The Emergence of Neutral Ground-State Organic …...The Emergence of Neutral Ground-State Organic...

The Emergence of Neutral Ground-State Organic Super-Electron-Donors and their Application in

Organic Synthesis!

Francisco J. Sarabia!Literature Seminar!19 February 2015!

E0 = +0.32, +0.71 V in CH3CN

N(CH3)2

(H3C)2N

E0 = -0.78 V, -0.61 V in CH3CN;-0.62 V in DMF

CH3 CH3

E0 = -0.76 V, -0.82 V in DMF

(H3C)2N

N(CH3)2

E0 = -1.24 V in DMF

E0 = -1.20 V in DMF

(H3C)2N

N(CH3)2H3C

E0 = -1.50 V in DMF

Reduction potential values shown are vs SCE.

TDAETTF

Neutral Ground-State Organic Electron Donors

organic super-electron-donors (SEDs)!

Emergence!!!!Preparation!!!!Application!

Review: Broggi, J.; Terme, T.; Vanelle, P. Organic Electron Donors as Powerful Single-Electron Reducing Agents in Organic Synthesis. Angew. Chem., Int. Ed. 2014, 53, 384-413.!!Perspective: Murphy, J. A. Discovery and Development of Organic Super-Electron-Donors. J. Org. Chem. 2014, 79, 3731-3746.!

Prof.Dr.JohnA.MurphyProfessor,UniversityofStrathclydeTrinityCollege,Dublin(BA1976)

UniversityofCambridge(PhD1980)DSc2002

*Art by graphic artist Maxime Py and the Super-Kamiokande Collaboration!

Single Electron Transfer!-- Metals in low oxidation state (Li, Na, K) --!

!- Harsh reagents -!!!

-- Tin reagents (HSnBu3) --!!- Toxic -!

-- Electrochemical reduction (metal cathode) --!!- Specific glassware, fouling of electrodes -!

-- Light assisted electron transfer [photoredox catalysis (Ru, Ir)] --!!- Expensive metals* -!

-- Dyes --!- High molecular weight -!

SET: Rowlands, G. J. Tetrahedron 2009, 65, 8603–8655. Rowlands, G. J. Tetrahedron 2010, 66, 1593–1636.!Dyes: Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355-360. Fukuzumi, S.; Ohkubo, K. Org. Biomol. Chem. 2014 , 12, 6059-6071.!Photoredox Catalysis: Prier, C. K.; Rankic, D. A.; Macmillan, D. W. C. Chem. Rev. 2013, 113, 5322-5363.!Earth Abundant: Stevenson, S. M.; Shores, M. P.; Ferreira, E. M. The Development of Photooxidizing Chromium Catalysts for Promoting Radical Cation Cycloadditions, Just Submitted.!

other alternatives?!

(super) organic electron donors!

-- Neutral electron donors with ground state reducing power --!-- Highly selective and tolerant to a variety of functional groups --!

-- Soluble in organic solvents (pure organic solids or liquids) --!-- Redox potentials are tunable --!

Murphy, J. A. J. Org. Chem. 2014, 79, 3731-3746.!

E0 = +0.32, +0.71 V in CH3CN

N(CH3)2

(H3C)2N

CH3 CH3

E0 = -0.76 V, -0.82 V in DMF

(H3C)2N

N(CH3)2

E0 = -1.24 V in DMF

E0 = -1.20 V in DMF

(H3C)2N

N(CH3)2H3C

E0 = -1.50 V in DMF

TDAETTF

single electron transfer reactions!

Broggi, J.; Terme, T.; Vanelle, P. Angew. Chem., Int. Ed. 2014, 53, 384-413.!

D R–D Y R–YRER–E

H Solvent

single-electron transferdouble-electron transfer

reductive termination

electrophilic conversionnucleophilic conversion

reduction potential!

