.
Angewandte
Communications
31P{1H} NMR spectroscopy). Although the free N-isocyanides
are unstable,[17] their iron(II) complexes show no signs of
decomposition over several months at room temperature. As
compared to 3 f, 3g–i are slightly less active in the ATH of
acetophenone (4a), but the enantioselectivity reached 98%
ee under otherwise identical conditions (Table 1, entries 7–9).
This is, to the best of our knowledge, the highest enantiose-
lectivity ever observed in the ATH of acetophenone with
well-defined iron catalysts.
When the loading was lowered to 0.1 mol%, the most
promising catalysts 3 f and 3g hydrogenated 4a with the same
enantioselectivity, even at higher temperatures (50 and 608C
for 3 f and 3g, respectively) to maintain high activity
(Supporting Information, Tables S2 and S3). Under optimized
conditions, 3 f gave 5a with 96% ee and 90% yield within
1.5 h at 508C. Catalyst 3g gave 5a with 98% ee and higher
yield (93%) after 2.0 h at 608C. Periodical sampling of the
reaction solutions showed that ee erosion approaching
equilibrium was marginal (see the Supporting Information).
A broad scope of aryl alkyl ketones 4a–w was reduced
with high yield and excellent enantioselectivity (Scheme 2;
Supporting Information, Chart S1). Substitution by methyl,
methoxy, or chloro is well tolerated, and the corresponding
products were obtained in high yield and with excellent
enantioselectivity. With the exception of 2’-methoxyaceto-
phenone 4g, for which the C-isonitrile catalyst 3 f was more
selective (99% ee), the N-isonitrile derivative 3g was superior
and afforded the corresponding alcohols 5b–g with 94 to 99%
ee. Challenging substrates such as ortho-substituted aceto-
phenones 4d and 4g gave the lowest rates, but were hydro-
genated in more than 80% yield with up to 99% ee within 2.5
to 5 h (TOF > 160 hÀ1).
Figure 2. ORTEP of the dication of 3b (ellipsoids are set at 30%
probability). Selected bond lengths [ꢁ] and angles [8]: P1–Fe
2.1899(17), P2–Fe 2.2169(17), N1–Fe 2.042(4), N2–Fe 2.053(5), C35–
Fe 1.889(6), C46–Fe 1.842(6); C35-Fe-C46 89.0(2), P2-Fe-N1 92.15(14).
Table 1: Catalyst screening in the asymmetric transfer hydrogenation of
acetophenone 4a.
Entry[a]
Catalyst
Yield[b]
ee[b]
1
2
3
4
5
6
7
8
9
3a (R=tBu)
3b (R=1-Ad)
3c (R=Ph)
3d (R=2,6-Xyl)
3e (R=CMe2neoPent)
3 f (R=CEt3)
3g (R=NiPr2)
3h (R=NCy2)
3i (R=TMP)
91
90
9
79
82
65
76
88
96
98
98
98
6
86
88
69
33
39
Ketones with larger aryl groups, such as 2- and 1-
acetonaphthone (4k and 4l), were easily reduced by 3g to
give the corresponding alcohols 5k and 5l in high yield (93
and 98%) and with 98 and 99% ee, respectively. Catalyst 3 f
gave the trifluoromethyl-substituted alcohols 5m and 5n,
which are important synthons for fungicides[18] and NK1
antagonists,[19] in quantitative yield and with 96% and 98%
ee, respectively.
[a] Reactions were performed on a 1.0 mmol scale in iPrOH (0.25m).
[b] Yield and ee values were determined by GC.
A preliminary screening in the ATH of acetophenone
(4a) in basic isopropanol at 408C (S/C/B = 200/1/5; under
argon) showed that 3a, 3b, and 3e are very active, but the
enantioselectivity was moderate (79 to 88% ee, Tables 1;
Supporting Information, Table S1). Complexes 3c and 3d
bearing aryl-substituted isonitriles were barely active (< 10%
yield). The significant influence of the isonitrile substituents
on the enantioselectivity was exploited for optimization.
With 3-ethylpentyl isonitrile,[16] [Fe(CNCEt3)2(1a)](BF4)2
(3 f) gave (S)-1-phenylethan-1-ol with 96% ee and 88% yield
after 1 h when all other conditions were the same (Table 1,
entry 6). Possibly, the ethyl groups of 3 f protrude more
toward the metal center than the adamantyl groups of 3b,
which are constrained in the syn-pentane conformation
(Figure 2), thus increasing the enantioselectivity.
Acyl-substituted heterocycles were also investigated.
Although pyridine- or thiophene-substituted ketones tend
to coordinate to the metal center and thus poison it, 3 f
hydrogenated acyl pyridines 4o–q rapidly (the TOF was up to
1960 hÀ1 in the case of 4o) and with enantioselectivities
between 90 and 98% ee. The conversion of acyl thiophenes 4r
and 4s was modest (66% for 4r and 76% for 4s), but the
products were obtained with 95 and 97% ee, respectively. The
low conversions are not attributed to catalyst poisoning, but
rather to the electron-rich nature of these aromatics that
stabilizes the ketone with respect to the alcohol and shifts the
equilibrium toward the former.
An aryl alkyl ketone of the type BzR’’ containing bulkier
alkyl groups such as propiophenone 4t was hydrogenated
with high enantioselectivity (97% and 98% ee for 3 f and 3g,
respectively) within 1.5 to 2.5 h, whereas substrates with
secondary or tertiary alkyl substituents (4u–w) reacted
sluggishly under standard conditions. However, at higher
temperature (758C) and catalyst loading (0.4 mol%), 3g gave
Furthermore, the bulky N-isocyanides CNR (R is NiPr2,
TMP, or NCy2)[16,17] gave the complexes [Fe(CNR)2(1a)]-
(BF4)2 (R = NiPr2, 3g; TMP, 3h; NCy2, 3i) as diamagnetic,
orange solids (Scheme 1) as a single L-cis-b isomer (by
5172
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 5171 –5174