carbon bond forming reaction were known long ago and have been ...... and Biology, Minisci, F. Ed., NATO ASI Series; Kluver Academic Pub.; Dordrecht, 1989,.
The Oxidative Radical Approach to Carbon-Carbon Bond Formation: A Personal Account Renzo Ruzziconi Dipartimento di Chimica, Università di Perugia, via Elce di Sotto, 8, 06123- Perugia, Italy Dedicated to Prof. Manfred Schlosser in honor of his scientific achievements within his career
Abstract Among the different methods to form carbon-carbon bond homogenically, those based on the mono-electronic metal oxidant-promoted addition of carbonyl compounds to unsaturated systems has got a considerable success. Owing to its high reduction potential, its solubility in most common organic solvents and the very mild conditions required, cerium(IV) ammonium nitrate (CAN) is able to generate -, -, and -carbonyl alkyl radicals from enol ethers and silyloxycyclopropanes allowing the approach to high functionalized molecule often with remarkable regio- and stereoselectivity. The aim of this review is to afford an overview of the potentiality of this approach in synthetic organic chemistry. Keywords: Mono-electronic metal oxidant, oxidative addition, cerium(IV) ammonium nitrate, carbonyl alkyl radicals, homolytic aromatic substitution, enol ethers, silyloxycyclopropanes. Table of contents 1. Introduction 2. Carbonyl Coumpounds as Source of -Carbonylalkyl Radicals 2.1 Oxidative addition of carbonyl compounds to carbon-carbon double bonds 2.2 Oxidative addition of simple ketones to electron-rich alkenes 2.3 Oxidative addition of 1,3-dicarbonyl compounds to electron-rich carbon-carbon double bonds 3. Trimethylsilyl Enol Ethers as Source of -Carbonylalkyl Radicals 3.1 Oxidative cross-coupling reactions 3.2 Synthesis of 1,4-dicarbonyl compounds 3.3 Synthesis of -unsaturated carbonyl compounds 3.4 Synthesis of aromatic ketones and polycyclic aromatic compounds 4. Hydroxy- and Alkoxycyclopropane Derivatives as Source of -Carbonylalkyl Radicals 5. Silyl Dienol Ethers as a Source of Carbonylallyl Radicals 6. Aromatic Homolytic Substitution 7. References
In the last two decades, radical chemistry has seen a considerable development in organic synthesis mainly due to the well-known advantages of radical reactions compared with ionic ones. Nowadays, the high constant rates and, above all, the compatibility of organic radicals with most of functional groups, assign a prominent role to radical chemistry in modern organic synthesis. The increased option for processes involving radical species as a valuable tool for sophisticated organic syntheses is a consequence of the recent developments of the measuring techniques of very fast reactions with second order rate constants ranging from 10-1 to 109 M-1s-1. 1 Among the different methods developed to form carbon-carbon bonds homogenically, those referring to the Stork,2 Barton,3 Curran,4 Giese,5 Porter6 leading work, involve radical chain reactions and base their success on the selectivity exhibited by the different radical species (generated in the various reaction steps) in attacking non radical reaction partners. (Scheme 1).7
Scheme 1. General sketch of a reductive radical-chain reaction.
Also intensively investigated were non-chain processes where radical species are generated, but also slaked, through a redox process involving strong monoelectronic metal oxidants.8 Generated by oxidation of a neutral molecule with a strong monoelectronic metal oxidant, the first formed radical species 1 usually exhibit a substantial electrophilic character having the carbon-center radical bonded to an electron withdrawing group. The low SOMO energy makes this species resistant to further oxidative processes, giving it enough time to attack preferably an electron rich -bond. The new radical adduct 2, now a nucleophilic species, is then oxidized by the metal to the a carbocation 3 which, in turn, evolves into the final products by reaction with any nucleophilic species present in the medium(Scheme 2) .
Scheme 2. General sketch of an oxidative radical reaction promoted by monoelectronic metal oxidants.
Over the past twenty years, oxidative addition reactions of enolizable carbonyl compounds to alkenes, promoted by one-electron metal oxidants, have received considerable attention as a valuable tool for both inter- and intramolecular carbon-carbon bond formation. Many metal salts such as Mn(III), Cu(II), Ag(II), V(V), Ce(IV) suited this purpose. Mn(III), in particular, was intensively studied by Snider 10 (mainly as the acetate salt) and was used in several of organic transformations. Scheme 3 is just one example of the synthetic pontentialities of this metal oxidant.11,12 The Mn(OAc)3-promoted oxidation of the enolizable dicarbonyl compound 4 generates an -dicarbonylalkyl radical 5 that cyclizes to give the adduct 6 which, in turn, attacks the adjacent aromatic ring leading to the tricyclic ketone 7 after a second oxidative step.
Scheme 3. Mn(OAc)3-promoted oxidative two-fold consecutive cyclization forming polycyclic ketones. Indeed, the use of Mn+3 salts is subject to some limitations, that rests mainly in its scarce solubility in most organic solvents. As a consequence, Mn(OAc)3-promoted carboncarbon bond forming reactions are usually carried out at a relatively high temperature in acetic acid, making the process unsuited to heat- and acid-sensitive molecules. Some peculiarities of Ce+4 salts as effective mono-electronic metal oxidant in carbon carbon bond forming reaction were known long ago and have been intensively investigated throughout the past two decades. The research in this field draws inspiration from the pioneering work of Heiba and Dessau,13 who showed that ceric ammonium nitrate (CAN)
stands out as a powerful one-electron oxidizing reagent in oxidative carbon-carbon bond forming reactions. They also showed that carbonyl compounds having at least one hydrogen to the carbonyl group can be oxidized by CAN generating an -oxoalkyl radical. The latter, an electrophilic species, is able to attack a carbon-carbon double bond before being oxidized in turn. In the cited example (Scheme 4) 14 the electrophilic carboxymethyl radical 8 attacks a terminal alkene to generate a -carboxyalkyl radical 9, now a nucleophilic species, which is rapidly oxidized by a second molecule of CAN to the corresponding carbocation 10. Ultimately, the intramolecular nucleophilic attack by the carboxylic group leads to the expected lactone 11.
