Iridium-catalyzed allylic alkylations

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Iridium-catalyzed, enantioselective allylic alkylations involve the combination of an allylic electrophile and carbon nucleophile in the presence of an iridium catalyst. An iridium-catalyzed nucleophilic substitution process takes place, during which the nucleophile displaces a leaving group such as methyl carbonate. Allylic ester electrophiles generally yield branched products with high site selectivity with the important exception of linear (Z)-allylic esters, which yield linear (Z) products.[1]


Allylic substitution refers to the displacement of a leaving group by a nucleophile at either end of an allylic system. Either branched or linear substrates may be used and the product of substitution may be either branched (B) or linear (L) itself (Eq. 1). In transition-metal catalyzed allylic substitution reactions, selectivity for a single constitutional isomer of product is highly desirable.


Although the majority of transition metal catalyzed allylic substitution reactions involve palladium catalysts, other transition metals have recently attracted attention as alternatives. Allyl complexes of these newer metals, including molybdenum, ruthenium, and iridium, undergo much slower π-σ-π isomerization than palladium allyl complexes and thus expand the scope of enantioselective allylic substitution reactions. In particular, iridium catalysts may be used with linear allylic esters as electrophiles for enantioselective allylic substitutions. Generally, these reactions are selective for branched products, which have the advantage of dense functionalization at the newly created stereogenic center. For allylic alkylation reactions, stabilized carbon acids such as malonates are generally used.

Mechanism and Stereochemistry

Iridium-catalyzed allylic substitutions proceed with retention of configuration when chiral branched allylic carbonates are used as substrates.[2] However, experiments have demonstrated that the observed retention of configuration arises from a double-inversion mechanism, in which the iridium catalyst first displaces the leaving group in an invertive (SN2) manner and then the nucleophile displaces iridium with inversion.[3]

Chiral phosphoramidites have emerged as a privileged class of ligands for enantioselective allylic alkylation reactions employing iridium catalysts. Although phosphoramidites appear to be monodentate ligands, it has been shown that these ligands undergo C–H activation to form a bidentate complex C-III containing Ir–C and Ir–P bonds, which is the active catalytic species (Eq. 2).[4] Coordination of the allylic electrophile to this complex yields C-IV; departure of the leaving group from this complex affords iridium(III) complex C-V. The nucleophile approaches the face of the allylic ligand opposite iridium to forge the C–Nu bond and complex C-VI, which undergoes loss of the product to regenerate C-III.


Extensive studies of the structures of Ir-allyl complexes as well as the kinetics of iridium-catalyzed allylic substitutions have elucidated the origins of stereochemical control in these reactions.[5][4][6] A general rule useful for predicting the major enantiomer of product in these reactions is provided in Eq. 3 below, with the corresponding configurations of phosphoramidite ligands L1L3.


Scope and Limitations

Malonic esters are a heavily studied class of pronucleophiles in these reactions. They have been used with a wide variety of allylic electrophiles and are useful for the assessment of electrophile scope (Eq. 4).[7] Enantioselectivity is uniformly high when phosphoramidite ligand L1b is used. Although the branched product typically forms selectively, allylic electrophiles containing linear alkyl groups require modification of the reaction conditions to achieve high selectivity for the branched isomer.


Anions derived from diphenyliminoglycinates can also be used as nucleophiles. Although allylic phosphates were the original electrophiles in these reactions, more recently developed approaches employ allylic carbonates with ligand L1d under salt-free conditions (see Typical Conditions below). Moderate diastereoselectivity is observed (Eq. 5).[8]


Sulfone-substituted acetate esters are effective pronucleophiles in Ir-catalyzed allylations (Eq. 6).[9] Removal of the sulfone group through reductive desulfurization results in net allylation of an acetate ester; the product can also be subjected to Julia olefination.


Much effort has been directed at expanding the scope of nonstabilized carbon nucleophiles that may be applied in Ir-catalyzed allylic alkylations. A dual catalysis strategy has been applied in the stereoselective allylation of aldehydes via enamine intermediates. The amine and iridium catalysts independently control the configurations of the nucleophilic and electrophilic carbons, respectively (Eq. 7).[10]


Silyl enol ethers can also be employed as nucleophiles in the presence of zinc fluoride and cesium fluoride (Eq. 8).[11] The combination of fluoride salts suppresses allylation of the product; interestingly, cesium fluoride alone encourages diallylation. Fluoride is also used as a base for C–H activation of the phosphoramidite ligand in this context.


