A general approach towards catechol and pyrogallol through ruthenium- and palladium-catalyzed C-H hydroxylation by weak coordination

Article abstract of DOI:10.1002/adsc.201300999

An efficient ruthenium(II)- and palladium(II)-catalyzed C-H hydroxylation of aryl carbamates has been developed for the facile synthesis of catechols and pyrogallols. The reaction demonstrates excellent reactivity, regio- and chemoselectivity, good functional group compatibility and high yields. The practicality of this method has been proved by a gram-scale synthesis.

Full text of DOI:10.1002/adsc.201300999

UPDATES
DOI: 10.1002/adsc.201300999
A General Approach towards Catechol and Pyrogallol through
À
Ruthenium- and Palladium-Catalyzed C H Hydroxylation by
Weak Coordination
Xinglin Yang,a Yonghui Sun,a Zhang Chen,a and Yu Raoa,*
a
MOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of
Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+86)-10-6278-3404; phone: (+86)-10-6278-2025; e-mail: yrao@mail.tsinghua.edu.cn
Received: November 9, 2013; Revised: March 14, 2014; Published online: May 7, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300999.
Abstract: An efficient ruthenium(II)- and palladi-
um(II)-catalyzed C H hydroxylation of aryl carba-
and useful addition to current protocols for catechol
synthesis.
À
mates has been developed for the facile synthesis of
catechols and pyrogallols. The reaction demon-
strates excellent reactivity, regio- and chemoselec-
tivity, good functional group compatibility and high
yields. The practicality of this method has been
proved by a gram-scale synthesis.
Recently, our group have reported examples of
Ru(II)-, Rh(II)- and Pd(II)-catalyzed ortho-hydroxyl-
ation of benzoates, benzamides and aryl ketones in
the trfluoroacetic acid/trifluoroacetic anhydride
(TFA/TFAA) system.[6] Accordingly, based on our ex-
perience and understanding of this chemistry, we en-
visaged that ruthenium[7] and palladium[8] catalysts,
À
under certain acidic conditions, could promote C H
À
Keywords: catechol; C H hydroxylation; palladi-
bond activation via an ortho-metalation process
through weak coordination with the carbonyl oxygen
of phenol carbamates,[9] carbonates or esters. Follow-
um; ruthenium; weak coordination
À
ing that step, a potential subsequent C O bond for-
mation via a reductive elimination could afford the
Catechols are common structural motifs found in corresponding catechol derivatives with suitable acids
many natural products and drugs.[1] Classic ap- and oxidants[10] (Scheme 1). Herein, we report a novel
proaches[2] to the synthesis of catechols generally in- catechol and pyrogallol synthesis through Ru(II)- and
À
volve (i) an ortho-formylation of phenols followed by Pd(II)-catalyzed regio- and chemoselective C H hy-
a subsequent Dakin oxidation or (ii) the oxidation of droxylation reaction.[11,12]
phenols into ortho-quinones followed by a reduction.
To test our hypothesis, different protected phenol
However, these reactions lack site selectivity and esters, carbonates and carbamates were explored
always provide a mixture of ortho-, meta- and para- under previously reported conditions (Scheme 2). De-
isomers. In 2009, Que and Akimova disclosed an iron- lightfully, most substrates can be transformed into the
promoted hydroxylation of benzoic ac ids with corresponding desired products, albeit in relatively
H2O2.[3a] In the same year, Yuꢀs group discovered
a novel Pd(II)-catalyzed hydroxylation of benzoic
acids with O2 or air as the oxidant under non-acidic
conditions.[8i] More recently, Gevorgyan and co-work-
ers reported an elegant Pd-catalyzed silanol-directed
À
ortho-C H oxygenation which features high site se-
lectivity and a broad functional group tolerance.[3b,c]
In 2013, Martin group developed a formal copper-cat-
À
alyzed C H hydroxylation assisted by benzoic
acids.[3d] In our continuous studies of developing new
general tools for functionalized phenol synthesis, we
are particularly interested in the development of an
[4,5]
À
alternative C O bond formation
as an interesting
Scheme 1. Developing a new approach for catechols by Ru,
Pd catalysis.
