Ruthenium-catalyzed tandem-isomerization/asymmetric transfer hydrogenation of allylic alcohols

Article abstract of DOI:10.1002/chem.201405207

A one-pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem-isomerization/ asymmetric transfer hydrogenation process is efficiently catalyzed by [{Ru(p-cymene)Cl₂}₂] in combination with the a-amino acid hydroxyamide ligand 1, and performed under mild conditions in a mixture of ethanol and THF. The saturated alcohol products are isolated in good to excellent chemical yields and in enantiomeric excess up to 93%.

Full text of DOI:10.1002/chem.201405207

DOI: 10.1002/chem.201405207
Communication
&
Asymmetric Catalysis
Ruthenium-Catalyzed Tandem-Isomerization/Asymmetric Transfer
Hydrogenation of Allylic Alcohols
Tove Slagbrand, Helena Lundberg, and Hans Adolfsson*[a]
plosive molecular hydrogen or moisture-sensitive hydride re-
Abstract: A one-pot procedure for the direct conversion
agents.[18–20] Asymmetric transfer hydrogenation (ATH) of pro-
of racemic allylic alcohols to enantiomerically enriched sa-
chiral ketones provides enantiomerically enriched products
turated alcohols is presented. The tandem-isomerization/
under relatively environmentally friendly conditions.[21–25] Over
asymmetric transfer hydrogenation process is efficiently
the last decade, we have studied and developed catalysts
catalyzed by [{Ru(p-cymene)Cl2}2] in combination with the
based on ruthenium- and rhodium-arene complexes combined
a-amino acid hydroxyamide ligand 1, and performed
with simple a-amino acid ligands for this transformation. One
under mild conditions in a mixture of ethanol and THF.
of the most successful catalysts is formed in situ from the
The saturated alcohol products are isolated in good to ex-
amino acid hydroxyamide ligand 1 (Figure 1a), and [{Ru(p-cym-
cellent chemical yields and in enantiomeric excess up to
93%.
The chemical industry and chemists in academia are constantly
in need of simple preparative routes that provide complex
molecules in few reaction steps. Therefore, the search for and
optimization of new synthetic pathways, which allow for short
reaction routes, is of high importance. It is beneficial if such
synthetic procedures contain steps that can be combined in
Figure 1. a) The amino acid hydroxyamide ligand (1) (Boc=tert-butyloxycar-
a sequential manner, called tandem or cascade reactions,
bonyl). b) The proposed 6-membered transition state for the ATH.
which makes it possible to use unstable intermediates, pro-
duce less waste, use less solvent, and allow for faster formation
of the desired product.[1] Here, we present a catalytic cascade
protocol, which allows for the formation of enantiomerically
enriched secondary alcohols by initial isomerization of racemic
allylic alcohols, followed by reduction of the resulting ketones.
There are several protocols available for the catalytic isomer-
ization of allylic alcohols into aldehydes and ketones. The most
common catalysts are based on late transition metals such as
iridium, rhodium, ruthenium, and palladium.[2–10] The dimeric
ruthenium complex, [{Ru(p-cymene)Cl2}2] is commonly em-
ployed as an isomerization catalyst, either on its own or in
combination with different ligands and bases. Furthermore,
several asymmetric isomerization protocols for the generation
of enantiomerically enriched aldehydes and ketones have been
developed, in which the stereogenic centers are in close prox-
imity to the newly formed carbonyl functionality.[11–17]
ene)Cl2}2] in the presence of base.[26–30] The ATH of aryl alkyl ke-
tones in 2-propanol was positively influenced by the addition
of catalytic amounts of lithium chloride, and mechanistic inves-
tigations strongly support a hydride transfer via the bimetallic
6-membered transition state shown in Figure 1b.[31,32]
The combination of the isomerization of allylic alcohols with
a consecutive ketone reduction would allow for the formation
of saturated alcohols in a straightforward manner as depicted
in Scheme 1. The same type of compounds can, in principle,
be reached by direct hydrogenation of the allylic alcohol; how-
ever, the sensitivity of the substrate being both allylic and ben-
Transfer hydrogenations of unsaturated compounds are op-
erationally simple and safe alternatives to reductions using ex-
[a] T. Slagbrand, H. Lundberg, Prof. Dr. H. Adolfsson
Dept. of Organic Chemistry
Stockholm University
The Arrhenius Laboratory
10691 Stockholm (Sweden)
E-mail: hansa@organ.su.se
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405207.
