“…Examples of secondary amide/aldehyde cyclizations are shown in eqs 13, 16, 18−20, and 36, ,,,,,,,, and examples of secondary amide/ketone cyclizations are shown in eqs 4, 7, 10, and 11. ,,,, Reactive aldehydes, such as formaldehyde or ethyl glyoxylate, can combine with secondary amides that bear a suitable nucleophile, under acidic conditions, to furnish cyclized products directly . This reaction is featured in several tetrahydroisoquinoline syntheses − (e.g., eq 66 294 ). …”
Section: 11 Reaction Of Amides With Aldehydes or Ketonesmentioning
confidence: 99%
“…Tetrahydroisoquinolines are also obtained in good yields from the reaction of 294 with acetaldehyde (52%) or benzaldehyde (48%); however, the more reactive 295 results in higher yields (66% and 59%, respectively) . The N -formyliminium ion reaction is favored for the synthesis of 3-aryltetrahydroisoquinolines (e.g., eq 66) because it eschews a problem with elimination to stilbenes under harsh conditions; in fact, yields are generally good to excellent (>70%). , Another advantage is the tolerance for electron-rich 3-aryl substituents and bulky quaternary formamides, such as PhCH 2 CMe(Ph)NHCHO. , Similarly, N -sulfonyliminium ion cyclizations effectively provide tetrahydroisoquinolines. − A special version of the N -formyliminium ion cyclization is depicted in eq 69, wherein bis-aldehyde adducts of formamide, masked as trimethylsilyl ethers, double cyclize with good yields to generate the azabicyclic pavine alkaloid skeleton …”
Section: 23 Effect Of Substituents On the Iminium Ionmentioning
confidence: 99%
“…23,26,27,45,52 Reactive aldehydes, such as formaldehyde or ethyl glyoxylate, can combine with secondary amides that bear a suitable nucleophile, under acidic conditions, to furnish cyclized products directly. 15 This reaction is featured in several tetrahydroisoquinoline syntheses [292][293][294][295][296][297] (e.g., eq 66 294 ).…”
Section: Reaction Of Amides With Aldehydes or Ketonesmentioning
confidence: 99%
“…364 N-Formyliminium ions have proven to be synthetically versatile. [293][294][295] The ring closure of 294 and 295 with formaldehyde leads to 296 (57%) and 297 (73%), with a higher yield for the more reactive aromatic nucleophile. 293 Tetrahydroisoquinolines are also obtained in good yields from the reaction of 294 with acetaldehyde (52%) or benzaldehyde (48%); however, the more reactive 295 results in higher yields (66% and 59%, respec-tively).…”
Section: Effect Of Substituents On the Iminium Ionmentioning
effectively in cyclizations with N-acyliminum species. Electron-attracting substituents other than N-acyl, such as N-sulfonyl, can also be employed in analogues of N-acyliminium ion reactions. However, this review will concentrate on cyclizations of the N-acyl type, encompassing groups such as alkanoyl, aroyl, carbalkoxy, and N,N-dialkylcarbamyl, with limited coverage of sulfonyl groups. Most significantly, this review will focus on intramolecular reactions of N-acyliminium ions that result in the formation of new carbon-carbon bonds, rather than new carbonheteroatom bonds. Although β-lactam synthesis based on the cyclocondensation of imines with acid halides, Bruce E. Maryanoff earned B.S. (1969) and Ph.D. (1972) degrees from Drexel University and then conducted postdoctoral studies at Princeton University, working with Prof. Kurt Mislow. He joined McNeil Laboratories, a Johnson & Johnson subsidiary, in 1974 and advanced to Distinguished Research Fellow, the highest scientific position in the company. From 1976 to 1992, he principally worked on discovering drugs for treating central nervous system disorders; in 1992, he moved into cardiovascular research and presently leads the Vascular Research Team. Dr. Maryanoff is recognized for his work in organic and medicinal chemistry, especially the Wittig olefination reaction; peptides and peptidomimetics; antiepileptics and antidepressants; thrombin