Intermolecular Markovnikov-Selective Hydroacylation of Olefins Catalyzed by a Cationic Ruthenium-Hydride Complex

Article abstract of DOI:10.1021/acscatal.6b00856

The cationic Ru-H complex was found to be an effective catalyst for the intermolecular hydroacylation of aryl-substituted olefins with aldehydes to form branched ketone products. The preliminary kinetic and spectroscopic studies elucidated a ruthenium-acy

Full text of DOI:10.1021/acscatal.6b00856

Letter
pubs.acs.org/acscatalysis
Intermolecular Markovnikov-Selective Hydroacylation of Olefins
Catalyzed by a Cationic Ruthenium−Hydride Complex
Junghwa Kim and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
S
* Supporting Information
ABSTRACT: The cationic Ru−H complex was found to be
an effective catalyst for the intermolecular hydroacylation of
aryl-substituted olefins with aldehydes to form branched
ketone products. The preliminary kinetic and spectroscopic
studies elucidated a ruthenium-acyl complex as the key
intermediate species. The catalytic method directly afforded
branched ketone products in a highly regioselective manner
while tolerating a number of heteroatom functional groups.
KEYWORDS: hydroacylation, alkene, aldehyde, ruthenium catalyst, branched ketone
kov-selective hydroacylation technology remains a largely
unsolved problem in the homogeneous catalysis field.
he transition-metal-catalyzed hydroacylation reaction
Tconstitutes a highly expedient protocol for introducing
acyl group to unsaturated organic substrates.1 For the
hydroacylation of olefins, the intramolecular version of the
reaction has been effectively used to form cyclic ketone
products.2 Since the pioneering reports on the intermolecular
hydroacylation of olefins,3 a number of late-transition-metal
catalysts have been found to mediate anti-Markovnikov
hydroacylation of alkenes to form the linear ketones.4−6 One
of the most debilitating problems on the olefin hydroacylation
reaction resides in competing decarbonylation of aldehyde
substrates, which often leads to the deactivation of metal
catalysts. A number of clever strategies have been implemented
to circumvent the decarbonylation problem. One successful
approach has been to employ aldehyde substrates with a
heteroatom chelate group to promote the hydroacylation
reaction.4 Employing aldimines as a synthetic equivalent to
aldehydes5 and using activated olefin substrates1c,6 have also
been shown to be effective strategies for promoting
regioselective hydroacylation reaction while limiting the
decarbonylation side reaction. Because most of these catalytic
methods generally exhibit anti-Markovnikov selectivity in
forming linear ketone products, much research effort has
been directed to develop Markovnikov-selective hydroacylation
reaction to form the branched ketone products.7,8 Even though
the Markovnikov-selective asymmetric hydroacylation reaction
has been achieved under intramolecular conditions,8 relatively
few examples of intermolecular Markovnikov-selective hydro-
acylation methods have been reported. Moreover, the substrate
scope for the Markovnikov-selective hydroacylation reaction
has been generally limited to either aldehydes with heteroatom
chelate group or activated olefin substrates. Very recently, Zhou
and co-workers reported the first example of Ni-catalyzed
Markovnikov-selective hydroacylation of styrene derivatives.9
Designing highly effective and generally applicable Markovni-
We recently devised a number of dehydrative C−H coupling
reactions of olefins with alcohols by using a well-defined
cationic ruthenium−hydride complex [(C6H6) (PCy3) (CO)-
10
−
RuH]+BF4 (1) as the precatalyst. In an effort to extend the
scope of C−H acylation of phenol and related arenes,11 we
have been exploring the coupling reaction of aldehydes with
olefin substrates. Herein, we disclose a highly Markovnikov-
selective intermolecular hydroacylation of aryl-substituted
olefins to yield branched ketone products. The catalytic
method provides an atom-economical acylation protocol for
styrene derivatives without employing any reactive reagents or
directing groups.
