Homologation Reaction of Ketones with Diazo ... - ACS Publications

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Homologation Reaction of Ketones with Diazo Compounds Nuno R. Candeias,*,† Roberta Paterna,‡ and Pedro M. P. Gois‡ †

Department of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, Tampere, FI-33101 Finland Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidad of Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal

‡

ABSTRACT: This review covers the addition of diazo compounds to ketones to afford homologated ketones, either in the presence or in the absence of promoters or catalysts. Reactions with diazoalkanes, aryldiazomethanes, trimethylsilyldiazomethane, α-diazo esters, and disubstituted diazo compounds are covered, commenting on the complex regiochemistry of the reaction and the nature of the catalysts and promoters. The recent reports on the enantioselective version of ketone homologation reactions are gathered in one section, followed by reports on the use of cyclic ketones ring expansion in total synthesis. Although the first reports of this reaction appeared in the literature almost one century ago, the recent achievements, in particular, for the asymmetric version, forecast the development of new breakthroughs in the synthetically valuable field of diazo chemistry.

CONTENTS 1. Introduction 2. Reaction of Ketones with Diazoalkanes 2.1. Acyclic Ketones 2.2. Monocyclic Ketones 2.3. Bridged Cyclic Ketones 2.4. Polycyclic Ketones 3. Reaction of Ketones with Aryldiazomethanes 3.1. Monocyclic Ketones 3.2. Polycyclic Ketones 4. Reaction of Ketones with Trimethylsilyldiazomethane 4.1. Acyclic Ketones 4.2. Monocyclic Ketones 4.3. Polycyclic Ketones 5. Reaction of Ketones with Unsubstituted α-Diazo Ketones, Esters and Derivatives 5.1. Acyclic Ketones 5.2. Monocyclic Ketones 5.3. Polycyclic Ketones 6. Reaction of Ketones with Disubstituted Diazo Compounds 7. Asymmetric Homologations 7.1. Reactions with Monosubstituted Diazo Compounds 7.2. Reactions with Disubstituted Diazo Compounds 8. Ring Expansions with Diazo Compounds in Total Synthesis 8.1. Ring Expansions with Trimethylsilyldiazomethane 8.2. Ring Expansions with Ethyl Diazoacetate 9. Conclusions Author Information © 2016 American Chemical Society

Corresponding Author Notes Biographies Acknowledgments References

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1. INTRODUCTION Alkyl diazo compounds are ambiphilic reagents, and their use in organic synthesis has been extensively studied. In the presence of dipolarophiles, these compounds can be used in 1,3-dipolar cycloadditions (Hüisgen reactions) to deliver pyrazoline derivatives, if the fast dediazoniation process is avoided.1−4 Despite the importance of this reaction,5−7 alkyl diazo compounds can be used in a myriad of different reactions when considering a dediazoniation process. These compounds are successful partners for the one-carbon homologation of carbonyl compounds; cyclopropanation of alkenes,8−15 alkynes,16−24 and aromatic rings;25−29 aziridination;30−33 X− H34,35 (X = C,36−40 O,41,42 S,43−45 N,46−50 etc.) bond insertion reactions; and sigmatropic rearrangements51−54 to name a few. Due to the very reactive nature of the carbene species in most of these processes, transition metals able to stabilize the carbene are often employed. Despite the seminal reports on the use of copper as catalysts in the decomposition of diazo compounds more than 100 years ago,55 dirhodium carbenoids were reported in the 1970s as viable alternatives10,56 to the more reactive copper carbenoids and they have been extensively investigated.36,37,57−67 Other metal complexes including palladium,68,69 iridium,70−74 cobalt,75 iron,35,76−78

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Received: June 30, 2015 Published: February 8, 2016 2937

DOI: 10.1021/acs.chemrev.5b00381 Chem. Rev. 2016, 116, 2937−2981

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Figure 1. General reactivity of diazo compounds.

and ruthenium79−85 centers have also been successfully reported to moderate the reactivity of the carbene moiety. Despite being synthetically very useful, diazo compounds are often associated with their acute toxicity and explosion hazards, especially in the case of the volatile diazomethane. Thus, several methods for in situ preparation have been developed.68,76,86−93 The appealing properties of flow processes, namely, efficient mixing, superior heat and mass transfer, short resident times of the products in the reaction zone, high safety, reproducibility, and scale-up, have been combined to the preparation and reactions of diazo compounds. The safety features of such processes, especially when combined with microreactor technology, allow the in situ formation or feeding of diazo compounds in low spatiotemporal concentrations inside the reactor, greatly diminishing the chances of accidents.94−96 As ambiphilic reagents, diazo compounds have a partial negative charge located on the carbon to which the diazo group is attached (1). This makes such carbon the reactive center toward electrophilic attacks to deliver intermediates such as 3 in processes that can also be promoted by Lewis or Brønsted acids in the case of less reactive partners, having metal stabilized alkoxide or hydroxy diazonium cations as intermediates, respectively. On the other hand, the terminal nitrogen of the diazo group can be attacked by nucleophiles. Diazo compounds are usually not stable in acidic medium, as they can be typically protonated at the carbon of the diazo group (4) or the terminal nitrogen atom. The stability of the diazo group toward acids will depend greatly on the carbon substituents. Diazoalkanes are much more acid-sensitive than any other diazo compounds, and the presence of carbonyl functional group confers some degree of stability to α-diazo carbonyl compounds. Nevertheless, the strength and nature of the solvent play a determinant role in the fate of the protonated diazo compound 4, which can typically be trapped by reaction with a nucleophile, as in the case of esterification reactions with diazoalkanes.97 Analogously, the nucleophilicity of diazo compounds is inversely correlated to their stability toward acids, and unsubstituted diazomethane is 10 orders of magnitude more nucleophilic than diethyl diazomalonate.98 On the other hand, they are relatively stable to basic conditions and bases can be used to deprotonate α-diazo carbonyl compounds, delivering a stronger nucleophile (5) that can be attached to other molecules in order to transpose the diazo functional group for utility in other transformations.99 The nucleophilic addition of diazo compounds is often used as a way to achieve the one-carbon homologation of carbonyl derivatives. Several related reactions are (Figure 2) the Arndt-

Figure 2. One-carbon homologation reactions with diazo compounds.

Eistert reaction,52,100 Buchner-Curtius-Schlotterbeck reaction,101−106 Tiffeneau-Demjanov rearrangement,107,108 and Roskamp reaction.109−111 The addition of diazo compounds to aldehydes and ketones will result in the formation of a tetrahedral intermediate that can undergo rapid 1,2-rearrangement in order to reestablish the CO functional group driven by extrusion of molecular nitrogen. The fate of such intermediate is dependent on the migratory aptitude of the substituents of the diazonium betaine intermediate and the reaction conditions. When starting from an aldehyde, an 1,2hydrogen shift is usually observed, together with some epoxide derived from direct nucleophilic attack of the oxygen to the diazonium carbon. On the other hand, the C−C bond formation can be promoted by formation of anion species resultant from treatment of the diazo compound with base in an aldol-type condensation, delivering an alkoxide that can be neutralized, isolated, and further manipulated. Naturally, such strategy requires the use of somewhat acidic diazo compounds such as acyl diazomethanes, and strong bases such as lithium bases or hydrides are typically employed.99 When starting from ketones, the analogous process may result in the one-carbon chain extension for acyclic ketones or the ring expansion for cyclic ketones (Figure 3), considered as 2938


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discussion on the preparation of noncarbonyl-stabilized diazoalkanes was published by Kingsbury,122 although its coverage of the reactions discussed herein was more limited. This review covers reactions of compounds, intermediates, or transient species derived from the nucleophilic attack of diazo compounds to ketones (Figure 4) and extended to related ketimines derived from condensation of amines with ketones. Classical reports on homologation of ketones with diazo compounds explored the carbon natural nucleophilicity induced by the diazo functional group, resulting in formation of diazonium betaine (I, X = −). Soon, it was noticed that the electrophilicity of the carbonyl group could be greatly improved by adding a protic solvent to the reaction medium.123,124 Strong Lewis acids such as BF3·OEt2 and aluminum salts were described long ago as effective promoters for the same reaction having metal-stabilized alkoxides as intermediates (I, X = B, Al). More recently less oxophilic scandium-based Lewis acids were identified as suitable catalysts for the ring expansion of cycloalkanones with mono- and disubstituted diazo compounds involving similar intermediates (I, X = Sc). β-Hydroxy diazo compounds (II, X = H) can be formed by a base-promoted aldol-type condensation, and in several cases, these compounds are stable enough to be isolated such as in the silyl ether form (II, X = SiR3) or reacted subsequently with a suitable promoter such as Lewis or Brønsted acids to induce ring expansion. Homologation reactions by addition of diazo compounds to ketones can be applied to acyclic ketones to some extent, simple cyclic ketones, bridged cyclic ketones, isatins, squaric acid, steroid ketones, tetramic acids, fluorenone, modified cyclonucleotides, and quinones among others. This review will be organized considering the nature of the diazo compound used for the homologation reaction starting from the more reactive diazomethane toward the less reactive α-diazo carbonyl compounds, covering both catalyzed and noncatalyzed methods. The text is organized starting with acyclic ketones, moving to ring expansion of small member cyclic ketones toward larger rings, and ultimately focusing on polycyclic structures. The homologation of four-membered rings by Leemans, D’hooghe, and De Kimpe125 in 2011, expansion to seven-membered rings by Kantorowski and Kurth126 in 2000, and expansions of bridged cyclic ketones by Krow116 in 1987 have been previously compiled. Such topics are herein covered as updates of those reviews, and the reader is kindly encouraged to consult such reviews for previous reports. Asymmetric homologation reactions and ring expansion with diazo compounds in total synthesis have been gathered in the last sections of this review.

Figure 3. Homologation of carbonyl compounds with diazo compounds.

homologation along the manuscript. Such ring expansion process might require presence of a promoter (usually acting as a Lewis acid) or not, depending mostly on the reactivity of the starting diazo compound but also on the carbonyl electrophilicity. Homologation reactions with diazo compounds are synthetically very useful and have been explored for many years, with many reports in total synthesis. When comparing aldehydes with acyclic ketones in such homologation processes, reaction with ketones is more sluggish than aldehydes and have a greater tendency to form epoxides. More electrophilic ketones react faster than less electrophilic ones (mostly toward formation of epoxides), and more electron-rich substituents are typically the ones to undergo migration. Although carbonchain extension of acyclic ketones with diazo compounds is very sensitive to the chain length, where only simplest ketones can be homologated with diazoalkanes, the ring expansion of cyclic ketones is a more general, controllable, and studied process.112−114 Several reviews covering the homologation of ketones and aldehydes can be found in the literature. The first attempts to compile such kind of reports were made by Gutsche covering the early studies in reactions of diazoalkanes with aldehydes and ketones112 and later on the diazoalkane ring expansion of cycloalkanones.115 Since then, despite the numerous original reports on the ring expansion of cycloalkanones with diazo compounds, such studies have not been compiled in one single review besides the excellent one built by Krow on the one carbon ring expansion of bridged cyclic ketones, also including the Tiffeneau-Demjanov reaction.116 Relevant examples of homologation reactions by addition of diazo compounds to ketones have been mentioned in several other reviews focused on the transformations and reactivity of diazo compounds,99,114,117 semipinacol rearrangements,118,119 or the extensive literature surveys done by McKervey and coworkers.95,120,121 Recently, a lengthy review on diazoalkane− carbonyl homologation containing a historical perspective toward the development of modern catalytic methods and a

2. REACTION OF KETONES WITH DIAZOALKANES Some of the more severe limitations found in the ring expansion of cyclic ketones with diazomethane86,127−130 are poor reactivity, the possibility for multiple homologation, and the formation of epoxide byproducts. The use of protic solvents

Figure 4. Scope of this review. 2939


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Scheme 1

formation of the cyclopropane containing structures. Less reactive ethyl diazoacetate failed to be a partner in this homologation process.134 Even though oxophilic organoaluminums are known to react with diazoalkanes to yield insertion products, sterically hindered organoaluminum complexes have been described as suitable promoters of the homologation of acyclic ketones as in the case of acetophenone (Scheme 3). Bulky methylaluminum

such as alcohols and water was described as early as 1928 as a suitable strategy to increase the reaction rate.123,124 Moreover, the ability of protic and Lewis acids to facilitate diazoalkane 1,2 addition to carbonyls has been widely documented in the literature.122 2.1. Acyclic Ketones

Seminal work from House demonstrated the potential of using boron trifluoride as a promoter in the homologation of acyclic ketones, where the epoxide formation was suppressed and the reaction times were decreased from days to minutes. The migratory aptitudes of the acyclic ketones substituents for this BF3 promoted process were reported to be Ph ∼ MeC = CH > Me > Pr > i-Pr ∼ Bn ∼ t-Bu.131 The reactivity of acyclic ketones toward diazoalkanes is Cl3CCOCH3 > CH3COCH3 > PhCOCH3, and the introduction of electron-deficient substituents greatly enhanced formation of the epoxide sideproduct.112,114 The homologation of nonan-5-one with diazoethane is a representative example of the intrinsic challenges on the homologation of acyclic ketones. In a process promoted by stoichiometric amounts of aluminum salts, the desired ketone was obtained together with the epoxide and overhomologated products (Scheme 1).132,133 Selenoesters were successfully homologated with diazomethane promoted by stoichiometric amounts of copper or cuprous iodide in diethyl ether, with preferential migration of the C−Se bond (Scheme 2). The homologated selenium

