Recent Advances in Transition-Metal-Catalyzed

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Recent Advances in Transition-Metal-Catalyzed [2+2+2]-Cyclo(co)trimerization Reactions review

Daniël L. J. Broere, Eelco Ruijter* Transition-Metal-Catalyzed [2+2+2] Cyclo(co)trimerizations

Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines & Systems (AIMMS), VU University Amsterdam, de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands Fax +31(20)5987488; E-mail: [email protected] Received: 18.04.2012; Accepted after revision: 24.05.2012

1

Introduction

2

Synthesis of Benzene Derivatives

2.1

Mechanistic Insight

2.2

Regioselectivity

1

Introduction

Transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions have become a powerful synthetic tool to form highly functionalized cyclic frameworks in a single step with optimal atom-efficiency. After Bertholet’s discovery of the thermal cyclotrimerization of acetylene to form benzene in 1866,1 research in the field remained dormant for nearly a century. Even though the reaction is highly exothermic (∆H = –594 kJ·mol–1), high temperatures were required because of entropic and kinetic considerations. Moreover, the reaction was troubled by low product yields and formation of many side products.2 In 1948, Reppe and Schweckendieck discovered that transition metals could catalyze [2+2+2]-cyclotrimerization reactions of alkynes towards substituted benzenes (Scheme 1).3 This discovery paved the way for an alternative methodology to synthesize polysubstituted benzenes. Since then, the substrate scope of transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions has expanded significantly, making it applicable for the synthesis of substituted pyridines, pyridones, indolizidines and various other cyclic molecules.

2.3

Synthesis of Chiral Systems

2.4

Other [2+2+2] Approaches

2.5

Synthesis of (Iso)quinolines

3

Synthesis of Pyridine Derivatives

3.1

Mechanistic Insight

R3

3.2

Regioselectivity

3.3


Scheme 1 A transition-metal-catalyzed [2+2+2]-cyclotrimerization reaction towards substituted benzenes

4

Synthesis of Pyridone Derivatives

4.1

Mechanistic Insight

4.2

Regioselectivity

4.3


5

Applications

6

Future Directions

7

Conclusion

Key words: alkynes, cyclization, cycloaddition, homogeneous catalysis, transition metals

SYNTHESIS 2012, 44, 000A–00AH Advanced online publication: 09.08.20120039-78 1 437-210X DOI: 10.1055/s-0032-1316757; Art ID: SS-2012-E0363-R © Georg Thieme Verlag Stuttgart · New York

R1

R1 R2

[MLn] isomers R3

R2

Probably the most powerful aspect of transition-metalcatalyzed [2+2+2]-cyclotrimerization reactions has also proven to be their greatest weakness. The ability to create a large amount of structural diversity and complexity in a single reaction is accompanied by the possibility to form a large number of isomers. Fortunately, several advances have been made over the course of time to overcome this problem, making transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions a powerful alternative for functionalization of aromatic molecules via electrophilic and nucleophilic aromatic substitution reactions. A wide range of transition metals have been successfully employed as catalysts; moreover, by employing chiral transition-metal complexes it is possible to perform asymmetric transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions.

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Abstract: Transition-metal-catalyzed [2+2+2] cyclo(co)trimerization reactions are a powerful methodology to synthesize various complex multi-substituted (poly)cyclic molecules in a single step with optimal atom efficiency. Ever since the discovery, the reaction has been plagued by issues concerning regio- and chemoselectivity. Over the last decades many advances have been made to overcome these issues by, for example, employing regio-directing groups or tethering the reaction partners together in an intramolecular approach. These solutions, however, have certain limitations. Nowadays, it is also possible to synthesize chiral molecules by performing an asymmetric transition-metal-catalyzed [2+2+2]-cyclo(co)trimerization reaction. This review focuses on the recent advances in mechanistic insight, solving the regioselectivity issue, synthesis of chiral molecules and alternative approaches for the synthesis of substituted benzenes, pyridines and 2-pyridones. In addition, recent applications in areas such as total synthesis of natural products are also described, demonstrating that the transition-metalcatalyzed [2+2+2]-cyclo(co)trimerization reaction is a powerful tool and a welcome addition to the chemist’s ‘synthetic toolbox’.

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D. L. Broere, E. Ruijter

Over the past decades there has been a significant interest in the field, judging by the number of articles and reviews published. Reviews have focused on the synthesis of benzene derivatives,4 pyridine derivatives5 and natural product targets.6 The range of transition metals,7 applications2 and the stereo-/chemo-8 and enantioselectivity9 of [2+2+2]-cyclotrimerization reactions have also been the object of focus. The aim of this review is to cover recent advances in the field and provide useful references. The focus is on transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions towards benzenes, pyridines and 2-pyridones providing mechanistic insight, descriptions of recent advances and applications.10 Moreover, throughout the text there will be no clear distinction made between intermolecular, partially intramolecular and totally intramolecular [2+2+2]-cyclotrimerization reactions (Scheme 2).

description of this type of reaction. This name does not give an incorrect presumption on the mechanism and will therefore be used throughout this review.

2

While the cyclotrimerization of acetylene towards benzene is not particularly interesting apart from a mechanistic point of view, substituted benzenes are part of many drugs and other compounds encountered daily. The transition-metal-catalyzed [2+2+2]-cyclotrimerization reaction can be considered a highly efficient and atomeconomic method for the construction of substituted benzenes. In this section, recent advances in mechanistic insight, regioselectivity, chemoselectivity and synthesis of chiral systems are described.

2.1 intermolecular

partially intermolecular

fully intramolecular

Scheme 2 Three types of cyclotrimerization reactions of alkynes and tethered alkynes

Throughout the literature many different names are used for the type of reaction depicted in Scheme 1. Considering the most recent studies on the mechanistic aspects of the reaction, the name ‘transition-metal-catalyzed [2+2+2]cyclotrimerization reaction’ is probably the most accurate

Synthesis of Benzene Derivatives

Mechanistic Insight

Several density functional theory (DFT) calculations on the reaction mechanism of alkyne cyclotrimerization have been reported in the last decade. Resulting from these DFT calculations and isolation of intermediates, a generally accepted mechanism, depicted in Scheme 3, has been established. The mechanism starts with the substitution of two auxiliary ligands (e.g., CO, C2H4, cod or a phosphine) by two alkynes (II). Experimental and theoretical studies indicate that the substitution can be associative or dissociative, depending on the nature of the transition-metal complex. Oxidative coupling of the two coordinated alkynes results in the formation of a five-membered metallacycle. In all DFT studies to date, this step has been found to be rate-determining for the intermolecular reaction. The metallacycle has two resonance structures, namely a metallacyclopentadiene (IIIa) or a metallacyclopentatriene (IIIb) having a biscarbene structure. Which of the two

Biographical Sketches█

Synthesis 2012, 44, A–AH

Daniël L. J. Broere was born in 1988 in Woerden, The Netherlands. He studied chemistry at the HU University of Applied Sciences Utrecht, where he re-

ceived his bachelor’s degree with honors in 2010. He obtained his master’s degree cum laude in 2012 at the VU University Amsterdam. In May 2012, he started his

PhD research at the University of Amsterdam under the supervision of Prof. Joost Reek.

Eelco Ruijter was born in 1977 in Barsingerhorn, The Netherlands. He studied chemistry at the VU University Amsterdam, the Netherlands. He obtained his PhD in the group of L. A. Wessjohann at the VU University Amsterdam and the Institute

of Plant Biochemistry in Halle, Germany. In 2004, he joined the group of R. M. J. Liskamp at Utrecht University, as a postdoctoral fellow working on chemical proteomics. In December 2006, he was appointed assistant professor at the VU Univer-

sity Amsterdam. His research interests include the use of multicomponent and cascade reactions and novel catalytic reactions for the efficient construction of complex small molecules.

© Georg Thieme Verlag Stuttgart · New York


B

Transition-Metal-Catalyzed [2+2+2] Cyclo(co)trimerizations

resonance structures more accurately represents the actual metallacycle depends on the nature of the transition-metal complex. Coordination of an additional alkyne to metallacycle IV is followed by either: insertion, forming a planar homoaromatic metallacycloheptatriene (V) as proposed by Schore;11 [4+2] cycloaddition, forming 7-metallanorbornadiene VI; or [2+2] cycloaddition, forming compound VII. A final reductive elimination gives the arene VIII and the transition-metal complex. Actually, reductive elimination for intermediate VII is symmetry forbidden and proceeds via a seven-membered metallacycle. This is commonly not shown in the generally accepted mechanism, possibly to create some order in the scheme. Through which pathway the catalytic cycle proceeds can depend on the choice of substrate or transition-metal complex. It is very difficult to predict via which pathway a reaction will proceed because subtle changes in substrate, ligand or metal will affect the course of the reaction. A possible problem of the reaction is that the intermediates IIIa and IIIb can undergo reductive elimination to form a very stable η4-bound cyclobutadiene species, which is a thermodynamic trap of the catalytic cycle. -L,

–L,

MLn+2

MLn+1

MLn

I

MLn

or

IIIa

II

MLn

MLn IV

IIIb

MLn MLn V

or

MLn

or VI

2 II

VII

VIII

Scheme 3 A schematic representation of the generally accepted reaction mechanism of the transition-metal-catalyzed [2+2+2]-cyclotrimerization reaction of alkynes, as commonly encountered in the literature

C

In 2009, Saá and Varela reviewed how a combination of experimental and computational methods was used to elucidate the mechanism of transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions.12 In this review, reactions catalyzed by CpRuCl and CpCo are described, showing how changes in metal, substrate or ligands affect the mechanism. For example, in the case of CpRuCl the mechanism proceeds via intermediate IIIb and VII. For CpCo-catalyzed reactions, the reaction proceeds via intermediate IIIa. However, the subsequent reaction can proceed via two pathways (Scheme 4, MLn = CpCo): (a) with strong sigma-donor solvents or ligands, the metallacyclopentadiene is trapped to give 18-electron complex IIIa′ which reacts in an intermolecular [4+2] cycloaddition with electron-poor alkynes to form intermediate VI; (b) in the absence of strong donor ligands or solvents, intermediate IV is formed which reacts in a metal-assisted intramolecular [4+2] cycloaddition with electron-poor alkynes to form intermediate IX in which a six-membered arene ring is coordinated in a η4 fashion to the metal. Based on these more recent studies, the generally accepted mechanism depicted in Scheme 3 is no longer complete because it does not consider the intermolecular [4+2]-cycloaddition pathway nor the η4 bound intermediate IX. Therefore, the possible mechanisms depicted in Scheme 4 are more suitable to show the possible pathways. Because some other recent studies are not covered in the above-mentioned review, these will be briefly discussed below. The first of these studies was reported by Bickelhaupt and co-workers who studied the cyclotrimerization reaction towards benzene catalyzed by rhodium(I) half-sandwich complexes.13 Using DFT calculations they showed that the rate-determining step is the formation of a coordinatively unsaturated 16-electron metallacycle which reacted in a fashion similar to pathway (b) for the CpCo analogue mentioned above. Solà and co-workers published a DFT study on the cyclotrimerization catalyzed by Wilkinson’s catalyst, RhCl(PPh3)3.14 Results similar to those reported by Bickelhaupt and colleagues regarding the mechanism

MLn+2

2

I

MLn+1

MLn+1

2

or V or VII

MLn +

+

MLn+1

MLn+1

IX

-L LnM

Ln+1M II'

LnM

II

IV

VI LnM

IIIb or

Ln+1M IIIa' LnM

IIIa

Scheme 4 The possible catalytic cycles for transition-metal-catalyzed [2+2+2] cyclotrimerization of alkynes © Georg Thieme Verlag Stuttgart · New York



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were found. The effect of substituting triphenylphosphine with phosphine as ligands, which reduces the computational cost by one order of magnitude, was also investigated showing no significant differences for the examined reaction. A comparison between the cyclotrimerization towards benzene and an earlier study was also made. In this study, cyclotrimerizations of 15-, 20- and 25-membered azamacrocycles (1) catalyzed by Wilkinson’s catalyst (Scheme 5) were studied experimentally and theoretically with DFT calculations.15 In contrast to the 15- and 25-membered azamacrocycle 1 (n = 1 and 3, respectively) which yielded the expected product, the 20membered azamacrocycle 2 (n = 2) only yielded decomposition products and starting materials. DFT calculations showed this was the result of a large kinetic barrier due to formation of a strained ten-membered ring and a more stable delocalized HOMO of the azamacrocycle.

of the second step. Although it was not mentioned by the authors, the reaction could also proceed via an alternative mechanistic pathway due to the change in substrate.

2.2

After the discovery of transtition-metal-catalyzed [2+2+2]-cyclotrimerization reactions, the synthesis of substituted arenes was initially limited to alkyne homocyclotrimerization (use of a single alkyne). In these reactions only two possible isomers can form, namely the 1,3,5-isomer 7 and the 1,2,4-isomer 8 (Scheme 7). Attempts to prepare substituted benzenes via alkyne heterotrimerization (using two or more different alkynes) were troubled by the formation of complex mixtures due to many possible products. Full product selectivity is hard to achieve because it is difficult to control both the chemoselectivity in the initial formation of the five-membered metallacycle and the subsequent regioselective addition or insertion of the third alkyne. The use of stoichiometric amounts of transition-metal complexes has been successfully demonstrated to overcome the problem formation of several metallacycles by addition of the third alkyne at the end.17 This solution, however, is not applicable in a catalytic system for obvious reasons and is beyond the scope of this review.

SO2Ar ArO2S

N

N

N

SO2Ar

SO2Ar N

[RhCl(PPh3)3] N ArO2S

N SO2Ar

n–1

N n

SO2Ar

1

Regioselectivity

2

Scheme 5 Cyclotrimerization of azamacrocycles by Wilkinson’s catalyst. n = 1, 2 or 3.

R1

In contrast with all the theoretical studies on intermolecular cyclotrimerizations, Jutand and colleagues found that for a partial intermolecular [2+2+2] cyclotrimerization reaction with unhindered diynes (3, R = H), the rate-determining step was not the oxidative coupling to form the rhodacyclopentadiene.16 Kinetic data from electrochemical experiments, on the reaction depicted in Scheme 6, showed that the rate-determining step of the reaction with unhindered diyne 3 was the reaction of rhodacyclopentadiene 4 with monoalkyne 5 to form the product (6) with subsequent recovery of the catalyst. However, when the nitrogen atoms in diyne 3 were substituted with a Boc group, the oxidative coupling to form rhodacyclopentadiene 4 was shown to be rate-determining. The explanation for the results was that the additional bulk would promote dissociation of a phosphine ligand necessary for coordination of the monoalkyne, thus lowering the kinetic barrier

R1

R1

R1

[MLn]

R1

R1

R1

R1

R1 [MLn]

R2

isomers R3

R3

Several other strategies to control the substitution pattern of the product in a catalytic system have been reported. Nowadays, the most common and easiest way to gain full control of the substitution pattern in the product is achieved by tethering the three alkynes in a fully intramolecular approach (Scheme 2). In such a system often only a single isomer is possible as a result of highly strained alSO2Ar

ArO2S N

N HO

[RhCl(PPh3)3]

R

5

OH ArO2S N

RhCl(PPh3)2

CH2OH

N SO2Ar

PPh3 ArO2S N

[RhCl(PPh3)3]

N

R

SO2Ar

R 3

R CH2OH

PPh3 ArO2S N

R

R2

Scheme 7 Possible regioisomers that can form for alkyne homotrimerization (top) and alkyne heterotrimerization (bottom)

R N

R1 8

7

ArO2S N

SO2Ar

R1

4

6

Scheme 6 A partially intermolecular cyclotrimerization catalyzed by Wilkinson’s catalyst. R = H or Boc. Synthesis 2012, 44, A–AH



D

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E

Transition-Metal-Catalyzed [2+2+2] Cyclo(co)trimerizations RO R1

B

9

RO

RO 10

R1

RO R1

B

[Cp*RuCl(cod)]

Cp* Ru Cl

B

O

O

HO R2

O

11

12

R1

RO Pd cat.

