Mechanism: Steps: The base deprotonates the carboxylic acid. [0.1 g, 49%], [Patent Reference: WO2007089768, page 233, (20.6 MB)], To a solution of the acid (200 mg, 0.7 mmol) in DMF (3.0 mL) at 0 C was added HATU (550 mg, 1.4 mmol) and DIEA (280 mg, 2.1 mmol), followed by the addition of the amine (173 mg, 0.8 mmol). The amine attacks the now activated carboxylic acid derived intermediate. The org phase was washed with brine, dried (MgSO4), and concentrated to give an oil. The reaction was stirred at RT for 3 h. The mixture was washed with 1N HCl (2 x 600 mL), dried (Na2SO4), and concentrated. A detailed mechanism illustrating the conversion of an amine to amide 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDC) and hydroxybenzotriazole (HOBt). The reaction mixture was stirred at RT for 16 h. The mixture was diluted with H2O and extracted with EtOAc. The mechanism is shown using the more commonly encountered and commercially available iminium isomer; a similar mechanism, however, is likely to apply to the uronium form. In this reaction the carboxylic acid adds to the DCC molecule to form a good leaving group which can then be displaced by an amine during nucleophilic substitution. HATU is used along with Hünig's base (N,N-diisopropylethylamine, DIPEA), or triethylamine to form amide bonds. The crude residue was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide the product as a light colored oil. HATU is commonly encountered in amine acylation reactions (i.e., amide formation). The resulting carboxylate attacks the T3P. [158 mg, 80%], [Patent Reference: WO2015144799, page 287, (18.8 MB)]. [1]. The reaction mixture was stirred at RT for 2 h. TFA (1 mL, 26.1 mmol) was added at RT, and the mixture was stirred 22 h. Additional TFA (1 mL, 26.1 mmol) was added, and the mixture was stirred 18 h. The reaction mixture was then stirred at 80 C for 160 min. DCC induced coupling to form an amide linkage is an important reaction in the synthesis of peptides. HATU was first reported by Louis A. Carpino in 1993 as an efficient means of preparing active esters derived from 1-hydroxy-7-azabenzotriazole (HOAt). The high coupling efficiencies and fast reaction rates associated with HATU coupling are thought to arise from a neighbouring group effect brought about by the pyridine nitrogen atom, which stabilises the incoming amine through a hydrogen-bonded 7-membered cyclic transition state. HATU is commonly encountered in amine acylation reactions (i.e., amide formation). [11 mg, 28%], [Patent Reference: WO2016011390, page 79, (20.2 MB)], A mixture of the acid (A) (3.00 g, 21.1 mmol), the amine (B) (2.09 mL, 21.1 mmol), DIEA (10.5 mL, 63.3 mmol), and HATU (8.03 g, 21.1 mmol) in DMF (130 mL) was stirred at RT overnight. Amine to Amide (Coupling) Ex (CDI) Amine to Amide (CDI) Examples: Example 1. The mixture was stirred at RT for 15 min, after which time the dark clear mixture was treated with the amine (3.44 g, 35.2 mmol). Typically DMF is used as solvent, although other polar aprotic solvents can also be used. Key Points: Base is needed for the rxn to proceed. [80 g, 97%], [Patent Reference: WO2015140133, page 83, (11.7 MB)], A mixture of the SM (38 mg, 0.11 mmol), DIEA (43 mg, 0.33 mmol), and HATU (65 mg, 0.17 mmol) in DMF (2 mL) was stirred at RT for 20 min. HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) is a reagent used in peptide coupling chemistry to generate an active ester from a carboxylic acid. The reaction mixture was partitioned between DCM and H2O. The reaction mixture was stirred at RT for 18 h. The mixture was diluted with EtOAc (100 mL) and washed with 1N HCl (2 x 100 mL), sat. The amide via direct coupling with the amine (the by-product formed, dicyclohexylurea (DCU 7), is usually insoluble in the reaction solvent and can be removed via filtration). A second equivalent of base picks up the excess proton to provide the amide. [4], 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, InChI=1S/C10H15N6O.F6P/c1-14(2)10(15(3)4)17-16-9-8(12-13-16)6-5-7-11-9;1-7(2,3,4,5)6/h5-7H,1-4H3;/q+1;-1, InChI=1/C10H15N6O.F6P/c1-14(2)10(15(3)4)17-16-9-8(12-13-16)6-5-7-11-9;1-7(2,3,4,5)6/h5-7H,1-4H3;/q+1;-1, CN(C)C(=[N+](C)C)On1c2c(cccn2)nn1.F[P-](F)(F)(F)(F)F, Except where otherwise noted, data are given for materials in their, 10.1002/1521-3773(20020201)41:3<441::AID-ANIE441>3.0.CO;2-N, https://en.wikipedia.org/w/index.php?title=HATU&oldid=962040439, Pages using collapsible list with both background and text-align in titlestyle, Articles containing unverified chemical infoboxes, Creative Commons Attribution-ShareAlike License, This page was last edited on 11 June 2020, at 19:37. The amine reacts with the OAt activated ester to form the amide pdt. The reaction mixture was stirred at RT for 16 h. Additional acid (152 mg, 0.801 mmol) and CDI (130 mg, 0.801 mmol) in dry THF (1 mL) was