This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2+2 +2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio-and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddolbased to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

Excess substrate has been identified as an unintended spectator ligand affecting enantioselectivity in the [2+2+2] cycloaddition of alkenyl isocyanates with tolanes. Replacement of excess substrate with an exogenous additive affords products with consistent and higher ee's. The increase in enantioselectivity is the result of a change in composition of a proposed rhodium(III) intermediate on the catalytic cycle. The net result is a rational probe of a short-lived rhodium(III) intermediate, and gives insight that may have applications in many rhodium catalyzed reactions.The efficacy of transition-metal catalyzed transformations relies ultimately on the ability to finetune the chemical environment of a metal catalyst in different ways. One can alter catalyst activity both electronically and sterically by manipulating the ligand environment, which can lead to changes in product, chemo-, regio-and enantioselectivity. Understanding the mechanistic details of these observed changes can lead to synthetically useful solutions resulting from manipulation of unobserved reaction intermediates. Additives have been recognized as indispensible tools in an effort "towards perfect asymmetric catalysis". 1 A handful of reports describe changes in selectivity with the introduction of spectator (chiral or achiral) ligands, but the source of these effects remains unaddressed. In the context of our recent studies on asymmetric rhodium-catalyzed [2+2+2] cycloadditions involving alkenyl isocyanates, 5,6 we had occasion to study diaryl acetylenes (tolanes). The advent of GUIPHOS (L1) proved crucial for obtaining high enantioselectivities with product selectivity favoring vinylogous amide adduct 3 (Fig. 1). 7 An initial substrate screen revealed extreme variation in enantioselectivity (Fig. 1). No linear trend was reconcilable on the basis of either sterics or electronics. Sterically, the parasubstituent is much too distant to undergo through-space interactions with either the ligand or the olefin-metal bond, while electronic communication through π bonds is restricted since the arene rings are likely bent out of coplanarity due to strong A 1,3 strain (I in Fig. 2). Alternately, this variation may be explained by coordination of a second alkyne on an octahedral rhodium (III) intermediate (II or III) rather than a 5-coordinate intermediate (I) (Fig. 2). 8Olefin insertion into the rhodacycle thus occurs through several possible diastereomers, via transition states whose relative energy is affected by the close electronic and steric communication with the spectator alkyne, leading to product with variant ee's. 9As a test of this hypothesis, we designed a competition experiment between two different alkynes, which alone give products of different ee (Fig. 3). In this experiment, the ee of 3a was affected by the presence of 2f in the reaction mixture. This result is consistent with a second alkyne present during the enantiodetermining step (Fig. 2).During the course of these studies, we noted that electronically similar substrates 2e ...

The dechlorination of substituted aryl chlorides using a homogeneous palladium catalyst system and sodium formate in refluxing methanol is described. The catalyst was formed in situ from the air-stable precursors 2-(di-tert-butylphosphino)biphenyl and Pd(OAc)2. The reaction conditions were successful for a range of aryl chlorides with activating and deactivating groups at a position para to the chloride. The reactions gave high yields (90−98%) of the product of reduction within several hours.

Excess Substrate Is a Spectator Ligand in a Rhodium-Catalyzed Asymmetric [2 + 2 + 2] Cycloaddition of Alkenyl Isocyanates with Tolanes. -Methyl nicotinate proves to be the ideal additive to achieve high yields and enantioselectivities of the products, regardless of the electronic effects in the alkyne part. In the case of (IIa) a higher yield is obtained using 4 equiv. of PhCN. -(OINEN, M. E.; YU, R. T.; ROVIS*, T.; Org. Lett. 11 (2009)

Caution, alkyl acyl azides can rapidly decompose with heat to release large amounts of nitrogen. Care should be taken during handling: do not attempt to convert neat and avoid handling neat.