Synthesis of N-trifluoroacetyl-2-hydroxynoraporphine by radical reaction of p-quinol acetate of N-trifluoroacetyl-1-(2-iodoveratryl)methyl-1, 2, 3, 4-tetrahydro-7-methoxyisoquinolin-6-ol

Article abstract of DOI:10.3987/COM-04-S(P)37

Radical reaction of p-quinol acetate (8b) of N-trifluroroacetyl-1- (2-iodoveratryl)methyl-1, 2, 3, 4-tetrahydro-7-methoxyisoquinolin-6-ol (7b) using tributyltin hydride gave the corresponding noraporphine (9)(45%), while that of the bromo congener (8a) failed. Similar reaction of 8b using tris(trimethylsilyl)silane improved the yield (75%) of 9.

Full text of DOI:10.3987/COM-04-S(P)37

HETEROCYCLES, Vol. 64, 2004
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HETEROCYCLES, Vol. 64, 2004, pp. 61 - 64
Received, 13th September, 2004, Accepted, 2nd November, 2004, Published online, 9th November, 2004
SYNTHESIS OF N-TRIFLUOROACETYL-2-HYDROXYNORAPORPHINE
BY RADICAL REACTION OF p-QUINOLACETATE OF N-TRIFLUORO-
ACETYL-1-(2-IODOVERATRYL)METHYL-1, 2, 3, 4-TETRAHYDRO-7-
METHOXYISOQUINOLIN-6-OL †
Akiko Moriya and Osamu Hoshino*,1
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641,
Yamazaki, Noda-shi, Chiba 278-8510, Japan
Abstract
Radical reaction of p-quinol acetate (8b) of N-trifluroroacetyl-1-
(2-iodoveratryl)methyl-1, 2, 3, 4-tetrahydro-7-methoxyisoquinolin-6-ol (7b) using
tributyltin hydride gave the corresponding noraporphine (9)(45 %), while that of the
bromo congener (8a) failed. Similar reaction of 8b using tris(trimethylsilyl)silane
improved the yield (75 %) of 9.
Previously,2 we reported that lead tetraacetate (LTA) oxidation of N-trifluoroacetyl-1-veratrylmethyl-
tetrahydro-7-methoxyisoquinolin-6-ol (1) in CH2Cl2 gives rise to the corresponding o-quinol acetate (o-
O
O
HO
AcO
N
N
N
MeO
MeO
Pb( OAc)4
AcOH
COCF3
CO CF3
COCF3
MeO
MeO
AcO
OMe
30-40°C
CH2Cl2
rt
MeO
MeO
2
3
1
OMe
OMe
Scheme 1
† Dedicated to Dr. Pierre Potier on the occasion of his 70th birthday.

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HETEROCYCLES, Vol. 64, 2004
QA)(2) in good yield, reaction of which with AcOH at 30-40°C produces p-QA (3)(Scheme 1).
Although treatment3 of p-QAs (5) of N-acyltetrahydroisoquinolin-7-ols (4) with CF3CO2H in CH2Cl2
OAc
MeO
O
MeO
HO
MeO
HO
N
N
N
Pb(OAc)4
AcOH, rt
CF3CO2H
COR'
COR'
COR'
CH2Cl2, rt
RO
R = Me
R + R = CH2
RO
RO
6
4
5
OR
OR
OR
R' = Me, CF3 etc
Scheme 2
afforded the corresponding 1-hydroxynoraporphines (6)(Scheme 2), attempts4 to synthesize 2-hydroxy-
noraporphine by reaction of 2 or 3 under a variety of acidic conditions were unfruitful, in which the
reaction gave only undetermined complex mixtures along with reversed 1.
Therefore, in order to synthesize 2-hydroxynoraporphine from p-QA (8) and to examine its reactivity,
radical reaction of 1-(2-bromo- and iodoveratryl)methyl p-QAs (8)5 was performed. This paper deals
with successful formation of N-trifluroacetyl-2-hydroxynoraporphine (9) from 1-(2-iodoveratryl)methyl p-
QA (8b).
LTA oxidation of N-trifluoroacetyl-1-(2-bromo- and iodoveratryl)methyltetrahydro-7-methoxyisoquinolin-
6-ols (7)(7a,6, 7 mp 157-158°C; 7b,6, 9 mp 190-191°C) in AcOH at 30-40°C for 5 h furnished the
corresponding 1-(2-haloveratryl)methyl p-QAs (8)(8a,6 mp 162-163°C; 8b,6 mp 175-176°C) in good yield
(Scheme 3).
HO
O
N
N
MeO
MeO
Pb(OAc)4
COCF3
MeO
MeO
COCF3
AcO
AcOH
8
7
30-40°C, 5 h
MeO
X
Me O
a: X = Br (83 %)
X
a: X = Br
b: X = I
b: X = I (quant. yield)
Scheme 3
Unexpectedly, reaction of 8a in boiling benzene (1 mmol %) containing AIBN (0.55 eq.) and tributyltin
hydride (1.5 eq.) for 4 h and purification on preparative TLC (SiO2; developing solvent: benzene : EtOAc
= 1 : 1) gave reversed 7a (54 %) and untact 8a (13 %), respectively (Scheme 4).
O
N
MeO
MeO
Bu3SnH (1.5 eq.)
COCF3
8a
7a
AcO
+
AIBN (0.55 eq.)
(54 %)
(13 %)
8a
benzene, reflux, 4 h
MeO
Br
Scheme 4

