Regioselective Hydrohydroxyalkylation of Styrene with Primary Alcohols or Aldehydes via Ruthenium-Catalyzed C?C Bond Forming Transfer Hydrogenation

Article abstract of DOI:10.1002/anie.201609056

Transfer hydrogenative coupling of styrene with primary alcohols using the precatalyst HClRu(CO)(PCy₃)₂modified by AgOTf or HBF₄delivers branched or linear adducts from benzylic or aliphatic alcohols, respectively. Related

Full text of DOI:10.1002/anie.201609056

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Communications
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International Edition: DOI: 10.1002/anie.201609056
German Edition: DOI: 10.1002/ange.201609056
Cross-Coupling
Regioselective Hydrohydroxyalkylation of Styrene with Primary
À
Alcohols or Aldehydes via Ruthenium-Catalyzed C C Bond Forming
Transfer Hydrogenation
Hongde Xiao+, Gang Wang+, and Michael J. Krische*
Abstract: Transfer hydrogenative coupling of styrene with
primary alcohols using the precatalyst HClRu(CO)(PCy3)2
modified by AgOTf or HBF4 delivers branched or linear
adducts from benzylic or aliphatic alcohols, respectively.
Related 2-propanol mediated reductive couplings also are
described.
B
eginning with the work of Butlerov and Grignard, the use
of premetalated C-nucleophiles in carbonyl addition has
opened vast volumes of chemical space and is now a long-
standing cornerstone of chemical synthesis.[1,2] The catalytic
reductive coupling of p-unsaturated reactants with carbonyl
compounds represents an alternative to classical carbonyl
addition that potentially avoids stoichiometric organometallic
reagents and the issues of safety, selectivity and waste that
attend their use.[3,5c] Hydroformylation,[4] the largest volume
application of homogenous catalysis, is a powerful example of
metal-catalyzed reductive coupling that illustrates several
important characteristics of a scalable process: the abilty to
transform abundant chemical feedstocks in a byproduct-free
manner and, less obviously, the importance of utilizing
terminal reductants that are less costly than the coupling
partners themselves. Accordingly, the discovery and develop-
ment of transfer hydrogenative carbonyl additions wherein
alcohols serve dually as reductants and carbonyl precursors
represent a major focus of research in our laboratory
(Figure 1).[5]
Figure 1. Carbonyl addition using non-stabilized carbanions and their
equivalents.
the transfer hydrogenative coupling of styrene with primary
alcohols,[11,12]
a series of experiments were conducted
While the transfer hydrogenative coupling of primary
alcohols with diverse olefin pronucleophiles have been
developed (1,3-dienes[5,7] and 1,3-enynes),[5,8] related reac-
tions of styrene, an abundant petrochemical feedstock (> 25 ꢀ
106 tons/2010)[6] have proven challenging and are restricted to
the use of a-hydroxy-carbonyl compounds,[9] that is, precur-
sors to highly activated vicinal dicarbonyl compounds. We
were inspired by Yiꢁs observation[10] that the addition of
HBF4·OEt2 to the ruthenium-hydride complex HClRu(CO)-
(PCy3)2 dramatically enhances catalytic activity in alkene
hydrogenation[10a] and hydrovinylation.[10b] As corroborated
by Yiꢁs mechanistic studies, HBF4 opens a coordination site at
ruthenium by protonating a tricyclohexylphosphine ligand.[10]
In the hope that such coordinative unsaturation would unlock
using the HClRu(CO)(PCy3)2/HBF4·OEt2 catalyst system
[Scheme 1, Eq. (1)]. Whereas exposure of heptanol 1a to
styrene 2a in the presence of commercially available HClRu-
À
(CO)(PPh3)3 did not lead to products of C C coupling in the
absence or presence of HBF4·OEt2, HClRu(CO)(PCy3)2/
À
HBF4·OEt2 delivered the product of C C bond formation
3a in 73% yield as a single linear regioisomer. In the absence
of HBF4·OEt2, adduct 3a was not formed. Other Brønsted
acids were assayed, but were uniformly less effective. It was
reasoned that cationic ruthenium(II) complexes derived from
HClRu(CO)(PCy3)2 and AgOTf might also display enhanced
catalytic activity due to coordinative unsaturation.[13] Hence,
the coupling of 1a and 2a was attempted using HClRu(CO)-
(PCy3)2 in the presence of AgOTf. Here, the linear regioiso-
mer 3a was not formed, yet a small quantity of the
corresponding branched regioisomer was detected. This
result supported the feasibility of optimizing a catalytic
pathway to branched adducts. While aliphatic alcohols were
recalcitrant partners for branch-selective coupling, the cou-
pling of benzylic alcohol 1g with styrene 2a to form the
branched adduct 3g was amenable to optimization [Scheme 1,
Eq. (2)].
[*] H. Xiao,[+] G. Wang,[+] Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry
105 E 24th St. A5300, Austin, TX 78712-1167 (USA)
E-mail: mkrische@mail.utexas.edu
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609056.
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Table 2: Ruthenium-catalyzed C C coupling of benzylic alcohols 1g–1l
with styrene 2a to form secondary alcohols 3g–3l.[a]
[a] Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further details. [b] HClRu(CO)(PCy3)2
(10 mol%), AgOTf (9 mol%).
Scheme 1. Selected optimization experiments for the ruthenium-cata-
À
lyzed C C coupling of 1-heptanol 1a and benzyl alcohol 1g with
styrene 2a. Yields are of material isolated by silica gel chromatography.
See the Supporting Information for further details.
substituted styrenes bearing either electron withdrawing or
electron releasing groups. The coupling of benzylic alcohols
1g–1l with styrene 2a delivered adducts 3g–3l in good to
excellent yields with complete branched regioselectivity
(Table 2). Here, electron deficient benzylic alcohols were
