[a] Reaction was conducted using 1a (0.2 mmol), TIPSOTf
(0.28 mmol),
[Ir(dF(CF3)-ppy)2(4,4’dCF3-bpy)]PF6(1 mol%), Co(dmgH)2(DMAP)Cl (5 mol%), 2,4,6-tri-Me-Pyr
(0.52 mmol) for 10 h in DCE/DCM = 3:2 (0.4 M) under two 30 W blue LEDs
at rt unless otherwise stated. n.d. = not detected. [b] 1H NMR yield
of crude mixture of reaction using 1,3,5-trimethoxybenzene as internal
standard. [c] Isolated yield.
reagent, 2,4,6-collidine (2.6 eq) as base in DCE:DCM = 3:2 (0.4 M) under
blue LED irradiation at room temperature as the optimal reaction
conditions, affording the desired phenol product 2 in 85%
isolated yield (Table 1, entry 1). Replacing
Ir(dF(CF3)ppy2(4,4’dCF3bpy)
with other IrIII based photocatalysts could mediate
the reaction, albeit leading to inferior results (Table 1, entries 2-4).
Next, a survey of cobalt catalysts revealed that the cobalt catalyst
with a pyridine coordination significantly enhanced the reaction. Other
cobalt catalysts, such as Co(dmgH)2Cl2and Co(dmgBF2)2·H2O,
could also catalyze the reaction, albeit with lower efficiency (Table 1,
entries 5-7). Interestingly, evaluation of the activating reagent
R3SiOTf disclosed that the steric hindrance of the R
group has a great influence on the reaction. Bulkier TBSOTf as the
activating reagent delivered 2 in 82% yield (Table 1, entry
8). Using less hindered triethylsilyltriflate or trimethylsilyltriflate
as activating reagents resulted in poor yields of 2 (Table 1,
entries 9-10). This may be due to the stability of the corresponding
enol silyl ether. The base was of critical importance for the reaction.
Using 2,6-lutidine as base delivered 2 in 81% yield, yet the
use of other organic or inorganic bases, such as DABCO, DIPEA and KOAc
were totally ineffective (Table 1, entries 11 to14). Solvent effect
evaluation revealed that both 1,2-dichloroethane (DCE) and
dichloromethane (DCM) are good solvents for this reaction, allowing the
formation of 2 in 77% and 61% yields (Table 1, entries
15-17). Control experiments showed that light, photocatalyst and
Co-catalyst are essential to this phenol synthesis (Table 1, entries 18
and 19).
With the optimized reaction conditions in hand, we set out to explore
the scope of this transformation. First, the scope of cyclohexanone
(1 ) was examined (Scheme 2). para -Substituted phenols,
including alkyl- and aryl-substituted phenol derivatives
(2 -5 ), were accessed via
the photocatalyzed
dehydrogenative aromatization of the corresponding cyclohexanone
derivatives. Cyclohexanones with an ester group at para -position
were readily converted to the corresponding phenol products in 71%-91%
yield (6 -13 ). To our delight, alkenyl (7 ) and
alkynyl groups (8 ) remain intact in this transformation,
leaving chemical space for further elaboration. Notably, alkyl-Cl
(9 ), aryl-Cl (10 ), and aryl-Br (11 ) were
well-tolerated, providing further functionalized handles for
cross-coupling reaction. Notably, 2-substituted cyclohexanones were
successfully transformed corresponding ortho -substituted phenols
(14 -16 ) in 40%-67% yields. Next, aryl fused
cyclohexanones were tested.
Electron-withdrawing and
electron-donating groups on
aromatic rings can be tolerated, affording corresponding 1- and
2-naphthol products (17 -24 ) in 50%-92% yields.
Moreover, heterocycles including thiophenes (12 and25 ), furans (13 ) and pyrroles (26 ), were also
compatible in the reaction. Interestingly, 1,2-, 1,3-, and
1,4-cyclohexanediones could be applied to this reaction, furnishing the
corresponding diphenol products (27 -30 ) in synthetic
useful yields. Finally, complex molecule-derived cyclohexanones were
also successfully applied to the reaction. Cyclohexanones containingL -menthol, (+)-fenchol, diacetonefructose, cholesterol and
diosgenin, were smoothly converted to the corresponding phenol products
(31 -35 ) in 69-81% yields.
Next, further extension of this phenol synthesis protocol to
cyclohexenones was examined (Scheme 3).
2-Aryl
substituted cyclohexenones, with different substituent groups on the
benzene ring were good substrates for this photocatalytic
dehydrogenative reaction, affording corresponding 2-arylphenol products
(16 , 36 -39 ) in 63-71% yields. Diverse 3-aryl
substituted phenols (40 -45 ) were also obtained in
moderate yields via the dehydrogenation of corresponding 3-aryl
cyclohexenones. Additionally, 3,5-disubstituted phenols
(46 -56 ) could be obtained from cyclohexenones in
synthetic useful yields. It is noteworthy that 3,5-disubstituted phenol
derivatives are ubiquitous core structures for many bioactive
molecules,[18] yet are inaccessible
Scheme 2. Scope for the synthesis of phenols from
cyclohexanones. For the details of ”standard conditions”, see Table 1,
entry 1. [a] 2,6-di-Me-Pyr as base. [b] 24 h. [c] TIPSOTf
(1.6 eq), 2,4,6-tri-Me-Pyr (2.8 eq), CH3CN (0.4 M).
