HETEROCYCLES

Review | Regular issue | Vol. 85, No. 5, 2012, pp. 1017-1043
Received, 17th January, 2012, Accepted, 20th February, 2012, Published online, 22nd February, 2012.
DOI: 10.3987/REV-12-729

■ Rhodium-Catalyzed [2+2+2] Cycloaddition for the Synthesis of Substituted Pyridines, Pyridones, and Thiopyranimines

Ken Tanaka*

Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo184-8588, Japan

Abstract

The transition-metal-catalyzed [2+2+2] cycloaddition of alkynes with nitriles is a useful and atom-economical method for the synthesis of substituted pyridines. The use of isocyanates and isothiocyanates in place of nitriles affords substituted pyridones and thiopyranimines, respectively. This review comprehensively covers the [2+2+2] cycloaddition reactions catalyzed by rhodium complexes for the synthesis of substituted pyridines, pyridones, and thiopyranimines. Asymmetric variants of these rhodium-catalyzed [2+2+2] cycloaddition reactions are also described.

CONTENTS
1. Introduction
2. Synthesis of Substituted Pyridine by [2+2+2] Cycloaddition of Alkynes with Nitriles
2-1. Intermolecular Reactions
2-2. Partially Intramolecular Reactions
2-3. Completely Intramolecular Reactions
3. Synthesis of Substituted Pyridones by [2+2+2] Cycloaddition of Alkynes with Isocyanates
3-1. Intermolecular Reactions
3-2. Partially Intramolecular Reactions
4. Synthesis of Substituted Thiopyranimines by [2+2+2] Cycloaddition of Alkynes with Isothiocyanates
5. Conclusion

1. INTRODUCTION
The transition-metal-catalyzed [2+2+2] cycloaddition of alkynes with nitriles has been actively investigated to date for the synthesis of substituted pyridines.1 Because different substituents can be introduced through the formation of the pyridine ring in the transition-metal-catalyzed [2+2+2] cycloaddition, this method is occasionally more advantageous than the conventional substitution or cross-coupling method for the synthesis of densely substituted pyridines. Since the pioneering works by Yamazaki and Wakatsuki,2 Vollhardt,3 and Bönnemann,4 cobalt catalysts have been most widely used for this transformation and a number of useful synthetic applications, including the synthesis of natural products5 and oligopyridines,6 have been reported.7 Not only cobalt complexes but also other transition-metal complexes have been employed. For example, ruthenium complexes are highly efficient catalysts for the reactions between tethered 1,6-diynes and activated nitriles under mild reaction conditions.8 Nickel,9 titanium,10 and tantalum11 complexes are also effective for this transformation, although stoichiometric amounts of metals are required. Recently, nickel/N-heterocyclic carbene complexes12a,b and a nickel/Xantphos complex12c are found to catalyze the [2+2+2] cycloaddition of internal alkynes with inactivated nitirles at room temperature.

Rhodium-based catalysts are known to be effective catalysts for the [2+2+2] cycloaddition.13 In 1974, Müller reported the synthesis of substituted benzenes via the rhodium-mediated [2+2+2] cycloaddition of alkynes with rhodacyclopentadienes, which were prepared via the oxidative cyclization of tethered diynes with Wilkinson’s complex [RhCl(PPh3)3].14 After this pioneering work, in 1982, Grigg and co-workers reported a catalytic variant of this reaction using Wilkinson’s complex as a catalyst.15 The first example of the rhodium-catalyzed [2+2+2] cycloaddition of alkynes with nitriles was accomplished in 1987 by Ingrosso and co-workers using a cyclopentadienyl rhodium(I) complex as a catalyst.16 In 2003, Tanaka and co-worker discovered that cationic rhodium(I)/biaryl bisphosphine complexes are highly active and selective catalysts for the [2+2+2] cycloaddition of alkynes.17 After this discovery, in 2006, the cationic rhodium(I)/biaryl bisphosphine complexes were successfully applied to the [2+2+2] cycloaddition of alkynes with nitriles.18

