Iridium-catalyzed asymmetric hydrogenation of pyridinium salts

Article abstract of DOI:10.1002/anie.201205187

Highly efficient iridium-catalyzed asymmetric hydrogenations of simple 2-substituted pyridinium salts gives the chiral 2-substituted piperidines with up to 93 % ee (see picture; cod=1,5-cyclooctadiene; synphos=(5,6),(5',6')- bis(ethylenedioxy)-2,2'-bis(di

Full text of DOI:10.1002/anie.201205187

Angewandte
Chemie
DOI: 10.1002/anie.201205187
Asymmetric Hydrogenation
Iridium-Catalyzed Asymmetric Hydrogenation of Pyridinium Salts**
Zhi-Shi Ye, Mu-Wang Chen, Qing-An Chen, Lei Shi, Ying Duan, and Yong-Gui Zhou*
As one of the most straightforward and powerful approaches
for the preparation of optically active compounds, asymmet-
ric hydrogenation has been successfully used for different
types of aromatic compounds, including quinolines, isoquino-
lines, quinoxalines, indoles, pyrroles, furans, imidazoles, and
aromatic carbocyclic ring, with excellent enantioselectivi-
stoichiometric amount of hydrogen bromide generated in situ
would effectively inhibit the coordination ability of the
desired product through the formation of its piperidine
hydrogen bromide salt (Scheme 1). Also, the benzyl protect-
ing groups could be conveniently removed by hydrogenolysis.
Herein, we disclose the iridium-catalyzed asymmetric hydro-
genation of 2-substituted pyridinium salts with excellent
enantioselectivity.
[
1–9]
ties.
Despite these advances, direct hydrogenation of
simple pyridines is still a challenge. The inherent problems
are apparent: First, substrates and corresponding products
that possess strong coordination ability might cause the
deactivation of catalysts. Second, pyridines have a stabilizing
aromatic structure that might impede the reduction. There-
fore, only limited examples of hydrogenation of specific
pyridine derivatives bearing powerful electron-withdrawing
substituent at the 2- or 3-position have been previously
described. In 2000, Studer et al. reported the first homoge-
neous rhodium-catalyzed asymmetric hydrogenation of pyr-
[
10]
idines, but only poor enantioselectivity was obtained.
Zhang and co-workers described an efficient three-step
rhodium-catalyzed asymmetric hydrogenation of nicoti-
Scheme 1. The strategy for hydrogenation of simple pyridines. CA=
coordination ability, M=metal.
[11]
nates.
Subsequently, the group of Rueping documented
the first enantioselective organocatalytic transfer hydrogena-
tion of 3-cyano- or carbonyl-substituted pyridines using
[
12]
Hantzsch esters as hydrogen sources, and our group also
Our investigation started with the asymmetric hydro-
employed [{Ir(cod)Cl} ]/(S)-MeO-biphep/I2 catalyst system
genation of N-benzyl-2-phenylpyridinium bromide using
2
for asymmetric hydrogenation of specific pyridines with
[{Ir(cod)Cl} ]/(R)-MeO-biphep as the catalyst (Table 1). To
2
[
13]
excellent enantioselectivities.
Additionally, an elegant
our delight, when CH Cl was employed as the solvent, the
2
2
asymmetric hydrogenation of activated pyridines, that is,
N-iminopyridinium ylides, was developed by Charette et al.
reaction proceeded smoothly to give the target product in
84% yield and a moderate enantioselectivity (66% ee;
Table 1, entry 1). A survey of different solvents indicated
that the 1:1 mixture of PhMe/CH Cl was the best choice with
[14]
As chiral piperidines are important building blocks for the
synthesis of biologically active molecules and natural prod-
2
2
[
15]
ucts, the development of an efficient strategy for the highly
challenging hydrogenation of the simple pyridines is still of
great significance.
Table 1: Screening of solvents and counterions for asymmetric hydro-
[a]
genation of 2-phenylpyridinium salt.
