Palladium Catalyzed Triple Domino: “ALAMAR” Sequence

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Pd-Chemistry and Annulation Reactions

Annulation reactions are among the most important transformations in organic synthesis.[3] However, only few of the reported methods are of general scope. In particular, palladium catalysis offers a convenient and versatile way to obtain a wide range of carbo- and hetero-cycles via annulations. This chapter will first give a brief introduction on palladium catalysis. Then, I will try to present the state of the art of Pd-catalyzed annulations through some selected examples. Due to the huge amount of literature existing on this subject, I will mainly focus on three strategies: a) annulations involving bis-nucleophile-bearing vinyl/aryl halides, b) annulations involving bis-nucleophiles and allylic systems, and c) annulations involving zwitterionic trimethylenemethane-palladium complex and cyclopropanes.

Palladium-catalysis

The construction of complex molecular structures in a facile and efficient method remains an overarching goal of the chemical sciences. Cascade (or domino) reactions allow improved atom and step economy in organic synthesis and therefore represent significant progress toward this goal.[4] Palladium is a transition metal of the nickel triad, located in the second row of the periodic table. Except rare exceptions, palladium complexes exist in the three oxidation states: Pd(0), Pd(II), Pd(IV), each oxidation state exhibiting different chemical properties. The main elementary steps involving palladium complexes are: a) dative ligand coordination, b) ligand exchange, c) oxidative addition / reductive elimination [Pd(0)/Pd(II) or Pd(II)/Pd(IV)], d) π-system (alkene/alkyne) cis-palladation (migratory insertion), e) π-system trans-nucleopalladation and f) dative ligand 1,1-insertion (Scheme 3).[5]
As a function of the nature of the ligands and reagents involved, the equilibria of these reactions may be more or less displaced to the left or right side, reversible or irreversible. All the Pd-catalyzed reactions feature a combination of the above elementary steps. The starting elementary step of the catalytic cycle can be the oxidative addition, the ligand coordination, or the ligand exchange, while the closing elementary step may be the reductive elimination or the depalladation step (usually dehydropalladation).
Thus, for example, phosphine- or NHC-ligated Pd(0) complexes are d10 electron-rich, nucleophilic species and can oxidatively add to electrophilic partners to give square planar Pd(II) 16 valence-electron (VE) complexes. This is for example the case of: a) allylic derivatives, which form η3-allylpalladium(II) complexes B; b) aryl halides (or pseudo-halides), which to form σ-arylpalladium(II) halides C; and c) molecular oxygen, which forms the η2-peroxopalladium(II) complex D (Scheme 4).
Scheme 4. Oxidative addition of Pd(0) complexes.
The η3-allylpalladium(II) complexes B and the σ-arylpalladium(II) halides C are important electrophilic intermediates in organic chemistry. The former ones, reversibly formed by oxidative addition of Pd(0) complexes and allylic systems (see above), as a function of the nature of the nucleophile, can suffer two types of allylic substitution: a) exterior attack of the nucleophile at the allylic ligand, anti to the Pd atom (alias anti-reductive elimination) (observed with soft nucleophiles); or b) ligand displacement at Pd atom, followed by syn-reductive elimination (observed with hard nucleophiles). σ-Arylpalladium(II) halides C, usually irreversibly formed by oxidative addition of Pd(0) to aryl halides or pseudo-halides (see above), also suffer ligand substitution on palladium followed by reductive elimination. On the other hand, C(sp3) organopalladium complexes bearing a β-H atom, tend to undergo a very easy dehydropalladation (Scheme 5).
Pd(IV) complexes are quite rare, although a few complexes are known. These complexes have hardly been isolated, but transient Pd(IV) species are increasingly considered as intermediates in palladium-catalyzed reactions (Scheme 6).
Palladium-catalyzed couplings have proven to be powerful and key reactions for the synthesis of a great number of targets, including carbo- and heterocycles.[6] In the following sections, I will review a selection of published works dedicated to Pd-catalyzed annulations.

