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Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

bonding and non-bonding MOs of PH3 bonding and non-bonding MOs of PH5

# of R

P(III) ← → P(V) O P P R R R R R R phosphine oxide D3h C3v C2v O O JACS. 1972, 3047. P P P P R NH R OH R OH R NH Chem. Rev. 1994, 1339. R 2 R R R 2 D C phosphineamine phosphinamide 3h 4v O O O

R P R P R P R P R P R P NH2 NH2 OH OH NH2 NH2 H2N HO HO HO HO H2N phosphinediamine phosphonamidite phosphonamidate phosphonamide O O O O H N P P P P P P P P 2 NH HO HO HO HO HO HO H2N H N 2 NH2 NH2 OH OH NH2 NH2 NH2 2 H2N HO HO HO HO H2N H2N phosphinetriamine phosphorodiamidite phosphite phosphorodiamidate more N O more O Useful Resources more N P P P Corbridge, D. E. C. : Chemistry, Biochemistry and H OH H H H H H H H Technology, 6th ed.; CRC Press Majoral, J. P. New Aspects In Phosphorus Chemistry III.; Springer phosphinous phosphane phosphane Murphy, P. J. Organophosphorus Reagents.; Oxford acid oxide Hartley, F. R. The chemistry of organophosphorus compounds, O O volume 1-3.; Wiley P P P Cadogan. J. I. G. Organophosphorus Reagents in Organic H OH H OH H OH HO HO H Synthesis.; Academic Pr phosphonate phosphonus acid phosphinate Not Going to Cover ↔ (phosphite) Related GMs Metal complexes, FLP, OPV Highlights in Peptide and Protein NH S R • oxidation state +5, +4, +3, +2, +1, 0, -1, -2, -3 Synthesis (Malins, 2016) R P-Stereogenic Compounds P P R P • traditionally both +3 and -3 are written as (III) R • 13/25th most abundant element on the earth (Rosen, 2014) R • but extremely rare outside of our solar system in Transition Metal phosphine phosphine phosphorane Catalysis (Farmer, 2016) Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Me P Me Me Low-Coordinate Low Oxidation State P tBu tBu P P phosphaalkyne R N P PivCl 2 P Me Cl TMS OTMS NaOH R = tBu Nb N tBu PTMS3 P O H O P NR2 then Na/Hg tBu N -2 Nb tBu R2N Me Nb N tBu 5x10 mbar, 160 ºC NR2 95% R2N Me N O 1. Tf2O Me Nb 2. Δ tBu R2N O 1. LAH NR2 2. DBU R = Me R2N P recyclable Me EtO HP P R EtO J. Chem. Soc. Chem. JACS. 2000, 13916. Commun. 1992, 415. PPh3 20-80 ºC PPh3 Cl JACS. 2012, 134, 13978. P R P 1. Me2NPCl2 Mg 2. HCl JACS. 2014, 13586. R JACS. 2018, 17985.: P31 nuclear spin- rotation coupling (J = 0←1) (R = Me) R ≠ H, tBu

