Chapter 21 RETROSYNTHESIS — DISCONNECTION APPROACH Muhammad Akash : and Matloob Ahmad De] it of Ct uma partment of Chemistry, Government College University, Faisalabad. gl INTRODUCTION Disconnection approach or retrosynthesis is the process of breaking down a sarget molecule into readily available starting material by means of imaginary ing of bonds (disconnections) and by the conversion of one functional group into er by efficient chemical reactions (FGI). The ability to synthesize a particular compound from commercially available starting materials is fundamental to nearly al aspects of organic chemistry. To synthesize a target molecule using convenient snd efficient procedure, following points should need to be taken in consideration: 1, The syhthetic design must lead to the construction of required carbon skeleton with all substituents and functional groups in the correct positions (region-chemistry) and with requisite 3-D orientation. 2, Ideally the shortest synthetic route to the product is required. Like a ten step synthesis with 80% yield give only a 10.7% overall yield of the final product. 3. _ Each stage of synthesis should ideally give only desired product. Technical Terms for Disconnection Approach Target molecule (TM): The molecule to be synthesized. Retrosynthetic analysis: The process of breaking down a target molecule in available starting material by FGI and disconnections. FGI (functional group interconversion): The process of converting one functional ‘soup in to another by substitution, addition, elimination, oxidation or reduction and the reverse operation used in analysis. Disconnection: The reverse operation to a reaction. The imagined cleavage of a bond to break the molecule into possible starting materials. >: Symbol for disconnection and FGI. Smmthon; An idealized fragment usually a cation or anion, resulting from a ‘sconnection. May or may not be an intermediate in the corresponding reaction. oct Compound used in practice for a synthon. For example, Mel is a reagent for n Met etc, 215> ganic Chemisty Vole © 216 Advanced 0 | 3 NING : | 91.2: STRATEGY AND pe 4 planning should be kept in mind while py Following strategies o” ne, synthesis: spilities. 1, Consider a'wide range of pose) " i es thesis in © 2, Use convergent YM! LINEAR CONVERGENT . Dif SS “ee x, c on . wo Fe +F re RQP Ae | “fp +0 pe +e | pe. 08 uF 1 A+B ap MF ! J c+D E+F 3 step synthesis A+B Sstep synthesis Figure, 21.1 Schematic representation of convergent and linear synthetic pathwar 1. The aim should be for greatest simplification (use readily available stariss materials). 2, Use any inherent symmetry in the target molecule. 3. Induce functional groups when and where required. Retrosynthesis: Oy 9H ° 9313 RETROSYNTHETIC ANALYsig Following six differen t diphenylpentan-1-ol. = OF 1,5-DIPHENYLPENTAN-1-OL Se available for the retrosynthesis of 1,5: Route 1: ‘petrosynthesis: OH Pre, wnnom 9 sr col en : prot on i ll ' : i Ph a : es pk ‘i Big" Synthesis: 3 OMgBr Ho Ph BAG Brg py AAA pn a aaa ert Pn Route 2: Retrosynthesis: OH % n Sinthons Pht — HOS ~~ ~_-Ph Il lll bg XS pr | HOLALAC Ph i ll py PhMgBrRoute i ctrosyntesi Q Retreat ie Des om meen Il Ul © ph— v on the Oe Wepihe Wil the yam Hn, pn etl ero ~) ieSIS OF 1,4 DIMETHOXYBENTALDEHYDE went added to the benzene ring At i te wh chonoe expe tt die tet 24.1.4 SYNTH ne carbon ator subetit Ie ty osu alchyde, use of HCOCL 8 Bot 8 ator Sr ie mon rate method chlor tormaléchyte HCI giving # CHsCl group which can be o ized to CHO. 3.4-dimethoryberzaldehnts tere made ints Retrosyathesle: C1 CHO cc cy) = ° cS a 1 re jcLROPHILIC AROMATIC SURSTITUTION crrily, the 8d charm ie grtrale for romatic secre wy. Sc peng he te Dean our eae” roma tr fm dno eso Aad