.
Angewandte
Communications
rated. The crude material was purified by column chromatography on
silica gel, eluting with hexane/EtOAc mixtures.
rium-enriched substrate [D]-7a to the reaction conditions and
observed deuterium incorporation in the product, implicating
the ene mechanism as the principal reaction mode for ortho-
arylation.[13]
5-Benzylbiphenyl-2-amine (9e): Purification by column chroma-
tography (hexane/EtOAc 9:1) gave the desired product in 70% yield
1
as a brown oil. H NMR (500 MHz, CDCl3): d = 7.53–7.46 (m, 4H),
The product o-arylanilines are important components of
natural product and medicinal chemistry syntheses. To
exemplify the power of the aryne arylation we carried out a
short synthesis of the antibiotic and antifungal natural
product glycozoline[14] (Scheme 6). Arylation of tritylated p-
toluidine with 3-methoxyaryne proceeded in an excellent
7.40 (m, 1H), 7.36–7.32 (m, 2H), 7.28–7.25 (m, 2H), 7.24 (t, J =
7.2 Hz, 1H), 7.06–7.03 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 3.98 (s,
2H), 3.68 ppm (br s, 2H). 13C NMR (126 MHz, CDCl3): d = 141.8,
141.5, 139.6, 131.5, 131.0, 129.0, 128.9, 128.8, 128.5, 128.0, 127.9, 127.2,
126.0, 116.0, 41.1 ppm. HRMS (ES+) calcd for C19H18N+ [M+H]+:
260.1434, found: 260.1434.
Received: August 30, 2011
Revised: October 31, 2011
Published online: December 12, 2011
ꢀ
Keywords: anilines · arynes · C H bond activation
.
Kapdi, Angew. Chem. 2009, 121, 9976 – 10011; Angew. Chem. Int.
Ed. 2009, 48, 9792 – 9826; d) X. Chen, K. Engle, D. H. Wang,
[2] a) T. Satoh, M. Kawamura, M. Miura, M. Nomura, Angew.
Angew. Chem. Int. Ed. 2005, 44, 4046 – 4048; e) H. A. Chiong,
Q.-N. Pham, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 9879 –
9884; f) L. V. Desai, K. J. Stowers, M. S. Sanford, J. Am. Chem.
[3] a) F. Kakiuchi, S. Kan, K. Igi, N. Chatani, S. Murai, J. Am. Chem.
d) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B.
e) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G.
Tyler, M. R. Gagnꢂ, G. C. Lloyd-Jones, K. I. Booker-Milburn,
Tredwell, M. Gulias, N. Gaunt Bremeyer, C. C. C. Johansson,
2207 – 2210; c) C. S. Yeung, X. Zhao, N. Borduas, V. M. Dong,
[5] a) D. McAusland, S. Seo, D. G. Pintori, J. Finlayson, M. F.
Greaney, Org. Lett. 2011, 13, 3667 – 3669; b) A. A. Cant, L.
d) A. A. Cant, G. V. H. Bertrand, J. L. Henderson, L. Roberts,
Scheme 6. Synthesis of glycozoline. TBAF=tetrabutylammonium
fluoride.
95% yield, followed by sulfonylation to give the biaryl 12.
ꢀ
Treatment of 12 with Younꢀs C H amination conditions
(Pd(OAc)2, oxone)[15] selectively afforded the carbazole in
high yield, which was desulfonylated to give glycozoline (13)
in four steps and 71% overall yield from 7c.
In conclusion, we have developed a new direct arylation
reaction for anilines. The method is distinct from existing
methods of arylation, requiring neither stoichiometric metal-
ation with strong lithium or magnesium bases, nor transition-
metal catalysis with associated ligands and additives. As a
result, the reaction displays excellent functional-group com-
patibility and operational simplicity. An ene mechanism is
implicated, which produces singly ortho-arylated products
with no possibility of para regioisomers. Further studies on
ꢀ
aryne C H arylation are in progress.
Experimental Section
General procedure for ortho-arylation: In a vial the N-trityl aniline
(0.60 mmol, 1 equiv) was dissolved in toluene and acetonitrile (3:1)
(0.1m). The benzyne precursor (1.07 mmol, 1.8 equiv) and caesium
fluoride (1.79 mmol, 3 equiv) were then added. The vial was then
flushed with nitrogen, sealed and stirred at 1108C for 48 h. The
volatiles were removed under vacuum and the crude material treated
with TFA (1.6 mL). The reaction was then stirred at room temper-
ature for 20 min. [For the preparation of compounds 9a, 9b, 9c and
9d 2.5 equiv (1.49 mmol) of the aryne precursor was used]. The
reaction was diluted with diethyl ether and extracted with HCl 2m (ꢁ
3). The combined aqueous phases were basified with NaOH aq. 10%
and extracted with diethyl ether (ꢁ 3). The combined organic phases
were washed with brine, dried over magnesium sulfate and evapo-
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1006 –1009