Nitro compounds as useful reagents for the synthesis of dicarbonyl derivatives

The reaction of functionalized nitroalkanes with electrophiles such as Michael acceptors and aldehydes is one of the most exploited procedures for the synthesis of new carbon-carbon bonds. Conversion of the nitro group in the adduct into a carbonyl derivative usually provides a rapid entry to dicarbonyl systems that are amenable to further synthetic transformation into a plethora of important targets


Introduction
][3][4][5][6][7][8] Classical methods for the synthesis of dicarbonyl derivatives usually involve an addition reaction of a metal enolate with a carboxylic acid ester or with a Michael acceptor.The former procedure is also referred as the Claisen condensation and provides a straightforward entry to 1,3dicarbonyl derivatives, 9,10 and the latter leads to the formation of 1,5-dicarbonyl frameworks. 11A viable access to 1,4-dicarbonyl systems using such procedures is not an easy task since it would involve a conjugate addition between an umpoled acyl anion synthon and a Michael acceptor.
Nitroalkanes are a valuable source of stabilized carbanions since the high electron-withdrawing power of the nitro group provides an outstanding enhancement of the hydrogen acidity at the αposition (cf.3][14][15][16] Nitronate anions 2 that can be generated from nitroalkanes 1 using a wide range of bases, act as carbon nucleophiles with common electrophiles including haloalkanes, 17 aldehydes, 18,19 and Michael acceptors, 20 leading to carbon-carbon bond formation (Scheme 1).
A further option is represented by the conversion of the nitro group into a carbonyl group, leading to carbonyl derivatives 6-8, a transformation widely known as the Nef reaction, that ultimately leads to a reversal in the polarity of the neighboring carbon atom from nucleophilic to electrophilic. 21,22The original procedure for the nitro to carbonyl transformation, as described by Nef, was essentially the hydrolysis in strongly acidic conditions of a nitronate salt produced by basic treatment of a nitroalkane.The harsh conditions in which this conversion is usually carried out (pH < 1) have spurred on the development of alternative methods that can be performed in oxidative, reductive, as well as almost neutral, conditions.The aim of this review is to discuss the utilization of nitroalkanes as nucleophilic reagents for the synthesis of dicarbonyl derivatives using a strategy involving a nucleophilic addition of the nitro derivative followed by a nitro to carbonyl conversion.Although these procedures are usually accomplished by a two-step synthesis, there are several examples in which this overall transformation can be carried out in a 'one-pot' system thus realizing a more efficient process.

1,2-Dicarbonyl and 1,3-dicarbonyl derivatives
Nitro compounds have been used only occasionally in the synthesis of 1,2-and 1,3-dicarbonyl derivatives.The oxidative Nef reaction carried out on the products of nitroaldol addition such as 9 affords α-keto acids 10 or aldehydes using molecular oxygen in the presence of copper salts (Scheme 2).

Scheme 3
The reaction of the nickel acylate complex 14 with nitroalkenes such as 13 gives the corresponding addition products 15 that, by treatment with iodine, afford the 1,3-dicarbonyl derivatives 16.Iodine provides cleavage of the nickel adduct and of the nitronate anion in a tandem process (Scheme 4). 25 The reduction of nitroalkenes such as 17 with Bu 3 SnH occurs in neutral conditions, giving the corresponding stannylnitronates 18. 26 These nitronates can be oxidized to the parent carbonyl derivatives using ozone at low temperatures.This procedure is particularly effective in the synthesis of β-lactam building blocks 19 (Scheme 5).As previously stated, conjugate addition of nitroalkanes to enones and enoates provides a rapid entry to the corresponding γ-nitro carbonyl derivatives that can undergo a Nef reaction giving 1,4-dicarbonyl compounds.This procedure represents one of the most exploited methods to prepare such difunctionalized derivatives that find a number of applications in the synthesis of important target molecules.2][33][34] Besides these procedures that work in homogeneous conditions a number of methods using basic catalysts that operate in heterogeneous systems can be employed profitably to carry out a conjugate addition.Basic alumina is a formidable promoter of such nucleophilic additions that can be accomplished even in solvent-less conditions.

