyde26 by conventional methods via
the corresponding benzyl alcohol 5a (98%), benzyl chlo-
ride 9a , benzyl cyanide 10a (91%), and phenylacetic acid
11a (92%). N-Acylation of 3,4-dimethoxyphenethylamine
13 with this acid chloride 12a gave acetamide 14a (91%),
which was subjected to Bischler-Napieralski cyclization
with POCl3 in boiling toluene. The resultant dihydroiso-
quinoline (15a ) (85%) was subsequently exposed to
singlet oxygen27 to produce 16a in good yield. Methiodide
17a was readily obtained in 82% yield by heating 16a
with excess CH3I in CH3CN (Scheme 2). Similar trans-
formations yielded methiodides 17b-17f in good yields.
Additional iminium salts such as benzyl bromides 17g
and 17h and propyl iodide 17i were easily prepared from
16a or 16d , respectively.
Treatment of 17a with excess fresh NaBH4 in MeOH
gave a mixture of erythro- (19a ) and threo- (20a ) amino
alcohols in a ratio of 97:3,28 in contrast to the results of
NaBH4 reduction of the analogous compounds
reported.27b,29 Changing the solvent to AcOH produced a
remarkable exclusive erythro-selectivity even in the
reduction of other methiodides 17 and ketone 16a (Table
(18) (a) Gawronski, J . K. Tetrahedron Lett. 1984, 25, 2605-2608.
(b) Picotin, G.; Miginiac, P. J . Org. Chem. 1987, 52, 4796-4798;
Tetrahedron Lett. 1987, 28, 4551-4554. (c) Knochel, P.; Yeh, M. C. P.;
Berk, S. C.; Talbert, J . J . Org. Chem. 1988, 53, 2390-2392. (d) J ubert,
C.; Knochel, P. J . Org. Chem. 1992, 57, 5431-5438. (e) Knochel, P.;
Roozema, M. J.; Tucker, C.; Retherford, C.; Furlong, M. T.; AchyuthaRao,
S. Pure Appl. Chem. 1992, 64, 361-369. (f) Takai, K.; Kakiuchi, T.;
Uchimoto, K. J . Org. Chem. 1994, 59, 2671-2673.
Ta ble 2. Na BH4 Red u ction of 3,4-Dih yd r oisoqu in olin es
16 a n d 17
ratio of 19:20 (isolated yield of 19)
substrate
in MeOHa
in AcOHb
(19) Muzart, J .; Riahi, A. Synth. Commun. 1991, 21, 1247-1250.
(20) Takai, K.; Ueda, T.; Hayashi, T.; Moriwake, T. Tetrahedron Lett.
1996, 37, 7049-7052.
17a
17b
17c
17d
17e
17f
17g
17h
17i
97:3 (83%)
80:20
97:3 (92%)
95:5
100:0 (89%)
90:10 (80%)
(21) Schneider, M. E.; Mo¨hring, U.; Werner, H. J . Organomet. Chem.
1996, 520, 181-186.
100:0 (80%)
100:0 (87%)
100:0 (92%)
100:0 (88%)
100:0 (95%)
97:3
(22) Koide, K.; Ohno, M.; Kobayashi, S. Synthesis 1997, 1175-1176.
(23) (a) Feghouli, A.; Fort, Y.; Vanderesse, R.; Caubu`re, P. Tetra-
hedron Lett. 1988, 29, 1379-1382. (b) Fort, Y.; Feghouli, A.; Vander-
esse, R.; Caubu`re, P. J . Org. Chem. 1990, 55, 5911-5915.
(24) Ohkuma, T.; Hashiguchi, S.; Noyori, R. J . Org. Chem. 1994,
59, 217-221.
95:5 (85%)
16a
90:10 (80%)
(25) Effects of bulky amines as bases in a palladium(0)-catalyzed
carbonylation were reported, see: Murahashi, S.; Imada, Y.; Taniguchi,
Y.; Higashiura, S. J . Org. Chem. 1993, 58, 1538-1545.
(26) Sinhababu, A. K.; Borchardt, R. T. J . Org. Chem. 1983, 48,
2356-2360.
(27) (a) Martin, N. H.; J efford, C. W. Helv. Chim. Acta 1981, 64,
2189-2192. (b) Wert, K. L.; Chackalamannil, S.; Miller, E.; Dalton,
D. R.; Zacharias, D. E.; Glusker, J . P. J . Org. Chem. 1982, 47, 5141-
5150.
a
b
5 mol equiv of NaBH4. 10 mol equiv of NaBH4.
2). Treatment of N-benzyl bromide salt 17g or 17h with
NaBH4 in AcOH gave only N-benzyl erythro-amino
alcohol (19g or 19h ) in good yield, though the reduction
(28) When partially decomposed NaBH4, such as that in an old
bottle, was used for these reductions, the erythro-selectivity became
lower.
(29) (a) Moniot, J . L.; Shamma, M. J . Org Chem. 1979, 44, 4337-
4342. (b) McMahon, R. M.; Thornber, C. W. J . Chem. Soc., Perkin
Trans. 1 1982, 2163-2167.

6586 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
Ta ble 3. Red u ction of Meth iod id es 17a -d a n d Keton e
in MeOH failed. We were rather surprised that not only
17a -17f and 16a but also similar compounds with more
bulky N-substituents such as 17g, 17h , and 17i showed
high erythro-selectivity on NaBH4 reduction (Table 2),
since it has been reported that the relative yields of the
threo-alcohols were augmented consistently with the
increasing size of the N-substituent of norhydrastine
methyl ester.29a
Treatment of 17a with 1 mol equiv of NaBH4 gave
ketone 18a together with 19a in a 70:30 ratio. This
ketone 18a (92%) was decomposed during separation
from 19a on preparative TLC. The quantitative reduction
of 17a to 18a was best accomplished by catalytic hydro-
genation in MeOH in the presence of the Adams catalyst,
without further reduction to 19a or 20a . Ketone 18d was
also isolated as a colorless crystal in 90% yield by
catalytic hydrogenation. Reduction of ketone 18a with
NaBH4 in MeOH under the same conditions as those
described above gave a mixture of 19a and 20a (94:6)
[19a in 90% isolated yield (19d from 18d in 80%)],
proving that the reduction of 17 to 19 proceeded via the
corresponding ketones 18.
18a w ith Hyd r id e Rea gen ts in THF
ratio of products
substrate
reagent
i-Bu2AlHa
19:20
17a
17a
17a
17b
17c
17d
18a
76:24
40:60
29:71
33:67
17:83
25:75
28:72
a
NaAl(OCH2CH2OCH3)2H2
b
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
b
b
b
b
a
b
4 mol equiv at rt for 30 min. 2 mol equiv at rt for 5 min.
Sch em e 3
In general, ketones 18 were sensitive to air. N-Benzyl
ketones 18g and 18h were thus labile and could not be
isolated. When a stirred solution of 18a in MeOH was
treated with oxygen for 1 h at room temperature, it was
transformed to N-methylcorydaldine30 and 2-bromo-3,4-
dimethoxybenzoic acid almost quantitatively. When 19a
and 20a were heated under reflux in toluene in the
presence of the mild oxidant CuCl2 (2 equiv), a 3,4-
dihydroisoquinolinium salt and the corresponding benz-
aldehyde were almost quantitatively formed.31
When 17a was treated with 2 mol equiv of LiAlH4 in
THF at room temperature for 5 min, the threo-amino
alcohol 20a was obtained in preference to the erythro-
amino alcohol 19a in a 5:2 ratio (>90%). Because of the
close Rf values of both isomers on TLC, a mixture was
converted with Ac2O-pyridine to the corresponding
acetates which were separated on silica gel TLC as
described in detail in the Experimental Section. Saponi-
fication of each acetate with 5% potassium hydroxide in
MeOH at 50 °C for 5 min gave pure threo- (20a ) and
erythro- (19a ) amino alcohols, respectively.
Reduction of 17a was also examined using DIBALH
and bis(2-methoxyethoxy)alminum hydride. As shown in
Table 3, the latter reagent showed threo-selectivity
similar to that of the LiAlH4 reduction. The erythro-
selectivity in the reduction of the salts 17a with NaBH4
can be well explained according to Cram’s rule by the
attack (route a, Scheme 4) of hydride from the open
side.32a The opposite selectivity by aluminum hydride
reduction has not yet been clearly explained, but the
reduction may proceed via the formation of an oxygen-
aluminum-nitrogen complex. Alternatively, there may
be a similar chelation holding a lithium (or sodium) atom
(30) (a) Spa¨th, E.; Epstein, H. Ber. 1926, 59, 2791-2800. (b)
Kupchan, S. M.; Kubota, S.; Fujita, E.; Kobayashi, S.; Block, J . H.;
Telang, S. A. J . Am. Chem. Soc. 1966, 88, 4212-4218. (c) Reference
35b.
(31) A similar oxidative cleavage of laudanosine with ceric am-
monium nitrate has been reported. See Ralph, I.; Bick, C.; Bremner,
J . B.; Cava, M. P.; Wiriyachitra, P. Aust. J . Chem. 1978, 31, 321-326.
With 2 mol equiv of CuCl2, CuCl, CuBr2, CuBr, CuI2, or CuI in boiling
toluene, oxidative cleavages of 19j, the debromo derivative of 19a , and
N-methylephedrine were also observed.
(32) (a) Cram, J . D.; Abd Elhafez, F. A. J . Am Chem. Soc. 1952, 74,
5828-5835. (b) Cram, D. J .; Wilson, D. R. J . Am. Chem. Soc. 1963,
85, 1245-1249.
between the intermediate ketone (18) and aluminum
hydride in accordance with Cram’s chelate model,32b
followed by the attack (route b) of “internal” hydride on
the carbonyl group to give threo-alcohol 20 (Scheme 4).
Reduction with DIBALH showed erythro-selectivity, prob-

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids
J . Org. Chem., Vol. 64, No. 18, 1999 6587
Sch em e 4
Sch em e 5
ably owing to the attack of hydride from the open side.
Treatment of other methiodides, 17b, 17c, and 17d , with
LiAlH4 gave the corresponding threo-alcohols 20 in
preference to erythro-alcohols 19 in ratios of 2:1-5:1.
Syn t h esis of P h t h a lid eisoq u in olin e Alk a loid s.
Carbonylation of 19a (Scheme 3) with CO (1 atm) in the
presence of Pd(OAc)2 (20 mol %), PPh3 (40 mol %), and
tion and Bischler-Napieralski cyclization,42 which give
either 9,10-dialkoxyindolo[2,1-a]isoquinolines or a mix-
ture of 9,10- and 10,11-dialkoxy-substituted derivatives.
Our present method is able to produce 8,9-dialkoxy-
substituted indolo[2,1-a]isoquinolines or their 9,10-di-
alkoxy regioisomers selectively.
K2CO3 (2 mol equiv) in boiling toluene under nearly
standard conditions2a proceeded very slowly and 24 h
later gave the lactone 1a in a yield lower than 10%,
contrary to the expectation described above. However,
this was again overcome by the addition of TMSCl (2
equiv) and a large excess of K2CO3 (20 molar equiv),
which dramatically accelerated the reaction rate to
produce (()-cordrastine II (1a ) (from 19a ) and (()-
cordrastine I (2a ) (from 20a ) in almost quantitative
yields. The debromo derivative of 18a or 19a , which was
the expected byproduct corresponding to the aldehyde 7a
or alcohol 8a described above, was not detected. Applica-
tion of this procedure to other erythro-amino alcohols
19b-f gave almost the same results. When the afore-
mentioned threo-amino alcohol-rich mixture (19a :20a )
1:2.5) was subjected to the accelerated lactonization, the
products 1a and 2a were separable from each other on
silica gel TLC, and 2a was provided in 63% yield starting
from methiodide 17a . An attempt to perform the direct
lactonization to norcordrastine (1j) of amino alcohol 19j
having a secondary amino group gave an intractable
mixture including a small amount of 1j. However, similar
lactonizations of N-benzyl erythro-amino alcohols 19g and
19h , followed by removal of an N-benzyl group of the
resultant phthalide 1g (91%) and 1h (75%) by palladium-
catalyzed hydrogenolysis, gave (()-norcordrastine II
(1j)33,34 and (()-norbicuculline (1k ), respectively, in good
yields (Scheme 3).
erythro-1-(2′-Bromo-3′,4′-dimethoxy-R-hydroxybenzyl)-
6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 19a
was treated with Pd(OAc)2, PPh3, and excess K2CO3 in
boiling DMF in an atmosphere of carbon monoxide.
However, the expected carbonylation leading to the
formation of a phthalide ring did not occur at all, and
instead, a new compound 3a with no N-methyl group was
obtained. After careful examination to clarify the reaction
pathway, it was found that this reaction took place slowly
without CO gas, Pd(OAc)2, and PPh3, and it was com-
pleted in 3 days. On the basis of 1H and 13C NMR analysis
in comparison with the spectral data reported for a
similar system,38d,g,40 the structure of the exclusive
product was determined to be 2,3,8,9-tetramethoxy-5,6-
dihydroindolo[2,1-a]isoquinoline 3a (Scheme 5). This was
also supported by measuring the nuclear Overhauser
effect as follows. Irradiation of the signal of the proton
at position 12 (δ 6.67) resulted in an enhancement of the
signal areas of 1-H (20%, δ 7.18) and 11-H (10%, δ 7.24).
Irradiation of the doublet signal of the proton at position
10 (δ 6.81) resulted in an enhancement of the signal areas
of the aforementioned 11-H (19%) and the methoxy
protons (14%, δ 3.95) at position 9.
Methylenedioxy derivatives 19b, 19c, and 19d were
also transformed to the corresponding indolo[2,1-a]iso-
quinolines 3b, 3c, 3d in good yields under the conditions
described above. The N-H derivative of 19a (19j) gave
3a in 13% yield, while the N-benzyl derivative (19g)
failed to give 3a . This reaction appears to require a fairly
Syn th esis of In d olo[2,1-a ]isoqu in olin es.35 Indolo-
[2,1-a]isoquinolines have a structural feature of the so-
called dibenzopyrrocoline alkaloids, such as cryptausto-
line and cryptowoline, isolated from the bark of Crypto-
carya bowiei.36 Syntheses of these unique tetracyclic
structures have been accomplished by several methods,37
such as a benzyne reaction38 of 1-(2′-bromo-4′,5′-dialkoxy-
benzyl)isoquinolines, oxidative coupling of 1-benzyliso-
quinolines,39 enamine photocyclization,40 addition of benz-
yl anion to 3,4-dihydroisoquinoline,41 and radical cycliza-
(38) (a) Kametani, T.; Ogasawara, K. J . Chem. Soc. (C) 1967, 2208-
2212. (b) Benington, F.; Morin, R. D. J . Org. Chem. 1967, 32, 1050-
1053. (c) Kametani, T.; Fukumoto, K.; Nakano, T. J . Heterocycl. Chem.
1972, 9, 1363-1366. (d) Kametani, T.; Shibuya, S.; Kano, S. J . Chem.
Soc., Perkin Trans. 1 1973, 1212-1214. (e) Ahmad, I.; Gibson, M. Can.
J . Chem. 1975, 53, 3660-3664. (f) Kessar, S. V.; Batra, S.; Nadir, U.
K.; Gandhi, S. S. Ind. J . Chem. 1975, 13, 1109-1112. (g) Mak, C.-P.;
Brossi, A. Heterocycles 1979, 12, 1413-1416. (h) Ambros, R.; von
Angerer, S.; Wiegrebe, W. Arch. Pharm. 1988, 321, 481-486. (i)
Meyers, A. I.; Sielecki, T. M. J . Am. Chem. Soc. 1991, 113, 2789-2790.
(39) (a) Robinson, R.; Sugasawa, S. J . Chem. Soc. 1932, 798-805.
(b) Harley-Mason, J . J . Chem. Soc. 1953, 1465-1466. (c) Hess, U.;
Hiller, K.; Schroeder, R. S. J . Prakt. Chem. 1977, 319, 568-572.
(40) Ninomiya, I.; Yasui, J .; Kiguchi, T. Heterocycles 1977, 6, 1855-
1860.
(33) Kerekes, P.; Gaa´l, G.; Bogna´r, R.; To¨ro´, T.; Costisella, B. Acta
Chim. Acad. Sci. Hung. 1980, 105, 283-291.
