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!

S

SS

S

E0 = +0.32, +0.71 V in CH3CN

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

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

N

N

N

N

CH3 CH3

E0 = -0.76 V, -0.82 V in DMF

N

(H3C)2N

N

N(CH3)2

E0 = -1.24 V in DMF

N

N

N

N

E0 = -1.20 V in DMF

NCH3

NN

(H3C)2N

H3C

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.!

S

SS

S

E0 = +0.32, +0.71 V in CH3CN

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N


N

N

N

N

CH3 CH3

E0 = -0.76 V, -0.82 V in DMF

N

(H3C)2N

N

N(CH3)2

E0 = -1.24 V in DMF

N

N

N

N

E0 = -1.20 V in DMF

NCH3

NN

(H3C)2N

H3C

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.!

R–X

D

D+e

R–X

X

R

R–H

+e

D R–D Y R–YRER–E

H Solvent

single-electron transferdouble-electron transfer

reductive termination

electrophilic conversionnucleophilic conversion

D

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

N(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F

F

– e

SET

– e

DET

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

radical cation dication

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N


TDAE

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!

S

SS

S

SHPAA

acetone, 0.5 h, 0 ˚C

82% yieldHSO4

Et3N

S

S

S

S

CH3CN

50% yield

S

S

S

S

S

S

S

S


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.!

N2 S

SS

S

S

SS

S

+e

TTF

R R

N2

R– N2

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

S

SS

S

SHPAA

acetone, 0.5 h, 0 ˚C

82% yieldHSO4

Et3N

S

S

S

S

CH3CN

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!!

S

SS

SS

SS

S S

SS

S

– e – e

SET DET

N2 S

SS

S

S

SS

S

+e

TTF

R R

N2

R– N2

Cu(II) analogy!

Cu(II)X2

Cu(I)X

N2+e

R R

N2

R– N2

MeerweinArylaLon

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

N2 S

SS

S

S

SS

S

+e

TTF

R R

N2

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.!

NMs

N2

H–N2

NHCOCF3BF4

NMs

N2

H

NHCOCF3

NMs

H

NHCOCF3

NMs

H

NHCOCF3

NMs

H

F3COCHNS

S

S

S

NMs

H

F3COCHN

NMs

H

F3COCHNOH

NH H

N

CH3

(±) aspidospermidine

BF4

S

SS

S

S

SS

S

+e

TTF

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.!

Cl

Br

I N2

-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.!

S

S

S

S

S

SS

SS

SS

S

– e

SET

– e

SET S

S

S

S

vs.

N2S

S

S

S

S

S

S

S

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.!

N

S

CH3

N

S

H3CCH3

CH3SOCH2K

N

S

CH3

S

N CH3

H3C

N

S

CH3

S

NH3C

H

H

(Epa = +0.300 V)

(Epa = +0.120 V)

(Epa = -0.040 V)

N

S

H3CCH3

S

N CH3

H3C

(pKHA = 9)

(pKHA = 13)

added in smallaliquots

+

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N


TDAE

S

S

S

S

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

TTF

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

N(CH3)2

N(CH3)2

(H3C)2HN

(H3C)2N

electron rich olefins (EROs)!

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2NNH

CH3H3CCl F

F F -78 ˚C to 32 ˚C; then heat

+

TDAE

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

NR2R2N

NR2R2N O2O

R2N

R2NNR2

NR2R2NR2N

O O

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.!

TDAE!

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

N(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F

F

– e

SET

– e

DET

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

F3C

F3C

CF3

CF3F

FF

F

F3C

F3C

CF3

CF3

F

F

0 ˚C to RTCH2Cl2

90% yield

TDAE

TDAE!


N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F

F

– e

SET

– e

DET

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

F3C

F3C

CF3

CF3F

FF

F

F3C

F3C

CF3

CF3

F

F

D

D

FFSET

DET

FF

– FF3C

F3C

CF3

CF3

F

F

*All unmarked bonds are to fluorine.

0 ˚C to r.t.CH2Cl2

90% yield

+e

+e

TDAE

single electron transfer reactions!

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

R–X

D

D+e

R–X

X

R

R–H

+e


H Solvent




D

TDAE!N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N

F

F

– e

SET

– e

DET

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

I

R

TDAEH

R


F3C

F3C

CF3

CF3F

FF

F

F3C

F3C

CF3

CF3

F

F

0 ˚C to RTCH2Cl2

90% yield

TDAE

F3C IN(CH3)2

(H3C)2N

(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)---

SiCH3

CH3F3C

H3C

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

(H3C)2N

N(CH3)2

O

R'R

F3C

CF3R R'

HO

NR

R'SO2Tol

R

O OS

O O

CF3HO

R

CF3R

R'NHSO2Tol

RS

SR

RSe

SeR

Ar NS

Ar'

O

RS

CF3 or RSe

CF32 2

Ar NH

SAr'

OCF3

or

H

O

CF3IN(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

H

HO CF3

-35 ˚C to RT, DMF

10% yield

+ +

H

O

CF3IN(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

H

HO CF3

+ +-20 ˚C to RT,

DMF

80% yield

hυ, 12 h

TDAE + light!

charge-transfer complex (red)

N(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2

I

F3C

CF3IN(CH3)2

(H3C)2N

(H3C)2N

N(CH3)2+

hυ

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

BrBr

CO2Et CO2EtTDAEcat. I2

+THF, 67 ˚C, 6 h

97% yield

OBr

O

O

TDAE

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

(H3C)2N

N(CH3)2

pharmaceutical analogs!

