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Amidation Reactions from the Direct Coupling of Metal Carboxylate Salts with Amines Jordan D

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Amidation Reactions from the Direct Coupling of Metal Carboxylate Salts with Amines Jordan D Article pubs.acs.org/joc Amidation Reactions from the Direct Coupling of Metal Carboxylate Salts with Amines Jordan D. Goodreid, Petar A. Duspara, Caroline Bosch, and Robert A. Batey* Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada, M5S 3H6 *S Supporting Information ABSTRACT: A general method for the synthesis of amides involving the direct coupling of alkali metal carboxylate salts with amines is described. Amidation of a wide variety of carboxylate salts with either free amines or their ammonium hydrochloride salts can be achieved using HBTU as a coupling agent in combination with Hünig’s base. The reaction is highly efficient and is generally complete in as little as 1−2 h, giving the products in good to excellent yields. The protocol is valuable for the coupling of carboxylates for which the corresponding carboxylic acids or acyl chlorides are unstable, less conveniently manipulated/isolated, or are not commercially available. For example, the coupling of amines and α-amino acids with lithium 5- bromo-1H-pyrrole-2-carboxylate, whose corresponding acid that is prone to decarboxylation, allowed for the synthesis of 5- bromo-1H-pyrrole-2-carboxamides, which are analogues of the pyrrole-2-aminoimidazole marine alkaloids. The protocol can be combined with other reactions in a sequenced fashion, as exemplified by the synthesis of acetylenic amides, in a one-pot procedure, via the coupling of a lithium carboxylate salt formed initially by the addition of carbon dioxide to a lithiated terminal alkyne. ■ INTRODUCTION with PPTS (3 equiv)/tertiary amine (2 equiv of Hünig’s base or N-methylmorpholine) additives.10 Although effective, neither Carboxylic amides constitute one of the most important and method is appropriate when the corresponding acyl chloride is ubiquitous of organic functional groups, occurring in natural unstable or the system is acid-sensitive. Herein, we report the products, both peptidic and nonpeptidic, pharmaceuticals, first general method for the direct coupling of metal carboxylate agrochemicals, materials, and polymers. The privileged nature salts with amines or amine hydrochloride salts. The newly of the amide functional group is apparent, for example, from its 1 developed protocol enables amidations using metal carboxylate occurrence in an estimated 25% of available drugs. Most amide salts for which the corresponding acids or acyl chlorides may be bond formations utilize the reaction of amines in the presence 2 unstable or inconvenient to manipulate or isolate. Application of acylating agents, such as acyl chlorides, or the reaction of of the method for the formation of acetylenic carboxamides, carboxylic acids with amines in the presence of coupling 3 through a one-pot protocol involving an initial reaction of an agents. The importance of amides has ensured continued acetylide anion with carbon dioxide, demonstrates its potential advances in protocols and reagents based upon these 4 for multistep one-pot amidation reactions from metalated approaches, as well as the development of alternative methods intermediates.11 for amide bond formation.5 In contrast to the use of carboxylic acids, acyl chlorides, and RESULTS AND DISCUSSION other activated acylating agents, metal carboxylate salts have ■ found limited utility for the synthesis of amides. Indeed, the As part of our recent total synthesis of the marine alkaloid diminished nucleophilicity of the carboxylate functionality has agelastatin A, a method for the formation of a bromopyrrole enabled carboxylate salts of α-amino acids to be used as a amide was required, which culminated in the development of a protected carboxylic acid functionality in peptide couplings.6 direct reaction between diammonium hydrochloride salt 1 with For example, alkaline earth metal carboxylate salts of α-amino lithium bromopyrrole carboxylate salt 2, in the presence of the acids have been used in reactions with Boc-protected α-amino uronium coupling reagent TPTU (2-(2-pyridon-1-yl)-1,1,3,3- acid activated esters (N-hydroxysuccinimidyl or p-nitrophenyl tetramethyluronium tetrafluoroborate), to give amide 3 with 12 esters).7 Similar approaches using tetraalkylammonium carbox- good regioselectivity in 54% yield (Scheme 1). Encouraged ylate salts for peptide couplings have also been reported.8 by the success of this preliminary study, we became interested Carboxylate salts have also been employed for the synthesis of in whether a general protocol for the direct coupling of alkali amides via in situ acid chloride formation.9 Finally, couplings of metal carboxylate salts could be developed. A method that methyl red sodium carboxylate and other alkali metal dye carboxylates with amines using N,N-diisopropylcarbodiimide Received: October 24, 2013 (DIC)/N-hydroxybenzotriazole (HOBt) have been achieved Published: December 19, 2013 © 2013 American Chemical Society 943 dx.doi.org/10.1021/jo402374c | J. Org. Chem. 2014, 79, 943−954 The Journal of Organic Chemistry Article Scheme 1. Selective Acylation of Diammonium Hydrochloride 1 with Lithium Bromopyrrole Carboxylate 2 in the Total Synthesis of (±)-Agelastatin A Table 1. Optimization Experiments for the Synthesis of Amide 5a Using Lithium Bromopyrrole Carboxylate 2 and Ammonium Salt 4 i a entry method coupling reagent Pr2NEt (equiv) 4:5a:6:7:8 1 A HBTU 1.1 45:40:5:10:0 2 A EDC·HCl 2.1 40:10:−:30:20 3b A EDC·HCl 2.1 20:55:0:15:10 4 A PyBOP 1.1 20:35:0:25:20 5 B HBTU 1.1 0:100:0:0:0 6 B TPTU 1.1 20:60:15:5:5 7 B EDC·HCl 2.1 50:15:−:30:5 8b B EDC·HCl 2.1 15:75:0:10:0 9 B PyBOP 1.1 25:65:0:10:0 aRatios determined by 1H NMR analysis of the crude reaction mixtures and are reported to the nearest 5%. Ratios of compounds 4, 5a, and 8 were b measured by integration of the Hα signals, whereas 6 and 7 were measured by integration of the H-4 and H-3 pyrrole signals, respectively. 1.0 equiv of HOBt was added to the reaction. HBTU = 1-[(dimethylamino)(dimethyliminio)methyl]-1H-benzo[d][1,2,3]triazole 3-oxide hexafluorophos- phate, EDC·HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, PyBOP = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate. utilizes such salts would be advantageous for a number of 4- and 5-monobromo and 4,5-dibromopyrrole-2-carboxa- reasons. First, metal carboxylate salts can serve as bench-stable mides are present in a large family of structurally complex and 16 surrogates to free acids or acid chlorides that are unstable bioactive pyrrole-2-aminoimidazole (P2AI) marine alkaloids, (prone to decarboxylation/decomposition pathways). For but the corresponding pyrrole-2-carboxylic acids have poor fi example, both the free acid and the acid chloride species of stability pro les, limiting their application in some syntheses. − bromopyrrole 2 are reported to be unstable,13 15 whereas the Lithium 5-bromo-1H-pyrrole-2-carboxylate 2 was thus chosen corresponding lithium carboxylate salt provides access to a for the initial optimization study. Coupling of 2 with L- 15 phenylalanine tert-butylester hydrochloride 4 was employed as bench-stable alternative that is stable for months. Second, a model reaction for optimization studies, using aminium some carboxylic acids are more conveniently manipulated as (HBTU), uronium (TPTU), phosphonium (PyBOP), and the corresponding carboxylate salts, or the carboxylate salts are carbodiimide (EDC·HCl) coupling reagents (Table 1). Proton more readily available as precursors. Finally, direct (in situ) NMR analysis of the crude reaction mixtures after 1 h revealed activation of a metal carboxylate salt using an appropriate that premixing of the starting materials and coupling reagent(s) coupling reagent will often be more time- and cost-effective prior to the addition of Hünig’s base (Method A) resulted in than methods utilizing preformed activated esters (e.g., N- poor conversion to the desired amide 5a. In addition to hydroxysuccinimidyl or pentafluorophenyl esters), which significant amounts of remaining amine 4, anhydride 7 and urea require additional steps to synthesize. 8 were also formed as side-products (Table 1, entries 1−4).17 944 dx.doi.org/10.1021/jo402374c | J. Org. Chem. 2014, 79, 943−954 The Journal of Organic Chemistry Article Scheme 2. Control Experiments for Urea Formation Table 2. One-Pot Synthesis of Amides 5a−5f Using Lithium Bromopyrrole Carboxylate 2 and Various α-Amino Ester a Hydrochloride Salts (Method B) aIsolated yields after column chromatographic purification. Formation of anhydride 7 presumably proceeds through the Further optimization revealed that activation of 2 with the homocoupling of carboxylate 2 via an activated ester coupling reagent prior to the addition of ammonium salt 4 and species.18,19 Control experiments carried out under similar Hünig’s base (Method B) was essential in obtaining a higher conditions demonstrate that urea 8 did not result through the conversion to amide 5a (Table 1, entries 5−9). The order of reaction of excess ammonium salt 4 with EDC·HCl in the addition was found to greatly suppress the formation of presence of Hünig’s base, but did form through the analogous anhydride 7 and resulted in improved yields of amide 5a. Use reaction with HBTU (27% conversion by 1H NMR) (Scheme of this method, with HBTU as a coupling reagent, resulted in 2, Eq 1). Formation of urea 8 could instead occur from in situ full conversion to 5a while avoiding the formation of anhydride 7 decarboxylation of 2 and subsequent reaction with 4 using entirely (Table 1, entry 5). HBTU was thus chosen as the standard reagent for all further amidation reactions. This result PyBOP or EDC·HCl. Support for this hypothesis is provided was confirmed in an analogous 1H NMR experiment utilizing 8 4 by the formation of in the reaction of ammonium salt , DMF-d as solvent.
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