A one-pot copper(II)-catalyzed tandem synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones

Article abstract of DOI:10.1002/ejoc.201500422

A one-pot copper(II)-catalyzed tandem synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones from N-aminopyrroles was developed. This tandem reaction involves a Conrad-Limpach-type reaction, including the thermal condensation of N-aminopyrroles with the carbonyl group of β-oxo esters followed by the cyclization of Schiff base intermediates. Compared to the traditional Conrad-Limpach quinoline synthesis, we herein successfully applied copper(II) as a catalyst in this transformation to furnish 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones for the first time. Most of the substrates bearing electron-donating (EDG) and electron-withdrawing (EWG) groups worked well with this procedure. The corresponding products could be converted directly into diverse pyrrolo[1,2-b]pyridazine for drug discovery and materials science. A copper(II)-catalyzed tandem synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-ones from N-aminopyrroles was developed, and the corresponding products could be converted directly into diverse pyrrolo[1,2-b]pyridazine for drug discovery and materials science.

Full text of DOI:10.1002/ejoc.201500422

Job/Unit: O50422
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Date: 07-05-15 12:33:01
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500422
A One-Pot Copper(II)-Catalyzed Tandem Synthesis of 2-Substituted
Pyrrolo[1,2-b]pyridazin-4(1H)-ones
Cun Tan,[a] Haoyue Xiang,[a] Qian He,[a] and Chunhao Yang*[a]
Keywords: Synthetic methods / Tandem reactions / Nitrogen heterocycles / Pyrroles / Pyridazines
A one-pot copper(II)-catalyzed tandem synthesis of 2-sub-
stituted pyrrolo[1,2-b]pyridazin-4(1H)-ones from N-amino- rolo[1,2-b]pyridazin-4(1H)-ones for the first time. Most of the
pyrroles was developed. This tandem reaction involves a substrates bearing electron-donating (EDG) and electron-
Conrad–Limpach-type reaction, including the thermal con- withdrawing (EWG) groups worked well with this procedure.
densation of N-aminopyrroles with the carbonyl group of β- The corresponding products could be converted directly into
oxo esters followed by the cyclization of Schiff base interme- diverse pyrrolo[1,2-b]pyridazine for drug discovery and
catalyst in this transformation to furnish 2-substituted pyr-
diates. Compared to the traditional Conrad–Limpach quinol-
ine synthesis, we herein successfully applied copper(II) as a
materials science.
As a result, considerable efforts have been devoted to
developing efficient synthetic approaches for this privileged
Introduction
Pyrrolo[1,2-b]pyridazine and its derivatives, a considerably structure.[7c,7e,8a,8b] One of the most used methods reported
important class of heterocycles, have been intensively before for the assembly of pyrrolo[1,2-b]pyridazine moieties
studied on account of their various bioactivities, including typically relied on condensation reactions, such as the con-
as JAK inhibitors,[1] HER-2 tyrosine kinase inhibitors,[2] densation of cyanoacetic hydrazide with nitriles[9] and the
DGAT1 inhibitors,[3] MEK inhibitors,[4] TRPV1 antago- condensation of oxazolo[3,2-b]pyridazinium perchlorates
nists,[5] CRF1 receptor antagonists[6] etc. Meanwhile, with malononitrile, ethyl cyanoacetate or ethyl malonate.[10]
numerous pyrrolo[1,2-b]pyridazines have been discovered to Additionally, cycloaddition reactions,[7a,11] such as the 1,3-
possess remarkable optical and electrochemical properties dipolar cycloaddition of substituted pyridazines or me-
and are thus being broadly utilized in materials science, soionic oxazolo[3,2-b]pyridazines to acetylenic es-
including as sensors and biosensors, electroluminescent ters,[7a,7b,12] were other versatile synthetic routes for ob-
materials, lasers, and other semiconductor devices.[7]
taining pyrrolo[1,2-b]pyridazine. As an alternative, diversi-
Scheme 1. Conrad–Limpach reaction used in the synthesis of pyrrolo[1,2-b]pyridazin-4(1H)-ones.
[a] State Key Laboratory of Drug Research, Shanghai Institute of
fied pyrrolo[1,2-b]pyridazines could also be synthesized di-
Materia Medica, Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Shanghai 201203, P. R. China
E-mail: chyang@simm.ac.cn
rectly from pyrrolo[1,2-b]pyridazin-4(1H)-ones after mod-
ifying the 4-position of these precursors.[4,6] However, the
methods reported for the synthesis of pyrrolo[1,2-b]pyrida-
zin-4(1H)-ones are quite rare.[13] Recently, our group con-
http://www.simm.ac.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500422.
