Palladium-Catalyzed Arylation of Enoates with Iodobenzene: Stereoselective Synthesis of Trisubstituted Olefins

The Heck reaction between E- and Z-enoates and iodobenzene was studied in the presence of Pd(OAc)2. The stereochemistry in resulting adducts was dependent on the enoate geometry (stereospecific reaction). Best yields were obtained from Z-isomers in acetone using Ag2CO3 as base. The main cationic palladium intermediates possibly involved in the catalytic cycle could be intercepted and characterized by electrospray ionization mass spectrometry (ESI-MS). The stereoselectivity observed was rationalized through the classic mechanism of the Heck reaction.


Introduction
Heck and collaborators described in 1968 the preparation of methyl cinnamate by the reaction of phenylmercuric chloride with methyl acrylate in the presence of stoichiometric amounts of PdCl 2 /LiCl. 1 Mizoroki, et al. in 1971 2 and Heck and Nolley in 1972 3 reported the arylation of styrene by iodobenzene in the presence of catalytic amounts of palladium salts.Since then, the scope of the Heck reaction has been extensively expanded and new sources of organopalladium species as well as new types of olefins have been incorporated into the set of starting materials suitable for this reaction. 4,5tramolecular Heck reaction allows the preparation of heterocycles and molecules bearing tertiary and quaternary centers, via carbopalladation of 1,2-disubstituted and trisubstituted double bonds. 6In contrast, we found scattered examples involving the intermolecular Heck reaction of conjugate double bond bearing substituents at the b-position, such as crotonates and cinnamates. 7tereoselective synthesis of 1,2 disubstituted olefins is a well established process and these products can be synthesized via Wittig-type reactions, 8 using organometallics 9 and more recently by metathesis. 10In contrast, stereocontrol in construction of trisubstituted olefins remains a challenge. 11n this article we report stereoselective arylation of a series of enoates with iodobenzene.These reactions were studied under classical Heck conditions, 3 in which the Vol.24, No. 3, 2013   neutral mechanism is favored and the results are compared with those obtained in conditions favoring the cationic mechanism (in the presence of Ag 2 CO 3 or using water as solvent). 4,12A mechanistic rationalization was proposed based on electrospray ionization mass spectrometry (ESI-MS) monitoring.

