Junta de Castilla y Leon (BU021A09 and GR-172), Ministerio de Educacion y Ciencia (MEC), FEDER (CTQ2007-61436/BQU and CTQ2009-09949/BQU), MEC (FPU grant), Juan de la Cierva, Ramon y Cajal and "Young Foreign Researchers" (SB2009-0186) contract

Fernández Rodríguez, Manuel A.

García García, Patricia

Martínez Cuezva, Alberto

Rashid, Muhammad A.

Rodríguez, Félix

Sanz Díez, Roberto

Chemical Communications

Roberto Sanz

Alberto Martínez

Patricia García-García

Manuel A. Fernández-Rodríguez

Muhammad A. Rashid

Félix Rodríguez

Crossref

Halocyclization of o-(alkynyl)styrenes. Synthesis of 3-halo-1H-indenes

Repositorio Institucional de la Universidad de Burgos

CREATED USING THE RSC COMMUNICATION TEMPLATE (VER. 3.1) - SEE WWW.RSC.ORG/ELECTRONICFILES FOR DETAILS ARTICLE TYPE www.rsc.org/xxxxxx  |  XXXXXXXX This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00  |  1 Halocyclization of o-(Alkynyl)styrenes. Synthesis of 3-Halo-1H-indenes Roberto Sanz,*a Alberto Martínez,a Patricia García-García,a Manuel A. Fernández-Rodríguez,a Muhammad A. Rashid,a and Félix Rodríguezb Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X First published on the web Xth XXXXXXXXX 200X 5 DOI: 10.1039/b000000x o-(Alkynyl)styrenes undergo halocarbocyclization processes via a 5-endo-dig ring closure. By this strategy an efficient synthesis of 3-halo-1H-indene derivatives has been developed. The electrophilic cyclization of heteroatomic nucleophiles 10 with alkynes, mainly with iodine-containing electrophiles, is a useful method for the synthesis of functionalized heterocyclic compounds.1 However, the analogous carbocyclization reactions, i.e. the internal nucleophile is a carbon-based moiety, have been much less developed. Few examples have 15 been reported involving the use of arenes2 and malonates3 as nucleophilic partners. Remarkably, the use of olefins4 for triggering this type of cyclization reactions has remained unknown until very recently, when Kirsch and co-workers have established that 1,5-enynes can undergo a iodonium-20 induced carbocyclization via 6-endo-dig processes.5 On the other hand, we have recently described the (enantioselective) synthesis of 1H-indene derivatives by an unprecedented gold(I)-catalyzed 5-endo-dig cyclization of ortho-(alkynyl)styrenes 1.6 In this context, and considering that the 25 presence of an halogen atom at the C-3 position of the final indene derivative could be of interest for further funcionalization, we wondered about the feasibility of synthesizing 3-halo-1H-indenes7 from the same o-(alkynyl)styrenes 1 as proposed in Scheme 1. 30  Gratifyingly, we found that 3-iodoindene 3a (R = Ph) was selectively formed and isolated in high yield when 1a (R = Ph) was treated with an excess of NIS in CH2Cl2 at room temperature for 24 h, in the absence of any catalyst. This result shows that a direct halocyclization has occurred, 35 probably through the formation of a stabilized carbocation 2 that undergoes proton elimination to afford the functionalized indene moiety (Scheme 1). It should be noted that in contrast to those examples recently reported by Kirsch and co-workers that proceed through a 6-endo cyclization process,5 our 40 reaction implies an unprecedented 5-endo halocyclization reaction of an enyne derivative.8 The stability of the tertiary carbocation intermediate 2 could be the key for the success of the proposed 5-endo cyclization.  