Synthesis of Functionalized Chromeno[2,3-b]pyrrol-4(1H)-ones by Silver-Catalyzed Cascade Reactions of Chromones/Thiochromones and Isocyanoacetates

Article abstract of DOI:10.1021/acs.orglett.5b02795

A novel and convenient approach to the synthesis of chromeno[2,3-b]pyrrol-4(1H)-ones has been developed. Furthermore, the method involves a facile silver-catalyzed cascade cyclization reaction including an intramolecular C-O bond formation. The silver sal

Full text of DOI:10.1021/acs.orglett.5b02795

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Chromeno[2,3‑b]pyrrol-4(1H)‑ones by
Silver-Catalyzed Cascade Reactions of Chromones/Thiochromones
and Isocyanoacetates
Xueyu Qi, Haoyue Xiang, and Chunhao Yang*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai, 201203, China
*
S Supporting Information
ABSTRACT: A novel and convenient approach to the
synthesis of chromeno[2,3-b]pyrrol-4(1H)-ones has been
developed. Furthermore, the method involves a facile silver-
catalyzed cascade cyclization reaction including an intra-
molecular C−O bond formation. The silver salt acts as a key
promoter.
n the past decades, structurally complex and functionally
diverse heterocycles have made a great contribution to
discovering lead compounds which play important roles in
developing new pharmaceutical agents. The benzopyranopyr-
role structure was first reported as a core structure of TAN-
field of synthetic application and reaction diversity, which5
makes them highly attractive objects for investigation.
However, the cycloaddition of isocyanides always met with
challenges, including the easy dimerization of isocyanides to
produce imidazoles in the presence of a base or transition-metal
I
6
8
76A isolated from a Streptomyces sp. by a group from the
catalyst. Moreover, only a few methods that could make a
1
Takeda Company. Subsequently this unique structure was
found in pyralomicins which were a set of antibiotics isolated
from the soil bacterium Nonomuraea spiralis by Takeuchi and
transition metal coordinate to the isocyano group and activate
isocyanides in some cycloaddition reactions are known so far,
while transition-metal-catalyzed cascade cyclization reactions
2
7
co-workers in 1996 (Scheme 1). Surprisingly, few synthetic
gained little attention. Thus, we focused our attention on the
metal-catalyzed cascade reaction of isocyanoacetate.
In an earlier study, our group was devoted to the
Scheme 1. Chemical Structures of the Pyralomicins and
Other Related Compound
development of new synthetic pathways for constructing
8
heterocyclic scaffolds. In addition, chromones are a class of
greatly useful and versatile starting materials for constructing
9
various heterocycles. On the basis of these efforts, we
envisioned that 3-iodochromone 2a, containing the superior
iodine leaving group, would react with ethyl isocyanoacetate 1a
in the presence of silver salts and bases to form the ethyl 4-(2-
hydroxybenzoyl)-5-iodo-2H-pyrrole-2-carboxylate 3a which
would be easily converted to ethyl 4-oxo-1,4-dihydrochromeno-
[
2,3-b]pyrrole-2-carboxylate 4a via a cascade silver-catalyed C−
O bond-forming cyclization process (Scheme 2).
To our delight, we observed that the silver-catalyzed cascade
cyclization reaction between ethyl isocyanoacetate 1a and 3-
iodochromones 2a produced chromeno[2,3-b]pyrrol-4(1H)-
one 4a in good yields. Notably, in this reaction, only a few
approaches to obtain the benzopyranopyrrole scaffold or its
analogues have been reported. Therefore, it is desirable to
continue to devote efforts to developing new synthetic
methodologies, which is considered a challenging task in
organic synthesis.
