A Mixed Ligand Approach for the Asymmetric Hydrogenation of 2-Substituted Pyridinium Salts

Article abstract of DOI:10.1002/adsc.201600348

Herein we describe a new methodology for the asymmetric hydrogenation (AH) of 2-substituted pyridinium salts. An iridium catalyst based on a mixture of a chiral monodentate phosphoramidite and an achiral phosphine was shown to hydrogenate N-benzyl-2-arylp

Full text of DOI:10.1002/adsc.201600348

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DOI: 10.1002/adsc.201600348
A Mixed Ligand Approach for the Asymmetric Hydrogenation of
2-Substituted Pyridinium Salts
a,b
a,b
b
Marc Renom-Carrasco, Piotr Gajewski, Luca Pignataro,
c
d
b
a,
Johannes G. de Vries, Umberto Piarulli, Cesare Gennari, and Laurent Lefort *
DSM Innovative Synthesis BV, P. O. Box 18, 6160 MD Geleen, The Netherlands
a
E-mail: laurent.lefort@dsm.com
Universitꢀ degli Studi di Milano, Dipartimento di Chimica, via C. Golgi 19, 20133 Milan, Italy
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Universitꢀ degli Studi dell’Insubria, Dipartimento di Scienza e Alta Tecnologia, via Valleggio 11, 22100 Como, Italy
b
c
d
Received: April 1, 2016; Revised: May 2, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600348.
Abstract: Herein we describe a new methodology
for the asymmetric hydrogenation (AH) of 2-substi-
tuted pyridinium salts. An iridium catalyst based on
a mixture of a chiral monodentate phosphoramidite
and an achiral phosphine was shown to hydrogenate
N-benzyl-2-arylpyiridinium bromides to the corre-
sponding N-benzyl-2-arylpiperidines with full con-
version and good enantioselectivity. The mechanism
of the reaction under optimized conditions was in-
vestigated via kinetic measurements and isotopic la-
beling experiments. Our study suggests that the hy-
drogenation starts with a 1,4-hydride addition and
that the enantiodiscriminating step involves the re-
duction of an iminium intermediate.
A successful strategy in the AH of pyridines has
[
3]
been quaternization of the substrate.
Although
some AHs of non-quaternized pyridines have been re-
[
4]
ported for very specific substrates, most of the work
[
5]
involves pyridinium salts based on ylide formation,
[
6]
[7]
N-benzylation or protonation. In some cases, a sec-
ondary coordinating group introduced during the qua-
ternization appeared to be crucial to obtain high
[
6a]
enantioselectivities.
In 2000, chiral monodentate phosphorus ligands
were rediscovered and appeared to be as efficient as
[
8]
bidentate ligands in AH. Since the active AH cata-
lytic species based on bidentate phosphines contained
2 phosphorus atoms per metal center, the use of mon-
odentate ligands led to the development of the so-
[
9]
Keywords: asymmetric catalysis; homogeneous cat-
alysis; hydrogenation; pyridines; reaction mecha-
nisms
called mixed ligand strategy. Pioneered by the group
of Reetz and us, this approach consists of performing
the hydrogenation with a catalyst formed in situ from
a metal precursor and a mixture of 2 different mono-
dentate ligands with at least one of them being chiral.
In the reaction mixture, a catalytic species containing
both ligands (mixed ligand catalyst) is formed and in
The asymmetric hydrogenation (AH) of substituted some cases exhibits improved performances compared
[
9]
N-heteroarenes is an attractive route towards chiral to the corresponding single ligand species. Here we
cyclic amines that are ubiquitous motifs in nature and report the application of the mixed ligand strategy in
[
1]
in active pharmaceutical ingredients. Among N-het- the AH of 2-substituted N-benzylated pyridinium
eroarenes, 2- and 3-substituted pyridines are probably salts using a catalyst formed in situ from [Ir(cod)Cl] ,
2
[
10]
the most challenging AH substrates. Their six-mem- a chiral phosphoramidite and an achiral phosphine.
bered ring has indeed an aromatic resonance energy While the mechanism of the AH of N-heteroarenes
[
2]
[11]
close to that of benzene, and their reduction to pi- has been extensively studied, we noticed that mech-
peridines requires the hydrogenation of three differ- anistic studies dealing with pyridine substrates were
[
12]
ent double bonds. In addition, pyridines and piperi- scarce. Therefore we performed a range of experi-
dines can deactivate the catalyst via strong coordina- ments to uncover the mode of action of our most effi-
tion to the metal center. Finally, these substrates also cient mixed ligand catalyst.
lack secondary coordinating groups that can contrib-
ute to improving the enantioselectivity.
