Cationic-palladium catalyzed regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes

π-Extended tetrasubstituted olefins are widely found motifs in natural products, leading drugs, and agrochemicals. Thus, development of modular strategies for the synthesis of complex all-carbon-substituted olefins always draws attention. The difunctionalization of unsymmetrical alkynes is an attractive approach but it has remained faced with regioselectivity issues. Here we report the discovery of a regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes. A cationic Pd-catalyzed three-component coupling of aryl diazonium salts, aryl boronic acids (or olefins) and yne-acetates enables access to all-carbon substituted unsymmetrical olefins. The transformation features broad scope with labile functional group tolerance, building broad chemical space of structural diversity (94 molecules). The value of this synthetic method is demonstrated by the direct transformation of natural products and drug candidates containing yne-acetates, to enable highly substituted structurally complex allyl acetate analogues of biologically important compounds. Synthetic versatility of the carboxylate bearing highly substituted olefins is also presented. The reaction outcome is attributed to the in situ formation of stabilized cationic aryl-Pd species, which regulates regioselective aryl-palladation of unsymmetrical yne-acetates. Control experiments reveal the synergy between the carboxylate protecting group and the cationic Pd-intermediate in the regioselectivity and reaction productivity; density functional theory (DFT) studies rationalize the selectivity of the reaction. Methods to regioselectively difunctionalize unsymmetrical alkynes with two diverse carbon-based substituents are rare. Here the authors show a method to add two C(sp2)-based units in a syn, regioselective fashion across a triple bond, via palladium catalysis without an added ligand.

