N-Alkyl Ketimine Hydrogenation
COMMUNICATION
Table 2. The asymmetric hydrogenation of acyclic N-benzyl ketimines
with 2 f in 1,2-dichloroethane or under solvent-free conditions.[a]
After a survey of a variety of catalysts for the hydrogenation
of 5a (Table S2 in the Supporting Information), catalyst 2b
was found to be the optimal catalyst in terms of both re-
ACHTUNGTRENNUNGactivity and enantioselectivity (Table 1, entry 6). Notably,
both of the Ir- and Rh-catalysts showed much lower enantio-
selectivities under otherwise identical reaction conditions
(Table 1, entries 7 and 8). Furthermore, it was found that
weakly coordinating counterions influenced the enantiose-
lectivity, and a higher enantioselectivity was obtained with
BArFÀ as the counterion (Table 1, entries 6 and 9–12).[25] In
addition, the solvent effect was studied and the results are
sumarized in Table S3 in the Supporting Information. It was
found that weakly polar solvents, such as CH2Cl2,
ClCH2CH2Cl, and toluene, are suitable for to obtain high
enantioselectivities (Table 1, entries 12–14). Interestingly,
the reaction can be carried out under solvent-free condi-
tions.[26,27] Remarkably, in comparison with the reaction in
CH2Cl2, significantly higher reactivity and enantioselectivity
were observed if the hydrogenation was carried out at a sub-
strate/catalyst ratio of 1000:1, under solvent-free conditions
(Table 1, entry 15 vs. entry 16). Even if the catalyst loading
was reduced to 0.05 mol%, the reaction still gave the prod-
uct in full conversion and 89% ee after prolonged reaction
time (Table 1, entry 17). To the best of our knowledge, this
is the highest turnover number for an asymmetric hydro-
Entry
Imine (E/Z ratio)
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a (12:1)
5b (11:1)
5c (12:1)
5d (2:1)
95 (99)
93 (96)
92 (98)
93 (97)
93 (98)
93 (97)
90
92 (97)
93 (97)
90 (95)
92 (96)
91 (97)
92
95 (93)
94 (90)
95 (91)
91 (90)
96 (91)
94 (91)
90
93 (91)
96 (90)
86 (84)
92 (92)
94 (89)
91
5e (12:1)
5 f (20:1)
5g (25:1)
5h (22:1)
5i (40:1)
5j (35:1)
5k (11:1)
5l (28:1)
5m (22:1)
5n (16:1)
5o (16:1)
5p (>100)
A
clic N-benzyl ketimines were efficiently hydrogenated in the
presence of (R,R)-2 f (1.0 mol%) to afford the correspond-
ing chiral Boc-protected N-benzylamines with unprecedent-
ed high enantioselectivities (86–97% ee, Table 2, entries 1–
16). It was found that the introduction of an electron-donat-
ing or electron-withdrawing group on the N-benzyl ring had
no apparent effect on the enantioselectivity (Table 2, en-
tries 1–3). However, an electron-withdrawing substituent on
the a-phenyl ring of the ketimines decreased both the re-
92 (95)
96
96 (98)
95 (89)
96
97 (95)
[a] Reaction conditions: substrate (5a–p; 0.2 mmol) in 1,2-dichloroethane
(1 mL) or under solvent-free conditions (2.5 mmol), catalyst ((R,R)-2 f; 1
mol%), H2 (50 atm), (Boc)2O (1.1 equiv), stirred at 408C for 10 h, except
for entries 7 and 10, which were stirred for 20 h. [b] Isolated yields in 1,2-
dichloroethane. Data in parentheses correspond to the reactions conduct-
ed under solvent-free conditions. [c] The enantiomeric excesses were de-
termined by HPLC with a chiral AD-H column. [d] Data in parentheses
were obtained with catalyst (0.2 mol%) after 20 h under solvent-free
conditions.
ACHTUNGTRENNUNGactivity and the enantioselectivity (Table 2, entries 7 and
10). Notably, the hydrogenation of the ketimine of propio-
phenone (5d), which had an E/Z ratio of 2:1, afforded the
corresponding Boc-protected amine in 91% ee (Table 2,
entry 4). The highest enantioselectivity (97% ee) was
achieved in the hydrogenation of 2-thiophene ketone imine
(5p; Table 2, entry 16). Notably, most of these substrates
can be efficiently hydrogenated in the presence of 0.2 mol%
catalyst, under solvent-free conditions, in excellent enantio-
selectivities that are only slightly lower than those obtained
in 1,2-dichloroethane.
These remarkable results prompted us to apply our new
protocol to the synthesis of (+)-cis-(1S,4S)-1-methylamino-
4-(3,4-dichlorophenyl)tetralin (Sertraline),
a chiral anti-
depressant drug,[2] as an example of the N-alkyl amine class
It should be noted that Ru complex 2 f was also an effec-
tive catalyst for the hydrogenation of exocyclic N-alkyl keti-
mines. As shown in Table 3, the N-benzyl ketimine derived
from indanone (7a) was hydrogenated in the presence of
(R,R)-2 f (2 or 1 mol%) at 408C to afford the corresponding
Boc-protected amine in up to 98% ee (Table 3, entry 1).
Similarly, hydrogenation of N-alkyl ketimines derived from
tetralone analogues gave the corresponding N-benzyl-, N-
isobutyl-, or N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine
derivatives in 92–97% ee (Table 3, entries 2–5).
of biologically important compounds. To our delight, the
asymmetric hydrogenation of racemic imine precursor 7 f in
the presence of catalyst (R,R)-2 f (1 mol%) afforded the
chiral amine isomers cis-8 f and trans-8 f in 62 and 98% ee
and a ratio of approximately 3:2 (Table 3, entry 6). Encour-
aged by these results, we then employed enantiopure imine
(S)-7 f as the substrate for the hydrogenation. It was found
that catalyst (R,R)-2 f showed trans diastereoselectivity
(80:20 d.r.), affording each isomer in >99% ee (Table 3,
entry 8). Significantly, catalyst (S,S)-2 f exhibited extremely
Chem. Eur. J. 2011, 17, 1109 – 1113
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