A Mild meta-Selective C–H Alkylation of Catechol Mono-Ethers

Article abstract of DOI:10.1002/ejoc.201600760

Catechol mono-ethers are an important class of phenols. They are found in a number of pharmaceuticals, flavoring agents, perfumes, and are used for the preparation of numerous drugs. Herein, we report a mild meta-selective C–H alkylation of these phenols, which is enabled by a cascade of oxidative dearomatization – radical addition – rearomatization process. The method is compatible with reactive functional groups on the parent arenol, such as olefins and halides. Primary, secondary, and teriary alkyl groups can be used, the source of which is most commonly an alkylborane. This process is operationally simple, does not require heating and generally proceeds in good yields.

Full text of DOI:10.1002/ejoc.201600760

DOI: 10.1002/ejoc.201600760
Communication
Meta Alkylation
A Mild meta-Selective C–H Alkylation of Catechol Mono-Ethers
Edon Vitaku[a] and Jon T. Njardarson*[a]
Abstract: Catechol mono-ethers are an important class of process. The method is compatible with reactive functional
phenols. They are found in a number of pharmaceuticals, flavor- groups on the parent arenol, such as olefins and halides. Pri-
ing agents, perfumes, and are used for the preparation of nu- mary, secondary, and teriary alkyl groups can be used, the
merous drugs. Herein, we report a mild meta-selective C–H alk- source of which is most commonly an alkylborane. This process
ylation of these phenols, which is enabled by a cascade of oxi- is operationally simple, does not require heating and generally
dative dearomatization – radical addition – rearomatization proceeds in good yields.
Introduction
C–H functionalizations of aromatic compounds have relied on
their electronic nature for over a century, in which electron-rich
substrates have high selectivity for electrophilic attack at the
ortho/para positions, while electron-deficient substrates un-
dergo electrophilic attack at the meta position. Nevertheless,
site-selective C–H functionalization of arenes, in which only one
C–H bond is differentiated from the rest of the C–H bonds to
give a single regioisomer, remains of particular interest. This is
especially the case when the desired position of functionaliza-
tion is contrary to the electronic bias of the arene. Of the select-
ive C–H functionalizations of arenes, meta-selective C–H func-
tionalization remains the most significant challenge, for which
a number of state-of-the-art solutions have recently been re-
ported.[1] Interestingly, phenol and its derivatives appear to be
the most difficult arenes to undergo selective meta-functionali-
zation. This is not entirely surprising as their electron-donating
hydroxyl group directs the functionalization to ortho and para
positions, for which a number of methods have been re-
ported.[2]
One of the important classes of phenols are catechol mono-
ethers, which include guaiacol, eugenol, vanillin, capsaicin, eto-
poside, and morphine and its analogues, among other com-
pounds (Figure 1). Guaiacol is the most abundant catechol
mono-ether, commonly obtained from the pyrolysis of lignin,
and is used as a precursor to various other catechol mono-
ethers. Due to the high demand and various uses of these
phenol derivatives,[3] such as in pharmaceuticals, drug prepara-
tions, and flavor and fragrance industries, methods for selective
functionalization of this class of phenols are of high value.
Recently, inspired by their work on meta-functionalization of
arenes, Yu and co-workers[4] described a meta-functionalization
Figure 1. Examples of important catechol mono-ethers.
of phenols using an “end-on template.” Here, an α-phenoxy
acetamide bearing two nitrile-chelating groups is used to direct
C–H palladation in the meta-position, upon which a 13-mem-
bered cyclopalladated intermediate forms and directs the addi-
tion of olefins (Scheme 1). Thereafter, Larossa and co-workers[5]
reported a one-pot meta-arylation of phenols using a traceless
directing group relay strategy. This method uses the well-estab-
lished ortho/para-directing effect of a phenol to install a tran-
sient carboxyl group, allowing palladium-enabled cross-cou-
pling arylation ortho to the carboxyl group, and thus meta to
the hydroxyl group, which is then followed by a decarboxyl-
ation. Most recently, Wang and co-workers[6] have reported a
meta-functionalization of naphthols using a carbamate-direct-
ing group, which allows ortho-palladation, and a sequential
transmetallation to yield meta-arylated naphthols.
We hypothesized that the selective meta-functionalization of
catechol mono-ethers (1) could be possible by means of polar-
ity inversion, or an umpolung strategy (Scheme 2). By oxidative
dearomatization,[7] the inherent ortho/para-directing “donor”
nucleophilic catechol mono-ethers, could be changed into elec-
trophilic meta “acceptors” (2). Our goal was to use a mild tin-
free, radical addition – rearomatization cascade to furnish net
meta-alkylation products (3). This C(sp3)–C(sp2) bond forming
process is not feasible by the currently reported methods
shown in Scheme 1, thus it presents a new strategy for meta-
functionalization of this class of phenol derivatives.
[a] Department of Chemistry and Biochemistry, University of Arizona
1306 E. University Blvd., Tucson, AZ 85721, USA
E-mail: njardars@e-mail.arizona.edu
http://njardarson.lab.arizona.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600760.
