1
[2+2+2] Cycloadditions of Alkynes with Heterocumulenes and Nitriles

Nicholas D. Staudaher Ryan M. Stolley and Janis Louie

Department of Chemistry, University of Utah, Salt Lake City, UT, 84112

1. Acknowledgments
2. Introduction
3. Mechanism and Stereochemistry
4. Transition-Metal-Catalyzed Cycloadditions
5. Cycloadditions of Alkenyl Isocyanates and Alkynes
6. Low Valent Titanium-Mediated Cycloadditions of Alkynes and Nitriles
7. Nucleophile-Catalyzed Cycloadditions
8. Isocyanate Trimerization
9. Cycloaddition of Carbon Disulfide with Two Ketenes
10. Scope and Limitations
11. Cycloadditions of Isocyanates
12. Diynes and Isocyanates
13. Alkynes and Isocyanates
14. Alkenyl Isocyanates
15. Multiple Isocyanates
16. Cycloadditions of Other Heterocumulenes
17. Carbodiimides
18. Carbon Disulfide
19. Isothiocyanates
20. Carbon Dioxide
21. Ketenes
22. Ketenes and Carbon Disulfide
23. Diynes and Ketenes
24. Cycloadditions of Nitriles and Oximes
25. Alkynes and Nitriles
26. Diynes and Nitriles
27. Alkyne-Nitriles and Alkynes
28. Alkyne-Nitriles and Nitriles
29. Alkyne-Alkyne-Nitriles
30. Diynes and Oximes
31. Applications to Synthesis
32. Comparison With Other Methods
33. Experimental Conditions
34. Experimental Procedures
35. 4,7-Dimethyl-5-phenyl-2-(toluene-4-sulfonyl)-1,2,3,5-tetrahydropyrrolo[3,4-c]pyridin-6-one [Ni-NHC Catalyzed Cycloaddition of a Diyne and an Isocyanate]. 36
36. 5-n-Butyl-4-methyl-7-phenylfuro[3,4-c]pyridine-3,6(1H,5H)-dione [Ir-Biphosphine Catalyzed Cycloaddition of an Unsymmetrical Diyne and an Isocyanate]. 39
37. (Z)-11-Phenyl-11,12-dihydro-6,10-dioxa-1(4,6)-pyridina-8(1,2)-benzenocyclotetradecaphan-12-one and (13Z,15Z)-11-Phenyl-11,12-dihydro-6,10-dioxa-1(3,6)-pyridina-8(1,2)-benzenocyclotetradecaphan-12-one [Synthesis of Pyridoneophanes by Co-Catalyzed Cycloaddition of an Isocyanate and a Diyne with a Long Tether]. 41
38. 1-Ethyl-4,6-di((E)-prop-1-en-1-yl)-3,5-bis(trimethylsilyl)pyridin-2(1H)-one [Regioselective Ni-Catalyzed Cycloaddition of Two Molecules of an Enyne and an Isocyanate]. 47
39. 1-Benzyl-4,5-di(cyclohex-1-en-1-yl)pyridin-2(1H)-one [Rh-Catalyzed Regioselective Cycloaddition of a Terminal Monoalkyne and an Isocyanate]. 37
40. (R)-5-Phenyl-2,3,8,8a-tetrahydroindolizin-7(1H)-one (major) and (S)-7-Phenyl-2,3,8,8a-tetrahydroindolizin-5(1H)-one (minor) [Enantioselective Rh-Catalyzed Cycloaddition of a Terminal Monoalkyne with an Alkenyl Isocyanate]. 52
41. 1,3,5-Tris(4-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione [NHC-Catalyzed Trimerization of an Isocyanate]. 32
42. 2,4-Tolyl-3,4-tolylimino-2,3,5,7-tetrahydro[2]pyrindine-6,6-dicarboxylic Diacid, Dimethyl Ester [Rh-Catalyzed Cycloaddition of a Diyne and a Carbodiimide]. 60
43. 6,6-Bis((benzyloxy)methyl)-1,4-dimethyl-6,7-dihydrocyclopenta[c]pyran-3(5H)-one [Ni-Catalyzed Cycloaddition of Carbon Dioxide and a Diyne]. 65
44. Tetramethyl 6-Ethyl-6-(4-methoxyphenyl)-5,8-dimethyl-7-oxo-1,4,6,7-tetrahydronaphthalene-2,2,3,3-tetracarboxylate [Ni-Catalyzed Cycloaddition of a Diyne and a Ketene]. 68
45. 3,6-Bis(4-fluorophenyl)-N,N-dimethylpyridin-2-amine [Cycloaddition of a Terminal Monoalkyne and a Cyanamide Catalyzed by Fe]. 73
46. Diethyl 3-Methyl-1-phenyl-4-trimethylsilyl-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate [Cycloaddition of an Unsymmetrical Diyne and a Nitrile Catalyzed by a Co-Catalyst Generated in Situ]. 82
47. 1,4-Dimethyl-3-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridine [Ni-Xantphos Catalyzed Cycloaddition of a Diyne and a Nitrile]. 88
48. Dimethyl 3-(Fluoromethyl)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate [Ru-Catalyzed Cycloaddition of a Terminal Diyne with a Halonitrile]. 91
49. Dimethyl 2,3-Diethyl-4-methyl-5,7-dihydro-6H-cyclopenta[b]pyridine-6,6-dicarboxylate [Fe-PDAI Catalyzed Cycloaddition of an Alkyne-Nitrile and an Alkyne]. 94
50. Benzyl 6-Tosyl-5-(trimethylsilyl)-1,3,6,7,8,9-hexahydro-2H-pyrrolo[3,4-f][1,7]naphthyridine-2-carboxylate [Co-Catalyzed Intramolecular Cycloaddition of an Alkyne-Alkyne-Nitrile]. 96
51. Tabular Survey

