review of pummerer rearrangement, padwa, chem. rev. 2004

8/9/2019 Review of Pummerer rearrangement, Padwa, Chem. Rev. 2004

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The Pummerer Reaction: Methodology and Strategy for the Synthesis ofHeterocyclic Compounds

Scott K. Bur

Gustavus Adolphus College, 800 West College Avenue, St. Peter, Minnesota 56082

Albert Padwa*

Emory University, 1515 Pierce Drive, Atlanta, Georgia 30322

Received September 1, 2003

Contents

1. Introduction 24012. Modification of Existing Rings 24023. Formation of Five-Membered Ring Heterocycles 2404

3.1. Furan Derivatives 24043.2. Pyrrolidine Derivatives 24083.3. Mesoionic Betaines 2412

4. Formation of Six-Membered Ring Heterocycles 24134.1. Isoquinoline Derivatives 24134.2. Indole Alkaloids 24164.3. Chromene Derivatives 24174.4. 1,3-Oxathianes 24184.5. Rearrangements 2418

5. Generation of Other Heterocyclic Ring Systems 24195.1. -Lactam Formation 24195.2. Benzazepine Derivatives 24205.3. Indole Alkaloids 2422

6. General Methods for the Formation of Five- andSix-Membered Rings

2423

6.1. Pummerer/N-Acyliminium Ion Cascades 24236.2. Vinylogous Pummerer Reaction 24256.3. Additive Pummerer Reaction 24256.4. Hypervalent Iodine-Promoted Cyclizations 2426

7. Related Processes 24277.1. Interrupted Pummerer Reactions 24277.2. Morin Processes 24297.3. [4+3]-Cycloadditions 2429

8. Conclusion 24309. Acknowledgment 2430

10. References 2430

1. Introduction

The use of heteroatom-stabilized carbocations asreactive intermediates represents one of the funda -mental tools available for the synthesis of complexmolecules. The Pummerer rearrangement, exempli-fied by the reaction of a sulfoxide, 1, w i t h a n a c i danh ydride, produces a n R-substituted sulfide, 4, via

a n elimina tion/a ddition mechan ism involving thion-ium ion 3 (eq 1).1

The recognition that thionium ion intermediatescan act as electrophiles in cyclization reactions ha sgreatly expanded the synthetic utility of this reac-tion.2 The Pummerer process generally involves ad-dit ion of a nucleophile to the t hionium ion, a nd t heover a l l pr oces s r epr es ent s a pow er ful s y nt het icmethod. Examples of both inter- and intramolecularreactions a re now w idespread, a nd stra tegies incor-porat ing h eteroat om or carbon nucleophiles havefound broad applicat ion. As Pumm erer chemistry ha smatured, much effort has focused on novel ways togenera te th ionium ions to expand t he reactions scopebeyond the use of sulfoxide substrates. Concomi-t ant ly , new s t r a t egies t ha t employ P ummer er -l ikeprocesses for the synthesis of complex natural andunnatural products have emerged.

Heterocyclic compounds, both naturally producedand synthetically derived, often display importantbiologica l act ivi t y . In fact , mor e t han 67% of t hecompounds listed in the Comprehensive MedicinalChemistr y (CMC) dat aba se contain heterocyclic rings,and nonaromatic heterocycles a re tw ice as a bundantin this database as heteroaromatics.3 Consequently,the development of new methodology and the stra-tegic deployment of known methods for the syn thesisof complex heterocyclic compounds continue to drivesynthetic organic chemistry. The rich chemistry ofthionium ions ha s earned the P ummerer reaction a nimporta nt place in the repertoire of synth etic orga nictransformations, 2 including reactions tha t form h et-erocyclic rings.

Several review papers ha ve outlined recent progressusing P ummerer-based chemistry,2 including t hesynthesis of nitrogen heterocycles.4 Since our las t

* To whom correspondence should be a ddressed. P hone: (404) 727-0283. Fa x: (404) 727-6629. E-mail: [email protected].

2401Chem. Rev. 2004, 104, 24012432

10.1021/cr020090l CCC: $48.50 2004 American Chemical SocietyPublished on Web 03/12/2004


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review detailing the use of Pummerer chemistry togenerat e heterocycles,5 addit ional examples haveappea r ed in t he l i t era t ur e in r ecent y ea r s w hichf ur t h er d ef in e t h e s cop e a n d a p pl ica t i on of t h e

P umm erer reaction. The focus of this review centersabout P ummerer-based t ra nsforma tions for t he con-s t r uct ion and ma nipula t ion of het er ocyclic com-pounds, especially intramolecular Pummerer reac-t ions (e .g . , eq 2) , and pay s par t icular a t t ent ion t o

recent developments in this area. Attention is givento both new methodology a nd t he a pplicat ion of th eP ummerer reaction towa rd t he synthesis of complexna tura l products. An at tempt ha s been ma de to showhow t he Pummer er r eact ion has been ut i l ized forna tura l product synthesis. While this review a rt icleis pr imar ily or ganized by r ing s ize, much of t hemethodology is also useful for the construction ofvaria bly sized heterocycles, a nd these reactions w illbe presented separ at ely.

2. Modification of Existing Rings

O ne of t he mor e bas ic a pplica t ions of t he Pum-merer rea ction involves the refunctionalization ofexisting heterocyclic rings. A recent review of thio-nucleoside chemistry underscores the primary im-porta nce of the P ummerer reaction as a w ay to accesscomplex tetrahydrothiophene derivatives.6 I n a d d i-tion, electron-rich heterocycles ar e part icularly usefulreagents for the t ra pping ofR-a cylthionium ions.7-9

For example, when the -keto sulfoxide-substitutedindole 5 w a s t r ea t ed w it h t r ichlor oacet ic a cid inboiling dichloroethane, the cyclized tricyclic deriva-tive 6 was formed in 68% yield (Scheme 1). This

transformation proceeded by an intramolecular cy-clization of the indole ring onto the initially generated

R-acylthionium ion. I nterestingly, when the r elat edN-methylindole derivative 7 w a s h e a t e d w i t h p-toluenesulfonic acid (p-TsOH) in dioxane at reflux,the carbazole analogue 8 was formed in 54%yield.In t his case, the initially formedR-methylthio ketoneundergoes aromat ization wit h concomita nt elimina-tion of metha nethiol.

Py r r ole and t hiophene r ings a ls o par t icipat e inthese cyclization reactions. In fact, exposure of sul-foxide 9 to 0.4 equiv of p-TsOH produced the tet-r ahy dr oindole der iva t ive 10 (Scheme 2). Underha rsher conditions, sulfoxide 11 w as conver t ed t oindole 12 in 91%yield. Benzothiophene-substitutedder ivat ives w er e a ls o obt a ined by us ing t he s ame

Scott K. Bur received his B.S. from the University of Michigan in 1994,and worked as an extern with Parke-Davis Pharmaceuticals in Ann Arborfor one year. He then earned his Ph.D. from the University of Texas atAustin in 2000 under the supervision of Professor Stephen F. Martin.After an NIH postdoctoral fellowship in the laboratories of Professor AlbertPadwa at Emory University, he joined the faculty at Gustavus AdolphusCollege in 2003. His research interests include heterocyclic methodology,natural product synthesis, and the application of computational methodsto the solution of synthetic organic problems.

Albert Padwa was born in New York City. He received both his B.A. andPh.D. degrees from Columbia University. After an NSF postdoctoralposition at the University of Wisconsin, he was appointed AssistantProfessor of Chemistry at the Ohio State University in 1963. He movedto SUNY Buffalo in 1966 as Associate Professor and was promoted toProfessor in 1969. Since 1979, he has been the William Patterson TimmieProfessor of Chemistry at Emory University. He has held visiting positionsat University Claude Bernard, France, the University of California atBerkeley, the University of Wurzburg, Germany, and the Imperial Collegeof Chemistry, U.K. Professor Padwa has been the recipient of an AlfredP. Sloan Fellowship, a John S. Guggenheim Fellowship, an Alexandervon Humboldt Senior Scientist Award, a Fulbright Hays Scholarship, aSenior Award in Heterocyclic Chemistry from the International Society ofHeterocyclic Chemists, and an ACS Arthur C. Cope Scholar Award andis the coauthor of more than 600 publications. He served as the Chairman

of the Organic Division of the ACS and as President of the InternationalSociety of Heterocyclic Chemistry. He has also served as a member ofthe editorial boards of the Journal of the American Chemical Society,Journal of Organic Chemistry, andOrganic Letters, has been the volumeeditor ofComprehensive Heterocyclic Chemistry, the Synthesis of Science(Vol. 27), and is currently one of the Associate Editors of the Journal ofOrganic Chemistry. His research interests include heterocyclic chemistry,dipolar cycloadditions, alkaloid synthesis, tandem transformations, orga-nometallic chemistry, and organic photochemistry. Aside from chemistry,his other passion is mountain climbing in various parts of the world.

Scheme1

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reaction sequence. Thus, hea ting -keto sulfoxide 13w i t h TF A a t r ef lu x i n b en z en e r es u lt e d i n t h eisolat ion of the a nnula ted th iophene14in 54%yield.When p-TsOH w a s used as th e Pum merer promoter,intramolecular cyclization occurred onto the R-acyl-thionium ion generated from sulfoxide 15, and t hisw a s fo l low ed by ar omat iza t ion w it h los s of met h-an ethiol to provide benzoth iophene 16 in good yield.These exa mples demonstra te t ha t t he judicious selec-

tion of acid and solvent is important for accessingcerta in heterocyclic compounds.B a r i h a s u sed a P u m m er er v a r ia n t t o a l ly la t e

-lacta m derivatives.10 E x pos u re of t h e R-chlorosulfide 17 to a Lewis acid in the presence of allyl-trimeth ylsilane produced 18a s a single diast ereomerin 86%yield (Scheme 3). The stereochemistry of thefinal product a rises from a ddition of the allyl nucleo-phile t o t he leas t h inder ed s ide of t he r a t her f la tt hionium ion int er media t e , r es ult ing in a t r a n s -

relationship between the allyl and phenyl substitu-ents. The sulfide moiety was then removed by heating18w ith R a ney nickel to stereoselectively provide19,in which the olefinic -bond had also been reduced.Alternatively, heating 18 w it h t r ibut y l t in hy dr ide(B u 3SnH ) in t he presence of 2,2-azobisisobutyroni-trile (AIBN) provided 20 as a single diastereomer.The s t er eos elect ivi t y in t hes e r educt ions can beexplained by t he delivera nce of hydrogen to the least

hindered face (t r a n s to t he directing phenyl group)of the radical intermediate.Ohno and Ishida ha ve reported results dealing with

th e 1,3-dipolar cycloadd ition of thiocarbony l ylide 22,generated from the thermolysis of 21, to [60]fullerene,giving rise to t etrah ydrothiophene23 (Sch eme 4).11

Oxidat ion of 23 to sulfoxide 24by t r ea t m e n t w i t hm-chloroperbenzoic acid (m-CPBA), followed by an

acet ic a nhy dr ide-media t ed P ummer er r ear r ange-ment , pr ovided t he R-acyloxy derivative 25. Theacyloxy group allows for further derivatization (e.g.,26) by exposure to either cam phorsulfonic acid (CSA)or t r imet hy ls ily l t r i f luor omet ha nes ulfonat e (TM-SOTf) in the presence of a nucleophile. Nucleophilessuch as alcohols, thiols, allylsilanes, and enol ethersalso participate in this reaction.12

Although simple substitution reactions are wellestablished, the thionium ion intermediate generat edin t he P ummer er r eact ion can evoke unex pect edrearrangements when neighboring groups partici-pate. With the intention of using the ionization ofR-chloro sulfides 27 to introduce additiona l function-

ality on the heterocycle, McCarthy and co-workersobserved some int eresting rearra ngement products(Scheme 5).13 The distr ibution of products w as foundto be dependent upon the na ture of the ary l substitu-ent. Exposure of 27a (Ar ) P h) to a slight excess ofS n C l4 in C H 2C l2 a t room t emperat ure produced t heelimina tion product 28a in 69%yield. Reaction of27b(Ar ) 4-MeOP h) under simila r conditions, however,produced a mixtur e of28b (12%yield) an d 29b (40%yield). Fura none27c (Ar ) 3,4-(MeO)2Ph) affordeda mixture of 28c(7% yield), 30 (35% yield), a nd 31(15%yield) when treat ed with SnC l4. The forma tionof products 30a nd 31 is peculiar in tha t a n aroma ticsubstitution reaction has occurred. Exposure of 27c

Scheme2

Scheme3

Scheme4

The Pummerer Reaction Chemical Reviews, 2004, Vol. 104, No. 5 2403


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to ZnB r2changed the product distribution in tha t 28cpredominated (49% yield). Chloride 31 w a s s t il lisola ted (11%yield), w hile 30was not detected. Theforma tion of31suggests tha t chlorine tran sfer mightbe a n int r a molecular pr oces s , but t he mechanis mcould not clearly be delineated on the basis of theexperimental data.

