Palladium(0)‐Catalyzed Anti‐Selective Addition‐Cyclizations of Alkynyl Electrophiles

Abstract

Palladium(0)/monophosphine complexes catalyze anti‐selective alkylative, arylative, and alkynylative cyclizations of alkynyl electrophiles with organometallic reagents. The remarkable anti‐selectivity results from novel oxidative addition, that is, the nucleophilic attack of electron‐rich palladium(0) on the electrophile across the alkyne followed by transmetalation and reductive elimination (“anti‐Wacker”‐type cyclization). With regard to 5‐alkynals, triphenylphosphine (PPh₃)‐ligated palladium(0) catalyzes the cyclization of terminal alkynes and conjugated alkenyl‐ or alkynyl‐substituted ones to afford 2‐cyclohexen‐1‐ol and 2‐alkylidene‐cyclopentanol derivatives, respectively. For 6‐alkyl‐ or 6‐aryl‐5‐alkynals, the cyclization does not proceed with the palladium/PPh₃ catalyst; however, it does proceed with palladium/tricyclohexylphosphine (PCy₃), to yield the former products predominantly. Remarkably, the latter catalyst completely switches the regioselectivity in the cyclization of the conjugated diyne‐aldehydes. Notably, palladium/PPh₃‐catalyzed cyclizations also proceed with other organometallics or even without them.

Palladium(0)/monophosphine complexes catalyze anti‐selective arylative cyclizations of alkynyl electrophiles with organometallic reagents. Remarkably, the regioselectivity in the cyclization of conjugated diyne‐aldehydes can be controlled by a choice of the phosphine ligand, with triphenylphosphine and tricyclohexylphosphine leading to the exclusive formation of 2‐alkylidene‐cyclopentanol and 2‐cyclohexen‐1‐ol derivatives, respectively.

Introduction

Transition‐metal‐catalyzed, three‐component coupling reactions among alkynes, carbonyls, and organometallic reagents[ ¹ , ² , ³ , ⁴ , ⁵ , ⁶ ] serve as an effective one‐step method to prepare synthetically useful allylic alcohols. Particularly interesting are intramolecular versions of this process using less nucleophilic organometallics containing Zn, Zr, and B, which transform simple precursors 1 into complex, cyclic allylic alcohols 2–4 (Scheme 1). Montgomery pioneered the three‐component coupling reaction and developed a nickel(0)‐catalyzed alkylative cyclization of alkyne‐aldehydes 1 with organozinc reagents to form cycloalkanols 2 with a stereodefined tri‐ or tetra‐substituted exo‐olefin at the C‐2 position.[ ¹ , ² ] The syn‐selective cyclization proceeds through the oxidative addition of 1 to the Ni(0) catalyst to form oxanickelacycle(II), which undergoes transmetalation followed by reductive elimination (path A). Hayashi and Murakami independently discovered that a combination of a Rh(I) catalyst and an arylboronic acid also promoted a similar stereoselective transformation of 1 into 2. ^[3] The mechanism of the Rh(I)‐catalyzed reaction is different from that of the Ni(0)‐catalyzed one and involves transmetalation between arylboronic acid and the Rh(I) catalyst and successive insertions of the alkyne and carbonyl group (path B). The Rh(I) catalyst can be replaced by Pd(II). ^[4] The efficiency of the latter syn‐carbometalation pathway B depends strongly on the alkyne substituents.[ ³ , ⁷ ] In particular, an electron‐withdrawing aryl group at the alkyne terminus is unsuitable, as it guides the alkyne insertion in an undesired direction. In addition, the organometallic reagent is limited to sp²‐hybridized carbonucleophiles.

Scheme 1.

Transition‐Metal‐Catalyzed Alkylative and Arylative Cyclizations of Alkyne‐Carbonyl Compound 1.

Although migratory insertion with carbon‐carbon triple bonds occur in a syn fashion, the alkenyl‐metal intermediates generated by syn‐selective carbometalation of alkynes can undergo cis‐trans isomerization (formal anti‐carbometalation).[ ⁸ , ⁹ , ¹⁰ ] Lam's group developed a Ni(II)‐catalyzed anti‐selective arylative cyclization of alkynyl electrophiles with arylboronic acids, wherein the cis‐trans isomerization of the alkenylnickel(II) species was followed by addition to the adjacent electrophiles (path C). ^[5] In contrast to the Rh(I)‐catalyzed cyclization, an aryl substituent at the alkyne terminus is essential for the regioselective alkyne insertion leading to successful cyclization.[ ⁵ , ¹⁰ ]

