N Ring-Forming Reactions by Transition Metal-Catalyzed

C-N Ring-forming Reactions by Transition Metal-catalyzed Intramolecular Alkene Hydroamination 

Alkene hydroamination has been known for many years, but has been little used as a method in organic synthesis. Tobin Marks of Northwestern recently published a series of three papers that will make this transformation much more readily accessible. In the first (J. Am. Chem. Soc. 125 12584, 2003) he describes the use of a family of lanthanide-derived catalysts for intermolecular hydroamination of alkynes (to make imines, not illustrated) and alkenes. With aliphatic amines, the branched (Markownikov) product is observed, 1 — 2. With styrenes, the linear product is formed. When two alkenes are present, the reaction can proceed (3 — 4) to form a ring, with impressive regioselectivity. 

The products from alkene hydroamination are inherently lightly functionalized. To address this possible deficiency, Professor Marks also reported (J. Am. Chem. Soc. 125 15878, 2003) the cyclization of amino dienes such as 5. The cyclizations proceed with high selectivity for the cis-2,6-dialkyl piperidines, and with a little lower selectivity for the trans 2,5-dialkyl pyrrolidine. The product alkenes are -95% E, the balance being a little Z alkene and the terminal alkene. 

More complex substrates can also be cyclized efficiently using these catalysts. Professor Marks and his colleague Frank McDonald, now at Emory University, report (J. Org. Chem. 69, 1038, 2004) that the amino diene 7 cyclizes to 8 with 81 19 diastereoselectivity. It is particularly 

The diterpene (+)-Phomactin A 4 is an antagonist of platelet activating factor. The preparation of 4 recently reported (J. Am. Chem. Soc. 125 1712, 200.3) by Randall Halcomb of the University of Colorado elegantly illustrates the use of readily-available natural products as starting materials for natural product synthesis. 

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C-N Ring-Forming Reactions by Transition Metal-Catalyzed Intramolecular Alkene Hydroamination... 

Based on these precedents for C—X bond formation between C=N and alkene intermediates (derived from alkynes), the Larock group developed the first transition-metal-mediated pyridine ring formation by direct reaction between C=N and alkynes. Using terminal alkynes 11, rcrt-butylimines 10 were subjected to Sonogashira coupling followed by Cu(I)-catalyzed annulation to afford isoquinolines or pyridines 12 in moderate to good yields (46 to 95%, Scheme 19.5) [5]. A variety of terminal alkynes and aryl/alkenyl halides can be used in the reaction. The stepwise reaction also worked well to form the same products. Similarly, p- and y -carbolines were synthesized effectively, as shown in Scheme 19.6 [6]. 

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