Table of Contents

1. Table of Contents

1. Introduction
2. Preparation of Conjugated Nitroalkenes
   1. From Carbonyl Compounds
   2. From Alkenes
   3. Miscellaneous Methods
3. Reduction of Conjugated Nitroalkenes
   1. Preparation of Nitroalkanes
   2. Preparation of Oximes
   3. Preparation of Carbonyl Compounds
   4. Preparation of N-Substituted Hydroxylamines and Amines

1. References

I. Introduction

Nitroalkenes have proven to be valuable precursors to a wide variety of target molecules. Historically, the nitroalkenes were of interest because of their biological activity; it was demonstrated that they have a detrimental effect on insects^1,2 and on the growth of fungi^1,3-5. Soon thereafter it was reported that they possessed antibacterial^6,7, rodent-repelling⁸ and antitumor⁹ characteristics. The versatility of nitroalkenes in organic synthesis is largely due to the ease with which they are transformed into a variety of diverse functionalities. For example, they provide access to useful synthetic precursors such as nitroalkanes¹⁰, N-substituted hydroxylamines¹¹, amines¹², ketones¹³, oximes¹⁴, α-substituted oximes¹⁵ and α-substituted ketones¹⁶. They also react with a variety of nucleophiles, and their electron-deficient character renders them powerful dienophiles in Diels-Alder reactions^17,18. β-Nitrostyrenes have found recent application in the syntheses of 3-nitrochromenes¹⁹, 3-chromanone oximes²⁰, 3-nitrochromans, 3-hydroxyaminochromans, 3-aminochromans²¹ and other heterocyclic systems²².

Several reviews^22-30 have focused on aliphatic nitro compounds which also encompass nitroalkenes. A few highly specialized reviews have also been written. For example, Yoshikoshi reviewed the condensation reactions of nitroalkenes with enol silanes, ester enolates, and anions derived from β-dicarbonyl compounds.³¹ Another review highlights the application of nitroalkenes in the synthesis of heterocyclic compounds.²² Although Barrett's recent review^32a covers many of the topics discussed in the present survey, no review is devoted solely to the preparation of nitroalkenes as synthetically useful precursors and to the reduction of nitroalkenes from a synthetic standpoint. Thus the present review complements Barrett's review and will hopefully stimulate further investigation in the nitroalkene area. Although coverage focuses primarily on the literature since 1980, significant earlier contributions are included. Reactions of nitroenamines have been covered^32b and only a few most recent examples are included here.

II. Preparation of Nitroalkenes

A. From Carbonyl Compounds

The classic route to nitroalkenes involves the base-catalyzed aldol condensation of nitroalkanes possessing, a hydrogen alpha to the carbonyl group in the aldehyde or ketone. This condensation is known as the Henry reaction^33,34 and provides β-nitroalcohols which, upon dehydration, afford nitroalkenes (Eq. 1).

A variety of basic catalysts have been utilized which influence the nature of the products obtained; these include alkali metal hydroxides, carbonates, bicarbonates and alkoxides.³⁵ Alcoholic potassium hydroxide³⁶, aqueous sodium hydroxide³⁷, calcium hydroxide^38,39, aluminum ethoxide⁴⁰, magnesium aluminum ethoxide⁴⁰ and anion-exchange resins^41,42 have also shown promise as catalysts in the Henry reaction. Among the organic bases, primary amines^43-46 and ammonium acetate⁴⁷ have proven to be useful.

In their search for new bacterial agents, Schales and Graefe investigated the condensation reactions of nitromethane or nitroethane with aromatic and heterocyclic aldehydes under a variety of conditions using basic catalysts such as methylamine and aniline⁶. It appears that some modification of conditions is required for different aldehydes⁶. Several instances have been reported in which the type and quantity of the base influenced the nature of the products obtained. Two recent investigations dealing with these classical condensation reactions deserve mention.

The first involves a new and unusual formation of 5-methyl-3-aryl-1,2,4-oxadiazoles (4), from the reaction of aromatic aldehydes with nitroethane in the presence of ammonium acetate, reported recently by Young and Beidler⁴⁸.

The condensation of 2,5-dimethoxybenzaldehyde (1) with nitroethane and ammonium acetate in glacial acetic acid has been found to give three different products, depending on reactant ratio and reaction time. Using a ratio of 1:1.5:0.8 between the aldehyde, nitroethane, and ammonium acetate, a normal Knoevenagel condensation was observed yielding 70% of the expected 2,5-dimethoxyphenyl- 2-nitropropene (2). At a reactant ratio of 1:3:2 (same reactant sequence), the major product was 2,5-dimethoxybenzonitrile (3) (62%), and at a reactant ratio of 1:40:8, with extended reflux time, the major product was 3-(2,5-dimethoxyphenyl)- 5-methyl-1,2,4-oxadiazole (4) (26%). The mechanism is believed to be dependent on a preliminary reaction wherein the nitroalkane, in the presence of ammonium acetate and acetic acid is converted into the corresponding alkanoic acid and hydroxylamine. Hydroxylamine then converts the aromatic aldehyde, via the intermediary nitrile, to the oxadiazoles following reactions of established precedent (Scheme 1). The second reaction is one reported by Wadia and co-workers.⁴⁹

They note that the mere change of catalyst from ammonium acetate to sodium acetate, results in the formation of nitriles (5) instead of the expected β-methyl-β-nitrostyrenes (6) (Eq. 2).

