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DOI: 10.1055/s-0030-1258147
Synthesis of New [2,3′:6′,3′′]Terpyridines Using Iterative Cross-Coupling Reactions
Publication History
Publication Date:
02 July 2010 (online)
Abstract
An efficient, regioselective, and global route to prepare terpyridines is described. A predictable strategy was developed, which is based on iterative cross-coupling reactions between bifunctional pyridylboronic acids as promising platforms and halobipyridines as key intermediates.
Key words
boron - cross-coupling - palladium - pyridines - regioselectivity
Oligopyridines are widely described in the literature because of their great importance in metallosupramolecular chemistry as metal chelates (essentially bi-, ter-, and quarterpyridines). [¹] [²] Their complexes serve as luminescent probes in biochemical, medicinal diagnostics, or materials science. [³] Despite their great importance, there is no general strategy to prepare all possible isomers. We are presently interested in iterative cross-coupling (ICC) reactions to promote the simple, efficient, and flexible construction of these small molecules [4] in order to explore their biological features in the light of properties of some natural terpyridines such as nicotelline or quaterpyridines such as nemertelline (Figure [¹] ). [5]
Figure 1 Some natural oligopyridines
Concerning terpyridines, they can be classified into two groups. On the one hand, there are 6 unsubstituted symmetric terpyridine families (2,2′:6′,2′′-; 3,2′:6′,3′′-; 4,2′:6′,4′′-; 2,3′:5′,2′′-; 3,3′:5′,3′′-; and 4,3′:5′,4′′-) classified according to positions and sites of linkage (Figure [²] ). Their preparation has been described with the implementation of various methodologies such aza-Diels-Alder, condensation, or cross-coupling reactions. [6-¹0]
Figure 2 Unsubstituted symmetric terpyridine families
On the other hand, there are 42 unsubstituted unsymmetric terpyridine families, which are classified in Figure [³] (according to the same criteria and nomenclature rules). In the literature, only few unsubstituted unsymmetric terpyridine families have been prepared using different methods including aza-Diels-Alder, condensation, or cross-coupling reactions [6a] [7a] [d] [¹¹] and we have found only 11 references concerning 16 compounds.
Therefore, the global study of syntheses of these compounds represents a fantastic ‘lego’ game. In our laboratory, a regiocontrolled [¹²] iterative Suzuki-Miyaura cross-coupling methodology is used, which we have recently published and named as Garlanding concept (Scheme [¹] ). [¹³]
This methodology takes advantage of the nature and the position of the halogen atom on the pyridine in the cross-coupling reaction to prepare halobipyridines. This method uses bifunctional pyridylboronic acids, which represent a highly promising platform for this type of synthesis strategy. The knowledge gained in the synthesis and the reactivity of these species allowed us to predict the regioselectivity of the reaction and this permitted us to prepare numerous mono- and dihalobipyridines in good yields.
Figure 3 42 Unsubstituted unsymmetric terpyridine families
Scheme 1 The Garlanding concept
More recently, we have also demonstrated that these halobipyridines could be engaged in cross-coupling reactions to give new terpyridines; however, this strategy was limited to the use of various picolines. [¹4-¹6]
In this paper, we wish to extend our methodology for the preparation of new [2,3′:6′,3′′]terpyridines, particularly, the unsubstituted parent compound IV and its 5-bromo, 6′′-bromo and 5,6′′-dibromo[2,3′:6′,3′′] congeners V (Scheme [²] ). The chemistry of these compounds is yet unknown, only theoretical electronic properties are reported for the terpyridine IV. [¹7]
Scheme 2 General strategy to prepare terpyridines
To set up our strategy to produce terpyridines IV and V, we had to prepare bipyridines III, which constitute the core of the sequence (Scheme [²] ). These mono- or dihalobipyridines III can be obtained by the cross-coupling reaction between monohalo- or dihalopyridines I and halogenated pyridylboronic acid II as illustrated in Scheme [³] for the preparation of 6′-bromo[2,3′]bipyridine (IIIb), which was obtained in 60% yield using the 2-iodopyridine versus 11% yield using the 2-bromopyridine as described by Parry et al. [¹8]
Scheme 3 Synthesis of 6′-bromo[2,3′]bipyridine (IIIb). Reagents and conditions: IIb (1.25 equiv), Ia or Ib (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 4 Preparation of [2,3′:6′,3′′]terpyridine (IV) and 5-bromo[2,3′:6′,3′′]terpyridine (Va). Reagents and conditions: IIa (1.25 equiv), IIIa or IIIb (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 5 Preparation of 5,6′′-dibromo[2,3′:6′,3′′]terpyridine (Vb) and 6′′-bromo[2,3′:6′,3′′]terpyridine (Vc). Reagents and conditions: IIb (1.25 equiv), IIIa or IIIb (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 6 Synthesis 5,6′-bromoiodo[2,3′]bipyridine (IIIc) and 6′-iodo[2,3′]bipyridine (IIId). Reagents and conditions: AcCl (2 × 2 equiv), NaI (2 × 4 equiv), MeCN, reflux, 2 × 24 h.
Scheme 7 Preparation of 5,6′′-dibromo[2,3′:6′,3′′]terpyridine (Vb) and 6′′-bromo[2,3′:6′,3′′]terpyridine (Vc). Reagents and conditions: IIb (1.25 equiv), IIIc or IIId (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
In a similar way, we obtained the 5,6′-dibromo[2,3′]bipyridine (IIIa) in 73% yield from the boronic acid IIb and 5-bromo-2-iodopyridine. [¹4] Then, we considered two possibilities to prepare terpyridines IV and V from the key bipyridines III. In the first one (Scheme [4] ), the bromobipyridines IIIa and IIIb were engaged in a cross-coupling reaction with the 3-pyridylboronic acid (IIa). The regioselectivity of the reaction is good due to the absence of a halogen atom in the α-position of the boronic acid and the best reactivity of the halogen in C-2 position. In this way, the parent [2,3′:6′,3′′]terpyridine IV and the 5-bromo[2,3′:6′,3′′]terpyridine Va were obtained in good yields.