Reduction Potential: ChemWiki: The Dynamic Chemistry E-textbook!Médebielle, M.; Dolbier, W. R. J. Flu. Chem. 2008, 129, 930-942.!Murphy, J. A. J. Org. Chem. 2014, 79, 3731-3746.

standard reduction potential: tendency for a chemical species to be reduced (measured in volts at standard conditions). The more positive the potential is the more likely it will be reduced (oxidant). The more negative the potential is the more likely it will be oxidized (reductant).!

E0 = -0.62 V in DMF

(H3C)2N

(H3C)2N N(CH3)2N(CH3)2

TDAE2+

N(CH3)2

(H3C)2N

N(CH3)2

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

E0 = -0.78 V in CH3CN E0 = -0.61 V in CH3CN

radical cation dication

N(CH3)2

(H3C)2N

TTF as organic single electron donor!

E0 = +0.37 V, +0.67 V in CH2Cl2 vs SCE!

1,3-Dithiolium Hydrogen Sulfate: E. Klingsberg, J. Am. Chem. Soc. 1964, 86, 5290-5292.!Tetrathiafulvalene: Wudl, F.; Smith, G. M.; Hufnagel, E. J. Chem. Commun. 1970, 1453-1454.!Wanzlick Equilibrium: Böhm, V. P. W.; Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 4036-4038.!Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Chem. Commun. 1993, 295-297.!Fletcher, R. J.; Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Perkin Trans 1, 1995, 623-633.!

Wanzlick-Equilibrium!

acetone, 0.5 h, 0 ˚C

82% yieldHSO4

50% yield

1,3-Dithiolium Hydrogen Sulfate: E. Klingsberg, J. Am. Chem. Soc. 1964, 86, 5290-5292.!Tetrathiafulvalene: Wudl, F.; Smith, G. M.; Hufnagel, E. J. Chem. Commun. 1970, 1453-1454.!Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Chem. Commun. 1993, 295-297.!Fletcher, R. J.; Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Perkin Trans 1, 1995, 623-633.!

R– N2

E0 = +0.37 V, +0.67 V in CH2Cl2 vs SCE!

acetone, 0.5 h, 0 ˚C

82% yieldHSO4

50% yield

1,3-Dithiolium Hydrogen Sulfate: E. Klingsberg, J. Am. Chem. Soc. 1964, 86, 5290-5292.!Tetrathiafulvalene: Wudl, F.; Smith, G. M.; Hufnagel, E. J. Chem. Commun. 1970, 1453-1454.!Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Chem. Commun. 1993, 295-297.!Fletcher, R. J.; Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Perkin Trans 1, 1995, 623-633.!

driving force: aromaticity!!

– e – e

SET DET

R– N2

Cu(II) analogy!

Cu(II)X2

Cu(I)X

R– N2

MeerweinArylaLon

Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms. Elsevier Academic, 2005. Print.!

R– N2

radical-polar crossover mechanism!

Fletcher, R.; Kizil, M.; Lampard, C.; Murphy, J. A.; Roome, S. J. J. Chem. Soc., Perkin Trans. 1, 1998, 2341-2351. !Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. J. Chem. Soc., Perkin Trans. 1, 1999, 995-1001.!Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. Tet. Lett., 1999, 40, 161-164.!

H–N2

NHCOCF3BF4

NHCOCF3

F3COCHNS

F3COCHN

F3COCHNOH

(±) aspidospermidine

acetone, H2O, 2 d

45% yield

TTF (1.1 equiv)-2.2%overallyield-

10stepsfromaryldiazonium

super electron donors (SEDs)!

"If a neutral organic molecule could be found that would reduce iodobenzene, we resolved to call it a "super-electron-donor" (SED)"- Prof. John A. Murphy!