O

CO

13

R1

R1

R2

47–73% 15

Ar

Pd cat.

B O R2

ArI

HO

R2 53–76%

14

16

ternative isomers. Tethering two alkynes in a partially intermolecular approach often reduces the number of possible metallacycle intermediates to one. This is due to the favored formation of one metallacycle by geometrical and entropic restrictions induced by the tether, similar to the ‘chelate effect’. In addition, the tether is often substituted, further enhancing formation of a favored metallacycle by the Thorpe–Ingold effect. The two latter strategies can be considered to be very powerful based on their dominance in applications of transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions (section 5). However, a limitation of these two methods is the inevitable formation of one or two secondary fused rings, which is not always desired. In the past decades the goals of most studies have been to achieve regioselective intermolecular alkyne cyclotrimerization catalytically, or to avoid forming the secondary fused ring. In 2009, an excellent highlight by Rovis and Galan focused on the latter which will therefore not be discussed extensively here.8b However, some examples described in that review as well as more recent ones will be briefly discussed. An ingenious example of a partially intermolecular approach that avoids the secondary fused ring in the final product was reported by Itoh and co-workers (Scheme 8).18 By treating an alkynyl borate 9 in situ with propargyl alcohol (10), a temporary boron-tethered diyne 12 was formed. The tethered intermediate subsequently reacted with a ruthenium catalyst to form boraruthenacycle 13. Complete regioselective insertion to give arylboronate 14 was, based on DFT calculations, attributed to the steric and electronic directing effect of the unsymmetrical boraruthenacycle 13. The arylboronate 14, not isolated because of its sensitivity towards hydrolysis, successfully underwent functionalization by Suzuki–Miyaura cross coupling or palladium-catalyzed carbonylation to give biaryls (16)18a or phthalides (15),18b respectively. With this reaction, an equivalent of a completely regioselective intermolecular cyclotrimerization is achieved, tolerating a variety of substrates. The approach above, though ingenious, suffers from the limitation of requiring a covalent linkage. Success in in© Georg Thieme Verlag Stuttgart · New York

termolecular hetero-cyclotrimerizations is limited. Therefore, developments regarding intermolecular cyclotrimerization reactions mainly concern regioselective alkyne homo-cyclotrimerization reactions. The two possible isomers that can be formed in such a reaction are the 1,2,4-substituted benzene and the 1,3,5-substituted benzene. The 1,3,5-isomer could be considered the least sterically hindered but is often the minor product. The rationale behind this is evident from the possible metallacycle intermediates depicted in Scheme 9. Three possible metallacycles can be formed but only one gives access to the 1,3,5-isomer, while all three can lead to the formation of the 1,2,4-isomer. R M

R R

R R 2

only R

R

M R R

R

R

R and

M R R

R

R

Scheme 9 The origin of the 1,2,4- and 1,3,5-isomers in alkyne homotrimerization

Two models for the regioselectivity for the formation of the metallacycle, depicted in Scheme 10, have been proposed that provide more insight into metallacycle formation. The model proposed by Stockis and Hoffman, based on calculations and correlations with experimental data, states that the oxidative coupling preferably occurs with the largest LUMO coefficients of the alkyne β to the metal.19 This is due to enhanced mixing of the π* with a metal d-orbital. The second model, proposed by Wakatsuki, Yamazaki and co-workers, is based on observations and calculations on CoCp complexes. In their model, sterics determine the major product favoring the bulkiest substit-



Scheme 8 A highly regioselective cyclotrimerization reaction employing a temporary boron tether. R1 = Me, n-Bu, CH2OMe or (CH2)3Cl; R2 = n-Bu, CH2OMe, (CH2)3Cl or (CH2)3CO2Me.

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uents to be either both α or α and β to the metal to minimize steric interaction between the substituents.20 These models, however, are best applicable for alkyne (homo-) cyclotrimerizations or in stepwise processes using stoichiometric amounts of transition metals and are scarcely used in recent literature. Stockis–Hoffmann model EWG δ+ EWG

R

R

R

Et

R 17

R

R

18

a R = Ph b R = tBu

EWG

M

EWG

δ+ EWG

EWG

EWG

Wakatsuki–Yamazaki model L s L

L

Cp Co

L s

s

L

s

s s

s L s

s Cp Co

Cp Co

Cp Co

s Cp Co

Cp Co L

R

Et

19 R = Ph 7:93 R = tBu 95:5

EWG M

s

cat.

Et ArO Ti ArO Et

L

L

s

L

L

L

Cp Co

L

L

s

R E

R [Ir(cod)Cl]2 + L

L s

Scheme 10 Two models to predict the regioselectivity in metallacycle formation proposed by Stockis and Hoffman (top) and Wakatsuki and Yamazaki (bottom). Scheme graphics are based on graphical illustration in ref. 74g.

The first regioselective transition-metal-catalyzed [2+2+2] cyclotrimerization was reported by Rothwell and co-workers in 1993 (Scheme 11).21 Treatment of a single unsymmetrical alkyne with a titanium catalyst (< 0.05 mol%) provided substituted benzenes in quantitative yield. Which regioisomer was the major product proved to be dependent on sterics. Upon treatment of 17a with the titanium complex, the 1,2,4-isomer 19 was formed as the major product. In contrast, cyclotrimerization of 17b resulted in formation of the less sterically hindered 1,3,5isomer 18 as the major product, albeit with increased temperature, reaction time and slightly higher catalyst loading.


An example where electronics determine the chemoselectivity was reported by Takeuchi and Nakaya, who studied a ligand-controlled chemoselective iridium-catalyzed [2+2+2] cyclotrimerization of an electron-deficient (20) and electron-rich alkyne (21).22 The reaction, depicted in Scheme 12, could be directed towards either 22 or 23 by varying the ligand. When 1,2-bis(diphenylphosphino)ethane (DPPE) was used as a ligand, solely 23 was obtained. In contrast, employment of the electron-deficient analogue of DPPE, 1,2-bis(dipentafluorophenylphosphino)ethane (DPFPPE), resulted in nearly perfect regioselectivity in favor of 22. The rationale behind these observations is that the electron-deficient iridium/DPFPPE complex prefers to coordinate electron-rich alkynes, such as 21, and subsequently undergoes metallacycle formation to eventually give 22. The opposite applies when DPPE is used, resulting in the formation of 23.

s L Cp Co

s

Scheme 11 A regioselective cyclotrimerization reaction dependent on sterics

96–98% E

R

20

21

E

E R

E

R

or E

R R 22

E

R E 23

L = DPFPPE 99:1 L = DPPE 0:100

Scheme 12 A ligand-controlled chemoselective iridium-catalyzed [2+2+2]-cyclotrimerization reaction. R = CH2OMe; E = CO2Me.

Another interesting example, where the regioselectivity could be affected by using different solvents with a certain ligand [1,2-bis(4-methoxyphenylthio)ethane], was reported by Hess and colleagues (Scheme 13).23 When the reaction was performed in acetonitrile, a strong preference for formation of the 1,2,4-isomer 26 was observed. In contrast, performing the reaction in dichloromethane provided the 1,3,5-isomer 25 as the major product. This indicates that the coordination ability of the solvent can have a significant influence on the regioselectivity of the reaction. The change in regioselectivity when dichloromethane was used as the solvent is thought to be due to a different geometrical conformation of the cobalt complex. The effect of using different disulfide ligands on the regioselectivity



F

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was also investigated, showing dependence in both the steric and electronic nature of the ligands. Computational studies towards the ligand and solvent dependence are said to be undertaken to gain more insight into the reaction.

1) n-BuLi (2 equiv) 2) I2 (1 equiv)

H R1 H

Li R1

3) [NiCl2(PPh3)2] 4) R2 R3

I

13–65%

G

28

27

n

Bu

2

Ph

S

S Co Br2

R

OMe

Ph

99%

N Cl

R1

Ph

Zn, ZnI2

3

Ni

R3

Ph

N

Ni

R2 Ph

24

Ph

29

R3

30

Ph 26

25 CH2Cl2: 86:14 4:96 MeCN:

Scheme 13 A solvent-controlled regioselective cobalt-catalyzed [2+2+2]-cyclotrimerization reaction

Carboryne (1,2-dehydro-ortho-carborane), a benzyne analogue derived from the cluster compound carborane (27) is an interesting molecule from a scientific point of view. Among other reactions, a nickel carboryne complex has been shown to react in a regioselective [2+2+2]-cyclotrimerization reaction with two equivalents of alkyne.24 This approach, however, required using stoichiometric amounts of the nickel complex. Recently, the same research group developed the first metal-catalyzed [2+2+2] cyclotrimerization of carboryne with alkynes (Scheme 14).25 Through treatment of carborane 27 with n-butyllithium and a single equivalent of iodine, the carboryne precursor was successfully prepared in the form of 1-iodo-2-lithiocarborane (28). Subsequently, a broad range of transition-metal complexes and reaction conditions were investigated. Only nickel complexes provided the desired product, with [NiCl2(PPh3)2] giving the best result. Under the optimized reaction conditions, a variety of asymmetric alkyne reaction partners afforded a wide range of products with excellent regioselectivity, albeit in moderate yields. The regioselectivity seemed to be dependent on the electronic nature of the alkyne.

nBu

Scheme 14 A nickel-catalyzed regioselective [2+2+2]-cyclotrimerization reaction with a carboryne. R1 = H, Cl or Ph; R2 = Et, n-Pr, nBu, Ph, CH2OMe, i-Pr, Me or C≡CPh; R3 = Et, n-Pr, n-Bu, Ph, CH2OMe, Me, 4-MeC6H4 or 4-F3CC6H4

A mechanism very different from that depicted in Scheme 4 was also proposed, based on the observed regioselectivity and the isolation of a key intermediate (30) with a fascinating crystal structure. Intermediate 30 was identified as a square planar nickelacycle containing the carboryne unit. In the proposed mechanism, the alkyne carbon with the largest LUMO coefficient ends up β to the metal as in the model19 by Stockis and Hofmann. Steric factors, however, seemed to have no effect on the regioselectivity and only affected the yield of the reaction. An example that also involves a reaction with a benzyne, and where sterics do play a major role in the metallacycle formation, has been reported by Guitián and co-workers.26 They reported a palladium-catalyzed [2+2+2] cyclotrimerization towards sterically congested polycyclic aromatic hydrocarbons (PAHs), depicted in Scheme 15. Because selective formation of 33 and 34 was observed, without observation of 35, the researchers concluded that there was a preference for the formation of palladacycle 32. In this palladacycle, an unfavorable steric interaction of the phenanthrene and triphenylphosphine ligands coordinated to the metal center is avoided. However, and although not mentioned by the authors, it can also be explained by initial formation of a metallacycle with two arynes according to the Wakatsuki–Yamazaki model20 (Scheme 10).

E E

E

E

E

E

DMAD Pd(PPh3)4

Pd(PPh3)2 E E

31

32

E = CO2Me

33

70:30

34

35 (not observed)

Scheme 15 A palladium-catalyzed [2+2+2]-cyclotrimerization reaction towards PAHs © Georg Thieme Verlag Stuttgart · New York



MeO

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When poor or no regioselectivity is observed, installation of a regiodirecting group can be helpful. Such a regiodirecting group can provide better regioselectivity induced by steric hindrance or by acting as a chelating group. Whichever is used, one of the possible intermediates is stabilized, thereby favoring the formation of one regioisomer. An example employing a regiodirecting group was reported by Deiters and co-workers in their study on microwave-assisted synthesis of phenanthridines 38 via transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions.27 The reported reaction, depicted in Scheme 16, is a partially intermolecular cyclotrimerization of diyne 36 and a terminal alkyne (37) promoted by Wilkinson’s catalyst. Initial attempts to achieve cyclotrimerization (R1 = R2 = H) resulted in high yields but no regioselectivity. Placing a methyl substituent as a regiodirecting group on the R2 position in diyne 36 resulted in an improvement in regioselectivity in favor of the 9-isomer. Inspired by the results, the authors placed a more sterically demanding TMS group on the R1 or R2 position. Unfortunately, with the TMS group on the R1 position, all attempted reactions failed. This was explained by a steric repulsion between the proton at the 1-position and the TMS group in both the metallacycle intermediate and the product. In contrast, when a TMS group was placed solely on the R2 position, the desired cyclotrimerization product was formed. In addition, a substantial increase in regioselectivity in favor of the 9-isomer was observed (80:20 → 95:5 compared with R2 = Me), albeit in lower yields. Another problem, encountered earlier by the same research group, was the lower reactivity of internal alkynes in cyclotrimerization reactions with diyne 36. The lower reactivity induced the diyne to undergo homocyclotrimerization, resulting in lower yields. Whereas the researchers solved this problem in an earlier study through spatial separation of the diyne on a polymer support,28 here, the slow addition of a solution of diyne 36 to the reaction mixture (using open-vessel microwave conditions) doubled the yield.

approach. Achieving complete regioselectivity for intermolecular reactions has remained elusive and may remain a challenge for years to come. A recent example of a lack of regioselectivity is found in the synthesis of multisubstituted fluoroalkylated aromatic compounds reported by Ishihara and colleagues.29 Nonetheless, the reported rhodium(I)-catalyzed reaction is an interesting example of broadening the substrate scope of transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions.

2.3


Synthesis of chiral systems via transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions can be achieved in the four ways depicted in Scheme 17: (A) with substrates containing chiral groups yielding a chiral product; (B) with sterically demanding prochiral substrates and a chiral catalyst providing chiral products; (C) with an achiral symmetrical substrate and chiral catalyst to obtain a chiral substrate by enantioselective desymmetrization; or (D) enantioselective synthesis of helicenes by using a chiral catalyst. Since the chirality is already present prior to the reaction in approach A, approaches B, C and D have received more attention in the recent literature and are powerful methods to introduce chirality during the reaction. Whereas approaches B and D have been discussed in, or have been the subject of, several reviews,5a,c,6,8a,9 approach C has only recently been reported. The focus in this section will be on recent examples of approaches B, C and D.

R*

A

R*

[MLn]

R1 R1 1

R R2

[MLn]*

R3 R1

R3

1

37

[RhCl(PPh3)4] N Ac

R2

36

R1

R1

2

R3

R

R1

9

R1

R1

1

R B

R1 R1

8

1

R3

R2 N Ac 38

R1

R2

[MLn]* C

R1

R2

Scheme 16 A partially intermolecular [2+2+2]-cyclotrimerization reaction towards phenanthridines. R1 = H or TMS; R2 = H, Me or TMS; R3 = Et, Bu, Ph, (CH2)3CN, (CH2)4Cl, CH2NHBoc, CH2OTBS, (CH2)2OTBS or (CH2)3OTBS

Several advances have been made to gain chemo- and regiocontrol in transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions. However, these all apply to very specific reactions. To say that full control over the regioselectivity has been demonstrated is only true for the fully intramolecular reactions. The partially intermolecular reactions are troubled by regioselectivity, but this can be solved by using regiodirecting groups or a temporary tether. The latter, however, is in fact a fully intramolecular Synthesis 2012, 44, A–AH

D

[MLn]*

Scheme 17 Four approaches to synthesize chiral systems via transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions © Georg Thieme Verlag Stuttgart · New York


H

Enantioselective synthesis of axially chiral biaryls, requiring an axially chiral biaryl ligand has been reported by Tanaka and co-workers (Scheme 18).30 They reported an enantioselective rhodium(I)-catalyzed [2+2+2]-doublecyclotrimerization reaction between internal 1,6-diynes 39 and a substituted buta-1,3-diyne 40 to give axially chiral biaryl diphosphonates and dicarboxylates 41. The best results were obtained when (R)-SEGPHOS was used as a ligand and three equivalents of 1,6-diyne 39 were used to obtain the products 41 with excellent enantiomeric excess and in moderate to good yields. The rhodium complex showed high activity, providing comparable yields when only 1 mol% was used. Furthermore, the reaction towards the axially chiral biaryl diphosphonate was also performed on a large scale (15.2 g of 1,3-diyne 40) affording the product in nearly identical yield and enantiomeric excess as compared to the smaller scale reaction. The products are of interest because they can be functionalized to give axially chiral ligands which can be employed in asymmetric catalysis, as was demonstrated in the reported reaction. A similar, but sequential, double cyclotrimerization was reported by Clegg and co-workers using a rhodium–BINAP complex as the catalyst.31 An advantage of this sequential approach is that it provides the possibility to prepare asymmetric axially chiral biaryls in high yields and excellent enantiomeric excess. An obvious disadvantage is that it requires an additional synthetic step. Z E

Me [Rh(cod)2]BF4 (R)-Segphos

Me 2

I


Z Me

54–81% yield 98–99% ee

Me

E

Me

E

high yield with excellent enantio- and diastereoselectivity. The latter was achieved by using a N,N-dialkylalkynylamide bearing an ortho-substituted phenyl group in the R2 position.