Scheme 7
Amberlyst A21 is a macroreticular resin that is particularly efficient in promoting conjugate addition of nitro derivatives 1 to acrylate esters 29 (Scheme 8). 37The resulting adducts 30 can be easily converted into the 1,4-dicarbonyl compounds 31.

Scheme 9
Allylrethrone 39 is an important component of an insecticidal pyrethroid and its preparation can be realized in three distinct steps, starting from the nitroalkene 36 and methyl vinyl ketone (Scheme 10). 39The obtained Michael adduct 37 is converted into the diketone 38 by a hydrolytic Nef reaction and is then cyclized to allylrethrone 39 under basic conditions.Alternatively, the same process can be realized in a 'one-pot' reaction, using hydrogen peroxide to carry out the nitro to carbonyl conversion.

Scheme 10
The ability of DBU to promote a conjugate addition of nitroalkanes to enones as well as a Nef reaction on secondary nitroalkanes, can be used in a tandem process that permits the direct synthesis of γ-diketones and γ-keto esters 40 (Scheme 11). 40

Scheme 11
The allylic acetates 41 obtained from the Baylis-Hillman procedure, react with nitroalkanes through a conjugate addition-elimination process that leads to the formation of the unsaturated esters 42. 41An hydrolytic nitro to carbonyl conversion on these compounds efficiently affords the (E)-alkylidene-1,4-diketones 43 (Scheme 12).

Scheme 12
A related procedure involves ethyl (2-bromomethyl)acrylate 44 as a Michael acceptor that behaves similarly to the acetates 41 in the reaction with nitroalkanes, giving the nitro derivatives 45.The nitro group is then transformed into keto ester 46 by a procedure involving hydrolytic cleavage.A subsequent reduction with NaBH 4 in the presence of Na 2 HPO 4 leads to the corresponding alcohol that by a spontaneous lactonization gives exo-methylene butyrolactones 47 in good overall yields (Scheme 13).

Scheme 13
The enedione system is present in many natural products having an interesting biological activity.Conjugate addition of the chiral nitroacetate 48 to methyl propiolate gives the corresponding adduct 49 that is converted into the enedione 50 by a McMurry reaction involving utilization of TiCl 3 . 43This derivative can be converted into optically active (R,R)-(-)pyrenophorin 51, an antifungal macrolide dilactone (Scheme 14). 44A related strategy is also effective for the total synthesis of macrolide (R)-patulolide A. 45

Scheme 14
The cyclopentenone unit is a common motif in a wide array of biologically active substances.The cyclopentenone 52 reacts with nitromethane giving a trans-substituted nitro derivative that is protected at the carbonyl group as the ketal 53.A Nef reaction on 53 using TiCl 3 gives the aldehyde 54 which is converted into the cyclopentenone 55, which shows algicidal properties (Scheme 15).Primary nitroalkanes can be transformed into aldehydes or carboxylic acids depending on the method used to perform the Nef reaction.The aldehydes 57 can be obtained in good yield by oxidation of the potassium nitronate of primary 4-nitro esters 56 using dimethyldioxirane, a reagent that can be prepared readily by reaction of Oxone ® with acetone (Scheme 15). 47

Scheme 16
Buffered permanganate solutions (pH = 11) can oxidize primary nitroalkanes such as 58 into alkanoic acids 59 without affecting other functions such as esters, amides, primary alcohols or acetals (Scheme 17). 48This procedure is particularly useful in the preparation of monoesters of 2substituted succinic acids. 49

Scheme 18
Nitro-olefins can be converted directly into carbonyl derivatives using reductive methods. 51,52he chiral nitroenamine 62, obtained from L-proline, reacts with the zinc ester enolate 63, giving the corresponding adduct 64.The chiral nitroolefin lactone 64 can be transformed into the keto lactone 65 by a tandem nitroolefin reduction-nitronate hydrolysis (Scheme 19).The keto group is cleaved to the parent carboxylic acid 66 by a haloform reaction and ultimately leads to (S)ethosuximide 67. 53

Scheme 19
The same strategy can be used in the total synthesis of the oxindole alkaloid (-)-horsfiline 71.Protection of the indole nitrogen and reduction of nitroolefin 68 affords the nitroalkane 69 that is converted into the carboxylic acid 70 with NaNO 2 .Further synthetic transformations lead to the preparation of (-)-horsfiline 71 (Scheme 20).

