Asymmetric hydrogenation of disubstituted furans

Article abstract of DOI:10.1002/anie.201310985

An enantioselective hydrogenation of disubstituted furans has been developed by using a chiral ruthenium catalyst with N-heterocyclic carbene ligands. This reaction converts furans into valuable enantioenriched disubstituted tetrahydrofurans.

Full text of DOI:10.1002/anie.201310985

Angewandte
Chemie
DOI: 10.1002/anie.201310985
Asymmetric Hydrogenation
Asymmetric Hydrogenation of Disubstituted Furans**
Je˛drzej Wysocki, Nuria Ortega, and Frank Glorius*
Dedicated to the Max-Planck-Institut fꢀr Kohlenforschung celebrating its centenary
Abstract: An enantioselective hydrogenation of disubstituted
furans has been developed by using a chiral ruthenium catalyst
with N-heterocyclic carbene ligands. This reaction converts
furans into valuable enantioenriched disubstituted tetrahydro-
furans.
icals, agrochemicals, and materials. A pioneering study by
Takaya and co-workers in 1995 resulted in the first asym-
metric homogeneous hydrogenation of 2-methylfuran.[12a] An
enantioselectivity of 50% ee was achieved by utilizing a Ru-
binap catalyst system. Other significant examples were
reported by the Pfaltz research group, who successfully
hydrogenated two monosubstituted furans with up to
93% ee.[10b] Disubstituted furans have been even less
explored, with the sole example in the literature to date
being reported by Albert and co-workers (Scheme 1).[12c]
D
uring the past few decades the asymmetric hydrogenation
of heterocyclic aromatic compounds has received increasing
interest among synthetic organic chemists.[1] As a consequence
of its straightforwardness and excellent atom economy,
hydrogenation constitutes a highly attractive method for
obtaining enantioenriched organic compounds. Moreover,
the asymmetric hydrogenation of aromatic or heteroaromatic
compounds gives rapid access to saturated or partially
saturated cyclic systems of great importance in biology.[2]
When combined with well-established methods for the
functionalization of aromatic or heteroaromatic feedstocks,
asymmetric hydrogenation constitutes an elegant method for
the preparation of enantioenriched densely functionalized
cyclic compounds.
However, the asymmetric hydrogenation of aromatic
systems is inherently challenging in terms of reactivity
(dearomatization) and selectivity (shape and face recogni-
tion). In recent years, several impressive homogeneous
catalyst systems have been developed which enabled the
asymmetric hydrogenation of various heterocycles. Since 1987
efficient methods have been described for quinolines,[3]
isoquinolines,[4] quinoxalines,[5] pyridines,[6] indoles/pyrroles,[7]
phenanthrolines,[8] (benzo)thiophenes,[9] benzofurans,[10] and
carbocycles.[11] In contrast, however, the asymmetric hydro-
genation of furans has been notably less explored,[10b,12]
despite the importance of tetrahydrofurans as pharmaceut-
Scheme 1. Rare examples of the asymmetric hydrogenation of furans.
BArFÀ =[B[3,5-(CF3)2C6H3]4]À, cod=cycloocta-1,5-dienyl.
[*] J. Wysocki, Prof. Dr. F. Glorius
NRW Graduate School of Chemistry, Organisch-Chemisches Insti-
tut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
Recently, we reported a novel asymmetric hydrogenation
catalyst consisting of a RuII complex bearing the chiral N-
heterocyclic carbene ligand SINpEt (see Table 1). This
catalyst exhibited excellent activity and high selectivity in
the asymmetric hydrogenation of a range of heterocyclic
compounds: quinoxalines,[11b] benzofurans,[10c,d] benzothio-
phenes,[9c] thiophenes,[9c] flavones,[13] and indolizines.[14]
Encouraged by these results we sought to investigate whether
challenging furan substrates could also be reduced asym-
metrically using this privileged catalytic system.
