Desulfonylation of N-sulfonyl tetrahydroisoquinoline derivatives by potassium fluoride on alumina under microwave irradiation: Selective synthesis of 3,4-dihydroisoquinolines and isoquinolines

Article abstract of DOI:10.1055/s-2002-31923

In a solvent-free system, the microwave irradiation of mixtures of N-sulfonyl tetrahydroisoquinolines and 37% potassium fluoride supported on alumina selectively furnished 3,4-dihydroisoquinolines or isoquinolines, depending upon the reaction time.

Full text of DOI:10.1055/s-2002-31923

LETTER
907
Desulfonylation of N-Sulfonyl Tetrahydroisoquinoline Derivatives by
Potassium Fluoride on Alumina Under Microwave Irradiation: Selective
Synthesis of 3,4-Dihydroisoquinolines and Isoquinolines
D
esulfonylation o
l
f
N
-Su
a
lfonyl-Tetr
u
ahydroisoqu
d
inolines withi2 3
K
F/Al
o
O
C. Silveira,*a Carmem R. Bernardi,a Antonio L. Braga,a Teodoro S. Kaufman*b
a
Departamento de Quimica, Universidade Federal de Santa Maria, 97105.900, Santa Maria, RS, Brazil
Fax +55(55)2208754; E-mail: silveira@quimica.ufsm.br
b
Instituto de Química Orgánica de Síntesis (CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas, Suipacha 531,
(S2002LRK) Rosario, Argentina
Fax +54(341)4370477; E-mail: tkaufman@fbioyf.unr.edu.ar
Received 9 April 2002
Spengler synthesis11,12 and in many variations of the Po-
merantz–Fritsch sequence.13 Removal of the sulfonyl
moiety by taking advantage of the different oxidation
states of sulfur has been employed to broaden the scope of
these synthetic protocols, but only a few methods have
been described.11,13
Abstract: In a solvent-free system, the microwave irradiation of
mixtures of N-sulfonyl tetrahydroisoquinolines and 37% potassium
fluoride supported on alumina selectively furnished 3,4-dihydroiso-
quinolines or isoquinolines, depending upon the reaction time.
Key words: isoquinolines, 3,4-dihydroisoquinolines, KF on alumi-
na, microwave-assisted desulfonylation
Herein, we wish to report the selective elaboration of 3,4-
dihydroisoquinolines and isoquinolines (Scheme 1) by
the microwave-assisted oxidative desulfonylation and
subsequent dehydrogenation (for isoquinolines) of N-sul-
fonyl tetrahydroisoquinolines with KF/Al2O3 as solid sup-
ported reagent, in non-solvent conditions.
Chemical transformations carried out with supported re-
agents under dry conditions have several significant ad-
vantages over reactions traditionally run in solution; they
offer easier separation of the products, new or better selec-
tivities, faster processes or milder reaction conditions, less
waste problems and the possibility of working in a contin-
uous way.1
Potassium fluoride on alumina (KF/Al2O3) has been re-
ported as a solid supported reagent for alkylation,2 elimi-
nation,3 addition,4 condensation,5 enolization, desilyl-
ation,6 coupling7 and other useful reactions. It has been
shown that during the impregnation-activation procedure,
the salt reacts with aluminium oxide forming K3AlF6 and
an active mixture of KOH and potassium aluminate on the
surface of the solid support,8 which would contribute to
explain its reactivity.
Scheme 1 Reagents and Conditions: a) 37% KF/Al2O3, Micro-
waves (time: t1 < t2).
Starting tetrahydroisoquinolines consigned in Table 1
were prepared employing a modified activated Pictet–
Spengler procedure, by reaction of -phenylchalcogen- -
halocarbonyls as aldehyde surrogates with conveniently
substituted N-tosyl- -phenethylamines, under Lewis ac-
ids promotion.11b,12
On the other hand, the enhancement of chemical transfor-
mations by microwave irradiation of organic molecules
supported on inorganic solids has experienced an enor-
mous growth in recent years,9 as this technique is manip-
ulatively simple, can be conducted rapidly and provides
products in high yields employing solvent-free condi-
tions.
