Hydrogen peroxide or peracetic acid mediated self-titrating α-halogenation of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1055/s-0030-1258367

Efficient oxidative -halogenation of 1,3-dicarbonyl compounds has been achieved by employing a system comprising of sub-stoichiometric amounts of TiX₄ (X = Cl, Br) in conjunction with environmentally benign hydrogen peroxide (H₂O

Full text of DOI:10.1055/s-0030-1258367

PAPER
347
Hydrogen Peroxide or Peracetic Acid Mediated Self-Titrating a-Halogenation
of 1,3-Dicarbonyl Compounds
Ramulu Akula, Marc J. Galligan, Hasim Ibrahim*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4,
Ireland
Fax +353(1)7161178; E-mail: hasim.ibrahim@ucd.ie
Received 18 August 2010; revised 29 October 2010
in a recent study on the a-hydroxylation of b-keto esters
Abstract: Efficient oxidative a-halogenation of 1,3-dicarbonyl
catalysed by iron(III) chloride hexahydrate with hydrogen
peroxide as the oxidant, it was observed that increasing
compounds has been achieved by employing a system comprising
of sub-stoichiometric amounts of TiX4 (X = Cl, Br) in conjunction
with environmentally benign hydrogen peroxide (H2O2) or perace-
the iron(III) chloride hexahydrate loading led to competi-
tic acid (MeCO3H) as the oxidants. The end point of the reaction is tive a-chlorination.12
accompanied by a sharp colour change.
We reported recently on an efficient a-halogenation of
Key words: halogenation, peroxides, titanium, halides, electro-
philic
1,3-dicarbonyls using a system comprising of 0.25–0.3
equivalents of TiX4 and (diacetoxyiodo)benzene (DIB) as
a mild oxidant.13 A drawback of this procedure is that io-
dobenzene is formed as a stoichiometric byproduct, which
led us to investigate the possibility of employing alterna-
tive oxidants such as hydrogen peroxide or peracetic acid.
This enabled us to uncover an exceedingly simple and
atom-economic a-halogenation where the conversion to
the product can be monitored visually.
Electrophilic a-halogenation of 1,3-dicarbonyl com-
pounds is usually performed by treating them with an
electrophilic halogenating agent, most commonly N-halo-
succinimide, in the presence of a base, catalyst or an acti-
vating additive.1,2 Although very useful for small-scale
applications, these procedures become less attractive on a
large scale, especially when considering the waste
byproducts derived from the electrophilic halogenating
agent.
Reacting one equivalent of titanium(IV) chloride with an
acetonitrile solution of our test substrate, benzyl 2-meth-
yl-3-oxobutanoate, instantly gave a dark-red Ti(enolato)
complex. Upon the complete addition of 1.1 equivalents
of 30% aqueous hydrogen peroxide to this solution, an im-
mediate colour change to yellow was observed (Table 1,
entry 1). TLC analysis showed that the starting material
had been consumed and subsequent crude 1H NMR anal-
ysis confirmed complete conversion into the chlorinated
product, which was isolated in 94% yield after short-pad
column chromatography. No change in yield was ob-
served when carrying out the reaction under nitrogen and
in dry solvent; all subsequent reactions were conducted in
untreated solvents and in air (Table 1).
A conceptually different approach is the use of a halide
source in combination with an oxidant to affect the in situ
generation of a halonium ion (X+) equivalent. Examples
for such protocols include the AlCl3/Pb(OAc)4 and ZnBr2/
Pb(OAc)4 tandems,3 a biphasic a-bromination utilizing a
V2O5/H2O2/NH4Br combination4 and a microwave-
induced a-halogenation employing Koser’s reagent in
conjunction with magnesium halides via the preformed a-
tosyloxy compounds.5 Drawbacks of these procedures are
that in many cases the oxidants or additives are toxic, used
in excess or generate waste byproducts which renders
these protocols uneconomical.