Prior to Lam's discovery, we preliminarily reported a Pd(0)/monophosphine‐catalyzed anti‐selective cyclization of alkynyl aldehydes and ketones 1 with organoboron reagents to afford 2‐cyclohexen‐1‐ols 3 and/or 2‐alkylidene cyclopentanols 4 (Scheme 1). ^[6] If syn‐ and regio‐selective migratory insertion of the alkyne into a carbon‐palladium bond also participated in our cyclization, syn‐adduct 2 instead of anti‐adduct 4 should be obtained prior to cis‐trans isomerization. Furthermore, in contrast to the above‐mentioned arylative cyclizations under the catalytic effect of Rh(I), Pd(II), and Ni(II),[ ³ , ⁴ , ⁵ ] our cyclization reaction can incorporate not only sp²‐hybridized carbonucleophiles but also sp³‐hybridized ones derived from trialkylboranes. If an alkylpalladium species is somehow generated from the Pd catalyst and alkylborane bearing a β‐hydrogen in the initial step, a β‐hydride elimination can precede the alkyne insertion to result in reductive rather than alkylative cyclization.

These observations led us to propose an unusual reaction mechanism for our anti‐selective cyclization reaction, namely, nucleophilic attack of electron‐rich Pd(0) at the carbonyl functionality across the alkyne (“anti‐Wacker”‐type oxidative addition ^[11] ) followed by transmetalation and reductive elimination (Scheme 1, path D). This mode of oxidative addition without formation of oxapalladacycles presents a striking contrast to oxidative cyclization with a Ni(0) catalyst, although both zero‐valent catalysts involve Periodic group 10 elements. However, substitution of enone for the carbonyl electrophile led to syn‐selective cyclization with both of the catalysts through common oxidative cyclization.[ ¹ , ¹² ] These facts indicated that the “anti‐Wacker”‐type oxidative addition should be ascribed to the poor affinity of the carbon‐oxygen double bond for Pd(0).

Our cyclization also tolerates substituents at the alkyne terminus, although the product distribution of 2‐cyclohexen‐1‐ols 3 and 2‐alkylidene cyclopentanols 4 depends on the substituents as well as on the monophosphine ligand. In the preliminary report, triphenylphosphine (PPh₃), a less σ‐donating ligand, was shown to be effective only for the cyclization of terminal alkynes, leading to endocyclic products 3. With the more σ‐donating and bulky ligand PCy₃, primary alkyl‐substituted alkynes were converted to a mixture of endo‐ and exo‐cyclic products 3 and 4, while aryl‐substituted alkynes were transformed into 3 exclusively. The origin of the regioselectivity was unclear, and catalytic control of the regioselectivity, desirable for synthetic utility, was never achieved. It is also of concern that the reaction rate and product yield of the cyclization sometimes depend on the particular arylboronic acid used, with electron‐deficient ones leading to slow reaction and low yield. Although the electron density of the carbonucleophiles affects both the transmetalation and reductive elimination steps, a further possibility, which cannot be excluded, is that the organoboron reagents also cooperate with the Pd catalyst to promote the cyclization step. In this article, we present further findings on the effects of alkyne substituents, monophosphine ligands, and organometallics on the cyclization of alkynyl electrophiles, including carbonyls, enones, and iminium ions generated in situ. We expose the key factors influencing the regioselectivity as well as the reason for the use of electron‐deficient arylboronic acids inhibits the arylative cyclization. We also test the cyclization in the absence of organometallic reagents to determine whether they participate in the cyclization step.

Results and Discussion

Effect of solvents, organoboron reagents, and catalysts

The phenylative cyclization of terminal alkyne‐aldehyde 1  a proceeded on heating at 65 °C in the presence of an excess of phenylboronic acid (5  a) and a catalytic amount of Pd(PPh₃)₄ to afford a single endocyclic product 3  aa ^[6a] along with 6  aa, the product of hydroarylation (Table 1). ^[13] The yield of 3  aa was dramatically affected by the solvent, with reaction in methanol leading to exclusive formation of 3  aa. No other alcoholic solvent worked better than methanol and among zero‐valent group 10 elements, only Pd(0) catalysts showed this remarkable anti‐selectivity (see Table S2 and S11 in the Supporting Information). Arylboronic acids with an electron‐donating or ‐withdrawing group serve as nucleophiles in this process, leading to the formation of endocyclic products 3  ab‐ai in reasonable yields. Generally, electron‐rich boronic acids require shorter reaction times and give higher product yields than their electron‐deficient counterparts. p‐Chlorophenylboronic acid (5  e) effectively participates in the cyclization, but the p‐bromo counterpart (5  f) gave the product 3  af in a much lower yield. Among the isomeric bromophenylboronic acids, only the ortho‐substituted one gave a satisfactory result. ^[14] These differences are attributed to the susceptibility of the electronically and sterically favored m‐ and p‐substituted bromobenzene to competitive oxidative addition to Pd(0). The arylative cyclization of 1  a with 5  b proceeds comparably on a 1.0 g scale. The stereochemistry of the alkenylboronic acids is retained during the cyclization of 1  a, thus affording 2,4‐dien‐1‐ols 3  aj and 3  ak in high yields. Although alkylboronic acids did not effectively serve as sp³‐hybridized carbonucleophiles, trialkylboranes possessing β‐hydrogens participate in this process without undergoing competitive β‐hydride elimination to give 3  al and 3  am.

