Personal Observations on the Critical and Unusual Role of Palladium Environment on Reaction Pathways

This article summarizes some surprising palladoreactions occurring in a transition metal environment, discovered by our team, and the proposed corresponding mechanisms


Introduction
My interest in palladium in organic chemistry came from the reading of the 1977 Trost review *1+ during my postdoctoral research in Corey's laboratory. Back to my Alma matter in late 1978, I was looking for new research subjects. My knowledge in photochemistry, acquired during my doctoral thesis *2+, urged me to study the photoreactivity of η 3 -allylpalladium complexes. Having obtained 1,5-dienes from the UV light-mediated coupling of the allyl fragments in MeCN under the argon atmosphere *3+, I undertook the preparation of squalene from E,E-farnesol *4+. This work led to my first observation of the critical role of an unreactive remote ethylenic bond in a palladoreaction. This unexpected observation was an incident of serendipity − that is by accident *5+.
These studies were the outcome of forty-year research largely focused on palladium in organic chemistry. The initial topic was chosen, as I, unfortunately, was not aware of older papers from Hojabri who only observed the decomposition of the η 3 -allylpalladium complex of -pinene under UV irradiation in EtOH, without dimerization of the allyl ligands or effect of oxygen *6, 7+. Actually, we observed, under an oxygen atmosphere, the oxidation of the allyl moieties into conjugated carbonyl compounds *8, 9+ even in EtOH *10+.
The above role of a remote ethylenic bond and other unexpected results due to the Pd environment, which we observed over the years, are the matter of this short review.

Allylpalladium Isomerization
Using the preparation procedure of bis(-chloro)bis(η 3 -allyl)dipalladium complexes *11-13+, I treated E,E-farnesyl chloride (1) with substoichiometric amounts of Pd 2 (dba) 3 . CHCl 3 in benzene at room temperature. Surprisingly, a 1:1 mixture of syn-and anti-η 3 -allylpalladium complexes 1 2a and 2b was isolated ( Figure 1) *4+. Suspecting the possible role of one of the remote C=C bonds of 1 in the formation of the mixture, geranyl (3), neryl (4), and phytyl (5) chlorides were treated under the same conditions. A 1:1 mixture of 6a and 6b was obtained from 3 and 4, while 7a (7a/7b > 9) 2 was selectively produced from 5. RMN studies of the excess of allylic chlorides 3 and 4 recovered at the end of the reactions showed that they were not isomerized under the experimental conditions. Stirring the solution of 7a with a large amount (≈1000 equiv.) of cyclohexene or 2-methylbut-2-ene led only to very poor isomerization at room temperature. Then, a 6:4 mixture of 7a and 7b was isolated from the reaction of 5 with Pd 2 (dba) 3 . CHCl 3 in the presence of 100 equiv. of 2-methylbut-2-ene.
According to the above experiments, the formation of the syn and anti mixtures is promoted by the intra-or intermolecular participation of an isolated C=C bond. Isomerization preceding the formation of the dimeric complex is suspected. This could occur via the η 3 -η 1 -η 3 equilibrium of monomeric allylpalladium intermediates *16+ having an ethylenic bond as a ligand ( Figure 2).
Subsequently, Åkermark's team rediscovered the formation of the isomeric η 3 -allylpalladium complex mixture from geranyl and neryl chlorides *17, 18+, while Rovis and Johnson provided an overview of olefins influencing the outcome of various reactions *19+.