Results and Discussion
In contrast to acrylates, which under classical Heck conditions (neutral mechanism) are known to react with iodobenzene (2) leading to cinnamates in good yields, 3,13 enoate Z-1 furnished only traces of adduct E-3 in the presence of Pd(OAc) 2 , PPh 3 , Et 3 N and DMF (Dimethylformamide) at 70 ºC for 40 h (Scheme 1, Table 1, entry 1).Yield of E-3 did not increase when Z-1 and 2 were allowed to react under reflux in this solvent, leading to extensive isomerization from Z-1 to E-1 (data not showed).Enoate E-1 was completely recovered when allowed to react under these conditions (entry 2).Due to these disappointing results, we decided to try reaction conditions that would favor the cationic mechanism, using silver salts as bases.Indeed, the yield of E-3 obtained from Z-1 increased to 71% in the presence of Ag 2 CO 3 , PPh 3 and acetone (entry 3) and higher yield (79%) was obtained in the absence of PPh 3 (entry 4).Reaction times could not be reduced without decrease in yields.An excess of enoate is necessary but it can be recovered in the reaction purification.Enoate E-1 was much less reactive than Z-1 under these same conditions, leading to adduct Z-3 in moderate yield (entry 5).This difference in chemical reactivity between Z-1 and E-1 suggest that the transition state for the carbopalladation step of Z-1 is sterically less hindered.Since it has been accepted that Heck reactions in water also proceed through a cationic mechanism, 4,12 these reactions were also studied in water using Pd(OAc) 2 and Et 3 N.In contrast with Heck-lactonization reactions with enoate Z-1, which proceeds quite well in aqueous medium, 12 the yields of Heck reaction between Z-1 and 2 decreased in water.Cinnamate E-3 was obtained in 48% yield from Z-1 (entry 6), while E-1 furnished Z-3 in only 18% yield (entry 7).These reactions were stereospecific and only one geometric isomer was observed in crude spectra.
To further evaluate the scope of this Heck reaction, a few other enoates were selected to react with 2 (Scheme 2, Table 2).Methyl maleate (Z-4) led to adduct E-8 in 63% yield whereas its isomer Z-8 was obtained from E-4 in 35% yield (Scheme 2, Table 2, entries 1 and 2).Kondolff co-workers 7 described a mixture of stereoisomers in which the geometry of preferential product was independent on the starting material geometry in the reaction of these olefins with iodobenzene using a tedicyp-palladium complex in DMF. 7Methyl maleate (Z-4) produced the corresponding adduct in worse yields than Z-1 but in better yields than its isomer E-4.Only traces of the corresponding geometric isomers were observed in the purified products (they not appeared in crude mixtures).Adduct 9 was obtained from 5 in 40% yield in the presence of Ag 2 CO 3 but only 14% yield was obtained in water (entries 3 and 4).Methyl crotonate (6) and methyl cinnamate (7) led to the corresponding adducts 10 and 11, respectively, in poor yields (entries 5, 6 and 7). 14 Reaction mixtures were heated for 40 h in the presence of 10 mol% of Pd(OAc) 2 , 20 mol% PPh 3 and 3 equiv of base.a Isolated yields; b Reactions in DMF were heated to 70 o C; c Reactions in acetone were heated to 70 ºC (bath temperature); d Reactions in water were heated to 80 ºC in the absence of PPh 3 .The configuration at the double bond in 3 was established by nOe experiments (Figure 1).Irradiation at the olefinic hydrogen of E-3 (in red) led to enhanced signals for one of the methyl group at the dioxolane ring and hydrogen at chiral center (Figure 1a).Similarly, irradiation at this methyl group (in red, Figure 1b) led to enhanced signals for the other geminal methyl group, one hydrogen at the dioxolane ring, olefinic hydrogen and hydrogen attached at the chiral center.As expected, for NOE experiments with Z-3 no interference was observed in olefinic proton after irradiation at methyl groups at the dioxolane ring (Figure 1c and 1d).Configuration of Z-8 and E-8 were established by comparison with literature data. 15roducts 9, 10 and 11 are also described. 16FT (Density Functional Theory) calculations at M06-2X/6-311++G(d,p) level were carried out to confirm the NOE interpretation.Geometries of Z-3 and E-3 were fully optimized at this level and characterized as minimum on the potential energy surface by the absence of imaginary frequencies after vibrational analysis.Figure 2 shows the optimized geometries showing some selected distances.All calculations were made with the Gaussian 09 package. 17he intermolecular distances shown confirm the assignment made by the nOe experiments.
It was also performed an investigation of the mechanism of enoate arylations via direct infusion electrospray ionization mass spectrometry (ESI-MS) monitoring and its tandem version (ESI-MS/MS). 18This technique has become a major tool for mechanistic studies in organic and inorganic chemistry owing to its outstanding ability to "fish" ionic or ionized intermediates directly from reaction solutions into the gas phase with high sensitivity, speed,   and gentleness.The mechanism of Heck reactions has also been the subject of extensive investigation via ESI-MS. 12,19amples of the reaction solution were diluted in MeCN before recording the MS data.
As expected, cationic palladium species could be intercepted in Heck reaction between Z-1 and 2 in presence or absence of phosphines.Figure 3 shows some intermediates formed in oxidative addition and migratory insertion steps.The structures of these cationic species were confirmed by the characteristic Pd multi-isotopic pattern (only the m/z of the most abundant isotopologue ion is mentioned) and by ESI-MS/MS (supplementary information).
Based on the ESI-MS data and in the observed stereoselectivity, it was rationalized a mechanism for the Heck reaction between 1 and 2 in the presence of Ag 2 CO 3 (Scheme 3).The cationic phenyl palladium 12 is firstly formed, reacting subsequently with Z-1 via a regio and syn-stereoselective carbopalladation, to form the key cationic intermediate 13.Syn-elimination of HPd + from 13 (conformer C 2 ) leads stereoselectively to adduct E-3 (Scheme 3a). 4,5Similarly, Z-3 is formed when E-1 is used as the olefin (Scheme 3b).

Conclusions
This study has shown that Z-enoates are better substrates for the Heck reaction than E-enoates, which are more sterically hindered.The use of such enoates allowed the stereospecific synthesis of isomeric b-substituted cinnamates.These present results are in contrast with those previously reported for Heck reactions of cinnamates with haloarenes, in which the stereochemistry in the adducts is defined by isomerisation of products via thermodynamic control. 4The results are also in contrast with those previously reported for Heck reactions of maleates and fumarates with iodobenzene, in which a mixture of isomeric products was formed. 7Although it was used a limited number of variations, further studies with a large set olefins and iodoarens must be accomplished to confirm the suitability of this stereoselective methodology as an important tool to synthesize trisubstituted olefins.

General procedure of ESI-MS and ESI-MS/MS
All experiments were performed on a hybrid quadrupole time-of-flight mass spectrometer (Q-TOF, Waters).For typical electrospray ionization (ESI) conditions, the Teflonsealed microsyringe was put in a pump that delivered the reagent solution into the ESI source at a flow rate of 10 µL min −1 .ESI and the mass spectrometer was operated in the positive ion mode.Main conditions were capillary voltage, 3500 eV; cone voltage, 35 eV; source temperature, 100 o C; desolvation temperature, 100 o C. The cationic species were subjected to collision-induced dissociation (CID) with argon by using collision energies ranging from 5 to 45 eV.

Figure 2 . 3 m/z 645 Figure 3 .
Figure 2. Optimized geometries of the E and Z forms of the adduct 3.

Scheme 3 .
Scheme 3. Proposed mechanism for the Heck reaction between enoates Z-1 (a) and E-1 (b) with 2 in the presence of Ag 2 CO 3 .

Table 1 .
Yields and major conditions for the reactions shown in Scheme 1

Table 2 .
Yields and conditions for the reactions shown in Scheme 2Reaction mixtures were heated to 70 ºC for 40 h in the presence of 10 mol% of Pd(OAc) 2 , 20 mol% PPh 3 and 3 equiv of base.a Isolated yields; b Reactions in water were heated to 80 ºC; c PdCl 2 used as catalyst.