Insights into a surprising reaction: the microwave-assisted direct esterification of phosphinic acids

It is well-known that phosphinic acids do not undergo direct esterifications with alcohols under thermal conditions. However, the esterifications take place under microwave (MW) irradiation due to the beneficial effect of MW. As a comparison, maximum 12-15% conversions were observed on traditional heating. It was proved experimentally that the MW-assisted esterifications are not reversible under the conditions applied that may be the consequence of the hydrophobic medium established by the long chain alcohol/phosphinic ester. Neither the thermodynamic, nor the kinetic data obtained by high level quantum chemical calculations justify the direct esterification of phosphinic acids under thermal conditions. The thermodynamic data show that there is no driving force for the reactions under discussion. As a consequence of the relatively high values of activation enthalpy (102-161 kJ mol(-1)), these esterifications are controlled kinetically. Comparing the energetics of the esterification of phosphinic acids and the preparative results obtained under MW conditions, one can see the potential of the MW technique in the synthesis of phosphinates. During our study, a series of new cyclic phosphinates with lipophilic alkyl groups was synthesized.     

Triethylborane-initiated room temperature radical addition of hypophosphites to olefins: synthesis of monosubstituted phosphinic acids and esters

A novel and practical approach to monosubstituted phosphinic acid (alkylphosphonous acid) derivatives from hypophosphite salts or esters is described. Phosphorus-centered radical formation is initiated with Et(3)B/O(2), and the reaction is conveniently conducted at room temperature in an open flask. In contrast to previously reported conditions for the radical reaction of hypophosphorous acid and sodium hypophosphite (peroxide initiators, acid catalysis, heat), the method proceeds under neutral conditions and therefore tolerates a wide range of functional groups. Previously inaccessible phosphinic acids can be prepared in a single step from cheap starting materials. Excellent selectivity is observed for monoaddition, and symmetrical dialkyl phosphinates do not form in significant amounts. Monosubstituted phosphinic acids are usually obtained in better than 90% purity by a simple extractive workup; however, isolated yields are diminished if the substituent is polar. Because radicals derived from hypophosphites are electrophilic, the reaction is limited to the use of electron-rich olefins. The reaction conditions can also be employed in the room temperature radical reduction of alkyl halides and provide an exceptionally mild and environmentally friendly alternative to the use of tributyltin hydride. The remarkable mild nature of the reaction conditions allows for the radical reaction of sensitive alkyl hypophosphites to occur, in which case, a catalytic amount of Et(3)B suffices to deliver alkyl phosphinate esters in reasonable yield.     

A novel method for the separation of bis(alpha-hydroxyalkyl)phosphinic acid diastereoisomers via formation of novel cyclic phosphinic acids

The reaction of aromatic and aliphatic aldehydes with hypophosphorus acid under microwave irradiation was examined. The reaction gave a mixture of a racemic pair of bis(alpha-hydroxyalkyl)phosphinic acids and acetal derivatives from the corresponding bis(alpha-hydroxyalkyl)phosphinic acids of meso-stereochemistry in good yield. The difference in solubility in organic solvents due to polarity allowed us to readily separate these compounds. This method constitutes an easy, rapid, and good-yielding preparation and separation of bis(alpha-hydroxyalkyl) phosphinic acid diastereoisomers from simple starting materials using microwave irradiation.     

Synthesis and photoinduced deprotection of calixarene derivatives containing certain protective groups