(34) Clarke, S. I.; Kasum, B.; Prager, R. H.; Ward, A. D. Aust. J .
Chem. 1983, 36, 2493-2498.
(35) For a preliminary report, see Orito, K.; Miyazawa, M.; Sugi-
nome, H. Heterocycl. Commun. 1995, 1, 239-240.
(36) Ewing, J .; Hughes, G. K.; Ritchie, E.; Taylor, W. C. Nature 1952,
169, 618-619; Aust J . Chem. 1953, 6, 78-85.
(37) Elliott, I. W. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, 1987; Vol. 31; pp 101-116.
(41) Takano, S.; Satoh, S.; Ogasawara, K. Heterocycles 1987, 26,
1483-1485.
(42) (a) Mathew, K. K.; Menon, K. N. Proc. Indian Acad. Sci. 1949,
29A, 361-363. (b) Yasuda, S.; Hirasawa, T.; Yoshida, S.; Hanaoka,
M. Chem. Pharm. Bull. 1989, 37, 1682-1683.

6588 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
Sch em e 6
high nucleophilicity of the nitrogen atom but not a bulky
N-substituent. When a mixture of 19a and its threo-
isomer 20a was subjected to the present cyclization, the
latter (20a ) remained essentially unchanged, though a
small amount of the threo 20a may have been consumed
with the production of 3a through isomerization to the
erythro 19a .12 1-(2′-Bromo-3′,4′-dimethoxybenzyl)-2-me-
thyltetrahydroisoquinoline 22f and its regioisomer 22g
[(()-6′-bromotetrahydrolaudanosine38e] (Scheme 5) were
unreactive, while it was reported that the benzyne
reaction converted 22e and 22g to a regioisomer of 3a ,
2,3,9,10-tetramethoxy-5,6-dihydroindolo[2,1-a]isoquino-
line 3e (from 22e),38a,d,g and its N-methyl-5,6,12,12a-
tetrahydro derivative (from 22g).38e When methiodides
Narasimuhan,46 to give rather selectively 10,11-alkoxy
derivatives. Therefore, considerable efforts have been
directed toward the selective synthesis of berbines with
the natural substitution pattern, and several synthetic
methods,9,47,48
including
some
enantioselective
approaches,48a,d,e,i have been reported.
Palladium(0)-catalyzed carbonylation of 1-(2′-bromo-
4′,5′-dialkoxybenzyl)tetrahydroisoquinolines was reported
by Pandey.3i,j Carbonylation of a similar isoquinoline
system was also reported to be catalyzed with Fe3(CO)12
and Co2(CO)8.49 In the present study, we investigated the
carbonylation using 1-(2′-bromo-3′,4′-dialkoxybenzyl)tet-
rahydroisoquinolines 22a -d as substrates which were
easily prepared by NaBH4 reduction of the above-
mentioned dihydroisoquinolines 15a -d (Scheme 6). By
treatment with CO in the presence of Pd(OAc)2 (20 mol
%), PPh3 (40 mol %), and excess K2CO3 in boiling toluene,
2-bromo-3,4-dimethoxybenzyl derivatives 22a and 22c
underwent relatively slow carbonylation and, 26 h later,
gave 8-oxoberbines 23a in 75% and 23c in 85% isolated
21a and 21e38e were exposed to this K2CO3 treatment for
3 days, only traces of indolo[2,1-a]isoquinolines 3a and
3e (less than 3% yield for both) were observed on the H
1
NMR spectra of their reaction mixtures. These results
appear to show that the cyclization does not start with
the formation of N-methylenamine intermediate due to
a simple dehydration of 19. The reaction probably started
with a nucleophilic attack of the nitrogen atom on the
aromatic carbon bearing a bromine atom and may have
proceeded with an efficient relief of steric repulsions
between the Br atom, hydroxy, and N-methyl groups, for
instance, in one possible pathway shown in a preliminary
report.35,43 We later found that even 4′,5′-dialkoxy deriva-
tives 19e and 19f gave lower yields than those for 3a -d
the corresponding indolo[2,1-a]isoquinolines 3e and 3f,
which have four alkoxy groups at the same 2, 3, 9, 10
positions as the aformentioned natural products. Never-
theless, these methods provided a new route to the indolo-
[2,1-a]isoquinoline system.
(46) Narasimhan, N. S.; Mali, R. S.; Kulkarni, B. K. Tetrahedron
1983, 39, 1975-1982.
(47) For reviews, see (a) Kametani, T.; Ihara, M. Heterocycles 1979,
13, 497-530. (b) Pandey, G. D.; Tiwari, K. P. Heterocycles 1980, 14,
59-82. (c) Bhakuni, D. S.; J ain, S. In The Alkaloids; Brossi, A., Ed.;
Academic Press: Orlando, 1986; Vol. 28; pp 95-171.
(48) Selected articles published on and after 1986; Synthesis based
on the modified Pictet-Spengler, Bischler-Napieralski, or Pomer-
antz-Fritsch reaction, see (a) Czarnocki, Z.; Maclean, D. B.; Szarek,
W. A. Bull. Soc. Chim. Belg. 1986, 95, 749-769. (b) Orito, K.
Matsuzaki, T.; Suginome, H. Org. Prep. Proc. Int. 1989, 21, 309-314.
(c) Sotomayor, N.; Dom´ınguez, E.; Lete, E. Synlett 1993, 431-433. (d)
Czarnocki, Z.; Maclean, D. B.; Szarek, W. A. J . Chem. Res. (C) 1992,
234-335; J . Chem. Res. (M) 1992, 2801-2819. (e) Commins, D. L.;
Thakker, P. M.; Baevsky, M. F. Tetrahedron 1997, 53, 16327-16340.
Synthesis based on nucleophilic addition of carbanions to 3,4-dihy-
droisoquinolines, see (f) Warrener, R. N.; Lin, L.; Russell, R. A.
Tetrahedron 1988, 54, 7485-7496. (g) Pyne, G. S.; Branko, D. J . Org.
Chem. 1990, 55, 1932-1936. (h) Kessar, S. V.; Singh, P.; Vohra, R.;
Kaur, N. P.; Venugopal, D. J . Org. Chem. 1992, 57, 6716-6720.
Synthesis based on alkylation on a C-1 metalated tetrahydroisoquino-
line, see (i) Matulenko, M. A.; Meyers, A. I. J . Org. Chem. 1996, 61,
573-580. Synthesis based on photochemical cyclization of enamides,
see (j) Weimar, C.; von Angerer, S.; Wiegrebe, W. Arch. Pharm. 1991,
324, 907-912. Synthesis based on radial cyclization, see (k) Dai-Ho,
G.; Mariano, P. S. J . Org. Chem. 1987, 52, 706-707. (l) Takano, S.;
Suzuki, M.; Ogasawara, K. Heterocycles 1990, 31, 1151-1156. (m)
Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Tetrahedron Lett.
1990, 31, 2315-2318. (n) Nimgirawath, S.; Ponghusabun, O.-a. Aust.
J . Chem. 1994, 47, 951-955. Synthesis based on cycloaddition reaction
of isoquinoline-pyrroline-2,3-dione with benzyne, see (o) Cobas, A.;
Guitia´n, E.; Castedo, L. J . Org. Chem. 1992, 57, 6765-6769. Synthesis
based on palladium-catalyzed cyclization, see (p) Bombrun, A.; Sageot,
O. Tetrahedron Lett. 1997, 38, 1057-1060.
Syn th esis of P r otober ber in e Alk a loid s. Protober-
berines are known to have a variety of biological activi-
ties, including antileukemic and antitumor activities.44
Antitumor and anticancer activities of 8-oxoberbines have
also been reported.44b The natural berbines occur in a 9,-
10-alkoxy-substitution pattern45 which is obtained with
difficulty by the usual cyclization methods such as the
traditional Bischler-Napieralski, Pictet-Spengler, or
Pomeranz-Fritsch reactions, as briefly described by
(43) An alternative reaction pathway (i f ii f iii) with a leaving
group X on a nitrogen-containing ring system 3, based on the thermal
electrocyclization of a pentadienyl anion to a cyclopentenyl anion,
cannot be discarded. For selected references, see Stapp, P. R.; Kiein-
schmidt, R. F. J . Org. Chem. 1965, 30, 3006-3009; Slaugh, L. H. J .
Org. Chem. 1967, 32, 108-113; Bates, R. B.: McCombs, D. A.
Tetrahedron Lett. 1969, 977-978; Shoppee, C. W.; Henderson, G. N.
J . Chem. Soc., Perkin Trans. 1 1975, 765-772.
(44) (a) See ref 3 cited in ref 48i. (b) See ref 12 cited in ref 48i.
(45) See ref 1 cited in ref 48i.
(49) Trifonov, L. S.; Orehovats, A. S. Tetrahedron Lett. 1985, 26,
3159-3162.

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids
J . Org. Chem., Vol. 64, No. 18, 1999 6589
2-Br om o-3,4-d im et h oxyb en zyl Alcoh ol (5a ). Gen er a l
P r oced u r e. To a stirred solution of 2-bromo-3,4-dimethoxy-
benzaldehyde26 (8.466 g, 34.546 mmol) in THF (45 mL) and
MeOH (45 mL) was added NaBH4 (0.653 g, 17.273 mmol) in
portions. The mixture was stirred for 2 h and then concen-
trated to give an oily residue, which was dissolved in CH2Cl2
(150 mL) and water (50 mL) containing 2 N HCl (5 mL). The
organic layer was washed with water (50 mL × 2), dried (Na2-
SO4), and condensed to give a solid (8.532 g), mp 76-79 °C.
Recrystallization from Et2O-petroleum ether gave 5a (8.360
yield. Their methylenedioxy derivatives (22b and 22d )
were consumed within 18 h and gave the corresponding
8-oxoberbines 23b and 23d in good yields. Further, by
treating with excess LiAlH4 in the reported manner,48h,i,50,51
these lactams were converted almost quantitatively to
protoberberine alkaloids 4a -d .
Con clu sion s
g, 98%); mp 78-80 °C; IR (neat) 3378, 1596, 1489 cm-1 1H
;
A general route for synthesis of phthalideisoquinoline
alkaloids has been developed. The key steps are the
stereoselective reduction of 1-(2′-bromobenzoyl)-3,4-di-
hydroisoquinoline methiodide 18 with sodium borohy-
dride or lithium aluminum hydride, followed by a palla-
NMR (270 MHz) δ 2.18 (br s, 1H), 3.86, 3.87 (each br s, each
3H), 4.68 (s, 2H), 6.87, 7.16 (AB type, J ) 8.4 Hz, each 1H);
MS m/z (rel int) 248 (M+, 94), 246 (M+, 100), 231 [(M - CH3)+,
40], 229 [(M - CH3)+, 31], 167 [(M - Br)+, 60]. Anal. Calcd for
C9H11O3Br: C, 43.75; H, 4.49; Br, 32.34. Found: C, 43.87; H,
4.63; Br, 32.27.
dium(0)-catalyzed carbonylation of the resultant erythro-
or threo-amino alcohols 19 and 20 aided by chlorotrim-
ethylsilane. The synthesis of eight phthalideisoquinoline
alkaloids having methoxy- and/or methylenedioxy-sub-
stituents together with nor- and iso-types of the alkaloids
has been successfully demonstrated. Treatment of erythro-
amino alcohols 19 with potassium carbonate in boiling
DMF provided a new method for construction of the
indolo[2,1-a]isoquinoline skeleton characteristic of the
dibenzopyrrocoline alkaloids, such as cryptaustoline and
cryptowoline, isolated from Cryptocaria bowiei. Pal-
ladium(0)-catalyzed carbonylation of 1-(2′-bromo-3′,4′-
dialkoxybenzyl)tetrahydroisoquinolines 22 gave 8-oxo-
berbines 23, which were treated with excess LiAlH4 in
boiling THF to give protoberberine alkaloids 4 in good
yields.52
2-Br om o-3,4-(m eth ylen edioxy)ben zyl Alcoh ol (5b): 96%
yield from 2-bromo-3,4-(methylenedioxy)benzaldehyde;26 mp
1
114-115 °C (petroleum ether); IR 3270, 1617, 1497 cm-1; H
NMR (270 MHz) δ 1.95 (br s, 1H), 4.67 (s, 2H), 6.05 (s, 2H),
6.75, 6.94 (AB type, J ) 8.1 Hz, each 1H). Anal. Calcd for
C8H7O3Br: C, 41.59; H, 3.05; Br, 34.58. Found: C, 41.36; H,
2.97; Br, 34.58.
2-Br om o-3,4-d im eth oxyp h en yla ceton itr ile (10a ). Gen -
er a l P r oced u r e. To a solution of benzyl alcohol 5a (8.333 g,
33.7 mmol) in dry benzene (2 mL) was dropwise added SOCl2
(6.02 g, 50.55 mmol). After the mixture was stirred at room
temperature overnight, excess SOCl2 was removed by azeo-
tropic distillation with benzene under reduced pressure. The
crude oily benzyl chloride 9a [1H NMR (90 MHz) δ 3.86, 3.89
(s, each 3H), 4.69 (s, 2H), 6.85, 7.20 (AB type, J ) 8.4 Hz, each
1H] was dissolved in a mixture of DMSO (15 mL) and benzene
(7 mL). To this solution was added NaCN (powdered, 3.303 g,
67.4 mmol) in portions. The mixture was stirred for 2 h, poured
into water (100 mL), and extracted with benzene (15 mL ×
5). The combined benzene layers were washed with saturated
brine (20 mL × 5), dried (Na2SO4), and evaporated. The residue
was distilled under reduced pressure to give 10a as a colorless
oil (7.824 g, 91%), bp 125-127 °C (0.2 mmHg). IR 2250, 1597,
Exp er im en ta l Section
Gen er a l P r oced u r es. Infrared spectra were recorded as
Nujol mulls, unless otherwise specified. 1H (90, 270, 400 MHz)
and 13C NMR (67.5 MHz) spectra were measured in CDCl3
(99.8 atom % D, containing 0.03% v/v TMS, Aldrich). Mass
spectra were recorded with EI at 70 eV. TLC was carried out
on a Merck silica gel 60 PF254 (Nos. 7749 and 5554). The
following solvents and reagents were distilled prior to use:
THF (sodium benzophenone ketyl), benzene (P2O5), toluene
(P2O5), CH2Cl2 (P2O5), pyridine (CaH2), and Et3N (CaH2).
P a lla d iu m (0)-Ca ta lyzed Ca r bon yla tion of 2-Br om o-
3,4-d im eth oxyben zyl Alcoh ol (5a ). Bromo-3,4-dimethoxy-
benzyl alcohol 5a (24 mg, 0.1 mmol), Pd(OAc)2 (4.6 mg, 20 mol
%), PPh3 (10.6 mg, 40 mol %), and the appropriate additives
in dry toluene (2 mL) were charged in a 10-mL pair-shaped
flask, having a magnetic stirring bar in it, connected with a
condenser, on which a three-way stopcock was attached for a
CO gas balloon and an aspirator. After degassing with an
aspirator followed by charging with CO gas three times, the
reaction flask was dipped into an oil bath preheated at 140
°C, and the reaction mixture was refluxed with stirring for 24
h. The reaction mixture was allowed to cool to room temper-
ature and was then filtered through a Celite pad. The solvent
1490 cm-1 1H NMR (270 MHz) δ 3.79 (s, 2H), 3.86 (s, 3H),
;
3.89 (s, 3H), 6.90, 7.36 (AB type, J ) 8.4 Hz, each 1H). Anal.
Calcd for C10H10NO2Br: C, 46.90; H, 3.94; N, 5.47; Br, 31.2.
Found: C, 46.75; H, 3.98; N, 5.50; Br, 31.39.
2-Br om o-3,4-(m eth ylen ed ioxy)a ceton itr ile (10b): 89%
yield; mp 149-151 °C (CH2Cl2-Et2O); IR 2250, 1621, 1499
cm-1 1H NMR (270 MHz) δ 3.75 (s, 2H), 6.08 (s, 2H), 6.78,
;
6.99 (AB type, J ) 8.1 Hz, each 1H). Anal. Calcd for C9H6-
NO2Br: C, 45.03; H, 2.52; N, 5.84; Br, 33.29. Found: C, 44.87;
H, 2.48; N, 5.82; Br, 33.49.
