Domino reactions of tetrahydroisoquinoline difunctional compounds with 4-isothiocyanato-4-methyl-2-pentanone

Trans -9,10-Dimethoxy-3,3,4a-trimethyl-4,4a,6,7,11b,12-hexahydro-3 H -pyrimido[6’,1’:2,3]- imidazo[5,1-a ]isoquinoline-1(2 H )-thione, cis - and trans -9,10-dimethoxy-3,3,4a-trimethyl-4,4a,6,7,12,13-hexahydro-3 H ,11b H -pyrimido[6’,1’:2,3]pyrimido[6,1-a ]isoquinoline-1(2 H )- thione, trans -10,11-dimethoxy-2,2,14a-trimethyl-1,7,8,12b,13,14a-hexahydro-2 H -pyrimido- [6’,1’:2,3][1,3,4]oxadiazino[5,4-a ]isoquinoline-4(3 H )-thione and trans -9,10-dimethoxy-3,3,4a-trimethyl-4,4a,6a,7-tetrahydro-3 H ,6 H ,12 H -pyrimido[6’,1’:2,3][1,3,4]oxadiazino-[4,5-b ]- isoquino-line-1(2 H )-thione, previously unknown ring-annelated isoquinoline derivatives, were prepared by diastereoselective domino ring closures of tetrahydroisoquinoline diamines or hydrazinoalcohols with 4-isothiocyanato-4-methyl-2-pentanone. The relative configurations and predominant conformations of the prepared tetracycles were determined by means of NMR spectroscopy and molecular modeling calculations.


Scheme 1
Despite the numerous examples of the synthetic applicabilities of β-isothiocyanatoketones, their reactions with tetrahydroisoquinoline difunctional compounds have not yet been reported.Accordingly, as a continuation of our previous work on the preparation and structural analysis of tetrahydroisoquinoline-condensed saturated heterocycles, [6][7][8] our present aim was to study the reactions of 4-isothiocyanato-4-methyl-2-pentanone with tetrahydroisoquinoline diamines and hydrazinoalcohols.
The regioisomeric tetrahydroisoquinoline hydrazinoalcohols 10 and 12 were obtained by the standard two-step transformation (N-nitrosation and subsequent reduction) of the corresponding amino alcohols 9 and 11 (Scheme 3).When diamines 8a,b were refluxed with 4-isothiocyanato-4-methyl-2-pentanone 9 in toluene, diastereomers of the previously unknown ring systems pyrimido[6',1':2,3]imidazo-[5,1-a]isoquinoline-1(2H)-thione 13a,b and pyrimido[6',1':2,3] pyrimido [6,1-a]isoquinoline-1(2H)-thione 14a,b, differing in the position of the methyl group (Me-4a) and the hydrogen at the annelation (H-11b), were formed in moderate yields, but with considerable diastereo selectivities (Scheme 4).The size of the N,N-heterocyclic ring formed proved to exert a significant effect on the diastereomeric ratios, the trans isomer 13b being the main product in the ring closure of 8a, while the homologous diamine 8b gave the cis tetracycle 14a as the major diastereomer.Both the cis and the trans diastereomers of 14 could be separated by means of column chromatography, but only the major trans isomer 13b could be obtained from the mixture of homologous tetracycles 13; all of our efforts to date to isolate the minor cis compound 13a in diastereomerically pure form have failed.The geometries of the diastereomers were deduced from the presence or lack of the cross-peaks between H-11b and Me-4a in the NOESY spectra.In the reactions of regioisomeric hydrazinoalcohols 10 and 12 with 4-isothiocyanato-4methyl-2-pentanone, the trans isomers of the new ring systems pyrimido- [4,5-b]isoquinoline-1(2H)-thione 16b were formed in moderate yields.Not even traces of the corresponding cis counterparts 15a, 16a could be detected in the crude products.The trans arrangements of the hydrogen at the annelation of rings B/C (H-12b or H-6a) and the methyl substituent at the annelation of the rings C/D (Me-14a or Me-4a) were deduced from the lack of their cross-peaks in the NOESY spectra of the isolated tetracycles 15b and 16b.

Conformations
For nitrogen-bridged saturated heterocycles, the steric structure can be characterized by conformational equilibria of cis 1 -trans-cis 2 type.In the trans structure, rings B/C are transconnected, with the trans-diaxial arrangement of the hydrogen at the annelation and the nitrogen lone pair.In the two other configurations, rings B/C are cis-connected, where for the cis 1 conformation the hydrogen at the annelation is in the equatorial position, while for the cis 2 conformation it is in the axial position relative to tetrahydropyridine ring B. [6][7][8]10 For 13-16, only the geometries of the rings B/C could be determined, since the thioxo group makes the nitrogen at the neighboring annelation (rings C/D) nearly planar (for the meanings of rings B-D see the Schemes 4 and 5).
To determine the mode of connection of rings B/C, 2D NMR spectroscopic methods were used, since the cis or trans connections of these rings produce different patterns of the crosspeaks derived from the 1,3-diaxial protons in the NOESY spectra.proved that for 13 and 14 both isomeric structures are stable and that 15b and the 16b are more stable than 15a and 16a, as shown in Fig. 1.This is in good accordance with the observed diastereomeric ratios in the crude tetracylic products 13-16.
The steric structures of the typical minimum-energy molecular structures for 13-16 (Fig. 2) are in good accordance with the experimental results, involving trans-arranged rings B/C for 13b, 14a and 14b and the cis junction of rings B/C for 15b and 16b.

Experimental Section
General.NMR spectra were recorded in CDCl 3 at 298 K on a Bruker Avance III 600 spectrometer operating at 600.2 MHz for 1 H and 150.05 MHz for 13 C.Chemical shifts are reported in δ (ppm) relative to TMS as internal standard; the values of J are given in Hz.Mass spectra were recorded on a Finnigan MAT 95S instrument, using electron impact ionization.Elemental analyses were performed with a Perkin-Elmer 2400 CHNS elemental analyzer.Melting points were recorded on a Kofler hot-plate microscope apparatus and are uncorrected.For column chromatography, silica gel 60 (0.063-0.200 mm) was used.Routine thin-layer chromatography was performed on silica gel 60 F 254 plates (Merck, Germany).

Figure 1 .
Figure 1.The energy differences between the cis (a) and trans (b) diastereomeric structures of 13-16.