Ruthenium catalyzed hydrohydroxyalkylation of isoprene with heteroaromatic secondary alcohols: Isolation and reversible formation of the putative metallacycle intermediate

Article abstract of DOI:10.1021/ja4087193

Heteroaromatic secondary alcohols react with isoprene to form products of hydrohydroxyalkylation in the presence of ruthenium(0) catalysts generated from Ru₃(CO)₁₂ and tricyclohexylphosphine, enabling direct conversion of secondary to tertiary alcohols in the absence of premetalated reagents or stoichiometric byproducts. The putative oxaruthenacycle intermediate has been isolated and characterized, and reversible metallacycle formation has been demonstrated.

Full text of DOI:10.1021/ja4087193

Communication
pubs.acs.org/JACS
Ruthenium Catalyzed Hydrohydroxyalkylation of Isoprene with
Heteroaromatic Secondary Alcohols: Isolation and Reversible
Formation of the Putative Metallacycle Intermediate
Boyoung Y. Park, T. Patrick Montgomery, Victoria J. Garza, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: Heteroaromatic secondary alcohols react
with isoprene to form products of hydrohydroxyalkylation
in the presence of ruthenium(0) catalysts generated from
Ru3(CO)12 and tricyclohexylphosphine, enabling direct
conversion of secondary to tertiary alcohols in the absence
of premetalated reagents or stoichiometric byproducts.
The putative oxaruthenacycle intermediate has been
isolated and characterized, and reversible metallacycle
formation has been demonstrated.
itrogen-bearing heterocycles are ubiquitous substructures
1
Nin active pharmaceutical ingredients,
with pyridines
appearing most frequently.2 While numerous methods exist for
functionalization of the heteroaromatic nucleus through metal
catalyzed cross-coupling or related C-H activation initiated
processes,3 metal catalyzed C-C couplings that exploit the
LUMO-lowering effect of pyridines and higher azines to enable
functionalization of extranuclear substituents are less common.
oxidative coupling pathways in catalytic hydrogenative and transfer
Figure 1. LUMO-lowering effect of aromatic heterocycles promotes
Selected examples include the rhodium catalyzed addition of
organoboron reagents to 2-vinyl azines4 and 2-alkynyl azines5
as well as reductive aldol and Mannich type couplings of 2-vinyl
azines.6 In rhodium(I) catalyzed hydrogenative C-C couplings
developed in our laboratory,7 the LUMO-lowering effect of
pyridines, which is amplified by their capacity for chelation, was
essential in promoting alkyne-carbonyl oxidative coupling
pathways. Indeed, formation of the transient oxarhodacyclo-
pentene may be viewed as a rhodium(I) mediated reduction
across the alkyne and carbonyl functional groups (Figure 1,
top). In more recent work from our laboratory, a ruthenium(0)
catalyst was identified that promotes analogous transfer
hydrogenative C-C couplings, in which α-hydroxy esters or
1,2-diols engage in oxidative coupling to dienes by way of
transient α-ketoesters or 1,2-diones, respectively.8,9 The
structural homology between vicinal dicarbonyl compounds
and certain heteroaromatic ketones suggested the feasibility of
engaging heteroaromatic secondary alcohols in ruthenium(0)
catalyzed diene hydrohydroxyalkylation. Here, we report that
diverse heteroaromatic secondary alcohols engage in C-C
coupling to dienes in the presence of the ruthenium(0) catalyst
generated from Ru3(CO)12 and tricyclohexylphosphine, PCy3,
enabling direct conversion of secondary to tertiary alcohols.
Further, the putative oxaruthenacycle intermediate has been
isolated and characterized by single crystal X-ray diffraction, 1H
and 13C NMR and IR spectroscopy, and reversible metallacycle
hydrogenative C-C coupling.
formation has been demonstrated through exchange experi-
ments (Figure 1, bottom).
