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Z. Abbas et al. / Tetrahedron Letters 61 (2020) 151860
treatment with NaH in DMF followed with iodomethane,
iodoethane or chloromethyl ethyl ether afforded the corresponding
ligands (Rc,Rp)-L2-L4 in reasonable yields respectively. N-Boc pro-
tected ligand (Rc,Rp)-L5 was also prepared in high yield by the reac-
tion of (Rc,Rp)-L1 with (Boc)2O in CH2Cl2 in the presence of DMAP
and triethylamine at room temperature. Besides the easy prepara-
tion, another salient and practical feature of these diphosphine
ligands is their excellent air- and moisture-stability. Even after
being held at ambient temperature in open air for more than one
month, ligand (Rc,Rp)-L4 did not show any changes in its 1H or
31P NMR spectra and exhibited the same activity and enantioselec-
tivity in catalytic hydrogenation.
Fig. 1. New chiral ferrocene/indole-based diphosphine ligands (Rc,Rp)-IndoFerro-
Phos (L).
In the first set of experiments, we used the Rh-catalyzed asym-
metric hydrogenation of a variety of ethyl (Z)-acetamidocinna-
mates 7 to benchmark the potential of these newly developed
diphosphine ligands in the asymmetric catalysis [9], and the
results are summarized in Table 1. Hydrogenation was conducted
in ClCH2CH2Cl at room temperature under
a H2 pressure of
10 bar in the presence of 1.0 mol% of catalyst prepared in situ from
Rh(COD)2BF4 and 1.1 equiv of (Rc,Rp)-IndoFerroPhos L. To our
delight, these new ligands showed high efficiency in the hydro-
genation of ethyl (Z)-2-acetamido-3-phenylacrylate 7a (entries
1–5). In all cases, full conversions were observed with good to high
enantioselectivities. Among them, (Rc,Rp)-IndoFerroPhos L4 dis-
played the best result (>99% yield and 96% ee). In comparison, N-
phosphinated diphosphine ligand (Rc,Rp)-5 led to only moderate
enantioselectivity of 63% ee (entry 6).
We next evaluated the effect of the solvent on the reaction out-
come. In all solvents tested, hydrogenations led to good perfor-
mance. However, no result was superior to that in ClCH2CH2Cl
(entries 7–10). Under the optimized conditions (entry 4), we
hydrogenated a variety of ethyl (Z)-acetamidocinnamates 7 to
Scheme 1. Initial attempt for the synthesis of chiral ferrocene/indole-based
diphosphine ligands.
obtain the corresponding
a-amino acid esters. The substitution
pattern of the substituent on the phenyl ring had no obvious influ-
ence on the hydrogenation performance. Thus, all three substrates
with a chloro group at the ortho, meta or para position gave the sat-
isfactory results (entries 11–13). The electronic property of para-
substituent on the phenyl ring less affected the hydrogenation out-
come, and all substrates exhibited high yields and enantioselectiv-
ities (entries 13–19). 2-Naphthyl substrate 7k also served well,
leading to the hydrogenation product 8k in 93% yield and with
93% ee (entry 20). Heteroaromatic 2-thienyl substrate 7l was well
tolerated, giving the product 8l in >99% yield and with 93% ee (en-
try 21). However, 2-furyl substrate 7m led to the unsatisfactory
enantioselectivity of 59% ee (entry 22).
To further show the synthetic utility of (Rc,Rp)-IndoFerroPhos,
we then investigated their efficiency in the Rh-catalyzed asym-
metric hydrogenation of
a-enamides 9. Good enantioselectivities
were also observed in this reaction, and the results are summa-
rized in Table 2. Different with the hydrogenation of ethyl (Z)-
acetamidocinnamates 7, (Rc,Rp)-L1 displayed better enantioselec-
tivity than (Rc,Rp)-L4 in some cases. For example, in the hydro-
genation of N-(1-phenylvinyl)acetamide 9a, 98% ee was
achieved with (Rc,Rp)-L1 (entry 1), while only 90% ee was
observed with (Rc,Rp)-L4 (entry 2). The substitution pattern of
the substituent on the phenyl ring had some influence on the
hydrogenation (entries 3–5). Thus, para-substituted 9d led to
lower enantioselectivity in comparison with its orthro- and
meta-analogues (9b and 9c). The electronic property of para-sub-
stituent also affected the hydrogenation outcome (entries 5–10).
4-MeO-substituted substrate 9f gave a decreased enantioselectiv-
ity of only 82% ee (entry 7). 2-Naphthyl substrate 9j worked well,
giving the hydrogenation product 10j in 92% yield and with 91%
ee (entry 11). Heteroaromatic 2-thienyl substrate 9k was not so
compatible with the hydrogenation, leading to the product 10k
in 85% yield and with 81% ee (entry 12).
Scheme 2. Synthesis of new chiral ferrocene/indole-based diphosphine ligands, (Rc,
Rp)-IndoFerroPhos (L).
nucleophilic substitution of (Sc,Rp)-2 on the ferrocenylmethyl posi-
tion with 2-(diphenylphosphino)-1H-indole (6) could be per-
formed smoothly in a 1:1 mixture of toluene and 1,4-dioxane at
95 °C in the presence of FeCl3, thus leading to the desired ligand
(Rc,Rp)-L1 in good yield. The derivatization of (Rc,Rp)-L1 by the
Abbas, Zaheer
