Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

1. Introduction

Organic electron donors (OEDs) are neutral, ground state organic molecules that reduce substrates by single electron transfer.

Reactions with OEDs thus involve the intermediacy of radicals, which can ultimately end up getting either reduced, converted into nucleophiles, or converted into electrophiles.

D or D•+ or 1D•+1 D2+ E+ R– R–E D D•+ X– SET R–X [R–X]•– R• R–H Dr. John A. Muphy Dr. William R. Dolbier, Jr. Dr. Patrice Vanelle SET HAT University of Strathclyde University of Florida Aix-Marseille University R–D+ R–Nuc Several reviews on OEDs as they pertain to organic synthesis have been recently published. D•+ Nuc– D Comprehensive review: Vanelle, Angew. Chem. Int. Ed. 2014, 384 Additional review: Murphy, "Organic Electron Donors." In Encyclopedia of Radicals in Chemistry, Biology, and Materials *Photoinduced electron transfer will be minimally covered, see "Photoinduced Electron Perspective on super electron donors: Murphy, J. Org. Chem. 2014, 3731 Transfer in the Days of Yore," Yan 2014 group meeting for more. Perspective on super electron donors: Murphy, Chem. Commun. 2014, 6073

OEDs are typically electron rich alkenes, although there are some reports of aliphatic amines bearing weak OED properties. Shown below are some of the OEDs discussed along with their corresponding redox potentials (E) and typical parent substrates for a qualitative reference.

+ Cl Br I N2

MeBr MeI CBr4

–3.5 –3.0 –2.5 –2.0 –1.5 –1.0 –0.5 0.0 +0.5 1.0 E (V)

Me Me N N N N Me N NMe S S N N Me N N 2 2 H N Ph Me Me N N N N Me2N NMe2 S S N N Me Me2N NMe2 Me Me Me Murphy Murphy Murphy TDAE TTF DMBI 1,4-DMP nPr3N E = –1.24 V E = –1.20 V E1 = –0.82 V E1 = –0.78 V E1 = +0.32 V E = +0.33 V E = +0.89 V E = +0.95 V E2 = –0.76 V E2 = –0.61 V E2 = +0.71 V Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

2. Amines 3. Tetrathiafulvalene (TTF) The reductive cleavage of halides from α-haloketones, esters, and acids using DBMI was initially The first studies on TTF centered on its oxidation (Wudl, Chem. Commun. 1970, 1453). believed to proceed via S 2 displacement with a hydride (Chikashita, J. Org. Chem. 1986, 540). n + + S S Cl2 S S S S Cl2 S S Me O O S S CCl S S S S CCl S +S DMBI N H N,N-dimethylaniline, 4 4 Ph H Ph H benzylamine also facilitate TTF, yellow solid TTF•+, deep purple solid TTF 2+, yellow solid THF, Δ N Ph facilitate similar reactions Br (89%) H TTF facilitiated cyclizations of aryldiazonium salts via a radical-polar crossover mechanism DMBI Me (Murphy, J. Chem. Soc. Perkin Trans. 1 1995, 623). 2 R1 R However, later experiments supported the intermediacy of radicals and led to the proposal of a R1 OH ROH and MeCN could also be SET-initiated pathway (Tanner, J. Org. Chem. 1989, 3842). N + TTF 2 R2 used as nucleophiles, but others Me O acetone (N -, HO-, malonate) were The addition of radical H O 3 N H O 2 unsuitable (Murphy, Chem. initiators/inhibitors H Ph O altered yields ca. ±50% O 1a: R1 = R2 = H 2b: R1 = Me, R2 = H, (73%) Commun. 1997, 1923). N Ph Me Br 1b: R1 = Me, R2 = H 2c: R1 = R2 = Me, (58%) Also: Ph Me 1 2 1c: R = R = Me S S O Me Me Me H O Cl O TTF -N2 2 Ph N N SET •+ H -TTF S S 1 1 Ph Ph Ph R R R2 O DMBI N N Me 3a Me R2 Me Me Me Mech? NaN3, acetone O N O O H Me O -TTF Ph Ph Br N3 N N Ph S – 2 Br Me Ph R1 R Me Me R2 R1 S N +TTF•+ S Br– Me O + S S S S 1,4-DMP was proposed to dehalogenate trichloroacetamides through an analogous pathway O O S S (Ishibashi, Tetrahedron Lett. 2008, 7771). 3a: R1 = R2 = H, (75%) (0.5 equiv) H OAc The presence of heteroatom adjacent to the aryl group was required for termination by OAc 1,4-DMP H Reaction can still Me proceed at 65 °C nucleophilic substitution (Murphy, Chem. Commun. 2000, 627). (neat) Cl N N CCl Cy 3 133 °C N Cl N S S Me DBU effects similar TTF S S (52%) reactivity at rt + O O 1,4-DMP acetone S N + OMe H2O S 2 (48%) (32%) Similarly, solvent quantities of nPr3N could facilitate SET to fragment PhSSPh (Ishibashi, Org. •+ Lett. 2009, 3298). -TTF -MeOH +TTF•+ PhSSPh Me PhSSPh Me -N2 nPr N TsHN nPr N, H O PhS Me Cy 3 3 2 S S TsHN Me S 1 140 °C SPh 140 °C RN + (68%) O (45%) O OMe OMe Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