As shown in Table 1, submission of the N-sulfonyl hetero-
cycles to microwave irradiation (490 Watts) provided
good yields of the corresponding 3,4-dihydroisoquino-
lines upon a short reaction period (10–20 s), uncontami-
nated with the related isoquinolines; interestingly,
however, increasing the irradiation time completely trans-
formed the starting materials into the corresponding iso-
quinolines, providing a highly selective and convenient
strategy to access both classes of compounds. In spite that
hydrolytic cleavage of the N-S bond with formation of the
desulfonylated tetrahydroisoquinolines10 could not be
completely ruled out, such compounds could neither be
detected or isolated.
Recent work informed that under microwave assistance
KF/Al2O3 cleaves sulfonamides to the corresponding
amines in dry conditions.10 However, the irradiation of
mixtures of N-sulfonyl isoquinoline derivatives and KF/
Al2O3 has not been studied to date.
N-sulfonyl-type protecting groups are widely used in iso-
quinoline chemistry, specially in the N-activated Pictet–
In order to assure that these results were not due to a pure-
ly thermal effect, conventional heating experiments were
performed. It has been reported that the temperature of an
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0907,0910,ftx,en;S09801ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

908
C. C. Silveira et al.
LETTER
Table 1 Synthesis of 3,4-Dihydroisoquinolines and Isoquinolines by Microwave-Assisted Reaction of N-Sulfonyl Tetrahydroisoquinoline
Derivatives with KF Supported on Alumina22
Entry
R1
R2
R3
Dihydroisoquinolines
Isoquinolines
Time (t2, s)a
Time (t1, s)a
Yield (%)b
Yield (%)b
1c
2
H
H
H
H
C6H5
10
15
10
20
–
60
71
87
92
–
20
30
30
60
120
–
56
73
86
69
49
–
tBu
3
-OCH2O-
-OCH2O-
-OCH2O-
C6H5
4d
5e
6f
3-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
MeO
MeO
10
77
a Irradiation time at 490 W in a domestic microwave oven.
b Isolated yield after column chromatography.
c The resulting isoquinoline has been previously synthesized.14
d Conventional heating of the N-sulfonyl tetrahydroisoquinoline with KF/Al2O3 in toluene afforded the related 3,4-dihydroisoquinoline after a
48 h reflux period.
e The resulting isoquinoline is a natural product isolated from Oocotea pulcella, mp 152–154 ºC (Lit.15 152–153 ºC).
f The resulting 3,4-dihydroisoquinoline is O,O-dimethyl longifolonine, mp 91–92 ºC; IR and 1H NMR spectra are in agreement with those re-
ported in the literature.16b
alumina bath (heat sink) inside a Sears Kenmore micro- and submitted to microwave irradiation, with the results
wave oven equipped with a turntable at full power (900 consigned in Table 2.
W) was found to be 65 ºC after 30 s of irradiation;17
In the cases of N-sulfonyl N,S- and N,O- acetals (entries 1
therefore, the tetrahydroisoquinoline depicted in entry 4
and 2), it was observed that while the thio compound fur-
of Table 1 was mixed with KF/Al2O3 and aliquots of the
nished an isoquinoline with concomitant loss of the 1-
resulting powder were heated at 90 ºC in an oil bath or
thiophenyl moiety, the 3-methoxy tetrahydroisoquinoline
quickly lost methanol, giving the related N-sulfonyl-1,2-
dihydroisoquinoline in good yield, but no isoquinoline
heated under reflux in toluene. In the first case, no reac-
tion was observed after heating for 24 h; in the experiment
employing toluene as solvent, however, it was noticed that
was produced, even under prolonged microwave heating,
at the same time the reaction consisted of a 2:1 mixture of
which caused complete product decomposition. The 1-
the 3,4-dihydroisoquinoline and the starting tetrahy-
phenyl tetrahydroisoquinoline of entry 3, however, fur-
droisoquinoline. Complete consumption of the starting
nished the expected isoquinoline in moderate yield after 6
material was achieved in 48 h, but no 1-benzoylisoquino-
minutes of irradiation.
