Weinreb Amides Research Articles

Ru(ii)/PEG-400 as a highly efficient and recyclable catalytic media for annulation and olefination reactions via C–H bond activation

In this report synthesis of isoquinolinones, isocoumarins, and N-methyl isoquinolinones and olefination of Weinreb amides by C–H bond activation using Ru(ii)/PEG-400 as green and recyclable media are documented.

Bromomethyllithium-mediated chemoselective homologation of disulfides to dithioacetals

An efficient, chemoselective homologation of disulfides and diselenides to the corresponding dithio- and diselenoacetals has been developed via the addition of bromomethyllithium. Chemoselectivity is fully preserved in the presence of concomitant electrophilic sites decorating the substrates. The synthetic potential of selected dithioacetals has been evaluated in Feringa-Fañanas-Mastral-type Pd-catalyzed coupling with an organolithium and in the unusual 1,4-addition to a Weinreb amide.

Catalytic asymmetric formal synthesis of beraprost.

The first catalytic asymmetric synthesis of the key intermediate for beraprost has been achieved through an enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of the tricyclic core were controlled via Rh-catalyzed stereoselective C–H insertion and the subsequent reduction from the convex face.

ChemInform Abstract: One‐Pot Unsymmetrical Ketone Synthesis Employing a Pyrrole‐Bearing Formal Carbonyl Dication Linchpin Reagent.

AbstractA wide range of ketones and Weinreb amides are synthesized from various organolithium and Grignard reagents in one‐pot without the need of a transition‐metal catalyst.

ChemInform Abstract: Fujiwara—Moritani Reaction of Weinreb Amides Using a Ruthenium‐Catalyzed C—H Functionalization Reaction.

AbstractThe directed oxidative Heck coupling of Weinreb amides is studied in the presence of Ru/Ag‐catalyst system.

Total Synthesis of (–)‐C/D‐cis‐De­hydro‐3‐O‐methyl‐estradiols

AbstractA convergent synthesis of (–)‐dehydro‐3‐O‐methyl‐C/D‐cis‐estradiol started from stereochemically defined substituted optically active 3‐(2‐arylethyl)‐γ‐butyrolactones. Regioselective bromination of the anisyl moiety, reductive ring opening of the iodolactone, and protecting‐group changes led to a Weinreb amide. This then underwent an intramolecular Grignard reaction closing the B‐ring to give a tetralone with defined configuration. Introduction of C‐11 through an allyl Grignard addition and subsequent ring‐closing metathesis gave a tetrahydro phenanthrene derivative. Oxidation of the side‐chain alcohol resulted in the key aldehyde group, and a final samarium‐diiodide‐mediated reductive D‐ring annulation resulted in the generation of the target dehydro‐C/D‐cis‐estradiol derivatives with high stereoselectivity. Structure elucidation was carried out using NOEDS (nuclear Overhauser enhanced differential spectroscopy) analysis on the one hand, and conversion into known 3‐O‐methyl‐13β‐estradiols by double‐bond hydrogenation on the other. Further efforts to use this estradiol synthetic strategy to generate more complex steroidal natural products and pharmaceutically interesting compounds are in progress.

Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One‐Pot Synthesis of Differentiated 1,3‐Diketones, Pyrans, and Spiroketals

AbstractThe design, synthesis, and validation of new highly effective bifunctional linchpins for type II anion relay chemistry (ARC) has been achieved. The mechanistically novel negative‐charge migration that comprises the Brook rearrangement is now initiated by a stabilized tetrahedral intermediate, which is generated by nucleophilic addition to a Weinreb amide, rather than by a simple oxyanion that is generated from an epoxide. As a result, the linchpin preserves the carbonyl functionality in the ARC adducts, thus permitting access to functionally complex systems in a single flask without the need for further chemical manipulations. This tactic was validated with the one‐pot preparation of monoprotected 1,3‐diketones as well as pyran and spiroketal scaffolds, depending on the choice of nucleophile, electrophile, and work‐up conditions.

Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One-Pot Synthesis of Differentiated 1,3-Diketones, Pyrans, and Spiroketals.

The design, synthesis, and validation of new highly effective bifunctional linchpins for type II anion relay chemistry (ARC) has been achieved. The mechanistically novel negative-charge migration that comprises the Brook rearrangement is now initiated by a stabilized tetrahedral intermediate, which is generated by nucleophilic addition to a Weinreb amide, rather than by a simple oxyanion that is generated from an epoxide. As a result, the linchpin preserves the carbonyl functionality in the ARC adducts, thus permitting access to functionally complex systems in a single flask without the need for further chemical manipulations. This tactic was validated with the one-pot preparation of monoprotected 1,3-diketones as well as pyran and spiroketal scaffolds, depending on the choice of nucleophile, electrophile, and work-up conditions.

Quantitative Synthesis of Aldehydes from Weinreb Amides Using Lithium Diisobutyl‐t‐Butoxyaluminum Hydride (LDBBA)

Aldehydes are prepared by partial reduction of Weinreb amides without over-reduction to alcohols in short time and with quantitative yields.

ChemInform Abstract: Optimization of Reaction and Substrate Activation in the Stereoselective Cross‐Coupling of Chiral 3,3‐Diboronyl Amides.

AbstractSubstrate (I) which bears a Weinreb amide undergoes a direct coupling of the Bpin moiety with inversion of the stereochemistry.