The prospect of adapting conditions previously developed
for diene hydrohydroxyalkylation employing aryl substituted α-
hydroxy esters8 to corresponding reactions of heteroaryl
substituted secondary alcohols was rendered uncertain by the
typically strong chelation of pyridyl ligands to ruthenium. That
is, the catalytic intermediates or reaction products may bind
ruthenium so strongly as to inhibit turnover. Despite this
concern, conditions for highly efficient hydrohydroxyalkylation
were eventually identified (Table 1). Specifically, exposure of
phenyl-(2-pyridyl)-methanol 1a to isoprene 2a in the presence
of Ru3(CO)12 and PCy3 in toluene solvent at 130 °C provided
the product of diene hydrohydroxyalkylation 3a in 90% isolated
yield as a single regioisomer (Table 1, entry 13). As
contamination of PCy3 with the phosphine oxide contributed
to variation in yield, crystallization of commercial PCy3 from
ethanol under an atmosphere of argon was necessary to ensure
for consistent results. Notwithstanding this caveat, these
conditions for ruthenium(0) catalyzed hydrohydroxyalkylation
could be applied across a diverse range of substituted-(2-
Received: August 29, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4087193 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Table 1. Selected Optimization Experiments in the
Ruthenium(0) Catalyzed Hydrohydroxyalkylation of
Isoprene 2a Employing Phenyl-(2-pyridyl)-methanol 1a
Table 2. Direct Conversion of Secondary Alcohols 1a−1l to
Tertiary Alcohols 3a−3l via Ruthenium(0) Catalyzed
a
a
Hydrohydroxyalkylation of Isoprene 2a
entry Ru3(CO)12 (mol %) ligand (mol %) T (°C) time (h) yield 3a
1
2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
0.5
0.5
0.25
0.25
−
130
130
130
130
130
140
120
130
130
130
130
130
130
130
130
130
130
130
24
24
24
24
24
24
24
24
24
24
24
24
18
12
24
48
24
48
49%
52%
50%
45%
85%
75%
50%
90%
87%
76%
72%
91%
90%
81%
75%
88%
42%
84%
bipy (6.0)
terpy (6.0)
phen (6.0)
PCy3 (12.0)
PCy3 (12.0)
PCy3 (12.0)
PCy3 (10.0)
PCy3 (8.0)
PCy3 (6.0)
PCy3 (4.0)
PCy3 (5.0)
PCy3 (5.0)
PCy3 (5.0)
PCy3 (2.5)
PCy3 (2.5)
PCy3 (1.25)
PCy3 (1.25)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a
Yields are of material isolated by silica gel chromatography. See
Supporting Information for further details.
pyridyl)-methanols 1a−1l (Table 2). This includes electro-
neutral (1a), electron-deficient (1b−1e) and electron-rich (1f,
1g) aryl-(2-pyridyl)-methanols as well as heteroaryl-(2-
pyridyl)-methanols (1h, 1i) and alkyl-(2-pyridyl)-methanols
(1j−1l). Beyond the 2-pyridyl group, it was found that other
heteroaryl substituted benzyl alcohols engage in efficient diene
hydrohydroxyalkylation, as illustrated in reactions of the
indicated pyrimidine, benzoxazole, and thiazole containing
secondary alcohols 1m−1o, respectively (Table 3). It was also
found that the products of C-C coupling are accessible via
ketone-diene reductive coupling employing isopropanol as
terminal reductant, as demonstrated in the conversion of oxo-1a
to tertiary alcohol 3a (eq 1).
a
Yields are of material isolated by silica gel chromatography.
Ru3(CO)12 (2 mol %), PCy3 (10 mol %), 24 h. Ru3(CO)12 (2
b
c
mol %), PCy3 (10 mol %), 48 h. See Supporting Information for
further details.