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
Dr. N. Ortega
Bayer Pharma AG, Medicinal Chemistry
Aprather Weg 18 A, 42113 Wuppertal (Germany)
[**] We thank Dr. Matthew N. Hopkinson for helpful discussions during
preparation of this manuscript and Prof. Dr. Klaus Ditrich (BASF)
for donation of precious chiral amines (ChiPros). This work was
supported by the NRW Graduate School of Chemistry in Mꢁnster
(J.W.).
In our initial experiments the hydrogenation was con-
ducted on the easily accessible disubstituted furan 2-(4-
fluorophenyl)-5-methylfuran (1a), which was treated with the
active ruthenium precatalyst (preformed from [Ru(cod)(2-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310985.
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methylallyl)2], SINpEt·HBF4, and KOtBu) in n-hexane under
65 bar H2 pressure at 408C. Pleasingly, the corresponding
tetrahydrofuran 2a was delivered as a 4:1 diastereomeric
mixture (cis/trans) in 60% conversion with an e.r. value of
85:15.[15] An extensive screening of the reaction parameters
was carried out to optimize the yield and enantioselectivity
(see the Supporting Information for more details). In analogy
with our previous studies, an evaluation of different chiral
NHC ligands confirmed the remarkable efficiency of the
SINpEt ligand. The other tested ligands resulted in a dramatic
decrease in the e.r. value or the yield.
dramatic increase in conversion was achieved upon elevating
the pressure of H2 to 130 bar (entry 9). Under this pressure
and using a 1:1 (v/v) mixture of t-amylOH and n-hexane as
solvent, the conversion into 2a was 80%, with no erosion of
the e.r. value (entry 10). To our surprise, full conversion could
be obtained under these conditions upon lowering the
temperature to 258C (entry 11).
A range of 2,5-disubstituted furans were hydrogenated to
their corresponding products under these conditions
(Scheme 2). Changing from an electron-withdrawing fluorine
atom to an electron-donating OMe group gave rise to product
The effect of changing the solvent, H2 pressure, and
temperature was then investigated. In each case the hydro-
genation was a very clean process, with no side reactions or
decomposition of the starting material being detected. The
conversion, however, was highly sensitive towards the reac-
tion medium. For example, THF, which chemically resembles
the product, resulted in only a trace amount of a nearly
racemic product 2a, even at an elevated temperature of 608C
(Table 1, entry 1). The use of CH2Cl2, a very popular solvent
Table 1: Optimization study.
Entry[a]
Solvent
Conv. [%][b]
d.r.[c]
e.r.[d]
1[e,f]
THF
CH2Cl2
DME
PhCF3
PhCH3
n-hexane
t-amylOH
n-hexane
11
0
37
40
48
60
66
90
n.d.
–
3.2:1
3:1
3.7:1
4:1
4.2:1
4.1:1
4.1:1
4.2:1
4.5:1
54:46
–
2[e,g]
3[e,g]
4[e,g]
5[e,g]
6[e,g]
7[e,g]
8[g,h]
9[g,h]
10[g,h]
11[h,i]
89:11
87:13
86:14
85:15
87:13
85:15
87:13
87:13
88.5:11.5
t-amylOH
t-amylOH/n-hexane (1:1)
t-amylOH/n-hexane (1:1)
75
80
99 (84%)
Scheme 2. Substrate scope of 2,5-disubstituted furans. General condi-
tions: [Ru(cod)(2-methylallyl)2] (0.015 mmol), SINpEt·HBF4
(0.032 mmol), and KOtBu (0.045 mmol) were stirred at 708C in n-
hexane (0.5 mL) overnight, after which t-amylOH (0.5 mL) was added
and the mixture was added to a vial containing a substrate (1a–m,
0.30 mmol). The hydrogenation reaction was performed under the
shown conditions in a steel autoclave. The conversions given were
estimated by 1H NMR spectroscopy; the e.r. values for the cis products
were estimated by HPLC on a chiral
[a] General conditions: [Ru(cod)(2-methylallyl)2] (0.015 mmol), SIN-
pEt·HBF4 (0.032 mmol), and KOtBu (0.045 mmol) were stirred at 708C
in n-hexane (1 mL) overnight, after which the solvent was exchanged for
the indicated one (except for entries 7 and 9). The resulting mixture was
then added to 1a (0.30 mmol) and hydrogenated under the shown
conditions for 24 h. [b] Determined by 1H NMR spectroscopy; yield of
isolated product in parentheses. [c] Determined by 1H NMR spectros-
copy; n.d.=not determined. [d] e.r. value for the cis product; determined
by HPLC on a chiral stationary phase. [e] At 65 bar. [f] At 608C. [g] At
408C. [h] At 130 bar. [i] At 258C. DME=1,2-dimethoxyethane.
