Development of Highly Efficient Platinum Catalysts for Hydroalkoxylation and Hydroamination of Unactivated Alkene


 Hydrofunctionalization, the direct additon of an X–H (e.g., X = O, N) bond across an alkene, is a desirable strategy to make heterocycles that are important structural components of naturally occurring molecules. Described here is the design and discovery of “donor–acceptor”-type platinum catalysts that are highly effective in both hydroalkoxylation and hydroamination of unactivated alkenes over a broad range of substrates under mild conditions. A number of alkene substitution patterns were accommodated, including tri-substituted, 1,1-disubstituted, (E)-disubstituted, (Z)-disubstituted and even mono-substituted double bonds. Detailed mechanistic investigations suggest a plausible pathway that includes an unexpected dissociation/re-association of the electron-deficient ligand to form an alkene-bound “donor–acceptor”-type intermediate. These mechanistic studies help understand the origins of the high reactivity exhibited by the catalytic system, and provide a foundation for the rational design of chiral catalysts towards asymmetric hydrofunctionalization reactions.

electron-de cient "acceptor" ligand to the Pt center would make a soft and stable cationic system [50][51] , thus leading to a more effective activation of soft Lewis bases, such as C-C multiple bonds. Herein, we disclose readily accessible "donor-acceptor"-type platinum catalysts that are highly active in both hydroalkoxylation and hydroamination, along with mechanistic studies that reveal the origins of the high reactivity of the catalytic system. The hydroalkoxylation and hydroamination reactions catalyzed by the new Pt-complexes typically proceed at mild temperatures (23-50 o C), and encompass a remarkably broad substrate scope, including alkenes with various substitution patterns ( Figure 1C). Mechanistic data reveals an unusual dissociation/re-association of the electron-de cient mono-phophine, and that a polarizable alkene-bound "donor-acceptor"-type intermediate could be formed, thus facilitating activation of simple alkenes 52 . In addition, chiral platinum catalysts bearing (R)-BINAP or (R)-Di uorphos and an electron-de cient monodentate ligand with hydrogen-bonding site allows the asymmetric hydroalkoxylation and hydroamination with enantioselectivities, likewise supporting that a more complex metal catalyst than tri ic acid is involved [53][54][55][56] .

Results
Screening of the optimal catalysts. In Grubbs' previous studies on hydration of nitriles and cyanohydrins, more electron-rich groups in the "donor" moiety was discovered to increase the activity of the catalysts 49 .
Therefore, we take the electron-rich 1.1'-[bis(5-methyl-2-furanyl)phosphine]ferrocene "donor" ligand and modulate the electronic nature of the monodentate "acceptor" ligands. As shown in Figure 2, ve Ptcatalysts A-E were synthesized via the reaction of 1.1'-[bis(5-methyl-2-furanyl)phosphine]ferrocene platinum dichloride (dmfpfPtCl 2 ) with the corresponding monodentate phosphine ligands (in blue) in the presence of silver tri ate, respectively (See Supporting Information). Then the activity of the newly synthesized platinum catalysts was evaluated by performing hydroalkoxylation of 1 and hydroamination of 2 ( Figure 2). The results show that catalyst A, with triphenylphosphine as the monodentate ligand, has the worst reactivity for both hydroalkoxylation of 1 and hydroamination of 2. Catalyst B that bears electron-de cient monodentate tris(4-(tri uoromethyl)phenyl)phosphine slightly improved the reactivity for both hydroalkoxylation and hydroamination. Catalyst C harbouring the more electron-de cient monodentate tris(3,5-bis(tri uoromethyl)phenyl)phosphine displays noticeably increased catalytic activity, providing hydroalkoxylation product 1a and hydroamination product 2a in 46% and 44% yields, respectively. The observation that more electron-de cient tri-aryl phosphine ligand in the "acceptor" moiety resulted in higher catalytic activity as demonstrated by the improved performance of catalysts A, B and C supports Grubbs' "donor-acceptor" catalyst design 49 . Catalysts D and E bearing other two different electron-de cient monodentate ligands, tris(3,4,5-tri uorophenyl)phosphine and tris(3,5-di uoro-4-(tri uoromethyl)phenyl)phosphine, also show good reactivity for both hydroalkoxylation and hydroamination, and have their own advantages for different substrates. The trend that more elelctronrich group in the "donor" part and/or the more electron-de cient group in the "acceptor" part increased the activity of the Pt-catalysts could be explained: the cationic Pt(II) was stabilized by the strong σ donating from the electron-rich bidentate ligand, while the electron-de cient monodentate ligand which acts as weak σ donor but strong π acceptor makes the Pt(II) center more electrophilic towards multiple bonds4 51 .
