Thioorthoesters in the activated Pictet-Spengler cyclization. Synthesis of 1-thiosubstituted tetrahydroisoquinolines and carbon-carbon bond formation via sulfonyl iminium ions generated from N,S-sulfonyl acetals

Article abstract of DOI:10.1016/S0040-4039(03)01452-7

The elaboration of 1-alkylthio- and 1-arylthio-tetrahydroisoquinolines by means of the activated Pictet-Spengler reaction of N-sulfonyl-β-phenethylamines with thioorthoesters as electrophiles, and their use as sulfonyl iminium ion precursors for carbon-carbon bond formation, leading to 1-substituted tetrahydroisoquinoline derivatives, is reported.

Full text of DOI:10.1016/S0040-4039(03)01452-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6137–6140
Thioorthoesters in the activated Pictet–Spengler cyclization.
Synthesis of 1-thiosubstituted tetrahydroisoquinolines and
carbonꢀcarbon bond formation via sulfonyl iminium ions
generated from N,S-sulfonyl acetals
Claudio C. Silveira,a,* Carmem R. Bernardi,a Antonio L. Bragaa and Teodoro S. Kaufmanb,*
aDepartamento de Quimica, Universidade Federal de Santa Maria, 97105.900 Santa Maria, RS, Brazil
bInstituto de Qu´ımica Orga´nica de S´ıntesis (CONICET-UNR), Suipacha 531, (S2002LRK) Rosario, Argentina
Received 8 April 2003; revised 6 June 2003; accepted 6 June 2003
Abstract—The elaboration of 1-alkylthio- and 1-arylthio-tetrahydroisoquinolines by means of the activated Pictet–Spengler
reaction of N-sulfonyl-b-phenethylamines with thioorthoesters as electrophiles, and their use as sulfonyl iminium ion precursors
for carbonꢀcarbon bond formation, leading to 1-substituted tetrahydroisoquinoline derivatives, is reported.
© 2003 Elsevier Ltd. All rights reserved.
The controlled formation of new carbonꢀcarbon bonds
is of great importance in organic chemistry and thus it
constitutes a major area of research. In this respect, the
generation of N-acyliminium and N-sulfonyliminium
ions from suitable precursors, as reactive intermediates
towards carbon nucleophiles, has become an attractive
approach to this problem. This is amply documented
by the unusually high number of natural product syn-
theses reported involving such strategy, which allows
building structural complexity under mild and conve-
nient conditions.1
equivalents, such as acetals and enol ethers,4
chloro(methylthio)acetate3 and various a-chloro-a-
phenylchalcogeno
components.
carbonyls,5
as
electrophilic
The participation of thioorthoester derivatives as nucle-
ophiles is well documented in the chemical literature;
they are valuable synthetic tools for the introduction of
masked carbonyl functions.6 On the contrary, the use of
thioorthoesters as precursors of electrophilic species has
only few and scattered precedents.7
The condensation of N-acyl or N-sulfonyl b-phenethyl-
amines with aldehydes, known as the activated Pictet–
Spengler reaction, is a well established procedure for
the elaboration of tetrahydroisoquinolines.2 In spite of
the fact that alternative mechanisms may account for
its outcome,3a the transformation probably proceeds by
intramolecular nucleophilic attack of the aromatic ring
to an iminium-type intermediate, formed by reaction of
the aldehyde with the activated nitrogen moiety, under
Lewis acid promotion.
The original strategy has been modified and recently
extended to the use of masked aldehydes and aldehyde
Keywords: thioorthoesters; 1-substituted tetrahydroisoquinolines; sul-
fonyl iminium ions; activated Pictet–Spengler.
