Organic Reactions Vol. 5, Chapter 10 p. 413-440 (1949) THE DARZENS GLYCIDIC ESTER CONDENSATION ‘Muwviy 8. Newnan ‘The Ohio State University and Banwer J. Macenus The Unjoton Company ConTENTS Isrmoneerion ae Scorn an Lnrnstions 416 Cartons! Components a8 Halogenated Esters 47 Other Halogenated Compounds 48 Side Resetions Dil a0 ‘Sounoriow oF Exrenaurseta, Conprrions 20 Convansiow oF Gueiic Esrens ro Ato aa ‘Reactions oF Guretsie Berens. coe 23 ‘Rearrangement 93 Reactions with Hydrogen Haldie 3 Reactions with Ammon and Amines at Reduction - 25 Grignard Reaction oh a5 Hydration 25 Renction with Active Methiylane Groupe 20 ‘Twn Dicmtonoscerarn Serrnnsis . - a) [Exrenneiray Procrounes. ce ar Metin eAthyhaeporseydabexsienmentate a7 Ethyl Methyl -p-taiveiyedate = «= = fll ar Ethyl pMethslephensleyeidato | |. SS 33 Hydatropaldehyde« co ans Ethyl fp. Chlorophenslivcdate 28 ‘Hall ee Chloroyehydrory-2-phonglbatyrate Do) a8 iBa ORGANIC REACTIONS: xasrues o sa Danaxes Gexette Baten Companion ey 1. Glyiie Haters 0 UL. Glee Amides a TL, Chore 2 Byraay Haters ry mrRopucTION ‘The Darzens glyciie ester condensation involves the condensation of fm aldehyde or ketone with an echalo ester to produce an a,f-epoxy ester Chast Themen toque wed ontnngepetane stm SSS ad Post emit recon” + WvcHIXcO,cat SS, ee foot + ax + Caton wl! No an “The elycidi esters are of interest primarily because they ean be eon verted into aldehydes and ketones having higher eatbon content than the original aldehydes or ketones, This transformation occurs after [hydrolysis to and decarboxylation of the epoxy acids and is socompenied bby rearrangement when an aldehyde is formed. ee ™ mK econ ty Nentcon 2 ecw0 ZN, “ f a ww we “ho fs ynthes ofa yc exer was pormed by ener? who obtained ethyl p-phenyl-a,Bepoxypropionate Dy condensing Denzaldehyde with ethyl chloracetate hy meansof sodium. It emained for Darzens, however, to develop and generalize this reaction He Balmmayer, de Ann Mt 18 1802 2 Dacann Cop od 98, B14 0 Daren, Compt rend HE 100100. "Darmonand Eroy Compe ren i 812 (192) ‘Daren, Comps ond 18, 24 C02), ‘THE DARZENS GLYCIDIC ESTER CONDENSATION =— 415, prcfered sodium ctor a the condensing agent. Shorty after the Epprrance of Darzes) St per, Chien ropored tha rium tg sould bo wel asthe condensing age. Tho lsd com- Uematon snot ben appied as wid none woul! eet Inver ethene and ait of compounds tat can be prepared yt Darens i as dbl note proce which ives tho reaction of ldhydes and Ketnes wth ey dhorectate and dite tanga amalgam, ‘The at pred of eration ia yoy thir eter which a quntatvly converted to mie etr by Greatmnt with atu elon Alternately, te hyreny ero tsters may be dehyde to yield elo unstated exter x Roo” + cucco,cats 22% Neccroo,ca fi who nbs \ f\ tr Joon \ we "cH 00.08, Re ‘The mechanism of glysdie ester formation probably involves the ‘addition of the enolate of the halo ester to the carbonyl group of the ‘aldehyde o ketone,* followed by an intramolecular nucleophilic dis ‘Puy io invvng ait of he sndaning age to the carton! ou of he alice ketone, Pourens a Bly ter chim, Franc (8) 1610 (1090, ‘Beconvenion ofthese or kton te nalts by te bam, stoma and Dew, bBo, et, ovo (0a), apprarinulguatSeabr ad Tutamiachy Bey 6, 2015 (sity ft mest ow fatwa the lata of Sb tar, ba ee tae ‘elas appear anger empl "Chasen, Bar 38 28 1S) Dareemy Compl rnd, 18 85 (1010. Daren, Comp 20, 174 UE, Dassen