Scheme 4. Synthesis of -lactones by CANpromoted oxidative addition of acetic acid to alkenes. This review aims to illustrate the manifold synthetic opportunities offered by CAN through selected examples coming from thirty years of research in this field.
2. Carbonyl Coumpounds as a Source of -Carbonylalkyl Radicals The synthesis of lactones by oxidative addition of acetic acid to alkenes reported by Heiba in 1971 represent a milestone in the use of CAN for carbon-carbon bond forming reactions. Indeed, the very high reduction potential (1.61 vs NHE), its substantial solubility in the most common organic solvents (including acetic acid, acetonitrile, methanol or ethanol) as well as the very simple operational mode make CAN a very attractive reagent for this kind of processes.
2.1. Oxidative addition of carbonyl compounds to carbon-carbon double bonds
2.1.1 Oxidative addition of simple ketones to electron-rich alkenes. Like acetic acid, simple ketones 12 bearing -hydrogens, used both as reagent and solvent, were shown to undergo a slow oxidation by CAN in generating -carbonylalkyl radicals 13 even at room temperature. Once trapped with a variety of unsaturated hydrocarbons, the oxidative process evolves into different kinds of addition products whose features depend on the nature of both the reaction partners and conditions (Scheme 5).
Scheme 5. General sketch of the CAN promoted oxidative addition of carbonyl compounds to alkenes. If an electron-transfer mechanism is operating, the radical adduct 14 is converted into a carbocation 15 (Scheme 5, path a) by CAN which, in turn, can evolve either into an unsaturated carbonyl compound 16 through an oxidative -elimination process, path c), or into a new poly-functionalized saturated product 17 by attack of any nucleophilic species present in the medium (path d). The positive charge could also be intramolecularly saturated by the carbonyl oxygen by loss of an acidic -proton leading to 4,5-dihydrofurans 18 (path e). This is what usually occurs in the reactions involving 1,3-dicarbonyl compounds. A ligand transfer mechanism could also operate (path b) giving a saturated addition product 19 where the substituent Y is the ligand of the oxidizing metal. This is the typical outcome of the CANpromoted oxidative addition in aprotic and weakly nucleophilic solvent, in such case, Y is the nitroxy group. A certain reluctance in the synthetic exploitation of this process could originate by the use of two equivalents of a high molecular weight oxidant, such as CAN. Nevertheless, it can be overcome by the advantage of attaining highly functionalized reaction products, sometimes with a remarkable regio- and stereoselectivity. Oxidative addition of simple ketones to vinylic acetates in a 2:1 ketone-methanol mixture constitutes a valid approach to 1,4-dicarbonyl compounds 20 (Scheme 6, Table 1).16 A similar strategy was pursued by Heiba using Mn(OAc)3 in acetic acid at 70°C. However, CAN resulted more effective than Mn(OAc)3 and, more importantly, the method, can also be
extended to the synthesis of 4-oxoaldehydes dimethyl acetals 21 simply by employing vinyl acetate as a radical acceptor.
Scheme 6. 1,4-Dicarbonyl compounds from CAN-promoted oxidative addition of ketones to vinylic acetates. Table 1. CAN-Promoted Reaction of Carbonyl Compounds with Vinyl and Isopropenyl acetate. Product, Yield (%) a
Carbonyl compound OCOCH3
O OCH3 O
O OCH3 OCH3
69 Yield of isolated product calculated with respect to CAN
Another advantage of CAN over Mn(OAc)3 is the remarkable regioselectivity in generating -carbonylalkyl radical from non-symmetric ketones. In the absence of substantial steric effects, the oxidation always involves the most substituted -carbon exclusively. This finding was considered a crucial piece of evidence in favor of the involvement of the enolic form of the ketone in the rate-determining first oxidative step. Thermodynamic and kinetic factors were invoked to account for such high regioselectivity, among which: (i) a certain proportionality between the enol content of the ketone and its oxidation rate (Table 2); and (ii) the substantial decrease of the ionization potential as a function of the alkyl substitution around the enolic double-bond. Both factors entail an increasing oxidation rate.17
Table 2. Relative Oxidation Rates as a Function of Enol Content of Carbonyl Compounds. Carbonyl compound Acetone 2-butanone Cyclopentanone Cyclohexanone Diethyl malonate Ethyl acetoacetate 2,4-pentandione
Enol Content, % 6 × 10-7 1 × 10-6 1× 10-5 7.7 × 10-3 8.4 80
Relative Ox. Rate 1 2.3 17 34 24 > 200 >300
The CAN-promoted oxidative addition of light ketones to 1,3-dienes was found to give a nearly equimolar mixture of 1,2- 23 and 1,4-nitroxy 24 adducts that certainly derives from the CAN-promoted oxidation of the allyl radical adduct 22 according to a ligand transfer mechanism (Scheme 7)18
Scheme 7. Product from CAN-promoted oxidative addition of ketones to 1,3-butadiene.
While 1,2-nitroxy-adduct tends to decompose in a relatively short time, the more stable 1,4-nitroxy-adduct inspired interesting synthetic applications. For instance, it was transformed into a number of high functionalized -unsaturated ketones by nuclophilic substitution of the allylic nitroxy group (Scheme 8).19
Scheme 8. Conversion of nitroxy adducts into various oxo- and hydroxy-susbstituted allyl derivatives.
2.1.2. Oxidative addition of 1,3-dicarbonyl compounds to electron-rich carboncarbon double bonds. Owing to the a higher content of the active enolic form, 1,3-dicarbonyl compounds are oxidized by CAN much faster than simple ketones. This may very well explain why they have been so intensively investigated in the past thirty years. As the previous, statement suggests, the oxidation rate by CAN in generating -dioxoalkyl radicals is inversely proportional to the pKa value of the active methylene group and follows a decreasing order: 1,3-diketones > alkyl 3-oxoesters >> dialkyl malonates. The strong electrophilic character of -dicarbonylalkyl radicals was thoroughly assessed by determining the Hammett value of the malonyl radical addition to meta- and para-substituted styrenes in two comparative kinetic studies where the attacking radical was generated either by oxidation of dimethyl malonate 29 with CAN in methanol or by tributyltin hydride-induced C-Cl bond homolytic breaking of diethyl 2-chloromalonate 30, also in methanol. (Scheme 9).20,21 In the former case, a mixture of dimethyl 2-[(2-nitroxy-2-aryl)ethyl]- and 2-[(2methoxy-2-aryl)ethyl]malonate 31b was obtained, whereas the tributyltin hydride-promoted reductive addition gave diethyl 2-(2-arylethyl)malonate 32 (Scheme 9).