Calixarene derivatives 1a , 1b , and 1c containing pendant tert‐butoxycarbonyl (t‐BOC) groups were synthesized in 81, 93, and 83% yields, respectively, by the reaction of C‐methylcalix[4]resorcinarene (CRA), p‐methylcalix[6]arene (MCA), and p‐tert‐butylcalix[8]arene (BCA) with di‐tert‐butyl dicarbonate using triethylamine as a base in pyridine. Calixarene derivatives 2a , 2b , and 2c containing pendant trimethylsilyl ether (TMSE) groups were obtained in 58, 50, and 82% yields, respectively, by the reaction of CRA, MCA, and BCA with 1,1,1,3,3,3‐hexamethyldisilazane using chlorotrimethylsilane as an accelerator in tetrahydrofuran. Calixarene derivatives 3a , 3b , and 3c containing pendant cyclohexenyl ether (CHE) groups were also prepared in 65, 78, and 84% yields, respectively, by the reaction of CRA, MCA, and BCA with 3‐bromocyclohexene using potassium hydroxide as a base as well as tetrabutylammonium bromide as a phase‐transfer catalyst in N‐methyl‐2‐pyrolidone. The photoinduced deprotection of calixarene derivatives 1a – c was examined with bis‐[4‐(diphenylsulfonio)phenyl]sulfide bis(hexafluorophosphate) as a photoacid generator on UV irradiation followed by heating in the film state, and it was found that the deprotection of the t‐BOC groups of 1a proceeded smoothly in high conversion. The deprotection rates of the t‐BOC groups of 1b and 1c were much lower than that of 1a under the same irradiation conditions. The photoinduced deprotection of calixarenes 2b – c containing tetramethylsilane groups as well as 3a – c containing CHE groups were also examined under similar reaction conditions in the film state, and it was found that the deprotection rates of calixarenes 2b – c and 3a – c were lower than those of the corresponding 1a – c calixarenes. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1481–1494, 2001     

Mild and efficient Lewis acid-promoted detritylation in the synthesis of N-hydroxy amides: a concise synthesis of (-)-Cobactin T

An efficient, high-yielding Lewis acid promoted deprotection of O-trityl hydroxylamine derivatives is described. A range of acid-labile protecting groups, such as N-Boc and O-TBS, were tolerated under these mild conditions. The present method is applicable to the synthesis of a broad range of hydroxylamine derivatives, including N-hydroxy amides (hydroxamic acids), N-hydroxy sulfonamides, and N-hydroxy ureas, which often exhibit significant biological activities. An application of this methodology for a concise synthesis of (-)-Cobactin T (18) is also demonstrated.     

A novel double deprotection-peptide cyclisation procedure and its application to the synthesis of analogues of the cyclic tetrapeptide HC-toxin.

A hydroxide-mediated Fmoc/methyl ester double deprotection procedure followed by an improved bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) cyclisation reaction are reported. This novel methodology was applied to the synthesis of three new HC-toxin analogues.     

Microwave‐Assisted Functionalization of Phosphinic Acids: Amidations versus Esterifications

Both the reaction enthalpies and enthalpies of activation obtained by high‐level quantum chemical calculations were against the direct amidation of phosphinic acids under traditional thermal conditions. However, the amidations, not expected to proceed on the basis of the endothermicity and the significantly high enthalpies of activation, did take place under microwave (MW) conditions in 30–36% conversions. As a comparison, the direct esterifications of phosphinic acids that are thermoneutral and have higher enthalpies of activation were quite efficient under MW conditions. The outcome of the MW‐assisted amidation is the balance of two effects. The local overheating effect could overcome the barrier meant by the enthalpy of activation, but the endothermicity works against this. Comparison of the results of the syntheses and the energetics calculated for the esterification and amidation of phosphinic acids enabled us to draw more general conclusions on the scope and limitation of the use of MW irradiation in organic syntheses. The traditional amidation of phosphinic acids via the phosphinic chloride intermediate gave the products in much better yields. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:91–99, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21068     

A stereoselective synthesis of phosphinic acid phosphapeptides corresponding to glutamyl-gamma-glutamate and incorporation into potent inhibitors of folylpoly-gamma-glutamyl synthetase

