Reaction with halo ketones

Reaction of halo ketones or diazo ketones with boranes 10-112 Carbonylation of alkyl halides... 

Reaction of halo ketones or diazo ketones with boranes 0-102 Carbonylation of alkyl halides 0-104 Reaction between acyl halides and organometallic compounds 0-105 Reaction between other acid derivatives and organometallic compounds... 

Six-membered ring cyclic thioamides react with -halo ketones to give the thiazolo[3,2- ]pyridinium system, e.g., 58 (Scheme 36). A similar reaction of 59 affords the thioisomnchnone 60 (Scheme 37) <2001J(P1)2055, CHEC-III (11.10.8.2)487>. 

Treatment with sodium ethoxide of thioethers 316, prepared by the reaction of l,2,5,6,7,8-hexahydro-l,6-naphthyridine-2thiones 317 with halo ketones, esters, amides or nitriles, resulted in the synthesis of thieno[2,3-Z>]-l,6-naphthyridines 318 (1993BCJ3716). 

Thiazole and its derivatives are useful compounds in medicinal and agricultural chemistry. The thiazolium ring is present in vitamin B1 and its coenzyme form is important for the decarboxylation of a-keto acids [74]. This heterocyclic system has broad application in drug development for the treatment of inflammation [75] and bacterial [76] and HIV infections [77]. Hence the thiazole nucleus has been much studied in organic and medicinal chemistry. Originally it was synthesized by the Hantzsch reaction (a-halo ketones with thioamides or thioureas) (Equation 4.38) [78]. 

With halo ketones and aldehydes it must be remembered that ammonia and primary amines may also react with the carbonyl group, but side reactions of that type can often be prevented by use of the acetal. 

Benzo[Z)]flirans are also accessible by reaction of phenolates with halo ketones followed by cyclodehydration with H2SO4, polyphosphoric acid or zeolites [11] ... 

Open-chain aUcanones and in particular those with methyl substituents are transformed into their corresponding carboxylic acids by treatment with hypohabte [250]. In this so-called haloform reaction, a-halo ketones are important intermediates. For example, by reaction with hypohaUte, methyl ketone 29 is converted into a,a,a-trihalo ketone 30, which is easily hydrolyzed to give carboxylate 31 and haloform 32 [Eq. (12)]. 

The possible ambiguities that may arise in ring syntheses based upon nueleophilic reaetions with a-halo ketones are also exemplified by the reactions with a-lithioaldimines leading to pyrrole formation, as shown in Scheme 73a 73TL3517). A simitar problem could well arise in the related carbazole synthesis indicated in Scheme 73b if a less symmetrical substrate was employed 81TL1475). 

Gasteiger and Herzig have investigated the reactions of halooxiranes with nucleophiles the oxiranes function as halo ketone equivalents (81AG(E)868, 81T2607). 

The second general method is the aluminum halide-catalyzed reaction of acid halides with ethylene to give g-halo ketones which are subsequently converted to ketals. ... 

A reaction which is of considerable importance for the selective labeling of a position adjacent to a carbonyl group is the treatment of a-halo ketones (mainly bromides) with zinc in acetic acid-OD, or deuteriobromic acid at... 

Halogenation of the double bond usually prevents the satisfactory preparation of vinylogous a-halo ketones by direct reaction of unsaturated ketones with... 

Until recently, pyridine-type bases have been commonly used to produce conjugated enones from 2-halo ketones yields are usually poor °° and these reactions are frequently accompanied by rearrangement, reduction and salt formation. Thus, Warnhoff found that dehydrobromination of (28) with 2,4-lutidine gave a mixture of (29), (30) and (31) in the ratio 55 25 20. Collidine gave a ratio of 38 25 37, whereas pyridine gave mainly the salt (32). 

A series of interesting pyrazolo[3,4-(f pyrimidine derivatives was obtained by a thermal denitrocyclization reaction of hydrazones, e.g. 164 or 166, easily formed from the corresponding aldehyde or ketone hydrazones with halo-nitrouracil derivatives, e.g. 163 (71CC1442, 72CC298). Intermediates 164 or 166 can be isolated and their cyclization in suitable solvents (methanol, DMF, DMSO) provided high yields of the products. Aldehyde hydrazones yielded the corresponding l,7-dihydropyrazolo[3,4-J]pyrimidines, e.g. 165, whereas ketone hydrazones gave l,5-dihydropyrazolo[3,4-pyrimidine derivatives, e.g. spirocyclic compound 167 (Scheme 26). 

With cyclic a-halo ketones, e.g. 2-chloro cyclohexanone 6, the Favorskii rearrangement leads to a ring contraction by one carbon atom. This type of reaction has for example found application as a key step in the synthesis of cubane by Eaton and Cole for the construction of the cubic carbon skeleton ... 

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone ... 

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

We found that the optimal reaction protocol was to add a solution of a-bromo ketone in THF to the amidine in aqueous THF in the presence of potassium bicarbonate under vigorous reflux. Using this procedure, 2,4-disubstituted imidazoles were isolated in excellent yields with >95% purity without column chromatography. Aromatic and aliphatic a-halo ketones participate in this reaction with a variety of aromatic amidines, as indicated in Table 1. Particularly noteworthy is that reactions involving pyridylamidines or chloroacetone are substantially more robust using this process (entries 3 and 4). We have successfully used this protocol on a multi-kilogram scale. 

The fact that the rate law of hydrogen bromide elimination is first order with respect to the base may be interpreted by an E2 mechanism. The antiperiplanar position of the hydrogen and the bromine atoms in Ih also makes this mechanism very likely. Earlier the same mechanism was proposed for the elimination reaction of some tertiary a-halo ketones (ref. 19). Other mechanism, such as ElcB or El, seems to be very improbable considering the lack of any deuteration at C-2 or the lack of any rearrangement and the fact that the generation of a-keto cations requires acidic conditions (ref. 20). 

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine followed by cleavage of the resulting salt with ethanolic HCl. The method, called the Delepine reaction, is most successful for active halides such as allylic and benzylic halides and a-halo ketones, and for primary... 

When diazo ketones are treated with HBr or HCl, they give the respective a-halo ketones, but HI does not give the reaction, since it reduces the product to a methyl ketone (10-87). a-Fluoro ketones can be prepared by addition of the diazo ketone to polyhydrogen fluoride-pyridine. This method is also successful for diazoalkanes. 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Although superficially this reaction resembles 10-94 it is likely that the mechanism is quite different, involving migration of an R group from boron to carbon (see also 18-23-18-26). The mechanism is not known with certainty, it may be tentatively shown as (illustrated for an a-halo ketone) ... 

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

The reaction of oc-halo ketones (chloro, bromo, or iodo) with alkoxide ions rearranged esters is called the Favorskii rearrangement. 

When unsymmetrical ketones were used in this reaction (with BF3 as catalyst), the less highly substituted carbon preferentially migrated. The reaction can be made regioselective by applying this method to the a-halo ketone, in which case only the other carbon migrates. The ethyl diazoacetate procedure has also been applied to the acetals or ketals of a, P-unsaturated aldehydes and ketones. ... 

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