The ambiphilic vinylcarbenoid reactivity of (α-(tributylstannyl)-π-allyl)palladium(II) species is demonstrated by the reaction of acetoxystannanes with Pd(dba)2, which promotes electrophilic metal−carbene reactions such as dimerization and cyclopropanation of strained alkenes. On the other hand, Pd(PPh3)4 and dppe revealed the nucleophilic nature of the dimetallic intermediates through sequential reactions of the carbon−metal bonds with dimethyl malonate.

New synthetic methods for the construction of novel heterocycles and tryptamines are described. Thus, N-Boc anilines (I) are sequentially converted to heterocycles II ((3-(2-aminophenyl)pyrrolidin-3-ol) derivatives), III (substituted 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines), and VI (2-(4,5-dihydro-1H-pyrrol-3-yl)aniline) derivatives through a route involving t-BuLi induced ortho-metalation/LaCl(3).2LiCl metal exchange, reaction with N-Boc pyrrolidin-3-one (5), and subsequent decarboxylative fragmentation. Labile intermediates VI are effectively converted to tryptamines Xa and Xb under controlled protic acid conditions. In addition to providing expedient access to the 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines (III), the method is applicable to the synthesis of the corresponding 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-piperidine series of spirocycles (e.g., 42) and their precursors (3-(2-aminophenyl)piperidin-3-ol derivatives, e.g., 43) by using N-Boc-protected piperidin-3-one (40). Applications of the developed synthetic technologies to the synthesis of regioisomeric spirocycles 87 and 90, tryptamines 88 and 91, Corey's aspidophytine tryptamine (97), and efavirenz (1) are also described.

The increasing number of heterocyclic natural products and the well known applications of heterocyclic chemistry to pharmaceutical research dictate the development of new synthetic methods for accessing heterocycles. Novel cascade reactions offer rapid assembly of molecular frameworks and have been employed in natural product and other complex molecule construction with impressive results.[1] In this communication, we report an expedient, cascade-based strategy for the construction of novel heterocyclic systems, including spiro-heterocycles, ortho-substituted anilines, and tryptamines.Scheme 1 depicts the general concepts for the construction of spiro-heterocycles (IV), ortho-substituted anilines (VIII), and tryptamines (XII) starting with readily available aniline derivatives (I). Thus, bis-metalation of aniline I to form reactive intermediate II, [2] and subsequent addition of N-Boc pyrrolidin-3-one (A) should lead to species III, whose ring closure as shown should offer an entry into spirocyclic system IV and derivatives thereof as stable chemical entities. Temporary capping of the active NH functionality within IV should allow a second cascade sequence initiated by regioselective base-induced deprotonation of intermediate V [3] to afford anionic species VI, whose collapse as shown should lead, sequentially, to intermediates VII (ring opening) and VIII (extrusion of CO 2 and hydrolysis of the N À X bond). The latter species represents a reactive class of ortho-substituted anilines whose potential remains relatively unexplored.[4] Scheme 1. General, cascade-based strategy for the construction of novel spiro-heterocycles (IV), ortho-substituted anilines (VIII), and tryptamines (XII). X = capping group; Boc = tert-butoxycarbonyl.