N

N

Cl O

O CO2H

CH3

Cl

N

N

NH

SO

O

NH2

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

(H3C)2N

N(CH3)2

H

O N

N

Br

Br

F3C

TDAE

DMF, -20 ˚C

79% yieldcis/trans

N

N

O

CF3TDAE

DMF, -20 ˚C

69% yield

N

N

O

Cl

CF3

N

N

Cl

ClCl




Cl

Br

I N2

-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!

N

N

CH3

I(CH2)3I

CH3CN, reflux, 3 d

95% yield

N

N

CH3

N

N

CH3

I I

NaH

DMF, 0 ˚C, 40 minN

N

CH3

N

N

CH3

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

R X R''

R'

R XR''

R'

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

5 examples

SED (1.2 equiv)

I

H3CO NMs

CH3

NMs

CH3

H3CO

PhCH3/DMF, 18 h, reflux

65-89% yield

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

67% yield

H3CO

O

I

R'

R

H3CO

OR'

R

PhCH3, 15 h 110 ˚C

83-88% yield

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

3 examples

SED (1.2 equiv)

SED (1.2 equiv)

SED!

N

N

CH3

N

N

CH3




Cl

Br

I N2

-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)

DET?!

N

N

CH3

N

N

CH3

N

N

CH3 CH3

N

NI I

N

N

CH3 CH3

N

NI

– 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.!

I

NMs

OCH3

D

D

NMs

OCH3

NMs

OCH3+ 1e

SET

D

D2+

NMs

OCH3

NMs

+ 1e

SET (DET)

NMs

OCH3

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.!

N

N

CH3

N

N

CH3

N

N

CH3

N

N

CH3

N

N

CH3 CH3

N

NI I

N

N

CH3 CH3

N

NI

– 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:!

N

N

CH3

N

N

CH3

N

N

CH3

N

N

CH3

N

N

CH3 CH3

N

NI I

N

N

CH3 CH3

N

NI

– 1e – 1e

+ 1e + 1e

E0 = -1.20 V in DMF !vs SCE!

N

N

N

NI(CH2)3I

N

N

N

NI I

CH3CN, reflux, 24 d

51% yield

N

N

N

NNaH

NH3(l), reflux, 2 h

98% yield

N

N

CH3

N

N

CH3

N

N

CH3

N

N

CH3

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:!

N

N

NN

NN

N

NI

II

I


N

N

N

NI(CH2)3I

N

N

N

NI I

CH3CN, reflux, 24 d

51% yield

N

N

N

NNaH

NH3(l), reflux, 2 h

98% yield

“it takes two to cyclize”!

N

N

N

N

N

N

N

NI I

N

N

N

NI

– 1e – 1e

+ 1e + 1e

N

N

CH3

N

N

CH3

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

O

CH3

CH3DMF, RT, 2 h +

N

N

N

N

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.!

N

N

N

N

I

O

CO2EtCH3

CH3DMF, RT, 2 h

H

O

CO2EtCH3

CH3O

O

CH3

CH3

51% yield 21% yield

+

DMF, RT, 2 h

I

OCO2CH3 O

O

+

H

OCO2CH3

45% yield 49% yield

SED (1.6 equiv)

SED (1.6 equiv)

RX

X = Br, Cl

RH

DMF, 100 ˚C, 1 h

86-99% yield

SED (1.5 equiv)

reactivity of bis-sulfones!

SO2Ph

SO2Ph

R

R'H

SO2Ph

R

R'

SED

then H2O

94-98% yield

S

SO2Ph

R

R'

O

O

Ph

SO2Ph

R

R'PhSO2

CH3IPhSO2CH3

+ e+ e

SO2Ph

R

R'PhSO2

+

+

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

N

N

N

N


mono-sulfones!N

N

N

N

PhO2S

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

PhO2S

Ph

Ph

H3C

NRPhO2S

CH3H3C

H3C

CH3

H Ph

H3C Ph

N–S scission!


NTs

NTs

Ph

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

Ts

NH

TsH

TsHNH

Ph

NR

+

+

N

N

N

N

in-situ SED!

N

N

CH3

N

N

CH3

N

N

CH3

N

N

CH3

WanzlickEquilibrium

N

N

CH3 CH3

N

NI I

N

N

CH3

CH3I

&

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

I

N

R

MsR = H or CH3

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

N

N

CH3 CH3

N

NI I

N

R

Ms

H

N

R

Ms

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

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

+

N

N

CH3 CH3

N

NI I

N

N

CH3

CH3I

orI

O(CH2)3Ph

NaH, DMF

79% yield

H

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.!