Unfortunately, when the 6-bromo-3-pyridylboronic acid (IIb), bearing a bromine atom in the α-position, was used with the same partners IIIa and IIIb as above, the lack of selectivity and reactivity led in poor yield to the desired terpyridines V, which were accompanied by side-products derived from homocoupling reactions (Scheme [5] ).
In the second approach, in order to improve the selectivity and the reactivity, prior to the coupling reaction we realized the iodo-bromo exchange according to the methodology we have previously described. [¹4] This exchange permitted us to obtain for the first time the 5-bromo-6′-iodo[2,3′]bipyridine (IIIc) and the 6′-iodo[2,3′]bipyridine (IIId) (Scheme [6] ).
Thus, these iodopyridines IIIc and IIId proved to be excellent coupling partners leading to the desired dibromoterpyridine Vb and monobromoterpyridine Vc in good yields (Scheme [7] ).
We present below two examples of our work currently under investigation in order to extend the scope of our methodology. In the first example, we engaged the dibromoterpyridine Vb in a cross-coupling reaction with the 3-pyridylboronic acid (IIa) leading to the first monobromoquaterpyridine VI (Scheme [8] ).
In the second example, we synthesized various substituted terpyridines and for this purpose we prepared the 2,5-dibromo-3-pyridinecarboxaldehyde (VII) [¹9] starting from the 2,3,5-tribromopyridine (VIII). This latter was obtained from the corresponding 2-amino-3,5-dibromopyridine (IX), which is commercially available.
Scheme 8 Preparation of 5-bromo[2,3′:6′,3′′:6′′,3′′′]quaterpyridine (VI). Reagents and conditions: IIa (1.25 equiv), Vb (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Compound VII was engaged in a Suzuki-Miyaura cross-coupling reaction with 1.25 equivalents of 3-pyridylboronic acid (IIa) giving the monobromobipyridine X or with 2.5 equivalents of IIa giving the terpyridine XI (Scheme [9] ). The carboxaldehyde compounds X and XI are stable under the cross-coupling reaction and purification conditions. They are currently used to prepare libraries of substituted terpyridines.
Scheme 9 Preparation of 2,3,5-tribromopyridine (VIII) and 2,5-dibromo-3-pyridinecarboxaldehyde (VII) and 5-bromo[2,3′]bipyridine-3-carboxaldehyde (X) and [3,3′:6′,3′′]terpyridine-3′-carboxaldehyde (XI). Reagents and conditions: (i) HBr (48%), NaNO2 (2.5 equiv), Br2 (3.3 equiv), r.t., 3 h; (ii) n-BuLi (1.25 equiv), DMF (1.15 equiv), Et2O, -78 ˚C; (iii) IIa (1.25 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h; (iv) IIa (2.5 equiv), aq Na2CO3 (5 equiv), Pd(PPh3)4 (0.1 equiv), 1,4-dioxane, reflux, 24 h.
In conclusion, we have applied with success our methodology in the preparation of new unsymmetric terpyridines. None of the compounds described in this paper showed a cytotoxic activity on KB cells at 10-5 M. Now, we are working towards the expansion of this method’s scope to prepare other new unsymmetric bi-, ter-, quater-, quinque-, and sexipyridines.
Commercial reagents were used as received without additional purification. Melting points were determined on a Kofler heating block. IR spectra were recorded on a PerkinElmer BX FT-IR spectrophotometer. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a JEOL Lambda 400 spectrometer. Chemical shifts are expressed in parts per million downfield from TMS as an internal standard and coupling constants in Hertz. Mass spectra were recorded on a JEOL JMS GCMate spectrometer at ionizing potential of 70 eV (EI) and with PFK (perfluorokerosene) as internal standard for high-resolution procedure, or were performed using a spectrometer LC-MS Waters Alliance 2695 (ESI+). Chromatography was carried out on a column using flash silica gel 60 Merck (0.063-0.200 mm) as the stationary phase. TLC was performed on 0.2 mm precoated plates of silica gel 60F-264 (Merck) and spots were visualized using an ultraviolet-light lamp. Elemental analyses for new compounds were performed at the ‘Institut de Recherche en Chimie Organique Fine’ (Rouen).
Halogen-Halogen Exchange; General Procedure (Scheme [6] )
A mixture of bipyridines 5,6′-dibromo[2,3′]bipyridine (IIIa; 1 equiv) or 6′-bromo[2,3′]bipyridine (IIIb; 1 equiv), NaI (4 equiv), and AcCl (2 equiv) in MeCN was refluxed for 24 h. The mixture was carefully quenched with H2O and treated with sat. aq NaHCO3 until pH 8. The product was extracted with EtOAc, the combined organic layers were dried (MgSO4), and concentrated. The residue was subjected again to the above reaction conditions and worked up as above. The combined organic extracts were washed with sat. aq NaHSO3, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (cyclohexane-EtOAc, 90:10) to afford halobipyridines IIIc or IIId.
5-Bromo-6′-iodo[2,3′]bipyridine (IIIc)
Following the general procedure, the following were used in the specified quantities: bipyridine IIIa (5.5 g, 17.5 mmol), NaI (10.5 g, 70 mmol), AcCl (1.25 mL, 17.5 mmol). Quench and workup: H2O (50 mL); EtOAc (3 75 mL); sat. aq NaHSO3 (25 mL).
