Iridium-catalyzed enantioselective hydrogenation of cyclic imines

Article abstract of DOI:10.1002/adsc.201000473

A catalytic complex made from [Ir(COD)Cl]₂ [di-μ-chloro- bis(1,5-cyclooctadiene)diiridium(I)] precursor and (S,S)-f-Binaphane ((R,R)-1,1′-bis{(R)-4,5-dihydro-3H-dinaphtho[1,2-c:2′,1′-e] phosphepino}ferrocene) ligand effectively catalyzed the en

Full text of DOI:10.1002/adsc.201000473

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DOI: 10.1002/adsc.201000473
Iridium-Catalyzed Enantioselective Hydrogenation of Cyclic
Imines
Mingxin Chang,a Wei Li,a Guohua Hou,a and Xumu Zhanga,*
a
Department of Chemistry and Chemical Biology & Department of Medicinal Chemistry, Rutgers, The State University of
New Jersey, Piscataway, New Jersey 08854, U.S.A.
Fax : (+1)-732-445-6312; e-mail: xumu@rci.rutgers.edu
Received: June 18, 2010; Revised: September 17, 2010; Published online: December 3, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000473.
À
Abstract:
[Ir(COD)Cl]2 [di-m-chloro-bis(1,5-cyclooctadiene)di-
iridium(I)] precursor and (S,S)-f-Binaphane ((R,R)-
1,1’-bis{(R)-4,5-dihydro-3H-dinaphtho[1,2-c:2’,1’-e]-
phosphepino}ferrocene) ligand effectively catalyzed
the enantioselective hydrogenation of cyclic imines
with high reactivity and good enantioselectivity.
A
catalytic complex made from
ric hydrogenation of N H imines using the Ir-f-Bina-
ACHTUNGTRENNUNG
phane catalyst[6b] and other reports on Ir(I)[11] and
G
IrACTHNGUTERNNUG
(III)[12] complexes with chiral phosphines in the
asymmetric hydrogenation of cyclic imines. We envi-
sioned that the ferrocene-based electron-donating bi-
sphosphine f-Binaphane could possibly minimize the
inhibitory effect from the amine product[13] and the
embedded axial chirality in the ligand could facilitate
the enantiocontrol. Herein, we report the efficient
enantioselective hydrogenation of a series of cyclic
imines using Ir-f-Binaphane catalyst with high enan-
tioselectivity (up to 89% ee).
ACHTUNGTRENNUNG
Keywords: asymmetric catalysis; cyclic imines;
enantioselectivity; hydrogenation; iridium
With 2-phenyl-1-pyrroline as the standard substrate,
initially several Ir(I) precursors with chiral f-Bina-
Catalytic asymmetric hydrogenation of cyclic imines
is a highly efficient approach for the synthesis of
chiral cyclic amines, which are ubiquitous moieties in
many natural products,[1] and in pharmaceutical drugs
and drug candidates,[2] for example, nicotine,[3] BMS-
394136[4] and LY-394681[5] (Figure 1). In contrast to
the progress achieved in the asymmetric hydrogena-
tion of acyclic imines,[6] there have been few reports
on the enantioselective hydrogenation of cyclic
imines.[7]
During the past two decades, Ti, Rh, Ru and Ir
complexes have been investigated in the asymmetric
hydrogenation of cyclic imines. The chiral titanocene
developed by Buchwald et al. showed good reactivity
and high enantioselectivity[8] for both cyclic imines
and acyclic imines. Highly enantioselective cationic
Rh(I) catalysts were applied by Xiao et al. in the
asymmetric hydrogenation of imines to afford tetra-
hydroisoquinolines and tetrahydro-b-carbolines.[9]
Catalyzed
by
{RuCl2[(S)-MeO-BIPHEP]ACTHNGUTERN[UNG (S,S)-
ANDEN]} system, the hydrogenation of 2,3,3-trime-
thylindolenine was achieved with up to 88% ee.[10] De-
spite the successful complexes from various metals in
asymmetric hydrogenation we decided to focus on Ir
Figure 1. Structures of nicotine, BMS-394136 and LY-
catalyst systems based on our studies of the asymmet- 394681.
Adv. Synth. Catal. 2010, 352, 3121 – 3125
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Mingxin Chang et al.
