Ketene acetals, reactions with amines

The reaction of amines and ketene acetals was used as a main synthetic approach to 1,1-enediamines in earlier years72. Both simple and conjugated 1,1-enediamines can be obtained by this route. Displacement reaction of ketene acetal 34 with two equivalents of piperidine furnishes 1,1-dipiperidinoethene (35) in 62% yield (equation 9)73. Primary amines and ammonia react with 34 to give amidine derivatives. Cyano-74 and trifluor-oacetyl-substituted enediamines75 have been synthesized from the corresponding ketene acetals in good to excellent yields (e.g. equation 10). 

The reactivity of the ethenediazonium salt 9.100 towards the nucleophiles mentioned shows that it has the properties of the corresponding carbocation, since it can ethylate the nucleophile and is prone to attack at the C()ff)-atom of the original ethene-l-diazonium ion. The thermal decomposition pattern is typical of that for an oxonium salt. Reactions with amines are similar to those of ketene acetals. No product that could be explained in terms of an azo coupling reaction, e.g., with 2-naphthol, could be observed. The electrophilicity of the diazonio group is, therefore, low. N-Azo coupling products with azide ions have been postulated with good arguments, however, by Kirmse and Schnurr (1977) with certain short-lived ethene diazonium intermediates produced from nitroso oxazolidones. 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

Scheme 2.9 gives some examples of use of enantioselective catalysts. Entries 1 to 4 are cases of the use of the oxazaborolidinone-type of catalyst with silyl enol ethers and silyl ketene acetals. Entries 5 and 6 are examples of the use of BEMOL-titanium catalysts, and Entry 7 illustrates the use of Sn(OTf)2 in conjunction with a chiral amine ligand. The enantioselectivity in each of these cases is determined entirely by the catalyst because there are no stereocenters adjacent to the reaction sites in the reactants. 

The silyl ketene acetal rearrangement can also be carried out by reaction of the ester with a silyl triflate and tertiary amine, without formation of the ester enolate. Optimum results are obtained with bulky silyl triflates and amines, e.g., f-butyldimethylsilyl triflate and (V-methyl-Af, /V-dicyclohcxylaminc. Under these conditions the reaction is stereoselective for the Z-silyl ketene acetal and the stereochemistry of the allylic double bond determines the syn or anti configuration of the product.243... 

The condensation of activated thiols onto adjacent nitriles is a common method for the preparation of amine-substituted thiophenes. A three component condensation was utilized to prepare a-aminothiophene 11 <00TL1597>. An alternate method for preparing amino-substituted thiophenes involved the treatment of ketene S,JV-acetal 12 with an activated carbonyl compound 13 which gave thiophene 14 <00JOC3690>. This type of reaction has also been utilized to prepare building blocks for the synthesis of fused thiophenes <00JHC363>. 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

This catalytic enamine formation is limited to aldehydes and ketones as starting materials - it does not appear to be possible to prepare corresponding enamines , i.e. A,0-ketene acetals, from esters in this fashion. Nevertheless, the preparation of simple, reactive nucleophiles from normally electrophilic species, aldehydes and ketones, in a catalytic fashion sounds highly attfactive. Furthermore, the catalytic nature of these reactions allows the use of chiral amines, and the further possibility that these reactions can be rendered enantioselective. Enamines react readily with a wide variety of electrophiles, and the range of reactions that can be catalyzed by enamine catalysis is summarized in Scheme 2. 

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

B. Reaction of Amines with Ketene Acetals and ge/w-Dihaloethylenes. .. 1314... 

Cyclic ketene acetals can also react with amines to give 1,1-enediamines with elimination of ethylene glycol76. Treatment of 2-[(methoxycarbonyl)cyanomethylene]-1,3-dioxolane (38) with 1,3-diaminopropane or with 4,5-dimethyl-1,2-phenylenediamine gives the hexahydropyrimidine and the benzimidazoline derivatives 39 and 40, respectively (equation 11). Similarly to the reaction of ketene dithioacetals with amines, the reaction between ketene acetals and amines proceeds via monoamino-substituted intermediates and ketene 7V,Oacetals can be isolated when one molar amine is used72. 

C. Reaction of Amines with Ketene N,S- or Af,0-Acetals and or-Haloenamines... 

Ketene N, O-acetals are converted to 1,1-enediamines when reacted with amines. For example, compound 45 has been prepared by substitution of the methoxy with amine (equation 16)79. Symmetric 1,1-enediamines are obtained when both the alkoxy and the amino substituents are displaced by the amine employed81. In this way, the reaction between ketene N, O-acetals 50 and piperidine leads to 1,1-dipipefidinoethylene (35) (equation 17)81. Alternatively, 35 can be prepared from the reaction of piperidine with triethyl orthoacetate82,83 or with ethoxyacetylene84, reactions which probably proceed via a ketene TV, 0-acetal intermediate. 

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

Benzenediazonium tetrafluoroborate has also been investigated as an electrophilic aminating reagent in the reaction with the ketene silyl acetal 2 derived from the /1-hydroxy ester 119. 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

We have found that the reaction between tr iethylor tho-acetate and excess piperidine or morpholine with acidic catalysis is not an equilibrium reaction. Ethanol generated need not be removed as it forms. Additionally, 1WR studies indicate that at 100°C the preparative reaction is ccnplete in 10 to 20 minutes with little or no substituted acetamide side products formed. Hie stability of these ccnpounds in the presence of alcohol and/or excess amine contrasts the behavior of ketene acetals which revert rapidly to orthoesters in the presence of alcohol. This of course speaks to the utility of these various compounds in the presence of hydroxyl functionalities from either RIM polyols or RIM glycol ooextenders. 

Ketene aminals can be prepared from the reaction of orthoesters, alkoxyacetylenes or ketene acetals with excess secondary amine. 

---