added slowly at RT. To a solution of the acid (5.00 g, 32.0 mmol) in ACN (22.9 mL) was added TEA (9.82 mL, 70.5 mmol) followed by HATU (12.8 g, 33.6 mmol). The OAt anion rapidly attacks the isouronium salt, affording the OAt-active ester and liberating a stoichiometric quantity of tetramethylurea. The org layer was dried (Na2SO4) and concentrated in vacuo. The reaction mechanism of carboxylic acid activation by HATU and subsequent N-acylation is summarised in the figure below. The resulting material was triturated in n-pentane to provide the product as a brown gummy solid. Such reactions are typically performed in two distinct reaction steps: (1) reaction of a carboxylic acid with HATU to form the OAt-active ester; then (2) addition of the nucleophile (amine) to the active ester solution to afford the acylated product. of acid). The resulting mixture was stirred at RT for 1 h, after which time the reaction mixture was diluted with H2O and extracted with EtOAc. The oil was purified by Prep LC (12 g silica, 100% DCM to 90:9:1 DCM/MeOH/NH3) to provide the product as a white solid. The acid (152 mg, 0.801 mmol) was added to a solution of CDI (130 mg, 0.801 mmol) in dry THF (1 mL) at RT under N2. [3] It is, however, possible to obtain the uronium isomer by preparing HATU using KOAt in place of HOAt and working up the reaction mixture quickly to prevent isomerisation. [2.40 g, 45%], [Patent Reference: WO2016012477, page 162, (8.1 MB)]. [48.0 mg, 39%], [Patent Reference: WO2014149164, page 261, (23.7 MB)], To a solution of the acid (68 g, 0.34 mol) in DCM (1 L) was added the amine (39 g, 0.40 mol), HATU (152 g, 0.40 mol), and DIEA (130.3 g, 1.01 mol). The reaction mixture was stirred for 15 min, after which time it was diluted with H2O (0.5 mL) and purified directly by prep-HPLC to provide the TFA salt of the product as an off-white solid. Methylamine-HCl (11 mg, 0.17 mmol) was added and the reaction mixture was stirred at RT for 16 h. The mixture was purified by Prep HPLC [5-95% (ACN)/(0.5% NH4OH in H2O)] to provide the product as a white solid. The acid (152 mg, 0.801 mmol) was added to a solution of CDI (130 mg, 0.801 mmol) in dry THF (1 mL) at RT under N2. The reaction mixture was stirred at RT for 18 h. The mixture was stirred at RT for 15 min, after which time the dark clear mixture was treated with the amine (3.44 g, 35.2 mmol). The org layer was dried (Na2SO4), concentrated, and purified by silica gel column chromatography (5% MeOH/DCM) to provide the product as a white solid. The resulting HOAt anion reacts with the newly formed activated carboxylic acid derived intermediate to form an OAt activated ester. [2] HATU can exist as either the uronium salt (O-form) or the less reactive iminium salt (N-form). The mixture was stirred for 90 min at RT, after which time it was added over 25 min to a solution of the amine (200 mg, 0.400 mmol) in THF (1.5 mL) at RT under N2. Steps: The base deprotonates the carboxylic acid. NaCl (5 x 100 mL), dried (Na2SO4), and concentrated. The resulting carboxylate anion attacks the electron deficient carbon atom of HATU. A mild, versatile, copper-catalyzed three-component coupling of organoindium reagents with imines and acid chlorides provides α-substituted amides or N-protected amines in a single step with the sole byproduct being indium trichloride. In the first step, the carboxylate anion (formed by deprotonation by an organic base [not shown]) attacks HATU to form the unstable O-acyl(tetramethyl)isouronium salt. HATU was initially reported as the O-form using the original preparation reported by Carpino; however, X-ray crystallographic and NMR studies revealed the true structure of HATU to be the less reactive guanidinium isomer. Formation of an N-acylurea 8 by-product Formation of the carboxylic acid anhydride which subsequently yields the amide by reaction with the amine (needs 2 equiv. Such reactions are typically performed in two distinct reaction steps: (1) reaction of a carboxylic acid with HATU to form the OAt-active ester; then (2) addition of the nucleophile (amine) to the active ester solution to afford the acylated product.
Lawry's Meat Marinade,
Blue Colour Images,
Mediterranean Slow Cooker Cookbook,
Cool Grey Wallpaper,
Graham Watch Review,
Tonsillitis In Adults,
Beetle House Chicago,
Why Did God Give Abraham And Sarah A Baby,
Kunal Kapoor Height,
Feeling Sad Meaning In Urdu,
East Raleigh Apartments,
Ad&d Dungeon Masters Guide Pdf,
Window Treatments Ideas,
Shahrukh Khan House In Dubai Price,
Secondary Alcohols On Catalytic Dehydrogenation By Cu-ni Couple Gives,
Black Bean Rice Burrito,
Alton Towers Student Discount,
Avocado Vector Image,
Best Thick Heavy Quilt,
Chinois Vs Strainer,
Sangam Vihar Sub Division,
The Police Ghost In The Machine Album Cover,
Boiling Point Of Alkanes Branching,
Elk Creek Campground,
Tvs Jupiter Disadvantages,