User:Cafiore1992/sandbox
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The Fukuyama indole synthesis is a versatile tin mediated chemical reaction that results in the formation of 2,3-disubstituted indoles.[1] A practical one-pot reaction that can be useful for the creation of disubstituted indoles.[2] Most commonly tributyltin hydride is utilized as the reducing agent, with azobisisobutyronitrile (AIBN) as a radical initiator. Triethylborane can also be used as a radical initiator.[3] The reaction can begin with either a o-isocyanostyrene or a 2-alkenylthioanilide derivative, both forming the indole through Radical cyclization via an alpha-stannoimidoyl radical.[4] The R group can be a range of both basic and acidic sensitive functional groups such as esters, THP ethers, and beta-lactams. In addition the reaction is not stereo specific, in that both the cis and trans isoform can be used to obtain the desired product.[5]
![Fukuyama Indole Synthesis with either starting material.](http://upload.wikimedia.org/wikipedia/commons/thumb/f/f9/Fukuyama_Indole_Synthesis_Showing_Both_Potential_Starting_Reagents.png/400px-Fukuyama_Indole_Synthesis_Showing_Both_Potential_Starting_Reagents.png)
Mechanism[edit]
The reaction mechanism begins with the creation of the tributyl tin radical with either AIBN or triethylborane, not shown in either step-wise mechanism. Following the radical attacks the o-isocyano carbon creating the alpha-stannoimidoyl radical. Through radical cyclization a five membered ring is formed followed by the propagation of a new tin radical. The final step is dependent on the desired outcome of the reaction. This reaction is a one-pot synthesis and results in yields ranging from 50% to 98 % depending on the substituent.[1]
![Step-wise mechanism of Fukuyama Indole Synthesis starting with the Isocyano substituent.](http://upload.wikimedia.org/wikipedia/commons/thumb/7/7f/Fukuyama_Indole_Synthesis_Mechanism_with_an_Isocyano_Group.png/500px-Fukuyama_Indole_Synthesis_Mechanism_with_an_Isocyano_Group.png)
The mechanism using 2-alkenylthioanilide is very similar, also starting with the formation of a bond, now between the tin radical and the sulfur. Followed by a similar radical cyclization resulting in a five membered ring, a new tin radical is produced and the original attacking radical leaves with the sulfur substituent. This part of the step-wise mechanism has yet to be detailed. The reaction yeild can range from 40% to 93% depending also on the desired substituent.
![Step-wise mechanism of the Fukuyama Indole Synthesis starting with the alkenylthioanilide substituent.](http://upload.wikimedia.org/wikipedia/commons/thumb/2/2e/Fukuyama_Indole_Synthesis_Mechanism_with_Alkenylthioanilide_Group.png/500px-Fukuyama_Indole_Synthesis_Mechanism_with_Alkenylthioanilide_Group.png)
Derivatives[edit]
The Fukuyama Indole synthesis can generate a range of different substituents at the 2,3 position that were previously unattainable without a protecting group on the nitrogen in the ring. One such example is the 2-iodoindole derivative, which can then lead to a variety of N-unprotected 2,3 substituted indoles. Before the discovery of this compound the chemistry involving 2-stannylindoles was not developed as there was no way to practically synthesis these N-unprotected 2,3-stannylindoles. One was limited to the production of N-proteced 2-stannylindoles through metallation by a process known as Stille coupling.[6] The N-unprotected 2-stannylindoles generated from the Fukuyama Synthesis can be readily oxidized with iodine opening up an area of chemistry that allows for the synthesis of a variety compounds utalizing the 2-iodoindoles as a starting reagent. This iodine substituted derivative can lead to aryl halides, vinyl iodides, vinyl triflates, benzyl bromides.
![Example Reaction for Fukuyama Synthesis.](http://upload.wikimedia.org/wikipedia/commons/thumb/1/12/Fukuyama_Indole_Synthesis_Example_with_Iodine_as_Substituent.png/400px-Fukuyama_Indole_Synthesis_Example_with_Iodine_as_Substituent.png)
In addition to acetylenes (Sonogashira coupling), and acrylates (Heck reaction) in the second position.[5]
![Possible next step synthesis reactions working with the 2-iodoindoles from the Fukuyama Synthesis.](http://upload.wikimedia.org/wikipedia/commons/thumb/0/02/Possible_Next_Step_Reaction_with_2-iodoindoles.png/400px-Possible_Next_Step_Reaction_with_2-iodoindoles.png)
Applications[edit]
The synthesis is one of the simplest methods for creating poly-substituted indoles, this procedure has been utilized in numerous natural product syntheses, including aspidophytine,[7] vinblastine[8], shown below, and strychnine[9]
inodolo 264 biindolysy 264
265
In addition to playing a role in the syntheses of indolocarbazoles, [5] biindolyls, < ref name = "Kobayashi" /> and the total synthesis of vincadifformine and tabersonine [10].
References[edit]
- ^ a b Fukuyama, T; Chen, X; Peng, G (1994). "A Novel Tin-Mediated Indole Synthesis". J. Am. Chem. Soc. 116 (7): 3127–3728. doi:10.1021/ja983681v.
- ^ Pindur, U; Adam, R. (1998). "Synthetically attractive indolization processes and newer methods for the preparation of selectively substituted indoles". J. Heterocycl. Chem. 25 (1): 1. doi:10.1002/jhet.5570250101.
- ^ Tokuyama, H; Yamashita, T; Reding, M. T; Kaburagi, Y; Fukuyama, T (1999). "Radical Cyclization of 2-Alkenylthioanilides: A Novel Synthesis of 2,3-Disubstituted Indoles". J. Am. Chem. Soc. 121 (15): 3791–3792. doi:10.1021/ja983681v.
- ^ Gribble, G (2000). "Recent developments in indole ring synthesis—methodology and applications". J. Chem. Soc, Perkin Transactions 1 (7): 1045–1075. doi:10.1039/a909834h.
- ^ a b c Kobayashi, T.; Fukuyama, T. (1998). "Development of a novel indole synthesis". J. Heterocycl. Chem. . 113 (0033): 1043–1055.
- ^ Trost, B.M; Fortunak, J. M. D. (1982). "Cyclizations initiated by a Pd2+-Ag+ mixed-metal system". Organometallics. 1 (7): 7–10.
- ^ Sumi, S; Matsumoto, K; Tokuyama, H; Fukuyama, T (2003). "Enantioselective Total Synthesis of Aspidophytine". Org. Lett. 5 (11): 1891–1893. doi:10.1021/ol034445e. PMID 12762679.
- ^ Yokoshima, S; Ueda, T; Kobayashi, S; Sato, A; Kuboyama, T; Tokuyama, H; Fukuyama, T (2002). "Stereocontrolled Total Synthesis of (+)-Vinblastine". J. Am. Chem. Soc. 124 (10): 2137–2139. doi:10.1021/ja0177049.
- ^ Kaburagi, Y; Tokuyama, H; Fukuyama, T (2004). "Total Synthesis of (-)-Strychnine". J. Am. Chem. Soc. 126 (33): 10246–10247. doi:10.1021/ja046407b. PMID 15315428.
- ^ Kobayashi, S; Peng, G; Fukuyama, T (1999). "Efficient total syntheses of (±)-vincadifformine and (-)-tabersonine". Tetrahedron Lett. 40: 1519–1522. doi:10.1016/S0040-4039(98)02667-7.
Category:Indole forming reactions Category:Free radical reactions Category:Name reactions