a
Table 2 Scope of the cathodic reduction-mediated ipso-hydroxylation
During our evaluation of the developed reaction, an
unexpected result was obtained when employing 3-hydroxymethyl
phenylboronic acid (1l) as a substrate. Surprisingly, under the
applied reductive conditions the benzylic alcohol of 1l was
selectively oxidized to the corresponding aldehyde (carboxylic acid
formation was not observed), furnishing 2j as the sole product,
albeit in a low yield (30%). A presumable mechanism involving the
superoxide ion as both a nucleophilic hydroxylation reagent as well
as an oxidant for the benzylic oxidation step is outlined in
Scheme 4.
b
Yield
(%)
Entry 1
2
1
2
3
4
5
6
7
8
9
1
1
1
Ph–B(OH)
4-I–C –B(OH)
4-Me–C –B(OH)
3-OiPr–C –B(OH)
2-CHO–C –B(OH)
6-OMe–2-naph-B(OH)
PhC B(OH) (1g)
(1h)
2
(1a)
Ph–OH (2a)
81 (27)
79 (26)
71 (24)
6
H
4
2
(1b)
(1c)
6 4
4-I–C H –OH (2b)
6
H
4
2
6
4-Me–C H
4
–OH (2c)
6
H
4
2
(1d) 3-OiPr–C
(1e) 2-CHO–C
6
H
4
–OH (2d) 96 (32)
–OH (2e) 60 (20)
(1f) 6-OMe–2-naph-OH (2f) 79 (26)
6
H
4
2
6
H
4
2
In conclusion, an efficient open-flask electrochemical ipso-
hydroxylation reaction of aryl and alkyl boronic acids has
been developed. Herein, traditional hydroxylation reagents
such as KOH and peroxides have been replaced with a green
alternative – molecular oxygen in air. Furthermore, mechanistic
insight based on experimental results has been provided.
This research was made possible by Aarhus University, the
Carlsberg Foundation and FNU. Thanks to Dr R. L. Davis
for helpful discussions.
2
H
4
2
PhC
2
H
4
OH (2g)
92 (31)
61(20)
74 (25)
0 (0)
cHex–B(OH)
Ph–Bpin (1i)
2
cHex–OH (2h)
Ph–OH (2a)
Ph–OH (2a)
Ph–OH (2a)
0
1
2
Ph–BF
Ph–B(OH)
4-CONMe
1k)
3
K (1j)
(1a)
–C
c
c
d
2
91 (61)
–OH 82 (54)
d
2
6
H
4
–B(OH)
2
4-CONMe
(2i)
2
–C
6
H
4
(
a
b
c
Reactions performed on the 0.5 mmol scale (20 mM, see ESI).
Yield of the isolated product. In parentheses are the faradic yields.
d
Performed on the 1 mmol scale (40 mM). Yield determined by
H NMR with an internal standard.
1
Notes and references
1
For selected reviews, see: (a) R. A. Sheldon, I. W. C. E. Arends,
G.-J. ten Brink and A. Dijksman, Acc. Chem. Res., 2002, 35, 774;
(b) S. S. Stahl, Angew. Chem., Int. Ed., 2004, 43, 3400; (c) M. S. Sigman
and M. J. Schultz, Org. Biomol. Chem., 2004, 2, 2551; (d) T. Mallat and
A. Baiker, Chem. Rev., 2004, 104, 3037; (e) B. Z. Zhan and
A. Thompson, Tetrahedron, 2004, 60, 2917; (f) M. J. Schultz and
M. S. Sigman, Tetrahedron, 2006, 62, 8227; (g) T. Matsumoto,
M. Ueno, N. Wang and S. Kobayashi, Chem.–Asian J., 2008, 3, 196;
¨
(h) J. Piera and J.-E. Backvall, Angew. Chem., Int. Ed., 2008, 47, 3506.
2
For selected examples, see: (a) Y. Imada, H. Iida and
S.-I. Murahashi, J. Am. Chem. Soc., 2003, 125, 2868;
(
b) R. H. Liu, X. M. Liang, C. Y. Dong and X. Q. Hu, J. Am.
Chem. Soc., 2004, 126, 4112; (c) Y. Imada, H. Iida, S.-I. Murahashi
and T. Noata, Angew. Chem., Int. Ed., 2005, 44, 1704;
Scheme 4 An unexpected benzylic oxidation during cathodic reduction.