As shown in Table 1, a variety of o-(alkynyl)styrenes 1 are 45 useful substrates for this iodocyclization. Reactions were performed at reflux in few hours under an air atmosphere. Different substituents at the alkyne (R1), including functionalized-aromatic, heteroaromatic, (functionalized)-alkyl, and heteroatomic ones are well tolerated (Table 1, 50 entries 16). Regarding the alkene, besides two methyl groups, R2 and R3 could be part of a cyclic alkyl moiety (Table 1, entries 8 and 9) as well as two different groups such  RR13RI2[AuL*]+ref. 6RII+5-endo¿ ? Scheme 1 Our proposal for the synthesis of 3-iodoindenes 55 as methyl and phenyl (Table 1, entries 7 and 14). However, terminal alkynes (R1 = H) proved to be unreactive under the reaction conditions, whereas substrates lacking a subsituent at the -position of the styrene moiety (R2 = H) gave rise to a complex mixture of products.10 In addition, substrates bearing 60 electron-withdrawing as well as electron-donating groups at the benzenoid moiety efficiently underwent the iodocyclization reaction (Table 1, entries 1014).  Table 1 Synthesis of 3-iodo-1H-indenes 3 by iodocyclization of o-65 (alkynyl)styrenes 1 R2R11R1INIS (3 eq)CH2Cl2, refluxR3R4R5R2R3R4R53  Entry 1 R1 R2 R3 R4 R5 t/h 3 Yield (%)a 1 1a Ph Me H H H 3 3a 85 2 1b 4-MeOC6H4 Me H H H 1 3b 92(71)c 3 1c 3-Thb Me H H H 2.5 3c 87 4 1d nBu Me H H H 2 3d 81 5 1e (CH2)3CN Me H H H 15 3e 71 6 1f SPh Me H H H 1 3f 80 7 1g Ph Ph H H H 4.5 3g 81 8 1h Ph (CH2)3 H H 2 3h 71 9 1i Ph (CH2)4 H H 3 3i 88 10 1j Ph Me H F H 15 3j 79 11 1k Ph Me H Br H 7 3k 84 12 1l Ph Me H -OCH2O- 1 3l 78(67)c 13 1m nBu Me H Br H 16 3m 82 14 1n nBu Ph H Br H 36 3n 55d a Isolated yield after column chromatography referred to starting material 1. b 3-Thienyl. c Carried out with I2/K3PO4 (3 equiv) at rt. d ~80% conversion.  2  |  Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]  The possibility of using molecular iodine as the electrophilic reagent was also demonstrated by the isolation of iodoindenes 3b and 3l, from treatment of substrates 1b and 1l with I2 and base instead of NIS (Table 1, entries 2 and 12). However, the yields were slightly lower and, moreover, in 5 some cases, such as the reaction of 1a, some side-products were formed along with the desired compound.  Interestingly, the same halocyclization reaction was observed when NBS was used. In this case, 3-bromo-1H-indenes 4a and 4j were isolated in good yields (Scheme 2). 10 Ph1a: R = H   j: R = FPhBrNBS (3 eq)CH2Cl2, refluxRR4a: R = H (65%)   j: R = F (74%) Scheme 2 Bromonium-mediated synthesis of 3-bromo-1H-indenes 4  We next decided to check the possibility of introducing further functionality on the C-1 substituent of the indene core by performing the iodocyclization in the presence of external 15 oxygen nucleophiles. After some optimization, we found that although the competitive elimination reaction that affords iodoindenes 3 could not be completely suppressed, 1-alkoxy-substituted 3-iodo-1H-indene derivatives 5 could be isolated in useful yields and in pure form by using a large excess of 20 MeOH (Table 2). In these cases, reactions are faster and could be performed at room temperature in 14 h. Better selectivities to 5 and therefore yields were obtained with substrates such as 1j and 1k bearing electron-withdrawing substituents at the aromatic nucleus (see entries 5 and 6 vs 1), 25 and with 1g (entry 4) that possess a phenyl group at the alkene. In addition, we have also demonstrated that I2/K3PO4 could be used as iodonium source in the alkoxyiodocyclization reaction of 1a (Table 2, entry 1), although with slightly lower selectivity. 