Keywords
Abstract
This review summarizes the latest advances in the chemistry of β,γ-ethylenic ketones, which have emerged over the last decade as valuable synthetic building blocks to create molecules of high complexity and diversity. This family of multifunctional γ-aryl-β,γ-ethylenic ketones has now become accessible owing to the discovery and systematic development of a new general C(sp3) – C(sp2) bond-forming reaction, namely superbase-mediated C-vinylation of ketones with alkynes. In the context of the Favorsky reaction (the addition of acetylenic carbanions to the carbonyl group of ketones), this discovery represents a chemical paradox in the form of temperaturecontrolled inversion of electrophilicity and nucleophilicity of acetylenes and ketones. Various transformations of β,γ-ethylenic ketones: nucleophilic addition reactions, inverse-electron-demand Diels–Alder reactions, reactions involving a carbonyl group followed by transformations of functionalized adducts, etc. are discussed. The review also highlights the cascade reactions, in which the in situ formed β,γ-ethylenic ketones, are key intermediates in the synthesis of various highly functionalized carbo- and heterocyclic systems.
The bibliography includes 102 references.
1. Introduction
The aim of this review is to draw attention of the synthetic community to the synthesis of functionalized unsaturated carbo- and heterocyclic systems and to promote further research in this area on the platform of diverse transformations of β,γ-ethylenic ketones. The latter have rapidly gained status as multifaceted reaction partners due to the discovery in 2010 and systematic development of the new C(sp3) – C(sp2) bond-forming reaction, representing superbase-catalyzed C-vinylation of ketones with alkynes. These compounds now occupy a prominent position in the toolkit of organic chemistry. The advantages of the reaction that leads to this family of β,γ-ethylenic ketones include its generality (it covers a practically inexhaustible range of ketones and diversely substituted aryl- and hetarylacetylenes), its high regio- and stereoselectivity, the availability and simplicity of transition-metal-free promoting systems (KOH/DMSO or KOBut/DMSO).
Despite significant progress in recent years in the study of β,γ-ethylenic ketones, a comprehensive survey of their rich chemistry is still lacking. Meanwhile, these newly accessible β,γ-ethylenic ketones are employed extensively in numerous chemical transformations, including the nucleophilic addition to various electrophiles, often accompanied by the cascade cyclizations; asymmetric inverse-electron-demand Diels – Alder reaction; the formation of the corresponding functionalized adducts of the carbonyl group (e.g., reactions with hydroxylamine, hydrazine, guanidine, etc.) and their further cyclizations; the cascade processes triggered by the nucleophilic addition of ketones to alkynes, in which the in situ generated β,γ-ethylenic ketones play a pivotal role as key intermediates in the synthesis of various practically important products.
2. Background of the discovery
For more than a century, the base-mediated C-vinylation of ketones with terminal alkynes was considered impossible because it was known that, in the presence of bases, the ketones react with alkynes to produce tertiary propargyl alcohols or diols (classic Favorsky reaction).[1-3] This reaction has found wide application in both fine organic synthesis (vitamins, carotenoids, fragrance materials, isoprene and isoprenoids, drugs)[4-8] and industry (isoprene rubbers, surfactants, corrosion inhibitors, adjuvants for pesticides),[9] and has therefore been thoroughly studied.
It should be emphasized that until 2010, no example of ketone addition (as C-nucleophiles) to a carbon-carbon triple bond in the presence of bases had been reported. The reasons why this issue had not arisen were of an experimental and theoretical nature. From an experimental perspective, it was common knowledge that acetylenic carbanions would aggressively attack an electrophilic carbonyl group (at room temperature or below) to form O-centred propargyl anions or the corresponding alkali metal alkoxides. Another reason was the understanding that acetylenic carbanions, partially present in the reaction mixture, cannot be attacked by nucleophiles (enolate anions). Theoretically, it was widely accepted that the carbanionic form of enolate anions was thermodynamically unfavorable compared to the O-centered one.[10]
However, the fact that Favorsky tertiary propargyl alcohols dissociate back into the starting ketones and alkynes when heated with bases (retro-Favorsky reaction) has not been considered.[11-14] Therefore, at elevated temperatures, the enolizable ketones can add to alkynes. It should also be taken into consideration that enolizable ketones are usually much more acidic than alkynes (by about 4 units of pKa, ~25 ([15]) and ~29,[16][17] respectively) and hence, in basic media, the enolate-anions prevail whereas the ionization of alkynes is suppressed, that is to say, alkynes are mostly present in the reaction mixture in the non-ionized form. Thus, at elevated temperatures, conditions actually arise for the formation of the ketone adducts to the triple bond of alkynes. It is noteworthy that all the aforementioned processes and effects are more pronounced in strongly basic (superbasic) media,[18] which we systematically exploit to dramatically accelerate classic reactions of acetylenes[19][20] and to discover new ones.[21][22] For these purposes, the superbasic compositions of the type MOR/polar complexing nonhydroxylic solvent (M = Na, K, R = H, Alkyl) have been successfully used. The most universal and convenient systems are KOH/DMSO and KOBut/DMSO, which ensure the pKa values of 25 – 35.[23][24] According to the quantum chemical calculations, in these compositions, the potassium cation is coordinated with hydroxide or alkoxide anion and five molecules of DMSO (Scheme 1)[25-27] which makes RO– anions more basic as they are separated from the cation by the solvent.
