DOI: 10.1002/ajoc.201200053

The Synthesis of Aromatic Heterocycles from Propargylic Compounds

Wen Jia-Jie, Yu Zhu, and Zhuang-Ping Zhan*[a]

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Abstract: It is well known that the aromatic heterocyclic compounds are the most ubiquitousmotifs and are found in many natural products and pharmaceuticals that exhibit remarkable bio-logical activities. Significant effort continues to be given to the development of new methods fortheir construction. Although a number of methods have been established to construct these com-pounds, the development of novel methods that allow the facile assembly of substituted hetero-cycles from readily available starting materials remains an important objective. In recent years,propargylic compounds that contain many reactive centers have attracted a lot of attention fortheir various transformations. Chemists have conducted a detailed investigation of their cycliza-tion with nucleophiles. The cyclization of propargylic compounds with a variety of nucleophilesis a very efficient method for producing furans, pyrroles, thiazoles, indoles, imidazoles, indoli-zines, oxazoles, pyridines, quinolines, thiophenes, and so on. In this review, we highlight the sub-stantial progress that has been made in this area between 2000 and mid-2012, and give examplesof the reactions of propargylic compounds with a variety of substrates to produce heterocycles.

Keywords: alkynes · cyclization · heterocycles · propargylic compounds · synthetic methods

1. Introduction

Propargylic compounds comprise one of the most impor-tant and most useful classes of substrates in organic synthe-sis. The p-nucleophilic character of the triple bond isa common functional group, which makes it a versatileentity for further chemical transformations. Furthermore,propargylic compounds are easily prepared by the reactionof terminal alkynes with an electrophilic carbon center. Thetransformation of various propargylic compounds has beendefined through careful studies in recent years.[1] The transi-tion-metal-catalyzed reaction of propargylic compoundswith various nucleophiles has emerged as an attractivemethod for constructing aromatic heterocycles.[2] Herein,we summarize the recent developments in the synthesis ofheterocycles from functionalized propargylic compounds.

In this review, we define some cyclization models(Figure 1). Before the main section, which is arranged byclass of aromatic heterocycle, first some concepts will bedefined. The bonds between C3 and X could be a single ordouble bond, as can those between X and Y, or Y and Z.When the aromatic heterocycles are directly formed by theattack of Z at the C2 position after the triple bond is acti-vated by a catalyst, we define this as the C2-Z cyclizationmodel. The C1-Y and C1-Z cyclization models are also de-

fined according to a similar rule. However, when the cycli-zation occurs after a Claisen rearrangement or a migrationprocess, we call it the rearrangement model. Thereby, weintroduce each of the five-membered heterocycles discussedin the following order: 1) C1-Y cyclization model; 2) C2-Zcyclization model, and 3) rearrangement model. The C1-Zcyclization model is only relevant for the six-memberedrings.

2 The Synthesis of Five-Membered Heterocycles

2.1. Furan

Furans are an important class of five-membered heterocy-cles that can be broadly found as a structural unit in numer-ous natural products and pharmaceuticals.[3] Furthermore,they have become important and useful synthetic buildingblocks.[4a] For these reasons, a tremendous number of effi-cient synthetic methods to construct the furan core and sub-stituted furans are known and continue attracting the inter-est of synthetic chemists.[4b,c] The vast majority of the routesto produce substituted furans have involved cyclization ap-proaches starting from acyclic precursors.

C1-Y Cyclization Model

In 2004, Larock and co-workers[5a] reported a highly effi-cient, Au-catalyzed (1 mol % AuCl3), atom-economical ap-proach to produce substituted furans (Scheme 1). Overall,ready access to a wide variety of polysubstituted furans 2was achieved upon reaction of various 2-(1-alkynyl)-2-alken-1-ones 1 with an unprecedented set of nucleophilesunder very mild reaction conditions. Alcohols and 1,3-dike-tones, as well as various electron-rich aromatics, serve as ef-ficient nucleophiles in this process. Similar results can alsobe achieved through an electrophile-induced cyclizationprocess.[5b] 3-Butyne-1,2-diols also can affords the corre-sponding substituted furans in high yields by a Ru-catalyzedintramolecular cyclization, but only terminal alkynes weretested.[5c]

[a] W. Jia-Jie, Y. Zhu, Prof. Dr. Z.-P. ZhanDepartment of ChemistryCollege of Chemistry and Chemical EngineeringXiamen University, Xiamen 361005, Fujian (P.R. China)Fax: (+86) 592-2180318E-mail : zpzhan@xmu.edu.cn

Figure 1. Illustration of the cyclization models.

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Propargylic oxirane derivatives[6] have played an impor-tant role in the construction of 2,3,5-trisubstituted furans.In 2001, Aurrecoechea et al.[6a] reported a practical and con-venient route to synthesize 2,3,5-trisubstituted furans 5 byusing 4,5-epoxyalk-2-ynyl esters 3 as precursors under mildreaction conditions. The reaction was performed in a one-pot sequence comprising SmI2-promoted reduction andPdII-mediated cycloisomerization of intermediate 2,3,4-trien-1-ols 4 (Scheme 2). In 2008, a fascinating strategy forthe synthesis of trisubstituted 3-iodofuran 7 was developedby Liang and co-workers[6b] based on iodocyclization ofpropargylic oxirane compounds 6 (Scheme 3). However,the reactant scope is limited, as the substituents on the oxir-ane must be aliphatic or cycloalkyls.

In 2011, Connell and co-workers[6c] succeeded in solvingthis problem. They developed an exciting method to syn-thesize various aromatic and aliphatic 2,3,5-trisubstitutedfurans 9 from acetylenic epoxides 8 by InCl3 catalysis(5 mol%) under mild and simple reaction conditions(Scheme 4). The starting materials are readily accessibleand are prepared by treatment of a-haloketones with lithi-um acetylides.

Abstract in Chinese:

Wen Jia-Jie was born in Zhanjiang,Guangdong province, China, in 1988. Aftergraduating from Shantou University, wherehe obtained his BS degree in 2010, he start-ed his postgraduate studies at Xiamen Uni-versity under the supervisor of Prof.Zhuang-Ping Zhan. He will be a Ph.D.candidate from September 2012.

Yu Zhu received his undergraduate degreein applied chemistry from Wuhan Universi-ty of Technology, Wuhan, in 2009. Current-ly, he is a Ph.D student with ProfessorZhuang-Ping Zhan in the College ofChemistry and Chemical Engineering ofXiamen University. His major research in-terest is the development of new methodsfor synthesizing heterocyclic compounds.

