Palladium-catalyzed Allylic Substitution Research Articles

Mechanism of palladium-catalyzed allylic substitution of tertiary allylic carbonates with sodium sulfinates: unusual bifunctional nucleophile-enabled inner-sphere pathway and origin of regio- and enantioselectivities

DFT calculations were performed to investigate Pd-catalyzed allylic sulfonylation of tertiary allylic carbonates. The bifunctional role of the sulfonate nucleophile enables the C–S bond formation via a unique inner-sphere pathway.

A first example of a palladium-catalyzed allylic substitution reaction at a perfluoroalkylene-attached asymmetric carbon center with carbon, nitrogen, and oxygen nucleophiles

Palladium-catalyzed allylic substitution reaction of ethyl tetrafluorocyclopentenyl carbonate or tetrafluorocyclopentenyl methanesulfonate with carbon, nitrogen, and oxygen nucleophiles was systematically investigated. As a result, malonate-derived enolates as a carbon nucleophile, primary and secondary amines as a nitrogen nucleophile, and phenoxide derivatives as an oxygen nucleophile participated all in the reaction very well to furnish the corresponding allylated malonates, allylic amines, and allyl aryl ethers in high yields, respectively. DFT calculations of the reaction mechanism indicate that the direction of nucleophile's attack in the case of carbon nucleophiles, unlike other nucleophiles, is considerably off from the ideal direction, and thus the distance of the newly formed carbon-carbon bond is also considerably longer than the commonly accepted one. It was found then that the activation energies for reactions with carbon nucleophiles were considerably larger than those for reactions with nitrogen or oxygen nucleophiles, and hence the reaction with carbon nucleophiles is less likely proceed.

N1-Allylation of Arylhydrazines via a Palladium-Catalyzed Allylic Substitution.

A direct and efficient method for constructing N,N-disubstituted hydrazines via a palladium-catalyzed allylic substitution of allyl acetates with arylhydrazines as nucleophiles has been developed. This method is highly selective in terms of both chemo- and regio-selectivity and is carried out under an open-air system with the use of the DPPPy phosphine ligand. Additionally, this reaction is compatible with a wide variety of substrates, including those bearing reactive groups such as Cl, Br, and I, to afford various N1-allylation products in moderate to good yields under simple and mild reaction conditions.

Palladium-catalyzed base- and solvent-controlled chemoselective allylation of amino acids with allylic carbonates

The utilization of readily available amino acids, which is not only an oxygen nucleophile but also a nitrogen nucleophile, in palladium-catalyzed allylic substitution is realized under mild conditions. The chemoselectivity and multiple allylation are controlled by adjusting the reaction conditions. This represents the first example of this convenient access to valuable N,O-diallylated amino acids. Under the title conditions, a range of amino acids (α-, β-, γ-) and dipeptides can be readily converted in to the corresponding allylic products with excellent yields (67 examples, up to 99% yield) as well as good functional group tolerance.

Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.

The preparation of ferrocene-containing phosphinamine ligands possessing central and planar chirality and their application in palladium-catalysed allylic substitution

The preparation of four novel ferrocenylphosphinamine ligands, possessing both planar and central chirality, is described. The absolute configuration of two of the ligands was confirmed by X-ray crystallographic analysis. The palladium complexes of these new ligands were applied in the allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate to study the effect of planar chirality and/or the trimethylsilyl group. Quantitative yields with ee s of up to 77% were obtained with the ligand that bears both ( R )-planar and ( R )-central chirality. Application of its trimethylsilyl analogue gave significantly lower ees, whereas the presence of the trimethylsilyl group in the ligand that bears ( S )-planar and ( R )-central chirality had a beneficial effect on enantioselectivity. Solution 1 H NMR spectroscopic studies of the 1,3-diphenylallyl palladium complexes of two of the ligands revealed the major diastereomer in solution does not give rise to the major product observed in allylic alkylation, assuming nucleophilic attack trans to phosphorus.

Sustainable Palladium-Catalyzed Tsuji-Trost Reactions Enabled by Aqueous Micellar Catalysis.