Inspired by enzymatic oxidative halogenation,6 the use of
‘green’ oxidants such as hydrogen peroxide has been in-
creasing.7 This is particularly the case in the oxidative ha-
logenation of aromatic compounds.7,8 However, the use of
atom-economical procedures employing green oxidants in
the halogenation of enolisable substrates and especially
1,3-dicarbonyls is still rare. Examples include a hydrogen
peroxide mediated a-bromination with potassium
bromide9 or hydrogen bromide10 as the halide source un-
der strong acidic conditions, and hydrogen peroxide en-
hanced a-iodination with iodine in water.11 Furthermore,
A screen of solvents showed that coordinating solvents
such as tetrahydrofuran and diethyl ether were suitable
solvents for this reaction (entries 2 and 3), whereas tolu-
ene, dichloromethane, and cyclohexane (entries 4–6) were
not as effective. An experiment with the neat reactants and
hydrogen peroxide gave a poor conversion of 32% after
30 minutes. Reactions with hydrogen peroxide were bi-
phasic in acetonitrile, consequently we decided to exam-
ine peracetic acid as an alternative to hydrogen peroxide.
Conducting the reaction with peracetic acid gave compa-
rable results to those obtained with hydrogen peroxide,
moreover, the reaction mixture remained homogenous
which simplified workup. We were pleased to find that
lowering the TiCl4/substrate ratio to 0.5 (Table 1, entry 8)
and even further to 0.25 when using peracetic acid or hy-
drogen peroxide (entries 9 and 10) as the oxidant gave
SYNTHESIS 2011, No. 2, pp 0347–0351
x
x
.
x
x
.2
0
1
1
Advanced online publication: 15.12.2010
DOI: 10.1055/s-0030-1258367; Art ID: T16410SS
© Georg Thieme Verlag Stuttgart · New York

348
R. Akula et al.
PAPER
Table 2 a-Chlorination of 1,3-Dicarbonyl Compounds Using Hy-
complete conversion, which indicated that the reaction
proceeded with 100% halogen incorporation.
drogen Peroxide or Peracetic Acid as the Oxidanta (continued)
Entry Substrate
Product
Yieldb (%)
Table 1 Reaction Parameter Optimisation Using Hydrogen Perox-
ide or Peracetic Acid as the Oxidantsa
Using Using
H2O2
MeCO3H
O
O
O
O
i) TiCl4
ii) oxidant
O
O
O
O
OBn
OBn
4
93
94
85
solvent, r.t.
Cl
Ph
OEt
Ph
OEt
Cl
Entry Solvent TiCl4 Oxidant
(equiv) (1.1 equiv)
Time
Conv.b Yieldc
O
O
O
O
(%)
98
98
98
92
56
63
98
98
98
98
(%)
5
6
–
OEt
OEt
1
2
MeCN
THF
1.0
1.0
1.0
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
<5 s
94
Cl
<5 s
92
O
O
O
O
3
Et2O
<5 s
82
77c
60d
93
OBn
OBn
O
d
4
toluene 1.0
CH2Cl2 1.0
20 min
20 min
15 min
–
Cl
d
5
–
O
O
O
d
6
C6H12
1.0
–
7
8
–
OEt
OEt
Cl
7
MeCN
MeCN
MeCN
MeCN
1.0
MeCO3H <5 s
MeCO3H <5 s
MeCO3H <5 s
92
93
94
97
8
0.5
O
O
O
O
O
86
92
9
0.25
0.25
Cl
O
10
H2O2
<5 s
O
O
a All reactions were performed using: substrate (1.0 mmol), specified
solvent (2 mL, 0.5 M).
9
10
11
12
93
98
93
92
93
97
94
95
b Determined by 1H NMR of the crude product.
c Yield of isolated product after short-pad column chromatography.
d Not determined.
Cl
O
O
O
O
O
O
NBn2
NBn2
NBn2
Cl
With the optimized conditions from entries 9 and 10 in
hand, the chlorination of a series of substrates was first at-
tempted with hydrogen peroxide, which included three b-
keto esters (Table 2, entries 1, 4 and 6) two 1,3-diketones
(entries 8 and 9), two b-keto amides (entries 10 and 11),
and a b-keto phosphonate (entry 12).
