Direct Introduction of an N,N′-Nonsubstituted Carboxamidine Group by Grignard Addition to Silylated Cyanamide

Abstract

A new, widely applicable method to substitute a halogen atom by a nonsubstituted carboxamidine group is presented. Grignard addition to N,N′-bis-trimethylsilylcarbodiimide gives amidinates, which split off the silyl groups during standard aqueous workup. The corresponding amidines are obtained in high yield with high selectivity. Examples for purification procedures are given.

Key words

amidines - Grignard reactions - cyanamide - carbodiimide - silylation - magnesium

• References and Notes

• 1 Grignard V. Annales de l’Universite de Lyon 1901; 6: 1
• 2 Hoffmann R. Angew. Chem., Int. Ed. Engl 1982; 21: 711
• 3a Busch M. Hobein R. Ber. Dtsch. Chem. Ges. 1908; 40: 4296
• 3b Abrams MB. WO 2006012052, 2006
• 3c Hagadorn JR. WO 2013077944, 2013
• 4a The Chemistry of Amidines and Imidates. Vol.1. Patai S. John Wiley and Sons; New York: 1975
• 4b The Chemistry of Amidines and Imidates. Vol. 2. Patai S. John Wiley and Sons; New York: 1991
• 5a Kroll P. Riedel R. Hoffmann R. Phys. Rev. B: Condens. Matter Mater. Phys. 1999; 60: 3126
• 5b Jansen M. Juengermann H. Z. Kristallogr. 1994; 209: 779
• 5c Obermeyer A. Kienzle A. Weidlein J. Riedel R. Simon A. Z. Anorg. Allg. Chem. 1994; 620: 1357
• 6a Pump J. Wannagat U. Justus Liebigs Ann. Chem. 1962; 652: 21
• 6b Birkofer L. Ritter A. Richter P. Tetrahedron Lett. 1962; 195
• 6c Mai K. Patil G. J. Org. Chem. 1987; 52: 275
• 6d Gordetsov AS. Martynova LN. Zimina SV. Moseeva EM. Skobeleva SE. Kulagina NV. Izv. Akad. Nauk, Ser. Khim. 1994; 3: 498
• 6e Guethner T. Krommer H. DE 19822281, 1999
• 7a Kottmair-Maieron D. Z. Anorg. Allg. Chem. 1991; 593: 111
• 7b Wilder CB. Reitfort LL. Abboud KA. McElwee-White L. Inorg. Chem. 2006; 45: 263
• 7c Wedler M. Knoesel M. Noltemeyer M. Edelmann FT. J. Organomet. Chem. 1990; 388: 21
• 7d Melen RL. Less RJ. Pask CM. Rawson JM. Inorg. Chem. 2016; 55: 11747
• 7e Lechler R. Hausen HD. Weidlein J. J. Organomet. Chem. 1989; 359: 1
• 7f Amo V. Andres R. De Jesus E. De la Mata FX. Flores JC. Gomez R. Gomez-Sal MP. Turner JF. C. Organometallics 2005; 24: 2331
• 7g Tunge JA. Czerwinski CJ. Gately DA. Norton JR. Organometallics 2001; 20: 254
• 7h Kristian KE. Iimura M. Cummings SA. Norton JR. Janak KE. Pang K. Organometallics 2009; 28: 493
• 7i Behrle AC. Schmidt JA. R. Organometallics 2013; 32: 1141
• 7j Yang J. Xie Z. Organometallics 2015; 34: 2494
• 7k Dehnicke K. Chem.-Ztg. 1990; 114: 295
• 8 Typical Reaction Procedure Magnesium turnings (12.2 g, 0.5 mol) are placed in dry Et₂O (160 g). Adding carefully an alkyl or aryl halogenide (0.51 mol) at about 35 °C gives a Grignard solution. At 35 °C BTSCD (3, 83.9 g, 0.45 mol) is dosed over 2 h and reacted at 35 °C for 18 h. The white suspension of the magnesium amidinate is evaporated to dryness up to 60 °C at 20 mbar vacuum. The obtained solid is carefully added to ice water (325 g) with external cooling. 25% HCl (135 g; or an equivalent amount of HBr) is added to yield pH 1. The obtained biphasic mixture is stirred for 3 h at 40 °C to complete hydrolytic deprotection of the silyl groups. The phases of the mixture are not separated, but simply evaporated up to 60 °C at 20 mbar. Organic byproducts and residues (mainly trimethylsilanol and/or hexamethyldisiloxane, residual ether, and hydrocarbons from Grignard side reactions) are distilled off together with most of the water resulting in an aqueous solution or suspension.
• 9 Workup Procedure Variations (See Table [1])
  Workup Procedure A: The mixture of the amidine hydrochloride and the magnesium chloride is dried at 60 °C in a vacuum oven. The resulting solid is used as such for further reaction. Workup Procedure B: After partial evaporation of water, the mixture forms a biphasic system, with a liquid or semisolid amidine salt phase. This phase is separated from the aqueous magnesium halide phase that contains only minor amounts of the amidine salt. The amidine phase is dried at 60 °C. Workup Procedure C: The amidine salt (chloride or bromide) that precipitates from the aqueous phase is filtered off, washed with water, and dried in vacuum.
