Substitution and Analysis of Additional Heteroatoms in 1,2λ5-Azaphosphinines by J. Nolan McNeill A dissertation accepted and approved in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Dissertation Committee: Ramesh Jasti, Chair Michael Haley, Advisor Darren Johnson, Co-Advisor Michael Pluth, Core Member Marian Hettiaratchi, Institutional Representative University of Oregon Summer 2024 2 © 2024 J. Nolan McNeill 3 DISSERTATION ABSTRACT J. Nolan McNeill Doctor of Philosophy in Chemistry Title: Substitution and Analysis of Additional Heteroatoms in 1,2λ5-Azaphosphinines Azaphosphinines are, simply put, six-membered heterocycles containing one nitrogen and one phosphorus atom. While garnering more attention in the last couple decades, they are still decidedly understudied. This lack of research is primarily due to the difficult and often intense reaction conditions required to synthesize them. This is especially true for the azaphosphinine moiety’s early iterations. In the Haley and Johnson groups we have found a facile synthetic pathway that allows us to circumvent these issues. In this dissertation I will discuss not only a history of the azaphosphinine functional group but also the results of my independent research. The main body of my Ph.D. work is concerned with the substitution of additional heteroatoms into our thoroughly studied azaphosphinines. These substitutions result in dramatic changes to both the supramolecular and photophysical properties of the heterocycles. While most of the work I will discuss is related to different orientations of pyrido-fused azaphosphinines, I also include a study on the thionation of the ubiquitous phosphoryl group. Chapter I is a holistic review of azaphosphinines. I begin by discussing the nomenclature and unusual electronic properties of these heterocycles before detailing a chronological progression of the literature concerning the three isomers and both valencies of the azaphosphinine functional group. In Chapter II I describe the synthesis and unexpected tautomerization effects observed in pyrido[2,3-e]-1,2λ5- azaphosphinines. Chapter III continues to explore the electronic effects of a pyrido- fusion, but in this case, we are now considering the internal charge transfer present in 4 pyrido[3,4-e]-1,2λ5-azaphosphinines. And lastly Chapter IV examines the thionating effect of Lawesson’s Reagent on our heterocycles and the dramatic impacts this transformation has on their photophysical properties. This dissertation includes previously published co-authored material. 5 CURRICULUM VITAE NAME OF AUTHOR: J. Nolan McNeill GRADUATE AND UNDERGRADUATE SCHOOLS ATTENDED: University of Oregon, Eugene University of Maryland, College Park DEGREES AWARDED: Doctor of Philosophy, Chemistry, 2024, University of Oregon Master of Science, Chemistry, 2021, University of Oregon Bachelor of Science, Chemistry, 2019, University of Maryland AREAS OF SPECIAL INTEREST: Organic Chemistry Heterocyclic Small Molecules Physical Organic Chemistry Mesodimerization and Supramolecular Assembly PROFESSIONAL EXPERIENCE: Graduate Employee, University of Oregon, 2019–2024 GRANTS, AWARDS, AND HONORS: Best Lecture, Exploration of Tautomerization in Pyridine-Bearing PN- Heterocycles, Organic pi-Electron Molecules and Materials Meetings, 2023 Semester Academic Honors, University of Maryland, 2018 Semester Academic Honors, University of Maryland, 2017 PUBLICATIONS: Rizzi, A.; Murkli, S.; McNeill, J. N.; Yao, W.; Sullivan, M.; Gilson, M. K.; Chiu, M. W.; Isaacs, L.; Gibb, B. C.; Mobley, D. L.; Chodera, J. D. Overview of the SAMPL6 host-guest binding affinity prediction challenge. J. Comput. Aided. Mol. Des. 2018, 32, 937–963. Murkli, S.; McNeill, J. N.; Isaacs, L. Cucurbit[8]uril•guest complexes: blinded dataset for the SAMPL6 challenge. Supramol. Chem. 2018, 31, 150–158. 6 Bard, J. P.; McNeill, J. N.; Zakharov, L. N.; Johnson, D. W.; Haley, M. M. Thionation of the 2-λ5‐Phosphaquinolin‐2‐one Scaffold with Lawesson’s Reagent. Isr. J. Chem. 2021, 61, 217–221. McNeill, J. N.; Karas, L. J.; Bard, J. P.; Fabrizio, K.; Zakharov, L. N.; MacMillan, S. N.; Brozek, C. K.; Wu, J. I.; Johnson, D. W.; Haley, M. M. Controlling Tautomerization in Pyridine-Fused Phosphorus-Nitrogen Heterocycles. Chem. Eur. J. 2022, 28, e202200472. McNeill, J. N.; Melanie, A. K.; Karas, L. J.; Zakharov, L. N.; Wu, J. I.; Johnson, D. W.; Haley, M. M. Impact of Internal Charge Transfer on the Photophysical Properties of Pyridine-Fused Phosphorus-Nitrogen Heterocycles. Chem. Eur. J. 2023, 29, e202203918. Bard, J. P.; Bolton, S. G.; Howard, H. J.; McNeill, J. N.; de Faria, T. P.; Zakharov, L. N.; Johnson, D. W.; Pluth, M. D.; Haley, M. M. 2-λ5- Phosphaquinolin-2-ones as Non-cytotoxic, Targetable, and pH-Stable Fluorophores. J. Org. Chem. 2023, 21, 15516–15522. McNeill, J. N.; Bard, J. P.; Johnson, D. W.; Haley, M. M. Azaphosphinines and their derivatives. Chem. Soc. Rev., 2023, 52, 8599–8634. 7 ACKNOWLEDGMENTS First and foremost, I need to acknowledge my partner, Rachel. We have been together since before this whole crazy experience. When it was decided that I was going to move from Maryland to Oregon for a 5-year degree, she packed up and came with me without hesitation. We drove across the country together with our two cats (Boots and Smallcat) and lived in a lofted shoebox. We weathered the challenges of living together for the first time while 3000 miles away from any family, a global pandemic, and countless other obstacles. But through all that she supported this dream of mine and I could not have done this without her. I would like to express my gratitude to Profs. Michael Haley and Darren Johnson. They have helped to stoke my scientific curiosity and blossom as a chemist while being infinitely patient with me. A Ph.D. program is a daunting task and cannot be finished without advisors supporting you every step of the way. Organized and regular group meetings, opportunities to give lectures, and networking with colleagues are just some of the ways that Mike and Darren have facilitated my growth as a scientist. For this I will always be grateful. My research on the azaphosphinine project was funded by the National Science Foundation (CHE-1607214 & 2107425). When I was an undergraduate, I was told that you could have two of three things in graduate school: engaging research, a good lab, or a good boss. I am happy to say that this is not the case. While I did enjoy my research and both of my advisors, the best part of this experience was certainly the people I was here with. During the first year of the program things could get chaotic with deadlines, cumulative exams, and teaching all swirling about. But finding a group of friends among my classmates grounded and made it all bearable. 8 In the later years of the program, the Haley Lab became my greatest asset. Countless hours of engaging and friendly discussion about chemistry, life, and foie gras helped to enrich my time here. The mentors I had in the lab (Dr. Josh Barker, Dr. Gabrielle Warren, and especially Prof. Jeremy Bard) kept me on track with constructive criticism and reminders about deadlines. Meanwhile, my colleagues in the lab (Prof. Joe Workman, Efrain Vidal, Bella Demachkie, Michael Miller, Nathan Boone, and Megan Rammer) provided an environment I was excited to work in every day. Of course, there are countless other chemists who have conspired to make this dissertation possible. From my high school chemistry teacher Mrs. Balimtas who first encouraged my interests, to my undergraduate mentor Dr. Steven Murkli and advisor Prof. Lyle Isaacs. And finally, I need to thank my family. My parents Chris and Patti my brother Henry, my grandparents Mimi and Pop, and everyone else too. They supported and encouraged me every step of the way from high school to here. I really cannot express how grateful I am to them, so hopefully this dissertation will stand in place of even sappier language. 9 Dedicated to my family, without whom none of this would have been possible. 10 TABLE OF CONTENTS Chapter Page I. AZAPHOSPHININES AND THEIR DERIVATIVES ........................................... 21 1.1 Introduction ............................................................................................................ 21 1.2 Azaphosphinine origins ...................................................................................28 1.3 1,2-Azaphosphinines ........................................................................................31 1.3.1 Reactivity with Alkynes .........................................................................31 1.3.1.1 Pericyclic / Cycloadditions .....................................................31 1.3.1.2 Transition Metal-Catalyzed C–H Activation ..........................36 1.3.2 Intramolecular Cyclization Reactions .....................................................51 1.4 1,3-Azaphosphinines .......................................................................................88 1.4.1 Heteroatom Exchange ............................................................................88 1.4.2 Pericyclic / Cycloadditions ....................................................................89 1.4.3 Intramolecular Cyclization Reactions ....................................................96 1.5 1,4-Azaphosphinines .......................................................................................98 1.6 Comparing Electronic Properties of the Azaphosphinine Isomers ..................103 1.7 Conclusions ......................................................................................................110 II. CONTROLLING TAUTOMERIZATION IN PYRIDINE-FUSED PHOSPHORUS-NITROGEN HETEROCYCLES ................................................115 2.1 Introduction ......................................................................................................115 2.2 Results and Discussion ....................................................................................118 2.2.1 Synthesis of PN-pyridines.......................................................................118 2.2.2 X-ray Crystallography ...........................................................................120 2.2.3 Heterocycle Alkylation ..........................................................................121 2.2.4 NMR Shift Comparison .........................................................................123 11 2.2.5 UV-Vis Spectroscopy Comparison ........................................................125 2.2.6 Solid-state UV-Vis Comparison ............................................................126 2.2.7 Calculations ............................................................................................127 2.3 Conclusion ......................................................................................................128 III. IMPACT OF INTERNAL CHARGE TRANSFER ON THE PHOTOPHYSICAL PROPERTIES OF PYRIDINE-FUSED PHOSPHORUS- NITROGEN HETEROCYCLES ...........................................................................130 3.1 Introduction ......................................................................................................130 3.2 Results and Discussion ....................................................................................133 3.2.1 Synthesis of 3-pyridine PNs....................................................................135 3.2.2 Absorption and Emission Data ...............................................................142 3.2.3 X-ray Crystallography ...........................................................................146 3.3 Conclusions ......................................................................................................146 IV. THIONATION OF THE 2-λ5-PHOSPHAQUINOLIN-2-ONE SCAFFOLD WITH LAWESSON’S REAGENT .......................................................................148 4.1 Introduction ......................................................................................................148 4.2 Results and Discussion ...................................................................................150 4.3 Conclusions ......................................................................................................156 APPENDICES .............................................................................................................157 A. SUPPLEMENTARY INFORMATION FOR CHAPTER II ............................157 B. SUPPLEMENTARY INFORMATION FOR CHAPTER III ...........................216 C. SUPPLEMENTARY INFORMATION FOR CHAPTER IV ..........................271 REFERENCES CITED ................................................................................................303 12 LIST OF FIGURES Figure Page 1. Figure 1.1. Phosphorus nomenclature commonly referred to in Chapter I. .......... 