more efficient partners for coupling. Finally, beyond the
redox-neutral couplings from the alcohol oxidation level, 2-
propanol mediated reductive couplings of styrene 2a with
alkyl- and aryl-substituted aldehydes also are possible, as
illustrated by the conversion of heptanal (dehydro-1a) to the
linear secondary alcohol 3a [Eq. (3)] and the conversion of
dehydro-1g to the branched adduct 3g [Eq. (4)].
The scope of this regioselective transfer hydrogenative
coupling of aliphatic and benzylic alcohols was briefly
surveyed (Tables 1 and 2). The reaction of styrene 2a with
aliphatic alcohols 1a–1 f provided adducts 3a–3 f in good
yield with complete levels of linear regioselectivity (Table 1).
Even alcohols with branching at the b-position, such as
À
cyclohexyl methanol 1e, participate in C C coupling
although higher temperatures (1208C) are required. In
contrast, diminished efficiencies were observed using para-
À
Table 1: Ruthenium-catalyzed C C coupling of aliphatic alcohols 1a–1 f
with styrene 2a to form secondary alcohols 3a-3 f.[a]
To gain insight into the catalytic mechanism, in particular
the origins of linear vs. branched regioselectivity, a series of
deuterium labelling experiments were performed (Scheme 2).
Exposure of deuterio-1a, which is deuterated at the carbinol
position (97% H), to styrene 2a under standard conditions
results in the formation of deuterio-3a [Scheme 2, Eq. (5)].
[a] Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further details. [b] HClRu(CO)(PCy3)2
(10 mol%), HBF4 (15 mol%). [c] styrene 2a (0.4 mL), 1208C. [d] 2-PrOH
(100 mol%).
2
Complete retention of deuterium at the carbinol methine
2
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Scheme 2. General catalytic pathways accounting for linear vs. branched regioselectivity as corroborated by deuterium labelling studies. Yields are
of material isolated by silica gel chromatography. Isotopic composition determined by HRMS, 1H and 2H NMR spectroscopy. See the Supporting
Information for further details.
(96% 2H) is accompanied by complete transfer of deuterium
to the benzylic methylene (> 98% 2H). These data are
consistent with a catalytic mechanism involving carbonyl–
styrene oxidative coupling to form an oxaruthenacycle, which
upon transfer hydrogenolysis mediated by deuterio-1a deliv-
ers deuterio-3a. Here, formation of a benzylic carbon–
ruthenium bond defines the regioselectivity of oxaruthena-
by deuterium labelling studies, linear regioselectivity stems
from catalytic mechanisms involving carbonyl-styrene oxida-
tive coupling to form oxaruthenacyclic intermediates,
whereas branched regioselectivity is a consequence of path-
ways involving styrene hydrometalation. Ongoing studies are
focused on the transfer hydrogenative coupling of alcohols
with other abundant p-unsaturated feedstocks, including a-
olefins.[5c]
À
cycle formation and, hence, the linear regioselectivity of C C
coupling. Although the primary alcohol reactant deuterio-1a
dehydrogenates upon oxaruthenacycle transfer hydrogenol-
ysis, the secondary alcohol product deuterio-3a appears
kinetically unreactive toward dehydrogenation, presumably
due to steric effects. A related deuterium labeling experiment
in which alcohol 1a is reacted with d8-styrene 2a provides
a result consistent with this mechanistic interpretation
[Scheme 2, Eq. (6)]. Exposure of deuterio-1h, to styrene 2a
under standard conditions for the coupling of benzylic
alcohols provides deuterio-3h [Scheme 2, Eq. (7)]. Significant
loss of deuterium is observed at the carbinol methine (61%
2H) and transfer of deuterium to the methyl hydrogen is
Acknowledgements
Acknowledgment is made to the Robert A. Welch Founda-
tion (F-0038) and the NIH (RO1-GM069445) for partial
support of this research.
À
Keywords: C C bond formation · cross-coupling ·
homogenous catalysis · hydrogenation · ruthenium
2
incomplete (11% H). Such loss of deuterium is consistent
with a mechanism involving rapid, reversible hydrogen trans-
fer between deuterio-1h and styrene 2a to form aldehyde–
benzylruthenium pairs in advance of turn-over limiting
carbonyl addition. Here, hydrometalation to form a benzylic
carbon–ruthenium bond defines the branched regioselectivity
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À
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À
[3] Metal Catalyzed Reductive C C Bond Formation, Topics in
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styrene 2a corroborates reversible transfer of hydrogen
between alcohol 1h and d8-styrene 2a [Scheme 2, Eq. (8)].
In summary, we report the first transfer hydrogenative
couplings of styrene with primary alcohols. Remarkably, the
ruthenium precatalyst HClRu(CO)(PCy3)2 delivers branched
or linear adducts from benzylic or aliphatic alcohols when
modified by AgOTf or HBF4, respectively. As corroborated
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Received: September 15, 2016
Published online: && &&, &&&&
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Cross-Coupling
H. Xiao, G. Wang,
M. J. Krische*
&&&& — &&&&
Regioselective Hydrohydroxyalkylation of
Styrene with Primary Alcohols or
À
Aldehydes via Ruthenium-Catalyzed C C
Bond Forming Transfer Hydrogenation
Feedstocks to building blocks: Transfer
hydrogenative coupling of styrene with
primary alcohols using the precatalyst
HClRu(CO)(PCy3)2 modified by AgOTf or
HBF4 delivers branched or linear adducts
from benzylic or aliphatic alcohols,
respectively. Related 2-propanol mediated
reductive couplings also are described.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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