stituted and 1,4-disubstituted 1,2-dihydroisoquinolines. There-
fore, the search for a new strategy for the direct synthesis of
1,2-dihydro- and tetrahydroisoquinolines from readily available
starting materials would be a highly valuable but challenging
subject.
One-Step Synthesis of Substituted Dihydro- and
Tetrahydroisoquinolines by FeCl3‚6H2O
Catalyzed Intramolecular Friedel-Crafts
Reaction of Benzylamino-Substituted Propargylic
Alcohols
Catalytic substitution of the hydroxy group in alcohols with
nucleophiles is an atom efficient and environmentally sound
transformation that is currently receiving increased attention.5-7
Recent works showed that propargylic alcohols can serve as
novel electrophilic alkyl equivalents for the intermolecular
Friedel-Crafts reactions.5h-k,6e,7 However, the related intramo-
lecular Friedel-Crafts reaction remains unexplored, possibly
due to the difficulty of the cycloalkyne formation. Previously,
we found that treatment of 1,3-dicarbonyl compounds with
tertiary propargylic alcohols in the presence of Lewis acids could
give the isomerized allenylation products.8 In this case it would
be expected that an intramolecular allenylation/cyclization would
be operating due to avoidance of the large ring strain. As a part
of our continuing research on making use of propargylic alcohols
Wen Huang,† Quansheng Shen,† Jialiang Wang,† and
Xigeng Zhou*,†,‡
Department of Chemistry, Shanghai Key Laboratory of
Molecular Catalysis and InnoVatiVe Materials, Fudan
UniVersity, Shanghai 200433, People’s Republic of China, and
State Key Laboratory of Organometallic Chemistry,
Shanghai 200032, People’s Republic of China
ReceiVed October 30, 2007
(2) For selected examples, see: (a) Diaba, F.; Houerou, C. L.; Grignon-
Dubois, M.; Rezzonico, B.; Gerval, P. Eur. J. Org. Chem. 2000, 2915. (b)
Diaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69, 3550. (c)
Hewavitharanage, P.; Danilov, E. O.; Neckers, D. C. J. Org. Chem. 2005,
70, 10653.
(3) The asymmetric version, see: (a) Funabashi, K.; Ratni, H.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 10784. (b) Taylor, M. S.;
Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6700. (c)
Lu, S.; Wang, Y.; Han, X.; Zhou, Y. Angew. Chem., Int. Ed. 2006, 45,
2260.
(4) (a) Ohtaka, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004,
45, 7339. (b) Asao, N.; Yudha S, S.; Nogami. T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2005, 44, 5526. (c) Asao, N.; Iso, K.; Yudha S, S. Org.
Lett. 2006, 8, 4149. (d) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y.
Angew. Chem., Int. Ed. 2006, 45, 3822. (e) Obika, S.; Kono, H.; Yasui, Y.;
Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462.
A mild, versatile, and efficient method for the one-step
synthesis of substituted dihydro- and tetrahydroisoquinolines
has been developed by the FeCl3‚6H2O catalyzed intramo-
lecular allenylation/cyclization reaction of benzylamino-
substituted propargylic alcohols, representing the first ex-
ample of the intramolecular Friedel-Crafts reaction of
propargylic alcohols.
(5) For selected examples of Lewis acid catalyzed substitution of alcohols,
see: (a) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int. Ed.
2004, 43, 1414. (b) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int.
Ed. 2006, 45, 793. (c) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J.
Org. Chem. 2006, 71, 8516. (d) De, S. K.; Gibbs, R. A. Tetrahedron Lett.
2005, 46, 8345. (e) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. AdV.
Synth. Catal. 2006, 348, 1033. (f) Rueping, M.; Nachtsheim, B. J.; Kuenkel,
A. Org. Lett. 2007, 9, 825. (g) Terrasson, V.; Marque, S.; Georgy, M.;
Campagne, J. M.; Prima, D. AdV. Synth. Catal. 2006, 348, 2063. (h) Georgy,
M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005, 127, 14180.
(i). Zhan, Z. P.; Yang, W. Z.; Yang, R. F.; Yu, J. L.; Li, J. P.; Liu, H. J.
Chem. Commun. 2006, 3352. (j) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y.
Y.; Yang, R. F.; Yang, W. Z.; Li, J. P. J. Org. Chem. 2006, 71, 8298. (k)
Liu, J.; Muth, E.; Flo¨rke, U.; Henkel, G.; Merz, K.; Sauvageau, J.; Schwake,
E.; Dyker, G. AdV. Synth. Catal. 2006, 348, 456. (l) Qin, H. B.; Yamagiwa,
N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2007, 46, 409.
(m) Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.; Beller, M. AdV. Synth.
Catal. 2007, 349, 865. (n) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem.
2007, 72, 5161. (o) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron
Lett. 2007, 48, 3969.
(6) For selected examples of related Brønsted acid catalyzed transforma-
tions, see: (a) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 2605. (b) Shirakawa, S.;
Kobayashi, S. Org. Lett. 2007, 9, 311. (c) Sanz, R.; Miguel, D.; Mart´ınez,
A.; AÄ lvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. Org. Lett. 2007, 9, 2027. (d)
Sanz, R.; Mart´ınez, A.; Miguel, D.; AÄ lvarez-Gutie´rrez, J. M.; Rodr´ıguez,
F. AdV. Synth. Catal. 2006, 348, 1841. (e) Sanz, R.; Mart´ınez, A.; AÄ lvarez-
Gutie´rrez, J. M.; Rodr´ıguez, F. Eur. J. Org. Chem. 2006, 1383.
(7) For selected examples of related metal catalyzed transformations,
see: (a) Bustelo, E.; Dixneuf, P. H. AdV. Synth. Catal. 2005, 347, 393. (b)
Nishibayashi, Y.; Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S. Angew.
Chem., Int. Ed. 2003, 42, 1495. (c) Kennedy-Smith, J. J.; Young, L. A.;
Toste, F. D. Org. Lett. 2004, 6, 1325.
Dihydro- and tetrahydroisoquinoline moieties are present in
a wide range of natural and unnatural compounds that exhibit
important biological activities and in an array of substances used
as intermediates in organic synthesis.1 Thus, a growing effort
has been directed toward the efficient and selective preparation
of various dihydro- and tetrahydroisoquinolines. Traditionally,
the 1,2-dihydroisoquinolines can be indirectly prepared by
nucleophilic addition to isoquinolinium salts, which are derived
from the corresponding isoquinolines by acylation or alkyla-
tion.2,3
Recently, it was found that Lewis acid-catalyzed tandem
intramolecular cyclization/nucleophilic addition or nucleophilic
addition then cyclization of 2-alkynylarylimines can provide a
concise and efficient method for the direct synthesis of 1,3-
and 1,3,4-substituted 1,2-dihydroisoquinolines.4 However, this
strategy is not suitable to the selective construction of 4-sub-
† Fudan University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc.
2006, 128, 87. (b) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
16796. (c) Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5,
2181. (d) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476.
(e) Scott, J. D.; Williams, R. M. Angew. Chem., Int. Ed. 2001, 40, 1463.
(f) Scott, J. D.; Williams, R. M. J. Am. Chem. Soc. 2002, 124, 2951. For
recent reviews, see: (g) Scott, J. D.; Williams, R. M. Chem. ReV. 2002,
102, 1669. (h) Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004,
104, 3341.
(8) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron 2007, 63,
11636.
10.1021/jo702342r CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/16/2008
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J. Org. Chem. 2008, 73, 1586-1589