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Tetrahedron 70 (2014) 8681e8689

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Tetrahedron

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Iridium-catalyzed [2þ2þ2] cycloaddition of a,u-diynes with alkynylketones and alkynyl esters

Toru Hashimoto, Arisa Okabe, Takeshi Mizuno, Mao Izawa, Ryo Takeuchi *

Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo, Sagamihara, Kanagawa 252-5258, Japan

a r t i c l e i n f o

Article history:Received 1 August 2014Received in revised form 12 September 2014Accepted 12 September 2014Available online 19 September 2014

Keywords:IridiumCycloadditionAlkyneAlkynyl ketoneAlkynyl ester

* Corresponding author. Tel.: þ81 42 759 6231; faaddress: takeuchi@chem.aoyama.ac.jp (R. Takeuchi).

http://dx.doi.org/10.1016/j.tet.2014.09.0380040-4020/� 2014 Elsevier Ltd. All rights reserved.

a b s t r a c t

We found that the combination of [Ir(cod)Cl]2 and rac-BINAP served as an efficient catalyst for the[2þ2þ2] cycloaddition of 2,7-nonadiyne derivatives and related compounds with alkynyl ketones andalkynyl esters. The corresponding products were obtained in high yields under mild reaction conditions.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Aromatic compounds play important roles in chemistry as wellas material science. They are valuable building blocks for the syn-thesis of pharmaceuticals, agrochemicals, and functional materials.Traditionally, the synthesis of aromatic compounds has been basedon the electrophilic substitution of a benzene ring under acidicconditions, which gives waste as a by-product.1 Multisubstitutedbenzene requires a tediousmulti-step synthesis. Itwould be useful iforganic chemists could synthesize the precise structure of suchcompounds in a minimum number of steps and in an atom-economical manner. Transition metal catalysis is a good solutionto this problem. The transition metal-catalyzed [2þ2þ2] cycload-ditionof alkynes is an efficient andatom-economical reaction for thesynthesis ofmultisubstituted benzenes, sincemultiple bonds can beformed in a single operation under neutral conditions.2 A wide va-riety of transition metal complexes such as those of Ni,3 Co,4 Rh,5

Ru,6 Pd,7 and Fe8 have been reported as catalysts for the construc-tion of an aromatic ring by alkyne cycloaddition. Despite this prog-ress, there is still a need to further improve the catalyst efficiencyand regio- and stereoselectivity. Newcatalysts are needed to addressthese issues. In 2001, we first reported that an iridium complex wasan efficient catalyst for the [2þ2þ2] cycloaddition of a,u-diyneswith monoynes to give benzenes.9 However, the scope of function-alized monoynes that were suitable for use in this reaction is stillrelatively unexplored. Propargylic alcohols and propargylic amines

x: þ81 42 759 6493; e-mail

can be used in this reaction. However, we did not previously ex-amine monoynes in which a functional group is directly connectedto an alkyne carbon. The [2þ2þ2] cycloaddition of suchmonoynes isespecially important, since this reaction would be an atom-economical and direct route to benzene substituted with a func-tional group. Further extension of the scope of this reaction wouldincrease the value of an iridium catalyst in alkyne cycloadditionchemistry.10 In this article, we report the [2þ2þ2] cycloaddition ofa,u-diynes with alkynyl ketones and alkynyl esters. We performeda systematic study of the reaction andwere able to extend the scopeof the iridium-catalyzed cycloaddition of alkynes. The reaction de-scribed here is an atom-economical alternative to FriedeleCraftsacylation and related reactions that give waste as a by-product.

2. Results and discussion

2.1. Optimization of the reaction conditions

Diyne 1a reacted with alkynyl ketone 2a to give 3aa. The phos-phine ligand had a profound effect on the reaction. Screening ofphosphine ligands was performed in the reaction of diyne 1a with2.0 equiv of alkynyl ketone 2a in the presence of 1 mol % [Ir(cod)Cl]2under refluxing benzene at a ratio of P/Ir¼2. The results are sum-marized in Table 1. [Ir(cod)Cl]2 without any ligand gave 3aa in 36%yield (entry 1). PPh3 was not an effective ligand (entry 2), and theyield of 3aawas only 10%. The reaction using DPPE gave 3aa in 49%yield (entry 3) with a dimer of 1a (0.18 mmol) and a trimer of 1a(0.04 mmol). The reaction with 2a competed with the dimerizationand trimerization of 1a. In our previous study, DPPE was the most

Table 1Reaction of diyne 1a with alkynyl ketone 2aa

Entry Ligand Conditions Yield of 3aab (%)

1 None Benzene, reflux, 24 h 362c PPh3 Benzene, reflux, 24 h 103 DPPE Benzene, reflux, 3 h 494 DPPP Benzene, reflux, 24 h 305 DPPB Benzene, reflux, 24 h 206 DPPF Benzene, reflux, 24 h 137 BIPHEP Benzene, reflux, 24 h 878 rac-BINAP Benzene, reflux, 12 h 949 F-DPPE Benzene, reflux, 24 h 3310 Xantphos Benzene, reflux, 24 h 011 rac-BINAP Benzene, 50 �C, 19 h 5612 rac-BINAP EtOH, reflux, 19 h 6813 rac-BINAP THF, reflux, 18 h 7214 rac-BINAP DCE, reflux, 18 h 7515d rac-BINAP Benzene, reflux, 1 h 75

a Reaction conditions: 1a (1 mmol), 2a (2 mmol) in the presence of catalyst in solvent (5 mL).b Isolated yield.c PPh3 (4 mol %).d Compounds 1a (0.5 mmol), 2a (0.6 mmol) in the presence of catalyst in solvent (2.5 mL).

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e86898682

effective ligand for the reaction of 1awith a simple terminal alkyneand an internal alkyne such as 1-hexyne or 3-hexyne. Themoderateyield of 3aa could be explained by the fact that [Ir(cod)Cl]2/DPPEeffectively promoted the dimerization and trimerization of 1a. Asthe number of methylene units between the two phosphorousatoms in diphosphine increased from 2 to 4, the yield of 3aa de-creased from 49% to 20% (entry 5). Biaryldiphosphine was moreeffective for the reaction than DPPE, DPPP, DPPB, and DPPF. Thereaction using BIPHEP gave 3aa in 87% yield (entry 7). rac-BINAPwas the best ligand (entry 8), and 3aa was obtained in 94% yield.Xantphos and F-DPPE were less effective (entries 9 and 10). Thus,the reaction conditions were optimized using rac-BINAP as a ligand.A reduction in the reaction temperature from 80 �C to 50 �C

Table 2Scope of alkynyl ketone 2a

Entry Alkynyl ketone 2 T

1 2b: R1¼n-Hex, R2¼Et 22 2c: R1¼n-Oct, R2¼Et3c 2d: R1¼Ph, R2¼Et 24d 2e: R1¼1-cyclohexenyl, R2¼Et 25 2f: R1¼n-Bu, R2¼Ph6 2g: R1¼n-Bu, R2¼CH]CHCH3 17 2h: R1¼n-Oct, R2¼Me 18 2i: R1¼n-Bu, R2¼2-thienyl 19 2j: R1¼n-Bu, R2¼isopropyl 110 2k: R1¼n-Bu, R2¼n-Pent 1

a Reaction conditions: 1a (1 mmol), 2 (2 mmol), [Ir(cod)Cl]2 (0.01 mmol), rac-BINAP (b Isolated yield.c Toluene (5 mL).d BIPHEP (0.02 mmol).

decreased the yield of 3aa from 94% to 56% (entry 11). Benzene gavebetter results than EtOH, THF, and DCE (entries 12e14).

The molar ratio of 2a to 1a was important for obtaining 3aa inhigh yield. A decrease in the molar ratio of 2a/1a from 2 to 1.2decreased the yield of 3aa from 94% to 75% (entry 15). Thus, a ratioof 2.0 equiv of 2a to 1a is needed to obtain 3aa in high yield.

2.2. Scope of alkynyl ketones 2 and alkynyl esters 4

We examined the reaction of 1a with various alkynyl ketones 2under the optimized reaction conditions described above. A widerange of alkynyl ketones could be used in the reaction, and theresults are summarized in Table 2. The effect of the substituent on

ime (h) Product 3 Yield of 3b (%)

4 3ab 918 3ac 924 3ad 704 3ae 891 3af 567 3ag 767 3ah 828 3ai 537 3aj 759 3ak 91

0.02 mmol) in benzene (5 mL).