Scheme 3

bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) greatly increased selectivity toward formation of the ketone resultant from the methyl migration, while the epoxide selectivity remained almost unaltered. On the other hand, by running the reaction in methanol/ether mixture, in absence of a Lewis acid promoter, the yield toward both monohomologated ketones dropped to 18% yield with negligible selectivity toward 1,2-phenyl and 1,2-methyl migrated ketones.132,133

Scheme 2

2.2. Monocyclic Ketones

Cyclic ketones react with diazomethane to afford the homologated ring expanded products. The preference for migration of one bond over the other is influenced by ring strain, steric effects, stereochemical relationships in the approach of the diazoalkane, and conformational effects in the tetrahedral intermediate. The reactivity of cyclic ketones in such processes follows the general order of 3 > 4 > 6 > 7 ≥ 5 membered rings.108 While the homologation of cyclopropanones and cyclobutanones125 can be achieved with diazomethane in reasonable reaction times (Scheme 4),135,136 larger rings need slightly harsher conditions and the desired product is usually accompanied by considerable amounts of the epoxide.113,137 Furthermore, due to the somewhat slow process, the newly formed cyclic ketones can undergo an additional ring expansion reaction affording mixtures of homologated products. Not surprisingly, α-substituents of cyclobutanone derivatives have a pivotal influence in the migration selectivity. Migration of the less substituted α-position is usually preferred, while the presence of electronegative substituents accelerates the reaction rate and increases such preference (Scheme 5).138−143,314 Along with these primary effects, the β-substituent can also play a role in the regioselectivity of this uncatalyzed process.

containing ketones were obtained in reasonable yields together with considerable amounts of selenium containing dimeric structures 13 suggested to be formed after the displacement of the selenolate ion in the diazonium betaine intermediate and further reaction with diazomethane. Surprisingly, given the presence of copper salts and their ability to catalyze cyclopropanation reactions of diazo compounds, the presence of a double bond in one of the ketone substituents led to trace 2940


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Scheme 4

Scheme 7

Scheme 8

Scheme 5

Scheme 9

Hegedus and Reeder demonstrated that a β-substituent can influence the regioselectivity of cyclobutanone ring expansion, although no clear evidence of correlation of such regioselectivity and the steric or electronic factors could be established (Scheme 6).142 A carbocyclic analogue of a chiral 2,3-dideoxy nucleoside has been prepared by the regioselective ring homologation of an enantiomerically pure 2,3-disubstituted cyclobutanone (Scheme 7). By running the reaction in the absence of a promoter in diethyl ether and methanol, the desired compound was obtained as a single isomer in 36% yield, leaving beyond a mixture of unidentified over-alkylated products and unreacted compound.144 The ring expansion of substituted cyclohexanones with diazomethane in ethyl ether and methanol was verified by McMurry and Coppolino in order to compare the selectivities with their cyanogen azide-ring expansion procedure (Scheme 8).145 While the selectivities achieved with the later method were smaller than with the diazomethane ring expansion, such study was elucidative in regarding the determination of the regioselectivities due to the use of gas chromatography techniques. Preferential migration of the more substituted carbon was observed for 2-methylcyclohexanone, while the introduction of a second methyl substituent at C2 greatly decreased the yield to 5% and the introduction of an additional methyl at C6 hampered the reaction. Bulky aluminum reagents were successful in suppressing the overhomologation reaction of cycloalkanones (Scheme 9) and favoring formation of ring expanded products in better selectivities than other methods. Although epoxide formation was not completely suppressed when using diazoethane in the

homologation of 4-tert-butyl cyclohexanone, the combination of other diazoalkanes and other cycloalkanones resulted in exclusive mono homologation in reasonable yields employing Me3Al as a Lewis acid promoter.132,133 The quantitative ring expansion of a series of 2-aryl substituted cyclohexanones in diethyl ether demonstrated that regardless of the aromatic substituent electronic nature, the migration of the least-substituted carbon−carbon bond is preferred (Scheme 10).146 For the acid-catalyzed ring expansion to take place, the catalyst used cannot be able to induce dediazoniation of the diazoalkane. Taking this principle into consideration, Kingsbury and co-workers developed the first protocol that required substoichiometric amounts of a Lewis acid [Sc(OTf)3] for the addition of aryl and alkyldiazo compounds to cyclic ketones, eventually resulting in the ring expansion reaction (Scheme 11). While Al- and B-based Lewis acids failed to achieve turnover, Sc(OTf)3 could be used at 5 mol % loading to generate the ring-expanded products. By changing from

Scheme 6

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Scheme 10

(1:1) as a solvent resulted in the exclusive formation of the oxirane 22 after reaction with diazomethane (Scheme 13). Replacing methanol by dichloromethane as a solvent delivered a mixture of ring-expanded products 23 and 24 in 36% together with the same oxirane in 40%, despite the presence of the bulky electron-withdrawing substituents at the α-positions of the ketone. The ring expanded products were further transformed into the corresponding oximes and deprotected to result in the isolation of the oxime derivative of 23 in 65% and of 24 in 16% yield.150 Gutsche and Tao reported an expeditious process for the in situ preparation of diazoalkanes through treatment of Nnitrosobutyrolactam 25 with methoxide (Scheme 14). The diazo compound formed was reacted with cyclohexanones 26 to afford the ring expanded cycloheptanones 27 in reasonable yields with only a small amount of the epoxide side-product. Although 3- and 4-methyl substituted N-nitrosolactams were reported to be suitable partners for the ring expansion reaction, the process failed to yield the ring-expanded products of cyclopentanone.151

Scheme 11

Sc(OTf)3 to Sc(acac)3 or to the tert-butyl-acac analogue [Sc(TMHD)3], the procedure could be successfully applied to the use of more nucleophilic diazoalkanes to provide 5, 6, 7, and 8-membered cyclic ketones in good to excellent yields after 18 h at room temperature using 2.2 equiv of the diazo compound.147 The in situ preparation of trifluoro diazoethane has been developed by Carreira and co-workers76,148 and applied to the homologation of cyclohexanones (Scheme 12).149 From several

2.3. Bridged Cyclic Ketones

Scheme 12

The ring expansion of bridged cyclic ketones by reaction with diazoalkanes follows the same mechanistic pathways as more simple cycloalkanones. The one carbon ring expansion of bridged cyclic ketones has been extensively covered,116 and only recent developments will be considered herein. The ring expansion of bridged bicyclic ketones can also be facilitated by Lewis acids promoters which suppress the epoxide formation. Generally, bicyclanones having the carbonyl group adjacent to a bridgehead are more reactive, although the methylene migration is usually preferred rather than migration of the bridgehead carbon. Besides its importance in total synthesis, the ring expansion of bicyclic ketones was also extensively studied to evaluate the effects of ring strain, steric, and electronic interactions (Scheme 15). Conformational factors assume a more determinant role in the regiochemistry of carbon migration than electronic factors. In fact, the general migratory aptitude of the methylene group is dominated by the relief of eclipsing interactions and preference for chairlike over boatlike transition-states.116 Distal 2-substituents in norbornan-7-ones were reported to have an effect in the migratory preference of the C−C bond in the ring expansion process with diazomethane. Electron-withdrawing substituents at the 2-position were observed to favor the migration of the C(4)−C(7) bond regardless their endo or exo position, although a slight increase in the selectivity was observed for C(2)-endo-substituted norbornan-7-ones.152

Lewis acids screened for the homologation of aldehydes, ZrCl4 showed the best results in a compatible process to the aqueous in situ diazo formation by reaction of F3CCH2NH2·HCl and NaNO2. Despite failing for the homologation of acyclic ketones, this highly innovative method allowed the preparation of trifluoroethyl cycloheptanones in excellent yields and regioselectivities. Although protic solvents are known to accelerate the reaction of ketones with diazomethane, the use of methanol as a cosolvent can change the selectivity of the reaction in the absence of any promoter. In an attempt to ring-expand Moz and Bz protected 5-keto arbekacin 21, the use of MeOH/Et2O 2942


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Scheme 13

regioselectivity with preferential migration of the lesssubstituted carbon. The high regioselectivity of this reaction was attributed to a thermodynamically controlled process resulting in preferential formation of the more stable isomer. Intrigued by the high reactivity of such system, Wiberg and Snoonian compared the migratory preference of a cyclopropyl group with a methylene group in cyclic and acyclic systems. While a preference for migration of the cyclopropyl was observed for acyclic ketones, even though in a modest 66:33 ratio, in the cyclic structure 31 the preference was reversed to yield preferentially the ring-expanded product 32 derived from methylene migration in a 75:25 ratio. The high reactivity of the bridged spiropentanone was attributed to the strain relief in the homologated product, as supported by computational calculations.153,154 7-Oxabicyclo[2.2.1]heptan-2-one derivatives 38 have been reported to be much more reactive toward ring expansion with diazomethane than norcamphor analogues 34 (Scheme 17). While addition of diazomethane to norcamphor is relatively slow at 20 °C in protic methanol, 7-oxa derivatives 38 react at −78 °C in THF without a protic additive to provide the ringexpanded product with high regioselectivity together with the corresponding epoxide. The nature of the C-3 substituent and the relative configuration of that position was determined to effect the regioselectivity of the ring expansion reaction. The ring-expanded product 39 failed to undergo an additional ring expansion reaction with diazomethane, and only the epoxide 40 could be detected.155,156 Interestingly, the all-carbon substrate variant bicyclo[3.3.1]nonan-2-one 41, also experiences uncatalyzed ring expansion with diazomethane in 5:1 regioselectivity by preferential migration of the less-substituted C−C bond, together with minor amounts of the epoxide.157 6,5′-Cyclopyrimidine nucleosides 43 can be easily oxidized to their carbonyl counterpart and their reaction with diazomethane leads mostly to the formation of the epoxide derivative instead of the ring-expanded product. The use of Lewis acids as promoters failed to attenuate the epoxide formation, and the yields of ring-expanded products remained the same (Scheme 18).158,159

Scheme 14

Scheme 15

Bridged spiropentanones can be homologated with diazomethane in the absence of any promoter and without the need to use a protic solvent as reported for other systems (Scheme 16). Despite the high reactivity of the system toward homologation, product 29 can be obtained in excellent Scheme 16

2.4. Polycyclic Ketones

Lupane derivatives 46 containing a α-diketonic system can also be ring expanded to six-membered rings 52 in absence of any 2943


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Scheme 17

steroids, where the ring-expanded products were obtained in a 56:44 ratio. Vinca alkaloid derivatives bearing an α-oxo acid moiety have been esterified with diazomethane but failed to undergo a ringexpansion reaction after ring closing. Instead, the dicarbonyl compound reacted preferentially in a diastereoselective process toward formation of the corresponding epoxides (Scheme 21).162 Isatins react with diazoalkanes to afford the corresponding quinolone without the need of a promoter. Seminal work by Heller163,164 and Eistert165−167 was later reinvestigated by Westwood,168 and reasonable yields of quinolone derivatives were reported together with little or no epoxide side-product formation (Scheme 22). Quinisatin, a larger homologue of isatin, also reacts with diazoalkanes to form the ring-expanded benzazepine in reasonable yields (up to 75%).169 Ring expansion of quinones with diazomethane can be achieved, in low yields, however, using boron trifluoride etherate as the reaction promoter (Scheme 23). β-Naphthoquinone 52 undergoes ring expansion in up to 26% yield when using a 1:1 mixture of ethyl ether/dichloromethane solvent to afford 53 (Scheme 23).170 Acenaphthoquinone reacts with diazoalkanes to form ring-expanded naphthenol derivatives.171,172 Seven-membered ring quinone 54 was reported to undergo the same rearrangement in yields as low as 1% in the presence of BF3 to afford 55 (Scheme 23). Replacing diazomethane with TMSCHN2 allowed for an increase in chemical yield to 5%. Starting from the same quinone derivative in the absence of such Lewis acid, pyrazoline derivative 56 was obtained in 20% yield (Scheme 23).173 Other β-diketonic systems can also undergo ring expansion. 2,3-Dioxo-meso-

Scheme 18

Lewis acid. The enol formed becomes methylated by the excess of diazomethane in a slow, room-temperature process that also delivers the epoxide side-products 48 in most cases (Scheme 19).160 Intrigued by the conflicting regioselectivities reported for the ring expansion of 3-keto steroids, Warnhoff and co-workers studied the ring expansion of several steroid derivatives with diazomethane in the absence of any promoter in ether and methanol (Scheme 20).161 The migration ratios were determined by proton-decoupled 13C NMR spectroscopy of the reaction mixtures, as it was advanced that previously reported selectivities have been wrongly determined due to the limitations of the methods used. Despite the different methods for preparation of diazomethane (DIAZALD or N-nitroso-Nmethylurea), the selectivities achieved did not exceed 3:2 being negligible in most cases or with a small preference for migration of C-4 over C-2. Such lack of selectivity was verified in the ring expansion of trans-2-decalone, a model substrate for 5α-3-keto Scheme 19

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Scheme 20

Scheme 21

3. REACTION OF KETONES WITH ARYLDIAZOMETHANES Although less reactive than diazoalkanes, aryldiazomethanes such as phenyldiazomethane are highly unstable, and decomposition can take place even at low temperatures such as −20 °C. Additionally, phenyldiazomethane is highly explosive, and accidents have been reported to happen during distillation procedures at 30 °C.175 Remarkably, it is stable enough in methanol to react with cycloalkanones present in solution.