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Figure 2. Structures of chiral phosphine ligands.
phane (Figure 2) were explored as hydrogenation cat- vestigated (Table 1, entries 4–8). The highest enantio-
alysts. Results are summarized in Table 1 (entries 1– selectivity was achieved from the combination of
3). The Ir catalyst prepared in situ from [IrACHTNUGTRNEUNG(COD)Cl]2 ethyl acetate/dichloromethane in a ratio of 2:1
precursor and f-Binaphane ligand developed by our (Table 1, entry 8). Interestingly no reaction occurred
group,[14] gave 85% ee with good conversion (Table 1, when dichloromethane itself was used as a solvent.
entry 1). f-Binaphane is featured with high electron The halide effect[15] was also explored. The reaction
donation and a flexible backbone allowing it to ac- was completed with a full conversion in the presence
commodate sterically demanding cyclic imines to the of 2 mol% of I2, but the enantiomeric excess dropped
Ir center. Subsequently the effect of solvents was in- dramatically (Table 1, entry 9). Inspired by the wotk
Table 1. Asymmetric hydrogenation of 2-phenyl-1-pyrroline by Ir-f-Binaphane.[a]
Entry
Ir precursor
[Ir(COD)Cl]2
Solvent
Additive
Conversion [%][b]
ee [%] (Config.)[b]
1
2
3
4
G
THF
THF
THF
Toluene
EtOAc
MeOH
CH2Cl2
EtOAc/CH2Cl2 2:1
EtOAc/CH2Cl2 2:1
EtOAc/CH2Cl2 2:1
EtOAc/CH2Cl2 2:1
EtOAc/CH2Cl2 2:1
EtOAc/CH2Cl2 2:1
–
65
>99
5
53
61
33
n.r.
89
>99
>99
>99
75
85 (+)
61 (+)
30 (+)
85 (+)
85 (+)
31 (+)
n.d.
88 (+)
68 (+)
83 (+)
73 (+)
72 (+)
84 (+)
[Ir(COD)2]BARF
[Ir(COD)2]BARF
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
T
10 mol% I2
–
–
–
–
–
–
E
N
N
R
5
6
7[c]
8
E
G
G
T
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
C
9
2 mol% I2
10[d]
11[e]
12[f]
13[g]
HI
HI
HI
–
>99
[a]
The reactions were carried out with 0.2 mmol of substrate in 2.4 mL of solvent in the presence of 1 mol% of in situ pre-
pared Ir catalyst under an initial hydrogen pressure of 50 atm for 25 h.
Conversions and enantiomeric excesses were determined by chiral GC after the amine products were converted to the
corresponding trifluoroacetamides.
[b]
[c]
[d]
n.r.=no reaction, n.d.=not determined.
HI was used for preparation of the iodine-bridged dimeric iridium complex [{Ir(H)
hance the catalytic reactivity according to ref.[12c] The [{Ir(H) (m-I)3]+IÀ loading is 1 mol%; S/C=100.
[(S,S)-f-Binaphane]}2A
(m-I)3]+IÀ loading is 0.1 mol%; S/C=1000; reaction temperature 508C.
2A
(m-I)3]+IÀ loading is 0.01 mol%; S/C=10000; reaction temperature 508C.
(m-I)3]+IÀ to en-
ACHUTGTNRENUN[G (S,S)-f-Binaphane]}2ACHTUNGTRENNUGN
G
CHTUNGTRENNUNG
[e]
[f]
The [{Ir(H)
The [{Ir(H)
C
2ACHTUNGTRENNUNG
CHTUNGTRENNUNG
[g]
Reaction temperature 508C.
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Iridium-Catalyzed Enantioselective Hydrogenation of Cyclic Imines
of GenÞt and co-workers,[12c] we prepared the iodine- lytic reactivity of this iodine-bridged dimeric iridium
bridged dimeric iridium complex [{Ir(H)
Binaphane]}2A
(m-I)3]+IÀ. As expected, this complex was Ir N bond of the hydrogenation intermediate by
more reactive and yielded 83% ee (Table 1, entry 10); HI.[12c]
ACHTUNGTREN[NUGN (S,S)-(f)- complex was assumed to be due to the cleavage of
À
CHTUNGTRENNUNG
using 0.1 mol% of Ir catalyst, the reaction still pro-
Other additives, such as acetic acid[16] and phthali-
ceeded smoothly but afforded lower ee (Table 1, mide[11g] were also investigated and proved to have no
entry 11); when the catalyst loading was further de- effect on this hydrogenation. Without any additive,
creased to 0.01 mol%, 75% conversion and 72% ee when the reaction temperature was increased to
were obtained (Table 1, entry 12). The enhanced cata- 508C, complete conversion was achieved with slightly
lower ee (Table 1, entry 13). In a control study,
[IrACTHNUTRGNEU(GN COD)Cl]2 with other chiral phosphines was inves-
Table 2. Screening of chiral phosphine ligands.[a]
tigated (Table 2). None of the ligands offered higher
enantioselectivity or conversion compared with f-Bi-
naphane. Two monodentate ligands (R)-MOP and
(R)-MonoPhos were tested and yielded poor conver-
sions and enantioselectivities (Table 2, entries 1 and
2). Interestingly BINAP (Table 2, entry 6) and its ana-
logues such as SegPhos (Table 2, entry 7) and
C3-TunePhos (Table 2, entry 8) showed good ees.
