Ketones ring closure

The most useful route to indoles is the Fischer indole synthesis, in which an aromatic phenylhydrazone is heated in acid. The phenylhydrazone is the condensation product from a phenylhydrazine and an aldehyde or ketone. Ring closure involves a cyclic rearrangement process. 

On condensation of 4,4-dialkylthiosemicarbazides with a-halo ketones, ring-closure reactions only at Nl, N2, or S as well as subsequent reactions to pyrazoles are possible on account of the double substitution at the amino group.31,32,44 Thus, A, 7V-dialkyl-6//-1,3,4-thiadiazin-2-amines 4 are the exclusive products of these reactions and undergo interesting ring transformations to afford pyrazoles31,32,44 (see Houben-Weyl, Vol. E8b, p 562). 

A series of reactions, which ultimately led to a partially asymmetric molecule without intermediate resolution has been recorded. The penultimate step was the conversion of the amide-aldehyde (146) into the cyclohexenone derivative (147) by heating first with L-proline pyrrolidide and then adding methyl vinyl ketone. Ring closure to 148 was finally achieved by means of ethanolic hydrogen chloride. The resulting mesembrine (148) was partially optically active and the pure (-I- )-base hydrochloride was obtained from it by fractional crystallization 171). 

Allenic esters readily react with dialkylzinc reagents in the presence of DIFLUORPHOS-complexed copper (from Cu(OAc)2) in THF at -20 While this initial adduct bears no new central chirality, the intermediate nonracemic copper/zinc enolate can then add in a stereocontrolled 1,2-fashion to unsymmetrical ketones. Ring closure to the resulting S-lactone completes the sequence. Both 4 A molecular sieves and 20 mol% Lewis basic Ph2S=0 (or DMSO, hexamethylphosphoramide [HMPA]) are required to direct attack at the y-position rather than the otherwise reversible aldol event at the a-site, thereby facilitating conversion to cyclic products. 

A related ring closure is also successful in the thiazole series. Treatment of a /3-amino-a,/3-unsaturated ketone with thiocyanogen gave the intermediate thiocyano compound (323) which underwent ring closure to the 2-iminothiazoline derivative (324) (83MI40300). Related reactions are described in Chapter 4.19, and for those involving potassium selenocyanate see Chapter 4.20. 

The Frasca method for obtaining 1-arylindazoles also involves a C(3)—C(3a) ring closure (67CJC697). It consists in the cyclization of p-nitrophenylhydrazones of ketones and aldehydes with polyphosphoric acid. The Barone computer-assisted synthetic design program has found several new methods for preparing indazoles (79MI40409). The selected method involves the transformation of jV, jV -diphenylhydrazides (596) into 1-phenylindazoles (597) by means of trifluoromethanesulfonic anhydride. The yields vary from 2% (R = H) to 50% (R = Ph). 

Tetrahydroharman, m.p. 179-80°, has been prepared by a number of workers by a modification of this reaction, viz., by the interaction of tryptamine (3-)5-aminoethylindole) with acetaldehyde or paraldehyde and Hahn et al. have obtained a series of derivatives of tetrahydronorharman by the use of other aldehydes and a-ketonic acids under biological conditions of pH and temperature, while Asahina and Osada, by the action of aromatic acid chlorides on the same amine, have prepared a series of amides from which the corresponding substituted dihydronorharmans have been made by effecting ring closure with phosphorus pentoxide in xylene solution. 

The reaction of 4,4-bis(tnfluoromethyl)-I,3-diaza-1,3-butadienes with certain a,P-unsaturated ketones yields pyrimidine derivatives A two-step mechanism, metathesis-electrocyclic ring closure and metathesis-intramolecular ene reaction, is a plausible explanation for the experimental results (pathway 4, equa-bon 25) [259]... 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

In the initial step " the a-halo ketone 1 is deprotonated by the base at the a -carbon to give the carbanion 4, which then undergoes a ring-closure reaction by an intramolecular substitution to give the cyclopropanone derivative 2. The halogen substituent functions as the leaving group ... 

Upon treatment of a divinyl ketone 1 with a protic acid or a Lewis acid, an electrocyclic ring closure can take place to yield a cyclopentenone 3. This reaction is called the Nazarov cyclization Protonation at the carbonyl oxygen of the divinyl ketone 1 leads to formation of a hydroxypentadienyl cation 2, which can undergo a thermally allowed, conrotatory electrocyclic ring closure reaction to give a cyclopentenyl cation 4. Through subsequent loss of a proton a mixture of isomeric cyclopentenones 5 and 6 is obtained ... 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

Michael additions followed by further Michael additions have become popular reactions and are usually referred to as Michael Michael Induced Ring Closure (MIM1RC) reactions. A three component Michael-Michael-aldol reaction of ketone enolates with acrylates can be achieved, resulting in the formation of six-membered ring compounds with good efficiency and high diastereoselectivites319. 

The mechanism for aldehyde-derived enamines involves a Michael-type 1,4-addition of the enamine to the alkenylcarbene complex to generate a zwit-terionic intermediate which evolves to the final product by cyclisation. On the other hand, ketone-derived enamines react through an initial 1,2-addition to the carbene carbon to generate a different zwitterionic intermediate. Then, a [l,2]-W(CO)5 shift-promoted ring closure produces a new intermediate which, after elimination of the metal moiety, furnishes the corresponding cyclopen-tene derivatives (Scheme 30). 

Poly(arylene ether ketone)s can also be modified by introducing the functional groups using similar approaches to polysulfones. For example, poly(arylene ether ketone)s were sulfonated.189 In addition, o-dibenzoylbenzene moieties in the poly(arylene ether)s can be transformed to heterocycles by cyclization with small molecules. These polymers can react with hydrazine monohydrate in the presence of a mild acid in chlorobenzene or with benzylamine in a basic medium.190 Another example of the use of the o-benzyl cyclization strategy is the intramolecular ring closure of poly(arylene ketone)s containing 2,2/-dibenzoylbiphenyl units to form poly(arylene ether phenanthrenes).191... 

Note. The term potential aldehydic carbonyl group refers to the hemiacetal group arising from ring closure. Likewise, the term potential ketonic caibonyl group refers to the hemiketal structure (see 2-Carb-5). 

A variant of the free-radical addition method has been used for ring closure. For example, treatment of 75 with the free-radical initiator hexamethylditin gave a mixture of cis- and tmns-76, with a small amount of cis- and trans-11 (total yield 83%). The reaction has been performed with a-iodo esters, ketones, and malonates. 

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