KODAK Laboratory Chemicals ISSN 0096-221 X Volume 55, No. 3, 1984 THE CHEMISTRY OF THE DDUCT Chem No. 50157 By Robert J . Clemens 2,2,6-Tr1methyi-4H-1 ,3-dloxln-4-one Exploratory Organic Chemlstly Re sea rch Labora1ory Eastman Chemicals Division Tennessee Eastman Company Kingsport, Tennessee CAS Registry Number: 5394-63-8 Introduction Typical Assay: 97% min Boiling Range: 65-67·c 0.2 Torr (typical) Diketene is widely used in synthetic Density (20.C): 1.09 g cml organic chemistry, especially for the Synonyms: Diketene-acetone Adduct; TKO preparation of acetoacetates and List Price: $15.50.500 g heterocycles. The extreme reactivity of diketene, along with its lachrymatory The incorporation of the elements of diketene into pigment, pharmaceutical, and nature and instability to room temperature agricultural chemicals is an important area of synthetic chemistry. In cooperation storage, make diketene inconvenient to with Eastman Chemicals Division. Kingsport, Tennessee, we are pleased to announce use. Unfortunately, few alternatives are the availability of 2,2,6-trimethyi-4H-1,3-dioxin-4-one, a versatile synthetic organic available. intermediate that can often be used in place of diketene. but which is much more Diketene reacts with acetone to form a convenient to store and handle. In addition, 2.2,6-trimethyi-4H-1,3-dioxin-4-one has a 1:1 adduct, 2,2,6-trimethyi-4H-1 ,3-dloxin-4- unique chemistry and can therefore be used to prepare new compounds not possible one (1), 1 in excellent yield. 2.3 This with diketenc. As illustrated in the accompanying article, reactions of this dioxinone dioxinone (l) is a nonlachrymatory liquid normally requ1re no catalyst. proceed m h1gh yteld, and provide high-purity products. which can be safely and conveniently Acetone is the only by-product when used for acetoacetylation and cyc/oaddition handled at room temperature, and which reactions. Whatever your needs, we assure rapid delivery of either laboratory or can often be used in place of diketene. industrial quantities. and at a very attractive price. Our 500-gram offering of 2,2,6- Furthermore, dioxinone 1 can also be used trimethyi-4H-1,3-<Iioxin-4-one is available directly from your local dealer. Please direct for the preparation of a vanety of all custom-size inquiries to (716) 724-4879. compounds not accessible from diketene. For Research and Development Purposes Only This article describes the chemistry of the diketene,ace tone adduct (1 ), a compound which is expected to become a very important synthetic The acetylketene (2) generated by the pyrolysis of dioxinone 1 organic intermediate in coming years. rapidly acetoacetylates alcohols and phenols in excellent yield - (Fig. 2).5 These acetoacetylations are usually run either neat Acetoacetylatlon Reactions (120-140•C) or in refluxing xylenes; the reactions are stoichiometric The diketenejacetone adduct (!) is frequently referred to as a and require no catalyst. Product qual ity is generally excellent if the diketene equivalent because of its exceptional abi lity to acetone is efficiently removed from the reaction mixture. acetoacetylate a variety of nucleophiles. At temperatures above 0 0 100"C, dioxinone decomposes via a retro Diels-Alder process to 0 l . H.coocCH.cCH, yield acetone and acetylketene (f).4 . H.cQOH J:'JcH 91 '- H C 0 CH, 0 r H c.O] 0 0 lH,C(: OH ! 0 SO% Fig. 1 H C{{~ page CH1 0 0 CH, 0 0 Chemistry of the Diketene-acetone HOCH,CCH,QH - CH,CCH,.COCH,CCH,OCCH,CCH Adduct by Robert J. Clemens. 1 H C{~ CH CH , Drimarene Red Z 2B. 5 New Products. 5 0 HOCH, 1-Phenyl-JH -tetrazole-5-thiol HO OH 97% Sodium Salt for Users of the HC~\~H · ~OH KODAVUE™ Kit .. ........... 6 5 ACS Reagent Chemicals . 6 Fig. 2 . Eastman Kodak Company, 1984 As expected, the acetylketene generated via pyrolysis of reaction. Dioxinone 1 reacts with water to form acetoacetic acid, dioxinone 1 is extremely reactive and therefore excellent for which rapidly decomlx>ses into acetone and carbon dioxide. acetoacetylating hindered alcohols and for peracetoacetylating polyols. Glucose, which cannot be pentaacetoacetylated with 6 0 diketene, is fully acetoacetylated with dioxinone 1. 0 0 0 1 Because of the reactivity of acetylketene, acetoacetylations with 2 £CNHPh 6 t.xCNHPh dioxinone 1 are not selective and would not generally be indicated LJ-cH, + Xylene H,C N CH, for use when only one of several hydroxyl groups is to be H C 0 CH Ph~ CH1 70% Ph functionalized. 1 ~ Thiophenols are also smoothly acetoacetylated in good yield ~ (Fig. 3). 