Carbon-carbon bond formation between secondary alcohols and aldehydes under ruthenium-catalyzed redox shuttle

Article abstract of DOI:10.1002/aoc.1829

Secondary alcohols are coupled with aldehydes in dioxane in the presence of a catalytic amount of a ruthenium catalyst along with KOH to give coupled ketones or coupled secondary alcohols depending on the molar ratio of secondary alcohols to aldehydes and the presence (or absence) of a sacrificial hydrogen acceptor. Copyright

Full text of DOI:10.1002/aoc.1829

Full Paper
Received: 19 May 2011
Revised: 20 June 2011
Accepted: 3 July 2011
Published online in Wiley Online Library: 10 August 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1829
Carbon–carbon bond formation between
secondary alcohols and aldehydes under
ruthenium-catalyzed redox shuttle
Chan Sik Choa∗, Bok Tae Kima and Nam Sik Yoonb
Secondary alcohols are coupled with aldehydes in dioxane in the presence of a catalytic amount of a ruthenium catalyst along
with KOH to give coupled ketones or coupled secondary alcohols depending on the molar ratio of secondary alcohols to
c
aldehydes and the presence (or absence) of a sacrificial hydrogen acceptor. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: aldehydes; carbon–carbon bond formation; redox; ruthenium catalyst; secondary alcohols
Introduction
5a and 6a in dioxane in the presence of RuCl2(PPh3)3 (2 mol%)
and KOH at 80 ◦C for 20 h afforded 3a (48% yield) and 4a (10%
yield) with concomitant formation of acetophenone (9%; entry 1).
The product yield and distribution were slightly increased by the
additionof1-dodeceneasahydrogenacceptor(entry2). However,
when the reaction was carried out in the presence of much greater
amount of 1-dodecene, no significant change in the product yield
and selectivity was observed (entry 3). It has been found that the
reaction rate on the coupling between secondary alcohols and pri-
mary alcohols towards coupled secondary alcohols is dramatically
enhanced by the addition of a sacrificial hydrogen acceptor.[8]
Treatment of equimolar amounts of 5a and 6a is desirable from an
atom economy point of view since the reaction under the molar
ratioof[5a]:[6a]=0.5resultsinaslightlyincreasedyieldof3a(68%
yield; entry 4). The best result in terms of both overall yield and
the selectivity of coupled ketone to coupled secondary alcohol is
best accomplished by further tuning of the reaction time (entry 5).
Finally, when the reaction was carried out under the molar ratio
of [5a]:[6a] = 3 in the absence of 1-dodecene, coupled secondary
alcohol 4a was selectively formed in preference to coupled ketone
3a (entry 6).
Reaction conditions having been established for the formation
of coupled ketone, various secondary alcohols 5 were subjected
to the reaction with 6a in order to investigate the reaction scope,
and several representative results are summarized in Table 2.
Various aryl(methyl) carbinols (5a–f) having electron-donating
and -withdrawing substituents on the aromatic ring were readily
coupledwith6atogivethecorrespondingcoupledketones(3a–f)
intherangeof42–63%yieldsalongwithasmallamountofcoupled
secondary alcohols 4 in several cases (<3%) and uncoupled
ketones(<11%)producedfrom5.Thereactionproceededlikewise
It is well known that the carbon–carbon bond forming reaction
plays a pivotal role in organic synthesis. Thus, many practical
methods catalyzed by transition metals have been developed for
suchacarbon–carbonbond-formingreaction.[1,2] Wealsorecently
found several sp3-carbon–sp3-carbon bond forming-reactions
between ketones (or secondary alcohols) and primary alcohols
under a ruthenium-catalyzed redox shuttle.[3,4] The cross-coupling
between ketones 1 and primary alcohols 2 selectively gives
coupled ketones 3 (α-alkylation of 1 with 2; Scheme 1, route a)[5]
or coupled secondary alcohols 4 (Scheme 1, route b)[6] according
to the molar ratio of [2]:[1]. An atom economical reductive cross-
coupling of 1 with 2 leading to 4 under the molar ratio of
[2]:[1] = 1–1.2 by the addition of ethylenediamine has also been
reported.[7] Similar one-pot multicatalytic cross-coupling between
secondary alcohols 5 and 2 leading to 4 (β-alkylation of 5 with 2)
wasalsodisclosedbytheadditionofasacrificialhydrogenacceptor
(Scheme 1, route c).[8] In addition, it was also demonstrated
that ketones 1 were found to be coupled with aldehydes 6
to give coupled ketones 3 (Scheme 1, route d).[9] Several other
transition metal precursors have also been introduced for such
sp3-carbon–sp3-carbon bond-forming reactions,[10–16] and this
coupling protocol could be applied to modified Friedla¨nder
quinoline synthesis.[17–26] Prompted by these findings, this report
describes another ruthenium-catalyzed one-pot multicatalytic
coupling mode between secondary alcohols 5 and aldehydes
6, leading to coupled ketones 3 or coupled secondary alcohols 4
by the tuning of the molar ratio of [5]:[6] and the presence (or
absence) of a hydrogen acceptor (Scheme 1, routes e and f).
Results and Discussion
∗
Correspondence to: Chan Sik Cho, Department of Applied Chemistry, Kyung-
Table 1 shows optimization of the conditions for the car-
bon–carbon bond formation between 1-phenylethanol (5a) and
benzaldehyde (6a) under a ruthenium-catalyzed redox shut-
tle leading to selective formation of either coupled ketone,
1,3-diphenylpropan-1-one (3a), or coupled secondary alcohol,
1,3-diphenylpropan-1-ol (4a). Treatment of equimolar amounts of
pookNationalUniversity,Daegu702-701,SouthKorea.E-mail: cscho@knu.ac.kr
a
Department of Applied Chemistry, Kyungpook National University, Daegu
702-701, South Korea
b
Department of Textile System Engineering, Kyungpook National University,
Daegu 702-701, South Korea
c
Appl. Organometal. Chem. 2011, 25, 695–698
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

