Aromatisation

Phenyl trichloromethyl mercury, often used as a source of dichlorocarbene, promotes dienone-phenol rearrangements in the normal sense, converting 

Bromination of 5-en-3) -ols (632) with l,3-dibromo-5,5-dimethylhydantoin, followed by dehydrobromination with collidine, gave the 2,4,6-triene (633), and its rearrangement product, the 4-methyl-l,3,5(10)-triene (634). The conversion of the l)9-methyl-5-en-3)9-ol (635) into the 3,4-dimethyloestra-l,3,5(10)-triene (636) shows that the aromatisation involves the usual C-5 spiran, and not a sequence of methyl migrations (10/ — 5)8— 4). Preliminary formation of a 4-bromo-derivative is implicated.  

Electrophilic addition of F onto a 4,9(1 l)-dien-3-one (637) caused 10/8-methyl migration to the electron-deficient C-9 (638), allowing aromatisation of ring A (639), although normal addition occurs with an isolated 9( 11 )-ene (p. 296).  

A unifying interpretation has appeared of the various results obtained in Favorskii rearrangements of 17a-halogenopregnan-20-ones e.g. 640) and related compounds. Two mechanisms appear to operate, their proportion being 

A Favorskii-like intermediate (655), and the rearranged product (657), arise in a novel way from fragmentation of the a-ketol enol-sulphite (654). Loss of sulphur dioxide is thought to afford the zwitterion (655), which gives the methoxy-ketone (656) in methanol, but the A-nor carboxylic ester (657) with sodium methoxide in ether.  

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This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

However, the ethoxy group of l-ethoxy-2-propylbuta-l,3-diene is no longer present. Evidently the p-toluensulphonyl eyanide (2) undergoes [4-1-2] eyeloaddition to l-ethoxy-2-propylbuta-l,3-diene (/). The resulting dihydropyridine 3 aromatises with 1,4-elimination of ethanol to form 2-p-lo y -sulphonyl-5-propylpyridine (4). 

The mechanism of the Cook-Heilbron reaction between a-aminonitriles and dithioformic ester 6 proceeds via an acyclic intermediate 7, as proven by its isolation in several cases. Nucleophilic attack of the amine function on the sulfur-bearing carbon leads to the elimination of hydrogen sulphide. Cyclization of the acyclic thiacetoamide results in a five membered ring which aromatises favourably to give 5-amino-2-benzylthiazole 8. 

Scheme 44 The role of acetic anhydride in the aromatisation of cyclohexadienone...

A plausible pathway is that the aromatisation of the cyclohexadienone 92 by a proton shift is accelerated in the presence of Ac20 under formation of acetate 93. The simultaneously generated acetic acid then cleaves the acetate to form the free phenol 94 (Scheme 44). This effect was observed for the first time during studies towards the total synthesis of the lipid-alternating and anti-atherosclerotic furochromone khellin 99 [64].The furanyl carbene chromium complex 96 was supposed to react with alkoxyalkyne 95 in a benzannulation reaction to give the densely substituted benzofuran derivative 97 (Scheme 45). Upon warming the reaction mixture in tetrahydrofuran to 65 °C the reaction was completed in 4 h, but only a dimerisation product could be isolated. This... 

A smdy of the halogenation of polyaza heterocycles is in progress. In the case of quinoxalino[2,3-c]cinnolines it has been found that using HCl or HBr in chloroform halogenation occurs at C-10, with protonation atiV-12, and subsequent oxidative aromatisation (Scheme 19) < 96JCS(P1)1699 >. 

Wo could have disconnected (b) in the same way, but we want eventually to get back to (1) so we aim to make ring B by oxidative aromatisation of (5) and bond (b) can then be disconnected because of the remaining 1,3-dicarbonyl relationship. 

In the synthesis, aromatisation of rlnfr B and oxidation to quinonc were two separate steps. 

Schneider, M., Zimmermann, K., Aquino, F., Bonrath, W. (2001) Industrial Application of Nafion-Systems in Rearrangement - Aromatisation, Transesterification, Alkylation, and Ring-Closure Reactions. Applied Catalysis A-General, 220, 51-58. 

THCs is converted to a earbonyl group and the C-ring is aromatised. Speeies differenees in CB2 binding aetivities of these eompounds were observed (372) and AM 1714 (373) showed 10- to 15-fold higher affinities at rat CB2 than human CB2 [230],... 

Parrott R. (1978). Courtship and copulation in pre-pubertally castrated male sheep (wethers) treated with 17a-estradiol, aromatisable androgens or DHT. Horn Behav 11, 20-27. 

It was unfortunate that we did not detect any product derived from a diketone in the reaction of w-dimethoxybenzene with tetrafluoroben-zyne. We therefore carried out a reaction of tetrafluorobenzyne with 1,3,5-trimethoxybenzene. The di-enol ether (80) could not be isolated, and after the removal of unreacted 1,3,5-trimethoxybenzene we isolated the phenolic acid (81) in good yield. This compound is undoubtedly formed by the hydrolysis of (80) followed by a retro-Claisen condensation, and aromatisation as shown below. 

Stabilisation, through delocalisation, can also occur through aromatisation. Thus l-bromocyclohepta-2,4,6-triene(tropylium bromide, 6),... 

The operation of (d) is seen in cyclopentadiene (14) which is found to have a pKa value of 16 compared with 37 for a simple alkene. This is due to the resultant carbanion, the cyclopentadienyl anion (15), being a 6n electron delocalised system, i.e. a 4n + 2 Hiickel system where n = 1 (cf. p. 18). The 6 electrons can be accommodated in three stabilised n molecular orbitals, like benzene, and the anion thus shows quasi-aromatic stabilisation it is stabilised by aromatisation ... 