Table 1.

Pd(PPh₃)₄‐Catalyzed Arylative‐, Alkenylative‐, and Alkylative Cyclizations of Terminal Alkyne‐Aldehyde 1  a.

Effect of alkyne substituent

We previously found that internal alkynes substituted by alkyl‐ or aryl groups at the terminal sp‐hybridized carbon did not undergo arylative cyclization under Pd/PPh₃ catalysis. ^[6a] In the previous report, we used a combination of the more σ‐donating PCy₃ and tris(dibenzylideneacetone)dipalladium(0) (Pd₂dba₃) for the arylative cyclization of the internal alkynes. Further screening of Pd sources revealed that (η³‐allyl)(η⁵‐cyclopentadienyl)palladium(II) ^[15] ((η³‐allyl)CpPd) was much more active than Pd₂dba₃, ^[6b] whose electron‐deficient dba ligand reduces the concentration of the active catalyst species LnPd(0). ^[16] Except for 1  f, internal alkynes 1  b–g bearing a primary alkyl or aryl substituent at the alkyne terminus undergo arylative cyclization on heating at 80 °C in the presence of the new catalyst to provide a mixture of endo‐ and exo‐cyclic products 3  bb–gb and 4  bb–eb in high combined yields (Table 2). The product distribution depends on the length of the alkyl substituent, with a longer chain leading to the predominant formation of 3  bb–db. In comparison with the propyl‐substituted substrate 1  c, the branched methyl group in 1  e retards the cyclization but increases the ratio of 3  eb to 4  eb. Although a secondary cyclohexyl group completely stops the reaction, the structurally similar phenyl group enhances the cyclization to give 3  gb exclusively. In contrast to alkyl‐ and aryl‐substituted alkyne‐aldehydes, terminal alkyne 1  a is converted to exo‐ and endo‐cyclic products 4  ab and 3  ab in the ratio of 2 to 1 under Pd/PCy₃ catalysis.

Table 2.

Pd/PCy₃‐Catalyzed Arylative Cyclization of 1  a–g.

Because the aryl‐substituted substrate 1  g showed enhanced reactivity and selectivity, ^[17] the effect of alkenyl groups as alternative sp²‐hybridized carbon substituents was investigated. Surprisingly, 1,4‐disubstituted 1,3‐enynes 1  h–m undergo arylative cyclization with 5  b even in the presence of the Pd(PPh₃)₄ and Pd/PCy₃ catalysts (Table 3). The reaction retains both alkene geometry and anti‐selectivity and affords cycloalkan‐1‐ol derivatives 4  hb–mb exclusively instead of 3‐aryl‐2‐cycloalken‐1‐ols. In comparison with terminal alkyne‐aldehydes, 1,3‐enyne substrates are more reactive toward cyclization, in which conformationally more flexible or longer tethers in 1  k–m are tolerated. In contrast, 1,1,4‐ and 1,2,4‐trisubstituted 1,3‐enynes 1  n and 1  o undergo cyclization under Pd/PPh₃ and Pd/PCy₃ catalyses to give exocyclic products 4  nb⋅ob and endocyclic ones 3  nb⋅ob as exclusive and predominant products, respectively. It is also noteworthy that the arylative cyclization of 2,4‐disubstituted 1,3‐enynes 1  p and 1  q with 5  b gives a mixture of anti‐adducts 4  pb⋅qb and syn‐adducts 2  pb⋅qb. The product distribution depends strongly on the tether length, and 6‐membered ring formation with 1  q leads to a much lower product ratio of 4  qb to 2  qb. In addition, the replacement of the electron‐rich arylboronic acid 5  b by electron‐deficient 5  i also results in a decrease in anti/syn‐selectivity. An effect of the arylboronic acid on the product distribution was observed only in the arylative cyclization of isopropenyl‐substituted alkyne 1  p. It is also confirmed that the stereochemistry of both syn‐ and anti‐adducts 4  pi and 2  pi are retained when these exo‐alkene products are resubjected to the reaction conditions. Notably, the arylative cyclization of deuterium‐labeled substrate 1  p‐d with 5  i afforded anti‐adduct 4  pi‐d and syn‐adduct 2  pi‐d′ having the alkene almost retained and inversed, respectively. The isomerization of the deuterium‐labeled isopropenyl group in syn‐adduct 2  pi‐d′ suggests that the cyclization does not proceed through a carbopalladation pathway (see below). For the structure determination, exo‐dienes 4 were prepared by Rh(I)‐catalyzed syn‐selective alkenylative cyclization of aryl‐substituted alkyne‐aldehydes with styrylboronic acid (see Table S13 in the Supporting Information). ^[3]

Table 3.

