A facile route to indolo[2,1-a]isoquinolines and dibenzopyrrocoline alkaloids

Article abstract of DOI:10.1021/ol005802d

(Formula presented) Treatment of 1-(2′-bromobenzyl)-3,4-dihydroisoquinolines 2 in the presence of K₂CO₃ in boiling DMF efficiently provided a variety of alkoxysubstituted indolo[2,1-a]isoquinolines 3. Application of this cyclization

Full text of DOI:10.1021/ol005802d

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1799-1801
A Facile Route to
Indolo[2,1-a]isoquinolines and
Dibenzopyrrocoline Alkaloids
Kazuhiko Orito,* Rika Harada, Shiho Uchiito, and Masao Tokuda
Laboratory of Organic Synthesis, DiVision of Molecular Chemistry,
Graduate School of Engineering, Hokkaido UniVersity, Sapporo 060-8628, Japan
orito@org-mc.eng.hokudai.ac.jp
Received March 14, 2000
ABSTRACT
Treatment of 1-(2′-bromobenzyl)-3,4-dihydroisoquinolines 2 in the presence of K2CO in boiling DMF efficiently provided a variety of alkoxy-
3
substituted indolo[2,1-a]isoquinolines 3. Application of this cyclization to 7-benzyloxyisoquinoline derivatives, followed by further elaboration
of the resultant 2-benzyloxy-5,6-dihydroindolo[2,1-a]isoquinolines 16a,b, led to the formal synthesis of dibenzopyrrocoline alkaloids, (±)-
cryptaustoline (1a) and (±)-cryptowoline (1b).
Indolo[2,1-a]isoquinoline has a unique nitrogen-containing
tetracyclic structure, characteristic of dibenzopyrrocoline
alkaloids, cryptaustoline 1a and cryptowoline 1b, isolated
As shown in Scheme 1, we initially encountered this
structure in the intramolecular cyclization products of
erythro-1-[(2′-bromopheny)hydroxymethyl]-1,2,3,4-tetra-
hydroisoquinolines 5, which were prepared in three more
(3) (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) Boente, J. M.; Castedo, L.; Rodriguez de Lera,
A.; Saa´, J. M.; Suau, R.; Vidal, M. C. Tetrahedron Lett. 1983, 24, 2295-
2298. (i) Ambros, A.; von Angerer, A.; Wiegrebe, W. Arch. Pharm.
(Weinheim, Ger.) 1988, 321, 481-486. (j) Meyers, A. I.; Sielecki, T. M. J.
Am. Chem. Soc. 1991, 113, 2789-2790.
(4) (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. Prackt. Chem. 1977, 319, 568-572.
(5) Ninomiya, I.; Yasui, J.; Kiguchi, T. Heterocycles 1977, 6, 1855-
1860.
from the bark of Cryptocarya bowiei.1,2 Several methods for
construction of this structure,3-8 including the well-known
benzyne reaction3 or oxidative coupling4 of 1-benzyl-
isoquinolines, have been reported. Antileukemic and anti-
tumor activities of such bases have been reported, and their
ammonium salts have been expected to enhance the
activities.3I,9
(6) Takano, S.; Satoh, S.; Ogasawara, K. Heterocycles, 1987, 26, 1483-
1485.
(7) (a) Matthew, K. K.; Menon, K. N. Proc. Ind. Acad. Sci. 1949, 29A,
361-363. (b) Yasuda, S.; Hirasawa, T.; Yoshida, S.; Hanaoka, M. Chem.
Pharm. Bull. 1989, 37, 1682-1683.
(8) Eliott, E. W., Jr. J. Org. Chem. 1982, 47, 5398-5400.
(9) Ambros, R.; von Angerer, S.; Wiegrebe, W. Arch. Pharm. (Weinheim,
Ger.) 1988, 321, 743-747.
(1) Ewing, J.; Hughes, G. K.; Ritchie, E.; Taylor, W. C. Nature 1952,
169, 618-619; Aust J. Chem. 1953, 6, 78-85.
(2) For a review, see: Eliott, I. W. In The Alkaloids; Brossi, A. Ed.;
Academic Press: Orlando, 1987; Vol. 31, pp 101-116.
10.1021/ol005802d CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/03/2000

