influence of stereoelectronic effects. Thus, to avoid the
development of strain A1,3 between the N-tosyl moiety and
the carboxyethyl group, the latter may adopt a conformation
in which the ester is pseudoaxially oriented in the intermedi-
ate iminium ion. Attack of the incoming nucleophile would
take place from the less hindered face of this intermediate
(Scheme 1), with the nitrogen lone-pair developing pseudo-
axial and trans-periplanar to it.16
In summary, this work has demonstrated the usefulness
of thioortho esters as electrophiles in a variation of the
Pictet-Spengler synthesis of tetrahydro-â-carbolines. Alkyl-
and arylthioortho esters were employed for the preparation
of 1-heterosubstituted â-carbolines, with the latter being more
effective. The resulting N,S-acetals were used as convenient
substrates for the elaboration of 1-substituted â-carboline
derivatives by carbon-carbon bond formation via to-
syliminium ions.
This tactical combination leading to the successful two-
step preparation of C1-functionalized â-carbolines 4 is
flexible and allows many variations at C1; it is also of
importance because despite the fact that iminium-ion-
mediated carbon-carbon bond formation has become part
of the current arsenal of efficient synthetic transformations,
examples of the preparation and use of N,S-sulfonylacetals
as iminium ion precursors are still relatively rare.17
(14) Synthesis of 4a is representative of a typical experimental procedure.
A solution of N-tosyltryptamine (314 mg, 1 mmol) and HC(SPh)3 (442
mg, 1.3 mmol) in anhydrous CH2Cl2 (8 mL) was cooled to -78 °C and
treated dropwise with SnCl4 (0.29 mL, 2.5 mmol). The reaction system
was allowed to attain room temperature; after stirring 5 h at rt, an aqueous
solution of NaHCO3 (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, affording the N,S-
sulfonylacetal 3a (416 mg, 0.96 mmol) as an oil: IR (neat, V) 3018, 2971,
1300 and 1140 cm-1; HRMS (CI) m/z calcd for C24H22N2O2S2 434.3001,
found 457.1023 (M + Na)+; 1H NMR (500 MHz, CDCl3, δ) 8.02 (s, 1H),
7.86 (dd, J ) 5.0 and 14.0 Hz, 1H), 7.53 (d, J ) 8.3 Hz, 2H), 7.41 (d, J
) 8.0 Hz, 2H), 7.33-7.10 (m, 7H), 7.28 (d, J ) 8.3 Hz, 2H), 6.73 (s, 1H),
3.91 (ddd, 1H, J ) 1.0, 4.0 and 13.0 Hz), 3.46-3.42 (m, 1H), 2.56-2.45
(m, 2H) and 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3, δ) 143.6, 138.0,
136.2, 134.9 (2C), 131.9 (2C), 129.6 (2C), 129.5, 129.2 (2C), 128.9, 127.3
(2C), 126.4, 123.1, 119.8, 118.7, 111.3, 110.9, 62.3, 39.5, 21.6 and 20.33.
Under a nitrogen atmosphere, an aliquot of the N,S-sulfonyl acetal 3a (217
mg, 0.5 mmol) was dissolved in dry CH2Cl2 (5 mL); SnCl4 (0.5 mmol,
0.06 mL) was added, and the system was cooled to -78 °C when it was
treated with allyl trimethylsilane (0.1 mL, 0.7 mmol). After stirring for 2
h, the reaction was quenched with water and extracted with CH2Cl2 (3 ×
10 mL). Drying (MgSO4), concentration, and flash chromatography of the
combined organic extracts furnished the tetrahydro-â-carboline 4a (172 mg,
Acknowledgment. The authors are indebted to Fundac¸a˜o
Vitae (Grant B-11487/9B004), FAPERGS, CNPq, and
CAPES for financial support of this research and are grateful
to Prof. Gary A. Molander (University of Pennsylvania) for
help with the HRMS determinations. T.S.K. also thanks
CONICET and ANPCyT (Grant 12532).
Supporting Information Available: Experimental pro-
cedures for the preparation of intermediates 3a-g and 3i
and final compounds 4a-j and spectra and characterization
of new compounds. This material is available free of charge
0.46 mmol) as an oil: IR (neat, V) 3059, 2924, 1731, 1328 and 866 cm-1
;
HRMS (CI) m/z calcd for C21H22N2O2S 366.2341, found 389.1315 (M +
Na); 1H NMR (500 MHz, CDCl3, δ) 7.89 (s, 1H), 7.66 (d, J ) 8.0 Hz,
2H), 7.34 (d, J ) 8.0 Hz, 1H), 7.29 (d, J ) 8.0 Hz, 1H), 7.16-7.12 (m,
3H), 7.06 (t, J ) 7.8 Hz, 1H), 6.01-5.92 (m, 1H), 5.21-5.16 (m, 3H),
4.15 (dd, J ) 5.5 and 14.0 Hz, 1H), 3.45-3.39 (m, 1H), 2.73-2.66 (m,
2H), 2.57-2.53 (m, 1H), 2.49-2.43 (m, 1H) and 2.30 (s, 3H); 13C NMR
(125 MHz, CDCl3, δ) 143.2, 138.0, 135.7, 133.9, 132.4, 139.5 (2C), 126.7
(2C), 126.4, 122.0, 119.4, 119.0, 118.1, 110.9, 108.0, 52.6, 40.4, 40.0, 31.3
and 20.0.
(15) Rychnovsky, R. D.; Crossrow, J.Org. Lett. 2003, 5, 2367-2370.
(16) (a) Kaufman, T. S. J. Chem. Soc., Perkin Trans. 1 1996, 2497-
2505. (b) Perrin, C. L.; Young, D. B. J. Am. Chem. Soc. 2001, 123, 4451-
4458.
OL051342I
(17) Lewis acid-promoted carbon-carbon 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) Yoshimatsu, M.; Yoshiuchi, T.; Shimizu, H.;
Hori, M.; Kataoka, T. Synlett 1993, 121-122. (c) Sato, T.; Otera, J.; Nozaki,
H. J. Org. Chem. 1990, 55, 6116-6121. (d) Braga, A. L.; Dornelles, L.;
Silveira, C. C.; Wessjohann, L. A. Synthesis 1999, 562-564. (e) Hermans,
B.; Hevesi, L. J. Org. Chem. 1995, 60, 6141-6147. (f) Silveira, C. C.;
Larghi, E. L. J. Braz. Chem. Soc. 1998, 9, 327-340 and references therein.
3704
Org. Lett., Vol. 7, No. 17, 2005