Unsaturated acid chlorides, acylation

Two papers describing the intramolecular ene cyclization for the preparation of C6 functionalized pteridines has appeared. Thus 4-amino-5-nitrosopyrimidines such as 249 reacted with a,/3-unsaturated acid chlorides acylating at the 6-amino group group to afford nitrosoamides 250 which on thermolysis in toluene underwent the pericyclic cyclization and subsequent loss of water to afford a mixture of the E- and Z-isomers of the 6-oxopteridine 251 in good yield <2006HCA1140, 2007HCA521>. 

Ullmann synthesis, ] 15 Unsaturated acid chlorides, acylation, 49 Uranium derivatives, 154 Uranyl ions, 108 Urea, with azothiazoles. 111 to thiazolyl urea, 56 see also Thiazolyl urea Urine, 2-aminothiazoles in, 85 metabolite in, 85... 

Acylation takes place similarly with a,/3-unsaturated acid chlorides such as 92 (260) and with ethylmalonyl chloride (93) (130) (Scheme 65). 

Acylation of pyridazinones and related compounds in the presence of weakly basic catalysts such as pyridine or sodium acetate produces IV-acylated products, while O-acylated products are obtained under strongly basic conditions. However, the reaction between 6-chloropyridazin-3(2//)-one with chlorocarbonates and that of maleic hydrazide with unsaturated acid chlorides or chloromethylsulfonyl chloride gives preferentially N-substituted products. 

Acylation of the enamine (113) with a,/9-unsaturated acid chlorides has been shown (57) to give bicyclo(3.3.1)nonan-2,9-diones. Acryloyl ehloride on reaction with the enamine (113) and subsequent hydrolysis gave bicyelo-(3.3.1)nonan-2,9-dione (123). Mechanistic studies suggest that C alkylation by the olefin precedes acylation (87). 

The preparation of imidazolides by acylation of imidazole with acid chlorides is sometimes limited by the inaccessibility or instability of the required acid chlorides (e.g., formyl chloride, highly unsaturated acid chlorides, etc.) or by side-reactions in the case of multifunctional systems. For these reasons and due to the availability of an easy and convenient procedure involving very mild conditions, imidazolides today are usually prepared directly from the corresponding carboxylic acids with jV -carbonyldiimida-zole (CDI) or one of its analoga (see page 16). Use of these reagents has become more and more the preferred method for activation of carboxylic acids to azolides and their further transacylation to esters, amides, peptides, etc. (see subsequent Chapters). 

Acylation of a usually non-nucleophilic cyclic sulfonamide 52 has also been achieved under by deprotonation of the N-H by butyllithium followed by addition of various unsaturated acid chlorides (Equation 10) <2005TA761>. 

Acylation of alkynes, cyclopentenones. Acylation of alkynes with a,a-disubsti-llllotE/f, y-unsaturated acid chlorides, catalyzed with A1C13> results in 5,5-disubstituted-2-cyclopentenones by an unexpected intramolecular cyclization-rearrangement.2 Example ... 

Dienamides are formed by the acylation of an a,/ -unsaturated imine or by the acylation of an imine by an a,/ -unsaturated acid chloride. Linear -dienamides were... 

Similar a,a -annulations were achieved from reaction of oc,/ -unsaturated acid chlorides with cyclic ketone enamines which afforded bicyclo[3.3.1]nonane-2,9-diones41,60 65 or bicyclo[4.3.1]decanones66. In this reaction, 7V-acylation of the enamine 109 occurs as the first step giving 110, followed by a [3,3] sigmatropic rearrangement to a ketene intermediate (111). Ketene 111 subsequently cyclized via 112 to a bicyclic immonium salt (113) which after hydrolysis gave the corresponding dione 11463. If there is an axially oriented electrophilic substituent at C-4 of the enamine (for example, R = COPh) the enolate anion 115 may cyclize to an adamantane derivative 116 (equation 20). 

Surprisingly little work appears to have been published on the acylation of dienamines. Annulations which may be effected with a,/ -unsaturated acid chlorides and diketene are discussed in Sections VII.C and VIII.C, respectively. 

