8 Heterocyclic Compounds By D. E. AMES Department of Chemistry Queen Mary College London Mile End Road London El 4NS 1 Introduction The review on heterocyclic compounds for 1988 is again highly selective and emphasizes developments in synthetic methods. A hint of the future is perhaps provided by a paper on CAMEO (Computer- Assisted Mechanistic Evaluation of Organic Reactions). This computer program has been expanded to treat and organize the major types of heterocycle-forming reactions.’ Useful reviews have been published on substitution reactions of aromatic N-heterocycles’ and on the synthesis of condensed heteroaromatic compounds by palladium-catalysed reaction^.^ Reviews on reactions of acetoa~etamides~ and azides’ also cover many heterocyclic syntheses.2 Three-membered Rings A synthesis of chiral epoxides6 involves asymmetric induction in the condensation of (-)-chloromethyl p-tolyl sulphoxide with carbonyl compounds (Scheme 1). RN~m 0 i ii -iii II -0 Ar&HRCi ArSII H Reagents i LiNPr; cyclohexanone; ii base; iii Bu”Li Scheme 1 Methyl(trifluoromethy1)dioxiranehas been generated by oxidation of methyl trifluoromethyl ketone with potassium peroxymonosulphate (‘oxone’).’ It is stable enough to be isolated stored and characterized but is much more reactive than dimethyldioxirane in oxygen-transfer reactions such as the stereospecific conversion of cis-oct-2-ene into the cis-epoxide. ’ M. G. Bures and W. L. Jorgensen J. Org. Chem. 1988 53 2504. ’ H. Vorbriiggen and M.Maas Heterocycles 1988 27 2659. T. Sakamoto Y. Kondo and H. Yamanaka Heterocycles 1988 27 2225. S. M. Hussain and A. M. El-Reedy J. Heterocycl. Chem. 1988 25 9. E. F. V. Scriven and K. Turnbull Chem. Rev. 1988 88 297. T. Satoh T. Oohara and K. Yamakawa, Tetrahedron Lett. 1988 29 2851. ’ R. Mello M. Fiorentino 0. Sciacovelli and R. Curci J. Org. Chem. 1988 53 3890. 191 192 D. E. Ames Selective oxidation of aflatoxin Bl with dimethyldioxirane' has given the 8,9-epoxide (l) which is regarded as the ultimate carcinogenic species. It is sufficiently stable for manipulation and storage. An efficient preparation of 2,3-epithio-alcohols (2) is based on a titanium-catalysed reaction of the epoxide (3) with thiourea.' 00 R3eOH 0 R' S,S-Diphenylsulphilimine reacts with sulphones (4) to form aziridines (5).1° N-Alkoxyaziridines (6) can be obtained by intramolecular cycloaddition to an oxime C=N bond when the sodium salt (7) of a tosylhydrazone is heated (Scheme 2)." (7) (6) Reagents i NaH; ii A PhCl Yield 73% Scheme 2 Dialkylaminoazirines (8) react with trimethylsilyl isocyanate (or isothiocyanate) to give imidazolinones (9) (or the thione).I2 Phenylmethyldiazirine (10) forms a stable solid complex with P-cy~lodextrin.'~ Pyrolysis or irradiation of the complex gives isomers of 1,2-diphenyl- 1 -methylcyclopropane.Selectivity in the formation of the trans-isomer (11) is ten times greater for the complex than for neat diazirine and this is attributed to generation of carbene inside the cyclodextrin.' S. W. Baertschi K. D. Raney M. P:Stone and T. M. Harris J. Am. Chem. SOC.,1988 110 7929. Y. Gao and K. B. Sharpless J. Org. Chem. 1988 53 4114. K. Buggle and B. Fullon J. Chem. Rex (S) 1988 49. I' G. B. Jones and C. J. Moody J. Chem. SOC.,Chem. Commun. 1988 1009. I* I. Handke E. Schaumann and R. Ketcham J. Org. Chem. 1988 53 5298. l3 C. J. Abelt and J. M. Pleier J. Org Chem.. 1988 53 2159. Heterocyclic Compounds Sulphonylimines ( 12) are efficiently oxidized to 2-sulphonyloxaziridines (13) by '~xone'.'~ These oxaziridines are useful selective aprotic oxidizing agents e.g. for epoxidation and for sulphide to sulphoxide reactions. 0 /\ RS02N=CHAr RS02N-CHAr (12) (13) Phosphirenes (14) have been obtained by a cycloaddition reaction of iminophos-phorane and a1k~ne.I~ The phosphatricyclo[2.1 .0.02*5]pentane ring system (1 5) has been formed by phosphaalkyne dimerization with carbon monoxide incorporation in the presence of a titanium catalyst.I6 R NAr 0 RP=NAr+ PhCECPh + \p&APh -Ph Bu'C + -P co CP*Ti(CO) ,,.&But P-P (14) (15) 3 Four-membered Rings The oxetane ( 16) is formed regiospecifically in boron trifluoride-catalysed ring opening-recyclization of epoxide (17).17 Among the cyclic peroxides (1,2-dioxetanes) prepared during the review year are the products (18; X = 0,S) obtained from 2,3-dimethyl-4,5-dihydrofuran(19; X = 0) and the corresponding thiophene." OCH2Ph OAc OAc I sensitizer 0 Me (19) (18) l4 F.A. Davis S.Chattopadhyay J. C. Towson S. Lal and T. Reddy J. Org. Chem. 1988 53 2087. Is E. Niecke and M. Lysek Tetrahedron Lett. 1988 29 605. A. R. Barron A. H. Cowley S. W. Hall and C. M. Nunn Angew. Chem. Int. Ed. En& 1988 27 837. '' S. Hatakeyama K. Sakurai H. Numata N. Ochi and S. Takano J. Am. Chem. SOC.,1988 110 5201. W. Adam A. G. Griesbeck K. Gollnick and K. Kutzen-Mies J. Org. Chem. 1988 53 1492. 194 D. E. Ames R2 Me R2 LIAIH t-- :j-fRYe KOBu (23) Scheme 3 P-Chloroimines (20) can be converted into azetidines (21) cyanoazetidines (22) and 1 -aryl-2-methyleneazetidines (23) (see Scheme 3).19 Reactions of the kinetically stabilized tri-t-butylazete (24) have been studied." Sterically non-demanding cycloaddition reagents attack at C2-C3 whereas reagents with bulky groups attack at Nl-C4 (see Scheme 4).B u' Bu' Buir302Me 4rTf' MeO2CC=CCO,Me b (1.4-addition) B u' B u' C02Me Bu' (24) Scheme 4 Li$e __+ R4 HO ClCHZ Roe 3-Hydroxyselenetanes (25) have been prepared2' from chloromethyloxiranes (26). The parent compound (25; R = H) could not be oxidized to 3-oxoselenetane which is presumably too unstable to be isolated. Insertion of a phosphorus electrophile into cyclopropanes provides an efficient synthesis of phosphetanes (Scheme 5).22 19 (a) P. Sulrnon N. de Kimpe N. Scharnp B. Tinant and J.