Aryl radical cyclizations of 1-(2′-bromobenzyl)isoquinolines with AIBN-Bu3SnH: Formation of aporphines and indolo[2,1-a]isoquinolines

Article abstract of DOI:10.1021/ol990360v

(matrix presented) Radical cyclization of alkoxy-substituted 1-(2′-bromobenzyl)-3,4-dihydroisoquinolines 1 with AIBN-Bu₃SnH gave 6a,7-dehydroaporphines 2 preferentially. A steric repulsion between the respective alkoxy groups at the 7- and 3′-positions gave 5,6-dihydroindolo[2,1-a]isoquinolines 3 in a disfavored 5-endo cyclization mode. Radical cyclizations of the related substrates, such as 1-(2′-bromobenzoyl)isoquinolines or 1-(2′-bromo-α-hydroxybenzyl)isoquinolines, were also found to give the corresponding oxoaporphines or oxyaporphines.

Full text of DOI:10.1021/ol990360v

ORGANIC
LETTERS
2000
Vol. 2, No. 3
307-310
Aryl Radical Cyclizations of
1-(2′-Bromobenzyl)isoquinolines with
AIBN−Bu3SnH: Formation of
Aporphines and
Indolo[2,1-a]isoquinolines
Kazuhiko Orito,* Shiho Uchiito, Yoshitaka Satoh, Takashi Tatsuzawa,
Rika Harada, 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 November 15, 1999
ABSTRACT
Radical cyclization of alkoxy-substituted 1-(2′-bromobenzyl)-3,4-dihydroisoquinolines 1 with AIBN−Bu3SnH gave 6a,7-dehydroaporphines 2
preferentially. A steric repulsion between the respective alkoxy groups at the 7- and 3′-positions gave 5,6-dihydroindolo[2,1-a]isoquinolines 3
in a “disfavored” 5-endo cyclization mode. Radical cyclizations of the related substrates, such as 1-(2′-bromobenzoyl)isoquinolines or 1-(2′-
bromo-r-hydroxybenzyl)isoquinolines, were also found to give the corresponding oxoaporphines or oxyaporphines.
A method for tin-mediated intramolecular aryl radical
cyclization was reported by Beckwith in 1975.1 Since then,
focusing on the synthesis of benzocyclic compounds with
biarylic and heterocyclic structures, various methods2 based
on intramolecular additions of aryl radicals onto aryl groups,3
CC double bonds4,5 (including enamines6), and CN or CO
double bonds,7 as well as the earlier discovery of photoin-
duced aryl-aryl couplings,8 have been developed.
Radical cyclizations of 1-(2′-bromobenzyl)-1,2,3,4-tet-
rahydroisoquinolines have been reported to give aporphines.3e,h,l
We have been interested in radical cyclization of 1-(2′-
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795-802.
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P. J.; Penkett, C. S. and Shell, A. J. Chem. ReV. 1996, 96, 195-206. (c)
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Sons: New York, 1996; Vol. 48, pp 301-856. (d) Fallis, A. G.; Brinza, I.
M. Tetrahedron 1997, 52, 17543-17594. (e) Banik, B. K. Current Org.
Chem. 1999, 3, 469-496.
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10.1021/ol990360v CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/20/2000

bromobenzyl)-3,4-dihydroisoquinolines, which will give us
an answer as to whether the CdN group accepts a generated
phenyl radical in a 5-endo cyclization mode. This paper deals
with the competitive intramolecular additions of an aryl
radical onto another aryl group vs onto a CdN group. The
latter radical cyclization offers the first example of a
“disfavored” 5-endo cyclization9,10 of an aryl radical onto
XdC bonds (Figure 1),11 leading to the versatile benzocyclic
systems shown below. New findings on the efficiency of
Figure 1.
aryl radical cyclizations in the related aporphine syntheses
are also discussed.
