Hexadehydro Diels–Alder reaction
In
Reaction mechanism
Depending on the substrate chosen, the HDDA reaction can be initiated thermally or by the addition of a suitable
The metal-catalyzed HDDA is thought to proceed through a similar pathway, forming a metal-stabilized benzyne, which is then trapped.The simplest model of an HDDA reaction is the cycloaddition of
The o-benzyne intermediate can be visualized in the two resonance (chemistry) forms illustrated above. The most commonly depicted form is the alkyne (1), but the cumulene (1’) form can be helpful in visualizing ring formation by [4+2] cycloaddition.
Thermodynamics and kinetics
The HDDA reaction is often thermodynamically favorable (
Furthermore, the benzyne trapping step is also thermodynamically favourable, calculated to be an additional -73 kcal mol−1 for trapping of an ester-substituted o-benzyne with
The HDDA [4+2] cycloaddition can occur via either a
Regiochemistry
The regiochemistry of non-symmetrical HDDA-derived benzyne trapping can be explained by a combination of electronic and ring distortion effects.[1] Computationally, the more obtuse angle (a) corresponds to the more electron deficient (δ+) benzyne carbon, leading to attack of the nucleophilic component at this site. Consequently, the electrophilic component adds at the more electron rich (δ-) site (b).
Terminology
The HDDA reaction is a derivative of, and mechanistically related to, the classical Diels–Alder reaction. As described by Hoye and coworkers, the HDDA reaction can be viewed conceptually as a member of a series of
Formally, the hexadehydro Diels–Alder reaction describes only the formation of the benzyne, but this species is an unstable intermediate that reacts readily with a variety of trapping partners, including reaction
Historical development
The first examples of the HDDA reaction were reported independently in 1997 by the groups of Ueda and Johnson.
While known for over a decade, the HDDA reaction did not come into wider synthetic use until 2012, when Hoye and co-workers conducted a thorough investigation into the scope and utility of this cycloaddition.[1] That paper referred to this diyne–diynophile reaction as the“hexadehydro Diels–Alder (HDDA) reaction, and this terminology has since come into more widespread use. Since 2012, the HDDA reaction has been an area of renewed interest and has attracted further study by a number of research groups.[4][5][7][16]
Reaction scope
One of the main advantages of the HDDA reaction over other methods of accessing benzynes is the simplicity of the reaction system. HDDA reaction of triynes or tetraynes forms benzynes without the direct formation of by-products. In comparison, the formation of benzyne through removal of ortho-substituents on arenes results in stoichiometric amounts of byproducts from those substituents. For example, formation of benzyne from 1 mole of 2-trimethylsilylphenyl
Additionally, the HDDA reaction can be useful for substrates with sensitive functionality that might not be tolerated by other benzyne formation conditions (e.g. strong base). The thermally-initiated HDDA reaction has been shown to tolerate
Green chemistry
The HDDA reaction can fulfill several principles of green chemistry.
- Atom economy – All of the atoms in the HDDA substrate remain in the product after the reaction and atoms of the trapping reagent are incorporated into the product.
- Reduced waste – Formation of the benzyne species produces no stoichiometric byproducts. Products are often formed in high yield with few side-products.
- Catalysis – HDDA reaction occurs thermally or with a sub-stoichiometric amount of catalyst.
Synthetic applications
Intramolecular trapping
The HDDA reaction can be used to synthesize multi-cyclic ring systems from linear precursors containing the diyne, diynophile, and the trapping group. For example, Hoye and co-workers were able to synthesize fused, tricyclic ring systems from linear triyne precursors in one step and high yields via a thermally-initiated, intramolecular HDDA reaction.[1] Furthermore, both nitrogen- and oxygen-containing heterocycles could be incorporated by use of an appropriate precursor. In this case, the pendant ilyl ether provided the trapping group, through a retro-Brook rearrangement.
