Açil osetaldehitlere nötral-asidik ortamda diazo transferi
Transdiazotization of acylacetaldehydes in neutral-acidic medium
Yazar: ÖZKAN SEZER
Danışman: PROF.DR. OLCAY ANAÇ
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü
Derece: Doktora, 1994
Konu: Kimya = Chemistry
Dizin: Asetaldehit = Acetaldehyde ; Asitik ortam = Acidic medium ; Diazo bileşikleri = Diazo compounds

Özet:
ÖZET Bu çalışmada 2-azido-l-etil piridinyum floroboratın açilasetaldehitlere karşı reaktivitesi altı değişik koşulda incelenmiştir. Sodyum asetatlı ortamda çalışıldığı takdirde bu tepkime, a-diazo-P-oksoaldehitler için bir preparatif yöntem olarak değer kazanmaktadır. Böylece, formil-aktif metilen bileşiklerine diazo transferinin deformilasyonsuz da gerçekleşebileceği gösterilmiştir. Birçok tepkimede a -diazo- (3- oksoaldehitlerin yanısıra 2-diazo-l-substitue-l-etanonlar (diazometil ketonlar), acil substituenti R'nin elektron verici etkisinin artmasıyla paralel olarak artan oranlarda oluşmaktadır, m- ve p-Substitue benzoilasetaldehitlerin tepkimelerinde, diazoketo- aldehit/diazometüketon oluşum oranının Hammett eşitliği ile korele olabilmesi dikkat çekicidir. o-Substitue benzoilasetaldehitlerin tepkimelerinde ise ürün dağılımının elektronik etkilere olduğu kadar sterik etkilere de bağlı olduğu gözlenmiştir, a- Substitue-a-açilaldehitler olan a-formilsikloalkanonlar ise her koşulda azot çıkışıyla birlikte çevrilme ürünleri vermiş, a -diazo sikloalkanonlar ise eser miktarlarda oluşmuştur. Triazolin ara ürünleri üzerinden yürüdüğü kesin olan tepkimede diazometil ketonların, triazolinin bir retro-[3+2] tepkimesi ile; diazoketoaldehitlerin, triazolinin deprotonasyonu ile; çevrilme ürünlerinin ise triazolinin diazonyum tuzu oluşturacak şekilde açılmasyla oluştuğu ileri sürülmüştür. Triazolin oluşumunu vurgulamak için l-fenil-3-(N-metil-N-fenil) amino-2-propen-l-on'un 2-azido-l-etil piridinyum ve 2- azido-3-etilbenzotiazolyum floroboratlar ile tepkimesi gerçekleştirilmiş, beklenildiği gibi diazoasetofenon ve N-metil-N-fenil-N'-(l-etilpiridinyum-2-il)formamidin floroborat ile N-metil-N-fenil-N'-(3-etilbenzotiazolyum-2-il)formamidin floroborat iyi verimlerle izole edilmiştir. Benzoilasetaldehitin bazı tepkimelerinden yan ürün olarak izole edilen 3,5- dibenzoilpirazol'ün ise, ketoaldehit dimeri olan l,5-difenil-4-hidroksimetilen-cis-2- penten-l,5-dion'un tepkimesinden kaynaklandığı öne sürülmüştür. vı

Abstract:
SUMMARY / TRANSDIAZOTIZATION of'ACYLACETALDEHYDES in NEUTRAL-ACIDIC MEDIUM Diazo compounds constitute an interesting class of organic compounds, which are the main precursors of carbenes and carbenoids. hv, A, or R-C-R' ? R-C-R' + N2 nj calalysis Numerous examples of cyclopropane syntheses via carbene/carbenoid intermediates, generated pliotolytically, thermally or catalytically from diazo compounds can be found in the literature. An interesting topic is the 1,3-dipol behavior of some carbene/carbenoid intermediates generated from a -diazo- P- dicarbonyl compounds. The parent class of the latter is a-diazo-P-oxoaldehydes. Rh2(OAc).i R-C-C-C-H - R-C-C-C-H 6 n, b -"> 6 " Ö "2 R-C=C-C-H. R-C-C=C-H I « II I "o " o O " o" With this reaction dihydrofurans, dioxalanes, and 1,3-oxazoles can be synthesized from enol ethers/esters, carbonyl compounds and nitriles respectively. oc-Diazo-p-oxoaldehydes are represented in the literature only with three examples: Ethylformyl diazoacetate (R=OEt) and benzoyldiazoacetaldehyde (R=Ph) were synthesized by Vilsmeier formylation of ethyldiazoacetate and diazoacetophenone respectively, yields being 50% stochiometrically. Use of diazocompounds as starting materials for this synthesis is somewhat impractical. Furthermore, decomposition of one equivalent of the starting diazo compound makes the actual yield 25%. Moreover, attempted forrnylations of diazomethane, phenyldiazomethane, diazoacetaldchyde, and diazoacetone failed to give the respective diazoaldehydes, proving the ingenerality of the method. vuThe parent compound diazomalonaldehyde was synthesized starting from glycine hydrochloride, with a total yield of 43%. This