Nitro Review
Nitro Review
Nitro Review
Introduction
This review covers areas of current interest in the use of nitro compounds and related derivatives. It is complementary to two reviews published in Contemporary Organic Synthesis.1 The research covered concentrates on new methodology, novel transformations and the intermediacy of nitro and related groups in the synthesis of biological targets. 2 2.1 Nitro compounds Aryl nitro compounds
A wide variety of primary aromatic amines, incorporating electron donating or electron accepting substituents are oxidised by the action of tert-butyl hydroperoxide as oxidant, in the presence of the catalyst zirconium tetra-tert-butoxide, to the corresponding aromatic nitro compounds in 3394%. The mild reaction conditions and commercial availability of the reagents make this an attractive method.2 1-Nitrofuranyl-3-sulfolene 2 has been prepared from furanyl3-sulfolene 1 using the new nitration conditions of nitrosyl tetrauoroborate and silver triate in acetonitrile in 37% yield (Scheme 1). The substitution did not markedly reduce the performance of the furan moiety in subsequent DielsAlder studies.3
Scheme 1
3-Nitrothiophene and other heteroaromatic nitro compounds have been synthesised by direct treatment of the corresponding organolithio or Grignard derivatives with dinitrogen tetroxide in 5787% yields. The mechanism is believed to proceed by dinitrogen tetroxide oxidation of the anion to a radical, followed by the radicals combination with NO2 (or N2O4).4 A new methodology for the synthesis of 3-nitropyridines, by dinitrogen pentoxide and a nucleophile (sulfur dioxide or sodium bisulte) in tetrahydrofuran or nitromethane mixtures has been studied. The nitration proceeds via the N-nitropyridinium salt and subsequent reaction with an aqueous solution of the nucleophile to furnish the intermediate 1,4dihydropyridine adduct which breaks down under the reaction conditions to the 3-nitropyridines in 768% yield.5,6 Another approach to 3-nitropyridines is described in section 4. The easily prepared dinitrogen tetroxide complexes of iron and nickel nitrates have been shown to selectively mono- or di-nitrate phenolic compounds in high yields. The process requires short reaction times and utilises simple work-up procedures to give the products in 62100%.7 Lanthanide triates have been used to catalyse the nitration of a range of simple aromatics with 69% nitric acid in an atom ecient process. The catalyst can be readily recycled and the only by-product is water.8 However, the substrate range is limited to mildly electron decient aromatics. Hydrated group metal triates (e.g. Hf or Zr) also catalyse similar nitrations, with greater catalytic activity. Hence nitration of o-nitrotoluene has been achieved using a combination of the catalyst and 1 equivalent of nitric acid, giving approximately a 2 : 1 mixture of 2,6- and 2,4-dinitrotoluene in 92% yield and >95% conversion.9 Various lanthanide nitrates have been used in the nitration of 3-substituted phenols to give regioselectively the 3-substituted 5-nitro derivatives. All the intermediates investigated had the oxygen of the phenol coordinated to the lanthanide() ion, and it is this eect that is thought to give the observed meta-selectivity in the nitration, irrespective of whether the substituent on the phenol is electron donating or withdrawing.10 The selective nitration of 4-hydroxybenzaldehyde to give the 3-nitro derivative has been achieved using iron() nitrate and a clay (dealuminated or natural) in quantitative yield. It is not necessary to support the iron() nitrate on the clay and it is suggested that the acidic nature of the clay acts in a catalytic role.11 A novel, mild system for the direct nitration of calixarenes has been developed using potassium nitrate and aluminium chloride at low temperature (0 C). The side products of decomposition seen when using more conventional, harsher conditions, such as sulfuric acidnitric acid mixtures, are not observed in this system and the p-nitrocalixarenes can be easily isolated in yields of 7589%.12 Nitrating mixtures have been developed to selectively nitrate azatricyclic systems 4 in novel positions. Classical nitrations, using potassium nitrate and sulfuric acid gave mainly the 9nitro derivatives 5, via the nitrosyl cation. However, the use of tetrabutylammonium nitrate (TBAN) and triuoroacetic J. Chem. Soc., Perkin Trans. 1, 1999, 749764 749
anhydride (TFAA) gives exclusively the 3-nitro compounds 3 (Scheme 2). It is suggested that the nitrating species in this case is the nitrosyl radical, generated from the homolytic decomposition of the TBAN/TFAA adduct. These 3-substituted derivatives have proved to be useful in the synthesis of potent farnesyl transferase inhibitors.13
(5098%) (vide supra, aryl nitro compounds).20 CH acidic nitro compounds are not epimerised under the mild reaction conditions. A facile synthesis of fully saturated 2-nitrosugar derivatives from the corresponding amino derivatives utilises a m-chloroperbenzoic acid and sodium sulfate reagent system, giving the products in excellent yields (6888%).21 A novel oxidation of a variety of oximes to nitroalkanes uses a molybdenum() oxodiperoxo complex in acetonitrile to give the products in 5092% yields. The only exception was uoren9-one oxime which gave the corresponding nitro derivative in only 25% yield, the main product being uoren-9-one.22 The conversion of oximes 9 into halonitro compounds 10 has been performed in one-step using the chloroperoxidase isolated from the fungus Caldaromyces fumago in aqueous media in the presence of halide ions and hydrogen peroxide (Scheme 4). The reaction proceeds in 2382% yield but is accompanied by the formation of the corresponding ketone 11.23
Scheme 2
Scheme 4
Polynitrobenzene has been prepared from poly(N,N-dimethylaniline) by the action of nitric acid in acetic anhydride in 94% yield.14 Aryl nitro compounds are converted into N-monosubstituted formamides by the action of metallic tin and formic acid in toluene heated to reux (2686%).15 A silane mediated double condensation of nitroarenes 6 with allylic cations, formed from cinnamyl derivatives 7, can be used for the synthesis of fused 6-membered nitrogen heterocycles 8. Yields ranging from as low as 13% to as high as 87% have been obtained (Scheme 3).16