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e8689 8683

alkyne was examined by using ethyl ketone. A longer alkyl groupsuch as an n-hexyl group or n-octyl group gave good results. Diyne1a smoothly reacted with 2b and 2c to give 3ab and 3ac in re-spective yields of 91% and 92% (entries 1 and 2). Phenyl-substitutedketone 2d gave the product in a lower yield than with longer alkyl-substituted ketones 2b and 2c. The reaction with 2d gave 3ad in70% yield (entry 3). Alkenyl-substituted ketone 2e gave the product3ae in a yield that was comparable to those with longer alkyl-substituted ketones 2b and 2c. The reaction with 2e gave 3ae in89% yield (entry 4). The substituent on ketone also affected thereaction. The reactions of 1a with phenyl ketone 2f and alkenylketone 2g gave lower yields than those with ethyl ketone (2aec)(entries 5 and 6). The reaction of 1a with methyl ketone 2h gave3ah in 82% yield (entry 7). The reactionwithmethyl ketone 2h gavea slightly decreased yield compared to that with ethyl ketone 2c.The reaction with 2-thienyl ketone 2i gave a yield comparable tothat with phenyl ketone 2f (entry 8). A thiophene ring could tol-erate the reaction conditions. Due to the steric hindrance of theisopropyl group, the reaction with isopropyl ketone 2j gave theproduct in a lower yield than that with ethyl ketone 2a (entry 9). n-Pentyl ketone 2k gave a result similar to that with ethyl ketone 2b.The reaction with 2k gave 3ak in 91% yield (entry 10).

We next examined the reaction of diyne 1awith alkynyl esters 4under the optimized conditions described above. The results aresummarized in Table 3. The reaction of 1a with 4a gave a complexmixture. This decrease in the yield of 5aa was due to the fact thatthe cyclotrimerization of 4a competed with the reaction of 1awith4a. A longer alkyl chain on alkyne inhibited the cyclotrimerizationof 4. As a result, the yield of 5 increased. The reactions with 4a and4b gave 5aa and 5ab in respective yields of 83% and 88% (entries 2and 3). When the substituent on alkyne was a phenyl or alkenylgroup, the yields of the products were slightly lower than thoseobtained with alkyl-substituted substrates 4a and 4b (entries 4 and5). We previously reported [2þ2þ2] cycloaddition with dimethylacetylenedicarboxylate (DMAD).10b Alkyne in which both alkynecarbons are substituted by carbonyl group such as DMAD is highlyreactive toward self-cyclotrimerization. Two molecules of DMADreacted with one molecule of another alkyne to give 2:1 couplingproduct. The reaction of diynes such as 1awith DMAD did not give1:1 coupling product such as 5.

2.3. Scope of diynes 1

Various diynes were subjected to cycloaddition with alkynylketones and alkynyl esters in the presence of a catalytic amount of[Ir(cod)Cl]2 and rac-BINAP. The results are summarized in Table 4.Alkynyl ketone 2a and alkynyl ester 4b were used as monoyne

Table 3Scope of alkynyl esters 4a

Entry Alkynyl ester 4 Time (

1 4a: R¼Me 242 4b: R¼n-Pent 23 4c: R¼n-Oct 24 4d: R¼Ph 165 4e: R¼1-cyclohexenyl 7

a Reaction conditions: 1a (1 mmol), 4 (2 mmol), [Ir(cod)Cl]2 (0.01 mmol), rac-BINAP (b Isolated yield.

components, since these substrates gave good results as describedabove. Phenyl-substituted diyne 1b underwent cycloaddition with2a and 4b to give 6a and 6b in respective yields of 89% and 85%(entries 1 and 2). Although a phenyl group is more hindered thana methyl group, the reactivity of phenyl-substituted diyne 1b wascomparable to that of methyl-substituted diyne 1a. A terarylstructure in which a central aromatic ring was substituted witha carbonyl group could be easily constructed by this reaction in anatom-economical manner. Heteroaromatic substituents could beused instead of a phenyl substituent. The reactions of thiophene-substituted diyne 1c and pyridine-substituted diyne 1d withalkynyl ketone 2a gave good results (entries 3 and 5). The reactionof 1d with alkynyl ester 4b gave lower yields than that with 2a(entry 6). A ter(hetero)aryl structure is usually constructed bya sequential cross-coupling reaction. An advantage of this reactionover cross-coupling is that the ring can be constructed and con-nected in a single operation. Ethyl-substituted diyne 1e reactedwith 2a and 4b to give 6g and 6h in respective yields of 82% and 81%(entry 7 and 8). Both aromatic-substituted diyne and alkyl-substituted diyne could be used as substrates. In contrast, termi-nally unsubstituted diyne 1f gave a disappointing result. The re-action of 1fwith 2a and 4b did not give the corresponding product.Instead, the self-dimerization and -trimerization of 1f occurredpreferentially over the reaction with 2a and 4b. To suppress theself-dimerization and -trimerization of a diyne, slowaddition of thediyne by a syringe-pump is generally used. Therefore, we per-formed the slow addition of a mixture of diyne 1f and 2a or 4b toa catalytic solution under refluxing benzene. Products 6i and 6jwere obtained in low yields (entries 9 and 10). We tried the re-action of 1f with 4a. The corresponding product was not obtained.We next examined the effect of the diyne backbone on the reactionof methyl-substituted diyne. Similar to the reaction of malonate-derived diyne 1a, acetylacetone-derived diyne 1g reacted with 2aand 4b to give 6k and 6l in respective yields of 81% and 77% (entries11 and 12). Diyne 1h bearing a methone moiety gave a resultcomparable to those with malonate-derived diyne 1a andacetylacetone-derived diyne 1f (entries 13 and 14).Hydroxymethyl-substituted diyne 1i gave the product in a loweryield than diynes 1a, 1g, and 1h (entries 15 and 16). These resultsshowed that the substituent at the 5-position in 2,7-nonadiynestrongly affects cyclization. It is clear that the ThorpeeIngold ef-fect11 plays an important role in this reaction. Nitrogen-tethereddiyne 1j could be used as a substrate, and reacted with 2a and 4bto give 6q and 6r in respective yields of 53% and 64% (entry 17 and18). The reaction of 1j is a convenient route to functionalized 2,3-dihydro-1H-isoindole, which is an important structure in phar-maceuticals and agrochemicals.12 On the other hand, the reaction of

h) Product 5 Yield of 5b (%)

5aa Complex mixture5ab 835ac 885ad 765ae 68

0.02 mmol) in benzene (5 mL).

Table 4Scope of diyne 1a

Entry Diyne Monoyne Conditions Product 6 Yield of 6b (%)

1 2a Toluene, reflux, 24 h 6a 89

2 1b 4b Toluene, reflux, 24 h 6b 85

3d 2a Toluene, reflux, 2 h 6c 88

4d 1c 4b Toluene, reflux, 16 h 6d 88

5d 2a Toluene, reflux, 24 h 6e 88

6d 1d 4b Toluene, reflux, 17 h 6f 58

7 2a Benzene, reflux, 24 h 6g 82

8c 1e 4b Benzene, reflux, 5 h 6h 81

9e 2a Benzene, reflux, 6 h 6i 22

10c,d,e 1f 4b Benzene, reflux, 23 h 6j 25

11c 2a Benzene, reflux, 24 h 6k 81

12 1g 4b Benzene, reflux, 18 h 6l 77

13d 2a Toluene, reflux, 21 h 6m 73

14d 1h 4b Toluene, reflux, 24 h 6n 69

15c,d 2a Toluene, reflux, 24 h 6o 32

16 1i 4b Toluene, reflux, 24 h 6p 26

17c,d 2a Benzene, reflux, 1 h 6q 53

18c,d 1j 4b Benzene, reflux, 2 h 6r 64

a Reaction conditions: 1a (1 mmol), 2a or 4b (2 mmol), [Ir(cod)Cl]2 (0.02 mmol), rac-BINAP (0.04 mmol) in solvent (5 mL).b Isolated yield.c [Ir(cod)Cl]2 (0.01 mmol), rac-BINAP (0.02 mmol).d Compound 2a or 4b (3 mmol).e Slow addition of 2a or 4b (2 mmol) for 1 h.

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e86898684

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e8689 8685

bis (2-butyn-1-yl) ether and 2,8-decadiyne with 2a did not give thecorresponding product.

Ph

MeO2C

11

EtO

n-Bu

2 mol% [Ir(cod)Cl]24 mol% (R)-BINAP

EtOn-BuPh

MeO2C*

12

Yield 87%

2a

benzene, reflux, 1 h

Scheme 3. The reaction of 11 with 2a in the presence of (R)-BINAP.

2.4. Reaction with alkynyl aldehyde

Alkynyl ketones and alkynyl esters are good coupling partnersfor diyne 1. The reaction is an atom-economical route to aryl ke-tones and aryl esters. If an alkynyl aldehyde can be used for thereaction, the product is an aromatic aldehyde. Considering thataldehyde functionality can be easily transformed to various otherfunctional groups, the cycloaddition of a diyne with an alkynyl al-dehyde should be an atom-economical route to synthetically im-portant aromatic aldehydes instead of the conventionalVilsmeiereHaack synthesis,13 which gives waste as a by-product.We examined the reaction of diyne 1 with alkynyl aldehyde 7.The result was shown in Scheme 1. Despite the use of more forcingreaction conditions than in the reaction of diyne 1 with alkynylketone 2 or alkynyl ester 4, the reaction of diyne 1 with aldehyde 7resulted in the formation of product 8 in a lower yield. This resultled to the disappointing conclusion that alkynyl aldehyde 7 is not asgood of a coupling partner as alkynyl ketone 2 or alkynyl ester 4.

