Tetrahedron report number 583Recent advances in the chemistry of ynamines and ynamides
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Introduction
Alkynes are among the most important building blocks in organic synthesis. The richness of this functional group renders it extremely versatile as a synthon for a diverse array of modern synthetic methods. Useful subgroups of alkynes are those containing heteroatom substitution, specifically ynamines. The electron donating ability of the nitrogen atom renders ynamines even more synthetically effective because of the electronic bias imposed by the heteroatom, allowing highly regioselective transformation of these molecules.
The first attempt at preparation of an ynamine was reported by Bode in 1892.1., 2. While well characterized ynamines were reported in 19583 and 1960,4 a practical synthesis was not achieved until the effort led by Viehe in 1963.5 For the twenty years thereafter, the synthetic utility of ynamines in organic and organometallic chemistry was firmly established by the work of many creative synthetic chemists, and reactivities of 1-aminoalkynes were thoroughly explored. These elegant pioneer works have been informatively and carefully reviewed by Viehe in 19676 and 1969,7 Ficini in 1976,8 Pitacco and Valentin in 1979,9 Collard-Motte and Janousek in 1985,10 and most recently, Himbert in 1993.11
Unlike enamines, the widespread synthetic use of ynamines has remained relatively limited, especially during the last 15 years. Reasons in part for the limited synthetic application of ynamines include the difficulty in preparation and handling of ynamines due to their sensitivity toward hydrolysis and their high reactivity—unlike its counterpart, the ynol ethers which are less reactive, owing to the stabilizing effect of the electronegative oxygen atom. Therefore, the focus of this particular review is to survey the development in the chemistry of ynamines since 1993 in Section 2, and particularly highlight the new advances that have occurred in employing a more stable variant of ynamines—ynamides in Section 3, which should bring an exciting future to the chemistry of ynamines.
During the last eight years, there have been limited new approaches to ynamine synthesis, although there are over 30 accounts on preparations of ynamines. The most notable approach would be the use of hypervalent iodine reagents. On the other hand, there are over 120 accounts citing various reactions involving ynamines, 10–12 of which published in very recent years are devoted to reactivities of ynamides. Although fewer in number than the accounts reported 15 years ago, many of these recent reactions remain elegant and demonstrate that ynamines have synthetic potential in various applications. The reactions of ynamines can be categorized, as in previous reviews, into two classes: Addition reactions of ynamines and cycloaddition reactions of ynamines.
As illustrated in Scheme 1, addition reactions of ynamines 1 typically involve the addition of reagents such as A+B− across the triple bond in the presence of promoters such as Lewis acids or protic acids to give products such as 2. These addition reactions are highly regioselective as demonstrated in previous reviews.6., 7., 8., 9., 10., 11. The sense of the regioselectivity may be readily predicted by the well-known electronic nature of ynamines (Scheme 1).8 By far, cycloaddition reactions of ynamines, [2+2], [4+2], and [3+n], have received the greatest attention, leading to unique heterocycles such as 4 that have synthetic potential. Mechanistically these cycloadditions follow mostly a step-wise pathway, joining appropriate atoms to match the electronic demand. There are also accounts on transition metal-mediated cycloadditions.11
One of the most interesting and synthetically useful cycloaddition is Ficini's thermal [2+2] cycloaddition reaction of ynamines with electron deficient alkenes 5, leading to cyclobutenamines such as 7 (Scheme 2).8 Ficini has demonstrated that these [2+2] cycloaddition reactions can be carried out diastereoselectively to give cyclobutenamines such as 8 as the major isomers.8 Although limited, there are attractive applications of this highly useful reaction.
Given the versatility of ynamines in organic synthesis, it is surprising that besides Genet's example of an intramolecular reaction involving addition of a hydroxyl group to an ynamine reported in 1980 (8→9 in Scheme 3),12 there are no other intramolecular reactions involving ynamines. In addition, there was only one account of stereoselective reaction with modest diastereomeric excess (de) involving chiral ynamines reported by Reinhoudt in 1987 (10+11→12)13 before another example appeared in 2000 [see Section 2].
