Asymmetric hydrogenation of ketones with H2 and ruthenium catalysts containing chiral tetradentate S2N2 ligands

Article abstract of DOI:10.1002/anie.201304844

Getting more for less: In the presence of H₂ and a base, air- and moisture-tolerant Ru^II complexes catalyze the hydrogenation of ketones and aldehydes with excellent activity and chemoselectivity, and with enantioselectivity of up to 95 % under mild conditions. The ratio of substrate to catalyst can be lowered to 10⁶:1. The reactions tolerate scale-up and can be carried out with almost no solvent. A base-free method is available for base-sensitive substrates. Copyright

Full text of DOI:10.1002/anie.201304844

Angewandte
Chemie
DOI: 10.1002/anie.201304844
Phosphine-Free Hydrogenation
Asymmetric Hydrogenation of Ketones with H2 and Ruthenium
Catalysts Containing Chiral Tetradentate S2N2 Ligands**
Ruth Patchett, Iris Magpantay, Lionel Saudan, Christoph Schotes, Antonio Mezzetti,* and
Francesco Santoro*
The ruthenium-catalyzed homogeneous hydrogenation of
carbonyl groups has established itself as a mature synthetic
method on an academic and industrial scale[1] for the selective
generation of stereogenic centers as an alternative to high-
energy, pyrophoric hydride reagents. The development of
such catalytic systems has gone hand in hand with that of
chiral bidentate diphosphine ligands,[2] which, however, are
often tedious and expensive to prepare because their multi-
step synthesis requires air- and moisture-free conditions. In
contrast, phosphine-free chiral catalysts that operate under
the industrially preferred and atom-economical hydrogena-
tion with H2 (HY) are still rare,[3–5] the most successful
examples being h5-cyclopentadienyl[3] and h6-arene[4] diamine
RuII complexes. Most of these catalysts, as with those
operating under transfer hydrogenation (TRHY) condi-
tions,[6] fail to match the efficiency and selectivity require-
Scheme 1. Ligands 1a–g and Ru complexes 2a–e,g used in this study.
ments of industrial application. Following the work carried
out at Firmenich[7] on the HYof ketones with [RuCl2(PNNP)]
catalysts,[8] where PNNP is a chiral tetradentate ligand with
a P2N2 donor,[9] we developed a family of ligands in which the
phosphines are replaced by thioethers (SNNS).[10] Such chiral
ligands are cheap, air- and moisture-stable, and easy to
prepare. This is a preliminary report of ruthenium/SNNS
complexes that catalyze the asymmetric HY of ketones and
aldehydes with good chemo- and enantioselectivity.[10–12]
Ligands 1a–f (Scheme 1) were conveniently obtained in
two quantitative steps without exclusion of air by nucleophilic
aromatic substitution of 2-nitro- or 2-bromobenzyl aldehydes
with the appropriate thiol, followed by condensation with the
chiral 1,2-cyclohexanediamine. Ligand 1g was obtained by
NaBH4 reduction of 1a in quantitative yield. The ruthenium
complexes [RuCl2(SNNS)] (2a–e,g) were prepared from the
reaction of [RuCl2(PPh3)3] with the appropriate tetradentate
ligand (SNNS = 1a–e,g) and were fully characterized,
whereas ligand 1 f was used in situ (see below), as its
complexation failed with a number of precursors. The
dichloro complexes 2a–e and 2g are stable for several hours
in CHCl3, toluene, and alcohol solutions when exposed to air.
The crystal structure of (R,R)-[RuCl2(1a)] (R,R)-(2a)
shows a weakly distorted octahedral coordination sphere
around ruthenium with a trans Cl-Ru-Cl unit, and the
R configuration at both Ru–thioether moieties (Figure 1).
Figure 1. ORTEP plot of (R,R)-[RuCl2(1a)] (R,R)-(2a). Ellipsoids set at
30% probability.
[*] R. Patchett, I. Magpantay, Dr. L. Saudan, Dr. F. Santoro
Corporate R&D Division, Firmenich SA
route des Jeunes 1, P.O. Box 239, 1211 Genꢀve 8 (Switzerland)
E-mail: francesco.santoro@firmenich.com
The “stepped” conformation of the tetradentate SNNS ligand
is reminiscent of the achiral diimino complex trans-[RuCl2-
(SNNS)] (SNNS = N,N’-bis(2-tert-butylthiobenzylidene)-1,3-
propanediamine)[11a] and of other chiral PNNP[8,13] and
salen[14] analogues.
