Highly Selective Synthesis of α-Hydroxy, α-Oxy, and α-Oxo Amides by a Post-Passerini Condensation Transformation

Abstract A post-Passerini condensation transformation can be employed in the synthesis of three types of amides: α-hydroxy, α-oxy, and α-oxo amides. K2CO3 efficiently promotes the solvolysis of α-acetoxy amides to form α-hydroxy amides in methanol. 2-Acetoxy-2-(2-alkynylquinolin-3-yl)acetamides in basic methanol are cyclized to 1,3-dihydrofuro[3,4-b]quinoline-1-carboxamides via deacetylation and 5-exo-dig cyclization. Treatment of 2-hydroxy-2-[2-(phenylethynyl)quinolin-3-yl]acetamides with I2 in basic media produces pyrrolo[2,3-b]quinoline-2,3-diones. This cyclization involves intramolecular cyclization, dealkynylative aromatization, and oxidation of the secondary alcohol.

Amides are important building blocks in pharmaceutical compounds, natural products, peptides, and proteins. 1 Owing to the potential biological applications of amides, the methods for the synthesis of these compounds have received much attention and rely on a number of effective transformations from various starting materials. 1 Among them, -oxygenated amides are valuable compounds, which represent a broad range of biologically active and natural products ( Figure 1). 2a,b Several interesting methods have been used for the synthesis and application of -oxygenated amides. 2c-h In this context, isocyanide-based multicomponent reactions (IMCRs) are tremendously powerful synthetic tools for the construction of structurally diverse complex amides. 3 Although the history of IMCRs goes back to Passerini's report in 1921, 4 in the last few decades this technique has emerged as a highly interesting research topic in organic synthesis. While the Passerini three-component reaction (P-3CR) is highly effective and economical, it not only enriches the range of syntheses of -acyloxy amides but, more importantly, its post-condensation transformation could also play an important role in diverse syntheses of amide derivatives. 5 Access to -hydroxy amides has been opened by a modification on the Passerini reaction by using TiCl 4 . 6 The use of mineral acids and other Lewis acids was reviewed by Banfi et al. 5 Moreover, the application of organic acids such as diphenylborinic acid 7 and boric acid 8 has been reported. Marcos detailed a zinc-catalyzed solvolysis of a Passerini three-component reaction of glyoxyl amides or esters. 9 A Passerini reaction-amine-deprotection-acyl-migration (PADAM) strategy in complex peptide-like structures containing an -hydroxy--amino acid unit was also

Special Topic Synthesis
reported. 10 The PADAM strategy was utilized in the synthesis of polyfunctionalized 2(1H)-pyrazinones. 11 After formation of -acylamino--hydroxy amides, the secondary alcohol oxidized to the corresponding ketone, followed by Boc deprotection; then spontaneous aromatization took place to form 2(1H)-pyrazinones. El Kaїm et al. reported the synthesis of -keto amides from Passerini adducts of cinnamaldehyde derivatives under basic microwave conditions. 12 As part of our interest in IMCRs, 13 herein, we report the use of Passerini adducts with or without alkynyl groups, which in different ways selectively produced -hydroxy, -oxy, and -oxo amides.
We initiated the investigation with the synthesis of the Passerini adduct 3a by using 4-chlorobenzaldehyde (1a), cyclohexyl isocyanide (2a), and acetic acid in MeOH, under reflux (Table 1). After 24 hours of reaction, K 2 CO 3 (2 equiv) was added and the mixture was stirred for 8 hours at room temperature to generate 3a (entry 1). After a short screening of conditions (entries 2-12), including solvents, such as MeOH, EtOH, THF, CH 2 Cl 2 , and H 2 O, and bases, such as K 2 CO 3 , Cs 2 CO 3 , KOH, NaHCO 3 , pyridine, Et 3 N, and DABCO, we found that the use of K 2 CO 3 in MeOH provides the best conditions to provide 2-(4-chlorophenyl)-N-cyclohexyl-2-hydroxyacetamide (3a) in 83% yield (entry 1). Notably, the solvents were not dried before use. Although the reaction did not work well in water as solvent (entry 12), the presence of water in the solvents may have a considerable influence on the hydrolysis.
Having established the optimized conditions, we further explored the scope and generality of the reaction by using various aldehydes and isocyanides. The results are summarized in Figure 2. 4-Methyl and 2-chlorobenzaldehydes resulted in the corresponding -hydroxy amides 3b and 3c. The Passerini adduct of 2-chloroquinoline-3-carbaldehyde bearing a relatively active chloro group selectively yielded -hydroxy amide 3d in 85% yield in basic media without any side product. Notably, during the past two decades, 2-chloroquinoline-3-carbaldehydes have been widely used as versatile starting materials in the construction of quinoline derivatives. 14 The yields obtained with 8-methyl-, 6-methyl-, and 6-methoxy-2-chloroquinoline-3-carbaldehydes are also comparable with those of other aldehydes. Additionally, primary and tertiary isocyanides also worked well to form the corresponding amides 3h-k ( Figure 2).
Interestingly, amide 5a, the Passerini adduct of oalkynyl aldehyde 4a, cyclohexyl isocyanide (2a), and acetic acid, in K 2 CO 3 in MeOH provided 6a in 87% yield (Scheme 1). To extend the use of this reaction, quinoline-3-carbaldehydes bearing substituents on the quinoline ring and the aryloxy part were subjected to this cascade reaction with different types of isocyanides, involving methanolysis and intramolecular hydroalkoxylation of the alkyne functionality (Scheme 1, Figure 3). Product 6b formed from the corresponding 6-methylquinoline via solvolysis and 5-exo-dig cyclization in 80% yield. By changing the isocyanide to n-butyl, isopropyl, and cyclopentyl isocyanides, the corresponding 1,3-dihydrofuro[3,4-b]quinoline-1-carboxamides 6c-i were isolated in good yields. Even utilizing a hindered tert-butyl isocyanide yielded the corresponding products 6j-n ( Figure 3). From a mechanistic point of view, after deacetylation, most probably the base assisted the generation of an O-allene, followed by cyclization with the hydroxy group in a 5-exo-dig fashion. Finally, 1,3-H migration furnished 6.