This was used in total synthesis of aspidospermine (Murphy, J. Chem. Soc. Perkin Trans. 1 However, the DTDAFs were prone to rapid cleavage if DTDAF•+ trapped an intermediate 1999, 995). radical (Murphy, J. Chem. Soc. Perkin Trans 1 1999, 3637). NHCOCF3 NHCOCF3 NHCOCF3 CO2Me OH O O O CO2Me TTF DTDAF S Me N + N acetone 2 acetone Me CHO N H2O N N H2O (50%) + (45%) H H O N2 Ms Ms Ms Mech? O

N N NCOCF3 4. Tetrakis(dimethylamino)ethylene (TDAE) Me TDAE had some illuminating properties (Pruett, J. Am. Chem. Soc. 1950, 3646). Me2N NMe2 N Me N N excess NMe2 H H H F F Me2N NMe2 O H Ms Ms Me2NH O NMe2 -hν aspidospermine O NMe2 Me N NMe F Cl Me2N NMe2 -TDAE 2 2 NMe2 (2 equiv) Radical translocations via a [1,5]-HAT were also demonstrated (Murphy, J. Chem. Soc. Perkin Me N NMe Trans. 1 1995, 1349). "This was a clear, slightly yellow, mobile 2 2 liquid which was strongly luminescent in "A small room can even be dimly lit for over + N2 O Me O Me O Me O Me contact with air." an hour... with about 10 mL of TDAE." TTF H2O N N N N acetone H Can perform similar radical cyclizations to TTF, however, a leaving group typically needs to be H Me H2O H Me H Me H incorporated into the substrate to terminate the reaction since TDAE•+ does not recombine with (85%) radical intermediates (Murphy, Beilstein J. Org. Chem. 2009, 1). Me N + Me Me TTF Me 2 N O N O TTF N O +S N O Br + TDAE Me N TDAE acetone S Me Me H2O Me Me Me S S Me Me N DMF N S O acetone + (74%) O MeOH (53%) (14%) N2 Ms Ms + N2 Bulking up the substitution around the TTF core led to a reduced rate of premature radical -N Br •+ 2 -Br• N trapping with TTF and its derivatives (Murphy, Tetrahedron Lett. 1997, 7635). -TDAE•+ + S O O PhS O PhS O N N H O OED Ms (33%) (60%) + OH + N2 acetone H2O However, TDAE was initially used to dehalogenate polyhalogenated molecules with the more O 4 O 5 O electropositive halogens being easier to remove (Carpenter, J. Org. Chem. 1965, 3082). – Me Me E Me E -Cl S S S S N S Cl CCl2 F3C F3C Cl Cl TDAE TDAE TDAE2+ +H+ S S S S S N BrCCl3 CHCl3 (22%) Me Me E E Cl pentane decane – – Me CF Cl CF Br CCl3 Cl 3 17 h 3 15 min BrCCl3 TTF TMTTF DTDAF (97%) CCl4 (31%) – 4 (19%), 5 (48%) 4 (8%), 5 (67%) 4 (0%), 5 (72%) -BrCCl2 Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