O
O
O
NBn2
Cl
O
O
P
O
P
OEt
OEt
Table 2 a-Chlorination of 1,3-Dicarbonyl Compounds Using Hy-
OEt
OEt
Cl
drogen Peroxide or Peracetic Acid as the Oxidanta
O
O
O
O
Entry Substrate
Product
Yieldb (%)
13
–
–
93
90
HN
OEt
HN
OEt
Using Using
Cl
H2O2
MeCO3H
O
O
O
O
O
O
O
O
14e
1
2
96
95
89
OBn
OBn
O
OBn
O
OBn
Cl Cl
Cl
a All reactions were performed using: substrate (1.0 mmol), TiCl4 (0.3
mmol), oxidant (1.1 mmol), MeCN (2 mL, 0.5 M).
b Yield of isolated product after short-pad column chromatography.
c Reaction was performed with TiCl4 (0.6 mmol) and H2O2 (1.1
mmol).
O
O
–
–
OBn
OBn
Cl
O
O
O
O
d Reaction was performed with TiCl4 (1.0 mmol) and MeCO3H (1.1
mmol).
3
74
Ot-Bu
Ot-Bu
e Reaction was performed with TiCl4 (0.6 mmol) and MeCO3H (2.2
mmol).
Cl
Synthesis 2011, No. 2, 347–351 © Thieme Stuttgart · New York

PAPER
a-Halogenation of 1,3-Dicarbonyl Compounds
349
Conversion to the products was complete upon the addi-
tion of hydrogen peroxide, as indicated by an immediate
colour change from dark red to yellow and the 1H NMR
spectrum of the crude material. The reaction mixture of
the allyl-substituted b-keto ester (entry 6), however, re-
mained dark red. All corresponding chlorinated products
were obtained in high yields.
Table 3 a-Bromination of 1,3-Dicarbonyl Compounds Using Per-
acetic Acid as the Oxidanta
Entry Substrate
Product
Yieldb (%)
90
O
O
O
O
O
O
1
OBn
OEt
OBn
OEt
Br
The reaction of 1,3-dicarbonyl compounds was next ex-
amined with peracetic acid. Again, all reactions were
complete after the addition of the oxidant as indicated by
a sharp colour change from dark red to yellow. The colour
change of the peracetic acid reaction of Table 2, entry 11
is shown in Scheme 1.
O
O
2c
92
95
85
Br
O
O
O
O
3
4
OEt
OEt
Br
O
O
O
O
O
Br
O
O
O
O
O
5
6
96
95
NBn2
NBn2
OEt
Scheme 1 Self-titrating chlorination mediated by peracetic acid
Br
O
P
O
P
In general, reactions with peracetic acid gave consistently
cleaner crude products than reactions with hydrogen per-
oxide as judged by 1H NMR. Most substrates gave suffi-
ciently pure crude products after aqueous workup;
however, short-pad column chromatography was routine-
ly performed to remove residual traces of titanium diox-
ide.
OEt
OEt
OEt
Br
a All reactions were performed using: substrate (1.0 mmol), TiBr4 (0.3
mmol), MeCO3H (1.1 mmol), MeCN (2 mL, 0.5 M).
b Yield of isolated product after short-pad column chromatography.
c Reaction was performed with substrate (17.6 mmol), TiBr4 (4.76
mmol), MeCO3H (19.4 mmol).
In the case of the allyl-substituted b-keto ester (Table 2,
entry 6), no colour change was observed and higher
amounts of titanium(IV) oxide were required to obtain a
moderate yield of the product. The reaction was lower
yielding, presumably due to the competing interaction of
the oxidant or the in situ generated halogenating agent
with the allyl group. In all other cases studied reactions
were selective and no benzylic or aromatic halogenation
was observed. A non-a-substituted b-keto ester (Table 2,
entry 14) was efficiently dichlorinated using 0.6 mmol of
titanium(IV) chloride and 2.2 mmol of peracetic acid and
the product was obtained in 90% yield. Attempted
monochlorination using 0.3 mmol of titanium(IV) chlo-
ride gave a 3:1 mixture of the mono- to the dichlorinated
products. This ratio could be improved to 5:1 upon con-
ducting the reaction at –30 °C as determined by 1H NMR
of the crude product.