We initially surveyed the coupling reaction of α-olefins with
aldehydes to probe the feasibility of the hydroacylation
reaction. The treatment of styrene (1.2 mmol) with
benzaldehyde (1.0 mmol) in the presence of the catalyst 1 (4
mol %) was heated at 120 °C for 8 h, after which the product
mixture was analyzed by both GC and NMR methods (eq 1).
The crude mixture showed high selectivity for the branched
product 2a over the linear product 3a (82% GC yield based on
the aldehyde, 2a:3a > 20:1), along with a trace amount of the
styrene dimer PhCH(Me)CHCHPh (<5%). The preliminary
screening of Ru catalysts confirmed uniquely high activity of the
complex 1 for the coupling reaction (Table S1, Supporting
Information (SI)).
Received: March 23, 2016
Revised: April 18, 2016
© XXXX American Chemical Society
3336
DOI: 10.1021/acscatal.6b00856
ACS Catal. 2016, 6, 3336−3339

ACS Catalysis
Letter
The catalyst 1 was used to explore the substrate scope of the
hydroacylation reaction (Table 1). Both aliphatic and aryl-
that the hydroacylation of styrene with simple aliphatic
aldehydes has been rarely achieved.9
To further demonstrate synthetic utility, we next explored
the hydroacylation of styrene with a number of biologically
active aldehyde substrates. The treatment of (1R)-(−)-myrtenal
and (S)-(−)-perillaldehyde with styrene formed a 1:1
diastereomeric mixture of the products 4a and 4b (Table 2).
a
Table 1. Markovnikov-Selective Hydroacylation of Olefins
Table 2. Hydroacylation of Styrene Derivatives with
a,b
Bioactive Aldehydes
a
Reaction conditions: alkene (1.2 mmol), aldehyde (1.0 mol), 1 (8−
b
10 mol %), toluene (2 mL), 120 °C, 12−14 h. Product yield is
calculated on the basis of aldehyde substrate. Ratio of branched vs
linear product is >20:1. Reaction time = 36 h. The absolute
c
stereochemistry of (−)-4f was not determined.
The reaction of biologically active helional with styrene and N-
methyl-3-indolecarboxaldehyde with methyl cinnamate also
yielded the products 4c and 4d, respectively. Bis-(2-
formylphenyl)ether with 3 equiv of styrene selectively formed
2:1 coupling product 4e, whereas vinylestrone with benzalde-
hyde formed a single diastereomer of (−)-4f. Both oxygen and
nitrogen groups are tolerated in forming these hydroacylation
products.
The following set of preliminary kinetic experiments was
performed to gain mechanistic insights on the acylation
reaction. First, we examined the H/D exchange pattern of the
hydroacylation reaction (eq 2). The product 2a was isolated
a
Reaction conditions: alkene (1.2 mmol), aldehyde (1.0 mmol), 1 (4−
6 mol %), toluene (2 mL).
