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A Concise Synthesis of 3,5-di-tert-butylphenol as a Model Substrate for Cu-Catalyzed Aerobic Oxygenation of Phenols into ortho-Quinones
Michael GlazermanSupervisor: Dr. Xavier Ottenwaelder
SACIQ 2015
August 8, 2015
2
Phenols in Nature
• They’re also inexpensive…. usually
O
O
HO
OH
HO
OH
Atromentin
(−)-trans-Δ9-tetrahydrocannabinol
Epicatechin
3
ortho-Quinones are Versatile
OO
OHOH
Nu
Addition
Diels-Alder OO
Condensation
NO
R
HO
OCleavageOH
O
McMurry, J. Organic chemistry;; Brooks/Cole, Cengage Learning: Belmont, CA, 2012.
4
Aerobic Oxidation of PhenolsPhenols can be conveniently converted into quinones:
Esguerra, K. V. N., Fall, Y., Lumb, J.-P. Angew. Chem., Int. Ed. 126, 5987–5991 (2014)
OH
R R
OO
O2 H2O
Cu Catalyst
• Atom economical
• Water is the only by-product
…. But O2 needs to be activated
5
Nature Provides Some Insight
OnlineFabricStore.net Blog, http://www.onlinefabricstore.net/blog/home-decor ating-the-lore- of-the-rooster/ (accessed Aug 7, 2015).
6
Tyrosinase: Reaction and Active Site
Matoba, Y. et al.. J. Biol. Chem. 2006, 281, 8981–8990.
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Aerobic Oxidation of PhenolsAn efficient method for the conversion of phenols into quinones:
Esguerra, K. V. N., Fall, Y., Lumb, J.-P. Angew. Chem., Int. Ed. 126, 5987–5991 (2014)
Oxygen and Copper: an ideal oxidant/catalyst combo• Both are abundant in nature• Inexpensive• Non-toxic byproducts
OH
R R
OO
O2 H2O
Cu Catalyst
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Effect of Varying the Substitution Pattern
Esguerra, K. V. N., Fall, Y., Petitjean, L., Lumb, J.-P. J. Am. Chem. Soc. 136, 7662–7668 (2014).
$300 per gram!
$0.06 per gram
$0.10 per gram
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Synthesis of 3,5-di-tert-butylphenol
H
O
But tBu
O
H+ 1) Aldol Condensation
H HO
2) Robinson Annulation
O
tBuBut
3% Pd(TFA)2/ 6% 2NH2py
O2 (1 atm)80 C, DMSO, 24 h
12% TsOH
OH
But tBu°
Y. Izawa, D. Pun, S.S. Stahl, Science Vol. 333, 209, 2011. DOI: 10.1126/science.1204183
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Benzene to 1-bromo-3,5-di-t-butylbenzene
tButBu
tBu
tButBu
BrtBuCl (10 equiv.)AlCl3 (0.5 equiv.)
-40 ºC, 20 mins-10 ºC, 2 h
Br2 (1.5 equiv.)SbCl5 (0.1 equiv.)
-5 ºC, 5 h
65 % 85 %
[1] Baas, J. et al. Recl. Trav. Chim. Pays-Bas 1969, 88, 1110-1114[2] Suzuki, T.;; Fujita, K. PCT Int. Appl., 2011111464, 2015.
[1] [2]
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Hydroxylation of 1-bromo-3,5-di-t-butylbenzene
tButBu
BrCuI (0.1 equiv.) KOH (6 equiv.)PEG-400 / H2O (4:1) 120 ºC, 8 h tButBu
OH
tButBu
Br
H2O / DMSO(1:1)150 ºC, 48 h
NaOH (6 equiv.)CuO (0.05 equiv.)Glycolic acid (0.3 equiv.)
tButBu
Br1. CuCl2 (5 mol%) K2CO3 (3 equiv.) ethylene glycol 130 ºC, 20h
2. KOH (3 equiv.) DMSO, 100 ºC, 3 h
0.1 %
[1] Chen, J.;; Yuan, T.;; Hao, W.;; Cai, M. Catalysis Communications 2011, 12, 1463-1465.[2] Xiao, Y.;; Xu, Y.;; Cheon, H.;; Chae, J. The Journal of Organic Chemistry 2013, 78, 5804-5809.[3] Liu, Y.;; Park, S.;; Xiao, Y.;; Chae, J. Organic & BiomolecularChemistry 2014, 12, 4747.
[1]
[2]
[3]
No reaction
No reaction
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Hydroxylation of 1-bromo-3,5-di-t-butylbenzene
tButBu
Br
tButBu
OH
H2O, 275 ºC, 36 h
NaOH(aq) (6.6 equiv.)Cu powder (0.2 equiv.)CuO (0.5 equiv.)
75%
Elder, J.;; Mariella, R. Canadian Journal of Chemistry 1963, 41, 1653-1656.
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Future Work: Mechanistic Studies
HN N
H
[(MeCN)4Cu]PF6
O2
10 mol%
5 mol%
OHtBu
tBu
OH
tBu tBu
OOtBu
tBu
tBu
tBu
OO
tBu tBu
viaNH
NH
tBu
tBu
CuIIO
OtBu
tBu
NH
NH
tBu
tBu
CuIIO
OtBu
tBuvia
Transient
Steady-state
Both lead to the same intermediate but yield different final products
Esguerra, K. V. N., Fall, Y., Petitjean, L., Lumb, J.-P. J. Am. Chem. Soc. 136, 7662–7668 (2014).
Acknowledgements
Concordia University •Xavier Ottenwaelder•Mohammad S. Askari•Yuxuan Li•XoRG members
McGill University•Jean-Philip Lumb•Kenneth Esguerra