N

N

CH3

CH3INaH

NH3 (l)

N

N

CH3

CH3

N

N

CH3

CH3

N

N

CH3

CH3

glass (H+ source)

N

N

CH3

CH2

N

N

CH3

CH3I

H

NaH

NH3 (l)N

N

CH3

CH2

N

N

CH3

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

N(CH3)2

I(CH2)3I

CH3CN, reflux, 12h

91% yield

NN

N(CH3)2(H3C)2N

I INaH

NH3 (l)

83% yield

NN

N(CH3)2(H3C)2N

DMAP derived SED!

I

O CH3

CO2EtCH3

1) SED (1.5 equiv), DMF, RT

2) KOH, CH3OH, H2O50 ˚C, 12h O

CH3

CH3

O

O

CO2H

CH3

CH3

83% yield 8% yield

+

Br

O(CH2)3Ph

H

O(CH2)3Ph

SED (3 equiv)

100 ˚C, DMF

82% yield

H

96% yield from bromideRT, SED (1.5 eq)

Ht-Bu

t-Bu

t-Bu

95% yield from iodideRT, SED (1.5 eq)

PhO2S

H3C

SO2Ph

SED (3 equiv)

100 ˚C, DMF

99% yield

H3C

SO2PhH

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

NN

N(CH3)2(H3C)2N

CV representation!


N

N

N

N

CH3 CH3

N

N

N

NN

(H3C)2N

N

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.!

NN

N(CH3)2(H3C)2N

O

NCH3

OCH3

n

SED (1.5 eq)

DMF, 100 ˚C

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

O

NCH3

H

n

N

OCH3

OCH3SED (1.5 eq)

DMF, 100 ˚C

43% yield

N

OCH3

H

O

OR

SED (1.5 eq)

DMF, 12h, 100 ˚C

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

O

OTfn

SED (1.5 eq)

RT, DMF, 3h

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

OHn

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 --!

NR

(H3C)2N

NEt

NR

N(CH3)2

NR

(H3C)2N

NEt

NR

N(CH3)2

– 1e

+ 1e

– 1e

+ 1e

X

NR

(H3C)2N

NEt

NR

N(CH3)2

X X

synthesis of tricyclic donor!

E0 = -1.50 V in DMF!vs SCE!


N

N(CH3)275% yield

N

N(CH3)2

Br

N

N(CH3)2

O

ON

N(CH3)2

N

(H3C)2N

NEt

N

N(CH3)2

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

N

ON

OCH3

OCH3

H3C

OCH3

-78 ˚C to RT, THF, t-BuLi, 13 h

49% yield

Et2NH

RT, CH3OH, 12 h

79% yield

CH3I

CH3CN, reflux, 12 h

95% yield

NCH3

(H3C)2N

NEt

NH3C

N(CH3)2

II

NCH3

(H3C)2N

NEt

NH3C

N(CH3)2

Na/Hg

DMF

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!


NCH3

(H3C)2N

NEt

NH3C

N(CH3)2

O NOCH3

CH3

O NH

CH3

SED (1.5 equiv)

DMF, RT, 18 h

96% yield

Ph

NPh SED (3 equiv)

DMF, 100 ˚C, 18 h

68% yield

N

SED (3 equiv)

DMF, 100 ˚C, 18 h

87% yield

NH

N

NTs2

SED (4 equiv)

DMF, 100 ˚C, 18 h

94% yieldNH

NHTs

Ph

NH

Ph

Ts

Ts

Ts

most recent developments!-- photoactivated SEDs --!

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

Cl

O(CH2)3Ph

H

O(CH2)3Ph

SED (3 equiv)

DMF, hυ, 72 h, RT

87% yield

NN

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

H

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

NN

N(CH3)2(H3C)2N

Cl

Br

I N2

-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

PhPh

K or NaHEtO2C

PhPh

SED (6 equiv)

DMF, hυ, 72 h, RT

75% yield

EtO2C

CO2Et

Ph

CNEtO2C

PhPh

SmI2EtO2C

PhPh

HSED (6 equiv)

DMF, hυ, 72 h, RT

75% yield

CN

EtO2CPh

NTs

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

HAr

M OtBu

ArAr

Ar X

H3CO I

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

H3CO

N

N

N

N

conclusion!

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

S

SS

S

E0 = +0.32, +0.71 V in CH3CN

N(CH3)2

N(CH3)2

(H3C)2N

(H3C)2N


N

N

N

N

CH3 CH3

E0 = -0.76 V, -0.82 V in DMF

N

(H3C)2N

N

N(CH3)2

E0 = -1.24 V in DMF

N

N

N

N

E0 = -1.20 V in DMF

NCH3

NN

(H3C)2N

H3C

N(CH3)2H3C

E0 = -1.50 V in DMF


TDAETTF


N

N

N

N

CH3 CH3

N

N

N

NN

(H3C)2N

N

N(CH3)2E0 = -1.69 V

E0 values in DMF vs Fe/Fe+.

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

R–X

D

D+e

R–X

X

R

R–H

+e


H Solvent




D

N(CH3)2

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 !

the emergence of neutral ground-state organic …...the emergence of neutral ground-state organic...

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