A new route to phenazines

Article abstract of DOI:10.1016/S0040-4039(99)02061-4

Phenazines were prepared by the palladium(II)-catalyzed intramolecular amination of aryl bromides 8, which were prepared with o-bromonitrobenzenes 3 and anilines 4 or 3 and o-bromoanilines 5 using palladium(II)catalyzed aniline arylation.

Full text of DOI:10.1016/S0040-4039(99)02061-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 355–358
A new route to phenazines†
Takahiro Emoto, Nobuo Kubosaki, Yoshiro Yamagiwa and Tadao Kamikawa ∗
Department of Chemistry, Faculty of Science and Technology, Kinki University, Kowakae, Higashi-Osaka 577-8502, Japan
Received 5 October 1999; revised 25 October 1999; accepted 29 October 1999
Abstract
Phenazines were prepared by the palladium(II)-catalyzed intramolecular amination of aryl bromides 8, which
were prepared with o-bromonitrobenzenes 3 and anilines 4 or 3 and o-bromoanilines 5 using palladium(II)-
catalyzed aniline arylation. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: phenazines; synthesis; Pd(II)-catalyzed cyclization.
Naturally occurring phenazines have attracted considerable attention because of their interesting
biological activities.1 One of the most promising methods for synthesizing polysubstituted phenazines
developed by Holliman and co-workers2 was the reductive cyclization of o-nitrodiphenylamines (Method
C in Scheme 1). However, the yield was poor when competitive cyclization occurred. Recently, N-
arylation has become more accessible owing to the advent of a new methodology developed by Hartwig
and Buchwald.3 Here, we report on the use of the new method to synthesize phenazines using sequential
aniline arylation.
For the total synthesis of benthocyanin A 1, a powerful radical scavenger from the mycelium of
Streptomyces prunicolor,4 we needed a method to construct phenazine 2.
Our method is based on the regiospecific bromination of o-nitrodiphenylamine 6, which is obtained
from 3 and 4 by aniline arylation, to give bromide 7 (Method A), which is also obtainable from
∗
†
Corresponding author. E-mail: kamikawa@chem.kindai.ac.jp (T. Kamikawa)
This paper is dedicated to Emeritus Professor, Dr. Takashi Kubota (Osaka City University) on the occasion of his 90th
birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02061-4
tetl 15989

356
Scheme 1.
3 and 5 (Method B). Subsequent chemoselective reduction of the nitro group on 7 followed by the
Hartwig–Buchwald aniline arylation affords the target phenazine 9 (Scheme 1).
Treatment of 10 and 115 with palladium(II) acetate under the condition of Buchwald6 gave the o-
nitrodiphenylamine 12 in 99% yield. Catalytic hydrogenation of 12 in the presence of Pd–C as a catalyst
gave the N-aryl-1,2-phenylenediamine 13 in quantitative yield. Selective bromination of 13 with bromine
in the presence of sodium hydrogencarbonate at 0°C gave the N-(2-bromophenyl)-1,2-phenylenediamine
14 in 91% yield. This was then subjected to the cyclization again using Buchwald’s condition6 to give
the desired phenazine 15 as a yellow powder together with the eliminated product 16 as orange needles
(50%, 15:16=3:1) (Scheme 2).7
Scheme 2.
Additional examples of phenazine synthesis using this sequence of reactions in comparison with those
of Holliman’s are given in Table 1.7 Our method gave yields comparable with those of Holliman’s
in spite of the rather longer reaction sequence. When the selectivity of the bromination was assured,

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phenazines were obtained in good yields. In entry 4, there was no selectivity at the bromination step in
Method A giving a complex mixture of phenazines. In Method C, 2-ethoxyphenazine was obtained in
46% yield instead of 2-methoxyphenazine. When 2-bromoanilines 5 were easily prepared, phenazines
were obtained in good yields (entries 5–7).
Table 1
Synthesis of phenazines
In summary, this aniline arylation followed by aniline arylative intramolecular cyclization offers an
alternative method for the synthesis of phenazines, especially when the substrate is susceptible to a strong
basic condition or when selectivity is not observed at the reductive cyclization step in Method C. Further
investigations are in progress.

358
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