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Ugi's amine

(R)- and (S)-enantiomers of Ugi's amine
Names
IUPAC name
[1-(Dimethylamino)ethyl]ferrocene
Other names
N,N-Dimethyl-1-ferrocenylethylamine
Identifiers
Properties
C14H19FeN
Molar mass 257.158 g·mol−1
Appearance orange-brown oil
Density 1.222 g/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Ugi’s amine is an organometallic compound with the formula (C5H5)Fe(C5H4CH(CH3)N(CH3)2. It is named for the chemist who first reported its synthesis in 1970, Ivar Ugi.[1] It is a ferrocene derivative. Ugi’s amine is a precursor to ligands, most notably, the Josiphos ligands, which have been used in asymmetric catalysis[2][3]

History

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In 1967, Schlӧg repurposed the term “planar chirality” for use in substituted ferrocene terminology, which is necessary for ferrocenes in which ferrocene's innate plane of symmetry is broken by introducing two different substituents to one of its ring.[4] Nozaki, et al. demonstrated that a ferrocene derivative bearing a chiral amine substituent could participate in directed ortho lithiation of the same ring of the ferrocene, yielding products with planar chirality diastereoselectively.[5] Nozaki’s ferrocene derivative provided products that were only 86% optically pure. Ugi, et al. improved the stereoselectivity by using [1-(dimethylamino)ethyl]-ferrocene, providing products that had an optical purity >95%. The utility of Ugi’s amine in forming ligands for asymmetric catalysis was first reported in 1974 by Kumada, et al.[6]

Synthesis

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Synthesis of [1-(dimethylamino)ethyl]-ferrocene by Ugi.

The first synthesis of Ugi’s amine was reported in 1970 by Ugi, et al. It begins by converting (±)1-ferrocenylethanol to (±)1-ferrocenylchloroethane. This is then substituted in situ with dimethylamine, resulting in a racemic mixture of [1-(dimethylamino)ethyl]-Ferrocene. The racemic mixture is subsequently resolved via recrystallization of the tartrate salt, providing both enantiomers in their enantio-pure form.[1]

Since the original report, other syntheses of Ugi’s amine have been reported. These are generally directed towards the synthesis of only one of the enantiomers rather than a racemic mixture. An enzymatic resolution of (±)1-ferrocenylethanol can be performed by Pseudomonas Fluorescens lipase-mediated acylation with vinyl acetate, providing unreacted (1S)-1-ferrocenylethanol (92% ee) and (1R)-[1-(acetyloxy)ethyl]-ferrocene (96% ee). The later can be easy hydrolyzed to (1R)-1-ferrocenylethanol.[7] Either stereoisomer of can be converted to Ugi’s amine first by conversion to the acetate, then displacement with dimethylamine with complete stereoretention (see below for stereochemical outcome). Additionally, Knochel, et al. reported a stereoselective synthesis of Ugi’s amine using the same acetylation/displacement strategy, but accesses (1R)-1-ferrocenylethanol from a Corey-Bakshi-Shibata reduction of acetylferrocene.[8]

Enzymatic resolution and stereoselective reduction in route to enantiopure Ugi's Amine.

Reactions

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Ugi’s amine is capable of promoting directed ortho lithiation diastereoselectively (with respect to planar chirality). [(1S)-(dimethylamino)ethyl]-ferrocene treated with n-BuLi, then quenched with TMSCl produces a planar chirality of (Rp). Treatment of [(1R)-(dimethylamino)ethyl]-ferrocene under these conditions produces a planar chirality of (Sp).[1][9] This selectivity is dictated by the orientation of the methyl substituent on the starting material in the conformation necessary for the nitrogen to be chelated to the lithiate. In one case this methyl substituent suffers from steric interactions with the other Cp ring, and in the other it points away from all other atoms. The high diastereoselectivity is independent of the electrophile used to trap the metalate, providing evidence for the stereoinductive step being lithiation and allowing broad synthetic utility of Ugi’s amine. If the (S,Sp) or (R,Rp) diastereomers are desired, the first metalate can be trapped with TMSCl to block the more favored lithiation position. Subsequent lithiation occurs at the only available, less favored site. Trapping with the desired electrophile and TBAF deprotection of the TMS group will provide the (S,Sp) or (R,Rp) diastereomer.

