Chloro esters

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

The anion produced by VNS of nitroarenes andct-chloro esters is hydroxylated by the ac of air and benzaldehyde, thereby producing ct-hydroxy esters fEq 9 37,... 

Williams and coworkers have reported a DKR of ot-bromo [56a] and a-chloro esters [56b]. In the latter case, the KR is catalyzed by commerdally available cross-linked enzyme crystals derived from Candida cylindracea lipase. The racemization takes place through halide 5 2 displacement. The DKR is possible because the racemization of the substrate is faster than that of the produd (carboxylate). For the ester, the empty ii (C=0) orbital is able to stabilize the Sn2 transition state by accepting... 

Acyl chlorides react with epoxides in the presence of a Eu(dpm)3 catalyst or a YCp2Cl catalyst (where Cp is cyclopentadienyl) to give chloro esters. A related reaction with epi-sulfides leads to 2-chlorothio-esters. Aziridines have been opened with MgBr2 to give 2-haloamides in a related reaction. 

Using this general method, the chloro esters shown in Equation 23 were made. This method of preparation is a rather important discovery and the reaction is not a simple one. 

The reaction shown in Equation 24 gives good yields, using both aqueous and non-aqueous media, in a much shorter time than that reported by Schrader 13). The intermediate chloro ester can be combined directly with paranitrophenol using alkali metal salts in order to prepare sodium nitrophenoxide, which is used in situ. 

Still another method was reported by Schrader 12) (Equation 31). Compounds prepared by the general method of reaction of the chloro esters with the nitrophenol, either in the presence of base or by using a salt of the phenol, are shown in Formula 32. 

Mebeverine (81), a smooth muscle relaxant, is prepared, i. a., by reacting sodium 3,4-dimethoxy-benzoate (77) with 1,4-dichlorobutane to form chloro-ester 78 which is in turn transformed to the corresponding iodide (79) on heating with Nal in methyl-ethyl ketone. Alkylation of 2-ethylamino-3-p-methoxy-phenylpropane (80) with 79 leads to mebeverine... 

Akabori and Yoshii (1978) used sodium hydride to generate the carbanions of cr-chloro esters [142], which reacted with cg -unsaturated esters to... 

The intramolecular cyclization of y-chloro esters, which normally requires strongly basic anhydrous conditions, is accomplished in high yield with aqueous sodium hydroxide and tetra-n-butylammonium bromide in toluene [31], Poor yields result when dichloromethane is used as the solvent. 

Method A (liquid liquid conditions) The a,p-unsaturated ketone, ester, or nitrile (5 mmol) and the a-chloro ester (or nitrile) (5 mmol) in CH2Cl2 (25 ml) are stirred with TBA-Br or TEBA-Cl (5 mmol) in aqueous NaOH (50%, 10 ml) for 1-2 h at room temperature. The organic phase is separated, washed well with H20, dried (Na2S04) and evaporated. The residue is triturated with Et20 (50 ml) and the filtered solution is evaporated to yield the cyclopropane. 

Method B (solid liquid conditions) The a,p-unsaturated ester (25 mmol) and the a-chloro ester (25 mmol) are added to K2CO, (6.9 g) and TEBA-Cl (0.3 g, 1.3 mmol) in DMF (10 ml) and the mixture is stirred at room temperature until the reaction is complete, as shown by TLC analysis (ca. 24 h). The mixture is then poured into H20 (50 ml) and extracted with Et20 (2 x 25 ml). The extracts are washed well with H20, dried (CaCl2), and evaporated to yield the cyclopropane (40-50%). 

Despite its high reactivity, the a-chloro ester 1-Me does not polymerize like simple acrylates. However, in close analogy to other 1,1-disubstituted methyl-enecyclopropanes [29], 1-Me slowly dimerizes in a head-to-head fashion even at room temperature to give the two diastereomeric dimethyl dispiro[2.0.2.2]oc-tanedicarboxylates (E)- and (Z)-16 (ratio 1 1) (Scheme 5), and at 120 °C the dimerization proceeds almost quantitatively (89% isolated yield) [15]. Apparently the dimerization of 1-Me occurs considerably more readily than that of methylenecyclopropane [4a,b] and of bicyclopropylidene [4 d]. Surprisingly, under high pressure (10 kbar) this dimerization did not proceed more efficiently (Scheme 5) [30], but more cleanly, which facilitated the separation of isomers. 

Reaction of the chloro ester 1-Me with the enol silyl ether 23 a in the presence of dimethylaluminum chloride afforded the [2-1-2] cycloadduct 20 (67% yield) (Scheme 6). Deprotection of the alcohol moiety with uBu4NF in THF gave an 83% yield of a mixture of the 5-keto ester 21a and the spiropentane derivative 22 (ratio 1 90). Upon running the reaction in a mixture of THF/water (ratio 1 1) instead of anhydrous THF, the 5-keto ester 21a was isolated exclusively [331. 

With diazoalkanes 34, as should be expected in view of the high polarity of its double bond, the chloro ester 1-Me demonstrated its reasonably good dipolaro-philicity. Indeed, mixtures of the regioisomeric pyrazolines 35 and 36 were obtained in good yields [26a, 33], when a solution of 1-Me was treated with any of the diazoalkanes 34a-e (Scheme 8). 

