Umpolung of halide reactivity: Efficient (diacetoxyiodo)benzene-mediated electrophilic α-halogenation of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/b915348a

An efficient high-yielding (diacetoxyiodo)benzene-mediated α-halogenation of 1,3-dicarbonyl compounds utilising titanium tetrahalides as the halide source has been developed. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b915348a

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COMMUNICATION
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Umpolung of halide reactivity: efficient (diacetoxyiodo)benzene-mediated
electrophilic a-halogenation of 1,3-dicarbonyl compoundsw
Ramulu Akula, Marc Galligan and Hasim Ibrahim*
Received (in Cambridge, UK) 29th July 2009, Accepted 22nd September 2009
First published as an Advance Article on the web 12th October 2009
DOI: 10.1039/b915348a
An efficient high-yielding (diacetoxyiodo)benzene-mediated
a-halogenation of 1,3-dicarbonyl compounds utilising titanium
tetrahalides as the halide source has been developed.
Table
1 Performance of Lewis acidic metal chlorides in the
a-chlorination of 1 mediated by DIB
a-Halogenated 1,3-dicarbonyl compounds are versatile building
blocks for organic synthesis. The introduction of an a-halo
substituent is typically achieved by electrophilic strategies
utilising an electrophilic halogenating agent, either alone or
in combination with an activating additive such as a Lewis
acid. Many electrophilic reagents and reagent combinations
have been studied, and selected examples include the use of
N-halosuccinimdes in combination with catalytic amounts of
titanium complexes,1 Mg(ClO4)2,2 ammonium acetate3 and
phenylselenides.4
MCln/
equiv.
DIB/
equiv.
Time/
min
Conv
(%)c
Yield
(%)d
Entry
MCln
1a
2a
3a
4b
5b
6b
CuCl
MgCl2
ZnCl2
TiCl4
TiCl4
TiCl4
1.1
1.1
1.1
1.0
0.5
0.25
1.1
1.1
1.1
1.2
1.2
1.2
120
90
30
3
3
3
79
Z 98
Z 98
Z 98
Z 98
Z 98
60
92
88
92
86
92
a
b
a 1 mmol scale. Reaction was
Reaction was performed on
c
In contrast, the a-halogenation of 1,3-dicarbonyl compounds
using halide sources (XÀ) in combination with readily available
oxidizing agents, thereby affecting the in situ generation of X+
equivalents, has received far less attention. Such protocols
include the AlCl3/Pb(OAc)4 and ZnBr2/Pb(OAc)4 tandems,5
performed on a 2 mmol scale. Determined by 1H NMR of the crude
d
product. Isolated yield after column chromatography.
M(enolato) complex with concomitant release of a halide ion,
which is oxidized in situ by DIB to an electrophilic halonium
ion equivalent, resulting in a net Umpolung of the halide
reactivity.
a
biphasic a-bromination utilising
a V2O5/H2O2/NH4Br
combination6 and
a
microwave-induced a-halogenation
employing Koser’s reagent in conjunction with magnesium
halides via the preformed a-tosyloxy compounds.7
We first tested this strategy with b-keto ester 1 using 1.1
equivalents of CuCl and 1.1 equivalents of DIB in MeCN.
After 2 h, a 79% conversion to the a-chlorinated b-keto
In light of the recent advances in the chemistry of hypervalent
iodine(III) compounds,8,9 and the quest for efficient and mild
halogenation reactions with a wide scope, we report here on an
exceedingly simple high-yielding protocol for the a-halogenation
of 1,3-dicarbonyl compounds. The presented (diacetoxyiodo)-
benzene10 (DIB)-mediated procedure utilises substoichiometric
amounts of an inexpensive Lewis acidic metal halide as the
halide source.
1
ester 2 was detected by H NMR, and after work-up, 2 was
isolated in a moderate 60% yield (Table 1, entry 1). With 1.1
equivalents of MgCl2, the reaction proceeded to completion
within 112 h, and 2 was isolated in an excellent yield of 92%
(Table 1, entry 2).
Comparable yields were obtained with ZnCl2; however, the
reaction was faster and complete conversion was detected after
30 min. We next examined inexpensive TiCl4. Treatment of
an acetonitrile solution of 1 with one equivalent of TiCl4
immediately gave a brick red solution of a Ti(enolato) complex.
When DIB was subsequently added, we observed a decrease in
the reaction time to 3 min, and 2 was obtained in 92% yield
(Table 1, entry 4). Running the reaction in dry solvents and
under an atmosphere of nitrogen gave comparable results. We
then investigated whether a decrease in the TiCl4/substrate
ratio would have an influence on the efficiency of the reaction.