tBu O N R’ tBu Ph O N R' Ph N O Ph Ph R X N P P R N PhMe, tBu P V tBu P [2+1] then O Cl Cl P O 100 ºC, 14 days X 1,3-X shift Cl P P tBu N Ph R R P R Ts tBu tBu P A B C Ts N N P P A C R 2TsN3 P P B [2+3] P N N N Δ or Zr cat R P P N tBu P tBu P R R P tBu P tBu N O N R Ts Ts H O ACIE. 1984, 900. P ene Weidner. S (2002) PhD thesis, University of Kaiserslautern R P R Chem. Rev. 1990, 191. Chem. Rev. 1990, 191. JACS. 1982, 4484. ACIE. 1987, 1257. ACIE 1989, Et3N Et3N LnM R ML [2+2] 225. Phosphorus Sulfur. 1987, 479. Bull. Soc. Chem. Br Br P P P n THF, -5 ºC Br THF, 40 ºC Fr. 1995, 652. Synthesis. 1998, 125. ACIE. 1986, Br Br P Br M = Co, Rh, Hf, Zr 644. ACIE, 1988. 1157. Chem. Ber. 1988, 637. ACIE. P TL. 1989 817. R Br Br 1995, 2227. ACIE. 1998, 1233. Chem. Eur. J. 2000, Polyhedron. 1990, 991 4558. ACIE. 1989, 1013. ACIE. 1992, 758. Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Phosphide Anion C, SiO2 1200-1400 ºC • reduction of energy inputs O O Cl2 O • less waste O HSiCl3 (neat) versatile 1 Mt/y O P P O • no elemental P P P organophosphorus O O 110 ºC, 72 h Cl Si SiCl • no Cl2 oxidation P O O 3 3 precursor 65%, gram scale O O •3TBA•2H2O O O Ph O 1. [TBA]3[P3O9]•2H2O, P Cl HSiCl , 64% (one-pot) P N 3 H Cy O O O H2SO4 HO 2. H O 2 2 HO2C Ph Ph Me Me Me 90 Mt/y fosinopril Direct Method original prep: 4-phenyl-1-butene, H3PO2, AIBN, 93% contaminated w/ 2% anti-Markovnikov regioisomer H3PO4, TBACl Oct Cl Oct PH2 JACS. 2019, 6375. OPRD. 1997, 315. Science 2018, 1383. JACS. 2019, 6375. HSiCl3, 110 ºC P-P bonds for detail see; Corbridge, D. E. C. Phosphorus: Chemistry, Low-Coordinate Hypervalent Phosphorus useful reviews Biochemistry and Technology, 6th ed.; CRC Press JACS. 1987, 627. Chem. Rev. 1994, 1215. TIPS P tBu tBu tBu tBu O O O O tBu Nb XH N N tBu X if X = OR N TIPS -2 tBu Ar Ar N P N P N P N P Phospha-Wittig P PMo(N[tBu]Ar) TIPS H O Ar 3 OR P P P O O reductive O O P tBu TIPS elimination tBu N Mo tBu tBu tBu tBu Mo tBu N tBu if X = H stable if N tBu N tBu N Ar JACS. 2009, 8764. X = H, NHR N Ar 10-P-3 ADPO R Ar Ar Ar N P • T-shaped O Ar O O hν P Me • strongly reducing N P iPrOH P OiPr P P P • formally dianionic P O O N P Me tBu P P hex, DMSO tBu • pseudo-TBP H P 15% (34% brsm) 8-P-3 8-P-3 Me Me Me O Me ACIE. 2010, 7516. w/o unsaturation JACS. 2014, 13586. 10-P3 not observed R stable Cl 1. AlCl P 3 2. LAH P Δ OH O O P P(OMe)3 H BH3•DMS 55% For P2 surrogate also see; NH N P N P Science 2006, 1276. OMe instead BH adduct recall: phosphaalkyne precursor 3 Inorg. Chem. 2007, 7387. OH O dimer was isolated - O P3 ; ACIE. 2010, 1595. Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

R = H active reductant tBu stepwise tBu R = Pr, O oxidative Naph Naph R R O= 2,6-diiPrC6H3 N N addition N N P NH R R H P 2 N H Me H Me ADPO N P N N R Me Me H H N P first-order w/ H no H cat. 1 mol%, HBpin ADPO, [NH R]3 O RH2N reductive N N 2 O H tBu elimination 91% JACS. 2019, 14083. tBu Ar N Br 91:1 er N Br also see; JACS. 2018, 652. tBu tBu tBu N H O O Ar Phosphine Me Ph P P H H N NH NH2 miscellaneous phosphine synthesis; for more info see GM by Rosen (2014) NH Bn N 3 N 2 N Ar P P tBu Ar N P N P P R R H Me H rt N 3RX P tBu tBu Ar P P N N Ar Ti tBu , rt R O NH2iPr O Ar = 2,6-diiPrC H P 6 3 tBu N 64-97% tBu tBu JACS. 2014, 4640. tBu 3,5-Me2C6H3 New J. Chem., 2010, 1533. other oxidative addition reactivities of ADPO JACS. 2014, 16764 R = Ph, Cy, TMS, Ph3Sn Org. Chem. Front. 2018, 3421. tBu Ph Cl 1. Et N O O O Cl O N P 3 P F 2. H O CO Et Cl O O O Br 2 2 F F C P N CO Et N P CF O 3 H 2 3 F C Ph 3. HSCH2CH2SH, S F 3 tBu Br O Cl F C O BF3•Et2O tBu P O 3 S O O O 4. Raney-Ni tBu O O 5. LAH tBu F O F N P 6. HCl NaOH F3C CF3 Ph w/ F CF3 w/ o-chloranil w/ Heteroat. Chem. 1993, 213. JACS. 1987, 627. JACS. 1987, 627. P P