To explore the applicability of this Ir-f-Binaphane
catalytic system, a range of substituted arylpyrrolines,
an alkylpyrroline, 2,3,4,5-tetrahydro-6- phenylpyridine
and 2-phenyl-4,5,6,7- tetrahydro-3H-azepine were
prepared and hydrogenated under the optimal condi-
tions. The results are summarized in Table 3. It is evi-
dent that the electronic properties of the substituents
at the para position of phenyl ring have no obvious
effects on conversion and enantioselectivity (Table 3,
entries 1–6). But when the substituents are located in
meta and ortho positions, the enantioselectivity varies
dramatically with different substituted groups
(Table 3, entries 7–10). On increasing the ring size of
Entry Ligand
Conv. [%][b] ee [%] (Config.)[b]
1
2
3
4
5
6
7
8
(R)-MOP
(R)-MonoPhos
(R,S)-JosiPhos
ACHTUNGTRENNUNG(R,R)-Me-DuPhos 46
(S)-C3-TunePhos
(R)-BINAP
10
13
20
4 (+)
9 (À)
G
13 (+)
2 (+)
58
64
63
69 (+)
74 (+)
78 (+)
88 (+)
(R)-SegPhos
ACHTUNGTRENNUNG(S,S)-f-Binaphane 89
[a]
The reactions were carried out with 0.2 mmol of sub-
strate in 2.4 mL of solvent in the presence of 1 mol% of
in situ prepared Ir catalyst under an initial hydrogen
pressure of 50 atm for 25 h.
Conversions and enantiomeric excesses were determined
by chiral GC after the amine products were converted to
the corresponding trifluoroacetamides.
[b]
Table 3. Asymmetric hydrogenation of cyclic imines by Ir-f-Binaphane.[a]
Entry
R
n
Conversion [%][b]
ee [%] (Config.)[b]
1
2
3
4
5
6
7
8
C6H5
1
1
1
1
1
1
1
1
1
1
1
2
3
>99
>99
>99
>99
>99
>99
99
98
96
98
>99
99
85 (+)
84 (+)
84 (+)
85 (+)
86 (+)
84 (+)
80 (+)
66 (+)
74 (+)
50 (+)
58 (+)
89 (+)
75 (+)
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-Cl-C6H4
3-Me-C6H4
3-MeO-C6H4
2-MeO-C6H4
n-Bu
9
10
11
12
13
C6H5
C6H5
99
[a]
The reactions were carried out with 0.2 mmol of substrate in 2.4 mL of solvent in the presence of 1 mol% of in situ pre-
pared Ir catalyst under an initial hydrogen pressure of 50 atm for 25 h at 508C.
Conversions and enantiomeric excesses were determined by chiral GC after the products were converted to the corre-
sponding trifluoroacetamides.
[b]
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residue was purified by column chromatography to give the
corresponding hydrogenation product. The chiral amine
products were reacted with trifluoroacetic anhydride to
yield the corresponding trifluoroacetamides, which were
then analyzed by chiral GC (Gamma Dex 225 or Beta Dex
390) to determine the enantiomeric excesses.
the cyclic imine from 5-membered to 6-membered,
the enantiomeric excess was slightly improved
(Table 3, entries 1 and 12); when it was 7-membered,
the enantioselectivity dropped to 75% (Table 3,
entry 13). This catalytic system does not work well for
alkyl-substituted pyrroline and only 58% ee was
achieved with one substrate (Table 3, entry 10).
In conclusion, an Ir-(S,S)-f-Binaphane catalyst has
been applied in the asymmetric hydrogenation of a
series of cyclic imines. With this system, readily pre-
Acknowledgements
pared from [IrACHTUNGTRENNUNG(COD)Cl]2 and air-stable (S,S)-f-Bina-
We gratefully thank the National Institutes of Health
phane ligand, high reactivity and good enantioselec- (GM58832) and Merck & Co., Inc. for the financial support.
tivity were achieved. Using HI as additive, high turn-
over number (>5000) was achieved. This highly reac-
tive catalytic system provides us with an efficient ap-
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