O O O O O Ph OCH3 O Ph OCH3 O O O (i) 76% ee = 91% 2 1 Scheme 1 Reagents (i) Oxone' 1 K 2 CO 3 MeCN Na 2 B 4 O 7 ·10H 2 O (0.05 M) 5 Heterocyclic chemistry By ANDREW MARSH Department of Chemistry University of Warwick Coventry UK CV4 7AL This review covers the chemistry of heterocyclic compounds published during 1997. The subject is divided according to ring size and further grouped according to reaction type or nature of the heterocycle to guide the reader through the diverse material covered. 1 Three-membered rings Asymmetric synthesis is an important theme within this and other areas of heterocyclic chemistry. Dioxiranes continue to be investigated for the stereocontrolled epoxidation of alkenes. Ketone 1 was used to epoxidise 2 with good enantioselectivity in a catalytic process although pH was found to be a key factor in determining the e¶ciency of conversion (Scheme 1).1 That dioxiranes are the active agents in ketonecatalysed epoxidations with Oxone' has been confirmed by careful 18O-labelling studies.2 A novel method for the generation of this useful class of reagents uses arenesulfonylimidazoles and hydrogen peroxide in the presence of the ketone usually acetone (Scheme 2).3 Yields of epoxidations carried out using this in situ generation of dimethyldioxirane were good and this may be a useful method when more valuable ketones are used.It has been found that poly-(L)-leucine will epoxidise enones with good enantioselectivity in the presence of urea and hydrogen peroxide (Scheme 3).4,5 Another important class of enantioselective oxidants are sulfonyloxaziridines and an improved method for their synthesis using hydrogen peroxide has been reported.6 155 O O O (i) Scheme 2 Reagents (i) ArSO 2 imidazole H 2 O 2 NaOH Ph Ph O O Ph H H Ph O (i) 85% er > 97:3 Scheme 3 Reagents (i) poly-(L)-leucine urea H 2 O 2 DBU (1.2 equivs.) THF r.t.3 h R O R O H H (i) 60–95% Scheme 4 Reagents (i) Et 2 Zn (2 equivs.) ICH 2 Cl (2 equivs.) tetrahydrothiophene (3 equivs.) Ph CH3 Mn O Ph CH3 X Ph CH3 O H H Mn O X Mn O Ph CH3 Path A Path B + reductive elimination collapse Path A Path B Path B Scheme 5 A novel application of Simmons–Smith reagents is the synthesis of terminal epoxides. 7,8 This process relies upon the generation of a sulfur ylide from tetrahydrothiophene which then reacts with an aliphatic or aromatic aldehyde to give epoxides (Scheme 4).The mechanism of the Jacobsen–Katsuki epoxidation has attracted some controversy9 and whilst there are a number of possible pathways by which it may proceed the simplest (Path A; Scheme 5) now appears to be favoured.10 Direct proof of the postulated manganese(V) oxo complex has also been o§ered.11 Aziridine precursors to 3 are now available in enantiomerically pure form by a number of routes. A problem with their application in organic synthesis has been the removal of the group used to activate their ring opening by nucleophiles. The use of nitroarenesulfonyl (nosyl) aziridines 3 alleviates this problem; cleavage was e§ected with thiophenol in good yield (Scheme 6).12 Some novel heterospirocyclic 3-amino-2H-azirenes 4 have been used as synthons for heterocyclic a-amino acids and incorporated into model tripeptides (Scheme 7).13 156 A.Marsh N R O2S NO2 R Nu HN NO2 R Nu H2N (45–99%) (i) (46–99%) (ii) R = Me R = Ph 3 Scheme 6 Reagents (i) NuH; (ii) PhSH K 2 CO 3 MeCN X O N Ph X N N Ph X NH S N Ph O Ph (i) (ii) (iii) (iv) 4 Scheme 7 Reagents (i) LDA THF 0 °C; (ii) DPPCl THF 0 °C; (iii) NaN 3 THF r.t. 3 days; (iv) PhCOSH CH 2 Cl 2 S Ar Ar CO2Me MeO2C O Ar Ar Ar Ar S CO2Me CO2Me H NHPh Ar Ar S CO2Me NHPh H CO2Me + + + (i) 5 6 Scheme 8 Reagents (i) phenyl azide 80 °C Diastereomeric thiiranes 5 and 6 were produced in the three-component reaction of a thioketone dimethyl fumarate and phenyl azide (Scheme 8).14 2 Four-membered rings Multi-component couplings such as the Ugi reaction used to generate b-lactams 7 continue to be investigated since they potentially allow considerable diversity to be introduced rapidly into a molecular framework (Scheme 9).15 A polymer-supported b-lactam 8 has been reported as an intermediate in the synthesis of 4-amino-3,4- dihydroquinolin-2(1H)-ones (Scheme 10).16 In the continued study of cyclisations onto the anomeric centre of glycosidic rings bicyclic oxetanes have been obtained through the closure of silyl enol ethers such as 9 in the presence of diethylaluminium chloride (Scheme 11).17 A four-membered ring which underwent an unusual base-induced reaction was thiazetidine 10.Treatment with sodium hydride gave the ring expanded 11 which could be trapped with dimethyl sulfate leading to 12 or allowed to react further to give 13 (Scheme 12).18 157 Heterocyclic