Domino N-H/C-H bond activation: Copper-catalyzed synthesis of nitrogen-bridgehead heterocycles using azoles and 1,4-dihalo-1,3-dienes

Article abstract of DOI:10.1021/ol1026365

Copper-catalyzed tandem coupling of 1,4-dihalo-1,3-dienes with azoles via an N-H bond and its adjacent C-H bond activation has been described. The reaction exhibits good regioselectivity when unsymmetrical 1,4-dihalo-1,3-diene is employed. This method provided a novel route to the synthesis of nitrogen-bridgehead azolopyridine derivatives.

Full text of DOI:10.1021/ol1026365

ORGANIC
LETTERS
2011
Vol. 13, No. 2
228-231
Domino N-H/C-H Bond Activation:
Copper-Catalyzed Synthesis of
Nitrogen-Bridgehead Heterocycles Using
Azoles and 1,4-Dihalo-1,3-dienes
Qian Liao, Liyun Zhang, Shutao Li, and Chanjuan Xi*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua UniVersity, Beijing 100084, China,
and State Key Laboratory of Elemento-Organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
cjxi@tsinghua.edu.cn
Received October 30, 2010
ABSTRACT
Copper-catalyzed tandem coupling of 1,4-dihalo-1,3-dienes with azoles via an N-H bond and its adjacent C-H bond activation has been
described. The reaction exhibits good regioselectivity when unsymmetrical 1,4-dihalo-1,3-diene is employed. This method provided a novel
route to the synthesis of nitrogen-bridgehead azolopyridine derivatives.
Direct transition-metal-catalyzed functionalization of C-H
bonds in heterocycles has received significant attention in
modern organic chemistry owing to its atom economy, high
functional group tolerance, and the possibilities for trans-
formation of the unreactive C-H bonds into diverse func-
tions in one operation. Significant progress was accomplished
by recently developed methodologies for the general use of
aryl (pseudo)halides in direct arylation reactions.1,2 In
contrast to the much more developed palladium-catalyzed
C-H arylation reaction of various heterocycles, direct
alkenylations of heteroaromatics with vinyl (pseudo)halides
have received much less attention.2a,3 In particular, copper-
catalyzed direct C-alkenylation of free (NH)-azoles with vinyl
halides was unknown, to the best of our knowledge. Cu-
catalyzed alkenylation of free (NH)-azoles to afford N-
alkenylation products has been reported.4 In this case, no
C-alkenylation products were obtained. As part of a general
(2) (a) Ackermann, L.; Barfu¨sser, S.; Pospech, J. Org. Lett. 2010, 12,
724. (b) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You,
J. Angew. Chem., Int. Ed. 2009, 48, 3296. (c) Kawano, T.; Yoshizumi, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 3072. (d) Ackermann,
L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627. (e) Candito,
D. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 6713.
(3) (a) Besselie`vre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S.
Org. Lett. 2008, 10, 4029. (b) Besselie`vre, F.; Lebrequier, S.; Mahuteau-
Betzer, F.; Piguel, S. Synthesis 2009, 3511. (c) Verrier, C.; Hoarau, C.;
Marsais, F. Org. Biomol. Chem. 2009, 7, 647. (d) Gottumukkala, A. L.;
Derridj, F.; Djebbar, S.; Doucet, H. Tetrahedron Lett. 2008, 49, 2926. (e)
Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guil-
laumet, G. Synthesis 2008, 2537. (f) Rodriguez, A.; Fennessy, R. V.; Moran,
W. J. Tetrahedron Lett. 2009, 50, 3942. (g) Mousseau, J. J.; Bull, J. A.;
Charette, A. B. Angew. Chem., Int. Ed. 2010, 49, 1115. (h) Mousseau, J. J.;
Fortier, A.; Charette, A. B. Org. Lett. 2010, 12, 516. (i) Cruz, A. C. F.;
Miller, N. D.; Willis, M. C. Org. Lett. 2007, 9, 4391.
(1) For recent reviews, see: (a) Bellina, F.; Rossi, R. Tetrahedron 2009,
65, 10269. (b) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009,
38, 2447. (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(d) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (e)
Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (f) Miura, M.;
Nomura, M. Top. Curr. Chem. 2002, 219, 211. (g) Miura, M.; Satoh, T. In
Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-VCH: Wein-
heim, 2005; Vol. 1, p 229. (h) Ackermann, L.; Vicente, R. In Modern
Arylation Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, 2009, p
(4) (a) Taillefer, M.; Ouali, A.; Renard, B.; Spindler, J.-F. Chem.sEur.
J. 2006, 12, 5301. (b) Liao, Q.; Wang, Y.; Zhang, L.; Xi, C. J. Org. Chem.
2009, 74, 6371.
311
.
10.1021/ol1026365  2011 American Chemical Society
Published on Web 12/09/2010

