Building molecular complexity via tandem ru-catalyzed isomerization/C-H activation

Article abstract of DOI:10.1021/ol900243x

A tandem isomerization/C-H activation of a My lie alcohols was performed using a catalytic amount of RuCI₂(PPh₃)₃. A variety of ortho alkylated ketones have been obtained in excellent yields. This tandem process relies on an in situ generation of a carbonyl functional group that directs the ortho C-H bond activation.

Full text of DOI:10.1021/ol900243x

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1749-1752
Building Molecular Complexity via
Tandem Ru-catalyzed Isomerization/C-H
Activation
Agnieszka Bartoszewicz and Bele´n Martín-Matute*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
106 91 Stockholm, Sweden
belen@organ.su.se
Received February 6, 2009
ABSTRACT
A tandem isomerization/C-H activation of allylic alcohols was performed using a catalytic amount of RuCl2(PPh3)3. A variety of ortho alkylated
ketones have been obtained in excellent yields. This tandem process relies on an in situ generation of a carbonyl functional group that directs
the ortho C-H bond activation.
The search for the most atom-economical ways1 to form
C-C bonds is a matter of increasing importance among
industrial and academic research groups.2 One way to achieve
clean, cheap, and atom-economical processes is to use “low
energy” starting materials. For example, the functionalization
of a C-H bond rather than a C-X bond is a highly desirable
alternative. Hence, the functionalization of C-H bonds has
attracted much attention in organic chemistry. In 1993, Murai
reported a highly efficient ruthenium-catalyzed coupling
reaction of aromatic C-H bonds with olefins.3 The key
feature of this reaction is the assistance by chelation. The
reaction is generally applicable, and a variety of coordinating
groups containing N or O can be used.4
A variety of Ru complexes, such as RuH2(CO)(PPh3)3,
Ru(CO)2(PPh3)3, Ru(CO)3(PPh3)2, RuH2(PPh3)4, Ru3(CO)12,
and RuH2(H2)(CO)(PCy3)2, have been used in aromatic C-H
activation.4 These complexes show very high selectivity and
reactivity. On the other hand, they are expensive, and some
of them, in particular the hydrides, are sensitive to moisture
and oxygen. Recently, ruthenium complex [Ru(p-cym)Cl2]2
(1a) (p-cym ) η6-p-cymene) has been used, from which the
active Ru dihydride was generated in situ, and excellent
(1) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
(4) For reviews using Ru complexes, see: (a) Park, Y. J.; Jun, C.-H.
Bull. Korean Chem. Soc. 2005, 26, 871–877. (b) Kakiuchi, F.; Chatani, N.
AdV. Synth. Catal. 2003, 345, 1077–1101. (c) Ritleng, V.; Sirlin, C.; Pfeffer,
M. Chem. ReV. 2002, 102, 1731–1770. (d) Kakiuchi, F.; Kochi, T. Synthesis
2008, 3013–3039. For other metals, see: (e) Ackermann, L. Top. Organomet.
Chem. 2007, 24, 35–60. (f) Satoh, T.; Miura, M. Top. Organomet. Chem.
2007, 24, 61–84. (g) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205.
(h) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–
238. (i) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173–
1193. (j) Bergman, R. G. Nature 2007, 446, 391–393. (k) Campeau, L.-C.;
Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35–41.
(2) (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester,
1995. (b) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (c) Brandsma, L.; Vaselevsky,
S. F.; Verkruijsse, H. D. Application of Transition Metal Catalysts in
Organic Synthesis; Springer: Berlin, 1998.
(3) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. For a review, see:
(b) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826–834. (c) Murai,
S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani,
N. Pure App. Chem. 1994, 66, 1527–1534.
10.1021/ol900243x CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society