Pd‐Catalyzed Arylative Cyclization of Conjugated Enyne‐Aldehydes 1  h‐q.

Next, our attention turned to sp‐hybridized carbon substituents. 1,3‐Diynes 1  r‐v were subjected to arylative cyclization (Table 4). Similar to alkenyl‐substituted substrates 1  h–o, diynes 1  r–u participated in the arylative cyclization with 5  b under Pd/PPh₃ catalysis to afford conjugated exo‐enyne products 4  rb–ub exclusively. Primary and secondary alkyl groups and aryl and alkenyl groups at the terminal sp‐hybridized carbon of the diyne are tolerated. Unfortunately, the silyl group in 1  v hampers the cyclization.

Table 4.

Pd‐Catalyzed Arylative Cyclization of Conjugated Diyne‐Aldehydes 1  r–v.

In contrast to 1,3‐enynes 1  h–m, the regiocontrol in the arylative cyclization of 1,3‐diynes 1  r‐v was accomplished by a choice of the phosphine ligand (Table 4). Substitution of PCy₃ for PPh₃ resulted in the exclusive formation of endocyclic products 3  rb–vb. The substituent at the terminal sp‐hybridized carbon of the 1,3‐diyne also affects the cyclization efficiency. Conjugated diyne 1  r with a primary alkyl group as substituent gives a higher yield than 1  s with a secondary alkyl substituent. In contrast to the cyclohexyl group, the structurally similar phenyl and 1‐cyclohexenyl groups act as more effective substituents for the cyclization. Interestingly, silyl‐substituted conjugated diyne 1  v also undergoes 6‐endo‐dig cyclization successfully in contrast to the 5‐exo‐dig cyclization. Notably, the product ratios in the Pd/PCyPh₂‐ and Pd/PCy₂Ph‐catalyzed cyclizations fall between those in the Pd/PPh₃‐ and Pd/PCy₃‐catalyzed ones (see Tables S15 and S16 in the Supporting Information). These observations indicate that the regioselectivity of the cyclization depends on the σ‐donating property of the phosphine ligands, which increases when a phenyl group of the phosphine ligand is replaced by a cyclohexyl group. ^[18]

As shown above, the regioselectivity in the arylative cyclization of 1,3‐diyne‐aldehydes 1  r–u can be changed by the choice of phosphine ligands, PPh₃ and PCy₃, whereas that for the alkyl‐substituted substrates 1  b–e depends on the substituents and cannot be controlled by a choice of the catalyst (Table 2). The regioselective arylative cyclization of 1  r followed by chemoselective hydrogenation of the internal alkyne in the presence of tetra‐substituted alkene provides an alternative way to prepare diversified products 3  db and 4  db (Scheme 2).

Scheme 2.

Regioselective Arylative Cyclization of Diyne 1  r Followed by Chemoselective Hydrogenation.

Cyclization of 4‐alkynals and 4‐alkynone

The arylative cyclization of 4‐alkynals and 4‐alkynone requires both the σ‐donating PCy₃ ligand and the sp²‐ or sp‐hybridized carbon substituent at the alkyne terminus (Table 5). ^[6b] o‐Ethynylbenzaldehyde 7  a bearing a phenyl group at the alkyne terminus reacts with electron‐rich 5  b and electron‐deficient 5  i equally. However, the less electrophilic acetophenone 7  b undergoes arylative cyclization with 5  b and 5  i to afford 8  bb and 8  bi in 85 % and 32 % yields, respectively. Gratifyingly, use of neopentyl glycol ester 5  i′ instead of 5  i dramatically improves the yields of 8  bi. The aromatic tether in 4‐alkynals 7  a is not necessary for arylative cyclization.

Table 5.

Arylative Cyclization of 4‐Alkynals and 4‐Alkynone 7  a–c.

It was also observed in the arylative cyclization of endo‐type iminium ion leading to the formation of N‐alkyl‐4‐aryl‐1,2,3,6‐tetrahydropyridines that electron‐rich 5  b participated in the cyclization much more effectively than electron‐poor 5  i. ^[6c] The above‐mentioned experimental results suggest that the inferior behavior of electron‐deficient arylboronic acids would stem from a reduction in the concentration of active catalyst species LnPd(0), which can undergo oxidative addition of their acidic O−H bond (see Tables S18 and S19 in the Supporting Information). ^[19] To the best of our knowledge, there is no report of oxidative addition of the O−H bond in an arylboronic acid to Pd(0), but this could rationalize the (hydrido)palladium‐mediated hydroarylation of alkynes in the absence of an acid catalyst ^[13] (see Table 1, 6  aa).

