Generation of benzoimidazo[1,5-a]imidazoles via a copper-catalyzed tandem reaction of carbodiimide and isocyanoacetate

Article abstract of DOI:10.1039/c2cc32135a

Carbodiimide reacts with isocyanide catalyzed by copper(i) iodide, leading to benzoimidazo[1,5-a]imidazoles in good yields. This reaction is efficient, and proceeds through a formal [3+2] cycloaddition and C-N coupling.

Full text of DOI:10.1039/c2cc32135a

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COMMUNICATION
Generation of benzoimidazo[1,5-a]imidazoles via a copper-catalyzed
tandem reaction of carbodiimide and isocyanoacetatew
Guanyinsheng Qiua and Jie Wu*ab
Received 23rd March 2012, Accepted 18th April 2012
DOI: 10.1039/c2cc32135a
Carbodiimide reacts with isocyanide catalyzed by copper(I)
iodide, leading to benzoimidazo[1,5-a]imidazoles in good yields.
This reaction is efficient, and proceeds through a formal [3+2]
cycloaddition and C–N coupling.
Development of general and efficient methodologies for rapid
Scheme 1 Retrosynthetic approach for the generation of
access to nitrogen-containing heterocycles is one of the central
benzoimidazo[1,5-a]imidazoles.
focuses in organic chemistry, due to their importance in
biologically active natural products and synthetic materials.1
Prompted by the above-mentioned results, we conceived that the
It is well known that many compounds with benzoimidazole
skeleton of benzoimidazo[1,5-a]imidazole could be constructed
or imidazole skeletons exhibit a broad range of biological
properties such as e.g. enzyme inhibitors and drugs.2 Addi-
via a copper-catalyzed tandem [3+2] cycloaddition–C–N
coupling reaction of carbodiimide 18 with isocyanoacetate 2
tionally, benzoimidazo[1,5-a]imidazoles, which incorporate
as presented in Scheme 1. Herein, we wish to disclose our
benzoimidazole and imidazole frameworks, show promising
biological activities as well.3 However, to our surprise, no
recent efforts for this projected route.
Our studies commenced with the reaction of bis-(2-iodoaryl)-
general and efficient method has been developed for the
carbodiimide 1a with methyl isocyanoacetate 2a. Initially, the
preparation of such core structural motifs. In conjunction with
reaction was catalyzed by CuI (10 mol%) in the presence of
of natural product-like compounds,4 we are interested in
L-proline (20 mol%) and Cs2CO3 (2.0 equiv.) in toluene under
our continuing efforts for the synthesis and biological evaluation
reflux. To our delight, the expected benzoimidazo[1,5-a]-
the development of methodologies for the generation of
imidazole 3a was obtained in 34% yield (Table 1, entry 1).
benzoimidazo[1,5-a]imidazoles.
A slightly higher yield was obtained when 1,10-phenanthroline
In the past decades, isocyanides have been widely used as
versatile building blocks in organic synthesis.5 Among the
was employed as the ligand (Table 1, entry 2). The reaction
was complex when pentane-2,4-dione (acac) was utilized
family of isocyanides, isocyanoacetates are attractive and are
(Table 1, entry 3). The result was improved when TMEDA
usually employed to go through a formal [3+2] cycloaddition
was used as a replacement (Table 1, entry 4). Further evalua-
process and protonation of organometallic intermediates to
form N-heterocycles (such as pyrrolines, oxazolines, etc.).6
tion showed that DMEDA was the best choice in the trans-
formation, affording the desired product 3a in 81% yield
In the transformations, an intermediate a-cuprioisocyanide
(Table 1, entry 5). A trace amount of the targeted product
could be easily generated by activation of the C–H bond of
was observed in a control experiment without the addition of
example, Yamamoto and co-workers6h developed a copper-
ligand (Table 1, entry 6). Different bases and solvents were
isocyanoacetate in the presence of a copper catalyst. For
screened subsequently (Table 1, entries 7–15). It was found
catalyzed reaction of electron-deficient alkynes and isocyano-
that the reaction worked most efficiently in toluene when
acetates to construct multi-substituted pyrrolines with high
K3PO4 was employed as the base (Table 1, entry 8). The
efficiency and regioselectivity. On the other hand, great progress
has been achieved in copper-catalyzed cross-coupling reactions.7
effects of copper catalysts were also considered. Lower yields
were obtained when copper(I) bromide, copper(I) chloride, or
copper(II) oxide was employed as the copper source (Table 1,
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
entries 16–18). Reducing the catalyst loading to 5 mol%
resulted in an inferior yield (Table 1, entry 19). No better
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
result was obtained when the reaction was performed at 80 1C
(54% yield, Table 1, entry 20).