-P. Declerq Tetrahedron 1988 44 3653; (b) P. Sulrnon N. de Kimpe and N. Scharnp J. Org. Chem. 1988 53 4462. U. J. Vogelbacher M. Ledermann T.Schach G. Michels U. Hees and M. Regitz Angew. Chem. Inr. 20 Ed. Engl, 1988 27 272. 2' G. Polson and D. C. Dittrner J. Org. Chem. 1988 53 791. 22 S. A. Weissman and S. G. Baxter Tetrahedron Lett. 1988 29 1219. Heterocyclic Compounds Both 3- and 4-alkylidene- 1,2-0xasiletanes can be obtained regiospecifically from alkylidenesilacyclopropanesby oxygen-insertion reactions (Scheme 6).23The prod- ucts are thermally stable and do not undergo retro [2 + 21 reactions. 0- Ar3i-O M~~+c,H, Butfl!'z Ph,SO 0-SiArz Bu'P-/ Scheme 6 p-Lactams.-Intense activity continues in this very specialized field and a short section such as this can only attempt to indicate some reactions of general interest. Nickel carbonyl has been used24 for a one-pot conversion of an aziridine into a p-lactam by carbonyl insertion (Scheme 7).Reactions of organometallic carbene complexes (27) with methyl isocyanide and an aminoalkyne lead to an azetidinone (Scheme 8).25 Me Me H I-NI CO Ni(CO) 0BIHzPh CH2Ph Scheme 7 MeNC (CO),M=C(OEt)Ph -(CO),M[MeN=C=C(OEt)Ph] (27) M = Co or W 1MeCrCNEt Scheme 8 A review26 of applications of organometallic reagents in p-lactam chemistry concentrates on the construction and ring system rearrangements of p-lactams. An efficient diastereoselective conversion (Scheme 9) of methyl 3( S)-hydroxy- butanoate into (3S,4S)-3-[(1S)-1-hydroxyethyl]-4-benzoylazetidin-2-one has been de~cribed.~' It is based on the addition of ketene (28) to an imine of phenylglyoxal to give (29) as the major product.Desilylation is then accompanied by epimerization at C4 to give the truns-3,4-disubstituted P-lactam (30). 23 H. Saso H. Yoshida and W. Ando Tetrahedron Lett. 1988 29 4747. 24 W. Chamchaang and A. R. Pinhas J. Chem. Soc. Chem. Comrnun. 1988 710. 25 R. Aumann E. Kuckert C. Kruger R. Goddard and K. Angermund Chem. Eer. 1988 121 1475. 26 A. G. M. Barrett and M. A. Sturgess Tetrahedron 1988 44,5615. '' D. M. Tschaen L. M. Fuentes J. E. Lynch W. L. Laswell R. P. Volante and I. Shinkai Tetrahedron Lett. 1988 29 2779. 196 D. E. Ames /1 + several EtNPri C02Me steps COCl C ArN=CHCOPh I HO OSiPrl 'HH 'HH *COPh BU,6F-/\F_S-COPh -&-NAr &NAr 0 0 Scheme 9 A highly stereoselective preparation of carbapenem intermediates (3 1) has been reported.28 (3S,4R)-4-Acetoxy-3-[ (1R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one (32) and 0-silyl enol ethers of thiopropanoate esters (33) undergo a Lewis-acid- mediated reaction in which the acetoxy-group is displaced by the propanoate unit to give the thioester (31).M = Bu'SiMe A palladium( 11) catalyst induces nucleophilic ring closure of an allene unit on to an azetidinone nitrogen in a synthesis29 of 2-functionalized carbapenems (Scheme 10). M = Bu'SiMe Scheme 10 The use of tributyltin hydride with a,a'-azobisisobutanonitrile (AIBN) has been widely applied during the year to effect radical cyclization processes in heterocyclic synthesis. 1,6-Bond couplings of this type provide routes to carbacepham and carbacephem systems (Scheme 1 l).30 28 A.Martel J.-P. Daris C. Bachand J. Corbeil and M. Menard Can. J. Chem. 1988 66 1537. 29 J. S. Prasad and L. S. Liebekind Tetrahedron Lett. 1988 29 257. 30 T. Kametani S. Chu A. Itoh S. Maeda and T. Honda J. Org. Chem. 1988 53 2683. 197 Heterocyclic Compounds SPh R I oev C02Me 0 C02Me C02Me Reagents i CH,=CHCH,Br base; ii Bu3SnH AIBN Scheme 11 3-Substituted cephems (34; R = alkenyl) have been obtained efficiently3' by coupling 3-triflyloxycephems with alkenyltributylstannanes in the presence of a palladium catalyst. The process is also of interest for introducing tri-(2-furyl)phos- phine as the ligand. PhCH2CONH R~CONHH H xx 0 0 R3 COzCHPhz C02R4 (34) (35) Cephalosporins (35; R' = H) can be converted into the 2-methoxy derivatives (35; R' = OMe) by electrolysis with tetraethylammonium tosylate in methanol- tetrahydrofuran or by oxidation with ceric ammonium nitrate in the same ~oIvents.~* 4 Five-membered Rings A shows that furans pyrroles and indoles can act as dienophiles in Diels- Alder reactions provided that there are electron-withdrawing groups in the &position and also as N-substituents in the nitrogen-compounds.For example 3-acetyl-l- benzenesulphonylpyrrole and isoprene give a 1 1 mixture of isomeric adducts in 51% yield (Scheme 12). PhS02 PhSOz PhSOz Scheme 12 A stereoselective synthesis of substituted tetrahydrofuran-2,5-dicarboxylateesters has been developed34 (Scheme 13) as part of a synthesis of the diacid unit of the pyrrolizidine alkaloid jacobine.An w-allenic p-keto-ester can be cyclized (Scheme 14) by the combined catalytic actions of a Lewis acid and a Brgjnsted acid3' to form 3' (a)V. Farina S. R. Baker and C. Sapino Terruhedron Leu. 1988 29,6043; (b) V. Farina S. R. Baker D. A. Benigni and C. Sapino ibid. p. 5739. 32 G. Pattenden A. Stapleton D. C. Humber and S. M. Roberts J. Chem. Soc. Perkin Trans. 1 1988,1685. 33 E. Wenkert P. D. R. Moeller and S. R. Piettre J. Am. Chem. SOC.,1988 110 7188. 34 L. L. KIein and M. S. Shanklin J. Org. Chem. 1988 53 5202.. 35 T. Delair A. Doutheau and J. Gore Bull. SOC.Chim. Fr. 1988. 125. 