Scheme 1. The reaction of 1a with 7.

2.5. Reaction with alkynyl amide and alkynyl carboxylic acid

We examined the reaction of diyne 1awith alkynyl amide 9 andalkynyl carboxylic acid 10. Both reactions did not give the corre-sponding product.

2.6. Mechanistic considerations

Metallacyclopentadiene is a common intermediate in the[2þ2þ2] cycloaddition of alkynes.14 Various metal-lacyclopentadienes have been isolated and their reactivities havebeen studied. It is reasonable to consider that iridacyclopenta-diene15 could act as an intermediate for the reaction. Oxidativecyclization of diyne gives iridacyclopentadiene. The reaction ofiridacyclopentadiene with monoyne gives a final product(Scheme 2).

Scheme 2. Plausible reaction mechanism.

2.7. The reaction in the presence of (R)-BINAP

We examined the reaction of 11 with 2a in the presence of2 mol % of [Ir(cod)Cl]2 and 4 mol % of (R)-BINAP. Product 12 wasobtained in 87% yield with 7% ee (Scheme 3).

3. Conclusion

In summary, we could extend the scope of iridium-catalyzed[2þ2þ2] cycloaddition to give benzene derivatives by choosinga suitable phosphine. We have shown that a monoyne in whicha carbonyl group is directly substituted to an alkyne carbon isa good coupling partner for a,u-diyne. This success gives an atom-economical route to functionalized benzene derivatives. This re-action is an alternative to the conventional FriedeleCrafts reaction.The experimental procedure is very simple and convenient. Theprocedure simply requires mixing of [Ir(cod)Cl]2 and an appropri-ate diphosphine ligand in solvent before the addition of substrates.The results described here should lead to new opportunities for theapplication of iridium complex catalysis in cycloaddition chemistry.

4. Experimental section

4.1. General

1H and 13C NMR spectra were measured on a JEOL JNM-ECP500A, JEOL ECS-400, and JEOL Excalibur 270 spectrometers usingTMS as an internal standard. Samples were dissolved in CDCl3. GCanalyses were performed on a Shimadzu GC-14B using3.2 mm�2 m glass columns packed with 5% OV-17 on 60/80 meshChromosorb WAW-DMCS. The products were purified by columnchromatography on 63e210 mesh silica gel (Kanto Kagaku; SilicaGel 60N). High-resolution mass spectra were obtained with a JEOLMstation JMS-700. All reagents and solvents were dried and puri-fied before use by the usual procedures. [Ir(cod)Cl]2 was preparedas described previously.16 Diynes 1a,10d 1e,17 1f,10d 1g,18 1j,18 and1117 were prepared as described in the literature. Diyne 1h wasprepared by reaction of the sodium salt of dimedonewith 1-bromo-2-butyne.19 Aldehyde 7 was prepared as described in the litera-ture.20 Amide 9 was prepared by the reaction of acid 10 with N,N-diethylamine.21 Esters 4aed and acid 10 were purchased.

4.2. Reaction of diyne 1a with alkynyl ketone 2

Representative procedure for the [2þ2þ2] cycloaddition of diyne1a with alkynyl ketone 2.

A flask was charged with [Ir(cod)Cl]2 (7.0 mg, 0.01 mmol) andrac-BINAP (12.2 mg, 0.02 mmol). The flask was evacuated and filledwith argon. To the flask were added benzene (5 mL) and 4-nonyn-3-one (2a) (279 mg, 2.0 mmol). Diyne 1a (234 mg, 1.0 mmol) wasadded to the reactionmixture. Themixturewas stirred under refluxfor 12 h. The progress of the reaction was monitored by GLC. After

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e86898686

the reaction was complete, the solvent was evaporated in vacuo.Column chromatography of the residue gave 3aa (n-hexane/AcOEt¼8:2, 348 mg, 0.93 mmol, 94% yield).

4.2.1. Dimethyl 5-butyl-4,7-dimethyl-6-propionyl-1H-indene-2,2-(3H)-dicarboxylate (3aa). Yellow oil; Rf¼0.46 (hexane/AcOEt¼7:3);IR (neat) 2954, 2933, 2873, 1732, 1704, 1593, 1431, 1274, 1249, 1199,1164, 1081, 1063, 950, 924, 859, 805, 731; 1H NMR (CDCl3,500 MHz) d 0.91 (t, J¼6.5 Hz, 3H), 1.19 (t, J¼7.0 Hz, 3H), 1.31e1.44(m, 4H), 2.05 (s, 3H), 2.17 (s, 3H), 2.34e2.37 (m, 2H), 2.69 (q,J¼7.0 Hz, 2H), 3.52 (s, 2H), 3.56 (s, 2H), 3.76 (s, 6H); 13C NMR(CDCl3, 125 MHz) d 7.6, 13.7, 15.1, 15.9, 23.1, 30.6, 33.0, 38.6, 39.7,40.3, 53.0, 59.2, 125.0, 129.6, 134.8, 136.6, 139.3, 141.9, 172.2, 211.7;HRMS (EI) m/z [M]þ calcd for C22H30O5 374.2093; found 374.2079.

4.2.2. Dimethyl 5-hexyl-4,7-dimethyl-6-propionyl-1H-indene-2,2-(3H)-dicarboxylate (3ab). Yellow solid; Rf¼0.50 (hexane/AcOEt¼7:3); IR (neat) 2955, 2932, 2871, 1745, 1724, 1701, 1593, 1428,1309,1255,1195,1173,1058, 957, 944, 856;mp56.8e58.2 �C; 1HNMR(CDCl3, 500 MHz) d 0.88 (t, J¼7.0 Hz, 3H), 1.19 (t, J¼7.5 Hz, 3H),1.26e1.44 (m, 8H), 2.05 (s, 3H), 2.17 (s, 3H), 2.33e2.36 (m, 2H), 2.69 (q,J¼7.0 Hz, 2H), 3.52 (s, 2H), 3.56 (s, 2H), 3.76 (s, 6H); 13C NMR (CDCl3,125 MHz) d 7.5, 14.0, 15.1, 15.9, 22.5, 29.8, 30.8, 30.9, 31.4, 38.5, 39.7,40.3, 53.0, 59.1, 124.9, 129.6, 134.9, 136.5, 139.3, 141.8, 172.2, 211.7;HRMS (EI)m/z [M]þ calcd for C24H34O5 402.2406; found 402.2402.

4.2.3. Dimethyl 4,7-dimethyl-5-octyl-6-propionyl-1H-indene-2,2-(3H)-dicarboxylate (3ac). Yellow oil; Rf¼0.40 (hexane/AcOEt¼4:1);IR (neat) 2952, 2930, 2871, 1730, 1693, 1592, 1432, 1276, 1245, 1197,1164, 1079, 1061, 950, 928; 1H NMR (CDCl3, 270 MHz) d 0.88 (t,J¼7.0 Hz, 3H), 1.17e1.44 (m, 15H), 2.05 (s, 3H), 2.17 (s, 3H),2.32e2.37 (m, 2H), 2.69 (q, J¼7.3 Hz, 2H), 3.52 (s, 2H), 3.56 (s, 2H),3.76 (s, 6H); 13C NMR (CDCl3, 67.8 MHz) d 7.5, 14.0, 15.1, 15.9, 22.6,29.1, 29.2, 30.1, 30.8, 30.9, 31.8, 38.5, 39.7, 40.3, 53.0, 59.1, 124.9,129.6, 134.9, 136.5, 139.3, 141.8, 172.2, 211.7; HRMS (EI) m/z [M]þ

calcd for C26H38O5 430.2719; found 430.2732.

4.2.4. Dimethyl 4,7-dimethyl-5-phenyl-6-propionyl-1H-indene-2,2-(3H)-dicarboxylate (3ad). Pale yellow solid; Rf¼0.43 (hexane/AcOEt¼7:3); IR (neat) 2979, 2950, 1729, 1707, 1600, 1432, 1275,1253,1200,1168,1081,1065, 941, 859, 771, 704; mp 148.2e150.0 �C;1H NMR (CDCl3, 500MHz) d 0.70 (t, J¼7.5 Hz, 3H), 2.00 (3H), 2.09 (q,J¼7.5 Hz, 2H), 2.12 (s, 3H), 3.61 (s, 4H), 3.79 (s, 6H), 7.14e7.16 (m,2H), 7.29e7.32 (m, 1H), 7.34e7.38 (m, 2H); 13C NMR (CDCl3,125 MHz) d 7.5, 16.0, 16.5, 38.0, 40.0, 40.3, 53.1, 59.1, 125.8, 127.2,128.1, 129.2, 130.2, 136.6, 138.3, 138.8, 139.4, 142.1, 172.2, 210.8;HRMS (EI) m/z [M]þ calcd for C24H26O5 394.1780; found 394.1772.

