Ruthenium-catalyzed asymmetric transfer hydrogenation of allylic alcohols by an enantioselective isomerization/transfer hydrogenation mechanism

Article abstract of DOI:10.1002/anie.201107910

Reducing hazards: A asymmetric transfer hydrogen reaction was developed to reduce prochiral allylic alcohols in high yield and excellent enantioselectivity (see example). Mechanistic studies indicate a novel enantioselective isomerization/transfer hydrogenation mechanism. This new reaction is much safer than high-pressure hydrogenation using H₂ gas. Copyright

Full text of DOI:10.1002/anie.201107910

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Angewandte
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DOI: 10.1002/anie.201107910
Asymmetric Catalysis
Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Allylic
Alcohols by an Enantioselective Isomerization/Transfer Hydrogenation
Mechanism**
Ruoqiu Wu, Marie G. Beauchamps, Joseph M. Laquidara, and John R. Sowa Jr.*
Asymmetric transfer hydrogenation (ATH) has emerged as
a major pathway in asymmetric catalysis since it can be
performed with a large variety of substrates, experimental
simplicity, and a high level of enantiocontrol. In addition, it
uses economical and environmentally friendly hydrogen
sources (isopropyl alcohol, formate), and the operational
safety is better than of traditional asymmetric hydrogenation
using hydrogen gas.[1] ATH has been applied to enantiose-
lective reduction of ketones/aldehydes,[2] imines,[3] activated
olefins,[4] and aromatic heterocycles.[5] However, in spite of
examples of gaseous asymmetric hydrogenation of allylic
alcohols,[6] and non-asymmetric Ru-catalyzed reduction of
allylic alcohols through an isomerization/transfer hydrogena-
tion mechanism recently reported by Cadierno et al.,[7] there
are no published cases of ATH of these important substrates.
Allylic alcohols are abundant in natural sources such as
essential oils, and widely used as starting materials and/or
major components in food, fragrance and pharmaceutical
industries.[8] Herein, we report the first ATH of allylic
alcohols—a reaction that occurs through an enantioselective
isomerization/transfer hydrogenation mechanism with high
enantioselectivity and yield.
It is remarkable to note that the yield, ee and config-
uration is equivalent to those of gaseous asymmetric hydro-
genation which must be performed at very high pressures of
70–100 atm.[9] However, the ATH conditions are much safer
as they are performed at only a slightly elevated pressure due
to the volatility of IPA at 1008C. As will be discussed later, the
reaction can be run effectively at the boiling point of IPA by
using [{(S)-tol-binap}RuCl2(p-cymene)].
According to Equation (1), a substrate/catalyst molar
ratio of 10:1 is necessary to obtain full conversion. As with
ATH reactions of ketones, the reaction is catalytic in KOH.[10]
The optimum amount of KOH is 2 equiv with respect to Ru.
For example, 1.4 equiv of KOH leads to less than 30%
conversion in 22 h. When KOH is increased to 2.9 equiv per
Ru, by-products rise to 12% and the ee decreases. One of the
major by-products is g-geraniol,[11] which is observed to
undergo ATH to citronellol in low ee (see below).
Other hydrogen donors tested were cyclohexanol and 2-
pentanol. Both alcohols convert geraniol to citronellol within
2 to 4 h in moderate ee (Table 1). However, the high boiling
point of cyclohexanol (1608C) made isolation difficult and the
Initially, we developed the ATH of geraniol (1; 0.01m) in
isopropyl alcohol (IPA) with 2 equiv of KOH per Ru atom by
using an in situ prepared mixture of [Ru(cod)Cl2]n and (S)-
(À)-2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl(Ru/(S)-tol-
binap) catalyst [Eq. (1); cod = cyclooctadienyl]. After degass-
ing, the reaction was run at 1008C for 2 h to produce (R)-
citronellol (2) in 78% isolated yield and 98% ee.
Table 1: Asymmetric transfer hydrogenation of geraniol in different
solvents/hydrogen donors.[a]
Entry
Solvent
T [8C]
Conv. [%][b]
ee[c] (R)
1
2
3
4
5
6
7
IPA
100
100
120
120
120
100
160
100
84
100
100
100
74
98
79
77
72
26
72
66
2-pentanol
2-pentanol
(S)-2-pentanol
(R)-2-pentanol
cyclohexanol[d]
cyclohexanol[d]
100
[a] Reaction time is 2 h. [b] Conversions measured by GC. [c] ee analysis
measured with a GC Column RT-BetaDEXsa 30 mꢀ0.32 mm
IDꢀ0.25 mm. [d] Reaction time is 4 h.
ee only ranged from 66 to 72%. An interesting effect occurs
with a chiral hydrogen donor, such as rac-, (S)- and (R)-2-
pentanol. The highest enantioselectivity occurs with either the
racemic alcohol (77–79% ee) or (S)-2-pentanol (72% ee),
whereas (R)-2-pentanol gives low selectivity (26% ee). This
indicates that the chirality of the hydrogen donor can play an
important role in the enantioselectivity of this process.