30 Table 2 Alkoxyiodocyclization of o-(alkynyl)styrenes 1 1R3R1INIS (3 eq), rtCH2Cl2 / MeOH5OMeR2R3R1R2 Entry 1 R1 R2 R3 t/h 5 Yield (%)a 1 1a Ph H H 2 5a 66(58)b 2 1b 4-MeOC6H4 H H 1 5b 70 3 1f SPh H H 1 5f 58 4 1gc Ph H Ph 3 5g 81d 5 1j Ph F H 2 5j 78 6 1k Ph Br H 4 5k 72 a Isolated yield after column chromatography referred to starting material 1. b Carried out with I2/K3PO4 as electrophilic source. c Used as a ca. 2:1 mixture of geometrical isomers. d Obtained as a ca. 2:1 mixture of diastereoisomers.   Having in mind that 2,3-diarylindenes are known to posssess biological activity,11 we decided to employ the synthesized 3-haloindenes as precursors for the introduction 35 of an aromatic substituent at the C-3 of the indene moiety by Pd-catalyzed cross coupling reactions. In this way, 2,3-diarylindene derivatives 6 were obtained in high yield from 3a and 3b through a Suzuki coupling12 with phenylboronic acid and Pd(OAc)2/SPhos as catalytic system (Scheme 3). 40 Interestingly, when bromoindene 4a underwent a Stille coupling13 with 2-(tributylstannyl)furan, the functionalized benzofulvene14 derivative 7 was obtained, in which further isomerization of the propenyl group at the C-1 position of the indene scaffold has occurred (Scheme 3). 45 PhBr4aPhO7 (77%)O SnBu3Pd(OAc)2 (1 mol%)XPhos (2 mol%)CsF (2 eq)RI3a (R = Ph)  b (R = 4-MeOC6H4)PhPh6a (90%)  b (87%)PhB(OH)2Pd(OAc)2 (2 mol%)SPhos (4 mol%)K3PO4 (2 eq), toluene Scheme 3 Synthetic applications of 3-haloindenes 3 and 4  In summary, we have reported the direct halocyclization of o-(alkynyl)styrenes to give 3-halo-1H-indene derivatives in good to high yields under mild conditions. These results 50 together with those recently reported by Kirsch and coworkers represent the first examples of electrophilic cyclizations of alkynes promoted by halonium ions where the nucleophilic counterpart is an alkene. In particular, our results represent the first examples of this type of halocyclization via a 5-endo-55 dig ring closure mechanism. The presence of a halogen in the final products allows further functionalization at the C-3 position of the indene through conventional palladium-catalyzed cross-coupling reactions. Current efforts in our lab are devoted to the development of an enantioselective version 60 of this reaction and further applications of the obtained haloindenes in the synthesis of complex molecules.  We gratefully thank Junta de Castilla y León (BU021A09 and GR-172) and Ministerio de Educación y Ciencia (MEC) and FEDER (CTQ2007-61436/BQU and CTQ2009-65 09949/BQU) for financial support. A. M., P. G.-G., M. A. F.-R. and M. A. R. also thank MEC for FPU grant, Juan de la Cierva, Ramón y Cajal and “Young Foreign Researchers” (SB2009-0186) contracts, respectively. Notes and references 70 a Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n, 09001-Burgos, Spain. Fax: (+34) 947258831; Tel: (+34) 947258036; E-mail: rsd@ubu.es b Instituto Universitario de Química Organometálica “Enrique Moles”, 75 Universidad de Oviedo, 33006-Oviedo, Spain.  This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00  |  3 † Electronic Supplementary Information (ESI) available: Experimental procedures, characterization data, and NMR spectra. See DOI: 10.1039/b000000x/ 1 F. Rodríguez, F. J. Fañanás in Handbook of Cyclization Reactions, Vol. 2 (Ed: S. Ma), Wiley-VCH, Weinheim, Germany, 2010, p. 951. 