Synthesis of 2-hydroxymethyl ketones by ruthenium hydride-catalyzed cross-coupling reaction of α,β-unsaturated aldehydes with primary alcohols

Article abstract of DOI:10.1021/ol902289r

Chemical Equation Presented The cross-coupling reaction of α,β-unsaturated aldehydes with primary alcohols to give 2-hydroxymethyl ketones was achieved using RuHCl(CO)(PPh₃₎₃ as a catalyst. This atom-economical reaction is likely to proceed via the hydroruthenation of α,β-unsaturated aldehydes followed by an aldol reaction of the resultant enolates with aldehydes to give r-formylated ketones, which undergo transfer hydrogenation with primary alcohols leading to α-hydroxymethyl ketones. The reduction step can generate aldehydes, participating in the next catalytic cycle.

Full text of DOI:10.1021/ol902289r

ORGANIC
LETTERS
2010
Vol. 12, No. 1
1-3
Synthesis of 2-Hydroxymethyl Ketones
by Ruthenium Hydride-Catalyzed
Cross-Coupling Reaction of
r,ꢀ-Unsaturated Aldehydes with Primary
Alcohols
Aure´lien Denichoux, Takahide Fukuyama, Takashi Doi, Jiro Horiguchi, and
Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received October 3, 2009
ABSTRACT
The cross-coupling reaction of r,ꢀ-unsaturated aldehydes with primary alcohols to give 2-hydroxymethyl ketones was achieved using
RuHCl(CO)(PPh3)3 as a catalyst. This atom-economical reaction is likely to proceed via the hydroruthenation of r,ꢀ-unsaturated aldehydes
followed by an aldol reaction of the resultant enolates with aldehydes to give r-formylated ketones, which undergo transfer hydrogenation
with primary alcohols leading to r-hydroxymethyl ketones. The reduction step can generate aldehydes, participating in the next catalytic
cycle.
Development of new catalytic coupling processes accom-
panied with atom economy is highly desirable in organic
synthesis.1,2 In this regard, we are interested in the potentials
of ruthenium hydride-catalyzed bond forming reactions in
conjunction with the use of readily available oxygenated
substrates, such as alcohols, ketones, and aldehydes.3-5
Recently, we have reported that dimerization of primary
unsaturated alcohols4a and reductive dimerization of R,ꢀ-
unsaturated aldehydes5 were effectively catalyzed by RuH-
Cl(CO)(PPh3)3. In the latter homocoupling reaction of enals,
secondary alcohols such as isopropanol act as a hydrogen
source, which is converted to acetone, an inert compound
in the system (Scheme 1, eq 1). Since the pioneering work
of Gregorio and co-workers on catalytic dimerization of
primary alcohols,6 many researchers have pursued the
potential of cross-coupling reactions of primary alcohols via
transfer hydrogenation.7 In this regard, recent work by
(1) Beller, M.; Bolm, C., Eds. Transition Metals for Organic Synthesis;
Wiley-VCH: Weinheim, 1998; Vols. 1 and 2. (b) Cornils, B.; Herrmann,
A. W., Eds. Applied Homogeneous Catalysis with Organometallic Com-
pounds; VCH: Weinheim, 1996; Vol. 1 and 2
.
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M.; Frederiksen, M. U.;
Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630
(4) For our previous work on the use of the ruthenium hydride catalyst,
see: (a) Doi, T.; Fukuyama, T.; Minamino, S.; Husson, G.; Ryu, I. Chem.
Commun. 2006, 1875. (b) Doi, T.; Fukuyama, T.; Horiguchi, J.; Okamura,
T.; Ryu, I. Synlett 2006, 721. (c) Fukuyama, T.; Doi, T.; Minamino, S.;
Omura, S.; Ryu, I. Angew. Chem., Int. Ed. 2007, 46, 5559. (d) Omura, S.;
Fukuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc.
2008, 130, 14094. (e) Omura, S.; Fukuyama, T.; Murakami, Y.; Okamoto,
H.; Ryu, I. Chem. Commun. 2009, 6741.
.
(3) For selected reviews of ruthenium-catalyzed C-C coupling, see: (a)
Bruneau, C.; Dixneuf, H. P., Eds. Ruthenium Catalysts and Fine Chemisty;
Springer-Verlag: Berlin, Heidelberg, 2004. (b) Naota, T.; Takaya, H.;
Murahashi, S.-I. Chem. ReV. 1998, 98, 2599. (c) Trost, B. M.; Toste, F. D.;
Pinkerton, A. B. Chem. ReV. 2001, 101, 2067. (d) Kondo, T; Mitsudo, T.-
a. Curr. Org. Chem. 2002, 6, 1163. (e) Trost, B. M.; Frederiksen, M. U.;
Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630. (f) Shibahara, F.;
Krische, M. J. Chem. Lett. 2008, 37, 1102.
(5) Doi, T.; Fukuyama, T.; Minamino, S.; Ryu, I. Synlett 2006, 3013.
(6) Gregorio, G.; Pregaglia, G. F.; Ugo, R. J. Orgnomet. Chem. 1972,
37, 385.
10.1021/ol902289r  2010 American Chemical Society
Published on Web 11/25/2009