It has been suggested that TDAE performs two sequential SETs to acceptor substrates (Hetero)aryl difluorochloromethyl ketones could also be added into activated electrophiles to generate anions. such as aryl aldehydes, α-ketoesters, and thiocyanates (Médebielle, Tetrahedron Lett. 2008, Me2N NMe2 589; for more examples, see Dolbier J. Fluorine Chem. 2008, 930). Me2N NMe2 Me2N NMe2 R3C–X SET Ph Ph Me N X NMe F Me N NMe -20 °C 2 2 ~0 °C Me N NMe Me Me F 2 2 2 2 N O O F O CR3 Me N TDAE TDAE•+ PhCHO 2 N N -Me N– N charge transfer complex – TDAE 2 CR3 + X CF2Cl O O

Me2N NMe2 DMF O– -HF OH – – -20 °C to rt + CR3 + X SET Me2N NMe2 O CF2Cl O Ph O Ph TDAE 2+ F F (60%) F F

– TDAE was used to generate HetCF2 , which could add into aldehydes, ketones (Médebielle, Reductive cleavage of electron-deficient benzyl chlorides leads to adducts with α-halocarbonyl J. Org. Chem. 1998, 5385), pyruvates, and thiocyanates (Médebielle, Synlett 2002, 1541 compounds and other electrophiles (Vanelle, Tetrahedron 2009, 6128). and Tetrahedron Lett. 2001, 3463). NO OEt CN Br O O 2 O S O NO2 TDAE Ph Ph O + N N N O DMF O N TDAE N O Cl + Me O -20 °C to 70 °C O N N CHO DMF N (68%) O CF2Br -20 °C to rt O OH (ca. 55% for both) (60%) F F NMe2 Irraditation could increase yields in certain cases, but it altered the reaction outcome in other Radical intermediates could be intercepted using dihydrofuran as a radical trap. ones (Vanelle, Eur. J. Med. Chem. 2010, 840). O NO2 O NO NO2 TDAE 2 O N Br N F N N no hν hν Br N + N 2h CO Et 48 h F F S N CO2Et 2 O F O F O F (51%) S N Cl (77%) S N CO2Et TDAE•+ HO from spontaneous E1 cb? The initial products of the anionic additions could also undergo rearrangements (Vanelle, Tetrahedron Lett. 2006, 6573). Sometimes light was believed to completely change the reaction mechanism (Vanelle, via: Tetrahedron Lett. 2008, 1016). 2-MePh O N N N OMe no hν TDAE Me Me no reaction Me Me DMF 4-NO2Ph O OMe N CCl3 N Cl N -20 °C to rt O Cl (60%) O Cl TDAE, DMF Me Me Me -20 °C to rt TDAE and Zn0 have similar reduction potentials, but offer different regioselectivities in vinylogous OMe hν O 4-NO Ph Me 2 Reformatsky reactions (Zhu, Tetrahedron Lett. 2004, 3677). Sulfonimine electrophiles only gave (82%) OMe O modest selectivities (Zhu, Synlett 2006, 296). O Proposed SET to aldehyde: OMe 2 OH OBn OBn OBn O 0 O O Me Me CO Et TDAE Br CO Et + Zn F CO2Et TDAE O Ar Cl Ph 2 2 DMF Ph DMF h O R F R ν R R Me F F -10 °C to rt F F 0 °C Ph OH (48%) (95%) OMe Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