Zhuang-Ping Zhan received his Ph. D.degree from Hangzhou University in 1998,and then performed postdoctoral researchat Tsinghua University Ttaiwan) and JohnsHopkins University. He is now a Professorat Xiamen University. His research interestsinclude the development of new methods inorganic synthesis and the synthesis of het-erocycles.

Scheme 1.

Scheme 2.

Scheme 3.

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C2-Z Cyclization Model

In 2007, our group[7] reported a straightforward syntheticroute to trisubstituted furans. This process first entails thenucleophilic substitution of propargylic acetates 10 withenoxysilanes 11 to form the g-alkynyl ketones 12 in thepresence of a catalytic amount of FeCl3 (Scheme 5). Thetransformation into trisubstituted furans 13 occurs througha cyclization procedure catalyzed by 4-toluenesulfonic acid(TsOH) without purification of the g-alkynyl ketones inter-mediates.

Starting from the reactants in the C1-Y cyclizationmodel, such as propargylic oxirane derivatives, or fromenoxysilanes in the C2-Z cyclization procedure, the intro-duction of substituents at the C4 position of the corre-sponding furans by a transition-metal-catalyzed cycloisome-rization approach is difficult. Conditions developed recentlyin investigations of a one-pot synthesis by Cadierno et al.[8a]

involve the initial propargylation of the 1,3-dicarbonyl com-pound 15 promoted by trifluoroacetic acid, and subsequentcycloisomerization of the resulting g-ketoalkyne 16 cata-lyzed by the 16-electron allyl–RuII complex [Ru(h3-2-C3H4Me)(CO) ACHTUNGTRENNUNG(dppf)]·SbF6 ([Ru]; dppf= 1,1’-bis(diphenyl-phosphino)ferrocene), to prepare the tetrasubstitutedfurans 17 (Scheme 6). However, the catalyst used was verycomplex and a large amount of trifluoroacetic acid was re-quired. The same reaction catalyzed by other catalysts, suchas the simple Brønsted acid p-toluenesulfonic acid (PTSA)monohydrate,[8b] has also been reported.

In 2009, our group[8c] reported a convenient one-potpropargylation/cycloisomerization tandem process to con-struct substituted furans derivatives 20 from 1,3-dicarbonylcompounds 19 with propargylic alcohols or acetates 18 cata-lyzed by a quite simple catalyst, CuII triflate (Scheme 7).

This type of reaction has a typical feature, that is, all theproducts contain a carbonyl group. In 2010, Ma and co-workers[9] reported a procedure to synthesize all alkyl- andalkenyl-tetrasubstituted furans 25 and 26. This method isbased on a stepwise Sonogashira coupling of (Z)-3-iodoalk-2-en-1-ols 21 with terminal propargylic alcohols 22 and sub-sequent AuI - or PdII-catalyzed cyclization-aromatization byelimination of H2O (Scheme 8).

Rearrangement Model

As mentioned above, introducing a substituent at the C4position of furans by using a transition-metal-catalyzed cy-cloisomerization approach is difficult. Synthetic methodsthat proceed through the rearrangement model provide analternative choice.

In 2004, Gevorgyan and co-workers[10a] wanted to use[3,3] acyloxy migration to produce 27 from allene 28 enroute to acyloxy-substituted furan 29 (Scheme 9). As ex-pected, furan 29 was formed, but was accompanied bytraces of the unexpected regioisomer 30. Addition of trie-thylamine to the reaction mixture shifted the product distri-bution toward predominant formation of furan 30. Themechanism was believed to be as shown in Scheme 10, asopposed to a 1,2 acyloxy migration. As part of this work,

Scheme 4. Bn=benzyl.

Scheme 5.

Scheme 6.

Scheme 7.

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Aromatic Heterocycles from Propargylic Compounds

ketones 35 smoothly underwent the postulated [3,3] shift/1,2-migration/cycloisomerization sequence to directly affordtetrasubstituted furans 37 in excellent yields (Scheme 11).The mechanism was proven by Fang et al.[11] by using DFT

calculations in 2011. Similar work, which uses a metal-cata-lyzed 1,2-shift of diverse migrating groups in allenyl systemsto construct densely functionalized furans or other hetero-cycles, was also reported by Gevorgyan and co-workers in2007.[10b]

Propargyl vinyl ethers are commonly used in a Claisenrearrangement process to furnish polysubstituted furansthat contain carbonyl or ester groups. In 2005, Kirsch andco-workers[12a] used [(PPh3)AuCl]/AgBF4 (2 mol%) as thecatalyst in the reaction of propargyl vinyl ethers to furnishtri- and tetrasubstituted furans in 72-99 % yield. The reac-tion is a cascade of a Claisen rearrangement and heterocyc-lization at room temperature. The typical structure of theseproducts must have a methyl group at the C5 position andan ester or a carbonyl group at the C3 position. The reac-tion proceeds well for secondary propargyl vinyl ethers thatcontain not only aryl groups, but also alkyl groups. Howev-er, lower yields are obtained when tertiary substrates areused. A similar synthesis of tetrasubstituted furans 41,which contain carbonyl or ester groups at the C2 or C3 po-sitions and a methyl group at the C5 position, was reportedby Jiang and co-workers[12b] in 2010. In this case, the reac-tion was catalyzed by AgOAc (5 mol %) in the presence ofPPh3 (10 mol %) at 50 8C and proceeds according to thesame reaction mechanism for propargyl vinyl ethers 40(which were formed in situ from alkynols 39 and diethylbut-2-ynedioate 38, Scheme 12). However, this achievementcannot change the fact that this protocol is also ineffectivewith tertiary propargyl vinyl ethers. Could this problem besolved? The answer was given by Garc�a-Tellado[12c] and co-workers in 2011, who reported a metal-free transformationof tertiary propargyl vinyl ethers 42 to form the trisubstitut-ed C2-chain functionalized furans 45 by a microwave-assist-ed tandem Claisen rearrangement/5-exo-dig O-cyclizationreaction (Scheme 13). Products 50, which contain a formylgroup or a carbonyl group at the C5 position, were pre-pared from the same substrates by Jiang and co-workers[12d]

Scheme 8. DMA=N,N-dimethylacetamide.

Scheme 9.

Scheme 10. TBS = tert-butyldimethylsilyl.

Scheme 11.

Scheme 12. DABCO =1,4-diazabicycloACHTUNGTRENNUNG[2.2.2]octane.