and vy, Comp ren 204, 2721897).40 ORGANIC REACTIONS placement on carbon. ‘The function of the basic condensing agent is to convert the halo ester to its enolate. CICHTCO,Cate + CalONe ~ [CICHLCO.C.T Nat + Catto. (va) ‘tt. ¢ neon + semaines =f Yates] ne \, mo So entooseats + x01 Bidens supporting the formation of the enlate of the chloro eter ia th fk that about 70% ofthe torial amount of amon i tlved on tenga siepnsion of satin amide in ether with th Ciloenctate™* Teas been shown that therm enolate of ketones react with chloro exer o give geld extern’ "This rel cone Stet withthe above mechanism potted hatte enolate of ihe Ketone eats with the elo exter to convert to ie enlat, ona 1 (CHAC=C, + CICH,CO.CsH, > CHCOC, + (C1 "HCO,CAEI-Net ‘SCOPE AND LIMITATIONS Carbonyl Components OF the many types of aldehydes and ketones from which the desired condensation products have been isolated, only formaldehyde, mono- substituted acotaldehydes* and a few terpene Ketones, such as earvone and pulegone give generally poor yields. Aromatic aldehydes eontain~ ing alkyl alkoxy, methylenedioxy, and chloro groups give fair to good yields. Although no study of tho effect of steric hindrance has been made, 2,4,6-simethylbenzaldehyde is reported to give the expected product, but in unstated yield. Aliphatic ketones, including methyl ketones, a,f-unsaturated ketones, and eyelic ketones, react smoothly. ‘The hypothe hat hl enters orm an ene apport by the onan that clromaonis ote may board tae bnalhlraone eer by rset ‘wilh Slum etal flowed by bea corn, Conrad, am, 08, 341 CS) ° Usps experiments by Nowman aod Maprcn othe Ono Stata Unive 2 Raton ad Daj, Ber 4680 On me elie Bers ete Pree ie am, 200 1880, ‘THE DARZENS GLYCIDIC ESTER CONDENSATION =— 417 “The succesful use of « Mannich base, 2imethylaminoeyclohexanone, hhas heen reported, but the analogous 4-dimethylamino-2-butanone failed to give the expocted ester" Aromatic and aromaticaliphatie eetones give very satisfactory yields, The presence of a nuclear chlorine ftom appears to improve the yield somewhat. Although a faiely representative group of aldehydes and ketones has been investigated, no systematic sty ofthe effet ofthe structure ofthe carbonyl component ‘on the yield of glycidie ester has been reported Halogenated Esters chloro esters are preferable to bromo or ido esters although bromo esters have been used successfully. With eyelohexanone, it has ‘been shown that the p-toluenesulfonate of ethyl glyeolate may be sub- stituted for the chloro ester With ethyl ehloroacetate, isobutyro- Phenone yields the glvcdie ester, whereas with ethyl iodoaoetate it ‘yields an alkylation product, ethyl 8.¢-dimethyl-g-benzoylpropionate; ‘vith ethyl bromoscotate « mixture ofthe tivo products resulta (cmcH 0, cxmscowany \, Senos cScnco.cats Cai COCTICHs cat MEMEO stcture of A and JEREMY, CH1,00C(CHCHLCO4CsH, ‘@ Very litte is known of the condensation of halo esters other than hhalo acetates, halo propionates, and halo butyrates, ethyl a-hloro- Taurate being the only example of «higher ester desribed.” ‘The effect of the alkyl group of the halo ester on reactivity or yield Ihas not been investigated to any extent. If sodium amide is the con- densing agent, the ethyl ester is preferable to the methyl ester because of ineressed formation of ehloroacetemice with the methyl ester." Tn experiments involving acetone, benzaldehyde, acetophenone, and