Palladium-catalyzed allylic substitution, or "Tsuji-Trost" reactions, can be run under micellar catalysis conditions featuring not only chemistry in water but also numerous combinations of reaction partners that require low levels of palladium, typically on the order of 1000 ppm (0.1 mol %). These couplings are further characterized by especially mild conditions, leading to a number of cases not previously reported in an aqueous micellar medium. Inclusion of diverse nucleophiles, such as N-H heterocycles, alcohols, dicarbonyl compounds, and sulfonamides is described. Intramolecular cyclizations further illustrate the broad utility of this process. In addition to recycling studies, a multigram scale example is reported, indicative of the prospects for scale up.

Palladium-catalyzed allylic substitution between C-based nucleophiles and 6-azabicyclo[3.1.0]-hex-3-en-2-oxy derivatives: A new selectivity paradigm

Abstract The reaction between α-hydroxy-(or α-acetoxy) cyclopenten-aziridines (6-azabicyclo[3.1.0]hex-3-en-2-ols or acetates) and C-based nucleophiles in the presence of Pd(0)-catalysis was investigated. In all the cases studied, the reaction was totally regio- and diastereo-selective, affording a single adduct in moderate to good yields. Specifically, attack of the nucleophile at position 3 of the cyclopentene moiety, anti to the vicinal oxy group, with vinylogous ring opening of the aziridine ring, was observed. When the carbon acid is a very acidic methylene (pKa (DMSO) ≤ 7.3), the resulting adduct is a zwitterion, resulting from an intramolecular proton transfer between the amino group and the carbon acid moiety taking place after the C–C bond formation. A plausible mechanism for this transformation is put forward.

Catalytic radical generation of π-allylpalladium complexes

Transition metal catalysed allylic substitution is one of the most powerful and frequently used methods in organic synthesis. In particular, palladium-catalysed allylic functionalization has become a well-established strategy for constructing carbon–carbon or carbon–heteroatom bonds, and its utility has been demonstrated in natural product synthesis, drug discovery and materials science. Several methods have been developed to generate π-allylpalladium complexes through ionic mechanisms; however, these methods typically require either prefunctionalized starting materials or stoichiometric oxidants, which naturally limits their scope. Here, we show a radical approach for the generation of π-allylpalladium complexes by employing N-hydroxyphthalimide esters as bifunctional reagents in combination with 1,3-dienes. Using this strategy, we report the 1,4-aminoalkylation of dienes. The remarkable scope and functional group tolerance of this redox-neutral and mild protocol was demonstrated across >60 examples. The utility of this strategy was further demonstrated in radical cascade reactions and in the late-stage modification of drugs and natural products. Palladium-catalysed allylic substitution is a widely used method in organic synthesis, although it requires prefunctionalized starting materials or stoichiometric oxidants. Here the authors report a radical route to form π-allylpalladium complexes, and develop a 1,4-aminoalkylation of dienes under redox-neutral conditions.

Exploring the Mechanism of the Palladium-Catalyzed 3-Butene-2-ol Amination Reaction: A DFT Study.

Palladium-catalyzed asymmetric allylic substitution, due to its valuable reactive profile, has become a quite useful tool in organic synthesis fields. In the present study, density functional theory (DFT) calculations were applied to investigate the important factors for palladium-catalyzed 3-butene-2-ol and methylaniline amination reaction, with tetrahydrofuran (THF) as solvent. We find that this catalytic protocol results in high regio- and stereoselectivity, which is in line with the experimental result. According to our calculations, the high regio- and stereoselectivity is caused by the steric hindrance between the substrate and the catalyst ligand. To verify this point, we further explore the reactive process with different axial chirality on the catalyst ligand (altering the steric hindrance), and the results suggest that the preponderant R chiral configuration product has reversed. These results could lead to a better understanding of the mechanism for 3-butene-2-ol amination reaction and are helpful for the design of the corresponding catalyst ligand in the industry.