2-Br om o-3,4-d im eth oxyp h en yla cetic Acid (11a ). Gen -
er a l P r oced u r e. A solution of 10a (7.760 g, 30.3 mol) in EtOH
(100 mL) and 4 N NaOH (50 mL) was refluxed for 20 h. The
cooled reaction mixture was diluted with water (200 mL) and
then washed with CH2Cl2 (50 mL). The water layer was
separated, acidified with concentrated HCl (20 mL), and
extracted with CH2Cl2 (30 mL × 3). The extracts were washed
with water (50 mL × 2), dried (Na2SO4), and concentrated to
give a solid (8.881 g). Recystallization from CH2Cl2-Et2O gave
11a (7.650 g, 92%): mp 154-155 °C; IR 3600-2800, 1710,
1596, 1490 cm-1; 1H NMR (270 MHz) δ 3.80 (s, each 1H), 3.86
(s, 3H), 3.87 (s, 3H), 6.85, 7.02 (AB type, J ) 8.4 Hz, each 1H);
(90 MHz) δ 5.30 (br s, 1H). Anal. Calcd for C10H11O4Br: C,
43.66; H; 4.03; Br, 29.05. Found: C, 43.50; H, 3.97; Br, 29.07.
2-Br om o-3,4-(m eth ylen ed ioxy)p h en yla cetic a cid (11b):
was removed on
a
rotary evaporator, and the 1H NMR
spectrum of the residue was measured for determination of
the product ratio. When Me3SiCl (22 mg, 0.2 mmol) was used
as an additive, such as in entries 9-11, the residue was then
dissolved in MeOH (3 mL) containing three drops of 2 N HCl,
and, 30 min later, the solution was evaporated at room
temperature. The oily residue was extracted with CH2Cl2 (5
mL) and water (5 mL), and the CH2Cl2 extracts were dried
(Na2SO4) and evaporated to give the crude products for 1H
NMR analysis.
89% yield; mp 183-185 °C (MeOH); IR 3200-2000, 1670 cm-1
;
1H NMR (270 MHz) δ 3.76 (s, 2H), 6.05 (s, 2H), 6.73, 6.79 (AB
q, J ) 7.7 Hz, each 1H). Anal. Calcd for C9H7O4Br: C, 41.73;
H, 2.72; Br, 30.84. Found: C, 41.78; H, 2.76; Br, 30.67.
N-(3,4-Dim eth oxyp h en eth yl)-2-br om o-3,4-d im eth oxy-
p h en yla ceta m id e (14a ). Gen er a l P r oced u r e. After a mix-
ture of 11a (550 mg, 2 mmol), SOCl2 (480 mg, 4 mmol), and
dry benzene (10 mL) was stirred at 50-60 °C for 2 h, excess
SOCl2 was removed under reduced pressure. The resulting acid
chloride 12a was dissolved in dry benzene (5 mL) and added
(50) Cushman, M.; Dekow, F. W. J . Org. Chem. 1979, 44, 407-409.
(51) Iwasa, K.; Gupta, Y. P.; Cushman, M. J . Org. Chem. 1981, 46,
4744-4750.
(52) Asymmetric reduction of imines 15-17 is under investigation,
and the results will be reported later.

6590 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
dropwise to a stirred solution of 3,4-dimethoxyphenethylamine
13a (290 mg, 1.8 mmol) and pyridine (237 mg, 3 mmol) in dry
benzene (5 mL). The mixture was continuously stirred at room
temperature overnight and then poured into water (30 mL).
The benzene layer was separated. The water layer was
extracted once with benzene (10 mL). The combined benzene
layers were washed with 0.5 N HCl (10 mL), 0.5 N NaOH (10
mL), and water (20 mL) and dried (Na2SO4). Evaporation of
benzene, followed by recrystallization of the crude product from
benzene-Et2O, afforded 14a (710 mg, 91%): mp 103-105 °C;
IR 3304, 1645, 1593, 1492 cm-1; 1H NMR (270 MHz) δ 2.70 (t,
J ) 7.0 Hz, 2H), 3.45, 3.47 (t, J ) 7.0 Hz, each 1H), 3.63 (s,
2H), 3.83, 3.84, 3.85, 3.87 (each s, each 3H), 5.42 (br s, 1H),
6.60 (dd, J ) 8.0, 1.8 Hz, 1H), 6.64 (d, J ) 1.8 Hz, 1H), 6.73
(d, J ) 8.0 Hz, 1H), 6.82, 6.98 (AB q, J ) 8.4 Hz, each 1H).
Anal. Calcd for C20H24NO5Br: C, 54.81; H, 5.52; N, 3.20; Br,
18.23. Found: C, 54.98; H, 5.46; N, 3.12; Br, 18.24.
δ 2.64 (t, J ) 7.6 Hz, 2H), 3.67 (t, J ) 7.6 Hz, 2H), 3.83 (s,
3H), 3.87 (s, 3H,), 4.07 (s, 2H), 5.94 (s, 2H), 6.66, (s, 1H), 6.91
(s, 1H), 6.77, 6.91 (AB type, J ) 8.4 Hz, each 1H). Anal. Calcd
for C19H18NO4Br: C, 56.45; H, 4.49; N, 3.48; Br, 19.77.
Found: C, 56.51; H, 4.42; N, 3.33; Br; 19.89.
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zyl]-6,7-(m eth yl-
en ed ioxy)-3,4-d ih yd r oisoqu in olin e (15d ): 83% yield; mp
171-175 °C (MeOH); IR 1640, 1615, 1604, 1503 cm-1; 1H NMR
(270 MHz) δ 2.63 (t, J ) 7.6 Hz, 2H), 3.66 (t, J ) 7.6 Hz, 2H),
4.01 (s, 2H), 5.95 (s, 2H), 6.03 (s, 2H), 6.67 (s, 1H), 6.66, 6.70
(AB type, J ) 8.3 Hz, each 1H), 6.90 (s, 1H). Anal. Calcd for
C
18H14NO4Br: C, 55.69; H, 3.63; N, 3.61; Br, 20.58. Found:
C, 55.56; H, 3.60; N, 3.72; Br; 20.81.
1-(2-Br om o-4,5-d im et h oxyb en zyl)-6,7-d im et h oxy-3,4-
d ih yd r oisoqu in olin e (15e): 89% yield from 14e by the
reported method;53
a
colorless oil [lit.53 mp 192-193 °C
(oxalate);38e 232-234 °C (HCl salt);48b 224-225 °C (HCl salt)];
IR (neat) 1645, 1625, 1607, 1561, 1508 cm-1 1H NMR (270
;
N-(3,4-Dim eth oxyp h en eth yl)-2-br om o-3,4-(m eth ylen e-
d ioxy)p h en yla ceta m id e (14b): 85% yield from 12b and 13a ;
mp 178-179 °C (benzene-Et2O); IR 3290, 1647, 1593, 1519
MHz) δ 2.73 (t, J ) 7.3 Hz, 2H), 3.62 (partly hiding t, J ) 7.6
Hz, 2H), 3.74 (s, 3H), 3.84 (s, 6H), 3.87 (s, 3H), 4.11 (s, 2H),
6.66, 6.87, 7.00, 7.04 (each s, each 1H). This was subjected to
1O2 oxidation without further purification.
cm-1 1H NMR (270 MHz) δ 2.70 (t, J ) 7.0 Hz, 2H), 3.46,
;
3.48 (t, J ) 6.6 Hz, each 1H), 3.58 (s, 2H), 3.84, 3.86 (s, each
3H), 5.36 (br s, 1H), 6.07 (s, 2H), 6.60 (dd, J ) 7.9, 2.0 Hz,
1H), 6.63 (d, J ) 2.0 Hz, 1H), 6.74 (d, J ) 7.9 Hz, 1H), 6.69,
1-[2-Br om o-4,5-(m eth ylen ed ioxy)ben zyl]-6,7-(m eth yl-
en ed ioxy)-3,4-d ih yd r oisoqu in olin e (15f): 89% yield from
14f;54 mp 120-126 °C (benzene-Et2O); IR (neat) 1660, 1616,
1598, 1504 cm-1; 1H NMR (270 Hz) δ 2.66 (t, J ) 7.6 Hz, 2H),
3.70 (t, J ) 7.6 Hz, 2H), 4.05, 5.92, 5.96 (each s, each 2H),
6.74 (AB type, J ) 7.9 Hz, each 1H). Anal. Calcd for C19H18
-
NO5Br: C, 54.04; H, 4.77; N, 3.32; Br, 18.92. Found: C, 53.82;
H, 4.73; N, 3.37; Br, 19.13.
N -[(3,4-Me t h y le n e d io x y )p h e n e t h y l]-2-b r o m o -3,4-
d im eth oxyp h en yla ceta m id e (14c): 86% yield from 12a and
13b; mp 163-165 °C (benzene); IR 3280, 1648, 1598, 1505,
6.67, 6.71, 6.93, 7.03 (each s, each 1H). Anal. Calcd for C18H14
-
NO4Br: C, 55.69; H, 3.63; N, 3.61; Br, 20.58. Found: C, 55.47;
H, 3.63; N, 3.61; Br; 20.79.
1498 cm-1 1H NMR (270 MHz) δ 2.66 (t, J ) 6.9 Hz, 2H),
;
1-(2-Br om o-3,4-d im eth oxyben zoyl)-6,7-d im eth oxy-3,4-
d ih yd r oisoqu in olin e (16a ). Gen er a l P r oced u r e. Dihy-
droisoquinoline 15a (2.750 g) was dissolved in CH2Cl2 (250 mL)
containing MeOH (7.5 mL) and methylene blue (7.5 mg) in a
Pyrex test tube (25 mm × 250 mm) equipped with a sintered
glass bubbler and was cooled with a stream of cold water on
the side of the tube. Oxygen gas was introduced through the
bubbler to the mixture, which was then irradiated with a
100-W tungsten lamp at 15 °C for 30 min, monitoring with
TLC on silica gel with 5% MeOH-CH2Cl2. The mixture was
treated with powdered activated charcoal (200 mg) and was
then filtered through a thin pad of powdered MgSO4. The
filtrate was concentrated to give crude 16a as a solid (2.943
g, ca. 100%), mp 120-125 °C. Recrystallization from benzene-
Et2O gave an analytical sample (2.708 g, 92%), mp 124-126
°C; Rf 0.6 with 5% MeOH-CH2Cl2; IR 1653, 1623, 1606, 1582,
3.41, 3.43 (t, J ) 6.8 Hz, each 1H), 3.63 (s, 2H), 3.85 (s, 3H),
3.88 (s, 3H), 5.39 (br s, 1H), 5.91 (s, 2H), 6.50 (dd, J ) 7.8, 1.5
Hz, 1H), 6.56 (d, J ) 1.5 Hz, 1H), 6.66 (d, J ) 7.8 Hz, 1H),
6.83, 7.00 (AB type, J ) 7.8 Hz, each 1H). Anal. Calcd for
C
20H24NO5Br: C, 54.81; H, 5.52; N, 3.20; Br, 18.23. Found:
C, 54.98; H, 5.46; N, 3.12; Br, 18.24.
N-[3,4-(Met h ylen ed ioxy)p h en et h yl]-2-br om o-3,4-(m e-
th ylen ed ioxy)p h en yla ceta m id e (14d ): 86% yield from 12b
and 13b; mp 103-105 °C (benzene-Et2O); IR 3290, 1636,
1
1549, 1506, 1492 cm-1; H NMR (400 MHz) δ 2.66 (t, J ) 6.8
Hz, 2H), 3.41, 3.44 (t, J ) 6.8 Hz, each 1H), 3.59 (s, 2H), 5.33
(br s, 1H), 5.93, 6.07 (s, each 2H), 6.50 (d, J ) 7.8 Hz, 1H),
6.71, 6.75 (AB type, J ) 7.8 Hz, each 1H). Anal. Calcd for
C
18H16NO5Br: C, 53.22; H, 3.97; N, 3.45; Br, 19.67. Found:
C, 53.31; H, 4.01; N, 3.66; Br, 19.64.
1
1515 cm-1; H NMR (270 Hz) δ 2.75 (t, J ) 7.7 Hz, 2H), 3.84
1-(2-Br om o-3,4-d im et h oxyb en zyl)-6,7-d im et h oxy-3,4-
d ih yd r oisoqu in olin e (15a ). Gen er a l P r oced u r e. A mixture
of acetamide 14a (7.013 g, 16 mmol), POCl3 (12.240 g, 80
mmol), and dry toluene (100 mL) was refluxed under N2 for 3
h. The cooled mixture was poured into ice-water (100 mL)
and stirred for 2 h. The organic layer was discarded. The water
layer and precipitates were then basified with 2 N NaOH (200
mL) and extracted with CH2Cl2 (50 mL × 3). The extracts were
washed with water (100 mL), dried (Na2SO4), and evaporated
to give 15a as a solid (5.731 g, 85%), mp 120-124 °C.
Recrystallization from benzene-Et2O gave an analytical sample,
mp 123-125 °C; Rf 0.15 on silica gel TLC plate (5% MeOH-
CH2Cl2): IR 1621, 1606, 1595, 1573, 1518 cm-1; 1H NMR (270
MHz) δ 2.67 (t, J ) 7.6 Hz, 2H), 3.72 (t, J ) 7.6 Hz, 2H), 3.79,
3.82, 3.85, 3.88 (each s, each 3H), 4.15 (s, 1H), 6.66, (s, 1H),
(t, J ) 7.7 Hz, 2H), 3.86, 3.88, 3.93, 3.94 (each s, each 3H),
6.74, 7.22 (s, each 1H), 6.96, 7.48 (AB type, J ) 8.5 Hz, each
1H). Anal. Calcd for C20H20NO5Br: C, 55.31; H, 4.64; N, 3.24;
Br, 18.40. Found: C, 55.19; H, 4.59; N, 3.26; Br, 18.18.
1-[2-B r o m o -3,4-(m e t h y le n e d io x y )b e n zo y l]-6,7-d i-
m eth oxy-3,4-d ih yd r oisoqu in olin e (16b): 83% yield; mp
161-163 °C (benzene); IR 1672, 1605, 1568, 1516, 1466 cm-1
;
1H NMR (270 Hz) δ 2.76 (t, J ) 7.8 Hz, 2H), 3.87 (t, J ) 8.0
Hz, 2H), 3.87 (s, 3H), 3.94 (s, 3H), 6.12 (s, 2H), 6.73 (s, 1H),
7.16 (s, 1H), 6.84, 7.34 (AB type, J ) 8.5 Hz, each 1H). Anal.
Calcd for C19H16NO5Br: C, 54.56; H, 3.86; N, 3.35; Br, 19.10.
Found: C, 54.43; H, 3.81; N, 3.53; Br, 19.03.
1-(2-Br om o-3,4-d im e t h oxyb e n zoyl)-6,7-(m e t h yle n e -
d ioxy)-3,4-d ih yd r oisoqu in olin e (16c): 89% yield; mp 126-
127 °C (MeOH-Et2O); IR 1674, 1655, 1585, 1501, 1486 cm-1
;
6.76, 6.98 (AB q, J ) 8.4 Hz, each 1H). Anal. Calcd for C20H22
-
1H NMR (270 MHz) δ 2.70 (t, J ) 7.8 Hz, 2H), 3.79 (t, J ) 7.6
Hz, 2H), 3.85 (s, 3H), 3.92 (s, 3H), 5.99 (s, 2H), 6.71 (s, 1H),
7.15 (s, 1H), 6.96, 7.46 (AB type, J ) 8.8 Hz, each 1H). Anal.
Calcd for C19H16NO5Br: C, 54.56; H, 3.86; N, 3.35; Br, 19.10.
Found: C, 54.54; H, 3.95; N, 3.20; Br, 18.89.
NO4Br: C, 57.15; H, 5.28; N, 3.33; Br, 19.01. Found: C, 57.16;
H, 5.30; N, 3.37; Br; 18.91.
1-[2-Br om o-3,4-(m eth ylen edioxy)ben zyl]-6,7-dim eth oxy-
3,4-d ih yd r oisoqu in olin e (15b): 89% yield; mp 162-164 °C
(benzene); IR 1626, 1606 1576, 1519, 1502 cm-1; 1H NMR (270
MHz) δ 2.66 (t, J ) 7.6 Hz, 2H), 3.71 (t, J ) 7.6 Hz, 2H), 3.83
(s, 3H), 3.89 (s, 3H), 4.09 (s, 2H), 6.02 (s, 2H), 6.67, (s, 1H),
6.93 (s, 1H), 6.66, 6.77 (AB type, J ) 8.2 Hz, each 1H). Anal.