O

Me

O

[Rh(cod)2]BF4 (S)-BINAP or (S)-SEGPHOS

N

R1 R2

Me

Me 81–99% > 99% ee

R2 42

Me Z

43

44

Scheme 19 Rhodium-catalyzed synthesis of axially chiral 2,6-disubstituted N,N-dialkylbenzamides. Z = O, NTs or C(CO2Bn)2; R1 = Me, Et, i-Pr or R1–R1 = (CH2)4; R2 = t-Bu, C(Me)2OMe or n-Bu.

A rhodium-catalyzed partially intermolecular [2+2+2]cyclotrimerization reaction, also resulting in double asymmetric induction by a single catalyst, was reported by Hsung and co-workers (Scheme 20).33 By reacting achiral conjugated aryl ynamide 45 with diynes 46, in the presence of rhodium(I)–xylyl-BINAP, a series of chiral N,O-biaryls were obtained in moderate yields but with excellent enantiomeric excess. The diastereomeric excess, however, does need improvement. The authors also envisioned the reaction being used for the synthesis of chiral N,O-biaryl ligands by removing the 2-oxazolidinone ring. However, successfully obtaining a chiral ligand proved not viable, owing to carbon–nitrogen bond rotation which results in loss of chirality. O O

N

[Rh(cod)2]BF4 (S)-xylyl-BINAP

Me Z

41

Scheme 18 Enantioselective synthesis of axially chiral biaryls via a double cyclotrimerization reaction. Z = O, NTs or NSO2(4-BrC6H4); E = P(O)(OEt)2 or CO2Et.

Hindered bond rotation resulting in atropisomerism is not limited to 2,6-disubstituted biaryls. Due to a high rotational barrier of the aryl–carbonyl single bond, 2,6-disubsituted N,N-dialkylbenzamides 44 exist as atropisomers as well. In 2008, Tanaka and co-workers reported the first catalytic enantioselective synthesis of these compounds by a rhodium(I)-catalyzed partially intermolecular [2+2+2]-cyclotrimerization reaction (Scheme 19).32 By a reaction between 1,6-diynes 42 and N,N-dialkylalkynylamides 43 catalyzed by a rhodium–BINAP or SEGPHOS system, 2,6-disubsituted N,N-dialkylbenzamides 44 were obtained in high yields with excellent enantiomeric excess. Notably, when the terminal methyl groups in diyne 42 were absent, the corresponding product was obtained but it did not possess axial chirality. Furthermore, using the same methodology the researchers were able to introduce both aryl–carbonyl and aryl–aryl axial chirality in © Georg Thieme Verlag Stuttgart · New York

R1

Z

Z 40

N

Me

E 39

R1

R1

70–96% (combined) dr 8:1 to 3:1

Me Me

MeO

45

46

Z

Z Me O

Me O O

N

Me Me

MeO

47

O Me

N OMe

Me

48

Scheme 20 A rhodium-catalyzed [2+2+2] cyclotrimerization with double asymmetric induction. Z = CH2, O or C(CO2Me)2.

In 2009, Tanaka et al. reported a rhodium-catalyzed partially intermolecular double [2+2+2] cyclotrimerization towards [9]helicenes (51), which contain nine fused rings (Scheme 21).34 Captivating is the fact that five successive Synthesis 2012, 44, A–AH


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J

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rings are constructed in a single step by a reaction between tetrayne 49 and diyne 50. Moreover, helicenes containing more than seven rings are difficult to synthesize through non-photochemical methods, making this reaction all the more impressive. The yields and enantiomeric excess values were moderate, the best results being obtained using (R)-SEGPHOS as the chiral ligand. However, enantiomerically pure crystals of both enantiomers could readily be prepared by crystallization. Both their unique crystal structures and photophysical properties were determined.

O P 2

R

R1

R2

R2 [Rh(cod)2]BF4 (R)-BINAP

O

O

R3

52

16–53% yield 9–73% ee Z

R3

O

O

53

P

2 R1 R

R3

R3

O

O 54

R Me O

Scheme 22 Enantioselective rhodium-catalyzed synthesis of helical phosphafluorenes. R1 = Me, OMe or Ph; R2 = Me or Ph; R3 = H or Me.

Z

R

49

50

Me O

Z R

[Rh(cod)2]BF4 (R)-SEGPHOS

O 26–61% yield 10–60% ee R

O Z Me

51

Scheme 21 Enantioselective rhodium-catalyzed synthesis of [9]helicenes. R = Me, n-Bu, Ph or CH2OMe; Z = CH2 or CO.

More recently, the same research group reported the asymmetric synthesis of helical phosphafluorenes 54 by a rhodium-catalyzed double [2+2+2] cyclotrimerization of dialkynyl phosphorus compounds 52 and linked tetraynes 53 (Scheme 22).35 Helical phosphafluorenes are of interest as potential organic semiconducting materials. The synthesized compounds were analyzed by the same methods as the example mentioned above. Both the yields and enantiomeric excess values were moderate, as in the previous study. However, an interesting feature of the synthesized phosphafluorenes is their higher resistance to racemization compared to the above-mentioned example, owing to their higher helical stability. In agreement with the observations, the recorded crystal structures of the phosphafluorenes show more overlap of the terminal fused rings than in the example above.


In addition to axially or helically chiral ligands, P-stereogenic ligands have also been employed in asymmetric transition-metal-catalyzed reactions.36 An example of approach C (Scheme 17) has been reported by Tanaka and co-workers in their study of the enantioselective synthesis of P-stereogenic alkynyl phosphine oxides, depicted in Scheme 23.37 After Imamato et al. reported that P-stereogenic ligands bearing an alkynyl group induced excellent enantioselectivity in several transition-metal-catalyzed reactions,38 the authors set out to synthesize P-stereogenic alkynyl phosphine oxides via transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions. An initial attempt, in the form of a reaction between a diyne (55) and a symmetric dialkynylphosphine oxide (56) catalyzed by a rhodium–H8-BINAP system, afforded the corresponding Pstereogenic alkynylphosphine 57 in good yield by enantioselective desymmetrization. Because the enantioselectivity was moderate, various biaryl biphosphine ligands were screened. The best enantioselectivity was observed when (R)-dtbm-SEGPHOS, an extremely sterically demanding phosphine, was used as a ligand. With the optimized system, a broad range of P-stereogenic alkynyl phosphine oxides were prepared in good to quantitative yields with excellent enantiomeric excess. However, when 56 (R1 = n-Bu) was used, a dramatic decrease in yield and enantioselectivity was observed. Because it was the only substrate not bearing an aromatic ring, the unfavorable results could be caused by the absence of a π–π interaction between the substrate and the SEGPHOS ligand. The group also employed the same methodology using a C2H4-tethered dimer of phosphine oxide 56 (tether as R2). The corresponding C2H4-tethered bisphosphine oxide was obtained in quantitative yield as a mixture of diastereomers with moderate enantioselectivity. However, the authors were able to isolate one of the isomers in high enantiomeric excess by crystallization.



Me O

O

Me

P

R1

Me

56 OMe tBu

O P

Z

tBu

R1

tBu

O

R2

P

O

Me

OMe tBu t

O

Bu OMe

P

O

tBu

57

tBu

tBu

OMe

(R)-dtbm-SEGPHOS

Scheme 23 Enantioselective rhodium-catalyzed synthesis of P-stereogenic alkynyl phosphine oxides. Z = O, CH2, NTs or NSO2(4BrC6H4); R1 = Ph, 4-MeOC6H4, 4-F3CC6H4 or n-Bu; R2 = Me, Ph or t-Bu.

An interesting example, not fitting in any of the four approaches depicted in Scheme 17, was reported by Endo and co-workers who described an enantioselective intramolecular rhodium-catalyzed [2+2+2] cyclotrimerization towards chiral tripodal cage compounds (Scheme 24).39 The best results were obtained when a cationic rhodium– Me-DUPHOS catalyst was used; this afforded the cage compounds 59 in high yields and excellent enantiomeric excess. Initial experiments resulted in lower yields due to an undesired intermolecular reaction. This could easily be prevented by raising the reaction temperature and adding 58 slowly to the reaction mixture. Even with the longest tether, no racemization of the cage compound was observed. The best yields were obtained using isolated rhodium–Me-DUPHOS, instead of preparing it in situ. In contrast, when the authors attempted to synthesize a pyridine cage compound (R = Me), by substituting the top alkyne by a nitrile, using rhodium–Me-DUPHOS as the catalyst did not yield the desired product. Fortunately, a rhodium–BINAP catalyst did afford the product in 54% yield with, again, excellent enantiomeric excess. OMe

O

n

N

[Rh(cod) ((S,S)-MeDUPHOS)]OTf R 54–95% yield 98–99% ee R

58

O

R n

OMe

N R 59

Scheme 24 Enantioselective rhodium-catalyzed synthesis of chiral tripodal cage compounds. n = 2, 3, 4, 8; R = Me, Ph, 4-BrC6H4 or 4MeOC6H4.


Other [2+2+2] Approaches

As evident from the examples above, transition-metal-catalyzed [2+2+2] cyclotrimerizations of alkynes have been widely used for several purposes. Alternatively, instead of an alkyne it is also possible to use an alkene bearing a leaving group or a 1,3-dicarbonyl compound acting as an alkyne equivalent. Through these methodologies, the substrate scope is broadened to allow transformations not possible when using solely alkynes. These two methodologies will not be discussed in great detail but some recent examples will be briefly described to illustrate the possibilities.

71–99% 35–95% ee

R1 55

2.4

[Rh(cod)2]BF4 (R)-dtbmSEGPHOS

R2

Z

Me

K


In 2008, Tanaka and colleagues reported chemo- and regioselective [2+2+2]-cyclotrimerization reactions between alkynes and enol ethers (61) or enol acetates (65) catalyzed by a rhodium–BINAP complex.40 The main advantage of the reported substrates is that the liquid enol compounds were used as analogues for gaseous alkynes. As a result, the compounds were easier to handle and no additional equipment was necessary. The reactions, depicted in Scheme 25, proceed by way of a cyclohexadiene intermediate which subsequently undergoes aromatization by loss of an alcohol or acetic acid. The products were isolated as single regioisomers for both partially and fully intermolecular reactions in moderate to good yields. The observed regioselectivity was explained by sterically induced regioselective formation of a metallacycle followed by regioselective insertion induced by coordination of the carbonyl or ether functionality. R1 R1

R2

R3O

Z

[Rh(cod)2]BF4 rac-BINAP

R2 Z

Me 60

(– R3OH) 65–100%

61

62

R2

E R2

AcO

E

R4

63

64

[Rh(cod)2]BF4 rac-BINAP (– AcOH)

65

Me

41–84%

E E 4 66 R

Scheme 25 Rhodium-catalyzed [2+2+2]-cyclotrimerization reactions between alkynes and enol ethers or enol acetates. R1 = Me or CO2Me; R2 = H, Me or OMe; R3 = Me or n-Bu; R4 = n-C10H21, Cl(CH2)3, Bn, Ph, or TMS; E = CO2Me or CO2t-Bu; Z = O, NTs or C(CO2Me)2.

More recently, the same research group further demonstrated the methodology in the synthesis of fused benzofuran derivatives.41 The reactions were again performed with perfect regioselectivity, albeit in moderate yields. Tanaka and co-workers also reported a similar methodology utilizing a different leaving group.42 This was achieved via a decarboxylative [2+2+2] cyclotrimerization between tethered alkynes 67 and vinylene carbonate (68) using the same catalyst system (Scheme 26). An interesting feature of this reaction is that it employs com-



REVIEW

REVIEW


pound 68 as a synthetic equivalent of the unstable hydroxyacetylene.

Me O

O

[ReBr(CO)5] DMA, MS4A OEt

R

O

R

O

O

Z

Z R

Zhang and Louie extended this approach to the synthesis of anilines 71 using 2-oxazolone (70), which can be used as an alternative for ynamides (Scheme 27).43 They also demonstrated that the reaction proceeds with full regioselectivity when two different R groups are used (e.g., H, Me). The sole regioisomer formed has the amino group in the ortho-position with respect to the larger R group. R R

O

Z R 67

[Rh(cod)2]BF4 rac-BINAP

NH2 Z

– CO2 30–99%

O 70

R

71

Scheme 27 Decarboxylative [2+2+2]-cyclotrimerization reaction towards substituted anilines. R = H, Me, i-Pr or Ph; Z = O, NTs, CH2, C(CH2OMe)2, C(CH2OBn)2, C(CN)2, C(SO2Ph)2, CHCO2Me, C(CO2Me)2 or [C(CO2Et)2]2.

In 2008, both Nakamura44 and Takai45 and their co-workers stumbled upon an unexpected side product when investigating metal-catalyzed reactions between 1,3-dicarbonyl compounds (such as 72) and alkynes. Nakamura and co-workers observed the reaction when studying indium-catalyzed addition reactions and were quite brief about the process. They did, however, do a significant amount of work in uncovering the mechanism as can be found below. Takai and co-workers discovered the reaction when studying the effect of additives in the rhenium(I)-catalyzed addition of 1,3-dicarbonyl compounds to terminal acetylenes. They found that by adding a catalytic amount of N,N-dimethylacetamide (DMA) and molecular sieves, a tetrasubstituted aromatic compound (74) was formed by a transition-metal-catalyzed [2+2+2] cyclotrimerization with subsequent dehydration (Scheme 28). Further investigations into the reaction showed that the best results could be obtained using a manganese(I) complex, MnBr(CO)5, as the catalyst. Furthermore, with this system the addition of DMA was no longer necessary. Tetrasubstituted benzenes could be prepared regioselectively by changing the substituents on the β-keto ester. A broad variety of substrates proved to be suitable for the reaction. However, whereas aromatic alkynes resulted in the formation of a single regioisomer, aliphatic alkynes afforded a mixture of regioisomers.


73

Ph 74

69

Scheme 26 Decarboxylative [2+2+2]-cyclotrimerization reaction towards substituted benzenes. R = H, Me, Et or Ph; Z = O, NTs, NAc, (CH2)2, C(CH2OMe)2, CAc2, C(CO2Me)2 or [C(CO2Et)2]2.

