Hydrogen Atom Transfer 4/12/14

Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

1. Introduction 2. Polarity Reversal Catalysis Hydrogen atom transfer (HAT) is a concerted movement of a proton and an electron (i.e., H•) A useful concept in HAT is radical polarity. Despite being uncharged species, radicals can in a single kinetic step from one group to another. (Mayer, J. Am. Chem. Soc. 2007, 5153) have nucleophilic or electrophilic tendancies. A—H + B• A• + B—H - e– + e– A A A nucleophilic electrophilic By definition, HAT is intimately linked to organic free readical chemistry, with one of the radicals radicals most useful hydrogen atom transfers in organic synthesis being the termination of a carbon A qualitative approach to determining the "philicity" of a radical centered radical with Bu SnH. (Curran, Tetrahedron Lett. 1985, 4991) 3 1. Consider the oxidized (cationic) and reduced (anionic) forms of A• Me Me Me Me 2. Determine which of the forms is more stable Br nBu3SnH H Me AIBN Me 3. Assign the "philicity" of the radical: a. If A+ is more stable, A• is a nucleophilic radical because it wants to lose an e– PhH, 80 °C b. If A– is more stable, A• is an electrophilic radical because it wants to gain an e– Me H Me H Me H Some practice: Me Me Me Me - e– + e– HH HH tBuO tBuO tBuO nBu SnH 3 nucleophilic electrophilic more stable radical radical HAT Quantitative treatments of radical "philicities" have also Me H Me H - e– + e– been developed. (Fisher, ∆9(12)-capnellene tBu tBu tBu Angew. Chem. Int. Ed. more stable nucleophilic electrophilic 2001, 1340; Héberger, J. radical radical Org. Chem. 1998, 8646; De Although nBu SnH is a great hydrogen atom 3 – – Proft, Org. Lett. 2007, 2721) donor (BDE = 78 kcal/mol), it's toxicity is a - e + e Et Si Et Si Et Si well-known problem and it can be difficult to 3 3 3 more stable nucleophilic electrophilic purify nBu3SnX byproducts away from the radical radical desired product.

Just like Sn2 reactions, polarities of the reactants should be matched for favorable reactivity. Procedures that are catalytic in tin have been El• + Nuc–H El–H + Nuc• developed. (Fu, J. Org. Chem. 1996, 6751) favored Nuc• + El–H Nuc–H + El• O O These classifactions nBu3SnH represent polar effects (10 mol%) El1• + El2–H El1–H + El2• in the transition states disfavored 1• 2 1 2• Me PhSiH3 (1.2 eq.) Me Nuc + Nuc –H Nuc –H + Nuc Me Me Me AIBN, PhMe, ∆ Me (80%) E.g., trialkyl silanes are typically awful at homolytic reduction of functional groups via HAT. Several reviews have been published on fast Et Si• + Et Si–X + • alternatives to Bu3SnH and other stannane 3 R–X 3 R reducing agents; several of these topics will unfavorable • • not be discussed. (Walton, Angew. Chem. Int. R + Et3Si–H R–H + Et3Si Replace with two steps polarity Ed. 1998, 3072; Studer, Synthesis 2002, 835; Nuc1• Nuc2–H Nuc1 –H Nuc2• that are polarity matched? Chatgilialagou, Chem. Eur. J. 2008, 2310) mismatch Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

