Palladium-Catalyzed Iminoannulation of Alkynes
TABLE 1. Op tim iza tion of th e P a lla d iu m -Ca ta lyzed
Recently, we have developed a general synthesis of
isoquinolines and pyridines by the palladium-catalyzed
iminoannulation of internal alkynes (eq 1).16 Our own
F or m a tion of 3,4-Dip h en yl-â-ca r bolin e (eq 2)
isolated
%
%
base
(equiv)
temp, °C; yield
entry
catalyst
catal PPh3
time, h
of 2, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(PhCN)2
Pd(PPh3)4
Pd(dba)2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
10
5
5
5
10
10
10
10
10
10
10
10
10
10
10
10
5
Na2CO3 (1)
Na2CO3 (1)
K2CO3 (1)
Cs2CO3 (1)
NaOAc (1)
KOAc (1)
100; 48
130; 48
100; 48
100; 48
100; 48
100; 48
100; 48
0
0
0
0
0
0
0
0
39
40
48
48
54
45
51
52
40
46
41
41
51
pyridine (1)
DTBMPa (1) 100; 48
NEt3 (1)
i-Pr2NEt (1) 100; 24
Cy2NEt (1)
n-Bu3N (1)
n-Bu3N (1)
100; 24
100; 50
100; 24
100; 10
100; 10
100; 8
100; 10
100; 10
100; 10
100; 10
100; 10
100; 10
interest in extending this type of iminoannulation reac-
tion prompted us to examine potential applications to the
synthesis of a wide variety of â- and γ-carbolines. A brief
communication on this work has been previously re-
ported.17 Herein, we wish to report the full details of this
palladium-catalyzed annulation of internal alkynes for
the synthesis of various â- and γ-carbolines, extension
of this methodology to terminal alkynes, and applications
to the synthesis of two biologically active â-carboline
alkaloids, ZK9342318 and abecarnil (ZK112119).19
2.5 n-Bu3N (1)
5
5
5
5
5
5
5
n-Bu3N (1)
n-Bu3N (2)
n-Bu3N (1)
n-Bu3N (1)
n-Bu3N (1)
n-Bu3N (1)
n-Bu3N (1)
5
5
5
Pd(dppe)2
a
2,6-Di-tert-butyl-4-methylpyridine.
Resu lts a n d Discu ssion
butylimine of 3-iodo-1H-indole-2-carboxaldehyde (1). The
reaction of diphenylacetylene and imine 1 was chosen as
the model system for optimization (eq 2). In the early
Our initial studies focused on the palladium-catalyzed
iminoannulation of internal alkynes employing the tert-
(9) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998, 63,
7652.
(10) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551. (b)
Roesch, K. R.; Larock, R. C. J . Org. Chem. 2001, 66, 412.
(11) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org.
Chem. 1995, 60, 3270.
(12) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(13) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett. 1998, 39,
5713.
(14) Larock, R. C.; Doty, M. J .; Cacchi, S. J . J . Org. Chem. 1993,
58, 4579.
(15) (a) Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org.
Chem. 1997, 62, 7536. (b) Larock, R. C.; Tian, Q. J . Org. Chem. 1998,
63, 2002.
(16) (a) Roesch, K. R.; Larock, R. C. J . Org. Chem. 1998, 63, 5306.
(b) Roesch, K. R.; Zhang, H.; Larock, R. C. J . Org. Chem. 2001, 66,
8042.
stages of this work, the reaction conditions examined
were similar to the conditions employed in our earlier
isoquinoline synthesis.16 For example, the reactions were
run with 0.25 mmol of the tert-butylimine, 2 equiv of
diphenylacetylene, 5 mol % of Pd(OAc)2, 10 mol % of
PPh3, and 1 equiv of Na2CO3 as a base in 5 mL of DMF
at 100 °C (Table 1, entry 1). However, these conditions
failed to produce any of the desired â-carboline 2. When
the reaction temperature was raised to 130 °C, still no
desired product was detected after 48 h (entry 2). We next
examined different inorganic bases in the reaction, since
the nature of the base often has a dramatic effect on these
palladium-catalyzed annulation reactions.8 All of the
inorganic bases we tried, including K2CO3, Cs2CO3,
NaOAc, and KOAc proved to be ineffective (entries 3-6).