Krische and co-workers that demonstrates Ru- and Ir-
catalyzed cross-coupling of alcohols with unsaturated C-C
double and triple bonds is noteworthy.8 We thought that if
primary alcohols, such as benzyl alcohol, are employed as a
hydrogen source, the resulting aldehydes would act as a
coupling partner to give cross-coupling products (Scheme
1, eq 2). We report herein the Ru-H-catalyzed atom-
economical cross-coupling reaction of R,ꢀ-unsaturated al-
dehydes with primary alcohols leading to R-hydroxymethyl
ketones.
Table 1. Cross-Coupling Reaction of R,ꢀ-Unsaturated
Aldehydes with Benzylic Alcoholsa
Scheme 1. Ru-H Catalyzed Coupling Reactions of Enals
When a benzene solution of benzyl alcohol (1a, 1.2 equiv)
and 2-hexenal (2a) in the presence of RuHCl(CO)(PPh3)3
(10 mol %) was heated under reflux for 2 h (Procedure A,
Scheme 2), 2-hydroxymethyl-1-phenyl-1-hexanone (3a) was
obtained in 40% yield. In this case, a significant amount of
dimer derived by reductive coupling of 2a was formed as
byproduct (3a/dimer ) 5/1). To suppress the undesired
dimerization course, 2a was added slowly using a syringe
pump over the period of 1 h, then the resulting mixture was
stirred for another 1 h (Procedure B). In this case, the desired
3a was obtained in 61% yield. Since in the initial stage of
the reaction 2a was consumed by transfer hydrogenation to
produce benzaldehyde, we decided to add a small amount
of aldehyde beforehand (Procedure C). This caused further
improvement of the yield of 3a up to 72%.
Scheme 2. Optimization of the Reaction Conditions
a Conditions: 1 (1.2 equiv), 2 (0.8 mmol), corresponding aldehyde (10
mol %), RuHCl(CO)(PPh3)3 (0.08 mmol), benzene (4 mL). A benzene
solution of 1 (5 mL) was added using a syringe pump over the period of
1 h, then the mixture was heated at reflux for 1 h. b Isolated yield after
flash chromatography on SiO2. c A benzene solution of 1g and 2a was added
over the period of 1 h.
Having an optimized procedure C in hand, we then
examined the generality of the present cross-coupling reaction
with various alcohols and enals (Table 1). The reactions of
2-hexenal (2a) with several benzylic alcohols, having an
2
Org. Lett., Vol. 12, No. 1, 2010