The compound chosen for study in this chapter is Enamide, a conventional name for the group of compounds having the structures of N-a,(i-unsaturated acylenamines and A -o,/ -unsaturated acylanilides. These ena-mides are readily prepared by acylation of the corresponding imines or anilines with a,/ -unsaturated acid chloride and are found to be considerably stable compounds, although losing reactivity to some extent when compared with the parent enamines. 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

A few instances of A-acylation are also known. 6-Chloro-3(2.H)-pyridazinone reacts preferentially on the nitrogen with chloro-carbonates and the structure of the products has been assigned on the basis of IR data. A-Acylations of maleic hydrazide are claimed to proceed with unsaturated acid chlorides in nitrobenzene at 160° or with chloromethylsulfonyl chloride. The acetylated 4-methyl analog of maleic hydrazide has been also assigned as the A-acyl derivative on the basis of spectroscopic evidence. Finally, N-acylated maleic hydrazides result from the rearrangement of the corresponding acylated A-aminomaleimides. ... 

Cyc/opentenones. Trimethylvinylsilane can function as an ethylene equivalent in an aliphatic Friedel-Crafts type of acylation with o,/3-unsaturated acid chlorides. 

Acyclic a,/3-unsaturated acid chlorides do not undergo this acylation. However, cyclic vinylsilanes also undergo Friedel-Crafts acylation with a,/S-unsaturated acid chlorides to give dienones of type a, which are cyciized by SnCl to cyclopentenones. A typical example is formulated for the reaction of 5-methyl-l-tri-methylsilylcyclopentene (3) with j3,iS-dimethylacryloyl chloride. The first step is conducted with AICI3 and gives 4, which after isolation is cyciized with SnCU to a mixture of 5 and 6. The cyclopentenone 6 is obtained in 55% overall yield after isomerization with RhCU. 

The acylation of alcohols, thiols, and amines with acetic anhydride, or directly with acetic acid, can be accomplished with the aid of catalytic (2.5 mol %) Cu(OTf)2 [40]. Copper(I) and (II) chloride has been used for the acylation of a variety of a,/8-unsaturated acid chlorides (Sch. 17). Copper powder is usually added to prevent polymerization. The A -silylsulfonamide 65 was directly acylated without first deprotection to afford 66 in high... 

The method was made considerably more general by inclusion of a catalytic amount of a palladium(O) complex during addition of the organometallic. Alkenylcopper reagents actually react relatively slowly with acid halides but, in a fashion analogous to other alkenyl metal species (see Section 1.13.4), they may be readily transmetallated to form an acylpalladium(II) complex which then undergoes reductive elimination to the product (Scheme 29)." A further discussion of acylation mediated by palladium complexes is included in Section 1.13.4. Interestingly, a,P-unsaturated acid chlorides react under these conditions to form divinyl ketones. 

Aromatic or a,p-unsaturated acid chlorides were found to undergo nqnd oxidative addition with these palladium complexes, and the subsequent acylation of an organotin proceeded smoothly in HMPA (1-60 min) or in acetone. Formation of simple aliphatic acylpalladium(II) complexes proceeds at markedly reduced rates and the acylation of organotins is slower but still use l (10-24 h). 

Aromatic, aliphatic and heterocyclic acid chlorides all give high yields of ketones, [1,4] addition not being observed with a,3-unsaturated acid chlorides. This leads to a potentially very useful synthesis of divinyl ketones since, in contrast to Lewis acid catalyzed acylations of alkenes, under the neutral reaction conditions for the acylation of alkenylstannanes, cyclizations to cyclopentenones do not occur. 

Disilylalkenes provide an access to acylated ( )-vinylsilanes. 1,3-Disilylpropenes tend to behave as 3-silylpropenes towards acylation, because of the lability of the a-silyl ketone formed initially.72 Divinyl ketones are isolated from reactions with unsaturated acid chlorides.73 Since these are cyclized under the reaction conditions, they are presumably formed during work up, possibly from silyl dienolate intermediates (Scheme 12). 

With mono(trimethylsilyl)acetylene the carbocation has the structure 10 which is stabilized by interaction between and SiMes (cf. structure 4). If the reaction starts from a 2,2-disubstituted-3-unsaturated acid chloride, cyclopentenones are obtained". (equation 13). In this case the intermediate carbocation is believed to cyclize to a cyclohexene (15). A 1,2-acyl shift leads to cation 16, which is stabilized either by addition of a chloride to give 12 or by loss of a proton to give 13 (equation 14). Similarly, compound 14 is formed. 

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