Allylic cross-coupling using aromatic aldehydes as α-alkoxyalkyl anions.

The allylic cross-coupling using aromatic aldehydes as α-alkoxyalkyl anions is described. The synergistic palladium/copper-catalyzed reaction of aromatic aldehydes, allylic carbonates, and a silylboronate produces the corresponding homoallylic alcohol derivatives. This process involves the catalytic formation of a nucleophilic α-silyloxybenzylcopper(I) species and the subsequent palladium-catalyzed allylic substitution.

A Mechanistic Analysis of the Palladium-Catalyzed Formation of Branched Allylic Amines Reveals the Origin of the Regio- and Enantioselectivity through a Unique Inner-Sphere Pathway.

A recently reported palladium-catalyzed allylic substitution of vinyl-substituted cyclic carbonates (VCCs) with aryl amines represents a rare example of a regio- and enantioselective synthesis of α,α-disubstituted allylic N-aryl amines. However, the underlying reasons for this unusual selectivity profile remain elusive. In the present work, density functional theory (DFT) calculations in combination with mechanistic control experiments were performed to elucidate in detail this allylic amination manifold and the origin of the regio- and enantioselectivity. The combined data show that after oxidative addition of the VCC to Pd0 , the nucleophilic attack via an originally proposed outer-sphere pathway gives, however, the opposite regioisomer compared to the experimental results. Instead, nucleophilic attack of the amine reagent via a unique type of chelation-assisted, inner-sphere pathway accounts for the experimentally observed "branched" regioselectivity and high enantio-control.

Palladium-Catalyzed Dearomative syn-1,4-Carboamination with Grignard Reagents.

A protocol for palladium-catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one-pot method features a visible-light-mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium-catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn-1,4-selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.

Chiral phosphine ligand libraries based on the Bull–James three-component supramolecular assembly

ABSTRACTAn approach to the synthesis of libraries of chiral phosphine ligands is described, using condensations of 2-formylarylboronic acids, diols or related compounds, and aminophosphines. The three-component nature of this condensation, along with the ready availability of the building blocks, enables the rapid generation of diverse structures. From a library of iminoboronate-derived phosphines, three ligands that gave 90% ee or greater in a benchmark palladium-catalyzed allylic substitution reaction were identified. Significant variation of selectivity as a function of the structure of each component was observed. 11B NMR spectroscopy was used to evaluate the existence of B–N interactions in the free ligands as well as their Pd-derived complexes. A bidentate P,N-coordination mode was inferred for ligands that gave high enantioselectivity in the allylic substitution reaction.Abbreviation: BINOL: 1,1'-bi-2-naphthol; BSA: N,O-bis(trimethylsilyl)acetamide; DIOP: (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane; HPLC: high-performance liquid chromatography; NMR: nuclear magnetic resonance; THF: tetrahydrofuran

Selective single C-F bond arylation of trifluoromethylalkene derivatives.

A strategically novel single C-F bond functionalization of CF3-derived molecules, which shows a prominent advantage for the expedient construction of difluoromethylene-bridged organic scaffolds, is disclosed. The reported protocol consists of SN2' amination, N-alkylation and palladium-catalyzed allylic substitution reactions, which enables straightforward arylation and alkenylation of vinyltrifluoromethane derivatives. Furthermore, this strategy is characterized by its broad substrate scope with respect to both CF3-alkene and arylboronic acid derivatives.

Non-Bonding Interactions Enable the Selective Formation of Branched Products in Palladium-Catalyzed Allylic Substitution Reactions.

Palladium-catalyzed allylic substitution reactions have become established as an important tool for the construction of carbon-carbon and carbon-heteroatom bonds in modern organic synthesis. However, controlling the regioselectivity of this type of transformation to afford chiral branched products, in addition to controlling the enantioselectivity, is a significant challenge. Excitingly, controlling nonbonding interactions between the substituents on the π-allyl-palladium intermediate and the nucleophile or palladium catalyst has been shown to be effective in achieving this goal. This Focus Review highlights representative advances in this field, according to the mode of non-bonding interaction, including hydrogen-bonding, electrostatic, and coordination interactions.