Scheme 1. A one-step procedure to obtain saturated alcohols from allylic al-
cohols that would otherwise require three or possibly two separate steps.
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zylic would often lead to a nonselective reaction.[33,34] The Ca-
dierno group has demonstrated that racemic saturated alco-
hols can be obtained in a two-step reaction sequence, starting
with isomerization of the allylic alcohol and, after isolation of
the formed ketone, a subsequent reduction leading to the
target compound.[35–38] Similarly, a two-step protocol for the
formation of racemic alcohols by initial isomerization of non-
aromatic allylic alcohols, followed by ketone reduction under
transfer hydrogenation conditions was presented by Lau et
al.[39]
Table 1. Optimization of solvent.[a]
Entry Solvent (ratio)
Conv- Alcohol ee
ersion 2b [%] [%] intermediate
[%]
Ketone
2c [%]
1
2
THF
toluene
95[b]
>99
50
24
83
>99
84
0
50
14
81
>99
82
>99
>99
>99
98
–
nd
>99
–
10
2
3
4
5
6
2-propanol:THF (1:1)
1-propanol:THF (1:1)
ethanol:THF (1:1)
ethanol:THF (3:1)
ethanol:THF (1:3)
93[d]
83[d]
89[c]
80[d]
90[c]
89[c]
89[c]
79[d]
–
2
–
–
–
2
7
Employing the Noyori catalyst, [Ru(p-cymene)TsDPEN]
(DPEN=1,2-diphenyl-1,2-diaminoethane), Williams and co-
workers showed that an allylic alcohol could be directly con-
verted into the desired saturated alcohol with a conversion of
58%, however, with an ee of 7%.[40] Furthermore, Sowa demon-
strated that the allylic alcohol moieties of simple isoprenoid al-
cohols were converted to the corresponding saturated alcohols
in moderate to excellent enantioselectivity by a combined iso-
merization/reduction sequence catalyzed by [{Ru(p-cymene)-
Cl2}2] in the presence of (S)-tol-binap (tol-binap=2,2’-bis(di-p-
tolylphosphino)-1,1’-binaphthyl). This particular transformation
is an example of an asymmetric isomerization, which is fol-
lowed by a transfer hydrogenation of the resulting aldehyde.[41]
Encouraged by the high efficiency and selectivity in ATH re-
actions of aryl alkyl ketones demonstrated by the ruthenium-
catalyst shown in Figure 1, we were interested in examining
this particular catalyst in a combined isomerization/reduction
sequence of allylic alcohols (Scheme 1). In an initial experimen-
tal setup, we used conditions developed for the reduction of
acetophenones and applied these on the allylic alcohol 2a
(Scheme 2). Under these conditions, no sign of the desired
product was observed; nevertheless, the expected ketone in-
8
ethanol:2-methyl THF (3:1) >99
9
10
11
ethanol:toluene (1:1)
ethanol:toluene (3:1)
ethanol:toluene (1:3)
>99
>99
>99
[a] Reaction conditions; [{Ru(p-cymene)Cl2}2] (2 mol%, 4 mol% rutheni-
um), ligand 1 (8.8 mol%), allylic alcohol 2a (0.5 mmol, 0.5m reaction solu-
tion), LiCl (10 mol%), dry THF/toluene/ethanol/1-propanol/2-propanol,
potassium tert-butoxide (0.5 mmol), 408C, reaction time 3 h. Conversion
was determined using 1H NMR spectroscopy. [b] A complex mixture of
products was obtained. [c] The ee was measured with chiral GLC (CP Chir-
asil DEX CB). [d] The ee was measured with HPLC (OB column).
enantiomeric excess (Table 1, entry 6). The use of 2-methyl-THF,
in combination with ethanol, gave an equally good result
(Table 1, entry 8). Since the isomerization step proceeded
smoothly in toluene, we examined mixtures of ethanol and tol-
uene as reaction media and comparably, as with THF, good re-
sults were obtained (Table 1, entries 9 and 10). However, THF
was chosen as co-solvent in further studies, due to workup
simplicity.