Calcd for C19H18NO4Br: C, 56.45; H, 4.49; N, 3.48; Br, 19.77.
Found: C, 56.39; H, 4.46; N, 3.33; Br; 19.72.
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zoyl]-6,7-(m eth yl-
en ed ioxy)-3,4-d ih yd r oisoqu in olin e (16d ): 87% yield; mp
165-167 °C (benzene-Et2O); IR 1675, 1662, 1603, 1589, 1503
(53) Cava, M. P.; Mitchel, M. J .; Havlicek, S. C.; Lindert, A.;
Spangler, R. J . I. J . Org. Chem. 1970, 35, 1175-1179.
(54) Cava, M. P.; Stern, P.; Wakisaka, K. Tetrahedron 1973, 29,
2245-2249.
1-(2-Br om o-3,4-dim eth oxyben zyl)-6,7-(m eth ylen edioxy)-
3,4-d ih yd r oisoqu in olin e (15c): 89% yield; mp 154-157 °C
(benzene); IR 1643, 1604, 1504, 1492 cm-1; 1H NMR (270 MHz)

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids
J . Org. Chem., Vol. 64, No. 18, 1999 6591
cm-1; 1H NMR (270 MHz) δ 2.72 (t, J ) 7.8 Hz, 2H), 3.82 (t, J
) 7.8 Hz, 2H), 6.00 (s, 2H), 6.11 (s, 2H), 6.71 (s, 1H), 7.09 (s,
1H), 6.84, 7.33 (AB type, J ) 8.4 Hz, each 1H). Anal. Calcd
for C18H12NO5Br: C, 53.75; H, 3.01; N, 3.48; Br, 19.87.
Found: C, 53.77; H, 2.82; N, 3.51; Br, 19.86.
1-(2-Br om o-4,5-d im eth oxyben zoyl)-6,7-d im eth oxy-3,4-
d ih yd r oisoqu in olin e (16e): 87% yield: mp 184-186 °C
(MeOH); IR 1671, 1595, 1570, 1509 cm-1; 1H NMR (270 Hz) δ
2.77 (t, J ) 7.7 Hz, 2H), 3.82 (partly hiding t, J ) 7.7 Hz, 2H),
3.87 (s, 3H), 3.92 (s, 6H), 3.94 (s, 3H), 6.74, 7.03, 7.15, 7.28
(each s, each 1H). Anal. Calcd for C20H20NO5Br: C, 55.31; H,
4.64; N, 3.24; Br, 18.40. Found: C, 55.45; H, 4.50; N, 3.06; Br,
18.37.
in CH3CN (8 mL) was refluxed for 2.5 h and was then
evaporated. A yellow glassy residue was crystallized from
MeOH-Et2O to give benzyl bromide 17g as yellow crystals
(1.10 g, 91%): mp 153-154 °C. IR 1666, 1617, 1598, 1573, 1553
cm-1; 1H NMR (270 MHz) δ 3.74, 3.90, 3.99, 4.00 (each s, each
3H), 6.75 (s, 1H), 6.85 (s, 1H), 7.31(AB type, J ) 8.8 Hz, 1H),
7.40-7.46 (m, 3H), 7.53-7.58 (m, 2H), 8.73 (AB type, J ) 8.8
Hz, 1H). Anal. Calcd for C27H27NO5Br2 + H2O: C, 52.03; H,
4.69; N, 2.25; Br, 25.64. Found: C, 52.06; H, 4.64; N, 2.15; Br,
25.72.
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zoyl]-6,7-(m eth yl-
en edioxy)-3,4-dih ydr oisoqu in olin e ben zyl br om ide (17h ):
89% yield from 16d ; mp 162-164 °C (Et2O); IR 1663, 1640,
1
1-[2-Br om o-4,5-(m eth ylen ed ioxy)ben zoyl]-6,7-(m eth yl-
en ed ioxy)-3,4-d ih yd r oisoqu in olin e (16f): 78% yield: mp
1608, 1591 cm-1; H NMR (400 MHz) δ 2.96, 3.61, 4.31, 4.83,
5.06, 5.86 (each br s, each 1H), 6.12 (s, 2H), 6.23 (s, 2H), 6.74
(s, 1H), 6.83 (s, 1H), 7.20 (AB type, J ) 8.3 Hz, 1H), 7.40-
7.45 (m, 3H), 7.49-7.55 (m, 2H), 8.57 (AB type, J ) 8.3 Hz,
1H). Anal. Calcd for C25H19NO5Br2: C, 52.38; H, 3.34; N, 2.44;
Br, 27.88. Found: C, 52.52; H, 3.33; N, 2.42; Br, 28.01.
1-(2-Br om o-3,4-d im eth oxyben zoyl)-6,7-d im eth oxy-3,4-
d ih yd r oisoqu in olin e P r op yl Iod id e (17i). A mixture of 16a
(218 mg, 0.5 mmol) and propyl iodide (0.2 mL, 1.8 mmol) in
CH3CN (1 mL) was refluxed for 4.5 h. Evaporation of the
solvent and crystallization of the residue from MeOH gave
benzyl bromide 17i as a yellow crystalline solid (288 mg,
95%): mp 95-97 °C; IR 1671, 1628, 1602, 1574, 1555, 1522
cm-1; 1H NMR (270 MHz) δ 0.99 (t, J ) 6.6 Hz, 3H), 1.93 (six,
J ) 6.6 Hz, 2H), 3.71 (s, 3H), 3.86 (t, J ) 6.6 Hz, 2H), 3.90,
3.99, 4.02 (each s, each 3H), 6.66 (s, 1H), 6.92 (s, 1H), 7.24,
176-179 °C (MeOH-Et2O); IR 1677, 1651, 1587, 1501 cm-1
;
1H NMR (270 Hz) δ 2.71 (t, J ) 7.9 Hz, 2H), 3.82 (t, J ) 7.9
Hz, 2H), 6.00 (s, 2H), 6.05 (s, 2H), 6.71, 7.01, 7.13, 7.15 (each
s, each 1H). Anal. Calcd. for C18H12NO5Br: C, 53.75; H, 3.01;
N, 3.48; Br, 19.87. Found: C, 53.90; H, 3.22; N, 3.20; Br, 19.72.
1-(2-Br om o-3,4-d im eth oxyben zoyl)-6,7-d im eth oxy-3,4-
d ih yd r oisoqu in olin e Meth iod id e (17a ). Gen er a l P r oce-
d u r e. The crude dihydroisoquinoline 16a (3.680 g, 6.4 mmol)
was refluxed in CH3CN (25 mL) containing CH3I (3.5 mL) for
75 min. Evaporation of the solvent and excess CH3I, followed
by recrystallization of the resultant solid from MeOH-Et2O,
gave methiodide 17a as yellow crystals (4.02 g, 82%): mp 142-
1
144 °C; IR 1638, 1601, 1572, 1560, 1525 cm-1; H NMR (270
MHz) δ 3.71 (s, 3H), 3.87, 3.90, 4.00, 4.02 (each s, each 3H),
3.80-4.20, 4.25-4.65 (br. m, each 2H), 6.66 (s, 1H), 6.91 (s,
1H), 7.25, 8.43 (AB type, J ) 8.8 Hz, each 1H). Anal. Calcd
for C21H23NO5BrI + H2O: C, 42.45; H, 4.23; N, 2.36; I + Br,
34.81. Found: C, 42.37; H, 4.05; N, 2.36; I + Br, 34.53.
1-[2-Br om o-3,4-d im e t h oxyb e n zoyl]-6,7-(m e t h yle n e -
d ioxy)-3,4-d ih yd r oisoqu in olin e m eth iod id e (17b): 85%
8.42 (AB type, J ) 8.9 Hz, each 1H). Anal. Calcd for C23H27
-
NO5BrI: C, 45.72; H, 4.50; N, 2.32; Br + I, 34.22. Found: C,
45.52; H, 4.64; N, 2.31; Br + I, 33.97.
Gen er a l P r oced u r e for P r ep a r a tion of Er yth r o-Am in o
Alcoh ols 19a -j. er yth r o-1-(2-Br om o-3,4-d im eth oxy-r-h y-
d r oxyb en zyl)-2-m et h yl-6,7-d im et h oxy-1,2,3,4-t et r a h y-
d r oisoqu in olin e (19a ). Meth od A (in MeOH). To a stirred
solution of 17a (1.728 g, 3 mmol) in MeOH (75 mL) in water
bath was added NaBH4 (567 mg, 15 mmol) in portions for 5
min. After the mixture was continuously stirred at room
temperature for 2 h, MeOH was evaporated. The residue was
dissolved in water (30 mL) and CH2Cl2 (30 mL). The water
layer was further extracted with CH2Cl2 (10 mL × 2). The
combined CH2Cl2 layers were washed with water (10 mL ×
2), dried (Na2SO4), and then evaporated. The resultant solid
(1.400 g) was found to be a 97:3 mixture of amino-alcohols 19a
and 20a by 1H NMR analysis and treated with benzene-Et2O
to give 19a (1.115 mg, 83%) as colorless crystals: mp 146-
148 °C; IR 3302, 3315, 1615, 1591, 1518, 1482 cm-1; 1H NMR
(270 MHz) δ 2.52-2.66 (m, 2H), 2.59 (s, 1H), 2.75 (s, 3H), 2.95-
3.16 (m, 3H), 3.23 (s, 3H), 3.82, 3.83, 3.86 (each s, each 3H),
4.06 (d, J ) 2.9 Hz, 1H,), 5.33 (d, J ) 2.9 Hz, 1H), 5.26 (s,
1H), 6.65 (s, 1H), 6.67, 6.72 (AB type, J ) 8.8 Hz, each 1H).
Anal. Calcd for C21H26NO5Br: C, 55.76; H, 5.79; N, 3.10; Br,
17.66. Found: C, 55.59; H, 5.77; N, 3.03; Br, 17.54.
Meth od B (in AcOH). NaBH4 (2.3 g, 10 mmol) was added
to a stirred solution of 17a (576 mg, 1 mmol) in AcOH (10 mL)
in water bath in portions for 1.5 h. After being stirred for 30
min, the mixture was treated with water (50 mL) and CH2Cl2
(25 × mL). The combined CH2Cl2 layers were washed with 2
N NaOH (5 mL) and water (10 mL × 2), dried (Na2SO4), and
then concentrated. The oily residue (470 mg) showed no signals
owing to 20a in its 1H NMR spectrum and was treated with
benzene-Et2O to give 19a (398 mg, 89%), mp 146-148 °C.
Other solvent systems did not show significant selectivities
[MeOH-THF (1:2), 46:54 for 19a :20a ; MeOH-DMSO (1:1),
50:50; DMF, 50:50; i-PrOH, 60:40].
yield; mp 197-198 °C (MeOH); IR 1600, 1648, 1617, 1598 cm-1
;
1H NMR (270 MHz) δ 3.73 (s, 3H), 3.86, 4.03 (s, each 3H), 6.22
(s, 2H), 6.65 (s, 1H), 6.95 (s, 1H), 7.16, 8.25 (AB type, J ) 8.4
Hz, each 1H). Anal. Calcd for C20H19NO5BrI: C, 42.88; H, 3.42;
N, 2.50; I + Br, 36.91. Found: C, 42.80; H, 3.55; N, 2.36; I +
Br, 36.72.
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zoyl]-6,7-d im eth -
oxy-3,4-d ih yd r oisoqu in olin e m eth iod id e (17c): 85% yield;
mp 163-164 °C (MeOH); IR 1648, 1617, 1598, 1574, 1506,
1491 cm-1 1H NMR (270 MHz) δ 3.84 (s, 3H), 3.90 (s, 3H),
;
4.01 (s, 3H), 6.66 (s, 1H), 6.90 (s, 1H), 7.25, 8.41 (AB type, J )
8.9 Hz, each 1H). Anal. Calcd for C20H19NO5BrI: C, 42.88; H,
3.42; N, 2.50; I + Br, 36.91. Found: C, 42.80; H, 3.55; N, 2.36;
I + Br, 36.93.
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zoyl]-6,7-(m eth yl-
en edioxy)-3,4-dih ydr oisoqu in olin e m eth iodide (17d): 89%
yield; mp 231-232 °C (benzene-Et2O); IR 1672, 1650, 1610,
1
1595, 1498 cm-1; H NMR (270 MHz) δ 3.84 (s, 3H), 6.12 (s,
2H), 6.22 (s, 2H), 6.68 (s, 1H), 6.88 (s, 1H), 7.17, 8.29 (AB type,
J ) 8.6 Hz, each 1H). Anal. Calcd for C19H15NO5BrI: C, 41.94;
H, 2.78; N, 2.57; I + Br, 38.00. Found: C, 41.86; H, 2.65; N,
2.60; I + Br, 37.73.
1-(2-Br om o-4,5-d im eth oxyben zoyl)-6,7-d im eth oxy-3,4-
d ih yd r oisoqu in olin e m eth iod id e (17e): 89% yield; mp
198-200 °C (MeOH); IR 1662, 1629, 1585, 1559, 1525, 1510
1
cm-1; H NMR (270 MHz) δ 3.67, 3.82, 4.01, 4.02, 4.05 (each
s, each 3H), 7.61, 7.15, 7.04, 6.53 (each s, each 1H). Anal. Calcd
for C21H23NO5BrI: C, 43.77; H, 4.02; N, 2.43; I + Br, 35.89.
Found: C, 43.57; H, 4.08; N, 2.34; I + Br, 35.92.
1-[2-Br om o-4,5-(m eth ylen ed ioxy)ben zoyl]-6,7-(m eth yl-
en edioxy)-3,4-dih ydr oisoqu in olin e m eth iodide (17f): 86%
1
yield; mp 202-205 °C (MeOH); IR 1646, 1610 cm-1; H NMR
er yth r o-1-(2-Br om o-3,4-d im eth oxy-r-h yd r oxyben zyl)-
2-m eth yl-6,7-(m eth ylen edioxy)-1,2,3,4-tetr ah ydr oisoqu in -
olin e (19b): 92% yield (method B), mp 148-150 °C (MeOH-
Et2O); IR 3550, 1611, 1513 cm-1; 1H NMR (270 MHz) δ 2.55-
2.70 (m, 2H), 2.74 (s, 3H), 2.90-3.20 (m, 2H), 3.35 (s, 3H), 3.83
(s, 3H), 4.00 (d, J ) 3.0 Hz, 1H), 5.29 (d, J ) 3.0 Hz, 1H), 5.40
(s, 1H), 6.04 (s, 2H), 6.57 (s, 1H), 6.51, 6.63 (AB type, J ) 8.2
Hz, each 1H). Anal. Calcd for C20H22NO5Br: C, 55.06; H, 5.08;
N, 3.21; Br, 18.31. Found: C, 54.85; H, 4.94; N, 3.19; Br, 18.38.
(270 MHz) δ 3.66, 4.54 (each br s, each 2H), 3.84 (s, 3H), 6.13
(s, 2H), 6.20 (s, 2H), 6.56, 6.91, 7.17, 7.76 (each s, each 1H).
Anal. Calcd for C19H15NO5BrI: C, 41.94; H, 2.78; N, 2.57; I +
Br, 38.01. Found: C, 41.84; H, 2.85; N, 2.85; I + Br, 37.92.
1-(2-Br om o-3,4-d im eth oxyben zoyl)-6,7-d im eth oxy-3,4-
d ih yd r oisoq u in olin e Ben zyl Br om id e (17g). Gen er a l
P r oced u r e. A mixture of dihydroisoquinoline 16a (868 mg,
2.0 mmol) and benzyl bromide (359 mg, 2.1 mL, 0.25 mmol)

6592 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
er yth r o-1-[2-Br om o-3,4-(m et h ylen ed ioxy)-r-h yd r oxy-
b en zyl]-6,7-d im et h oxy-2-m et h yl-1,2,3,4-t et r a h yd r oiso-
qu in olin e (19c): 92% yield (method A); mp 146-147 °C
(MeOH-Et2O); IR 3100, 1592, 1503 cm-1; 1H NMR (270 MHz)
δ 2.50-2.63 (m, 2H), 2.72 (s, 3H), 2.88-3.16 (m, 2H), 3.86 (s,
3H), 3.89 (s, 3H), 3.97 (d, J ) 3.3 Hz, 1H), 5.30 (d, J ) 3.3 Hz,
1H), 5.29 (s, 1H), 5.76, 5.80 (each d, J ) 1.5 Hz, each 1H),
6.54 (s, 1H), 6.72, 6.77 (AB type J ) 8.7 Hz, each 1H). Anal.