Rationale for the stereochemical outcome of directed lithiation of Ugi's Amine.

Further functionalization can take place at the carbon alpha to the ferrocene by substituting the dimethylamine with various nucleophiles. This is usually accomplished by quaternization of the amine with methyl iodide or acetic acid, which upon heating eliminates, resulting in a stable α-ferrocenylethyl cation intermediate. Addition of nucleophiles results substitution that is usually completely stereoretentive. Amines, carboxylates, alcohols, thiols, and phosphines are all competent nucleophiles.[1][10] This is a common phenomenon for α-substituted ferrocenes.[11]

Substitution of Ugi's Amine with stereoretention.

Ligands from Ugi's amine

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Ugi’s amine has found extensive use in the synthesis of metal binding ligands used in homogeneous catalysis. As its ring-substituted derivatives generally contain a chiral center as well as planar chirality, it often produces high levels of enantioinduction in these reactions. These two forms of chirality, in some cases, are thought to work synergistically for enantioinduction.[12] It is most commonly substituted with phosphorus to provide mono-, bi-, and tridentate phosphine ligands. The first report of such ligands was Kumada’s 1974 report of four mono- and bisphosphine ligands used for the rhodium-catalyzed asymmetric hydrosilation of ketones.[6] The most notable set of ligands synthesized from Ugi’s amine is the Josiphos class of ligands, which has found use in numerous catalytic reaction types[13] on both small and large scales. Below is a list of representative ligands derived from Ugi's amine:[3]

  • Josiphos[2]
  • Pigiphos
  • TRAP
  • Walphos
  • BoPhoz
  • Xyliphos
  • BPPFOH
  • Taniaphos

Asymmetric reactions utilizing ligands derived from Ugi's amine

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Reaction Type Metal Center(s)
Hydrosilation of ketones[6] Ru
Grignard Addition[14] Ni
Reduction of activated alkenes[15][16] Ru, Cu
Reduction of enamides[2] Ru
Reduction of ketones[17] Ru, Ir
Transfer hydrogenation of ketones[18] Re
Hydroalkynylation of allenes[19] Co
Allylic substitution[20] Pd
Coupling of ketoamides to aldehydes[21] Rh
Conjugate addition[22] Cu
Baylis-Hillman reaction[23] N/A (H-bonding)
[3+2] cycloaddition[24] Cu
Hydroboration[25] Cu

