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A Straightforward Route to E-γ-Aryl-α-oxobutenoic Esters by One-step Acid-catalysed Crotonisation of Pyruvates
Abstract
A new and highly simple method for the synthesis of E-γ-aryl-α-oxobutenoic esters is described. This unprecedented one-step procedure is based on an unexpected nucleophilic reactivity of alkyl pyruvates towards aromatic aldehydes in refluxing dichloromethane, when using catalytic amounts of Cu(OTf) 2 and in the presence of stoichiometric amounts of trimethyl orthoformate in the case of electron-rich aldehydes. Under these conditions, yields obtained are uniformly higher than those obtained by previous multistep procedures.
... Orthoesters are highly reactive owing to the electron-decient central carbon atom caused by the -I effect of the electronegative groups OR. 1 Among the ortheosters introduced above, TEOF involved maximal exploitation in the reactions based on our literature survey (109 reports) followed by TMOF (54 reports), TEOAc (21 cases), TMOAc (4 items), and triethyl orthopropionate (2 cases), and other kinds of alkyl orthoesters (1 case) (Fig. 1a). Several orthoesters were applied in various domains as dehydrating agents, [5][6][7][8][9][10][11][12][13][14][15][16][17][18] alkylating agents, [19][20][21][22][23][24] dialkoxymethylation agents, 25 esterication agents, 26 methoxy sources, 27 additives, [28][29][30] solvents, [31][32][33] and protecting groups. [34][35][36] This functional group is also necessary for some conversions such as the Johnson-Claisen rearrangement. ...
... 85 Tetrahydropyranyl acetals containing a phenyl diazoketone substituent (24) underwent Rh(II)-catalyzed C-H insertion through an unusual C-O bond generation to give spirocyclic orthoesters (25) (Scheme 6). 86 3,4,6-Tri-O-acetyl-1,2-O-(1-tocopheroxyethylidene)-a-D-glucopyranose (vitamin E sugar 1,2-orthoester) (33)(34)(35)(36) with exo-type stereoselectivity were synthesized through the reaction of sugar halides (26)(27)(28)(29) with various phenols, such as a-tocopherol (30), chroman-6-ol (31), and 2,6-dimethylphenol (32) by N,N-diisopropylethylamine (DIPEA) and tetrabutylammonium iodide (TBAI) or tetraethylammonium bromide (TEABr) in reuxing CH 2 Cl 2 for 4-24 h. The obtained peracetylated orthoesters (33)(34)(35)(36) were deprotected by utilizing aminolysis (NH 3 /MeOH) or by reduction in the presence of DIBAL-H (Scheme 7). ...
In this review we focus on applications of alkyl orthoesters as valuable and efficient substrates to perform various classes of two-component and multi-component organic reactions. The article has classified them according to two aspects, which are: (i) a focus on the reaction medium (solvent-free conditions, aqueous media, and organic solvents); and (ii) an examination of product structures. Reaction accomplishment under solvent-free conditions is an eco-friendly process with the absence of volatile toxic solvents, which puts it in line with green chemistry goals. Water is an interesting choice in organic transformations due to its inexpensiveness and safety. The authors hope their assessment will help chemists to attain new approaches for utilizing alkyl orthoesters in various organic synthetic methods. The review covers the corresponding literature up to the beginning of 2020.
... β,γ-Unsaturated-α-ketoesters have been employed in the asymmetric synthesis of biologically important subunits (e.g. β-unsaturated-and β-amino-αhydroxy esters) and natural products (Norlignans) [6][7][8][9], and β,γ-unsaturated-α-ketoesters have been previously reported by the reaction of alkyl pyruvates towards aromatic aldehydes in refluxing dichloromethane, when catalytic amounts of Cu(OTf) 2 are used [10]. Recently, Sánchez-Larios et al. [4] reported the synthetic procedure for the preparation of β,γ-unsaturated α-ketoesters by the reaction of aldehydes with sodium pyruvate followed by the addition of potassium hydroxide yields the desired compounds. ...
