Solid-Phase Organic Syntheses

38 Solid-Phase Synthesis of Ureas on MicroTubes

Appendix 3.3

Appendix 39

Appendix 3.3 (Continued)

40 Solid-Phase Synthesis of Ureas on MicroTubes

Appendix 3.3 (Continued)

Solid-Phase Organic Syntheses: Volume One. Edited by Anthony W. Czarnik Copyright # 2001 John Wiley & Sons, Inc.

ISBNs: 0-471-31484-6 (Hardback); 0-471-22043-4 (Electronic)

CHAPTER FOUR

SYNTHESIS OF p-BENZYLOXYBENZYL CHLORIDE RESIN

Submitted by JOHN ELLINGBOE, DEREK COLE,

and JOSEPH STOCK

Wyeth-Ayerst Research, Division of Chemical Sciences, 401 North Middletown Road, Pearl River, NY, USA 10965

Checked by KATHLEEN LIGSAY, KEVIN SHORT,

and TODD JONES

Ontogen Corporation, 2325 Camino Vida Roble,

Carlsbad, CA, USA 92009

REACTION SCHEME

Todd Jones current address: The R. W. Johnson Pharmaceutical Research Institute, 3210 Merryfield Row, San Diego, CA, USA 92121

41

42 Synthesis of p-Benzyloxybenzyl Chloride Resin

PROCEDURE

Lithium chloride (Aldrich, 99%) (1.27 g, 30 mmol) was added to a suspension of Wang resin (AnaSpec Inc. Cat. # 22990, 100–200 mesh, Lot # AM5000) (10 g, 1.0 m Eq/g) in DMF (100 mL) in a 500-mL Erlenmeyer flask. 2,4,6-Collidine (Aldrich, 99%) (4.0 mL, 30 mmol) was added, followed by slow addition (over

about 5	min) of	methanesulfonyl chloride	(Aldrich, 98%)
(2.3 mL,	30 mmol;	note 1). The flask was	flushed with N2,

stoppered, and allowed to mix overnight on an orbital shaker (note 2). The mixture was then filtered and washed with the following solvents: 2 9:1 DMF:H2O, 1 DMF, 1 DCM, 1 MeOH, 2 DMF, 2 DCM. A wash consisted of suspending the resin in the solvent ( 50 mL), stirring or swirling, then filtering. The resin was then dried in vacuo to give 10.1 g.

The resin was characterized by high-resolution magic angle spinning (HRMAS) NMR (Bruker 500 MHz): 1H NMR (CDCl3)1.43 (br s), 1.84 (br s), 2.83 (s), 2.87 (s), 2.94 (m), 4.51 (s), 4.91 (br s), 5.16 (s), 5.30 (m), 6.56 (br s), 7.03 (br s), 7.98 (d); 13C NMR (CDCl3) 40.3, 46.1 (CH2Cl), 70.0, 76.7, 76.9, 77.0, 77.2, 114.3, 115.6, 125.0, 126.2, 127.3, 128.4, 129.4, 129.8, 130.5, 133.9, 145.2, 158.9. Chlorine analysis: calculated, 3.47%; observed, 3.42%.

NOTES

1.The reaction warms slightly after the addition of methanesulfonyl chloride. For larger scale reactions, an ice bath is used during the addition.

2.Mechanical stirring can also be used.

DISCUSSION

Polystyrene resin with a hydroxymethylphenoxy linker (Wang resin)1 was originally developed for solid-phase peptide synthesis

References 43

but has proven to be useful for solid-phase organic synthesis as well. p-Benzyloxybenzyl chloride resin is useful for cases in which a Wang linker is needed but when attachment to the resin can only be achieved by nucleophilic displacement of a leaving group. For example, anthranilic acid cannot be attached to Wang resin with a carbodiimide because of side reactions involving the aniline nitrogen. However, the cesium salt of anthranilic acid can be directly attached to the Wang linker via the chloro derivative, without protection of the nitrogen. This approach has been extended to other aminobenzoic acids,2 phenols,3 and N-hydro- xyphthalimide (which can be converted to a hydroxylamine resin).

A synthesis of p-benzyloxybenzyl chloride resin using PPh3 Cl2 has been reported,4 and PPh3 Br2 has been used to prepare a bromo Wang resin.4, 5 Methods utilizing thionyl chloride or methanesulfonyl chloride/diisopropylethylamine have been reported more recently.6 The combination of methanesulfonyl chloride and lithium chloride described above provides a less expensive alternative and does not produce the triphenylphosphine byproduct.

REFERENCES

1.Wang, S.-S. J. Am. Chem. Soc. 1973, 95, 1328.

2.Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett. 1997, 38, 7963.

3.Chiu, C.; Tang, Z.; Ellingboe, J. W. J. Comb. Chem. 1999, 1, 73.

4.Mergler, M.; Tanner R.; Gosteli, J. Tetrahedron Lett. 1988, 29, 4005.

5.Ngu, K.; Patel, D. V. Tetrahedron Lett. 1997, 38, 973.

6.Raju, B.; Kogan, T. P. Tetrahedron Lett. 1997, 38, 4965.