C. S. Cho, B. T. Kim and N. S. Yoon
reacted with 6a to give 2-benzyl-1-tetralone (3i) in 49% yield.
With alkyl(methyl) carbinols (5j and 5k), the product yield was
lower than when aryl(methyl) carbinols were introduced. On the
other hand (not shown in Table 2), 5a was also cross-coupled with
aliphatic aldehyde and octyl aldehyde. However, in contrast to
the cross-coupling between aryl(methyl) carbinols and 6a, lower
reaction rate and yield were observed with octyl aldehyde (the
yield of 1-phenyldecan-1-one was 31%).
O
O
route a
route c
+
+
HO
R'
R'
R
R
R'
R'
R
R
1
2
3
OH
OH
HO
5
2
4
Table 3 shows the preferential formation of coupled secondary
alcohols 4 by the cross-coupling between various secondary
alcohols 5 and aldehydes 6 under the standard set of reaction
conditions (entry 6 of Table 1). The reactions of 5a with various
aromatic and heteroaromatic aldehydes (6a–e) proceeded to
give the corresponding coupled secondary alcohols (4a–e) in
the range of 32–81% yields along with coupled ketones. The
product yield and selectivity were considerably affected by the
electronic nature of the substituent on the aromatic ring of (6a–d).
With aldehyde having an electron-withdrawing Cl substituent, the
product yield and selectivity were lower than when aldehydes
having an electron-donating character were used. In the reaction
of ferrocenecarboxaldehyde (6f), the corresponding coupled
secondary alcohol 4f was also obtained in 75% yield with a
small amount of coupled ketone (19% yield). Various aryl(methyl)
and heteroaryl(methyl) carbinols (5b–h) were also reacted with
6a to give the corresponding coupled secondary alcohols (4g–m)
in the range of 64–88% yields. Here again, similar selectivity
in favor of coupled secondary alcohols to coupled ketones
was observed. Benzo-fused cyclic carbinol 5i and alkyl(methyl)
carbinol 5k were also coupled with 6a to give 2-benzyl-1,2,3,4-
tetrahydronaphthalen-1-ol(4n)asadiastereoisomericmixtureand
1,5-diphenylpentan-3-ol (4o), respectively. However, the product
yield and selectivity were lower than when aryl(methyl) carbinols
were employed.
O
O
route d
route f
+
+
R'CHO
R
R
R'
R'
R
R
1
6
3
OH
OH
R'CHO
5
6
4
Scheme 1. Cross-coupling routes.
OH
OH
O
+
R
R
R'
R
R'
4
3
5
[Ru]
[Ru]H2
O
O
KOH
R'CHO
R
R'
R
6
1
7
Scheme 2. A reaction pathway.
For the reaction pathway, it seemed to proceed via initial
oxidation of 5 to ketone 1 (Scheme 2). Compounds 1 and 6 then
underwent a cross-aldol reaction under KOH to give the α,β-
unsaturated ketone 7, which was hydrogenated to 3 and 4 by
a dihydridoruthenium species generated in the initial oxidation
stage of 5. A similar catalytic cycle has been proposed by us in
ruthenium-catalyzed cross-coupling reactions.[6,8,9]
with α-methyl-1-naphthalenemethanol (5g) to afford the coupled
ketone 3g in 40% yield. In the reaction of heteroaryl(methyl)
carbinol 5h with 6a, the corresponding coupled ketone 3h was
also obtained in similar yield. Benzo-fused cyclic carbinol 5i also
Table 1. Optimization of conditions for the reaction of 5a with 6aa
OH
O
OH
+
+
PhCHO
Ph
Ph
Ph
Ph
Ph
5a
6a
3a
4a
Yield (%)
Entry
[5a]:[6a]
1-Dodecene (mmol)
Time (h)
Conversionb (%) of 5a
3a
4a
1
1
–
1
5
5
5
–
20
20
20
40
40
40
75
82
82
90
85
69
48
60
59
68
63
15
10
6
2
1
3
4c
1
4
0.5
1
Trace
Trace
75
5
6d
3
a Reaction conditions: 6a (1 mmol), RuCl2(PPh3)3 (0.02 mmol), KOH (1 mmol), dioxane (2 ml), 80 ◦C.
b Determined by GLC.
c 6a (2 mmol).
d RuCl2(PPh3)3 (0.05 mmol), KOH (3 mmol).
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 695–698

