Chemoselective Reductive Nucleophilic Addition to Tertiary Amides, Secondary Amides, and N-Methoxyamides

• Published in: Chemistry : a European journal Vol. 20; no. 52; pp. 17565 - 17571
• Main Authors: Nakajima, Minami, Oda, Yukiko, Wada, Takamasa, Minamikawa, Ryo, Shirokane, Kenji, Sato, Takaaki, Chida, Noritaka
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 22.12.2014; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Alkaloids; Alkaloids - chemical synthesis; Alkaloids - chemistry; Amides; Amides - chemical synthesis; Amides - chemistry; Amines - chemistry; Carbonyls; Chemical Phenomena; Chemistry; Chemistry, Multidisciplinary; chemoselectivity; Compatibility; Esters; Functional groups; Molecular Structure; nitrogen; Nucleophiles; nucleophilic addition; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Physical Sciences; Science & Technology; sequential reactions; Spectrum analysis; Stereoisomerism; Synthesis (chemistry); chemoselectivity; amides; sequential reactions; nitrogen; ALKYLATION; BOND FORMATION; LACTAMS/AMIDES; ORGANOMETALLIC REAGENTS; DIRECT TRANSFORMATION; VERSATILE; ALPHA-ACETOXY ETHERS; nucleophilic addition; GRIGNARD-REAGENTS; ALKALOIDS
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201404648

As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N‐methoxyamides that uses the Schwartz reagent [Cp2ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups. A chemoselective nucleophilic addition to tertiary amides, secondary amides, and N‐methoxyamides was developed. The reaction showed high functional‐group compatibility despite the poor electrophilicity of the amide carbonyl center (see scheme; Boc=tert‐butoxycarbonyl, Cbz=carbobenzyloxy, Ts=tosyl, Ns=nosyl, MOM=methoxymethyl, THP=tetrahydropyran).