5 For some particular examples on the synthesis of heterocycles, see: Indoles: (a) J. Barluenga, M. Trincado, E. Rubio, J. M. González, Angew. Chem. Int. Ed. 2003, 42, 2406; Benzofurans: (b) D. Yue, T. Yao, R. C. Larock, J. Org. Chem. 2005, 70, 10292; Benzothiophenes: (c) K. Hessian, B. L. Flynn, Org. Lett. 2003, 5, 4377; Quinolines: (d) 10 Z. Huo, I. D. Gridnev, Y. Yamamoto, J. Org. Chem. 2010, 75, 1266; Isoquinolines: (e) D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil, Y. Yamamoto, Angew. Chem. Int. Ed. 2007, 46, 4764; Furans: (f) A. Sniady, K. A. Wheeler, R. Dembinski, Org. Lett. 2005, 7, 1769; Pyrroles: (g) D. W. Knight, H. C. Rost, C. M. Sharland, J. 15 Singkhonrat, Tetrahedron Lett. 2007, 48, 7906; For the synthesis of polyheterocyclic compounds and competition studies, see: (h) S. Mehta, J. P. Waldo, R. C. Larock, J. Org. Chem. 2009, 74, 1141; (i) S. Mehta, R. C. Larock, J. Org. Chem. 2010, 75, 1652. 2 (a) J. Barluenga, J. M. González, P. J. Campos, G. Asensio, Angew. 20 Chem. Int. Ed. 1988, 27, 1546; (b) J. Barluenga, M. Trincado, M. Marco-Arias, A. Ballesteros, E. Rubio, J. M. González, Chem. Commun. 2005, 2008; (c) X. Zhang, M. A. Campo, T. Yao, R. C. Larock, Org. Lett. 2005, 7, 763; (d) X. Zhang, S. Sarkar, R. C. Larock, J. Org. Chem. 2006, 71, 236. 25 3 (a) H.-P. Bi, L.-N. Guo, X.-H. Duan, F.-R. Gou, S.-H. Huang, X.-Y. Liu, Y.-M. Liang, Org. Lett. 2007, 9, 397; (b) J. Barluenga, D. Palomas, E. Rubio, J. M. González, Org. Lett. 2007, 9, 2823; (c) Z. A. Khan, T. Wirth, Org. Lett. 2009, 11, 229. 4 For single examples, see: (a) P. R. Schreiner, M. Prall, V. Lutz, 30 Angew. Chem. Int. Ed. 2003, 42, 5757; (b) C. Lim, S. Rao, S. Shin, Synlett 2010, 368. For iodonium-induced cyclization of two tethered CC bonds, see: (c) J. Barluenga, G. P. Romanelli, L. J. Álvarez-García, I. Llorente, J. M. González, E. Rodríguez-García, S. García-Granda, Angew. Chem. Int. Ed. 1998, 37, 3136. 35 5 B. Crone, S. F. Kirsch, K.-D. Umland, Angew. Chem. Int. Ed. 2010, 49, 4661. 6 A. Martínez, P. García-García, M. A. Fernández-Rodríguez, F. Rodríguez, R. Sanz, Angew. Chem. Int. Ed. 2010, 49, 4633. 7 For the synthesis of 3-iodoinenes, see: (a) S. Saito, M. Homma, V. 40 Gevorgyan, Y. Yamamoto, Chem. Lett. 2000, 722; (b) X. Zhou, H. Zhang, X. Xie, Y. Li, J. Org. Chem. 2008, 73, 3958. See also ref. 3c. 8 The first examples of iodonium-promoted 5-endo-dig carbocyclization of active methylene substrates onto alkynes have been described by Barluenga and co-workers in an elegant variant of 45 the Conia-ene reaction, see ref. 3b. 9 Reactions also occur at room temperature, although longer reaction times are required. 10 However, -methyl-2-phenylethynylstyrene gives rise to a 1-iodonaphthalene derivative through a 6-endo ring closure. See ref. 5. 50 11 H.-C. Huang, T. S. Chamberlain, K. Seibert, C. M. Koboldt, P. C. Isaakson, D. B. Reitz, Bioorg. Med. Chem. Lett. 1995, 5, 2377, and referenced cited therein. 12 S. Ye, K. Gao, H. Zhou, X. Yang, J. Wu, Chem. Commun. 2009, 5406. 55 13 J. R. Naber, S. L. Buchwald, Adv. Synth. Catal. 2008, 350, 957. 14 For a recent example of the synthesis of 1-methylene indene (benzofulvene) derivatives, see: S. Ye, X. Yang, J. Wu, Chem. Commun. 2010, 2950, and references cited therein. 

