Suneel P. Singh

The Directed ortho Metallation-Cross- Coupling Fusion: Development and Application in Synthesis

Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada *Email: victor.snieckus@chem.queensu.ca This review constitutes a detailed but non-exhaustive examination of the directed ortho metallation (DoM)– cross-coupling fusion in its many fl avours. Special attention is paid to the application of the concept of the linked reactions and the synthetic utility that it endows, particularly in the case of one-pot reactions that can greatly increase the ease and effi ciency of the process. Personal experience of particular issues that can arise from these reactions and examples of their solutions are given, as well as illustrations of the rapid access to complex molecules that the technique encourages.

Synthesis of 2-Trifluoromethylquinolines via a [2+3] Cycloaddition

13 Y . L I , L . Z HA N G , L . Z H A N G, Y . WU , * Y . G ON G * ( SH A N G H A I I N ST I T UT E O F O RG A N I C C H E M I S T R Y, H U AZ HO N G U N I V E R S I T Y O F S C I E N C E A N D TE C H N OL OG Y, WU HA N , A N D S H A N G H A I UN I V E R S I T Y, P. R . O F C H I NA ) Cu-Catalyzed Tandem Reactions of Fluorinated Alkynes with Sulfonyl Azides En Route to 2-Trifluoromethylquinolines Org. Biomol. Chem. 2013, 11, 7267–7270.

Pd-Catalyzed Synthesis of Indeno[1,2-c]chromenes from 2-Alkynylhalobenzenes

Significance: Reported is the synthesis of indeno[1,2-c]chromenes 3 and 4 via a palladiumcatalyzed reaction of 2-alkynylbromobenzenes 1 with either 2-(2-arylethynyl)phenols 2 or with water. A range of ligands was used during the optimization study to reveal that the reaction proceeds only with Cy3P as ligand (eq. 1). Sodium methoxide in toluene or 1,4-dioxane was better than other combinations. The substrate scope of this transformation was modestly demonstrated. The reaction also proceeded to give 3 in 78% yield by treatment of 1-chloro-2-(2-phenylethynyl)benzene with 2 (R3 = H, R4 = Ph). Surprisingly, re-optimization was required in the reaction of 1 with water (eq. 2). Both alkyland aryl-substituted alkynes were tolerated under the optimized conditions. However, the reaction parameters had to be rescreened to give a satisfactory yield of compounds with electron-withdrawing groups (R2 = 4-ClC6H4, 4-AcC6H4). Comment: The [6.5.6.6]-tetracyclic core of indenochromenes 3 and 4 is present in several bioactive compounds (B. S. Min et al. Bioorg. Med. Chem. Lett. 2012, 22, 7436). Very few synthetic methods such as iron-mediated [3+2]-annulation reactions are available to provide access to this tetracyclic system (Z.-Q. Wang et al. Org. Lett. 2011, 13, 14). The present method provides a rapid construction of various substituted indenochromenes from easily accessible starting materials. One drawback of this method is the lower yield for electron-poor substrates. Although, this work provides a facile synthesis of indeno[1,2-c]chromenes, it is strikingly similar to the authors’ previous work (Y. Luo, L. Hong, J. Wu Chem. Commun. 2011, 47, 5298) . 19 examples 63–96% yield

Palladium-Catalyzed C–N/C–C Coupling Route to Substituted Indoles

Significance: Reported is the one-pot synthesis of highly substituted indoles 4 via a sequential palladium-catalyzed C–N and C–C coupling reaction of o-bromoiodo arenes 1, carbonyl derivatives 3, and amines 2. The reaction is proposed to proceed by C–N coupling to generate aryleneamine intermediate 5 which undergoes an intramolecular arene–alkene coupling reaction (eq 1). This sequence of events is supported by an adequate number of experiments. The authors also suggest that the mechanism of the final step differs from a traditional Heck reaction. Among several ligands, bases and solvents tested, 1,1′-bis(diphenylphosphanyl)ferrocene (dppf) in combination with a weak base (Cs2CO3) in toluene was suited best. The addition of MgSO4 proved beneficial, presumably by favoring eneamine formation. The reaction failed when Pd(OAc)2 was used in place of Pd2dba3. Both aldehydes and cyclic/acyclic ketones gave moderate yields of indoles. Two examples of azaindoles (Y = N) were also reported. A pyridine derivative (R3 = 4-py) was also tolerated. Comment: The synthesis and functionalization of indoles has been a major area of focus for organic chemists due to its importance in the pharmaceutical field (see Book below). Numerous synthetic methods for indoles including Fischer indole synthesis and its modifications have been reported (see Review below). The current one-pot threestep method provides highly functionalized indoles in moderate yield using readily available starting materials. Although it was indicated that the reaction failed with a carbomethoxy derivative of 3, the reaction scope and limitations were not well investigated.