H N

72

(– H2O) 50%

Scheme 28 Rhenium-catalyzed dehydrative [2+2+2]-cyclotrimerization reaction between an alkyne and a β-keto ester

– CO2 14–88%

68

67

OH

OEt

2 Ph

R [Rh(cod)2]BF4 rac-BINAP

O

Ph

Initially proposed mechanisms had the reaction proceeding via a metallacyclopentadiene intermediate formed by oxidative coupling of two alkynes (pathway A) or by oxidative coupling between a β-keto ester and an alkyne followed by dehydration (pathway A′, Scheme 29). A third possible mechanism has been proposed based on addition of a metal enolate to an alkyne (pathway B).46 This third mechanism proceeds via addition of the manganese enolate of a 1,3-dicarbonyl compound (B1) to a terminal alkyne to give vinylmanganese complex B2 in which the metal is attached to the terminus of the alkyne. This is followed by insertion of a second alkyne into the vinyl–manganese bond, forming intermediate B3, in which the metal is attached on the substituted side of the alkyne. An intramolecular nucleophilic addition on the carbonyl group eventually affords the regenerated catalyst complex and the hydroxy-cyclohexadiene which can undergo dehydration to give the tetrasubsituted benzene. A recent mechanistic study by Nakamura and co-workers concludes that the reaction proceeds via pathway B.47 DFT calculations show that the latter pathway is greatly favored over pathway A when the alkyne is phenylacetylene or propyne. When acetylene is used, pathway A may occur competitively. In addition, pathway B explains all experimental observations, for example the high regioselectivity when aryl acetylenes are used, the moderate regioselectivity for aliphatic alkynes and the absence of reactivity for cyclic 1,3-diketones. The decreased regioselectivity for alkyl acetylenes is due to a lack of polarization in the alkyne necessary for a regioselective insertion of the second alkyne. The authors also briefly investigated pathway A′ but this was quickly excluded because formation of the metallacycle was accompanied by a high activation barrier and proved to be endothermic. Intriguingly, when a substituent is present on the active methylene moiety of the 1,3-dicarbonyl compound, the reaction has a different outcome.48 When β-keto esters 75 are used in the presence of alkynes and a rhenium(I) catalyst, pyranone adducts are formed which can undergo Diels–Alder reaction with an additional alkyne affording substituted benzenes 78 as single regioisomers (Scheme 30). The total reaction is a formal [2+1+2+1] cycloaddition. When 1,3diketones are used bearing a substituent on the active methylene moiety 79, again a different product is obtained. This reaction is a formal [2+2+1+1] cycloaddition and the corresponding aromatic compounds 81 are derived from 1,3-diketones, alkynes and a part of the 1,3diketone (Scheme 30). Although both are fascinating reactions and interesting methodologies to achieve full regioselectivity, they are beyond the scope of this review. © Georg Thieme Verlag Stuttgart · New York


L

REVIEW

M


OH

R1 A

2

MnLn

R1

2

O

O 3

R

MnLn

HO R2

R

O R3

R2

R3

H

R1

R1

R1

– H2O

– MnLn

R1

R1 OH A'

O

R2

R2

HO

R3

R1

O

– MnLn

– MnLn

R3

MnLn MnLn R1

R1

O O B

R2

MnLn

O

R3

O

MnLn

R1

O

O

2

R

O

R2 3

B1

R3 R1

R2

R3

MnLn

MnLn

R

O

R1 R1

B2

B3

Scheme 29 Proposed mechanisms for the cyclotrimerization of alkynes and 1,3-dicarbonyl compounds O

R1

R3

OEt

R4

R5

[ReBr(CO)3(thf)]2

R6

[2+1+2+1]

R2 76

75 O

5

R2

R

R1

R4

77

3

R

O ∗

R1 R2

R3

R1

80

R4

∗

[ReBr(CO)3(thf)]2

R4

[2+2+1+1] 79

78

∗

R3 R2 81

Scheme 30 Reactions between alkynes and 1,3-dicarbonyl compounds bearing a substituent on the active methylene moiety. R1 = Me, Ph or n-C5H11; R2 = H, Me or n-C5H11; R3 = H, Me, Ph or n- C6H13; R4 = Ph; R5 = CO2Et; R6 = H or CO2Et.

2.5

Synthesis of (Iso)quinolines

[2+2+2]-Cyclotrimerization reactions can also be used for the construction of fused bicyclic aromatics such as (iso)quinolines. In this case, either the benzene ring or the pyridine ring may be formed by the [2+2+2] cyclotrimerization, while the other ring is present in one of the reactants (i.e., a pyridine or a benzyne, respectively). The latter approach belongs in the next section, but some examples of the former approach are discussed below. The first example of such an approach was reported by Iwayama and Sato (Scheme 31).49 The synthesis involves the reaction between a 3,4-pyridyne (83), generated in situ from a silyl triflate precursor (84), and a tethered diyne (82) in the presence of a nickel catalyst to afford isoquinoline derivatives 85 in moderate to good yields. Initially, dimerization of the diyne resulted in lower yields. This could be solved by slow addition of the diyne, which significantly improved the yields. Besides the partially intermolecular reaction, a fully intramolecular reaction was also investigated. With the three reaction partners in a single molecule, lower catalyst loadings and temperatures were sufficient to achieve cyclotrimerization. An interesting feature is that lower yields were obtained when an oxygen atom was present in the tether. The authors speculated that coordination to the catalyst could retard the re© Georg Thieme Verlag Stuttgart · New York

action. In contrast, protected nitrogen groups such as sulfonamides did not result in significantly decreased yields.

Z 82

R

[Ni(cod)2] PPh3

N

38–65%

83

R Z

N 85

CsF Et3Si TfO

R N 84

Scheme 31 Synthesis of isoquinoline derivatives by reaction between a pyridyne and a tethered diyne. R = Me or CONEt2; Z = CH2, O, NTs or C(CO2Me)2.

An example where coordination of an oxygen atom did not have a negative effect, but was actually necessary, was recently reported by the same researchers.50 They developed the synthesis of isoquinoline derivatives via a nickel(0)-catalyzed intermolecular [2+2+2]-cyclotrimerization reaction. Using the same catalyst system as in the previous example, they were able to prepare several isoquinoline derivatives 89 in good yields. A small substrate Synthesis 2012, 44, A–AH


R6 O

N

REVIEW


R1

OR2

R3

Et3Si

N

TfO 86

R3

R1 [Ni(cod)2] CsF, PPh3

R2O

R1

OR2

R3

N Ni

10–82% R1

87

88

N OR2

R1

R2O

89

Scheme 32 Regioselective synthesis of isoquinolines by an intermolecular cyclotrimerization reaction. R1 = OMe, OMOM, Ph, n-Bu or (CH2)3OAc; R2 = Me or MOM; R3 = CH2OPiv, OMe or CONEt2. OTf

N

91

N+ –

R2 R1

41–99%

90

OTf

R2

[Rh(PPh3)3Cl] or [Ir(cod)Cl]2

N+ R1

59–88%

R1 92

–OTf

R2 93

scope was investigated and, interestingly, the alkyne coupling partners seemed to require a propargylic oxygen to induce reactivity and selectivity. Although poor reactivity and a complete lack of regioselectivity was observed when nonsymmetric alkynes were used, nonsymmetric diynes containing propargylic oxygens readily reacted with full regioselectivity (Scheme 32). In addition, for nonsymmetric diynes where only one alkyne contains a propargylic oxygen (86), full regio- and chemoselectivity was observed. The rationale behind both observations is that coordination of the propargylic oxygen induces regioselective formation of nickelacycle 88 which subsequently reacts with the 3,4-pyridyne to form a single isomer. A final example was very recently reported by Teplý and co-workers, who demonstrated the use of a transitionmetal-catalyzed [2+2+2] cyclotrimerization in the synthesis of nitrogen heteroaromatic cations.51 Although the reaction depicted in Scheme 33 does not form the pyridine ring, it is nonetheless an interesting example of a very short synthesis of the target molecules. Using a variety of reaction conditions, a wide range of nitrogen-containing heteroaromatic cations (i.e., pyridinium, quinolinium, thiazolium, benzothiazolium, imidazolium, and pyrimidinium) of general structural formula 93 were obtained in good yields. Some of the synthesized compounds were also shown to possess interesting electrochemical properties. In addition, lipophilic cations were also synthesized via the reported methodology with structural similarities to ‘push–pull’ dyes that are, for example, used as mitochondrial labelling agents.52

3

Synthesis of Pyridine Derivatives

Compounds containing pyridine rings are of great interest in medicinal chemistry and as ligands in catalysis. TransiSynthesis 2012, 44, A–AH

tion-metal-catalyzed [2+2+2] cyclocotrimerization (cyclotrimerization of alkynes with non-alkynes) of alkynes and nitriles have proven to be a powerful methodology for their synthesis. Earlier reviews have shown that these reactions can be performed in a highly regioselective manner and can be catalyzed by a broad range of transition metals.5 In this section, recent advances in mechanistic insight, regioselectivity, chemoselectivity and synthesis of chiral systems are described.

3.1

Mechanistic Insight

The mechanism of transition-metal-catalyzed [2+2+2]cyclocotrimerization reactions towards pyridines, depicted in Scheme 34, shows great similarity with that of alkyne cyclotrimerization. However, there are some subtle differences. The cycle again starts with coordination of alkynes to a transition-metal catalyst. The resulting complex (I) undergoes an oxidative coupling reaction to form a five-membered metallacycle (II or III). The nitrile can coordinate in two ways to the metallacycle, namely ‘endon’ acting as a σ-donor via the nitrogen lone pair (IV) or ‘side-on’ through the CN π-system (V). The coordinated nitrile can be inserted, forming an azametallacycloheptatriene (VI) which, after reductive elimination, gives compound VII. Alternatively, the coordinated nitrile can react in an intramolecular [4+2] cycloaddition, eventually forming VII. Another possibility is an intermolecular [4+2] cycloaddition from metallacycle II or III towards VII. Dissociation of the pyridine from intermediate VII gives the pyridine and the free catalyst, VIII. Competition between alkyne cyclotrimerization, nitrile cyclotrimerization and pyridine formation could, in theory, be a problem. Fortunately, nitrile cyclotrimerization is generally less favored due to lower stability of the diazametallacycle. Alkyne cyclotrimerization, which is often thermodynamically favored over the cyclocotrimeriza© Georg Thieme Verlag Stuttgart · New York


Scheme 33 Synthesis of nitrogen heteroaromatic cations by rhodium-catalyzed [2+2+2] cyclotrimerization. R1 = n-Bu or 4-MeC6H4; R2 = H, Me or Ph.

LnM

LnM

LnM

or LnM II

III

C

N

IV

donating groups on the nitrile stabilize side-on coordination (favoring the [4+2]-cycloaddition pathway).

LnM

or

N I

C

R

V

R + RCN

+2

LnM

MLn N

O


R

VIII

N

R

VII

LnM

N VI

R

Scheme 34 The proposed possible mechanistic pathways for transition-metal-catlyzed [2+2+2]-cyclocotrimerization reactions towards pyridines

tion, can be suppressed by adding an excess of the nitrile. After formation of the metallacycle, the equilibrium shown in Equation 1 occurs, which explains why adding an excess of nitrile can be used to obtain good yields of the pyridine.13

3.2

Regioselectivity

In analogy with transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions towards substituted benzenes, regio- and chemoselectivity is often a problem in cyclocotrimerization reactions towards substituted pyridines. Similar methodologies have also been employed to solve this, such as the use of stoichiometric amounts of transition-metal complexes. As for the mechanism of the reaction, there are some differences compared to alkyne cyclotrimerization. The main difference is obviously the incorporation of a heteroatom in the aromatic ring. As a result, if only a single nonsymmetric alkyne is incorporated in the product, there are already three possible regioisomers (Scheme 35). R1 R1

R1 MLn(C4H4)(C2H2) + RCN

MLn(C4H4)(RCN) + C2H2

N

[MLn]

H

H

Equation 1

Of course, there is also the possibility that first the nitrile and an alkyne coordinate to undergo an oxidative coupling to form an azametallacyclopentadiene. In all the DFT studies described below, these pathways were thermodynamically unfavorable or impossible. However, this pathway cannot be ruled out for the partially intermolecular or intramolecular reactions. In contrast to alkyne cyclotrimerization, Costa and coworkers found the addition of the nitrile to the metallacycle to be rate-determining.53 In this study, the formation of pyridines from acetylene and nitriles catalyzed by CpRuCl, CoCp and RhCp was investigated. The most favorable pathways were studied and initial formation of an azametallacycle was ruled out for RhCp. In contrast to the latter study, Bickelhaupt and co-workers found the oxidative coupling towards the five-membered metallacycle to be rate-determining, similarly to alkyne cyclotrimerization.13 In the same study, no significant solvent effects were found, which was explained by the absence of polar or charged intermediates. Itoh and colleagues found, in a combined experimental and theoretical study, that pyridine formation occurred readily with electron-deficient nitriles due to a lower activation barrier compared to electron-rich nitriles.54 As in the work of Bickelhaupt and coworkers, the oxidative coupling was also found to be ratedetermining. Based on the above, a DFT study was recently performed by Koga and Dahy on the reaction of cobaltacyclopentadienes with nitriles.55 They found a relationship between the electronic nature of the nitrile and the mechanistic pathway, namely that electron-withdrawing groups on the nitrile stabilize end-on coordination (favoring the insertion pathway), whereas electron-


N

N R1

N

H

H

Scheme 35 Possible regioisomers that can form with only a single asymmetric alkyne

Advances in solving the regioselectivity problem in the synthesis of substituted pyridines have been discussed in several reviews.5 These approaches do not differ from those for the synthesis of substituted benzenes described in the previous section. Therefore, only a number of recent examples will be briefly discussed. Obviously, the most straightforward way to achieve total regioselectivity is to tether the three components together. A recent example of such an intramolecular approach was reported by Aubert and colleagues in the synthesis of orthogonally protected nitrogen polyheterocycles (95).56 The cobalt-catalyzed intramolecular [2+2+2]-cyclocotrimerization reaction, depicted in Scheme 36, allowed the presence of a wide variety of protecting groups. The obtained yields were lower when an o-nitrobenzenesulfonyl (o-Ns) protecting group was present on 94 or when a fouror seven-membered ring had to be formed between the alkynes. The lowest yields were therefore obtained for a combination of both. A possible explanation is that it is PG1

PG1

N

N [CpCo(CO)2] hν

PG2

N

N 94

15–96%

PG2

N

N 95

Scheme 36 A fully intramolecular cyclocotrimerization towards orthogonally protected nitrogen polyheterocycles. PG1 = Cbz, COCF3, Boc, Bn, SO2-py or o-Ns; PG2 = Cbz, COCF3, Boc or Ts.



REVIEW

P

REVIEW

D. L. Broere, E. Ruijter Ts H

N

CN

N

Ts N H

[RhCl(PPh3)3] TsN TsN

N

NTs

N

H 96

Ts

TsN

CN

N Ts

H

97

98

microwave 73%

conventional heating

more difficult for the alkynes to form the metallacycle when a four- or seven-membered ring has to be formed (compared to five- or six-membered rings). Isolation of the compounds containing the o-Ns protecting group was accompanied by the observation of degradation products, explaining the lower yields. Another example of a fully intramolecular transitionmetal-catalyzed [2+2+2]-cyclocotrimerization reaction was recently reported by Parella and co-workers for the synthesis of fused tricyclic pyridines and bipyridines.57 This study is an excellent example of the sensitivity of the reaction of focus and shows the importance of fine-tuning the reaction conditions. In particular, the solvent and method of heating were shown to have a dramatic effect on the reaction outcome. An example, depicted in Scheme 37, is the rhodium(I)-catalyzed intramolecular cyclocotrimerization of tethered cyanodiyne 96. Using conventional heating with different reaction conditions afforded solely dimerization product 98. However, when the reaction was performed using microwave irradiation, the desired cyclocotrimerization product 97 was obtained in good yield. A final example of a fully intramolecular cyclocotrimerization from the recent literature is the synthesis of tricyclic fused 3-aminopyridines reported by Malacria and colleagues (Scheme 38).58 An interesting feature of the reaction is that it is the first reported transition-metalcatalyzed [2+2+2] cyclocotrimerization of alkynes, niZ n

TsN

Z N

[CpCo(C2H4)2]

n

TsN

50–100%

N TMS

TMS 99

100 Z

TsN

N Ar

Scheme 38 An intramolecular cyclocotrimerization reaction towards tricyclic pyridines with subsequent functionalization by a Hiyama cross-coupling reaction. n = 1, 2 or 3; Z = CH2, (CH2)2, O, NCbz or C(CO2Me)2.

