Neat conditions

Aliphatic trialkyl phosphites also reacted with HHT 25 under neat conditions and elevated temperatures (>100 °C) to produce glyphosate triesters such as 26 (27). However, the reaction proceeded at much lower temperatures (10 °C) when titanium tetrachloride was present in equimolar amounts (33). 

An interesting variation of this reaction that made use of a three-component, one-pot solventless procedure with the corresponding trialkyl phosphites gave dramatically improved yields of many heterosubstituted glyphosate phosphonate diesters (37). When exactly one equivalent of water, 25, and tris-p-chloroethyl phosphite were mixed and heated under neat conditions for a few hours, nearly quantitative yields of displaced p-chloroethanol and the desired triester product 27 were obtained. If desired, the displaced alcohol was first removed by vacuum distillation, or the mixture could be hydrolyzed directly to GLYH3. Various oxygen, sulfur, nitrogen, cyano, and carboxylate functionalities were similarly accommodated in the trialkyl phosphite. 

Considerably higher product yields resulted under much milder conditions when diaryl phosphites were condensed with ffilTs. Whereas vigorous neat conditions and temperatures exceeding 100 °C were usually necessary with aliphatic phosphites, often quantitative conversions to the desired glyphosate derivatives were obtained in common organic solvents using aromatic or benzylic phosphites (40). 

The herbicide activity ascribed to the 1,2,4-oxadiazole derivative 67 (60) has prompted the search for other biologically active derivatives. This example was prepared from the corresponding 5-chloromethyl-1,2,4-oxadiazole 63 via conversion to the HHT 65 through the aminomethyl analog 64. Reaction of the HHT 65 with diethyl phosphite under neat conditions produced the desired diethyl ester intermediate 66, which was hydrolyzed to 67. 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

Wang and co-workers [57,58] reported several Michael-type enantioselective additions with nitro-olefins. Under neat conditions, 1,3-dinitro compounds were generated in the 74 addition of nitroalkanes 75 to various P-substituted nitro-olefins (Scheme 15). Other Michael-type involving nitro-olefins reactions were illustrated using triazole donors 77 to offer good yields and high enantioselectivities (Scheme 16). 

Furthermore, to clarify the difference between task specific ionic hquids (or also called functionahzed ionic hquids) and chiral ionic hquids, one very successful example of a task specific ionic hquid 63 is presented in Scheme 65. This catalyst with a loading of 15 mol% under neat conditions gave up to 100% yield and 99% ee in the Michael addition of cyclohexanones to nitroolefms [179]. This catalyst belongs to the field of the prohne catalyzed reactions. 

Khurana JM, Magoo D (2009) pTSA-catalyzed one-pot synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo a xanthen-ll-ones in ionic liquid and neat conditions. Tetrahedron Lett 50 4777 780... 

Nagarajan AS, Reddy BSR (2009) Synthesis of substituted pyranopyrazoles under neat conditions via a multicomponent reaction. Synlett 2002-2004... 

Under optimized conditions regarding the choice of Br0nsted acid (mandelic acid 20), stoichiometry (1 1 ratio 9 and mandelic acid 20), solvent (the respective alcohol neat conditions), temperature (rt or 50°C), and catalyst loading (lmol% 9 and lmol% mandelic acid 20) electron-rich and electron-deficient styrene oxides underwent alcoholysis with simple aliphatic, stericaUy demanding as well as unsaturated and acid-labile alcohols. The completely regioselective (>99%) alcoholysis was reported to produce the corresponding P-aUcoxy alcohols 1-10 in moderate (41%) to good (89%) yields without noticeable decomposition or polymerization reactions of acid-labile substrates (Scheme 6.27). Notably, aU uncatalyzed reference experiments showed no conversion even after two weeks under otherwise identical conditions. 

Figure 6.34 Bis-(thio)ureas 111-114 derived from IPDA and results of the screening in the DABCO-promoted MBH reaction between cyclohexanecarbaldehyde and 2-cyclohexen-1-one under neat conditions at 10°C.

This neat condition provides a good guidance for the single spike method. 

The use of 3-methylpyrazole combined with 1-methylimidazole as the nitrogen bases has also recently been explored, giving very good results at low catalyst loading (0.2-0.3 mol%). It was shown that with this system in neat conditions, the desired epoxide can be obtained in very good yield (91%) [55],... 

Many microwave-assisted reactions have been described using neat conditions such conditions can be attractive from an environmental and process productivity point of view. Neat reactions may be assisted by the presence of, or by support on, a microwave active solid, such as a zeolite (e.g., a molecular sieve) or Montmorollinite clay. A great deal of processing flexibility is possible using combinations of the above with microwave irradiation inputs of varying intensity. 

We next carried out selective esterification of two substrates in this reaction system. When a 1 1 mixture of lauric acid and acetic acid was esterified with dodecanol in the presence of DBSA under neat conditions at 40°C for 48 h, the laurate ester and the acetate ester were obtained in 63% and 35% yields, respectively (Table 13.7, entry 1). On the other hand, when the same reaction was conducted in water, the laurate ester was predominantly obtained in 81% yield, and the yield of the acetate was only 4% (entry 2). Similar selective esterification of lauric acid over acetic acid was also observed in the reaction of another alcohol (entry 4), Furthermore, even cyclohex-anecarboxylic acid, which is an a-disubstituted acid, was preferentially esterified in the presence of acetic acid (entries 5 and 6). These selectivities are attributed to the hydrophobic nature of lauric acid and cyclohexanecarboxylic acid as well as to the high hydrophilicity of acetic acid. These unique selectivities became possible by using water as a solvent. Selective esterification based on the difference in hydrophobicity was also attained in the reaction of two alcohols, one of which is hydrophobic and the other water-soluble. 

Formaldehyde is employed in Mannich reactions either as an aqueous solution ( formalin ) or in the form of paraformaldehyde or trioxanc. The amine reactant is used as a free base or hydrochloride. The most commonly adopted solvents for the reaction are alcohols (ethanol mainly, methanol, and isopropanol), water, or acetic acid. Aprotic solvents or neat conditions are also occasionally used. 

The synthesis of 5-aryl-2-(2-hydroxyphenyl)-l,3,4-oxadiazoles (xL) reacting salicylic hydrazide (xxxix) with carboxylic acids in the presence of thionyl chloride under neat conditions is described [37]. 

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