Novel free-radical mediated carboalkenylation of olefins processes starting from ready available benzylketone and weinreb amide xanthate as a electrophilic radical precursors and E-sulfone acceptor

Novel free-radical mediated carboalkenylation of olefins processes starting from ready available benzylketone and weinreb amide xanthate as a electrophilic radical precursors and E-sulfone acceptor

Reductive N–O cleavage of Weinreb amides by sodium in alumina and silica gels: synthetic and mechanistic studies

The use of sodium in alumina and silica gels for the reductive cleavage of the N–O bond of N-methoxy-N-methylamides, commonly referred to as Weinreb amides, has been investigated. This method reduces a diverse set of Weinreb amides with different functional groups to give modest to excellent yields. In the course of the studies to explore mechanisms and functional group tolerance, an apparently novel group transfer emerged, implying base-promoted cleavage of the Weinreb amide to form formaldehyde, followed by aldol condensation.

Enantioselective Synthesis of syn-α-Aryl-β-hydroxy Weinreb Amides: Catalytic Asymmetric Roskamp Reaction of α-Aryl Diazo Weinreb Amides.

A convenient one-pot procedure to synthesize a variety of highly optically active syn-α-aryl-β-hydroxy Weinreb amides using an asymmetric Roskamp/reduction strategy is described. An oxazaborolidinium ion catalyzed asymmetric Roskamp reaction of α-aryl diazo Weinreb amides with aldehydes produced α-phenyl-β-keto Weinreb amides, which were in situ reduced with zinc borohydride to give syn-α-aryl-β-hydroxy Weinreb amides in good yields (up to 87%) with high enantioselectivities (up to 99% ee) and syn stereoselectivities (>20:1).

Modular synthesis of tetra-substituted furans from alkynes, Weinreb amides, and aldehydes

A method for the modular one-pot synthesis of tetra-substituted furans utilizing alkynes, Weinreb amides, and non-enolizable aldehydes has been developed. Under this titanium promoted method, furans were prepared in moderate yields with high levels of regioselectivity. The system showed good chemoselectivity tolerating aromatic and aliphatic bromides, chlorides, and fluorides, heteroaromatics, alkenes, and silyl ethers.

Facile Baeyer–Villiger oxidation of cyclic ketones: conventional versus microwave-assisted approach

The Baeyer–Villiger oxidation of cyclic ketones (I) to the corresponding lactones (II) can be improved using m-CPBA under microwave dielectric heating. A dramatic reduction of time—3min compared to 5days at room temperature—was observed to transform cycloheptanone into oxocan-2-one. Ω-Hydroxyalkyl hydroxamic acids (III), key intermediates for a rapid access to potent histone deacetylase inhibitors, are obtained in one-pot reaction of lactones using the Weinreb amidation.

ChemInform Abstract: Pd(II)‐Catalyzed C—H Functionalizations Directed by Distal Weakly Coordinating Functional Groups.

AbstractThe direct ortho‐C(sp2)‐H olefination or acetoxylation of phenylacetyl Weinreb amides, esters, and ketones as well as structurally closely related substrates is developed without the need for a directing group.

An efficient synthesis of 4-isochromanones via Parham-type cyclization with Weinreb amide

The synthesis of 4-isochromanones via Parham-type cyclization with Weinreb amide as the internal electrophilic group, t-BuLi as the lithium reagent was described. The reaction was efficient and could be completed in one minute. The application scope of this new protocol was investigated and the desired products could be obtained in good to excellent yields. Besides, the synthetic potential of this method was further demonstrated by the synthesis of natural product (±)-XJP, which was obtained in six steps with overall yield up to 54%.

Development of variously functionalized nitrile oxides.

N-Methylated amides (N,4-dimethylbenzamide and N-methylcyclohexanecarboxamide) were systematically subjected to chemical transformations, namely, N-tosylation followed by nucleophilic substitution. The amide function was converted to the corresponding carboxylic acid, esters, amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3-functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and formyl moieties.

Optimization of Reaction and Substrate Activation in the Stereoselective Cross-Coupling of Chiral 3,3-Diboronyl Amides.

A method has been developed for the chemo- and stereoselective Suzuki-Miyaura cross-coupling of optically enriched gem-diboronyl compounds with various aryl bromides. Experimental evidence suggests that the Lewis acidity of the second boron group in these substrates plays a significant role in facilitating these otherwise challenging cross-coupling processes. β-Diboronyl esters may be successfully cross-coupled in excellent yield and enantiomeric excess with prior conversion of the pinacol boronate to the corresponding trifluoroborate salt. In contrast, a substrate bearing a Weinreb amide can undergo direct coupling of the Bpin moiety, likely due to the stronger coordination of the more basic amide carbonyl group. The resulting optically enriched secondary boronate may be used in a second enantioselective cross-coupling to afford pharmaceutically relevant diarylmethane products. The use of a Weinreb amide substrate allows for facile postcoupling modification, as demonstrated by a transformation to the corresponding ketone.

Photoregulation of α-Chymotrypsin Activity by Spiropyran-Based Inhibitors in Solution and Attached to an Optical Fiber.

Here the synthesis and characterization of a new class of spiropyran-based protease inhibitor is reported that can be reversibly photoswitched between an active spiropyran (SP) isomer and a less active merocyanine (MC) isomer upon irradiation with UV and visible light, respectively, both in solution and on a surface of a microstructured optical fiber (MOF). The most potent inhibitor in the series (SP-3 b) has a C-terminal phenylalanyl-based α-ketoester group and inhibits α-chymotrypsin with a Ki of 115 nM. An analogue containing a C-terminal Weinreb amide (SP-2 d) demonstrated excellent stability and photoswitching in solution and was attached to the surface of a MOF. The SP isomer of Weinreb amide 2 d is a competitive reversible inhibitor in solution and also on fiber, while the corresponding MC isomer was significantly less active in both media. The ability of this new class of spiropyran-based protease inhibitor to modulate enzyme activity on a MOF paves the way for sensing applications.