Annulation reactions

Pioneering works

Out of the more than nine million organic compounds present on earth, many of them are, or incorporate, cyclic structures, and some of them are of relevance for steric or electronic properties, biological or pharmacological activity. Furthermore, occurrence of ring compounds in Nature is very high. For this reason, methods for the selective generation of cyclic structures are of utmost importance in organic chemistry and the development of new ones is more than justified.
In this context, annulation reactions are the most efficient methods for the generation of cyclic molecules. Pioneered by O. Diels and K. Alder,[7,8] and Sir R. Robinson,[9] (Scheme 7) allow building up a cyclic structure through the concerted or stepwise creation of two new bonds from two separated components.
Scheme 7. Pioneering annulation reactions.
A brief history of the definition of the annulation reaction is given here below. In 1973, B. P. Mundy[10] wrote a review on this type of reaction, naming it “annelation”. Three years later, M. E. Jung wrote another essay, changing the term from annelation to annulation (from the Latin word annulatus (ringed)).[11] In 1982, R. L. Danheiser proposed to define annulations as ring-forming processes in which two molecular fragments are joined with the formation of two new bonds,[12] and this same definition was later followed by D. P. Curran et al.[13] as well as by the International Union of Pure and Applied Chemistry (IUPAC).[14] In 1998, G. A. Molander[15] perfected the definition, stating that from the mechanistic viewpoint, the created bonds may be the result of a concerted process, or of two sequential elementary steps, as long as regiochemistry and stereochemistry can be controlled. In this latter case, the first elementary step is bimolecular, while the second one is unimolecular.
Many other annulation methods have been reported since, and this type of reaction constitutes a superior method to build-up cyclic structures from simpler components.[16]

Annulation reactions involving Pd-chemistry

Bis-nucleophile-bearing vinyl/aryl halides[17]

The palladium-catalyzed annulation between vinyl/aryl halides and π-systems as electrophiles, such as dienes, alkynes, alkenes, and arenes provides a very valuable route to a wide variety of heterocycles, which will be discussed in the following sections. It is worth noting that R. C. Larock made an undeniable contribution to the development of this chemistry.

Dienes as electrophiles

In 1983, H. A. Dieck reported the Pd-catalyzed annulation between 2-iodoaniline and 1,3-cyclohexadiene to give the corresponding tetrahydrocarbazole (Scheme 8, top).[18] This pioneering study was later pursued by R. C. Larock, who, from 1990 on, reported the heteroannulation between a wide range of cyclic and acyclic 1,3-dienes and appropriately functionalized 2-iodophenols or 2-iodoanilines (Scheme 8, bottom).[ 19 ] This strategy was applied some years latter for the synthesis of a variety of biologically interesting compounds such as dihydrofurocoumarins.
Scheme 8. Palladium-catalyzed annulations between nucleophile-bearing aryl halides and 1,3-dienes.
This annulation is expected to proceed as follows (Scheme 9). First, Pd(OAc)2 is reduced in-situ to an underligated Pd(0) species by the phosphine.[20] Oxidative addition of Pd(0) to the aryl halide generates the corresponding σ-arylpalladium complex. Alkene coordination followed by regioselective arylpalladation of the terminal alkene initially produces an σ-allylpalladium complex, which rapidly rearranges to the more stable η3-allylpalladium intermediate. Following intramolecular attack at Pd by the nucleophile, followed by reductive elimination forms the product and regenerates the Pd(0) starting catalyst.[21]
Scheme 9. Mechanism of the Pd-catalyzed annulation between 2-iodoanilines or 2-iodophenols and 1,3-dienes.
In 2016, the first asymmetric heteroannulation between aryl iodides with 1,3-dienes has been reported by Han and co-workers.[22] This strategy provided an efficient way to the construction of enantioenriched indolines and isochromans in the presence of BINOL-derived phosphoramidite ligand bearing electron-withdraw substituents (Scheme 10).
Scheme 10. Pd-catalyzed asymmetric heteroannulation between aryl iodides with 1,3-dienes.