ner i ring gives utrobensene which i reduced Yo aniline and 1 olive Sith drum raat Ya Um prose HCl Bee ot a annus salt very such face tarardenalepl dt et gy pt fn or Fg Bn 1S OF BENZENE DERIVATIVES BY USING DIAZONIUM. te sc compound made by nucleophilic daplacement of diszonium salts We > \4 reagenta used for nucleophilic dieplacement wos of duntoraum salta Aromat Nucleophile HoRESOL of pen ania Ef tea & 1 91.4.2..1 SYNTHESIS ore In designing the #7™ intermediate. rosynthesis: CH, Retrosy! a He i oy FGI CN é wwe 0 8 24, OQ NO, Nt ‘OH rt ‘Synthesis: ae CH : HypPA.C GH Noy ee NaNo, aa ae HC} NOz oe CH * Hye. 2 elas ‘OH Ne involving displacement alcohols and thiols on carbon Lgarln polarity with nucleophilic carbon EXYL-2,6-DINITRO-4- 2m eynthon but only with second ot third row 21.4,2.1.2 SYNTHESIS OF . \N-CYCLOHI a pry e fas cakes a TETHYL)ANILINE | ind Se. These synthons are represented by organometallic Fchloromethyljaniline can prepared by wig centimeter ticueeei, eo yor NOs, that corresponds to the nucleophilic displacement. nb Retrosynthe: | — 5 eo a al a q oc 21.5.1 COMPOUNDS MADE FROM ALCOHOL On. Nz Oni NO, 2 otal CN FGI = ‘Many nucleophilic heteroatom displaces a leaving group from a comp ros aos ie) => Q —= 0 Q (brived from alcohol. Alkyl halides are mainly used but tosylates from TsCl and Ch ‘mesylates from MsCl can be used too. es oe COs CHyRo oh, + | persis OF ETHERS reasonable disco the most reasonable disconnection ofan ether is the C-O bond because most eine canbe made fom aly] halide by nubettion with an alkoxide anion. 41 SYNTHESIS OF (ISOPENTYLOXOMETHYL)BENZENE | rte with the disconnect | a6 paren eo tion atay, | ‘thie reaction is carried out by treating the alcohol with a base strong enough he ermal Orton! the Faction of acid id and Se | yt anim, ou hydride avert the hye on GH) ese sete ri | 9 cu oly 0 a bate, never oy nude, Ether alcohol available, see Teo a | har toate & nuleophili anion, Either halide is avaale both rect well re “ ° sib eo Dissnneston (bch ore aay, wo pera nthe route . L cu Se Sarentions jie moe reactive and anna undergo cminatin, Jog SE ROHR C1+#RNH, ——$— RN, ada RoFOR i j retrosy™ sthe carboxylic acid derivations eyntesized io oe ae oy a reac fergie te derivatives and propared tot | ‘ PaoH + Br ‘Sr i! Sw Sie yn aay | ort . 2 arid, anhydrides o- CHAT 'aycept amides ean easily be made fom ty = heen, ane devine 8 =e | Par + Ho fide themselves | ‘ Moat | syntnesis: _ SOOLGtPC —- acoci A Chlorides | Me Oe Pole ; j 40 Ho = o~o z |__#e0 + peoocon Aaiydes (isopentyloxy)methyhbenzene on \ 2154 SYNTHESIS OF SULFIDES ‘Unsymmetrical sulfides need the same disconnection as just used for ethers, ‘The anion of a thiol will combine with an alkyl halide to make a new C-S bond. The reaction is much easier with sulfur. ‘Thiols are more acidic than alcohols, just as HaS is more acidic than water. 21.5.2.i SYNTHESIS OF ALKYL BENZOATE Sulfide anions are more nucleophilic towards saturated carbon than are alkoxid and the risk of elimination is much lese. Ccaroryic kid | —-B'QH_——e acon’ Esters \ co RWh-.---m RCONHR’ —AmiSes ‘asiy made drei Most stable ‘Alkyl benzoate ean be prepared by the reaction between benzoyl chloride sl alcohol in the presence of pyridine as x olin the presence of pyridine as base. oS = attal + SH ivot BENZYL)4-METHOXyp, aan rv) HR ut oF (TERT ny esis 4.1 SYNTH senyeulfane i8 disconnecteg », FANE senator Eccve tk abide. The ayn OS ctr pet gOBt at DO ant pe peor 21.5.5 SYNTHESIS OF SYMMETRICAL SULFIDES r 1 wulfdes ean be de from the aly! alide and Nass et Symmerithe fret step i the monoanion needed to make the second 0§ srt im 2 th oe dial! sulle Retrosynthesis: REsR > 2R 8+ S? Synthesis: abr ——> RS R 21.6, CHEMOSELECTIVITY Tf'a molecule