As shown in Table 3, alkenyl substituents at C‐6 of 5‐alkynals enhanced the carbon‐carbon bond formation between the internal alkyne carbon and aldehydes. We expected the arylative cyclization of 4‐alkynal would also be accelerated by introduction of a conjugated alkenyl group into a tether moiety. The cyclization of 1,3‐enyne 9 with a deactivating alkyl group at C‐4 proceeded upon heating at 100 °C under Pd/PCy₃ catalysis to give dienyl alcohol 10 in a moderate yield (Scheme 3).

Scheme 3.

Arylative Cyclization of 5‐Alkyl‐4‐Alkynal 9 Tethered by Conjugated Alkene.

Scope and limitations of electrophiles

A three‐component coupling reaction between an enolizable 5‐alkynal, an arylboronic acid, and a secondary aliphatic amine is also feasible. For the successful three‐component reaction, it is necessary to avoid direct cyclization without participation of the amine component. Use of an aprotic solvent such as DMF instead of methanol results in the exclusive formation of allylamines ^[6b] (Scheme 4). Phosphine ligands also affect the product yields in the coupling reaction, with PCy₂Ph leading to the best yield of endocyclic allylic amine 11  a–e (see Table S9 in the Supporting Information). Both cyclic and acyclic amines participate in the reaction with 1  w and 5  b. 1,3‐Enyne‐aldehyde 1  k with an ether tether is successfully converted to the exocyclic allylic amine S8 (see Supporting Information). The prenyl groups in 11  e can be removed without affecting the endocyclic allylic amine moiety, in the presence of stoichiometric 1,3,5‐trimethylbarbituric acid and catalytic Pd(PPh₃)₄ in methanolic solvent, ^[20] to afford primary amine 11  f (see Supporting Information).

Scheme 4.

Three‐Component Coupling Reactions.

In addition to the substituents at the alkyne terminus, a ketone as an electrophile significantly affected the product distribution in the arylative cyclization in Pd/PCy₃ catalysis; however, it did not affect the product distribution in the arylative cyclization in Pd/PPh₃ catalysis ^[6a] (Scheme 5 and Table S17 in the Supporting Information). The substitution of the aldehyde 1  a by methyl‐ and phenyl ketones 1  x and 1  y in the arylative cyclization improves the ratio of 4 to 3, with the latter ketone leading to a ratio of 30 to 1.

Scheme 5.

Pd/PCy₃‐Catalyzed Arylative Cyclization of Alkynyl Ketones 1  x⋅y.

An α,β‐unsaturated carbonyl group can also be employed as the electrophile (Scheme 6). While C3‐tethered substrate 12  a undergoes syn‐selective arylative cyclization (Scheme 6, left arrow) as reported previously, ^[12] C2‐tethered 12  b with an electron‐withdrawing aryl substituent at the alkyne terminus is successfully converted to anti‐adduct 14 (Scheme 6, right arrow). Like dibenzylideneacetone, the electron‐deficient alkenyl moiety in 12  a coordinates phosphine‐ligated Pd(0) and forms a palladacycle with the adjacent alkyne to construct a five‐membered ring in 13. In contrast, substrate 12  b with a short tether undergoes “anti‐Wacker”‐type cyclization instead of palladacycle formation, because a four‐membered ring is difficult to construct. Notably, the electron‐deficient p‐acetylphenyl group in 12  b works as an effective directing group under Pd/PCy₃ catalysis.

Scheme 6.

syn‐ and anti‐Selective Arylative Cyclizations of Alkyne‐Enones 12  a⋅b.

The regio‐ and stereoselectivity of the cyclization affected by electrophile moieties (Schemes 5 and 6) also supports the “anti‐Wacker”‐type cyclization rather than formal anti‐carbometalation.

Exclusion of formal anti‐carbopalladation pathway

o‐Formylphenylboronic acid acts as an appropriate probe to determine whether the anti‐selective arylative cyclization derives from formal anti‐carbometalation. Lam′s group reported that Ni(II)‐catalyzed coupling between an alkyne and the boronic acid furnished an indenol, which is a product of the syn‐carbonickelation of the alkyne followed by cyclization. ^[5]

The Pd(0)/monophosphine‐catalyzed cyclization of 1  a with o‐formylphenylboronic acid (5  o) furnished anti‐adduct 3  ao in high yield (Scheme 7, right arrow). If carbometalation of the alkyne operates in the arylative cyclization, an initially formed alkenylpalladium intermediate can undergo nucleophilic addition to the adjacent aromatic aldehyde prior to the cis‐trans isomerization. Diphosphine‐ligated Pd(II), which catalyzes [3+2] annulations between o‐formylphenylboronic acid and alkynes to afford indenols through transmetalation with 5  o and subsequent carbopalladation of alkynes, ^[21] actually transformed 1  a into indenol 15, not 3  ao (Scheme 7, left arrow). In contrast, the Pd(II) catalyst ligated with PPh₃ promoted not cyclization but hydroarylation of 1  a to give 6  ao (Scheme 7, down arrow). ^[22] These experimental results support that formal anti‐carbometalation similar to what occurs in Ni(II) catalysis ^[5] is not involved in our Pd(0)‐catalyzed cyclization.

