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. 2021;5(3):173-228.
doi: 10.1055/s-0040-1706051. Epub 2021 Aug 12.

C-H Bond Functionalization of Amines: A Graphical Overview of Diverse Methods

Subhradeep Dutta  1 , Bowen Li  1 , Dillon R L Rickertsen  1 , Daniel A Valles  1 , Daniel Seidel  1
Affiliations

C-H Bond Functionalization of Amines: A Graphical Overview of Diverse Methods

Subhradeep Dutta et al. SynOpen. 2021.

Abstract

This Graphical Review provides a concise overview of the manifold and mechanistically diverse methods that enable the functionalization of sp3 C-H bonds in amines and their derivatives.

Keywords: C–H bond functionalization; amines; catalysis; heterocycles; synthesis.

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Conflict of interest statement

Conflict of Interest The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Deprotonation of tertiary amines.
Figure 2
Figure 2
Deprotonation of protected amines, part I.
Figure 3
Figure 3
Deprotonation of protected amines, part II.
Figure 4
Figure 4
Deprotonation of protected amines, part III.
Figure 5
Figure 5
Deprotonation of protected amines, part IV.
Figure 6
Figure 6
Transition-metal-catalyzed reactions with substrates containing directing groups, part I.
Figure 7
Figure 7
Transition-metal-catalyzed reactions with substrates containing directing groups, part II.
Figure 8
Figure 8
Transition-metal-catalyzed reactions with substrates containing directing groups, functionalization of amino acid derivatives.
Figure 9
Figure 9
Transition-metal-catalyzed reactions with substrates containing directing groups, catalytic enantioselective approaches.
Figure 10
Figure 10
Transition-metal-catalyzed reactions involving transient directing groups (TDGs).
Figure 11
Figure 11
Native-amine-directed transition-metal-catalyzed reactions.
Figure 12
Figure 12
Undirected transition-metal-catalyzed reactions.
Figure 13
Figure 13
Hydroaminoalkylation.
Figure 14
Figure 14
Oxidative methods, stoichiometric metal-based oxidants.
Figure 15
Figure 15
Oxidative methods, stoichiometric nonmetallic oxidants.
Figure 16
Figure 16
Oxidative preparation of building blocks.
Figure 17
Figure 17
Metal-catalyzed cross-dehydrogenative-coupling (CDC) reactions.
Figure 18
Figure 18
Metal-catalyzed cross-dehydrogenative-coupling (CDC) reactions with oxygen as the terminal oxidant.
Figure 19
Figure 19
Iodine-catalyzed cross-dehydrogenative-coupling (CDC) reactions.
Figure 20
Figure 20
Acceptorless cross-dehydrogenative-coupling (CDC) reactions with hydrogen evolution.
Figure 21
Figure 21
Catalytic enantioselective cross-dehydrogenative-coupling (CDC) reactions.
Figure 22
Figure 22
Oxidative β-functionalization.
Figure 23
Figure 23
Oxidative formation of sulfur-rich heterocycles.
Figure 24
Figure 24
Reactions involving amine N-oxides.
Figure 25
Figure 25
Dehydrogenation/aromatization.
Figure 26
Figure 26
Hydrogen borrowing.
Figure 27
Figure 27
Condensation-based methods involving azomethine ylide intermediates, aromatization.
Figure 28
Figure 28
Condensation-based methods involving azomethine ylide intermediates, pericyclic reactions.
Figure 29
Figure 29
Condensation-based methods involving azomethine ylide intermediates, redox-neutral 3-component coupling reactions.
Figure 30
Figure 30
Condensation-based methods involving azomethine ylide intermediates, redox-annulations.
Figure 31
Figure 31
Internal redox transformations involving [1,n]-H transfers, the ‘tert-amino effect’.
Figure 32
Figure 32
Lewis and Brønsted acid catalyzed internal redox transformations involving [1,n]-H transfers.
Figure 33
Figure 33
Catalytic enantioselective internal redox transformations involving [1,n]-H transfers.
Figure 34
Figure 34
Internal redox transformations involving [1,n]-H transfers in non-conjugated systems.
Figure 35
Figure 35
(Redox-neutral) methods involving intermolecular hydride transfer.
Figure 36
Figure 36
Li-amide-based imine and 1-azaallyl anion generation from unprotected azacycles.
Figure 37
Figure 37
Reactions involving carbenes or metal carbenoids.
Figure 38
Figure 38
Hofmann–Löffler–Freytag (HLF) reaction.
Figure 39
Figure 39
Miscellaneous radical-based methods.
Figure 40
Figure 40
Electrochemical approaches, cation pool method.
Figure 41
Figure 41
Electrochemical approaches, 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO) catalysis.
Figure 42
Figure 42
Intramolecular hydrogen atom transfer (HAT).
Figure 43
Figure 43
Direct hydrogen atom transfer (HAT).
Figure 44
Figure 44
Photoredox approaches, part I.
Figure 45
Figure 45
Photoredox approaches, part II.
Figure 46
Figure 46
Indirect hydrogen atom transfer (HAT).
Figure 47
Figure 47
Deconstructive functionalization.
See this image and copyright information in PMC