Adding a catalyst that replaces the polarity mismatched step with two polarity matched ones Me R Me R should yield a net favorable reaction. This known as polarity reversal catalysis (PRC). (tBuO) , hυ R• + R'S–H R–H + R'S• Favorable polar effects in Me H 2 Me H • favorable • the transition states for the O Me N BH Thx O Nuc El–H Nuc–H El H H 3 2 H H two PRCed steps lowers no catalyst gives Me O O complex mixture • + + • the Ea of the overall R'S Et3Si–H R'S–H Et3Si only radical observed El• Nuc–H favorable El–H Nuc• unfavorable transformation An example that can best be rationalized by radical "philicities." Thus, adding a catalytic amount of thiol to Et3SiH reductions of alkyl halides dramatically (Roberts, J. Chem. Res. (S) 1988, 264) improves the yield. (Roberts, J. Chem. Soc. Perkin Trans. 1 1991, 103) R Me (tBuO)2, hυ Et SiH + + (anti)aromaticity of the 3 Me N BH Thx oxidized and reduced forms DLP (2 mol%) Me H 3 2 Me of the radicals can be used Me Br Me no cat. 1 25 tC12H25SH H H to rationalize the outcome cat. (1 mol%) 99% vs 10% 30 1 Br 86% C6H12, ∆ without RSH H Catalyst-controlled enantioselective HAT utilizing a polarity reversal catalyst. However, using R3SiH in Barton-McCombie reactions proceeds very efficiently. (Roberts, Tetrahedron Lett. 2001, 763) (Roberts, J. Chem. Soc., Perkin Trans. 1 1998, 2881) R Me R Ph SiH Me Me 3 R OAc O Me R TBHN H OAc H Ph SiH O O O 3 H 1 (5 mol%) O O AcO O O TBHN O O O O AcO SH O 60 °C SiPh MeS Me 3 1,4-dioxane Me 1 O O Me 60 °C R = Me 84%, 76% ee 90% O Me R = Ph 90%, 95% ee S H In situ formation of polarity reversal catalyst: O • O O 3. Reagents Derived from 1,4-Cyclohexadiene -MeSSiPh3 Ph3Si O C S "Pro-aromaticity" can be used to drive radical chain reactions. MeS SSiPh3 Ph3SiS MeS SSiPh3 (Walton, J. Chem. Soc., Chem. Commun. 1995, 27)

-CO H2O Me CO R CN 2 Me polarity Ph3SiH MeSH or Ph SiSH H CN Ph SiS H Ph SiS• 3 reversal cat. 3 3 + polarity reversal cat. competitive processes: (tBuO)2 R Me CO R CO2R Amine-alkylboranes can be used to alter regioselectivity of HAT via PRC. O H H 140 °C 2 (Roberts, J. Chem. Soc., Perkin Trans. 2 1989, 1953) 26–57% -Me 2 H H H tBuO Me N B Me O uncatalyzed O 2 Me3N B Me HAT 3 up to 51% tBuO• Me CN 2 Me Me R R H Me Me Me O Me CO2R • -CO CN Nuc 2 up to 37% O Me3N BH2Thx R catalyzed -PhMe R O Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

Replacing Me in 2 with Ph led to a cleaner reaction. III The BDE of H2O was proposed to decrease upon complexation with Ti . (Walton, J. Chem. Soc., Perkin Trans. 1 2002, 304) (Oltra, Angew. Chem. Int. Ed. 2006, 5522) O 2 • R Ph O O no observed loss of Ph tBuO2Bz Cp Cl Cp Cl + Ph Ph Cp 1 3 2 low (~20%) yields of H2O Ti R R H R Ti tAmylOH O Ti Cl Cp O H + Cp O intermolecular additions Cp R1 R3 100 °C 66% H H BDE = 49.4 kcal/mol The "pro-aromaticity" concept can also be applied to generate carbamoyl radicals. calc (Walton, J. Org. Chem. 2004, 5926) And the system was found to be applicable to reductive openings of other epoxides. OTr O N OH Me Me nC H DLP O 10 21 Me cat. RSH Me Bn O Me N PhH, ∆ N AcO AcO Me H H Mech? Bn Me Me Me Me OH nC10H21 O 43% 68% 85% Several other 1,4-cyclohexadiene derived reagents have been developed. Double HAT from the same Ti complex to conventional [H] catalysts allowed for (Walton, Acc. Chem. Res. 2005, 794) alkene and alkyne reduction. (Oltra, Org. Lett. 2007, 2195) R CO H Ph CO H Me TBS Me NHBoc 2 2 Cp Cl H MeO OMe R H H Ti MLn H R Works with Pd/C, 2 H R or Cp O H ML R Pd/Al2O3, Pd(dba)2, n or R R Wilkinson, Lindlar Me CO2Me H R R H alkyl radicals hydroxyformyl Bu3SnH substitute radical radicals transfer hydrosilation hydroamination A similar reductive epoxide opening has been developed that occurs via a catalytic bimetallic system using H2 as the terminal reductant (Gansäuer, J. Am. Chem. Soc. 2008, 6916) 4. HAT from Unlikely Sources Cp2TiCl2 (10 mol%) 0 HO The identification of a trace byproduct led to an interesting discovery. O Mn , Coll•HCl, H2 (4 atm) (Oltra, J. Org. Chem. 2002, 2566) Cl RhCl(PPh ) O OH OH Me 9 3 3 Cl Me Me (5 mol%) Me 9 Proposed mechanism: Me Cp2TiCl O + OH IV IV Me THF Me Me [Ti ] [Ti ] H H H + Collidine Coll•HCl Me O O Me O H O R R R O O O R [RhII] H O 3 4 H IV R [Ti ] [TiIV] Cl R IV H 3 4 [Ti ] 0 R O 0.5 Mn R A similar system employing Me H [RhIII] H anhydrous 97 3 IrCl(CO)(PPh3)2 allows for 0.5 MnCl O with H O (28 eq.) 85 2 IV cyclization of radical 2 15 [TiIII] [Ti ] with D2O (28 eq.) 25 75 (70% D) intermediate onto alkenes Me [RhI] H O R R H2 and alkynes. (Gansäuer, J. Me O Am. Chem. Soc. 2011, 416) O R R Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