Yield: 4.31 g (68%); white solid; mp 194 ˚C.
IR (KBr): 3060, 1571, 1570, 1455, 1371, 1345, 1092, 1080, 1006, 937, 822, 750, 687, 616 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.92 (dd, J = 2.9, 8.8 Hz, 1 H), 7.95 (dd, J = 2.9, 8.8 Hz, 1 H), 8.75 (d, J = 2.9 Hz, 1 H), 8.91 (d, J = 2.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 118.8, 120.6, 121.3, 133.4, 135.0, 135.7, 139.7, 148.7, 151.3, 152.2.
HRMS (EI): m/z calcd for C10H6BrIN2: 360.76585; found: 360.76517.
Anal. Calcd for C10H6BrIN2: C, 33.27; H, 1.68; N, 7.76. Found: C, 33.54; H, 1.54; N, 7.85.
6′-Iodo[2,3′]bipyridine (IIId)
Following the general procedure, the following were used in the specified quantities: bipyridine IIIb (2.7 g, 11.48 mmol), NaI (6.88 g, 45.94 mmol), AcCl (1.64 mL, 22.97 mmol). Quench and workup: H2O (25 mL); EtOAc (3 50 mL); sat. aq NaHSO3 (15 mL).
Yield: 2.36 g (73%); white solid; mp 105 ˚C.
IR (KBr): 3045, 1582, 1570, 1452, 1428, 1356, 1077, 1080, 1006, 985, 845, 780, 616 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.31 (m, 1 H), 7.72 (dd, J = 3.9, 7.8 Hz, 1 H), 7.78 (dd, J = 2.9, 8.8 Hz, 1 H), 7.82 (dd, J = 3.9, 7.8 Hz, 1 H), 7.98 (dd, J = 2.9, 8.8 Hz, 1 H), 8.71 (d, J = 2.9 Hz, 1 H), 8.92 (d, J = 2.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.4, 123.2, 124.2, 134.9, 135.9, 137.1, 148.0, 149.0, 150.2, 153.7.
HRMS (EI): m/z calcd for C10H7IN2: 281.96542; found: 281.96563.
Anal. Calcd for C10H7IN2: C, 42.58; H, 2.50; N, 9.93. Found: C, 42.75; H, 2.54; N, 9.84.
Cross-Coupling Reactions; General Procedure (Schemes [4] , [5] , [7] -9)
A mixture of pyridylboronic acid IIa or IIb (1.2 equiv), halopyridines (1 equiv), Pd(PPh3)4 (5 mol%), and sat. aq Na2CO3 (2.5 equiv) in 1,4-dioxane was heated at 80 ˚C for 1 h, and then under reflux until the complete consumption of aryl halide (TLC). The reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (cyclohexane-EtOAc, 90:10) to afford bipyridines IIIa and IIIb, and terpyridines IV, Va-c, VI, X, and XI.
5,6′-Dibromo[2,3′]bipyridine (IIIa)
Following the general procedure, the following were used in the specified quantities: boronic acid IIb (1.3 g, 6.44 mmol), 5-bromo-2-iodopyridine (1.52 g, 5.33 mmol), Pd(PPh3)4 (308 mg, 0.27 mmol), Na2CO3 (1.41 g, 13.30 mmol). Workup: EtOAc (3 50 mL).
Yield: 1.23 g (73%); yellow solid; mp 194 ˚C. Spectral data were in accordance with the literature. [¹4]
6′-Dibromo[2,3′]bipyridine (IIIb)
Following the general procedure, the following were used in the specified quantities: boronic acid IIb (4.35 g, 25.88 mmol), 2-iodopyridine Ia (4.32 g, 21.07 mmol), Pd(PPh3)4 (975 mg, 0.84 mmol), Na2CO3 (5.58 g, 52.64 mmol). Workup: EtOAc (3 100 mL).
Yield: 2.97 g (60%); white solid; mp 80 ˚C. Spectral data were in accordance with the literature. [¹8]
[2,3′;6′,3′′]Terpyridine (IV)
Following the general procedure, the following were used in the specified quantities: boronic acid IIa (157 mg, 1.28 mmol), halopyridine IIIb (250 mg, 1.06 mmol), Pd(PPh3)4 (62 mg, 0.053 mmol), Na2CO3 (282 mg, 2.67 mmol). Workup: EtOAc (3 20 mL).
Yield: 150 mg (61%); yellow solid; mp 132 ˚C.
IR (KBr): 3054, 1585, 1564, 1431, 1416, 1369, 1012, 988, 780, 702, 610 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.32 (dd, J = 4.9, 8.8 Hz, 1 H), 7.43 (dd, J = 4.9, 8.8 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.82 (m, 2 H), 8.39 (dd, J = 1.9, 8.8 Hz, 1 H), 8.45 (dd, J = 1.9, 8.8 Hz, 1 H), 8.67 (d, J = 4.9 Hz, 1 H), 8.75 (d, J = 4.9 Hz, 1 H), 9.28 (d, J = 1.9 Hz, 1 H), 9.30 (d, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.4, 120.5, 122.9, 123.6, 133.9, 134.3, 134.4, 135.3, 137.0, 148.3, 148.4, 150.0, 150.1, 154.3, 154.8.
HRMS (EI): m/z calcd for C15H11N3: 233.15423; found: 233.15352.
Anal. Calcd for C15H11N3: C, 77.23; H, 4.75; N, 18.01. Found: C, 77.43; H, 4.64; N, 17.94.
