10.1002/chem.201900450
Chemistry - A European Journal
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δ = 25.0 (q, 6-Me), 25.5 (t, 4-NCH2CH2), 47.1,* 47.5 (2 t, 4,4´´-NCH2CH2),
102.7, 104.2, 105.8 (3 d, C-3, C-3´, C-5), 153.1, 153.8, 156.2, 157.1, 157.6
(5 s, C-2, C-2´, C-4, C-4´,C-6) ppm; *signal with higher intensity. HRMS
(ESI-TOF): calcd. for C29H36N6: 469.3080 [M+H]+; found m/z = 469.3094.
4´-Bromo-6,6´´-dimethyl-4,4´´-bis(dimethylamino)-2,2´:6´,2´´-
terpyridine (2) and 6,6´´-Dimethyl-4,4´,4´´-tris(dimethylamino)-
2,2´:6´,2´´-terpyridine (3): A solution of bisnonaflate 4 (1.00 g, 1.07 mmol,
1 equiv.) in dimethylamine (2 M in THF; 15.0 mL, 29.9 mmol, 28 equiv.)
was stirred in a microwave vessel at 100 °C under irradiation for 3 h. After
cooling to room temperature, the mixture was concentrated under reduced
pressure and the residue was dissolved in CH2Cl2 (80 mL) and 1 M
aqueous NaOH solution (80 mL). The aqueous layer was separated and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were
dried (Na2SO4), filtrated and concentrated under reduced pressure.
Column chromatography (basic Al2O3, activity grade I; CH2Cl2/EtOAc 15:1
to 4:1, then CH2Cl2/MeOH 10:1) afforded 2 (0.209 g, 46%) and 3 (0.118 g,
28%) as colorless solids.
Data of 2: Rf = 0.63-0.45 (neutral Al2O3, activity grade I; CH2Cl2/EtOAc 3:1).
1H NMR (400 MHz, CDCl3): δ = 2.55 (s, 6 H, 6-Me), 3.09 (s, 12 H, NMe),
6.43 (d, J = 2.5 Hz, 2 H, 5-H), 7.73 (d, J = 2.5 Hz, 2 H, 3-H), 8.58 (s, 2 H,
3´-H) ppm. The data agree with those of the literature.[1]
Data of 3: Rf = 0.32 (neutral Al2O3, activity grade I; CH2Cl2/MeOH 25:1).
1H NMR (400 MHz, CDCl3): δ = 2.57 (s, 6 H, 6-Me), 3.10 (s, 12 H, 4-NMe),
3.20 (s, 6 H, 4´-NMe), 6.41 (d, J = 2.5 Hz, 2 H, 5-H), 7.73 (s, 2 H, 3´-H),
7.78 (d, J = 2.5 Hz, 2 H, 3-H) ppm. The data agree with those of the
literature.[1]
6,6´´-Dimethyl-4,4´´-bis(dimethylamino)-2,2´:6´,2´´-terpyridine (1): To
a solution of 2 (0.100 g, 0.235 mmol, 1 equiv.), Pd(OAc)2 (10.5 mg, 47.0
µmol, 0.2 equiv.) and 1,3-bis(diphenylphosphino)propane (39.0 mg, 94.0
µmol, 0.4 equiv.) in DMF (5 mL) were added Et3N (0.293 mL, 0.211 mmol,
9 equiv.) and HCO2H (64.8 mg, 53.1 µL, 141 µmol, 6 equiv.). The mixture
was stirred at 90 °C for 6 h. After cooling to room temperature, 0.5 M
aqueous NaOH solution (15 mL) was slowly added and the resulting
suspension was stirred for 15 min at room temperature. The precipitate
was filtered off, dissolved in MeOH (3 × 10 mL) and the methanolic filtrate
was concentrated under reduced pressure. Recrystallization from hot
CHCl3/Et2O afforded 2 (51 mg, 63%) as colorless crystals.
Rf = 0.43-0.18 (neutral Al2O3, activity grade I; CH2Cl2/MeOH 50:1).
