A-Bromoesters

Synthesis The CO2H group spells trouble. We would certainly have to use an ester, but the a-bromoester is too reactive to use with an acetylene. Also there is a danger that the double bond in A will move into conjugation. We can get round all these problems with an epoxide and then oxidise at the end ... 

The conversion of chiral boronic esters iato optically pure B-aIkyl-9-BBN derivatives followed by reaction with a-bromoketones, a-bromoesters, or a-bromonitriles leads to the homologated P-chiral ketones, esters, and nitriles, respectively (526). 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

Of interest is a recent report of a rapid synthesis of efaroxin (51), a potent, selective O2 adrenoceptor antagonist, using Darzens Reaction. Accordingly, a-bromoester 48 was condensed with aldehyde 47. The glycidic ester (49) was then hydrogenated to reduce the more labile epoxide bond to give alcohol 50. Subsequent standard transformations subsequently lead to a completed 4-step synthesis of efaroxin. o... 

Benzoxazine, an heterocycle present as structural subunit in many naturally occurring and synthetic bioactive compounds, was prepared under microwave irradiation from a mixture of 2-aminophenol 218 and an a-bromoester 219 (Scheme 80). The reaction proceeded through an initial base-catalyzed alkylation of the phenoUc OH followed by spontaneous amidation. Yields from 44 to 78% were reported for 17 different benzoxazines 220 [ 141]. 

The mesogenic units with methylenic spacers were prepared by reacting the sodium salt of either 4-methoxy-4 -hydroxybiphenyl or 4-phenylphenol with a bromoester in DMF at 82° C for at least 4 hours in the presence of tetrabutylammonium hydrogen sulfate (TBAH) as phase transfer catalyst. In this way, ethyl 4-(4-oxybi-phenyl)butyrate, ethyl 4-(4-methoxy-4 -oxybiphenyl)butyrate, ethyl 4-(4-oxybiphenyl)valerate, ethyl 4-(4-methoxy-4 -oxybiphenyl)-valerate, n-propyl 4-(4-oxybiphenyl)undecanoate and n-propyl 4-(4-methoxy-4 -oxybiphenyl)undecanoate were obtained. These esters were hydrolyzed with base and acidified to obtain the carboxylic acids. The corresponding potassium carboxylates were obtained by reaction with approximately stoichiometric amounts of potassium hydroxide. Experimental details of these syntheses were described elsewhere (27). 

Alternatively, reaction of A-(acylmethylene)naphthyridin-2-ones with ammonium acetate and acetic acid under microwave irradiation gives the imidazonaphthyridines 234 <2004JCM832>, and reaction of 2-amino[l,8]naphthyr-idines with a-bromoketones or a-bromoesters gives the same ring system (Scheme 56) <1996H(43)1229, 1997JHC765>. 

This procedure has been applied successfully to the synthesis of other a-nitroesters from a-bromoesters,3 as listed below ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate. 

The reaction mixture becomes homogeneous and turns deep red-brown shortly after the addition of the a-bromoester. The deep color is, presumably, due to nitrosated phloroglucinol however, this in no way interferes with subsequent isolation of product. 

R1 to R3 with yields ranging from 20% to 90%. For the reaction of acetophenone, allyl bromide can be replaced with propargyl bromide, benzyl bromide, or an a-bromoester, affording the corresponding tertiary alcohols in 86%, 86%, and 66% yields, respectively. 

Scheme 16 summarizes the results obtained by enantioselective radical reduction of a-bromoester by chiral binaphthyl-derived tin hydride. The reactions were generally performed at - 78 °C. An increase in the temperature resulted in the lowering of the selectivity. All reactions mediated by (S)-configured chiral tin hydride showed an (R)-selective preference in the product. The use of the opposite enantiomer of the chiral stannane resulted in a quantitative reversal of the selectivity (not shown). The selectivity remained modest on addition of magnesium Lewis acids. These reductions were also feasible when a catalytic amount of chiral tin hydride (1 mol %) was employed in combination with an excess of achiral hydride NaCNBH3, providing similar results. 

Metzger and co-workers have also described a reduction of a-bromoesters by chiral tin hydrides containing a diastereomeric mixture of 2-[(l-dimethyl-aminoalkyl)phenyl] (DAAP) ligands [51]. The observed enantioselectivities were dependent on the tin hydride used and on the substituents attached to the radical center. 

Recently, Kang and Kim developed new chiral ferrocenyl tin hydride derivatives 72 and 73 (Scheme 19) [60]. The authors screened the new chiral reagent in the reduction of a-bromoesters. Using one equivalent of 73 good ee s were obtained for ester 71. One drawback for this reagent, however, is the lengthy synthetic route for its preparation. 

Since the advent of the one step procedure for the preparation of various substituted thenaldehydes (44), the majority of the necessary starting materials were readily available. Consequently, the Reformatsky reaction was studied with these compounds. With the a-bromoesters the reaction was successfully carried out with four of the thenaldehydes and 2-acetothienone. The nature of the product seemed to depend on the degree of branching of the bromoester. In only one case, where ethyl bromoacetate was used, was a hydroxyester obtained. However, when the carbon atom adjacent to the carbethoxy group was substituted, the product usually contained a hydroxyl group. The dehydration by means of aqueous oxalic acid resulted in a nearly quantitative conversion to the unsaturated esters. 