With regard to the mechanism operating in the presented
oxidative halogenation, we propose that the addition of
TiX4 to an acetonitrile solution of the substrate results in
the formation of a dark red dihalobis(enolato)titanium
complex.14 This complex is likely present in a mixture of
several equilibrating Ti(enolato) complexes, the constitu-
tion of which is not clear at present. The subsequent addi-
tion of hydrogen peroxide or peracetic acid oxidizes the
liberated HX to HOX which acts as the halogenating
agent (Scheme 2).15
X4-n
Ti
O
O
O
O
O
O
TiX4
R1
R3
R1
R3
R1
R3
R2
X
R2
R2
n
Likewise, brominations were carried out with 0.3 equiva-
lents of titanium(IV) bromide using 1.1 equivalents of
peracetic acid. All a-brominated products were obtained
in high yields (Table 3). The reaction of ethyl 2-oxocyclo-
hexanecarboxylate (Table 3, entry 2) was run on a 17.6
mmol scale (3.0 g) with 0.27 equivalents of titanium(IV)
bromide in order to demonstrate that these reactions can
be scaled up without problems; the corresponding a-bro-
minated compound was isolated in 92% yield.
XH
HOX
X = Cl, Br
4 = H, Ac
R
R4OOH
R4OH
Scheme 2 Mechanistic rationale for the hydrogen peroxide or perace-
tic acid mediated a-halogenation using TiX4 as the halide source
In summary, we have developed a cost-effective, scalable,
and environmentally benign hydrogen peroxide or perace-
tic acid mediated a-halogenation of a series of 1,3-dicar-
bonyls, including substrates with low enol content such as
Synthesis 2011, No. 2, 347–351 © Thieme Stuttgart · New York

350
R. Akula et al.
PAPER
Ethyl 2-Bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(Table 3, Entry 3)
Short-pad flash column chromatography (silica gel, pentane–Et2O,
85:15); pale-yellow oil; yield: 269 mg (95%).
b-keto amides.16 The reaction is rapid, gives high yields of
the halogenated products, and proceeds with 100% halo-
gen atom economy. Titanium dioxide is the only waste
byproduct formed; moreover, the reaction is self-titrating
and can be monitored visually. The presented oxidative
halogenation leading to a-halo-1,3-dicarbonyls offers an
attractive alternative to existing electrophilic procedures
for this class of compounds. The utilization of this method
for the a-halogenation of other enolisable substrate class-
es is currently underway in our laboratory and will be re-
ported in due course.
IR (neat): 3076, 2983, 1748, 1723, 1604, 1466, 1274, 1242, 752
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 3.68 (d, J = 18.1 Hz, 1 H, ArCHH), 4.21 (d, J = 18.1
Hz, 1 H, ArCHH), 4.25–4.23 (m, 2 H, OCH2CH3), 7.42–7.51 (m, 2
H, ArH), 7.67–7.71 (m, 1 H, ArH), 7.83–7.91 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.9, 43.8, 58.4, 63.5, 125.9,
126.3, 128.5, 132.2, 136.2, 150.1, 167.0, 195.1.
HRMS-ESI: m/z [M + H]+ calcd for C12H12O3Br: 282.9970; found:
282.9979.
All reagents were obtained from commercial suppliers and used
without further purification. HPLC grade MeCN and ~39%
MeCO3H soln in AcOH were purchased from Sigma-Aldrich and
used as received. 30% H2O2 soln in H2O was purchased from Fluka
and used as received. b-Keto esters (Table 2, entries 1,17 2,1f 3,16 4,17
6,18 719), b-keto amides (Table 2, entries 10, 11),20 and diethyl 3-oxo-
butan-2-ylphosphonate21 were prepared according to literature pro-
cedures. TLC was performed on Merck Aluminium sheets (silica
gel 60 F254). Detection was by UV and/or by colouration with ceric
ammonium molybdate (CAM) or vanillin. Flash column chroma-
tography was performed using Merck silica gel 60 (230–400 mesh).
