Tetrahedron report number 584Synthesis of secondary amines
This review provides a comprehensive survey of the syntheses and uses of alkyl and aromatic secondary amines.
Introduction
Syntheses of amines have perhaps received more attention than the preparation of many other functional groups in organic chemistry.1 With the growing repertoire of biologically relevant nitrogenous molecules, so is the need for efficient synthetic methods to prepare amines as useful intermediates.2., 3. Due to their interesting physiological activities, secondary amines in particular are extremely important pharmacophores in numerous biologically active compounds, which have greatly been touted in the area of drug discovery.4 This field has also spurred intense activity on solid phase synthesis5 as well as combinatorial library generation,6 where the secondary amine can be utilized as an important scaffolding for further manipulations. However, despite the widespread interest, traditional methods for secondary amine formation are often problematic because of harsh reaction conditions, generally poor yields, and/or low chemical selectivities.7 Illustrated in Scheme 1 is a brief classification for the major traditional methods for the synthesis of secondary amines, among which suitable procedures and conditions can be properly chosen to prepare the desired amines efficiently. The purpose of this review is to provide a general overview for the formation of secondary amines utilizing pertinent examples highlighted from the literature, while discussing perspectives in the future development of improved methodologies and conditions for this functionality.
Section snippets
With alkyl halides
Direct N-alkylation is, in principle, the most common and straightforward route to secondary amine formation (Scheme 2).8 Treatment of primary amines with alkyl halides, or their equivalents (e.g. dialkyl sulfates or sulfonates) is commonly known as the ‘Hofmann alkylation’.9 However, although the conversion appears deceptively simple, it is well known that the synthetic value of this method is limited due to the concomitant overalkylations, giving rise to mixtures of primary, secondary, and
Conclusion
This review has given a comprehensive survey regarding the synthesis of alkyl and aromatic secondary amines as well as some their synthetic uses. Secondary amines have clearly demonstrated to be extremely useful synthons towards numerous natural products as well as bioactive molecules exhibiting unique properties. The common solution phase synthetic methods towards secondary amine formation have been discussed herein. Recently, the solid phase synthesis of this functionality has gained
Ralph Nicholas Salvatore received his Bachelor of Science degree in chemistry (1994) from Iona College in New Rochelle, New York. He received his Master of Science degree (1996) in physical organic chemistry from the State University of New York at Stony Brook, under the guidance of Professor William J. le Noble. Currently, he is finishing his doctoral studies at the University of South Florida under the supervision of Professor Kyung Woon Jung, working in the area of synthesis of
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Ralph Nicholas Salvatore received his Bachelor of Science degree in chemistry (1994) from Iona College in New Rochelle, New York. He received his Master of Science degree (1996) in physical organic chemistry from the State University of New York at Stony Brook, under the guidance of Professor William J. le Noble. Currently, he is finishing his doctoral studies at the University of South Florida under the supervision of Professor Kyung Woon Jung, working in the area of synthesis of peptidomimetics, artificial biomolecules, and the development of synthetic methodology. He has recently accepted a faculty appointment at Western Kentucky University as an Assistant Professor of Organic Chemistry.
Cheol Hwan Yoon received his Bachelor of Science and Master of Science degrees in chemistry from Seoul National University in 1990 and 1992, respectively. He earned his PhD degree in Organic Chemistry from the same institution under the supervision of Professor Eun Lee in 1995. During the period of 1995–1999, he worked as a Senior Research Scientist at Tae Kwang Research Center in Korea. Currently, he is a Postdoctoral Research Associate at the University of South Florida in Dr Jung's research group.
Kyung Woon Jung received his Bachelor of Science degree in chemistry (1985) from Seoul National University. He then received his Master of Science in chemistry (1987) from the same institution under the supervision of Professor Eun Lee. In 1994, Dr Jung was granted a Doctor of Philosophy in chemistry from the University of Wisconsin-Madison, where he was involved in the synthesis of halicondron B under the mentorship of Professor Steven D. Burke. He then went on to accept a research associate position at The Scripps Research Institute, where he worked under Professor Richard A. Lerner and Professor Kim D. Janda. Since 1996, Dr Jung has been an Assistant Professor at the University of South Florida, as well as holding a joint position as a member of the Drug Discovery Program at the H. Lee Moffitt Cancer Center and Research Institute. He has focused on the synthesis of natural products and artificial biomolecules as well as the development of synthetic methodologies.