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in 2009 by using CuI (2.5 mol %) as catalyst and O2 as theoxidant at 80 8C through a domino rearrangement/dehydro-genation oxidation/carbene oxidation procedure. The mech-anism is detailed in Scheme 14. A method that usesFe ACHTUNGTRENNUNG(ClO4)3·xH2O as the bifunctional catalyst was also dis-closed by Jiang et al.[12e] in 2010.

2.2. Pyrrole

Pyrrole is one of the most important simple heterocycles. Itis an indispensable structural motif in many natural prod-ucts and drug molecules,[13a] and also plays an importantrole in materials science[13b] as well as in heterocyclic chem-

istry.[13c] A huge effort has been made to develop efficientsyntheses of pyrroles.[14]

C1-Y Cyclization Model

In 2004, Agarwal and Knçlker[15a] developed a method toaccess pyrroles 55 by a AgI-promoted oxidative cyclizationof homopropargylamines 51 at room temperature. Themechanism for this process was proposed as shown inScheme 15. More recently, Trost et al.[15b] reported an atom-

economic route to 2,4-disubstituted pyrroles 60, which in-volves a cascade Pd-catalyzed addition reaction, 5-endo-digcyclization, and tautomerization process from electron-defi-cient propargyl amine 56 and alkynes 57 (Scheme 16). Byusing this strategy, 2,3,4-trisubstituted pyrroles also can beformed.

Propargylic aziridines can also be used in the synthesis ofthe substituted pyrroles. In 2009, Davies and Martin[16a] de-veloped an atom-economic pathway to construct aryl-sub-stituted N-tosyl pyrroles 62 and 63. This reaction is cata-lyzed by an Au catalyst and uses alkynyl aziridines 61 asstarting materials. The interesting result is that when

Scheme 13.

Scheme 14.

Scheme 15.

Scheme 16. Boc= tert-butyloxycarbonyl; TDMPP = tris(2,6-dimethoxy-phenyl)phosphine

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Aromatic Heterocycles from Propargylic Compounds

[PPh3AuOTs] is used as the catalyst, 2,5-substituted pyr-roles 62 are formed, however, catalyzed by [PPh3AuOTf](Tf = trifluoromethanesulfonate) the reaction will lead to2,4-substituted pyrroles 63 (Scheme 17). However, thescope is very limited and the reaction cannot tolerate func-tional groups. Furthermore, only disubstituted products canbe prepared. In 2010, Liu and co-workers[16b] reported anefficient route to synthesize 2,3,5-trisubstituted N-phthali-midopyrroles 66, including pyrrole-2-caboxyates or 2-pyr-rolyl ketones, by a Au/Ag-catalyzed cycloisomerization pro-cess (Scheme 18). This reaction is a good choice for the syn-thesis of 2,3,5-trisubstituted pyrroles, but when using alco-holic substrate 67 as the starting material, C�C bond cleav-age will occur and product 68, in which the R1 group is lost,will be afforded (Scheme 19).

An unusual tandem cyclization/ring-opening/Wagner–Meerwein approach to trisubstituted and cycloalkene-fusedpyrroles 74 from propargylic aziridines 69 was disclosed byTu and co-workers[16c] in 2009. The unique structures of theproducts demonstrated the potential applications of this re-action for synthesizing structurally diverse alkaloids. Aplausible mechanism for the reaction is outlined inScheme 20. More recently, in 2011, a similar method was

also used to synthesize cyclopenta[b]pyrroles by a Pd-cata-lyzed cascade cyclization/ring expansion of 2-alkynyl-1-azaspiroACHTUNGTRENNUNG[2.3]hexanes.[16d]

C2-Z Cyclization Model

In 2003, Gabriele et al.[17a] reported a general and regiose-lective synthesis of substituted pyrroles 76 by cycloisomeri-zation of (Z)-(2-en-4-ynyl) amines 75 (Scheme 21). The

result is very surprising; spontaneous cycloisomerizationleading to substituted pyrroles 76 b occurred in the courseof preparing enynamines 75 b, which contain a terminaltriple bond or a triple bond substituted with a phenyl ora CH2OTHP (THP = tetrahydropyranyl) group(Scheme 21 b). However, when the triple bond was substi-tuted with an alkyl or alkenyl group, enynamines 75 a werestable and could be converted into the corresponding pyr-roles 76 a by metal catalysis (Scheme 21 a). The interestingthing is that CuCl2 was found to be an excellent catalyst forcycloisomerization of substrates substituted at the C3 posi-tion, whereas PdX2 in conjunction with KX (X=Cl, I) wasthe better catalyst for the reaction of enynamines that arenot substituted at the C3 position. However, the reactions

Scheme 17.

Scheme 18. PIDA=phenyliodine ACHTUNGTRENNUNG(III) diacetate

Scheme 19.

Scheme 20.

Scheme 21.

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were usually carried out in a dipolar aprotic solvent such asDMA, and, especially for enynamines with a substituent atthe C3 position, a high temperature of 100 8C was required.On the other hand, the corresponding enynamines are gen-erally prepared from (Z)-enynols through tedious syntheticroute. Therefore, a simple methodology that uses mild con-ditions urgently needed. In 2009, Liu and co-workers[17b] de-veloped an efficient one-pot synthesis of multisubstitutedpyrroles 80 from suitably substituted (Z)-enynols 77 withamines or sulfonamides 78 under mild reaction conditions.The reaction is a cascade amination and cycloisomerizationin the same vessel (Scheme 22). Similar structures can alsobe obtained by the reaction of a propargylic alcohol,a ketone, and the amine.[17c]

In 2007, Cadierno et al.[18a] developed a synthetic route tofully substituted pyrroles 83 through a one-pot, three-com-ponent coupling reaction between easily accessible terminalsecondary propargylic alcohols 81, readily available 1,3-di-carbonyl compounds 82, and primary amines catalyzed bythe 16-electron allyl-RuII complex [Ru(h3-2-C3H4Me)(CO)(dppf)]·SbF6 ([Ru])/CF3CO2H (Scheme 23). However, twoor more catalysts are needed in these reactions and the Rucatalyst used is very complex. A similar reaction catalyzedby a single and very simple catalyst, InCl3, was reported byour group[18b] in 2008 (Scheme 24). Fully substituted pyr-roles 88 also can be produced from propargylic acetates 86,

enoxysilanes 87, and primary amines 84, by a regioselectivepropargylation/amination/cycloisomerization process cata-lyzed by ZnCl (Scheme 25). This protocol was also reportedby our group[19] in 2010.