The ATH of geraniol in IPA was evaluated with other
chiral diphosphine ligands. Table 2 shows that the bidentate
ligands (S)-tol-binap, (R)-binap and (S,S)-iPrDuPhos pro-
duced the highest conversions and enantioselectivities. With
[*] R. Wu, M. G. Beauchamps, J. M. Laquidara, Prof. J. R. Sowa Jr.
Department of Chemistry and Biochemistry, Seton Hall University
South Orange, NJ 07079 (USA)
E-mail: john.sowa@shu.edu
Homepage: http://pirate.shu.edu/~sowajohn
[**] We thank Dr. Mahavir Prashad, Head of Chemical Development
Unit, Novartis Pharmaceuticals Corporation (East Hanover, NJ), for
the support of R.W.’s Ph.D program. We also thank Merck and Co.,
Inc., for supporting a doctoral fellowship for J.M.L. We thank
Celgene Corp. for assistance with 2H NMR spectroscopy.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107910.
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ee (93% ee).[11] These results indicate that this reaction is most
Table 2: ATH of geraniol with different chiral ligands.
% Citronellol[a]
(conv. [%][a])
ee [%],[b]
config
suited for ATH of allylic alcohols and suggest a specific
mechanism (see below).
Entry
Ligand
t [h]
Since the in situ catalyst preparation method leads to an
imprecisely defined catalyst precursor, we were interested in
1
2
3
4
5
6
(S,S)-diop
20
29
2
2
2
2
2
24
31 (38)
20 (24)
80 (92)
56 (80)
98 (100)
92 (100)
50 (100)
98[d] (100)
0
9, R
75, R
31, R
(S)-PhanePhos
(S,S)-MeDuPhos
(S,S)-Et-bpe
(S)-tol-binap
(R)-binap
Table 3: ATH of various substrates with (S)-tol-binap (A) and (S,S)-
iPrDuPhos (B).
98, R (78%)[c]
87, S
Substrate
Product
Lig-
t
% Product[a] ee [%],
7
(S,S)-iPrDuPhos
(S,S)-iPrDuPhos
84, R
and [h] (conv. [%][a]) config[c]
8[c]
90, R[d]
[a] Conversions and yields measured by GC. [b] ee analysis measured on
the (R)-Mosher ester on a Chiralcel OJ-H column (Daicel,
250 mmꢀ4.6 mm). [c] 78% yield of isolated product by column
chromatography. [d] Yield and ee of dihydrocitronellol; molar ratio of
geraniol/[Ru(cod)Cl2]n/KOH/ligand = 2:1:2:2.
98 [78][b]
(100)
1
2
3
4
A
B
A
B
2
2
2
98, R
84, R
93, S
83, R
50 (100)
(S,S)-iPrDuPhos (entries 7 and 8, Table 2), the reduction of
the prochiral double bond is complete at 2 h but after 24 h
À
both the allylic and the unfunctionalized C6 C7 double bonds
are reduced (note: S/C is 2:1) to give (R)-dihydrocitronellol in
90% ee [Eq. (2)]. This indicates that Ru/iPrDuPhos is a more
reactive catalyst than Ru/tol-binap.
96 [70][b]
(100)
24 62 (100)
99 [90][b]
(100)
5
6
A
B
12
72, S
93, R
2
99 (100)
Catalysts with (S)-tol-binap and (S,S)-iPrDuPhos were
selected for further evaluation for ATH of allylic alcohols
nerol (3), 3-phenyl-2-buten-1-ol (4), trans-trans-farnesol (5),
and homoallylic alcohol g-geraniol (6).[11] Other prochiral
olefin substrates include 3-phenylbut-2-enoic acid (7), 3-
methylcyclohex-2-enone (8), and trans-methylstilbene (9).[12]
Table 3 shows the isolated/GC yields and enantioselectivities
for substrates 1 to 9. Nerol (3) is reduced to (S)-citronellol in
70% isolated yield and 93% ee with (S)-tol-binap and the
chirality of the product is the same as in the gaseous
asymmetric reaction.[9] DuPhos ligands are known to give
the same configuration with either E or Z olefins under
gaseous hydrogenation;[13] similarly, ATH of geraniol (1) and
nerol (3) with (S,S)-iPrDuPhos both give (R)-citronellol in
83–84% ee. The substrate 3-phenyl-2-buten-1-ol (4) gives
90% isolated yield but lower ee (72%) with (S)-tol-binap.