References

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  1. ^ a b c d Marquarding, Dieter; Klusacek, Hans; Gokel, George; Hoffmann, Peter; Ugi, Ivar (1970-09-01). "Stereoselective syntheses. VI. Correlation of central and planar chirality in ferrocene derivatives". Journal of the American Chemical Society. 92 (18): 5389–5393. doi:10.1021/ja00721a017. ISSN 0002-7863.
  2. ^ a b c Blaser, Hans Ulrich; Pugin, Benoît; Spindler, Felix (2021). "Having Fun (And Commercial Success) with Josiphos and Related Chiral Ferrocene Based Ligands". Helvetica Chimica Acta. 104. doi:10.1002/hlca.202000192. S2CID 229427019.
  3. ^ a b Xue-Long., Hou (2010-01-01). Chiral Ferrocenes in Asymmetric Catalysis. Wiley-VCH. ISBN 9783527322800. OCLC 320495292.
  4. ^ Schlögl, Karl (1967-01-01). "Stereochemistry of Metallocenes". In Allinger, Norman L.; Eliel, Ernest L. (eds.). Topics in Stereochemistry. Vol. 1. John Wiley & Sons, Inc. pp. 39–91. doi:10.1002/9780470147108.ch2. ISBN 9780470147108.
  5. ^ Aratani, T.; Gonda, T.; Nozaki, H. (1969). "Asymmetric lithiation of ferrocenes". Tetrahedron Letters. 10 (27): 2265–2268. doi:10.1016/s0040-4039(01)88137-5.
  6. ^ a b c Hayashi, Tamio; Yamamoto, Keiji; Kumada, Makoto (1974). "Asymmetric catalytic hydrosilylation of ketones preparation of chiral ferrocenylphosphines as chiral ligands". Tetrahedron Letters. 15 (49–50): 4405–4408. doi:10.1016/s0040-4039(01)92175-6.
  7. ^ Boaz, Neil W. (1989). "Enzymatic esterification of 1-ferrocenylethanol: An alternate approach to chiral ferrocenyl bis-phosphines". Tetrahedron Letters. 30 (16): 2061–2064. doi:10.1016/s0040-4039(01)93711-6.
  8. ^ Tappe, Katja; Knochel, Paul (2004-01-12). "New efficient synthesis of Taniaphos ligands: application in ruthenium- and rhodium-catalyzed enantioselective hydrogenations". Tetrahedron: Asymmetry. 15 (1): 91–102. doi:10.1016/j.tetasy.2003.11.004.
  9. ^ Battelle, Linda F.; Bau, Robert.; Gokel, George W.; Oyakawa, Ray T.; Ugi, Ivar K. (1973-01-01). "Stereoselective synthesis. VIII. Absolute configuration of a 1,2-disubstituted ferrocene derivative with planar and central elements of chirality and the mechanism of the optically active .alpha.-ferrocenyl tertiary amines". Journal of the American Chemical Society. 95 (2): 482–486. doi:10.1021/ja00783a030. ISSN 0002-7863.
  10. ^ Gokel, George W.; Marquarding, Dieter.; Ugi, Ivar K. (1972-10-01). "Stereoselective syntheses. VIII. Retentive nucleophilic displacements of .alpha.-substituted alkylferrocenes". The Journal of Organic Chemistry. 37 (20): 3052–3058. doi:10.1021/jo00985a002. ISSN 0022-3263.
  11. ^ Nugent, Maurice J.; Kummer, Rudolph; Richards, John Hall (1969-10-01). "Metallocenyl carbonium ions. Stereochemistry of participation by ferrocene in the solvolysis of 2-ferrocenylalkyl tosylates". Journal of the American Chemical Society. 91 (22): 6141–6145. doi:10.1021/ja01050a037. ISSN 0002-7863.
  12. ^ Gómez Arrayás, Ramón; Adrio, Javier; Carretero, Juan Carlos (2006-11-27). "Recent Applications of Chiral Ferrocene Ligands in Asymmetric Catalysis". Angewandte Chemie International Edition. 45 (46): 7674–7715. doi:10.1002/anie.200602482. ISSN 1521-3773. PMID 17115468.
  13. ^ Blaser, Hans-Ulrich; Lotz, Matthias (2001-01-01). Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons, Ltd. doi:10.1002/047084289x.rn00874. ISBN 9780470842898.
  14. ^ Hayashi, Tamio; Tajika, Masatoyo; Tamao, Kohei; Kumada, Makoto (1976-06-01). "High stereoselectivity in asymmetric Grignard cross-coupling catalyzed by nickel complexes of chiral (aminoalkylferrocenyl)phosphines". Journal of the American Chemical Society. 98 (12): 3718–3719. doi:10.1021/ja00428a061. ISSN 0002-7863.