line could be detected, 3,4-dihydroisoquinoline being the
In contrast with the known base-promoted desulfonyla-
the only reaction product. In addition, no reaction was ob-
tion of N-sulfonyl-1,2-dihydroisoquinolines in solu-
served when the tetrahydroisoquinoline was submitted to
tion,13a when compounds of entries 4–7 were irradiated,
microwave irradiation in the absence of KF/Al2O3.
poor yields of the corresponding isoquinolines were ob-
tained after comparatively long reaction times. Interest-
ingly, it has been reported the easy conversion of the N-
Many 1-benzoylisoquinolines and 1-benzoyl-3,4-dihy-
droisoquinolines have been isolated from different plants.
Noteworthy, this strategy provides new alternatives for
benzylsulfonyl dihydroisoquinolines of entries 5 and 6
the syntheses of these type of natural products and their
into isoquinolines when treated with Raney Nickel.13c
derivatives, as illustrated by the convenient elaboration of
Not quite unexpectedly, a base-promoted retroaldol-like
the unnamed base isolated from Oocotea pulcella,15 de-
reaction20 leading to an isoquinoline with simultaneous
picted in entry 5 and of O,O-dimethyl longifolonine,16 ob-
dehydroxymethylation was observed when the 1-hy-
droxymethyl-substituted dihydro- isoquinoline derivative
tained as shown in entry 6.
In order to explore more in depth the scope of the above
of entry 7 was exposed to microwave irradiation, hoping
transformations, a series of N-sulfonyl-1,2-dihydroiso-
to promote desulfonylation by assistance from the neigh-
boring carbinolic oxygen. Isoquinolines obtained as
quinolines and N-sulfonyl-1,2,3,4-tetrahydroisoquino-
lines was synthesized18 following Jackson’s protocol13
shown in entries 1 and 4–7 are known natural
produts.13a,c,19
Synlett 2002, No. 6, 907–910 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Desulfonylation of N-Sulfonyl Tetrahydroisoquinolines with KF/Al2O3
909
Table 2 Synthesis of Isoquinolines by Microwave-Assisted Reaction of N-Sulfonyl Dihydro- and Tetrahydroisoquinoline Derivatives with
KF Supported on Alumina
Entry
1c
Substrate
Time (s)a
30
Product
Yield (%)b
63d
2
3
60
86e
65
360
4c
5c
210
180
32f
24g
6c
7c
210
600
34f
16d
a Irradiation time at 490 W in a domestic microwave oven.
b Isolated yield after column chromatography.
c The resulting isoquinolines are natural products, displaying spectral data in agreement with the literature.13a,c,19
d Mp 89.5–91 ºC (Lit.13a 90–91 ºC; 89–90 ºC).
e Mp 112–113ºC (Lit.13a 112–113 ºC). Complete decomposition was observed after 420 s of irradiation time.
f Mp 118–119 ºC (Lit.19c 118–119 ºC).
g Mp 125–126 ºC (Lit.19a 125 ºC).
Although a complete picture of the mechanism of the re- Further analysis of the available examples seems to indi-
actions leading to isoquinolines remains unclear, it is evi- cate that the transformation of N-sulfonyl tetrahydroiso-
dent that desulfonylation occurs before the quinolines into their corresponding 3,4-dihydro- forms
dehydrogenation step; thus, reminiscing the results of and afterwards into isoquinolines is highly successful
Kohno and Yamada,11c 3,4-dihydroisoquinolines are se- when the C-1 substituent (carbonyl, phenyl) contributes to
lectively produced.
the acidity of H-1.