substituted aldehydes readily reacted with styrene derivatives to
form the branched acylation products 2 (entries 1−13). For
terminal olefins such as allylbenzene and 4-phenyl-1-butene,
apparently facile olefin isomerization had taken place prior to
the acylation to form the phenyl-substituted acylation products
2n−2p (entry 14−16). We previously showed that the Ru
catalyst promotes a very high olefin isomerization rate under
the comparable conditions.12 The coupling of indene with
aldehydes predictively afforded the 2-acylated products 2r and
2s (entries 18,19), whereas the acylation of cinnamic acid
derivatives proceeded smoothly to give the 1,4-diketone
products 2t−2v (entries 20−22). The hydroacylation of 4-
methylstyrene with a chiral aldehyde substrate (R)−
CH3CHPhCHO led to a 1:1 diasteromeric mixture of the
products 2w, resulted from the epimerization of the olefinic
carbon (entry 23). In most cases, the catalytic method achieves
very high regioselectivity toward the branched acylated
products over the linear ketone products without using any
chelate-directing group (2:3 > 20:1). It should be emphasized
from the reaction mixture of benzaldehyde-d1 (98% D, 0.5
mmol), styrene (0.6 mmol), and 1 (5 mol %) in toluene (2
mL) at 125 °C after 8 h. Deuterium content from the
benzaldehyde was redistributed to CH3 (42%) and CH (14%)
as well as the ortho-arene (29%) of the isolated product 2a, as
determined by 1H and 2H NMR (Figure S1, SI). Nearly 10% of
deuterium was also incorporated to the styrene dimer
byproduct. A substantially higher amount of deuterium
incorporation to CH3 position compared to the CH group of
2a suggests that the addition of aldehydic hydrogen to the
terminal olefinic carbon is favored over the internal one. Nearly
30% of deuterium was also incorpoated to the ortho-arene
postions, and such facile arene H/D exchange of arylketones
has been commonly observed in chelate-assisted arene C−H
insertion reactions.13
Next, we measured the kinetic isotope effect for the
hydroacylation reaction. The reaction rate was measured for
the hydroacylation reaction of styrene with PhCHO and
PhCDO separately. The first-order plots on the formation of 2a
3337
DOI: 10.1021/acscatal.6b00856
ACS Catal. 2016, 6, 3336−3339

ACS Catalysis
Letter
translated into a normal deuterium isotope effect of kH/kD = 2.6
0.1 (Figure 1). The results suggest that the aldehyde C−H
cleavage is the most likely turnover-limiting step for the
coupling reaction.14
The 13C{1H} NMR spectrum of the reaction mixture at −40
°C showed a distinctively upfield-shifted carbonyl peak at δ
196.5 (d, JPC = 18.4 Hz), which does not have any neighboring
protons as analyzed by 2D NMR techniques (Figure S3, SI).
We also detected a small amount of ethylbenzene (10%) and
free benzene (90%) in the reaction mixture. We tentatively
assigned the structure as a cationic Ru-acyl complex 5 on the
basis of these NMR spectroscopic data.15
On the basis of these results, we present a possible
mechanism of the hydroacylation reaction (Scheme 1). We
Scheme 1. Possible Mechanism for the Hydroacylation of
Styrene
Figure 1. First-order rate plots from the hydroacylation of styrene with
■
▲
benzaldehyde ( ) and benzaldehyde-d ( ).
To probe electronic influence on the aldehyde substrate, we
constructed a Hammett plot from the rate of a series of para-
substituted benzaldehydes p-X-C6H4CHO (X = OMe, Me, H,
F, Cl). A linear correlation from the relative rate vs Hammett σp
led to a positive ρ value of +0.8
0.1 (Figure 2). The
propose that the cationic Ru-acyl species 5 is initially generated
from the coordination of aldehyde and the dehydrogenation
steps. The spectroscopic detection of a Ru-acyl complex 5 from
the stoichiometric reaction of 1 with benzaldehyde and styrene
provides a strong argument for the acyl complex as catalytically
active species. Ruthenium-acyl complexes have been considered
as a key intermediate in hydroacylation and carbonylation of
olefins.1b,16 The regioselective migratory insertion of styrene
would form the five-membered metallacyclic species 6. Both
Hammett and deuterium isotope effect data suggest that the
aldehyde C−H bond cleavage is the turnover-limiting step, in
which the C−H cleavage step would be facilitated by an
electrophilic Ru center. The preferential deuterium incorpo-
ration to the methyl group of the product 2a, as described in eq
2, is also consistent with a reductive elimination step via the
metallacyclic species 6.17 A minor deuterium incorporation to
the methyne position of 2a can be explained via an alkene
insertion/β-H elimination from the intermediate 6 and its
concurrent H/D exchange with a Ru-D species.18
In conclusion, we successfully developed a highly Markovni-
kov-selective intermolecular hydroacylation protocol for the
aryl-substituted alkenes to form branched ketone products. The
catalytic method mediates high degree of Markovnikov
selectivity without using any chelate directing groups, and it
tolerates a number of oxygen and nitrogen functional groups in
forming the acylation products. Efforts to design Ru chiral
catalysts for the asymmetric version of the hydroacylation
reaction are currently underway.
