Cross-dehydrogenative coupling and oxidativeamination reactions of ethers and alcohols with aromatics and heteroaromatics

Cross-dehydrogenative coupling (CDC) is a process in which, typically, a C–C bond is formed at the expense of two C–H bonds, either catalyzed by metals or other organic compounds, or via uncatalyzed processes. In this perspective, we present various modes of C–H bond-activation at sp3 centers adjacent to ether oxygen atoms, followed by C–C bond formation with aromatic systems as well as with heteroaromatic systems. C–N bond-formation with NH-containing heteroaromatics, leading to hemiaminal ethers, is also an event that can occur analogously to C–C bond formation, but at the expense of C–H and N–H bonds. A large variety of hemiaminal ether-forming reactions have recently appeared in the literature and this perspective also includes this complementary chemistry. In addition, the participation of C–H bonds in alcohols in such processes is also described. Facile access to a wide range of compounds can be attained through these processes, rendering such reactions useful for synthetic applications via Csp3 bond activations

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From 31P{1H}, [18O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO− and AtO− produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO− is a nucleofuge, several Bt-OCH2Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd π–allyl complexes by departure of BtO− has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis

Synthesis and Evaluations of “1,4-Triazolyl Combretacoumarins” and Desmethoxy Analogs

1,4-Triazolyl combretacoumarins have been prepared by linking the trimethoxyarene unit of combretastatin A4 with coumarins, via a 1,2,3-triazole. For this, 4-azidocoumarins were accessed by a sequential two-step, one-pot reaction of 4-hydroxycoumarins with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), followed by reaction with NaN3. In the reaction with BOP, a coumarin-derived phosphonium ion intermediate seems to form, leading to an O4-(benzotriazolyl)coumarin derivative. For the CuAAC reaction of azidocoumarins with 5-ethynyl-1,2,3-trimethoxybenzene, catalytic [(MeCN)4Cu]PF6 in CH2Cl2/MeOH with 2,6-lutidine, at 50 oC, was suitable. The 4-azidocoumarins were less reactive as compared to PhN3 and the NBO coefficients of the azido groups were compared by DFT analysis. Compound solubility was a problem in biological assays. On the basis of the biological and solubility data of one 1,4-triazolyl combretacoumarin, four analogs lacking one or two methoxy groups were synthesized. Reactivity differences among the phenylacetylenes were noted and the NBO coefficients of the alkynes were compared by DFT analysis. In cytotoxicity assays, 1-phenyl-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole showed activity in CEM and MDA-MB-231 cell lines by apoptosis. The desmethoxy 6-bromo-4-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one also showed cytotoxicity against the two cell lines, but this did not appear to be consistent with apoptosis. The antiviral activity of the compounds was unremarkable

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active

Synthesis of Deuterated 1,2,3-Triazoles

The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a highly effective method for the selective incorporation of deuterium atom into the C-5 position of the 1,2,3-triazole structure. Reactions of alkynes and azides can be conveniently carried out in a biphasic medium of CH₂Cl₂/D₂O, using the CuSO₄/Na ascorbate system. The mildness of the method renders it applicable to substrates of relatively high complexity, such as nucleosides. Good yields and high levels of deuterium incorporation were observed. A reaction conducted in equimolar H₂O and D₂O showed 2.7 times greater incorporation of hydrogen atom as compared to deuterium. This is consistent with the H⁺ and D⁺ ion concentrations in H₂O and D₂O, respectively. With appropriately deuterated precursors, partially to fully deuterated triazoles were assembled where the final deuterium atom was incorporated in the triazole-forming step