Ruthenium-catalyzed aromatic c-h activation of benzylic alcohols via remote electronic activation

Article abstract of DOI:10.1021/ol101548a

Remote electronic activation of benzylic alcohols via temporary oxidation facilitates ruthenium-catalyzed arene C-H activation for a range of aromatic alcohols.

Full text of DOI:10.1021/ol101548a

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3856-3859
Ruthenium-Catalyzed Aromatic C-H
Activation of Benzylic Alcohols via
Remote Electronic Activation
Andrew J. A. Watson,*,† Aoife C. Maxwell,‡ and Jonathan M. J. Williams†
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath, BA2 7AY, U.K.,
and GlaxoSmithKline Research and DeVelopment, Gunnels Wood Road,
SteVenage, SG1 2NY, U.K.
ajaw20@bath.ac.uk
Received July 6, 2010
ABSTRACT
Remote electronic activation of benzylic alcohols via temporary oxidation facilitates ruthenium-catalyzed arene C-H activation for a range of
aromatic alcohols.
Hydrogen transfer is a powerful tool for the oxidation of
alcohols and reduction of ketones. Several groups includ-
ing our own have used catalytic hydrogen transfer to
activate alcohols toward C-C1 and C-N2 bond formation,
as well as a range of oxidative transfomations.3 Typically,
this involves alcohol oxidation followed by interception
of the newly formed carbonyl with nucleophiles before
further transformation. However, it can be used to activate
functional groups electronically;4 for example, an allylic
alcohol can be oxidized to an R,ꢀ-unsaturated ketone
making the double bond far more susceptible to Michael
additions. This allows the manipulation of less reactive
functional groups by altering the electronics of the
substrate indirectly, also known as “remote electronic
activation”. In contrast, applications of catalytic arene
C-H activation with ruthenium by Murai5 and others6
have been mainly limited to electronically activated rings
via the use of carbonyls and nitriles.7 This provides an
opportunity to combine both methodologies, allowing
electronic activation of the aromatic ring toward C-H
activation via the oxidation of an alcohol by hydrogen
transfer (Scheme 1). The ruthenium complex needs to
perform three separate functions to achieve this process,
catalyzing: (i) alcohol oxidation by hydrogen transfer to
† University of Bath.
(5) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatami, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. (b) Kakiuchi, F.;
Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett. 1995, 681–682. (c)
Kakiuchi, F.; Sato, T.; Igi, K.; Chatani, N.; Murai, S. Chem. Lett. 2001,
386–387. (d) Sonoda, M.; Kakiuchi, F.; Kamatani, A.; Chatani, N.; Murai,
S. Chem. Lett. 1996, 109–110. (e) Kakiuchi, F.; Tanaka, Y.; Sato, T.;
Chatani, N.; Murai, S. Chem. Lett. 1995, 679–680. Sato, T.; Kakiuchi, F.;
Chatani, N.; Murai, S. Chem. Lett. 1998, 893–894.
‡ GlaxoSmithKline Research and Development.
(1) (a) Hall, M. I.; Pridmore, S. J.; Williams, J. M. J. AdV. Synth. Catal.
2008, 350, 1975–1978. (b) Williams, V. M.; Leung, J. C.; Patman, R. L.;
Krische, M. J. Tetrahedron 2009, 65, 5024–5029. (c) Skucas, E.; Ngai,
M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394–
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O.; Williams, J. M. J. Org. Lett. 2009, 11, 2039–2042. (b) Watson, A. J. A.;
Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667–2670.
(3) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Chem. Commun.
2008, 624–625.
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Martinez, R.; Simon, M.-O.; Chevalier, R.; Pautigny, C.; Genet, J.-P.;
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Int. Ed. 2002, 41, 4740–4743. (c) Cami-Kobeci, G.; Williams, J. M. J. Synlett
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10.1021/ol101548a  2010 American Chemical Society
Published on Web 08/09/2010