Several reviews already summarized the pyridine synthesis via the transition-metal-catalyzed [2+2+2] cycloaddition,1 while a review covering comprehensively the synthesis of pyridines via the rhodium-catalyzed [2+2+2] cycloaddition has not been appeared. Very recently, our research group comprehensively summarized the synthesis of substituted benzenes via the rhodium-catalyzed [2+2+2] cycloaddition of alkynes.13a In this review, the rhodium-catalyzed [2+2+2] cycloaddition of alkynes with nitriles for the synthesis of substituted pyridines is comprehensively summarized by classifying the reaction patterns (Scheme 1). In addition to the pyridine synthesis, the rhodium-catalyzed [2+2+2] cycloaddition of alkynes with isocyanates and isothiocyanates for the synthesis of substituted pyridones and thiopyranimines, respectively, is also described (Scheme 1). Finally, asymmetric variants of these reactions catalyzed by the cationic rhodium(I)/axially chiral biaryl bisphosphine complexes are also presented.

2. SYNTHESIS OF SUBSTITUTED PYRIDINES
2-1. Intermolecular Reactions
The first report of the rhodium-catalyzed [2+2+2] cycloaddition of alkynes with nitriles is the intermolecular [2+2+2] cycloaddition of terminal alkynes 1 with nitriles 2 catalyzed by a cyclopentadienyl rhodium(I) ethylene complex, [CpRh(C2H4)2], which was reported by Ingrosso and co-workers in 1987 (Scheme 2).16,19 In order to suppress the undesired formation of benzene derivatives through the homo-[2+2+2] cycloaddition of alkynes, nitrile to alkyne molar ratios higher than 5 were employed. This reaction was moderately regioselective and two regioisomers 3 and 4 were generated. Although this complex is long-lived catalyst, high reaction temperature (150 °C) was required to promote the desired cycloaddition. The use of polymer-anchored cyclopentadienyl rhodium(I) complexes was also reported by Ingrosso and co-workers.20

After this report, Costa and co-workers reported that the use of a [MDMCpRh(C2H4)2] complex in place of the [CpRh(C2H4)2] complex improved the yield of the intermolecular [2+2+2] cycloaddition products 3aa and 4aa from terminal alkyne 1a and propionitrile (2a) (Scheme 3).21

In 2006, Tanaka and co-workers reported that a cationic rhodium(I)/BINAP complex was found to be a highly active catalyst for the intermolecular [2+2+2] cycloaddition of alkynes with nitriles under mild reaction conditions.18 The reaction of terminal alkyne 1b with electron-deficient nitrile 2b in the presence of [Rh(cod)2]BF4/BINAP (2.5 mol %) at 60 °C afforded the corresponding pyridines 3bb and 4bb in high yields, and 3bb was obtained as a major regioisomer (Scheme 4).

As terminal alkyne substrates, aryl ethynyl ethers can also be employed. The intermolecular [2+2+2] cycloaddition of aryl ethynyl ethers 5 with both electron-deficient and electron-rich nitriles 2 in the presence of the cationic rhodium(I)/H8-BINAP catalyst proceeded at room temperature to give 2,4-diaryloxypyridines 6 as a single regioisomer in good yields (Scheme 5).22

2-2. Partially Intramolecular Reactions
In 1987, Ingrosso and co-workers reported that the cyclopentadienyl rhodium(I) ethylene complex, [CpRh(C2H4)2], is able to catalyze the partially intramolecular [2+2+2] cycloaddition of 1,7-diyne 7a with propionitrile (2a) at 150 °C (Scheme 2).16 However, the desired bicyclic pyridine 8aa was obtained in low yield due to the formation of unidentified by-products.

In 2006, Tanaka and co-workers successfully applied the cationic rhodium(I)/biaryl bisphosphine (BINAP, Segphos, and H8-BINAP) catalysts to the partially intramolecular [2+2+2] cycloaddition of 1,6-diynes with nitriles under mild reaction conditions (Table 1).18 The reactions of various internal and terminal 1,6-diynes 7b–f with 2c afforded the corresponding pyridines in excellent yields (entries 1–5).