Scope for hydroalkoxylation. we next investigated the scope of intramolecular hydroalkoxylation with catalyst C, which contains the commercially available and inexpensive tris (3,5-bis(tri uoromethyl)phenyl)phosphine as the monodentate ligand (Table 1). All the reactions were conducted under mild conditions (either at 23 or 50 °C). The catalytic protocol displays excellent generality with Markovnikov regioselectivity, and is notably applicable to the synthesis of sterically hindered ethers with fused-, bridged-and spiro-ring systems ( Expanding our investigation to intermolecular hydroalkoxylation, we discovered that catalyst D was the optimal catalyst whereas C gave slightly reduced yields over a range of different substrates ( Table 2). Higher catalyst loadings (5 mol%) and slightly elevated temperatures are required for optimal conversion of the intermolecular reactions reported here. Alkenes with ring strain such as norbornene (23), comphene (24), and four-membered carbocycles (25) all productively undergo intermolecular hydroalkoxylation reactions with alcohols. Acyclic alkenes such as 26 and 27 that are less reactive substrates than their cyclic counterparts were coupled with alcohols in moderate yields. These reactions generally stalled at 30 to 70% conversions depending on the nature of the nucleophile used; longer reaction times or higher catalyst loadings do not help to convert the reactions further. Intermolecular hydroalkoxylation of norbornene (23) with para-substituted phenols were also investigated. Phenols have a potential to engage in hydroarylation reactivity 57 ; however, we only observed hydroalkoxylation products (ethers) when para-substituted phenols (CF 3 , F, Cl, Br) and norbornene (23) were treated with D/AgOTf at either room temperature or 50 °C. In contrast, bis-ortho-hydroarylation products were exclusively generated when tri ic acid (TfOH) alone was used as the catalyst (See the Supporting Information for further details). These results suggest a distinct mechanistic pathway for our catalytic system, different from that of a Brønsted acid-catalyzed hydroalkoxylation. Table 2 Substrate scope for intermolecular hydroalkoxylation a .
Substrate scope for hydroamination. The "donor-acceptor"-type Pt-catalysts not only are capable of catalyzing hydroalkoxylation, but can also effect hydroamination of unactivated alkenes in generally good yields. As complied in Table 3, the catalyst E, even used at lower loading of 1 mol%, was shown to be capable of effecting intramolecular alkene hydroamination with sulfonamides at ambient temperatures, providing various nitrogen-heterocycles that are important structraul motifs in naturally occuring and pharmaseuticals. A wide range of alkene substitution patterns are tolerated, including 1,1disubstitutied (Table 3, entries 1 to 8), 1,2-disubstituted (Table 3, entry 9), mono-substituted (Table 3, entries 10 and 11) and trisubstituted alkenes ( Table 3, entries 12 to 14). The relative stereochemistry of 41a was unambiguously con rmed by X-ray crystallography ( Table 3, entry 14). Next, we examined the viability of more di cult intermolecular alkene aminations with p-toluenesulfonamide, (ptolylsulfonyl)methylamine, N-tosyl-4-methoxyaniline and methanesulfonamide (  (Table 4, entries 5 to 7) and 1,2-disubstituted alkenes ( Table 4, entries 8 and 9). Both cyclic and acyclic alkene partners can be aminated successfully. The structure of 23f was veri ed by X-ray crystallogrphy. Mechanistic Studies. Recently, several groups have independently demonstrated that tri ic acid can catalyze the additions of oxygen-and nitrogen-based nucleophiles to simple alkenes with comparable e ciency/selectivity as some metal tri ates [53][54][55][56] . The aforementioned reports raised the question of a competitive acid-catalyzed pathway when metal tri ates are employed. Therefore, we elected to perform a detailed analysis of the possible mechanistic pathways for the "donor-acceptor" Pt-catalyzed hydroalkoxylation of alkenes.