(4) For reports of intramolecular additions of aryl radicals onto CdC
bonds since 1997, see: (a) Murphy, J. A.; Scott, K. A.; Sinclair, R. S.;
Lewis, N. Tetrahedron Lett. 1997, 38, 7295-7298. (b) Chattopadhyay, P.;
Mukherjee, M.; Ghosh, S. Chem. Commun. 1997, 2139-2140. (c) Andre´s,
C.; Duque-Soladana, J. P.; Iglesias, J. M.; Pedrosa, R. Synlett 1997, 1391-
1393. (d) Petel, V. F.; Andis, S. L.; Enkema, J. K.; Johnson, D. A.; Kennedy,
J. H.; Mohamadi, F.; Schultz, R. M.; Soose, D. J.; Spees, M. M. J. Org.
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Boyce, C. W. Cai, H.; Jin, Q.; Kitos, P. A. J. Org. Chem. 1997, 62, 8875-
8891. (f) Boger, D. L.; Boyce, C. W. Garbaccio, R. M. Searcey, M.
Tetrahedron Lett. 1998, 39, 2227-2230. (g) Butora, G.; Hudlicky, T.;
Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis 1998,
665-681. (h) Ikeda, M.; Ohtani, S.; Sato, T.; Ishibashi, H. Synthesis 1998,
1803-1806. (i) Rodr´ıguez, G.; Castedo, L.; Dom´ınguez, D. Saa´, C.
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Dom´ınguez, D. Saa´, C. J. Org. Chem. 1999, 64, 877-883. (k) Kizil, M.;
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First the substrates, alkoxy-substituted 1-(2′-bromo-benz-
yl)-3,4-dihydroisoquinolines 1a-i, were prepared by Bis-
chler-Napieralski cyclization of the corresponding aceta-
mides,12 and they were subjected to radical cyclization using
a stoichiometric amount of AIBN (1 molar equiv) and Bu3-
SnH (2 molar equiv) in boiling toluene (0.015 M) under
nitrogen for 4 h (Scheme 1). Dihydroisoquinolines 1a-d
Scheme 1
(5) For reports of intramolecular aryl radical additions onto CdC bonds
using SmI2, see: (a) Curran, D.; Fevig, T. L.; Totleben, M. Synlett 1990,
773-774. (b) Molander, G. A.; Harring, L. S. J. Org. Chem. 1990, 55,
6167-6176. (c) Inanaga, J.; Ujikawa, O.; Yamaguchi, M.; Tetrahedron Lett.
1991, 32, 1737-1740. (d) Curran, D.; Totleben, M. S. J. Am. Chem. Soc.
1992, 114, 6050-6058.
(6) For reports of intramolecular aryl radical additions onto enamine
double bonds since1997, see: (a) Ishibashi, H.; Kawanami, H.; Ikeda, M.
J. Chem. Soc., Perkin Trans. 1 1997, 817-821. (b) Ishibashi, H.; Kawanami,
H.; Nakagawa, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1997, 2291-
2295. (c) Ripa, L.; Halberg, A. J. Org. Chem. 1998, 63, 84-91. (d) Cassayre,
J.; Zard, S. Z. Synlett 1999, 501-503. (e) Brondney, M. A.; Padwa, A. J.
Org. Chem. 1999, 64, 556-565. (f) Rigby, J. H.; Deur, C.; Heeg, J. M.
Tetrahedron Lett. 1999, 40, 6887-6890. (g) Cid, M. M.; Dom´ınguez, D.;
Castedo, L.; Va´zquez-Lo´pez, E. M. Tetrahedron, 1999, 55, 5599-5610.
(7) For reports of intramolecular aryl radical additions onto CN and CO
double bonds since 1997, see: (a) McClure, C. K.; Kiessling, A. J.; Link
J. S. Tetrahedron 1998, 54, 7121-7126. (b) Ryu, I. Matsu, K.; Minakata,
S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, 5838-5839.