Scheme 20
Propargylation of the nitroalkenes 72 can be realized using (tributylstannyl)allenes in the presence of TiCl 4 . 55Nitronates 73 obtained as intermediates can be hydrolyzed to the corresponding ketones 74 using 3N HCl.The obtained α-propargylic ketones 74 are precursors of useful building blocks such as the 1,4-diketones 75 (Scheme 21). 75

Scheme 21
The chiral imine 76 obtained from 2-methylcyclopentanone reacts with 2-nitropropene in a highly regioselective fashion giving a diastereomeric mixture of epimers at C-2, 77.The subsequent Nef reaction carried out by acidic hydrolysis of the nitronate anion affords the diketone 78 in 95% ee (Scheme 22). 56

Scheme 22
The high reactivity of 2-nitropropene allows its reaction even with the silyl enol ether 79 in the presence of SnCl 4 to give the corresponding adduct, which is converted into diketone 80 using Oxone ® (Scheme 23). 57This compound is then transformed by an intramolecular aldol condensation into the bicycloketone 81 that is an important intermediate for the synthesis of polyquinane derivatives.

Synthesis of 1,4-dicarbonyls using a nitroaldol and alkylation reactions
The products obtained from a nitroaldol reaction are usually 1,2-nitro alcohols, unless these derivatives undergo elimination of water under the reaction conditions to afford the corresponding nitroalkenes. 58At this point, the introduction of a carbonyl group in the molecular framework can be realized by oxidation of the hydroxy group of the nitro alcohol, followed by a reductive denitration in order to eliminate the nitro group.Alternatively, the nitro group in the nitroalkene moiety can be converted directly into a carbonyl group by the usual Nef reaction.Condensation of the nitro dioxolane 82 with aldehydes 83 affords the corresponding nitro alcohols that can be oxidized in a 'one pot' procedure to the parent nitro ketones 84 (Scheme 24). 59,60This derivative can be denitrated using a procedure that involves its conversion into a tosylhydrazone 85 followed by reduction with LiAlH 4 . 61

Scheme 24
The ability of the nitro group to act as a good leaving group in elimination reactions can be used for the preparation of (E)-enediones that are valuable intermediates for the synthesis of biologically active compounds.(E)-Non-3-ene-2,5-dione 92 is the main component of the volatile compounds obtained from the cephalic secretion of workers of Trigona tataira.Nitroaldol reaction between aldehyde 88 and the nitro alcohol 89 affords the corresponding nitro diol 90 that upon oxidation under phase-transfer conditions of the hydroxy groups, leads to the nitro diketone 91 (Scheme 25). 62,63Base-assisted elimination of nitrous acid from compound 91 allows the total synthesis of enedione 92 in 70% overall yield.

Scheme 25
As previously stated, nitroalkenes such as 94 can be obtained directly by a nitroaldolelimination that can be carried out in a 'one pot' process from nitro derivative 93 and various aldehydes 83 (Scheme 26). 64Reduction of the nitroalkene double bond using NaBH 4 produces an intermediate sodium nitronate that can be oxidized using hydrogen peroxide in basic conditions to give ketone 95.The second carbonyl unit can be introduced by a Wacker oxidation using molecular oxygen in the presence of catalytic amounts of PdCl 2 and CuCl 2 thus affording the 1,4-diketone 96.NO

Scheme 26
Although C-alkylation of nitronate anions is a less common process than the nitroaldol condensation, it can be particularly effective in intramolecular reactions.Ring-closure, of the nitroiodide 97, using NaH to generate the nitronate anion, affords the nitrocyclohexane 98 that is converted into the cyclohexanone 99 using TiCl 3 .(Scheme 27). 65,66

