Diastereoselective synthesis of 1,1,4-trisubstituted-2,3,4,9- tetrahydrospiro-β -carbolines via glacial acetic acid catalyzed Pictet - Spengler reaction

The Pictet-Spengler reaction of substituted tryptamines with cyclic ketones using glacial acetic acid afforded only one diastereomer of unreported 1,1,4-trisubstituted-2,3,4,9-tetrahydrospiro-β - carbolines. The stereoselectivity in the reaction has been demonstrated using unsymmetrical ketones and single-crystal X-ray analysis of one of the spiro products in the form of base, its sulfate and hydrochloride salts, which indicated the formation of only the R , R diastereomer.


Results and Discussion
Use of silica gel as a solid and mildly acidic catalyst is well reported and is receiving considerable attention from synthetic chemists. 26,27In the present study silica gel was used for conjugate addition reaction.Thus, indole and nitro olefin 1 were loaded on silica gel and then heated for 2 min.at 150 o C to get a solid product in 97% yield.The structure was shown to be 8 by comparing with the reported 27d values.Further reactions of various other nitro olefins 2-7 and indole by using the same method furnished products 9-14 in good yields and in short time.The results are shown in Scheme Further reduction of the nitro compound 8-14 using freshly prepared Raney nickel in methanol furnished the β-phenyltryptamines 15-21.In the case of the nitro compound 12, initial reduction of aromatic nitro group furnished product 22.After continuing the reaction for longer time, both the nitro groups were reduced to give 19 (Scheme 1).
To check the catalytic activity of glacial acetic acid for Pictet-Spengler cyclization initially the condensation reaction of amine 15 and cyclohexanone in the presence of catalytic amount of glacial acetic acid was carried out by refluxing in toluene to furnish a new compound 23 (Scheme 2, Table 2) in 91% yield.The spectral and analytical data was consistent with the structure 23 which was confirmed by DEPT experiment.In the 13 C NMR, signal at 52.3 was assigned to the spiro carbon C1 which was absent in the DEPT experiment where all protonated carbons are seen.One CH at 40.8 for C4 and five -CH2 groups with one strong signal at 21.7 were observed in the aliphatic region of the DEPT experiment.This data supported for Pictet-Spengler cyclization in presence of glacial acetic acid.2).Although spiro compounds are known to show dissymmetry, only one racemic product was expected, as the ketones used were symmetric.
To explore the stereoselectivity in the reaction, unsymmetrical ketones such as isatin, αtetralone and 2-methylcyclopentane-1,3-dione were used for the Pictet-Spengler cyclization.Treatment of 15 with isatin in the presence of a catalytic amount of glacial acetic acid furnished a solid product. 1 H and 13 C NMR indicated it to be a single diastereomer of base 32 (Scheme 3).The stereochemistry of base 32 was investigated using single crystal X-ray analysis, indicating the R, R configuration at C1 and C4 (Figure 1).A literature survey revealed that there is a report for the formation of mixture of the two diastereomers of sulfate form of base 32 in a similar Pictet-Spengler condensation using sulfuric acid in water as a catalyst in 46% yield.In this report, 24 the major diastereomer was shown to have R,R configuration using 2D NMR of the mixture without isolating the individual isomers.
However, in the present study using acetic acid as a catalyst we could achieve the formation of only one diastereomer of base 32 in 88% yield exclusively and also confirmed the stereochemistry of base 32 as R,R unambiguously using single crystal X-ray analysis.The sterically preferred spiro transition state (Scheme 3) having the trans arrangement of substituents at C1 and C4 in presence of glacial acetic acid as a mild acidic catalyst explained the exclusive formation of diastereomer 32.

Scheme 3
To compare the reported 24 and the present results, base 32 was treated with sulfuric acid (conc.) in methanol to furnish the corresponding sulfate 33 in 95% yield (Scheme 4).The 1 H NMR and 13 C NMR data of sulfate 33 were consistent with that of the reported major isomer.The report 2 of good biological activity for the hydrochloride of similar base without a substituent at 4-position led us to convert base 32 to the hydrochloride 34 (94% yield, Scheme 4).In the 1 H NMR of salts 33 and 34, the assignments of C3H2 and C4H are different from those of base 32, as shown in Table 3.In both the salts, the protons at C3 are shifted downfield due to the proximity of quaternary nitrogen.The C4H appeared as a dd with J = 6.1 and 12.1 Hz as Ja,e and Ja,a, respectively showing coupling with two protons at C3.This indicated the axial position of C4H in both the salts 33 and 34.However, in base 32 C4H appeared at 4.41 as a triplet, J = 6.7 Hz, indicating rapid flipping of the nitrogen containing ring in solution.
As compared to the chemical shift of C4H in base, this proton, being axial was shifted to up field position in both the salts.In contrast to this the stereochemistry of salts 33 and 34 was shown to be same as the base 32 as R,R using X-ray analysis (Figure 1 and 2).The difference in the two results from 1 H NMR and X-ray analysis can be attributed to the solution state where rapid flipping is possible in 1 H NMR and rigid solid state in X-ray analysis.To generalize the stereoselectivity in the reaction using glacial acetic acid, the substituents at 1 and 4-positions were changed.Treatment of amino compounds 16, 17 and 20 with isatin and 15 and 16 with α-tetralone afforded products 35-37 and 38-39 respectively (Scheme 3, Table 2).The similarity in the 1 H and 13 C NMR of these products, with that of 32 indicated formation of only one diastereomer in each case.
Subsequently, treatment of amino compound 15 with 2-methylcyclopentane-1,3-dione, under the same conditions led to formation of a new product in 89% yield.The spectral data was not consistent with the expected structure.Even the attempts for cyclization using strong acid TFA were unsuccessful (Scheme 5).Thus single crystal X-ray analysis was used to assign structure 40 to the new unexpected product (Figure 3).The formation of compound 40 can be explained by bond isomerization in the imine intermediate to achieve the stable conjugated system.