Dienes (allenes) as electrophiles

In 1991, the Larock group described related Pd-catalyzed annulations between cyclic and acyclic 1,2-dienes (allenes) and a wide variety of aryl iodides carrying vicinal as well remote ortho-linked pro-nucleophiles such as alcohols, carboxylic acids, amines, phenols, tosylamides, amides and carbon acids, which allowed the formation of seven-, eight- and even nine-membered heterocycles (Scheme 11).[23]
Scheme 11. Palladium-catalyzed annulation between nucleophile-bearing aryl iodides and allenes.
Analogous annulations could be carried out by the Larock group by reacting allenes with vinyl halides (Scheme 12).[24]
Scheme 12. Palladium-catalyzed annulation between nucleophile-bearing vinyl halides and allenes.
The mechanism of the Pd-catalyzed annulation of allenes is similar to the previously shown mechanism involving 1,3-dienes. In both cases the palladation step generates a η3-allylpalladium complex, which implies that palladation of allenes leads to a3-allylpalladium complex substituted at the central position (Scheme 13).
Scheme 13. Palladation of 1,3- vs 1,2 dienes.
The same group subsequently developed the asymmetric palladium-catalyzed annulation of allenes with nucleophile-bearing aryl and vinylic iodides, accomplished in the presence of a chiral BOX ligand (Scheme 14).[25] The generality of this annulation was demonstrated by the use of a wide variety of aryl and vinyl iodides bearing nucleophilic substituents such as alcohols, tosylamides and carboxylic acids.
Scheme 14. Enantioselective palladium-catalyzed annulation of allenes.
Recently, the palladium-catalyzed annulation of allenes with 3-indole-2-carboxylic acid derivatives to produce indolo [2,3-c] pyrane-1-ones was reported by Swamy and co-workers.[26] This method was validated by the use of a wide range of allenes (Scheme 15).
Scheme 15. Palladium-catalyzed annulation between 3-indole-2-carboxylic acid derivatives and allenes.
Last year, a novel Pd-catalyzed [3+2] spiroannulation between phenol-based biaryl iodides with allenes was reported by Luan and co-workers.[27] This transformation tolerated a range of functional groups and took place with high chemo- and regioselectivity. Moreover, this strategy leads to the straightforward assembly of spiroindene cyclohexadienones, which are found in alkaloids and bioactive compounds such as (-)-Cannabispirennone A (Scheme 16).
Scheme 16. Palladium-catalyzed annulation between phenol-based biaryl iodides and allenes.

Dienes as electrophiles

The Larock group reported in 1993 the palladium-catalyzed annulation between 1,4-dienes and a variety of nucleophile-bearing aryl halides.[28] The regioselectivity of this annulation reaction was excellent (Scheme 17).
Scheme 17. Palladium-catalyzed annulation of 1,4-dienes.
In 1998, the Huang group reported a solid-phase synthesis of heterocycles via Pd-catalyzed annulation between aryl iodides with 1,4-dienes, which provided an efficient way to the synthesis of tetrahydroquinolines and hydrobenzopyrans (Scheme 18).[29]
Scheme 18. Pd-catalyzed annulation between 1,4-dienes with solid-phase linked o-iodoanilines or iodophenols.
The mechanism of this process is related to that observed with 1,3-dienes. However, in this case, the palladation of the 1,4-diene generates a homoallylpalladium complex. Subsequent β-H elimination followed by hydropalladation (with reversed regioselectivity with respect to the retro-β-H elimination step) forms a σ-allylpalladium complex, which evolves as previously observed for the 1,3-dienes (Scheme 19).
Scheme 19. The mechanism of the Pd-catalyzed annulation between nucleophile-bearing aryl iodides and 1,4-dienes.
Cyclic alkenes as electrophiles