The lack of attention that ynamines have received over the last 15–20 years can be attributed to their synthetic inaccessibility and sensitivity. The high reactivity and sensitivity toward hydrolysis are due to the ability of the nitrogen to donate its lone pair to the alkynyl moiety. Therefore, efforts aimed at improving the stability of ynamines without significantly diminishing their reactivity may be key to the future of this chemistry.
Reactivities and stabilities of a range of relatively electron-deficient ynamines such as 13–16 are known in literature. During the last 20 years, some very interesting chemistry has been described for the ‘push–pull’ ynamines 15 and 16 (Scheme 4).6., 7., 8., 9., 10., 11. Unfortunately, however, little has been gained in terms of stability. One can stabilize the ynamine to the point of being unreactive as in bis-trifluoromethyl substituted ynamine 14.
Toward the purpose of balancing reactivity and stability, some advances have been made very recently in exploring another class of electron-deficient ynamines, ynamides, in which the nitrogen atom is substituted with an electron withdrawing group such as a sulfonamide, an imidazolidinone, an oxazolidinone, or a lactam systems (17–19). The electron-withdrawing group serves to diminish the electron-donating ability of the nitrogen atom, thereby offering stability superior to traditional ynamines. These investigations have led to the development of highly stereoselective intermolecular as well as intramolecular reactions using a stable variant of ynamines [Section 3].
Although reactivities of ynamides are almost unknown, preparations and thermal stability of ynamides have been documented.11 The very first synthesis of ynamides was reported by Viehe in 1972 as shown in Scheme 5.14 Ynamides 23 could be attained from halogenated enamides such as 21 and 22 via base induced elimination, and were reported to possess much improved thermal stability and stabilities toward hydrolytic conditions.14 Zaugg's ynamine3 26 (Scheme 5, or vinylogous ynamide) was prepared by Galy et al. in 1979.15a A number of other reports have described its synthesis through the use of base-induced isomerization protocols.15., 16.
More recently, preparations of two other ynamides were reported in 198517 and 1991.18 For example, a Cu(I) mediated oxidative process that was intended for coupling t-butyl propiolate 27 to the alkyl halide 28 (Scheme 6) furnished instead an ynamide 29.17 Another involves the transformation of C-halogen substituted ketenimines 30 using a phase transfer agent.18
It is only recently that the reactivity of ynamides have begun to be examined. Research in this area could prove to be a fertile ground for developing useful synthetic methods because ynamides possess enhanced stability relative to ynamines by reducing the electron density on the nitrogen atom. This allows them to be prepared, isolated, and subjected to a variety of interesting reactions including intramolecular reactions. They possess more conformational rigidity than any other heteroatom-substituted alkynes. They can coordinate to metals and can be chiral, leading to the potential for the development of stereoselective methodologies. The investigations reviewed here and those that will appear in the future should help facilitate and revitalize interest in the chemistry of ynamines.
As this review is intended to examine chemistry that is of interest to the synthetic organic community, studies related to physical and spectroscopic properties of ynamines are not reviewed here.19 In addition, any reports of the use of ynamines as ligands for transition metals are also not included here.
Section snippets
Synthesis of chiral ynamines
The first synthesis of chiral ynamines since Reinhoudt's work13 was accomplished by Fischer et al. using an isomerization protocol in 1997.20 Beginning with chiral secondary amines (Scheme 7), ynamines 32 were obtained in moderate yields upon reaction with propargyl bromide and isomerization with potassium tert-butoxide.
The only other report of chiral ynamines since 1987 is the work of Pericàs21 wherein dichloroacetylene is reacted with a variety of chiral amines and n-BuLi, and the resulting
Synthesis of chiral ynamides
In 1996, Feldman95 and coworkers accomplished the first synthesis of a chiral ynamide since Novikov's18 work. The authors utilized iodonium triflate salts, reacting them with α-substituted ethyl-tosylamides 351 and 352 (Scheme 90). They obtained the ynamides 353 and 354 as undesired products in moderate yields in their attempts to synthesize pyrrole and indole targets.
