diphenylamines with Raney nickel,11 of o-nitrodiphenyl-
amines with NaBH4/NaOMe or FeC2O4/Pb12 and of o-nitro-
o′-fluorodiphenylamines with NaBH4/NaOEt13 as well as the
oxidative cyclization of o,o′-diaminodiphenylamines with
FeCl3/HCl.14 In turn, the substituted diphenylamines required
are traditionally accessible via nucleophilic aromatic sub-
stitution15 and Ullmann-Goldberg condensation.16 In general,
these methods require harsh reaction conditions and cause
problems ranging from restrictions with respect to the
substitution pattern of the substrates obtained through to
complex product mixtures and low yields.
Table 1. Pd-Catalyzed N-Arylation of o-Nitroaniline (8) with
Aryl Bromides 9a
These disadvantages should be avoidable if the diphenyl-
amines were synthesized via the Buchwald-Hartwig reac-
tion, i.e., Pd(0)-catalyzed N-arylation of aryl halides.17 To
produce 2-hydroxyphenazine (2) the synthesis and cyclization
of the diphenylamines 3-7 was strongly considered.
In this paper, a mild method for the efficient synthesis of
substituted phenazines is presented, which is based on the
Pd(0)- catalyzed transformation of o-nitroaniline with sub-
stituted aryl bromides and/or substituted anilines with
substituted 1-bromo-2-nitroarenes and their subsequent cy-
clization. This pathway also serves to produce 2-hydroxy-
phenazine (2) in a few steps and with high yields from
commercially available substrates.
A review of the literature showed that Pd(0)-catalyzed
reactions of nitro-substituted anilines with aryl bromides have
hardly been investigated. For example, not one Pd(0)-
catalyzed amination of o-nitroaniline (8) is known, and only
a few examples have been published of the transformation
of meta- and para-substituted nitroanilines.18 This might be
due to the fact that nitro groups are very sensitive to basic
reaction conditions.
a Reagents and conditions: (a) 5 mol % of Pd2(dba)3, 7.5 mol % of rac-
BINAP, 2 equiv of Cs2CO3, toluene 110 °C, 15-36 h. b 5 mol % of
Pd(OAc)2 was used as catalyst.
For this reason, the Pd(0)-catalyzed reaction of o-nitro-
aniline (8) with various substituted aryl bromides 9 to give
diphenylamines 10 was studied first. After some preliminary
experiments with different Pd(0) sources, phosphines, bases,
and solvents, we found that these transformations could best
be conducted with a combination of Pd2(dba)3 and rac-
BINAP with Cs2CO3 as a base and toluene as a solvent.
Further studies revealed that all reactions presented here can
be catalyzed with 5 mol % Pd2(dba)3 and 7.5 mol % rac-
BINAP. Under these conditions, 8 could be reacted with
bromobenzenes 9a-f to yield the diphenylamines 10a-f.
Reaction times varied between 15 and 36 h with yields
ranging from 30 to 95% (Table 1). To obtain suitable
precursors for the synthesis of 2 further studies focused on
the Pd(0)-catalyzed transformation of substituted anilines 8
(10) Urleb, U. In Methods of Organic Chemistry (Houben-Weyl), 4th
ed.; Schaumann, E., Ed.; Thieme: Stuttgart, 1998; Vol. E9b/Part 2, pp 266-
303.
(11) Cross, B.; Williams, P. J.; Woodall, R. E. J. Chem. Soc. C 1971,
11, 2085-2090.
(12) (a) Challand S. R.; Herbert, R. B.; Holliman F. G. J. Chem. Soc.,
Chem. Comun. 1970, 1423-1425. (b) Vivian, D. L. J. Org. Chem. 1956,
21, 565-566. (c) Waterman, H. C.; Vivian, D. L. J. Org. Chem. 1949, 14,
289-297.
(13) Rewcastle, G. W.; Denny, W. A. Synth. Commun. 1987, 17, 1171-
1179.
(14) (a) Gaertner, G.; Gray, A.; Holliman, F. G. Tetrahedron 1962, 18,
1105-1114. (b) Elderfield, R. C.; Gensler, W. J.; Birstein, O. J. Org. Chem.
1946, 11, 812-822. (c) Tomlinson, M. L. J. Chem. Soc. 1939, 158-163.
(15) McCombie, H.; Scarborough, H. A.; Waters, W. A. J. Chem. Soc.
1928, 353-359.
(16) (a) For a review see Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400-5449 and Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 2428-2439. (b) Goldberg, A. A.; Kelly, W. J. Chem. Soc. 1947,
595-597. (c) Goldberg, A. A.; Alan, A.; Kelly, W. J. Chem. Soc. 1946,
102-111.
(17) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-
209. (b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, 2002; pp 107-168. (c) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (d) Hartwig, J.
F. Acc. Chem. Res. 1998, 31, 852-860.
(18) (a) Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003,
68, 8416-8423. (b) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65,
1144-1157. (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158-1174.
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