1H NMR (400 MHz, CDCl3): δ = 2.55 (s, 6 H, 6-Me), 3.06 (s, 12 H, NCH3),
6.41 (d, J = 2.4 Hz, 2 H, 5-H), 7.76 (d, J = 2.4 Hz, 2 H, 3-H), 7.87 (t, J =
7.8 Hz, 1 H, 4´-H), 8.39 (d, J = 7.8 Hz, 2 H, 3’-H) ppm. The data agree with
those of the literature.[1]
6,6´´-Dimethyl-4,4´´-di(pyrrolidin-1-yl)-2,2´:6´,2´´-terpyridine (12): To a
solution of 10 (14 mg, 29 μmol, 1 equiv.), Pd(OAc)2 (1.3 mg, 5.8 µmol, 0.2
equiv.) and bis(diphenylphosphino)propane (4.8 mg, 12 µmol, 0.4 equiv.)
in DMF (0.4 mL) were added Et3N (36 µL, 0.27 mmol, 9 equiv.) and HCO2H
(8.3 mg, 6.8 µL, 0.18 mmol, 6 equiv.). The mixture was stirred at 90 °C for
36 h. After cooling to room temperature, the reaction mixture was diluted
with EtOAc (15 mL) and washed with 1 M aqueous NaOH solution (2 × 10
mL) and the combined aqueous layers were extracted with EtOAc (3 × 10
mL). The combined organic layers were dried (Na2SO4), filtrated and
concentrated under reduced pressure. Column chromatography (basic
Al2O3, activity grade I; CH2Cl2/EtOAc/MeOH 10:1:0 to 10:3:0 to 10:1:0.1)
afforded 12 (6.1 mg, 51%) as a colorless solid.
Rf = 0.54-0.27 (neutral Al2O3, activity grade I; CH2Cl2/MeOH 100:3). M.p.
>155 °C (decomp.). 1H NMR (700 MHz, CDCl3) δ = 2.04–2.08 (m, 8 H,
4-NCH2CH2), 2.56 (s, 6 H, 6-Me), 3.44 (s, 8 H, 4-NCH2CH2), 6.31 (d,
J = 2.2 Hz, 2 H, 5-H), 7.61 (s, 2 H, 3-H), 7.88 (s, 1 H, 4´-H), 8.38 (d,
J = 7.7 Hz, 2 H, 3´-H) ppm.
4´-Bromo-6,6´´-dimethyl-4,4´´-di(pyrrolidin-1-yl)-2,2´:6´,2´´-
terpyridine (10): According to the reaction leading to 2 and 3, a solution
of bisnonaflate 4 (0.200 g, 0.214 mmol, 1 equiv.) in pyrrolidine (1.06 mL,
12.8 mmol, 60 equiv.) was stirred in a microwave vessel at 120 °C under
irradiation for 1 h. Work-up and column chromatography (basic Al2O3,
activity grade I; CH2Cl2/EtOAc 5:1 to 1:1) afforded 10 (0.062 g, 61%) as
colorless crystals.
Rf = 0.21 (neutral Al2O3, activity grade I, CH2Cl2/EtOAc 4:1). M.p. >200 °C
(decomp.). 1H NMR (400 MHz, CDCl3):
δ = 2.02–2.08 (m, 8 H,
4-NCH2CH2), 2.54 (s, 6 H, 6-Me), 3.39–3.45 (m, 8 H, 4-NCH2CH2), 6.31 (d,
J = 2.3 Hz, 2 H, 5-H), 7.55 (d, J = 2.3 Hz, 2 H, 3-H), 8.56 (s, 2 H, 3´-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 24.8 (q, 6-Me), 25.5 (t, 4-NCH2CH2),
47.2 (t, 4-NCH2CH2), 102.8, 106.5, 124.1 (3 d, C-3´, C-5), 134.8, 153.2,
154.5, 157.1, 157.8 (5 s, C-2, C-2´, C-4, C-4´, C-6) ppm. HRMS (ESI-TOF):
calcd. for C25H29BrN5 [M+H]+: 478.1601, found 478.1618.
13C NMR (176 MHz, CDCl3) δ = 24.9 (q, 6-Me), 25.5 (t, NCH2CH2), 47.2
(t, NCH2CH2), 102.3 (d, C-3), 106.1 (d, C-5), 121.3 (d, C-3´), 137.9 (d, C-
4´), 153.6, 155.8, 156.0 (3 s, C-2, C-2´, C-4), 158.0 (s, C-6) ppm. HRMS
(ESI-TOF): calcd. for C25H29N5 [M+H]+: 400.2501; found 400.2506.
