Direct ruthenium-catalyzed C-C coupling of ethanol: Diene hydro-hydroxyethylation to form all-carbon quaternary centers

Article abstract of DOI:10.1021/ol101077v

(Figure presented) Under ruthenium-catalyzed transfer hydrogenation conditions, direct C-C coupling of ethanol and 2-substituted dienes occurs to furnish products of hydro-hydroxyethylation: anti-configured neopentyl homoallylic alcohols. Identical adduct

Full text of DOI:10.1021/ol101077v

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2844-2846
Direct Ruthenium-Catalyzed C-C Coupling
of Ethanol: Diene Hydro-hydroxyethylation
To Form All-Carbon Quaternary Centers
Hoon Han and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received May 11, 2010
ABSTRACT
Under ruthenium-catalyzed transfer hydrogenation conditions, direct C-C coupling of ethanol and 2-substituted dienes occurs to furnish
products of hydro-hydroxyethylation: anti-configured neopentyl homoallylic alcohols. Identical adducts are generated from acetaldehyde under
related conditions employing isopropanol as reductant.
The majority of chemical commodities are made from rapidly
depleting petrochemical feedstocks. The development of
byproduct-free catalytic C-C bond-forming processes that
exploit abundant, renewable resources would assist in
defining a sustainable paradigm for chemical production.1
With annual U.S. production now exceeding 10 billion
gallons (2009),2 ethanol is vastly abundant, yet its direct use
as a C2 building block in homogeneous catalytic C-C
coupling is largely unexplored.3 Here, as part of a broad
effort toward hydrogen-mediated C-C bond formations
beyond hydroformylation,4 we report the direct C-C cou-
pling of ethanol and 2-substituted dienes to furnish products
of hydroxyethylation: a ruthenium-catalyzed C-C bond-
forming transfer hydrogenation (Scheme 1). This method
enables diastereoselective formation of all-carbon quaternary
centers under catalytic conditions in the absence of premeta-
lated nucleophiles or resulting stoichiometric metallic byprod-
ucts. To our knowledge, this process, which enables direct,
byproduct-free access to anti-configured neopentyl homo-
allylic alcohols, has no stereoselective counterpart in con-
ventional allylmetal chemistry.5
In prior studies from our laboratory it was found that iridium
and ruthenium catalysts promote hydrogen exchange between
alcohols and π-unsaturated reactants to generate nucleophile-
electrophile pairs that engage in byproduct-free C-C coupling.4
This new pattern of reactivity availed the opportunity to explore
the direct activation of renewable alcohols, such as methanol
and ethanol, as C1 and C2 building blocks in catalytic C-C
couplings to π-unsaturated reactants. Our initial efforts toward
(1) For selected reviews on sustainable chemical synthesis, see: (a)
Anastas, P.; Eghbali, N. Chem. Soc. ReV. 2010, 39, 301. (b) Sheldon, R. A.
Green Chem. 2007, 9, 1273. (c) Clark, J. H. J. Chem. Technol. Biotechnol.
2007, 82, 603. (d) Lange, J.-P. ChemSusChem 2009, 2, 587.
(2) Renewable Fuels Association (RFA): http://www.ethanolrfa.org/
(accessed March 1, 2010).
(4) For selected reviews on C-C bond-forming hydrogenation and
transfer hydrogenation, see: (a) Shibahara, F.; Krische, M. J. Chem. Lett.
2008, 37, 1102. (b) Patman, R. L.; Bower, J. F.; Kim, I. S.; Krische, M. J.
Aldrichimica Acta 2008, 41, 95. (c) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34.
(3) Ethanol carbonylation to form propionic acid under the conditions
of homogenous catalysis has been described: (a) Patil, R. P.; Kelkar, A. A.;
Chaudhari, R. V. J. Mol. Catal. 1988, 47, 87. (b) Ubale, R. S.; Kelkar,
A. A.; Chaudhari, R. V. J. Mol. Catal. A: Chem. 1997, 118, 9.
(5) For isolated examples of stereoselective carbonyl allylboration to
furnish syn-configured neopentyl homoallylic alcohols, see: Ely, R. J.;
Morken, J. P. J. Am. Chem. Soc. 2010, 132, 2534, and ref 13.
10.1021/ol101077v  2010 American Chemical Society
Published on Web 05/21/2010