Intermolecular trapping
HDDA-generated benzynes can also be trapped intermolecularly by a variety of trapping reagents. Careful choice of trapping reagent can add further functionality, including aryl halides, aryl heteroatoms (phenols and aniline derivatives), and multiple ring systems.[1][18]
Ene reactions
The HDDA reaction can be used in a cascade reaction sequence with
Hoye and co-workers demonstrated a thermally-initiated triple HDDA-aromatic ene-Alder ene cascade that leads to heavily functionalized products in one-step with no additional reagents or by-products.[19]
Dehydrogenation
HDDA-derived benzynes have also been shown to
C-H activation
The HDDA reaction can also be used as a method of
Fluorination
The silver-catalyzed HDDA reaction has also been used to synthesize
The domino HDDA reaction
Properly designed polyyne substrate has been shown to undergo efficient cascade net [4+2] cycloadditions merely upon being heated.[21] This domino hexadehydro Diels–Alder reaction is initiated by a rate-limiting benzyne formation. Proceeding through naphthyne, anthracyne, and/or tetracyne intermediates, rapid bottom-up synthesis of highly fused, polycyclic aromatic compounds results.
The aza HDDA reaction
Nitriles can also participate in the HDDA reactions to generate pyridyne intermediates.[22] In situ capturing of pyridynes gives rise to highly substituted and functionalized pyridine derivatives, which is complementary to other classical approaches for construction of this important class of heterocycles.
Radial HDDA reactions
Designer multi-ynes arrayed upon a common, central template undergo sequential, multiple cycloisomerization reactions to produce architecturally novel polycyclic compounds in a single operation.[23] Diverse product topologies are accessible, ranging from highly fused, polycyclic aromatic compounds (PACs) to architectures having structurally complex arms adorning central phenylene or expanded phenylene cores.
References
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- ^ a b c d e Holden, C.; Greaney, M. F. Angew. Chem. Int. Ed. Engl., 2014, 53, 5746 [2]
- ^ Yeoman, J. T. S.; Reisman, S. E. Nature, 2012, 490, 179
- ^ a b c d Yun, S. Y.; Wang, K.-P.; Lee, N.-K.; Mamidipalli, P.; Lee, D. J. Am. Chem. Soc., 2013, 135, 4668 [3]
- ^ a b Vandavasi, J. K.; Hu, W.-P.; Hsiao, C.-T.; Senadi, G. C.; Wang, J.-J. RSC Adv., 2014, 4, 57547 [4]
- ^ a b c Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust, K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P. J. Org. Chem., 2011, 76, 9320 [5]
- ^ a b Liang, Y.; Hong, X.; Yu, P.; Houk, K. N. Org. Lett., 2014, 16, 5702 [6]
- ^ a b Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc., 1997, 119, 9917 [7]
- ^ Cahill, K. J.; Ajaz, A.; Johnson, R. P. Aust. J. Chem., 2010, 63, 1007 [8]
- ^ a b Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett., 1997, 38, 3943 [9]
- ^ Ueda, I.; Sakurai, Y.; Kawano, T.; Wada, Y.; Futai, M. Tetrahedron Lett., 1999, 40, 319 [10]
- ^ Miyawaki, K.; Kawano, T.; Ueda, I. Tetrahedron Lett., 2000, 41, 1447 [11]
- ^ K. Miyawaki, F. Ueno, I. Ueda, Heterocycles, 2001, 54, 887 [12]
- ^ Torikai, K.; Otsuka, Y.; Nishimura, M.; Sumida, M.; Kawai, T.; Sekiguchi, K.; Ueda, I. Bioorg. Med. Chem., 2008, 16, 5441 [13]
- ^ Kimura, H.; Torikai, K.; Miyawaki, K.; Ueda, I. Chem. Lett., 2008, 37, 662 [14]
- ^ a b c Karmakar, R.; Mamidipalli, P.; Yun, S. Y.; Lee, D. Org. Lett., 2013, 15, 1938 [15]
- ^ a b Wang, K.-P.; Yun, S. Y.; Mamidipalli, P.; Lee, D. Chem. Sci., 2013, 4, 3205 [16]
- ^ Niu, D.; Wang, T.; Woods, B. P.; Hoye, T. R. Org. Lett., 2014, 16, 254 [17]
- ^ a b Niu, D.; Hoye, T. R. Nat. Chem., 2014, 6, 34
- ^ a b Niu, D.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature, 2013, 501, 531 [18]
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