Screening of reaction conditions
Initially, we anticipated the necessity of employing a highly electrophilic palladium catalyst for the aza-Wacker reaction involving anilines and terminal olefins58–62. Through screening various additives capable of activating the electrophilic activity of the palladium catalyst, NaBArF4 was identified as an effective activator63–67, leading to the desired reaction and the formation of the target product 3a (See Chap. 3 of SI for more details).
The bidentate nitrogen ligands emerged as the privileged ligands for this reaction. When plain bipyridine L4 and o-phenanthroline L8 were employed, the target product was obtained in 34% and 24% yields, respectively (Scheme 2, Entries 4 and 8). Sterically hindered ligand L9 did not work. To our delight, the use of L5 and L6, featuring electron-withdrawing groups, increased the yields to 54% and 55%, respectively (Scheme 2, Entries 5–6), presumably due to the favorable electronic matching between the electron-deficient bidentate nitrogen ligands and the highly electrophilic palladium salt.68 More electron-deficient diazine bidentate nitrogen ligands were synthesized. As anticipated, both the bipyrimidine L7 and bipyrazine L1 successfully promoted the reaction, yielding the target products in 59% and 75% yields, respectively (Scheme 2, Entries 1 and 7). Interestingly, the more electron-deficient L2 or L3 did not work, resulting in trace product formation (Scheme 2, Entries 2–3). This observation suggests a potential failure of these ligands to form compatible complexes with the palladium catalyst, leading to a rapid deactivation of palladium. Further control experiments demonstrate the indispensability of PdCl2 catalyst, L1 ligand, NaBArF4 additive, and 2,5-DTBQ oxidant (Scheme 2, Entries 10–13). Additionally, the absence of Al2O3 was found to decrease the yield (Scheme 2, Entry 14), while the introduction of Lewis acids was not conducive to the reaction (See Chap. 3 of SI for more details). After a comprehensive screening process, the optimized reaction conditions are as follows: PdCl2 (10 mol%), bipyrazine (20 mol%), NaBArF4 (30 mol%), 2,5-di-tert-butyl-1,4-benzoquinone (1.5 equiv.), Al2O3 (300 mg/mmol) in DCM (0.1 M) at 70 oC under N2 for 72 h, affording an isolated yield of 79% with a diastereomeric ratio > 20:1 (Scheme 2, Entry 1).
Substrate scopes
With the optimized reaction conditions established, we investigated the functional group compatibility and substrate scope of the reaction (Scheme 3). A range of para-substituted anilines readily underwent reaction to afford the corresponding products 3a-3h. Substrates, bearing easily removable functional groups, such as iodine atom 1j, proved unsuitable for this transformation. The electron-deficient aniline substrate 1i with trifluoromethyl-substituted exhibited poor reactivity (see SI for more incompatible substrates). The reaction exhibited insensitivity to meta-steric hindrance, leading to poor regioselectivity observed for the product of the meta-substituted anilines 3k-3m, 3z-3ag. Anilines bearing ortho-substitution furnished the corresponding target products 3n-3q, 3ah-3ai in moderate yields. Notably, the reaction displayed compatibility with several sensitive functional groups, such as cyclopropyl 3s, alcohols 3t and 3w, Boc-protected alkylamine 3u, cyano 3v. Additionally, various aromatic amine substrates participated in the reaction, yielding target products 3aj-3an with moderate to good yields, including 1-naphthylamine, 2-naphthylamine, benzo[b]thiophen-5-amine, dibenzo[b,d]thiophen-3-amine, and benzofuran-5-amine. Intriguingly, these aromatic amine substrates exhibited excellent regioselectivity, affording predominantly single compounds.
To further demonstrate the robustness and compatibility of this reaction, late-stage functionalization modifications were conducted on a series of natural products and drug molecules. As expected, anilines derived from the monoterpenoids L-Menthol and L-Borneol, respectively, were efficiently post-modified, yielding the desired products 3ao and 3ap in good yields. Cholesterol is an important molecule in animal cells, and its derived aniline compound can also be successfully modified via this reaction to get 3au. Furthermore, the aniline derivative derived from Vitamin E, known for its susceptibility to oxidation as a plant-derived vitamin, underwent successful modification to yield the target products 3as, under the conditions of the palladium catalyzed oxidative amination. Both Podophyllotoxin and Galactopyranose-derived anilines, characterized by their oxygen-rich molecular structures, yielded the target products 3aq (24% yield, > 20:1 d.r.) and 3ar (29% yield, 6:1 d.r.) with acceptable yields and diastereoselectivity. Tigogenin possesses a spirocyclic structure and is renowned for its cytostatic activity69, whose aniline derivative underwent the reaction smoothly to form product 3at with a yield of 56% and a d.r. value of 11:1.