With the optimal conditions in hand (10 mol% of CuI,
20 mol% of DMEDA, K3PO4, toluene, reflux), we then
explored the generality and scope of the reactions of
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of com-
pounds 3–5. See DOI: 10.1039/c2cc32135a
c
6046 Chem. Commun., 2012, 48, 6046–6048
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Table 1 Initial studies for the copper-catalyzed reaction of carbodiimide
1a with isocyanide 2aa
Table 2 Generation of benzoimidazo[1,5-a]imidazoles 3 via a copper-
catalyzed tandem reaction of carbodiimide 1 and isocyanoacetate 2a
Entry
[Pd]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuO
CuI
CuI
CuI
CuI
L-Proline
1,10-Phen
Acac
TMEDA
DMEDA
/
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaHCO3
K3PO4
K2CO3
tBuONa
tBuOK
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Dioxane
MeCN
DCE
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
34
48
Complex
63
81
Trace
65
88
71
Complex
Complex
65
Trace
69
Complex
76
59
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
9
10
11
12
13
14
15
16
17
18
19c
20d
21e
22f
34
62
54
71
83
Acac: pentane-2,4-dione, TMEDA: N1,N1,N2,N2-tetramethylethane-
a
1,2-diamine, DMEDA: N1,N2-dimethylethane-1,2-diamine. Reaction
conditions: carbodiimide 1a (0.5 mmol), isocyanide 2a (1.2 equiv.),
copper catalyst (10 mol%), ligand (20 mol%), base (2.0 equiv.), reflux.
b
c
Isolated yield based on carbodiimide 1a. In the presence of CuI
d
e
(5 mol%). The reaction was performed at 80 1C. In the presence of
1.2 equiv. of K3PO4. In the presence of 3.0 equiv. of K3PO4.
f
a
Isolated yield based on carbodiimide 1
carbodiimides and isocyanoacetates. The results are presented
in Table 2. A range of benzoimidazo[1,5-a]imidazoles 3 was
obtained in moderate to good yields. Various isocyanoacetates
were demonstrated to be good partners in the transformation.
For instance, carbodiimide 1a reacted with tert-butyl isocyano-
acetate 2c leading to the corresponding product 3c in 73%
yield. However, a lower yield was obtained when 1-(isocyano-
methylsulfonyl)-4-methylbenzene 2d was used as a reactant
with carbodiimide 1a (3d, 40% yield). It might be the presence
of the sulfonyl group in the isocyanide which affected the
outcome. The influence of the substituents on the aromatic
ring of carbodiimides (1a–1g) was also examined, and all
reactions worked well to afford the expected products 3. For
instance, carbodiimide 1b reacted with isocyanoacetate 2b
leading to the desired product 3f in 92% yield. When an
unsymmetrical carbodiimide 1d was employed in the reaction,
a mixture of two products 3i–3i0 in a 2/1 ratio was obtained.
We noticed that the presence of the iodo group in the
carbodiimide 1 might have affected the transformation. The
yields were moderate when carbodiimides 1e–1g reacted with
isocyanoacetate 2. A trace amount of product 3n was detected
when a carbodiimide with an alkyl group attached was used,
which might be due to the lower reactivity of the substrate.
Additionally, a large-scale reaction (5 mmol) of carbodiimide
1a with methyl isocyanoacetate 2b was performed, which gave
rise to the desired product 3b in 75% isolated yield (data not
shown in Table 2).
With iodo-containing benzoimidazo[1,5-a]imidazoles 3 in
hand, we envisaged that more diversity could be introduced
in the molecules. Thus, Suzuki–Miyaura and Sonogashira
cross-coupling reactions were explored (Scheme 2). As expected,
the reactions proceeded smoothly to afford the corresponding
products 4 and 5 in good yields, respectively.