NMR spectra were recorded on Varian Inova 300 MHz, Varian 400
MHz FT spectrometers at r.t. with CDCl3 as the internal standard;
the reference values used for CDCl3 were d = 7.26 and 77.0 for 1H
and 13C NMR spectra, respectively. HRMS were measured on a
Waters/Micromass GCT and Waters 2996 Photodiode Array Detec-
tor instruments. IR spectra were recorded on a Varian 3100 FT-IR
spectrophotometer at r.t.
Benzyl 2,2-Dichloro-3-oxobutanoate (Table 2, Entry 14)22
TiCl4 (0.066 mL, 0.6 mmol) was added via a syringe to a stirred soln
of benzyl 3-oxobutanoate (192 mg, 1 mmol) in MeCN (2 mL),
which resulted in an immediate colour change to dark red. MeCO3H
(~39% soln in AcOH, 429 mg, 2.2 mmol) was added dropwise to
the above soln at r.t. Once the addition was complete, an immediate
colour change to pale yellow was observed. Work-up was as stated
in the general procedure. The crude product was purified by short-
pad flash column chromatography (silica gel, pentane–Et2O 90:10)
to give the title compound (235 mg, 90%) as a colourless oil.
Acknowledgment
This work was supported by Science Foundation Ireland (07/RFP/
CHEF394) and UCD’s School of Chemistry and Chemical Biology.
Oxidative Halogenation of 1,3-Dicarbonyl Compounds; Gener-
al Procedure22
References
TiX4 was added via a syringe (TiCl4, 56.9 mg, 33 mL, 0.3 mmol) or
as a solid in one portion (TiBr4, 111 mg, 0.3 mmol) to a stirred soln/
suspension of the substrate (1 mmol) in MeCN (2 mL), which re-
sulted in an immediate colour change to dark red. MeCO3H (~39%
soln in AcOH, 215 mg, 1.1 mmol) or H2O2 (30% soln in H2O, 125
mg, 1.1 mmol) was added dropwise to the above soln at r.t. Once the
addition was complete, a colour change to pale yellow was ob-
served, which indicated the completion of the reaction. The mixture
was diluted with Et2O (10 mL) and washed with H2O (10 mL). The
aqueous layer was extracted with Et2O (2 × 5 mL), the combined or-
ganic layers were dried (Na2SO4), and the solvent was removed un-
der reduced pressure. The crude product was purified by short-pad
flash column chromatography.
(1) For selected examples, see: (a) Meshram, H. M.; Reddy, P.
N.; Vishnu, P.; Sadashiv, K.; Yadav, J. S. Tetrahedron Lett.
2006, 47, 991. (b) Das, B.; Venkateswarlu, K.; Mahender,
G.; Mahender, I. Tetrahedron Lett. 2005, 46, 3041.
(c) Wang, C.; Tunge, J. Chem. Commun. 2004, 2694.
(d) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi,
K.; Horaguchi, T. Chem. Commun. 2004, 470. (e) Yang,D.;
Yan, Y.-L.; Lui, B. J. Org. Chem. 2002, 67, 7429.
(f) Hintermann, L.; Togni, A. Helv. Chim. Acta 2000, 83,
2425.
(2) For recent reviews on asymmetric electrophilic a-halogen-
ation, see: (a) Czekelius, C.; Tzschucke, C. C. Synthesis
2010, 543. (b) Ueda, M.; Kano, T.; Maruoka, K. Org.
Biomol. Chem. 2009, 7, 2005.
