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Related Reactions
Click Chemistry
Diels-Alder Reaction
Upjohn Dihydroxylation

Huisgen Cycloaddition
1,3-Dipolar Cycloaddition

The Huisgen Cycloaddition is the reaction of a dipolarophile with a 1,3-dipolar compound that leads to 5-membered (hetero)cycles. Examples of dipolarophiles are alkenes and alkynes and molecules that possess related heteroatom functional groups (such as carbonyls and nitriles). 1,3-Dipolar compounds contain one or more heteroatoms and can be described as having at least one mesomeric structure that represents a charged dipole.

Examples of linear, propargyl-allenyl-type dipoles

An example of an allyl-type dipole. See: Ozonolysis

Mechanism of the Huisgen 1,3-Dipolar Cycloaddition

2 π-electrons of the dipolarophile and 4 electrons of the dipolar compound participate in a concerted, pericyclic shift. The addition is stereoconservative (suprafacial), and the reaction is therefore a [2s+4s] cycloaddition similar to the Diels-Alder Reaction. Attention: many authors still use "[2+3] cycloaddition", which counts the number of involved atoms but does not follow IUPAC recommendations (DOI). IUPAC recommends the use of "(2+3)" for the number of involved atoms instead.

A condition for such a reaction to take place is a certain similarity of the interacting HOMO and LUMO orbitals, depending on the relative orbital energies of both the dipolarophile and the dipole. Electron-withdrawing groups on the dipolarophile normally favour an interaction of the LUMO of the dipolarophile with the HOMO of the dipole that leads to the formation of the new bonds, whereas electron donating groups on the dipolarophile normally favour the inverse of this interaction. Diazomethane as an electron-rich dipolar compound therefore rapidly reacts with electron-poor alkenes, such as acrylates. Relative reactivity patterns may be found in the literature  (R. Huisgen, R. Grashey, J. Sauer in Chemistry of Alkenes, Interscience, New York, 1964, 806-877.).

The regioselectivity of the reaction depends on electronic and steric effects and is somewhat predictable. For example, the addition of alkynes to azides, which is an interesting reaction for the generation of 1,2,3-triazole libraries by the simple reaction of two molecules ("click chemistry"), leads to regioisomers:

V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599.

The reaction has been modified to a more regioselective, copper-catalyzed stepwise process by the Sharpless and Fokin groups, which is no longer a classic Huisgen Cycloaddition (for a discussion of the nonconcerted mechanism see: click chemistry) . Another approach prefers the use of a directing electron withdrawing group, which is removable later:

D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, E. Zunino, L. Vaccaro, J. Org. Chem. 2005, 70, 6526-6529.

In summary, the 1,3-dipolar cycloaddition allows the production of various 5-membered heterocycles. Many reactions can be performed with high regioselectivity and even enantioselective transformations of prochiral substrates have been published. Some interesting examples may be found in the recent literature.

Recent Literature

Tris(pentafluorophenyl)borane-Catalyzed Synthesis of N-Benzyl Pyrrolidines
P. Srihari, S. R. Yaragorla, D. Basu, S. Chandrasekhar, Synthesis, 2006, 2646-2648.

Remarkable [3+2] Annulations of Electron-Rich Olefins with Unstabilized Azomethine Ylides
J. E. Davoren, D. L. Gray, A. R. Harris, D. M. Nason, W. Xu, Synlett, 2010, 2490-2492

Switching Diastereoselectivity in Catalytic Enantioselective (3+2) Cycloadditions of Azomethine Ylides Promoted by Metal Salts and Privileged Segphos-Derived Ligands
G. S. Caleffi, O. Larrańaga, M. Ferrándiz-Saperas, P. R. R. Costa, C. Nájera, A. de Cózar, F. P. Cossío, J. M. Sansano, J. Org. Chem., 2019, 84, 10593-10605.

Asymmetric 1,3-Dipolar Cycloaddition Reaction of Nitrones and Acrolein with a Bis-Titanium Catalyst as Chiral Lewis Acid
T. Kano, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc., 2005, 70, 11926-11927.

