Redox catalysis of halide ion for formal cross-dehydrogenative coupling: Bromide ion-catalyzed direct oxidative α-acetoxylation of ketones

Article abstract of DOI:10.1246/cl.2010.929

A novel catalytic approach for formal cross-dehydrogenative coupling using the redox property of bromide ion is reported. Simple bromide salts MBr can work as catalyst for direct oxidative α-acetoxylation of ketones.

Full text of DOI:10.1246/cl.2010.929

doi:10.1246/cl.2010.929
Published on the web July 24, 2010
929
Redox Catalysis of Halide Ion for Formal Cross-dehydrogenative Coupling:
Bromide Ion-catalyzed Direct Oxidative ¡-Acetoxylation of Ketones
Takashi Nagano,*1,2,³ Zhenhua Jia,1 Xingshu Li,1 Ming Yan,1 Gui Lu,1
Albert S. C. Chan,*1,3 and Tamio Hayashi*2,3
1Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences,
Sun Yat-sen University, Guangzhou 510006, P. R. China
2Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
3Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
(Received June 11, 2010; CL-100549; E-mail: tnagano@kochi-u.ac.jp,
bcachan@polyu.edu.hk, thayashi@kuchem.kyoto-u.ac.jp)
A novel catalytic approach for formal cross-dehydrogenative
(1)
Br2 + t-BuOH + H2O + 2AcOM
2MBr + 2AcOH + t-BuOOH
coupling using the redox property of bromide ion is reported.
Simple bromide salts MBr can work as catalyst for direct
oxidative ¡-acetoxylation of ketones.
S-H + Br2
S-Br + HBr (2)
HBr + AcOM
S-Br + AcOM
(3)
(4)
AcOH + MBr
S-OAc + MBr
"MBr cat."
Recent growing interest in green sustainable chemistry for
the next generation requires the development of organic trans-
formations using safe, environmentally benign, and abundant
elements and materials.1 In the course of our continuing studies
of the use of inexpensive and abundant metal catalysts for
organic transformations,2 we recently pursued the use of the
redox property of halide ions for organic synthesis and
uncovered that alkaline metal bromide and related bromide salts
MBr can be used as catalysts for dehydrogenative coupling
reactions. An outline of this MBr catalysis is shown in Chart 1.
The bromide ion in MBr is known to undergo oxidation by
various oxidants in an appropriate acidic medium. For example
H2O2 oxidation of KBr in aqueous H2SO4 gives molecular
bromine along with K2SO4 according to the following funda-
mental chemical equation: 2KBr + H2O2 + H2SO4 = Br2 +
2H2O + K2SO4.3 In this reaction H+ acts as an electron acceptor
(oxygen acceptor) at oxidation. When proton is provided from
organic substance having sufficient acidic hydrogen (NuH)
instead of inorganic strong Brønsted acid, the total oxidation
process should give molecular bromine and MNu. Incorporation
of bromine atom at higher oxidation state into a substrate
followed by nucleophilic attack by MNu, which is generated
from MBr in the oxidation step, will regenarate MBr along with
the formal dehydrogenative coupling product S-Nu (Scheme 1,
eqs 1-4). Although a few examples using atom transfer redox
catalysis using halide ions have been reported to date, external
nucleophiles were used in all cases,4 and to the best of our
knowledge there is no report on using nucleophile cogenerated
at the step of oxidation of bromide ion to molecular bromine.
Moreover, it is very surprising that such a catalysis has never
(1)-(4): S-H + H-OAc + t-BuOOH
S-OAc + t-BuOH + H2O
Scheme 1. Elementary step in MBr catalysis for cross-de-
hydrogenative coupling between S-H and AcOH (S-H = ketone
in this study).
been reported although each elementary reaction shown in eqs
1-4 is classical, fundamental, and well-known to organic
chemists. We chose direct oxidative ¡-acetoxylation of ketone5
as an initial trial for realizing such attractive and atom
economical catalytic reaction and for demonstrating our concept
of MBr catalysis for formal cross-dehydrogenative coupling.6
Initially, we carried out the optimization of reaction
conditions by using propiophenone (1a) as a model substrate.
