Synthesis of bridged benzoazabicyclic compounds using radical translocation/cyclization reactions of 1-alkynyl-2-(o- iodobenzoyl)tetrahydroisoquinolines

Article abstract of DOI:10.3987/COM-99-S91

Bu₃SnH-mediated radical translocation/cyclization reactions of 1- alkynyl-2-(o-iodobenzoyl)tetrahydroisoquinolines were examined. The 1- [3(trimethylsilyl)prop-2-ynyl]-(10a) and 1-[4-(trimethylsilyl)but-3-ynyl]- 1,2,3,4-tetrahydroisoquinoline d

Full text of DOI:10.3987/COM-99-S91

HETEROCYCLES, Vol. 52, No. 2, 2000, pp. 571 – 574, Received, 7th May, 1999
SYNTHESIS
COMPOUNDS
CYCLIZATION
OF
USING
REACTIONS
BRIDGED
RADICAL
OF
BENZOAZABICYCLIC
TRANSLOCATION/
1-ALKYNYL-2-(o-
ꢀ
IODOBENZOYL)TETRAHYDROISOQUINOLINES
1
Masazumi Ikeda, * Masahiro Hamada, Serry A. A. El Bialy, Katsuaki Matsui,
1
1
1
1
1
2
Shimpei Kawakami, Yuka Nakano, Said M. M. Bayomi, and Tatsunori Sato
1
1
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
2
AbstractꢀBu SnH-mediated radical translocation/cyclization reactions of 1-alkynyl-
3
2-(o-iodobenzoyl)tetrahydroisoquinolines
were
examined.
The
1-[3-
(trimethylsilyl)prop-2-ynyl]- (10a) and 1-[4-(trimethylsilyl)but-3-ynyl]-1,2,3,4-
tetrahydroisoquinoline derivatives (10b), with Bu SnH in the presence of
3
azobis(isobutyronitrile) in boiling toluene, gave regioselectively the 6,7,8,9-
tetrahydro-5H-benzocyclohepten-5,8-imine
(12a)
and
5,6,7,8,9,10-
hexahydrobenzocycloocten-5,9-imine (12b), respectively.
1
In a series of papers, we have reported that treatment of 1-(o-iodobenzoyl)-2-[3-(trimethylsilyl)prop-2-
ynyl]piperidine (1) with tributyltin hydride (Bu SnH) in the presence of azobis(isobutyronitrile) (AIBN) in
3
boiling toluene gave regioselectively the 8-azabicyclo[3.2.1]octane (4). The product was believed to arise
2
via the ꢁ-acylamino radical (3), resulting from a 1,5-hydrogen transfer of the initially formed aryl radical
(2), which undergoes a 5-exo-dig cyclization.
NCOPh
NCOPh
Bu3SnH
AIBN
N
O
SiMe
3
N
O
SiMe
3
5-exo
toluene
reflux
I
H
SiMe
3
SiMe
3
1
2
3
4 (75%)
ꢀ
This paper is dedicated to Professor Teruaki Mukaiyama, Science University of Tokyo, on the occasion of
his 73rd birthday.