4.2.5. Dimethyl 5-(cyclohex-1-en-1-yl)-4,7-dimethyl-6-propionyl-1H-indene-2,2-(3H)-dicarboxylate (3ae). White solid; Rf¼0.39(hexane/AcOEt¼4:1); IR (neat) 2932, 2856, 1731, 1696, 1585, 1435,1277,1251,1200,1162,1122,1078,1061, 956, 942, 920, 859, 805, 727,661, 576; mp 101.2e102.6 �C; 1H NMR (CDCl3, 500 MHz) d 1.12 (t,J¼7.0 Hz, 3H), 1.56e1.73 (m, 4H), 2.03e2.19 (m, 10H), 2.54e2.68 (m,2H), 3.54 (s, 4H), 3.77 (s, 6H), 5.48 (s, 1H); 13C NMR (CDCl3,125 MHz) d 7.7, 15.8, 16.0, 21.9, 22.8, 25.5, 30.3, 38.2, 39.8, 40.2, 53.0,59.2, 125.4, 128.8, 129.0, 136.6, 137.4, 138.7, 139.1, 141.4, 172.2,210.6; HRMS (EI) m/z [M]þ calcd for C24H30O5 398.2093; found398.2097.

4.2.6. Dimethyl 5-benzoyl-6-butyl-4,7-dimethyl-1H-indene-2,2-(3H)-dicarboxylate (3af). White solid; Rf¼0.39 (hexane/AcOEt¼4:1); IR (neat) 2953, 2934, 2874, 2856, 1732, 1662, 1594,1579, 1431, 1276, 1235, 1205, 1164, 1057, 916, 881, 716, 688, 672; mp79.4e81.2 �C; 1H NMR (CDCl3, 500 MHz) d 0.76 (t, J¼7.5 Hz, 3H),1.12e1.45 (m, 4H), 1.96 (s, 3H), 2.14e2.51 (m, 5H), 3.56 (s, 2H), 3.62

(s, 2H), 3.78 (s, 6H), 7.42e7.45 (m, 2H), 7.55e7.58 (m,1H), 7.79e7.81(m, 2H); 13C NMR (CDCl3, 125 MHz) d 13.6, 15.2, 16.2, 22.9, 30.5,32.6, 39.9, 40.6, 52.9, 59.3, 126.8, 128.6, 129.5, 129.6, 133.4, 136.5,136.6, 137.8, 138.9, 139.7, 172.3, 200.8; HRMS (EI)m/z [M]þ calcd forC26H30O5 422.2093; found 422.2087.

4.2.7. (E)-Dimethyl 5-(but-2-enoyl)-6-butyl-4,7-dimethyl-1H-in-dene-2,2-(3H)-dicarboxylate (3ag). White solid; Rf¼0.46 (hexane/AcOEt¼7:3); IR (neat) 3008, 2951, 2867, 1752, 1718, 1652, 1435,1378, 1314, 1251, 1195, 1082, 1066, 977, 963, 873, 753, 577; mp68.1e69.5 �C; 1H NMR (CDCl3, 500 MHz) d 0.88 (t, J¼7.0 Hz, 3H),1.29e1.37 (m, 4H), 1.90 (dd, J¼1.5, 7.0 Hz, 3H), 2.01 (s, 3H), 2.18 (s,3H), 2.29e2.45 (m, 2H), 3.53 (s, 2H), 3.57 (s, 2H), 3.77 (s, 6H), 6.33(dd, J¼1.5, 16 Hz, 1H), 6.49 (dq, J¼7.0, 16 Hz, 1H); 13C NMR (CDCl3,125 MHz) d 13.7, 15.2, 16.1, 18.4, 23.1, 30.5, 32.8, 39.8, 40.4, 53.0,59.1, 126.5, 129.4, 134.5, 136.2, 136.3, 139.1, 139.3, 148.0, 172.3,201.7; HRMS (EI) m/z [M]þ calcd for C23H30O5 386.2093; found386.2101.

4.2.8. Dimethyl 5-acetyl-4,7-dimethyl-6-octyl-1H-indene-2,2-(3H)-dicarboxylate (3ah). Pale yellow solid; Rf¼0.53 (hexane/AcOEt¼17:3); IR (neat) 2952, 2924, 2851, 1729, 1696, 1594, 1431,1281, 1261, 1244, 1162, 1080, 1063, 956, 866, 722, 630, 573; mp75.8e76.4 �C; 1H NMR (CDCl3, 500 MHz) d 0.88 (t, J¼7.0 Hz, 3H),1.27e1.35 (m, 10H), 1.39e1.45 (m, 2H), 2.09 (s, 3H), 2.17 (s, 3H),2.38e2.41 (m, 2H), 2.46 (s, 3H), 3.52 (s, 2H), 3.56 (s, 2H), 3.76 (s,6H); 13C NMR (CDCl3, 125 MHz) d 14.1, 15.2, 15.9, 22.6, 29.2, 29.3,30.1, 30.9, 31.0, 31.8, 33.0, 39.8, 40.4, 53.0, 59.2, 124.7, 129.7, 134.7,136.6, 139.4, 141.9, 172.2, 209.1; HRMS (FAB) m/z [M]þ calcd forC25H36O5 416.2563; found 416.2560.

4.2.9. Dimethyl 5-butyl-4,7-dimethyl-6-(thiophene-2-carbonyl)-1H-indene-2,2-(3H)-dicarboxylate (3ai). White solid; Rf¼0.41 (hexane/AcOEt¼7:3); IR (neat) 2953, 2860, 1734, 1638, 1434, 1405, 1248,1200, 1159, 1080, 1063, 1050, 846, 743, 671, 576; mp100.4e102.1 �C; 1H NMR (CDCl3, 400 MHz) d 0.80 (t, J¼7.2 Hz, 3H),1.21e1.31 (m, 3H), 1.41e1.49 (m, 1H), 2.04 (s, 3H), 2.20 (s, 3H),2.28e2.35 (m, 1H), 2.47e2.54 (m, 1H), 3.55 (d, J¼4.4 Hz, 2H), 3.61(d, J¼5.6 Hz, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 7.06e7.08 (m, 1H),7.30e7.31 (m, 1H), 7.70e7.71 (m, 1H); 13C NMR (CDCl3, 100 MHz)d 13.7, 15.2, 16.3, 23.0, 30.6, 32.8, 39.8, 40.5, 53.0, 53.1, 59.2, 126.8,128.2, 129.6, 134.9, 135.0, 136.4, 136.6, 138.7, 139.9, 145.5, 172.1,172.4, 193.1; HRMS (EI) m/z [M]þ calcd for C24H28O5S 428.1657;found 428.1662.

4.2.10. Dimethyl 5-butyl-6-isobutyryl-4,7-dimethyl -1H-indene-2,2-(3H)-dicarboxylate (3aj). White solid; Rf¼0.51 (hexane/AcOEt¼7:3); IR (neat) 2957, 2894, 2873, 1733, 1687, 1588, 1445,1433, 1385, 1271, 1250, 1167, 1081, 953, 929, 850, 714, 692; mp98.9e100.1 �C; 1H NMR (CDCl3, 270 MHz) d 0.91 (t, J¼6.8 Hz, 3H),1.17 (d, J¼7.0 Hz, 6H), 1.31e1.45 (m, 4H), 2.06 (s, 3H), 2.18 (s, 3H),2.28e2.45 (m, 2H), 2.91 (septet, J¼7.0 Hz, 1H), 3.53 (s, 2H), 3.57 (s,2H), 3.76 (s, 6H); 13C NMR (CDCl3, 67.8 MHz) d 13.7, 15.2, 16.5, 18.1,23.1, 31.1, 32.9, 39.8, 40.3, 42.7, 52.9, 59.1, 125.8, 129.6, 135.5, 136.6,139.4, 140.9, 172.2, 214.7; HRMS (EI) m/z [M]þ calcd for C23H32O5388.2250; found 388.2233.

