Palladium-catalyzed oxidative intramolecular C-C bond formation via double sp2 C-H activation between the 2-position of imidazoles and a benzene ring

Article abstract of DOI:10.1002/adsc.201100801

Oxidative intramolecular C-C bond formation via double sp² C-H activation between the 2-position of imidazoles and a benzene ring catalyzed by palladium(II) has been developed, which provides an atom-economical, concise and efficient methodology to synthesize imidazole- or benzimidazole-fused isoquinoline polyheteroaromatic compounds. Copyright

Full text of DOI:10.1002/adsc.201100801

COMMUNICATIONS
DOI: 10.1002/adsc.201100801
ꢀ
Palladium-Catalyzed Oxidative Intramolecular C C Bond
2
ꢀ
Formation via Double sp C H Activation between the
2-Position of Imidazoles and a Benzene Ring
Manman Sun,a Huandong Wu,a Junnan Zheng,a and Weiliang Baoa,*
a
Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; phone: (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
Received: October 17, 2011; Published online: March 13, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100801.
ꢀ
Abstract: Oxidative intramolecular C C bond for-
mation via double sp C H activation between the
on the inter- and intramolecular self-coupling or
cross-coupling with thiophene.[3a,7]
Heterocycles exist as fundamental motifs in the
scaffold of more than half of the biologically active
compounds produced by nature,[8] especially imid-
2
ꢀ
2-position of imidazoles and a benzene ring cata-
lyzed by palladium(II) has been developed, which
provides an atom-economical, concise and efficient
methodology to synthesize imidazole- or benzimid-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
2
ꢀ
Keywords: double sp C H activation; imidazole-
or benzimidazole-fused isoquinoline compounds;
intramolecular C C bond formation; palladium(II)
ꢀ
catalysis
ꢀ
Metal-catalyzed double C H activation, because of
its atom economy and environmental benefits, has at-
tracted increasing interest among chemists.[1] In the
past decade, it has become a powerful and efficient
ꢀ
strategy to construct C C bonds to form complex
molecules. Oxidative C C bond formation using two
Figure 1. Several reported biologically active imidazole- or
benzimidazole-fused isoquinoline polyheteroaromatic com-
ꢀ
ꢀ
different C H bonds has also been developed, such as pounds.
3
3
[2]
2
2
ꢀ
ꢀ
ꢀ
ꢀ
(i) sp C H with sp C H, (ii) sp C H with sp C
H,[3] (iii) sp C H with sp C H, and (iv) sp C H
3
2
[4]
3
ꢀ
ꢀ
ꢀ
with sp C H. Among them, coupling between sp2 have attracted considerable interest due to their out-
[5]
ꢀ
2
ꢀ
ꢀ
C H and sp C H that can form complicated conju- standing biological activities, such as anti-HIV-1, anti-
gated system has received substantial attention for or- cancer, antimicrobial, and antifungal properties.[9]
ganic community to find the biologically active struc- Generally, there are two routes to access the imida-
tures. These reaction sites are often located in the vi- zole- or benzACTHNUTRGNEUiGN midazole-fused isoquinoline structures:
cinity of a heteroatom, such as nitrogen, oxygen or one is the synthesis of the imidazole or benzimidazole
sulfur.[6] Therefore indole,[6a] benzofuran,[6b] pyrid- ring by condensation reactions,[8a,9a,10] and the other is
ACHTUNGTRENNUNG
ine,[6c] pyrazole,[6d] oxazole,[6f] and thiazole[6i] have the cross-coupling between an imidazole or benzimi-
been proven to be the important heterocyclic moieties dazole and an aryl ring.[11] Compared with the cross-
2
ꢀ
ꢀ
ꢀ
for the development of sp C H activation chemistry. coupling protocols between a C H bond and a C X
ꢀ
However, imidazole and benzimidazole are rarely (X=Cl, Br, I, OTf, CO2H) or C M bond (M=B, Sn,
ꢀ
ꢀ
found in the oxidative C H activation cross-coupling Si, Mg, Zn), the oxidative C C bond formation be-
ꢀ
reactions and the reported examples mainly focused tween two C H bonds would be a better choice due
Adv. Synth. Catal. 2012, 354, 835 – 838
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
835

Manman Sun et al.
