Oxidative photoredox catalysis: Mild and selective deprotection of PMB ethers mediated by visible light

Article abstract of DOI:10.1039/c1cc10827a

Herein we report an advancement in the application of visible light photoredox catalysts in the oxidation of electron-rich arenes resulting in the selective deprotection of para-methoxybenzyl (PMB) ethers. This method is highlighted by excellent functional group tolerance, protecting group orthogonality, mild reaction conditions and avoidance of stoichiometric redox byproducts.

Full text of DOI:10.1039/c1cc10827a

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COMMUNICATION
Oxidative photoredox catalysis: mild and selective deprotection of PMB
ethers mediated by visible lightw
Joseph W. Tucker, Jagan M. R. Narayanam, Pinkey S. Shah and Corey R. J. Stephenson*
Received 13th February 2011, Accepted 7th March 2011
DOI: 10.1039/c1cc10827a
Herein we report an advancement in the application of visible
light photoredox catalysts in the oxidation of electron-rich
arenes resulting in the selective deprotection of para-methoxy-
benzyl (PMB) ethers. This method is highlighted by excellent
functional group tolerance, protecting group orthogonality, mild
reaction conditions and avoidance of stoichiometric redox
byproducts.
Protecting group strategies have proven to be an invaluable
tool in the synthetic process.1 These strategies require the
development of a wide range of methods to afford the
protection and deprotection of a variety of functionalities, so
as to provide chemists with a broad set of tools to circumvent
inherent reactivity throughout a synthetic route. One widely
utilized hydroxyl protecting group is the para-methoxybenzyl
(PMB) ether.2 This protecting group is easily introduced via
Williamson ether synthesis3,4 and is typically removed under
oxidative conditions, which often employ stoichiometric
oxidants such as DDQ5 or CAN.6,7 Given the broad range
of redox transformations associated with the PMB ether
functionality,8 we hypothesized photoredox catalysis9 could
serve as a valuable alternative for the catalytic oxidation of
PMB ethers.
Photoredox catalysis is emerging as a powerful tool to
enable the use of visible light in promoting organic trans-
formations, and is gaining widespread attention from
Fig. 1 Application of photoredox catalysis in oxidative generation of
synthetic organic groups including those of MacMillan,10 Yoon,11
iminium and oxocarbenium ions.
and our group.12,13 Specifically, the single electron transfer
of valuable oxocarbenium intermediates under mild conditions
by the oxidation of benzylic ethers (Fig. 1).
(SET) processes of visible light active metal complexes can
make possible redox manipulation of organic molecules with-
out employing stoichiometric quantities of redox reagents or
producing excess chemical waste. In particular, recent efforts
from our group led to the application of photoredox catalysis
in a-amine functionalization, by means of the oxidative
generation of iminium ions.14 This work led us to postulate
that photoredox catalysts, via the oxidative quenching of the
visible light induced excited state, may promote the generation
Realization of our hypothesis required first the identification
of an appropriate visible light active metal complex.
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1)15 was chosen as a viable
photocatalyst given the strong redox potential of the excited
state (E1 [Ir(III)*/Ir(IV)] = À1.21 V vs. SCE) would allow for
the reduction of polyhalomethanes.16 In addition, the resulting
Ir(IV) complex is a sufficiently strong oxidant (E1 [Ir(IV)/Ir(III)] =
1.68 V vs. SCE) to afford the single electron oxidation of
electron-rich aromatic rings.17 Furthermore, we hypothesized
that the trihalomethyl radical generated in the oxidative
quenching process would serve as a competent H-atom acceptor,18
ultimately generating the oxocarbenium intermediate.
Department of Chemistry and Center for Chemical Methodology and
Library Development, Boston University, 590 Commonwealth Ave.,
Boston, MA, USA. E-mail: crjsteph@bu.edu; Fax: +1 617 353 6466;
Tel: +1 617 358 5089
w Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra for all new compounds. See
DOI: 10.1039/c1cc10827a
As shown in Scheme 1, it was found that subjecting 2 to
irradiation with a blue LED light source19 in the presence of
c
5040 Chem. Commun., 2011, 47, 5040–5042
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Table 1 Visible light mediated PMB deprotection
Entry Substrate Product
Yielda
1b
69
2b
3b
4b
5b
86
Scheme 1 Visible light mediated oxidation of PMB ethers.
92c
82
BrCCl3 in wet acetonitrile at room temperature cleanly
afforded the corresponding unprotected menthol, 3, in good
yield. Optimization studies revealed that blue light irradiation
of 2 with a variety of polyhalomethanes (including: CCl4,
BrCCl3, CBr4) in wet acetonitrile cleanly afforded the
deprotected menthol in similar yields. Our optimized reaction
conditions utilized BrCCl3 as the oxidative quencher as it is an
inexpensive and readily available halomethane. These preliminary
observations not only supported our mechanistic hypothesis, but
also demonstrated the applicability of photoredox methods in the
realm of protecting group chemistry.13e–f,20
80c
6b
81c
75
A variety of compounds bearing a PMB ether functionality
were synthesized in order to explore the scope of this trans-