[However, this unusual change of reaction pathway was not observed when nitromethane was used; the products were only 1-aryl-2-nitroethylenes even when sodium acetate was employed]. The generation of ethanehydroxamic acid from nitroethane could convert the aldehyde into an oxime derivative, which in turn could be cleaved to give the nitrile in the presence of sodium acetate. There are reports in the literature in which nitromethane/polyphosphoric acid⁵⁰, nitromethane/pyridine hydrochloride,⁵¹ and nitropropane/ammonium monohydrogen phosphate⁵² have been used to convert aldehyde to nitriles.

The search for novel dehydrating agents for use with nitroalcohols continues as nitroalkenes gain in importance. Numerous reagents have been introduced recently; these include methanesulfonyl chloride⁵³, phthalic anhydride^51,55, dicyclohexylcarbodiimide (DCC)⁵⁶, pivaloyl chloride^57,58 and a variety of solid support reagents on alumina^59-62.

McMurry reported that mesyl chloride in DCM⁵³ at 0°C, is a good dehydrating agent for nitroalcohols. It transforms the hydroxyl group into a more effective leaving group. Generally, good results are obtained (see examples below) using their approach with the exception of 1-nitro-1-propene, an unhindered nitroalkene, sensitive toward polymerization.

Knochel and Seebach⁵⁶ used DCC in the presence of copper(I)chloride catalyst, in ethereal solvents, for the dehydration of nitroalcohols as demonstrated in the synthesis of the following representative nitroalkenes.

They also synthesized 2-nitro-3-pivaloyloxypropene (NPP) derivatives and analogs (7b), (7c) and (9) which are versatile multi-coupling reagents⁵⁷. The alcohol (7a), obtained from the diol (10), was esterified with pivalic anhydride to yield (7b) (95%). The open chain, diastereomerically pure (E)-2-nitro-1-phenyl-3-pivaloyloxypropene (9) was obtained in 90% yield from the nitrodiol (11) by dehydration via esterification with pivaloyl chloride and subsequent elimination of pivalic acid using sodium acetate in diethyl ether.

The phthalic anhydride mediated dehydration of 2-nitroethanol, obtained from formaldehyde and nitromethane⁶³, gave consistently good yields of nitroethylene^54,55. Contrary to general belief, 2-nitroethylene is a stable reagent and a useful reactive synthon which can be prepared in 20-25g lots, stored in the cold, and used as a standard solution in benzene for several months⁵⁵.

2-(2-Nitroethenyl)phenols (13) were obtained under mild conditions by the reaction of (o-hydroxybenzaldehydes (12) with nitromethane in the presence of dimethylammonium chloride and catalytic amount of potassium fluoride in refluxing toluene⁶⁴ (Eq. 3).

Compound (16) was obtained from (phenythio)acetic acid in five steps by Yoshikoshi and co-workers⁶⁵ and was utilized for 3-methylfuran annulation in the synthesis of furanoterpenoids^31,66. The nitroolefin (16) preparation involved the addition of 3 molar equivalents of n-propyl nitrate to the dianion of phenylthioacetic acid at 0°C followed by acidification to give nitro(phenylthio)methane (14) (53%). Nitroaldol condensation of (14) with acetaldehyde in 5% methanolic potassium hydroxide followed by neutralization with acetic acid gave the nitroalcohol (15) (81%) which was dehydrated using McMurry's method to yield (16) in 80% yield⁶⁵.

1-Nitro-1-phenylthioalkenes (18) were also recently prepared by condensation of phenylthionitromethane (14) with aldehydes using potassium t-butoxide as a catalyst⁶⁷ (Eq. 4). The resulting isomeric mixture of nitroalcohols (17) was dehydrated by methanesulfonyl chloride and trimethylamine using Yoshikoshi's procedure.⁶⁵ Barrett and co-workers have demonstrated the application of (18) in the synthesis of S-phenyl thioesters⁶⁷ and bicyclic lactams.⁶⁸

A general synthesis of 1-ethylthio-2-nitroalkenes has been described recently by Fuji and co-workers which is applicable to both cyclic and acyclic systems.⁶⁹  For example, 2-nitrocyclohexanone (19) was converted into the S,S-acetal (20) by a reaction with ethanethiol catalyzed by zinc chloride or boron trifluoride etherate. Subsequent elimination of ethanethiol using potassium fluoride in refluxing 2-propanol afforded a mixture of isomeric compounds, 1-ethylthio-2-nitrocyclohexene (21) and 1-ethylthio-6-nitrocyclohexene (22) (Eq. 5). The isolated undesired product (22) (81%) can, in part, be isomerized to the desired olefin (21) by treatment with potassium fluoride in 2-propanol.