CF3 tBu Na spiro conjugation O N P O CF3 Tet. 1983, 4225. O CF 3 N P CN F C CF3 N P 3 H [2+3] CF3 Ph chemische berichte, CF3 CF3 N2 CF3 tBu CF Ph NaOMe 1966, 514. CF O 3 Ar P F C CF Δ O 3 Ph w/ 3 3 tBu P P tBu Ph CN JACS. 1987, 627. D symmetric orbitals Ph 2d π Ph NO2 NO JACS. 1967, 5208. S ≈ 20% of planar system 2 Phosphenium Cation; Chem. Rev. 1985, 367. styrene (10 eq), via tBu Me4NF (15 mol%), tBu P(CH OH) P Ph 2 3 [FpTHF][BF4] (10 mol%) P N P N P N tBu Fe CO BF 73%, >99:1 dr F 4 CH O BF4 CO Ph 2 Me Me ACIE. 1964, 384. Me JACS. 2019, 13336. Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Me Me Me Me 1. PhCCCO Me NHCbz 2 NHCbz Ph3P, Ph3P•HClO4 NHCbz Me Me 2. S PPh3 PhPX2 Δ 8 R Ar R CO2H 5 mA, DCM, -30 ºC R CHO P P O (+)graphite/(-)graphite TL. 1992, 1347. Ar Me Me O phosphol CO2H PBu3, MeSO3H, TBAB Me Ph Me Ph both non Ar substituted P P Ar 30 mA, DCM Ar substrate and 6-membered Ar Ar S ring formation failed O CO2Me (+)graphite/(-)graphite MeO2C CO2Me CL. 1994, 249. N O O PBu , MeSO H, OH O 3 3 Ph Ph PhCH Et NCl R CO2H 2 3 J. Chem. Soc. chem. commun. Tsuji-Trost Heck 1995, 871. w/ Ar = Ph, R = iPr w/ Ar = Ph, R = tBu OL. 2000, 2885. 20 mA, DCM, 0 ºC Chem. Pharm. Bull, 1997, 94%ee 93%ee (+)graphite/(-)graphite H 1729. Electrochemistry w/ ; Acc. Chem. Res. 1999, 72. CV Ph Ph not observed Ph P P Ph P Ph Bu Nu Ph Ph Ph H [lutidinium][X], K2CO3 NuX Ph TBAI, DMF, (-)Hg Ph P Ph PPh3 O Ph Ph P Ph P /H O, (+)SCE Ph Ph Ph 2 Ph P Ph 20 mA, DCM Ph X = H, SiMe3, Ac Ph -2.7 V Bu (+)graphite/(-)stainless steel Ph JACS.1968, 1118. miscellaneous O Eox (MeCN, SCE) [V] Me R PPh Me Me Me NHTs 3 PPh3 0.95 Ph NaH + R PPh3 N PBu3 0.90 2 PPh3 N N CHR' P(OR) 3 1.60 Ph N PPh P(NMe ) 0.91 tBu tBu 3 from from Ac enol 2 3 Me Me one-pot Wittig worked Phosphorus and Sulfur 1980, 55. S tBu TL. 1985, 2199. tBu non-diazo nucleophiles Chem. Pharm. Bull. J. Chem. Soc. Chem. 1987, 4960. Commun. 1990, 1310 J. Chem. Soc., Perkin Trans. 1, 1974, 1794. O conductivity B: HCl Tet. 1976, 1641. -3 O from allyTMS decrease detect 10 mol% H O in non basic organic solvent PPh TMSCl 2 3 PPh3 Chem. Lett. 1987, 1335. A: 2Ph P + CCl → Ph P=CCl + Ph PCl PhMe, Chem. Pharm. Bull. 3 4 3 2 3 2 A: Ph3PCl2 + H2O → Ph3PO + 2HCl O 150 ºC 1990, 2698. + - A: Ph3P=CCl2 + 2HCl → [Ph3PCHCl2] Cl + HCl from diketone Chem. Pharm. Bull. 1988, 613. J. Chem. Soc. Commun. 1988, 874. C