reactivity was obtained.5 Furthermore, 1a is stable and one
of the cheapest Ru complexes available. Activations of
aromatic C-H bonds not involving chelation have also been
reported, but these are less selective, giving mixtures of
regioisomers.4c,6 On the other hand, from a synthetic point
of view, the introduction of the directing group may increase
the number of synthetic steps, and thus limit the scope of
the transformation.
Table 1. Catalyst and Additives Screening
We have recently developed a very efficient one-pot Ru-
catalyzed isomerization/aldol reaction of allylic alcohols
(Scheme 1a). Ru enolates are key intermediates in this
time 3a+4a
(h)
entry
1
catalyst
additives (mol %)
(%)a
RuH2CO(PPh3)3
(1b)
RuH2(PPh3)4
(1c)
-
-
2
>99
(92/8)
86
2
3
4
2
2
2
(93/7)
>99
[Ru(p-cym)Cl2]2 HCO2Na (30)/
(1a)
PPh3 (15)
HCO2Na (30)
(62/38)
>99
Scheme 1. Tandem Ru-Catalyzed (a) Isomerization/Aldol
Reaction, and (b) Isomerization/C-H Activation in One Pot
RuCl2(PPh3)3
(1d)
1d
(67/33)
b
5
6
-
2
12
-
1d
Na2CO3 (30)
49
(96/4)
c
7
8
1d
1a
tBuOK (7)
Na2CO3 (30)/PPh3 (15)
12
12
-
90
(83/17)
>99
9
1a
1d
1d
1d
Na2CO3 (30)/iPrOH (30)/
PPh3 (15)
12
6
(80/20)
100
10
11
12
Na2CO3 (30)/iPrOH (30)
(83/17)
>99
HCO2Na (30)/
P(p-MeOC6H4)3 (7)
HCO2Na (30)/
PtBu3 (7)
2
(67/33)
>99
2
(40/60)
a Yield measured by 1H NMR (3a+4a); in parenthesis, 3a:4a ratio.
b Propiophenone (5a) was produced in 100% yield. c Complex reaction
mixture.
1-2) in very high yield after only 2 h. We were very pleased
to find that Ru-Cl complexes [Ru(p-cymene)Cl2]2 (1a) and
RuCl2(PPh3)3 (1d) in the presence of sodium formate,
HCO2Na, were even more active catalysts in the tandem
transformation (Table 1, entries 3-4).8 In the absence of a
hydride source, complex 1d gave only isomerization of the
allylic alcohol to produce the propiophenone intermediate
5a (entry 5). Because HCO2Na can act not only as a hydride
donor but also as a base, we studied the tandem transforma-
tion using other bases. With Na2CO3, the product could be
obtained, albeit in low yield, after 12 h (Table 1, entry 6).
tBuOK afforded complex mixtures (Entry 7). For 1a,
however, formate was not a requirement (Table 1, entry 8).
We then combined Na2CO3 as a base with iPrOH as a hydride
donor source. For both complexes 1a and 1d, the reaction
gave excellent results. However, the use of Na2CO3/iPrOH
resulted in slightly longer reaction times than when formate
was used (compare entries 9-10 with entries 3-4).
We continued our studies with catalyst 1d since it could
be easily prepared from cheap starting materials, RuCl3-
(H2O)n and PPh3.9 Despite the excellent results obtained with
1a and 1d (Table 1, entries 3-4), we observed that the
reactions sometimes lacked reproducibility (>99% yield could
always be obtained, but slightly longer reaction times, e.g.,
from 2 to 4 h). We thought that decomposition of the catalyst
may occur, and that addition of an extra phosphine could
transformation.7 In the absence of the electrophile, the Ru-
enolate intermediate is converted into the corresponding
ketone (Scheme 1b). We envisioned that the transformation
of allylic alcohols into ketones could broaden the scope of
the aromatic C-H activation processes, since the in situ
generated carbonyl functional group could assist the cleavage
of the ortho C-H bond by chelation. Ideally, both processes
could be catalyzed by the same Ru complex. In this way,
molecular complexity would be achieved in very few steps
starting from commercially available aldehydes. In this
article, we report a tandem isomerization of allylic alcohols
followed by ortho C-H bond activation directed by the in
situ formed carbonyl group using stable ruthenium precur-
sors.
In a systematic study, we found that a number of
commercially available Ru complexes efficiently catalyze
both the isomerization and the C-H activation (Table 1).
We also observed that the isomerization occurs within
minutes.
Thus, starting from allylic alcohol 2a, RuH2CO(PPh3)3 (1b)
and RuH2(PPh3)4 (1c) both yielded the product (a mixture
of the 1:1 adduct 3a and 1:2 adduct 4a) (Table 1, entries
(5) (a) Martinez, R.; Chevalier, R.; Darses, S.; Geneˆt, J.-P. Angew.
Chem., Int. Ed. 2006, 45, 8232–8235. (b) Martinez, R.; Geneˆt, J.-P.; Darses,
S. Chem. Commun. 2008, 3855–3857. (c) Simon, M. C.; Martinez, R.; Geneˆt,
J.-P.; Darses, S. AdV. Synth. Catal. 2009, 351, 153–157.
(6) Foley, N. A.; Ke, Z.; Gunnoe, T. B.; Cundari, T. R.; Petersen, J. L.
Organometallics 2008, 27, 3007–3017
.
(8) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521–2522.
(7) Bartoszewicz, A.; Livendahl, M.; Martín-Matute, B. Chem.-Eur.
J. 2008, 14, 10547–10550.
(9) Jardine, F. H. Prog. Inorg. Chem. 1984, 31, 265–370.
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Org. Lett., Vol. 11, No. 8, 2009

