Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions!...
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Transcript of Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions!...
![Page 1: Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions! Supplementary!Information!! Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea* aFaculty](https://reader031.fdocuments.us/reader031/viewer/2022022711/5c02ba9609d3f2a5198bf91f/html5/thumbnails/1.jpg)
Synthesis of 8-‐Heteroaryl Nitroxoline Analogues via One-‐Pot Sequential Pd-‐Catalyzed Coupling Reactions
Supplementary Information
Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea*
aFaculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana,
Slovenia
E-mail:[email protected]
Table 1. C–H activation of furan with 8-‐bromoquinoline (5 equivalents of furan were used).
Entry Pd-‐catalyst(mol-‐%) Ligand (mol-‐%) [additive] Base Solvent T (°C) Reaction
time (h) Conversion (%)a 4a:5a
1 Pd(OAc)2 (0.5) PPh3 (1.0) KOAc (2 eq) DMAc 150 24 0 -‐ 2 Pd(OAc)2 (0.5) -‐ KOAc (2 eq) DMAc 150 24 0 -‐ 3 Pd2(dba)3 (0.5) -‐ KOAc (2 eq) DMAc 150 24 0 -‐ 4 PdCl2 (0.5) PPh3 (1.0) KOAc (2 eq) DMAc 150 24 0 -‐ 5 Pd(acac)2 (0.5) PPh3 (1.0) KOAc (2 eq) DMAc 150 24 23 1:1 6 Pd(TFA)2 (0.5) PPh3 (1.0) KOAc (2 eq) DMAc 150 24 0 -‐ 7 Pd(PPh3)4 (0.5) -‐ KOAc (2 eq) DMAc 150 24 28 1:2 8 Catalyst A (0.5) -‐ KOAc (2 eq) DMAc 150 24 41 1:1.5 9 PdCl2(dippp) (0.5) PivOH (5.0) K2CO3 (2 eq) DMAc 150 24 33 2:1 10 PdCl2(dippp) (0.5) -‐ K3PO4 (2 eq) DMAc 150 24 29 1:1 11 PdCl2(dippp) (0.5) -‐ KAcO(2 eq) DMAc 150 24 23 1:1 12 Pd(OAc)2 (1.0) Dppe (1.0) KOAc (2 eq) DMAc 150 24 29 1:2 13 Pd(OAc)2 (5.0) SPhos (10) K3PO4 (2 eq) NMP 150 48 100 1:2.4 14 Pd(OAc)2 (5.0) SPhos (10) K3PO4 (2 eq) NMP 120 48 61 2:1
15 Pd(OAc)2 (5.0) SPhos (10) K3PO4 (2 eq) Dioxane/H2O 4/1 (v/v) 150 48 29 1:1
16 Pd(OAc)2 (5.0) SPhos (10)
[Bu4NBr (2 eq)] K3PO4 (2 eq) NMP 150 24 61 1:1
17 Pd(OAc)2 (5.0) SPhos (10)
[Bu4NBr (2 eq)] K3PO4 (2 eq) NMP 150 48 88 1:1
18 Pd(OAc)2 (5.0) PivOH (30 ) K2CO3 (2 eq) DMAc 120 24 52 3:1 19 Catalyst A ( 5.0) PivOH (30 ) K2CO3 (2 eq) DMAc 150 24 96 1:4.5
20 Pd(OAc)2 (5.0) (t-‐Bu)3P (10) K2CO3 (2 eq) Dioxane/H2O 4/1 (v/v) 150 24 33 0:1
aConversion was determined by 1H NMR spectroscopy.
NBr
N
4a
+
O
NN
+
5
1
O
3a
reactionconditions
Pd NH2SPhos Cl
Catalyst A
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2016
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Table 2. C–H activation of 3a, 3b, and 3d–3f with 8-‐bromoquinoline (5 equivalents of 3a, 3b, and 3d–3f were used).
Heteroarene 3 Conversion-‐%a (ratio 4:5)
furan (3a) 100 (1:2.4) thiophene (3b) 89 (3.3:1) 1-‐methyl-‐1H-‐pyrrole (3d) 82 (1:2) benzo[b]furan (3e) 73 (1:2.7) benzo[b]thiophene (3f) 100 (2:1)
aConversion was determined by 1H NMR spectroscopy.