22 2. Figure 1.2 Examples of (top) ionic nature in hexachlorophosphazene and (bottom) ylidic nature in PV phosphinine ...............................................................24 3. Figure 1.3 Examples of (top) 1,2- (1a), 1,3- (1b) and 1,4-azaphosphinines (1c) and (bottom) benzo[c]- (2a) and benzo[b]azaphosphinine (2b) isomers. ......27 4. Figure 1.4 Examples of nomenclature rules applied to more complex azaphosphinine derivatives such as 3 and 4. ..........................................................27 5. Figure 1.5 Representative meso-dimer of 98g. Blue dashed lines represent hydrogen bonds between phosphonamidate moieties. Nonparticipating hydrogen atoms omitted for clarity. .......................................................................76 6. Figure 1.6 Benzo[e]-1,2-dihydro-1,2λ5-azaphosphinine 2-oxide cellular imaging dyes. ......................................................................................................... 84 7. Figure 2.1 Phosphaquinolinone and analogous heterocycles (top), as well as previously derivatized PN-motif 1 and new pyridine-PN scaffold 2 (bottom) .. ...116 8. Figure 2.2 (a) The two tautomeric forms of heterocycle 2a; colors represent aromatic (blue) core vs nonaromatic (pink) core. (b) Hydrogen-bonding nature of the aromatic (left) and quinoidal (right) tautomers. ........................................ 117 9. Figure 2.3 X-ray crystal structures (173 K; ellipsoids at 30% probability) and corresponding ChemDraw representations of the pyridine-fused PN-heterocycles. Heterocycles 2a’ and 2c’ display quinoidal tautomerization in the solid state whereas 2e remains as the aromatic form. N1-C4 and N2-C4 bond lengths (Å) are shown inside the rings ........................................................ 119 10. Figure 2.4 X-ray crystal structure (100 K; ellipsoids at 30% probability) of 6a, displaying the pyridyl-nitrogen N-alkylation. N1-C4 and N2-C4 bond lengths (Å) are shown inside the rings and are the average of the values from two independent molecules ........................................................................ 122 11. Figure 2.5 Comparison of heterocycle absorbance (solid line) and emission (dashed line) data of pre- (2) and post-alkylation (6) of PN-heterocycles. ......... 125 12. Figure 2.6 Computed relative free energies (∆G, kcal mol–1) and NICS(0) (ppm) values for 2a vs. 2a' (top) and their protonated analogues (bottom) ........ 127 13. Figure 3.1 Coumarin, carbostyril, and phosphaquinolinone scaffolds ............... 131 14. Figure 3.2. a) 2-Pyridine PN (1) and its key tautomeric form 1'.[12] b) 13 3-Pyridine PN (2) and the highly-polarized quinoidal resonance form 2'. c) Comparison between imidate (I) and amidate (A) forms of the PN-heterocycle scaffold ................................................................................................................. 133 15. Figure 3.3 Electronic absorption spectra of imidates 6 (top) and amidates 2 (bottom) in CHCl3 (~10–5 M) at room temperature .............................................. 136 16. Figure 3.4 Absorption (solid) and emission (dashed) spectra of a solvatochromic study on 6d (top) and 2d (bottom) taken at room temperature .. 138 17. Figure 3.5 Emission spectra of 6 (top) and 2 (bottom) in CHCl3 at room temperature. ......................................................................................................... 140 18. Figure 3.6 Example of para-substituted stilbazole (left) and the motif superimposed on imidate PN 6 and amidate PN 2. .............................................. 140 19. Figure 3.7 Crystal structures of imidate 6d (top) and amidate 2d (bottom) with labeled atoms; ellipsoids drawn at the 30% probability level ..................... 144 20. Figure 3.8 Computed molecular electrostatic potential maps for 2a-2d at B3LYP-D3/6-311+G(d,p); the pyridine N atom is on the left ............................. 145 21. Figure 4.1 Lawesson’s Reagent and a sampling of commonly prepared thiocarbonyl compounds. ..................................................................................... 149 22. Figure 4.2 ORTEP drawing of the thioheterocycle 2e mesodimer; thermal ellipsoids drawn at 30% probability level ............................................................ 152 23. Figure 4.3 Stacked absorption and emission spectra of heterocycles 2 .............. 154 14 LIST OF TABLES Table Page 1. Table 1.1 Experimental details for reactions of rac-36 with various internal alkynes. Ar = 3,5-(CF3)2C6H3 ................................................................................ 41 2. Table 1.2 Emission data for measured heterocycles 49. ...................................... 50 3. Table 1.3 Substrate scope of cyclization of 74 to afford 75. ................................ 57 4. Table 1.4 Cyclization and subsequent allylation of give azaphosphinines 77 ..... 58 5. Table 1.5 Phosphite cyclization of ortho-ethynylanilines .................................... 68 6. Table 1.6 Fluorescence properties of selected 97, 98, and deprotonated 98 in CHCl3. .................................................................................................................... 69 7. Table 1.7 Photophysical properties of selected 100. ............................................71 8. Table 1.8 Photophysical properties of selected heterocycles 101–106 ...............74 9. Table 1.9 VC 1H and 31P NMR–measured dimerization constant for select azaphosphinines. ....................................................................................................76 10. Table 1.10 Photophysical properties of selected 109. ..........................................78 11. Table 1.11 Photophysical properties of selected 114 and 115. ............................ 80 12. Table 1.12 Association constants[a] (Ka, M–1) of receptors 117 with various anions in 10 vol% DMSO-d6/CDCl3 at room temperature .................................... 82 13. Table 1.13 Computed NICS values of relevant heterocycles computed by Le Floch (left) and Elguero (right) ............................................................................ 111 14. Table 1.14 Comparison of selected 1H and 31P NMR chemical shifts across selected azaphosphinine systems ......................................................................... 113 15. Table 2.1 Changes in the 1H NMR chemical shifts (ppm) before and after the alkylation reaction to give 6a-d ........................................................................... 123 16. Table 2.2 Photophysical properties of heterocycles 2a, 2e, 6a, and 6d .............. 126 15 17. Table 3.1 Experimental and computational photophysical properties of amidates 2 and imidates 6. ...................................................................................137 18. Table 3.2 Solvatochromic photophysical measurements of 6d and 2d. .............. 139 19. Table 3.3 Selected bond lengths (Å) and dihedral angle (°) of 2a-d, 2d', and 6d ......................................................................................................................... 141 20. Table 4.1 Photophysical properties of heterocycles 2. ........................................ 153 16 LIST OF SCHEMES Scheme Page 1. Scheme 1.1 Schenk and Michaelis’ first reported synthesis of a PN-heterocycle scaffold, dibenzo[b,e]1,4-dihydro-1,4λ5-azaphosphinine 4-oxide ...................................................................................................................28 2. Scheme 1.2 Synthesis of Dewar and Kubba’s early dibenzo[c,e]-1,2-dihydro- 1,2λ3-azaphosphinine 9 and comparison to the previously prepared boron- containing species 7 ...............................................................................................29 3. Scheme 1.3 Oxidation products of Dewar and Kubba’s azaphosphinine 9 with aromatic resonance structures ................................................................................30 4. Scheme 1.4 Campbell and Way’s synthesis of early azaphosphinines 9 and oxidation to 11 .......................................................................................................31 5. Scheme 1.5 Synthesis of 1,2-azaphosphinine 14 using the Staudinger reaction and subsequent Diels-Alder cycloaddition ............................................................32 6. Scheme 1.6 Preparation of heterocycles 16 using phosphazene 17 and formation of azaphosphininium salts 18 ................................................................33 7. Scheme 1.7 Synthesis of 2,2-diphenyl-1,2λ5-azaphosphinin-6-ones 20 through cycloaddition with DMAD ....................................................................................33 8. Scheme 1.8 (top) Synthesis of 1,2-azaphosphinines 24 through the formation and cycloaddition of a 1,3,2-diazaphosphinine. (bottom) Substrate scope of the heterocycles prepared in this way ..........................................................................34 9. Scheme 1.9 Preparation of tripodal 1,2λ3-azaphosphinine heterocycles (top) 27 and (bottom) 28 .................................................................................................36 10. Scheme 1.10 Aryl phosphonamide directed C–H activation to furnish 30 ..........37 11. Scheme 1.11 Formation of [c]-fused 1,2-dihydro-1,2λ5-azaphosphinine-2-oxide 32 ......................................................38 12. Scheme 1.12 Proposed mechanism for chiral C–H activation heteroannulation of achiral phosphinamide .......................................................................................39 13. Scheme 1.13 Chiral C–H activation heteroannulation to afford 36. For every entry, Ar = 3,5-(CF3)2C6H3 ....................................................................................40 14. Scheme 1.14 Enantiospecific reduction to chiral azaphosphinine 36p' ...............41 15. Scheme 1.15 Reactivity of bis-aryl functionalized chiral phosphinamide. Ar = 3,5-(CF3)2C6H3 ..............................................................................................43 17 16. Scheme 1.16 Asymmetric reductive aldol condensation of enone 40 and benzaldehyde using chiral benzo[c]-1,2-dihydro-1,2λ3-azaphosphinine additives as Lewis base (LB). Ar = 3,5-(CF3)2C6H3 ..............................................44 17. Scheme 1.17 Enantioselective reduction of 37a and its use as a chiral ligand in an asymmetric hydrogenation reaction. Ar = 3,5-(CF3)2C6H3 ...........................44 18. Scheme 1.18 Chiral C–H activation and heteroannulation using CoIII to afford 43 .................................................................................................................46 19. Scheme 1.19 Chiral resolution of phosphinamide 44 under standard reaction conditions. Ar = 8-quinolinyl .................................................................................46 20. Scheme 1.20 Heteroannulation with allene coupling partners. Ar = 8-quinolinyl ............................................................................................................47 21. Scheme 1.21 Ni0-mediated heteroannulation to afford azaphosphinines 49 and 51 .....................................................................................................................49 22. Scheme 1.22 Asymmetric [4 + 2] heteroannulation starting from chiral phosphanamines. Standard conditions of phosphanamine (1 equiv.), alkyne (2 equiv.), Ni(COD)2 (10 mol%), LiCl (1 equiv.), Cs2CO3 (3 equiv.), DMF, 130 °C ....................................................................................................................50 23. Scheme 1.23 Synthesis of indole-fused azaphosphinine 2-oxide 56 ....................51 24. Scheme 1.24 Proposed pathway to 1,2-dihydro-1,2λ3-azaphosphinines 57. No yield reported (n.y.r.) .......................................................................................52 25. Scheme 1.25 Oxidation and hydrolysis of heterocycles 57m and 57n ................53 26. Scheme 1.26 H2O2 and S8 oxidations of azaphosphinines 57 ..............................53 27. Scheme 1.27 Thermolytic synthesis of 1,2λ3-azaphosphinine 61 and its dihydro products 62-64 from attack of various nucleophiles ................................54 28. Scheme 1.28 Synthesis of benzo[e]-1,4-dihydro-1,2λ5-azaphosphinines 66 .......55 29. Scheme 1.29 Synthesis of 1,2λ3-azaphosphinine 69 and subsequent hydrolysis/oxidation ...............................................................................................55 30. Scheme 1.30 Phosphete and isothiocyanate cyclization into azaphosphinine 73............................................................................................................................ 