Steroidal nitrites, Barton nitrite photolysis

Scheme 76 Barton nitrite photolysis of a steroidal compound 277 to afford an oxime 199.

Note that this is not a chain process. The reaction, known as the Barton nitrite photolysis, was developed to functionalize steroids in positions that... 

Other examples from the group include the black light promoted selective halogenation of cydoalkenes, reporting the efficient mono-bromination using B12 and chlorinations using CI2 and SOCI2 within a biphasic reaction system, and the Barton nitrite photolysis used for the conversion of nitrite derivative (17) to steroid (18) (Scheme 6.7) [11]. 

It was shown by Barton et al. that the photolysis of steroidal nitrites 50 proceeding by formation of alkoxy radicals could result in hydrogen abstrae-tion from suitably situated methyl groups forming earbon-centered radicals, which then reacted with the NO generated to give oximes (equation 79). This permitted the functionalization of the unaetivated centers. 

Similarly, the products derived from the photolysis of steroidal nitrites (60 and 11/8) in toluene were mainly the result of intramolecular hydrogen abstraction (the Barton reaction). Kxothermicity calculations23 predict intermolecular hydrogen abstraction process (AH = 25 kcal./mole) to predominate over intramolecular hydrogen abstraction (AH = —3 to 5 kcal./mole). 

A functionalization that converts C—H bonds to C— NO bonds occurs when nitrite esters are photo-lyzed (the Barton reaction Scheme 4). Again an alkoxyl radical abstracts a 8-hydrogen, and the resulting carbon radical picks up NO. The product nitroso compounds convert easily to oximes. Particularly valuable examples have bMn studied in the steroid field. If the photolysis is performed in the presence of copperfll) acetate the intermediate carbon radical can be oxidized to an alkene, rather than capture NO. If the alcohol whose nitrite ester is photolyzed is part of a cyanohydrin, then the Heusler-Kalvoda reaction occurs, and the product is a ketone with a migrated cyano group (Scheme 5) ... 

The Barton reaction (photolysis of a nitrite) has been applied to the C(20)-alcoholic derivatives (490) and (491) in the c-nor-D-homo-steroid series, with the results indicated (Scheme 22). "" In the 20)3-series, attack upon C(15) also... 

The dimer of (74) is isolated as one of the products. In the flow ESR spectra, nitroxides (76) and (77) can be recognized. These are proposed to arise by H-abstraction from (74) by a cyclobutoxy radical, giving (75), which either reacts with a further molecule of (74), yielding (76), or undergoes, 5-exo ring closure to (77). The steroidal nitrite (78) (Scheme 17) yields 50% of the ketone (79) and 16% of the alcohol (80) when photolysed in the solid state (X > 300 nm), but only 5% of (79) and 52% of the Barton-type product (81) when photolysed in toluene solution. It is usual for ketones to be produced only in low yields from photoreactions of nitrites in solution, and so the promotion of this reaction pathway in solid-state photolysis is of considerable interest. Similar results were obtained for the solid-state photolyses of a number of other steroidal nitrites, but nitrites prepared from acyclic alcohols showed much less selectivity in favour of the corresponding ketones. 

The Barton reaction (photolysis of a nitrite ester ) has been employed to attack C-4 methyl substituents in 4,4-dimethyl-5a-steroids. Nitrites of the 6a-and 6)3-alcohols (714) afforded alkoxyl radical species, which attacked the 4a-and 4/ -methyl groups respectively, giving the corresponding aldoximes e.g. 715). Yields were quite high (56—60%) from the 6a-ol and the 19-nor-6 -ol, but attack... 

In a second example, Ryu and co-workers [87, 88] demonstrated the nitrite photolysis (Barton reaction) of the steroidal substrate 157 to afford 158 (Scheme 6.41), a key intermediate in the synthesis of an endothelin receptor antagonist, using a 300 W high-pressure mercury lamp. Maintaining a gap of 7.5 cm between the stainless-steel/glass reactor [channel dimensions = 1000 pm (width) x 107 pm (depth) x 2.2 m (length)] and the light source, an acetone solution of the nitrite... 

The Barton nitrite ester photolysis is undeniably one of the most popular and useful reactions in radical chemistry for the functionalization of remote and inactivated positions within steroids (Scheme 19). Photolysis of nitrite esters gives nitric oxide and an alkoxyl radical that abstracts an ideally positioned hydrogen atom (1,5-hydrogen atom abstraction). The resulting alkyl radical reacts with nitric oxide in a solvent cage to afford the nitroso-alcohol derivative that is finally isolated as an oxime [53]. Related cyclizations of alkoxyl radicals have been reported by Surzur photolysis of y,(5-alkenyl nitrite esters leads to alkoxyl radicals that undergo subsequent tandem 5-exo cyclization followed by NO-trapping [54, 55]. 

Section 12.5. in Part A describes some additional reactions that are of synthetic value and involve intramolecular hydrogen abstraction at unactivated groups. Of particular value is the nitrite photolysis method developed by Barton, which has been important in the functionalization of methyl groups in steroids. 

In a similar manner, 11/3-nitrites, on photolysis, attack Ci to furnish the corresponding oximes which, upon nitrous acid treatment, gave 18-oxygenated steroids. The most spectacular application of the Barton reaction has been a three-step synthesis of aldosterone.12 Irradiation of corticosterone-11-nitrite (27, R = NO), followed by nitrous acid treatment, gave aldosterone (29) in 15% overall yield. Comparable conversions of 11/3-hydroxyprogesterone to 21-desoxyaldosterone12 and A1-corticosterone to A aldosterone14 have also been achieved. 

Schemes 5 and 6 outline the functionalization of a 10/1-Me by a steroidal 6/f-ol [1] and a 2/3-61 nitrite [6], Functionalization of 13/i-Me by a 20a-ol nitrite [7] and functionalization in the terpenoid field [8] are outlined in Schemes 7 and 8. The last example involves a 7-membered cyclic transition state that seldom occurs. Scheme 9 outlines a recent application of the Barton reaction in the synthesis of a biologically active carbacepham [9]. The photolysis of acyclic 5-phenyl-1-pentanol nitrite gives, preferentially, a nitroso dimer arising as a result of the abstraction of a hydrogen attached to the d-carbon, rather than the e-carbon from which the better stabilized benzyl radical can be generated (Scheme 10) [10].

Recently, however, photolysis of nitrites has received tremendous impetus as a result of the introduction of the Barton reaction, which was originally conceived as a method of functionalisation at a distance in steroid chemistry. The photo-... 

Cycloartenol is the parent compound of a family of triterpenoids characterized by a 9, 10—cyclopropane ring, and has been suggested as an important intermediate in the biosynthesis of tetracyclic triterpenoids and steroids in plants. A key feature of the synthesis of cycloartenol by Barton etai is functionalization of the unactivated C-19 methyl group in lanosterol by photolysis of an 11/3-nitrite (A), followed by an intramolecular alkylation for closure of the cyclopropane ring. 

---