An analogous reaction sequence with nitroacetone (23) afforded the S,S-diethylacetal (24) which, gave two stereoisomeric 2-ethylthio-1-nitro-propenes, [(Z)-25] (56%) and [(E)-26] (39%) (Eq. 6).

Although successful with α-nitroketones, the method may not be applicable to α-nitroaldehydes because of their instability. Also, it is not possible to prepare 2-(alkylthio)-nitroethylene by this method. A recent report⁷⁰ describes the first synthesis of 1-nitro-2-(phenylthio)ethylene (27) and the oxidation products, 1-nitro-2-(phenylsulfinyl)ethylene (28) and 1-nitro-2-(phenylsulfonyl)ethylene (29) as shown in Scheme 2.

These new electron deficient olefins are good dienophiles in Diels-Alder reactions. For example, (27), (28) and (29) rapidly react with cyclopentadiene to give adducts in 75%, 97% and 82% yield respectively. Nitroalkene (29) is especially reactive due to activation by both the nitro and the sulfonyl groups. These olefins are also good Michael acceptors and they react with various nucleophiles. For example the reaction of (27), (28), and (29) with pyrrolidine gave the nitroenamine (30) in 81%, 89% and 71% yield respectively (Eq. 7).

The synthesis of 3-nitrocycloalkenones (33) and their utilization as Diels-Alder dienophiles have been reported by Corey and Estreicher.⁷¹ Peroxytrifluoroacetic acid oxidation of the oximes (31) in acetonitrile afforded nitroalcohols (32) which were oxidized in situ using pyridinium chlorochromate as shown in Scheme 3.

Recently another approach appeared which obviates the need for the potentially hazardous 90% hydrogen peroxide normally used to prepare the trifluoroperoxyacetic acid used for converting (31) to (32). Vankar and Bawa⁷² have utilized an olefinic acetal (34) which, upon treatment with mercuric chloride and sodium nitrite, underwent a regiospecific nitromercuration (discussed later) to give nitromercurial (35). The base catalyzed elimination then yielded the nitroalkene-acetal (36) which, upon hydrolysis with 5% sulfuric acid, afforded 3-nitrocycloalkenone (37) as shown in Scheme 4. However, 3-nitrocyclopentenone is reportedly not obtainable via this route.

A synthesis of cyclic nitroalkenes which is complimentary to those in the literature has been reported by Dampawan and Zajac⁷³ starting from β-nitroketones. The reaction sequence is part of the overall process designed by Hassner and co-workers for the transposition of a carbonyl group to an adjacent position⁷⁴ where isolation of the β-nitroalcohol or nitroalkene was precluded because of excess BH₄^-. In this approach β-nitroalcohols were not obtained by the classical Henry reaction which is not amenable to cyclic systems. 2-Nitrocyclohexanones, obtainable by nitration of enol acetates were reduced by sodium borohydride in ethanol. The subsequent elimination of water from the nitrocyclohexanols was affected by sodium hydride followed by acidification (pH 1-2) to afford nitroalkenes (72%) regioselectively as shown in Scheme 5.

Corey and Estreicher⁷⁵ reported an elegant synthesis or nitrocycloalkene from cyclic ketones which makes available unsaturated nitro compounds not previously accessible. Allyl nitro compounds can also be obtained using this methodology. The process is outlined in Scheme 6.

The general problems of low yields and complex mixtures in nitroalkene preparations via the condensation of nitromethane with aliphatic and alicyclic ketones^24,29, was overcome by Barton and co-workers in an unprecedented reaction^76,77. Bifunctional ethylenediamine was used in catalytic amounts, which probably helps to bring the reacting centers into close proximity then by overcoming steric barriers. The base also facilitates proton transfer as outlined in Scheme 7 thus assisting the addition of nitromethane anion and subsequently triggering the β-elimination of ethylenediamine. This explanation was supported by the absence of catalysis by simple primary amines.

Polymer supported reagents have also been used in the nitroaldol addition reactions. For example chromatographic alumina (Brockmann activity I) catalyzes the preparation of polyfunctional and labile 2-nitroalkanols in a mild and convenient heterogeneous reaction from nitroalkanes and aliphatic aldehydes in the absence of solvent⁵⁹ (Eq. 8).

