Isocyanoacetates

The Barton-Zard reaction refers to the base-induced reaction of nitroalkenes 1 with alkyl a-isocyanoacetates 2 to afford pyrroles 3. Solvents used are THF or alcohols (or mixtures) and the reaction often proceeds at room temperature. 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile... 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

The foregoing examples show that the nucleophilic attack to nitroarenes at theorr/io-posidcn followed by cyclizadon is a generid method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion dedved from ethyl isocyanoacetate as the reacdve anion for the preparadon of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyriirddines depending on the stnicture of nitroarenes fEqs. 9.56 and9.57. The synthesis of pyrroles is discussed in detail in Chapter 10. 

Barton and Zard found that the base-catalyzed reacdon of nitroalkenes or fi-n v/ith alkyl isocyanoacetate or TosMIC gives pyrrole-3-carboxylates or 3-suifonylpyrroles, respecdvely fsee Eqs 10 18 and 10 19) This reacdon is very convenient for the synthesis of... 

Benzyl isocyanoacetate is a nsefnl reagent for the preparadon of benzyl 5-nnsnbsdnited pyrrole-2-carboxylates, which are widely used In the synthesis of porphyrins." Ono and coworkers have prepared pyrroles snbsdnited with various snbsdnients at the fi-posidons."" Because the reqidsite fi-nitro acetates for nitroalkenesi are readily available by the Henry... 

This strategy using super nonionic strong base is also applied to less reac compounds The reaction of Tnitronaphthalenev/ith ethyl isocyanoacetate proceeds very slowly in the presence of DBU, but this reaction is accelerated by the use of phosphazene base to give the corresponding pyrrole in reasonable yield fEq 10 36 ... 

The 3-nitroindoles show interesting reactivity toward the anion of ethyl isocyanoacetate iV-sulfonyl derivatives give the pyrrolo[3,3-b indole ring system lEq. 10.38. " On the other hand, iV-alkoxycarbonyl derivatives give the normal product, the pyrrolo[3,4-li indole ring system fEq, 10,39, ... 

Reaction of l-diethylaimno-2-tutroalkenes with ethyl isocyanoacetate in the presence of DBU at room temperanire, followed by quenching with HCl, leads to l-hydtoxypyra2oles m good yield fEq 10 89 ... 

The copper and nickel nitroporphyrins 6 (M = Cu, Ni) undergo pyrrole ring annulation with isocyanoacetates according to the Barton-Zard condensation originally designed for the preparation of simple monopyrroles112 (cf. Houben-Weyl, Vol.E6a, p650). 

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

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

Essentially no forerun need be taken prior to collection of the product. The last few milliliters of distillate were slightly yellow, and 2-3 g. of intractable material remained in the distillation flask. A boiling point of 76-78° (4 mm.) has been reported for ethyl isocyanoacetate. The submitters have found the distilled product to be stable for up to 6 months when stored under nitrogen in a freezer at -20°. 

Ethylenedioxybutyl)-3-trichloro-acetamido-l-cyclohexene, 58, 9, 11 Ethylene glycol, 56, 44 Ethyl a-fluoro-l-naphthaleneacetate, 57, 73 Ethyl 2-fluoropropanoate, 57, 73 3-Ethylhexane, 58, 3, 4 3-ETHYL-l-HEXYNE, 58, 1, 2, 3, 4 Ethylidenecyclohexane, 59, 46 Ethyliodide, 59, 133 Ethyl 2-iodo-3-nitropropionate, 56,65 Ethyl isocyanide, 55, 98 Ethyl isocyanoacetate, 59,184 l-Ethyl-4-isopropylbenzene, 55,10 Ethyl levulinates, 5-substituted, 58, 81 ETHYL 2-METHYL1NDOLE-5CARBOXY-LATE, 56, 72... 

Thiol protection, 59, 190 Thiono esters, reaction with ethyl isocyanoacetate, 59,187 Thionyl chloride, 55, 27 Thiophenol, 55, 122 58, 144 Thorium dodecanedioate, 56,110 Toluene, 56, 86 58,125 p-Toluenesulfonates, reaction with organo-cuprates, 55,112 p-Toluenesulfonic acid, 58, 57, 63 p-Toluenesulfonic acid, monohydrate, 56,44... 

Thiazoles from Ethyl Isocyanoacetate and Thiono Esters Ethyl Thiazole-... 

THIAZOLES FROM ETHYL ISOCYANOACETATE AND THIONO ESTERS ETHYL THIAZOLE-4-CARBOXYLATE... 

The present procedure is illustrative of a mild and general method for preparing thiazoles substituted in the 4-position with electron-withdrawing substitutents such as carbethoxy, cyano, and p-toluenesulfonyl. Thus condensation of ethyl isocyanoacetate with various thiono esters affords the parent ethyl thiazole-4-carboxylate as well as a series of analogs bearing substituents in the... 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

Methyl formate Formic acid, methyl ester (8,9) (107-31-3) Ethyl isocyanoacetate Acetic acid, isocyano-, ethyl ester (8,9) (2999-46-4)... 

The commercially available biphei rl ketone and ethyl isocyanoacetate underwent a smooth condensation reaction and following protecting group manipulations the hydrogenation snbstrate was produced in excellent yield. ° Examination of the asymmetric hydrogenation of material produced using this protocol revealed that the... 

Methyl isocyanoacetate See Methyl isocyanoacetate Heavy metals See other metal oxonon-metallates, reducants... 

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