Condensation of carboxylic acids and non-nucleophilic N-containing heterocyclic amines involving Boc2O_Industrial additives

Background introduction to the condensation of carboxylic acids and non-nucleophilic N-containing heterocyclic amines involving Boc2O

As an important functional group, the amide bond is widely present in natural products , in proteins and other substances. To date, there are many reports on amide bond formation. However, methodologically, there are few reports on the direct condensation of carboxylic acids with substrates such as nitrogen-containing aromatic heterocycles (such as indole, pyrrole, pyrazole, and carbazole), lactams, or anilines. The main reason is that these substrates The lone pair of electrons on the medium nitrogen is delocalized, causing the nucleophilicity of the substrate to decrease.

In order to solve this problem, you can consider using a stoichiometric strong metal base such as n-BuLi or NaH to remove the hydrogen atom on the N-H bond, deprotonate it, and then react with the activated carboxylic acid derivative ( For example: acid chloride or active ester) condensation reaction occurs. For example, Snider reported the use of p-nitrophenyl ester as the acylating reagent to perform N-acylation on tryptophan derivatives. Recently, Sarpong discovered that the reagent carbonylazole can N-acylate indoles and oxazolidinones with high chemoselectivity.

We chose the reagent di-tert-butyl dicarbonate (Boc2O) to study the direct condensation of carboxylic acids and nitrogen-containing compounds with low nucleophilicity. Mainly based on the following considerations: in the presence of Boc2O and 4-(dimethylamino)pyridine (DMAP), on the one hand, nitrogen-containing compounds (including indole, pyrrole and lactam) containing tert-butoxycarbonyl (Boc) protecting group N-Boc-dimethylaminopyridinium ion and exposed tert-butanol anion can be generated with acid first, and then condensed. On the other hand, carboxylic acids react with primary amines, anilines, ammonia, alcohols or phenols to form corresponding mixed anhydrides, which then participate in condensation.

A new condensation method involving carboxylic acids and non-nucleophilic N-containing heterocyclic amines involving Boc2O is introduced

In the presence of Boc2O and DMAP, the above reaction can proceed smoothly. We speculate that Boc participates in activating carboxylic acid to form mixed anhydride 2 or N-acyldimethylaminopyridinium ion 3, and at the same time serves as an activating reagent to activate nitrogen-containing compounds with low nucleophilicity. Compound (Scheme1). At the same time, the indole 7 and/or tert-butyl ester 8 containing the tert-butoxycarbonyl (Boc) protecting group reacts competitively with the indole anion and N-Boc-dimethylaminopyridinium ion 5, respectively. Or it occurs between tert-butoxide and mixed acid anhydride 2, or the reagent ion 3 of N-acyldimethylaminopyridine. Literature survey found that the substrates of the condensation reactions in which Boc participates are mostly nucleophilic nitrogen-containing compounds, and there are no reports on non-acyldimethylaminopyridine. Report of nucleophilic nitrogen-containing substrates. Here, we report a novel and applicable method for the reaction of Boc2O-participating carboxylic acids with nitrogen-containing aromatic heterocycles, lactams, and oxazolidines under mild conditions without metal participation. Direct condensation of ketones and anilines.

Boc2O participates in the carboxylic acid and non- Screening of condensation conditions for nucleophilic N-containing heterocyclic amines

First, we used dimethyl succinate 9a and indole 1 as substrates (Table 1). First consider the impact of the Boc protecting group on the nitrogen on the reaction (entry 1). It was found that by adding Boc2O and 5mol% DMAP, the expected product N-acylindole 10a and a trace amount of N-Boc-indole 7 could be obtained, but no tert-butyl ester 9a was produced. We screened the catalysts and used N-methylimidazole (NMI), 1,4-, 1,8-diazabicyclo[2.2.2]octane (DABCO), diazabicyclo[5.4.0]ten Monocarbon-7-ene (DBU) (entry 2-4) is used as a catalyst, and the yield of the target product is low. We speculate that the low product yield may be due to the dissociation of hydrogen ions in the carboxylic acid, which protonates DMAP and hinders the reaction. Therefore, 10 mol% triethylamine was added to the reaction to obtain compound 10a with a yield of 87% (entry 5). Next, the types of bases were screened, and it was found that 2,6-dimethylpyridine had the best effect, and the corresponding N-acylindole 10a was obtained with a yield of 92% (entry 7). At the same time, we found that the reaction cannot proceed in the absence of DMAP (entry 12), thus indicating that it plays a key role in the reaction. The solvent was screened and it was found that when CH2Cl2 was used as the solvent, the yield decreased (entry 13). In the experiment, it was found that the dosage of indole and Boc2O is a necessary and sufficient condition to obtain N-acylindole 10a with high yield and selectivity. If equivalent amounts of compound 1 and Boc2O (1.5 equivalents) participate in the reaction, the product yield is 65%, while the by-product N-Boc-indole 7 (14%) and recovered compound 1 (21%) are obtained (entry 14). Using 5 g of carboxylic acid 9a, under this reaction condition, the target acylindole 10a (entry 15) was obtained almost quantitatively.