Rearrangement Model

Using the rearrangement model gives us an alternative pro-tocol by which to approach fully substituted pyrroles. In2006, Binder and Kirsch[20a] described a cascade reactionthat proceeds through a AgI-catalyzed propargyl-Claisen re-arrangement, an amine condensation, and a AuI-catalyzed5-exo-dig heterocyclization to afford fully substituted 5-methylpyrroles 91 from readily accessed propargyl vinylethers 89 and aromatic amines (Scheme 26). The resulting5-methylpyrroles can further be transformed into 5-formyl-

Scheme 22.

Scheme 23.

Scheme 24.

Scheme 25.

Scheme 26.

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Aromatic Heterocycles from Propargylic Compounds

pyrroles by 2-iodoxybenzoic acid (IBX)-mediated oxida-tion. More recently, a similar result was also achieved bythe direct amino-Claisen rearrangement of N-propargyl b-enaminone derivatives 92 and the cyclization of a-allenyl b-enaminone intermediates 93 (Scheme 27), as reported byA. Saito et al.[20b] in 2010. However, all of the productsmust have a carbonyl group at the C3 position and the di-versity of the products is limited. Therefore, exploiting newsubstrates to synthesize fully substituted pyrroles that con-tain different functional groups remains a tough task.

2.3. Indole

The indole core can be found in numerous drugs and natu-ral products, and marine indole alkaloids are potential newdrug leads for the control of depression and anxiety.[21]

Plenty of synthetic methodologies to approach substitutedindoles have been developed.[22]

C1-Y Cyclization Model

In 2003, Barluenga et al.[23a] described a robust route to fur-nish 3-iodoindoles 96 from N-protected ortho-(alkynyl) ani-lines 95, promoted by the iodinating agent IPy2BF4 and itsactivation reagent HBF4 (1 equiv, Scheme 28). It was the

first report of the addition of protected and unprotectedanilines to internal alkynes through a simple iodination re-action. However, the yield is very poor when R2 is a groupother than aryl or heteroaryl. On the other hand, the reac-tivity of substituted anilines hasn’t been exploited. Further-more, the iodinating agent used is expensive, plus HBF4 isvery toxic. A similar approach under mild reaction condi-tions was developed by Larock and co-workers.[23b] This

strategy is based on simple iodocyclization of N-substitutedortho-(alkynyl) anilines 97, which are prepared by the Pd/Cu-catalyzed cross-coupling of N,N-dialkyl-ortho-iodoani-lines and terminal alkynes. Alkyl-, aryl-, and vinyl-substitut-ed alkynes all react well, as do unsubstituted and substitut-ed anilines, including those that contain strong electron-withdrawing functional groups. The mechanism is also clear(Scheme 29).

C2-Z Cyclization Model

In 2007, Fensterbank and co-workers[24a] devised a new syn-thetic route to construct substituted indoles from 2-proparg-yl anilines catalyzed by PtCl2 or a proton catalyst. Theresult is intriguing. Whereas N-allyl precursor 101 furnishesa normal 5-exo-dig isomerization product 102(Scheme 30 a), N,N-diallyl precursor 103 provides rear-rangement product 104 by a cascade 5-exo-dig cyclizationand 3-aza-Cope rearrangement procedure, as do the N-methyl and N-allyl precursors (Scheme 30 b). To our sur-prise, these transformations also occur smoothly in excel-lent yields when SiO2 is used as the catalyst. When 105 isused as the substrate, another rearrangement product 113was obtained (Scheme 31), and the ratio of products de-pends on the catalysts used and reaction temperature.

Scheme 27.

Scheme 28.

Scheme 29.

Scheme 30.

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In 2010, Chan and co-workers[24b] described a versatileapproach for indole synthesis through the Au/Ag-catalyzedcycloisomerization reaction of 2-tosylaminophenylprop-1-yn-3-ols 114. This type of substrate is fascinating becausedifferently substituted groups furnish different indolesunder the same reaction condition (Scheme 32). When R1 =

Ar, indenyl-fused indole 119 will form through a protodeau-ration and intramolecular Friedel–Crafts alkylation proce-dure (route 1 in Scheme 32), but when R1 =CHR2R3, 2-vinyl-1H-indoles of the type 124 will be delivered by proto-deauration and dehydration steps (route 3 in Scheme 32). IfR1 = H, the reaction will provide the (1H-indol-2-yl) metha-nol product 121 from a more rapid protodeauration/1,3-al-

lylic alcohol isomerization (route 2 a in Scheme 32). On thecontrary, if a strong nucleophile is present, 2-alkyl-1H-indole adduct 122 will be obtained for the preferential SN2�substitution (route 2 b in Scheme 32). However, one draw-back is that when aniline moieties that contain an electron-donating group, such as methyl, a mixture of unknown sideproducts is obtained as well as the desired product.

Rearrangement Model

In 2007, A. Saito et al.[25a] reported a Rh-catalyzed aromaticamino-Claisen rearrangement of N-propargyl anilines 125to generate 2,3-disubstituted indoles 127 under mild condi-tions. A phosphine ligand is indispensable in this method. Itis believed that the reaction proceeds by a Rh-catalyzed ar-omatic amino-Claisen rearrangement of 125 and subsequentcyclization of ortho-allenylaniline 126 to furnish the targetproduct 127 (Scheme 33). This method gives excellentyields in the case of internal alkynes, but is not fit for termi-nal alkynes or those with alkyl substituents at the propar-gylic position. The chemoselectivity of this method is alsopoor. When a meta-OMe-substituted aniline derivative isused as the substrate, the para product (attack at the posi-tion para to the OMe group) is generated as the majorproduct as well as almost half the amount of the orthoproduct (attack at the ortho position to the OMe group).The same procedure was also be achieved catalyzed by[RhH(CO) ACHTUNGTRENNUNG(Ph3P)3]/ACHTUNGTRENNUNG(CF3)2CHOH in 2009.[25b] However, theproblems mentioned above have not been solved yet.

2.4. Indolizine

Indolizines are a class of compounds that all contain an N-bridgehead bicyclic ring, and these compounds have ex-tremely important applications in pharmaceutical use.[26]

Many synthetic routes have been reported.[27] Syntheticmethods that start from propargylic compounds almostalways use pyridine propargylic alcohols and derivatives assubstrates.

C1-Y Cyclization Model

Easy access to 1,3-disubstituted indolizines 129 by a simplecycloisomerization process from pyridine propargylic piva-loates 128 catalyzed by PtCl2 at 70 8C was described by Sar-pong and co-workers[28a] in 2007 (Scheme 34 a). The addi-tion of the bulky electron-rich phosphine ligands 2-(di-tert-butylphosphino)biphenyl or 2-(dicyclohexylphosphino)bi-

Scheme 31.