Lowering the TiCl4 amount to 0.5 equivalents gave the
product in comparable rates and yields. We were pleased to
find that lowering the TiCl4/substrate ratio even further to
0.25 gave similar results to those obtained with one equivalent,
which indicated that TiCl4 can provide four Cl+ equivalents
under our reaction conditions (Table 1, entry 6).
An outline of our strategy is summarized in Scheme 1. The
treatment of a 1,3-dicarbonyl substrate with MXn generates an
Scheme 1 Outline of the DIB-mediated Umpolung strategy.
Centre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, University College Dublin, Belfield, Dublin 04,
Ireland. E-mail: hasim.ibrahim@ucd.ie; Fax: 353 1 7161178;
Tel: 353 1 7162978
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation for selected new compounds. See
DOI: 10.1039/b915348a
With the optimized conditions from entry 6 in hand, we set
out to explore the substrate diversity tolerance (Table 2).
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Table 2 DIB-mediated a-chlorination of 1,3-dicarbonyl compoundsa
yields and in short reaction times. In addition, a non-
a-substituted b-keto ester gave a 5 : 1 ratio of the mono- to
the dichlorinated product, as determined by 1H NMR of
the crude material, with the monochlorinated product being
isolated in 75% yield (Table 2, entry 2). Performing the
reaction with 0.6 equivalents of TiCl4 and 2.2 equivalents of
DIB produced, within 2 min, the dichlorinated product in 93%
yield (entry 15). The alkene functionality is tolerated under the
reaction conditions (Table 2, entry 8). In addition, no aromatic,
allylic or benzylic chlorination was observed. b-Keto amides,
which are known for their low enol content,11 were also
chlorinated smoothly in high yields (entries 12 and 13).
The established reaction conditions for chlorinations could
be successfully applied to the analogous a-brominations using
0.3 equivalents of TiBr4 and 1.2 equivalents of DIB (Table 3).
All a-brominated products were obtained in high yields
and with markedly faster reaction times. The reaction of
2-ethoxycarbonyl-1-oxo-cyclohexane (Table 3, entry 2) was
run on a 15 mmol scale (2.5 g) with 0.26 equivalents of TiBr4 in
order to demonstrate that these reactions can be carried out on
a larger scale. The reaction produced, in less than 1 min, the
corresponding a-brominated product in 95% yield.
The reported transformation raises interesting mechanistical
questions with regard to (1) the active intermediates and (2)
the reaction pathway involved, i.e. a radical or ionic pathway.
It has been reported that the treatment of TiX4 (X = Cl, Br)
with two or more equivalents of 1,3-dicarbonyl compounds
results in the formation of monomeric cis-dihalobis(enolato)-
titanium(IV) complexes, with concomitant release of halide
ions.13 We propose that the addition of DIB to the reaction
mixture results in an exchange of the acetate by the halide ion
to generate a mixed-ligated l3-iodane of type 3 (Scheme 2).
A similar in situ generated [acetoxy(bromo)iodo]benzene from
Entry Substrate
Time/minb Product
Yield (%)c
1
3
90
2
3
4
5
2
2
75
87
85
95
50
4
6
7
3
3
91
89
81
97
88
8
3
9
50
3
10
Table 3 DIB-mediated a-bromination of 1,3-dicarbonyl compoundsa
11
12
13
14
3
20
25
85
98
94
Entry Substrate
Time/minb Product
Yield (%)c
1
o1
92
2
3
4
o1
o1
95d
83
3
2
95
15
93d
6
97
95
a
All reactions were performed with 1 mmol of substrate in MeCN
(2 mL, 0.2 M) using 0.3 mmol of TiCl4 and 1.2 mmol of DIB.
5
o2
b
c
Determined by TLC analysis (see the ESIw). Isolated yield after
d
column chromatography, yields are the average of two runs. Reaction
was performed with 0.6 mmol of TiCl4 and 2.2 mmol of DIB.
a
All reactions were performed with 1 mmol of substrate in MeCN
(2 mL, 0.2 M) using 0.3 mmol of TiBr4 and 1.2 mmol of DIB.
b
c
Determined by TLC analysis (see ESI). Isolated yield after column
d
chromatography; yields are the average of two runs. Reaction was
performed with 14.68 mmol of substrate, 3.82 mmol of TiBr4 and
17.61 mmol of DIB.
Various b-keto esters (Table 2, entries 1–8), 1,3-diketones
(entries 9–11), b-keto amides (entries 12 and 13) and a b-keto
phosphonate (entry 14) were smoothly chlorinated in high
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moment.18 Subsequent C–X bond-forming reductive elimination
from 4 releases the product and iodobenzene. Alternatively, a
direct SN2-type attack (path B) of a preformed Ti(enolato)
complex onto the halo ligand of an activated X–I(III) bond
could furnish the product directly.
In summary, we describe a highly efficient and operationally
facile method for the electrophilic a-halogenation of a series of
activated methylene compounds, most notably b-keto amides.
