Substituent Effects in Alpha-Amino and Hydroxyphosphonates Addition to Substituted Arylisocyanates: Theoretical Investigation

Abstract

Previously we have found [1] the possibility of the mechanism alteration for addition of aminophosphonate (iPrO)₂P(O)CH₂NHBu and hydroxyphosphonate (Hex0)2P(O)CH20H to substituted arylisocyanates XC₆H₄NCO. The alteration seems to be dependent on the nature of substituents in the isocyanates. We have performed the investigation of MO energy and distribution in the both phosphonates and all isocyanates by AM1 methods using HyperChem molecular modeling program. From results of our calculations of HOMO and LUMO energy and distribution, not charge control but MO control governs that reaction. Introducing electronodonating substituent to aromaticring of arylisocyanate increases the HOMO density of the nitrogen in NCO group, that makes Ad_E mechanism possible. However this alteration can be observed only for weak nucleophiles with low-energy HOMO - like hydroxyphosphonates. A possibility of HOMO(isocyanate)-LUMO(phosphonate) interaction has been shown for these compounds.     

Reactions of 2-amino-2-thiazolines with isocyanates and isothiocyanates. Chemical and computational studies on the regioselectivity, adduct rearrangement, and mechanistic pathways

2-Amino-2-thiazoline derivatives bearing alkyl or aryl substituents at exocyclic nitrogen have been condensed with different isocyanates and isothiocyanates. The addition occurs at ring endocyclic nitrogen in a regiospecific manner to afford kinetic and enthalpy-favored adducts. The unequivocal assignment of these structures has been confirmed by X-ray diffraction analyses of several compounds. The endo adducts do not rearrange on heating with the sole exception of adducts in which the exocyclic nitrogen remains unsubstituted. Trapping experiments in the presence of other isocyanates or isothiocyanates produce the formation of new endo adducts by acyl exchange in the reaction mixture. Semiempirical PM3 calculations full corroborate the higher stability of endo or exo adducts depending on the substitution pattern. The formation of adducts is compatible with a stepwise reaction mechanism, for which semiempirical transition structures could be located in the potential energy surface, and the global energetics of the process have been determined. The formation of the endo adducts proceeds with a smaller activation barrier.     

Palladium‐Catalyzed Enantioselective Decarboxylative Cycloaddition of Vinylethylene Carbonates with Isocyanates

An efficient method for the enantioselective construction of β‐substituted β‐vinylglycinol derivatives through palladium‐catalyzed decarboxylative cycloaddition of vinylethylene carbonates with isocyanates was developed. By using a palladium complex generated in situ from [Pd₂(dba)₃] ? CHCl₃ (dba=dibenzylideneacetone) and (S)‐Segphos as a catalyst under mild reaction conditions, the process provided 4‐substituted‐4‐vinyloxazolidin‐2‐ones in high yields with a high level of enantioselectivity. The stereochemical outcome of the reaction was explained by DFT calculations and the synthetic utility of the process was demonstrated by the gram‐scale transformation and formal synthesis of MK‐0731 as a kinesin spindle protein inhibitor.     

Synthesis and polymerization mechanism of bisacetoacetamides

Bisacetoacetamides were prepared, and their polymerization was investigated. The acetoacetyl groups were introduced to diamines by the reaction with diketene to give bisacetoacetamides. They were polymerized under high pressure (34.5 MPa) at 200 °C for 30 min to create the crosslinked films. The polymerization mechanism was studied by a model reaction of acetoacetanilide. The model‐reaction results indicated that the polymerization of bisacetoacetamides proceeded by addition reactions of the isocyanates formed as intermediates and in part by condensation reactions between the acetoacetamido groups. The isocyanates also reacted with the urea groups on the polymer chains to form biurets, which would cause crosslinking. In the presence of a diamine, the reaction produced a soluble oligourea. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1456–1462, 2001     

运用NMR和DFT研究Michael加成反应的动力学行为及反应机理：(CO)5W=C(OEt)C2Ph作为底物

利用核磁共振方法研究了取代吡唑对炔基Fischer卡宾化合物的Michael加成的动力学行为，该反应为典型的二级反应。当吡唑的3，5-位由较大基团取代时，反应速率常数变小，而活化焓和活化熵明显增大。利用密度泛函理论研究了炔基钨卡宾为底物的Michael加成反应机理，发现吡唑上取代基团的增大可以导致第三步反应的活化能大于第一步，从而使反应的决速步骤由原来的第一步转变为第三步。     

Application of bis(iminophosphorane) in heterocyclic synthesis: new entries to symmetrically or unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones

The bis(carbodiimides) 4, obtained from bis-aza-Wittig reactions of bis(iminophosphorane) 3 with 2 equiv of aromatic isocyanates, were reacted with secondary amine to give symmetrically substituted 2,7-diaminothieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-dione 6 in the presence of a catalytic amount of EtO(-)Na(+). Reactions of 4 with phenols or ROH in the presence of a catalytic amount of potassium carbonate or RO(-)Na(+) gave symmetrically substituted 2,7-diaryl(alkyl)oxythieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 6 in satisfactory yields. However, iminophosphoranes 9 were obtained via reaction of bis(iminophosphorane) 3 with 1 equiv of aromatic isocyanate and subsequent reaction with an amine in the presence of a catalytic amount of EtO(-)Na(+). Further reaction of iminophosphoranes 9 with aromatic isocyanates and various nucleophile generated unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 12 in good yields.     

Addition–elimination versus Tishchenko reaction in the gas phase

Gas phase reactions of the substituted phenide ions with methyl formate have been studied. It was found that the results of these reactions depend mainly on the basicity of the phenide ion, which is related to the presence of the electron‐accepting or electron‐donating substituents in the benzene ring. It was shown that the phenide ions substituted with electron‐withdrawing groups react with methyl formate in the gas phase in a two‐step reaction. The first step that proceeds according to the typical addition–elimination mechanism results in the formation of the anion of the respective benzaldehyde derivative with the negative charge located either in the aldehyde group (acyl anion) or in the benzene ring (phenide anion) in position ortho to an aldehyde moiety. In the second step, the preliminary‐formed anion reacts with the second molecule of methyl formate yielding formally product of the second addition–elimination reaction. Theoretical calculations as well as collision induced dissociation spectra of the model compounds suggest that this reaction proceeds according to the Tishchenko reaction mechanism yielding the respective phthalide anion. According to our knowledge, this is the first example of the Tishchenko‐type reaction in the gas phase. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis of derivatives of 4-alkylthiouracil,cytosine, pyrido[2,3-d]pyrimidine,and pyrimido[4,5-d]pyrimidine from the N,S- and N,N-acetals of diacetylketene and isocyanates

The action of alkyl and aryl isocyanates on the N,S-acetals of diacetylketene leads to the formation of 4-alkylthio-5-acetyl-1-alkyl(aryl)-6-methyl-1H-pyrimidin-2-ones (derivatives of 4-alkylthiouracils). The reaction of the synthesized thiouracils with amines or the reaction of the N,N-acetals of diacetylketene (N,N-ADK) with an equi-molar amount of aryl isocyanates leads to the formation of substituted 4-amino-5-acetyl-1H-pyrimidin-2-ones (derivatives of cytosine). From the latter and isocyanates or directly from N,N-ADK and an excess of the isocyanate, derivatives of 4-methylene-1H,3H, 4H-pyrimido[4,5-d]pyrimidine-2,7-dione were obtained. The exception was the condensation of 3-[N-(4,6-dimethyl-2-pyrimidinyl)diaminomethylene]pentane-2,4-dione with aryl isocyanates, which led to 3H,8H-pyrido[2,3-d]pyrimidine-2,5-diones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2593–2599, November, 1991.     

Complex formation between catalysts,alcohols, and isocyanates in the preparation of urethanes

The mechanism of the catalyzed reaction between alcohols and isocyanates was investigated by means of NMR, infrared, and ultraviolet spectroscopy. The shift of the ? OH proton resonance in the NMR spectra indicated the existence of a 1 : 1 complex in the system dibutyltin dilaurate (DBTDL)–1-methoxy-2-propanol. Complex formation was also observed when lead naphthenate or triethylamine (TEA) were substituted for the DBTDL. Mixtures of the DBTDL–TEA catalysts caused a shift of the ? OH proton resonance greater than that observed for either catalyst alone. This correlates with the synergistic effect noted when preparing urethanes with a mixture of these catalysts. No direct evidence of alcohol–catalyst complex formation could be obtained by infrared spectroscopy. Efforts were also made to detect complex formation in mixtures of phenyl isocyanate and catalysts. These complexes could not be detected by NMR, infrared, or ultraviolet spectroscopy.     

