pling conditions. First, a Sonogashira reaction takes place
(C-C bond formation) followed by a spontaneous intramo-
lecular hydroamination of the triple bond (C-N) bond
formation).
Table 1. Base screening for 2-Amidoindole Synthesis
Scheme 1
entry
base
time (h)
yielda (%)
1
2
3
4
5
6
7
8
9
KOAc
t-BuNH2
Et3N
morpholine
diisopropylamine
Cs2CO3
Cs2CO3
DIPEA
Na2CO3
K2CO3
22
22
22
22
22
3
24
22
22
22
17
22
55
32
0
0
0
30
48
0
24
41
81
32
Ynamides have recently been demonstrated to be a
versatile synthon for a number of synthetic transformations
providing access to a variety of important functional groups
and cyclic systems.10-12 Their success as a building block
stems mainly from the development of new and more
efficient methods for accessing such starting materials.11b,13
Major contributions in this respect comes from the group of
Hsung14 and Danheiser.15
10
11
12
Bu4NOAc
K3PO4
a Isolated yields after column chromatography.
In recent work, we observed that certain nitrogen-contain-
ing heterocycles can add to ynamides in a highly regio-
selective manner providing ketenaminals in the presence of
Table 2. Catalyst, Ligand, And Solvent Optimization
(10) For a special issue dedicated ynamides, see: (a) Tetrahedron-
Symposium-In-Print: “Chemistry of Electron-Deficient Ynamines and
Ynamides.” Tetrahedron 2006, 62,Issue No. 16. For reviews on ynamides,
see: (b) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.;
Wei, L. L. Tetrahedron 2001, 57, 7575. (c) Zhang, Y.; Hsung, R. P.
ChemTracts 2004, 17, 442. (d) Katritzky, A. R.; Jiang, R.; Singh, S. K.
entry catalyst
ligand
solvent time (h) yielda (%)
Heterocycles 2004, 63, 1455
.
(11) For some recent examples, see: (a) Saito, N.; Katayama, T.; Sato,
Y. Org. Lett. 2008, 10, 3829. (b) Istrate, F. M.; Buzas, A. K.; Jurberg,
I. D.; Odabachian, Y.; Gagosz, F. Org. Lett. 2008, 10, 925. (c) Hashmi,
S. K.; Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.; Oeser, T.
Chem.sEur. J. 2008, 14, 6672. (d) Couty, S.; Meyer, C.; Cossy, J. Synlett
2007, 2819. (e) Tanaka, K.; Takeishi, K. Synlett 2007, 2920. (f) Kohnen,
A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L. Tetrahedron
2006, 62, 3815. (g) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed.
2006, 45, 6726. (h) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem.
1
2
3
4
5
6
7
8
9
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
DMF
17
23
22
23
23
24
24
22
22
22
22
81
64
65
75
77
81b
74c
80
0
CH3CN
toluene
THF
dioxane
DMF
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(dba)2 PPh3
Pd(OAc)2 HBF4-t-Bu3P DMF
Pd(OAc)2 (o-tol)3P
Pd(OAc)2 X-Phos
DMF
DMF
Soc. 2006, 128, 4586
.
(12) Recent applications of ynamides from the group of Hsung: (a)
Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa, R.
Org. Lett. 2008, 10, 3477. (b) Al-Rashid, Z. F.; Hsung, R. P. Org. Lett.
2008, 10, 661. (c) Li, H.; You, L.; Zhang, X.; Johnson, W. L.; Figueroa,
R.; Hsung, R. P. Heterocycles 2007, 74, 553. (d) You, L.; Al-Rashid, Z. F.;
Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett 2007, 1656.
(e) Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.; Yao,
P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361. (f) Song, Z.; Lu, T.;
Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int. Ed.
2007, 46, 4069. (g) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007,
23, 2420. (h) Tracey, M. R.; Oppenheimer, J.; Hsung, R. P. J. Org. Chem.
2006, 71, 8629. (i) Zhang, X.; Li, H.; You, L.; Tang, Y.; Hsung, R. P. AdV.
Synth. Catal. 2006, 348, 2437. Zhang, X.; Hsung, R. P.; You, L. Org.
Biomol. Chem. 2006, 8, 2679. Kurtz, K. C. M.; Frederick, M. O.; Lambeth,
R. H.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P. Tetrahedron 2006, 62,
10
11
DMF
DMF
0
0
a Isolated yields after column chromatography. b Bu4NOAc (3 equiv)
c Bu4NOAc (2 equiv).
potassium phosphate, as examplified in Scheme 1.16 With
this in mind, we speculated whether this addition reaction
could be performed intramolecularly with anilines possessing
an o-ynamide substituent and thereby providing the corre-
sponding indole ring under mild basic conditions.
To examine this possibility, several ynamides were con-
structed according to the Hsung protocol14b,16 involving the
coupling of alkynyl bromides with amides using CuSO4·5H2O
and 1,10-phenanthroline as the catalyst system. Initial
attempts for the two-step cyclization to indoles were made
with the ynamide 1 and 2-iodoaniline, using Pd(OAc)2 and
3928. Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231
.
(13) (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833. (b) Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
For reviews on the synthesis of ynamides, see: (c) Mulder, J. A.; Kurtz,
K. C. M.; Hsung, R. P. Synlett 2003, 1379. (d) Zificsak, C. A.; Mulder,
J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57,
7575
.
(14) Sagamanova, I. K.; Kurtz, K. C. M.; Hsung, R. P. Org. Synth. 2007,
84, 359. (b) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey,
M. R. J. Org. Chem. 2006, 71, 4170. (c) Zhang, Y.; Hsung, R. P.; Tracey,
M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151.
(15) (a) Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007,
84, 88. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(16) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org.
Chem. 2008, 73, 9447.
222
Org. Lett., Vol. 11, No. 1, 2009