Under similar conditions, 1-(2-furyl)-2-nitroalk-1-enes (38) are obtained directly⁶⁰ (Eq. 9).

Recently, it has been disclosed that an excess of potassium fluoride and alumina dramatically increases the otherwise slow nitroaldol condensation⁷⁸. 6-Nitropiperonal reportedly reacts with nitromethane in less than five minutes to give the corresponding dinitrostyrene in 80% yield after dehydration. In a separate study involving the case of α,β-unsaturated carbonyl compounds, conjugate addition of nitroalkanes occurs on the alumina surface in the absence of a solvent resulting in the preparation of 4-nitroketones and 4-nitro-aldehydes⁶¹ (39) (Eq. 10).

Recently, a preparation of α-nitroalcohols on potassium fluoride doped alumina was described⁶²; the nitroalcohols were subsequently oxidized to nitroketones using montmorillonite supported chromium trioxide (Eq. 11). The procedure can be extended to aromatic aldehydes without dehydration of the nitroalcohols into nitroalkenes.

In situ generated nitroalkenes have also been utilized in syntheses. On the basis of a report⁷⁹ that sodium nitromalonaldehyde is readily acylated with acetic anhydride via the enolic hydroxy tautomer to give the acylal derivative of 3-acetoxy-2-nitroacrolein, 1,3,3-triacetoxy-2-nitro-1-propene, a synthesis of 3-nitropyridines was developed.⁸⁰ Under anhydrous conditions, tosyl chloride reacted with sodium nitromalonaldehyde in dimethylformamide and pyridine, to produce 3-chloro-2-nitroacrolein which reacted with 4-amino-3-butene-2-one to afford 3-nitro-5-acetylpyridine (53%), Scheme 8. The formation of the initial intermediate, 3-chloro-2-nitro-acrolein, was confirmed by the characterization of a Diels-Alder adduct with cyclopentadiene.

B. From Alkenes

1-Nitro-2-alkyl nitrates, readily obtainable in high yields from 1-alkenes, have been converted to nitroalkanes by sodium borohydride reduction.⁸¹ The reaction presumably proceeds via the nitroalkene intermediate resulting from a base-induced nitric acid elimination (Eq. 12).

In a study of limited scope, a direct nitromethylation of alkenes via a radical addition was accomplished by using Mn(III)-Cu(II) (as co-oxidants) and nitromethane.⁸² However, the reaction proceeded only in poor yields (35-38%) and was limited to cycloalkenes; with terminal alkenes and styrene, nitromethylation was not a favorable process.

Nitryl iodide, a pseudohalogen reagent, available via the reaction of silver nitrite with iodine was introduced in 1932⁸³. The synthetic application of the reagent under mild conditions was described by Hassner and co-workers⁸⁴ for the selective synthesis of β-iodonitro-, vinylnitro- and nitroalkanes.

Two other reports have appeared on the use of this reagent with unsaturated carbohydrate derivatives^85,86. More recently, nitration of substituted styrenes by nitryl iodide was described providing regioselective addition products; iodonitro compounds (40), upon treatment with base, generated the 3-nitrostyrene⁸⁷ (41) (Eq. 13).

The formation of hydroxynitro compounds (42) and nitroketones (43), occasional by-products in the reaction, could be suppressed by treatment of the crude addition product with trimethylamine immediately following the disappearance of the styrene substrate thereby increasing the yield of 6-nitrostyrene.

Selenium chemistry has been used in the synthesis of nitroalkenes. Tomoda and Nomura reported a novel method for the preparation of conjugated nitroalkenes (46) from unactivated alkenes via nitroselenylation. Initial attempts using benzeneselenyl bromide and silver nitrite resulted in a mixture of 2-nitroalkyl phenylselenide (44) and 2-hydroxyalkyl phenylselenide (45) with the latter being predominant⁸⁸ (Eq. 14). The authors, however, soon discovered that formation of (45) could be completely suppressed using mercury(II)chloride, although its mechanistic role is not clear.⁸⁹ The nitroselenylation (anti) and the subsequent elimination of selenoxide (syn) were stereospecific. (E)- and (Z)-4-octenes each afforded a single stereoisomer as confirmed by the ¹³C NMR spectra of (44, R₁ = H, R₂ = R₃ = C₃H₇) and (44, R₁=R₂=C₃H₇, R₃=H) and the ¹H NMR of the nitroalkenes (46, R₁=H, R₂=R₃=C₃H₇) and (46, R₁ = R₂ = C₃H₇, R₃ = H).

Unsymmetric alkenes, for example 1-hexene, gave a regioisomeric mixture of Markovnikov (47) and anti-Markovnikov (48) isomers in the ratio of 78:22, although styrene provided the regiospecific product (49) with the phenylseleno group occupying the terminal carbon atom.