Calcd for C20H22NO5Br: C, 55.06; H, 5.08; N, 3.21; Br, 18.31.
Found: C, 54.97; H, 5.03; N, 3.20; Br, 18.03.
er yth r o-1-(2-Br om o-3,4-d im eth oxy-r-h yd r oxyben zyl)-
6,7-d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin e (19j): 80%
yield (method A from 16a ); mp 153-155 °C (MeOH-Et2O);
1
IR 3302, 1607, 1590, 1512, 1485 cm-1; H NMR (400 MHz) δ
2.58-2.65 (m, 1H), 2.85-3.00 (m, 2H), 3.30-3.38 (m, 1H), 3.41,
3.84, 3.86, 3.87 (s, each 3H), 4.64, 5.12 (AB type J ) 3.9 Hz,
each 1H), 5.76, 6.58 (each s, each 1H), 6.83, 7.02 (AB type J )
8.3 Hz, each 1H). Anal. Calcd for C20H24NO5Br: C, 54.81; H,
5.52; N, 3.20; Br, 18.23. Found: C, 54.66; H, 5.52; N, 3.18; Br,
18.09.
er yth r o-1-[2-Br om o-3,4-(m et h ylen ed ioxy)-r-h yd r oxy-
b en zyl]-2-m et h yl-6,7-(m et h ylen ed ioxy)-1,2,3,4-t et r a h y-
d r oisoqu in olin e (19d ): 80% yield (method B); mp 187-189
°C (benzene-Et2O); IR 3570, 3080, 1617, 1500, 1489 cm-1; 1H
NMR (270 MHz) δ 2.53-2.62 (m, 2H), 2.72 (s, 3H), 2.92-3.17
(m, 2H), 3.94 (d, J ) 3.0 Hz, 1H), 5.26 (d, J ) 3.0 Hz, 1H),
5.37 (s, 1H), 5.78, 5.82 (each d, J ) 1.3 Hz, each 1H), 6.06,
6.10 (each d, J ) 1.5 Hz, each 1H), 6.55 (s, 1H), 6.53, 6.65 (AB
type J ) 8.3 Hz, each 1H). Anal. Calcd for C19H18NO5Br: C,
54.30; (H, 4.32; N, 3.33; Br, 19.02. Found: C, 54.12; H, 4.25;
N, 3.26; Br, 19.32.
Red u ction of Meth iod id e 17a by Ca ta lytic Hyd r oge-
n a tion in th e P r esen ce of Ad a m s Ca ta lyst. Gen er a l
P r oced u r e for P r ep a r a tion of Keton es 18a a n d 18d . A
stirred solution of 17a (288 mg, 0.5 mmol) in MeOH (20 mL)
was hydrogenated in the presence of PtO2 (11.4 mg, 0.05 mmol)
at 17 °C. Consumption of hydrogen ceased (16.0 mL, 1.04 M)
3 h later. The catalyst and solvent were removed, and the
residue was dissolved in CH2Cl2 (20 mL), washed with water
(20 mL), and dried (Na2SO4). Evaporation of the solvent gave
the crude ketone 18a (206 mg, 92%) as a colorless oil: IR (neat)
1
1674, 1608, 1585, 1520 cm-1; H NMR (270 MHz) δ 2.44 (s,
er yth r o-1-(2-Br om o-4,5-d im eth oxy-r-h yd r oxyben zyl)-
2-m et h yl-6,7-d im et h oxy-1,2,3,4-t et r a h yd r oisoq u in olin e
(19e): 87% yield (method B); mp 141-142 °C (MeOH); IR
3540, 1612, 1600, 1571, 1519, 1499 cm-1; 1H NMR (270 MHz)
δ 2.53-2.66 (m, 2H), 2.75 (s, 3H), 3.96-3.15 (m, 2H), 3.28,
3.57, 3.82, 3.87 (each s, each 3H), 4.00 (d, J ) 3.0 Hz, 1H),
5.29 (d, J ) 3.0 Hz, 1H), 5.39 (s, 1H), 6.49 (s, 1H), 7.06 (s,
1H). Anal. Calcd for C21H26NO5Br: C, 55.76; H,5.79; N, 3.10;
Br, 17.68. Found: C, 55.60; H, 5.76; N, 3.06; Br, 17.51.
er yth r o-1-[2-Br om o-4,5-(m et h ylen ed ioxy)-r-h yd r oxy-
b en zyl]-2-m et h yl-6,7-(m et h ylen ed ioxy)-1,2,3,4-t et r a h y-
d r oisoqu in olin e (19f): 92% yield (method B); mp 169-171
3H), 2.55-3.30 (m. 4H), 4.42 (s, 1H), 6.59, 6.65 (s, each 1H),
6.68, 7.21 (AB type, J ) 8.4 Hz, each 1H); MS m/z (rel int)
451 (M+, 0.5), 449 (M+, 0.9), 206 {[M - COC6H2(OCH3)2Br]+,
100}; HRMS m/z 449.0827 (calcd for C21H24NO5Br: 449.0838).
This oil was gradually decomposed in air to N-methylcorydal-
dine and 2-bromo-3,4-dimethoxybenzoic acid, as described
below.
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zoyl]-6,7-(m eth yl-
en ed ioxy)-2-m eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e (18d ):
90% yield from 17d ; mp 149-150 °C (MeOH-Et2O); IR 1679,
1604, 1597, 1503 cm-1; 1H NMR (90 MHz) δ 2.40 (s, 3H), 2.50-
3.20 (m, 4H), 4.35 (s, 1H), 5.89 (s, 2H), 6.05 (s, 2H), 6.59 (s,
1H), 6.61 (s, 1H), 6.59, 7.21 (AB type, J ) 8.1 Hz, each 1H).
Anal. Calcd for C19H16NO5Br: C, 54.56; H, 3.86; N, 3.35; Br,
19.10. Found: C, 54.50; H, 3.76; N, 3.22; Br, 19.30.
Tr ea tm en t of Meth iod id es 17a a n d 17d w ith 1 Mol
Equ iv of Na BH4 in MeOH. F r om 17a : To a stirred solution
of 17a (288 mg, 0.5 mmol) in MeOH (16 mL) was added NaBH4
(19 mg, 0.5 mmol). After 2 h, the mixture was worked up in
the same manner as those noted above for reduction of 17a
using excess NaBH4. The crude products (225 mg) were found
to comprise essentially 18a and 19a in a 70:30 ratio by 1H
NMR analysis. Attempts to isolate 18a by preparative TLC
were unsuccessful.
F r om 17d : A similar treatment of 17d (544 mg, 1 mmol),
followed by two crystallizations of the crude reaction products
(400 mg) from MeOH-Et2O, gave ketone 18d (233 mg, 56%),
mp 149-150 °C.
Na BH4 Red u ction of 18a . 1-Benzoyltetrahydroisoquino-
line 18a (30 mg, 0.067 mmol) was treated with NaBH4 (9 mg,
0.237 mmol) in method A. The crude product, a solid (30 mg),
was found to be essentially erythro-amino alcohol (19a ) in a
16:1 mixture of 19a and 20a . A fractional crystallization from
benzene-hexane gave 19a (27 mg, 90%) as colorless crystals,
mp 146-148 °C.
1
°C (MeOH); IR 3584, 1621, 1610, 1503, 1471 cm-1; H NMR
(270 MHz) δ 2.51-2.61 (m, 2H), 2.69 (s, 3H,), 2.88-3.13 (m,
2H), 3.96 (d, J ) 3.0 Hz, 1H), 5.22 (d, J ) 3.0 Hz, 1H), 5.42 (s,
1H), 5.80 (s, 2H), 5.92 (s, 2H), 6.51 (s, 1H), 6.55 (s, 1H), 7.02
(s, 1H). Anal. Calcd for C19H18NO5Br: C, 54.30; H, 4.32; N,
3.33; Br, 19.02. Found: C, 54.32; H, 4.44; N, 3.22; Br, 19.26.
er yth r o-2-Ben zyl-1-(2-br om o-3,4-d im eth oxy-r-h yd r oxy-
benzyl)-6,7-dim eth oxy-1,2,3,4-tetr ahydr oisoqu in oline (19g):
88% yield (method B); mp 137-139 °C (benzene-Et2O); IR
3530, 1609, 1594, 1514 cm-1; 1H NMR (270 MHz) δ 2.42-2.60
(m, 2H), 2.83-2.98 (m, 1H), 3.13-3.23 (m, 1H), 3.28, 3.82, 3.84,
3.87 (each s, each 3H), 3.79 (d, J ) 13.2 Hz, 1H), 4.38 (d, J )
13.2 Hz, 1H), 4.32 (d, J ) 3.3 Hz, 1H), 5.37 (s, 1H), 5.42 (d, J
) 3.3 Hz, 1H), 6.57 (s, 1H), 6.69, 6.73 (AB type, J ) 8.8 Hz,
each 1H). Anal. Calcd for C27H30NO5Br: C, 61.37; H, 5.72; N,
2.65; Br, 15.12. Found: C, 61.55; H, 5.73; N, 2.49; Br, 15.06.
Crystallization from MeOH gave colorless crystals containing
one molar equiv of MeOH, mp 80-82 °C; 1H NMR (270 MHz)
δ 3.48 (br s, 3H). Anal. Calcd for C27H30NO5Br‚CH3OH: C,
60.00; H, 6.11; N, 2.50; Br, 14.26. Found: C, 59.83; H, 6.11;
N, 2.34; Br, 14.44.
er yth r eo-2-Ben zyl-1-[2-br om o-3,4-(m eth ylen ed ioxy)-r-
h yd r oxyb en zyl]-6,7-(m et h ylen ed ioxy)-1,2,3,4-t et r a h y-
d r oisoqu in olin e (19h ): 95% yield (method B); mp 77-79 °C
Na BH4 Red u ction of 18d . 1-Benzoyltetrahydroisoquino-
line 18d (125 mg, 0.3 mmol) was treated with NaBH4 (67 mg,
1.5 mmol) in method B. Recrystallization of the product (138
mg) from benzene-Et2O gave erythro-amino alcohol 19d (101
mg, 80%), mp 187-189 °C.
1
(benzene-hexane); IR 3530, 1594, 1514, 1486 cm-1; H NMR
(270 MHz) δ 2.47-2.63 (m, 2H), 2.74-2.92, 3.12-3.30 (m, each
1H), 3.78, 4.23 (AB type, J ) 13.7 Hz, each 1H), 5.33 (d, J )
3.3 Hz, 1H), 5.57 (s, 1H), 5.80, 5.83 (each d, J ) 1.5 Hz, each
1H), 6.06, 6.10 (each d, J ) 1.2 Hz, each 1H), 6.17 (s, 1H),
6.55, 6.65 (AB type, J ) 8.3 Hz, each 1H), 7.26-7.41 (m, 5H).
Anal. Calcd for C25H22NO5Br: C, 60.50; H, 4.47; N, 2.82; Br,
16.10. Found: C, 60.46; H, 4.49; N, 2.62; Br, 16.38.
Tr ea tm en t of 18a w ith Oxygen . Oxygen gas was intro-
duced to a solution of the aforementioned crude ketone 18a
(30 mg) in MeOH for 1 h. After evaporation of MeOH, the
residue was shaken with a mixture of CH2Cl2 (5 mL) and 0.5
N NaOH (4 mL). The CH2Cl2 layer was washed with water (5
mL), dried over anhydrous Na2SO4, and evaporated to dryness.
The crude product was crystallized from petroleum ether to
give N-methylcorydaldine (12 mg, 81%), mp 126-127 °C (lit.30a
mp 123-124 °C;27b,30b 125-126 °C). The alkaline layer was
once washed with CH2Cl2 (5 mL) and then acidified with 0.5
N HCl solution (2 mL). The resultant solid was collected and
recrystallized from EtOH to give 2-bromo-3,4-dimethoxyben-
zoic acid (13 mg, 75%) as colorless crystals: mp 201-203 °C;
IR 1700, 1694, 1665, 1588, 1563, 1491 cm-1; 1H NMR (90 MHz,
er yth r o-1-(2-Br om o-3,4-d im eth oxy-r-h yd r oxyben zyl)-
6,7-d im et h oxy-2-p r op yl-1,2,3,4-t et r a h yd r oisoq u in olin e
(19i): 85% yield (method A); mp 95-97 °C (EtOH-hexane);
1
IR 3390, 1610, 1594, 1517, 1488 cm-1; H NMR (270 MHz) δ
1.01 (t, J ) 7.4 Hz, 3H), 1.65 (six, J ) 7.4 Hz, 2H), 2.43-2.65
(m, 2H), 2.56-3.06 (m, 4H), 3.24, 3.82, 3.83, 3.87 (each s, each
3H), 4.16, 5.24 (d, J ) 3.2 Hz, each 1H), 6.57 (s, each 1H),
6.64, 6.70 (AB type, J ) 8.7 Hz, each 1H). Anal. Calcd for
C
23H30NO5Br: C, 57.51; H, 6.29; N, 2.92; Br, 16.63. Found:
C, 57.51; H, 6.30; N, 2.78; Br, 16.86.

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids
J . Org. Chem., Vol. 64, No. 18, 1999 6593
CDCl3-DMSO-d6) δ 3.84, 3.92 (each s, each 3H), 4.63 (br s,
1H), 6.87, 7.71 (AB type, J ) 8.8 Hz, each 1H). Anal. Calcd
for C9H90O4Br: C, 41.40; H, 3.48; Br, 30.61. Found: C, 41.17;
H, 3.52; Br, 30.40.
This acid was obtained in 76% yield by treatment of
2-bromo-3,4-dimethoxybenzaldehyde26 (37 mg, 0.15 mmol) with
J ones reagent (0.5 mL) in acetone (10 mL) at room tempera-
ture for 80 min.
Anal. Calcd for C21H26NO5Br: C, 55.76; H, 5.79; N, 3.10; Br,
17.66. Found: C, 55.78; H, 5.69; N, 2.98; Br, 17.54.
LiAlH4 Red u ction of 17b: 19b and 20b (33:67) >90%
yield; 1H NMR spectrum (270 MHz) for threo-amino alcohol
20b ; δ 2.56 (s, 3H), 2.48-2.60 (m, 1H), 2.84-3.04 (m, 2H),
3.33-3.51 (m, 1H), 3.42 (d, J ) 8.3 Hz, 1H), 3.42 (s, 3H), 3.83
(s, 3H), 4.91 (d, J ) 8.3 Hz, 1H), 5.60 (s, 1H), 6.00 (dd, J )
8.9, 1.2 Hz, 2H), 6.56 (s, 1H), 6.88, 7.20 (AB type, J ) 8.3 Hz,
each 1H).
Tr ea tm en t of 19a w ith Cu Cl2. A mixture of 19a (23 mg,
0.05 mmol) and CuCl2 (13.4 mg, 0.1 mmol) in toluene (1 mL)
was heated in a test tube with shaking in an oil bath at 140
°C for 2 min. During this time, the color of the solution turned
to green and then yellow, and it finally became colorless. The
toluene layer, which was separated from the insoluble materi-
als, was washed once with water (2 mL) and dried (Na2SO4).
Toluene was evaporated to give 2-bromo-3,4-dimethoxyben-
zaldehyde as a crystalline solid (10 mg, 81%). The insoluble
residue was dissolved in MeOH (4 mL), and then NaBH4 (10
mg, 0.26 mmol) was added. After the mixture was stirred at
room temperature for 2 h, MeOH was evaporated. The residue
was extracted with CH2Cl2 (3 mL) and water (5 mL). The
organic layer was washed with water (5 mL), dried (Na2SO4),
and concentrated to give an oil (10 mg, 93%), which was
identical in all respects with an authentic sample of 6,7-
dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.31
LiAlH4 Red u ction of Meth iod id e 17a . Gen er a l P r oce-
d u r e. To a stirred solution of 17a (288 mg, 0.5 mmol) in dry
THF (50 mL) was added LiAlH4 (40 mg, 1.0 mmol) at once.