eyelo- hhexanone the following alkyl ehloroacetates and chloropropionates gave Yiels comparable to those obteined with methyl and ethyl esters: {Yoon JO hem, 1 5701040. {Newman nagar dm. Chom Ss, 68, 40919. ‘ead Ramar Lacy Gp os 8,18 0) Oa, pb, BIOS ra, 0, 1 coa8 ORGANIC REACTIONS propyl and isopropyl, aly, cyclohexyl, nam, benzyl, and 2-thythexy}; With @methally and tetrahydrofurfuryl esters the yields were lower, ‘There i some evidence that better yields of condensation products may bo obtained with halo amides. An 80% yield of glide amide is ob- tained from acetone and the diethylamide of chloroaeetic acid * whereas with ethyl chloronestste 4 much lower yiekls result, However, it has not been shown that the give amides can be hydrolyzed and deearboxylated to give aldehydes or ketones in iiproved yields ‘More complex halo esters, such as ethyl g-hydroxy-<-chloropron ate,® ethyl eB-ichloropropionate, and ethy! a-beomo-8j-diethoxs= propionate" have failed to undergo the glyedie ester condensation. Other Halogenated Compounds Certain other halogenated compounds have been used in place of halo esters. a-Halo ketones have been condensed with a variety of aldehydes to yield «2-epoxyketones °. emorny nef; £223 net Seucow CHO + CICH.CoW ‘Theso epoxyketones may condense with second molecule of halo ketone to yield «,i;riepoxyketones* °. 4 exon Roftcucor’ + pics,con 2", ©. é Non neh Sen—enrcon b When t,f-dibromo-L(-libenzoylbutane is treated with sodium, cyanide," diethylamine,* sodium acetate" or the sodium derivative yon Sel, Be, 68, 971 (199, 2 Yul and Wali Oe he 296 (109. Oro mt pont J. Ch a 6 21 (ON idan, a) ts 86 Deaton, Bere 8 vane () Bor th 202 "SMusaanl wo ,Proe Top eat, 1, 68 (196 (24,98, 289 ORD. Kao and Foson, 7 dw, Chem, Sec, By 310 Gi). ‘THE DARZENS GLYCIDIC ESTER CONDENSATION 419 of malonie ester ® a eyclic epoxyketone is produced; with molecular ver the debrominated analog is obtained” ° X ch K CHLCHB COCKE — yyy Ofle Catts Exxcusscocat, “=” Cxte—Coocate Br & | Z poate sont, Ml sire” CHty—CHCOCats A number of substituted halides of the benzyl %5% and bensal types has been condensed with aldehydes and Ketones to give epoxy and erhaloeposy compounds in yields which, although wsslly not stated, ‘vere often good. Stereoisomerie forms of the epexy compounds were ‘oveasionaly separate. ©. ottis ao nem,cl+ Reno 28% nofi—cur 9. ZX, roca a orto + wero Si ‘The aldehydes sod include benzaldehyde, o» m-, and pritrobenzal dehyde, pmethoxybenzaldehyde, diphenylacclaldehyde, cinnamalde- Inyle, and furfural; the Ketones were Mluorenone and 2,7-libromo- fluorenone. As halides, and p-aitrobensyl chloride, 8-ehloroluorene, ‘nd O-bromo-t0-anthrone were used a, J Am, hom Se 2861040. ‘ty Hse imal tat, Sesour, 10H, Baro, ema tio Stora 10.) Chet, lonagl dation, Sabor, 1 ‘smelt Ca ‘% Bergimann and Hervey, Ber, 8, 902 (1820)- ORGANIC REACTIONS: ‘Side Reactions Fear investgntors have studiad the non-lyeidicester portion of the ‘eaotion products. Some unchanged Ketone may usally be recovered Possible contaminants of the glycidie estrs are tho isomevi oxygen of carbon alkylation products formed hy alkylation of the enolate of the ketone by the halo ester. The boiling anges reported forthe glyciie ‘esters usually cover 8-10°, so that such contamination is entively pose sible. ‘Tho condensation product from f-ionone and ethyl chloroneetate fs