Alkyl isocyanoacetates

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... 

Isocyanides have also been used to prepare unsaturated 5(4//)-oxazolones and they are particularly useful for the synthesis of 4-(aminomethylene)-5(4//)-oxazo-lones 374. For instance, cyclization of an unsaturated isocyanide obtained from condensation of alkyl isocyanoacetates and lactam acetals has been reported (Scheme 7.120). ° ... 

This unique pattern is represented in a rather special 2 1 condensation of alkyl isocyanoacetates with aldehydes (equation 129). Mechanistically, an initial conjugate addition followed by an anionic cyclization is likely. Yields of around 60% are obtained (74JOC1980). 

The Barton Zard condensation is one more important and marvelous SnH heterocyclization leading to pyrrole ring annulation to nitroalkenes, nitroarenes or nitrohetarenes on being treated with alkyl isocyanoacetates in the presence of a base (85CC1098, 90T7587). The reaction starts with nucleophilic attack of alkyl isocyanoacetate carbanion 160 ortho to the NCT group of substrate 161. The... 

Pyrrole synthesis. A new route to pyrroles1,2 is based on a base-catalyzed Michael addition of an alkyl isocyanoacetate to a nitroalkene to give an intermediate that cyclizes to a pyrrole. The nitroalkene is generally obtained from a P-acetoxy nitroalkane (1), prepared by a nitro aldol reaction of an aldehyde with a nitroalkane. The synthesis of ethyl 3,4-diethylpyrrole-2-carboxylate (2) is typical. 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

Pyrrole-2,4-dicarboxylates. In the presence of this base, aldehydes condense with alkyl isocyanoacetates to form alkyl pyrrole-2,4-dicarboxylates in 50-70% yield. 

Alkyl isocyanoacetates, 158 Alkyl 4-methylphenyl sulfones, 567 d-Alkyl-a-methylacroleins, 14 Alkyl orthotitanates, 11 2-Alkyl-l-oxo-2-cyclopentenes, 284... 

Polycyclic nitroaromatic compounds 99 and 100 have been found to react with alkyl isocyanoacetates into the corresponding pyrroles 101 [82] and 102 [81, 84] (Scheme 46). 

Alkyl isocyanoacetates are important building blocks in the synthesis of ox-azoles. Marcaccini [1196] employed N-methylisocyanoacetanilide 1588 as an iso-cyanoacetate derivative to prepare 2,4-diarylthio-5-N-alkyl-N-phenylaminooxazoles 1589.1588 was prepared in 69% yield from its formamide 1587 [1196]. 

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. 

Base-induced reaction of nitroalkenes with alkyl a-isocyanoacetates to afford pyrroles. 

The Barton-Zard pyrrole synthesis <1990T7587> was applied in the syntheses of pyrrolo[3,4- ]indoles 423 from 3-nitroindoles 422. Treatment of appropriate alkyl 3-nitroindole-l-carboxylates 422a-c with ethyl isocyanoacetate and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the corresponding pyrrolo[3,4- ]indole 423a-c (Equation 12) <1997CC1873, 1999S1117>. 

Reaction of the anion of tert-butyl isocyanoacetate with oxiranes gives the y-hydroxy products 11, which upon mesylation can be transformed by an intramolecular alkylation to the iso-cyanocyclopropanecarboxylates 12, the precursors of 1-amino-cyclopropanecarboxylates100. The cyclization 11 — 12 shows a relatively high degree of stereoselectivity due to the difference in bulkiness betwen the isocyano and the tert-butoxycarbonyl groups. 

Ito and Hayashi noticed that Au(I)-chiral fenocenylphosphine complexes are remarkably efficient in the Knoevenagel reaction between aldehydes and isocyanoacetic esters to form 5-alkyl-2-oxazoline-4-car-boxylates with high enantio- and diasteieoselectivity (Scheme 116)... 