Novel and efficient method for the synthesis of a series of β,γ-unsaturated-α-ketoesters under mild conditions was developed. This one-step protocol was achieved by the reaction of electron-rich aromatic aldehydes and pyruvates in the presence of 10 mol% of molecular iodine in solvent-free condition at 80 °C temperature. A wide variety of substrates bearing electron releasing groups on aromatic ring were well tolerated and delivered corresponding β,γ-unsaturated-α-ketoesters in moderate to good yields. These β,γ-unsaturated-α-ketoesters have been further utilized in the synthesis of 4,5-dihydropyrazole derivatives.
... These acids are of continuing interest as intermediates in pharmacological, industries and chemical syntheses, in development of enzyme inhibitors and drugs, as model substrates of enzymes [2][3][4]. Synthesis and investigation of several metal-ion complexes of phenylsubstituted derivatives of BP, have been carried out in aqueous solutions [5] and in solid state [2,[7][8][9][10][11]. In aqueous solutions, these works reported mainly the thermodynamic stability (β 1 ) and spectroscopic parameters (ε 1max , λ max. ...
Resumo
Solid state M(2-MeO-BP)2 compounds, where M stands for bivalent alkali earth metal ions (Mg, Ca, Srand Ba) and 2-MeO-BP is 2-methoxybenzylidenepyruvate, have been synthesized. Simultaneous thermogravimetry and differential thermal analysis (TG-DTA), differential scanning calorimetry (DSC), infrared spectroscopy, elemental analysis and complexometry, were used to investigate these compounds. The dehydration of magnesium, strontium and barium compounds occurs in a single step, while for calcium compound the dehydration occurs in two steps. The thermal decomposition of the anhydrous compounds occurs with the formation of carbonate as intermediate, except for the magnesium compound. The results also provided information about the composition, coordination mode, thermal behaviour and thermal decomposition of isolated compounds.
... 20 Although there is sufficient literature evidence available for synthesis of R, -unsaturated keto esters, the present set of conditions afforded compounds 38, 39, and 75-84 in better yields and are scalable. [21][22][23][24][25][26][27][28] As dihydropyrazole analogues 4-24 contained a chiral center at position 5, the above synthesis provides a target compound in the form of racemic mixture. To further explore the stereochemical (chiral) requirements/consequences for binding to the CB1 receptor, the key compound 9 was synthesized as a chiraly pure moiety by introducing resolution at suitable stage. ...
A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.
A concise synthetic method for dihydropyrans has been developed by inverse-electron-demand oxa-Diels-Alder reaction of α-keto-β,γ-unsaturated esters with α,β-unsaturated hydrazones as electron-rich olefins. This reaction is catalyzed by Eu(hfc)3 and proceeds in an endo-selective manner. This umpolung cycloaddition affords a variety of substituted dihydropyrans stereoselectively in high yields. In addition, indirect synthesis of formyl-substituted dihydropyran was achieved by dehydrazonation of the cycloadduct. This method is expected to be useful for the synthesis of dihydropyrans and tetrahydropyrans with unusual substitution patterns.
Solid state M-4-Me-BP compounds, where M stands for bivalent Mn, Fe, Co, Ni, Cu, Zn, Pb and 4-Me-BP is 4-methylbenzylidenepyruvate, have been synthesized. Simultaneous thermogravimetry-differential thermal analysis (TG-DTA), differential scanning calorimetry (DSC), X-ray powder diffractometry, infrared spectroscopy, elemental analysis, and complexometry were used to characterise and to study the thermal behaviour of these compounds. The results led to information about the composition, dehydration, thermal stability and thermal decomposition of the isolated complexes.
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Metal triflate catalyzed addition reaction of pyrrole to methyl 2-oxo-4-phenylbut-3-enoate and substituted derivatives generated the related novel alkylated pyrroles regioselectively at C(2) of pyrrole. Among the studied metal triflates, Cu(OTf)2 was found to be more effective in the addition reaction. The synthesized methyl 2-oxo-4-phenyl-4-(1H-pyrrole-2-yl)butanoate esters underwent self-cyclization by heating and yielded the corresponding methyl 3-hydroxy-1-phenyl-2, 3-dihydro-1H-pyrrolizine-3-carboxylate and substituted derivatives. This reaction procedure allowed easy access to pyrrolizine structure in mild reaction conditions.