C8H17 B: 2Ph3P + CCl4 → Ph3P=CCl2 + Ph3PCl2 Me + - Me B: Ph3P=CCl2 + HCl → [Ph3CHCl2] Cl Ph3P, Ph3P•HX Me H Cl A: HCl 30 mA, DCM, C: 3Ph P + CCl → Ph PCl + H (+)graphite/(-)Pt Ph PO increase 3 4 3 2 Cl 3 H Ph3P PPh3 HO H Chem. Phar. Bull. 1995, 1076. natureforsch. 1978, 33b, 1205 Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19 phosphine catalysis Wittig and Staudinger type reactivities Morita Baylis Hillman type reactivities base reductant additive T [ºC] ref useful reviews; Chem. Rev. 2018, 10049. Beilstein J. Org. Chem. 2014, 2089. Me first cat Wittig Na2CO3 Ph2SiH2 – 100 cat. PBu3, ACIE. 2009, 6836. DIPEA, F O O Ph SiH – Chem. Eur. J. (p-F-Ph)3BiCl2 P DIPEA 2 2 100 2013, 15281 Ph O JACS. 2004, 5350. Et3N PhSiH3 Et3•HCl 50 OL. 2016, 3758. BnN BnN for paroxetine Tet. 2006, 10594. OMe

Me O Me O MeO C 2 Me O MeO2C P Ph SiH – cat. PBu3 H for hirsutene NaOBoc 2 2 110 ACIE. 2014, 12907 Me ACIE. 2003, 5855.

Me H Me Me 4-NO2 Chem. Eur. J. Me DIPEA PhSiH3 rt CO Me C6H4CO2H 2013,19, 5854. O 2 O P CO Me Bu O Me Me 2 Me cat. dppf Me O O Me Me Me P O N N PhSiH – ACS Catal. DIPEA 3 rt 2019, 9237. CO2Me CO2Me Me O O JACS. 2017, 14893. Me Me Me Ph EtO2C 9-BBN cat. PBu3 P 9-BBN EtO C R' CO2Et R 2 CO Et O Me 2 CHO PhCO2H, HSi(OMe)3 Ar Ph Ar CO2Et CO Et EtO2C 9-BBN EtO2C 9-BBN EtO2C 9-BBN 2 PhMe, 100 ºC Chem. Eur. J. 2016, 2458

Ph Ph 1. PPh3 (5 mol%), TMDS O O O Ph CbzN Ti(OiPr)4 (10 mol%), PhMe, reflux N N F OTBS OMe 2. TBAF N JACS. 2014, 10605. N3 vasicinone OH watch out for side reactions Adv. Synth. Catal. 2014, 1098. O O Ph P 3 ARKIVOC. 2011, 183. Ar Ph Ar H O, rt, 3 h Ph 2 Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Mitsunobu reaction pKa yield% watch out for side reactions Me CO iPr iPrO path a 2 < 10 > 80 OMe N A NC NC NH EtO2C CO2Et Me N O N CO2iPr productive O HN N RDS b CO2iPr 10 - 13 60 - 40 NBoc from a Me OH EtO2C CO2Et DIAD, PPh3, THF, rt Me Me R OPPh HN N OL. 2005, 495. A H 3 path b > 13 0 Wittig from ketone R CMMP, PhMe, rt - 100 ºC OH PMe3, 2 h, 75% more basic DEAD variants dead end TL. 2000, 235. H PPh Me, 48 h, 60% O 2 Me Me O PhSiH3 Ph P, 72 h, NRX Me Me Ph CO2Me 3 Me O O Me “catalytic Mitsunobu” P(OEt) , 72 h, NRX N N 3

N N X N N Chem. Commun., 2006, 1218. N N Me N N Me N N HO2C PR3 (10 mol%) O Ph3P Me Me Me Me P O O CL. 1994, 539. O Ph NO Ph O TIPA DHTD no oxadiazole formation 2 Ph OH R N EtO C NH NO Ts 2 2 MeO C CO Me THF, MS 5Å, N R HN Cl OH Ts 2 2 MeN 68% (original report) MeHN PBu3, 70 ºC, 48 h 38% (reproduction) Ph Ph (10 mol%) pKa = 11.7 Cl benzene, 100 ºC, 67% not reproducible Fe(pc) (10 mol%), O2