chemistry Ph CHO Ph N CONH c-C6H11 R O Cl Ph N R O CONH c-C6H11 (i) (ii) 7 Scheme 9 Reagents (i) ClCH 2 CO 2 H c-C 6 H 11 NC RNH 2 ; (ii) KOH MeOH NH O R1 N O2N R2 NH O R1 N OR3 O NO2 R2 NH O R2 HN R3O R1 O (i) (ii) 8 Scheme 10 Reagents (i) R3OCH 2 COCl triethylamine,CH 2 Cl 2 ; (ii) SnCl 2 DMF r.t.O SO2 Ph O TIPSO O O But OTBDMS O TIPSO O O O H H CO2But O TIPSO O O O H H CO2But 4 (i) 1 9 Scheme 11 TIPS\triisopropysilyl. Reagents (i) Et 2 AlCl r.t. An even more exotic four-membered heterocycle was produced in excellent yield when phosphorous substituted 2H-azirine 14 was exposed to light (Scheme 13). The azirine had been made by the unprecedented cycloaddition reaction of a carbene to a nitrile.19 3 Five-membered rings The use of tandem palladium-catalysed cross-couplings and base-mediated cyclisations has been extended to the synthesis of a number of classes of heterocycles.In particular ring closures leading to indoles have been reported by several authors. The cyclisation of oxygen-substituted aromatic o-tert-butoxycarbonylaminoalkynes 15 158 A. Marsh S NH O O O S N O O O R N S O O O NH S O O O N S O O O R CH3 CH3 R R N S O O O R R HN O H (i) (ii) (iii) (43–91%) (iv) 11 10 12 13 Scheme 12 Reagents (i) NaH RCH 2 Br; (ii) NaH DMF 0 °C; (iii) MeOSO 2 OMe [20 °C; (iv) 0 °C P SiMe3 R R N P SiMe3 R R Ph P N R R SiMe3 Ph (i) R = ( c-C6H11)2N 98% 85% (ii) 14 Scheme 13 Reagents (i) PhCN 25 °C; (ii) hm NHBoc RO TMS NH RO 15 (i) 70–79% Scheme 14 Reagents (i) ButOK ButOH took place e¶ciently in the presence of potassium tert-butoxide (Scheme 14).20 This augments previous work which had demonstrated a concise synthesis of indole derivatives using similar chemistry.Tetramethylguanidine was the base of choice to e§ect closure of amide 16 on solid phase resin (Scheme 15),21 but when a more potent electron withdrawing group such as trifluoroacetamide is used the cyclisation becomes possible in the presence of potassium carbonate in dimethylformamide.22 Sodium hydride was used for the cyclisation of a related series of trifluoroacetamides on solid phase resin.23 An alternative disconnection was used to make indoles 17 on Rink amideAMresin this time through closure of iodoaromatic 18 using palladium(II) (Scheme 16).24,25 This strategy also featured in the asymmetric Heck-type cyclisation of iodide 19 or triflate 20 in the presence of an (R)-BINAP palladium(0) catalyst to give 21 with impressive 159 Heterocyclic chemistry NH TMS I NH O CH3 O CH3 N O CH3 (i) in situ 16 Scheme 15 Reagents (i) Pd(PPh 3 ) 2 Cl 2 CuI dioxane tetramethylguanidine I X O HN X CONH2 18 X = O NH (i) (ii) 17 Scheme 16 Reagents (i) PdII; (ii) CF 3 COOH N O RO X CH3 N CH3 OR O 19 X = I 20 X = OTf (i) 45–76% ee = 43–95% 21 Scheme 17 Reagents (i) Pd0-(R)-BINAP (10 mol%) 1,2,2,6,6-pentamethylpiperidine N,N-dimethylacetamide 100 °C selectivity (Scheme 17).26 The enhanced enantioselectivity observed by the addition of halide salts gave some additional mechanistic insight.Two groups have independently developed the cyclisation of propargyl tosyl carbamates 22 (propargyl\prop-2-ynyl) (Scheme 18) using palladium(0)27 or palladium(II) catalysis in the presence of potassium tert-butoxide.28 Similar yields were obtained in either case.The closure of a carboxylic acid function onto an alkyne gave butenolide products 23 (Scheme 19) in the presence of either tetrakis(triphenylphosphine)palladium or even silver nitrate in methanol which led to the synthesis of rubrolides A C,Dand E.29 The competing formation of a six-membered ring was found to be catalyst dependent. A one-pot procedure for the preparation of functionalised pyrazoles has been reported using a palladium dichloride-mediated ring closure (Scheme 20).30 The investigation of alternatives to organotin-promoted radical cyclisations continues to be an active area of research. An example of a radical cyclisation leading to benzofuran and indole products has been described using trialkylmanganate initiation 160 A.Marsh NHTs O H R1 R2 NTs O O R1 R2 O Ar ArI (i) 22 Scheme 18 Reagents (i) either Pd(PPh 3 ) 4 K 2 CO 3 DMF 60 °C (50–80%) or Pd(OAc) 2 But OK CH 3 CN 25 °C (46–76%) COOH Ph Ph O O Ph O O Ph Ph Ph + catalyst solvent PdCl2(PhCN)2 CH3CN 50% 44% Pd(PPh3)4 CH3CN 83% 6% AgNO3 CH3OH 95% 5% 23 Scheme 19 N NH2 Ts NH N Ar ArX + (i) (ii) (iii) 28–69% Scheme 20 Reagents (i) Pd(OAc) 2 (PPh 3 ) 2 Et2 NH THF r.t.; (ii) PdCl 2 MeCN 90 °C; (iii) ButOK DMF r.t. O O I (i) 88% Scheme 21 Reagents (i) Bun3 MnLi or Bun3 MnMgBr (Scheme 21).31 A catalytic variant was also reported through the addition of manganese( II) chloride to a Grignard reagent in the presence of oxygen leading to 70% yield vs. 88% for the stoichiometric