method is not applicable for the preparation of the other members of the family. Therefore, a general synthetic method is necessary for this interesting and less studied class of diazo compounds. In the present study we approached the problem using the diazo transfer method, which is shown retro-synthetically below. R-C-C-C-H > R-C-CH2-C-H + R'-N, (5n,ö 6 Ö This route, selected especially among other possibilities for several reasons, is a challenging one, because it is generally used to prepare oc-diazoketones from a- formyl-ketones and sulfonyl azides, namely the so-called deformylative diazo transfer. This well-known behavior of acylacetaldehydes to eliminate their formyl group during transdiazotization in basic medium could be explained by two mechanisms, according to the literature: The only diazo compound formed througout the reaction is the a-diazoketone, resulting from the cycloadduct of sulfonyl azide and the ketoaldehyde tautomer. Alternatively, an a-diazo-P-oxoaldehyde is formed first, probably via a triazene intermediate, which upon solvolysis in basic conditions yields the a-diazo-ketone. The second possibility is out of the question if the transdiazotization is carried out in neutral-acidic medium. Thus, 2-azido-l -ethyl pyridinium fluoroborate was chosen as the transdiazotization agent, and the reactivity of this azidinium salt towards acylacetaldehydes was investigated at six different conditions. + RCO-CH=CH-OH - > RCO-C-CHO + RCO-C-H » II N2 N2 The reaction of the in situ generated 2-azido-l -ethylpyridinium salt with acylacetaldehydes in aqueous methanol yielded diazomethylketones as the only products, when no additives were used (pH«5. 3-5.5). Reactions of three ortho- substituted benzoylacetaldehydes (R=2,4-C12-C6H3, 2,4-Br2-QH3 and 2,4,6-Me3-C6H2), which yielded significant amounts of diazoketoaldehydes along with diazomethyl ketones are exceptions. Under the same conditions, the reactions of a- formylcycloalkanones yielded rearrangement products, and traces of (if any) a- diazocycloalkanones formed. C=0 " /--C^0"-H ^- C"°^H (CH2)n I J*±L» (CH2)n | |,_* (CH2)n || Ö Py® NH-Py9 C=CH-OH "N* V__CH^/N V_C^r^O VlllThese observations indicate the formation of a triazoline intermediate, which results via the dipolar cycloaddition of the azidinium salt to the (3-oxoaldehyde tautomer. The reaction of the triazoline from a-formylcycloalkanones prove that this intermediate may open ring to form a diazonium structure, also revealing the elimination inability of CH(OH)-N=Py group to form an a-diazocycloalkanone (Scheme 1.). (CH2)n C-CH-OH >(CH2)n C-CH-OH ^.rearrangement VN' Py® J v3>N2 *N-Py® SCHEME 1. Mechanism of rearrangement The triazoline from the reaction of acylacetaldehydes, therefore, does not ring- open to form a diazonium structure, and the diazomethylketones should result from a synchronous cycloelimination (retro-[3+2]) reaction (Scheme 2.). retro-f?*2] _. RCO-CH-CH-OH ^RCO-C-H*,0H ' > J'. H-C *N' -Py® yt l N-Py i t RCO-CH-CH-OH :, rearrangement ®N2 N*Py SCHEME 2. Mechanism of diazomethylketone formation This difference in reactivity can be explained by the structures of these hypothetical diazonium intermediates: The intermediate from the reaction of an acylacetaldehyde has (he carbon atom bearing the diazonium group with a hydrogen substituent; whereas the same carbon carries an alkyl substituent, whose electron releasing character is expected to stabilize the neighboring cation in the intermediate resulting from a formylcycloalkanone. This stabilization should result in a much faster ring-opening, competing with the slower retro-[3+2] reaction. IXAnother proof for the triazoline formation was provided from the reactions of 2-azido-l-ethylpyridinium and 2-azido-3-ethylbenzothiazolium fluoroborates with P-(N-methylanilino)acrylophenone which is iso-electronic with the enolic acylacetaldehydes. The expected diazoacetophenone and the two formamidine derivatives were isolated from the mixtures in good yields(Scheme 3.). PhCO-CH=CH-N-Me Het®= rf^S J\ L Et PhCO-CH-CH-f h Het-N* NTMe \s^" V SHet® Ph E t or