Conclusions
In conclusion, catalytic activity of glacial acetic acid in Pictet-Spengler reaction has been demonstrated using symmetric ketones like cyclohexanone and cyclopentanone which furnished new spiro products.Using the same catalyst with unsymmetrical ketones, such as isatin and tetralone, one diastereomer of new THSβCs resulted exclusively.The structures of the base 32, sulfate 33, and hydrochloride 34 were confirmed using single crystal X-ray analysis, from which the absolute configuration of the products 32, 33 and 34 was confirmed as R,R.Thus, in the present study a diastereoselective and high yielding method for the synthesis of THSβCs was established using glacial acetic acid.

Experimental Section
General.Melting points recorded are uncorrected.All solvents were of reagent grade and, when necessary, were purified and dried by standard methods.Commercially available glacial acetic acid (from Merck) was used.Reactions and products were routinely monitored by thin layer chromatography (TLC) on silica gel (Kieselgel 60 F254, Merck).Column chromatographic purifications were performed using 60-120 mesh silica gel.Visualization was made with UV light (254 and 365nm) or with an iodine vapor.IR spectra were recorded on Shimadzu 8400 instrument. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded on Varian Mercury instrument using TMS as internal standard. 1H NMR peaks expressed as s, bs, d, dd, t, m correspond to singlet, broad-singlet, doublet, doublet of doublet, triplet, and multiplet, respectively.Mass were recorded on Shimadzu QP 5050.Elemental analyses were recorded on a Vario EL III elemental analyzer instrument.

General procedure for Michael addition of indole on nitro olefins and further reduction to β-substituted tryptamines
A mixture of indole (2.4 mmol) and nitro olefin (2 mmol) was loaded on silica gel (60-120 mesh, 0.25 g) and heated in silica gel bath at 150 o C.After the reaction was complete as judged by TLC, the same silica gel was loaded on a silica-gel column.Chromatographic separation using hexane/ethyl acetate (9:1) furnished the products 8-14.The β-Substituted tryptamines 15-21 were prepared using reported 25 procedure.

General procedure for the Pictet-Spengler cyclization
The mixture of the amino compound 15-21, (2 mmol), ketone (8 mmol), and glacial acetic acid (0.1-0.5 equiv.), was heated at 120 o C in dry toluene under nitrogen atmosphere in a Dean-Stark apparatus for 7.5-18.5 h.The heating was continued till the full consumption of the amino compound.Completion of the reaction was confirmed by TLC.The reaction mixture was diluted with ethyl acetate, washed with 10% NaHCO3 and brine.The combined organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure.The crude product obtained was submitted to column chromatography using hexane/ethyl acetate to give the products 23-32 and 35-40.

General procedure for preparation of compounds (33 and 34)
A few drops of concentrated H2SO4 or HCl were added to compound 32 (0.2 g, 0.55 mmol) dissolved in methanol (3 mL).The reaction mixture stirred with heating till the solution became clear and kept at room temperature for 24 h.Completion of the reaction was confirmed by TLC.The solvent was removed and the crystals were washed twice with methanol to furnish the expected product 1,1-isatyl-4-phenyl-2,3,4,9-tetrahydrospiro-β-carboline sulfate 33 or hydrochloride 34.

Crystallography
Crystallographic data in this paper have been deposited with the Cambridge Crystallographic Data Centre.Deposition numbers are CCDC 752864 for 33, CCDC 752865 for 40, CCDC 752866 for 32 and CCDC 752867 for 34.Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or email: deposit@ccdc.cam.ac.uk.Crystal data.The X-ray data of all the four compounds were collected at T = 296 K, on SMART APEX CCD Single Crystal X-ray diffractometer using Mo-K radiation ( = 0.7107 Å) to a maximum  range of 25.00.The structures were solved by direct methods using SHELXTL.All the data were corrected for Lorentzian, polarization and absorption effects.SHELX-97 (ShelxTL) 28 was used for structure solution and full matrix least squares refinement on F 2 .Hydrogen atoms were included in the refinement as per the riding model.The refinements were carried out using SHELXL-97.
1 and Table 1.Thus, a new efficient method was established for the conjugate addition of indole on nitro olefins.

Table 1 .
Time and yield for the Michael addition reactions using nitro olefins 1-7

Table 2 .
Time and yield for Pictet-Spengler reactions using β-substituted tryptamines

Table 3 .
Comparison of 1 H NMR spectra of compounds 32, 33 and 34