– TDAE can reduce CF3I to CF3 , which adds into various electrophiles (Dolbier, Org. Lett. 2001, TDAE can be used as a reductant for transition metals, as demonstrated by the Pd-catalyzed 4271 and J. Fluorine Chem. 2008, 930). oxidative dimerization of (hetero)aryl bromides (Tanaka, J. Org. Chem. 2003, 3938). O O O no h required: ν S cat. PdCl (PhCN) TDAE (2.2 equiv) S O O Br 2 2 O O N p-tol TDAE (2 equiv) CF3I (2.2 equiv) HO CF3 OHC CHO DMF, 50 °C Ar Cl Ar H alkyl OHC (Het)Ar R DMF, hν (Het)Ar R (88%) -20 °C to rt R = H or Ph (68–95%) (48–98%) (ca. 70%, (ca. 50% after Pd0 TDAE can also be used for NHK ca. 85:15 dr) hydrolysis) reactions substoichiometric in Cr TDAE -1 The CF – could also be added into disulfides and diselenides (Dolbier, Org. Lett. 2004, 301). PdIIBr Pd0 (Tanaka, Synlett 1999, 1930 and 3 Tetrahedron Lett. 2000, 81). – CF3 Ar—Br TDAE (2.2 equiv) SCF3 OHC OHC RS–SR TDAE2+ N S CF3I (5 equiv) S N DMF RSCF + RS– 0 °C to rt N 3 5. Bisimidazolidinylidenes (200% based CF3I on disulfide) RSCF 3 A few other aliphatic tetraaminoethylenes are known, but most exist as their NHC monomers. – TDAE can reduce (CF3S)2 to form a complex that can be used as a CF3S source (Kolomeitsev, R R R Et Et J. Chem. Soc. Perkin Trans. 1 2000, 2183). N N N N N SCF3 SCF3 strongly Exception when NMe PhCH2Cl or favored R = Me or Et: 2 N N N N N TDAE Me N pyridine or F3CS SCF3 2 NMe R R R Et Et DME 2 DMF, MeCN - N 6 -20 °C to rt NMe2 2CF3S 0 °C to rt (98%) (95%) (80%) Little is known about the redox chemistry of species like 6, but they can cleave P–Cl bonds to form radicals (Goldwhite, J. Organomet. Chem. 1986, 21). Reductive debromination in the presence of dienophiles can lead to the formation of Diels-Alder adducts (Nishiyama, Tetrahedron Lett. 2005, 867). Ph Ph Cl 6 CO Me P Ph P CO2Me 2 P Ph 6 6 Me Ph (88%) Cl Ar Ar Ph Ar Cl (1 equiv) P (excess) P TDAE (32%) P Me tBu tBu quant. P quant. P Br cat. I2 tBu Cl Cl Ar Cl Ar P 6 P P Br THF Ar = 2,4,6-tri(tBu)Ph EtO2C CO2Et CO Et Cl (57%) P P 67 °C 2 tBu tBu

