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ry. Whereas the ruthenium-based catalysts have been success-
fully applied to the asymmetric hydrogenation of 2-arylbenzo-
furans, iridium-based catalysts showed only very low or no re-
activity towards these substrates. For 2-alkyl-substituted ben-
zofurans
iridium
complex
C1
induces
higher
enantioselectivities than ruthenium catalysts, whereas for dis-
ubstituted furans, ruthenium complexes are superior catalysts.
On the other hand, no Ru-catalyzed hydrogenations have been
reported for monosubstituted furans, a substrate class we have
shown to be well suited to Ir catalysis. Taken together, these
ruthenium and iridium catalysts enable asymmetric hydrogena-
tion of a wide range of furans and benzofurans with high effi-
ciency and enantioselectivity.
Scheme 4. Formal total synthesis of 1.
the starting material the temperature had to be increased to
obtain full conversion of the intermediate tertiary alcohol to
benzofuran 31.
Experimental Section
Typical procedure for Ir-catalyzed hydrogenation
Screening of different iridium catalysts confirmed that com-
plex C3 was the most suitable catalyst for the hydrogenation
of 31. Although complex C1 gave higher conversion under
standard conditions (95%), the enantioselectivity was distinctly
lower (46% ee). Catalyst C3 afforded the desired product (S)-
(À)-2 with 89% ee, albeit in only 57% conversion under the
standard conditions. However, increasing the hydrogen pres-
sure to 100 bar and the catalyst loading to 3 mol% resulted in
full conversion. By using this protocol, hydrogenation on
a 1 mmol scale led to enantioenriched dihydrobenzofuran 2
with 92% ee in 95% yield after column chromatography
(Scheme 4). In this way, dihydrobenzofuran 2, which had been
used as an intermediate in the total synthesis of 1 by Schobert
and co-workers,[7] was prepared in an overall yield of 48%
from commercially available hydroxyacetophenone 29. This
route compares favorably to the published synthesis of 2,
which required ten steps and gave an overall yield of only 7%,
and illustrates the potential of Ir-catalyzed hydrogenation for
the asymmetric synthesis of chiral tetrahydrofurans and dihy-
drobenzofurans.
Catalyst screening was performed on a 0.1 mmol scale. Catalyst C
(1.0 mmol, 1 mol%) was added to a solution of the substrate
(0.1 mmol) in dry CH2Cl2 (0.5 mL). The reaction vial was equipped
with a magnetic stirrer bar and placed in an autoclave that was
pressurized to 50 or 100 bar H2. The reaction mixture was stirred
for 24 h at 608C before hydrogen gas was released. The solvent
was removed under reduced pressure and the residue filtered
through a plug of silica gel (0.5ꢂ3 cm) with a 4:1 mixture of
hexane/MTBE (5 mL) as the eluent. After concentration of the fil-
trate, the obtained hydrogenation product was analyzed.
Bromination of 29
A 50 mL round-bottom flask was equipped with a magnetic stirrer
bar and charged with
a solution of 29 (1.00 g, 6.66 mmol,
1.00 equiv) in CHCl3 (10 mL). At À108C, a solution of bromine
(1.06 g, 6.66 mmol, 1.00 equiv) in CHCl3 (2.5 mL) was added drop-
wise, so that the temperature did not exceed À58C. After stirring
for 3 h at À58C, the reaction mixture was poured into water and
the phases were separated. The organic layer was washed with
water (10 mL), an aqueous saturated solution of sodium sulfite (2ꢂ
10 mL) and water (10 mL), dried over MgSO4, and concentrated.
The remaining solid was recrystallized from hot n-hexane (10 mL)
to obtain 30 as colorless crystals (1.45 g, 6.33 mmol, 95%). Rf =0.64
Conclusion
1
(SiO2, 6:4 cyclohexane/EtOAc); m.p. 79–818C; H NMR (400.1 MHz,
Iridium complexes derived from chiral pyridine–phosphinite li-
gands proved to be efficient catalysts for the asymmetric hy-
drogenation of furans and benzofurans. Catalyst C1 with steri-
cally demanding electron-rich P(tBu)2 groups, a five-membered
carbocyclic ring, and a phenyl group next to the pyridine nitro-
gen atom emerged as the most versatile catalyst, and gave
high yields and good-to-excellent enantioselectivities for
a range of monosubstituted alkyl- and arylfurans and 2-alkyl-
benzofurans. Complex C3, which contains a six-membered
rather than a five-membered carbocyclic ring and a methyl
group next to the pyridine nitrogen atom, gave the best re-
sults for the hydrogenation of 3-methyl-substituted benzofur-
ans. This catalyst was successfully applied in the hydrogenation
of a 5-bromobenzofuran derivative to give an intermediate
used in a previous synthesis of 1.
CDCl3, 300 K): d=12.09 (s, 1H), 7.85 (s, 1H), 6.88 (s, 1H), 2.60 (s,
3H), 2.39 ppm (s, 3H); 13C NMR (100.6 MHz, CDCl3, 300 K): d=
203.2, 161.6, 147.6, 133.9, 120.6, 119.5, 113.6, 26.8, 23.8 ppm; IR:
n˜ =3075, 2964, 2360, 2342, 1700, 1635, 1616, 1475, 1371, 1331,
1312, 1264, 1252, 1215, 1023, 945, 887, 859, 784, 744, 714,
636 cmÀ1; GCMS (EI, 70 eV, 5% polyphenylmethylsiloxane, 100 kPa,
, 2508C, 5 min, retention time (tR)=
8.0 min): m/z (%): 230 (50), 228 (52), 215 (97), 213 (100), 106 (11),
78 (21), 77 (19), 51 (12), 43 (21).
508C, 2 min, 308CminÀ1
Synthesis of 31
A 250 mL three-necked round-bottom flask was charged with
sodium hydride (60%w/w in paraffin oil; 0.38 g, 9.49 mmol,
1.50 equiv) under argon. The NaH was washed with n-pentane (3ꢂ
5 mL) and the flask was equipped with a magnetic stirrer bar,
reflux condenser, and septum. Trimethyloxosulfonium iodide
(2.08 g, 9.49 mmol, 1.50 equiv) was added and the equipment was
assembled under inert atmosphere. Absolute DMSO (60 mL) was
The scope of these iridium catalysts and the ruthenium cata-
lysts developed by Glorius and co-workers[8i–k] is complementa-
Chem. Eur. J. 2015, 21, 1482 – 1487
1486
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