Copper-catalyzed tandem reactions of 1-(2-iodoary)-2-yn-1-ones with isocyanides for the synthesis of 4-oxo-indeno[1,2-b ]pyrroles

Article abstract of DOI:10.1021/ol102826f

A novel copper-catalyzed tandem reaction of 1-(2-iodoaryl)-2-yn-1-ones with isocyanides is described. The reaction is through a formal [3 + 2] cycloaddition/coupling tandem process and leads to efficient formation of 4-oxo-indeno[1,2-b]pyrroles.

Full text of DOI:10.1021/ol102826f

ORGANIC
LETTERS
2011
Vol. 13, No. 2
340-343
Copper-Catalyzed Tandem Reactions of
1-(2-Iodoary)-2-yn-1-ones with
Isocyanides for the Synthesis of
4-Oxo-indeno[1,2-b]pyrroles
Qian Cai,* Fengtao Zhou, Tianfeng Xu, Liangbing Fu, and Ke Ding*
Key Laboratory of RegeneratiVe Biology and Institue of Chemical Bioology,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
No. 190 Kaiyuan AVenue, Guangzhou Science Park, Guangzhou, 510530, China
cai_qian@gibh.ac.cn; ding_ke@gibh.ac.cn
Received November 22, 2010
ABSTRACT
A novel copper-catalyzed tandem reaction of 1-(2-iodoaryl)-2-yn-1-ones with isocyanides is described. The reaction is through a formal [3 +
2] cycloaddition/coupling tandem process and leads to efficient formation of 4-oxo-indeno[1,2-b]pyrroles.
A large demand exists in drug discovery and other types of
research programs for novel, structurally diverse molecules.
This demand continues to stimulate the development of
conceptually innovative synthetic strategies. Tandem or
multicomponent reactions of isocyanides,1 which form
multiple bonds in a one-pot manner, have remarkable
versatility in producing structurally appealing heterocycles.
Since the time of the initial discoveries by Scho¨llkopf and
Gerhart about 40 years ago,2 R-metalated isocyanides have
been observed to participate in various types of cycloaddition
reactions that lead to a diverse array of nitrogen-hetero-
cycles.3 Recently, great progress has been made in the use
of transition-metal-catalyzed reactions of isocyanides.4,5 The
transition-metal-catalyzed cycloaddition reactions of isocya-
nides with double or trible bonds were proposed to go
through a formal [3 + 2] process involving organometal
intermediates, which are highly active and undergo rapid
protonation to form the stable cyclized products, such as
pyrrolines, oxazolines, etc.3-6 One example was indepen-
dently reported by de Meijere et al.5e and Yamamoto et
al.:5f oligosubstituted pyrroles can be readily prepared by
using copper-catalyzed cycloaddtion reactions of isocyanides
with electron-deficient alkynes. A cyclized organocopper
intermediate was proposed to be invloved in these reactions.
However, no further work extensions of these highly active
organometal intermediates were reported. Perhaps this is
(4) For representative examples of transition metal-catalyzed reaction
of isocyanides, see: (a) Takaya, H.; Kojima, S.; Murahashi, S. Org. Lett.
2001, 3, 421. [Rh](b) Motoyama, Y.; Kawakami, H.; Shimozono, K.; Aoki,
K.; Nishiyama, H. Organometallic 2002, 21, 3408. [Pt, Rh](c) Ito, Y.;
Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. [Au](d)
Sawamura, M.; Hamashima, H.; Ito, Y. J. Org. Chem. 1990, 55, 5935. [Ag]
.
(5) For representative copper-catalyzed reaction of isocyanides, see: (a)
Lygin, A. V.; Larionov, O. V.; Korotkov, V. S.; de Meijere, A. Chem.sEur.
J. 2009, 15, 227. (b) Bonin, M.-A.; Gigue`re, D.; Roy, R. Tetrahedron 2007,
63, 4912. (c) Kanazawa, C.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc.
2006, 128, 10662. (d) Benito-Garagorri, D.; Bocokiae, V.; Kirchner, K.
Tetrahedron Lett. 2006, 47, 8641. (e) Larionov, O. V.; de Meijere, A. Angew.
Chem., Int. Ed. 2005, 44, 5664. (f) Kamijo, S.; Kanazawa, C.; Yamamoto,
Y. J. Am. Chem. Soc. 2005, 127, 9260. (g) Ito, Y.; Matsurra, T.; Saegusa,
T. Tetrahedron Lett. 1985, 26, 5781. (h) Saegusa, T.; Ito, Y.; Kinoshita,
(1) For comprehensive reviews, see: (a) Marcaccini, S.; Torroba, T. Org.
Prep. Proced. Int. 1993, 25, 141. (b) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168. (c) Do¨mling, A. Chem. ReV. 2006, 106, 17.
(2) Scho¨llkopf, U.; Gerhart, F. Angew. Chem., Int. Ed. 1968, 7, 805.
(3) For a review, see: Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.;
Nenajdenko, V. G. Chem. ReV. 2010, 110, 5235.
H.; Tomita, S. J. Org. Chem. 1971, 36, 3316
.
(6) Scho¨llkopf, U. Angew. Chem., Int. Ed. 1977, 16, 339
.
10.1021/ol102826f  2011 American Chemical Society
Published on Web 12/17/2010