Figure 2. Hammett plot from the hydroacylation reaction of p-X-
C6H4CHO (X = OCH3, CH3, H, F, Cl) with styrene.
promotional effect from electron-withdrawing group suggests
that electrophilic nature of carbonyl group facilitates the
aldehyde C−H activation. Dong and co-workers recently
reported a similar Hammett ρ value in the catalytic hydro-
acylation of 4-nitro-2-vinylphenol with para-substituted ben-
zaldehydes.7g
In an effort to elucidate the structure of catalytically relevant
intermediate species, we monitored the reaction of 1 with
styrene and aldehyde substrates. In a NMR tube, 1 (0.1 mmol),
styrene (0.1 mmol), and 13C-enriched benzaldehyde (0.1
mmol, 99% 13C) were dissolved in CD2Cl2 (0.5 mL), and the
tube was heated at 90 °C for 3 h, during which time, the
formation of a new Ru complex was observed at the expense of
the starting complex 1 as monitored by NMR (eq 3).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b00856.
■
S
Experimental procedures and full characterization data of
compounds (PDF)
3338
DOI: 10.1021/acscatal.6b00856
ACS Catal. 2016, 6, 3336−3339

ACS Catalysis
Letter
(13) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(b) Albrecht, M. Chem. Rev. 2010, 110, 576.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chae.yi@marquette.edu.
(14) (a) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41,
222. (b) Garralda, M. A. Dalton Trans. 2009, 3635. (c) Jia, X.; Zhang,
S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11, 3120. (d) Chan,
C.-W.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926.
(e) Santhoshkumar, R.; Mannathan, S.; Cheng, C.-H. J. Am. Chem. Soc.
2015, 137, 16116.
(15) The complete structural assignment of 5 was very difficult
because the peaks due to styrene and unreacted benzaldehyde
overlapped with the peaks for 5. The complex 5 also slowly
decomposes at room temperature within 12 h.
(16) (a) Kakiuchi, F.; Chatani, N. In Topics in Organometallic
Chemistry: Ruthenium Catalysts and Fine Chemistry; Bruneau, C.,
Dixneuf, P. H., Eds; Springer-Verlag: Berlin, 2004, Vol. 11, pp 45−79.
(b) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879.
(17) As indicated earlier, we have previously found that the complex
1 is an exceptionally effective catalyst for the olefin isomerization
reaction (ref 12). The observed deuterium scrambling pattern can be
readily explained by an olefin isomerization mechanism, as illustated in
SI (Figure S2).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science of Foundation
(CHE-1358439) and the National Institute of Health General
Medical Sciences (R15 GM109273) is gratefully acknowledged.
We thank Dr. Sheng Cai for help in running the NMR
experiments on the characterization of 5.
REFERENCES
■
(1) Recent reviews: (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(b) Willis, M. C. Chem. Rev. 2010, 110, 725. (c) Leung, J. C.; Krische,
M. J. Chem. Sci. 2012, 3, 2202.
(2) (a) Bosnich, B. Acc. Chem. Res. 1998, 31, 667. (b) Kundu, K.;
McCullagh, J. V.; Morehead, A. T., Jr. J. Am. Chem. Soc. 2005, 127,
16042. (c) Murphy, S. K.; Bruch, A.; Dong, V. M. Angew. Chem., Int.
Ed. 2014, 53, 2455. (d) Chen, Q.-A.; Kim, D. K.; Dong, V. M. J. Am.
Chem. Soc. 2014, 136, 3772.
(3) (a) Marder, T. B.; Roe, D. C.; Milstein, D. Organometallics 1988,
7, 1451. (b) Kondo, T.; Akazome, M.; Tsuji, Y.; Watanabe, Y. J. Org.