Since 4 it is not susceptible to over-reduction, it is best
reduced with (S,S)-iPrDuPhos giving (R)-3-phenylbutan-1-ol
in 99% yield (GC), 93% ee.
82 [65][b]
(100)
7
A[f] 16[g]
81, R
2
19 (41)
36 (51)
34, R
33, R
8
A
6
2
64 (88)
64 (87)
7, R
8, R
9[e]
A
6
10[c]
11
A
B
96 93 (98)
12, R
9, R
2
96 (100)
Low enantioselectivity is observed for other prochiral
substrates 6–9. Better results have been reported for a,b-
unsaturated acids[4g,14] and ketones.[1h,15] The ATH of g-
geraniol (6) occurs in 41% conversion in 2 h and 51% in
6 h. At higher base concentration (4 equiv KOH), the extent
of conversion increases to 88% in 2 h, but the ee decreases to
8%. These results are in contrast with the gaseous hydro-
genation of g-geraniol which is very rapid and occurs in high
17, cis,
S,R
16, trans,
R,R
23
6 (97)
12
13
A
B
48
8, cis, S,R
14, trans,
R,R
34
9 (98)
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Table 3: (Continued)
Substrate
Product
Lig-
t
% Product[a] ee [%],
and [h] (conv. [%][a]) config[c]
14
B
24 18 (18)
0
[a] Conversions and yield determined by GC. [b] Yield of isolated
products. [c] ee of entries 1–4, 8, and 9 were measured by HPLC with the
(R)-Mosher ester on an OJ-H column or GC column RT-BetaDEXsa
30 mꢀ0.32 mm IDꢀ0.25 mm; ee of entries 5 and 6 were measured with
the acetate on an OJ-H column; ee of entries of 10, 11, and 14 were
measured directly on an OJ-H column; for entries 12 and 13 the cis/trans
isomers were measured by GC on a DB-23 column (J&W Scientific,
15 mꢀ0.32 mm) and the ee of the trans isomer was measured by proton-
decoupled 13C NMR spectroscopy. [d] 2.5 equiv of KOH per substrate
was used. [e] 4 equiv of KOH per substrate was used. [f] [RuCl2{(S)-tol-
binap}(p-cymeme)] as catalyst. [g] Reaction temperature 838C.
Several deuterium labeling experiments were then per-
formed. The ATH of geraniol with [D8]IPA [Eq. (5)] pro-
duced [D3]citronellol (12) as the major product after aqueous
workup. This structure was confirmed by GC/MS and NMR
spectroscopy.
performing ATH with a pre-made catalyst. With [{(S)-
binap}RuCl2] geraniol was converted to (R)-citronellol in
93% ee and 85% isolated yield. This ee is higher than that
obtained from the in situ prepared (R)-binap complex
(Table 2 entry 6, 87% ee) with, of course, the opposite
configuration. This catalyst also converts nerol (3) to (S)-
citronellol in 91% ee. So far, [{(S)-tol-binap}RuCl2(p-
cymene)] has proven to be the easiest to handle catalyst as
indicated by the ability to use higher concentrations of
geraniol (0.1m), lower catalyst loading (3 mol%), and lower
temperature (838C) [Eq. (3)].
The GC/MS showed a molecular ion peak with a mass of
159, which indicated the formation of [D3]citronellol (12). The
1H NMR spectrum indicated only one hydrogen was present
on C1. The presence of two deuteriums on C2 and the absence
of deuterium on C3 was confirmed by 13C NMR and HMQC
spectroscopy. Because of 12, we can rule out both gaseous
hydrogenation and outer-sphere hydrogen transfer mecha-
nisms.[6]
ATH of geraniol with iPrOD [Eq. (6)] produced after
aqueous workup [D2]citronellol (13) as confirmed by GC/MS
and NMR spectrsocopy.
It is intriguing that the reaction gives the same stereo-
chemical configuration as the gaseous reaction but that the
scope is limited to allylic alcohols. Thus, we investigated the
reaction mechanism. Enantioselective isomerization of allylic
amines to enamines is a well-developed transformation and
has been applied at industrial scale.[9c,16] The isomerization of
allylic alcohols has been extensively studied in recent
years,[7,17] and there are several reports of the asymmetric
version of this process.[18] As previously discussed, Cadierno
et al. reported a nonchiral ruthenium-catalyzed isomeriza-
tion/transfer hydrogenation of allylic alcohols in which
a ketone intermediate was clearly identified.[7] Experiments
to determine the reaction mechanism are described below.