inhibitors; and protease-activated receptors. He discovered TOPAMAX topiramate, which is marketed worldwide for the treatment of epilepsy and is being developed for migraine headache. He has published 200 scientific papers, is an inventor on 60 U.S. patents, and has received two national awards, the ACS Heroes of Chemistry Award (2000) and the ACS Award in Industrial Chemistry (2003). Dr. Maryanoff is a Fellow in the American Association for the Advancement of Science and the Royal Society of Chemistry. Han-Cheng Zhang received B.S. and M.S. degrees in chemistry from Xiamen University, P.R.C., and served as a faculty member there for 5 years. He came to the United States and earned a Ph.D. degree in organic chemistry from Rensselaer Polytechnic Institute (1992), working with Prof. Doyle Daves. He joined the R. W. Johnson Pharmaceutical Research Institute as a Postdoctoral Scientist with Dr. Bruce Maryanoff and, after one year, as a Scientist. Dr. Zhang has worked as a medicinal chemist in the areas of G-protein-coupled receptors, proteases, and kinases to discover new drug candidates, recently leading a project that identified the first potent, selective antagonists for the thrombin receptor, proteaseactivated receptor 1. He is now at the level of Principal Scientist in Johnson & Johnson Pharmaceutical Research & Development. Dr. Zhang has published over 40 scientific papers and is an inventor on 13 U.S. patents (issued or pending). His scientific interests include the design and synthesis of novel therapeutic agents, heterocycles, stereoselective reactions, organometallic chemistry, and solid-phase organic synthesis. Judi...
“…Examples of secondary amide/aldehyde cyclizations are shown in eqs 13, 16, 18−20, and 36, ,,,,,,,, and examples of secondary amide/ketone cyclizations are shown in eqs 4, 7, 10, and 11. ,,,, Reactive aldehydes, such as formaldehyde or ethyl glyoxylate, can combine with secondary amides that bear a suitable nucleophile, under acidic conditions, to furnish cyclized products directly . This reaction is featured in several tetrahydroisoquinoline syntheses − (e.g., eq 66 294 ). …”
Section: 11 Reaction Of Amides With Aldehydes or Ketonesmentioning
confidence: 99%
“…Tetrahydroisoquinolines are also obtained in good yields from the reaction of 294 with acetaldehyde (52%) or benzaldehyde (48%); however, the more reactive 295 results in higher yields (66% and 59%, respectively) . The N -formyliminium ion reaction is favored for the synthesis of 3-aryltetrahydroisoquinolines (e.g., eq 66) because it eschews a problem with elimination to stilbenes under harsh conditions; in fact, yields are generally good to excellent (>70%). , Another advantage is the tolerance for electron-rich 3-aryl substituents and bulky quaternary formamides, such as PhCH 2 CMe(Ph)NHCHO. , Similarly, N -sulfonyliminium ion cyclizations effectively provide tetrahydroisoquinolines. − A special version of the N -formyliminium ion cyclization is depicted in eq 69, wherein bis-aldehyde adducts of formamide, masked as trimethylsilyl ethers, double cyclize with good yields to generate the azabicyclic pavine alkaloid skeleton …”
Section: 23 Effect Of Substituents On the Iminium Ionmentioning
confidence: 99%
“…23,26,27,45,52 Reactive aldehydes, such as formaldehyde or ethyl glyoxylate, can combine with secondary amides that bear a suitable nucleophile, under acidic conditions, to furnish cyclized products directly. 15 This reaction is featured in several tetrahydroisoquinoline syntheses [292][293][294][295][296][297] (e.g., eq 66 294 ).…”
Section: Reaction Of Amides With Aldehydes or Ketonesmentioning
confidence: 99%
“…364 N-Formyliminium ions have proven to be synthetically versatile. [293][294][295] The ring closure of 294 and 295 with formaldehyde leads to 296 (57%) and 297 (73%), with a higher yield for the more reactive aromatic nucleophile. 293 Tetrahydroisoquinolines are also obtained in good yields from the reaction of 294 with acetaldehyde (52%) or benzaldehyde (48%); however, the more reactive 295 results in higher yields (66% and 59%, respec-tively).…”
