Upjohn process

Figure 8.46 Upjohn process for production of the precursor of 9a-fluorocorticosteroids. ...

Inclusion in the reaction of a cooxidant serves to return the osmium to the osmium tetroxide level of oxidation and allows for the use of osmium in catalytic amounts. Various cooxidants have been used for this purpose historically, the application of sodium or potassium chlorate in this regard was first reported by Hofmann [7]. Milas and co-workers [8,9] introduced the use of hydrogen peroxide in f-butyl alcohol as an alternative to the metal chlorates. Although catalytic cis dihydroxylation by using perchlorates or hydrogen peroxide usually gives good yields of diols, it is difficult to avoid overoxidation, which with some types of olefins becomes a serious limitation to the method. Superior cooxidants that minimize overoxidation are alkaline t-butylhydroperoxide, introduced by Sharpless and Akashi [10], and tertiary amine oxides such as A - rn e t h y I rn o r p h o I i n e - A - o x i d e (NMO), introduced by VanRheenen, Kelly, and Cha (the Upjohn process) [11], A new, important addition to this list of cooxidants is potassium ferricyanide, introduced by Minato, Yamamoto, and Tsuji in 1990 [12]. 

Other reoxidants which minimize overoxidation are f-butyl hydroperoxide in the presence of Et4NOH [4], tertiary amine oxides, and most importantly N-methylmorpholine A -oxide (NMO) (Upjohn process) [14], although for tri- and particularly tetrasubstituted alkenes as substrates, trimethylaminoxide is superior to NMO [14 c], The introduction of potassium hexacyanoferrate(III) in the presence of potassium carbonate [15] substantially improved the selectivities in chiral dihydroxylations [16], although it was first reported as a co-oxidant in 1975 [17]. Industrial efforts led to an electrochemical oxidation of potassium ferrocyanide to ferricyanide in order to use electricity as the actual co-oxidant [18]. 

These issues are summarized in the extremely simplified mechanism given in Scheme 8.14. All osmylation reactions ultimately afford the osmate ester shown, although the mechanism for this step has been controversial. Note that the osmium is reduced over the course of the reaction. In efforts to minimize the amount of toxic osmium used in these reactions, catalytic methods using a variety of stoichiometric reoxidants for osmium were introduced, beginning with the introduction of KCIO4 in 1917 by Hofmann [66] and including the convenient Upjohn process, which uses N-methylmorpholine-A-oxide for this purpose [67]. 

In the second stage the poly(amic acid) is cyclized in the solid state to the polyimide by heating at moderately high temperatures above 150°C. A different approach, avoiding the intermediate poly(amic acid) step, was pioneered by Upjohn. The Upjohn process involves the self-condensation of the isocyanate of trimellitic acid, and the reaction by-product is carbon dioxide (Figure 4.19b). 

If trimellitic anhydride is used instead of pyromellitic dianhydride in the reaction shown in Figure 4.19a, then polyamide-imide is formed (see Figure 4.20a). Other possible routes to this type of product involve the reaction of trimellitic anhydride with diisocyanates, (Figure 4.20b) or diurethanes (Figure 4.20c). Closely related is the Upjohn process for polyimide by self-condensation of the isocyanate of trimellitic acid, as illustrated in Figure 4.19b, although the product in this case is a true polyimide rather than a polyamide-imide. 

---