Synthesis of fused N-heterocycles via tandem C-H activation

Article abstract of DOI:10.1039/c2cc34158a

The synthesis of fused N-heterocycles has been developed using an intramolecular cyclisation of purines or benzimidazoles. A range of medium and large rings were prepared.

Full text of DOI:10.1039/c2cc34158a

View Online / Journal Homepage
ChemComm
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Chemical Communications
www.rsc.org/chemcomm
Volume 46
| Number 32 | 28 August 2010 | Pages 5813–5976
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
J. Fraser Stoddart et al.
Directed self-assembly of
ring-in-ring complex
Wenbin Lin et al.
a
Hybrid nanomaterials for biomedical
applications
1359-7345(2010)46:32;1-H
www.rsc.org/chemcomm
Registered Charity Number 207890

ChemComm
Page 1 of 5Journal Name
Dynamic Article Links ►
View Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Synthesis of Fused N-Heterocycles via Tandem C-H Activation
Ge Meng,a Hong-Ying Niu,b Gui-Rong Qu,a John S. Fossey,a,c Jian-Ping Li,*a and Hai-Ming Guo,*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
50 conditions.
6ꢀMethoxyꢀ9ꢀbenzyl purine (1a) was initially selected as
5
A novel and convenient method for the synthesis of fused N-
heterocycles has been developed through highly efficient
intramolecular cyclization of purines or benzimidazoles
catalyzed by Pd(OAc)2 in normal acidic condition without any
base or ligand. A range of medium and large rings, including
substrate (Table 1). To our delight, we found that an
intramolecular cyclisation took place in the presence of a catalytic
amount of PdCl2 (2 mol%）and 1 equiv of CuCl as an oxidant
55 albeit in a poor yield (15%, entry 1). Other palladium sources
were also screened, such as Pd(OAc)2 and Pd(PPh3)4, which
revealed Pd(OAc)2 to be the best choice (entries 1ꢀ6). Silver
acetate was the best oxidant of those tried with 2 equiv proving
optimal reaction effect (entries 4 versus 9ꢀ13). Raising the
60 loading of palladium acetate proved less than effective (entry 4
versus 7ꢀ8) in this reaction, acetic acid was used as solvent since
one of its functions is believed to be that it serves to attenuate
poisoning of the catalyst by the nitrogen atoms of the Nꢀ
heterocycles.16
10 five- to nine-membered rings, are prepared by this process.
Fused Nꢀheterocyclic building blocks are ubiquitous in
natural products and play a significant role in the pharmaceutical
industry and material science.1 Coupling strategies have
15 previously been used for the construction of Nꢀfused
heterocycles (Scheme 1, (a)).2 Tiecco employed a cobaltꢀ
catalysed reductive cyclisation of diphenylethene to successfully
deliver a phenanthrene structure,3 which was followed by a large
number of fused ring structures were constructed via coupling
20 reactions, e.g. radicalꢀmediated reductive coupling,4 Negishi
coupling,5 domino coupling6 and Suzuki coupling.7 Since the
1990s, the transition metalꢀcatalysed single CꢀH bond activation
has emerged as an appealing complementary approach for the
synthesis of Nꢀfused heterocycles (Scheme 1, (b)).8 A convenient
25 aspect to this strategy was that CꢀC bonds could be formed by
intramolecular direct arylꢀaryl bond formation between an actived
CꢀH bond and its coupling partners (CꢀX, X = Cl, Br, I, OTf etc).9
As a result, numerous substrates with electronꢀwithdrawing and
electronꢀdonating groups were used in order to obtain the
30 corresponding cyclisation products.10 However, besides these
fruitiful accomplishments, both of the approaches did have
drawbacks. Scope was limited to indoles, pyrroles and benzenes,
in this context, some efforts have been directed to the
development of transition metalꢀcatalysed intramolecular double
35 CꢀH activation with the purpose of higher efficiency and
generality.11 Greaney and coꢀworkers reported an elegant indoleꢀ
fused rings synthesis via intramolecular double CꢀH activation
under basic conditions,12 but there is still room for improved
efficiency and extended generality and scope.
65
Scheme 1. Strategies for the Synthesis of NꢀFused Heterocycles
With the optimised condition in hand, a variety of 2,6ꢀ
substitutedꢀ9ꢀbenzyl purines were used as substrates to examine
the scope of the reaction, the results are shown in Table 2. All
70 substrates were smoothly transformed into the corresponding
products via intramolecular double CꢀH activation, and most of
the yields were satisfactory. Purines with methoxyl, methyl,
piperidyl or ethoxy groups were all applicable to fiveꢀmembered
ring formation (entries 1ꢀ4). But the yield was a little lower when
75 the C2ꢀposition was occupied by groups like methoxy, ethoxy,
benzylamino or dibenzylamino (70ꢀ82%, entries 5ꢀ10). Notably,
substituents on benzyl group did not affect the reaction too much,
both 2k and 2l were obtained in excellent yields (entries 11ꢀ12).
Most importantly, the cyclisation could also proceed successfully
80 to deliver medium sized rings 2m and 2n when the N9ꢀcarbon
chain was extended.
40
Cyclic nucleosides exist in biological metabolites13 and
synthetic intermediates14 which have been extensively
investigated for their significant antiviral activities. Herein, we
report our recent findings15 on the synthesis of multiꢀfused rings
via intramolecular double CꢀH activation in purines and
45 benzimidazole structures (Scheme 1, (c)). The biggest challenge
remains enhancemnt of the selectivity and the activity, since
multiple nitrogen atoms of purine or benzimidazole may result in
complicated reactions and low activity. Herein we report on
palladium catalysed double CꢀH cyclisation under acidic
Table 1. Intramolecular cyclisation of 9ꢀbenzyl purine via Pdꢀcatalysed
double CꢀH activationa
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