Benzene: Mortensen, J.; Heinze, J. Angew. Chem. Int. Ed. Engl. 1984, 23, 84-85.!Halobenzenes: Allongue, P.; Delamar, M.; Desbat, B.; Fagebaume, O.; Hitmi, R.; Pinson, J.; Savéant, J-M. J. Am. Chem. Soc. 1997, 119, 201-207.!Aryl Diazonium Salts: Pause, L.; Robert, M.; Savéant, J-M. J. Am. Chem. Soc. 1999, 121, 7158-7159.!Alkyl Halides: Isse, A. A.; Lin, C. Y.; Coote, M. L.; Gennaro, A. J. Phys. Chem. B 2011, 115, 678-684.!Sulfone/sulfonamide: Shoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyoma, Y.; Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368-13369.!Murphy, J. A. J. Org. Chem. 2014, 79, 3731-3746.!

-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0

Reduction Potential (Volts)

(E0= -3.42 V )

(E0= -2.2 V) (EP~ 0 V)

(E0= -2.4 V)

(E0= -2.78 V)

Alkyl Halides(E0 = -1.37 V to -0.37)

ArSO2Ror

RSO2NR2(E0 = -2.3 V)

designing a “stronger” TTF derivative!

1)  Preexisting aromaticity from benzene-fused rings, lessens the stabilization effect gained from aromaticity.!

RR Rx!

designing a “stronger” TTF derivative!

Murphy, J. A. J. Org. Chem. 2014, 79, 3731-3746.!Bordwell, F. G.; Satish, A. V. J. Am. Chem. Soc. 1991, 113, 985-990.!

H3CCH3

CH3SOCH2K

(Epa = +0.300 V)

(Epa = +0.120 V)

(Epa = -0.040 V)

H3CCH3

(pKHA = 9)

(pKHA = 13)

added in smallaliquots

N(CH3)2

(H3C)2N

E0 = +0.37 V, +0.67 V in CH2Cl2 vs SCE

2) Similarly sized C and N orbitals lead to better orbital overlap and greater stability (better reductant).!

N(CH3)2

(H3C)2HN

(H3C)2N

electron rich olefins (EROs)!

N(CH3)2

(H3C)2N

(H3C)2NNH

CH3H3CCl F

F F -78 ˚C to 32 ˚C; then heat

-yellow liquid!-strongly luminescent!-air (O2) and H2O sensitive!-”vigorous” reactant (ROH, Br2, I2)!

NR2R2N

NR2R2N O2O

R2NNR2

NR2R2NR2N

TDAE Discovery: Pruett, R. L.; Barr, J. T.; Rapp, K. E.; Bahner, C. T.; Gibson, J. D.; Lafferty, R. H., Jr. J. Am. Chem. Soc. 1950, 72, 3646-3650.!O2 reactivity: Carpenter, W.; Bens, E. M. Tetrahedron 1970, 26, 59-65.!

Briscoe, M. W.; Chambers, R. D.; Mullins, S. J.; Nakamura, T.; Vaughan, J. F. S.; Drakesmith, F. G. J. Chem. Soc., Perkin Trans. 1 1994, 3115-3118.!

N(CH3)2

(H3C)2N

N(CH3)2

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

E0 = -0.78 V, -0.61 V in CH3CN vs SCE!

0 ˚C to RTCH2Cl2

90% yield

N(CH3)2

(H3C)2N

N(CH3)2

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

E0 = -0.78 V, -0.61 V in CH3CN vs SCE!

– FF3C

*All unmarked bonds are to fluorine.

0 ˚C to r.t.CH2Cl2

90% yield

single electron transfer reactions!

Broggi, J.; Terme, T.; Vanelle, P. Angew. Chem., Int. Ed. 2014, 53, 384-413.!

H Solvent

TDAE!N(CH3)2

N(CH3)2

(H3C)2N

N(CH3)2

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

E0 = -0.78 V, -0.61 V in CH3CN vs SCE!