Radical addition of H3PO2 to N-/C-protected vinyl glycine led to the corresponding H-phosphinic acid in excellent yield. The non-nucleophilic H-phosphinic acid was converted to a nucleophilic P(III) species, RP(OTMS)2, which was used in two approaches to the target phosphinic acid containing pseudopeptide. New methodology was developed that led to excellent yields in the reaction of RP(OTMS)2 with unactivated electrophiles, including an acyclic homoallylic bromide. However, en route to the target pseudopeptide, Arbuzov reaction of RP(OTMS)2 with a cyclic homoallylic bromide, (R)-3-(bromomethyl)-cyclopent-1-ene, led to a rearranged allylic phosphinic acid rather than the desired homoallylic derivative, a putative glutarate surrogate. Conjugate addition of RP(OTMS)2 to alpha-methylene glutarate containing a chiral auxiliary resulted in only modest diastereoselectivity. Purification by flash chromatography provided protected derivatives of both diastereomers of the pseudopeptide. Following global deprotection, coupling of (S)-H-Glu-gamma-[Psi(P(O)(OH)(CH2))]-(S)-Glu-OH and (S)-H-Glu-gamma-[Psi(P(O)(OH)(CH2))]-(R)-Glu-OH to (4-amino-4-deoxy-10-methyl)pteroyl azide led to the target compounds for biochemical study as inhibitors of the ATP-dependent ligase, folylpoly-gamma-glutamate synthetase.     

Efficient microwave-assisted two-step procedure for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones

A general method has been developed for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones. This process involves initial microwave-assisted quinazolinone formation between anthranilamide and various Boc- or acylamino acids, followed by intramolecular cyclodehydration under acidic conditions. In the case of 3-monosubstituted-imidazoquinazolinones, the procedure needs the formation of the formamide derivatives by deprotection and formylation of the Boc-intermediates.     

Chloral Hydrate as a Water Carrier for the Efficient Deprotection of Acetals,Dithioacetals, and Tetrahydropyranyl Ethers in Organic Solvents

The efficient deprotection of several acetals, dithioacetals, and tetrahydropyranyl (THP) ethers under ambient conditions, using chloral hydrate in hexane, is described. Excellent yields were realized for a wide range of both aliphatic and aromatic substrates. The method is characterized by mild conditions (room temperatures or below), simple workup, and the ready availability of chloral hydrate. High chemoselectivity was also observed in the deprotection, acetonides, esters, and amides being unaffected under the reaction conditions. Products were generally purified chromatographically and identified spectrally. These results constitute a novel addition to current methodology involving a widely employed deprotection tactic in organic synthesis. It seems likely that the mechanism of the reaction involves adsorption of the substrate on the surface of the sparingly soluble chloral hydrate.     

Facile N-derivatization of alpha-amino esters and amides via benzotriazolylmethyl derivatives

Alpha-(N-substituted amino)esters were prepared in a two-step procedure from available unsubstituted alpha-amino esters. alpha-Amino esters are first converted into the corresponding N-benzotriazolylmethyl derivatives; in the second step, the benzotriazole group is substituted by various nucleophiles with or without the presence of a Lewis acid to give substituted alpha-amino esters in high overall yield under mild conditions with no signs of racemization. Boc-protected amino acids were converted into alpha-amino amides; subsequent deprotection allowed the conversion into N-substituted derivatives analogously to the alpha-amino esters, without racemization in high yields under mild conditions.     

Sonochemistry: a powerful way of enhancing the efficiency of carbohydrate synthesis

Using sonication as a means of facilitating organic reactions in carbohydrate chemistry was explored under the conditions used for traditional organic synthesis. An array of representative reactions, including hydroxy group manipulation (acylation, protection/deprotection, acyl group migration), thioglycoside synthesis, azidoglycoside synthesis, 1,3-dipolar cycloaddition and reductive cleavage of benzylidene, commonly used in the synthesis of carbohydrate derivatives was examined. A series of glycosylation reactions that employ thioglycosides, glycosyl trichloroacetimidate, glycosyl bromide and glycosyl acetate as the glycosyl donors was also examined. Our results demonstrate that sonication can significantly shorten the reaction time, enhance the reactivity of reactant and lead to superior yield and excellent stereoselectivity. More importantly, a general protocol of glycosylation may finally be developed. Sonication is compatible to the conditions used for traditional organic synthesis. We believe that sonication can also be applied to other areas of synthetic processes.     