The optimizations were continued by screening the amount
of base (see the Supporting Information), and it was found
that using potassium tert-butoxide (30 mol%) was optimal. In
order to further improve the outcome of the reaction, addi-
tional reaction parameters such as concentration and the [Ru]/
ligand ratio were screened (Table 2). Control experiments were
performed without the ligand, without ruthenium, and one
Scheme 2. Starting point for the optimization based on the reduction of
acetophenones, which only gave the isomerized product.
Table 2. Further optimization of reaction parameters.[a]
Entry Ru
Ligand Allylic
Conv- Alcohol ee
Ketone
[mol%] [mol%] alcohol ersion 2b [%] [%][b] intermediate
termediate (2c) was detected. Changing the base to potassium
tert-butoxide and increasing the amount to one equivalent,
gratifyingly resulted in the formation of the desired product
2b (Table 1, entry 3).
[M]
[%]
2c [%]
1
2
3
4
5
6
7
8
9
4
4
–
-
4
4
4
4
2
8.8
–
8.8
–
8.8
8.8
4.4
2.2
1.1
0.5
0.5
0.5
0.5
0.1
0.05
0.5
0.5
0.5
>99
92
>99
–
92
–
–
–
92
–
0
0
–
–
Further optimizations included evaluation of different sol-
vents and hydride sources. As shown in Table 1, isomerization
can occur in the absence of a hydride source (Table 1, entries 1
and 2). In order to get the saturated asymmetric alcohol, a hy-
dride source is required and, therefore, we examined
a number of simple alkyl alcohols in combination with THF as
co-solvent (Table 1, entries 3–5). Performing the reaction in
a 1:1 mixture of ethanol and THF led to an acceptable yield of
alcohol 2b (Table 1, entry 5), and increasing the amount of eth-
anol gave the saturated alcohol as the sole product in good
–
–
82
62
>99
>99
>99
63
29
91
>99
95
91
84
92
93
92
19
33
9
–
5
[a] Reaction conditions: Allylic alcohol 2a (0.5 mmol, 0.5m reaction solu-
tion), LiCl (10 mol%), dry ethanol:dry THF (3:1), potassium tert-butoxide
as base (30 mol%), temperature 408C, reaction time 3 h. Conversion was
determined using 1H NMR spectroscopy. [b] The ee was measured with
chiral GLC (CP Chirasil DEX CB).
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with neither of the two species
(Table 2, entries 2–4). The reac-
tion did not proceed in the ab-
sence of the ruthenium complex,
as would be expected (Table 2,
entries 3 and 4). However, it was
found that isomerization was
taking place even without ligand
present, resulting in 92% con-
version of the allylic alcohol into
the ketone (Table 2, entry 2). This
result clearly shows that the
ligand is crucial for the reduction
of the ketone, whereas it may or
may not play a role for the iso-
merization process. Ongoing
mechanistic studies will answer
this question in due time. The
reaction concentration was also
evaluated (Table 2, entries 5 and
6), showing that lower concen-
tration results in a slower reac-
tion. Since the isomerization can
occur without the ligand present
(Table 2, entry 2), the [Ru]:ligand
ratio was changed (Table 2, en-
tries 7 and 8). With almost equi-
molar amounts of the ruthenium
precursor and ligand, there was
still some ketone left in the reac-
tion mixture after 3 h reaction
time (Table 2, entry 7). However,
with the metal precursor in
excess, the reaction went to
completion (Table 2, entry 8)
and, gratifyingly, the catalyst
loading could now be decreased
to 2 mol% without dramatically
changing the outcome (Table 2,
entry 9). Further decrease in cat-
alyst loading resulted in incom-
plete reaction, along with a sig-
nificant amount of ketone (20%)
left in the reaction mixture after
3 h reaction time.