56 31. Scheme 1.31 Palladium catalyzed C–H activated heteroannulation to furnish chiral azaphosphinines 79. Conditions A: Pd(OAc)2 (5 mol%), L2 (10 mol%), K3PO4 (1.5 equiv.), PivOH (30 mol%), toluene, 80 °C. Conditions B: Pd(dba)2. (8 mol%), L3 (10 mol%), Cs2CO3 (1.5 equiv.), PivOH, (40 mol%), hexanes, 60 °C. [a]Reaction performed at room temperature ................................................60 18 32. Scheme 1.32 P–N bond cleavage to furnish chiral phosphane oxides 80 ............62 33. Scheme 1.33 Transition-metal free heteroannulation reaction to give azaphosphinines 81 ................................................................................................63 34. Scheme 1.34 Proposed mechanism for radical C–H activation heteroannulation and subsequent iodination ..........................................................64 35. Scheme 1.35 Cleavage of P–N bond and racemization at different temperatures ...........................................................................................................65 36. Scheme 1.36 CAN-mediated heteroannulation to afford 88. [a]10 equiv. of water added. [b]5 equiv. of CAN added and conducted at 60 °C. [c]Run for 2 h ....66 37. Scheme 1.37 Post-synthetic modification of 88a to furnish chiral acyclic species 90 and 91, and PIII species 93 ....................................................................67 38. Scheme 1.38 Asymmetric catalyst 88a used in condensation reaction ................68 39. Scheme 1.39 Difunctionalized azaphosphinines 100 ...........................................70 40. Scheme 1.40 Scope of arene-core extended azaphosphinines ..............................72 41. Scheme 1.41 P-phenyl substitution to afford azaphosphinines 105 .....................72 42. Scheme 1.42 P-phenyl substituted PN-fused pyrenes 106 ...................................73 43. Scheme 1.43 Lawesson’s reagent-mediated thionation ........................................77 44. Scheme 1.44 Pyrido-fused azaphosphinines 111 and their trapped tautomeric forms 112 ...............................................................................................................79 45. Scheme 1.45 Pyrido[3,4-e]-fused azaphosphinines ..............................................80 46. Scheme 1.46 Synthesis of azaphosphinine-based anion receptors 117 ................81 47. Scheme 1.47 Synthesis of azaphosphinine 125 ....................................................85 48. Scheme 1.48 Pd-catalyzed heteroannulation of achiral phosphanamines 126 to furnish dibenzo[c,e]-1,2λ5-azaphosphinines 127 ...............................................86 49. Scheme 1.49 Retention of stereogenic P-center in heteroannulation of phosphanamine 128 ...............................................................................................87 50. Scheme 1.50 Conversion of azapyrilium tetrafluoroborate salts to 1,3λ3- azaphosphinines 131 ..............................................................................................89 51. Scheme 1.51 Probing the reactivity of azaphosphinine 131a ...............................89 52. Scheme 1.52 Diels-Alder route to 1,3λ3-azaphosphinines 136 ............................90 19 53. Scheme 1.53 Complex synthetic pathway leading to either 1,3λ3- or 1,4λ3- azaphosphinines .....................................................................................................91 54. Scheme 1.54 Diels-Alder mediated synthesis of amine-bearing 1,3λ3- azaphosphinine 145 ................................................................................................91 55. Scheme 1.55 Consecutive cycloaddition / cycloreversion pathway to furnish heavily substituted 1,3λ3-azaphosphinines 148. No yields reported for 148 .........92 56. Scheme 1.56 Post-synthetic modification of 148 to either phosphinine 149 (left) or azaphosphabarrelene 150 (right) ..............................................................92 57. Scheme 1.57 Generation of heavily substituted 153 via zwitterionic intermediate ............................................................................................................93 58. Scheme 1.58 Oxidation of 131 to PV heterocycle 154 (left) or conversion to polycyclic 155 (right) .............................................................................................93 59. Scheme 1.59 Conversion of triazine 149 to mixture of corresponding 1,3λ3- and 1,4λ3-azaphosphinines .....................................................................................95 60. Scheme 1.60 Use of 2-pyridyl directing group to dramatically favor 1,4λ3 product 158 ............................................................................................................95 61. Scheme 1.61 Reversed trend in selectivity for azaphosphinine isomer based on substitution pattern of starting triazine 156 ......................................................96 62. Scheme 1.62 Use of 1,2,3-triazine 159 to give exclusively 1,3λ3 product 160 ....96 63. Scheme 1.63 Synthetic pathway to π-extended 1,3λ3 azaphosphinine 167 and corresponding 1,3λ5 azaphosphinine sulfide 168 ...................................................97 64. Scheme 1.64 Synthesis of dimethoxy 169 (left) and consecutive Diels-Alder / oxidation to give product 171 (right) .....................................................................98 65. Scheme 1.65 Synthesis of 1,4-dihydro-1,4λ5-azaphosphinine 4-oxide 174 .........99 66. Scheme 1.66 Synthesis of 2,6-diphenyl-1,4λ3-azaphosphinine 178 .....................100 67. Scheme 1.67 Dihydro-products resulting from attack of various nucleophiles ...100 68. Scheme 1.68 Synthesis of 2,4,4,6-tetraphenyl-1,4λ5-azaphosphinine 184 ...........101 69. Scheme 1.69 Ozonolysis-based approach to 1,4-dihydro-1,4λ5-azaphosphinine 4-oxides 174a and 187 ...........................................................................................102 70. Scheme 1.70 Additional examples of ring-fused 1,4-dihydro-1,4λ5-azaphosphinine 4-oxides ..........................................................102 20 71. Scheme 1.71 Synthesis of azaphosphinines 194 ..................................................103 72. Scheme 1.72 One-pot cyclization to form 1,4-dihydro-1,4λ5-azaphosphinines 196..........................................................................................................................104 73. Scheme 1.73 Synthesis of secondary 1,4λ5-azaphosphinine 4-oxide 196' ...........104 74. Scheme 1.74 Cycloaddition/intramolecular cyclization route to 2-oxo-1,4λ5- azaphosphinines 201. R3 is either Me or Et ...........................................................105 75. Scheme 1.75 Proposed general mechanism to generate tetrahydro species 204 ..106 76. Scheme 1.76 Phosphazene 205 heteroannulation with benzyne to give azaphosphinines 206 ..............................................................................................106 77. Scheme 1.77 Phosphete route to benzo[b]-1,4λ5-azaphosphinine 207 .................107 78. Scheme 1.78 Pd-catalyzed heteroannulation to give 1,2,4,6-tetraphenyl-1,4- dihydro-1,4λ3-azaphosphinine 209 ........................................................................108 79. Scheme 1.79 Intramolecular cyclization of o-diarylphosphinoaryl isocyanide ylides ......................................................................................................................109 80. Scheme 1.80 Cyclization of isocyanide 213a into dicationic 216 ........................110 81. Scheme 2.1 Synthetic pathway for the preparation of pyridine-containing PN heterocycles (a) 2a-d and (b) 2e ............................................................................119 82. Scheme 2.2 Synthesis of alkylated pyridine-PNs 6a-d .........................................122 83. Scheme 3.1. Synthesis of 3-Pyridine PNs .............................................................134 84. Scheme 3.2 Synthesis of N-methyl pyridinium PN heterocycle 2d' .....................144 85. Scheme 4.1 Conversion of oxo-heterocycles 1 to thio-heterocycles 2 with Lawesson’s Reagent (LR) ......................................................................................150 21 CHAPTER I AZAPHOSPHININES AND THEIR DERIVATIVES This chapter includes previously published and co-authored materials from McNeill, J. N.; Bard, J. P.; Johnson, D. W.; Haley, M. M. Azaphosphinines and their derivatives. Chem. Soc. Rev. 2023, 52, 8599–8634. This manuscript was written by J. Nolan McNeill with assistance from Dr. Jeremy P. Bard, Prof. Darren W. Johnson, and Prof. Michael M. Haley. 