The formation of a range of synthetically useful nitroalkenes has been achieved from the corresponding alkenes by their reaction with nitric oxide in the presence of zeolites with yields of 6881%.24 The use of the inexpensive zeolites also results in a simple work-up and ready separation of the products. The lack of corrosiveness and the ability to regenerate and re-use the catalyst make this an attractive system. N-Hydroxyphthalimide has been shown to catalyse the nitration of adamantane, under an atmosphere of nitric oxide and dioxygen in benzonitrile.25 In the absence of dioxygen the corresponding benzamide is formed. Nitration of the steroid canrenone 12 using acetic anhydride with nitric acid occurs at the 4-position in 52% yield (Scheme 5). Most other reagent systems tend to react at the 6 position. The unexpected product 13 gave enhanced inhibitory activity against the target enzyme.26
Scheme 3
The reductive cyclisations of 2-nitrobenzaldehydes (or 2 nitroacetophenone) to 2,1-benzisoxazoles can be accomplished in the presence of 2-bromo-2-nitropropane and zinc in methanolic solution in yields of 3898%.17 A low yielding (24%) synthesis of an indole utilizing the reaction of vinylmagnesium bromide with an arylnitro compound has been reported.18 A comparative study of the reaction time and yields of the nitration of selected heterocyclic compounds using microwaves and conventional heating has been reported. A range of inorganic nitrates in glacial acetic acid were investigated with copper() nitrate proving to be the superior reagent. In all cases the products were obtained in improved yields and in shorter reaction times using microwave radiation rather than those synthesised by heating. The procedure is cited as a safer and more convenient method for the nitration of heterocycles.19 2.2 Alkyl nitro compounds
Scheme 5
A facile, regioselective synthesis of the synthetically versatile -iodo--nitroalkenes 15 from acetylenes 14 has been developed (Scheme 6) using sodium nitratepotassium iodide mixtures. The method gives predominantly (E) products in 972% overall yield. This system is safer than the previously used, highly toxic mixture of iodinedinitrogen tetroxide and the method can be applied to substituted and terminal alkynes.27
The oxidation of primary aliphatic amines has been achieved using the same catalyst system based on zirconium tetratert-butoxide and tert-butyl hydroperoxide on molecular sieves 750 J. Chem. Soc., Perkin Trans. 1, 1999, 749764
Scheme 6
A substituted 2,2,4-trinitro-2,5-dihydro-thiophene 1,1dioxide 17 has been synthesised from the corresponding 2oxime derivative 16 using nitric acid in 49% yield (Scheme 7).28 Primary nitroalkanes (or primary alkyl bromides) can be readily converted into the corresponding carboxylic acids in a novel transformation utilizing sodium nitrite in acetic acid dimethylsulfoxide. Yields of the corresponding acids from 72 to 96% are observed.29
Scheme 7
The oxidation of secondary nitro compounds to the corresponding ketones can be achieved in 5289% using a catalytic amount of TPAP (tetrapropylammonium perruthenate) in combination with the co-oxidant N-methylmorpholine N-oxide and in the presence of silver acetate, potassium carbonate and 4 molecular sieves in acetonitrile.30 Primary nitro compounds are converted into nitriles in 5186% yield by the action of a mixture of isocyanides with isocyanates in the presence of a base. The reaction is believed to proceed through an in situ formation of a nitrile oxide followed by fast oxygen transfer with the isocyanide.31 2.3 - and -Substituted nitro compounds
Scheme 9
A catalytic asymmetric nitroaldol reaction has been used to generate a key intermediate 26 in the synthesis of (R)arbutamine, a pharmacological stress agent, in 93% yield and with an enantioselectivity of 92% ee (Scheme 10). The condensation of nitromethane 25 with a suitably protected benzaldehyde 24 is promoted by a heterobimetallic asymmetric catalyst, lanthanide lithium (binaphthoxide) (where the lanthanide is typically gadolinium or samarium).36
The nitroaldol (Henry) reaction has been performed with a variety of substrates in aqueous media to give yields of 6694% in short reaction times. This system of sodium hydroxide and cetyltrimethylammonium chloride (CTACl) is applicable for large scale.32 The methodology is compatible with several functional groups and has also been utilised in the conjugate addition reactions of nitroalkanes with electrophilic alkenes. Good yields (5090%) are obtained, even with hindered substrates.33 A diastereoselective modication of an intramolecular nitroaldol cyclisation has been used as the key-step in the synthesis of the C-ring of the valuable anti-tumour alkaloids pancratistatin and trans-dihydrolycoricidine. The desired nitroaldehyde 18 was cyclised in the presence of alumina to give the required diastereomer 19 with a diastereoselectivity of 90% de (Scheme 8), opposite to that seen in the base promoted case.34 The mechanism is proposed to proceed via a chelation controlled chair-like 6-membered transition state.
Scheme 10
A new catalytic asymmetric approach to the Michaeladdition of -nitroesters to ,-unsaturated esters has been developed using Al-Li-(R,R )-2,2 -dihydroxy-1,1 -binaphthyl (AlLiBINOL) as a heterobimetallic chiral catalyst.37 The synthetically useful products are produced in high yields (81 87%) with the enantioselectivity proving to be extremely dependent upon temperature and solvent. Potential precursors 29 and 30 of Erythrina alkaloids can be assembled in a 6-membered annulation reaction, by sequential 3-allylpalladium alkylationMichael addition of a lithium nitronate 27 and diester 28 (Scheme 11).38
Scheme 8
The key-step in the synthesis of 1,4-dideoxy-1,4-imino-mannitol (DIM) 23 and other amino analogues is the diasteroselective Henry reaction of either enantiomer of 2-O-benzylglyceraldehyde 20 with an optically active nitro compound 21 (Scheme 9).35 This is a useful strategy for the synthesis of iminopolyols.