Deracemisation of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates using Candida parapsilosis ATCC 7330 resulted in the formation of one enantiomer in high enantiomeric excess [up to >99% ee] and isolated yields [up to 79%]. The absolute configuration of the enantiomerically pure (3E)-ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate as determined by 1H NMR of the Mosher esters was found to be (S).
Solid-state M-2-Cl-BP, where M stands for Mn, Fe, Co, Ni, Cu, Zn and Pb and 2-Cl-BP is 2-chlorobenzylidenepyruvate, have been synthesized. Thermogravimetry
and derivative thermogravimetry (TG/DTG), simultaneous thermogravimetry and differential thermal analysis (TG-DTA), X-ray
powder diffractometry, infrared spectroscopy, elemental analysis, and complexometry were used to characterize and to study
the thermal behaviour of these compounds. The results led to information about the composition, dehydration, thermal stability
and thermal decomposition of the isolated compounds.
Solid-state
compounds of general formula LnL3⋅nH2O,
where Ln represents heavier lanthanides
and yttrium and L is 2-chlorobenzylidenepyruvate,
have been synthesized. Chemical analysis, simultaneous thermogravimetry-differential
analysis (TG-DTA), differential scanning calorimetry (DSC), X-ray powder diffractometry,
elemental analysis and infrared spectroscopy have been employed to characterize
and to study the thermal behaviour of these compounds in dynamic air atmosphere.
On heating these compounds
decompose in four (Gd, Tb, Ho to Lu, Y) or five (Eu, Dy) steps. They lose
the hydration water in the first step and the thermal decomposition of the
anhydrous compounds up to 1200C occurs with the formation of the respective
oxide, Tb4O7 and Ln2O3
(Ln=Eu, Gd, Dy to Lu and Y) as final residue.
The dehydration enthalpies found for these compounds (Eu, to Lu and Y) were:
65.77, 55.63, 86.89, 121.65, 99.80, 109.59, 131.02, 119.78, 205.46 and 83.11
kJ mol-1, respectively.
The structure of the title compound, C11H10O3, shows pseudo-symmetry. Since the molecule is nearly planar and all non-H atoms lie close to an approximate mirror plane perpendicular to the crystallographic b axis, the structure could almost (85%) be described in space group P21/m. However, the correct space group is P21.
Bacterial metabolites of phenanthrene and anthracene include benzochromenones, o‐carboxyvinylnaphthoates, and o‐substituted aryl α‐oxobutenoates, which were synthesized with the Wittig reaction, the Heck reaction, and coupling of aromatic aldehyde with pyruvate.
The carboxypolystyrene-bound vinyl ether of 1,4-butanediol smoothly underwent an efficient endo-selective hetero-Diels−Alder reaction, under Lewis-acid conditions, with heterodienes bearing methyl ester, trifluoromethyl and para-tolylsulfinylmethyl groups at the C-2 position. Reductive cleavage of the supported adducts afforded functionalized dihydropyrans, which are of particular interest for diversity-oriented parallel synthesis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
A very simple and efficient synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2- ones is reported. These cyclic dehydro-amino acid derivatives with a stereogenic center at the 5-position were obtained by the addition of two equivalents of amine to β,γ-unsaturated keto esters. These cyclic enamines can also be obtained by the three-component reaction of ethyl pyruvate, amines and aldehydes.
Solid-state M-4-Cl-BP compounds, where M stands for bivalent Mg, Ca, Sr, Ba and 4-Cl-BP is 4-chlorobenzylidenepyruvate, have been synthesized. Simultaneous thermogravimetry-differential thermal analysis (TG-DTA), differential scanning calorimetry (DSC), infrared spectroscopy, elemental analysis and complexometry were used to characterize and to study the thermal behaviour of these compounds. The results led to informations about the composition, dehydration, thermal stability and thermal decomposition of the isolated complexes.