Special Topic Synthesis
Less active 1,2-diarylalkyne 8a in basic methanol only solvolyzed to -hydroxy amide 9a (Table 2). Surprisingly, 9a in the presence of I 2 and K 2 CO 3 in MeCN afforded an unprecedented product 1-cyclohexyl-6-methyl-1H-pyrrolo[2,3b]quinoline-2,3-dione (10a) (entry 1). Changing the solvent to dioxane, THF, or toluene did not improve the yield of product (entries 2-4). Increasing the amount of I 2 to 4 equivalents and using DMF improved the yield of 10a to 85% after 24 hours at 100 °C (entry 7). Removing the base discontinued the reaction (entry 8) and changing the base to Cs 2 CO 3 , NaOt-Bu, DABCO, or Et 3 N did not provide a better yield. Notably, AgNO 3 only produced a small amount of desired product (entry 14).
Using tolylacetylene instead of phenylacetylene in this process afforded the same results. Using the optimized reaction conditions from Table 2, we examined the scope and limitations of the cyclization reaction. As shown in Figure 5, the reaction succeeded in the presence of an electron-withdrawing group such as chloro and electron-donating groups, including methyl and methoxy at various positions on the quinoline ring (10a-e). The reaction was also successful with benzoquinoline (10f). The reaction with cyclopentyl and n-butyl isocyanides proceeded well (10gk), but hindered tert-butyl isocyanide did not work at all under our optimized conditions.
A possible mechanistic pathway is outlined in Scheme 2. First, it would involve the nucleophilic addition of a nitrogen of quinoline 9 to iodine to form intermediate I, followed by base-mediated intramolecular cyclization to give intermediate II. Aromatization of the quinoline ring via nitrogen-assisted elimination of phenylacetylene and I + and,

Scheme 2
In conclusion, we have developed effective methods for the synthesis of -hydroxy, -oxy, and -oxo amides using Passerini adducts. The common -acetoxy amides hydrolyze to the corresponding -hydroxy amides in basic methanol. Employing 2-alkynyl-3-formylquinolines in the construction of the Passerini adduct, followed by treatment with basic methanol, results in cyclization to form dihydrofuro[3,4-b]quinolines via deacetylation and then intramolecular hydroalkoxylation. N-Alkyl-2-hydroxy-2-[2-(arylethynyl)quinolin-3-yl]acetamides in the presence of molecular iodine afford pyrrolo[2,3-b]quinoline-2,3-diones via dealkynylative cyclization and oxidation of the secondary alcohol. This suggests that post-Passerini transformations are highly useful techniques for the synthesis of structurally complex molecules possessing useful and interesting properties.
All purchased solvents and chemicals were of analytical grade and used without further purification. 2-Chloroquinoline-3-carbaldehydes 17 and 2-alkynylquinoline-3-carbaldehydes 18 were prepared by reported procedures. Melting points were measured with an Electrothermal 9100 apparatus. IR spectra were recorded with a Shimadzu-IR 460 spectrophotometer. A Leco CHNS, model 932 was used for elemental analysis. The NMR spectra were acquired on a Bruker Avance spectrometer, running at 300 MHz for 1 H NMR and 75 MHz for 13 C NMR. Mass spectra were recorded on a Bruker Maxis Impact mass spectrometer using electrospray ionization (ESI + ).

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M. Shiri et al.