A curious observation was made en route to the phomoidrides. The authors originally proposed an "ate" complex to be responsible for HAT, but it was not (Wood, J. Am. Chem. Soc. 2005, 12513) observed by 11B NMR—only the methanolysis products were. E Et (Renaud, Chem. Commun. 2010, 803) desired E E C4H9 Et E O OMe E Et O OH C H B H O MeOH 4 9 R3B E O O C4H9 O O B OMe + (MeO)3B O S air, O Me O OH O PhH E not observed! O Et SMe E C H not 4 9 Therefore, the following mechanism was proposed: desired O O H O B R R R H 99% for Me B OH O O R O 3 B O OH Upon extensive deuterium labeling studies, authors found that adventitious H2O was O • OH the H source, and proposed: OH SH2 Me Me H Me Me H2O Me Me -Me For entire process, B O B O B O 4-tert-Butylcatecol was shown to be superior to catechol (J. Am. Chem. Soc. 2011, 5913) B ∆H = 73 kcal/mol Me Me Me H Me H Me H calc Schwartz's reagent was found to serve as an efficient HAT donor in radical cyclizations. BDEcalc = 86 kcal/mol (Oshima, J. Am. Chem. Soc. 2001, 3137) The reaction was shown to be general. H O O O O Me Cp2ZrCl2/Red-Al competitive Me R 72–94% hydrozirconation O Me R Me X Et B, air, THF was rarely O H 3 H H O O S SMe SMe R observed! Me H X = Br, I R R SMe O S SMe O S H H Proposed mechanism: O O O O O O C12H25 Me Me S O R R Me Me 91% 77% 71% 42% X X R R X + IV A similar system was used to reduce alkyl iodides (3º, 2º, 1º) to the corresponding alkanes Cp2Zr IV in good yields (65–97%). (Wood, Org. Lett. 2007, 4427) Cp2Zr Cl Et Et H Cl H IV III O O It was found that B-alkylcathecholboranes could be reduced to alkanes via a Cp2Zr Cp2Zr radical decomposition pathway. (Renaud, J. Am. Chem. Soc. 2005, 14204) Cl Cl R B(cat) Me Me H R O (cat)BH O MeOH H + O Me DMA air, DCM, ∆ O Me Me Me Me (10 mol %) H H Me Me Me 9 1 R H R IV H Cp2Zr R Cl R Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

5. Olefin Reduction by Transition Metal Hydrides Differences in deuterium labeling studies showed that HAT to the allene was irreversible. D A general mechanism for HAT reduction of activated alkenes was supported by CIDNP effects. Me Me DCo(CO) Me (Halpen, J. Am. Chem. Soc. 1977, 8335) 4 D/H?