Iminium salts generally exhibit higher activity than the
[
15b–l,16]
corresponding imines in hydrogenation,
therefore we
envisioned that the activation of simple pyridines as the
corresponding N-benzyl-pyridinium bromides would effec-
tively eliminate coordination ability of the substrate and thus
the reactivity could be greatly enhanced. Moreover, the
[
b]
[c]
Entry
Solvent
CH Cl
MeOH
THF
PhMe
PhMe/CH Cl 2:1
PhMe/CH Cl 1:1
2 2
PhMe/CH Cl 1:2
2 2
X
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
I
84
17
86
53
91
97
97
13
<5
66
5
2
2
[*] Z.-S. Ye, M.-W. Chen, Q.-A. Chen, L. Shi, Y. Duan, Prof. Y.-G. Zhou
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences (CAS)
67
77
72
75
71
57
–
2
2
457 Zhongshan Road, Dalian 116023 (China)
E-mail: ygzhou@dicp.ac.cn
Homepage: http://www.lac.dicp.ac.cn/
PhMe/CH Cl 1:1
2 2
PhMe/CH Cl 1:1
OTf
[
**] Financial support was provided by the National Natural Science
Foundation of China (21032003, 20921092 and 21125208) and the
National Basic Research Program of China (2010CB833300).
2
2
[
a] 1 (0.25 mmol), [{Ir(cod)Cl} ] (1 mol%), (R)-MeO-biphep (2.2 mol%),
H (600 psi), solvent (3 mL), 24 h, 288C. [b] Yield of the isolated product.
2
2
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205187.
[c] Determined by HPLC. cod=1,5-cyclooctadiene, Tf=trifluorometh-
anesulfonyl.
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respect to the yield and enantioselectivity (Table 1, entries 2–
). Interestingly, replacement of the bromide counterion by
Table 3: Iridium-catalyzed asymmetric hydrogenation of 2-substituted
pyridinium salts 1.
[
a]
7
iodide had a negative impact on reactivity and enantioselec-
tivity (Table 1, entry 8). The trifluoromethanesulfonate anion
also failed to promote the hydrogenation reaction (Table 1,
entry 9).
Next, the influence of different activating groups on
enantioselectivity was explored (Table 2). In particular,
[b]
[c]
Entry
R
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Ph
4-MeC H
3-MeC H
2-MeC H
99 (2a)
99 (2b)
88 (2c)
82 (2d)
99 (2e)
93 (2 f)
95 (2g)
99 (2h)
99 (2i)
96 (2j)
99 (2k)
99 (2l)
99 (2m)
60 (2n)
93 (S)
89 (À)
86 (À)
78 (À)
92 (À)
92 (À)
92 (À)
93 (À)
87 (À)
93 (À)
84 (À)
91 (À)
59 (+)
65 (À)
introducing an electron-withdrawing substituent (CO Me) at
2
6
4
4
4
the 2-position of the benzyl group led to a significant increase
6
6
4-MeOC H
6
4
Table 2: Screening of activating groups and ligands for asymmetric
[
a]
3-MeOC
4-ClC
4-FC H
2-naphthyl
4-CF C H
4-tBuC H
4-PhC H
Bn
iPr
6
H
4
hydrogenation of 2-phenylpyridinium salts.
6
H
4
6
4
[
[
d]
d]
10
11
12
13
14
3
6
4
4
6
6
4
[
b]
[c]
Entry
Ar
Ligand
Yield [%]
ee [%]
[
d]
1
2
3
4
5
6
7
8
9
Ph
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
97
93
99
95
98
96
98
98
98
99
75
70
89
79
92
93
93
85
91
91
2-MeOC H4
2-(MeO C)C H
4-(MeO C)C H
2-(iPrO C)C H
2-(iPrO C)C H
2-(iPrO C)C H
2-(iPrO C)C H
2-(iPrO C)C H
[a] 1 (0.25 mmol), [{Ir(cod)Cl} ] (1 mol%), (R)-synphos (2.2 mol%), H2
(600 psi), PhMe/CH Cl (1:1; 3 mL), 24 h, 288C. [b] Yields of the isolated
product. [c] Determined by HPLC. [d] Determined by HPLC of product
6
2
2
6
4
4
2
2
2
6
2
6
4
after derivatization with LiAlH . Bn=benzyl.
4
2
6
4
4
4
4
4
2
6
2
6
With the highly active catalytic system established, we
turned our attention to examine the scope of substrates
2
6
1
0
2-(iPrO C)C H
2 6
(Table 3). As expected, various substrates were performed
[
a] 1 (0.25 mmol), [{Ir(cod)Cl} ] (1 mol%), L (2.2 mol%), H (600 psi),
2
2
very well under the standard reaction conditions. The
electronic properties of the substituent on the aromatic ring
had little effect on the catalytic activity and enantioselectivity
PhMe/CH Cl (1:1, 3 mL), 24 h, 288C. [b] Yield of the isolated product.