In light of the above rationale, one might expect the addition of deprotonated ketones to alkynes to be feasible. Indeed, our experiments confirmed this: when acetophenone was allowed to contact with phenylacetylene in the KOH/DMSO system at 100°C for 1 h, (E)-1,4-diphenyl-3-buten-1-one 1a, a representative of γ-aryl-β,γ-ethylenic ketones, was isolated in 83% yield (Scheme 1).[28]
This was the discovery of the base-mediated C-vinylation of ketones with alkynes.
3. Characteristic features of C-vinylation of ketones with alkynes
This reaction appeared to be a general one, covering aliphatic, cycloaliphatic (including macrocyclic), aromatic, condensed aromatic, and heteroaromatic ketones, as well as various aryl and hetaryl alkynes.[28][29] Later,[30] the KOBut/DMSO system was found to be more versatile and convenient than KOH/DMSO and other superbasic systems. This allowed the C-vinylation of ketones to be carried out in a shorter time (30 min). Consequently, a wide variety of the corresponding β,γ-ethylenic ketones 1 became readily accessible right away.
The discovered reaction, involving the addition of the enolate-anions to terminal alkynes, should follow the classic nucleophilic trans-addition rule[31] to afford Z-adducts 2 (Scheme 3). The later, apparently, tend to undergo the Z → E isomerization in their deprotonated form 3, wherein a free rotation of the aryl group (R3) around the former double bond is allowed. The driving force of such an isomerization may be the chelation of the potassium cation with the participation of the carbonyl group and the arylethenyl moiety in the six-π-electron quasi-aromatic dienolates 4, which fixe the E-configuration.
Importantly, the adducts of ketones to alkynes, (E)-γ-aryl-β,γ-ethylenic ketones 1, are by virtue substituted styrenes. This means that despite the possibility of its migration towards the carbonyl group to form α,β-ethylenic isomers, the double bond remains conjugated with the aryl moiety (R3 in Scheme 3). This stereo- and regioselective synthesis of β,γ-ethylenic ketones 1 results from the energetically more favourable conjugation of the double bond with aryl substituent rather than with the carbonyl function that was supported by quantum chemical calculations.[30]
The efficient straightforward transition metal-free C-vinylation of ketones with terminal alkynes using inexpensive starting materials under operationally simple conditions makes β,γ-ethylenic ketones 1 an easily accessible class of compounds, which represent valuable reagents due to their multifaceted reactivity. The unusual stability of these β,γ-ethylenic ketones, which are not prone of transforming into α,β-isomers, substantially extends the application potential of these new synthetic building blocks.
Before the above C-vinylation of ketones with alkynes become the public knowledge,[28-30] a number of syntheses of β,γ-ethylenic ketones were known, particularly those employing allyl- [32][33] or alkenylmetals,[34][35] oxidation of homoallylic alcohols,[36][37] ruthenium-catalyzed hydroacylation of dienes,[38][39] dimerization/hydration of aryl acetylenes catalyzed by [Cp*Ru(NCMe)3+PF6–]/p-TSA (Cp* is pentamethylcyclopentadienyl, TSA is p-toluenesulfonic acid).[40] A common approach to the synthesis of β,γ-ethylenic ketones is the acylation of olefins,[41-43] but this is complicated by the prototropic migration of the double bond, which gives rise to conjugated α,β-ethylenic isomers. Relatively accessible β,γ-ethylenic ketones were prepared by allylation of acyl chlorides,[44-47] however these protocols were characterized[48] as having limited applications since they are tedious and time-consuming.
It is no surprise that none of these methods allowed β,γ-ethylenic ketones to become popular synthons in organic synthesis. As mentioned above, a fundamental cause of this is the easy transformation of β,γ-ethylenic ketones into their α,β-isomers, which are usually thermodynamically more stable, and which often occurs in the course of the process. At the same time, most β,γ-ethylenic ketones of type 1 synthesized according to Scheme 3, are stable with respect to the migration of the double bond, because it is in a stronger conjugation with the aromatic moiety than with the carbonyl group.
4. γ-(Het)aryl-β,γ-ethylenic ketones in organic synthesis
The three different reaction centers of ketones 1 (carbonyl function, double bond and a-CH active group) promise these compounds to have a rich and intriguing chemistry. Overall, the β,γ-ethylenic ketones 1, synthesized by the base-mediated C-vinylation of ketones with aryl alkynes, have all the prerequisites to become versatile synthons in current organic synthesis.