has two reactive groups and we want to react only one of thea ‘apd not the other, we need chemoselectivity. Chemoselectivity is to react only om reactive group ou of two functional groups which are present in the same com" Ratrosynthesis — Disconnection Approach _229 guNTHESIS OF PARACETAMOL 8S gno eFOUPY HAVE unegua reactivity, i mines aro mich more the more reactive can be made to alot mot es ‘nucleophilic than phenols (compare asic sag ena The sya ee ane ge noe wenggute tric acid and the reduction ia het cared otestaiionde Po esos wa Meee Oe Oa or” I 40 woos SS 0 cess ar He NO, tyiP¢,¢ 0 WH wo he 40 g Ho 31.62 SYNTHESIS OF SULFIDES fone functional group can react twice, the product of the first reaction will cznpete with the reagent. The reaction will stop clesrly after reaction of only one ‘Sole of functional group, if the starting material is more reactive than the product. the reaction of an alkyl halide with NaSH or NaxS cannot usually be made to stop ther one elkylation as the anion of the frst product is comparably nucleophilic a HS or S*. This is obvious in reactions with NasS. Lese obviously with NaSH the first reaction gives the thiol but thie is in equilibrium with RS: and a second displacement gives the oulide RBr+ HS'—» RSH +HS'—==" Rg'+ RBr —> RSR Some reactions of this sort are successful. The eynthesis of chloroformates from alcohols and phosgene is a useful example. As itis an ester, disconnection to tenayl alcohol and phosgene looks good. But the producti itself also an acid chloride tnd looks as though it might react again to form benzyl carbonate. But in this case there is delocalization in the product that is not present in phosgene and the carbonyl roup is much lese electrophilic than that of phosgene. The synthesis 1s euccessful. ‘The hdlogenation of ketones in acidic eclution is another example where a reaction curs only once.NG GROUP the lose reactive BrOUP of two fy tera Tengen TEN once yl Roy, re vcting gFOUP i8 SPecific reagens = Regt | tliminates unwanted renege | mess ayn ‘yD waka se duces oF group that Fea" eh adding two more ste partic remove, athous! PS to the to add and eaty 107 rotecting ETOUPS a ee head Bat jut rote, ae potenmoderately complex mclecule and nq receniy publshe protecting eroUPs wad dn ie one example 58 SIN, oxylate group is used as a nucle 4 han he carbone NP erat certonecloidate ie chen Mle mat protect the amite, FO pe amino OUP 0 3¢ carbamate whoae sy! the eegue of further conjugation, The gy. {COs in basic solution) with slectophig awe a NH2 deka « Ay ve Gye oO 3 } CONNECTION KYLTHIO)BUTAN-2-ONE enable disconnection of 4(alkylthio)butan-2-one is ‘Sos gone between the sulfur ‘and the aliphatic rl | tom There is nothing wrong with this eppmai Taeapt that it ignores the other functional goo To ketone in the target m ere ah opportunity for a tworgroup disoonnection. ‘The general concept, a conthesis is that the two-group disconnecton® better than one-gay retroaynthett idea wth tworgroup dgconnectins is that we recrult the ae Fanctional group to discover a better reagent. Here the carbonyl group can make the el of a double bond to the cationic center. The rea thiolate anion to the enone making an enolate inter Tear RSH to give the target molecule and regenerate the nucleophile well now react at OxsBeh 21,7. TWO GROUP CX DISt 21.7.1 SYNTHESIS OF 44(AL! ‘The most rea bond of sulfide group, choosing molecule to ensure a good Sx? res Jectrophilic center by simply add» ction is conjugate addition of th mediate that captures a pros | vei 0 it ea eroup b have pally 088 1p but it could be ‘an electron-withdrawin srl geal aman the°” CS 4p, inthe ght poi, Tho cx i ae 7 ‘two-group 1,9-diaconnections are the apni forward reaction These