Organic Letters
Letter
derivatives so far. A broad substrate scope as well as high
efficiency and enantioselectivity are highly desirable for the
synthesis of chiral hydantoin derivatives. Herein we wish to
report an efficient and enantioselective hydrogenation of 5-
alkylidene-2,4-diketoimidazolidines catalyzed by the Rh-(R,R)-
f-spiroPhos complex, providing chiral hydantoin derivatives
with high enantioselectivities of up to 96% ee. Moreover, this
catalyst also exhibits excellent performance in the hydro-
genation of 3-alkylidene-2,5-diketopiperazines, affording chiral
2,5-diketopiperazines with up to 99.9% ee (Scheme 1).
complete conversion (entry 2). Remarkably, a lower hydrogen
pressure of 20 atm could still provide full conversion with a
slightly higher enantioselectivity (entry 3). Even when this
hydrogenation was carried out under 10 atm hydrogen
pressure, 94% conversion with similar enantioselectivity
could be achieved (entry 4). It was noteworthy that under
20 atm H2, the complete conversion could still be achieved in 6
h with 96% ee remaining (entry 5). Subsequently, some other
chiral phosphorus ligands including monodentate and
bidentate ligands containing various skeletons (Figure 2),
Scheme 1
Initially, the substrate 1a, (Z)-5-benzylideneimidazolidine-
2,4-dione, was chosen as the model substrate for the conditions
optimization, and the hydrogenation was performed in CH2Cl2
under 80 atm of H2 at room temperature for 24 h using the
complex generated in situ from [Rh(COD)Cl]2 with (R,R)-f-
spiroPhos, which was proved to be very efficient in the
hydrogenation of various substrates.12 Despite the full
conversion obtained, only poor enantioselectivity, 6% ee, was
achieved (Table 1, entry 1). Delightedly, changing the
precursor to the cationic [Rh(COD)2]BF4 achieved dramat-
ically increased enantioselectivity as high as 95% ee with
Figure 2. Structure of chiral phosphine ligands screened.
such as (S)-MonoPhos, (S)-Binap, (S,R)-DuanPhos, (R)-
JosiPhos, were also evaluated (entries 6−9). However, most
of them exhibited poor activity, and only a maximum
conversion of 10% could be given. The analogue ligand,
(S,S)-f-Binaphane, was also employed, but a moderate
enantioselectivity with 15% conversion was obtained (entry
10). As revealed by these results provided by the ligands, the
chiral ligand was required to be both rigid and electron-rich to
achieve the higher activity and enantioselectivity. It was found
that 2,2,2-trifluoroethanol (TFE) was suitable for this
hydrogenation in addition to CH2Cl2, and it afforded similar
enantioselectivity (entry 12). Although good to high
enantioselectivities were achieved in THF and 1,4-dioxane,
moderate conversions were obtained (entries 13 and 14). So
far, the optimized reaction conditions of this hydrogenation
have been established to be the complex of [Rh(COD)2]BF4
and (R,R)-f-spiroPhos as the catalyst in CH2Cl2 under 20 atm
hydrogen pressure for 6 h.
Table 1. Asymmetric Hydrogenation of (Z)-5-
Benzylideneimidazolidine-2,4-dione 1a, Optimizing
a
Reaction Conditions
b
c
entry
ligand
solvent
PH2 (atm)
conv. (%)
ee (%)
Inspired by the exciting result achieved in the hydrogenation
of substrate 1a, we synthesized and hydrogenated a series of 5-
alkylidene-2,4-diketoimidazolidines (hydantoins) 1a−1m
under the optimized reaction conditions (Table 2). The
corresponding chiral hydantoin derivatives 2a−2m were
afforded in high yields with up to 97% ee. It was revealed
that the meta- or para-substituted substrates showed higher
reactivity regardless of the electron properties of the
substituents. For instance, the substrates 1b, 1c, 1d, and 1e
bearing an electron-donating substituent Me or MeO at the
meta or para position of the aryl group provided the products
quantitatively with high enantioselectivities of 90−94% ee.
Likewise, the substrates containing an electron-withdrawing
substituent (F, 1f, 1g; Cl, 1h) could be smoothly hydrogenated
to produce the desired chiral hydantoin derivatives with full
conversions and high enantioselectivities of 94−97% ee. The
asymmetric hydrogenation of ortho-substituted substrates was
also conducted (1i, 1j, and 1k). The substituent at the ortho
position resulted in a slightly lower reactivity and enantiose-
lectivity. The substrates 1i and 1k with a bulkier substituent
d
1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
TFE
80
80
20
10
20
20
20
20
20
20
20
20
20
20
>99
>99
>99
94
>99
trace
trace
trace
10
15
2
>99
31
42
6
95
96
94
e
2
f
3
g
4
5
6
7
8
96
ND
ND
ND
ND
54
ND
94
80
9
10
11
12
13
14
THF
1,4-dioxane
92
a
Reaction conditions: [Rh(COD)2]BF4/diphosphine (monophos-
phine)/substrate 1.0:1.1 (2.1):100, 6 h. Determined by GC analysis.
Determined by SFC or HPLC analysis using a chiral stationary
b
c
d
e
f
phase. [Rh(COD)Cl]2, 80 atm H2. 80 atm H2, 24 h. 20 atm H2, 24
g
h. 10 atm H2, 24 h.
5735
Org. Lett. 2021, 23, 5734−5738