EtO2C CO2Et Me CO Et O N Me CO Et MeO2C CO2Me 2 as above 2 2 NC PR 4% yield, 12% inversion 3 = 0.5% Mitsunobu product OH O Bu3P Tsunoda reagent Ph original report; ACIE. 2015, 13041. R = Bu: CMBP pKa = 13.3 O counter argument; OL. 2016, 4036. Me: CMMP w/ DEAD 2% catalytic Mitsunobu HO O CMBP 54% O CF Nu Ph 3 Ts SMe Ph P Nu H Me CN NHTs TL. 1995, 2531. Ph P Ph Ph Ts TL. 1996, 2457. R R F3C O Hex Me Hex Me TL. 1996, 2459. H2O redox-free Mitsunobu reagent pKa = 23.4 pKa = 12.0 pKa = 10.2 Chem. Commun. 2014, 7340. w/ DEAD, TIPA, w/ DHTD 50% w/ DEAD Ph3PNTs formation DHTD 0% CMBP 99% (120 ºC) CMBP 89% (80 ºC) CF3 CMBP 72% (120 ºC) 100% stereoinversion Ph Ph O CF O 3 P P Me O H Ph P O pKa = 10.2 OH Ph Me CO2Et w/ DIAD 11% R R O CMBP 75% (110 ºC) from phosphonate + Tf2O 2 J. Nat. Prod. 2017, 2335 Nu OH phosphonium salt as LA cat for DA Science 2019, 910. R R Tet. 2006, 401. Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Cadogan reaction TMSO O from NO and O 2 O P(OTMS)3 TMSO O P N Br w/ cat. P, PhSiH3 OTMS N JACS. 2017, 6839. OTMS O HO TMSO O O PhHN H H O JOC. 1982, 3453. N CN TMSO H Ph Phosphinetriamine Me P P N from NO and C-H from NO2 and B(OH)2 2 review; Tet. 2003, 7819. H w/ cat. P, PhSiH stereoretention promots (3+1) 3 w/ cat. P, PhSiH Me Me JACS. 2018, 3103. 3 N Verkade base (0.2 eq), quant cheletropic addition JACS. 2018, 15200. MeN P TBSClO NMe 4 Bz O Me N from NH and CO H TBSCl, imidazole, DMF 10% from NO2 and B(OH)2 2 2 N w/ cat. P, DEBM, PhSiH JACS. 1996, 12832. Verkade base 99% stereoretention 3 DMAP 76% w/ cat. P, PhSiH JACS. 2019, 12507. pKa = 32.9 Me O TBS 3 N P4-tBu 49% cat Me JACS. 1989, 3478. J. Org. Chem. 1996, 2963 MeO JACS. 1990, 9421. Me P Me Me JOC. 2000, 5431. Me N Me Kukhtin−Ramirez reaction H R3 PR3 Phosphite R EtO C O O P O S 2 O O O O N Ph S Ph P(OEt) R R R R R R N 3 S R R N MeO catalytic esterification Ph OTBS N N N w/ O NO2 TsN Me R = CO Et H 2 R = H JOC. 1976, 129. O Me P N Ph CO2Me N S Me P(OEt)3 Me Me J. Chem. Soc., Perkin Trans. 1, CO2Et w/ P(NMe2)3 Me N Ph CO2Me N 1975, 2396 Me ACIE. 2012, 10605. JACS. 2015, 616. NO2 N O 98%ee w/ NO Me O2N 2 N N N O H p-MeOC6H4 NMe N N P(OEt)3 O N O Cl 63% 3% Ph *CO2Me P NMe2 Cl Cl N Me N NO2 N NMe O O H OMe Ph p-MeOC6H4 JOC. 1977, 1791. O MeO OMe CO Me Br 2 N Me CO Me O H 2 Ph NMe N OH MeO P(OEt)3 Ph CO2Me Ph CO2Me MeO H Ph CO2Me MeO w/ P(NMe ) 2 3 w/ P(NMe ) OL. 2013, 3090. w/ P(NMe2)3, RBr 2 3 OL. 2015, 3810. JOC. 2011, 2548. MeO NO2 MeO JOC. 1968, 4446. Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

