Acyl nitroso compounds

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

C-Acyl nitroso compounds are highly reactive species and no examples of stable and isolable C-acyl nitroso compounds have been reported. Charge-reversal and neutraHzation-reionization mass spectrometry experiments provided the first spectroscopic evidence for the existence of acyl nitroso compounds in the gas phase [30,... 

Recently, time-resolved infrared spectroscopic measurements revealed evidence for the first direct observation of an acyl nitroso compound in solution [22]. Pho-... 

Scheme 7.3 Alternative methods of C-acyl nitroso compound formation.

Scheme 7.4 Nucleophilic substitution of a C-acyl nitroso compound with nitroxyl formation.

Extensive structure-activity relationships for the oxidative formation of C-acyl nitroso compounds or the release of NO or HNO from C-acyl nitroso compounds do not exist. However, the -R group of the cycloadducts of acyl nitroso compounds and 9, 10-dimethylanthracene (4, Scheme 7.3) appears to strongly influence the rate that these compounds undergo retro-Diels-Alder reactions to produce acyl nitroso compounds. 

In general, C-acyl nitroso compounds-9,10-dimethylanthracene cycloadducts derived from hydroxamic acids (-R = alkyl, aryl, ti/2 = 4.1 h for -R = -Ph at 60°C) decompose more slowly than those derived from N-hydroxycarbamates or N-hydroxyureas [11, 13, 14]. Further addition of alkyl groups to the N atom of N-hydroxyurea-derived cycloadducts produces a further increase in the rate of the retro-Diels-Alder reaction of these cycloadducts [36]. These general trends suggest the possibility of the development of acyl nitroso compound-9, 10-dimethylanthracene cycloadducts as a general class of HNO or NO donors with varied release profiles. 

Acyl-nitroso-compounds are deoxygenated by triphenylphosphine to give isocyanates, and reaction via the zwitterion (46) was postulated.54... 

SCHEME 10. The three lowest-energy rotamers of the acyl-nitroso compounds, 106a (upper row) and 106b (lower row), as calculated by MM2. Relative energies are in kcal mol-1... 

Cycloadditions of the transient acyl nitroso compound (256), obtained by oxidation of hy-droxamic acids, with an excess of 2,5-dimethylfuran afford the unstable intermediates (257) which readily rearange to the cw-enones (180). The intermediate (257) may be either the primary adduct, or be produced by a [3,3]-sigmatropic shift from the other possible primary adduct (258) (Scheme 50) <80JCS(PI)2408, 86JOC2351>. 

Although all attempts to effect the direct conversion of 491 to the acyl nitroso compound 492 and thence into the desired ene product 493 were unsuccessful, this problem was expeditiously resolved by oxidizing 491 with tetrapropylam-monium periodate in the presence of 9,10-dimethylanthracene to afford the Diels-Alder adduct 496 in high yield. Thermolysis of 496 in refluxing toluene then generated the requisite acyl nitroso compound 492 in situ, and the subsequent ene reaction that ensued spontaneously delivered the cyclic hydroxamic... 

Oxidation of aryl hydroxamic acids in the presence of excess 2,5-dimethylfuran leads to transient acyl nitroso compounds, which undergo cycloaddition and subsequent rearrangement to 1,3,4-dioxazolines (177) having a side chain with cis configuration (Scheme 49) (80JCS(P112408). 

The use of acyl nitroso compounds as dienophiles was first described by Kirby. The primary method for generating these highly reactive, unstable species is by periodate oxidation of hydroxamic acids. The acyl nitroso compounds can be trapped in a Diels-Alder reaction with 9,10-dimethylanthracene to give adduct (95) (equation 36) which can act as an alternative source of the dienophile, since retro [4 + 2] cycloaddition occurs under mild thermal conditions. 

A few examples of cycloadditions of acyl nitroso compounds with unsymmetrical dienes have been described and it generally qrpears that the process shows good regioselectivity. Boger et al. found that... 

Studies on the addition of acyl nitroso compounds to 1,2-dihydropyridine derivatives have been described, and some of the results are shown in equation (38). It was found that the nitroso dienophiles produced from hydroxamic acids (100) reacted with dihydropyridine (99) at di erent rates and afforded the ratios of regioisomeric products indicated. Both the relative reaction rates and orientation are in accord with a HOMO-diene/LUMO-dienophile controlled process. 

Brief reports of cycloadditions with chiral acyl nitroso dienophiles have recently appeared. - In one study, acyl nitroso compound (101) derived from the corresponding hydroxamic acid was added to cy-clohexadiene to afford a 3.5 1 mixture of diastereomeric adducts (102) and (103). It was proposed that dienophile (101) reacts in the cyclic chelated form shown, since the related methyl ether which cannot internally hydrogen bond shows much lower diastereoselectivity. ... 

Nitrosyl cyanide (109) has been briefly examined as a dienophile by Kirby et This intermediate can be generated from nitrosyl chloride and silver cyanide (equation 42) and trapped with 9,10-diinethyl-anthracene to yield adduct (110). As with acyl nitroso compounds, this adduct can be used as a stable source of (109) via a retro Diels-Alder reaction. 

Jenkins, N. E., Ware, R. W., Jr., Atkinson, R. N., King, S. B. Generation of acyl nitroso compounds by the oxidation of N-acyl hydroxylamines with the Dess-Martin periodinane. Synth. Common. 2000, 30, 947-953. 

A related application of the reagent is in the preparation of (V-acyl nitroso compounds from hydroxamic acids. ... 

---