Seebach and co-workers have achieved the oxo-selenation of nitroalkenes (50) using phenylselenyl chloride/silver trifluoroacetate (phenylselenyl trifluoroacetate).⁹⁰ Methanolysis of (51) provided (52) and subsequent regioselective elimination of phenylselenyl group with hydrogen peroxide gave the allylic alcohol (53) (Scheme 9).

This key step permitted an overall regioselective allylic pivaloyloxylation of nitroalkenes thereby making either isomer accessible. Derivatives with conjugated (9, 54, 55) and non-conjugated (7) substituents were shown to be useful as multiple coupling reagents for highly convergent syntheses.⁵⁸

In an exact reversal of a well-known reaction,⁹¹ Sakakibara and co-workers have reported the trifluoroperacetic acid oxidation of α-halo-ketoximes (56) to nitroalkenes⁹² (57). Since α-haloketoximes are readily available from alkenes via reaction with nitrosyl chloride in the presence of hydrochloric acid⁹³ or from α-haloketones via standard oximation using hydroxylamine salts,⁹² the reaction has a broad scope for the regioselective introduction of a nitro group. Several cyclic and acyclic nitroalkenes were obtained in moderate yield (31-66%) using this approach (Scheme 10) which bears close resemblance to one described earlier by Corey.⁷¹

In a related procedure, Russian workers⁹⁴ oxidized 1,1-disubstituted alkenes using alkyl nitrites in acetic acid to produce nitroalkenes (58a) and (58b) in poor yields (27% and 48% respectively).

Corey converted 1-lithio-2-bromocyclopentene (59b), obtained by lithiation of 1,2-dibroroocyclopentene, to 2-bromo-1-nitrocyclopentene (59d) via an earlier described nitrodestannylation methodology using tetranitromethane.⁷⁵

In a preliminary report, Kunai and co-workers⁹⁵ described an electrochemical method employing a well-known alkene nitrosation approach. The anodic oxidation of cyclic and acyclic alkenes at a platinum anode in a divided cell containing aqueous sodium nitrite and sodium nitrate solution provided modest yields of 1-nitrocyclohexene (41%), 1-nitrocyclooctene (57%),and 1-nitro-1-hexene (63%).

There are very few reports describing 1,2-dinitroalkenes in the literature due to their inherent thermal instability. The few examples of isolated 1,2-dinitroalkenes include 1,2-dinitrocyclohexene,⁹⁶ 1,2-dinitroethene,⁹⁷ 2,3-dinitro-2-butene,⁹⁸ 3,4-dinitro-3-hexene⁹⁸ and dinitrostilbene.^99,100

Similarly, the preparation and utility of 1-nitro-1,3-dienes has not been developed; the only exception being a few Russian reports involving addition of N₂O₅¹⁰¹, NO₂/I₂¹⁰² or NO₂/O₂¹⁰² to 1,3-dienes followed by elimination, and a patent describing the preparation of 2-methyl-1-nitro- 1,3-butadiene.¹⁰³ Recently, Bloom and Mellor developed the synthesis of 1-nitro-1,3-dienes via nitrotrifluoroacetoxylation of 1,3-dienes.¹⁰⁴ Nitrotrifluoroacetate adducts, obtained by reaction of 1,3-dienes with in situ generated trifluoroacetyl nitrate (from ammonium nitrate and trifluoroacetic anhydride),¹⁰⁵ readily eliminate trifluoroacetic acid to give 1-nitro-1-3-dienes in high yield (Scheme 11).

C. Miscellaneous Methods

Mixtures of cis- and trans-dinitroalkenes have been obtained by the addition of dinitrogen tetroxide to dialkylacetylene¹⁰⁰ (Eq. 15). The reaction presumably proceeds via free radical intermediates and fails in the case of terminal acetylenes.

An earlier preparation of tetranitroethylene¹⁰⁶ was improved when Baum, Baum and Tzeng¹⁰⁷ synthesized it in 50% yield via the flash vacuum pyrolysis of hexanitroethane (Eq. 16).

The optimum conditions for the synthesis involve passing hexanitroethane vapor, at 1 mm Hg, through a pyrolysis tube heated to 240-270°C and condensing the product, a greenish yellow solid, in a cold trap. Tetranitroethylene reacts with acetylenes and alkenes to give 3-nitroisoxazoles and 3-nitro-2-isoxazolines, respectively, and other reactions typical of a powerful dienophile and electron acceptor. The known oxidative conversion^108,109 of carbonyl groups into nitro functionalities via oximes using trifluoroperoxyacetic acid has been extended to α,β-unsaturated compounds by Takamoto and co-workers¹¹⁰ (Scheme 12).