Scheme 11
751
2.4
Diastereo- and enantioselective syntheses of protected vicinal diamines 34 from ,-unsaturated nitro compounds have been developed to give these synthetically useful compounds in 5981% yields with high enantioselectivity (9396% ee). The process proceeds via aza-Michael addition of a novel chiral ammonia equivalent 32 to nitroalkenes 31 (Scheme 12). The chiral auxiliary, a functionalised pyrrolidine, is removed by reductive NN bond cleavage with Raney nickel, which also reduces the nitro group in situ.39
Scheme 14
Scheme 15
Scheme 12
In a similar strategy, a highly stereoselective conjugate addition of the potassium salt of (R)- or (S)-4-phenyl-1,3oxazolidin-2-one 35 to various nitroalkenes 31 has been achieved.40 The products of these additions 36 are useful precursors for the synthesis of --amino acids 37 (Scheme 13), and can be easily converted to the corresponding amino acids in 699% yields with high enantiomeric purity (>95% ee).41
lactone via an additionelimination process of a chiral nitroenamine to the zinc enolate of the lactone, leads to ( )- and ( )-ethosuximide, pharmacologically active targets.44 An extension of this work, focussing on 3-substituted 2-oxo-2,3dihydroindoles 47, leads to other interesting targets, notably ( )-esermethole, a precursor of the clinically important physostigmine, used to treat glaucoma. The steric bulk of the side chain on the nitroenamine 46 has a dramatic eect on the stereoselectivity of the nitro-olenation (Scheme 16).45
Scheme 13
Octahydrobenzo[b]furans 41 have been constructed via tandem conjugate addition of 1-nitrocyclohex-1-ene 38 with 4-hydroxybut-2-ynoates 39 in 32100% yields. The reaction is thought to proceed by an initial addition of alkoxide to the nitroalkene followed by a second addition of the resulting anion to the conjugated ester (Scheme 14). Pyrroles 44 have been obtained by the cycloaddition of suitably functionalised ,-unsaturated nitro compounds 42 and isocyanates or tosylmethyl isocyanide (TosMIC) 43 in 6198% yields (Scheme 15).43 The methodology aords trisubstituted pyrroles with electron withdrawing groups which are dicult to prepare directly from pyrroles. The pyrroles themselves are biologically useful compounds in their own right, and are useful intermediates for the preparation of porphyrins. An improved method for the construction of an asymmetric quaternary carbon at the -position of a lactone has been reported. Asymmetric nitro-olenation of -methyl--butyro752 J. Chem. Soc., Perkin Trans. 1, 1999, 749764
Scheme 16
Various disubstituted -nitroalkenes 49 can be converted into the corresponding aziridines 51 by the action of ethyl [(4-nitrobenzenesulfonyl)oxy]carbamate 50. The use of calcium oxide, in place of triethylamine, allows equimolar amounts of the reagent to be used in solvent-free, environmentally friendly conditions giving yields of 489% (Scheme 17).46 It is noted that higher stereoselectivity, but poorer yields, can be achieved by thermolysis of ethyl azidoformate. 1,2-Diamines are conveniently prepared in a two step, one-pot procedure from nitro-olens. The method initially
Nitramines
When N-nitropyridinium nitrate 59 is treated with sodium hydroxide then the stable sodium salt of 5-nitraminopenta-2,4dienal 60 is formed. The reaction of this sodium salt with sodium bisulte at pH 4 leads to the formation of 3nitropyridine 61 (Scheme 20).51
Scheme 17
relies on a Michael addition of an O-alkylhydroxylamine to the nitro olen followed by a reduction of the resultant -nitrohydroxylamine species. This is conducted practically by treating the nitro olen with O-alkylhydroxylamine hydrochloride and sodium hydrogen carbonate in tetrahydrofuran. Once the Michael addition is complete, palladium on carbon and ethanol are added and the resultant mixture stirred under an atmosphere of hydrogen. This one-pot procedure gives 1,2-diamines in 7792% yield.47 3 Nitrate esters
Scheme 20
A novel route to 4-alkoxytrinems has been devised using the intermediacy of the 4-nitrate ester as a masked alcohol (Scheme 18). The nitrate esters 53 were obtained by the regioselective opening of the corresponding epoxides 52 with ceric ammonium nitrate (CAN) in acetonitrile. Removal of the nitro protecting group by catalytic hydrogenation revealed the free hydroxy group at the end of the synthesis. This strategy was used because the direct opening of the epoxides was only successful with simple alcohols.48
Photolysis of the nitramine 62 results in formation of the p-nitro-N-methylaniline 63 and o,p-dinitro-N-methylaniline 64 in approximately equimolar amounts (Scheme 21). The nature of the solvent and the presence or absence of oxygen inuences the product composition range in photolysis of N-nitroso and N-nitro anilines.52
Scheme 21
Scheme 18
The 11-nitrate esters of estrone acetates have been synthesised by CAN absorbed onto silica gel in yields of 2439%.49 A study of the factors that inuence the formation of carbon-centered amino acid radicals 57 has been reported. The radicals themselves are derived from the -scission of -alkoxy amino acid radicals 55 which are in turn formed by the action of tin hydrides on the corresponding -nitrate esters 54 (Scheme 19). The rates of -scission relative to the competing H-abstraction have been studied.50 The new strategy could be used for the generation of radicals in peptides, where other methods would lack this regioselectivity.
