Abstract
A method for deprotection of several N-benzyl derivatives of amines to the corresponding amino derivatives with ammonium formate and 10% Pd-C is reported.
In our studies of efficient and rapid synthetic methods for radiopharmaceutical molecules labeled with the short-lived isotope 11C (half-life = 20.4 min). we have developed a catalytic deprotection procedure for N-benzyl derivatives of amines which is carried out under neutral conditions. Previous methods have either involved traditional high pressure catalytic hydrogenation3,4 or, more recently, formic acid as the hydrogen donor5. The later reaction gives formate salts from protected Z-amino acid precursors rather than free amino acids due to the acidic medium of the system. The general type of catalytic hydrogenation we report has been used successfully for removal of an O-benzyl group from peptides using cyclohexene, 1,4-cyclohexadiene, hydrazine hydrate and ammonium formate as hydrogen donors6-11.
Table 1
Debenzylation of N-benzyl Amine Derivatives
| N-Benzyl Derivs. (Bz = CH2C6H5) |
Productsb | Reaction Time |
Yielda |
Rf Values Productsc |
| C6H5CH2CH2NHBz | C6H5CH2CH2NH2 | 10 min | 90% |
0.4d |
| C6H5NHBz | C6H5NH2 | <10 min | 76% |
0.74f |
| HOCH2CH2CH2NHBz | HOCH2CH2CH2NH2 | 10 min | 95% |
0.05e |
| HOCH2CH2NHBz | HOCH2CH2NH2 | 10 min | 86% |
0.29g |
| HOCH2CH2N(Bz)CH3 | HOCH2CH2NHCH3 | 10 min | 83% |
0.11e |
| HN(CH2CH2)2NBz | HN(CH2CH2)2NH | 10 min | 92% |
0.11e |
(a) Isolated yields are based on the single experiment and
yields were not optimized;
(b) products were characterized by
comparison with authentic samples (IR, 1H-NMR, TLC and mp);
(c) relative Rf value = distance travelled by product
chromatogram/distance travelled by starting material
chromatogram, using E. Merck silica gel plates; mobile
phase: CHCl3:MeOH:58% NH4OH;
(d) 9:1:3 drops;
(e) 8.5:1.5:3 drops;
(f) 9.5:0.5;
(g) 7:3:6 drops.
Our deprotection method for N-benzyl amines which gives the free amine directly using ammonium formate is shown in Scheme 1 (R1 = H/CH3; R2 = Alkyl/Aryl).
These results demonstrate a rapid and versatile system for removal of an N-benzyl group from a wide variety of compounds under moderate reaction conditions. It should also be noted that this procedure has also been used successfully in the synthesis of 3-(N-methyl)-1-phenyl-1,3,8- triazaspiro[4,5]decan-4-one12 from 1-phenyl-1,3,8-triaza- spiro[4,5]decan-4-one, which is a key intermediate in the synthesis of 3-N-methylspiperone.
Experimental
General procedure for the debenzylation of I to II:
To a stirred suspension of an appropriate N-benzyl compound (3 mmol) and an equal weight of 10% Pd-C in dry methanol (20 ml), anhydrous ammonium formate (15 mmol) was added in a single portion under nitrogen. The resulting reaction mixture was stirred at reflux temperature and the reaction was monitored by TLC. After completion of reaction, the catalyst was removed by filtration through a celite pad, which was then washed with 20 ml of chloroform. The combined organic filtrate, on evaporation under reduced pressure, afforded the desired amino derivative. Characterization of this new procedure is shown in Table 1.