Solid-Phase Organic Syntheses: Volume One. Edited by Anthony W. Czarnik Copyright # 2001 John Wiley & Sons, Inc.

ISBNs: 0-471-31484-6 (Hardback); 0-471-22043-4 (Electronic)

CHAPTER FIVE

SOLID-PHASE MANNICH REACTIONS OF A RESIN-IMMOBILIZED ALKYNE

Submitted by SCOTT L. DAX and MARK A. YOUNGMAN

Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads, Spring House, PA, USA 19477

Checked by PETR KOCIS and MATTHEW NORTH

International Lead Drug Discovery Department, Zeneca

Pharmaceuticals, 1800 Concord Pike, Wilmington, DE,

USA 19850-5437

LIBRARY SYNTHESIS ROUTE

a: propargyl amine (8 molar Eq.) / DMF.

b: 20 Eq. aldehyde, 10 Eq. amine, 5 Eq. 1,4-dimethylpiperazine, 1 Eq. Cu(I)Cl, dioxane, 75 C.

c: TFA / DCM (1:3).

45

46 Solid-Phase Mannich Reactions of a Resin-Immobilized Alkyne

BUILDING BLOCKS

PROCEDURES

2-Cl Trityl Chloride resin (17.33 g, NovaBiochem, Lot # A20915, 200 – 400 mesh, 1% DVB, 1.33 mmol / g, 23.0 mmol) was placed in a 500-mL round-bottom flask. N,N-Dimethylformamide (200 mL) was added, which caused the resin to swell; this suspension was gently stirred by a magnetic stir bar. Propargyl amine (10 g,

Procedures

47

180 mmol) was added, and the reaction vessel was flushed with argon, capped, and stirred gently for 20 h. The resin was removed by filtration through a sintered glass funnel and washed with DMF (3 100 mL) and then with methylene chloride (3 100 mL). The resin was dried under vacuum overnight to remove residual solvents. The 2-Cl trityl resin-bound propargyl amine prepared in this manner has a theoretical loading of 1.30 mmol /g.

The 2-Cl Trityl resin-bound propargyl amine described above was mixed with DMF-dichloroethane (3 : 7 v/v) with gentle stirring to provide a uniform suspension of the resin. Using a wide-bore pipette, a calculated volume of this suspension was transferred to each reaction vessel to provide 0.077 g (0.10 mmol) of the resin-bound propargyl amine. Each portion of resin was then rinsed with methylene chloride (2 4 mL) and air dried. Copper(I) chloride (0.010–0.015 g, 0.10–0.15 mmol; note 1) was added to each reaction vessel followed by dioxane (1 mL) and 1,4- dimethylpiperazine (0.068 mL, 0.50 mmol; note 2). The aldehyde component was added (2 mL of a 1.0 M solution or suspension in the case of formaldehyde) followed by the amine component (1 mL of a 1.0 M solution in dioxane), thus bringing the final volume of each reaction to 4 mL. The reaction vessels were capped, agitated, and heated at 75 C for approximately 6 h. After cooling the resins were filtered and washed sequentially with dioxane (1 4 mL), 10% piperidine in DMF (v/v) (4 4 mL), 5% aqueous acetic acid (1 4 mL), 10% piperidine in DMF (1 4 mL), methanol (3 4 mL), and methylene chloride (3 4 mL).

The Mannich products were cleaved from the resin into tared tubes by reaction with 4 mL of 25% trifluoroacetic acid in methylene chloride (v/v) at ambient temperature for 1 min. Each resin was filtered and rinsed with methylene chloride (2 mL). The filtrate was concentrated under a stream of nitrogen gas to a brown residue. This material was dissolved in acetonitrile (4 mL), and the product was concentrated again under a stream of nitrogen. This procedure was repeated two more times using methanol

48 Solid-Phase Mannich Reactions of a Resin-Immobilized Alkyne

(4 mL) to dissolve the residue (note 3). The resultant products were dried under vacuum overnight, and the tubes were weighed to obtain the final yields of the products (Tables 5.1 and 5.2). The products were typically obtained as brown glassy solids (note 4). A portion of the solid was removed and dissolved in methanol for HPLC and MS analysis. The remainder of the product was dissolved in d4-methanol for NMR analysis.

TABLE 5.1. Percent Yields a

Component	A	B	C	D	E
1	57/46	51/54	34/53	63/55	36/62
2	57/57	68/65	62/65	42/66	24/74
3	61/47	59/55	58/55	66/56	37/64
4	51/42	44/50	15/49	42/51	28/58
5	60/49	65/57	41/57	25/58	21/66
6	75/66	87/74	105/74	58/75	27/83

a Isolated weight (mg)/theoretical weight (mg).

TABLE 5.2.	Purity a
Component	A	B	C	D	E
1	>95%	> 95%	95%	>95%	>95%
2	>95%	>95%	>95%	>95%	45%
3	>95%	>95%	>95%	>95%	>95%
4	>95%	>95%	>95%	>95%	71%
5	>95%	>95%	80%	47%	17%
6	>95%	>95%	69%	>95%	53%

a Determined by reverse-phase HPLC (acetonitrile–water gradient containing 0.1% TFA; 220 nM).