Halocyclization of o-(Alkynyl)styrenes. Synthesis of 3-Halo-1H-indenes

Martínez de Pedro, Alberto

Fernández Rodríguez, Manuel Ángel

Rodríguez Iglesias, Félix

Repositorio Institucional de la Universidad de Oviedo

This journal is c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 7427–7429 7427Halocyclization of o-(alkynyl)styrenes. Synthesis of 3-halo-1H-indeneswRoberto Sanz,*a Alberto Martı´nez,a Patricia Garcı´a-Garcı´a,aManuel A. Ferna´ndez-Rodrı´guez,a Muhammad A. Rashida and Fe´lix Rodrı´guezbReceived 15th July 2010, Accepted 18th August 2010DOI: 10.1039/c0cc02590ao-(Alkynyl)styrenes undergo halocarbocyclization processes viaa 5-endo-dig ring closure. By this strategy an eﬃcient synthesisof 3-halo-1H-indene derivatives has been developed.The electrophilic cyclization of heteroatomic nucleophiles withalkynes, mainly with iodine-containing electrophiles, is auseful method for the synthesis of functionalized heterocycliccompounds.1 However, the analogous carbocyclization reac-tions, i.e. the internal nucleophile is a carbon-based moiety,have been much less developed. Few examples have beenreported involving the use of arenes2 and malonates3 asnucleophilic partners. Remarkably, the use of oleﬁns4 fortriggering this type of cyclization reactions has remainedunknown until very recently, when Kirsch and co-workershave established that 1,5-enynes can undergo an iodonium-induced carbocyclization via 6-endo-dig processes.5 On theother hand, we have recently described the (enantioselective)synthesis of 1H-indene derivatives by an unprecedentedgold(I)-catalyzed 5-endo-dig cyclization of ortho-(alkynyl)-styrenes 1.6 In this context, and considering that the presenceof an halogen atom at the C-3 position of the ﬁnal indenederivative could be of interest for further functionalization, wewondered about the feasibility of synthesizing 3-halo-1H-indenes7 from the same o-(alkynyl)styrenes 1 as proposed inScheme 1.Gratifyingly, we found that 3-iodoindene 3a (R = Ph) wasselectively formed and isolated in high yield when 1a (R = Ph)was treated with an excess of NIS in CH2Cl2 at room tempera-ture for 24 h, in the absence of any catalyst. This result showsthat a direct halocyclization has occurred, probably throughthe formation of a stabilized carbocation 2 that undergoesproton elimination to aﬀord the functionalized indene moiety(Scheme 1). It should be noted that in contrast to thoseexamples recently reported by Kirsch and co-workers thatproceed through a 6-endo cyclization process,5 our reactionimplies an unprecedented 5-endo halocyclization reaction of anenyne derivative.8 The stability of the tertiary carbocationintermediate 2 could be the key for the success of the proposed5-endo cyclization.As shown in Table 1, a variety of o-(alkynyl)styrenes 1 areuseful substrates for this iodocyclization. Reactions wereperformed at reﬂux in few hours under an air atmosphere.9Diﬀerent substituents at the alkyne (R1), including functionalized-aromatic, heteroaromatic, (functionalized)-alkyl, and hetero-atomic ones, are well tolerated (Table 1, entries 1–6). Regardingthe alkene, besides two methyl groups, R2 and R3 could bepart of a cyclic alkyl moiety (Table 1, entries 8 and 9) aswell as two diﬀerent groups such as methyl and phenyl(Table 1, entries 7 and 14). However, terminal alkynes(R1=H) proved