Cu(I)-Catalyzed Highly Exo-selective and Enantioselective [3 + 2] Cycloaddition of Azomethine Ylides with Acrylates
W. Gao, X. Zhang, M. Raghunath, Org. Lett., 2005, 7, 4241-4244.

A copper(I)/ClickFerrophos complex catalyzed the asymmetric 1,3-dipolar cycloaddition of methyl N-benzylideneglycinates with electron deficient alkenes to give exo-2,4,5-trisubstituted and 2,3,4,5-substituted pyrrolidines in good yields with high diastereo- and enantioselectivities.
S.-i. Fukuzawa, H. Oki, Org. Lett., 2008, 10, 1747-1750.

l-tert-Leucine-Derived AmidPhos-Silver(I) Chiral Complexes for the Asymmetric [3+2] Cycloaddition of Azomethine Ylides
Z. Zhou, X. Zheng, J. Liu, J. Li, P. Wen, H. Wang, Synlett, 2017, 28, 999-1003.

Highly Endo-Selective and Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylide with α-Enones Catalyzed by a Silver(I)/ThioClickFerrophos Complex
I. Oura, K. Shimizu, K. Ogata, S.-i. Fukuzawa, Org. Lett., 2010, 12, 1752-1755.

Hydrogen-Bonding Directed Reversal of Enantioselectivity
W. Zeng, G.-Y. Chen, Y.-G. Zhou, Y.-X. Li, J. Am. Chem. Soc., 2007, 129, 750-751.

2-Phospha[3]ferrocenophanes with Planar Chirality: Synthesis and Use in Enantioselective Organocatalytic [3 + 2] Cyclizations
A. Voituriez, A. Panossian, N. Fleury-Brégeot, P. Retailleau, A. Marinetti, J. Am. Chem. Soc., 2008, 130, 14030-14031.

Oxidation of Oximes to Nitrile Oxides with Hypervalent Iodine Reagents
B. A. Mendelsohn, S. Lee, S. Kim, F. Tayssier, V. S. Aulakh, M. A. Ciufolini, Org. Lett., 2009, 11, 1539-1542.

Generation of Nitrile Oxides from Oximes Using t-BuOI and Their Cycloaddition
S. Minakata, S. Okumura, T. Nagamachi, Y. Takeda, Org. Lett., 2011, 13, 2966-2969.

Acid-Catalyzed 1,3-Dipolar Cycloaddition of 2H-Azirines with Nitrones: An Unexpected Access to 1,2,4,5-Tetrasubstituted Imidazoles
A. Angyal, A. Demjén, J. Wölfling, L. G. Puskás, I. Kanizsai, J. Org. Chem., 2020, 85, 3587-3595.

Synthesis of Pyrrole via a Silver-Catalyzed 1,3-Dipolar Cycloaddition/Oxidative Dehydrogenative Aromatization Tandem Reaction
Y. Liu, H. Hi, X. Wang, S. Zhi, Y. Kan, C. Wang, J. Org. Chem., 2017, 82, 4194-4202.

An Efficient One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles
L.-L. Wu, Y.-C. Ge, T. He, L. Zhang, X.-L. Fu, H.-Y. Fu, H. Chen, R.-X. Li, Synthesis, 2012, 44, 1577-1583.

An Efficient One-Pot Synthesis of 3,5-Diaryl-4-bromopyrazoles by 1,3-Dipolar Cycloaddition of In Situ Generated Diazo Compounds and 1-Bromoalk-1-ynes
Q. Sha, Y. Wei, Synthesis, 2013, 45, 413-420.

Cycloaddition of Trifluoroacetaldehyde N-Triftosylhydrazone (TFHZ-Tfs) with Alkynes for Synthesizing 3-Trifluoromethylpyrazoles
H. Wang, Y. Ning, Y. Sun, P. Sivaguru, X. Bi, Org. Lett., 2020, 22, 2012-2016.

Regioselective Synthesis of 5-Trifluoromethylpyrazoles by [3 + 2] Cycloaddition of Nitrile Imines and 2-Bromo-3,3,3-trifluoropropene
H. Zeng, X. Fang, Z. Yang, C. Zhu, H. Jiang, J. Org. Chem., 2021, 86, 2810-2819.

