2-Bromo-7-boronate

In addition to the AA-BB cross-coupling method used by Dow, an AB-type Suzuki coupling of a 2-bromo-7-boronate 17 could also be used to make PDAFs. However, this method has so far been used only for preparing end-capped low molecular weight PF rods e.g., 18 as macroiniators in the synthesis of rod-coil copolymers (Scheme 6). 

Chiral cyclic boronic esters with (dichloroniethyl)lithium at —100 C form borate complexes4. Borate complexes cart also be formed by generation of (dichloromethyl)lithium from dichloro-methane and lithium diisopropylamide in the presence of a boronic ester at —78 C to — 5 C (Section 1.1.2.1.2.2,)28,19. In situ generation of (dibromomethyl)lilhium is required for preparing a-bromo boronic esters (see Sections 1.1.2.1.1.2. and 1.1.2.1.3.2.). 

Carboxylic Ester Enolates with a-Bromo Boronic Esters... 

Ester enolates replace bromide from a-bromo boronic esters with remarkable diastereoselcctiv-ity. (Dibromomethyl)lithium is generated by addition of lithium diisopropylamide to dibro-momethane in the presence of a boronic ester at — 78 "C to produce an a-bromo boronic ester. Reaction of the a-bromo boronic ester with lithium 1-tert-butoxy-Tpropen-l-olate yields a product that is almost exclusively the threo-isomer (d.r. = 15 1 to 60 1), as shown by conversion to the / -hydroxy carboxylic ester24. It is worth noting the facility with which a-bromo boronic esters racemize in the presence of halide ions72. 

A solution of LDA is prepared by the addition of 12 mmol of 1.6 M butyllithium in hexane to a stirred solution of 1.5 g (15 mmol) of diisopropylaminc in 15 mL of THF at 0°C, then cooled to —78 °C. A solution of 10 mmol of the benzyloxy boronic ester and 10-17 g (60-100 mmol) of dibromomethane is stirred at — 78 °C during dropwise addition of the LDA solution via a cannula. The solvent is distilled at <0.75 Torr <0 °C. The solid residue of borate complex is cooled to — 78 CC and treated with a 0.5-0.7 M solution of anhyd zinc chloride (Section 1.1.2.1.1.1.) [(1 On + 8) mmol, where n is the number of benzyloxy groups in the boronic ester] in THF. The mixture is stirred for 16-20 h at 20-25 °C. An equal volume of petroleum ether (bp 30-60 °C) is added, followed by 100 mL of sat. aq NH4C1. The aqueous phase is further extracted with 4 1 petroleum cthcr/diethyl ether, and the combined organic phase is filtered through a 5-cm column of MgS04 with the aid of additional petroleum ether/diethyl ether. After concentration, the residue of labile a-bromo boronic ester should be used promptly in the next step. 

In a synthetic application of this double inversion sequence, tris(benzyloxy)bromo boronic ester 6 obtained in the ribose sequence (Section 1.1.2.1.3.2.) is converted to the 4-methoxyphenyl-methoxy derivative 7 in the usual way. 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone cleaves the protecting group to furnish the a-hydroxy boronic ester 8. Conversion of the a-hydroxy boronic ester 8 to the methanesulfonate 9 followed by displacement of the sulfonate by phenylmethoxide yields a-benzyloxy boronic ester 10, which is a diastereomer of one of the ribose intermediates37. 

Allylic a-bromo boronic l,l,2,2-tctramethyl-l,2-ethanediyl esters are too labile to permit preparation in high stereochemical purity. Finacol l-bromo-2-propenylboronate with sodium methoxideyields 1-methoxy-2-propenyl boronic l,l,2,2-tetramethyl-l,2-ethanediyl ester54. Attempted conversion of the corresponding chloro boronic ester to alkoxy derivatives failed54. 

Two isomers of chirally deuterated glycerol have been synthesized from a common boronic ester intermediate 1 (synthesis Section I.I.2.1.3.I.)71. (15,25)-Glycerol-l-fi results if the carbon to which the label is attached is derived from dibromomethane and incorporated into an a-bromo boronic ester intermediate 2, which is then reduced with potassium triisopropoxyborodeuteride to the (1 / ,2/ )-l-deutero boronic ester 3. The synthesis of (lS,25)-glycerol-l- / is completed efficiently by dcboronation with hydrogen peroxide and debenzylation with hydrogen over palladium. 