Scheme 9. value determination of the malonyl radical addition to meta and parasubstituted styrenes.
Besides strengthening the remarkable electrophilicity of the malonyl radical, the negative and practically identical values (-1.05 and -1.06) observed for the above processes suggest that, contrary to what happens with Mn(OAc) 3,22-25 the coordination, if any, of the carbonylalkyl radical to the metal does not play a significant role in the CAN-promoted radical additions. The outcome of CAN-promoted oxidative addition of 1,3-dicarbonyl compounds to unsaturated carbon-carbon bonds is substantially different compared to that of the corresponding reaction with simple ketones. The much higher oxidation rate allows the 1,3dicarbonyl compound to be used in stoichiometric amount (0.5 eq with respect to the oxidant). Moreover, different reaction products are obtained depending on the nature of both dicarbonyl compounds and the radical acceptor partner.
CAN-promoted oxidative addition of diethyl malonate 33 to vinylic acetates in methanol at ambient temperature was claimed to be the best approach to 4-oxoalcanoates 34.16 With vinyl acetate, dialkyl 2-(2,2-dimethoxyethyl)malonates 35 are obtained in good yield (Scheme 10).
Scheme 10. 4-Oxoesters from CAN-promoted malonyl radical addition to vinyl and isopropenyl acetate. Noteworthy, since 2-alkyl-sustituted malonic ester is oxidized by CAN much slower than the unsubstituted dialkyl malonate, the above radical process allows dialkyl 2alkylmalonates to be obtained, exclusively, contrary to what occurs in the reaction of dialkyl malonate anion with bromoacetaldehyde dimethyl acetal which gives the same product but contaminated to a greater or lesser extent by the double alkylation by-product. The radical approach was also adopted by Linker in a one-step synthesis of 2-Cbranched carbohydrates using glycals as the reaction partners of dimethyl malonate. In addition, he claimed that CAN is superior to Mn(OAc)3 for many applications in carbohydrate chemistry.26 thanks to the mild reaction conditions. As in the reaction with ketones, CAN-promoted oxidative addition of dialkyl malonates to 1,3-butadiene in acetonitrile affords 1,2- 37 and 1,4-nitroxyallyl 38 adducts in nearly equimolar amounts. Heating of the crude mixture with Na2CO3 in DMF, in the presence of bromide ions, was reported to convert the crude mixture into dialkyl 2-vinylcyclopropane-1,1dicarboxylate 39 with good yield. Similar results were obtained in the oxidative addition of dialkyl malonate to styrene leading to 2-[(2-nitroxy-2-phenyl)ethyl]malonate 40. Treatment of the resulting 2-nitroxy adduct in alkaline medium gives the corresponding 2arylcyclopropane-1,1-dicarboxylate 41 in good yields (Scheme 11).19
Scheme 11. The radical approach to alkyl vinyl- and arylcyclopropane-1,1-dicarboxylates. -Lactones can also be obtained as a by-product, but this seems to be a peculiarity of CAN-promoted oxidative addition of dialkyl malonates to both -alkyl substituted styrenes and 2-alkyl-1,3-butadienes in polar solvents.21,27 -Diketones and -ketoesters are oxidized by CAN much faster than malonic esters. In the presence of an electron-rich alkene, the dicarbonylalkyl radical quickly attacks the carboncarbon double bond at the less substituted sp2 carbon to give a radical adduct - a nucleophilic species - which is rapidly oxidized by CAN into the final product. Once again, the outcome of the oxidative addition process depends on the nature of alkene, as well as on the reaction conditions. The author of this paper found that the oxidative addition of ethyl acetoacetate 42 to 1,3-butadiene in acetonitrile provides a mixture of 1,2- (43a) and 1,4-nitroxy (43b) adducts. However, whereas the latter was quite a stable product, the former undergoes a slow decomposition with the release of nitric acid to give 3-ethoxycarbonyl-2-methyl-5-vinyl-4,5dihydrofuran (Scheme 12).18
Scheme 12. Product from CAN-promoted oxidative addition of 1,3-dicarbonyls to 1,3butadiene in MeCN at room temperature. Later on, this process was intensively investigated and exploited in the synthesis of several five-member heterocyclic compounds. Nair discovered that CAN is very effective in
promoting oxidative addition of 1,3-diketones 45 to alkenes and cycloalkenes and developed a simple approach to several dihydrofuran derivatives 46 (Scheme 13).28
Scheme 13. 3-Acyl-4,5-dihydrofurans by CAN-promoted oxidative addition of 1,3-dicarbonylcompounds to alkenes.
Similarly, Mane was able to prepare norbisabolide 48 by CAN-promoted oxidative addition of Meldrum’s acid 47 to (R)-(+)-limonene (Scheme 14).29
Scheme 14. CAN-promoted oxidative radical approach to norbisabolide. The same strategy was adopted in the preparation of several spirodihydrofurans using different alkylidenecycloalkanes as radical acceptors (Scheme 15).30,31
Scheme 15. Polycyclic spiro-compounds by CAN promoted oxidative addition of 1,3dicarbonyl componds to methylidenecycloalkanes.
The author of this paper applied the same procedure to prepare regioselectively substituted 3-acylfuranes and alkyl 3-furoates using alkyl substituted vinylic acetates as the reaction partners of either 1,3-diketones or 3-oxoesters, respectively.32 The first formed dihydrofuran was easily transformed into the final product by refluxing the crude reaction mixture in toluene in the presence of pyridinium tosylate (Scheme 16, Table 3).
