Trihaloisocyanuric acids as convenient reagents for regioselective halogenation of β-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2008.11.045

The reaction of β-dicarbonyl compounds (β-ketoesters and β-diketones) with 0.34 mol equiv of trichloro- and tribromoisocyanuric acids produced regioselectively the corresponding α-monohalo β-dicarbonyl compound. On the other hand, utilization of 0.68 mol equiv of the trihaloisocyanuric acid produced the α,α-dihalo β-dicarbonyl compound.

Full text of DOI:10.1016/j.tetlet.2008.11.045

Tetrahedron Letters 50 (2009) 473–475
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Trihaloisocyanuric acids as convenient reagents for regioselective
halogenation of b-dicarbonyl compounds
Gabriela F. Mendonça, Haryadylla C. Sindra, Leonardo S. de Almeida,
*
*
Pierre M. Esteves , Marcio C. S. de Mattos
Instituto de Química, Departamento de Química Orgânica, Universidade Federal do Rio de Janeiro, Cx. Postal 68545, 21945-970 Rio de Janeiro, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of b-dicarbonyl compounds (b-ketoesters and b-diketones) with 0.34 mol equiv of trichloro-
Received 31 October 2008
Revised 11 November 2008
Accepted 12 November 2008
Available online 18 November 2008
and tribromoisocyanuric acids produced regioselectively the corresponding
compound. On the other hand, utilization of 0.68 mol equiv of the trihaloisocyanuric acid produced the
-dihalo b-dicarbonyl compound.
a-monohalo b-dicarbonyl
a,a
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to W. Bruce Kover, Emeritus
Professor of UFRJ.
Keywords:
Halogenation
Regioselectivity
b-Diketones
b-Ketoesters
a
-Halo carbonyl compounds are versatile compounds in organic
synthesis that can be transformed into a variety of useful struc-
tures.1 Recently,
-halo and -dihalo b-dicarbonyl compounds
O
X
X
X = Cl (TCCA)
X = Br (TBCA)
X = I (TICA)
N
N
a
a,a
have received considerable attention due to their biological activ-
ity2 and possible organic transformations.3 Several methodologies
are described in the literature for the halogenation of b-ketoesters
O
N
X
O
Figure 1. Trihaloisocyanuric acids.
and b-diketones.4 However, direct
a-monohalogenation of b-dicar-
bonyl compounds remains a challenge as
a,a-dihalogenated prod-
handled stable solids and also present a very good atom economy,
once they can transfer most part of their mass to the substrate
(TCCA can transfer up to 45.5% and TBCA up to 65%).11 Further-
more, in these reactions, cyanuric acid precipitates as a by-product,
which can be recovered by filtration and reused to prepare more
trihaloisocyanuric acid.12
ucts are often obtained as by-products.5
N-halo reagents (amides, saccharins, sulfonamides, etc.) are
widely used to perform halogenation of organic substrates.6
Among the N-halo reagents, the trihaloisocyanuric acids (Fig. 1)
are very efficient halogenating agents, due to their capability of
transferring halogen atoms to unsaturated substrates in electro-
philic reactions.7 Besides, trihaloisocyanuric acids proved to be
very useful oxidizing reagents too.8
Trichloroisocyanuric acid (TCCA) is a stable and inexpensive
solid frequently used for swimming pool disinfection and is easily
available in pool supply and in some hardware stores.9 Tribromoi-
socyanuric acid (TBCA) is easily and safely prepared from cyanuric
acid, KBr, and oxone.10 These trihaloisocyanuric acids are very
interesting from a Green Chemistry point of view, as they are easily
Some years ago, Hiegel and Peyton showed that ketones react
with TCCA to produce
a-mono-, a,a-di- or a,a,a-trichlorinated
products by just an adjustment of the mol equiv of the halogenat-
ing reagent employed.13 Herein, we show our results on the
utilization of TCCA and TBCA as efficient reagents for regioselective
mono- and dihalogenation of 1,3-dicarbonyl compounds (b-keto-
esters and b-diketones).
The reaction of diverse b-dicarbonyl compounds (ethyl aceto-
acetate, diethyl malonate, acetylacetone, benzoylacetone, 1,3-
cyclohexanodione, and dimedone) with 0.68 mol equiv of the
trihaloisocyanuric acids produced regioselectively the correspond-
* Corresponding authors. Fax: + 55 21 25627133 (M.C.S.d.M).
E-mail addresses: pesteves@iq.ufrj.br (P. M. Esteves), mmattos@iq.ufrj.br (M. C.
S. de Mattos).
ing
proceeded very smoothly at room temperature. Water was the
a,a
-dihalo b-dicarbonyl compounds (Table 1).14 The reactions
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.045