We have now applied this reaction to the synthesis of the 6,7,8,9-tetrahydro-5H-benzocyclohepten-5,8-
3
4
imine and 5,6,7,8,9,10-hexahydrobenzocycloocten-5,9-imine ring systems, which are of interest for the
medicinal chemistry.
The
radical
precursor
2-(o-iodobenzoyl)-6,7-dimethoxy-1-[3-(trimethylsilyl)prop-2-ynyl]-1,2,3,4-
tetrahydroisoquinoline (10a)
was prepared
5
starting from methyl 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-1-acetate (5).
Thus, protection of 5 with a tert-butoxycarbonyl (Boc) group
followed by reduction with LiAlH and oxidation of the resulting alcohol with pyridine-SO /DMSO gave
4
3
the aldehyde (6a), which was treated with bromoform and triphenylphosphine in the presence of potassium
6
tert-butoxide to give the dibromide (7a). Treatment of 7a with butyllithium and quenching with
trimethylsilyl
chloride
gave
tert-butyl
6,7-dimethoxy-1-[3-(trimethylsilyl)prop-2-ynyl]-1,2,3,4-
tetrahydroisoquinoline-2-carboxylate (8a), which was converted into 10a by deprotection followed by N-
acylation of the resulting 9a with o-iodobenzoyl chloride. The 6,7-dimethoxy-1-[4-(trimethylsilyl)but-3-
ynyl]-1,2,3,4-tetrahydroisoquinoline derivative (10b) was prepared from 1-(but-3-enyl)-6,7-dimethoxy-
7
1,2,3,4-tetrahydroisoquinoline (11).
Protection of 11 with the Boc group followed by OsO /NaIO
4 4
oxidation gave the aldehyde (6b). Repetition of the same sequence from the aldehyde (6b) as that
described for the preparation of 10a produced the radical precursor (10b).
Scheme 1
MeO
NH
MeO
i,ii
MeO
MeO
MeO
MeO
MeO
MeO
MeO C
2
NBoc
NBoc
5
iii
NBoc
iv
MeO
MeO
( )n
Br
( )n
( )n
i,vii
OHC
NH
Me Si
3
Br
8a : n = 1 (75%)
8b : n = 2 (61%)
6a : n = 1 (76%in 3 steps)
6b : n = 2 (40%in 2 steps)
7a : n = 1 (62%)
7b : n = 2 (73%)
( )2
11
MeO
MeO
MeO
I
NH
N
v
vi
MeO
( )n
( )n
O
Me Si
3
Me Si
3
9a : n = 1
9b : n = 2
10a : n = 1 (94%)
10b : n = 2 (75%)
Reagents and Conditions : i, Boc O, Et N, DMAP, AcOEt, rt, 1 day; ii, (a) LiAlH , THF, rt, 1 h, (b) pyridine-SO , DMSO,
2
Et N, CH Cl , 0 ꢀC, 2 h; iii, PPh , CHBr , t-BuOK, toluene, -20 ꢀC, 1 h; iv, n-BuLi, TMEDA, THF, -78 ꢀC, 1 h then
3
4
3
3
TMS-Cl, rt, 1 day; v, TMS-I, MeCN, rt, 15 min; vi, o-iodobenzoyl chloride, Et N, DMAP, benzene, rt, 1 day; vii, 4% aq.
2
2
3
3
3
OsO , THF-H O, 0 ꢀC, 15 min then NaIO , rt, 1 day.
4
2
4

A toluene solution of Bu SnH (1.25 equiv.) and a small amount of AIBN (0.1 equiv.) was added slowly to
3
a boiling solution of 10a in toluene over a period of 2 h, and the mixture was refluxed for an additional 2
h.
benzocyclohepten-5,8-imine (12a) in 87% combined yield as a diastereomeric mixture. The structure of
12a was confirmed by the following chemical transformation. Treatment of 12a with trifluoroacetic acid
in dichloromethane gave the methylene derivative (13a), which was then oxidized with OsO and NaIO
The crude material was chromatographed on silica gel to give the 6,7,8,9-tetrahydro-5H-
4
4
to afford the ketone (14a) as a viscous oil. The ketone (14a) showed a strong carbonyl absorption at 1758
-1
cm (a five-membered ketone) in addition to an absorption due to an N-benzoyl group at 1631 cm in the
-1
IR spectrum.
A similar treatment of the compound (10b) with Bu SnH/AIBN gave exclusively the 5,6,7,8,9,10-
3
hexahydrobenzocycloocten-5,9-imine (12b) in 65% yield as a diastereomeric mixture. The compound
(12b) was again converted into the corresponding ketone (14b), mp 136-137 ꢀC, via the methylene
derivative (13b). The IR spectrum of 14b showed two carbonyl absorption bands at 1720 (a six-
-1
membered ketone) and 1629 cm (an amide).
The smooth exo-selective cyclization can be rationalized as follows: 1) the alkynyl group in the radicals
1,3
derived from 10a,b may occupy a quasi-axial position in order to avoid allylic 1,3-strain (A strain) with
8
the N=C double bond in the amide and 2) the internal position of the alkynic bond is closer to the radical
center formed at the 3-position of the tetrahydroisoquinoline ring than the external position is. The
regioselective formation of the radical at the 3-position may arise from the preferred conformer A that
minimizes steric interaction between the 1-alkynyl and benzoyl groups, rather than from the less favorable
conformer B.
Scheme 2
MeO
MeO
I
MeO
MeO
MeO
MeO
N
ii
i
NBz
NBz
SiMe
3
O
( )n
( )n
( )n
Me Si
3
13a : n = 1 (78%)
13b : n = 2 (48%)
10a : n = 1
10b : n = 2
12a : n = 1 (95%)
12b : n = 2 (65%)
MeO
MeO
MeO
MeO
MeO
MeO
iii
O
NBz
N
N
O
( )n
( )n
O
( )n
14a : n = 1 (27%)
14b : n = 2 (77%)
Me Si
3
Me Si
3
A
B
Reagents and Conditions : i, Bu SnH, AIBN, toluene, reflux, 2 h; ii, TFA, CH Cl , rt, 2 h; iii, 4% aq. OsO , THF-H O,
2
3
0 ꢀC, 15 min then NaIO , rt, 1 day.
2
4
2
4