Scheme 16. Regioselectively alkylated 3-acylfurans and 3-furoic esters by CAN-promoted 1,3-dicarbonyl compounds to vinylic acetates.
Table 3. 3-Acylfurans from CAN-Promoted Oxidative Addition of 1,3-Dicarbonyl Compounds to Vinylic Acetates. 1,3-Dicarbonyl compound
O OCOCH3 O
OCOCH3 O a
Yield of isolated product calculated with respect to CAN
The same procedure was exploited by S. C. Roy to obtain fused polycyclic acetals 50 through the addition cyclic and acyclic 1,3-dicarbonyl compounds to cyclic vinyl ethers (Scheme 17).33
Scheme 17. Oxidative radical addition of 1,3-dicarbonyl compounds to cyclic enol ethers giving polycyclic acetals.
High-HOMO unsaturated hydrocarbons were assessed as the ideal partners of electrophilic radical species in carbon-carbon bond forming reactions. 34 Thus, the choice of electron rich alkenes as the reaction partners of mono- and 1,3-dicarbonyl compounds was common in oxidative carbon-carbon bond formation by monoelectronic metal oxidants. Nevertheless, as shown by S. C. Roy, -dicarbonyl radicals are also able to attack 3-arylsubstituted acrylates 51, provided strong electron releasing groups are bound to the aromatic ring (Scheme 18).35
Scheme 18. CAN-promoted oxidative addition of 1,3dicarbonyl compounds to alkyl 3-arylacrylates.
As expected for the most favorable SOMO-HOMO frontier orbital interaction, the attack involves the acrylate -carbon leading to 3-acyl-5-aryl-4-alkoxycarbonyl-4,5dihydrofurans 52 in good yields. Surprisingly, the process is highly stereoselective, providing
cis-2,3-substituted dihydrofurans, exclusively. Subsequently, Lee showed that, contrary to other oxidants such as Mn(OAc)3, Cu(OAc)2 or Ag2CO3/celite, CAN is very effective in promoting oxidative addition of 1,3-dicarbonyl compounds to -alkyl-substituted acrylates as well.26 Once again, the radical attack is characterized by a very high regioselectivity, but now, it involves the -carbon of the -unsaturated ester leading to 3-acyl-5-alkyl-5alkoxycarbonyl-4,5-dihydrofurans 53 in satisfactory yields (Scheme 19).
Scheme 19. CAN-promoted oxidative addition of 1,3-cyclopentadiones to alkyl methacrylates.
Here, a SOMO-LUMO interaction seems the most favorable molecular orbital combination, which is why the presence of an alkyl substituent to the alkoxycarbonyl group becomes crucial for the success of the process. It was also applied to prepare several biologically active furonaphthoquinone-based natural products.36 As a rule, any electron-withdrawing group bonded to the -carbon of a ketone or an ester favors the formation of the enolic form which, once oxidized by CAN, generates a very electrophilic -carbonylalkyl radical. Thus, replacement of one carbonyl group of a 1,3dicarbonyl compound with the electron-withdrawing diethoxyphosphoryl group makes the resulting -phosphoryl ketone 54 smoothly oxidizable by CAN. The addition of the resulting -keto--phosphoryl radical to vinylic acetates provides regioselectively alkyl substituted diethyl 3-(furyl)phosphonates 55 in satisfactory yields after cyclization of the intermediate carbocation (Scheme 20, Table 4).37
Scheme 20. Alkyl-substituted 3-diethoxyphosphoryl-furans by CANpromoted oxidative addition of -diethoxyphosphoryl ketones to vinylic acetates.
Table 4. 3-Acylfurans from CAN-promoted oxidative addition of diethyl 2-oxopropyl-phosphonate to vinylic acetates. 1,3-Dicarbonyl compound PO(OEt)2
Product, %a PO(OEt)2
C6H4-p-F 80 PO(OEt)2
Yield of isolated product calculated with respect to CAN.
Trimethylsilyl Enol Ethers as a Source of -Carbonylalkyl Radicals
In principle, carbon-carbon double bond exhibiting ionization potentials (IP) lower than 8.6 eV (roughly equivalent to an electrochemical potential E of ca. 1.6 V) can be smoothly oxidized by CAN generating a transient radical-cation. Therefore, aromatic compounds bearing electron-releasing substituents, alkyl- and aryl-substituted dienes and polyenes, and enol ethers can be oxidized by CAN. In this respect, trialkylsilyl enol ethers can be considered
versatile building blocks in synthetic radical organic chemistry. The oxidation rate of silyl enol ethers by CAN is a bit lower than that of the corresponding enol, the second order rate constants falling in the range 10-3 − 10-1 depending on the number and nature of the substituent around the carbon-carbon double bond, as well as on the reaction conditions.38 The electron transfer generates a transient radical-cation, which rapidly evolves into an -oxoalkyl radical after releasing the trialkylsilyl group. Therefore, the use of trimethylsilyl vinyl ether in place of the parent ketone represents a substantial improvement in carbon-carbon bond forming radical reactions. This stratagy affords significant advantages: (i) the trimethylsilyl vinyl ether can be used in stoichiometric amount with respect to the oxidant, allowing this procedure to be applied to any carbonyl compound; (ii) the reaction times are considerably reduced; and (iii) the generation of the -oxoalkyl radical from non-simmetrical ketones can be regioselectively controlled by the use of easily accessible "thermodynamic" (56) or "kinetic" (57) silyl enol ethers since it was demonstrated that the -carbon bearing the unpaired electron is always the one previously involved in the enolic double bond and the one forming the new carbon-carbon bond 58 and 59, respectively. This means that the radical addition is much faster than a plausible equilibration by hydrogen exchange at the position of the carbonyl group (Scheme 21).
Scheme 21. Regioselective generation of -carbonylalkyl radicals by CAN-promoted oxidation of thermodynamic and kinetic silyl enol ether.
