Ketenes, preparation tables

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

Schollkopf and co-workers have synthesized a number of cyclopropanone acetals by the addition of various sulfur- and oxygen-containing carbenes to ketene diethylacetals (Table 3).26>27> Similarly, cyclopropanone dithioacetals may be prepared by the addition of the Ws-thiomethyl and Ws-thiobenzylcarbenes 12a, b to olefins.29) However, cyclopropanone acetal formation by this method requires double bonds with considerable electron enrichment and the yields are generally low. With unsubstituted olefins such as cyclohexene, the carbenes 12 a, b tend to form dimeric and trimeric products such as 13 and 14, instead of the double bond addition products. 

The procedure illustrates a general method for the preparation of ketene S,N-acetals via thioamides and their crystalline quaternary iodides some other examples are shown in Table I. 2,2-Dialkyl-substituted ketene S,N-acetals cannot be prepared by this method because the nature of the products makes rigorous purification impractical. Ketene S,N-acctals are useful starting materials for many syntheses.11,13 15... 

Photolysis or thermolysis of heteroatom-substituted chromium carbene complexes can lead to the formation of ketene-like intermediates (cf. Sections 2.2.3 and 2.2.5). The reaction of these intermediates with tertiary amines can yield ammonium ylides, which can undergo Stevens rearrangement [294,365,366] (see also Entry 6, Table 2.14 and Experimental Procedure 2.2.1). This reaction sequence has been used to prepare pyrrolidones and other nitrogen-containing heterocycles. Examples of such reactions are given in Figure 2.31 and Table 2.21. 

Intramolecular acylation reactions with ketene complexes, generated, for instance, by thermolysis or photolysis of carbene complexes, can also be used for the preparation of six-membered rings. Illustrative examples are shown in Table 2.23. 

Table I records the results obtained in the preparation of 30 cycloaddition products from the acridizinium cation. As was demonstrated by Fields, Regan, and Dignan, even preparative experiments done at different temperatures and in different solvents are adequate to prove the inverse electron demand character of the reaction. Nucleophilic alkenes, like ketene diethyl acetal, reacted in minutes at room temperature while the strongly electrophilic alkene, tetracyanoethylene, failed to react under any conditions.

Divinylethyl orthoacetate is prepared in 80 % yield in a similar manner by reacting ketene divinyl acetal and ethanol under acid catalysis at 0°-5°C. (See Table VI [124].)... 

The carbenoid from Et2Zn/CH2I2 [17], particularly when generated in the presence of oxygen [18], is more reactive than the conventional Simmons-Smith reagents. The milder conditions required are suitable for the preparation of 1-[16, 19] or 2-alkoxy-l-siloxycyclopropanes [20], which are generally more sensitive than the parent alkyl substituted siloxycyclopropanes (Table 2). Cyclopropanation of silyl ketene acetals is not completely stereospecific, since isomerization of the double bond in the starting material competes with the cyclopropanation [19]. 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

Sulfonyl chlorides having an a-hydrogen are unstable under basic reaction conditions and can give variable results [96,97]. For base-labile sulfonyl chlorides, the use of O-silyl ketene acetals as scavengers for HC1 has been recommended [96]. Table 8.7 lists some illustrative procedures for the preparation of sulfonamides from primary amines on solid phase. Further examples have been reported [98-101]. 

Diazocarbonyl compounds can also be prepared by C-acylation of diazoalkanes with polystyrene-bound acyl halides (Entry 6, Table 10.19). As an alternative to diazomethane, the more stable a-(trimethylsilyl)diazomethane may be used, which is sufficiently nucleophilic to react with acyl halides. On heating, the resulting a-(trimethyl-silyl)diazo ketones undergo Wolff rearrangement to yield ketenes, and have also been used as starting materials for the preparation of oxazoles [368]. 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

The reduction of a-amino mixed anhydrides with lithium tri-/ert-butoxyaluminum hydride in THF at —70 °C is a very efficient method for synthesis of amino aldehydes (Table 9). 551 Three approaches were taken for the reduction of a-amino mixed anhydrides. 55 The first approach reduced Boc-Ala-OC02Et with lithium tri-terf-butoxyaluminum hydride was unsuccessful due to intramolecular rearrangements that gave Boc-Ala-OEt in addition to the Boc-Ala-H. The second approach involved reduction of diphenylacetic anhydride derivatives, which were prepared from Boc amino acids and diphenyl ketene, gave a diphenylacetic acid byproduct that was very difficult to remove unless the aldehyde was converted into its semicarbazone and separated chromatographically yields were 51-69%. The last and... 

