A new synthetic route to 1-chlorophenazines. The electrochemical monodechlorination of 3,3,6,6-tetrachloro-l,2-cyclohexanedione as a key step

Article abstract of DOI:10.1016/S0040-4039(00)01097-2

A convenient new method for the synthesis of 1-chlorophenazines has been established. The first step involves an almost quantitative electrochemical reduction of 3,3,6,6-tetrachloro-1,2-cyclohexanedione 1 to 3,6,6-trichloro-2-hydroxy-2-cyclohexen-1-one 2. The reaction of 2 with aromatic 1,2-diamines followed by aromatisation through treatment with 2,6-lutidine leads to the title compounds in high yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01097-2

Tetrahedron Letters 41 (2000) 6579±6582
A new synthetic route to 1-chlorophenazines.
The electrochemical monodechlorination of
3,3,6,6-tetrachloro-1,2-cyclohexanedione as a key step
Antonio Guirado,* Alfredo Cerezo and Raquel Andreu
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Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Murcia, Campus de Espinardo,
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30071 Murcia, Apartado 4021, Spain
Received 18 May 2000; accepted 29 June 2000
Abstract
A convenient new method for the synthesis of 1-chlorophenazines has been established. The ®rst step
involves an almost quantitative electrochemical reduction of 3,3,6,6-tetrachloro-1,2-cyclohexanedione 1 to
3,6,6-trichloro-2-hydroxy-2-cyclohexen-1-one 2. The reaction of 2 with aromatic 1,2-diamines followed by
aromatisation through treatment with 2,6-lutidine leads to the title compounds in high yields. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: phenazines; electrosynthesis; dehydrohalogenation; aromatisation.
We have recently reported a new entry to 1,4-dichlorophenazines.1 As a further result of our
research project in improved synthesis of chlorophenazines a new, highly ecient and versatile
method for the synthesis of 1-chlorophenazines is reported here. It should be remarked that both
very low yields and lack of versatility are common features of all precedent methods for the
synthesis of this class of compounds. This determines the few members pertaining to the
1-chlorophenazine family previously prepared. The synthesis of the parent compound 4a has been
achieved by di€erent methods involving thermal cyclation of 20-chloro-2-nitrodiphenylamine in
the presence of ferrous oxalate2 (4.4%), a Wohl±Aue reaction3 (18%), treatment of phenazine-N-
oxide with thionyl chloride4 (23%), chlorination of catechol followed by oxidation with silver
oxide and treatment with 1,2-phenylenediamine5 (16% overall yield) or direct chlorination of
phenazine6 (negligible yield). Some low yield preparations of polychlorinated phenazines bearing
a chlorine substituent at C-1 have also been reported.7,8 All the above procedures seem to be
incompatible with the synthesis of functionalized 1-chlorophenazines.
Phenazine has a general reluctance to be attacked by electrophiles.9 This peculiar reactivity
notably enhances the interest of chlorophenazines since incapable functualization processes via
* Corresponding author. Fax +34 968364148; e-mail: anguir@fcu.um.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01097-2

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direct electrophilic substitution can be replaced by nucleophilic displacement reactions. In fact,
chlorophenazines provide good entries to many functionalized phenazine derivatives via
nucleophilic substitution.9 However, 1-chlorophenazines still remain almost inaccessible.
Given the interest of the expansion of the number of 1-chlorophenazines available, a new and
general entry to this class of compounds was attempted, as shown in Scheme 1. 3-Chloro-1,2-
benzoquinone 6 is a rare and dicultly accessible compound.5,10 12 However, 3,6,6-trichloro-2-
hydroxy-2-cyclohexen-1-one 2 was found to be an excellent synthetic equivalent of 6. Inter-
mediate 2 could be quantitatively prepared13 by electrochemical reduction of 3,3,6,6-tetrachloro-
1,2-cyclohexanedione 1, which is a cheap, readily available starting material that can be quanti-
tatively generated by simple chlorination of commercial trans-cyclohexanediol.9 Reaction of 2
with 1,2-phenylenediamines gave the corresponding intermediates 3 in high yields. In the case of
the reaction with 3,4-diaminobenzophenone the two possible isomers 3d and 3e were formed in a
similar ratio. Intermediates 3 were isolated and eciently converted into the corresponding
1-chlorophenazines 4 by simple treatment with 2,6-lutidine. In contrast to previously reported
methods a wide range of functionalized 1-chlorophenazines are presumably accessible by this
approach. It should be noted that compounds 5 could not be directly converted into the inter-
mediates 3 since their electrochemical reductions were non-selective towards monodechlorination.
Scheme 1.
On working in the conversion of intermediates 3 into the ®nal products 4 a surprising
competitive aromatization mode involving only one dehydrochlorination process was observed.
For example, 3a (Scheme 2) reacted with pyridine yielding the expected 1-chlorophenazine 4a
(62%) but accompanied by 1,4-dichlorophenazine1 10 (26%). A similar result gave the reaction
with sodium methoxide.

