Synthesis of Divinyl Ketones

Vinyl iodides/triflates have been reported to undergo carbonylative palladium-catalyzed coupling reaction with organostannanes, organoboron derivatives, and metal acetylide. The palladium-catalyzed three-component coupling reaction of vinyl iodides with trimethyl- or tributylvinylstannanes gives unsymmetrical divinyl 

The methodology was applied to total synthesis of natural products [90]. The presence of a doubly unsaturated ketone in a arboalkoxy-a,a -dienone scaffold 54, recognized within the skeleton of important cytotoxic natural products of the eleustide family, suggested the application of the palladium-catalyzed carbonylative coupling between the electron-poor (carboalkoxy-substituted) unsaturated triflate 52 

The palladium-catalyzed three-component cross-coupling reaction between organoboron compounds, carbon monoxide, and electrophiles represents a straightforward route to the synthesis of unsymmetrical ketones [93], Recently, new catalytic systems have opened up new opportunities [94], However, there are only sporadic results for the applications of this protocol to the synthesis of alkyl- and aryl-1-alkenyl ketones [95]. Alkyl- 

1- alkenyl ketones have been synthesized by the reaction of 9-alkyl-9-BBN with 1-alkenyl iodides in the presence of Pd(PPh3)4 and K3PO4 as a base. Intramolecular reaction afforded cyclic ketones. The triethyl(l-methylindol-2-yl)borate, generated in situ from 

The reaction showed a strong dependence on the solvent. By using Pd(OAc)2-dppf as a catalytic system, the complete ketone selectivity was obtained with DMF. A further interesting feature noticed was that the increased carbon monoxide 

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Friedel-Crafts acylation of alkenes (Daizens-Nenitzescu reaction ) with unsaturated acylium ions generated from acid halides and Lewis acids constitutes a general synthesis of divinyl ketones. 

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. 

For the preparation of divinyl ketones, as required for the Nazarov reaction, various synthetic routes have been developed. A large variety of substituted divinyl ketones, including vinylsilane derivatives, can thus be prepared. The Nazarov cyclization, and especially the vinylsilane variant, has found application for the synthesis of complex cyclopentanoids. 

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

The acid-catalyzed cyclization of divinyl ketones 1 (or their precursors) via pentadienyl cations 2, is known as the Nazarov cyclization. It is a commonly used method for the synthesis of cyclopentenones 3. 

The hydrosi(ly)lations of alkenes and alkynes are very important catalytic processes for the synthesis of alkyl- and alkenyl-silanes, respectively, which can be further transformed into aldehydes, ketones or alcohols by estabhshed stoichiometric organic transformations, or used as nucleophiles in cross-coupling reactions. Hydrosilylation is also used for the derivatisation of Si containing polymers. The drawbacks of the most widespread hydrosilylation catalysts [the Speier s system, H PtCl/PrOH, and Karstedt s complex [Pt2(divinyl-disiloxane)3] include the formation of side-products, in addition to the desired anh-Markovnikov Si-H addition product. In the hydrosilylation of alkynes, formation of di-silanes (by competing further reaction of the product alkenyl-silane) and of geometrical isomers (a-isomer from the Markovnikov addition and Z-p and -P from the anh-Markovnikov addition. Scheme 2.6) are also possible. 

Much milder conditions are used in the double Michael addition approach, in which a divinyl ketone is condensed with hydrogen sulfide in mildly basic medium (equation 77) (77JOC2777). Enol acetates (R1 = MeCC>2) may be used, and the product obtained then contains a 2-mercapto function (R1 = SH see also equation 82) (59% yield). Although this is a very versatile synthesis, its biggest drawback is the lability of simple divinyl ketones, and phenyl substitution at position 2 is frequently used to overcome this. 

The Nazarov Cyclization allows the synthesis of cyclopentenones from divinyl ketones. 

Salicylaldehyde reacts with trimethylsilylketene dithioacetal in the presence of a Lewis acid to form the chroman 502, the product of a deoxygenative divinylation (Equation 208) <2001JOC3924>. This reaction can also be applied to salicylaldimines <2003JOC4947>. Treatment of 3,5-dibromosalicylaldehyde with methyl vinyl ketone (MVK) in the presence of DABCO leads to a chroman-4-ol as the major product <2002J(P1)1318>. A stereoselective one-pot synthesis of vy/z-fused chromans from salicylaldehydes, aromatic amines and cyclic enol ethers is carried out in the... 