Table 3. Direct Conversion of Secondary Alcohols 1m−1o to
Tertiary Alcohols 3m−3o via Ruthenium(0) Catalyzed
Hydrohydroxyalkylation of Isoprene 2a
a
Based on our prior studies of the ruthenium(0) catalyzed
hydrohydroxyalkylation of dienes employing α-hydroxy esters,8
a catalytic mechanism involving diene-carbonyl oxidative
coupling was proposed (Scheme 1). A discrete monometallic
ruthenium(0) complex should be formed from the combination
of Ru3(CO)12 and tricyclohexylphosphine.10 To initiate
oxidative coupling pathways, phenyl-(2-pyridyl)-methanol 1a
must oxidize to form 2-benzoylpyridine oxo-1a. Such
Ru3(CO)12 catalyzed alcohol oxidations employing olefins
and alkynes as hydrogen acceptors are known,11 as are related
Ru3(CO)12 catalyzed transfer hydrogenations of ketones12 and
aminations of secondary alcohols, which proceed by way of
a
Yields are of material isolated by silica gel chromatography. See
b
c
Supporting Information for further details. 120 °C. Ru3(CO)12 (2
mol %), PCy3 (10 mol %), 24 h.
transient ketones.13 Diene-carbonyl oxidative coupling14
involving 2-benzoylpyridine oxo-1a and isoprene 2a delivers
B
dx.doi.org/10.1021/ja4087193 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Scheme 1. Postulated Catalytic Mechanism Involving Diene-Carbonyl Oxidative Coupling
secondary σ-allyl oxaruthenacycle I, which exists in equilibrium
with the indicated haptomers. Related oxidative couplings
mediated by ruthenium(0) complexes derived from Ru3(CO)12
find precedent in Pauson-Khand-type reactions of 1,2-diones
and alkenes, as described by Chatani and Murai.15 The
proposed diene-carbonyl oxidative coupling pathway also
finds precedent in our prior studies on the prenylation of α-
hydroxy esters.8a Protonation of the primary σ-allyl oxaruthena-
cycle I by phenyl-(2-pyridyl)-methanol 1a delivers the
ruthenium alkoxide II, which suffers β-hydride elimination to
generate the ruthenium hydride III and 2-benzoylpyridine oxo-
1a. Finally, C-H reductive elimination delivers the product of
hydrohydroxyalkylation 3a and the starting ruthenium(0)
complex to complete the catalytic cycle. Reversible pyridine
coordination is probable at the stage of each catalytic
intermediate.16
Figure 2. Single crystal X-ray diffraction data of the oxaruthenacycle
Ia-π-allyl derived from Ru3(CO)12, 2-benzoylpyridine oxo-1a, and
isoprene 2a. Displacement ellipsoids are scaled to the 50% probability
level. Hydrogen atoms have been omitted for clarity.
To corroborate the proposed mechanism, an attempt to
isolate the allyl-oxaruthenacycle I was made. Toward this end,
Ru3(CO)12 (33 mol %), 2-benzoylpyridine oxo-1a (100 mol
%), and isoprene 2a (200 mol %) were combined in toluene
and heated to 130 °C for 1 h (eq 2). After cooling, vapor-vapor
diffusion with pentane induced crystallization. To our delight,
single crystal X-ray diffraction revealed the oxaruthenacycle Ia-
π-allyl (Figure 2).14 In the crystal structure, there is a water
molecule hydrogen-bonded to the alkoxide, suggestive of the
protonation of I-1o-σ-allyl to form II (Scheme 1). This complex
was relatively stable and could be isolated from the crude
reaction by conventional silica gel chromatography, albeit with
significant loss of material. In contrast, the oxaruthenacycle Ib-
π-allyl, prepared from butadiene 2b, was significantly more
robust and could be isolated by silica gel chromatography in
42% yield. To corroborate the catalytic competence of these
oxaruthenacycles, phenyl-(2-pyridyl)-methanol 1a was exposed
to isoprene 2a in the presence of Ib-π-allyl (6 mol %) and PCy3
(10 mol %). The product of hydrohydroxyalkylation 3a was
isolated in 77% yield (eq 3).
Figure 3. Conversion of Ib-π-allyl to Ia-π-allyl corroborates reversible
formation of the oxaruthenacycle intermediate.
