Organic Letters
Letter
Table 1. Optimization Parameters
entry
conc. 5a (mM)
base (equiv)
current density (mA·cm−2
)
Faradays (F·mol−1
)
electrodes (+/-)
yield 8a (%)
a
1
36
36
36
18
18
9
1
1
1
1
1
2
2
36
18
36
36
36
36
36
15
15
15
15
30
30
30
Pt/Ni
Pt/Ni
C/C
C/C
C/C
C/C
C/C
21
20
28
42
58
99
76
a
2
b
3
b
4
b
5
b
6
b
7
181
a
b
No workup. Solvent removed under reduced pressure after electrolysis. Reaction mixture quenched with aqueous NaHCO3 and subsequently
extracted with hexanes.
sufficiently pure to be used without further purification in the
next reaction step.
Scheme 5. Possible Mechanism
Because of their inherent instability, NMR yields have been
measured for the orthoesters using dibromomethane as an
internal standard.
The concentration of 5a was shown to be a crucial parameter.
Salient results are summarized in Table 1. On a small scale (∼0.1
mmol) (entries 1−7), diluted conditions (9 mM) gave the best
results (entry 7). Surprisingly, when 1.81 mmol of 5a was
electrolyzed in 10 mL of methanol (181 mM), only a minor drop
in yield was observed (entry 8).
As expected, carbon graphite electrodes (entry 3) have been
shown to be superior to platinum electrodes at achieving a
multielectron transfer (entry 2). Presumably, this is because the
substrate is better adsorbed on carbon than on a metallic surface.
The current density was shown to have very little impact on the
reaction as long as it was ≥18 mA·cm−2 (entries 1, 2, 5, and 6).
No significant difference in yield was observed upon the
exchange of NaOMe for ammonia as the base; however, a
notable decrease was observed upon the use of t-BuOK,
presumably due to its limited solubility in methanol (see
Although, in theory, a catalytic amount of base should be
sufficient because methoxide ions are continuously produced at
the electrode by the reduction of the methanol at the cathode,
we found that using two equivalents helps to reduce the
impedance of the system and minimize the Joule effect.
Similar to what we have observed during our previous
investigations, oxygen and moisture have little to no effect on the
electrolysis.32,33
by undergoing an intramolecular electron transfer from the
carboxylate to the sulfur radical cation (see Figure M1 in the
With these conditions in hand, we explored the scope and
limitations of the anodic oxidation of dithiane carboxylic acid
derivatives.
Scheme 5 shows a possible mechanism. The reaction starts
with the oxidation of one of the two sulfur centers of 5− because
their oxidation potential is much lower than that of a
carboxylate. The dithiane then opens to form the corresponding
thionium B. This intermediate is then attacked by the solvent to
form the mixed S,O-acetal C, which quickly decomposes into the
oxonium D by releasing a disulfide, which is oxidized into the
corresponding dithiolane 9. Alternatively, C’s sulfur moiety can
be oxidized and release the oxonium D as well as a 1,3-
propandithiyl radical that cyclizes into 9. Finally, another
molecule of solvent adds onto the oxonium D to form a
carboxylic acetal that decarboxylates to form the desired
orthoester 8 following a classical Kolbe/Hofer−Moest decar-
boxylation. Alternatively, a reviewer made the interesting
suggestion that the intermediate A could decarboxylate rapidly
A large number of functional groups, such as alkenes, alkynes,
silyl ethers, Boc carbamates, and nitriles, are not tolerated by the
classic Pinner reaction due to the highly acidic conditions used.
In addition, the Pinner reaction is known to be unsuccessful for
the preparation of aromatic orthoesters.14 As can be seen from
Figure 2, our methodology is compatible with both aliphatic and
aromatic substituents. The anodic oxidation of 5 tolerates a wide
variety of functional groups such as alkenes (8b), alkynes (8h),
silyl groups (8e), halides (8c,d,k,l,r,s,t,z7), fluorinated groups
(8m,q), nitriles (8j,p), ethers (8x,y,v), and amides (8n). For the
cyclic ether 8y and amide 8n, the electrolyses were only
undertaken for 15 F·mol−1 because prolonged electrolysis of
these compounds led to the formation of the Shono-type
oxidation product (α-methoxylation of the ether or amide).34
Replacing the dithiane with the less expensive dibenzyl
C
Org. Lett. XXXX, XXX, XXX−XXX