Michael acy from the carbonyl group, and are mnthon. far posible because they correspond e ‘lors have an electrophilic aie two atoms Shion ey the reagents corresponding to ‘This type of reaction is available on! i ly when the eeoronidhdeaing group null carton bat can te ite ee a eetection in avaiable only at this oxidation lee, NT “PaRise te: THe Tho naseopla rengnn will depend al probably be neceneary, but XN, the amin nl heat te neceopatcencegh wid conjugate addition, An exemple would be the nie cant ag ae sprnt-yoropncat, Thi ete 9 ree pawl prblem fa Sip i eo ia gt Ne oaks the aie na ae \ lo we control whether the nucleophile add: ery eur by ne in Ing verry ofthe copie iol Yee omen i yan tend to refer direct addition while less electroy nat hare or fn dre aon ee his compounds noch eo ates cr ating Retrosynthe: iS 13 = + Frcoet v N’ Aco hewnone :LATIONSHIP yx (12-DIX) REI TIONS) elaionship prevent a difren, ction ( ity used to make the right cael a functionality ht cane y cond fang leobols all fit the patery ei to the usual heteroatom nny! thi an be disconnect matt 12d ge KOK XENRay SR OR spat C-} used to make C2 electrophilic? o, Oeil tna i “Jpetrophilic eyathon to form a three-meqy, ae ide, Bpoxides are strained ee the epoxi to give thine to give the amino alcohol, a How the other She anewer is t0 visu olden cattat could Lose 8 PPO sing enc with nuceorble ch sina THE 13-DISCONNECTION (q.1-aiX) RELATIONSHIP ina an ok een but al it means isi The tanned tothe wae CATDON ‘Acetalesynthesid yi wo fant PET anal, Uke et eal act season fam lee, ON Peat teth C0 tons, This feel a la disennet gt te evo heteroatoms Jones the same carbon atom ara information that to sad the TM is probaly made from a carbonyl compel, carbonyl oxi riyois and expulsion of one OR gray jcetal io followed by expulsea is the ‘The Key atep in acetal formation i t is, tion of the hemi the other. Inthe synthesis, protonat act i evel cried 1m in reverse. Acetals arm water molecule and the addition of - ee ee ecu oth i ie ce ere taon ofthe tno HO ou jal ‘to the same carbon atom. of acetals: OMe 1,1-diX as ‘OMe Retrosynthe R-CHO + 2MeOH PEPE pests OF Rotrosynth acetals: thes Disconnection Approach 289 8 Aner RCHO MeOH OMe Hee RY ‘ome 16 srEREOSELECTIVITY ae 7 a ee ine sean me an Weal i of ersaoae Sa en sere’ eee transformation of pre-existing sereocenter enna a 200" he selectivity arioes from dite aot Ores depend on th a Mee depend on their sterechems ekg pheromones, plant growth regulator, pes eeeiprell compounds having bla sei. ‘and flavoring compounds, a3 yuat ENANTIOMERICALLY PURE COMPOUNDS ‘Two atéategies will be discussed in the feingle enantiomer ea starting materia, T™? the synthesis oF we woos enue Enantiomers cannot be separated by doer caret the normal processes of ene aan cree amatoraphy but distereiamers can Reston easing an enantiomerically pure rething agent to ener the race pound into ture of diattereolsmere that can be operated ‘by theoe cnr feparated by these ‘When Cram wanted to study the ster reochemistry of elimination rea ate tong nentomerely ure be that eauiast ceistineten spmmeuteyrsin of LD Eis shoe ium 0 neopents0-phenlethyd) amide, Ia he BuCOut andthe se ack to the acid chloride of available 4 SOR me £8 su fF, Sh me * Ss OPH H Pr He prepared amine by a reductive aminati reductive amination of the Ketone via the N-formyl amine and made it enantiomerically pure by resolution ri olution with malic acid, a chea tnantiomerically pure compound. ” ne | | | | |>” } cremisy voume _ u_hanances ’ OH. NH, ° NSO HC! a eon ination gives uetiv Amore gorse ey al om mie oeerly perfect resolution tallization of theron, In fac ov esraiaton, 1s eereouomere and have differen ay ma a8 Hand th alot amers of eine. TH