III. Photochemical Electron Transfer to Carboxylic Acid Esters

A. Acetates and Pivalates

Photochemical electron transfer from excited hexa­methyl­phos­phor­amide (HMPA) to an O-acyl group in a carbohydrate begins a series of events that result in replacing each O-acyl group with a hydrogen atom. An example of a typical reaction is shown in eq 5.²⁷ The temperature at which this reaction can be conducted (~25 ^oC) is synthetically far more attractive than the 140 ^oC needed for the corresponding thermal reaction of an acetylated carbohydrate (eq 3).²³ Pho­to­­chem­ical electron transfer to acetates has been used for the synthesis of a number of deoxy sugars.^27–34 Esters of pivalic acid, which also can serve as substrates in this type of reac­tion,^28,35–41 sometimes give better yields than the corres­ponding acetates.^28,35,36

1. Reaction Mechanism

Photochemical electron transfer begins with absorption of light by HMPA to produce a highly reactive, electronically excited molecule that ejects an electron into the solution (Scheme 5).^42.43 The ejected electron is captured by the acylated carbohydrate to pro­duce a radical anion that cleaves to give a carboxylate anion and a carbo­hy­drate radical (R·).⁴³ Hydro­gen-atom abstraction by the carbo­hy­drate radical then com­pletes the replacement process (Scheme 5). The water present in the reaction mixture extends the lifetime of the solvated electron and, in so doing, increases the probability that this electron will be captured by a molecule of ester.⁴³ (The importance of water to the success of this process is demonstrated by the yields of the reactions shown in eq 6.^44,45)

2. Alcohol Regeneration

Ester photolysis in aqueous HMPA sometimes regenerates the alcohol from which the ester was synthe­sized (eq 7).³⁴ In some instances, alcohol formation may be due to nonphotochemical ester hydrolysis. Nonphoto­chem­ical reac­tion provides a reasonable explanation for the easily hydrolyzed, anomeric acetate shown in eq 8 undergoing only hydrolysis (no deoxy­gen­ation) when photo­lyzed in aqueous HMPA.³⁴ Even though simple hydrolysis may be significant for some compounds, as described below, alcohol regen­er­ation during photolysis of other, probably most, esters must occur in a different way.

Alcohol formation during ester photolysis cannot be explained, in general, by simple hydrolysis because, as is shown by the reaction pictured in Scheme 6, the yield of the alcohol can depend on the concentration of the starting ester.⁴³ One explanation for this dependence begins with the ester 5 capturing a solvated electron to form the radical anion 6. This radical anion then abstracts a hydrogen atom from a second molecule of 5 to produce the anion 7, which then forms an alkoxide ion that proton­ates to give the observed alco­hol.⁴³ Since, according to this explanation, raising ester concen­tration should increase the rate of hydrogen-atom abstraction to give 7 but not the rate of the competing β-cleavage that forms R·, greater ester concen­tration should increase the amount of alcohol (ROH) produced at the expense of the deoxygenated product (RH).

A critical question about the mechanism for alcohol formation presented in Scheme 6 con­cerns whether the radical anion 6 can abstract a hydrogen atom from the ester 5. The evidence found in eq 9 supports the idea that 5 can function as a hydrogen-atom donor. Irradiation of 5 in HMPA‑d₁₈/D₂O gives a 27% yield of 8, a reduction product that contains no deuterium. Since the only source for the second hydrogen atom at C-3 in 8 is one of the carbohydrates in the reaction mixture and since the ester 5 is the only carbohydrate present at the beginning of the reaction, abstraction from 5, at least in the early stages of reaction, seems unavoidable. If 5 can act as a hydrogen-atom donor in the formation of 8, it becomes a strong candidate for the same role in the conversion of the radical anion 6 into the alkoxide ion 7 (Scheme 6).

3. Competition From Light-Absorbing Chromophores

If an ester contains a strongly absorbing chromophore, HMPA exci­tation will be effectively precluded because most of the incident light will be absorbed by the ester. Failure to excite HMPA will fore­stall replacement of the acyloxy group with a hydrogen atom by preventing electron trans­fer. The light absorbing prop­er­ties of the benzoyloxy group, for example, render benzoates much less desirable par­ticipants in these electron-transfer reactions because far less incident light reaches the HMPA. This means that an impor­tant factor in reaction of simple acetates and pival­ates is that these com­pounds contain no strongly absorbing chromophore.⁴² An example of an ester that fails to undergo replace­ment of the acyloxy group due to the presence of a light-absorbing sub­stituent (i.e., the 4,6-O-benzylidene group) is shown in eq 10.⁴¹ Even though the benzylidene group is removed during photolysis, the aromatic chromophore remains in the solution and con­tinues to absorb the incident light. Changing 4,6-O-benzylidene to 4,6-O-isopro­pylidene protec­tion allows reaction to proceed in the normal fashion (eq 11).⁴¹

B. m-(Trifluoromethyl)benzoates

A m-(trifluoromethyl)benzoate will accept an electron ­from excited N‑meth­yl­carbazole (11) in a reaction that leads to replacement of the acyloxy group with a hydrogen atom; for example, pho­to­lysis of 2',3',5'-tri-O-[m-(tri­fluoro­methyl)­benzoyl]-adenosine (9) produces the 2',3'-di­de­oxy­aden­o­sine der­iv­ative 10 (eq 12).⁴⁶ (Most,^46–52 but not all,⁴⁸ compounds reported to under­go this type of reaction are nucleosides.) Reactions, such as the one shown in eq 12, are regioselective because the radical anion generated from a m-(trifluoro­methyl)benzoyl group does not fragment to give a primary radical.

Photochemical electron transfer involving m-(trifluoro­methyl)­benzo­ates and N-methyl­car­bazole (11) has several advan­tages over electron transfer between HMPA and ace­tates or pival­ates. One of these is that N‑methyl­car­ba­zole has greater molar absorptivity than HMPA, a fact that renders the car­bohydrate reac­tant less likely to stop the reaction by absorbing the incident light.⁵² From a safety point of view, elim­inating HMPA from the reac­tion mix­ture avoids handling a highly toxic, cancer-suspect agent. Because the m‑(tri­fluoro­­meth­yl)ben­zoyl group is an effective electron acceptor (better than an acetyl or pivaloyl group) few substituents in the carbo­hydrate will compete with this group for an electron donated by excited N-methyl­carba­zole (11); consequently, reactions of m-(trifluoromethyl)benzoates usually are highly chemo­selective. An example of this selectivity is shown in eq 13, where the benzoyl group remains bonded to C-3' while the m‑(tri­fluor­o­methyl)ben­zoyl group at C-2' is replaced by a hydrogen atom.⁴⁹

When reaction is conducted in the presence of Mg(ClO₄)₂, it is possible to replace even an unsubstituted benzoyloxy group with a hydrogen atom (eq 14⁵⁰).^50–52 Magnesium perchlorate affects this reaction by hindering back elec­tron transfer, a process that competes with the frag­men­tation of the radical anion 13 (Scheme 7). Another factor that affects the reaction of a benzoyloxy group is the choice of the electron donor; thus, replacing N-methylcarbazole (11) with 3,6-di­methyl-9-ethylcarbazole (12) causes deoxygenation to take place more rapidly.⁵⁰ Compound 12 is superior to 11 because it forms a more stable radical cation upon electron transfer.^50,53,54