fn \ Rb @ # : Unit “WW reperatron of Sythetic Litter diatas Benzil Rrom Benzotdelyde : i HO ahollic Ken ‘i oes Gyles Benzein Cordensabion i \ ‘ OH oO Ce 2 ae Benzoin wydoo hl? | Oxidakton AOR (28 Nasi c-¢—o) Bee ae po Coe FN SE Bassi ° | Font go, Fasgers = ch ein Condensakion # [ er al wt oz ce alcsholic KON 1 | 0 Tuvned= aldelyple. ae raped Fuasin \ oxidation Nt i 1} ft } {7 Gq ° oO oO Fuoe|— — — . CKefer R® Vannilin Yom Gtecho! parr ot) pn t tae Reimer Tierra Reackion oH Se CH), + Kot Cokechol A HO Roast with CHT (CH, So, Rimited r vy te) AS axneunt Porahucoy mudonaet eo ott, jae Canna lin) cho YQ Grenine prt nde, fr RN oe) ile g } ~ ee, Cal 2 ’ Heto+ CH NH en 2 CH, q DimeethyPamine F7 H Undole Ry st nes | Ogre genie et Bet fem henoxidative decarboxylation and last in last product become found out is vanillin ‘Synthesis of vanillin from gualacol: ‘A more modern method react guaiacol, obtained fom catechol, with glyorylic acd. and that is bow a lot of ‘vanillin is prodiced today. At the present time, the most siznificant of these isthe two-step process practiced by Rhoda since the (1970), in which guaiacol reacts with elyoxylie acid by electrophilic aromatic substation. The resulting vanillylmandelic acid is then converted 4-Hy 3. syphenylglyoxylic_acid to vanillin by oxidative decarbosylation and last in lst product becom fount otis vanillin. (15] Lumite Umer G Skee wae Tad (esas ‘HO. COOH 2 ° Cardve’ ee La i. re cataled ‘OCH; "OCH oH on oH Marte) Ao gebey pag Nanstylmandckt <4 Gramine from indole Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan. oO -cw7 co ws w ie : g OzcK \ Nj

sve Spats of acid etvated Ny anh catalyst (AFA) from My aph, ye SC if f : on + 0c “ne oe Cs a aanet SA wa 2. ea) Aeabhn Pant Salsas Phony sles ate ) (satel Powe 2: stein eae wih phentover AAFASw oe Be Everton of aly al wh pheno ese FN eee Cae sacs ation of salicylic acid with pheno using AAFA was carried out ina liquid phase bach reactor. Inthe procedure: Sarr i and phenol (molar ratio of salicylic acid and phenol = 1:2) were taken ina 100 mi round botom Mask. capred ‘wih magnetic steer and condenser, immersed in a constant temperake oil bath. The catalyst (salicylic acid to catalyst weight” \ (> Tato = 10), activated at $80°C for 2h prior to the reaction in static ar, was added inthe reaction misture. The rostcn minors ane to Ei £00d yield ofthe product. Afer a stipulated time the reaction mixture was cooled to room tempcraine, setae ‘ave dolye the umes aye aid inthe econ vive and ire soar the catJi’ ae Preperation of Malonyt Via AD - = OO = i CHCOrGHe MH, Hace CODGH COs - S = A AAG Ht. OH O= = om: Malling? Uren ee el a (Epitopey doug’) Unmr nn enti Mm @ Maire. geen press Ce et OP Chiovinalton Ce la coae > CH cH — CoH oT Se) Pavyienic aud Trost with may Ammonia \ C= Gil ga CooH Nk 2 ManineMs Sndole to Hélewauwin (Route-2) cd, kot cHO Glee area = 1 Reimer Tiemann oe 4 Rea ckroy H Indole Indle- g-aldehyde Gabi | Na/Hy wv cH,OH a me ies 2 \ \ foal v CHEN Mendius Recuction KK 4G) cHCtNH 2 sara? COLD | NafGgh,oH | H 1 H | Hono J (Nano,t tl) CHACHO cH HOH ore & oy \ : cH COOH (3 eG LS> Coy ' 4 Indole -2— acetic aud (Heteeoaunas.)Gyothests af CRtoramphantest » (8% methorls ) \) Ww 4 Bathy synitests Bea St Invetves the sypiticsia ob wcAlotarephers cot using benataehyce an\ niGioeinanct os the anki ok . Shereow nts One weactants - : : Hs Nw eycre + OgNchackaoh Ocotss rs er Qa, 2-Nibioelhanat OW CHgOH Bates 2 -NitHO - I~ y % CH? propane - 143-diot Q- o-* ee - CAn- OF eatin Ip | e ho gare Soa Gye -CHNHCOCH, en a0220 gen maiey RG fee | pystctne HgCOCO Chgocochiz On kaape | writes OW = Ameo = 17 pocopane ars? | ¥ _ ext) ow Ni. = 4 a | On! <> enrncocts on «4 cH20coc Hg 5 eh HgcOCO ae = not | Hydrol yse ee ae Jpneott [iyceotyess . a vv & a 0 che” aren nen Ne ig ewe | ou cHgot _cag® | é2 ago | Age HEOOc hs pechiow eat ara, 4 C8 Bcd Chiloreun phon of = =a —e-He & on) éw nn eg OH ChgoH chtosnphonicat t sptetAed Pipes 0 sanemre, mature ant it pBC-> daomor £ ebtained ag nach Ak wit DC-> Camprersuttoric aed,cA : ee Longs synthionls Se TAs veypthesia Invetves p-nitotectopfcnone as On iniGial vreactank: Te