Our method utilizes inexpensive titanium tetrahalide as a
Lewis acidic halide source in conjunction with readily available
DIB. We are currently applying the presented Umpolung
strategy to pseudohalides and results from these studies will
be reported in due course.
This work was supported by Science Foundation Ireland
and UCD’s School of Chemistry and Chemical Biology.
Scheme 2 Mechanistic rational for the a-halogenation mediated by
DIB based on the proposed intermediate 3.12
Notes and references
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Y.-J. Yoon, Synlett, 2006, 194–200.
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7 J. C. Lee, J. Y. Park, S. Y. Yoon, Y. H. Bae and S. J. Lee,
Tetrahedron Lett., 2004, 45, 191–193.
8 (a) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008, 108,
5299–5358; (b) Hypervalent Iodine Chemistry, ed. T. Wirth,
Springer-Verlag, Berlin, 2003.
Scheme 3 a-Chlorination of b-keto ester 1 and 2-acetyl-1-tetralone
with benziodoxole 5.
9 For recent examples of iodine(III)-mediated a-functionalisation of
carbonyls, see: (a) D. Kumar, S. Sundaree, V. S. Rao and
R. S. Varma, Tetrahedron Lett., 2006, 47, 4197–4199;
(b) I. Kieltsch, P. Eisenberger and A. Togni, Angew. Chem., Int.
Ed., 2007, 46, 754–757.
10 J. G. Sharefkin and H. Saltzman, Org. Synth., 1973, Coll. Vol. V,
660.
11 For example, see: D. A. Evans, M. D. Ennis and T. Le, J. Am.
Chem. Soc., 1984, 106, 1154–1156.
12 An alternative pathway involving the formation of acetyl hypo-
halite (AcOX) from 3, which acts as the electrophilic halogenating
agent, cannot be rigorously excluded. For an example on the use of
sodium hypohalites in the a-halogenation of 1,3-dicarbonyls, see:
M. L. Meketa, Y. R. Mahajan and S. M. Weinreb, Tetrahedron
Lett., 2005, 46, 4749–4751.
13 (a) R. C. Fay and R. N. Lowry, Inorg. Chem., 1967, 6, 1512–1519;
(b) D. W. Thompson, W. A. Somers and M. O. Workman, Inorg.
Chem., 1970, 9, 1252–1254.
14 D. C. Braddock, G. Cansell, S. A. Hermitage and A. J. P. White,
Chem. Commun., 2006, 1442–1444.
15 M. Ochiai, T. Sueda, K. Miyamoto, P. Kiprof and V. V. Zhdankin,
Angew. Chem., Int. Ed., 2006, 45, 8203–8206.
DIB and LiBr has been recently postulated to be a source of
Br+ in a mild bromination of alkenes and activated arenes.14
Furthermore, l3-iodanes of this type have been predicted to be
labile, presumably due to the unfavorable combination of
X/OAc trans influences,15 and efforts to isolate such iodanes
have been fruitless to date.14
In order to investigate whether 3 is an intermediate in our
halogenation studies we synthesized the stable benziodoxole
516 in an approximation to the proposed acyclic structure 3,
and proceeded to examine its reactivity with b-keto ester 1 and
2-acetyl-1-tetralone in the absence of a Lewis acid (Scheme 3).
We were pleased to find that b-keto ester 1 was chlorinated
within 48 h in a high yield of 92%. As expected, the reaction
showed a correlation with the enol content of the starting
1,3-dicarbonyl compound so that 2-acetyl-1-tetralone was
chlorinated within 1 h and the product was isolated in 92%
yield.17
16 X.-Q. Li and C. Zhang, Synthesis, 2009, 1163–1169.
17 Enol content was determined by 1H NMR spectroscopy. Enol
content of 1 in CD3CN: 6% and in CDCl3: 7%. Only the enol form
(Z98%) was detected for 2-acetyl-1-tetralone in CD3CN and in
CDCl3.
Based on these findings, we propose two mechanistic
scenarios for the presented halogenations (Scheme 2). The
first (path A) involves a direct nucleophilic attack of a
preformed Ti(enolato) complex onto the iodine centre of
intermediate 3, with concomitant release of an activated
acetate to furnish intermediate 4. Such activation can be
accomplished by coordination of a titanium Lewis acid present
in the reaction mixture, the nature of which is not clear at the
18 For examples of such
a Lewis acid-assisted activation, see:
(a) M. Kida, T. Sueda, S. Goto, T. Okuyama and M. Ochiai,
Chem. Commun., 1996, 1933–1934; (b) R. Koller, K. Stanek,
D. Stolz, R. Aardoom, K. Niedermann and A. Togni, Angew.
Chem., Int. Ed., 2009, 48, 4332–4336.
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Chem. Commun., 2009, 6991–6993 | 6993