* Corresponding authors. Fax: 55-55-220-8754; e-mail: silveira@
quimica.ufsm.br; tkaufman@fbioyf.unr.edu.ar
Scheme 1. Activated Pictet–Spengler with thioorthoesters.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01452-7

6138
C. C. Sil6eira et al. / Tetrahedron Letters 44 (2003) 6137–6140
Here, we wish to report the synthesis of 1-arylthio- and
1-alkylthio-tetrahydroisoquinoline derivatives (2) by
reaction of N-sulfonyl-b-phenethylamines (1) with
thioorthoesters as electrophiles, under Lewis acid pro-
motion, in a new modification of the activated Pictet–
Spengler type cyclization process. We also disclose the
use of the resulting 1-heterosubstituted tetra-
hydroisoquinoline intermediates as sulfonyliminium ion
precursors for the elaboration of 1-substituted tetra-
hydroisoquinolines (3) upon the reaction of 2 with
suitable carbon nucleophiles (Scheme 1), under Lewis
acid assistance.
after 5–48 h.10 The results, consigned in Table 1,
revealed that unactivated tetrahydroisoquinoline pre-
cursors (entries 1–3) were unreactive even when submit-
ted to reaction in refluxing 1,2-dichloroethane, while
aromatics carrying the oxygenated substitution patterns
most commonly found in natural products, furnished
the expected products in moderate to good yields.
Interestingly,
comparison
between
analogous
dimethoxy and methylenedioxy substituted substrates
(entries 6 and 10) evidenced the poor performance of
the latter, while examination of the results obtained
using HC(SPh)3 and HC(SEt)3 indicated that the for-
mer was more efficient, requiring milder conditions and
shorter reaction times.
Thioorthoester-stabilized carbocations have not been
explored to date as electrophilic partners in the acti-
vated Pictet–Spengler reaction. A close analogy to this
is the use of ethyl orthoformate under tosic acid cataly-
sis for the synthesis of quinazolino-tetrahydro-b-carbo-
lines;8 in principle, this could improve the scope of the
cyclization and lead to new classes of products. In
addition, the enhanced stability of the cyclizing inter-
mediate due to the presence of a second heteroatom in
the carbenium ion may facilitate its formation, leading
to cyclized products in better yield.
These results could be ascribed to the better charge
stabilization ability of the phenylthio moiety, vis-a`-vis
its ethylthio congener. The group of Hevesi, while
studying methyl and phenyl selenoorthoesters, previ-
ously noted a similar but less evident trend.7a
Noteworthy, the more rigorous conditions required for
cyclization with tris(ethylthio)-methane brought about
the selective demethylation of the ortho-disubstituted
methyl ether function of the starting material in the
experiment of entry 12, probably as a consequence of
the formation of a type of Lewis acid-thiol ether cleav-
ing reagent.11
To begin the study, tris(ethylthio)- and tris(phenylthio)-
methane were synthesized by the known boron trifl-
uoride
etherate-catalyzed
reaction
of
ethyl
orthoformate with ethyl mercaptan and thiophenol,
respectively.9 Then, they were reacted with various N-
sulfonyl-b-phenethylamines, bearing different sub-
stituents and substitution patterns under tin(IV)
chloride catalysis, smoothly affording cyclized products
The synthesis of optically active intermediates was also
pursued with both tested thioorthoesters, employing a
chiral b-phenethyl sulfonamide derivative (mp 109.5–
Table 1. Activated Pictet–Spengler synthesis of 1-thiosubstituted tetrahydroisoquinolines (2) employing thioorthoesters as
electrophiles
a
Entry no
R1
R2
R3
R4
R5
R6
Solvent
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
H
Cl
Me
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
H
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Cs
Cs
Ts
Ts
Ts
Ts
Ph
Ph
Ph
Ph
Ph
Ph
Et
Ph
Et
Ph
Ph
Et
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH2Cl2
Reflux
Reflux
Reflux
8
8
8
6
6
5
20
5
20
6
6
–
–
–
−78°C“rt
−78°C“rt
−78°C“rt
Reflux
−78°C“rt
Reflux
−78°C“rt
−78°C“rt
Reflux
54
44
82
47
93b
53c
29
65
25
OMe
OMe
OMe
OMe
-OCH2O-
OMe
OMed
OMe
9
10
11
12
13
OMe
OMe
OMe
48
6
e
Ph
−78°C“rt
–
a Ts: toluene-p-sulfonyl; Cs: (1S)-10-camphorsulfonyl (see text).
b Diastereoisomeric ratio=2:1.
c Diastereoisomeric ratio :1:1.
d The mono demethylated product (R3=OH) was obtained.
e Tris(phenylseleno)methane was employed, resulting in a complex mixture of inseparable products.