Scheme 7.

Pd(0)‐ and Pd(II)‐Catalyzed Arylative Cyclizations of 1  a with 5  o.

Cyclization without organometallic reagents

The remaining question of interest in the reaction mechanism is whether or not organometallic reagents cooperate with the Pd catalyst to promote the cyclization step of the catalytic cycle. The cyclization reaction in the absence of an organometallic reagent was therefore examined. In methanol, the cyclization should afford a (methoxo)palladium intermediate, which would be reluctant to undergo reductive elimination before or after β‐hydrogen elimination.[ ²³ , ²⁴ ] To promote the reductive elimination, the cyclization reaction was performed in a carbon monoxide atmosphere ^[25] to afford methoxycarbonyl product 18 in moderate yield (Scheme 8). This result indicates that organometallic reagents are not involved in the cyclization step.

Scheme 8.

Methoxycarbonylative Cyclization of 1  l.

Cyclization with organometallics other than organoboron reagents

To expand the scope of carbonucleophiles, introduction of other organometallics was explored. Because methylborane is not commercially available and cannot be prepared by hydroboration of an alkene, methylzinc was chosen as the nucleophile. It is necessary to develop alternative reaction conditions owing to the susceptibility of the methylzinc reagent to methanolysis. We assumed that a Lewis acid, which not only activates the carbonyl group but also produces a counter anion appropriate for transmetalation with methylzinc, could be used in place of methanol. According to the reaction conditions for cross‐coupling reactions, including Suzuki‐Miyaura, ^[26] Negishi, ^[27] and Stille, ^[28] organometallic reagents have their own favorite counter anions for transmetalation with organopalladium(II). Although the less nucleophilic boron requires an alkoxo ligand for transmetalation, zinc and tin reagents favor halogens as the ligand for Pd(II). ^[29] As expected, a stoichiometric amount of chlorotrimethylsilane in THF promotes the methylative cyclization of alkyne‐aldehyde 1  a with dimethylzinc to afford 3  ap along with its trimethylsilyl ether 3  ap′ (Table 6). ^[30]

Table 6.

Cyclization of 1  a with Organo‐Zinc, ‐Tin, and ‐Copper Reagents.

Finally, an sp‐hybridized carbonucleophile was tested. Alkynylboron reagents are not compatible with a methanolic solvent because of its tendency to cause protodeboration. ^[31] In contrast, alkynylzinc undergoes competitive 1,2‐addition in an aprotic solvent. ^[32] Use of an alkynyltin reagent and chlorotrimethylsilane solved the problem and successfully converted 1  a to 3  aq (Table 6). ^[33]

According to the Sonogashira coupling reaction, ^[34] alkynylmetal species can be generated in situ from terminal alkynes and a catalytic amount of a copper(I) salt. We expected this combination could substitute for a stoichiometric amount of the alkynyltin reagent. The alkynylcopper species, generated in situ from a combination of an excess of phenylacetylene and a catalytic amount of CuI, is compatible with methanol and converts 1  a to conjugated enyne 3  aq effectively (Table 6). N‐Tosyl‐o‐ethynylaniline also participates in the alkynylative cyclization of 1  a to give indole 3  ar via well‐established 5‐endo‐dig cyclization. ^[35] It is important for the alkynylative cyclization of 1  a to utilize a relatively acidic aryl acetylene, because 1  a is a terminal alkyne itself.

Plausible reaction mechanism

A plausible mechanism for the arylative‐ and alkylative‐ cyclizations of alkynals 1 with organoboron reagents 5 starts with a novel nucleophilic attack by the electron‐rich Pd(0)/monophosphine complex on the electrophile across the alkyne (i. e., “anti‐Wacker”‐type oxidative addition) (Scheme 9).[ ⁶ , ¹¹ ] The nucleophilic attack would proceed via a palladacyclopropene intermediate formed by coordination of the alkyne to the palladium(0) complex. Carbonyl electrophiles also need to be activated by a hydrogen‐bonding interaction with a methanolic solvent, which forms alkenyl(methoxo)palladium(II) intermediates 19 and/or 20. Subsequent transmetalation with organoboron reagents produces diorganopalladium complexes 21 and/or 22. Reductive elimination then gives 3 and/or 4 and the Pd(0) complex. Methanol used as the solvent can also protect boronic acid in the form of methyl boronate to prevent hydroarylation. ^[36] An alkynylcopper species generated in situ from terminal alkynes and a catalytic amount of CuI also act as an sp‐hybridized carbonucleophile. A Lewis acid can also activate carbonyl electrophiles in an aprotic solvent and give its counter anion to the alkenylpalladium(II) intermediates. Use of chlorotrimethylsilane in an aprotic solvent gives chloride as the anionic ligand, which should be appropriate for transmetalation with methylzinc and alkynyltin reagents. Iminium ions generated in situ from aldehydes and secondary amines are more electrophilic than the parent aldehydes ^[37] and do not need further activation. Hydroxide as a counter anion of the iminium ions can act as the anionic ligand to Pd(II) to promote transmetalation with organoboron reagents.