Tsuji-Trost Reaction of Non-Derivatized Allylic Alcohols.

Palladium-catalyzed allylic substitution of non-derivatized enantioenriched allylic alcohols with a variety of uncharged N-, S-, C- and O-centered nucleophiles using a bidentate BiPhePhos ligand is described. A remarkable effect of the counter ion (X) of the XPd[κ2 -BiPhePhos][η3 -C3 H5 ] was observed. When ClPd[κ2 -BiPhePhos][η3 -C3 H5 ] (complex I) was used as catalyst, non-reproducible results were obtained. Study of the complex by X-ray crystallography, 31 P NMR spectroscopy, and ESI-MS showed that a decomposition occurred where one of the phosphite ligands was oxidized to the corresponding phosphate, generating ClPd[κ1 -BiPhePhosphite-phosphate][η3 -C3 H5 ] species (complex II). When the chloride was exchanged to the weaker coordinating OTf- counter ion the more stable Pd[κ2 -BiPhePhos][η3 -C3 H5 ]+ +[OTf] - (complex III) was formed. Complex III performed better and gave higher enantiospecificities in the substitution reactions. Complex III was evaluated in Tsuji-Trost reactions of stereogenic non-derivatized allylic alcohols. The desired products were obtained in good to excellent yields (71-98 %) and enantiospecificities (73-99 %) for both inter- and intramolecular substitution reactions with only water generated as a by-product. The methodology was applied to key steps in total synthesis of (S)-cuspareine and (+)-lentiginosine. A reaction mechanism involving a palladium hydride as a key intermediate in the activation of the hydroxyl group is proposed in the overall transformation.

