Efficient, multigram-scale synthesis of three 2,5-dihalobenzoquiones

Article abstract of DOI:10.1081/SCC-120013751

2,5-Dibromo-, 2,5-dichloro- and 2,5-diiodobenzoquinone were conveniently prepared from 1,4-dimethoxybenzene in 87%, 97% and 84% overall yields. None of the two steps of the synthesis required purification.

Full text of DOI:10.1081/SCC-120013751

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EFFICIENT, MULTIGRAM-SCALE SYNTHESIS OF THREE
2,5-DIHALOBENZOQUINONES
Pilar López-Alvarado a , Carmen Avendaño b & J. Carlos Menéndez c
a Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad
Complutense, Madrid, 28040, Spain
b Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad
Complutense, Madrid, 28040, Spain
c Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad
Complutense, Madrid, 28040, Spain
Published online: 16 Aug 2006.
To cite this article: Pilar Lpez-Alvarado , Carmen Avendao & J. Carlos Menndez (2002) EFFICIENT, MULTIGRAM-SCALE
SYNTHESIS OF THREE 2,5-DIHALOBENZOQUINONES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:20, 3233-3239, DOI: 10.1081/SCC-120013751
To link to this article: http://dx.doi.org/10.1081/SCC-120013751
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 20, pp. 3233–3239, 2002
EFFICIENT, MULTIGRAM-SCALE
SYNTHESIS OF THREE
2,5-DIHALOBENZOQUINONES
*
Pilar Lopez-Alvarado, Carmen Avendano,
*
and J. Carlos Menendez
Departamento de Quımica Organica y Farmaceutica,
Facultad de Farmacia, Universidad Complutense,
28040 Madrid, Spain
ABSTRACT
2,5-Dibromo-, 2,5-dichloro- and 2,5-diiodobenzoquinone
were conveniently prepared from 1,4-dimethoxybenzene in
87%, 97% and 84% overall yields. None of the two steps of
the synthesis required purification.
Key Words: Benzoquinones; Halogenated quinones; Cerium
ammonium nitrate
2,5-Dibromo- and 2,5-dichlorobenzoquinone have been employed as
Diels–Alder dienophiles, e.g., in the preparation of several types of natural
or unnatural quinones, including juglone derivatives,[1] quinolinequinone
derivatives[2] and 1,5-diazaanthraquinones with potent antitumor activity,[3]
or in the synthesis of polycyclic hydrocarbons, including 1,8-bishomocu-
bane[4] and halogenated precursors of triquinanes and polynitrocubanes.[5]
*Corresponding authors. Fax: 34 91 394 18 22; E-mail: josecm@eucmax.sim.ucm.es
3233
DOI: 10.1081/SCC-120013751
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3234
LOPEZ-ALVARADO, AVENDANO, AND MENENDEZ
Haloquinone substructures can be found in many biologically interesting
compounds, including antitumor agents.[6,7] Furthermore, the proton and
electron transfer (PET) of halogenated 1,4-benzoquinhydrones under high
pressure has yielded new materials with interesting solid state properties.[8]
The traditional method for the preparation of 2,5-dibromo- or
2,5-dichlorobenzoquinone consists on treatment of benzoquinone with
hydrochloric or hydrobromic acid.[9] In a related procedure, 2,5-dichloro-
benzoquinone was obtained in 50% yield (together with polyhalogenated
products) by treatment of benzoquinone with copper(II) chloride on
alumina at 110ꢀC for 6 h.[10] Alternative methods involve halogenation of
hydroquinones followed by oxidation. Thus, 2,5-dibromobenzoquinone
can be obtained in low yield, together with other products, by treatment
of hydroquinone with bromine followed by oxidation with iron(III)
chloride.[11] Similarly, several 2,5-dihalohydroquinones (obtained by
demethylation of dialkoxybenzenes) have been oxidized with Cr(VI) oxide
in sulfuric acid.[12] Solid-state bromination of hydroquinone with N-bromo-
succinimide also provides 2,5-dibromobenzoquinone in 50% yield; however,
the reaction is limited in that it takes place only at the surface of the crystals
but it is unable to proceed to the crystal interior.[13] Occasionally, other
starting materials have been employed; for instance, both 2,5-dibromo-
and 2,5-dichlorobenzoquinone can be isolated in ca. 20% yields as part
of complex mixtures obtained from oxidation of anilines with chromyl
chloride.[14]
In the course of a project aimed at studying the Diels–Alder chemistry
of indolylquinones we required multigram amounts of 2,5-dibromobenzo-
quinone, which we could not obtain efficiently through the above mentioned
literature methods. We therefore needed to develop a new procedure, which
we hoped to be able to extend to the preparation of 2,5-dichloro- and 2,5-
diiodobenzoquinone. We were surprised at noticing that application of the
mild oxidant cerium ammonium nitrate to the oxidative demethylation of
1,4-dihalo-2,5-dimethoxybenzenes has not been reported, although it has
been widely used for related substrates like methoxyhalobenzoquinones,[12]
perhaps because of the poor solubility of the starting 2,5-dihalo-1,4-
dimethoxybenzenes in acetonitrile–water. Indeed, we found that addition
of aqueous cerium ammonium nitrate to a refluxing solution of the
known[15] 2,5-dibromo-1,4-dimethoxybenzene (1) in acetonitrile followed
by cooling to room temperature gave 2,5-dibromobenzoquinone (4) in
97% yield (87% overall for the two steps), the desired product precipitating
in pure form from the reaction medium. Furthermore, the oxidation could
be carried out in a 15-g scale without any noticeable loss of yield. Similarly,
treatment of 1,4-dimethoxybenzene with sulfuryl chloride gave 2,5-dichloro-
1,4-dimethoxybenzene (2), which afforded 2,5-dichlorobenzoquinone (5)