0 1 0 0 (XC0 EI H,C I N CH, 0 H ,(~CH 1 1 H C 0 CH, I' Fig. 6 Dioxinone l reacts with N-morpholino-1-cyclohexene to provide Fig. 3 the chromone§ in good yield (Fig. 7).9 Dioxinone 1 acetoacetylates amines, both aliphatic and aromatic,5 and is the reagent of choice for acetoacetylating amides (Fig. 4).7 0 Primary aliphatic amines are best acetoacetylated in refluxing H,c-CO toluene; the lower temperature lengthens the reaction time, but --7-~'~~~-- also dramatically reduces side reactions such as enamine formation. Although p-nitroaniline and diketene do not react in the absence of a catalyst, p-ni troacetoacetanilide is easily prepared from 1 without Fig. 7 any catalyst. - In another type of heterocyclization reaction, the acetylketene undergoes a 14 + 2] cycloaddition reaction. The simplest example 0 0 of such a reaction is the formation of dehydroacetic acid (7) via 6 10 n-C,H,.NH., (n-C,H.,)NHCH,CCH,CCH, dimerization of acetylketene (Pig. 8). This is an interesting 1~CH , Toluene H,C 0 CH 14 tv example of a reaction in which two reactive intermediates combine 73% ! to provide a single product in excellent yield. 0 0 0 NHCCH,CCH, 0 OHO ~CCH, ,(JcH, Xyteno 6 JOITIIn./93% /,:~ cH , ----=-=---- 97% H,C 0 CH, 6' 0 H,c 0 CH H,cA.o-Ao NO, NO, 1 z 0 0 0 0 0 Fig. 8 + RCNH , RCNHCCH,CCH, L,tcH, Xylene H.C 0 CH 71).9()% Dioxinone 1 via acetylketene, also reacts with ketene acetals and vinyl ethers at elevated temperatures to afford the corresponding 1 R• aryt. all<yt dihydropyrones (§) and pyrones (~), respectively (Fig. 9).9 Tetramethoxyethylene affords a dihydropyrone derivative (10) upon Fig . 4 reaction with l ·4c - Preparation of Heterocycles from Dloxlnone ~ 0 0 CH, 6 The elevated temperatures used for acetoacetylation with dioxinone + L_tcH A 70% HC 1 often result in spontaneous cycl ization of intermediate H,C 0 CH EIO OEI ~-eo acetoacetates to provide heterocycles, as seen in the preparation of ' ~1:. 6-methyluraci l @ from dioxinone ! and urea (Fig. 5).7 1 0 0 0 CH, I ~ NH + + NH,CNH1 LJ-cH, A 30% AcOH - H c)LN__.lO H,C 0 CH, Ph OEI H,C L~CHcH, 0 68% I H Neal 74% Fig. 5 ).., + H,COXOCH, 6 ~~ . .Jl~~cH , --38-=~~~>'--- )LJ~ Dioxinone l also reacts with 3-anilinocrotonanilide (4) to provide H,C 0 CH · H,CO OCH, H,C 0 OCH~ ' the 4-pyridone 5 (Fig. 6);8 several other 3-aminocrotonates and P-aminoenones also give 4-pyridones in a sim ilar manner.9 In the 1 preparation of 5, the yield was greatly improved by adding an additional equivalent of dioxinone l to remove water from the Fig . 9 2 Dioxinone 1 reacts with simple carbonyl compounds such as Dioxinone 1 also reacts with pyridinium or isoquinolinium ylides cyclohexanone to afford new dioxinones (Pig. 10}, providing further to provide either new ylides or fused heterocycles (Fig. 13)_13 evidence for a reversible thennal dissociation of 1 into acetylketene and acetone. Dioxinone !lis much less labile than 1 and is stable at temperatures in excess of 150"C."' The more highly enolized 2,4-pentanedione reacts with 1 to fonn two products, resulting from I' both cycloaddition with the carbonyl group (12} and with the vinyl 71 .. alcohol (13}.9 - 0 0 Fig. 13 0 99% other Reactions of DloxJnone 1 !! Not all reactions of dioxinone l involve thennal processes and acetylketene. Dioxinone 1 is expected to become valuable as a protected fJ-keto ester, aS illustrated below: 0 Dioxinone 1 is readily halogenated at either the 5-position14 or 0 OH 5 ~ on the 6-methyl group (Fig. 14)_1 ,('1cH. H ,C CH, H.C 0 CH 0 0 0 0 ("yCCH, + .C.+CH,CCH, H,C-'--o)..CH, H.C 0 CH, j1(1~) Fig. 10 Fig. 14 lmines also react with dioxinone 1 and yield 1,3-oxazin-4-ones as These halogenated dioxinones have been used for the the major product (Fig. 11}. 11 Temperature control is important in preparation of 2-haloacetoacetate esters (Fig. 15) and for the these reactions, since some of the product oxazinones are unstable synthesis of acyl tetramic adds such as 14. under the reaction conditions. 0 0 I 0 Ct, O,No-oo ifCHCCH, + CH,• NPh ;i.j_C --7-=~%~- H,Co..Ph l,tcH, ~ D. (),N Cl H,CJ.O. ~H, H,C 0 CH, &I 'll> 1 1 0 0 1)~ ~IO),P()Na 2)CA ,.(';.CH, + PhCH • NPh H,Cla'J.:, -~~.c(l~· H,C 0 CH, 1 OH 0 0 CCIH,P(OEih 0 0 0 0 Fig. 11 (EIO),PCH,CCH,CNHCH,CCH, (j-o I Oxazine derivatives can also be prepared by the reaction of (<15'11> from ll H dioxinone l with isocyanates, cyanates, and cyanamides (Fig. 12).12 Fig. 15 0 R ~ Finally, dioxinone 1 undergoes photocycloaddition reactions in {o • A- N-c-o H.C 0~~ 5().~ H,C~ good yield (Fig.