Ynamides: Versatile and Enabling Building Blocks for Chemical Synthesis

Introduction

The development of original and versatile reagents in modern organic synthesis is of crucial importance for the design of new chemical transformations that enable the fast and efficient assembly of a variety of complex molecules. In this context, nitrogen-substituted alkynes, commonly named “ynamides,” certainly represent one of the most versatile classes of alkynes and are especially appealing candidates for the design of innovative chemical transformations. In collaboration with Professor Gwilherm Evano, we are pleased to offer a collection of ynamides (805572, 805580, 805599, 805602). Ynamides have recently emerged as key building blocks in organic synthesis, as exemplified by the ever-increasing number of new and original processes based on the peculiar chemistry of ynamides that have been reported during the last decade, usually proceeding with almost surgical precision.1,2,3

original processes based on the peculiar chemistry of ynamides

The electron-donating ability of the nitrogen atom strongly polarizes the triple bond, allowing for transformations to proceed with levels of chemo-, regio-, and stereo-selectivities that cannot be reached with classical alkynes. Unlike ynamines, the high reactivity of ynamides is yet tempered by the presence of an electron-withdrawing group on the nitrogen which can, as an added bonus, also act as an efficient directing group, chiral auxiliary, or even participate in the reaction. Ynamides are therefore extremely versatile reagents which can notably be used for the generation of highly reactive and otherwise inaccessible intermediates and for the inclusion of nitrogen-based functionalities into organic molecules. Their use as starting materials for the elaboration of nitrogen-containing heterocycles had a dramatic impact in heterocyclic chemistry and resulted in the emergence of new paradigms.4 Interestingly, they are now starting to be used in natural product synthesis where the use of ynamides allows for unprecedented and original bond disconnections and net shortcuts in synthetic routes5 as well as in medicinal chemistry. Selected examples shown below are representative of intermediates, molecular scaffolds, and natural/biologically relevant products that can now be accessed from ynamides.

The electron-donating ability of the nitrogen atom strongly polarizes the triple bond

Advantages

  • Bench-stable reagents (air, moisture, heat)
  • Stable surrogates of ynamines
  • Strongly polarized and highly reactive alkynes
  • Useful building blocks in a vast array of chemical transformations

Representative Applications

Selected representative applications of the use of ynamides in chemical synthesis are shown below.

  1. The use of ynamides as reagents for the olefination of aldehydes16 and imines,17 with the stereochemistry of the resulting alkene being tuned by the choice of the acid catalyst in the last case.
acid catalyst in the last case

2. The use of chiral ynamides in asymmetric synthesis, which notably brought a general solution to the long-standing problem of the synthesis of aldol products possessing a quaternary stereocenter18

aldol products possessing a quaternary stereocenter

3. An example of the use of ynamides as precursors of highly reactive keteniminium ion which initiates a polycyclization yielding to complex nitrogen heterocycles12

yielding to complex nitrogen heterocycles

Special thanks to Cédric Theunissen, Morgan Lecomte, and Professor Gwilherm Evano for contributing this technology spotlight!