4.1. Synthesis of carbocyclic compounds
The chiral squaramide (Cat1)-catalyzed regio-, diastereo-, and enantioselective double Michael addition of β,γ-ethylenic ketones 1 to nitro alkenes 5 was achieved (Scheme 4).* [49] This cascade reaction provided pentasubstituted cyclobutanes 6 bearing four contiguous stereocentres in good yields with a diastereomeric ratio of > 20 : 1 and high enantioselectivities. The reaction starts with the addition of the γ-CH group of ethylenic ketone 1 to nitroolefin with subsequent cyclization involving the β-carbon atom of the same ketone to form the [2 + 2] cycloaddition adducts.
The tertiary phosphine-catalyzed [4 + 1] annulation of β,γ-ethylenic ketones 1 with β'-acetoxy allenoate 7 was reported.[50] In this reaction, the β,γ-ethylenic ketones serve as α-C,α-C'-bisnucleophiles. The reaction proceeds in toluene at room temperature using (4-MeOC6H4)3P as a catalyst and Na2CO3 as a base to afford functionalized cyclopentenes 8 in moderate to good yields (Scheme 5).[50]
Apparently, this annulation involves the nucleophilic attack of deprotonated ketones 1 at the vinyl phosphonium intermediate 9 to form zwitterionic adducts 10 (Scheme 6).[50] Next, the intermediate zwitterions 11 undergo cyclization to afford cyclopentenes 8 and regenerate the phosphine catalyst.
A similar (4-MeOC6H4)3P-catalyzed [4 + 1] annulation of β,γ-ethylenic ketones 1 with allenyl imide 12 was implemented to furnish substituted 2-cyclopent-2-en-1-ones 13 (Scheme 7).[51]
In the presence of CaCO3, β,γ-ethylenic ketones 1 undergo a cascade reaction with alkynyl 1,2-diketones 14 to give 2-acyloxycyclopent-3-enones 15 (Scheme 8),[52] which are key units in a variety of natural products and pharmaceutically active compounds.[53]
This process starts with the addition of deprotonated ketones 1 to alkynyl 1,2-diketones 14 followed by aldol-type intramolecular cyclization and the C – C bond cleavage (Scheme 9).[52]
Upon heating in the KOBut/DMSO (100°C, 4 h)[54] or Cs2CO3/dioxane (90°C, 13 h)[55] systems, β,γ-ethylenic ketones 1 smoothly convert to acylated terphenyls 16, which are actually dimers of ketones 1 without the substituted toluene moiety (Scheme 10).
Dimerization of β,γ-ethylenic ketones 1 proceeds via a crotonic condensation. The resulting trienes 17 then undergo base-catalyzed cyclization to dihydrobenzenes 18 (Scheme 11). The latter then undergo aromatization via the elimination of methyl aromatics from the dihydrobenzene moiety. The final stage of this cascade sequence was confirmed experimentally.
The synthesis of acyl terphenyls 16 including complex polyaromatic systems 16a – c (important building blocks for materials science)[56-58] was performed via base-promoted C-vinylation of acetyl(het)arenes with aryl alkynes in a one-pot manner without isolating intermediate β,γ-ethylenic ketones 1 (Scheme 12).[59]
* Hereinafter, the C – C bonds formed during the reaction are highlighted with bold black lines.
4.2. Synthesis of heterocyclic compounds
4.2.1. Synthesis of oxygen heterocycles
The formation of 2,5-disubstituted furans 19 from the in situ generated β,γ-ethylenic ketones 1 was first described by the reaction of acetophenone or 2-acetylnaphtalene with 2-nitrophenyl acetylene in the presence of the KOH/DMSO system (Scheme 13).[28] Here, the intermediate dienolates 20 undergo cyclization to dihydrofurans 21, which are further oxidized (probably by the NO2 moiety) to give furans 19 (see Scheme 13).
Subsequently, various 2,5-di(het)aryl substituted furans 19 were synthesized through the oxidative cyclization of ketones 1 in the presence of (NH4)2[Ce(NO3)6]/KBr oxidizing composition (Scheme 14).[60]
A chiral dipeptide-phosphonium salt (Cat2)-catalyzed regio- and stereoselective reaction of β,γ-ethylenic ketones 1 with 2-nitroindoles, 2-nitrobenzofurans, and 2-nitrobenzothiophenes afforded three types of dihydrofuro-fused [2,3-b]-hetarene systems 22 in high yields and with excellent stereoselectivities (Scheme 15).[61]
This reaction cascade involves a nucleophilic attack of deprotonated ketones 1 on the 2-nitro substituted heterocycle followed by the intramolecular substitution of the nitro group by the O-centered anion of intermediates 23 (Scheme 16).[61]
In the presence of the 1,4-diazabicyclo[2.2.2]octane (DABCO)/Cs2CO3 catalytic dyad (DABCO is 1,4-diazabicyclo[2.2.2]octane), β,γ-ethylenic ketones 1 undergo the [3 + 3] annulation with allenyl imides 24 providing tetrasubstituted 2-pyranones 25, in generally high yields (Scheme 17).[51]
The reaction is initiated by the addition of DABCO to allenyl imides 24 with the release of the 2-oxazolidinyl anion and generation of adducts 26.[51] Then, these adducts 26 are attacked by deprotonated β,γ-ethylenic ketone 1 leading to zwitterionic intermediates 27 (Scheme 18). After that, the latter eliminates DABCO to produce ketenyl derivatives 28. Intramolecular nucleophilic addition into enolates 29, isomerization, and protonation finalize the process.
