Bimolecular Coupling Reactions Involving

Single Electron Oxidations:

Method Development and Mechanistic Studies

Brian M. Casey

November 29, 2011

Outline of presentation

• Background and significance

• Objective 1: Synthetic and mechanistic studies involving the solvent-dependent chemoselective oxidative coupling of 1,3-dicarbonyls to styrene via Ce(IV) reagents

• Objective 2: Determination of the mechanistic factors involved in

the non-statistical oxidative heterocoupling of lithium-stabilized enolates

• Concluding remarks

2

Some initial perspective

3

Origins

• Faraday – Electrolysis of acetate

– Experimental observations

• Kolbe reaction

4 Faraday, M. Philosophical Transactions of the Royal Society of London. 1834, 124, 77.

Kolbe, H. Justus Liebigs Ann .Chem. 1849, 69, 257.

Interconversion of reactive intermediates

5

Anionic Radical

Cationic

Jahn, U.; Hartmann, P. Journal of the Chemical Society-Perkin Transactions 1. 2001, 2277.

Metal-based oxidants

6

Lanthanide (IV) metals

7

Ce(IV)-based reagents • Oxidation of functional groups

– Aromatics, alcohols, olefins/styrenes, hydroquinones, carbonyls, etc.

• Cerium(IV) ammonium nitrate [CAN] – Solubility – Cerium(IV) tetra-n-butylammonium nitrate [CTAN]

8

Ce(IV)-mediated bond forming reactions

• Carbon-carbon

• Carbon-heteroatom

9

Influencing reaction pathways

• Preferential oxidation of substrates

• Role of solvent

Zhang, Y.; Raines, A.J.; Flowers, R.A. Org. Lett. 2003, 5, 13, 2363.

Zhang, Y.; Raines, A.J.; Flowers, R. A. J. Org. Chem. 2004, 69, 6267

Organic chemist’s toolbox

10

11

Objective 1: Synthetic and mechanistic studies involving the

solvent-dependent chemoselective oxidative coupling of 1,3-dicarbonyls to styrene via Ce(IV) reagents

Objective 2: Determination of the mechanistic factors involved in

the non-statistical oxidative heterocoupling of lithium-stabilized enolates

12

Scope of synthesis

• Solvent-dependent chemoselectivity

• Yields and distributions (4:1 / 1:4)

• CTAN in CH2Cl2

Mechanism elucidation: time-resolved UV-Vis

13

Mechanism elucidation: observed rate constants in the absence of styrene

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Substrate Intermediate Oxidant Solvent

Rate constant of

Ce(IV) decay at

380 nm

k1 (sec-1

)b

Rate constant of

radical cation

formation at 460

nm

k2 (sec-1

)b

Rate constant

of radical

cation decay at

460 nm

k3 (sec-1

)b

1

CAN

CTAN

MeOH

MeCN

MeCN

CH2Cl2

5.8 ± 0.6 x 102

8.3 ± 0.2

6.0 ± 0.3

3.4 ± 0.3

6.0 ± 0.2 x 102

8.7 ± 0.1

6.2 ± 0.1

3.4 ± 0.1

4.1 ± 0.1 x 10-2

5.8 ± 0.2 x 10-3

5.1 ± 0.5 x 10-3

1.7 ± 0.1 x 10-3

a[Ce(IV)]=1 mM, [substrate]=20 mM at 25oC. bAverage of at least two runs

MeOH > MeCN > CH2Cl2

15

Mechanism elucidation: kinetic isotope effect studies

• Monitor decay of radical cation

• Primary KIE:

MeCN and CH2Cl2: kH/kD > 2 MeOH: kH/kD ≈ 1.5

Mechanism elucidation: rate order of styrene in radical cation decay

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Oxidant Solvent Styrene Rate Ordera,b

CAN MeOH 0.28 ± 0.01

CAN MeCN 0.97 ± 0.05

CTAN CH2Cl2 1.02 ± 0.06

Oxidant Solvent MeOH Rate Ordera,b

CTAN CH2Cl2 0.94 ± 0.05 aAverage of at least 2 runs.

bDetermined from the slope for the plot of lnkobs vs. ln[styrene].

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What do we know?