T etrasubstituted and π-extended olefins are widespread in numerous natural products, leading drugs, and agrochemicals. They also hold potential applications in electron-transport materials and light-emitting diodes [1][2][3][4] . The carbometallation of unsaturated C-C bonds has always been a gateway to biologically valuable feedstocks. In this regard, the carbopalladation has been the most prominent and widely used process 5 . The transition metal-catalyzed alkyne dicarbofunctionalization by interrupting two cross-couplings [for example: Suzuki and Heck] offers a potential entry to highly substituted olefins. However, in contrast with the directed olefin dicarbofunctionalization [5][6][7][8][9][10][11][12][13][14] , this approach often suffers from insolvable regioselectivity issues. Mostly, the state-of-the-art regioselective carbometallation of unsymmetrical alkynes is restricted to inherently polarized substrates (Fig. 1a-i) 15-30 , 2-pyridylsilyl alkynes (Itami; Fig. 1a-ii) [31][32][33] or sterically hindered borylated alkynes (Wang; Fig. 1a-iii) 34 . The Larock's Pd-catalyzed syn-1,2-diarylation of unsymmetrical alkynes is also a great strategy to access all-carbon-substituted olefins (Fig. 1a-iv); however, it suffers from several limitations 35,36 . For instance, syn-1,2-diarylation of diaryl-substituted alkynes occurs at an elevated temperature to deliver a mixture of regioisomers in moderate selectivity ( Fig. 1a-iv). In case of aryl-alkyl alkynes, the arylation takes place at the less-hindered site of alkyne, resulting in better regioselectivity ( Fig. 1a-iv), but only with Me and Et groups. Thus, the syn-1,2-diarylation of unsymmetrical alkynes is substrate specific. An interesting aminopyridine directing group (DG) guided regioselective hydroarylation of alkynes with aryl boronic acids for the construction of trisubstituted olefins has also been described (Engle, Fig. 1b) 37,38 . Overall, DG, ligand and the electron-bias of the alkyne are essential features in regioselective alkyne difunctionalization. The recent reports of Lan and Cheng feature an impressive DG free anti-carbopalladation of internal alkynes, the steric clash between the ortho-substituted aryl halide Fig. 1 Comparison between hydro-and difunctionalization of alkynes and the conceptual blueprint of a general cationic Pd-catalyzed dicarbofunctionalization of Yne-acetates. a (i) Difunctionalization of electronically polarized alkynes: the incoming aryl group forms bond at the electrondeficient carbon center. (ii) Difunctionalization of 2-pyridylsilyl alkynes: the metal coordination to the pyridyl-N makes the C-aryl bond β to silyl group. (iii) Difunctionalization of N-methylimidodiacyl boron alkynes: the aryl group approaches the less-hindered side of borylated-alkyne. (iv) syn-1,2-Diarylation of diaryl-substituted alkynes occurs at an elevated temperature, providing a mixture of regioisomers. In case of aryl-alkyl alkynes, only the smaller alkyl groups (i.e., methyl/ethyl) allow the aryl-moiety to approach from the less-hindered side of the alkyne. b Pd-catalyzed aminopyridine-directed regioselective hydroarylation of alkynes happens through proximity-driven carbopalladation followed by protodemetalation. c anti-carbopalladation of alkyne driven by steric repulsion between ortho-substituted aryl halide and bulky-ligands. d Our strategy: regioselective dicarbofunctionalization of yne-acetates: because of the non-covalent lone pair repulsion between ligated Pd and the carbonyl of acetate group, the ligated cationic Pd species preferably approaches at the β -carbon over α-carbon of the yne-acetate; as a result, intermediate II is favored over intermediate III. and the bulky ligated Pd(II) species making the anti-addition to alkyne possible at an elevated temperature 39 . In addition, Werz and co-workers designed an anti-carbopalladation reaction within a cascade process via 14 valence electron Pd species as crucial intermediates [40][41][42] . In this context, the development of a ligand free regioselective syn-1,2-dicarbofunctionalization of unsymmetrical alkynes to build tetrasubstituted olefins appears to be a worthwhile endeavor.
We herein report a cationic Pd-catalyzed 1,2-dicarbofunctionalization of unsymmetrical alkynes (Fig. 1c). As per DFT studies (vide infra), the reaction relies on a site-selective coordination of a cationic Pd(II) species, generated in situ by the oxidative addition of an aryl diazonium salt 43,44 to Pd(0), to an yne-acetate (I) (Fig. 1c).
The lone pair repulsion between the carboxylate moiety and the Pdcomplex possibly excludes syn-β-arylated-Pd-intermediate III.
Further functionalization of vinyl-Pd(II)-cationic species II with aryl boronic acids (or olefins) delivers highly substituted olefins (or dienes). This strategy leads to structurally diverse all-carbonfunctionalized olefins (94 molecules) in a single step from readily available yne-acetates. The transformation is highly regio-and stereoselective, even in the absence of external ligand and DG. A comparativereactivity profile and mechanistic pathway of the current method over Larock's strategy for high regioselectivity throughput is established by various control experiments.
Scope of pharmacophore-coupled alkynes and synthetic applications. Late-stage difunctionalization of unsymmetrical alkynes having biologically relevant motifs (BRMs) is invaluable for the sustainable development of complex molecules with enhanced pharmacokinetic properties. However, BRMs with polar groups and unsaturated moieties often cause problems for cross-coupling reactions, as the TM binding ability could lead to substrate decomposition and affect the difunctionalization efficiency. We were therefore intrigued by the viability of the cationic Pd-catalyzed double arylation of pharmacophore-coupled alkynes 1 (Fig. 5). Once again, the title reaction proved reliable: tetrasubstituted allyl acetates encapsulated fatty alcohol [vitamin-Etocopherol (96)], steroid [cholesterol (97)], and terpenoid [geraniol (98)] were produced in 45-72% yields from the diarylation of respective BRMs-coupled PAs with 2a and 3c. We further probed the efficacy of the regioselective diarylation using marketed drug molecules containing unsymmetrical alkynes. Thus, reaction of the anti-epileptic drug, bipolar disorder, and migraine preventer valproic acid coupled PA with 2a and 3c provided highly substituted allyl acetate 99 in 65% yield. Likewise, nonsteroidal anti-inflammatory drug containing allyl acetate 100 was made in good yield.
To further validate the importance of the acetate group, sterically hindered phenyl cyclohexyl alkyne 1ay was subjected to PMP-I, and PhB(OH) 2 under Larock's reaction conditions (eq. 6, Fig. 6c); the respective product 116 (28%, 74% re) was isolated in low yield and moderate regioselectivity (eq 6, Fig. 6c). By contrast, reaction of 1y, exhibiting an acetate group at the propargyl position of 1ay, with PMP-N 2 BF 4 and PhB(OH) 2 under the SC furnished 58 (51%) in 100% re (eq 7, Fig. 6c). Moreover, 1y failed to give the desired diarylation product 58 under Larock condition, thus, cationic Pd species is essential (eq 8, Fig. 6c). From the mechanistic discussions highlighted in eqs 1-8, Fig. 6, we conclude that the outcome and regioselectivity of syn-1,2diarylation of unsymmetrical alkynes are strongly influenced by the carboxylate protecting group and the in situ formation of a stabilized cationic Pd intermediate.