Dr. C. Schotes, Prof. Dr. A. Mezzetti
Department of Chemistry and Applied Biosciences, ETH Zꢁrich
8093 Zꢁrich (Switzerland)
E-mail: Mezzetti@inorg.chem.ethz.ch
A preliminary screening of catalysts 2a–e and 2g in the
HYof acetophenone (3a) identified iPrOH as the solvent and
tBuOK and KOH as the bases of choice with a base-to-
catalyst ratio of 10:1 and 100:1, respectively (Table 1; see also
the Supporting Information). The catalytic reactions were
[**] The Authors thank Mr. Rino Schwenk for his assistance with the X-
ray structure of complex 2a and Dr. Alec Birkbeck for the generous
donation of substrate 3l.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304844.
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Table 1: Hydrogenation of acetophenone (3a).[a]
Table 2: Hydrogenation of substrates 3b–o.[a]
Entry
Cat.
3a/base/cat.
T [8C]
t [h]
Conv. [%]
ee[b] [%]
1
2
2a
2a
2a
2b
2c
2d
2e
2g
2a
2a
2g
2g
2000:10:1
2000:10:1
2000:100:1
2000:10:1
2000:10:1
2000:10:1
2000:100:1
2000:10:1
105:450:1
106:450:1
105:450:1
106:450:1
60
23
23
60
60
60
23
60
60
60
60
60
1
1
99
99
96
99
99
99
99
99
99
90
99
15
72
77[c]
81
33
59
44
88
69
64
68
61
63
3[d]
4
1.5
1.5
2
1.5
4
1
4
7
4
5
6
7[d]
8
9[e]
10[e]
11[e]
12[e]
7
[a] Conditions (unless otherwise stated): 3a (20 mmol), cat. 2a–e,g
(0.05 mol%), tBuOK, iPrOH (10 mL), H2 (50 bar, initial pressure).
[b] (R,R)-2 gave (S)-4a as the major enantiomer. [c] Reactions in MeOH
or EtOH gave 4a (70% ee) quantitatively after 2 h. [d] KOH as base.
[e] 3a (40 mmol), iPrOH (20 mL total volume); see also Ref. [15].
Entry Cat.
3
3/base/cat. T [8C] t [h] Conv. [%] ee[b] [%]
1
2
3
4
5
6
7
2e
2e
2e
2e
2e
2e
2e
2a
2a
2a
2a
2a
2a
2a
3b
3c
3d
3e
3 f
3g
3h
3i
2000:100:1 23
2000:100:1 23
2000:100:1 23
2000:100:1 23
2000:100:1 23
2000:100:1 23
2000:100:1 23
3
3
2
3
3
3
3
16
2
2
98
99
99
98
99
98
98
99
99
99
99
99
99
99
90
95
83
90
79
91
95
–
–
–
–
–
carried out at an initial H2 pressure of 50 bar and, whenever
possible, they were run to maximal conversion. All hydro-
genations showed a variable induction period of 10–30 min,
during which no H2 was consumed.
8[c,d]
9[c,e]
10[c]
11[c]
12[c]
13[c]
14[c]
2000:10:1
2000:10:1
2000:10:1
2000:10:1
23
60
60
60
60
60
60
The screening of precatalysts 2a–e and 2g showed that
a bulky tBuS group is necessary to achieve high enantiose-
lectivity (entries 1–3), whereas ligands bearing smaller alkyl
groups (Cy, iPr, Me) on the sulfur give lower ee (entries 4–6).
Lowering the temperature to 238C with precatalyst 2a
improved the enantioselectivity from 72% to 77% ee
(entry 2). The use of KOH instead of tBuOK with a sub-
strate/catalyst/KOH ratio of 2000:1:100 gave 1-phenylethanol
(4a) with 81% ee (entry 3). Complex 2e, whose ligand bears
bulky substituents in the aryl backbone, gave the highest
enantioselectivity achieved with acetophenone (3a; 88% ee,
entry 7).
3j
3k
3l
2
2
2
2
3m 2000:10:1
3n
3o
2000:10:1
2000:10:1
–
–
[a] Conditions (unless otherwise stated): 3 (20 mmol), 2 (0.05 mol%),
KOH (5 mol%), iPrOH (10 mL), H2 (50 bar, initial pressure). [b] (R,R)-2e
gave (S)-4a–h as the major enantiomer. [c] tBuOK (0.5 mol%) was used
as base. [d] The d.r. of 4i is 54:46. [e] (E,E)/(E,Z) ratio of 4j is 95:5.
unsaturated ketones (3e and 3g) gave the corresponding
alcohols 4e and 4g with high enantioselectivity (90 and 91%
ee, entries 4 and 6). Additionally, using precatalyst 2a, enals
3j–3o were hydrogenated to the corresponding unsaturated
alcohols 4i–4o with excellent chemoselectivity.