AU ies out from MeO) cote hiperbee, One taal Ty formed in making fhe fare fuse, iste SNE VGH oe pure amine an tartaric acid Sinple ne ee asso a NaB(CNIHs wcemic mixture of, ‘amine a Sthnna ives enantiomerically pn, alt of att L QH 4 rey yoni NHAC )H iN’ J Oo ‘MeOH & | Bing Taina Iwe are dealing with dasteres Sei, | apleylobexsl 4-methybenzenen rgomers the came thing appli rufonate i not chiral 0. the liastereomers of 4-methyleycloheryl 4- fives a different diastereomers of 4- Compound 4- question of Crytatea (soe bre HN Me and reducing the amide. Both, Cram finished this synthesis by making nizati peal 6 ev in ent pnd mre ini why caved ialccd | able 2.4 il ba eo eeerga involved in either step. The involv lc able 21.4 Different types of stereospe er types of stereospecific reactions in chiral compounds | [Reaction | Chemistry he wate A Me UAH, Stan | [sa =i Paki eee — > R aversion | Spey pa fo al: RON 21.9 STEREOSPECIFIC REACTIONS: Be “Antipri. Whether you are dealing with enantiomerically pure or racemic compra, ‘once the first chiral center is in place, new chiral centeré may be introduc mx : Stereospecific reactions give specific and predictable stereochemical outs | [> 7 = because the mechanism ofthe reaction demands this. Starting with enantiom® aon 7 pure materials, each enantiomer of the (1R)-2-ethyleyclohesy! * | | 5) onto aa methylbenzenerulfonate reacts with AcO> following a Sx2 reaction meee a ee eet give an inverted acetate. Enantiomer (R) of 2-ethylcycloben) ‘etpbensenlinteernpacialy gee )-2ethloydohr exit Eerie Trans F enantiomer )-2-ethyleyclohes -t mnesulfonate set 7 (IR)-2-ethyleyclohexyl acetate. ee eee eee ae a p+ gta JA, se FF, CONNECTION OF 1,5-DIFUNCTIONALISED 11.18 TWO-GROUP C-C DIS et || Addition and Robinson Annelation) COMPOUNDS (Conjugate Michae! “Another odd-numbered relationship méans we can still uso eynthons ¢ naturel polarity, The 16-diketone disconnecta to an enolate, and an a, B-unseturaeg Kanne, The conjugation in the enone makes the terminal carbon atom electrophilic / i 0 + 1,5:diC0 L w Re R eS ae ec é g The only new thing in this hea the combination of these two rea ts 0 that a C-C bond ie made by conjugate addition of an enolate to the enone ing enolate of the product that gives the 1,5-diketone on protonation. 9 wef ° o ° ° 2A, ay —1A, », Js This raises the regioselectivit ic vty question of whether the enolate will adé ine | cue ia ket shots Yoneda cae nolate and which types of enone (Michael acceptors) are good tt | Mechanism: 21,13.2 ROBINSON ANNELATION ‘The Robinson Annulation is a useful reaction for the formation of six- ‘membered ringe in polyeyclic compounds, such asteroids. It combines two reactions: the Michael Addition and the Aldol Condensation. | |a Rotrosynthes ynthesls — Disconnection Approach 245 7 ie HO . oe ie 10%" (aH (quo) kr HOR] HO HAN’ ‘on = POH “ayat 7 | (eee oust) a wo al Despite this versatility, eynaide adds only one carbon atom of ane ‘one carbon atom of course and we pec thermore general te anion equivalents. Avery simple example i the nesfayteton that could come from th ctylnic leh hy Hydration and ence e with the anion of acetylene acting asthe acy anion equivalent. wey oto Ag ro OY saico —> = — Sy hydration 4 ‘he sodium aul of acetylene adds to acetone and alehol can by hydrated in id with Har catalysis ° : Nat scstone H _ in 0 ants, TWO-GROUP DISCONNECTIONS (1,2:DIFUNCTIONALISED et i , WHO “fe COMPOUNDS): UNS grout anenite athe aren muleopile en Wemalgy oir Acyl Alon Banani ‘of a bond between the ira casbecy! For In the sleet Cyanide (one carbon) and acetylene (two carbons) are limited and other acyl isin not possible. le caer, sajgn equivalents are more versatile Dthiana are thoacetale of aldehydes that