Isocyanides esters

Other functional groups that are easily differentiated are cyanide (5c =110-120) from isocyanide (5c = 135- 150), thiocyanate (5c =110-120) from isothiocyanate (5c = 125 - 140), cyanate (5c = 105- 120) from isocyanate (5c = 120- 135) and aliphatic C atoms which are bonded to different heteroatoms or substituents (Table 2.2). Thus ether-methoxy generally appears between 5c = 55 and 62, ester-methoxy at 5c = 52 N-methyl generally lies between 5c = 30 and 45 and. S-methyl at about 5c = 25. However, methyl signals at 5c = 20 may also arise from methyl groups attached to C=X or C=C double bonds, e.g. as in acetyl, C//j-CO-. 

The addition of isocyanides and azide to aldehyde-derived enamines has led to tetrazoles (533,536). On the other hand the vinylogous amide of acetoacetic ester and related compounds reacted with aldehydes, isocyanides and acids to give a-acylaminoamides (534). Iminopyrrolidones and imino-thiopyrrolidones were obtained from the addition of cyclohexylisocyanide and isocyanates or isothiocyanates to enamines (535). An interesting method for the formation of organophosphorus compounds is found in the reactions of imonium salts with dialkylphosphites (536). 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

Malonic acid, amino-, diethyl ester, HYDROCHLORIDE, 40, 24 Malonic acid, bts(hydroxymethyl)-, DIETHYL ETHER, 40, 27 Malonitrile, condensation with tetra-cyanoethylene, 41, 99 2-Mercaptopyrimidine, 43, 6S hydrochloride of, 43, 68 Mercuric oxide in preparation of bromo-cyclopropane, 43, 9 Mesityl isocyanide, 41,103 5-Methallyl-l,2,3,4,5-pentachlorocyclo-pentadiene, 43, 92 Methane, dimesityl-, 43, 57 Methanesiileinyl chloride, 40, 62 Methanesulfonic acid, solvent for making peroxybenzoic acid from benzoic acid, 43, 93... 

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [4]. 

Mono- and dilithio derivatives of p-tosylmethyl isocyanide 297a were shown to display interesting reactions. Reaction of the monoanion with unsaturated esters was shown to give pyrrole derivatives . Dianion 297b was found to add to the carbon-nitrogen double bonds of isoquinoline, quinoline and quinoxaline affording compounds 298, 299 and 300, respectively. In the reactions with pyridine iV-oxide and pyridazine iV-oxide, unstable open-chain products 301 and 302 were obtained . 

For the dehydration of TV-formylamino compounds to give isocyanides the CDI is activated by protonation into its bisimidazolium form (CH3CN, room temperature, 4h). Thus, chiral a-isocyano esters and other base-sensitive isocyanides are obtained in high yield. CDI itself did not produce this dehydration. 

For the preparation of the 2,5-diketopiperazines 9-57 and 1,4-benzodiazepine-2,5-diones 9-58, respectively, the isocyanide 9-54 was either treated with an aldehyde and an amino acid, or with an aldehyde and an anthranilic acid, to give either 9-55 or 9-56, using the conditions depicted in Scheme 9.11. Further transformations include liberation from the resin with KOtBu forming N-acyloxazolidones and treatment with NaOMe to afford the corresponding esters, which are then cy-clized to the desired products 9-57 and 9-58 under acidic conditions. 

A classical non-isocyanide-based multicomponent process is the Biginelli dihydropyrimidine synthesis from 3-keto esters, aldehydes and urea or thiourea [63], The transformation was first reported in 1893 [64], but during the early part of the... 