Carreira and co-workers reported novel Ti(lV) complexes 69 derived from Ti(0 Pr)4, tridentate ligands 67, and salicylic acids such as 68. The complexes serve as competent catalysts for the addition of the methyl acetate-derived silyl ketene acetal to a large range of aldehydes (Eqs. 8B2.16 and 8B2.17) [22]. The salient features of this system include the wide range of functionalized aliphatic and aromatic aldehydes that may be used the ability to carry out the reaction with 0.2-5 mol % catalyst-loading and experimental ease with which the process is executed (Table 8B2.8). Thus the reaction can be carried out at -10 to 0°C, in a variety of solvents, without recourse to slow addition of reagents. The adducts from the catalytic reaction were isolated with excellent enantiopurities up to 99% ee. The original catalyst-preparation... 

Recently, Corey and coworkers prepared the cinchonidine-derived bifluoride 20 from the corresponding bromide by passage of a methanolic solution through a column of Amberlyst A-26 OH- form, and subsequent neutralization with 2 equiv. of 1 N HF solution and evaporation (the modified method C in Scheme 9.5). The catalytic activity and chiral efficiency of 20 (dried over P205 under vacuum) have been demonstrated by the development of a Mukaiyama-type aldol reaction of ketene silyl acetal 21 with aldehydes under mild conditions, giving mostly syw-P-hydroxy-a-amino esters 22 as the major diastereomer with good to excellent enantiomeric excesses (Table 9.4) [23],... 

A versatile synthesis of cyclopropanones and closely related derivatives is provided by the diazoalkane-ketene reaction as shown in Scheme 2. Using this method, the parent ketone 2>3> and alkyl-substituted cyclopropanones 1()) have been prepared in yields of 60—90% based upon the concentration of diazoalkaneb) (Table 2). The reaction is rapid at Dry Ice-acetone temperatures and is accompanied by evolution of nitrogen. Although most cyclopropanones are not isolable, dilute solutions of 3 (0.5—0.8 M) may be stored at — 78 °C for several days or at room temperature in the presence of suitable stabilizing agents.15) The hydrate and hemiketal derivatives are readily prepared by the addition of water or alcohols to the solutions of. .2>8>5)... 

Cyclopropanone acetals may also be prepared by the addition of other one-carbon species to ketene acetals as shown in Table 3. Thus, McElvain and Weyna have synthesized several cyclopropanone deriv-... 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

Examples of the application of this chemistry to the preparation of cyclobutanones, cyclobutenones, and P-lactams are presented in the Table. The mesityl thiol ester has proven to be particularly effective in reactions with less ketenophilic alkenes, although with the more reactive ketenophiles nearly identical results are obtained using either the mesityl a-diazo thiol ester or the more readily available thiophenyl ester. In the case of readily available ketenophiles, the reaction is best conducted using excess alkene, alkyne, or imine, but in other cases the cycloaddition can be carried out with excess diazo thiol ester. The efficiency of the reaction with unactivated alkenes is especially notable, and compares favorably with results obtained previously employing dichloroketene. For example, addition of dichloroketene to methylenecyclohexane is reported to proceed in 55% yield," while up to 81% of the desired [2-1-2] cycloadduct is produced in the reaction of (mesitylthio)ketene with this olefin under our conditions. 