R1

[Cp*RuCl(cod)] (2–10 mol%)

n

101


R1 +

Hiyama cross-coupling one example 77% (n = 3; Z = C(CO2Me)2 Ar = 4-MeOC6H4

triles and ynamides. The cobalt(I)-catalyzed reactions yielded orthogonally protected compounds of general structure 100 in good to quantitative yields. Although the use of ynamides required the incorporation of a TMS protecting group, it offered the possibility of functionalizing the pyridine by a Hiyama cross-coupling reaction, which was successfully demonstrated, yielding compound 101. The additional fused rings resulting from the tether in an intramolecular approach are not always desired. An elegant solution would be a completely regioselective intermolecular approach. Because all mechanistic studies to date have shown that initial formation of an azametallacyclopentadiene is thermodynamically unfavored but cannot be ruled out for all systems, as described above, the Stockis–Hoffmann model together with the Wakatsuki– Yamazaki model (Scheme 10) can be used with caution. Careful choice of the ligands can also affect the regioselectivity, when substituted alkynes and nitriles are used, by stabilization or destabilization of a sterically congested intermediate. For CpCo catalysts, donor substituents on the Cp result in a larger preference for alkyne cyclotrimerization. Acceptor substituents, however, increase the preference for cocyclization towards pyridines but decrease regioselectivity. Intriguingly, the exact opposite has been observed for CpRh complexes.59 Yamamoto et al. reported a highly efficient and regioselective ruthenium-catalyzed [2+2+2] cyclocotrimerization of 1,6-diynes 102 and nitriles 103 bearing a coordinating group (Scheme 39).60 Many examples of pyridines 104 were obtained in this manner in generally good yield. Most reactions proceeded smoothly with only 2 mol% of the ruthenium catalyst at ambient temperature. The authors demonstrated that a coordinating group, such as a nitrile, halide, or (thio)ether, was required for efficient reaction.

NC

Y

X DCE 23–97%

N

Z

Y

Z 102

103

X

104

Scheme 39 [2+2+2] Cyclocotrimerization of 1,6-diynes and nitriles bearing a coordinating group. X = CN, Cl, F, Br, OMe or SMe; Y = CH2, (CH2)2, (CH2)3, C6H4 (1,2-, 1,3-, or 1,4-arrangement) or (E)-CH=CH; Z = CH2, O, S, NTs or C(CO2Me)2; R1 = H, Me, Ph or TMS.



Scheme 37 An intramolecular cyclocotrimerization reaction that requires microwave heating

REVIEW

Q


The use of a regiodirecting chelating group has been successfully demonstrated by Saá and co-workers in their synthesis of bipyridines 108 via the double partially intermolecular cobalt(I)-catalyzed [2+2+2]-cyclocotrimerization reaction depicted in Scheme 40.61 The rationale behind the observed regioselectivity is that coordination of the nitrogen of the dimethylamino group to the cobalt center favors formation of cobaltacycle 107. An example of using a sterically demanding group to direct regioselectivity, as described for the synthesis of substituted benzenes, was demonstrated in the total synthesis of the ergot alkaloids (±)-lysergene and (±)-LSD by Vollhardt and colleagues.62 Me Me Me

Me

Co

Cp

N

N

NC N

O

R1

R2

R1 R2 R5

[CpCo(CO)2] THF

Si

N

O

3

R

n

11 to >98%

N 109

R5

n

R4

110 R4

R3

111

1

R N

TBAF, THF 67 to >98%

OH

R5

n

R4

R3

112

Scheme 41 Using a temporary silyl ether tether to induce regioselectivity. R1 = Me, Ph, i-Pr, n-C6H13 or 2-MeC6H4; R2 = i-Pr; R3 = Et or CH2O-3-F3CC6H4; R4 = H, Me or Et; R5 = several substituted heterocycles

N [CpCo(CO)2] hν

105

R2 Si

N Me

Me

Me

Me 106

107 Me

N

Me

Deiters, Nascone-Yoder and co-workers recently reported the identification of a novel TGF-β signaling inhibitor discovered using a multi-phenotype screen in frog embryos.64 The inhibitor (116), named heterotaxin by the authors, was a member of a series of 2,4,6-trisubstituted pyridines constructed using a regioselective, partially intramolecular [2+2+2] cyclocotrimerization of silyl-tethered diyne 113 with various nitriles (Scheme 42). Further elaboration provided compounds 115, including heterotaxin.

N

N

O Si Me

N

R1CN CpCo(CO)2

Me 108

Scheme 40 Regioselectivity induced by a regiodirecting chelating group in the synthesis of bipyridines

The use of a temporary tether, as found in the synthesis of substituted benzenes, has also been demonstrated in the synthesis of substituted pyridines. In 2008, Schreiber and co-workers reported the use of a temporary silyl ether tether in the synthesis of small library of complex pyridines 112 (Scheme 41).63 The tether was used for regioselective synthesis and to expand the small library. Initially, poor yields were obtained and the authors postulated it was due to the hindered nature of the substrates, resulting in competitive catalyst decomposition. In an attempt to stabilize the process, a range of solvents was investigated, and this revealed a dramatic solvent effect. Where often non-coordinating solvents give the best result for this type of reaction, the use of coordinating solvents significantly increased the yield. Using tetrahydrofuran provided the best results, also making catalyst activation by irradiation redundant. With the optimized protocol, a small library of substituted pyridines was successfully produced and the individual compounds were tested. This revealed a potent inhibitor for neuregulin-induced neurite outgrowth.


xylenes microwave 82–98%

TrO

O Si R1

N OTr

113

114

R2 N OH heterotaxin (116)

R1

N OH 115

Scheme 42 Partially intramolecular [2+2+2] cyclocotrimerization towards 2,4,6-trisubstituted pyridines. Tr = trityl (triphenylmethyl). R1, R2 = Me, Et, n-Pr, Ph or CH2OH.

In 2009, Komine, Tanaka and Kamisawa reported the synthesis of benzofuran derivatives via a rhodium(I)– H8-BINAP-catalyzed partially intermolecular [2+2+2]cyclocotrimerization reaction.41 The reaction, depicted in Scheme 43, between phenol-linked 1,6-diynes 117 and alkynes 118 or nitriles 119, yielded the corresponding dibenzofurans 120 and 121 or azadibenzofurans 122, respectively. In contrast to the reactions towards the dibenzofurans, the synthesis of the azadibenzofurans proceeded with excellent regioselectivity and moderate to good



N

R2

R

REVIEW


R1

R2

R2 or

O

R3

117

118

R1

[Rh(cod)2]BF4 H8-BINAP

R2

R3

R1

N R3

N

R2

O

119

O

121

122 single regioisomers 20–84%

combined yields 49–82%

R1

R1 Rh

R2

or

O

120

+

R1

Rh+ N

119

R2 O

O 123

124

yields. The excellent regioselectivity was explained by the formation of metallacycle 123 followed by regioselective insertion of the nitrile. The regioselective insertion can be explained by a less sterically demanding approach of the nitrile and by preference to form a bond between the nitrogen and cationic rhodium. In an attempt to further improve the yields, the group also investigated the use of different phosphine ligands. Although the regioselectivity remained the same, the yields dropped significantly. In addition, the authors demonstrated the reaction between diyne 117 and an isocyanate, affording the corresponding dibenzofuran derivative in good yield with complete regioselectivity. A more recent example reported by Komine and Tanaka that employs the same catalyst system is depicted in Scheme 44.65 The reaction between two molecules of aryl ethynyl ether 125 and nitriles or isocyanates at room temperature yielded substituted pyridines 128 or 2-pyridones 129, respectively, as single regioisomers. A broad range of arylethynyl ethers and nitriles were investigated and afforded the corresponding products in moderate to good yield. When lower yields were obtained, this was often due to homocyclotrimerization of 125. The yield of the desired product could be increased by adding an excess of nitrile or isocyanate, suppressing the homocyclotrimer-

O 2

125

1

N

N

R

or

R3

[Rh(cod)2]BF4 H8-BINAP

ization. The authors’ rationalization of the observed perfect regioselectivity is that the mechanism proceeds via the sterically least demanding metallacycle formation and insertion pathway. In 2008, Kotora and co-workers reported the synthesis of (pyridin-2-yl)purines via a partially intermolecular cobalt(I)-catalyzed [2+2+2] cyclocotrimerization of nitriles and 6-(diynyl)purines.66 By using a catalytic (or, in some cases, stoichiometric) amount of [CpCo(CO)2] combined with microwave irradiation, a variety of substituted (pyridin-2-yl)purines were obtained in moderate to good yields. In the same year, Okamoto and colleagues reported the synthesis of bipyridines by partially intermolecular cobalt-catalyzed [2+2+2]-cyclocotrimerization reactions (Scheme 45).67 Bipyridines were prepared via both single and double cyclocotrimerization reactions of nitriles and tethered diynes (130 and 133) or tetraynes (136), respectively. A broad variety of bipyridines were obtained in moderate to high yields with exclusive regioselectivity. The observed regioselectivity was explained by the electronic nature of the intermediate metallacycle and nitrile. Since the two alkynes are tethered, the models for metallacycle formation are redundant.

O

R1

N

C

R2

O

126

127

R1

N

or R2

O

O

R1

128 15 examples 32–82%

O

R3

R1

O 129

7 examples 16–53%

Scheme 44 A regioselective intermolecular cyclocotrimerization reaction towards substituted pyridines and 2-pyridones. R1 = Me, OMe, (CH)4, or CF3; R2 = Me, Ph, CO2Et, Bz, Ac, CH2CN or CO2Et.




Scheme 43 A regioselective partially intermolecular cyclocotrimerization reaction towards benzofuran derivatives. R1 = n-Bu, Ph or TMS; R2 = Me, Ph, CH2OH, CO2Et, CH2CN or Bz; R3 = CO2Et or CH2OH.

R1


R2

R1

CoCl2⋅6H2O DPPE, Zn powder

N

N N

47–91% Z

N 131

130

R2 132 R1

R1

N

R3

CoCl2⋅6H2O DPPE, Zn powder

R3

N

54–89%

N

N Z 133

134

135 R1

Z

R3 CoCl2⋅6H2O DPPE, Zn powder

R3

R1 R1

N

41–90%

N Z

Z

N

Z

R3 136

134

137

R1

Scheme 45 Partially intermolecular cyclocotrimerization reactions towards bipyridines. R1 = H, Me, n-Bu, Ph or TMS; R2 = H, Me, n-Bu or Ph; R3 = Me, Ph, CH2CN or C7F15.

A model proposed by the authors considering the relative electron densities on the α-positions of the metallacycle explains the observed regioselectivity. The model considers the different possible mechanisms and basically states that the nitrile nitrogen, more electron-rich than the nitrile carbon, will end up attached to the relatively electrondeficient α-position of the metallacycle. The researchers were also able to prepare tri- and terpyridines by reaction of tetraynes 136 and nitriles 134 with exclusive regioselectivity, albeit with moderate and low yields, respectively. The examples described above are, although powerful, specially designed and hence only applicable for each specific target molecule. In 2007, Young and Deiters reported ‘a general approach to chemo- and regioselective cy-

R1 TrtN N 138

139

N or C Y

R2

clotrimerization reactions’ (emphasis added).28 The reported methodology, depicted in Scheme 46, involves spatial separation of a diyne on a solid support and the use of microwave irradiation. With the described protocol, catalyst activation (by light or additives), long reaction times, high-dilution conditions, high temperatures or an inert atmosphere all proved to be redundant. With the developed methodology, a wide range of compounds were synthesized, namely pyridines (141), 2-pyridones (142a), 2-iminopyridines (142b) and highly substituted pyridines (145), in high yields and complete regioselectivity. All transformations were performed with the commercially available [CpCo(CO)2] without the use of specially designed ligands. However, all reactions had to be performed under microwave irradiation as the authors observed a strong ‘non-thermal microwave effect’ and were unable to recreate the results using conventional heating. In addition, the enhancing effects of the spatial separation were also validated by solution-phase control experiments which led to the formation of complex mixtures and decreased yields. Surprisingly (or unfortunately), the reported methodology has not been applied or put to its limits, judging by the absence of citing articles employing it.

3.3


In 2004, a graphical illustration of the first asymmetric synthesis of axially chiral biaryls by a transition-metalcatalyzed [2+2+2]-cyclocotrimerization of alkynes and nitriles appeared on the cover of Angewandte Chemie.68 In the corresponding article, Sundermann and co-workers concluded, after a short literature survey, that axially chiral pyridines are useful ligands in asymmetric synthesis but that a direct synthesis (i.e., without optical resolution) was not available.69 Therefore, they set out to develop such a synthesis employing an asymmetric transitionmetal-catalyzed [2+2+2]-cyclocotrimerization reaction. In an initial screening of various chiral cobalt(I) catalysts, solvents, temperatures, irradiation durations and amounts of catalyst showed that none of these factors, except the R3

1. [CpCo(CO)2], MW 2. 1% TFA, CH2Cl2

R1 HN

N

R3

140

R4

O n

N

143

R5 144

HN

N

R2

142a Y = O 142b Y = N 87–96%

141

HO

1. [CpCo(CO)2], MW 2. 1% TFA, CH2Cl2 71–91%

Y or

87–95%

O Trt

S

R5 O n

N

R4

145

Scheme 46 A chemo- and regioselective cyclocotrimerization reaction by spatial separation of the diyne on a solid support. R1 = Me, Ph, CH=CH2 or CH2Pip; R2 = Ph, n-Bu, Cy or i-Pr; R3 = i-Pr, Cy or a lone pair; R4 = n-Bu, Ph or t-Bu; R5 = H or Ph; Y = O or N; n = 1 or 2.




REVIEW

T

REVIEW


Co

R

R O

Me

N

hν

148

O

147

74–88% 82–93% ee 146

N

Co

Me

O Me

147

150

149

Scheme 47 The first asymmetric synthesis of axially chiral biaryls via a cyclocotrimerization reaction. R = Me, Ph or t-Bu.