1,5-Dicarbonyl and 1,6-dicarbonyl derivatives
2-Nitro-ketones form the corresponding nitronate anion in weakly basic conditions, as a result of the additional activating effect of the carbonyl group. 67,68The nitro group in 2-nitro ketones is particularly prone to undergoing a radical-induced denitration using Bu 3 SnH, giving rise to the corresponding reduction product. 69Michael addition of the α-nitro ketones 101 with enones affords the nitro diketones 102 that upon denitration give the 1,5-dicarbonyl derivatives 103, usually in good yield (Scheme 28).

Scheme 28
The conjugate addition of 2-nitro ketones is usually carried out in basic conditions, 72 but the easy enolization of these compounds offers the opportunity to realize this process even under solid acidic catalysis by SiO 2 . 73he nitroaldol condensation can be used to prepare 1,5-dicarbonyl derivatives from 1,4homologues.Reaction of aldehyde 104 with 1-nitrododecane followed by dehydration gives the nitroalkene 105 (Scheme 29). 74The nitroalkene 105 is then converted into the ketoester derivative 106, a pivotal intermediate for the synthesis of the pancreatic lipase inhibitor tetrahydrolipstatin, 107.

Scheme 29
Organozinc reagents bearing a terminal ester function can be profitably used for the preparation of the 1,6-dicarbonyl compound 109 by reaction with nitroalkenes 108 followed by a Nef reaction (Scheme 30). 75 NO 2 ZnI CO 2 Et 1.

Scheme 30
The nitroalkene 110 is a common product obtained by a nitroaldol-elimination reaction that under a reductive Nef reaction gives the keto ester 111 in satisfactory yield (Scheme 31). 76The alkyl appendage linked to the keto group can be suitably changed using different aldehydes during the nitroaldol reaction.A retro-nitroaldol reaction on the nitrocyclohexanol 112 gives the open-chain nitro ketone 113 that undergoes a tandem Michael addition-Nef reaction upon reaction with NaOMe, followed by quick acidification with H 2 SO 4 to give the keto ester 114.This derivative is a key intermediate in the synthesis of optically active (R)-α-lipoic acid 115 (Scheme 32). 77

Scheme 32
The dianion of the β-enamino ketone 117, prepared from 116, reacts with nitrostyrene 118 at low temperature giving the corresponding nitronate adduct 119.Upon quenching of this intermediate at 0°C with 2N H 2 SO 4 , the initially formed aldehyde, 120, undergoes a rapid cyclization to the dihydropyrrole 121 in 60% overall yield (Scheme 33). 78

α,ω-Dicarbonyl derivatives by ring cleavage of 2-nitrocycloalkanones
Retro-Claisen condensation of 2-nitrocycloalkanones represents a straightforward route to functionalized terminal nitro esters. 79Coupling the ring cleavage of the cycle with a Nef reaction allows a direct preparation of α,ω-diester derivatives having an alkyl chain length that depends on the ring size of the starting 2-nitrocycloalkanone. Potassium persulfate in methanol in the presence of sulfuric acid is able to cleave the 2-nitrocycloalkanones, 122, giving the corresponding α,ω-dicarboxylic acid methyl esters 123 (Scheme 34). 80The utilization of hydrogen peroxide in the presence of potassium carbonate starting from compounds 122 allows the preparation of α,ω-dicarboxylic acids and keto acids.

Scheme 36
A related procedure using different nitro esters 131 allows an efficient synthesis of [n+2]keto esters 132 (n = 1-3) (Scheme 37). 84ethyl 8-nitrooctanoate 133 can be used as starting material for the preparation of (E)-9oxo-2-decenoic acid 137, an important sex attractant of the queen bee, also implicated as a pheromone of termites (Scheme 38). 85The overall procedure involves a nitroaldol reaction of 133 with acetaldehyde to give nitro alcohol 134 that is oxidized to the corresponding 2-nitro ketone 135.Reductive denitration of compound 135 gives the 9-ketoester 136 that is subsequently converted into acid 137 in few steps.

