New Applications of Methyl 2-Chloro-2-cyclopropylideneacetate Towards the Synthesis of Biologically Important Heterocycles

Abstract

The work in this thesis starts with the advanced synthesis of methyl 2-chloro- and 2-bromo-2-cyclopropyledeneacetate (4-Me and 5). The cyclopropanol derivative (31) obtained by Kulinkovich reductive cyclopropanation of 3,3-diethoxy propionate, was easily converted to 2-(1"-mesyloxycyclopropyl)-acetic acid (28) by mesylating the alcohol group followed by oxidation. ?Chlorination of the in situ formed acid chloride of the acid 28 with N-chlorosuccinamide in presence of catalytic amount of HCl generated the chloride 32a which under basic elimination furnished the methyl 2-chloro-2-cyclopropyledeneacetate (5). In the similar way the bromo analogue 4-Me was prepared by using N-bromosuccinamide.A series of different amidines (34b f) was easily prepared from the corresponding nitriles which underwent Michael addition followed by domino transformation in presence of triethyl amine to afford cyclobutene annelated pyrimidinones (35a j). These pyrimidinones were reacted with phenyl vinyl sulfone to produce 6-sulfone substituted tetrahydroquinazolinones (37a h) under thermal or microwave assisted conditions. Basic elimination of 37a h followed by hydrogenation led to 2-substituted 5,6,7,8-tetrahydroquinazolinones (39a f). Alkylation of the tetrahydro- ring was done by use of base such as n-BuLi to get the alkylated product (40, 42a,b). Nucleophilic substitution of SMe group of the compound 37h with different secondary amines produced the 2-amino derivative of 5,6,7,8-tetrahydroquinazolinones 46a c. Michael addition of indole onto methyl 2-chloro-2-cyclopropylideneacetate (5) in presence of a Lewis acid furnished the methyl 2-chloro-2-[1-(1H-indol-3-yl)cyclopropyl]acetate (55). The cyclopropanated tryptophane methyl ester 56 was prepared by nucleophilic substitution of the chloride 55 with sodium azide under phase transfer catalysis followed by subsequent reduction of the azido ester 57. The Pictet Spengler reaction of the ester 56 with p-anisaldehde or piperonal produced the tetrahydro-?-carbolines (59a,b) with greater efficiency than the corresponding non-cyclopropanated precursor. In both cases products were obtained as a mixture of two diasteriomers (cis/trans = 1 : 1.7 for 59a and 1 : 2.5 for 59b) from which the trans-isomers were easily separated by crystallization from ethyl acetate. Treatment of the tetrahydro-?-carboline 59a with n-butyl isocyanate gave the cyclopropanated hydantoin lead structure to Tadalafil (25). The tetrahydro-?-carboline 59b was efficiently converted to the spirocyclopropanated analogue of Tadalafil (26) in two steps with a very good yield.Michael addition of carboxamides with compound 5 gave the spirocyclopropanated oxazoline carboxylate methyl esters (13a e), from which free carboxylic acids (64a e) were obtained under basic hydrolysis. Coupling reaction of 64a e with different anilines in presence of HOAt/EDC and colidine gave the amide 68a j with very good yields. The coupling products with ?-hydroxy anilines under Mitsunobu reaction conditions (Ph3P/DEAD) gave the benzoxazole derivatives of oxazolines (69a e). The bromide group present in the N-methylated products of 70a,b were reacted with varieties of amines under Buchwald reaction conditions to give the amino-aryl derivatives 71a j. Similarly, Suzuki reaction conditions were successfully applied to synthesize the biary-derivatives of oxazolines (72a d).Sequential Michael reaction of Grignard reagent and aldol reaction with the compound 5 produced the ?-chloro alcohols 75a l and in most cases single diasteriomers (> 97%, anti 2S*,2R*) were obtained. The structure was deduced from a single crystal X-ray structure analysis. These ?-chloro alcohols 75a l are good precursors for the synthesis of ?,?-epoxyesters. The ?-chloro alcohol 75b-iPr underwent clean cyclization under basic condition to produce diasteriomerically pure ?,?-epoxyester 79b-iPr. The analogous a,b-epoxyester 79a-iPr was obtained directly from methyl 2-bromo-2-cyclopropylideneacetate (4-Me) upon treatment with isopropylmagnesium chloride and benzaldehyde. Apparently, the bromohydrine analogous to 75a-iPr is not stable under the work-up conditions and undergoes cyclization by intramolecular nucleophilic displacement.The orthogonally protected diamine exo-6-(N,N-dibenzylamino)-3-aza-bicyclo[3,1,0]hexane-3-carboxylic acid tert-butyl ester (82) was also prepared from N-tert-butoxycarbonyl-3-pyrroline (81). Selective deprotection of either the tert-butoxycarbonyl group or dibenzyl group provided monoprotected derivatives 83 and 84 with good yields. The phenylation reaction of 83 catalyzed by CuI was found to be more efficient than the corresponding Pd2(dba)3 catalyzed reaction to produce 87 Unlike in the case of 84 the debenzylation reaction was successful in dimethy acetamide to give the product 88.