3
Scheme 2. Outline of the Synthesis of Benzopyranopyrrole
Cascade reactions involving multiple-bond forming events in
a single pot are a means to achieve green chemistry and a way
to develop economical processes for the manufacture of
4
pharmaceuticals and other organic structures. Moreover,
cascade reactions, being artistically appealing, are often
associated with cost savings in terms of reagents, catalysts,
and solvents, as well as time and effort. In recent years,
isocyanoacetate derivatives occupy an important place in the
Received: September 25, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02795
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Organic Letters
Letter
,
ab
byproducts resulting from dimerization of isocyanides were
observed. Inspired by this finding, we continued optimizing the
reaction conditions (Table 1). A variety of silver salts were
Scheme 3. Scope of the Cascade Reaction of 1 with 2
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat. (equiv)
temp (°C)
solvent
base
yield (%)
1
2
3
4
Ag CO (0.2)
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
140
60
DMSO
DMSO
DMSO
DMSO
NMP
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
K CO
62
2
3
2
3
3
3
3
3
3
3
3
3
AgNO (0.2)
K CO
2
63
3
Ag O (0.2)
2
K CO
2
70
AgOAc (0.2)
K CO
2
66
c
5
−
K CO
2
0
6
7
8
9
Ag O (0.2)
2
K CO
2
66
Ag O (0.2)
2
K CO
2
79
Ag O (0.1)
2
K CO
2
55
Ag O (1.0)
2
K CO
2
52
10
11
12
13
14
15
16
17
18
Ag O (0.2)
2
KOtBu
trace
54
Ag O (0.2)
2
Cs CO
2
3
Ag O (0.2)
2
KOAc
DBU
35
Ag O (0.2)
2
trace
74
d
e
e
e
e
Ag O (0.2)
2
K CO
2
3
3
3
3
3
Ag O (0.2)
2
K CO
2
87
Ag O (0.2)
2
K CO
2
60
Ag O (0.2)
2
K CO
2
trace
63
Ag O (0.2)
2
100
K CO
2
a
Reaction condition: 1a (0.6 mmol, 1.5 equiv), 2a (0.4 mmol, 1.0
a
Reaction condition: 1a (0.6 mmol, 1.5 equiv), 2a (0.4 mmol, 1.0
equiv), base (1.5 equiv), and silver salts (20 mol %) in solvent (2.0
equiv), K CO (0.8 mmol 2.0 equiv), and Ag O (20 mol %) NMP (2.0
mL) at 130 °C for 1 h under air. Isolated yields. The procedure was
scaled up to 4 mmol.
2
3
2
b
c
b
c
mL) under air. Isolated yields. The reaction was carried out without
silver salt. 1.0 equiv of base was used. 2.0 equiv of base were used.
d
e
on the chromone ring had a profound effect on the efficiency of
the silver-catalyzed annulation reaction. For example, as we
changed the substituents at C-6 of 3-iodochromone from fluoro
to bromo groups, the yields of corresponding products were
gradually reduced (4g−4i, Scheme 3). Meanwhile, the presence
of an electron-withdrawing fluoro group at the C-7 position of
the chromone ring system delivered the corresponding product
in diminished yield (4m, Scheme 3). In addition, chromone
with multisubstituents were compatible with the reaction
process as well, providing the corresponding products in
good yields (4n, 4o, Scheme 3). The aryl-substituted
compound 1p was found to be a suitable substrate. On the
basis of these results, we extended the reaction scope to
thiochromones. However, the thiochromones had an obvious
impact on the efficiency of this reaction for uncertain reasons
(4q, 4r, Scheme 3). Perhaps it weakened the stability of the
intermediate during the cyclization process. However, both 3-
iodoquinolin-4(1H)-one and 3-iodo-1-methylquinolin-4(1H)-
one failed to give promising results under the present
conditions. Besides, we also tried other isocyanides with an
electron-withdrawing group such as methyl 2-isocyanoacetate,
tosylmethyl isocyanide, and diethyl isocyanomethyl-
phosphonate. The methyl 2-isocyanoacetate 1s could react
satisfactorily and gave the product in a good yield (4s, Scheme
3). Tosylmethyl isocyanide 2t could be tolerated to access the
benzopyranopyrrole derivative (4t, Scheme 3). However, when
diethyl isocyanomethylphosphonate was used under the
optimal conditions, it failed to give the desired compound.
To highlight the efficiency and practicability of the strategy, we
initially examined for the reaction of ethyl isocyanoacetate 1a
and 3-iodochromone 2a in the presence of K CO (1.5 equiv)
2
3
in DMSO at 130 °C for 1 h, and Ag O provided the best result
2
(
entries 1−4, Table 1). It was noteworthy that the reaction
would not occur in the absence of silver salts (entry 5, Table 1).
Afterward some solvents were screened such as dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N-
methyl-2-pyrrolidone (NMP), while NMP gave the product in
a higher yield (entry 7 vs 3/6, Table 1). Increasing or
decreasing the amount of Ag O resulted in a reduced yield
2
(
entry 3 vs 8/9, Table 1). Moreover the effect of the base was
also investigated. When strong bases were employed for this
conversion, 4a could not be generated (entries 10 and 13,
Table 1). The screened results led to the identification of
K CO as the optimal base (entries 7, 10−13, Table 1). Further
2
3
studies showed that increasing the amount of K CO (2.0
2
3
equiv) obtained a comparably higher yield (entries 7, 14, 15,
Table 1). Finally the investigation of reaction temperature
indicated that the optimal temperature was 130 °C (entries
1
5−18, Table 1). Thus, the optimal reaction conditions were
determined, including Ag O (0.2 equiv), K CO (2.0 equiv) in
2
2
3
NMP (2.0 mL) at 130 °C for 1 h.
With the optimal reaction conditions in hand, the scope of
substrates for this new reaction was then examined (Scheme 3).
