Lewis Acid Mediated Vinyl‐Transfer Reaction of Alkynes to N‐Alkylimines by Using the N‐Alkyl Residue as a Sacrificial Hydrogen Donor

A variety of N‐alkyl‐α,α‐dichloroaldimines were vinylated by terminal acetylenes in the presence of Lewis acids such as In(OTf)₃ or BF₃ ? OEt₂ and hexafluoroisopropanol (HFIP) as an additive. The reaction proceeds at ambient temperature and leads to geometrically pure allylic β,β‐dichloroamines. This approach is complementary to previously reported transition‐metal‐catalyzed vinyl‐transfer methods, which are not applicable to aliphatic imines and are restricted to imines that contain an electron‐withdrawing nitrogen substituent. In the present approach, terminal alkynes were used as a source of the vinyl residue, and the N‐alkyl moiety of the imine acts as a sacrificial hydrogen donor. The additional advantage of this methodology is the fact that no external toxic or hazardous reducing agents or molecular hydrogen has to be used. This new methodology nicely combines a C(sp²)? C(sp) bond formation, hydride transfer, and an unusual cleavage of an unactivated C? N bond, thereby giving rise to functionalized primary allylic amines. A detailed experimental study supported by DFT calculations of the mechanism has been done.     

Regio‐ and Stereoselectivity in the Lewis Acid‐ and NaH‐Induced Reactions of Thiocamphor with (R)‐2‐Vinyloxirane

The reaction of the enolizable thioketone (1R,4R)‐thiocamphor (= (1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 1 ) with (R)‐2‐vinyloxirane ( 2 ) in the presence of a Lewis acid such as SnCl₄ or SiO₂ in anhydrous CH₂Cl₂ gave the spirocyclic 1,3‐oxathiolane 3 with the vinyl group at C(4′), as well as the isomeric enesulfanyl alcohol 4 . In the case of SnCl₄, an allylic alcohol 5 was obtained in low yield in addition to 3 and 4 (Scheme 2). Repetition of the reaction in the presence of ZnCl₂ yielded two diastereoisomeric 4‐vinyl‐1,3‐oxathiolanes 3 and 7 together with an alcohol 4 , and a ‘1 : 2 adduct’ 8 (Scheme 3). The reaction of 1 and 2 in the presence of NaH afforded regioselectively two enesulfanyl alcohols 4 and 9 , which, in CDCl₃, cyclized smoothly to give the corresponding spirocyclic 1,3‐oxathiolanes 3, 10 , and 11 , respectively (Scheme 4). In the presence of HCl, epimerization of 3 and 10 occurred to yield the corresponding epimers 7 and 11 , respectively (Scheme 5). The thio‐Claisen rearrangement of 4 in boiling mesitylene led to the allylic alcohol 12 , and the analogous [3,3]‐sigmatropic rearrangement of the intermediate xanthate 13 , which was formed by treatment of the allylic alcohol 9 with CS₂ and MeI under basic conditions, occurred already at room temperature to give the dithiocarbonate 14 (Schemes 6 and 7). The presented results show that the Lewis acid‐catalyzed as well as the NaH‐induced addition of (R)‐vinyloxirane ( 2 ) to the enolizable thiocamphor ( 1 ) proceeds stereoselectively via an S_N2‐type mechanism, but with different regioselectivity.     

Some Aspects of the Chemistry of Nitro Compounds

The present brief account relates our discovery of new reactions revolving around the chemistry of the NO₂ group. It covers the condensation of MeNO₂ with hindered ketones, and the synthesis of pyrroles, triazoles, and enamides. It also describes new transformations of allylic nitro compounds, such as their conversion to allylic sulfones and unsaturated lactones, their sigmatropic rearrangement into allylic nitrites and thence into allylic alcohols, as well as their use in a short synthesis of nitroestrone derivatives. This is followed by an unusual reduction method furnishing unsubstituted amines (RR′C?NH) under conditions where these hydrolytically labile species can be captured inter‐ or intramolecularly. Finally, a mechanistic study of a strange alkyne‐forming reaction, first reported by Abidi and later shown by Corey and co‐workers to proceed through allylic nitro intermediates, ultimately led to a practical and powerful synthesis of alkynes starting from β‐keto esters.     