fettowing Wweaction Sequence Sql SP ee ysl formation : \ is: ; OY EH eee 8 regia an coca Be Can —- coctian va Is Fen we i zw a) Nagcog or 8 aM ’ crol. ak an) ce AArucnana Aes = t Rectuctioo cHaAOH vv f 8 -we-cn— nc, tH = H£COHN re 2, eye HORE O# the stacotzomars ans separated ; Ba fractivoad exysatigativo ob Ate =“ ate’ Or v RactS002 5 pc) cRlosan- OgN <> au —N a Ov CKgOH CR OF > cada Aide etipets > > Nausea Now’ Weg » Akar hoea . AD Bens porno demersien , that ie in ty fymative af, blre ALY WhreS tn bet, e hae WN Aw) aAnYYt \ a Sunt ye 44 St ( ee) OA 0 a © Oe GH mh et Synthesis of acyloins (a-hydroxy carbonyl com pounds) OH oe q -2NaOCH. 2 +4Na abou. — : R Corebony is merely! co The bimolecular reductive coupling of carboxylic esters b inert solvent under reflux gives an a-hydroxyketone, is favoured when R is an alkyl. With longer alkyl chains, The intramolecular version of this reaction has been used sizes, e.g. paracyclophanes or catenanes, oO Yr tra moe teeter (coon Na Ho aac me any lets COOH NAV 000H TGF ee y reaction with metallic sodium in an which is known as an acyloin. This reaction higher boiling solvents can be used. extensively to close rings of different If the reaction is carried out in the presence-of a proton donor, such as alcohol, simple reduction of the ester tothe alcohol takes place (Bo ral Bae ea alco Reduction). The Benzoin Condensation Produces similar products, although with aromatic substituents and under different conditions. Mechanism of Acyloin CondensationTal Synthesis of acyloins (a-hydroxy carbonyl compounds) OH Mechanism of Acyloin Condensation oe OT Nat OT Nat 2a Kom 2 cig a fe Rt Coley Ci + 107 di a oO net 10 COT net aoc, nat ') i =NaOCH, Meo: OMe MeQ: R (F/O R R +O G- Nat Net 1 Na 0 HO PH tautomerism HP . R >2NaOH gy R R R |ony \letom ae oo byanar UF) a\dewy asi \2 S Chapter 17: pienvdes and Ketones. Nucleophilic Addition to C=O. y The eievudinr Reaction g g 3 2 + — woe R--R' cHg’o0n oR Hg0-0H tAw ketone peracid Org ame 9° 9° ° ° oi get Seagate one ifs 3) CH; “OOH R--*O" CH3 “OH 2 Pad aldehyde peracid carboxylic acid Reaction type: Oxidation-reduction via Nucleophilic addition 5 | Summary \ + Ketones, RCOR’, are oxidised by peracids (or hydrogen peroxide) to give esters, \ RCO:R' | + Aldehydes, RCHO, are oxidised under the same conditions to give carboxylic x acids, RCO:H. + For ketones, it can be viewed as the insertion of O into one of the C-C bonds adjacent to the carbonyl. + For non-symmetrical systems, there is a selectivity issue to be aware of, and A experimental evidence shows that it is usually the more highly substituted alkyl..— + group that migrates and becomes attached to the inserted O atom. : i.e. (more likely) H > 3° R > 2°R, Ar> 1° R > -CHs (less likely) + This is described as the migratory aptitude of the group and relates to the ability of the group to stablise +ve charge (nucleophilicty), In this example the primary ethyl ° ° : CH3CO3H group migrates in preference to the CHC” Bays methyl group so we end up with an ethyl ester. + Cyclic ketones give cyclic esters which are also known as lactones. ese capt Sywetete Cerons.CHsCOsH CHE, lactone ay ° x ERes O° Z che,” In this example the O ends up on the more substituted side. ‘Study Tip: It's easy to make an avoidable mistake here, especially with the cyclic systems and loose a C atom. Count C atoms! In the example above, the membered ring becomes a 6-membered ring because an O atom has been added to the cyclic system Related Reactions + Epoxidation of Alkenes . v a THE BAEYER-VILLAGER REACTION cw’ we es Step 1: An acid/base reaction. Protonation of the carbonyl activates it while creating a more reactive nucleophile, the percarboxylate. Step 2: Now the nucleophilic © attacks the carbonyl C with the’electrons from the C=O 1 bond going to the positive O. )EAA AO TN RI A OER SAAN BERRA tt NT 6 EE NOTES TOTO a MR G om Step 3: Electrons from the O come back (this reforms the m bond of the C=O) and we migrate the C-C electrons to form a new C-O bond displacing the carboxylate as a leaving group. Step 4: Finally an acid/base reaction reveals the C=O and therefore the ester