Scheme 22

Scheme 23


Despite the homologation of acyclic ketones with aryldiazomethanes being an unsolved issue, the first catalytic ring expansion of cycloalkanones was developed by Moebius and Kingsbury employing Sc salts as catalysts. While such methodology requires the use of 2.2 equiv of the alkyldiazo nucleophile to achieve excellent yields (Scheme 11), only 1.1 equiv of the more stable aryldiazo counterparts are needed in the ring expansion of cyclobutanones (Scheme 25). Several cyclopentanones could be prepared by this methodology employing different aryldiazo compounds, but electron-rich aryldiazo compounds seem to be more challenging, suggested by the somewhat lower yield obtained in the same reaction conditions when using 4-methoxyphenyl diazomethane.147 The same procedure was later applied to the Roskamp reaction with

tetraphenylchlorin has been ring expanded in good yields using a large excess of diazomethane, in a fairly selective process with residual formation of an epoxide side-product (Scheme 24).174 Scheme 24

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yields (up to 15%). Exposure of epoxide 59 to BF3 results in C−C bond cleavage to the corresponding aldehyde and 2-keto3-hydroxy derivative. The use of BF3 or other Lewis acids in the ring-expansion process was not assessed.180,181

Scheme 25


Both isatin and thioisatin react with phenyldiazomethane to provide the ring-expanded product as reported by Eistert (Scheme 28).165,166,182 Despite the low yield observed for the

aldehydes176 and coupled with flash pyrolysis of paraformaldehyde in the preparation of symmetric ketones177 being successful for aryldiazomethanes and disubustituted diazoalkanes. Even in the absence of any promoter, aryldiazomethanes react with cyclohexanone to afford α-aryl cycloheptanones in up to 76% yield after 24 h at room temperature in methanol.178 For larger rings, AlCl3 Lewis acid is needed as promoter to perform the transformation, providing the corresponding α-aryl cycloalkanones in up to 60% yields (Scheme 26). Cyclo-

Scheme 28

Scheme 26

later (16%), the main product reported was the one resulting from attack at the thioester carbonyl functionality. The reaction of isatins with phenyldiazomethane led to formation of viridicatins upon 1,2-rearrangement of the diazonium betaine, itself resulting from nucleophilic attack of the diazo compound at the more reactive carbonyl of isatin. 3-Methoxyphenyl diazomethane was also reported to react with isatin in a similar way, to be later converted to viridicatol after demethylation.183 1- and 2-substituted 5-(diazomethyl)tetrazoles were reported to undergo nucleophilic addition to isatins followed by ring expansion in the presence of either sodium hydroxide solution or HCl. The corresponding 3-hydroxyquinolinones 61 containing a tetrazole moiety were obtained in reasonable yields (54−63%).184,185

alkanones containing as many as 14 ring atoms can be obtained this way, although the concentration of the diazo compound needs to be kept low to avoid overhomologation of the product.179 Even though the use of catalytic amounts is referred in the original literature, unambiguous information about the exact amount of promoter used is not found in the procedures described. Grevellin analogues 57, containing a tricarbonyl system, were reported to undergo ring expansion after reaction at room temperature with aryldiazomethanes (Scheme 27). The Scheme 27

Figure 5.

As previously described for large monocyclic ketones (Scheme 26), also α,β-unsaturated cholesterol derivatives can have their ketone ring expanded with phenyldiazomethane using AlCl3 Lewis acid as a promoter. Using such a procedure, where the diazo compound is kept at low concentration, testosterone acetate (62) affords the seven-membered ring compound 63 although in very low yield (Scheme 29).186 Scheme 29

requirement for an excess of the aryldiazomethane leads to the formation of enol ether 58 after O-alkylation of the ringexpanded derivative. In order to find alternative ways of preparing the same kind of azagrevellin derivatives, since the ring expansion efficiency remained low (up to 50%), epoxide derivatives 59 were treated with triethyloxonium tetrafluoroborate to furnish more of the desired compounds 60 in low 2946


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4. REACTION OF KETONES WITH TRIMETHYLSILYLDIAZOMETHANE Being more stable than diazomethane and commercially available, trimethylsilyldiazomethane (TMSCHN2)187,188 has been explored by several authors as a safer alternative to diazomethane in the homologation of ketones. Although nonvolatile and less likely to explode than diazomethane, their toxicity has been described to be similar and TMSCHN2 has been reported to be implicated in two fatal incidents.189

resulting in the isolation of a single product in reasonable yield (65%) after acidic workup (Scheme 32).191 Moreover, multiple homologation is suppressed for two reasons: only a slight excess of the diazo agent is needed and the initial products are less reactive α-silylketones. Scheme 32

4.1. Acyclic Ketones

Despite the almost general better performance of trialkyl aluminum salts than boron trifluoride etherate in the homologation of ketones, a different scenario is observed for homologation of methyl ketones (Scheme 30). In such case,

Despite the numerous examples found in the literature concerning ring expansion of cyclic ketones with alkyl diazo compounds, scarce are the methods that lead to efficient regiocontrol in expansion of unsymmetrical cyclic ketones. αAryl-substituted cyclobutanones were reported to undergo Sc(OTf)3-catalyzed ring expansion with TMSCHN2 in high regiocontrol (Scheme 33). Dichloromethane and toluene were

Scheme 30

Scheme 33

trimethyl aluminum leads to the same selectivities as boron trifluoride and stoichiometric amounts of MAD result in better regioselectivities after preferential migration of the methyl substituent.132,133 Oxazaborolidinium ions were also reported to be efficient catalysts in the homologation of ketones with TMSCHN2, affording the corresponding silyl enol ethers in excellent yields (Scheme 31). The procedure was developed for the stereoselective preparation of (Z)-silyl enol ethers, by reacting alkyl aryl ketones with the diazo compound. A strong dependency of the migration selectivity on the Lewis acid employed was observed for the reaction of TMSCHN2 and acetophenone. After screening common Lewis acids such as BF3·OEt2, Sc(OTf)3, Sn(OTf)2, and EtAlCl2, several oxazaborolidium ions were successfully tested and the amount of catalyst needed reduced from 20 to 5 mol % with 64. This highly stereoselective method leads to almost exclusive formation of the (Z)-silyl enol ethers after preferential migration of the aryl substituent, followed by 1,3-Brook rearrangement. However, when increasing the alkyl chain from a methyl to ethyl substituent, the alkyl migration starts to increase.190

identified as the best solvents for this reaction, while highly coordinative solvents such as Et2O, THF, or MeCN were not effective. The reaction time and regioselectivity are dependent on the substituents of the aryl ring due to inductive effects. The reported procedure was applied to a wide substrate scope, with α-tertiary, α-quaternary cyclobutanones, and even highly sterically hindered diphenylcyclobutanone reacting to afford the corresponding cyclopentanones in high yields. Nevertheless, the presence of an aryl substituent at the α-carbonyl position is of pivotal importance to achieve good levels of regioselectivity. Changing the scandium salt to Sc(tmhd)3 failed to provide the desired products, while scandium hexafluoroacetylacetonate [Sc(hfac)3] provided the ring-expanded αtrimethylsilyl ketone. Taking in mind this result, the authors suggested that the 1,3-Brook isomerization might be catalyzed by the slight excess of Lewis basic TMSCHN 2. The


TMSCHN2 has proven superior to diazomethane in the expansion of certain cyclic ketones. For instance, a spirocyclobutanone derivative reported not to have undergone a ring expansion reaction with diazomethane did react with TMSCHN2 in the presence of diethylaluminum chloride, Scheme 31

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regioselectivity of the process was proposed to be based exclusively on steric effects.192 Trimethylaluminum was reported to be a better promoter than boron trifluoride etherate for expansion of cyclopentanone with TMSCHN2 (Scheme 34). While the former afforded the

Scheme 36

Scheme 34

corresponding cyclohexanone in 68% yield with only traces of cycloheptanone, boron trifluoride could only provide a 35% yield of a mixture of six- and seven-membered expanded ketones.132,133 Boron trifluoride etherate was nevertheless observed to be a suitable promoter for the expansion of several cycloalkanones (Scheme 35, Table 1).193,194 The combination of boron the desired homologated product 65 when using BF3·OEt2 as promoter, making the use of diazomethane preferential for that particular homologation.195 The ring expansion of α-substituted cyclohexanones with TMSCHN2 is somehow regioselective, and the trimethylsilylmethylene is predominantly inserted at the less-hindered site. Nevertheless, the ratio of regioisomers formed can be strongly dependent on the Lewis acid used. Such regioselectivity has been explored for the enantioselective synthesis of the hydroazulene core of a rippertene derivative, and BF3·OEt2 was reported to provide the highest selectivities of the cycloheptanone after hydrolysis of the silyl enol ether using 1.5 equiv of the Lewis acid promoter (Scheme 37).196,197 On the other hand, organoaluminum Me3Al led to the formation of both regioisomers in 1:1 ratio and longer reaction times (16 h instead of 1 h needed for the other Lewis acids tested). Stoichiometric amounts of trimethylaluminum were applied to the ring expansion of difluorinated heptanone for the preparation of difluorinated cyclooctynes, highly useful reagents for copper-free click reactions (Scheme 38).198 Despite the 48% moderate yield achieved in the homologation reaction promoted by trimethylaluminum followed by desilylation, the new protocol avoided the use of pyrophoric periodic acid and diethyl zinc needed for the previously established processes.199 The newly formed difluorinated cyclooctyne could be homologated once more using the same reaction conditions to afford the less reactive cyclononyne. The presence of additional fluorine substituents at the α-carbonyl positions hampered the ring expansion reaction, delivering the epoxides as the main products. Even when changing the diazo compound and the promoter, the homologation of the tri- and tetrafluorinated cycloheptanone failed to provide the desired homologated compounds. After being used for the homologation of acyclic ketones, oxazaborolidiniums were further explored as catalysts in the ring expansion of cyclic ketones (Scheme 39). The procedure was applied to the homologation of 5-, 6-, 7-, and 12-membered cyclic ketones, affording the corresponding homologated silyl enol ether products in good yields and little or no overhomologated side-products. Unfortunately, the methodology was only tested for reaction with symmetric ketones, and

Scheme 35

Table 1. Ring Expansion of Cycloalkanones with TMSCHN2

trifluoride etherate and TMSCHN2 as a method for the successful homologation of ketones is evident from the exclusive homologation of 2-undecanone, although without regioselectivity, when compared with the metal free homologation process with diazomethane that retrieved only the epoxide. Dichloromethane is typically used as the reaction solvent, and its replacement by ethyl ether results in reaction rate decrease.193,194 A similar trend was observed for other 4-alkyl substituted cyclohexanones, in which the combination of boron trifluoride etherate and TMSCHN2 typically led to better conversions and chemoselectivities when compared with the diazomethane in ether and ethanol approach (Scheme 36). In such reactions, the preferential formation of the homologated cycloheptanone was achieved, even though formation of some overhomologated cyclooctanones together with the epoxide could be observed. The ring expansion of the derivative 64 decorated with a ketal in the 4-position of the cyclohexanone resulted in low yield of 2948


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Scheme 37

Scheme 38

Scheme 39

in the α-carbonyl substituent led to a slight increase in regioselectivity for insertion at the more hindered site.200 A new two-step procedure for homologation of cyclic ketones that employs a nucleophile strategy was recently developed (Scheme 41). By performing an extensive study on the protonation of the adduct derived from reaction of lithium

the regioselectivity of the process with unsymmetrical cyclic ketones remains to be studied.190 Cycloheptenones can be produced by a similar strategy if the generated silyl enol ether is subjected to dehydrosilylation with palladium instead of the standard hydrolytic cleavage (Scheme 40). Although poor regioselectivity was reported for the process when using trimethylaluminum, the presence of a benzyl ether

Scheme 41

Scheme 40

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(trimethylsilyl)diazomethane (LTMSD) with a cyclohexanone and several Brønsted acids, Lee and co-workers demonstrated a strong correlation between the acidity of the proton source and the ratio of products derived from O-protonation and Cprotonation. While quenching of the diazo adduct with stronger acids led to almost exclusive formation of the epoxide, weaker acids as methanol inverted the selectivity to deliver only traces of the epoxide and mostly the ring-expanded product. Silica gel was superior to several other acids tested for the ring expansion (84% yield), whereas SnCl4 and TiCl4 provided the product in 47% yield. BF3·OEt2 provided the ring expansion product in only 37% yield. The methanol quench at low temperature and silica gelpromoted ring expansion sequence was applied to several symmetrical cyclohexanones and cyclobutanones, delivering the monohomologated compounds in reasonable-to-excellent yields (Scheme 42). With regard to the regioselectivity of

Scheme 44

employed as the Lewis acid (Scheme 45). Interestingly, the regioselectivity of the reaction changes when performed in the dark, and homologation at the most hindered carbon is favored.203 Scheme 45

Scheme 42

Mori and co-workers have recently demonstrated that an equatorial attack of the TMSCHN2 is the first step of the BF3· OEt2 promoted ring expansion of cyclohexanones (Scheme 46). The conformationally fixed six-membered 81 ketone was used as the model compound and transformed with several diazomethane derivatives. According to the authors, the small amounts of spiroepoxide side-products observed in the ring expansion reaction suggests that the major 7-membered cycloalkanone isomer results from an equatorial attack on the ketone. Aided by density functional theory calculations, the relative energy profiles were described and an equatorial attack mode was determined to be more favorable (by 3.2 kcal/mol) than axial attack. Additionally, the regio- and diastereoselectivity of the process was also evaluated by computational calculations. The diastereoselectivity was attributed to steric hindrance caused by the interaction of the alkyl moiety of the diazo compound and the O-coordinated BF3. On the other hand, the regioselectivity of the reaction was explained on the basis of steric hindrance between the same alkyl moiety of the diazo compound and the α-substituent flanking the carbonyl group.204 TMSCHN2 was reported to react with cyclic β-alkoxyenals in the presence of TMSOTf as a catalyst to induce ring homologation (Scheme 47). Although the reaction itself does not involve a nucleophilic addition to a cyclic ketone, the similarity of both transformations is worth noting. According to the authors, the β-oxyenal is activated by the catalyst to generate the highly reactive dioxocarbonium ion 86, which is then trapped by nucleophilic attack of the diazo compound. The electron rich alkoxy group migrates to the vicinal carbon

unsymmetrical cyclic ketones, preferential migration of the lesssubstituted carbon was observed for the most part, although in variable amounts for α-monosubstituted cyclohexanones (Scheme 43). As in previous cases, the reaction regioselectivity seems to be mostly a consequence of conformational and stereoelectronic effects. Nevertheless, even to a minor extent, electronic effects seem to play a role in the regioselectivity, because substituents with higher migratory aptitudes or those that are able to stabilize a transition state of cationic character influence the reaction outcome. Hence, in cases where the αcarbon had sp2 hybridization or a silyl group was present at the β-carbonyl position, a preference toward migration of the more substituted carbon was detected.201 4.3. Polycyclic Ketones

