Hindered aromatic aldehydes

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

The criss-cross addition of azines of aromatic aldehydes with various electron-deficient olefins in which the double bond is terminal, for example, methyl acrylate, acrylonitrile, or in which allylic substituents do not sterically hinder the reaction, for example, maleic anhydride, is well known and was duly covered in CHEC-II(1996)<1996CHEC-II(8)747>, as well as in a review <1997ALD97>. Recently, the reaction has been used for the preparation of hyperbranched polymers <1998MI2655, 2002MAC712>. 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

Hindered aliphatic aldehydes R CIIO (R1 = i-Pr or i-Bu) react with benzotriazole and anhydrous methanolic ammonia to yield the secondary amines 115, which are transformed into the phenylated amines 116 by the action of phenyllithium. Benzotriazole, aromatic aldehydes and ammonia give the imines 117, which react with lithium aluminium hydride to form dibenzylamines 118122. 

It has been reported by Patel and Gordon " that SPPS is limited by poor yields with hindered amines, deactivated aromatic aldehydes and slight over alkylation with aliphatic aldehydes. Johnson et al argued that because of the speed and convenience of automated SPPS, support-bound cyclization protocols are ideal for the preparation of numerous cyclo peptide analogues. 

A straightforward method for aldolizing unsymmetrical ketones on the more hindered side involves the use of catalytic titanium(lV) chloride in toluene at room temperature. For examples using acyclic and cyclic ketones, and linear, branched, and aromatic aldehydes, the regioselectivity varied from 7 1 to >99 1, while the symanti ratios were moderate to good, and yields were in the range 62-91%. In contrast to other methods, base is not required, and the ketone can be used as is (i.e. the silyl enol ether is not required). 

The activated Ba(OH)2 was used as a basic catalyst for the Claisen-Schmidt (CS) condensation of a variety of ketones and aromatic aldehydes (288). The reactions were performed in ethanol as solvent at reflux temperature. Excellent yields of the condensation products were obtained (80-100%) within 1 h in a batch reactor. Reaction rates and yields were generally higher than those reported for alkali metal hydroxides as catalysts. Neither the Cannizaro reaction nor self-aldol condensation of the ketone was observed, a result that was attributed to the catalyst s being more nucleophilic than basic. Thus, better selectivity to the condensation product was observed than in homogeneous catalysis under similar conditions. It was found that the reaction takes place on the catalyst surface, and when the reactants were small ketones, the rate-determining step was found to be the surface reaction, whereas with sterically hindered ketones the adsorption process was rate determining. 

In contrast to the epoxides, preparative routes to the aziridines are fairly evenly split between the [C=N + C] and the [C=C + N] routes. Among contributions in the former category, aziridine carboxylate derivatives 110 can be prepared through the lanthanide-catalyzed reaction of imines with diazo compounds, such as ethyl diazoacetate (EDA). In this protocol, iV-benzyl aryl aldimines and imines derived from aromatic amines and hindered aliphatic aldehydes are appropriate substrates <99T12929>. An intramolecular variant of this reaction (e.g.. Ill —> 112) has also been reported <990L667>. 

Except in the case of isobutyraldehyde, where the non-optimized poor yield may be due to the high volatility of the resulting product, the alcohols are formed in good yields. When the aldehyde is sterically hindered (entries 1-2), a-allylation is observed. Conversely, branched alcohols result from unhindered or aromatic aldehydes (entries 4 to 6). Starting from 3-methyl-2-butenal (entry 5), a fluorinated analog of Artemisia alcohol is formed in one step27. 

The Sorghum (S)-oxynitrilase exclusively catalyzes the addition of hydrocyanic acid to aromatic aldehydes with high enantioselectivity, but not to aliphatic aldehydes or ketones [519, 526], In contrast, the Hevea (S)-oxynitrilase was also found to convert aliphatic and a,/ -unsaturated substrates with medium to high selectivity [509, 527]. The stereocomplementary almond (R)-oxynitrilase likewise has a very broad substrate tolerance and accepts both aromatic, aliphatic, and a,/ -unsaturated aldehydes [520, 521, 523, 528, 529] as well as methyl ketones [530] with high enantiomeric excess (Table 9). It is interesting to note that this enzyme will also tolerate sterically hindered substrates such as pivalaldehyde and suitable derivatives 164 which are effective precursors for (R)-pantolactone 165 [531],... 

Several studies have been made of the effect of added metal ions on the pinacol/alcohol ratio. Addition of antimony(m) chloride in catalytic amounts changes the product of the electrochemical reduction of acetophenone in acidic alcohol at a lead electrode from the pinacol in the absence of added metal salt to the secondary alcohol in its presence53. Antimony metal was suspected to be an intermediate in the reduction. Conversely, addition of Sm(in) chloride to DMF solutions of aromatic aldehydes and ketones54 and manganese(II) chloride to DMF solutions of hindered aromatic ketones55 results in selective formation of pinacols in excellent yields. When considering these results one should keep in mind the fact that aromatic ketones tend to form pinacols in DMF even in the absence of added metal ions1,29,45. 

Enantioselectivities of 21-70% ee were observed in the reaction of ethyl- and methyl-vinylketone with aromatic aldehydes 22 using the chiral hydroxy-pyrrolizidine-catalyst 24 which was prepared in four steps starting from BOC-I-prolinol (Scheme 5) [32]. The enan-tioselectivity was explained by the predominant formation of intermediate 26-A, which is less sterically hindered than the isomeric intermediate 26-B. The employment of a reaction temperature of -40 °C, the use of NaBF4 as a co-catalyst, and the presence of a hydroxy group in the base (which allows the formation of intramolecular hydrogen bonds) resulted in good conversions and rates. 