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THREE 2,5-DIHALOBENZOQUINONES
3235
Scheme 1.
in 97% overall yield when submitted to the same oxidative demethylation
conditions. Although 2,5-diiodo-1,4-dimethoxybenzene (3) has been pre-
pared from 1,4-dimethoxybenzene in 85% yield by treatment with iodine,
potassium iodate and sulfuric acid in refluxing acetic acid,[16] we chose to
employ the Ipyr2BF4 reagent developed by the Barluenga group,[17] which
gave 96% of the desired diiodo derivative under much milder conditions.
Oxidative demethylation of 3 gave 87% yield of 2,5-diiodobenzoquinone (6)
(84% overall) (Sch. 1).
In conclusion, we have developed syntheses of 2,5-dibromo-, 2,5-
dichloro- and 2,5-diiodobenzoquinone that proceed in excellent yields and
give pure products without the need for any purification step.
EXPERIMENTAL
All reagents were of commercial quality (Aldrich, Fluka, SDS,
Panreac) and were used as received. The Ipyr2BF4 reagent was prepared

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3236
LOPEZ-ALVARADO, AVENDANO, AND MENENDEZ
according to the literature.[18] Solvents (SDS) were dried and purified using
standard techniques. Reactions were monitored by thin layer chro-
matography, on aluminium plates coated with silica gel with fluorescent
indicator (Macherey-Nagel Alugram Sil G/UV254). Separations by flash
chromatography were performed on silica gel (SDS 60 ACC, 230–40
mesh). Melting points were measured with a Reichert 723 hot stage micro-
sope, and are uncorrected. Infrared spectra were recorded on a Perkin Elmer
Paragon 1000 FT-IR spectrophotometer, with all compounds examined in
KBr pellets. NMR spectra were obtained on a Bruker AC-250 spectrometer
(Servicio de Resonancia Magnetica Nuclear, Universidad Complutense).
2,5-Dibromo-1,4-benzoquinone (4). To a solution of 1,4-dimethoxyben-
zene (10 g, 72.5 mmol) in CH3CO2H (20 mL) was dropwise added Br2
(23.15 g, 145 mmol) in CH3CO2H (7 mL), at room temperature. After stir-
ring for 2 h, the solution was cooled and the fine, white precipitate (16.2 g) of
2,5-dibromo-1,4-dimethoxybenzene (1)[15] was filtered. The filtrate was
diluted with water (15 mL) and extracted with CHCl3, which was washed
with 10% aqueous NaHCO3, dried over Na2SO4 and evaporated, yielding
an additional amount (3.1 g) of 1. A part of the compound 1 thus obtained
(15 g, 50.7 mmol) was dissolved in CH3CN (150 mL) in an oil bath at 100ꢀC.
A solution of cerium ammonium nitrate (75.0 g, 136.8 mmol) in water
(300 mL) was added to the boiling CH3CN solution. After completion of
the addition, the reacting mixture was left to cool to room temperature while
stirred over 30 min. The precipitate that formed was filtered and washed
with water (50 mL), yielding 11.5 g (87% overall) of 2,5-dibromobenzo-
quinone, as a yellow solid.
2,5-Dichloro-1,4-benzoquinone(5).NeatSO2Cl2(15.17 mL,188.17 mmol,
2.6 eq) was slowly added at room temperature to 1,4-dimethoxybenzene