198 D. E. Ames c1 Me02C C02Me c1 c1 I iii C02Me Reagents i A; ii 0,-MeOH; iii Raney Ni Scheme 13 Scheme 14 a reduced furan with an enol-ether structure.3-Acyl- and 3-alkoxycarbonylfurans can be prepared by cerium( iv) ammonium nitrate-promoted addition of 1,3-dicar- bony1 compounds to vinyl acetate (Scheme 15).36 Condensation of enolate dianions with cyclohexadiene cobalt(tricarbony1) tetrafluoroborate (Scheme 16) gives fused- ring dihydr~furans.~' The chemistry of isobenzofurans has been reviewed38 and cycloaddition routes to fused heterocycles have been For example in Scheme 17 the 1,2,4- triazine ring acts as the diene component in an internal Diels-Alder reaction with the acetylene unit. Loss of nitrogen gives a fused-ring system with the trimethylsilyl group available for methathesis.Scheme 15 + -0$OR Q M' M2 = Li Na or SiMe (CO)&o+BF; Scheme 16 36 E. Baciocchi and R. Ruzziconi Synth. Commun. 1988 18 1841. 37 L. S. Barinelli and K. M. Nicholas J. Org. Chem. 1988 53 2114. 38 R. Rodrigo Tetrahedron 1988 44 2093. 39 E. C. Taylor Bull. SOC.Chim. Belg. 1988 97 599. Heterocyclic Compounds %Me3 5ime3 -RA-0 y-tJ-l=-J R NO Scheme 17 Radical cyclization processes using tributyltin hydride mentioned above have been particularly useful in syntheses of hydrofuran ring systems as shown in Schemes 1840and 19.4' An aryl radical generated by the tin reagent initiates a tandem radical cyclization process (Scheme 20) to convert the aromatic ether (36) into a furano- phenanthrene (37).42 OCH,(CH,),CH,SePh Bu,SnH ___+ 0 Scheme 18 Scheme 19 (37) Scheme 20 Furano[3,4-b]furans having a new diheteropentalene system have been pre- pared43 by thermal isomerization of an oxirane-alkyne system (38).Like related fused furans the products (39) show high reactivity in Diels-Alder additions across the diene unit in ring B. 40 D. S. Middleton and N. S. Simpkins Tetrahedron Left. 1988 29 1315. 41 A. Gopalsamy and K. K. Subramanian J. Chem. SOC.,Chem. Commwn. 1988 28. 42 K. A. Parker D. M. Spero and J. Van Epp J. Org. Chem. 1988 53 4628. 43 W. Eberbach H. Fritz and N. Laber Angew. Chem. Inf. Ed. Engl. 1988 27 568. 200 D. E. Ames An enantioselective synthesis of (+)-biotin in twelve steps from L-cystine dimethyl ester has been reported.44 The sterically overcrowded 3,4-di-t-butylthiophene (40) has been prepared45 by internal reductive coupling of diketone (41).X-Ray analysis showed the diol intermediate to be the cis-isorner (42). Thiophene (40) can be nitrated and halogen- ated but with aluminium chloride it rearranges to the 2,4-di-t-butyl-isomer. OH OH Iodine-induced cyclization of ?,&unsaturated secondary thioamides (43)46 pro- ceeds regio- and chemoselectively to form imine salt (44). Dehydroiodination and acetylation then complete a general route (Scheme 21) to alkyl-substituted 2- acetamidothiophenes (45). ,R2 ,R2 R5& NHR’ i R4 R3 S (43) (44) (45) Reagents i I ;ii DBU (=1,8-diazabicyclo[ 5,4,0]undec-7-ene); iii MeCOCI DBU Scheme 21 2,3-Dimethylenethiophene(46) has been generated as a transient species (Scheme 22) which can be trapped to form a ben~othiophene.~’ Michael addition of 2- mercaptothiophene to a$-unsaturated acids (rather than the esters) gives acid (47) (Scheme 23).Cyclization of the acid chloride provides an efficient synthesis of thieno[ 2,341 thiopyrans (48) .48 44 E. J. Corey and M. M. Mehrotra Tetrahedron Left. 1988 29 57. 45 J. Nakayama S. Yamaoka and M. Hoshino Tetrahedron Lett. 1988 29 1161. 46 H. Takahata T. Suzuki M. Maruyama K. Moriyama M. Mozumi T. Takamatsu and T. Yamazaki Tetrahedron 1988 44,4777. 47 A. M. van Lensen and K. J. van den Berg Tetrahedron Lett. 1988 29 2689. 48 G. S. Ponticello M. B. Freedman C. N. Habecker M. K.Holloway J. S. Amato R. S. Conn and J. J. Baldwin J. Org. Chem. 1988 53 9. Heterocyclic Compounds (46) Reagents i F-; ii MeO2CCH=CHCO2Me Scheme 22 0 (47) Reagents i I ISH; ii (COCI),; iii SnCl, LJ Scheme 23 In a general synthesis of substituted pyrr~lidines:~ transmetallation of the stannyl- imine (49) with butyllithium is used to generate 2-azaallyl anions (50) which readily undergo cycloaddition with alkenes (Scheme 24). Pyrrolidine (51) is obtained in 62% yield as a 1 :1 mixture of isomers. The process can also be applied to effect stereospecific intramolecular condensation (Scheme 25). BuLi PhCH ICH Ph PrCH=NCH,SnR -flG-b Pr (49) (50) Scheme 24 BuLi+ & 'n N SnBu3 HH Scheme 25 The preparation of lactam acetals and their uses in heterocyclic synthesis have been re~iewed.~' Regio- and stereospecific cycloaddition of the imine (52) of an amino-ester to a dipolarophile has been rep~rted.~' The reaction which probably proceeds uia a 4Y W.H. Pearson D. P. Szura and W. G. Harter Tetrahedron Lett. 1988 29 761. so N. Anand and J. Singh Tetrahedron 1988 44 5975. 51 D. A. Barr R. Grigg H. Q. N. Gunaratne J. Kemp P. McMeekin and V. Sridharan Tetrahedron 1988 44 551. 202 D. E. Ames ,co,~t Et02C --<-ArCH= NCHRC0,Me Ar (52) (53) metallo-l,3-dipole is catalysed by silver acetate and triethylamine and yields pyr- rolidines (53). A promising approach to cyclic systems from open-chain diynes5’ has been used mainly for carbocycles but also for a pyrrole synthesis (Scheme 26).The diynylamine (54)is condensed with benzaldehyde in the presence of nickel(0) biscyclooctadiene and tricyclohexylphosphine to form nickel complex (55) and thence pyrrole (56) in 97% yield. Another synthesis of pyrrole~~~ is based on a [4+11 annelation reaction of 2,3-di(phenylsulphonyl)buta-l,3-dienewith primary amines (Scheme 27). Conju- gate addition and then 5-endo-trig cyclization of amine on to the adjacent vinyl COPh Et I Et I I 1 N Pr Pr (54) (55) Reagents i PhCHO Ni(cod) Scheme 26 pho2y-J SOzPh ii SOzPh [=jSOzPh --+ 4 N N N R R R SOzPh (57) (58) (59) Reagents i RNH,; ii NaOMe; iii DDQ Scheme 27 sulphone unit produces di(phenylsulphony1)pyrrolidine (57).Base-catalysed elimin- ation of benzenesulphinic acid to form pyrroline (58) is followed by dehydrogenation to pyrrole (59). The phenylsulphonyl group facilitates 2-lithiation so that reaction with electrophiles then leads to various 2-substituted pyrroles from which the phenylsulphonyl group can be removed. A synthesis of the red pigment pr~digiosin~~ introduces an elegant route to 2,2’-bipyrrolyls. A polymer-supported palladium catalyst is used to promote intramolecular dehydrogenative cyclization of the dipyrrolylimide (60). Removal of 52 T. Tsuda T. Kiyoi T. Mujane and T. Saegusa J. Am. Chem. Soc. 1988 110 8570. 