title: Developing ligands for palladium(II)-catalyzed C-H functionalization: intimate dialogue between ligand and substrate.
abstract: Homogeneous transition-metal-catalyzed reactions are indispensable to all facets of modern chemical synthesis. It is thus difficult to imagine that for much of the early 20th century, the reactivity and selectivity of all known homogeneous metal catalysts paled in comparison to their heterogeneous and biological counterparts. In the intervening decades, advances in ligand design bridged this divide, such that today some of the most demanding bond-forming events are mediated by ligand-supported homogeneous metal species. While ligand design has propelled many areas of homogeneous catalysis, in the field of Pd(II)-catalyzed C-H functionalization, suitable ligand scaffolds are lacking, which has hampered the development of broadly practical transformations based on C-H functionalization logic. In this Perspective, we offer an account of our research employing three ligand scaffolds, mono-N-protected amino acids, 2,6-disubstituted pyridines, and 2,2'-bipyridines, to address challenges posed by several synthetically versatile substrate classes. Drawing on this work, we discuss principles of ligand design, such as the need to match a ligand to a particular substrate class, and how ligand traits such as tunability and modularity can be advantageous in reaction discovery.
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Keary M
authors.initials: KM
authors.lastname: Engle
authors.forename: Jin-Quan
authors.initials: JQ
authors.lastname: Yu
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002384:Catalysis; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D008024:Ligands; D009942:Organometallic Compounds; D011725:Pyridines; D010165:Palladium
references.citation: J Am Chem Soc. 2012 Mar 14;134(10):4600-6
references.pmid: 22324814
references.citation: J Org Chem. 1997 Jan 10;62(1):2-3
references.pmid: 11671356
references.citation: Org Lett. 2013 Feb 15;15(4):788-91
references.pmid: 23350934
references.citation: Org Lett. 2012 Apr 6;14(7):1760-3
references.pmid: 22409653
references.citation: Chem Commun (Camb). 2012 Oct 25;48(83):10343-5
references.pmid: 22983263
references.citation: Angew Chem Int Ed Engl. 2012 Sep 3;51(36):8960-9009
references.pmid: 22887739
references.citation: Acc Chem Res. 2009 Aug 18;42(8):1074-86
references.pmid: 19552413
references.citation: J Am Chem Soc. 2005 Dec 28;127(51):18020-1
references.pmid: 16366550
references.citation: J Am Chem Soc. 2010 Jan 20;132(2):460-1
references.pmid: 20017549
references.citation: J Am Chem Soc. 2005 Dec 21;127(50):17778-88
references.pmid: 16351107
references.citation: Nature. 2012 Jun 27;486(7404):518-22
references.pmid: 22739317
references.citation: J Am Chem Soc. 2009 Dec 2;131(47):17052-3
references.pmid: 19899771
references.citation: Chemistry. 2001 Mar 2;7(5):945-50
references.pmid: 11303874
references.citation: Org Lett. 2011 Oct 21;13(20):5504-7
references.pmid: 21950683
references.citation: J Am Chem Soc. 2010 Jul 28;132(29):9982-3
references.pmid: 20593901
references.citation: Angew Chem Int Ed Engl. 2008;47(34):6411-3
references.pmid: 18618531
references.citation: J Am Chem Soc. 2013 Jan 30;135(4):1236-9
references.pmid: 23305171
references.citation: Acta Crystallogr Sect E Struct Rep Online. 2008 Apr 04;64(Pt 5):m621
references.pmid: 21202176
references.citation: J Am Chem Soc. 2007 Sep 12;129(36):11006-7
references.pmid: 17705495
references.citation: Angew Chem Int Ed Engl. 2011 Dec 16;50(51):12236-9