ACKNOWLEDGEMENT
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports and Culture of Japan.
REFERENCES AND NOTES
1. T. Sato, T. Mori, T. Sugiyama, H. Ishibashi, and M. Ikeda, Heterocycles, 1994, 37, 245; T. Sato, Y.
Kugo,E. Nakaumi, H. Ishibashi, and M. Ikeda, J. Chem. Soc., Perkin Trans. 1, 1995, 1801; M.
Ikeda, Y.Kugo, and T. Sato, J. Chem. Soc., Perkin Trans. 1, 1996, 1819; M. Ikeda, Y. Kugo, Y.
Kondo, T. Yamazaki, and T. Sato, J. Chem. Soc., Perkin Trans. 1, 1997, 3339.
2. For the generation of the ꢀ-acylamino radicals by 1,5-hydrogen-transfer reactions of o-halobenzamides,
see: V. Snieckus, J. -C. Cuevas, C. P. Sloan, H. Liu, and D. P. Curran, J. Am. Chem. Soc., 1990,
112, 896; D. P. Curran and W. Shen, J. Am. Chem. Soc., 1993, 115, 6051; D. P. Curran and H.
Liu, J. Chem. Soc., Perkin Trans. 1, 1994, 1377.
3. For the synthesis of the 6,7,8,9-tetrahydro-5H-benzocyclohepten-5,8-imine system, see: J. W. Lown
and K. Matsumoto, Chem. Commun., 1970, 692; J. Lown and K. Matsumoto, J. Org. Chem., 1971,
36, 1405; N. Dennis and A. R. Katritzky, J. Chem. Soc., Perkin Trans. 1, 1972, 2054; D. L. Garling
and N. H. Cromwell, J. Org. Chem., 1973, 38, 654; K. Undeheim and P. E. Hansen, Chem. Scr.,
1973, 3, 113; P. E. Hansen and K. Undeheim, J. Chem. Soc., Perkin Trans. 1, 1975, 305; N. Dennis,
A. R. Katritzky, and S. K. Parton, Chem. Pharm. Bull., 1975, 23, 2899; G. L. Grunewald, D. J.
Sall, and J. A. Monn, J. Med.Chem., 1988, 31, 433.
4. For the synthesis of the 5,6,7,8,9,10-hexahydrobenzocycloocten-5,9-imine ring system, see: N.
Yoneda, Chem. Pharm. Bull., 1964, 12, 1478; W. Schneider and R. Sauerbier, Arch. Pharm.,
(Weinheim) 1981, 314, 26.
5. T. Sano, J. Toda, N. Kashiwada, Y. Tsuda, and Y. Iitaka, Heterocycles, 1981, 16, 1151; T. Sano, J.
Toda, N. Kashiwada, T. Ohshima, and Y. Tsuda, Chem. Pharm. Bull., 1987, 35, 479.
6. E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 3764; E. J. Trybulski, R. H. Kramss, R. M.
Mangano, and A. Rusinko, III, J. Med. Chem., 1990, 33, 3190; D. S. Garvey, J. T. Wasicak, J. Y.-
L. Chung, Y.-K. Shue, G. M. Carrera, P. D. May, M. M. McKinney, D. Anderson, E. Cadman, L.
Vella-Rountree, A. M. Nadzan, and M. Williams, J. Med. Chem., 1992, 35, 1550; M. C.
McIntosh and S. M. Weinreb, J. Org. Chem., 1993, 58, 4823.
7. Compound (11) was prepared by the Bischler-Napieralski reaction of N-[2-(3,4-
dimethoxyphenyl)ethyl]-4-pentenamide (POCl in benzene at 80 °C) followed by NaBH reduction of
3
4
9
the resulting imine, and this compound was used in the next step without further purification.
8. M. Natsume and M. Ogawa, Chem. Pharm. Bull., 1982, 30, 3442; P. Beak and W. K. Lee, J. Org.
Chem., 1993, 68, 1109.
9. J. Quirante, C. Escolano, A. Merino, and J. Bonjoch, J. Org. Chem., 1998, 63, 968.