The ring expansion of the heterocyclic ketone 76 promoted by trimethylaluminum was reported to yield the ring-expanded product 77 in 63% isolated yield (Scheme 44). The product derived from migration of the less electron-rich carbon was obtained as the major isomer, in this case the more substituted one, although other isomers were observed in the reaction mixture prior to desilylation.202 The regioselectivity in the ring expansion of cyclohexanone derivatives is also ruled by other substituents in the ring. For instance, the protecting group of decalone 78 has been reported to affect the isomer distribution of the ring-expanded products when trimethylaluminum is Scheme 43

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Scheme 46

Scheme 47

Scheme 49

with concomitant extrusion of nitrogen, and subsequent silane elimination affords the homologous silyl enol ether. This methodology was applied to carboxaldehyde scaffolds derived from aucubin (Scheme 48). It was found that, the regioselectivity of the transformation was strongly dependent on stereoelectronic factors, namely on the nature of the substituent at C-6 and its configuration. Application of 4 Å molecular sieves increases the selectivity of the process in favor of the ring-expanded product 88 at the expense of exocylic homologation.205 The ring expansion reaction of cyclobutanone derivative 91 leads to the exclusive formation of triquinane 92 after acidic workup (Scheme 49). In this case, the regioselectivity of the migration opposes the expected one, and the main isomer formed results from migration of the more substituted carbon.206

Homologation of the B-ring of 6-oxo-steroids can be achieved with TMSCHN2 in the presence of a large excess of BF3·OEt2 (4.2 equiv) in dichloromethane. The 6-oxo-7ahomosteroids 95 and 97 can be obtained in high yields and good regioselectivities after desilylation with an acidic workup (Scheme 50). Attempts to further homologate 97 with increased amounts of the Lewis acid promoter resulted in low yield (15%) of a single regioisomer resultant from migration of the less-substituted carbon, which could not be increased with extended reaction times or higher temperatures. Such sluggish reactivity when comparing the 6- and the 7membered ketones was suggested by the authors to be a result of generally lower reactivity of cycloheptanones toward ring homologation, together with the higher steric hindrance on the β-face of the cycloheptanone derivative that hampered the nucleophilic attack to the carbonyl functionality.207,208 Bezofused systems such as tetralones can be homologated with TMSCHN2 as demonstrated in the synthesis of antiviral agent TAK-779 (Scheme 51). Using BF3·OEt2 as the promoter allowed preparation of a single regioisomer of the 7-membered benzofused ketone in 47% yield without needing an additional desilylation step.209

Scheme 48

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Scheme 50

A benzocyclic difluorinated heptanone was reported to undergo ring expansion with TMSCHN2 in the presence of stoichiometric ammounts of trimethylaluminum (Scheme 53).

Scheme 51

Scheme 53

Despite the numerous examples where the main fate of the diazo alkoxide is the ring expansion due to carbonyl formation and dediazoniation process, Nemoto and co-workers reported the formation of 2,3-benzodiazepin-5-ones resultant from an 4π-8π tandem electrocylization process with the diazo functional group (Scheme 52). The nucleophilic addition of

This procedure was used as one of the synthetic steps toward preparation of highly reactive difluorobenzocyclooctyne, since a silyl group at the α-carbonyl position was needed to be installed in one of the synthetic precursors. Despite the excellent yield achieved in that transformation, the replacement of the geminal difluoro groups with methyl substituents hampered the ring expansion reaction. Changes in the Lewis acid, diazo compound, and temperature did not provide the desired ringexpanded compounds. Moreover, variation on the ring size seems to have a detrimental effect on the reaction, and the eight-membered ring homologue could not be efficiently expanded to the cyclononanone.211 BF3·OEt2 was applied as promoter in the ring expansion of dibenzosubernone 99a and its brominated analogue 99b (Scheme 54). While both ring-expanded desilylated products

Scheme 52

Scheme 54

LTMSD to benzocyclobutenone triggers a conrotatory 4πelectrocyclic ring opening followed by an 8π electrocyclization reaction to provide the benzodiazepines in good yields in mild reaction conditions and without any promoter. The unstable character of the hydroxy diazo compound precluded its isolation, and any attempt resulted in isolation of the 5membered ring homologated cycloalkanones. Nevertheless, when applying the same method using ethyl lithiodiazoacetate as the nucleophile, similar high yields of the benzodiazepine were observed and the β-hydroxy-α-diazo compound was stable enough to be isolated. While the deprotonation of the diazo ester with LDA resulted in formation of the corresponding benzodiazepine, the thermal reaction in reflux benzene delivered a mixture of unidentified ring-expanded products.210

could be obtained in reasonable 67−70% yields, the ring expansion of the brominated compound delivered a regioisomeric mixture of 11- and 12-bromo enones.212,213 N-alkyl or aryl-substituted isatins and their imine derivatives can be efficiently expanded to 3-functionalized quinolin-2-ones with TMSCHN2 using Sc(OTf)3 as a catalyst (Scheme 55). Although only the corresponding expanded amines are obtained starting from imines [Scheme 55, X = N(4MeOC6H4)], 5-halide-substituted isatins (Scheme 55, XO, R2 = halide) provided mainly the ring-expanded compounds 2952


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direct use of EDA without anion formation has been explored in many transformations. Warnoff described in 1964215 boron trifluoride as a successful promoter for homologation of acyclic and cyclic ketones with EDA, while the nonpromoted and copper-promoted reactions delivered mainly the enol ethers. The homologation of acetophenone delivered the homologated β-keto ester after preferential phenyl migration in 38% yield. Although being more efficient than previous procedures, the attempted homologation of acetone resulted in a little selective process yielding a mixture of the β-keto ester and epoxide (Scheme 56). Some years later, Mock and Hartman reported

Scheme 55

together with considerable amounts of the spirocyclic oxiranes 102. A DFT study of the isatin expansion mechanism suggests that the nucleophile addition/nitrogen extrusion/ring expansion takes place in two elementary steps via the scandium Ocoordinated alkoxide intermediate. The nitrogen extrusion/ ring-expansion process demands an antiperiplanar rearrangement between the migratory substituent and the diazonium cation, and the regioselectivity of the reaction was attributed to kinetic control.214

Scheme 56

the superior performance of triethyloxonium tetrafluoroborate as a more general promoter of the homologation process.223 The Meerwein reagent allowed almost complete suppression of the epoxide formation and was successfully applied to the homologation of acyclic and cyclic ketones. Although homologation of ketones with EDA can be achieved using boron trifluoride in diethyl ether,215 a complete different scenario is observed when using acetonitrile as the reaction solvent in decomposition of α-diazo-β-hydroxy esters (Scheme 57). In a continuation of their work, Pellicciari and coworkers reported the formation of β-enamino ester derivatives after trapping of α-aryl-α-phenylvinyl cation 103.224 Although this process seems to be limited by its regioselectivity, the electronic nature of the aryl substituent at the 4-position is highly responsible for the 1,2-aryl migration. While the products resultant from 1,2-aryl migration were less formed when decorating the aryl substituent with the nitro group at the 4-position, the introduction of electron-rich 4-methoxy substituent resulted in better selectivities toward 105. Meerwein’s reagent was applied to the homologation of several symmetrical and nonsymmetrical ketones in excellent yields, although in low-to-reasonable regioselectivities when considering alkyl-substituted ketones (Scheme 58).221,225 The homologation of sterically hindered ketones such as tert-butylsubstituted showed high regioselectivity with preferential migration of the less-substituted C−C bond, although in very low yields. Mechanistic studies of the transformation showed that the O-alkylation of ketone by trialkyloxonium salt is the rate-determining step, since the reaction rate was linearly dependent to the concentration of the promoter and not directly dependent on the concentration of the diazo ester. When considering a series of substituted acetophenones, the electronic effect on the migratory aptitude of the aryl substituent were small and the diazonium ion conformation was proposed to be the determinant factor of the reaction regioselectivity. Several metal complexes such as Rh2(OAc)4, Wilkinson’s catalyst (RhCl[P(C6H5)3]3), PdCl2, and CoCl2 were reported to efficiently promote the rearrangement of α-diazo-β-hydroxy esters after testing a long series of catalysts (Scheme 59). This two-step protocol consisted in the preparation and isolation of the aldol type compounds after addition of lithiodiazoacetates to ketones and further rearrangement to provide the

5. REACTION OF KETONES WITH UNSUBSTITUTED α-DIAZO KETONES, ESTERS AND DERIVATIVES Being 5 orders of magnitude less nucleophilic than diazomethane and 4 orders of magnitude less nucleophilic than TMSCHN2,98 the use of ethyl diazoacetate (EDA) in the nucleophilic addition to ketones is more challenging. In the absence of a promoter or in the presence of copper, ketones react with EDA to afford enol ethers in spite of β-keto esters.215−217 Hence, the use of a base to deprotonate the αcarbonyl position or stronger Lewis acids than the abovementioned ones to increase the electrophilicity of the ketone is usually needed. The use of lithium bases to deprotonate LDA was first described by Schölkopf and Frasnelli,218 by using butyl lithium and then reacting the formed lithium salt with benzaldehyde to provide the aldol addition type product. While such procedure requires the use of low-temperature setups, due to the high reactivity of the lithium salt, Wenkert and McPherson219,220 later showed that milder conditions could be used for preparation of the same α-diazo-β-hydroxy esters. Despite the simplicity of such practice, where an ethanolic potassium hydroxide solution is used at room temperature in a one-pot process, LDA became the common base for deprotonation of EDA and other α-diazo esters. In practical terms, the lower reactivity of EDA when compared with other diazo compounds usually allows the isolation of the α-diazo-β-hydroxy esters. Additionally, the ringexpanded products become less reactive than the starting ketones and the presence of the carboxylic ester allows further manipulation of the reaction products. As the typical products from EDA insertion to cycloalkanones are β-keto-esters, these can usually be hydrolyzed and decarboxylated to afford the unsubstituted homologated cyclic ketones. This two-step protocol is usually superior to the single-step ring expansion with diazomethane.221 Although less explored for the same purpose, benzyl and allyl diazoacetates can also be used in the homologation processes and then decarboxylated after removal of the benzyl group by metal/ammonia reduction or catalytic hydrogenolysis, or removal of the allyl group by metal/ ammonia reduction.222 5.1. Acyclic Ketones

Despite the lower reactivity of unsubstituted α-diazo esters when compared with noncarbonyl-stabilized diazoalkanes, the 2953


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Scheme 57

Scheme 58

Scheme 59

homologated compounds in good yields. Although CoCl2 was somewhat less effective in promoting the formation of the ketone, the other above-mentioned complexes delivered the desired ketones in reasonable yield. Of notice is the fact that Rh2(OAc)4 showed higher catalytic activity as this reaction could be performed in pentane at room temperature, while the other complexes required refluxing benzene. However, no clear

trend between the catalyst employed and the regioselectivity was observed.226 Later, in an extensive study on the reactivity of α-diazo-β-hydroxy esters with dirhodium complexes, Padwa and co-workers reported the efficient use of Rh2(OAc)4 as catalyst in the ring expansion of aldol-derived adducts of EDA and cyclopentantone in quantitative yields.227 When considering acyclic ketones, the quaternary diazo adducts derived from 2954


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Scheme 60

Scheme 61

Scheme 62

acetone and acetophenone were efficiently homologated under the same reaction conditions in quantitative yields for the former and 75% for the later. Notably, only the regioisomer resultant from phenyl migration was observed in the case of acetophenone derivative when running these reactions in dichloromethane at room temperature. Few examples can be found about the use of α-diazoketones in homologation reactions. LDA can be successfully used to deprotonate the α-carbonyl terminal position of α-diazo ketone 110 and further reacted by aldol type reaction with pentan-3one (Scheme 60), which in the presence of catalytic amounts of dirhodium acetate results in the homologated diketone formation 111 in 62% yield. Dirhodium tetraacetate has been recently reported as a successful partner in an enantioselective relay process combining the rearrangement of α-diazo-β-hydroxy esters with an enantioselective Michael addition with nitroalkenes catalyzed by quinine-based squaramide 112 (Scheme 61). Despite the high enantioselectivities achieved for secondary alcohols, both syn and anti isomers were obtained in equimolar ratios regardless of the organocatalysts tested. The acyclic tertiary alcohol 113 resulted in homologated product formation 114 in low 3:1 diastereoselectivity, although in excellent enantioselectivities.228 The preparation of functionalized resorcinols have been recently developed by exploring the surprising reactivity of α,βunsaturated ketones 115 (Scheme 62).229 After observing the lack of stability of that enedione that hampered its isolation by chromatography, Doyle and co-workers screened several reaction conditions in order to find an efficient promoter for the cyclization process. A catalytic amount of NaOH (10 mol %, aqueous solution) delivered the carboxyethyl resorcinol derivative 116 in 83% yield, while changing the ester substituent resulted in a mixture of the desired products and

1,2-diazepines. A mechanistic proposal based on the following sequence of events was suggested by the authors (Scheme 63): Scheme 63

deprotonation, double bond isomerization, and pericyclization, followed by loss of molecular nitrogen concerted with methyl migration. Of special interest in this process is the methyl migration that is delivered to the more distant sp2 carbon in spite of migrating to the quaternary sp3 carbon. Six- and seven-membered cyclic ketonitrones can be prepared by a sequence of nucleophilic addition with in situ formed ethyl lithiodiazoacetate to yield isolable β-diazo cyclic hydroxylamines, followed by metal-catalyzed ring expansion (Scheme 64). Dirhodium, copper, and silver complexes were screened as catalysts for formation of cyclic nitrones by ring expansion of the diazo compounds. Cu(CH3CN)4PF6 was identified as a particular efficient catalyst, providing the ringexpanded products in excellent yields after up to 30 min of reaction and overcoming the results obtained with Rh2(OAc)4. Silver salts also proved effective catalysts in the process, where the catalyst activity of AgOTf was reported to be superior to AgOBz or AgBF4. The protocol was particularly successful in 2955


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TMSOTf, Rh2(OAc)4, and photochemical activation were tested in the ring expansion of cyclobutenone 118 to provide the five-membered β-diketone 119 or 120 in reasonable yields together with 2(5H)-furanone 121 in most cases (Scheme 66).