SCHEME 3. Reaction of P-(N-Methylanilino)acrylophenone with azidinium salts By repeating the acylacetaldehyde experiments at pH=4.3-4.4 using AcOH- NaOAc buffer, significant amounts of diazoketoaldehydes formed along with diazomethylketones. When the same pH value was attained using two-fold concen trated buffer, increased formation ratios of diazoketoaldehyde/diazomethylketone were observed (Acidic-A and B). Clarification of this buffer concentration effect came through the Acidic-C experiments, in which the buffer reagent amounts of Acidic-B were changed (same amount of AcOH, but one-fourth amount of NaOAc, pH=3.9-4.0). At this condition diazoketoaldehyde formation was greatiy suppressed, even compared to Acidic-A, indicating that diazoketoaldehyde formation would be largely induced by NaOAc. This prognosis was proved by the results of the experiments in which NaOAc was used as the only additive (pH=7.4-7.8). This condition-E is most convenient for the preparation of diazoketoaldehydes, since the observed formation ratios of diazoketoaldehyde/diazomethylketone are the highest among all the conditions tried. Thus it has been shown that transdiazotization of acylacetaldehydes could go without deformylation, and 16 original diazo ketoaldehydes were isolated. oc-Forrnylcycloalkanones again gave rearrangement 'products, and a-diazocycloalkanones formed (if any) in trace amounts. Increasing electron-withdrawing character of the acyl R group induces the formation of diazoketoaldehydes. A search for a quantitative relationship between the data resulted in a good correlation using the Hammett equation in the benzoylacetaldehyde series (equation 1.; Acidic-A: p = 1.47; Acidic-B: p = 1.40; Acidic-C: p=0.78; Condition-E: p=1.58). log(DKA/DMK)x-log(DKA/DMK)M=p ox (I) (DKA: Diazoketoaldehyde, DMK:Diazomethylketone)ÜJ X3 C O o I X o II X O O o o o < X o ı X o II X o o er I < C O O °v X 5* D. x ' -J- U-2 / O O I + X * X i X O X o 0=2 O O tr x X cm X 2 ı e û. O X o 'cm z: u o a: O N '.& CO c CO.0 Ü a> xıIt is interesting to have such a correlation, because the usual data applied to the Hammett equation are either equilibrium constants or reaction rates, but not end- product formation ratios. Therefore this indicates the presence of two intermediates in the reaction, which are in equilibrium, and each is expected to yield one of the products. A plausible mechanism proposed for the reaction is visualized in Scheme 4. As mentioned before, diazomethylketones result from a retro-[3+2] reaction of the triazoline intermediate. Removal of the triazoline hydrogen, activated both by the acyl and azo (-N=N-) groups, leads to the formation of diazoketoaldehydes. The acidity of this hydrogen is the meaning of the substituent effect and the Hammett correlation. Buffer concentration effect can be rationalized if it is taken as reagent concentration(amount). Reactivities of the three aforementioned ortho-substituted benzoylacetaldehydes were explained by steric effects. As an example, the two ortho-methyl groups of mesitoylacetaldehyde prevent the acyl-phenyl coplanarity, thus the hyperconjugative electron donation of the methyl groups cannot be delocalized over the acyl group. The intermediate triazoline has its active hydrogen onto which the ortho-methyls employ steric pressure. Therefore, deprotonation of the triazoline is achieved even in the absence of additives. 3,5-Dibenzoyl pyrazole was isolated from some of the reactions of benzoyl- acetaldehyde with erratic yields. Formation of this unexpected product was attributed to dimerization of the somewhat unstable ketoaldehyde to l,5-diphenyl-l,4-hydroxy- methylene-cis-2-pentene- 1,5-dion. Deformylative transdiazotization of the latter is expected to give the vinylogous dibenzoyldiazomethane which yields the dibenzoyl pyrazole upon ring-closure and hydrogen shift (Scheme 5.). -HoO 2 PhCO-CH=CH-OH ?* PhCO-CH-C^ CHO PhCO ^CH X H CH ^, 11 1 -OH COPh COPh Py-N3 PhCO-C-CH H OH COPh II X CH PhCO-C *CH 11 COPh 1 ) 1,5- closure 2) ~H PhCO-j^)-COPh N- N H SCHEME 5. Mechanism of 3,5-dibenzoyl pyrazole formation xu