Scheme 32.

Scheme 33. HFIP=hexafluoro-2-propanol

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Aromatic Heterocycles from Propargylic Compounds

phenyl results in increased yields and shorter reactiontimes. An alternative protocol was introduced by Liu andco-workers,[28b] whose method involves Cu-catalyzed cyclo-isomerizations of 2-pyridylsubstituted propargylic acetatesand its derivatives 130 at room temperature in the presenceof Et3N (1 equiv, Scheme 34 b). The base- and ligand-freeconditions of this process were developed by Gevorgyanand co-workers[28c] in the same year (Scheme 35).

1,2,3-Trisubstituted indolizines cannot be prepared byusing the methods mentioned above or the rearrangementstrategies (see “rearrangement model” in this section,below). One of the possible ways to synthesize such com-pounds was developed by Gevorgyan and co-workers[29] in2010. They found that treatment of 2-pyridylsubstitutedpropargylic acetates and its derivatives 134 with ArI 135(1.5 equiv) and [PdCl2 ACHTUNGTRENNUNG(PPh3)2] (5 mol %) in N,N-dimethyl-formamide (DMF) at 120 8C for 4 h provides 1,2,3-trisubsti-tuted indolizines 136 in high yield (Scheme 36). Two equiv-alents of base (K2CO3), one equivalent of additive tetrabu-tylammonium iodide (TBAI) and PPh3 (40 mol %) werealso required in this protocol, as these reagents can remark-ably improve the yield. It is believed that this reaction pro-ceeds by the Pd-catalyzed coupling of aryl halides withpropargylic esters or ethers and subsequent 5-endo-dig cyc-lization (Scheme 37).

Rearrangement Model

A Pt-catalyzed cascade 1,2-migration/cycloisomerizationprocedure to synthesize 2,3-disubstituted indolizines 143 ac-companied with small amount of 1,3-disubstituted products144 was reported by Hardin and Sarpong (Scheme 38).[30] Inthis protocol, PPh3 was required to improve the yield, andthe iodide counterion played a crucial role in remarkably

Scheme 34. TMS= trimethylsilyl.

Scheme 35.

Scheme 36.

Scheme 37.

Scheme 38.

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increasing the ratio of 2,3-/1,3-disubstituted products. Eventhough the electronic effect of the acyl, alkyne, and propar-gylic carbon substituents has a significant effect on control-ling the product ratio, it cannot change the fact that the 2,3-disubstituted indolizine is the major product. The reactionmechanism was also investigated (Scheme 39).

2.5. Imidazole, Oxazole & Thiazole

Newly discovered and structurally diverse natural productsthat contain imidazole, oxazole, or thiazole units havea wide variety of biological activities.[31] Various methodshave been developed for the synthesis of these com-pounds.[32]

Imidazole

Rapid access to highly substituted 2-aminoimidazoles 156from propargyl cyanamides 153 and amines 154 was devel-oped by Looper and co-workers[33a] in 2009 by using aLa ACHTUNGTRENNUNG(OTf)3 catalyst (Scheme 40). This reaction proceeds bythe addition of amine 154 to cyanamide 153 to form thepropargyl guanidine 155, then a subsequent hydroamina-tion/isomerization process, which provides a unique discon-nection for rapid access to more complex natural productskeletons. However, this process also has its intrinsic disad-vantages, that is, a high catalyst loading (30 mol%) and

excess amine (3–5 equiv) were required. Primary amineswere not favored in this procedure. In 2011, the samegroup[33b] developed another strategy to construct the samesubstituted 2-aminoimidazoles 160 by a Ag-catalyzed 5-exo-dig cyclization of di-Boc-protected propargylguanidine 157(Scheme 41). This procedure was conducted in the presenceof AgOAc (10 mol %) in CH2Cl2 at room temperature andresulted in 5-exo-dig product 158. Compound 158 has theZ-alkene configuration and Boc protecting groups on thetwo N atoms, which can lead to substituted 2-aminoimida-zoles 160 after deprotection. However, the 5-exo-dig prod-uct is not exclusive (it is accompanied by the 6-endo prod-uct 159), and the chemoselectivity is not so ideal. On theother hand, other synthetic routes to the products sub-strates are tedious and complex.

More recently, Wu and co-workers[33c] presented an Au/Ag-mediated synthetic route to 2,4-disubstituted imidazoles164 and 165, which contain fluoroalkyl groups at the C2 po-sition, from propargylic amidines 163. Amidines 163 can beeasily prepared from imidoylchlorides 161 and secondarypropargylamine 162 (Scheme 42). 2-Fluoroalkyl-5-methyli-midazoles 164 were formed by a simple 5-exo-dig cycliza-tion process at 60 8C by using [PPh3AuCl] (5 mol%) and

Scheme 39.

Scheme 40.

Scheme 41. PMB=para-methoxybenzyl.

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Aromatic Heterocycles from Propargylic Compounds

AgBF4 (10 mol %) as the catalysts. However, when the re-action was catalyzed by the same catalysts in the presenceof N-iodosuccinimide (NIS)/K2CO3 in air 2-fluoroalkyl imi-dazole-5-carbaldehydes 165 were obtained. Further investi-gation revealed that the carbonyl oxygen atom was derivedfrom atmospheric O2. The mechanism is detailed inScheme 43. However, the scope is limited to strongly elec-tron-withdrawing groups Rf as well as the secondary termi-nal propargylamine. Therefore, developing a facile protocolfrom readily available substrates to prepare diverse substi-tuted 2-aminoimidazoles still remains an attractive chal-lenge.

Oxazole

The synthesis of 2,5-disubstituted oxazoles 173 from thecorresponding propargylcarboxamides 171 catalyzed byAuCl under mild reaction conditions was described byHashmi et al.[34a] in 2004 (Scheme 44 a). It is noteworthythat an intermediate 5-methylene-4,5-dihydrooxazole 172can be detected and accumulated in up to 95 % prevalencewhen monitoring the conversion by 1H NMR spectroscopy.This result indicates a cyclization/isomerization reactionmechanism. It is also the first direct and catalytic prepara-tive approach to such intermediates, which could react withelectrophiles other than a proton to give different function-alized products (Scheme 44 b).[34b] However, the internal

alkyne does not react under the same conditions, whichmeans that the terminal alkyne[34c] is crucial for this process.The direct synthesis of 2-substituted 5-oxazolecarbalde-hydes 175 by using a similar substrate was conducted bytreatment with [PdCl2ACHTUNGTRENNUNG(MeCN)2] (5 mol %) in the presenceof a stoichiometric amount of benzoquinone (BQ) oxidantor CuCl2/O2, as reported by Broggini and co-workers(Scheme 45).[34d] The mechanism is detailed in Scheme 46.