1. Rates of oxidation of substrates are solvent dependent

2. Rates of decay of radical cations are solvent dependent

3. In the absence of styrene, deprotonation of the radical cation is involved in the rate-limiting step

4. Styrene is first order in both MeCN and CH2Cl2 for the rate-limiting step

5. In the absence of styrene, MeOH is first order in CTAN/CH2Cl2 for the rate-limiting step

Proposed mechanism

18 Casey, B.M.; Eakin, C. A.; Jiao, J.; Sadasivam, D. V. ; Flowers, R.A. Tetrahedron. 2010, 66, 5719.

Significance

• Stability of radical cation

• Importance of intermediates

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20

Objective 1: Synthetic and mechanistic studies involving the

solvent-dependent chemoselective oxidative coupling of 1,3-dicarbonyls to styrene via Ce(IV) reagents

Objective 2: Determination of the mechanistic factors involved in

the non-statistical oxidative heterocoupling of lithium-stabilized enolates

Oxidation of enolates

• Efficient bond formation

• Intramolecular couplings

• Intermolecular homocouplings

21

Kobayashi, Y.; Taguchi, T.; Morikawa, T.; Tokuno, E.; Sekiguchi, S. Chem Pharm Bull. 1980, 28, 262.

Baran, P.S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678.

Intermolecular heterocouplings

• Superstoichiometric

• Tethered silylenol ethers

• Limitations 22

23

Selective intermolecular oxidative heterocoupling of enolates

• Baran work

• Statistically predicted product distributions Baran, P.S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083.

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Heterocouplings based on preferential oxidation

• Dual nature of silylenolethers

• Extension to heterocoupling of enolates

Rates of enolate oxidations

• “Informatively unsuccessful”

• CTAN, Cu(OTf)2, and Fe(III)Cp2PF6

• Preliminary data on silylenol ethers

25

Common factor

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Lithium enolates

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Lithium enolate aggregates

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• Dimeric

• Tetrameric

• Higher order aggregates

Liou, L.R.; McNeil, A. J.; Ramirez, A.; Toombes, G. E. S.; Gruver, J. M.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 4859.

Dimeric lithium enolate aggregate distributions

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• Non-statistical dimeric aggregates

• Bimolecular process to unimolecular (Thompson)

Gruver, J.M.; Liou, L. R.; McNeil, A. J.; Ramirez, A.; Collum, D. B. J. Org. Chem. 2008, 73, 7743.

Extension to heterocoupling reactions of lithium enolates

• State of enolate aggregates

• 7Li NMR

• Experiments/conditions

• Energy barrier for rearrangement

30

31 A4 A3B1 A2B2 A1B3 B4

32 A4 A3B1 A2B2 A1B3 B4

7Li NMR results

33

Ketone A Ketone B 𝑨𝟐𝑩𝟐

𝑨𝟒 + 𝑩𝟒

15.7 : 1

14.7 : 1

14.3 : 1

8.5 :1

4.4 : 1

a Distributions obtained by integrating

7Li NMR spectra at -30

oC

b [A] = [B] = 0.15 M and [LiHMDS] = 0.304 M in 2.0 M THF:Toluene

Synthetic results

34

Ketone A Ketone B Heterocoupled Product Product

Distributionb

Yield

(%)c, d

13.8 : 1 62

12.8 : 1 58

12.4 : 1 62

7.0 : 1 46

3.0 : 1 47

a [A] = [B] = 0.12M in THF, [LiHMDS] = 0.26M in THF, [I2] = 0.12M in THF

b Ratios (heterocoupled product:homodimer of B) were determined by

1H NMR. Trace, if any, amounts of

homodimer of ketone A were observed by GC and 1H NMR.

c Determined by

1H NMR with ± 5 % error.

d 15-25% of ketone A was recovered in these reactions.

Impact of lithium aggregation on oxidative heterocouplings

0 5 10 15

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(Heterodimer/Homodimer)35

Additional synthetic observations

• Effect of counterion

• Effect of warming

• Effect of molar ratio

36

37

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Previously reported synthesis (revisited)

39

Significance

• “Atom economy” and “protecting-group-free”

40

Significance (cont’d)

• 1,4-Dicarbonyls in natural products and pharmaceuticals

• Impact in fine chemicals industry

41

Conclusions

• Importance of understanding reactive intermediates in synthesis

• Role of solvent

• Impact of lithium enolate aggregate distributions

42

Acknowledgements

43

Dr. Robert Flowers Dr. Dhandapani Sadasivam Dr. Lawrence Courtney Dr. Esther Pesciotta Kimberly Choquette James Devery Cynthia Kearse Gabrielle Haddad Todd Maisano Niki Patel Sherri Young NIH