Angewandte
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Chemie
Table 1: Selected deviations from optimized conditions.
We approached this problem by using two different
catalytic systems fulfilling distinct tasks in the sought-after
transformation to the desired fused bicycle. The first catalyst
would partially reduce the heterocyclic core yielding a 2,3-
dihydrobenzofuran, rendering this compound as a chiral
intermediate, while the second catalyst would perform a full
hydrogenation of the remaining six-membered all-carbon
ring. We envisioned that the second catalyst would be able to
utilize the installed stereocenter to guide a downstream
diastereoselective reduction,[9] for example, on a solid surface
under a Horiuti–Polanyi mechanism.[10]
To catalyze the first step we chose the established
Ru((R,R)-SINpEt)2 catalyst 3,[11] which features two N,N’-
bis(naphthylethyl)imidazolidinium-2-ylidene (NHC) ligands
and was previously shown to catalyze the partial hydro-
genation of benzofurans with high enantiomeric excess under
mild conditions (TOF 1092 hÀ1).[5c,11a] To prevent a racemic
background reaction in a one-pot approach, the second
(heterogeneous) catalyst in our envisioned process would
need to be formed or activated in situ after the transformation
of the starting material to the intermediate 2,3-dihydroben-
zofuran is complete. In case of in situ formation, a suitable
precursor needs to be chosen, and reaction conditions need to
be adjusted such that they match the induction periods of the
two catalysts. We found the Rh-CAAC (cyclic alkyl amino
carbene) precursor 4, which was studied in depth by Zeng,
Bullock, us, and others to be a perfect match.[12]
Entry Deviation
Yield A [%] Yield B [%] d.r.
e.r.
1
2
3
4
5
6
7
–
64
14
49
55
–
26
76
56
48
2
94:6 95:5
95:5 50:50
90:10 51:49
92:8 51:49
Ru/C instead of 4
Rh/C
Pd/C
Pt/C
–
–
[Rh(COD)Cl]2
SiO2 instead of
molecular sieves
Alumina A
Alumina N
73
62
25
36
94:6 50:50
98:2 50:50
8
9
63
64
29
33
4
94:6 50:50
94:6 95:5
–
10
11
458C instead of 608C 12
5 mol% 4 33
–
13
94:6 93:7
The reaction was started with 10 bar H2 pressure and 258C. After 3 h
reaction time the initial conditions were adjusted to the final indicated
values. Yield of product A and by-product B, d.r., and e.r. values were
determined by GC-FID. COD=1,5-cyclooctadiene, MS=molecular
sieves.
hydrogen pressure as external stimuli. Hence, it can be
described as an assisted cascade catalysis.[14,15]
We started our investigation on 2-methyl-5-fluorobenzo-
furan 1x as the test substrate to be able to study the
preservation of the fluoro substituent in addition to yield and
stereochemical outcome of the reaction. Early screening
attempts confirmed our hypothesis, as the proposed and
subsequently optimized system successfully transformed 1x
to the fully saturated analog (see Table 1). Several controls
show how unique the achieved match of catalysts is, since all
other tested common catalysts for arene hydrogenation failed
to yield the desired product in an asymmetric fashion
(Table 1, entries 2–6). Although the high chemoselectivity of
catalyst 4 could be leveraged to preserve the sensitive fluoro
moiety, defluorination levels were still comparatively high.
The beneficial effect of silica gel as supporting material in
these terms, which we observed in earlier studies,[13] could not
be exploited in the dual catalytic system, since it deactivated
catalyst 3 and yielded a racemic product mixture (similarly for
acidic alumina, Table 1, entries 7 and 8). In the course of our
optimization we observed that an elevated reaction temper-
ature of 608C was necessary to activate the rhodium catalyst
in the presence of 3, lower temperatures were not sufficient to
achieve full conversion (Table 1, entry 10). An increased
amount of 4 was necessary to overcome a disadvantageous,
deactivating interaction of both catalytic systems and deliver
complete conversion of the 2,3-dihydro intermediate
(Table 1, entry 11). However, this remarkable activity was
imperative in the development of a one-pot protocol for the
complete enantioselective hydrogenation of benzofurans. In
essence, this procedure resembles a type of sequential
catalysis in which precursors for both catalysts are present
in the reaction mixture from the beginning and their
activation is solely controlled by changing temperature and
With the optimized conditions in hand, we continued our
investigation into the scope of the reaction (Figure 2). The
method tolerates various substitutions on the six-membered
ring. Next to 2-methylbenzofuran 1a, the influence of
primary, secondary, and tertiary alkyl substituents was inves-
tigated systematically for the 5-position, all giving high yield
and very good d.r.- and e.r.-values (2a–e). Furthermore, the
synthetically accessible 7-position (2 f,g) as well as multiple
substituents (2h) were tolerated well with excellent selectiv-
ity.
This method mainly yields only two of all possible
diastereomers and the observed e.r. was identical for major
and minor species. Next, we investigated functional group
tolerance. A phenyl group was reduced under the reaction
conditions, giving the fully saturated product (2i). Concom-
itantly, a methyl ester group was preserved without reduction
(2m). Tertiary amino functions were tolerated well (2n, o). A
crystal of the hydrochloride salt of 2n could be used to
determine the absolute configuration of the hydrogenated
products to be 2R,3aS,5R,7aS (see Figure S2, remaining scope
entries were assigned in analogy). When using acetamide-
protected primary amine 1p as the starting material, excellent
yield and diastereoselectivity were observed. Yet, the product
was obtained as racemic mixture (2p).[16] However, this
limitation could be overcome by using the free primary amine
as starting material for hydrogenation yielding the enantioen-
riched product 2q after subsequent protection with trifluoro-
acetic anhydride to ease isolation efforts. We were very
pleased when discovering that a boryl ester was tolerated
giving the corresponding product 2r with 96:4 e.r. Both
primary amines as well as protected boryl esters constitute
2
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Angew. Chem. Int. Ed. 2021, 60, 1 – 6
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