Preparation of annulated nitrogen-containing heterocycles via a one-pot palladium-catalyzed alkylation/direct arylation sequence

Article abstract of DOI:10.1021/ol060447y

A palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp² C-H functionalization as the key step is described, in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one pot. A variety of hig

Full text of DOI:10.1021/ol060447y

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2043-2045
Preparation of Annulated
Nitrogen-Containing Heterocycles via a
One-Pot Palladium-Catalyzed Alkylation/
Direct Arylation Sequence
Christophe Blaszykowski, Evangelos Aktoudianakis, Cyril Bressy,
Dino Alberico, and Mark Lautens*
DaVenport Laboratories, Chemistry Department, UniVersity of Toronto, Toronto,
Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received February 20, 2006
ABSTRACT
A palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2
C−H functionalization as the key step is
described, in which an alkyl−aryl bond and an aryl−heteroaryl bond are formed in one pot. A variety of highly substituted six- and seven-
membered annulated pyrroles and pyrazoles were synthesized in a one-step process in good yields from readily accessible N-bromoalkyl
pyrroles or pyrazoles and aryl iodides.
Nitrogen-containing heterocycles are of substantial interest
in organic chemistry as they are integral components of
natural products, dyes, agrochemicals, and pharmaceuticals.
The pyrrole core represents one of the most important
heterocycles because it is present in a wide variety of
biologically active natural compounds.1 Recently, increasing
attention has been devoted to the 5,6-dihydro-pyrrolo[2,1-
a]isoquinoline framework 1 since its unique tricyclic structure
has been found in several natural and biologically active
compounds including Crispine A (2),2 Lettowianthine (3)3
and Lamellarin D (4)4 (Figure 1).5
using radical,6 metal-catalyzed,7 or base-induced processes,8
few examples of direct synthesis are known.9 Herein, we
report a new and straightforward one-step synthesis of highly
functionalized 5,6-dihydro-pyrrolo[2,1-a]isoquinoline deriva-
tives 7 using readily accessible starting materials 5 and 6.
Our strategy is based on a palladium-catalyzed/norbornene-
mediated sequential aromatic alkylation (I)/aryl-heteroaryl
coupling (II) reaction10 and involves an aromatic sp2 C-H
functionalization10,11 as the key step (Scheme 1).
Although annulated pyrroles of type 1 have been prepared
via intramolecular cyclization of advanced intermediates
(1) For reviews, see for instance: (a) Gribble, G. W. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. S.
V., Eds.; Pergamon Press: New York, 1996; Vol. 2, pp 207-257. (b) Le
Quesne, P. W.; Dong, Y.; Blythe, T. A. Alkaloids: Chem. Biol. Perspect.
1999, 13, 237-287. (c) Janosik, T.; Bergman, J. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Joule, J. A., Eds.; Pergamon: Amsterdam, 2003;
Vol. 15, pp 140-166.
(2) (a) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58,
6795-6798 and references therein. (b) Szawkalo, J.; Zawadzka, A.;
Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.; Czarnocki, Z. Tetrahe-
dron: Asymmetry 2005, 16, 3619-3621.
(3) Nkunya, M. H. H.; Jonker, S. A.; Makangara, J. J.; Waibel, R.;
Achenbach, H. Phytochemistry 2000, 53, 1067-1073.
Figure 1. Natural compounds containing tricyclic structure 1.
10.1021/ol060447y CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/14/2006

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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Org. Lett., Vol. 8, No. 10, 2006

iodide 30 resulted in a low yield (<10%) of expected
annulated pyrazole 31 using standard conditions A (see Table
1). This low yield may result from catalyst poisoning by the
second nitrogen atom.17 We then ran the reaction using a
slow addition (syringe pump for 20 h) of pyrazole 29.
Preliminary results showed annulated pyrazole 31 could be
isolated in 54% yield (entry 1, Table 2). Iodides 32, 34, and
36 gave comparable yields (entries 2-4).
Scheme 2. Proposed Mechanism for the Synthesis of
Annulated Pyrroles
Finally, we wish to report our initial result involving an
iodo-heteroaromatic partner. Indeed, iodo-uracil 38 could also
undergo the reaction and gave a modest but unoptimized 39%
yield (Scheme 3). To the best of our knowledge, this is the
Scheme 3. Iodo-uracil 38 as the Iodo-Partner
first coupling with a heteroaromatic as the iodo-partner.
In summary, we have developed a new, straightforward
and efficient one-step approach to highly substituted six- and
seven-membered annulated pyrroles using readily available
starting materials. This method is based on a palladium-
catalyzed/norbornene-mediated sequential aromatic alkyl-
ation/aryl-heteroaryl coupling reaction and involves a C-H
functionalization as the key step. This convenient strategy
could also be applied to other nitrogen-containing hetero-
cycles, such as N-alkylated pyrazoles, as well as iodo-
heteroaromatics, such as iodo-uracil, which constitutes a new
class of iodo-partner. Those projects, as well as the use of
1- and 2-substituted pyrroles, are under investigation in the
laboratory and will be reported in due course.
3),15 a slow final cyclization allows the formation of linear
ortho-alkylated products of type F. This observation suggests
that ortho-alkylation most likely precedes aryl-heteroaryl
coupling.
We next turned our attention to reacting pyrazoles (Table
2), since they constitute an important class of compounds
that possess widespread pharmacological properties.16 How-
ever, to the best of our knowledge, no C-H functionalization
reaction involving pyrazole derivatives has been reported.
Our initial attempt employing bromoalkyl pyrazole 29 and
Table 2. Synthesis of Annulated Pyrazolesa
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the Natural Sciences and Engineering
Research Council (NSERC) of Canada, the Merck Frosst
Centre for Therapeutic Research for an Industrial Research
Chair, and the University of Toronto. C. Bressy thanks Le
Ministe`re des Affaires Etrange`res Franc¸ais for a postdoctoral
fellowship.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060447Y
(14) The nature of the final cyclization has already been discussed in
detail. See ref 10.
(15) Unpublished results.
(16) Stefani, H. A.; Pereira, C. M. P.; Almeida, R. B.; Braga, R. C.;
Guzen, K. P.; Cella, R. Tetrahedron Lett. 2005, 46, 6833-6837 and
references therein.
(17) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.; Wora-
kun, T. Tetrahedron 1990, 46, 4003-4018.
a All reactions were run under the following conditions: at 90 °C, to a
MeCN (2 mL) solution of iodoarene (0.60 mmol, 1.5 equiv), Pd(OAc)2
(10 mol %), tri-2-furylphosphine (22 mol %), Cs2CO3 (2 equiv), and
norbornene (2 equiv) was added dropwise (20 h addition) bromoalkyl
pyrazole (1 equiv) in MeCN (2 mL) using a syringe pump. b Isolated yield.
Org. Lett., Vol. 8, No. 10, 2006
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