474
G. F. Mendonça et al. / Tetrahedron Letters 50 (2009) 473–475
Table 1
Table 3
a
,a
-Dihalogenation of b-dicarbonyl compounds
a-Monohalogenation of b-dicarbonyl compounds
O
O
X
X
X
X
O
O
O
O
O
O
O
O
N
N
N
N
solvent
r.t.
solvent
r.t.
+
+
R1
R2
R1
R2
R1
R2
R1
R2
O
N
X
O
O
N
X
O
X R3
R3
X
X
0.68 mol equiv
0.68 mol equiv
R1
R2
R3
X
Solvent
T (h)
Yielda
(%)
R1
R2
X
Solvent
T (h)
Yielda,b
(%)
744c
764c
814a
834a
824c
544c
Me
Me
OEt
OEt
Me
Me
Me
OEt
OEt
OEt
OEt
Ph
Ph
Me
–
Br
Cl
Br
Cl
Br
Cl
Br
Br
Cl
H2O
20
15
3
18
20
1
15
6
1.5
6018
10018
8116
7316
9416
8116
704b
5719
7618
Me
Me
Me
Me
Me
OEt
OEt
–(CH2)4–
–(CH2)4–
Ph
H
H
Br
Cl
Br
Cl
Cl
Br
H2O
CHCl3
H2O
0.8
6
21
1.25
1.7
20
H2O/Me2CO (5:2)
H2O
H2O/Me2CO (5:2)
H2O
H2O/Me2CO (5:2)
H2O
H2O
H2O/Me2COb
CHCl3
H2O
H
H
–(CH2)3–
a
Yield of pure product based on the b-dicarbonyl compound.
–(CH2)3
b
1:5.
–CH2–CMe2–CH2–
H2O/Me2CO (5:2)
a
Yield of pure product based on the b-dicarbonyl compound.
Reference to product.
b
Table 2
Halogenation of ethyl acetoacetate
O
X
X
O
O
O
O
O
O
N
N
solvent
+
+
OEt
OEt
OEt
O
N
X
O
r.t.
X
X
X
0.34 mol equiv
Solvent
X
Selectivity (%)a
-halo/ -dihalo
a
a,a
H2O
Br
100/0b
0b/100
0b/100
79/21
76/24
100/0b
H2O/Me2CO (5:2)
MeCN
HOAc
Hexane
CHCl3
Cl
Cl
Cl
Cl
Cl
a
Determined by HRGC.
Not detected.
b
solvent for
was employed for
a
,
a
-dibromination using TBCA, while aqueous acetone
mild, and the quantity of halogen incorporated in the substrate is
dependent on the ratio of trihaloisocyanuric acid/substrate.
a,a-dichlorination by TCCA. Conversely to
previous works,5b,16 there was no need of acid-catalysis, even for
substrates with low enol content, such as diethyl malonate.17
Ethyl acetoacetate was chosen as a model substrate to the
Acknowledgments
reaction conditions for performing the
b-dicarbonyl compounds using 0.34 mol equiv of trichloro- and
tribromoisocyanuric acids (Table 2). The reaction with TBCA in
a-monohalogenation of
We thank PIBIC-UFRJ, CNPq, and FAPERJ for fellowships and
financial support.
water produced the
at the same conditions, TCCA produced only the
compound along with unreacted substrate. Changing the solvent
in this reaction produced a mixture of -cloro- and -dichloro-
ethyl acetoacetates in different proportions. The selective -mono-
a
-monobromo compound. On the other hand,
References and notes
a,a-dichloro
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a
a,a
a
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chlorination of ethyl acetoacetate was accomplished by using
CHCl3 as solvent.
Based on the above results, the preparation of
a-monohalo
b-dicarbonyl compounds was accomplished using 0.34 mol equiv
of TCCA at room temperature in CHCl3, whilst the
a-bromo com-
pound was obtained using H2O as solvent (Table 3).20
In conclusion, the present work describes the utilization of
trihaloisocyanuric acid as an efficient halogenating reagent for
b-dicarbonyl compounds. The reaction conditions are safe and