P(III)/P(V) Transition Chem. Ber. 1943, 218. Chem. Ber. 1928, 1264. O OPh MeO Ph OPh H J. Organomet. Chem. 1973, 113. OMe OPh O O OPh Me Me O P PhO P P P O PV O O PIII OH OMe OPh O O OPh scrambling OMe OPh Me O O 9 : 1 O O MeO OPh DCM, rt O O HN P H HN P H • temp increase favors P(III) NH O S S S • basic solvents favors P(III) O O Me P P P Ph Ph Me • unsaturation (aromatic backbones) favors P(V) Me Me 205 ºCPh Me • higher symmetry favors P(V) Me Me Me JACS.1969, 6878 • more substituion/sterics favors P(V) P(III)% at 100 ºC: 0 / 20 • harder ligand favors P(V) Acc. Chem. Res. 1971, 288. Higher Apicophilicity • higher electron negativity 90º F Ph instantaneous O H • good π-acceptor F P F P N N O O F CF3COPh Me O • small size (hard to predict) F F N P N N P N CF3 Me Acc. Chem. Res.1971, 288. small ring favors large ring favors NH -70ºC N H Me ap-eq spaning eq-eq spaning Me N N Me Me P Ph 100% P(III) H Me Ph HO O O OH- Ph slow Ph Me P Ph P N N P Ph P Ph H CF COPh CF O 3 3 enantioselective Me Ph OH Me N P N N P N hydro phosphorylation OH inversion N rt N from hydridophosphorane Ph Me Me Me Me Me Me Me 90% ee, JACS. 1990, 6142. OH- O 100% P(V) JACS. 1974, 2268. Me P Me P Me Inorg. Chem. 1988, 1099. P Ph Ph Ph Me Me Me Geometry of P(V) Me Me OH Ph JACS. 1971, 6341. retention Berry Me Me pseudorotation Me Me OEt (EtO)2 Me Me Me PMe Me OEt P P P Me rt Me OEt P OEt Me OEt MeP(OEt) Me OEt 2 JACS. 1972, 9264. Me Turnstile rotation P radical geometry D hν O OP(OMe)2 P(OMe)2 JACS. 2009, 3418. Ph 100% conv Ph D [(p-MeC6H4)3N][PF6] O2 O1 (25 mol%) O1 P BPR O P phosphonate P Ph P Ar inversion barrier O 2 Ph Ph Ar 5 kcal/mol O O n = 1 <1% Me MeCN, rt, 30 min Me Ph P O n = 2 72% thermodynamically n = 3 83% 99-51%ee 0-18%ee JACS. 2013, 9354. O 1-3 Ph most stable JACS. 1996, 6192. Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

