Hydroxy group-enabled highly regio- and stereo-selective hydrocarboxylation of alkynes

Hydrogen bonding-enabled highly regio- and stereo-selective hydrocarboxylation of alkynes has been successfully developed to afford 3-hydroxy-2(E)-alkenoates with up to 97% yield.


Introduction
As one of the most abundant and fundamental chemical feedstock, alkynes are widely applied in biochemistry, materials sciences, pharmacology, and medicine. 1 Among many reactions, their addition reactions with another molecule, X-Y, perfectly suit the demand for green chemistry due to the 100% atom economy, thus leading to tremendous interest in this area due to the high importance of stereo-dened olens. 2 However, regioselectivity is the issue when it comes to non-symmetric alkynes (Scheme 1a). Electronic and steric effects help in solving this type of problem (Scheme 1b and c). 3 Using a preinstalled directing group, such as carbonates, pyridyl groups, amides, alkenes, etc., is another feasible way to control regioselectivity through coordination with metal catalysts (Scheme 1d). 4,5 As we know hydrogen bonding interactions have been widely used in organocatalysis, 6 and recent publications also demonstrate their capacity in regioselective addition reactions. 7 Herein, we report our recent observation on hydroxy group-enabled regioselectivity control in highly stereoselective hydrocarboxylation of readily available 2-alkynylic alcohols affording highly functionalized 3-hydroxy-2(E)-alkenoates (Scheme 1e).
Unfortunately, this set of reaction conditions did not work very efficiently for 2-alkynylic alcohols with R 1 and R 2 both being alkyl groups-the reaction of 1k resulted in the formation of the desired (E)-2k in only 35% yield ( Table 3, entry 1). Lowering the temperature increased the yield up to 49% (Table 3, entry 2). Then, the ligand effect was re-investigated to address this issue. As shown in Table 3, mono-phosphine ligands were not efficient for the hydrocarboxylation (Table 3, entries 3 and 4). It is also worth noting that the efficiency strongly depends on the electronic properties and the backbone structure of the bisphosphine ligands. Compared to 2,2 0 -bis(dicyclohexyl-phosphino)-Scheme 1 Addition reactions of alkynes-approaches for regioselectivity control (only syn-additions are shown for clarity).
, more rigid or more exible backbone structures both made the reaction slower (Table 3, entries 5-7). Furthermore, a relatively electron-decient ligand, BIPHEP, gave only 5% yield of the product with 95% recovery of 1k (Table 3, entry 8). Finally, when the reaction was carried out with 4 equiv. of MeOH at 60 C, (E)-2k could be obtained with the highest yield (Table 3, entry 9). Under this set of new optimal reaction conditions, more examples of 2-alkynylic alcohols were examined. As shown in Table 4, R 2 and R 3 are both compatible with an alkyl or aryl group (Table 4, entries 1-9). The structure of (E)-2q was further conrmed by its single crystal X-ray diffraction analysis (Fig. 2). In addition, a 2-alkynylic alcohol with a four-membered cyclobutyl ring also survived affording (E)-2s in 87% yield (Table 4, entry 10). Reaction with more sterically hindered 1,1-diphenylhept-2-yn-1-ol proceeded smoothly to give (E)-2t in 86% yield and 9% recovery of 1t (Table 4, entry 11). It is noteworthy that secondary 2-alkynylic alcohols also afforded the target products in good to excellent yields with the same regio-and stereoselectivity (Table 4, entries 12-15). Interestingly, even the C-Br bond could survive in this reaction (Table 4, entries 2, 3, and 15). The reaction could be easily executed on a gram scale, delivering (E)-2l in 89% yield (Table 4, entry 3).
In addition to methanol, some other alcohols were also examined. Ethanol and TMSCH 2 OH work well to obtain the   target products in 95-97% yield (Table 5, entries 1 and 2). Sterically hindered i-PrOH is also tolerated with 76% yield (Table 5, entry 3). Phenol behaves worse, and only 30% yield was detected (Table 5, entry 4). 9 Furthermore, as shown in Table 6, racemization of the chiral center in substrates (S)-1 10 was not observed-the reaction of optically active propargylic alcohols afforded optically active 3hydroxy-2(E)-alkenoates with excellent ee values and high yields.
As we know that 2-alkenoates are important intermediates in organic synthesis, their synthetic potential has been further demonstrated for the synthesis of different stereo-dened functionalized olens. Owing to the presence of the C-Br bond in (E)-2l, Suzuki coupling reactions could easily afford (E)-7 in 80% yield. 11 The ester unit could be hydrolyzed with KOH at 50 C for 2 hours to afford the corresponding acid (E)-8 in 80% yield, 12 or reduced with DIBAL-H at À78 C delivering the corresponding 1,4-diol (E)-9 in 80% yield. 13 Fluorination of the hydroxyl group could also be easily conducted with DAST to furnish (E)-10 in 94% yield 14 (Scheme 2).
To gain insight into the reaction mechanism and the effect of the hydroxyl group, a couple of control experiments were conducted (Scheme 3). No desired hydrocarboxylation products were obtained when propargylic methyl ether 3, acetate 4, or internal alkyne 5 was utilized (Scheme 3a and b), indicating that the hydrogen bonding originating from the free hydroxyl groups in propargylic alcohol and methanol might have played a critical role in this transformation. Isotopic labeling studies reinforce the notion that methanol was the hydrogen donor (Scheme 3c). We reasoned that the low D incorporation was caused by adventitious water in the reaction mixture. Furthermore, the 1 H NMR signals of 1-phenyl-3-methyloctyn-3-ol 1k were measured with respect to different amounts of MeOH and 1k: an obvious shi of the hydroxy signal in 1k and MeOH was observed, indicating hydrogen bonding between the two hydroxyl groups (Fig. 3).