study of the construction of heterocyclic compounds using
1,4-dihalo-1,3-dienes,5 we envisioned that a domino reaction
of free (NH)-azole with 1,4-dihalo-1,3-diene could afford
an annulated heterocycle through N-H and C-H cleavage.
Herein, we report a novel copper-catalyzed domino
reaction2d,e,6 for the synthesis of N-bridgehead azolopyri-
dine.7 This approach involves a consecutive N-alkenylation
and C-alkenylation by using readily available azoles and 1,4-
dihalo-1,3-dienes (Scheme 1).
lectivity and stereoselectivity through halogenation of
zirconacyclopentadienes derived from two alkynes, ac-
cording to the reported methods.8
As summarized in Table 1, substrate 1a and 2a were
first subjected to the following typical conditions: 10 mol
% of CuI, 20 mol % of acetyl acetone (acac), dimethyl-
formamide (DMF) as a solvent, and Cs2CO3 as a base at
140 °C. 5,6,7,8-Tetraethylimidazo[1,2-a]pyridine 3a was
obtained in 65% yield after 24 h (entry 1). Prolonging
the reaction time to 48 h did not help (entry 2). However,
when the reaction was carried out in DMF at 160 °C for
24 h, the expected coupled product 3a was achieved in
78% yield (entry 13). Other polar solvents also resulted
in the formation of the product (entries 6-7), while they
are not as efficient as DMF. Among the bases, Cs2CO3
proved to be superior. Usually, ligands play an important
role in the copper-catalyzed coupling reactions; thus
different types of ligands were screened. Surprisingly, all
the ligands screened gave similar results (entries 1, 8-12).
These results let us suspect that the ligands might not
participate in the coupling reaction. Indeed, we were
pleased to find that, in the absence of a ligand, the reaction
proceeded smoothly, and azolopyridine 3a formed also
in high yield (entry 14). The above data also suggested
that azole itself might function as the ligand in the
reaction. Increasing the amount of imidazole to 1.5 equiv
gave a product 3a in excellent yield (entry 15). On the
other hand, without the use of CuI, the reaction did not
proceed (entry 16).
Scheme 1
To probe the viability of the envisioned domino
reaction, imidazole 1a and (3Z,5Z)-4,5-diethyl-3,6-diio-
doocta-3,5-diene 2a were used as the model substrates
for the optimization of the reaction conditions (Table 1).
Table 1. Optimization of the Reaction Conditionsa
Having established an effective catalytic system for the
coupling reactions, we next synthesized a variety of 1,4-
dihalo-1,3-dienes8 to explore the scope of tandem alkeny-
lation under the optimized conditions (CuI as a catalyst,
Cs2CO3 as a base, and DMF as a solvent, with the reaction
temperature at 160 °C). The results are summarized in Table
2. At the beginning, 1,4-diiodo-1,3-dienes with an ethyl and
a propyl substituent were examined, and the corresponding
azolopyridine formed in high yields (entries 1-2). When a
diiododiene fused with a six-membered ring 2c was used,
the reaction smoothly occurred to afford imidazo[1,2-
b]isoquinoline derivative 3c in a high yield (entry 3). When
2,2′-diiodobiphenyl 2d9 was used, and the reaction also
proceeded smoothly under the conditions to afford imi-
dazo[1,2-f]phenanthridine 3d in moderate yield (entry 4). The
reaction of 1,4-dibromo-1,3-diene 2e with azole 1a also
(5) (a) Liao, Q.; Zhang, L.; Wang, F.; Li, S.; Xi, C. Eur. J. Org. Chem.
2010, 5426. (b) You, W.; Yan, X.; Liao, Q.; Xi, C. Org. Lett. 2010, 12,
3930.
(6) (a) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661.
(b) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007,
46, 2295. (c) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292. (d) Ramana, T.; Saha, P.; Das, M.;
Punniyamurthy, T. Org. Lett. 2010, 12, 84. (e) Verna, A. K.; Kesharwani,
T.; Singh, J.; Tandon, V.; Larock, R. C. Angew. Chem., Int. Ed. 2009, 48,
1138.
a Reaction conditions: 1,4-diiodo-1,3-diene (1.0 equiv), imidazole (1.0
equiv), CuI (10 mol %), Ligand (20 mol %), Cs2CO3 (3 equiv), DMF (2
b
mL). 1H NMR yields using Cl2CdCHCl as an internal standard; the
isolated yields are given in parentheses. c Imidazole (1.5 equiv). d Without
CuI.
(7) (a) Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J. Org. Chem.
2003, 68, 3498. (b) Barun, O.; Ila, H.; Junjappa, H.; Singh, O. M. J. Org.
Chem. 2000, 65, 1583. (c) Chezal, J. M.; Moreau, E.; Delmas, G.; Gueiffier,
A.; Blache, Y.; Grassy, G.; Lartigue, C.; Chavignon, O.; Teulade, J. C. J.
Org. Chem. 2001, 66, 6576. (d) Johns, B. A.; Gudmundsson, K. S.; Turner,
E. M.; Allen, S. H.; Jung, D. K.; Sexton, C. J.; Boyd, F. L.; Peel, M. R.
Tetrahedron 2003, 59, 9001.
It is noted that the requested 1,4-dihalo-1,3-dienes were
conveniently prepared in high yields with high regiose-
Org. Lett., Vol. 13, No. 2, 2011
229