After 5 min, THF (5 mL) containing 1 mL of water was added
to the stirred reaction mixture, which was then allowed to be
stirred for 30 min. Precipitates were removed by suction
filtration, and the solvent was evaporated. The residue was
dissolved in CH2Cl2 (15 mL) and washed with water (10 mL).
The CH2Cl2 layer was dried (Na2SO4) and concentrated to give
an oil (233 mg), which comprised erythro- and threo-amino
alcohols 19a and 20a (29:71) (>90%).
LiAlH4 Red u ction of 17c: 19c and 20c (17:83) >90% yield;
1H NMR spectrum (270 MHz) for threo-amino alcohol 20c; δ
2.47 (s, 3H), 2.50-2.63 (m, 1H), 2.76-2.99 (m, 2H), 3.35-3.47
(m, 1H), 3.37 (d, J ) 8.6 Hz, 1H), 3.77 (s, 3H), 3.91 (s, 3H),
4.96 (d, J ) 8.6 Hz, 1H), 5.56 (s, 1H), 5.79 (dd, J ) 4.0, 1.3
Hz, 2H), 6.54 (s, 1H), 6.98, 7.40 (AB type, J ) 8.6 Hz, each
1H).
LiAlH4 Red u ction of 17d : 19d and 20d (25:75) >90%
yield; 1H NMR spectrum (270 MHz) for threo-amino alcohol
20d ; δ 2.47 (s, 3H), 2.52-2.65 (m, 1H), 2.76-2.99 (m, 2H),
2.76-2.99 (m, 2H), 3.31-3.49 (m, 1H), 3.45 (d, J ) 8.6 Hz,
1H), 4.84 (d, J ) 8.6 Hz, 1H), 5.71 (s, 1H), 5.83 (dd, J ) 7.3,
1.3 Hz, 2H), 6.04 (dd, J ) 7.6 Hz, 2H), 6.55 (s, 1H), 6.87, 7.15
(AB type J ) 8.3 Hz, each 1H).
LiAlH4 Red u ction of 18a . To a stirred solution of 18a (12
mg, 0.027 mmol) in dry THF (2 mL) was added LiAlH4 (2 mg,
0.053 mmol) at once in an atmosphere of N2. After 30 min,
workup in the same manner as that noted above for LiAlH4
reduction of 17a gave an oil (12 mg), which was found to be a
mixture of 19a and 20a in a ratio of 28:72.
Red u ction of Meth iod id e 17a w ith DIBALH. To a
stirred solution of methiodide 17a (28 mg, 0.05 mmol) in dry
CH2Cl2 (5 mL) was added DIBALH (1.5 M in hexane, 0.133
mL, 0.2 mmol, Aldrich) under argon. After 30 min, water (0.1
mL) was added, and the mixture was allowed to be stirred for
30 min. Precipitates were removed by suction filtration, and
the filtrate was concentrated. The residue was dissolved in
CH2Cl2 (2 mL) and washed with water (3 mL). Dryness (Na2-
SO4) and evaporation of the solvent gave an oil (16 mg, ca.
100%), which comprised 19a and 20a in a ratio of 76:24.
Red u ction of Meth iod id e 17a w ith Sod iu m Bis(2-
m eth oxyeth oxy)a lu m in u m Hyd r id e. To a stirred solution
of methiodide 17a (28 mg, 0.05 mmol) in dry THF (5 mL) was
added sodium bis(2-methoxyethoxy)aluminum hydride (3.5 M
in toluene, 0.057 mL, 0.2 mmol, Nippon Alkylaluminum Co.)
in an atmosphere of argon. After 5 min, THF (1 mL) containing
0.2 mL of water was added, and the mixture was allowed to
be stirred for 30 min. Precipitates were removed by suction
filtration, and the filtrate was concentrated. The residue was
dissolved in CH2Cl2 (2 mL), washed with water (3 mL), and
dried (Na2SO4). Evaporation of the solvent gave an oil (23 mg,
ca. 100%), which comprised 19a and 20a in a ratio of 40:60.
Gen er a l P r oced u r e for Syn th esis of Er yth r o-P h th a li-
d eisoqu in olin e Alk a loid es 1a -f a n d th e N-Ben zyl De-
r iva tives 1g a n d 1h by P a lla d iu m (0)-Ca ta lyzed Ca r bon -
yla tion of Er yth r o-Am in o Alcoh ols 19a -h . Syn th esis of
(()-Cor d r a stin e-II (1a ). A stirred mixture of 17a (45 mg, 0.1
mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (10.5 mg, 0.04
mmol), K2CO3 (276 mg, 2 mmol), and Me3SiCl (22 mg, 0.2
mmol) in toluene (2 mL) was refluxed in an atmosphere of
carbon monoxide for 24 h in a manner similar to that described
for carbonylation of benzyl alcohol 5a . Precipitates were
removed by suction filtration through a Celite pad, and the
This was treated with acetic anhydride (1 mL) and pyridine
(0.2 mL) at room temperature overnight, and then EtOH (5
mL) was added to decompose excess acetic anhydride. The
solvents were removed by azeotropic distillation using benzene.
The residue was dissolved in benzene (10 mL), washed with
5% NaHCO3 solution (2 mL) and water (10 mL × 2), and dried
(Na2SO4). Evaporation of the solvent gave an oil (271 mg),
which was subjected to preparative TLC on silica gel (5%
MeOH-CH2Cl2). A band with Rf 0.7 gave acetate of 19a (63
mg) [IR (neat) 1745, 1683, 1596, 1518, 1490 cm-1 1H NMR
:
(270 MHz) δ 2.02, 2.60, 3.51, 3.85, 3.86, 3.87 (each s, each 3H),
3.96 (d, J ) 4.4 Hz, 1H), 6.37 (d, J ) 4.4 Hz, 1H), 5.82 (s, 1H),
6.60 (s, 1H), 6.72, 6.78 (AB type, J ) 8.8 Hz, each 1H). MS
m/z (rel int) 494, 492 [each (M - H)+, each 0.04], 436, 434 [each
(M - OAc)+, each 0.80], 435, 433 [each (M - HOAc)+, 2.4],
420, 418 [each (M - HOAc - CH3)+, 1.2], 206 [(M - benzoyl
group)+, 100]. HRMS m/z 494.1001 (calcd for C23H27O6NBr;
494.0974]. A less mobile band with Rf 0.5 gave acetate of 20a
(127 mg) [IR (neat) 1738, 1681, 1612, 1596, 1518, 1491 cm-1
:
1H NMR (270 MHz) δ 2.06, 2.40, 3.55, 3.74, 3.83, 3.86 (each s,
each 3H), 3.83 (partially hiding d, J ) 6.6 Hz, 1H), 6.36 (d, J
) 6.6 Hz, 1H), 6.04 (s, 1H), 6.53 (s, 1H), 6.85, 7.06 (AB type,
J ) 8.8 Hz, each 1H); EI-MS m/z (rel int) 494, 492 [each (M -
H)+, each 0.02), 436, 434 [each (M - OAc)+, each 0.3], 206 [(M
- benzoyl group)+, 100]; HRMS m/z 492.1001 (calcd for
C
23H27O6NBr: 492.1021). Acetate of 19a was dissolved in 5%
1
KOH-MeOH (2 mL) and was heated to 50 °C for 5 min. MeOH
was then evaporated, and the residue was treated with water
(5 mL) and CH2Cl2 (10 mL × 3). The extracts were washed
with water (10 mL), dried (Na2SO4), and evaporated. The
resultant crude oily product (49 mg) was crystallized from
benzene-Et2O to give 19a (41 mg, 16%), mp 146-148 °C. A
similar treatment of acetate of 20a afforded the crude alcohol
(101 mg), which was crystallized from benzene-Et2O to give
20a (91 mg, 36%); mp 133-135 °C; IR 3380, 1609, 1596, 1516
filtrate was concentrated to give an oily residue (60 mg), H
NMR analysis of which revealed that this was essentially a
mixture of 1a , PPh3, and its oxide. The starting material was
not detected. This was dissolved in MeOH (5 mL) containing
5% KOH and refluxed for 5 min. MeOH was removed on a
rotary eveporator, and then water (5 mL) was added to the
residue, which was washed with CH2Cl2 (3 mL × 2). The water
layer, after addition of 2 N HCl (2 mL), was allowed to stand
at room temperature for 3 h and was then basified with
aqueous 2 N NaOH by adjusting to pH 9 and extracted with
CH2Cl2 (3 mL × 3). The combined CH2Cl2 layers were washed
with water (7 mL), dried (Na2SO4), and evaporated. The
residue (43 mg) was crystallized from MeOH to give (()-
1
cm-1; H NMR (270 MHz) δ 2.51 (s, 3H), 2.58-2.63 (m, 1H),
2.83-3.02 (m, 3H), 3.37 (s, 3H), 3.43 (d, J ) 8.4 Hz, 1H), 3.75,
3.82, 3.89 (each s, each 3H), 4.99 (d, J ) 8.4 Hz, 1H), 5.59 (s,
1H), 6.55 (s, 1H), 6.99, 7.41 (AB type, J ) 8.8 Hz, each 1H).

6594 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
cordrastine II (1a ), (39 mg, 98%), as colorless crystals; mp
117-119 °C from MeOH (lit.55 mp 110-114 °C;34 112-115 °C;56
117-118 °C;33 117-119 °C;57 118-119 °C). 1H NMR (270 MHz)
δ 2.30-2.40 (m, 1H), 2.58 (s, 3H), 2.55-2.70 (m, 2H), 2.90-
3.00 (m, 1H), 3.67, 3.87, 3.88, 4.03 (each s, each 3H), 4.02, (d,
J ) 3.3 Hz, 1H), 5.54 (d, J ) 3.3 Hz, 1H), 6.19 (s, 1H), 6.54 (s,
1H), 6.56, 7.09 (AB type, J ) 8.3 Hz, each 1H).12e,33,34,55,56,58,59
(()-Cor lu m in e (1b): 80% yield from 19b; mp 178-181 °C
(MeOH) (lit.34 173-176 °C;60 174 °C;61 175-176 °C;5,62 178-
N-Ben zyl er yth r o-la cton e 1g: 91% yield from 19g; mp
119-120 °C (MeOH-Et2O); IR 1757, 1610, 1602, 1517, 1498
cm-1; 1H NMR (270 MHz) δ 2.24-2.45 (m, 1H), 2.65-2.83 (m,
2H), 2.90 (m, 1H), 3.81, 4.18 (AB type, J ) 13.7 Hz, each 1H),
3.65, 3.87, 3.88, 4.04 (each s, each 3H), 4.16, 5.64 (each d, J )
3.7 Hz, each 1H), 6.19 (s, 1H), 6.62 (s, 1H), 6.57, 7.10 (AB type,
J ) 8.4 Hz, each 1H), 7.23-7.40 (m, 5H). Anal. Calcd for
C
28H29NO6: C, 70.72; H, 6.15; N, 2.95. Found: C, 70.65; H,
6.16; N, 3.00.
1
181 °C;63 193.5-195 °C; H NMR (270 MHz) δ 2.28-2.40 (m,
N-Ben zyl er yth r o-la cton e 1h : 85% yield from 19h ; mp
195-196 °C (MeOH-Et2O) (lit.5 mp 194-196 °C). This com-
pound was identified on direct comparison with an authentic
sample prepared by us.5
1H), 2.55-2.70 (m, 2H), 2.92-3.03 (m, 1H), 2.59 (s, 1H), 3.69
(s, 6H), 4.11 (d, J ) 3.3 Hz, 1H), 5.67 (d, J ) 3.3 Hz, 1H), 6.15
(s, 2H), 6.38 (s, 1H), 6.60 (s, 1H), 6.28, 6.95 (AB type, J ) 7.9
Hz, each 1H).10d,h,64
P a lla d iu m (0)-Ca ta lyzed Ca r bon yla tion of Th r eo-Am i-
n o Alcoh ol 20a . Syn th esis of (()-Cor d r a stin e I (2a ). In a
manner similar to the above, the aforementioned threo-alcohol
20a (23 mg) was converted to (()-cordrastine I (2a ) (18 mg,
90%), mp 155-156 °C (MeOH) (lit.34 mp 153-157 °C;33 154-
155 °C;57 155-156 °C;55,56,58,69 156-157 °C). 1H NMR (400 MHz)
δ 2.30-2.40 (m, 1H), 2.55-2.70 (m, 2H), 3.00-3.10 (m, 1H),
2.65 (s, 3H), 3.71, 3.81, 3.82, 3.90 (each s, each 3H), 4.03, (d,
J ) 3.3 Hz, 1H), 5.51 (d, J ) 3.3 Hz, 1H), 6.36, 6.69 (each s,
each 1H), 7.00, 7.31 (AB type, J ) 8.3 Hz, each 1H).12e,33,55,56,58
Gen er a l P r oced u r e for Syn th esis of Th r eo-P h th a lid e-
isoqu in olin e Alk a loid s 2a -d . Syn th esis of (()-Cor d r a s-
tin e I (2a ). A stirred mixture (92 mg, 0.2 mmol) of erythro-
(19a ) and threo-alcohols (20a ) in a ratio of 2:5 [prepared almost
quantitatively by treatment of 17a (119 mg, 0.2 mmol) with
LiAlH4 (15.2 mg, 0.4 mmol) in dry THF (20 mL) for 5 min],
Pd(OAc)2 (9.0 mg, 0.04 mmol), PPh3 (21.0 mg, 0.08 mmol), K2-
CO3 (552 mg, 4 mmol), and Me3SiCl (44 mg, 0.4 mmol) in
toluene (3 mL) was refluxed in an atmosphere of carbon
monoxide for 24 h. The reaction mixture was allowed to be
cooled to room temperature and filtered through a Celite pad.
Toluene was removed on a rotary evaporator, and the residue
was treated with water (10 mL) and CH2Cl2 (5 mL × 3). The
organic layers were washed with water (10 mL), dried over
anhydrous Na2SO4, and concentrated. An oily residue (148 mg,
19a :20a ) 29:71) was separated by preparative TLC (5%
MeOH-CH2Cl2). A band with Rf 0.9 gave (()-cordrastine I (2a ,
50 mg, 62.5%) and another band with Rf 0.5 gave (()-
cordrastine II (1a , 18 mg, 22.5%).
