10.1002/cbic.202000408
ChemBioChem
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combined organic phases were dried over MgSO4 and the solvent
removed in vacuo to yield the diester product 1a as a white solid
(16.712 g, yield = 71.5%). 1H-NMR (600 MHz, CDCl3): δ 9.24 (dd,
J = 2.1, 0.7 Hz, 1H), 8.39 (dd, J = 8.1, 2.1 Hz, 1H), 8.15 (dd, J =
8.1, 0.7 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H). 13C-NMR (151 MHz,
CDCl3): δ 164.9, 164.8, 150.8, 150.7, 138.3, 128.6, 124.7, 53.2,
52.7.
J = 7.4, 4.9, 0.9 Hz, 1H), 4.71 (s, 2H), 3.99 (s, 2H), 3.97 (s, 2H).
13C-NMR (151 MHz, CDCl3): δ 195.8, 149.4, 148.3, 136.6, 135.6,
122.4, 122.3, 122.2, 63.0, 54.8, 54.62.
5-Hydroxomethyl-tris-(2-pycolyl)amine (5a)
4a (0.130 g, 0.57 mmol) was dissolved in CH3CN (15 mL) and
stirred with NaHCO3 (0.097 g, 1.15 mmol). 2-pycolylchloride
(0.072 g, 0.57 mmol) in CH3CN (15 mL) was added dropwise and
the mixture was stirred at 50 °C for 72 h. The solution was filtered
and the filtrate evaporated to afford 5a as a brown oil. (0.135 g,
2,5-Bis(hydroxymethyl)pyridine (2a)
2a was synthesized according to a procedure previously reported
by Kramer et al.[50] NaBH4 (0.390 g, 10.30 mmol) was added
slowly to a suspension of 1a (0.502 g, 2.57 mmol) in EtOH (10
mL) at 0 °C. The solution was stirred for 1 h at 0 °C, then for 3 h
at room temperature, and finally at reflux overnight. The solvent
was removed and the resulting yellow oil was dissolved in a
mixture of acetone (50 mL) and saturated aqueous solution of
K2CO3 (50 mL), refluxed for 1 h and the yellow organic phase
collected from a bi-phasic mixture. The solvent was removed and
the crude product purified via dry column vacuum
chromatography (DCVC silica gel, CH2Cl2:MeOH, 7:1 v/v) to yield
the diol 2a as a yellow, hygroscopic oil (0.204 g, yield = 57.0%).
1H-NMR (600 MHz, MeOD-d4): δ 8.46 (d, J = 1.6 Hz, 1H), 7.84
(dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H),
4.65 (s, 2H). 13C-NMR (151 MHz, MeOD): δ 161.2, 148.1, 137.6,
137.3, 121.8, 65.4, 62.4.
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yield = 74.4%) H-NMR (600 MHz, CDCl3): δ 8.51 (dq, J = 4.8,
1.6, 0.8 Hz, 2H), 8.47 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 8.0, 2.2
Hz, 1H), 7.64 (td, J = 7.7, 1.8 Hz, 2H), 7.57 (d, J = 2.7 Hz, 2 H),
7.55 (d, J = 2.9 Hz, 1 H), 7.13 (qd, J = 7.4, 4.9, 1.1 Hz, 2H), 4.68
(s, 2H), 3.85 (s + s, 6H).
5-Chloromethyl-tris-(2-pycolyl)amine (6a)
A modification of the literature procedure by Sprakel et al. was
employed.[52] A solution of 5a (0.396 g, 1.24 mmol) in CHCl3 (5
mL) was added dropwise at 0 °C to a solution of SOCl2 (0.450 mL,
6.18 mmol) in CHCl3 (10 mL) and stirred overnight at room
temperature. The solvent was removed in vacuo and the green
product was dissolved in THF (5 mL) and DIPEA (0.808 mL) and
stirred under argon for 3 h at room temperature and filtered
through a celite pad (25 mL THF wash). Solvent was removed in
1
vacuo to yield 6a as a brown solid. (0.381 g, yield = 90.9%) H
2-Formyl-5-hydroxymethylpyridine (3a)
NMR (600 MHz, CDCl3): δ 8.54 (dq, J = 4.8, 1.8, 0.9 Hz, 2H), 8.52
(d, J = 1.9 Hz, 2H), 7.69 (dd, J = 8.1, 2.3 Hz, 1H), 7.65 (td, J =
7.7, 1.8 Hz, 2H), 7.60 (d, J = 8.1 Hz, 1 H), 7.56 (d, J = 7.8 Hz, 2
H), 7.14 (qd, J = 7.4, 4.9, 1.2 Hz, 2H), 4.56 (s, 2H), 3.89 (s, 2H),
3.88 (s, 4H).