G. F. Mendonça et al. / Tetrahedron Letters 50 (2009) 473–475
475
5790; (e) Khan, A. T.; Ali, M. A.; Goswami, P.; Choudhury, L. H. J. Org. Chem.
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by the color disappearance of a wet iodide-starch test paper treated with an
aliquot of the reaction media15), the product was extracted with CH2Cl2
(2 Â 15 mL) and the organic layer was subsequently washed with saturated
solution of NaHSO3, water, and then dried (Na2SO4). After filtration and
evaporation of the solvent at reduced pressure, the product was characterized
by standard analytical techniques. Selected analytical data: Diethyl 2,2-
dibromomalonate: dH (CDCl3, 200 MHz) = 1.32 (t, 1H, J 7.03 Hz), 4.33 (q, 2H, J
7.03 Hz) ppm. dC (CDCl3, 50 MHz) = 13.7, 50.7, 64.8, 163.2 ppm. Ethyl 2,2-
dichloroacetoacetate: dH (CDCl3, 200 MHz) = 1.31 (t, 1H, J 7.00 Hz), 2.46 (s, 3H),
4.33 (q, 2H, J 7.00 Hz) ppm. dC (CDCl3, 50 MHz) = 14.0, 23.6, 64.8, 82.0, 163.5,
7. For our works on electrophilic halogenation with trihaloisocyanuric acids see:
(a) Mendonca, G. F.; Magalhães, R. M.; de Mattos, M. C. S.; Esteves, P. M. J. Braz.
Chem. Soc. 2005, 16, 695; (b) de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S.
Synlett 2007, 1687; (c) de Souza, A. V. A.; Mendonça, G. F.; Bernini, R. B.; de
Mattos, M. C. S. J. Braz. Chem. Soc. 2007, 18, 1575; (d) Ribeiro, R. S.; Esteves, P.
M.; de Mattos, M. C. S. Tetrahedron Lett. 2007, 48, 8747; (e) Ribeiro, R. S.;
Esteves, P. M.; de Mattos, M. C. S. J. Braz. Chem. Soc. 2008, 19, 1239.
8. Recent examples: (a) Zolfigol, M. A.; Chehardoli, G.; Ghaemi, E.; Madrakian, E.;
Zare, R.; Azadbakht, T.; Niknam, K.; Mallakpour, S. Monatsh. Chem. 2008, 139,
261; (b) Pore, D. M.; Mahadik, S. M.; Desai, U. V. Synth. Commun. 2008, 38, 3121;
(c) Bigdeli, M. A.; Dostmohammadi, H.; Mahdavinie, G. H.; Nemati, F. J.
Heterocycl. Chem. 2008, 45, 1203; (d) Niknam, K.; Zolfigol, M. A.; Madrakian, E.;
Ghaemi, E. South Afr. J. Chem. 2007, 60, 109; (e) Zolfigol, M. A.; Niknam, K.;
Bagherzadeh, M.; Ghorbani-Choghamarani, A.; Koubaki, N.; Hajjami, M.;
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191.5 ppm.
2,2-Dichloro-5,5-dimethyl-1,3-cyclohexanodione:
dH
(CDCl3,
500 MHz) = 1.04 (s, 6H), 2.96 (s, 4H) ppm. dC (CDCl3, 125 MHz) = 28.2, 30.6,
49.1, 100.2, 192.4 ppm.
15. Mendonça, G. F.; Sanseverino, A. M.; de Mattos, M. C. S. Synthesis 2003, 45.
16. Kim, J.-J.; Kweon, D.-H.; Cho, S.-D.; Kim, H.-K.; Lee, S. G.; Yoon, Y.-J. Synlett
2006, 194.
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and Structure; John Wiley: New York, 2001; pp 73–74.
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19. Nazarov, I. N.; Zav’yalov, S. I. Izv. Akad. Nauk. Sssr, Ser. Khim. 1959, 668.
20. General procedure for monohalogenation of b-dicarbonyl compounds: To a
stirred solution of the b-dicarbonyl compound (2 mmol) in the appropriate
solvent (30 mL—see Table 3) was added the trihaloisocyanuric acid
(0.34 mmol) at room temperature in small portions. After the end of the
reaction (determined by the color disappearance of a wet iodide-starch test
paper treated with an aliquot of the reaction media15), the workup was similar
to that described above. Selected analytical data. Ethyl 2-bromoacetoacetate: dH
(CDCl3, 200 MHz) = 1.30 (t, 3H, J 6.92 Hz), 2.42 (s, 3H), 4.25 (q, 2H, J 6.92 Hz),
5.75 (s, 1H) ppm. dC (CDCl3, 75 MHz) = 14.0, 26.5, 49.2, 63.3, 165.2, 196.4 ppm.
2-Chloro-2-acetylcyclohexanone: dH (CDCl3, 200 MHz) = 1.70–2.33 (m, 6H),
2.50–2.69 (m, 1H), 2.85–3.05 (m, 1H), 2.35 (s, 3H) ppm. dC (CDCl3,
50 MHz) = 21.7, 26.9, 27.1, 37.9, 39.0, 77.0, 201.3, 203.2 ppm.
9. Wengert, M.; Sanseverino, A. M.; de Mattos, M. C. S. J. Braz. Chem. Soc. 2002, 13,
700.
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Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S. Synthesis 2006, 221.
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Soc. 2007, 18, 675.
13. Hiegel, G. A.; Peyton, K. B. Synth. Commun. 1985, 15, 385.
14. General procedure for dihalogenation of b-dicarbonyl compounds: To a stirred
solution of the b-dicarbonyl compound (2 mmol) in the appropriate solvent
(30 mL—see Table 1) was added the trihaloisocyanuric acid (0.68 mmol) at
room temperature in small portions. After the end of the reaction (determined