Hindered aromatic thioesters may be lithiated in a similar way to hindered aromatic esters 25.29 Thioimidate 117 is lithiated to give an organolithium 118 which reacts with aldehydes and ketones to form thiiranes 119.86>87... 

A new microwave-assisted protocol for the generation of diversely substituted 3,4-dihydropyrimidine-5-carboxylic acid esters 40 has been developed by Kappe and co-workers [88, 89] using trimethylsilyl chloride (TMSCl) as a mediator for the Biginelli MCR. This involved the reaction of S-ethyl acetothioacetate or ethyl acetoacetate, an aromatic aldehyde and (monosubstituted) urea or thiourea as building blocks. Also sterically hindered aromatic and heterocyclic aldehydes... 

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with Af,A -dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48]. 

The transition metal complex bis(triphenylphosphine)copper(I) borohydride, (Ph3P)2CuBH4, has also been shown to be effective for the reduction of tosylhydrazones to hydrocarbons under mild conditions (refluxing chloroform). Yields from unhindered aliphatic aldehyde and ketone tosylhydrazones are generally in the range 48-84%. Reductions of hindered ketones (e.g. camphor) and aromatic aldehydes were less successful giving 0-20% of reduced products. ... 

Reactions of piperazine-2,5-diones with phosphorus pentachloride and phosphorus pentabromide have been described in Sections V.ID and V.IF, respectively. Aromatic aldehydes condense with 3-methylpiperazine-2,5-dione in the presence of acetic anhydride to form mainly mono-A -acetyl derivatives of trans-3-arylidene-6-methylpiperazine-2,5-diones (e.g., 96, R = Ac) (1066). In these products the acetyl group was shown to be attached to position 1 and the 4,5-amide group was found to be sterically hindered. Photolysis formed the cis isomers. Both isomers were deacetylated with methanolic potassium hydroxide (1066). Condensation of 1,4-diacetylpiperazine-2,5-diones with aldehydes has been applied to the synthesis of unsymmetrical 3,6-diarylidenepiperazine-2,5-diones and the reaction has been extended to l,4-diacetyl-3,6-dimethylpiperazine-2,5-diones (1624). Treatment of (96, R = H) with triethyloxonium tetrafluoroborate in dichloromethane gave the monoimino ether, 5-benzylidene-6-ethoxy-3-hydroxy-2-methyl-2,5-dihydropyrazine (97) (1066). l-Methylpiperazine-2,5-dione similarly treated gave 5-ethoxy-l-methyl-2-oxo-l,2,3,6-tetrahydropyrazine (which was condensed with anthranilic acid at 150° to 2-methyl-l,2-dihydropyrazino[2,l-fi]quinazoline-3(4/0.6-dione (98) (1625), and l,4-dimethylpiperazine-2,5-dione gave 5-ethoxy-l,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrazine and 5,5-diethoxy-l,4-dimethylpiperazin-2-one (1626). 

Chiral oxazolidinone auxiliaries based on D-glucose were used for aldol reactions by Koell et al. [160]. The highest select vities were observed with auxiliaries equipped with the pivaloyl protecting group. The pivaloylated oxazolidinone 228 was transformed into the boron enolate according to the procedure of Evans [161] and subsequently reacted with aliphatic and aromatic aldehydes. The best results were obtained with isobutyric aldehyde (Scheme 10.77). The syn-dldo 229 was formed in 16-fold excess over the a/i Z-diastereomer and with an acceptable yield of 59%. The authors explain the stereoselectivity by a chair-like transition state according to Zimmermann-Traxler. The electrophile approaches at the less hindered r -face of the (Z)-configured enolate double bond. For A -phenacetyl substituents, an inversed stereoselectivity was observed as described above for these oxazolidinone auxiliaries. 

Hindered phenolates have low nucleophilicity and in aprotic solvent may act usefully as EGBs. 2,6-Di-t-butyl-/ -cresol = 16.8) was reduced directly with concomitant hydrogen evolution to give, ex situ, the corresponding tetraethylammonium phenolate [59,60], which was clearly capable of deprotonating aromatic ketones and in the presence of aromatic aldehydes promoted aldol reaction to a, /3-unsaturated ketones which underwent Michael addition. The initial proton transfer from the aromatic ketone ] K = 24.7) is thermodynamically very unfavorable. Even so, aldol reaction took place within a matter of hours upon addition of an aromatic ketone together with an aromatic aldehyde leading to or, /3-unsaturated ketones which subsequently underwent Michael addition with a sec-... 

The direct selenoacetalization of carbonyl compounds by selenols is by far the shortest and most convenient route to selenoacetals. The reaction is usually carried out at 20 C with zinc chloride (0.5 equiv. versus the carbonyl con x>und) and delivers rapidly (<3 h) and in reasonably good yields methyl and phenyl selenoacetals derived from aliphatic aldehydes and ketones and cyclic ketones (Scheme 69). Selenoacetalization is more difficult to achieve with hindered ketones, such as adamantanone and diisopropyl ketone, and with hindered aromatic carbtmyl compounds. In these cases the reaction is best achieved with titanium tetrachloride instead of zinc chloride and is often limited to the methylseleno derivatives (Scheme 78). Tris(methylseleno)borane offers the advantage of not requiring an acid catalyst and is particularly useful for the selenoacetalization of acid labQe aldehydes such as citronellal (Scheme 70, e). 

Hindered rotation occurs on the NMR time scale for numerous other systems with partial double bonds, including carbamates, thioamides, enamines, nitrosamines, alkyl nitrites, diazoketones, aminoboranes, and aromatic aldehydes. Formal double bonds can exhibit free rotation when alternative resonance structures suggest partial single bonding. The calicene 5-5, for example, has a barrier to rotation about the central bond of only 20 kcal mol . ... 

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