references.pmid: 22038700
references.citation: J Am Chem Soc. 2010 May 5;132(17):5926-7
references.pmid: 20387895
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13197-202
references.pmid: 18768813
references.citation: Chem Commun (Camb). 2011 Oct 7;47(37):10257-9
references.pmid: 21860880
references.citation: J Am Chem Soc. 2008 Oct 29;130(43):14082-3
references.pmid: 18834125
references.citation: Angew Chem Int Ed Engl. 2011 Aug 1;50(32):7438-41
references.pmid: 21726030
references.citation: J Am Chem Soc. 2005 Oct 12;127(40):13754-5
references.pmid: 16201772
references.citation: Chem Commun (Camb). 2011 Nov 7;47(41):11483-5
references.pmid: 21927738
references.citation: Beilstein J Org Chem. 2012;8:1844-8
references.pmid: 23209521
references.citation: Org Lett. 2007 Jun 21;9(13):2529-31
references.pmid: 17536810
references.citation: Angew Chem Int Ed Engl. 2005 Dec 1;44(45):7420-4
references.pmid: 16247822
references.citation: J Am Chem Soc. 2002 Feb 27;124(8):1586-7
references.pmid: 11853427
references.citation: Chem Sci. 2013 Jun 1;4(6):2374-2379
references.pmid: 23691269
references.citation: Angew Chem Int Ed Engl. 2003 Jun 30;42(25):2892-5
references.pmid: 12833351
references.citation: Angew Chem Int Ed Engl. 2006 Jan 9;45(3):489-91
references.pmid: 16323236
references.citation: J Am Chem Soc. 2011 Aug 17;133(32):12406-9
references.pmid: 21766826
references.citation: J Am Chem Soc. 2011 Nov 30;133(47):19090-3
references.pmid: 22059931
references.citation: Angew Chem Int Ed Engl. 2010 Aug 16;49(35):6169-73
references.pmid: 20632344
references.citation: J Am Chem Soc. 2011 Dec 21;133(50):20218-29
references.pmid: 22112165
references.citation: Angew Chem Int Ed Engl. 2008;47(28):5215-9
references.pmid: 18523942
references.citation: J Am Chem Soc. 2012 Jan 25;134(3):1690-8
references.pmid: 22148424
references.citation: Angew Chem Int Ed Engl. 1998 Dec 31;37(24):3387-3388
references.pmid: 29711304
references.citation: Angew Chem Int Ed Engl. 2005 Mar 29;44(14):2112-5
references.pmid: 15729724
references.citation: J Am Chem Soc. 2012 Aug 29;134(34):14118-26
references.pmid: 22830301
references.citation: Science. 2011 Jul 8;333(6039):209-13
references.pmid: 21659567
references.citation: J Med Chem. 1969 Jul;12(4):647-52
references.pmid: 5793157
references.citation: J Am Chem Soc. 2012 Jul 25;134(29):11948-51
references.pmid: 22780303
references.citation: Angew Chem Int Ed Engl. 2011 Mar 1;50(10):2387-91
references.pmid: 21351361
references.citation: Synthesis (Stuttg). 2012 Jun;44(12):1778-1791
references.pmid: 27397938
references.citation: Angew Chem Int Ed Engl. 2013 Jan 21;52(4):1245-7
references.pmid: 23239120
references.citation: J Am Chem Soc. 2009 Oct 21;131(41):14654-5
references.pmid: 19788192
references.citation: Angew Chem Int Ed Engl. 2012 Sep 3;51(36):9141-5
references.pmid: 22893545
references.citation: J Am Chem Soc. 2012 Jan 11;134(1):134-7
references.pmid: 22148883
references.citation: J Am Chem Soc. 2009 Apr 15;131(14):5072-4
references.pmid: 19296661
references.citation: J Am Chem Soc. 2001 Jan 17;123(2):337-8
references.pmid: 11456523
references.citation: Science. 2000 Mar 17;287(5460):1992-5
references.pmid: 10720319
references.citation: J Am Chem Soc. 1977 Sep 14;99(19):6262-7
references.pmid: 893889
references.citation: J Am Chem Soc. 2012 Feb 29;134(8):3683-6
references.pmid: 22313324
references.citation: Angew Chem Int Ed Engl. 2012 Feb 27;51(9):2225-8
references.pmid: 22298436
references.citation: Chemistry. 2012 Apr 10;18(15):4480-4