to be unreactive under the reaction conditions,whereas substrates lacking a substituent at the b-position ofthe styrene moiety (R2 = H) gave rise to a complex mixture ofproducts.10 In addition, substrates bearing electron-withdrawingas well as electron-donating groups at the benzenoidmoiety eﬃciently underwent the iodocyclization reaction(Table 1, entries 10–14).The possibility of using molecular iodine as the electrophilicreagent was also demonstrated by the isolation of iodoindenes3b and 3l, from treatment of substrates 1b and 1l with I2 andbase instead of NIS (Table 1, entries 2 and 12). However, theyields were slightly lower and, moreover, in some cases, suchas the reaction of 1a, some side-products were formed alongwith the desired compound.Interestingly, the same halocyclization reaction was observedwhen NBS was used. In this case, 3-bromo-1H-indenes 4a and4j were isolated in good yields (Scheme 2).We next decided to check the possibility of introducingfurther functionality on the C-1 substituent of the indene byperforming the iodocyclization in the presence of externaloxygen nucleophiles. After some optimization, we found thatalthough the competitive elimination reaction that aﬀordsiodoindenes 3 could not be completely suppressed, 1-alkoxy-substituted 3-iodo-1H-indene derivatives 5 could be isolated inuseful yields and in pure form by using a large excess of MeOH(Table 2). In these cases, reactions are faster and could beperformed at room temperature in 1–4 h. Better selectivities to5 and therefore yields were obtained with substrates such as 1jand 1k bearing electron-withdrawing substituents at thearomatic nucleus (see entries 5 and 6 vs. 1), and with 1gScheme 1 Our proposal for the synthesis of 3-iodoindenes.aDepartamento de Quı´mica, A´rea de Quı´mica Orga´nica,Facultad de Ciencias, Universidad de Burgos,Pza. Misael Ban˜uelos s/n, 09001-Burgos, Spain. E-mail: rsd@ubu.es;Fax: +34 947258831; Tel: +34 947258036b Instituto Universitario de Quı´mica Organometa´lica ‘‘Enrique Moles’’,Universidad de Oviedo, 33006-Oviedo, Spainw Electronic supplementary information (ESI) available: Experimentalprocedures, characterization data, and NMR spectra. See DOI:10.1039/c0cc02590aCOMMUNICATION www.rsc.org/chemcomm | ChemCommDownloaded by Universidad de Oviedo on 26 December 2012Published on 08 September 2010 on http://pubs.rsc.org | doi:10.1039/C0CC02590AView Article Online / Journal Homepage / Table of Contents for this issue7428 Chem. Commun., 2010, 46, 7427–7429 This journal is c The Royal Society of Chemistry 2010(entry 4) that possess a phenyl group at the alkene. Inaddition, we have also demonstrated that I2/K3PO4 could beused as iodonium source in the alkoxyiodocyclization reactionof 1a (Table 2, entry 1), although with slightly lowerselectivity.Having in mind that 2,3-diarylindenes are known to possessbiological activity,11 we decided to employ the synthesized3-haloindenes as precursors for the introduction of an aromaticsubstituent at the C-3 of the indene moiety by Pd-catalyzedcross-coupling reactions. In this way, 2,3-diarylindenederivatives 6 were obtained in high yield from 3a and 3bthrough a Suzuki coupling12 with phenylboronic acid andPd(OAc)2/SPhos as catalytic system (Scheme 3). Interestingly,when bromoindene 4a underwent a Stille coupling13 with2-(tributylstannyl)furan, the