Phosphine-Catalyzed Domino Regio- and Stereo-Selective Hexamerization of 2-(Bromomethyl)acrylates to 1,2-Bis(cyclohexenyl)ethenyl Derivatives

A phosphine-catalyzed domino assembly of six units of 2-bromomethyl acrylates afforded polyalkenyl adducts containing two cyclohexenyl rings. This reaction occurs under mild conditions providing the final product by formation of seven carbon–carbon bonds and four stereocenters. Experimental and computational studies support an initial dimerization of the substrate, which in turn trimerizes involving two totally regio- and stereocontrolled Diels–Alder cycloadditions. The yield of the hexamerization of the 2-bromomethyl acrylates depends on the size of the ester function. The protocol has also proved to be practicable on a gram scale.

Such a striking totally regio-and stereoselective hexamerization involving the generation of seven C−C bonds and the control of four stereocenters prompted us to further investigate this reactivity.By extending the reaction time to 72 h, the yield was increased to 81% (Table 1, entry 1).By increasing the reaction temperature to 40 °C for 7 h or using 1.0 mmol of PPh 3 for 24 h did not improve the yield (Table 1, entries 2, 3).Conversely, the use of a catalytic amount of PPh 3 (10 mol %) gave only traces of the pentaenic product and a complex mixture of degradation products (Table 1, entry 4).The use of DIPEA, Na 2 CO 3 , or K 2 CO 3 as bases, instead of TEA, led to unsatisfactory results (Table 1, entries 5−7).Replacing Ph 3 P with Cy 3 P, nBu 3 P, or JohnPhos furnished only tarry products (Table 1, entries 8−10).On the other hand, the use of tri-2furylphosphine led to 2 in 69% yield (Table 1, entry 11).The use of (±)-BINAP gave only traces of 2 at r.t., while heating the mixture at 40 °C allowed only a moderate yield improvement (Table 1, entries 12 and 13).
A set of additional experiments completed our initial study (Scheme 3).The hexamerization process also took place from methyl 2-chloromethyl acrylate 1b, providing 2 in 78% yield.Conversely, the corresponding MBH acetate or carbonate was not reactive.Finally, repetition of the hexamerization of 1a on a 3.0 mmol scale gave 2 in 76% yield after a 120 h reaction.
A possible reaction mechanism is proposed in Scheme 4 for compound 2. Conjugate addition of triphenylphosphine to 2-(bromomethyl)acrylate followed by bromide elimination generates phosphonium bromide II via I, which, in the presence of triethylamine, gives the corresponding ylide III.A second conjugate addition/elimination sequence takes place between III and a new unit of acrylate to generate adduct IV.Subsequent deprotonation of IV by triethylamine triggers triphenylphosphine elimination with generation of conjugated triene VI via V.However, as the most acidic H atom in IV is on the carbon atom directly linked to the phosphorus atom, the generation of V may pass through the reversible formation of an unproductive ylide (not shown), or ylide formation is followed by a 1,2 proton shift.
From this point, the generation of pentaenic product 2 appears to derive from two consecutive Diels−Alder (DA) cycloadditions involving three units of key triene VI.In particular, while two units of VI act as dienes, the third one plays the role of a double dienophile.The formation of 2 as single regio-and stereoisomer of C i point group symmetry implies that an exo-control (C2 dienophile/C4 diene Si*/Re*) is at work during the first cycloaddition to give intermediate VII, while an opposite exo-control (C5 dienophile/C4 diene Re*/Si*) takes place in the second cycloaddition.This means that besides the regioselectivity, a total diastereoselectivity is at work in both of the cycloadditions.
Since the proposed mechanism is based on the involvement of triene VI, it was essential to prove the formation of this key intermediate.Despite several trials, detection of VI in crude reaction mixtures, even after short reaction times, was fruitless.Hence, indirect detection of VI was planned.We chose a nitrile oxide as a trapping agent, as this 1,3-dipole is known to regioselectively react with electron-poor dipolarophiles. 11    Organic Letters phosphine and triethylamine, the addition of chloroxime 7 and triethylamine (to generate benzonitrile oxide) afforded the centrosymmetric bis-isoxazoline 8 as the sole product (Scheme 5).Again, the double cycloaddition was totally regio-and stereoselective, as confirmed by X-ray diffraction analysis of a single crystal of 8.