• Et rapid Phosphonium synthetic applications review; Org. Biomol. Chem., 2012, 5327 RO Et -scission Et P(OR) α Adv. Synth. Catal. 2009, 1469. n 3-n P Etn-1P(OR)4-n Et hν Et El or ArI, cat. Pd JOC. 2008, 590. OtBu slow or R Adv. Synth. Catal. 2008, 2967. Org. Lett., 2010, 1568. α-scission Ph P Ph Ph P Ph + Chem. Commun., 2016, 4987 OtBu Et Ph benzyne or Ar2I Ph Et OtBu OtBu P P or tBuO P Et OtBu Et OtBu Et Et R' R = CH2CHCHR’; R = PhOH R = CH2Cl; LAD OH- OtBu Et H Et OtBu α-scission D OPh OH P P Ph Ph Ph OtBu OtBu P P P OtBu OtBu Ph Ph Ph Ph Ph Cl Ph OtBu 70 ºC 200 ºC OtBu β-scission P tBu R’ O O tBu D D Ph OtBu Ph P 10% + Ph PO 70% O OtBu O OtBu O OtBu Ph 3 n P n P n P + tBu n = 1 a:b = 0/100 n = 2 a:b = 50/50 TL. 1961, 724. J. Organomet. Chem. 1972, 77. O O tBu O O tBu O O J. Organomet. Chem. 1975, 93. Chem. Commun., 1998, 1973. a b a b Cl Me Me • radical is most stable at eq OH O • > scission + Me α β Ph P Cl Ph P Cl H2C O Ph P Cl O Me • α scission at apical P-C O • β scission at eq P-C Cl 21% Cl 51% TL. 1961, 724. O P Cl Me • 5-membered ring is exceptionally stable O OH O O O Me J. Chem. Soc. Perkin II. 1972 2225. Ph Cl J. Chem. Soc. Perkin II. 1974, 1101. P P Cl P Cl P P Cl Ph Ph Ph Cl Ph Me Me J. Chem. Soc. Perkin II. 1975, 140. Ph Ph Ph Ph no β-scission up to 130 ºC J. Chem. Soc. Perkin II. 1975, 808. Cl 2-5% 8-10% 40-48% 10% Ph Acc. Chem. Res. 1982, 117. I Me HSnBu , Me O O 3 Me Ph P, OH - Me AIBN 3 P O Ar/EWG Ph R Ph Me Δ P O Ph J. Chem. Soc. C. 1971, 1059. H O O H H O P Ph3P=CH2 MeO O Me CHO NaOMe PPh2 H Me O Ph O MeOH, 70% O P O H O H JOC. 1971, 4028. JACS. 2004, 13190. H 2/1 Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Me Me Me Me Me Me Me Me Me O OH- Me R2Li N N Me P N Me R1 N N P Me P Me P R1 N R2 Ph Me py THF, reflux P R1/R2 Me Ph Me OH Me O R2 py/Ph 65% + 0.2% OLi p-MeC6H4CH2/ Me Me Me Me Me Me BnMgCl 3% + 65% Me R1 = Bn - Me MeI Me Chem. Comm., TL. 1989, 567. JACS. 1987, 5567. OH Me Me Ph P Me Ph 1967, 1113 P P Me Chem. Ber. Ph Me Me Me 1961, 1465. HN O Ph O Ph N py/HO HN N P N Me py P Ph OH O from POR3, HCl aq. reflux 39% Me Me Me py Ph + 60 ºC Me from PR4 , HCl aq. reflux 73% O O O Me TL. 1989, 6365. O Me O Me Me OMe OMe O O P P El, rt O PPh NR OR SR Me OMe Me OMe Me P OMe 2 N N 2 Me Me OMe OMe OMe Me X X X X Me N N X = Br, SCSMe, CO2Me, Me N N N N Ph Ph Ph Ph Ph JACS. 1968, 5924. P P D/T X JACS. 2016, 13806. ACIE. 2017, 9833. 200 ºC Science 2018, 799. JACS. 2018, 1990. JACS. 2018, 8020. OL. 2018, 2607. Ph ACIE. 2018, 12514.ACIE. 2019, 58. N N 10.1021/jacs.9b08504. Ph doi.org/10.26434/chemrxiv.9722603.v1 also known w/ S… 160 ºC Me N P R P P 2 N RM N N N w/ PhMgBr 79% S w/ pyLi 59% R N SOMe OM TL. 1984, 2549. Chem. Ber. 1964, 747. R = H R = NMe2 not observed Ph Ph Ph P PhLi P 120 ºC Ph Ph 85%