Chem. 1990, 55, 1286. (c) Lenges, C. P.; Brookhart, M. J. Am. Chem.
Soc. 1997, 119, 3165. (d) Lenges, C. P.; White, P. S.; Brookhart, M. J.
Am. Chem. Soc. 1998, 120, 6965.
(18) Ryu and co-workers proposed an alternate mechanism via a π-
allyl-ruthenium species to explain Markovnikov selectivity for the
hydroacylation of dienes.7b We cannot rigorously eliminate this
mechanistic possibility, although it cannot readily explain the detection
of the Ru-acyl species.
(4) (a) Jun, C.-H.; Lee, D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem., Int.
Ed. 2000, 39, 3070. (b) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem. -
Eur. J. 2002, 8, 2422. (c) Willis, M. C.; McNally, S. J.; Beswick, P. J.
Angew. Chem., Int. Ed. 2004, 43, 340. (d) von Delius, M.; Le, C. M.;
Dong, V. M. J. Am. Chem. Soc. 2012, 134, 15022.
(5) (a) Suggs, J. W. J. Am. Chem. Soc. 1979, 101, 489. (b) Jun, C.-H.;
Lee, H.; Hong, J.-B. J. Org. Chem. 1997, 62, 1200. (c) Jun, C.-H.; Huh,
C.-W.; Na, S.-J. Angew. Chem., Int. Ed. 1998, 37, 145. (d) Yang, J.; Seto,
Y. W.; Yoshikai, N. ACS Catal. 2015, 5, 3054.
(6) Anti-Markovnikov selective hydroacylation with with nonchelate-
assisted aldehydes: (a) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.;
Hirano, M. Org. Lett. 2007, 9, 1215. (b) Shibata, Y.; Tanaka, K. J. Am.
Chem. Soc. 2009, 131, 12552.
(7) (a) Tanaka, M.; Imai, M.; Yamamoto, Y.; Tanaka, K.;
Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H. Org. Lett.
2003, 5, 1365. (b) Omura, S.; Fukuyama, T.; Horiguchi, J.; Murakami,
Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094. (c) Shibahara, F.;
Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14120.
(d) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009,
131, 14190. (e) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V.
M. J. Am. Chem. Soc. 2010, 132, 16330. (f) Murphy, S. K.; Petrone, D.
A.; Coulter, M. M.; Dong, V. M. Org. Lett. 2011, 13, 6216. (g) Murphy,
S. K.; Bruch, A.; Dong, V. M. Chem. Sci. 2015, 6, 174.
(8) (a) Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.;
Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821. (b) Kim, I.
S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6340.
(c) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc.
2009, 131, 6932. (d) Piel, I.; Steinmetz, M.; Hirano, K.; Frohlich, R.;
̈
Grimme, S.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 4983.
(e) Hoffman, T. J.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
10670. (f) Yang, J.; Yoshikai, N. J. Am. Chem. Soc. 2014, 136, 16748.
(9) Xiao, L.-J.; Fu, X.-N.; Zhou, M.-J.; Xie, J.-H.; Wang, L.-X.; Xu, X.-
F.; Zhou, Q.-L. J. Am. Chem. Soc. 2016, 138, 2957.
(10) (a) Lee, D.-H.; Kwon, K.-H.; Yi, C. S. Science 2011, 333, 1613.
(b) Lee, D.-H.; Kwon, K.-H.; Yi, C. S. J. Am. Chem. Soc. 2012, 134,
7325. (c) Kim, J.; Lee, D.-H.; Kalutharage, N.; Yi, C. S. ACS Catal.
2014, 4, 3881.
(11) Lee, H.; Yi, C. S. Eur. J. Org. Chem. 2015, 1899.
(12) Lee, D. W.; Yi, C. S. Organometallics 2010, 29, 3413.
3339
DOI: 10.1021/acscatal.6b00856
ACS Catal. 2016, 6, 3336−3339