Scheme 64

Scheme 66

the expansion of five-membered rings but also in the homologation to seven-membered rings.230 5.2. Monocyclic Ketones

A mechanism accounting for ring opening followed by recyclization and reductive elimination of the metal was suggested by the authors for the role of the dirhodium catalyst. The tert-butyl ester group was easily cleaved under the reaction conditions due to the good leaving group ability of the cyclopentenedione moiety.233 A tandem electrocyclization reaction of cyclobutenones with lithiodiazoacetate allows the preparation of 1,2-diazepines in good yields and good regioselectivities (Scheme 67). While the

Although BF3·OEt2 can be used to efficiently promote ring expansion of α-diazo-β-hydroxy esters derived from addition of EDA to cyclobutanones, lower yields are observed in the ring expansion of larger cycloalkanones (Scheme 65). For instance, Scheme 65

Scheme 67

use of LDA as base to form ethyl lithiodiazoacetate always resulted in preferential formation of diazepines 122 together with the isomer 123, replacing the lithium base by n-BuLi allowed the single formation of 122. On the other hand, pyridine was identified as a suitable base for the isomerization process from 122 to more stable 123.234 McKervey and Ye reported the successful use of LDA to deprotonate the α-carbonyl terminal position of α-diazo ketones and further aldol-type reaction with symmetrical acyclic and cyclic ketones (Scheme 68).235 The α-diazo-βhydroxy carbonyl compounds were then submitted to Rh2(OAc)4 catalysis to deploy the carbon-substituent migration affording the α-amino-β-diketones in good yield. Despite scarce reports on the use of α-diazoketones in homologation reactions, Mock and Hartmann reported the intramolecular ring expansion of α-diazoketone 124 promoted by Meerwein salt (Scheme 69).223 Wilkinson’s catalyst and other metals have been reported as equally effective catalysts in the ring expansion of β-hydroxy-α-diazo esters derived from addition of ethyl lithiodiazoacetate to cyclic ketones. Rh2(OAc)4, PdCl2, and CoCl2 were reported to provide ring expansion products for 6-membered cyclic ketones in very good yields and excellent regioselectivities with selective migration of

the ring expansion of cyclopentanone with such Lewis acid could be achieved in no more than 44% yield in ethyl ether at low temperatures (from −40 °C to −70 °C).215 The preparation of the α-diazo-β-hydroxy esters can be efficiently reached by aldol-type condensation of ethyl lithiodiazoacetate with cyclic ketones. Decomposition of the diazo intermediate with BF3·OEt2 leads to an unusual array of products that depends on several factors, such as the ring size of the cycloalkanone and solvent of the reaction. Instead of following synchronous migration of one of the substituents together with molecular nitrogen extrusion, the Lewis acid complexed alcohol follows a neighboring-group participation in the diazo moiety to generate a cycloalkylidene diazonium salt that eventually results in a highly reactive linear vinyl cation after nitrogen extrusion. A series of rearrangements leads to formation of a more stable allylic cation that can be trapped by the solvent of the reaction.231,232 Concerning the ring expansion of four-membered derivatives, other chemicals were shown to be superior to BF3·OEt2. TFA, 2956


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Scheme 68

excellent enantioselectivities (Scheme 70). Five-to-sevenmembered cyclic ketones were obtained in excellent yields and enantioselectivities, and the reaction proved to be successful for a variety of aryl nitroalkenes employed, with the stereoinduction being more effective to 2- and 3-substituted aryl nitroolefins than to their 4-substituted counterparts.228 As observed for other diazoalkanes, the ring expansion of cyclopentanones and cyclohexanones with EDA promoted by boron trifluoride usually proceeds through migration of the less-substituted carbon (Scheme 71). When having both αcarbonyl positions substituted with simple methyl substituents, homologation of the ketone is more difficult, while the presence of two methyl substituents in the same carbon increase the regioselectivity toward exclusive migration of the methylene carbon.238 The ring expansion reaction of α-diazo-β-hydroxy esters to form α-(ethoxycarbonyl) cyclohexanone, cycloheptanone, and cyclotridecanone was reported by Schöllkopf to proceed by simple treatment of the α-diazo-β-hydroxy esters with hydrochloric acid in reasonable yields (52−79%) with no need to isolate the intermediate diazo compound.239 Meerwein’s reagent Et3O+BF4− as well as trimethyl- and tripropyloxonium fluoroborates were reported to be effective promoters for the ring expansion of cycloalkanones with EDA, although without clear influence of the α-carbonyl substituents in the regioselectivity outcome (Scheme 72). Decreasing the bulkiness of diazo ester analogs, such as diazoacetonitrile, results in lower regioselectivities in the ring expansion of 2-methylcyclohexanone while being barely affected by the alkyl substituents of the promoter. The procedure was applied to the ring expansion of several cycloalkanones in higher regioselectivities than for the acyclic ketones and could be further increased by using antimony pentachloride at lower temperatures (−78 °C instead of 0 °C needed for tetrafluoroborates). The tetrafluoroborate salt also promoted the formation of bicyclo[5.3.0]decane-1,2-dione 125 by a ring expansion after ring closing of diazo ketone 124 (Scheme 69)221,223,225 and later reproduced by Padwa using 10 mol % of tin chloride.240 Tin chloride was shown to be a good catalyst for the Roskamp homologation of aldehydes. Interestingly, despite

Scheme 69

the less-substituted carbon (Table 2, entries 1−8). Other metal salts that were tested resulted in product formation only after Table 2. Ring Expansion of β-Hydroxy-α-Diazo Esters with Different Metals

a

After treatment with SiO2 in hexane. bOverall yield after hydrolysis and decarboxylation.

long reaction times, higher temperatures, or in lower regioselectivities.226 Rh2(OAc)4 was also reported to catalyze the ring expansion of 2-caranone diazo derivative (Table 2, entry 9)236 and of a six-membered organosilicon after in situ formation of the β-hydroxy-α-diazo ethyl ester (Table 2, entry 10).237 The above-mentioned enantioselective relay process developed by Gong and co-workers that combined the quinine-based squaramide 112 and dirhodium tetraacetate (Scheme 61) was also applied in the ring expansion of several cyclic tertiary alcohols in diastereoselectivities as high as 50:1 and good-toScheme 70

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Scheme 71

Scheme 72

Scheme 73

Scheme 74

reaction times (12 h). The procedure was successfully applied to α-diazo-β-hydroxy compounds derived from substituted benzophenones in good yields. More significantly, diazo compounds derived from nonsymmetrical ketones were tested providing the α-aryl-α-halo-β-keto esters in excellent regioselectivities with preferential migration of the aryl substituent over the alkyl ones. Chlorination and bromination reactions were both successful, the later process being superior to the former. One example of an iodination was also reported in excellent yields for the benzophenone derivative using Niodosuccinimide as the iodine source.242 After observing the preferential migration of aryl substituents over alkyl ones in the dirhodium-mediated decomposition of β(N-tosyl)amino diazo carbonyl compounds, which was applied to the decomposition of primary aldimines and one secondary

the higher reactivity of aldehydes to be attacked by the diazo compound, competitive cyclization experiments of ketone 124 in the presence of aldehyde showed that the intramolecular trapping of the ketone is preferable to the intermolecular process with an aldehyde. Lewis bases have recently been reported by Murphy to catalyze the gem-diiodination of diazo esters.241 Taking that literature precedent, Zhu and co-workers developed a halogenation/semipinacol rearrangement of β-hydroxy-α-diazo esters using electrophilic 1,3-dihalide-5,5-dimethylhydantoins in THF at room temperature (Scheme 73). Although good yields were observed for the uncatalyzed halogenation-aryl migration process in THF, the reaction times were greatly reduced from 2 h to 20 min in the presence of 10 mol % of DABCO, while triethylamine had an inhibitor effect resulting in prolonged 2958


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Scheme 75

Scheme 76

ketimine in good yields and selectivities (Scheme 74),243,244 Wang and co-workers exploited this method for expansion of cyclic ketimines. α-Diazo esters resultant from addition of EDA to N-tert-butylsulfonyl ketimines can be efficiently converted to β-enamino esters by dirhodium complexes or other metals, although greatly influencing the chemoselectivity of the transformation. Expansion of symmetric ketimines leads to the formation of N-tert-butylsulfonyl enamines in excellent yields after addition of ethyl lithiodiazoacetate and expansion of the α-diazo ester with the dirhodium catalyst in refluxing dichloromethane. The use of superstoichiometric amounts of HMPA was reported to be beneficial for both yields and reaction times in the ethyl lithiodiazoacetate addition reaction. On the other hand, the expansion reaction was observed to be sensitive to steric hindrance around the diazo moiety, and γmethyl-substituted sulfonyl amines needed higher reaction temperatures (refluxing dichloroethane). Only moderate regioselectivities (up to 80:20) were observed for such cases.245

Scheme 77


classical less regioselective Tiffeneau-Demjanov ring enlargement.247 Although not used as much for EDA addition as for diazoalkanes addition, BF3·OEt2 also promotes the addition of EDA to cyclic ketones and further ring expansion (Scheme 78). Presence of a halide or an acetoxy group at the α-carbonyl position results in the controlled migration of the lesssubstituted carbon due to electronic effects. This procedure was tested for preparation of A-homo steroid ketones in reasonable yields and high regioselectivities after reductive removal of the halide with Zn-HOAc.248 Polycyclic cage compounds also undergo ring expansion with EDA promoted by BF3·OEt2, as extensively studied by Marchand and co-workers (Scheme 79). The presence of a substituent at C1 leads to the addition of the diazo compound to the less sterically hindered carbonyl, ultimately resulting in the regioselective formation of the six-membered ketone, although in low yields. Dihalo derivatives of the same class of compounds lead to formation of cyclopent[a]indene derivatives in the presence of excess EDA.249−251 As previously mentioned, the 4π-8π tandem electrocyclic reaction of the adduct derived from the aldol-type reaction of lithiodiazo compounds and cyclobutenones is an expeditious

EDA can also be added to fused cyclobutanones in the presence of strong Lewis acids such as BF3·OEt2, triethyloxonium tetrafluoroborate, or antimony pentachloride (Scheme 75). The regioselectivity is highly dependent on the Lewis acid promoter, even though selectivity toward migration of the less-substituted carbon is usually observed with SbCl5, leading to better regioselectivities than other Lewis acids and providing cycloalkanones 127 in 63% overall yield.140 The ring expansion of bicyclo[4.2.0]octanones 129 was reported to proceed with high regioselectivity promoted by BF3·OEt2 in ethyl ether at room temperature for 3 h (Scheme 76), providing mainly product 130 resultant from migration of the less-substituted carbon. The presence of a methyl substituent at the carbonyl α-position resulted in either lower levels or inversion of the regioselectivity.246 D-Homo steroid derivatives can be prepared by dirhodiumcatalyzed expansion of the D-ring after reaction of the cyclic ketone with ethyl lithiodiazoacetate (Scheme 77). This high regioselective method results in exclusive migration of the lesssubstituted carbon and can also be combined with the decarboxylative process affording a viable alternative to the 2959


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Scheme 78

Scheme 79

Scheme 80

the sp2 aromatic carbon was observed, leading to formation of homologated ketones in up to 96% yield.242 While the addition of EDA to iso- and thiochroman-4-one failed when using bases or Lewis acids, the aldol addition type of product could be prepared after reaction of the ketone with in situ formed ethyl lithiodiazoacetate (Scheme 82). The treatment of the α-diazo-β-hydroxy compound with methanolic hydrogen chloride led to formation of ring-expanded products in the enol form in 22 and 33% yield.253

way to prepare 2,3-benzodiazepines (Scheme 52). Focusing on the use of ethyl lithiodiazoacetate as the nucleophile and having the cyclobutenone substituted with an aryl moiety and a silyl ether at the α-carbonyl position, the same methodology can be applied for the successful preparation of 1-aryl-substituted 2,3benzodiazepin-5-ones after silanol elimination with camphorsulfonic acid (Scheme 80).252 The halogenation/semipinacol rearrangement of β-hydroxyα-diazo esters protocol developed by Zhu and co-workers was further extended to the ring expansion of diazo compounds derived from unsymmetrical ketones such as α-tetralone and other benzofused ketones (Scheme 81). In such cases, the preferential migration of the less-substituted carbon instead of