This too is a Hiickel 4n + 2 p electron system (n = 2, this time) and shows quasi-aromatic stability stabilisation by aromatisation has again taken place, remarkably this time in a doubly charged carbanion (18). 

In addition to the expected o-aldehyde (68), it is also possible to isolate the unhydrolysed dichloro compound (69). Attack by CC12 at the p-position in (67c) yields the intermediate (70) which, unlike the intermediate for o-attack, has no H atom that can be lost, as H , to allow the ring to re-aromatise (70) thus just acquires a proton, on final acidification, to yield (69). The dichloro compound (69) owes its resistance to hydrolysis partly to its insolubility in the aqueous base medium, but also to the sterically hindered, neopentyl-type environment (cf. p. 86) of the chlorine atoms. 

This reaction also is concerted and proceeds via a six-membered transition state, but here the species (59), corresponding to the ene-one intermediate (53a) in the aromatic Claisen rearrangement, is in fact the end-product. This is so because there is in (59) no energetic driving force, comparable to re-aromatisation in (53a— 52a), to promote its enolisation. 

Calorimetric investigation of a Diels Alder reaction between propenal and a triene, which had caused problems on scale-up, showed, after the exotherm due to the Diels Alder reaction, and from a temperature a litle above 200°C, a second, more exothermic, reaction with a very fast pressure rise which burst the ARC can employed. This is presumably aromatisation of the alkenylcyclohexenealdehyde first formed, with probable liberation of hydrogen and carbon monoxide. 

In Roman times tar and pitch from Pinaceae resinous wood were used to treat the inner surface of amphorae to store fluids such as wine [ 145,149] and to seal ship planks [89,144], Heating treatments applied to natural resins and resinous wood profoundly modify the chemical composition of the original material. Diterpenoid compounds undergo aromati-zation, demethylation and decarboxylation reactions, with the formation of new compounds of a lower molecular weight that show a high degree of aromatisation [87,88]. In tar and pitch produced from Pinaceae resin and woods, retene is considered as a stable end product of these reaction pathways and nor-abietatrienes, simonellite and tetrahydroretene represent the intermediates of these reactions [87,89,150]. 

Conversion of other heterocyclic systems into pyridazines has also been used, for example the reaction of 3-aminopyrone 9 with hydrazine, followed by oxidative aromatisation <06T9718> and the more unusual utilisation of a 1,2,4-triazole 10 as the source of the N-N unit <06T8966>. In this latter transformation, the intermediate quaternary salt 11 was isolable. An even more unusual example was the reaction of the diazetidine 12 with enolates <06S2885>. 

Reaction of 1-tetralone with aryl cyanides or methyl thiocyanate, followed by aromatisation with DDQ gave good yields of benzoquinazolines. The further transformation of the methylthio product 31, via oxidation and selective sequential nucleophilic substitution of the resulting sulfones, illustrates the utility of this substituent. 2-Tetralone reacted similarly but substantial amounts of by-products were formed <06T2799>. 

Quinazolines 51 have been prepared by the condensation of A-aryl carbamates with hexamine, followed by aromatisation of the dihydro intermediate. A variety of mono- and di-substituted anilides were used, mefa-substituted starting materials giving 7-substituted quinazolines <06T12351>. Benzoquinazolines were also prepared similarly from naphthylamine carbamates <06OL255>. 

A variation on the usual synthesis of pyrazines, reaction of 1,2-diones with diamines, was the use of the diazabutadiene 81 in place of the dione <06JOC5897>. In another paper, the same diaza compound 81 reacted with sarcosine methyl ester, in a complex set of reactions, to produce quite good yields of 5-oxy-pyrazine-2-carboxamides 82. The A-methyl was lost and direct aromatisation occurred, presumably, due to cleavage oftheN-N bond <06SL2403>. 

In a new reaction of the pyrano[2,3-c]azepines 40 with hydrazine hydrate, the first derivatives of the pyridazino[4,3-c]azepine system 42 (for example R1 = R2 = Me) have been described (Scheme 10). The rearrangement probably involves initial ring opening to the intermediate 41. Aromatisation of this system was achieved by further oxidation with thallium (III) nitrate or copper(II) acetate . 

The electrocyclic ring opening is prevented by the energetically more favourable process, the aromatisation. The cis-hexa-1,3 diene is stable at 100°C but undergoes electrocyclic closure at higher temperature. 

One approach to interfere with ER signalling is to reduce the circulating level of its ligand estradiol by inhibiting the enzyme aromatase. Aromatisation is the last step in the synthesis of estradiol. This reaction is catalysed by the P450 aromatase mono-oxygenase complex that is present in the smooth endoplasmic... 

Fig. 6 Enzymatic reactions leading to aromatisation, according to Brueggemeier [73]...

Fadel F, Titouani SL, Soufiaoui M, Ajamay H, Mazzah A (2004) Synthese de nouveaux derives tetrahydroquinoleines et quinoleines via la reaction d aza-Diels-Alder suivie d aromatisation. Tetrahedron Lett 45 5905-5908... 

The system Ru2(OAc) Cl/O2/toluene/50°C oxidisedR CH NHR to imines R CH=NR converted 1,2,3,4-tetrahydroisoquinoline to the 3,4-dihydroisoquinoline with isoquinoline, and 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline to 6,7-dimethoxy-3,4-dihydro-iso-qninoline (cf. mech. Ch. 1) [18], Such oxidations were also catalysed by TPAP/NMO/PMS/CH3CN, e.g. the conversion of indoline to indole (in which indoline nndergoes a donble-bond shift and aromatisation), and the oxidation of 1,2,3,4-tetrahydroqninoline to 3,4-dihydroquinoline (Fig. 5.1, Table 5.1) [19]. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

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