Decreasing the reaction temperature resulted in an increase in enantiomeric excess but was unfortunately accompanied by a dramatic decrease in yield. A small catalyst screen revealed that cobalt complex 148 provided the best results. In an attempt to obtain better results, bulkier substrates were used in the reaction (Scheme 47). Diyne 146 was prepared to be reacted with different sterically demanding nitriles 147. Indeed, better results were obtained, affording the axially chiral 1-aryl-5,6,7,8-tetrahydroisoquinolines 150 in good yields and high enantiomeric excess. Surprisingly, the temperature had little effect on the enantioselectivity. Lowering the reaction temperature did have a small effect but was limited, owing to the fact that the reaction became sluggish when the temperature was lowered further. In addition, the steric bulk and electronic nature of the nitrile had no effect on the enantioselectivity, giving the same enantiomeric excess for acetonitrile and trimethylacetonitrile. The latter was explained by the formation of the diastereomeric intermediate, cobaltacyclopentadiene 149. Looking at the intermediate, the observed complete regioselectivity can also be explained by steric interactions. Recently, Heller and co-workers investigated the scope of the asymmetric cobalt-catalyzed partially intermolecular [2+2+2] cyclocotrimerization towards axially chiral 1aryl-5,6,7,8-tetrahydroquinolines 150 depicted in Scheme 47.70 Performing the reaction at –20 °C with cobalt catalyst 148 and irradiation with visible light resulted in the highest enantiomeric excess values. Increasing the temperature resulted in higher yields but was again accompanied with lower enantiomeric excess. The use of nitriles containing an additional heteroatom able to coordinate, such as 2-cyanopyridine, resulted in low yields or no conversion at all. The authors argued that this was due to formation of a bidentate ligand, after cyclocotrimerization, that could coordinate to yield an inactive cobalt complex. To prove this, additional experiments were performed that confirmed the possibility of formation of an inactive bidentate cobalt complex. Attempts to protect the corresponding heteroatoms were unsuccessful. The research group also investigated the use of a shorter tether between the alkynes that would result in a five-membered fused ring in the product. Although the corresponding products Synthesis 2012, 44, A–AH

were obtained, no enantioselectivity could be measured, owing to a loss of axial chirality caused by free rotation around the biaryl carbon–carbon axis. Although the above methodology has frequently been applied in the recent literature for the synthesis of axially chiral benzenes (section 2.3), recent examples towards the synthesis of axially chiral pyridines are – with the exception of the above-mentioned example – absent, to the best of our knowledge. Therefore, examples that have already been described in focused reviews on asymmetric synthesis via transition-metal-catalyzed [2+2+2] cyclotrimerizations will be described below. Besides their work on the enantioselective synthesis of axially chiral biaryls by transition-metal-catalyzed [2+2+2] cyclotrimerization of tethered alkynes depicted in Scheme 18, Tanaka et al. also demonstrated the same methodology for the synthesis of axially chiral bipyridines (Scheme 48).71 A rhodium-catalyzed double cyclocotrimerization reaction of tetrayne 151 and ethyl cyanoformate (152) afforded axially chiral bipyridine 153 with excellent enantiomeric excess, albeit in moderate yield. More interesting, however, is the compound obtained when the authors attempted a double cyclotrimerization of phenylsubstituted tetrayne 154 and three equivalents of alkyne 155 (Scheme 49). In the presence of 5 mol% of rhodium(I)–(S)-SEGPHOS complex, solely the mono-cyclotrimerization product 156 was obtained in 35% yield. Using a rhodium(I)–BINAP complex as the catalyst for this reaction instead, yield of 156 improved to 52%. With isolated 156 in hand, a subsequent reaction with nitrile 157 or isocyanate 159 afforded axially chiral pyridine 158 in good yield with excellent enantiomeric excess and axially chiral 2-pyridone 160 in moderate yield with good enantiomeric excess. O

N CO2Et

Me Me

O

151

N

152

[Rh(cod)2]BF4 (S)-SEGPHOS

EtO2C

38% 98% ee

O

O CO2Et N 153

Scheme 48 Synthesis of an axially chiral bipyridine via a double rhodium-catalyzed cyclocotrimerization reaction



catalyst and temperature, had an influence on the enantiomeric excess.

REVIEW


U

Ph N

O

EtO2C CO2Et 157 Ph Ph

CO2Me

52%

O

158 76%, 98% ee


Ph

O

CO2Me

O CO2Me

154

CO2Me Ph

CO2Me Ph

O

N

O

[Rh(cod)2]BF4 BINAP

O

CO2Me

156

155

Ph

n

Bu

N C 159 O

nBu

O

N

CO2Me O CO2Me Ph 160 63%, 67% ee

Enantioselective synthesis of C2-symmetric spiropyridine ligands 162 by means of a rhodium(I)-catalyzed [2+2+2] double cyclocotrimerization has been reported by Tanaka and co-workers.72 The fully intramolecular double cyclocotrimerization of compound 161, depicted in Scheme 50, afforded a variety of enantioenriched ligands in good to nearly quantitative yields. The best enantioselectivity was observed when either (R)-SEGPHOS or (R)-H8-BINAP, depending on the substrate, was used as a chiral ligand for the rhodium(I) catalyst. Although the reactions are intramolecular, diluted reaction conditions or slow addition proved to be unnecessary. R R O NC NC

n n

O

[Rh(cod)2]BF4 (R)-SEGPHOS or (R)-H8-BINAP

n

85–99% 40–71% ee

n

N

O

R

O

N

R 161

162

Scheme 50 Asymmetric synthesis of C2-symmetric spiropyridine ligands via a double cyclocotrimerization reaction. R = H, Me, Ph, 4ClC6H4 or 4-MeOC6H4; n = 1 or 2.

Several other examples employing transition-metal-catalyzed [2+2+2] cyclocotrimerization for the synthesis of axially chiral bipyridine N,N′-dioxides can be found in the recent literature.73 However, all examples involve achiral cyclocotrimerization reactions followed by oxidation and optical resolution, and will therefore not be described here.


4

Synthesis of Pyridone Derivatives

Like pyridines and benzenes, pyridones are often encountered in biologically active compounds. Another similarity is that a wide variety of transition metals have been shown to catalyze the [2+2+2] cyclocotrimerization of alkynes and isocyanates to form pyridone derivatives.7 Transition metal-catalyzed [2+2+2] cyclocotrimerization towards pyridones have also been discussed in several reviews.2,4b,5a,b,7,9b Most of the recent literature on transitionmetal-catalyzed [2+2+2]-cyclocotrimerization reactions involving isocyanates has been reported by the group of Rovis.74 However, these all involve reactions between alkynes and alkenylisocyanates towards indolizidine and quinolizidine derivatives. Recent advances in asymmetric synthesis of the latter have recently been extensively reviewed by Perrault and Rovis6 and are beyond the scope of this review. Because recent publications in this field, considering the reaction of focus in this section, have not been as numerous as those discussed in previous sections, a few older examples are also briefly described below.

4.1

Mechanistic Insight

Earlier DFT studies have led to proposed mechanisms similar to those described in the previous sections.75 These involve oxidative coupling to form a five-membered metallacycle followed by addition or insertion of the isocyanate. Because these show little difference from the mechanisms in Schemes 4 and 33, they will not be described again. However, there are some recent publications containing proposed mechanisms, based on experimental observations, that are not in agreement with the standard mechanism.



Scheme 49 Synthesis of asymmetrical axially chiral pyridines and 2-pyridones by sequential cyclo(co)trimerization reactions

V

REVIEW

D. L. Broere, E. Ruijter O VI R1

R1

N R2

R1

1

R

R'

R2 NCO

R1

2

R

R1

N R2

III

MLn VII

O

N

MLn VII

MLn V

O LnM R1

R1

R2

R1

C

N

N R2 I

IV

O R2

O

MLn CO

R1

R2 O

N

MLn

N

R1

R1

MLn

VIII R1

R1

II

N R2

III

O

An interesting, unexpected observation was the formation of 4-pyridones in cyclocotrimerization reactions of alkynes and isocyanates. Because no plausible pathway from the standard mechanism could be found, Rovis et al. proposed a different mechanism depicted in Scheme 51.74g,76 The mechanism involves coordination of the alkyne and isocyanate followed by an oxidative coupling to give metallacycle II. The metallacycle can undergo a subsequent reaction with an alkyne yielding 2-pyridone III, or CO migration via intermediate IV to give metallacycle V. Reaction with an alkyne regenerates the catalyst VII and gives 4-pyridone VI. Another pathway to form pyridone III is via formation of metallacycle VIII followed by reaction with an alkyne. The formation of 4-pyridone proved to be dependent on the electron-deficiency of the R2 group, resulting in more CO migration when the group is electron-withdrawing.

4.2

Regioselectivity

Once again, issues regarding regioselectivity in the synthesis of pyridones via transition-metal-catalyzed [2+2+2]-cyclocotrimerization reactions are similar to those for benzenes and pyridines. Furthermore, the situation depicted in Scheme 35 also applies to pyridones.

Kotora and co-workers reported a highly regioselective synthesis of pyridones and thus overcame the problem of forming multiple regioisomers.77 However, they achieved the latter by using stoichiometric amounts of zirconium and nickel, and their report is therefore beyond the scope of this review. An often-encountered problem in the synthesis of pyridones using terminal alkynes is cyclotrimerization or dimerization of the alkynes to form substituted benzenes and enynes, respectively. In 2009, Rovis and co-workers reported a regioselective intermolecular rhodium(I)-catalyzed [2+2+2]-cyclocotrimerization reaction of terminal alkynes and isocyanates to form 2-pyridones 165 (Scheme 52).76 A test reaction between phenylacetylene and benzyl isocyanate using a nickel–triphenylphosphine complex as the catalyst resulted in poor yields and predominant formation of an undesired enynamide. A ligand screen revealed that the best yields were obtained when phosphoramidite ligand 167 was used, resulting in almost no formation of the enynamide. A subsequent investigation of the alkyne scope showed that the best results were obtained when electron-poor alkynes were used. Using electron-rich alkynes resulted in lower yields and internal alkynes afforded no product at all. A final investigation of the isocyanate scope showed that as the electron-with-

major

minor

R1 O

[Rh(C2H4)2Cl]2 rac-167

C R1

163

N

R2

164

19–92% (165)

R1

N

Me

tBu

Me

O

Me

O

Me

tBu

O

O

R1

N 2

R2

R

165

166

R1

Me P N Me

167

Scheme 52 A regioselective intermolecular cyclocotrimerization reaction employing a phosphoramidite ligand. R1 = Ph, 3-FC6H4, 4-MeOC6H4, 2-MeOC6H4, 2-thienyl, 1-cyclohexenyl, n-Hex, Bn or OEt; R2 = Bn, PMB, Ph, 4-MeOC6H4, 4-F3CC6H4, n-Hex or Cy.




Scheme 51 Proposed mechanisms by Rovis et al. for the formation of 2- and 4-pyridones by transition-metal-catalyzed [2+2+2] cyclocotrimerization of alkynes and isocyanates

drawing ability of aryl isocyanates increased, an increase in the CO migration resulting in the formation of 4-pyridones 166 was observed. Although all performed reactions proceeded with complete regioselectivity, no explanation was provided. An example of tethering two alkynes in the synthesis of 2pyridones to prevent the formation of multiple regioisomers was reported by Itoh et al. in 2005.54 This was achieved by a reaction between tethered diynes 168 and isocyanate 169 in the presence of [Cp*RuCl(cod)] (Scheme 53). Interestingly, while there still was the possibility for the formation of two regioisomers, in all reactions only a single regioisomer (170) was obtained in high yield. The authors concluded that this was due to a preference of performing the [2+2] cycloaddition between the ruthenacycle, derived from the tethered diyne, and the isocyanate to take place at the more negatively charged αcarbon. This conclusion was based on the observed regioselectivity and DFT calculations on the [2+2] cycloaddition between methylisocyanate and the tethered diyne. With the developed protocol, the authors also reacted diynes 168 with isothiocyanates yielding the corresponding thiopyranimines in moderate to high yields. To the best of our knowledge, no reactions that intentionally employ a temporary tether for the regioselective synthesis of pyridones have been reported. However, in the abovementioned paper by Itoh et al., a diyne containing an ester functionality in the tether was employed (not shown). The presence of the ester allows for subsequent opening of the additional fused ring, thus functioning as a temporary tether. R

nPr

R X

N C

168

W


n

[Cp*RuCl(cod)]

X

N

80–88%

O 169

Pr

The regioselectivity proved to be mainly dependent on the chain length of diyne 171. R1

R3

N or

X

Y

R2 171

R2

[CpCo(CO)2]

C

172

173

R3

X

or

R1

N

Y 174

175

Scheme 54 Synthesis of m- and p-pyridonophanes via a cobaltcatalyzed [2+2+2]-cyclocotrimerization reaction. X = N or C; Y = N or O.

4.3


In 2005, Tanaka et al. reported the first enantioselective transition-metal-catalyzed [2+2+2] cyclocotrimerization of tethered diynes 176 and isocyanates 177 towards axially chiral 2-pyridones 178 (Scheme 55).79 In addition, the reaction was completely regioselective. This was achieved by employing a rhodium(I)–(R)-dtbm-SEGPHOS catalyst. The axial chirality was induced by using a diyne bearing an ortho-substituted aryl moiety. A wide range of axially chiral 2-pyridones were prepared in high yields and enantioselectivity. The complete regio- and enantioselectivity is explained by the formation of chiral rhodacycle 179 which induces a preferred approach of the isocyanate.

O 170

Scheme 53 A partially intramolecular ruthenium-catalyzed [2+2+2]-cyclocotrimerization reaction. R = Me or Ph; Z = C(CO2Me)2, NTs or O.

R1 N

R2

C O

[Rh(cod)2]BF4 (R)-dtbm-SEGPHOS 58–89% yield 85–92% ee

R1 R2 Z

N O

Z

New methodologies for the synthesis of macrocycles are of great interest due their application in host–guest chemistry and supramolecular chemistry. In addition, biologically active macrocycles such as the macrolide antibiotics, are also of high interest. In 2005, Maryanoff and co-workers reported the synthesis of m- and p-pyridonophanes 174 and 175 via cobalt-catalyzed [2+2+2] cyclocotrimerizations of diynes 171 with nitriles, isocyanates or cyanamides (Scheme 54).78 They were faced with a paradox regarding the bimolecular macrocyclization: while high dilution would favor macrocyclization, a sufficient concentration was necessary to favor a bimolecular reaction. The yield of the macrocycles indeed proved to be highly dependent on the concentration. The authors experimentally determined that the best yields were obtained in concentrations of 0.002–0.005 M. A wide variety of m- and ppyridonophanes were prepared in moderate to high yields. © Georg Thieme Verlag Stuttgart · New York

176

177

178

Ar 1 Ar R P

P Rh+

Ar

Ar N C O 179 Z

R2

Scheme 55 Enantioselective synthesis of axially chiral 2-pyridones by a partially intermolecular cyclocotrimerization reaction. Z = CH2, O or C(CO2Me)2; R1 = Cl or Br; R2 = Bn, n-Bu or n-C8H17.

Another approach towards axially chiral 2-pyridones, depicted in Scheme 56, was reported by the same group in 2008.80 Where an aryl-substituted diyne was used in the reaction above, this reaction used ortho-substituted aroSynthesis 2012, 44, A–AH


REVIEW

REVIEW


served even when the mixture was stirred at 80 °C for 24 hours.

Z N

O

C

Me

Me [Rh(cod)2]BF4 (R)-BINAP

R

Z

Me

N

R

27–92% 30–87% ee

Me 180

As already mentioned in section 3.3, Tanaka et al. reported the enantioselective synthesis of axially chiral biaryls by rhodium-catalyzed [2+2+2] cyclotrimerization reactions.71 However, besides the synthesis of asymmetric axially chiral biaryl 160 (Scheme 49), the group also prepared symmetric axially chiral bipyridone 185 in high yield with modest enantioselectivity (Scheme 57).74 This was achieved by the reaction of tetrayne 183 and isocyanate 184 in the presence of 5 mol% [Rh(cod)2]BF4–(S)SEGPHOS complex.