Overall, products 4b–4o were formed quantitatively or
nearly so. Neither olefin hydrogenation nor isomerization
competes with the carbonyl reduction, even in the case of
sensitive terminal olefins or conjugated enones or enals.
Interestingly, the potentially coordinating thiophene group in
3o does not interfere.
The catalyst tolerates scale up, and substrates and solvents
can be used without previous purification. Thus, alcohols 4g
and 4m were prepared on a larger scale in excellent yield
using a lower loading of catalyst 2a and industrial-grade
substrates.[20a] Notably, these scale-up conditions did not
lower the enantioselectivity of 4g.[20b]
The SNNS ligands can also be used without base by
preparing the catalyst in situ from [Ru(methallyl)2(cod)]
(cod = 1,5-cyclooctadiene) and the appropriate ligand in
iPrOH (Scheme 2). This method, which was primarily devised
Upon increasing the S/C ratio to 106:1, precatalyst 2a gave
1-phenylethanol (4a) in 90% yield with nearly the same ee
obtained under otherwise analogous conditions (entries 1,
10).[15] The diamino complex 2g is less enantioselective (at
least with 3a, entry 8) than its diimino analogue 2a and
significantly less active when the S/C ratio was increased to
106:1 (entry 12), giving 4a in only 15% yield after 7 h. The
hydrogenation of 3a was also carried out in EtOH and MeOH
with minor erosion of enantioselectivity (70% ee at 238C with
both solvents).[16] Remarkably, 4a was also quantitatively
obtained with 70% ee when using commercial solutions of
NaOMe or KOMe in MeOH[17] as base without additional
solvent.[18]
Precatalysts 2a and 2e were tested in the hydrogenation
of unsaturated carbonyl compounds 3b–3o to the corre-
sponding alcohols 4b–4o, which are of relevance in fragrance
chemistry (Table 2). Using the best-performing precatalyst
2e, the highest enantioselectivity was obtained with a-
tetralone (3c, 95% ee) and 2,4,4-trimethylcyclohexenone[19]
(3h, 95% ee; entries 2 and 7), whereas other nonaromatic
2
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higher than that of the closely related Ru/PNNP systems,[24]
which give 1-phenylethanol (4a) in ca. 18% ee under HY
conditions.[7b]
A final issue concerns the variable induction periods
observed both with the diimino (2a–f) and diamino (2g)
catalysts. A series of experiments with 2a showed that the H2
pressure can be lowered to 20 bar with no impact on yield or
enantioselectivity, but no product is formed at 5 bar. How-
ever, when 2a (0.01 mmol) was treated with tBuOK
(0.1 mmol) in acetone/iPrOH (3:7 ratio) under H2 (50 bar)
at 608C for 40 min, followed by addition of 3a (20 mmol) to
the resulting yellow solution, the induction period was
suppressed, and the yield was quantitative after 1 h (50 bar
H2, 608C, 71% ee). With the same preactivation, complete
conversion was observed at lower H2 pressure (5 bar constant
pressure H2, quant. yield after 2 h at 608C, 68% ee; 68% yield
after 2.5 h at 258C, 74% ee).[22] We conclude that hydrogen
pressure is needed to generate the active form of the catalyst,
but is not limiting for the hydrogenation reaction after
catalyst activation.[25] The nature of the species formed under
these conditions is currently under investigation.
Scheme 2. In situ catalysis with 1a or 1 f.
for the hydrogenation of base-sensitive compounds,[21] allows
testing of ligand 1 f, which does not form an isolable dichloro
complex.[22]
In view of the formal analogy with the Ru/PNNP catalysts,
and to check whether TRHY may interfere in the above HY
reactions, precatalysts 2a and 2g were also tested under
standard[7b] TRHY conditions in iPrOH (Table 3).
In conclusion, the Ru/SNNS complexes presented herein
are the first example of phosphorus-free, air- and moisture-
tolerant catalysts for the asymmetric hydrogenation of
carbonyl groups with H2, the activity and enantioselectivity
of which are comparable to state-of-the-art Ru/diphosphine
complexes. The Ru/SNNS catalysts show excellent chemo-
selectivity in the reduction of the carbonyl groups of
unsaturated ketones and aldehydes, and are effective at S/C
ratios of up to 106:1, which allows for multimole-scale
reactions.
