Dehydrogenative cross-coupling of primary and secondary alcohols

Article abstract of DOI:10.1002/adsc.201300656

Homo-and cross-coupling of alcohols resulting in the formation of the corresponding ketones in very good to excellent yield was realized through the one-pot sequence of dehydrogenation/ aldol condensation/hydrogenation accompanied by the release of molecular hydrogen. The dehydrogenation and hydrogenation steps are catalyzed by the previously reported ruthernium-and iridiumbased ligand-metal cooperating catalysts.

Full text of DOI:10.1002/adsc.201300656

UPDATES
DOI: 10.1002/adsc.201300656
Dehydrogenative Cross-Coupling of Primary and Secondary
Alcohols
Sanaa Musa,a Lutz Ackermann,b and Dmitri Gelmana,*
a
Institute of Chemistry, The Hebrew University, Edmond Safra Campus, 91904 Jerusalem, Israel
Fax : (+972)-2-658-5279; e-mail: dmitri.gelman@mail.huji.ac.il (homepage: http://chem.ch.huji.ac.il/~dgelman/)
Georg-August-Universitꢀt Gçttingen, Institut fꢁr Organische und Biomolekulare Chemie, Tammannstrasse 2, 37077
b
Gçttingen, Germany
Received: July 25, 2013; Revised: August 31, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300656.
Abstract: Homo- and cross-coupling of alcohols re-
sulting in the formation of the corresponding ke-
tones in very good to excellent yield was realized
through the one-pot sequence of dehydrogenation/
aldol condensation/hydrogenation accompanied by
the release of molecular hydrogen. The dehydro-
genation and hydrogenation steps are catalyzed by
the previously reported ruthernium- and iridium-
based ligand-metal cooperating catalysts.
significantly faster than the hydrogenation of polar
bonds. For example, selective homo- and cross-cou-
pling of alcohols to b-alkylated ketones was achieved
under relatively mild conditions using heterogeneous
catalytic systems.[10]
Homogenously catalyzed coupling of secondary al-
cohols appeared in the literature only recently. As re-
ported, aliphatic and aromatic secondary alcohols
self-couple yielding racemic b-alkylated ketones
under mild heating in the presence of 1 mol% of the
catalyst derived from RuCl2IACHTUNTRGENN(GU i-Pr)ACHTUTGNREN(NUGN p-cymene)/PCy3
Keywords: acceptorless dehydrogenation; cross-
coupling; innocent ligands; ligand-metal coopera-
tion; pincer ligands
and KOH as a base, while coupling of primary alco-
hols under the same reaction conditions resulted in
the formation of esters.[11] Noteworthy as well, the
cross-coupling version of this transformation was not
reported under homogenous conditions.
There is no argument that, generally, homogenous
Alcohols are among the most versatile classes of com- catalysis, upon being ligand-dependent, provides more
pounds as they can be easily transformed into a varie- synthetic flexibility and, even more important, stereo-
ty of functionalized compounds using classical organic chemical control. We, therefore, wish to report a com-
transformations.[1] Alcohols became even more attrac- plementary catalytic system capable of promoting se-
tive starting materials for the synthesis of bulk and lective and efficient dehydrogenative cross-coupling
fine chemicals after the discovery of novel acceptor- of alcohols under mild reaction conditions using
less dehydrogenative methods based on ligand-metal a new ligand-metal cooperating system.[12]
cooperating catalysis because they provide atom-eco-
nomical, straightforward, green and mild accesses to Ir- and Ru-based PC
aldehydes,[2] ketones,[3] esters,[4] acetals,[5] (poly)am- ligand-metal cooperating catalysts[13,14] for efficient ac-
Some time ago, our group disclosed a series of new
AHCTUNGTRENNUNG
ides,[6] amines,[7] imines,[8] etc.
ceptorless dehydrogenation (AD) of alcohols to ke-
Catalytic dehydrogenative carbon-carbon bond- tones and esters (TON=3600)[14] and dehydrogena-
forming processes represent an elegant extension of tive coupling of primary amines and alcohols to
this chemistry. For example, one-pot acceptorless de-
hydrogenation of alcohols to the corresponding car-
bonyl compounds followed by aldol condensation and
subsequent hydrogenation under the same reaction
conditions, known as the Guerbet reaction, leads to
the formation of b-alkylated alcohols (Scheme 1).[9]
Both homo- and cross-coupling reactions were report-
ed.
Yet, b-alkylated ketones may be prepared selective-
ly when hydrogenation of non-polar double bonds is Scheme 1. Dehydrogenative coupling of alcohols.
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Sanaa Musa et al.
Table 1. Representative cross-coupling results.[a–c]
UPDATES
imines (TON=830).[15] These catalysts can activate/
form chemical bonds via intramolecular interactions
between the metal center and the ligandꢃs functional
sidearm (Figure 1).
Figure 1. Catalysts used in this work.
Upon experimentation with the catalyst 1,[16] we ob-