by silica gel chromatography. Under these conditions, ethanol
was coupled to dienes 1a-1i. With the exception of myrcene
1f and diene 1h, constitutional isomers 2 are the major products
formed. Diastereoselectivities for adducts 2a-2i range from 4:1
to >20:1 in favor of the indicated anti-isomer (Scheme 2). The
Scheme 1
.
Carbonyl Addition via Ruthenium-Catalyzed C-C
Coupling of Dienesa
Scheme 2
.
Ruthenium-Catalyzed Coupling of Ethanol to
2-Substituted Dienes 1a-1ia
a For oxidative ruthenium-catalyzed diene-alcohol C-C coupling to form
ꢀ,γ-enones, see ref 7c.
direct activation of methanol proved unfruitful, likely because
methanol dehydrogenation is energetically demanding.6 Indeed,
whereas attempted C-C couplings of methanol fail, corre-
sponding reactions of paraformaldehyde employing isopropanol
as terminal reductant proceed readily, as demonstrated in
ruthenium-catalyzed hydroxymethylations of 1,1-disubstituted
allenes and 2-substituted dienes.7b,d As ethanol dehydrogena-
tion occurs more readily than the dehydrogenation of
methanol (∆H ) +68 vs +84 kJ/mol, respectively),6 the
direct activation of ethanol in couplings to 2-substituted diene
1c was explored.7-11
a Cited yields are of material isolated by silica gel chromatography.
Conditions: (a) 80 °C, 20 h; (b) 90 °C, 20 h; (c) 90 °C, 40 h; (d) 100 °C,
40 h. See Supporting Information for detailed experimental procedures.
Using RuH(O2CC7F15)(CO)(dppb)(PPh3) as catalyst,12
a
stereochemical assignment of adducts 2a-2i is tentatively
assigned in analogy to that determined for the product obtained
from the coupling of benzyl alcohol to myrcene 1f.13
complex that was effective in related diene-formaldehyde
couplings,7b diene 1c was converted to the C-C coupling
product 2c and 3c in 78% isolated yield as a 6:1 mixture of
constitutional isomers. Notably, 2c appears as a single diaste-
reomer. Thus, C-C coupling occurs predominantly at the
2-position of the diene, resulting in diastereoselective formation
of an all-carbon quaternary center. In most cases, regioisomers
2c and 3c differ substantially in polarity and are easily separated
For most C-C bond-forming transfer hydrogenations
developed in our laboratory,4,7 carbonyl addition is possible
from the alcohol or aldehyde oxidation level. In the latter
case, a stoichiometric reductant such as isopropanol or formic
acid is required. Accordingly, it was found that the reductive
coupling of dienes 1a-1i to acetaldehyde can be conducted
using the same ruthenium catalyst under essentially identical
conditions employing isopropanol/acetone (1:1) as solvent
to furnish an equivalent set of adducts 2a-2i with similar
trends in regio- and diastereoselectivity (Scheme 3).
(6) For methanol dehydrogenation, DH ) +84 kJ/mol. For ethanol
dehydrogenation, DH ) +68 kJ/mol: (a) Qian, M.; Liauw, M. A.; Emig,
G. Appl. Catal. A 2003, 238, 211. (b) Lin, W.-H.; Chang, H.-F. Catal. Today
2004, 97, 181.
(7) For ruthenium catalyzed C-C bond-forming transfer hydrogenation
developed in our laboratory, see the following. Dienes: (a) Shibahara, F.;
Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6338. (b) Smejkal,
T.; Han, H.; Breit, B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 10366.
(c) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 14120. Allenes: (d) Ngai, M.-Y.; Skucas, E.; Krische, M. J. Org. Lett.
2008, 10, 2705. (e) Skucas, E.; Zbieg, J. R.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 5054. (f) Grant, C. D.; Krische, M. J. Org. Lett. 2009, 11,
4485. (g) Zbieg, J. R.; McInturff, E. L. Org. Lett. 2010, published ASAP,
DOI:, 10.1021/ol1007235. (h) Alkynes:; Patman, R. L.; Chaulagain, M. R.;
Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066. (i)
Williams, V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J. Tetrahedron
2009, 65, 5024. (j) Enynes: Patman, R. L.; Williams, V. M.; Bower, J. F.;
(8) For related catalytic C-C couplings that occur by way of nucleophilic
ruthenium p-allyls, see: (a) Tsuji, Y.; Mukai, T.; Kondo, T.; Watanabe, Y.
J. Organomet. Chem. 1989, 369, C51. (b) Kondo, T.; Ono, H.; Satake, N.;
Mitsudo, T.-a.; Watanabe, Y. Organometallics 1995, 14, 1945. (c) Kondo,
T.; Hiraishi, N.; Morisaki, Y.; Wada, K.; Watanabe, Y.; Mitsudo, T.-a.
Organometallics 1998, 17, 2131. (d) Yu, C.-M.; Lee, S.; Hong, Y.-T.; Yoon,
S.-K. Tetrahedron Lett. 2004, 45, 6557. (e) Omura, S.; Fukuyama, T.;
Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094.
(9) For selected reviews of ruthenium-catalyzed C-C coupling beyond
olefin metathesis, see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem.
ReV. 2001, 101, 2067. (b) Kondo, T.; Mitsudo, T.-a. Curr. Org. Chem.
2002, 6, 1163. (c) De´rien, S.; Monnier, F.; Dixneuf, P. H. Top. Organomet.
Chem. 2004, 11, 1.
Krische, M. J. Angew. Chem., Int. Ed. 2008, 47, 5220
.
Org. Lett., Vol. 12, No. 12, 2010
2845