reaction. A review covering the synthesis of heterocycles by radical cyclisation has been published.32 The use of dipolar cycloadditions in the controlled synthesis of five-membered heterocycles has produced a number of particularly striking results.An azomethine ylide is implicated33 in the unusual process shown in Scheme 22. Heating b-lactam- 161 Heterocyclic chemistry N CO2R H O N CO2R H O R R N O CO2R O (i) 32% + via 24 25 Scheme 22 Reagents (i) MeCN heat O N O CH3 Bn O SiMe3 O N Bn CH3 SiMe3 N Bn O SiMe3 O OH O (i) (ii) 39–67% 26 27 Scheme 23 Reagents (i) Ac 2 O 70 °C 1 h; (ii) 125 °C 3 h N CH3 O O NH Ph HO O N NMe O O O Ph R2Si O N O O O Ph NMe O R2Si (ii) 30 (i) 29 28 Scheme 24 Reagents (i) hl quartz MeCN; (ii) HF MeCN 0 °C based azolidinone 24 in the presence of an alkene gave compound 25; other 1,3- dipolarophiles were also used.34,35 Azomethine ylides e.g.26 have been cyclised onto a tethered alkene which after elimination of carbon dioxide gave bicyclic pyrroles 27 in moderate yields (Scheme 23).36A silicon-tethered variant allows the temporary connection of the 1,3-dipole and dipolarophile.37 Hence in this work a mu� nchnone was generated from the corresponding aziridine 28 which led to the formation of 29 (Scheme 24). Removal of the tether allowed cyclisation to the pyrrolidine 30. The diasterofacial selectivity of the process was controlled by the length of the tether with shorter tethers leading to the desired endo-re adduct. Intramolecular nitrone cycloadditions have been used to generate heterocycles e.g. 31.38 The dipolarophile was generated by extrusion of sulfur dioxide from sulfolene (2,5-dihydrothiophene 1,1-dioxide) 32 (Scheme 25).The type of complex molecule which can be rapidly constructed using an intramolecular nitrone cycloaddition is illustrated by 33 (Scheme 26). This isoxazolidine was formed cleanly upon heating epoxide 34 in toluene.39 An intramolecular dipolar cycloaddition under mild conditions has been used to access pyrrolidine N-oxides in a diastereoselective fashion (Scheme 27).40 162 A. Marsh S O2 S(O) xPh O H S(O) xPh N+ R O– N O H H S(O) xPh R n = 1 2 x = 0 2 (i) (ii) 60–73% 31 32 ( ) n ( ) n Scheme 25 Reagents (i) RNHOH·HCl (R\Me R\Bn) MeONa r.t.; (ii) PhMe 95 °C N OH O N O– OH N O OH H (i) 90% 33 34 Scheme 26 Reagents (i) xylene 140 °C N O H Ph PhSO2 N PhSO2 Ph O– N PhSO2 Ph O– + 88 12 (i) >95% Scheme 27 Reagents (i) CHCl 3 20 °C 96 h N Ph O– CH3 N O Ph H3C X H X (i) X = CN SO2Ph CO2Et Scheme 28 Reagents (i) MeCN reflux (X\CN 100%; X\CO 2 Et 91%; X\SO 2 Ph 92%) Analogues of cocaine have been produced using pyridinium betaine-based dipolar cycloadditions.Regiochemical control in the cycloaddition was reasonable although diastereoselection was not as good. In the case where the electron withdrawing group X was a nitrile (Scheme 28) the a-isomer was isolated in 42% yield compared with 37% for the b-isomer with the other regioisomers totalling 21%.41 The regioselectiv- 163 Heterocyclic chemistry N O Me2N Me N2 O CO2Me O N O Me Me2N CO2Me N O Me2N Me MLn O CO2Me N N O Me CO2Me O Me Me O MeO2C CO2 Me CO2Me N Me Me N O Me O Me2N CO2 Me CO2Me CO2Me 35 (i) (iv) (ii) 37 38 (iii) or (iv) 36 Scheme 29 Reagents (i) Rh 2 (OAc) 4 ; (ii) PhMe reflux (65–70%); (iii) DMAD; (iv) DMAD Rh 2 (OAc) 4 O N O N2 CO2Et O O Ph H O N O CO2Et O Ph H N O O O R O N O CO2Et O Ph H N O O O R (i) R = Me 54% 20% R = Ph 56% 24% 39 + Scheme 30 Reagents (i) Rh 2 (OAc) 4 (1 mol%) dipolarophile PhH reflux ity for the addition of the corresponding enantiomerically pure vinyl sulfoxide dienophile was found to be complete and the b-isomer was isolated in 44% yield.42 Isomu� nchnones have been used in the preparation of a variety of five-membered rings.Interestingly the isolation of a stable N-acylammonium ylide 35 allowed the elucidation of its X-ray crystal structure. Reaction of isolated 35 with dimethyl acetylenedicarboxylate (DMAD) gave 36. In the presence of DMAD and dirhodium tetraacetate however the isomu� nchnone 37 is formed and reacts with the dipolarophile to give after the loss of methyl isocyanide the highly substituted oxazole 38 along with the product of the other pathway 36 (Scheme 29).These observations allowed the preparation of a stable yet dipolarophile-reactive isomu� nchnone.43 The addition of dipolarophiles to the isomu� nchnone derived from 39 gave moderate selectivity (Scheme 30).44 In the case of the [3]2] cycloaddition of the 1,3-dipoles derived from 40 the diastereofacial selectivity was found to depend upon the nature of the stereogenic centre and exo-selectivity was enhanced by the inclusion of substituents at any position of the five-membered ring betaine (Scheme 31).45 164 A. Marsh O R3 