C O M M U N I C A T I O N S
Table 3. Effects of Microwave Irradiation and Ring Size on the
Formation of Various Carbo- and Heterocycles via
Palladium-Catalyzed Intramolecular Cyclization
Acknowledgment. We thank Merck Frosst Canada, the NSERC
IRC program, the Swiss National Fund, and the University of
Toronto for support of this research program.
Supporting Information Available: Experimental procedures,
spectroscopic characterization of substrates and products, and deter-
mination of configuration. This material is available free of charge via
References
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In Organometallics in Synthesis: A Manual; Schlosser, M., Ed.; Wiley:
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and references therein.
yieldb (%)
entry
n
X
R
Ar
mwc
ctd
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
3
3
3
1
O
O
O
NTs
H
Naph
Ph
Ph
Ph
Ph
Naph
Naph
Ph
Ph
Ph
a
b
c
d
e
f
g
h
i
56
61
66
74
67
62
72
65
73
33
20
36
74
CF3
CO2Me
H
H
H
H
H
H
H
C(CO2Et)2
O
46
49
O
NTs
(2) Yokoyama, Y.; Ito, S.; Takahashi, Y.; Murakami, Y. Tetrahedron Lett.
1985, 26, 6457.
C(CO2Et)2
CH2O
(3) Trost, B. M.; Walchli, R. J. Am. Chem. Soc. 1987, 109, 3487.
10
j
45
(4) Ikegami, R.; Koresawa, A.; Shibata, T.; Takagi, K. J. Org. Chem. 2003,
68, 2195.
a CHCl3 adduct was used. b Isolated yields. c Microwave-assisted condi-
(5) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201.
tions. d Conventional thermal conditions. Ph ) phenyl, Naph ) Naphthyl.
(6) (a) Gomes, P.; Gosmini, C.; Pe´richon, J. Org. Lett. 2003, 5, 1043. (b)
Gomes, P.; Gosmini, C.; Pe´richon, J. J. Org. Chem. 2003, 68, 1142 and
references therein.
steps from the same iodinated aromatic derivatives.15 The benzylic
oxygen-containing substrate 5 was prepared from the 2-iodobenzylic
alcohol following a procedure similar to the one used for the
preparation of five-membered-ring precursors.15
(7) Review: Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
52, 15031.
(8) Recent examples of diastereoselective synthesis of substituted 1,2,3,4-
tetrahydroquinolines: (a) Ori, M.; Toda, N.; Takumi, K.; Tago, K.; Kogen,
H. Angew. Chem., Int. Ed. 2003, 42, 2540. (b) Fabio, R. D.; Alvaro, G.;
Bertani, B.; Donati, D.; Giacobbe, S.; Marchioro, C.; Palma, C.; Lynn, S.
M. J. Org. Chem. 2002, 67, 7319. (c) Stevenson, P. J.; Nieuwenhuyzen,
M.; Osborne, D. Chem. Commun. 2002, 444. (d) Cheng, D.; Zhou, J.;
Saiah, E.; Beaton, G. Org. Lett. 2002, 4, 4411. (e) Takamura, M.;
Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
6801. (f) Sundararajan, G.; Prabagaran, N.; Varghese, B. Org. Lett. 2001,
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J. Org. Chem. 2001, 66, 2822.
(9) Although this process is rare, several examples have been reported. For
an intramolecular cross-coupling reaction between alkenyl bromide and
allyl acetate, see: Steinig, A. G.; Meijere, A. Eur. J. Org. Chem. 1999,
1333. For an intramolecular Heck cyclization, followed by a palladium-
â-alkoxy elimination see: Sinou, D.; Bedjeguelal, K. Eur. J. Org. Chem.
2000, 4071 and references therein.
Oxygen-containing substrates 3a-c gave the cyclized products
6a-c in poor yields (Table 3, entries 1-3), probably due to the
competitive formation of the π-allyl complex that generates the
corresponding phenol. In an effort to improve these yields, we
subjected the reaction to microwave irradiation, which is known
to accelerate transition-metal-catalyzed homogeneous reactions.16
Carrying out the reaction in the microwave at 160 °C for 1 min
was found to improve the yield in each case (entries 1-3) by as
much as 41% for 6b (entry 2). According to this procedure, five-
membered rings 6a-e (entries 1-5) as well as six- and seven-
membered rings 6f-j (entries 6-10) were efficiently formed.
Variation of the X group did not affect the cross-coupling process
since nitrogen- and carbon-containing cycles, 6d,h and 6e,i,
respectively (entries 4, 8 and 5, 9), were obtained in good yields.
The cyclization also proceeded with a benzylic oxygen-containing
substrate to form the six-membered heterocycle 6j (entry 10). We
found that the yields increased as the ring size increased from five
to seven (6a,f,g, entries 1, 6, and 7).
In conclusion, palladium-catalyzed intramolecular cross-coupling
reactions between aryl iodides and allyl moieties were successfully
demonstrated. We describe a new rapid synthetic approach to a
variety of trans-2,4-disubstituted 1,2,3,4-tetrahydroquinolines 2 with
excellent diastereoselectivities as well as to various five- to seven-
membered carbo- and heterocycles 6 Via conventional thermal and
microwave-assisted conditions. We are currently investigating the
mechanism of the reaction but believe the role of the amine base
is to reduce Pd(II) back to Pd(0) after each catalytic cycle.
(10) Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345. Lautens,
M.; Tayama, E.; Nguyen, D. Tetrahedron Lett. 2004, 45, 5131.
(11) The configuration was determined by preparation of trans- and cis-4-
isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, respectively. For details,
see the Supporting Information.
(12) By our experimental studies, we expect that the tertiary amine generates
Pd(0) from Pd(II). Reaction of Pd(II) and tertiary amines: McCrindle,
R.; Ferguson, G.; Arsenault, G. J.; McAlees, A. J. J. Chem. Soc., Chem.
Commun. 1983, 571.
(13) Prepared according to procedures described in the literature: (a) Adimur-
thy, S.; Ramachandraiah, G.; Ghosh, P. K.; Bedekar, A. V. Tetrahedron
Lett. 2003, 44, 5099. (b) Cockerill, G. S.; Levett, P. C.; Whiting, D. A.
J. Chem. Soc., Perkin Trans. 1 1995, 1103. (c) Zenner, J. M.; Larock, R.
C. J. Org. Chem. 1999, 64, 7312.
(14) (Z)-BrCH2CHdCHCH2OCO2Et was prepared by monoprotecting the (Z)-
1,4-butenediol with pyridine and ethylchloroformate, followed by OH/Br
exchange according to the procedure described in the literature: Oppolzer,
W.; Fu¨rstner, A. HelV. Chim. Acta 1993, 76, 2329. See Supporting
Information for details.
(15) See Supporting Information for details.
(16) (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717.
(b) Walla, P.; Kappe, O. C. Chem. Commun. 2004, 564.
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