References

    1. Peterson DJ; Hays HR J. Org. Chem 1965, 30, 1939.
    2. Lepley AR; Giumanini AG J. Org. Chem 1966, 31, 2055.
    3. Ahlbrecht H; Dollinger H Tetrahedron Lett. 1984, 25, 1353.
    4. Gessner VH; Strohmann C J. Am. Chem. Soc 2008, 130, 14412. - PubMed
    5. Kessar SV; Singh P; Vohra R; Kaur NP; Singh KN J. Chem. Soc., Chem. Commun 1991, 568.
    6. Kessar SV; Vohra R; Kaur NP Tetrahedron Lett. 1991, 32, 3221.
    7. De Ceglie MC; Musio B; Affortunato F; Moliterni A; Altomare A; Florio S; Luisi R Chem. Eur. J 2011, 17, 286. - PubMed
    8. Singh KN; Singh P; Singh P; Deol YS Org. Lett 2012, 14, 2202. - PubMed
    9. Lepley AR; Khan WA J. Org. Chem 1966, 31, 2061.
    10. Lepley AR; Khan WA Chem. Commun 1967, 1198.
    11. Kessar SV; Singh P Chem. Rev 1997, 97, 721. - PubMed
    12. Katritzky AR; Qi M Tetrahedron 1998, 54, 2647.
    13. Ferey V; Toupet L; Le Gall T; Mioskowski C Angew. Chem., Int. Ed. Engl 1996, 35, 430.
    14. Vedejs E; Kendall JT J. Am. Chem. Soc 1997, 119, 6941.
    15. Ebden MR; Simpkins NS; Fox DNA Tetrahedron 1998, 54, 12923.
    16. Kessar SV; Singh P; Singh KN; Venugopalan P; Kaur A; Bharatam PV; Sharma AK J. Am. Chem. Soc 2007, 129, 4506. - PubMed
    17. Harmata M; Carter KW; Jones DE; Kahraman M Tetrahedron Lett. 1996, 37, 6267.
    18. Kovács E; Huszka B; Gáti T; Nyerges M; Faigl F; Mucsi Z J. Org. Chem 2019, 84, 7100. - PubMed
    19. Kovács E; Faigl F; Mucsi Z J. Org. Chem 2020, 85, 11226. - PMC - PubMed
    1. Keefer LK; Fodor CH J. Am. Chem. Soc 1970, 92, 5747.
    2. Seebach D; Enders D Angew. Chem., Int. Ed. Engl 1972, 11, 301.
    3. Seebach D; Enders D Angew. Chem., Int. Ed. Engl 1972, 11, 1101.
    4. Seebach D; Wykypiel W Synthesis 1979, 423.
    5. Seebach D; Enders D J. Med. Chem 1974, 17, 1225. - PubMed
    6. Fraser RR; Passannanti S Synthesis 1976, 540.
    7. Wykypiel W; Seebach D Tetrahedron Lett. 1980, 21, 1927.
    8. Savignac P; Dreux M; Leroux Y Tetrahedron Lett. 1974, 15, 2651.
    9. Savignac P; Leroux Y J. Organomet. Chem 1973, 57, C47.
    10. Magnus P; Roy G Synthesis 1980, 575.
    11. Seebach D; Yoshifuji M Helv. Chim. Acta 1981, 64, 643.
    12. Beak P; Zajdel WJ J. Am. Chem. Soc 1984, 106, 1010.
    13. Meyers AI; Edwards PD; Rieker WF; Bailey TR J. Am. Chem. Soc 1984, 106, 3270.
    14. Meyers AL; Dickman DA; Boes M Tetrahedron 1987, 43, 5095.
    15. Meyers AI Tetrahedron 1992, 48, 2589.
    16. Seebach D; Enders D Angew. Chem., Int. Ed. Engl 1975, 14, 15.
    17. Beak P; Reitz DB Chem. Rev 1978, 78, 275.
    18. Beak P; Zajdel WJ; Reitz DB Chem. Rev 1984, 84, 471.