The first example of an asymmetric [2 + 2] cycloaddition of a ketene to an aldehyde was reported in 1994 by Miyano and coworkers [28]. They found that chiral aluminum catalysts prepared from different 3,3 -disubstituted BINOL derivatives resulted in low to modest asymmetric induction for a range of aliphatic and aromatic aldehydes. There does not seen to be a correlation between asymmetric induction and the size of the aldehyde. The data in Table 5 show that the optimum ligand for this reaction is triphenylsilyl substituted BINOL. It is curious that the catalyst prepared from this ligand and the catalyst prepared from BINOL result in opposite facial selectivity with... 

The number of chiral diazaaluminolidine catalysts has been extended by Dymock, Kocienski and Pons, who introduced the more convenient to handle trimethylsilyl-ketene [31]. The catalysts in this study were prepared from slightly different sulfonamides but asymmetric induction was comparable with that obtained with the ketene and similar aldehydes. With trimethylsilylketene, two diastereomers are possible and in all examples studied the cis isomer 126 was the predominate product. TTie reactions in Table 7 were performed with 30 mol % catalyst—with 20 mol % catalyst the reaction is incomplete. A more active catalyst can be prepared from the bis-trifluoro-methylsulfonyl derivative of 128, but asymmetric induction was low. It was reported that ortho substituents on the aryl sulfonamide were necessary for higher induction but data were provided only for the aryl sulfonamide substituents summarized in Table 7. Both symmetrical and unsymmetrical diazaaluminolidines were examined as catalysts in an attempt to optimize asymmetric induction but significant differences were not found. The catalyst prepared from the symmetric bis-sulfonamide 128 with Ar = 2,4,6-tri-/yo-propylphenyl did not give any reaction even at 100 mol %. 

The chemical history of the a-peroxylactones is almost as long. Derivatives (3a, b) were postulated as labile reaction intermediates in the autoxidation of ketenes (Eq. 6) to explain the formation of ketones and carbon dioxide. Indeed, very recent work confirmed these claims, except that singlet oxygenation of ketenes is preparatively more effective. However, the first stable a-peroxylactone that was isolated and characterized was the tert-butyl derivative (4), obtained from the corresponding a-hydroperoxy acid via dicyclohexylcarbodiimide (DCC) dehydration (Eq. 7). In the meantime, a number of stable a-peroxylactones have been reported (Table 2). 

Examples of sulfanyl-substituted 1,1-dichlorocyclopropanes 1 are collected in Table 20 the adduct of dichlorocarbene to ketene dithioacetal is also included. Rather unexpectedly, the chloroform/base/phase-transfer catalyst method is seldom used for their preparation. ... 

For acyl halides or anhydrides which do not afford ketenes in the presence of base (such as perfiuoroacyi halides), however, the a-acylmethylenephosphoranes can be prepared directly in one step from the phosphonium salts by using two equivalents of base by the present procedure (Table I).2 Both tetrahydrofuran and methylene chloride have been used as solvents and in the case of the title compound, tetrahydrofuran provides the best results. Good yields of the phosphoranes are generally obtained when is an electron-withdrawing group such as ester or nitrile. The yields of phosphoranes obtained for the thiomethyl or phenyl cases can be... 

As is shown in Scheme 6 and Table 1, alkynyl sulfides can be employed in the asymmetric [2-1-2] cycloaddition reaction however, the reactivity of alkynyl sulfides is largely dependent on the substituent at sulfur. A phenyl sulfide, 1-phenylthio-l-hexyne (5e), does not react with 2a, while the alkynyl methyl sulfides 5a-d react smoothly with fumaric and acryUc acid derivatives 2a,c, yielding cyclobutenes 6. Trisubstituted cyclobutenes are prepared in good yield and in almost enantiomerically pure forms with only a catalytic amount of the chiral titanium reagent. For the preparation of tetrasubstituted cyclobutenes, however, an equimolar amount of the chiral titanium is required for the reaction to go to completion. Compared with the ketene dimethyldithioacetal 3a, alkynyl methyl sulfides 5 are less reactive and the reaction between the crotonoyloxazo-lidinone 2b and 5 fails even in the presence of an equimolar amount of the catalyst. 

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