ChemComm
Page 2 of 5
View Online
9
82
80
80
87
entry
1
catalyst(mol %)
PdCl2 (2)
oxidant(equiv)
CuCl (1)
yield/%b
10d
11c
12
15
OCH3
2
PdCl2 (5)
CuCl (2)
27
N
N
N
N
H3
C
3
Pd(OAc)2 (2)
Pd(OAc)2 (5)
No Palladium
Pd(PPh3)4 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
CuCl (2)
40
2k
4
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (5)
BQ (2)
87
5
6c
N.R.c
N.R.c
86
7
13
85
83
8
43
9
86
14d
10
11
12
35
Cu(OAc)2 (2)
FeCl3 (2)
44
a
Unless otherwise mentioned, all of the reactions were carried
26
out with 1a (0.3 mmol), catalyst (5 mol %), AgOAc (2 equiv),
b
AcOH (1.8 mL) in a Schlenk tube at 110 oC for 36 h. Isolated
13
Oxone (2)
trace
yield. c 110 oC for 24 h. d 120 oC for 48 h.
a
o
Conditions: 1a (0.3 mmol), AcOH (1.8 mL), in a sealed tube at 110 C
for 36 h. b Isolated yields. c N.R. = No Reaction.
10
A possible mechanism for the reaction is outlined in Scheme 2.
It was speculated that palladation of purine at C8 formed the
complex I. Then the intermediate II was formed from I through a
metalationꢀdeprotonation process. After which the target
compound III and Pd(0) were produced by reductive elimination,
To extend the substrate scope, the protocol was extended to the
formation of other fused heterocycles such as benzimidazole. As
shown in Table 3, the reactions proceeded effectively and the
anticipated fiveꢀ, sixꢀ and sevenꢀmembered fused rings were
obtained in moderate to good yields (58ꢀ81%).
5
15 Pd(0) is then reoxidized to Pd(II) by AgOAc and took part into
the catalyst circle.
Table 2. Intramolecular cyclisation of various 2,6ꢀsubstitutedꢀ9ꢀbenzyl
purinesa
Table 3. Intramolecular cyclisation of 1ꢀsubstituted benzimidazolesa
entry
1c
substrate
product
yield/%b
58
entry
1
substrate
product
yield/%b
87
N
2
81
75
N
4b
2
91
80
3
3c
a
Unless otherwise mentioned, all of the reactions were carried
out with 1a (0.3 mmol), catalyst (5 mol %), AgOAc (2 equiv),
b
AcOH (1.8 mL) in a Schlenk tube at 110 oC for 36 h. Isolated
yield. c 120 oC for 48 h.
4
88
78
78
70
Encouraged by the above results, a novel strategy for the
20 construction of larger rings was envisaged. Iodobenzene was
chosen as a preꢀarylation reagent, which might afford a phenyl
group to the C8 position of purine before the intramolecular
cyclization (Table 4). It was pleasing to find that both the purine
and benzimidazole substrates were smoothly transformed into the
25 anticipated products. This method presents a promising new
approach to largeꢀring compounds since it is synthetically
difficult to efficiently construct sevenꢀ, eightꢀ, or nineꢀmembered
rings in compound 6 otherwise.
5c
6d
7
OC2H5
In summary, we have developed a novel and convenient
30 method for highly efficient intramolecular cyclisation of purines
and benzimidazoles catalysed by Pd(OAc)2 to synthesise Nꢀfused