(8) For reports of intramolecular aryl-aryl couplings by photolysis related
to this study, see: (a) Kupchan, S. M.; Kanojia, R. M. Tetrahedron Lett.
1966, 44, 5553-5556. (b) Kupchan, S. M.; Kim, C.-K.; Miyano, K. J. Chem.
Soc., Chem. Commun. 1976, 91-92. (c) Cava, M. P.; Mitchell, M. J.;
Havlicek, S. C.; Lindert, A.; Spengler, R. J. J. Org. Chem. 1970, 35, 175-
179. (d) Hara, H.; Hoshino, O.; Umezawa, B. Tetrahedron Lett. 1972, 49,
5031-5034. (e) Rajeswari, S.; Suguna, H.; Pai, B. R. Indian J. Chem. 1977,
15B, 592-594. (f) Govindachari, T. R.; Nagarajan, K.; Rajeswari, S.;
Suguna, H.; Pai, B. R. Indian J. Chem. 1977, 15B, 873-875. (g)
Govindachari, T. R.; Nagarajan, K.; Rajeswari, S.; Suguna, H.; Pai, B. R.
HelV. Chim. Acta 1977, 60, 2138-2150. (h) Trifonov, L. S.; Orahovats, A.
S. Izu. Khim. 1978, 11, 297-304. (i) Kessar, S. V.; Gupta, Y. P.; Yadav,
V. S.; Nalula, M.; Mohammad, T. Tetrahedron Lett. 1980, 21, 3307-3308.
(j) Kessar, S. V.; Gupta, Y. P.; Mohammad, T. Indian J. Chem. 1981, 20B,
984. (k) Castedo, L.; Saa´, C.; Saa´, J. M.; Suau, R. J. Org. Chem. 1982, 47,
513-517. (l) Kessar, S. V.; Mohammad, T. Gupta, Y. P.; Indian J. Chem.
1983, 22B, 321-324. (m) Smidrkal, J. Collect. Czech. Chem. Commun.
1984, 49, 1412-1420. (n) Dai-Ho, G.; Mariano, P. S. J. Org. Chem. 1987,
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with a 2′-bromo-3′,4′-dialkoxybenzyl group at their C-1
position underwent an intramolecular aryl-aryl radical
coupling at C-8 and/or a 5-endo cyclization on an N atom
of the CN double bond to gave air-sensitive 6a,7-de-
hydroaporphines 2b-d13 and/or 5,6-dihydroindolo[2,1-a]-
isoquinolines 3a-d12 almost quantitatively. The product
ratios were determined by immediate 1H NMR measurements
of the crude products and are shown together with the
isolated yields in Table 1. Compound 1a, which has two
vicinal dimethoxy groups at the 3′,4′- and 6,7-positions, did
not give 2a at all, but produced 3a exclusively. Compounds
1b-d gave 2b-d and 3b-d in ratios of 55:45, 30:70, and
60:40, respectively. These results are well accounted for by
a large steric repulsion (a so-called buttressing effect14)
between two vicinal dimethoxy groups at the 1,2- and
10,11-positions of the assumed aporphine 2a.
In contrast, a similar treatment of 1e-h which have no
substituents at the 3′-position of the benzyl group preferen-
tially gave the corresponding dehydroaporphines 2e-h.
Minor products, 5,6-dihydroindolo[2,1-a]isoquinolines 3e-
h, occurred in a 2,3,9,10-tetraalkoxy substitution pattern
characteristic of the dibenzopyrrocoline alkaloids cryptaus-
(12) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.; Suginome,
H. J. Org. Chem. 1999, 64, 6583-6596.
(9) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L. Silberman, L.;
Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 738-738.
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Chem. Commun. 1980, 482-483. (b) Beckwith, A. L. J. Tetrahedron 1981,
37, 3073-3100.
