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. Author manuscript; available in PMC: 2009 Sep 24.
Published in final edited form as: Organic Synth. 2009 Jan 1;86:141–150.

SYNTHESIS OF 2-[3,3′-DI-(TERT-BUTOXYCARBONYL)-AMINODIPROPYLAMINE]-4,6,-DICHLORO-1,3,5-TRIAZINE AS A MONOMER AND 1,3,5-[TRIS-PIPERAZINE]-TRIAZINE AS A CORE FOR THE LARGE SCALE SYNTHESIS OF MELAMINE (TRIAZINE) DENDRIMERS

Abdellatif Chouai, Vincent J Venditto, Eric E Simanek, Ruth E McDermott, John A Ragan
PMCID: PMC2750910  NIHMSID: NIHMS116944  PMID: 19784386

graphic file with name nihms116944u1.jpg

1. Procedure

Caution! Cyanuric chloride is a lachrymator and causes burns on contact with the skin. All operations with this reagent should be carried out in a well-ventilated hood.

A. 3,3′-Di-(tert-butoxycarbonyl)-aminodipropylamine

A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, a 500-mL addition funnel, a temperature probe and a static nitrogen inlet is charged with 3,3′-diaminodipropylamine (28.2 mL, 0.20 mol, 1.0 equiv) (Note 1), 300 mL of tetrahydrofuran (Note 1), and N,N-diisopropylethylamine (100 mL, 0.57 mol, 2.8 equiv) (Note 1). A 500-mL Erlenmeyer flask is charged with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) (100 g, 0.41 mol, 2.0 equiv) (Note 1) and 300 mL of tetrahydrofuran. The resulting solutions are separately stirred at 0 °C for 30 min (Note 2). The BOC-ON solution is then transferred to the addition funnel and added dropwise to the solution of 3,3′-diaminodipropylamine over a 90–100 min period. After addition is complete, the solution is left to stir at 0 °C for 3 h, warmed to ambient temperature, and left to stir for an additional 20 h. The solvent is removed using a rotary evaporator at 39 °C (Note 3) and the residue is dissolved in 400 mL of dichloromethane (Note 1). The organic solution is washed with 10% NaOH (3 × 200 mL) (Notes 1 and 4), a saturated, aqueous solution of sodium chloride (1 × 300 mL) (Note 1), and dried over sodium sulfate (Note 1). Following filtration, the solvent is removed using a rotary evaporator at 32–39°C (Note 3) to afford the product as an oily material which is precipitated as an off-white solid by addition of hexane (500 mL) (Note 1) and traces of MeOH (3 mL) (Note 1). After standing in the freezer for 24 h, the solids are filtered, washed with hexane, and dried under vacuum overnight to provide the product as an off-white solid (54.2–55.9 g, 82–84 %), mp 68.1–70.0 °C (Notes 5 and 6).

B. 2-[3,3′-Di-(tert-Butoxycarbonyl)-aminodipropylamine]-4,6-dichloro-1,3,5-triazine

A 3-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, static nitrogen inlet and 1-L addition funnel is charged with cyanuric chloride (30.5 g, 0.165 mol, 1.00 equiv) (Note 1) and 300 mL of acetone (Note 1). The resulting solution is left to stir at 0 °C for 1 h (Note 7). A cooled solution of 3,3′-di-(tert-butoxycarbonyl)-aminodipropylamine (54.9 g, 0.166 mol, 1.01 equivalent) in acetone (686 mL) is then added dropwise to the cyanuric chloride solution over a period of 3 h (the internal temperature remained at or below 2 °C during this addition). A white suspension forms during the course of addition. Sodium bicarbonate (13.9 g, 0.166 mol, 1.00 equiv) (Note 1) in water (195 mL) is added dropwise over a period of 1 h. A yellow mixture is obtained after complete addition. The resulting solution is left to stir at 0 °C for 3 h, which resulted in the formation of a white suspension. The mixture is allowed to warm to ambient temperature and stirred for an additional 15 h. The reaction mixture is concentrated without filtration (to approximately 200 mL) on a rotary evaporator at 31–40 °C (Note 3). The resulting aqueous suspension is filtered. The solids are dissolved in 600 mL of dichloromethane (Note 1). The organic phase is washed with water (3 × 250 mL), and a saturated, aqueous solution of sodium chloride (300 mL) (Note 1). The organic layer is dried with sodium sulfate (Note 1), filtered, and the solvent is concentrated using a rotary evaporator at 40 °C (Note 3). The resulting solids are dried under vacuum (Note 5) to provide the product as an off-white solid (76.5 g, 0.160 mol, 96 %), mp 122.4–125.7 °C (Notes 8, 9 and 10).