With respect to nitriles, the reactions of electron-deficient nitriles 2b–d with 7b afforded the corresponding pyridines in almost quantitative yields (entries 1, 6, and 7). In the cases of electron-rich nitriles 2e,f, the reactions proceeded in good yields using terminal diyne 7f and excess nitriles 2e,f (entries 8 and 9). Sulphur contaning nitriles 2g and 2h could participate in this cycloaddition, although high catalyst loading and elevated temperature were required (entries 10 and 11). Cyanamide 2i was more reactive than sulphur contaning nitriles to give the corresponding aminopyridine 8fi at 40 °C (entry 12). The reactions of 1,6-diynes 7b,f with malononitrile (2j) in the presence of the cationic rhodium(I)/H8-BINAP catalyst selectively afforded the corresponding monopyridines 8bj and 8fj, respectively, without the formation of bipyridines (entries 13 and 14).

In the above cationic rhodium(I)/biaryl bisphosphine complex-catalyzed [2+2+2] cycloaddition of 1,6-diynes with nitriles, electron-deficient nitriles showed high reactivity. Commercially available electron-deficient perfluoroalkylnitrile 2k was found to be a suitable cycloaddition partner with 1,6-diynes 7 to give the corresponding perfluoroalkylated pyridines 8 at room temperature in good yields (Table 2).23

It was found that phenol-linked 1,6-diynes 9 smoothly react with monoynes in the presence of the cationic rhodium(I)/H8-BINAP catalyst to give substituted dibenzofurans.24 The use of nitriles 2 in place of monoynes could furnish substituted azadibenzofurans at room temperature in good yields (Table 3).24 These reactions were highly regioselective and the corresponding meta-disubstituted azadibenzofurans 10 were obtained in good yields with excellent regioselectivities (entries 1, 2, and 4–9). However, the reactions of trimethylsilyl-substituted 1,6-diyne 9c with 2b furnished desilylated product 12cb along with ortho-disubstituted product 11cb in moderate yield (entry 3).

The formation of not only a five-membered ring but also six- and seven-membered rings was possible using 1,7-diyne 7i and 1,8-diyne 7j, respectively (Schemes 7 and 8).18 Importantly, these reactions smoothly proceed without Thorpe-Ingold effect.25

Grigg and co-workers reported that a 1,6-diyne selectively reacted with the double bond of acrylonitrile (2l) by using the RhCl(PPh3)3 catalyst.26 On the contrary, 1,6-diyne 7f selectively reacted with the cyano group of 2l in the presence of the cationic rhodium(I)/BINAP catalyst to give vinylpyridine 8fl in good yield (Scheme 9).18

Like acrylonitrile, the cyano group of 1-cyanovinyl acetate (2m) selectively reacted with 1,6-diyne 7b to give bicyclic 2-(1-acetoxyvinyl)pyridine 8bm in high yield (Scheme 10).27

The cationic rhodium(I)/biaryl bisphosphine complex-catalyzed [2+2+2] cycloaddition of unsymmetrical 1,6-diyne 7k, bearing the methyl and phenyl groups at each alkyne terminus, with ethyl cyanoformate (2b) proceeded at room temperature to give the corresponding pyridines 8kb and 8kb’ in good yield preferably 8kb over 8kb’ by using Segphos as a ligand (Scheme 11).18 Similarly, the reaction of 7k with malononitrile (2j) afforded 8kj as a predominant regioisomer (Scheme 11).18

The cationic rhodium(I)/Segphos catalyst was also effective for the regioselective [2+2+2] cycloaddition of unsymmetrical 1,6-diyne 7l, bearing the methyl and methoxycarbonyl groups at each alkyne terminus, with perfluoroalkylnitrile 2k to give the corresponding pyridine 8lk as a single regioisomer (Scheme 12).23