product. (5 es SR Re _o% es ta saroe v Alkylation of Phthalimide (Gabriel synthesis ee Amines) 1. KOH N-H 2. R-X 3. NH,NH, ° reer Cr ae ariew Phthalimide Reaction type: Nucleophilic substitution then Nucleophilic Acyl Substitution Summary + The advantage of this method is that over alkylation is avoided (see previous page) + Reaction of phthalimide with KOH removes the N-H proton giving an imide ion, a good nucleophile. + Nucleophilic substitution by the imide ion on the alkyl halide generates an intermediate, N-alkyl phthalimide. + Hydrolysis or hydrazinolysis liberates a primary alkyl amine + Arylamines cannot be prepared via this method since aryl halides do not undergo simple nucleophilic substitution. Related reactions + Alkylation of Ammonia + Substitution reactions of Alkyl Halides MECHANISM OF THE GABRIEL SYNTHESIS Step 1: An acid/base reaction. Deprotonation of the imide N-H proton by the base, hydroxide. This proton is more acidic than a simple amine due to the resonance stabilisation by the two adjacent C=O groups. This generates a strong nucleophile, the -ve N. Step 2: The N nucleophile attacks the electrophilic C of the alkyl halide displacing the bromide and creating the new C-N bond. This product can be compared to an N- alkyl amide Step The imide can be cleaved via a mechanism analogous to that of amides. Hydrolysis creates the dicarboxylic acid and the required amine. éw Le i “A! 0 H ci of NE : ei 4 ' SEN MiB beere SO Me | mbes. f ; ( \ f \ ( \ 0 0 | I | = ~~ |Bartoli Indole Synthesis Alex Predeus February 20, 2009Bartoli Reaction vey we air Nivoy) & ain awe Ro he 1 pivg7X-Pe (80a) Rs THF, 40°C Y R, a G..... 2) NH.Cl (aq,) q Ry Ry pritiro Ahi ; wren ee ows vreenuan - presence of ortho-substituent is crucial; erere - yields are moderate; | RES wb me i - R,- Ry have to be tolerated by Grignard reagents.Reaction Mechanism o 2S ad, oe vo A NOA 3 Q 2 Naar - Oe ae eg a. H Brig SS A . Wm Soa 8 | MgB BrMg SS / Ey ee comes \ y : r HO . y a i QThe Bartoli indole synthesis (also called the Bartoli reaction) is the chemical reaction of ortho- substituted nitroarenes with vinyl Grignard reagents to form substituted indoles, WII The reaction is unsuccessful without substitution ortho to the nitro group. Three equivalents of the vinyl Grignard reagent are also necessary for good yields. This method has become one of the shortest and most flexible routes to 7-substituted indoles“ The Leimeruber-Batcho indole synthesis gives similar flexibility and regiospecificity to indole derivatives. One advantage of the Bartoli indole synthesis is the ability to produce indoles substituted on both the carbocyclic ring and the pyrrole ring, which is difficult to do with the Leimgruber-Batcho indole synthesis. Reaction mechanism ‘The reaction mechanism” of the Bartoli indole synthesis is illustrated below using o- nitrotoluene (1) and propenyl Grignard (2) to form 3,7-dimethylindole (13),m7 ‘OMgBr Z ‘OMgBr Ba cE S SW N’ +H,0 y a \ MgBr 10 yy 42 13 1 ‘The mechanism begins by the addition of the Grignard reagent (2) onto the nitroarene (1) to form intermediate 3. Intermediate 3 spontaneously decomposes to form a nitrosoarene (4) and a magnesium salt (5). (Upon reaction workup, themagnesium salt will liberate a carbonyl compound (6).) Reaction of the nitrosoarene (4) wif a second equivalent of the Grignard reagent 2) forms intermediate 7. The steric bulk of the ortho group causes a [3.3]-sigmatropic rearrangement forming the intermediate 8. Cyclization and tautomerization give intermediate 10, which will react with a third equivalent of the Grignard reagent (2) to give a dimagnesium indole salt (12). Reaction workup eliminates water and gives the final desired indole (13). Therefore, three equivalents of the Grignard reagent are necessary, as one equivalent becomes a carbonyl compound (6), one equivalent gets protonated forming an alkene (11), and one equivalent gets incorporated into the indole ring. ‘The nitroso intermediate (4) has been isolated from the reaction. Additionally, reaction of the nitroso intermediate (4) with two equivalents of the Grignard reagent produces the expected indole.