N R2 O N2 R1 O +O N R3 O O R1 R2 N B A O O R2 R3 COR1 (i) (ii) 40 Scheme 31 Reagents (i) Rh2`; dipolarophile (A–– B) heat O O H H OH (i) 70% 41 Scheme 32 Reagents (i) c-Hex 2 BH PhH cat.2,6-di-tert-butyl-4-methylphenol re- flux O Si R O Si R O R R1 O R R1 + 91–95% (i) (ii) 73–84% 75 25 dr > 42 43 Scheme 33 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) CH 2 Cl 2 r.t.; (ii) R1CHO Lewis acid CH 2 Cl 2 An intramolecular Diels–Alder approach to a number of bicyclic systems including trans-fused tetrahydrofurans 41 has been reported (Scheme 32).46 The key steps are addition of dicyclohexylborane and thermolysis in benzene followed by oxidation. The remarkable diastereofacial selectivity of this process was rationalised through the involvement of boron in the transition state. A diastereoselective route to functionalised tetrahydrofurans has been reported through the Lewis-acid promoted addition of aldehydes to conformationally controlled seven-membered allylsilanes 42.47 These compounds were produced through ring closing metathesis of dienes 43 with the now commercialised Grubbs’ catalyst (Scheme 33).Other saturated heterocycles have been produced by a variety of other carbon –heteroatom ring closures. A biomimetic haloetherification gave tetrahydrofuran 44 which was an intermediate in the synthesis of trans-(])-deacetylkumausyne (Scheme 34).48 Closure of 45 by very brief exposure to potassium tert-butoxide (Scheme 35) was found to give pyrrolidine 46 an intermediate in this enantiospecific synthesis of (])-monomorine.49 A change of plan was required in the total synthesis of the enantiomer of the furanocembrane rubifolide.50 Due to the failure of a planned enynol cyclisation a new strategy emerged based on the cyclisation of the macrocyclic allene 47 (Scheme 36).In the event this was achieved in a very respectable yield and taken further to demon- 165 Heterocyclic chemistry HO OTIPS OTHP O BrOTIPS OTHP O H H (i) then (ii) 79% 44 Scheme 34 Reagents (i) as Scheme 33; (ii) HCl MeOH PhSO2 OAc NHAc N Bz PhSO2 (i) 46 45 73% Scheme 35 Reagents (i) ButOK ButOH,\1 min • CH3 H O MOMO H3C MeO2CO O MOMO H3C (i) 89% 47 Scheme 36 Reagents (i) AgNO 3 SiO 2 strate the absolute stereochemistry of rubifolide. An unusual 1,2-silyl migration led to the stereoselective intramolecular addition of an alcohol to a vinylsilane. The thermodynamic product of this rearrangement 48 was obtained in good yield and excellent diastereoselectivity (Scheme 37).51 A succinct route to stereodefined oligotetrahydrofurans has been reported.52 Lewisacid promoted addition of a furan to 49 gave after reduction of the double bonds a 60 40 mixture of the erythro and threo isomers 50 and 51 respectively (Scheme 38).After suitable derivatisation this was repeated and an array of conformationallycontrolled tetrahydrofurans was rapidly generated. When organic chemists use Hu� nig’s base (diisopropylethylamine 52) they do so usually because they want an unreactive nitrogen base. In the presence of disulfur dichloride and 1,4-diazabicyclo[2.2.2]octane (DABCO) however the isopropyl 166 A. Marsh HO R SiMeR1R2 O R SiMeR1R2 34–93% >99:1 trans cis (i) 48 Scheme 37 Reagents (i) TiCl 4 CHCl 3 r.t. O O O C10H21 OTBDMS OAc C10H21 OTBDMS O O O C10H21 OTBDMS O (ii) 92% (i) + O OTMS 50 51 49 Scheme 38 Reagents (i) TiCl 4 (cat.); (ii) H 2 Pd/C N S N S S S S S S N S S S S S S (i) 40% (ii) 52 53 54 Scheme 39 Reagents (i) S 2 Cl 2 DABCO ClCH 2 CH 2 Cl; (ii) heat groups (only) become functionalised in a remarkable synthesis of di[1,2]dithiolopyrroles 53 (Scheme 39).53 The initial product is a di[1,2]dithiolo[1,4]thiazine 54 which was characterised by X-ray crystallography.Variation of the solvent and reaction time allowed selective replacement of the thiocarbonyl with an oxygen atom. It was noted that whatever the precise mechanism of this conversion it requires some 15 (very high yielding!) separate steps.54 Methods for the formation of heterocycles on solid supports55 are of current interest especially for the rapid production of pharmaceutical analogues.56 Substituted thiophenes 55 have been prepared from intermediate resin-bound isothiocyanates (Scheme 40).57 In an example of a resin-bound [3]2] cycloaddition reaction to an intermediate nitrile oxide the formation of isoxazoles 56 from alkynes 57 was monitored by the loss of the acetylenic C–H stretch in the infrared spectrum (Scheme 41).58 At the end of a sequence carried out on a polymer support a rearrangement analogous to an ‘aspartamide’ reaction seen in peptides takes place after cleavage from the resin.Prolonged treatment of 58 with trifluroacetic acid–water (9 1) gave succinimide 59 (Scheme 42).59 Methods for the