(()-Ad lu m in e (2b): 60% yield; mp 195-198 °C (MeOH-
CHCl3) (lit.34 mp 187-189 °C;61 189-190 °C;63 190 °C;60 191
°C;62 191.5-193.5 °C). 1H NMR (270 MHz) δ 2.35-2.85 (m,
3H), 2.64 (s, 3H), 3.03-3.10 (m, 1H), 3.76 (s, 3H), 3.81 (s, 3H),
4.08, (d, J ) 3.3 Hz, 1H), 5.68 (d, J ) 3.3 Hz, 1H), 6.07 (s,
2H), 6.38 (s, 3H), 6.70 (s, 1H), 6.88, 7.17 (AB type, J ) 7.9 Hz,
each 1H).64
(()-r-Hyd r a stin e (2c): 74% yield, mp 152-154 °C (MeOH)
(lit.12a mp 150 °C;65 150-151 °C;62 150-154 °C;57,66 151-152
°C). 1H NMR (270 MHz) δ 2.40-2.80 (m, 3H), 2.55 (s, 3H),
3.00-3.10 (m, 1H), 3.84 (s, 3H), 3.98 (s, 3H), 4.00, (d, J ) 3.3
Hz, 1H), 5.54 (d, J ) 3.3 Hz, 1H), 5.78, 5.83 (each d, J ) 1.3
Hz, each 1H), 6.37 (s, 1H), 6.65 (s, 1H), 7.04, 7.29 (AB type, J
) 8.3 Hz, each 1H).64
(()-â-Hyd r a stin e (1c): 80% yield from 19c; mp 135-137
°C (MeOH) (lit.12a mp 135 °C;62 136-140 °C;10c 135-137 °C;65
137-138 °C;57,66 138-139 °C;67 138-140 °C;5 150-151 °C;11b,c
151-152 °C). 1H NMR (270 MHz) δ 2.22-2.32 (m, 2H), 2.42-
2.65 (m, 2H), 2.85-2.94 (m, 1H), 2.55, 3.89, 4.06 (each s, each
3H), 3.99, (d, J ) 3.6 Hz, 1H), 5.48 (d, J ) 3.6 Hz, 1H), 5.90
(s, 2H), 6.38 (s, 1H), 6.58 (s, 1H), 6.52, 7.08 (AB type, J ) 8.2
Hz, each 1H).10c,56,64
(()-Bicu cu llin e (1d ): 85% yield from 19d ; mp 227-229
°C (MeOH-Et2O) (lit.68 mp 215 °C;61 215-216 °C;60 216 °C;62
1
217-220 °C;5 227-229 °C). H NMR (270 MHz) δ 2.22-2.30
(m, 1H), 2.52-2.62 (m, 2H), 2.84-2.91 (m, 1H), 2.55 (s, 3H),
4.04, 5.56 (each d, J ) 4.0 Hz, each 1H), 5.93 (d, J ) 1.0 Hz,
1H), 6.16 (d, J ) 1.7 Hz, 2H), 6.20, 6.92 (AB type, J ) 7.9 Hz,
each 1H), 6.46 (s, 1H), 6.58 (s, 1H).12e,69
(()-Isocor d r a stin e II (1e): 87% yield from 19e; mp 167-
169 °C (EtOH) (lit.70 mp 157-159 °C;59,71 166-167 °C;5 167-
1
169 °C;62 169-170 °C;67 169-171 °C;72 170-171 °C). H NMR
(270 MHz) δ 2.28-2.40 (m, 1H), 2.57-2.72 (m, 2H), 2.93-3.03
(m, 1H), 2.60 (s, 3H), 3.72, 3.79, 3.86, 3.91 (each s, each 3H),
4.12, 5.58 (each d, J ) 4.0 Hz, each 1H), 6.23, 6.42, 6.62, 7.23
(each s, each 1H).59,70-72
(()-Isobicu cu llin e (1f): 89% yield from 19f; mp 166-169
°C (MeOH-Et2O); IR 1752, 1613, 1502 cm-1 1H NMR (270
;
MHz) δ 2.27-2.43 (m, 1H), 2.58-2.64 (m, 2H), 2.91-2.98 (m,
1H), 2.53 (s, 3H), 3.93 (d, J ) 4.6 Hz, 1H), 5.43 (d, J ) 4.6 Hz,
1H), 5.92 (s, 2H), 6.08 (d, J ) 4.9 Hz, 2H), 6.33, 6.50, 6.60,
7.17 (each s, each 1H). MS m/z (rel int) 190 (100). Anal. Calcd.
for C20H17NO6; C, 65.39; H, 4.66; N, 3.81. Found: C, 65.49; H,
4.58; N, 3.80.
(55) Prager, R. H.; Trippett, J . M.; Ward, A. D. Aust. J . Chem. 1981,
34, 1085-1093.
(56) Smula, V.; Cundasawmy, N. E.; Holland, H. L.; MacLean, D.
B. Can. J . Chem. 1973, 51, 3287-3293.
(57) Haworth, R. D.; Pinder, A. R. J . Chem. Soc. 1950, 1776-1780.
(58) Shono, T.; Usui, Y.; Hamaguchi, H. Tetrahedron Lett. 1980, 21,
1351-1354.
(59) Kametani, T.; Honda, T.; Inoue, H.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1976, 1221-1225.
(60) Nalliah, B.; MacLean, D. B.; Rodrigo, R. G. A.; Manske, R. H.
Can. J . Chem. 1977, 55, 922-924.
(61) Nalliah, B.; MacLean, D. B.; Holland, H. L.; Rodrigo, R. Can.
J . Chem. 1979, 57, 1545-1578.
(()-Ad lu m id in e (Ca p n oid in e) (2d ): (Capnoidine is optical
antipode of adlumidine): 63% yield; mp 201-203.5 °C (MeOH-
CHCl3) (lit.61 mp 198-199 °C;62 200-203 °C;60 199 °C). 1H
NMR (270 MHz) δ 2.40-2.80 (m, 1H), 2.53 (s, 3H), 3.00-3.10
(m, 1H), 4.03, (d, J ) 3.3 Hz, 1H), 5.62 (d, J ) 3.3 Hz, 1H),
5.84 (s, 2H), 6.10 (s, 2H), 6.40 (s, 1H), 6.67 (s, 1H), 6.94, 7.14
(AB q, J ) 7.9 Hz, each 1H).12e,73,74
Gen er a l P r oced u r e for Hyd r ogen olysis of N-Ben zyl
La cton e 1g a n d 1h . Syn th esis of (()-Nor cor d r a stin e II
(1j). A suspension of N-benzyl lactone 1g (10 mg, 0.02 mmol)
and 10% Pd-C (10 mg) in AcOEt (2 mL) was stirred in an
atmosphere of hydrogen at room temperature for 8 h. Filtra-
tion of the catalyst and evaporation of the solvent in vacuo
gave an oily residue, which was dissolved in CH2Cl2 (3 mL),
(62) Slemon, C. E.; Hellwig, L. C.; Ruder, J .-P.; Hoskins, E. W.;
MacLean, D. B. Can. J . Chem. 1981, 59, 3055-3060.
(63) Wheley, W. M.; Meadow, M. J . Chem. Soc. 1953, 1067-1070.
(64) Seitanidi, K. L.; Yagudaev, M. R.; Israilov, I. A.; Yunusov, M.
S. Khim. Prirodu. Soedin. 1978, 465-471; Chem. Abstr. 1979, 90,
6585z.
(65) Hope, E. Pyman, F. L. Remfry, F. G. P.; Robinson, R. J . Chem.
Soc. 1931, 236-247.
(66) Haworth, R. D.; Pinder, A. R.; Robinson, R. Nature 1950, 165,
529.
(67) Shono, K.; Hamaguchi, H.; Sasaki, M.; Figita, S.; Nagami, K.
J . Org. Chem. 1983, 48, 1621-1628.
(68) Groenewoud, P. W. G.; Robinson, R. J . Chem. Soc. 1936, 199-
202.
(69) Mehra, K.; Garg, H. S.; Bhakuni, D. S.; Khanna, N. M. Ind. J .
Chem. 1976, 14B, 844-848.
(70) Shamma, M.; Georgiev, V. St. Tetrahedron Lett. 1974, 27, 2339-
2342; Tetrahedron 1976, 32, 211-215.
(71) Kametani, T.; Ohsawa, T.; Hirata, S.; Premila, S. M.; Ihara,
M.; Fukumoto, K. Chem. Pharm. Bull. 1977, 25, 321-326.
(72) Marsden, R.; MacLean, D. B. Can. J . Chem. 1984, 62, 306-
308.
(73) Ibragimova, M. U.; Yunusov, M. S.; Yu, S. Khim. Prirodu.
Soedin. 1970, 438-440; Chem. Abstr. 1971, 74, 54046r.
(74) Margvelashvili, N. N.; Kirjanova, A. T.; Tolkachev, O. N. Khim.
Prirodu. Soedin. 1972, 127-128; Chem. Abstr. 1972, 77, 58825d.

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids
J . Org. Chem., Vol. 64, No. 18, 1999 6595
washed with water (5 mL), and dried (Na2SO4). The solvent
was evaporated to give (()-norcordrastine II (1j) as a colorless
oil [9 mg, lit.33 mp 180-182 °C;70 183-185 °C;34 202-204 °C
(HCl salt)], which appeared as one spot on silica gel TLC (5%
7.12 (each s, each 1H); MS m/z (rel int) 308 [(M + H)+, 24.9],
307 (M+, 100), 248 (17.9), 154 (23.6). Anal. Calcd for C18H13
-
NO4; C, 70.35; H, 4.26; N, 4.56. Found; C, 70.47; H, 4.40; N,
4.37.
MeOH-CH2Cl2, Rf 0.4). IR (neat) 1757 cm-1
;
1H NMR (90
1-(2-Br om o-3,4-d im et h oxyb en zyl)-6,7-d im et h oxy-3,4-
h yd r oisoqu in olin e Meth iod id e (21a ). To a stirred solution
of 15a (210 mg, 0.5 mmol) in CH3CN (2 mL) was added CH3I
(0.2 mL, 3.2 mmol). After the mixture was gently refluxed for
10 min, the solvent was removed on a rotary evaporator.
Crystallization of the residue from MeOH gave methiodide 21a
as yellow crystals (203 mg, 75%), mp 206-208 °C; [IR 1639,
MHz) δ 2.43-2.60, 2.71-2.91 (m, each 2H), 3.82, 3.85, 3.89,
4.08 (each s, each 3H), 4.69 (d, J ) 3.6 Hz, 1H), 5.72 (d, J )
3.6 Hz, 1H), 6.62 (s, 1H), 6.68 (s, 1H), 6.15, 6.97 (d, J ) 8.2
Hz, each 1H).33,34
(()-Nor bicu cu llin e 1k : 87% yield from 1h ; a colorless oil;
1
IR (film) 3360, 1763, 1649, 1616, 1503, 1477 cm-1; H NMR
1
(270 MHz) δ 2.40-2.58, 2.75-2.90 (each m, each 2H), 4.71 (d,
J ) 3.6 Hz, 1H), 5.92 (s, 2H), 5.95 (d, J ) 7.9 Hz, 1H), 5.96,
5.98 (each s, each 1H), 5.75 (d, J ) 3.6 Hz, 1H), 6.61 (s, 1H),
6.71 (s, 1H), 6.85 (d, J ) 7.9 Hz, 1H); MS m/z (rel int) 353
(M+, 6.1), 335 (21.2), 320 (14.8), 176 (100); HRMS m/z 353.0914
(calcd for C19H15NO6: 353.0899).
1606, 1592, 1561, 1514 cm-1; H NMR (270 MHz) δ 3.42 (t, J
) 7.7, 2H), 3.76 (s, 3H), 3.85, 3.86, 3.97, 3.99 (each s, each
3H), 4.34 (t, J ) 7.7, 2H), 4.66 (s, 2H), 6.86, 7.05 (s, each 1H),
6.91, 7.10 (AB type, J ) 8.8 Hz, each 1H). Anal. Calcd for
C
21H25NO4BrI: C, 4.86; H, 4.48; N, 2.49; I + Br, 36.78. Found;
C, 44.58; H, 4.47; N, 2.34; I + Br, 36.86.
2,3,8,9-Tetr a m eth oxy-5,6-d ih yd r oin d olo[2,1-a ]isoqu in -
olin e (3a ). Gen er a l P r oced u r e. A mixture of 19a (45 mg,
0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (2 mL) was
refluxed under N2 for 3 days. After evaporation of the solvent,
the residue was extracted with CH2Cl2 (35 mL × 2), washed
with water (10 mL × 3), and dried (Na2SO4). Evaporation of
the solvent and crystallization of the oily residue (38 mg) from
EtOH gave 3a (27 mg, 79%), mp 190-194 °C, which gradually
colored to dark green at room temperature. Recrystallization
from EtOH gave the analytical sample (17 mg), mp 193-195
°C. IR 1609, 1575, 1556, 1508 cm-1; 1H NMR (270 MHz) δ 3.09,
4.63 (each t, J ) 6.6 Hz, each 2H), 3.92, 3.93, 3.95, 3.97 (each
s, aech 3H), 6.67 (s, 1H), 6.75 (s, 1H), 6.81, 7.24 (AB type, J )
8.6 Hz, each 1H), 7.18 (s, 1H); 13C NMR (67.5 MHz) δ 29.3 (t),
42.1 (t), 56.0 (q), 56.0 (q), 57.0 (q), 61.5 (q), 95.5 (d), 107.1 (d),
108.3 (d), 111.1 (d), 115.4 (d), 121.6 (s), 125.0 (s), 126.0 (s),
130.1 (s), 135.6 (s), 136.3 (s), 148.0 (s), 148.2 (s), 148.6 (s); MS
m/z (rel int) 339 (M+, 100), 324 (68.7), 170 (23.5); FD-MS 340
[(M + H)+, 24.1], 339 (M+, 100). Anal. Calcd for C20H21NO4;
C, 70.78; H, 6.24; N,4.13. Found; C, 70.78; H, 6.28; N, 4.05.
2,3-Dim eth oxy-8,9-(m eth ylen edioxy)-5,6-dih ydr oin dolo-
[2,1-a ]isoqu in olin e (3b): 80% yield; mp 198-200 °C (MeOH-
1-(2-Br om o-3,4-d im e t h oxyb e n zyl)-6,7-d im e t h oxy-2-
m eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e (22f). To a stirred
solution of methiodide 21a (54.2 mg, 0.1 mmol) in MeOH (2
mL) was added NaBH4 (10 mg, 0.25 mmol). After the mixture
was continuously stirred for 30 min, MeOH was removed on
a rotary evaporator, and the residue was treated with water
(10 mL) and CH2Cl2 (5 mL). The water layer was further
extracted with CH2Cl2 (3 mL). The combined CH2Cl2 layers
were washed with water (10 mL) and dried (Na2SO4). Evapo-
ration of the solvent gave a crystalline solid (43 mg), which
was treated with benzene-Et2O to give 22f (39 mg, 87%), mp
126 °C; IR 1605, 1572, 1511 cm-1; 1H NMR (270 MHz) δ 2.58
(s, 3H), 2.61-2.73 (m, 1H), 2.84-2.97 (m, 3H), 3.26-3.40 (m,
1H), 3.52 (s, 3H), 3.85 (s, 9H), 3.85 (s, 2H), 5.89 (s, 1H), 6.58
(s, 1H), 6.71, 6.74 (AB type, J ) 8.3 Hz, each 1H); MS m/z (rel
int) 437, 435 [each (M - H)+, 0.3], 231, 229 (each 2.5), 206
(100). Anal. Calcd for C21H26NO4Br: C, 57.81; H, 6.01; N, 3.21;
Br, 18.31. Found: C, 57.63; H, 5.95; N, 3.08; Br, 18.18.
Tr ea tm en t of a Mixtu r e of 19a a n d 20a w ith K2CO3 in
Boilin g DMF . A stirred suspension of an oily mixture (50 mg,
>90% yield) of 20a and 19a (3:2) [obtained by treatment of
methiodide 17a (56 mg, 0.1 mmol) with LiAlH4 (7.6 mg, 0.2
mmol) in the manner described above], K2CO3 (28 mg, 0.2
mmol), and DMF (2 mL) was refluxed in an atmosphere of
nitrogen. After 36 h, a part of the reaction mixture (0.5 mL)
was poured into brine (10 mL), extracted with CH2Cl2 (2 mL
× 3), washed with brine (5 mL × 5), and dried (Na2SO4). The
extract was concentrated to give an oil (13 mg), which was
found to be a mixture of 20a , 19a , and 3a in a ratio of 3:1:1 in
1
Et2O); IR 1596, 1552, 1503 cm-1; H NMR (270 MHz) δ 3.11,
4.39 (each t, J ) 6.6 Hz, each 2H), 3.91 (s, 3H), 3.95 (s, 3H),
6.00 (s, 2H), 6.68 (s, 1H), 6.74 (s, 1H), 6.74, 7.06 (AB type, J )
8.6 Hz, each 1H), 7.18 (s, 1H); MS m/z (rel int) 323 (M+, 100),
308 (17.5). Anal. Calcd for C19H17NO4; C, 70.35; H, 4.26; N,
4.56. Found; C, 70.32; H, 4.36; N, 4.57.
8,9-Dim eth oxy-2,3-(m eth ylen edioxy)-5,6-dih ydr oin dolo-
[2,1-a ]isoqu in olin e (3c): 82% yield; mp 177-180 °C (MeOH-
1
its H NMR (270 MHz) analysis. The other part of the reaction
1
Et2O); IR 1623, 1576, 1502 cm-1; H NMR (270 MHz) δ 3.06,
mixture was refluxed for an additional 24 h, and a similar
workup to the above gave an oil, which comprised 20a , 19a ,
and 3a in a ratio of 2:0:4.
4.58 (each t, J ) 6.3 Hz, each 2H), 3.93 (s, 3H), 3.96 (s, 3H),
5.97 (s, 2H), 6.62 (s, 1H), 6.72 (s, 1H), 6.80, 7.20 (AB type, J )
8.6 Hz, each 1H), 7.19 (s, 1H); MS m/z (rel int) 323 (M+, 100),
308 (93.0), 265 (35.2), 162 (20.5). Anal. Calcd for C19H17NO4;
C, 70.35; H, 4.26; N, 4.56. Found; C, 70.27; H, 4.30; N, 4.49.