1.1 Introduction Historically, heterocycle chemistry is inseparable from organic chemistry. The first isolated heterocyclic species, alloxan, discovered by Gaspare Brugnatelli in 1818,1 predates the Kekulé model of benzene by roughly 50 years. These humble beginnings of a small nitrogenous poison isolated from uric acid kicked off an intense interest that has yet to subside. In the last 200 years, heterocycles have spread and flourished into every facet of chemistry—organic, medicinal, metal coordination, and otherwise. Much of the heavy lifting done in the field of heterocycles is done by pnictogen-based species. Simple five- and six-membered nitrogen-containing ring systems such as pyrrole, piperidine, and pyridine commonly act as solvents and/or bases in synthetic processes as well as fundamental building blocks to all manner of pharmaceuticals, dyes, ligands, and pesticides.2–12 In comparison to their 2nd row counterparts, phosphorus heterocycles are considerably less common in the literature. However, this is not to say that these molecules do not find important uses in the modern world. A few specific examples include the use of phospholes in optoelectronic applications and phosphinines in catalysis and photophysical applications.13–21 Nitrogen and phosphorus together serve 22 as an interesting pair in heterocycles as well. In particular, the nature of the PV=N bond has been a hotly researched phenomenon. This review will reference phosphorus-specific nomenclature extensively. Many of the functional groups have alternative common names that have risen and fallen out of popularity in the last few decades or even centuries. For the sake of consistency, the nomenclature applied in the review will adhere to the following guide (Figure 1.1). This is not an exhaustive list of phosphorus nomenclature but rather establishes the naming for the functional groups referred to frequently in this review. More elaborate descriptions of azaphosphinine nomenclature are found below (Figures 1.3 and 1.4). It should be noted that the term phosphine is generally used interchangeably with phosphane in the current literature; however, over a decade ago IUPAC decided that phosphane is the preferential term for the PR3 functional group. For the sake of standardizing phosphorus nomenclature in this review, phosphane naming is used exclusively. This also extends to the pentavalent P(O)R3, dubbed phosphane oxides. Figure 1.1 Phosphorus nomenclature commonly referred to in this chapter. An intriguing example of what makes the PV=N bond so unique are cyclophosphazenes.22–24 They are cyclic species with the chemical formula (X2PN)n (Figure 1.2, top), that at first glance, present the qualities one would expect in an aromatic ring. Prepared by Liebig et al. in 1834, hexachlorophosphazene is one of the P R R R P OR RO OR P OR RO OR O P R R NR2 O P NR2 R NR2 O P OR R NR2 O X XX NR P phosphane phosphite phosphazene phosphate phosphinamide phosphonamide phosphonamidate P NR R R phosphanamine 23 best examples, with the ring being totally planar, containing 6π electrons, and all ring bond-lengths being uniform.25 For many years following its discovery, it was assumed that these qualities resulted from true delocalization of π-electrons from the nitrogen atoms into the participating 3d orbitals of the adjacent phosphorus atoms. However, it has become well understood in recent decades that a pentavalent phosphorus species has little-to-no participation of the 3d orbitals in its bonding. Instead, the nature of the PV=N bond can be better described as highly polarized, bordering on ionic. The electronegativity difference in nitrogen and phosphorus atoms results in a transfer of the π electron to the nitrogen atom which can then participate in negative hyperconjugation. Popularized by Schleyer and Kos in 1983, negative hyperconjugation is the donation of π orbitals into adjacent σ* orbitals. This ultimately results in a stabilizing effect for the π-bond and a weakening of the σ-bond.26 In the context of cyclophosphazenes, the lone pair orbitals of the nitrogen donate back into the σ*P–N and σ*P–X. In total, this ionic character of each PV=N bond and the consistent negative hyperconjugation from each nitrogen into each adjacent σ* creates a facsimile of aromaticity despite there being no delocalization through the phosphorus center (Figure 1.2, top). However, the heterocycles discussed in this review are not the inorganic cyclophosphazenes but are rather azaphosphinines containing just one nitrogen and phosphorus atom each. This difference adds two levels of complexity that must be addressed. While it would be appropriate to translate the cyclophosphazene example to 1,2λ5-azaphosphinines with a PV=N bond, we must also consider the other isomers. 24 Figure 1.2 Examples of (top) ionic nature in hexachlorophosphazene and (bottom) ylidic nature in PV phosphinine. It is commonly recognized that PIII phosphinines are aromatic heterocycles in the same vein as pyridine. However, PV phosphinines are just as commonly understood to be nonaromatic. Several publications27–29 have addressed the cyclic-phosphonium ylide nature of PV phosphinines (Figure 1.2, bottom), describing the partial negative charge buildup on the 2-, 4-, and 6-carbons with corresponding positive charge on the phosphorus. The result is a nonaromatic system that does not delocalize through the phosphorus like cyclophosphazenes. This situation would apply directly to the 1,4λ5- azaphosphinines discussed in this review as there is no direct bond between the phosphorus and nitrogen in these cases, yet the electronegative nitrogen atom would be even more accepting of the negative character of the ylide. In this case it would be appropriate to conclude that the isolated 1,4λ5-azaphosphinine ring could not be aromatic. The last consideration to address is the phosphonyl (PV=O) bond found in many of the heterocycles discussed in this review. Like the PV=N bond, the phosphonyl bond is known to be extremely polarized30 and exhibits negative hyperconjugation from the oxygen lone pairs back into the adjacent σ* of the other phosphorus bonds. While there are no thorough computational investigations into the electronics of azaphosphinines with exocyclic PV=O bonds, we can imagine the resultant heterocycle shares the combined properties of phosphinines and phosphane oxides in which all the bonds to the phosphorus exhibit a high degree of ionic character while simultaneously being P N P N P N Cl Cl Cl Cl ClCl P R R P RR P N P N P N Cl Cl Cl Cl ClCl 25 stabilized by negative hyperconjugation from not only the oxygen but also the nitrogen atom. The conclusion of these considerations being that ultimately no PV azaphosphinine ring of any form could truly be considered aromatic because of the consistent lack of π-delocalization through the phosphorus atom. Despite this, many of the species discussed in this review have aromatic rings fused to the azaphosphinine rings, which result in an overall aromatic structure. Azaphosphinines have a history that spans back 135 years, yet for much of their existence they have remained little more than a synthetic curiosity (e.g., Scheme 1.1).31 Early work on these molecules was generally fueled by a desire to explore the definition of aromaticity and its existence in unusual heteroaromatic environments. However, the initial synthetic pathways that were developed by the likes of Campbell, Dewar, Märkl, and more provided the necessary groundwork for translating azaphosphinines into modern heterocyclic chemistry.32–36 Since the start of the 21st century, azaphosphinines have begun to find increasingly diverse uses in the fields of asymmetric catalysis, supramolecular association, cellular imaging, and even medicinal chemistry.37–39 The primary goal of this review is to shed light on where the science of azaphosphinines originated, illustrate both older fundamental studies and numerous recent advances, and offer insights of what is yet to come. Most of the research done on this class of molecules comes from the last 25-30 years. The compounds surveyed in this review will contain at least one six-membered ring with no more than one endocyclic phosphorus and nitrogen atom. Only compounds with high degrees of unsaturation in the PN ring will be considered. Heterocycles with partial saturation will be included as necessary to give useful counterpoints and context when discussing reactivities or properties of the heterocycles such as aromaticity. Despite the propensity for PV-azaphosphinines to be P-stereogenic, stereochemistry will typically only be 26 shown for chiral centers (i.e., non-identical P-substituents) generated by asymmetric reactions where the enantiomeric or diastereomeric excess can be determined. A secondary goal of this review is to provide a standardized nomenclature for azaphosphinines. While several names have been used to describe the same general system, it is the opinion of the authors that the terminology of azaphosphinine should be used to describe any six-membered ring containing one phosphorus and one nitrogen atom. This can be further divided into the isomers of 1,2-, 1,3-, and 1,4-azaphosphinine 1a-c (Figure 1.3, top), where the “1-” is in reference to the position of the nitrogen atom and the second number refers to the position of the phosphorus atom. The commonly observed benzo fusion aptly results in the name benzo[x]azaphosphinines 2a-b (Figure 1.3, bottom). The bracketed letter refers to the bond (Figure 1.3, top) on which ring fusion occurs, with the N–X bond being “a”, where x is either the phosphorus atom or the closest carbon to it. In the case of naming fused ring systems, Hantzch-Widman nomenclature rules should be used.40 Further π-extension via ring fusion will continue appropriately. The phosphorus atom in every compound discussed will exist in one of two valences, either PIII or PV. This is denoted by the superscript number on the λ inserted into the chemical name. Examples of this nomenclature system are given below (Figure 1.4) for compounds 3 and 4. As apparent, while these naming conventions are accurate, they rapidly become encumbered with substituents and substitution patterns. As such, when referring to libraries of synthesized azaphosphinines, the authors of this review will typically refer to them as azaphosphinines or benzo[x]azaphosphinines with key substituents as appropriate. 27 Figure 1.3 Examples of (top) 1,2- (1a), 1,3- (1b) and 1,4-azaphosphinines (1c) and (bottom) benzo[c]- (2a) and benzo[b]azaphosphinine (2b) isomers. Figure 1.4 Examples of nomenclature rules applied to more complex azaphosphinine derivatives such as 3 and 4. This review is divided primarily into three sections concerned with the three isomeric forms of azaphosphinine. The 1,2-isomer is by far the most studied of the three, likely because of the wealth of reactions that have been developed to afford this scaffold. The inherent difference in electronegativities between the phosphorus and nitrogen atoms increases their electrophilicity and nucleophilicity, respectively. This increased reactivity aids reactions such as heteroannulation and C–H activation. These factors could help explain why there are several more publications for the 1,4-isomer than 1,3-isomers, with the latter being quite rare in the current literature. For the purposes of organization, each isomer’s section will be divided into subcategories to distinguish between the different methods of synthesis applied to form the azaphosphinine ring. P N P N N P 1a 1b 1c a b c d e f P N P N 2a Benzo[c]-1,2λ3-azaphosphinine 2b Benzo[b]-1,4λ3-azaphosphinine a b c d e f a b c d e f P N 3 thieno[2,3-c]-1,2λ3-azaphosphinine N N P 4 pyrido[2,3-e]-3-phenyl-1,2λ3-azaphosphinine S 28 1.2 Azaphosphinine origins The first published example of a six-membered PN-heterocycle dates to 1888 with the work of Schenk and Michaelis on what are commonly referred to as dihydrophenophosphazines (Scheme 1.1).31 This heterocyclic scaffold could also be classified as dibenzo[b,e]-1,4-dihydro-1,4λ5-azaphosphinine under the naming scheme used in this review. The synthesis proceeds through an addition of PCl3 to diphenylamine at elevated temperatures. This reaction yields the P-chloro species 5, which can be subsequently hydrolyzed/oxidized into the corresponding 1,4λ5- azaphosphinine 4-oxide 6. Due to technological constraints, the structure of 6 was not definitively confirmed until nearly a century later thanks to the work of Häring.41 The dihydrophenophosphazine scaffold stands somewhat alone among azaphosphinine derivatives, as the 1970s and 1980s saw three excellent review articles detailing the chemistry of these species, which we encourage those with further interest to read.42–44 Since then, the literature has been extremely sparse on publications concerning these chemicals.45,46 Due to the wealth of previously compiled research and a dearth of recent studies, dihydrophenphosphazines will be excluded from the remainder of this review. Scheme 1.1 Schenk and Michaelis’ first reported synthesis of a PN-heterocycle scaffold, dibenzo[b,e]1,4-dihydro-1,4λ5-azaphosphinine 4-oxide. The oldest example of a 1,2-azaphosphinine comes from Dewar and Kubba in 1960.47 Their synthesis follows a similar pathway to that laid out by Schenk and H N PCl3 250 °C P H N Cl 5 H2O P H N O H 6 29 Michaelis nearly a century