Amidoximation

Ion-Exchange Resins. Some attempts have been carried out to recover galHum by ion exchange (qv). Only the commercially available amidoxime resin has proved to be effective for the recovery of galHum from Bayer Hquor. The process has been developed and patented (13) and is reported to be under operation in Japan. 

Cyanopyridazines add ammonia, primary and secondary amines and hydroxylamine to give amidines or amidoximes. Substituted amides, thioamides and carboximidates can be also prepared. With hydrazine, 3-pyridazinylcarbohydrazide imide is formed and addition of methylmagnesium iodide with subsequent hydrolysis of the imine affords the corresponding pyridazinyl methyl ketone. 

Beckmann rearrangement of amidoximes to urea derivatives in the presence ol acids (benaene suMonyl chloride). 

Amino-4-cyanofurazan has been prepared by treatment of amidoxime 77 with Pb02 in acetic acid (94CHE608, 94KGS693) (Scheme 43). 

The mononuclear heterocyclic rearrangement (MHR) of isoxazole-3-amidoxime 108 in the presence of a base and hydroxylamine with concomitant removal of the amide moiety affords furazan acetaldoxime 109 (Scheme 56) (91CHE651, 91KGS827). 

To this mixture, under continuous stirring and controlling of the reaction temperature to remain beyond 15°C, there is slowly added (3-chloropropionyl chloride. After addition of the acid chloride, stirring is continued for a further hour. Then with cooling there is added portionwise a small amount of water. Further amounts of water are introduced into the reaction mixture and the chloroform solution containing the /3-chloropropionyl a-ethylbenz-amidoxime is separated. 

In 2005, a group of researchers at Abbott turned their attention to the synthesis of a different regioisomer, the 1,2,4-oxadiazoles [75]. These heterocycles are normally prepared by reaction (mediated by a couphng reagent) of a carboxyhc acid with an amidoxime, followed by based-catalyzed cychzation at high temperature (Scheme 11). 

An alternative reported in the same publication involves the in situ conversion of the carboxylic acids to the corresponding acyl chlorides using PS-PPh3 and CCI3CN (THE, 10 °C, 5 min) before treatment with the amidoxime in the presence of DIEA (THE, 150 °C, 15 min). The resin-bound phosphine not interfering with the second step, and THF being the best solvent for both steps, the two-steps sequence could be performed one-pot with yields comparable to those obtained using the HBTU/PS-BEMP combination (Scheme 12). 

Scheme 12 Synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using PS-reagents...

The first A/ -oxides of the 1,2,4-thiadiazole ring system have been reported and were prepared by condensation of benzamidoximes (86) with 4,5-dichloro-l,2,3-dithiazohum chloride (87). A -labelling showed the compounds to be 4-oxides (88) and a mechanism was proposed for their formation. Alkyl amidoximes and arylamidoximes with electron-withdrawing substituents did not give A/ -oxides, but only the dithiazolone (89) and the dithiazolthione (90) <96CC1273>. 

C. Nucleophilic Attack on Other Atoms.—Amidoximes have been shown to react with tris(dimethylamino)phosphine by displacing dimethylamine to give the phosphine oxides (52), but some N-substituted aromatic amidoximes give derivatives of (53). ... 

Aminophosphines and amidoximes are reported to form the phos-phoramide derivative (63) however, a similar reaction with amidoxime ethers gives the diazadiphosphetidine (64). ... 

Michael addition of amidoxime 7 to DMAD, followed by thermal rearrangement. 

Literature reports on synthetic methods for the construction of the pyrimidinone core were very limited. Most of the synthetic strategies toward the densely functionalized core fell into two methodologies, which start from the same amidoxime 13 (Scheme 6.3). Route A is a three-step sequence that involves hydrogenation of 13 to prepare amidine 14. Claisen condensation of commercially available a-benzyloxy acetate and methyl tert-butyl oxalate provides the dihydroxyfumarate... 

E- and Z-Amidoxime DMAD adduct issues for the thermal rearrangement The... 

Scheme 6.5 Thermal rearrangement of - and Z-amidoxime-DMAD adducts.

The solvent and temperature effects for the Michael addition of amidoxime 7 to DMAD were probed because the reaction itself occurs without any other catalysts. As shown in Table 6.2, the reaction gave a high ratio of 8E in strongly aprotic polar solvents such as DMF and DMSO (entry 1 and 2). 8E was also found as the major product in MeCN (entry 3), dichloromethane (entry 4), and xylenes (entry 5). To our delight, the desired 8Z was obtained as the major component in methanol (entry 6). The stereoselectivity of 8Z versus 8E was better at low temperature (entry 7). A similar result was observed when the reaction was run in THF or dichlo-roethane in the presence of a catalytic amount of DABCO (entries 9 and 10). 

HIV Integrase Inhibitor Raitegravir Table 6.2 Optimization of stereoselective amidoxime addition to DMAD. 

Since the key thermal rearrangement was optimized, we turned our attention to earlier steps. The synthesis of amidoxime 7 was optimized from acetone cyanohydrin 4 (Scheme 6.6). The original Strecker reaction was carried out with ammonia... 

An efficient and practical synthesis of Raltegravir (1) was developed via a key thermal rearrangement of amidoxime DMAD adducts to construct the key highly functionalized hydroxpyrimidione 3. 

The thermal rearrangement of the amidoxime DMAD Z-adduct 8Z was more robust to be converted to the desired product 3 than the corresponding E-adduct 8E. This discovery opened a new door for us to revisit this old chemistry. 

Table 6.4 Scope of selectivity of amidoxime addition to DMAD and hydroxypyri midi none formation via microwave-accelerated thermal rearrangement. 

In another example using the isomeric amidoxime substrate 61, the formation of the expected [3,3]-rearrangement product 63 was not observed (Scheme 6.22). Instead the Z-adduct 62Z cyclized to oxadiazoline 64. Interestingly, the E-adduct 62E rearranged to hydroxypyrimidinone 60 and imidazole 66 instead of 63. The rearrangement of the substrate 62E was proposed to occur via intermediate 65 via a [l,3]-sigmatropic rearrangement which, after cyclization, led to the observed products 60 and 66. 

Since the exact mechanism of the rearrangement of unsubstituted amidoxime DMAD adduct 51 was unclear, we decided to undertake our own studies. These... 

Scheme 6.24 Corrected B3LYP energies and relevant transition structures and intermediates in the possible rearrangement mechanisms of amidoximes-DMAD adducts 68Z/E.

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