Preparation of Solid,Substituted Allylic Zinc Reagents and Their Reactions with Electrophiles

The treatment of various allylic chlorides or bromides with zinc dust in the presence of lithium chloride and magnesium pivalate (Mg(OCOtBu)₂) in THF affords allylic zinc reagents which, after evaporation of the solvent, produce solid zinc reagents that display excellent thermal stability. These allylic reagents undergo Pd‐catalyzed cross‐coupling reactions with PEPPSI‐IPent, as well as highly regioselective and diastereoselective additions to aryl ketones and aldehydes. Acylation with various acid chlorides regioselectively produces the corresponding homoallylic ketones, with the new C? C bond always being formed on the most hindered carbon of the allylic system.     

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

The enantioselective intermolecular C2‐allylation of 3‐substituted indoles is reported for the first time. This directing group‐free approach relies on a chiral Ir‐(P, olefin) complex and Mg(ClO₄)₂ Lewis acid catalyst system to promote allylic substitution, providing the C2‐allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2‐allylation, rather than C3‐allylation followed by in situ migration. Steric congestion at the indole‐C3 position and improved π–π stacking interactions have been identified as major contributors to the C2‐selectivity.     

Synthesis of Branched Alkylboronates by Copper‐Catalyzed Allylic Substitution Reactions of Allylic Chlorides with 1,1‐Diborylalkanes

Reported herein is a copper‐catalyzed S_N2′‐selective allylic substitution reaction using readily accessible allylic chlorides and 1,1‐diborylalkanes, a reaction which proceeds with chemoselective C?B bond activation of the 1,1‐diborylalkanes. In the presence of a catalytic amount of [Cu(IMes)Cl] [IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene] and LiOtBu as a base, a range of primary and secondary allylic chlorides undergo the S_N2′‐selective allylic substitution reaction to produce branched alkylboronates. The synthetic utilities of the obtained alkylboronates are also presented.     

Preparation and Application of Solid,Salt‐Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

The treatment of various N‐morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t _1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd‐ and Cu‐catalyzed cross‐couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N‐morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti‐breast‐cancer drug candidate in six steps and 23 % overall yield.     

Anilines as C‐Nucleophiles in Ir‐Catalyzed Intramolecular Asymmetric Allylic Substitution Reactions

Anilines generally act as N‐nucleophiles in transition‐metal‐catalyzed allylic substitution reactions. In this paper, a highly enantioselective intramolecular Friedel–Crafts‐type allylic alkylation of aniline derivatives was realized by using an iridium catalyst derived from [Ir(cod)Cl]₂ and (R _a)‐BHPphos. Various tetrahydroisoquinilin‐5‐amines were obtained in moderate to good yields, excellent enantioselectivity and regioselectivity under mild reaction conditions. BHPphos=N ‐benzhydryl‐N ‐phenyldinaphthophosphoramidite.     

DFT Rationalization of the Diverse Outcomes of the Iodine(III)‐Mediated Oxidative Amination of Alkenes

A computational study of the mechanism for the iodine(III)‐mediated oxidative amination of alkenes explains the experimentally observed substrate dependence on product distribution. Calculations with the M06 functional have been carried out on the reaction between PhI(N(SO₂Me)₂)₂ and three different representative substrates: styrene, α‐methylstyrene, and (E)‐methylstilbene. All reactions start with electrophilic attack by a cationic PhI(N(SO₂Me)₂)⁺ unit on the double bond, and formation of an intermediate with a single C?I bond and a planar sp² carbocationic center. The major path, leading to 1,2‐diamination, proceeds through a mechanism in which the bissulfonimide initially adds to the alkene through an oxygen atom of one sulfonyl group. This behavior is now corroborated by experimental evidence. An alternative path, leading to an allylic amination product, takes place through deprotonation at an allylic C?H position in the common intermediate. The regioselectivity of this amination depends on the availability of the resonant structures of an alternate carbocationic intermediate. Only in cases where a high electronic delocalization is possible, as in (E)‐methylstilbene, does the allylic amination occur without migration of the double bond.     

Asymmetric Synthesis of Allylic Sulfonic Acids: Enantio‐ and Regioselective Iridium‐Catalyzed Allylations of Na2SO3

An enantioselective allylation reaction of allylic carbonates with sodium sulfite (Na₂SO₃) catalyzed by Ir complex was accomplished, providing allylic sulfonic acids in good to excellent yields with a high level of enantio‐ and regioselectivities. (R)‐2‐Phenyl‐2‐sulfoacetic acid, a key intermediate for the synthesis of Cefsulodin and Sulbenicillin, was synthesized as well.     

