Synlett 2017; 28(12): 1437-1440
DOI: 10.1055/s-0036-1589000
letter
© Georg Thieme Verlag Stuttgart · New York

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

Thomas Guethner*, Eva Huber, Juergen Sans, Franz Thalhammer
Further Information

Publication History

Received: 26 January 2017

Accepted after revision: 17 March 2017

Publication Date:
19 April 2017 (eFirst)

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.

 
  • References and Notes

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  • 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.