Table 1. Optimization of Organocatalytic Dehydrohalide
Coupling
Figure 1. Pyrrolophenanthridine based Amaryllidaceae alkaloids.
attention to accomplish this goal. In this context, the
synthesis of biaryls through direct CꢀH bond functiona-
lization10 is of significant interest because of their wider
abundance in natural products, pharmaceuticals, and ma-
terials. Recently, Itami et al.11 first described an unprece-
dented account on KOtBu-mediated biaryl coupling of aryl
halides and electron-deficient heterocyclic substrates in the
absence of a transition metal catalyst. Following this report,
a few pioneering reports also revealed that the biaryl
couplings could be promoted in the presence of KOtBu
and a diamine ligand.12 These pairs presumably initiate
single electron transfer (SET) to a CꢀX bond at elevated
temperatures,13a initially providing a radical anion that
gives rise to a radical species for further propagation.13b
The impetus for syntheses of biaryl compounds lies in
their exhaustive use as building blocks in many alkaloids
and natural products. Specifically, here, we have targeted
the indole based alkaloids of the Amaryllidaceae family
(11) (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673. (b) For coupling of nitrogen heteroaromatics with
cycloalkanes, see: Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li,
C.-J. Chem.;Eur. J. 2009, 15, 333. (c) Yanagisawa, S.; Itami, K.
ChemCatChem 2011, 3, 827.
(12) (a) 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. (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) Roman, D. S.; Takahashi, Y.; Charette, A. B. Org. Lett. 2011, 13,
3242. (e) For a KOtBu-cuproine promoted synthesis of biaryls, see: Sun,
C.-L.; Gu, Y.-F.; Huang, W.-P.; Shi, Z.-J. Chem. Commun. 2011, 9813.
(13) (a) For a KOtBu-mediated MizorokiꢀHeck type reactions, see:
Shirakawa, E.; Zhang, X.; Hayashi, T. Angew. Chem., Int. Ed. 2011, 50,
4671. (b) For an essay on organocatalytic cross-coupling, see: Studer, A.;
Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018.
(14) (a) Ghosal, S.; Lochan, R.; Ashutosh, K.; Yatendra, S.; Radhey,
S. Phytochemistry 1985, 24, 1825. (b) Ghosal, S.; Rao, P. H.; Jaiswal,
D. K.; Kumar, Y.; Frahm, A. W. Phytochemistry 1981, 20, 2003. (c)
Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.;
Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 523. (d)
Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike, K.; Akamatsu, H.;
Hori, A.; Abe, H.; Takeuchi, Y. Synthesis 2002, 237. (e) Bellocchi, D.;
Macchiarulo, A.; Costantino, G.; Pellicciari, R. Bioorg. Med. Chem.
2005, 13, 1151. (f) Ishida, J.; Hattori, K.; Yamamoto, H.; Iwashita, A.;
Mihara, K.; Matsuoka, N. Bioorg. Med. Chem. Lett. 2005, 15, 4221.
(15) For synthesis of pyrrolophenanthridone based Amaryllidaceae
alkaloids, see: (a) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V.
Org. Lett. 2003, 5, 1899. (b) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005,
7, 4777. (c) Mentzel, U. V.; Tanner, D.; Tønder, J. E. J. Org. Chem. 2006,
71, 5807. (d) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem.
Soc. 2010, 132, 4068. (e) Umemoto, H.; Dohshita, M.; Hamamoto, H.;
Miki, Y. Heterocycles 2011, 83, 1111. (f) Miki, Y.; Umemoto, H.;
Dohshita, M.; Hamamoto, H. Tetrahedron Lett. 2012, 53, 1924 and
references cited therein.
a Reactions were carried out with 0.25 mmol of 5a, 0.10 mmol of
catalyst, and 0.75 mmol of KOtBu in 2 mL of solvent in a sealed tube at
80ꢀ100 °C for a specified time, unless otherwise stated. b In most of the
cases the reactions were associated with the cleavage of amides, yielding
18ꢀ20% of indoline. c Condition A. d Condition B. e Condition C.
having a pyrrolophenanthridinone core such as 1aꢀj
(Figure 1) due to their interesting biological activities, such
as cytotoxicity and inhibition of male fertility.14,15 Herein,
we demonstrate a methodology for intramolecular biaryl
synthesis from N-dihydroindolyl/benzyl amine deriva-
tives, having a halogen at the ortho-position, using KOtBu
as the sole coupling promoter in the presence or absence of
a catalytic amount of organic molecules. Utilizing this
coupling strategy, we were able to synthesize several
pyrrolo- and dihydrophenanthridines which are vital
structures for several Amaryllidaceae alkaloids, through
addition of aryl radicals to arene derivatives.
Our studies began with 2-bromobenzoylindoline (5a) as
the substrate in the presence of 2ꢀ4 and KOtBu to access
corresponding pyrrolophenanthridine (6a) (Table1). After
extensive optimization, 40 mol % of DMEDA 2a with
3 equiv of KOtBu in mesitylene (condition A) as solvent
afforded the required product in 63% yield (entry3, Table 1).
Thus, mesitylene was chosen for further optimization
studies (entries 1ꢀ3). Under similar conditions, 2b, 2cꢀd,
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