Palladium-Catalyzed Double Cross-Coupling of E-vinylic Dibromides with PhZnCl and the Synthesis of Tamoxifen

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).


Introduction
The 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.
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. 14Accordingly, Rossi and coworkers 15 described the utilization of tetrasubstituted (E)- 2,3-dibromopropenoates in the palladium-catalyzed crosscoupling with aryl and alkynylzinc species.The stereoselectivity of these reactions was found to be dependent upon the substituent present at C-3 of the propenoates.

Results and Discussion
Due to the availability of E-1,2-dibromoalkenes from the bromination of the corresponding acetylenes, we were attracted to the possibility of preparing (Z)-tamoxifen (1)  from (E)-9 via the palladium-catalyzed tandem crosscoupling with phenylzinc chloride (Scheme 1).4-Iodophenol (3) was straightforwardly protected as the corresponding chloroethylether 4 before the Sonogashira coupling with trimethylsilylacetylene which afforded acetylene 5 in 99% yield.TMS-deprotection followed by alkylation of the terminal acetylene 6 with ethyl iodide provided disubstituted acetylene 7 (83% yield, 2 steps).
At this juncture, the stereoselective conversion of 7 to the corresponding (E)-dibromoalkene 8 was needed.While our preliminary attempts with molecular bromine in either CHCl 3 or CCl 4 afforded mixtures of (E)-and (Z)-1,2dibromoalkenes as well as the corresponding tribromoderivatives when alkylacetylenes were employed, the use of pyridinium tribromide 16 in a 1:1 mixture of CCl 4 -MeOH at -10 o C provided (E)-1,2-dibromoalkene 8 in 86% yield without formation of the corresponding 1,1-dibromo-2,2-dimethoxyalkane as previously reported when the reaction was carried out in methanol. 17The protocol above proved to be equally efficient for the bromination of either alkyl-or aryl-substituted alkynes 10a-f (Table 1).The (E)-configuration of 1,2-dibromo alkenes 11a-e was assigned based on literature data 18 while the stereochemistry of 11f was assumed by analogy.
With a stereoselective route to (E)-9 secured, we explored its Pd(0)-catalyzed double cross-coupling with PhZnCl (8 equiv.)generated in situ by transmetallation of a 0.5 mol L -1 solution of phenyllithium in THF with ZnCl 2 .The cross-coupling was carried out in refluxing toluene with 10 mol% of Pd(PPh 3 ) 4 and afforded a 2.3:1 mixture of (Z)-tamoxifen (1) and (E)-tamoxifen (2) in 52% yield. 19he diastereoisomeric ratio was determined by capillary GC analysis and the configuration of the major diastereoisomer established by comparison of the NMR data of the synthetic mixture with an authentic sample of (Z)-tamoxifen (1).The loss of stereochemical integrity during the Pd(0)-catalyzed cross-coupling is reminiscent of the observations by Rossi and coworkers 15 who described similar behavior during the cross-coupling of tetrasubstituted (E)-2,3-dibromopropenoates with arylzinc chlorides.However, Rathore and coworkers described that the Pd(0)-catalyzed coupling of aryl Grignard reagents bearing ortho methyl groups and (E)-1,2-dibromoalkenes efficiently provides (Z)-tetrasubstituted alkenes. 20While (Z)-tamoxifen (1) is formed through a double Negishi coupling, the competitive formation of (E)-tamoxifen (2) seems to involve syn-carbopalladation of alkyne 13 which is observed to be formed from (E)-9 (GC analyses) under the reaction conditions employed (Scheme 2).In fact, although attempts to carry out Pd(0)-catalyzed coupling with alkyne 13 under the reaction conditions employed failed, we were able to observe exclusive formation of (E)-tamoxifen (2) when 13 was treated with Pd(PPh 3 ) 4 /PhBr, followed by addition of PhZnCl (Scheme 2).
We have also examined the formation of tri-and tetrasubstituted olefins 14a-e from the corresponding (E)-11a-e.As depicted in Table 2, in all cases good yields of the corresponding tri-and tetrasubstituted olefins 14a-e were obtained with retention of the double bond configuration being observed when alkyl substituted 1,2-dibromo alkenes (E)-11a,b were employed.
The low level of diastereoselection reported in the double Negishi coupling of vinylic dibromide (E)-9 with phenylzinc chloride calls for a more efficient catalytic system in order to carry out the coupling reaction.The highest stereoselective methodologies described so far in the literature for the total synthesis of (Z)-tamoxifen (1) rely on either syn carbometallation, 6,12 hidroxymethyl directed anti carbometallation 11 or anti stannylcupration. 8However, when compared with the routes based on dehydration 4 or McMurry coupling, 5 the results described herein display about the same level of diastereoselection.Considering the availability of methods for separation of (E)-and (Z)-tamoxifen and for the interconversion of (E)-to (Z)-tamoxifen, our results are an useful asset to those already known as it allows the preparation of tamoxifen as a 2.3:1 mixture of Z-and E-isomers in 7 steps and 30% overall yield from commercially available 4-iodophenol (3).

