Diene hydroacylation from the alcohol or aldehyde oxidation level via ruthenium-catalyzed C-C bond-forming transfer hydrogenation: Synthesis of β,γ-unsaturated ketones

Article abstract of DOI:10.1021/ja805356j

Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic and aliphatic alcohols 1a-g to deliver β,γ-unsaturated ketones 3a-g in good to excellent isolated yields. Under identical conditions, aldehydes 2a-g couple to isoprene to provide an identical set of β,γ-unsaturated ketones 3a-g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene, and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in transfer hydrogenative coupling to form β,γ-unsaturated ketones. In all cases, complete branch regio-selectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish branched homoallylic alcohols. Thus, under transfer hydrogenative coupling conditions, all oxidation levels of substrate (alcohol or aldehyde) and product (homoallyl alcohol or β,γ-unsaturated ketone) are accessible.

Full text of DOI:10.1021/ja805356j

Published on Web 10/08/2008
Diene Hydroacylation from the Alcohol or Aldehyde Oxidation
Level via Ruthenium-Catalyzed C-C Bond-Forming Transfer
Hydrogenation: Synthesis of ꢀ,γ-Unsaturated Ketones
Fumitoshi Shibahara, John F. Bower, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received July 10, 2008; E-mail: mkrische@mail.utexas.edu
Abstract: Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic
and aliphatic alcohols 1a-g to deliver ꢀ,γ-unsaturated ketones 3a-g in good to excellent isolated yields.
Under identical conditions, aldehydes 2a-g couple to isoprene to provide an identical set of ꢀ,γ-unsaturated
ketones 3a-g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene,
and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in
transfer hydrogenative coupling to form ꢀ,γ-unsaturated ketones. In all cases, complete branch regio-
selectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not
detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation
level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl
partners from the alcohol or aldehyde oxidation level to furnish branched homoallylic alcohols. Thus, under
transfer hydrogenative coupling conditions, all oxidation levels of substrate (alcohol or aldehyde) and product
(homoallyl alcohol or ꢀ,γ-unsaturated ketone) are accessible.
Introduction
alcohols to aldehydes. These studies represent a departure from
the use of preformed organometallics in an ever-increasing range
We have found that diverse unsaturated compounds are
subject to reductive C-C coupling under the conditions of
rhodium- and iridium-catalyzed hydrogenation.1,2 More recently,
we have found that catalytic C-C coupling may be achieved
under the conditions of transfer hydrogenation employing
iridium3 or ruthenium catalysts.4 A remarkable feature of such
“transfer hydrogenative couplings” resides in the ability to
promote C-C bond formation between unsaturates and carbonyl
compounds from the alcohol or aldehyde oxidation level, thereby
circumventing redox manipulations often required to convert
of carbonyl additions and are unique in their ability to promote
direct C-H functionalization of alcohols at the carbinol carbon.5
Recently, we disclosed a method for the direct coupling of
acyclic dienes to carbonyl partners from the alcohol or aldehyde
oxidation level to furnish branched products of carbonyl addition
with complete levels of regiocontrol.4a Here, 1,3-butadiene,
isoprene, and 2,3-dimethylbutadiene were found to deliver
products of carbonyl crotylation, isoprenylation, and reverse
(methyl)prenylation. These studies establish the use of acyclic
dienes as surrogates to preformed allyl metal reagents in
carbonyl allylations from the alcohol or aldehyde oxidation level.
In this article, we report a related catalytic system based on
ruthenium that promotes branch-selective coupling of 1,3-
butadiene, isoprene, 2,3-dimethylbutadiene, and myrcene to
diverse alcohols and aldehydes to furnish ꢀ,γ-unsaturated
ketones, representing a formal hydroacylation of acyclic dienes
(1) For selected reviews of hydrogenative C-C coupling, see: (a) Ngai,
M.-Y.; Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (b)
Iida, H.; Krische, M. J. Top. Curr. Chem. 2007, 279, 77. (c) Skucas,
E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007,
40, 1394.
(2) For recent examples, see the following. CdX vinylation: (a) Kong,
J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718.