The organocatalytic reaction of β,γ-ethylenic ketones 1 with hydroxynitroolefins 30 provided access to functionalized tetrahydropyrans 31 (Scheme 19).[62] High diastereo- (> 20 : 1 dr) and enantioselectivities (in most cases, 93 – 97% ee) were achieved using a bifunctional squaramide (Cat1)/Et3N catalytic pair. Mechanistically, this cascade reaction involves the initial addition of the deprotonated ketones 1 to nitroolefin 31 followed by cyclization involving the carbonyl carbon atom.[62] Synthetic applications of tetrahydropyran products 31 were demonstrated by their transformation to a series of polycyclic compounds, including the euroticin B[63] analogue.
Polycondensed pyrans of higher complexity (functionalized 1,3-dioxolochromans 33) were assembled stereoselectively by the chiral phosphonium salt (Cat3)-catalyzed reaction of β,γ-ethylenic ketones 1 with ortho-quinone methides 32 (Scheme 20).[64]
The reaction proceeds via the prototropic isomerization/deprotonation of β,γ-ethylenic ketones 1 and the addition of γ-carbanions 34 thus formed to the activated double bond of ortho-quinone methide 32 followed by the intramolecular addition of O-centered anions 35 to the β-carbon atom of the ethylenic ketone counterpart (Scheme 21).[64]
The synthesis of 1,3-dioxolochromans 33 was also realized via the asymmetric domino oxidation/annulation of β,γ-ethylenic ketones 1 with 2-alkenyl phenols 36 (precursors of ortho-quinone methides 32). The process employed silver oxide as the oxidant and the same chiral phosphonium salt Cat3 as catalyst (Scheme 22). This modified synthesis is highly efficient, affording polycondensed pyrans 33 in high yields, and with good diastereo- and enantioselectivities.[64]
An asymmetric organocatalytic cascade reaction of fluorine-containing β,γ-ethylenic ketones 1 with a,β-unsaturated ketoesters 37 leading to fluorinated chiral pyrans 38 under mechanochemical activation was accomplished (Scheme 23).[65]
In the first step of pyrans 38 assembly, dienolates of β,γ-ethylenic ketones add to ketoester 37 (Scheme 24). The pyrane ring is then formed by the intramolecular addition of O-centered anions of intermediates 39 to the activated double bond. The quinine organocatalyst binds preferentially only dienolate and thus antiperiplanar arrangement in the transition state is preferred leading to (S,S,S)-configured pyrans 38.
β,γ-Ethylenic ketones 1 find a wide application as dienophiles in the asymmetric inverse-electron-demand Diels – Alder reaction with various functionalized dienes. This universal strategy ensures the synthesis of pharmaceutically valuable richly functionalized pyran derivatives.
Along this line, the Diels – Alder reaction of β,γ-ethylenic ketones 1 and alkenyl 1,2-diketones 40 in the presence of a chiral bifunctional thiourea catalyst Cat5 provides highly functionalized dihydropyrans 41 bearing three consecutive stereocentres with good to excellent enantioselectivities (Scheme 25).[66]
A similar transformation of β,γ-ethylenic ketones 1 with unsaturated keto esters 42, promoted by the same bifunctional thiourea catalyst Cat5 under mechanochemical activation, affords tetrasubstituted chiral dihydropyrane derivatives 43 (Scheme 26).[67]
The catalyst Cat5 was successfully employed in the [4 + 2] cycloaddition of β,γ-ethylenic ketones 1 with alkylidene pyrazolones 44 to produce tetrahydropyrano[2,3-c]pyrazoles 45 with high diastereo- and enantioselectivities and in moderate to good yields (Scheme 27).[68]
The catalyst Cat5 was found to be effective in the enantioselective inverse-electron-demand oxa-Diels – Alder reaction of β,γ-ethylenic ketones 1 with 5-alkenyl thiazolones 46 to afford highly functionalized pyrano[2,3-d]thiazoles 47 with excellent enantioselectivity (Scheme 28).[69]
Enantioenriched 3,4´-pyranyl spirooxindole derivatives 48 bearing three contiguous chiral centres were synthesized via the chiral bifunctional squaramide (Cat6)-catalyzed asymmetric inverse-electron-demand oxa-Diels-Alder reaction of structurally diverse β,γ-ethylenic ketones 1 and β,γ-unsaturated α-keto esters 49 (Scheme 29).[70]
The asymmetric inverse-electron-demand Diels – Alder reaction between ketones 1 and unsaturated a-ketoamides 50 assisted by a chiral bifunctional Zn-ProPhenol catalyst Cat7 leads to various biologically important dihydropyrans 51 in good yields and with good stereoselectivity (Scheme 30).[71]
In the presence of the DBU/DMSO system (DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene), β,γ-ethylenic ketones 1 react with β-phenyl ethenesulfonyl fluoride 52 to afford γ-alkenylated δ-sultones 53 in close to quantitative yields (Scheme 31).[72]
The formation of δ-sultones 53 (Scheme 32)[72] is initiated by the Michael addition of deprotonated ketones 1 to the double bond of ethenesulfonyl fluoride 52. Subsequent 1,3-prototropic shift/enolization generates intermediates 54, which undergo an intramolecular nucleophilic substitution of the fluorine atom to produce the final δ-sultones 53.