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C. Tan, H. Xiang, Q. He, C. Yang
SHORT COMMUNICATION
centrated on developing novel strategies for the synthesis of desired product 4a was obtained in a moderate yield by
heterocyclic scaffolds from N-aminopyrroles, such as pyr-
rolo[2,1-f][1,2,4]triazin-4(3H)-ones[14] and pyrrolo[1,2-
b]pyridazines.[15] In a retrosynthetic analysis for the synthe-
sis of pyrrolo[1,2-b]pyridazin-4(1H)-ones, we envisaged that
this useful skeleton could be accessed from N-aminopyr-
roles through C–N/C–C bond formation by a Conrad–Lim-
pach-type reaction as well [Scheme 1, Equation (1)]. The
Conrad–Limpach reaction is a general approach to 4-hy-
droxyquinolines, but usually requires two steps and high
temperatures over 200 °C [Scheme 1, Equation (2)].[16] Ac-
cordingly, there is still a high demand for facile one-pot
synthetic methods for diverse pyrrolo[1,2-b]pyridazin-
4(1H)-ones under mild conditions. Toward this goal, we
herein first applied copper(II) as catalyst in the Conrad–
Limpach reaction to furnish pyrrolo[1,2-b]pyridazin-4(1H)-
ones in a one-pot procedure at a lower temperature of
140 °C [Scheme 1, Equation (1)].
using toluenesulfonic acid monohydrate as the catalyst (En-
try 1). Then, a range of Lewis acids as catalysts were exam-
ined (Entries 2–8), and the results indicated that the cata-
lysts had a significant effect on this reaction. Interestingly,
different pathways were observed when different Lewis
acids were employed in this process. The screened trifluoro-
methanesulfonates (Entries 2–6), except Zn(OTf)2, resulted
in the formation of Schiff base intermediate 3a by attacking
the very reactive oxo group, leading to the desired pyr-
rolo[1,2-b]pyridazin-4(1H)-one 4a by undergoing subse-
quent cyclization of 3a in a one-pot reaction (path a).
Among these Lewis acids, Cu(OTf)2 proved to be the best
catalyst for this kind of transformation (Entry 5), but the
others resulted in lower yields (Entries 2–4). In contrast, no
corresponding compound 4a was detected when the reac-
tion was carried out in the presence of other catalysts, such
as Cu(OAc)2, CuI and Zn(OTf)2 (Entries 6–8). And in these
cases, the amino group of 1a actually first attacked the less
reactive ester group rather than the oxo group, giving the
thermodynamically preferred product amide 3aЈ in a good
yield. However, compound 3aЈ failed to further convert into
the corresponding product pyrrolo[1,2-b]pyridazin-2(1H)-
one 4aЈ (path b). After that we surveyed the effect of the
solvents on the reaction, and this transformation performed
Results and Discussion
At the outset of our study, the reaction of N-amino-1H-
pyrrole-2-carbonitrile (1a) with ethyl 3-(3-methoxyphenyl)-
3-oxopropanoate (2a) was used as a model reaction to opti-
mize the reaction conditions (Table 1). Encouragingly, the
Table 1. Investigation of the reaction conditions.[a]
Entry
Catalyst
Solvent
Temp. [°C]
Yield [%][b]
4a
3aЈ
1
2
3
4
5
6
7
8
9
10
11
12
13
14
TsOH·H2O
Er(OTf)3
Yt(OTf)2
AgOTf
Cu(OTf)2
Zn(OTf)2
CuI
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
PhCl
140
140
140
140
140
140
140
140
140
140
140
140
140
120
0
0
0
0
0
70
85
60
0
45
15
25
58
70
0
0
0
41
0
76
66[c]
69[d]
22
DMF
0
Cl2(CH)2Cl2
Cl2(CH)2Cl2
Cl2(CH)2Cl2
Cl2(CH)2Cl2
[a] Reaction conditions: 1a (0.25 mmol, 1.0 equiv.), 2a (0.275 mmol, 1.1 equiv.), catalyst (0.05, mmol, 0.2 equiv.), solvent (5.0 mL), 140 °C,
3 h. [b] Isolated yields. [c] 0.1 equiv. of Cu(OTf)2 was used. [d] 0.5 equiv. of Cu(OTf)2 was used.