Scheme 1
.
Proposed Transformation Using Alcohols to Access
Alkylated Ketones or Alcohols
Table 1. Tandem Oxidation/C-H Activation of Benzylic
Alcoholsa
an alkene, (ii) C-H activation/alkene insertion step, and
(iii) reduction of the carbonyl group by hydrogen transfer
to restore the alcohol.
Kim and co-workers8 have reported the use of Wilkinson’s
catalyst to conduct tandem oxidation/alkyl C-H activation,
whereas our work focuses on arene C-H activation and is
the first example with a ruthenium-based catalyst. Initial
experiments involved the tandem alcohol oxidation/C-H
activation of a range of benzylic alcohols.
Initial screening of reported ruthenium-based C-H
activation catalysts showed that commercially available
Ru(PPh3)3(CO)(H)2 was active for the tandem oxidation/
C-H activation. Previously, we have found that this
catalyst is more active in the presence of bidentate
phosphine ligands such as xantphos.1a However, when
applied to this system only oxidation was observed and
no tandem C-H activation. This suggests that the use of
diphosphine ligands shuts down the C-H activation
pathway. One equivalent of alkene is incorporated into
the product with an additional equivalent required as a
hydrogen acceptor; optimization experiments revealed that
2.3 equiv of alkene was suitable.
a Reaction conditions: alcohol (1 mmol), alkene (amount shown in the
table), Ru(PPh3)3(CO)(H)2 (5 mol %), toluene (1 mL), 135 °C for time
indicated. b Isolated yield of product after column chromatography is based
on alcohol.
Having optimized the tandem oxidation/C-H activation,
the conditions were then applied to a range of benzylic
alcohols (Table 1). Using a large excess of alkene (Table 1,
entry 1) with acetophenone gave the expected dialkylated
product, while the introduction of a methoxy group in the
para position (Table 1, entry 7) significantly increased the
reactivity of the monoalkylated intermediate such that it was
never observed in significant quantities and hence was also
isolated as the dialkylated product. Sterically hindered
alcohols (Table 1, entries 2, 4, and 5) were also isolated in
high yields as well as a heterocyclic example (Table 1, entry
6).
isopropanol is butane-1,4-diol,9 and while showing conversion
to the desired product, the reaction was sluggish.
Scheme 2. Catalytic Hydrogen Transfer of Ketone to Alcohol
Having optimized the initial two steps, we turned our attention
to a hydrogen source for the final reduction back to the alkylated
alcohol. While ruthenium catalysts have been shown to perform
direct hydrogenations of ketones with H2 gas, we wished to
avoid this to maintain a relatively simple reaction setup. The
use of isopropanol was favorable (Scheme 2), although it was
unable to drive the reaction to completion. An alternative to
However, we were pleased to find that the catalyst was
able to hydrogenate the ketone using formic acid (Scheme
2). The use of HCO2H/Et3N (5:2) was also screened and was
found to be equally as effective, although we chose to use
formic acid due to relative ease.
(8) Jun, C.-H.; Lee, D.-Y.; Kim, Y.-H.; Lee, H. Organometallics 2001,
20, 2928–2931.
Org. Lett., Vol. 12, No. 17, 2010
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After optimizing the conditions, they were applied to a range
of benzylic alcohols (Table 2). Entries 1-3 posed a potential
effects for the disubstituted aryl ketone, allowing easy separation
of the products. The product formed in entry 4 required the
reduction of the ketone between two bulky groups and part of
three consecutive sp2 centers.
The reduction did not occur with isopropanol, but with
HCO2H we were pleased to see at least some conversion into
the alcohol. Meta-substituted products (Table 2, entries 5-7)
were formed in good yields after 3 h, while the introduction of
electron-donating groups (Table 2, entry 8) led to a mixture of
regioisomers. Interestingly, the electronically similar dioxane
substrate (Table 2, entry 9) was isolated as a single regioisomer
despite two regioisomers10 being present after the oxidation/
C-H activation, again demonstrating the selectivity of the
reduction favoring unhindered ketones. Finally, the use of
heterocycles (Table 2, entries 10 and 11) was tolerated and gave
the products in reasonable yields.
Table 2. Consecutive Oxidation/C-H Activation/Reduction of
Benzylic Alcoholsa
The scope of the catalyst toward C-H activation has been
studied extensively by Murai.11 This allowed a selection of
alkenes to be chosen, demonstrating that previously successful
(Table 3, entries 1, 3, 5, and 6) and unsuccessful (Table 3, entry
2) alkenes were in agreement with expected results. However,
some of these products (Table 3, entires 2-4) proved difficult
Table 3. Alkene Scopea b
,
a Reaction conditions: alcohol (1 mmol), alkene (2.1-3 mmol),
Ru(PPh3)3(CO)(H)2 (5 mol %), toluene (1 mL), 135 °C for time indicated,
then HCO2H (5 mmol), 135 °C, 3 h. b Time for the tandem oxidation/C-H
activation only. A further 3 h was required for reduction. c Isolated yield
of product after column chromatography is based on alcohol. d Mixture of
regioisomers with the major isomer shown.
a Reaction conditions: alcohol (1 mmol), alkene (amount shown in the
table), Ru(PPh3)3(CO)(H)2 (5 mol %), toluene (1 mL), 135 °C, (x h).
b Reaction conditions: alcohol (1 mmol), alkene (x mmol), Ru(PPh3)3-
(CO)(H)2 (5 mol %), toluene (1 mL), 135 °C (x h), then HCO2H (5 mmol),
135 °C, 3 h. c Time for the tandem oxidation/C-H activation only. A further
3 h was required for reduction. d Isolated yield of product after column
chromatography is based on alcohol. e Conversion based on the alcohol
challenge as the mixture of product from the initial oxidation/
C-H activation step gave a mixture of mono- and disubstituted
aryl ketones, as seen previously. However, the monosubstituted
aryl ketone was selectively reduced, presumably due to steric
and determined by H NMR. f Mixture of mono- and dialkylated material
1
(9) (a) Maytum, H. C.; Tavassoli, B.; Williams, J. M. J. Org. Lett. 2007,
9, 4387–4389. (b) Maytum, H. C.; Francos, J.; Whatrup, D. J.; Williams,
J. M. J. Chem. Asian J. 2010, 5, 538–542.
with the major product shown.
3858
Org. Lett., Vol. 12, No. 17, 2010

