Azaindoles

Anthony CarestiaGroup Meeting Presentation

What are Azaindoles?

• Indole bioisostere

• Not prevalent in nature

• 7-azaindole is the most common• Uses as organometallic ligand

• Interesting photophysical properties

• Kinase Inhibitors

Heterocyclic Chemistry, Fifth Edition, 2010Chem. Rev. 2009, 109, 3080–3098Molecules 2014, 19, 19935-19979

Kinase

ATP

Retrosynthetic Analysis

N1-C2 Bond Forming Reactions• Modified Reissert Synthesis

• Modified Batcho-Leimbgruber Synthesis

Arkivoc, 2004, v, 286-300Bioorg. Med. Chem. Lett. 2005, 15, 977-982

Eli Lily’s Synthesis of 5-HT1 Receptor Agonists

• 5-HT1 receptor agonist

• Anti-migrane compounds

• Exhibit undesired side effects

J. Med. Chem. 2003, 46, 3060-3071

N1-C2 Bond Forming Reactions• Lithiation of methylamino pyridines

• Lithiation to form the N1-Pyridine Bond

Chem. Soc. Rev., 2007, 36, 1120–1132

Retrosynthetic Analysis

N1-Pyridine Bond Forming Reactions• Modified Hemetsberger-Knittel Synthesis

• Scope of pyridyl substitution

Synthesis 2005, 16, 2751–2757

Total Synthesis of Variolin B

Chem. Rev. 2009, 109, 3080–3098

Retrosynthetic Analysis

Building the Pyridine Ring• Ruthenium cycloisomerization

• Combinatorial approach

J. Am. Chem. Soc. 2006, 128, 4592-4593ACS Comb. Sci. 2012, 14, 434−441

Building the Pyridine Ring• Ruthenium cycloisomerization

• Combinatorial approach

• 22 aldehyde• 4 aminopyrroles• Yields range from 22-97%• 65 different examples

J. Am. Chem. Soc. 2006, 128, 4592-4593ACS Comb. Sci. 2012, 14, 434−441

Retrosynthetic Analysis

Azaindoles from Alkynes

• Tandem Sonogashira-Cyclization

Chem. Soc. Rev., 2007, 36, 1120–1132

Alkyne Cyclization to Form Azaindoles• Base mediated cyclization

• Electrophile mediated cyclization

• Amino-palladation cyclization

Synlett, 2005, 20, 3121Tetrahedron Lett., 2004, 45, 539J. Comb. Chem., 2005, 7, 510

Larock Heteroannulations• Larock Heteroannulation Mechanism

• First heteroannulation to form azaindoles

• Higher yields are attained with LiCl additives

Tetrahedron Lett., 1993, 34, 2823Tetrahedron Lett., 1998, 39, 627

Merck’s Synthesis of GnRH Antagonists• 7-azaindole GnRH antagonist

• 6-azaindole GnRH antagonist

Tetrahedron Lett., 2001, 42, 6441-6445

Conclusions• Azaindole cores are interesting motifs found in man-made biologically active compounds

• There’s not one best method for making azaindoles

• Reissert and Batcho-Leimgruber are the most common

• Larock Heteroannulation seems the most versatile

• Building off pyrrole core is very underrepresented