3. Formation of Five-Membered RingHeterocycles

While the refunctionalization of exist ing hetero-cycles is certainly an important process, use of theP ummerer reaction as a key stra tegy in the forma tionof heterocycles continu es to int rigue resea rchers. Thes y nt hes is of numerous complex nat ur a l pr oduct srelies on the int ra molecula r t ra pping of nucleophilesby thionium ion intermediates. Research into Pum-merer reactions that form five-membered ring het-erocycles has been considerable. Often, these hetero-cycles are tra nsient intermediat es in cascad e reactionstha t produce polycyclic a rra ys. Frequent ly, however,

the P ummerer reaction provides a convenient stra t-egy for forming five-membered ring heterocyclescont a ining funct iona li t y t ha t can be lever aged forfurther manipulation.

3.1. Furan Derivatives

An interesting application of a Pummerer discon-nection for the synthesis of the benzofuran core ofthe diazonamides 32 (Scheme 6) has been reportedby Magnus a nd Kr eis ber g .14 Although several ex-am ples of constru cting oxindoles via an intra molecu-lar P ummerer cyclizat ion a re known, 15 no a na logoussyntheses of benzofuran derivatives had been previ-

ously disclosed. A model system was therefore ex-am ined. Init ial at tempts t o form the five-memberedheterocycle from sulfoxide 33 under nor mal Pum-merer conditions (e.g., tr ifluoroacetic an hydride)failed to provide34. How ever, exposure of th e R-chlo-ro sulfide 35, derived from the pa rent R-methylthioes t er b y t r ea t m e n t w i t h N-chlorosuccinimide, toS n C l4 resulted in the format ion of34 in 45%yield.The use of stoichiometric S nCl 4 caused significantdecompos it ion, w her eas ca t a ly t ic amount s of t hisLewis a cid provided a cleaner rea ction m ixture.

Applicat ion of this method t o a syst em tha t m oreclosely resembles the dia zonamide IH G core wa s a lsosuccessful. Thus , rea ction of36w it h NC S in C C l4for

2 h f ol low e d b y h ea t i n g a t r ef lu x w i t h ca t a l yt i camount s of SnC l4 afforded 37 in 67%yield. Severalother examples with varying substitution on the arylmoiety w ere also reported. This P ummerer stra tegyallows for use of the m ethylthio functional group infurther transformations that form the bond linkingt he F a nd H r ings in the natural product.

A ta ndem P ummerer cyclizat ion sequence ha s alsobeen us ed for a gener a l py r r ole s y nt hesis via t heinitial format ion of a reactive furan derivat ive (Scheme

7).16

Dihydrofuran 38 w a s p re pa r e d b y M ich a e l

a d d i t ion of a -ket o est er anion t o pheny l viny lsulfoxide followed by a sequential acid-induced Pum-merer reaction in which the thionium ion was trappedby t he oxy gen a t om of t he enol t aut omer . Fur t herr eact ion of dihy dr ofur an 38 w i t h H g C l2 inducedcarbon-sulfur bond cleavage and generation of theoxonium ion intermediate39. Rea ction of this speciesw it h e i t her an ammonium s a l t or a pr imar y amine

Scheme5 Scheme6

Scheme7



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gave rise to the disubstitut ed pyrroles40-43 in goodyields.

The Marino group has developed a novel additiveP ummerer reaction (vide infra) tha t produces -bu-tyrolactones by the reaction of dichloroketene wit hvinyl sulfoxides.17 In general, the oxygen of a vinylsulfoxide such as 44 first a t ta cks dichloroketene toproduce in situ th e salt 45 (Scheme 8). The r esult ing

enolate 45 then undergoes a 3,3-sigmatr opic rear -rangement to provide thionium ion intermediate 46.Finally, the result ing carboxylate anion adds to theneighboring thionium ion to furnish but yrolactone 47,which reta ins the geometry of the sta rting olefin. Theuse of chira l sulfoxides44leads to the enantiospecificformation of butyrolactones 47.18,19

An int er est ing applica t ion of t his addit ive P um-merer method was carried out by the Marino groupfor t he s y nt hes is of phy sos t igmine.20 Addit ion ofindole sulfoxide 48 to a heated solution of zinc dust,C uI , and t r ichlor oacet y l chlor ide r es ult ed in t he

isolation of the tricyclic indole derivative 49 in 54%yield (Scheme 9). Dechlorina tion a nd dethiomethy-

lation w as accomplished in one step using Bu 3S n H /AIBN. Straightforward functional group manipula-tion of 50 eventua lly afforded physostigmine.

The P ummerer/lactonization procedure wa s alsoapplied in an a symmetric manner.20 It wa s found thatonly alkyl sulfoxides were capable of generating thelactone ring in an enantiospecific fashion. Appar-ently, th e indolyl R-phenyl sulfoxide derivative wasnot rea ctive enough t owa rd dichloroketene to produce

the d esired product. The low rea ctivity encount eredduring this w ork was eventua lly solved by using th eisopropyl-substit uted sulfoxide 51, w hich could belact onized under t he s t a nda r d condit ions t o g ivelactone53. Treat ment of this compound wit h 2 equivo f B u 3SnH under r adica l condit ions a f for ded t hedechlorinated lactone in 75% ee (Scheme 10). The

preferred formation of stereoisomer 53wa s attr ibutedto the dominance of conformer 52b of the init iallyfor med int er media t e in t he eq uil ibr ium mixt ur e .Conformation 52a appear s t o ha ve a dest a biliz ing

A1,2

-interaction between the Boc protecting group andthe isopropyl functionality.This uniq ue s t r a t egy has r ecent ly been applied

towa rd the synth esis of (+)-a spidospermid ine. In t hisapproach, enantiomerically pure sulfoxide 54 w a streated with trichloroacetyl chloride in the presenceof zinc-copper couple (Zn-Cu) t o ena ntiospecificallyproduce lactone 55 in 78% yield (Scheme 11).21

Subsequent removal of the chloro substituents fol-lowed by th e deprotection of the keta l afforded 56 in96% yield. Rea ction of 56 with pyrrolidine effecteda n O- t o N-tra nsacylat ion with a subsequent elimina-tion of thiolat e to give the am ido aldehyde 57in 86%yield. Furth er exposure of 57 to pyrrolidine in the

presence of 33% aqueous AcOH an d 2-propanolpr omot ed an int r amolecular a ldol r eact ion and s i-multa neously hydrolyzed the am ide group to furnishan intermediate carboxylic acid. Conversion of thecarboxylic a cid to a m ixed anhy dride followed by theaddition of 3-chloropropylamine gave58 in 64%yieldfrom 57. E xposure of 58 t o NaH init ia t ed a t a ndemintr a molecula r conjugat e add ition/a lkylat ion to pro-duce 59 in 86%yield. Subjection of t he silyl enol eth erof 59 to modified Segusa oxidation conditions deliv-ered 60 (85%), wh ich wa s subsequ ent ly car ried on to(+)-aspidospermidine.

Another ta ndem P umm erer/int ra molecula r oxygentrapping sequence was cleverly used by Burke and

Scheme8

Scheme9

Scheme10



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co-workers for the synthesis of a venaciolide (63;Schem e 12).22 Treat ment of sulfoxide61wit h TFAAresulted in t he forma tion of a mixtur e (5:1) of la ctones62 in 84% over a l l y ield . Aft er chr oma t ogr aphicsepar at ion, each diast ereomer wa s converted into the3-normethylene analogue of 63 us ing s t a ndar d or -ganic transformations.

In an early report, de Groot and co-workers estab-lished th at the P ummerer reaction could be used toconstruct substituted furans.23 Thus, treatment ofsulfoxide 64 w it h a c et i c a n h y d r id e g a v e r i se t o at r a n s i e n t t h i o n i u m i o n t h a t w a s a t t a c k e d b y t h eneighboring aldehy dic ca rbonyl group to produce the

oxy-sta bilized ca tion 65 (Scheme 13). The next stepinvolved proton loss to generate 2-phenylthiofuran66. Hyd rolysis of 66w it h H gC l2ultimately providedisodrimerin.

The method was further extended by de Groot tothe regioselective synt hesis of several other na tura llyoccurring butenolides. By altering the reaction condi-

tions, regioisomeric butenolides could be producedf r o m t h e s a m e s t a r t i n g v i n y l s u l f o x i d e , a n d t h i smethod wa s a pplied to th e synthesis of (()-conferti-folin (Scheme 14).24 Under aqueous thermal condi-

tions, vinyl sulfoxide 67 under w ent t he P ummer err eact ion t o for m t he expect ed t hionium ion. The

cationic center present in 68 w a s a t t a c k e d b y t h eneighboring hydroxyl group of the hydrated aldehyde.Elimination of thiophenol produced the 2-hydroxy-furan derivative69, w hich sponta neously ta utomer-ized to give (()-confertifolin.

O ur r es ea r ch g rou p a t E m or y h a s a l so m a d eextensive use of this met hodology for casca de cycliza-t ions w her ein highly r eact ive fur an int er media t esundergo D iels-Alder cycloadditions.25 The lithiumenola t e of cy cl ic a mides s uch as 70, for example,added cleanly to bis(methylsulfanyl)acetaldehyde (71)to a fford aldol products 72 (S cheme 15).26 Reactionof 72 with commercially available dimethyl(meth-ylthio)sulfonium tetra fluoroborate (DMTSF) tr ig-

ger ed a Pummer er ca s cade by f ir s t t r ans fer r ing amethylthio group in 72. This w as fo l low ed by t heeliminat ion of methy l disulfide to produce a r eactivethionium ion intermediate that was intercepted bythe proxima l carbonyl group to furnish t he dihydro-furan derivative73. Elimina tion of acetic acid underthe reaction conditions gave furans 74 in 70-80%isolated yields.