• 10 Purification Procedures (See Table [2]) Purification Procedure D: The raw product from a batch based on Mg turnings (0.5 mol) and BTSCD (0.45 mol) is dissolved in dry MeCN (100 g). At 50 °C dry 1,4-dioxane (100 g) is slowly added to precipitate the magnesium halides as 1,4-dioxane complexes. After cooling to 20 °C the suspension is filtered and washed with MeCN–1,4-dioxane (125 g, 1:1). The filter cake is discarded. The filtrates are evaporated in vacuum to a crystal slurry. Filtration at 20 °C (no washing due to high solubility!) and drying at 60 °C in vacuum gives the pure product. Purification Procedure E: The raw product from a batch based on Mg turnings (0.5 mol) and BTSCD (0.45 mol) is suspended in water (200 g), acidified with HCl or HBr to pH 2.0 and warmed to 60 °C. The product is fully (5f) or partly (5g) dissolved. Cooling to 10 °C, filtration, washing with water, and drying at 60 °C in vacuum gives the pure product.
• 11 Weiss S. Krommer H. Neuhauser KH. DE 3815084, 1989
• 12 One-Pot Synthesis of a 1,3,5-Triazine 1-Chloro-octane 1c (0.51 mol) was reacted to form the dry magnesium amidinate 4c according to the typical reaction procedure. The obtained semisolid intermediate was added to ice water (400 g), giving a suspension with two liquid phases. To this, methyl N-cyanacetimidate (6, 44.2 g, 0.45 mol) was dosed over 1 h at 0 °C. Postreaction for 1 h at 0 °C and 2 h at 40 °C. The thick white suspension formed was acidified with HCl to pH 4, stirred for 1 h at 40 °C to complete hydrolysis of all remaining silyl groups and to dissolve all Mg(OH)₂, and adjusted to pH 6 by addition of some NaOH. The product separated as a sticky solid, was filtered off, washed with water, and dried at 60 °C in vacuum. Recrystallization from abs. EtOH (100 g) gave 59.7 g of 2-amino-4-methyl-6-octyl-1,3,5-triazine (7c, 60% yield based on BTSCD). Melting range 68.8–72.3 °C. ¹H NMR (500 MHz, CDCl₃, r.t.): δ = 8.56, 8.34 (s, 2 H, NH₂), 2.50 (t, 2 H), 2.21 (s, 3 H), 1.72 (m, 2 H), 1.37 (m, 2 H), 1.29–1.24 (m, 8 H), 0.86 (t, 3 H). ¹³C NMR (126 MHz, CDCl₃, r.t.): 181.2, 170.9, 170.8, 31.87, 31.22, 28.49, 28.43, 26.30, 22,75, 22.09, 13.97 ppm.
• 13 NMR Data of the Amidine Salts Prepared All data recorded at 500 MHz (¹H NMR) and 126 MHz (¹³C NMR) in DMSO-d ₆ at r.t. Isobutyramidine Hydrochloride (5a) ¹H NMR: δ = 9.15, 8.88 (s, 2 H each), 2.72 (sept, 1 H), 1.15 (d, 6 H) ppm. ¹³C NMR: δ = 175.8, 31.95, 19.26 ppm. 2,2-Dimethylpropanamidine Hydrochloride (5b) ¹H NMR: δ = 9.12, 8.78 (s, 2 H each), 1.21 (s, 9 H). ¹³C NMR: δ = 171.7, 36.38, 27.06.1-Nonanamidine Hydrochloride (5c) ¹H NMR: δ = 9.05 (b, 4 H), 2.38 (t, 2 H), 1.58 (tt, 2 H), 1.23 (m, 10 H), 0.83 (t, 3 H) ppm. ¹³C NMR: δ = 171.3, 31.53, 31.24, 28.53, 28.49, 28.21, 26.36, 22.09, 13.98 ppm. 3-Methyl-1-heptanamidine hydrochloride (5d) ¹H NMR: δ = 9.03, 8.78 (s, 2 H each), 2.28 (m, 2 H), 1.80 (m, 1 H), 1.31–1.16 (m, 8 H), 0.86 (d, 3 H), 0.83 (t, 3 H) ppm. ¹³C NMR: δ = 170.73, 36.49, 36.36, 31.51, 27.68, 24.84, 22.35, 13.89, 10.07 ppm. Cyclopentylcarboxamidine hydrochloride (5e) ¹H NMR: δ = 9.18, 8.95 (s, 2 H each), 2.84 (tt, 1 H), 1.90 (m, 2 H), 1.71 (m, 4 H), 1.51 (m, 2 H) ppm. ¹³C NMR: δ = 174.46, 42.15, 30.59, 25.21 ppm. 4-Methylbenzamidine hydrobromide (5f) ¹H NMR: δ = 9.40, 9.20 (s, 2 H each), 7.78 (d, 2 H), 7.40 (d, 2 H), 2.39 (s, 3 H) ppm. ¹³C NMR: δ = 165.5, 144.5, 129.5, 128.1, 124.9, 21.1 ppm. 5-Chloro-2-methoxybenzamidine hydrobromide (5g) ¹H NMR: δ = 9.26, 9.08 (s, 2 H each), 7.66 (m, 2 H), 7.27 (d, 1 H), 3.85 (s, 3 H) ppm. ¹³C NMR: δ = 163.1, 155.58, 133.29, 129.05, 124.06, 119.60, 114.33, 56.59 ppm.
• 14 NMR Data of Typical N,N′-Bistrimethylsilyl Magnesium Amidinates All data recorded at 500 MHz (¹H NMR) and 126 MHz (¹³C NMR) in DMSO-d ₆ at r.t. Compound 4a ¹H NMR: δ = 2.36 (sept, 1 H), 1.06 (d, 6 H), 0.09 (s, 9 H), 0.01 (s, 9 H) ppm. ¹³C NMR: δ = 172.3, 64.9, 20.2, 2.19, 0.11 ppm. Compound 4e ¹H NMR: δ = 1.93 (m, 1 H), 1.7–1.4 (m, 8 H), –0.03 (s, 18 H) ppm. ¹³C NMR: δ = 124.1, 39.95, 30.58, 24.65, 2.68 ppm. The intermediates contained residual Et₂O.