Oxidative cross-coupling reactions 3.1.1 synthesis of 1,4-dicarbonyl compounds. Oxidative cross-coupling between 1,2dialkylsubstituted-1-silyloxy alkenes and 1-substituted 1-silyloxyalkenes affording 1,4diketones (Scheme 22, Table 5), shows how much the scope of the above radical process can be widened simply by replacing the ketones with the parent silyl enol ethers. 39 The oxidation rate of trimethylsilyl enol ethers by CAN is very sensitive to the electronic effects and the alkyl substitution around the carbon-carbon double bond make the HOMO energy of the alkene increase with consequent decrease of the oxidation potential. 40 Accordingly, trialkyl-substituted silyl enol ethers 60 are oxidized by CAN ca. 70 times faster than 2-alkyl substituted silyloxyalkenes 61.39 This finding accounts for the success of the
above cross-coupling processes allowing the less substituted silyl enol ether to be used in large excess as a radical acceptor leading to 1,4-diketones 62. As expected, oxidative addition of silyl enol ethers to ethyl vinyl ether in methanol yields complex mixtures of cyclic and acyclic acetals which converge to the corresponding 4-oxo aldehydes 64 in good yields further to the acidic hydrolysis (Scheme 22).41
Scheme 22. CAN-promoted oxidative cross-coupling of silyl enol ethers.
Table 5. 1,4-dicarbonyl compounds from CAN-promoted oxidative cross-coupling of Silyl enol ethers with vinylic ethers. Silyl enol ether
4-oxoaldehyde (Yield,%) a OSi(CH3)3
1,4-diketone (Yield, %) a O
78 a b
Yield of isolated product calculated with respect to CAN. 3-Trimethylsilyloxy-2-cholestane.
3.1.2 Synthesis of -unsaturated carbonyl compounds. The synthesis of highly functionalyzed -unsaturated carbonyl compounds by CAN-promoted oxidative addition of silyl enol ethers into conjugated dienes constitutes a further applicative example of this strategy. The -carbonylalkyl radical, generated by oxidation of the silyl enol ether, attack 1,3-butadiene at the less substituted terminal to generate an allyl radical 65, a high SOMO species, which undergoes a rapid oxidation by a second molecule of CAN. Here, acetonitrile is the most suitable solvent inasmuch as it allows to obtain nearly equimolar amounts of 1,266 and 1,4-nitroxy 67 adducts susceptible to further transformations. Indeed, nitroxy group, like acetoxy, nitro, phosphate-, and other poor-leaving groups, can be easily removed by palladium(0)-catalyzed nucleophilic substitution reactions transforming the crude mixture into highly functionalyzed -unsaturated carbonyl compounds 68 with high regio- and stereoselectivity (Scheme 23, Table 6).
Scheme 23. -Unsaturated carbonyl compounds from CAN-promoted oxidative addition of silyl enol ethers to 1,3-butadiene Table 6. Pd(0)-Catalyzed Malonylation of Nitroxy Adducts from CAN-Promoted Oxidative Addition of Silyl Enol Ethers to 1,3-Butadiene.
Silyl enol ether
Product Yield, % (1,2-adduct, %) a O
62 (7) OSi(CH3)3
46 (8) OSi(CH3)3
49 (7) O
42 (5) O OSi(CH3)3
CO2CH3 CO2CH3 OSi(CH3)3
32 (< 1)
Overall yield of isolated product calculated with respect to CAN.
3.1.3 Synthesis of aromatic ketones and polycyclic aromatic compounds. In theory, whenever it is possible to put nucleophilic functionality in a suitable position along the chain of a 1-trimethylsilyloxyalkene, its CAN-promoted oxidative addition to a vinylic ether should allow access to a variety of acylated homo- and heterocyclic compounds. Following this idea, the author and his co-workers developed an original two-step synthesis of polycyclic aromatic ketones.42 Again, the CAN-promoted oxidative addition of 3-aryl-1-trimethylsilyloxypropenes 69 (easily prepared by the Reetz’s protocol43) to ethyl vinyl ether initially gives a complex mixture of acyclic and cyclic acetals that converts into a unique aromatic ketone 70 after acid catalyzed electrophilic cyclization in 80% aqueous H2SO4 and in the presence of dichlorodicyanobenzoquinone (DDQ) (Scheme 24).
Scheme 24. CAN promoted radical approach to polycyclic ketones.
Of course, due to the weak electrophilic character of a protonated formyl group, the cyclization step is feasible only when aryl derivatives are activated by powerful electronreleasing groups, as shown by the synthesis of substituted phenanthren-1-ones from 3oxocyclohexene (Scheme 25, Table 7).
Scheme 25. CAN-promoted radical approach to regioselectively substituted phenanthrenones. Table 7. Substituted 3,4-Dihydro-1(2H)-phen-anthrenones from CAN Promoted Oxidative Addition of 3-Aryl-1-trimethylsilyloxycyclo-hexene to Ethyl Vinyl Ether. Time, min Yield,a % Y Y H
4-F 120 7-F a Yield of isolated product. b A product of polymeric nature was recovered.
The mixture of acyclic and cyclic acetals (73+74) constitutes itself a source of molecular diversity provided that different sequences of the cyclization and aromatization steps are adequately respected. Thus, in the presence of catalytic amount of p-toluensulphonic acid, treatment of the acetal mixture with DDQ in refluxing benzene gives 4(fluoroaryl)benzofurans 75 in fairly good yield as the only reaction product (Scheme 26), whereas, regioselectively substituted 1-phenanthrenols 76 can be obtained in moderate yields when the same mixture is refluxed in benzene in the presence of DDQ before the crude product is dispersed in 80 % aq. sulphuric acid. 44
Scheme 26. Versatility of the acetal mixture obtained by CA-promoted oxidative addition of 3-aryl-1-trimethylsilyloxycyclohexene to ethyl vinyl ether. Owing to the remarkable regioselectivity observed in the cyclization of some fluoroarylsubstituted acetals, 6-fluoro- 72 (Y = 6-F) and 6,8-difluoro-3,4-dihydrophenanthren-(2H)-1one 72 Y = 6,8-F2)were easily prepared starting from both 3-fluoro- and 3,5-difluorophenyl magnesium bromide and 3-oxocyclohexene. They were used as valuable building blocks in
the synthesis of several nucleus- and side-chain-fluorinated phenanthrene-based profens 77ah (Scheme 27). 45
Scheme 27. Nucleus and side-chain regioselecticvely fluorinated phenanthrene-derived profens. Following the reaction sequence reported in Scheme 24, starting from 4-(fluoroaryl)-2(trimethylsilyloxy)-2-butenes, the same authors were able to prepare regioselectively fluorinated 2-acylnaphthalenes 78 (Table 8) to be used as valuable building blocks in the synthesis of several fluoronaphthyl derivatives 79 (Scheme 28), among which, a number of imidazole derivatives 80. 46 Some of these proved very effective inhibitors of the enzyme aromatase.47
Scheme 28. 2-Acyl naphthalenes as a source of several regioselectively fluorinated naphthyl derivatives. Table 8. Regioselectively Fluorinated 2-Acenaphthones and 2-Naphthaldehydes by CAN-Promoted Oxidative Addition of 3-Fluoroaryl-1-trimethylsilyloxyalkenes to Ethyl Vinyl Ether. Silyl enolether Carbonyl Compound Yield, % O
Yield of isolated product calculated with respect to trimethylsilyloxy alkene.