A variety of 2-methylthio-5-am idofuran systemswere prepared that contained a -bond t ethered onthe am ido nitrogen in a m ann er tha t w ould allow foran intra molecular D iels-Alder rea ction.27 Thus, ex-posure of imides 75 to D MTSF produced furans 76in 40-70%yields (Scheme 16). Therm olysis of 76 in

Scheme11a

a R e a g ent s a nd c ond it ions : (a ) Zn-C u , C l3CC OCl; 78%. (b)B u 3S n H , E t 3B ; 92%. (c) p-TsOH, acetone; 96%. (d) P yrr olidine;86%. (e) Py rrolidine, 2-propanol, 33% aqueous AcOH. (f) i-B u O C O C l, E t 3N, 3-chloropropylam ineHC l; 64%for tw o steps. (g)NaH ; 86%. (h) KHMD S, TMSC l, th en P d(OAc)2/O2, D MS O; 80%.

Scheme12

Scheme13

Scheme14



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toluene at reflux init iated a n intr am olecular Diels-Alder reaction (IMDAF) to afford an intermediateoxabicycle. Subsequent fragmentation of the inter-mediate oxabicycle followed by a 1,2-thio shift pro-vided the bicyclic amides 77 in good y ield (ca . 70%).

In a n an alogous ma nner, the cycload dition chemistryof furans 78 provided tricyclic products 79.Our research group has exploited this thio-substi-

tuted fura n-forming P ummerer cascade for th e syn-thesis of several natural products. For example, int h e t o t a l s y n t h e s i s o f (()-stenine, t he reaction ofimide 80with DMTSF provided azapinoindole 82 in80%yield a s a mixtur e (1:1) of epimers a bout t he C(9)stereocenter (Scheme 17).28 Int erestingly, the inter-media t e fur an 81 could not be isolated as it sponta-neously cyclized a nd rea rra nged under t he DMTSFreaction conditions (


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duce isoquinoline derivative.33 In their study, expo-sure of sulfoxide 95 t o a cet i c a n h yd r id e i n t h epresence of catalytic amounts of p-TsOH produced

an intermediate pyridofuran derivative 96 t h a t u n -dergoes a subsequent cycloaddition with added dim-ethyl ma leate t o afford the polysubstituted isoquin-oline98 in 44%yield (Scheme 19). The intermediateoxabicycle 97 was not isolated.

The use of aryl ketones 99a-c a s s t a r t i n g s u b -stra tes, h owever, produced oxa bicycles100a-c ar is -ing from a n endoDiels-Alder reaction. The efficiencyof furo[3,4-c]p yr id i ne f or m a t i on w a s f ou n d t o b esensitive to the conditions employed with these arylketones. For exam ple, oxabicycles 100a-c w er eisolated in 33-40% yield when the tra nsforma tionwas carried out using trifluoroacetic anhydride; yieldswere lower (17-20% yield) w hen acetic a nhydride

was employed. Electron-releasing substituents on thear oma t ic r ing enhanced t he overa l l r eact ion. Sub-s t r a t e99a (R) H) afforded 100a in 33%yield in th epresence of t r ifluoroacetic anh ydride, while com-pound 99c(R ) OMe) furnished 100c in 40%yieldunder t he s a me r eact ion condit ions . O xa bicy cles100a-c under w ent fr agment a t ion and s ubs eq uentaroma tizat ion to give isoquinoline derivat ives (e.g.,98) by th e action of DB U in toluene at reflux.

3.2. Pyrrolidine Derivatives

The int r amolecula r t r a pping of t hionium ionscont inues to be employed for the sy nth esis of indole

a l k a loi d s. Th e u s e o f P u m m e r er ch em i st r y a s amethod to close th e five-membered pyr rolidine ring,while forming one of the quaternary centers foundin t he as pidos per ma and s t r y chnos a lkaloids , w asf ir s t s t udied by Magnus and co-w or ker s.34 Theyeffectively used this methodology for the synthesisof the kopsane alka loids.35 When sulfoxide 101 w a sexposed to tr ifluoroacetic anhy dride, the homoann u-lar diene 102was produced in 78%yield (Scheme 20).

Forma tion of the C(11)-C(12) bond was proposed toproceed prior to the elimination of HCl, since it wasknown that the 1,4-dihydrocarbazole system, result-ing from eliminat ion of HC l, would rea dily aroma tizeunder t he r eact ion condit ions . Ally la t ion of ket osulfide102 resulted in the introduction of the allylictether on t he concave fa ce of the diene. Int ra molecu-lar [4+2]-cycloa ddit ion of t he -bonds present in 103

Scheme18a

a Reagen ts a nd conditions: (a) TFAA, TEA. (b) BF 3E t 2O. (c)KH, P hNTf2. (d) (PP h3)2P d C l2, TEA, HC O2H. (e)TiCl4, AcOH, H 2O.

Scheme19

Scheme20



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produced the basic kopsane structure 104 in 86%yield.

This appr oach has a ls o been us ed for t he as pi-dosperma alka loids, a nd wa s employed by dAngeloto synth esize (+)-aspidospermidine.36 More recently ,Rodrguez and U rrutia h ave incorporat ed this strat -egy into their synthesis of (()-18-noraspidospermi-d i n e (113) a s p a r t of a n e ff or t t o d ev el op u s ef ulanalogues (Scheme 21).37 The key transformation in

t he s y nt hesis involves t he conjugat e addit ion ofdimethylcuprat e to the R,-unsaturated aldehyde 105to provide106 (63%yield), a strategy that allows forthe introduction of a variety of angula r substituentsin t he f ina l pr oduct . Sever a l funct ional gr oup ma -nipulations provided access to ketal 107. The in dole

ring was subsequently introduced via a Fischer indolereaction to give 108. Benzylic oxidation followed bynickel boride reduction of the nitro group providedimine 109. After considerable experimentation, it wasfound t ha t a mixt ur e of LiAlH 4/AlC l3 could reduceimine 109 t o t h e ci s-fused amine 110with modeststereoselectivit y (93%yield, 3:1 ci s/t r a n s ) in a toluene/THF (30:1) solvent mixtu re. With a mine 110 in hand,t he E r ing wa s installed by acylat ion with phenylth-ioa cetyl chloride followed by oxidat ion of the sulfideto t he sulfoxide111 us ing NaIO4. Exposure of 111t o t r i f luor oa cet ic a nhy dr ide effect ed a P ummer ercyclizat ion to provide112 in 68%yield. To finish thesynthesis, 112 w as des ulfur ized by t he act ion of

Ra ney nickel. Furt her reaction with LiAlH 4 cleavedthe tosyl protecting group and stereoselectively re-duced the enamine functionality to give the target113.

In a recent report , t he Sh ibasa ki group describedan elegant synthesis of (-)-strychnine that employsa v a r i a t i o n o n t h e M a g n u s a p p r o a c h t o f o r m t h espirocyclic pyrrolidine moiety.38 H ighlight s o f t hesynt hesis are depicted in Scheme 22. An a symmet ric

Micha el ad dit ion of dimethyl ma lona te t o cyclohex-enone provided enant iomerically pure 114 in 91%yield. In a series of reactions, 114 w a s t r a ns for medinto ketone 115. C onversion of the prima ry alcoholin 115 t o t he cor r esponding t r i f la t e , fol low ed bydisplacement with 2,2-bis(ethylthio)ethylamine af-forded bicyclic amin e 117via the intermediacy of116.Reduction of the nitro moiety followed by a condensa-tion of the resulting amine w ith t he adjacent carbonylgroup provided indole 118 in 77%yield from ketone115. Tr eat ment of 118 w it h DMTSF pr omot ed aPummerer cyclization to form the spirocyclic C ringof 119 in 86%yield. P rotecting group ma nipulat ionan d removal of th e ethylthio moiety furnished pen-

Scheme21a

a R ea g en t s a n d con d it ion s: (a ) M e2C u Li, E t2O; 63%. (b)P hNH NH3Cl ; 81%. (c) DD Q; 80%. (d) NiC l26H 2O/Na B H 4/NH 2NH 2H 2O; 91%. (e) TsCl, NaOH , Bu 4NH 4I; 74%. (f) LiAlH4-AlCl3,tolu ene/TH F (30:1); 93%. (g) P hS C H 2COC l; 96%. (h) NaI O4; 72%.(i) TFAA, P hC l; 68%. (j) Ra ney Ni; 82%. (k) Li AlH4; 50%.

Scheme22a

a Reagents a nd condit ions: (a) Tf2O, i-P r 2NEt ; 2,2-bis(ethylt h-io)ethyla mine. (b) Zn, MeOH-aqueous NH 4Cl; 77%for two steps.(c) D MTSF ; 86%. (d) SO 3P y r , E t 3N, DMSO. (e) HF E t 3N, THF;83%for two steps. (f) NaOMe, MeOH. (g) Malonic acid, NaOAc,Ac2O, AcOH; 42%for two steps.



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tacycle 120. Oxidat ion of the alcohol group in 120,with concomitant epimerization of the C(16) stereo-center, followed by deprotection of the TIPS etherestablished the hemiaceta l 121 in 83%yield. Remova lof the acetyl protecting group followed by exposureto malonic acid under buffered conditions provided(-)-str ychnine in 42% yield from 121.

Bosch and co-workers carried out an interestingand novel approach to the pentacyclic r ing system

pr es ent in t he s t r y chnos a lka loid fa mily us ing ata ndem P ummerer intra molecular nucleophilic r ingclosure reaction.39 Reaction of -keto sulfoxide 122with TFAA afforded R-tr ifluoroacetyl sulfide 123(90%yield, eq 3). The fa ilure of122 to cyclize on t he

indole ring wa s at tr ibuted to the fact tha t cyclizationof the t hionium ion onto th e indole at the 3-positionw ould dis t ur b t he planar i t y o f t he amide car bony lgroup. The ring closure reaction was also expectedto be inhibited by the lower conforma tional flexibilitypresent in the rigid bridged strychnos skeleton. 39a

However, it was possible to overcome these difficul-ties by preparing the dimethylthioacetal derivative124 (Scheme 23). Treatment of 124 w it h DMTSF

gave r is e t o t he pent acy clic s y s t em 126 by a n i n-t r amolecular r ing clos ur e of t he indole r ing ont othionium ion 125. Reduct ive des ulfur iza t ion w it hRaney Ni provided tubifolidine in good yield.

The ibophyllidine alkaloids have also been con-structed using a r ing-closing P ummerer reaction tofashion the C ring. Bosch and co-workers started thesynt hesis of (()-deethylibophyllidine by employing adissolving meta l reduction of pheneth yla mine 127 t oprovide the dihydrobenzene derivative 128 (Scheme24).40 Addition of128 to phenyl viny l sufoxide yielded129. H ea t ing 129with 2 N HCl a t 90 C , followed by

a basic workup, gave the ci s-ocatahydroindolone130in 54% from 127. A regioselective acid-cata lyzedFischer indole reaction afforded the NH-indole 131(60% y ield), w hich w a s pr ot ect ed on t he indolenit r ogen by t r ea t ment w it h LDA follow ed by t headdition of Manders reagent to give132 in 76%yield.

It should be noted th at neither the hydrolysis of thee nol e t h er n or t h e F i sh er i n dol e r ea c t ion , b ot hconducted under acidic conditions, effected a P um-merer reaction of the pendant sulfoxide. This wasat tributed t o the higher sta bility of sulfoxides lackingan activating group at the R-position, t hereby a llow-ing for the ear ly introduction of a sulfur atom a t t heproper oxidation state. The desired Pummerer cy-clization could easily be t riggered, however, by expos-in g 132 to a mixtur e of TFA a nd TFAA (3 equiv) at80 C for 2 h. Under these conditions, a mixture ofpenta cyclic isomers (i.e.,133)epimeric at C(7) wa sobta ined in 63% yield. The now superfluous phe-nylth io group present in 133was readily removed by

the a ction of Raney Ni in etha nol at reflux to afford134 in 63%yield. Irra diat ion of134using a medium-pressure mercury lamp delivered deethylibophylli-dine in 50%yield.

