Application: Scavenging nucleophiles including primary amines, hydrazines, reducing agents
Scavenging Conditions: 3 equivalents relative to carbonyl, 1–3 h, 20 ˚C, DCM. Ketones and hindered aldehydes are accelerated by the addition of HOAc (~10%) and/or heat.
PS-Benzaldehyde1,2 is the resin-bound equivalent of benzal-dehyde. This resin is useful for scavenging various nucleo-philes, including primary amines (selectively compared with secondary amines), hydrazines (Scheme 1) also carbon-based nucleophiles such as Meldrum’s acid and organometallics. The capacity of the resin is typically 1.2 mmol/g, based on uptake of phenylhydrazine. Scavenging reactions typically use 3 equivalents of resin per equivalent of substrate to be scavenged. Various solvents can be used, including DCE, DCM, and DMF with a temperature range from 20 to 50 ˚C. PS-Benzaldehyde is stable at room temperature with no loss of activity observed.
Representative ProcedurePhenylhydrazine ScavengingPS-Benzaldehyde resin (3 equivalents) in DCE was allowed to react with phenylhydrazine (1 equivalent) in the presence of a catalytic amount of glacial HOAc. The reaction was monitored by TLC and was complete after stirring for approximately 1 h at room temperature. The reaction may also be run without HOAc by heating for 1 h at 50 ˚C.
Scavenging Various SubstratesPS-Benzaldehyde (3 equivalents) was added to a solution of the substrate in DCE along with a catalyst if necessary. The mixture was stirred for the specified time and temperature, and the filtrate was analyzed by TLC for disappearance of the substrate by comparison with standards.
Reductive Alkylation of Primary Amines (Table 2, Entry 3)A THF solution (0.50 M) of N-(3-aminopropyl)morpholine (1.2 mL, 0.60 mmol) was added to a THF solution (0.50 M) of 1,4-cyclohexanedione mono-ethylene ketal (1.0 mL, 0.50 mmol). MP-Triacetoxyborohydride (2.0 mmol/g, 0.625 g, 1.25 mmol) was then added and the mixture was agitated for 16 h at room temperature. When the reaction was complete, PS-Benzaldehyde (0.42 g, 0.5 mmol) and THF (2 mL) were added and the mixture was further agitated for 6 h. The resin was filtered and washed with THF (2 x 4 mL). The combined solution was concentrated to afford the product secondary amine as the acetate salt in 77% yield and 100% purity. The secondary amine was characterized by gas chromatography and H NMR.
1.3 Good
La
boratory Practice
Shelf Life Capacity (mmol/g) BSE/TSE Scalable Particle Size
Table 1. Comparative scavenging of nucleophiles with PS-Benzaldehyde. *Reactions were judged complete when substrate was no longer observable by TLC. Merck silica gel 60 F254 plates were used and detection was by short-wave UV or iodine. Scavenging of phenylmagnesium chloride was monitored by quenching an aliquot with benzophenone, followed by TLC analysis and comparison with an authentic tri-phenylmethanol sample.
Traditional Chemistry Resin Bound Chemistry
R1NH2
R2 R3
O
1-1.2 equiv.
+
i. 1.4 equiv. NaBH(OAc)3 (1
equiv. HOAc), RT, 1-16 hrs
ii. 1M NaOHiii. Ether extractioniv. Wash. dryv. Column purification
R3R2
HNR1
3i. 2.5 equiv. MP-BH(OAc) , RT, 1-16 hrs, THF
ii. 1 equiv. PS-CHO, 6hriii. Filter, wash, concentrate