The reaction of 1a with aq. TBHP in the presence of 100 mol %
of NaBr in AcOH gave the corresponding ¡-acetoxylation
product 2a in 48% yield as expected, while no reaction occurred
in the absence of NaBr (Table 1, Entries 1 and 2). In the case of
using H2O2 as oxidant very poor conversion was observed
although the color change of the reaction mixture from colorless
to brown suggested that oxidation of bromide ion to Br2
occurred (Entry 3). In this case rapid decomposition of H2O2
in the presence of Br2 was probably the main reason.7 LiBr, KBr,
and NH4Br also gave the product but efficiency was low (Entries
4-6). Low efficiency observed in Entries 1, 4, 5, and 6 were
undoubtedly attributed to remaining intermediate ¡-bromoke-
¹
tone 3, which retarded the effective catalytic turnover of Br .
These results are consistent with the well-known fact that
nucleophilicity of hard ionic nucleophiles decreases in protic
solvent because of solvation of the anion via hydrogen bonding.8
Among the bromide salts tested, n-Bu4NBr was found to be a
good candidate. In this case, no by-product 3 was observed,
indicating the rate of the reaction of n-Bu4NOAc with 3 was fast
enough even in protic solvent, probably because of the minimal
Higher oxidation state leads to
incorporation into the substrate
[O]
+ Nu−M+
+
M+Br−
+
[Br ]
Nu−H
ion pairing between bulky n-Bu4N+ and AcO (Entry 7).9 With
¹
served as electron acceptor
Nucleophilic attack
the conditions giving complete conversion of 3 in hand, we then
tried to reduce the catalyst loading. In the presence of 50 mol %
of n-Bu4NBr, the reaction proceeded with similar efficiency
although conversion was still not satisfactory (Entries 8 and 9).
Longer reaction time did not improve the conversion signifi-
Formation of
Nucleophile
S-Br
Chart 1. Concept of MBr catalysis.
Chem. Lett. 2010, 39, 929-931
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

930
¹
Table 1. Optimization of conditionsa
Table 2. Substrate scope of Br -catalyzed direct ¡-acetoxyla-
tiona
O
O
oxidant
O
3: R = Br, R' = H
4: R = OH, R' = H
5: R = R' = Br
R'
MBr cat.
O
70% aq. TBHP (1.3 equiv)
n-Bu4NBr (30 mol%)
O
+
Ph
Ph
AcOH
110 °C
R2
OAc
Ph
R2
R1
R
R1
OAc
1a
2a
AcOH (0.25 mL), 110 °C, 24 h
2
1
Yield/%b
Oxidant
(equiv)
AcOH Time Conv.
/mL /h /%b
Entry R1
R2
¡-Acetoxyketone (2) Yield/%b
Entry MBr/mol %
2a 3
4
5
1
2c
3
4
5
6
7
8
9e
10f
Ph
Ph
Ph
Ph
p-BrC6H4
p-ClC6H4
p-MeOC6H4 Me
p-TfOC6H4 Me
2-naphthyl
t-Bu
Me
n-Pr
Ph
H
Me
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
74
63
1
2
3
4
5
6
7
8
9
NaBr (100)
none
NaBr (100)
LiBr (100)
KBr (100)
NH4Br (100)
n-Bu4NBr (100) TBHP (5)
n-Bu4NBr (100) TBHP (2)
n-Bu4NBr (50) TBHP (2)
TBHP (5)
TBHP (5)
H2O2 (5)
TBHP (5)
TBHP (5)
TBHP (5)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
16
82 48 19
5
3
16 N.R.e
0
0
0
8
0
0
4
4
0
0
0
8
41d
15
16
16
16
16
16
16
16
43
8
61 38 16
89 61 10
68
70
67
69
96 37
88 68
77 67
83 69
7
0
0
2
0 30
9
5
4
0
3
2
1
Me
Me
63
10 n-Bu4NBr (50) TBHP (2)
88 65 0 12
2j
40 (52)g
11 n-Bu4NBr (50) TBHP (1.3) 0.25 24
12 n-Bu4NBr (50) TBHP (1.3)c 0.25 24
13 n-Bu4NBr (30) TBHP (1.3)d 0.25 24
14 n-Bu4NBr (20) TBHP (1.3)d 0.25 24
66 54
95 77
94 76
90 68
0
0
0
0
5 <1
4 <1
5 <1
3 <1
aReaction scale: 1.5 mmol of 1. 0.25 equiv of TBHP was added
5
times once every 3 h. bIsolated yield after column
chromatography. c0.25 equiv of TBHP was added 7 times
a1a (1.5 mmol), 70% aq. TBHP or 30% aq. H2O2 were used.