transition state for carbonyl addition from π-allyl A by way of
the (Z)-σ-allyl A is likely disfavored because of the pseudoaxial
orientation of the R-substituent. In contrast to all other pathways,
carbonyl addition from the (E)-σ-allyl A involves pseudoequa-
torial placement of the R-substituent, which directs preferential
formation of anti-isomers 2. Only through rapid interconversion
of π-allyls and σ-allyls A and B can the minimum energy
pathway en route to anti-isomers 2 be traversed (Scheme 4).
Scheme 3
.
Ruthenium-Catalyzed Coupling of Acetaldehyde to
2-Substituted Dienes 1a-1ia
Scheme 4. Regio- and Diastereoselective
Hydro-hydroxyethylation via Selective Carbonyl Addition from
Isomeric Ruthenium π-Allyl and σ-Allyl Intermediates
a Conditions: (a) 90 °C, 20 h; (b) 100 °C, 40 h. Otherwise, as described
in Table 1.
Our collective data reveal that regioselectivity varies in
response to steric features of the aldehyde, with small aldehydes
such as formaldehyde7b delivering the greatest proportion of
isomers 2. These data are consistent with a Curtin-Hammett
scenario involving rapid interconversion of isomeric π-allyls
A and B.14 Here, the relative energies of the competing
transition structures for carbonyl addition determine regiose-
lectivity. If one presumes a chairlike transition structure,
additions from π-allyl B by way of (E)- and (Z)-σ-allyls B are
likely disfavored as a result of strain arising from nonbonded
interactions between the pseudoaxially oriented R-substituent
with groups attached to the ruthenium center. Similarly, the
In summary, we report a direct catalytic C-C coupling
of ethanol, an abundant, renewable alcohol, which results
in the diastereoselective formation of anti-configured ho-
moallylic alcohols possessing all-carbon quaternary centers.
These studies represent an important step toward the long-
term objective of defining catalytic systems for the byprod-
uct-free C-C coupling of abundant alcohols (methanol and
ethanol) to R-olefins.15 Future studies will focus on the
development related hydro-hydroxyalkylations, including
enantioselective variants of the process described herein.
(10) For catalytic intermolecular diene-aldehyde reductive coupling, see:
(a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998,
120, 4033. (b) Takimoto, M.; Hiraga, Y.; Sato, Y.; Mori, M. Tetrahedron
Lett. 1998, 39, 4543. (c) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.;
Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38,
397. (d) Kimura, M.; Shibata, K.; Koudahashi, Y.; Tamaru, Y. Tetrahedron
Lett. 2000, 41, 6789. (e) Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y.
Angew. Chem., Int. Ed. 2001, 40, 3600. (f) Loh, T.-P.; Song, H.-Y.; Zhou,
Y. Org. Lett. 2002, 4, 2715. (g) Sato, Y.; Sawaki, R.; Saito, N.; Mori, M.
J. Org. Chem. 2002, 67, 656. (h) Jang, H.-Y.; Huddleston, R. R.; Krische,
M. J. Angew. Chem., Int. Ed. 2003, 42, 4074. (i) Bareille, L.; Le Gendre,
P.; Mo¨ıse, C. Chem. Commun. 2005, 775. (j) Kimura, M.; Ezoe, A.; Mori,
M.; Iwata, K.; Tamaru, Y. J. Am. Chem. Soc. 2006, 128, 8559. (k) Yang,
Y.; Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, L.-X.; Zhou, Q.-L. J. Am.
Chem. Soc. 2007, 129, 2248. (l) Sato, Y.; Hinata, Y.; Seki, R.; Oonishi,
Y.; Saito, N. Org. Lett. 2007, 9, 5597.
Acknowledgment. The authors thank the Robert A. Welch
Foundation and the NIH-NIGMS (RO1-GM069445) for
partial support of this research.
Supporting Information Available: 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.
OL101077V
(11) For a recent review encompassing nickel-catalyzed diene-aldehyde
reductive coupling, see: Kimuara, M.; Tamaru, Y. Top. Curr. Chem. 2007,
279, 173.
(14) For isomerization of ruthenium p-allyls, see: Xue, P.; Bi, S.; Sung,
H. H. Y.; Williams, I. D.; Lin, Z.; Jia, G. Organometallics 2004, 23, 4735,
and ref 7e.
(12) RuH(O2CC7F15)(CO)(dppb)(PPh3) is prepared in situ from
RuH2(CO)(PPh3)3, HO2CC7F15, and dppb: Dobson, A.; Robinson, S. R.;
Uttley, M. F. J. Chem. Soc., Dalton Trans. 1974, 370.
(15) For related amine-mediated “hydro-aminoalkylation” of R-olefins,
see: (a) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 14940.
(b) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 6690, and
references therein.
(13) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
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