    19. Clayden J Organolithiums: Selectivity for Synthesis, In Tetrahedron Organic Chemistry Series, Vol. 23; Clayden J, Ed.; Pergamon: Amsterdam, 2002, 9.
    20. Fraser RR; Boussard G; Postescu ID; Whiting JJ; Wigfield YY Can. J. Chem 1973, 51, 1109.
    21. Lyle RE; Saavedra JE; Lyle GG; Fribush HM; Marshall JL; Lijinsky W; Singer GM Tetrahedron Lett. 1976, 17, 4431.
    22. Seebach D; Lubosch W Angew. Chem., Int. Ed. Engl 1976, 15, 313.
    23. Seebach D; Hassel T Angew. Chem., Int. Ed. Engl 1978, 17, 274.
    24. Meyers AI; Ten Hoeve W J. Am. Chem. Soc 1980, 102, 7125.
    25. Seebach D; Lohmann J-J; Syfrig MA; Yoshifuji M Tetrahedron 1983, 39, 1963.
    26. Gawley RE; Hart G; Goicoechea-Pappas M; Smith AL J. Org. Chem 1986, 51, 3076.
    27. Gawley RE; Rein K; Chemburkar S J. Org. Chem 1989, 54, 3002.
    28. Meyers AI; Milot G J. Org. Chem 1993, 58, 6538.
    29. Nain Singh K; Singh P; Kaur A Synth. Commun 2006, 36, 3339.
    1. Beak P; Lee W-K Tetrahedron Lett. 1989, 30, 1197.
    2. Beak P; Lee WK J. Org. Chem 1990, 55, 2578.
    3. Beak P; Lee WK J. Org. Chem 1993, 58, 1109.
    4. Xiao D; Lavey BJ; Palani A; Wang C; Aslanian RG; Kozlowski JA; Shih N-Y; McPhail AT; Randolph GP; Lachowicz JE; Duffy RA Tetrahedron Lett. 2005, 46, 7653.
    5. Aeyad T; Williams JD; Meijer AJHM; Coldham I Synlett 2017, 28, 2765.
    6. Beak P; Wu S; Yum EK; Jun YM J. Org. Chem 1994, 59, 276.
    7. Dieter RK; Li S Tetrahedron Lett. 1995, 36, 3613.
    8. Dieter RK; Li S J. Org. Chem 1997, 62, 7726.
    9. Dieter RK; Dieter JW; Alexander CW; Bhinderwala NS J. Org. Chem 1996, 61, 2930. - PubMed
    10. Dieter RK; Velu SE J. Org. Chem 1997, 62, 3798. - PubMed
    11. Dieter RK; Lu K; Velu SE J. Org. Chem 2000, 65, 8715. - PubMed
    12. Barker G; O’Brien P; Campos KR Org. Lett 2010, 12, 4176. - PubMed
    13. Kwong A; Firth JD; Farmer TJ; O’Brien P Tetrahedron 2021, 81, 131899.
    14. Stead D; O’Brien P; Sanderson AJ Org. Lett 2005, 7, 4459. - PubMed
    15. Berkheij M; van der Sluis L; Sewing C; den Boer DJ; Terpstra JW; Hiemstra H; Iwema Bakker WI; van den Hoogenband A; van Maarseveen JH Tetrahedron Lett. 2005, 46, 2369.
    16. Hodgson DM; Humphreys PG; Xu Z; Ward JG Angew. Chem. Int. Ed 2007, 46, 2245. - PubMed
    17. Li X; Leonori D; Sheikh NS; Coldham I Chem. Eur. J 2013, 19, 7724. - PubMed
    18. Pizzuti MG; Minnaard AJ; Feringa BL Org. Biomol. Chem 2008, 6, 3464. - PubMed
    19. Krishnan S; Bagdanoff JT; Ebner DC; Ramtohul YK; Tambar UK; Stoltz BM J. Am. Chem. Soc 2008, 130, 13745. - PMC - PubMed
    20. Dieter RK; Sharma RR; Ryan W Tetrahedron Lett. 1997, 38, 783.
    21. Dieter RK; Lu K J. Org. Chem 2002, 67, 847. - PubMed
    22. Coldham I; Leonori D Org. Lett 2008, 10, 3923. - PubMed
