A simplified isoquinoline synthesis
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Scheme I.
(t, J
=
5 HZ, 2H), 2.40 (s, 3H); MS role (rel. intensity): 230 (24),
Since the documented instability of benzylic mesylates6
and the lability of benzylic iodides often make them
unattractive intermediates, an optimal and practical pro-
cedure for the use of benzylic bromides was developed.
Rapid, clean alkylation of benzylic bromides and
chlorides occurs in dimethylformamide (DMF) at 25°,
1-3 hr, Table 1. The ease with which benzylic bromides
may be prepared or handled and their efficient alkylation
of the sodium salt of 2 in dimethylformamide makes this
the practical procedure of choice.
Although the acid-catalyzed cyclization of N-tosyl
benzylamino-acetals has been carefully investigated3~ a
few comments are in order. Our first attempts to
reproduce this work on a 100-200 mg scale (6 N aqueous
HCl/dioxane--two phase system) resulted in erratic
yields. Subsequently, we discovered that all reactions
run at or above the scale descri•bed3z (2g) reproducibly
afford the isoquinolines in high yield. Our problems on
the smaller scale arose presumably from an ineffective
mixing of the two phases. Additionally, in one instance,
3c, the loss of p-toluenesulfonic acid required unusually
long reaction times and resulted in a diminished yield of
isoquinoline 4c. This was remedied by exposure of 3c to
the acidic cyclization conditions (2 hr, 6 N HCI/dioxane,
110°, 3c-,N-tosyl dihydroisoquinoline) followed by base
catalyzed elimination of p-toluenesulfonic acid (potas-
sium t-butoxide/t-butanol, 10 hr) to give isoquinoline 4c in
83% overall yield.
228 (-(K~H3, 7), 171 (10), 155 (17), 139 (34), 91 (63), 76 (31), 75
(100), 65 (27). (Found: C, 50.84; H, 6.54; N, 5.24. Cole. for
C,H~7NO4S: C, 50.95; H, 6.61; N, 5.40.)
General procedure for the preparation of isoquinolines is illus-
trated with 6,7-methylenedioxyisoquinoline (410
N - (2,2 - Dimethoxyethyl)
- N - [(3,4 - methylenedioxy-
phenyl)methyl] toluenesulfonamide (3g). Compound 2
-
p -
(3.24 g, 12.5 mmole, 1.05 equiv) in 20ml dry DMF was added to a
suspension of Nail (60% oil dispersion, 0.5g, 12.5 mmole, 1.05
equiv) in 10 ml dry DMF under N2 at 25°. After Hz evolution
ceased (5 rain), piperionyl bromide (2.56g, 11.9 mmole) in 20 ml
dry DMF was added and the resulting mixture was stiffed for
2hr (25°) under Nz before being poured onto water and extracted
with ether (3x). The combined etheral layers were washed with
satd NaCI aq, dried (MgSO4) and concentrated/n vacua. Chroma-
tography (25x250mm mplc, 40:60 ether:hexane eluant)
afforded 4.33 g (93% yield) of pure 3g as a white solid identical in
all respects to that previously reported.3~
6,7-Methylenedioxyisoquinoline
(4g))s A soln of 3g (2.0g,
5.1 tamale) in 48 ml dioxane was treated with 6N HCI (3.7 ml)
and the resulting mixture was warmed at reflux under N2 in the
dark for 24 hr before being cooled and poured onto water. The
aqueous phase was washed with ether (2x), CH2C12 (2x) and
made alkaline with the addition of 10% NaOH aq and extracted
with ether (2x) and CHzCIz (2x). The combined organic phase
(from the latter extractions) were washed with satd NaCI aq, dried
(MgSO4) and concentrated in vacua. Chromatography (25x
250mm topic, ether eluant) afforded 0.72 g (81% yield) of pure 4g3z
identical in all respects to that reported previously.
Aside from the practical improvements in yield and
convenience resulting from this two-step variation of the
Acknowledgements--This work was assisted financially by a
grant from the Anna Fuller Fund, the University of Kansas
General Research Allocation No. 3783-x0-0038, and by a Biome-
dical Research Grant (RR 5606). We are grateful to the Research
Corporation for funds used in the purchase of equipment. Ac-
knowledgement is made to the Donors of the Petroleum
Research Fund,administered by the American Chemical Society,
for the partial support of this research.
Pomeranz-Fritsch cyclization, there is
a covert im-
provement in the flexibility of the methodology. All
current, reliable Pomeranz-Fritsch type isoquinoline
preparations involve catalytic reduction of an imine, thus
limiting functionality that may be present in the sub-
strate. For instance, olefins, enones, benzylic alcohols,
-amines, -ethers, or -sulfides, and aromatic halides
potentially interfere with this reduction. This newly
developed methodology, which does not depend on a
catalytic reduction, circumvents these problems and
opens new opportunities in our current investigations.
REFERENCES
l°Searle Scholar recipient, 1981-1984; bNatioual Institute of
Health predoctoral trainee, NIH Trainee Grant No. GM-07775;
CNational Science Foundation undergraduate research parti-
cipant.
2Recent reviews on the preparation and chemistry of isoquinol-
ines include: aG. Grethe, The Chemistry of Heterocyclic Com-
pounds, Vol. 38, pt. 1. Wiley, New York (1981); bT. Kametani,
The Total Synthesis of Natural Products (Edited by J. ApSi-
man) Vol. 3, pp. 1-272, Wiley, New York, (1977); CM. Shamma
and J. L. Moniot, lsoquinoline Alkaloid Research, 1972-1977.
Plenum Press, New York, N.Y. (1978); see also dW. J. Gensler,
Org. Reactions 6, 191 (1951); "W. M. Whaley and T. R. Govin-
dachari, Ibid. 6, 74 (1951); IF. D. Popp and W. E. McEwen,
Chem. Rev., 58, 328 (1958); ~J. M. Bobbit, Advances in Hereto-
cyclic Chemistry (Edited by A. R. Katritzky and A. J. Boulton),
Vol. 15, p. 99. Academic Press, New York (1973).
EXPERIMENTAL
N - (2,2 - Dimethoxyethyl) - p - toluenesulfonamide(2,N, tosyl
aminoacetaldehyde dimethyl acetal)
Aminoacetaldehyde dimethyl acetal (.~.25g, 50tamale), p-
toluenesulfonyl chloride (11.44 g, 60 tamale) and Na2CO3 (106g,
Imole) were added sequentially to 400ml dry THF and the
resulting slurry was stirred for 3 days (25°) under N2. After
filtration (CH2CI2 wash), the filtrate was washed with water, satd
NaCI aq, dried (Na2SO4) and concentrated in vacua. Chromato-
graphy (25 x 1000 mm mplc, 60:40 ether:hexane eluant) afforded
12.32g (95% yield) of pure 2 as a white powder; m.p. 45--47°. IR
(CHCI3): 3370, 3020, 2930, 2830, 1596, 1320, 1145, 1075, 790 cm-I;
aH NMR (CDCI3, ppm): 7.6 and 7.12 (two d, J = 8 Hz, 4H), 4.75
(broadened t, 1H, -NH-), 4.25 (t, J = 5 Hz, IH), 3.30 (s, 6H), 2.95
3°Bischler-Napieralski cycl/zation, see: Ref. 2a; 2b, pp. 4-34; 2c,
pp. 4-6; 2e; ~Pictet-Spengler cyclization, see: Ref. 2a; 2b, pp.
34-58; 2c, pp. 2--4; CPomeranz-Fritsch cyclization: C.