Table 3. Substrate scope.[a]
Entry
Substrate
Product
Conversion [%] Isolated
ee [%][b] Absolute
yield [%]
config.[c]
1
2
3
2a
3a
4a
2b
3b
4b
>99
85
93
88
82
S
S
S
>99
91
83
>99[d]
4
5a
6a
5b
6b
>99
>99
94
95
89
84
S
S
5[e]
6
7
7a
8a
7b
8b
>99[f]
>99
53
86
84
–
S
–
8[g]
9a
9b
>99
>99
>99
97
97
91
22
11
61
R
R
S
9
10a
11 a
10b
11 b
10
11
12a
12b
>99[h]
63
74
S
[a] Reaction conditions: [{Ru(p-cymene)Cl2}2] (1 mol%), ligand 1 (1.1 mol%), allylic alcohol (1 mmol, 0.5m reac-
tion solution), LiCl (10 mol%), dry ethanol and dry THF (3:1) as solvent, potassium tert-butoxide as base
(30 mol%), 408C, reacted 16–24 h. Conversion was determined using 1H NMR spectroscopy. [b] The ee was
measured with chiral GLC (CP Chirasil DEX CB). [c] Absolute configuration was determined by optical rotation.
[d] Ketone (6%). [e] Reaction time 10 h. [f] For product distribution, see Scheme 3. [g] Reaction time 5 h.
[h] Ketone (25%).
Scheme 3. The product distribution for the naphthyl allylic alcohol (7a).
With the optimized conditions
in hand we focused on evaluat-
ing the tandem isomerization/
ATH on a series of different racemic allylic alcohols (Table 3).
The protocol works well for allylic alcohols substituted with
electron-withdrawing or electron-releasing substituents on the
aryl moiety (Table 3, entries 2–5), yielding products with ee in
the range of 82–89%. Interestingly, the naphthyl derivative 7a
gave rise to a mixture of different compounds, of which alco-
hol 7b was the major product, along with the ketone 7c, and
the alkylated ketone 7d (Table 3, entry 6, and Scheme 3).
Ketone 7d is the condensation product from the enolate of
the ketone, which reacted with acetaldehyde formed from oxi-
dized ethanol.
The primary allylic alcohol 8a was efficiently converted into
the saturated product (Table 3, entry 7). Furthermore, the iso-
merization/reduction reaction was successfully performed on
the secondary allylic alcohols 9a and 10a (Table 3, entries 8
and 9). In the latter two entries, low enantiomeric excess of
the formed secondary-saturated alcohols were obtained, which
is in line with previous results from performing ATH on sub-
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strates that lack an aromatic moiety next to the ketone. The
heteroaromatic allylic alcohols 11 a and 12a were also exam-
ined, and we found that these compounds were efficiently
converted to the corresponding saturated alcohols, albeit with
slightly lower ee (Table 3, entries 10 and 11).
substrate behaves in a similar way to the intermediate formed
from the allylic alcohol under these conditions.
To conclude, we have developed an efficient protocol for
the ruthenium-catalyzed tandem isomerization/asymmetric
transfer hydrogenation of allylic alcohols into the correspond-
ing saturated alcohols. The methodology provides enantiomer-
ically enriched saturated alcohols in up to 93% ee, from simple
racemic allylic alcohols under relatively mild reaction condi-
tions. The protocol is complementary to previously published
methods, being applicable to secondary as well as primary al-
lylic alcohols. The one-pot reaction setup allows for the direct
formation of chiral target alcohols without the need for isola-
tion and purification of intermediates.