Ethyl 2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(Table 2, Entry 7)
Short-pad flash column chromatography: silica gel (pentane–Et2O,
(3) Kim, J.-J.; Kweon, D.-H.; Cho, S.-D.; Kim, H.-K.; Lee,
S.-G.; Yoon, Y.-J. Synlett 2006, 194.
(4) Khan, A. T.; Goswami, P.; Choudhury, L. H. Tetrahedron
Lett. 2006, 47, 2751.
85:15); colourless oil; yield: 222 mg (93%).
(5) Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y. H.; Lee, S. J.
Tetrahedron Lett. 2004, 45, 191.
IR (neat): 3077, 2985, 1756, 1732, 1605, 1428, 1274, 1248, 733
cm–1.
(6) Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-
Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364.
(7) For an excellent review on oxidative halogenation with
green oxidants, see: Podgorek, A.; Zupan, M.; Iskra, J.
Angew. Chem. Int. Ed. 2009, 48, 8424.
(8) For aerobic oxidative halogenations of organic molecules
catalysed by NaNO2, see: (a) Iskra, J.; Stavber, S.; Zupan,
M. Tetrahedron Lett. 2008, 49, 893. (b) Zhang, G.; Liu, R.;
Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 348, 862.
(9) Kirihara, M.; Ogawa, S.; Noguchi, T.; Okubo, K.; Monma,
Y.; Shimizu, I.; Shimosaki, R.; Hatano, A.; Hirai, Y. Synlett
2006, 2287.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 3.55 (d, J = 17.8 Hz, 1 H, ArCHH), 4.09 (d, J = 17.8
Hz, 1 H, ArCHH), 4.21–4.32 (m, 2 H, OCH2CH3), 7.45–7.49 (m, 2
H, ArH), 7.65–7.75 (m, 1 H, ArH), 7.85 (d, J = 7.7 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.9, 43.4, 63.4, 67.9, 125.9,
126.3, 128.5, 132.5, 136.4, 150.5, 167.1, 195.1.
HRMS-ESI: m/z [M + H]+ calcd for C12H12O3Cl: 239.0475; found:
239.0473.
Synthesis 2011, No. 2, 347–351 © Thieme Stuttgart · New York

PAPER
a-Halogenation of 1,3-Dicarbonyl Compounds
351
(10) Podgorek, A.; Stavber, S.; Zupan, M.; Iskra, J. Green Chem.
2007, 9, 1212.
(11) Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun. 2004,
2614.
(16) For example, see: Evans, D. A.; Ennis, M. D.; Le, T. J. Am.
Chem. Soc. 1984, 106, 1154.
(17) Wyman, W. E.; Davis, R.; Patterson, J. W. Jr.; Pfister, J. R.
Synth. Commun. 1988, 18, 1379.
(12) Schröder, D.; Li, K.; Bitterlich, B.; Kin Tse, M.; Beller, M.
Tetrahedron Lett. 2008, 49, 5976.
(13) Akula, R.; Galligan, M.; Ibrahim, H. Chem. Commun. 2009,
6991.
(18) Queignec, R.; Kirschlerger, B.; Lambert, F.; Aboutaj, M.
Synth. Commun. 1988, 18, 1213.
(19) Nieman, J. A.; Keay, B. A. Tetrahedron: Asymmetry 1995,
6, 1575.
(14) (a) Fay, R. C.; Lowry, R. N. Inorg. Chem. 1967, 6, 1512.
(b) Thompson, D. W.; Somers, W. A.; Workman, M. O.
Inorg. Chem. 1970, 9, 1252.
(15) For an example on the use of sodium hypohalites in the a-
halogenation of 1,3-dicarbonyls, see: Meketa, M. L.;
Mahajan, Y. R.; Weinreb, S. M. Tetrahedron Lett. 2005, 46,
4749.
(20) Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793.
(21) Mathey, F.; Savignac, P. Synthesis 1976, 776.
(22) For full analytical data of all products from Tables 2 and 3
with the exception of the products in Table 2, entry 7 and
Table 3, entry 3, see reference 13.
Synthesis 2011, No. 2, 347–351 © Thieme Stuttgart · New York