One-pot,three-component synthesis of highly functionalized pyrimidone derivatives and access to indole fused pyrimidones via palladium-catalyzed intramolecular Heck reaction

A simple and facile approach to highly functionalized pyrimidone derivatives and indole fused pyrimidones has been developed. The synthesis of substituted pyrimidone derivatives in moderate to good yields involves [4+2] cycloaddition of 1,4-dipoles generated from α,β-unsarurated imines and dimethyl acetylenedicarboxylate (DMAD) with isocyanates as dipolarophiles. Furthermore, the pyrimidones resulted from 2-bromophenyl isocyanate could be transformed into various indole fused pyrimidones via intramolecular palladium-catalyzed Heck reaction under different conditions.     

Reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide heterocyclic system: a combined experimental and theoretical study

The reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide (or beta-amino-gamma-sultone) heterocyclic system has scarcely been studied. Here we describe the reactivity of this system towards electrophiles and amines on readily available model substrates differently substituted at the C-5 position. A variety of C-electrophiles, carbonyl electrophiles (such as acyl chlorides, isocyanates, or aldehydes) and halogen or nitrogen electrophiles have been explored. Both the C-3 and 4-amino positions of the beta-amino-gamma-sultone system are able to undergo electrophilic reactions, and the reaction products depend on the electrophile used and on the reaction conditions. On the other hand, nucleophilic attack of amines occurs at the C-4 position of the beta-amino-gamma-sultone system only in spiranic substrates bearing alicyclic substituents at the C-5 position. A comparative computational study between spiranic and non-spiranic substrates suggests that conformational changes, undergone on intermediate compounds, account for the observed reactivity differences. Moreover, these conformational changes seem to bring about an increase of electron density on the N-4 and C-3 atoms of the enaminic system, and a possible enhancement in the reactivity of spiranic substrates towards electrophiles in the presence of amines. Experimental data consistent with this predicted enhanced reactivity is also presented.     

Parallel synthesis of diarylureas and their evaluation as inhibitors of insulin-like growth factor receptor

Diarylurea (DAU) compounds, particularly species composed of a heteroaryl ring system conjugated through a urea linkage to a substituted arene, were previously identified by the screening of a diverse chemical library to be active against the insulin growth factor receptor (IGF-1R). DAU compounds 4{a,b} were synthesized in parallel by the coupling of aryl amines 2{a} with aryl isocyanates 3{b}. Preparative RP-HPLC purification was found necessary to remove an impurity 5{b}, the symmetric urea resulting from the hydrolytic degradation of aryl isocyanates. Two libraries of DAU compounds were prepared to perform preliminary optimization of the two-ring systems for inhibitory activity against IGF-1R. In the first library, we explored a series of heteroaryl ring systems and found the 4-aminoquinaldine ring system to be optimal among those evaluated. The second library fixed the 4-aminoquinaldine ring system and we evaluated a series of substituted arenes conjugated to it. Overall, eight compounds based on the 4-aminoquinaldine heteroaryl system were found to have moderate activity against IGF-1R with IC(50) values better than 40 microM.     

Halogenation of N-substituted p-quinone monoimines and p-quinone monooxime esrers: XI. Synthesis and halogenation of 4-[aryl(alkyl)aminocarbonyl-oxyimino]cyclohexa-2,5-dien-1-ones

4-[Aryl(alkyl)aminocarbonyloxyimino]cyclohexa-2,5-dien-1-ones were synthesized by treatment of various substituted p-quinone monooximes with aryl isocyanates. The selectivity in the halogenation of the obtained p-quinone monooxime esters depended on the substrate structure and was either completely (syn addition) or partly regioselective (syn or anti addition). In all cases, the effect of steric factor was crucial, and the reaction was accompanied by halogenation of the aryl fragment.     

A new approach for the synthesis of N-sulfonyl hydantoins

Two methods are described for the synthesis of a new series of hydantoins using the same reagents. The best process is based on the addition of N-aryloxy(alkoxy)sulfonyl isocyanates to an equimolar mixture of bromoamides and triethylamine dissolved in anhydrous acetone. This reaction is violent and provides the urea salts in situ which are transformed into the corresponding substituted hydantoins.     

[2 + 2] Cycloaddition reactions of unsymmetrically substituted carbodiimides

N-Alkyl-N′-arylcarbodiimides add alkyl and aryl isocyanates to the N-alkyl substituted CN double bond to yield 4-arylimino-1,3-diazetidine-2-ones 3. In the case of bulky alkyl substituents the reaction still proceeds across the sterically hindered CN double bond. N-Aryl-N′-[(4-dimethylamino)phenyl]carbodiimides form [2 + 2] cycloadducts with aryl isocyanates preferentially across the CN double bond not attached to the electron-rich aryl groups. However, steric crowding on this CN double bond directs the reaction to the adjacent double bond of the heterocumulative system. The rate of the [2 + 2] cycloaddition reaction of N'-methyl-N′-phenylcarbodiimide with 4-nitrophenylisocyanate is about 2.5 times faster in acetonitrile than in benzene.     