4.2.11. Dimethyl 5-butyl-6-hexanoyl-4,7-dimethyl-1H-indene-2,2-(3H)-dicarboxylate (3ak). Yellow oil; Rf¼0.40 (hexane/AcOEt¼4:1);IR (neat) 2955, 2931, 2871, 1736, 1700, 1581, 1435, 1404, 1381, 1274,1248, 1199, 1164, 1081, 1062, 958, 863, 730; 1H NMR (CDCl3,500 MHz) d 0.90e0.92 (m, 6H), 1.34e1.43 (m, 8H), 1.69e1.76 (m,2H), 2.06 (s, 3H), 2.17 (s, 3H), 2.32e2.42 (m, 2H), 2.67 (t, J¼8.0 Hz,2H), 3.52 (s, 2H), 3.56 (s, 2H), 3.76 (s, 6H); 13C NMR (CDCl3,125MHz) d 13.7,13.9,15.1,15.9, 22.5, 22.9, 23.1, 30.5, 31.3, 33.0, 39.8,40.4, 45.4, 53.0, 59.2, 125.0, 129.6, 134.8, 136.6, 139.3, 142.0, 172.2,

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e8689 8687

211.1; HRMS (EI) m/z [M]þ calcd for C25H36O5 416.2563; found416.2560.

4.3. Reaction of diyne 1a with alkynyl ester 4

Representative procedure for the [2þ2þ2] cycloaddition of diyne1a with alkynyl ester 4.

A flask was charged with [Ir(cod)Cl]2 (7.0 mg, 0.01 mmol) andrac-BINAP (12.2 mg, 0.02 mmol). The flask was evacuated and filledwith argon. To the flask were added benzene (5 mL) and methyl 2-undecynoate (4c) (444mg, 2.3 mmol). Diyne 1a (234mg,1.0 mmol)was added to the reaction mixture. The mixture was stirred underreflux for 2 h. The progress of the reaction was monitored by GLC.After the reaction was complete, the solvent was evaporated invacuo. Column chromatography of the residue gave 5ac (n-hexane/AcOEt¼85:15, 378 mg, 0.87 mmol, 88% yield).

4.3.1. Trimethyl 4,7-dimethyl-6-pentyl-1H-indene-2,2,5(3H)-tri-carboxylate (5ab). White solid; Rf¼0.44 (hexane/AcOEt¼4:1); IR(neat) 2953, 2927, 2872, 1597, 1747, 1721, 1432, 1309, 1253, 1195,1167, 1058, 958, 859, 816, 789, 732, 672, 629; mp 76.3e77.8 �C; 1HNMR (CDCl3, 500 MHz) d 0.90 (t, J¼7.5 Hz, 3H), 1.32e1.35 (m, 4H),1.45e1.49 (m, 2H), 2.14 (s, 3H), 2.18 (s, 3H), 2.46e2.49 (m, 2H), 3.53(s, 2H), 3.56 (s, 2H), 3.76 (s, 6H), 3.89 (s, 3H); 13C NMR (CDCl3,125 MHz) d 14.0, 15.3, 16.3, 22.3, 30.2, 31.1, 32.3, 39.8, 40.4, 51.8,53.0, 59.2, 127.1, 129.4, 133.6, 136.4, 136.7, 140.2, 171.3, 172.1; HRMS(EI) m/z [M]þ calcd for C22H30O6 390.2042; found 390.2032.

4.3.2. Trimethyl 4,7-dimethyl-6-octyl-1H-indene-2,2,5(3H)-tricarbox-ylate (5ac). Yellow oil; Rf¼0.50 (hexane/AcOEt¼7:3); IR (neat) 2952,2925, 2854, 1731, 1593, 1434, 1280, 1247, 1196, 1162, 1063, 955, 913,863, 834, 733, 650, 576; 1H NMR (CDCl3, 500MHz) d 0.88 (t, J¼7.0 Hz,3H), 1.28e1.36 (m, 10H), 1.44e1.50 (m, 2H), 2.13 (s, 3H), 2.18 (s, 3H),2.46e2.49 (m, 2H), 3.53 (s, 2H), 3.56 (s, 2H), 3.75 (s, 6H), 3.88 (s, 3H);13C NMR (CDCl3,125MHz) d 14.1,15.3,16.3, 22.6, 29.2, 29.3, 30.1, 30.5,31.2, 31.8, 39.8, 40.4, 51.8, 53.0, 59.2, 127.1, 129.4, 133.6, 136.4, 136.7,140.2, 171.2, 172.1; HRMS (EI)m/z [M]þ calcd for C25H36O6 432.2512;found 432.2501.

4.3.3. Trimethyl 4,7-dimethyl-6-phenyl-1H-indene-2,2,5(3H)-tri-carboxylate (5ad). White solid; Rf¼0.38 (hexane/AcOEt¼17:3); IR(neat) 2997, 2946, 1730, 1600, 1431, 1280, 1251, 1200, 1167, 1082,1066, 1056, 1022, 955, 861, 769, 747, 701, 672, 632, 603, 569; mp147.2e149.4 �C; 1H NMR (CDCl3, 500 MHz) d 1.98 (s, 3H), 2.22 (s,3H), 3.41 (s, 3H), 3.60 (s, 2H), 3.62 (s, 2H), 3.79 (s, 6H), 7.16e7.17(m, 2H), 7.29e7.37 (m, 3H); 13C NMR (CDCl3, 125 MHz) d 16.3, 16.7,39.9, 40.4, 51.5, 53.1, 59.3, 127.0, 127.3, 127.9, 129.3, 129.4, 133.8,138.0, 138.5, 139.4, 140.2, 170.3, 172.1; HRMS (EI) m/z [M]þ calcdfor C23H24O6 396.1573; found 396.1570.

4.3.4. Trimethyl 6-(cyclohex-1-en-1-yl)-4,7-dimethyl-1H-indene-2,2,5(3H)-tricarboxylate (5ae). White solid; Rf¼0.45 (hexane/AcOEt¼7:3); IR (neat) 2996, 2935, 2855, 1731, 1589,1429,1278, 1250,1196,1164,1079,1055,1019,953,922,861, 799,769,737,690,663, 634,604, 574; mp 122.1e123.8 �C; 1H NMR (CDCl3, 500 MHz) d 1.55e1.61(m, 1H), 1.65e1.73 (m, 3H), 2.09e2.18 (m, 10H), 3.54 (s, 2H), 3.55 (s,2H), 3.76 (s, 6H), 3.79 (s, 3H), 5.47e5.48 (m, 1H); 13C NMR (CDCl3,67.8MHz) d 15.7,16.2, 22.0, 22.9, 25.4, 29.9, 39.8, 40.1, 51.6, 53.0, 59.2,126.7, 127.1, 128.7, 133.0, 137.1, 137.4, 140.0, 140.6, 170.6, 172.1; HRMS(EI)m/z [M]þ calcd for C23H28O6 400.1886; found 400.1888.

4.4. Reaction of diyne 1 with alkynyl ketone 2a or alkynylester 4b

4.4.1. Dimethyl 5-butyl-4,7-diphenyl-6-propionyl-1H-indene-2,2(3H)-dicarboxylate (6a). Yellow oil; Rf¼0.51 (hexane/AcOEt¼7:3); IR

(neat) 2955, 2872, 1734, 1697, 1602, 1578, 1434, 1270, 1243,1200, 1162, 1072, 954, 931, 752, 703; 1H NMR (CDCl3, 500 MHz)d 0.62 (t, J¼7.0 Hz, 3H), 0.74 (t, J¼7.0 Hz, 3H), 0.99e1.06 (m,2H), 1.24e1.30 (m, 2H), 2.18 (q, J¼7.0 Hz, 2H), 2.28e2.31 (m,2H), 3.29 (s, 2H), 3.47 (s, 2H), 3.67 (s, 6H), 7.24e7.30 (m, 4H),7.33e7.46 (m, 6H); 13C NMR (CDCl3, 125 MHz) d 7.6, 13.4, 22.8,30.2, 33.8, 38.5, 40.3, 40.8, 52.9, 59.6, 127.1, 127.6, 128.40,128.44, 129.0, 129.5, 133.4, 135.8, 135.9, 138.25, 138.29, 139.2,139.8, 141.8, 171.9, 210.4; HRMS (EI) m/z [M]þ calcd forC32H34O5 498.2406; found 498.2410.

4.4.2. Trimethyl 6-pentyl-4,7-diphenyl-1H-indene-2,2,5(3H)-tri-carboxylate (6b). Yellow solid; Rf¼0.38 (hexane/AcOEt¼4:1); IR(neat) 2952, 2925, 2871, 1736, 1723, 1603, 1573, 1498, 1431, 1270,1246, 1200, 1154, 1128, 1071, 963, 874, 757, 702, 623, 603, 561; mp116.3e119.0 �C; 1H NMR (CDCl3, 400 MHz) d 0.72 (t, J¼7.2 Hz, 3H),1.01e1.12 (m, 4H), 1.30e1.38 (m, 2H), 2.40e2.45 (m, 2H), 3.29 (s,2H), 3.46 (s, 2H), 3.47 (s, 3H), 3.67 (s, 6H), 7.23e7.26 (m, 2H),7.32e7.46 (m, 8H); 13C NMR (CDCl3,125MHz) d 13.7, 21.9, 30.8, 30.9,31.9, 40.3, 40.8, 51.6, 52.9, 59.7, 127.2, 127.4, 128.2, 128.4, 128.6,128.9, 133.3, 135.2, 135.9, 137.3, 137.9, 138.7, 139.0, 140.6, 170.4,171.8; HRMS (EI) m/z [M]þ calcd for C32H34O6 514.2355; found514.2344.