A plausible mechanism for this copper-catalyzed tandem
reaction of carbodiimides 1 and isocyanoacetates 2 is illustrated
in Scheme 3. We conceived that activation of the C–H bond of
Scheme 2 Suzuki–Miyaura and Sonogashira cross-coupling reactions
of benzoimidazo[1,5-a]imidazoles 3b.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6046–6048 6047

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D. M. Kowal, A. H. Katz, J. A. Moyer and M. Abou-Gharbia,
J. Med. Chem., 2001, 44, 1516; (b) J. VelIk, V. Baliharova, J. Fink-
Gremmels, S. Bull, J. Lamka and L. Skalova, Res. Vet. Sci., 2004,
76, 95, and references therein.
3 For recent selected examples, see: (a) M. R. Ibrahim, T. F. Al-Azemi,
A. Al-Atabo, O. M. E. Ei-Dusoqui and N. A. Al-Awadi, Tetrahedron,
2010, 66, 4243; (b) P. Mlina, M. Alajari, C. Lopez-Leonardo, I. Madrid
and C. Foces-foces, Tetrahedron, 1989, 45, 1823.
4 For recent selected examples, see: (a) S. Li and J. Wu, Org. Lett.,
2011, 13, 712; (b) Z. Chen, D. Zheng and J. Wu, Org. Lett., 2011,
13, 848; (c) H. Ren, Y. Luo, S. Ye and J. Wu, Org. Lett., 2011,
13, 2552; (d) G. Qiu, G. Liu, S. Pu and J. Wu, Chem. Commun.,
2012, 48, 2903; (e) S. Ye, G. Liu, S. Pu and J. Wu, Org. Lett., 2012,
14, 70.
5 For recent selected examples, see: (a) C. Saluste, R. Whitby and
M. Furber, Angew. Chem., Int. Ed., 2000, 39, 4156;
(b) K. Komeyama, D. Sasayama, T. Kawabata, K. Takehira and
K. Takaki, Chem. Commun., 2005, 634; (c) M. Tobisu, A. Kitajima,
S. Yoshioka, I. Hyodo, M. Oshita and N. Chatani, J. Am. Chem.
Soc., 2007, 129, 11431; (d) H. Kuniyasu, K. Sugoh, M. Su and
H. Kurosawa, J. Am. Chem. Soc., 1997, 119, 4669; (e) Y. Wang,
H. Wang, J. Peng and Q. Zhu, Org. Lett., 2011, 13, 4604; (f) C. Zhu,
W. Xie and J. Falck, Chem.–Eur. J., 2011, 17, 12591;
Scheme 3 A plausible mechanism for the copper-catalyzed tandem
reaction of carbodiimides 1 and isocyanoacetates 2.
isocyanide 1 in the presence of copper(I) iodide would occur to
generate the intermediate a-cuprioisocyanide A or its tautomer
A0, which would trigger the catalytic cycle. A formal [3+2]
cycloaddition would then take place to produce an intermediate
B or its tautomer B0. Protonation of the C–Cu bond of the
intermediate B or its tautomer B0 by isocyanoacetates 1 would
afford the compound C with regeneration of the copper-
intermediate A or A0. The subsequent copper-catalyzed intra-
molecular C–N coupling reaction would furnish the desired
product 3.