Substrates on the diene were explored and evaluated in Scheme 4. Compound 2av, featuring a methyl substituent at the ortho-position, and compound 2ay, substituted with a phenyl group at the para-position, underwent the reaction to afford the target molecule 3av and 3ay with good yield and excellent diastereoselectivity. Elevating the temperature to 80 oC, resulted in the formation of 3aw, bearing an ortho-methoxy group, and 3az, bearing a para-trifluoromethoxy group, in moderate yields. It is worth noting that substrates bearing other aromatic substituents are also suitable for this system. For instance, diene substrates substituted with 2-naphthalene or 1-naphthalene yielded the target products 3ba (74% yield, > 20:1 d.r.) and 3bb (75% yield, > 20:1 d.r.) in good yields and excellent diastereoselectivity respectively. Electron-rich thiophene-substituted dienes can also provide the target product 3bc in acceptable yields. Despite testing diene substrates with different carbon chain lengths, only 1,6-diene and 1,7-diene were suitable for this reaction. The 1,7-diene substrate afforded octahydroacridine in 30% yield with > 20:1 diastereoselectivity.
Synthetic applications
We conducted several synthetic applications using the obtained products (Scheme 5). Initially, the standard reaction was upscaled, yielding 1.10 grams of product 3b at a scale of 5 mmol with an isolated yield of 56%. Subsequently, 3b was hydrolyzed with LiOH to afford the corresponding crude diacid product 3be-1, which was further benzyl-modified with benzyl bromide to produce product 3be in a 64% yield over two steps. The trifluoroformylation of 3a yielded the product 3bf, which formed a beautiful monoclinic crystal. The skeleton structure and relative configuration of the three diastereomeric centers were determined via X-ray single-crystal diffraction. Reduction of 3b using lithium aluminum hydride provided the corresponding diol product 3bg in a 79% yield. Subsequent modification of the diol with TBSCl and 2,2-dimethoxypropane afforded products 3bh and 3bi, respectively, in yields exceeding 90%.
Mechanistic investigations
To elucidate the mechanistic of the reaction, a series of controlled experiments were designed. In the absence of palladium catalysis, the reaction failed to proceed, with both the aniline and diene almost completely recovered (Scheme 6a). Ketone 4 was introduced into the standard reaction instead of the diene, yielding the corresponding product 3b with a satisfactory yield of 73%. However, the yield drastically decreased in the absence of a palladium catalyst. By comparing Scheme 6a, b, palladium not only catalyzed the aza-Wacker process but also acted as a Lewis acid to promote the cyclization process. The intermediate 4 cannot be obtained without the presence of aniline (Scheme 6c), which excludes the possibility of a Wacker reaction between the H2O in "wet" solvent and the olefin.
A series of deuteration experiments are as follows. Surprisingly, upon addition of D2O (10 equiv.), the resulting product d-3b-1 exhibited deuterium incorporation at four positions: the ortho and para positions of the aniline, the methyl group, and the CH2 adjacent to the methyl group (Scheme 6d). The incorporation of 1.77 and 1.06 deuterons suggests an interaction between D2O and intermediate 4. Further exploration of the deuteration mechanism on the aniline was conducted by subjecting 1b and 3b to standard conditions containing D2O (Scheme 6e). The recovered d-1b and d-3b-2 were both found to be deuterated, indicating that anilines are susceptible to Friedel-Crafts attack by certain electrophiles under the reaction conditions (more exploration on deuteration process is in progress).
Presumably, this deuterated property is associated with the activating effect of NaBArF4 on palladium. By controlling the amount of palladium catalyst to 10 mol% and varying the quantity of NaBArF4, it was observed that the reaction failed to proceed in the absence of NaBArF4. Additionally, when the ratio of NaBArF4/PdCl2 equalled 1.0, the reaction yield was low, which resembled that obtained using 5 mol% PdCl2/10 mol% NaBArF4. (Scheme 6f). It is hypothesized that under the conditions of 10 mol% PdCl2/10 mol% NaBArF4, only half of the PdCl2 is activated by NaBArF4 and functions as a catalyst. This suggests that two molecules of NaBArF4 react with one molecule of palladium catalyst, liberating two molecules of NaCl to form LnPd(BArF4)2 active catalytic species. Finally, equimolar amounts of aniline and 5d-aniline were subjected to standard conditions to conduct intermolecular KIE experiments, yielding product d-3b-3 (Scheme 6g). Based on the deuteration rate of aniline meta-position, the calculated KIE value is 1.0, indicating that the rate-determining step of this reaction does not involve the removal of the ortho-position hydrogen of aniline.
Based on these mechanistic insights, the proposed mechanism unfolds as follows: initially, the palladium catalyst engages with NaBArF4 and ligand to generate active catalytic species. Following this, species I, formed upon coordination of the palladium species with the diene, undergoes nucleophilic attack by aniline to yield intermediate II. Subsequently, β-H elimination occurs, leading to isomerization and the formation of intermediate IV. The released Pd-H is oxidized to regenerate PdII species. PdII species act as a Lewis acid, facilitating the intramolecular Mannich reaction and subsequent ring closure to furnish intermediate VI. The resulting benzylic carbocation undergoes intramolecular Friedel-Crafts alkylation to afford intermediate VII, which is subsequently deprotonated to yield the target product 3.