4.4.3. Dimethyl 5-butyl-6-propionyl-4,7-di(thiophen-2-yl)-1H-indene-2,2(3H)-dicarboxylate (6c). Brown oil; Rf¼0.43 (hexane/AcOEt¼7:3);IR (neat) 2955, 2872, 1734, 1698, 1580, 1434, 1273, 1245, 1199, 1163,1070, 1051, 848, 835, 729, 699; 1H NMR (CDCl3, 500 MHz) d 0.72 (t,J¼7.0 Hz, 3H), 0.87 (t, J¼7.0 Hz, 3H), 1.09e1.17 (m, 2H), 1.36e1.42 (m,2H), 2.29 (q, J¼7.5 Hz, 2H), 2.36e2.39 (m, 2H), 3.43 (s, 2H), 3.64 (s,2H), 3.70 (s, 6H), 6.93e6.94 (m, 2H), 7.05e7.07 (m,1H), 7.10e7.12 (m,1H), 7.39e7.41 (m, 2H); 13C NMR (CDCl3, 125 MHz) d 7.8, 13.5, 22.9,30.7, 34.4, 38.0, 40.8, 41.0, 53.0, 59.4, 125.8, 126.7, 127.0, 127.1, 127.3,129.2,131.4,137.0,138.1,138.8,141.9,142.5,171.7, 209.7; HRMS (EI)m/z [M]þ calcd for C28H30O5S2 510.1535; found 510.1534.

4.4.4. Trimethyl 6-pentyl-4,7-di(thiophen-2-yl)-1H-indene-2,2,5(3H)-tricarboxylate (6d). Brown solid; Rf¼0.42 (hexane/AcOEt¼7:3); IR(neat) 2952, 2927, 2873,1736,1720,1578,1431,1269,1248,1197,1154,1071, 1047, 960, 850, 828, 796, 704, 626, 580; mp 122.5e124.8 �C; 1HNMR (CDCl3, 500 MHz) d 0.78 (t, J¼7.0 Hz, 3H), 1.12e1.18 (m, 4H),1.43e1.49 (m, 2H), 2.50e2.53 (m, 2H), 3.44 (s, 2H), 3.60 (s, 3H), 3.62(s, 2H), 3.68 (s, 6H), 6.93e6.94 (m, 1H), 7.03e7.06 (m, 2H), 7.10e7.11(m, 1H), 7.36e7.37 (m, 1H), 7.39e7.40 (m, 1H); 13C NMR (CDCl3,125 MHz) d 13.7, 21.8, 31.1, 31.3, 31.9, 40.6, 40.9, 51.7, 52.8, 59.3, 77.2,125.8, 126.2, 126.8, 127.0, 127.3, 128.6, 130.9, 134.4, 137.2, 138.3, 138.4,139.2, 142.5, 169.7, 171.4; HRMS (EI) m/z [M]þ calcd for C28H30O6S2526.1484; found 526.1485.

4.4.5. Dimethyl 5-butyl-6-propionyl-4,7-di(pyridin-2-yl)-1H-indene-2,2(3H)-dicarboxylate (6e). White solid; Rf¼0.21 (hexane/AcOEt¼1:3); IR (neat) 2956, 2938, 2865, 1739, 1726, 1695, 1585,1566, 1478, 1429, 1275, 1254, 1200, 1161, 1068, 1048, 954, 785, 749,616, 604; mp 127.8e130.0 �C; 1H NMR (CDCl3, 500 MHz) d 0.62 (t,J¼7.5 Hz, 3H), 0.85 (t, J¼7.0 Hz, 3H), 0.99e1.07 (m, 2H), 1.22e1.31(m, 2H), 2.28 (q, J¼7.5 Hz, 2H), 2.37e2.40 (m, 2H), 3.36 (s, 2H), 3.61(s, 2H), 3.67 (s, 6H), 7.24e7.32 (m, 2H), 7.35e7.36 (m,1H), 7.38e7.39(m, 1H), 7.73e7.75 (m, 1H), 7.78e7.82 (m, 1H), 8.67e8.68 (m, 1H),8.72e8.73 (m, 1H); 13C NMR (CDCl3, 125 MHz) d 7.8, 13.4, 22.8, 29.9,33.6, 38.7, 40.0, 40.2, 53.0, 60.0, 122.1, 122.3, 124.5, 124.8, 133.4,136.3, 136.4, 136.5, 137.7, 140.1, 141.8, 149.5, 149.6, 156.8, 158.1, 171.7,209.6; HRMS (EI) m/z [M]þ calcd for C30H32N2O5 500.2311; found500.2328.

4.4.6. Trimethyl 6-pentyl-4,7-di(pyridin-2-yl)-1H-indene-2,2,5(3H)-tricarboxylate (6f). Brown solid; Rf¼0.43 (hexane/AcOEt¼1:2); IR

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e86898688

(neat) 2954, 2924, 2856, 1734, 1586, 1567, 1480, 1453, 1435, 1247,1225, 1199, 1175, 1135, 1068, 1050, 992, 965, 877, 781, 752, 707, 688,613; mp 119.3e122.1 �C; 1H NMR (CDCl3, 500 MHz) d 0.72 (t,J¼7.0 Hz, 3H), 1.00e1.07 (m, 4H), 1.33e1.39 (m, 2H), 2.53 (t,J¼8.0 Hz, 2H), 3.36 (s, 2H), 3.53 (s, 3H), 3.61 (s, 2H), 3.67 (s, 6H),7.23e7.26 (m, 1H), 7.30e7.32 (m, 1H), 7.32e7.34 (m, 1H), 7.74e7.81(m, 2H), 8.67e8.68 (m, 1H), 8.72e8.73 (m, 1H); 13C NMR (CDCl3,125 MHz) d 13.7, 21.9, 30.4, 30.7, 31.8, 40.0, 40.1, 51.6, 53.0, 60.0,122.05, 122.14, 123.7, 124.5, 133.1, 135.1, 136.2, 136.3, 137.5, 138.4,141.0, 149.3, 149.6, 157.2, 157.9, 170.0, 171.6; HRMS (EI) m/z [M]þ

calcd for C30H32N2O6 516.2260; found 516.2255.

4.4.7. Dimethyl 5-butyl-4,7-diethyl-6-propionyl-1H-indene-2,2(3H)-dicarboxylate (6g). Pale yellow solid; Rf¼0.50 (hexane/AcOEt¼4:1);IR (neat) 2961, 2935, 2874, 1732, 1702, 1587, 1451, 1430, 1251, 1197,1167, 1130, 1102, 1065, 960, 857, 714; mp 76.8e78.9 �C; 1H NMR(CDCl3, 500 MHz) d 0.91 (t, J¼7.5 Hz, 3H), 1.11 (t, J¼8.0 Hz, 3H), 1.14(t, J¼8.0 Hz, 3H), 1.20 (t, J¼7.5 Hz, 3H), 1.32e1.46 (m, 4H), 2.31e2.39(m, 4H), 2.57 (q, J¼8.0 Hz, 2H), 2.72 (q, J¼7.5 Hz, 2H), 3.54 (s, 2H),3.56 (s, 2H), 3.76 (s, 6H); 13C NMR (CDCl3, 125 MHz) d 7.7, 13.7, 14.4,14.8, 22.7, 23.3, 24.3, 30.1, 34.4, 38.98, 39.0, 39.4, 53.0, 59.9, 131.8,134.2, 136.1, 136.5, 139.3, 141.9, 172.1, 211.6; HRMS (EI) m/z [M]þ

calcd for C24H34O5 402.2406; found 402.2396.

4.4.8. Trimethyl 4,7-diethyl-6-pentyl-1H-indene-2,2,5(3H)-tri-carboxylate (6h). Yellow oil; Rf¼0.42 (hexane/AcOEt¼4:1); IR(neat) 2955, 2874, 1730, 1588, 1434, 1286, 1247, 1196, 1163, 1065,1027, 952, 867, 780, 732, 703, 627, 600; 1H NMR (CDCl3, 500 MHz)d 0.90 (t, J¼7.5 Hz, 3H), 1.13 (t, J¼7.5 Hz, 6H), 1.33e1.36 (m, 4H),1.48e1.53 (m, 2H), 2.45e2.49 (m, 4H), 2.58 (q, J¼7.5 Hz, 2H), 3.55 (s,2H), 3.57 (s, 2H), 3.75 (s, 6H), 3.88 (s, 3H); 13C NMR (CDCl3,125 MHz) d 13.9, 14.3, 14.5, 22.3, 22.9, 24.8, 30.5, 31.5, 32.4, 38.9,39.5, 51.6, 52.9, 59.9, 133.4, 133.6, 135.8, 136.1, 136.2, 140.1, 171.3,171.9; HRMS (EI) m/z [M]þ calcd for C24H34O6 418.2355; found418.2352.