before.31 This team had released a publication two years earlier describing aromatic resonance forms in boron-containing 7 and were interested in developing analogous PN species.48 The work was aimed at trying to develop a phenanthrene-like dibenzo[c,e]-1,2-dihydro-1,2λ3-azaphosphinine 9a with hypothetical resonance structure 9a', in which the lone pair of the nitrogen atom would resonate through phosphorus to give some additional π-delocalization through the hypervalent P resonance structure 9a' (Scheme 1.2). Starting from 2-aminobiphenyl, the authors generated an acyclic intermediate by reacting with phosphorus trichloride in benzene. This was then cyclized crude with AlCl3 at elevated temperatures to furnish 8a. Finally, replacement of the chlorine with PhMgBr resulted in the desired compound 9a. Scheme 1.2 Synthesis of Dewar and Kubba’s early dibenzo[c,e]-1,2-dihydro-1,2λ3- azaphosphinine 9 and comparison to the previously prepared boron-containing species 7. Comparison of UV-Vis spectra of 7 and 9a indicated that while the electronic structures of the two species were similar, they were not identical. However, the authors noted that when left exposed to air for extended periods of time, two oxidation products (10 and 11a) were generated from 9a (Scheme 1.3). Interestingly, the spectra of these NH2 NH P Cl 1) PCl3 benzene reflux 2) AlCl3 220 °C 8a: 42% PhMgBr CH2Cl2 reflux NH P Ph 9a: 58% NH P Ph 9a' NH B OH NH B OH 7 7' 30 oxidation products were nearly identical when compared to that of 7. This emergent electron delocalization was rationalized by Dewar and Kubba through proposed resonance structures 10' and 11a'. By convention, PV-oxo compounds are represented as P=O double bonds; however, due to the nature of the hypervalent bonding of these atoms, it can be argued that the phosphonyl moiety exists as P+–O– in most cases. As discussed previously, it is unlikely any true aromaticity is occurring in these PV heterocycles, but rather electron delocalization from the lone pairs of the oxygen and nitrogen to adjacent bonds via negative hyperconjugation. Further consideration of aromaticity in different azaphosphinine isomers is discussed at the end of the review. A majority of the azaphosphinines discussed in this review will feature this negative hyperconjugation phenomenon. Scheme 1.3 Oxidation products of Dewar and Kubba’s azaphosphinine 9 with aromatic resonance structures. That same year, Campbell and Way significantly expanded upon the previous work laid out by Dewar and Kubba.49 Starting from one of two P-chloro species 8 (R=H or Me), they arylated the system directly with several different aryl lithiates to furnish a family of corresponding azaphosphinines 9. The authors found that they could induce the oxidation observed by Dewar and Kubba by exposing the heterocycles to a mixture NH P Ph [O] [O]NH P OPh NH P Ph O O 10 11a NH P OPh O NH P Ph O 10' 11a' 9a 31 of H2O2 and EtOH at room temperature (Scheme 1.4). No yields were reported for the final oxidation to furnish 11. Scheme 1.4 Campbell and Way’s synthesis of early azaphosphinines 9 and oxidation to 11. 1.3 1,2-Azaphosphinines 1.3.1 Reactivity with Alkynes 1.3.1.1 Pericyclic / Cycloadditions When considering the different synthetic approaches used in the development of 1,2-azaphosphinines, few are as prevalent in the early literature as the [4 + 2] cycloaddition, more commonly known as the Diels-Alder reaction. The earliest example of this reaction being applied to the 1,2-isomer of azaphosphinine is from Kobayashi and Nitta in 1985 to furnish three 1,2λ5-azaphosphinine derivatives.34 While not the first reported synthesis of this family of heterocycle, it did lay the groundwork for what would become a very typical method. The researchers used an N-vinyl- phosphazene (13) as their diene (Scheme 1.5), which was generated through the Staudinger reaction of azidostyrene 12 and trimethyl phosphite. The Diels-Alder reaction was then carried out using various substituted alkynes to yield 2,2-dimethoxy- 1,2λ5-azaphosphinines 14 in modest to good yields. The observed regioselectivity of NH P R Cl ArLi 8 NH P R Ar 9a-e H2O2 EtOH r.t. NH P R Ar 11a-e O 9a: R = H, Ar = Ph, 11% 9b: R = Me, Ar = Ph, 25% 9c: R = H, Ar = p-MeC6H4, 5% 9d: R = H, Ar = p-BrC6H4, 9% 9e: R = H, Ar = p-(NMe2)C6H4, 23% 11a: R = H, Ar = Ph 11b: R = Me, Ar = Ph 11c: R = H, Ar = p-MeC6H4 11d: R = H, Ar = p-BrC6H4 11e: R = H, Ar = p-(NMe2)C6H4 32 14b is ascribed to the ylidic nature of the phosphazene diene and the comparatively electrophilic β-carbon of the ester dienophiles. When heated to high temperatures, azaphosphinines 14a-b underwent a methyl shift to yield the corresponding dihydro derivatives 15 in excellent yields. Scheme 1.5 Synthesis of 1,2-azaphosphinine 14 using the Staudinger reaction and subsequent Diels-Alder cycloaddition. Over a decade later, Nitta and coworkers returned to their work on the cycloadditions of N-vinyl-phosphazenes and substituted alkynes to explore further modifications.50 They synthesized a similar series of 2,2-diphenyl-1,2λ5- azaphosphinines 16 in modest yields by using phosphazene 17 as the phosphorus source for diene preparation (Scheme 1.6). Besides the new azaphosphinines, this paper also served to demonstrate potential post-synthetic modifications to these heterocycles. Unlike 14, azaphosphinines 16 did not rearrange but instead could be reversibly protonated to give the corresponding azaphosphininium tetrafluoroborate salts 18. Ph N3 P(OMe)3 benzene Ph N P(OMe)3 R1 R2 benzene N P Ph R1 R2 MeO OMe 14a: R1 = R2 = CO2Me, 58% 14b: R1 = H, R2 = CO2Me, 57% 14c: R1 = R2 = COPh, 17% 14a-c N P Ph R1 R2 MeO OMe OMe —MeOH 12 13 180 °C N P Ph R1 R2 O OMe Me 15a: R1 = R2 = CO2Me, 85% 15b: R1 = H, R2 = CO2Me, 87% 15a-b 33 Scheme 1.6 Preparation of heterocycles 16 using phosphazene 17 and formation of azaphosphininium salts 18. In 1996, López-Ortiz and coworkers published an interesting alternative pathway to the 2,2-diphenyl-1,2λ5-azaphosphinine scaffold by using N-methoxycarbonyl alkyldiphenylphosphazenes 19 as the pnictogen source in the cycloaddition.51 The key difference in this procedure from previous work was the generation of a stable ylide by deprotonation of the phosphazene with n-BuLi. The ylide then cyclized with dimethyl acetylenedicarboxylate (DMAD) to form the corresponding 2,2-diphenyl-1,2λ5- azaphosphinin-6-one 20 in very good to excellent yields (Scheme 1.7). The authors concluded that only alkyldiphenylphosphazenes will react accordingly, as the substitution of a hydrogen inhibits the process. The authors noted that they had no explanation for the lack of reactivity in their system when R = H. Ph N3 P(OMe)Ph2 benzene Ph N PPh2 R1 R2 benzene N P Ph R1 R2 Ph Ph 16a: R1 = R2 = CO2Me, 36% 16b: R1 = H, R2 = CO2Me, 27% 16a-b N P Ph R1 R2 Ph Ph OMe —MeOH OMe HBF4 (aq), Ac2O silica gel HN P Ph R1 R2 Ph Ph BF4 18a: R1 = R2 = CO2Me, 92% 18b: R1 = H, R2 = CO2Me, 97% 18a-b 12 17 R P NCO2Me PhPh n-BuLi, THF –20 °C DMAD –70 °C R P NCO2Me PhPh Li P N CO2Me MeO2C CO2Me R P NHPh Ph O CO2MeMeO2C R Ph Ph 20a: R = Me, 90% 20b: R = Et, 91% 20c: R = n-Pr, 90% 20d: R = i-Pr, 92% 20e: R = CH2CH=CH2, 75% 20f: R = Bn, 75% 20a-f 19H 34 Scheme 1.7 Synthesis of 2,2-diphenyl-1,2λ5-azaphosphinin-6-ones 20 through cycloaddition with DMAD. Following this work from López-Ortiz, the chemistry of 1,2λ3-azaphosphinines began to flourish with the seminal 1996 publication from Mathey and coworkers in which 1,3,2-diazatitana-cyclohexa-3,6-dienes 21 were reacted with an equivalent of PCl3 at low temperature to furnish the corresponding 1,3,2-diazaphosphinines 22 (Scheme 1.8, top).52 These diazaphosphinines can then be subjected to [4 + 2] cycloaddition conditions to yield a diazaphosphabarrelene intermediate 23, which undergoes a subsequent [4 + 2] cycloreversion to extrude an equivalent of t-BuCN to yield 1,2λ3-azaphosphinines 24. Interestingly, this reaction can be repeated through the same conditions and extrude another equivalent of t-BuCN and furnish the corresponding phosphinine. This finding was similar to that of Märkl several years earlier who observed similar nitrile-extrusion properties in 1,3λ3-azaphosphinines, as will be discussed in a later section of this review.53 This mild synthesis offered several distinct advantages in the forms of regioselectivity, functional group tolerance, and high yields. Ti NN t-But-Bu Cp Cp 1) PCl3, – 20 —> 25 °C 2) Et3N toluene, 70 °C N P N t-Bu t-Bu Δ, toluene N P t-Bu R2 R1 24a-k N P N t-But-Bu R2 R1 —t-BuCN N P t-Bu Ph H N P t-Bu Et Et N P t-Bu Me CH(OEt)2 N P t-Bu Me Me N P t-Bu SiMe3 Fe N P t-Bu PPh2 PPh2 N P t-Bu P PhPh P N t-Bu Ph N P t-Bu P N t-Bu Me3Si SiMe3 N P t-Bu Si Ph P N t-Bu PhMe MeN P t-Bu Ph SiMe2 Ph P PhPh SiMe2Me2Si P NN P PhPh t-Bu t-Bu 24a 24b 24c 24d 24e 24f 24h 24i 24j24g 24k R2R1 21 22 23 35 Scheme 1.8 (top) Synthesis of 1,2-azaphosphinines 24 through the formation and cycloaddition of a 1,3,2-diazaphosphinine. (bottom) Substrate scope of the heterocycles prepared in this way. In 1997, Mathey and coworkers released a follow-up publication that dramatically expanded the substrate scope.54 Despite demonstrating how titanocenes with either diphenyl or di-t-butyl substitution could be applied to the initial cycloaddition- cycloreversion reaction, the authors only used the di-t-butyl substituted derivative for the sake of purification. This resulted in a library of diverse 6-t-butyl-1,2λ3- azaphosphinine derivatives 24, highlighting the benefits of this synthetic approach (Scheme 1.8, bottom). The previously inaccessible derivatives include ferrocene, exocyclic phosphane, and silane-containing species. An interesting facet of the synthesis was discovered when comparing conjugated vs. nonconjugated diynes in the reaction. The authors found that use of conjugated diynes such as 2,4-butadiyne only facilitated a reaction from one of the triple bonds, leading to a 4-ethynyl azaphosphinine. Conversely, by using nonconjugated diynes, the reaction occurs at both alkyne sites resulting in bisazaphosphines (24h-k). It should be noted that every azaphosphinine generated through this method can be further transformed into the corresponding phosphinine as described above. Unfortunately, only the yields of the terminal phosphinines are reported. Application of this cycloaddition-cycloreversion strategy with nonconjugated diynes to generate more complex bisazaphosphinine heterocycles begged the question as to whether it could be extended to higher order systems. In 2000, Le Floch and coworkers provided the answer by performing the same reaction on tripodal species 25 and 26 to generate 1,2λ3-azaphosphinine heterocycles 27 and 28 (Scheme 1.9).55 36 Scheme 1.9 Preparation of tripodal 1,2λ3-azaphosphinine heterocycles (top) 27 and (bottom) 28. 