In recent years, our research group at Emory hasexamined the combination of Pummerer-based cy-clizations and N-acyliminium ion cyclizations in ata ndem sequence to form pyrrolidine-conta ining rings y s t ems . In a t y pica l example, enamide 135 w a st r ea t ed w it h p-TsOH in benzene at reflux tempera-t ur e t o pr oduce t hionium ion 136. A s ubs eq uentNa za rov-like ring closure of 136 furnished iminiumion 137. Finally, interception of this cation by thependa nt a r omat ic r ing pr oduced 138 a s a s in g le

Scheme23

Scheme24a

a R e a g ent s a nd c ond it ions : (a ) Li , NH 3, E t O H , -78 C . ( b )phenyl vinyl sulfoxide, EtOH, rt . (c) 2 N HCl, 90 C; 54% from127. (d) PhNHNH 2, E t O H , ; t hen AcOH, 95 C; 60%. (e) LDA,NC-C O2Me, THF-H MP A,-78 C ; 76%. (f) TFA (3 equ iv), TFAA(3 equiv), 80 C, 2 h; 63%. (g) Raney Ni, E tOH, ; 63%. (h) h;50%.



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diastereomer in 78%yield (Scheme 25). 41 The ster-eochemistry of 138, es t ablis hed by X-r ay cr y s t a l-lographic analysis , suggests a conrotatory ring clo-sure. Other -bonds were also found to efficientlyterminat e the cascade. For exam ple, a llylsilane 139provided bicycle 140 in 61%yield when heat ed with

p-TsOH. The t ermina l a lkene 141cyclized to give 142(80%yield), where the resultant secondary carboca-tion was captured by sulfonate anion. In each case,only one diastereomer w as isolated, suggesting th ata concerted 4-electrocyclization reaction results fromthe intermediat e thionium ion.

The Padwa group used this methodology to con-s t r uct t he r epor t ed s t r uct ur e of t he a lkaloid jam-tine.42 Th e k ey i n t er m ed ia t e w a s a s s em b le d b ycondensation of aldehyde 143 with 3,4-dimeth ox-yphenethyla mine followed by a cylat ion w ith (ethyl-sulfanyl)acetyl chloride to give enamide 144 a s amixt ure (4:1) ofZ- a n d E-isomers in wh ich the formerpredomina ted (Scheme 26). E xposure of144 to NaIO4

resulted in oxidation of the sulfide to a sulfoxide withconcomit a nt clea vage of t he TBS et her , a f for dingalcohol 145. This a lcohol w as converted t o the cor-responding bromide using CB r4/P P h 3, providing ena -mide 146 whereby the sulfoxide functionality hadalso been reduced. Reoxidation, followed by heatingthe result ing sulfoxide with CSA, produced severaltricyclic products (98%yield) as a mixture (5:2:1:1)of diastereomers in which 147w a s i sol a t e d a s t h ema jor diastereomer. The stereochemistry of 147,secured by X-ray crystallographic analysis , is con-sistent with a Nazarov-type conrotatory 4-electro-cyclizat ion followed by a tt a ck of the nu cleophilicallydisposed a romatic r ing from t he least hindered side

of the intermediat e iminium ion. Reaction ofR-eth-ylthio amide147with NaH effected a n intra molecu-lar alkylation to provide tetracycle 148. Oxidativeeliminat ion of t he et hy lt hio gr oup deliver ed t herequired unsaturat ed amide 149. Removal of th e nowsuperfluous ca rbonyl group wa s accomplished by firstconverting 149 to a thioamide followed by a subse-quent reduction using methyl Meerweins salt andN a B H 4 to complete the synthesis of (()-jamtine.

Preparation of the skeletal framework of the pyr-rolizidine alka loid fam ily wa s carried out by Ishibashiusing a mido sulfoxide150.43 The P ummerer r eaction

of 150 provided t he bicyclic lacta m 151 in 31%yield(Scheme 27). Conversion of 151 t o 152 w a s a c -complished by reducing the thiomethyl group withRaney Ni. I nt er media t e 152 wa s subsequently con-verted into both (()-isoretronecanol and (()-trach-elanthamidine.

Scheme25 Scheme26a

a Reagents and condit ions: (a) 2,2-Dimethoxyphenethylam ine,(ethylsu lfan yl)acetyl chloride; 92%. (b) Na IO 4, MeOH /H 2O; 99%.(c) CB r4, P P h 3; 83%. (d) Na IO 4, M eOH /H 2O; 99%. (e) CS A, P hMe,reflux; 98%. (f) Na H, THF , r eflux; 99%. (g) Na IO 4, MeOH /H 2O;heat ; 90%. (h) L aw essons r eagent ; 99%. (i) Meerweins salt ,

N a B H 4, M eOH; 61%.

Scheme27



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A relat ed method wa s employed a s the key step fort h e s y nt h e si s of (-)-tra chelant ha midine (Scheme28).44 Sulfoxide 153 w a s t r ea t ed w it h TFAA, andlact a m 154 was isolated in 87%yield. This bicycliclactam was then converted into trachelanthamidinein several addit ional steps.

3.3. Mesoionic BetainesI n a s er ies of pa p er s, P a d w a a n d co-w or ker s

examined the use of a Pummerer-init iated cascadereaction t o generat e isomunchnones, a class of me-soionic beta ines,45-47 and further studied their abilityto par ticipate in 1,3-dipolar cycloaddit ion chemistr y.For example, treatment of sulfoxide 155with aceticanhy dr ide r es ult ed in t he for mat ion of a r eact ivethionium ion tha t enga ged the distal a mide car bonylgroup to produce is omunchn one 156 (Scheme 29).46

Further exposure of 156 to a dipolarophile, such asN-phenylma leimide (NP M), induced a 1,3-dipolarcycloadd it ion a nd ga ve157 as a single diast ereomerin 85%yield.

The specific conditions required to successfullyeffect this transformation were important and war-

r a n t com m en t . Th e i n it i a l a t t e m pt s t o f or m t h eint ermed ia te isomunchn one employed TFAA to pro-mote the cyclizat ion a nd E t 3N t o form th e dipole fromthe oxonium ion intermediate. These conditions,however, failed to produce a viable dipole. Rather,cyclic ketene a cetal 158, in which the tr an sient dipolefirst react ed w ith excess TFAA followed by deproto-nation, was obtained. After considerable experimen-ta tion, it w as discovered that the slow a ddition of155to a mixture of acetic an hydride, a cata lytic amountof p-TsOH, and the appropriate dipolarophile at thereflux temperat ure of toluene gave consistent ly goodyields of the 1,3-cycloadduct. Severa l different dipo-larophiles w ere found t o participate in these cycloa d-

ditions. When 156wa s allowed to react with D MAD,t he ini t ia l ly for med ox abicy cle under w ent a r apidfragmentation reaction to produce furan 159(41%yield) and methyl isocyanate. The reaction of iso-mu nch non e 156 with 1,4-naphthoquinone produced160 in 73%yield. Other dipola rophiles tha t w ere usedincluded vinyl sulfones, maleic anhydride, and acry-lat e derivat ives. Una ctivated olefins also par ticipat edin the cycloaddit ion w hen they w ere tethered to th e

isomunchnone dipole. F or example, wh en sulfoxide161wa s treat ed with a cetic anhyd ride, polycyclic162was isolated as a single diastereomer in 73%yield.

The oxabicyclic products could be further trans-for med int o highly s ubs t i t ut ed py r idones. Thus ,exposure of cycloa dduct 163 t o a mixt ur e of a cet icanhy dr ide and B F 3OE t 2produced a mixt ure (5:1) ofpyridones164a nd 165 in 96%combined yield (Scheme30). In experiments with related cycloadducts, the

preferentia l forma tion of either t he acetoxy (e.g.,164)or ethylthio (e.g., 165) s ubs t it ut ed py r idone w a sfound to be substra te dependent. The products a risefr om differ ent ia l clea vage of t he br idging bond ineither the N,O-a ceta l (bond a) or S,O-a ceta l (bond b).Accordingly, when bond a in oxabicycle 166 is rup-tured, loss of a cetic acid and furt her ta utomerizat ionof thionium ion 167 produces the ethylthio-substi-tuted pyridone 168. Alternat ively, fra gmenta tion of

bond b produces iminium ion 169. Deprotonationfollowed by acyla tion of the resulting car bonyl groupgives170. The preference for pyridone 170 is thoughtt o hinge upon t he abil i t y o f t he a mide nit r ogen t oassist in the breaking of bond b. Thus, cycloadductswith geometries in which the nitrogens lone pair ofelectrons are a n t i -periplanar to the nucleofuge pro-vide gr ea t er q uant i t ies o f t he acet ox y -s ubs t i t ut edproduct 170.

The a bove P umm erer-initia ted cycloaddit ion/cas-cade strategy was used for the synthesis of severalalkaloid natural products. For example, the formalsynthesis of (()-a na gyrin e involved exposure of imide171 t o a m i xt u r e o f a ce t ic a n h y d ri d e a n d m et h y l

Scheme28

Scheme29

Scheme30



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acr y la t e t o pr ovide ox a bicy cle 172 in 61% yield(Schem e 31).47 Oxidation of the sulfide group presentin 172w it h NaIO4/RuC l3furnished sulfone173 (91%yield). Exposure of 173 t o B F 3OE t 2and subsequentr ea ct ion w it h C omins r eagent gave t r i f la t e 174in80%overall yield. Palladium-catalyzed cross couplingof 174 with 2-(tri-n-butylsta nnyl)pyridine afforded175 in 70% y ield. C at a ly t ic hy dr ogenat ion of t hepyridone ring in 175 us ing Pt O2 followed by a base-

induced equilibrat ion delivered 176 (85% overally ield), a compound pr evious ly conver t ed t o (()-ana gy r ine.

Another example that makes use of this strategyfor natural product chemistry involves the synthesisof (()-cost a clav ine (S cheme 32).47 The methyl amidefunctionality present in 177w a s acy la t ed w it h (et h-ylsulfanyl)acetyl chloride, and subsequent oxidationof the sulfide wit h Na IO4provided sulfoxide 178. Thekey ta ndem P ummerer cyclizat ion/cycloa ddition cas-cade was init iated by exposing 178 t o a cet ic a nhy -dr ide and a t r ace of p-TsOH, which gave tetracycle179 in 64% yield. A sequence of functional groupinterconversions (hydrolysis of the acetate, conver-

s ion t o t he viny l t r i f la t e , and a St i l le coupling forinstallation of a methyl group) provided 180 in 59%overall yield. Platinum oxide-mediated hydrogenationof the pyridone moiety present in 180 followed byremoval of th e benzoyl group under a cidic condit ionsfurnished181a s a separa ble mixtur e (4:1) of epimersa bout t he C (8) meth yl group in 85%overa ll yield. Theam ido group of th e ma jor diastereomer of 181 w a sreduced with LiAlH 4, a n d s u bs eq u en t m a n g a n e sedioxide oxidat ion of the d ihydroindole delivered (()-cost a clav ine in 12 st eps wit h a n overa ll yield of 17%.The synthesis of several other a lkaloids, includingonychine, dielsquinone, (()-lupinine, an d pumil-iotoxin C, were also described by the Padwa group. 47

In a s omew ha t r ela t ed s t udy , Kim and P ar k ha vereported the use of the P ummerer reaction a s a keystep for the synthesis of tr iazapentalenes, anotherclass of mesoionic betaines.48 In t his ex ample, t hebenzotria zole-substituted allyl sulfide 182 (Ar )4-MeOC 6H 4) was first oxidized to sulfoxide 183 i n94%yield usin g m-CPBA (Scheme 33). Treatment of

183 with TFAA at room temperature provided tr i-azapent a lene 184 in 91% y ield. The P ummer er -init iated cyclization w orked equa lly w ell on stereo-chemica lly pure sam ples of either the (E)-or (Z)-allylsulfoxides 183. A variety of other aryl substituentson the olefin were studied, and yields of the corre-sponding t ria za penta lenes ran ged from 34%to 91%,wit h t he typical y ield being near 80%.