references.pmid: 22407525
references.citation: J Am Chem Soc. 2011 May 25;133(20):7652-5
references.pmid: 21520961
references.citation: Org Lett. 2001 Aug 9;3(16):2579-81
references.pmid: 11483065
references.citation: J Am Chem Soc. 2008 Nov 12;130(45):14926-7
references.pmid: 18855360
references.citation: J Am Chem Soc. 2008 Jan 9;130(1):52-4
references.pmid: 18067305
references.citation: Science. 2003 Mar 14;299(5613):1691-3
references.pmid: 12637734
references.citation: J Am Chem Soc. 2013 Jan 9;135(1):86-9
references.pmid: 23253097
references.citation: J Am Chem Soc. 2011 May 11;133(18):6964-7
references.pmid: 21491938
references.citation: Angew Chem Int Ed Engl. 2010 Sep 24;49(40):7261-5
references.pmid: 20725922
references.citation: Org Lett. 2011 Dec 2;13(23):6144-7
references.pmid: 22039976
references.citation: Acc Chem Res. 2000 Jun;33(6):336-45
references.pmid: 10891051
references.citation: J Am Chem Soc. 2010 Sep 1;132(34):12068-73
references.pmid: 20690595
references.citation: Chem Soc Rev. 2011 Apr;40(4):1885-98
references.pmid: 21390391
references.citation: Science. 2010 Jan 15;327(5963):315-9
references.pmid: 19965380
references.citation: Chem Sci. 2012;3:887-891
references.pmid: 22690316
references.citation: Science. 2007 May 25;316(5828):1172-5
references.pmid: 17525334
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5723-6
references.pmid: 15069193
references.citation: J Am Chem Soc. 2011 Apr 20;133(15):5767-9
references.pmid: 21443224
references.citation: J Org Chem. 2008 Jan 4;73(1):298-300
references.pmid: 18052297
references.citation: J Org Chem. 1999 Jul 23;64(15):5575-5580
references.pmid: 11674624
references.citation: J Am Chem Soc. 2012 Nov 14;134(45):18570-2
references.pmid: 23116159
references.citation: J Am Chem Soc. 2008 Jan 30;130(4):1156-7
references.pmid: 18183987
references.citation: J Am Chem Soc. 2010 Nov 3;132(43):15116-9
references.pmid: 20929224
references.citation: Acc Chem Res. 2012 Jun 19;45(6):788-802
references.pmid: 22166158
references.citation: J Am Chem Soc. 2007 Mar 28;129(12):3510-1
references.pmid: 17335217
references.citation: J Am Chem Soc. 2010 Aug 4;132(30):10565-9
references.pmid: 20662529
references.citation: Acc Chem Res. 2008 Nov 18;41(11):1534-44
references.pmid: 18681463
references.citation: Org Lett. 2009 Aug 6;11(15):3346-9
references.pmid: 19719183
references.citation: J Am Chem Soc. 2003 Feb 12;125(6):1476-7
references.pmid: 12568597
references.citation: J Am Chem Soc. 2006 May 31;128(21):6790-1
references.pmid: 16719450
references.citation: Acc Chem Res. 2001 Jan;34(1):18-29
references.pmid: 11170353
references.citation: J Org Chem. 2012 Oct 5;77(19):8750-5
references.pmid: 22950832
references.citation: J Am Chem Soc. 2011 Dec 14;133(49):19598-601
references.pmid: 22059375
references.citation: Acc Chem Res. 2008 Nov 18;41(11):1461-73
references.pmid: 18620434
references.citation: Chem Commun (Camb). 2012 Feb 14;48(14):1991-3
references.pmid: 22179114
references.citation: Angew Chem Int Ed Engl. 2002 Jan 4;41(1):164-6
references.pmid: 12491473
references.citation: Org Lett. 2012 Jul 20;14(14):3680-3
references.pmid: 22780880
references.citation: J Am Chem Soc. 1977 Aug 3;99(16):5483-4
references.pmid: 886107
references.citation: J Am Chem Soc. 2010 Feb 17;132(6):1822-4
references.pmid: 20102197
references.citation: J Org Chem. 2012 Oct 5;77(19):8815-20
references.pmid: 22973881
references.citation: Chem Rev. 2007 Jan;107(1):174-238
references.pmid: 17212475