-Nitroxyalkylnitramines have been prepared by the action of a mixture of sulfuric and nitric acids on the corresponding potassium sulfonamide salts.53 Dinitrogen pentoxide has been used in an inert solvent as a nitrating agent for silylamines (and silyl ethers). The resultant nitrodesilylation reaction leads to nitramines (and nitrate esters) in 3791% yield. [CARE! The authors recommend the use of an armoured cupboard for these nitrodesilylation experiments].54 5 Nitroso compounds
A study on the nitrosation of simple aromatics has demonstrated the regioselective nature of the reaction in triuoroacetic acid or acetic acidsulfuric acid mixtures. The nitroso products can be simply oxidised to the corresponding nitro compounds, and hence provide a selective nitration method. The accompanying, non-selective nitrous acid catalysed nitration can be avoided by the use of nitric oxide as a purging gas.55 A novel method for the preparation of 5-substituted oxadiazole-3-carboxylates has been developed utilising the nitrosation of the corresponding 3-dimethylaminopropenoates 65 (Scheme 22). The resulting alkyl N-acyl substituted hydroxyimidic acids 66 aord the oxadiazoles on treatment with aqueous acid.56
Scheme 22
Scheme 19
Various arenesulfonyl hydrazines have been nitrosated by the new nitrosating agent sodium hexanitrocobaltate(), Na3Co(NO2)6, giving the corresponding azides in 6096% J. Chem. Soc., Perkin Trans. 1, 1999, 749764 753
yields in aqueous solutions. Aromatic amines produced diaryltriazines (8699%) but aliphatic amines were not nitrosated, the substrates forming a complex with the reagent.57 A synthesis of 2,5-disubstituted thiazolines 69 has been developed by the cyclisation of -chloronitroso compounds 68 and N-allylthioureas 67; oximes 70 are obtained as by-products (Scheme 23).58
N-nitrosation. Treating a polyfunctional amide with dinitrogen tetroxide leads to the nitrosamine. The nitrosamine is then treated with lithium hydroperoxide and reduced with sodium sulte to give the carboxylic acid in 78% overall yield.62 N-Nitrosamides can be synthesised from the corresponding amide by a reaction with nitric oxide in aprotic and nonethereal solvents in yields of 1195%.63 7 Nitrones
Scheme 23
A novel, asymmetric synthesis of a synthetically useful amino alcohol 74 has been approached via the hetero Diels Alder reaction of a chloronitroso compound derived from -mannitol 71 and cyclopentadiene 72 (Scheme 24). The intermediate bicyclic compound 73 is produced in 64% yield with 84% ee, and is easily converted into the functionalised amino alcohol.59
-N-Diaryl nitrones have been synthesised from the Montmorillonite clay catalysed condensation of the respective aryl ketone and aryl hydroxylamines in 7385% yields.64 The reactions are very clean and the catalyst is easily recycled. N-Butylidenebutylamine N-oxide has been synthesised by the electro-oxidation of the corresponding N-hydroxylamine. The system used consists of sodium tungstatesodium bromide di-H-sodium orthophosphatedioxygen in water and is prepared in either divided or undivided cells with very high current eciences (>180%).65 Nitrones have been generated in 6993% yields from the corresponding aldimines by the photooxidation [6 W medium pressure mercury lamp] of a solution of the substrate in acetonitrile containing a titanium dioxide suspension.66 Aldimines are formed from nitrones under reducing conditions, with retention of stereochemistry, when the system is purged of oxygen by nitrogen. Secondary hydroxylamines can be selectively oxidised under mild conditions using polymer supported perruthenate. If dipolarophiles are present then isoxazolidines are produced in a one-pot process in 8191% yields.67 The reaction of methyl nitroacetate 78 with 4-nitronitrosobenzene 79 has been demonstrated to eectively produce a N(methoxycarbonylmethylidene)-p-nitrophenylamine N-oxide 80 in 67% yield (Scheme 26).68
Scheme 24
The reaction of halogenated cyclopropanes with nitrosyl tetrauoroborate furnishes the corresponding isoxazoles in good yields (4397%). The presence of the halogen groups in the substrate leads to the formation of the fully aromatised products.60 The nucleophilic addition of nitroso compounds 76 to conjugated azoalkenes 75 generates the corresponding substituted pyrazol-5(4H)-ones 77 in one-pot, with yields of 5293% (Scheme 25).61
Scheme 26
Scheme 25
Nitrosamines
A new method for the hydrolysis of secondary amides to carboxylic acids uses a sequence of reactions based around 754 J. Chem. Soc., Perkin Trans. 1, 1999, 749764
Two discrete methods for the synthesis of chiral nitrones from the corresponding chiral O-protected -hydroxy nitriles have been developed. The rst involves the one-pot reduction transimidation with a suitable hydroxylamine to give the aldonitrone in 8299% yields with 9799% ee. In the second, ketonitrones are produced by a one-pot Grignard addition transimidation sequence (4751% yield, 9799% ee).69 The chiral, cyclic nitrone 83 is the minor component (30% yield) of the condensation of hydroxylamine, dimethyl acetonide and the isopropylidene derivative of -erythrulose 81 via the (Z)-oxime (Scheme 27). The dioxazine 82 (35% yield) arises from the (E)-oxime. Organolithium and magnesium reagents add stereoselectively to the C N bond of 83 and provide useful intermediates 84 for the synthesis of ,-disubstituted -amino acids.70 A mild method for the formation of CN bonds has been developed via the ene reaction of nitrosocarbonyls with substituted olens in yields of 1099%. The nitrosocarbonyls are formed by the mild oxidation of the corresponding nitrile oxides.71 The trimethylsilyl triate-promoted addition of a 2-silyloxyfuran to a nitrone, derived from glycolaldehyde, aords the synthetically useful tetrahydrofuro[2,3-d]isoxazol-5(2H)-ones, after desilylation of the protected intermediate. These products can be modied to furnish polyhydroxylated lactams or piperidines, such as rac-fagomine.72
Scheme 29
resulting carbonyl oxide, the rst reported addition of this kind.80 8 Reduction of nitro groups
Scheme 27
Fully protected N-hydroxy -amino esters have been synthesised in high selectivity in a stereodivergent process in which the key-step involves the addition of an acetylide to a nitrone. The N-benzyl nitrone, derived from isopropylidene--glyceraldehyde, undergoes the addition with high diastereoselectivity, and the subsequent hydroxylamines are converted into the desired products in three further, high yielding steps.73 The rst direct route to 1,3-thiazolidine N-oxides 87 has been achieved by the reverse-Cope cyclisation of suitably substituted allylthiols 85 with nitrones 86 in 7986% yields (Scheme 28).74 Direct oxidation of thiazolidines normally results in the S-oxides.