    1. Kerrick ST; Beak P J. Am. Chem. Soc 1991, 113, 9708.
    2. Beak P; Kerrick ST; Wu S; Chu J J. Am. Chem. Soc 1994, 116, 3231.
    3. Dearden MJ; Firkin CR; Hermet J-PR; O’Brien P J. Am. Chem. Soc 2002, 124, 11870. - PubMed
    4. Campos KR; Klapars A; Waldman JH; Dormer PG; Chen C-Y J. Am. Chem. Soc 2006, 128, 3538. - PubMed
    5. Seel S; Thaler T; Takatsu K; Zhang C; Zipse H; Straub BF; Mayer P; Knochel P J. Am. Chem. Soc 2011, 133, 4774. - PubMed
    6. Kasten K; Seling N; O’Brien P Org. React 2019, 100, 255.
    7. Wong JYF; Barker G Tetrahedron 2020, 76, 131704.
    8. Gallagher DJ; Beak P J. Org. Chem 1995, 60, 7092.
    9. Wilkinson TJ; Stehle NW; Beak P Org. Lett 2000, 2, 155. - PubMed
    10. Phuan P-W; Ianni JC; Kozlowski MC J. Am. Chem. Soc 2004, 126, 15473. - PubMed
    11. Coldham I; Leonori D J. Org. Chem 2010, 75, 4069. - PubMed
    12. Sheikh NS; Leonori D; Barker G; Firth JD; Campos KR; Meijer AJHM; O’Brien P; Coldham I J. Am. Chem. Soc 2012, 134, 5300. - PubMed
    13. Kizirian J-C; Caille J-C; Alexakis A Tetrahedron Lett. 2003, 44, 8893.
    14. Hermet J-PR; Porter DW; Dearden MJ; Harrison JR; Koplin T; O’Brien P; Parmene J; Tyurin V; Whitwood AC; Gilday J; Smith NM Org. Biomol. Chem 2003, 1, 3977. - PubMed
    15. McGrath MJ; Bilke JL; O’Brien P Chem. Commun 2006, 2607. - PubMed
    16. McGrath MJ; O’Brien P J. Am. Chem. Soc 2005, 127, 16378. - PubMed
    1. Coldham I; Raimbault S; Whittaker DTE; Chovatia PT; Leonori D; Patel JJ; Sheikh NS Chem. Eur. J 2010, 16, 4082. - PubMed
    2. Millet A; Larini P; Clot E; Baudoin O Chem. Sci 2013, 4, 2241.
    3. Cordier CJ; Lundgren RJ; Fu GC J. Am. Chem. Soc 2013, 135, 10946. - PMC - PubMed
    4. Mu X; Shibata Y; Makida Y; Fu GC Angew. Chem. Int. Ed 2017, 56, 5821. - PMC - PubMed
    5. Beak P; Basu A; Gallagher DJ; Park YS; Thayumanavan S Acc. Chem. Res 1996, 29, 552.
    6. Campos KR Chem. Soc. Rev 2007, 36, 1069. - PubMed
    7. Mitchell EA; Peschiulli A; Lefevre N; Meerpoel L; Maes BUW Chem. Eur. J 2012, 18, 10092. - PubMed
    8. Coldham I; Dufour S; Haxell TFN; Howard S; Vennall GP Angew. Chem. Int. Ed 2002, 41, 3887. - PubMed
    9. Beng TK; Gawley RE J. Am. Chem. Soc 2010, 132, 12216. - PMC - PubMed
    10. Millet A; Dailler D; Larini P; Baudoin O Angew. Chem. Int. Ed 2014, 53, 2678. - PubMed
    11. Watson RT; Gore VK; Chandupatla KR; Dieter RK; Snyder JP J. Org. Chem 2004, 69, 6105. - PubMed
    12. Klapars A; Campos KR; Waldman JH; Zewge D; Dormer PG; Chen C-Y J. Org. Chem 2008, 73, 4986. - PubMed
    13. Barker G; McGrath JL; Klapars A; Stead D; Zhou G; Campos KR; O’Brien P J. Org. Chem 2011, 76, 5936. - PubMed