Scheme 9.

Plausible Mechanism for Arylative‐ and Alkylative Cyclizations of Alkyne‐Aldehyde 1 Leading to anti‐Adducts 3 and 4.

PPh₃‐ligated palladium(0) catalyzes the alkylative cyclization of terminal alkyne‐carbonyls to provide endocyclic products 3 (R=H) exclusively (Table 1). The formation of 3 requires nucleophilic attack of the Pd catalyst at the hindered internal alkyne carbon. Previously, we assumed that addition of the less nucleophilic Pd(0) with the less σ‐donating PPh₃ ligand to the internal alkyne carbon of 1 would require activation of the alkyne by overlap of its π‐system with the carbonyl π*‐orbital, leading to Markovnikov‐type selectivity (Figure 1, A). ^[38] However, this electronic rationale cannot explain why cyclization was not observed for alkyl‐substituted alkyne‐aldehydes under the same conditions. The cyclization step consists of the simultaneous formation of carbon‐carbon and carbon‐palladium bonds. The regioselectivity should result from steric repulsion in the formation of the carbon‐carbon bond between the alkyne carbon and carbonyl electrophile, rather than from steric repulsion in the formation of the carbon‐Pd bond. The less nucleophilic PPh₃‐ligated palladium can promote carbon‐carbon bond formation between the unsubstituted terminal alkyne carbon and the carbonyl electrophile to minimize the steric repulsion occurring in the cyclization step (Figure 1, B).

Figure 1.

Regioselectivities of “Anti‐Wacker”‐Type Cyclizations under Pd/PPh₃ Catalysis.

In contrast, an alkenyl substituent at the alkyne terminus enables sterically unfavored carbon‐carbon bond formation between the internal alkyne carbon and aldehyde to give exocyclic products 4 exclusively (Table 3). Except for isopropenyl‐substituted substrates, the anti‐selective addition and the geometry of the alkenyl group are retained in the cyclization. The successful cyclization of substrates with a long and flexible tether also indicates that the alkenyl group enhances the cyclization. The alkenyl substituent can interact with PPh₃‐ligated palladium(0) and undergo its back donation to enhance and guide the regioselective cyclization (Figure 1, C). Related regioselectivity and enhanced reactivity were also reported for Ni(0)‐ and Rh(I)‐catalyzed reductive couplings between 1,3‐enynes and aldehydes, but the couplings proceeded in a syn fashion, which is different from the stereoselectivity of the Pd(0)‐catalyzed cyclization.[ ³⁹ , ⁴⁰ ] The formation of minor syn‐adduct 2  pi‐d′ with the inversed alkene geometry from isopropenyl‐substituted alkyne‐aldehyde 1  p‐d (Table 3) can be mediated by exo‐alkylidene‐π‐allylpalladium(II) ^[41] through π‐σ‐π isomerization (see Scheme S1 in the Supporting Information).

Like the π‐electrons of the conjugated alkenyl group, those of the conjugated alkynyl group also assists the regioselective arylative cyclization under Pd/PPh₃ catalysis, leading to the exclusive formation of exocyclic products 4 (Table 3 and Figure 1, D). Moreover, although the stereoselectivity is different, related regioselectivity for the Rh(I)‐catalyzed reductive coupling between 1,3‐diynes and aldehydes under hydrogen was reported by Krische. ^[42] It was also reported that silyl‐substituted 1,3‐diynes underwent regioselective coupling, wherein the sp‐hybridized carbons in positions α‐ and β‐ to the silyl group are connected to the aldehyde and hydrogen, respectively, via oxarhodacycle(III) formation. In our cyclization, the silyl group at the diyne terminus does not promote the cyclization, in contrast to alkyl‐, alkenyl‐, or aryl substituents in that position. The ¹³C NMR chemical shift of the β‐carbon to the silyl group is located at 87 ppm, while the chemical shifts of the carbon atom in the same position β to other substituents are located between 64 and 71 ppm (see Table S1 in the Supporting Information). A d_π‐p_π or π‐σ* interaction in the alkynylsilane ^[43] moves the chemical shift downfield and guides the nucleophilic attack of Pd(0) to the electron‐deficient β‐carbon rather than the α‐carbon, resulting in failure of the cyclization.

