LETTER
Regioselective Addition of Grignard Reagents to Isoquinolinium Salts
1705
In a similar way, we have also studied the quaternization
reaction of 1a with 1,2-dibromoethane (7a) (n = 1) and
1,3-dibromopropane (7b) (n = 2) using solventless reac-
tion conditions (Scheme 2). Reaction of 1a with the dibro-
moalkanes 7 (2.5 equiv.) at 90 °C during 4 hours affords
directly the respective precipitated 1-oxo-3,4-dihydro-
1H-2-oxa-4a-azonia-anthracene bromide (10a)20 and the
10-oxo-6,7,8,10-tetrahydro-9-oxa-5a-azonia-cyclohep-
ta[b]naphthalene bromide (10b) in good yields (10a: 90%
and 10b: 75%) via the intermediates 8 and 9 which could
not be isolated. We tried to analyze this domino reaction
by 1H NMR and we could observe the formation of 10 and
the disappearance of the signal for the ethyl ester group
(C-3) of 1a. This “one-pot” process involves successively:
(a) a quaternization reaction between 1a and 7 to give in
situ 8 followed by (b) a nucleophilic substitution to pro-
duce 9 which undergoes (c) lactonization to provide salt
10.
References
(1) (a) Liu, J. M.; Young, J. J.; Li, Y. J.; Sha, C. K. J. Org. Chem.
1986, 51, 1120. (b) Hayaski, K.; Ozaki, Y.; Nuniami, K. I.;
Yoneda, N. Chem. Pharm. Bull. 1983, 31, 312.
(2) (a) Aleza, V.; Bonin, M.; Micouin, L.; Husson, H. P.
Tetrahedron Lett. 2001, 42, 2111. (b) Czombos, J.;
Aelterman, W.; Tkachev, A.; Martins, J. C.; Tourvé, D.;
Peter, A.; Toth, G.; Fülöp, F.; De Kimpe, N. J. Org. Chem.
2000, 65, 5469.
(3) (a) Biagini, S. C. G.; North, M. Amino Acids, Peptids and
Proteins Specialist Periodicals Reports, Vol. 27; Davies, J.
S., Ed.; The Royal Society of Chemistry: London, 1996,
Chap. 3. (b) Liskamp, R. M. J. Rec. Trav. Chim. Pays-Bas
1994, 113, 1.
(4) Rozwadoska, M. D. Heterocycles 1994, 39, 903.
(5) (a) Barbier, D.; Marazano, C.; Riche, C.; Bhupesh, C. D.;
Potier, P. J. Org. Chem. 1998, 63, 1767. (b) Comins, D. L.;
Badawi, M. Heterocycles 1991, 32, 1869. (c)Polniaszek, R.
P.; Pillard, L. W. Tetrahedron Lett. 1990, 31, 797.
(6) Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron:
Asymmetry 1996, 7, 53.
We have also examined the direct synthesis of the lactone
salts21 10 by a quaternization reaction with a mixture of 1a
and the respective halogenoalcohol 13(a,b) (2.5 equiv.)
using the same reaction conditions (Scheme 2). After 4
(7) Evans, P.; Grigg, R.; York, M. Tetrahdron Lett. 2000, 41,
3967.
(8) (a) Yamagushi, R.; Nakayasu, T.; Hatano, B.; Nagura, T.;
Kozima, S.; Fujita, K. Tetrahedron 2001, 57, 109.
(b) Wanner, K. T.; Praschak, I. Heterocycles 1989, 29, 29.
(9) Dyke, S. F. Adv. Heterocycl. Chem. 1972, 14, 279.
(10) Perschonok, C. D.; Lantos, I.; Finkelstein, J. A.; Holden, K.
G. J. Org. Chem. 1980, 45, 1950.
1
hours at 90 °C with 2-bromoethanol (13a), the H NMR
spectrum of the crude reaction mixture exhibits signals
which can be assigned to 10a (n = 1), but with 3-chloro-
propanol (13b), 1a was only converted into 3-ethoxycar-
(11) Bazureau, J. P.; Leroux, J.; Le Corre, M. Tetrahedron Lett.
1988, 29, 1921.
bonyl-2-(3-hydroxy-propyl)-isoquinolinium
chloride
(14b) (n = 2) in moderate yield (53%) after a reaction time
of 3 days (Table 1). Initial attempts to force the reaction to
completion were unsuccessful (no amount of the corre-
sponding lactone salt 11b was detected in the 1H NMR of
the reaction mixture).
