Preliminary experiments

A principal possibility of the 5-exo-trig/3-exo-trig cyclization of 1,6-enynes towards bicyclo[3.1.0]hexylacrylates had been recently reported by GRIGG.^[114] Later, OPPOLZER^[115]

has developed this approach towards diastereoselective synthesis of enantiomerically pure (−)-α-Thujone. This article was chosen as a starting point for further investigations in this field because actually it was the only published example of the titled cyclization afforded various bicyclo[3.1.0]hexyl acrylic moiety in high yield by complete conversion of the starting 1,6-enines. Moreover, the viable procedures concerned the used catalytic system preparation had been documented in details.

First, a principal possibility to involve into the titled cyclization an unsubstituted enyne, which never before were cyclized to the respective bicyclo[3.1.0]hexane moiety via Pd-catalyzed process, was tested. There is a suggestion that unsubstituted 1,6-enynes would not undergo cyclization readily because of two reasons. Enyne conformation enabling this process (when unsaturated fragments are next to each other) is sterically disfavored unlike the widely used for this purposes 5-mono- and 5,5-disubstituted precursors.^[114-116] On the other hand, a complexation of the hard nucleophilic substituent (for example, alkoxycarbonyl group of a gem-5,5-EWG-disubstituted 1,6-enyne) was suggested to stabilize an intermediate Pd-specie, thus preventing the β-hydride elimination of PdLn resulted in a “Pd-black” formation.^[116] In order to clear this question up, enyne 196 was subjected to the previously described by GRIGG^[114] simple protocol for anionic capture of bicyclo[3.1.0]hexyl-Pd spices with sodium tetraphenylborate. Thus, heating of enyne 196 at 80 °C for 18 h in the presence of 10 mol%

Pd(OAc)2 and 20 mol% PPh3 with 1 equivalent of NaBPh4, resulted in desired cyclized

Scheme 68

O OMe

O

35%

NaBPh₄, Pd(OAc)₂ PPh₃, 80 °C, 18 h

196 197

After the successful formation of desired product 197 had been evidenced, attempts to involve bicyclic vinyl palladium species into carbonylation process were undertaken.

Preliminary GRIGG’s^[114] original protocol for methoxycarbonylative trapping of [3.1.0]bicyclohexyl palladium unit had been tested to produce only a complex mixture of unidentified products along with the starting material. In general, after the various reaction conditions were screened, it was concluded (besides, almost in the all cases target acrylate was found, but in a very low yield; <20% according to ¹H NMR spectra of reaction mixture), that the yield of a cyclized product was reduced at increased temperature and pressure.

Increased temperature decreased “life-time” of the catalytic Pd-species, resulting in fast formation of the “Pd-black” as β-elimination product. An increased pressure gives rise a simple non-cyclized allenic methoxycarbonylation product, that was previously reported by TSUJI^[117] (Scheme 69, cycle I→II'→II). Later it was also found that introduction of hard basic or nucleophilic groups into substrate (in the first approximation, it may be connected with the quantity of heteroatoms, namely oxygen atoms, in substrate, and their steric accessibility to be coordinated with Pd) significantly decreased the yield of bicyclic product and required an increased catalyst loading.

From these preliminary considerations is clear that only the nature of the catalytic species and its concentration had to be chosen as variable parameters for the process optimization.

Thus, methylcarbonate leaving group had been already shown^{[116, 117]} is actually the best one (it has the highest lability, that means lowest activation parameters for the oxidative addition of [Pd⁰] to the substrate; step I'→II'). It is also obvious that characterized with clearly negative ∆S double cyclization process should be therefore conducted at the lowest possible temperature and CO pressure to avoid the by-product II formation (Scheme 69).

Scheme 69

Thus, the further investigations were switched over to search an appropriate ligand. It was found that only tri-(2-furyl)phosphine used by OPPOLZER for the same purposes,^[115] provided almost 100% conversion of 196 towards the cyclized product 130. Less expensive substituted phosphine (PPh3, P(o-tolyl)3, P[2,6-di-(MeO)2Ph]3) along with the HERMANN’s catalyst^[118]

turned to be inefficient because of immediate “Pd-black” formation.

Some attempts were also undertaken to avoid the usage Pd2(dba)3. Its clear drawbacks are air sensitivity, high price, and occurrence of dibenzalacetone in the reaction mixture that sometimes complicated target product isolation. Taking in consideration a fact that a required

reduction of Pd^II to Pd⁰, the another two are consumed to complexate with Pd⁰),^[119] it was decided to search for some promoting substance, which would reduce the Pd(OAc)2 in the presence of 2 eq. of the P(2-furyl)3 giving “Pd[P(2-furyl)3]2” stable for a longer time under reaction conditions. Thus, trimethyl phosphite was found to be an efficient Pd^II-reducing and, at the same time, catalyst supporting dopand, which enabled the required cascade cyclization of unsubstituted 1,6-enynes I (X = CH2, O) towards the respective methyl 2-(bicyclo[3.1.0]hex-1-yl)acrylates IV (Scheme 69). 5,5-EWG disubstituted precursors were found to be unreactive towards the titled catalytic system (CSA), and only an unchanged starting material was recovered after continuous stirring under standard reaction conditions.

Nevertheless, a combination of P(2-furyl)3 with tetramethyl ammonium bromide (CSB) was found to be useful to afford the corresponding gem-3,3-disubstitutes bicyclo[3.1.0]hex-1-yl acrylate (X = C(CO2Et)2) in high yield with a complete conversion of the starting material.

This outcome is essential for preparative synthesis of the pure product, because all the participants of presented cyclization (starting material, by-products and product) have the very close to each other Rf-values.

In general, it should also be noted that any bulky species, being able for coordination bonding with the Pd⁰-catalytic species, would decrease the yield of cyclization product (Scheme 69, steps II'→III'→IV'→IV) due to sterical reasons. Thus, in addition to negative influence of increased basic and nucleophilic substrate hardness onto yield of IV noted in the following range X = CH2 > O >> C(CO2Et)2 > C(CO2Me)2 (from left to right yield is decreased, reaction time is increased and Lewis base strength of the substrate is increased), it was found that, in spite of clearly higher reaction rate, a significant amount (up to 15%) of allene II was detected in the reaction mixture, after the unsubstituted 1,6-enyne was allowed to react in the presence of CSB. Moreover, a slightly increased yield of allene II (X = CH2, O) was also noted, when more bulky cetyltrimethylammonium bromide was used as an activator instead of the tetramethylammonium bromide.