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Abstract A modular platform for facile access to 1,2,3,9‐tetrahydro‐4H‐carbazol‐4‐ones (H₄‐carbazolones) and 3,4‐dihydrocyclopenta[b]indol‐1(2H)‐ones (H₂‐indolones) is described. The requisite 6‐ and 5‐membered 2‐arylcycloalkane‐1,3‐dione precursors were readily obtained through a Cu‐catalyzed arylation of 1,3‐cyclohexanediones or by a ring expansion of aryl succinoin derivatives. Enolization of one carbonyl group in the diones, conversion to a leaving group, and subsequent azidation gave 2‐aryl‐3‐azidocycloalk‐2‐en‐1‐ones. This two‐step, one‐pot azidation is highly regioselective with unsymmetrically substituted 2‐arylcyclohexane‐1,3‐diones. The regioselectivity, which is important for access to single isomers of 3,3‐disubstituted carbazolones, was analyzed mechanistically and computationally. Finally, a Rh‐catalyzed nitrene/nitrenoid insertion into theorthoC−H bond of the aryl moiety gave the H₄‐carbazolones and H₂‐indolones. One carbazolone was elaborated to an intermediate reported in the total synthesis ofN‐decarbomethoxychanofruticosinate, (−)‐aspidospermidine, (+)‐kopsihainanine A. With 2‐phenylcycloheptane‐1,3‐dione, prepared from cyclohexanone and benzaldehyde, the azidation reaction was readily accomplished. However, the Rh‐catalyzed reaction unexpectedly led to a labile but characterizable azirine rather than the indole derivative. Computations were performed to understand the differences in reactivities of the 5‐ and 6‐membered 2‐aryl‐3‐azidocycloalk‐2‐en‐1‐ones in comparison to the 7‐membered analogue, and to support the structural assignment of the azirine. 

Abstract Several naturally occurring purine and pyrimidine nucleosides contain an amide linkage as part of the heterocyclic aglycone. Enolization of the amide and conversion to leaving groups at the amide carbon atom permits base modification by addition‐elimination types of processes. Although a number of methods have been developed over the years for accomplishing such conversions, the present Personal Account describes efforts from the Lakshman laboratories. Facile activation of the amido groups in nucleobases can be achieved with peptide‐coupling agents. Subsequent reaction with nucleophiles then accomplishes the base modifications. In many cases, the activation and displacement steps can be done as two‐step, one‐pot processes, whereas in other cases, discrete storable activated nucleosides can be isolated for subsequent displacement reactions. Using such an approach a wide range of nucleoside base modifications is readily achievable. In many instances, mechanistic investigations have been conducted so as to understand the activation process. 

The purinyl nitrogen atom is an effective metalation director, which in the presence of Pd(OAc)₂,t-BuOOH, and aryl aldehydes, leads to acylation of the aryl ring at the C6 position of the purine. 

Synthesis of the COVID drug β-d-N⁴-hydroxycytidine (NHC) and its prodrug, molnupiravir, has been achievedviatwo chemical routes. 

The described laboratory experiment has been designed to introduce undergraduate students to multiple organic chemistry laboratory techniques by conducting catalytic hydrogenation of the E-isomer of cinnamyl alcohol, but without the use of compressed hydrogen gas. The combination of tetrahydroxydiboron (B2(OH)4, a solid), a tertiary amine (4-methylmorpholine, 4-MM), and 5% Pd/C allows the harvested hydrogen gas produced in situ to reduce the olefin. This protocol allows a demonstration of this powerful addition reaction that is taught early in sophomore organic chemistry, while eliminating the hazards associated with the storage and use of compressed hydrogen gas. The key laboratory techniques incorporated, besides the reaction setup, are development and visualization of thin-layer chromatograms, column chromatography over silica-gel, and solvent extraction. For product analysis, the 1H, 13C{1H}, and HMQC NMR spectra of cinnamyl and the hydrogenated hydrocinnamyl alcohols are obtained. Herein, we show two spectra of products obtained, one containing only product and the other containing an overreduction product. This provides an opportunity to discuss calculation of product ratios and to reinforce NMR spectroscopy concepts. The entire protocol would constitute activities associated with conducting a reaction, isolating, and evaluating the product. In our labs two undergraduate students, one with two semesters of undergraduate organic chemistry and the other with no prior organic chemistry laboratory experience performed the laboratory protocol and the collection and analysis of NMR data. At the end of the experiment, they were evaluated by a post-laboratory report. 

Cross-dehydrogenative coupling reactions have been utilized to alkylate 4(3H)-quinazolinones with ethers and amides, using catalytic n-Bu4¬NI and t-BuOOH as oxidant. Reactions with amides represent the first examples under such conditions. Studies via inter- and intramolecular competitive experiments with protio and deuterio reactants, as well as radical inhibition experiments, provided mechanistic insight. Also, an understanding of the relative reactivities of ethers was obtained by pairwise competitions with 4(3H)-quinazolinone. 

The potentially versatile N-unprotected 8-formyl derivatives of adenosine and 2’-deoxyadenosine are highly underexploited for C8 modifications of these nucleosides. Only in situ formation of 8-formyladenosine is known and a single application of an N-benzoyl derivative has been reported. On the other hand, 8-formyl-2’-deoxyadenosine and its applications remain unknown. Herein, we report straightforward, scalable syntheses of both N-unprotected 8-formyladenine nucleoside derivatives, and demonstrate broad diversification at the C8 position by hydroxymethylation, azidation, CuAAC ligation, reductive amination, as well as olefination and fluoroolefination with modified Julia and a Horner-Wadsworth-Emmons reagents. 

Among the C6 halo purine ribonucleosides, the readily accessible 6-chloro derivative has been known to undergo slow SNAr reactions with amines, particularly aryl amines. In this work, we show that in 0.1 M AcOH in EtOH, aryl amines react quite efficiently at the C6 position of 2’,3’,5’-tri-O-(t-BuMe2Si)-protected 6-chloropurine riboside (6-ClP-riboside), with concomitant cleavage of the 5’-silyl group. These two-step processes proceeded in generally good yields and notably, reactions in the absence of AcOH were much slower and/or lower yielding. Corresponding reactions of 2’,3’,5’-tri-O-(t-BuMe2Si)-protected 6-ClP-riboside with alkyl amines proceeded well but without desilylation at the primary hydroxyl terminus. These differences are likely due to the acidities of the ammonium hydrochlorides formed in these reactions, and the role of AcOH was not desilylation but possibly only purine activation. With 50% aqueous TFA in THF at 0 oC, cleavage of the 5’-silyl group from 2’,3’,5’-tri-O-(t-BuMe2Si)-protected N6 alkyl adenosine derivatives and from 6-ClP-riboside was readily achieved. Reactions of the 5’-deprotected 6-ClP-riboside with alkyl amines proceeded in high yields and under mild conditions. Because these complementary methodologies yielded N6 aryl and alkyl adenosine derivatives containing a free 5’-hydroxyl group, a variety of product functionalizations was undertaken to yield N6,C5’ doubly modified nucleoside analogues.