In addition to the allylic alcohols presented in Table 3, the
isomerization/reduction sequence was performed on com-
pounds 13a–15a (see Scheme 4). Poor conversion was ob-
tained running the reaction on allylic alcohol 13a, which can
Experimental Section
Scheme 4. Poorly reactive substrates.
All reactions were performed under nitrogen with oven-dried
glassware.
be explained by increasing steric hindrance next to the inter-
mediate ketone, a situation that severely hampers the final re-
duction step. The isomerization/reduction did not work at all
on compounds 14a and 15a. The lack of reactivity of 14a can
be explained by steric hindrance that prevents the isomeriza-
tion from occurring, whereas in allylic alcohol 15a there is
a possible inhibition of the reaction due to coordination of the
nitro moiety to the ruthenium center. The latter has been ob-
served previously in attempts to reduce nitro-substituted ace-
tophenones under transfer hydrogenation conditions with this
class of catalysts.
General procedure for the tandem isomerization/asymmetric
transfer hydrogenation of allylic alcohols: The catalyst precursor
[{Ru(p-cymene)Cl2}2] (6.2 mg, 0.01 mmol) and LiCl (4.4 mg,
0.10 mmol, 10 mol%) were treated under vacuum in a microwave
vial for 10 min. Dry THF (0.50 mL) and dry ethanol (1.10 mL) were
added, followed by a 0.11m stock solution of ligand 1 in dry etha-
nol (0.10 mL, 0.011 mmol, 1.1 mol%) and the allylic alcohol
(1.0 mmol), and the resulting mixture was stirred for 15 min at
408C. The reaction was initiated by addition of a 1.0m stock solu-
tion of KtBuO in dry ethanol (0.30 mL, 0.30 mmol, 30 mol%). Ali-
quots were withdrawn at suitable intervals (see details in the
tables) and were then pressed though a pad of silica with ethyl
acetate as the eluent. The resulting solutions were analyzed by
1H NMR spectroscopy, chiral GLC (CP Chirasil DEX CB) or chiral
HPLC (OB column).
The mechanisms of the individual reaction steps in the
ruthenium-catalyzed tandem isomerization/ATH process have
been carefully studied.[42,43] For the isomerization of allylic alco-
hols into the corresponding aldehydes/ketones, there are sev-
eral different mechanistic possibilities, in which the transition
metal center of the catalyst can either interact with the olefinic Acknowledgements
or the hydroxyl functionality of the substrate. It has been pro-
posed in the literature that the isomerization can proceed via
an a,b-unsaturated ketone intermediate, as depicted in
Scheme 1.[44,45] Therefore, we investigated whether ketone 16
could be an intermediate of the process by using this com-
pound as substrate to see whether the fully reduced alcohol
would be formed (Scheme 5). Performing the reaction under
optimized conditions, compound 16 was converted to the
target alcohol 2b. The saturated alcohol was formed in 91%
ee, hence, approximately the same selectivity as starting with
allylic alcohol 2a. This result indicates that ketone 16 could be
an intermediate in the isomerization mechanism, or that this
The Swedish Research Council, the Knut and Alice Wallenberg
Foundation, and Stockholm University are gratefully acknowl-
edged for financial support.
Keywords: allylic alcohols
·
asymmetric catalysis
·
isomerization · reduction · ruthenium
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Received: September 10, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
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Asymmetric Catalysis
T. Slagbrand, H. Lundberg, H. Adolfsson*
&& – &&
Ruthenium-Catalyzed Tandem-
Isomerization/Asymmetric Transfer
Hydrogenation of Allylic Alcohols
Less is more: The combination of
[{Ru(p-cymene)Cl2}2] with an amino acid
hydroxyamide ligand allows for the
direct catalytic tandem-isomerization/
asymmetric transfer hydrogenation of
racemic allylic alcohols to saturated
enantiomerically enriched alcohols. A
series of racemic allylic alcohols are con-
verted into saturated alcohols under
mild reaction conditions in a mixture of
ethanol and THF (see scheme).
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Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!