[d] TIPSOTf (2.6 eq), 2,4,6-tri-Me-Pyr (3.8 eq). [e]
2,6-di-Me-Pyr as base,14 h.
by electrophilic aromatic substitution of
phenols.[19] The structure of 51 was
ambiguously confirmed by X-ray diffraction analysis.To further
demonstrate practicality of the protocol for the synthesis of phenols,
the reaction was scaled up to 2.0 mmol scale using
4-acetoxycyclohexanone 1e , delivering corresponding phenol6 in 78% yield (Scheme 4a). Next, the reaction of
3,5-diaryl-substituted phenol product 47 with cyclopentyl
isocyanate afforded biologically active compound LUF5771 in 76% yield
(Scheme 4b).[20]
To shed light on the reaction mechanism, a series of controlled
experiments were conducted. First, the reaction was carried out in the
presence of TEMPO as a radical scavenger under otherwise identical to
standard conditions, the desired transformation was completely inhibited
(Scheme 5a). Second, 4-methylcyclohexanone 1a delivered silyl
enol ether 1bf in 97% yield in dark under otherwise identical
to standard conditions (Scheme 5b). Interestingly,1bf was successfully
converted to phenol 2 in 78%% yield in the presence of 20
mol% trifluoromethanesulfonic acid under otherwise identical to
standard conditions (Scheme 5b). These experiments suggest that the
silyl enol ether may serve as key intermediate in the reaction.
Moreover, the reaction of silyl enol ether 1be under standard
conditions in the presence of benzalmalononitrile 1bg delivered57 in 85% yield (dr = 2:1). Alternatively, the reaction of
silyl enol ether 1be under standard conditions in the presence
of α,β-unsaturated sulfones 1bh afforded β-substituted
cyclohexanone 58 in 69% yield (Scheme 5c). The results
indicate the reaction is likely to undergo an allylic radical
intermediate. In
Scheme 3. Scope for the synthesis of phenols from
cyclohexenones. See Table 1, entry 1 for detailed conditions. [a] 24
h. [b] TIPSOTf (1.6 eq), 2,4,6-tri-Me-Pyr (2.8 eq),
CH3CN (0.4 M).
addition, Stern–Volmer luminescence quenching experiments were
performed. Both 4-methylcyclohexanone and 2,4,6-collidine did not show
significant quench of the excited state of photocatalyst
[Ir(Ⅲ)]*. Silyl enol ether showed a relatively
strong quenching effect to the excited photocatalyst (Scheme 5d). These
observations confirmed that the reaction was initiated by the
single-electron oxidation of silyl enol ether by photocatalyst.
Based on literature reports and the above mechanistic investigations, a
plausible mechanism is proposed and depicted in Scheme
6.[21] First, reaction of 4-methylcyclohexanone1 and TIPSOTf led to the in situ generation of silyl enol etherA , which was oxidized by the excited-state photosensitizer
[Ir(Ⅲ)]* to
give radical cation species B and [Ir(Ⅱ)]. Next, Bwas deprotonated at the acidic β-methylene position in the presence of a
base to give the allylic radical C , which was then trapped by
Co(Ⅱ), followed by β-H elimination to deliver the silyl dienol
ether intermediate D and
cobalt(Ⅲ) hydride species. Subsequently, Co((Ⅲ)-H species was protonated
to release H2 and regenerate
CoⅢ(dmgH)2(DMAP)Cl. Single electron
transfer between Ir(Ⅱ) and
CoⅢ(dmgH)2(DMAP)Cl generated Ir(Ⅲ) and
Co(II) to close the photoredox catalysis cycle. Silyl dienol etherD repeated first catalytic cycle to give the silyl ether of
phenol F , which was deprotected by tetrabutylammonium fluoride
to give the target phenol product 2 .
In summary, a general photocatalytic dehydrogenative aromatization of
cyclohexanones or cyclohexenones phenols has been developed. The
mechanistic investigations indicate that the reaction undergoes a dual
catalyzed free radical cation process of the enol silyl ether. The
reaction features the synthesis of phenols from cyclohexanones and
cyclohexenones with diverse
Scheme 4. Scale-up and application experiments.
substitution patterns, which are difficult to access otherwise. This
one-pot precedure circumvents the preformation of silyl enol ethers from
cyclohexanones, providing a direct and straightforward access to
phenols.
Scheme 5. Mechanistic investigations.
Scheme 6 . Proposed mechanism for the reaction.
Acknowledgements
Financial support from NSFC
(21971101 and 22171127), Guangdong Basic and Applied Basic Research
Foundation (2022A1515011806), Department of Education of Guangdong
Province (2021KTSCX106), Guangdong Province Graduate Education
Innovation Program (2022JGXM054), The Pearl River Talent Recruitment
Program (2019QN01Y261), Shenzhen Science and Technology Innovation
Committee (JCYJ20220519201425001) and Guangdong Provincial Key
Laboratory of Catalysis (2020B121201002) is sincerely acknowledged. We
acknowledge the assistance of SUSTech Core Research Facilities. We thank
Hai-Wu Du and Huan Meng (SUSTech) for X-ray crystallographic analysis of51 (CCDC 2254790).
Keywords: Phenols •
Photocatalysis • Dehydrogenation • Cyclohexanone • Cobalt catalyst