Daniel A. Clark

Regiodivergent Synthesis of Functionalized Indene Derivatives via Pt-Catalyzed Rautenstrauch Reaction of Propargyl Carbonates

A regiodivergent synthesis of functionalized indene derivatives from a Pt-catalyzed Rautenstrauch reaction of propargyl carbonate is described. A one-pot Rautenstrauch/Tsuji-Trost reaction delivering 2-indanones was realized efficiently using this methodology.

Synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-b]pyrazines by palladium catalyzed amidation of 2-chloro-3-amino-heterocycles

A facile synthesis of imidazo[4,5-b]pyridines and -pyrazines is described using a Pd-catalyzed amide coupling reaction. This reaction provides quick access to products with substitution at N1 and C2. A model system relevant to the natural product pentosidine has been demonstrated, as well as the total synthesis of the mutagen 1-Me-5-PhIP.

Total synthesis of pentosidine.

Pentosidine, a biologically important advanced glycation endproduct, has been accessed in a rapid, high-yielding manner. The synthesis was accomplished via a six-step sequence starting with 3-amino-2-chloropyridine and features a palladium-catalyzed tandem cross-coupling/cyclization to construct the imidazo[4,5-b]pyridine core.

Ruthenium catalyzed cycloisomerization of silicon-tethered 1,7-enynes to give exocyclic 1,3-dienes.

The cycloisomerization of vinyl silicon-tethered 1,7-enynes has been accomplished using catalytic Cp*Ru(COD)Cl. The products possess a new silane moiety and trisubstituted alkenes as part of the diene system. The reaction scope includes aryl, alkyl, vinyl, and cyclopropyl alkyne functionalities. Silicon was found not to be a mandatory component of the tether. The utility of the products was demonstrated through manipulation of the vinyl silane and Diels-Alder chemistry.

Ethylene transposition: ruthenium hydride catalyzed intramolecular trans-silylvinylation of internal alkynes.

A highly selective intramolecular trans-silylvinylation of internal alkynes catalyzed by RuHCl(CO)(SIMes)(PPh3) has been accomplished. The use of methyl vinyl ketone as an additive increased the efficiency of this transformation. This process was used to successfully form five-, six-, and seven-membered oxasilacycles by a formal anti-exo-dig cyclization.

Stereo- and Regioselective Formation of Silyl-Dienyl Boronates

The intramolecular trans-silylruthenation of internal alkynes and subsequent insertion of vinyl boronates is described. This approach provides complete regiocontrol through a stereoselective trans-5-exo-dig cyclization which affords a tetrasubstituted olefin as a vinylsilane and a highly functionalized Z,E diene motif.

Copper- and Palladium-Catalyzed Amidation Reactions for the Synthesis of Substituted Imidazo[4,5-c]pyridines

Imidazo[4,5-c]pyridines were synthesized in three steps utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl substrates were synthesized using copper-catalyzed amidation of 3-amino-N-Boc-4-chloropyridine. Complementary protocols for the selective chlorination of imidazo[4,5-c]pyridines at the C2 and C7 positions were also developed.

Synthesis of 2-amino-imidazo[4,5-b]pyridines

The C2 amination of imidazo[4,5-b]pyridines was accomplished through C2 halogenation followed by substitution (SNAr) with functionalized primary and secondary amines. This regioselective sequence is operationally simple and provides an easy access to derivatives of protected imidazo[4,5-b]pyridines.

Ruthenium Hydride Catalyzed Silylvinylation of Internal Alkynes Using Ethylene as an Additive

An efficient synthetic strategy for the regiospecific silylvinylation of internal alkynes is described. This transformation is catalyzed by RuHCl(CO)(SIMes)PPh3 and provides a net 5-exo-dig trans-silylvinylation of internal alkynes. Ethylene was used to decrease reaction times and displayed altered selectivity at increased pressure. Furthermore, alkyl-substituted alkynes were acceptable substrates at 80 psi of ethylene.

Synthesis of N-Substituted 3-Amino-4-halopyridines: A Sequential Boc-Removal/Reductive Amination Mediated by Brønsted and Lewis Acids

N-Substituted 3-amino-4-halopyridines are valuable synthetic intermediates, as they readily provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of N-substituted 3-amino-4-halopyridines is problematic, as reductive aminations and base-promoted alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described, providing access to a wide scope of N-substituted 3-amino-4-halopyridines. This protocol furnishes many reaction products in high purity without chromatography. Similar reductive amination conditions were also established for deactivated anilines.