C. 1,3,5-[Tris-N-(tert-butoxycarbonyl)-piperazine]-triazine

A 2-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, reflux condenser, temperature probe, glass stopper and static nitrogen inlet is charged with cyanuric chloride (10.0 g, 54.2 mmol, 1.00 equiv) (Note 1) and tetrahydrofuran (1 L) (Note 1?). N-(tert-Butoxycarbonyl)-piperazine (34.0 g, 183 mmol, 3.38 equiv) (Note 1) is added in ~10 g portions over 17 min (during the addition, the temperature rose from 20 to 28 °C; an ambient temperature water bath was used to moderate the exotherm). White solids are formed in the reaction mixture during the addition of the piperazine. N,N-Diisopropylethylamine (96.2 mL, 552 mmol, 10.2 equiv) (Note 1) is added, and the reaction mixture is stirred at ambient temperature for 1 h, then heated to an internal temperature of 66 °C for 20 h at which point the reaction was judged to be complete by HPLC (Note 11). Upon cooling to ambient temperature, a white precipitate forms (Note 12). The solvent is removed using a rotary evaporator at 31 °C (Note 3). The white residue is taken up in dichloromethane (300 mL) (Note 1) and washed with water (2 × 150 mL), 10% NaHSO4 (2 × 150 mL) and a saturated, aqueous solution of sodium chloride (2 × 100 mL) (Note 1). The organic layer is dried over anhydrous sodium sulfate (Note 1), filtered, and the solvent is removed using a rotary evaporator at 35–41 °C (Note 3). The resulting white solids are granulated in EtOAc (35 mL, ca. 1 mL/g) (Note 1) to yield a white crystalline material (31.0–32.0 g, 90–93 %), mp 223.4–226.1 °C (Note 13).

D. 1,3,5-[Tris-piperazine]-triazine

A 1-L, three-necked, round-bottomed flask, fitted with a magnetic stirrer, condenser, nitrogen inlet, and 250 mL addition funnel is charged with 1,3,5-[N-(tert-butoxycarbonyl)-piperazine]-triazine (27.9 g, 44.1 mmol, 1.00 equiv) and 286 mL of methanol (Note 1). The solution is left to stir at 0 °C for 30 min. A solution of 153 mL (0.918 mol, 21 equiv) of 6N hydrochloric acid (Note 1) is then added over 70 min keeping the temperature at ~ 1 °C and the resulting light yellow slurry is left to stir at 0 °C for 2 h (Note 2). The reaction slurry is then allowed to warm to ambient temperature over 3 h and then slowly heated to an internal temperature of 40 °C for 12 h (the slurry became homogeneous at 27 °C). Off-gassing was observed as the temperature increased. The volatile organic components are removed using a rotary evaporator 34–40 °C (Note 3) until only ca. 100 mL of water remains. The resulting aqueous solution is cooled to 0 °C and made alkaline (pH = 14) by addition of 237 mL (657 mmol, 15 equiv) of a 10% NaOH solution (Note 1). The resulting alkaline solution is extracted with chloroform (3 × 250 mL) (Note 1), and the organic phases are combined and dried over sodium sulfate (Note 1). The solvent is filtered and evaporated at 34 °C (Note 3) to afford the product as a white solid (14.1 g, 96 %), mp 200–208 °C (Notes 14 and 15).