The in situ generated β,γ-ethylenic ketones 1, the adducts of 2-fluorophenylacetylenes and various ketones, are converted to functionalized benzo[b]oxepines 55 in moderate to high yields via an intramolecular nucleophilic substitution of the fluorine atom by an enolate anion (Scheme 33).[73] This methodology features a wide substrate scope and a high functional group tolerance.
A special group of diastereoisomerically pure β,γ-ethylenic ketones 57 with a dihydropyran moiety was obtained by the base-mediated reaction of 2-acetyl-3,4-dihydropyrans 56 with aryl alkynes. These ketones undergo acid-catalyzed (in the presence of NH4Cl) stereoselective cyclization to dienyl bicyclic structures 58 (Scheme 34),[74] which are closely related to naturally abundant DOBCO molecules (6,8-dioxabicyclo[3.2.1]octanes).[75] The cyclization involves protonation of the enol form of ketones 59 followed by intramolecular cyclization of carbocations 60 (see Scheme 34).[74] The diastereoselectivity of the ring-closing reaction is predetermined by the cyclic structure of the starting ketones 57, in which the hydroxyl group attacks position 6 of the pyran ring only from the axial direction, leading to a single configuration of this carbon atom.
4.2.2. Synthesis of nitrogen heterocycles
The reaction between oximes of β,γ-ethylenic ketones 61 (prepared from ketones 1 and hydroxylamine hydrochloride) with acetylene was successfully used for the stereoselective synthesis of 3-styryl-1H-pyrroles 62 and 1-vinyl-3-styrylpyrroles 63 (Scheme 35).[76]
The pyrrole synthesis[77][78] begins with the O-vinylation of oximes 61 with acetylene (Scheme 36). This is followed by a cascade sequence involving a 1,3-prototropic shift in O-vinyloximes 64, a 3,3-sigmatropic rearrangement of intermediate dialkenylhydroxylamines 65, the cyclization of iminoaldehydes 66, the dehydration of hydroxypyrrolines 67, and aromatization of 3H-pyrroles 68.
The annulation of substituted β,γ-ethylenic ketones 1 with unsaturated cyclic imines 69 via the inverse-electron-demand hetero-Diels – Alder reaction stereoselectively afforded the polycondensed heterocyclic systems, viz., tetrahydrobenzofuro[3,2-b]pyridine-substituted systems 70 (Scheme 37).[79] The reaction was realized under organocatalytic (Cat8) conditions and proceeded in a highly stereo- and site-selective manner.
The base-promoted C-vinylation of ketones with electron-deficient acetylenes (alkynones), which leads to the formation of 1,5-diketones 71, was used in the preparation of Kröhnke pyridines[80-82] (2,4,6-triarylpyridines).[83] The methodology tolerates diversely substituted ketones and alkynones, enabling the synthesis of a variety of 2,4,6-triarylpyridines 72, including tetrasubstituted and fused ones, in good to excellent yields (Scheme 38).
The one-pot synthesis of substituted pyridines 72 involves the nucleophilic addition of ammonia (generated from NH4Cl) to a one carbonyl function of the in situ formed unsaturated 1,5-diketones 71, followed by the intramolecular cyclization of intermediate amines 73 involving the second carbonyl group and elimination of a water molecule (Scheme 39).[83]
The simple straightforward one-pot synthesis of diversely substituted 4,5-dihydropyrazoles 74 via the reaction of β,γ-ethylenic ketones 1 with aryl hydrazines was achieved. Ketones 1 were generated in situ by the C-vinylation of the starting ketones with alkynes in the presence of KOBut/DMSO system (Scheme 40).[84]
The reaction involves the formation of hydrazones 75, which undergo intramolecular cyclization (Scheme 41).84
A modified sequence of similar transformations was used for the three-component one-pot synthesis of 4,5-dihydropyrazole-1-carbothioamides 76 from acetophenones, phenylacetylene and thiosemicarbazides in the presence of KOH/DMSO catalytic pair (Scheme 42).[85]
β,γ-Ethylenic ketones 1 were the key reaction partner in the assembly of 1-formyl-4,5-dihydropyrazoles 77 directly from ketones, arylacetylenes, hydrazine, and formic acid in a one-pot procedure (Scheme 43).[86]
The assembly of pyrazolines 77 comprises the formation of hydrazones 78 and their acylation with formic acid. The acylated unsaturated hydrazone intermediates 79 then undergo the ring closure to the functionalized dihydropyrazole ring (Scheme 44).[86] This mechanistic hypothesis was proved by the synthesis of intermediate β,γ-unsaturated hydrazones 78, which did readily cyclize to the corresponding pyrazolines 77 in the presence of formic acid under the above conditions.