bEstimated by 1H NMR analysis of crude material using
CH3NO2 as internal standard. c0.25 equiv of TBHP was added
in portions every 2.5 h. 0.25 equiv of TBHP was added in
portions every 3 h. N.R.: no reaction.
d
once every 3 h (total 1.8 equiv). 1,2-Diphenylethandione was
also isolated in 22% yield. eAcOH (0.30 mL) was used.
f3.0 mmol scale. GC yield in parenthesis.
g
d
e
Br2 (1 equiv)
2a (not observed) + 3 (93%)
2a (50%) + 3 (3%) + 5 (8%)
(5)
(6)
AcOH, 110 °C, 20 h
cantly, suggesting that the decomposition of TBHP occurred
under the conditions (Entry 10). Indeed stepwise addition of
TBHP was found to be clearly effective, resulting in high
conversion and good yield of the desired ¡-acetoxy ketone by
using only 1.3 equiv of TBHP (Entries 11 and 12). Finally we
were able to reduce the catalyst loading to 30 mol % without loss
of efficiency of the catalysis (Entry 13).
1a
Br2 (1 equiv)/n-Bu4NOAc (2 equiv)
AcOH, 110 °C, 20 h
O
Pr
O
Ph
6 (30 mol%)
aq. TBHP
(1.3 equiv)
Pr
OAc
Br
Ph
n-Bu4NOAc (30 mol%)
AcOH, 110 °C, 6 h
2a
77%
(7)
+
This catalytic system was applicable to a variety of ketones
including aryl alkyl ketones with both electron-donating and
electron-withdrawing groups on the aromatic ring to give the
corresponding ¡-acetoxyketone in moderate to good yields
except for acetophenone (Table 2). In the case of acetophenone,
rapid overbromination retarded the catalysis under the present
conditions and this issue is to be resolved in the future.10
As shown in Scheme 2, the reaction of 1a with Br2 in acetic
acid gave 93% of ¡-bromoketone 3 with no 2a, suggesting that
the present system did not proceed via simple solvolysis of
3 with acetic acid (eq 5). On the other hand, addition of n-
Bu4NOAc in the above reaction gave 2a instead of 3 as a major
product (eq 6). Moreover, the reaction of 1a with TBHP in the
presence of both n-Bu4NOAc and ¡-bromovalerophenone (6)
gave the corresponding ¡-acetoxyketones 2a and 2b in good
yields (eq 7). These results clearly showed that regeneration of
n-Bu4NBr and subsequent reoxidation, incorporation of result-
ing Br2 into 1a, and nucleophilic substitution reaction occurred
as proposed in Scheme 1 (from eqs 4 ! 1 ! 2,3 ! 4).
In summary, we have demonstrated a novel catalytic
approach for formal dehydrogenative coupling using the redox
property of bromide ions in MBr. This system also showed the
oxidative recycling of MBr waste generated from the substitu-
tion reaction between MNu and RX, which was originally not
an atom-economical reaction, enabling it to be a net atom-
economical transformation.11 Further applications of this con-
cept are now in progress in our laboratory.