Finally, a reaction should be mentioned in which a nucleophile gives support to another reacting species without appearing in the final product. Diphenyl cyclopropenone interacts with 2,6-dimethyl phenyl isocyanide only in the presence of tri-phenylphosphine with expansion of the three-ring to the imine 344 of cyclobutene-dione-1,2229,230 Addition of the isocyanide is preceded by formation of the ketene phosphorane 343, which can be isolated in pure formss 231 it is decomposed by methanol to triphenyl phosphine and the ester 52. 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

The 3-(isocyanomethyl)-l,2,4-oxadiazoles 176 (Scheme 23) have received widespread interest because of their ability to allow access to 3-imidazolyl-l,2,4-oxadiazoles 178 after isocyanide cyclization and phosphate elimination with imino phosphate esters 177. Typical examples are compounds 179-181, although well over 20 other examples have been synthesized <2002M1205, 2002M653, 2001H(40)1963, 1996JME4654>. 

The reactions of dimethyl phenylphosphonite with acid chlorides, a-halogeno-ketones, and iV-(bromomethyl)phthalimide have been used to prepare acyl phos-phinates, /3-keto-alkylphosphinates, and phthalimidomethylphosphinates as intermediates in the synthesis of a-diazophosphinic esters.39 a-Amino-phosphonates have also been prepared by the addition of secondary phosphites to nitriles40 and to isocyanides.41... 

In 1979, Schollkopf et al. " formed a-isocyano- 3-dimethylamino-acryl methyl esters 86, and Bienayme prepared many similar isocyanides,which can undergo a variety of heterocycles, forming reactions like the synthesis of 88 from 84-87 (Scheme 1.20). 

Synonyms AI3-28280 Aliphatic isocyanate BRN 0605318 CCRIS 1385 EINECS 210-866-3 Isocyanatomethane Isocyanic acid, methyl ester Methyl carbonimide Methyl carbylamine Methyl isocyanide MIC Monoisocyanate NSC 64323 RCRA waste number P064 TL 1450 UN 2480. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

The scope and limitations of the solid-supported symthesis of bicyclic diketopi-perazines 165 as peptide p-tum mimetic were further investigated by Golebiowski et al. [52]. The four-component Ugi reaction of a-iV-Boc-diaminopropionic acid resin ester 160 (an amine input) and optically active a-bromoacid 163 with various isocyanides 166 and aldehydes 167 yields a series of bicyclic diketopiperazines 165 (Scheme 28). 

Among the a-acidic isocyanides, isocyano esters (1) (for the first isolated example of a-acidic isocyano ester see [24]), isocyano amides (2) (for the first isolated example of a-acidic isocyano amide see [25]), and arylsulfonyl methyl isocyanides (3) (for the first report of TosMlC see [26]) have been studied predominantly, and therefore this mini review will mainly focus on the MCRs involving these species. 

Fig. 3 General methods for the preparation of isocyano esters (1), isocyano amides (2), and arylsulfonyl methyl isocyanides (3) (R = afkyl and/or H)...

Arylsulfonyl methyl isocyanides (3) and isocyano esters (1) can also be prepared by the deprotonation of alkylisocyanides (5) by strong bases (nBuLi or NaH) followed by the addition of TosF and dialkyl carbonates or ethyl chloroformate, respectively (pathB) [37, 38]. However, the use of small and foul-smelling alkyl isocyanides makes this route less attractive. 

For arylsulfonyl methyl isocyanides (3), [3 + 2] cycloadditions with aldehydes yielding 4,5-disubstituted oxazoles (N) have been reported [115]. The cycloaddition takes place in the same manner as with the use of isocyano esters (A, = H) ... 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

George and co-workershave investigated the reaction of cyclohexyl isocyanide (185) with DMAD and have shown that a major constituent of the product mixture is the 2 3 adduct (186) formed through a [6 -i- 4] addition of the initially formed intermediate (182) with the dipolar species (181, R = cyclohexyl). Thermal isomerization of 186 in refluxing xylene results in an isomeric spiro compound (187), whereas at higher temperatures, other valence isomers of 186 are formed (Scheme 29). - Winterfeldt had earlier isolated a 1 2 adduct (188) from the reaction of cyclohexyl isocyanide with DMAD. The reaction of some alkyl and aryl isocyanides with acetylenic esters in protic solvents, such as methanol, has been reported to give open-chain adducts with the incorporation of one or two solvent molecules. 

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