prevent unwanted decomposition pathways. On the other
hand, the phosphine can hinder the catalytic cycle by
blocking the metal center. Furthermore, the electronic and
steric properties of the added ligand may change the outcome
of the reaction. Thus, we evaluated the effect of added
phosphines (Table 1, entries 11-12 and Supporting Informa-
tion), and it was observed that the addition of electron rich-
phosphines, such as PtBu3 (Table 1, entry 12) or P(p-
MeOC6H4)3 (Table 1, entry 11) did not dramatically decrease
the reaction time of the tandem transformation,10 but more
importantly for us, the reactions became reproducible. On
the other hand, electron-poor phosphines slowed the reaction
down, and bidentate phosphines completely suppressed the
transformation.
Table 2. Scope of the Tandem Ru-Catalyzed Isomerization/
C-H Activation/C-C Bond Formationa
With the optimal conditions established (Table 1, entry
12), we examined the substrate scope (Table 2). The tandem
process works very well for a variety of aromatic allylic
alcohols (Table 2, entries 1-15). The 1:1/1:2 adduct ratio
(i.e., 3/4) can easily be improved in favor of the former by
lowering the amount of triethoxyvinylsilane (Table 2, entries
3, 6, 8). The temperature can be lowered to 100 °C, although
longer reaction times are needed (Table 2, entry 2). More
substituted substrates give good results (Table 2, entries 14
and 15). The allylic alcohol moiety is not a requirement for
the tandem transformation to occur: the double bond can be
placed more than one bond away from the carbinol (Table
2, entry 16). We believe the double bond can migrate to the
allylic position and then rearrange to the corresponding
ketone. Lower catalyst loading can be used, although longer
reaction times are required (when 2.5 mol % of Ru complex
1d was used, the reaction time to achieved 100% conversion
increased from 2 to 12 h for 2a).
The feasibility of the reaction was also tested using styrene
(Scheme 2).5b In this case, the added phosphine had a strong
influence on the outcome of the reaction, and good yields
of a mixture of linear (6) and branched (7) products are
obtained only upon the addition of PtBu3. Disubstituted
product (1:2 adducts) were not detected.
The isomerization of 2a-d1 under similar conditions was
performed (Scheme 3). Careful analysis by mass spectros-
copy indicated that a mixture of nondeuterated, monodeu-
terated and dideuterated ketones 5a had been produced in
>95% yield.11 Traces (∼2%) of unsaturated ketones were
also detected by 1H NMR spectroscopy. Further analysis by
quantitative 13C NMR spectroscopy helped us to estimate
the ratio and the structure of the monodeuterated and
dideuterated ketones (Scheme 3).
The deuterium distribution obtained in the isomerization
of 2a-d1 may be explained by more than one mechanism.
During the tandem process, the isomerization of 2a to ketone
5a takes place within a very short reaction time (<5 min).
We believe that this isomerization is catalyzed by Ru(II)
complexes (Ru monohydrides, dihydrides or alkoxides)
a Alcohol 2and triethoxyvinylsilane (2 equiv) were added to a suspension
of HCO2Na (30 mol %), 1d (5 mol %), and PtBu3 (7 mol %) in toluene (0.5
mL) under a N2 atmosphere. The flask was quickly introduced into an oil bath
at 140 °C, and stirred for the time indicated. The arrows indicate the position
where substitution takes place. b Measured by 1H NMR, in parenthesis isolated
yields(3+4).c Measuredby1HNMR.d Inanoilbathat100°C.e Triethoxyvinylsilane
(1.4 equiv) was employed. f Product 3l is identical to 3j.
(10) Although the reaction times for the isomerization/C-H activation
did not change much in the presence of electron rich-phosphines, when
only C-H activation from propiophenone was studied, the reaction time
was decreased by a factor of 2. See Supporting Information.
(11) The height of the m/z peaks were corrected for the natural 13C
content (see Supporting Information).
(Scheme 4 and Supporting Information). In a Ru dihydride
mechanism, both the O-H and R-C-H(D) hydrogen atoms
Org. Lett., Vol. 11, No. 8, 2009
1751

