2-Nitroenamines

An excellent method for producing methyl indole-4-carboxylate from commercially available 3-nitro-2-methylbenzoic acid involves reduction of an intermediate nitroenamine (57). 

In a similar system, Melhado and Leonard (64) obtained better results if the enamine (13) were first converted to a semicarbazone (14) before hydrogenation and cyclization to the indole (15). 

Takamoto, Y. Yokota, R.Sudoh,andT. Nakagawa,Bull. Chem. Soc. Jpn.46, 1532(1973). 

Yoshimura, K. Sato, K. Kobayashi, andC. Shin, Bull. Chem. Soc. Jpn. 46, 1515 (1973). 

Aromatic rings can be reduced without difficulty. Major problems connected with these reductions concern maintenence of other functions, control of regioselectivity in polycyclic aromatics, and control of stereochemistry. 

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Nitroenamines and related compottnds have been used for synthesis of a variety of heterocyclic compottnds. Rajappahassummaiized the chemistry of nltroenamines fseeSecdon4.2. Anga and coworkers have developed the synthesis of heterocycles based on the reacdon of nltropytidones or nltropyrimldmone v/ith nucleophiles. For example, 2-subsdntted 3-nltro-pyridmes are obtained by the reacdon of l-methyl-3,5-dinitro-2-pyridones wiih ketones in the presence of ammonia fEq. 10.82. ... 

Alternatively, the 3-carboethoxy derivatives 35 are synthesized by the reaction of nitroenamines 34 with ethyl isocyanoacetate 6JCR(S)76>. 

The addition-elimination reaction of hetero-atom-substituted nitroalkenes provides functionalized derivatives of unsaturated nitro compounds.26 Nitroenamines are generally prepared from a-nitro ketones and amines (see Chapter 5 regarding acylation of nitro compounds).26... 

The addition of alkoxides to 2-nitro-l-phenylthio-l-alkenes affords P-nitro-aldehyde acetals.276 The reaction of the same nitroalkenes with amines gives nitroenamines.270 They are important intermediates for organic synthesis and are generally prepared by the reaction of nitroalkanes with triethylorthoformate in the presence of alcohols or secondary amines.2"1 0 The methods of Eqs. 4.20 and 4.21 have some merits over the conventional methods, for variously substituted (3-nitro-aldehydes acetals or nitroenamines are readily prepared by these methods. 

A new synthesis of [i-nitroenamines by amination of nitroalkenes with methoxyamine in the presence of base is reported (Eq. 4.23).29... 

Nitroalkenes with potential leaving groups in (3-position such as a dialkylamino, an alkylthio, or a phenylsulfonyl group undergo addition-elimination reactions with nucleophiles. The chemistry of nitroenamines has been extensively investigated, and their potential utility in organic synthesis has been well established.2613 116 Severin and coworkers have developed the addition of elimination reactions of nitroenamines with carbon nucleophiles in 1960-1970, as exemplified in Eq. 4.94.117... 

Node and Fuji have developed stereoselective nitroolefination of various carbonyl compounds using (3-nitroenamines (Eq. 4.95).118... 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

Nitromethane reacts with triethyl orthoformate in the presence of secondary amines to give nitroenamines (Eq. 5.9).20... 

Complex 1 1 is considered the only complex present, but the hydrogen bond may be either two (76) or three center (77). Nitroenamines are more prone to complex with 4-fluorophenol than the nitroanilines and they form the strongest hydrogen bond presently known for nitro-bases. In particular, l-piperidino-2-nitroethylene (78) and 1-dimethylamino-2-nitroethylene (79) (both in E form) present a hydrogen bond basicity comparable to that of tributylamine. 

Nitroenamines are affected by the isomerism204 shown in equilibrium 22. Compounds with primary (R1 = R2 = H) or secondary amino (R1 = H, R2 = alkyl) groups exist as mixtures of the intramolecularly hydrogen bonded Z and E forms, in an equilibrium (equation 22) depending on the solvent properties. The E form of a nitroenamine with a tertiary amino group is the more populated form. 

The (—)-sparteine-lithium compounds 409 undergo a facile conjugate addition to 1-nitroalkenes 410 with high enantio- and diastereoselectivity (equation n 1)289,295,296 (lZ)-3,4-5yw-diastereomers 411 are produced. A manifold of synthetically useful transformations of nitroenamines 411 has been worked out. Equation 112 presents a few of them utilizing the diphenyl derivatives 411a . The enantiomers ent-412-ent-416 are available via inversion of 409 by stannylation/lithiodestannylation with slightly decreased overall selectivities . 

Recent studies on the phototautomerization mechanism of the nitroenamine functionality in 2-(nitromethylene)-tetrahydro-l,3-thiazine were performed using complete active space self-consistent field reaction path computations... 