Treatment of α-unsubstituted α,β-epoxyketoximes with trifluoroperoxyacetic acid afforded the corresponding γ-hydroxy-α-nitroalkenes in high yield. For example, (63) gave (64). Corey and Estreicher employed similar methodology for the synthesis of 3-nitrocycloalkenones⁷¹ (vide supra).

An oxidative transformation of nitroalkanes to nitroalkenes has been reported by Sakakibara and co-workers who used selenium chemistry.¹¹¹ Phenylselenenyl bromide reacted with the nitronates (66) derived from nitroalkanes (65) to give nitro(phenylseleno)alkanes (67) which upon an oxidative regioselective elimination, using hydrogen peroxide, afforded 1-nitroalkenes (68) in high yield (67-83%) (Scheme 13).

The method is applicable to a variety of acylic and cyclic compounds. For example, 3-methoxy-2-nitrocyclohex-1-ene (70) was obtained from 1-methoxy-2-nitrocyclohexane (69) (Eq. 17).

The intermediate nitro(phenylseleno)alkanes (71), bearing an acidic hydrogen, were found to be valuable intermediates for hydroxymethylation¹¹². The α-nitroselenide (71) underwent a smooth condensation with aqueous formaldehyde to give relatively stable 2-nitro-2-phenylselenoalkanols (72). Subsequent selenoxide elimination provided a facile entry to useful hydroxynitroalkenes (73) (Scheme 14).

1-Nitro-1-phenylseleno-1-alkenes, a novel group of 1-nitroalkenes bearing a selenyl group at the 1-position have been prepared.¹¹³ The α-nitroselenide (74) , on Henry condensation with aldehydes (alkyl and aryl), afforded isomeric mixtures of nitroalcohols (75) which upon acetylation and elimination of acetic acid provided (Z)-1-nitro-1-phenylseleno-alkenes (76) (Scheme 15).

β-Nitroenamines occupy a central position³² among 1-nitro-1-alkenes with hetero atoms at the 1-⁶⁶ or 2- position.^114,115 Rover and co-workers have described a methodology to synthesize nitroenamines (77) via the condensation of triethyl orthoformate, with nitromethane and amines.¹¹⁶ (Scheme 16).

In an approach directed towards the synthesis of the pharmacologically active β-(2-thienyl)ethylamine, the preparation of the precursor, 1-(2-thienyl)-2-nitropropene (78), was improved using 2-thienaldehyde, nitroethane and n-amylamine as the catalyst⁴⁶ (Eq. 18).The reaction time, at room temperature, is about two weeks.

1-Phenylsulfonylpyrrole-3-carboxaldehyde or 1-phenylsulfonyl pyrrole-2-carboxaldehyde were condensed with nitroalkanes in the presence of ammonium acetate or glacial acetic acid to afford nitroalkenes¹¹⁷ (79).

In a continuation of their investigations into the chemistry of cyano-nitroalkenes¹¹⁸, a Russian group has attained the alkenylation of nitro-acetonitrile with a variety of heterocyclic carboxaldehydes in a mixture of absolute ethanol and ether at 20-25°C without the participation of an acidic or basic catalytic agent¹¹⁹. A series of heterylcyanonitroalkenes, i.e. 3-(2-furyl)-, 3-(2-thienyl)-, 3-(2-pyrrolyl)-, (80a-d) etc. were obtained in good yields using this methodology.

Recently Jung and Grove¹²⁰ disclosed the preparation and utility of β-phenylsulfinyl- nitroalkenes (81) as nitroacetylene equivalents in Diels-Alder reactions with dienes (Eq. 19). The nitroalkenes were obtained in four steps from acylimidazoles.

III. Reduction of Conjugated Nitroalkenes

The reduction of α,β-unsaturated nitroalkenes provides easy access to a vast array of functionalities including nitroalkanes¹⁰, N-substituted hydroxylamines¹¹, amines¹², oximes¹⁴, ketones¹³, α-substituted oximes¹⁵ and ketones.¹⁶

A. Preparations of Nitroalkanes

The reduction of nitroalkenes to nitroalkanes has been achieved in a variety of ways. Initial attempts, utilizing the inverse addition of lithium aluminum hydride to nitroalkenes¹²¹, resulted in poor yields of the corresponding saturated analogs. In view of the relative inertness of the borohydrides towards nitro groups, a detailed investigation was carried out using sodium trimethoxyborohydride, lithium borohydride and sodium borohydride¹²². In most cases, dimeric products were also formed which arose via the Michael addition of the nitronate intermediate to the parent nitroalkene. The main theme of the several reports was the selective reduction of the double bond while avoiding the formation of Michael by-products. Careful control of the pH of the reduction medium¹²³ and the use of sodium cyanoborohydride¹²⁴ as the reducing agent yielded modest improvements.