C. C. Sil6eira et al. / Tetrahedron Letters 44 (2003) 6137–6140
6139
111.0°C, [h]D=+25.3, c=0.93, CHCl3) derived from
(1S)-10-camphorsulfonyl chloride (entries 8 and 9). Not
unexpectedly, however, poor diastereoisomeric product
ratios were obtained,5 being 2:1 that recorded when
tris(phenylthio)-methane was employed, while forma-
tion of an equimolecular amount of diastereoisomers
was observed when tris(ethylthio)-methane was used.
This outcome is probably a result of both, the ability of
tris(phenylthio)-methane to produce cyclized products
at lower temperature and the bulk of the phenylthio
moiety.
Unfortunately, attempts to prepare related 1-phenylse-
lenyl tetrahydroisoquinoline derivatives employing
tris(phenylseleno)-methane (prepared from phenylse-
lenol, ethyl orthoformate and boron trifluoride ether-
ate)9 under similar conditions met with failure, resulting
in a complex mixture of inseparable products (entry
13).
Scheme 2. Synthesis of 1-substituted tetrahydroisoquinolines.
Interestingly, the 1-phenylthio-tetrahydroisoquinolines
obtained by the reported activated Pictet–Spengler
cyclization with tris(phenylthio)-methane can be
regarded as sulfur analogs of 1-benzyl-tetra-
hydroisoquinolines. The latter have been intensive
targets for organic synthesis because they constitute an
important and widespread family of natural products,
with many of its members displaying interesting physio-
logical and pharmacological actions.12
precedents.15 This successful C-1 functionalization of
the tetrahydroisoquinoline nucleus is also of impor-
tance because in spite that iminium-ion mediated car-
bonꢀcarbon bond formation has become part of the
current arsenal of efficient synthetic organic transfor-
mations, examples of the preparation and use of N,S-
sulfonylacetals as iminium ion precursors are still
rare.19
Although very few cases are documented in the litera-
ture, N,S-acetals can be useful carbonꢀcarbon bond
forming precursors. We have recently shown that 3-het-
erosubstituted tetrahydroisoquinolines bearing N,O-
and N,S-sulfonylacetal moieties are capable of generat-
ing N-tosyliminium ions under Lewis acid promotion13
which, in turn, can react with a variety of carbon
nucleophiles, offering convenient entries to polyfunc-
tionalized simple tetrahydroisoquinolines. In addition,
the participation of phenylsulfanyllactams in car-
bonꢀcarbon bond formation via radical chemistry has
been reported a few years ago.14
In conclusion, we have developed a new variation of
the activated Pictet–Spengler tetrahydroisoquinoline
synthesis, in which alkyl and aryl thioorthoesters were
employed as electrophiles for the preparation of 1-het-
erosubstituted tetrahydroisoquinolines. In turn, these
were used as convenient substrates for the elaboration
of 1-substituted tetrahydroisoquinoline derivatives by
carbonꢀcarbon bond formation via sulfonyliminium
ions. Application of this strategy to the synthesis of
natural products is under study and will be reported in
due time.