Palladium‐Catalyzed Cascade Double C—N Bond Activation: A New Strategy for Aminomethylation of 1,3‐Dienes with Aminals

A new palladium‐catalyzed selective aminomethylation of conjugated 1,3‐dienes with aminals via double C—N bond activation is described. This simple method provides an effective and rapid approach for the synthesis of linear α,β‐unsaturated allylic amines with perfect regioselectivity. Mechanistic studies disclosed that one palladium catalyst cleaved two distinct C—N bond to furnish a cascade double C—N bond activation, in which an allylic 1,3‐diamine and allylic 1,2‐diamine were initially formed as key intermediates through the palladium‐catalyzed C—N bond activation of aminal and the α,β‐unsaturated allylic amine was subsequently produced via palladium‐catalyzed C—N bond activation of the allylic diamines.     

Preparation of planar‐chiral multidonor phosphanylferrocene carboxamides and their application as ligands for palladium‐catalysed asymmetric allylic alkylation

Amide coupling of (S_p)‐2‐(diphenylphosphanyl)ferrocene‐1‐carboxylic acid with appropriate terminal amines mediated by 1‐hydroxybenzotriazole and a carbodiimide affords multi‐donor amides terminally functionalized with planar‐chiral (S_p)‐2‐(diphenylphosphanyl)ferrocen‐1‐yl moieties in good to excellent yields. Palladium catalysts based on these ligands efficiently promote asymmetric allylic alkylation of 1,3‐diphenylallyl acetate with in situ generated dimethyl malonate anion to give the C‐alkylated product with ees up to 93% at room temperature. Copyright © 2010 John Wiley & Sons, Ltd.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

Pentacoordinated Carboxylate π‐Allyl Nickel Complexes as Key Intermediates for the Ni‐Catalyzed Direct Amination of Allylic Alcohols

Direct amination of allylic alcohols with primary and secondary amines catalyzed by a system made of [Ni(1,5‐cyclooctadiene)₂] and 1,1′‐bis(diphenylphosphino)ferrocene was effectively enhanced by adding nBu₄NOAc and molecular sieves, affording the corresponding allyl amines in high yield with high monoallylation selectivity for primary amines and high regioselectivity for monosubstituted allylic alcohols. Such remarkable additive effects of nBu₄NOAc were elucidated by isolating and characterizing some nickel complexes, manifesting the key role of a charge neutral pentacoordinated η³‐allyl acetate complex in the present system, in contrast to usual cationic tetracoordinated complexes earlier reported in allylic substitution reactions.     

Chiral Lithiated Allylic α‐Sulfonyl Carbanions: Experimental and Computational Study of Their Structure,Configurational Stability,and Enantioselective Synthesis

X‐ray crystal structure analysis of the lithiated allylic α‐sulfonyl carbanions [CH₂?CHC(Me)SO₂Ph]Li ? diglyme, [cC₆H₈SO₂tBu]Li ? PMDETA and [cC₇H₁₀SO₂tBu]Li ? PMDETA showed dimeric and monomeric CIPs, having nearly planar anionic C atoms, only O?Li bonds, almost planar allylic units with strong C?C bond length alternation and the s‐trans conformation around C1?C2. They adopt a C1?S conformation, which is similar to the one generally found for alkyl and aryl substituted α‐sulfonyl carbanions. Cryoscopy of [EtCH?CHC(Et)SO₂tBu]Li in THF at 164 K revealed an equilibrium between monomers and dimers in a ratio of 83:17, which is similar to the one found by low temperature NMR spectroscopy. According to NMR spectroscopy the lone‐pair orbital at C1 strongly interacts with the C?C double bond. Low temperature ⁶Li,¹H NOE experiments of [EtCH?CHC(Et)SO₂tBu]Li in THF point to an equilibrium between monomeric CIPs having only O?Li bonds and CIPs having both O?Li and C1?Li bonds. Ab initio calculation of [MeCH?CHC(Me)SO₂Me]Li ? (Me₂O)₂ gave three isomeric CIPs having the s‐trans conformation and three isomeric CIPs having the s‐cis conformation around the C1?C2 bond. All s‐trans isomers are more stable than the s‐cis isomers. At all levels of theory the s‐trans isomer having O?Li and C1?Li bonds is the most stable one followed by the isomer which has two O?Li bonds. The allylic unit of the C,O,Li isomer shows strong bond length alternation and the C1 atom is in contrast to the O,Li isomer significantly pyramidalized. According to NBO analysis of the s‐trans and s‐cis isomers, the interaction of the lone pair at C1 with the π* orbital of the CC double bond is energetically much more favorable than that with the “empty” orbitals at the Li atom. The C1?S and C1?C2 conformations are determined by the stereoelectronic effects n_C–σ_SR* interaction and allylic conjugation. ¹H DNMR spectroscopy of racemic [EtCH?CHC(Et)SO₂tBu]Li, [iPrCH?CHC(iPr)SO₂tBu]Li and [EtCH?C(Me)C(Et)SO₂tBu]Li in [D₈]THF gave estimated barriers of enantiomerization of ΔG^≠=13.2 kcal mol^?1 (270 K), 14.2 kcal mol^?1 (291 K) and 14.2 kcal mol^?1 (295 K), respectively. Deprotonation of sulfone (R)‐EtCH?CHCH(Et)SO₂tBu (94 % ee) with nBuLi in THF at ?105 °C occurred with a calculated enantioselectivity of 93 % ee and gave carbanion (M)‐[EtCH?CHC(Et)SO₂tBu]Li, the deuteration and alkylation of which with CF₃CO₂D and MeOCH₂I, respectively, proceeded with high enantioselectivities. Time‐dependent deuteration of the enantioenriched carbanion (M)‐[EtCH?CHC(Et)SO₂tBu]Li in THF gave a racemization barrier of ΔG^≠=12.5 kcal mol^?1 (168 K), which translates to a calculated half‐time of racemization of t_1/2=12 min at ?105 °C.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

