A One-Pot Copper(II)-Catalyzed Tandem Synthesis of 2-Substituted Pyrrolo[1,2- b ]pyridazin-4(1 H )-onesby Cun Tan, Haoyue Xiang, Qian He, Chunhao Yang

European Journal of Organic Chemistry


Physical and Theoretical Chemistry / Organic Chemistry


Job/Unit: O50422 /KAP1 Date: 07-05-15 12:33:01 Pages: 6


DOI: 10.1002/ejoc.201500422

A One-Pot Copper(II)-Catalyzed Tandem Synthesis of 2-Substituted


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-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 βoxo 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


Pyrrolo[1,2-b]pyridazine and its derivatives, a considerably important class of heterocycles, have been intensively studied on account of their various bioactivities, including as JAK inhibitors,[1] HER-2 tyrosine kinase inhibitors,[2]

DGAT1 inhibitors,[3] MEK inhibitors,[4] TRPV1 antagonists,[5] CRF1 receptor antagonists[6] etc. Meanwhile, numerous pyrrolo[1,2-b]pyridazines have been discovered to possess remarkable optical and electrochemical properties and are thus being broadly utilized in materials science, including as sensors and biosensors, electroluminescent materials, lasers, and other semiconductor devices.[7]

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

Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China

E-mail: chyang@simm.ac.cn http://www.simm.ac.cn/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201500422.

Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 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 electronwithdrawing (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.

As a result, considerable efforts have been devoted to developing efficient synthetic approaches for this privileged structure.[7c,7e,8a,8b] One of the most used methods reported before for the assembly of pyrrolo[1,2-b]pyridazine moieties typically relied on condensation reactions, such as the condensation of cyanoacetic hydrazide with nitriles[9] and the condensation of oxazolo[3,2-b]pyridazinium perchlorates with malononitrile, ethyl cyanoacetate or ethyl malonate.[10]

Additionally, cycloaddition reactions,[7a,11] such as the 1,3dipolar cycloaddition of substituted pyridazines or mesoionic oxazolo[3,2-b]pyridazines to acetylenic esters,[7a,7b,12] were other versatile synthetic routes for obtaining pyrrolo[1,2-b]pyridazine. As an alternative, diversified pyrrolo[1,2-b]pyridazines could also be synthesized directly from pyrrolo[1,2-b]pyridazin-4(1H)-ones after modifying the 4-position of these precursors.[4,6] However, the methods reported for the synthesis of pyrrolo[1,2-b]pyridazin-4(1H)-ones are quite rare.[13] Recently, our group conJob/Unit: O50422 /KAP1 Date: 07-05-15 12:33:01 Pages: 6

C. Tan, H. Xiang, Q. He, C. YangSHORT COMMUNICATION centrated on developing novel strategies for the synthesis of heterocyclic scaffolds from N-aminopyrroles, such as pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones[14] and pyrrolo[1,2b]pyridazines.[15] In a retrosynthetic analysis for the synthesis of pyrrolo[1,2-b]pyridazin-4(1H)-ones, we envisaged that this useful skeleton could be accessed from N-aminopyrroles through C–N/C–C bond formation by a Conrad–Limpach-type reaction as well [Scheme 1, Equation (1)]. The

Conrad–Limpach reaction is a general approach to 4-hydroxyquinolines, but usually requires two steps and high temperatures over 200 °C [Scheme 1, Equation (2)].[16] Accordingly, there is still a high demand for facile one-pot synthetic methods for diverse pyrrolo[1,2-b]pyridazin4(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)].

Results and Discussion

At the outset of our study, the reaction of N-amino-1Hpyrrole-2-carbonitrile (1a) with ethyl 3-(3-methoxyphenyl)3-oxopropanoate (2a) was used as a model reaction to optimize the reaction conditions (Table 1). Encouragingly, the

Table 1. Investigation of the reaction conditions.[a]

Entry Catalyst Solvent Temp. [°C] Yield [%][b] 3a 4a 1 TsOH·H2O o-xylene 140 0 45 2 Er(OTf)3 o-xylene 140 0 15 3 Yt(OTf)2 o-xylene 140 0 25 4 AgOTf o-xylene 140 0 58 5 Cu(OTf)2 o-xylene 140 0 70 6 Zn(OTf)2 o-xylene 140 70 0 7 CuI o-xylene 140 85 0 8 Cu(OAc)2 o-xylene 140 60 0 9 Cu(OTf)2 PhCl 140 0 41 10 Cu(OTf)2 DMF 140 0 0 11 Cu(OTf)2 Cl2(CH)2Cl2 140 76 12 Cu(OTf)2 Cl2(CH)2Cl2 140 66[c] 13 Cu(OTf)2 Cl2(CH)2Cl2 140 69[d] 14 Cu(OTf)2 Cl2(CH)2Cl2 120 22 [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. www.eurjoc.org © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 0000, 0–02 desired product 4a was obtained in a moderate yield by using toluenesulfonic acid monohydrate as the catalyst (Entry 1). Then, a range of Lewis acids as catalysts were examined (Entries 2–8), and the results indicated that the catalysts had a significant effect on this reaction. Interestingly, different pathways were observed when different Lewis acids were employed in this process. The screened trifluoromethanesulfonates (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 pyrrolo[1,2-b]pyridazin-4(1H)-one 4a by undergoing subsequent cyclization of 3a in a one-pot reaction (path a).