In 1998, Catellani and Del Rio described the first Pd-catalyzed annulation between ortho-nucleophile-bearing aryl halides and norbornene and norbornadiene, to afford indolines and 2,3-dihydrobenzofurans.[30] This method was later revisited and extended by Larock[31] in 2004 (Scheme 20).
Scheme 20. Pd-catalyzed annulation of cyclic alkenes with aryl iodides.
It should be noted that this method is expected to be successful only for alkenes unable to undergo dehydropalladation from the alkylpalladium intermediate (that would otherwise give the classical Heck-type product). This is the case of alkenes incorporated into small cycles, or lacking allylic hydrogens (Scheme 21).
Scheme 21. Bias of alkylpalladium complexes derived from conformationally rigid cyclic alkenes.
Alkynes as electrophiles
The palladium-catalyzed annulation reaction between alkynes and ortho-functionalized aryl or vinyl halides has proven very useful for the synthesis of a number of carbo- and heterocycles, including benzofuran, benzopyran, isocoumarin, isoquinoline, pyridine and indole derivatives (Scheme 22).[32,33,17]
Several ortho-located functional groups can be used with this chemistry, such as aldehydes, esters, carboxylic acids, imines, amines and some resonance stabilized acid carbons.
Scheme 22. Pd-catalyzed annulation between alkynes and ortho-functionalized aryl halides.
More recently, the group of Luan reported a Pd-catalyzed dynamic kinetic asymmetric annulation between tropos (racemic) biaryl bromides and alkynes in the presence of chiral Pd-NHC complexes to produce a series of enantioenriched spirocyclic (Scheme 23). [34]
Scheme 23. Pd-catalyzed dynamic kinetic asymmetric annulations between racemic biaryl bromides with alkynes.
This efficient and powerful strategy was applied for the key steps in the synthesis of some alkaloids or natural products.[35]
Recently, the Jia group used a Pd-catalyzed Larock indole annulation as the key step for the total synthesis of a range of the ergot alkaloids endowed of a broad spectrum of potent pharmacological activities, such as, festuclavine, pyroclavine, costaclavine, fumigaclavine G (Scheme 24).[36]
Scheme 24. Synthesis of ergot and alkaloids via Pd-catalyzed intramolecular Larock indole annulation.
Besides, the asymmetric total synthesis of (-)-galanthamine and (-)-lycoramine as the representative member of the Amaryllidaceae alkaloids was also achieved by using this annulation as the key step (Scheme 25).[37]
Scheme 25. Synthesis of amaryllidaceae alkaloids via Pd-catalyzed intramolecular Larock indole annulation.
The Boger group exploited this annulation as the key step for the total syntheses of dihydrolysergic acid and dihydrolysergol, which are alkaloids of interest in the treatment of a range of neurological diseases (Scheme 26).[38]
Scheme 26. Synthesis of dihydrolysergic acid and dihydrolysergol via Pd-catalyzed intramolecular Larock indole annulation.
The mechanism of these transformations is analogous to that previously described in the case of alkenes.
However, in this case, palladation of the alkyne produces a σ-vinylpalladium intermediate (Scheme 27).
Scheme 27. Mechanism of the Pd-catalyzed annulation between an ortho-halo phenol and an alkyne.
The mechanism of the following cyclization step may depend on the nature of the ortho-located functional group. Thus, for example, in the case of an aldehyde, the authors proposed an oxidative addition to afford a Pd(IV) intermediate, which is than deprotonated by the base before undergoing reductive elimination to give the indenone product. In contrast, in the case of a tert-butyl imine, an initial ligand substitution is expected to produce an N-Pd-iminium complex, which then undergoes a base promoted elimination of isoprene to afford the final isoquinoline (Scheme 28).
Scheme 28. Evolution of the vinylpalladium intermediate as a function of the aryl ortho-substituent.