Table 3. Coupling of 1 with (furan-‐3-‐yl)boronic acid under different reaction conditions.
Entry Catalyst Ligand Solvent Conversion (%)a 1 Pd2(dba)3 / Toluene 50 2 PdCl2 PPh3 Toluene 33 3 Pd(acac)2 PPh3 Toluene 83 4 Pd(TFA)2 PPh3 Toluene 100 5 Pd(C), 10% / Toluene 0 6 Pd(OAc)2 PPh3 Toluene 53 7 Pd(PPh3)4 / Toluene 45 8 Pd(OAc)2 PPh3 1,4-‐Dioxane 77 9 Pd(OAc)2 PPh3 N-‐methyl-‐2-‐pyrrolidone 23 10 Pd(OAc)2 PPh3 2-‐Propanol 100 11 Pd(OAc)2 PPh3 Water 75 12 Pd(OAc)2 PPh3 1,4-‐Dioxane/water 4:1 (v/v) 95 13 Pd(TFA)2 PPh3 1,4-‐Dioxane 100 14 Pd(TFA)2 PPh3 N-‐methyl-‐2-‐pyrrolidone 11 15 Pd(TFA)2 PPh3 2-‐Propanol 100 16 Pd(TFA)2 PPh3 Water 63 17 Pd(TFA)2 PPh3 1,4-‐Dioxane/water 4:1 (v/v) 80
aConversion was determined by 1H NMR spectroscopy.
NBr
O S N
O S
Me
Pd(OAc)2 (5 mol-%)SPhos (10 mol-%)
K3PO4 (2equiv)NMP24 h, 150 oC
+3a 3b 3d
3e 3f
+NN
5
N
4
X
1
NBr
Pd catalyst, ligandK2CO3, solvent100ºC, 1 h
N
1
O
B(OH)2
O
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Figure 1. X-‐ray crystal structure of compound 4l’.
Synthesis of Pd catalyst A1,2
A mixture of Pd(OAc)2 (84 mg, 0.375 mmol) and 2-‐amino-‐biphenyl (63 mg, 0.375 mmol) in toluene (anhydrous, 2
mL) was heated at 60 oC for 1 h, at which the initial red color of the reaction mixture faded and a grey precipitate
had formed. The mixture was allowed to cool to r.t., at which the solvent was removed via cannula. The
remaining solid was washed with toluene (anhydrous, 2 x 2 mL) and further suspended in acetone (anhydrous, 2
mL). After the addition of lithium chloride (48 mg, 1.125 mmol) the reaction mixture was stirred at room
temperature for 24 h to give a dark orange homogenous solution. SPhos (162 mg, 0.394 mmol) was added
portionwise over 5 min to which white precipitate had formed. The mixture was stirred for an additional 24 h
after which 90 % of the solvent was removed under reduced pressure and the remaining solid was suspended in
methyl tert-‐butyl ether (MTBE, 3 mL) and acetone (anhydrous, 0.3 mL). The product was collected by suction
filtration, washed with water (3 x 3 mL) and dried under vacuum. White solid (205 mg, 76 %); mp = 181–183 oC;
Rf (dichloromethane/methanol = 10/1) 0.28. FT-‐IR (ATR, neat): 3396, 3316, 2912, 2844, 1489, 1246, 1109, 1035,
1001, 780, 758, 723 cm–1. 1H NMR (500 MHz, CDCl3): δ 7.47–7.45 (m, 1H), 7.40–7.31 (m, 2H), 7.22–7.17 (m, 5H),
7.06–7.05 (m, 2H), 6.94–6.91 (m, 1H), 6.70–6.59 (m, 4H), 4.79–4.61 (m, 2H), 3.76–3.66 (m, 6H), 2.04–0.80 (m,
20H). 13C NMR (125 MHz, CDCl3): δ 157.9, 151.5, 140.0, 139.6, 138.5, 138.2, 136.2, 135.3, 133.3, 133.2, 129.5,
128.9, 127.8 (2C), 127.6, 126.5, 126.4, 125.6, 125.1 (2C), 125.0, 124.5, 120.2, 118.9, 104.1, 103.5, 55.3 (2C), 37.0,
35.2, 31.4, 30.9, 28.6, 27.7, 27.6, 27.2 (2C), 26.2. 31P NMR (202 MHz, CDCl3): δ 53.2. HRMS (ESI+): m/z calcd for
C38H45NO2PPd (M -‐ HCl)+: 680.2238; found: 680.2236.