cyclisation of peptidic substrates to generate diversity have also been reported including the reduction of amide bonds with borane then cyclisation with carbonyldiimidazole to 60 (Scheme 43)60 and the reduction of ester 61 followed by cyclisation (Scheme 44).61 167 Heterocyclic chemistry S R2 O N R1 H Z NH2 N H CN S O R2 Z R1 (iv) (v) 55 N H H R1 (i) (ii) (iii) Scheme 40 Reagents (i) CSCl 2 Pr* 2 NEt; (ii) ZCH 2 CN DBU DMF; (iii) R2CH 2 Br; (iv) DBU; (v) CF 3 COOH O O O2N OTHP O O N O R (i) PhNCO 56 57 Scheme 41 Reagents (i) PhH reflux Et 3 N (cat.) S O NH H2N O SBn O NHBn S O NH NBn O O BnS (i) 90% 58 59 Scheme 42 Reagents (i) CF 3 COOH–H 2 O 9 1 or 1% conc.HCl MeOH N O HN O NH R3 R4 O R1 R2 N N R4 X NH R1 R2 (i) (ii) (iii) X = O S 60 Scheme 43 Reagents (i) B 2 H 6 THF 65 °C; (ii) carbonyldiimidazole or thiocarbonyldiimidazole; (iii) HF anisole Ion exchange resins have proven useful as temporary supports for the formation of a variety of heterocycles and one example is the synthesis of pyrrolidine-2,4-diones 62 by Amberlyst base-mediated Dieckmann condensation (Scheme 45).62 Imidazoles e.g.63 have been made in a useful synthesis from the addition of monosubstituted amidines to 2-halo-3-alkoxyprop-2-enals and propionitriles (Scheme 46).63 Although the yields were modest there was no evidence of competing pyrimidine formation under the cyclisation conditions. An intramolecular entry to imidazoles was possible in good to excellent yield through the treatment of 64 with methyl iodide and base or oxidation under basic conditions (Scheme 47).64 This method also allows access to unusual 4,4-disubstituted imidazoles. The synthesis of benzisoxazoles 65 was achieved through dehydration of nitroaromatics 66 with trimethylsilyl chloride and triethylamine (Scheme 48).65 Following abstraction of the benzylic proton the ring closure and dehydration to form the 168 A.Marsh R NH NH OAlkyl X R1 O NH N X R R1 H X = O S 64–93% (i) (ii) 61 Scheme 44 Reagents (i) Bu*2 AlH PhMe–CH 2 Cl 2 [78 °C; (ii) H 3 O` O RO N R2 O R3 R1 N O R1 R2 HO R3 (i) (ii) 62 Scheme 45 Reagents (i) Amberlyst A-26 (OH~); (ii) H` NH R1 NHR2 N N R2 R1 X N N R2 R1 X OR Br X + X = CHO X = CN 63 8 1 2 9 Scheme 46 Reagents (i) K 2 CO 3 H 2 O CHCl 3 N N S R2 R4 R3 R1 N N R1 R2 R4 R3 (i) or (ii) or (iii) 64 Scheme 47 Reagents (i) H 2 O 2 MeOH; (ii) I 2 Et 3 N; (iii) MeI base NO2 Y R O N Y R (i) 20–71% Y = CN SO2Ar CO2R1 66 65 Scheme 48 Reagents (i) Me 3 SiCl Et 3 N DMF 169 Heterocyclic chemistry NC NC NH3•OTs R O OH N O CN NH2 R (i) 67 22–86% Scheme 49 Reagents (i) dicyclohexylcarbodiimide pyridine HN N R2 O R1 N HN NH R2 O R1 CN HN NH2 R1 (i) (ii) (iii) 35–62% 39–95% 68 Scheme 50 Reagents (i) BrCN Et 2 O; (ii) R2COCl Et 3 N; (iii) heat N N N N R N N N N R N3 CHO 78–95% (i) (ii) 27–95% 69 70 71 Scheme 51 Reagents (i) RCH 2 CN piperidine or NaOEt CH 3 CN 0 °C; (ii) RCH 2 CN piperidine or NaOEt in EtOH O MeO2C SPh O MeO2C SO2Ph (i) 85% 72 Scheme 52 Reagents (i) m-CPBA oxazole is facilitated by silylation of an oxygen atom of the nitro group.Highly functionalised 1,3-oxazoles 67 have been synthesised in a one-pot procedure from aminomalononitrile tosylate (Scheme 49).66 A sigmatropic rearrangement of 1-aryl-2-acyl-2-cyanohydrazines led to a convenient synthesis of benzimidazole derivatives 68 (Scheme 50).67 Addition of cyanocarbanions to 2-azidoarylaldehyes 69 has been found to give either 1,2,3-triazolo[1,5-a]- quinazolines 70 or tetrazolo[1,5-a]quinazolines 71 in aprotic or protic solvents respectively (Scheme 51).68 In protic solvents initial Knoevenagel condensation of the anion with the aldehyde is believed to take place followed by an intramolecular 1,3-dipolar cycloaddition.In the absence of a proton source however reaction across the azide takes place first followed by closure onto the aldehyde. 2-Alkylthiopyrroles have been prepared by metallation of allyl isothiocyanate using LDA followed by alkylation. A second equivalent of base in the form of potassium tert-butoxide was found to be necessary to promote the isomerisation to the prod- 170 A.Marsh NH Cbz Pr N Pr Cbz N Pr H (i) (ii) 52% 98% 74 73 Scheme 53 Reagents OsO 4 NaIO 4 ; (ii) H 2 Pd/C Ts O NH2 N O Ts H (i) (ii) 75 Scheme 54 Reagents (i) NaH DMF; (ii) Br(CH 2 ) 3 Br N O CHO R N O H OSiR3 N O H OSiR3 + (i) 1 76 + 1 Scheme 55 Reagents (i) Ni(cod) 2 (20 mol%) PPh 3 (40 mol%) R 3 SiH (5 equivs.) THF uct.69 A direct synthesis of tetrazoles has been found to be possible from aryl primary amides using triazidochlorosilane in acetonitrile.70 Intramolecular cyclisation of alkynone 72 was promoted by an electron-withdrawing group attached to the unsaturated bond. Thus oxidation of the sulfide to a sulfone with