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Annulations between bis-nucleophiles and bis-allylic electrophiles

The palladium-catalyzed allylation of nucleophiles (Pd-AA) is one of the most useful transformations for organic synthesis (Scheme 29, top).[39] Indeed, this key reaction has been used by chemists in a great number of syntheses, and developed in a number of variations, including X-C and C-C bond formations, as well as asymmetric variants (Pd-AAA). In particular, when the substrate is a bis-allylic system, its interaction with a bis-nucleophile may allow accomplishing an annulation reaction via a Pd-catalyzed cascade process (Scheme 29, bottom).
Scheme 29. Top: generic Pd-catalyzed allylation. Bottom: generic Pd-catalyzed cascade allylic alkylation using a bis-allylic system and a bis-nucleophile.
Various combinations of carbon, nitrogen and oxygen bis-nucleophiles have been used for the construction of a variety of vinyl substituted annulated systems. Although this chemistry can in principle lead to a number of regioisomeric products, the use of symmetric electrophiles and/or nucleophiles allowed to avoid of such issue, and to adopt this strategy in total syntheses.[40]
Acyclic bis-allylic electrophiles[41]
In 1987, the Lu group reported the Pd(0)-catalyzed annulation between 2-methylene propan-1,3-diol diacetate and β-diketones or β-ketoesters (Scheme 30),[42] which gave dihydropyran derivatives in a one pot reaction.
Scheme 30. Di-allylic alkylation of 2-methylene propan-1,3-diol diacetate with β-diketones or β-ketoesters.
Furthermore, the analogous reaction of this 2-methylene propan-1,3-diol diacetate with various dicarbanionic nucleophiles allowed to generate five- or six-membered rings (Scheme 31).[43]
Scheme 31. Di-allylic alkylation of 2-methylene propan-1,3-diol diacetate with dicarbanions.
In 1992, the Sivaramakrishnan group achieved the synthesis of bicyclo[3,3,1]nonanes through a Pd-catalyzed AA between 2-methylene propan-1,3-diol diacetate and a variety of cyclic β-ketoesters.[44] This method was used by Kozikowski and Tückmantel in the synthesis of the Chinese nootropic agent Huperzine A and its analogs (Scheme 32).[45]
Scheme 32. Synthesis of Chinese Nootropic Agent Huperzine A and its analogues.
Morpholines, piperazines and 1,4-benzodioxanes are heterocyclic structures present in a large number of molecules of biological and/or therapeutic relevance. In 1990, Saegusa reported the palladium-catalyzed annulation reaction between allylic 1,4-diacetates (or dicarbonates) and 1,2-bifunctional nucleophiles such as 1,2-aminoalcohols or ethylenediamines (Scheme 33).[ 46 ] Analogous Pd-catalyzed diastereoselective syntheses of 2-vinyl-1,4-benzodioxanes, 2-vinylmorpholines and 2-vinylpiperazines were reported by Hayashi,[47] Sinou,[48] Achiwa [49] and Muzart.[50]
Scheme 33. Synthesis of morpholines or piperazines.
In 1995, the Salaün group reported an approach to 1-aminocyclopropanecarboxylic acids through the Pd-catalyzed annulation between 1,4-dichlorobut-2-ene and N-(diphenylmethylene)aminoacetonitrile. The reaction occurs through two subsequent Pd-catalyzed allylations of the bis-nucleophile (Scheme 34).[51]
Scheme 34. Synthesis of 1-aminocyclopropanecarboxylic acid.
In 1999, the Sinou group developed a facile palladium-catalyzed annulation between various substituted benzene-1,2-diols, or N,N-bis(arylsulfonyl)-o-phenylenediamines, and 1,4-bis(methoxycarbonyloxy)but-2-ene to form substituted 2-vinyl-2,3 dihydro-benzo[1,4]dioxins[52] or 1,2,3,4-tetrahydro-2-vinylquinoxalines[53] in good yields (Scheme 35).
Scheme 35. Synthesis of 2-vinyl-2,3 dihydro-benzo[1,4]dioxins and 1,2,3,4-tetrahydro-2-vinylquinoxalines.
Cyclic allylic electrophiles
In 1995, the Mori group reported a smart strategy for the synthesis of tetrahydrobenzofurans and tetrahydroindolones through the Pd-catalyzed annulation reaction between 1,4-dibenzoyloxycyclohex-2-ene and 3-oxoglutarate, or monomalonamide. Use of the chiral enantiopure ligand BINAPO gave a mediocre (~50%) enantiodiscrimination. The same group exploited this method as the key steps for synthesis of the natural product (+)-γ-lycorane (Scheme 36).[54]
Scheme 36. Pd-catalyzed annulation to give tetrahydrobenzofurans and tetrahydroindolones.