N-Benzyl-2-phenylpyiridinium bromide (1a), pre-
pared by reaction of 2-phenylpyridine with benzyl
bromide, was chosen as model substrate. [Ir(cod)Cl]2
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was selected as metal precursor. An initial screening promote the formation of the mixed ligand catalyst.
of 24 different monodentate chiral phosphoramidites Gratifyingly, some improvements in terms of activity
was performed using high-throughput experimenta- and enantioselectivity were obtained upon addition of
tion (see the Supporting Information). Three BINOL- aromatic phosphines (entries 4–12). The triphenyl-
based phosphoramidites were selected as starting phosphine bearing trifluoromethyl groups in the para-
point for a mixed ligand approach: PipPhos (PA1, position led to the best enantioselectivities (entries 11
entry 1) which gave the highest ee at full conversion, and 12). Remarkably, the three phosphoramidites
and PA2/PA3 (Table 1, entries 2 and 3) which were PA1–3 were differently affected by combination with
identified as the most enantioselective ligands, albeit the same achiral phosphine (entries 4–6): no signifi-
with uncomplete conversion.
cant change was observed when PA1 was combined
All combinations between the three most enantio- with PPh (entry 1 vs. 4). With PA2, the addition of
3
selective phosphoramidites PA1–3 and 13 different PPh3 improved the activity without affecting the
achiral phosphines and phosphites (see the Support- enantioselectivity (entry 2 vs. 5). On the contrary, the
ing Information) were tested with [Ir(cod)Cl] as the addition of PPh to PA3 improved the enantioselec-
2
3
metal precursor. Considering that the phosphine is tivity without affecting the yield (entry 3 vs. 6).
a stronger donor ligand than the phosphoramidite, The ratio between iridium and the two ligands was
a phosphoramidite:phosphine ratio of 2:1 was used to investigated with PA3 and P(p-CF C H ) . For the
3
6
4 3
phosphoramidite ligand alone, the optimal amount
was 2 equivalents per iridium (entries 3, 13 and 14). A
larger excess of PA3 led to lower yields and enantio-
selectivities (entry 14). Remarkably, the achiral phos-
phine used alone led to no conversion (entries 15 and
Table 1. Selected results for the ligand screening in the AH
of 1a to 2a.
[a]
16). Since the Ir-phosphine complex appeared to be
inactive, we investigated lower phosphoramidite:phos-
phine ratios. The optimal iridium:PA3:phosphine
ratio was determined to be 1:1:1 (entry 17), leading to
full conversion to 2a and 77% ee. An excess of phos-
phine or phosphoramidite (entries 12–18) led to a de-
crease in activity, probably due to the saturation of
the metal complex by the extra ligand. In agreement
with the lack of activity of the phosphine homo-com-
plex, an excess of phosphine did not affect the enan-
tioselectivity (entry 18). On the other hand, an excess
of phosphoramidite led to a lower ee (entry 12) which
is also consistent with the Ir complex containing two
phosphoramidites being less enantioselective.
Entry PA [equiv./
PR , R=[equiv./ Yield
ee
[%]
3
[b]
[b]
[c]
[c]
Ir]
Ir]
[%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
PA1 [2]
PA2 [2]
PA3 [2]
PA1 [2]
PA2 [2]
PA3 [2]
PA2 [2]
PA3 [2]
PA2 [2]
PA3 [2]
PA2 [2]
PA3 [2]
PA3 [1]
PA3 [4]
–
–
–
–
99
49
86
94
87
88
88
86
51
47
83
86
60
31
3
30
À52
39
An extensive screening of solvents and additives
did not result in an improved catalytic performance
Ph [1]
Ph [1]
Ph [1]
p-MeOC H [1]
p-MeOC H [1]
p-ClC H [1]
p-ClC H [1]
p-CF C H [1]
31
À49
of the Ir/PA3/P(p-CF C H ) system. Decreasing the
50
3
6
4 3
À56
55
pressure of H led to a lower conversion without af-
2
6
4
6
4
fecting the enantioselectivity. Decreasing the temper-
ature improved the ee to 83% but at the expense of
the conversion (see the Supporting Information).
