Palladium-catalyzed double cross-coupling of E-vinylic dibromides with PhZnCl and the synthesis of tamoxifen

Abstract

Compostos (E)-1,2-dibromo vinílicos 11a-f foram preparados estereosseletivamente via reação de bromação de alcinos empregando-se tribrometo de piridínio em MeOH/CCl 4 a baixa temperatura e utilizados na reação de duplo acoplamento com PhZnCl catalisada por Pd(0), segundo protocolo de Negishi, fornecendo as respectivas olefinas tri e tetrassubstituídas 14a-e. Tamoxifeno, um agente antiestrogênico de uso clínico na terapia do câncer de mama, foi preparado na forma de uma mistura Z:E de proporção 2.3:1, em 7 etapas em um rendimento global de 30% a partir do 4-iodofenol (3).(E)-1,2-vinylic dibromides 11a-f were stereoselectively prepared via bromination of acetylenic compounds with pyridinium tribromide in MeOH/CCl 4 at low temperature and double crosscoupled with PhZnCl under Pd(0) catalysis (Negishi protocol) to afford tri-and tetrasubstituted olefins 14a-e. Tamoxifen, a selective estrogen receptor modulator clinically prescribed in breast cancer therapy, was prepared in 7 steps and 30% overall yield from 4-iodophenol (3) as a 2.3:1 mixture of (Z)-and (E)-isomers. Keywords: (E)-1,2-vinylic dibromides, double cross-coupling, palladium catalysis, tri-and tetrasubstituted olefins, tamoxifen IntroductionThe stereoselective synthesis of tri-and tetrasubstituted olefins is of great interest in the domain of biologically active compounds where the E and Z isomers may have completely different biological properties as represented by tamoxifen, a tetrasubstituted stilbene which acts as a selective estrogen receptor modulator (SERM): while (Z)-tamoxifen (1) displays antiestrogenic activity and is prescribed as the corresponding citrate as an adjuvant for breast cancer therapy, (E)-isomer 2 has estrogenic activity and stimulates the proliferation of hormone-responsive breast cancer cells (Figure 1). 1 Methods are available for the separation of (E)-and (Z)-isomers as well as for isomerization of estrogenic (E)-tamoxifen (2) 2 to antiestrogenic (Z)-tamoxifen (1), [3][4][5] including large scale operations. Among the routes already described in the literature, the method by Knochel and coworkers 6 is by far the more efficient one: starting from 1-phenyl-1-butyne, (Z)-tamoxifen (1) is prepared in three steps and 71% yield via Ni(II)-catalyzed syn carbozincation, followed by Negishi coupling of the corresponding vinylic iodide with 4-triisopropylsililoxyphenylzinc bromide.Despite the different approaches already reported for the stereoselective synthesis of tamoxifen (dehydration, 4 McMurry 5 and metal-catalyzed coupling protocols 6-13 ), we were attracted by the possibility of preparing (Z)-tamoxifen (1) from the corresponding (E)-1,2-vinylic dibromide via an one-pot tandem coupling with a phenylorganometallic species with retention of configuration.1,2-Dihaloalkenes are potentially useful starting materials for the preparation of tri-and tetrasubstituted olefins via transition metal catalyzed cross-coupling with organometallic species. 14 Accordingly, Rossi and coworkers 15 described the utilization of tetrasubstituted (E)- ...

Selectivity studies in the reaction between iodobenzene and phenylacetylene: Sonogashira coupling vs hydroarylation

“…The industrial production of these compounds involves air-sensitive Grignard reagents. [7] Other approaches to the synthesis of triarylethylenes include carbometallation of alkynylsilanes, [8] McMurry reaction, [9] dehydration of 1-(p-alkoxyphenyl)-1,2-diphenylbutan-1-ols, [10] use of superbase-metalated propylbenzene, [11] solid support synthesis, [12] palladium-catalyzed double cross-coupling of (E)-vinylic dibromides with PhZnCl [13] and coupling of alkynes and boronic acids employing either rhodium, [14] nickel [15] or palladium catalysts. [16] Cacchi's group was the first to report the synthesis of triphenylethylene by reaction of iodobenzene and phenylacetylene, employing Et 3 N, Pd(OAc) 2 , PPh 3 and HCOOH in acetonitrile.…”

Synthesis and Cytotoxic Activity of Some New 2,6-Substituted Purines

“…Reaction of appropriate phenylboronic acid with 9-(tetrahydropyran-2-yl)-6-chloropurine under Suzuki-Miyaura cross coupling methodology afforded 6-(4'-methoxyphenyl), 6-(4'-fluorophenyl)-purines ( Scheme 2 ). The reported procedure of pyridiniumtribromide bromination of the acetyleneic compounds [ 11 ] was adopted with minor modifications to furnish the vinylicdibromides 13 , 14 ( Scheme 3 ).…”

Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

“…A new methodology has been developed by Pilli et al for the construction of tamoxifen by palladium-catalyzed Negishi reaction of (E)-vinylic dibromides and phenyl zinc chloride with overall yield of 30% and E/Z = 1/2.3 (Scheme 1). [33] The reaction involved the conversion of 4-iodophenol (13) to corresponding chloroethyl ether (14) in 91% yield followed by Sonogashira coupling afforded acetylene derivative (15) in quantitative yield (99%). Deprotection of trimethylsilyl of 15 in basic medium afforded compound 16 in 92% yield which on alkylation with ethyl iodide gave 17 in 90% yield.…”

“…The utility of this intermediate is to synthesis of tamoxifen analogue 32 in the presence of bromine and sodium ethoxide without change its stereoselectivity. On the other hand, reaction of bis(pinacolate)diboran (33) with acetylene ester (29) in the presence of PBu 3 afforded corresponding transα,β-diboryl acrylate 34 in 64% yield wherein selective Suzuki reaction was followed for the substitution of aryl moiety in 2 steps to afford the target triaryl ethylene derivative 36 in good yield and E-selectivity. The first step involved the α-arylation due to the week interaction of the carbonyl oxygen and the Bpin group at the β-carbon atom to give 35 which was followed by the replacement of the Bpin group to give 36 with excellent E/Z ratio of more than 99/1 (Scheme 5).…”