The results showed that 3-iodochromones bearing electron-
donating substituents on the aromatic rings gave the
corresponding products in good to excellent yields (4b−4f,
4j−4l, Scheme 3). However, the electron-withdrawing groups
B
DOI: 10.1021/acs.orglett.5b02795
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Letter
successfully scaled up the procedure to 4 mmol and obtained
Scheme 5. Plausible Reaction Mechanism
8
40 mg of 4a after 1 h in 82% isolated yield (Scheme 3).
Additionally, the structure of 4a was unambiguously confirmed
by X-ray crystallographic analysis (Figure 1).
10
Figure 1. X-ray crystal structure of 4a.
To gain insight into the mechanism of this cascade reaction, a
series of controlled experiments were performed. First, ethyl
isocyanoacetate 1a and 3-iodochromones 2b produced a
complicated mixture through a highly inefficient process
without silver salts (Scheme 4, eq 1). Under standard
Scheme 4. Mechanism Investigations
7b
reaction. Subsequently, the cycloaddition between complex A
and 2a could afford the key intermediate complex C through a
Michael addition reaction. Then intermediate D along with A
are generated from C to end the catalytic cycle. Based on the
12
literature precedent, we know that acyl chlorides reacting with
isocyanides can afford the corresponding α-addition products,
the acyl imidoyl chlorides. Thus, an insertion reaction of
isocyanide to the C−I bond might occur giving the complex E.
Next the complex E experienced a subsequent 1,5-hydrogen
shift to generate intermediate 3a. Finally ethyl 4-(2-hydroxy-
benzoyl)-5-iodo-2H-pyrrole-2-carboxylate 3a could be easily
converted to ethyl 4-oxo-1,4-dihydrochromeno[2,3-b]pyrrole-
2
-carboxylate 4a via intramolecular C−O bond formation
under alkaline and high temperature conditions.
conditions, the reaction of ethyl isocyanoacetate 1a with 3-
iodochromone 2a would produce ethyl 4-(2-hydroxybenzoyl)-
In conclusion, we have developed a novel silver catalyzed
cascade reaction of ethyl isocyanoacetate on an activated
double bond of 3-iodochromanone, involving nucleophilic
conjugate addition of an isocyanoacetate anion on the activated
double bond of chromanone followed by ring opening of the
chromanone ring, subsequent pyrrole ring formation, and
reconstruction of the chromanone ring via intramolecular C−O
bond formation leading to diverse chromeno[2,3-b]pyrrol-
5
1
-iodo-1H-pyrrole-2-carboxylate 3a in a moderate yield within
0 min (Scheme 4, eq 2). The intermediate 3a could be
smoothly transformed to the target molecule 4a in high yield
under alkaline and high temperature conditions without the
presence of silver oxide (Scheme 4, eq 3), which demonstrated
that this step reaction depended on the base and temperature
instead of the silver catalyst. The structure of 3a was also
confirmed by X-ray crystallographic analysis (Figure 2).
On the basis of the above observations and considerations, a
plausible reaction mechanism is proposed in Scheme 5. In this
pathway, the silver−isocyanide complex A could be generated
from 1a, in the presence of a silver catalyst, according to some
papers demonstrating that silver salts could coordinate to the
isocyano group and activate isocyanides 1 in the cycloaddition
4
(1H)-ones. The reaction represents an extremely simple,
practical, efficient, and atom-economic way to construct
benzopyranopyrroles. Further studies of the detailed mecha-
nism and application of this transformation are under
investigation in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02795.
General experimental information, copies of H and 13C
1
NMR of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: chyang@simm.ac.cn.
Notes
11
Figure 2. X-ray crystal structure of 3a.
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b02795
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Organic Letters
Letter
ACKNOWLEDGMENTS
■
This study was supported by the National Natural Science
Foundation of China (Grant Number 81321092) and SKLDR/
SIMM (SIMM1403ZZ-01).
REFERENCES
■
(
1) Funabashi, Y.; Takizawa, M.; Tsubotani, S.; Tanida, S.; Harada,
S.; Kamiya, K. Takeda Kenkyushoho 1992, 51, 73.
(
2) Kawamura, N.; Sawa, R.; Takahashi, Y.; Sawa, T.; Naganawa, H.;
Takeuchi, T. J. Antibiot. 1996, 49, 657.
3) (a) Sheng, J.; Chao, B.; Chen, H.; Hu, Y. Org. Lett. 2013, 15,
508. (b) Engqvist, R.; Bergman, J. Tetrahedron 2003, 59, 9649.
c) Sun, J.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2015,
0, 1200. (d) Lowe, W.; Witzel, S.; Tappmeyer, S.; Albuschat, R. J.
Heterocycl. Chem. 2004, 41, 317.
