Cyano-ethoxycarbonylation

Experimental Procedure 3.1.4. Preparation of a Molybdenum Vinylidene Complex from a Carbyne Complex Tetrabutylanunoniuih Cyano(ethoxycarbonyl) vinylidene (dicarbonyl) hydro-tris(3,5-dimethyl-1 -pyrazblyl)borato molybdenum [526] [37] pp 151 and 188... 

Heating ethyl 5-fluoro-4-[cyano(ethoxycarbonyl)methyl]-2,3-dihydro-l-methyl-7-oxo-l//,7//-pyrido[3,2,l-i7]cinnoline-8-carboxylate (83, R = COOEt) in a mixture of cone. HCl and acetic acid gave the 8-carboxy-4-acetic acid derivative (92EUP470578). The acetic acid group was decarboxylated by heating in boiling ethanol in the presence of NEts to give the 4-methyl derivative. When the 4-[cyano(tert-butoxycarbonyl)methyl]-8-carboxylate 83 (R = COOrBu) was treated with trifluoroacetic acid in methylene chloride at room temperature, the 4-cyanomethyl-8-carboxylate 83 (R = H) was obtained. 

Absorption spectra for mesoionic 3-phenyl-1,2,3,4-thiatriazolium-5-cyano(ethoxycarbonyl) methylide, 5-di(ethoxycarbonyl) methylide, 5-/ -toluenesulphonamidate, and 5-(Y-methylanilino) iodide have been reported <93MRC447>. See also Section 4.19.2.3. 

The related cyclization of 2-ethynylanilines 67 also represents one of the usefiil methods for the synthesis of 2-substituted indoles since the precursors are easily prepared from 2-haloanilines 66 by Pd-catalyzed cross-coupling with terminal alkynes. Althou cyclizations of such alkynes are normally effected using Cu(I) or Pd(II) species, Sakamoto showed that in the absence of such metals, base catalysis (e.g., NaOEt) alone can accomplish the same goal. This author now reports that tetrabutylammonium fluoride (TBAF) is capable of inducing cyclization to the indoles 68 without affecting functionalities such as bromo, cyano, ethoxycarbonyl, and ethynyl <99JCS(P1)529>. 

Cyan-difluoro-methyl)-pentafluoro-ElOa, 265 (2H -> 2F) 4-(Cyano-ethoxycarbonyl-melhyl)-3-nitro-l-trifiuoromcthyl- E6b/I, 566 (Ar - Cl + NC-CH2 -COOR)... 

An important issue with respect to the Knovenagel condensation is that a mixture of isomeric disubstituted 3-methyleneoxindoles can be obtained. NMR measurements, including nOe experiments, and quantum chemical calculations have also shown that 3-[cyano(ethoxycarbonyl)methylene]-2-oxindoles, which are obtained from the reaction of isatin or from 1-methylisatin with ethyl cyanoacetate, exist as a mixture of the E and Z isomers, and that the E isomer exists in an equilibrium between two conformers, trans-s-cis and (rans-s-/ram431 (Scheme 100). 

Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid (0.29 mmol) dissolved in 2 ml DMF was treated with A-ethylmorpholine (1.16 mmol), 1 -pyridin-4-ylmethyl-piperazine (0.29 mmol), and 0-((cyano(ethoxycarbonyl)methylene)amino)-l, 1,3,3-tetramethyluronium tetrafluoroborate (0.3 mmol), then stirred 60 minutes at ambient temperature. The mixture was concentrated, then dissolved in CH2C12, washed three times with saturated NaHC03 solution, dried with Na2S04, and reconcentrated. The residue was purified by chromatography with silica gel using n-heptane/EtOAc, 1 1, then EtOAc, and finally EtOAc/methyl alcohol, 10 1, and 102 mg product isolated. MS ES+, m/z = 500 (M+)... 

Cyano(ethoxycarbonyl)methylene)amino)-N,N,N, N -tetramethyluronium tetrafluo-roborate (1.42 mmol) and N,N-diisopropylethylamine (1.35 mmol) were added successively with ice cooling to a solution of the product from Step 6 (1.42 mmol) and ethyl (S)-3-amino-3-phenylpropionate (1.42 mmol) dissolved in 20 ml DMF. After 1 hour at ambient temperature the solvent was removed and the residue dissolved in EtOAc. The solution was successively washed twice with aqueous solutions of KHSO4, NaHC03, and brine. The organic phase was dried, concentrated, the product isolated by chromatography on silica gel using EtOAc/heptane, 1 1, and the product isolated in 85% yield. 

Tetrahydropyridines. This reagent selectively reduces various pyridinium salts substituted at the 4-position to 1,2,5,6-tetrahydropyridines in 50-90% 5deld. The reaction probably occurs in two steps. Nitro, amido, cyano, ethoxycarbonyl, and even keto groups are not affected. 

Fig. 23.3 Acid/base catalyst from the Iwasawa group, containing organic amines tethered to acidic sihca-alumina. This material was found to catalyze the cyano-ethoxycarbonylation (best when R = Me) and nitroaldol reaction (best when R=H) of benzaldehyde [10]...