Hydroxy- and Alkoxycyclopropane Derivatives as a Source of -Carbonylalkyl Radicals
Cyclopropanes are claimed to exhibit strong analogies with alkenes both from the electronic and reactivity point of view. The similarity is even more cogent in the presence of powerful electron-donating groups. Just as enol ethers react with metal salt Lewis acid generating the corresponding nucleophilic metal enolates, in the same way, cyclopropanol (or even silyloxycyclopropanes) reacts with Lewis acids like Ti+4, Zn+2, Cu+2 Ag+, Pd+2 salts, to give the nuclophilic metal homoenolate further to the ring opening, (Scheme 29). This framework was at the basis of outstanding strategies for carbon-carbon-bond formation. 48-52
Scheme 29. Analogies between silylenol ethers and alkoxycyclopropanes in the reaction catalized by Lewis acid transition metals.
The analogy between silyl enol ethers and silyloxycyclopropanes also persists in oxidative processes. S. E. Schaafsma first found that cyclopropanone hydrate, as well as its hemiacetals 81 are smoothly oxidized by copper(II) and iron(III) salts giving both oxidative addition and elimination products through a homolitic cyclopropane ring opening (Scheme 30). 53-55 Conclusive evidence for the generation of an intermediate -carbonylalkyl radical was later obtained by cyclic voltammetry (CV) and ESR-experiments.53.
Scheme 30. Copper(II)- and Fe(III)-promoted oxidative opening of cyclopropane hemiacetals giving homocoupling, elimination and addition products. Since then, the oxidative generation of -ketoalkyl radicals from cyclopropanol derivatives were not extensively explored until, in 1991, K. Narasaka reported a successful procedure to prepare a number of 1,5-dicarbonyl compounds 84 by manganese(III)-2pyridinecarboxylate [Mn(pic)3]-promoted oxidative addition of cyclopropanol derivatives to trialkylsilyl enol ethers (Scheme 31).56
Scheme 31. Mn(III)-promoted oxidative addition of cyclopropanols to silyl enol ethers according to Narasaka Just as strong mono-electronic metal oxidants such as Mn+3 and Ce+4 salts, oxidized the enol ethers to generate -carbonylalkyl radical, analogously, electron rich cyclopropanols are oxidized by the same oxidants, generating the homologue -carbonylalkyl radicals 83 (Scheme 32) through an electron transfer process.
Scheme 32. Monoelectronic metal oxidantpromoted oxidation of cyclopropyl alkyl ethers generating -carbonylalkyl radicals. The potentialities of this strategy in carbon-carbon bond forming reactions were stressed by the Perugia group in the cerium(IV) ammonium nitrate-promoted oxidative addition of several trimethylsilyloxycyclopropanes 85 to 1,3-butadiene.57 As expected, by analogy with the reaction of trimethylsilyl enol ethers, equimolar mixtures of 1,2- (86) and 1,4-nitroxy (87) adducts were obtained in good yields. The latter were easily converted into highly functionalyzed -unsaturated carbonyl compounds 88 by palladium(0)-catalyzed nucleophilic allylic substitution reactions with good regio- and stereoselectivity (Scheme 33, Table 9).
Scheme 33. Synthesis of polyfunctionalized unsaturated carbonyl compounds based on the CAN-promoted oxidative addition of silyloxycyclopropanes 85 to 1,3-butadiene. Table 9. -Unsaturated Carbonyl Compounds from CAN-promoted Oxidative Addition of Silyloxycyclopropanes to 1,3-Butadiene R
R = OC2H5, R1 = H
R = C6H5, R1 = H
R, R1 = -(CH2)-
Yield of isolated regioisomeric mixture. oxocycloalkyl
Determined by GLC analysis.
Nu = 2-
As Narasaka showed, Mn(pic)3 is also able to generate a -carbonylalkyl radical by oxidative opening of an hydroxycycloprpane 82.58 The nucleophilic character of this species was pointed out by its reaction with electron-poor carbon-carbon double bonds that proved to be faster than its oxidation by the metal oxidant. The resulting -carbonylalkyl radical adduct 83, now an electrophilic species, can be trapped in different way before it is oxidized by the metal. Narasaka used tributyltin hydride to trap the adduct radical in the Mn(pic)3-promoted addition of 1-alkylsubstituted cyclopropanols to acryl derivatives, obtaining 1,6-diketones in satisfactory yields (Scheme 34). 58
Scheme 34. Narasaka’s addition of oxidatively generated -carbonylalkyl radical to electron poor alkenes.
The nuclephilic character of -carbonylalkyl radicals was also pointed out by Yus in a valid radical alternative approach to the classical Michael-type addition reaction (Scheme 35).59
Scheme 35. Reductive -carbonylalkyl radical to electron-poor carbon-carbon double bonds.
