Phosphonates Knoevenagel reaction

A one-pot reaction between the phosphonodithioacetate 58 and a,P-unsaturated aldehydes proceeds via a Knoevenagel reaction and a 1,6-electrocyclisation and leads to a 277-thiopyran-5-yl phosphonate (Scheme 42). When 5-membered heterocyclic aldehydes are used, the intermediate is obtained admixed with the thiopyran or as the only product <07EJO4948>. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

K2CO3. No side reactions like the Cannizzaro or Knoevenagel reactions are observed on treatment with C-200. In the reaction with benzaldehyde and furfural the products 71 (R = Ph and 2-furyl) are formed nearly quantitatively. Bulky aromatic aldehydes such as pyrene-l-carboxaldehyde and aliphatic aldehydes are also suitable substrates for this process. ( )-acyclic a,/ -unsaturated ketones 74 can be prepared by use of a similar HWE reaction of 2-oxoalkanephosphonates 72 with aliphatic aldehydes 73 under the influence of barium hydroxide C-200 (Scheme 5.14) [36]. The HWE procedure employing activated Ba(OH)2 is applicable to the structurally complex, base-sensitive aldehydes which are susceptible to elimination and/or epimerization under the traditional basic conditions of the HWE reaction using NaH. For instance, when phosphonate 75 and aldehyde 76 are exposed to 0.8 equiv. activated Ba(OH)2 in aqueous THF at 20°C, (//-enone 77 is obtained in 70% yield (Scheme 5.14) [37]. 

Reaction of salicylaldehydes (488) with the tetraethyl ester of methylene-bisphosphonic add (489), under Knoevenagel reaction conditions, has provided the corresponding l,2-benzoxaphosphorin-3-phosphonates (490) in good yields. The [3 -I- 2] regio- and stereoselective cycloaddition reaction of (490), (491) and (492) with ethyl diazoacetate produced the corresponding epiineric pyrazoline bisphosphonate tetraethyl esters (Scheme 125). ... 

Scheme 5.36. Domino-Knoevenagel-hetero-Diels-Alder reaction of a-carbonylated phosphonates 183 and a-phosphonodithioesters 187 with aromatic aldehydes 184 and enol ethers 88.

Milder reaction conditions have been developed for the HWE reaction of phosphonate-stabilized carbanions to increase yields, accommodate sensitive substrates and to minimize undesired side reactions such as double bond migrations, the Cannizzaro reaction, Knoevenagel condensation and Michael addition. For example, a number of different bases have been employed to generate the carbanion. These include sodium hydroxide under phase-transfer conditions, potassium carbonate, barium hydroxide, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene (see Protocol 10).22... 

The synthesis of phosphonate analogues of phosphates and carboxylic acids is becoming increasingly important. Intramolecular olefination of the diphosphonate (161), itself prepared by a Knoevenagel condensation of D-lyxose S-aldehyde with methylene[bis(diethyl phosphonate)], provides a novel synthesis of the phosphonate analogue (162) of shikimic acid.7 8 Olefination of the a-D-mannopyranoside (163) with methylene[bis(diethyl phosphonate)] has been used as a key step in the synthesis of the monophosphonate analogue (164) of L-myo-inositol-l,4,S-triphosphate.79 Attempts to carry out the olefination reaction directly on the diphosphate (165) failed. 

Keywords Aldehydes, active methylene compounds, Bestmann-Ohira reagent [dimethyl(dia-zomethyl)phosphonate], potassium hydroxide, methanol, room temperamre, Knoevenagel condensation, one-pot multicomponent reaction, click chemistry, cycloaddition, phospho-nates, regioselective synthesis, phosphonyl pyrazoles... 

Condensation of aldehydo-pentose derivatives with cyanomethyl-phosphonate esters in a Knoevenagel type reaction led to the... 

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