NMR SPECTRAL ASSIGNMENTS AND X-RAY CRYSTALLOGRAPHY OF 4,5,8,12b- TETRAHYDRO-ISOINDOLO[1,2-a]ISOQUINOLINE AND DERIVATIVES

12b-Hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (4), 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline (5) and 12b-hydroxy-5,6,8,12btetrahydroisoindolo[1,2-a]isoquinoline (6) were obtained by reduction of 4,5,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (3) with LiAlH4/THF/N2. The precursor and products were characterized by NMR spectroscopy and the X-ray crystal structure of 5 hydrochloride monohydrate (5a) was determined. 1H and 13C NMR spectra were completely assigned for compounds 3, 4, and 5a, using two-dimensional experiments (H-H COSY, HMQC, HMBC and H-H NOESY). e-mail: [email protected] INTRODUCTION The isoindolo[1,2-a]isoquinoline structure (1) is a rigid tetracyclic ring system that has been poorly investigated. This system, as the 5,6-dihydro8(12bH)one derivative, was first reported in 1968,1 and later found in a natural product named nuevamine (2), isolated from an extract of Berberis darwinii Hook., native to south-central Chile and Argentina.2,3 Several syntheses of 2 and, generally, the isoindolo[1,2-a]isoquinoline skeleton have been reported, but a systematic study of its analogues has been lacking in spite of the likelihood of some of these products having interesting pharmacological properties.3-5 Scheme 1. Reagents and conditions: a) LiAlH4/THF, reflux, N2, 72 h. RESULTS AND DISCUSSION Reduction of 4,5,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8one (3) with LiAlH4/THF for 48 h under N2 generated, in moderate yield, 12b-hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (4, 55%), plus small amounts of 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline (5, 6%) and a previously undocumented product,6 12b-hydroxy-5,6,8,12btetrahydroisoindolo[1,2-a]isoquinoline (6) in 3% yield. Walker and Kempton carried out this reduction under slightly different conditions, reporting 23% and 18% yields of 4 and 5, respectively.6 Compound 5 oxidizes rapidly in the presence of air, and therefore its hydrochloride 5a was prepared and studied. The complete 1H and 13C NMR assignments of compounds 3-5a, based on oneand two-dimensional NMR experiments (e.g. Figures 1 and 2; Figure 1 gives the atom numbering), are shown in Tables 1-3. The synthesis of a series of (±)-5,6,8,12b-tetrahydroisoindolo[1,2-a] isoquinoline-8-ones (3) bearing one to three methoxyl groups, a methylenedioxy group, a methoxyl and a hydroxyl, or two hydroxyl groups on ring A was reported a couple of years ago,4 following a general route that involved acid-catalyzed cyclization of the corresponding 3-hydroxy-2-(substituted phenyl)ethylisoindol-1-ones. The reactivity of these systems has been poorly investigated.1 A particularly surprising observation was that attempts to obtain the corresponding tertiary amine (5) from 3 by treatment with LiAlH4 in THF generated the 12b-hydroxy derivative (4) of 3 as the major product, plus a very low yield of 5 (Scheme 1).6 We have now confirmed that the LiAlH4 reduction of lactam 3 generates the expected 5 and a high yield of 4, together with the previously unreported 6. In particular, we have provided convincing proof of the structure of 5 (as its hydrochloride monohydrate 5a) based on a complete study of its 1H and 13C NMR spectra, those of 3 and 4, and an X-ray crystallographic analysis of 5a. In addition, 6 was found to participate in a ring-breaking tautomeric equilibrium that hindered its spectral assignments. Tertiary amines related to 5 and 6 have not been found in nature, and to the best of our knowledge only one direct synthesis of such compounds has been reported very recently.7 Figure 1. a) Numbering schemes of the 5,6,8,12b-tetrahydroisoindolo[1,2-a] isoquinolin-8-one skeleton and b) COSY correlations in 3. J. Chil. Chem. Soc., 57, No 1 (2012) 973 Figure 2. a) COSY and b) NOESY correlations for 5a. Table 1. 1H chemical shifts (d) [H-X, multiplicity, J(H,H) (Hz)]a and 13Ca chemical shifts (d) of 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (3). 3 Carbon d 1H d 13C HMBCb COSYc NOESYd 1 7.75 [H-1, d, J(1,2) = 7.5] 125.7 3, 4a, 12b 2, 12b 12, 12b 2 7.28 [H-2, t, J(2,3) = J(2,1) = 7.5] 126.5 4, 12c 1, 3 3 7.22 [H-3, t, J(3,4) = J(3,2) = 7.5] 127.1 1, 4a 2, 4 4 7.19 [H-4, d, J(3,4) = 7.5] 129.1 2, 5, 12c 3 5 (both) 4a 134.4 1, 3, 6, 12b 5 2.83 [H-5α, m], 2.98 [H-5β, m] 28.79 4, 4a, 6, 12c 6α, 6β 4, 6 (both) 6 3.56 [H-6α, ddd, J = 12.9, 11.5, 4.5 Hz, 1H], 4.32 [H-6β, ddd, J = 13.0, 6.1, 2.2 Hz, 1H] 37.58 4a, 5, 8, 12b 6 (both), 5 5, 12b(α) 7 8 166.7 6, 9, 12b 8a 132.1 10, 12, 12b 9 7.67 [H-9, d, J(9,10) = 7.5] 131.7 8, 11, 12a 10 10 7.53 [H-10, t, J(10,9) = J(10,11) = 7.3] 128.5 8a, 12 9, 11 11 7.72 [H-11, t, J(11,10) = J(11,12) = 7.5] 122.9 9, 12a 10, 12 12 8.10 [H-12, d, J(12,11) = 7.6] 124.3 8a, 10, 12b 11,12b 1, 12b 12a 144.6 9, 11, 12b 12b 5.85 [H-12b, s] 58.48 1, 4a, 6, 8a, 12, 12a, 12c 1,12 1, 12 12c 134.5 2, 4, 5, 12b a In ppm from TMS; b H,C HMBC, c H-H COSY and d H-H NOESY connectivities. Table 2. 1H chemical shifts (d) [H-X, multiplicity, J(H,H) (Hz)]a and 13Ca chemical shifts (d) of 12b-hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin8-one (4). 4 Carbon d 1H d 13C HMBCb COSYc 1 8.02 [H-1, d, J(1,2) = 7.6] 127.9 3, 4a, 12b 2 2 7.29 [H-2, t, J(2,3) = J(2,1) = 7.5] 126.4 4, 12c 1, 3 3 7.23 [H-3, t, J(3,4) = J(3,2) = 7.5] 128.0 1, 4a 2, 4 4 7.16 [H-4, d, J(3,4) = 7.5] 129.0 2, 5, 12c 3