0 ˚C to RTCH2Cl2

90% yield

F3C IN(CH3)2

(H3C)2N

N(CH3)2F3C+

trifluoromethylation!“manyfluorinatedanaloguesofbiologicalcompoundsexhibitadrama@cenhancementoftheirbioac@vity”

Fluorine: Fluorine in Bioorganic Chemistry (Eds.: Welch, J. T.; Eswarakrishnan, S.), Wiley, New York, 1991; Bioorganic and Medicinal Chemistry of Fluorine (Eds. : Bégué, J.-P.; Bonnet-Delpon, D.), Wiley, Hoboken, 2008.!

---comparabletoTMSCF3(Ruppert-Prakashreagent)---

CH3F3C

Aldehydes/Ketones: Aït-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. R. Org. Lett. 2001, 3, 4271-4273.!Cyclic Sulfates: Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W. R. Org. Lett. 2002, 4, 4671-4672.!Trifluoro ethers: Pooput, C.; Medebielle, M.; Dolbier, W. R. Org. Lett. 2004, 6, 301-303.!Imines: Xu, W.; Dolbier, W. R. J. Org. Chem. 2005, 70, 4741-4745.!Imines: Pooput, C.; Dolbier, W. R.; Medebielle, M. J. Org. Chem. 2006, 71, 3564-3568.!Reagents for Fluorination. Aldrich ChemFiles 2007, 7.1, 11. Nucleophilic Trifluoromethylation.!

N(CH3)2

(H3C)2N

N(CH3)2

CF3R R'

R'SO2Tol

R'NHSO2Tol

CF3 or RSe

CF32 2

CF3IN(CH3)2

(H3C)2N

N(CH3)2

HO CF3

-35 ˚C to RT, DMF

10% yield

CF3IN(CH3)2

(H3C)2N

N(CH3)2

HO CF3

+ +-20 ˚C to RT,

80% yield

hυ, 12 h

TDAE + light!

charge-transfer complex (red)

N(CH3)2

(H3C)2N

N(CH3)2

CF3IN(CH3)2

(H3C)2N

N(CH3)2+

Aldehydes/Ketones: Aït-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. R. Org. Lett. 2001, 3, 4271-4273.!

CO2Et CO2EtTDAEcat. I2

+THF, 67 ˚C, 6 h

97% yield

THF, 67 ˚C, 0.5 h

94% yield

cat. I2, MgSO4

Tetrahydronapthalene: Nishiyama, Y.; Kawabata, H.; Kobayashi, A.; Nishino, T.; Sonoda, N. Tet. Lett. 2005, 46, 867-869.!1,4-diketones: Nishiyama, Y.; Kobayashi, A. Tet. Lett. 2006, 47, 5565-5567.!

*1,4-diestersalsoformedinlowyield.

diketones & esters!N(CH3)2

(H3C)2N

N(CH3)2

pharmaceutical analogs!

O CO2H

XK469 CQS

quinoxaline anti-cancer drug candidates!

Montana, M.; Terme, T.; Vanelle, P. Tet. Lett. 2005, 46, 8373-8376.!Montana, M.; Terme, T.; Vanelle, P. Tet. Lett. 2006, 47, 6573-6576.!

N(CH3)2

(H3C)2N

N(CH3)2

DMF, -20 ˚C

79% yieldcis/trans

CF3TDAE

DMF, -20 ˚C

69% yield

-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0

(E0= -3.42 V )

(E0= -2.2 V) (EP~ 0 V)

(E0= -2.4 V)

(E0= -2.78 V)

ArSO2Ror

RSO2NR2(E0 = -2.3 V)

tetraazafulvalene!

Ames, J. R.; Houghtaling, M. A.; Terrian, D. L.; Mitchell, T. P. Can. J. Chem. 1997, 75, 28-36.!Murphy, J. A.; Khan, T. A.; Zhou, S.; Thomson, D. W.; Mahesh, M. Angew. Chem. Int. Ed. 2005, 44, 1356-1360.!

E0 = -0.76 V, -0.82 V in DMF vs SCE!