ean anigtorotonated between the two eulfur atoms by strong bases auch as Buli. @hydrolyis of the thioacetal by acid, unvlly disconnection ; jonship 1,2-diCO relate there ia only one C-C bond between ty ‘even-numbereé Lfediketone or an or ized carbons 80, while we can use acid derivative or an aidehydefarm | egtion with a eooond aldehyde an sr Hel), gives the a-hydroxyketone. The disconnection is that fynthon of unnatural polarity they Bea SS ual o the lithium derivative acts as the acyl anion, Unlike previous hhydroxy-ketone, facts half of the molecule, we are forced to use a ‘anion for the other half. Sfown on dingram an ° 4,2-diC0 Ry ° methods, R does not have to be H or Me. ey ry 3° te gee Oe ee ROH Fs RSH Ru R 120100 RL. 9 ae => 7 Jer [reer OH °O ° Oye a Acyl Anion Equivalen ‘The simplest reagent for an acyl anion is cyanide ion, one of the few genitt | j carbanions, After addition to an aldehyde, say, the resulting cyanohydrin a # | converted into a range of compounds. The cyanide ion represents the gynthons sb in frames next to each product, |Het och seman eon a ae ene 2S Go ata more reduced Cridaton Ef if 80, is. si ym the alkene bya l th ctionalised como asily come from toe fain en at Wo mihi hin of «Wittig yn we du ‘equivalent to the bond betwee". a 4 iisconnection £0 ne, tweey ion Se seals that we weuld be coupling an ag disconnection Tae many other ways fo make alkeneg thay te dehyde. There wou nections groups. swith an al ‘use different diseo wna tA ra ofl a SE aon + Pre, Ke ae San, ® be lecrnmle vse many 2fancanalised compounds With cont Boxes sve Pe pond give the ant tereochemisty in ag stereochemistry. Rear reohemistzy in cis-diol. Other compounds mae jes sn contrat zromides and bromohydrins fom reaction with bromine lags bromine and water a a Se) st we ew, ff Xn teaed ee OS ae ‘sion «-Funetonaization of Carbonyl Compounds: swo-group CX disconnections We wed thio stratery under (8O-STOUD act sven te tthe wel fucionalizaton, More relevant bee trominaton 1 Aonyl empounds into 12-dicarbonyl compounds by reaction mia conten de Se0. oF by nitrosation. So, acetophenone gives the Ketoalehie aera thee 12-dicarbonyl compounds are unstable but the crystalline hye rae ee et decane reformed on Beating. Since aromatic ketones wait tie by a Friedel-Crafts reaction the disconnection of ketoaldebyie certainly be ma tot between the two carbonyl groupe and offers an alternative strategy. Se) 9 recrystallise 9 a Cdoaie Phy Pr Gone” er ScHO. trem tet wale be \Nitrosation of the enol of Ketone in acid solution and tautomerisation ofthe |i omg ees th nite Hyd ef the oxime ves the iene. j ONO | ° Menowicy i ‘& RONO Retrsynthesis — Disconnection Approach _ 247 penzoin Condensation: an a-hydroryketone is symmetrical the 2a the aa aon metal the dionneton offers an intriguing wilt from the ald ost enol aldehyde?” The ; esti gas no enolisable hydrogens, eonecs ‘newer is ‘yes! fig uh nye yds eee ie rome So, eat ‘pent ‘symmetrical a-hydroxyketone in one pot . ° R’ Roa ye ge R oH R 3 catNacn rN gor wy on cyanide adds to the aldehyde forming tetrahedral intermediate w Sfeenzaldehyde. Exchange ofa proton allows the release ofthe cyanide eo that it can ed again. This reaction the benzoin condensation isthe nearest we have come to *efiing the simplest strategy of acyl anion and carbonyl electropile in one step. NY ee x prorat ND) ot sn eres a km Gs ft ° ody hh Introduction to Ring Synthesis (Saturated Heterocycles): ‘This heading is about intramolecular reactions and, in particular, about making heterocycles by cyclisation reactions. ‘Three-Membered Rings: You are already familiar with the simple formation of epoxides by the action of peroxyacids such as mCPBA on alkenes. They can equally well