(
M. Kakimoto, Angew. Chem., Int. Ed., 2010, 49, 436.
(a) Y.-Q. Zou, J.-R. Chen, X.-P. Liu, L.-Q. Lu, R. L. Davis, K. A.
Jørgensen and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 784;
(b) Rearrangement via a bridged peroxy species has also been proposed
(ref. 3a and 7); however, this occurs with a barrier of 41.5 kcal mol
d) Y. Kuang, N. M. Islam, Y. Nabae, T. Hayakawa and
side reactions with the accumulating superoxide anions, elec-
trolysis at lower constant currents was attempted (entries 4
and 5). This led to a more controlled reaction effectively
reducing the discrepancy between substrate conversion and
yield of the reaction.
3
4
À1
.
For selected examples, see: (a) J. Simon, S. Salzbrunn, G. K. S. Prakash,
N. A. Petasis and G. A. Olah, J. Org. Chem., 2001, 66, 633; (b) G. K.
S. Prakash, S. Chacko, C. Panja, T. E. Thomas, L. Gurung, G. Rasul,
T. Mathew and G. A. Olah, Adv. Synth. Catal., 2009, 351, 1567;
(c) J. Xu, X.-Y. Wang, C.-W. Shao, D.-Y. Su, G.-L. Cheng and
Y.-F. Hu, Org. Lett., 2010, 12, 1964; (d) H. Yang, Y. Li, M. Jiang,
J. Wang and H. Fu, Chem.–Eur. J., 2011, 17, 5652.
For reviews on superoxide chemistry, see: (a) D. T. Sawyer and
J. S. Valentine, Acc. Chem. Res., 1981, 14, 393; (b) D. T. Sawyer,
A. Sobkowiak and J. L. Roberts, Electrochemistry for Chemists,
Wiley Interscience, New York, 2nd edn, 1995, ch. 9.
For selected reviews, see: (a) T. P. Yoon, M. A. Ischay and J. Du,
Nat. Chem., 2010, 2, 527; (b) J. M. R. Narayanam and C. R. J.
Stephenson, Chem. Soc. Rev., 2011, 40, 102; (c) J. W. Tucker and
C. R. J. Stephenson, J. Org. Chem., 2012, 77, 1617.
K. Hosoi, Y. Kuriyama, S. Inagi and T. Fuchigami, Chem.
Commun., 2010, 46, 1284.
For hydroxylation of alkyl boronic acids, see: H. R. Snyder,
J. A. Kuck and J. R. Johnson, J. Am. Chem. Soc., 1938, 60, 105.
For selected examples, see: (a) D. T. Sawyer and L. V. Interrante,
J. Electroanal. Chem., 1961, 2, 310; (b) I. M. Kolthoff and
T. B. Reddy, J. Electrochem. Soc., 1961, 108, 980; (c) D. L. Maricle
and W. G. Hodgson, Anal. Chem., 1965, 37, 1562; (d) M. E.
Peover and B. S. White, Electrochim. Acta, 1966, 11, 1061;
With the optimized conditions in hand, a wide range of
boronic acids was evaluated in order to demonstrate the scope
and limitation of the developed reaction (Table 2). Aryl-
boronic acids with both electron-donating (entries 3, 4 and 6)
and electron-withdrawing substituents (entries 2, 5 and 12)
proved to be compatible with the developed protocol. It is
noteworthy that traditionally sensitive functional groups such
as iodide and formyl groups were well-tolerated in the
bulk electrolysis under these conditions. More importantly,
aliphatic boronic acids also underwent the desired ipso-
hydroxylation giving access to both primary and secondary
alcohols (entries 7 and 8). As a further validation of the
proposed mechanism, it was revealed that the presence of an
empty lone-pair on the boron atom is crucial for the reactivity
of the substrates. For example, the pinacol ester of phenyl
boronic acid participates readily in the reaction, while the
corresponding potassium trifluoroborate remains completely
inert (entries 9 and 10). Finally, we show that a two-fold
increase in current efficiency could be achieved by performing
the reaction at the 1 mmol scale (40 mM) under otherwise
identical conditions (entries 11 and 12).
5
6
7
8
9
(e) D. T. Sawyer and J. L. Roberts Jr., J. Electroanal. Chem., 1966,
1
2, 90; (f) P. S. Jain and S. Lal, Electrochim. Acta, 1982, 27, 759.
3 could be
1
0 A suggestion to the identity of intermediate
Ph–B(OH)OOH.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7203–7205 7205