As a further development of this rewarding approach to the construction of functionalized pyrazoline derivatives, a one-pot synthesis of a previously unknown family of cycloalka[c]pyrazoline-2-carbaldehydes 80 via the sequence of the reactions between cyclic ketones, phenylacetylene, hydrazine hydrate, and formic acid was implemented (Scheme 45).[87]
Later, hydrazones 78, prepared from β,γ-ethylenic ketones 1, underwent I2/DMSO-mediated oxidative cyclization to produce either substituted 5,6-dihydropyridazines 81 or N-arylaminopyrrole derivatives 82 (Scheme 46).[88] Pyridazines 81 were formed from hydrazones 78 with electron-withdrawing substituents, whereas pyrroles 82 were obtained from those with electron-donating substituents. According to the Density Functional Theory (DFT) calculations,[88] this regioselective substituent-controlled switching of the cyclization path was explained by the different stability of the two corresponding transition state structures and the different nucleophilicity of the two nitrogen atoms, which depends on the electronic effects of the substituents.
The solvent-controlled oxidative cyclization of the same unsaturated hydrazones 78 in the presence of molecular oxygen and Cu(OAc)2 catalyst gave two different groups of pyrazoles. 1,3,5-Trisubstituted pyrazoles 83 with an acyl functionality at the C-5 position were obtained as the major products when carrying out the reaction in ethanol, whereas 1,3-disubstituted pyrazoles 84 were exclusively formed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (Scheme 47).[89]
A new general strategy for the one-pot synthesis of substituted 4,5-dihydroisoxazoles 85 based on β,γ-ethylenic ketones 1 and their oximes 61, generated in situ from ketones, aryl alkynes, and hydroxylamine hydrochloride (Scheme 48),[90] was one of the first synthetic applications of the superbase-promoted C-vinylation of ketones with alkynes.[28-30] This strategy has been proven to be applicable to the preparation of a wide range of 4,5-dihydroisoxazoles 85 due to a great diversity of both starting ketones (dialkyl, cycloalkyl, and alkylaryl) and aryl alkynes.[90]
The assembly of 4,5-dihydroisoxazoles 85 involves first the KOBut/DMSO-mediated addition of deprotonated ketones to arylacetylenes to form β,γ-ethylenic ketones 1, which further react with NH2OH. Intermediate oximes 61 further undergo KOH/DMSO-catalyzed cyclization (Scheme 49).
The radical cyclization of β,γ-ethylenic ketones 1 with sodium nitrite in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) allowed a broad range of differently substituted 3-acylisoxazoles 86 to be constructed (Scheme 50).[91] The mechanistic studies revealed that the reaction proceeds via the nitrosation of the α-CH bond of ketones 1 followed by the radical 5-endo-trig cyclization of the resulting oximes 87 and aromatization, the native carbonyl group being intact.
A number of functionalized 1,2,3-triazoles 89 were synthesized by the DBU/DMSO-catalyzed formal [3 + 2] cycloaddition of various substituted β,γ-ethylenic ketones 1 with different substituted aryl azides 88 (including those sugar-derived) (Scheme 51).[92] All the substrates underwent the cycloaddition very smoothly (room temperature) to give the corresponding functionally rich C-styryl-1,2,3-triazoles 89 of the stilbenoid type in excellent yields.
This nonconventional click reaction involves first the enolization of β,γ-ethylenic ketones 1 to dienols 90, the addition of azides 88 to the enol double bond and the elimination of a water molecule from the intermediate adducts 91 (Scheme 52).
The reaction of β,γ-ethylenic ketones 1 with guanidine nitrate was successfully employed to obtain two types of 2-aminopyrimidines (Scheme 53):[93] 4-benzyl-substituted (92) and 4-unsubstituted (93). The latter result from the elimination of methylbenzenes.
The assembly of 2-aminopyrimidines 92 and 93 (Scheme 54)[93] involves the formation of adducts of β,γ-ethylenic ketones 1 with guanidine (94), which then undergo the ring-closure to afford dihydropyrimidines 95. Aromatization of the latter occurs via two pathways: when R2 = H, intermediates 95 typically lose a hydrogen molecule to give 2-amino-4-benzylpyrimidines 92. In contrast, when R2 ≠ H, elimination of methylbenzenes from the dihydropyrimidine ring takes place to deliver 4-unsubstituted 2-aminopyrimidines 93. The final step in the formation of 2-aminopyrimidines 93 (the unusual elimination of methyl aromatics) has been proved experimentally.