I(CH2)3I

CH3CN, reflux, 3 d

95% yield

DMF, 0 ˚C, 40 minN

tetraazafulvalene!

Ames, J. R.; Houghtaling, M. A.; Terrian, D. L.; Mitchell, T. P. Can. J. Chem. 1997, 75, 28-36.!Murphy, J. A.; Khan, T. A.; Zhou, S.; Thomson, D. W.; Mahesh, M. Angew. Chem. Int. Ed. 2005, 44, 1356-1360.!

E0 = -0.76 V, -0.82 V in DMF vs SCE!

R X R''

R XR''

X = O or NMsR = H or OCH3R' = H, CH3, or (CH2)3R'' = H or (CH2)3

5 examples

SED (1.2 equiv)

H3CO NMs

PhCH3/DMF, 18 h, reflux

65-89% yield

PhCH3/DMF, 18 h, reflux; then, p-TSA

67% yield

PhCH3, 15 h 110 ˚C

83-88% yield

R = H, CH3, or (CH2)3R = H or (CH2)3

3 examples

SED (1.2 equiv)

-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0

(E0= -3.42 V )

(E0= -2.2 V) (EP~ 0 V)

(E0= -2.4 V)

(E0= -2.78 V)

ArSO2Ror

RSO2NR2(E0 = -2.3 V)

CH3 CH3

– 1e – 1e

+ 1e + 1e

Ames, J. R.; Houghtaling, M. A.; Terrian, D. L.; Mitchell, T. P. Can. J. Chem. 1997, 75, 28-36.!Murphy, J. A.; Khan, T. A.; Zhou, S.; Thomson, D. W.; Mahesh, M. Angew. Chem., Int. Ed. 2005, 44, 1356-1360.!

OCH3+ 1e

SET (DET)

90% yield

tetraazafulvalene 2.0!

Murphy, J. A.; Zhou, S; Schoenebeck, F. Angew. Chem. Int. Ed. Engl. 2007, 46, 5178-5183.!Ames, J. R.; Houghtaling, M. A.; Terrain, D. L.; Mitchell, T. P. Can. J. Chem. 1997, 75, 28-36.!

CH3 CH3

– 1e – 1e

+ 1e + 1e

Carbene: Taton, T. A.; Chen, P. Angew. Chem. Int. Ed. Engl. 1996, 33, 1011-1013.!Wanzlick Equilibrium: Böhm, V. P. W.; Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 4036-4038.!Murphy, J. A.; Zhou, S; Schoenebeck, F. Angew. Chem. Int. Ed. Engl. 2007, 46, 5178-5183.!Ames, J. R.; Houghtaling, M. A.; Terrain, D. L.; Mitchell, T. P. Can. J. Chem. 1997, 75, 28-36.!

Synthesis of Doubly-Bridged TAF:!

CH3 CH3

– 1e – 1e

+ 1e + 1e

E0 = -1.20 V in DMF !vs SCE!

NI(CH2)3I

CH3CN, reflux, 24 d

51% yield

NH3(l), reflux, 2 h

98% yield

Wanzlick-Equilibrium!

Carbene: Taton, T. A.; Chen, P. Angew. Chem. Int. Ed. Engl. 1996, 33, 1011-1013.!Wanzlick Equilibrium: Böhm, V. P. W.; Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 4036-4038.!Murphy, J. A.; Zhou, S; Schoenebeck, F. Angew. Chem. Int. Ed. Engl. 2007, 46, 5178-5183.!Ames, J. R.; Houghtaling, M. A.; Terrain, D. L.; Mitchell, T. P. Can. J. Chem. 1997, 75, 28-36.!

Synthesis of Doubly-Bridged TAF:!

NI(CH2)3I

CH3CN, reflux, 24 d

51% yield

NH3(l), reflux, 2 h

98% yield

“it takes two to cyclize”!

