Scheme 1. Synthesis of
5,6-Dihydro-pyrrolo[2,1-a]isoquinoline Derivatives
Table 1. Synthesis of Annulated Pyrroles via
Palladium-Catalyzed Tandem Alkylation/Direct Arylation
Reactiona
Our initial attempts to effect a tandem alkylation/direct
arylation employed bromoalkyl pyrrole 8. Use of aryl iodide
9 under the optimized reaction conditions [iodoarene (0.20
mmol, 1 equiv), PdCl2 (10 mol %), tri-2-furylphosphine (22
mol %), Cs2CO3 (2 equiv), norbornene (2 equiv), and
bromoalkyl pyrrole (2 equiv) in acetonitrile (0.1 M) at 90
°C in a sealed tube for 23 h] afforded six-membered
annulated pyrrole 10 in 77% yield (entry 1, Table 1).
The generality of this reaction sequence was first dem-
onstrated for unsubstituted pyrroles by varying the substit-
uents on the iodoarene (entries 1-7) and the length of the
alkyl chain (entries 8 and 9). Both electron-withdrawing and
electron-donating groups are tolerated at various positions
on the iodoarene and give good to excellent yields when
reacted with alkyl pyrrole 8. However, substrate 19, bearing
an o-methoxy substituent, gave a modest yield (entry 6). The
chloro-derivative 21 gave the product in 75% yield, and the
resulting compound 22 represents a very useful partner for
further functionalizations.12 Seven-membered annulated pyr-
roles 24 and 25 were also constructed with comparable yields
using Pd(OAc)2 as the catalyst (entries 8 and 9). The
1-substituted pyrrole 26 afforded the product 28 in 59% yield
(reaction run on a 2 mmol scale), and the resulting product
28 represents an interesting advanced intermediate for the
synthesis of biologically active Lamellarin derivatives4b,7b
(entry 10).
(4) (a) Facompre´, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.;
Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392-7399.
(b) Pla, D.; Marchal, A.; Olsen, C. A.; Albericio, F.; AÄ lvarez, M. J. Org.
Chem. 2005, 70, 8231-8234.
(5) For other related natural and/or biologically active compounds, see:
(a) Chen, C.-C.; Huang, Y.-L.; Lee, S.-S.; Ou, J.-C. J. Nat. Prod. 1997, 60,
826-827. (b) Almerico, A. M.; Mingoia, F.; Diana, P.; Barraja, P.;
Montalbano, A.; Lauria, A.; Loddo, R.; Sanna, L.; Delpiano, D.; Setzy, M.
G.; Musiu, C. Eur. J. Med. Chem. 2002, 37, 3-10. (c) Yang, Y.-L.; Chang,
F.-R.; Wu, Y.-C. HelV. Chim. Acta 2004, 87, 1392-1399.
(6) (a) Fiumana, A.; Jones, K. Tetrahedron Lett. 2000, 41, 4209-4211.
(b) Allin, S. M.; Bowman, W. R.; Elsegood, M. R. J.; McKee, V.; Karim,
R.; Rahman, S. S. Tetrahedron 2005, 61, 2689-2696.
a Unless otherwise noted, all reactions were run under the following
conditions: iodoarene (0.20 mmol, 1 equiv), PdCl2 (10 mol %), tri-2-
furylphosphine (22 mol %), Cs2CO3 (2 equiv), norbornene (2 equiv), and
bromoalkyl pyrrole (2 equiv) in acetonitrile (2 mL) were heated in a sealed
tube at 90 °C for 23 h (conditions A). b Isolated yield. c Pd(OAc)2 was used
as the catalyst. d Reaction run on a 2 mmol scale.
(7) (a) Kno¨lker, H.-J.; Agarwal, S. Tetrahedron Lett. 2005, 46, 1173-
1175. (b) Olsen, C. A.; Parera, N.; Albericio, F.; AÄ lvarez, M. Tetrahedron
Lett. 2005, 46, 2041-2044.
(8) ( a) Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53,
5951-5962. (b) Orito, K.; Harada, R.; Uchiito, S.; Tokuda, M. Org. Lett.
2000, 2, 1799-1801.
(9) See however: Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun.
1997, 23, 2259-2260.
(10) This strategy has previously been applied with success to the
preparation of annulated indole derivatives: Bressy, C.; Alberico, D.;
Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148-13149.
(11) For reviews on aromatic sp2 C-H functionalizations, see: (a) Dyker,
G. Angew. Chem., Int. Ed. 1999, 38, 1699-1712. (b) Miura, M.; Nomura,
M. Top. Curr. Chem. 2002, 219, 211-241. (c) Campeau, L.-C.; Thansan-
dote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857-1860.
(12) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685-4696. For a review on palladium-
catalyzed coupling reactions of aryl chlorides, see: (b) Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
The ortho alkylation likely proceeds through the mecha-
nism previously described by Catellani13 and involves an
aromatic sp2 C-H activation (A f B) as the key step10
(Scheme 2). Intermediate E arises from the reductive
elimination of the proposed Pd(IV) complex C followed by
expulsion of norbornene (D f E). Aryl-heteroaryl coupling
of E via C-H functionalization of the pyrrole C-2 hydrogen
finally provides annulated pyrroles.14 In some cases (n g
(13) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl.
1997, 36, 119-122.
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