O

181

182

Scheme 56 Enantioselective synthesis of axially chiral 2-pyridones by a rhodium-catalyzed cyclocotrimerization reaction. R = Me, Et, iPr, OMe, Cl or Br; Z = O, NTs, C(CO2Me)2, C(CH2OMe)2 or (CH2)2.

matic isocyanate 181 to create axially chiral biaryls. The reaction between 181 and diynes 180, in the presence of a rhodium(I)–(R)-BINAP complex, afforded the corresponding enantioenriched N-aryl-2-pyridones with C–N axial chirality in low to high yields. Increasing the steric bulk of the alkyl groups on the arylisocyanate resulted in higher enantiomeric excess but was accompanied by a decrease in yield due to competing homocyclotrimerization of diyne 180. Moreover, when 2-(tert-butyl)phenylisocyanate was used, no N-aryl-2-pyridone was formed. Oxygen- or nitrogen-tethered diynes reacted readily, affording the corresponding N-aryl-2-pyridones in similar yields. However, lower enantiomeric excess values were observed when these diynes were employed. The authors also demonstrated a complete intermolecular [2+2+2] cyclocotrimerization of two molecules of terminal monoyne and one molecule of 181. The reaction yielded a single axially chiral regioisomer with good enantiomeric excess, albeit in low yield. The synthesized N-aryl-2-pyridones were also investigated with regard to their stability towards racemization. Notably, no racemization was ob-

Ph O

O nBu

Ph


N Ph

C

O

183

nBu

89% yield 52% ee

O

O

N

nBu

N

O

O Ph

184

185

Scheme 57 Enantioselective synthesis an axially chiral bipyridone by a double cyclocotrimerization reaction

5

Applications

Proof that transition-metal-catalyzed [2+2+2]-cyclo(co)trimerization reactions have truly been implemented in the chemist’s ‘synthetic toolbox’ is best provided by showing their applications. Over the past decades the re-

Me TMS

Me

H H

[CpCo(CO)2] 82%

CN

N

N

N

Bn

Bn

TMS TMS 186

187

TMS

188

Me TMS

H

Me

OHC

N

N

Me H

N

H N

N

CN

N

Bn

[CpCo(CO)2]

N Bn

H

Me 191

H

CHO

Me

Me +

H

TMS N 189

190

N

OHC

N

N H

Bn H

191/192 = 3.3:1, 47% with 8 equiv Ph3P 191/192 = 1:3.0, 56%

TMS

N

HN

Me

H

N

Me

N 192

(+)-complanadine A

Scheme 58 Total synthesis of (+)-complanadine A by cobalt-catalyzed cyclocotrimerization reactions




X


action of focus has mainly been applied in natural product synthesis. Early examples are the total synthesis of the well-known natural products camptothecin,81 (±)-lysergene,62 (±)-LSD62 and (±)-strychnine82 by Vollhardt and co-workers. Although natural product synthesis applications have only increased in the recent literature, the reaction has also found use in supramolecular chemistry, in polymer chemistry, and in the synthesis of pharmaceutically interesting compounds and ligands for asymmetric synthesis. Because the latter application has already been described extensively in previous sections, it is not described here. t

BuO2C O

CO2Me

NC-CO2Me [Cp*RuCl(cod)] (10 mol%) N

Ts

N N

CH2Cl2, 40 °C, 18 h 97%

O

Ts

193

CO2tBu

194

HO O N

N N H

O

N H isoperlolyrine (196)

perlolyrine (195)

HO

Scheme 59 Total synthesis of perlolyrine and isoperlolyrine using [2+2+2] cyclocotrimerizations

Probably the most powerful example is the synthesis of (+)-complanadine A (Scheme 58) by Siegel and colleagues in 2010.83 The synthesis of this almost symmetrical alkaloid, potentially interesting for treatment of diseases of the central nervous system such as Alzheimer’s disease, was highlighted in both Nature84 and Nature Chemistry.85 In the synthesis, two cobalt-catalyzed partially intermolecular [2+2+2] cyclocotrimerizations, depicted in Scheme 58, are employed. After the synthesis of the cyanoalkyne 186, the reaction with diyne 187 proceeded smoothly, affording pyridyl alkyne 188 in good yield with excellent regioselectivity. Several attempts to

achieve a second [2+2+2] cyclocotrimerization of pyridyl alkyne 188 and diyne 187 failed. Cyclocotrimerization after removal of both TMS groups on pyridyl alkyne 188 also failed. However, when a single TMS group was present on the alkyne, a cyclocotrimerized product (191) was obtained, albeit the wrong regioisomer. After significant experimentation, it was found that using formyl derivative 190 yielded the desired product 192 together with the symmetric 191 in a 1:1 ratio. Surprisingly, it was found that addition of an excess of triphenylphosphine provided an increase in regioselectivity toward the desired product. After removal of the TMS group, debenzylation and deformylation, (+)-complanadine A was obtained. How the addition of excess triphenylphosphine resulted in higher regioselectivity requires further study. Nonetheless, this is an excellent recent example of the successful application of transition-metal-catalyzed cyclocotrimerization reactions in total synthesis. Detert and co-workers employed Yamamoto’s catalyst ([Cp*RuCl(cod)]) in a highly efficient and regioselective [2+2+2] cyclocotrimerization of an alkynylynamide and methyl cyanoformate as the key step in the total synthesis of the β-carboline alkaloid perlolyrine (195, Scheme 59).86 The authors used a very similar strategy for the total synthesis of the isomeric γ-carboline known as isoperlolyrine (196). The same methodology was used by Nissen and Detert in the total synthesis of lavendamycin (199, Scheme 60).87 In this case, 2 mol% of Yamamoto’s catalyst was sufficient to afford the [2+2+2]-cyclocotrimerization product 198 in excellent yield as a single regioisomer. In 2007, Gonnade and co-workers reported the total synthesis of (–)-bruguierol A (204) by a partially intermolecular [2+2+2] cyclotrimerization catalyzed by Wilkinson’s catalyst (Scheme 61).88 Because the absolute configuration of the isolated natural product could not be determined, the group set out to determine this by total synthesis. After asymmetric synthesis of chiral diyne 201, a catalyst screen revealed that the best results were obtained by using Wilkinson’s catalyst. Diyne 201 was reacted with terminal alkyne 200, affording 202 and 203 as a mixture of inseparable regioisomers. Subsequent oxidation and treatment with m-chloroperoxybenzoic acid, followed by separation of the isomers, afforded (–)Me

Me

NC-CO2Me [Cp*RuCl(cod)] (2 mol%)

OMe Me N N

NO2 OMe

Ts

CH2Cl2, r.t. 92%

CO2H

CO2Me

N

N N H

N Ts

N

N O

MeO

O

OMe H2N

O2N 197

Y

198

lavendamycin (199)

Scheme 60 Total synthesis of lavendamycin




REVIEW

Z

REVIEW

D. L. Broere, E. Ruijter O

O HO 1. MnO2 2. MCPBA 3. aq NaOH, THF

Me

O

202

[RhCl(PPh3)3] 67%

OH

HO Me (–)-bruguierol A (204), 21% O

O

Me 200

201 Me

HO

Me

HO

205, 21%

203

Scheme 61 Total synthesis of (–)-bruguierol A employing a rhodium-catalyzed cyclotrimerization reaction

OAc O O

O OAc

OBn

O

Cl OTBS

206

207

OH OH

O O

O

87%

O

Cl

O

MeO [Cp*RuCl(cod)]

BnO MeO

OH

BnO

O

Me

HO 208

O O

Cl

MeO

O

O

OH

OH

OAc

HO

sporolide B TBSO

OBn

Scheme 62 Synthesis of a key intermediate for the total synthesis of sporolide B via a cyclotrimerization reaction. X = CH2.

bruguierol A (204) in 9% overall yield. The spectroscopic data of the synthetic product were in agreement with those of the natural product. The optical rotation was similar, but of opposite sign, indicating that the synthetic sample was the enantiomer of the natural product. In addition to the total synthesis of (–)-bruguierol A, the Gonnade research group also demonstrated the rhodium(I)-catalyzed [2+2+2] cyclotrimerization as a practical strategy towards 8-oxabicyclo[3.2.1]octane systems by reacting diyne 201 with a variety of alkynes. Because compounds 202 and 203 have to undergo three additional steps to reach 204 and 205, the synthesis would be shortened significantly if compound 68 (Scheme 26) could be used instead of 200. In 2009, Nicolaou et al. reported the total synthesis of sporolide B, a marine chlorinated polyketide, using a ruthenium-catalyzed [2+2+2] cyclotrimerization as a key step (Scheme 62).89 Combining compounds 206 and 207 in 1,2-dichloroethane in the presence of [Cp*RuCl(cod)] afforded compound 208 in 87% yield as a single regioisomer after stirring at room temperature for 30 minutes. The high regioselectivity was explained by steric hindrance of the chlorine upon reaction of the ruthenacycle with 206, accompanied by possible coordination of the propargylic alcohol in 206. More recently, Nicolaou et al. published a more extensive paper in which a similar approach for the synthesis of 9-epi-sporolide B was also described.90


Recently, Reisman and co-workers reported the synthesis of the norcaradiene core (211a) of salvileucalin B, a compound of great interest due to its biological activity.91 One of the key steps in the synthesis of compound 211 was a copper(I)-catalyzed cyclopropanation reaction beyond the scope of this review. Another key step was the intramolecular cyclotrimerization of triyne 209 to give 210 (Scheme 63). After several additional steps, both the norcaradiene core and a silyl analogue 211b were synthesized, each using a different catalyst for the cyclotrimerization reaction, namely Pd(PPh3)4 and [Cp*RuCl(cod)], respectively. Both compounds were obtained in good yields but there was no mention by the authors as to the reason for the different choice of catalyst. Another cobalt-catalyzed [2+2+2] cyclotrimerization used as a key step in total synthesis was reported by Groth and co-workers, who carried out the asymmetric total synthesis of (+)-rubiginone B2, (–)-8-O-methyltetrangomycin and (–)-tetrangomycin (Scheme 64).92 These compounds belong to the class of angucycline antibiotics, which are interesting compounds because of their wide range of biological activities. In the precursor of 212, both terminal alkynes were protected with TMS groups. However, that substrate proved unsuitable for the cyclotrimerization reaction. Deprotection afforded 212, and this substrate was then subjected to various reaction conditions. Overall, the best results were obtained in diethyl ether at low temperatures using CpCo(C2H2) or CpCo(CO)2 as the catalyst. Large R1 and R2 groups also gave difficulties, requiring © Georg Thieme Verlag Stuttgart · New York


Me

OAc

REVIEW


AA

O O

O Z

MeO2C

Z

H

Z

[MLn] MeO2C

78–90%

O 209

210

CN 211

Scheme 63 Synthesis of a key intermediate towards the norcaradiene core of salvileucalin B via an intramolecular cyclotrimerization reaction. Z = CH2 (a) or Si(i-Pr)2 (b); MLn = Pd(PPh3)4 or [Cp*RuCl(cod)]. R2 [CpCo(CO)2] or [CpCo(C2H2)2]

TBSO

OTBS

O

R2

R2

91–98% O

O R1

O

R1

212

213

R1

O

(+)- rubiginone B2 R1 = Me R2 = H; 15%, 92% ee (–)-9-O-methyltetrangomycin R1 = Me R2 = OH; 9%, 91% ee (–)-tetrangomycin R1 = H R2 = OH; 9%, 90% ee

stoichiometric amounts of catalyst to obtain good yields. Using the optimized conditions, the required compounds of structure 213 were obtained in excellent yields. Roulland and colleagues recently reported a synthesis of the skeleton (215) of landomycin, which is another example of an angucycline antibiotic.93 The synthesis involves three transition-metal-catalyzed steps, namely a Suzuki– Miyaura cross-coupling, a [2+2+2] cyclotrimerization catalyzed by Wilkinson’s catalyst, and a ring-closing metathesis (RCM) reaction. In the study, a partial intramolecular approach was initially attempted. Different catalysts and substrates were tried but only low yields were obtained for the required (bulky) substituted alkynes. When less bulky alkynes were used, the products were obtained in high yields. These, however, obviously did not contain the desired functional groups. Because of the discouraging partially intramolecular approach, a fully intramolecular approach using an ester as a temporary tether was adopted (Scheme 65). The latter had the desired effect, and afforded the 215 in high yield. O

OTBS

O

OTBS O

O [RhCl(PPh3)3] 93%

OMe

OTBS

OMe

214

OTBS

215

Scheme 65 Synthesis the landomycin skeleton via a intramolecular cyclotrimerization reaction employing a temporary tether Me Me Si

EtO

OEt CoBr2, Zn

Si Me Me 216

87%

Kawamoto and co-workers reported a large-scale synthesis of 1,1,3,3,6-pentamethyl-1,3-disilaindan-5-ol (219) using a cobalt(II) bromide and zinc catalyzed [2+2+2] cyclotrimerization of diyne 216 (901 mmol, 162.6 g) and alkyne 217 (1.35 mol, 192.3 g) followed by hydrolysis, Baeyer–Villiger oxidation and again hydrolysis (Scheme 66).94 Compound 219 is an important precursor of silasubstituted drugs such as GnRH antagonists. This report is interesting because examples of large-scale transitionmetal-catalyzed [2+2+2] cyclotrimerizations are rare.95 Formation of polymeric side products, an encountered side reaction, was not observed when cobalt(II) bromide was slowly added to a solution of the other reactants and reagents in acetonitrile. The fact that the reaction was performed in acetonitrile shows that the catalyst system is not suitable for the synthesis of pyridines with these reagents. Recently, the total synthesis of cryptoacetalide (222), a terpene natural product, was reported by Zou and Deiters.96 A key step in the synthesis, depicted in Scheme 67, is a ruthenium(II)-catalyzed [2+2+2] fully intramolecular cyclotrimerization reaction. After studying the reaction with model triynes, of which one did not even require a catalyst to undergo cyclotrimerization, the required triyne 220 was successfully prepared. Subsequent treatment with [Cp*RuCl(cod)] under microwave irradiation provided the desired tricyclic product 221 in high yield. After two additional steps, cryptoacetalide (222) was obtained as a 2:1 mixture with epi-cryptoacetalide (epi-222) which proved to be inseparable as reported earlier.

OEt

Me Me Si

OEt

Si Me Me

217

218

3 steps

Me Me Si

OH

Si Me Me 219

Scheme 66 A large-scale synthesis of a precursor for sila-substituted drugs © Georg Thieme Verlag Stuttgart · New York



Scheme 64 Preparation of key intermediates in the synthesis of three angucycline antibiotics

AB

REVIEW

D. L. Broere, E. Ruijter Me

Me

O

Me O

[Cp*Ru(cod)Cl] MW 90%

Me PMBO

O

O

OPMB 1. DDQ 2. I2, PhI(OAc)2, hν

O

O

84% Me

O

220

Me

Me

221

Me 222/epi-222 = 2:1

Scheme 67 Total synthesis of cryptoacetalide using an intramolecular cyclotrimerization reaction

The same research group also reported a partially intermolecular transition-metal-catalyzed [2+2+2] cyclotrimerization of alkynes and cyclocotrimerization of alkynes and nitriles towards anthracenes and 2-azaanthracenes, respectively (Scheme 69).98 Subsequent oxidation (and methylation for the 2-azaanthracenes) yielded the conjugated compounds 231 and 229, respectively. The synthesized compounds show unique photochemical as well as biological properties and several applications are envi-

R1

sioned by the authors. They found that the use of microwave irradiation was necessary to obtain good yields, suggesting that there was a non-thermal effect. However, Kappe and colleagues investigated this and found no difference between using microwave irradiation or conventional heating as the heating source (with carefully executed experiments).99 An enantioselective synthesis of the tetracyclic benzo[d]xanthene core of anti-influenza natural products has recently been reported by Cramer and co-workers.100 Because of the growing resistance to anti-influenza agents, these sesquiterpenes and analogues are of great interest. The authors demonstrated a ruthenium-catalyzed [2+2+2]-cyclotrimerization reaction of alkyne 232 and diyne 233, depicted in Scheme 70, which could be used to access more substituted derivatives. The reaction is an example of the methodology, mentioned in section 2.3, to synthesize chiral substituted benzenes by using a chiral substrate which therefore does not introduce the chirality in the reaction process. Nonetheless, it is a fine example of the implementation of the reaction.

OMe

R2

MeO

Ni(CO)2(PPh3)2

R1

63–94%

R3 or

or R3

N

R2

N

CpCo(CO)2

MeO

69–100%

223

N

224

225

OMe

226 (tylophorine)

Scheme 68 Synthesis of (aza)triphenylenes by [2+2+2] cyclo(co)trimerization. R1 = n-Bu, 2-pyridyl, CH2NHBoc, CH2OH, (CH2)3CN or CH2OMe; R2 = H or CH2OMe; R3 = Me, Et, CH=CH2, Ph, (CH2)3OH or CH2CO2Et. N R1

R1 ] O) 2

(C Co [Cp MW 94% 80–

227

N

74– (CO 86% )2 (P MW Ph3 )

R2

2]

R3 230

Me

229

R2

R3

N+

53–85%

228

[Ni

R1

1. DDQ, MW 2. MeI

R2 1. DDQ, MW 70–79%

R3 231

Scheme 69 Synthesis of anthracenes and 2-azaantracenes via partially intermolecular cyclo(co)trimerization reactions. R1 = Me, n-Pr, (CH2)2OH, CH=CH2, Ph or Py; R2 = n-Bu, Ph, CH2OH, (CH2)3CN, (CH2)3OH or (CH2)2Ph; R3 = H or Ph. Synthesis 2012, 44, A–AH



[2+2+2] Cyclotrimerizations can also be used to construct polycyclic aromatic hydrocarbons. Deiters and co-workers reported the cyclotrimerization of 2,2′-diethynylbiphenyl (223) and alkynes or nitriles to give triphenylenes 224 and azatriphenylenes 225, respectively (Scheme 68).97 Both reactions were conducted under microwave irradiation and provided the polycyclic aromatic products in good to excellent yield. A nickel catalyst was used for reactions with alkynes, whereas reactions with nitriles were conducted under cobalt catalysis. The authors further demonstrated the utility of this reaction by applying it as a key step in an elegant total synthesis of the natural products dehydrotylophorine and tylophorine (226).