2,3,8,9-Bis(m eth ylen ed ioxy)-5,6-d ih yd r oin d olo[2,1-a ]-
isoqu in olin e (3d ): 83% yield; mp 205-206 °C (EtOH); IR
1598, 1562, 1544, 1502 cm-1; 1H NMR (270 MHz) δ 3.08, 4.37
(each t, J ) 6.6 Hz, each 2H), 5.97 (s, 2H), 5.99 (s, 2H), 6.64
(s, 1H), 6.72 (s, 1H), 6.75, 7.06 (AB type, J ) 8.3 Hz, each 1H),
7.16 (s, 1H); MS m/z (rel int) 308 [(M + H)+, 23.2], 307 (M+,
100), 248 (24.0), 153 (24.6). Irradiation of a signal at δ 6.64
caused a NOE enhancement (20 and 7%) of signals owing to
1-H and 11-H at δ 7.16 and 7.06, respectively. Anal. Calcd for
Gen er a l P r oced u r e for Red u ction of Dih yd r oisoqu in -
olin e 15a -e w it h Na BH4. 1-(2-Br om o-3,4-d im et h oxy-
ben zyl)-6,7-dim eth oxy-1,2,3,4-tetr ahydr oisoqu in olin e (22a).
To a stirred solution of freshly prepared 1-benzyldihydroiso-
quinoline 15a (84 mg, 0.2 mmol) in MeOH (2 mL) was added
NaBH4 (3.8 mg, 0.1 mmol). After the mixture was stirred for
15 min, the solvents were evaporated at room temperature.
The oily residue was dissolved in water (3 mL) and extracted
with CH2Cl2 (3 mL × 3). The organic layers were washed with
water (5 mL), dried (Na2SO4), and concentrated to give 22a
(84 mg, ca. 100%) as a colorless oil, IR (neat) 3380, 1601, 1492
cm-1; 1H NMR (270 MHz) δ2.76 (t, J ) 5.9, 2H), 2.93 (dd, J )
13.6, 10.3 Hz, 1H), 2.98 (dd, J ) 11.6, 5.9 Hz, 1H), 3.24 (dd, J
) 12.15, 5.9 Hz, 1H), 3.34 (dd, J ) 13.6, 3.7 Hz, 1H), 3.84,
3.87, 3.876, 3.881 (each s, each 3H), 4.23 (dd, J ) 10.3, 3.7
Hz, 1H), 6.60 (s, 1H), 6.76 (s, 1H), 6.85, 6.99 (AB type, J ) 8.4
Hz, each 1H); MS m/z (rel int) 422, 420 [each (M - H)+, 0.2],
C
18H13NO4; C, 70.35; H, 4.26; N, 4.56. Found; C, 70.23; H, 4.46;
N, 4.79.
2,3,9,10-Tetr am eth oxy-5,6-dih ydr oin dolo[2,1-a ]isoqu in -
olin e (3e): 57% yield; mp 207-208 °C (MeOH-CH2Cl2) (lit.36
mp 199 °C;39a 201-203 °C;38d 202-203 °C;38a 202-204 °C;38g,h
1
209-210 °C). IR 1623, 1609, 1547, 1503 cm-1; H NMR (270
192 (100); HRMS m/z 421.0896 (calcd for C20H24NO4Br:
421.0889).
1-[2-Br om o-3,4-(m eth ylen edioxy)ben zyl]-6,7-dim eth oxy-
MHz) δ 3.12 (t, J ) 6.6 Hz, 2H), 3.91, 3.93 (each s, each 3H),
3.96 (s, 6H), 4.17 (t, J ) 6.6 Hz, 2H), 6.64, 6.75, 6.80, 7.07,
7.17 (each s, each 1H).38a
1,2,3,4-tetr a h yd r oisoqu in olin e (22b): 94% yield; mp 187-
1
2,3,9,10-Bis(m eth ylen ed ioxy)-5,6-d ih yd r oin d olo[2,1-a ]-
isoqu in olin e (3f): 33%; mp 219.5-222.5 °C (MeOH); IR 1540,
187.5 °C (MeOH); IR (neat) 3312, 1612, 1518, 1502 cm-1; H
NMR (270 MHz) δ2.75 (t, J ) 5.6, 2H), 2.91 (dd, J ) 10.2,
13.9 Hz, 1H), 2.97 (dd, J ) 5.6, 12.8 Hz, 1H), 3.23 (1H, dd, J
) 5.6, 12.8 Hz, 1H), 3.30 (dd, J ) 13.9, 3.6 Hz, 1H), 3.86 (s,
1
1498 cm-1; H NMR (270 MHz) δ 3.07, 4.09 (each t, J ) 6.6
Hz, each 2H), 5.93 (s, 2H), 5.96 (s, 2H), 6.59, 6.71, 6.77, 6.98,

6596 J . Org. Chem., Vol. 64, No. 18, 1999
Orito et al.
3H), 3.87 (s, 3H), 4.19 (dd, J ) 10.2, 3.6 Hz, 1H), 6.05 (s, 2H),
6.60 (s, 1H), 6.75 (s, 1H), 6.73, 6.77 (AB type, J ) 7.3 Hz, each
1H); MS m/z (rel int) 406, 404 [each (M - H)+, 0.2], 192 (100).
Anal. Calcd for C19H20NO4Br: C, 56.17; H, 4.96; N, 3.45; Br,
19.67. Found; C, 56.12; H, 5.01; N, 3.32; Br, 19.54.
1-(2-Br om o-3,4-dim eth oxyben zyl)-6,7-(m eth ylen edioxy)-
1,2,3,4-tetr a h yd r oisoqu in olin e (22c): 86% yield; a colorless
oil; IR (neat) 3316, 1595, 1504 cm-1; 1H NMR (270 MHz) δ2.66
(t, J ) 5.6, 2H), 2.81 (dd, J ) 10.6, 13.9 Hz, 1H), 2.87 (dd, J )
5.6, 12.2 Hz, 1H), 3.13 (dd, J ) 5.6, 12.2 Hz, 1H), 3.24 (dd, J
) 13.9, 3.3 Hz, 1H), 3.81 (s, 6H), 4.12 (dd, J ) 10.6, 3.3 Hz,
1H), 5.83 (s, 2H), 6.50 (s, 1H), 6.78 (s, 1H), 6.78, 6.92 (AB type,
J ) 8.6 Hz, each 1H); MS m/z (rel int) 406 [(M - H)+, 0.5],
404 (0.4), 324 (6.1), 176 (100); HRMS m/z 404.0484 (calcd for
(()-8-Oxostylop in e (23d ): 18 h; 82% yield; mp 267-270
1
°C (MeOH); IR 1647, 1597, 1486 cm-1; H NMR (270 MHz) δ
2.69-3.14 (m, 5H), 4.75 (dd, J ) 13.2, 3.3 Hz, 1H), 4.93 (dd, J
) 9.2, 3.3 Hz, 1H), 5.95 (s, 2H), 6.07, 6.17 (each d, J ) 1.3 Hz,
each 1H), 6.66 (s, 1H), 6.69 (s, 1H), 6.68, 6.86 (AB type, J )
7.6 Hz, each 1H); MS m/z (rel int) 337 (M+, 51.9), 174 (23.8),
162 (77.2), 134 (100). Anal. Calcd for C19H15NO5: C, 67.65: H,
4.48; N, 4.15. Found: C, 67.65: H, 4.48; N, 4.15.
Gen er a l P r oced u r e for LiAlH4 Red u ction of 8-Oxober -
bin es 23a -d . (()-Tetr a h yd r op a lm a tin e (4a ). To a stirred
solution of 23a (35 mg, 0.1 mmol) in dry THF (10 mL) was
added LiAlH4 (19 mg, 0.5 mmol). This suspension was refluxed
for 45 min under N2, cooled to room temperature, and then
treated with THF (2.5 mL) containing water (0.5 mL). The
resultant precipitates were removed by suction filtration, and
the filtrate was concentrated. The residue was shaken with
water (5 mL) and CH2Cl2 (5 mL). The organic layer was dried
(Na2SO4) and concentrated to give an oil (36 mg), which was
crystallized from MeOH-Et2O to give 4a (31 mg, 87%), mp
150-151 °C (lit.78 mp 145-146 °C;79-81 147 °C;82 148 °C;83 148-
150 °C;84 149.5-150.5 °C;48h 150-151 °C;85 151-151.5 °C). The
1H NMR spectrum of this sample was identical with the
reported data.78,81,82,85
(()-Sin a ctin e (4b): 90% yield; mp 168-170 °C (MeOH)
(lit.86 mp 155-156 °C;46 163-165 °C;81 166 °C;80,87 167-168
°C;84,88 169-170 °C; lit.56d 257-258 °C (HCl salt). The 1H NMR
spectrum of this sample was identical with the reported
data.54j,59c,60c
(()-Ca n a d in e (4c): 82% yield; mp 172-174 °C (EtOH)
(lit.50 mp 163-165 °C;51 164-165 °C;89 165 °C;87 mp 164-166
°C;46 167-168 °C;76 168-170 °C;48h,i 172-173 °C. The 1H NMR
spectrum of this sample was identical with the reported
data.46,48i,89
C
19H20NO4Br: 404.0497).
1-[2-Br om o-3,4-(m eth ylen ed ioxy)ben zyl]-6,7-(m eth yl-
en edioxy)-1,2,3,4-tetr ah ydr oisoqu in olin e (22d): 97% yield;
1
mp 173-175 °C (MeOH); IR 3318, 1617, cm-1; H NMR (270
MHz) δ2.67-3.19 (m, 5H), 4.74 (dd, J ) 12.9, 3.3 Hz, 1H), 5.03
(d, J ) 11.2 Hz, 3.0 Hz, 1H), 5.90 (s, 2H), 5.94 (s, 2H), 6.57 (s,
1H), 6.69 (s, 1H), 6.69 (d, J ) 7.9, 1.6 Hz, 1H), 6.74 (d, J ) 1.6
Hz, 1H), 6.77 (d, J ) 7.9 Hz, 1H); MS m/z (rel int) 390, 388
[each (M - H)+, 0.2], 308 (0.9), 213 (1.5), 176 (100). Anal. Calcd
for C18H16NO4Br: C, 55.40; H, 4.13; N, 3.59; Br, 20.48. Found;
C, 55. 34; H, 4.02; N, 3.61; Br, 20.34.
Gen er a l P r oced u r e for P a lla d iu m (0)-Ca ta lyzed Ca r -
bon yla tion of 1-(2-Br om oben zyl)-1,2,3,4-tetr a h yd r oiso-
qu in olin es 22a -d . (()-8-Oxotetr a h yd r op a lm a tin e (23a ).
A stirred mixture of freshly prepared tetrahydroisoquinoline
22a (41 mg, 0.1 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3
(10.5 mg, 0.04 mmol), and K2CO3 (14 mg, 0.1 mmol) in toluene
(2 mL) was refluxed in an atmosphere of carbon monoxide for
26 h. The reaction mixture was allowed to cool to room
temperature and filtered through a Celite pad. Toluene was
removed on a rotary evaporator, and the residue was treated
with water (5 mL) and CH2Cl2 (2 mL × 3). The organic layers
were washed with water (5 mL), dried (Na2SO4), and concen-
trated. The oily residue (61 mg) was purified by preparative
TLC (5% MeOH-CH2Cl2). A fraction with Rf 0.5 gave an oil
(32 mg), which was crystallized from MeOH-Et2O to give (()-
8-oxotetrahydropalmatine 23a , as colorless crystals (28 mg,
75%), mp 171-172 °C (lit.48h mp 167-168 °C;67,75 170-171 °C);
(()-Stylop in e (4d ): 86% yield: mp 211-214 °C (MeOH)
(lit.87 mp 191-192 °C;46 194-195 °C;48p 213-215 °C;80 217-
1
218 °C;88 219 °C). The H NMR spectrum of this sample was
identical with the reported data.46
Ack n ow led gm en t. We thank the Akiyama Founda-
tion for generous financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1a -h ,j,k , 2a -d , 3a -f, 4a -d , and 23a -d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
IR (neat) 1648, 1592, 1516, 1486 cm-1; H NMR (270 MHz) δ
2.70-3.15 (m, 1H), 3.87 (s, 9H), 3.89 (s, 3H), 4.73 (dd, J )
13.0, 3.3 Hz, 1H), 5.04 (dd, J ) 8.6, 2.3 Hz, 1H), 6.68 (s, 1H),
6.69 (s, 1H), 6.95, 7.01 (AB type, J ) 8.3 Hz, each 1H).75
(()-8-Oxosin a ctin e (23b): 18 h; 77% yield; mp 198-202
°C (MeOH) (lit.76 mp 198-200 °C); IR (Nujol) 3004, 1646, 1600,
J O982451W
(77) Perkin, W. H.; Ray, J . N.; Stauton, J .; Hirst, M. J . Chem. Soc.
1925, 127, 740-744.
1
1514 cm-1; H NMR (270 MHz) δ 2.72-3.17 (m, 5H), 3.89 (s,
3H), 3.90 (s, 3H), 4.80 (dd, J ) 12.9, 3.3 Hz, 1H), 4.98 (dd, J
) 8.6, 3.0 Hz, 1H), 6.12, 6.17 (each d, J ) 1.3 Hz, each 1H),
6.68 (s, 2H), 6.70, 6.87 (AB type, J ) 7.9, each 1H); MS m/z
(rel int) 353 (M+, 100), 338 (31.7), 322 (11.0), 190 (22.4), 162
(85.2), 134 (71.5).
(78) Dean, R. T.; Rapoport, H. J . Org. Chem. 1978, 43, 2115-2122.
(79) Haworth, R. D.; Koepfli, J . B.; Perkin J r., W. H. J . Chem. Soc.
1927, 548-554.
(80) Bradsher, C. K.; Dutta, N. L. J . Org. Chem. 1961, 26, 2231-
2234.
(81) Kiparissides, Z.; Fichtner, R. H.; Poplawski, J .; Nalliah, B. C.;
MacLean, D. B. Can. J . Chem. 1980, 58, 2770-2779.
(82) Tani, C.; Imanishi, I.; Nishijo, J . Yakugaku Zasshi 1970, 90,
407-411; Chem. Abstr. 1970, 73, 25719m.
(83) Narasimuhan, N. S.; Ranade, A. C.; Bhide, B. S. Indian J .
Chem. 1981, 20B, 439-440.
(84) Ninomiya, I., Naito, T.; Takasugi, H. J . Chem. Soc., Perkin
Trans 1 1975, 1720-1724.
(85) Kametani, T.; Ihara, M. J . Chem. Soc. (C) 1967, 530-532.
(86) Lentz, G. R. J . Org. Chem. 1974, 39, 2846-2851.
(87) Rajaraman, R.; Pai, B. R.; Premila, M. S.; Suguna, H. Indian
J . Chem. 1977, 15B, 876-879.
(88) Haworth, R. D.; Perkin, W. H., J r. J . Chem. Soc. 1926, 1769-
1784.
(()-8-Oxoca n a d in e (23c): 26 h, 85% yield; mp 209-211
°C (EtOH) (lit.48h mp 199-200 °C;48h,i 217-218 °C;66 222-223
°C); IR (Nujol) 1651, 1577, 1504, 1486 cm-1 1H NMR (270
;
MHz) δ 2.70-3.06 (m, 5H), 3.84 (s, 3H), 4.01 (s, 3H), 4.70 (dd,
J ) 12.9, 3.3 Hz, 1H), 4.98 (dd, J ) 8.6, 3.0 Hz, 1H), 6.66,
6.67 (s, each 1H), 6.93, 7.00 (AB type, J ) 8.3, each H);48h,i
MS m/z (rel int) 353 (M+, 36.8), 178 (100), 176 (56.6), 135 (64.0),
120 (57.9), 90 (63.8).
(75) Shono, T.; Usui, Y.; Mizutani, T.; Hamaguchi, H. Tetrahedron
Lett. 1980, 21, 3073-3076.
(76) Govindachari, T. R.; Nagarajan, K.; Charubala, R.; Pai, B. R.
Ind. J . Chem. 1970, 8, 763-765.
(89) Kametani, T.; Noguchi, I.; Saito, K.; Kaneda, S. J . Chem. Soc.
(C) 1969, 2036-2038.