4.4.9. Dimethyl 5-butyl-6-propionyl-1H-indene-2,2(3H)-dicarbox-ylate (6i). Yellow oil; Rf¼0.30 (hexane/AcOEt¼17:3); IR (neat) 2955,2934, 2872, 1735, 1687, 1616, 1434, 1566, 1280, 1250, 1199, 1160,1067, 1053, 919, 891, 813, 709; 1H NMR (CDCl3, 500 MHz) d 0.91 (t,J¼7.0 Hz, 3H), 1.17 (t, J¼7.5 Hz, 3H), 1.32e1.39 (m, 2H), 1.48e1.54 (m,2H), 2.71e2.74 (m, 2H), 2.86 (q, J¼7.5 Hz, 2H), 3.58 (s, 4H), 3.75 (s.6H), 7.08 (s, 1H), 7.36 (s, 1H); 13C NMR (CDCl3, 125 MHz) d 8.4, 13.9,22.7, 33.5, 34.2, 35.2, 40.1, 40.5, 52.9, 60.3, 123.6, 126.5, 137.1, 137.7,141.5, 142.9, 171.7, 205.4.

4.4.10. Trimethyl 6-pentyl-1H-indene-2,2,5(3H)-tricarboxylate(6j). White solid; Rf¼0.32 (hexane/AcOEt¼4:1); IR (neat) 2955,2921, 2854, 1733, 1715, 1622, 1573, 1428, 1281, 1244, 1227, 1180,1155, 1128, 1067, 1054, 909, 890, 837, 798, 714, 639, 600, 572; mp82.5e84.2 �C; 1H NMR (CDCl3, 500 MHz) d 0.89 (t, J¼7.0 Hz, 3H),1.32e1.36 (m, 4H), 1.54e1.57 (m, 2H), 3.56 (s, 2H), 2.87e2.90 (m,2H), 3.59 (s, 2H), 3.75 (s, 6H), 3.87 (s, 3H), 7.08 (s, 1H), 7.68 (s, 1H);13C NMR (CDCl3, 125 MHz) d 14.0, 22.5, 31.6, 32.0, 34.4, 40.0, 40.5,51.8, 53.0, 60.4, 126.2, 126.6, 128.4, 137.4, 144.1, 144.2, 168.2, 171.8;HRMS (EI) m/z [M]þ calcd for C20H26O6 362.1729; found 362.1720.

4.4.11. 1,10-(5-Butyl-4,7-dimethyl-6-propionyl-2,3-dihydro-1H-in-dene-2,2-diyl)diethanone (6k). White solid; Rf¼0.38 (hexane/AcOEt¼17:3); IR (neat) 2957, 2932, 2872, 1696, 1588, 1435, 1360,1201, 1189, 1151, 1129, 962, 947, 928, 824, 713, 624, 590; mp46.3e48.8 �C; 1H NMR (CDCl3, 400 MHz) d 0.91 (t, J¼6.8 Hz, 3H),1.19 (t, J¼7.2 Hz, 3H), 1.32e1.44 (m, 4H), 2.07 (s, 3H), 2.19 (s, 9H),2.30e2.38 (m, 2H), 2.69 (q, J¼7.2 Hz, 2H), 3.41 (s, 2H), 3.45 (s, 2H);13C NMR (CDCl3,100MHz) d 7.6,13.7, 15.2, 16.0, 23.1, 26.5, 30.6, 33.0,36.6, 37.2, 38.6, 73.7, 125.2, 129.8, 134.9, 136.4, 139.2, 142.0, 204.7,

211.7; HRMS (EI) m/z [M]þ calcd for C22H30O3 342.2195; found342.2197.

4.4.12. Methyl 2,2-diacetyl-4,7-dimethyl-6-pentyl-2,3-dihydro-1H-indene-5-carboxylate (6l). White solid; Rf¼0.39 (hexane/AcOEt¼17:3); IR (neat) 2951, 2929, 2872, 1721, 1696, 1593, 1433,1360, 1335, 1302, 1252, 1200, 1164, 1152, 1123, 1047, 1018, 964, 831,732, 711, 624, 592, 570; mp 79.5e81.8 �C; 1H NMR (CDCl3,400 MHz) d 0.90 (t, J¼6.8 Hz, 3H), 1.31e1.35 (m, 4H), 1.43e1.51 (m,2H), 2.15 (s, 3H), 2.18 (s, 6H), 2.20 (s, 3H), 2.45e2.50 (m, 2H), 3.42 (s,2H), 3.45 (s, 2H), 3.89 (s, 3H); 13C NMR (CDCl3,100MHz) d 14.0,15.3,16.4, 22.3, 26.4, 30.2, 31.2, 32.2, 36.7, 37.3, 51.9, 73.7, 127.3, 129.7,133.7, 136.2, 136.8, 140.1, 171.2, 204.6; HRMS (EI) m/z [M]þ calcd forC22H30O4 358.2144; found 358.2148.

4.4.13. 50-Butyl-4,4,40,70-tetramethyl-60-propionyl-10,30-dihydrospiro[cyclohexane-1,20-indene]-2,6-dione (6m). White solid; Rf¼0.38(hexane/AcOEt¼4:1); IR (neat) 2959, 2936, 2873, 1726, 1693, 1592,1443, 1322, 1234, 1128, 1078, 1063, 982, 945, 927, 872, 825, 801, 671,635, 599, 577;mp140.9e142.1 �C; 1HNMR(CDCl3, 400MHz) d0.90 (t,J¼7.2 Hz, 3H),1.04 (s, 3H),1.05 (s, 3H),1.18 (t, J¼7.2 Hz, 3H),1.31e1.43(m, 4H), 2.03 (s, 3H), 2.16 (s, 3H), 2.32e2.35 (m, 2H), 2.67 (q, J¼7.2 Hz,2H), 2.72 (s, 4H), 3.35 (s, 2H), 3.39 (s, 2H); 13C NMR (CDCl3, 100 MHz)d 7.6, 13.7, 15.2, 16.0, 23.1, 28.3, 28.4, 30.5, 30.6, 33.0, 37.9, 38.1, 38.6,51.4, 70.1,124.9,129.6,134.9,136.1,139.0,141.9, 206.5, 211.7;HRMS(EI)m/z [M]þ calcd for C25H34O3 382.2508; found 382.2514.

4.4.14. Methyl 4,4,40,70-tetramethyl-2,6-dioxo-60-pentyl-10,30-dihy-drospiro[cyclohexane-1,20-indene]-50-carboxylate (6n). White solid;Rf¼0.38 (hexane/AcOEt¼4:1); IR (neat) 2947, 2871, 1724, 1692,1593, 1431, 1322, 1301, 1242, 1196, 1186, 1164, 1078, 1061, 1042, 1017,949, 831, 737, 584, 563; mp 129.2e130.8 �C; 1H NMR (CDCl3,400 MHz) d 0.89 (t, J¼7.2 Hz, 3H), 1.02 (s, 3H), 1.05 (s, 3H), 1.29e1.36(m, 4H), 1.42e1.50 (m, 2H), 2.12 (s, 3H), 2.17 (s, 3H), 2.44e2.48 (m,2H), 2.67e2.75 (m, 4H), 3.36 (s, 2H), 3.40 (s, 2H), 3.87 (s, 3H); 13CNMR (CDCl3, 100 MHz) d 14.0, 15.3, 16.4, 22.3, 28.2, 28.5, 30.2, 30.5,31.1, 32.3, 37.9, 38.2, 51.3, 51.8, 70.1, 127.1, 129.4, 133.6, 135.8, 136.8,140.0, 171.2, 206.4; HRMS (EI) m/z [M]þ calcd for C25H34O4398.2457; found 398.2463.

4.4.15. 1-(6-Butyl-2,2-bis(hydroxymethyl)-4,7-dimethyl-2,3-dihydro-1H-inden-5-yl)propan-1-one (6o). White solid; Rf¼0.41(hexane/AcOEt¼1:1); IR (neat) 3288, 2956, 2929, 2871, 1699, 1591,1417, 1376, 1340, 1226, 1126, 1050, 1035, 926, 903, 701; mp84.0e86.3 �C; 1HNMR (CDCl3, 500MHz) d 0.91 (t, J¼9.0 Hz, 3H),1.19(t, J¼7.0 Hz, 3H), 1.30e1.44 (m, 4H), 2.01 (s, 3H), 2.14 (s, 3H),2.34e2.37 (m, 2H), 2.69e2.74 (m, 6H), 3.33e3.54 (br, 2H), 3.69 (s,4H); 13C NMR (CDCl3, 125 MHz) d 7.5, 13.7, 15.1, 15.9, 23.1, 30.6, 33.0,37.6, 38.3, 38.6, 47.6, 69.2,125.4,130.2,134.1,138.3,141.1,141.3, 212.7;HRMS (EI)m/z [M]þ calcd for C20H30O3 318.2195; found 318.2196.