Alkyl and aryl substituents at the alkyne terminus completely hinder the cyclization under Pd/PPh₃ catalysis. These substituents not only generate the steric repulsion in the cyclization but also have no π‐electrons able to interact with Pd(0).

However, the use of PCy₃ as the ligand restores the reactivity to afford a mixture of 3 and 4 (Table 2). Pd(0) with the more σ‐donating PCy₃ ligand should be sufficiently nucleophilic to form carbon‐carbon bonds between the substituted alkyne carbons and the carbonyl electrophile. In the cyclization of highly reactive alkynyl aldehydes, the product distribution depends on the regioselectivity of the nucleophilic attack of the Pd/PCy₃ rather than on carbon‐carbon bond formation in the cyclization step. The carbon‐palladium bond formation occurs at the less hindered alkyne carbon (Figure 2, A and B). A longer primary alkyl chain or a branched alkyl group at the alkyne terminus leads to a higher ratio of 3 to 4 under Pd/PCy₃ catalysis (Figure 2, B).

Figure 2.

Regioselectivities of “Anti‐Wacker”‐Type Cyclizations under Pd/PCy₃ Catalysis.

Instead of alkyl groups, sp²‐hybridized aryl and sp‐hybridized alkynyl substituents at the alkyne terminus enhance the cyclization and guide the nucleophilic attack of the Pd/PCy₃ complex to the β‐carbon to afford endocyclic products 3 (Tables 2, 4 and Figure 2, C). The aryl group also activates the arylative cyclization of 4‐alkynals to afford 3‐aryl‐2‐cyclopenten‐1‐ol derivatives (Table 5). It is noteworthy that the cyclization mode of 1,3‐diynes can be controlled by the phosphine ligands (Table 4). Both the π‐electron‐donating property and electron‐withdrawing property of the sp‐hybridized alkynyl substituent would make this possible. Although π‐σ* interaction in the alkynylsilane leads to no cyclization under Pd/PPh₃ catalysis, it favors the nucleophilic addition of Pd/PCy₃ to the δ‐position to the silyl group, leading to successful cyclization.

In contrast to the alkynyl group, the cyclization mode of alkenyl‐substituted alkyne‐aldehydes depends on the number of substituents on the alkene moiety (Table 3). As with Pd/PPh₃ catalysis, PCy₃‐ligated palladium catalyzes the arylative cyclization of disubstituted alkenes to give exocyclic products 4 (Figure 2, D). In contrast, trisubstituted alkenes resemble the aryl group in guiding the nucleophilic attack of PCy₃‐ligated palladium (Figure 2, C). The trisubstituents would hamper coordination with the sterically demanding Pd/PCy₃ complex. In addition to alkyne substituents, ketones instead of aldehydes also affect the cyclization mode under Pd/PCy₃ catalysis, probably because of greater steric repulsion generated in endocyclic closure (Scheme 5 and Figure 2, E).

Conclusion

This study has uncovered anti‐selective, arylative, alkylative, and alkynylative cyclizations of alkynyl electrophiles in detail. The functional group compatibility, availability, stability, and non‐toxicity of the organoboron reagents, and the fact that no additives are needed, make the process highly practical. The cyclization reactions tolerate a wide variety of alkyne substituents, including hydrogen, alkyl, aryl, alkenyl, and alkynyl groups, although the product distribution depends on the substituents as well as on the phosphine ligands. It is noteworthy that regiocontrol in the cyclization of conjugated diyne‐aldehydes is accomplished by a choice of the phosphine ligand, with PPh₃ and PCy₃ leading to exo‐ and endo‐cyclic closures, respectively. The proposed mechanism, involving a novel oxidative addition without oxametallacycle formation, is different from that of the corresponding Ni(0)‐catalyzed reaction. The syn‐selectivity observed in the Pd(0)‐ as well as Ni(0)‐catalyzed cyclizations of alkynyl‐enones indicates that the carbon‐oxygen double bond forms a complex with Ni(0) but not with Pd(0). Neither a formal anti‐carbometalation pathway similar to that in the Ni(II) catalysis nor cyclization by the cooperation of organometallics and catalysts is consistent with the observation of methoxycarbonylative cyclization in the absence of organometallics. We also found that the slow reaction rates and low product yields observed with electron‐deficient arylboronic acids were overcome by use of their neopentyl glycol esters. Instead of the organoboron reagents and in situ generated alkynylcopper species, organo‐zinc and ‐tin reagents also participate in the cyclization with the aid of chlorotrimethylsilane in an aprotic solvent. A computational study on the proposed reaction mechanism, and development of the asymmetric cyclization under cocatalysis of the Pd and organic molecules, are underway.

Experimental Section

Full experimental details and characterization data for all compounds are included in the Supporting Information.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

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Supporting Information

Tsukamoto H., Ito K., Ueno T., Shiraishi M., Kondo Y., Doi T., Chem. Eur. J. 2023, 29, e202203068.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.