  15. ^ Lipshutz, Bruce H.; Servesko, Jeff M. (2003-10-13). "CuH-Catalyzed Asymmetric Conjugate Reductions of Acyclic Enones". Angewandte Chemie International Edition. 42 (39): 4789–4792. doi:10.1002/anie.200352313. ISSN 1521-3773. PMID 14562350.
  16. ^ Shultz, C. Scott; Dreher, Spencer D.; Ikemoto, Norihiro; Williams, J. Michael; Grabowski, Edward J. J.; Krska, Shane W.; Sun, Yongkui; Dormer, Peter G.; DiMichele, Lisa (2005-08-01). "Asymmetric Hydrogenation of N-Sulfonylated-α-dehydroamino Acids: Toward the Synthesis of an Anthrax Lethal Factor Inhibitor". Organic Letters. 7 (16): 3405–3408. doi:10.1021/ol050869s. ISSN 1523-7060. PMID 16048303.
  17. ^ Nie, Huifang; Zhou, Gang; Wang, Quanjun; Chen, Weiping; Zhang, Shengyong (2013-12-31). "Asymmetric hydrogenation of aromatic ketones using an iridium(I) catalyst containing ferrocene-based P–N–N tridentate ligands". Tetrahedron: Asymmetry. 24 (24): 1567–1571. doi:10.1016/j.tetasy.2013.10.012.
  18. ^ Mejía, Esteban; Aardoom, Raphael; Togni, Antonio (2012-11-01). "Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Rhenium Complexes with Chiral Ferrocenylphosphane Ligands". European Journal of Inorganic Chemistry. 2012 (31): 5021–5032. doi:10.1002/ejic.201200693. ISSN 1099-0682.
  19. ^ Sawano, Takahiro; Ou, Keiyu; Nishimura, Takahiro; Hayashi, Tamio (2013-09-20). "Cobalt-Catalyzed Asymmetric Addition of Silylacetylenes to 1,1-Disubstituted Allenes". The Journal of Organic Chemistry. 78 (18): 8986–8993. doi:10.1021/jo401604n. ISSN 0022-3263. PMID 23984966. S2CID 35612412.
  20. ^ Lam, Fuk Loi; Au-Yeung, Terry T. L.; Cheung, Hong Yee; Kok, Stanton H. L.; Lam, Wing Sze; Wong, Kwok Yin; Chan, Albert S. C. (2006-02-20). "Easily accessible ferrocenyl N-P/S type ligands and their applications in asymmetric allylic substitutions". Tetrahedron: Asymmetry. Asymmetric Catalysis. 17 (4): 497–499. doi:10.1016/j.tetasy.2005.12.037. hdl:10397/16669.
  21. ^ Kou, Kevin G. M.; Le, Diane N.; Dong, Vy M. (2014-07-02). "Rh(I)-Catalyzed Intermolecular Hydroacylation: Enantioselective Cross-Coupling of Aldehydes and Ketoamides". Journal of the American Chemical Society. 136 (26): 9471–9476. doi:10.1021/ja504296x. ISSN 0002-7863. PMC 4091274. PMID 24937681.
  22. ^ Sorádová, Zuzana; Máziková, Jana; Mečiarová, Mária; Šebesta, Radovan (2015-03-28). "Stereoselective domino conjugate addition of Grignard reagents to lactones followed by reaction with activated alkenes catalyzed by ferrocenyl carbene ligands". Tetrahedron: Asymmetry. 26 (5–6): 271–275. doi:10.1016/j.tetasy.2015.01.015.
  23. ^ Li, Chuang; Ma, Peng-Fei; Lei, Yang; Chen, Hui; Guan, Shao-Yu; Jiang, Ru; Chen, Wei-Ping (2016-08-01). "Enantioselective Morita–Baylis–Hillman Reaction of Acrylates with Nitrobenzaldehydes Promoted by the Bifunctional Ferrocene-Based Phosphinothiourea Organocatalysts". Catalysis Letters. 146 (8): 1429–1434. doi:10.1007/s10562-016-1759-9. ISSN 1011-372X. S2CID 100359605.
  24. ^ Han, Fu-Zhong; Yu, Sai-Bo; Zhang, Cheng; Hu, Xiang-Ping (2016-05-26). "Chiral ferrocenyl P,S-ligands for highly efficient copper-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides". Tetrahedron. Chiral Sulfur Ligands/Catalysts in Asymmetric Catalysis. 72 (21): 2616–2622. doi:10.1016/j.tet.2015.01.003.
  25. ^ Lee, Hyesu; Lee, Byoung Yoon; Yun, Jaesook (2015-02-06). "Copper(I)–Taniaphos Catalyzed Enantiodivergent Hydroboration of Bicyclic Alkenes". Organic Letters. 17 (3): 764–766. doi:10.1021/ol503598w. ISSN 1523-7060. PMID 25603172.
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