(51%) CO Et 2 • Under irradiation, similar donors could reduce Ar3SiCl, Ar3GeCl, and Ar3SnCl to Ar3M α-Bromoketones and esters could be dimerized using TDAE (Nishiyama, Tetrahedron Lett. (Lappert, J. Organomet. Chem. 1980, 5). 2006, 5565). Dithianyliums also underwent dimerization (Kirsch, J. Fluorine Chem. 2004, 1025). Me Me TDAE O Mes Mes N N Mes Mes O cat. I TDAE S S + Si 2 Ph S S+ 4-FPh Si Br Ph 4-FPh Mes Cl N N hν Mes Ph MgSO4 MeCN S S O Me Me ESR only THF, 67 °C (94%) 4-FPh -15 °C to rt (91%) Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15 6. Tetraazafulvalenes (TAFs) Although 8 was unable to perform a second SET to form aryl anions, a more powerful SED was identified that could (Murphy, Angew. Chem. Int. Ed. 2007, 5178). Early studies on the redox potentials of bisimidazolium salts supported the notion that 2 I – 2 X– I introducing unsaturation into the rings of cyclic tetraaminoethylenes would result in strong N N I N N NaH N N 2 e– N N OEDs (see Vanelle, Angew. Chem. Int. Ed. 2014, 384). N N MeCN, Δ N N NH3(l) N N N N 0.003 M (98%) N N +e– N N +e– N N 24 days 9, (51%) 10 N N -e– N N -e– N N Cyclization supported the formation of an aryl anion, as aryl radicals do not add into esters. Me Me Me Me Me Me Even polycyclic aryl bromides and chlorides could be reduced with 10. aromatic nonaromatic O I H Less planar salts were harder to reduce (shown with corresponding E in MeCN vs SCE): CO2Et 10 Me CO Et + 2 Me O DMF Me Me Me O O N N N N N N The TAF giving this dication 100 °C (51%) (21%) Me would have the highest Br H Cl H N N N N N N reduction potential 9, NaH 9, NaH DMF, rt; DMF, rt; Me Me Me Me Me Me –1.21 V –1.31 V –1.44 V substrate substrate DMF, Δ DMF, Δ (86%) (99%) The earliest TAFs contained methylene bridges, which were essential in keeping the two NHC halves dimerized (Murphy, Angew. Chem. Int. Ed. 2005, 1356). Unfortunately, much like with TTF, 10•+ could trap intermediate alkyl radicals and hydrolyze, resulting in the formylation (Murphy, J. Am. Chem. Soc. 2009, 6475). 2 I – 2 I – Me Me CHO N N N N N N KHMDS I2 9, NaH I 9, NaH PhO Br DMF, rt; PhO CHO DMF, rt; N N PhMe N N N N DMF 6 substrate; 6 substrate; (61%) N N Me Me Me Me Me Me HCl workup HCl workup Ms 7 8 Ms (13%) no deuteration Proposed mechanism: with d -DMF TAF 8 proved to be strong enough to reduce aryl iodides, which were previously unable to be 7 reduced by OEDs, making it the first "super electron donor" (SED). N N N N N N N N -H+ I OMe 7, KHMDS OMe + DMF, rt; N N N N N N +H N N R R R N CH2R substrate N N Ms PhMe, Δ 10•+ O O 11 Ms Ms O N H N (90%) not observed R H OH + H -CO2 H3O N N – R HAT -MeO R +e– -I– OMe Evidence against SET pathway involving 11: OMe – OMe +e Me above N N cond. O O N R Ms N Ms Ms N HO R H R Me (2%) not formed Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

Reductive cleavage of SO2Ph group from (di)sulfones and sulfonamides was possible with 10 7. Bispyridinylidenes (Murphy, J. Am. Chem. Soc. 2007, 13368). The previous SEDs were not amenable to analog production, but similar SED synthesis PhO2S SO2Ph 9, NaH PhO2S H 9, NaH strategies could be used to generate different scaffolds (Murphy, Org. Lett. 2008, 1227). DMF, rt; DMF, rt; substrate N substrate N 2 I – I – DMF, 110 °C Ts DMF, 110 °C H (96%) (91%) N N NaH N N N N