Therefore, in order to examine the synthetic utility of
the new N,S-sulfonylacetals as sulfonyliminium ion
precursors for the preparation of 1-subtituted tetra-
Acknowledgements
The authors acknowledge the financial support pro-
vided by Fundac¸a˜o VITAE (Grant No B-11487/9B004),
FAPERGS, CNPq and CAPES. T.S.K. also thanks
CONICET.
hydroisoquinolines,
the
1-phenylthio
tetra-
hydroisoquinoline 2a, obtained as shown in entry 6 of
Table 1, was reacted with the silyl enol ethers derived
from pinacolone and acetophenone, as well as with allyl
trimethylsilane (Scheme 2). Under Lewis acids assis-
tance, these reactions furnished 90% of the expected
allyl derivative 3a,15 as well as ketones 3b and 3c in
yields of 58 and 67%, respectively.16 Phenethyl iso-
quinoline 3c is reminiscent of several natural products,
some of them isolated from Colchicum szovitsii and C.
ritchii.17
References
1. (a) Hiemstra, H.; Speckamp, W. N. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-
mon Press: Oxford, 1991; Vol. 2, pp. 1047–1082 and
references cited therein; (b) Sisko, J.; Henry, J. R.; Wein-
reb, S. M. J. Org. Chem. 1993, 58, 4945–4951; (c) Lu,
Z.-H.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1993,
The iminium ion-based elaboration of C-1 substituted
tetrahydroisoquinolines has been previously accom-
plished by Grignard addition to iminium, acyliminium
and tosyliminium intermediates;18 however, the use of
silyl derivatives for the same purpose has only a few
,
593–596; (d) Somfai, P.; Ahman, J. Tetrahedron Lett.
1992, 33, 3791–3794; (e) Bianchi, D. A.; Kaufman, T. S.
Can. J. Chem. 2000, 78, 1165–1699; (f) Kaufman, T. S. J.
Chem. Soc., Perkin Trans. 1 1996, 2497–2505.

6140
C. C. Sil6eira et al. / Tetrahedron Letters 44 (2003) 6137–6140
16. The elaboration of 3,3-dimethyl-1-[6,7-dimethoxy-2-
2. (a) Orazi, O. O.; Corral, R. A.; Giaccio, H. J. Chem. Soc.,
(tosyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-butan-2-one
(3b) is representative of a typical experimental procedure.
A solution of 3,4-dimethoxy-N-tosyl-b-phenethylamine
(335 mg, 1 mmol) and HC(SPh)3 (442 mg; 1.3 mmol) in
anhydrous CH2Cl2 (5 mL) was cooled to −78°C and treated
dropwise with SnCl4 (0.47 mL, 4 mmol). The reaction
system was left to attain room temperature; after stirring
5 h, water (10 mL) was added, the organic layer was
separated, and the aqueous phase was extracted with
CH2Cl2 (3×20 mL), washed with brine and dried (MgSO4).
The solvent was removed under reduced pressure and the
residue was flash chromatographed, resulting in the N,S-
sulfonylacetal 2a (374 mg, 82%), as a white solid, mp
143.0–145.0°C. IR (KBr, w): 2936, 1610, 1595, 1581, 1519,
Perkin Trans. 1 1986, 1977–1982; (b) Zinczuk, J.; Sorokin,
I. H.; Orazi, O. O.; Corral, R. A. J. Heterocyclic Chem.
1992, 29, 859–866; (c) Ito, K.; Tanaka, H. Chem. Pharm.
Bull. 1977, 25, 1732–1739; (d) Lukanov, L. K.; Venkov, N.
M. Synthesis 1987, 204–206.
3. (a) Kohno, H.; Sekine, Y. Heterocycles 1996, 42, 141–144;
(b) Kohno, H.; Yamada, K. Heterocycles 1999, 51, 103–
117.
4. (a) Cho, S.-D.; Song, S.-Y.; Hur, E.-J.; Chen, M.; Joo,
W.-H.; Falck, J. R.; Yoon, Y.-J.; Shin, D.-S. Tetrahedron
Lett. 2001, 42, 6251–6253; (b) Comins, D. L.; Thakker, P.
M.; Baevsky, M. F.; Badawi, M. M. Tetrahedron 1997, 53,
16327–16340.
5. (a) Silveira, C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman,
T. S. Tetrahedron Lett. 1999, 40, 4969–4972; (b) Silveira,
C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman, T. S.