be made by cyclisation of chloro-alcohols as in the Cornforth addition of a Grignard reagent to a- Slaewne sad cyan be A, iB 4a were oe. a 3 ” clRotrosyntheste. Disconnection A wide. When treated with base, ae 2 sed | yaroonlo lactam. this gives the fr yori lata. ree amine which promptly FourMombered RIE savorable Ot aoe PPR ang on Though cote are th ig resent Tp analgesic end angen in 8 oeN ee ty red ter ed eae ae an azetig = usualy Prable ing CAP Oe onbere fing and then the ena, Sit me ane 7H sore arene 8 ONE oar member enone, yee nh tazadoline, come ponds bre Or chyde a 7 | disconnection pexanane and Pe mm Ce base OE \ Series a atte = ie = Q HN COnE Fi Gar i a caw? LA, oO | ot 2 Oh~/ Res foe __arembered Rings i 7 Tt was better to use th ee tie demon : avegy works. ° di dramat wtration of the advantages of - gurprisinaly this trabedy Tr and reductive amination of ite Jn the synthesis of tetramethyl piperidone, Remon] a tee coe ath seen Lane te mois Pad whe amine A Maga? oy anton efammoxa oe dinate open ine pacbaiy eto sa pal 68 ribo OH t@ Br whereupon ocean “yg don te eveal three males acaane = ten ofa dou raat treatment with 7 ° tazadoline. ul I 2x1. 3-5% ae } acoot . 2x2 2 aldol ° ° ' wy Oy, 2 OS aca ae iene Ve Le H | ‘qreatment of acetone with ammonia and the mi i: ani mild dehydrating agent e PrP te rium ‘hei trem terete ges he pene in oe wp, resahy et Peri calcitjone dimerioes and trimerises but the incipient pelymeraation is ripped in oH ae ad by the capture of one or more of these intermediates by ammonia and the Hyx~OH Se Neo 4 the Bion ofthe only possible stable six-membered ring ete la The pill eeeme ae by pert acne aon recovered in the isolation and the yield is 70% if that is ‘efen into account. | ive Membered Rings — the muet favorable of all and tho precursors, euch asthe These are the most fayeha ugh the carboxylate salts are stable. Te oy om cannot usual be pe ocdatin level af the precuror right, Using cue 5 ee fully saturated ring would come from an alkylation rag amines as examples, fon amine having a leaving group. x hy ts Q Ro t CN Sy pci pr Ce imine HaN- | N Lactams come from acid derivatives. Compounds such as amino estes rot stable as the free amine but are usually isolated as salte such # it bf ae ‘Three-Membered Rings Cyclopropanes By Alkylation Of Enolates ‘Three-membered rings are kinetically favoured but thermodynamically unstable eo that they are often destroyed under the conditions of their formation. Since most carbonyl condensations are reversible, they are generally not good routes tothree-membered rings. But the alkylation of enolate is usually irreversible so that these can be excellent methods. Cyclopropyl ketones can be made by cyclisation of some derivative of they-hydroxy-ketone. Notice that we proposing to make a three membered carbocyclic ring from an easily made three-membered heterocyclic ring,Retros Disconnection Approach 251 a sso sli volume 250 Advanced Oriole cron y . . Rin — conection Aprosch_ 251 °. =— V+ £f tion 1 Phosphoni aa A sort ene in the Wit reaction, Th wus ee armation of P-O bond R smd od the $0 Bond a mach wenn ge Fm aay formato of 2 erm by reaction of diethyl slnde wit Mel, on TH eulonium eal : We, ‘ste Me 0 oP ae i . 