Given the presence of five ethylenic bonds in 2, we considered its functionalization via 1,3-dipolar cycloaddition to increase the molecular complexity.Accordingly, treatment of 2 with benzonitrile oxide (in situ generated from 7 and TEA) afforded the tetracyclic centrosymmetric bis-isoxazole 9 in 56% yield as the sole product, whose structure was confirmed by Xray diffraction analysis (Scheme 6, path B).So, once again, the reaction was totally regio-and stereoselective.Compound 9 could also be obtained in good yield (48%) in a one-pot process by generating in situ benzonitrile oxide in the presence of 2, which was in turn in situ generated from 1a, providing on the whole a dimerization/double DA cycloaddition/double 1,3dipolar cycloaddition process (Scheme 6, path A).
To understand the reason for such a total stereoselectivity, DFT calculations were performed. 12,13The lowest energy geometry (Table S1, Supporting Information (SI)) for each ground state and transition state (TS) was used for evaluating the enthalpy (Figure 1A and B) and free energy (Figure S1A and B; SI) paths of the first and second cycloaddition.As to the first cycloaddition, we modeled the reaction between two molecules of monomer VI to provide intermediate VII in both the 3R,4R (VII-RR) and 3R,4S (VII-RS) stereochemistries.We found that the path leading to the former stereoisomer was kinetically favored over the second, with activation barriers (ΔH ‡ ) = 9.2 and 15.6 kcal/mol, respectively, from the activated complex (AC-VII vs TS-VII).No relevant difference was found in reaction enthalpy (ΔH), suggesting that VII-RR and VII-RS are thermodynamically equivalent (Figure 1A).As to the second cycloaddition, we investigated the reaction between the kinetically favored VII-RR and monomer VI, leading to the 2-RRSS and 2-RRRR diastereoisomers (Figure 1B).In this case, the former compound was favored over 2-RRRR both kinetically (ΔH ‡ = 9.3 and 16.9 kcal/mol, respectively; AC-2 vs TS-2) and thermodynamically (ΔH = −33.0 and −23.3 kcal/mol, respectively; 2 vs AC-2).
We analyzed the difference between TS-2-RRSS and TS-2-RRRR by performing a topological analysis of the electron density using the Bader's Quantum Theory of Atoms in Molecules (QTAIM). 14,15In QTAIM, both covalent and noncovalent interactions are defined by a bond path (BP) and by a bond critical point (BCP).The value of electron density ρ(r) at the BCP is a measure of the strength of the interaction.Results are summarized in Figure S2A, B (SI) and Table S2 (SI), where BPs connecting noncovalently bound oxygen and hydrogens (HB) are reported with the corresponding BCPs.From the molecular graphs, it can be observed that four HB BCPs (BCP1−4) are found for TS-2-RRRR (Figure S2A  RRSS, six of which were intermolecular.Additionally, the total electron density ρ(r) of HB BCPs is 0.066659 and 0.047609 au for TS-2-RRSS and TS-2-RRRR, respectively.This indicates stronger, as well as more numerically abundant, interactions among the reactants in the former TS, justifying the selectivity observed both theoretically and experimentally.
In conclusion, we have disclosed a highly effective phosphine-catalyzed procedure that allows assembly, in a totally regio-and stereoselective way, of six molecules of 2-(bromomethyl)acrylates through the formation of seven carbon−carbon bonds and four stereocenters.The resulting sole product is a centrosymmetric pentaene containing two cyclohexenyl units derived from a dimerization/double DA cycloaddition sequence.A key intermediate of this domino sequence is the 2,5-dicarbomethoxy-1,3,5-triene VI, whose formation was evidenced by its trapping through a 1,3-dipolar cycloaddition with benzonitrile oxide.Furthermore, adduct 2 was also found to undergo a double and totally selective 1,3dipolar cycloaddition with benzonitrile oxide, generating a tetracyclic bis-isoxazole adduct as the sole product.DFT computations of the two DA steps supported the proposed mechanism.Computed ΔH ‡ are consistent with a reaction occurring at room temperature as well as with the observed selectivity.Future studies will be directed toward expanding the scope of the reaction between 1 and other 1,3-dipoles to achieve new structures and higher complexity.

Figure 1 .
Figure 1.DFT and QTAIM analysis of the reaction mechanism leading to experimentally isolated and nonisolated stereoisomers.(A) Enthalpy path and stationary points for the dimerization of VI, leading to VII-RS and VII-RR.(B) Enthalpy path and stationary points for the addition of VII-RR to VI, leading to 2-RRRR (not isolated) and 2-RRSS (isolated) stereoisomers.ΔH values relative to the isolated reactants are reported in parentheses in kcal/mol.