Synthesis and Properties of Some New Nicotinoyl Isocyanates and Their Fragmentation under Electron Impact

A convenient preparative route for synthesis has been developed and nicotinoyl isocyanates (NIC) have been obtained for the first time by the action of oxalyl chloride on amides of substituted nicotinic acids. A procedure has been found for suppressing the formation of hydrochlorides of nicotinoyl amides by the competing reaction of HCl with the initial amides of nicotinic acids. The special features of the fragmentation of nicotinoyl isocyanates under electron impact have been studied.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 549–553, April, 2005.     

A theoreticalab initio study of the reaction of formation of 2-fluoroethanol from oxirane and HF

The reaction of ring opening of epoxides under the action of a halogenic acid has been investigated using as model the system C₂H₄O + HF → CH₂OHCH₂F. The physical conditions chosen for the model more directly correspond to the gas phase reaction and under these conditions the preferred mechanism leads to the formation of a halohydrine having the same configuration at the C atom as the reagent. Parallel investigations have been performed on other mechanisms which postulate the preliminary formation of the conjugate acid of the oxirane (C₂H₄OH⁺) and proceed via the well known mechanismsA ₁ orA ₂. In this case the best mechanism corresponds to the so-called “borderlineA ₂” mechanism. This last type of mechanism probably is the dominant one in protic solutions, but by coupling the present calculations with experimental conductometric measurements in anhydrous aprotic media one could consider the first concerted mechanism as a possible candidate also for the reaction in “inert” media. A qualitative analysis of the transition state indicates, in addition, that the propension for the retention path, is probably emphasized by the use of HF as reactant, and that with other acids, like HC1, or even by assuming the presence of dimers like HF·HF, the inversion path could be preferred. The investigations have been done by determining the geometry of the transition state and the reaction coordinate withab initio SCF STO-3G calculations on the whole nuclear configuration space (21 dimensions). These calculations have been supplemented by a few CI calculations on the same basis set and by a few SCF calculations with a larger basis set.     

A new multicomponent reaction catalyzed by a [Lewis Acid](+)[Co(CO)(4)](-) catalyst: stereospecific synthesis of 1,3-oxazinane-2,4-diones from epoxides, isocyanates, and CO

The use of mechanistic information to develop a new, catalytic multicomponent reaction is described. The complex [(salph)Al(THF)2]+[Co(CO)4]- (1, salph = N,N'-o-phenylenebis(3,5-di-tert-butylsalicylideneimine), THF = tetrahydrofuran), which is known to carbonylate epoxides, aziridines, and beta-lactones, was used to catalyze the synthesis of 1,3-oxazinane-2,4-diones from epoxides, isocyanates, and CO. Under optimized conditions, the reaction was both selective and high-yielding. 1,3-Oxazinane-2,4-diones were synthesized from a variety of epoxides and isocyanates, including some epoxides that do not undergo simple ring-expansion carbonylation. The best results were obtained using highly electrophilic isocyanates. The mechanism of the multicomponent reaction was investigated using labeling and stereochemistry, and the data obtained were consistent with the 1-catalyzed formation of beta-lactone and 1,3-oxazinane-2,4-dione from a common intermediate.     

N-(5-巯基-1，3，4-噻二唑-2-基)-N'-取代苯甲酰基脲与取代的苯氧乙酰基脲的合成与生物活性

通过2-氨基-5-巯基-1,3,4-噻二唑与取代苯甲酰基异氰酸酯及取代苯氧乙酰基异氰酸酯反应,合成了21种新的取代苯甲酰基脲与取代苯氧乙酰基脲,其结构用红外光谱、核磁共振氢谱和元素分析进行了确证,初步的生物活性测定试验表明,部分目标化合物具有良好的植物生长调节活性.     

Conjugated schiff's bases.20 cycloaddition of heterocomulenes to some 1,3-heterodienes involving unusual assistance of methyl group

Highly substituted 1,Δ-diazabutadienes react with aroyl isothiocyanates in a 1,3-dipolar cycloaddition node yielding five-membered thiohydantoin-type heterocycles. The cycloaddition is accompanied by 1,4 shift of hydrogen from a methyl group attached to C2 of the 1,C-diazabutadiene moiety. The mechanism of this reaction is discussed in comparison with similar cycloadditions with aryl isocyanates.