J . Org. Chem. 1999, 64, 1407-1409
1407
with N-bromosuccinimide. The reaction proceeded regio-
selectively and in high yield at room temperature. The
benzylic hydroxyl group was protected as the methoxy-
methyl (MOM) ether using a procedure described by
Kluge et al.7 to afford 4 in excellent yield. Lithium-
bromine exchange proceeded smoothly at -78 °C. Quench-
ing with trimethyl borate followed by slow neutralization
with aqueous 1 M sodium hydrogen sulfate solution
furnished the boronic acid 5 in essentially quantitative
yield. An NMR spectrum of the crude boronic acid from
this reaction showed it to be sufficiently pure to be used
in the next step without further purification.
Alter n a tive F or m a l Syn th esis of th e P oten t
D1 Dop a m in e Agon ist
Dih yd r oxy-2,3,7,11b-tetr a h yd r o-1H-
n a p h th [1,2,3-d e]isoqu in olin e: Din a p solin e
Amjad M. Qandil,† Debasis Ghosh,‡ and
David E. Nichols*,†
Department of Medicinal Chemistry and Molecular
Pharmacology, School of Pharmacy and Pharmacal
Sciences, Purdue University, West Lafayette, Indiana 47907
Received October 14, 1998
Using typical conditions for the Suzuki cross-coupling
reaction, a mixture of 4-bromoisoquinoline, the aryl-
boronic acid, degassed aqueous sodium carbonate, and a
catalytic amount of tetrakis(triphenylphosphine)palladium-
(0) was heated to reflux in degassed 1,2-dimethoxy-
ethane.8 After extraction and evaporation of the solvents,
the crude residue was treated with trifluoroacetic acid
in dichloromethane to afford the desired product 6 in very
good yield as an off-white solid. Reduction using sodium
cyanoborohydride in methanolic-HCl gave the 1,2,3,4-
tetrahydroisoquinoline 7 in quantitative yield, as shown
in Scheme 3. The amine 7 was then treated with
p-toluenesulfonyl chloride in the presence of N,N-diiso-
propylethylamine to afford N-p-toluenesulfonylamide 2
in excellent yield.
In tr od u ction
We have previously reported the synthesis and phar-
macological evaluation of 8,9-dihydroxy-2,3,7,11b-tet-
rahydro-1H-naphth[1,2,3-de]isoquinoline, dinapsoline (1),1
a potent full dopamine D1 agonist containing a rigid
â-phenyldopamine pharmacophore, with potential anti-
parkinsonian activity. The original synthesis was rather
long and unsuitable for production of large quantities.
This note describes the highly efficient preparation of key
intermediate 2 in the original synthetic pathway for
dinapsoline comprising therefore an alternative formal
synthesis of dinapsoline.
Con clu sion s
This synthesis proved to be highly efficient to prepare
large quantities of intermediate 2. This intermediate will
be used to obtain dinapsoline and other dinapsoline
analogues.
Resu lts a n d Discu ssion
Exp er im en ta l Section
The new retrosynthetic route is illustrated in Scheme
1. In 1994 Miller and Svoboda2 described the synthesis
of a 4-phenyl-1,2,3,4-tetrahydroisoquinoline from 4-bro-
moisoquinoline based on the Miyaura-Suzuki cross-
coupling reaction (more commonly known as the Suzuki
cross-coupling reaction) for the preparation of diaryl
compounds.3,4 Their report provided the elements for an
improved synthesis of dinapsoline, with the challenge
being in our case to prepare the necessary boronic acid.
This synthesis is illustrated in Scheme 2.
Gen er a l Com m en ts. Melting points are uncorrected. High-
resolution CI and EI mass spectra were obtained within 0.0015
m/z, unless otherwise noted. The ionization gas for CIMS and
high-resolution CIMS was isobutane.
6-Br om o-2,3-d im eth oxyben zyl Alcoh ol (3). To a solution
of 45 g (0.268 mol) of 2,3-dimethoxybenzyl alcohol in 200 mL of
THF was added 47.6 g (0.268 mol) of N-bromosuccinimide (NBS).
The suspension was stirred until all the NBS had dissolved. The
THF was then evaporated, and the residue was taken up in 500
mL of diethyl ether. The insoluble succinimide was removed by
filtration, and the ethereal layer was washed twice with 2 N
aqueous NaOH. The organic layer was dried (MgSO4) and
filtered, and the solvent was evaporated. The residue was
crystallized from ethyl acetate-hexane to yield 61.47 g (93%)
The benzyl alcohol 3 was previously prepared through
a five-step synthesis.5,6 As illustrated in Scheme 2, we
were able to obtain the same intermediate by brominat-
ing commercially available 2,3-dimethoxybenzyl alcohol
1
as a white solid: mp 76 °C (lit. 74-75 °C). H NMR: δ 2.32 (t,
1H, -OH, J ) 7 Hz); δ 3.84 (s, 3H, O-CH3); δ 3.89 (s, 3H,
O-CH3); δ 4.81 (d, 2H, Ar-CH2-O, J ) 7 Hz); δ 6.76 (d, 1H,
Ar-H, J ) 9 Hz); δ 7.25 (d, 1H, Ar-H, J ) 9 Hz). CIMS m/z:
(M, M + 2) 246 and 248, ((M + H) - 18) 229, ((M + H + 2) -
18) 231.
* Corresponding author. Phone: (765) 494-1461. Fax: (765) 494-
1414. E-mail: drdave@pharmacy.purdue.edu.
† Purdue University.
‡ Present address: AVI BioPharma Inc., 4575 Research Way, Suite
200 Corvallis, OR 97333.
6-B r o m o -2,3-d im e t h o x y (m e t h o x y m e t h o x y )m e t h y l-
ben zen e (4). Sodium hydride (8.55 g; 60% suspension in mineral
oil; 0.213 mol) was rinsed with hexane several times and then
suspended in 250 mL of dry THF, and the mixture was placed
under argon and cooled in an ice bath. A solution of 44 g (0.178
mol) of 3 in 250 mL of dry THF was added, and the mixture
(1) Ghosh, D.; Snyder, S. E.; Watts, V. J .; Mailman, R. B.; Nichols,
D. E. J . Med. Chem. 1996, 39, 549-555.
(2) Miller, R. B.; Svoboda, J . Synth. Commun. 1994, 24, 1187-1193.
(3) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(4) Stavenuiter, J .; Hamzink, M.; Hulst, R.; Zomer, G.; Westra, G.;
Kriek, E. Heterocycles 1987, 26, 2711-2716.
(5) Kametani, T.; Honda, T.; Inoue, H.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1976, 1221-1225.
(6) Kunitomo, J .-I.; Miyata, Y.; Oshikata, M. Chem. Pharm. Bull.
1985, 33, 5245-5249.
(7) Kluge, A. F.; Untch, K. G.; Fried, J . H. J . Am. Chem. Soc. 1972,
94, 7827-7832.
(8) Wustrow, D. J .; Wise, L. D. Synthesis 1991, 993-995.
10.1021/jo982067z CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/30/1999