5-Bromo[2,3′;6′,3′′]terpyridine (Va)
Following the general procedure, the following were used in the specified quantities: boronic acid IIa (113 mg, 0.92 mmol), halopyridine IIIa (250 mg, 0.796 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol), Na2CO3 (211 mg, 1.99 mmol). Workup: EtOAc (3 30 mL).
Yield: 130 mg (53%); white solid; mp 184 ˚C.
IR (KBr): 3057, 3036, 1586, 1461, 1419, 1351, 1288, 1098, 1006, 869, 845, 815, 762, 705 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.43 (dd, J = 4.9, 8.8 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.94 (dd, J = 1.9, 8.8 Hz, 1 H), 8.39 (dd, J = 1.9, 8.8 Hz, 1 H), 8.42 (dd, J = 1.9, 8.8 Hz, 1 H), 8.68 (d, J = 4.9 Hz, 1 H), 8.79 (d, J = 1.9 Hz, 1 H), 9.27 (d, J = 1.9 Hz, 1 H), 9.28 (d, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.3, 120.4, 121.5, 123.7, 132.8, 134.3, 134.4, 135.1, 139.6, 148.2, 148.3, 150.2, 151.3, 152.7, 155.2.
HRMS (EI): m/z calcd for C15H10BrN3: 311.00576; found: 311.00483.
Anal. Calcd for C15H10BrN3: C, 57.71; H, 3.23; N, 13.46. Found: C, 57.79; H, 3.14; N, 13.39.
5,6′′-Dibromo[2,3′;6′,3′′]terpyridine (Vb)
Following the general procedure, the following were used in the specified quantities: boronic acid IIb (1.40 g, 6.93 mmol), halopyridine IIIc (2 g, 5.54 mmol), Pd(PPh3)4 (320 mg, 0.27 mmol), Na2CO3 (1.47 g, 13.86 mmol). Workup: EtOAc (3 100 mL).
Yield: 1.09 g (51%); beige solid; mp 248 ˚C.
IR (KBr): 3043, 2920, 1568, 1452, 1354, 1095, 1006, 818, 768, 753, 622 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 9.26 (d, J = 1.9 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.94 (dd, J = 1.9, 8.8 Hz, 1 H), 8.27 (dd, J = 1.9, 8.8 Hz, 1 H), 8.42 (dd, J = 1.9, 8.8 Hz, 1 H), 8.79 (d, J = 1.9 Hz, 1 H), 9.01 (d, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.3, 120.4, 121.5, 128.2, 133.2, 133.6, 135.3, 136.9, 139.6, 142.9, 148.3, 148.5, 151.3, 152.6, 153.9.
HRMS (EI): m/z calcd for C15H9Br2N3: 388.89547; found: 388.89615.
Anal. Calcd for C15H9Br2N3: C, 46.07; H, 2.32; N, 10.74. Found: C, 46.23; H, 2.41; N, 10.81.
6′′-Bromo[2,3′;6′,3′′]terpyridine (Vc)
Following the general procedure, the following were used in the specified quantities: boronic acid IIb (895 mg, 4.43 mmol), halopyridine IIId (1 g, 3.54 mmol), Pd(PPh3)4 (205 mg, 0.18 mmol), Na2CO3 (939 mg, 8.85 mmol). Workup: EtOAc (3 50 mL).
Yield: 631 mg (57%); beige solid; mp 183 ˚C.
IR (KBr): 3045, 1588, 1446, 1425, 1362, 1285, 1154, 1086, 1003, 985, 833, 780, 744, 616 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.31-7.34 (m, 1 H), 7.61 (d, J = 8.8 Hz, 1 H), 7.82-7.83 (m, 2 H), 7.85 (d, J = 8.8 Hz, 1 H), 8.27 (dd, J = 1.9, 8.8 Hz, 1 H), 8.45 (dd, J = 1.9, 8.8 Hz, 1 H), 8.75 (d, J = 1.9 Hz, 1 H), 9.01 (d, J = 1.9 Hz, 1 H), 9.29 (d, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.2, 120.5, 123.1, 128.1, 133.7, 134.2, 135.4, 136.8, 137.1, 142.7, 148.5 (2C), 150.2, 153.5, 154.1.
HRMS (EI): m/z calcd for C15H10BrN3: 311.00576; found: 311.00454.
Anal. Calcd for C15H10BrN3: C, 57.71; H, 3.23; N, 13.46. Found: C, 57.94; H, 3.51; N, 13.34.
5-Bromo[2,3′:6′,3′′:6′′,3′′′]quaterpyridine (VI)
Following the general procedure, the following were used in the specified quantities: boronic acid IIa (145 mg, 1.18 mmol), halopyridine Vb (400 mg, 1.02 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol), Na2CO3 (271 mg, 2.55 mmol). Workup: EtOAc (3 25 mL).
Yield: 159 mg (40%); yellow solid; mp 230 ˚C.
IR (KBr): 3044, 1585, 1456, 1352, 1275, 1095, 1007, 841, 807, 767, 699, 616 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.45 (dd, J = 4.8, 7.8 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.96 (dd, J = 1.9, 7.8 Hz, 1 H), 8.41 (dt, J = 1.9, 7.8 Hz, 1 H), 8.45 (dd, J = 1.9, 7.8 Hz, 1 H), 8.52 (dd, J = 1.9, 7.8 Hz, 1 H), 8.69 (dd, J = 1.9, 4.8 Hz, 1 H), 8.80 (d, J = 1.9 Hz, 1 H), 9.29 (d, J = 1.9 Hz, 1 H), 9.31 (d, J = 1.9 Hz, 1 H), 9.38 (d, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.3 (2 C), 120.4, 121.5, 123.7, 132.9, 133.4, 134.4, 135.2 (2 C), 135.4, 139.6, 148.4 (2 C), 148.6, 150.2, 151.3, 152.8, 154.8, 155.2.