The mechanistic study commenced with monitoring the reaction of norbornene and 4tri uromethylphenol catalyzed by D and AgOTf in deuterated dichloromethane at 23 o C by 31 P, 19 F and 1 H NMRs (Figure 3 and please also see Supporting Information). When equal molar of AgOTf was added into catalyst D in deuterated dichloromethane, 31 P NMR revealed the appearance of a new peak at d -22.5 (s, 1 J Pt-P = 4022 Hz) ppm (Figure 3c). This peak was con rmed to be complex G that can be generated independently by mixing 1 equivalent of 1,1'-[bis(5-methyl-2-furanyl)phosphine]ferrocene platinum dichloride (dmfpfPtCl 2 ) with 2 equivalents of AgOTf (Figure 3b). It is worth to note that when the chloride ion in the catalyst D was abstracted by AgOTf, a more electron-de cient Pt(II) center was formed; as a result, the monodentate phosphine ligand was dissociated from the Pt center and coordinated with Ag(I) ion to form new complexes such as [(Ar 3 P) x AgOTf] n (H) with 19  4 equivalents of norbornene were then added to the above solution which led to rapid disappearance of complexes G and H, and 1 H NMR analysis revealed that diagnostic alkene peaks move down eld ( Figure   3d and also see 19 F and 1 H NMRs in Supporting Information). These results together indicate that the mono-phosphine ligand re-combined to the Pt center when the alkene was coordinated to the Pt. Finally, when 4-tri uoromethylphenol was added, 1 H NMR con rmed that the hydroalkoxylation product 23b was formed with the concurrent regeneration of complexes G and H (Figure 3e and also see Supporting Information).
To ascertain whether the nucleophile is reacting or coordinating with the Pt center, we changed the sequence of adding 4-tri uoromethylphenol and norbornene (Figure 4). When 4 equivalents of 4tri uoromethylphenol were added into the solution of D and AgOTf, there was no change in 1 H, 19 F and 31 P NMRs (Figure 4b and also see Supporting Information). Next, 4 equivalents of norbornene were added and the resulting solution was immediately analyzed: 31 P and 19 F NMRs revealed that both the 31 P signal for complex G and 19 F signals for complex H decreased (Figure 4c and see Supporting Information). These results suggest that both the mono-phosphine ligand and norbornene were coordinating to the Pt center. As the reaction proceeds for 1 hour, the hydroalkoxylation product 23b was formed, and both complexes G and H were generated again (Figure 4d, and also see 1 H and 19 F NMRs in Supporting Information).
Based on the NMR experiments, we propose a plausible mechanism for "donor-acceptor"-type Ptcomplex catalyzed hydroalkoxylation of unactivated alkenes ( Figure 5). Catalyst D reacts with AgOTf to form Pt(II) species F and precipitates AgCl. Since complex F is more electron-de cient and unstable, the monodentate phosphine ligand dissociates from the Pt center and reacts with an additional equivalent of AgOTf to generate complexes G and H. Then complex G coordinates with the alkene to form complex I. Due to its s-donating nature, the alkene makes the Pt center in complex I more electron-rich than in complexes F and G. Therefore, the electron-de cient mono-phosphine re-associates to form a 16-electron, "donor-acceptor"-type Pt complex J, thus further activating the alkene. Nucleophilic attack on the bound alkene by a free alcohol provides complex K. Proton transfer thereafter provides the hydroalkoxylation product and regenerates complexes G and H.
Finally, we explored the catalytic asymmetric hydroalkoxylation 14, 5 9-63 and hydroamination6 4-69 with the "donor-acceptor" catalytic system ( Figure 6). Various chiral Pt-complexes generated in situ from chiral bisphosphine platinum dichlorides with electron-de cient tris(3,4,5-tri uorophenyl)phosphine were examined in the reaction of 21 and 2 under standard conditions. Disappointingly, none of the chiral Ptcatalysts produced enantioselectivities (See Supporting Information). We envisioned that a bi-functional catalysis where the monodentate ligand has a basic group that can form a hydrogen-bonding with the nucleophile would assist recognition of prochiral faces of the alkenes 61,70 . To our delight, catalysts N and M bearing (R)-BINAP and (R)-Di uorphos as "donor" ligands and the monodentate "acceptor" ligand with a hydrogen bonding site induced moderate enantioselectivities in both hydroalkoxylation of 21 and hydroamination of 2. The observed enantioselectivity strongly supports our proposed mechanism that "donor-acceptor" Pt-catalyzed hydroalkoxyations and hydroaminations are true metal-catalyzed processes [53][54][55][56] .