Two pyridine bases, namely pyridine and 2,6-di-tert-
butyl-4-methylpyridine (DTBMP), also failed to produce
any of the desired product (entries 7 and 8). When the
tertiary amine base triethylamine was employed, a 39%
yield of the desired product was isolated (entry 9). Several
other tertiary amine bases, including N,N-diisopropyl-
ethylamine (i-Pr2NEt), N-ethyldicyclohexylamine (Cy2-
NEt), and tri-n-butylamine (n-Bu3N), generated the
desired product, but in relatively low yields (entries 10-
12). Comparing entries 11 and 12, we noticed that the
use of n-Bu3N not only required shorter reaction times
(17) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083.
(18) (a) Huang, Q.; He, X.; Ma, C.; Liu, R.; Yu, S.; Dayer, C. A.;
Wenger, G. R.; McKernan, R.; Cook, J . M. J . Med. Chem. 2000, 43, 71.
(b) Cox, E. D.; Diaz-Arauzo, H.; Huang, Q.; Reddy, M. S.; Ma, C.;
Harris, B.; McKernan, R.; Skolnick, P.; Cook, J . M. J . Med. Chem. 1998,
41, 2537. (c) Huang, Q.; Zhang, W.; Liu, R.; McKernan, R. M.; Cook, J .
M. Med. Chem. Res. 1996, 6, 384. (d) Fryer, R. I.; Wang, C.-G.; Chia,
N.-C.; Basile, A. S.; Gu, Z.-Q.; Skolnick, P. Med. Chem. Res. 1995, 5,
296. (e) Liu, R.; Zhang, P.; McKernan, R. M.; Wafford, K.; Cook, J . M.
Med. Chem. Res. 1995, 5, 700. (f) Hollinshead, S. P.; Trudell, M. L.;
Skolnick, P.; Cook, J . M. J . Med. Chem. 1990, 33, 1062.
(19) (a) Koek, W.; Patoiseau, J .-F.; Assie, M.-B.; Cosi, C.; Kleven,
M. S. J . Pharmacol. Exp. Ther. 1998, 287, 266. (b) Thompson, S.-A.;
Bonnert, T. P.; Whiting, P. J .; Wafford, K. A. Toxicol. Lett. 1998, 100,
233. (c) Haffer, G.; Nickisch, K.; Tilstam, U. Heterocycles 1998, 48, 993.
(d) Scholze, P.; Ebert, V.; Sieghart, W. Eur. J . Pharmacol. 1996, 304,
155. (e) Witkin, J . M.; Acri, J . B.; Wong, G.; Gleeson, S.; Barrett, J . E.
J . Pharmacol. Exp. Ther. 1996, 277, 87. (f) Wafford, K. A.; Thompson,
S. A.; Sikela, J .; Wilcox, A. S.; Whiting, P. J . Mol. Pharmacol. 1996,
50, 670. (g) Mehta, A. K.; Shank, R. P. Life Sci. 1995, 57, 2215. (h)
Mumford, G. K.; Rush, C. R.; Griffiths, R. R. J . Pharmacol. Exp. Ther.
1995, 272, 570. (i) Dazzi, L.; Motzo, C.; Imperatoi, A.; Serra, M.; Gessa,
G. L.; Biggio, G. J . Pharmacol. Exp. Ther. 1995, 273, 241. (j) Stephens,
D. N.; Schneider, H.; Kehr, W.; Andrews, J . S.; Rettig, K. J .; Truski,
L.; Schmiechen, R.; Turner, J . D.; J ensen, L. H.; Petersen, E. N.;
Honore, T.; Hansen, J . B. J . Pharmacol. Exp. Ther. 1990, 253, 334.
(k) Truski, L.; Stephens, D. N.; J ensen, L. H.; Petersen, E. N.; Meldrum,
S. B.; Patel, S.; Hansen, J . B.; Losher, W.; Schneider, H.; Schmiechen,
R. J . Pharmacol. Exp. Ther. 1990, 253, 344. (l) Krause, W.; Mengel,
H.; Nordholm, L. J . Pharm. Sci. 1989, 78, 622.
J . Org. Chem, Vol. 67, No. 26, 2002 9319