Scheme 41
The 2-nitrocycloalkanones 122 react with enones in the presence of triphenylphospine to give the Michael adducts 148 that, by the simple addition of a methanolic solution of KOH, are cleaved to the corresponding open-chain nitronate anions 149 (Scheme 42). 90,91These intermediates undergo a Nef reaction using KMnO 4 to afford the triketo derivatives 150.This overall transformation is realized in a 'one-pot' procedure and avoids the isolation of any intermediates.

Scheme 42
An unusual behavior can be observed upon reaction of the nitroalkanes 1 with dimethyl citraconate 151 in the presence of DBU.As observed by 1 H-NMR analysis, in the presence of DBU there is an equilibrium between 151 and its regioisomer 152 that is probably more reactive towards Michael addition with nitroalkanes.The adducts 153 formed by the usual conjugate addition are therefore subsequently transformed into the keto diesters 154 by a Nef reaction (Scheme 43). 92

Scheme 43
Stable-isotope-labeled L-glutamic acid can be prepared from 13 C-enriched compounds, following a strategy involving the conjugate addition of ethyl nitroacetate 155 to ethyl acrylate.Oxidative Nef conversion of the 2-nitroglutarate 156 to diethyl 2-oxoglutarate, and ester hydrolysis, gives 2-oxoglutaric acid 157.This diacid is transformed into L-glutamic acid 158 using the commercially available enzyme glutamic dehydrogenase, in the presence of ammonium ions (Scheme 44). 93

Conclusions
Many synthetic approaches directed to the preparation of dicarbonyl derivatives enjoy the utilization of nitroalkanes as useful reagents for building up the alkyl framework.Conjugate addition to electron-poor alkenes and nitroaldol condensation are the most exploited procedures to attain this important result.The ability of the nitro group to be converted into a carbonyl group represents the key step of most of the procedures devoted to the preparation of 1,4-dicarbonyl derivatives.This synthetic opportunity is not limited to simple nitroalkanes but can be extended to nitroalkenes, easily obtained by dehydration of the corresponding nitro alcohols.In functionalized reagents such as 2-nitro ketones, the nitro group in the final adduct can be easily removed by reductive denitration or elimination as nitrous acid allowing the preparation of dicarbonyl compounds having a variable distance between the carbonyl groups.All these procedures involving the utilization of nitroalkanes as pivotal reagents for the synthesis of dicarbonyl compounds make the use of these nitrogenated derivatives a formidable tool in organic chemistry.
This intermediate can be transformed into (+)-podocarpic acid 100 in a few steps.
83carboxylic acids or their methyl monoesters such as 125 can be obtained regioselectively starting from 2-nitrocycloalkanones 124 using Oxone ® in buffered conditions.The carbon atom originally bearing the nitro group is always converted into a free acid function (Scheme 35).82Suchunsaturatedderivatives are transformed into ketones 129 and, upon cleavage of the dioxolane ring, are finally converted into 1,n-diketones 130 (Scheme 36).83 88,89gate addition of 2-nitrocycloalkanones 122 to acrolein gives the corresponding aldehydes 138 that upon reduction with NaBH 4 afford alcohols 139 (Scheme 39).86An intramolecular retro-Claisen cleavage promoted by NaH allows the preparation of macrolactones 140 that are converted into keto esters 141 by oxidative Nef reaction using cerium ammonium nitrate (CAN).The strategies described above for the preparation of 1,n-dicarbonyl derivatives are often amenable for the synthesis of compounds containing three or more carbonyl groups.Double conjugate addition of nitromethane to enones 142 followed by in situ Nef reaction of the resulting adducts provides a straightforward entry to 1,4,7-triketo derivatives 143 (Scheme 40).87Reaction of the γ-nitro ketone 144 with cyclic β-ketoesters 145 directly affords bicyclic compounds 146 through a conjugate addition-aldol condensation reaction (Scheme 41).88,89These derivatives are important precursors of the germination stimulant strigol and its synthetic analogs.