6 cae ° Re amt de to the enolate adtion of ethylene oxide 1 1 tation and formation of the in empies Seatbo. oe yo 2 test base 4 * Es what hae thin got to do wi So ith cyclopropanes? If sulfur ylide react with pane my be formed, The general rule os either the epoxide orth eylpe e700 onium glide from give epoxides but ren oxides but eulfoxonium ylde give cyclopropane, ° + MesSH=0 oe wt, te a Re base Re base # treatment with ane pot ie) pen A MY R NaOEt me a 4 & Carbene Insertion Into alkenes used oo far all depend vs eyelisation methods we, BYE pee f Tae coat epee epelprvpene into carbon group sn | disconnection of carbon sree, But the sane general CIs ef cutat ery different way that is revealed?! dene and a carbine. ld alislating 203! = substituted eylopropane C8? TY ese an Gtsconnection of two C-C R cc: ‘ R R Pp ——— * ‘ation R Ry Br | [Set ht are protonated at carton ge ated compound - R | eee. intermediatc. in the Arndt-Bistert chain extension procedure. Now we are goin ce a wider view of their value in esi one it y Nu R aoc Rt £ : > —— It née carbene : R in insertion org Carbenes have divalent carbon with a Ione pair and hence only six electos in the oor shell ofthe carbon atom. They are normally clectrophilic and can fore aoe oreet once with a pisyatem. One way to make carbenes is by lose of nitepn sa insscempounds such as diazoketones. The formation of very stable nitrogen hinted by heat or light and compensates for the formation of the unstable cartes Diazohotones are easily made by acylation of diazomethane with an acid chlor ‘Loss ofa very acidic proton from the diazonium salt gives intermediate. Normally tie diazoketone and the alkene are combined and treated with heat or light. ew eo nestor 8 light He-OR Nu Ketones are rarely isolated as they dimerize easily. Ketene itself gives the lactone but dimethylketene gives the diketone. Other ketenes may give either type of Re dimer. Only a few ketenes, such as diphenyl ketene, are normally isolated. Ketenes are normally prepared by the base-catalyzed elimination of HCl from an acid chloride or by elimination of chlorine from a chloroalky! acid chloride with zine dust, often assisted by ultrasound. For reactions with nucleophiles, the solution would already contain the nucleophile before the ketene was generated. CHy=N*= Sulfonium Ylide Chemistry ‘The simplest sulfur ylides are formed from sulfonium salts by deprotonation in base. These ylids react with carbonyl compounds to give epoxides. Nucleop! ie attack on the carbonyl group is followed by elimination of dimethylsulfide and[2 + 2] Thermal Cycloadditions of Ketenes Unlike ordinary alkenes, ketenes do 2 + 2 cycloadditions with y dimerization above and with other alkenes. Reaction of dich t™ cyclobutadiene to give the dichloroketone shows that they profer 9"°K¢teng ‘hs cycloadditions and also shows off the regioselectivity you would expe 2 + 2 tp Mi reacts with the most nucleophilic end of the alkene. The ‘mechact, th ap qa.*2 major orbital interaction as the two reagents approach each other: the, showy nt -actic well be a concerted cycloaddition. 7 3 Ray o 9 CHCLCoc! ag ac ae Sa BLN 0, \ bal akg YS cr ha Six-Membered Rings : There are three general methods of making carbocyclic six-memb and each produces rings with a characteristic substitution pattern, The a Tings St sey carbonyl condensations and the best of these is the Robinson annelat, disconnections are aldol and conjugate (Michael) addition. The target mole”, Te conjugated cyclohexenone. Seale is Q ° ‘0 aldol 1,5-dicO Oo =, EE oy” + a ‘0 The second method is the Diels-Alder reaction. Suppose the target molecul has a carbonyl group and an alkene but now only the alkene is in the ring. The carbonyl group is outside the ring and remote from the alkene. The simplest way do the disconnection is to draw the mechanism of the imaginary reverse reaction. R Diels- a 9 Alder gr SC, The third is partial or total reduction of an aromatic ring. Any catalogue list a vast number of available substituted benzene rings. Saturated six membered ring can obviously be made by total reduction of but it may not be obvious that partial reduction allows the enone also to be made from. 0 OR? total OR? Birch oe fo Fy, eeductoy eaten = Rg fi