to reduce and so were isolated as ketones. We were surprised
to find that the use of trimethylvinylsilane (Table 3, entry 4)
gave a mixture (21:79) of mono- and disubstituted ketone,
respectively, in contrast to the selectivity of the carbon
equivalent (Table 3, entry 1). We attributed this to the increased
C-Si bond length, allowing easier insertion into the more
crowded position between the ketone and methyl group.
Having screened a series of alcohols and alkenes, we were
confident that the reaction was indeed proceeding via our
proposed scheme, having observed no trace of alkylated alcohol
in any of the reactions. However, to rule out any possibility of
C-H activation at the alcohol oxidation level occurring, we
devised three test substrates (Figure 1). The ether (1) and tertiary
dynamically unfavorable. In all cases, relatively forcing con-
ditions (5 equiv of alkene, reflux, 24 h) were applied, and no
oxidation or C-H activation was observed. Thus, we can
conclude that the initial oxidation occurs before any C-H
activation can occur.
From the results obtained, we have demonstrated that
Ru(PPh3)3(CO)(H)2 is active for the catalysis of up to three
consecutive reaction steps. Further research into the tempo-
rary electronic activation of arenes toward other reactions is
now underway.
Acknowledgment. We thank GSK and the EPSRC for
funding through the Pharma-Synthesis Network. We also
thank Dr. Anneke Lubben for essential help with mass
spectrometry and Dr. Mike Whittlesey for encouragement.
Supporting Information Available: Details of experi-
mental procedures and characterization data are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. Inert substrates.
OL101548A
(10) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. J. Organomet.
Chem. 1995, 504, 151–152.
alcohol (2) would both be inert to oxidation and maintain the
same oxidation level as the model alcohol, while the R-triflu-
oromethyl group in substrate (3) makes the oxidation thermo-
(11) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatami, A.; Sonoda, M.;
Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62–83.
Org. Lett., Vol. 12, No. 17, 2010
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