The scope of nonstabilized nucleophiles includes enamines,[12] alkenes,[13] (hetero)aromatic compounds,[14] organozinc reagents[15], and allylsilanes[16] as well. In some cases, careful choice of the electrophile and/or ligand is needed to ensure efficient reactivity and high selectivity.

Synthetic Applications

The products of enantioselective allylic substitution reactions often have high synthetic utility. For example, the alkene group may be modified using olefin metathesis or Heck cross-coupling. Enantioselective Ir-catalyzed allylic substitution was used to set the configuration of the lone stereocenter in (–)-preclamol, a drug candidate for the treatment of schizophrenia, with remarkably high enantioselectivity (Eq. 9).[17]


A cascade cyclization displaying excellent stereoselectivity was employed to form the bicyclic core of asperolide C, starting from a substrate containing allylic alcohol and allylic silane groups (Eq. 10).[18] This reaction is potentially applicable to the synthesis of other terpene natural products as well.


Comparison to Other Methods

Metal catalyzed allylic substitution reactions most commonly involve palladium complexes. Because π-σ-π isomerization of allylpalladium complexes is rapid, isomeric allylic electrophiles typically give rise to a single product (Eq. 11).[19] In addition, Pd-catalyzed reactions exhibit a strong preference for the linear isomer; in contrast, Ir-catalyzed reactions tend to favor branched products.


Several catalyst systems have recently been developed for enantioselective ruthenium-catalyzed allylic alkylation reactions. Although ruthenium complexes exhibit high functional group tolerance in general, effective ligands tend to be more difficult to synthesize than phosphoramidites used in Ir-catalyzed reactions. As a result, Ru-catalyzed reactions have been applied less broadly. Allylic alcohols may be employed as electrophiles in the presence of an acid co-catalyst (Eq. 12).[20]


Experimental Conditions and Procedure

Typical Conditions

Early examples use linear allylic carbonates or carboxylates with catalysts prepared in situ from [Ir(cod)Cl]2, a phosphoramidite, a base, and a salt of a CH-acidic pronucleophile such as a sodium malonate. Although THF was the most common solvent used, the advent of modern solvent purification systems has widened the scope of solvents that can be employed. Use of a pronucleophile salt can be avoided (i.e., the nucleophile can be added in neutral form) when allylic carbonates are combined with a transition metal catalyst. The carbonate and metal complex react to form an alkoxide, which is capable of deprotonating relatively acidic pronucleophiles such as malonates.[21] Allylic alcohols may be employed as electrophiles under acidic conditions that do not generally require activation of the ligand with base.[22]

Example Procedure[23]


The activated catalyst complex was prepared in situ by stirring a solution of [Ir(dbcot)Cl]2 (17.2 mg, 20 μmol, 2 mol %), (R,R,R)-L1b (24.0 mg, 40 μmol, 4 mol %), and TBD (11.2 mg, 80 μmol, 8 mol %) in THF (1 mL) for 10 min. (E)-Hex-2-en-1-yl methyl carbonate (161mg, 1.02 mmol) and dimethyl malonate (173mg, 1.01mmol, 1.0 equiv) were next added to the red solution. After stirring for 24 h at rt, TLC showed complete conversion [petroleum ether/ethyl acetate, 4:1, Rf (carbonate) 0.5, Rf (product) 0.4, KMnO4]. The crude product was purified by column chromatography (50g silica gel, n-pentane/Et2O, 7:1) to afford a mixture of the branched and the linear isomers as a colorless oil (176mg, 82%) in a ratio of 98:2 (by 1H NMR analysis): [α]20D –3.9 (c 0.98, CHCl3), er 98:2; 1H NMR (200MHz, CDCl3) δ 5.60 (ddd, J = 17.6, 9.8, 9.2 Hz, 1H), 5.05 (dd, J = 17.7, 1.7 Hz, 1H), 5.04 (dd, J = 11.0, 1.7 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.35 (d, J = 9.0 Hz, 1H), 2.75 (qd, J = 9.0, 3.0Hz, 1 H), 1.44–1.13 (m, 4 H), 0.93–0.82 (t, 3 H); 13C NMR (50MHz, CDCl3) δ 168.9, 168.7, 138.2, 117.5, 57.1, 52.5, 52.4, 44.17, 34.6, 20.3, 13.9; HRMS-ESI (m/z): [M]+ calcd for C11H18O4, 214.1205; found, 214.1206.


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