Scheme 3 Mechanistic studies.
excess of MeOH to ensure pseudo zero order in MeOH, indicating rst-order dependence of the reaction rate with respect to propargylic alcohol (Fig. 4b). An experiment was also carried out to measure the rate of H/D-scrambling. By adding MeOD into the solution of 1k in CDCl 3 and then subjecting the mixture to 1 H NMR analysis immediately, the H/D-exchange process was found to reach an equilibrium state within 3 minutes (for details, see the ESI †), which is much faster than the rate of this hydrocarboxylation reaction (Fig. 4a). Based on this, parallel reactions of 1k and 1k-d in separate reaction vessels monitored by 1 H NMR analysis of the reaction prole could help determine the value of k H and k D , and then the KIE was calculated to be k H /k D ¼ 16 (Fig. 5), indicating the primary isotope effect of H/D.
In order to further identify the rate-determining step, the electronic effect of substrates on the Pd-H insertion step was investigated (Table 7). Then, kinetic studies of the substrates with different substituents on the para-position of the phenyl ring such as Br, CO 2 Me, Me, and OMe were carried out. Linear relationships were obtained for ln{c 0 /(c 0 À [(E)-2k])} vs. reaction time, and show signicantly different reaction rates, that is, the more electron-rich the substituent is, the faster the reaction rate is (Fig. 6). These results also indicate that Pd-H insertion has a large effect on the reaction rate. However, we are still not able to exclude the oxidative addition of O-H with Pd as the ratedetermining step.
In order to further unveil the mechanism, solvents without hydrogen bonding 7b were also screened-lower yields were detected in comparison with the data for toluene. The stronger the polarity of the solvent is, the lower the yield would be, and nothing but a large amount of substrate recovery was observed   when using DMSO, further supporting the irreplaceable role of hydrogen bonding in this transformation (Table 3, entries 10-14).
Other than this, a Hammett study with phenols bearing various substituents has also been carried out ( Table 8). The negative value for r points out that the rate-determining step favors phenols with electron-donating groups (Fig. 7). 15 This seems reasonable to us because phenols with electron-donating groups would result in a higher electron density on the oxygen atom, thus leading to stronger hydrogen bonding with the hydrogen atom in the hydroxyl group and/or nucleophilicity (see step 3 in Scheme 4).
Based on these studies, a plausible mechanism is proposed (Scheme 4). Hydrogen bonding between the hydroxyl group of methanol and that of 2-alkynol combined with the coordination of the C-C triple bond to the Pd 0 species would form complex A. Subsequent oxidative addition of the O-H bond in methanol with Pd 0 in A affords complex B. Subsequent regioselective synhydropalladation of the C-C triple bond delivers the H atom to the sp carbon atom closer to the hydroxy group in 1k, and then nucleophilic attack of CO by the methoxy anion generates Int 2. Reductive elimination would then furnish (E)-2k and regenerate the Pd 0 species to nish the catalytic cycle. Of course, further studies are needed to fully verify this mechanism.

Conclusions
In summary, we have developed hydroxy group-enabled highly regio-and stereo-selective hydrocarboxylation of 2-alkynylic alcohols, exploiting a previously unrecognized regioselectivity control strategy. The remarkable substrate scope, atom economy, and good to excellent yields make this reaction a facile synthetic M e ( 1z-A) 9 6 ( 2z-A) 5 OMe (1z-B) 9 7 ( 2z-B) a Isolated yield. b 14% recovery of 1y was detected.   method to produce highly functionalized 3-hydroxy-2(E)-alkenoates and the observed regioselectivity may arise from hydrogen bonding, which needs further investigation. Due to the versatility of the functionality in the products, the importance of the stereoselective construction of C]C bonds, and the nature of regioselectivity control, this method will be of high interest to organic and medicinal chemists. Further studies in this area are currently ongoing in our laboratory.

Conflicts of interest
There are no conicts to declare.