formation. Given the mild and chemoselective nature of
transformations mediated by photoredox catalysts, we
observed excellent functional group tolerance and protecting
group orthogonality. The standard reaction conditions allow
for the selective removal of the PMB group in the presence of
benzyl ethers (entry 3) and pivalate esters (entry 7) as well as
substituted olefins (entry 8). In addition, acid sensitive
functionalities, such as THP acetals (entry 5) and t-butyl-
dimethylsilyl (TBS) ethers (entry 6), are stable with the addition
of 2.0 equiv of 2,6-lutidine to buffer the HBr generated during
the course of the reaction. In addition, a variety of amine
protecting groups, including: Boc, Fmoc and Cbz (entries 9–12),
are stable under the reaction conditions (Table 1).
7b
8b
84
9b
71c
10b
79c
Our proposed mechanism is outlined in Fig. 2. The visible
light induced excited state, Ir(III)*, is oxidatively quenched by
BrCCl3 to afford the trichloromethyl radical along with Ir(IV).
The electron-deficient Ir(IV) complex then oxidizes the PMB
functionality to close the photocatalytic cycle and generate the
corresponding arene radical cation. Hydrogen atom abstraction
by the trichloromethyl radical produces the oxocarbenium ion
11b
76
91
12b
1
along with CHCl3 [observed by in situ H NMR and GC-MS
analysis]. Subsequent hydrolysis produces the final deprotected
alcohol. Furthermore, the selectivity observed in the oxidation
of PMB ethers in the presence of benzyl ethers (Table 1, entry 3)
supports the proposed order of oxidation steps. If H-atom
abstraction occurs in advance of the single electron oxidation
of the aromatic moiety, it is likely the same selectivity would
not be observed.
a
b
Isolated yield after chromatography on SiO2. 1 (1.0 mol%),
BrCCl3 (2.0 equiv), H2O (10 equiv), CH3CN, blue LED irradiation,
c
12–18 h. Reaction run with the addition of 2,6-lutidine (2.0 equiv).
In conclusion, we have presented a practical, operationally
simple and highly functional group tolerant application of
photoredox catalysis in the oxidative cleavage of PMB ethers.
This method is a valuable synthetic tool to afford the selective
deprotection of hydoxyl groups under mild reaction
conditions. In addition, the generation of CHCl3, as the
c
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8 For selected examples of oxidative functionalization of benzylic
ethers, see: (a) L. Lei and P. E. Floreancig, Angew. Chem., Int. Ed.,
2010, 49, 5894; (b) W. Tu and P. E. Floreancig, Angew. Chem., Int.
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Chem., Int. Ed., 2008, 47, 4184; (d) Y. Zhang and C. J. Li, J. Am.
Chem. Soc., 2006, 128, 4242; (e) Y. Zhang and C. J. Li, Angew.
Chem., Int. Ed., 2006, 45, 1949; (f) B. P. Ying, B. G. Trogden,
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9 For recent reviews on photoredox catalysis, see: (a) J. M. R.
Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40,
102; (b) T. P. Yoon, M. A. Ischay and J. Du, Nature Chem., 2010,
2, 527; (c) K. Zeitler, Angew. Chem., Int. Ed., 2009, 48,
9785.
10 (a) D. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322,
975; (b) D. A. Nagib, M. E. Scott and D. W. C. MacMillan, J. Am.
Chem. Soc., 2009, 131, 10875; (c) H.-W. Shih, M. N. Vander Wal,
R. L. Grange and D. W. C. MacMillan, J. Am. Chem. Soc., 2010,
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Fig. 2 Proposed mechanism of oxidative cleavage of PMB ethers
mediated by photoredox catalysts.
stoichiometric oxidation byproduct is advantageous as it
allows for simplified purification. Further studies focusing
on exploring the oxidative formation of oxocarbenium inter-
mediates mediated by photoredox catalysis and exploring their
reactivity are underway.
11 (a) M. A. Ischay, M. E. Anzovino, J. Du and T. P. Yoon, J. Am.
Chem. Soc., 2008, 130, 12886; (b) J. Du and T. P. Yoon, J. Am.
Chem. Soc., 2009, 131, 14604; (c) M. A. Ischay, Z. Lu and
T. P. Yoon, J. Am. Chem. Soc., 2010, 132, 8572; (d) Z. Lu,
M. Shen and T. P. Yoon, J. Am. Chem. Soc., 2011, 133, 1162.
12 (a) J. M. R. Narayanam, J. W. Tucker and C. R. J. Stephenson,
J. Am. Chem. Soc., 2009, 131, 8756; (b) J. W. Tucker, J. M. R.
Narayanam, S. W. Krabbe and C. R. J. Stephenson, Org. Lett.,
2010, 12, 368; (c) J. W. Tucker, J. D. Nguyen, J. M. R.
Narayanam, S. W. Krabbe and C. R. J. Stephenson, Chem.
Commun., 2010, 46, 4985; (d) L. Furst, B. S. Matsuura, J. M. R.
Narayanam, J. W. Tucker and C. R. J. Stephenson, Org. Lett.,
2010, 12, 3104; (e) C. Dai, J. M. R. Narayanam and C. R. J.
Stephenson, Nature Chem., 2011, 3, 140; (f) J. D. Nguyen,
J. W. Tucker, M. D. Konieczynska and C. R. J. Stephenson,
J. Am. Chem. Soc., 2011, 133, DOI: 10.1021/ja108560e.
Financial support from Boston University and partial
funding from the NIGMS (P50-GM067041) is gratefully
acknowledged. NMR (CHE-0619339) and MS (CHE-0443618)
facilities at BU are supported by the NSF. JWT thanks Vertex
for a graduate fellowship. PSS thanks the Boston University
Undergraduate Research Program for research support.
Notes and references
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19 Blue LED light strips are commercially available for B$13. See
supporting information for more details on the reaction apparatus.
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¨
c
5042 Chem. Commun., 2011, 47, 5040–5042
This journal is The Royal Society of Chemistry 2011