A Polymer-Bound 1,3-Diketone: A Highly Efficient Scavenger for Hydrazines, and Primary Amines

Abstract

A 1,3-diketone resin was developed as the basis for a selective scavenger for hydrazines. In addition, it can be employed for the selective removal of primary amines in the presence of secondary amines which is of fundamental importance in the purification of reductive alkylations. The resin’s specificity is based on the sequestration of the hydrazine via their polymer-attached pyrazoles and of the primary amines via their enamines.

amines - combinatorial chemistry - hydrazines - polymer supported reagent - scavenger resin

References

<A NAME="RG02103ST-1A">1a</A> Kirschning A. Monenschein H. Wittenberg R. Angew. Chem. Int. Ed.  2001,  40:  650 

<A NAME="RG02103ST-1B">1b</A> Ley SV. Baxendale IR. Bream RN. Jackson PS. Leach AG. Longbottom DA. Nesi M. Scott JS. Storer RI. Taylor SJ. J. Chem. Soc., Perkin Trans. 1  2000,  3815 

<A NAME="RG02103ST-1C">1c</A> Drewry DH. Coe DM. Poon S. Med. Res. Rev.  1999,  19:  97 

Reviews:

<A NAME="RG02103ST-2A">2a</A> Fletcher PDI. Haswell SJ. Pombo-Villar E. Warrington BH. Watts P. Wong SYF. Zhang X. Tetrahedron  2002,  58:  4735 

<A NAME="RG02103ST-2B">2b</A> DeWitt SH. Curr. Opin. Chem. Biol.  1999,  3:  350 

<A NAME="RG02103ST-3">3</A> Kirschning A. Altwicker C. Dräger G. Harders J. Hoffmann N. Hoffmann U. Schönfeld H. Solodenko W. Kunz U. Angew. Chem. Int. Ed.  2001,  40:  3995 

<A NAME="RG02103ST-4A">4a</A> Flynn DL. Devraj RV. Parlow JJ. In Solid Phase Organic Synthesis   Burgess K. Wiley; New York: 2000.  p.149-194  

<A NAME="RG02103ST-4B">4b</A> Parlow JJ. Devraj RV. South MS. Curr. Opin. Chem. Biol.  1999,  3:  320 

<A NAME="RG02103ST-4C">4c</A> Flynn DL. Devraj RV. Naing N. Parlow JJ. Med. Chem. Res.  1998,  8:  219 

<A NAME="RG02103ST-5A">5a</A> Kaldor SW. Siegel MG. Fritz JE. Dressman BA. Hahn PJ. Tetrahedron Lett.  1996,  37:  7193 

<A NAME="RG02103ST-5B">5b</A> Creswell MW. Bolton GL. Hodges JC. Meppen M. Tetrahedron  1998,  54:  3983 

<A NAME="RG02103ST-6A">6a</A> Yu Z. Alesso S. Pears D. Worthington PA. Luke RWA. Bradley M. Tetrahedron Lett.  2000,  41:  8963 

<A NAME="RG02103ST-6B">6b</A> Yu Z. Alesso S. Pears D. Worthington PA. Luke RWA. Bradley M. J. Chem. Soc., Perkin Trans. 1  2001,  1947 

<A NAME="RG02103ST-7">7</A> Coppola GM. Tetrahedron Lett.  1998,  39:  8233 

<A NAME="RG02103ST-8">8</A> Booth RJ. Hodges JC. J. Am. Chem. Soc.  1997,  119:  4882 

<A NAME="RG02103ST-9">9</A> Dahmen S. Bräse S. Angew. Chem. Int. Ed.  2000,  39:  3681 

<A NAME="RG02103ST-10">10</A> Dräger G. Solodenko W. Messinger J. Schön U. Kirschning A. Tetrahedron Lett.  2002,  43:  1401 

<A NAME="RG02103ST-11">11</A> Sakai T. Miyata K. Tsuboi S. Utaka M. Bull. Chem. Soc. Jpn.  1989,  62:  4072 

<A NAME="RG02103ST-12">12</A>

Preparation of 2,4-pentandione resin 3: To a suspension of Merrifield polymer (2.5 g, 4.3 mmol chloride/g, 2% DVB, 200-400 mesh) in dry DMSO (25 mL) was added sodium bicarbonate (9.24 g, 110 mmol) and gentle stirring was continued at 155 °C under nitrogen for 20 h. Ice-cold water was added, the resin was filtered and successively washed with water, methanol, dichloromethane, methanol, and dried in high vacuum at 30 °C over P₂O₅.
The dried resin (ca. 2.2 g) was suspended in dry dichloromethane (30 mL) and sodium iodide (8.24 g, 55 mmol) was added. Gentle stirring was continued under nitrogen and trimethylchlorosilane (6.98 mL, 55 mmol) and acetylacetone (1.65 mL, 16 mmol) were added separately during 6 h via a syringe pump. The mixture was gently stirred overnight at r.t. and then treated with water (50 mL). After 10 min the resin was filtered and successively washed with methanol, water, methanol, acetone, dichloromethane, methanol, and dried in high vacuum.
It has to be pointed out that after thorough optimization we had to notice the need for excessive washing of the resin before use, because it tends to bind impurities including iodine. Resin 3 can be stored at 4 °C and stays active for months. The commercial Merrifield resin 5 as well as 1,3-diketone resin 3 were analyzed by combustion analysis. Found for 5: C 77.63, H 6.37, Cl 15.69 (equals about 4.42 mmol/g loading); found for 3: C 79.55, H 7.17, Cl 0.47 (equals about 3.37 mmol/g loading).

<A NAME="RG02103ST-13">13</A>

In addition, resin 3 is also able to scavenge hydroxylamine such as the HCl salt of benzylhydroxylamine, which was removed in CH₂Cl₂ at room temperature within eight hours.

<A NAME="RG02103ST-14">14</A>

Typical scavenger procedure with 1 : To a solution of ethylcarbazate (16 mg, 0.165 mmol) in dichloromethane
(1 mL) was added benzaldehyde resin 1 (150 mg, 3.0 mmol aldehyde/g) and stirred at r.t. until all hydrazine has reacted. The procedure was monitored with TLC or GC. After 72 h the suspension was filtered, the resin was washed with dichloromethane (3 × 2 mL), and the combined filtrates were evaporated in high vacuum. No residue remained in the flask.
Typical scavenger procedure with 3: To a solution of ethylcarbazate (17 mg, 0.165 mmol) in dichloromethane
(1 mL) was added 2,4-pentandione resin 3 (100 mg, 3.3 mmol diketone/g) and stirred at r.t. until all hydrazine has reacted. The procedure was monitored with TLC or GC. After 3 h the suspension was filtered, the resin was washed with dichloromethane (3 × 2 mL), and the combined filtrates were evaporated under high vacuum. No residue was found in the flask.

<A NAME="RG02103ST-15">15</A>

Commonly, hydrazines were completely scavenged within the given time. Occasionally, we observed a residue after filtration and evaporation of the solvent which originated from resin impurities.

<A NAME="RG02103ST-16">16</A> Texier-Boullet F. Klein B. Hamelin J. Synthesis  1986,  409 

<A NAME="RG02103ST-17">17</A> Kirschning A. Monenschein H. Wittenberg R. Chem.-Eur. J.  2000,  6:  4445