(11) A radical addition to azo nitrogen has been reported for only one
example of 5-endo aryl radical cyclization, see: Kunka, C. P.; Warkentin,
J. Can. J. Chem. 1990, 68, 575-580.
(13) For reviews for the aporphine alkaloids, see: (a) Guinaudeau, H.;
Leboeuf, M.; Cave, A. Lloydia 1975, 38, 275-338. (b) Guinaudeau, H.;
Leboeuf, M.; Cave, A. J. Nat. Prod. 1979, 42, 325-360. (c) Kametani, T.;
Honda, T. In The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando,
1985; Vol. 24, pp 153-251.
(14) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997,
62, 2604-2610 and references cited therein.
308
Org. Lett., Vol. 2, No. 3, 2000

Scheme 2
Table 1. Radical Cyclization of
1-(2′-Bromobenzyl)-3,4-dihydroisoquinolines 1
toline and cryptowoline.15 Isoquinoline 1i which has no
alkoxy group on the benzyl group gave dehydroaporphine
2i together with 3i in a ratio of 11:1. This ratio is in good
agreement with the results of the above-mentioned radical
cyclizations of the R3 ) H series (1e-h).
In each case the corresponding debrominated reactant was
not produced, although in the radical cyclizations of tetra-
hydroisoquinolines, regardless of the type of substituent on
the N atom, such as an alkyl or acyl group, they have
occurred as the regular byproducts in significant yields.2,3
As depicted in Figure 2, this unique 5-endo ring closure into
2). Dihydroisoquinoline 4 gave oxoaporphine 6 together with
the debrominated reactant (7) in a ratio of 46:31 in 77%
conversion of 4 and in 40% and 18% isolated yields.
Table 2. Radical Cyclization of Compounds 4, 8, and 9
Figure 2.
indolo[2,1-a]isoquinolines is considered to be initiated mainly
by the stabilization of radical 3′, which is generated by
addition of a phenyl radical onto a CN double bond, on a
carbon bearing an N atom and an aryl group and to be
completed by the formation of a double bond at the
12-position into 3. Another radical species, 2′, formed at a
center of the conjugated system by aryl-aryl coupling in
an 6-exo manner was transformed with the isomerization of
the initial CN double bond into aporphine 2.
Isoquinoline 8 also gave 6 together with alcohol 9 and the
debrominated alcohol 9 (10) in a ratio of 58:38:4 (45, 28
and 2% yields). A similar treatment of ketone 8 without
AIBN gave alcohol 9. Radical reaction of the isolated 916
Radical reactions of ∆1-isoquinolines with a 1-benzoyl
group, 4 and 8, were next examined (Scheme 2 and Table
(16) Compound 9: colorless crystals; mp 143-145 °C (benzene-
hexane); IR (Nujol) 3477-3370, 1510 cm-1; 1H NMR (270 MHz, CDCl3)
δ 3.88 (s, 3H), 3.99 (s, 3H), 6.71 (s, 1H), 6.88-6.69 (m, 1H), 7.05-7.13
(m, 4H), 7.54 (d, J ) 5.6 Hz, 1H), 7.61-7.64 (m, 1H), 8.41 (d, J ) 5.6
Hz, 1H); EI-MS m/z (rel intensity) 373 (M+, 14), 294 [(M - Br)+, 100],
278 (12), 262 (5).
(15) For a review of the dibenzopyrrocoline alkaloids, see: Eliott, I. W.
In The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando, 1987; Vol.
31, pp 101-116.