Table 3: Transfer hydrogenation of acetophenone (3a).[a]
Entry
Cat.
3a/base/cat.
t [h]
Conv. [%]
ee [%]
1
2
3
4
2a
2g
2a
2g
400:2:1
15
15
6
88
36
n.r.
n.r.
70
52
–
400:2:1
105:450:1
105:450:1
6
–
[a] Reaction conditions: 3a (2 mmol), base=tBuOK, 608C, iPrOH
(20 mL overall). n.r.=no reaction.
Received: June 5, 2013
Published online: && &&, &&&&
Complex 2a catalyzes the TRHY of 3a to give 1-phenyl-
ethanol (4a) with similar enantioselectivity as in HY (70% vs.
72% ee, respectively), but the reaction was much slower
(Table 3, entry 1 vs. Table 1, entry 1). Also, no TRHY
reaction was observed with lower catalyst loading (Table 3,
entry 3), leading to the conclusion that TRHY cannot
interfere in the HY reactions discussed above. Interestingly,
the diamino precatalyst 2g is much less active (36%
conversion after 15 h, entry 2) and enantioselective (52%
ee) than its diimino analogue 2a. This trend is opposite to that
of the Ru/PNNP series, in which the diamino complex is
a much more active and enantioselective TRHY catalyst than
the diimino analogue.[7b]
The data in Table 1 show that the Ru/SNNS catalytic
system is more active than other reported chiral phosphine-
free complexes.[3–5] A preliminary kinetic analysis of the HY
of 3a with 2a as precatalyst at a S/B/C ratio of 400000:2000:1
indicated a maximum TOF of 68 sÀ1.[22,23] This result is
excellent, and is comparable to the TOF values found for
benchmark enantioselective hydrogenation catalysts such as
[RuCl2(PPh3)2(dpen)] (6.4 sÀ1; dpen = 1,2-diphenylethylene-
diamine),[1d] [RuCl2{(R,R)-dpen}{(R)-tolBinap}] (63 sÀ1 at
30% conversion; tolBinap = 2,2’-bis(di-p-tolylphosphanyl)-
1,1’-binaphthyl),[1e] and [RuCl2(PNNP)] (ca. 40 sÀ1).[24] Also,
Keywords: alcohols · asymmetric hydrogenation ·
.
homogeneous catalysis · ruthenium · S ligands
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[1d–e,2]
that of [RuCl2{(R,R)-dpen}{(R)-tolBinap}]
and much
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cible results. Hence, a larger amount of base was used.
[16] No reaction was observed in the complete absence of alcohol.
[17] With 5 mol% of base vs. substrate 3a; see the Supporting
Information.
[18] Running the hydrogenation reaction (almost) without solvent
allows a more efficient use of reactors (higher process produc-
tivity) and is an important feature in the fine chemical industry.
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[20] a) Alcohol 4g was isolated in 92% yield and 85% ee from 3g
(0.4 mol) using a 3g/EtONa/2a ratio of 18700:100:1 in iPrOH.
The synthetic sandalwood ingredient 4m was isolated in 96%
yield from 3m (5.27 mol) using
a 3m/NaOH/2a ratio of
29300:1083:1 in MeOH; b) under conditions described in
Table 2, catalyst 2a gave 4g in quantitative yield and 86% ee.
See the Supporting Information for further experimental details.
[21] C. Saudan, L. Saudan, WO 2010/038209, 2010.
[22] See the Supporting Information.
[23] TOF is defined as mol of the product per mol of catalyst per
second.
[24] PNNP = (R,R)-bis[-2-(diphenylphosphino)benzylidene]cyclo-
hexane-1,2-diamine. For the determination of TOF, see the
Supporting Information.
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pathway.
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4
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Phosphine-Free Hydrogenation
R. Patchett, I. Magpantay, L. Saudan,
C. Schotes, A. Mezzetti,*
F. Santoro*
&&&& — &&&&
Asymmetric Hydrogenation of Ketones
with H2 and Ruthenium Catalysts
Containing Chiral Tetradentate S2N2
Ligands
Getting more for less: In the presence of
H2 and a base, air- and moisture-tolerant
RuII complexes catalyze the hydrogena-
tion of ketones and aldehydes with
excellent activity and chemoselectivity,
and with enantioselectivity of up to 95%
under mild conditions. The ratio of sub-
strate to catalyst can be lowered to 106:1.
The reactions tolerate scale-up and can be
carried out with almost no solvent. A
base-free method is available for base-
sensitive substrates.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!