Oxidation Inhibition
In 1995, we disclosed the oxidation of alcohols using catalytic amounts of both PdCl 2 and Adogen 464 3 in 1,2-dichloroethane (DCE) containing sodium carbonate *20+. The insoluble palladium dichloride reacts with ammonium salt to yield the soluble palladium salt *PdCl 4 + 2-*21+, which further oxidizes the alcohol. The resulting reduced Pd species gets inserted into a C-Cl bond of DCE. Subsequent elimination of ethylene regenerates the active catalyst *20, 22+. Using the procedure for the lactonization of 1,4-and 1,5-diols, we surprisingly obtain the formation of lactol 9u exo from cis-endo-2,3-bis(hydroxymethyl)bicyclo*2.2.1+hept-5-ene (8u) although cis-endo-2,3 bis(hydroxymethyl)bicyclo*2.2.1+heptane (8s) provided lactone 10s ( Figure 3) *23, 24+. Furthermore, 9u exo was almost unchanged under the same experimental conditions without production of 10u, whereas the latter was effectively produced from 9u exo using pyridinium dichromate in CH 2 Cl 2 ( Figure 3) *25, 26+ or by the Swern oxidation method *27+. Moreover, our Pd procedure led to the effective oxidation of lactol 11 into the corresponding lactone *24+. The above results clearly demonstrated that the lack of formation of 10u from 8u under Pdconditions was attributable to the C=C bond. In order to explain this unusual role, we considered the plausible intermediates of the process ( Figure 4; the absence of a juxtaposed u or s letter as suffix to compound numbers of Figure 4 and corresponding text means that these numbers correspond indifferently to either the unsaturated or the saturated substrate.). Hydroxyaldehyde HAd may be in equilibrium with lactols 9 exo and 9 endo and may react with *PdCl 4 + 2to give alkoxypalladium aldehyde PAd. The low reactivity of aldehyde 13 under the reaction conditions ( Figure 3) is not in favor of the formation of hydroxyacid HAc from Had 4 . Furthermore, unsaturated HAcu is expected to spontaneously generate lactone 10u *29, 30+, which, in fact, was not produced from the Pd-catalyzed reaction of 8u. The pallado-intermediates, P9 exo and P9 endo, may be produced from 9 exo and 9 endo (path b) or Pad (path a). Subsequent -H elimination would afford 10, but this only occurs for the formation of 10s.
The analysis of the literature led us to reject some hypotheses 5 and to propose that (i) palladation of HAd (path a) is preferred over that of lactols (path b), and (ii) the intramolecular reaction of PAd occurs through the stereoselective approach of the alkoxypalladium moiety to one face of the aldehyde to afford P9 endo . When the latter is obtained from 8s, the -H elimination easily occurs to deliver 10s. In contrast, P9u endo obtained from 8u undergoes a ligand exchange leading to palladacycle PCu ( Figure 5). The syn relationship between O-Pd and C-H bonds, which would allow the -H elimination leading to the carbonyl unit *31, 32+, is prevented in PCu. That favors alkoxyde exchange with diol 8u to afford 9u endo . The latter evolves towards 9u exo which is a more stable isomer *33-35+. The apparent absence of 9u exo evolution under the aforementioned Pd-catalyzed reaction conditions is a "no reaction" reaction *36, 37+, which involves HAdu, 9u endo , PCu, alcoholysis and equilibration regenerating the starting substrate.

Figure 6
Influence of the Pd environment on the reaction pathways of 1-indanol. 5 See discussion and references in [24].
We rationalized the formation of 16 and 17 through two competitive pathways catalyzed by L 2 PdCl 2 (L = Clor RCN), i.e., with *PdCl 4 + 2and (RCN) 2 PdCl 2 , respectively ( Figure 7) *38+. In contrast to the anionic catalyst (L = Cl -), the neutral catalyst (L = RCN) is electrophilic *39-42+. The exchange of ligand between L 2 PdCl 2 and 15 affords 7 A. The evolution of 7 A depends on the electrophilicity of L 2 PdCl 2 . Transition metals having Lewis acid properties mediate the formation of ethers from alcohols *43, 44+. Consequently, 7 A formed from the anionic catalyst evolves toward 16 via the ketonization pathway *20, 22+, while 7 A formed from (RCN) 2 PdCl 2 undergoes heterolytic cleavage of the C-OH bond leading to the ionic species 7 B. The latter reacts with 15 to give ether 17, water and the starting catalyst.

Halide Exchange Versus Alkylation
As pointed out in the introduction of the present discourse, the irradiation of a bis(chloro)bis(η 3 -allyl)dipalladium complex in deoxygenated MeCN leads to the allyl coupling. Thus, the I-carvone complex 18 provided 19 ( Figure 8, path a) *3+. Then, we looked for different photoreactions *45+. Having observed the lack of photoreactivity of 18 in CH 2 Cl 2 in the absence of additive, this solvent was firstly chosen for reactions in the presence of organic halides. Halogenexchanged complexes 20 were thus isolated ( Figure 8, path b). Changing CH 2 Cl 2 for DMF 6 , the reaction with benzyl bromide led to a 1:1 mixture of allylic alkylation and allyl coupling products 21 and 19, respectively (Figure 8, path c). These results showed that the species able to temporarily coordinate to palladium, such as MeCN or DMF, are required to form the C-C bonds under these irradiation conditions. In fact, we obtained the results similar to those in DMF when the photolysis in CH 2 Cl 2 was carried with PPh 3 as an additive (Figure 8, path c). The analysis of these reactions by EPR (electron paramagnetic resonance) *51+ and CINDP (chemically induced dynamic nuclear polarization) *52+ spectroscopies demonstrated their radical character.