Solid-state Ln(2-MeO-BP) compounds, where Ln stands for trivalent Eu to Lu and Y(III) and 2-MeO-BP (which is 2-methoxybenzylidenepyruvate) have been synthesized. Simultaneous
thermogravimetry and differential thermal analysis (TG-DTA), differential scanning calorimetry (DSC), X-ray powder diffraction,
infrared spectroscopy and other methods of analysis were used to characterize and to study these compounds. On the base of
the obtained results an Ln(2MeO-BP)3·nH2O general formula can be established.
The development of small molecule inhibitors of the viral protease is of considerable interest for the treatment of emergent flaviviral diseases such as Dengue or West Nile fever. Until today little progress has been made in finding drug-like compounds that inhibit the protease and provide a starting point for lead optimization. We describe here the initial steps of a drug discovery effort that focused on the styryl pharmacophore, combined with a ketoamide function to serve as electrophilic trap for the catalytic serine. This resulted in a fragment-like lead compound with reasonable target affinity and good ligand efficiency, which was extensively modified to explore structure-activity relationships. Selected compounds were cross-tested against the West Nile virus protease and thrombin, indicating that selectivity for one or more flaviviral proteases can be achieved. Finally, the antiviral activity of several protease inhibitors was confirmed in a cell-culture model of Dengue virus replication. The SAR presented here may serve as starting point for further drug discovery efforts with the aim of targeting flaviviral proteases.
Under smooth Eu(fod)(3)-catalyzed conditions, the inverse-electron demand hetero-Diels-Alder reactions between enantiopure N-vinyl-2-oxazolidinones 1a-f and representative beta,gamma-unsaturated alpha-ketoesters proceed with a high degree of endo and facial diastereoselectivity. The elucidation of the stereostructure of these adducts, performed by X-ray analysis or chemical correlation, shows that the endo-selective cycloaddition process is facially controlled in favor of the (2S,4S)-adduct when starting from a (4S)-dienophile or vice versa. The specific interest of the adducts 10a-e, derived from (E)-4-tert-butoxymethylene pyruvic acid methyl ester 9, has been exemplified by the two-step and highly stereoselective transformation of these adducts into the new and valuable N-2-deoxyglycosyl-oxazolidinones 12a-e, isolated in a pure diastereo- and enantiomeric form.
Addition of ethoxalyl chloride (ClCOCOOEt) to terminal alkynes at 60 degrees C in the presence of a rhodium(I)-phosphine complex catalyst chosen from a wide range affords 4-chloro-2-oxo-3-alkenoates regio- and stereoselectively. Functional groups such as chloro, cyano, alkoxy, siloxy, and hydroxy are tolerated. The oxidative addition of ethoxalyl chloride to [RhCl(CO)(PR(3))(2)] proceeds readily at 60 degrees C or room temperature and gives [RhCl(2)(COCOOEt)(CO)(PR(3))(2)] (PR(3) = PPh(2)Me, PPhMe(2), PMe(3)) complexes in high yields. The structure of [RhCl(2)(COCOOEt)(CO)(PPh(2)Me)(2)] was confirmed by X-ray crystallography. Thermolysis of these ethoxalyl complexes has revealed that those ligated by more electron-donating phosphines are fairly stable against decarbonylation and reductive elimination. [RhCl(2)(COCOOEt)(CO)(PPh(2)Me)(2)] reacts with 1-octyne at 60 degrees C to form ethyl 4-chloro-2-oxo-3-decenoate. The catalysis is therefore proposed to proceed by oxidative addition of ethoxalyl chloride, insertion of an alkyne into the Cl--Rh bond of the resulting intermediate, and reductive elimination of alkenyl-COCOOEt.
The hetero-Diels-Alder reaction of 1-oxabutadienes 1a-e bearing an electron-withdrawing group at C-2 or C-3 with (E)- and (Z)-2-ethoxyvinylacetate (2a and 2b) yields the highly functionalized 3,4-dihydro-2H-pyrans 3a-h and 4a-h in mostly excellent yield and modest to good endo/exo selectivity. The cycloadducts 3a and 3c are easily transformed by stereoselective hydrogenation to the ezoaminuroic acid and desosamine derivatives 5 and 7, respectively. The phthalimido-protecting group in 5 and 7 can be removed by reductive cleavage to give 6 and 8. Transformation of 4f by chloro hydrogen exchange affords the corresponding dichloro- as well as the monochloro-compound.
