The Chemistry of α-Haloketones and Their Utility in Heterocyclic Synthesis

The molecular structures and spectral properties of α-haloketones as well as their syntheses are analyzed and reviewed. Their reactivity towards oxygen, nitrogen, and sulfur nucleophiles, carboxylic acids, carbon nucleophiles, alkenes, and alkynes are discussed.


I. Introduction
α-Haloketones, first obtained and described as early as the end of the eighteenth century [1], have been attracting increasing attention in view of their high reactivity as building blocks for the preparation of compounds of various classes due to their selective transformations with different reagents. Although over a century has been passed since the discovery of α-haloketones, no comprehensive review articles on their synthetic potential in heterocyclic synthesis have been published. Much information describing the synthesis and the chemistry of α-halogenated carbonyl compounds are scattered throughout the literature. There are short chapters dealing with the synthesis and reactivity of halogenated ketones in Patai's series [2] and in Houben-Weyl's series "Methoden der Organischen Chemie" [3,4]. In addition, the Favorskii rearrangement of α-haloketones has been reviewed by several articles [5][6][7][8][9], and the reactivity of α-haloketones towards nucleophiles was described by Tchoubar in 1955 [10]. It is our hope that by asembling a comprehensive survey of the widely scattered information on the chemistry of α-haloketones as versatile synthons in heterocyclic synthesis, this will focus new attention on the broad potential of these compounds in the synthesis and mechanistic studies of heterocyclic compounds. This review will be restricted to halogenated ketones which carry one halogen atom on the carbon atom α-to a carbonyl function. The α-halogenated aldehydes and carboxylic acids will not be treated in this article. Phenacyl halides are discussed in particular depth due to their frequent appearance in the literature.

II. Molecular Structures and Spectral Properties
A series of papers have investigated the rotation isomerism of α-haloketones using Raman [11], IR [11][12][13][14][15][16][17][18][19][20][21][22][23] and NMR [24,25] spectroscopy. Although α-haloketones can exist as two stereoisomers [11], it has been established, however, that the steric repulsion between the Cl-atom and O-atom, in the liquid state, is much less than that between Cl-atom and an alkyl group. Both of the Cl and O atoms tend to adopt the cisoid-form (θ ~ 0°) which makes it more stable than the transoid-form ( Figure 1).   Tables 1 and 2 show that the carbon in 4-substituted phenacyl bromides exhibits an upfield shift compared with the corresponding acetophenones. This is due to the inductive effect of the bromine atom [26][27][28].  On the scale of carbonyl electrophilicities, measured by 17 O-NMR spectroscopy [29], the presence of halogen atoms α-to the carbonyl group decreases the electron density around the oxygen atom (Table 3) [29,30]. The strength of the electric fields at the bromine atoms in the series of phenacyl bromides were also measured by 79 Br-NQR spectroscopy which shows that the presence of carbonyl group decreases the electric fields at the bromine atom (Table 4) [31].

III. Synthesis of α-Haloketones
A well-documented review by De Kimpe and Verhé [2] described in detail the synthesis of αhalogenated ketones. We shall mention here references dealing with newer methods in addition to some common synthetic methods.

A. General Methods
In general, reaction of aliphatic ketones with halogen most commonly affords mono-substituted haloketones with some side products (Eq 1) [2,34].
Direct fluorination, by using F 2 , often gives rise to side reactions leading to polyfluorinated and degradation products and are therefore of limited use. However, a number of reviews have been published by Erian [34] and others [35-37] on the preparation of α-fluoroketones.
During the monochlorination of acetone, minor amounts of dichloroacetone are always isolated [38]. However, good results for the monochlorination of acetone and higher ketones are possible when the chlorination was carried out in aqueous solution of calcium carbonate .

B. Miscellaneous Halogenating Agents
The nucleophilic fluorination of alkyl iodides, bromides and of α-bromo-or α-chloroketones is smoothly affected by tetrabutylammonium hydrogen difluoride in the presence of a catalytic amount of pyridine, in dioxane, to give good yield of fluorinated compounds (Eq 2) [76].