COMMUNICATIONS
Scheme 1. Retrosynthetic analysis of imidazole- or benzimidazole-fused isoquinoline compounds.
2
ꢀ
ꢀ
to the atom economy and fewer synthetic steps. Early of two sp C H bonds to form a C C bond (Table 1,
in the 1976, Cooper and Irwin had reported a photo- entry 1). Hence a lot of reaction conditions such as
cyclization of 1-styrylimidazoles.[12] To the best of our Pd catalysts, oxidants, solvents and temperature, were
ꢀ
knowledge, no examples of C C bond-forming cross- studied to obtain the optimal conditions (Table 1).
coupling between imidazoles or benzimidazoles and Eventually, the satisfactory reaction conditions came
a benzene ring via two C H bonds activation have to our sight, that is, the reaction should be promoted
been documented to form these heteroaromatic struc- by PdCl2/Cu
ꢀ
(OAc)2 in the mixed solvent of p-xylene/
tures.
HOAc (6/1) at 1408C (Table 1, entry 2).
The previous studies concerning the heterocyclic
With the optimized reaction conditions in hand, we
compounds, reported by our group and others,[3a,11b,13] selected some representative substrates to explore the
proved that the 2-position of imidazole or benzimid- scope of the method (Scheme 2). Comparing 4a with
ACHTUNGTRENNUNGazole could be a good site to be activated (Scheme 1). 4c and 4k, we could see that both electron-donating
Hence, we designed a coupling reaction between the and electron-withdrawing substituents worked compa-
2-position of imidazole or benzimidazole and a ben- ratively well. Then the substituent effects on the imi-
zene ring. We chose the (Z)-1-styryl-1H-imidazole dazole and benzimidazole rings were studied (4m–
(3a) as the starting material, which could be prepared 4p). However, the coupling between (Z)-2-bromovi-
easily via the cross-coupling of (Z)-2-bromovinylben- nylbenzene and 4-methyl-1H-imidazole or 5-methyl-
zene
(Scheme 1).[14]
As CuACHTUNGTRENNUNG(OAc)2/O2 is a very nice oxidative system for (from NMR spectra). Separation of these isomers was
with
imidazole
catalyzed
by
FeACHTUNTGRENNUNG
the self-coupling of imidazoles,[4a] we firstly applied not easy, so they were used in the next step without
this system to examine the reaction, but unfortunate- separation. Cyclization reaction also produced a pair
ly, no expected product was observed. Further exami- of isomers in moderate yield in nearly the same ratio
nation showed that the PdACHTNUGTRENNUG(OAc)2/CuACHTUNGTREN(NUGN OAc)2 might be as with the fomer step (4m and 4m’: 0.60/0.40; 4n and
the more promising system for the oxidative coupling 4n’: 0.45/0.55; 4o and 4o’: 0.45/0.55) (see the corre-
Table 1. Optimization of the reaction conditions.[a]
Entry
Pd catalyst
Pd(OAc)2
Oxidant
Solvent
Temperature [oC]
Yield [%]
1
2
3
4
5
6
7
8
G
Cu
Cu
Cu
N
p-xylene/HOAc (6/1)
p-xylene/HOAc (6/1)
p-xylene/HOAc (6/1)
p-xylene/HOAc (6/1)
p-xylene/HOAc (6/1)
p-xylene/HOAc (6/1)
p-xylene/HOAc (6/1)
DMSO/HOAc (6/1)
DMA/HOAc (6/1)
n-PrCN/HOAc (6/1)
HOAc
140
140
140
140
140
140
140
140
140
140
140
140
120
63
96
51
87
trace
trace
trace
27
trace
57
PdCl2
Pd(dppf)Cl2
E
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Ag2CO3
Cu(OTf)2
G
BQ
O2
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
N
R
A
9
10
11
12
13
67
29
16
p-xylene
p-xylene/HOAc (6/1)
[a]
Reaction conditions: (Z)-1-styryl-1H-imidazole (0.4 mmol), Pd catalyst (0.04 mmol) and oxidant(0.48 mmol) in solvent
(2 mL) under air for 24 h.
