BASIC KNOWLEDGE OF ORGANIC REACTIONS AND RETROSYNTHESIS | 5 | 4.1_ INTRODUCTION Several compounds ae commercially available, inexpensive and are smal, containing six or fewer carbon atoms, Therefore, the most frequent Synthesis of pyrazoles and task facing the organic chemist isthe synthesis ofa lager, complicated Comune anolecules from smaller, simple fragments, The best approach for the ‘Weenie wth oe synthesis of the target molecule is to plan its synthesis huckwanf na wincat kiko wena te paper an approach called retroxynthetic analysis (rev Latin, backward. The term was coined by Prof ideally made from 1,3- rvard —_ dicarbonyl compounds by University, Nobel Prize 1990, reaction with hydrazine. ible intermediate starting materials, {8 Chapter 9) ‘sor Elias J, Corey (b. 1928), Ha Retrosynthesis thus identifies po which themselves then become the goal of the synth R After suitable intermediates or the Starting materials have been FE identified, the planning process e + N toconsider what reaction is required to convert the reactants o products, RI’. Two important drugs, the tranquiliser diazapam better known as Valium teh I nervous system (CNS) sedativerhypnotic. This lp xC—N © Most over prescribed drugs of modern times, lines with the synthesis of ae x lives. ay +HJN—NH, Considering e.g., the complex molecule of viagra it contains a = R © Hydrazine sulphonamide and a benzene ring joined to a bicyclic aromatic system 5 of apyrazole fused to a pyrimidine and would essentially require a sound Pyrimidines are made knowledge of synthesis and chemistry of pyrazoles and pyrimidines, eae The sulphonamide group is introduced from the sulphonic acid which compound with an can be introduced in the be nzene ring by electrophilic aromatic ‘etphonation. [Synthesis of viagra is in (Scheme 11.23-11.27)] suiphorSiga\ NS Me Diazapam Viagra (Awell-known, tranquiliser) (Pfizer's treatment for male erectile dysfunction) SCHEME 1.1ORGANIC SYNTHESIS THROUGH DISCONNECTION APPRO 4, 1.2 APLAN FOR THE SYNTHESIS OF A COMPOUN IS CALLED RETROSYNTHESIS In this synthetic analysis, strategic carbon-carbon bonds in the larg, molecule (TM) are “broken” at points where bond formation possible, Thus, the synthesis of the compound (the target) involves jx planning called retrosynthetic analysis. This involves working backwar, from the compound to be synthesised (the target) to simpler compoung, which are readily available in the laboratory. In a retrosynthetic analysis therefore, a chemist dissects a molecule into smaller and smaller pieces to arrive at readily available starting materials (Scheme I.1a). =, >> * > w (SRG CE Starting materials Zz Target molecule The retrosynthetic open arrow —> points from the target to the reactantis) Usually the reagents that cause the transformation(s) are not specified, although it is necessary to have some method in mind that will accomplish the transformation(s). The actual synthesis is then written in the forward direction and all the necessary reagents are included. SCHEME 1.1a 1.3 RETROSYNTHESIS INVOLVES DISCONNECTION OEE NUUUNNEC TION ‘A useful step in a retrosynthetic analysis involves a disconnection ie. breaking a bond to generate two imaginary fragments. Typically, one fragment is positively charged while the other is negatively charged. The fragments of a disconnection are called synthons, Synthons are often not real compounds. For example, if we consider the retrosynthetic : of th cyclohexanol (Sch disconnection gives two synthons—an rlydrorycarbocene Rela hydride ion. The curved line drawn through the bond being bow), 284 & the proposed disconnection (Scheme 1.2), 8 broken depicts Recall that reactions usually used to cor . mstruct bonds involve compounds with nucleophilic (§-) aay, ©%P°8-carbon Rt r BASIC Kt ell) T™() Synthons, The TM (I) can be formed from a nucleophilic R™ and an electrophilic C* Tpectes, So, the general disconnection for these type of compounds (TMI, Scheme 1.2) as shown looks promising. The target molecule || A curved line drawn through the (™ 1) bond showing disconnection HQ _H Disconnection (ID) Cyclohexanol a) Open arrow represents a retrosynthetic operation ‘A good disconnection on cyclohexanol, (the target molecule TM) to produce synthons a o-hydroxycarbocation and a hydride fon SCHEME 1.2 4.4 ASYNTHETIC EQUIVALENT In the synthesis of cyclohexanol (Scheme 1.3), cyclohexanone is the synthetic equivalent for the c-hydroxycarbocation and sodium (A; Scheme 112) borohydride is the synthetic equivalent for hydride ion. Thus, for cyclohexanol (the target molecule) a feasible synthesis involves the reaction of cyclohexanone with sodium borohydride. ‘Synthetic equivalents in the synthesis of cyclohexanol OH (1) NaBH, NY (2) H,0° Cyclohexanone Target molecule (Cyclohexanol) {As guided by retrosynthetic analysis, disconnection (Scheme 1.2) and the formation of synthons guides a chemist to select a reagent/2 synthetic equivalent to carry out the function of a synthon, and the synthesis is then written in the forward direction. SCHEME 11c SYNTHESIS THROUGH DISCONNECTION APPROACH ORGAN ually an ion produced by a ‘A synthon is a generalised fragment 1s on dismnectin: A synthetic equivalent is reagent which carries out the fonction of a synthon which cannot itself be used it being too unstable, but these can be intermediates agents, ‘Thus, synthons are not themselves reagents, ina reaction pathways when one disconnects bonds to generate synthons, the polarity of the ‘bond forming reaction is realised without having to specify the details of the reagents. S mpound which reacts to give an intermediate ‘A reagent represents a compo Cetera { petosynthetic analysis or the target molecule itself and isthe synthetic equivalent | te must lead to readily Sodium borohydride and cyclohexanol are thus the reagents in the planned obtainable synthetic synthesis of cyclohexanol (Scheme 13). | equivalents (Reagents) ~ | and ato ead $9 * 4.5 RETROSYNTHETIC STEPS. The hardest tskto desig 3» important aspect of retrosynthetic analysis is the identification of Sere ce bond fee sits in ‘ target molecule which could have complementary Cleavage, ie. where to (opposite) charges; the ready availability of synthetic equivalents and make a disconnection. the overall feasibility of the planned systesis (restrosynthetic plan). s—— Cyclohexanol was best disconnected as in (Scheme 1.2). In [Schemes 1.2 and 1.3(a), (A) and (B)] are drawn both as achydrocarbocation and c-hydrocarbanion. To determine as to which disconnection is preferred to the other, one focuses on translating the fragments into real molecules. To distinguish these possibilities take advantage of natural bond polarisation for every key bond. Since O is more electronegative than C the natural polarity here is ce_—OF®, and thus using this as a guide the disconnection (Scheme 1.2) leading to the formation of (A) is more logical than that in the formation of (B, Scheme 14). oO Natural bond polarity in (C*—O*> is as shown (A and C), since oxygen is more electronegative than carbon. SCHEME 1.32 In the retrosynthetic analysis of cyclohexanol one could imagine an Sa disconnection than in (Scheme 1.2) i.e., the positive charge coul e given to the hydrogen, the other synthon being a- hydroxycarbanion (Scheme 1.4). u{5 AND RETROSYNTHESIS BASIC KNOWLEDGE OF ORGANIC REACTION: “in = ‘Assynthetic equivalent for this synthon (achydroxycarbanion) is unlikely and not readily available see Scheme 1.3 (a) Not a good disconnection, since one synthon a-hydroxycarbanion is an unlikely species in a real reaction. SCHEME 1.4 One could disconnect the target molecule cyclohexanol by breaking the C—O bond (Scheme 1.5) instead rather than the C—H bond as done before (See, Schemes 1.2 and 1.4). OH H =—_ + OH Cyclohexanol (™) ‘A somewhat not satisfactory disconnection compared to that in (Scheme 1.2). Since though synthetic equivalents cyclohexyl bromide ‘and OH" are well-known the yield of the product is low. SCHEME 1, The synthetic equivalent for the carbocation (a positively charged synthon would require an electron