The use of the cationic rhodium(I)/axially chiral biaryl bisphosphine catalysts enabled asymmetric variants of the [2+2+2] cycloaddition of alkynes with nitriles. The enantioselective desymmetrization of monosubstituted malononitrile 2n with 1,6-diyne 7b proceeded at room temperature in the presence of a [Rh(cod)2]BF4/(R)-xyl-Solphos catalyst to give enantioenriched bicyclic pyridine (+)-8bn, possessing the tertiary stereocenter, in high yield with moderate ee value (Scheme 13).18 The reaction of 7b with sterically demanding disubstituted malononitrile 2o also proceeded at room temperature in the presence of a [Rh(cod)2]BF4/(R)-BINAP catalyst to give enantioenriched bicyclic pyridine (+)-8bo, possessing the quarternary stereocenter, in good yield, although the product ee value was low (Scheme 13).18

Subsequently, the atropselective arylpyridine synthesis were accomplished by using the cationic rhodium(I)/(R)-Segphos catalyst (Scheme 14).28 The reaction of 1,6-diyne 13, bearing the aryl groups at each alkyne terminus, with ethyl cyanoformate (2b) proceeded at room temperature to give axially chiral arylpyridine (+)-14 in good yield with excellent ee value.

The atropselective synthesis of a C2-symmetric acxially chiral bipyridine via the double [2+2+2] cycloaddition was also accomplished by using the same rhodium catalyst (Scheme 15).28 The reaction of tetrayne 15 with ethyl cyanoformate (2b) proceeded at room temperature to give axially chiral bipyridine (+)-16 with excellent ee value, although the product yield was low due to the formation of achiral regioisomers as by-products.

2-3. Completely Intramolecular Reactions
Heteroatom-containin C2-symmetric axially chiral spiranes are valuable compounds for efficient chiral ligands.29 However, their catalytic enantioselective synthesis is scarce.30 In 1999, Saá and co-workers reported a novel approach to spirobipyridine ligands via the cobalt(I)-catalyzed double partially intramolecular [2+2+2] cycloaddition of bis-alkynenitriles with monoynes, although the synthesis afforded racemates and the product yields were low.31

In 2007, Tanaka and co-workers reported the enantioselective synthesis of C2-symmetric spirobipyridines via the completely intramolecular double [2+2+2] cycloaddition of bis-diynenitriles by using the cationic rhodium(I)/axially chiral biaryl bisphosphine catalysts.32 The [2+2+2] cycloaddition of various aryl-substituted bis-diynenitriles 17a–c proceeded at room temperature to give the corresponding C2-symmetric spirobipyridines 18a–c in high yields with good ee values by using (S)-Segphos as a ligand (Scheme 16). Not only aryl-substituted bis-diynenitriles but methyl-substituted and terminal bis-diynenitriles 17d,e could also participate in this process to give the corresponding C2-symmetric spirobipyridines 18d,e in high yields with moderate ee values by using (R)-H8-BINAP as a ligand (Scheme 16).

Furthermore, C2-symmetric spirobipyridines 20, possessing six-membered spiro skeletons, could be synthesized from bis-diynenitriles 19 in high yields by using (S)-Segphos or (R)-H8-BINAP as a ligand, although lower enantioselectivities were observed (Scheme 17).32

In 2010, Pla-Quintana, Roglans, and co-workers reported the synthesis of tricyclic pyridines via the completely intramolecular [2+2+2] cycloaddition of diynenitriles by using RhCl(PPh3)3 as a catalyst.33 The [2+2+2] cycloaddition of tosylamide-linked internal diynenitriles 21a–c proceeded at elevated temperature to give the corresponding tricyclic pyridines 22a–c in moderate to high yields (Scheme 18). However, tosylamide-linked terminal diynenitrile 21d did not afford the corresponding tricyclic pyridine 22d at all (Scheme 18).

In these reactions, the microwave heating dramatically enhanced the catalytic efficiency and broadened the substrate scope.33 Both internal and terminal diynenitriles 21, possessing tosylamide, oxygen, and malonate linkages, smoothly cyclized in the presence of the RhCl(PPh3)3 catalyst to give the corresponding tricyclic pyridines 22 in high yields (Scheme 19).