Based on these results (see Scheme 53, Scheme 54),[93] the one-pot synthesis of substituted 2-aminopyrimidines 92, 93 via a sequential three-component reaction of ketones, aryl alkynes, and guanidine mediated by the KOBut/DMSO catalytic dyad was developed (Scheme 55).[94] The strategy proved effective for a diversity of ketones such as aliphatic, cycloaliphatic, and alkylaromatic as well as for the substituted arylacetylenes.
4.3. Miscellaneous reactions
The organocatalytic enantioselective Michael reactions of β,γ-ethylenic ketones 1 as a-C-nucleophiles significantly expanded the scope of their synthetic applications. Within this approach, various ketones 1 were utilized in a chiral tertiary amine (e.g., Cat9)-promoted Michael addition to nitro styrenes 96. The reaction is regioselective to produce adducts 97 with two vicinal tertiary carbon stereocentres in diastereomeric ratios of up to > 20 : 1 and enantioselectivities in the 90 – 98% ee range (Scheme 56).[95]
Using a chiral tertiary amine catalyst (Cat10), cyclic β,γ-ethylenic ketones 1, including those fused with benzene rings, were smoothly added as α-C-nucleophiles to vinyl bis(sulfone) 98 affording the corresponding all-carbon quaternary adducts 99 in good yields, and with enantioselectivity of up to 99% ee (Scheme 57).[96]
The regio-, diastereo-, and enantioselective Mannich-like reaction of ketones 1 with cyclic imines 100 under Lewis acid/Brønsted base cooperative catalysis was realized.[97] This reaction selectively involves the α-position of ketones 1 leading to the corresponding adducts 101 with two consecutive tertiary carbon stereocentres with 20 : 1 dr and up to 99% ee (Scheme 58).
Under catalyst- and solvent-free conditions, β,γ-ethylenic ketones 1 (as Michael acceptors) regioselectively add secondary phosphine chalcogenides 102 affording γ-ketophosphine chalcogenides 103 in high yields (Scheme 59).[98] The addition exclusively occurs across the double bond, leaving the carbonyl function intact and providing ample opportunity for further functionalization of the resulting compounds.
The synthetic potential of β,γ-ethylenic ketones 1 was demonstrated through the regioselective ligand-free AgOTf-catalyzed Friedel – Crafts hydroarylation with electron-rich arenes 104 to provide the corresponding γ-diarylated ketones 105 (Scheme 60).[40]
Polyconjugated electron-deficient dienes (2-acylbuta-1,3-dienes 106), which are synthetically attractive but less accessible compounds than the well-explored 1-acylbutadienes, were obtained regioselectively from aromatic and heteroaromatic β,γ-ethylenic ketones 1 by their condensation (as active methylene compounds) with aromatic and heteroaromatic aldehydes (Scheme 61).[99] The reaction proceeds smoothly with piperidine/acetic acid catalytic pair in boiling toluene. Piperidine, acting as a base, increases the acidity of the methylene group in the a-position of ketones 1, while the addition of acetic acid enhances the electrophilicity of the aldehyde function. 2-Acylbuta-1,3-dienes 106 (yields from good to high) are formed as a mixture of E- and Z-isomers relative to the newly formed C=C bond, while the existing C=C bond of the starting ketones 1 remained in the E-configuration.
Diverse (het)arylsubstituted β,γ-ethylenic ketones 1, readily accessible from (het)aromatic ketones and (het)aryl alkynes, were used to synthesize polyarylated α-alkenyl-β-diketones 107 via the regio- and stereoselective acylation with acyl chlorides in the presence of magnesium bromide etherate/N,N-diisopropylethylamine (DIPEA) system (Scheme 62).[100]
This approach (a soft enolization) involved the initial formation of a coordination complex 108 between Lewis acid (magnesium bromide) and ketone 1, providing stronger polarization of the carbonyl function. Consequently, the acidity of the α-protons increases, ensuring enolization with mild organic bases (Scheme 63).[100]In addition, the Lewis acid blocks the oxygen nucleophilic centre, thus securing C-regioselective acylation of the intermediate enolates 109.
As a versatile synthons, β,γ-ethylenic ketones 1 successfully undergo DABCO-catalyzed allylation with Morita –Baylis – Hillman carbonates 110 to give 2-alkoxycarbonylallyl β,γ-unsaturated ketones 111 in high yields and with excellent diastereoselectivities (see Scheme 63).[101] Starting ketones 1 bearing aromatic substituents with diverse electronic properties were tolerant to this nucleophilic substitution reaction. The reaction features mild reaction conditions (room temperature, no strict water-free or oxygen-free conditions) and short reaction times in most cases. Depending on the reaction conditions, double allylation products, a,a-(112) and a,γ-di(2-alkoxycarbonyl)allyl (113) β,γ-ethylenic ketones, were obtained in overall yield of 33 – 91% (Scheme 64).