m-CPBA led to the formation of a furan in excellent yield (Scheme 52).69 4 Six-membered rings Many saturated six-membered nitrogen heterocycles have important biological activity which is one reason why methods for their synthesis are pursued with such interest.The alkaloid coniine 74 has been synthesised in enantiomerically pure form by the cyclisation of protected amine 73 onto the aldehyde derived from oxidative cleavage of the alkene (Scheme 53).71 A one-pot synthesis of another class of alkaloid namely indolizidine derivatives has been developed from vinyl sulfone 75 (Scheme4).72 A formal total synthesis of the indolizidine alkaloid ([)-elaeokanine C was accomplished using the novel nickel-promoted cyclisation of aldehyde 76 with a 1,3-diene (Scheme 55).73 The ring closure of a urethane derivative 77 was found to occur in the presence of palladium(II) to give a single diastereoisomer 78 in good yield.This was then transformed into (])-prospinine (Scheme 56).74 Two-step four-component 171 Heterocyclic chemistry HN O MOMO O H OCOPh N O H OCOPh H O (i) 72% 77 78 Scheme 56 Reagents (i) PdCl 2 (CH 3 CN) 2 (20 mol%) THF r.t. OTMS EtS R1 R2 O SEt N R3 O R4 R1 R2 O SEt + + (i) (ii) SEt R3 O R1 R2 NHR4 O SEt + R3 N R4 79 Scheme 57 Reagents (i) SbCl 5 –Sn(OTf) 2 CH 2 Cl 2 ,[78 °C; (ii) Sc(OTf) 3 ,[78 to 0 °C O BnO CH3 H H OH OH O H H OH O BnO H CH3 H (i) 42–52% 80 Scheme 58 Reagents (i) Pd(OAc) 2 HOAc CH 2 Cl 2 couplings led to the formation of d-lactams 79 in good yield. The first process is a Lewis-acid catalysed Michael addition followed by an imino–aldol reaction catalysed by a second Lewis acid (Scheme 57).75 Following the failure of a planned tungsten-mediated ring closure the enantioselective formation of bicyclic oxygen heterocycle 80 a substructure of the marine poison brevetoxin was carried out using palladium(II) catalysis in moderate yield (Scheme 58).76Aring-closing metathesis reaction has also been used to access this bicyclic motif (Scheme 59) as well as larger rings from the same class of natural products.77,78 The Grubbs ruthenium catalyst was found not to be e§ective in this instance.Hydroboration then allows the process to be repeated. The isomerisation of the double bond produced from the ring closing metathesis reaction of 81 will similarly also allow an iterative process to be carried out (Scheme 60).79 The compatibility of the Grubbs and Schrock metathesis catalysts with sulfur functionality has been demonstrated through the formation of cyclic disulfides.80 172 A.Marsh O O R2 R1 O O H H R1 R2 O O H H R1 OH H R2 (i) + diastereomer (ii) (iii) 41–67% Scheme 59 Reagents (i) Schrock [Mo] cat. C 5 H 12 25 °C; (ii) RBH 2 ; (iii) NaOH H 2 O 2 O O BnO OMe BnO O O H H OMe OBn OBn (i) 81 93% Scheme 60 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) PhMe r.t. O R CO2 Me O OAc R CO2 Me Me3Si O OAc R CO2 Me SiMe3 O R CO2 Me (i) dr > 95:5 (i) dr > 89:11 82 83 Scheme 61 Reagents (i) BF 3 ·OEt 2 or SnCl 4 The geometry of the vinylsilane moiety was found to strongly influence the boron trifluoride-induced cyclisation of 82 or 83 to cis- or trans-dihydropyrans respectively (Scheme 61).81 Cycloaddition reactions naturally play a central role in the synthesis of many classes of heterocycles. Trifluoromethanesulfonic acid was found to be an e¶cient catalyst in the hetero Diels–Alder reaction of aldehydes (Scheme 62).82 Enantioselective catalysis was observed using a range of oxazolidine ligands (e.g.84 85) in the copper(II)- mediated hetero Diels–Alder reaction of Danishefsky’s diene 86 with aldehyde 87 (Scheme 63).83 The product stereochemistry was 2S from 84 (85% ee) and 2R from 85 (87% ee). Ytterbium triflate was used to promote the cycloaddition of N-acryloyl dienophile 88 with 89 with excellent diastereoselectivity (Scheme 64).84–86 The generation of ortho-thioquinones has allowed a regiospecific synthesis of 1,4-benzoxathiines through an inverse electron-demand Diels–Alder reaction (Scheme 65).87 173 Heterocyclic chemistry O R O R + (i) 5–85% Scheme 62 Reagents (i) 80% HOTf (1 mol%) PhMe 20 °C TMSO OCH3 O S S O S S O H N N O O N N O O (i) 5–85% + 84 85 86 87 Scheme 63 Reagents (i) Cu2` ligand (10 mol%) S Ph Ph O O N O Ph S Ph Ph O O N O Ph + (i) > 99% de 88 89 Scheme 64 Reagents (i) Yb(OTf) 3 (20 mol%) OH S NPhthalimido Y S O Y + Y = OR SR OSiR3 NCOR Ar (i) CH3O CH3 O 58% Scheme 65 Reagents (i) pyridine CHCl 3 60 °C 50 h 3-Methoxy-6-methylthio-1,2,4,5-tetrazine has been prepared and found to undergo a regioselective [4]2] cycloaddition based on the electron-rich character of the dienophile (Scheme 66).88 2-Aminopyridines and 2-pyridones have been accessed through the reaction of benzotriazole-substituted