Utilization of wieland furoxan synthesis for preparation of 4-aryl-1,2,5-oxadiazole-3-yl carbamate derivatives having potent anti-HIV activity

doi:10.1016/0960-894X(96)00355-1

Bioorganic & Medicinal Chemistry Letters

Volume 6, Issue 16, 20 August 1996, Pages 1993-1996

https://doi.org/10.1016/0960-894X(96)00355-1 Get rights and content

Abstract

The classical Wieland furoxan synthesis was reinvestigated and this procedure was applied to the preparation of 4-aryl-1,2,5-oxadiazole-3-yl N,N-dialkylcarbamate derivatives, which were found to exhibit potent anti-HIV-1 activity.

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Furoxans are distinctive heteroaromatic compounds in that they are potentially capable of releasing nitric oxide under physiological conditions. In order to utilize the furoxan scaffold for the development of functional molecules, synthetically relevant functional groups are required for access to diverse furoxans. In this report, a facile route to furoxans with sulfonyloxy groups, which are halide surrogates, has been developed. The key features of this strategy include the synthesis and utilization of bench-stable hydroxyfuroxan salts, the use of sulfonyl anhydrides in the sulfonylation step instead of sulfonyl chlorides, and the photochemical isomerization of one regioisomer to another in order to gain access to both.
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Diverse furoxans (1,2,5‐oxadiazole 2‐oxides) were synthesized from the corresponding styrenes using nitrosonium tetrafluoroborate as the nitrosation reagent in pyridine (basic media) or dichloromethane (neutral media). Acid‐sensitive functional groups were tolerated under these conditions. The probable reaction mechanism was elucidated. The experimental results support an ionic reaction pathway in contrast to the conventional acidic conditions with a radical mechanism.
Side-chain prototropic tautomerism of 4-hydroxyfuroxans in methylation reactions
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In summary, a facile and highly efficient method for the synthesis of practically unknown 3-aryl-4-hydroxyfuroxans by nucleophilic substitution of the nitro group in readily available 3-aryl-4-nitrofuroxans under the action of NaOH in H2O-THF has been developed. The methylation of these products using different methylating reagents (CH2N2,25 MeI, (MeO)2SO2) under very mild conditions, demonstrated for the first time that hydroxyfuroxans are prone to side-chain prototropic tautomerism, resulting in the formation of the first representatives of a new type of furoxan derivatives containing substituents on the N(5) nitrogen atom, N(5)-alkylfuroxan-4-ones, as well as O-alkylation products. In all cases, the latter were formed regioselectively and the molar ratio of O-Me and N-Me regioisomers were dependent on the aromatic ring substituents and the nature of the methylating reagents.
A general and simple method for the preparation of under explored 3-aryl-4-hydroxyfuroxans by nucleophilic substitution of the nitro group in 3-aryl-4-nitrofuroxans using NaOH in H₂O-THF has been developed. The methylation of 3-aryl-4-hydroxyfuroxans was studied with various methylating reagents (CH₂N₂, MeI, (MeO)₂SO₂) which showed for the first time that 3-aryl-4-hydroxyfuroxans are prone to side-chain prototropic tautomerism. Furoxan derivatives of a novel type, N(5)-alkylation products (3-aryl-5-methyl-1,2,5-oxadiazol-4(2H)-one 2-oxides), were synthesized under mild conditions, along with regioselective formation of the O-alkylation products (3-aryl-4-methoxyfuroxans).
Synthesis of furoxan derivatives: DABCO-mediated cascade sulfonylation/cyclization reaction of α-nitro-ketoximes
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Ultimately, it was demonstrated that the replacement of phenyl group on 1a with benzyl group was also feasible for the sulfonylation/cyclization cascade process to give 3o in 82% yield (entry 14). When the R1 group of 1 was H, the corresponding substrate 1p reacted with TsCl 2a under the standard reaction conditions, disappointingly, the expected furoxan product 3p was not able to be obtained (entry 15).13 The results of this case suggested the R1 (R1≠H) group in α-nitro-ketoximes 1 was crucial for the generation of furoxan heterocyclic ring.
A convenient and efficient method for the synthesis of furoxan derivatives from α-nitro-ketoximes and sulfonyl chlorides is reported. A wide variety of furoxan derivatives were smoothly obtained in good yields via a DABCO-mediated cascade sulfonylation/cyclization process under mild conditions. The usefulness of this method was also demonstrated by the conversions of the furoxan products into other promising compounds.
Conformation analysis and computation of energy barrier to rotation about CN bond in para-methylphenyl carbamate and its solvent dependence in comparison with tertiary carbamates and tertiary amides
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On the other hand, carbamates are more common among methods of protecting amines owing to stabilization toward hydrogenation and acidic-basic medium [7]. Particularly, the importance of syn and anti rotation in carbamates is highlighted in investigation of excited biological activities since changes in molecular conformers act similar to molecular switches [8–11]. Thus studies of energetic and spatial properties of carbamates are of great importance for improving our understanding of their biological activities and enhancing our ability to design new drugs.
Barrier to rotation about conjugated CN bond in p-Methyl phenyl carbamate (PMPC) was computed 14–16 kcal/mol at three levels of HF, B3LYP and MP2 using 6-311++G^∗∗ basis set. The solvent effect and energy barriers about CN bond in PMPC were compared to the case of tertiary carbamates and tertiary amides. Moreover, it is shown that in primary carbamates such as PMPC and tertiary amides isomerisation process passes through TS2 and TS1 respectively, while in tertiary carbamates goes through a combination of both TSs. Furthermore, X-ray analysis which is reported for the first time for primary aryl carbamates demonstrated that the inclusive plane of carbamate functional group is perpendicular to the plane of phenyl ring. The results of computations are completely in agreement with the X-ray data.
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Utilization of wieland furoxan synthesis for preparation of 4-aryl-1,2,5-oxadiazole-3-yl carbamate derivatives having potent anti-HIV activity

Abstract

J. Med. Chem.

Science

J. Med. Chem.