2. Notes

  1. All solvents and reagents were purchased from commercial suppliers and used as received. Acetone (99.5%), 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON), chloroform (99.8%), 3,3′-diaminodipropylamine (98%), dichloromethane (99.6%), N,N-diisopropylethylamine (99%), methanol (99.8%), sodium chloride, sodium sulfate (anhydrous) and tetrahydrofuran (99.9%, anhydrous) were purchased from Sigma-Aldrich. Cyanuric chloride was purchased from Alfa Aesar. N-Boc-piperazine was purchased from AK Scientific. Hydrochloric acid and sodium bicarbonate were purchased from J. T. Baker. Sodium hydroxide was purchased from Fisher Scientific. Hexanes (98.5%) were purchased from Mallinckrodt.

  2. All reactions were performed in an ambient-temperature lab (ca. 23 °C). The submitters performed all experiments in a walk-in cold room (0 °C).

  3. All solvent evaporations were performed using a rotary evaporator using appropriate temperature and pressure to afford efficient concentration (THF: 75–150 mmHg; CH2Cl2: 200–300 mmHg; acetone: 200–300 mmHg; CHCl3 and methanol: 15–75 mmHg).

  4. The first and second extractions resulted in a yellow aqueous solution (color of the byproduct of BOC-ON), while the third extraction gave a clear aqueous solution.

  5. All products were dried using a Büchi vacuum pump with a vacuum pressure of 76 mmHg.

  6. The product has the following spectral characteristics: TLC Rf = 0.0 (silica gel 60 F254, EMD Chemicals, Inc. in 5:95 methanol:dichloromethane); IR (neat) cm−1: 3342, 2975, 2931, 1686, 1518, 1365, 1273, 1250, 1168; 1H NMR (400 MHz, CDCl3) δ: 1.41 (s, 18 H), 1.60–1.66 (m, 4 H), 2.63 (t, 4 H, J = 6.6), 3.15–3.20 (br, 4 H), 5.2 (br, 2 H); 13C NMR (100 MHz, CDCl3) δ: 28.4(s), 29.7 (s), 38.9 (s), 47.4 (s), 78.9 (s), 156.1 (s); MS (CI), m/z 332.2 (M+H). Anal. Calcd for C16H33N3O4: C, 57.98; H, 10.04; N, 12.68. Found: C, 57.86; H, 9.84; N, 12.51.

  7. The submitters noted that after 1 h at 0 °C, undissolved cyanuric chloride remained visible in the reaction flask (estimated at 10–20% of the initial charge). The presence of this material does not adversely affect the reaction. The checkers observed a homogeneous solution at this stage.

  8. During melting point determination, some bubbling was observed above 125 °C.

  9. The product has the following characteristics: TLC Rf = 0.3 (silica gel 60 F254, EMD Chemicals, Inc. in 5% methanol:dichloromethane); IR (neat) cm−1: 3349, 2976, 1691, 1573, 1475, 1233, 1160, 847, 733; 1H NMR (400 MHz, CDCl3) δ: 1.41 (s, 18 H), 1.77 (tt, apparent quintet, 4 H, J = 6.6), 3.07–3.12 (br/quartet-depending on sample concentration, 4 H), 3.60 (t, 4 H, J = 7.1), 5.05 (br, 2H); 13C NMR (100 MHz, CDCl3) δ: 27.7 (s), 28.3 (s), 37.3 (s), 44.9 (s), 79.3 (s), 156.0 (s), 164.7 (s), 170.1 (s); MS (CI): m/z 479, 379. Anal. Calcd for C19H32Cl2N6O4: C, 47.60; H, 6.73; N, 17.54; Cl, 14.79. Found: C, 47.87; H, 6.82; N, 17.48; Cl, 14.47.

  10. In a second run using 53.2 g of the starting di-(BOC)-dipropylamine, 71.5 g of product was obtained (93%).

  11. The reaction was monitored by HPLC on a 4.6 × 50 Zorbax C-8 column at 30 °C with a flow rate 0.7 mL per min of eluent composed of 95% of 0.5% HClO4 and 5% ACN. RT cyanuric chloride = 6.68 min, RT product =11.54 min. Also TLC (silica gel, 5% methanol:dichloromethane), Rf (product) = 0.35, Silica Gel 60 F254, EMD Chemicals, Inc.