Synthesis of 6,6´´-Dimethyl-4,4´,4´´-tris(dimethylamino)-2,2´:6´,2´´-
terpyridine (3) by Buchwald-Hartwig Amination: To a solution of 2
(0.190 g, 0.446 mmol, 1 equiv.), NaOtBu (0.090 g, 0.936 mmol, 2.1 equiv.),
Pd(dba)2 (12.8 mg, 22.0 µmol, 0.05 equiv.) and 2-dicyclohexylphosphino-
2´,6´-dimethoxybiphenyl (18.3 mg, 45.0 µmol, 0.1 equiv.) in toluene (5 mL)
dimethylamine (2 M in THF, 446 µL, 0.891 mmol, 2 equiv.) was added. The
resulting red mixture was stirred at 90 °C for 3 d in an ACE pressure tube.
After cooling to room temperature, the mixture was quenched by the
addition of 2 M aqueous NaOH solution (40 mL) and extracted with CH2Cl2
(3 × 40 mL). The combined organic layers were dried (MgSO4), filtrated
and concentrated under reduced pressure. Recrystallization of the
resulting solid from hot CHCl3/Et2O afforded 3 (0.141 g, 81%) as colorless
crystals.
Copies of NMR spectra of all compounds and details concerning the
computations can be found in the Supporting Information.
Acknowledgements
Generous support of this work by the Deutsche
Forschungsgemeinschaft and Bayer HealthCare is most
gratefully acknowledged. Marta Marin-Luna thanks Xunta de
Galicia for her postdoctoral contract (ED481B 2016/166-0). We
also thank Jonas Haag, Julian F. Hille, Linda Barany, Kamar
Shakeri and Niklas Limberg for experimental contributions.
Synthesis of 6,6´´-Dimethyl-4,4´,4´´-tri(pyrrolidin-1-yl)-2,2´:6´,2´´-
terpyridine (11) by Buchwald-Hartwig Amination: According to the
Buchwald-Hartwig amination of 2, to a solution of 10 (15 mg, 31 µmol,
1 equiv.), NaOtBu (6.9 mg, 72 µmol, 2.3 equiv.), Pd(dba)2 (0.9 mg, 1.6
µmol, 0.05 equiv.) and 2-dicyclohexylphosphino-2´,6´-dimethoxybiphenyl
(1.3 mg, 3.1 µmol, 0.1 equiv.) in toluene (1 mL) was added a solution of
pyrrolidine (5.1 µL, 4.4 mg, 63 µmol, 2.0 equiv., dissolved in 0.1 mL of
toluene). The resulting mixture was stirred at 100 °C for 16 h. Work-up and
recrystallization from hot CHCl3/Et2O afforded 11 (14 mg, 95%) as
colorless crystals.
Rf = 0.36-0.24 (neutral Al2O3, activity grade I; CH2Cl2/MeOH 25:1).
M.p. >215 °C (decomp.). 1H NMR (500 MHz, CDCl3): δ = 1.98–2.07 (m, 12
H, 4-NCH2CH2), 2.53 (s, 6 H, 6-Me), 3.37–3.47 (m, 8 H, 4-NCH2CH2),
3.52–3.57 (m, 4 H, 4´-NCH2CH2), 6.27 (d, J = 2.3 Hz, 2 H, 5-H), 7.52 (s, 2
H, 3´-H), 7.61 (d, J = 2.3 Hz, 2 H, 3-H) ppm. 13C NMR (126 MHz, CDCl3):
Keywords: Terpyridine • Amination • Palladium Catalysis •
Methyl Cation Affinity • Lewis Bases
[1]
[2]
P. Hommes, C. Fischer, C. Lindner, H. Zipse, H.-U. Reissig, Angew.
Chem. 2014, 126, 7778-7782; Angew. Chem. Int. Ed. 2014, 53, 7647-
7651.
Reviews: a) G. Höfle, W. Steglich, H. Vorbrüggen, Angew. Chem. 1978,
90, 602-615; Angew. Chem. Int. Ed. Engl. 1978, 17, 569-583. b) A. C.
Spivey, S. Arseniyadis, Angew. Chem. 2004, 116, 5552-5557; Angew.
Chem. Int. Ed. 2004, 43, 5436-5441. c) N. D. Rycke, F. Couty, O. R. P.
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