HRMS (EI): m/z calcd for C20H13BrN4: 388.0323; found: 388.03193.
Anal. Calcd for C20H13BrN4: C, 61.71; H, 3.37; N, 14.39. Found: C, 62.26; H, 3.40; N, 14.51.
5-Bromo[2,3′]bipyridine-3-carboxaldehyde (X)
Following the general procedure, the following were used in the specified quantities: boronic acid IIa (204 mg, 1.66 mmol), halopyridine VII (400 mg, 1.51 mmol), Pd(PPh3)4 (87 mg, 0.075 mmol), Na2CO3 (400 mg, 3.77 mmol). Workup: EtOAc (3 25 mL).
Yield: 239 mg (60%); beige solid; mp 128 ˚C.
IR (KBr): 3057, 2872, 1693, 1588, 1421, 1394, 1245, 1199, 1129, 1010, 915, 887, 776, 710, 672, 619 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.51 (dd, J = 4.9, 7.8 Hz, 1 H), 7.96 (dt, J = 1.9, 7.8 Hz, 1 H), 8.47 (d, J = 1.9 Hz, 1 H), 8.79 (d, J = 4.9 Hz, 1 H), 8.81 (d, J = 1.9 Hz, 1 H), 8.97 (d, J = 1.9 Hz, 1 H), 10.03 (s, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.7, 123.5, 130.4, 132.0, 137.3, 138.5, 150.6, 150.9, 154.9, 157, 189.1.
HRMS (EI): m/z calcd for C11H7BrN2O: 261.87065; found: 261.87112.
Anal. Calcd for C11H7BrN2O: C, 50.22; H, 2.68; N, 10.65. Found: C, 50.35; H, 2.81; N, 10.63.
[3,3′:6′,3′′]Terpyridine-3′-carboxaldehyde (XI)
Following the general procedure, the following were used in the specified quantities: boronic acid IIa (464 mg, 3.77 mmol), halopyridine VII (400 mg, 1.51 mmol), Pd(PPh3)4 (175 mg, 0.151 mmol), Na2CO3 (800 mg, 7.55 mmol). Workup: EtOAc (3 25 mL).
Yield: 285 mg (72%); white solid; mp 172 ˚C.
IR (KBr): 3042, 2848, 1705, 1587, 1573, 1451, 1432, 1372, 1190, 1135, 1011, 910, 805, 778, 708, 625 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 7.49 (dd, J = 4.9, 7.8 Hz, 1 H), 7.54 (dd, J = 4.9, 7.8 Hz, 1 H), 8.0 (dt, J = 1.9, 7.8 Hz, 1 H), 8.04 (dt, J = 1.9, 7.8 Hz, 1 H), 8.56 (d, J = 1.9 Hz, 1 H), 8.75 (dd, J = 1.9, 4.9 Hz, 1 H), 8.81 (dd, J = 1.9, 4.9 Hz, 1 H), 8.89 (d, J = 1.9 Hz, 1 H), 8.97 (d, J = 1.9 Hz, 1 H), 9.17 (d, J = 1.9 Hz, 1 H), 10.03 (s, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 123.5, 124.0, 129.6, 131.8, 132.4, 133.2, 134.3, 134.5, 137.5, 148.1, 150.1, 150.8, 150.9, 151.9, 158.1, 190.2.
HRMS (EI): m/z calcd for C16H11N3O: 261.28905; found: 261.29012.
Anal. Calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 72.15; H, 4.30; N, 16.64.
2,3,5-Tribromopyridine (VIII)
To a solution of 2-amino-3,5-dibromopyridine (IX; 25.41 g, 0.1 mol, 1 equiv) in 48% HBr (150 mL), cooled in an ice bath at -5 ˚C, was added Br2 (17.41 mL, 0.34 mol, 3.36 equiv). After stirring for 1 h at this temperature, a solution of NaNO2 (17.40 g, 0.25 mol, 2.5 equiv) in H2O (50 mL) was added dropwise. The mixture was stirred at this temperature for 2 h before allowing to warm to r.t. during 30 min. Then, the mixture was cooled to 0 ˚C before adding aq 1 M Na2S2O3 (200 mL). The resulting mixture was extracted with Et2O (2 × 300 mL), the combined organic layers were washed with H2O until neutral pH of the aqueous phase, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (cyclohexane-EtOAc, 95:5) to afford VIII. Yield: 25.48 g (80%); beige solid; mp <50 ˚C. Spectral data were in accord with the literature. [²0]
2,5-Dibromo-3-pyridinecarboxaldehyde (VII)
To a 2.5 M solution of n-BuLi (19.79 mL, 39.58 mmol, 1.25 equiv) in anhyd Et2O (150 mL) cooled to -78 ˚C was added a solution of 2,3,5-tribromopyridine (VIII; 10 g, 31.67 mmol, 1 equiv) in Et2O (50 mL). The resulting mixture was allowed to react at this temperature for over 90 min. Anhyd DMF (6.12 mL, 79.17 mmol, 2.5 equiv) was then added dropwise, the mixture was stirred at this temperature for 90 min and then allowed to warm to r.t. and finally left to react for an additional hour. The mixture was poured into aq 3 M HCl (200 mL) cooled in an ice bath and then stirred for 15-20 min. The resulting mixture was extracted with Et2O (3 × 100 mL), the combined organic layers were dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (cyclohexane-EtOAc, 95:5) to afford VII. Yield: 4.28 g (51%) white solid; mp 108 ˚C.