because the organometal intermediate is too active to be
available long enough for further transformation.
Table 1. Synthesis of Ethyl 3-(Cyclohexylmethyl)-4-oxo-1,
4-dihydroindeno[1,2-b]pyrrole-2-carboxylate 3a by Using the
Copper-Catalyzed Tandem Reactiona
In the past decade, copper-catalyzed coupling reactions7
have come into a renaissance. However, copper-catalyzed
aryl C-C formation reactions are still great chanllenges and
the reaction scope is relatively limited. Novel aryl C-C bond
formation reactions are highly attractive in copper-catalyzed
coupling chemistry. In conjunction with our continuing
interest in the area of copper-catalyzed coupling chemistry,8
we realized that the organocopper intermediate produced in
isocyanide chemistry may also act as some kind of active
substrate for further aryl C-C coupling.9 Below, we describe
the results of an effort aimed at exploring and developing a
novel copper-catalyzed tandem reaction based on this
hypothesis, which demonstrates that the process comprises
a facile method for the synthesis of 4-oxo-indeno[1,2-
b]pyrrole derivatives (Scheme 1).10
yieldb
entry catalyst
1
base
solvent
t (°C) 3a%
4a%
n.d.c 81d
n.d.c 15d
Cs2CO3
-
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
90
100
r.t.
60
90
90
90
90
90
90
90
90
2
CuI
CuI
CuI
CuI
CuBr
Cu2O
CuI
CuI
CuI
CuI
CuI
3
4
5
6
62
76
93
76
35
20
trace
19
Cs2CO3 DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaOH
DMF
DMF
Dioxane
MeCN
DMSO
DMF
7
8
9
n.d.c 40
n.d.c 90
n.d.c 89
Scheme 1. Design of Copper-Catalzyed Tandem Reaction
through Rapid Intramolecular Capture of Highly Active
Organocopper Intermediate
10
11
12
77
20
34
15
75
28
DMF
a 1a (0.55 mmol, 1.1 equiv), 2a (0.5 mmol, 1.0 equiv), catalyst (10 mol
%), base, (1.0 mmol, 2.0 equiv), solvent (1 mL), 10 min. b Isolated yields.
c No desired product was detected. d 2-6 h.
obtained in DMF at room temperature, accompanied by
35% of protonolysis byproduct 4a (Table 1, entry 3).
Although the selectivity was low, however, it confirmed
our assumption that the proposed highly active organo-
copper intermediate can be rapidly captured through an
intramolecular aryl C-C coupling reaction, which greatly
inspired us for further studies. In order to increase the
selectivity of insertion to the aryl C-I bond, further
screenings of reaction conditions were performed, which
revealed that the combination of CuI, Cs2CO3, and DMF
is the best choice for the tandem reaction and the reaction
temperature played a critical role in the selectivity (Table
1, entry 5). We found that a higher temperature can greatly
increase the ratio of coupling product 3a, which can reach
73% at 60 °C and 93% at 90 °C, with only a trace amount
of byproduct 4a being detected. The use of other Cu(I)
sources or organic solvents led to lower yields and/or
poorer 3a:4a selectivity (Table 1, entries 6-12).
An exploratory study evaluating the scope of the new
methodology provided the results displayed in Table 2.
The observations show that in most cases the desired
4-oxo-indeno[1,2-b]pyrrole products 3 are produced in
good to excellent yields when using 1-(2-iodoaryl)ynones
as substrates.11 Alkyl and functionalized alkyl substituents
on the alkyne moieties of the alkynylketones 2 were well
tolerated, and the reactions selectively formed the desired
tandem products 3 in excellent yields. However, when aryl
groups are present on the alkyne carbons of 2, the
processes take place in only moderate yields (Table 2,
The investigation was initiated by exploring the copper-
catalyzed reaction of ethyl isocyanoacetate 1a with
4-cyclohexyl-1-(2-iodophenyl)but-2-yn-1-one 2a. No de-
sired coupling product 4-oxo-indeno[1,2-b]pyrrole 3a was
detected in the absence of either a necessary base or
copper catalyst, and the only product was the protonated
pyrrole 4a (Table 1, entries 1 and 2). However, with the
assistance of Cs2CO3, the reaction was completed in
several minutes and 62% of the desired product 3a was
(7) For recent reviews about copper-catalyzed coupling reactions, see:
(a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
(c) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054. (d)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (e) Ma,
D.; Cai, Q. Acc. Chem. Soc. 2008, 41, 1450.
(8) (a) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K. Org.
Lett. 2010, 12, 1500. (b) Li, Z.; Fu, L.; Wei, J.; Ha, C.; Pei, D.; Cai, Q.;
Ding, K. Synthesis 2010, 3289. (c) Cai, Q.; Li, Z.; Wei, J.; Ha, C.; Pei, D.;
Ding, K. Chem. Commun. 2009, 7581.
(9) In the reaction of o-iodophenols with ethyl propiolate, an intermediate
cupriated benzofuran was proposed to go through intermolecular coupling
with additional o-iodophenol in the presence of an excess of copper(I) tert-
butoxide, and the product lactonized to isocoumestan. See: Haglund, O.;
Nilsson, M. Synlett. 1991, 723.
(10) For some examples of syntheses of indeno[1,2-b]pyrrole systems,
see: (a) Lash, T. D.; Quizon-Colquitt, D. M.; Shiner, C. M.; Nguyen, T. H.;
Hu, Z. Energy Fuels 1993, 7, 172. (b) Chatterjie, N.; Shapiro, R.; Quo,
S.-G.; Stephani, R. A. Tetrahedron Lett. 1975, 30, 2535. (c) Azizian, J.;
Hatamjafari, F.; Karimi, A. R.; Shaabanzadeh, M. Synthesis 2006, 5, 765.
(d) Wollweber, H.-J.; Wentrup, C. J. Org. Chem. 1985, 50, 2041. (e) Bo¨s,
M.; Jenck, F.; Martin, J. R.; Moreau, J.-L.; Sleight, A. J.; Wichmann, J.;
Widmer, U. J. Med. Chem. 1997, 40, 2762.
(11) Poor results were obtained (25-30% yields) when 1-(2-bromophe-
nyl)ynones were used as substrates.
Org. Lett., Vol. 13, No. 2, 2011
341