  12. The precipitate corresponds to the formation of the hydrochloride salt of N,N-diisopropyl ethylamine.

  13. The product has the following characteristics: TLC, Rf 0.35 (silica gel 60 F254, EMD Chemicals, Inc. in 5% methanol:dichloromethane); IR (neat) cm−1: 1679, 1535, 1419, 1227, 998, 725; 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 27 H), 3.42 (m, 12 H), 3.72 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ: 28.4, 43.0, 79.9, 154.8, 165.2; MS (CI) m/z 634.3; Anal. Calcd for C30H51N9O6: C, 56.85; H, 8.11; N, 19.89. Found: C, 56.69; H, 8.26; N, 19.82.

  14. In a second run, 29.2 g of starting triazine provided 14.5 g of product (94%).

  15. The product has the following characteristics: TLC Rf = 0.0 (silica gel 60 F254, EMD Chemicals, Inc. in 10% methanol:dichloromethane); IR (neat) cm−1: 3278, 2846, 1523, 1433, 1242, 1007, 806, 728; 1H NMR (400 MHz, CDCl3) δ: 1.62 (s, 3 H), 2.81 (t, 12 H, J = 5.0), 3.68 (t, 12 H, J = 5.0); 13C NMR (100 MHz, CDCl3) δ: 44.3, 46.0, 165.2; MS (CI) m/z 334.4 Anal. Calcd for C15H27N9: C, 54.03; H, 8.16; N, 37.81. Found: C, 53.72; H, 8.32; N, 37.48.

Safety and Waste Disposal Information

All hazardous materials should be handled and disposed of in accordance with “Prudent Practices in the Laboratory”; National Academy Press; Washington, DC, 1995.

3. Discussion

s-Triazines have seen applications as precursors for polymers,2 as scavenging resins in organic manipulations,3 as components of host–guest assemblies,4 as ligand scaffolds for catalysis,5 and in medicinal chemistry.6 The appeal of the s-triazine core is largely due to the ease of systematic substitution of the chlorine atoms with amine nucleophiles to generate a variety of structures. Consecutive substitution reactions with amine nucleophiles can proceed in a one-pot procedure: the first substitution on cyanuric chloride occurs in minutes at 0 °C; the second substitution occurs in 12–24 hours at ambient temperature; the third substitution typically occurs in 12–24 hours and requires temperatures above 80 °C.7

Our interest in s-triazines derives from their use in dendrimer synthesis.8 Triazine dendrimers offer distinct advantages including tractable syntheses and reactivity that can be efficiently manipulated in a stepwise manner to construct pure monodisperse products with unique compositional diversity.9 This paper describes the use of 1,3,5-triazine in the synthesis of 2-[3,3′-di-(tert-butoxycarbonyl)-aminodipropylamine]-4,6,-dichloro-1,3,5-triazine as a building block and 1,3,5-[tris-piperazine]-triazine as a core.

The building block, a dichloro-1,3,5-triazine substituted with a branching group presenting two Boc-protected amines, is available in 96% overall yield from the reaction of cyanuric chloride with 3,3′-di-(tert-butoxycarbonyl)-aminodipropylamine in acetone-water, without chromatographic purification. The latter is prepared from the reaction of 3,3′-diaminodipropylamine with BOC-ON in THF under simple experimental conditions. This building block can be regarded as AB2B′ (where A is the first chloride displaced via nucleophilic aromatic substitution, B′ is the second chloride to be displaced, and B represents the BOC-protected amines). It undergoes clean, stepwise nucleophilic aromatic substitution (SNAr) reactions to afford intermediate monochlorotriazine bearing macromolecules.