3. SYNTHESIS OF SUBSTITUTED PYRIDONES
3-1. Intermolecular Reactions
The transition-metal-catalyzed [2+2+2] cycloaddition of alkynes with isocyanates has also been actively investigated to date for the synthesis of substituted 2-pyridones.1 The pioneering work for such a catalytic formation of 2-pyridones was first reported by Yamazaki using cobalt catalysts34 and by Hoberg using nickel catalysts.35 Subsequently, Vollhardt reported the cobalt-catalyzed partially intramolecular [2+2+2] cycloaddition of 5-isocyanatoalkynes.36 Takahashi reported the selective preparation of 2-pyridones from two different internal alkynes and isocyanates via formation of azazirconacyclopentenones followed by transmetalation with Ni(PPh3)2Cl2 using stoichiometric amounts of zirconiumu and nickel.37 Yamamoto and Itoh reported the ruthenium-catalyzed [2+2+2] cycloaddition of 1,6-diynes with isocyanates under mild reaction conditions.38 Recently, Louie demonstrated that a Ni(cod)2/SIPr [1,3-bis-(2,6-diisopropylphenyl)imidazolin-2-ylidene] complex efficiently catalyzes the [2+2+2] cycloaddition of alkynes with isocyanates at room temperature.39

The first example of the rhodium-catalyzed [2+2+2] cycloaddition of alkynes with isocyanates was reported in 1985 by Flynn and co-workers.40 They found that the intermolecular [2+2+2] cycloaddition of methyl 2-butynoate (23a) or 3-phenylpropiolate (23b) with aryl isocyanates 24 proceeds at elevated temperature to give the corresponding 2-pyridones 25 as a single regioisomer by using neutral rhodacycle A as a catalyst, while the product yields were low (Scheme 20).

In 2006, Kondo, Mitsudo, and co-workers reported a more efficient rhodium(I) catalyst for this transformation. They found that a neutral rhodium(I) complex, [RhCl(C2H4)2]2/PPh3, is able to catalyze the intermolecular [2+2+2] cycloaddition of excess 3-hexyne (23c) with both alkyl and aryl isocyanates 24 at 120 °C to give the corresponding 2-pyridones 25 in moderate to good yields (Scheme 21).41

Interestingly, the use of excess isocyanate 24a afforded not the corresponding 2-pyridones 25 but the corresponding pyrimidine-2,4-diones 26 in good yields with good regioselectivity (Scheme 22). 41

In 2009, Rovis and co-workers reported a highly regioselective catalyst for this transformation. They found that a neutral rhodium(I)/phosphoramidite (B) complex is an effective catalyst for the highly regioselective intermolecular [2+2+2] cycloaddition of terminal alkynes with isocyanates.42 A wide variety of terminal alkynes 1 reacted with benzylisocyanate (24b) at 110 °C to give the corresponding 2-pyridones 27 in moderate to high yields with perfect regioselectivities (Scheme 23).

With respect to isocyanates, both alkyl and aryl isocyanates 24 could participate in this regioselective [2+2+2] cycloaddition.42 Interestingly, 4-pyridones 28 were also generated in these reactions, especially in the cases of aryl isocyanates, through a CO migration in the rhodacycle intermediate (Scheme 24).43

The above-mentioned catalysts required elevated temperature to promote the desired cycloaddition reactions. In 2005, Tanaka and co-workers reported that a cationic rhodium(I)/H8-BINAP complex is able to catalyze the intermolecular [2+2+2] cycloaddition of terminal alkynes with isocyanates at room temperature (Scheme 25).44 Regioselectivities were highly dependent on the alkynes used. Although the reaction of conjugated alkyne (R1 = 1-cyclohexenyl) furnished isomer 27 as a sole product, the reaction of nonconjugated alkyne (R1 = n-C10H21) furnished a mixture of isomers 27 and 29. On the other hand, the reaction of (trimethylsilyl)acetylene furnished isomer 30 as a sole product.