(b) Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2007,
129, 7242. (c) Barchuk, A.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2007, 129, 8432. (d) Barchuk, A.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2007, 129, 12644. Aldol and Mannich addition: (e)
Jung, C.-K.; Garner, S. A.; Krische, M. J. Org. Lett. 2006, 8, 519. (f)
Jung, C.-K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051. (g)
Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J. J. Am. Chem.
Soc. 2008, 130, 2747. C)O allylation: (h) Skucas, E.; Bower, J. F.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12678.
(5) Alcohols participate in formal substitution under the conditions of
hydrogen autotransfer to furnish products of C-C bond formation.
These processes employ preformed nucleophiles that olefinate the
transient carbonyl, which is then reduced to the saturated adduct. In
contrast, the processes developed in our laboratory employ unsaturates
as pronucleophiles and deliver products of carbonyl addition. For
reviews of hydrogen autotransfer, see: (a) Guillena, G.; Ramo´n, D. J.;
Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2358. (b) Hamid, M. H. S. A.;
Slatford, P. A.; Williams, J. M. J. AdV. Synth. Catal. 2007, 349, 1555.
(6) For intermolecular ruthenium-catalyzed hydroacylation, see: (a) Isnard,
P.; Denise, B.; Sneeden, R. P. A.; Cognion, J. M.; Durual, P. J.
Organomet. Chem. 1982, 240, 285. (b) Isnard, P.; Denise, B.; Sneeden,
R. P. A.; Cognion, J. M.; Durual, P. J. Organomet. Chem. 1983, 256,
135. (c) Kondo, T.; Tsuji, Y.; Watanabe, Y. Tetrahedron Lett. 1987,
28, 6229. (d) Kondo, T.; Akazome, M.; Tsuji, Y.; Watanabe, Y. J. Org.
Chem. 1990, 55, 1286. (e) Kondo, T.; Hiraishi, N.; Morisaki, Y.; Wada,
K.; Watanabe, Y.; Mitsudo, T.-A. Organometallics 1998, 17, 2131.
(3) For iridium-catalyzed transfer hydrogenative C-C couplings, see: (a)
Bower, J. F.; Skucas, E.; Patman, R. L.; Krische, M. J. J. Am. Chem.
Soc. 2007, 129, 15134. (b) Bower, J. F.; Patman, R. L.; Krische, M. J.
Org. Lett. 2008, 10, 1033. (c) Kim, I. S.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 6340.
(4) For ruthenium-catalyzed transfer hydrogenative C-C couplings, see:
(a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6338. (b) Patman, R. L.; Williams, V. M.; Bower, J. F.; Krische,
M. J. Angew. Chem., Int. Ed. 2008, 47, 5220. (c) Ngai, M.-Y.; Skucas,
E.; Krische, M. J. Org. Lett. 2008, 10, 2705.
9
14120 J. AM. CHEM. SOC. 2008, 130, 14120–14122
10.1021/ja805356j CCC: $40.75
2008 American Chemical Society

ꢀ,γ-Unsaturated Ketones from Alcohols and Aldehydes
A R T I C L E S
Table 1. Ruthenium-Catalyzed Transfer Hydrogenative Coupling of
Isoprene to Alcohols 1a-g or Aldehydes 2a-g To Furnish
ꢀ,γ-Unsaturated Ketones 3a-ga
Table 2. Ruthenium-Catalyzed Transfer Hydrogenative Coupling of
Butadiene, Myrcene, and 1,2-Dimethylbutadiene to Representative
Alcohols 1b, 1c, and 1e To Furnish ꢀ,γ-Unsaturated Ketones
3h-j, 3k-m, and 3n-pa
a Cited yields are of material isolated by silica gel chromatography.
See Supporting Information for detailed experimental procedures.
a Cited yields are of material isolated by silica gel chromatography.
See Supporting Information for detailed experimental procedures. b The
reaction product 3j was contaminated with approximately 10% of the
R,ꢀ-unsaturated ketone.
from the alcohol or aldehyde oxidation level.6,7 Thus, under
the conditions of transfer hydrogenative coupling, all oxidation
levels of substrate (alcohol or aldehyde) and product (homoallyl
alcohol or ꢀ,γ-unsaturated ketone) are accessible (Scheme 1).