Scheme4.34. Relative rates of SnI and Sn2 reactions of a-bromo boronic esters [138,140].

In a subsequent investigation by the author with others (2) (+)-pinanediol 4-bromo-(R)-aminobutane boronate hydrochloride and other cr-bromo boronic esters have been used as intermediates in the preparation of peptide derivatives (2). 

In earlier work, we had shown that lithium enolates of esters react with a-bromo boronic esters in a highly diastereoselective manner (25). A similarly high level of diastereocontrol prevails in the cyclization of cyano substituted boronic esters (24). We chose to concentrate first on closure of cyclobutanes. 

The possibility of double inversion to produce opposite stereochemistry at one stereocenter was also investigated. Conversion of bromo boronic ester 55 (the same precursor used for synthesis of 52) into the (3,4-dimethoxybenzyl)oxy derivative 56 was straightforward, and dichlorodicyanoquinone (DDQ) oxidation readily yielded the a-hydroxy boronic ester 57. Conversion of 57 into the methane sulfonate 58 and reaction with lithium benzyl oxide furnished 59, a diastereomer of 52 (Scheme 8.13) [41]. 

The Suzuki coupling of arylboronic acids and aryl halides has proven to be a useful method for preparing C-aryl indoles. The indole can be used either as the halide component or as the boronic acid. 6-Bromo and 7-bromoindolc were coupled with arylboronic acids using Pd(PPh3)4[5]. No protection of the indole NH was necessary. 4-Thallated indoles couple with aryl and vinyl boronic acides in the presence of Pd(OAc)j[6]. Stille coupling between an aryl stannane and a haloindole is another option (Entry 5, Table 14.3). 

Fluorochloro, fluorobromo, and fluoroiodoalkanes react selectively with aromatics under boron trifluoride catalysis to provide chloro-, bromo- and iodoalkylated products (48). The higher reactivity of the C—F bond over C—Cl, C—Br, and C—I bonds under Lewis acid catalysis results in the observed products. 

Alternatively, radiohalogen-labeled compounds may be prepared by way of isotopic labeling from the unlabeled bromo or iodo derivatives by various two-step reaction sequences. Examples include the use of trialkylsilyl synthons as described in References 10—13, and the use of boronic acid synthons as described in References 14 and 15. 

Bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44 0. 2g), is dissolved in formic acid, 2 ml of boron trifluoride etherate is added and the mixture is stirred vigorously at 0° for 2 hr. A brown mass ca. 0.12 g) is obtained after evaporation of the solvents at reduced pressure. This material is diluted with water and extracted with chloroform. The chloroform extracts are washed successively with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure to give 95 mg of a product which is purified by filtration through a column of neutral alumina and crystallization of the residue after evaporation of the solvent from ethyl acetate-petroleum ether. The resulting A-homo-estra-l(10),2,4a-triene-4,17-dione (45), mp 143-146°, is identical to the tropone (45) prepared from monoadduct 17-ketone (43a). 

Better results can be obtained by genetaling die boronate species widi die aid of sodium medioxide. In diis case, satisfactory transmetalalion occurs on treatment widi Cut. Hills, die ftinctionalized copper reagent 55 can be alkyuylaied widi 1-bromo-l-bexyne at -40 C, ftirnisbing die etiyue 56 in 7596 yield (Sdieme 2.15) [32]. 

One year later Van der Eycken and Dehaen described the smooth microwave-assisted borylation of 4, 5, 6 and 7-bromo-lff-indole using PdCl2(dppf) as a precatalyst and KOAc as a base (Scheme 30) [48]. With 5, 6, and 7-bromo-lH-indole, DMSO was used as solvent at a temperature of 150 °C (with a set power of 150 W) for 17-27 min, resulting in the corresponding boronate esters in good yields. For 4-bromo-lH-indole, DME gave a better result at the same temperature (with a set power of 250 W). 

The mechanism of these alkylations involves a tetracoordinate boron intermediate formed by addition of the enolate of the a-bromo ester 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.23... 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

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