More recently, our group reported an analogous Pd-catalyzed annulation strategy by the reaction between N-tosyl malonamide and 1,4-dibenzoyloxycyclohex-2-ene. Further functional group modifications of the annulation product gave analogs of the 2-carboxyl-6-hydroxyoctahydroindole (CHOI) unit, which in turn is a substructure of aeruginosins, a family of molecules found in cyanobacteria (Scheme 37).[2]
Scheme 37. Palladium-catalyzed annulation toward CHOI analogs.
In 2013, the Harvey group developed a Pd-catalyzed annulation between cyclic β-dicarbonyls and dihydropyrans that gave regioselectively furo[3,2-c]pyrans (Scheme 38). It should be noted that inherent steric and stereoelectronic factors in the pyran substrates favor a faster ionization at the allylic carbonate site than that at the anomeric OTBS group, which in turn determines the structure of the transient π-allyl-Pd species generated in the cascade, and thus the subsequent regioselective substitution by the nucleophile at C3 position. Interestingly, the cis-fused furopyrans were formed from either the cis- or the trans-substituted bis-electrophiles.[55]
Scheme 38. Palladium-catalyzed cascade allylic alkylation of dihydropyrans.
Allylic / Michael acceptor electrophiles
Despite the number of palladium-catalyzed annulations reported, Pd-catalyzed allylation / Michael sequences are still rare. In 1998, the Desmaële group reported a palladium-catalyzed allylation followed by spontaneous intramolecular Michael addition to produce six-member rings. A variety of combinations between active methylene compounds and methyl 6-acetoxymethyl-hepta-2,6-dienoate were investigated, which provided a new access to cyclohexane derivatives.[ 56 ] The authors applied this strategy to the synthesis of erythramine, an alkaloid of the family of erythrines (Scheme 39).
Scheme 39. Pd-catalyzed annulation of methyl 6-acetoxymethyl-hepta-2,6-dienoate with active methylene compounds.
In 2004, the Fürstner group achieved the total synthesis of the antitumor agent TMC-69-6H.[57] The key step of this synthesis was a Pd-catalyzed [3+2]-C−C/O−C bond-forming annulation between 4-hydroxy-2-pyridone and pyranyl acetate, which involved a palladium-catalyzed allylic alkylation followed by a spontaneous oxa-Michael reaction. In the presence of the chiral ligand – (S,S)-Trost DACH ligand – and allylpalladium chloride dimer, a key tricyclic product was obtained in 65% yield and excellent enantioselectivity (Scheme 40).
Scheme 40. Pd-catalyzed [3+2]-C−C/O−C bond-forming annulation for synthesis of TMC-69-6H x.
Similarly, in 2016 Tong reported the synthesis of furopyranones through Pd-catalyzed oxa-[3+2]-annulation between acetoxy-2-pyranones and 1,3-dicarbonyl compounds. Here again, the annulation involves a palladium-catalyzed allylation followed by an intramolecular oxa-Michael reaction (Scheme 41, left).[58] The authors also found that using quinine as catalyst instead of the palladium system afforded another regioisomers of furopyranones , deriving from an intermolecular Michael addition followed by SN2-type cycloacetalization (Scheme 41, right).
Scheme 41. [3+2]-C−C/O−C bond-forming annulation for synthesis of furopyranones derivatives.
Two, initially separated, electrophilic components
In 2004, the Catellani group presented the one-pot synthesis of tetrahydrobenzazepines and tetrahydroisoquinolines by the Pd-catalyzed reaction between an o-iodoalkylbenzene, an N-protected bromoalkylamine and an electron-poor olefin (Scheme 42).[59]
Scheme 42. [Pd-cat o-alkylation / Pd-cat alkenylation / aza-Michael] strategy to tetrahydrobenzazepines and tetrahydroisoquinolines.
A plausible mechanism of this transformation involves a Pd-catalyzed ortho-alkylation, followed by a Pd-catalyzed alkenylation and a final intramolecular aza-Michael reaction (Scheme 43). More precisely, i) oxidative addition of the aromatic iodide to Pd(0) gives the corresponding σ-arylpalladium iodide complex A; ii) norbornene insertion and subsequent intramolecular ortho-palladation formes palladacycle B; iii) oxidative addition of B to N-Cbz-bromoalkylamine leads to the palladium(IV) metallacycle C; iv) reductive elimination generates the-alkylpalladium intermediate D; v) decarbopalladation affords the corresponding-arylpalladium complex E and regenerates norbornene; vi) carbopalladation of the electron-poor olefin followed by dehydropalladation completes the catalytic cycle, generating the final alkene and Pd(0); vii) finally, intramolecular aza-Michael addition cab furnish the final annulation bicycle product.
Scheme 43. The Pd-catalyzed strategy to tetrahydroisoquinolines.

