for the synthesis of a wide variety of carbo- and heterocycles.
We hereby wish to report that the palladium-catalyzed cross-
coupling of N-tert-butyl-o-(1-alkynyl)benzaldimines and a
variety of organic halides offers an efficient, direct route to
3,4-disubstituted isoquinolines (eq 1).
4-iodonitrobenzene (Table 1, entry 2). The reaction of the
bromide is also slower than the iodide reaction. The reactions
of substrate 1 and aryl iodides with an electron-withdrawing
group in the ortho position (Table 1, entries 6 and 7) fail to
produce any of the desired 3,4-disubstituted isoquinolines.
We assume that this is due to steric hindrance to coordination
of the arylpalladium intermediate to the alkyne triple bond
(see the later mechanistic discussion). When 4-iodoanisole
is employed in the reaction with substrate 1 (Table 1, entry
8), the corresponding product 10 and the side product
3-phenylisoquinoline (3) are isolated in 13% and 14% yields,
respectively. Thus, electron-rich aryl iodides give poor results
in this cyclization chemistry.
Our initial studies of this process focused on developing
an optimum set of reaction conditions for the palladium-
catalyzed cross-coupling reaction. All optimization reactions
were carried out using N-tert-butyl-o-(phenylethynyl)ben-
zaldimine (1) and phenyl iodide in DMF as the solvent. When
5 mol % of Pd2(dba)3 was utilized as the catalyst at 100 °C
with the addition of 10 mol % of PPh3 and 3 equiv of Na2-
CO3, 3,4-diphenylisoquinoline (2) was isolated in only a
modest yield. A side product, 3-phenylisoquinoline (3), was
also generated, and the selectivity between the two isoquino-
line products was not satisfactory.
The reactions of N-tert-butyl-o-(phenylethynyl)benzaldi-
mine (1) and allylic halides or esters have also proven
successful. Allyl chloride or bromide and diallyl carbonate
have all generated the corresponding 4-allyl-3-phenyliso-
quinoline (11) in decent yields (entries 9-11). Substituted
allylic chlorides, such as methallyl chloride, work equally
well (entry 12). Benzylic halides and alkynyl iodides have
also been successfully employed in this process. For example,
the reaction of benzyl chloride produces a modest 45% yield
of the cross-coupled isoquinoline product 13 (entry 13). The
alkynyl iodide 1-iodo-1-decyne affords 4-(1-decynyl)-3-
phenylisoquinoline (14) in a 56% yield (entry 14).
On the other hand, 5 mol % of Pd(PPh3)4 gave the desired
product 2 in a 49% yield and none of the 3-monosubstituted
isoquinoline 3, when the reaction was run using 5 equiv of
K2CO3 as the base at 100 °C (Table 1, entry 1). Changing
the base to KOAc, Na2CO3, Li2CO3, Cs2CO3, or organic
amine bases failed to improve the yield of the product 2.
Raising the temperature to 120 °C only promoted the
formation of more 3-phenylisoquinoline (3). The optimum
reaction conditions thus far developed employ 1 equiv of
the o-(1-alkynyl)benzaldimine (0.25 mmol), 5 equiv of the
organic halide, 5 mol % of Pd(PPh3)4, and 5 equiv of K2-
CO3 in DMF (5 mL) at 100 °C. Phenyl triflate failed to afford
3,4-diphenylisoquinoline (2) under these standard reaction
conditions.
We have also investigated the reactions of imino alkynes
containing different R1 groups at the end of the triple bond
with an aryl iodide and an allylic halide. With 4-iodoni-
trobenzene, imino alkyne 17 bearing a 1-cyclohexenyl group
affords the corresponding 3,4-disubstituted isoquinoline (18)
in a good yield, 59% (entry 16). Imine 20 containing an
n-butyl group affords the desired product 21 in only a 35%
yield (entry 18). The reactions of these two starting materials
and methallyl chloride have given quite different results.
Imine 17 affords a 30% yield (entry 17), while imine 20
with an n-butyl group gives over twice that yield (62%, entry
19).
By employing this protocol, aryl iodides bearing an
electron-withdrawing group in the para or meta position
afford the corresponding 4-aryl-3-phenylisoquinolines in
good to high yields and very little of the side product 3 is
observed (Table 1, entries 2-5). 4-Bromonitrobenzene
affords 4-(4-nitrophenyl)-3-phenylisoquinoline (4) in a lower
yield, 48%, compared to the 75% yield obtained from
The mechanism shown in Scheme 1 is proposed for this
process. It consists of the following key steps: (1) oxidative
addition of the organic halide to the Pd(0) catalyst, (2)
coordination of the resulting palladium intermediate A to
the alkyne triple bond to form complex B, which activates
the triple bond toward nucleophilic attack, (3) intramolecular
nucleophilic attack of the nitrogen atom on the activated
carbon-carbon triple bond to afford intermediate C, (4)
reductive elimination to form the carbon-carbon bond
between R2 and the isoquinoline ring in D with simultaneous
regeneration of the Pd(0) catalyst, and (5) cleavage of the
tert-butyl group from the nitrogen to release the strain
between the tert-butyl group and the R1 group to produce
the 3,4-disubstituted isoquinoline.
(9) For recent leading references, see: (a) Arcadi, A.; Cacchi, S.; Fabrizi,
G.; Marinelli, F. Synlett 2000, 3, 394. (b) Monteiro, N.; Balme, G. Synlett
1998, 746. (c) Monteiro, N.; Arnold, A.; Belme, G. Synlett 1998, 1111. (d)
Larock, R. C.; Pace, P.; Yang, Hoseok, Russell, C. E. Tetrahedron 1998,
54, 9961. (e) Cacchi, S.; Fabrizi, G.; Moro, L. J. Org. Chem. 1997, 62,
5327. (f) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001.
(g) Cacchi, S.; Fabrizi, G.; Marinetlli, F.; Moro, L.; Pace, P. Synlett 1997,
1363. (h) Cacchi, S.; Fabrizi, G.; Moro, L. Synlett 1998, 741. (i) Cacchi,
S.; Fabrizi, G.; Moro, L. J. Org. Chem. 1997, 62, 527 and references therein.
(j) Arcadi, A.; Anacardio, R.; D’Anniballe, G.; Gentile, M. Synlett 1997,
1315. (k) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli,
F. J. Org. Chem. 1996, 61, 9280 and references therein. (l) Belme, G.;
Bouyssi, D. Tetrahedron 1994, 50, 403. (m) Arcadi, A.; Cacchi, S.;
Carnicelli, V.; Marinelli, F. Tetrahedron 1994, 50, 437. (n) Arcadi, A.;
Cacchi, S.; Larock, R. C.; Marinellil, F. Tetrahedron Lett 1993, 34, 2813.
(o) Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.; Pietroni,
B. R. J. Org. Chem. 1992, 57, 976. (p) Arcadi, A.; Cacchi, S.; Marinelli,
F. Tetrahedron Lett. 1992, 33, 3915. (q) Wei, L.-M.; Lin, C.-H.; Wu, M.
J. Tetrahedron Lett. 2000, 41, 1215. (r) Bouyssi, D.; Gore, J.; Balme, G.
Tetrahedron Lett. 1992, 33, 2811.
The strong dependence of the reaction yields on the
electronic nature of the aryl halides employed can be easily
understood by this mechanism. For aryl iodides containing
a para or meta electron-withdrawing substituent, the electron-
deficient intermediate A more strongly coordinates to the
triple bond in the imine substrate to produce complex B.
The coordination step is most likely crucial to the forma-
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Org. Lett., Vol. 3, No. 25, 2001