– 1e – 1e

+ 1e + 1e

ICO2Et

CH3CH3

DMF, 120 ˚C, 2 h

HCO2Et

CH3CH3

67% yield

Murphy, J. A.; Zhou, S.; Thomson, D. W.; Schoenebeck, F.; Mahesh, M.; Park, S. R.; Tuttle, T.; Berlouis, L. E. A. Angew. Chem. Int. Ed. Engl. 2007, 46, 5178-5183.!

ICO2Et

CH3CH3

HCO2Et

CH3CH3

70% yield16% yield

CH3DMF, RT, 2 h +

confirmation of aryl anion!

Murphy, J. A.; Zhou, S.; Thomson, D. W.; Schoenebeck, F.; Mahesh, M.; Park, S. R.; Tuttle, T.; Berlouis, L. E. A. Angew. Chem. Int. Ed. Engl. 2007, 46, 5178-5183.!

CO2EtCH3

CH3DMF, RT, 2 h

CO2EtCH3

51% yield 21% yield

DMF, RT, 2 h

OCO2CH3 O

OCO2CH3

45% yield 49% yield

SED (1.6 equiv)

X = Br, Cl

DMF, 100 ˚C, 1 h

86-99% yield

SED (1.5 equiv)

reactivity of bis-sulfones!

then H2O

94-98% yield

R'PhSO2

CH3IPhSO2CH3

+ e+ e

R'PhSO2

Shoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyoma, Y.; Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368-13369.!

mono-sulfones!N

CH3H3C SED (3 equiv)

DMF, 110 ˚C, 18 h

79% yield

SED (3 equiv)

DMF, 110 ˚C, 18 h

97% yield

SED (3 equiv)

110 ˚C, 18 h

NRPhO2S

CH3H3C

H3C Ph

N–S scission!

Shoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyoma, Y.; Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368-13369.!

SED (6 equiv)

DMF, 110 ˚C, 4 h

91% yield

SED (6 equiv)

DMF, 110 ˚C, 18 h

74% yield

SED (6 equiv)

DMF, 110 ˚C, 18 hN

in-situ SED!

WanzlickEquilibrium

CH3 CH3

Jolly, P.I.; Zhou, S.; Thomson, D. W.; Garnier, J.; Parkinson, J. A.; Tuttle, T.; Murphy, J. A. Chem. Sci. 2012, 3, 1675-1679.!

MsR = H or CH3

NaH, DMF for R = HKHMDS, DMF/PhCH3 for R = CH3

CH3 CH3

R = H, 0%R = CH3, 22%

R = H, 41%R = CH3, 24%

CH3 CH3

O(CH2)3Ph

NaH, DMF

79% yield

O(CH2)3Ph

in-situ SED!

Jolly, P.I.; Zhou, S.; Thomson, D. W.; Garnier, J.; Parkinson, J. A.; Tuttle, T.; Murphy, J. A. Chem. Sci. 2012, 3, 1675-1679.!

CH3INaH

NH3 (l)

glass (H+ source)

NH3 (l)N

CH3I I

Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.; Zhou, S.; Turner, A. T. Org. Lett. 2008, 10, 1227-1230.!

DMAP derived SED!

E0 = -1.24 V in DMF vs SCE!

N(CH3)2

I(CH2)3I

CH3CN, reflux, 12h

91% yield

N(CH3)2(H3C)2N

I INaH

NH3 (l)

83% yield

N(CH3)2(H3C)2N

DMAP derived SED!

CO2EtCH3

1) SED (1.5 equiv), DMF, RT

2) KOH, CH3OH, H2O50 ˚C, 12h O

83% yield 8% yield

O(CH2)3Ph

SED (3 equiv)

100 ˚C, DMF

82% yield

96% yield from bromideRT, SED (1.5 eq)

95% yield from iodideRT, SED (1.5 eq)

SED (3 equiv)

100 ˚C, DMF

99% yield

SO2PhH

Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.; Zhou, S.; Turner, A. T. Org. Lett. 2008, 10, 1227-1230.!

