Cyanoester

IZV2087) 4-chloroquinazoline and benzyl sodiocyanoacetate give the cyanoester... 

Surprisingly, arylhydrazones 88a-d, upon treatment with 1-benzenesulfonyl-hydrazide 89 in refluxing ethanol, afforded very good yields of pyrazol-3-ones 90a-d (85JIC54) (Scheme 25). 5-Aminopyrazol-3-(Mies have also been synthesized from /3-cyanoesters (Section II,A,2) and from /3-iminoesters (Section II,A,3). 

A somewhat more complex side chain is incorporated by alkylation of the carbanion of the substituted cyanoacetate, 148, with 2-chloroethylmethyl sulfide. Condensation of the resulting cyanoester (149) with thiourea followed by hydrolysis of the resulting imine (150) affords methitural (151)... 

Because of difficulties in adjusting an ordinary glass stopcock to avoid leakage and to maintain a drop rate that would add the un-saturated cyanoester solution over a 40-hour period, the checkers recommend the use of a funnel equipped with a Teflon stopcock. 

An alternative is the strategy outlined above for (20) via (21), Since the two enolates needed are the same, a malonate derivative supplies them both and in practice cyanoester (30) is the most convenient. The version with ammonia to trap the intermediate as (31) i he Guaresci reaction. 

Fig. 31 Bis-Pd(II)-catalyzed asymmetric Michael addition of a-cyanoesters 57 to enones...

The present study reports the anti-inflammatory activity of vanilhn ethers, benzofuranyl coumarins, and unsaturated cyanoesters of 4-aryloxymethyl coumarins 36. When compared with the control all the compounds showed reduction in edema volume. 

It can be seen that though the aldehydic function is important for antiinflammatory activity as observed in compoimd 36, its conversion to the unsaturated cyanoesters 37 shows an increase in the activity. Similarly, the ethers 39 with the ortho aldehydic group upon conversion to benzofurans 6 show a sHght increase in activity. None of the compounds tested showed any analgesic activity. 

Both overt carbanions and organometallic compounds, such as Grignard reagents, are powerful nucleophiles as we have seen in their addition reactions with C=0 (p. 221 et seq.) they tend therefore to promote an SN2 pathway in their displacement reactions. Particularly useful carbanions, in preparative terms, are those derived from CH2(C02Et)2, (3-ketoesters, l,3-( 3-)diketones, e.g. (55), a-cyanoesters, nitroalkanes, etc.—the so-called reactive methylenes ... 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

Unsaturated cyanoketone 40 forms pyran 60 in reactions only with benzalmalononitrile 30 cyanoester 31 gives complex mixtures (86M247) (Scheme 10). 

Recently, Smulik and Vedejs have reported that sodium and potassium salts of phenylacetates, phenylacetonitriles, malonates and / -cyanoesters can be converted to their a-amino derivatives in good yields using 4a and 4b as amination reagents (Scheme 45) . Amination can be accomplished at lower temperature using 4b. 

Successful amination of chiral a-cyanoesters with 4a has been reported (Scheme 46) ". Appropriate reduction and removal of the chiral auxiliary give a,/3-diaminopropionic acids with good yield and enantiomeric excess. 

Scheme 6.129 Products prepared from the 121- and 124-catalyzed stereoselective Michael additions of a-chloroacrylonitrile and acrylonitrile to a variety to cyclic a-cyanoketones and acyclic a-substituted cyanoesters.

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to... 

The reaction is usually carried out in acid solution, but may also be base catalysed. This is the condensation between aldehydes, ammonia or a primary or secondary amine and a compound containing at least one active hydrogen atom e.g., ketones, b-ketoesters, b-cyanoesters, nitroalkanes, alkynes with C°H). For example. 

MI51800, 79AP514) and -cyanoesters (75MI51800). The l,4-benzodiazepin-3-one (150) has been prepared by the sequence shown (68CRV747, p. 763, 77JHC1139). 

Formation of the d bond by the reductive cyclization of a,oj- nitroketones (68CRV747, p. 778), -cyanoketones and -cyanoesters (74MIP51800) has been used in the preparation of both 1,4- and 1,5-benzodiazepines. 

Ring closure of certain thiophene diesters 74a or cyanoesters 74b under Dieckmann conditions (EtOH/EtONa) has recently been shown to give thieno[2,3-6]pyrroles (75a, b) in high yield (65-90%).72 A thieno-[2,3-6]pyrrole diester (75 R5 = OCH2COzEt) prepared in this way failed to undergo further cyclization to the tricyclic system 76 under the same conditions.7215... 

Dieckmann condensation of appropriately substituted diesters or cyanoesters has been reported to give good yields of some thieno[2,3-6]pyrrole derivatives. For example, thiophene diester (186) afforded the thieno[2,3- ]pyrrole derivative (187) in good yield upon... 

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