served that dehydrogenation of 1-phenylethanol per-
formed under longer reaction times and in the pres-
ence of a catalytic base (e.g., 24 h versus the usual 6 h
in the presence of 5 mol% of Cs2CO3, as was disclosed
in our original protocol) gives rise to the formation of
a homo-coupled by-product, 1,3-diphenylbutan-1-one
in low yield. A brief optimization study showed that
with the use of an equimolar amount of KOH, KO-t-
Bu or Cs2CO3 (organic bases, such as DBU, Et3N or
morpholine were found to be inefficient) in the pres-
ence of 1 mol% of 1 and molecular sieves,[17] this
product forms exclusively after heating in xylene at
1308C for 12 h [Eq. (1)]. As in our previous studies,
[a]
1 mol% of 1 or 2 mol% of 2, R1OH/R2OH/KOH=1/1/1,
xylene, 1308C, molecular sieves.
Isolated yields are reported.
[b]
[c]
Yields are an average of two runs.
we found that the ruthenium-based 2 is less efficient,
but still capable of catalyzing this transformation if showed a diminished reactivity. However, an attempt-
used in a higher loading (2 mol%) and allowed to ed reaction between 1-phenylethanol and diphenyl-
react for longer reaction times (24 h) (Table 1, en- methanol yielded the mixture of 1,3-diphenylbutan-1-
tries 1 and 2). Apparently, this can be explained by one and benzophenone with no traces of the desired
a slow dissociation of the CO ligand required to adduct indicating that electrophilicity of the coupling
create a vacant coordination site.
partner maybe decisive even at a relatively high reac-
Fortunately, we found that the same reaction condi- tion temperature. A similar negative outcome was ob-
tions are applicable to the cross-coupling of the pri- served during an attempted self-coupling of ethyl
mary and secondary alcohols according the same phenyl ketone (Table 1, entries 16 and 17).
scheme. Thus, a stoichiometric mixture of benzyl alco-
We also found that aliphatic primary alcohols are
hol and 1-phenylethanol resulted in the formation of suitable coupling partners despite the fact that upon
1,3-diphenylpropan-1-one in 94–95% yield, the reac- dehydrogenation they acquire an enolizable nature.
tion being catalyzed by 1 or 2 (Table 1, entry 3). Ex- Thus, no self-coupling was observed under the sug-
cellent yields (87–94%) of the corresponding cross- gested conditions, indicating again the importance of
coupled products were obtained between 1-phenyl- the electrophilicity over other parameters (Table 1,
ACHTUNGTRENNUNGethanol and differently substituted benzyl alcohols, be entries 7, 10–12). Also aliphatic alcohols show satis-
they electron-rich and electron-deficient (Table 1, en- factory reactivity under the suggested reaction condi-
tries 4–6). Remarkably, in all cases, the Ru-based 2 tions. For example, cyclohexanol, 3,4-dihydronaphtha-
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Dehydrogenative Cross-Coupling of Primary and Secondary Alcohols
len-1(2H)-one and ethyl phenyl ketone couple with
benzyl alcohol in excellent yield (Table 1, entries 13–
15). The presence of electron-donating or electron-re-
leasing substituents on either of the coupling partners
does not play a significant role and the corresponding
products were isolated in equally high yields (Table 1,
entries 8–10).
The mechanism of AD of the primary and secon-
dary alcohols was discussed previously in detail. Thus,
we believe that overall sequence proceeds as follows: secondary alcohols. The transformation is catalyzed
a) H2-forming step via intramolecular interaction of by new bifunctional Ir- and Ru-based PCACTHNUTRGNEUNG
(sp3)P pincer
an acidic side-arm with the metal-hydride site, leading complexes and proceeds via a ligand-metal coopera-
to the formation of the arm-closed species b; b) tive mechanism. Further studies toward the develop-
ligand exchange step, leading to the arm-open iridium ment of an enantioselective version of this reaction
ꢀ
alkoxide species; c) regeneration of the Ir H catalyst are under way.
a by b-hydride elimination with subsequent formation
of the carbonyl product; d) metal independent cross-
aldol condensation; and e) transfer of H2 from a to Experimental Section
the aldol condensation product to form the b-alkylat-
ed ketone with regeneration of the species General Procedure for the Homo- and Cross-
b (Scheme 2).
Coupling of Alcohols
A Schlenk tube was charged with catalyst 1 or 2 (1–2 mol%,
correspondingly), alcohols (1 mmol each), molecular sieves
(200 mg) and potassium hydroxide (1 mmol) in ca. 2 mL of
p-xylene. The tube was heated to 1308C on oil bath for 12 h.
The reaction mixture was cooled to room temperature and
the product was purified by column chromatography
(hexane!1:1 hexane:CH2Cl2).
Acknowledgements
This research was partially supported by the Israel Science
Foundation (ISF) and the German-Israeli Science Foundation
(GIF).
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