IR (KBr): 3051, 2877, 1683, 1560, 1411, 1359, 1249, 1103, 1057, 912, 894, 719 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 1.9 Hz, 1 H), 8.64 (d, J = 1.9 Hz, 1 H), 10.27 (s, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 120.7, 131.1, 140.2, 143.0, 155.2, 189.7.
HRMS (EI): m/z calcd for C6H3Br2NO: 262.72076; found: 262.72354.
Anal. Calcd for C6H3Br2NO: C, 27.20; H, 1.14; N, 5.29. Found: C, 27.6; H, 1.27; N, 5.01.
Acknowledgment
This work was supported by the ‘Conseil Régional de Basse-Normandie’ and SERVIER Laboratories. We thank BoroChem team for fruitful exchanges during this study and the ‘Institut de Chimie des Substances Naturelles’ for cytotoxic activity evaluations.
- 1a
Constable EC. Angew. Chem. Int. Ed. 2007, 46: 2748 - 1b
Constable EC. Prog. Inorg. Chem. 1994, 42: 67 - 1c
Constable EC. Adv. Inorg. Chem. 1986, 30: 69 - 2
Fang YQ.Polson MIJ.Hanan GS. Inorg. Chem. 2003, 42: 5 - 3
Kozhevnikov VN.Kozhevnikov DN.Rusinov VL.Chupakhin ON.Koenig B. Synthesis 2003, 2400 - 4a
Noguchi H.Hojo K.Suginome M. J. Am. Chem. Soc. 2007, 129: 758 - 4b
Gillis PE.Burke MD. J. Am. Chem. Soc. 2007, 129: 6716 - 4c
Araki H.Katoh T.Inoue M. Tetrahedron Lett. 2007, 48: 3713 - 4d
Lee SJ.Gray KC.Paek JS.Burke MD. J. Am. Chem. Soc. 2008, 130: 466 - 4e
Wang C.Glorius F. Angew. Chem. Int. Ed. 2009, 48: 5240 - 4f
Iwadate N.Suginome M. Org. Lett. 2009, 11: 1899 - 4g
Tobisu M.Chatani N. Angew. Chem. Int. Ed. 2009, 48: 3565 - 4h
Gillis EP.Burke MD. Aldrichimica Acta 2009, 42: 17 - 4i
Daykin LM.Siddle JS.Ankers AL.Batsanov AS.Bryce MR. Tetrahedron 2010, 66: 668 - 5a
Kem WR.Soti F. Hydrobiologia 2001, 456: 221 - 5b
Pictet A.Rotschy A. Ber. Dtsch. Chem. Ges. 1901, 34: 696 - 5c
Pictet A. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1906, 244: 375 - 5d
Cruskie MP.Zoltewicz JA.Abboud KA. J. Org. Chem. 1995, 60: 7491 - 5e
Zoltewicz JA.Cruskie MP. Tetrahedron 1995, 51: 11401 - 6a
Jameson DL.Guise LE. Tetrahedron Lett. 1991, 18: 1999 - 6b
Yamamoto Y.Tanaka T.Yagi M.Inamoto M. Heterocycles 1996, 42: 189 - 6c
Cargill Thompson AMW. Coord. Chem. Rev. 1997, 160: 1 - 6d
Adrian JC.Hassib L.De Kimpe N.Keppens M. Tetrahedron 1998, 54: 2365 - 6e
Gunther R.Pagen S. Tetrahedron 1998, 137: 6687 - 6f
Fang YQ.Hanan GS. Synlett 2003, 852 - 6g
Cook MW.Wang J.Theobald I.Hanan GS. Synth. Commun. 2006, 36: 1721 - 7a
Ishikura M.Ohta T.Terashima M. Chem. Pharm. Bull. 1985, 33: 4755 - 7b
Matondo H.Ouhaja N.Souirti S.Baboulene M. Main Group Met. Chem. 2002, 25: 163 - 7c
Kudo N.Perseghini M.Fu GC. Angew. Chem. Int. Ed. 2006, 45: 1282 - 7d
Zhao LX.Sherchan J.Park JK.Jahng Y.Jeong BS.Jeong TC.Lee CS.Lee ES. Arch. Pharm. Res. 2006, 29: 1091 - 8
Koizumi TA.Tomon T.Tanaka K. Bull. Chem. Soc. Jpn. 2003, 76: 1969 - 9
Zhang J.Wu Y.Zhu Z.Ren G.Mak TCW.Song M. Appl. Organomet. Chem. 2007, 21: 935 - 10a
Kubota Y.Biradha K.Fujita M.Sakamoto S.Yamaguchi K. Bull. Chem. Soc. Jpn. 2002, 75: 559 - 10b
Thebault F.Barnett SA.Blake AJ.Wilson C.Champness NR.Schroeder M. Inorg. Chem. 2006, 45: 6179 - 11a
Yamamoto Y.Azuma Y.Mitoh H. Synthesis 1986, 564 - 11b
Eichinger K.Nussbaumer P.Vytlacil R. Spectrochim. Acta, Part A 1987, 43: 731 - 11c
Bauer R.Nussbaumer P.Neumann-Spallart M. Z. Naturforsch., B: Chem. Sci. 1988, 43: 475 - 11d
Rodinovskaya LA.Bogomolova OP.Shestopalov AM.Litvinov VP. Dokl. Akad. Nauk 1992, 324: 585 - 11e
Zoltewicz JA.Dill CD. Tetrahedron 1996, 52: 14469 - 11f
Farina V.Krishnamurthy V.Scott WJ. Org. React. 1997, 50: 1 - 11g
Karig G.Thasana N.Gallagher T. Synlett 2002, 808 - 11h
Beauchamp DA.Loeb SJ. Supramol. Chem. 2005, 17: 617 - 11i
Pierrat P.Gros PC.Fort Y. J. Comb. Chem. 2005, 7: 879 - 11j
Kozhevnikov VN.Kozhevnikov DN.Shabunina OV.Vladimir LR.Chupakhin ON. Terahedron Lett. 2005, 46: 1791 - 11k
