One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones by a Smiles Rearrangement

Abstract

A simple and convenient synthesis of indole-fused pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones is described. A range of 2-(1H-indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible with this reaction. A Smiles rearrangement is proposed as a key step in the highly regioselective construction of the products. The easy availability of the starting materials makes this an appealing method in ­organic synthesis.

Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-one analogues are among the most attractive structural motifs to the organic synthesis community, because these compounds are valued for their diverse biological activities.[1] [2] [3] [4] [5] [6] In the recent decades, a great deal of effort has been devoted toward their synthesis.[7–10] However, heterocycle-fused pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones have attracted surprisingly little attention. In this regard, indoles are important heterocyclic units that exhibit a wide range of biological activities.[11] [12] Fusion of an indole skeleton with a pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-one would lead to a new heterocycle library (Figure [1]). To the best of our knowledge, no synthesis of this new fused heterocycle system has been reported and, consequently, the development of an economic and efficient method for their preparation is in high demand.

Table 1 Optimization of the Reaction Conditions^a

Entry	Temp (°C)	Base	Solvent	Yieldb (%)
1	50	K2CO3	DMF	81
2	80	K2CO3	DMF	90
3	100	K2CO3	DMF	87
4	80	Na2CO3	DMF	71
5	80	Cs2CO3	DMF	82
6	80	K2CO3	DMSO	71

^a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), base (2.5 equiv), ­solvent, 3 h.

^b Isolated yield after column chromatography.

The Smiles rearrangement is a powerful and important tool for the construction of fused heterocycles.[13] [14] [15] [16] [17] In comparison with stepwise transformations, one-pot syntheses are much preferred due to their convenience. Consequently, the Smiles rearrangement has been introduced into one-pot syntheses of fused heterocycle systems.[18–21] On the basis of this concept, many N- and O-containing fused heterocycles have been conveniently produced with high efficiencies.[8,22–24] Inspired by the reported works,[9] [10] [25] we developed a one-pot, highly regioselective protocol for the construction of indole-fused pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones through a Smiles rearrangement, using readily available starting materials.

We began our study by using 2-(1H-indol-2-yl)phenol (1a) and 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2a) as model substrates. To our delight, the desired product 3a was obtained in 81% yield under our initial conditions (Table [1], entry 1). Raising the reaction temperature slightly improved the yield (entries 2 and 3), and the best result was achieved at 80 °C (entry 2). Next, a screen of bases indicated that potassium carbonate was the optimal base among those tested (entries 2, 4, and 5). The use of dimethyl sulfoxide as solvent gave an inferior result (entry 6). We therefore concluded that the best results were obtained with potassium carbonate as base and N,N-dimethylformamide as solvent at 80 °C, which gave the desired product 3a in 90% yield.

With the optimal reaction conditions in hand, we next examined the substrate scope. Various alkyl-substituted 4,5-dichloropyridazin-3-ones 2a–f reacted smoothly with 2-(1H-indol-2-yl)phenol (1a) to give the corresponding products 3a–f in good to excellent yields (Scheme [1]). It was noteworthy that the allyl-substituted 4,5-dichloropyridazin-3-one 2f was also tolerated in this transformation, giving the corresponding product 3f in 76% yield.

On the basis of these preliminary results, we then evaluated the scope of the 2-(1H-indol-2-yl)phenols with various substituents 1b–m in this transformation (Scheme [2]). To our satisfaction, all the tested 2-(1H-indol-2-yl)phenols worked well in the reaction, delivering the corresponding product 3g–o in 63–84% yield. Remarkably, the structure of 3n was unambiguously confirmed by X-ray crystallographic analysis (Figure [2]).[26] The substrates were not limited to 2-(1H-indol-2-yl)phenols; interestingly, this method could also be extended to 2-(1H-benzimidazol-2-yl)phenols, and under the same reaction conditions, the product 3p was produced in 52% yield. Similarly, substituents on the 2-(1H-benzimidazol-2-yl)phenol had no deleterious effect on the outcome (3q, 3r).

To probe the reaction mechanism, two control experiments were carried out (Scheme [3]). When attempts were made to react 2-(2-methoxyphenyl)-1H-indole or 2-phenyl-1H-indole with substrate 2a under the standard conditions, no reaction occurred and the indole starting material was recovered in 80% and 69% yield, respectively. These experiments indicated that the indole nitrogen cannot serve as a nucleophilic center under the optimal reaction conditions, and that a hydroxy group in the substrate is indispensable for this transformation. We therefore deduced that a Smiles rearrangement is involved in this reaction.