53 A. Padwa and B. H. Norman Tetrahedron Lett. 1988 29 3041. s4 D. L. Boger and M. Patel J. Org. Chem. 1988 53 1405.Heterocyclic Compounds 203 the carbonyl group from cyclic imide (61) gives unsymmetrical 2,2’-bipyrrolyl (62) in high yield (Scheme 28). Two useful reviews have been published covering aspects of recent work on synthesis of substituted in dole^.^^ Tributyltin hydride has been used again for cyclization reactions in indoline syntheses (Scheme 29). Unsaturated amides (63) of alkylbromoaniline give indolines (64),56 whereas reaction in the presence of ethyl acrylate leads to ester (65).57 R R N -NH PCO2Me I pC02Me &C02Me I1 N\ \ 4 -co co Reagents i,@-Pd(OAc),; ii LiOMe Scheme 28 R2 R2 Ac Ac (65) Reagents i Bu3SnH AIBN; ii CH,=CHCO,Et Scheme 29 A tandem cyclization- hydride capture process provides a general approach to carbocyclic and heterocyclic syntheses.’* The method is illustrated by the conversion of acetylenic iodoamide (66) into 1-acetyl-3-methyleneindoline(67)by reaction with pyrrolidine and formic acid (hydride ion source) in the presence of palladium(I1) acetate and triphenylphosphine.55 (a) U. Pindur and R.Adam J. Hererocycl. Chem. 1988 25 1; (b) L. S. Hegedus Angew. Chem. Znr. Ed. Engl. 1988 27 1113. 56 J. P. Dittami and H. Ramanathan Tetrahedron Lerr. 1988 29 45. 57 H. Togo and 0. Kikuchi Tetrahedron Lett. 1988 29 4133. 58 B. Burns R. Grigg V.Sridharan and T. Worakun Tetrahedron Lett. 1988 29 4325. 204 D. E. Ames Ac (67) Palladium catalysis is also employed in both steps of a valuable new synthesis of 4-substituted indoles (Scheme 30)59from the 3-substituted 2-bromoaniline derivative (68).Condensation with tributylvinylstannane gives a rather unstable vinyl com- pound (69) which is cyclized directly by an oxidative process to 4-substituted-l- tosylindole (70). Yields range from 49 to 87% for C02Me OAc CH(OAc), OMe and Me groups as the 4-substituent. R R R Reagents i Bu3SnCH=CH2 (Ph,P),Pd; ii PdCI2( MeCN) ,LiCI benzoquinone Scheme 30 2-Vinylindole has been synthesized for the first time6’ by an intramolecular Wittig reaction of phosphonium salt (71). The vinylindole reacts with dienophiles; for example dimethyl acetylenedicarboxylate gives dihydrocarbazole (72) by [4 + 21 addition followed by [1,3]-H shift (Scheme 31). (71) Reagents i PhMe A; ii MeO,CC=CCO,Me Scheme 31 It has been shown6’ by n.m.r.and X-ray studies that chlorosulphonation of l-acetyl-5-bromoindoline occurs at the 6-position and not C7 as previously reported. 7-Aminosulphonyl-derivatives of indoline and indole have now been prepared61 from indoline with a C(0)NHS02CI unit attached to the ring nitrogen by an intramolecular suphonation. 59 M. E. Krolski A. F. Renaldo D. E. Rudisill and J. K. Stille J. Org. Chem. 1988 53 1170. U. Pindur and M. Eitel Helu. Chim. Acra 1988 71 1060. A. L. Borror E. Chinoporos M. P. Filosa S. R. Herchen C. P. Petersen and C. A. Stern J. 0%.Chem. 60 61 1988 53 2047. Heterocyclic Compounds Reduction of phthalimide with borane in tetrahydrofuran6* provides an improved synthesis of isoindoline (50% yield by a ‘one-pot’ process).Condensation of 2-ethylindole with methyl vinyl ketone in the presence of pal-ladium charcoal and molecular sieves63 yields 1,2-dimethylcarbazole (73) in 8 l ‘/o yield. It has been that lithiation of N-[(dialkylamino)methyl] carbazoles with t-butyllithium occurs exclusively at the protonated carbon adjacent to the ring nitrogen atom (74). Reactions with electrophiles give C-substitution products and removal of the N-protecting group then affords 1 -substituted carbazoles. R2 (73) (74) An ingenious synthesis of 1,8-diarnino~arbazole~~ has been developed (Scheme 32). The rather unstable product was isolated as its diacetyl derivative. A general chiral synthesis (Scheme 33) of bicyclic systems with a nitrogen atom at the ring junction has been reported.66 An o-chloroacyl unit is attached at N3 of an auxiliary 4-(S)-isopropyl-l,3-thiazolidine-2-thione as in (75; rn = 1 or 2).Reac- tion with tin( 11) trifluoromethylsulphonate gives complex (76) which is stereo- specifically condensed with a 2-acetoxy-lactam (77; n = 1 or 2) to form (78). Reagents i S4N4;ii Sn HCI H20; iii H3P04 Scheme 32 62 R. E. Gawley S. R. Chemburkar A. L. Smith and T. V. Anklekar J. Org. Chern. 1988 53 5381. J. Bergman and B. Pelcman Tetrahedron,1988 44 5215. 64 A. R. Katritzky G. W. Rewcastle and L. M. V. de Miguel J. Org. Chern. 1988 53 794. 65 K. Takahashi H. Eguchi S. Shiwaku T. Hatta E. Kyoya T. Yonemitsu S. Mataka and M. Tashiro J.Chem. SOC.,Perkin Trans. 1 1988 1869. 66 Y. Nagao W.-M. Dai M. Ochiai. S. Tsukagoshi and E. Fujita J. Am. Chern. SOC.,1988 110 289. 