Table 2. Investigation of the Scope of Reactions of 1-(2-Iodoaryl)-2-yne-1-ones 2 with Isocyanides 1 Leading to Formation of
4-Oxo-indeno[1,2-b]pyrroles 3a
a For entries 1-14, ethyl isocyanoacetate 1a wa used; for entry 15, tert-butyl isocyanoacetate 1b was used; for entries 16-18, TOSMIC 1c was used;
for entries 19-20, diethyl isocyanomethylphosphonate 1d was used. b Isolated yields. c For 1-(2-bromophenyl)-2-yn-1-ones, about 25-30% yields of coupling
products 3b and 3c were isolated. d About 20-30% of corresponding uncoupling byproducts were isolated.
3f-3h), and about 30% of the protonated byproducts were
isolated. The results also show that the electronic proper-
ties of the 1-(2-iodophenyl) ring have little effect on the
reaction. Specifically, reactions of 1-(2-iodoaryl)but-2-yn-
1-ones 2, containing both electron-donating and -with-
drawing substituents (e.g., cyano, alkoxycarbonyl, nitro,
halo, alkyl, and alkoxyl) on the iodophenyl ring, occur
smoothly to produce the corresponding products 3i-3o
in good yields. Furthermore, other isocyanides (e.g., tert-
butyl isocyanoacetate, tosylmethyl isocyanide, and diethyl
isocyanomethylphosphonate) also participate in tandem
reactions with a variety of 1-(2-iodoaryl)-2-yne-1-ones to
produce the corresponding products 3n-3p in moderate
to good yields.
Based on the experimental observations and literature
precedent, the plausible mechanism for the cascade process
342
Org. Lett., Vol. 13, No. 2, 2011