(g) G. V. Baelen, S. Kuijer, L. Ry´ cek, S. Sergeyev, E. Janssen,
F. J. J. de Kanter, B. U. W. Maes, E. Ruijter and R. V. A. Orru,
Chem.–Eur. J., 2011, 17, 15039; (h) T. Vlaar, E. Ruijter, A. Znabet,
E. Janssen, F. J. J. de Kanter, B. U. W. Maes and R. V. A. Orru,
Org. Lett., 2011, 13, 6496; (i) G. Qiu, G. Liu, S. Pu and J. Wu,
Chem. Commun., 2012, 48, 2903; (j) G. Qiu, Y. He and J. Wu,
Chem. Commun., 2012, 48, 3836; (k) F. De Moliner and C. Hulme,
Org. Lett., 2012, 14, 1354; (l) T. Soeta, K. Tamura and Y. Ukaji,
Org. Lett., 2012, 14, 1226; (m) J. Peng, L. Liu, Z. Hu, J. Huang and
Q. Zhu, Chem. Commun., 2012, 48, 3772.
6 For recent selected examples, see: (a) U. Schollkopf, Angew. Chem.,
¨
Int. Ed., 2000, 39, 3168; (c) A. Domling, Chem. Rev., 2006, 106, 17;
¨
Int. Ed., 1977, 16, 339; (b) A. Domling and I. Ugi, Angew. Chem.,
In conclusion, we have developed a copper-catalyzed tandem
[3+2] cycloaddition–C–N coupling of carbodiimides and iso-
cyanoacetates, leading to benzoimidazo[1,5-a]imidazoles in
good yields. The resulting iodo-containing benzoimidazo[1,5-a]-
imidazoles could be further decorated via a palladium-catalyzed
cross-coupling reaction. Currently, studies involving isocyanide
chemistry for the generation of other N-heterocycles are
ongoing in our laboratory.
¨
(d) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and
V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235; (e) A. V. Lygin,
O. V. Larionov, V. S. Korotkov and A. de Meijere, Chem.–Eur. J.,
2009, 15, 227; (f) C. Kanazawa, S. Kamijo and Y. Yamamoto,
J. Am. Chem. Soc., 2006, 128, 10662; (g) O. V. Larionov and
A. de Meijere, Angew. Chem., Int. Ed., 2005, 44, 5664;
(h) S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem.
Soc., 2005, 127, 9260; (i) H. Takaya, S. Kojima and S. Murahashi,
Org. Lett., 2001, 3, 421; (j) M.-A. Bonin, D. Giguere and R. Roy,
Tetrahedron, 2007, 63, 4912; (k) D. Benito-Garagorri, V. Bocokiae
and K. Kirchner, Tetrahedron Lett., 2006, 47, 8641; (l) Y. Ito,
T. Matsurra and T. Saegusa, Tetrahedron Lett., 1985, 26, 5781;
(m) D. Zheng, S. Li, Y. Luo and J. Wu, Org. Lett., 2011, 13, 6402;
(n) Q. Cai, Z. Tao, T. Xu, L. Fu and K. Ding, Org. Lett., 2011,
13, 340.
Financial support from the National Natural Science
Foundation of China (No. 21032007 and 21172038) is gratefully
acknowledged.
Notes and references
1 Recent reviews for the synthesis of heterocycles: (a) A. Armstrong
and J. C. Collins, Angew. Chem., Int. Ed., 2010, 49, 2282;
(b) A. R. Katritzky and S. Rachwal, Chem. Rev., 2010, 110, 1564;
(c) M. A. P. Martins, C. P. Frizzo, D. N. Moreira, L. Buriol and
P. Machado, Chem. Rev., 2009, 109, 4140; (d) M. Alvarez-Corral,
M. Munoz-Dorado and I. Rodrıguez-Garcıa, Chem. Rev., 2008,
108, 3174; (e) A. Minatti and K. Muniz, Chem. Soc. Rev., 2007,
36, 1142; (f) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644;
(g) E. Ruijter, R. Scheffelaar and R. V. A. Orru, Angew. Chem.,
Int. Ed., 2011, 50, 6234.
7 For recent reviews on copper-catalyzed cross-couplings, see:
(a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003,
42, 5400; (c) G. Evano, N. Blanchard and M. Toumi, Chem. Rev.,
2008, 108, 3054; (d) F. Monnier and M. Taillefer, Angew. Chem.,
Int. Ed., 2009, 48, 6954; (e) D. Ma and Q. Cai, Acc. Chem. Soc.,
2008, 41, 1450.
8 (a) F. Zeng and H. Alper, Org. Lett., 2010, 12, 1188; (b) B. Roberts,
D. Liptrot, T. Luker, M. J. Stocks, C. Barber, N. Webb, R. Dods
and B. Martin, Tetrahedron Lett., 2011, 52, 3793; (c) L. Xin and
W. Bao, J. Org. Chem., 2009, 74, 5618; (d) G. Shen and W. Bao,
Adv. Synth. Catal., 2010, 352, 981; (e) F. Zeng and H. Alper, Org.
Lett., 2010, 12, 3642.
2 For recent selected example, see: (a) R. B. Baudy, H. Fletcher III,
J. P. Yardley, M. M. Zaleska, D. R. Bramlett, R. P. Tasse,
c
6048 Chem. Commun., 2012, 48, 6046–6048
This journal is The Royal Society of Chemistry 2012