(12) Barbier, D.; Marazano, C.; Bhupesh, C.; Bas, B. C.; Potier,
P. J. Org. Chem. 1996, 61, 9596.
(13) For regioselective addition of Grignard reagent on
pyridinium salt substituted by an electron withdrawing
group, see: Hilgeroth, A.; Baumeister, U. Angew. Chem. Int.
Ed. 2000, 39, 576.
In the same way, subsequent anion methathesis of salt 10a
with C4F9SO3K (1.5 equiv.) in refluxed ethanol (12 hours)
afforded the soluble salt 11a in high yields but with 11b
the anion metathesis failed and gave exclusively the 3-
ethoxy-2-(3-hydroxypropyl)-isoquinolinium perfluorob-
utanesulfonate (14’b, Table 1). Finally, regioselective ad-
dition of methylmagnesium iodide (4 equiv.) in dry THF
at room temperature has also been successfully applied to
the lipophilic salts 11a after 12 hours. Under these condi-
tions the new compound 12a was obtained in moderate
yield (53%) and was stable after purification by chroma-
tography on silica gel.
(14) Hiebl, J.; Kollmann, H.; Levinson, S. H.; Offen, P.;
Shetzline, S. B.; Badloni, R. Tetrahedron Lett. 1999, 40,
7935.
(15) Aït Amer Meziane, M.; Bazureau, J. P. Tetrahedron Lett.
2001, 42, 1017.
(16) Experimental procedure for the preparation of 3-ethoxy-
carbonyl-2-phenylmethyl-isoquinolinium bromide (3d):
A mixture of ethyl isoquinoline-3-carboxylate (1a; 1 g, 10
mmol) and benzyl bromide (2d; 1.7 g, 10 mmol) in dry Et2O
(25 mL) was refluxed with vigorous magnetic stirring during
3 days under nitrogen. The reaction mixture was allowed to
cool down at ambient temperature. The insoluble salt 3 was
filtered off, washed twice with Et2O(20 mL) and dried in a
dessicator over CaCl2 which gave 3 in 90% yield as white
needles (mp 132-134 °C). 1H NMR (300 MHz, CDCl3,
TMS) 1.32 (t, 3 H, J = 7 Hz); 4.42 (q, 2 H, J = 7 Hz); 6.63
(s, 2 H); 7.31 (m, 5 H, Ar); 8.08 (t, 1 H, J = 7.6 Hz, H-6, H-
7); 8.29 (t, 1 H, J = 7.4 Hz, H-6, H-7); 8.46 (d, 1 H, J = 8 Hz,
H-5, H-8); 8.97 (d, 1 H, J = 7.4 Hz, H-5, H-8); 8.98 (s, 1 H,
H-4); 11.82 (s, 1 H, H-1). 13C NMR (75 MHz, CDCl3, TMS)
14.00 (qt, J = 128, 2.4 Hz); 62.55 (tq, J = 149 Hz); 65.54
(tq, J = 149, 4.4 Hz); 128.26 (dm, J = 139 Hz); 128.46 (m,
In summary, we have developed an efficient method for
the preparation of new and stable ethyl 1,2-disubstituted
1,2-dihydroisoquinoline-3-carboxylates22 via regioselec-
tive addition reactions of Grignard reagents to the corre-
sponding lipophilic isoquinolinium salts 4 and 11a. The
extension of this strategy to other nucleophilic reagents
with chiral isoquinolium salts bearing an electron with-
drawing group is underway.
Cipso, Ar); 128.56 (dd, J = 136, 4.3 Hz, C-2’, C-3’); 129.30
(dd, J = 162, 4.6 Hz, C-2’, C-3’); 129.60 (dm, J = 161 Hz, C-
6, C-7); 130.44 (dm, J = 114 Hz, C-6, C-7); 132.27 (dd, 134,
4.5 Hz, C-5, C-8); 133.20 (m, C-4a, C-8a); 133.34 (m, C-4a,
C-8a); 133.54 (dd, J = 167, 7.9 Hz, C-5, C-8); 136.76 (m, C-
3); 138.70 (dd, J = 166, 8 Hz, C-4); 156.00 (dm, J = 195, 5.4
Hz, C-1); 161.00 (m, CO).
Acknowledgement
Much of the work described in this paper was supported by Merck
Eurolab, Div. Prolabo (F). We also thank Professor Jack Hamelin
for fruitful discussions.
Synlett 2001, No. 11, 1703–1706 ISSN 0936-5214 © Thieme Stuttgart · New York