1.3.1.2 Transition Metal-Catalyzed C–H Activation While the preparation of azaphosphinines via cycloaddition reactions was the most popular method in the 1980s and 1990s, this route has been supplanted by more modern techniques in recent years. One of the biggest synthetic advances across all of organic chemistry has been the advent and popularization of transition metal-mediated reactions stemming from pioneering works of Heck, Suzuki, Sonogashira, and more. One popular recent advance is transition-metal based C–H activation. A common technique for such reactions is the use of ortho-directing groups in aryl systems. By having an appropriate functional handle, specific aryl C–H bonds can be selected and reacted upon. In 2013, Glorius and coworkers published their work using phosphoryl-related directing groups in RhIII-catalyzed C–H activation.56 They reasoned that because there was a plethora of carbonyl-based directing groups for C–H activation, phosphonyl-based systems may work as well. After screening conditions, the authors found that the catalyst RhCp*(MeCN)3(SbF6)2 was able to effect C–H activation reactions directed by different aryl phosphonamides. Within the scope of this review, when this reaction was performed on phosphonamide 29 and various bis-functionalized alkynes, the corresponding benzo[c]-1,2-dihydro-1,2λ5-azaphosphinines 30 were furnished in good yields (Scheme 1.10). There was no apparent preference in electronic character of the 22 toluene, ∆ —3 t-BuCN 27a: R = Ph 27b: R = Me P N PhSi t-BuR 3 N P t-Bu MeMe2 SiHC 3 26 RPhSi 3 SiHC MeMe Me 3 —3 t-BuCN 22 toluene, ∆ 25 28 37 alkyne. While the authors note that the desire to synthesize 30 was fueled by the biological relevance of the analogous isoquinolinone, this paper served more as a foray into phosphonyl-directed C–H activation and was not focused on the azaphosphinines outside of their application in reaction scope. Scheme 1.10 Aryl phosphonamide directed C–H activation to furnish 30. In the same year as the work from Glorius, Lee and coworkers sought to use phosphinamides for C–H activation and heteroannulation using a different Rh catalyst.57 Unlike the work from Glorius and coworkers, this publication was entirely focused on the construction of azaphosphinines. The goal was to use the lone pair of the phosphinamide as a directing group for the heteroannulated benzo[c]-1,2-dihydro- 1,2λ5-azaphosphinine 2-oxides. After optimizing the reaction conditions, Lee and coworkers examined a variety of phosphinamide substrates 31 (Scheme 1.11) and generated several derivatives of azaphosphinine 32 in good to excellent yields. There was no apparent preference for electron density or steric bulk in the alkyne coupling partner, and they observed excellent functional group tolerance. In several instances, they obtained heterocycles containing aryl chlorides and bromides that are available for further manipulation. They also proceeded to show how more complex, heterocyclic phosphinamides tolerate the reaction as with P-thiophene derivatives 32o and 32p. P O i-PrHN NHi-Pr 29 Cu(OAc)2 RhCp*(MeCN)3(SbF6)2 DCE, 130 °C NP R1 R2 O NHi-Pr i-Pr R1 R2 30a-e 30a: R1 = R2 = Ph, 71% 30b: R1 = R2 = p-MeC6H4, 77% 30c: R1 = R2 = p-OMeC6H4, 74% 30d: R1 = R2 = p-ClC6H4, 73% 30e: R1 = Me, R2 = Ph, 76% 38 Scheme 1.11 Formation of [c]-fused 1,2-dihydro-1,2λ5-azaphosphinine-2-oxide 32. Electron lone pairs, particularly those on pnictogen atom centers, are commonly used to effect ligation. However, while many pnictogen-based ligands exist, the phosphinamide motif is rarely accessed for this purpose. Despite underutilization, the propensity of PV to form chiral centers combines well with an adjacent directing lone pair. In 2017, Cramer and coworkers aimed to take the previous work from Lee and use it to develop a new class of benzo[c]-1,2-dihydro-1,2λ5-azaphosphinine 2-oxide based P-stereogenic ligands.58 To accomplish this, Cramer took advantage of prochiral molecule 33 to carry out the transition metal-catalyzed heteroannulation reaction. By using the nitrogen to direct the chiral catalyst to one of the two ortho aryl C–H bonds 34, chiral intermediate 35 is formed, which is then carried through the reaction to give chiral benzo[c]-1,2-dihydro-1,2λ5-azaphosphinine 2-oxide 36 (Scheme 1.12). R2R2 P O NHPh R1 R1 [Cp*RhCl2]2 Ag2CO3, KHPO4 NPhP O R2 R2 R1 H 32a-p 32a-h: R1 = H 32a: R2 = Et, 71% 32b: R2 = n-Bu, 68% 32c: R2 = Ph, 81% 32d: R2 = m-MeC6H4, 83% 32e: R2 = p-MeC6H4, 79% 32f: R2 = p-OMeC6H4, 99% 32g: R2 = m-ClC6H4, 69% 32h: R2 = p-BrC6H4, 87% 32i: R1 = o-Me, R2 = p-OMeC6H4, 87% 32j: R1 = p-OMe, R2 = p-OMeC6H4, 83% 32k: R1 = p-OMe, R2 = p-BrC6H4, 84% 32l: R1 = p-F, R2 = p-OMeC6H4, 89% 32m: R1 = p-CF3, R2 = p-OMeC6H4, 74% 32n: R1 = 3,5-(Me)2, R2 = p-OMeC6H4, 60% NPhP O S S R2 R2 32o: R2 = p-OMeC6H4, 93% 32p: R2 = p-BrC6H4, 58% R1 31 39 Scheme 1.12 Proposed mechanism for chiral C–H activation heteroannulation of achiral phosphinamide. Optimization experiments determined that Rh1 was the most appropriate catalyst for good enantioselectivity of the products, and thus a wide substrate scope was examined (Scheme 1.13). From the results of the synthetic trials, there does not seem to be a large electronic preference of substrate. Regardless, the high enantioselectivity of the reaction is undeniable, with enantiomeric excess being greater than 10:1 (S:R) for every derivative of 36 synthesized. P O N H H Ar [CpxRh] (BzO)2 P O N Ar Rh Cpx OBz —BzOH Enantioselective Activation R R Trapping NP R R O Ph Ar 36 33 34 35 H P O N Ar Rh Cpx 40 Scheme 1.13 Chiral C–H activation heteroannulation to afford 36. For every entry, Ar = 3,5-(CF3)2C6H3. Because the primary aim of the Cramer paper was to generate useful chiral phosphinamide ligands for further chemistry, they also reported reducing the benzo[c]azaphosphinine from PV to PIII. Although the authors found that the heterocycles were prone to racemization under certain conditions, the optimal method (Scheme 1.14) used 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and trichlorosilane, resulting in 92% yield of PIII product and 97% retention of the initial configuration. The authors concluded this is a feasible pathway to enantiospecific benzo[c]-1,2-dihydro- 1,2λ3-azaphosphinines ligands 36'; however, they have not reported additional studies on this system to date. P NHAr O R1 R3R2 Rh1, (BzO)2 Ag2CO3, K2CO3 NP R2 R3 O Ar R1 R1 Ar = 3,5-(CF3)2C6H3 36a-g: R2 = R3 = Ph 36a: R1 = m-Me, 80%, 96:4 e.r. 36b: R1 = o-Me, 76%, 94:6 e.r. 36c: R1 = p-Me, 85%, 93:7 e.r. 36d: R1 = p-t-Bu, 45%, 94:6 e.r. 36e: R1 = p-OMe, 81%, 95:5 e.r. 36f: R1 = p-F, 60%, 96:4 e.r. 36g: R1 = m-Br, 40%, 95:5 e.r. 36h-r: R1 = H 36h: R2 = R3 = p-OMeC6H4, 86%, 94:6 e.r. 36i: R2 = R3 = p-ClC6H4, 50%, 92:8 e.r. 36j: R2 = R3 = n-Pr, 55%, 96:4 e.r. 36k: R2 = n-Bu, R3 = p-CF3C6H4, 37%, 95:5 e.r. 36l: R2 = n-Bu, R3 = p-OMeC6H4, 75%, 95:5 e.r. 36m: R2 = CH2OMe, R3 = p-OMeC6H4, 60%, 95:5 e.r. 36n: R2 = i-Pr, R3 = p-OMeC6H4, 78%, 95:5 e.r. 36o: R2 = cyclopropyl, R3 = p-OMeC6H4, 44%, 96:4 e.r. NP Me Ph O Ph Ar NP n-Bu O Ph Ar N Me NP n-Bu O Ph Ar S OMe OMe Rh Rh1 36p: 55%, 96:4 e.r. 36r: 42%, 96:4 e.r. 36q: 42%, 96:4 e.r. 36a-o 332 41 Scheme 1.14 Enantiospecific reduction to chiral azaphosphinine 36p'. In 2018, Cramer and Sun published a follow-up study that revealed a promising application for their system.38 Previously, the syntheses of chiral azaphosphinines 36 via this method were limited to the desymmetrization of achiral phosphinamides with two identical aryl P-substituents 33. The authors hypothesized that if the selectivity for the reactive enantiomer could be great enough, then one would be able to take a racemic mixture of chiral phosphinamide and generate two enantiomerically-pure materials, the heteroannulated reactive enantiomer 37 and the purified unreactive enantiomer of the starting racemate 38 (Table 1.1). In this study the chiral catalyst Rh1 did not give sufficient selectivity, so Rh complexes with bulky trisubstituted Cpx ligands (to deactivate reactivity on the mismatched substrate) were screened, with Rh2 proving to be the most effective. Table 1.1 Experimental details for reactions of rac-36 with various internal alkynes. Ar = 3,5-(CF3)2C6H3. rac- 38 R1 R2 R3 R4 Time [h] Conv. [%] e.r 37 (% yield) e.r. 38 (% yield) rac- 38a H Me Ph Ph 8.5 51 93:7 (46) 95:5 (46) NP Ph Ph O Ph CF3 CF3 DBU, HSiCl3 1:1 toluene/THF 100 °C, 14 h 92% 97:3 e.r. NP Ph Ph Ph CF3 CF3 36p 36p' P R2 O NHAr R1 R4R3 + P R2 R1 O ArHNNP Ar O R2 R3 R4 rac-38 37 38 Rh2, (BzO)2 Ag2CO3, K2CO3 OMe OMe Rh Rh2 t-Bu R1 42 rac- 38b p-Me Me Ph Ph 10.5 55 89:11 (50) 98:2 (42) rac- 38c p-F Me Ph Ph 10.5 55 90:10 (48) 98:2 (40) rac- 38d p-Cl Me Ph Ph 10.5 55 89:11 (45) 97:3 (40) rac- 38e p- OMe Me Ph Ph 8.5 54 91:9 (48) 99:1 (42) rac- 38f p- NMe2 Me Ph Ph 9.5 42 95:5 (36) 83:17 (50) rac- 38g m-Me Me Ph Ph 10.5 58 85:15 (53) 99:1 (38) rac- 38h m-Br Me Ph Ph 14 55 91:9 (42) 99:1 (38) rac- 38i o-Me Me Ph Ph 10 53 77:23 (42) 79:21 (44) rac- 38j H Bn Ph Ph 4 59 84:16 (53) 99.5:0.5 (37) rac- 38k H (CH2)2OBn Ph Ph 6.5 51 93:7 (47) 93:7 (44) rac- 38l H N- pyrrolidinyl Ph Ph 5 57 79:21 (52) 89:11 (40) rac- 38m H N- morpholinyl Ph Ph 3.5 61 79:21 (55) 95:5 (37) rac- 38n H OMe Ph Ph 24 60 81:19 (55) 97:3 (37) rac- 38o H OPh Ph Ph 14 53 86:14 (48) 91:9 (44) rac- 38p H Me p- OMeC6H4 p- OMeC6H4 8.5 51 89:11 (46) 95:5 (46) rac- 38q H Me n-Bu p- OMeC6H4 8.5 50 95:5 (46) 90:10 (46) rac- 38r H Me i-Pr p- OMeC6H4 8.5 43 94:6 (37) 82:18 (52) 43 rac- 38s H Me n-Bu 5-indolo 8.5 54 96:4 (48) 98:2 (43) Much like their previous publication, this 2018 Cramer paper featured a large library of derivatives to emphasize the efficacy of their system. Varying the electronic and steric properties of both the alkyne and chiral phosphinamide led to moderate but consistent yields (36-55%) and enantioselectivities, in some cases exceeding 99:1. This included the use of various heterocycles and alkyl chains on both stating materials. The reaction was also performed on achiral diaryl phosphinamide 38t to explore any possible regioselectivity for which ring results in the benzo fusion (Scheme 1.15). The authors found that there was an almost 1:1 distribution between the two possible products with an excellent overall yield for the transformation. Scheme 1.15 Reactivity of bis-aryl functionalized chiral phosphinamide. Ar = 3,5- (CF3)2C6H3. To investigate the application of this newly synthesized series as chiral phosphorus- based reagents for asymmetric catalysis, 37a and 39 were added as a Lewis base (LB) to a reductive aldol condensation of chalcone 40 and benzaldehyde to furnish 41 (Scheme 1.16). Interestingly, the methyl-bearing 37a gave not only a higher overall yield (95%) of product but also a dramatically improved enantioselectivity (96:4 e.r. of major diastereomer) compared to less selective 39. P O NHAr PhPh Rh2, (BzO)2 Ag2CO3 K2CO3 NP Ar O p-MeC6H4 Ph Ph NP Ar O Ph Ph Ph + rac-38t 37t: 50%, 93:7 e.r. 37t': 47%, 96:4 e.r. Me Me 44 Scheme 1.16 Asymmetric reductive aldol condensation of enone 40 and benzaldehyde using chiral benzo[c]-1,2-dihydro-1,2λ3-azaphosphinine additives as Lewis base (LB). Ar = 3,5-(CF3)2C6H3. Continuing their investigation into asymmetric applications of their materials, the authors reduced 37a from the PV to PIII valence via thionation to 37a' and reduction to 37a'', which was then used as a ligand for asymmetric hydrogenation (Scheme 1.17). This hydrogenation reaction proceeded with quantitative yield and decent enantioselectivity, suggesting promising future applications for azaphosphinines in the field of organic catalysis. Scheme 1.17 Enantioselective reduction of 37a and its use as a chiral ligand in an asymmetric hydrogenation reaction. Ar = 3,5-(CF3)2C6H3. While these studies generated a large body of work that furthered the science of azaphosphinines considerably, the one potential drawback was the reliance on Ph O Ph PhCHO 10 mol% LB 5 equiv. HSiCl3 CH2Cl2, MeCN –78 °C, 12 h Ph O Ph Bn OH Ph O Ph Bn OH + LB NP Ar O Me Ph Ph NP Ar O Ph Ph Ph 37a 39 95%: 13 (96:4 e.r.) : 1 (55:45 e.r.) 89%: 1 (63:37 e.r.) : 4 (51:49 e.r.) 40 syn-41 anti-41 37a'' 37a Lawesson’s reagent toluene, 90 °C 99% (99.5:0.5 e.r.) NP Ar S Me Ph Ph 1) MeOTf CH2Cl2 2) P(NMe2)3 NP Ar Me Ph Ph 90% (99.5:0.5 e.r.) CO2Me CO2Me 1 mol% [Rh(COD)2]BF4 2 mol% 37a'' H2, CH2Cl2, 23 °C, 12 h 99% (86:14 e.r.) CO2Me CO2Me Me 37a' 45 expensive RhI catalysts. In 2022, Shi and coworkers reported the design and application of a in situ-generated CoIII catalyst for the asymmetric heteroannulation of achiral phosphinamides 42 to benzo[c]-1,2-dihydro-1,2λ5-azaphosphinine 2-oxides 43.59 Similar to Cramer’s initial work, the early substrates are diphenylphosphinamides that rely on the enantiotopic aryl C–H bonds to generate a chiral intermediate.57 Much of this work is dedicated to the logical design of an appropriate chiral ligand. Previous research suggested that monoanionic bidentate ligands were necessary for the in situ- generation of chiral CoIII active species.60,61 After screening a number of ligands, the authors eventually decided upon salicyloxazoline (Salox) (S)-L1. This ligand, along with the Co(OAc)2•4H2O precatalyst and Mn(OAc)2•4H2O oxidant, were applied to many substrates where both the achiral phosphinamide and alkyne were varied to form 43 (Scheme 1.18). In the case of every substrate, the aryl substituent is an 8-quinolinyl motif. 