Scheme 82

Scheme 81

The high electrophilic nature of isatin’s carbonyl allows the direct nucleophilic addition of EDA without the need to prepare the lithium salt. In the seminal works of Eistert, diethylamine was used as a catalyst for the aldol addition while the ring expansion could be achieved either by addition of acids or zinc chloride.165,166,254 The base-catalyzed aldol addition of EDA to isatin was recently studied and from several conditions tested, 15 mol % of DBU in ethanol was reported to provide the α-diazo-β-hydroxy ester in reasonable yields after 3 h at room temperature.255 2960


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Scheme 83

Scheme 84

Scheme 85

Rh2(OAc)4 is an effective catalyst for the ring expansion of αdiazo-β-hydroxy esters derived from isatins. The catalyst can be combined in a sequential protocol affording the ethyl 3hydroxy-2(1H)-oxoquinoline-4-carboxylates 136 in good yields after in situ formation of the diazo derivative catalyzed by DBU in ethanol (Scheme 84). A one-pot relay protocol of the same reaction proved to be less efficient when using Rh2(OAc)4 as the catalyst. The quenching of the dirhodium catalyst by DBU and the competition between the β-hydroxy-α-diazo intermediate and EDA for the metal catalyst were suggested as possible complications of the tandem protocol. From other dirhodium complexes tested, one complex containing an electron-donating NHC ligand in the dirhodium axial position was identified as a suitable catalyst for the one-pot reaction in ethanol, affording the desired products 126 in up to 92% yield.255 A mechanism including participation of a metallocarbene was studied by DFT calculations and compared with other mechanisms, accounting for participation of the dirhodium catalyst as a Lewis acid. Higher energies were determined for the transition states where the dirhodium complex acts as a

An extensive screening of Lewis acids as promoters for decomposition of an isatin-derived α-diazo-β-hydroxy ester was recently performed (Scheme 83). The nature of the Lewis acid and the solvent polarity were observed to have a pivotal influence on the chemoselectivity of the decomposition. A cationic cascade mechanism, or a concerted 1,2-aryl migration followed by dinitrogen release was suggested as possible paths for formation of ring-expanded product 133. In accordance with the proposed mechanism, hard Lewis acids such as BF3· OEt2 and SnCl4 favor the cationic process, resulting in formation of products 135 derived from vinyl cation intermediate 136 after 1,2-aryl shift and subsequent trapping by the solvent. More polar and more nucleophilic solvents favored formation of 134 due to the increased stabilization of the vinyl cation intermediate 136. Solvent adducts derived from dihalomethanes and nitriles were obtained in 12−40% yields, while acetylene compound 135 was the major product. Use of MeOH as solvent in the presence of BF3·OEt2 resulted in exclusive formation of 133 due to proton-induced expansion by the in situ formed [BF3·OMe]-H+.256 2961


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Scheme 86

6. REACTION OF KETONES WITH DISUBSTITUTED DIAZO COMPOUNDS Due to the less nucleophilic nature of disubstituted diazo compounds, and the lack of hydrogens to create the anion, these compounds have been less explored in the ring expansion of cycloalkanones. Moebius and Kingsbury147,259 reported the catalytic activity of scandium triflate for the homologation of cycloalkanones with disubstituted diazomethanes (Scheme 87).

Lewis acid relative to the ones determined for the metallocarbene pathway. The less energy-demanding process for metallocarbene formation with the β-hydroxy-α-diazo intermediate was compared with the metallocarbene formation derived from EDA in order to explain the selectivities achieved in the one-pot relay system.255 Despite being less nucleophilic than EDA due to electronic and steric effects, dialkyl (diazomethyl)phosphonates can be added to imino isatins 137 under base catalysis conditions, and the intermediate formed expanded to 3-amino-4-phosphono-2quinolinones 138 under acid catalysis (Scheme 85). Peng and co-workers studied both reactions in a sequential manner and observed that from a series of bases tested, a catalytic amount of K2CO3 (20 mol %) could be used to achieve the corresponding addition product in excellent 98% yield after 3 h in toluene at room temperature. The use of stronger bases such as n-BuLi, tBuOK, or NaOH led to decomposition of the starting material while Li2CO3, NaOAc, and NaHCO3 delivered only traces of product. The optimization of the ring-expansion step under acid catalysis resulted in identification of salicylic acid as an efficient catalyst, providing the ring-expanded product 138 in up to 98% yield after 22 h at 50 °C. Combination of both protocols resulted in the development of a one-pot nucleophilic addition and regioselective ring enlargement sequence regardless of the N-substituents of imino isatin or the substitution pattern of the isatin aromatic ring, except for the highly deactivated 5-nitro isatin derivative. With regard to the influence of the phosphoryl substituents, the reaction proceeds in good yields for dimethyl, diethyl, and diisopropyl analogues, but a significant yield drop was reported for the dibenzyl phosphonate (72% yield).257 The reactivity of β-methylene-β-silyloxy-β-amido-α-diazoacetates 139 with different catalysts have been studied recently. The nitrogen extrusion of these amido diazoacetates, derived from [3 + 2] cycloaddition of azomethine imines with silyl enol diazoacetates, and concomitant rearrangements was observed to be strongly dependent on the metal center of the catalyst. Formation of three different products, resultant from migration of C−C (140), O−C (141), or N−C (142) bonds were observed in different ratios. In an attempt to find a suitable catalyst to provide selectively each of the different possible products, Doyle and co-workers screened several dirhodium complexes, copper, and silver salts. While copper salts were highly efficient in delivering selective formation of N−C migration products, dirhodium catalysts resulted in mixtures of products of different ratios dependent on the electronic and stereochemical features of the rhodium ligands. A coordination of the copper carbene intermediate with the carbonyl oxygen of the pyrazolidinone ring was suggested to be on the basis of the highest selectivity of the copper complexes.258

Scheme 87

Contrary to previous reports on the use of diazomethanes, a small excess of the diazo compound (1.1 equiv) could be used in several transformations to afford the ring-expanded product in good-to-excellent yields. The process could be successfully applied to the ring expansion of 4-, 6-, and 12-membered cyclic ketones, even with challenging bulky diphenyldiazomethane and to the preparation of spiro cyclic compounds. Simultaneous to the above-mentioned report, Maruoka and co-workers reported the use of α-substituted diazoacetates in the ring expansion of cyclohexanone derivatives and heteroanalogues (Scheme 88).260 The Lewis acid BF3·OEt2 was successfully employed as a catalyst for the ring expansion reaction of 6-membered ketones in dicloromethane at −78 °C and further extended to the diastereoselective ring expansion of 4-substituted cyclohexanones. Although applied successfully for several esters, the α-alkyl substituent of the diazo compound influences the reaction outcome. While linear alkyl substituents in the diazo acetate are tolerable, branched substituents such as iso-propyl or aryl groups do not result in product formation. With consideration of the expansion of 4-substituted cyclohexanones, different levels of diastereoselectivity were achieved, depending on those substituents. While alkyl and aryl 4substituted cycloalkanones provide mainly the diastereomer with a trans relation between the carboxyl ester and the alkyl substituent, the diastereoselectivity is reversed to cis when the 2962


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organized by the decreasing reactivity of diazo compounds, starting from more reactive phenyldiazomethanes toward less reactive disubstituted α-diazo carbonyl compounds, while increasing the complexity level of the ketone substrates from acyclic to monocyclic and benzofused substrates. Despite not being the main topic of this review, the excellent levels of enantioselectivity achieved in the recent reports on the asymmetric homologation of aldehydes is worth noting. Namely, the Roskamp reaction can provide either αsubstituted-β-ketoesters and derivatives with chiral catalysts263−267 or auxiliaries268 or chiral all-carbon quaternary centers.266,269 A similar approach using a chiral oxazaborolidinium ion as catalyst has been recently applied to the more challenging asymmetric homologation of aldehydes with noncarbonyl-stabilized aryldiazoalkanes.270

Scheme 88

7.1. Reactions with Monosubstituted Diazo Compounds

Ring expansion reactions of cyclic ketones with phenyldiazomethane can be performed to provide the corresponding α-aryl cycloalkanones in good-to-excellent yields by using scandium Lewis acids with loadings as low as 0.5 mol % and in up to 5 mmol scalable procedures (Scheme 89). Bis- and tris(oxazoline)-based ligands can be paired with Sc(OTf)3 to provide the ring-expanded products in excellent enantioselectivities regardless of the substituents present in the aryl diazomethane. The mild procedure established for such reaction delivers the enantiomerically enriched α-arylcycloalkanones that would otherwise be difficult to obtain due to the easy epimerization of the α-carbonyl stereogenic center. Notably, the procedure was demonstrated to be suitable for the ring expansion of 4-, 6-, 7-, and 8-membered cyclic ketones. As previously mentioned for the uncatalyzed reaction with diazomethane, the high reactivity of cyclohexanone toward homologation leads to an overhomologation of cyclopentanone and a mixture of products is also obtained by this method. The presence of moisture or Lewis basic impurities was reported to have a detrimental effect in the turnover number of the catalyst, and catalyst loading of 1 mol % can be used for the racemic transformation. However, due to the presence of Lewis basic functionalities on the chiral ligand, catalyst loading of 5−10 mol % is needed.259,271 Maruoka and co-workers developed an α-diazocarbonyl compound containing a (+)-camphorsultam moiety to act as a chiral auxiliary for the ring-expansion desymmetrization of cyclohexanones (Scheme 90). Stoichiometric amounts of BF3· OEt2 were employed as a promoter in the expansion reaction of 4-substituted cyclohexanones to provide the corresponding

alkyl substituent is replaced by siloxy or alkoxy groups. This change in diastereoselectivity is a result of the more favorable axial orientation of these substituents in cyclohexanones due to the electrostatic interaction between the nonbonding orbital of the oxygen moiety and the π*-orbital of the carbonyl group.261,262

7. ASYMMETRIC HOMOLOGATIONS Although the addition of diazo compounds to cyclic ketones, and consequent ring expansion reaction, has been around for almost 100 years,112 only in the past decade have there been successful efforts, developed mainly by Maruoka, Kingsbury, and Feng, for the enantioselective version of these transformations. While the widely developed addition of diazomethane cannot lead to formation of a new stereogenic center, and the synthetic analogue trimethylsilydiazomethane leads to the unstable silyl enol ether that eventually collapses to the corresponding ketone, other diazo compounds can in principle be used to provide the ring-expanded ketones, containing a stereogenic center at the α-carbonyl position. However, once formed, the chiral ketones can often suffer easy racemization or epimerization of the newly formed stereogenic center at the αcarbonyl position. Although less reactive than monosubstituted diazo compounds, disubstituted diazo compounds, especially those stabilized by the presence of a carbonyl group, have been under the spotlight in enantioselective catalysis and methods that allow the preparation of cycloalkanones in excellent levels of enantioselectivity have been recently developed. Following the same reasoning as for the previous sections, this section is Scheme 89

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equatorial positions, while trans OTBS-derivative preferentially places the OTBS and OH group in axial positions. As the OH group is needed in an axial position in order to trigger the expansion reaction, most of the trans diastereomers failed in the process.273 In an attempt to develop a method for the enantioselective preparation of α-halo-quaternary cycloalkanones, Zhu and coworkers tested the halogenation/semipinacol rearrangement of α-diazo-β-hydroxy esters with chiral Lewis bases. After screening of several cinchona alkaloid derivatives for an acyclic α-diazo-β-hydroxy ester, dimeric phthalazine derivative was identified as the best catalyst and applied to the formation of ring-expanded α-halo-cycloalkanone 149 in good yield and moderate enantioselectivity, using N-bromophthalimide as the bromine source (Scheme 92).242

Scheme 90

Scheme 92 cycloheptanones bearing the 2- and 5-substituents in a trans relationship as single diastereomers. On the other hand, 4siloxy substituents in the cyclohexanone are known to assume an axial position, in contrast to alkyl and aryl 4-substitutents, resulting in the formation of cycloheptanones with a cis relationship. The success of this strategy was attributed to the selective equatorial attack of the diazo compound to the cyclohexanone due to the shielding of one prochiral face of the diazo carbon by the chiral auxiliary, and the stability of the αcarbon of the 7-membered ring that allowed purification of the product without epimerization. While cyclopentanones failed to react with the chiral diazo compound, cyclobutanone could be expanded to the 5-membered ring. Unfortunately, it had to be trapped by nucleophilic addition to the ketone carbonyl in order to avoid epimerization of the α-carbonyl position.272 Symmetrically substituted, six-membered tertiary alcohols prepared by addition of ethyl lithiodiazoacetate to cyclohexanones can be desymmetrized with axially chiral dicarboxylic acids as catalysts (Scheme 91). The cis isomer of 4-substituted 1-hydroxy cyclohexane derivatives 145 can be enantioselectively protonated with 5 mol % of chiral Brønsted acids in toluene to afford a single enantiomer of the ring-expanded cycloalkanone 147 after decarboxylation with lithium chloride. The electronic nature of the 3,3′-substituents of the binapthalenyl moiety of the catalyst was determinant in the enantioselectivity of the process. The 3,5-dinitrophenylsubstituted catalyst 144 was reported to afford the enantiomerically enriched cycloheptanone in good yield and enantioselectivities in the presence of one equivalent of water after 48 h at −40 °C. The same methodology failed in the expansion of trans diastereomers, except when a bulky substituent such as OTBS was present in the 4-position of the cyclohexane ring. DFT calculations suggested that 4-aryl-substituted trans-cyclohexanes preferentially place the hydroxyl and the aryl groups in

