Uses
2,6-dichloro-4-iodopyridine has useful structural, electronic, and optical properties， can be used for polysubstituted pyridines.
Synthesis
The general procedure for the synthesis of 2,6-dichloro-4-iodopyridine from 4-amino-2,6-dichloropyridine is as follows:
Reagents and conditions:
a) n-BuLi, ArBr; ZnCl2; followed by addition of 2,6-dibromopyridine and catalyst Pd(PPh3)4 (95% yield).
b) LiOH, THF/H2O (100% yield).
c) (COCl)2; NaN3; TFA.
d) K2CO3, CH3OH (78% yield).
e) HCl, CH3CN, NaNO2; KI (52% yield).
f) n-BuLi, ArBr; ZnCl2; followed by the addition of 13 and catalyst Pd(PPh3)4 (98% yield).
g) ArB(OH)2, catalyst Pd2(dba)3, catalyst P(t-Bu)3, Cs2CO3 (82% yield);.
h) Same as step f (71% yield).
i) Same as step g (31% yield).
j) n-BuLi, ArBr; ZnCl2; followed by addition of 12 (80% yield); and
k) 2-aminophenol, EDCI (97% yield); l) 230°C (87% yield); n-BuLi, ArBr; ZnCl2; followed by 12 (80% yield)
l) 230°C (87% yield).
m) ArB(OH)2, catalyst Pd2(dba)3, catalyst [HP(t-Bu)3]BF4, Cs2CO3 (78% yield).
The synthesis of 4 began with the pyridine derivative citric acid. Treatment with POCl3 at elevated temperatures afforded the corresponding 2,6-dichloroisonicotinoyl chloride. To facilitate purification, the reaction was quenched with methanol; after passing a silica plug to remove colored impurities, the methyl ester 1 was isolated in 76% yield. Saponification then provided acid 2 in quantitative yield without purification. Conversion to 3 was achieved by conversion to acyl azides, thermal Curtius rearrangement and hydrolysis of the resulting trifluoroacetamide to give 2,6-dichloro-4-aminopyridine (3) (Pfister, JR, Wymann, WE Synthesis 1983,38). Although this method for converting 2 to 3 is nominally a 3-step process, it requires only a single post-extraction treatment so that these steps can be performed in rapid succession. Direct conversion of 3 to 4 by diazotization and reaction with potassium iodide (which must be stirred in cold hydrochloric acid for 3 h prior to diazotization to obtain acceptable yields) provides 4 in reasonable yields and with excellent purity after grinding with acetone. This short reaction sequence permits the preparation of 4 in 35% overall yield, does not require chromatography except for a single filtration through a silicone plug, and permits the routine preparation of 5-10 g amounts of this intermediate. Unlike many 4-halopyridines, 4 is stable at room temperature for several months if protected from light.4 can be readily converted to the fluorophore of this invention.
References
[1] Organic Letters, 2001, vol. 3, # 26, p. 4263 - 4265
[2] Patent: WO2004/46103, 2004, A2. Location in patent: Page 33-34; 39-40
[3] Organic Letters, 2003, vol. 5, # 7, p. 967 - 970
[4] Roczniki Chemii, 1959, vol. 33, p. 387,392
[5] Chem.Abstr., 1959, p. 18954