N(CH3)2(H3C)2N

CV representation!

CH3 CH3

(H3C)2N

N(CH3)2E0 = -1.69 V

E0 values in DMF vs Fe/Fe+.

E0 = -1.65 V E0 = -1.27, -1.21 V

N–O, C–O, & S–O!

Weinreb Amides: Cutulic, S. P. Y.; Murphy, J. A.; Farwaha, H.; Zhou, S.; Chrystal, E. Synlett 2008, 2132-2136.!C–O reduction: Cutulic, S. P. Y.; Findlay, N. J.; Zhou, S.; Chrystal, E. J. T.; Murphy, J. A. J. Org. Chem. 2009, 74, 8713-8718.!S–O reduction: Jolly, P. I.; Fleary-Roberts, N.; O’Sullivan, S.; Doni, E.; Zhou, S.; Murphy, J. A. Org. Biomol. Chem. 2012, 10, 5807-5810.!

N(CH3)2(H3C)2N

SED (1.5 eq)

DMF, 100 ˚C

n = 0, 77% yieldn = 1, 67% yield

OCH3SED (1.5 eq)

DMF, 100 ˚C

43% yield

SED (1.5 eq)

DMF, 12h, 100 ˚C

R = Ms, 91% yieldR = Ac, 93% yieldR = Piv, 85% yield

SED (1.5 eq)

RT, DMF, 3h

n = 2, 91% yieldn = 3, 93% yieldn = 4, 85% yield

toward superb SEDs!

Farwaha, H. S.; Bucher, G.; Murphy, J. A. Org. Biomol. Chem. 2013, 11, 8073-8081.!

- TS and oxidation product stabilization from 5 nitrogen atoms -!

-- Aromaticity in 3 heterocycles --!

(H3C)2N

N(CH3)2

(H3C)2N

N(CH3)2

– 1e

(H3C)2N

N(CH3)2

synthesis of tricyclic donor!

E0 = -1.50 V in DMF!vs SCE!

N(CH3)275% yield

N(CH3)2

(H3C)2N

N(CH3)2

BF3•Et2O, THF, 0.5h RT to -78 ˚C, n-BuLi; thenCBr4 -78 ˚C to RT 12 h

-78 ˚C to RT, THF, t-BuLi, 13 h

49% yield

RT, CH3OH, 12 h

79% yield

CH3CN, reflux, 12 h

95% yield

(H3C)2N

N(CH3)2

(H3C)2N

N(CH3)2

CV representation!

Comparison of cyclic voltammograms of 25 (purple) and 14 (green) vs. Ag/AgCl in DMF at 50 mV s−1 scan rate.!

scope!

(H3C)2N

N(CH3)2

O NOCH3

SED (1.5 equiv)

DMF, RT, 18 h

96% yield

NPh SED (3 equiv)

DMF, 100 ˚C, 18 h

68% yield

SED (3 equiv)

DMF, 100 ˚C, 18 h

87% yield

SED (4 equiv)

DMF, 100 ˚C, 18 h

94% yieldNH

most recent developments!-- photoactivated SEDs --!

-- SEDs for transition metal-free coupling --!

O(CH2)3Ph

SED (3 equiv)

DMF, hυ, 72 h, RT

87% yield

N(CH3)2(H3C)2N

Cahard, E.; Schoenebeck, F.; Garnier, J.; Cutulic, S. P. Y.; Zhou, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2012, 51, 3673-3676.!Doni, E.; O’Sullivan, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2013, 52, 2239-2242.!O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Angew. Chem., Int. Ed. 2014, 53, 474-478.!Doni, E.; Mondal, B.; O’Sullivan, S.; Tuttle, T.; Murphy, J. A. J. Am. Chem. Soc. 2013, 135, 10934-10937.!

photoexcited SEDs!Cl

O(CH2)3Ph

SED (3 equiv)

DMF, 16 h, 100 ˚C

0% yield

λmax = 260, 345, 520 nm !