DFT calculations.
To gain insight into the reaction mechanism and notably the stereo/regioselectivity of the 1,2-diarylation of PAs, DFT calculations were performed at the M06L/def2-TZVPP(SMD)//BP86/LANL2DZ(Pd)_6-31G(d,p) level of theory (Fig. 7, see also the SI for the cross-coupling part, the case of substrates with longer tethers and the case of an unreactive methylalkyne). The transformation begins with the barrierless oxidative addition of Pd(DMSO) 2 (a) to the phenyl diazonium salt b to provide the cationic Pd-complex 1 A. 6a Next, coordination of 1 A to PA 1c is possible by substitution of N 2 . However, this process could happen in three different ways, via (i) the coordination of the C≡C bond of 1c to form complex 1 B by releasing 6.7 kcal/mol of free energy ( Fig. 7; blue) (ii) the coordination of both the C≡C bond and the ester group in 1c to provide 1 E with the release of 4.5 kcal/mol of free energy ( Fig. 7; red), and (iii) the coordination of the ester group in 1c to generate 1 G, this step being endergonic by 1.8 kcal/mol ( Fig. 7; gray). Thus, the ester group participation for the replacement of N 2 in 1 A is not necessary. Next, a suprafacial α-aryl migration from Pd to the C≡C bond of 1 B (syn-insertion) proceeds through transition state 1 TS α BC , found at 6.3 kcal/mol on the free energy surface, and results in the Pd-alkenyl ester complex 1 C α . This complex lies at -19.1 kcal/mol on the free energy surface with trans-relationship of two phenyl groups. Intramolecular neighboring group participation of the ester group at C α of 1 B can provide the Pd-alkenyl heterocyclic complex 1 D through 1 TS BD (12.6 kcal/mol); however, this process needs an additional 6.3 kcal/mol activation energy and is thus ruled out.
Alternatively, α-aryl migration of ester chelate 1 E forms The energy barrier is 4.4 kcal/mol higher than 1 TS α BC ; this pathway is thus not preferred. A detailed comparison of all the options justifies the feasibility of the bottom pathway 1 B! 1 C α (marked in blue). Like normal Suzuki reactions, transmetalation of 1 C with aryl . We have studied various tether lengths of the yne-acetate and found that the C αarylation process is always favored over the C α -arylation ( Supplementary Schemes 10-15). To rationalize this selectivity, a distortion/interaction and non-covalent interactions analysis of the aryl migration transition states 1 TS α BC and 1 TS β BC (that includes substrate fragment and aryl-palladium fragment) was performed (see right side in Fig. 7 and Supplementary Figs. 14-16). The large rotation angle for β-aryl migration (see the SI: 36.12°for 1 TS β BC and 7.34°for 1 TS α BC ) contributes to excess distortion energy [+6.0 kcal/mol; that includes both aryl -palladium (+3.68 kcal/ mol) and substrate (+2.32 kcal/mol) distortion]. In addition, a large level of non-covalent lone pair repulsion of the carboxylate moiety with ligated DMSO for 1 TS β BC (+4.1 kcal/mol) relative to 1 TS α BC was detected.
In summary, a regio-and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical alkynes involving structurally distinct carbon functionalities has been developed. The cationic Pd II -catalyst plays an essential role in modulating the regioselective insertion of aryl-diazonium salts and boronic acids/olefins to the unsymmetrical alkynes. The transformation proceeds at room temperature and tolerates oxidizable halo-species (I/Br), easily transformable functionalities (CO 2 Me, CN) and strained rings, thus opening a broad chemical space [94 examples]. It is even successful on the gram scale. Carboxylate protecting group and the in situ formation of a stabilized cationic Pd intermediate solely responsible for the outcome and regioselectivity of syn-1,2-diarylation of unsymmetrical alkynes. DFT studies rationalize the α-arylation preference over β-arylation of PAs and discard direct participation of the acetate as a DG. The highly substituted olefins are subsequently used for the construction of functionalized indene, methyl-vinyl ketone, and acrolein skeletons. The current finding paves the way to the discovery of unknown difunctionalization strategies of unactivated alkynes.  2 , Pd 2 (dba) 3 , K 3 PO 4 , 1,4-dioxane:DMSO (9:1), rt]}, and {SC of current reaction: eq 3 [PMP-I instead of PMP-N 2 BF 4 ]}. Excellent regioselectivity has been observed in eq 2; thus, PMP-N 2 BF 4 and cationic palladium species are pivotal. b Two comparative reactions were performed with electronically diverse aryl-butyl alkynes using Larock's reaction conditions (eq 4) and the SC of current reaction (eq 5). c Two comparative reactions were independently performed with sterically hindered Ph-cyclohexyl alkyne and cyclohexyl tethered PA under the Larock's reaction conditions (eqs. 6 and 8) and SC current reaction (eq. 7), respectively. d Trapping of cationic vinylic Pd(II) species in the absence of aryl boronic acid. Note: inseparable regioisomers are isolated as mixture and the regioisomeric excess (re) is determined by 1 H NMR. PMP p-methoxyphenyl.

Methods
General procedure for the syn-1,2-difunctionalization reactions. To a mixture of alkyne 1 (0.3 mmol), aryl diazonium tetrafluoroborate 2 (0.9 mmol), aryl boronic acid 3 or olefin 72 (0.45 mmol), Pd catalyst (0.015 mmol) and base (0.45 mmol) was added the respective solvent. The resulting reaction mixture was stirred at 25°C for 6 h. The reaction progress was periodically monitored by TLC. The solvent was next removed either by water workup or by evaporation under reduced pressure. The organic layer was extracted in ethyl acetate (3 × 10 mL) and dried over Na 2 SO 4 . The organic layer was evaporated and purified by column chromatography over neutral alumina to afford 4-100 and 112-113. The compounds are sensitive to acidic silica gel and thus, final product purification was carried out on neutral alumina.

Data availability
Data relating to the characterization of materials and products, general methods, optimization studies, experimental procedures, mechanistic studies and NMR spectra are available in the Supplementary Information. Crystallographic data for compound 58 is available free of charge from the Cambridge Crystallographic Data Centre under reference number 2096145.