Kozhevnikov VN.Shabunina OV.Kopchuk DS.Ustinova MM.König B.Kozhevnikov DN. Tetrahedron 2008, 64: 8963 - 12
Schröter S.Stock C.Bach T. Tetrahedron 2005, 61: 2245 - 13
Voisin-Chiret AS.Bouillon A.Burzicki G.Célant M.Legay R.El-Kashef H.Rault S. Tetrahedron 2009, 65: 607 - 14
Burzicki G.Voisin-Chiret AS.Sopkovà-de Oliveira Santos J.Rault S. Tetrahedron 2009, 65: 5413 - 15a
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2002, 58: 2885 - 15b
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2002, 58: 3323 - 15c
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2002, 58: 4369 - 15d
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2003, 59: 10043 - 16a
Voisin AS.Bouillon A.Berenguer I.Lancelot JC.Lesnard A.Rault S. Tetrahedron 2006, 62: 11734 - 16b
Cailly T.Fabis F.Bouillon A.Lemaître S.Sopková-de Olivieira Santos J.Rault S. Synlett 2006, 53 - 17
Wang SL.Li M.Shen W.Li Y.Zhang BH. Xinan Daxue Xuebao, Ziran Kexueban 2007, 29: 25 - 18
Parry PR.Wang C.Batsanov AS.Bryce MR.Tarbit B. J. Org. Chem. 2002, 67: 7541 - 20
Roduit JP. In e-EROS Encyclopedia of Reagents for Organic Synthesis Wiley; New York: 2001.
References
Compound VII is commercially available, but its synthesis is unknown in the literature.
- 1a
Constable EC. Angew. Chem. Int. Ed. 2007, 46: 2748 - 1b
Constable EC. Prog. Inorg. Chem. 1994, 42: 67 - 1c
Constable EC. Adv. Inorg. Chem. 1986, 30: 69 - 2
Fang YQ.Polson MIJ.Hanan GS. Inorg. Chem. 2003, 42: 5 - 3
Kozhevnikov VN.Kozhevnikov DN.Rusinov VL.Chupakhin ON.Koenig B. Synthesis 2003, 2400 - 4a
Noguchi H.Hojo K.Suginome M. J. Am. Chem. Soc. 2007, 129: 758 - 4b
Gillis PE.Burke MD. J. Am. Chem. Soc. 2007, 129: 6716 - 4c
Araki H.Katoh T.Inoue M. Tetrahedron Lett. 2007, 48: 3713 - 4d
Lee SJ.Gray KC.Paek JS.Burke MD. J. Am. Chem. Soc. 2008, 130: 466 - 4e
Wang C.Glorius F. Angew. Chem. Int. Ed. 2009, 48: 5240 - 4f
Iwadate N.Suginome M. Org. Lett. 2009, 11: 1899 - 4g
Tobisu M.Chatani N. Angew. Chem. Int. Ed. 2009, 48: 3565 - 4h
Gillis EP.Burke MD. Aldrichimica Acta 2009, 42: 17 - 4i
Daykin LM.Siddle JS.Ankers AL.Batsanov AS.Bryce MR. Tetrahedron 2010, 66: 668 - 5a
Kem WR.Soti F. Hydrobiologia 2001, 456: 221 - 5b
Pictet A.Rotschy A. Ber. Dtsch. Chem. Ges. 1901, 34: 696 - 5c
Pictet A. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1906, 244: 375 - 5d
Cruskie MP.Zoltewicz JA.Abboud KA. J. Org. Chem. 1995, 60: 7491 - 5e
Zoltewicz JA.Cruskie MP. Tetrahedron 1995, 51: 11401 - 6a
Jameson DL.Guise LE. Tetrahedron Lett. 1991, 18: 1999 - 6b
Yamamoto Y.Tanaka T.Yagi M.Inamoto M. Heterocycles 1996, 42: 189 - 6c
Cargill Thompson AMW. Coord. Chem. Rev. 1997, 160: 1 - 6d
Adrian JC.Hassib L.De Kimpe N.Keppens M. Tetrahedron 1998, 54: 2365 - 6e
Gunther R.Pagen S. Tetrahedron 1998, 137: 6687 - 6f
Fang YQ.Hanan GS. Synlett 2003, 852 - 6g
Cook MW.Wang J.Theobald I.Hanan GS. Synth. Commun. 2006, 36: 1721 - 7a
Ishikura M.Ohta T.Terashima M. Chem. Pharm. Bull. 1985, 33: 4755 - 7b
Matondo H.Ouhaja N.Souirti S.Baboulene M. Main Group Met. Chem. 2002, 25: 163 - 7c
Kudo N.Perseghini M.Fu GC. Angew. Chem. Int. Ed. 2006, 45: 1282 - 7d
Zhao LX.Sherchan J.Park JK.Jahng Y.Jeong BS.Jeong TC.Lee CS.Lee ES. Arch. Pharm. Res. 2006, 29: 1091 - 8
Koizumi TA.Tomon T.Tanaka K. Bull. Chem. Soc. Jpn. 2003, 76: 1969 - 9
Zhang J.Wu Y.Zhu Z.Ren G.Mak TCW.Song M. Appl. Organomet. Chem. 2007, 21: 935 - 10a
Kubota Y.Biradha K.Fujita M.Sakamoto S.Yamaguchi K. Bull. Chem. Soc. Jpn. 2002, 75: 559 - 10b
Thebault F.Barnett SA.Blake AJ.Wilson C.Champness NR.Schroeder M. Inorg. Chem. 2006, 45: 6179 - 11a
Yamamoto Y.Azuma Y.Mitoh H. Synthesis 1986, 564 - 11b
Eichinger K.Nussbaumer P.Vytlacil R. Spectrochim. Acta, Part A 1987, 43: 731 - 11c