A brief list of some new methods for the reduction of the nitro group is presented in Table 1. The reduction can be stopped at the hydroxylamine if borohydrides are used in conjunction with suitable catalysts (metallic antimony powder 81 or bismuth() chloride 82), or it can be reduced to the amine. There are several new procedures which are generally mild, tolerate other functionality and proceed in high yields. These procedures include reductions in supercritical carbon dioxide 83 and the use of hydrazine hydrate 84,85 as the hydrogen source in addition to the use of hydrogen gas and a suitable catalyst. A novel allylic amination of cyclohexene 91 has been shown to be catalysed by ruthenium complexes. Reduction of the aryl nitro compounds 90 to give the corresponding anilines is a competing reaction with yields of 2277% of arylallylamine 93 contaminated with 1542% of the aniline by-products (Scheme 30).86
Scheme 28
Scheme 30
The regioselective [3 2] cycloadditions of nitroso compounds and substituted diazabutadienes or amidines aord highly functionalised cyclic nitrones in yields of 7690%. The products can be thermolysed to imidazoles or amidines depending on the substitution pattern.75 The asymmetric addition of alkyl zinc reagents to various nitrones has been achieved by the use of catalytic dicyclopentyl (R,R)-tartrate. The corresponding (S)-hydroxylamines are produced in good yields (8495%) with high selectivity (6394% ee).76 Stereo-complementary amino diols have been synthesised by the stereoselective addition of Grignard reagents to -hydroxy nitrones. The use of zinc bromide and diethylaluminium chloride as precomplexing agents aords the corresponding syn- or anti- adducts respectively, which can be transformed into the required products.77 A similar, stereocontrolled addition of benzylmagnesium chloride to a nitrone 88 derived from phenylalanine using diethylaluminium chloride in diethyl ether gave a high yield (97%) of the desired C-benzylhydroxylamine 89 in excellent diastereoselectivity (94% de) (Scheme 29).78 This product was then used as the 1,3-diaminopropan-2-ol core unit for HIV protease inhibitors. A novel approach to -amino acid derivatives has been developed via the reaction of an optically pure nitrone with a suitable ketene-acetal. (2S,3S)-N-Protected phenylisoserine has been synthesised using this strategy.79 Hydroperoxynitrones have been synthesised by a one-pot process with variable yields (2080%). The reaction involves the tetraphenylporphyrin-sensitised photooxygenation of 2methoxyfuran followed by the addition of an oxime to the
9 9.1
It is clear from Table 2 that one of the most successful uses of the nitro group in cyclisations is exemplied by the work of Denmark where a tandem [4 2]/[3 2] cycloaddition approach is used. Simple variations in the substituents on the nitroalkenes 49 and olens 95 can lead to very dierent products via fused mode, spiro mode or bridged mode constructions. In the bridged mode (-tether) case the inter [4 2]/intra [3 2] sequence may be followed by hydrogenation to give highly functionalised aminocyclohexanes 98 (Scheme 31).95 A similar strategy with the -tethered analogue leads to aminocyclopentanes 99.96
Scheme 31
755
Table 1
Reduction of nitro groups Products Amines Comments Mild procedure using diethyl chlorophosphite and a tertiary amine followed by treatment with hydrogen chloride in methanol with a subsequent work-up using sodium hydroxide. Yields are 2095%. The Cp2TiCl2samarium metal system provides mild and neutral conditions to synthesise anilines in 7391%. Sodium borohydride in the presence of antimony cleanly provides hydroxylamines in 7388% yields. Yields of 5789% are obtained from this partial reduction using potassium borohydridebismuth() chloride. PalladiumDeloxan and hydrogen gas in supercritical carbon dioxide results in a quantitative reduction. The zincaluminium chloride heptahydrate in tetrahydrofuranwater system provides a convenient and mild route to anilines in 7595% yields. Reduction using 200 psi hydrogen over nickel supported catalysts at 110 C in 8594% yields. Reduction using hydrazine hydrate in the presence of iron() oxidemagnesium oxide catalyst. Yields are 96100%. Activated nickel (prepared in situ by the reduction of nickel() chloride with potassium using ultrasound) in the presence of hydrazine hydrate accomplishes the reduction in 90100% yields. A poly[N-(5-hydroxypentyl)pyrrole] lm coated electrode incorporating palladium microparticles has been shown to be highly eective in electrocatalytic hydrogenation in 98100% yields. In situ reduction with Raney Nickel/hydrogen in the presence of the bis-bisulte adduct of glyoxal resulted in the formation of the product in 79% yield. A reductive cyclisation using sodium dithionite followed by hydrogenation on a palladium on carbon catalyst, leads to the formation of the products. If there are two alkyl groups attached to the cyanomethyl group then 6-amino-7,7-dialkyl7H-pyrrolo[3,2-d]pyrimidines result. An intramolecular reductive carbonylation with carbon monoxide under ca. 120 atmospheres pressure, in the presence of a solvent and a catalytic system (sulfur, or a low molecular weight derivative of sulfur, a basic medium and optionally a vanadium() compound). The rate of carbonylation increases with temperature and a yield of 86% is obtained after 4 h at 150 C. Ref. 87
88 81 82 83 89
90 84 85
Nitroarenes
Anilines
91
1,2-Dinitroaromatic
Quinoxaline
92
6-(1-Cyanoalkyl)-5nitropyrimidines
7-Alkyl-5H-pyrrolo[3,2-d]pyrimidines
93
o-Nitroaniline
Benzimidazol-2(3H)-one
94
Indole-3-carbaldehyde oximes 103 act as Michael donors with electrophilic alkenes/alkynes aording isoxazolidines 104 and 105, through a tandem nitrone generation1,3-dipolar cycloaddition process. The highest yielding reaction gave 64% of the desired isoxazolidine (Scheme 33).108 9.2 Cycloadditions involving nitrone groups
N OH O N N H 104 + CO2R2 O N N H 105 CHCH2CO2R2 R1 CHCH2CO2R2 R1
As seen from Table 3 the 1,3-dipolar cyclisation of nitrones onto olens continues to be a tremendously powerful method for the synthesis of isoxazolines. When the nitrone 100 is part of a ring system then bicyclic systems 102 can be readily formed (Scheme 32). The 1,3-dipolar cycloadditions are usually performed by heating but alternative energy sources such as ultrasound or microwave radiation may also be employed. A comparison of these methods has been conducted by Prajapati, Sandhu and co-workers in a limited study.107
CO2R2 CHCO2R2
R1HC N H 103
Scheme 32
Scheme 33
756
Table 2
Nitro cycloadditions Product 6-Substituted 3,3a,4,5,6pentahydrocyclopent[c]isoxazol-5ylphosphates ( )-Crotanecine (after further elaboration) ( )-Platynecine Isoxazolines ( )-Detoxinine ( )-Mesembrine Comments Intramolecular silyl nitronate olen cycloaddition in 4566% yield. Lewis acid promoted tandem [4 2]/intra [3 addition is the key step in the total synthesis. 2] cycloRef. 97
Tandem [4 2]/[3 2] cycloaddition of a nitroalkene with a vinyl ether in 40% yield. Stereoselective one-pot consecutive Michael addition1,3dipolar cycloaddition strategy. Tandem [4 2]/[3 total synthesis. 2] cycloaddition is the key step in this
Construction of the octahydroindole framework of mesembrine features a tandem inter [4 2]/intra [3 2] cycloaddition. High pressure promoted three component one-pot tandem [4 2]/[3 2] cycloaddition of nitroalkenes with enol ethers.