Efficient synthesis of tetrazole derivatives of cytisine using the azido-Ugi reaction

The azido-Ugi reaction with natural alkaloid cytisine was investigated. It was demonstrated that the reaction could be performed with various carbonyls (both aldehydes and ketones) and isocyanides. The transformation proceeded under mild conditions in methanol using TMSN3 as a source of hydrazoic acid to give target tetrazole derivatives of cytisine in up to 98% yield. The diastereoselectivity of this reaction was studied using both aliphatic and aromatic aldehydes. A family of tetrazole derived cytisine compounds was prepared. Selective deprotection of tetrazoles was elaborated to synthesize the corresponding NH-tetrazoles.     

Synthesis of α1-(Cbz-aminoalkyl)-α2-(hydroxyalkyl)phosphinic esters

A synthesis of α₁-(Cbz-aminoalkyl)-α₂-(hydroxyalkyl)phosphinic esters was achieved by the 1,2-addition of the appropriate aldehyde to Cbz-protected phosphinic analogues of amino acid esters in the presence of at least three equivalents of trimethylsilyl chloride and NEt₃. The complete deprotection of the product esters could be achieved in one step using 35% HBr in acetic acid.     

Aryldithioethyloxycarbonyl (Ardec): a new family of amine protecting groups removable under mild reducing conditions and their applications to peptide synthesis

The development of phenyldithioethyloxycarbonyl (Phdec) and 2-pyridyldithioethyloxycarbonyl (Pydec) protecting groups, which are thiol-labile urethanes, is described. These new disulfide-based protecting groups were introduced onto the epsilon-amino group of L-lysine; the resulting amino acid derivatives were easily converted into N alpha-Fmoc building blocks suitable for both solid- and solution-phase peptide synthesis. Model dipeptide(Ardec)s were prepared by using classical peptide couplings followed by standard deprotection protocols. They were used to optimize the conditions for complete thiolytic removal of the Ardec groups both in aqueous and organic media. Phdec and Pydec were found to be cleaved within 15 to 30 min under mild reducing conditions: i) by treatment with dithiothreitol or beta-mercaptoethanol in Tris.HCl buffer (pH 8.5-9.0) for deprotection in water and ii) by treatment with beta-mercaptoethanol and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in N-methylpyrrolidinone for deprotection in an organic medium. Successful solid-phase synthesis of hexapeptides Ac-Lys-Asp-Glu-Val-Asp-Lys(Ardec)-NH2 has clearly demonstrated the full orthogonality of these new amino protecting groups with Fmoc and Boc protections. The utility of the Ardec orthogonal deprotection strategy for site-specific chemical modification of peptides bearing several amino groups was illustrated firstly by the preparation of a fluorogenic substrate for caspase-3 protease containing the cyanine dyes Cy 3.0 and Cy 5.0 as FRET donor/acceptor pair, and by solid-phase synthesis of an hexapeptide bearing a single biotin reporter group.     

Microwaves as “Co-Catalysts” or as Substitute for Catalysts in Organophosphorus Chemistry

The purpose of this review is to summarize the importance of microwave (MW) irradiation as a kind of catalyst in organophosphorus chemistry. Slow or reluctant reactions, such as the Diels-Alder cycloaddition or an inverse-Wittig type reaction, may be performed efficiently under MW irradiation. The direct esterification of phosphinic and phosphonic acids, which is practically impossible on conventional heating, may be realized under MW conditions. Ionic liquid additives may promote further esterifications. The opposite reaction, the hydrolysis of P-esters, has also relevance among the MW-assisted transformations. A typical case is when the catalysts are substituted by MWs, which is exemplified by the reduction of phosphine oxides, and by the Kabachnik–Fields condensation affording α-aminophosphonic derivatives. Finally, the Hirao P–C coupling reaction may serve as an example, when the catalyst may be simplified under MW conditions. All of the examples discussed fulfill the expectations of green chemistry.     