3a was synthesized according to a procedure reported by
Dawson et al.[51] Under inert atmosphere, 2a (8.277 g, 59.49
mmol) was dissolved in 1,4-dioxane (80 mL) and H2O (2 mL) and
SeO2 (3.386 g, 30.51 mmol) was added. The mixture was
degassed and heated under argon at 100 °C for 3 h. The solution
was then filtered through a celite pad (30 mL dioxane wash),
reduced in volume to ~ 5 mL, and purified via DCVC (silica gel,
hexane:ethylacetate, gradient 50:50 to 25:75 v/v). The fractions
of the product were combined, and solvent removed in vacuo to
yield 3a as a pale yellow solid (6.633 g, yield = 81.3%). 1H-NMR
(600 MHz, CDCl3): δ 10.1 (d, J = 0.8 Hz, 1H), 8.77 (dd, J = 2.0,
0.7 Hz, 1H), 7.97 (dd, J = 8.0, 0.7 Hz, 1H), 7.90 (dq, J = 8.0, 2.1,
0.8 Hz, 1H), 4.87 (s, 2H, CH2). 13C-NMR (151 MHz, CDCl3): δ
193.2, 152.4, 148.8, 140.9, 135.4, 121.8, 62.5.
5-Azidomethyl-tris-(2-pycolyl)amine (7a)
To a solution of 6a (0.381 g, 1.12 mmol) in CH3CN (20 mL), NaN3
(0.219 g, 3.37 mmol) was added. The mixture was stirred in the
dark at 50 °C overnight, filtered through a celite pad and solvent
removed. The product was dissolved in CHCl3 (20 mL) and
washed with H2O (3 x 10 mL). The organic phase was dried to
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yield 7a as a brown solid (0.148 g, yield = 38.3%) H NMR (600
MHz, CDCl3): δ 8.54 (dq, J = 7.2, 2.3, 1.2 Hz, 2H), 8.47 (s, 1H),
7.66 (td, J = 11.5, 2.7 Hz, 4H), 7.63 (d, J = 2.8 Hz, 4H), 7.56 (d, J
= 11.6 Hz, 2 H), 7.15 (qd, J = 11.1, 7.4, 1.7 Hz, 2H), 4.35 (s, 2H),
3.90 (s, 2H), 3.89 (s, 4H).
5-Hydroxomethyl-di-(2-pycolyl)amine (4a)
To a solution of 2-picolylamine (0.179 g, 1.65 mmol) in MeOH (20
mL), a solution of 3a (0.229 g, 1.67 mmol) in MeOH (20 mL) was
added at 0 °C, stirred for 1 h at room temperature and NaBH4
(0.063 g, 1.66 mmol) was added at 0 °C. The reaction was stirred
at room temperature overnight. A minimal volume of H2O was
added and MeOH was removed in vacuo. The solution was
acidified with conc. HCl to pH ~ 4 and extracted with CH2Cl2 (6 x
20 mL). NaHCO3 was slowly added to the aqueous layer to reach
pH ~ 8, extracted with CH2Cl2 (3 x 100 mL) and the combined
organic layers were dried over MgSO4. The solvent was removed
to afford 4a as a yellow oil (0.170 g, yield = 44.9%). 1H-NMR (600
MHz, CDCl3): δ 8.56 (dq, J = 4.9, 1.5, 0.8 Hz, 1H), 8.53 (d, J = 1.8
Hz, 1H), 7.67 (dd, J = 8.0, 2.2 Hz, 1H), 7.64 (td, J = 7.6, 1.8 Hz,
1H), 7.37 (d, J = 7.9, Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.16 (qd,
Route B: Synthesis of N-6-(azidomethyl)pyridine-N-di-(2-
picolyl)amine (6N3-TPMA)
Synthesis of di-(2-picolyl)amine (DPA)
Di-(2-picolyl)amine was synthesized according to a procedure
reported by Hamann et al.[53] To a solution of 2-picolylamine
(2.011 g, 18.6 mmol) in MeOH (10 mL), a solution of 2-
pyridinecarboxaldehyde (2.025 g, 18.9 mmol) in MeOH (10 mL)
was added dropwise at 0 °C. The solution was stirred for 1 h at
room temperature, NaBH4 (0.704 g, 18.6 mmol) was added slowly
at 0 °C and stirred at room temperature overnight. A minimal
volume of water was added and MeOH was removed in vacuo.
The solution was acidified with conc. HCl to pH ~ 4 and extracted
with CH2Cl2 (6 x 20 mL). Na2CO3 was added slowly to the
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