4) (a) Tyagi, V.; Khan, S.; Giri, A.; Gauniyal, H. M.; Sridhar, B.;
(
4
(
8
̈
(
Chauhan, P. M. Org. Lett. 2012, 14, 3126. (b) Li, M.; Cao, H.; Wang,
Y.; Lv, X.-L.; Wen, L.-R. Org. Lett. 2012, 14, 3470. (c) Xie, J.; Jiang, H.;
Cheng, Y.; Zhu, C. Chem. Commun. 2012, 48, 979. (d) Cheng, H. G.;
Lu, L. Q.; Wang, T.; Yang, Q. Q.; Liu, X. P.; Li, Y.; Deng, Q. H.; Chen,
J. R.; Xiao, W. J. Angew. Chem., Int. Ed. 2013, 52, 3250. (e) Zhu, Z.-Q.;
Wang, T.-T.; Bai, P.; Huang, Z.-Z. Org. Biomol. Chem. 2014, 12, 5839.
(
5
f) Prasad, B.; Adepu, R.; Sharma, A. K.; Pal, M. Chem. Commun. 2015,
1, 1259. (g) Tietze, L. F. Chem. Rev. 1996, 96, 115. (h) Pellissier, H.
Chem. Rev. 2013, 113, 442. (i) Volla, C. M. R.; Atodiresei, I.; Rueping,
M. Chem. Rev. 2014, 114, 2390. (j) Chen, J.-R.; Yu, X.-Y.; Xiao, W.-J.
Synthesis 2015, 47, 604.
(
5) (a) Zheng, D.; Li, S.; Wu, J. Chem. Commun. 2012, 48, 8568.
b) de la Campa, R.; Ortín, I.; Dixon, D. J. Angew. Chem., Int. Ed. 2015,
4, 4895. (c) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.;
(
5
Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235. (d) Lygin, A. V.; de
Meijere, A. Angew. Chem., Int. Ed. 2010, 49, 9094. (e) Shao, P.-L.; Liao,
J.-Y.; Ho, Y. A.; Zhao, Y. Angew. Chem., Int. Ed. 2014, 53, 5435.
(
f) Liao, J.-Y.; Shao, P.-L.; Zhao, Y. J. Am. Chem. Soc. 2015, 137, 628.
(
g) Boyarskiy, V. P.; Bokach, N. A.; Luzyanin, K. V.; Kukushkin, V. Y.
Chem. Rev. 2015, 115, 2698.
6) (a) Kanazawa, C.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc.
006, 128, 10662. (b) Grigg, R.; Lansdell, M. I.; Thornton-Pett, M.
Tetrahedron 1999, 55, 2025.
7) (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc.
005, 127, 9260. (b) Gao, M.; He, C.; Chen, H.; Bai, R.; Cheng, B.;
(
2
(
2
Lei, A. Angew. Chem., Int. Ed. 2013, 52, 6958. (c) Liu, J.; Fang, Z.;
Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953.
(
8) (a) Hou, C.; He, Q.; Yang, C. Org. Lett. 2014, 16, 5040.
(
b) Xiang, H.; Qi, J.; He, Q.; Jiang, M.; Yang, C.; Deng, L. Org. Biomol.
Chem. 2014, 12, 4633. (c) Chen, X.; Huang, X.; He, Q.; Xie, Y.; Yang,
C. Chem. Commun. 2014, 50, 3996.
(
9) (a) Zhang, X.; He, Q.; Xiang, H.; Song, S.; Miao, Z.; Yang, C.
Org. Biomol. Chem. 2014, 12, 355. (b) Qi, X.; Xiang, H.; He, Q.; Yang,
C. Org. Lett. 2014, 16, 4186. (c) Liu, Y.; Jin, S.; Huang, L.; Hu, Y. Org.
Lett. 2015, 17, 2134. (d) Mao, Z.; Lin, A.; Shi, Y.; Mao, H.; Li, W.;
Cheng, Y.; Zhu, C. J. Org. Chem. 2013, 78, 10233.
(
10) CCDC-1412630 contains the supplementary crystallographic
data for compound 4a. Copies of these data can be obtained free of
charge via www.ccdc.cam.ac.uk.
(
11) CCDC-1412633 contains the supplementary crystallographic
data for compound 3a. Copies of these data can be obtained free of
charge via www.ccdc.cam.ac.uk.
(
12) (a) Tian, W.-S.; Livinghouse, T. J. Chem. Soc., Chem. Commun.
1
989, 819. (b) Westling, M.; Smith, R.; Livinghouse, T. J. Org. Chem.
1
986, 51, 1159. (c) dos Santos, A.; El Kaim, L.; Grimaud, L.;
Ronsseray, C. Chem. Commun. 2009, 3907.
D
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