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of Ma a r t i c l e i n f o Article history: Received 10 November 2008 Revised 1 December 2008 Accepted 9 December 2008 Available online 16 December 2008 a b s t r a c t A simple, robust and high-yiel methylmorpholinium tetrafluo developed, which avoids the u In recent years, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-meth- 1 pletely dissolved). For further qualitative stability studies on DMTMM, see Kunishima et al.2b This degradation will of course have an impact on the stoichiometry of the reaction. The produc- tion of chloromethane will also have ramifications for the yield and purity of the final products as it could methylate carboxylate substrates (giving the corresponding esters) or alkylate elsewhere in the substrate or product.2d practical, robust, high-yielding process for the generation of 1b ruptions in transfer will have significant impact on such a sensi- tive first stage. (3) Use of AgBF4 may be prohibitively expensive on multi-kilo scale. The second method7b involves long reaction times (normally 20 h) and requires N-methylmorpholinium tet- rafluoroborate, which is not commercially available (presumably this is synthesised from N-methylmorpholine and tetrafluorob- oric acid). The yield reported is 75%. Unlike in most organic solvents, DMTMM Cl 1a is stable as an aqueous solution for significant time periods, i.e., over 24 h at ambient temperature.2b,6 It was postulated that DMTMM BF4 1b * Corresponding author. Tel.: +44 (0)1625 232848. O N O O Tetrahedron Letters 50 (2009) 946–948 Contents lists availab ro .e l E-mail address: Steven.Raw@astrazeneca.com. The second order rate constants for this degradation in DMF and DMSO at ambient temperature have been determined as 1.06 ± 0.48 � 10�2 and 1.42 ± 0.12 � 10�3 dm3 mol�1 s�1, respectively.6 So, for example, at a typical process concentration of 0.1 M, DMTMM Cl 1a would degrade by 50% in approximately 15 min in DMF and approximately 120 min in DMSO (assuming 1a is com- cess research and development. One method7a employs initial formation of DMTMM Cl 1a in dichloromethane followed by pre- cipitation of DMTMM BF4 1b by addition of silver tetrafluorobo- rate suspended in acetonitrile. This is followed by isolation by filtration and a subsequent recrystallisation. The yield reported is 73%. The issues here are: (1) Given its sensitivity in chloro- form, one may expect significant degradation of the DMTMM Cl 1a to occur in dichloromethane, even at the suggested tem- perature of 5 �C, distorting stoichiometry and eroding yield. (2) Slurry transfers can be problematic in a pilot plant, and any dis- O 1a 2 Scheme 1. Self-immolative degradation of DMTMM Cl. N N N O N Cl e.g. CHCl3 0040-4039/$ - see front matter � 2008 Elsevier Ltd. A doi:10.1016/j.tetlet.2008.12.047 was required. The two published methods7 for the preparation of DMTMM BF4 1b have significant drawbacks, especially if one intends to operate on large scale, and these impact upon its utility in pro- N N N O + MeCl ylmorpholinium chloride 1a (DMTMM Cl) has come to promi- nence as an effective coupling agent, finding applications in amidation,2 esterification,2b,3 glycosidation4 and phosphonylation5 methodology. However, the utility of DMTMM Cl 1a as a coupling agent is compromised, especially at large scale, by its instability in organic solution as it undergoes self-immolative degradation, yielding 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-morpholine 2 and chloromethane (Scheme 1). In chloroform at ambient temperature, this results in complete degradation in just 3 h1a (97% degradation is observed in 2 h6). An improved process for the synthesis Steven A. Raw * AstraZeneca, Process Research and Development, Silk Court Business Park, Charter Way, Tetrahed journal homepage: www ll rights reserved. DMTMM-based coupling reagents cclesfield, Cheshire, SK11 