A Cyclative Cleavage Approach to the Solid Phase Synthesis of 2-Oxo-1,4-piperazines

Abstract

A new facile solid phase synthesis of 2-oxo-1,4-piperazines is described. α-N-Boc-amino aldehydes, which were generated in situ by oxidation of commercially available α-amino alcohols promoted by a polymer supported bromite, were used for the reductive amination of Merrifield-resin bound amino acids. N-substitutions of the resulting secondary amine followed by Boc removal and finally, basic promoted cyclative cleavage affords trisubstituted 2-oxo-1,4-piperazines in good yields and excellent purity. The procedure utilizes readily available building blocks and is amenable to generate large libraries in a discrete manner.

combinatorial chemistry - solid-phase synthesis - heterocycles - cyclative cleavage - polymer-supported reagent

References

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<A NAME="RG07802ST-6">6</A> The preparation of reagent 1 was achieved following the procedure published in: Menenschein H. Sourkouni-Argirusi G. Schubotte KM. O’Hare T. Kirsching A. Org. Lett.  1999,  1:  2101 ; using a polymer-bound bromide purchased from Fluka which was previously vacuum dried over anhydrous P₂O₅ for 2 days

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<A NAME="RG07802ST-10">10</A>

Data for 12: ¹H NMR (CDCl₃) δ 0.54 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.5 Hz, 3 H), 2.39 (dd, J = 13.6, 10.3 Hz, 1 H), 2.73-2.96 (m, 3 H), 3.19 (d, J = 7.1 Hz, 1 H exch.), 3.29 (dd, J = 13.7, 2.7 Hz, 1 H), 3.45 (q, J = 6.6 Hz, 1 H), 3.72-3.82 (m, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 4.50 (d, J = 10.2 Hz, 1 H), 5.74 (s, 1 H exch.), 6.70 (d, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 2 H), 7.11-7.31 (m, 5 H), 7.82 (s, 1 H exch.).

<A NAME="RG07802ST-11">11</A>

General procedure for the synthesis of 2-oxo-1,4-piperazine library: Eight α-N-Boc-amino alcohols (18 mmol) were dissolved in CH₂Cl₂ (160 mL) and treated with polymer bound diacetoxybromite (1) (3.5 mmol/g, 25 g) and a catalytic amount of TEMPO (1.8 mmol), after 4 h the reactions were completed. The suspensions were filtered through glass wool and the filtrates were added in 20 mL portions to each of 8 reactors containing a suspension of the resin bound amino acid (4.8 g/reactor, 1.5mmol/g) in TMOF (20 mL) and shaken for 30 min at r.t., then a 0.5 M solution of NaBH(OAc)₃ (288 mmol) in 5% AcOH-DMF was added (72 mL/reactor) and shaken for further 16 h r.t. The suspensions were then transferred to four 96er FlexChem blocks (the resin contained in one reactor in the same row of all four blocks, 100 mg resin/reactor) and the resins were washed with DMF (3 ×), MeOH (3 ×) and CH₂Cl₂ (3 ×). The resulting resin bound amines were submitted to the following substitutions:
Block 1: A 0.5 M solution of 12 different isocyanates (6 mmoL) in CH₂Cl₂ was added to each column (1.5 mL/reactor), the block was sealed and shaken 16 h at r.t., the resin was then washed with CH₂Cl₂ (3 ×), MeOH (3 ×) and CH₂Cl₂ (1 ×).
Block 2: A 0.5 M solution of 12 different acyl chlorides (6 mmol) in CH₂Cl₂ was added to a column, then Et₃N (1.5 mmol) was added to each reactor, the block was sealed and shaken overnight, the resin was then washed as usual.
Block 3: The resin was suspended in pyridine (1.5 mmol/reactor) and treated with bromoacetyl bromide (72 mmol) 0.5 M in CH₂Cl₂, the block was sealed and shaken for 2 h at r.t., the resin was then washed as usual. A 1 M solution of 12 different secondary amines (12 mmol) in DMSO was then added in each column, the block sealed and shaken overnight, then washed as usual.
Block 4: A 1 M solution of 12 different aldehydes (6 mmol) in TMOF was added to each column and shaken for 30 min, then a 0.75 M degassed solution of NaBH(OAc)₃ (72 mmol) in 5% AcOH-DMF was added, the block was sealed and shaken overnight, the resin was then washed as usual.
For Boc deprotection the resin was suspended in 50% TFA in CH₂Cl₂ 30 min, filtered and washed with CH₂Cl₂ (3 ×) and 1% Et₃N in CH₂Cl₂ (1 ×). Then the resin was suspended in CH₂Cl₂ containing 4% triethylamine, then the block was sealed and shaken overnight at r.t. The solution was collected in microtiter plates and the resin washed with CH₂Cl₂ (3 × 1mL). The filtrate and collected washings were concentrated under reduced pressure to afford pure 2-oxo-1,4-piperazines.

<A NAME="RG07802ST-12">12</A>

A compound was considered to fulfill the requirements when the LC-MS peak with correct MW have an UV214-purity >80% and the crude yield was superior to 25 µmol.