4. Formation of Six-Membered Ring Heterocycles

As seen from some of th e a bove schemes, rea ctivefive-membered ring heterocycles are often involved

a s intermedia tes for the generat ion of six-memberedr ing pr oduct s . Pummer er cy cliza t ions can a ls o beused to access these structures directly. Ma ny n at u-ra l products feat ure nitrogenous a nd oxygena ted six-membered rings that a re fused to aroma tic rings. Forthese compounds, Pummerer cyclizations are fre-quently employed. In contrast to thionium ion cy-clizations t ha t produce five-membered rings, productstha t a rise from C-S bond formation often accompanythe desired six-membered ring closure adducts.

4.1. Isoquinoline Derivatives

The format ion of isoquinoline derivatives via P um-merer-induced cyclizations has been studied by sev-

Scheme31a

a Reagents a nd condit ions: (a) Ac2O, meth yl a crylat e; 61%. (b)Na I O 4-R u C l3; 91%. (c) B F 3OE t 2. (d) (Tf)2N P h , E t 3N; 80%for twosteps. (e) 2-(tri-n-butylstan nyl)pyridine, P d 2(dba)3, TFP ; 70%. (f)H 2, P t O2. (g) NaOMe, MeOH; 85%for tw o steps.

Scheme32a

a Reagents and condit ions: (a) (Ethylsulfanyl)acetyl chloride,. (b) NaIO4. (c) Ac2O, p-TsOH (tr a ce); 64%. (d) K 2C O3, MeOH.(e) N-(5-chloro-2-pyri dyl)tr iflim ide, Et 3N. (f) Pd(Ph 3)2C l2, Me 4S n,LiCl; 59%over three st eps. (g) H 2, P t O2. (h) HCl, H 2O; 45%fortw o steps. (i) LiAlH 4. (j) MnO 2.

Scheme33



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eral resear ch groups, including those of Ta mura a ndC r a ig .15a,49 Sano and co-workers have also employedthis strategy to construct a series of tetrahydroiso-quinoline alkaloids that are thought to be involvedin the pathogenesis of Parkinsons disease. Theirsynthesis began with a Ti(i -P r O )4-media ted conden-sat ion of benzyl ketones185 (R1 ) H, OMe; R 2 ) Me ,P h, Bn) w it h 2-pheny lt hioet hy lamine fol low ed byr ed u ct i on of t h e r es u lt i n g i m in e w i t h N a B H 4 t o

provide a mines 186 (Scheme 34).50

In previous stud-

i es b y S h i n oh a r a , 51a it w a s fou nd t h a t N-formylderivat ives provided th e best yields in th e P ummerercyclization. Accordingly, formylation of the aminogroup present in186a nd subsequent oxidat ion of thesulfide moiety with NaIO4 a fforded substrates 187for the Pummerer cyclization. Reaction of 187 (R1 )

OMe) with TFAA in benzene at 25 C provided 188(R1 ) O Me) in q uant i t a t ive y ield. For Pummer ercyclizations onto aromatic r ings that are devoid ofactivat ing groups, the addition of B F 3OE t 2wa s foundto be critical for the success of the cyclizat ion. Thus,aft er exposure of 187 (R1 ) H , Me) t o TFAA inbenzene for 1 h , BF 3OE t 2 w a s added t o ef fect t hedesired cyclization, furnishing 188 in 94-97%yields.Compounds 188 were desulfurized using a nickelboride-mediated reductive eliminat ion to give 189.The formyl group in 189 could be either hydrolyzed( H C l o r N a O H ) t o t h e s e c o n d a r y a m i n e s 190 orreduced w ith L iAlH 4to deliver t he N-methyl deriva-tives 191. This method, employing TFAA and BF 3

OE t 2, for ma king th ese isoquinoline derivatives ha sa dist inct a dvant age over other methods such a s thePictet-Spengler, Bischler-Napierelski, or P omer-a nz-Fritsch approaches, because it allows for thesynt hesis of isoquinolines, such a s 188 (R1 ) H, Me),t hat ar e devoid of a ct iva t ing gr oups , in high y ield(94-97%).

Furt her studies by Sa no a nd co-workers revealedsome interesting electronic effects w hen t hree meth-oxy groups were present on the aromatic cyclizationpartner. Thus, when compound 192w a s t r ea t ed w it hTFAA followed by exposure to BF 3OE t 2, t e t r a h y -droisoquinoline 193 w as pr oduced in 76% y ield(Scheme 35).51b Although the reaction proceeded

w it hout BF 3OE t 2, the a ddit ion of this Lewis a cid tothe reaction medium greatly accelerated th e rat e ofthe cyclization. Similarly, when 194 wa s subjectedto similar conditions, 195wa s formed in 99%yield.52

Upon treatm ent with TFAA an d B F 3OE t 2, however,

196only produced 197 in low yields. After the crudereaction mixture conta ining 197wa s subjected to thenickel boride reduction conditions, the isoquinolinederivative198was isolated in only 17%yield. Inter-estingly, when the dimethoxy-substituted aromatic199 wa s treat ed w ith the TFAA/B F 3OE t 2 mixture,compound 200, a r is ing fr om C-S bond formation,was isolated as the major product.

The isoquinoline ring system is found in severalfamilies of na tura l products, including the erythr inaalkaloids . Wit h t his t a r get clas s in mind, t he S anogroup has applied the Pummerer methodology to-w a r d t h e p r ep a r a t i on of a k ey e ry t h r in a a l k a l oi dintermediate. In t his approach, -keto est er 201w a s

condensed w ith 2-phenylthioethyla mine to give vi-nylogous a mide 202 (Schem e 36).53 Treatment of202wit h oxa lyl chloride produced dioxopyrroline 203 in81%overall yield. Photolysis of 203 an d 2-trimeth-ylsilyloxybutadiene afforded cyclobuta ne 204 a s asingle dia stereomer in 79%yield. The st ereochemis-try of204wa s established by compa rison of its NMRspectra l dat a t o those of a similar photoadduct w hosestructure had been secured by X-ray analysis. Reduc-tion of the C(7) carbonyl group wit h Na B H 4afforded205 (93%), wh ich under w ent a 1,3-sigm a tr opic rea r-rangement upon exposure to TBAF to deliver thering-expanded product 206 in 99%yield. Mesylat ionof the C (7) hydr oxyl gr oup in206 followed by oxida -

Scheme35

Scheme34a

a Reagents a nd condit ions: (a) 2-P henylthioethyla mine, Ti(i-P rO )4. (b)Na BH 4. (c)H CO2H, Ac2O. (d)Na IO4. (e)TFAA, B F 3OE t 2(R1 * OMe). (f) NiCl2-N a B H 4. (g) NaOH or HCl. (h) LiAlH 4.



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t i on of t h e s u lf id e m o iet y w i t h N a I O4 g a v e t h ePummerer cyclization precursor 207 in 97%overallyield. The TFAA-promoted thionium ion cyclizationof su lfoxide 207 produced 208a a nd 208b a s amixture (1:87) of epimers about the C(11) stereo-center in 88% combined yield. Ra dical reduction ofthe major diastereomer 208b afforded 209 in 77%yield, w hile208aa ls o ga ve 209 in 59%yield underthe same conditions. Exposure of 209 to D B U a f -forded cycloerythrinan210, wh ich has been employedas a key int er media t e in t he s y nt hes es of s ever a lnatural products.

The relative stereochemistry of compounds 208a,b

w a s est a blis hed by compar is on of t heir 1

H N M Rs pect r a t o t hose of s imilar compounds of know nstereochemistr y. The preferentia l forma tion of208b(H) was rat iona lized in t erms of steric interactionsin the corresponding transit ion states. Transit ions t a t eA, leading to 208a, suffers from an unfa vorablesteric interaction betw een the phenylthio group andthe a ngula r methoxycarbonyl substituent (Figure 1).This int er a ct ion is r e l ieved in t r ans it ion s t a t e B,which leads to structure 208b.

A Pummer er cy cliza t ion a ppr oach w as a ls o em-ployed a s a key str at egic disconnection by Desma elea n d J ou s se i n t h ei r s y n t he si s of t h e e ry t h r in a nalkaloid skeleton.54 In t his investiga tion, nitro enoat e

211 w a s cyclized via an int r amolecular Michael

addit ion t o a f for d es t er 212 (68%) a s a separa blemixture (1:1) of diastereomers about the C(6) stereo-center (Scheme 37). Other bases were also examined,

but t hey r esult ed in low er y ields of t he des ir edpr oduct a long w it h ot her s t r uct ur es in w hich t henitro group had been oxidatively hydrolyzed to thecorresponding aryl ketone. It should be noted that

the C (6) center is genera lly sp2

hybridized in m ost ofthe erythrina alka loid ta rgets (e.g., erysotra midine,Scheme 18), so both d ias tereomers can be employedin t he r emainder of t he s y nt het ic s eq uence. Forclarity, however, only the R-isomer with respect tothe C (6) substituent is shown in the rea ction scheme.Reduction of th e nitro group in 212 by exposure toRaney nickel provided 213. Although it was expectedt hat a s pont a neous O- t o N-transacylation wouldoccur to give 214, i t w a s d i scov er ed t h a t t h er m a lactivat ion wa s required. Heating a sample of 213 intoluene at reflux provided 214. Rea ction of 214w i t hvinyl sulfoxide215 afforded the 1,4-a ddition product216. After some experimentat ion, it wa s ult ima tely

Scheme36a

a Reagents and condit ions: (a) 2-Ph enylthioethylam ine; 90%.(b) (COCl)2; 90%. (c) 2-TMS O-buta dien e, h , 79%. (d) Na B H 4; 93%.(e) TB AF, -30 C ; th en rt ; 99%. (f) MsCl, pyr idine. (g) Na IO4; 97%over tw o st eps. (h) TFAA, CH 2C l2, r t ; 88%. (i) Bu 3S nH , AI B N,toluene, ; 77%(208b), 59%(208a). (j) D B U ; 60%.

Figure 1. Transition states leading to 208a,b.

Scheme37a

a Reagen ts a nd conditions: (a) TBAF, THF, rt , 18 h; 68%. (b)Raney Ni. (c) Toluene, , 1 h; 42%over two st eps. (d) NaH MDs,TH F/H MP A, -78 C , then215; 55%. (e) Ac2O, . (f) Sn Cl 4, C H 2C l2,0 C; 56%. (g) Bu 4SnH , AlBN, toluene, ; 75%.