references.citation: Org Lett. 2000 Sep 21;2(19):2927-30
references.pmid: 10986074
references.citation: Angew Chem Int Ed Engl. 2008;47(10):1932-4
references.pmid: 18228236
references.citation: Chem Sci. 2011 Aug 1;2(8):1606-1610
references.pmid: 25580208
references.citation: Science. 2006 Feb 3;311(5761):642-4
references.pmid: 16339409
references.citation: Org Lett. 2011 Jul 1;13(13):3506-9
references.pmid: 21657245
references.citation: J Am Chem Soc. 2005 Sep 28;127(38):13154-5
references.pmid: 16173737
references.citation: J Am Chem Soc. 2008 Feb 27;130(8):2448-9
references.pmid: 18247621
references.citation: Angew Chem Int Ed Engl. 2012 Dec 14;51(51):12842-5
references.pmid: 23161777
references.citation: Acc Chem Res. 2011 Feb 15;44(2):91-100
references.pmid: 21028871
references.citation: Science. 2011 Sep 30;333(6051):1875-8
references.pmid: 21960632
references.citation: Chem Commun (Camb). 2013 Jan 25;49(7):662-4
references.pmid: 23146996
references.citation: Angew Chem Int Ed Engl. 2003 Aug 4;42(30):3512-5
references.pmid: 12900968
references.citation: J Am Chem Soc. 2008 Jul 23;130(29):9254-6
references.pmid: 18582040
references.citation: Angew Chem Int Ed Engl. 2012 Feb 27;51(9):2238-42
references.pmid: 22308174
references.citation: Chemistry. 2013 Jan 21;19(4):1189-93
references.pmid: 23238950
references.citation: J Am Chem Soc. 1969 Dec 1;91(25):7166-9
references.pmid: 27462934
references.citation: Angew Chem Int Ed Engl. 2009;48(33):6097-100
references.pmid: 19591182
references.citation: Chem Rev. 2010 Feb 10;110(2):1147-69
references.pmid: 20078038
references.citation: Angew Chem Int Ed Engl. 2012 Oct 15;51(42):10610-4
references.pmid: 23002028
references.citation: Chem Asian J. 2012 Jun;7(6):1256-60
references.pmid: 22334438
references.citation: Org Lett. 2011 Jun 3;13(11):2830-3
references.pmid: 21534607
references.citation: J Am Chem Soc. 2010 Nov 24;132(46):16377-9
references.pmid: 21033755
references.citation: Adv Synth Catal. 2010 Dec 17;352(18):3223-3229
references.pmid: 21399704
references.citation: Angew Chem Int Ed Engl. 2009;48(48):9139-42
references.pmid: 19859927
references.citation: Angew Chem Int Ed Engl. 2013 Mar 25;52(13):3672-5
references.pmid: 23423740
references.citation: Isr J Chem. 2010 Dec;50(5-6):605-616
references.pmid: 21552359
references.citation: J Am Chem Soc. 2011 May 11;133(18):7222-8
references.pmid: 21488638
references.citation: J Am Chem Soc. 2010 Oct 13;132(40):14006-8
references.pmid: 20831188
references.citation: Chem Commun (Camb). 2012 Oct 28;48(84):10437-9
references.pmid: 22991693
references.citation: Org Lett. 1999 Sep 23;1(6):953-6
references.pmid: 10823227
references.citation: Angew Chem Int Ed Engl. 2000 Oct 2;39(19):3440-3442
references.pmid: 11091382
references.citation: J Am Chem Soc. 2005 May 4;127(17):6178-9
references.pmid: 15853316
references.citation: Chem Commun (Camb). 2013 May 21;49(41):4634-6
references.pmid: 23576109
references.citation: Angew Chem Int Ed Engl. 2009;48(28):5094-115
references.pmid: 19557755
references.citation: Chem Sci. 2010;1(1):13-31
references.pmid: 22384310
references.citation: J Am Chem Soc. 2007 May 2;129(17):5332-3
references.pmid: 17411050
references.citation: Org Lett. 2011 Mar 4;13(5):1214-7
references.pmid: 21302903
references.citation: Angew Chem Int Ed Engl. 2002 Feb 1;41(3):472-5
references.pmid: 12491382
references.citation: Angew Chem Int Ed Engl. 2011 Sep 19;50(39):9081-4
references.pmid: 21748831
references.citation: Org Lett. 2007 Mar 29;9(7):1407-9
references.pmid: 17346060