Not so surpringly, unlike the reaction of Mn(pic)3, CAN-promoted oxidative addition of trimethylsilyloxycyclopropanes 82 to enol ethers to obtain 5-oxoesters turned out to be impracticable. The failure was imputed to the nucleophilic character of the -carbonylalkyl radical due to a reduced electron-withdrawing effect of the carbonyl group. Thus, the direct oxidation of the -carbonylalkyl radical by CAN competes effectively with the addition to the carbon-carbon double bond of the reaction partner. A complex mixture of both -substituted carbonyl compounds, formed further to the nucleophilic attack by the solvent, and a nitroxycarbonyl compound, ensuing the oxidation of the -carbonylalkyl radical by CAN, is formed together with a byproduct -unsaturated carbonyl compound coming from by an oxidative elimination processes (Scheme 31).60 Clearly, Mn(pic)3 results less effective than CAN in oxidizing -carbonylalkyl radicals, therefore, the latter has enough time to attack either an electron rich or an electron poor reaction partner. The remarkable selectivity exhibited by CAN in oxidizing different kinds of radicals, the minor propensity of -carbonylalkyl radicals to attack electron rich alkenes and the high reactivity of -carbonylalkyl radicals towards these very alkenes cued the Perugia team to develop a simple one-pot protocol to attain highly functionalyzed 2,3-substituted cycloalkanones in satisfactory yields and excellent regio- and stereoselectivity.60 All that needs to be done is simply add a mixture of 1-ethoxy-1-trimethylsilyloxycyclopropane (85; R = OEt, R’ = H), 3-oxocycloalkene 71 and an electron-rich alkene to a methanolic solution of CAN at ambient temperature and wait for the reaction mixture to bleach (Scheme 35, Table 10).
Table 10. 2,3-Substituted Cycloalkanones from CAN-Promoted Oxidative Addition of 1-Ethoxy-1-trimethylsilyloxycyclopropane to 3-Oxocycloalkannes in the presence of electron-rich alkenes. O
Product, trans/cis ratiob
Yield of isolated product. Determined by H NMR and GLC analysis. c Solvent, CH3OH. d Solvent CH3CN.
In this multi-component reaction, the nucleophilic character of the -carbonylalkyl radical 83 R = OEt, R’ = H), generated by CAN-promoted oxidative opening of 1-ethoxy-1trimethylsilyloxyclopropane, is quite evident. It prefers to attack the electron poor unsaturated cycloalkenone at its -carbon, generating the -carbonylalkyl radical 90. The latter - as an electrophilic species - quickly attacks the electron-rich carbon-carbon double bond of the third reaction component before being oxidized, in turn, by CAN. Finally, the resulting adduct 91, now anucleophilic species, is rapidly oxidized by CAN to the final 2,3substituted cycloalkanone 92 (Scheme 36).
Scheme 36. The CAN-promoted domino addition of silyloxycyclopropanes to -unsaturated carbonyl compound in the presence of electron rich alkenes.
Silyl Dienol Ethers as a Source of Carbonylallyl Radicals
Trialkylsilyl dienol ethers are frequently used in synthetic organic chemistry as effective nucleophiles in Lewis acid-catalyzed vinylogous aldol condensation (Mukaiyama reaction). 6165 Although this process of a radical species was envisaged to be involved in some cases, the mechanism was never investigated in-depth and the oxidative generation of carbonylallyl radicals from trialkylsilyl enol ethers as an alternative way to form carbon-carbon bonds was little exploited. Chan and co-workers reported that 1,3-bis(trimethylsilyloxy)-1-methoxybuta-1,3-diene react with TiCl4 in acetonitrile to give dimeric dimethyl 3,5-dioxooctanedioate as the only reaction product.66 The reaction mechanism was not established; however, a homocoupling radical process appeared quite likely, all the more so because the involvement of an carbonylalkyl radical in the homocoupling of less nucleophilic titanium enolate was previously envisaged 67 - unequivocally demonstrated - by both cyclic voltammetry (CV) and ESR experiments. 68 Ten years later, it was reported that the addition of 1-(trimethylsilyloxy)-1,3-butadiene 93 to a solution of CAN in acetonitrile at 0°C smoothly gave (2E, 6E)-octa-2,6-dienedial 96 in good yield.69 According to the suggested mechanism, a carbonylallyl 94 radical is rapidly generated by oxidation of the dienol ether by CAN. Compared with the homologue carbonylalkyl radical, the carbonylallyl radical still exhibits a slightly electrophilic character, though to a lesser extent, which make it able to add to very electron rich multiple bonds before being oxidized in turn (Scheme 37). The resulting high-SOMO radical adduct 95 is then oxidized by CAN to the dienedial 96.
Scheme 37. CAN promoted oxidative homocoupling of 1-trimethylsilyloxy-1,3butadiene giving (2E,6E)-octa-2,6-dienedial.
This process was further exploited by P. Langer who devised a complex synthesis of alkoxycarbonyl-substituted hydroquinones based on CAN-promoted oxidative cyclization of the dianion equivalent 1,3-bis(trimethylsilyloxy)buta-1,3-dienes 97 (Scheme 38).70
Scheme 38. CAN promoted oxidative homocoupling according to Langer.
The substantially high HOMO energy of trialkylsilyl dienol ethers 98 makes these species a valuable source of vinylogous radicals and, at the same time, formidable radical acceptors. Hence, the formation of homocoupling products 99 would appear the foregone outcome of the oxidation of conjugate dienol ethers by monoelectronic metal oxidants even in the presence of very electron-rich unsaturated compounds. Nevertheless, the author and his co-workers were able to achieve cross-coupling products using alkyl-substituted trimethylsilyloxy alkenes as reaction partners of the 1-trimethylsilyloxy-1,3-butadiene 102. (Scheme 39). 69
Scheme 39. CAN promoted oxidative cross-coupling of 1-trimethylsilyloxy-1,3butadiene with silyloxyalkenes.
This time, the slow addition of the CAN solution in acetonitrile to a mixture of trimethylsilyl dienol ether and excess of trimethylsilyl enol ethers was considered crucial for the success of the cross-coupling process. Noteworthy, the attack of the carbonylallyl radical to the silyl enol ether was found to occur with high regio- and stereoselectivity, (E)-6-oxo--unsaturated carbonyl compounds were formed, exclusively (Table 11), making the method an effective way for extremely selective vinilogous carbon-carbon bond formations.