Scheme 1. Carbonyl Allylation and Hydroacylation from the
Aldehyde or Alcohol Oxidation Level via Transfer Hydrogenative
C-C Coupling of Dienes
Results and Discussion
In our prior studies of the ruthenium-catalyzed transfer hydro-
genative coupling of acyclic dienes to carbonyl partners employing
RuHCl(CO)(PPh3)3 as precatalyst, oxidation of the initially formed
homoallylic alcohol was observed to give the corresponding ꢀ,γ-
unsaturated ketones as a side product. It was found that ketone
formation is suppressed upon introduction of additional phosphine
ligand, which presumably occupies coordination sites required for
ꢀ-hydride elimination. A corollary to this effect is that ketone
formation should be favored for ruthenium complexes that are more
highly coordinatively unsaturated. To challenge this hypothesis,
isoprene was coupled to p-methoxybenzyl alcohol (1c) using
RuHCl(CO)(PPh3)3 as the precatalyst, but in the absence of added
phosphine. To our delight, the ꢀ,γ-unsaturated ketone 3c was
produced in 55% isolated yield, accompanied by 28% isolated yield
of the homoallylic alcohol. Again, predicated on the assumption
that coordinative unsaturation should promote oxidation of the
initially formed homoallylic alcohol, a ruthenium complex pos-
sessing a counterion less strongly coordinating than chloride was
sought. As it is known that RuH2(CO)(PPh3)3 reacts with acids
HX to generate complexes of the type RuHX(CO)(PPh3)3,8 an assay
of acidic additives was undertaken. It was found that coupling of
(7) Concurrent with submission of our work, an aligned study was disclosed
by Ryu: Omura, S.; Fukuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu,
I. J. Am. Chem. Soc. 2008, 130, in press (http://dx.doi.org/10.1021/
ja806929y).
(8) Dobson, A.; Robinson, S. R.; Uttley, M. F. J. Chem. Soc., Dalton Trans.
1974, 370.
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J. AM. CHEM. SOC. VOL. 130, NO. 43, 2008 14121

A R T I C L E S
Shibahara et al.
Scheme 2. (Left) Ru-Catalyzed Coupling of Isoprene to deuterio-1h To Provide Deuterated Ketone 3q and Deuterated Alcohol 4aa and
(Right) A Simplified Catalytic Mechanism Accounting for the Formation of deuterio-3q
a Cited yields are of pure isolated material. See Supporting Information for detailed experimental procedures.
isoprene to p-methoxybenzyl alcohol (1c) performed in the presence
of trifluoroacetic acid (TFA) gives the ꢀ,γ-unsaturated ketone 3c
in 70% isolated yield, accompanied by 12% isolated yield of the
homoallylic alcohol. Here, RuH2(CO)(PPh3)3 presumably reacts
with TFA to generate RuH(O2CCF3)(CO)(PPh3)3. Finally, by
performing the coupling at higher temperature, which should further
enhance the degree of coordinative unsaturation via ligand dis-
sociation, using RuH2(CO)(PPh3)3 (5 mol%) and TFA (5 mol%),
the desired ꢀ,γ-unsaturated ketone 3c was generated in 81% yield
in the absence of any homoallylic alcohol (Table 1, entry 1). Under
these optimized conditions, isoprene couples to alcohols 1a-g to
deliver ꢀ,γ-unsaturated ketones 3a-g in good to excellent isolated
yields. Remarkably, under identical conditions, aldehydes 2a-g
couple to isoprene to provide an identical set of ꢀ,γ-unsaturated
ketones 3a-g in good to excellent isolated yields (Table 1).