In 2004, Wipf et al.[35a] reported a method to synthesize

2,4,5-trisubstituted oxazoles 185 catalyzed by SiO2 at roomtemperature (Scheme 47). This reaction, which is also suita-ble for the synthesis of 2,5-disubstituted oxazoles, proceeds

Scheme 42.

Scheme 43.

Scheme 44.

Scheme 45.

Scheme 46.

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by simple cycloisomerization of propargyl amides 183. Thescope is limited and the synthetic route to substrates is tedi-ous and intricate. All the products contain a carbonyl groupon the C5 position. In 2009, an efficient one-pot propargy-lation/cycloisomerization tandem process for the synthesisof 2,4,5-trisubstituted oxazoles 189 from propargylic alco-hols 186 and amides 187 in the presence of PTSA (1 equiv)in toluene at reflux was conducted by our group(Scheme 48).[35b] This reaction is tolerant of air and giveswater as the only byproduct. Propargylic alcohols that con-tain terminal or internal alkyne groups underwent this reac-tion successfully. More recently, a strategy mediated byCeCl3·7 H2O/NaI/I2 under microwave irradiation to synthe-size 2,4,5-trisubstituted oxazoles which can have a carbonylgroup at the C4 position has also been reported by Giovan-nini and co-workers[35c] in 2012.

Thiazole

In 2009, Yoshimatsu et al.[36a] developed a new strategy forthe preparation of 2,4,5-trisubstituted thiazoles 193 by reac-tion of 3-sulphanyl and 3-selanylpropargyl alcohols 190with thioamides 192 (Scheme 49). The use of Sc ACHTUNGTRENNUNG(OTf)3

(5 mol%), MeNO2/H2O (10:1), and Bu4NHSO4 (10 mol %)at reflux provided the best yield of the product. This reac-

tion is believed to proceed by unprecedented intermediatea-sulphanyl or a-selanyl propadienyl cations 191. All theproducts contain a 5-sulphanyl or a 5-selanyl group. Addedto this is that the substrate scope is limited to secondary ar-omatic propargylic alcohols. Phase-transfer reagentBu4NHSO4 was also required. A more flexible and rapidroute to three different 2,4,5-trisubstituted thiazoles weredescribed by our group[36b] in 2010. The different structure

of thiazoles 196, 197, and 198 was quite dependent on thesubstrate structure (Scheme 50). A wide range of secondarypropargylic alcohols or tertiary propargylic alcohols that

contain not only terminal alkyne groups, but also internalalkyne groups can effectively be used, and a number offunctional groups, such as cyclopropyl, cyclohexenyl,bromo, chloro, ester, and methoxy are tolerated under thereaction conditions. The mechanism is detailed inScheme 51. A similar synthetic route to approach thiazolescatalyzed by p-TsOH·H2O (5 mol %) was developed byChan and co-workers.[36c]

Scheme 47.

Scheme 48.

Scheme 49.

Scheme 50.

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Aromatic Heterocycles from Propargylic Compounds

2.6. Isoxazole & Pyrazole

Isoxazoles and pyrazoles are two kinds of important heter-ocyclic compounds for their interesting biological activi-ties.[37] For this reason, many synthetic routes have been ex-tensively exploited in the past.[38] Because of their similarstructure as well as their same C1-Y cyclization model (de-fined by us), isoxazoles and pyrazoles will be introduced to-gether.

Isoxazole

The traditional synthesis of 4-haloisoxazoles was by halo-genating the corresponding isoxazoles, which requires harshreaction conditions. A new procedure that uses mild condi-tions for the synthesis of 3,5- disubstituted 4-haloisoxazoles233 was developed by Waldo and Larock[39a] in 2005(Scheme 52). This strategy required three steps from the in-itial starting materials (acid chloride/terminal acetylene orlithium acetylide/aldehyde). The electrophilic cyclization isthe key step to construct the 233 in the presence of differ-ent electrophiles at room temperature, which are very mildconditions. The best result was obtained when using ICl as

the electrophile. The resulting 4-iodoisoxazoles undergovarious Pd-catalyzed reactions to yield 3,4,5-trisubstitutedisoxazoles.[39b] A more convenient and time-saving approachto 3,4,5-trisubstituted isoxazoles 237 was described byVrancken and co-workers[39c] in 2011. This procedure usesreadily available propargylic alcohols 234 and Fe- and Pd-catalytic systems sequentially in an uninterrupted one-potsubstitution/annulation/cross-coupling/hydrogenolysis/oxi-dation sequence (Scheme 53). More recently, in 2012, Chen

and co-workers[39d] synthesized 4-alkenyl-3,4,5-trisubstitutedisoxazoles 240 from the reaction of O-methyl oximes 238with alkenes 239 by a Pd-catalyzed cascade 5-endo-dig cyc-lization-alkenylation process. The addition of one equiva-lent of nBu4NBr can significantly increase the yields. Oneexample of the synthesis of a naphthoisoxazole 241 was re-ported by a cascade cyclization-alkenylation-Heck reactionfrom the special structure of the substrates (Scheme 54).

Pyrazole

The first example of the synthesis of pyrazoles 243 frompropargyl N-sulfonylhydrazones 242 catalyzed by an AgI

catalyst was described by Lee and Chung[40a] in 2008. Thisprocedure was conducted in the presence of AgSbF6

Scheme 51.

Scheme 52. PCC =pyridinium chlorochromate; TIPS = tetraisopropylsil-yl.

Scheme 53. Cbz=carboxybenzyl; dba= dibenzylideneacetone; bpy=bi-pyridyl.

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(5 mol%) at room temperature for 3–5 h, during whicha migration of sulfonyl groups (Ts, Ms) was detected(Scheme 55). This method allows the efficient and regiose-

lective synthesis of 1,3- disubstituted pyrazoles as well as1,5- and 1,3,5-trisubstituted pyrazoles. However, thismethod cannot be used to synthesize pyrazoles substitutedat the C4 position. In 2010, Wada and co-workers[40b] dis-closed switchable access to substituted dihydropyrazoles245 and pyrazoles 246 from common hydrazides 244 by a re-agent-controlled iodocyclization process (Scheme 56 a).When NIS (3 equiv) is used as the catalyst and BF3·OEt2

(3 equiv) as the additive, substituted 4-iodopyrazoles 246with a 1-isopropyloxycarbonyl group will be obtained,which is one of the disadvantages of this method. A similarprocedure driven by I2 as the catalyst in the presence ofNaHCO3 was reported by Zora et al.[40c] in 2011, whoseproducts 249 can contain not only alkyl groups but also arylgroups at the N1 position (Scheme 56 b). Though iodine-containing products can be further elaborated to a widerange of fully functionally substituted pyrazoles, the directsynthesis of fully aryl- or alkyl-substituted pyrazoles re-mains an unsolved challenge.