Witulski96 utilized iodonium triflate salt 355 in reactions with various electron-deficient amines to provide ynamides 356 in
Acknowledgements
R. P. H. thanks American Chemical Society Petroleum Research Fund [Type-G] for financial support. R. P. H. also thanks R. W. Johnson Pharmaceutical Research Institute for a generous grant from the Focused Giving Award. J. A. M. thanks the University of Minnesota for a Graduate Dissertation Fellowship.
Craig A. Zificsak was born in Stevens Point, Wisconsin in 1976. He received a BS in Chemistry from the University of Wisconsin—Stevens Point in 1998. He is currently enrolled in the PhD program at the University of Minnesota under the supervision of Professor Richard P. Hsung. His thesis research involves the development of new methodology and the synthesis of natural products.
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Craig A. Zificsak was born in Stevens Point, Wisconsin in 1976. He received a BS in Chemistry from the University of Wisconsin—Stevens Point in 1998. He is currently enrolled in the PhD program at the University of Minnesota under the supervision of Professor Richard P. Hsung. His thesis research involves the development of new methodology and the synthesis of natural products.
Jason A. Mulder was born in Cadillac, Michigan in 1975. He received a B.S. in Chemistry from Calvin College, Grand Rapids, MI in 1997. He is currently enrolled in the Ph.D. program at the University of Minnesota under the supervision of Professor Richard P. Hsung. His research involves synthetic studies of ynamides and their reactivity in rearrangement and cycloaddition reactions.
Richard P. Hsung graduated with an Honors B.S. degree in Mathematics and Chemistry from Calvin College [Grand Rapids, Michigan] in 1988. He attended The University of Chicago [Chicago] for graduate study in organic chemistry and obtained his M.S. degree [synthetic approaches to taxusin] in 1990 under the supervision of Professor Jeffrey D. Winkler. He received his Ph.D. degree [asymmetric benzannulation reactions of Fischer’s chromium carbenes] in 1994 under the supervision of Professor William D. Wulff. After pursuing research in the area of surface chemistry as a post-doctoral fellow in the laboratory of Professor Lawrence R. Sita at The University of Chicago between 1995 and 1996, he joined the laboratory of Professor Gilbert Stork as a National Institutes of Health post-doctoral fellow at Columbia University [New York City]. In 1997, he moved to University of Minnesota [Minneapolis, Minnesota] as an assistant professor of organic chemistry. His research interests involve cycloaddition approaches to synthesis of natural products and developing stereoselective methods using allenamides and ynamides. He is a recipient of R. W. Johnson Pharmaceutical Research Institute Focused Giving Award in 1998. In 2001, he received a McKnight Junior Faculty Award from University of Minnesota and a Camille Dreyfus Teacher-Scholar Award from Camille and Henry Dreyfus Foundation. Recently, he was also given a National Science Foundation Career Award.
C. Rameshkumar was born in Nadoorkarai, Tamil Nadu, India. He obtained his BSc degree in Chemistry from Pioneer Kumaraswamy College, Nagercoil (India) and MSc degree in Organic Chemistry from Annamalai University. He received his PhD degree from the University of Hyderabad in 2000 under the supervision of Professor M. Periasamy. He is currently working as a postdoctoral associate under the supervision of Professor Richard P. Hsung.
Lin-Li Wei was born in Guangxi, P.R. China. She obtained her BS and MS degree in Chemistry from Peking University in 1992 and 1995, respectively. In 1999, she received her PhD degree in Organic Chemistry from the National University of Singapore. From September 1998 to April 2001, she was a postdoctoral associate in Professor Hsung's group at the University of Minnesota, Minneapolis. Her research mainly focused on natural product synthesis and developments of novel methodologies, i.e. the chemistry of allenamides and ynamides, and formal [3+3] cycloadditions for constructing heterocylces. Currently, she is working for Selectide, a subsidiary of Aventis Pharmaceuticals Inc.
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Recipient of 2000–2001 University of Minnesota Graduate Dissertation Fellowship.