To further evaluate the scope of this process, butadiene,
myrcene, and 1,2-dimethylbutadiene were coupled to represen-
tative alcohols 1b, 1c, and 1e under the optimum conditions
cited in Table 1. The corresponding ꢀ,γ-unsaturated ketones
3h-j, 3k-m, and 3n-p were produced in good to excellent
isolated yields. In all cases, complete branch regioselectivity is
observed, and, with the exception of adduct 3j, isomerization
to the conjugated enone is not detected. The efficient formation
of all-carbon quaternary centers, as demonstrated by the
formation of ketones 3n-p, is noteworthy (Table 2).
The coupling of isoprene to deuterio-1h under standard
conditions delivers the ꢀ,γ-unsaturated ketone deuterio-3q,
which incorporates deuterium primarily at the allylic methyl
(34%) and the allylic methine (12%). This pattern of deuterium
incorporation closely matches that obtained in the related
coupling reaction of deuterio-1h to furnish homoallylic alcohol
4a.4a Hence, a mechanism akin to that previously postulated
appears operative. A simplified account is as follows. Ruthenium
hydride Ia hydrometalates the less substituted olefin of isoprene
to deliver the secondary σ-allyl haptomer IIa, which isomerizes
the more stable primary σ-allyl haptomer IIb. Carbonyl addition
from the primary σ-allyl haptomer occurs through a six-centered
transition structure with allylic inversion to deliver ruthenium
alkoxide III, which upon ꢀ-hydride elimination delivers the ꢀ,γ-
unsaturated ketone deuterio-3q along with ruthenium deuteride
Ib. The reaction of Ib with deuterio-1h provides the ruthenium
alkoxide IV, from which ꢀ-hydride is eliminated to provide the
deuterated aldehyde with concomitant regeneration of 1a. Partial
deuteration of the allylic methyl (34%) and the allylic methine
(12%) is attributed to reversible and regio-promiscuous hydro-
metalation of isoprene (Scheme 2).
It should be noted that a conventional hydroacylation mechanism
was proposed by Kondo in closely aligned studies on ruthenium-
catalyzed diene-aldehyde hydroacylation.6e However, the selective
formation of homoallylic alcohols under our previously described
conditions,4a along with the fact that activated ketones such as
isatins couple to dienes to form homoallylic alcohols (albeit in poor
yield) in reactions employing isopropanol as terminal reductant,
suggests that such pathways are not operative under the conditions
we report.
Summary
Through transfer hydrogenative C-C coupling, one may tran-
scend the boundaries imposed by oxidation level and the use of
stoichiometric organometallic reagents. In the specific case of
carbonyl allylation,9 addition may be achieved from the alcohol
or aldehyde oxidation level using acyclic dienes as surrogates to
preformed allyl metal reagents. Further, one may access the product
of carbonyl allylation as the homoallylic alcohol or, as established
in the present study, as the ꢀ,γ-unsaturated ketone. Thus, all
oxidation leVels of substrate (alcohol or aldehyde) and product
(homoallyl alcohol or ꢀ,γ-unsaturated ketone) are accessible.
Future studies are aimed at the development of catalytic systems
applicable to the transfer hydrogenative coupling of petrochemical
and renewable feedstocks, such as R-olefins and ethanol.
Acknowledgment. Acknowledgment is made to Johnson & Johnson,
Merck, the Welch Foundation, the ACS-GCI, the NIH (RO1-GM069445),
and the Donald D. Harrington Faculty Fellows Program for partial support
of this research. Oliver Briel of Umicore is acknowledged for the generous
donation of various ruthenium complexes.
Supporting Information Available: Experimental procedures
and spectral data for all new compounds (1H NMR, 13C NMR,
IR, HRMS). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA805356J
(9) For reviews on enantioselective carbonyl allylation, see: (a) Ramachan-
dran, P. V. Aldrichimica Acta 2002, 35, 23. (b) Kennedy, J. W. J.;
Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732. (c) Denmark, S. E.;
Fu, J. Chem. ReV. 2003, 103, 2763. (d) Yu, C.-M.; Youn, J.; Jung,
H.-K. Bull. Korean Chem. Soc. 2006, 27, 463. (e) Marek, I.; Sklute, G.
Chem. Commun. 2007, 1683. (f) Hall, D. G. Synlett 2007, 1644.
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