The synthesis of the core proceeds by the reaction of cyanuric chloride with N-(tert-butoxycarbonyl)-piperazine in THF at 66 °C in the presence of N,N-diisopropyl ethylamine at moderate reaction times (16 h) (Step C). Cleavage of the BOC-group using 6N hydrochloric acid in methanol at 0 °C for 3 h and at room temperature for 12 h followed by neutralization affords the desired product in high yield (Step D). The synthesis of higher generation dendrimers relies on iterative addition of the AB2B′ building block to core structure followed by capping and deprotection steps.10

Biographies

graphic file with name nihms116944b1.gif Eric E. Simanek was born in 1969 in Tuscola, IL. He obtained a B.S. in Chemistry in 1991 from the University of Illinois at Urbana-Champaign while working in the laboratories of the late Dr. Kenneth L. Rinehart, Jr. After completing doctoral studies with Dr. George M. Whitesides at Harvard University in 1997, he joined Dr. Chi-Huey Wong’s laboratory at The Scripps Research Institute. Since joining Texas A&M University in 1998, he has risen through the ranks to Professor of Chemistry. His interests lie in drug delivery and K-20 education.

graphic file with name nihms116944b2.gif Abdellatif Chouai was born in 1971 in Morocco. He earned a B.S. in Chemistry in 1995 from the University of Sidi Mohamed Ben Abdellah, Morocco, and a Ph.D. in Organic Chemistry from University of Houston in 2003 under Dr. Randolph P. Thummel. He joined Dr. Kim R. Dunbar’s group at Texas A&M University as a postdoctoral research associate where he worked on reversible DNA biosensors complexes and bimetallic complexes as photodynamic therapy agents. He then moved to a research scientist position in 2006 in Dr. Simanek’s laboratory. His research focused on an industrial scale production of triazine-based dendrimers and application in drug delivery. Currently, Dr. Chouai holds a professional development chemist position with BASF Corporation.

graphic file with name nihms116944b3.gif Vincent J. Venditto was born in 1981 in Philadelphia, PA. He earned a B.S. in Chemistry from Gettysburg College in 2003 and began working in the laboratory of Dr. Martin W. Brechbiel in the Radioimmune and Inorganic Chemistry Section of the National Cancer Institute within the NIH. After two years at the NIH, Vincent joined of Dr. Simanek’s laboratory at Texas A&M University to pursue a graduate degree in chemistry. His graduate work focuses on the synthesis of triazine-based dendrimers as drug carriers for a range of therapeutic applications.

graphic file with name nihms116944b4.gif Ruth McDermott was born in Boston, MA and received a B.S. in Chemistry from the University of Massachusetts at Boston. She completed her undergraduate research under the direction of J.-P. Anselme. She is currently part of the Chemical Research and Development group at Pfizer in Groton, CT where she has been employed for 20 years. She enjoys photography and participating in short-term mission trips in the US and abroad.

Appendix Chemical Abstracts Nomenclature; (Registry Number)

3,3′-Diaminodipropylamine; (56-18-8)

2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile; (58632-95-4) Cyanuric chloride; (108-77-0)

N-(tert-Butoxycarbonyl)-piperazine; (57260-71-6) N,N-Diisopropyl ethylamine; (7087-68-5)

2-[3,3′-Di-(tert-butoxycarbonyl)-aminodipropylamine]-4,6-dichloro-1,3,5-triazine; 12-Oxa-2,6,10-triazatetradecanoic acid, 6-(4,6-dichloro-1,3,5-triazin-2-yl)-13,13-dimethyl-11-oxo-, 1,1-dimethylethyl ester; (947602-03-1)

1,3,5-[Tris-piperazine]-triazine: 1,3,5-Triazine, 2,4,6-tri-1-piperazinyl-; (19142-26-8)