Annulation from Pd-TMM or cyclopropanes

Pd-catalyzed [3+2]-annulation reactions from 3-acetoxy-2-trimethylsilylmethyl-1-propene are one of the most effective methods for synthesis of five-membered carbocycles and heterocycles.
Pd-catalyzed [3+2]-annulation from 3-acetoxy-2-trimethylsilylmethyl-1-propene
The interaction between 3-acetoxy-2-trimethylsilylmethyl-1-propene (ASMP) and a Pd(0) complex generates a zwitterionic complex (Pd-TMM) (Scheme 44).[60] The positive charge is stabilized by palladium, which prevents ring closing to methylidenecyclopropane and Pd(0). This chemistry was discovered and mainly developed by Prof. B. M. Trost.
Scheme 44. Generation of TMM-Pd.
This stable 1,3-dipole favors the singlet state, which has a nucleophilic nature and reacts with a number of electrophilic dipolarophiles to provide five-membered ring systems (Figure 1).
Figure 1. Qualitative molecular orbital interaction diagram between the π-system of Pd-TMM and that of a generic electrophilic dipolarophile.
Pd-TMM, generated in-situ from ASMP, gives [32+22π] cycloaddition with a number of electron-deficient olefins. For example, the reaction with dimethyl fumarate led to exclusively the trans cycloadduct, whereas with dimethyl maleate produced cis/trans mixtures of methylenecyclopentanes. This lack of stereospecificity suggests a stepwise, non-concerted mechanism (Scheme 45).
Scheme 45. Stepwise non-stereospecific mechanism in the cycloaddition of Pd-TMM.
The in-situ generated Pd-TMM could be also react with α,β-unsaturated–ketones, nitriles, esters, imines, aldehydes and ynones to form substituted 5-membered carbo- or heterocycles (Scheme 46).
Scheme 46. Overview of Pd-catalyzed [3+2]-annulations from Pd-TMMs.
Pd-catalyzed [3+2]-annulation from methylenecyclopropanes
It is also possible to obtain Pd(0)-catalyzed cycloadditions by the reaction between methylenecyclopropanes and alkenes and carbonyl derivatives (Scheme 47).
Scheme 47. Pd-catalyzed cycloaddition between methylenecyclopropanes and alkenes or carbonyl derivatives.
This chemistry was pioneered by Binger and co-workers,[61] who studied α,β-unsaturated esters as electrophiles. Yamamoto later reported analogous Pd-catalyzed [3+2]-cycloadditions between methylenecyclopropanes and aldehydes or N-tosylimines (Scheme 48).[62]
Scheme 48. Pd-catalyzed [3+2]-cycloaddition of methylenecyclopropanes.
Although, at a first glance, it is tempting to think at a mechanism involving the previously described zwitterionic Pd-TMM complexes, these two approaches show different selectivities. Thus, for example, methylenecyclopropanes substituted at the exo alkene led to the following regioisomerically pure products (Scheme 49).[62b,63]
Scheme 49. Pd-catalyzed [3+2]-cycloaddition of dibutyl- or diphenyl-methylenecyclopropanes.
These results suggest that the mechanism of this transformation involves a rapid σ-π-σ scrambling between the allylpalladium complexes, the most reactive one being a function of the substitution of the methylenecyclopropane (Scheme 50).
Scheme 50. The mechanism of the Pd-catalyzed cycloaddition between methylenecyclopropanes and alkenes.
Pd-catalyzed [3+2]-annulation from vinylcyclopropanes
In addition, the Pd-catalyzed [3+2]-annulation of 1,3-dipolar species generated from vinylcyclopropanes with dipolarophiles has become a highly efficient strategy for the synthesis of five membered ring compounds.
In 1985, the first Pd-catalyzed [3+2]-annulation of vinylcyclopropanes with α,β-unsaturated ketones or esters was reported by Tsuji and co-workers.[64] Upon interaction with a Pd(0) complex, the doubly EWG-activated cyclopropanes generate through C-C bond cleavage a zwitterionic π-allylpalladium complex bearing a carbanion as its counteranion. Following annulation with an electron-deficient alkene generates the cyclopentane (Scheme 51).

Table of contents :