2
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Tandem Synthesis of 2-Substituted Pyrrolo[1,2-b]pyridazin-4(1H)-ones
best in 1,1,2,2-tetrachloroethane, giving the desired product
Under the optimized reaction condtions [1.0 equiv. of N-
4a in 76% yield. A moderate yield was obtained when aminopyrrole, 1.1 equiv. of β-oxo ester, 0.2 equiv. of catalyst
chlorobenzene was used, but no desired product 4a or by- Cu(OTf)2, 5.0 mL of 1,1,2,2-tetrachloroethane at 140 °C],
product 3aЈ were observed when DMF was used as the sol- the scope of this tandem reaction was explored, and the
vent (Entry 10). Then the amount of Cu(OTf)2 was taken results are summarized in Table 2. In general, a series of
into consideration, suggesting that both increasing and functional groups on the phenyl ring of compound 2 includ-
decreasing the amount of the catalysts decreased the yield ing methyl, ethyl, methoxy, chloro, fluoro and trifluoro-
slightly (Entries 12–13). Finally, the reaction temperature methyl were well tolerated, and the desired products were
was lowered to 120 °C, leading to an inferior yield of the obtained in moderate to good yields (4a–b, 4d–g and 4i–p).
corresponding product 4a (Entry 14).
The position of the substituents on the phenyl ring of the
Table 2. Exploration of the substrate scope.[a,b]
[a] Reaction conditions: 1 (0.25 mmol, 1.0 equiv.), 2 (0.275 mmol, 1.1 equiv.), catalyst (0.05, mmol, 0.2 equiv.), solvent (5.0 mL), 140 °C,
0.5–5 h. [b] Isolated yields.
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C. Tan, H. Xiang, Q. He, C. Yang
SHORT COMMUNICATION
and the crude product was eluted on silica gel with petroleum ether/
ethyl acetate (10:1 to 2:1, v/v) to give target compounds 4.
β-oxo ester affected the reaction yields significantly. Com-
pared to substituents at other positions, ortho substituents
provided lower yields due to steric hindrance (4c vs. 4a–b,
4h vs. 4f–g and 4m vs. 4k–l), whereas substrates with the
bulkier ortho-substituted trifluoromethyl group failed to
give the corresponding products (4q vs. 4o–p). Heterocyclic
β-oxo esters such as thiophene- and furan-substituted sub-
Acknowledgments
This work was financially supported by the Chinese Academy of
Sciences (“Interdisciplinary Cooperation Team” Program for Sci-
strates also gave moderate yields under the reaction condi- ence and Technology Innovation), the National Natural Science
Foundation of China (grant numbers 81321092, and 21072205),
and the State Key Laboratory of Drug Research/Shanghai Institute
of Materia Medica (SKLDR/SIMM) (SIMM1403ZZ-01).
tions (4r–s). Notably, cyclic β-oxo esters were found to be
suitable substrates as well, providing fused polycyclic pyr-
rolo[1,2-b]pyridazin-4(1H)-ones 4t–v in acceptable yields.
Further studies illustrated that compounds 1 with ester,
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substrate was also
a sterically encumbering group.
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We have developed the first copper(II)-catalyzed tandem
synthesis of 2-substituted pyrrolo[1,2-b]pyridazin-4(1H)-
ones by a Conrad–Limpach-type reaction. Compared to the
traditional Conrad–Limpach quinoline synthesis, this reac-
tion is the first example to apply Lewis acidic copper salts,
which was further used to construct pyrrolo[1,2-b]pyrid-
azin-4(1H)-ones. Moreover, the desired pyrrolo[1,2-b]pyrid-
azin-4(1H)-ones could be converted into diverse pyr-
rolo[1,2-b]pyridazines for drug discovery and materials
science.
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Experimental Section
General Procedure for Compounds 4: To a mixture of N-aminopyr-
roles 1 (0.5 mmol) and β-aryl-β-oxo esters 2 (0.6 mmol) in dry
1,1,2,2-tetrachloroethane (10.0 mL) was added Cu(OTf)2
(0.1 mmol). Then the mixture was stirred vigorously at 140 °C.
When the reaction was complete, the solvent was removed in vacuo,
4
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Tandem Synthesis of 2-Substituted Pyrrolo[1,2-b]pyridazin-4(1H)-ones
Pidathala, R. Amewu, B. Pacorel, G. L. Nixon, P. Gibbons, [17]
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CCDC-1044805 (for 4d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: April 1, 2015
Published Online: ᭿
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Pages: 6
C. Tan, H. Xiang, Q. He, C. Yang
SHORT COMMUNICATION
Nitrogen Heterocycles
C. Tan, H. Xiang, Q. He,
C. Yang* ........................................... 1–6
A One-Pot Copper(II)-Catalyzed Tandem
Synthesis of 2-Substituted Pyrrolo[1,2-b]-
pyridazin-4(1H)-ones
A copper(II)-catalyzed tandem synthesis of
2-substituted pyrrolo[1,2-b]pyridazin-
4(1H)-ones from N-aminopyrroles was de-
could be converted directly into diverse
pyrrolo[1,2-b]pyridazine for drug discovery
and materials science.
Keywords: Synthetic methods / Tandem re-
actions / Nitrogen heterocycles / Pyrroles /
Pyridazines
veloped, and the corresponding products
6
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