Tetrahedron Lett. 2001, 42, 8947–8950.
6. For some recent references, see for example: (a) Barbero,
M.; Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R. J.
Org. Chem. 1995, 60, 6017–6024; (b) Cohen, T.; McNa-
mara, K.; Kuzemko, M. A.; Ramig, K.; Landi, J. J.; Dong,
Y. Tetrahedron 1993, 49, 7931–7942; (c) Liu, H.; Cohen,
T. Tetrahedron Lett. 1995, 36, 8925–8928; (d) Kim, W.-K.;
Paik, S.-C.; Lee, H.; Cho, Ch.-G. Tetrahedron Lett. 2000,
41, 5111–5114; (e) Rahim, M. A.; Taguchi, H.; Watanabe,
M.; Fujiwara, T.; Takeda, T. Tetrahedron Lett. 1998, 39,
2153–2156.
7. (a) Hevesi, L.; Nsunda, K. M. Tetrahedron Lett. 1985, 26,
6513–6514; (b) Barbero, M.; Cadamuro, S.; Degani, I.;
Fochi, R.; Gatti, A.; Regondi, V. Synthesis 1988, 22–25;
(c) Silveira, C. C.; Fiorin, G. L.; Braga, A. L. Tetrahedron
Lett. 1996, 37, 6085–6088; (d) Kiriliuk, B. A.; Mel’nitskii,
I. A.; Golub, N. M.; Kiladza, T. K.; Kantor, E. A.;
Rakhmankulov, D. L. J. Org. Chem. (USSR) 1987, 23,
1754–1758.
1
1463, 1159, 1113, 872, 735 and 567 cm−1; H NMR (200
MHz, CDCl3, l): 2.33 (s, 3H), 2.39–2.63 (m, 2H), 3.79 (s,
3H), 3.82 (s, 3H), 3.75–3.79 (m, 2H), 6.40 (s, 1H), 6.58 (s,
1H), 6.72 (s, 1H), 7.06–7.10 (m, 2H), 7.29–7.32 (m, 3H) and
7.54–7.52 (m, 4H); 13C NMR (50 MHz, CDCl3, l): 21.39,
26.04, 38.06, 55.80, 55.90, 65.79, 110.17, 111.06, 125.04,
125.73, 127.18 (2 C), 128.37, 128.90 (2 C), 129.32 (2 C),
133.15, 134.47 (2 C), 137.33, 143.19, 147.35 and 148.79.
HRFABMS: [M+Na]+ m/z 478.1105; calcd for
C24H25NO4S2Na 478.1123. Under a nitrogen atmosphere,
an aliquot of the N,S-sulfonyl acetal 2a (228 mg, 0.5 mmol)
was dissolved in dry CH2Cl2 (3 mL), pinacolone TMS enol
ether (234 mg, 1.5 mmol) was added and the system was
cooled to −78°C, when it was treated with SnCl4 (0.25 mL).
After stirring for 2 h, the reaction was quenched with water,
warmed, and the reaction products were extracted with
CH2Cl2 (3×15 mL). Drying (MgSO4), concentration and
flash chromatography of the extracts furnished 3b (129 mg,
0.29 mmol, 58%), as a solid, mp 163.0–165.0°C. IR (KBr,
w): 2957, 2929, 1736 (w), 1674, 1518, 1337, 1227, 1161, 991
and 659 cm−1; 1H NMR (200 MHz, CDCl3, l): 1.01 (s, 9H),
2.35 (s, 3H), 2.61–2.70 (m, 2H), 2.89 (dd, J=7 and 17 Hz,
1H), 3.10 (dd, J=7 and 17 Hz, 1H), 3.43–3.57 (m, 1H),
3.50–3.80 (m, 1H), 3.77 (s, 3H), 3.78 (s, 3H), 5.50 (dd,
J=4.7 and 8 Hz, 1H), 6.43 (s, 1H), 6.57 (s, 1H), 7.18 (d,
J=8 Hz, 2H) and 7.66 (d, J=8 Hz, 2H); 13C NMR (50
MHz, CDCl3, l): 21.39, 25.88 (3 C), 27.11, 40.53, 44.09,
46.29, 51.61, 55.78, 55.86, 109.59, 111.18, 124.83, 127.15 (2
C), 128.75, 129.42 (2 C), 136.97, 143.10, 147.49, 147.83 and
212.38. HRFABMS [M+Na]+ m/z 468.1815; calcd for
C24H31NO5SNa 468.1821.