functionalized benzofulvene14derivative 7 was obtained, in which further isomerization ofthe propenyl group at the C-1 position of the indene scaﬀoldhas occurred (Scheme 3).In summary, we have reported the direct halocyclization ofo-(alkynyl)styrenes to give 3-halo-1H-indene derivatives ingood to high yields under mild conditions. These resultstogether with those recently reported by Kirsch and coworkersrepresent the ﬁrst examples of electrophilic cyclizations ofalkynes promoted by halonium ions where the nucleophiliccounterpart is an alkene. In particular, our results representthe ﬁrst examples of this type of halocyclization via a 5-endo-digring closure mechanism. The presence of a halogen in the ﬁnalproducts allows further functionalization at the C-3 positionof the indene through conventional palladium-catalyzed cross-coupling reactions. Current eﬀorts in our lab are devoted tothe development of an enantioselective version of this reactionand further applications of the obtained haloindenes in thesynthesis of complex molecules.We gratefully thank Junta de Castilla y Leo´n (BU021A09and GR-172) and Ministerio de Educacio´n y Ciencia (MEC)and FEDER (CTQ2007-61436/BQU and CTQ2009-09949/BQU) for ﬁnancial support. A.M., P.G.-G., M.A.F.-R.and M.A.R. also thank MEC for FPU grant, Juan de laCierva, Ramo´n y Cajal and ‘‘Young Foreign Researchers’’(SB2009-0186) contracts, respectively.Notes and references1 F. Rodrı´guez and F. J. Fan˜ana´s, in Handbook ofCyclization Reactions, ed. S. Ma, Wiley-VCH, Weinheim,Germany, 2010, vol. 2, p. 951. For some particular examples onTable 1 Synthesis of 3-iodo-1H-indenes 3 by iodocyclization ofo-(alkynyl)styrenes 1Entry 1 R1 R2 R3 R4 R5 t/h 3Yielda(%)1 1a Ph Me H H H 3 3a 852 1b 4-MeOC6H4 Me H H H 1 3b 92(71)c3 1c 3-Thb Me H H H 2.5 3c 874 1d nBu Me H H H 2 3d 815 1e (CH2)3CN Me H H H 15 3e 716 1f SPh Me H H H 1 3f 807 1g Ph Ph H H H 4.5 3g 818 1h Ph (CH2)3 H H 2 3h 719 1i Ph (CH2)4 H H 3 3i 8810 1j Ph Me H F H 15 3j 7911 1k Ph Me H Br H 7 3k 8412 1l Ph Me H –OCH2O– 1 3l 78(67)c13 1m nBu Me H Br H 16 3m 8214 1n nBu Ph H Br H 36 3n 55da Isolated yield after column chromatography referred to startingmaterial 1. b 3-Thienyl. c Carried out with I2/K3PO4 (3 equiv.) at rt.d B80% conversion.Scheme 2 Bromonium-mediated synthesis of 3-bromo-1H-indenes 4.Table 2 Alkoxyiodocyclization of o-(alkynyl)styrenes 1Entry 1 R1 R2 R3 t/h 5Yielda(%)1 1a Ph H H 2 5a 66(58)b2 1b 4-MeOC6H4 H H 1 5b 703 1f SPh H H 1 5f 584 1gc Ph H Ph 3 5g 81d5 1j Ph F H 2 5j 786 1k Ph Br H 4 5k 72a Isolated yield after column chromatography referred to startingmaterial 1. b Carried out with I2/K3PO4 as electrophilic source.c Usedas a ca. 2 : 1 mixture of geometrical isomers. d Obtained as a ca. 2 : 1mixture of diastereoisomers.Scheme 3 Synthetic applications of 3-haloindenes 3 and 4.Downloaded by Universidad de Oviedo on 26 December 2012Published on 08 September 2010 on http://pubs.rsc.org | doi:10.1039/C0CC02590AView Article OnlineThis journal is c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 7427–7429 7429the synthesis of heterocycles, see: Indoles: (a) J. Barluenga,M. Trincado, E. Rubio and J. M. Gonza´lez, Angew. Chem., Int.Ed., 2003, 42, 2406; Benzofurans: (b) D. Yue, T. Yao andR. C. Larock, J. Org. Chem., 2005, 70, 10292; Benzothiophenes:(c) K. Hessian and B. L. Flynn, Org. Lett., 