8AA, UK ding process for the preparation of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- roborate (DMTMM BF4) and hexafluorophosphate (DMTMM PF6) has been se of expensive or unusual reagents. � 2008 Elsevier Ltd. All rights reserved. To avoid this degradation, Kamin´ski et al. have developed DMTMM BF4 1b as an alternative to 1a.7 The non-nucleophilic BF4 � counterion does not take part in the degradation process and organic solutions of 1b are stable for several days at least.6 DMTMM BF4 1b has been shown to be equally effective in peptide couplings as 1a7a and can be considered as a direct replacement. As part of a recent multi-kilogram scale development pro- gramme, the use of a DMTMM-based amidation was investigated. In early development, some of the main issues encountered when using DMTMM Cl 1a were, as mentioned above, the distortion of stoichiometry and esterification of our carboxylate coupling part- ner by methyl transfer. Consequently, the use of DMTMM BF4 1b was considered. In order to complete the development studies, a le at ScienceDirect n Letters sevier .com/ locate / tet let dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight sodium tetrafluoroborate. Initial small-scale trials (approximately 250 mg) showed immediate success: when aqueous NaBF4 was added dropwise to an aqueous solution of 1a at ambient tempera- ture, DMTMM BF4 1b precipitated immediately, and was easily recovered in a good yield (approximately 75%). Though DMTMM Cl 1a is commercially available, even in the so- lid state it can degrade via the mechanism discussed above,7a and so we were keen to develop a synthesis of 1b from the cheaper and more stable precursor, 2-chloro-4,6-dimethoxy-1,3,5-triazine With a viable process for the synthesis of DMTMM BF4 1b in hand, we were keen to investigate its application to other related salts. Accordingly, synthesis of DMTMM PF6 1c was attempted by NO Cl CDMT 3 Water, 20 oC, 20 min 1a/b DMTM(M/P) Cl 20 oC, 5 min NaX(aq) N N N O O N Y X 1 1b, X=BF4-, Y=O, 80% 1c, X=PF6-, Y=O, 89% 1d, X=BF4-, Y=CH2, 68% Scheme 2. Synthesis of DMTMM BF4, DMTMM PF6 and DMTMP BF4. Lette an analogous procedure (Scheme 2). Gratifyingly, the desired prod- uct 1cwas isolated in 89% yield. Furthermore, the protocol is appli- cable to other amines, such as N-methylpiperidine, delivering DMTMP BF4 1d7a in an unoptimised yield of 68%, using a slightly modified procedure.9 To prove that the novel DMTMM PF6 1c is as active as DMTMM BF4 1b in coupling reactions, both salts were employed in the ami- dation of benzoic acid with pyrrolidine (Scheme 3), following a protocol developed by Kamin´ski et al.7a In directly comparable reactions, the yields obtained were essentially identical, being 78% with 1b and 79% with 1c. In conclusion, a new practical, robust and high-yielding process OH O i) 1b/1c, NMM, MeCN, RT, 2 h ii) Pyrrolidine, RT, 2 h N O Scheme 3. Amidations with DMTMM BF4 and PF6. (CDMT) 3. Furthermore, the ideal was a one-stage, two-step pro- cess, avoiding any isolation of 1a. Given the initial success of the precipitation of DMTMM BF4 1b from aqueous solution and the proven stability of aqueous solutions of 1a to degradation, the for- mation of 1a from 3 in aqueous media was investigated. To this end, CDMT 3 was suspended in water and N-methylmorpholine (NMM) added. Analysis by HPLC showed complete consumption of the CDMT 3 in just 20 min. Dropwise addition of an aqueous solution of NaBF4 to this mixture over 5 min caused precipitation of DMTMM BF4 1b. The product was isolated by filtration in an overall yield of 80% from CDMT 3 (Scheme 2). N N O N Y could be precipitated from an aqueous solution of 1a by addition of 8 S. A. Raw / Tetrahedron for the production of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-meth- ylmorpholinium tetrafluoroborate (DMTMM BF4) 1b,10 its hexa- fluorophosphate (DMTMM PF6) 1c12 and 