IV. Chemical Reactivity
On treatment of an α-haloketone with various nucleophiles, the attack can take place at six possible electrophilic sites [2]: the nucleophile is able to attack the carbon of the carbonyl function (position 1), the carbon atom carrying the halogen atom (position 2) and the halogen atom (position 3). In addition, due to the presence of two polar electron-withdrawing groups, the hydrogen atoms at the α-, α'-and β-positions also become susceptible to attack by nucleophiles or bases (positions 4, 5, and 6).
The isolation of stable epoxides in the reaction of an α-haloketone with sodium methoxide and the evidence that these epoxides are reactive intermediates leading to other products gives rise to another explanation by Pearson [90] and others (Eq. 6) [6,[91][92][93][94].
It is noteworthy that the reactivity of α-haloketones is due to the inductive effect of the carbonyl group which enhances the polarity of the carbon-halogen bond by increasing the electron deficiency at the α-carbon atom. Also, the more polar the C-X bond, the faster the reaction with nucleophiles [95]. The data shown in Table 5 summarize the enhanced reactivity of α-halogenated ketones relative to the corresponding alkyl halides in bimolecular nucleophilic substitution reactions [96][97][98][99].

V. Reactions of α-Haloketones with Oxygen, Nitrogen and Sulfur Nucleophiles
The reactions of α-haloketones with oxygen, nitrogen and sulfur nucleophiles are classified separately in one category due to the huge number of references. We have arranged this huge volume of data in terms of the type of the heterocycles formed, starting with five and six membered rings in order of increasing number of heteroatoms. Such systematic treatment provides a clear idea about the synthetic possibilities of the method and may be useful in selecting the direction of further research.
A. Synthesis of Five-Membered Rings with One Heteroatom

Furans and Their Fused Derivatives
The condensation of o-hydroxyacetophenone derivatives 12 with phenacyl bromides under PTC (phase transfer catalysis) conditions in a two phase system, using aqueous K 2 CO 3 (20%) as a base, dichloromethane or benzene as solvent and tetrabutylammonium hydrogen sulfate as the phase transfer catalyst, furnished 2-aroylbenzofurans 15 in a good yield and high purity as well (Scheme 3) [100][101][102].

Scheme 16
N H

117
Br Br

D. Synthesis of Six-Membered Rings with One Heteroatom
The literature survey on the reactions of α-haloketones with oxygen, nitrogen or sulfur nucleophiles offers a few examples for the synthesis of six-membered heterocycles with one heteroatom. For example, 2-hydroxychalcone dibromides 152 gave 8-bromoflavone 159 on treatment with pyridine. It is assumed that the first stage involved both debromination and dehydrobromination, ring closure and dehydrobromination (Scheme 45) [358]. Similar results have been reported [359,360]. The synthesis of substituted 1,6-dioxapyrenes 162 from 2,6-dialkyl-1,5-naphthalenediols 160 is described by Christensen and co-workers (Scheme 46) [361].

X. Miscellaneous Reactions of α-Haloketones
Although some of the following reactions of α-haloketones do not give heterocyclic products directly, but it is worthy important to give short notes on such reactions to show up the importance of α-haloketones as versatile synthons in the synthetic organic chemistry field.

343
The electrochemical reduction of a mixture of aryl halides and α-chloroketones in DMF in the presence of NiBr 2 leads to the cross-coupling products 345 in good yields (Scheme 102) [723].

XI. Conclusions
The data considered in this review clearly demonstrate the high synthetic potential of α-haloketones. Many biologically active heterocyclic compounds have been obtained based on these reagents [62,114,122,126,131,458,508,618,626,[724][725][726][727][728][729][730][731]. This suggests that α-haloketones can be particularly promising synthons in combinatorial synthesis of functionalized carbo-and heterocyclic compounds used in the design of novel highly effective pharmaceuticals with a broad spectrum of bioresponses. The great interest of chemists in such reagents is confirmed by the facts that more than 500 articles of 731 cited in this review are dated in the last two decades, along with a multitude of patents.