6 The Homolytic Aromatic Substitution (HArS) In two pioneering works, E. I. Heiba, and R. M. Dessau showed that carboxylates of monoelectronic metal oxidants, such as Ce(OAc)4, Mn(OAc)3 Pb(OAc)4 thermally decompose in refluxing acetic acid in the presence of toluene giving a mixture of benzyl acetate 105, acethoxyxylene 107 and tolylacetic acid 108.71,72 Clearly, the latter two compounds (the main reaction products) form by attack of the alkoxymethyl radical to toluene, according to the reaction mechanism described herein (Scheme 40), with the alkoxymethyl radical being generated by CAN-promoted oxidation of the acetic acid. Cyclopentadienyl radical intermediate 104, a low potential energy species, is formed and rapidly oxidized to the classic Wheland carbocation intermediate 105 by the metal. In part, the resulting cerium tolylacetate undergoes decarboxylation in that energetic reaction condition leading to the acetoxyxylene.
Scheme 40. Products from the oxidation of toluene with Mn(OAc) 3 in ACOH at 110 °C.
Indeed, as M. E. Kurz later showed, electrophilic .CH2X type radicals, with X an electronwithdrawing group such as -COOH, -COCH3, -NO2, are able to attack not only electron-rich alkenes but also electron rich aromatic rings giving the so-called homolytic aromatic substitution reaction (HArS). 73-76 Though Mn(OAc)3 proved to be the most effective monoelectronic metal oxidant in promoting the homolytic acetonylation (109) of aromatic hydrocarbons,76 Cerium(IV) ammonium nitrate is by far superior in promoting the nitromethylation (110) of activated benzenes. The reaction resulted very sensitive to the electronic effects (Scheme 41). Accordingly, nitromethylation of benzene in refluxing acetic acid gave -nitrotoluene in 50% yield, whereas in the same condition at controlled reaction time, toluene afforded -nitroxylenes in quantitative yields.75
Scheme 41 Mn(III)- and Ce(IV)-promoted acetonylation and nitromethylation of aromatic hydrocarbon Much milder conditions can be used when more electrophilic radical species are involved in the hemolytic aromatic substitution. In this case, Cerium(IV) is the elective oxidant. The author of this paper obtained 2-arylmalonic ester 111 in fairly good yields of moderate regioselectivity, simply by adding a mixture of dimethyl malonate and the aromatic hydrocarbon to a solution of CAN in methanol at room temperature (Scheme 42, Table 11).77
Scheme 42. CAN-promoted malonylation of aromatic hydrocarbon Table. Formation of Dimethyl Arylmalonates 111 from the Reaction of Aromatic Compounds with Dimethyl Malonate Promoted by Cerium(IV) Ammonium Nitrate in MeOH.
Aromatic Compound Benzene Tolueneb Anisoleb Chlorobenzene Mesitylene Naphthalene
Yield of Arylmalonates,%a 53 59 87 33 66 50
Isomeric Distribution ortho
50.8 82.3 50.0
21.4 27.8 1.7 16.0 50 (meta + para) c
(a) Yield of isolated product calculated compared to reacted CAN by -ArH stoichiometry. (b) Isomeric distribution determined by vpc analysis of the mixture of isomeric methyl arylacetates (comparison with authentic specimens) obtained by decarboxymethylation of the crude reaction product. (c) Isomeric distribution estimated by the 1H NMR spectrum of the crude reaction product. Since the signals of benzylic CH of meta- and para-chlorophenylmalonate coincide, only the overall percent of meta and para isomer is given.
Homolytic aromatic substitution of 1,3-dicarbonyl compounds was also exploited to build both homo- and hetero-polycyclic compounds. For instance, Citterio and his co-workers, obtained good yields of polyfunctionalized tetrahydronaphthalenes 113 by either Mn(OAc)3or CAN-promoted direct oxidative cyclization of 2-(4-phenylpropyl)malonic esters and aryltailed 1,3-dicarbonyl compounds 112 (Scheme 43).78,79
Scheme 43. CAN and Mn(OAc)3-promoted oxidative cyclization of ethyl 3-oxo-5-phenyl pentanoate. Starting from diethyl -benzylmalonates 114 or picolylmalonates 115, the same author developed an original method to prepare both dihydronaphthalenes 116 80 and dihydroquinolines and dihydroisoquinoline 117 81 in multicomponent reactions involving electron rich alkenes as the third reaction partner (Scheme. 44) and using Mn(III), Ce(IV) and Fe(III) salts as oxidizing reagents.
Scheme 44. Naphthalenes and quinolines from Mn+-promoted oxidative cyclization.
-Carbonylalkyl radical generated by oxidation of the corresponding silyl enol ethers are able to attack aromatic substrates, especially if they are activated by electron releasing groups allowing to avoid homocoupling processes. Uneyama and co-workers used this method to obtain good yields of heteroaryldifluoromethyl aryl ketones 119 by cross-coupling of -aryl-difluoroenol silyl ethers 118 with five-member heteroaromatics in acetonitrile in the presence of Cu(OTf)2 as the metal oxidant (Scheme 45).82
Scheme 45. Cu(OTf)2-promoted -carbonyldifluoromethylation of five member heterocycles. In the same year, D. I. Wright reported an intramolecular version of the anodic silyl enol ether addition to furan giving tricyclic furan derivatives. 83 Silyl enol ethers 120 were prepared by Michael addition of Grignard reagent, derived from 3-substituted bromoalkyl furan, to unsaturated ketones in the presence of ClTMS. Interestingly, whereas the common monoelectronic metal oxidants such as Mn(OAc) 3 and CAN failed to give the expected
cyclization products due to either hydrolysis or an extensive decomposition, the anodic cyclization on carbon anode at low current density afforded tricyclic benzofurans 121 in fairly good yields (Scheme 46).
Scheme 46. Anodic trimethyosilyloxycyclopentene.
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