206 D. E. Ames Sn-OS02CF3 f c1 / U (79) (78) (77) iv v T Reagents i Sn(OS02CF,)2 base; ii LiAIH (small excess); iii (Bu,Sn), EtI hv;iv EtC0,Cs; v LiAIH Scheme 33 Cyclization and reduction with lithium aluminium hydride remove the auxiliary unit to give bicyclic system (79) in good yield. Each ring in (79) may be five- or six-membered. Alkaloid (-)-trachelamanthamidine (79; m = n = 1) has also been synthesized stereo~electively~~ by atom-transfer annulation of iodo-amide (80). The ratio of cis (81) to trans (82) isomers was 30 1. Caesium propanoate was used to displace iodine by propanoate in the mixed isomers and then lithium aluminium hydride reduction gave the alcohols.After chromatography cis-isomer (79; rn = n = 1) was obtained in 46% overall yield. A convergent biomimetically patterned synthesis of indolizidines6' is shown in Scheme 34. The bis-acetal (83) is hydrolysed at pH5.5 to the pyrrolinium salt (84) the aldehyde group of which condenses with a P-keto-ester and cyclizes to 67 R. S. Jolly and T. Livinghouse J. Am. Chem. Soc. 1988 110 7536. 68 G. W. Gribble F. L. Switzer and R. M. SOH,J. Org. Chem. 1988 53 3164. Heterocyclic Compounds OMe (86) Reagents i 1.4MHCI; ii PrCOCH,CO,CH,Ph; iii 8M HCI Scheme 34 indolizidine (85). In strongly acidic conditions elimination of water ester hydrolysis and decarboxylation occur to produce (*)-elaeokanine A (86) (56%).Tributyltin hydride is used in both steps of an efficient synthesis69 of benzo[f]in-dolizidin-1-ones (87) (Scheme 35). Reductive acylation of an isoquinoline gives iodo-amide (88) which is converted by a radical cyclization process into (87) (55% yield from the isoquinoline). 3,6-Di-t-butyl-l,4-diazapentalene (89) has been obtained by oxidation of the dihydro-derivative (90). It is only inductively stabilized. The spectra and MNDO calculations show that KekulC structure (89) dominates i.e. the bonds are fixed.” Reagents i I(CH,),COCI. Bu,SnH; ii Bu,SnH AIBN Scheme 35 NiOz @ hydroquinone BU‘ H But Scheme 36 69 R. Yamaguchi T. Hamasaki and K. Utimoto Chem. Lett. 1988 913.70 S. Tanaka K. Satake A. Kiyomine T. Kumagi and T. Mukai Angew. Chern. Inr. Ed. Engl. 1988 27 1061. 208 D. E. Ames A tetra-donor-substituted 2,5-diazapentalene has been synthesized (Scheme 37).71 The double bonds of (91) are delocalized even though the system contains eight welectrons (antiaromatic). A series of cross-conjugated mesomeric betaines have been prepared (Scheme 38)72 and their properties studied (dipole moments as well as n.m.r. and X-ray methods). Me2N Me2N 0 NMe2 EtO NMe2 (911 Reagents i NaH; ii Et,O+ BF4-Scheme 37 Reagents i O=C=C=C=O; ii CICOCPh=C=O (phenyl chlorocarbonyl ketene) Scheme 38 X- Me c0r2 R‘ H R2 Me02C C02Me Reagents i PhSiH, CsF; ii MeO2CC=CCO2Me Scheme 39 The [3 + 23 nitrone-olefin cycloaddition reaction to form isoxazolidines has been reviewed.73 Treatment of oxazolium salts (92) with phenylsilane and caesium fluoride gener- ates 4-oxazolines (93).74Ring-opening occurs spontaneously to form azomethine ylides (94) which form [2 + 31 cycloadducts e.g.(95) with dipolarophiles. Stereoselective contra-steric conversion of epoxides into cis-4,5-disubstituted oxazolidin-2-ones (96) has been achieved7’ by an ingenious use of 2-methoxynaphth-l-yl isocyanate (Scheme 40). The bulky naphthyl unit is subsequently removed by oxidation with cerium(rv) ammonium nitrate. At least 89% of the product is the ” F. Closs R. Gompper H. Noth and H.-U. Wagner Angew. Cheh. Int. Ed. Engl. 1988 27 842. 72 (a) K. T. Potts P. M. Murphy and W. R.Kuehnling J. Org. Chem. 1988 53 2889; (6) K. T. Potts P. M. Murphy M. R. De Luca and W. R. Kuehnling ibid. p. 2898. 73 P. N. Confalone and E. M. Huie Org. React. (N.Y.) 1988 36 1. 74 E. Vedejs and J. W. Grissom J. Am. Chem. SOC.,1988 110 3238. ’’ B. M. Trost and A. R. Sudhakar J. Am. Chem. SOC.,1988 ii0 7933. Heterocyclic Compounds 0-c0 0-c0 R I 2R1* ~ Ar +ii R1* H \ 'H RZ \ 'H R2 ' (96) Reagents i ArNCO Pd,(dba) P(OPr'),; ii (NH4),Ce(N03) Scheme 40 cis-isomer (96) whether the epoxide used is cis or trans and this is attributed to the rapid interconversion of two diastereoisomeric .rr-ally1 palladium complexes. Treatment of azlactones with o-aminobenzenethiol in acetic acid gives benzo- thiazoles efficiently (Scheme 41).76 The oximes of 2-acylthioanisoles are converted into benzisothiazoles (Scheme 42)77 by heating with acetic anhydride and pyridine.Scheme 41 Scheme 42 Chlorine dioxide a gaseous free radical that can easily be generated and stored has been used7' to effect oxidative cyclization of amino-alcohols via an iminium ion (Scheme 43). Another convenient synthesis of similar 0,N-heterocycles is based on the reaction of proline with an aldehyde in dimethyl ~ulphoxide.~~ The azomethine ylide generated undergoes a 1,3-dipolar cycloaddition to a second molecule of aldehyde to form a 1-oxapyrrolizidine (Scheme 44). n = lor2 Scheme 43 76 A. R. Katritzky K. Sakizadeh J. Swinson S. M. Heilmann L. R. Krepski and S. V. Pathre Synth. Commun. 1988 18 651. 77 D.M. McKinnon and K. R. Lee Can. J. Chem. 1988 66 1405. 78 C.-K. Chen A. G. Hortmann and M. R. Marzabadi J. Am. Chem. Soc. 1988 110 4829. 79 F. Orsini F. Pelizzoni M. Forte R. Destro and P. Gariboldi Tetrahedron 1988 44 519. 210 D. E. Ames ArCHO -co, -n -k" N (--Qcoi Arc HO 0CO.H II ArCH '. H I Arc H Ar Scheme 44 Work on rings with less common heteroatoms includes the preparation of a stable dihydro-1,3-diborofulvene80 as shown in Scheme 45. The organic chemistry of phospholes has been reviewed.81 Novel phosphorus- containing heterocycles (97),82 (98),83 and (99)84 have been synthesized. Compound (99) is a 10 .rr-electron planar heterocycle which exhibits stable 3pT-3p bonding between phosphorus and sulphur.An efficient synthesis of selenophenes (Scheme 46) is based on reductive coupling of diketones (100) to form cis-diols (101) which are dehydrated to give the aromatic R' R' I -I BC1 (Me,Sn),C=CMe 'X>C=CMe2 n2 =-I I R' R' Scheme 45 P\,-J C02Me I OH OH R1xooxR1 i_ R'Q-R2 Se R2 R2 Reagents i TiCI, Zn; ii TsOH A Scheme 46 80 V. Schafer H. Pritzkow and W. Siebert Angew. Chem. Int. Ed. Engl. 1988 27 299. 