withdrawing group just at the right Position and one can think of cyclohexyl bromide as the synthetic equivalent (Scheme 1.6). Cyclohexanol, therefore, can be prepared by treating cyclohexyl bromide with hydroxide ion. This route, however, is Not as satisfactory as the first synthesis (Scheme 1.2, reduction of cyclohexanone), because some of the alkyl halide is converted into an alkene, so the overall yield of the target compound is thus lower, cee ‘The actual synthesis of the tar 'yclohexano! from the disconnectior get molecule cyck 7 is fi (Scheme 1.).The yield of target molecule is however, iow due to elimination. Oe_ JRGANIC SYNTHESIS THROUGH DISCONNECTION APPROACH, OFAN NTE EE cing rotroeynthesis, the TM must be evaluated for bonds where teconnection hetween their atoms will give fragments that can be Srnbined ‘hy actual reactions to be used in the synthesis, One has fearnt about a “logical synthon in (Scheme 1.34), there will he more on this type of synthons as one progresses with the subject Anat their easily available equivalents (See, Schemes 4.7, 5,294 and Chapter §). The synthon COOH is similarly “illogical”, since the carbon pears a negative change inspite of being bonded to more electronegative ‘atoms However, its equivalent is CN ion from which it can be easily derived Thus the proposed retrosynthesis and synthesis of TM (1) looks workable (Scheme L.6a, also see page 47-49 and 98), [Rerenrninens] On On $cooH => ,, AK + COOH Pry Koos Pho SCH, “itlogicar ™() tl 9 oon, OH OH q UES Ho! _££00H + HCN —* Ph cH, ——> Ph “cH, Son, . ™ SCHEME 1.62 (A) Knowledge of Synthesis of Alkynes—the Alkynide Anion A Carbon-Carbon Bond Formation with Acetylide lon Alkynide ions e.g., acetylide ion (HC=C? ) acts as a nucleophile (is a nucleophilic synthon) to displace halide from methyl halide or a primary alkyl halide to give other alkynes (Scheme 1.7). If this S,2 reaction is to produce a good yield, the alkyl halide must be primary, with no bulky substituents or branches close to the reaction center to avoid E2 elimination. 82 la + R'CH,— Br ——"—_>R—C=c— CH,R’ + NaBr —Me [nats Ph—CH,Cl + Na” =—Me Based on disconnection \ (@,, Scheme 1.98) OR Ph—CH,—==—Me Ph—Br T™M (1, Scheme 1.94) ( Ph—MgBr + CICH,;—==— Me Based on disconnection (b2, Scheme 1.9a) Best disconnection on a TM (I, Scheme 1.9a) is based on the best availability of the reagents for the desired synthesis. SCHEME 1.95HACHHON any 4.10 FUNCTIONAL GROUP INTERCONVERSION (Fq)) ‘ Reet. IN RETROSYNTHESIS USE OF KNOWLEDGE THAT A KETONE CAN BE FORMED BY THE ACip, ‘ydoborston CATALYSED ADDITION OF WATER TO an atl oF shynvetigaranen ALKYNE—SYNTHESIS OF ALDEHYDES AND ne ‘ arnt eho efoto pois ay KETONES—CHANGE OF CH,CO TO C=C ‘ye Boron red rma ely ost + Mpbeborain cing alkynes stops ater the ston oe of 4+ The ndtion stereo. shim in ChorceaccricH, Mey i! scheme ised ydtatlon ofa tor Te carbon oye He 7 AW By SO Sed NS Tiveo carbons of 2Heptanone Synthons, ° 8 mothy ketone, CHCH, © CH CH, i ep 7 a rr ® [pm = snore. ‘Acid catalysed hydration H#-c=c—H 2-Meptar : veil we 2-nepionone ‘envione——‘Bromopentine ; Peete cHscH,cn.con.cH, srosyests of M1 Ye methy etone group (wo carbons) i changed fo C=C (two carbons) pias rere tac an ane nar ne tpl bond to ove an acetide anon eeing a re] AES nas fonctions as» nulegpie In 5,2 reactions wih hades and sulphonate. eimai SCHEME 1.191s 1k SCONNCHION agg, 1.10 FUNCTIONAL GROUP INTERCONVERS| IN RETROSYNTHESIS USE OF KNOW! THAT A KETONE CAN BE FORMED BY CATALYSED ADDITION OF WATE, ALKYNE—SYNTHE: ‘SIS_OF ALDEHYDE: __KETONES—CHANG| 1E OF CH,CO TO Com yasic ANOW susie anions oN Acid catalysed hydration of Three methyl ketone Homme: o TM (1 Schome 1.19) Ikyne obeys Markovaihov rule SCHEME 1.20 ie will give the product as a mixture of anone (Scheme 1.21), ‘carbons of will i 2:heptanone and 3-heptanone SCHEME +94 oration oxidation alkynes-Hydration of alkynes to ketones. ‘The following points may CH,CH,C==CCH,CH, 3Hoxyno ror, leas i CH.CH,CH.CCH,CH, Horenone° Ou HQ cH, cmon ABs ons: Me cxyuger Se Pe O one a a a Pa] ow