References

  • 1.Department of Chemistry, Texas A&M University, College Station, TX 77843. simanek@mail.chem.tamu.edu
  • 2.(a) Hirschberg JHKK, Ramzi A, Sijbesma RP, Meijer EW. Macromolecules. 2003;36:1429–1432. [Google Scholar]; (b) Berl V, Schmutz M, Krische MJ, Khoury RG, Lehn J-M. Chem Eur J. 2002;8:1227–1244. doi: 10.1002/1521-3765(20020301)8:5<1227::aid-chem1227>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]; (c) Choi IS, Li X, Simanek EE, Akaba R, Whitesides GW. Chem Mater. 1999;11:684–690. [Google Scholar]
  • 3.Marsh A, Carlisle SJ, Smith SC. Tetrahedron Lett. 2001;42:493–496. [Google Scholar]
  • 4.(a) Linton B, Hamilton AD. Curr Opin Chem Biol. 1999;3:307–312. doi: 10.1016/S1367-5931(99)80047-7. [DOI] [PubMed] [Google Scholar]; (c) Simanek EE, Isaacs L, Li X, Wang CCC, Whitesides GW. J Org Chem. 1997;62:8994–9000. [Google Scholar]
  • 5.(a) Gamez P, de Hoog P, Lutz M, Spek AL, Reedijk J. Inorg Chim Acta. 2003;351:319–325. [Google Scholar]; (b) Britovsek GJP, Gibson VC, Hoarau OD, Spitzmesser SK, White AJP, Williams DJ. Inorg Chem. 2003;42:3454–3465. doi: 10.1021/ic034040q. [DOI] [PubMed] [Google Scholar]
  • 6.(a) Pattarawarapan M, Reyes S, Xia Z, Zaccaro MC, Saragovi HU, Burgess K. J Med Chem. 2003;46:3565–3567. doi: 10.1021/jm034103e. [DOI] [PubMed] [Google Scholar]; (b) Pitts WJ, Guo J, Dhar TGM, Shen Z, Gu HH, Watterson SH, Bednarz MS, Chen B-C, Barrish JC, Bassolino D, Cheney D, Fleener CA, Rouleau KA, Hollenbaugh DL, Iwanowicz EJ. Bioorg Med Chem Lett. 2002;12:2137–2140. doi: 10.1016/s0960-894x(02)00351-7. [DOI] [PubMed] [Google Scholar]
  • 7.(a) Blotny G. Tetrahedron. 2006;62:9507–9522. and references therein. [Google Scholar]; (b) Steffensen MB, Hollink E, Kuschel F, Bauer M, Simanek EE. J Polym Sci, Part A: Polym Chem. 2006;44:3411–3433. doi: 10.1002/pola.21333. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Steffensen MB, Simanek EE. Org Lett. 2003;5:2359–2361. doi: 10.1021/ol0347491. [DOI] [PubMed] [Google Scholar]; (d) Chen H-T, Neerman MF, Parrish AR, Simanek EE. J Am Chem Soc. 2004;126:10044–10048. doi: 10.1021/ja048548j. [DOI] [PubMed] [Google Scholar]; (e) Umali AP, Simanek EE. Org Lett. 2003;5:1245–1247. doi: 10.1021/ol034161u. [DOI] [PubMed] [Google Scholar]; (f) Cuthbertson WW, Moffatt JS. J Chem Soc. 1948;561–:564. doi: 10.1039/jr9480000561. [DOI] [PubMed] [Google Scholar]
  • 8.(a) Hollink E, Simanek EE. Org Lett. 2006;8:2293–2295. doi: 10.1021/ol060559p. [DOI] [PubMed] [Google Scholar]; (b) Chouai A, Simanek EE. J Org Chem. 2008;73:2357–2366. doi: 10.1021/jo702462t. [DOI] [PubMed] [Google Scholar]
  • 9.(a) Lim J, Simanek EE. Org Lett. 2008;10:201–204. doi: 10.1021/ol7024907. [DOI] [PubMed] [Google Scholar]; (b) Steffensen MB, Simanek EE. Angew Chem Int Ed. 2004;43:5178–5180. doi: 10.1002/anie.200460031. [DOI] [PubMed] [Google Scholar]
  • 10.Crampton H, Hollink E, Perez LM, Simanek EE. New J Chem. 2007;31:1283–1290. doi: 10.1039/b617875h. [DOI] [PMC free article] [PubMed] [Google Scholar]

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