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discovered that a stepwise ring closure provided thebest results for the conversion of 216 t o 217. Thus,hea t ing216with acetic anhydride followed by expo-sure to SnCl4a t 0 C delivered 217 in 56%yield. Thephenylthio moiety present in 217wa s removed underradical reducing conditions to furnish t he erythrinaskeleton 218.

As p a r t of t h e ir i n ve st i ga t i on s i n t o N,S-fusedpolycyclic ring systems, Daich and co-workers have

r ep or t ed a t a n d e m P u m m e r er /N-a cyliminium ioncy cliza t ion t hat w a s us ed t o cons t r uct int er es t ingisoquinolinone structures.55 Addition of benzylmag-nesium bromide to 219provided 220 in 51% yield(Scheme 38). Oxidat ion of t he sulfide functiona lity

to the corresponding sulfoxide was accomplished byexposure of220 t o m-CP B A for short periods of time(1-2 min) to furnish 221 as a mixture of diastereo-mers. Treatment of sulfoxide221w ith TFAA in C H 2-C l2 a t r oom t emper at ur e for 8 h fo l low ed by t headdition of TFA produced 223 in 42%yield throughthe int ermediacy of 222. I f the reaction was carriedout under buffered conditions (TFAA, pyridine),compound 222 could be isolated in 56% yield. AnN-acyliminium ion intermediate could then be gener-a t e d b y t r e a t i n g 222 w it h neat TFA. Subs eq uentcyclizat ion of the iminium ion ga ve223 in 58%yield.O t h er a r y l t h io g r ou ps w e r e a l s o e x a m in ed , w i t hcompounds 224 a nd 225 being obt a ined fr om t heTFAA/TFA condit ions i n 62%a nd 41%yiel d, r espec-tively.

4.2. Indole Alkaloids

Intramolecular addit ion of nitrogen nucleophilesonto thionium ions derived from P ummerer rea ctionshave also been used for the format ion of the C(6)-C(7) bond in an at tempted synthesis of the akuam-miline family of alkaloids. For example, treatment

of sulfoxide 226 with TFAA produced the novelheterocycle227 in 24%yield (Scheme 39).56,57 Reduc-t i on of t h e s u lf id e l in k a g e u s i ng N iB H 4 affordedindole 228. Compound 227 arises from intramolecu-lar trapping of the init ially generated thionium iononto the indole nitrogen at om.

The construction of the indolo[2,3-a]quinolizidine

system

56b

and the pentacyclic ring system of apogeisso-schizine56c by formation of the C(6)-C(7) bond ha salso been reported. In this context , an interestingapplication of the Pummerer cyclization to fashionthe C ring of the corynant hean a lkaloid (()-akagerinew a s r epor t ed by B ennas a r a nd B os ch.58 As outlinedin S cheme 40, their a pproach involves t he a ddit ionof the enolat e derived from 1-acetylind ole (229) ont opyridinium triflate 230 to provide 231 in 25%yield.Exposure of 231 t o p-TsOH a nd LiI effected cycliza-

Scheme38a

a Reagents a nd condit ions: (a) B nMgBr ; 51%. (b) m-CPBA, 0 C , 1-3 min; -100%. (c) TFAA, C H 2C l2, rt , 8 h; TFA, rt , 12 h;42%. (d) TFAA, p yr idi ne; 56%.

Scheme39

Scheme40a

a Reagents a nd condit ions: (a) LDA, THF, -30 C ; t he n 230;25%. (b)p-TsOH , L iI, MeOH /C 6H 6; 58%. (c) Tf2O, 1,8-bis(dimethy -lamino)naphthalene,-30 to -10 C. (d) Bu3S nH , P d ( P P h 3)4, LiCl;45% over two steps. (e) m-CPBA, -70 C. (f) TFAA, 2,6-di(tert-butyl)pyridine, rt, 30 min; then ; 71%over t wo st eps. (g) Bu 3S n H ,AIBN, C 6H 6, reflu x; 72%.



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t ion of th e dihydropyridine residue onto the indolewith concomitant loss of fluoride to furnish 232 in58%yield. The enol functiona lity in232was reducedto alkene233 in 45%overall yield by first converting232 to the corresponding enol triflate followed by apalladium-mediated reduction wit h B u3SnH. In prepa-ration for the Pummerer cyclization, the sulfide groupin 233wa s oxidized wit h m-CP B A. Subjection of th eresulting sulfoxide to buffered P umm erer condit ionsgave pentacycle 234 in 71% yield as a mixture ofepimers about the C(6) stereocenter. The extraneousphenylthio group in 234 w a s t h e n r e m o v e d b y aradical reduction procedure to deliver 235 (72%

yield), a known intermediate used in the synthesisof a kagerine.In a mor e det a i led a ccount of t he inves t iga t ions

t h a t l e d t o a k a g e r i n e , a f o r m a l t o t a l s y n t h e s i s o fgeissoschizine was also presented. 59 In this sequence,the enolat e of acetylindole wa s ad ded to a pyridiniumsalt w hich lacked the fluoro substituent a nd insteadcontained an acrylate substituent, to give dihydro-pyridine236 in 22%yield (Scheme 41). Acid-inducedcyclization provided tetracyclic amine 237 in 50%yield. Heating 237 in aqueous HCl followed by theaddition of NaBH 4stereoselectively pr oduced t he (E)-ethylidenepiperidine238 in 33%yield. To chemose-lectively oxidize th e sulfide functiona lity, the basic

nitrogen a tom w as first protona ted w ith TFA beforer eact ion w it h m-C P B A t o d el iv er t h e P u m m er ercyclization precursor 239 in 80% y ield. Ini t ia l a t -tempts t o effect the cyclization by heating 239 w i t ha mixt ure of TFAA a nd TFA in C H 2C l2a t r eflux failedto produce 240. Rat her , a mix t ur e of 238a nd 242was isolated (vide infra). However, exposure of 239to TMSOTf a nd Hu nigs ba se did effect th e desiredcyclizat ion. Adduct 240wa s isolat ed as a mixture of

epimers about the C(6) stereocenter in 64% yield.Opening of the la ctone ring w ith subsequent desulfu-rization by a radical pathw ay provided241, a knownintermediate in the synthesis of geissoschizine.

The product distribution of the above P ummerercycliza ti on at tem pts us ing TFAA/TFA deserves somecomment. As was seen from Sanos studies (Scheme35),53 formation of a C-S bond (i.e.,200) ca n competew i t h C-C bond formation. The reduction of 239 t o238 and t he gener at ion of 242 bot h ar is e fr om t henucleophilic a ddit ion of t he indole -bond t o t heacyloxysulfonium ion 243 to give intermediate 244(Scheme 42).60 Hydrolytic cleava ge of the C-S bond

then provides 242. Ca pture of the sulfonium ion bytrifluoroaceta te, however, affords a t etrava lent sulfurcompound, 245. Subsequent protonation of the indolering by TFA produces th e iminium ion246. Trifluo-roacetat e anion effects ru pture of the O-S bond withsubsequent breaking of the C-S bond to regenerat e238 a nd t rifluoroa cetyl peroxide. Although t his C-Sbond formation represents an undesired pathway forthe syn theses of aka gerine and geissoschizine, thisinterrupted Pummerer reaction has been furtherexploited for heterocyclic synt hesis by other inv esti-gators (vide infra).

4.3. Chromene Derivatives

A recent report by Bernard, Piras, and co-workersdescribes an interesting Wagner-Merwein-type rear-r angement t ha t w as us ed t o t r igger a s ubs eq uentP ummerer cyclization.61 For example, when phenyl-sulfanylcyclopropane 247 w a s h ea t e d w i t h p-TsOHin dry benzene a t reflux, ionizat ion of th e hydroxylgroup occurred w ith concomita nt r ing expansion to

Scheme41a

a Reagents and condit ions: (a) p-TsOH, C 6H 6, L iI ; 22%. (b) 2.5N HCl, MeOH, ; t he n Na B H 4, 0 C ; 33%. (c) TFA, C H 2C l2, 0 C ;then m-CPBA,-78 C ; 80%. (d) TMS-OTf, i -P r 2NE t , C H 2C l2, r t ;64%. (e) Na OMe, MeOH , rt . (f) B u 3SnH , AIB N, C6H 6, ; 52%overtwo steps.

Scheme42



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give the tra nsient thionium248 ion that was subse-q u en t ly ca p t ur ed b y t h e pen d a n t a r y l g rou p t ofurnish 249 in 77%yield (eq 4). Other aryl groups,such a s th ose conta ining a p-Me or p-Cl substituentalso participated in this reaction, as did the unsub-stituted analogue (67-80%yield). Int erestingly, if t heet her l inka ge in t he t e t her w a s r emoved, only cy -clobutanone 250 wa s isolat ed in 80%y ield.

These phenylsulfa nylcyclobuta ne derivat ives have

high pot ent ia l a s s y nt het ic int er media t es . In t hereport detailing this methodology, chromene 249w a sconverted to t he core structure of th e ra dulanins.61

For ex a mple, t he t r ea t ment of 249 w i t h m-C PBAproduced sulfoxide 251 in 70% yield (Scheme 43).

Thermolysis of251 in t oluene resulted in eliminat ionof P hSOH to give 252 in 83%yield. E xposure of 252t o m-C P BA induced a r ing cont r act ion r eact ion,presumably through the intermediacy of epoxide253,providing254wh ose carbon skeleton is found in t heradulanin family of natural products.

4.4. 1,3-Oxathianes

For ma t ion of t he 1,3-ox at hiane r ing has beenachieved through a P ummerer cascade. Alkylat ion ofpotassium thiolate255wit h a va riety of alkyl halides(R ) M e, E t , B n , P h C OC H 2-, H O C H 2C H 2-) g a v esulfides 256 in high yield (85-96%; S chem e 44).62a

Subsequent oxida tion of256w it h m-CP B A producedthe corresponding sulfoxides 257. Rea ction of thesesulfoxides with p-Ts O H in t he pr es ence of 3 molecular sieves provided 1,3-oxathianes 258 in 50-95%yields. Because S,O-acetals are easily removed

ma sks for car bonyl functional gr oups, this m ethodol-ogy is useful for t he synt hesis of protected aldehy desfrom derived a lkyl ha lides. The ra nge of alkyl ha lidessuccessfully used suggests tha t this procedure ma ybe quite useful for the synthesis of protected alde-hydes tha t ar e more complex.

I n ea r l ie r s t u d i es , A be a n d H a r a y a m a d em on -stra ted the fa cility wit h w hich 1,3-oxat hian es261a re

formed by exposing ,-unsaturated sulfinyl com-pounds of type 259 t o p-TsOH (eq 5).62b,c The sulfo-

nium salt 260wa s postulat ed as a reaction interme-diate.

These a uthors recognized tha t electrophilic re-agents other tha n protic acids could effect t he sametra nsforma tion, and th e use of an iodonium ion wa s

examined. The init ial studies employed moleculariodine and N-iodosuccinimide (NIS) as the electro-philic source of iodine. When sulfoxide 259 w a st r ea t e d w i t h N I S o r I 2, t he expect ed P ummer erproduct 262was isolated in only 23%yield (Scheme45).63 O ne of t he by pr oduct s cor r es ponded t o t he

iodohydrin 263. Conditions were then optimized fort h e f or m a t i on of t h i s b y pr od u ct , a n d 263 couldeventually be generated in 80%yield by using NISa t -78 C. Subsequent exposure of 263 t o p-TsOHin t he presence of 3 molecular sieves furnish ed262in 63% yield as a mixture (10:1) of diastereomersabout t he S,O-acetal.