As shown in Scheme 5, aryl ethynyl ethers are reactive substrates in the cationic rhodium(I) complex-catalyzed [2+2+2] cycloaddition. The intermolecular [2+2+2] cycloaddition of aryl ethynyl ethers 5 with both electron-deficient and electron-rich nitriles 24 proceeded at room temperature in the presence of the cationic rhodium(I)/H8-BINAP catalyst to give the corresponding 4,6-diaryloxy-2-pyridones 31 with perfect regioselectivity, although the product yields were low to moderate (Scheme 26).22

3-2. Partially Intramolecular Reactions
The cationic rhodium(I)/H8-BINAP complex is the highly effective catalyst for not only intermolecular [2+2+2] cycloaddition but also partially intramolecular one (Table 4).44 The reactions of both internal 1,6-diynes 7b,d (entries 1–3, 6, and 7) and terminal 1,6-diynes 7f,m (entries 4, 5, and 8) with both alkyl isocyanates 24b,c,e (entries 1, 2, and 4–8) and aryl isocyanate 24d (entry 3) afforded the desired 2-pyridones 32 in good yields. In general, the reactions of internal 1,6-diynes 7b,d proceeded in higher yields than those of terminal 1,6-diynes 7f,m, due to the lower reactivity toward the homo-[2+2+2] cycloaddition.

As shown in Table 3, phenol-linked 1,6-diynes can be employed in the cationic rhodium(I) complex-catalyzed [2+2+2] cycloaddition. The reaction of phenol-linked 1,6-diyne 9a with isocyanate 24b afforded the corresponding 2-pyridone-fused benzofuran 33 in good yield as a single regioisomer (Scheme 27).24

Not only 1,6-diynes but also 1,7- and 1,8-diynes 7 could be employed for this reaction to give six- or seven-membered ring fused 2-pyridones 32 in moderate to high yields (Schemes 28 and 29).44 Like the pyridine synthesis, these reactions smoothly proceed without Thorpe-Ingold effect.25

The use of the cationic rhodium(I)/axially chiral biaryl bisphosphine catalyst enabled the atropselective 2-pyridone synthesis (Table 5).44 The reactions of 2-chlorophenyl (entries 1–3, 5, and 6) or 2-bromophenyl-substituted unsymmetrical 1,6-diynes 7 (entry 4) with alkyl isocyanates 24 in the presence of a cationic rhodium(I)/(R)-DTBM-Segphos catalyst proceeded at –20 °C to give sterically demanding and axially chiral regioisomers (+)-32 with good yields and ee values.

The high catalytic activity of the cationic rhodium(I)/axially chiral biaryl bisphosphine catalyst allowed the atropselective synthesis of a sterically more demanding tetra ortho-substituted 2-pyridone (Scheme 30).28 The reaction of 1,6-diyne 13, bearing the aryl groups at each alkyne terminus, with isocyanate 24c proceeded at room temperature in the presence of the cationic rhodium(I)/(S)-Segphos catalyst to give axially chiral 2-pyridone (+)-33 with moderate yield and ee value

The atropselective double [2+2+2] cycloaddition for the synthesis of a C2-symmetric axially chiral bipyridone was also reported (Scheme 31).28 The reaction of tetrayne 15 with isocyanate 24c proceeded at room temperature in the presence of the cationic rhodium(I)/(S)-Segphos catalyst to give axially chiral bipyridone (–)-34 in high yield, although the product ee value was moderate.