Materials
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References

1.
Evano G, Coste A, Jouvin K. 2010. Ynamides: Versatile Tools in Organic Synthesis. Angewandte Chemie International Edition. 49(16):2840-2859. http://dx.doi.org/10.1002/anie.200905817
2.
DeKorver KA, Li H, Lohse AG, Hayashi R, Lu Z, Zhang Y, Hsung RP. 2010. Ynamides: A Modern Functional Group for the New Millennium. Chem. Rev.. 110(9):5064-5106. http://dx.doi.org/10.1021/cr100003s
3.
Evano G, Theunissen C, Lecomte M. 2015. Aldrichimica Acta. 49, in press..
4.
Wang X, Yeom H, Fang L, He S, Ma Z, Kedrowski BL, Hsung RP. 2014. Ynamides in Ring Forming Transformations. Acc. Chem. Res.. 47(2):560-578. http://dx.doi.org/10.1021/ar400193g
5.
Evano G, Theunissen C, Pradal A. 2013. Impact of copper-catalyzed cross-coupling reactions in natural product synthesis: the emergence of new retrosynthetic paradigms. Nat. Prod. Rep.. 30(12):1467. http://dx.doi.org/10.1039/c3np70071b
6.
Gourdet B, Lam HW. 2009. Stereoselective Synthesis of Multisubstituted Enamides via Rhodium-Catalyzed Carbozincation of Ynamides. J. Am. Chem. Soc.. 131(11):3802-3803. http://dx.doi.org/10.1021/ja900946h
7.
Peng B, Huang X, Xie L, Maulide N. 2014. A Brønsted Acid Catalyzed Redox Arylation. Angew. Chem. Int. Ed.. 53(33):8718-8721. http://dx.doi.org/10.1002/anie.201310865
8.
Das JP, Chechik H, Marek I. 2009. A unique approach to aldol products for the creation of all-carbon quaternary stereocentres. Nature Chem. 1(2):128-132. http://dx.doi.org/10.1038/nchem.131
9.
Mulder JA, Hsung RP, Frederick MO, Tracey MR, Zificsak CA. 2002. The First Stereoselective Ficini?Claisen Rearrangement Using Chiral Ynamides. Org. Lett.. 4(8):1383-1386. http://dx.doi.org/10.1021/ol020037j

10.
Gati W, Rammah MM, Rammah MB, Couty F, Evano G. 2012. De Novo Synthesis of 1,4-Dihydropyridines and Pyridines. J. Am. Chem. Soc.. 134(22):9078-9081. http://dx.doi.org/10.1021/ja303002a
11.
IJsselstijn M, Cintrat J. 2006. Click chemistry with ynamides. Tetrahedron. 62(16):3837-3842. http://dx.doi.org/10.1016/j.tet.2005.11.090
12.
Theunissen C, Métayer B, Henry N, Compain G, Marrot J, Martin-Mingot A, Thibaudeau S, Evano G. 2014. Keteniminium Ion-Initiated Cascade Cationic Polycyclization. J. Am. Chem. Soc.. 136(36):12528-12531. http://dx.doi.org/10.1021/ja504818p
13.
Yun SY, Wang K, Lee N, Mamidipalli P, Lee D. 2013. Alkane C?H Insertion by Aryne Intermediates with a Silver Catalyst. J. Am. Chem. Soc.. 135(12):4668-4671. http://dx.doi.org/10.1021/ja400477r
14.
Zhang Y, Hsung RP, Zhang X, Huang J, Slafer BW, Davis A. 2005. Brønsted Acid-Catalyzed Highly Stereoselective Arene-Ynamide Cyclizations. A Novel Keteniminium Pictet?Spengler Cyclization in Total Syntheses of (±)-Desbromoarborescidines A and C. Org. Lett.. 7(6):1047-1050. http://dx.doi.org/10.1021/ol0473391
15.
Mak XY, Crombie AL, Danheiser RL. 2011. Synthesis of Polycyclic Benzofused Nitrogen Heterocycles via a Tandem Ynamide Benzannulation/Ring-Closing Metathesis Strategy. Application in a Formal Total Synthesis of (+)-FR900482. J. Org. Chem.. 76(6):1852-1873. http://dx.doi.org/10.1021/jo2000308
16.
Hsung R, You L, Al-Rashid Z, Figueroa R, Ghosh S, Li G, Lu T. 2007. A Two-Carbon Homologation of Aldehydes and Ketones Using Ynamides. Synlett. 2007(11):1656-1662. http://dx.doi.org/10.1055/s-2007-984513
17.
Shindoh N, Kitaura K, Takemoto Y, Takasu K. 2011. Catalyst-Controlled Torquoselectivity Switch in the 4? Ring-Opening Reaction of 2-Amino-2-azetines Giving ?-Substituted ?,?-Unsaturated Amidines. J. Am. Chem. Soc.. 133(22):8470-8473. http://dx.doi.org/10.1021/ja202576e
18.
Minko Y, Pasco M, Lercher L, Botoshansky M, Marek I. 2012. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature. 490(7421):522-526. http://dx.doi.org/10.1038/nature11569

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