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UPDATES
Xinglin Yang et al.
Scheme 2. Investigating directing groups.
low yields. Among them, phenyl dimethylcarbamate estingly, it was noticed that the reaction can be car-
gave the best yield. Encouraged by promising prelimi- ried out at room temperature (entry 13), although at
nary results, next, we started an optimization of the a much slower rate. It was apparent that the transfor-
reaction conditions with phenol carbamate 1. A varie- mation cannot happen in the absence of the rutheni-
ty of oxidants was examined in the reaction, such as um catalyst (entry 14). It was observed that the reac-
Na2S2O8, (NH4)2S2O8, PhI
(Table 1). Among them, (NH4)2S2O8 and PhI
have similar and moderate capacities, but were less
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
efficient than K2S2O8. It was found that a ratio of to survey the reaction scope. As showed in Table 2,
TFA/TFAA of around 1:1 is most suitable for the re- a variety of phenol carbamates was efficiently trans-
action. Except for the desired products, no double-hy- formed into the desired catechol derivatives in good
droxylation products were observed in all cases. Inter- to excellent yields. In comparison to PdACHTUNRGTNEUNG(OAc)2, the
Table 1. Optimization of the reaction conditions.
[a]
Conversion ratio.
Isolated yield.
2.0 equiv.
No metal.
[b]
[c]
[d]
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A General Approach towards Catechol and Pyrogallol
Table 2. Reaction scope.
[a]
[b]
Isolated yields.
PhI(OAc)2 (1.5 equiv.) as oxidant instead of K2S2O8.
AHCTUNGTRENNUNG
overall catalytic activity of [RuCl2ACTHNUTRGENUNG(p-cymene)]2 is mates gave only one regioisomeric product (11–16),
better in terms of efficiency and both catalysts share due to steric hindrance. Interestingly, when several
similar selectivity. The scope of the substituents was carbamates containing two different potential direct-
found to be very broad. The ortho-, meta-, and para- ing groups were examined in this reaction system, the
substituted carbamates, as well as those with electron- carbamate group was superior over the ester and
withdrawing and electron-donating functional groups ketone groups in terms of directing ability (23–25).
(methoxy, methyl, halides, CF3, ester, nitro etc.) were This new method provides new route for the construc-
well tolerated. For example, carbamates containing tion of some biologically important molecules. For in-
strong electron-withdrawing groups, such as NO2 and stance, l-DOPA (a biological active molecule in our
CF3 (10, 12) could be smoothly transformed to the body and a psychoactive drug used in the clinical
ortho-hydroxylated products in satisfactory yields. Im- treatment of Parkinsonꢀs disease and dopamine-re-
pressively, the aldehyde and acetyl functional groups sponsive dystonia) can be easily accessed from cate-
(17, 23) were also compatible in this reaction, which chol derivative 26 which was synthesized from pro-
demonstrated both the excellent regio- and chemose- tected l-tyrosine under the reaction conditions. Addi-
lectvity of this reaction. All meta-substituted carba- tionally, catechols can be further converted into syn-
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Xinglin Yang et al.
Table 3. Room temperature reaction by palladium(II) catalysis.[a]
[a]
Unoptimized yields.
Scheme 3. Gram-scale synthesis.
Scheme 5. Separate rate constants study.