Nitrostyrene or 1-phenyl-2nitropropene
5,6-Dihydro-4H-1,2-oxazine Noxide, hexahydroisoxazolo[2,3b][1,2]oxazine and tetrahydro-4Hfuro[3,2-e][1,2]oxazine N-oxide Functionalised aminocyclopentanes Bicyclic system
103
Tandem [4
2]/intra [3
96 104
Asymmetric tandem cycloaddition of a chiral carbohydrate nitroalkene with ethyl vinyl ether in the presence of an alkene possessing electron withdrawing groups. The spiro mode of the tandem inter [4 cycloadditions. Inter [4 inter [3 2]/intra [3 2]
105 106
2] cycloaddition with a vinyl ether followed by an 2] cycloaddition with an electron decient alkene.
9.3
Nitrile oxides provide ready access to oxazolines via inter- or intramolecular nitrile oxide cycloaddition (INOC) with olens (Table 4). The nitrile oxides are usually prepared in situ from the corresponding nitro compound by the action of an isocyanate in the presence of an amine base (e.g. triethylamine). A variety of dehydration agents have also been successfully employed for the conversion of nitro to nitrile oxides (Burgess salt, DAST, acetic anhydride and oxalyl chloride).140 Nitrile oxides have also been prepared from the action of aqueous sodium hypochlorite on oximes. One example of the INOC procedure has been used to prepare 2-isoxazoline intermediates from aryl aldoximes 106 in the synthesis of 3-arylthienoisoxazoledione 108 (Scheme 34).141
Scheme 35
Scheme 34
10
Miscellaneous
A novel dipolar cycloaddition of the munchnone 3-methyl-2-(4nitrophenyl)-4-phenyl-1,3-oxazolium-5-olate 109 with chiral nitroalkenes 110 derived from -galacto- or -manno-hept-1enitols proceeds to give pyrrole C-nucleosides 111 in satisfactory yields (6569%) (Scheme 35).165 Nitro heteroaromatic compounds (quinoxalines, benzathiadiazoles and benzaselenadiazoles) react with ethyl isocyanoacetate in the presence of DBU (1,8-diazabicylo[5.4.0]undec-7-ene) to give the corresponding pyrimidine N-oxides in 1532% yields. Changing the base from DBU to stronger nonnucleophilic bases (proazaphosphatane or iminophosphorane) resulted in the formation of pyrroles (3046% yield).166 Novel transformations of the imidazole ring in 1-alkyl-4-
nitroimidazole and 1-aryl-4-nitroimidazole following nucleophilic amination by hydroxylamine or 4-amino-1,2,4-triazole result in the formation of 3-substituted-5-alkyl/aryl-oxa-2,4diazole ring systems in 4087% yields.167 In a synthetic approach to 13-azasteroids 114 an intramolecular reductive cyclisation of a nitro group onto a ketone resulted in the formation of a conjugated nitrone 113. This was then able to undergo a thermally induced 1,7-cyclization followed by a multistep rearrangement of the primary cycloallenic intermediate to give the corresponding 13-azasteroid 114 (Scheme 36).168 An improved synthesis for 1-hydroxy-4-nitro-6-triuoromethylbenzotriazole has been demonstrated using the action of hydrazine hydrate on 1-chloro-2,6-dinitro-4-triuoromethylbenzene in 64% yield. Similarly 1-hydroxy-4,6-dinitrobenzotriazole can be prepared from 1-chloro-2,4,6-trinitrobenzene although a reduced yield of 50% is obtained.169 A one-pot synthesis of the benzoxazinecarboxylic acid 116, an intermediate for the antibacterial agent Levooxacin, from J. Chem. Soc., Perkin Trans. 1, 1999, 749764 757
Table 3
Nitrone cycloadditions Product Isoxazoline fused C-60 derivatives Bicyclic isoxazolidine Comments First example of a nitrone cycloaddition onto (60)fullerene in 42% yield. 1,3-Dipolar cycloaddition of chiral acrylates derived from 9-anthrylcarbinol to a cyclic nitrone (major product 52%, 4 diastereomers). 1,3-Dipolar cycloaddition with maleic anhydride is the key step in this total synthesis. Asymmetric 1,3-dipolar cycloaddition of a nitroalkane with a chiral enone stereoselectively provides an isoxazolidine with the desired stereochemistry. 1,3-Dipolar cycloaddition with uorinated olenic and acetylenic compounds in the two phase medium of chloroform aqueous sodium perchlorate. Cyclised products are obtained in 7085%. Ti-TADDOLate catalysed cycloaddition. The structure of the reactive intermediate is discussed. Intramolecular 1,3-dipolar cycloaddition of nitrones to allylsilanes. Asymmetric nitronevinyl sulfoxide cycloadditions. Highly stereospecic 1,3-dipolar cycloaddition of cyclic nitrones with acetylenes. The cyclic nitrone was prepared from -( )-prolinol with dimethyldioxirane. Complete diastereoface dierentiation in the 1,3-dipolar cycloaddition is observed with several 1,2-disubstituted electron decient olens. Improvement of the TADDOLate-titanium() chloride catalysed 1,3-dipolar nitrone cycloaddition reactions by substitution of the oxazolidinone auxiliary of the alkene with succinimide. Yields of 3876% are obtained with an exo : endo ratio of 64 : 36 to 95 : 5. Asymmetric 1,3-dipolar cycloaddition reactions with chiral triuoromethylated ,-unsaturated arylsulfones with nitrones (5880% yields). Microwave induced 1,3-dipolar cycloaddition reactions of nitrones with styrene in yields of 7690%. The asymmetric 1,3-dipolar cycloaddition of nitrones possessing electron withdrawing groups to allyl alcohol was achieved using (R,R)-tartrate as a chiral auxiliary. A short synthetic route to ( )-bulgecinine was established using a 1,3-dipolar cycloaddition of the nitrone with an allylic alcohol. Alkenyl boronic esters undergo regio- and stereoselective 1,3-dipolar cycloadditions with nitrones in 4583% yields. An examination of the hydrophobic eect on 1,3-dipolar cycloaddition reactions (4595% yields). [3 2] Dipolar cycloaddition of nitrones to N-9-vinyladenine (577% yields). Ytterbium() triate catalyses the 1,3-dipolar cycloaddition and gives the highest endo-selectivity. Scandium() triate shows the highest rate accelerations. Chiral ligands result in moderate enantioselectivities (up to 73% ee). Sequential condensation of -lithiosulfones with nitrones to give unsaturated hydroxylamines followed by reverse Cope-elimination (6895% over the two steps). Chiral 6- and 7-membered nitrogen containing heterocycles via intramolecular N-allyl nitrone cycloaddition (7885%). Intermolecular 1,3-dipolar cycloaddition of nitrones onto allyl groups. The nitrones are prepared from secondary amines by the action of sodium tungstate and hydrogen peroxide. Electrogenerated 1-sulfonylcyclobutenes undergo 1,3-dipolar cycloadditions to nitrones in 5082% yields. Facial-, regio- and stereoselective cycloadditions with alkenes in 5590% yields. Ref. 109 110