Boc2O participates in carboxylic acids and non-nucleophilic N-containing heterocyclic amines Expansion of condensation substrates

After optimizing the reaction conditions, we first expand the scope of the substrate carboxylic acid (Table 2). Introduce different functional groups to the linear carboxylic acid (9b-q ), such as ketones, esters, silicon ethers, alkenyl, alkynyl, bromoalkyl, substituted phenyl and thienyl, etc. It was found that the reaction functional group has good compatibility and the product yield is high. Even if the sterically hindered β- (9r) or α-branched (9s and 9t) calcium carbonate carboxylic acid can also react well with high yield.�Get 10r, 10s and 10t. Especially for N-benzyloxycarbonyl-proline derivative 10t, the optical purity remains unchanged before and after the reaction. Aromatic carboxylic acids (9u-9w) have lower reactivity, and the amount of base can be increased in the reaction (20mol% DMAP and 30mol% 2,6-dimethylpyridine). It is worth noting that heterocyclic aromatic carboxylic acids, 2-pyridinecarboxylic acid (9v) and 2-quinolinecarboxylic acid (9w), can also obtain the corresponding target products 10v and 10w in high yields under these conditions.

Next, expand the substrate range of nucleophilic nitrogen-containing compounds (Table 3). 6-, 5- or 3-substituted indoles containing halogen or electron-withdrawing functional groups, the reaction is not affected and the yield is high (12a-e). Importantly, steric hindrance has no effect on the reaction of 2- and 7-substituted indoles (12f–j), except for 2-phenylindole (11h). Similar non-nucleophilic nitrogen-containing heterocyclic aromatic compounds, such as pyrrole, pyrazole and carbazole, can also successfully complete the reaction, and N-acyl products (12k-n) are obtained in high yields.

In addition, we found that this reaction is also applicable to other non-nucleophilic nitrogen-containing compounds, such as γ-lactams, oxazolidinones and anilines. γ-lactams (13a and 13b) and oxazolidinones (13c-e) can obtain the corresponding N-acyl products 14a, 14b and 14c-e in high yields under these conditions (Table 4). Anilines (13f-p) containing substituents at the ortho, meta or para positions on the benzene ring gave the corresponding imide compounds (14f-p) in almost quantitative yields. Importantly, the sterically hindered 2,6-dimethylaniline derivative 13n can also be used to obtain the corresponding imide 14n in high yield. For suitable substrates such as 1-aminonaphthalene derivative 13o and 2-pyridine amide 13p, the reaction was as expected, affording the corresponding products (14o and 14p) in high yields, respectively. However, for substrates such as oxazolidinones (13d and 13e) and anilines (13k, 13l and 13o), when reacted with equimolar amounts of nucleophiles and Boc2O (1.5 equivalents), the product yield (80-91%) is still Very satisfying.

Condensation mechanism of carboxylic acids and non-nucleophilic N-containing heterocyclic amines involving Boc2O Explore

Based on the above results, we speculate on the reaction mechanism (Scheme 2). It is believed that DMAP acts as a nucleophile to attack Boc2O to obtain N-Boc-dimethylaminopyridinium ion 5, and at the same time The naked tert-butanol anion 4 is produced, which takes away the proton on the carboxylic acid 15 to obtain the carboxylic acid anion 16. An addition and elimination reaction between 16 and 5 occurs to obtain the mixed anhydride 2. This is followed by the nucleophilic attack of the nitrogen atom on the DMAP ring 2 The carbonyl carbon atom produces N-acyldimethylaminopyridinium ion 3 and exposed tert-butanol anion 4. At this time, 4 takes away the proton on the non-nucleophilic nitrogen-containing compound 17 to obtain a more nucleophilic anion. 18 and tert-butanol. Finally, the anion 18 attacks the acyl carbon on 3, and the addition and elimination gives the condensation product amide. In the whole process, the nitrogen-containing compound 17 plays a dual activation role, and the N-acyl-dimethyl obtained through the conversion The intermediate activated carboxylic acid after the aminopyridinium ion 3 and the exposed tert-butanol anion 4 steal the proton from N-H. The key to selectively forming the amide and avoiding competing reactions lies in the three acyl donors 2, 3 and 5 3 has the highest activity, which is caused by steric and electronic reasons. According to a series of experimental results in Table 1, we believe that the role of the base (2,6-dimethylpyridine) is mainly as a proton capture agent to prevent DMAP Protonation (Scheme2b).

In order to demonstrate the practical application value of this method, we expanded the reaction scale (Scheme 3). Acid 9j and equimolar amounts of N-anilide 13o and Boc2O (1.5 equivalents) were reacted under optimized conditions. As expected, the reaction went very smoothly and the corresponding product 14o was obtained with a yield of 94%.

Summary of the condensation of carboxylic acids and non-nucleophilic N-containing heterocyclic amines involving Boc2O

In summary, we found In the presence of B calcium carbonate oc2O/DMAP/lutidine, carboxylic acids and various non-nucleophilic N-containing heterocycles such as indole, pyrrole, pyrazole, carbazole, lactam and oxazolidinone can be directly condensed . In addition, the substrate can be expanded to aniline. The Boc2O/DMAP/2,6-dimethylpyridine system plays a key role in the in-situ dual activation, activating the carboxylic acid into N-acyldimethylaminopyridinium ion and using the exposed tert-butanol anion as a base to produce corresponding Non-nucleophilic nitrogen-containing compounds formed from anions. The method is simple to operate, and the condensation reaction does not require the use of a metal base to abstract the proton hydrogen on the nitrogen-containing nucleophile to form the corresponding anion and activate the carboxylic acid into an acid halide or ester.

TAG: Boc2O, carboxylic acid, condensation,

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