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Scheme 3. Stepwise meta-alkylation of catechol mono-ethers.
temperatures, and the resulting radicals are more compatible
with a broad range of functional groups than typically em-
ployed anion or organometallic-based nucleophiles. For our ini-
tial studies, we employed triethylborane as a source of an ethyl
radical due to its commercial availability. We found that the
radical addition step is compatible in various solvents with non-
radical abstractable protons, such as dichloromethane (DCM),
ethyl acetate, and trifluorotoluene, whereas solvents such as
tetrahydrofuran (THF) and toluene proved to undergo competi-
tive radical addition reactions.[14a] Therefore, our solvent of
choice was DCM so both oxidative dearomatization and radical
addition steps could be performed in the same solvent. We
discovered that four equivalents of triethylborane ensured full
consumption of ortho-quinone acetates, and that allowing the
reaction to stir under open atmosphere proved most optimal.
Addition of methanol demonstrated to reduce formation of
polymers and other undesired products. Using these conditions,
the reaction works at ambient conditions, but we chose to run
the reaction at –42 °C to room temperature since it showed
to be most reproducible. Trifluoroacetic acid (TFA) then helped
protonate any remaining boron phenolate (7) to give the meta-
alkylated phenol (8a) in a good yield upon isolation.[15]
Scheme 1. meta-Selective C–H functionalization of phenols.
Scheme 2. meta-Selective alkylation via oxidative dearomatization – radical
addition – rearomatization of catechol mono-ethers.
Results and Discussion
Based on our previous dearomatization – rearomatization inves-
tigations,[8] we decided to use the more stable ortho-quinone
acetates[9] (5) as the radical acceptors (Scheme 3). They are
readily generated using lead(IV) acetate[10] as the oxidant,
For our reaction scope, we chose substrates containing hal-
which is our preferred method, and as shown by Quideau and ides (F, Cl, Br and I), and alkyl (methyl) groups in all three re-
co-workers, they can also be generated using phenyliodine di- maining available positions, as well as different mono-ether
acetate (PIDA) in presence of acetic acid for a subset of sub- alkyl substituents (methyl, ethyl, allyl). These studies reveal that
strates due to PIDA's lower reactivity compared to lead(IV) acet- the method is compatible with halide substituents in all three
ate.[11] Accordingly, we optimized the oxidative dearomatization positions, methyl substituents in two positions, and all mono-
reaction to telescope the isolation of the ortho-quinone ace- ether alkyl substituents. When R4 is a methyl substituent, a mix-
tates. This was accomplished by the addition of potassium carb- ture of the desired product 8k along with other products
onate and pinacol, which were used to quench the in-situ- formed, from which 8k proved difficult to isolate. Additionally,
formed acetic acid, and consume the leftover lead(IV) acetate, substituents on the R4 position make the resulting ortho-quin-
respectively. This protocol then allows filtration of the resulting one acetates less reactive towards ethyl radicals, thus for sub-
insoluble potassium and lead(II) salts, providing an opportunity strates 4k–4o the radical addition step was performed at room
to recycle the oxidant by converting lead(II) acetate back into temperature. On the other hand, substrates with strong elec-
lead(IV) acetate.[12] The resulting filtrate now contains the de- tron-donation or -withdrawing groups proved difficult to un-
sired ortho-quinone acetate, along with acetone, and traces of dergo complete dearomatization, or the resulting ortho-quin-
unreacted pinacol, neither of which interfere with the radical one acetates were too labile under our reaction conditions.
addition – rearomatization steps.
We also investigated whether ortho-quinone ketals, which
For our radical addition step, we chose trialkylboranes[13] be- are typically generated using PIDA in presence of an alcohol,
cause they can easily be converted to alkyl radicals under mild were compatible with the radical addition step. When the dime-
conditions upon treatment with molecular oxygen (O2).[14] The thoxy ortho-quinone ketal (5a′) of guaiacol (4a) was treated
radical formation is very facile, commonly taking place at low with triethylborane in the same pot, 8a was obtained in 47 %
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yield. Although this makes the method more attractive, this re- lized ortho-quinone ketals could be reacted with aryl and enol-
sults in a lower yield due to the inherent reactivity difference ate nucleophiles to furnish meta-functionalized catechol mono-
of the ortho-quinone ketal 5a′ compared to the ortho-quinone ethers.[16] Here, the use of stabilized ortho-quinone ketals, such
acetate 5a. Additionally, as expected, this protocol cannot be as 3- and 4-substituted alkyl or ketal ortho-quinone ketals, is
used for ortho-quinone mixed ketals, as exposing 4p to the necessary to avoid the competing Diels–Alder self-dimerization
same conditions gives a 2:1 mixture of 8p and 8a, due to the (Scheme 4).
similar leaving group ability of methoxy and ethoxy groups.