Based on the reaction of β,γ-ethylenic ketones 1 with acylacetylenes 114 in the Cs2CO3/DMSO system, protocol for the stereoselective synthesis of a broad range of substituted 1,3,5-trienes 115 has been developed (Scheme 65).[102]
A possible reaction mechanism for the formation of 1,3,5-trienes 115 involves the initial nucleophilic attack of deprotonated β,γ-ethylenic ketones 1 on the triple bond of acetylenic ketones 114 (Scheme 66).[102] After that, vinyl carbanions 116 intramolecularly add to the carbonyl function. Then, ring opening occurs in anions 117 to give intermediates 118, which undergo tautomerization and protonation to produce conjugated trienes 115.
5. Conclusion
Since the discovery of the base-mediated C-vinylation reaction of ketones with alkynes in 2010, the chemistry of γ-aryl-β,γ-ethylenic ketones and their synthetic applications has become an intensively researched area. The three different reaction centres (carbonyl function, double bond and α-CH active group) provide a rich and intriguing chemistry of these compounds. An overview of the current state of the art in this field shows that the multifaceted reactivity of β,γ-ethylenic ketones opens up almost unlimited opportunities for the synthesis of a wide variety of new classes of complex functionalized compounds. As further possible progress in this field, there is envisioned the realization of a range of nucleophilic additions of β,γ-ethylenic ketones to various functionalized electrophiles, especially in an asymmetric manner, wherein the nucleophilic centre is the deprotonated α-CH2-group. In turn, β,γ-ethylenic ketones may behave as electrophiles when attacked at their double bond by N-, P-, S-, and Se-centered nucleophiles that will provide numerous functionalized, so far inaccessible, nitrogen-, phosphorus-, sulfur-, and selenium-containing ketones, promising synthetic building blocks and ligands for new metal complexes.
This review provides first examples of successful application of β,γ-ethylenic ketones as dienophiles in asymmetric hetero-Diels – Alder cycloaddition that promises further spreading of this rewarding approach to the optically active functionalized compounds. As follows from few cases of arylation with electron-rich arenes, this methodology may by successfully applied to the preparation of densely functionalized aromatic and heteroaromatic systems. Almost unlimited possibilities for the design of tetra(het)aryl substituted benzenes are expected from the crotonic autodimerization of β,γ-ethylenic ketones as evidenced from the review. A lot of interesting synthetic surprises can be met upon investigation of dienol forms of β,γ-ethylenic ketones, i.e. hydroxy-1,3-dienes, especially those stabilized as silyl ethers. Such functionalized dienes capped by aromatic or heteroaromatic substituents can find wide applications in organic synthesis. Various families of dienes, both conjugated and skipped, can be obtained by a simple crotonic condensation of β,γ-ethylenic ketones with aldehydes or ketones. The Favorsky reaction of β,γ-ethylenic ketones with acetylene can afford vinylacetylenic alcohols, which, after dehydration, should furnish functionalized acetylenic dienes (hexa-1,3-dien-5-ynes).
Thus, the superbase-mediated C-vinylation of ketones (hydrocarbonylation of acetylenes) represents a kind of silent breakthrough in the acetylene chemistry, which for more than a century did not admit the inversion of the Favorsky reaction. This novel feature of the acetylene reactivity became a base for the readily scalable and technologically feasible synthesis of β,γ-ethylenic ketones, which now paves the ways to new directions of not yet explored acetylene-related fine and industrial organic synthesis. No doubt, this reaction and the fascinating chemistry of its products, β,γ-ethylenic ketones, will bring many prospective and diverse discoveries in the coming years.
6. List of abbreviations
The following abbreviations and designations are used in the review:
All — allyl,
Boc — tert-butoxycarbonyl,
Cp* — pentamethylcyclopentadienyl,
DABCO — 1,4-diazabicyclo[2.2.2]octane,
DBU — 1,8-diazabicyclo[5.4.0]undec-7-ene,
DFT — density functional theory,
DIPEA — N,N-diisopropylethylamine,
dr — diastereomeric ratio,
EDG — electron-donating groups,
ee — enantiomeric excess,
er — enantiomeric ratio,
Fu — furyl,
HFIP — 1,1,1,3,3,3-hexafluoro-2-propanol,
MS — molecular sieves,
Ms — methanesulfonyl (mesyl),
Naph — naphthyl,
Py — pyridyl,
TBDPS — tert-butyldiphenylsilyl,
TEMPO — 2,2,6,6-tetramethylpiperidine-1-oxyl,
Tf — trifluoromethanesulfonyl (triflyl),
Th — thienyl,
Ts — p-toluenesulfonyl (tosyl),
p-TSA — p-toluenesulfonic acid.
References