4.4.16. Methyl 2,2-bis(hydroxymethyl)-4,7-dimethyl-6-pentyl-2,3-dihydro-1H-indene-5-carboxylate (6p). White solid; Rf¼0.43 (hex-ane/AcOEt¼1:1); IR (neat) 3236, 2951, 2928, 2871, 1717, 1590, 1436,1378, 1308, 1243, 1201, 1166, 1107, 1090, 1041, 1016, 948, 831, 741,728, 682; mp 101.8e103.3 �C; 1H NMR (CDCl3, 500 MHz) d 0.90 (t,J¼7.0 Hz, 3H), 1.32e1.35 (m, 4H), 1.45e1.51 (m, 2H), 2.10 (s, 3H), 2.14(s, 3H), 2.45e2.49 (m, 2H), 2.70 (s, 2H), 2.74 (s, 2H), 3.26e3.53 (br,2H), 3.68 (s, 4H), 3.88 (s, 3H); 13C NMR (CDCl3,125MHz) d 13.9,15.2,16.3, 22.3, 30.2, 31.1, 32.2, 37.6, 38.3, 47.6, 51.8, 69.1, 127.5, 130.0,132.9, 136.0, 138.0, 142.0, 171.8; HRMS (EI) m/z [M]þ calcd forC20H30O4 334.2144; found 334.2153.

4.4.17. 1-(6-Butyl-4,7-dimethyl-2-tosylisoindolin-5-yl)propan-1-one(6q). White solid; Rf¼0.46 (hexane/AcOEt¼2:1); IR (neat) 2961,2927, 2858, 2832,1699,1597,1455,1343,1158,1134,1096,1065, 948,

T. Hashimoto et al. / Tetrahedron 70 (2014) 8681e8689 8689

930, 813, 710, 664, 582, 553; mp 126.2e128.6 �C; 1H NMR (CDCl3,500MHz) d 0.89 (t, J¼7.5 Hz, 3H),1.18 (t, J¼7.0 Hz, 3H),1.33e1.38 (m,4H),1.99 (s, 3H), 2.11 (s, 3H), 2.33e2.36 (m, 2H), 2.42 (s, 3H), 2.65 (q,J¼7.5 Hz, 2H), 4.54 (s, 2H), 4.58 (s, 2H), 7.32 (d, J¼8.0 Hz, 2H), 7.78 (d,J¼8.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) d 7.5, 13.7, 15.0, 15.7, 21.5,23.1, 30.4, 32.9, 38.5, 53.6, 53.9,124.2,127.5,128.6,129.8,133.1,133.7,135.8, 135.9, 142.6, 143.7, 210.7; HRMS (EI) m/z [M]þ calcd forC24H31NO3S 413.2025; found 413.2025.

4.4.18. Methyl 4,7-dimethyl-6-pentyl-2-tosylisoindoline-5-carboxylate(6r). Yellow solid; Rf¼0.53 (hexane/AcOEt¼2:1); IR (neat) 2951,2929, 2871, 1732, 1597, 1455,1433,1344, 1316,1266, 1158, 1097, 1062,953, 814, 734, 709, 664, 589, 554; mp 97.1e99.5 �C; 1H NMR (CDCl3,500 MHz) d 0.88 (t, J¼7.0 Hz, 3H), 1.29e1.33 (m, 4H), 1.40e1.45 (m,2H), 2.07 (s, 3H), 2.11 (s, 3H), 2.41 (s, 3H), 2.44e2.48 (m, 2H), 3.87 (s,3H), 4.56 (s, 2H), 4.58 (s, 2H), 7.31e7.33 (m, 2H), 7.76e7.78 (m, 2H);13C NMR (CDCl3, 125MHz) d 13.9,15.1, 16.1, 21.5, 22.3, 30.1, 30.9, 32.2,52.0, 53.6, 54.0, 126.3, 127.5, 128.4, 129.8, 132.9, 133.7, 134.4, 136.6,137.8, 143.7, 170.5; HRMS (EI) m/z [M]þ calcd for C24H31NO4S429.1974; found 429.1970.

4.4.19. Dimethyl 5-butyl-6-formyl-4,7-dimethyl-1H-indene-2,2(3H)-dicarboxylate (8). Colorless oil; Rf¼0.50 (hexane/AcOEt¼7:3); IR(neat) 2955, 2873,1735,1700,1580,1435,1380,1274,1249,1199,1163,1061, 953,926,869,802,726, 664,621,607; 1HNMR(CDCl3, 500MHz)d 0.95 (t, J¼7.5 Hz, 3H), 1.40e1.51 (m, 4H), 2.22 (s, 3H), 2.42 (s, 3H),2.85e2.88 (m, 2H), 3.59 (s, 2H), 3.60 (s, 2H), 3.77 (6H),10.5 (s,1H); 13CNMR (CDCl3, 125 MHz) d 13.8, 15.2, 16.6, 23.0, 28.2, 33.7, 39.9, 41.0,53.1, 58.8,130.1,132.3,133.2,137.5,143.5,144.2,172.1,194.6;HRMS(EI)m/z [M]þ calcd for C20H26O5 346.1780; found 346.1787.

4.5. [2D2D2] Cycloaddition of diyne 11 with alkynyl ketone2a in the presence of (R)-BINAP ligand

A flask was charged with [Ir(cod)Cl]2 (13.6 mg, 0.02 mmol) and(R)-BINAP (25.0 mg, 0.04 mmol). The flask was evacuated and filledwith argon. To the flaskwere added benzene (5mL) and 4-nonyn-3-one (2a) (296mg, 2.1mmol). Diyne11 (256mg,1.0mmol)was addedto the reactionmixture. Themixturewas stirred under reflux for 1 h.The progress of the reaction was monitored by GLC. After the re-action was complete, the solvent was evaporated in vacuo. Columnchromatography of the residue gave 12 (n-hexane/AcOEt¼20:1,344 mg, 0.87 mmol, 87% yield, 7% ee). The ee value was determinedbyHPLC analysiswith a Chiralcel OZ-H column (eluant: n-hexane/2-propanol¼99:1, flow rate: 0.4 mL/min, column temperature: 35 �C,retention time: 20.42 min (major) and 22.20 min (minor)).

4.5.1. Methyl 5-butyl-4,7-dimethyl-2-phenyl-6-propionyl-2,3-dihydro-1H-indene-2-carboxylate (12). Yellow oil; Rf¼0.59 (hex-ane/AcOEt¼5:1); IR (neat) 2954, 2935, 2872,1730, 1699, 1598,1445,1379, 1343, 1269, 1218, 1166, 1130, 1048, 924, 862, 805, 730, 697,634; 1H NMR (CDCl3, 500 MHz) d 0.91 (t, J¼7.5 Hz, 3H), 1.20 (t,J¼7.5 Hz, 3H), 1.32e1.46 (m, 4H), 2.10 (s, 3H), 2.22 (s, 3H), 2.35e2.38(m, 2H), 2.71 (q, J¼7.5 Hz, 2H), 3.22 (d, J¼11.0 Hz, 1H), 3.26 (d,J¼11.0 Hz, 1H), 3.62 (s, 3H), 3.93 (d, J¼16.0 Hz, 1H), 3.98 (d,J¼16.0 Hz, 1H), 7.24e7.27 (m, 1H), 7.31e7.34 (m, 2H), 7.37e7.39 (m,2H); 13C NMR (CDCl3, 125 MHz) d 7.6, 13.8, 15.2, 16.0, 23.2, 30.7, 33.1,38.6, 41.7, 42.4, 52.7, 58.4, 124.9, 126.5, 127.0, 128.5, 129.6, 134.5,137.8, 140.6, 141.7, 143.1, 176.0, 212.1; HRMS (EI) m/z [M]þ calcd forC26H32O3 392.2351; found 392.2348.

Acknowledgements

This research was supported by Grant-in-Aid for Scientific Re-search (C) (25410119) from the Japan Society for the Promotion ofScience and the Ministry of Education, Culture, Sports, Science, and

Technology of Japan. We thank Prof. Nishibayashi and Dr. Nakajimafor measuring NMR spectra of 3ac and 3aj. We thank Mr. KoujiItabashi for his experimental work.

Supplementary data

Supplementary data associated with this article can be found inthe online version, at http://dx.doi.org/10.1016/j.tet.2014.09.038.

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