4. SYNTHESIS OF SUBSTITUTED THIOPYRANIMINES
The transition-metal-catalyzed [2+2+2] cycloaddition of alkynes with isocyanates leading to substituted 2-pyridones has been developed using a number of transition-metal complexes.1 In sharp contrast, only a few examples have been reported for the corresponding reaction with isothiocyanates in place of isocyanates to produce substituted thiopyranimines.45,46 The pioneering work for such a transition-metal-catalyzed or mediated [2+2+2] cycloaddition of alkynes with isothiocyanates was first reported by Yamazaki using a stoichiometric amount of a cobaltacyclopentadiene.45 Subsequently, Yamamoto and Itoh realized the catalytic version of this reaction using a Cp*Ru(cod)Cl complex as a catalyst.46

In 2006, Tanaka and co-workers reported that the neutral rhodium(I)/BINAP complex is a highly effective catalyst for the [2+2+2] cycloaddition of 1,6-diynes with isothiocyanates (Table 6).47 Interestingly, the neutral rhodium(I)/BINAP complex showed higher catalytic activity than the cationic rhodium(I)/BINAP complex for this cycloaddition. Malonate-linked terminal 1,6-diyne 7f reacted with a wide variety of isothiocyanates 35a–f at 80 °C in the presence of a neutral rhodium(I)/BINAP catalyst to give the corresponding bicyclic thiopyranimines 36 in good yields (entries 1–6). With respect to 1,6-diynes, 1,3-diketone derivative 7s and the 1,3-diol derivative 7t gave the corresponding thiopyranimines 36sa and 36ta in high yields (entries 7 and 8). On the contrary, tosylamide- and ether-linked 1,6-diynes could not participate in this reaction. Thus, the aid of the Thorpe-Ingold effect25 induced by the quaternary center at the 4-position of 1,6-diynes is necessary for this reaction. In addition to isothiocyanates, carbon disulfide 35g could also be employed in this cycloaddition (entries 9–11).

An asymmetric variant of this reaction was also reported in the enantioselective desymmetrization of a 1,6-diyne (Scheme 32).47 The reaction of phenylacetate-derived 1,6-diyne 7u with phenyl isothiocyanate (35a) in the presence of the neutral rhodium(I)/(R)-BINAP catalyst proceeded at 60 °C to give enantioenriched thiopyranimine (R)-(+)-36ua in excellent yield with moderate ee value (Scheme 32). However, Interestingly, the reactions using alkyl isothiocyanates gave the corresponding cycloaddition products with <10% ee values.

5. CONCLUSION
As described in this review, several rhodium-based catalysts have been developed for the rhodium-catalyzed [2+2+2] cycloaddition reactions of alkynes with nitriles, isocyanates, and isothiocyanates. In the pyridines synthesis, the cyclopentadienyl rhodium(I) complexes are able to catalyze the intermolecular [2+2+2] cycloaddition of terminal alkynes with nitriles at elevated temperature. Wilkinson’s complex, RhCl(PPh3)3, is effective for the intramolecular [2+2+2] cycloaddition of diynenitriles under microwave heating. The cationic rhodium(I)/biaryl bisphosphine complexes are widely applicable catalysts for both intermolecular and intramolecular [2+2+2] cycloaddition of alkynes with nitriles under mild reaction conditions. In the pyridone synthesis, the neutral rhodium(I)/monophosphine complexes are effective for the regioselective intermolecular [2+2+2] cycloaddition of terminal alkynes with isocyanates at elevated temperature. The cationic rhodium(I)/biaryl bisphosphine complexes are widely applicable catalysts for both intermolecular and intramolecular [2+2+2] cycloaddition of alkynes with isocyanates under mild reaction conditions. Interestingly, not the cationic rhodium(I)/biaryl bisphosphine complex but the neutral rhodium(I)/biaryl bisphosphine complex is effective for the [2+2+2] cycloaddition of 1,6-diynes with isothiocyanates. Importantly, the use of the cationic or neutral rhodium(I)/axially chiral biaryl bisphosphine complexes as catalysts allowed developing asymmetric variants of these reactions. Although the rhodium-based catalysts are expensive, these are highly stable and readily handled by using conventional laboratory equipments. Therefore, I believe that the rhodium-catalyzed [2+2+2] cycloaddition will be one of the useful strategies for the synthesis of conjugated nitrogen heterocycles.

ACKNOWLEDGEMENTS
I am grateful to the financial support by a Grant-in-Aid for Scientific Research (No. 20675002) from MEXT, Japan.

References

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