8. Beugelmans-Verrier, M.; Potier, P. Tetrahedron 1987, 43,
3465–3470.
9. (a) Seebach, D.; Geiss, K.-H.; Beck, A. K.; Graf, B.; Daum,
H. Chem. Ber. 1972, 105, 3280–3300; (b) Dailey, O. D.;
Fuchs, P. L. J. Org. Chem. 1980, 45, 216–236.
10. All new compounds gave single spots on TLC and were
fully characterized by HRMS, IR, 1H and 13C NMR,
furnishing data in complete agreement with their assigned
structures.
11. Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249–282.
12. (a) Bentley, K. W. In Chemistry and Biochemistry of
Organic Natural Products; Ravindranath, B., Ed. The
Isoquinoline Alkaloids. Harwood Academic Publishers:
Amsterdam, The Netherlands, 1998; Vol. 1, pp. 33–58; (b)
Herbert, R. B. In The Chemistry and Biology of Isoquinoline
Alkaloids; Philipson, J. D.; Roberts, M. F.; Zenk, M. H.,
Eds.; Springer Verlag: Berlin, 1985; p. 213.
13. Ponzo, V. L.; Kaufman, T. S. Synlett 1995, 1149–1150.
14. Ewin, R. A.; Jones, K.; Newton, C. G. J. Chem. Soc.,
Perkin Trans. 1 1996, 1107–1111.
15. (a) Itoh, T.; Miyazaki, M.; Nagata, K.; Hasegawa, H.;
Ohsawa, A.; Nakamura, K. T. Heterocycles 1998, 47,
125–128; (b) Itoh, T.; Nagata, K.; Miyazaki, M.; Ohsawa,
A. Synlett 1999, 1154–1156; (c) Itoh, T.; Nagata, K.;
Miyazaki, M.; Kameoka, K.; Ohsawa, A. Tetrahedron
2001, 57, 8827–8839.
17. (a) Freyer, A. J.; Abu Zarga, M. H.; Firdous, S.;
Guinadeau, H.; Shamma, M. J. Nat. Prod. 1987, 50,
8
684–689; (b) Tojo, E.; Onur, M. A.; Freyer, A. J.; Shamma,
M. J. Nat. Prod. 1990, 53, 634–637.
18. (a) De Costa, B. R.; Radesca, L. Synthesis 1992, 887–890;
(b) Comins, D. L.; Badawi, M. M. Heterocycles 1991, 32,
1869–1873; (c) Craig, D.; Robson, M. J.; Shaw, S. J. Synlett
1998, 1381–1383.
19. The Lewis acid-promoted carbonꢀcarbon bond formation
employing (S,S), (Se,Se) and mixed (O,S) and (O,Se) acetals
has been studied. See, for example: (a) Hunter, R.; Michael,
J. P.; Walter, D. S. Tetrahedron Lett. 1994, 35, 5481–5484;
(b) Sato, T.; Otera, J.; Nozaki, H. J. Org. Chem. 1990, 55,
6116–6121; (c) Braga, A. L.; Dornelles, L.; Silveira, C. C.;
Wessjohann, L. A. Synthesis 1999, 562–564; (d) Hermans,
B.; Hevesi, L. J. Org. Chem. 1995, 60, 6141–6147; (e)
Silveira, C. C.; Larghi, E. L. J. Braz. Chem. Soc. 1998, 9,
327–340 and references cited therein.