stationary phase.
2b in a slightly diminished conversion but with a higher
e.r. value of 93:7. Modifying the alkyl substituent from
a methyl to an n-butyl group resulted in a significantly
lower conversion (2c). By comparing the results for 2a and
2b, we hypothesized that an increase in the polarity of the
substrate could be beneficial for the stereochemical outcome.
However, the di- and trimethoxy-substituted furans 1d and 1e
did not follow this trend, furnishing the corresponding
in numerous Ir-catalyzed asymmetric hydrogenations, also
returned only starting material (entry 2). More promising
results emerged when DME, PhCF3, or toluene were
employed as solvents (entries 3–5). Quite surprisingly, the
tertiary alcohol t-amylOH was a suitable alternative to n-
hexane, and resulted in a slight increase in conversion as well
as the diastereo- and enantioselectivity (entry 7). A more
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tetrahydrofurans with slightly diminished enantioselectivities.
A wide range of diversely substituted aryl-alkyl furans could
be successively hydrogenated, and a strong correlation
between the electronic properties of the aromatic substituents
and the level of enantioselectivity was observed. For example,
the furans 1l and 1m bearing strongly electron-withdrawing
CF3 groups were quantitatively converted into the corre-
sponding products with diminished e.r. values. Interestingly,
a simple plot of enantioselectivity (e1/e2) against the relevant
s Hammett parameter of the aryl substituent(s)[16] reveals an
almost linear correlation (R2 = 0.9374; Figure 1).
Scheme 3. Possible mechanistic pathways (shortened) for the asym-
metric hydrogenation of 2,5-disubstituted furans.
major 2R,5R-cis isomer could also continue without decom-
plexation of the Ru catalyst, through the formation of a Ru-p-
allyl complex (Scheme 4) and its hydrodemetalation (reduc-
tive elimination) with formation of the second stereocenter.
The second less-favored intermediate I2 might undergo
Figure 1. Hammett plot for selected 2,5-disubstituted products.
Consequently, furan 1 f with a strongly electron-donating
NMe2 group (s = À0.82) was synthesized and subjected to the
standard hydrogenation conditions. As predicted, the corre-
sponding product 2 f was delivered with an excellent e.r. value
of 95:5 in a yield of 73% of the isolated product. The absolute
configuration of all three stereoisomers formed (major and
minor enantiomer of cis product together with the one trans
enantiomer; see Scheme 2) has been assigned by comparison
with the literature optical rotation data for compound 2k.[17]
The absolute configuration of all other compounds was
assigned by analogy.
Scheme 4. Possible involvement of a hypothetic Ru-p-allyl species in
the formation of the main product.