81 F. Mathey Chem. Rev. 1988 88 429. 82 N. Maigrot L. Ricard C. Charrier and F. Mathey Angew. Chem. Int. Ed. Engl 1988 27 950. 83 G. Markl S. Dietl M. L. Ziegler and 9. Nuber Tetrahedron Lett. 1988 29 5867. h4 N. Burford B. W. Royan A. Linden and T. S. Cameron. J. Chem. Soc. Chem. Commun. 1988 842. Heterocyclic Compounds 211 structures (102).s5 Thermal reactions of the sterically protected 1,2,3-~elenadiazole (103) with elemental sulphur and seleniums6 produce 1,2,3-trithiole (104) and 1,2,3-triselenole (105) structures respectively.5 Six-membered Rings The chromanochromanol acetate (106) the core structure of a rotenoid alcohol has been synthesized (Scheme 47).” The cis-arrangement of all three hydrogens at the contiguous chiral centres is obtained by an intramolecular 6-ex0 aryl radical addition. A synthesis of the elusive fungal metabolite patulin (107) has been achieved via Scheme 48.” Ketone (108; X = 0),from arabinose gave (108; X = CHC0,Me) by a Wittig reaction. Ketal cleavage and cyclization produced a mixture (109; R = H and CH,Ph) which was debenzylated.Dehydration of (109; R = H) then gave patulin (107). I 9% I I -Iq.lla i”p&J 0 / i,ii,iii 0 / + 0 / 0 0 0 Reagents i NaBH,; ii pyridinium chlorochromate; iii CH,=CMe(OAc); iv Bu3SnH AIBN Scheme 47 OR w 1 + -ko zPh Obo ~ HO Reagents i HCIO,; ii CF,CO,H Et3N Scheme 48 n5 J. Nakayama F. Murai and M. Hoshino Tetrahedron Lett. 1988 29 1399. 86 N. Tokitoh H. Ishizuka and W. Ando Chem. Lett. 1988 657. 87 S. A. Ahmad-Junan and D. A. Whiting J. Chem. SOC.,Chem. Commun. 1988 1160. an G. B. Gill G. Pattenden and A. Stapleton Tetrahedron Lett. 1988 29 2875. 212 D. E. Ames New syntheses of 2-pyranones have been reported and are summarized in Schemes 49,8950,’’ and 51.’l Interesting visible laser photochemical reactions of 4,4-dimethylpyran-2-one have been described.’* In the presence of benzoquinone oxetanes (110) and (111) are formed but in the presence of dioxygen the intermediate biradical (112) gives trioxanes (1 13) and (1 14).New syntheses of thiopyrans (Scheme 53)93 and benzothiopyrans (Scheme 54)94 have been reported. The sulphoxide (115) has been converted via (116) into (117) which has a new heterocyclic skeleton 2,6-epithi0-3-benzazocine.~~ Reagents i LiCH2C02Li; ii (CF,C0)20 Scheme 49 4 CO,H R’ R’ R’ R’ 0 Reagents i R2CH2N02 Et3N; ii NaBH,; iii HZSO, MeOH; iv Ac20 H+ Scheme 50 Reagents i C02 bis-( 1,5-cyclooctadiene)nickel(0) Scheme 51 89 R. K. Dieter and J. R. Fishpaugh J. Org.Chem. 1988 53,2031. 90 F.M.Hauser and V. M. Baghdanov J. Org. Chem. 1988 53,4676. 91 T.Tsuda S. Morikawa R.Sumiya and T. Saegusa J. Org. Chem. 1988 53,3140. 92 W. Adam U. Kliem T. Mosandl E.-M. Peters K. Peters and H. G. von Schnering 1. Org. Chem. 1988 53,4986. 93 K.R. Lawson B. P.McDonald 0. S. Mills R. W. Steele J. K. Sutherland T. J. Wear A. Brewster and P. R. Marsham J. Chem. SOC.,Perkin Trans. 1 1988 663. 94 A. Arnoldi and M. Carughi Synthesis 1988 155. 95 M. Hori T. Kataoka H. Shimizu E. Imai N. Iwata N. Kawamura and M. Kurono Heterocycles 1988 27 2091. Heterocyclic Compounds 213 (112) (113) (114) Reagents i hv (visible laser) benzoquinone; ii O2 Scheme 52 Scheme 53 NaOMe aR2 R1 Scheme 54 Scheme 55 There has been continued interest in directed metallation of pyridines as synthetic intermediates.1-Methylpyrid-4-one gives the 2-lithio-derivativeg6 while 2-methoxy- pyridineg7 and 2-fluoropyridine9* both give 3-lithio-compounds. These intermediates provide an attractive approach to functionalization of the pyridine ring. 96 P. Meghani and J. A. Joule J. Chem. SOC.,Perkin Trans. I 1988 1. 97 F. TrCcourt M. Mallet F. Marsais and G. Queguiner J. Org. Chem. 1988 53 1367. 98 L. Estel F. Marsais and G. QuCguiner J. Org. Chem. 1988 53 2740. 214 D. E. Ames A mixture of titanium( IV) and tin( 11) chlorides deoxygenates heteroaromatic N-oxides effi~iently.~~ Oxidation of N-alkylpiperidines and other cyclic tertiary amines with mer-cury( 11)-ethylenediamine tetracetic acid complex gives lactams.lOO For example 1-methyl-4-t-butylpiperidine gives the corresponding piperid-2-one in 90% yield.Thermal 6~-electrocyclic rearrangement of o-vinyl anils with air oxidation of dihydro-intermediates provides a synthesis of quinolines under non-acidic condi- tions (Scheme 56)."' R' R' R' Scheme 56 The skeleton of 1,2-~ecoergolinehas been constructed in eight steps starting from /?-naphthol."* The heterocycle-forming process is shown in Scheme 57. A Beckmann rearrangement of oxime (118) provides an improved ~ynthesis"~ of benzomorphan (I19). Steric factors preclude the usual formation of isoxazole from diketone monoxime. Me Me Me I I I fNCOCF3 rNCOCF3 rNCOCF3 CH2NO2 CHzNO2 Reagents i MeNO, base; ii CF3S03H Scheme 57 Reagents i Polyphosphoric acid A Scheme 58 99 L.Kaczmarek M. Malinowski and R. Balicki Bull. Soc. Chim. Belg. 1988 97 787. I00 E. Wenkert and E. C. Angell Synrh. Commun. 1988 18 1331. 101 L. G. Qiang and N. H. Baine J. Org. Chem. 1988 53,4218. 102 D. H. R. Barton A. Fekih and X. Lusinchi Bull. SOC.Chim. Fr. 1988 681. I03 C. W. Bird and K. Naidoo Svnth. Commun. 