Based on previous reports[8] [25] and on our preliminarily mechanistic experiments, a possible reaction mechanism was proposed (Scheme [4]). Under basic conditions, the inter­mediate A is initially formed through direct nucleo­philic substitution of the phenolic oxygen anion with the 4,5-dichloropyridazin-3-one. The indole nitrogen anion B is then generated under the same reaction conditions. Next, a Smiles rearrangement occurs preferentially (path a), rather than direct nucleophilic cyclization (path b), to give inter­mediate C. Finally, the phenolic oxygen anion undergoes a second nucleophilic substitution to afford the desired product.

In summary, we have successfully developed a highly regioselective synthetic route for the construction of ­indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-ones through a Smiles rearrangement under transition-metal-free conditions.[27] A range of substrates with various functional groups were compatible in this reaction and the corresponding products were obtained in good to high yields. A probable involvement of a Smiles rearrangement in this reaction was established by control experiments. Further studies on applications of this reaction in synthesizing other fused heterocyclic compounds are currently in progress.

• References and Notes

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• 16 Zuo H. Li Z.-B. Ren F.-K. Falck JR. Meng L. Ahn C. Shin D.-S. Tetrahedron 2008; 64: 9669
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• 26 CCDC 1581528 contains the supplementary crystallographic data for compound 3n. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 27 Indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-ones 3a–r; General Procedure The appropriate 2-(1H-indol-2-yl)phenol 1 (0.30 mmol), 2-tetra­hydropyranylpyridazin-3-one 2 (0.30 mmol), and K₂CO₃ (2.5 equiv.) were successively added to a 10 mL Schlenk tube. DMF (2 mL) was then added from a dropper and the resulting solution was stirred at 80 °C for 3 h. The mixture was cooled to r.t. then extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na₂SO₄), and filtered. The solvent was then removed in vacuoto give a crude mixture that was purified by column chromatography (silica gel). 8-(Tetrahydro-2H-pyran-2-yl)indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-one (3a) Light-yellow solid; yield: 104 mg (90%); mp 122–124 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.72–7.70 (m, 2 H), 7.66 (d, J = 8.2 Hz, 1 H), 7.54–7.52 (m, 1 H), 7.40–7.27 (m, 4 H), 6.98 (s, 1 H), 6.15–6.13 (m, 1 H), 4.17–4.14 (m, 1 H), 3.81–3.76 (m, 1 H), 2.23–2.15 (m, 1 H), 2.07–2.04 (m, 1 H), 1.80–1.71 (m, 3 H), 1.60–1.58 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.55, 157.02, 144.65, 136.58, 135.94, 133.09, 131.39, 130.48, 129.45, 129.39, 126.36, 123.99, 123.54, 122.82, 122.15, 121.69, 111.56, 105.97, 83.32, 68.98, 28.99, 24.89, 22.83. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀N₃O₃: 386.1499; found: 386.1491.