Scheme 4. Semi-one-pot syntheisis of catechols.
matic substrate reacted slower than its eletron-rich
thetically challenging pyrogallols (27, 28), which pro- counterparts to give hydroxylated products. In addi-
vides an alternative and efficient synthetic route to tion, to probe the reaction mechanism, an intramolec-
access valuable pyrogallol derivatives.
ular isotope effect study was conducted and only
As displayed in Table 3, we are very pleased to find a small KIE value of 1.3 was observed (see the Sup-
that actually phenol carbamates can be converted into porting Information for more details). These results
À
the desired catechol products effectively by palladium suggested that C H activation may not be involved in
catalysis at ambient temperature within a couple of the rate-limiting step of this transformation.
hours, albeit in lower yields. Notably, this protocol
was conducted without the need for air- or moisture- clear, a plausible mechanism (Scheme 6) for this reac-
free reaction conditions. tion can be demonstrated as follows. Step (i) involves
Although details about the mechanism remain un-
To further prove practicality of this new approach, chelation of Pd(II)/Ru(II) to the carbonyl oxygen
compound 12 was prepared on a gram scale (70% atom from the carbamate substrate and the following
À
yield) under the optimized reaction conditions with chelate-directed C H activation of the substrate
only a 1 mol% [RuCl
2A
(Scheme 3). As shown in Scheme 4, the applicability mediate. In the next steps (ii and iii), Pd(II)/Ru(II)
and effectiveness of this reaction was further demon- was oxidized into a possible Pd(IV)/Ru(IV) inter-
strated in a sequential semi-one-pot hydroxylation/de- mediate. The final step (iv) involves carbon-oxygen
protection procedure which can directly transform bond-forming reductive elimination to afford the tri-
carbamates to unprotected catechols (29, 30) in good fluoroacetylated product and turned Pd(IV)/
yields.
Ru(IV)[13,14] back into Pd(II)/Ru(II). The trifluoroace-
As shown in Scheme 5, parallel competition experi- tylated product was converted to catechol derivatives
ments have demonstrated that an electron-poor aro- after an aqueous work-up.[6a]
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A General Approach towards Catechol and Pyrogallol
Scheme 6. Plausible mechanism.
added and the reaction mixture was stirred at room temper-
ature for 8 h. Then H2O was added and the resulting mix-
ture was slowly acidified with concentrated HCl to pH=
1 and extracted with ethyl acetate, the organic layer was
dried over anhydrous Na2SO4 and concentrated on a rotava-
por under reduced pressure. Finally, the residue was purified
by silica gel column chromatography to give the desired
products.
In summary, a unique Ru(II)- and Pd(II)-catalyzed
regio- and chemoselective hydroxylation reaction has
been developed for the synthesis of catechol and py-
rogallol derivatives from easily accessible phenols.
The reaction demonstrates excellent reactivity, ortho-
selectivity, high yields and good functional group tol-
erance. The practicality of this new method was
tested by a gram-scale synthesis. Further studies into
the synthetic applications of this reaction are in prog-
ress in our laboratory.
Acknowledgements
Experimental Section
This work was supported by the national ꢀ973ꢁ grant from the
Ministry of Science and Technology (grant # 2011CB965300),
National Natural Science Foundation of China (grant #
21302106) and Tsinghua University Initiative Scientific Re-
search Program. We thank Mrs. C. Wang for her help in our
studies.
General Procedure I for Ruthenium- and Palladium-
Catalyzed ortho-Hydroxylation of Carbamates
To a 15-mL sealed tube were added carbamate (1.0 equiv.),
K2S2O8 (2.0 equiv.) or PhI
A
ACHTUNGTRENN(UNG p-cyme-
ne)Cl2]2 (0.025 equiv.) and TFA/TFAAAHCUTNGTRENNUNG
was sealed and heated at 808C. The reaction was monitored
by TLC (petroleum ether:ethyl acetate:triethylamine=
50:10:1). After completion of the reaction, H2O (10 mL)
was added and the reaction mixture was stirred for another
half an hour. Then NaHCO3 was added to neutralize TFA
and TFAA and the mixture was extracted with DCM (3ꢂ
15 mL). Then the organic layer was dried over anhydrous
Na2SO4 and concentrated on a rotavapor under reduced
pressure. Finally, the residue was purified by silica gel
column chromatography to give the desired products. When
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