Antifungal agent SCH-38516 N-Protected (4S)-4-hydroxy -glutamic acid diester Peruorinated isoxazolines and isoxazoles
111 112
Arylaldoximes
113
N-Benzylidenephenylamine N-oxide - or -Unsaturated nitrones Cyclic nitrones -Substituted cyclic nitrones (S)-5-Hydroxymethyl-1pyrroline N-oxide
N-Benzylidenephenylamine N-oxide
Carboxamides
119
Various nitrones
Isoxazolidines
120
Various nitrones Nitrones possessing an electron withdrawing group N-Benzyl--methoxycarbonylmethanimine N-oxide Various N-alkyl and N-aryl nitrones N-Benzylidenephenylamine N-oxide Various nitrones C-Arylnitrones
Isoxazolidines Isoxazolidines
107 121
( )-Bulgecinine
122
Pyrrolidine N-oxides
127
128 129
130 131
758
Table 3
(Contd ) Product Tetrahydropyrans and oxepanes 3-Substituted isoxazolidin-5-one Comments Intramolecular nitronealkene cycloaddition of acyclic 3-O-allylmonosaccharides (4155% yields). Quantitative yield of the [3 2] dipolar cycloaddition product obtained from the nitrone reaction with the sodium enolate of methyl acetate. Reaction of nitrones with electron decient alkynes to give the products in good yield (3090% yields). Intramolecular [3 2] cycloaddition of the nitrone with the alkene in 83% yield followed by reductive cleavage of the NO bond with zinc in acetic acid in 76% yield. 2-Chloro-2-cyclopropylideneacetates undergo a 1,3-dipolar cycloaddition reaction with nitrones in 70% yield. Hydroxylamines bound to a Rink amide resin are condensed with aldehydes to give nitrones which are then trapped with various dipolarophiles. endo : exo selectivity is 3 : 2. [3 2] cycloaddition of phenylnitrone with dec-1-ene to give the desired isoxazolidine in 89% yield (with the undesired trans product in 3%). Intramolecular [3 2] cycloaddition as a technique to provide enantiomerically pure uoromethyl substituted -amino acids. Ref. 132 133
Starting material N-Methylhydroxylamine hydrochloride N-Benzylnitrone derived from -glyceraldehyde N-(Hydroperoxyalkyl)nitrones N-Benzylidene-N-cyclohexyl-C-homoallylnitrone Pyrroline N-oxide Immobilised nitrones
134 135
136 137
Isoxazolidines
138
139
The interaction of camphene 117 with dinitrogen tetroxide in the presence of zeolites leads to a mixture of an isoxazoline 118 in 51% yield and a nitrovinylcamphene adduct 119 in 18% yield (Scheme 38).172
Scheme 38
Scheme 36
a nitrobenzoylacrylate 115 can be accomplished in 92% (Scheme 37). This one-pot sequence occurs after an addition of powdered potassium hydroxide in THF to induce the intramolecular displacement of the nitro group by the vinyl amine to form a quinoline intermediate. This is followed by the addition of an aqueous solution of potassium hydroxide to hydrolyse the acetate and induce a second cyclisation to form the desired intermediate 116.170
2,5-Dimethoxy-6-nitrobenzaldehyde 120 undergoes a cyclisation in the presence of methyl thioglycolate to give 4,7-dimethoxybenzo[b]thiophene 121 in 84% yield. The same cyclisation procedure, using potassium carbonate in dimethylformamide, can also be used for 2,5-dimethoxy-6-nitroacetophenone. The benzo[b]thiophene adducts 121 are useful precursors for benzo[b]thiophene-4,7-quinones 122 (Scheme 39).173 The reaction of 1-ethoxycarbonyl-3-nitroindole 123 with ethyl isocyanoacetate 124 in the presence of DBU gives the
Scheme 37
A synthesis of 2-methyl-5-(methylthio)benzothiazole from the action of acetic anhydride on 1-chloro-2-nitro-4-methylthiobenzene in the presence of sodium sulde in acetic acid and water gives the cyclized product in 67% yield.171
Scheme 39
759
Table 4
Nitrile oxide cycloadditions Product 3,4-Dehydropyrrolidin-2-ones and 1,2-dehydropyrrolizidin-3-ones Isoxazoline containing heterocycles Comments Intramolecular nitrile oxide cycloaddition (INOC) followed by Raney nickel reduction. Solid phase synthesis involving heterocycles linked via an amide bond to a resin. The heterocycles contain an allylic olen which undergoes cycloaddition on treatment with a nitroalkane and phenylisocyanate. Iterative application of nitrile oxide 1,3-dipolar cycloaddition and selenide oxidationelimination steps. N-Protected ethyl (2E,4S)-4-amino-5-phenylpent-2-enoate undergoes cycloaddition with nitrile oxides to produce a syn : anti ratio of 2 : 1 of the isoxazolines in 6266% yield. An iron tricarbonyl complex of a 1,3-diene allows the reaction of a nitrile oxide, prepared from the nitro compound with phenylisocyanate and triethylamine, with a terminal olen to give the isoxazoline intermediate. Reductive cleavage of the NO bond results in the desired fragment. Conversion of the nitro into nitrile oxide by phenyl isothiocyanate and triethylamine allows INOC to provide the key intermediate in this anti-feedant synthesis in 73% yield. Conversion of nitro to nitrile oxide (phenyl isocyanate and triethylamine) is followed by 1,3-dipolar