η 1 -Versus η 3 -Allylpalladium
Our synthesis of enantiopure vinylmorpholines by the Pd 0 -catalyzed diastereoselective disubstitution of (Z)-1,4-diacetoxy-2-butene (22) with chiral amino alcohols in THF *53+ urged us to examine the isomerization of the substrate *54+. Golding's team briefly reported that treatment of 22 with catalytic Pd(PPh 3 ) 4 in PhH at room temperature gave (E)-1,4-diacetoxy-2-butene (23) *55+. At 70-72°C in THF, we obtained a mixture of 23 and 1,2-diacetoxy-3-butene (24). The two compounds were also produced in DMF. Monitoring these reactions by 1 H NMR resulted in unexpected observations. While 23 and 24 were produced in DMF at a constant 23/24 ratio, the latter varied with time in THF ( Figure 9). After 15 min, the amount of 23 decreased to afford the 23/24 equilibrium, indicating that, in THF, 24 was mainly produced from 23 rather than from 22. Subsequent treatments of 23 and 24 with Pd(PPh 3 ) 4 in THF showed an equilibrium between them. According to these results, the isomerization of 22 occurs as depicted in Figure    Allypalladium intermediates with the η 3 -η 1 -η 3 mechanism were proposed for the Z/Eisomerization and the 1,3-transposition of allylic acetates *56+. The proposed reaction pathways of 22 was based on the demonstration given by Amatore and Jutand about the influence of solvent on the species formed from allyl acetate, Pd(dba) 2 and PPh 3 : ''in THF, the acetate ion sticks on the palladium(II) complex (ion pair)'' while ''in DMF (free ions), the acetate is located far from the cationic η-allylpalladium(II) center'' *57, 58+. The reaction of 22 with the catalyst leads to cationic η 3 -allylpalladium intermediate 11 A that is in equilibrium with the η 1 -allyl palladium species 11 B (Figure 11). The rotation around the AcOC-C(allyl)Pd bond gives 11 C that may afford either 23 by nucleophilic addition of the acetate anion to the external terminus of the allyl group, or η 3allylpalladium complex 11 D. The latter may also be formed from 23. 11 C being a tight ion-pair in THF, the close proximity of the acetate anion with the allyl moiety favors the efficient addition leading to 23. Whereas in DMF, the separation of the two entities favors the formation of 11 D. The latter evolves toward 23 and 24.

Figure 11
Dependence on the solvent of isomerization intermediates.

Selectivity
While only allyl alcohol 25 and allyl ether 26 were obtained in the presence of acetylacetonate (acacH) from the reaction of 1-acetoxy-1,3-diphenylpropene (27) in MeOH under basic conditions, the addition of H 2 O provided a 55:40 mixture of 26 and the cross-coupling product 28 ( Figure 12, paths a and b, respectively) *61+. Thus, water may promote a Tsuji-Trost-type reaction under metalfree conditions. The selectivity in 28 was strongly increased (Figure 12, path c) *62+ by catalytic amounts of both (MeCN) 2 PdCl 2 and the highly hydrophilic ligand L H (Figure 13) that we previously used for Cu-catalyzed allylic acetoxylations in water *63+. Repeating the reaction in the absence of water dramatically decreased the yield of the Tsuji-Trost adduct with the production of the compounds obtained in MeOH under metal-free conditions ( Figure 12, path d). Thus, water also promotes the Pd catalyzed addition of acacH to 27.  ESI-MS (electrospray ionization mass spectrometry) analysis of these reactions led us to assume the possibility of in situ formation of palladium acetylacetonate complex 29 and the absence of η 3allylpalladium intermediates (Figure 14) *62+. As a result, it was proposed that 29, which would be a more effective nucleophile than acacK and MeOK, reacts with the water-activated substrate. The efficient recycling of the catalyst *62+ showed that a Pd II complex is truly immobilized in water, and led to assume the production of water-coordinated palladium species such as 30 as intermediates of the catalytic cycle.

Conclusion
The above examples highlight the unexpected observations made in the course of our studies, on the effect of the palladium environment on the outcome of reactions. Of course, several critical roles of the palladium environment have also been documented in the literature. These influences on the reactivity have attracted tremendous attention toward palladium in organic chemistry. New reactions and mechanisms are often serendipitously discovered but nevertheless, in most cases, they are the outcomes of deep investigations and reflections rather than good fortune *5+.