While this work was underway, Chittimalla reported that stabi-
Having chosen triethylborane as a source of an ethyl radical
due to its commercial availability, we next explored triisopropyl-
borane as a source of an isopropyl radical,[17] to showcase a
difference between primary and secondary alkyl radical addi-
tion. When 4a was exposed to the same conditions as those in
Table 1, 5-isopropylguaiacol (9) was isolated in a 71 % yield
(Scheme 5). Yet, it is our belief that this method should not be
limited to trialkylboranes as evidence shows that under similar
mild conditions, other B-alkylborane derivatives could also be
used to generate alkyl radicals, including B-alkylcatecholbor-
anes,[18] B-alkylboracyclanes,[19] and B-alkyldiphenylboranes.[20]
Scheme 4. PIDA-mediated meta-alkylation of catechol mono-ethers.
Table 1. Substrate scope.[a–c]
Scheme 5. meta-Isopropylation of guaiacol with triisopropylborane.
We also explored whether selective alkyl radical addition is
possible when alkyl halides are used in presence of triethyl-
borane.[21] When isopropyl iodide (15.0 equiv.) was used in pres-
ence of triethylborane, 4a gave a 2:1 mixture of 9:8a
(Scheme 6). Attempts to optimize this reaction, such as by in-
creasing the equivalents of isopropyl iodide, increasing the tem-
perature of the reaction, slow addition of triethylborane, as well
as running the reaction in neat isopropyl iodide, yielded no
significant improvement. When tert-butyl iodide was used in
presence of triethylborane, 5-tert-butylguaiacol (10) was formed
almost selectively (> 30:1), and isolated in a great yield. How-
ever, when other catechol mono-ethers were used (brominated
guaiacols) under the same conditions, the ratio of tert-butylated
to ethylated products ranged from 3:1 to 10:1. These results
[a] Reaction conditions: substrate (1.0 mmol, 1.0 equiv.), lead(IV) acetate
(1.1 mmol, 1.1 equiv.), potassium carbonate (3.0 mmol, 3.0 equiv.), DCM
(10.0 mL), 0 °C, 30 min, then pinacol (0.25 mmol, 0.25 equiv.), r.t., 1 h, then
filter through alumina plug (1.0 × 1.0 cm; basic, activity III), DCM (10.0 mL),
methanol (1.0 mL), triethylborane (4.0 mmol, 4.0 equiv.), - 42 °C to r.t., over-
night, then TFA (10.0 mmol, 10.0 equiv.), r.t., 1 h. [b] Radical addition step is
run at room temp. instead of –42 °C to r.t. for substrates 4k–4o. [c] Yield of
isolated product is given. [d] Mixture of desired product and other products
from which 8k proved hard to be isolated.
Scheme 6. Alkyl iodides as source of alkyl radicals.
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reveal that the selectivity of alkyl radical addition is controlled
by the difference between the rates of ethyl radical addition vs.
iodine atom abstraction. Therefore, to selectively deliver an
alkyl group of choice, it is best if a B-alkylborane derivative,
such as a trialkylborane, is used as the alkyl radical source.
Keywords: C–H substitution · Alkylation · Oxidative
dearomatization · Radicals · Regioselectivity
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Experimental Section
General Procedure for meta-Ethylation of Catechol Mono-Ethers
with Triethylborane: To a flame-dried 50 mL round-bottom flask
equipped with a stir bar, anhydrous potassium carbonate (414 mg,
3.0 mmol, 3.0 equiv) and lead(IV) acetate [95 %] (513 mg, 1.1 mmol,
1.1 equiv.) were added, the flask capped with a septum, cooled to
0 °C and purged with N2. DCM (8 mL) was syringed in, and the
slurry was vigorously stirred. To this slurry, a catechol mono-ether
derivative (1.0 mmol, 1.0 equiv) in DCM (2 mL) was syringed in over
30 sec and the reaction was vigorously stirred at 0 °C until TLC
showed complete consumption of the starting material (typically
less than 30 min). The ice bath was removed, and pinacol (30 mg,
0.25 mmol, 0.25 equiv) in DCM (0.5 mL) was syringed in to consume
left-over lead(IV) acetate and the reaction was stirred at room tem-
perature for 1 h. To remove the insoluble solids, the slurry was
then filtered through an alumina plug [1.0 × 1.0 cm] (Basic Alumina,
Activity III) into a flame dried 100 mL round-bottom flask equipped
with a stir bar, and the solids were thoroughly washed with DCM
(10 mL). The filtrate was then equipped with an air condenser, and
the flask cooled to –42 °C (dry ice/acetonitrile bath). Methanol
(1.0 mL) was added, and the reaction mixture was stirred at –42 °C
under open atmosphere (substrates 4k–4o were ran at room tem-
perature in absence of an air condenser and methanol). Triethylbo-
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Acknowledgments
Financial support for this work was provided by The University
of Arizona. The authors thank Dr. Neil E. Jacobsen for valuable
NMR discussions.
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Received: June 22, 2016
Published Online: ■
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Meta Alkylation
E. Vitaku, J. T. Njardarson* .............. 1–6
A Mild meta-Selective C–H Alkyl-
ation of Catechol Mono-Ethers
Catechol mono-ethers are dearoma- and tertiary radicals can be added, and
tized via lead(IV) acetate then reacted the method is compatible with react-
with trialkylboranes to give net meta- ive groups on the parent arene.
alkylated products. Primary, secondary
DOI: 10.1002/ejoc.201600760
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