Mn(CO)5 Me Me Me Me Me Me Me Me + HMn(CO)5 + Mn(CO)5 DCo(CO)4 Me Ph Ph Me cage Ph Me D escape Me Me solvent caged Me Me ("geminate") radical pair HMn(CO)5 fast Like most other reactions, the rate of HAT reduction by HCrCp(CO)3 was substantially affected by olefin substitution. (Norton, J. Am. Chem. Soc. 2007, 234) Deuterium studies with DMn(CO)5: 1. First HAT to alkene is reversible H Me substrate krel substrate krel substrate krel 2. Inverse deuterium effect observed Mn2(CO)10 Mn(CO)5 + consistant with the proposed RDS (C–H fast Ph Me Ph Me bond being formed is stronger than the Me 1 134 Me ≤5 x 10-4 CO Me M–H bond being broken) Ph Ph 2

Later studies on different early TM–H generally supported analogous mechanisms and Ph Me provided additional evidence to disprove alternative pathways... 780 Ph 27 Me ~0.02 (Orchin, J. Organomet. Chem. 1979, 299) Ph CO2Me Against hydrometallation mech.: Against polar mech.: But failed radical trapping: Me Me -4 -3 nC6H13 ≤2 x 10 ≤5 x 10 24 Ph HCo(CO) Ph H solvent krel Me CO Me 4 2 nC5H11 CO2Me H tBu Ph DCM 1.0 Ph N Ph N2 or CO hexanes 1.1 DCM, 0 °C O The kinetic data was used to develop substrates that could participate in a HAT-mediated krel(N2) = 1.0 acetone 0.9 N tBu O cyclization. (Norton, J. Am. Chem. Soc. 2007, 770 and Tetrahedron 2008, 11822) krel(CO) = 1.1 MeCN 0.9 CO2Me MeO2C MeO2C Me Ph But revealed that the reversibility of the 1st HAT was dependent on the TM–H. HCrCp(CO)3 Me (Sweany, J. Organomet. Chem. 1981, 57; Norton, J. Am. Chem. Soc. 2007, 234) Ph (7 mol%) Ph

Me DWCp(CO)3 or Me Ph DCrCp(CO)3 Ph Ph 2 atm H2 R 50 °C R MOMO D D R R Ph DMoCp(CO)3 Ph Ph Ph Me CO Me R = H, 4 days, 62% 2 not observed! observed! (23%) R = CO2Me, 1.5 days 95%

HMn(CO)5 and HCo(CO)4 can also undergo a HAT to allenes. (Garst, J. Am. Chem. Soc. 1986, 1689) HCrCp(CO)3 was also shown to reduce alkynes, but the substitution pattern on the H H alkyne sometimes led to odd products. (Norton, J. Am. Chem. Soc. 2012, 15512) Me Me Me Me Me Me Me Me HCrCp(CO) Ph Ph MLn 3 Me Me Ph + Me Me Me Me Me Me PhH Me 9 1

HCrCp(CO) CO2Me Me 3 MeO2C CO2Me CO Me PhH Ph 2 Me Me Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

Different mechanisms were proposed to account for the different outcomes: Additionally, a later report provided evidence for a radical-based pathway initiated by HAT. (Isayama, J. Synth. Org. Chem. Jpn. 1992, 190) HCrCp(CO) SET 3 HAT Ph • E E + cat. O2 or CoLnOO R = Ph Co(acac)2 OH R = CO2Me R R' PhO SN R' = CO Me R' = H PhO2SN 2 2 PhSiH , O PhO2SN HAT 3 2 Me DME, rt Me 50% E H E E Ph Could a cobalt hydride Co(acac)2 + NaBH4 LnCo–H E be responsible for HAT? (Chung, J. Am. Chem. Soc. 1979, 1014) Ph

The product distribution arising from the reduction of PhC≡CPh was dependent on time. Electron difficient olefins were also hydrated, but some substrate dependent regioselectivity was observed. (Mukaiyama, Chem. Lett. 1990, 1869) high H Ph Ph cat. Mn(dpm)2 cat. Mn(dpm)2 [HCrCp(CO)3] HO PhSiH , O R1 PhSiH , O OH CO Et 3 2 CO R 3 2 OC Cr 2 2 Me OC Ph Ph R1 = Ph 2 R1 = Me CO Bn CO Ph Ph R 2 73%, exclusive R2 = Ph R2 = H 91%, exclusive Selectivity seems to follow Norton's observations! cage escape low H Mn(dpm)3 also catalyzed the same reaction, but the products formed were dependent on the [HCrCp(CO)3] presence or absence of oxygen. (Magnus, Tetrahedron Lett. 2000, 9725 and Tetrahedron Ph Ph Ph Lett. 2000, 9731) Ph HO Me Me Me "We have also O cat. Mn(dpm)3 O cat. Mn(dpm)3 O observed that the 6. Olefin Hydrofunctionalizations PhSiH3 PhSiH3 way in which the reaction flask is A simple olefin hydration has spurred a plethora of research in the area of HAT-based olefin with O2 without O2 washed influences hydrofunctionalizations. (Mukaiyama, Chem. Lett. 1989, 1071) iPrOH iPrOH the product Me Me Me distribution."