4.5. Rearrangements

The isola tion of C-S bonded products such as 200(Scheme 35) and 242 (Schemes 41 and 42) demon-

Scheme43a

a Reagents and condit ions: (a) m-CPBA,-20 C , C H 2C l2; 70%.(b) Toluene, ; 83%. (c) m-C P B A, 0 C , C H2C l2; 46%.

Scheme44

Scheme45



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s t r a t es t ha t s ome s ulfox ides a ct unexpect edly inP ummerer-induced reactions.64,65 Ai t ke n a n d co-workers also observed a rather unusual rearrange-m en t w h e n t h e y e xa m i n ed t h e b eh a v i or of d ih y -drotetrathiofulvalene under Pummerer conditions. 64

Oxidation of 264w i t h m-CP B A delivered t he t hion-ium ion precursor 265 (Scheme 46). Reaction of 265with TFAA was expected to deliver compound 266.Unexpectedly, however, products 264 a nd 267w er eisolated in 38% an d 42% yield, respectively. Therearrangement product 267wa s thought to originatefrom a m echa nism w herein a sulfur-assisted 1,2-a cylshift of the intermediate sulfonium salt 268produces269. C lea va ge of t he t r i f luor oacet a t e t r igger ed asubsequent r ing expansion, a ffording 1,4-dithian e267 and TFAA. The reduction product 264 a r isesfrom a nucleophilic displacement of the tr ifluoro-a c e t y l g r o u p w h e r e t h e o x y g e n a t o m a c t s a s t h eelectrophile to produce264 as well as tr ifluoroacetyl

peroxide. This reduction is closely relat ed to thereduction previously described in Scheme 42 where239 was reduced to 238.

5. Generation of Other Heterocyclic RingSystems

5.1. -Lactam Formation

There ha ve been severa l reports in t he literat uredealing w it h t he as y mmet r ic conver s ion of chir a l-a mido sulfoxides int o-lacta ms using an intra mo-lecular Pummerer cyclization process.66-70 Kita dem-ons t r a t ed t hat a highly as y mmet r ic Pummer er r e-

action of acyclic sulfoxides can be induced using anO-silylated ketene acetal.69,70 The reaction of sulfox-id e 270 w it h s i ly lox y ket ene acet a l 271 in t h epr es ence of a ca t a ly t ic a mount of ZnI2 i n C H 3C Nprovided a mixture (88:12) of the syn- a n d a n t i -R-silyloxy sulfides 272 a nd 273 in 75%yield (Scheme47). Various syn a nd a n t i -substituted sulfoxideswere treat ed with the O-silylated ketene acetal undersimilar reaction conditions to give high yields of thecorrespondingR-silyloxy sulfides. Although t he exactmechanistic details of this process are unclear, the

transformation appears to involve silylat ion of thechiral sulfoxide followed by proton removal at theR-carbon fr om th e fa ce opposite t he sulfoxide groupby th e ester enolat e. The siloxy group then migr at est o t h e R-position by one of the following possibili-ties: (i) an intima te ion pair mechanism, (ii) a ra dicaldissociation-recombina tion m echanism , or (iii) directcar ba nion a t t a ck.64

Kita has used this asymmetric Pummerer to con-struct enantiomerically enriched -lactams278 a nd280 s t a r t ing fr om t he chir a l , nonr acemic -amidosulfoxides 277 a nd 279 (Scheme 48).70-72 The chira lsulfoxides 277 a nd 279 w er e pr epar ed fr om t he

Scheme46 Scheme47

Scheme48



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known chiral carboxylic acids by condensation w ith(S)-phenethylamine in the presence of 1,3-dicyclo-hexylcarbodiimide (DCC) using DMF as the solvent.Treatment of the pure (S)-sulfoxide277 under s t a n-dard Pummerer conditions (ZnI 2, C H 3C N, 271) gave

t h e (R)--lactam 278 in 75% yi el d a n d i n 60%enantiomeric excess. Changing the reaction condi-tions to ZnCl2in CH 2C l2improved th e ee to 80-85%.N-B enzyl am ides (S)-281 a n d (R)-283 produced (R)-282 a n d (S)-284 in 54%yield with 80%and 82%ee,respectively.

The proposed mechanism involves silylation of thesulfoxide to give intermediate 286a t ha t is s ubs e-q u e n t l y a t t a c k e d b y t h e a m i d e n i t r o g e n a t o m t oproduce the chiral isothiazolone 286b(Scheme 49).This tra nsient species undergoes preferentia l 1,2-rearrangement from the R-face to provide-lactam287.71

5.2. Benzazepine Derivatives

While the generation of five-membered ring het-erocycles using the Pummerer reaction is clearly anefficient process, the isolation of C-S bonded andrearranged products often accompanies formation ofsix-membered rings. Although relatively few inves-tigat ions into the synt hesis of larger r ing sizes havebeen reported, it would appear as though the Pum-merer-promoted cyclizat ion leading to these la rgersystems is less efficient t ha n for the correspondingsix-membered rings. Neverth eless, severa l lar ger ringheterocyclic compounds that are difficult to synthe-

s ize in ot her w ay s have been pr epar ed us ing P um-merer cyclizations.

As previously noted (cf. S chemes 1 an d 2), P um-mer er cycliza t ions ont o a r oma t ic r ings ar e q uit egener al . Sever a l r esear ch gr oups have lever agedP ummerer m ethodology to construct benzazepinederivatives. Ishibashi, for exam ple, employed t hemethod t owa rd the synthesis of 1,3,4,5-tetra hydro-2H-3-benzazepin-2-one, a pharmacologically impor-t a n t t a r g e t .73 When the phenethylamido sulfoxidederivative 288was exposed to TFAA or p-TsOH , a nintramolecular Friedel-C r aft s cycliza t ion ont o t heR-acylth ionium int ermediat e occurred to furnish t et-rahydro-2H-3-benzazepin-2-one289 in modest yield

(Scheme 50). A number of structura lly related an a-

logues (290, 291, a n d 292) w er e access ed fr omsubstrate 289. Reduction of289with LiAlH 4providedtetrahydro[3]benzazepine-2(2 H)-one290. Further re-act ion w it h Raney Ni gave 292. Sodium periodateoxidation of the thiomethyl ether group present in289 followed by a Pummerer reaction afforded thedicarbonyl derivative 291 in 35%yield.

An i n t er e st i n g a p p li ca t i o n of t h e P u m m e r er /Friedel-Cra fts a lkylation methodology for the prepa-r a t ion of a s even-member ed het er ocycle w a s de-s c r i b e d b y I s h i b a s h i i n a n a p p r o a c h t o w a r d (()-cephalotaxine (eq 6).74 The key step in t he synt hesis

involved the ring closure of sulfoxide293 by meansof a TFAA-initiated R-acylthionium ion cyclization togive the seven-membered lactam 294 t h a t w a s s u b-s eq uent ly conver t ed t o cephalot ax ine by s t anda r dsynthetic tra nsforma tions. Ishibashi and co-workersha ve us ed t his s a me s t r a t egy for t he s y nt hes is o frelated benzazepines.74-76

Similarly, 1,4-benzoxathiepins 297 a nd 298 weresynt hesized from sulfoxides 295a nd 296 in 53%and55%yield, respectively (eq 7).77

As an ex t ens ion of t heir ear l ier w or k w it h is o-quin olines (Schemes 34 a nd 35), S a no a nd co-workersha ve applied their BF 3OE t 2-assisted Pummerer cy-

Scheme49 Scheme50



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cliza t ion s t r a t egy t ow ar d t he s y nt hes is o f s ever a lbenza zepine der iva t ives . In t his s t udy , phenet hy -lamine 299 (R ) H o r O M e ) w a s a l k y l a t e d w i t h2-chloroethylphenyl sulfide t o furn ish 300 (Scheme51).78 Amine 300 wa s t hen protected by exposing itto a mixture of formic acid and acetic anhydride togive 301, which was oxidized to sulfoxide 302 usingN a I O4. When 302a was treated with TFAA in ben-zene a t 25 C , t he Pummer er cy cliza t ion pr oduct303a was isolated in 80%yield. As was encounteredin previous work,50 however, these conditions failed

to produce cyclized products when the nucleophilicary l group la cked electron-donating groups. Thus,when302bwa s subjected to the same conditions tha tproduced 303a, only bissulfide 304 w a s for med in38% yield. Addition of BF 3OE t 2 t o t he mix t ur e of302b a nd TFAA, however, a fforded303b in 47%yieldalong w it h t r aces of 304 and sulfide 301b. As withthe isoquinoline synth esis, t his P ummerer meth odol-ogy is r emar ka ble in i t s abil it y t o gener at e benza-zepine derivatives that lack activating groups on thear yl moiety. This rea ction sequence, however, is notas e ff icient a s t he for ma t ion of t he is oq uinolinederivatives described in Scheme 34.

More recently, S an o a nd co-workers ha ve a pplied

t his met hodology t o t he for mal s y nt hes is o f cap-sazepine, a n a nta gonist of th e sensory n euron exci-tants capsaicin and resinferatoxin.79 Reductive a m-inat ion of aldehyde 305with 3-phenylthiopropylaminea nd AcOH/Na B H 4 provided a mine 306 in 74%yield(Scheme 52). Treatment of 306 w i t h a m i xt u r e o ffor mic acid a nd acet ic a nhy dr ide fur nis hed for ma-mide 307 (q uant i t a t ive y ield), w hich w a s s ubse-quent ly oxidized t o sulfoxide308 in 84%yield usingNaIO4. Although exposure of 308 to TFAA in benz eneat 25 C produced the desired cyclization product 309in 56% yield, vinyl sulfide 310 w a s a l s o s im u lt a -neously formed in 31%yield. By adding BF 3OE t 2t othe mixture of TFAA and 308, t he yield of309 w a s

incr eas ed t o 66%. C oncomit ant ly , t he amount of310produced under t hese conditions wa s reduced to5%. Reductive elimination of th e sulfide group in309 under nickel bor ide condit ions gave 311 in80% yield. Removal of the formyl protecting groupunder a queous base conditions delivered 312, wh ichis a know n int er media t e in t he s y nt hes is o f cap-sazepine.

Use of the P ummerer reaction for the synt hesis ofnaturally occurring seven-membered ring derivativesof the erythrina alka loids, the homoerythrinan s, hasalso been reported. The Sano group has applied thePummer er r eact ion t ow a r d t he s y nt hes is o f an ad-vanced intermediate for t hese alkaloids.53 Following

a similar reaction sequence that was used for con-structing cycloerythrinan (Scheme 36), -keto ester201wa s condensed w ith 3-phenylthiopropylam ine togive the vinylogous a mide 313 in 82%yield. Subse-quent reaction of313 with oxalyl chloride provideddioxopyrroline 314 in 96% yield (Scheme 53).80 A[2+2]-photocycloaddition of 314 and 2-trimethylsily-loxybutadiene afforded cyclobutane 315 as a s inglediastereomer in 83% yield. Reduction of the C(7)car bony l gr oup w it h NaB H 4 ga ve 316 (89%), w hi chunderwent an anionic 1,3-sigmatropic rearrangementto a fford 317(86%) upon expos ur e t o TB AF. The C (7)hydroxyl group was converted to the correspondingmesylate 318 in 89%yield, and this was followed by

Scheme51a

a Reagents and condit ions: (a) 2-Chloroethyl phenyl sulfide,Na 2C O3, N a I , B u 4NBr, dioxane, . (b) HCO2H-Ac2O, 70 C. (c)

Na I O4, MeOH-

H 2O. (d) TFAA, C 6H 6, r t; 80%. (e) TFAA, B F 3OE t 2,C 6H 6, r t; 47%.