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Compound 2 1H NMR
13C NMR
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Compound 4a 1H NMR
13C NMR
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Compound 4b 1H NMR
13C NMR
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Compound 4c 1H NMR
13C NMR
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Compound 4d 1H NMR
13C NMR
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Compound 4e 1H NMR
13C NMR
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Compound 4f 1H NMR
13C NMR
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Compound 4g 1H NMR
13C NMR
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Compound 4h 1H NMR
13C NMR
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Compound 4i 1H NMR
13C NMR
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Compound 4j 1H NMR
13C NMR
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Compound 4k 1H NMR
13C NMR
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Compound 4l 1H NMR
13C NMR
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Compound 4m 1H NMR
13C NMR
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Compound 4n 1H NMR
13C NMR
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Compound 4o 1H NMR
13C NMR
![Page 20: Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions! Supplementary!Information!! Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea* aFaculty](https://reader031.fdocuments.us/reader031/viewer/2022022711/5c02ba9609d3f2a5198bf91f/html5/thumbnails/20.jpg)
Compound 4p 1H NMR
13C NMR
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Compound 4q 1H NMR
13C NMR
![Page 22: Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions! Supplementary!Information!! Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea* aFaculty](https://reader031.fdocuments.us/reader031/viewer/2022022711/5c02ba9609d3f2a5198bf91f/html5/thumbnails/22.jpg)
Compound 4r 1H NMR
13C NMR
![Page 23: Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions! Supplementary!Information!! Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea* aFaculty](https://reader031.fdocuments.us/reader031/viewer/2022022711/5c02ba9609d3f2a5198bf91f/html5/thumbnails/23.jpg)
Compound 4l’ 1H NMR
13C NMR
![Page 24: Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions! Supplementary!Information!! Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea* aFaculty](https://reader031.fdocuments.us/reader031/viewer/2022022711/5c02ba9609d3f2a5198bf91f/html5/thumbnails/24.jpg)
Compound 7a 1H NMR
13C NMR
![Page 25: Synthesisof8 …NitroxolineAnalogues)via)One-Pot) Sequential)Pd-Catalyzed)Coupling)Reactions! Supplementary!Information!! Helena Brodnik,a Franc Požgan,a and Bogdan Štefanea* aFaculty](https://reader031.fdocuments.us/reader031/viewer/2022022711/5c02ba9609d3f2a5198bf91f/html5/thumbnails/25.jpg)
Compound 7b 1H NMR
13C NMR
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Compound 7c 1H NMR
13C NMR
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Compound 7d 1H NMR
13C NMR
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Compound 7e 1H NMR
13C NMR
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Compound 7f 1H NMR
13C NMR
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Compound 7g 1H NMR
13C NMR
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Compound 7h 1H NMR
13C NMR
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Compound 7ca 1H NMR
13C NMR
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Compound 7ea 1H NMR
13C NMR
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Compound 7i 1H NMR
13C NMR
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Compound 7j 1H NMR
13C NMR
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Compound 7k 1H NMR
13C NMR
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Compound 7l 1H NMR
13C NMR
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Compound 7m 1H NMR
13C NMR
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Compound 7n 1H NMR
13C NMR
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Compound 7o 1H NMR
13C NMR
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Compound 7p 1H NMR
13C NMR
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Compound 7q 1H NMR
13C NMR
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Compound 7s 1H NMR
13C NMR
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Compound 7t 1H NMR
13C NMR
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Compound 7qa 1H NMR
13C NMR
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Compound 7ra 1H NMR
13C NMR
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Compound 7u 1H NMR
13C NMR
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Compound 8 1H NMR
13C NMR
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Compound 9 1H NMR
13C NMR
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Pd catalyst A 1H NMR
13C NMR
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31P NMR
1 T. Kinzel, Y. Zhang, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 14073. 2 J. Albert, J. Granell, J. Zafrilla, M. Font-‐Barida, X. Solans, J. Organometallic Chem. 2005, 690, 422.