Catalytic one-pot procedure. Since in the described teUuronium ylide olefmation tellurox-ide is formed as a by-product, and the telluroxide is susceptible to reduction by triphenyl phosphite, a catalytic procedure can be employed, providing a practical one-pot synthesis of a, -unsaturated esters and ketones (method E). By this procedure, a catalytic amount of n-dibutyl telluride reacts with the a-bromoester or a-bromoketone, and the formed tel-luronium salt is converted in situ under phase transfer conditions (solid KjCOj/trace HjO) into the ylide, which reacts in turn with the aldehyde, giving the olefin. Since the reaction is performed in the presence of triphenyl phosphite, the formed dibutyl telluroxide is reduced back to the dibutyl telluride, which is then recycled. 

The mechanism of these alkylations involves a tetracoordmate boron intermediate formed by addition of the enolate of the a-bromoester to the organoborane. The migration then occurs with displacement of bromide ion. In agreement with this mechanism, retention of configuration of the migrating group is observed.21... 

Photochemical cyclization of (78) with formation of the C(3)—N(4) bond leads to oxapenam (79) (78TL4233) (see also Section 5.12.3.4.2). Another method of oxapenam formation involves closure of the C(3)—N(4) bond by base-induced cyclization of a-bromoesters (77CC359, 77CC405). 

Alkylation of 3-methyl-1,2,4,5-tetrahydro-3//-3-benzazepin-2-one in THF-DMF solution containing sodium hydride, with primary and secondary alkyl halides and with a-bromoesters, results predominantly in 1-monoalkyl derivatives, whereas with w,w-dibromoalkanes, 1,1-spiro derivatives are formed (80T1017). Apparently, 6,7-dihydro-5//-dibenz[6,rf]azepin-6-one does not condense with benzaldehyde or with nitrosobenzene at the active methylene group (55JA3393). 

The formation of arylzinc reagents can also be accomplished by using electrochemical methods. With a sacrificial zinc anode and in the presence of nickel 2,2-bipyridyl, polyfunctional zinc reagents of type 36 can be prepared in excellent yields (Scheme 14) . An electrochemical conversion of aryl halides to arylzinc compounds can also be achieved by a cobalt catalysis in DMF/pyridine mixture . The mechanism of this reaction has been carefully studied . This method can also be applied to heterocyclic compounds such as 2- or 3-chloropyridine and 2- or 3-bromothiophenes . Zinc can also be elec-trochemically activated and a mixture of zinc metal and small amounts of zinc formed by electroreduction of zinc halides are very reactive toward a-bromoesters and allylic or benzylic bromides . ... 

Dichloromethane has been found to be an efficient solvent for the activation and for subsequent coupling reactions. Indeed, in dichloromethane, these reactions can be carried out at room temperature in the presence of nitriles and a-bromoesters taken in the same molar ratio, and lead to /3-ketoesters in good yields (40-60%). Conversely, in dimethyl-formamide, and even with an excess of nitrile, only very low yields of ketoester could be obtained (<20%). 

Unlike usual processes, the coupling reaction does not need any excess of halide (the carbonyl compound and the a-bromoester are used in the same molar ratio), or, most remarkably, any excess of zinc as reducing agent, which is also consumed stoichiometri-cally. 

The method is also applicable to the coupling of a-bromoesters with anhydrides as depicted in equation 15. 

In the typical old-fashioned Reformatsky protocol12a d, a mixture of a-bromoester, carbonyl compound and zinc powder is heated in a solvent, generally benzene, for several hours. Under these conditions, the chemical yields often suffer from the concurrence of side-reactions, such as self-condensation of enolizable aldehydes, Claisen condensation of bromoesters or crotonization of the Reformatsky products. However, ever since the outset of Reformatsky studies, chemists have been aware about the need to activate the zinc surface in order to get higher reaction rates and shorter induction times before the process starts, with lower by-product formation. Thus, it became common practice to... 

The authors observed that the applied quantity of electricity (0.2-0.5 F) was always lower than the expected quantity on the basis of Zn consumed (1 g atom). This difference reflects the concurrence of two processes at the anode surface, where the electrochemically promoted reaction (Figure 4) coexists with a classic zinc metal-promoted Reformatsky reaction. Indeed, the electrochemical process produces at the working anode a perfectly clean zinc metal surface, very reactive towards the a-bromoester. 

An analogous non-electrochemical Ni(0)-catalysed process, exploited in a Mannich/ Reformatsky multicomponent process58, will be discussed in Section III (equation 41). In the third study, the a-bromoester Id is simply electrolysed in the presence of a carbonyl compound in DMF/THF in a 1 2 ratio using both indium and zinc rods as sacrificial anodes. While aldehydes afford the expected 3-hydroxyesters in high yield, aliphatic, aromatic and cyclic ketones, with the exception of acetone, directly afford /3-lactones,... 

A number of low-valent or zero-valent metals are able to promote Reformatsky-type reactions of a-bromoesters with carbonyl compounds and related electrophiles60. Starting with calcium and moving rightward along the fourth row of the periodic table, the following metal species have been reported to promote Reformatsky-type reactions ... 

A further chiral auxiliary-based tactic exploited tricarbonyl( 76-arene)chromium complexes of aromatic imines 71, which reacted under ultrasound (US) irradiation with a-bromoesters in a predictable stereochemical course to give comparable amounts of /S-aminoesters and / -lactams, as outlined in equation 44127. Chromium decomplexation is eventually achieved by photochemical oxidation under air. 

The influence of a Lewis acid in favouring the ring closure was confirmed by the use of a catalytic amount of CpiTiCL in imino-Reformatsky reactions with a-bromoesters, -bromocrotonates and a-bromomethylacrylates the corresponding cis /9-lactams were obtained in excellent yields in THF at rt129. 

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