The substrate scope was investigated to some
extent with the optimized system (Table 2). Indeed,
the mixed ligand catalyst was efficient for a range of
À54
6
4
0
1
2
3
4
5
6
7
8
56
6 4
À58
60
17
2
–
–
77
77
3
6
4
p-CF C H [1]
–
–
3
6
4
2-arylpyridinium salts. Yields and enantioselectivities
p-CF C H [1]
3
6
4
were very similar for these substrates, i.e., not drasti-
cally influenced by the electronic properties of the
aryl substituent (Table 2, entries 1–6). Increasing the
steric bulk of the aryl substituent led to a decrease of
the enantioselectivity (Table 2, entry 7).
A mechanistic study was performed with the opti-
mized catalyst. The AH of pyridinium salt 1a was
monitored over time by GC and NMR (Figure 1).
–
p-CF C H [2]
2
3
6
4
PA3 [1]
PA3 [1]
p-CF C H [1]
99
71
3
6
4
p-CF C H [2]
3
6
4
[
a]
Reaction conditions: 1a (0.05 mmol), [Ir(cod)Cl]2
1 mol%), phosphoramidite (PA), phosphine (PR ),
(
3
DCM (1 mL), 508C, 50 bar H , 18 h.
Equivalents of ligand per atom of iridium.
Determined by chiral GC analysis and dodecane as inter-
2
[
[
b]
c]
nal standard. Positive values correspond to R configura- The substrate was fully consumed in roughly 10 h,
tion.
with concomitant formation of piperidine 2a, whose
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Table 2. Substrate screening for AH of N-benzyl-2-arylpyri- mum after 1.5 h. Although it could not be isolated, its
[a]
dinium salts.
mass (m/z=249) determined by GC-MS was consis-
tent with an N-benzylated tetrahydropyridine isomer.
NMR analysis allowed us to identify TH as N-benzyl-
6
-phenyl-1,2,3,4-tetrahydropyridine (Figure 1, see the
Supporting Information). During the course of the re-
action, the sum of 1a, 2a and TH matched well with
the initial amount of substrate used, suggesting that
no other intermediates are formed and that the hy-
drogenation of TH is the rate-limiting step.
[b]
[b]
Entry
Ar
Yield [%]
ee [%]
[
c]
1
2
3
4
5
6
7
Ph (1a)
99 (92)
98
99
97
98
77 (R)
71 (+)
82 (+)
70 (+)
74 (+)
74 (+)
58 (À)
4-MeC H (1b)
To get further insight into the mechanism, two iso-
6
4
4-MeOC H (1c)
3,5-di-MeOC H (1d)
6
4
topic
Scheme 1). When the optimized reaction was carried
out with H in the presence of CD OD (Scheme 1A),
labeling
experiments
were
conducted
6
3
(
4-CF C H (1e)
3
6
4
2
3
4-ClC H (1f)
99
99
6
4
a high deuterium incorporation was observed at C-3
1.07 deuteriums) and C-5 (0.30 deuteriums), com-
2-naphthyl (1g)
(
[
a]
Reaction conditions: 1 (0.1 mmol), [Ir(cod)Cl] (1 mol%), pared to the other carbons (<0.12 deuteriums each).
PA3 (2.2 mol%), P(p-CF C H ) (2.2 mol%), DCM
2
3
6
4
3
This suggests that enamine-iminium tautomerizations
take place during the reaction leading to the addition
of a proton from the reaction medium into the posi-
tions 3 and 5 in agreement with previous studies for
(
2 mL), 508C, 50 bar H , 18 h.
2
[
[
b]
c]
Yield and ee determined by chiral GC, HPLC or SFC
with dodecane as internal standard.
In brackets, isolated yield of a 500-mg-scale reaction.
[
11]
other N-heteroaromatic substrates.