8
80
N
N
N
N
NH
Bn
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 5
ChemComm
View Online
heterocycles. This intramolecular direct double CꢀH activation is 20 Excellent Youth Foundation of Henan Scientific Committee (No.
conducted under normal acidic conditions without any base or
ligand. A range of medium and large rings were formed from
purine or benzimidazole containing substrates, which extended
the substrate scope of the available methods and shows the
generality of the process. Additionally the sevenꢀ, eightꢀ and
nineꢀmembered rings could have potential biological activity
which will be investigated separately. Further mechanistic
investigation and synthetic application will be attempted in our
114100510012), the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1061), the Program
for Innovative Research Team in University of Henan Province
(2012IRTSTHN006).
5
25 Notes and references
a
College of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions of Ministry of Education, Henan
Normal University, Xinxiang 453007, Henan, China. Fax: 86 373
3329276; Tel: 86 373 3329255; E-mail: jplig@163.com;
30 guohm518@hotmail.com.
10 laboratory.
b
School of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang 453003, China.
c
School of Chemistry, University of Birmingham, Edgbaston,
Birmingham,
West
Midlands,
B15
2TT,
UK.
E-mail:
35 j.s.fossey@bham.ac.uk.
† Electronic Supplementary Information (ESI) available: [Experimental
1
procedures, compound characterizations, and the copies of H NMR and
13C NMR spectra.]. See DOI: 10.1039/b000000x/
1
(a) K.ꢀI. Takao, R. Munakata, K.ꢀI. Tadano, Chem. Rev., 2005, 105,
4779; (b) A. Mieczkowski, V. Roy, L. A. Agrofoglio, Chem.Rev.,
2009, 110, 1828.
40
45
50
55
60
65
70
75
80
2
(a) G. R. Cahiez, A. Moyeux, Chem.Rev., 2010, 110, 1435; (b) E.ꢀI.
Negishi, L. Anastasia, Chem. Rev., 2003, 103, 1979; (c) S. Cacchi,
G. Fabrizi, Chem. Rev., 2005, 105, 2873.
3
4
M. Tiecco, Chem. Commun., 1965, 555.
Scheme 2. Proposed mechanism of double CꢀH activation.
(a) M. Okabe, M. Abe, M. Tada, J. Org. Chem., 1982, 47, 1775; (b)
M. Okabe, M. Tada, J. Org. Chem., 1982, 47, 5382; (c) F. F.
Kneisel, Y. Monguchi, K. M. Knapp, H. Zipse, P. Knochel,
Tetrahedron Lett., 2002, 43, 4875; (d) G. Hilt, J. Treutwein, Angew.
Chem., Int. Ed., 2007, 46, 8500.
E.ꢀI. Negishi, M. Ay, T. Sugihara, Tetrahedron., 1993, 49, 5471.
K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett., 1975, 16,
4467.
Table 4. Intramolecular cyclisation of purines and benzimidazoles with
iodobenzenea
5
6
15
entry
1c
substrate
product
yield/%b
45
7
8
S. Thielges, E. Meddah, P. Bisseret, J. Eustache, Tetrahedron Lett.,
2004, 45, 907.
(a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev., 2007, 107,