Phosphorus-containing Ring Systems. - A range of new chiral oxazaphospholidine oxides 266 and 267 have been synthesised and used as catalysts in asymmetric reductions of ketones with diborane. Mannich-type cyclisation reactions of 5-amino-3-benzylthio-4-cyano(ethoxycarbonyl)pyrazoles with dichlorophenylphosphine and aromatic aldehydes in the presence of cation exchange resin have been used to prepare a number of 6-oxo-6-phospha-4,5,6-trihydroimidazolo[l,2-b]pyrazoles, e.g. 268. Some of these compounds have herbicidal activity and this report is typical of a number of similar ones in the Chinese literature. A number of metallocycles, e.g. 269, have been reported as products from reactions of transient zirconocene-benzyne intermediates with phosphaimines followed by sulfuration or selenation. ... 

In a related reaction, ethyl cyanoacetate is the source of the cyano(ethoxycarbonyl)methylene unit which is transferred to alkenes by a radical mechanism, e.g. synthesis of 3. This transformation is mediated by copper(II) chloride or acetate, accompanied by lithium chloride. Synthesis of diethyl cyclopropane-1,1-dicarboxylates from diethyl malonate and alkenes is much less efficient. ... 

The reaction of ethyl [4,5-dihydro-4-oxothiazol-2-yl]acetate with 2-cinnamoyl-2-(hydroxyimino)-acetonitrile is reported to yield ethyl 3-[cyano(ethoxycarbonyl)methyl]-5.6-dihydro-5-hydroxy-7-phcnylpyrido[2,3-6]pyrazinc-2-carboxyIate.71... 

The reactions of l-aminocarbonylmethylene-3,4-dihydro- and 1,2,3,4-tetrahydroisoquinolines with lV,lV-dimethylcarboxamide diethyl acetals, triethyl orthoformate, and diethyl carbonate yielded 6,7-dihydro-2//-pyrimido[6,l-a]isoquinolin-2-ones [81KFZ(5)44 82KGS1095 84JMC1470] and 9,10-dimethoxy-3,4,6,7-tetrahydro-2//-pyrimido[6,l-n]isoquinoline-2,4-dione (84JMC1470), respectively. A mixture of l-ethoxycarbonyl-9,10-dimethoxy-3,4,6,7-tetrahydro-27/-pyrimido[6,l-fl]isoquinoline-2,4-dione and l-[cyano(ethoxycarbonyl)methylene]-l,2,3,4-tetrahydroisoquinoline was obtained when 6,7-dimethoxy-l-aminocarbonylmethylene-l,2,3,4-tetrahydroisoquinoline was reacted with ethyl chloroformate in methylene chloride in the presence of pyridine (84JMC1470). 

Cyano ethoxycarbonyl (phthalazin-2-io)methanide (61) gave dimethyl 3-ethox-ycarbonylpyrrolo[2,l-fl]phthalazine-l,2-dicarboxylate (62) (for details and possible mechanism, see original). 

The mechanism of reaction of a variety of triphenylphosphinealkyl-gold(i) complexes, and of triphenylphosphinetrimethylgold(iii), with mercury(n) chloride in a variety of solvents is St2. But when the alkyl group is cyano(ethoxycarbonyl)pentyl then the mechanism is dissociative. Decomposition of triphenylphosphine-n-butylcopper must involve initial formation of butene and a transient copper hydride rather than of n-butyl radicals, since no octane can be detected in the ultimate products. ... 

Acid and base pairs are known to activate molecules simultaneously and efficiently via dual coordination to promote reactions [1, 2, 43]. Acid and base sites on amorphous SA-supported aminopropyl groups (SA-NEt2), prepared by the treatment of SA with 3-(diethoxyamino)propyltrimethoxysilane, promoted the cyano-ethoxycarbonylation reaction in nonpolar solvents such as toluene and diethyl ether (Scheme 6.17) [121]. A proposed mechanism involves the dual activation of donor and acceptor substrates at the amine base site and the neighboring Bronsted acid site on the SA surface, respectively. 

It was proposed that the pyridine nitrogen is protonated by the strongest acid sites on SA, while the remaining acid sites and unprotonated pyridine nitrogen act as a highly active acid and base, respectively (Scheme 6.20). This mechanism has been extended to cyano-ethoxycarbonylation [123, 124], 1,4-addition reactions of nitroalkanes and thiols to electron-deficient alkenes such as methyl vinyl ketone and cyclic a,fl-unsaturated ketones [125], Diels-Alder [126], and nitro-aldol reactions [97, 123]. 

Figure 7.6 Proposed catalytic mechanism of surface acid/base interaction for cyano-ethoxycarbonylation [64].

Table 7.6 Cyano-ethoxycarbonylation and Michael reaction using a site-isolated amine catalyst and related compounds [64].

Cyano-ethoxycarbonylation Michael reaction yield %] yield %]... 

The lanthanide (or yttrium)-lithium heterobimetallic complexes, LnLB was found to promote catalytic asymmetric cyano-ethoxycarbonylation reaction and cyano-phosphorylation reaction of aldehydes [164]. In these reactions, H2O, BuLi, and Ar3P(0) (Ar = 2,6-dimethoxyphenyl) were essential to achieve high enantioselectivity as well as good reactivity (Scheme 13.53). A total synthesis of patulolide C was achieved using the catalytic asymmetric cyano-ethoxycarbonylation reaction... 

Scheme 13.53 Catalytic asymmetric cyano-ethoxycarbonylation reactions.

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