Although complexes Ia-π-allyl and Ib-π-allyl could exist as
diastereomeric mixtures, especially given the fluxional nature of
1
such π-allyls, a single stereoisomer is observed by H and 13C
exposure of Ib-π-allyl (100 mol %) to isoprene 2a (88 mol %)
in benzene-d6 at 100 °C, the gradual formation of Ia-π-allyl
could clearly be observed by 1H NMR (Figure 3). After 6 h, no
NMR. This fact facilitated exchange experiments aimed at
probing the reversibility of oxaruthenacycle formation.14 Upon
C
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Journal of the American Chemical Society
Communication
(6) (a) Komanduri, V.; Grant, C. D.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 12592. (b) Saxena, A.; Choi, B.; Lam, H. W. J. Am. Chem.
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(7) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448.
(8) (a) Leung, J. C.; Geary, L. M.; Chen, T.-Y.; Zbieg, J. R.; Krische,
M. J. J. Am. Chem. Soc. 2012, 134, 15700. (b) Chen, T.-Y.; Krische, M.
J. Org. Lett. 2013, 15, 2994. (c) Geary, L. M.; Glasspoole, B. W.; Kim,
M. M.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 3796.
(9) Recent reviews on C-C bond forming hydrogenation and transfer
hydrogenation: (a) Hassan, A.; Krische, M. J. Org. Proc. Res. Devel.
2011, 15, 1236. (b) Moran, J.; Krische, M. J. Pure Appl. Chem. 2012,
84, 1729.
(10) Exposure of Ru3(CO)12 to dppe in benzene solvent provides
Ru(CO)3(dppe): Sanchez-Delgado, R. A.; Bradley, J. S.; Wilkinson, G.
J. Chem. Soc., Dalton Trans. 1976, 399.
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further conversion was observed suggesting equilibrium was
established. These data suggest that the development of
enantioselective variants of this process may require especially
high kinetic stereoselectivities to offset erosion of enantiomeric
excess stemming from reversible C-C bond formation. Studies
aimed at probing this question are ongoing and will be reported
in due course.
In summary, we report the ruthenium(0) catalyzed hydro-
hydroxyalkylation of dienes with heteroaryl substituted
secondary alcohols. This process enables direct conversion of
secondary to tertiary alcohols in the absence of stoichiometric
byproducts or premetalated reagents. The oxaruthenacycle
postulated as a key intermediate has, for the first time, been
isolated and characterized. Furthermore, its reversible for-
mation has been demonstrated through exchange experiments.
These studies provide deeper insight into the structural-
interactional features of the catalytic system, which will
accelerate the development of improved catalysts for the
hydrohydroxyalkylation of π-unsaturated reactants with alco-
hols.
(13) (a) Baehn, S.; Tillack, A.; Imm, S.; Mevius, K.; Michalik, D.;
Hollmann, D.; Neubert, L.; Beller, M. ChemSusChem 2009, 2, 551.
(b) Pingen, D.; Muller, C.; Vogt, D. Angew. Chem., Int. Ed. 2010, 49,
̈
8130. (c) Zhang, M.; Imm, S.; Bahn, S.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2011, 50, 11197.
(14) Oxidative coupling occurs reversibly in stoichiometric reactions
of nickel(0) with dienes and aldehydes to provide isolable π-
allylalkoxynickel(II) complexes that have been characterized by single
crystal X-ray diffraction analysis: Ogoshi, S.; Tonomori, K.-i.; Oka, M.-
a.; Kurosawa, H. J. Am. Chem. Soc. 2006, 128, 7077.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectral data. This material is available
(15) (a) Chatani, N.; Tobisu, M.; Asaumi, T.; Fukumoto, Y.; Murai,
S. J. Am. Chem. Soc. 1999, 121, 7160. (b) Tobisu, M.; Chatani, N.;
Asaumi, T.; Amako, K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 2000, 122, 12663.
(16) Under standard conditions, the 3- and 4-substituted constitu-
tional isomers of phenyl-(2-pyridyl)-methanol 1a dehydrogenate but
do not participate in C-C coupling, suggesting that chelation, which
amplifies the LUMO lowering effect of the pyridine, is a prerequisite to
C-C coupling in transformations of this type.
■
S
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research.
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