174; b) M. Lafrance, N. Blaquiere, K. Fagnou, Chem. Commun.,
2004, 2874; c) L.ꢀC. Campeau, K. Fagnou, Chem. Commun., 2006,
1253; d) C.ꢀL. Sun, Y.ꢀF. Gu, W.ꢀP. Huang, Z.ꢀJ. Shi, Chem.
Commun., 2011, 47, 9813; e) A. Sharma , P. Appukkuttan, E. Van
der Eycken, Chem. Commun., 2012, 48, 1623.
(a) D. E. Ames, A. Opalko, Tetrahedron., 1984, 40, 1919; (b) D. D.
Hennings, S. Iwasa, V. H. Rawal, J. Org. Chem., 1997, 62, 2; (c) L.ꢀ
C. Campeau, M. Parisien, M. Leblanc, K. Fagnou, J. Am. Chem.
Soc., 2004, 126, 9186.
Me
2
63
9
N
N
N
N
6b
10 (a) C. Pierre, O. Baudoin, Org. Lett., 2011, 13, 1816; (b) Z.ꢀJ. Wang,
J.ꢀG. Yang, F. Yang, W. Bao, Org. Lett., 2010, 12, 3034; (c) H.
Ohno, M. Iuchi, N. Fujii, T. Tanaka, Org. Lett., 2007, 9, 4813; (d) I.
3
4
69
49
79
Čerňa, R. Pohl, B. Klepetářová, M. Hocek, J. Org. Chem., 2010, 75,
2302; (e) N. Barbero, R. SanMartin, E. Dominguez, Org. Biomol.
Chem., 2010, 8, 841.
11 (a) S. M.Kupchan, A. J. Liepa, R. F. Bryan, J. Am. Chem. Soc.,
1973, 95, 6861; (b) F. Churruca, R. SanMarti, E. Domínguez, J. Org.
Chem., 2005, 70, 3178; (c) T. Watanabe, S. Ueda, S. Inuki, S. Oishi,
N. Fujii, H. Ohno, Chem. Commun., 2007, 4516; (d) K. K. Gruner,
H.ꢀJ. Kn¨olker, Org. Biomol. Chem., 2008, 6, 3902; (e) B. Liegault,
D. Lee, M. P. Huestis, D. R. Stuart, K. Fagnou, J. Org. Chem., 2008,
73, 5022; (f) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn, B.
DeBoef, Org. Lett., 2007, 9, 3137; g) L. L. Welbes, T. W. Lyons, K.
A. Cychosz, M. S. Sanford, J. Am. Chem. Soc., 2007, 129, 5836; h)
S. Potavathri, A. Kantak, B. DeBoef, Chem. Commun., 2011, 47,
4679. i) J. Kim, J. S. Schneekloth, E. J. Sorensen, Chem. Sci., 2012,
DOI: 10.1039/C2SC20669B.
N
N
5
a
Unless otherwise mentioned, all of the reactions were carried
out with 1a (0.3 mmol), catalyst (5 mol %), AgOAc (2 equiv),
b
AcOH (1.8 mL) in a Schlenk tube at 110 oC for 36 h. Isolated
yield.
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos 21072047, and
21172059), the Program for New Century Excellent Talents in
University of Ministry of Education (No. NCETꢀ09ꢀ0122),
12 D. G. Pintori, M. F. Greaney, J. Am. Chem. Soc., 2011, 133, 1209.
85 13 R. J. Capon, N. S. Trotter, J. Nat. Prod., 2005, 68, 1689.
14 B. B. Jarvis, J. B. Yount, T.ꢀH. Yang, J. Org. Chem., 1972, 37, 797.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

ChemComm
Page 4 of 5
View Online
15 (a) H.ꢀM. Guo, P.ꢀY. Xin, H.ꢀY. Niu, D.ꢀC. Wang, Y. Jiang, G.ꢀR.
Qu, Green Chem., 2010, 12, 2131; (b) H.ꢀM. Guo, W.ꢀH. Rao, H.ꢀY.
Niu, L.ꢀL. Jiang, G. Meng, J.ꢀJ. Jin, X.ꢀN. Yang, G.ꢀR. Qu, Chem.
Commun., 2011, 47, 5608.
5
16 H.ꢀM. Guo, L.ꢀL. Jiang, H.ꢀY. Niu, W.ꢀH. Rao, L. Liang, R.ꢀZ. Mao,
D.ꢀY. Li, G.ꢀR. Qu, Org. Lett., 2011, 13, 2008.
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 5
ChemComm
View Online
Graphical Abstract