ORGANIC
LETTERS
2012
Vol. 14, No. 7
1892–1895
Transition-Metal-Free Intramolecular
N-Arylations
ꢀ
Isabelle Thome and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg1, D-52074
Aachen, Germany
Received February 28, 2012
ABSTRACT
N-Substituted phenoxazines and related aza analogs have been prepared from N-acetylated aryloxy anilides by transition-metal-free, base-
catalyzed cyclization reactions. In the presence of a mixture of 10 mol % of N,N0-dimethylethylenediamine (DMEDA) and 2 equiv of K2CO3 in
toluene at 135 °C the products are obtained in high yields.
Transition-metal-catalyzed cross-coupling reactions to
form carbonꢀheteroatom bonds constitute a powerful
tool in pharmaceutical and medicinal chemistry.1 In the
past, numerous protocols for inter- and intramolecular
CꢀN, CꢀO, and CꢀS bond formations have been de-
veloped, and most of them involve the catalytic use of Pd
complexes or Cu salts. Despite remarkable advances the
oftentimes needed high catalyst loadings in combination
with sophisticated ligands as well as the strict demand for
the absence of any transition metal impurity in the final
product can render such processes cost-intensive and affect
their practicability. Thus, the development for alternative
approaches toward “cross-coupling products” is highly
desirable, and in this context, transition-metal-free
protocols appear particularly attractive. Recently, various
groups reported significant progress in this area in-
cluding transition-metal-free CꢀH arylations to construct
biphenyl frameworks.2,3 Our own work has been focused
on the use of the simple mixture of KOH and DMSO as a
superbasic medium4 for the transition-metal-free prepara-
tion of cross-coupling products.5 Here, we describe
DMEDA-catalyzed intramolecular CꢀN bond formations
with K2CO3 as a base leading to a wide range of acetylated
phenoxazine derivatives and aza analogs thereof.6
Phenoxazines are tricyclic heterocycles which have
found use as therapeutic agents and scaffolds in medici-
nal chemistry.7 Due to their photophysical properties8
(3) For overviews, see: (a) Studer, A.; Curran, D. P. Angew. Chem.,
Int. Ed. 2011, 50, 5018. (b) Yanagisawa, S.; Itami, K. ChemCatChem
2011, 3, 827.
(4) For a review on KOH/DMSO mixtures as “super bases”, see:
Trofimov, B. A. Sulfur Rep. 1992, 74, 207.
ꢀ
(5) (a) Yuan, Y.; Thome, I.; Kim, S. H.; Chen, D.; Beyer, A.;
Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth. Catal.
2010, 352, 2892. (b) Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett.
ꢀ
2011, 13, 2876. (c) For a related study, see: Cano, R.; Ramon, D. J.; Yus,
M. J. Org. Chem. 2011, 76, 654.
(6) For a DMEDA-catalyzed activation of benzene with KOt-Bu as
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Corbet, J.-P.;
Mignani, G. Chem. Rev. 2006, 106, 2651. (c) Surry, D. S.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (d) Torborg, C.; Beller, M.
Adv. Synth. Catal. 2009, 351, 3027. (e) Slagt, V. F.; de Vries, A. H. M.;
de Vries, J.; Kellogg, R. M. Org. Process Res. Dev. 2010, 14, 30.
(2) (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673. (b) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu,
X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2,
1044. (c) Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 15537. (d) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.;
Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc.
2010, 132, 16737. (e) Qiu, Y.; Liu, Y.; Yang, K.; Hong, W.; Li, Z.; Wang, Z.;
Yao, Z.; Jiang, S. Org. Lett. 2011, 13, 3556. (f) Rueping, M.; Leiendecker,
M.; Das, A.; Poisson, T.; Bui, L. Chem. Commun. 2011, 47, 10629.
base, see ref 2d.
(7) (a) Hendrich, A. B.; Stanczak, K.; Komorowska, M.; Motohashi,
N.; Kawase, M.; Michalak, K. Bioorg. Med. Chem. 2006, 14, 5948 and
€
references therein. (b) Prinz, H.; Chamasmi, B.; Vogel, K.; Bohm, K. J.;
€
€
Aicher, B.; Gerlach, M.; Gunther, E. G.; Amon, P.; Ivanov, I.; Muller,
K. J. Med. Chem. 2011, 54, 4247. (c) Moosmann, B.; Skutella, T.; Beyer,
K.; Behl, C. Biol. Chem. 2001, 382, 1601.
(8) (a) Shelkovnikov, V. V.; Kolchina, E. F.; Gerasimov, T. N.;
Eoshkin, V. T. Nucl. Instrum. Methods 1987, A261, 128. (b) Dass, C.;
Thimmaiah, K. N.; Jayashree, B. S.; Seshadri, R.; Israel, M.; Houghton,
P. J. Biol. Mass Spectrom. 1994, 23, 140. (c) Marinina, L. E.; Alekseeva,
V. I.; Savvina, L. P.; Luk’yanets, E. A. Khim. Geterotsikl. Soedin. 1988, 2,
262 (Engl. Transl.).
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10.1021/ol3005134
Published on Web 03/21/2012
2012 American Chemical Society