Furthermore, the chloro ester 1-Me also readily reacted with the nitrile ylide 37 at room temperature, however, the pyrrole derivative 40 was the only isolated product (Scheme 9) [26 a]. The latter was obviously formed from the primary cycloadduct 38 by a cyclopropylcarbinyl to homoallyl rearrangement [1]. 

But the trimethylsilyloxycyclohexadienes (51 a,b) reacted with the chloro ester 1-Me only under more drastic conditions to give in moderate yield about equal amounts of the regioisomeric cycloadducts 52 and 53, each as a mixture of endo-and exo-isomers (Scheme 13) [281. Upon treatment with acid or acidic work-up of the reaction mixture, compounds 52 and 53 were converted to the tricyclic keto esters 54a and 54b in 25 and 28% yield, respectively (cf. Sect. 4.4). 

Another useful synthetic application of a Diels-Alder adduct of the chloro ester 1-Me is the facile preparation of the spirocyclopropanated analog 75 of so-called naked sugar 76 [50] (Scheme 19) [30]. The transformation of the adduct endo-59a of 1-Me onto furan (57) into a-chloroamide 74 followed by fragmentation of the latter under basic conditions allowed to prepare the versatile building block 75 in 71 % overall yield. Starting from isomer exo-59a, the yields were 82 and 52% for the first and the second step, respectively. The analogous trans-... 

Scheme 19. Useful chemical transformations of Diels-Alder adducts endo-59a and 56b, respectively, of the chloro ester 1-Me onto furan (57) and 77-Boc-protected pyrrole (55b) [30]...

Thus, in a competition experiment, the chloro ester 1 -Me reacted with thiophenolate anion 216 times faster than methyl 3,3-dimethylacrylate (Fig. 4). Part of this enhanced reactivity is due to the a-chloro substituent in 1-Me, as the parent methyl cyclopropylideneacetate (3-H) reacts only 18 times faster than 3,3-dimethylacrylate, while 3-SPh reacts 5160 times more rapidly [5b,c, 15b,271. 

It is not surprising that chloro esters 1, 2 readily add thiols, catalyzed by sodium thiolates or triethylamine, to give the corresponding 2-(r-organylthiocy-clopropyl)-2-chloroacetates 85,86 (Scheme 22) [15 b, 22b, 27]. This reaction with thiophenol has been used to quantify the Michael reactivity of 1-Me, 2-Me, 3-X in comparison to simple acrylates (see above). With an excess of PhSH, the nucleophilic substitution of the chlorine in 85 a (but not in 85h) proceeded to give the corresponding bis(phenylthio) derivative in 63% yield [15bj. Alkali thiolates (e.g. NaSMe, NaSBn) add smoothly onto 1-Me, 2c-Me and 2p-Me at - 78 °C, because at this temperature subsequent nucleophilic substitution of the chlorine is much slower [7l, 9]. The Michael additions of sodium phenylselenide and sodium arylsulfenates onto 1-Me and their synthetic utility have been discussed above (see Table 1). 

Scheme 23. Addition of alcohols onto chloro esters 1-Me and 1-Bn [9,15b]...

The Michael adducts of dibenzylamine onto chloro esters 1-fBu, 2i-Me, and 2k-Me were also prepared in methanol in reasonably good yields (67, 79 and 77%, respectively) [7k, 26b]. However, like for the addition of primary amines, THF turned out to be the best solvent for the preparation of the Michael monoadducts 91 of secondary amines onto chlorocyclopropylideneacetates 1,2 (Scheme 27) [9,11 b, 21 b, 22b, 53,56,57]. 

Scheme 28. Addition of ammonia equivalents onto the chloro ester 1-Me [9,53]...

The addition of 95 onto 2m-Me in THF at ambient temperature (89% yield) was not stereoselective [53]. All attempts to add the chiral cyclic benzylamine derivative 96 and 97 onto the spirocyclopropanated chloro ester 2c-Me were unsuccessful [21b]. Although it was possible to add heterocycles (S)-4-phenyloxa-zolidine-2-one (98) and its thio analog 99 onto the chloro esters 1-Me and 2j-Me (Scheme 30) [10b, c] and to substitute or reductively remove the chlorine atom in the adducts 101, all attempts to deprotect the amino functions in 101 and the products of their transformations under various conditions were unsuccessful. 

Scheme 31. (4E,5S)-4,5-Diphenyloxazolidine-2-one (100) as a Michael donor in addition reactions onto chloro esters 1-Me, 2 [10,21,62]...

The second synthetically useful general transformation of any of the chloro esters 1,2 consists of an intra- or intermolecular nucleophilic substitution of the chlorine atom in any of the Michael adducts. Several examples of such reactions have been mentioned above (Table 1 and Scheme 26), and substitutions of any specific importance (for example, with hydride or azide anion [9,10,62]) as well as subsequent transformations of such substitution products will be discussed in the corresponding Sections [66]. 

Scheme 35. Preparation of diaminoacid derivatives 106 via nucleophilic substitution of chlorine in )8-amino-a-chloro esters 91 [11,57]...

---