The low deuterium incorporation at C-4 is consis-
tent with an initial 1,4-hydride addition to 1a leading
to the formation of N-benzyl-2-phenyl-1,4-dihydropyr-
idine (DH, Scheme 2). The dihydropyridine DH can
tautomerize into the two iminium ions DH’ and DH’’.
Since TH is the only detectable intermediate, it is rea-
sonable to think that the 1,2-hydride addition to DH’
occurs faster than to the more sterically hindered
DH’’. The difference of reactivity between DH’ and
DH’’ is also consistent with the higher deuterium in-
corporation at C-3 compared to C-5. Since DH’’ is
a more stable intermediate, it can incorporate more
deuterium at C-3 via multiple enamine-iminium inter-
conversions.
Figure 1. Evolution of the yield and ee of different reaction
species over time. Reaction conditions: 1a (1.5 mmol),
[
Ir(cod)Cl]2 (1 mol%), PA3 (2.2 mol%), P(p-CF C H )
3 6 4 3
(
2.2 mol%), DCM (30 mL), 508C, 50 bar H , 10 h. Con-
2
sumption of 1a determined by NMR with dimethyl tereph-
thalate as internal standard. Yield and ee of 2a and TH
monitored by chiral GC analysis with dodecane as internal
standard.
ee increased slightly at the beginning of the reaction
and then remained constant. The reaction profile fits
st
well with a 1 order reaction, with a small induction
period during the first minutes.
Scheme 1. Isotopic labeling experiment for the AH of N-
A reaction intermediate (labeled TH in Figure 1) benzyl-2-phenylpyridinium bromide 1a in the presence of
was detected by GC. Its concentration reaches a maxi- CD OD (A) or D (B).
3
2
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A second isotopic labeling experiment was per- was capped with a PTFE septum, removed from the glove-
box and placed into a Premex 96er Multireaktor. After
formed by reacting 1a with D gas under the opti-
2
flushing it 5 times with N (10 bar) and 5 times with H2
mized conditions (Scheme 1B): all the ring positions
were deuterated, with a total amount of five deuteri-
um atoms incorporated. No ring-face preference for
the deuterium incorporation is observed in any of the
carbons suggesting that the stereogenic center is not
formed until the last step.
2
(
10 bar), it was pressurized to 50 bar of H and the mixture
2
stirred at 508C for 18 h. The crude mixture was washed with
a saturated aqueous solution of Na CO and extracted with
2
3
DCM. The organic extracts were dried, concentrated and
purified by flash column chromatography using hexane/
EtOAc (from 99:1 to 95:5).
Based on these experimental results, the following
mechanism can be proposed (Scheme 2): an initial
1,4-hydride addition to 1a, forming the dihydropyri-
dine DH; the rapid hydrogenation of DH into TH via Acknowledgements
an iminium intermediate DH’; the enantioselective
1
,2-hydride addition to the iminium TH’ to the final We thank the European Commission [ITN-EID “REDUC-
piperidine 2a.
TO” PITN-GA-2012–316371] for financial support and for
predoctoral fellowships (to M. R.-C. and P. G.).
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2
Scheme 2. Proposed mechanism for the asymmetric hydro-
genation of 1a.
In conclusion, we have developed a new catalytic
system based on a mixture of ligands for the asym-
metric hydrogenation of 2-arylpyridines. Using an iri-
dium complex in the presence of two different mono-
dentate ligands (a chiral phosphoramidite and an
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[
General Procedure
Inside the N2 glovebox,
a
solution of [Ir(cod)Cl]2
(
(
3
0.0015 mmol), PA3 (0.0033 mmol) and P(p-CF C H )
0.0033 mmol) in DCM (1 mL) was stirred at 458C for
0 min. The preformed catalyst was added to a 5-mL-vial
3
6
4 3
containing a solution of the corresponding N-benzyl-2-aryl-
pyridinium bromide (0.15 mmol) in DCM (2 mL). The vial
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[12] An isotopic labeling experiment has been reported for
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A Mixed Ligand Approach for the Asymmetric
Hydrogenation of 2-Substituted Pyridinium Salts
Adv. Synth. Catal. 2016, 358, 1 – 6
Marc Renom-Carrasco, Piotr Gajewski, Luca Pignataro,
Johannes G. de Vries, Umberto Piarulli, Cesare Gennari,
Laurent Lefort*
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢃ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!