Org. Lett., Vol. 2, No. 3, 2000
309

also gave oxoaporphine 6 (57%), and in this case the amount
of unchanged 9 was smaller (62:22:16) compared with that
obtained by an identical treatment of 8, proving that a
significant amount of Bu3SnH was consumed for reduction
of 8 to 9 prior to the radical cyclization. A similar Bu3SnH
treatment converted 4 more easily, even at room temperature,
to labile alcohol 5,17 which on exposure to air was oxidized
back to 4 quantitatively. Thus, in this radical cyclization of
1-(2′-bromobenzoyl)-∆1-isoquinoline 4 or 8, a coupling
between an imine nitrogen and a 2′ carbon did not occur,
but oxoaporphines were formed in good yields probably
along the main pathway via the alcohol 5 or 9.18
Scheme 4
Radical cyclizations of 1-benzyltetrahydroisoquinolines
have been reported by Castedo’s and Comins’ groups.3e,h,l
Reexamination under our conditions as described above gave
rather similar results. All the substrates of type 11a (X )
H) gave aporphines 12a in 22-35% yields, together with
the respective debrominated reactants. Substrates 11b (X )
H) which have a more bulky N-substituent, such as a COOEt
group, gave the corresponding aporphine 12b in 50% yield.
Substrates 11c which have an N-methyl and an R-hydroxy
group (X ) OH) gave oxyaporphines 12c in 57-68% yields.
The intramolecular hydrogen bonding between the R-OH and
an N atom8j as well as the steric block with a substituent on
the N atom is considered to work for the aryl radical coming
close to a benzene ring of the isoquinoline part, reflecting
the enhanced yields for 12b and 12c. This fixed conformation
is in agreement with the above-mentioned reaction mecha-
nism for the radical cyclization of 4 and 8 via benzyl alcohols
5 and 9.
N-H group by an aryl radical was easily proved by a
deuterium incorporation experiment. As shown in Scheme
4, when the radical reaction of 13a was carried out using
Bu3SnD, toluene-2-d 16a′ was obtained, and the radical
reaction using Bu3SnH of the N-D derivative of 13a gave
toluene-R-d 16a′′. From 13c (X ) OH), 15 (77%), benzyl
alcohol 16c (45%), and benzaldehyde 17c (10%) were
obtained as the main products, and as expected, the corre-
sponding oxyaporphine 18c was also produced in 14%
yield,8i,l suggesting again the occurrence of the above-
mentioned hydrogen bonding.
Scheme 3
In summary, radical cyclization of alkoxy-substituted 1-(2′-
bromobenzyl)-3,4-dihydroisoquinolines with AIBN-Bu3SnH
gave 6a,7-dehydroaporphines preferentially owing to an
aryl-aryl coupling. A steric repulsion between the respective
alkoxy groups at the 7- and 3′-positions induced an aryl-
imino coupling in a “disfavored” 5-endo cyclization mode
to give 5,6-dihydroindolo[2,1-a]-isoquinolines. Radical cy-
clizations of the related substrates, such as 1-(2′-bromo-
benzoyl)isoquinolines and their 3,4-dihydro and 1-(2′-
bromobenzyl)-1,2,3,4-tetrahydo derivatives, were found to
give the corresponding oxoaporphines or oxyaporphines
being directed by the steric bulk of the N-substituents and
hydrogen bonding between an OH group at the R-position
and the N atom.
In contrast, radical cyclizations of tetrahydroisoquinolines
(13a,b, X ) H) with no substituent on the N atom were
unsuccessful,3f and they gave 3,4-dihydroisquinoline 15
(60%) and toluene 16a or 16b (60%). The reaction mech-
anism based on a hydrogen abstraction from the isoquinoline
(17) Compound 5: a colorless oil; 1H NMR (270 MHz, CDCl3) δ 2.27-
2.77 (m, 2H), 3.65-3.72 (m, 1H), 3.76 (s, 3H), 3.87 (s, 3H), 4.03-4.13
(m, 1H), 6.21 (d, J ) 2.3 Hz, 1H), 6.67 (s, 1H), 6.79 (s, 1H), 7.07-7.20
(m, 3H), 7.56-7.60 (m, 1H).
(18) This is also proved by the fact that the photoinduced cyclization,
which has no hydride reagent, of a bromide similar to 4 was unsuccessful.
See ref 8i.
Supporting Information Available: Characterization
data for products 2, 3, 4, 6, 9 12, and 18c. This material is
available free of charge via the Internet at http://pubs.acs.org.
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