(10 g, 72.37 mmol). The mixture was warmed at 40ꢀC and stirred for 3.5 h.
Excess SO2Cl2 was removed by attaching the flask to a water pump for 1 h.
The residue was triturated with Et2O (10 mL), filtered and washed with Et2O
(10 mL), yielding 10.27 g of 2,5-dichloro-1,4-dimethoxybenzene 2 as a white
solid. A further amount of 2 (4.44 g) precipitated from the ether solution. An
aliquot of 0.5 g (2.4 mmol) of compound 2 thus obtained was dissolved in
CH3CN (7 mL) at 50ꢀC. A solution of cerium ammonium nitrate (7.28 g,
12.0 mmol) in water (7 mL) was added, and the reacting mixture was stirred
at room temperature for 1 h. The yellow precipitate was filtered and washed
with water (1 mL), yielding 417 mg (97% overall) of quinone 5 as a yellow
solid.
2,5-Diiodo-1,4-benzoquinone (6). To a solution of 1,4-dimethoxyben-
zene (0.5 g, 3.63 mmol) in dry CH2Cl2 (17 mL) was added CF3SO3H (2.28 g,
15.20 mmol) and Ipy2BF4 (2.83 g, 7.59 mmol). The solution was stirred at
room temperature for 3 h, under argon, and then it was poured on water

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THREE 2,5-DIHALOBENZOQUINONES
3237
Table 1. 1H-NMR, 13C-NMR (CDCl3), and M.P. Data of Compounds 4–6
13C-NMR
Compound
1H-NMR (H3,6
7.16 (s)
)
C1,4
C2,5
C3,6
M.P.
4
177.7
145.1
133.4
158–160ꢀC
(Lit.[11] 160–161ꢀC)
190–192ꢀC
5
6
7.49 (s)
7.90 (s)
177.4
177.5
138.2
119.6
137.4
143.5
(Lit.[13] 188ꢀC)
202–204ꢀC
(Lit.[12], not given)
(50 mL). The aqueous phase was extracted with CH2Cl2 (3 Â 50 mL) and
then with AcOEt (3 Â 50 mL). The combined organic extracts were
washed with a saturated aqueous solution of Na2S2O3 (50 mL), dried
(Na2SO4) and evaporated. The residue was washed with Et2O (10 mL)
and acetone (10 mL), yielding 1.35 g of 2,5-diiodo-1,4-dimethoxybenzene
3.[12] A part of this compound 3 (0.58 g, 1.49 mmol) was dissolved in
CH3CN (15 mL) in an oil bath at 100ꢀC. A solution of cerium ammonium
nitrate (2.24 g, 4.09 mmol) in water (9 mL) was added to the boiling CH3CN
solution. After completion of the addition, the reacting mixture was left to
cool to room temperature over 30 min. Water (20 mL) was added, and the
precipitated solid was filtered and washed with water (10 mL), yielding
325 mg of quinone 6, as a dark yellow solid. A further amount of 6
(143 mg) precipitated from the CH3CN/water solution (84% overall). An
analytical sample was obtained by recrystallization from CH2Cl2.
Characterization data of quinones 4–6 are given in Table 1.
ACKNOWLEDGMENT
Financial support of this research from CICYT (project 2FD-1997-
2032) is gratefully acknowledged.
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LOPEZ-ALVARADO, AVENDANO, AND MENENDEZ
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THREE 2,5-DIHALOBENZOQUINONES
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Received in the UK August 15, 2001

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