The first experiment involved using the ATH conditions in
THF solvent [Eq. (4)] and resulted in 47% conversion to give
13% of citronellol (2), 21% of citronellal (10), and 13% of
citral (11). This result indicates geraniol itself becomes the
hydrogen donor giving the hydrogenated product citronellol
(2) and the dehydrogenated product citral (11). Citronellal
(10) forms as an intermediate in the isomerization of
geraniol.[7]
The GC/MS showed a molecular ion peak of 158
1
corresponding to [D2]citronellol (13). The H NMR, COSY
and 13C-DEPT135 results showed no detectable hydrogen on
the C2 position; the 13C NMR spectrum showed clear
coupling between C2 and two deuterium atoms.
Finally, another key deuterium labeling experiment was
the ATH of 2-deuteriogeraniol[19] (14) [Eq. (7)]. The only
molecular ion found in GC/MS is at 157 corresponding to the
1
mono-deuterated citronellol 15 and 16. The H NMR spec-
trum showed increased amount of hydrogen (from 1.0 to 1.3)
on C1; the 13C NMR and DEPT135 spectra clearly showed
a mixture of 15 and 16 with a triplet for C1 (one H/one D)
corresponding to 15 and a singlet for C1 (with 2 hydrogens)
2
corresponding to 16. The H NMR spectrum confirmed the
presence of deuterium at C3.
These observations lead us to conclude that the ATH of
geraniol proceeds through a new combination of mechanisms.
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Experimental Section
Under an atmosphere of argon or nitrogen, a degased solution of
geraniol (0.01m, 10 mL) in isopropyl alcohol (IPA), [Ru(cod)Cl2]n
(0.001m), KOH (0.002m), and chiral ligand (0.002m) (alternatively,
0.001m of [{(S)-tol-binap}RuCl2(p-cymene)]) was added to a Schlenk
flask equipped with a magnetic stirbar and covered with a fresh
rubber septum. Three freeze(liquid N2)–pump–thaw cycles were
performed and the flask was transferred to an oil bath at 1008C and
stirred in a closed system for 2 h. (With [{(S)-tol-binap}RuCl2(p-
cymene)] degassing was performed by three pump–fill cycles and
heating occurred at 838C.) The solvent was evaporated under vacuum
and the product was purified by chromatography on silica gel with
pentane/ethyl acetate as the eluent. Enantiomeric purity determina-
tions are indicated in the footnotes of the Tables and in the
Supporting Information.
First, there is an enantioselective 1,3-intramolecular hydrogen
shift.[18] Second, there is transfer hydrogenation which pro-
vides the reduced product. The combined enantioselective
isomerization/transfer hydrogenation results in an overall
ATH process which, to our knowledge, has not been reported.
Scheme 1 shows a proposed stepwise mechanism consis-
tent with the deuterium incorporations found in Equa-
tions (5)–(7). Initially, the allylic alcohol coordinates to the
Received: November 9, 2011
Revised: December 2, 2011
Published online: January 20, 2012
Keywords: allylic alcohols · asymmetric catalysis ·
.
asymmetric transfer hydrogenation · isomerization ·
phosphine ligands
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Ru after deprotonation with KOH base (a–c). The asymmet-
ric induction step occurs during the Ru-assisted 1,3-hydrogen
shift through enal intermediate d to enolate e and enol f.[20]
Deuterium incorporation on C2 occurs in two equilibrium
tautomerization steps with the enol giving aldehydes g and h.
Finally, transfer hydrogenation of the aldehyde through
a [Ru]–D intermediate gives i. This mechanism indicates
allylic isomerization as the key asymmetric induction step and
is the reason for excellent selectivity for allylic alcohols and
low selectivity for other unsaturated substrates.
In conclusion, we report a new asymmetric transfer
hydrogen reaction that enables reduction of allylic alcohols
in high yield and excellent enantioselectivity. We have
developed a screening process that prepares the catalyst
in situ by supplying a metal source, a chiral bidentate
phosphine ligand, base, and hydrogen donor solvent. Also,
the reaction may be performed using a commercially avail-
able chiral catalyst complex, [{(S)-tol-binap}RuCl2(p-
cymene)]. The configuration of the product is the exact
same as in the gaseous hydrogenation reaction which makes it
very convenient to predict stereochemistry. Mechanistic
studies reveal an enantioselective isomerization/transfer
hydrogenation process which is a new combination of
mechanisms. Compared with conditions of high-pressure
hydrogenation that is often necessary for asymmetric reduc-
tion of allylic alcohols, this new reaction is very promising as it
occurs in high yield, high ee and does not require hydrogen
gas.
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