Abstract
Short-step and scalable transformations from 2,6-dibromopyridine
to 6-bromopyridine-2-sulfonamide by means of halogen-metal
exchange and subsequent reaction with sulfuryl chloride followed
by amidation are established. Application of the method for the
synthesis of various pyridine sulfonamides is also described.
Key words
sulfonyl chlorides - sulfonamides - pyridines - Grignard reaction - large-scale synthesis
References and Notes
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Large-Scale Preparations
of Sulfonamide 2: n-BuLi (1.6 M,
737 mL), n-Bu2Mg (2.0 M, 1176
mL), and THF (70 mL) were charged into a nitrogen-filled reaction
vessel at r.t. After cooling at -11 ˚C, a solution
of 2,6-dibromopyridine (700 g, 2.95 mol) in THF (2.7 L) was added
dropwise over 1 h and 40 min and the mixture was stirred at -10 ˚C
for 1 h. The resulting mixture was added to a solution of SO2Cl2 (364 mL,
4.53 mol) in toluene (2.8 L) at -12 ˚C over 1
h and 15 min and the mixture was stirred for 20 min. To the reaction mixture
was added H2O (2.8 L) over 40 min. After removal of the
aqueous layer, the organic phase was dried over MgSO4 (180
g). The mixture was filtered and concentrated affording the crude
sulfonyl chloride 5a (736.5 g). To a solution
of the sulfonyl chloride (713 g) in EtOAc (2.1 L) at 0 ˚C
was added a solution of HN(PMB)2 (571.2 g, 2.22 mol) and
Et3N (385 mL, 2.76 mol) in EtOAc (2.1 L), and the mixture
was stirred for 1 h and 10 min. The crude product obtained by extraction
and concentration was purified by crystallization from EtOH and
H2O giving the sulfonamide 2 (855.8
g, 64%).
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General Procedure: n-BuLi (2.3 M, 0.139 mL) and n-Bu2Mg (1.0 M, 0.321 mL)
were charged into a nitrogen-filled reaction tube at r.t. A solution
of halopyridine (0.8 mmol) in THF (0.76 mL) was added dropwise to
the n-Bu3MgLi solution at -10 ˚C
and the mixture was stirred at
-10 ˚C
for 1 h. The resulting mixture was added to a solution of SO2Cl2 (0.096
mL, 1.2 mmol) in toluene (0.76 mL) at -10 ˚C and
the mixture was stirred for 10 min. After allowing the temperature
of the reaction mixture to rise to 10 ˚C, Et2NH (0.414
mL, 4.0 mmol) was added and the mixture was stirred for 30 min.
Extraction and purification by silica gel chroma-tography afforded
the product.
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