• References and Notes

• 1 Hallinan EA. Stapelfeld A. Savage MA. Reichman M. Bioorg. Med. Chem. Lett. 1994; 4: 509
  CrossrefSearch in Google Scholar
• 2 Ouyang X. Tamayo N. Kiselyov AS. Tetrahedron 1999; 55: 2827
  CrossrefSearch in Google Scholar
• 3 Dols PP. M. A. Folmer BJ. B. Hamersma H. Kuil CW. Lucas H. Ollero L. Rewinkel JB. M. Hermkens PH. H. Bioorg. Med. Chem. Lett. 2008; 18: 1461
  CrossrefSearch in Google Scholar
• 4 Dorn A. Schattel V. Laufer S. Bioorg. Med. Chem. Lett. 2010; 20: 3074
  CrossrefSearch in Google Scholar
• 5 Gijsen HJ. M. Berthelot D. Zaja M. Brône B. Geuens I. Mercken M. J. Med. Chem. 2010; 53: 7011
  CrossrefPubMedSearch in Google Scholar
• 6 Binaschi M. Boldetti A. Gianni M. Maggi CA. Gensini M. Bigioni M. Parlani M. Giolitti A. Fratelli M. Valli C. Terao M. Garattini E. ACS Med. Chem. Lett. 2010; 1: 411
  CrossrefPubMedSearch in Google Scholar
• 7 Lu S.-M. Alper H. J. Am. Chem. Soc. 2005; 127: 14776
  CrossrefPubMedSearch in Google Scholar
• 8 Liu Y. Chu C. Huang A. Zhan C. Ma Y. Ma C. ACS Comb. Sci. 2011; 13: 547
  CrossrefPubMedSearch in Google Scholar
• 9 Liu Y. Ma Y. Zhang C. Huang A. Ma C. Synlett 2012; 23: 255
  Thieme ConnectSearch in Google Scholar
• 10 Sapegin AV. Kalinin SA. Smirnov AV. Dorogov MV. Krasavin M. Synthesis 2012; 44: 2401
  Thieme ConnectSearch in Google Scholar
• 11 Kochanowska-Karamyan AJ. Hamann MT. Chem. Rev. 2010; 110: 4489
  CrossrefSearch in Google Scholar
• 12 Li S.-M. Nat. Prod. Rep. 2010; 27: 57
  CrossrefSearch in Google Scholar
• 13 Cho S.-D. Park Y.-D. Kim J.-J. Lee S.-G. Ma C. Song S.-Y. Joo W.-H. Falck JR. Shiro M. Shin D.-S. Yoon Y.-J. J. Org. Chem. 2003; 68: 7918
  CrossrefPubMedSearch in Google Scholar
• 14 Cho S.-D. Song S.-Y. Park Y.-D. Kim J.-J. Joo W.-H. Shiro M. Falck JR. Shin D.-S. Yoon Y.-J. Tetrahedron Lett. 2003; 44: 8995
  CrossrefSearch in Google Scholar
• 15 Cho S.-D. Park Y.-D. Kim J.-J. Joo W.-H. Shiro M. Esser L. Falck JR. Ahn C. Shin D.-S. Yoon Y.-J. Tetrahedron 2004; 60: 3763
  CrossrefSearch in Google Scholar
• 16 Zuo H. Li Z.-B. Ren F.-K. Falck JR. Meng L. Ahn C. Shin D.-S. Tetrahedron 2008; 64: 9669
  CrossrefSearch in Google Scholar
• 17 Zuo H. Meng L. Ghate M. Hwang K.-H. Cho YK. Chandrasekhar S. Reddy CR. Shin D.-S. Tetrahedron Lett. 2008; 49: 3827
  CrossrefSearch in Google Scholar
• 18 Zhao Y. Wu Y. Jia J. Zhang D. Ma C. J. Org. Chem. 2012; 77: 8501
  CrossrefPubMedSearch in Google Scholar
• 19 Zhao Y. Dai Q. Chen Z. Zhang Q. Bai Y. Ma C. ACS Comb. Sci. 2013; 15: 130
  CrossrefPubMedSearch in Google Scholar
• 20 Yang B. Tan X. Guo R. Chen S. Zhang Z. Chu X. Xie C. Zhang D. Ma C. J. Org. Chem. 2014; 79: 8040
  CrossrefSearch in Google Scholar
• 21 Niu X. Yang B. Li Y. Fang S. Huang Z. Xie C. Ma C. Org. Biomol. Chem. 2013; 11: 4102
  CrossrefPubMedSearch in Google Scholar
• 22 Kitching MO. Hurst TE. Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 2925
  CrossrefPubMedSearch in Google Scholar
• 23 Zhou Y. Zhu J. Li B. Zhang Y. Feng J. Hall A. Shi J. Zhu W. Org. Lett. 2016; 18: 380
  CrossrefPubMedSearch in Google Scholar
• 24 Zhan C. Jia J. Yang B. Huang A. Liu Y. Ma C. RSC Adv. 2012; 2: 7506
  CrossrefSearch in Google Scholar
• 25 Sang P. Yu M. Tu H. Zou J. Zhang Y. Chem. Commun. 2013; 49: 701
  CrossrefPubMedSearch in Google Scholar
• 26 CCDC 1581528 contains the supplementary crystallographic data for compound 3n. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 27 Indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-ones 3a–r; General Procedure The appropriate 2-(1H-indol-2-yl)phenol 1 (0.30 mmol), 2-tetra­hydropyranylpyridazin-3-one 2 (0.30 mmol), and K₂CO₃ (2.5 equiv.) were successively added to a 10 mL Schlenk tube. DMF (2 mL) was then added from a dropper and the resulting solution was stirred at 80 °C for 3 h. The mixture was cooled to r.t. then extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na₂SO₄), and filtered. The solvent was then removed in vacuoto give a crude mixture that was purified by column chromatography (silica gel). 8-(Tetrahydro-2H-pyran-2-yl)indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-one (3a) Light-yellow solid; yield: 104 mg (90%); mp 122–124 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.72–7.70 (m, 2 H), 7.66 (d, J = 8.2 Hz, 1 H), 7.54–7.52 (m, 1 H), 7.40–7.27 (m, 4 H), 6.98 (s, 1 H), 6.15–6.13 (m, 1 H), 4.17–4.14 (m, 1 H), 3.81–3.76 (m, 1 H), 2.23–2.15 (m, 1 H), 2.07–2.04 (m, 1 H), 1.80–1.71 (m, 3 H), 1.60–1.58 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.55, 157.02, 144.65, 136.58, 135.94, 133.09, 131.39, 130.48, 129.45, 129.39, 126.36, 123.99, 123.54, 122.82, 122.15, 121.69, 111.56, 105.97, 83.32, 68.98, 28.99, 24.89, 22.83. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀N₃O₃: 386.1499; found: 386.1491.

• Supplementary Material