46 Scheme 1.18 Chiral C–H activation and heteroannulation using CoIII to afford 43. Shi and coworkers then performed a kinetic resolution experiment like Cramer, reacting a racemic mixture of compound 44 with phenylacetylene under conditions identical to the above trials (Scheme 1.19). The experimental results were excellent, with a near-quantitative overall yield and high enantioselectivity in forming just the (S)- enantiomer of the product 45 while ignoring the unreactive enantiomer of the starting phosphinamide (R)-44. P NHAr O NP Ar O R R OH N O Ph (S)-L1 NP Ar O R R 43a: R = p-MeC6H4, 99%, >99% e.e. 43b: R = p-OMeC6H4, 99%, >99% e.e. 43c: R = p-CNC6H4, 97%, 98% e.e. 43d: R = p-BrC6H4, 98%, 98% e.e. 43e: R = m-OMeC6H4, 99%, 98% e.e. 43f: R = Et, 96%, 99% e.e. 43g: R = n-Pr, 99%, >99% e.e. 43h: R = CH2OMe, 99%, 99% e.e. NP Ar O R R 43i: R = n-Pr, 99%, >99% e.e. 43j: R = Ph, 99%, >98% e.e. NP Ar O S S 43k: 96%, 98% e.e. NP Ar O H R 43l: R = Ph, 97%, 98% e.e. 43m: R = p-OMeC6H4, 95%, >99% e.e. 43n: R = p-ClC6H4, 94%, >99% e.e. 43o: R = H, 72%, >99% e.e. 43p: R = n-Bu, 98% (9:1), >99% e.e. 43q: R = c-pentyl, 91%, >99% e.e. 43r: R = SiMe3, 89%, >99% e.e. O ArP N OAr PN 43s: 94%, >99% e.e. NP Ar O H Fe 43t: 92%, >99% e.e. NP Ar O H H H H Me O 43u: 89%, >99% d.e. F O OH F N H OAr PN 43v: 93%, >99% d.e. NP Ar O O O O O n = 16 43w: 99%, >99% e.e. NP Ar O Et Et R R 43x: R = p-Me, 99%, >99% e.e. 43y: R = p-OMe, 97%, >99% e.e. 43z: R = p-F, 95%, >99% e.e. 43aa: R = o-Me, 92%, >99% e.e. 43ab: R= 4,5-(Me)2, 92%, >99% e.e. 43ac: R = 2-naphthyl, 97%, >99% e.e. 43a-y N Ar = RR 42 (S)-L1 Co(OAc)2•4H2O Mn(OAc)2•4H2O NaOPiv, t-BuOH (S)-L1, . Co(OAc)2•4H2O Mn(OAc)2•4H2O NaOPiv, t-BuOH P NHAr O NP Ar O Me Ph Me Ph rac-44 + P NHAr OMe (R)-44, 46% 99% e.e. 45, 46% 95% e.e. 47 Scheme 1.19 Chiral resolution of phosphinamide 44 under standard reaction conditions. Ar = 8-quinolinyl. Shi and coworkers also showed that the heteroannulation would proceed when the alkyne was replaced with a variety of allene coupling partners 46 (Scheme 20), affording 47 in good to excellent yields with high e.e. values. Scheme 1.20 Heteroannulation with allene coupling partners. Ar = 8-quinolinyl. Very recently in 2023, Shi and coworkers reported similar transition-metal catalyzed [4 + 2] heteroannulation reactions on phosphanamines 48 and functionalized alkynes.62 There are several important distinctions that separate this work from earlier publications. The design of the starting material is quite different, notably that the P NH2Ar O + R (S)-L1 Co(OAc)2•4H2O Mn(OAc)2•4H2O NaOPiv, t-BuOH 47a-o NP Ar O H R NP Ar O H CO2R 47a: R = Et, 89%, 98% e.e. 47b: R = Bn, 61%, 99% e.e. 47c: R = p-OMePh, 72%, 98% e.e. 47d: R = (-)-menthyl, 90%, 97% d.e. NP Ar O H R 47e: R = OBn, 73%, 99% e.e. 47f: R = NHBoc, 71%, 94% e.e. 47g: R = NPhth, 71%, 98% e.e. 47h: R = NCarb, 65%, 98% e.e. NP Ar O H CO2Et S S 47i: 75%, 99% e.e. NP Ar O H CO2Et 47j: R = p-Me, 78%, 98% e.e. 47k: R = p-OMe, 76%, 90% e.e. 47l: R = p-i-Pr, 78%, 98% e.e. 47m: R = p-t-Bu, 80%, >99% e.e. 47n: R = p-Br, 72%, 98% e.e. R R NP Ar O H S S N 47o: 45%, 98% e.e. 42 46 48 phosphorus atom of the phosphanamines is trivalent and is oxidized to pentavalence during the reaction. Secondly, the heteroannulation is conducted on ortho-halo- phosphanamines where the reactive bond is adjacent to the nitrogen instead of the phosphorus. This results in an inversion of the product atom geometry relative to the other species in similar publications. Although initially probed using tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) as the catalyst, screening studies revealed that Ni(COD)2 gave dramatically improved yields. Further optimization of conditions showed that stoichiometric amounts of LiCl aided in the reduction of the Ni catalyst, and that elevated temperatures were required for optimal yield. The main body of explored substrates comprised of achiral phosphanamines with two identical alkyl or aryl substituents to furnish benzo[e]-1,2λ5-azaphosphinines 49 (Scheme 1.21, top). The scope of functionalized alkynes includes not only aryl but also heteroaryl and alkyl substituents, indicating the wide degree of functional group tolerance. A dual heteroannulation was also conducted on 50 to furnish 51 with good to excellent yields (Scheme 1.21, bottom). 49 Scheme 1.21 Ni0-mediated heteroannulation to afford azaphosphinines 49 and 51. Shi and coworkers continued to explore the heteroannulation of P-stereogenic phosphanamines as well by protecting the PIII as borane complexes 52 and 53. The starting materials were deprotected in situ and proceeded with moderate yields but excellent enantioselectivities for retention of the geometry of the chiral center in heterocycles 49s and 49ak-an (Scheme 1.22). Unlike most of the azaphosphinines covered in this review, this paper does provide analysis of the photophysical properties of the molecules. Density functional theory (DFT) provided the computed HOMO and LUMO energy levels of 49a, which showed a clear distinction between HOMO and LUMO localization, with the HOMO predominantly on the benzo[c]azaphosphinine core while the LUMO is distributed across all the aromatic rings. This reasoning led to H N P X R2 R2 R3R3 PN R2 R2’ R3 R3 49a-aj 49a-o: R2 = t-Bu, R3 = Ph 49a: R1 = H, 87% 49b: R1 = p-Me, 69% 49c: R1 = m-Me, 76% 49d: R1 = 3,5-(Me)2, 83% 49e: R1 = p-i-Pr, 79% 49f: R1 = p-t-Bu, 78% 49g: R1 = m-OMe, 65% 49h: R1 = p-F, 80% 49i: R1 = 3-F, 4-Me, 81% 49j: R1 = 3,4-F2, 69% 49k: R1 = m-Cl, 59% 49l: R1 = p-OCF3, 76% 49m: R1 = m-CF3, 87% 49n: R1 = p-CN, 64% 49o: R1 = p-COMe, 78% 49p-s: R1 = H, R3 = Ph 49p: R2 = i-Pr, 87% 49q: R2 = Cy, 82% 49r: R2 = Ph, 63% rac-49s: R2 = Ph, R2’ = t-Bu 49t-aj: R1 = H, R2 = t-Bu 49t: R3 = p-MeC6H4, 78% 49u: R3 = m-MeC6H4, 82% 49v: R3 = p-t-BuC6H4, 87% 49w: R3 = p-OMeC6H4, 71% 49x: R3 = p-SMeC6H4, 80% 49y: R3 = p-FC6H4, 90% 49z: R3 = p-ClC6H4, 83% 49aa: R3 = m-ClC6H4, 81% 49ab: R3 = p-BrC6H4, 90% 49ac: R3 = p-CF3C6H4, 80% 49ad: R3 = p-OCF3C6H4, 89% 49ae: R3 = p-NH2C6H4, 46% 49af: R3 = 2-thienyl, 33% 49ag: R3 = 3-pyridyl, 57% 49ah: R3 = Me, R2’ = Ph, 71% 49ai: R3 = n-Pr, R2’ = Ph, 66% 49aj: R3 = Et, 27% P N PN t-Bu t-Bu t-Bu t-Bu R R R RCl Cl HN NH P(t-Bu)2 (t-Bu)2P RR 51a: R = Ph, 64% 51a: R = p-OMeC6H4, 84% 51a: R = p-FC6H4, 81% R1 48 50 R1LiCl, Cs2CO3 DMF LiCl, Cs2CO3 DMF Ni(COD)2 Ni(COD)2 50 the conclusion that the LUMO and subsequent photophysical properties could be modulated through the identity of the aryl-substituent. Six heterocycles with varied aryl-substituents were measured for their emission in both solution and the solid state (Table 1.2). While the solution-state quantum yields of the analyzed species were rather low (4%-13%), the solid-state quantum yields were comparatively quite high with 49y reaching 90%. Scheme 1.22 Asymmetric [4 + 2] heteroannulation starting from chiral phosphanamines. Standard conditions of phosphanamine (1 equiv.), alkyne (2 equiv.), Ni(COD)2 (10 mol%), LiCl (1 equiv.), Cs2CO3 (3 equiv.), DMF, 130 °C. Table 1.2 Emission data for measured heterocycles 49. Substrate Aryl group λem (nm)[a,b] φ (%)[b] λem (nm)[a,c] φ (%)[c] 49a Ph 514 40 547 5 49t p-MeC6H4 530 30 539 4 49w p-OMeC6H4 518 11 536 4 49y p-FC6H4 515 90 543 13 49ab p-BrC6H4 561 66 560 7 H N P t-Bu PhBr MeO BH3 standard conditions R1R 52 (>99% e.e.) PN Ph t-Bu R R1 49s: R = R1 = Ph, 50%, 99% e.e. 49ak: R = R1 = p-FC6H4, 45%, >99% e.e. 49al: R = Me, R1 = Ph, 67%, >99% e.e. H N P t-Bu Ph Cl BH3 MeO standard conditions PhPh PN Ph t-Bu Ph Ph (R)-53 (>99% e.e.) (S)-49am: 43%, 99% e.e. H N P t-Bu Ph Cl BH3 MeO (S)-53 (>99% e.e.) standard conditions p-OMeC6H4OMeC6H4 PN Ph t-Bu OMe OMe (R)-49an: 58%, >99% e.e. p- MeO MeO 51 49ac p-CF3C6H4 551 24 582 6 [a]Emission maxima upon excitation at maximum absorption wavelength. [b]Measured in solid state. [c]Measured in CH2Cl2. 1.3.2 Intramolecular cyclization reactions Intermolecular heteroannulation reactions, particularly those catalyzed by transition metals, have the decided benefit of extremely varied substrate scopes and in many cases enantioselectivity. However, in terms of published methods, intramolecular cyclization reactions to form benzo[x]azaphosphinine systems remains the most popular. Like cycloaddition reactions, these intramolecular cyclizations are generally transition-metal free. Besides this, lack of reliance on an added alkyne allows for different substitutions made directly on the PN-heterocycle such as O- and N-substitutions, as well as fusion to larger conjugated systems. In 1966, a very early example of an azaphosphinine synthesis from Shavel and coworkers was the intramolecular Bischler-Napieralski cyclization of indole derivative 54 via dichloro intermediate 55, ultimately furnishing 1,2-dihydro-1,2λ5-azaphosphinine 2-oxide 56 (Scheme 1.23).63 Due to the time period, there is little analytical data for 56, but it is one of the earliest examples of a PN- heterocycle prepared by an intramolecular route. Scheme 1.23 Synthesis of indole-fused azaphosphinine 2-oxide 56. MeO MeO HN O NH POCl3 reflux MeO MeO N NH P O Cl Cl EtOH reflux MeO MeO N P NH O OEt 54 55 56: 13% 52 Twenty years later, Bourdieu and Foucaud reported in 1986 a concise synthesis to several 1,2-dihydro-1,2λ3-azaphosphinines 57.33 This pathway was influenced by an earlier study from Nurtdinov et al. that prepared 2-oxo-1,2-azaphospholenes using dichlorophosphanes and N-butylimines.64 In their adaption, Foucaud combined dichlorophenylphosphane with two equivalents of various alkyl imines 58 to furnish 1,2-dihydro-1,2λ3-azaphosphinines 57 (Scheme 1.24). Several of these compounds featuring different alkyl substituents were synthesized in low to very good yields, with the corresponding azaphosphole generated as a side product. In a follow-up study the authors incorporated much larger number of N-alkylimines.65 Overall, variation of chain length led to little discernable trend in the yields of the products. Scheme 1.24 Proposed pathway to 1,2-dihydro-1,2λ3-azaphosphinines 57. No yield reported (n.y.r.) Bourdieu and Foucaud also performed several experiments with alternative phosphane and phosphinite reagents, namely P(CH2Ph)Cl2 and P(OMe)Cl2, respectively; however, neither of the desired PIII heterocycles (57m and 57n) were N R2 R3PhCl2(2 equiv.) N R1 Cl(R3)P NH2 R1 Cl —R1NH2 N R2 R1 Cl(R3)P N P R3 R1 R2 57 R2 R2 R2 57a-l: R3 = Ph 57a: R1 = t-Bu, R2 = Me, 64% 57b: R1 = i-Bu, R2 = Me, 5% 57c: R1 = t-Oct, R2 = Me, 70% 57d: R1 = i-Pr, R2 = Me, 42% 57e: R1 = Bn, R2 = Me, 25% 57f: R1 = n-Bu, R2 = Et, 6% 57g: R1 = t-Bu, R2 = Et, 60% 57h: R1 = i-Bu, R2 = Et, 8% 57i: R1 = t-Bu, R2 = n-Pr, 68% 57j: R1 = i-Bu, R2 = n-Pr, 10% 57k: R1 = t-Bu, R2 = n-Bu, 63% 57l: R1 = i-Bu, R2 = n-Bu, 8% 57m: R1 = t-Bu, R2 = Me, R3 = Bn, n.y.r. 57n: R1 = t-Bu, R2 = Me, R3 = OMe, n.y.r. R1 58 R2 53 stable enough to be isolated and instead underwent oxidation in air to furnish the corresponding PV oxo-compounds 57m' and 57n' (Scheme 1.25). Compound 57n would also hydrolyze in the presence of acid to give 57n''. Finally, the authors also showed how the PIII heterocycles could be intentionally oxidized to PV using either H2O2 or S8 to form the corresponding oxide 59 or sulfide 60 (Scheme 1.26). Scheme 1.25 Oxidation and hydrolysis of heterocycles 57m and 57n. Scheme 1.26 H2O2 and S8 oxidations of azaphosphinines 57. A third paper from Bourdieu and Foucaud in 