α-O-t-Butyldiphenylsilyl-(D)-erythronolactone [(+)-25] (a new chiral vector) was esterified with 4-methoxybenzylidene pyruvic acid (19). Eu(fod)3 catalyzed [4+2] heterocycloaddition of the latter 1-oxabutadiene with 4-methoxystyrene (as the dienophile), afforded high yields of the endo adduct 23c with diastereofacial ratio. Five further steps led to enantiomerically pure natural (−)-O-dimethylsugiresinol (−)-2 in 12% overall yield from the acid 19.
The alkyl vinyl ethers 2b–8b (deriving from the alcohols 2a–8a) smoothly reacted with methyl E-benzylidenepyruvate 10 in the presence of catalytic amounts of Eu(fod)3 or Yb(fod)3 in refluxing hexane, thus leading to the dihydropyran adducts 13–19 in high yields (80–95%). The -cycloadducts 13–17 were obtained with diastereofacial selectivities (ds) ranging from 76/24 to 87.5/12.5. Asymmetric induction was found to culminate with the vinyl ether (−)-7b deriving from -butyl (R)-(⊃-mandelate: the best ds (92.5/7.5) was obtained for the corresponding adduct 18 after 6 days at room temperature. The absolute configurations of the major isomers of the dihydropyrans 16–18, 20 and 21 were established by oxydative degradation to optically active α-phenylsuccinic acid derivatives.
Trisubstituted pyrroles of type 8 have been prepared in a regiospecific fashion by a two step sequence involving Diels-Alder reaction of 2-oxo-3-butenoate esters 1 with 2-alkoxy-1,3-pentadiene derivatives 13, followed by ozonolysis and Paal-Knorr cyclization.
Hetero-Diels-Alder reactions of methyl 2-oxo-4-phenyl-3-butenoate with styrene to give dihydropyran derivatives were found to proceed through an exo-selective concerted as well as an ionic stepwise mechanisms concurrently.
The boron trifluoride etherate catalyzed aldol reaction of methyl 2-(trimethylsiloxy)acrylate with aldehydes proceeded smoothly in the presence of primary, secondary and tertiary alcohol to give corresponding γ-alkoxy-α-ketoesters.
α-Oxo-β,γ-unsaturated esters have been prepared in moderate to good yields via a two-step procedure consisting of the boron trifluoride-promoted reaction of 2-(trimethylsiloxy)acrylic esters with acetals, followed by treatment with silica gel in benzene under reflux.
The reaction of 2-(trimethylsiloxy)acrylate esters, prepared by the silylation of pyruvate esters, with acetals proceeded in the presence of diethyl ether-boron trifluoride complex to afford γ-alkoxy-α-keto esters (alkyl 4-alkoxy-2-oxoalkanoates) in good yield.
The demonstration and full investigation of the scope of the accelerated 4π participation of methyl trans-4-methoxy-2-oxo-3-butenoate (1) and methyl trans-4-phenyl-2-oxo-3-butenoate (2), electron-deficient 1-oxa-1,3-butadienes bearing a C-2 electron-withdrawing substituent, in productive endo selective inverse electron demand Diels-Alder reactions suitable for the preparation of 2-alkoxy-3,4-dihydro-2H-pyran-6-carboxylates are detailed.
O-t-Butyldimethylsilyl enol ethers derived from simple cyclic ketones acted as efficient dienophiles in the Lewis acid-catalyzed heterocycloaddns. with methylbenzylidenepyruvate 1. Good selectivities were obsd. with cyclohexanone derivs. E.g., methylbenzylidenepyruvate reacted with dienophile enol ether, e.g., (1-cyclohexen-1-yloxy)(t-butyl)dimethylsilane, in the presence of Eu(fod)3 catalyst in petrol ether to give 93% yield of the expected endo adduct I, while using SnCl4 catalyst produced an 89% yield of bicyclic adduct II having a trans ring junction. [on SciFinder(R)]