1988 18 1119. Heterocyclic Compounds Reduction of isoquinoline with sodium triethylborohydride gives the boron- activated enamine ( 120) which has been usedlo4 to prepare 4-substituted isoquino- lines (Scheme 59). In a palladium( 11)-silver fluoroborate-catalysed process,lo5 ben- zaldimines and alkynes are converted into isoquinolinium salts (Scheme 60).r 1 L _J Scheme 59 H I Reagents i PdCI, AgBF,; ii R2CzCR2 Scheme 60 A convenient synthesis of pyrido[ 3,4-g]isoquinoline has been effected by a novel ortho-metallation-dimerization reaction of N,N-diethylnicotinamide (Scheme 61).lo6 0 Reagents i LiNR2; ii HI; iii Pd/C A Scheme 61 A definitive monograph entitled 'Fused Pyrimidines Pteridines' has been pub- 1i~hed.l'~ Thionation of pyrimidine-2,4( 1 H,3 H)-dione derivatives with the Lawesson reagent is highly regioselective and occurs at the 4-po~ition.l~~ 5-Bromopyrimidines have been converted into the 5-lithio and 5-stannyl derivatives; palladium-mediated condensation with alkenylstannane then gives the 5-alkenylpyrimidine.'09 In another 104 D.E. Minter and M. A. Re J. Org. Chem. 1988 53 2653. 10s G. Wu S. J. Geib A. L. Rheingold and R. F. Heck J. Org. Chem. 1988 53 3238. 106 V. Bolitt C. Mioskowski S. P. Reddy and J. R. Falck Synthesis 1988 388. 107 D. Brown 'Fused Pyrimidines Pteridines' Wiley New York 1988. 108 K. Kaneko H. Katayama T. Wakabayashi and T. Kurnonaka Synthesis 1988 153. I09 J. Sandosham T. Benneche B. S. Mbller and K. Undheirn Acta Chem. Scand. Ser. B,1988 42 455. 216 D. E. Ames palladium-catalysed process"o an alkenylurea (121) is converted into a hydro- pyrimidone (122) by reaction with carbon monoxide and methanol in the presence of palladium( 11) and copper(I1) chlorides. VO2Me PhCH2NKNHMe 0 0 PhCH2NKNMe (121) (122) Reagents i CO MeOH WCI, CuCI Scheme 62 An annelation approach to the synthesis of fused-ring pyrimidines'" is based on electrocyclic ring closure of a conjugated heterocumulene (Scheme 63).Aroylpyrazines are conveniently prepared by a homolytic substitution process,' l2 as shown in Scheme 64. Ph Reagents i CS,; ii R'NCO Ph Scheme 63 HO2C N, Ho2cx) lNACoAr-QOA Reagents i ArCHO Bu'02H FeSO, H,SO,; ii. Cu A Scheme 64 Recent progress in quinoxaline chemistry has been reviewed113 and in a new synthesis of cinnoline~,"~ diazo-compound (123; X = N2) has been condensed with tributylphosphine to form iminophosphorane (123; X = N-N=PBu3) and thence cinnoline (124). Pyrrolo[ 1,2-b]cinnolines (125) have been prepared' l5 by fluoride ion displacement to close the central ring (Scheme 65).I10 Y. Tamaru M. Hojo H. Higashimura and Z. Yoshida J. Am. Chem. Soc. 1988 110 3994. Ill P. Molina A. Arques M. V. Vinader J. Becher and K. Brondum J. Org. Chem. 1988 53 4654. 112 G. Heinisch and G. Lotsch Synthesis 1988 119. 113 G.Sakata K. Makino and Y. Kurasawa Heterocycles 1988 27 2481. I14 T. Miyamoto and J.-I. Matsumoto Chem. Fharm. Bull. 1988 36 1321. I15 R. R. L. Hamer D. Sekerak R.C. Effland and J. T. Klein J. Heterocycl. Chem. 1988 25 991. Heterocyclic Compounds 0 0 N/ ' N' 1 R (125) Reagents i KOH H20;ii HCI H20 Scheme 65 Reaction of 2-alkylaminobenzonitrilewith chlorosulphonyl isocyanate provides an efficient one-pot synthesis of l-alkyl-4-amino-2( 1 H)-quinazolinone.1'6 Silylation of pteridines makes efficient hydrogenation of the pyrazine ring possible (Scheme 66)."' Yield 85% Reagents i H2-Pt; ii HCI H,O Scheme 66 Protection of the ring nitrogen as =NCO,Li during lithiation allows C1 metallation for the preparation of 1-substituted phenothiazines."* Phenothiazines and 1,4-benzothiazines are the subjects of a book."' 3,6-Dichloro-4-pyridazinecarbonyl chloride can be converted into a wide variety of condensed heterocycles (Scheme 67).I2O 6 Seven-membered Rings The synthesis of seven-membered-ring heterocycles via pericyclic reactions has been reviewed.121A stereoselective route to oxepanes by Lewis-acid-mediated condensa- tion of aldehydes with alkenols (Scheme 68) has been described.'** An enzymatic I16 A.V. N. Reddy A. Kamal and P. B. Saltur Synth. Commun. 1988 18 525. 117 P. H. Boyle and M. F. Kelly Tetrahedron 1988 44 5179. 118 A. R. Katritzky L. M. V. de Miguel and G. W. Rewcastle Synthesis 1988 215. 1 I9 R. R. Gupta 'Phenothiazines and 1,4-Benzothiazines' Elsevier Amsterdam 1388. 120 W. Ried and T. A. Eichorn Chem. Ber. 1988 121 2049. ''I K. Hassenruck and H. D. Martin Synfhesis 1988 569. I22 L. Coppi A. Ricci and M. Taddei J. Org. Chern. 1988 53 911. 218 D. E. Ames c1acl COCl c1 0 0 NHOH Reagents i NH3; ii 2-H2NC,H4C02Me; iii R-C / 'NH Scheme 67 Yield 51% Reagents i Me,CHCHO AIC13; ii H20 Scheme 68 Baeyer-Villiger ~xidation'~~ of cyclic ketones is highly enantioselective in producing seven- (as well as five- and six-) membered-ring lactones.A palladium-catalysed cy~lization'~~ of the tin complex of unsaturated trio1 derivative (126) gives both diastereoisomers of hydroxyoxepane ( 127) (Scheme 69). HOk OC02Me (26) HO Reagents; i Bu2SnO; ii (dba),Pd,CHCI Scheme 69 (127) 123 M. J. Taschner and D. J. Black J. Am. Chern. Soc. 1988 110 6892. 124 B. M. Trost and A. Tenaglia Tetrahedron Lett. 1988 29 2927. Heterocyclic Compounds Irradiation of dithiono-esters (128) involves cyclizati~n'~~ with loss of S2to form enol-ether (129) and thence ketone (130) a fused-ring oxepane. In another photolytic process'26 the 0-bridge compound (131) gives 8H-3-oxaheptalen-8-one (132) an oxepine condensed with tropone.Reagents i hv; ii Bu,N+ F- H20 Scheme 70 N-Substituted azepines have been obtained'27 by reductive condensation of adipaldehyde with primary amine using tetracarbonylhydridoferrate as selective reducing agent. Photolysis of 3,6-di-t-butyl-l-methoxycarbonylazepine (133)12* produces cyclo- butapyrrole (134) a 'Dewar azepine'. Hydrolysis and thermolysis lead to 3,6-di-t- butyl-3 H-azepine (135) (Scheme 71). Azepino[3,4,5-cd]indoles (136) have been ~btained"~ by intramolecular photocyclization of chloro-amide (137). u Bu' C02Me C02Me (133) (134) (135) Reagents; i hv; ii KOH; iii A Scheme 71 A remarkably stable 1O.n- aromatic system 1,3,5-2,4,6-trithiatriazepine is formed13' by action of sulphur nitride on dimethyl acetylenedicarboxylate.The product ester (138; R = CO,Me) on hydrolysis and decarboxylation gives the parent compound (138; R = H). 