considered to be a mixture of three isomeric products: glyciie eter; ‘rketo ester; and the enolic form of the latter “Halogen in the con ddensation products indicates the presence of nn a-halogen a,S-insnti- rated ester" High-boiling prodiets, including resinous material, are frequently noted. “These may result from self-eandensation of the alde- hyde or ketone * or of the halo ester; eth chloreacetate in ether reacts with sodium to yield an ethoxy ehloro neetoacetate of sndetermined structure Vacuum distillation of high-boilingglyeidie esters should Do done at as low a temperature as possible in over to gud against rearrangement to an aketo ester SELECTION OF EXPERIMENTAL CONDITIONS. ‘Tho reactions are eared out under strictly anhydrous conditions preferably in an inert atmosphere. Often no solvent is used, care being taken to provont undue temperature rte when the condensing agent is added. It seema lat to add the condensing agent to mixtte of the reaction components, of which the halo ester is preferably im some excess Tt has been found * advantageous to use 1.6 moles of ehloro ester and 1.6 moles of alkoxide to I mole of ketone, During the frst stago of the reaction itis well to koop the mixture cold, temperatures as low as ~80" being recommended However, in afew eases no reaction occurs at —80°, and a temperature of 0 appears to be preferable “After reaction periods ranging from afew hours to afew days, the mix- ‘ture is usually heated foran hour ona steam bath, ‘The restion mixture is then treated with dilute acd and the organic products are generally must ts, 'Weseh ad Dai Bos Yamal ae Wal Ont Cham 4,20 (100, ‘THE DARZENS GLYCIDIC ESTER CONDENSATION 42 separated hy vacuum distillation, Ab least one glyeidic ester re- artanged into an keto ester at the high temperature needed for vacuum s =| 47 | | —Axo*nOHO"IO— sxomeogoPOLEHETE w | =| a@ | SHO NOHD'O— HeoommoRe RHODE : =|" a) | —uo"aoHo— Soom wo | -| a z | a] ¥ x] Ho —H9 euosagdoney wis; oa ' «| y H 4 —39) epsopremog w | »] 9 n n| —onto4! epkoprroanorirt wo | a] ¥ m0 x] So spkgoprereocttre e =| ¥ =| 5 —r%9| ¥ joe] y = | aoe w | ose] y = Steno! a | ssf ¥ =D aa ¥ so} ¥ wo | mf) ay H —"eH01— ¥ a] “y Ho X oro a | ml y¥ H x =a wf] oe] a x] po =°9| x | «| a x] 0 —n'9| 2 | =| 9 x} So] mon & =| ¥} up| 80 =H wf ool ¥ H —"6H0)— 2 s| oy zl Ho =o = ty =H # -ow © ¥ 0 2 8 H ow ot a w v n| | —H0 — 20 e y suo] AD Ho ¥ v XH H a9 ¥ v Ho H HO a y 9 x) —H0 10 cuooy : al 9 80 suey 9 Ei H = epson v = H H opsyepreas0H oat a ra may msg 9 PAD sosup moody ug, 109 ft 0 ON a sunieg oraa4p, 1 a1av433, ‘THE DARZENS GLYCIDIC ESTER CONDENSATION ORGANIC REACTIONS S| eo] HO H au -| ¥ x9 | H HB] —*HO*O'O) sp kgpprentogcxopouna-e's 00 =| 9 x9 | x] = up| Hr00'HO ‘suouoydorsouAioysoy(-d o wl ov —tHo| Ho H| = —HrO0'HO + =) ¥ —Hto| HO u| — —H'00"HO t ain |e] ov Ho) ul —H9) BD enone pamper He =| 4@ oF wl ov Ho x] Ho) 9 | soouaydordony oF =| 9 HO H H 89 | epdieprermon equ y's oF =| 9 HO H H 9 | physprarmquarnt a ow] ¥ Ho) —n9) H n°] pageprint a -| ¥ c | ero | ¥ HO ul HO 9 | soon n -| a sis [ec] oy no} to] = HO. 9 y =| oy e sr | bh Ho] Ho) H 08RD y Er ul —H9 =n o HD nl HO WO v HO) = HO || —FHO}'HOHOFeHO)— a v —o| Ho] #8) HOHO*HO— v | HO CHO! OHO v Hr | Ho HO v v Ho | Hu) —HO v HO | ul HO 2 HD H H ¥ =o] —o H ‘sphyopreraaq’ v Ho] HO H ep cypprezageompaTy-o a v #9 ul a9 ououaydornoy a ar i 1 ‘spduoprenor at v 10) HO H ‘opsqopreeog, 