electron-donating substituent or an electron-withdrawing
substituent, gave the 2-hydroxymethyl ketone 3 in good
yields (entries 1-6). The reaction also worked well with
alcohols having heteroaromatic rings such as 2-thiophen-
emethanol (1g) and 2-furanmethanol (1h) (entries 7 and 8).
In the case of the alcohol 1g, transfer hydrogenation of 1g
and 2a leading to 2-thiophenecarboxyaldehyde and 1-hexanol
was fast with the procedure C. Thus, syringe pump addition
of a mixture solution of 1g and 2a was examined, giving
the desired coupling product 3g in good yield. Disubstituted
enal 2c also reacted with 1a, whereas the yield of 3j was
rather modest (entry 10). Enals having an aromatic substitu-
ent at the ꢀ-position, such as 2d and 2e, gave the corre-
sponding 2-hydroxymethyl ketones in good yields (entries
11 and 12). The reaction of nonbenzylic type alcohol 1i also
gave the coupling 3m in 30%, which requires further efforts
for yield optimization.
A possible mechanism for this enal/alcohol coupling
reaction is shown in Scheme 3 with an example of the
reaction of 1a and 2a. The hydroruthenation of 2a would
give ruthenium enolate A,9,10 which then undergoes aldol
reaction with benzaldehyde.11,12 ꢀ-Elimination from the
resulting aldol adduct B would lead to the keto aldehyde C.
Finally, transfer hydrogenation13 between the aldehyde
moiety of C and benzyl alcohol (1a) gives 2-hydroxymethyl
ketone 3a and benzaldehyde which then reacts with another
molecule of ruthenium enolate A, creating a catalytic cycle.
(7) For reviews, 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. AdV. Synth. Catal. 2007, 349, 1555 For recent examples.
(c) Cho, S. K.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J. Org. Chem. 2001,
66, 9020. (d) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.;
Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72. (e) Fujita, K.; Asai, C.;
Yamaguchi, T.; Hanasaka, F.; Yamaguchi, R. Org. Lett. 2005, 7, 4017. (f)
Cho, C. S. J. Mol. Catal. A: Chem. 2005, 240, 55. (g) Mart´ınez, R.; Ramo´n,
D. J.; Yus, M. Tetrahedron 2006, 62, 8988. (h) Lo¨fberg, C.; Grigg, R.;
Whittaker, M. A.; Keep, A.; Derrick, A. J. Org. Chem. 2006, 71, 8023. (i)
Hall, M. I.; Pridmore, S. J.; Williams, J. M. J. AdV. Synth. Catal 2008,
350, 1975. (j) Pridmore, S. J; Williams, J. M. J. Tetrahedron Lett. 2008,
49, 7413. (k) Jensen, T.; Madsen, R. J. Org. Chem. 2009, 74, 3990. (l)
Grigg, R.; Lofberg, C.; Whitney, S.; Sridharan, V.; Keep, A.; Derrick, A.
Tetrahedron 2009, 65, 849. (m) Shimizu, K.; Sato, R.; Satsuma, A. Angew.
Chem., Int. Ed. 2009, 48, 3982.
Scheme 3. Possible Mechanism for the Coupling of 1a and 2a
(8) (a) Bower, J. F.; Skucas, E.; Patma, R. L.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 15134. (b) Shibahara, F.; Bower, J. F.; Krische,
M. J. J. Am. Chem. Soc. 2008, 130, 6338. Also see recent reviews: (c)
Bower, J. F.; Kim, I. S.; Patman, R. L; Krische, M. J. Angew. Chem., Int.
Ed 2009, 48, 34, and ref 3f and references therein.
(9) For studies on ruthenium enolate complexes, see: (a) Hartwig, J. F.;
Andersen, R. A.; Bergman, G. B. J. Am. Chem. Soc. 1990, 112, 5670. (b)
Hartwig, J. F.; Bergman, R. G.; Andersen, R. A. Organometallics 1991,
10, 3326. (c) Tasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics
1996, 15, 2852.
(10) For examples of catalytic transformations based on ruthenium
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1988, 340, C5. (b) Sato, S.; Matsuda, I.; Shibata, M. J. Organomet. Chem.
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M.; Cre´visy, C.; Gre´e, R. Tetrahedron Lett. 2001, 42, 3069.
In summary, we have shown that a novel cross-coupling
reaction of enals with primary alcohols is effectively
catalyzed by RuHCl(CO)(PPh3)3, which leads to good yields
of 2-hydroxymethyl ketones. The reaction is likely to proceed
via an aldol reaction of a ruthenium enolate followed by a
transfer hydrogenation, where primary alcohols act as both
a hydrogen source and a latent aldehyde. The simplicity, atom
efficiency, mild reaction conditions, and short reaction times
make this an appealing methodology for accessing 2-hy-
droxymethyl ketones. Synthetic applications of the present
reaction are currently underway in this laboratory.
(11) For Ru-catalyzed aldol type reactions, see: (a) Naota, T.; Taki, T.;
Mizuno, M.; Murahashi, S.-I. J. Am. Chem. Soc. 1989, 111, 5954. (b)
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M.; Yang, X.-F.; Li, C.-J. Eur. J. Org. Chem. 2003, 998. (d) Yang, X.-F.;
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Wang, M.; Varma, R. S.; Li, C.-J. J. Mol. Catal. A: Chem. 2004, 214, 147.
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Chem.sEur. J. 2005, 11, 5832. (g) Bartoszewicz, A.; Livendahl, M.; Mart´ın-
Matute, B. Chem.sEur. J. 2008, 14, 10547.
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erwell, W. B. Pure Appl. Chem. 2002, 74, 135. (b) Huddleston, R. R.;
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Acknowledgment. A.D. thanks a Grant-in-Aid for JSPS
Fellows. T.F. and I.R. thank JSPS and MEXT Japan for
funding.
(13) For reviews on transfer hydrogenation, see: (a) Brieger, G.; Nestrick,
T. J. Chem. ReV. 1974, 74, 567. (b) Zassinovich, G.; Mestroni, G.; Gladiali,
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(g) Gordon, E. M.; Gaba, D. C.; Jebber, K. A.; Zacharias, D. M.
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Supporting Information Available: Experimental pro-
cedure and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
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