1987 rounded out the story by briefly describing a protocol for the conversion of the dihydro heterocycles to the corresponding fully conjugated azaphosphinine 61 (Scheme 1.27).66 Pyrolysis of 1,2- dihydro-1,2λ3-azaphosphinine 57c at 600 °C thermolytically cleaved the substituents on both the 1 and 2 positions; however, product 61 was highly electrophilic and added a variety nucleophiles (water, isopropylamine, or methylmercaptan) across the reactive P=N bond, affording heterocycles 62-64. Interestingly, both P-amino 63 and P-thio 64 N P R t-Bu Me Me [O]H3O+ N P H t-Bu Me N P R t-Bu Me O O MeMe R = Bn, OMeR = OMe 57m',n'57n'' 57m,n N P Ph R1 R2 H2O2 S8 N P Ph R1 R2 N P Ph R1 R2 SO 57a-k59a-i 60a,d R2R2 R2 59a: R1 = t-Bu, R2 = Me, 83% 59b: R1 = i-Bu, R2 = Me, 78% 59c: R1 = t-Oct, R2 = Me, 86% 59d: R1 = i-Pr, R2 = Me, 75% 59e: R1 = Bn, R2 = Me, 70% 59f: R1 = n-Bu, R2 = Et, n.y.r. 59f: R1 = n-Bu, R2 = Et, n.y.r. 59g: R1 = t-Bu, R2 = Et, n.y.r. 59h: R1 = t-Bu, R2 = n-Pr, n.y.r. 59i: R1 = t-Bu, R2 = n-Bu, n.y.r. 60a: R1 = t-Bu, R2 = Me, 49% 60d: R1 = i-Pr, R2 = Me, 44% 54 also hydrolyzed to furnish 62 when exposed to water. No yields were reported for the reactions. Scheme 1.27 Thermolytic synthesis of 1,2λ3-azaphosphinine 61 and its dihydro products 62-64 from attack of various nucleophiles. Also in 1987, Barluenga et al. published their work on the first example of benzo[e]- 1,4-dihydro-4-oxo-1,2λ5-azaphosphinines, which was achieved via intramolecular cyclization of N-aryl phosphazene (Scheme 1.28).67 These imides were prepared via Staudinger reaction of methyl o-azidobenzoate 65 with various alkyldiphenylphosphanes. The phosphazenes were then cyclized with KH under mild temperatures to furnish the final heterocycles 66. The authors found that the benzo[e]azaphosphinine resulting from a P-methylphosphazene was unstable and could not be isolated. Similar to previously discussed early works, this brief publication provides little-to-no subsequent analysis of the new compounds besides NMR chemical shifts. Despite that, the Barluenga study proved to be a key publication that opened the door for several additional reports to further develop the scaffold. N P MeMe Ph 600 °C N P MeMe N H P MeMe O H N H P MeMe SMeN H P MeMe NHi-Pr 57c 61 62 6463 t-Oct H2O MeSH i-PrNH2 55 Scheme 1.28 Synthesis of benzo[e]-1,4-dihydro-1,2λ5-azaphosphinines 66. In 1991, Bedel and Foucaud published the oxidation of their previously prepared 1,2-dihydro-1,2λ3-azaphosphinines from PIII to PV,68 building upon the knowledge gained from their thermolysis of these heterocycles.66 Methylation of azaphosphinines 57 generated P-methyl phosphonium salts 67, which afforded 68 after thermolysis at 210-230 °C (Scheme 1.29). This system was deprotonated under mildly basic conditions to furnish 1,2λ5-azaphosphinines 69 in good-to-excellent yields. Upon exposure to air and/or water, the azaphosphinines slowly decomposed to give one equivalent of formamide and the corresponding phosphane oxide 70. Scheme 1.29 Synthesis of 1,2λ3-azaphosphinine 69 and subsequent hydrolysis/oxidation. Fluck et al. published an entirely novel approach to the synthesis of 1,2λ5- azaphosphinines in 1995, exploring the reactions between isothiocyanates 71 and N3 PPh2 R —N2 N PPh2 O OMe O OMe R N H P O R Ph Ph 66a-c 66a: R = Me, 97% 66b: R = CH=CH2, 92% 66c: R = Ph, 87% 65 i) KH THF ii) MeOH H2O N Pt-Bu R R Ph MeI toluene N Pt-Bu R R PhMe I 210-230 °C N P R R PhMe H I N P R R PhMe K2CO3 Et2O, MeCN 67 68 69a-d [O]/H2O RP H O O Ph Me R + O NH2 70 69a: R = Me, 97% 69b: R = Et, 86% 69c: R = n-Pr, 80% 69d: R = n-Bu, 83% 57a,g,i,k 56 1,1,3,3-tetrakis(dimethylamino)-1λ5,3λ5-diphosphete 72 (Scheme 1.30).69 Depending on the molar ratio of starting materials used, exotic azaphosphinine derivatives 73 are furnished. Despite not having an apparent application, this synthesis stands as a unique example of reactivity to obtain the typical azaphosphinine core. The resultant heavily substituted 1,2λ5-azaphosphinines are notably stable with melting points near or at 200 °C. Scheme 1.30 Phosphete and isothiocyanate cyclization into azaphosphinine 73. The first example of benzo[c]-1,2-dihydro-1,2λ5-azaphosphinine 2-oxides were published by Tang and Ding in 2006.37 Their goal was to explore the azaphosphinine analogues of isoquinolin-1-ones, which they termed phosphaisoquinolin-1-ones. To generate these species, the authors first synthesized a library of o-(1- alkynyl)phenylphosphonamidate 74. These were prepared in two steps by chlorinating the starting o-(1-alkynyl)phosphonic acid monoester with thionyl chloride and subsequently aminating with various primary amines. The phosphonamidates were then cyclized in a Pd-catalyzed reaction to yield 75 (Table 1.3). Because this was the first reported instance of the PV–NH intramolecular heteroannulation, a variety of transition metals and temperatures were investigated, revealing the use of PdCl2(MeCN)2 at 80 °C as optimal. Although, the reaction times varied from entry to entry, there was little notable effect on yield resulting from the R group identities. One noted exception was P P NMe2Me2N Me2N NMe2 + S C N R (2 equiv.) N NS P P S NMe2 NMe2 NMe2 NMe2R R N P S R NH P R NMe2 S NMe2 NMe2 NMe2 72 73a-b 73a: R = Et, 46% 73b: R = Ph, 35% 71 57 for 75k where only 15% yield was isolated under normal optimized conditions, but the addition of a few drops of AcOH led to the dramatically improved yield of 65%. The authors proposed that this was a result of an external proton source aiding the cleavage of the vinylpalladium intermediate and regeneration of the PdCl2(MeCN)2. For these reactions only the six-membered product was generated, which is consistent with a 6- endo-dig cyclization. A potential explanation for the regioselectivity of cyclization is that the long C–P and P–N bonds would favor the transition state that leads into the six- membered product. The authors studied the antitumor properties of 75 in vitro, noting at high concentrations these species had very high inhibition ratios of A-549 lung cells in SRB (sulforhodamine B) assay; however, this inhibition fell off dramatically at lower concentrations, so further analysis is warranted. Table 1.3 Substrate scope of cyclization of 74 to afford 75. R1 R2 R3 Product Yield [%] H Ph Bn 75a 80 H Ph H 75b 68 H Ph n-Pr 75c 72 H n-Bu Bn 75d 87 Cl Ph Bn 75e 85 Cl Ph n-Pr 75f 67 Cl n-Bu Bn 75g 85 Cl p-EtC6H4 Bn 75h 72 Cl p-EtC6H4 n-Pr 75i 70 Cl cyclopropyl Bn 75j 90 Cl CH2OΜe n-Pr 75k 65 OΜe Ph Bn 75l 79 P R2 O OEt NHR3 P N R2 R3 O OEt PdCl2(MeCN)2 (10 mol%) 74 75a-l R1 R1MeCN 80 °C 58 In 2008, Ding and coworkers published a follow-up study that now included added allyl halide 76 in stoichiometric excess.70 This reaction yielded the same benzo[c]1,2- dihydro-1,2λ5-azaphosphinine scaffold as previously observed but with a 4-allyl substitution leading to series 77 (Table 1.4). A screen of reaction conditions showed that with excess methyloxirane the desired product 77 was formed in very good yield, with 75 generated in small amounts. Increasing the equivalents of both methyloxirane and allyl halide improved the yield of 77 and decreased formation of 75. The reaction is decidedly robust with a large functional group tolerance and good yields. Much like the previous entry from Ding, it appears that the electron density of the phosphonamidate starting material has little bearing on the yield of the product. This reaction also tolerates N-unsubstituted phosphonamidates, as is the case with 77b. It is also worth noting that the reactivity of the system is selective for the allyl halide over the aryl halide even when both are the same (e.g., 77i-l). The authors do note that the use of the substituted allyl chlorides (e.g., 3-chloro-1-butene) leads to an internal alkene in the final heterocycle with a consistent 77:23 distribution of E to Z isomers across all such products. Table 1.4 Cyclization and subsequent allylation of give azaphosphinines 77. R1 R2 R3 R4 X Product Yield [%] H Ph Bn H Br 77a 90 H Ph H H Br 77b 69 P R2 O OEt NHR3 X PdCl2(CH3CN)2 methyloxirane MeCN 80 °C P N R2 R3 O OEt 77a-q R1 R4 R4 R1 74 76 59 Cl Ph Bn H Br 77c 92 Cl Ph n-Pr H Br 77d 87 Cl p-EtC6H4 Bn H Br 77e 88 Cl n-Bu Bn H Br 77f 82 OMe Ph Bn H Br 77g 85 H Ph Bn Me Cl 77h 85a H n-Bu Bn Me Cl 77i 78a Cl Ph Bn Me Cl 77j 86a Cl Ph n-Pr Me Cl 77k 81a Cl p-EtC6H4 n-Pr Me Cl 77l 83a H Ph Ph H Br 77m 83 Cl Ph Ph H Br 77n 80 OMe Ph Ph H Br 77o 78 H Ph CH2CO2Et H Br 77p 82 Cl Ph CH2CO2Et H Br 77q 85 [a]Products isolated as (E/Z= 77:23). As with their previous work, the authors also tested the biological properties of nine derivatives of 77. At a concentration of 20 µg/mL, the enzyme Src homology 2- containing phosphatase-1 (SHP-1) inhibition ratios varied from 20.2% (77a) to 54.3% (77i). The heterocycles were then tested against melanin-concentrating hormone receptor-1 (MCH-1R) with IC50 values varying from 3.78 (77d) to 10.23 µmol (77e). The benzo[c]-4-allyl-1,2-dihydro-1,2λ5-azaphosphinine 2-oxides showed no MCH-1R activities and are reported in the publication as the first example of using phosphorus analogues of heterocyclic natural products as MCH-1R inhibitors. An in-depth screen of a variety of antagonists of MCH-1R by Wang and coworkers in 200871 showed that of the derivatives of 75 and 77 tested, only 75a' (Cl on C(4)) showed significant binding affinity (Ki = 115.7 nmol/L) and potent antagonism (KB = 23.8 nmol/L). The authors note that the benzo[c]-2-ethoxy-1,2λ5-azaphosphinine 2-oxide core may prove to be a 60 powerful motif in MCH-1R binding in the future despite being structurally quite different from previously found MCH-1R modulators. Scheme 1.31 Palladium catalyzed C–H activated heteroannulation to furnish chiral azaphosphinines 79. Conditions A: Pd(OAc)2 (5 mol%), L2 (10 mol%), K3PO4 (1.5 equiv.), PivOH (30 mol%), toluene, 80 °C. Conditions B: Pd(dba)2 (8 mol%), L3 (10 mol%), Cs2CO3 (1.5 equiv.), PivOH, (40 mol%), hexanes, 60 °C. [a]Reaction performed at room temperature. In 2015, Duan and coworkers and Ma and coworkers kicked off what would become a period of great activity for azaphosphinine chemistry.72,73 The two groups submitted P N O R3 Br R1 R1 R2 P N O R3 R1 R1 R2 78 79a-x Conditions A (Duan) 79a-l: R3 = Me 79a: R1 = H, R2 = H, 94%, 90% e.e. 79b: R1 = H, R2 = p-Me, 88%, 93% e.e 79c: R1 = H, R2 = p-OMe, 80%, 91% e.e 79d: R1 = H, R2 = m-F, 94%, 90% e.e 79e: R1 = H, R2 = m-CF3, 92%, 92% e.e. 79f: R1 = H, R2 = p-Cl, 88%, 93% e.e. 79g: R1 = p-OMe, R2 = H, 88%, 89% e.e. 79h: R1 = p-Cl, R2 = H, 87%, 91% e.e.[a] 79i: R1 = p-CF3, R2 = H, 91%, 91% e.e.[a] 79j: R1 = o-Me, R2 = H, 62%, 85% e.e. 79k: R1 = 3,5-(CF3)2, R2 = H, 79%, 83% e.e. 79l: R1 = 3,5-(CF3)2, R2 = m-Me, 58%, 86% e.e. 79m: R1 = H, R2 = H, R3 = p-OMeC6H4, 81%, 91% e.e. Conditions B (Ma) 79b: R1 = H, R2 = p-Me, 99%, 95% e.e. 79d: R1 = H, R2 = m-F, 99%, 95% e.e. 79e: R1 = H, R2 = m-CF3, 99%, 95% e.e. 79f: R1 = H, R2 = p-Cl, 98%, 95% e.e. 79n-u: R1 = H 79n: R2 = H, R3 = Et, 94%, 89% e.e. 79o: R2 = H, R3 = n-Bu, 61%, 88% e.e. 79p: R2 = m-Me, R3 = Me, 72%, 92% e.e. 79q: R2 = p-t-Bu, R3 = Me, 99%, 97% e.e. 79r: R2 = p-Ph, R3 = Me, 68%, 93% e.e. 79s: R2 = p-CN, R3 = Me, 64%, 96% e.e. 79t: R2 = p-CF3, R3 = Me, 83%, 96% e.e. 79u: R2 = H, R3 = Bn, 12%, 92% e.e. 79v: R1 = p-Ph, R2 = H, R3 = Me, 90%, 95% e.e. 79w: R1 = p-Me, R2 = H, R3 = Me, 92%, 96% e.e. 79x: R1 = m-OMe, R2 = H, R3 = Me, 54%, 91% e.e. O OMe Me O O Ph Ph Ph Ph P NMe2 L2 Conditions A or Conditions B O OMe Me O O Ph Ph Ph Ph P NEt2 L3 61 and published their papers within a week of one another and the content of both is very similar, with some identical derivatives being prepared. These works were conceptual continuations of the studies of not only Lee57 and Cramer38,58 but also the very early systems from Dewar47 and Campbell,49 with the aim being the generation of chiral, dibenzo[c,e]1