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methylpiperidinium tetrafluoroborate (DMTMP BF4) 1d13 has been developed, which provides material of high quality. The process avoids all the drawbacks associated with pre- vious syntheses,7 as it does not involve the use of expensive AgBF4, unstable solutions of DMTMM Cl 1a and non-commercially avail- able reagents. It also delivers the products 1b and 1d in higher yields than previously reported syntheses.7 An added benefit from a process perspective is that the only effluent stream is aqueous, and the main by-product of the process is NaCl (alongside small excesses of N-methylmorpholine and NaBF4 or NaPF6). Acknowledgements The author would like to thank Ian W. Ashworth and Brian R. Meyrick for their contributions to the investigations concerning the degradation of DMTMM salts in various solvents6 and for the useful discussions with respect to the work reported herein. The author also thanks Anthony W.T. Bristow for HRMS analysis. References and notes 1. (a) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tetrahedron Lett. 1999, 40, 5327–5330; (b) Kamin´ski, Z. J.; Paneth, P.; Rudzin´ski, J. J. Org. Chem. 1998, 63, 4248–4255. 2. (a) For recent examples see: Štimac, A.; Mohar, B.; Stephan, M.; Bevc, M.; Zupet, R.; Gartner, A.; Krošelj, V.; Smrkolj, M.; Kidemet, D.; Sedmak, G.; Benkicˇ, P.; Kljajicˇ, A.; Plevnik, M. Int. Pat. Appl., 2008, WO2008/089984; Chem. Abstr. 2008, 149, 224074.; (b) Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.; Tani, S. Tetrahedron 1999, 55, 13159–13170; (c) Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani, S. Tetrahedron 2001, 57, 1551–1558; (d) Kjell, D. P.; Hallberg, D. W.; Kalbfleisch, J. M.; McCurry, C. K.; Semo, M. J.; Sheldo, E. M.; Spitler, J. T.; Wang, M. Org. Proc. Res. Dev. 2005, 9, 738–742. 3. (a) For recent examples see: Yasude, Y. Int. Pat. Appl., 2007, WO2007/126154; Chem. Abstr. 2007, 147, 522516.; (b) Kolesinska, B.; Kaminski, Z. J.; Kaminska, J. E. Int. Pat. Appl., 2004, WO2004/056790; Chem. Abstr. 2004, 141, 106635. 4. For recent examples see: (a) Tanaka, T.; Noguchi, M.; Kobayashi, A.; Shoda, S.-I. Chem. Commun. 2008, 2016–2018; (b) Paoline, I.; Nuti, F.; de la Cruz Pozo- Carrero, M.; Barbetti, F.; Kolesin´ska, B.; Kamin´ski, Z. J.; Chelli, M.; Papini, A. M. Tetrahedron Lett. 2007, 48, 2901–2904. 5. For a recent example see: Wozniak, L. A.; Góra, M.; Stec, W. J. J. Org. Chem. 2007, 72, 8584–8587. 6. Ashworth, I. W.; Meyrick, B.; Raw, S. A., Unpublished results. Our investigations into the degradation kinetics of DMTMM Cl 1a and related salts in a variety of solvents will be fully disclosed in due course. 7. (a) Kamin´ski, Z. J.; Kolesin´ska, B.; Kolesin´ska, J.; Sabatino, G.; Chelli, M.; Rovero, P.; Błaszczyk, M.; Głowka, M. L.; Papini, A. M. J. Am. Chem. Soc. 2005, 127, 16912–16920; (b) Kamin´ski, Z. J.; Papini, A. M.; Jastrabek, K.; Kolesin´ska, B.; Kolesin´ska, J.; Sabatino, G.; Bianchini, R. Int. Pat. Appl., 2007, WO2007/051496; Chem. Abstr. 2007, 146, 482097. 8. NaBF4 is a very economic commercial source of BF4 � (being marginally cheaper than HBF4 and less than 1% of the cost of AgBF4). Furthermore, it is far easier to handle than HBF4. 9. Preliminary small-scale studies indicate that DMTMP BF4 1d is more soluble than the analogous DMTMM BF4 1b in both acetonitrile and water. When the unmodified process is used, the isolated yield of 1d is 47%, product loss to the mother liquors accounting for this significantly lower yield. Conducting the reaction at higher concentration significantly improves recovery. 10. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate (1b): 2-Chloro-4,6-dimethoxy-1,3,5-triazine 3 (7.39 g, 41.4 mmol) was suspended in water (110 mL). To this was added N-methylmorpholine (5.0 mL, 45.6 mmol) in one portion. After 20 min, the solid had dissolved to give a colourless solution (analysis by HPLC showed complete consumption of 3). Sodium tetrafluoroborate (5.57 g, 49.7 mmol) was dissolved in water (37 mL), and the resulting solution charged to the reactor dropwise over 5 min. Crystallisation began immediately and continued throughout the addition. The mixture was stirred for a further 45 min before the solid was collected by vacuum filtration. The cake was washed sequentially with water (2 � 22 mL) and methanol (37 mL). The material was dried to a constant weight in vacuo to give the title compound 1b (11.12 g, 97.4% (w/w) strength,11 33.0 mmol, 80% yield) as a colourless crystalline solid: 1H NMR (400 MHz, MeCN-d3): d(ppm) 3.39 (3H, s), 3.68–3.79 (4H, m), 3.95–4.04 (2H, m), 4.12 (6H, s), 4.40–4.49 (2H, m); 13C NMR (100 MHz, MeCN-d3): d(ppm) 56.9, 57.8, 61.1, 62.8, 171.2, 175.0. The data are in good agreement with those published in the literature.7a 11. Material strength was determined by 1H NMR spectroscopic assay in DMSO-d6, using 1,2,4,5-tetrachloro-3-nitrobenzene as an internal standard. 12. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium hexafluorophosphate (1c): This was synthesised in a manner analogous to that rs 50 (2009) 946–948 947 described above for 1b, using 2-chloro-4,6-dimethoxy-1,3,5-triazine 3 (7.50 g, 42.0 mmol) and sodium hexafluorophosphate (8.56 g, 50.4 mmol) with the other reagents scaled accordingly. This gave the title compound 1c (14.85 g, dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight dhxgroup Highlight 96.9% (w/w) strength,11 37.3 mmol, 89% yield) as a colourless crystalline solid: 1H NMR (400 MHz, DMSO-d6): d(ppm) 3.47 (3H, s), 3.78 (2H, ddd, J 13.3 Hz, J 10.2 Hz, J 1.6 Hz), 3.88 (2H, ddd, J 12.7 Hz, J 10.2 Hz, J 2.8 Hz), 4.01 (2H, ddd, J 13.3 Hz, J 2.8 Hz, J 2.8 Hz), 4.10 (6H, s), 4.36 (2H, br d, J 12.7 Hz); 13C NMR (100 MHz, DMSO-d6): d(ppm) 55.2, 56.6, 59.5, 61.3, 170.2, 173.4; 19F NMR (470 MHz, DMSO-d6): d(ppm) �70.6 (6F, d, J 710 Hz); 31P NMR (200 MHz, DMSO- d6): d(ppm) �143.0 (1P, septet, J 710 Hz); 1H NMR (400 MHz, MeCN-d3): d(ppm) 3.38 (3H, s), 3.66–3.79 (4H, m), 3.93–4.05 (2H, m), 4.11 (6H, s), 4.44 (2H, br d, J 10.6 Hz); 13C NMR (100 MHz, MeCN-d3): d(ppm) 56.9, 57.8, 61.1, 62.8, 171.2, 175.0; m/z (Positive ion ESI) 241 (DMTMM+) [HRMS (Positive ion ESI) calcd for C10H17N4O3 241.1295. Found 241.1297 (0.6 ppm error)]. 13. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylpiperidinium tetrafluoroborate (1d): 2-Chloro-4,6-dimethoxy-1,3,5-triazine 3 (7.55 g, 42.3 mmol) was suspended in water (60 mL). To this was added N-methylpiperidine (5.7 mL, 46.6 mmol) in one portion. After 20 min, the solid had dissolved to give a colourless solution (analysis by HPLC showed complete consumption of 3). Sodium tetrafluoroborate (5.69 g, 50.8 mmol) was dissolved in water (15 mL), and the resulting solution charged to the reactor dropwise over 5 min. Crystallisation began after approximately 40% of the solution had been charged and continued throughout the remainder of the addition. The mixture was stirred for a further 75 min at ambient temperature. It was then cooled to 0 �C (ice/acetone bath) and stirred for a further 30 min before the solid was collected by vacuum filtration. The cake was washed twice with chilled water (15 mL and 8 mL). The material was dried to a constant weight in vacuo at 40 �C to give the title compound 1d (9.75 g, 99.2% (w/w) strength,11 28.6 mmol, 68% yield) as a colourless crystalline solid: 1H NMR (500 MHz, MeCN-d3): d(ppm) 1.50–1.81 (4H, m), 1.85–1.96 (2H, m), 3.29 (3H, s), 3.52 (2H, ddd, J 12.5 Hz, J 12.5 Hz, J 2.7 Hz), 4.11 (6H, s), 4.41 (2H, br d, J 12.5 Hz); 13C NMR (125 MHz, MeCN-d3): d(ppm) 21.3, 21.9, 55.5, 57.7, 62.6, 171.8, 175.0. The data are in good agreement with those published in the literature.7a 948 S. A. Raw / Tetrahedron Letters 50 (2009) 946–948 An improved process for the synthesis of DMTMM-based coupling reagents Acknowledgements References and notes