125 K. C. Nicolaou C.-K. Hwang and D. A. Nugiel Angew. Chem. Znt. Ed. Engl. 1988 27 1362. 126 T. Nakazawa M. Ishihara M. Jinguji M. Yamaguchi H. Yamochi and I. Murata Chem. Lerr. 1988 1647. 127 S. C. Shim C. H. Doh T. J. Kim and H. K. Lee J. Heterocycl Chem. 1988 25 1383. 128 K. Satake H. Saitoh M. Kimura and S. Morosawa J. Chem. Soc. Chem. Commun. 1988 1121. 129 S. E. Klohr and J. M. Cassady Synth. Commun. 1988 18 671. 130 P. J. Dunn J. L. Morris and C. W. Rees J. Chem. SOC.,Perkin Trans. I 1988 1745. 220 D. E. Ames 7 Larger Rings A flexible and efficient synthesis of 9- lo- and 1 1-membered-ring unsaturated macrolides has been de~eloped'~' and is illustrated by Scheme 72.An intramolecular Nozaki coupling reaction has been used'32 to prepare 4-epibrefeldin C (139) (Scheme 73). (+)-Brefeldin C the epimer at C4 is also formed as the minor product (4 1 ratio). . .. ... aCoEt I II 111 Reagents i LiSnBu3; ii CH,=CHCOEt; iii MeCHO; iv Pb(OAc) Scheme 72 Reagents i CrCI, Ni(acac) Scheme 73 New natural large-ring compounds reported during the year include two cytotoxic macrolide~'~~ and the first 20-membered-ring lac tone^,'^^ all isolated from marine sponges. In a Wittig reaction the phsophorane-ketene (140) yielded'35 20% of the 'dimer' (141) which was converted into (-)-pyrenophorin (142) (Scheme 74). 131 G.H. Posner K. S. Webb E. Asirvatham S. Jew and A. Degl'Innocenti J. Am. Chem. SOC.,1988,110 4754. 132 S. L. Schreiber and H. V. Meyers J. Am. Chem. Soc. 1988 110 5198. 133 D. G. Corley R. Herb R. E. Moore P. J. Scheuer and V. J. Paul J. Org. Chem. 1988 53 3644. 134 E. Quiiioi Y. Kakou and P. Crews J. Org. Chem. 1988 53 3642. I35 M. Yoshida N. Harada H. Nakamura and K. Kanematsu Tetrahedron Lett. 1988 29 6129. Heterocyclic Compounds 221 H ii iii 0 0 H (142) Reagents i DIBAH MeCu; ii m-CIC,H4C03H; iii Cr03 Scheme 74 Yield 36% Reagents i (BU~S~)~S, CsF 18-crown-6 MeCN Scheme 75 R' R' R2 R3 Reagents i R2C( N2)COR3 Rh(OAc) Scheme 76 Two interesting syntheses of sulphur-containing macrocycles are summarized in Schemes 75i36and 76.13' A reviewi3* of azadienes covers the synthesis of eight- (as well as five- and six-) membered rings.Rings with eight nine and ten members including nitrogen and two oxygens have been prepared (Scheme 77).'39 Meisenheimer rearrangement of N-oxides (143;n = 2) of 5-aryl-4-methyl-2,3,4,5-tetrahydro-l,4-benzoxazepines has given the 2H,6H-1,5,4-benzodioxazocine(144;n = 2).14* A nine-membered ring I36 R. Gleiter and S. Rittinger Tetrahedron Lett. 1988 29 4529. 137 0. Meth-Cohn and E. Vuorinen J. Chem. Soc. Chem. Commun. 1988 138. 138 J. Barluenga Bull. SOC.Chim. Belg. 1988 97 545. I39 K. E. Krakowiak B. Kotelko J. S. Bradshaw and N. K. Dalley X Heterocycl. Chem. 1988 25 1327. 140 J. B. Bremner E. J. Browne L.M. Engelhardt I. W. K. Gunawardana and A. H. White Aust. J. Chem. 1988 41 293. 222 D. E. Ames (CH,),,OH /(CHz),?,-o\ I -RIN R d CHR' \ \ / (C Hz) n0H (CH2)n-O m,n = 2or3 Reagents i R'CHO or BrCH,Br Scheme 77 system (n = 3) was prepared similarly. Another nine-membered ring structure pyrrolo[ 1,2-~][3,1,6]benzothiadiazanonine,has also been synthesized (Scheme 78).I4l In the very active host-guest chemistry and porphyrin areas it is only possible to draw attention to a few papers. Crown thioethers have been reviewed'42 and crown ether structures incorporating ~yran'~~ and indazole'44 units have been reported. 0 Reagents i Cu(CNS),; ii NaBH Scheme 78 The synthesis chemical reactivity and electrochemical behaviour of porphyrins with metal-carbon bonds have been reviewed.145 Tripyrrin macrocycles related to proposed intermediates in porphyrin biosynthesis have been ~ynthesized.'~~ Caesium fluoroxysulphate has been used14' to fluorinate the -CH= ring-linking groups of octaethylporphyrin.The main product is the 5-fluoro-derivative (-CF= link) but di- tri- and tetrafluoro-compounds are also formed. Much attention has 141 G. W. H. Cheeseman and G. Varvonnis J. Heferocycl. Chem. 1988 25 431. 142 S. R. Cooper Acc. Chem. Res. 1988 21 141. I43 P. J. Dijkstra H. J. den Hertog J. van Eerden S. Harkema and D. N. Reinhoudt J. Org. Chem. 1988 53,374. 144 J. C. Cuevas J. de Mendoza and P. Prados J. Org. Chem. 1988 53 2055. 145 R. Guilard and K. M. Kadish Chem.Rev. 1988 88 1121. 146 W. M. Stark M. G. Baker F. J. Leeper P. R. Raithby and A. R. Battersby J. Chem. SOC. Perkin Trans. I 1988 1187. 147 L. E. Andrews R. Bonnett A. N. Kozyrev and E. H. Appelman J. Chem. SOC. Perkin Trans. I 1988 1735. Heterocyclic Compounds 223 been given to bridged porphyrin systems both to study distortion of the macr~cycle'~~ and to influence the properties by forming cavities in structures with or two'50 porphyrin units. I 48 T. P. Wijesekera J. B. Paine and D. Dolphin J. Org. Chem. 1988 53 1345. 149 T. P. Wijesekera S. David J. B. Paine B. R. James and D. Dolphin Can. J. Chem. 1988 66 2063. 150 (a) C. A. Hunter M. N. Meah and J. K. M. Sanders J. Chem. Soc. Chem. Commun. 1988 692; (b) ibid.p. 694.