When substrates 2a-d with an alkoxy group at their 3′
position or substrates 2e-j without the alkoxy group,
including the compounds 2i and 2j having no substituent on
the phenyl group except for a Br atom, were heated in the
presence of 2 mol equiv of K2CO3 in boiling DMF for 3
days (Scheme 2), the corresponding 5,6-dihydroindolo[2,1-
a]isoquinolines 3 were obtained in 76-95% isolated yields
by crystallization. Dimeric products at their C-12 position
were not detected at all.3g,4c,7b The cyclization did not proceed
without alkali. K3PO4 worked well, similarly to K2CO3, but
stronger bases such as BuLi and KOtBu, did not. Replace-
ment of DMF with DMSO resulted in the formation of a
black tar.
Scheme 1. Preceding Studies10-12
Under the same conditions, the 2′-iodo derivative 6a was
consumed much faster than the bromide 2a, and the
cyclization finished within 1.5 days. However, its 2′-methoxy
derivative 6b was recovered unchanged. The cyclization of
a readily accessible 3′-bromopapaverine 713 also proceeded
smoothly to give a fully aromatized indolo[2,1-a]isoquinoline
8, mp 225.5-228.0 °C (MeOH, lit.3i mp 210 °C), within 2
days quantitatively (Scheme 3), although DDQ oxidation of
3e gave 8 (65%).
steps of reactions from 2′-bromobenzyl-3,4-dihydroisoquino-
lines 2, in the presence of K2CO3.10,11 Recently, we reported
Bu3SnH-induced aryl radical cyclization, which competitively
gave 5,6-dihydroindolo[2,1-a]isoquinolines 3 and aporphines
4 from 2.12 In the present study, we developed a convenient
method for selective preparation of a variety of alkoxy-
substituted indolo[2,1-a]isoquinolines 3 from the same
substrates 2, involving 3a-d, which cannot be obtained by
the benzyne method noted above.3
Scheme 3. Synthesis of Indolo[2,1-a]isoquinoline 8
Scheme 2. Synthesis of 5,6-Dihydroindolo[2,1-a]isoquinolines
3
It had been reported that the thermal electrocyclization of
a pentadienyl anion gave a cyclopentenyl anion.14 We had
assumed that such an effect might have contributed to these
cyclizations (Scheme 4), until the following fact was
disclosed. 1-Benzyldihydroisoquinoline 9, having two methyl
Scheme 4. An Assumed Thermal Electrocyclization Process12
1800
Org. Lett., Vol. 2, No. 13, 2000

groups at the benzyl position, also underwent a similar cycli-
zation with loss of one methyl group to give 12-methyl-
indolo[2,1-a]isoquinoline 10, mp 224-226 °C (MeOH-
CH2Cl2, lit.9 216-217 °C) (Scheme 5). The dehydro deriva-
Scheme 6. A Probable Pathway to Indolo[2,1-a]isoquinolines
3, 8, and 10
Scheme 5. Formation of Indolo[2,1-a]isoquinoline 10
a]isoquinolines 16a, mp 146-148 °C (MeOH), and 16b, mp
159-161 °C (MeOH, lit.3b mp 157-158 °C), almost
quantitatively (82% and 83% isolated yields by crystalliza-
tion). Dihydroisoquinolines 16a and 16b were further
converted by treatment with excess NaBH3CN in AcOH
almost quantitatively to air-sensitive tetrahydroindolo[2,1-
a]isoquinolines 17a and 17b, respectively (Scheme 7). In
Scheme 7. Synthesis of Dibenzopyrrocoline Alkaloids
Cryptaustoline 1a and Cryptowoline 1b
tive (11) did not cyclize and was recovered unchanged. The
dihydro derivatives of 2e, 1,2,3,4-tetrahydroisoquinolines (12,
13),11 were also recovered unchanged. An attempt to produce
a quinoline ring using the homologue 14 failed, and it was
recovered unchanged. On the basis of these results, a reaction
pathway via i, ii, and iii (Scheme 6) which starts with a
nucleophilic addition of the isoquinoline nitrogen and ends
up in the formation of a stable conjugated system, “indole
ring”, was proposed for this versatile cyclization.
Application of this cyclization on 7-benzyloxy-3,4-dihy-
droisoquinoline 15a3a and 15b3b gave 5,6-dihydroindolo[2,1-
view of the previous conversion of these compounds into
(()-cryptaustoline (1a) and (()-cryptowoline (1b),3a,b,i,7b this
constitutes a formal synthesis of the alkaloids.
(10) Orito, K.; Miyazawa, M.; Suginome, H. Heterocyclic Commun.
1995, 1, 239-240;
(11) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.; Suginome,
H. J. Org. Chem. 1999, 64, 6583-6596.
(12) Orito, K.; Uchiito, S.; Satoh, Y.; Tatsuzawa. T.; Harada, R.; Tokuda,
M. Org. Lett. 2000, 2, 307-310.
Supporting Information Available: Characterization
data for products 3, 8, 10, and 16. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Anderson, O. Justus Liebigs Ann. Chem. 1854, 94, 235-240.
(14) (a) Stapp, P. R.; Kleinschmidt, R. F. J. Org. Chem. 1965, 30, 3006-
3009. (b) Slaugh, L. H. J. Org. Chem. 1967, 32, 108-113. (c) Bates, R.
B.; McCombs, D. A. Tetrahedron Lett. 1969, 977-978. (d) Shoppee, C.
W.; Henderson, G. N. J. Chem. Soc., Perkin Trans. 1 1975, 765-772.
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