Proposed mechanism (later radical clock experiments suggested fragmentation to NH3(l) (83%) form aminyl radicals is favored in the case of sulfonamides): Me2N NMe2 Me2N NMe2 Me2N 13 NMe2 R1 12 – SO2Ar + X 1 1 Bispyridinylidene 13 could do everything that the other SEDs could do, but better and had R – R R2 +e +e– +e– the advantage of being more "bottleable." ArO2S X ArO2S X 1 1 R2 R2 R + R I H/D – +H 13 I 13 O SO2Ar + X H X tBu tBu(1.5 eq) tBu tBu CO2Et (1.5 eq) R2 R2 Me Me DMF, rt O DMF, rt Me O Me Attempts to prepare analogs of 10 showed that its double methylene bridge was essential (D2O) (95%) for stability (Chen, Angew. Chem. Int. Ed. Engl. 1996, 1011). tBu (95%) tBu It could even do some things that other SEDs couldn't (Murphy, Synlett 2008, 2132). O 12, NaH O O N N N N N N N N Me DMF; Me Me Ph N Ph N N N N N N N N N N substrate OMe (94%) H H Me Me Me Me N (81%) not isolated isolated not isolated isolated Proposed mechanism: O O O O However, it was found that mono- and even untethered species could be generated in situ that Me Me SET Me Me Ph N showed SED reactivity (Murphy, Chem. Sci. 2012, 1675). R N R N R N H OMe OMe OMe 100 °C, (77%) 2 I – Ph -MeO– N N NaH N N O O Me Me DMF (79%) + O O N N N N N Ph Me +H SET I O R N Me Me H Me Me Me Me R N R N H 5 equiv 12, 100 °C, (43%) Me – Me Me I H O Similarly, acyloin derivatives could be deoxygenated by 13 (Murphy, J. Org. Chem. 2009, 8713). N NaH N N "even a surface hydroxyl group O 12, NaH O O 12, NaH O DMF (61%) N N N on glass could catalyze [the Ph DMF; Ph O Me DMF; Me Me Me decomposition of these TAFs]" Ph substrate Ph Ph substrate O H Me Me OR R = Ms, (93%) O (86%) Ph R = Ac, (98%) Me Me R = Piv, (97%) Basicity occasionally problematic Baran Group Meeting Julian Lo Organic Electron Donors 1/10/15

S–O (instead of C–O) bond cleavage of alkyl triflates was also possible (Murphy, Org. Biomol. Additionallly, π-stacking interactions between 13 and aryl groups in the substrates can lead to Chem. 2012, 5807). chemoselectivities opposite of conventional reagents (Murphy, J. Am. Chem. Soc. 2013, 18 + 10934). OTf 13 OH O-DMF Me2N OR H2O Me2N OR R OTf O DMF H OH CO Et CO Et 18 H 2 2 Ph (91%) Ph O-DMF labeling 13, hν Na0 OEt SET; CO2Et CO2Et disproved a pathway H O CO2Et OTf Ph HAT 2 DMF or K0 N Bn invoking C–O bond Ph Ph Ph Tf cleavage by DMF Me N OR H O Br 2 2 ROH 3 equiv 13 (84%) CO Et H 100°C, (40%) H H not observed! H 2 CO Et CO Et 2 2 O OEt Once again, photoactivation (UV) of these SEDs enhances their strength (Murphy, Angew. Chem. Int. Ed. 2012, 3673)... Ph Ph CO Et CO2Et Ph Ph 2 +H+ +H+ Ph Cl 13 (3 equiv), DMF H (75%) CO2Et Ph no hν, 100 °C (0%) O with hν, rt (87%) O Which even allows for SET to ground state benzenes, raising the possibility of a future OED Birch-type reduction.

-e–

cis:trans 98:2 cis:trans 70:30 (66%) 13, hν +e–

(6%) It was found that benzyl esters, ethers, and sulfonamides could be debenzylated by this approach (Murphy, Angew. Chem. Int. Ed. 2013, 2239 and Angew. Chem. Int. Ed. 2014, 474). O Me MeO N Cy Et O O Me Me Ms nBu OMe OMe OMe 13 (3 equiv) 13 (6 equiv) 13 (6 equiv) hν, DMF, 24 h hν, DMF, 72 h hν, DMF, 72 h (91%) (73%) (80%) O HO Me H Et N Cy HO Me Me Ms nBu