shown in Figure 1 is proposed. In this pathway, reaction of
the isocyanide with CuI in the presence of base forms the
Scheme 2
.
Failure of Attempt for Intermolecular Capture of
Organocopper Intermediate
Figure 1. A plausible mechanism for the copper-catalyzed tandem
reaction.
under the reaction conditions and did not proceed in the
intermolecular C-C coupling reactions.
In summary, the investigation described here is a success-
ful example of the rapid intramolecular capture of a highly
active organocopper intermediate produced in the formal [3
+ 2] cycloaddition of isocyanides to ynones, which lead to
the formation of an intramolecular aryl C-C bond. This
reaction also represents a new type of copper-catalyzed
tandem reaction, which offered a simple and efficient method
for the synthesis of 4-oxo-indeno[1,2-b]pyrroles. The process
takes place efficiently when a variety of 1-(2-iodoaryl)-2-
yne-1-ones are used, and it displays a wide functional group
compatibility. Further studies and applications of this
methodology are currently underway in our laboratory.
cuprioisocyanide A or its tautomer A′. This intermediate
reacts through a formal [3 + 2] cycloaddition process with
the 1-(2-iodoaryl)ynones to generate the organocopper
intermediate B which is then transformed to intermediates
C by intramolecular insertion of Cu into the aryl C-I bond.
The pyrrole byproducts are produced by competitive proto-
nolysis of B.12 Intermediate D along with A or A′ are then
generated from C to end the catalytic cycle. Finally, 4-oxo-
indeno[1,2-b]pyrroles are produced by tautomerization.
Although we successfully captured the proposed organo-
copper intermediate intramolecularly, our attempt for inter-
molecular capture failed. As shown in Scheme 2, by adding
a large excess of 4-iodoanisole (10 equiv) into the copper-
catalyzed reaction of ethyl isocyanoacetate with 1,3-diphe-
nylprop-2-yn-1-one, no corresponding intermolecular C-C
coupling product 5 was detected after 24 h at 90 °C. The
products isolated were protonated product 6 and N-arylated
product 7. We thought the reason for this is that the copper-
catalyzed intermolecular C-C coupling is much slower when
compared with intramolecular C-C coupling, while the
proposed organocopper intermediate was quickly protonated
Acknowledgment. The authors are grateful to The Knowl-
edge Innovation Program of the Chinese Academy of
Sciences, National Natural Science Foundation (Grant
21002102), and State Key Laboratory of Bioorganic and
Natural Products Chemistry, Shanghai Institute of Organic
Chemistry (Grant 10184), Chinese Academy of Sciences for
their financial support.
Supporting Information Available: Full experimental
procedures, characterization data for all the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) The pyrrole byproducts cannot be transformed into 4-oxo-in-
deno[1,2-b]pyrroles under the copper-catalyzed reaction conditions. This
observation indicates that formation of the highly reactive organocopper
intermediate is required in order for the tandem process to take place.
OL102826F
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