7.2. Reactions with Disubstituted Diazo Compounds

The enantioselective homologation of α-aryl-α-keto esters with α-alkyl-α-diazo esters was reported by Feng and co-workers (Scheme 93).274 The screening of several Lewis acids in the Scheme 93

presence of N,N′-dioxide-based ligand 150 have showed that Sc(OTf)3 is an active catalyst for this transformation. After achieving excellent enantioselectivity levels with the combination of 150 and Y(OTf)3, the more simple ligand 151a combined with the former Lewis acid led to the formation of the quaternary carbon center containing ketones. The

Scheme 91

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introduction of a bulky ester substituent on the diazo compound was beneficial to achieve higher yields and enantioselectivity, and the protocol was applied to the homologation of α-aryl and α-methyl-α-keto esters using the adamantyl α-diazo ester. The enantioselectivity of the homologation of α-aryl-α-keto esters was observed to be somewhat dependent on the electronic nature and steric bulk of the aryl substituents. When replacing the methyl substituent at the α-position of the diazo ester by other longer alkyl chains, a slight decrease in the enantioselectivity was observed and the process became more demanding requiring the increase of the amount of catalyst from 2 to 5 mol % in order to achieve reasonable yields. The less favorable 1,2-methyl migration in the homologation of the pyruvic ester (R1 = Me) was also achieved in good yields (70−81%) and excellent enantioselectivities (88−94% ee) replacing 151a ligand by 5 mol % of 151b. Recently, the same group reported the catalytic intramolecular version of the same reaction resulting in preparation of cyclopentanones promoted by chiral N,N′-dioxide-Sc(OTf)3 complex formed by combination of the metal salt with ligand 150 (Scheme 94).275 This method provides a construction of

Scheme 95

The same group also developed a catalytic asymmetric version of the same reaction (Scheme 96). A chiral Lewis acid formed in situ by stirring a solution of 3,3′-bis(trimethylsilyl)BINOL and Me3Al (in a 1:2 ratio) efficiently catalyzed the asymmetric ring expansion of cyclohexanones in reasonable yields and good enantioselectivities.261,276 Despite the success when using methyl α-benzyl-α-diazoacetate, changing the ester substituent to other alkyl groups such as t-Bu or benzyl resulted in lower levels of asymmetric induction. The presence of the benzyl moiety in the α-position of the diazo compounds was reported to be a determinant factor in reaching good enantioselectivies, as its replacement by a simple alkyl group such as methyl or i-Bu resulted in lower enantioselectivity levels. The methodology was further extended to the desymmetrization of 4-substituted cyclohexanones providing the enantiomerically enriched cycloheptanones 153 in up to 93% ee. Despite extensive research performed on the reaction of isatins with diazo compounds in the early 20th century, only recently the asymmetric ring expansion version was reported. Feng and co-workers developed a highly efficient method for the construction of functionalized 2-quinolone derivatives (Scheme 97). A chiral catalyst derived from Sc(OTf)3 and N,N′-dioxide-based ligand was efficiently employed in ring expansion of N-benzyl isatin derivatives with several α-alkyl-αdiazo esters, with catalyst loadings as low as 0.05 mol % to obtain the corresponding C4-quaternary 2-quinolones 154 with excellent enantioselectivies. Besides the excellent levels of stereocontrol achieved with α-benzyl-α-diazo esters, with several substitution patterns in the benzyl group, diazo esters bearing very different functional groups such as cinnamyl, allyl, alkynyl or terminal ester, nitrile, and silyl ether functional groups were tolerant to the reaction conditions. Furthermore, they were not detrimental to the reaction stereoselectivity and the desired compounds were obtained in 93 to 99% ee. On the other hand, the position and electronic nature of the isatin substituents were identified to have a significant effect on the enantioselectivity and reactivity. Ring expansion of C5substituted isatins resulted in lower levels of enantioselectivity and reactivity than C6 or C7-substituted ones. The presence of halides at the 5-position resulted in a decrease of reactivity and enantioselectivity in the order 5-F > 5-Cl > 5-Br > 5-I. The reaction also tolerated different N-substituents on the isatin as N-benzyl, N-methyl, and unprotected isatins were efficiently expanded, although longer reaction times were needed for the unprotected isatin.277 The high levels of enantioselectivity were explained based on coordinative activation of the 1,2-dicarbonyl group of isatin with the scandium center in a bidentate fashion, where the Re face of the isatin is shielded by one of the bulky 2,6-

Scheme 94

α-aryl- and α-alkyl-substituted 2-oxocyclopentanecarboxylates with a chiral all-carbon quaternary center in up to 96% yield and ee. After the intramolecular nucleophilic addition of the diazo moiety to the carbonyl group, a 1,2-aryl shift extrudes molecular nitrogen, providing the β-keto esters using catalyst loadings as low as 0.5 mol % in a moisture- and oxygen-tolerant process. Competing 1,2-alkyl shift (ring contraction) and epoxidation reactions were detected only when performing the reaction at gram scale. The reaction is tolerant to several aryl substituents, although longer times were needed for electronrich substituted aryl compounds. On the other hand, the ester substituent was observed to decrease the reaction yield due to steric hindrance, as demonstrated by the lower yields obtained with the tert-butyl ester. Alkyl ketones were also reported to undergo the addition/rearrangement reaction, and longer alkyl chains were observed to be beneficial for enantioselectivity. Even though the linking-carbon-chain length demonstrated a strong impact on the reaction outcome, and the desired cyclic β-ketoesters could only be obtained with 2-diazo-6-ketoalkanoates, the applicability of this method to selective aryl and alkyl migration is a remarkable entry for preparation of chiral αsubstituted 2-oxocyclopentenecarboxylates. In order to achieve an enantioselective preparation of cycloheptanones bearing a stereogenic carbon at the α-position, Maruoka and co-workers tested a chiral auxiliary strategy in preparation of enantioenriched cyclic ketones containing an αcarbonyl quaternary carbon. The BF3·OEt2 catalyzed diastereoselective addition of (−)-phenylmenthyl-α-benzyldiazoacetate to cycloalkanones and derivatives provided in several cases a single diastereisomer (dr higher than 20:1) of the ringexpanded cycloheptanones in 68−94% yield (Scheme 95).260 2965


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Scheme 96

Scheme 97

diisopropylaniline groups of the ligand. The prochiral faces of the diazo compound are differentiated by the repulsive interaction between the ester group of the diazo compound and the amide of the ligand, resulting in the Re face attack of the diazo compound. Interestingly, when applying this procedure to the expansion of tetralones 155, the diazo compound reacted as an electrophile to provide the compound 156 derived from C− N bond formation (Scheme 98). This unexpected reactivity of

α-diazo esters under mild reaction conditions was confirmed by the authors through control experiments and theoretical calculations. The ester group is crucial for the coordination of the diazo ester with the Sc catalyst that greatly increases the electrophilicity of the α-diazo ester and thus promotes this unusual reaction. The use of a catalytic amount of base increased the reaction yield, and this procedure was explored in the α-hydrazonation of several tetralones in excellent yields and enantioselectivities.278

Scheme 98

8. RING EXPANSIONS WITH DIAZO COMPOUNDS IN TOTAL SYNTHESIS Despite several reported selectivity issues, the one carbon homologation of acyclic and cyclic ketones with diazo compounds have been extensively used in total synthesis. The reliability of diazo intermediate derived from nucleophilic attack of the diazo compound to cyclic ketones to preferentially migrate the less-substituted carbon have resulted in several total

Scheme 99

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Scheme 100

Scheme 101

Scheme 102

synthesis where the ring expansion reaction can sometimes be seen as a key step. Although being used also for installation of other rings, this transformation got special notoriety for formation of 7-membered rings from cycloketone derivatives in the synthesis of many natural products. This section is organized according to the increased number of rings in the starting material, ultimately leading to examples of bridged cyclic ketones.

selective reduction of the less-substituted double bond resulted in formation of the desired natural product.280 The tricyclic core of nerve growth factor-inducing cyathane diterpenes was asymmetricaly constructed having an enantioselective Michael addition, an intramolecular Heck reaction, and an organoaluminum-promoted ring expansion with TMSCHN2 as key steps (Scheme 101). Interestingly, the homologation of the α,β-unsaturated ketone led to preferential formation of the 7-membered ring 160 derived from migration of the sp2 carbon in 60% together with only 15% of the regioisomeric ketone 161.281,282 The construction of the tricyclic skeleton of the artemisolide core was attempted through combination of an intramolecular anodic olefin coupling of a dithioketal and subsequent ring expansion of the unprotected ketone (Scheme 102). Several conditions were screened for the anodic cyclization process of the furan derivative 162, and a 0.5 M solution of LiClO4 identified as the best electrolyte to provide the desired tricyclic structure in good yields. The use of less polar electrolytes was determinant in lowering the concentration of methanol in the region of the reaction around the anode in order to achieve better selectivities in the carbon−carbon bond-forming processes. While cyclization toward formation of the 7membered ring in the anodic process resulted in 9% yield of the product, the ring expansion of the 6-membered ring allowed the formation of the homologated compounds in 60% yield. Despite the observed preferential migration of the lesssubstituted carbon, the 7-membered ketones were formed in poor 62:38 regioselectivity.283 The combination of TMSCHN2 and BF3·OEt2 has also been applied as one of the key steps in the total synthesis of

8.1. Ring Expansions with Trimethylsilyldiazomethane

The first total synthesis of (+)-Frondosin A was accomplished by Trost by combination of Ru-catalyzed [5 + 2] cycloaddition, a Claisen rearrangement, and a ring expansion with TMSCHN2 (Scheme 99).279 The last key step of the synthesis, the expeditious ring expansion reaction of a 5- to a 6-membered ring together with double bond isomerization to afford the desired α,β-unsaturated ketone 157 was achieved in moderate regioselectivity using BF3·OEt2 as promoter, followed by desilylation with TBAF. The construction of the seven-membered skeleton of (+)-βhimachalene by using a ring expansion procedure with TMSCHN2 and boron trifluoride was introduced in the enantioselective total synthesis of that sesquiterpene (Scheme 100). After obtaining the desired homologated silyl and nonsilyl ketones 158 as single regioisomers, with migration of the lesssubstituted carbon, the authors exploited the presence of the silyl substituent to confer diastereoselectivity to the ketone reduction step with sodium borohydride. The resultant diastereoselectively formed β-hydroxysilane was reacted under Peterson elimination conditions affording the triene. Final 2967


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Scheme 103

Scheme 104

Scheme 105

The ring expansion protocol using TMSCHN2 was also applied to the linear total synthesis of hemibrevetoxin B natural product (Scheme 104). Such a strategy was first used in the expansion of tricyclic ketone 164 and later in the expansion of tetracyclic ketone 166 to provide the seven-membered rings.285−287 The method was later employed in the synthesis of gambierol for the ring expansion to the seven-membered ether E ring,288−292 in the construction of the BC293 and KLMN294 ring systems of 168 and 169, respectively, toward total synthesis of gymnocin-A and on the oxepane core in a enantiodivergent synthesis of (+)- and (−)-isolaurepan.295,296 A divergent synthesis of trans-fused octacyclic polyether 170 and derivatives was recently achieved by introducing the ringexpansion procedure at suitable stages. The reaction was applied to the expansion of six- and seven-membered ether rings at several stages along the synthetic path, with preferential migration of the less-substituted carbon.297 In a related

rippertenol (Scheme 103), a polycyclic terpene containing seven stereogenic centers and a compact polycyclic framework.284 The ring expansion of compound 163 could be achieved only under specific conditions (1 equiv each of BF3· OEt2 and TMSCHN2 in CH2Cl2 from −78 °C to −50 °C), while changing the solvent to benzene or toluene or using other Lewis acids [Sc(OTf)3 or AlMe3] resulted in product formation in reduced yields. Moreover, the use of higher amounts of TMSCHN2 resulted in formation of the 8-membered cyclic ketone. In accordance with the authors, this fact was due to the enhanced accessibility of the 7-membered ring ketone compared to the one present in 163 or the absence of the silyl enol ether that could prevent the multiple ring expansion. The regioselective nature of the expansion was suggested to be controlled by the location of the migrating bond relative to the central alkene. 2968


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Figure 6.