Conclusion
In summary, we have described herein the newly synthesized "donor-acceptor"-type platinum catalysts that are superior in effecting both hydroalkoxylation and hydroamination with respect to mild reaction conditions and generality in substrate scope. Mechanistic studies suggested a plausible pathway that includes an unusual dissociation/re-association of the electron-de cient mono-phosphine ligand to generate an alkene bound "donor-acceptor" type intermediate. Efforts to improve the reactivity and enantioselectivity of the chiral platinum catalysts based on bi-functional catalysis for asymmetric hydrofunctionalization will be the subject of future studies.

Methods
General procedure for preparing "donor-acceptor" Pt catalyst. In an argon lled glovebox, to a 4 mL vial with a magnetic stir bar were added (dmfpf)PtCl 2 (100 mg, 0.12 mmol), silver tri uoromethanesulfonate (31 mg, 0.12 mmol, 1.0 equiv.), monophosphine ligand (0.13 mmol, 1.05 equiv.) and CH 2 Cl 2 (2 mL). Then the vial was taken outside of the glovebox and was stirred at 23 o C for 12 h. The orange solution was ltered and CH 2 Cl 2 was evaporated to provide orange solid, which was recrystallized in CH 2 Cl 2 and hexane to give yellow precipitate.
General procedure for intramolecular hydroalkoxylation. In an argon lled glovebox, to a 4 mL vial with a magnetic stir bar were added catalyst C (0.001 mmol, 1 mol%), silver tri uoromethanesulfonate (0.002 mmol, 2 mol%), the substrate (0.1 mmol), and ClCH 2 CH 2 Cl (1 mL). Then the vial was taken outside of the glovebox and stirred at 23 o C for 24 h. The mixture was diluted with CH 2 Cl 2 , ltered through a pad of celite and concentrated. The residue was puri ed by silica gel chromatography to give the desired product.
General procedure for intermolecular hydroalkoxylation. In an argon lled glovebox, to a 4 mL vial with a magnetic stir bar were added catalyst D (0.01 mmol, 5 mol%), silver tri uoromethanesulfonate (0.012 mmol, 6 mol%), alkenes (0.2 mmol), alcohols (0.3 mmol, 1.5 equiv.) and ClCH 2 CH 2 Cl (1 mL). Then the vial was taken outside of the glovebox and stirred at 50 o C for 16 h. THe reaction mixture was cooled to room temperature (23 o C) and diluted with CH 2 Cl 2 , ltered through a pad of celite and concentrated in vacue.
The residue was puri ed by silica gel chromatography to give the desired product.
General procedure for intramolecular hydroamination. To a 4 mL vial equipped with a magnetic stir bar were added the catalyst E (0.001mmol, 1 mol%), silver tri uoromethanesulfonate (0.002 mmol, 2 mol%) and ClCH 2 CH 2 Cl (1.0 mL) in an argon lled glovebox. The mixture was stirred at 23 °C for 1 h. Then to the mixture was added a solution of 37 (30.7 mg, 0.1 mmol) in ClCH 2 CH 2 Cl (0.5 mL). The vial was taken outside of the glovebox and stirred at 23 o C for 24 h. The mixture was diluted with CH 2 Cl 2 and concentrated under reduced pressure. The residue was puri ed by ash chromatography to afford the desired product.
Then the vial was taken outside of the glovebox and stirred at 23 °C or 50 °C for 6 to 48 h. The reaction mixture was diluted with CH 2 Cl 2 , ltered through a pad of celite and concentrated. The residue was puri ed by silica gel chromatography to afford the desired product.

Data availability
The data that support the ndings of this study are available within the paper and its supplementary information les. Raw data are available from the corresponding author on reasonable request. Materials and methods, experimental procedures, characterization data, 1 H, 13