Protection of the Hydroxyphosphinyl Function of Phosphinic Dipeptides by Adamantyl. Application to the Solid-Phase Synthesis of Phosphinic Peptides

To develop solid-phase synthesis of phosphinic peptides, different FmocXaaPsi{PO(OAd)CH(2)}XaaOH building blocks have been prepared, where Fmoc is (fluorenylmethoxy)carbonyl. In this respect, the protection of the hydroxyphosphinyl function in these phosphinic dipeptides by the adamantyl group turns out to be convenient. The phosphinic adamantyl esters are completely stable in basic conditions and can be removed under relatively mild acidic conditions. Using these building blocks, despite the bulkiness of the adamantyl group, no particular problem of coupling was observed during the solid-phase synthesis of phosphinic peptides by the Fmoc strategy. The developed methodology is of particular interest to facilitate the development of potent inhibitors of zinc-metalloproteases.     

Metallocene-DNA: synthesis,molecular and electronic structure and DNA incorporation of C5-ferrocenylthymidine derivatives

Ferrocenylthymidine derivatives have been prepared by Pd-catalysed cross-coupling between ethynylferrocene or vinylferrocene and 5-iodo-2'-deoxyuridine. In the latter case a mixture of trans (2a) and gem (2b) isomers was obtained. The cis-vinylferrocenyl (2c), and ethylferrocenyl (3) derivatives were obtained by catalytic hydrogenation of ethynylferrocenyl-dT (1a), and 2c respectively. Single-crystal X-ray data for 1a, the ferrocenyl-2'furano-pyrimidone 1b, and 2a show that the nucleobase is essentially co-planar with the substituted Cp ring of the metallocene. The selective reduction of the linkage between the ferrocenyl and thymidine moieties, from -C identical to C- to -CH2CH2-, causes a shift in the reduction potential of -124 mV. DFT calculations for the one-electron oxidised species indicate that the diminished conjugation reduces the spin transfer onto the bridging C2 group, but has less effect on the extent transferred to the nucleobase from the ferrocenyl group. Compound 1a was incorporated site-specifically into DNA oligonucleotides by using automated solid-phase methods. However, some interconversion of 1a-->1b occurs, even under rapid mild conditions of deprotection.     

Practical Synthesis of Phosphinic Amides/Phosphoramidates through Catalytic Oxidative Coupling of Amines and P(O)−H Compounds

Herein, we report a highly efficient ZnI₂-triggered oxidative cross-coupling reaction of P(O)−H compounds and amines. This operationally simple protocol provides unprecedented generic access to phosphinic amides/phosphoramidate derivatives in good yields and short reaction time. Besides, the reaction proceeds under mild conditions, which avoids the use of hazardous reagents, and is applicable to scale-up syntheses as well as late-stage functionalization of drug molecules. The stereospecific coupling is also achieved from readily available optically enriched P(O)−H compounds.     

Rhodium‐Catalyzed Oxidative C–H Activation/Cyclization for the Synthesis of Phosphaisocoumarins and Phosphorous 2‐Pyrones

Rhodium‐catalyzed cyclization of phosphinic acids and phosphonic monoesters with alkynes has been developed. The oxidative annulation proceeds with complete conversion of phosphinic acid derivatives and allowed the atom‐economic preparation of useful phosphaisocoumarins with high yield and selectivity. The reaction is tolerant of extensive substitution on the phosphinic acid, phosphonic monoester and alkyne, including halides, ketone, and hydroxyl groups as substituents. Furthermore, we found that alkenylphosphonic monoesters proceed to give a wide range of phosphorus 2‐pyrones through oxidative annulation with alkynes. Mechanistic studies revealed that C? H bond metalation was the rate‐limiting step.