Synthesis of 3,4-Disubsituted Isoxazoles via Enamine [3+2] Cycloaddition
Q.-f. Jia, P. M. S. Benjamin, J. Huang, Z. Du, X. Zheng, K. Zhang, A. H. Conney, J. Wang, Synlett, 2013, 24, 79-84.

1,4-Diazabicyclo[2.2.2]octane (DABCO) as an Efficient Reagent for the Synthesis of Isoxazole Derivatives from Primary Nitro Compounds and Dipolarophiles: The Role of the Base
L. Cecchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem., 2006, 4852-4860.

Efficient Access to Isoxazoles from Alkenes
J. Xu, A. T. Hamme II, Synlett, 2008, 919-923.

Novel Microwave-Assisted One-Pot Synthesis of Isoxazoles by a Three-Component Coupling-Cycloaddition Sequence
B. Willy, F. Rominger, T. J. J. Müller, Synthesis, 2008, 293-303.

An Efficient Synthesis of 2-Diazo-2-(trimethylsilyl)ethanols and Their Application to Pyrazole Synthesis
Y. Hari, S. Tsuchida, R. Sone, T. Aoyama, Synthesis, 2007, 3371-3375.

A 1,3-dipolar cycloaddition of phenyl vinylic selenide to nitrile oxides and subsequent oxidation-elimination furnished 3-substituted isoxazoles with good yields in a one-pot, two-step transformation.
S.-R. Sheng, X.-L. Liu, Q. Xu, C.-S. Song, Synthesis, 2003, 2763-2764.

Synthesis of 1,2,3-Triazoles by Cycloadditions of Azides with Enol Ethers
D. R. Rogue, J. L. Neill, J. W. Antoon, E. P. Stevens, Synthesis, 2005, 2497-2502.

Microwave Irradiation as an Effective Means of Synthesizing Unsubstituted N-Linked 1,2,3-Triazoles from Vinyl Acetate and Azides
S. G. Hansen, H. H. Jensen, Synlett, 2009, 3275-3278.

Cu-Enabled [3 + 2] Annulation of In Situ Formed Nitrile Ylides with Aryldiazonium Salts: Access to 5-Cyano-1,2,4-Triazoles
L.-N. Zhou, F.-F. Feng, C. W. Cheung, J.-A. Ma, Org. Lett., 2021, 23, 739-744.

Zinc Mediated Azide-Alkyne Ligation to 1,5- and 1,4,5-Substituted 1,2,3-Triazoles
C. D. Smith, M. F. Greaney, Org. Lett., 2013, 15, 4826-4829.

Iron Nitrate-Mediated Selective Synthesis of 3-Acyl-1,2,4-oxadiazoles from Alkynes and Nitriles: The Dual Roles of Iron Nitrate
Q. Bian, C. Wu, J. Yuan, Z. Shi, T. Ding, Y. Huang, H. Xu, Y. Xu, J. Org. Chem., 2020, 85, 4058-4066.

[3+2]-Cycloaddition of α-Diazocarbonyl Compounds with Arenediazonium Salts Catalyzed by Silver Nitrate Delivers 2,5-Disubstituted Tetrazoles
S. Chuprun, D. Dar'in, G. Kantin, M. Krasavin, Synthesis, 2019, 51, 3998-4005.

Switchable Synthesis of 3-Substituted 1H-Indazoles and 3,3-Disubstituted 3H-Indazole-3-phosphonates Tuned by Phosphoryl Groups
G. Chen, M. Hu, Y. Peng, J. Org. Chem., 2018, 83, 1591-1597.

Synthesis of Indazoles by the [3+2] Cycloaddition of Diazo Compounds with Arynes and Subsequent Acyl Migration
Z. Liu, F. Shi, P. D. G. Martinze, C. Raminelli, R. C. Larock, J. Org. Chem., 2008, 73, 219-226.

Benzyne Click Chemistry: Synthesis of Benzotriazoles from Benzynes and Azides
F. Shi, J. P. Waldo, Y. Chen, R. C. Larock, Org. Lett., 2008, 10, 2409-2412

A New Use of Wittig-Type Reagents as 1,3-Dipolar Cycloaddition Precursors and in Pyrrole Synthesis
D. J. St. Cyr, B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129, 12366-12367.