836
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 835 – 838

2
ꢀ
ꢀ
Palladium-Catalyzed Oxidative Intramolecular C C Bond Formation via Double sp C H Activation
Scheme 3. The occurrence of isomers.
Scheme 4. The (E)-1-styryl-1H-imidazoles could not form
the corresponding product.
methodology for palladium-catalyzed oxidative intra-
2
ꢀ
ꢀ
molecular C C bond formation via double sp C H
activation between the 2-position of imidazoles and
a benzene ring. It will open a new field to synthesize
imidazole- or benzimidazole-fused isoquinoline poly-
heteroaromatic compounds.
Experimental Section
General Procedure
Compound
10 mol%) and CuACHTUNGTRENNUNG
3
(0.4 mmol), PdCl2 (7.1 mg, 0.04 mmol,
(OAc)2 (56.6 mg, 0.48 mmol, 1.2 equiv.) in
the mixed solvent of p-xylene/HOAc (6/1) (2 mL) were
stirred in a sealed tube at 1408C for 12–24 h. When the reac-
tion mixture was cooled, H2O (5 mL) was added. And the
resulting mixture was extracted with EtOAc (3ꢂ15 mL).
The combined organic layers were washed with saturated
aqueous NaHCO3 (50 mL), dried over MgSO4, filtered and
concentrated under vacuum. The residue was purified by
a quick flash chromatography on silica gel with petroleum
ether/EtOAc (1/1!1/3) as an eluent to afford 4. For more
details, see the Supporting Information.
Scheme 2. Synthesis of diversely substituted compounds 4
catalyzed by PdCl2. Reaction conditions: 3 (0.4 mmol), PdCl2
(0.04 mmol) and CuACTHNUTRGNEUNG(OAc)2 (0.48 mmol) in p-xylene/HOAc
(6:1) (2 mL) under air for the given reaction time.
sponding NMR spectra in the Supporting Informa-
tion) (Scheme 3).It was worth mentioning that the
pure two components 4m and 4m’ were obtained after
careful separation. And their structures could be de-
termined by NOE spectra whereby 5-H in 4m’
showed a correlation with methyl hydrogen while 4m
did not. As a limitation of our method, (Z)-1-(2-phe-
Acknowledgements
nylprop-1-enyl)-1H-benzimidazole
which
had
a methyl group in the olefinic bond showed a low
yield of the corresponding product 4q.
This work is financially supported by the Natural Science
Foundation of China (No. 21072168).
Furthermore, we prepared the (E)-1-styryl-1H-
imidACHTUNGTRENNUNGazole and conducted the reaction under the same
conditions, but no expected fused product was detect-
ed and only the substrate was recovered (Scheme 4).
In conclusion, we have developed a novel, efficient,
atom-economic and environmentally benign synthetic
References
[1] For recent reviews, see: a) V. Ritleng, C. Sirlin, M.
Pfeffer, Chem. Rev. 2002, 102, 1731; b) I. V. Seregin, V.
Adv. Synth. Catal. 2012, 354, 835 – 838
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
837

Manman Sun et al.
COMMUNICATIONS
Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173; c) G. P.
McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38,
2447; d) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem.
Soc. Rev. 2011, 40, 5068; e) C. S. Yeung, V. M. Dong,
Chem. Rev. 2011, 111, 1215; f) C. Liu, H. Zhang, W.
Shi, A. Lei, Chem. Rev. 2011, 111, 1780.