2003, 5, 4377;Quinolines: (d) Z. Huo, I. D. Gridnev and Y. Yamamoto,J. Org. Chem., 2010, 75, 1266; Isoquinolines: (e) D. Fischer,H. Tomeba, N. K. Pahadi, N. T. Patil and Y. Yamamoto, Angew.Chem., Int. Ed., 2007, 46, 4764; Furans: (f) A. Sniady,K. A. Wheeler and R. Dembinski, Org. Lett., 2005, 7, 1769;Pyrroles: (g) D. W. Knight, H. C. Rost, C. M. Sharland andJ. Singkhonrat, Tetrahedron Lett., 2007, 48, 7906; For the synthesisof polyheterocyclic compounds and competition studies, see:(h) S. Mehta, J. P. Waldo and R. C. Larock, J. Org. Chem.,2009, 74, 1141; (i) S. Mehta and R. C. Larock, J. Org. Chem., 2010,75, 1652.2 (a) J. Barluenga, J. M. Gonza´lez, P. J. Campos and G. Asensio,Angew. Chem., Int. Ed. Engl., 1988, 27, 1546; (b) J. Barluenga,M. Trincado, M. Marco-Arias, A. Ballesteros, E. Rubio andJ. M. Gonza´lez, Chem. Commun., 2005, 2008; (c) X. Zhang,M. A. Campo, T. Yao and R. C. Larock, Org. Lett., 2005, 7,763; (d) X. Zhang, S. Sarkar and R. C. Larock, J. Org. Chem.,2006, 71, 236.3 (a) H.-P. Bi, L.-N. Guo, X.-H. Duan, F.-R. Gou, S.-H. Huang,X.-Y. Liu and Y.-M. Liang, Org. Lett., 2007, 9, 397;(b) J. Barluenga, D. Palomas, E. Rubio and J. M. Gonza´lez,Org. Lett., 2007, 9, 2823; (c) Z. A. Khan and T. Wirth, Org. Lett.,2009, 11, 229.4 For single examples, see: (a) P. R. Schreiner, M. Prall and V. Lutz,Angew. Chem., Int. Ed., 2003, 42, 5757; (b) C. Lim, S. Rao andS. Shin, Synlett, 2010, 368. For iodonium-induced cyclizationof two tethered CRC bonds, see: (c) J. Barluenga, G. P.Romanelli, L. J. A´lvarez-Garcı´a, I. Llorente, J. M. Gonza´lez,E. Rodrı´guez-Garcı´a and S. Garcı´a-Granda, Angew. Chem., Int.Ed., 1998, 37, 3136.5 B. Crone, S. F. Kirsch and K.-D. Umland, Angew. Chem., Int. Ed.,2010, 49, 4661.6 A. Martı´nez, P. Garcı´a-Garcı´a, M. A. Ferna´ndez-Rodrı´guez,F. Rodrı´guez and R. Sanz, Angew. Chem., Int. Ed., 2010, 49, 4633.7 For the synthesis of 3-iodoindenes, see: (a) S. Saito, M. Homma,V. Gevorgyan and Y. Yamamoto, Chem. Lett., 2000, 722;(b) X. Zhou, H. Zhang, X. Xie and Y. Li, J. Org. Chem., 2008,73, 3958. See also ref. 3c.8 The ﬁrst examples of iodonium-promoted 5-endo-dig carbocycliza-tion of active methylene substrates onto alkynes have beendescribed by Barluenga, Gonza´lez and co-workers in an elegantvariant of the Conia-ene reaction, see ref. 3b.9 Reactions also occur at room temperature, although longer reac-tion times are required.10 However, a-methyl-2-phenylethynylstyrene gives rise to a 1-iodo-naphthalene derivative through a 6-endo ring closure. See ref. 5.11 H.-C. Huang, T. S. Chamberlain, K. Seibert, C. M. Koboldt,P. C. Isaakson and D. B. Reitz, Bioorg. Med. Chem. Lett., 1995, 5,2377, and references cited therein.12 S. Ye, K. Gao, H. Zhou, X. Yang and J. Wu, Chem. Commun.,2009, 5406.13 J. R. Naber and S. L. Buchwald,Adv. Synth. Catal., 2008, 350, 957.14 For a recent example of the synthesis of 1-methylene indene(benzofulvene) derivatives, see: S. Ye, X. Yang and J. Wu, Chem.Commun., 2010, 46, 2950, and references cited therein.Downloaded by Universidad de Oviedo on 26 December 2012Published on 08 September 2010 on http://pubs.rsc.org | doi:10.1039/C0CC02590AView Article Online

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Halocyclization of o-(Alkynyl)styrenes. Synthesis of 3-Halo-1H-indenes

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