Ts N Ts

O

N

[Cp*Ru(cod)Cl] O

78%

232

233

234

Scheme 70 A partially intermolecular cyclotrimerization reaction with potential applicability in the synthesis of anti-influenza natural products

Finding new methodologies to synthesize non-proteinogenic amino acids is of great interest as these amino acids are important building blocks in drug discovery. In 2009, Roglans and co-workers reported a rhodium-catalyzed [2+2+2] cyclotrimerization towards new non-proteinogenic phenylalanine derivatives (Scheme 71).101 This was achieved by the reaction of several racemic and optically pure propargylglycine derivatives 236 with 1,6-diynes 235 in the presence of Wilkinson’s catalyst. The study is an excellent example of the solvent-, catalyst- and substrate-dependence of transition-metal-catalyzed [2+2+2]cyclotrimerization reactions. When trying to find optimal reaction conditions, the research was plagued by homocoupling of the diyne with no formation of the desired product. However, a solution was found using Wilkinson’s catalyst in ethanol; this afforded the desired products 237 in high yields within 30 minutes. When homocoupling of the diyne was observed, it could be preNHFmoc R1

R1

COOR2

NHFmoc 1

[RhCl(PPh3)3]

COOR2

R

64–100% R1

Z 235

Z

236

237

Scheme 71 Synthesis of non-proteinogenic phenylalanine derivatives via a cyclotrimerization reaction. R1 = H, Me or Et; R2 = H or Me; Z = NTs, NDs, C(CO2Et)2, O, CH2 or N-Ses.

O

O

O

vented by slow addition of the diyne. Furthermore, the mild reaction conditions proved compatible with acidand base-labile protecting groups commonly encountered in peptide synthesis, making this approach a powerful methodology for the synthesis of non-proteinogenic phenylalanine derivatives. An example of applying the transition-metal-catalyzed [2+2+2]-cyclotrimerization reaction in the synthesis of enantiopure tri- and tetracyclic systems containing the isochroman (242) or dihydroisobenzofuran (243–245) units integrated with a sugar template was recently reported by Ramana and co-workers (Scheme 72).102 The reaction between diynes 238–241 and alkynes in the presence of Wilkinson’s catalyst afforded the corresponding products in moderate yields. These were modified, using simple synthetic steps, to give tricyclic nucleosides which are of interest for several pharmaceutical applications (e.g., antiviral, antisense therapeutic and diagnostic agents). When symmetrical alkynes were employed in the reaction, the products were obtained in moderate yields. The reaction was troubled by poor regioselectivity when nonsymmetric alkynes were used, yielding inseparable mixtures of regioisomers. When the reaction was performed with sterically crowded alkynes (R = Ph or TMS), homocyclotrimerization of the diyne was observed. An occasionally encountered side-product of transitionmetal-catalyzed [2+2+2]-cyclotrimerization reactions was the final goal in a recent study by Okamoto and coworkers: they wanted to synthesize new polymers.103 By means of a cobalt-catalyzed [2+2+2] partially intramolecular cyclotrimerization reaction, a wide range of polymerizable molecules (monomers) were synthesized. These new monomers could, after polymerization or co-polymerization, provide new polymers with potentially interesting properties. Use of transition-metal-catalyzed [2+2+2]cyclotrimerization reactions has not been limited to the synthesis of relatively small molecules. The reaction has also found its way into the synthesis of hyperbranched polymers. In 2009, Tang and co-workers reported their development of the first effective ruthenium catalyst for polycyclotrimerization reactions.104 The newly developed

O

O

O

O

O

R2

O

R1 239

O

R1

242 R2

or

R1

O

O

O

O

O

O 240

O

43–76%

O O 241

243

or

[RhCl(PPh3)3] O

O O

O

O

R2

O

O

238

O

O

O

O O

TBSO

AC


TBSO

O

O

R2

O

O O

O

O

O

O R1

244

245

R1 R2

Scheme 72 Synthesis of enantiopure tri- and tetracyclic systems via partially intermolecular cyclotrimerization reactions. R1 = H, CH2OH, CH2OAc, CH2OMe, n-C5H11, TMS, n-C14H29 or CH2-N-Phth; R2 = H, CH2OH, CH2OAc, CH2OMe, n-C5H11 or TMS. © Georg Thieme Verlag Stuttgart · New York



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catalysts were employed in the polymerization of an arylene bipropiolate (ABP) monomer yielding a soluble polyaroxycarbonyl-phenylene (PACP) with a high molecular weight and hyperbranched or crosslinked structure (Scheme 73). An interesting feature of these polymers is that they effectively trap small molecules in their internal cavities by non-covalent interactions, functioning as molecular containers. In addition, the guest molecules can be rapidly released by a process described as ‘bursting hydrolysis’. While linear polyesters often take days to decompose, this hyperbranched example is hydrolyzed within minutes, releasing the guest molecules in a ‘bursting’ fashion. The latter makes the hyperbranched polymer an interesting candidate for targeted drug delivery. Obviously, further modification of the polymer is needed to prevent premature release of the drug.

O

sion of product selectivity, albeit with low yield and enantiomeric excess. Based on the promising initial results, the ligand scope was further investigated. Phosphoramidite 248 provided the best results and was employed in reactions with several alkynes (Scheme 74). All tested substrates afforded the indolizinones 249 in good product selectivity and enantiomeric excess. The results showed that the reaction is highly sensitive to both electronic and steric effects. Electron-deficient alkynes showed less product selectivity in favor of the indolizinone 249. Sterically hindered alkynes, however, improved product selectivity. An interesting feature is that the developed catalyst was able to promote the reaction with sterically demanding alkynes to furnish highly congested 5-alkyl indolizinones. Furthermore, one of the obtained products was also successfully converted into the natural product indolizidine (–)-209D, thus resulting in the shortest asymmetric synthesis of this alkaloid.

O O

ABP

O

O

N R1

Ru cat.

246

R1

[Rh(C2H4)Cl]2 (R)-248

C

R2 247

15 examples 44–87% 79–91% ee

N O

R2 249

PACP

PACP PACP

Me

tBu

Me

O

Me

O

Me

t

O

O O

O

Me P N Me

Bu

(R)-248

O

O

O

O

O PACP

Scheme 74 Synthesis of indolizinones due to promotion of CO migration by ligand selection. R = Bn, n-Hex, (CH2)4CO2Me, (CH2)4Cl, (CH2)4OTBS, (CH2)3CON(OMe3), Me, (CH2)5C≡CH or (CH2)2Ph.

O

O O

PACP

Scheme 73 Synthesis of hyperbranched polymers via a rutheniumcatalyzed polycyclotrimerization reaction

Although beyond the scope of this review, the intriguing work performed by Rovis and colleagues on developing a universal strategy towards indolizinones cannot go unmentioned.74e As described in section 4, unexpected formation of 4-pyridones in the transition-metal-catalyzed [2+2+2] cyclocotrimerization of alkynes and isocyanates, due to CO migration, provided better understanding of the mechanism. This unexpected, but welcome, finding inspired the authors to tune the product selectivity by ligand design. First, a proof-of-concept was obtained for a single system also providing a catalyst system suitable for facilitating CO migration. Switching from a TADDOL-based ligand to a BINOL derivative resulted in complete inverSynthesis 2012, 44, A–AH

Although most transition-metal-catalyzed [2+2+2]-cyclotrimerization reactions are carried out in organic solvents under an inert atmosphere, they can also be performed under mild conditions in water using an open flask. This was recently demonstrated by Tsai and coworkers who reported a novel catalyst system (Scheme 75).105 The importance of greener production methods is steadily increasing. Besides the fact that water is readily available, using it as a solvent also has the advantage that it allows easy separation of often expensive metal catalysts.106 The research group previously developed the water-soluble cationic 2,2′-bipyridyl ligand 252 that is able to bring transition-metal salts or complexes into the aqueous phase for employment as reusable catalysts. After demonstrating a broad range of transition-metal-catalyzed reactions in water using ligand 252, the authors then used it for several partially intermolecular rhodium(I)-catalyzed [2+2+2]-cyclotrimerization reactions. Tri- and tetrasubstituted benzenes were obtained in moderate to good yields. An interesting and noteworthy feature is that after © Georg Thieme Verlag Stuttgart · New York


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simple extraction of the products and unconsumed substrate from the reaction mixture with an organic solvent, the remaining aqueous layer – still containing the active catalyst – could be used again. This reuse was demonstrated up to two times, albeit with decreased yields. However, the ‘green factor’ of this reaction is questionable since the rhodium source, [Rh(cod)Cl]2, is first dissolved in dichloromethane to be transferred into the reaction mixture, followed by evaporation of the dichloromethane.

further elucidation of the reaction mechanism and synthetic utility of the reaction. R2 R1

R2

[RhOH(cod)] PPh3

R2

40–88%

Z Br

BF3K 254

NMe3+

Me3N

Br R1 Z R2 251

N

N

[Rh(cod)Cl]2 KOH, H2O, air

R2

Z

255

R1 Z

th

pa

R2

38–90%

Br path a

253

As described in the previous sections, nearly all transition-metal-catalyzed [2+2+2]-cyclotrimerization strategies have certain limitations, either in regioselectivity, substrate scope, chemoselectivity or other areas. Therefore, it is important to develop new strategies to broaden the scope of the reaction and demonstrate the potential of transition-metal catalysis. With this thought in mind, Tong and co-workers set out to develop such a strategy which they recently reported.107 Instead of using an alkyne to react with a diyne, potassium (Z)-(2-bromovinyl)trifluoroborate (254) was used as an alkyne equivalent. In the rhodium(I)-catalyzed reaction, depicted in Scheme 76, compound 254 is thought to first react with the rhodium catalyst to form the corresponding vinyl–rhodium(I) intermediate A. A subsequent alkyne insertion results in the formation of intermediate B. From here, two routes towards rhodacycloheptatriene E are proposed: (1) a second insertion of the alkyne forming intermediate C followed by an intramolecular oxidative addition (path ‘a’); (2) intramolecular oxidative addition forming rhodacyclopentadiene D followed by insertion of the alkyne (path ‘b’). The authors speculate that the reaction occurs via path ‘a’, based on the isolation of a side product that can only form via an intermediate of type C. However, they duly note that they do not have sufficient evidence to exclude the mechanism operating via path ‘b’. With the developed reaction, a variety of diynes 255 and two potassium (Z)-(2bromovinyl)trifluoroborates 254 were reacted, affording the corresponding substituted benzenes in moderate to high yields. Tong and colleagues are currently working on

RhI Z

R

b

D

RhIII R1

Z

R2

E

Br

B R2

R1

Z

R2

R1

R2

Future Directions


I A Rh

Br–

R1

2

Scheme 75 A cyclotrimerization reaction in water with a water- and air-stable catalyst. R1 = H, Et, n-Pr, t-Bu or CH2CO2Me; R2 = Et, nPr, n-Hex, Ph, (CH2)2OH, CH2CO2Me, t-Bu or CH2OH; Z = O, NTs, C(CH2OMe)2 or C(CO2Me)2.

6

– RhI RhIII

252

R2

Br–

R1

Br–

Br–

R1 256

RhI R2

C

Scheme 76 A rhodium-catalyzed cyclotrimerization between a diyne and a (Z)-(2-bromovinyl)trifluoroborate. Z = NTs, O, C(CO2Et)2; R1 = n-Bu or Ph; R2 = H, n-Bu, Ph, CH2OMe or CH2OAc.

Catalysis in [2+2+2]-cyclotrimerization reactions is not limited to the use of transition-metal catalysts. A recent example of a lanthanide-catalyzed [2+2+2]-cyclotrimerization reaction has been reported by Zhou and co-workers (Scheme 77).108 They found that when a catalytic amount of the Lewis acid, iron(III) chloride, is added to a mixture of Y[N(TMS)2]3 and a terminal alkyne (257), the reaction switches from alkyne dimerization109 to cyclotrimerization. The reaction using the heterobimetallic catalyst system was able to cyclotrimerize various terminal aromatic alkynes in good to nearly quantitative yield and excellent regioselectivity for the 1,2,4-isomer 258. Electron-withdrawing substituents on the alkyne seemed to have a positive effect on the yields. Aliphatic alkynes also underwent cyclotrimerization, albeit with low regioselectivity. Interestingly, cyclotrimerization also occurred smoothly using yttrium(III) chloride and Fe[N(TMS)2]3. However, no cyclotrimerization product was detected when only one of the metals was present. This indicates that both yttrium(III) and iron(III) are part of the catalytic cycle. The proposed catalytic cycle shows no similarity with those described in earlier sections. The rationale behind the change from dimerization to cyclotrimerization is that coordination of iron(III) to the alkyne favors insertion of a second alkyne. This is achieved by reducing the basicity of lanthanide intermediates, preventing protonation of alkynyl-substituted alkenyl lanthanide intermediates 260 which would lead to the dimerization products. Skeptics might argue that yttrium is a transition metal. However, the authors also successfully demonstrated the reaction with samarium, which is most definitely a lanthanide.



+

Z

255 R2

250

AE


REVIEW


R R

Y(N(TMS)2)3 FeCl3

R

60–99% 257

R

R

[Y] R

R

258

FeCl3

R 259 R

260

52:48 to 99:1

Scheme 77 A heterobimetallic-catalyzed alkyne cyclotrimerization reaction. R = Ph, n-Bu, n-Hex, Cy, TMS, 4-ClC6H4, 4-F-3-MeC6H4, 4-MeC6H4, 4-(C5H11)C6H4, 4-MeOC6H4 or 4-(t-Bu)C6H4OCH2.

7

Conclusion

Transition-metal-catalyzed [2+2+2]-cyclo(co)trimerization reactions are a powerful tool in the chemist’s synthetic toolbox. However, the chemist that possesses the tool should be well aware of its limitations. A significant number of studies have provided a great deal of mechanistic insight into the reaction of focus. However, a truly general mechanism, applicable for all cyclo(co)trimerization reactions, is absent and might remain that way. This is because the reaction might be too sensitive to small changes in substrate, reaction conditions and catalyst to establish a generally applicable mechanism. More studies, especially for the synthesis of pyridones, are needed and might prove this wrong. Intermolecular cyclo(co)trimerizations are still, and may always remain, plagued by poor regioselectivity. There are exceptions to this, but these are commonly very substrate- or product- specific. Fortunately, this can be solved by a (partially) intramolecular approach. The use of temporary tethers, regiodirecting groups, careful choice of substrates or the use of alkyne analogues can also provide a solution. This is especially well demonstrated by their recent applications. Asymmetric cyclo(co)trimerization reactions have been demonstrated to be a powerful tool for enantioselective synthesis, especially for axially chiral biaryls. This is still a field with room for novel discoveries and it would be fascinating to see it applied beyond the synthesis of axially chiral ligands. Despite their limitations, [2+2+2]-cyclo(co)trimerization reactions are a welcome alternative for other reactions such as electrophilic aromatic substitution reactions in the synthesis of substituted benzenes, pyridines, and pyridones. Without a doubt, new developments in the field will continue to broaden the applicability of the reaction as it fits perfectly with modern society’s demand for atom-efficiency.

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AF


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