2b
110 °C, 24 h
90% conv.
95% based on 6
Scheme 2. Support for expected mechanism.
This work was supported by the project 2009ZX09501-017
from the Ministry of Science and Technology of China.
References and Notes
³
1
2
Present address: Department of Chemistry, Faculty of
Science, Kochi University, Akebono-cho, Kochi 780-8520
P. T. Anastas, J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, Oxford, 1998.
a) T. Nagano, T. Hayashi, Org. Lett. 2004, 6, 1297. b) T.
Nagano, T. Hayashi, Org. Lett. 2005, 7, 491. c) T. Nagano,
S. Kobayashi, Chem. Lett. 2008, 37, 1042.
3
4
W. C. Bray, Chem. Rev. 1932, 10, 161.
a) J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B.
Sharpless, J. Am. Chem. Soc. 1998, 120, 6844. b) B. F. Sels,
D. E. De Vos, P. A. Jacobs, J. Am. Chem. Soc. 2001, 123,
8350. c) C. Varszegi, M. Ernst, F. van Laar, B. F. Sels, E.
Schwab, D. E. De Vos, Angew. Chem., Int. Ed. 2008, 47,
1477.
There are a few methods for direct oxidative ¡-acetoxylation
of ketones, see: a) D. J. Rawlinson, G. Sosnovsky, Synthesis
1973, 567. b) F. Mizukami, M. Ando, T. Tanaka, J. Imamura,
Bull. Chem. Soc. Jpn. 1978, 51, 335. c) A. S. Demir, N.
5
Chem. Lett. 2010, 39, 929-931
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

931
Camkerten, H. Akgun, C. Tanyeli, A. S. Mahasneh, D. S.
Watt, Synth. Commun. 1990, 20, 2279. d) J. C. Lee, Y. S. Jin,
J.-H. Choi, Chem. Commun. 2001, 956. e) A. S. Demir, H.
Hamamci, O. Sesenoglu, F. Aydogan, D. Capanoglu, R.
Neslihanoglu, Tetrahedron: Asymmetry 2001, 12, 1953. f)
A. S. Demir, Ö. Reis, A. C. Igdir, Tetrahedron 2004, 60,
3427. g) M. Ochiai, Y. Takeuchi, T. Katayama, T. Sueda, K.
Miyamoto, J. Am. Chem. Soc. 2005, 127, 12244. h) J. Sheng,
X. Li, M. Tang, B. Gao, G. Huang, Synthesis 2007, 1165. i)
A. S. Demir, H. Findik, Tetrahedron 2008, 64, 6196. j) A. S.
Demir, A. Aybey, Tetrahedron 2008, 64, 11256.
8
9
F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry
Part A: Structure and Mechanisms, 5th ed., Springer, New
York, 2007, p. 411.
a) Significant rate enhancement in the reaction of alkyl
bromide with acetates by using R4NOAc in AcOH, see: M.
Botta, F. D. Angelis, I. Grgurina, M. Marzi, R. Nicoletti, J.
Heterocycl. Chem. 1985, 22, 1001. b) Study on the differ-
ence between K+ and Bu4N+ in nucleophilic substitution in
aprotic solvent, see: J. Ugelstad, T. Ellingsen, A. Berge, Acta
Chem. Scand. 1966, 20, 1593.
10 Bromination of acetophenone in AcOH in the presence of
NaOAc was reported for the synthesis of tribromoacetophe-
none, see: J. G. Aston, J. D. Newkirk, J. Dorsky, D. M.
Jenkins, J. Am. Chem. Soc. 1942, 64, 1413.
6
7
Recent reviews on cross-dehydrogenative coupling, see:
a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335. b) C. J.
Scheuermann, Chem. Asian J. 2010, 5, 436.
Hydrogen peroxide works as reducing agent for bromine
according to the following equation: H2O2 + Br2 = O2 +
11 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
¹
2Br + 2H+, see ref. 3.
Chem. Lett. 2010, 39, 929-931
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/