Experimental
General All reactions of air-and water-sensitive materials were performed in flame dried glassware under an atmosphere of argon.Triethylamine was distilled from CaH 2 , tetrahydrofuran was previously treated with CaH 2 and distilled from sodium, toluene was distilled from sodium.DMPU and bromobenzene were previously treated with CaH 2 , distilled from CaH 2 and stored over molecular sieves.4-iodophenol (3), 1,2-dichloroethane,trimethylsilylacetylene,dichloro(triphenylphosphine)palladium(II), ethyl iodide, pyridinium tribromide, tetrakis(triphenylphosphine) palladium(0) and alkynes 10a-e were commercially available.The compounds were by column chromatography on silica gel (70-230 mesh).The 1 H-NMR and 13 C-NMR spectra were recorded on a Varian Gemini (7.05T), Varian Inova (11.7T) spectrometers.Chemical shifts (δ) are recorded in ppm with the solvent resonance as the internal standard and coupling constants (J) recorded in Hz.The infrared spectra were recorded as films in KBr cells on a Nicolet Impact 410 (FTIR).High resolution mass spectroscopy (HRMS) were performed on a VG Autoespec-Micromass-EBE.The melting points were measured on an Electrothermal 9100 apparatus.The gas chromatography analyses (FID detector) were performed using a Hewlett Packard 5890-II equipament.Gas chromatography-mass spectrometry (GC-MS) analyses were performed on a Hewlett Packard 5890/ Hewlett Packard 5970 MSD.

General procedure for the bromination of alkynes 10a-f with PyHBr 3 (Table 1)
To a solution of alkyne 10a-f (1.00 mmol) in CCl 4 (5.0 mL) at -10 ºC pyridinium tribromide (1.20 mmol) was added, followed by MeOH (5.0 mL).The reaction mixture was kept at -10 o C for 30-60 min and quenched with 10% aqueous sodium thiosulfate.After extraction with CH 2 Cl 2 , the combined organic phase was extracted with brine and dried over anhydrous MgSO 4 .The crude mixture was chromatographed on silica gel to afford dibromo alkenes 11a-f.

General procedure for the palladium-catalysed double cross-coupling of (E)-vinylic dibromides 11a-e with PhZnCl (Table 2)
To a solution of bromobenzene (8.0 equiv.) in dry THF at -78 ºC was added butyllithium (8.2 equiv.).After 15 min., a solution of ZnCl 2 (9.0 equiv.) in dry THF was added then the temperature was allowed to room temperature.After 30 min, a solution of vinylic dibromide 11a-e (1.0 equiv.)and tetrakis(triphenylphosphine)palladium(0) (0.1 equiv.) in dry THF was added and the conditions described in Table 2 were followed.The reaction was periodically monitored by GC analysis of samples previously hydrolysed with an aqueous NH 4 Cl solution and extracted with Et 2 O.After completion of the reaction, the mixture was treated at room temperature with an aqueous NH 4 Cl solution and extracted with Et 2 O.The organic was extracted with brine and dried over