Chapter 1: Pd
Chemistry and Annulation Reactions
1.Palladium catalysis
2. Annulation reactions
2.1 Pioneering works
2.2 Annulation reactions involving Pd chemistry
2.2.1 Bis nucleophile bearing vinyl/aryl halides
2.2.2 Annulations between bis nucleophiles and bis allylic electrophiles
2.2.3 Annulation from Pd TMM or cyclopropanes
2.2.4 Pd catalyzed [3+2] C−C/N−C bond forming annulations base d on C H activation
Chapter 2: Palladium Catalyzed [3+2] C−C/N−C Bond Forming Annulation
1. Conception of the new [3+2] C C/N C annulation plan
2. First studies and optimization of the reaction conditions
3. S cope and limitations of the Pd catalyzed [3+2] annulation
3.1 From resonance stabilized N sulfony l acetamides
3.2 The influence of the substitution at the N position of the N amido ester
3.3 Scope of cyclic α,β unsaturated γ oxycarbonyl derivatives
4. Mechanism
5. Studies of enanti oselectivity
5.1 Concepts in the asymmetric Pd catalyzed allylation
5.2 Pd catalyzed asymmetric [3+2] annulations with chiral phosphine ligands
5.3 Pd catalyzed asymmetric [3+2] annulations with chiral phosphoramidite ligands
6. Conclusion
Chapter 3: Palladium Catalyzed Triple Domino: “ALAMAR” Sequence
1. Introduction
2. Toward a multiple pseudo domino
2.1 The concept
2.2 Th e α arylation of enolizable nucleophiles
2.2.1 Introduction and early studies
2.2.2 The Pd catalyzed intermolecular α arylation of ketones
2.2.3 The Pd catalyzed intramolecular α arylation of ketones
3. Study of the [Allylation / AzaStudy of the [Allylation / Aza–Michael / Arylation] (ALAMAR) Domino sequenceMichael / Arylation] (ALAMAR) Domino sequence
3.1 Preliminary studiePreliminary studiess
3.2 Study of the sequential PdStudy of the sequential Pd–catalyzed [3+2] annulation / arylation from 1s and 2acatalyzed [3+2] annulation / arylation from 1s and 2a
3.3 Study of the ALAMAR domino sequence from 1s and 2aStudy of the ALAMAR domino sequence from 1s and 2a
3.4 Scope of the oneScope of the one–pot domino sequencepot domino sequence
3.5 MechanismMechanism
3.6 Conclusion and PerspectivesConclusion and Perspectives
Chapter 4: Palladium–Catalyzed [3+2]Catalyzed [3+2]–C−C/O−C and C−C/C−C BondC−C/O−C and C−C/C−C Bond–Forming AnnulationForming Annulation
1. Introduction and ObjectivesIntroduction and Objectives
2. Studies of PdStudies of Pd–catalyzed [3+2] annulation betweecatalyzed [3+2] annulation between 3n 3–oxoglutarate and 2oxoglutarate and 2–cyclohexenone 4cyclohexenone 4–benzoate
2.1 Optimization of the Optimization of the [3+2][3+2]–C−C/O−C annulationC−C/O−C annulation
2.2 Scope and limitations of the PdScope and limitations of the Pd–catalyzed [3+2] annulationcatalyzed [3+2] annulation
2.2.1 PdPd–catalyzed [3+2]catalyzed [3+2]–C−C/O−C annulationsC−C/O−C annulations
2.2.2 PdPd–catalyzed [3+2]catalyzed [3+2]–C−C/C−C annulationsC−C/C−C annulations
2.2.3 PdPd–catalyzed [3+2] annulation between 2a and 1,3catalyzed [3+2] annulation between 2a and 1,3–activated propanactivated propan–22–ones bisones bis–nucleophiles other than
2.2.4 PdPd–catalyzed [3+2] annulation of 2a and biscatalyzed [3+2] annulation of 2a and bis–nucleophiles 19nucleophiles
2.3 MechanismMechanism
3. Conclusion and PeConclusion and Perspectivesrspectives
General Conclusion
Experimental Section
1. General remarksGeneral remarks
2. General proceduresGeneral procedures
2.1 SyntheSynthesis of starting materialssis of starting materials
2.1.1 Synthesis of bisSynthesis of bis–nucleophiles 1nucleophiles 1
2.1.2 Synthesis of bisSynthesis of bis–electrophiles 2electrophiles 2
2.2 Procedures of Procedures of Pd(0)Pd(0)–catalyzed [ 3 + 2 ]catalyzed [ 3 + 2 ]–C−C/N−C bondC−C/N−C bond–forming annulationforming annulation
2.3 Procedures of PdProcedures of Pd(0)(0)–catalyzed triple domino reactionscatalyzed triple domino reactions
2.3.1 Synthesis of tricyclic Synthesis of tricyclic silyl ether silyl ether productsproducts
2.3.2 Synthesis of tricyclic productsSynthesis of tricyclic products
2.4 Procedures of PdProcedures of Pd(0)(0)–catalyzed [3+2]catalyzed [3+2]–C−C/C−C/OO−−CC or or C−C/C−C/CC−−C bondC bond–forming annulationforming annulation 123123
2.4.1 Procedures of PdProcedures of Pd(0)(0)–catalyzed [3+2catalyzed [3+2]]–C−C/C−C/OO−−C bondC bond–forming annulationforming annulation
2.4.2 Procedures of PdProcedures of Pd(0)(0)–catalyzed [3+2]catalyzed [3+2]–C−C/C−C/CC−−C bondC bond–forming annulationforming annulation
3. Analytical dataAnalytical data
3.1 Analytical data of bisAnalytical data of bis–nucleophilesnucleophiles
3.2 Analytical data of bisAnalytical data of bis–electrophileselectrophiles
3.4 Chiral HPLC Chromatograms of compounds relating to Chapter 2Chiral HPLC Chromatograms of compounds relating to Chapter 2
3.5 Analytical data of compounds relating to Chapter Analytical data of compounds relating to Chapter 33
3.6 Analytical data of compounds relAnalytical data of compounds relating to Chapter ating to Chapter 4

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