Hebach and Kazmaier reported the synthesis of cyclic peptidomimetics containing an alkylated amino acid via Ugi-4CR of N-terminal-protected aloc-amino acids, allyl isocyanoacetate, and chiral amines in trifluoroethanol. Allylic esters of tripeptides 193 were obtained in high yields and good stereoselectivity. Metathesis with 5% of Grubbs first-generation catalyst gave 16-membered cyclic peptides 194 in 30-50% yield (Scheme 2.69) [101]. 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

The oxidation of the alcohol was performed with supported perruthenate (8.48, Fig. 8.46) to produce clean aldehydes 8.91 after filtration. The Henry reaction was performed in the presence of a commercially available, supported strong base 8.92 and an excess of volatile nitroalkenes, giving clean nitroalcohols 8.93 after filtration and evaporation. The reaction mixtures from the trifluoroacetylation/elimina-tion steps were purified with commercially available amino PS resin 8.58 to scavenge the trifluoroacetates and with acidic ion-exchange resin 8.76 to remove the TEA-derived salts. Again, the nitrostyrenes 8.94 were obtained cleanly after filtration and evaporation. Cycloaddition with isocyanoacetate was promoted by the commercially available, supported guanidine base 8.95, while the subsequent N-alkylation of the pyrroles 8.96 was performed with an excess of halide in the presence of the commercially available, supported phosphazene 8.97. In this case, the excess halide was removed by treatment with supported 8.58, and filtra-... 

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with Af,A -dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48]. 

Analogous to the TOSMIC reactions is the cyclocondensation of an isothiourea with the enolate of ethyl isocyanoacetate (12) to give an alkyl 5-aminoimidazole-4-carboxylate (13). This regioselective synthesis provides... 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

Ruthenium(ll)-catalyzed cycloaddition reactions of Y-sulfonylimines 1308 with methyl isocyanoacetate 1309 gave /ra r-2-imidazolines 1310 stereoselectively in 75-90% yields under neutral, mild conditions [R = phenyl, substituted phenyl, 2-furyl, lrans-PhCH=CH, tert-Bu R = tosyl, PI1SO2] (Scheme 333) < 1997JOG1799>. In contrast, the same reaction catalyzed by 1 mol% AuCl(( -HexNG) provides 4-methoxycarbonyl-5-alkyl-2-imidazolines 1321 with over 98% -selectivity (Scheme 333) <1996TL4969>. 

Both /ranj-selectivity and enantioselectivity depend on the structure of the terminal amino group, six-membered ring amines represented by piperidino 8g and morpholino 8h generally being most selective [71]. Substituted aromatic aldehydes, a,i -unsaturated aldehydes, and secondary and tertiary alkyl aldehydes can be converted into the corresponding /ranj-oxazolines with high enantioselectivity. Enantiomeric purities and transjcis ratios obtained for the aldol reaction of several aldehydes in the presence of Au/(R)-(S)-8h are shown in Scheme 2-51. The gold-catalyzed aldol reaction of isocyanoacetate has been applied to the synthesis... 

For the aldol reaction of small alkyl aldehydes such as acetaldehyde, the enantioselectivity is improved by the use of Ar,A -dialkyl-oe-isocyanoacetamides instead of isocyanoacetate esters (Scheme 2-54) [76]. For example, the reaction of acetaldehyde with AT,iV-dialkyl-a-isocyanoacetamides 64 in the presence of R)- S)-8g/gold catalyst gives the corresponding /ranj-oxazoline 65 of 99% ee, which is much higher than the enantioselectivity (85% ee) observed in the reaction with methyl isocyanoacetate under the same reaction conditions. 

Carbanions derived from isocyanoacetates formed in situ using NaH react with acylphosphonates to give l-alkyl-2-ethoxycarbonyl-2-formylaminoeth-l-enylphosphonates [45]. Cu20 catalysis provided stereoselectivity, giving mainly the Z-isomer. 

Alkyl- and arylisothiocyanates react with methyl a-isocyanoacetate (302) in the presence of potassium t-butoxide to give 5-amino-4-ethoxycarbonylthiazoles (303) (Equation (53)) <82S874>. 

Use of isocyanoacetamide 5 instead of isocyanoacetate 3 improves the enan-tioselectivity of the aldol reaction with acetaldehyde and primary alkyl aldehydes (R=Me 99% ee, trans cis=9H9, R=Et 96% ee, trans cis=95 5, R=z-Bu ... 

Gold(I)/ferrocenylphosphine 2a-d complexes are applicable to asymmetric aldol reactions of a-alkyl substituted a-isocyanoacetates 12. Although the dependency of stereoselectivity on the structures of the substrates is fairly large, some combinations of 12 and aldehydes show high enantio- and diastereoselec-tivity (Scheme 3). The reaction with paraformaldehyde yields (S)-4-alkyl-2-ox-azoHne-4-carboxylates in 64 to 81% ee, which can be readily transformed to the... 

---