2
2
[c] Determined by HPLC.
(Table 3, entries 5 and 10). However, presumably as a result
of steric hindrance, the substrate 1d containing a substituent
at the ortho position of the aromatic ring resulted in
diminished yield and ee value (Table 3, entry 4). Notably,
although the 2-alkylpyridine derivatives were suitable reac-
tion partners, only moderate enantioselectivity were obtained
(Table 3, entries 13 and 14).
To further evaluate the practical utility, the hydrogenation
of N-benzyl-2-phenylpyridinium bromide (1a) was carried
out on gram scale, and the desired product was furnished with
9
3% yield and 92% ee [Eq. (1); S/C = substrate/catalyst,
TOF = turnover frequency, TON = turnover number].
of enantioselectivity (89% ee; Table 2, entry 3). The CO Me
2
group at the 2-position is probably coordinated with catalyst,
and thus is favorable to the control of enantioselectivity
(
Table 2, entry 3 versus 4). Gratifyingly, when there was
a CO iPr group in the 2-position the enantioselectivity was
2
improved slightly, possibly because of steric hindrance
To broaden the application of our methodology, we were
keen to explore the formal synthesis of piperidine 5, an orally
active NK1 receptor antagonist (Scheme 2). Reduction of 2a
with lithium aluminum hydride gave the product 3a, and
subsequent hydrogenolysis and protection yielded 4a with up
to > 99% ee after a single crystallization. 4a was the key
intermediate for the formal synthesis of the NK1 receptor
(
Table 2, entry 5). Lastly, various commercially available
chiral bisphosphine ligands were also evaluated (Table 2,
entries 6–10). Among all the tested ligands, (R)-binap only
gave 85% ee. Pleasingly, the electron-rich diphosphine
ligands (R)-segphos and (R)-synphos displayed the highest
enantioselectivity (Table 2, entries 6 and 7).
2
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Scheme 2. The formal synthesis of NK1 receptor antagonist 5. Boc=
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[
[
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antagonist 5 reported in literature. The absolute config-
uration of 4a was assigned to be S by comparison of the sign
[
18]
of the observed optical rotation with the reported data.
In conclusion, we have successfully developed a highly
efficient iridium-catalyzed hydrogenation of 2-substituted
pyridinium salts, to provide chiral piperidines with high
enantioselectivity. The key feature of this strategy was the
activation of simple pyridines as the pyridinium bromide, thus
efficiently avoiding inhibition of the catalyst by the substrate
and improving the reactivity of the substrate. Moreover, the
stoichiometric hydrogen bromide generated in situ is believed
to effectively inhibit coordination ability of the desired
product. Efforts to expand this strategy to other hetero-
aromatic compounds are underway in our laboratory.
[
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Experimental Section
Typical procedure for asymmetric hydrogenation of pyridinium salt:
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In a nitrogen-filled glove box, a mixture of [{Ir(cod)Cl}
.0025 mmol) and (R)-SynPhos (3.5 mg, 0.0055 mmol) in PhMe/
CH Cl (1:1, 1.0 mL) was stirred at room temperature for 20–30 min,
2
] (1.7 mg,
0
2
2
the mixture was transferred by a syringe to a stainless steel autoclave,
in which substrate 1 (0.25 mmol) had been placed beforehand. The
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2
combined organic extracts were dried over Na SO and concentrated
2
4
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Published online: && &&, &&&&
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Keywords: asymmetric synthesis · hydrogenation · iridium ·
piperidines · pyridines
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Asymmetric Hydrogenation
Z.-S. Ye, M.-W. Chen, Q.-A. Chen, L. Shi,
Y. Duan, Y.-G. Zhou*
&&&& — &&&&
Iridium-Catalyzed Asymmetric
Hydrogenation of Pyridinium Salts
Highly efficient iridium-catalyzed asym-
metric hydrogenations of simple 2-sub-
stituted pyridinium salts gives the chiral
lenedioxy)-2,2’-bis(diphenylphosphino)-
1,1’-biphenyl). The key feature of this
strategy is the activation of simple pyr-
idines as the pyridinium salts, thus
eliminating substrate inhibition and
enhancing the reactivity.
2
9
-substituted piperidines with up to
3% ee (see picture; cod=1,5-cyclooc-
tadiene; synphos=(5,6),(5’,6’)-bis(ethy-
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!