cycloaddition with vinyl nucleoside bases (2968%). Addition of nitrile oxides to (60)fullerenes. Nitrile oxide addition to methylenespiropentane in 44% yield. The nitrile oxide is prepared in situ from the nitro precursor. INOC in 99% yield provides the key intermediate in a ( )pumiliotoxin C synthesis Dipolar cycloadditions of nitrile oxides, isolated from the dehydrogenation of aldoximes by chloramine-T, with phenyl vinyl sulfone in 1592% yield. Burgess salt, DAST, acetic anhydride and oxalyl chloride were shown to be useful dehydrating agents for the formation of nitrile oxides from nitro compounds. In situ trapping with olens provides an expedient route to isoxazolines. INOC strategy is used to provide the key intermediate in a trans hydrindane synthesis. A new procedure for the generation of nitrile oxides in situ from nitroalkanes uses the reaction of di-tert-butyl dicarbonate with 4-dimethylaminopyridine catalysis in the presence of dipolarophiles at room temperature to aord the cycloadducts in 2790%. 1,3-Dipolar cycloaddition reactions with 1,1- and 1,2disubstituted alkenes in 5685% yield. INOC strategy to provide the key intermediate in the synthesis of the desired 6- and 7-membered ring systems. Intramolecular silylnitronate cycloaddition whereby the nitro compound is treated with trimethylsilyl chloride and triethylamine gave greater stereoselectivity (96 : 4 diastereomers) than the corresponding INOC procedure (85 : 15 diastereomers). The addition of Lewis acids to the dipolar cycloaddition reactions of mesitylnitrile oxide with ,-unsaturated 2-acyl-1,3dithiane 1-oxides can reverse the sense of induced stereoselectivity. Catalytic eciency, ligand acceleration and concentration eects in magnesium ion mediated 1,3-dipolar cycloadditions of mesitonitrile oxide to allylic alcohols have been examined. 3-Sulfolene a undergoes a [3 2] cycloaddition with arylnitrile oxides (prepared in situ from the aryl oximes and sodium perchlorate and triethylamine) in 5080% yields. Regiospecic INOC to give 2-isoxazolines in 6070% yields. Ref. 142 143
144 145
2-(2 -Nitroethyl)-1,3-dioxane
146
1,3,3-Trimethyl-2propylnitrocyclohexene Nitroalkanes
CDE tricyclic fragment of 12hydroxyazadiradione Dihydroisoxazole nucleosides and nucleotide analogues Substituted (60)fullerene Dihydroisoxazoles Tricyclic isoxazoline 3-Substituted-5-phenylsulfonyl4,5-dihydroisoxazole Isoxazolines
147
148
140
1-Vinyl-2-ethylnitrocyclohexane Nitroalkanes
153 154
Mesitylnitrile oxide
Isoxazolines
158
Mesitylnitrile oxide
Isoxazolines
159
Arylnitrile oxides
2-Isoxazolines
141
2-Isoxazoline-containing bicycle
160
2-Isoxazolines or isoxazoles
Treatment of -nitrostyrenes with Grignard or organolithium reagents generates nitronates by 1,4-addition. Addition of the nitronates to ice-cold 85% sulfuric or concentrated hydrohalic acids gave 2095% of the corresponding nitrile oxide. The nitrile oxide is then trapped with olens or acetylenes.
161
760
Table 4
(Contd ) Product Highly functionalised cis-decalin Comments A key intermediate in this functionalised cis-decalin synthesis is prepared by a highly diastereoselective intramolecular [3 2] dipolar cycloaddition of a chiral nitrile oxide. The Wang resin bound aldoximines were treated with commercial bleach in tetrahydrofuran to give the nitrile oxide in situ which was then trapped with the olenic dipolarophile. The complementary strategy of using a resin bound dipolarophile was also examined. A new route to nitrile oxides from primary alkyl halides for in situ dipolar cycloadditions. The procedure uses sodium nitrite and acetic acid in DMSO and gives the isoxazolines in 3568% yield. Ref. 162
163
2-Isoxazolines
164
used in a 1,3-dipolar cycloaddition with ethyl acrylate giving the tricycle 129 in 53% yield (Scheme 41).175 o-Nitro substituted phenylazobenzenes 130 have been converted in a reductive cyclisation to 2-aryl-2H-benzotriazoles 131 in 8497% yield using samarium() iodide (Scheme 42).176
Scheme 42
Scheme 40
New work on chiral nitronic acids and esters has demonstrated their use in a variety of applications. The nitronic acid 126 can be converted to the O-methyloxime 127 using sodium methoxide in ethanol in the presence of silica gel in 22% yield. The nitronic acid 126 has been utilized for an ,-elimination to the butenolactone 128 in 7286% yield and it has also been
In another reductive cyclization an o-nitroaniline 132 can be treated with isopropylsulfonyl chloride 133 in the presence of cyanogen bromide under reductive conditions to give a benzimidazole 134 in 45% yield (Scheme 43).177 A series of nitrofuroxanes have been prepared by subjecting unsaturated compounds to sodium nitrite and an acid with heating. Although the yields are generally low (1337%) in one instance a yield of 95% was obtained.178 3,7-Dinitro-11-oxatricyclo[6.2.1.01,6]undec-9-ene 136 has been prepared from the dinitrofuran 135 by an intramolecular DielsAlder reaction (Scheme 44). The dinitrofuran 135 is itself prepared in a 5 step procedure from furfuraldehyde. This tricyclic intermediate was found to be a versatile synthetic tool
Scheme 41
761
in the preparation of ergot alkaloids and valienamine bicyclic analogues.179 The rst evidence for the ambident DielsAlder activity of 4,6-dinitrobenzofuroxan 137 has been reported. The substrate acts as a dienophile in Normal Electron Demand DA reactions, or as a heterodiene in the Inverse Electron Demand case. The reactivity is determined by the reaction conditions employed and the reaction partners used (Scheme 45).180
Scheme 43
Scheme 44
Scheme 45
11
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