[7] a) P.-H. Xi, F. Yang, S. Qin, D.-B. Zhao, J.-B. Lan, G.
Gao, C.-W. Hu, J.-S. You, J. Am. Chem. Soc. 2010, 132,
1822; b) D. G. Pintori, M. F. Greaney, J. Am. Chem.
Soc. 2011, 133, 1209.
[8] a) A. D. C. Parenty, L. Cronin, Synthesis 2008, 1479;
b) A. R. Katritzky, C. W. Rees, (Eds.), Comprehensive
Heterocyclic Chemistry Elsevier, New York, 1984, Vol.
4, 1–38.
[9] a) H.-C. Ouyang, R.-Y. Tang, P. Zhong, X.-G. Zhang,
J.-H. Li, J. Org. Chem. 2011, 76, 223; b) S. M. Rida,
S. A. M. El-Hawash, H. T. Y. Fahmy, A. A. Hazzaa,
M. M. M. El-Meligy, Arch. Pharmacal Res. 2006, 29,
826; c) Z. X. Lu, N. H. Quazi, L. W. Deady, G. M.
Polya, Biol. Chem. Hoppe-Seyler. 1996, 377, 373;
d) R. L. Weinkauf, A. Y. Chen, C. Yu, L. Liu, L. Bar-
rows, E. J. LaVoie, Bioorg. Med. Chem. 1994, 2, 781;
e) P. Molina, E. Aller, A. Lorenzo, C. Foces, A. L. L.
Saiz, Tetrahedron 1996, 52, 13671.
[10] a) A. D. C. Parenty, Y.-F. Song, C. J. Richmond, L.
Cronin, Org. Lett. 2007, 9, 2253; b) N. Okamoto, K. Sa-
kurai, M. Ishikura, K. Takeda, R. Yanada, Tetrahedron
Lett. 2009, 50, 4167; c) L. G. Voskressensky, L. N. Kuli-
kova, A. V. Listratova, R. S. Borisov, M. A. Kukaniev,
A. V. Varlamov, Tetrahedron Lett. 2010, 51, 2269; d) N.
Chernyak, V. Gevorgyan, Angew. Chem. 2010, 122,
2803; Angew. Chem. Int. Ed. 2010, 49, 2743.
[2] For selected examples, see: a) Z. Li, C.-J. Li, J. Am.
Chem. Soc. 2005, 127, 3672; b) J. Xie, Z.-Z. Huang,
Angew. Chem. 2010, 122, 10379; Angew. Chem. Int. Ed.
2010, 49, 10181; c) Z. Li, L. Cao, C.-J. Li, Angew.
Chem. 2007, 119, 6625; d) Z. Li, L. Cao, C.-J. Li,
Angew. Chem. 2007, 119, 6625; Angew. Chem. Int. Ed.
2007, 46, 6505; e) Z. Li, C.-J. Li, J. Am. Chem. Soc.
2006, 128, 56; f) D.-P. Cheng, W.-L. Bao, Adv. Synth.
Catal. 2008, 350, 1263.
[3] For selected examples, see: a) Y. Li, J. Jin, W.-X. Qian,
W.-L. Bao, Org. Biomol. Chem. 2010, 8, 326; b) K. L.
Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129,
11904; c) H. A. Chiong, O. Daugulis, Org. Lett. 2007, 9,
1449; d) T. Yokota, M. Tani, S. Sakaguchi, Y. Ishii, J.
Am. Chem. Soc. 2003, 125, 1476; e) D. R. Stuart, E. Vil-
lemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129, 12072;
f) D. R. Stuart, K. Fagnou, Science 2007, 316, 1172.
[4] For selected examples, see: a) Z. Li, C.-J. Li, J. Am.
Chem. Soc. 2005, 127, 6968; b) B. DeBoef, S. J. Pastine,
D. Sames, J. Am. Chem. Soc. 2004, 126, 6556; c) J.-G.
Yang, Z.-J. Wang, F.-Y. Pan, Y.-M. Li, W.-L. Bao, Org.