Acknowledgments

We thank Gary Molander, Tom Rovis, Linda Press, and the other members of the Organic Reactions Editorial Board for useful input at all stages in the preparation of this article. We are also grateful to Wenxing Guo for detailed English translations of several German journal articles.

Introduction

The [2+2+2] cycloaddition of unsaturated systems has proven to be an atom-economical way to create carbocycles and heterocycles rapidly. In 1866, Berthelot discovered that acetylene could be thermally converted to benzene.1 Over 80 years later, in 1948, nickel complexes were found to catalyze the same trimerization at much lower temperatures.2 The first examples of [2+2+2] cycloadditions using heterocumulenes emerged in the 1970s, and the number of publications in this area has increased dramatically over the last decade. The heterocumulenes that have been utilized as substrates include isocyanates, isothiocyanates, carbodiimides, carbon dioxide, carbon disulfide, and ketenes. Although a wide array of 6-membered heterocycles can be prepared, little is known about how transition-metal catalysts facilitate the cycloaddition reactions. In contrast, reactions of nitriles, a class of substrates believed to undergo cycloadditions with alkynes by a similar mechanism as heterocumulene substrates, have been mechanistically well-explored. Overall, these reactions typically create six-membered heterocycles from two alkynes and a heterocumulene. The types of heterocycles that can be constructed with this chemistry are quite broad (Scheme 1). In addition, these heterocyclic products are useful synthetic building blocks because they are prevalent in a wide array of natural products, pharmacologically important compounds, transition-metal ligands, and organic light-emitting diode materials.

Scheme 1

This chapter is limited to the [2+2+2] cycloadditions involving heterocumulenes with one exception: the cycloadditions of nitriles are included. Several reviews on [2+2+2] cycloadditions have appeared recently. These reviews tend to be general to [2+2+2] cycloadditions,3-6 or specific to a substrate, product, or catalyst. For example, metal-catalyzed pyridine synthesis has been reviewed in depth.7-13 Construction of macrocycles has been reviewed,14 as well as enantioselectivity in [2+2+2] cycloadditions.15,16 The rhodium-catalyzed cycloaddition of alkenyl isocyanates and alkynes has also been reviewed.17 Tanaka has written a thorough treatment of [2+2+2] cycloadditions.18 No reviews specifically on [2+2+2] cycloaddition of heterocumulenes are extant. In this chapter the literature from the 1970s through early 2014 is covered in the case of heterocumulenes. Cycloadditions of nitriles are reviewed in a separate Organic Reactions chapter,19 which covers the literature through 2004. This chapter will therefore include the literature from 2004 to early 2014 where nitriles are concerned.

Mechanism and Stereochemistry

Transition-Metal-Catalyzed Cycloadditions

Owing to the broad scope of transition-metal-catalyzed cycloadditions, the specific details of each reaction mechanism can vary greatly. Yet, despite the large number of catalysts (Ni, Co, Rh, Ru, Fe, and Ir), the number and identity of nitriles or heterocumulenes (isocyanates, carbodiimides, carbon disulfide, isothiocyanates, carbon dioxide, ketenes) incorporated into the product, the identity of the coupling partners (alkenes or alkynes), and whether two or more coupling partners are tethered, all...