Amination of o-alkynylhalobenzene is a useful and
widely used method for generation of N-heterocycles.7
For example, 2-substituted indoles can be formed through
palladium- or copper-catalyzed amination of o-alkynylhalo-
benzene and intramoleular cyclization.7a,b We hypothesized
that the 5H-cyclopenta[c]quinoline 3 could be formed as
well via a reaction of o-alkynylhalobenzene with amine.
would allow a direct transformation of easily accessible o-
alkynylhalobenzenes and amines to5H-cyclopenta[c]quin-
oline derivatives. Additionally, diversity and complexity
could be introduced easily. However, several challenges
remained in this strategy: (1) the indole could be easily
produced via Buchwald-Hartwig amination8 and intra-
molecular cyclization,9 as previously reported; (2) the
control of insertion into the triple bond with high chemo-
selectivity and regioselectivity under such sterically hindered
circumstances would be a major concern. Herein, we wish
to report our recent efforts for the formation of 5H-cyclo-
penta[c]quinoline 3 via a palladium-catalyzed domino
reaction of o-alkynylhalobenzene with amine.
Scheme 1. Proposed Synthetic Route to 5H-Cyclopenta-
[c]quinoline 3 via a Palladium-Catalyzed Reaction of o-Alky-
nylhalobenzene with Amine
Table 1. Initial Studies for the Palladium-Catalyzed Reaction of
1-Bromo-2-(phenylethynyl)benzene (1a) with p-Toluidine (2a)
entry ligand
1
base
solvent
temp (°C) yield (%)a
t-BuONa 1,4-dioxane
t-BuONa 1,4-dioxane
reflux
80
trace
11
2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PPh3
3
K2CO3
K2CO3
t-BuOK
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
trace
trace
trace
99
4
reflux
reflux
reflux
reflux
reflux
reflux
105
5
6
t-BuONa 1,4-dioxane
7
KOH
1,4-dioxane
1,4-dioxane
95
8
K3PO4
38
9
CH3ONa 1,4-dioxane
t-BuONa toluene
t-BuONa DMF
61
10
11
12
13
14
15
16
75
The proposed synthetic route is described in Scheme 1. We
reasoned that amination of o-alkynylhalobenzene would
occur first to afford o-alkynylbenzeneamine B, which then
reacted with intermediate A via intermolecular insertion of
the triple bond, leading to the intermediate C. Intramole-
cular insertion of the triple bond and amination took place
subsequently to furnish the expected compound 3 and
Pd(0), which would re-enter the catalytic cycle. This route
105
trace
trace
93
t-BuONa DMSO
105
DPPF t-BuONa 1,4-dioxane
DPPP t-BuONa 1,4-dioxane
reflux
reflux
reflux
reflux
80
PPh3
t-BuONa 1,4-dioxane
90
XPhos t-BuONa 1,4-dioxane
53
a Isolated yield based on p-toluidine (2a). XPhos = 2-(dicyclohexyl-
phosphino)-20,40,60-triisopropyl-1,10-biphenyl.
(6) For selected examples, see: (a) Chen, Z.; Wu, J. Org. Lett. 2010,
12, 4856. (b) Qiu, G.; Ding, Q.; Ren, H.; Peng, Y.; Wu, J. Org. Lett. 2010,
12, 3975. (c) Chen, Z.; Yu, X.; Wu, J. Chem. Commun. 2010, 46, 6356. (d)
Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 5238. (e) Ye, S.; Yang,
X.; Wu, J. Chem. Commun. 2010, 46, 2950. (f) Ye, S.; Gao, K.; Wu, J.
Adv. Synth. Catal. 2010, 352, 1746. (g) Yu, X.; Ye, S.; Wu, J. Adv. Synth.
Catal. 2010, 352, 2050. (h) Yu, X.; Chen, Z.; Yang, X.; Wu, J. J. Comb.
Chem. 2010, 12, 374. (i) Ye, S.; Ren, H.; Wu, J. J. Comb. Chem. 2010, 12,
670. (j) Yu, X.; Ding, Q.; Wu, J. J. Comb. Chem. 2010, 12, 743. (k) Yu, X.;
Wu, J. J. Comb. Chem. 2010, 12, 238.
To verify the feasibility of the hypothesis as shown in
Scheme 1, 1-bromo-2-(phenylethynyl)benzene (1a) and p-
toluidine (2a) were used as the model substrates (Table 1).
The reaction was initially performed in the presence of
5 mol % of palladium acetate in 1,4-dioxane under reflux,
using t-BuONa as the base (Table 1, entry 1). However,
only a trace amount of product was detected. Gratifyingly,
the expected product3a was isolated in 11% yield when the
reaction occurred at 80 °C with tricyclohexylphosphine
(PCy3) added as the ligand (Table 1, entry 2). The structure
(7) (a) Tang, Z.-Y.; Hu, Q.-S. Adv. Synth. Catal. 2006, 348, 846. (b)
Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem., Int.
Ed. 2008, 47, 4906. (c) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008,
€
10, 5281. (d) Ackermann, L.; Barfusser, S.; Potukuchi, H. K. Adv. Synth.
ꢀ
Catal. 2009, 351, 1064. (e) Halland, N.; Nazare, M.; R’kyek, O.; Alonso,
J.; Urmann, M.; Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48,
6879. (f) Siebeneicher, H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed.
2003, 42, 3042. (g) Ackermann, L. Org. Lett. 2005, 7, 439. (h) Sanz, R.;
Castroviejo, M. P.; Guilarte, V.; Perez, A.; Fananas, F. J. J. Org. Chem.
2007, 72, 5113. (i) Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org.
Lett. 2008, 10, 4275. (j) Ackermann, L.; Sandmann, R.; Kondrashov,
M. V. Synlett 2009, 1219. (k) Kaspar, L. T.; Ackermann, L. Tetrahedron
2005, 61, 11311. (l) Ackermann, L.; Sandmann, R.; Schinkel, M.;
Kondrashov, M. V. Tetrahedron 2009, 65, 8930.
(8) For selected reviews, see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J. F.
Acc. Chem. Res. 1998, 31, 852. (c) Hartwig, J. F. Synlett 1997, 329.
(d) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(e) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (f) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
ꢀ
~
ꢀ
(9) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
Org. Lett., Vol. 13, No. 5, 2011
1151