JACS. 1970, 6701 Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Phosphate for CPA see; Chem. Rev. 2007, 5744. First synthesis of ATP; Nature 1948, 761. Chem. Commun. 2008, 4097. Aldrichimica Acta, 2008, 41, 31-39. Me TBAClO4 NH2 CO2Et same O O (-)Pt/(+)Hg, N N 3. Ag salt formation CO2Et O BzO P P(OEt)2 EtO C 1. Cl 4. P -2.05V, DMF 2 O CO2Et BzO AgO P O N O N ATP O P(OEt)2 OBz O 2. hydrolysis 5. hydrolysis JACS. 1989, 740. Nitrogen Containing P(V) Syn. Commun. 1994, 1465 OH R for CBA catalysis see; Chem. Rev. 2015, 9277. ACIE. 2019, 12761. for phosphazenes see; Ishikawa, T. Superbases for Organic Synthesis: O O [TBA][P2O7H], nucleoside; O Guanidines, Amidines, Phosphazenes and Related Organocatalysts,; Wiley I , py, H O P O 2 2 O O NMe2 NtBu NMe2 NtBu NMe2 Me N P NMe P Chem. Commun. 20011, 8142 O P P O Me N P NMe 2 2 F O Cl O 2 2 Me2N P N P N P NMe2 JMC. 2002, 5384. O O R NMe2 N NMe2 NMe2 NMe2 N NMe2 O MstCl, DABCO; tBu-P1 Me2N P N P N P NMe2 O Me2N P NMe2 P nucleoside; phthalimide pKa = 26.9 NMe2 N NMe2 O O NMe 3TBA 2 Me2N P NMe2 O P P O OL. 2016, 580. NMe tBu-P4 O NtBu pKa = 42.6 NMe2 O O P N Schwesinger base tBu-P5 N O Me ACIE. 1987, 1167. pKa = 46 O O 1. PyAOP O Me Ph Me Ph P 2. Nu P BEMP Ph P N P Ph O O O O pKa = 27.6 HO tBu Ph Ph 3 O P P O O P P Nu tBu-P4 1 h, 91% Nu = NR2, OR, CHPPh3 O TMS O O CsF 24 h, 0% O O no nucleotides/nucleosides O tBuCHO, base 24 h, 0% JACS. 2019, 1852. BEMP O O N P nucleoside, N DMF, rt Chem. Commun., 2006, 4850 X O Me N O O F C S O P P S N P Nu HO CF 3 O N Me Me H X O O DMF 3 O CF CF MeCN, <10 min; O P P O 3 2 Ph Ph = F, N3, NR2, Me N Cl 2TBA Me Me oxidant O 2 CF3 O Y R imidazole, w/ tBu-P4, CF H from (ArS) - stable 3 2 X = O, CH2, CF2, CCl2, NH Y = O, S, Se OR, OPO2F in THF, -30 ºC w/ tBu-P4, CF3H O + [HtBu-P4] + F + CF2 (0% w/ KOtBu) in THF, -10 ºC Me O O O Org. Biomol. Chem. 2013, 1446. NH Nu P X P O P O NBoc R O O O w/ tBuXPhos Pd G3, N P N O O O O R RP N A O P O P O P O O Et-P2, THF, rt, 67% 3Na MeN NH OL. 2015, 3370. N PR O 3 O O 2 RP N not synthesized yet from P-imidazolide O N NCO2Et N 10.1021/jacs.9b08273 Me N PR interesting w/ ZnCl2, ATP 3 S P N properties? R Baran lab Group Meeting Yuzuru Kanda Organophosphorus Chemistry 09/20/19

Sulfur Containing P F3C CF F C CF3 R = 3 3 S S F3C R P P R p-OMeC6H4 Lawesson’s reagent J. Chem. Soc. Chem. LiNaph; F3C Commun. 1982, 457. O O X DO S S SMe (or ) Davy’s H2O; Et4NBr P D2O, AcOH SPh (or p-OMeC6H4) Japanese Synthesis. 1984, 827. P H O X P H p-OPhC6H4 Belleau's TL. 1983, 3815 F3C DO O RCHO S Cl S HO D F3C S F3C O CF Me H CF 3 SMe O N SPh F3C 3 Ph X = H N CO2H Me H • no H2 X = D O one-pot w/ Japenese • worked in presence of 100 eq H2O • converted H+ to H- JACS. 2009, 16623. w/ P2S5, MeOH, w/ Japenese SMe from CO2H Cl3C6H3, 130 ºC THF, 20 ºC PhMe, 110 ºC Ar 10 min 90 min 5 min O2S Ph F C O N H • ()2 N Me Me 3 Ph O Me Ph X1 N P N O Cl N Ph H X4 NMe MeN Me Lawasson’s PhMe, 110 ºC w/ N O CF3 X1 = X2 = X3 = X4 = S cat (2 mol%), DCM, Me Ph SO2 -90 ºC, 96%ee O O O Belleau’s, THF, rt Ar Ar = 3,5-Ph2C6H3 JACS. 2018, 2765. O X = S, X = X = X = O Me 1 2 3 4 Pest. Manag. Sci. 2001, 1000. Me NMe MeN X2 O X3 Me O Me Me

Phosphate Ion no racemization at rt Cl + ACIE. 1997, 608. Cl Cl O O Cl O Cl O Cl O P P O O P O O O Cl O O Cl + Cl first phosphate anion hexacoordinated Chem. Ber. 1965, 576 Cl Cl phosphate cation Cl OL. 2002, 2309