One‐Pot Synthesis of O‐Allylhydroxylamines through the Organocatalytic Oxidation of Tertiary Allylic Amines Followed by a [2,3]‐Meisenheimer Rearrangement

A cheap, green, and highly efficient one‐pot method for the synthesis of O‐protected allylic alcohols is described. By utilizing 2,2,2‐trifluoroacetophenone as the organocatalyst and H₂O₂ as the oxidant, a variety of allylic amine N‐oxides were synthesized, which upon heating are converted to the final products through a [2,3]‐Meisenheimer rearrangement.     

Synthesis of a Novel C2‐Symmetric Bis‐oxazoline (=Bis[4,5‐dihydrooxazole]) and Its Application as Chiral Ligand in Asymmetric Transition Metal Catalysis

The new C₂‐symmetric bis‐oxazoline (=bis[4,5‐dihydrooxazole]) 2 with a chiral trans‐(2R,3R)‐2,3‐bis(3,5‐diphenylphenyl)cyclopropylidene (=trans‐(2R,3R)‐2,3‐bis([1,1′: 3′,1″‐terphenyl]‐5′‐yl)cyclopropylidene) backbone was efficiently synthesized (Scheme). All synthetic steps were easy to perform and led to the desired product in good overall yields. Compound 2 was tested and compared as ligand in several enantioselective catalytic reactions such as palladium(0)‐catalyzed enantioselective allylic alkylations and copper(I)‐catalyzed enantioselective cyclopropanations and aziridinations.     

Ruthenium‐Catalyzed Oxidant‐Free Allylation of Aromatic Ketoximes with Allylic Acetates at Room Temperature

Substituted aromatic ketoximes reacted efficiently with allylic acetates in the presence of {[RuCl₂(p‐cymene)]₂} and AgSbF₆ in 1,2‐dichloroethane at ambient temperature, providing ortho‐allyl aromatic ketoximes in a highly regioselective manner without an oxidant. In the reaction, the acetate group of allyl acetate acts as a base to activate the C?H bond of aromatics. Later, ortho‐allyl aromatic ketoximes were converted into ortho‐allyl aromatic ketones in the presence of HCl.     

Enantioselective Synthesis of Pyrrole‐Based Spiro‐ and Polycyclic Derivatives by Iridium‐Catalyzed Asymmetric Allylic Dearomatization and Controllable Migration Reactions

The first highly diastereo‐ and enantioselective synthesis of five‐membered spiro‐2H‐pyrroles was achieved using an Ir‐catalyzed asymmetric allylic dearomatization reaction. The spiro‐2H‐pyrrole derivatives readily undergo a controllable and stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values. Additionally, the novel Ir‐complex K1 , derived from [Ir(cod)Cl]₂ (cod=1,5‐cyclooctadiene) and N‐benzhydryl‐N‐phenyldinaphthophosphoramidite (BHPphos), showed excellent control of both diastereo‐ and enantioselectivities.