insertion of the olefins into the Ru-H bonds can explain
the ratio of nondeuterated, monodeuterated and dideuterated
ketones that was obtained in the labeling studies shown in
Scheme 3.13 The intermediacy of Ru dihydrides has been
further supported when RuH2(PPh3)4 was used as the catalyst
(Table 1, entry 3). A Ru(0)/Ru(II) mechanism is probably
involved in the C-H activation.3c Ru(0) complexes can be
produced by reaction of Ru(II) dihydrides with a hydride
acceptor. We did not detect formation of alcohol byproduct
Scheme 2. Use of Styrene As the Olefin
Isomerization of Deuterium Labeled Allylic Alcohol
Scheme 4. Proposed Mechanism
14
1
in the H NMR spectra of the crude reaction mixtures.
Therefore, we propose that triethoxyvinyl silane, which is
used in excess, can also act as hydride acceptor and mediate
the reduction of Ru(II) to Ru(0) (Scheme 4).15,16
In conclusion, we have described a general tandem
isomerization of allylic alcohols/C-H activation catalyzed
by the stable RuCl2(PPh3)3 complex. The tandem process
affords the products in excellent yields in very short reaction
times. Moreover, allylic alcohol can be produced in situ by
migration of a double bond placed more than one bond away
from the carbinol. The catalytically active Ru hydride
intermediates are generated under the reaction conditions
allowing the use of stable ruthenium precursors.
Scheme 3
.
Acknowledgment. Financial support from the Swedish
Research Council (Vetenskapsrådet) and the Berzelius Center
Exselent is gratefully acknowledged.
Supporting Information Available: Details of experi-
mental procedures, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900243X
(12) RuCl2(PPh3)3 reacts with isopropanol to produce the corresponding
dihydride, see: Aranyos, A.; Gsjernyik, G.; Szabo´, K. J.; Ba¨ckvall, J.-E.
J. Chem. Soc., Chem. Commun. 1999, 351–352.
(13) For a similar mechanistic study using Ni complexes, see: Cuperly,
D.; Petrignet, J.; Cre´visy, C.; Gre´e, R. Chem.-Eur. J. 2006, 12, 3261–
3274. See also scheme in Supporting Information.
of the allylic alcohol can be transferred to the metal yielding
a Ru dihydride and an R,ꢀ-unsaturated ketone.12 As a result,
the hydrogens are scrambled and lose their identity. Ru
monohydrides or dihydrides can also be formed by reaction
of Ru dichloride 1d with HCO2Na.8 This latter pathway could
account for some of the deuterium loss during the isomer-
ization of deuterated 2a-d1. Nonregioselective and reversible
(14) See crude NMR spectra in Supporting Information.
(15) Theoretical study of the mechanism, see: Matsubara, T.; Koga, N.;
Musaev, D. G.; Morokuma, K. J. Am. Chem. Soc. 1998, 120, 12692–12693
.
(16) For direct arylations without involving Ru(0) species, see: (a)
¨
Ozdemir, I.; Demir, S.; C¸ etinkaya, B.; Gourlaouen, C.; Maseras, F.; Bruneau,
C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157. (b) Ackermann,
L.; Vicente, R.; Althammer, A. Org. Lett. 2009, 102, 2299–2302
.
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