Biomol. Chem. 2010, 8, 2975.
[11] a) Q. Liao, L.-Y. Zhang, S.-T. Li, C.-J. Xi, Org. Lett.
2011, 13, 228; b) I. Cerna, R. Pohl, B. Klepetarova, M.
Hocek, J. Org. Chem. 2010, 75, 2302; c) B. Liu, X.-R.
Qin, K.-Z. Li, X.-Y. Li, Q. Guo, J.-B. Lan, J.-S. You,
Chem. Eur. J. 2010, 16, 11836.
[5] For selected examples, see: a) A. C. Correia, C.-J. Li,
Adv. Synth. Catal. 2010, 352, 1446; b) Z. Li, C.-J. Li,
Org. Lett. 2004, 6, 4997; c) Z. Li, C.-J. Li, J. Am. Chem.
Soc. 2004, 126, 11810.
[12] G. Cooper, W. J. Irwin, J. Chem. Soc. Perkin Trans.
[6] For selected examples, see: a) S. Potavathri, K. C. Per-
eira, S. I. Gorelsky, A. Pike, A. P. LeBris, B. DeBoef, J.
Am. Chem. Soc. 2010, 132, 14676; b) T. A. Dwight,
N. R. Rue, D. Charyk, R. Josselyn, B. DeBoef, Org.
Lett. 2007, 9, 3137; c) G. Deng, L. Zhao, C.-J. Li,
Angew. Chem. 2008, 120, 6374; Angew. Chem. Int. Ed.
2008, 47, 6278; d) D. Shabashov, O. Daugulis, Org. Lett.
2005, 7, 3657; e) S. Oi, E. Aizawa, Y. Ogino, Y. Inoue,
J. Org. Chem. 2005, 70, 3113; f) K. M. Gericke, D. I.
Chai, N. Bieler, M. Lautens, Angew. Chem. 2009, 121,
1475; Angew. Chem. Int. Ed. 2009, 48, 1447; g) M. Yu,
Z.-J. Liang, Y.-Y. Wan, Y.-H. Zhang, J. Org. Chem.
2011, 76, 4987; h) T.-J. Gong, B. Xiao, Zh.-J. Liu, J.
Wan, J. Xu, D.-F. Luo, Y. Fu, L. Liu, Org. Lett. 2011,
13, 3235; i) F.-Z. Zhang, M. F. Greaney, Angew. Chem.
2010, 122, 2828; Angew. Chem. Int. Ed. 2010, 49, 2768.
1 1976, 75.
[13] For selected examples, see: a) M. Miyasaka, K. Hirano,
T. Satoh, R. Kowalczyk, C. Bolm, M. Miura, Org. Lett.
2011, 13, 359; b) Z.-J. Wang, J.-G. Yang, F. Yang, W.-L.
Bao, Org. Lett. 2010, 12, 3034; c) C. C. Malakar, D.
Schmidt, J. Conrad, U. Beifuss, Org. Lett. 2011, 13,
1378; d) L. Ackermann, Angew. Chem. 2011, 123, 3926;
Angew. Chem. Int. Ed. 2011, 50, 3842; e) X. Zhao, G.-J.
Wu, Y. Zhang, J.-B. Wang, J. Am. Chem. Soc. 2011,
133, 3296; f) M. Ohta, M. P. Quick, J. Yamaguchi, B.
Wunsch, K. Itami, Chem. Asian J. 2009, 4, 1416; g) X.
Bugaut, F. Glorius, Angew. Chem. 2011, 123, 7618;
Angew. Chem. Int. Ed. 2011, 50, 7479.
[14] J.-C. Mao, G.-L. Xie, J.-M. Zhan, Q.-Q. Hua, D.-Q. Shi,
Adv. Synth. Catal. 2009, 351, 1268.
838
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 835 – 838