Aryne Formation from 2-Bromolaudanosine. Fate of the 5,6,12,12a-Tetrahydrodibenzo[b,g]indolizinium Ion and an Alternative Synthesis of Glaucine

Abstract

A synthesis of 2-bromolaudanosine (10) is described. The aryne formed from 10 and amide ion in ammonia yields the corresponding 5,6,12,12a-tetrahydrodibenzo[b,g]indolizinium ion (13) by intramolecular capture, and 2-aminolaudanosine (11) by external addition of amide ion. Compound 13 is converted insitu to 5,6-dimethoxy-2-(4,5-dimethoxy-2-vinylphenyl)-1-methylindoline (14) and 5,6-dimethoxy-2-(4,5-dimethoxy-2-ethylphenyl)-1-methylindole (15). Compound 11 provides an alternative source of glaucine (12).

The synthesis of 2′,2′-bis-benzylisoquinolines and their cytostatic activities

“…12 The iodides 6 and 7 are new compounds, while the corresponding 2'-bromo analogues of these compounds are known. 13 Heating compound 7, or its corresponding 2'-bromo derivative, in the presence of copper-bronze at 220 o C under solvent free conditions for 1.5 h lead to quantitative decomposition of the material and no recognisable products could be isolated. An alternative and successful synthesis of 2 and 3 is shown in Scheme 3, this synthesis involved formation of the key biaryl bond early in the synthesis and then construction of the isoquinoline rings.…”

“…An alternative and successful synthesis of 2 and 3 is shown in Scheme 3, this synthesis involved formation of the key biaryl bond early in the synthesis and then construction of the isoquinoline rings. To this end several methods to prepare the known biphenyl 9 [13][14][15] were examined (Scheme 2). Under traditional Ullmann coupling reaction conditions, 13 heating compound 8 in the presence of copper-bronze at 220 o C under solvent free conditions for 1.5 h gave the desired biphenyl 9 in 69 % yield.…”

“…To this end several methods to prepare the known biphenyl 9 [13][14][15] were examined (Scheme 2). Under traditional Ullmann coupling reaction conditions, 13 heating compound 8 in the presence of copper-bronze at 220 o C under solvent free conditions for 1.5 h gave the desired biphenyl 9 in 69 % yield. When the corresponding bromo analogue of 8 was employed the yield of 9 was reduced to 45 % due to the formation of the debromo-derivative 10.…”

“…1 H NMR: δ 7.19 (s, 1H, Ar-H-3), 6.77 (s, 1H, Ar-H-6), 6.71 (d, 1H, J = 8.1 Hz, Ar-H-5'), 6.64 (d, 1H, J = 2.1 Hz, Ar-H-2'), 6.58 (dd, 1H, J = 8.1, 2.1 Hz, Ar-H-6'), 5.41 (t, J = 6.9Hz, 1H, NH), 3.87 (s, 3H, OCH 3 -4), 3.85 (s, 3H, OCH 3 -4'), 3.84 (s, 3H, OCH 3 -3'),3.82 (s, 3H, OCH 3 -5), 3.60 (s, 2H, Ar-CH 2 ), 3.47 (q, 2H, J = 6.9 Hz, Ar-CH 2 -CH 2 -NH), 2.71 (t, 2H, J = 6.9, Ar-CH 2 -CH 2 -NH) 13. C NMR: δ 169.6 (C=O), 149.6 (Ar-C-OCH 3 -5), 149.0 (Ar-C-OCH 3 -3'), 148.7 (Ar-C-OCH 3 -4), 147.6 (Ar-C-OCH 3 -4'), 130.9 (Ar-C-1), 130.5 (Ar-C-1'), 121.6 (Ar-C-H-3), 120.5 (Ar-C-H-6'), 113.0 (Ar-C-H-6), 111.7 (Ar-C-H-5'), 111.1 (Ar-C-H-2'), 88.8 (Ar-C-2), 56.1 (Ar-OCH 3 ), 55.9 (Ar-OCH 3 ), 55.84 (Ar-OCH 3 ), 55.81 (Ar-OCH 3 ), 48.1 (Ar-CH 2 -CO), 40.6 (Ar-CH 2 -CH 2 -NH), 35.8 (Ar-CH 2 -CH 2 -NH).…”

“…M.P. 162-164 o C. Hz, Ar-H-2), 6.58 (s, 1H, Ar-H-6'), 6.55 (dd, J = 8.1, 2.1 Hz, Ar-H-6), 5.78 (t, 1H, J = 5.4 Hz, NH), 3.87 (s, 3H, OCH 3 -4'), 3.85 (s, 3H, OCH 3 -4), 3.81 (s, 3H, OCH 3 -3), 3.80 (s, 3H, OCH 3 -5'), 3.35 (dt, 2H, J = 6.9, 5.4 Hz, Ar-CH 2 -CH 2 -NH), 3.23 (ABq, 2H, J = 15.3Ar-CH 2 -CO), 2.66 (t, 2H, J = 6.9, Ar-CH 2 -CH 2 -NH) 13. C NMR:  171.1 (C=O), 148.Ar-C-OCH 3 -5'), 148.5 (2x Ar-C-OCH 3 -4, 4'), 147.6 (Ar-C-OCH 3 -5), 132.6 (Ar-C-2'), 131.0 (Ar-C-1), 125.7 (Ar-C-1'), 120.5 (Ar-C-H-6), 113.2 (Ar-C-H-6'), 112.4 (Ar-C-H-3'), 111.6 (Ar-C-H-2), 111.1 (Ar-C-H-5), 56.0 (Ar-OCH 3 ), 55.9 (Ar-OCH 3 ), 55.8 (Ar-OCH 3 ), 55.7 (Ar-OCH 3 ), 40.8 (Ar-CH 2 -CH 2 -NH), 40.6 (Ar-CH 2 -CO), 34.9 (Ar-CH 2 -CH 2 -NH).…”