references.citation: Acc Chem Res. 2012 Jun 19;45(6):936-46
references.pmid: 22554114
references.citation: J Am Chem Soc. 2007 Dec 19;129(50):15434-5
references.pmid: 18027947
references.citation: J Am Chem Soc. 2009 May 6;131(17):6076-7
references.pmid: 19364100
references.citation: Chemistry. 2010 Jul 19;16(27):8155-61
references.pmid: 20533457
references.citation: Angew Chem Int Ed Engl. 2008;47(14):2556-88
references.pmid: 18348325
references.citation: J Am Chem Soc. 2010 Sep 1;132(34):11887-9
references.pmid: 20690626
references.citation: J Am Chem Soc. 2010 Oct 6;132(39):13666-8
references.pmid: 20822182
references.citation: Angew Chem Int Ed Engl. 2006 Aug 4;45(31):5194-7
references.pmid: 16823781
references.citation: Chem Soc Rev. 2009 Nov;38(11):3010-21
references.pmid: 19847337
references.citation: Angew Chem Int Ed Engl. 2002 Nov 15;41(22):4176-211
references.pmid: 12434342
references.citation: J Am Chem Soc. 2010 Mar 24;132(11):3680-1
references.pmid: 20187642
references.citation: J Am Chem Soc. 2010 Dec 8;132(48):17092-5
references.pmid: 21077625
references.citation: J Am Chem Soc. 2008 Dec 10;130(49):16474-5
references.pmid: 19554684
references.citation: Chem Rev. 2008 Aug;108(8):3054-131
references.pmid: 18698737
references.citation: Angew Chem Int Ed Engl. 2002 Apr 15;41(8):1290-309
references.pmid: 19750753
references.citation: J Org Chem. 1999 Sep 3;64(18):6750-6755
references.pmid: 11674682
references.citation: J Am Chem Soc. 2009 Mar 18;131(10):3452-3
references.pmid: 19275254
references.citation: J Am Chem Soc. 2009 Oct 7;131(39):13888-9
references.pmid: 19746974
references.citation: Org Biomol Chem. 2006 Nov 21;4(22):4041-7
references.pmid: 17312954
references.citation: J Am Chem Soc. 2010 Sep 8;132(35):12203-5
references.pmid: 20715820
references.citation: J Am Chem Soc. 2001 Mar 21;123(11):2685-6
references.pmid: 11456947
references.citation: Org Lett. 2009 Dec 17;11(24):5626-8
references.pmid: 19905004
references.citation: Chem Soc Rev. 2009 Nov;38(11):3242-72
references.pmid: 19847354
references.citation: J Am Chem Soc. 2001 Aug 22;123(33):8149-50
references.pmid: 11506585
references.citation: Chem Soc Rev. 2011 Apr;40(4):1976-91
references.pmid: 21298176
references.citation: J Am Chem Soc. 2010 Oct 13;132(40):14137-51
references.pmid: 20853838
references.citation: Nature. 2012 Feb 29;483(7387):70-3
references.pmid: 22382981
references.citation: J Am Chem Soc. 2011 Jun 22;133(24):9250-3
references.pmid: 21609019
references.citation: J Am Chem Soc. 2009 Jul 29;131(29):9886-7
references.pmid: 19580277
references.citation: J Am Chem Soc. 2010 Apr 28;132(16):5916-21
references.pmid: 20359184
references.citation: Angew Chem Int Ed Engl. 2002 Jun 17;41(12):2008-22
references.pmid: 19746595
references.citation: J Am Chem Soc. 2003 Aug 13;125(32):9578-9
references.pmid: 12904010
references.citation: Angew Chem Int Ed Engl. 2010 Feb 8;49(7):1275-7
references.pmid: 20082399
references.citation: J Am Chem Soc. 2005 Mar 23;127(11):3648-9
references.pmid: 15771470
references.citation: Org Lett. 2005 Jul 7;7(14):3123-5
references.pmid: 15987221
references.citation: Chem Soc Rev. 2010 Aug;39(8):3305-16
references.pmid: 20593074
references.citation: Angew Chem Int Ed Engl. 2010 Feb 1;49(6):1115-8
references.pmid: 20029870
references.citation: Chemistry. 2011 Feb 7;17(6):1783-8
references.pmid: 21274927
references.citation: Angew Chem Int Ed Engl. 2008;47(26):4882-6
references.pmid: 18484582
references.citation: Org Lett. 2013 Apr 5;15(7):1528-31
references.pmid: 23496033