Bauer R.Nussbaumer P.Neumann-Spallart M. Z. Naturforsch., B: Chem. Sci. 1988, 43: 475 - 11d
Rodinovskaya LA.Bogomolova OP.Shestopalov AM.Litvinov VP. Dokl. Akad. Nauk 1992, 324: 585 - 11e
Zoltewicz JA.Dill CD. Tetrahedron 1996, 52: 14469 - 11f
Farina V.Krishnamurthy V.Scott WJ. Org. React. 1997, 50: 1 - 11g
Karig G.Thasana N.Gallagher T. Synlett 2002, 808 - 11h
Beauchamp DA.Loeb SJ. Supramol. Chem. 2005, 17: 617 - 11i
Pierrat P.Gros PC.Fort Y. J. Comb. Chem. 2005, 7: 879 - 11j
Kozhevnikov VN.Kozhevnikov DN.Shabunina OV.Vladimir LR.Chupakhin ON. Terahedron Lett. 2005, 46: 1791 - 11k
Kozhevnikov VN.Shabunina OV.Kopchuk DS.Ustinova MM.König B.Kozhevnikov DN. Tetrahedron 2008, 64: 8963 - 12
Schröter S.Stock C.Bach T. Tetrahedron 2005, 61: 2245 - 13
Voisin-Chiret AS.Bouillon A.Burzicki G.Célant M.Legay R.El-Kashef H.Rault S. Tetrahedron 2009, 65: 607 - 14
Burzicki G.Voisin-Chiret AS.Sopkovà-de Oliveira Santos J.Rault S. Tetrahedron 2009, 65: 5413 - 15a
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2002, 58: 2885 - 15b
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2002, 58: 3323 - 15c
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2002, 58: 4369 - 15d
Bouillon A.Lancelot JC.Collot V.Bovy PR.Rault S. Tetrahedron 2003, 59: 10043 - 16a
Voisin AS.Bouillon A.Berenguer I.Lancelot JC.Lesnard A.Rault S. Tetrahedron 2006, 62: 11734 - 16b
Cailly T.Fabis F.Bouillon A.Lemaître S.Sopková-de Olivieira Santos J.Rault S. Synlett 2006, 53 - 17
Wang SL.Li M.Shen W.Li Y.Zhang BH. Xinan Daxue Xuebao, Ziran Kexueban 2007, 29: 25 - 18
Parry PR.Wang C.Batsanov AS.Bryce MR.Tarbit B. J. Org. Chem. 2002, 67: 7541 - 20
Roduit JP. In e-EROS Encyclopedia of Reagents for Organic Synthesis Wiley; New York: 2001.
References
Compound VII is commercially available, but its synthesis is unknown in the literature.
Figure 1 Some natural oligopyridines
Figure 2 Unsubstituted symmetric terpyridine families
Figure 3 42 Unsubstituted unsymmetric terpyridine families
Scheme 1 The Garlanding concept
Scheme 2 General strategy to prepare terpyridines
Scheme 3 Synthesis of 6′-bromo[2,3′]bipyridine (IIIb). Reagents and conditions: IIb (1.25 equiv), Ia or Ib (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 4 Preparation of [2,3′:6′,3′′]terpyridine (IV) and 5-bromo[2,3′:6′,3′′]terpyridine (Va). Reagents and conditions: IIa (1.25 equiv), IIIa or IIIb (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 5 Preparation of 5,6′′-dibromo[2,3′:6′,3′′]terpyridine (Vb) and 6′′-bromo[2,3′:6′,3′′]terpyridine (Vc). Reagents and conditions: IIb (1.25 equiv), IIIa or IIIb (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 6 Synthesis 5,6′-bromoiodo[2,3′]bipyridine (IIIc) and 6′-iodo[2,3′]bipyridine (IIId). Reagents and conditions: AcCl (2 × 2 equiv), NaI (2 × 4 equiv), MeCN, reflux, 2 × 24 h.
Scheme 7 Preparation of 5,6′′-dibromo[2,3′:6′,3′′]terpyridine (Vb) and 6′′-bromo[2,3′:6′,3′′]terpyridine (Vc). Reagents and conditions: IIb (1.25 equiv), IIIc or IIId (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 8 Preparation of 5-bromo[2,3′:6′,3′′:6′′,3′′′]quaterpyridine (VI). Reagents and conditions: IIa (1.25 equiv), Vb (1 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h.
Scheme 9 Preparation of 2,3,5-tribromopyridine (VIII) and 2,5-dibromo-3-pyridinecarboxaldehyde (VII) and 5-bromo[2,3′]bipyridine-3-carboxaldehyde (X) and [3,3′:6′,3′′]terpyridine-3′-carboxaldehyde (XI). Reagents and conditions: (i) HBr (48%), NaNO2 (2.5 equiv), Br2 (3.3 equiv), r.t., 3 h; (ii) n-BuLi (1.25 equiv), DMF (1.15 equiv), Et2O, -78 ˚C; (iii) IIa (1.25 equiv), aq Na2CO3 (2.5 equiv), Pd(PPh3)4 (0.05 equiv), 1,4-dioxane, reflux, 24 h; (iv) IIa (2.5 equiv), aq Na2CO3 (5 equiv), Pd(PPh3)4 (0.1 equiv), 1,4-dioxane, reflux, 24 h.