A tentative mechanistic pathway for the hydrogenation of
2,5-disubstituted furans is shown in Scheme 3. Keeping in
mind the absolute configuration of the major cis enantiomer
formed and the enantioinduction of the related asymmetric
hydrogenation of 2-substituted benzofurans with a similar
catalyst system,[10c] it seems likely that the hydrogenation
sequence starts at the alkyl-substituted double bond. Thus, in
a stepwise process, the coordination of the substrate to the
chiral Ru-NHC catalyst is followed by the enantiodetermin-
ing hydrometalation by a Ru-hydride species at the less
sterically hindered side of the furan ring, thereby leading to
two dihydrofuran stereoisomers (I1 and I2). It is unclear if the
major product enantiomer (2R,5R-cis) is then formed by
a sequence of hydrodemetalation (reductive elimination) of
I1, recoordination at the remaining double bond, hydro-
metalation, and hydrodemetalation. Naturally, recoordina-
tion from the other face of the heterocycle would lead to the
2S,5R-trans isomer. Alternatively, the hydrogenation to the
a similar sequence. In this case, the two possibilities can
lead to either the corresponding 2S,5S-cis product or, as a very
disfavored step, the 2R,5S-trans product. Remarkably, the
2R,5S enantiomer was not detected by HPLC with any of the
substrates tested (Scheme 2).
At this stage we sought to investigate other substitution
patterns of our model furan 1a.[18] The 2,4-disubstited furan
3a was treated with hydrogen gas in the presence of the Ru-
NHC catalyst. Although a high conversion of 98% was only
observed after 48 h at the higher reaction temperature of
408C, the corresponding tetrahydrofuran 4a was furnished as
a single cis diastereoisomer with an outstanding e.r. value of
99:1 (Scheme 5). Similar results were obtained for a series of
2-methyl-4-aryl-substituted furans. In all cases, the enantio-
meric ratio of the obtained products was around 99:1. In
contrast to the 2,5-disubstituted substrates, where the elec-
tronic properties of the aryl group had a large effect on the
level on enantiocontrol, excellent e.r. values were observed
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[3] For selected examples of the asymmetric hydrogenation of
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Scheme 5. Substrate scope of 2,4-disubstituted furans. General condi-
tions: [Ru(cod)(2-methylallyl)2] (0.015 mmol), SINpEt·HBF4
[5] For selected examples of the asymmetric hydrogenation of
quinoxalines, see a) S. Murata, T. Sugimoto, S. Matsuura,
Heterocycles 1987, 26, 763; b) C. Bianchini, P. Barbaro, G.
Scapacci, E. Farnetti, M. Graziani, Organometallics 1998, 17,
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2009, 121, 9299; Angew. Chem. Int. Ed. 2009, 48, 9135; f) N.
(0.032 mmol), and KOtBu (0.045 mmol) were stirred at 708C in n-
hexane (0.5 mL) overnight, after which t-amylOH (0.5 mL) was added
and the mixture was added to a vial containing the substrate (3a–f,
0.30 mmol). The hydrogenation reaction was performed under the
shown conditions in a steel autoclave. The conversions were estimated
by 1H NMR spectroscopy (yields of isolated product in parentheses).
The e.r. values were determined by HPLC on a chiral stationary phase.
for all these furans. However, in some cases the reactivity was
lower (4e, 4 f) and, because of the volatile character of some
of the products, the yields of the isolated products lie in the
range 55–82% (Scheme 5).
In conclusion we have developed an efficient procedure
for the previously underexplored hydrogenation of disubsti-
tuted furans. This process gives access to biologically impor-
tant tetrahydrofurans in high yields and with excellent
e.r. values up to 99:1. The asymmetric hydrogenation of
furans and other ubiquitous aromatic heterocycles should be
of synthetic value.
ˇ ´
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Received: December 18, 2013
Published online: && &&, &&&&
Keywords: asymmetric catalysis · furans · heterocycles ·
.
homogeneous catalysis · hydrogenation
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monosubstituted furan afforded the corresponding product with
full conversion, although with a low ee value (20%).
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Communications
Asymmetric Hydrogenation
J. Wysocki, N. Ortega,
F. Glorius*
&&&& — &&&&
Asymmetric Hydrogenation of
Disubstituted Furans
Pump it up! An asymmetric hydrogena-
tion of disubstituted furans has been
developed by using a Ru-NHC based
catalyst system (NHC=N-heterocyclic
carbene). This reaction converts flat
furans into enantioenriched tetrahydro-
furans of relevance in biology and mate-
rial science.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!