The thiophene ring is opened and sulfur extruded as hydrogen sulfide when 3,4-dinitrothiophene is reacted with piperidine. The product contains two nitroenamine units coupled to each other (Scheme 140). Other secondary amines react similarly (69CC549). Secondary aliphatic amines also react with 2-nitrothiophene to form the nitrodienamines (426) in 50-80% yield. It is believed that the reaction involves addition of the amine at position 5, followed by proton transfer and ring opening to give the thiol which, in the presence of air, oxidatively dimerizes to (426) (Scheme 141). In one case the thiol has been trapped as the silver salt and methylated (74JCS(P1)2357). 

Nitropyrrole derivatives are obtained by reaction of nitroenamines with propargyl bromide [95JCS(P1)1725]. 

JPR711). Also, nitroenamines can be used as the starting materials for the synthesis of thiazoles (85JOC1547) (Scheme 12). 

The addition of Grignard reagents or organolithiums (alkenyl, alkyl, alkynyl, allyl or aryl) to nitroenamines (281)213 was reported by Severin to afford P-substituted-a-nitroalkenes.214 b Similarly, ketone enolates (sodium or potassium), ester enolates (lithium) and lactone enolates (lithium) react to afford acr-nitroethylidene salts (294) which, on hydrolysis with either silica gel or dilute acid, afford 7-keto-a,(3-unsaturated esters or ketones (295)2l4c-d or acylidene lactones (296).214 Alternatively, the salts (294, X s CH2) can be converted to -y-ketoketones (297) with ascorbic acid and copper catalyst. 

In contrast, a-nitroalkenation adducts (298) are obtained with thermodynamic enolates of a-sub-stituted ketones or esters in addition, Fuji reports that enantioselective addition of a-subsdtuted lactone enolates to chiral nitroenamines is cation dependent with zinc affording maximum enantioselectivity.213... 

Reaction of arylidenemalononitriles 29 with some nitroenamines 30 leads to polyfunctionally substituted pyrido[l,2-tf]-l,3-diazepines 31 (Figure 13) <2005KGS1850>. 

The 3-( 7-butylamino)-2-nitroacrylaldehyde is a synthetic equivalent to nitromalonaldehyde that reacts with substituted ethylenediamines in MeOH at 25 °C to provide the first examples of 6-nitro-2,3,4,5-tetrahydro-l//-l,4-diazepines in excellent yield (Scheme 54) <2004JOC8382, 2002H(56)425>. The slow addition of a solution of the diamine to the nitroenamine was required in order to minimize oligomer formation. 

When azadienamines 6 is charged on a silica gel column at room temperature, formylated nitroenamine 10 is effectively produced by half hydrolysis [25] (Scheme 7). Formylnitroenamine 10 can be used as the building block for built-in method to afford versatile nitro azaheterocyclic compounds [26] and nitrophenols [27] in reactions with dinucleophilic reagents. 

Nitropyrimidinone 3 has also electrophilic sites, the 2-and the 6-positions, which are attacked by amines to yield nitro enamines having a carbamoyl group 11 in good yields [28]. Nitroenamine 11 is converted to polyfunc-tionalized pyridone 12a upon treatment with sodium enolate of ethyl 3-oxobutanoate 13a [29]. 

Nitroenamine derivatives are typical push-pull alkenes, and have been widely used in organic syntheses [3,30,31]. Although their synthetic utility is quite high, functionalized ones are not often employed because of their difficult preparation. Hence, the aminolysis of pyrimidinones 2 and 3 is regarded as a new preparative method for functionalized nitroenamines 10 and 11. 

All of the RTF reactions mentioned so far involve a combination of dielec-trophilic substrates and dinucleophilic reagents, namely dinitropyridone 1 and nitropyrimidinone 3 cause RTF reactions upon treatment with dinucleophilic reagents. Meanwhile, nitropyrimidinones 2 and 3 readily react with primary amines to afford functionalized nitroenamines as shown in Sect. 4. Since the nitroenamines 10 and 11 have both nucleophilic and electrophilic sites, this structural feature is applicable to development of the new type of RTF reaction by use of regents having both electrophilic and a nucleophilic sites. 

A new approach to 6-nitro-l//-[l,4]-diazepines 192 based on reaction of the formylated nitroenamine 190 with the 1,2-diamines 191 has been reported yields were generally good in... 

I -Organyl -4-ni tr< tpyra/olcs have been prepared by the reaction of /3-nitroenamines having a formyl group at the /(-position and hydrazines in methanol [496] (Scheme 71). 

Analogically, the interaction of the same nitroenamine with hydroxylamine hydrochloride in methanol gives 4-nitroisoxazole [496],... 

Nitroenamines have also been used for the synthesis of nitroimidazoles [497] (Scheme 72). 

Di(benzylammo)-2-nitroacrylonitrile is converted by the action of hydrazine into 3(5)-benzylamino-5(3)-amino-4-nitropyrazole [502, 503] (Scheme 76). Cyclic nitroenamines react similarly with hydrazine [502] (Scheme 76). 

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