afforded azolopyridine 3a in high yield (entry 5). Further-
more, when (Z)-1-iodo-2-(2-iodovinyl)benzenes10 (2f and 2g)
were used, the reactions smoothly occurred to afford imi-
dazo[1,2-a]quinoline derivative 3e and 3f in high yields,
respectively (entries 6-7). The structure of product 3e was
Table 2. Tandem Synthesis of Diversely Substituted
Azolopyridines Catalyzed by CuIa
1
confirmed by H NMR, 13C NMR, HSQC, and HMBC
experiments,11 which indicated that aryl iodide coupled with
the N-H bond and then the alkenyl iodide coupled with the
C-H bond. The reaction could be extended to substituted
imidazole and other azoles, such as pyrrole, pyrazole, and
triazole. The reaction of 4-methylimidazole 1b with 2a gave
5,6,7,8-tetraethyl-2-methylimidazo[1,2-a]pyridine 3g regi-
oselectively, which could be rationalized by steric hindrance
(entry 8). When 4-nitro-1H-imidazole and 1H-imidazole-4-
carbaldehyde were treated under the condition, the desired
products were not observed. Pyrazole 1c and 3-methylpyra-
zole 1d reacted with 2a to form pyrazolo[1,5-a]pyridine 3h
and its methyl substituted derivative 3i (entries 9-10),
respectively. 1,4-Dibromo-1,3-dienes 2e also reacted under
the conditions with a slow reaction rate (entry 11). When
1,2,4-triazole 1e was employed, N-1, C-2 annulated products
were formed in moderate yields (entries 12-13) with a high
loading of CuI and other ligand. The coupling reaction
occurred in the N-1 position, other than N-3. These results
are consistent with those reported by Buchwald.12 Pyrrole
1g could also perform in these conditions, and pyrrolo[1,2-
a]quinoline 3m was obtained with low yield.
To investigate the reaction process, a reaction of (3Z,5E)-
4,5-diethyl-3-iodoocta-3,5-diene 2g and imidazole 1a was
treated under the conditions. In this case N-coupled product
3n was obtained as the sole product (Scheme 2). It is
Scheme 2
important to note that under the conditions we did not detect
any formation of the C-coupled product. This result indicated
that the N-H bond was activated preferentially in the
(8) (a) Xi, C.; Huo, S.; Afifi, T. H.; Hara, R.; Takashashi, T. Tetrahedron
Lett. 1997, 38, 4099. (b) Takahashi, T.; Sun, W.-H.; Xi, C.; Ubayama, H.;
Xi, Z. Tetrahedron 1998, 54, 715. (c) Ubayama, H.; Sun, W.-H.; Takahashi,
T.; Xi, Z. Chem. Commun. 1998, 1931. (d) Xi, Z.; Liu, X.; Lu, J.; Bao, F.;
Fan, H.; Li, Z.; Takahashi, T. J. Org. Chem. 2004, 69, 8547. (e) Xi, Z.;
Song, Z.; Liu, G.; Liu, X.; Takahashi, T. J. Org. Chem. 2006, 71, 3154. (f)
Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870. (g)
Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121,
7342.
(9) Neugebauer, W.; Kos, A. J.; von Schleyer, P. R. J. Organomet. Chem.
1982, 228, 107.
a Reaction conditions: diiododiene (1.0 equiv), azole (1.5 equiv), CuI
(10) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am. Chem. Soc.
1986, 108, 7411.
b
(10 mol %), Cs2CO3 (3 equiv), DMF (2 mL). 1H NMR yields, using
Cl2CdCHCl as an internal standard; the isolated yields are given in
parentheses. c Azole (2.0 equiv), CuI (20 mol %), N-phenylpyridin-2-
methylimine (20 mol %) as ligand.
(11) HSQC and HMBC showed cross-peak correlation for product 3e.
See Supporting Information for details.
(12) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578.
230
Org. Lett., Vol. 13, No. 2, 2011

reaction conditions. Therefore a proposed reaction course is
first N-H bond alkenylation followed by a sequent C-H
bond alkenylation on azole with 1,4-dihalo-1,3-diene.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20972085
and 21032004).
In summary, we have reported a novel copper-catalyzed
domino reaction for the synthesis of annulated heterocycles that
consists of N-H bond alkenylation and C-H bond alkenylation
with readily available azoles and 1,4-dihalo-1,3-dienes. Notably,
this approach constitutes an unprecedented direct alkenylation-
based domino process that is applicable to synthesize nitrogen-
bridgehead azolopyridine derivatives.
Supporting Information Available: Experimental pro-
cedures and full characterization including 1H NMR and 13
C
NMR data for compounds 3a-3c, 3e-3l, and 3n. HSQC
and HMBC for 3e. This material is available free of charge
via the Internet at http://pubs.acs.org.
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