2.7. Thiophene

Thiophenes are an important class of five-membered het-erocycles that are the parent compounds of a very largenumber of alkaloids and medicinally important com-pounds.[41] Numerous synthetic methodologies exist for thesynthesis of thiophenes.[42]

C1-Y Cyclization Model

In 2002, Yue and Larock[43a] reported a method to synthe-size substituted benzo[b]thiophenes 252 by the electrophiliccyclization of ortho-(1-alkynyl)thioanisole derivatives 251,which can be easily prepared by coupling of terminal acety-lenes with commercially available ortho-iodothioanisole 250in the presence of a Pd/Cu catalyst (Scheme 57). Electro-philes I2, N-bromosuccinimide (NBS), as well as sulfur andselenium electrophiles all reacted well to afford the corre-sponding products in high yields within a short time at25 8C. The resulting 3-iodo products can be elaborated toa wide range of 2,3-disubstituted products through a simplecoupling reaction.[43b] However, it is difficult to attach an

Scheme 55.

Scheme 56. coll=2,4,6-collidine

Scheme 57.

Scheme 54.

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Aromatic Heterocycles from Propargylic Compounds

alkyl group. A facile synthesis of benzo[b]thiophenes 254that contain an alkyl group at the C3 position was describedby Nakamura et al.[43c] in 2006. This reaction proceeds bycyclization of (a-alkoxyalkyl)(ortho-alkynylphenyl) sulfides253 and a subsequent migration of the a-alkoxyalkyl groupin the presence of AuCl (2 mol%) at 25 8C (Scheme 58).

(para-Methoxyphenyl)methyl sulfide as well as allyl sulfidealso reacted well, which led to the corresponding products254 with (para-methoxyphenyl)methyl or allyl sulfide at theC3 position, respectively. These compounds cannot be pre-pared by the electrophilic cyclization method. Although tri-substituted silyl sulfide[43d] also reacted smoothly, a highertemperature (45 8C) was required. The mechanism is de-tailed in Scheme 59.[43c]

C2-Z Cyclization Model

In 2003, Hessian and Flynn[44] disclosed a remarkably effec-tive synthetic route to give selective access to 2-acyl or 2-(1-iodoalkenyl)benzo[b]thiophene from 2-thioxyphenyl pro-pynols by a 5-exo-iodocyclization then subsequent tandemrearrangement and elimination or substitution processes(Scheme 60). Different types of product were obtained de-pending on the structure of the substrates and the condi-tions used. In the cases where R2 is an aryl group, 2-acylproducts are obtained in the presence of I2 at 18 8C in

CH2Cl2 as the solvent. When R2 is an alkyl group, 2-(1-io-doalkenyl) products will be obtained under the same condi-tions, but changing the solvent to ethanol will result in the2-acyl products (Scheme 61).

Rearrangement Model

A thio-Claisen rearrangement (TCR) used to synthesizethe substituted thiophenes 268 was described by Zhouet al.[45] in 2010. This protocol uses propargylic compounds267 as the starting materials and is conducted in the presentof 1,8-diazabicyclo ACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU, 1.2 equiv) atroom temperature by a sulfur-assisted five-reaction cascadesequence. In this sequence, the allenyl allyl sulfides generat-ed in situ undergo TCR, intramolecular Michael addition,and 1,5-proton migration/aromatization to obtain allyl thio-

Scheme 58. MPM= (p-methoxyphenyl)methyl; TMSE =2-(trimethylsil-yl)ethyl.

Scheme 59.

Scheme 60.

Scheme 61.

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phen-2-yl acetates, propionates, and ketones 268 as thefinal products (Scheme 62). An isotope-labeling experimentwas also conducted to examine the mechanism(Scheme 63). This method provides a very convenient way

to prepare substituted thiophenes with an electron-with-drawing group and an olefin, but the R3 group at the prop-argylic position must have a a proton to undergo successfulenolization of the intermediate enethione to enethiol.Meanwhile, steric hindrance of the allyl group with a sub-stituent at the C3 position (see intermediate 269,Scheme 63) will prevent the reaction occurring.

3. The Synthesis of Six-Membered Heterocycles

3.1. Quinoline & Isoquinoline

Quinoline and isoquinoline are extremely common structur-al motifs in various natural products and biologically activepharmaceuticals.[46] Much attention has been focused on de-veloping diverse synthetic methods.[47] The C1-Z cyclizationmodel will be discussed in this section.

Quinoline

In 2004, Akiyama and co-workers[48a] described a protocolto produce 2-arylated quinolines 274 from alkynyl imines273. The imines underwent [4+2] electrocyclization in thepresence of [W(CO)5ACHTUNGTRENNUNG(THF)] (20 mol %, Scheme 64). It isbelieved that the reaction proceeds via a tungsten–vinyli-dene complex, according to the deuterium-labeling study.However, the scope is limited to terminal alkynyl iminesand only 2-substituted products can be formed.

In 2007, Sandelier and DeShong[48b] reported a syntheticroute to access 2-substituted and 2,4-disubstituted quino-lines 276 from ortho-nitrophenyl propargyl alcohols 275 bya cascade reduction/Meyer–Schuster rearrangement/hetero-annulation procedure in the presence of reductants underacidic condition (Scheme 65 and 66). The use of secondary

propargyl alcohols gave much lower yields of the desiredproducts relative to tertiary propargyl alcohols. The synthe-sis of 3-substituted quinolines has remained a big challengein the case of using propargylic compounds as the startingmaterials. Substituted quinolines 285 that contain an iodoor phenylseleno group at the C3 position, prepared frompropargylic aniline 284 through electrophilic cyclization inthe presence of an electrophile (2–3 equiv) and NaHCO3

(2 equiv), were described by Larock and co-workers[48c] in2005 (Scheme 67). The resulting 3-iodoquinolines 285 offerconsiderable potential for further elaboration to furnish the3-substituted quinolines. However, this method cannot offerthe unique chemoselectivity when meta-substituted propar-gylic anilines are used as the substrate, and the yields arelower for substrates that contain an alkyl group at the al-kynyl position.

Scheme 62.