Scheme 106

Scheme 107

membered spirocyclic epoxide 173 in a 60:40 ratio (Scheme 105).298 The construction of the oxepane core present in the ABCDEF ring system of yessotoxin and adriatoxin has been

approach to the E-ring structures of ciguatoxins, the ring expansion of a seven-membered ether ring with TMSCHN2 in the presence of trimethylaluminum resulted in formation of the desired homologated product 172 together with the seven2969


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Scheme 108

Scheme 109

Scheme 110

achieved either by a ring expansion of cycloalkanone 168 with TMSCHN2 and BF3·OEt2 in a late stage of an iterative synthesis299 and later on a shorter convergent synthesis in homologation of 176 (Scheme 106).300 The preparation of the E ring of those polycyclic ether marine toxins was achieved after protonolysis of the expanded keto silane with PPTS in methanol delivering preferentially the 7-membered ring compounds derived from migration of the methylene carbon. With concern to the chemoselectivity of both homologations, the ring expansion protocol was superior when applied later in the synthetic route since no epoxide formation was observed and the desired ketones 175 and 177 were obtained in similar regioselectivities and yields in both processes. A previous attempt to construct the E ring of the same system starting from ketone 179a containing a hydroxyl protected with a benzyl group resulted in formation of the desired homologated ketone 180a in only 43% yield together with the debenzylated epoxide 181 (Scheme 107). Replacing the hydroxyl protecting group by the bulkier t-butyldiphenylsilyl group resulted in ring expansion of the 6-membered ketone 179b in 72% yield toward the desired ketone 180b, and only 5% of the isomeric ketone was observed.301

Ring expansion of a tropinone derivative, obtained from synthetic modification of cocaine, was performed using trimethylaluminum as promoter in a high-yielding, regioselective process (Scheme 108). The ring expanded, silyl enol ether product was further modified to achieve the synthesis of highly neurotoxic (+)-anatoxin-a.302 A total synthesis of the racemic marine metabolite nakafuran8 was achieved using a double ring expansion strategy starting from bridged bicyclic ketone 182 (Scheme 109).303,304 While better regioselectivities were achieved in the first ring expansion using the Tieffeneau-Demjanov reaction, the ring enlargement from [3.2.2]nonane (183) to [4.2.2]decane skeleton (185) with TMSCHN2 promoted by BF3·OEt2 delivered the desired homologated ketone in moderate 67% yield and 67:33 regioselectivity with preferential migration of the lesssubstituted carbon. The introduction of phenyl or butyl substituent in C1 of 182 allowed the exclusive formation of the analogue 183, demonstrating the trend of the migratory aptitudes from secondary > tertiary > quaternary carbons in bicyclic systems. 2970


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Scheme 111

Scheme 112

8.2. Ring Expansions with Ethyl Diazoacetate

The 7-member ring installation in the enantiospecific total synthesis of clavukerin A was achieved by ring homologation of cyclohexanone derivative 192 with EDA followed by decarboxylation (Scheme 114). While the dirhodium-catalyzed process required the formation of the ethyl lithiodiazoacetate in the homologation of the ketones containing protected hydroxyl groups, the desired homologated compound could be achieved in excellent 93% yield employing boron trifluoride as a promoter. Either the dirhodium-catalyzed or the Lewis acid promoted processes delivered only one regioisomer of the ringexpanded cycloalkanones with migration of the less-substituted carbon.310 The first total synthesis of (±)-linderol A was achieved in 6.6% overall yield over 19 steps. The construction of the sixmembered carbocylic portion was accomplished by ring expansion of the 5-membered ketone 194 with EDA using boron trifluoride etherate as a promoter (Scheme 115). Since the attempted direct decarboxylation of the enolate 195 failed to provide the desired product in more than 27% yield, the decarboxylation was achieved after hydrolysis of the ester having the enol group protected as a silyl enol ether totaling 61% for the overall process. A different approach based on the homologation with benzyl diazoacetate followed by hydrogenolysis delivered the desired compound in only 22% yield. Both described ring expansions resulted in single formation of the homologated compound derived from expansion of the less-substituted carbon.311 Ring expansion of pinenone 196 was explored in the synthesis of taxol (Scheme 116). The six-membered ketone was first homologated with ethyl lithiodiazoacetate followed by treatment with HCl. The decarboxylation of the ketoesters formed provided a mixture of the ring-expanded ketones in a 9:1 ratio in 25% overall yield. The construction of a third cycle in the cyclohexanone 197 was possible due to the presence of a diazoacetoacetate moiety and subsequent treatment with sodium methoxide. The ring expansion of the six-membered ring, with concomitant contraction of the newly formed lactone, was achieved in 91% yield with 5 mol % of

The construction of the seven-member ring of isoclovene was achieved in 80% yield by ring expansion of a cyclohexanone derivative with EDA using Meerwein’s reagent as promoter (Scheme 110), followed by hydrolysis and decarboxylation. Further synthetic manipulation of the cycloheptanone derivative resulted in another method for the total synthesis of the racemic tricyclic ketone.305 The ring expansion protocol using Meerwein’s reagent as promoter in the homologation of cyclooctanone with EDA was adopted as the first synthetic step in the seven step total synthesis of azamacrolide 187 produced by the pupa of the Mexican bean beetle (Scheme 111). The carbon skeleton construction was finished by a ring expansion of the Nhydroxyethyl lactam under acidic conditions, driven by the relief of the transannular ring strain and avoiding the reversibility by protonation of the basic product.306 SbCl5 was explored in the ring expansion of 188 (Scheme 112) toward a stereoselective synthesis of 9-acetoxyfukinanolide,307 while BF3·OEt2 was used in the synthesis of (−)-khusimone providing the ring-expanded products 191 in 86% yield but low 66:33 regioselectivity.308 Monotherpene thujone can be regioselectively homologated to the six-membered homothujone in reasonable yields with EDA using boron trifluoride etherate as the promoter, followed by decarboxylation (Scheme 113). Subsequent stereoselective Robinson annulation of homothujone and further functionalization provides naphthalenone derivatives, intermediates in the total synthesis of (−)-Ambrox and (−)-polygodial.309 Scheme 113

2971


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Scheme 114

Scheme 115

Scheme 116

more nucleophilic anion. (ii) The electrophilicity of the ketone: reactivity of less electrophilic ketones can be greatly increased if combined with a Lewis acid. However, the Lewis acid can also lead to dediazoniation of the starting diazo compound prior to its reaction with the carbonyl component. Hence, careful choice of the right Lewis acid is greatly important. Typically boronand aluminum-based salts are employed as Lewis acids in stoichiometric quantities, while scandium-based can be used to allow a fully catalytic transformation. (iii) Solvent nature: while protic solvents are known to lead to faster reaction rates for the addition of diazoalkanes, dichloromethane and toluene have become the most used solvents for the Lewis acid catalyzed addition and ring expansion protocol, and coordinative solvents are usually avoided. (iv) Migration regioselectivity and side reactions: even though some reports have shown a relationship between the nature of the catalyst and the regioselectivity, migration of the less-substituted α-substituent is usually observed in cycloalkanones, and conformational and stereoelectronic factors assume a more determinant role than electronic ones. Moreover, for cycloalkanones, the regioselectivity of the ring expansion can be highly influenced by the position of other substituents in the ring. The presence of Lewis acids have been reported to greatly decrease the amount of epoxide formed, while the over homologation products can

CF3CO2H and 84% using 0.5 mol % of Wilkinson’s catalyst [RhCl(PPh3)3]. Further ring expansion of the obtained 7membered product was also performed using ethyl lithiodiazoacetate to afford 60% of only one regioisomer.312

9. CONCLUSIONS This review covers the homologation of ketones with the main emphasis on the most recent development in ring expansion by addition of diazo compounds to cyclic ketones to afford homologated products that are useful building blocks in the synthesis of fine chemicals, spanning simple biologically active compounds to complex natural products. Complexity in the regiochemistry of this addition/rearrangement reaction, competing epoxidation or over homologation, not to mention the challenges to reactivity and enantioselectivity, were all discussed. The success of the homologation of ketones with diazo compounds depends on several related effects that can be exposed in chronological order in the following way. (i) The nucleophilicity of the diazo compound: while diazoalkanes, aryldiazomethanes, and trimethylsilyldiazoalkanes are usually nucleophilic enough to react with electrophilic ketones to form the betaine intermediates, less nucleophilic, unsubstituted αdiazo esters and ketones might need base assistance to form the 2972


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be diminished by maintaining low concentrations of the alkyldiazo compound. The use of TMSCHN2 or unsubstituted α-diazo esters are superior alternatives for the ring expansion reaction since the homologated product is less reactive than the starting ketone, avoiding over homologation issues. Although excellent achievements have been reported for the asymmetric version of the reaction, where chiral N,N′-dioxideSc(OTf)3 and bis(oxazoline)-Sc(OTf)3 catalysts appear as remarkable systems for high levels of enantioselective induction, more effort is needed to improve the asymmetric version of the nucleophilic addition of diazo compounds to the carbonyl of ketones. The main challenges remain for the asymmetric addition of unsubstituted α-diazo esters and ketones as the products can easily epimerize due to the increased acidity of the α-carbonyl position. Moreover, the asymmetric homologation of acyclic ketones is still an open issue. Nevertheless, the reaction potential to generate C−C bonds with chiral centers is an enormous motivation for such investments. Concerning future prospects on this issue, it is envisioned that other stable diazo compounds such as dialkyl (diazomethyl)phosphonates will be further explored as nucleophiles in the addition to cyclic ketones. It seems reasonable to foresee that some of the herein described procedures will be adapted in the near future to the in situ formation of the diazo partner, considering the known safety issues related with the handling of such compounds and the recent achievements in this matter.76,88,89,313 With consideration of the developments of flow systems, it might also be expected that new methods on the combinations of such technology and homologation reactions with diazo compounds will be reported. In the asymmetric version of this reaction, one could expect that the chiral dirhodium catalysts developed for C−H insertion reactions would be explored as chiral inductors in the ring expansion reaction. Although the first reports of this ring expansion reaction appeared in the literature almost one century ago, the recent achievements, in particular for the asymmetric version, forecast the development of new procedures and catalysts.

Roberta Paterna was born in Palermo, Italy, in 1985. She graduated in Chemistry and Pharmaceutical Technology from Faculty of Pharmacy University of Palermo in 2010 and began her Ph.D. in Medicinal Chemistry under the supervision of Dr. Pedro Gois and Professor Rui Moreira at Faculty of Pharmacy, University of Lisbon. Her current interests are the development of synthetic methodologies and biological evaluation of isatin derivatives. Pedro M. P. Gois was born in Portugal in 1977 and studied chemistry at the New University of Lisbon where he also received his Ph.D. in 2005 in organic chemistry under the supervision of Prof. Carlos Afonso. From May 2005 to May 2008, he worked as a postdoctoral research fellow at the University of Sussex with Prof. F. Geoffrey N. Cloke, at the University College of London with Prof. Stephen Caddick, and at the Instituto Superior Técnico (Technical University of Lisbon) with Prof. Carlos Afonso. In May 2008, he joined the Pharmacy Faculty of the Lisbon University as an assistant research fellow of the medicinal chemistry group (iMed.UL - Research Institute for Medicines and Pharmaceutical Sciences), and in July 2013, he was appointed Principal Investigator at the same institution and head of the Bioorganic group. In 2013, he received the Portuguese Young Organic Chemist Award of Portuguese Chemical Society, and in 2012, he received the Vicente Seabra Medal also from the Portuguese Chemical Society.

ACKNOWLEDGMENTS Fundaçaõ para a Ciência e Tecnologia (SFRH/BD/78301/ 2011; PTDC/QUI-QUI/118315/2010; Pest-OE/SAU/ UI4013/2011; P.M.P.G. is a FCT Investigator) and the Academy of Finland (Decision No. 287954, N.R.C. is an academy research fellow) are thanked for financial support. REFERENCES (1) Zollinger, H. Diazo Chemistry II: Aliphatic, Inorganic and Organometallic Compounds; VCH: Weinheim, 1995. (2) Ledwith, A.; Shih-Lin, Y. 1−3-Dipolar Cycloaddition Reactions of Diazoalkanes. Part III. Substituent Effects on the Kinetics of Reactions Between Diazomethane and some Unsaturated Esters. J. Chem. Soc. B 1967, 1967, 83−84. (3) Huisgen, R. Kinetics and Mechanism of 1,3-Dipolar Cycloadditions. Angew. Chem., Int. Ed. Engl. 1963, 2, 633−645. (4) Huisgen, R. 1,3-Dipolar Cycloadditions. Past and Future. Angew. Chem., Int. Ed. Engl. 1963, 2, 565−598. (5) Koumbis, A. E.; Gallos, J. K. 1,3-Dipolar Cycloadditions in the Synthesis of Carbohydrate Mimics. Part 3: Azides, Diazo Compounds and Other Dipoles. Curr. Org. Chem. 2003, 7, 771−797. (6) Ruchardt, C.; Sauer, J.; Sustmann, R. Rolf Huisgen: Some Highlights of His Contributions to Organic Chemistry. Helv. Chim. Acta 2005, 88, 1154−1184. (7) Stanley, L. M.; Sibi, M. P. Enantioselective Copper-Catalyzed 1,3Dipolar Cycloadditions. Chem. Rev. 2008, 108, 2887−2902. (8) Doyle, M. P.; Protopopova, M. N. New Aspects of Catalytic Asymmetric Cyclopropanation. Tetrahedron 1998, 54, 7919−7946. (9) Maas, G. Ruthenium-Catalysed Carbenoid Cyclopropanation Reactions With Diazo Compounds. Chem. Soc. Rev. 2004, 33, 183− 190. (10) Hubert, A. J.; Noels, A. F.; Anciaux, A. J.; Teyssie, P. Rhodium(II) Carboxylates: Novel Highly Efficient Catalysts for the Cyclopropanation of Alkenes with Alkyl Diazoacetates. Synthesis 1976, 8, 600−602. (11) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Correlations Between Catalytic Reactions of Diazo Compounds and Stoichiometric Reactions of Transition-Metal Carbenes with Alkenes. Mechanism of the Cyclopropanation Reaction. Organometallics 1984, 3, 53−61.

AUTHOR INFORMATION Corresponding Author

*E-mail: nuno.rafaelcandeias@tut.fi. Notes

The authors declare no competing financial interest. Biographies Nuno R. Candeias, born in Lisbon, Portugal, in 1981, graduated in Applied Chemistry from New University of Lisbon (2004) and received his Ph.D. in Chemistry from Technical University of Lisbon, under the supervision of Prof. Carlos A. M. Afonso (2008). After 6 months as an invited assistant professor at Cooperativa de Ensino Egas Moniz, he took his postdoc at the Pharmacy Faculty of the Lisbon University under the supervision of Dr. Pedro M. P. Góis for 3 years and at Scripps Research Institute under the supervision of Prof. Carlos F. Barbas, III for one year. In 2012, he moved to Tampere University of Technology in Finland as a University Lecturer, where he was later appointed Adjunct Professor. In 2015, he was awarded with an Academy of Finland Research Fellowship. His current research interests are in the field of more sustainable methodologies in organic transformations and multicomponent reactions. 2973


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