2 HO H H (quuomedsd) spqopresmegcoompo STONE o v Ho] HO 7 ‘suousHGOIAD a au al | a esnow | 9 | amy ‘snag sais PPS tema | pix [28° ‘ouodiey [u0q20- a at aa AOI a swuisg, a1e295 pomunog 1 SIEVE,435 ‘THE DARZENS GLYCIDIC ESTER CONDENSATION oh ORGANIC REACTIONS 8 v 9 BH) Ho os | 88 v HD x] Ho z | coo} ¥ = x) HO 4 =| ¥ = ul] —H Hoe ono vanaaens TAT L | ¥ n° nu) —HO HT ouoey Laer TE w -| ¥ Ho nu) HD C4 =| 9 saz joo! ¥ 9 x] HO % ar =| ¥ =| HO SOs 00 a) =H B| HD) 1 ee or} ¥ i) 2) H : o =| ¥ = a H sar oF =| 9 =H H H =n =| 9 =m z H =H, o -| 9 lise} ee) 5 e -| ¥ no) +n) * 6 | 9 ver'er | 205 | ¥ nH u >Matod 2 a | shy, = | —aro B| —nY90%n0| © =|" 9 =n H) | SHO z | sow] ¥ E70 nu] Ho z | so} ¥ 9 nu) HD 2 a) oy | nto x] HD & =|) 4a <9 BH) Eto 2 we) ¥ Eig on yu) e =| ¥ to] Ho) —H0 | & =) ¥ —H9 H z = & =| ¥ x9 B z = wwe | —| vo = H E a 0 wl) ¥ | —n'9 E ee a} ¥ no) 9) B| —'H'9Ho) e =| ¥ =| —p) = Ho) : z | cow} ¥ =n rn) " —HoenFO)HO 1 or) oy | HDHD zn) 9 9 uy w | see] ¥ BD 1B) —GHO}HO)N"HOHO— some opto viqyomongemsTIoEREE a -| 4a —H'9| —tu'9]—- #Cup)tHOHO'HO— snoumsaror Srsman-e a a a a guy menog 35H PAID od ‘auodimeg (00g) 109, a NAN, Na ponusnog—1 TIGVE‘THE DARZENS GLYCIDIC ESTER CONDENSATION 437 ORGANIC REACTIONS ‘Fresh ad wes hon BON 1188 ees bautii << 0044 o«0mm Oo uormpoapavospsyect suouegdonoy snomereaeF6) spkpraaaq oy sean SONNE an CoC avowed PMomoqopcxtmomnr-g et suomoy¢ 000-0 snowing ¢-(uqdsoxdostd-y opaqoprerwoqnSdaxdoencr-¥, uous dost, oommepig-z uovodmeg 1Au0q0-) swsasq 11x10) ponumwog—1 aTEVL438 ORGANIC REACTIONS ‘THE DARZENS GLYCIDIC ESTER CONDENSATION 490 ‘TABLE IE ‘TABEE TE Garerne Asors Cuomo pronoxy Berens “ae rata ind he a nh ie tein ‘The seni te ‘The procdare nels the ation a amis of kone nl pede eter wale ne hoe habe” © in eth to into (to 0) tages sani Althe shloe fipdony ess vero cml ia high ped to epony ent by trates ith aie rages (Caxbonyl Component Produce Ya Cote Compan mu] ae, eee Accalishyde cuscHoNcHcico,cat ” Aone (Clissconcnercoscith, = satya (GinkenchoncHGcozcm, | os | Grelopentanone Cha contentcicoxcatt = wl Fetches {Clisysconcucicoscat, a gle Benak eaticontcnercoxci = “| 8 epee fcinicrp,cuoncnccocn, | & =| 8 Acstophencae CalCONCHCICO.CE, % =| % Detgtomndonterone - pn] it co a ™ Pitrocon se who pneu wad, a Ma Cine Fda, [REFERENCES TO TABLES Neate, ona 3, £50 (100. ‘Arann Pues Phorm: Se Jepan, No, 400, 1066 (023) (Ay 1, 2678 oom" ‘Mol ar pat. 708,07 (6 8 5 010). 1 (a) nitena and Antwan Sf Tyo Buniba Dale, 24, 128 187) {est, 851 Gun: @) Crmaman, Halon Say ad Lacey Chm, Set 188, "demon, J An. Chom Se, 87,728 (198), ‘Demme nt Pee Cho So 997,100, ‘cm Awe uy di, 1 C01, © Newman, Mor nd Whew J. Chem, Su, 64 2112 (14D, ‘omer and Drea Ber 740 (40, 1 nd me Gero me, CDE Retr ad Pr Ber 8,207 0 2 Vests hin Free, [3 68100, a oem le Femmes, fhmarmen U8. pa. 80219 C4. 254 QOL Barun, Gr pt 04270 (Ct C1007) 2 Data mi Che Sy 38 263108, Aue J ral hom, 08 i Rs an Kaper Cham, Se, 1831 2 Bradt: Plat, ad Some J Chi 1 "nc nd Trobe, Hats Chet, (102). "fase and Kovtun, th Chin A194 (1 atin, U3 pots 2h casa 3 S04 1D) US at. 8.300100-2.9007 fn (CA, 39,5086 KD) U, 8p BASAL, a, HF CT "Sil and Tueastac, Ber 6 2016 (10), ‘Rbinen and Lowe, Eng at 519804 (CA 96,873 (180) Yarn and Wally in, Chom, Ss, 68 Q51 (57); Yamal and Wall, J, Or haa 37 0009. ‘onrans lear, nd owt J. pharm, cin 19 (000 (CA, 2, 81791900, Mir nd Rag, Ch Ata, 3,184 (1080); Cheng Tay, 8,276 can.