Cyano-ethoxycarbonylation reactions

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. 

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.

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). 

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). 

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. ... 

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]. 

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

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

Because of the weak interaction between the H" " site and immobilized tertiary amine group, both the acid site and the amine group can act as catalytically active species. On the other hand, a nonimmobilized tertiary amine, such as triethylamine, strongly adsorbed on the acid site and deactivated each other. Therefore, SA-NEtj showed much higher activity for the above-mentioned Michael reaction and cyano-ethoxycarbonylation. These reactions hardly occurred with only siHca-alumina or the tertiary amine. The catalytic reaction pathway including acid-base cooperative activation is shown in Scheme 1.10. Similar to the case of silica-alumina, Al-MCM-41 was also reported as a support, which can enhance the amine-catalyzed nitroaldol reaction [14]. 

Reaction of various pyridazine derivatives with nitromethane or nitroethane in DMSO affords the corresponding 5-methyl and 5-ethyl derivatives. The reaction proceeds as a nucleophilic attack of the nitroalkane at the position 5. In this way, 3,6-dichloro-4-cyano-pyridazine, 4-carboxy- and 4-ethoxycarbonyl-pyridazin-3(2//)-ones and 4-carboxy- and 4-ethoxycarbonyl-pyridazin-6(lH)-ones can be alkylated at position 5 (77CPB1856). 

Thiophene, 2-amino-3-cyano-5-phenyl-synthesis, 4, 888-889 Thiophene, 3-amino-4,5-dihydro-cycloaddition reactions, 4, 848 Thiophene, 2-amino-3-ethoxycarbonyl-ring opening, 4, 73 Thiophene, 2-amino-5-methyl-synthesis, 4, 73 Thiophene, 2-anilino-synthesis, 4, 923-924 Thiophene, aryl-synthesis, 4, 836, 914-916 Thiophene, 2-(arylamino)-3-nitro-synthesis, 4, 892 Thiophene, azido-nitrenes, 4, 818-820 reactions, 4, 818-820 thermal fragmentation, 4, 819-820 Thiophene, 3-azido-4-formyl-reactions... 

Reaction of 2-aminopyridine with ethyl 2-cyano-3-ethoxy-3-methyl-, -3-ethyl-, -3-phenylacrylates and ethyl 2-ethoxycarbonyl-3-ethoxy-3-methyl-, -3-phenylacrylates in boiling xylene yielded 2-substituted 4/f-pyrido[l,2-u]pyrimidine-3-carbonitriles and -3-carboxylates (99MI7). Similar reactions of 2-aminopyridine with 2-cyano-3-ethoxyacrylonitrile and its 3-methyl, 3-ethyl, -3-phenyl derivatives in boiling MeCN afforded 4-imino-4//-pyrido[l,2-u]-pyrimidine-3-carbonitrile and its 2-substituted derivatives. 

In this method, the 1,2-N-S bond and the 2,3-N-C bond are formed. This is a useful method for the preparation of 3-hydroxy- or 3-amino-5-substituted-l,2,4-thiadiazoles starting from either an ethoxycarbonyl or a cyano thioimino-carbonate. Thus the condensation reaction of the ethoxycarbonyl thioiminocarbonate 100 with chloramine at low temperatures affords 3-hydroxy-5-substituted-l,2,4-thiadiazoles 100 (Equation 28) <2004HOU277>. 

Since the pyrido[2,3-pyrimidine ring system is found to exist in a number of biologically active compounds, these rearrangements were extensively studied. Reaction of compound 86 with malononitrile leads to 7-amino-6-cyano-l,3-dimethylpyrido[2,3-ethyl cyanoacetate, 7-amino-6-ethoxycarbonyl-l,3-... 

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

A number of reduced pyrazolo[3,4-c]pyridines have been prepared by cyclization of 3-piperidones substituted in the 4-position. For example, reaction of 4-ethoxycarbonyl- or 4-cyano-3-piperidones (125 X = C02Et or CN) with hydrazine afforded the pyrazolones 126a (R1 = H)119 or amines 127,120 respectively. 

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