s 2 a aj prot more ‘bed ase {Sronan of rn tn forms a inte fsx tthe ese ‘cess shen Rycyceree he go pote SCHEME 1215pasic KNOW ——_——— [Revvntate ass] — AND RETROSYN THESIS. r Synthesis l zs L tots ot acrytene| Fat * acetyde anion ats a5 | | FSLs cu,ch, CC CH—cH, pow = Bo KA {nea aac he all 4 Scropuicentor ace ‘aunasteirene ca om The caso bond ™ Syninons breaks to give the alkoxide aad ' sonar THcH, CHC! + CH cH, [r= “oN ectopic becouse sythons fleconesatve. ongen . Ragen Geen a AL c008 + R—cmch eee “UNAM. y,cH,C=E CCH,CH, E> a i 180. Ragen eerie a el ss ‘ R Functional group addition FGA of ester group to enolate of acetone SCHEME 1.23 I cHCHE=OHCH,CH, —¥® CHC CH,CH, TW (Scheme 1.23) SCHEME 123 SH ~~ 4.44, FUNCTIONAL GROUP ADDITION (FGA) ALKANE 111 OISCONNECTION AND USE OF KNOWLEDGE THAT A KETONE CAN BE SYNTHESISED BY USING ACETOACETIC ESTER. A FGA OF (COOE1) TO CH,COCH, TO GIVE (CH,COCH,COOEt) eee TTT jon give the product. (Scheme 1.23b). °° NaOEL_, _o-Bube Ho" ae "OCH, EIOH Hy FO" ‘Synthesis of methyla: try acotoaceate bhydroxy ketones 9 ‘ea myrton © © w]e AA hee «rm 2eptarone | Scweme 1230 acetoacetic ester reactions as well asoncanc syNTHESIS THROUGH DSSCONNECTION Arey, i a |e GROUP C—X DISCONNECTION, OSYNTHETIC ANALYSIS AND SYNTHEg, /L DERIVATIVES (RCOX), ESTERS DISCONNECTION WITH KNOWy CTIONS IN MIND) 2.3 ON RETR OF CARBONY! AND AMIDES ( RELIABLE REA‘ | one Group ¢—X tisconnection on ald cerivatives | he bond between the ‘andthe | carbonyl group Is discon. Sected, Thus esters and | Tides are made (rom | seo ae ako! ‘or amines. eSo— 9 ° l CoN IL cnc Enno, CH= cH—CO + Nn, Thmide” ropenon 4 © one Te trget molec The obvious amae mae “The bond between the heteroatom ‘nd the carbon group is disconnected i i CH,=CHCC! + 2CH,NH, —> CH)=—=CHCNHCH, + CHAK uMenyeropnamice Reaction ofan acid chore af standard es same way, reaction of an ale and benzoyl chloride. These acts as a solvent and a catalyst i... i e1C ANALYSIS=CHOOSING DIsCONN NECTIONS emer 009 tater, Se sng bn atl he wort A KNOWN Vinee Ri IEACTION Paracetamol (An A “ie {ay Disconnect “ by-prod i i “sume, m s A ce a Pracetarolia =z . AT LY HO- e (A) ™ al a ‘Consider the synthesis of benzocaine (Scheme 2.6) which is used a2 local ansesthetic. One immediacy locates an cece grove, 2 irost | OREN lor fo get the alkyl bromide Recall thatthe best dsconection Land love cS) Retrosynthetic analysis of benzocaine SCHEME 26 * cn, SO see J ON ON Towene: (8) LT HN Hw “ Benaocaine TH SCHEME 27 3. Retrosynthesis of a Compound which is both an Ester and an Amine Consider the retrosynthesis of (TM I, Scheme 2.8), 2 molecule which contains both an ester and an amine group. One disconnects next to theSaNiC SYNTHESIS THROUGH DISCOMNECTION ay pen syMTHETIC ANALYS= CHOOSING DICONNCTIONS 1ao1 24-0 GA Dihornbe + nal aon Ever Grp none ai since S,2 reacton cannot occur | | ion can readily attack the allylic Sa Sfecseeten Tale (See, Scheme 1.90) | Sar epee pel Ss oe + +f00H = = Recall that $2 reactions at carbon are impossible (Scheme 2.12) gy —— ot dard ‘ag TWO GROUP C-X DISCONNECTIONS (1.2-a Trin es INVOLVEMENT OF TWO FUNCTIONay RU RENINVOLVE LOGICAL SYNTHONGSCHEME 2.25 y. 2 yS0On AG AREACTION \ proper ° cI do one on cu, "O° ‘SCH,C,H, saty2yconanerone Mol Conjugate adaition with weak SCHEME LATIONSHIP IN TWO GROUP 1HE 130 ON SUGGESTS CONJUGATE rmonton -ou | Seonoer 4.2 If one considers (eq, slain ofthe thiol cate intermediate whic eet molecule and re ‘pups and having conjugate shown in (A, Scheme 2,28).ism DISCONNECTION ROUGH PRONG, etrosyntheic analysis of propranota (1,2 provide heteroatom nucleoph (Scheme 2.25) from thi [naphthol displaces the Then the epoxide ring 1 28 IN SCON' SDITION ie a-diX RELATIONSHIP IN TWO GROUP IECTION SUGGESTS CONJUGATE HE 1 ‘AS A REACTION her base or NE) usually the carbon-carbon double j BE ci ° ° Wa, AN l : GAsOHCHEGHS “Eh” CHMVEHCHLECAH, eat sctteacd | agnor 2oropent-one 4010-24 . Dichenyiutanentie If one considers (eq. 2, Scheme 2.26). ‘The react sation ofthe thiolate anion to the enone shown in (A, Scheme 2,28),