Carbon–carbon bond formation between secondary alcohols and aldehydes
Table 2. Ruthenium-catalyzed oxidative cross-coupling between
secondary alcohols and benzaldehyde leading to coupled secondary
alcoholsa
Table 3. Ruthenium-catalyzed cross-coupling between secondary
alcohols and aldehydes leading to coupled secondary alcoholsa
Secondary Aldehydes
Yieldb
(%)
Yieldb (%)
alcohols 5
6
Products 4
Secondary alcohols 5
Products 3
RꢁCHO
OH
OH
OH
R
O
R
R
R'
R
Ph
5a
Rꢁ = Ph (6a)
4a
4b
4c
4d
4e
4f
75 (15)
75 (13)
81 (9)
R = Ph (5a)
3a
3b
3c
3d
3e
3f
63 (trace)
42 (2)
Rꢁ = 4-MeC6H4 (6b)
R = 2-MeC6H4 (5b)
R = 3-MeC6H4 (5c)
R = 4-MeC6H4 (5d)
R = 4-MeOC6H4 (5e)
R = 4-FC6H4 (5f)
R = 2-naphthyl (5g)
R = 2-thienyl (5h)
Rꢁ = 4-MeOC6H4 (6c)
56 (1)
Rꢁ = 4-ClC6H4 (6d)
32 (21)
63 (9)
48 (2)
Rꢁ = 2-furyl (6e)
50 (trace)
47 (3)
Rꢁ = ferrocenyl (6f)
75 (19)
72 (15)
86 (8)
5b
5c
5d
5e
5f
6a
6a
6a
6a
6a
6a
6a
4g
4h
4i
3g
3h
40 (3)
50 (2)
88 (7)
OH
O
4j
78 (6)
4k
4l
76 (8)
Ph
5g
5h
64 (9)
4m
64 (15)
5i
3i
49 (2)
OH
OH
O
Ph
Ph
5i
6a
6a
4n
54 (29)
35 (22)
5j
3j
36 (2)
OH
OH
O
Ph
Ph
Ph
Ph
Ph
5k
4o
5k
3k
20 (trace)
a Reaction conditions:
5 (3 mmol), 6 (1 mmol), RuCl2(PPh3)3
(0.05 mmol), KOH (3 mmol) in dioxane (3 ml), 80 ◦C, 40 h.
b Isolated yield. Numbers in parentheses indicate the corresponding
coupled ketones.
a Reaction conditions: 5 (1 mmol), 6a (1 mmol), 1-dodecene (5 mmol),
RuCl2(PPh3)3 (0.02 mmol), and KOH (1 mmol) in dioxane (2 ml), 80 ◦C,
40 h.
b Isolated yield. Numbers in parentheses indicate the corresponding
coupled secondary alcohols.
General Experimental Procedure
A mixture of secondary alcohols (1–3 mmol), aldehydes (1 mmol),
RuCl2(PPh3)3 (0.02–0.05 mmol), KOH (1–3 mmol) and 1-dodecene
(0–5 mmol)indioxane(2–3 ml)wasplacedina5 mlscrew-capped
vial and the system was allowed to react at 80 ◦C for an appropriate
time. The reaction mixture was filtered through a short silica gel
column (ethyl acetate) to eliminate inorganic salts. Removal of
the solvent left a crude mixture, which was separated by thin-
layer chromatography (silica gel, ethyl acetate–hexane mixture)
to give coupled secondary alcohols and coupled ketones. All
coupled ketones and secondary alcohols were identified by GLC
andspectroscopiccomparisonwithauthenticsamplessynthesized
by recent reports.[5,7–9,27]
Conclusion
In summary, it has been shown that secondary alcohols undergo
a one-pot multicatalytic carbon–carbon bond forming reaction
with aldehydes under a ruthenium-catalyzed redox shuttle to give
preferentially coupled ketones or coupled secondary alcohols
according to the molar ratio of substrates and whether a sacrificial
hydrogen acceptor is added or not.
Experimental
1H and 13C NMR (400 and 100 MHz) spectra were recorded on a
Bruker Avance Digital 400 spectrometer using Me4Si as an internal
standard. GLC analyses were carried out with Shimadzu GC-17A
(FID) equipped with a CBP10-S25-050 column (Shimadzu, a silica
fused capillary column, 0.33 mm × 25 m, 0.25 µm film thickness)
using N2 as carrier gas. The isolation of pure products was carried
out via thin-layer (silica gel 60 GF254, Merck) chromatography.
Commercially available organic and inorganic compounds were
used without further purification. Secondary alcohols (5b–h)
were prepared by reduction of the corresponding ketones with
NaBH4 in MeOH.
Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea funded by the
Ministry of Education, Science and Technology (2011-0005123).
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Appl. Organometal. Chem. 2011, 25, 695–698