Co(acac)2 OH O Ph O (5 mol%) Ph O Ph O Authors proposed that oxygen activation of the Mn hydride is responsible for the divergent 4 Me + Me outcomes: 4 4 O PhSiH3, O2 2 THF, rt O O R 84% 14% no H 1 R2 R2 O2 O O O R iPrOH The intermediacy of a cobalt peroxide O Mn (dpm)2Mn O SiPhH2 OH O O O R1 O R1 adduct was suggested: CoL2 H O O R Me R Me Mn R2 O O O O CoLn H HO R O O 1 R2 P(OEt)3 R2 O2 Mn O R O O R Me O O (dpm) Mn O H -H• O O 2 O R1 O R1 O R Me R Me Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

Additionally, similar conditions have been shown to proceed through a HAT mechanism. 7. Transition Metal Oxo Compexes (Shenvi, J. Am. Chem. Soc. 2014, 1300) Me CO Et When the rates of benzylic C–H oxidation by MnO - in nonaqueous solutions were examined, cat. Mn(dpm) H 2 Me 4 3 they were found to show a Polanyi relationship. (Mayer, Inorg. Chem. 1997, 2069) PhSiH3 Me CO2Et CO2Et O TBHP Me CO2Et Me iPrOH H Me rt Me + nBu NMnO MnO + O + O 10:1 dr 4 4 2 1 week (31%) (trace) A hydrohydrazidonization and hydroazidonation using similar conditions have been reported. (Carreira, J. Am. Chem. Soc. 2006, 11693) The Polanyi relationship is Boc N specific to HATs that states for a N Boc L H given system, there is a linear O N cat. Mn(dpm) or 5 Boc Co Me relationship between activation 3 N N O parameters (log k) and BDEs NHBoc O Me PhSiH3 (∆H°) of the substrates 0 °C or rt Me O Mn(dpm)3: 98% Me O So if a Polanyi relationship is 5: 66% 5 observed, the reaction is likely to Boc involve a HAT as the rate- Some opening of vinyl Ph determing step cyclopropanes was observed, Ph N NHBoc + ring-opened suggesting that radical mixture intermediates are involved. Me 5: 48% 20–30% A HAT mechanism (molecule-assisted homolysis) was proposed to occur based on the Polanyi relationship and other kinetic evidence. (Mayer, Science 1995, 1849) Mn(dpm)3: 60% 20% However, neither of the proposed mechanisms invoked HAT : H H H H H H + + O MnO3 Ph H HO MnO3 SiPhH2 Ph H Ph H O MnO3 N Boc N Boc Boc N EtOH Boc N no radical character...... but two radical species generated?

R Me R Me PhSiH For metal oxo species, HAT reactivity is determined by strength of bond being formed, not 3 CoIII electronic structure of oxidant. N Boc R CoIII H The bond strength of the formed Boc N II Co - H–OMnO3 was calculated to be R Me 80 kcal/mol [between that of ROOH (89 kcal/mol) and HI (70 CoIII H N Boc kcal/mol)] N Boc Boc N Boc N R R Me Another Polanyi relationship - • path A shows that MnO4 abstracts H at approximately the same rate as a CoIII path B theoretical O-centered radical that H R R Me N Boc also has a O–H BDE of 80 CoII Boc N kcal/mol Baran Group Meeting Julian Lo Hydrogen Atom Transfer 4/12/14

Other transition metal oxo complexes that react via HAT mechanisms:

O O W N N O Fe O O O N N N O O W O O W O W O O O O Cyclohexane oxidation W (Que, J. Am. Chem. Soc. 2004, 472) O O O O O W O O Ar O W O W O Ar O O O N O W N Mn N O O O N O Ar W Ar F O Aliphatic C–H bond fluorination Multiple HAT-initiated transformations (Groves, Science 2012, 3122) (Hill, Synlett 1995, 127)

Drug metabolism (Cytochrome P450 enzymes)