For isoquinoline synthesis from dihydroisoquinolines, the In conclusion, we have developed a rapid, mild and envi-
reaction takes place more easily by dehydrogenation of ronmentally friendly method for the rapid and selective
3,4-dihydro-isoquinolines than by oxidative desulfonyla- synthesis of 3,4-dihydroisoquinolines and isoquinolines
tion of the 1,2-dihydro derivatives; the latter reaction is by microwave irradiation of mixtures of N-sulfonyl tet-
known to successfully occur in solution, being promoted rahydroisoquinolines and 37% potassium fluoride sup-
by strong bases.11c,13a On the other hand, participation of ported on alumina. Good yields of product were obtained
alumina and fluoride-modified alumina as catalyst in de- when H-1 was acidic enough to allow a facile first step,
hydrogenation reactions has been documented;21 this consisting in an oxidative desulfonylation.
could contribute to explain the transformation of 3,4-dihy-
droisoquinolines into the related isoquinolines.
Synlett 2002, No. 6, 907–910 ISSN 0936-5214 © Thieme Stuttgart · New York

910
C. C. Silveira et al.
LETTER
(15) Botega, C.; Pagliosa, F. M.; Bolzani, V. da S.; Yoshida, M.;
Gottlieb, O. R. Phytochemistry 1993, 32, 1331.
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Acknowledgement
The authors acknowledge the financial support provided by
Fundação VITAE (grant Nº B-11487/9B004), FAPERGS, CNPq
and CAPES. T.S.K. We also thank CONICET.
(17) Varma, R. S.; Dahiya, R. Tetrahedron Lett. 1997, 38, 2043.
(18) The N,S-acetal depicted of entry 1 was prepared by reaction
of N-tosyl-3,4-phenethylamine with (PhS)3CH in CH2Cl2
under SnCl4 catalysis (unpublished results from this
laboratory). For the synthesis of the sulfonamido acetal of
entry 2 (mp 104–106 ºC), see: Ponzo, V. L.; Kaufman, T. S.
Synlett 1995, 1149.
(19) (a) Marsaioli, A.; Magalhães, A. F.; Rúveda, E. A.; Reis, F.
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M. J. Nat. Prod. 1986, 49, 745. (c) Rahman, A.-U.; Malik,
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alumina (10 weight equivalents, prepared as reported by
Schmittling and Sawyer6) were mixed in a Pyrex test tube
and subjected to microwave irradiation (490 W) during 10 s
in a domestic microwave oven (Panasonic NN 6556). The
solid was allowed to cool to room temperature and washed
with CH2Cl2 (3 10 mL). The combined organic washings
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flash-chromatography, affording 1-benzoyl-3,4-dihydro-
isoquinoline as an oil in 60% yield; IR (film, cm–1): 3056,
2924, 1670, 1448, 1248, 923, 839, 716; 1H NMR (200 MHz,
CDCl3): 2.89 (2 H, t, J = 7 Hz), 3.98 (2 H, t, J = 7 Hz),
7.27–7.60 (7 H, m) and 8.02–8.05 (2 H, m); 13C NMR (50
MHz, CDCl3): 25.57, 47.28, 126.59, 127.18, 127.82,
128.55, 130.34, 131.64, 133.87 (2C), 135.50, 137.17, 165.34
and 193.81. Increasing the reaction time to 20 s, followed by
the same work-up procedure and flash-chromatography
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74–76 ºC (ref.14a 78–79 ºC; ref.14b 76–77 ºC; ref.14c 76–77
ºC); IR (film, cm–1): 3054, 1669, 1580, 1498, 1448, 1352,
1227, 1247, 1155, 923, 829, 715, 686; 1H NMR (200 MHz,
CDCl3): 7.43–7.51 (2 H, m), 7.57–7.65 (2 H, m), 7.71–7.83
(2 H, m), 7.91–7.93 (3 H, m), 8.22 (1 H, d, J = 8 Hz) and 8.66
(1 H, d, J = 8 Hz); 13C NMR (50 MHz, CDCl3): 122.57,
126.20, 126.41, 127.08, 128.31, 128.46, 130.74 (2C),
133.65, 136.62, 136.70, 141.14, 156.43 and 194.71.
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Synlett 2002, No. 6, 907–910 ISSN 0936-5214 © Thieme Stuttgart · New York