Scheme 63.

Scheme 64. NMO=N-methylmorpholine-N-oxide.

Scheme 65.

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Aromatic Heterocycles from Propargylic Compounds

Isoquinoline

In 2002, Roesch and Larock[49] used iminoalkynes 286 toform 3-substituted isoquinolines 287 by a simple cyclizationprocedure in the presence of CuI (10 mol %) at 100 8C. Thisprotocol is suitable for most cases other than R=alkyl(Scheme 68). By using the same substrates, 3,4-disubstitutedproducts can be formed by using different protocols. Prod-ucts that contain an iodo, PhS, p-O2NC6H4S, or PhSe groupat the C4 position, which can be transformed to other sub-stituted groups, were synthesized through an electrophile-induced cyclization process.[50a]

More directly, 3,4-disubstituted products can be formedby the Pd-catalyzed cross-coupling of N-tert-butyl-ortho-(1-

alkynyl) benzaldimines with aryl, allylic, and alkynyl hali-des.[50b, c] Similarly, the 3-substituted 4-aroylisoquinolinescan be prepared by treating N-tert-butyl-2-(1-alkynyl) ben-zaldimines with aryl halides in the presence of CO anda Pd catalyst.[50d] However, this method is not useful toobtain products that contain substituents at the C1 positionbecause of the inherent structural defect of iminoalkynes.In 2008, Yamamoto and co-workers[51a] used 2-alkynyl-1-methylene azide aromatics 288 to react with iodine and/orother iodide donors to achieve the synthesis of 1,3-disubsti-tuted 4-iodoisoquinolines 291, which can be further trans-formed to 1,3,4-trisubstituted isoquinolines (Scheme 69).Similar results also can be achieved by an Ag-catalyzedprocess.[51b]

3.2. Pyridine & Pyrimidine

Substituted pyridines and pyrimidines constitute two kindsof compounds which have extremely important biologicaland pharmaceutical properties.[52] Many synthetic methodshave been exploited[53] and the C1-Z cyclization model willbe discussed in this section.

Pyridine

In 2006, Movassaghi and Hill[54a] used a Ru complex to me-diate the cyclization of 3-azadienynes 293, which can beprepared from the reaction of N-vinyl or N-aryl amides 292with copper acetylide, to construct pyridine rings. This reac-tion was conducted in the presence of [CpRu ACHTUNGTRENNUNG(PPh3)2Cl](10 mol%), SPhos (10 mol %), and NH4PF6 (1 equiv) at105 8C (Scheme 70). This route provides a direct conversion

Scheme 67.

Scheme 68.

Scheme 69.

Scheme 66.

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FOCUS REVIEWZhuang-Ping Zhan et al.

of C-silyl alkynyl imines to the corresponding azaheterocy-cles, which can avoids the isolation of the more sensitiveterminal alkynyl imines. To our delight, even reactions withhighly sensitive N-vinyl/heterocyclic imines can provide ex-cellent results by using this protocol. However, the scope islimited to C-silyl alkynyl imines or the terminal alkynylimines and only 2,5-disubstituted and 2,3-fused-5-substitut-ed products can be prepared. The synthesis of 2,3,4-trisub-stituted pyridines 298 was reported by Cacchi et al.[54b]

whose method involves the cyclozation of N-propargylicenaminones 297 and a subsequent oxidation step catalyzedby CuBr at 60 8C or 80 8C (Scheme 71). The mechanism isdetailed in Scheme 72. This route provides a good methodto construct pyridine rings that contain a carbonyl group at

the C3 position. However, a method to obtain 5-substitutedand fully substituted pyridines still remains undeveloped.

Pyrimidine

In 2009, Gr�e and co-workers[55] presented a syntheticroute to prepare chiral pyrimidines (�)-304 with a fluorineatom in the benzylic position in high enantiomeric excessesfrom optically active propargylic compounds (�)-302. Theinteresting thing is that both the use of optically activepropargylic fluorides (�)-305 and the fluorination of thechiral pyrimidine (�)-303 in the final stage give excellentresults in terms of enantiocontrol (Scheme 73). By using

this method, pyrimidines with difluoromethyl side chainsalso can be synthesized. In 2011, our group[52b] also dis-closed a new approach to the tandem synthesis of 2,4-disub-stituted or 2,4,6-trisubstituted pyrimidines 308 from propar-gylic alcohols 306 with amidine 307. This reaction proceedsthrough a cascade propargylation-cyclization-oxidation se-quence catalyzed by CuACHTUNGTRENNUNG(OTf)2 (20 mol %) under very mildreaction conditions. The mechanism is detailed inScheme 74. However, a synthetic method obtain the 5-sub-stituted product from propargylic compounds continues tobe a big challenge.

3. Conclusion

In this Focus Review, we have summarized the recent re-search progress on the construction of aromatic heterocy-cles from propargylic compounds. Taking a panoramic look

Scheme 71.

Scheme 72.

Scheme 73. DAST=Diethylaminosulfur trifluoride.

Scheme 70.

Scheme 74.

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Aromatic Heterocycles from Propargylic Compounds

at this review, we can see that aromatic heterocycles, in-cluding five-membered rings and six-membered rings, canbe easily prepared under mild reaction conditions in satis-factory yields by using easily available propargylic com-pounds as the starting materials. Furthermore, as a result oftheir unique structure, propargylic compounds can be fur-ther elaborated to relevant nature products or drugs withinfew steps, such as in the synthesis of Naamine A by Looperand co-workers.[33b]

Despite lots of achievement having been made in thepast, much endeavor is still required. Firstly, reliable syn-theses of many aromatic heterocycles that contain substitu-ents at specific positions have not yet been developed, suchas the direct synthesis of fully aryl- or alkyl-substituted pyr-azoles, as well as 5-substituted pyridines and pyrimidines.The synthesis of heterocycles that contain diverse function-al groups also needs further development.

Secondly, the synthesis of chiral aromatic heterocycliccompounds by the asymmetric nucleophilic substitution re-action of propargyl alcohols and subsequent cyclizationprocedure, or direct synthesis from optically active propar-gylic compounds still remains a big challenge. This area isattracting interest, but only a little research has been re-ported so far.[55]

Finally, exploiting new synthetic routes to natural prod-ucts and drugs is still an important objective, althoughsome targets have already been achieved. This is also anongoing interest in our group.

Acknowledgements

We thank the NSFC (No. 21072159), the 973 Projects(No.2011CB935901) for financial support of this project.

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Received: June 15, 2012Published online: September 3, 2012

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Aromatic Heterocycles from Propargylic Compounds