Use of Dibutyl[¹⁴C]formamide as a Formylating Reagent in the Vilsmeier–Haack Reaction and Synthesis of a ¹⁴C‐Labeled Novel Phosphodiesterase‐4 (PDE‐4) Inhibitor

Abstract

A simple, high‐yielding synthesis of dibutyl[14C]formamide ([14C]DBF; 1) from 14CO2 was developed (Scheme 1): reaction of LiBEt3H and 14CO2 followed by aqueous workup gave H14CO2H in high yield. Conversion of the [14C]formic acid to 1 was effected by a standard carbodiimide coupling procedure. The utility of 1 as an alternative to dimethyl[14C]formamide ([14C]DMF) in alkylation reactions and in the [14C]Vilsmeier–Haack reaction was demonstrated for several substrates (Table 2). A 14C‐labeled phosphodiesterase‐4 (PDE‐4) inhibitor, [14C]‐2, was synthesized by application of this technology (Scheme 2).

Stereochemical Course of Tryptophan Dehydrogenation during Biosynthesis of the Calcium-Dependent Lipopeptide Antibiotics

“…The synthesis of (2‘ S ,3‘ R )-[3‘- 2 H 1 ]-tryptophan 1 was achieved via the Vilsmeier formylation of indole 2 with deuterated dimethylformamide (DMF- d 7 ) (Scheme ). Literature procedures for this formylation typically utilize DMF as the solvent . However, to conserve the labeled precursor, the reaction was optimized using toluene as a solvent, such that a 1.2:1 molar ratio of indole to DMF- d 7 was required to generate indole-3-deuterocarboxaldehyde 3 in 64% yield (based on DMF- d 7 ).…”

Synthesis of (2-mercaptoacetyl)-L-[2-14C]tryptophan as a selective metallo-β-lactamase inhibitor via [2-14C]indole based on chiral pool strategy

“…Barium [ 14 C]carbonate (24 mmol, 20 MBq/mmol, 480.3 MBq) was converted to formic [ 14 C]acid (18.37 mmol, 367.4 MBq) in the presence of LiBEt 3 H (36.6 mL, 1 mol/L) in THF according to known procedure in 76.5% radiochemical yield, and product was collected for the next step …”

“…Formic [ 14 C]acid 3 was prepared from barium [ 14 C]carbonate 2 under standard procedure by reduction of 14 CO 2 by LiEt 3 BH . N ‐ [ 14 C]formyl‐o‐toluidine 5 was derived from reaction of o‐toluidine 4 and formic [ 14 C]acid 3 .…”

“…Formic [ 14 C]acid 3 was prepared from barium [ 14 C]carbonate 2 under standard procedure by reduction of 14 CO 2 by LiEt 3 BH. 33 35 2 | RESULTS AND DISCUSSION 1-(Tert-butyldimethylsilyl)-1H-[2-14 C]indole 6 was prepared by reaction between 1H-[2-14 C]indole and tertbutyldimethylsilyl chloride in good yield. The conversion of compound 6 to 3-bromo-1-(tert-butyldimethylsilyl)-1H-[2-14 C] indole 7 was performed from reaction of N-Bromosuccinimide with 6 in tetrahydrofuran(THF) at low temperature.…”

1,2,3-Triazoles

“…Some of the dehydrating agents used in the process are also derivatives of HOBt 1298–1301 . In some instances, these derivatives, HBTU 1298 2002JOC1184 , 2004NAR623 , TBTU 1299 2005HCA447 , 2005HCA1040 , 2005TL6239 , 2006OL2851 , 2006TL1737 and BOP 1300 2005JA17894 , 2005JOC3660 , 2006JA3011 , 2006OL239 , 2006OL511 are used alone without addition of HOBt. Combinations of HOBt with dehydrating agents, especially DIC 2005JOC9622 , 2005TL7443 , 2006JCO150 , 2006JME1833 , 2006JME2388 , HBTU 2005AGE2534 , 2005JCO697 , 2005JOC7654 , 2005TL4053 , 2006TL2671 and BOP 2002BML2855 , 2005AGE2887 , 2005JCO703 are common reagents in solid-phase synthesis of peptides.…”