A complementary approach, developed by Paquette, - uses substituted acryloyl chlorides as addends in reaction with structii ly embellished vinylsilanes. A general route to the vinylsilanes (87) was found in the silylation of vinyllithiums generated by the Shapiro reaction.The acylation with acryloyl chlorides takes place readily with aluminum trichloride to afford the divinyl ketones which are subsequently cyclized with tin tetrachloride. The Nazarov cyclization products were formed as a mixture of double tend isomers (equation 47). The best results were obtained with p,p-dimethylacryloyl chloride. Crotonyl chloride could be employed, but acryloyl chloride proved impractical. This metl owes much of its utility to the regiocontroUed synthesis of Ae vinylsilmes, thereby clearly establishing the loci of cyclopentannulation. 

The Nazarov cyclization has been featured in a variety of synthetic endeavors involving both natural and unnatural products. In the area of polyquinane natural products ( )-hirsutene (88), ( )-mod-hephene (89), ( )-silphinene (90), ( )-A 2)-capnellene (91) and ( )-cedrene, have all been prepared (Scheme 37). The synthesis of (91) is noteworthy in the iterative use of the silicon-directed Nazarov cyclization. TIk divinyl ketones were constructed by the carbonylation-coupling of enol triflates (92) and (95) with the -silylvinylstannane (Scheme 38). llie diquinane (94), obtained from Nazarov cyclization of (93), was transformed into enol triflate (95) which was coupled with the -silylvinylstaimane as before. Silicon-directed Nazarov cyclization of (96) was highly diastereoselective to provide the cis,anti,cis isomer of (16). The synthesis was completed by routine manipulations. 

Free radical-induced additions have been used in the synthesis of a range of phosphines bearing other nucleophilic groups, e.g., (41), useful for specific peptide bond cleavage of proteins.A further example of the formation of the phosphorinanone system by addition of phenylphosphine to a divinyl ketone derivative has been described.Two reports have appeared of the addition of secondary phosphines to maleic anhydride and related activated olefins, to give functionalised tertiary phosphines, e.g., (42). A route to allylphosphines is provided by base-... 

Kang, H. T., Kim, S. S., Lee, J. C., U, J. S. Synthesis of a-methylenecyclopentanones via silicon-directed Nazarov reaction of a-trimethylsilylmethyl-substituted divinyl ketones. Tetrahedron Lett. 1992, 33, 3495-3498. 

Nazarov cyclization reaction. Synthesis of cyclopentenones by the acid-catalyzed electrocyclic ring closure of divinyl or allylvinyl ketones available by hydration of divinylacetylenes. 

Kuroda, C.. Sumiya, II.. Murase, A., and Koito, A., Iron(ni)-induced tandem Nazarov cyclization-rearrangement of a-(triincLhylsilylmethyl)divinyl ketone. Synthesis of the bicyclo[4.3.0]nonane ring system via spiro[4.4]nonanc, J. Chem. Soc., Chem. Commun.. 1177. 1997. 

Acylations by a,3-unsaturated acyl halides provide routes to a,3,a, 3 -unsaturated ketones. Care must be taken in choice of reaction conditions, since Lewis acids are excellent catalysts for Nazarov cy-clizations to cyclopentenones (Scheme 2). Indeed, this can be exploited as a synthesis of the five-mem-bered ketones without isolation of the intermediate divinylic ketones. Cyclizations are also observed after acylations of cyclohexenes with vinylacetyl chloride derivatives (equation The acylation-cycloalkylation sequence provides a complement for the Robinson annelation, since the carbonyl function is located adjacent to the bridgehead position. This potential has been realized in natural product syntheses. ... 

In lipase-catalyzed transesterifications, enol esters have been used as acyl agents (4), since the leaving unsaturated alcohol irreversibly tautomerizes to an aldehyde or a ketone, leading to the desired product in high yields. Bis(enol ester)s were reported to be much effective for the enzymatic synthesis of polyesters imder mild reaction conditions (Fig. 6) (108) the polymerization of divinyl adipate and 1,4-butanediol proceeded by lipase PF at 45°C, and adipic acid and diethyl adipate did not afford the pol5mieric materials under the similar reaction conditions. 

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