Scheme52a

a Reagents a nd conditions: (a) 3-P henylthiopropylamine, AcOH,E t O H , , 23 h; then NaBH 4, 0 C; 74%. (b) Ac2O , H C O2H , 70 C ;quan tita t ive. (c) NaIO 4, MeOH-H 2O, r t; 84%. (d) TFAA, C 6H 6, rt ,30 min; then B F 3OE t 2, rt , 45 min ; 66%. (e) NiCl26H 2O , Na B H 4,MeOH-THF, 0 C, 80%. (f) aqueous NaOH, EtOH , ; 98%.



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r ea ct ion of t he s ulf ide funct ionali t y in 318 w i t hN a I O4 to provide sulfoxide 319 in 91% yield. Whenthe rea ction of 319with TFAA was carried out at 25 C, t he desired benzazepine320wa s only isolat ed in16%yield together wit h th e elimina tion product 321(41%). The y ield of 320 could be improved by con-ducting the reaction a t higher temperatures a nd forlonger r ea ct ion t imes , pr es umably becaus e of t heestablishment of an equilibrium between the initiallyformed 321 and the reactive thionium ion present inthe acidic media. B y heat ing a mixture of319, TFAA,a n d C H 2C l2 i n a s e a l e d t u b e a t 8 0 C f o r 4 8 h ,compound320could be isolat ed in 51%yield togetherwith sma ll amounts of 322. Extended reaction times(120 h) resulted in th e exclusive forma tion of 322 in67% yield. The thiophenyl group in 320 could ber em ov ed b y t h e a c t ion of B u 3S n H a n d A I B N t oprovide 323 in 61%yield. Exposure of 323 t o D B Ueffected t he desired cyclopropana tion t o deliver 324in 52% yield. Alternat ively, 322 could be convertedt o 324 in 53% over al l y ield by f ir s t for ming t hecyclopropa ne ring using DB U followed by pa lladium-mediated hydrogenation of the olefinic -bond. Asimilar compound, w hich conta ins a m ethylenedioxys ubs t i t ut ion pat t er n on t he ar y l gr oup, had been

previously converted to alkaloids such as schelham-mericine.

5.3. Indole Alkaloids

One of the ma in adva nta ges of using the Pum merercy cliza t ion for t he for mat ion of s ix- and s even-membered rings that are fused to aromatic r ings istha t t he high reactivity of thionium ions permits theuse of unactivated aromatics as nucleophiles. Ben-

nasar and Bosch have taken advantage of the inher-ently higher reactivity of thionium ions to generat ean eight-membered ring in their synthesis of secoakua-mmilan alkaloids.81 The akuammilan alkaloids, ofwhich catha foline is a n exam ple (Figure 2), belong

t o t he cor y a nt hean family and ar e char a ct er ized byan addit iona l C(7)-C(15) bonded ring. The secoakua-millan a lkaloids, such a s 3,4-secoca brucra line, differfrom the a kuamillan series in tha t th ey lack a bondbetw een the C(3) a nd N(4) cent ers. Forma tion of the

C(6)-C(7) bond to establish the quaternary centerat a late sta ge of the synthesis wa s considered to bean efficient strategy for the synthesis of this familyof alkaloids.

C ons t r uct ion of t he key s ulfox ide int er media t ecommenced w it h t he expos ur e of amine 32556 t obenzyl chloroforma te, which resulted in a fragment a-tion reaction that produced 326 (Scheme 54).82 Re-duction of th e C(3)-C(14) olefinic -bond in 326 viathe a ction of Et 3SiH a nd TFA gave sulfide 327 in 65%yield from 325. The thiophenyl group in 327wa s thenoxidized usin g m-CPBA to provide sulfoxide 328.When sulfoxide 328wa s subjected to the P ummerercondit ions (TFAA in CH 2C l2 a t 0 C f o r 1 5 m i n )

follow ed by NaC NBH 3 reduction, only sulfide 327w a s obt a ined. Similar ly , t he r ela t ed s ulfox ide 329a ls o fa i led t o cy clize under a var iet y of r eact ionconditions. Moreover, the cyclization of dithioacetal330 d i d n o t t a k e p l a c e w h e n i t w a s t r e a t e d w i t hDMTSF . The high degree of conforma tiona l flexibilitypresent w ith these cyclization substra tes (i.e., 328,329, a n d 330) was thought to be problematic. Ac-cordingly, substra te 331, w hich conta ined a confor-mationally more restrict ive amido tether, was con-structed. When 331 w a s t r ea t e d w i t h TF AA i nC H 2C l2 a t 0 C fol low ed by expos ur e t o NaC NB H 3,the desired t etracycle332wa s isolat ed in 23%yieldas a single diastereomer w hose stereochemistry wa s

Scheme53a

a Reagen ts an d conditions: (a) 3-P henylt hiopropylamine; 82%.(b) (COCl)2; 96%. (c) 2-TMS O-buta dien e, h; 83%. (d) Na B H 4; 89%.(e) TB AF, THF; 86%. (f) MsC l, py rid ine; 89%. (g) Na IO 4; 91%. (h)TFAA, CH 2C l2, 80 C, 48 h; 51% (320) or 120 h; 67% (320). (i)B u 3Sn H, AIB N; 61%. (j) DB U ; 52%. (k) H2, 10%P d-C; 53%from

320.

Figure 2. Akuammiline-type alkaloids.



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ba s ed upon ext ens ive NMR s pect r oscopy . Sma llamount s of t he cor r esponding s ulf ide w er e a ls odetected. Removal of the t hiophenyl group in332w a saccomplished using Raney nickel to deliver the 3,4-secoakuammilan derivative 333 in 80%yield.

I t s hould be not ed a l t hough t hat t he y ield in t hekey cyclizat ion step w a s only 23%. Attempt s to effectsimilar cyclizations, using substra tes such as 334a nd335 under radical conditions, failed to occur (eq 8).

Thus, th e irra dia tion of indole 334produced the novelcompound 337 in w hich t he t e t her ed r a dica l int er -media te cyclized onto th e C(4) position of th e indolering. Heating a mixture of iodide 335 a n d B u3S n-S n B u 3 in toluene produced the reduced product 336.This observa tion demonstra tes the rela tive merits ofusing a P ummerer cyclization as a key bond discon-nection for the synthesis of complex natural products.The successful cyclization of 317, wh en compared t o

the failure of compounds 328-330 to produce thedesired tetra cycle, underscores the subt le conforma -tional effects tha t can influence the course of theselarger sized ring forming rea ctions.

6. General Methods for the Formation of Five-and Six-Membered Rings

Although m a ny m ethodologies ha ve been developed

tha t specifically form five-membered rings (videsupra), Pummerer reactions that produce a varietyof heterocyclic ring sizes are becoming increasinglyimpor t ant . A s t r a t egy s imilar t o t ha t us ed by S anoto const ruct isoquinoline deriva tives (Schemes 34 a nd35) ha s a ls o been employ ed t o for m benzazepinean alogues (Schemes 50 and 51). Benn asa r a nd B oschused the same synt hetic strat egy for a ppending a six-membered ring onto an indole core (Schemes 39 an d40) as they did for eight-membered ring annulation(Scheme 54).

6.1. Pummerer/N-Acyliminium Ion Cascades

In severa l examples, Kita a nd co-workers reportedan efficient Pummerer cyclization wherein the ini-t ia l ly gener at ed t hionium ion w as int er cept ed bya p en d a n t s econ d a r y a m i d e t o p rod u ce a n S,N-acet a l .70-72,83 B ecause of our long-sta nding interestin tandem processes,4,25 our resea rch group a t E morycarried out a related study using R-th iophenyl a midesas pr ecur s or s for t he for mat ion of N-acyliminiumions, wh ich were then employed as int ermediat es forsubsequent cyclizat ion chemistr y. A typical exam pleinvolves the t reatm ent of a mido sulfoxide338 w i t hsilyl ketene acetal271 in t he presence of ZnI 2to givelact am 339 in excellent yield (>90%; S chem e 55).84

The act ion of BF 32AcOH on 339 led t o fur t herionization of the phenylth io group, an d cyclization oft he r es ult ant iminium ion ont o t he ar omat ic r ingfurnished 340 in 98%(n) 1) a nd 79%(n) 2) yield,respectively. In a similar manner, the indole-substi-tuted amido sulfoxide 341 furnished 343 vi a t h eintermediacy of 342 in good overa l l y ield , w hensubjected t o the sa me sequence of reaction condit ions.

D u r in g t h e c ou r se o f o u r w or k i n t h i s a r ea , w en ot e d t h a t n on a r om a t i c -s y st e m s a l s o a ct e d a snucleophiles in the im inium ion cyclizat ion step. For

Scheme54a

a Reagents and condit ions: (a) BnCO 2Cl, toluene, . (b) Et 3S iH ,TFA; 65%for two steps. (c) m-CP B A; 83%. (d) TFAA, C H 2C l2, 0 C . ( e) Na C NB H 3; 23%over t wo s teps. (f) Raney Ni; 80%.

Scheme55a

a Reagents an d condit ions: (a) ZnI2, (b) BF 32AcOH.



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example, t he r eact ion of 271 w i t h Z n I 2 a n d t h ecyclohexene-substit uted a mido su lfoxide344afforded345 in 76%(n ) 1) and 54%(n) 2) yield. La ctam345delivered compound 346 in 54%(n) 1) a nd 52%(n) 2) yield w hen treat ed with B F 32AcOH (Scheme56).84 In a n a na logous manner , t r ea t ment of viny lbromide 347wit h a mixture of ZnI2a nd271producedlact a m 348in 80% (n ) 1) a nd 72% (n ) 2) yield.Interestingly, when 348wa s exposed to B F 32AcOH,the subsequent Mann ich-like cyclization w as termi-nat ed by the addit ion of phenylthiolat e, rather tha nby a deprotonat ion event, to furnish 349. This bromo-and phenylthio-substituted indolizidine w as subse-quently converted t o ketolacta m 250 in 64%(n) 1)

and 58%(n) 2) yield by reaction with Hg(OAc)2 i nacetic a cid.U sing this sequentia l Pu mmerer/Ma nnich cycliza-

tion methodology, the P ad wa group reported a rapidsynthesis of th e protoberberine a lkaloid gusa nlungD. Accordingly, the P ummerer cyclization of351w a spr omot ed by r eact ion w it h TMSO Tf and Et 3N t oprovide R-phenylthio la ctam 352 in 64%yield (Scheme57).85 When amido sulfoxide 351 w a s t r e a t e d w i t h

silyl ketene a ceta l 271 and ZnI 2, however, pyridone353 was produced in 85% yield. The Lewis acid-induced elimination of thiophenol from the initiallyformed S,N-acetal 352 a p pe a r s t o b e f a ci li t a t e dby the genera tion of t he a romatic 2-pyridone. Thisresult contrasts with other Pummerer cyclizationsconducted under similar conditions but which lackthe ar omatic moiety in the tethered sulfoxide (e.g.,Schemes 55 a nd 56). S,N-Acetal 352 w a s e a s i l y

converted to 353 by exposure to ZnI 2, thereby sup-p o r t i n g t h e r o l e o f t h i s L e w i s a c i d i n t h e d i r e c tt r a nfor ma t ion fr om 351t o 353. S t i r ri n g a s a m p leof

review of pummerer rearrangement, padwa, chem. rev. 2004

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