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Scheme 2.
The crucial in¯uence of the site where a ®rst deprotonation takes place is the most plausible
explanation that may be o€ered for these facts. Thus, deprotonation at C-3 would promote the
formation of intermediate 7, which would lead exclusively to the targeted product 4a. However,
deprotonation at C-2 would generate intermediate 8 which could reasonably undergo dehydro-
chlorination to 4a but also rearrangement to 1,4-dichloro-5,10-dihydrophenazine 9, whose
oxidation explains the formation of product 10. This reactivity scheme is well supported by the
facts: (1) the great proclivity of 5,10-dihydrophenazines towards undergoing oxidation yielding
phenazines is well known;14 (2) when a sample of 1,4-dichloro-5,10-dihydrophenazine15 9 was
exposed to similar experimental conditions to those operating in the conversion of 3 to 4, an
almost instantaneous and quantitative formation of 10 was observed even when working under
nitrogen; and (3) the generation of product 10 was fully prevented by using 2,6-lutidine instead of
pyridine. In this case the exclusive formation of 1-chlorophanazine (96%) occurred. This result is
in excellent agreement with the expected e€ect of a bulky base determining regioselectivity
towards the less hindered reactive site. It seems reasonable, therefore, in this case to assume a
process with the exclusive generation of 7 without participation of 9.
To conclude, a convenient new method for the synthesis of 1-chlorophenazines is reported.
Versatility, good yields, easy availability of starting materials, mildness and simple experimental
procedure are noteworthy advantages of this approach, which has high potentiality in the access
to previously unattainable phenazines.
1. Experimental
Electrochemical reduction of 1: A reductive electrolysis was carried out under a constant
cathodic potential in a concentric cylindrical cell with two compartments separated by a circular
glass frit (medium) diaphragm. A mercury pool (diameter 5 cm) was used as the cathode and a
platinum plate as the anode. The catholyte was magnetically stirred. The temperature was kept at
approximately 18ꢀC by external cooling. The reduction was performed in MeCN (40 mL)±AcOH

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(10 mL)±LiClO4 (3 g); 35 mL and 15 mL were placed in the cathodic and the anodic compartments,
respectively. Sodium acetate (0.2 g) was placed in the anode compartment. A solution of 1
(5 mmol) was electrolyzed under a cathode potential of ^0.05 V versus SCE. The electricity
consumption was 2 F/mol. Isolation of product 2 was carried out by removing the solvent in
vacuo, adding water (150 mL) and extracting the mixture with chloroform (3Â40 mL). The
combined organic layers were washed with cold water and dried on anhydrous sodium sulphate.
After evaporation of chloroform under reduced pressure the solid residue was crystallized from
petroleum ether, mp 119±120ꢀC. Preparation of products 3: A benzene solution (75 mL) of 2 (5.56
mmol) and the appropriate diamine (5.48 mmol) was re¯uxed with a Dean±Stark water separator
for 24 h. Then the solvent was evaporated under reduced pressure and the residue was shaken
with ether (75 mL). The small amount of a white solid remained in suspension was removed by
®ltration. After evaporation of ether, highly pure products 3 were isolated and crystallized from
appropriate solvent. Products 3d and 3e were isolated by column chromatography (silica gel
dichloromethane:ethyl acetate:hexane, 8:1:1). Compound 3a (pet. ether) mp 135±137ꢀC; 3b (pet.
ether) mp 197±198ꢀC; 3c (pet. ether) mp 152±153ꢀC; 3d (chloroform±pet. ether) mp 161±162ꢀC,
3e (ether±hexane) mp 138±140ꢀC. Preparation of products 4: A dimethylformamide solution (30
mL) of the corresponding intermediate 3 (3.5 mmol) and 2,6-lutidine (2 ml) was re¯uxed for 2 h.
After cooling the reaction products were isolated by dropping the solution onto cold brine (400
mL) and ®ltration. The directly collected solid crude products were washed with cold ꢀwater, dried
and crystallized from the appropriate solvent. Compound 4a (hexane) mp 123±124 C (lit.2 mp
121±122ꢀC); 4b (pet. ether±chloroform) mp 224±225ꢀC; 4c (pet. ether) mp 237±238ꢀC; 4d
(chloroform) mp 184±186ꢀC; 4e (chloroform) mp 277±279ꢀC.
All novel compounds gave satisfactory IR, 1H NMR, 13C NMR, mass spectra, and
elemental analyses. Structures of isomers 3d±e and 4d±e were established on the basis of X-ray
crystallography16 of 3d.
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16. Details of the structure determination will be reported in a future full paper.