Varma and Kabalka^10a have reported the use of trialkylborohydride reagents (such as triethylborohydride and tri-sec-butylborohydride) to generate nitronate intermediates via a 1,4-addition of hydride; the corresponding nitroalkanes were most easily obtained by using silica gel to protonate the nitronate salts. Another silica gel assisted sodium borohydride reduction, in a mixed chloroform-propanol solvent system, was reported in which 2-aryl-1-nitroalkanes were generated from nitrostyrenes in high yields.¹²⁵

Varma and Kabalka^10b introduced a manipulatively simple approach which utilizes sodium borohydride in a mixed solvent system of methanol and tetrahydrofuran. Gradual addition of sodium borohydride at room temperature to the nitroalkene solution in this mixed solvent system provided clean reaction products (62-82%); the methodology has been extended to the selective reduction of 3-nitrochromenes to 3-nitrochromans (51-85%).¹²⁶ The formation of methoxyborohydride species is implicated in the reaction^10b. In a related approach, reverse addition of β-nitrostyrenes to sodium borohydride in dioxane/ethanol provided the corresponding phenylnitroethanes in good yields.¹²⁷

The selective reducing properties of 2-phenylbenzimidazoline (PBI), prepared in situ from o-phenylenediamine and benzaldehyde, was used for reduction of arylnitroalkenes (82) to the corresponding nitroalkanes (70-91%) (83) without side reactions.¹²⁸ The reaction, however, is not applicable to aliphatic nitroalkenes (Eq. 20).

Ohno and co-workers¹²⁹ discovered that the Hantzsch ester (84), an NAD(P)H model, reduces various nitroalkenes in good yield in the presence of silica gel. Both, aliphatic and aromatic nitroalkenes were smoothly reduced, without dimerization, via this chemoselective method which tolerates functionalities such as aldehydes and ketones.

Among various reducing agents employed for the preparation of nitroalkanes, sodium borohydride appears to be the most extensively used. The relatively low cost and the manipulative ease with which it can be handled (one of the least moisture sensitive hydrides) makes it ideally suited for selective reductions. For example, the reduction of (85) to the corresponding nitro sugar (90%), an intermediate in the synthesis of 4-deoxydaunosamine and 4-deoxyristosamine¹³⁰, and nearly the quantitative conversion of the steroidal nitroalkene (86) to its corresponding saturated derivative⁷⁷ were achieved using sodium borohydride.

B. Preparation of Oximes

The catalytic hydrogenation of nitrostyrenes to oximes had been reviewed earlier^131,132. Substituted nitrostyrenes, upon hydrogenation with palladium on carbon in pyridine, provide the corresponding oximes¹³³. The catalytic hydrogenation of straight-chain and cyclic nitroalkenes with palladium on carbon in a variety of solvents afforded mixtures of oximes and the corresponding saturated nitroalkanes.¹³⁴

Tin(II)chloride has been used under conventional acidic conditions to produce a mixture of α-substituted oximes and the corresponding saturated nitro compounds^135,136. Varma and Kabalka carried out an extensive investigation using tin(II)chloride under a variety of conditions. The tin(II)chloride reduction of conjugated nitroalkenes in alcoholic (and thiol) media afforded α-alkoxy (α-alkylthio) oximes in high yields¹⁵ (Eq. 21). Unsubstituted oximes were obtained by using tin(II)chloride in acetone^14c.

Tin(II)chloride under basic conditions (sodium stannite) afforded unsubstituted ketoximes in high yield^14a. However, aldoximes were not obtainable under these reaction conditions. A general synthesis of oximes was recently reported which provides moderate yields of both aldoximes and ketoximes, the reaction involves a palladium assisted transfer reduction using sodium hypophosphite^14d.

It has been reported that a few steroidal nitroalkenes¹³⁷ produce α-hydroxy oximes upon reduction with chromium(II)chloride^77,138,139 (Eq. 22).

A recent report¹⁴⁰ outlined an unusual reduction of 3-nitroflavenes by chromium(II)chloride to flavonols which presumably occurs via an α-hydroxy oxime intermediate. A detailed investigation revealed that chromium(II)chloride rapidly reduces β-nitrostyrenes to oximes (Scheme 17) rather than to α-hydroxy oximes when the reactions were run under milder conditions^14b (room temp, 10 min).

Electrochemical methods have also been used to convert nitroalkenes to oximes and/or ketones and aldehydes. Shono and co-workers¹⁴¹ reduced a variety of functionally substituted nitroalkenes to the corresponding oximes using a platinum cathode in methanolic sulfuric acid. However, the process leads to modest yields and to the formation of acetals and ketones as byproducts. Another electrochemical approach afforded either ketoximes or ketones (depending upon the workup conditions) from nitroalkenes by utilizing aqueous perchloric acid in a dichloromethane and dioxane solvent system and a lead electrode¹⁴² (Eq. 23).