HETEROCYCLES, Vol. 64, 2004
63
However, similar reaction10 of 8b followed by purification gave desired N-trifluroacetyl-2-hydroxy-
noraporphine (9) in 45 % yield, in which starting material (8b) and reversed 7b were not determined
(Scheme 5). Furthermore, an analogous reaction of 8b in boiling benzene (1 mmol %) using (TMS)3SiH
(1.5 eq.) in place of Bu3SnH afforded 9 in 70 % yield (Scheme 5).
O
HO
Bu3SnH (1.5 eq.)
AIBN (0.5 eq.), benzene,
reflux, 7 h (45 %)
N
N
MeO
MeO
MeO
COCF3
CO CF3
AcO
or
D
(TMS)3SiH (1.5 eq.)
AIBN (0.5 eq.), benzene,
reflux, 2 h (70 %)
8b
MeO
MeO
9
I
OMe
Scheme 5
The difference in reaction would be attributable to the reactivity11 of aryl bromide and iodide in radical
reaction. Also this assumption is supported by formation of reversed 7a, which would be produced by
reductoin of a carbonyl group in 8a with Bu3SnH followed by elimination of AcOH.
A pathway on formation of 9 is considered to proceed via an intermediate (10)(Scheme 6), although a
pathway via direct cyclization of 7b, which might be formed from 8b by reaction similar to that described
for 8a, could not be excluded completely.
Because reaction of 7b with AIBN (0.5 eq.) and Bu3SnH (1.5
eq.) in boiling benzene (1 mmol %) for 7 h gave 9 (11 %) together with 1 (24 %).
O
O
Bu3SnH
or
H
MeO
H
MeO
N
N
R
R
(TMS)3SiH
- AcOH
H
AcO
8b
9
AIBN
benzene
reflux
MeO
R = COCF3
MeO
OMe
OMe
10
Scheme 6
In conclusion, synthesis of noraporphine (9) by radical reaction of 1-(2-iodoveratryl)methyl p-QA (8b)
was accomplished successfully. Thus, the reaction promises the preparation of noraporphine bearing
no substituent(s) in D ring, which has been not yet synthesized by acid treatment of p- QA.
ACKNOWLEGEMENTS

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HETEROCYCLES, Vol. 64, 2004
The authors are grateful to Mrs. F. Hasegawa of this faculty for MS spectral measurements.
REFERENCES AND NOTES
1.
2.
3.
Present address: 683-56, Sashi-ougi, Nishi-ku, Saitama-shi, Saitama 331-0047, Japan.
O. Hoshino, M. Suzuki, and H. Ogasawara, Tetrahedron, 2001, 57, 265.
O. Hoshino, H. Ogasawara, M. Suzuki, and B. Umezawa, Heterocycles, 1987, 25, 151; O. Hoshino,
H. Ogasawara, M. Suzuki, M. Arasawa, and B. Umezawa, Heterocycles, 1990, 30, 385; O. Hoshino,
H. Ogasawara, M. Arasawa, M. Suzuki, and K. Iizima, Heterocycles, 1993, 35, 1005.
F. Mutoh, H. Ogasawara, and O. Hoshino, unpublished data.
4.
5. Since p-QA was more stable than o-QA, the former was used in the reaction.
6. All new compounds described in this text gave satisfactory 1H- and 13C-NMR, and HRMS spectral
data.
7. Starting material (7a) was prepared by N-trifluoroacetylation (trifluoroacetic anhydride, K2CO3,
CH2Cl2; K2CO3, MeOH) of 1-(2-bromoveratryl)methyltetrahydroisoquinolin-6-ol8 from benzyloxy-
phenethylamine and 2-bromohomoveratric acid in a usual manner (Bischler-Napieralski reaction,
NaBH4 reduction, and debenzylation with conc. HCl).
8. M. S. Premila and B. R. Pai, Indian J. Chem., 1975, 13, 13.
9. Starting material (7b) was prepared from benzyloxyphenethylamine and 2-iodohomoveratric acid in
a manner similar to that noted for 7a.
10. A solution of 8b (50 mg, 0.08 mmol) in benzene (8 mL) containing AIBN (6.7 mg, 0.04 mmol) and
Bu3SnH (35.8 mg, 0.12 mmol) was refluxed for 7 h. A residue remained on removal of the solvent
in vacuo was dissolved in MeCN. The MeCN solution was washed with hexane. Usual work-up
of the MeCN layer gave an oily product, which was purified on preparative TLC (SiO2; developing
solvent: benzene : EtOAc = 1 : 1) to produce 9 (15.5 mg, 45 %, mp 177-178°C); 1H-NMR (270
MHz)(CDCl3) δ: 3.61 (3H, s), 3.93 (6H, s), 5.90, 6.72, 6.80, and 7.99 (each 1H, s); 13C-NMR (62.5
MHz)(CDCl3) δ: 30.1, 32.8, 41.4, 52.6, 55.8, 56.1, 60.2, 110.8, 111.5, 113.2, 123.3, 123.4, 126.8,
128.9, 129.7, 142.8, 148.0, 148.6, 148.8, and 156.3; EI MS m/z (M+): 423; HRMS m/z calcd for
C21H20NO5F3 (M+) 423.1293, found: 423.1302.
11. M. Poutsma, in ‘Free Radicals’, Vol. 2, ed. by J. K. Kochi, Wiley, N. Y., 1973, p.113; W. C. Danen,
in ‘Methods in Free Radical Chemistry’, Vol. 5, ed. E. L. S. Huyser, Dekker, N. Y., 1974, p. 1.