Arjan W. Kleij

Angewandte Chemie International EditionVolume 57, Issue 18 p. 4832-4832 Author ProfileFree Access Arjan W. Kleij First published: 23 November 2017 https://doi.org/10.1002/anie.201711677AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “My favorite author (fiction) is Stephen King, simply a genius. My top three films of all time are Pulp Fiction, The Lord of the Rings (trilogy) and The Piano ...” This and more about Arjan W. Kleij can be found on page 4832. Arjan W. Kleij The author presented on this page has published more than 10 articles in Angewandte Chemie in the last 10 years, most recently: “Copper-Catalyzed Synthesis of γ-Amino Acids Featuring Quaternary Stereocenters”: J. E. Gómez, W. Guo, S. Gaspa, A. W. Kleij, Angew. Chem. Int. Ed. 2017, 56, 15035; Angew. Chem. 2017, 129, 15231. The work of A. W. Kleij has been featured on the back cover of Angewandte Chemie: “Effective Chirogenesis in a Bis(metallosalphen) Complex through Host–Guest Binding with Carboxylic Acids”: S. J. Wezenberg, G. Salassa, E. C. Escudero-Adán, J. Benet-Buchholz, A. W. Kleij, Angew. Chem. Int. Ed. 2011, 50, 713; Angew. Chem. 2011, 123, 739. Date of birth: November 8, 1971 Position: ICREA Professor and Group Leader at the Institute of Chemical Research of Catalonia (ICIQ), Tarragona E-mail: akleij@iciq.es Homepage: http://www.iciq.org/research/research group/prof-arjan-w-kleij/ ORCID: 0000-0002-7402-4764 Education: 1996 Undergraduate degree, Utrecht University, The Netherlands 2000 PhD degree supervised by Prof. Gerard van Koten, Utrecht University 2002–2003 Postdoc with Prof. Javier de Mendoza, Universidad Autónoma de Madrid 2003–2005 Postdoc with Prof. Joost Reek, University of Amsterdam Awards: 2001 NWO Talent Fellowship; 2006 ICREA Junior Fellowship; 2011 ICREA Professorship Research: Small-molecule catalysis, stereo- and enantioselective synthesis, biopolymers Hobbies: Running, music, chemistry, spending time with family and friends My favorite author (fiction) is Stephen King, simply a genius. My top three films of all time are Pulp Fiction, The Lord of the Rings (trilogy) and The Piano. The downside of my job is the endless and sometimes completely overrated and annoying bureaucracy. My favorite food is Asian, too many good flavors! My favorite motto is “focus on the solution rather the problem”. When I'm frustrated, I go for a run to calm down, which is a perfect remedy. The most important thing I learned from my parents is to respect anyone regardless of status or origin. If I were not a scientist, I would be doing something in the music business, though it would surely not be singing. I lose track of time when I am listening to music. The best advice I have ever been given is to start with the right key experiment in a simplified way. I celebrate success by sharing with others, especially my family and friends, or my co-workers. My 5 top papers: 1“A Powerful Aluminum Catalyst for the Synthesis of Highly Functional Organic Carbonates”: C. J. Whiteoak, N. Kielland, V. Laserna, E. C. Escudero-Adán, E. Martin, A. W. Kleij, J. Am. Chem. Soc. 2013, 135, 1228. (This discovery has allowed us to advance significantly in the area of catalytic CO2 conversion over the last four years.) 2“Nanorings and rods interconnected by self-assembly mimicking an artificial network of neurons”: M. V. Escárcega-Bobadilla, G. A. Zelada-Guillén, S. V. Pyrlin, M. Wegrzyn, M. M. D. Ramos, E. Giménez, A. Stewart, G. Maier, A. W. Kleij, Nat. Commun. 2013, 4, 3648. (A simple metal-based building block can create highly sophisticated and controlled three-dimensional networks.) 3“Substrate Controlled Product Divergence in CO2 Conversion to Heterocyclic Products”: J. Rintjema, R. Epping, G. Fiorani, E. Martín, E. C. Escudero-Adán, A. W. Kleij, Angew. Chem. Int. Ed. 2016, 55, 3972; Angew. Chem. 2016, 128, 4040. (The substrates themselves may be utilized to enhance both the potential as well as divergent reactivity of the CO2 conversion process.) 4“Stereoselective and Versatile Preparation of Tri- and Tetra-Substituted Allylic Amine Scaffolds under Mild Conditions”: W. Guo, L. Martínez-Rodríguez, R. Kuniyil, E. Martin, E. C. Escudero-Adán, F. Maseras, A. W. Kleij, J. Am. Chem. Soc. 2016, 138, 11970. (The mechanistic insights we obtained in this study demonstrate a unique ligand-controlled reactivity.) 5“Asymmetric Synthesis of α,α-Disubstituted Allylic Amines through Palladium-Catalyzed Allylic Substitution”: W. Guo, A. Cai, J. Xie, A. W. Kleij, Angew. Chem. Int. Ed. 2017, 56, 11797; Angew. Chem. 2017, 129, 11959. (Use of the right leaving group in the substrate and a phosphoramidite ligand to induce typically high asymmetric induction were key here.) Volume57, Issue18April 23, 2018Pages 4832-4832 ReferencesRelatedInformation

Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates.

Acyclic nucleoside phosphonates have been prepared in a straightforward manner and in high yields by an enantioselective palladium-catalyzed allylic substitution involving nucleic bases as nucleophiles followed by cross-metathesis reaction with diethyl allylphosphonate.

ChemInform Abstract: Synthesis of Chiral Fluorine‐Containing Compounds via Pd‐Catalyzed Asymmetrical Allylations of Dimethyl 2‐Fluoromalonate Using Sulfonamide‐Pyridine Ligands.

Abstract Chiral o -aniline sulfoxides serving as chiral sulfurous source were synthesized, from which new sulfonamide-pyridine ligands were made in three-steps. These compounds proved to be efficient S , N -ligands for enantiocontrol of palladium-catalyzed allylic substitutions of dimethyl 2-fluoromalonate. The induced effect of the Pd/ S , N -ligand catalyst on the enantioselectivity depends on the steric demand of the substituent on the sulfoxide moiety. This method provided the fluorine-containing allylic products with up to 94% ee .