Section: Effect Of Substituents On the Iminium Ionmentioning
effectively in cyclizations with N-acyliminum species. Electron-attracting substituents other than N-acyl, such as N-sulfonyl, can also be employed in analogues of N-acyliminium ion reactions. However, this review will concentrate on cyclizations of the N-acyl type, encompassing groups such as alkanoyl, aroyl, carbalkoxy, and N,N-dialkylcarbamyl, with limited coverage of sulfonyl groups. Most significantly, this review will focus on intramolecular reactions of N-acyliminium ions that result in the formation of new carbon-carbon bonds, rather than new carbonheteroatom bonds. Although β-lactam synthesis based on the cyclocondensation of imines with acid halides, Bruce E. Maryanoff earned B.S. (1969) and Ph.D. (1972) degrees from Drexel University and then conducted postdoctoral studies at Princeton University, working with Prof. Kurt Mislow. He joined McNeil Laboratories, a Johnson & Johnson subsidiary, in 1974 and advanced to Distinguished Research Fellow, the highest scientific position in the company. From 1976 to 1992, he principally worked on discovering drugs for treating central nervous system disorders; in 1992, he moved into cardiovascular research and presently leads the Vascular Research Team. Dr. Maryanoff is recognized for his work in organic and medicinal chemistry, especially the Wittig olefination reaction; peptides and peptidomimetics; antiepileptics and antidepressants; thrombin inhibitors; and protease-activated receptors. He discovered TOPAMAX topiramate, which is marketed worldwide for the treatment of epilepsy and is being developed for migraine headache. He has published 200 scientific papers, is an inventor on 60 U.S. patents, and has received two national awards, the ACS Heroes of Chemistry Award (2000) and the ACS Award in Industrial Chemistry (2003). Dr. Maryanoff is a Fellow in the American Association for the Advancement of Science and the Royal Society of Chemistry. Han-Cheng Zhang received B.S. and M.S. degrees in chemistry from Xiamen University, P.R.C., and served as a faculty member there for 5 years. He came to the United States and earned a Ph.D. degree in organic chemistry from Rensselaer Polytechnic Institute (1992), working with Prof. Doyle Daves. He joined the R. W. Johnson Pharmaceutical Research Institute as a Postdoctoral Scientist with Dr. Bruce Maryanoff and, after one year, as a Scientist. Dr. Zhang has worked as a medicinal chemist in the areas of G-protein-coupled receptors, proteases, and kinases to discover new drug candidates, recently leading a project that identified the first potent, selective antagonists for the thrombin receptor, proteaseactivated receptor 1. He is now at the level of Principal Scientist in Johnson & Johnson Pharmaceutical Research & Development. Dr. Zhang has published over 40 scientific papers and is an inventor on 13 U.S. patents (issued or pending). His scientific interests include the design and synthesis of novel therapeutic agents, heterocycles, stereoselective reactions, organometallic chemistry, and solid-phase organic synthesis. Judi...
“…Our initial studies showed that the reaction of N- [2-(3,4-dimethoxyphenyl)ethyl]formamides (1) 17 and carboxylic acids in PPA for 2 h at 80 o C leads to a mixture of N- [2-(2-acyl-4…”
N-Formylenamides of isoquinoline (6) were obtained from N-[2-(2acyl-4,5-dimethoxyphenyl)ethyl]formamides (5) by cyclization in the presence of catalytic amount of p-toluensulfonic acid. The starting keto formamides (5) were obtained by acylation of a N-[2-(3,4-dimethoxyphenyl)ethyl]formamides (1) with carboxylic acids or their anhydrides in polyphosphoric acid (PPA).
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