nitriles 90 with unsaturated ketones (Scheme 67).89 Intermolecular Diels–Alder reactions of tetrazines have been carried out with silyl- 174 A.Marsh Ph OTMS N N N N OCH3 SCH3 N N OCH3 SCH3 + (i) 90% Scheme 66 Reagents (i) dioxane 100 °C 20 h O Ph R N Bt N R NR1 R2 Ph HN R O Ph + (i) (ii) 90 Scheme 67 Reagents (i) R1R2NH EtOH; (ii) NaOH EtOH N N N N R1 R2 N N R1 R2 N N Ar (i) + (ii) 51–93% R1 = SnBu3 R2 = H 76% 91 92 Scheme 68 Reagents (i) toluene r.t.12 h; (ii) ArX Pd(PPh 3 ) 4 germyl- and stannyl-substituted alkynes leading to the synthesis of synthetically useful metallated 1,2-diazines 91. These were readily cross-coupled under palladium(0) catalysis to give aryl substituted diazines 92 (Scheme 68).90 The synthesis of a pyridine ring through the intramolecular addition of an oxazole to a dienophile was found to proceed in good yield leading to the first chiral synthesis of the alkaloid ([)-normalindine (Scheme 69).91 The intramolecular Diels–Alder reaction of furan 93 was found to take place upon silica gel chromatography–an example of exceptionally mild Lewis acid catalysis in such a process (Scheme 70).92 The oxidation of nitrogen heterocycles is a well established process but two interesting examples have appeared in the literature.Firstly a highly stereoselective formation of pipecolic acid N-oxide was possible by simple oxidation of amine 94 with m-CPBA (Scheme 71).93 Secondly the sterically congested monochloro-1,10-phenanthroline di-N-oxide 95 long believed to be inaccessible has been prepared (Scheme 72) and found to be stable under neutral or basic conditions.94 The production of abasic sites in nucleosides is one method for inducing DNA cleavage and the self-cleaving nucleoside 96 seems to be able to do just that (Scheme 73).95 The supramolecular structure of the complex of the unusual boron heterocycle 97 with cytosine has been investigated using 1H NMR titration in acetonitrile and indicated Watson–Crick-like base pairing as the most likely mode of association.96 The conformation adopted by a heterocyclic molecule has potential for the induction of higher order structure in polymers for example and 98 has been found to be helical in solution as well as the solid state.97 175 Heterocyclic chemistry NH N Me O N CO2Et NH N N EtO2C Me NH N N EtO2C Me O (i) (ii) 40% (18%) Scheme 69 Reagents (i) heat; (ii) HOAc heat O HO O S O O OCH3 S O OCH3 OHC O O S OCH3 O (i) 31% (ii) 60–80% 93 Scheme 70 Reagents (i) LiBr PhMe reflux 10 min; (ii) SiO 2 N Ph CO2R N CO2 R Ph O– N CO2 R Ph O– (i) 53% + 94 R = H R = Me R = Bu t 100 8.5 25 1 1 1 Scheme 71 Reagents (i) m-CPBA CH 2 Cl 2 ,[78 °C N N Cl N N Cl Cl N N Cl Cl –O –O N N Cl –O (i) (ii) –O (iii) 95 Scheme 72 Reagents (i) NaOCl; (ii) m-CPBA,[25 °C; (iii) Pr*ONa 0 °C 176 A.Marsh N N N N N H O O P O O O O DNA N N N+ N N H O O P O O O O DNA I N N N N N H I O O DNA O OH + (ii) (i) DNA DNA DNA Scheme 73 Reagents (i) I 2 ; (ii) H 2 O N NH NH2 H3C S N OH H3C N N NH2 H3C S N O H3C H N N H3C N NH S CH3 OH Cl– Cl– (i) (ii) 100 99 101 Scheme 74 Reagents (i) NaBH(OCH 3 ) 3 [12 °C MeOH–H 2 O; (ii) Na 2 CO 3 H 2 O heat N N B O H H O N N ribose N H H 97 N N N N N N N N N 98 177 Heterocyclic chemistry N N Br OCH3 N N R3Sn OCH3 (i) 85–91% 102 Scheme 75 Reagents (i) R 3 Sn–SnR 3 Pd(PPh 3 ) 4 DME 15 h 80 °C N Cl Cl NH NH2 PhSO2 CO2Me CO2Me H N Cl Cl N NH O CO2Me PhSO2 N Cl Cl N N O Et (i) (ii) 53–65% steps + 103 104 105 Scheme 76 Reagents (i) HCl DMF; (ii) NaHCO 3 EtO O HN OEt N N NH2 NH2 N N HN N O NH2 + (i) 80% 106 107 Scheme 77 Reagents (i) EtOH reflux 2 h The reduction of vitamin B 1 thiamine 99 with borohydride reducing agents has apparently been the subject of long-standing controversy.The publication of the X-ray crystal structures of the initial reduction product 100 and the product of rearrangement with base and heat 101 corrects previous mis-assignments (Scheme 74).98 The generation of organotin intermediates often involves a two-step lithiation procedure but direct stannylation of bromopyridines such as 102 has been found to be possible with the aid of palladium(0) catalysis (Scheme 75).99 The pyrimidinone herbicide 103 resisted attempts at its synthesis by the usual methods and required the development of a new route involving the addition of amidine 104 to the extremely active Michael acceptor 105 (Scheme 76).100 178 A.Marsh O O NEt2 G O G O (i) 60–93% 109 108 Scheme 78 Reagents (i) LDA (2.4 –3.3 equivs.) THF 0 °C N OH S S N Cl O N CN S N CN + (i) or (ii) 110 111 112 Scheme 79 Reagents (i) NaH THF reflux 111 112 55 5 (44%); (ii) PPh 3 (2 equivs.) CH 2 Cl 2 reflux 111 112 0 100 (58%) N S N R O CN N N S O H R N N S O O O F3C R CN O CF3 (i) 35% 113 via Scheme 80 Reagents (i) (CF 3 CO) 2 O CH 2 Cl 2 0 °C N O O SO2Ph N2 N SO2Ph O Me HO SO2Ph + (i) 68% 114 Scheme 81 Reagents (i) Rh 2 (OAc) 4 dipolarophile Pteridinones such as 106 have been conveniently prepared with complete regioselectivity from diamines through the addition of ethoxycarbonylformimidate 107 (Scheme 77).101 The lithiation of 108 gives a regiospecific route to xanthen-9-ones 109 (Scheme 78).102 Chemoselective cyclisation of 110 was observed to give either 111 or 112 depending on whether sodium hydride or triphenylphosphine was used for the cyclisation (Scheme 79).103 An unusual ring-enlargement reaction of 113 with trifluoroacetic anhydride has been found to give rise to novel 5,6-dihydro-2H-1,2,4-thiadiazin-3(4H)-ones (Scheme 80).104 Rhodium(II) carbenoid chemistry has found new application in the synthesis of 2-pyridones such as 114 via an isomu� nchnone intermediate (Scheme 81).105 A range of pyrimidines including the amino acid L-lathyrine has been prepared by the addition of amidines to acetylenic ketones 115 (Scheme 82).106 A similar reaction has also been reported on a polymeric support (Scheme 83).107 179 Heterocyclic chemistry N N X R CO2 H NH2 O R CO2But NHBoc H2N NH2 X n n + (i) (ii) (iii) 115 28–95% X– Scheme 82 Reagents (i) EtOAc or MeCN Na 2 CO 3 H 2 O (cat.) reflux; (ii) CF 3 COOH anisole; (iii) Dowex 50X8-100 ion-exchange resin S NH2 NH2 O R COOBut S N N COOH R Cl– + (i) (ii) Scheme 83 Reagents (i) Pr*2 NEt DMF 24 h r.t.; (ii) CF 3 COOH (50%) CH 2 Cl 2 r.t.15 h O X X HO RO RO RO RO X = S NBoc (i) X = S 91% ee = 89% 116 117 Scheme 84 Reagents (i) chiral lithium amide base PhH 5 °C 1 h NH R N R O R2 NH O R2 R (i) (ii) 73–85% 2 steps 118 Scheme 85 Reagents (i) (R2CO) 2 O Et 3 N DMAP CH 2 Cl 2 ; (ii) LiHMDS THF [78 °C to r.t.5 Seven-membered rings Seven-membered rings are less common in heterocyclic chemistry but nonetheless a number of novel approaches to their synthesis have been reported. When meso-bicyclic heterocycles such as 116 are treated with a chiral base the result is the enantioselective synthesis of azepines or thiepines 117 (Scheme 84).108 Exposure of aziridines 118 to strong base at low temperature results in a stereoselective aza-[3,3]-Claisen rearrangement giving seven-membered lactams in good yield (Scheme 85).109 Another route to this class of heterocycles is by the ring expansion of ketone 119 via an oxaziridine intermediate (Scheme 86).110 The intramolecular Diels–Alder reaction of oxazoline 120 generated 121 an intermediate in this synthesis of (^)-stemoamide (Scheme 87).111 180 A.Marsh O BocNH N O CO2Me R BocNH H2N CO2 Me R (i) (ii) (iii) + 119 Scheme 86 Reagents (i) Bu 2 SnCl 2 (20 mol%) NaHCO 3 (2 equivs.) 5Å molecular sieves; (ii) m-CPBA; (iii) hl N Me H O N MeO Me O N O Me O O H H (i) (ii) 53% 120 121 Scheme 87 Reagents (i) 182 °C (ii) H 2 O Si O R O Si R n m (i) n m >90% 122 Scheme 88 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) O O O O O O O O n (i) mixture of geometric isomers n Scheme 89 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) (5 mol%) Li`/Na`/K` ClO 4 ~ (5 equivs.) 6 Larger rings Ring closing metathesis reactions have dominated the new methods for the synthesis of larger rings. Treatment of acyclic silicon-tethered dienes 122 where n\0–2 and m\0–4 takes place in excellent yield with the ruthenium-based catalyst (Scheme 88).112 A template e§ect was observed in the synthesis of unsaturated crown ether analogues in the presence of monovalent cations of di§erent ionic radii (Scheme 89).113 The mild conditions of this reaction are demonstrated by the closure of 123 to give medium ring annulated b-lactams (Scheme 90).114 Very large [2]catenanes were the 181 Heterocyclic chemistry N O X N X O n n (i) 123 X = CH2 n = 0 81% Scheme 90 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) (5 mol%) CH 2 Cl 2 N N O O O O O O N N N N Cu2+ (i) (ii) 124 Scheme 91 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) (5 mol%); (ii) CN~ N N N N H H H H N N N N H H O R O R (i) 40–98% Scheme 92 Reagents (i) RCOCl pH\2–3 N N N N O O O O Ph Ph Ph Ph Eu3+ 125 182 A.Marsh result of the copper(II) templated ring-closing metathesis reaction of 124 using the ruthenium catalyst (Scheme 91).115 The pH-controlled selective protection of polyaza macrocycles has been achieved thanks to the predictable protonation behaviour of the di§erent amine nitrogens in the ring (Scheme 92).116 Finally the complexation properties of large heterocycles are often even more exciting than their synthesis and the phenomenon of chiral luminescence from the rigid europium(III) complex 125 upon irradiation has been demonstrated.117 References 1 Z.X. 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