Zinc and methanolic ammonia has also been used to obtain ketoximes from steroidal nitroalkenes in high yield¹⁴³.

C. Preparation of Carbonyl Compounds

The reverse addition of lithium aluminum hydride to 1-phenyl-1-nitropropene was studied in detail¹²¹. A variety of products was isolated by varying the reaction temperature and the reactant ratios. By using acidic hydrolysis of the intermediate organometallic complex, phenylacetone was obtained via a modified Nef reaction.

α-Alkoxy or α-alkylthio oximes obtained by tin(II)chloride reduction of nitroalkenes (vide supra, Eq. 21) have been conveniently hydrolyzed by levulinic acid¹⁴⁴ to produce α-substituted ketones¹⁶.

In contrast to the formation of the usual α-hydroxy oximes from cyclic nitroalkenes (steroidal^137-139 and chromene derivatives¹⁴⁰), the chromium(II)chloride reduction of nitroalkenes produced the corresponding unsubstituted carbonyl compounds¹³⁶.

Monti and co-workers¹⁴⁵ have also converted nitroalkenes directly into the corresponding saturated ketones or aldehydes. They found that Raney nickel and sodium hypophosphite, at pH 5 in ethanol, provided a high yielding chemoselective route to a variety of aldehydes and ketones from nitroalkenes. Using this methodology, oximes can be reduced to carbonyl compounds and nitroalkanes to amines in the presence of alkene, ester, and ketone functionalities.

The reaction of lithium tri-sec-butylborohydride with a nitroalkene produces a nitronate intermediate (87) which upon hydrolysis with 4N sulfuric acid affords yet another route to ketones from nitroalkenes (Eq. 24).

Interestingly, the reduction of β-nitrostyrene derivatives under similar reaction conditions produces white precipitates¹⁴⁶ which yield the saturated nitroalkanes upon acid hydrolysis; only traces of aldehydes were obtained.

D. Preparation of N-Substituted Hydroxylamines and Amines

N-Substituted hydroxylamines are obtainable by the reduction of oximes^147a-c and nitro salts¹⁴⁸ or by the oxidation of amines^149a-b. The methods are involved and are not readily amenable to the synthesis of many desired target molecules. A more appropriate route would be the reduction of conjugated nitroalkenes^121,150. It is known that sodium borohydride reduces α,β-unsaturated nitroalkenes to the corresponding nitroalkanes (Section III-A). Also, Feuer reported¹⁴⁸ that nitro salts (nitronates) are easily reduced to hydroxylamines by borane complexes (Eq. 25).

These reactions presumably occur through a common intermediate (88), which can then be hydrolyzed directly to nitroalkanes or reduced with a borane complex to yield hydroxylamines after hydrolysis. Indeed, it was found that sodium borohydride catalyzes the reaction of borane complexes with conjugated nitroalkenes^11a (Eq. 26).

This straightforward approach afforded pure hydroxylamines in high yields. Subsequent modification by in situ generated borane in tetrahydrofuran (from NaBH₄ and BF₃·Et₂O), obviated the need for BH₃·THF^11b which is not universally available.

Alkylamines are generally accessible via the reduction of nitroalkenes by lithium aluminum hydride^121,151-153. Substituted thienylethylamines⁴⁶ were obtained using this methodology. Catalytic hydrogenation¹⁵⁰ has also been used on occasion with limited success.

Earlier studies¹⁵⁴ demonstrated that hydroxylamines, as well as their precursor oxime derivatives, are reduced by diborane to amines at elevated temperature (105-110°C). Varma and Kabalka^12a utilized their earlier reported reaction¹¹³ to reduce hydroxylamines (89) to amines. It was found that excess borane reduced the nitroalkenes to amines in the presence of a catalytic amount of sodium borohydride (Eq. 27). The reaction, which generally takes 6 days at room temperature, can be accelerated by running it in refluxing tetrahydrofuran.¹⁵⁵ This reduction can also be achieved utilizing in situ generated BH₃·THF¹² (from sodium borohydride and boron trifluoride etherate). The reaction yields are comparable to those obtained using BH₃·THF and the reaction can be carried out in one pot in five hours.

A general synthesis of β-(2- or 3-pyrryl)alkylamines (90) containing an unsubstituted pyrrole N atom was developed from 1-phenylsulfonylpyrrole-2- or -3-carbaldehyde via the reduction of the corresponding nitroalkene¹¹⁷. Using lithium aluminum hydride as the reducing agent, concomitant removal of the phenyl sulfonyl protecting group takes place.

Recently, an efficient reduction of aliphatic nitro compounds to amines was described which included the reduction of 1-nitrocyclohexene¹⁵⁶. The combination of sodium borohydride with catalytic amounts of nickel chloride was employed; nickel boride (Ni₂B) generated in situ was implicated as the active catalyst.