SED at 7.7x10-5 M and 1.9x10-5 M.!

SED (3 equiv)

DMF, hυ, 72 h, RT

N(CH3)2(H3C)2N

-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0

(E0= -3.42 V )

(E0= -2.2 V) (EP~ 0 V)

(E0= -2.4 V)

(E0= -2.78 V)

ArSO2Ror

RSO2NR2(E0 = -2.3 V)

reducing “PhH” !

Cahard, E.; Schoenebeck, F.; Garnier, J.; Cutulic, S. P. Y.; Zhou, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2012, 51, 3673-3676.!Doni, E.; O’Sullivan, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2013, 52, 2239-2242.!O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Angew. Chem., Int. Ed. 2014, 53, 474-478.!Doni, E.; Mondal, B.; O’Sullivan, S.; Tuttle, T.; Murphy, J. A. J. Am. Chem. Soc. 2013, 135, 10934-10937.!

--Reduce:benzylicethersandesters,S–N,C–Nbond--

Photoexcitation: Cahard, E.; Schoenebeck, F.; Garnier, J.; Cutulic, S. P. Y.; Zhou, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2012, 51, 3673-3676. Doni, E.; O’Sullivan, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2013, 52, 2239-2242. O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Angew. Chem., Int. Ed. 2014, 53, 474-478. Doni, E.; Mondal, B.; O’Sullivan, S.; Tuttle, T.; Murphy, J. A. J. Am. Chem. Soc. 2013, 135, 10934-10937.![K or Na]: Krollpfeiffer, F.; Rosenberg, A. Ber. Dtsch. Chem. Ges. 1936, 69, 465-470.![SmI2]: Kang, H.-Y.; Hong, W. S.; Cho, Y. S.; Koh, H. Y. Tetrahedron Lett. 1995, 36, 7661-7664.!

photoexcited SEDs! NN

N(CH3)2(H3C)2N

CO2EtEtO2C

K or NaHEtO2C

SED (6 equiv)

DMF, hυ, 72 h, RT

75% yield

CNEtO2C

SmI2EtO2C

HSED (6 equiv)

DMF, hυ, 72 h, RT

75% yield

EtO2CPh

SED (3 equiv)

DMF, hυ, 72 h, RT

65% yieldNH

transition metal-free coupling!

Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537−15539.!Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018−5022.!Zhou, S.; Anderson, G. M.; Mondal, B.; Doni, E.; Ironmonger, V.; Kranz, M.; Tuttle, T.; Murphy, J. A. Chem. Sci. 2014, 5, 476−482.!

Ar X ArPhH

M OtBu

H3CO I

SED (0.05 equiv)

KOtBu, PhH, 130 ˚C, 15 h

79% yield

SED (0.2 equiv)

KOtBu, PhH, 180 ˚C, 5 h

82% yield

conclusion!

*Art by graphic artist Maxime Py and the Super-Kamiokande Collaboration!

E0 = +0.32, +0.71 V in CH3CN

N(CH3)2

(H3C)2N

CH3 CH3

E0 = -0.76 V, -0.82 V in DMF

(H3C)2N

N(CH3)2

E0 = -1.24 V in DMF

E0 = -1.20 V in DMF

(H3C)2N

N(CH3)2H3C

E0 = -1.50 V in DMF

TDAETTF

CH3 CH3

(H3C)2N

N(CH3)2E0 = -1.69 V

E0 values in DMF vs Fe/Fe+.

E0 = -1.65 V E0 = -1.27, -1.21 V

H Solvent

N(CH3)2

(H3C)2HN

(H3C)2N

Emergence!Preparation!Application!

!-Asymmetric products?!-Photoactivation?!-Nonmetallic Cross!Couplings?!-Catalytic?!!

ACKNOWLEDGMENTS

Prof. Eric M. Ferreira!&!

The Ferreira Research Group !

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