Optimized Scalable Synthesis of Chiral Iridium Pyridyl-Phosphinite (Pyridophos) Catalysts

Article abstract of DOI:10.1002/hlca.202000181

Iridium catalysts with chiral P,N ligands have greatly enhanced the scope of asymmetric olefin hydrogenation because they do not require a coordinating group near the C=C bond like Rh and Ru catalysts. Pyridophos ligands, possessing a conformationally restricted annulated pyridine framework linked to a phosphinite group, proved to be particularly effective, inducing high enantioselectivities in the hydrogenation of a remarkably broad range of substrates. Here we report the development of an efficient scalable synthesis for the two most versatile Ir-pyridophos catalysts, derived from 2-phenyl-8-hydroxy-5,6,7,8-tetrahydroquinoline or the analogue with a five-membered carbocyclic ring, respectively, by modification and optimization of the original synthetic route. The optimized route renders both catalysts readily accessible in multi-gram quantities in analytically pure form in overall yields of 26–37 %, starting from acetophenone and cyclopentanone or cyclohexanone, respectively. A major advantage of the new synthesis is the efficient and practical kinetic resolution of the late-stage pyridyl alcohol intermediates with commercial immobilized Candida antarctica lipase B, giving access to both enantiomers of these catalysts as essentially enantiopure compounds. The catalysts are obtained as crystalline solids, which are air-stable and can be stored for years at ?20 °C without notable decomposition.

Full text of DOI:10.1002/hlca.202000181

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chimica acta
Accepted Article
Title: Optimized scalable synthesis of chiral iridium pyridyl-phosphinite
(pyridophos) catalysts
Authors: Andreas Pfaltz, Marc-André Müller, Adnan Ganić, Esther
Hörmann, Stefan Kaiser, Matthias Maywald, Marcus G.
Schrems, Andreas Schumacher, David Woodmansee, and
Stephen J. Roseblade
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To be cited as: Helv. Chim. Acta 10.1002/hlca.202000181
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10.1002/hlca.202000181
Helvetica Chimica Acta
HELVETICA
Optimized scalable synthesis of chiral iridium pyridyl-phosphinite
(pyridophos) catalysts
Marc-André Müller,a Adnan Ganić,a Esther Hörmann,a Stefan Kaiser,a Matthias Maywald,a Stephen J.
Roseblade,a Marcus G. Schrems,a Andreas Schumacher,a David Woodmansee,a and Andreas Pfaltz*a
a Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland, andreas.pfaltz@unibas.ch
Dedicated to Prof. Antonio Togni on the occasion of his 65th birthday
Iridium catalysts with chiral P,N ligands have greatly enhanced the scope of asymmetric olefin hydrogenation because they do not require a
coordinating group near the C=C bond like Rh and Ru catalysts. Pyridophos ligands, possessing a conformationally restricted annelated
pyridine framework linked to a phosphinite group, proved to be particularly effective, inducing high enantioselectivities in the hydrogenation
of a remarkably broad range of substrates. Here we report the development of an efficient scalable synthesis for the two most versatile Ir-
pyridophos cataysts, derived from 2-phenyl-8-hydroxy-5,6,7,8-tetrahydroquinoline or the analogue with a five-membered carbocyclic ring,
respectively, by modification and optimization of the original synthetic route. The optimized route renders both catalysts readily accessible
in multi-gram quantities in analytically pure form in overall yields of 26-37%, starting from acetophenone and cyclopentanone or
cyclohexanone, respectively. A major advantage of the new synthesis is the efficient and practical kinetic resolution of the late-stage pyridyl
alcohol intermediates with commercial immobilized Candida antarctica lipase B, giving access to both enantiomers of these catalysts as
essentially enantiopure compounds. The catalysts are obtained as crystalline solids, which are air-stable and can be stored for years at –20 °C
without notable decomposition.
Keywords: asymmetric catalysis • hydrogenation • iridium • P,N ligands • synthesis (org.)
Introduction
Asymmetric hydrogenation is one of the best established enantioselective catalytic methods in academia and industry.[1-4] Numerous
efficient rhodium and ruthenium catalysts have been developed that enable highly enantioselective reduction of a wide range of olefins
and many of them have become commercially available. However, the substrate scope of these catalysts is limited to functionalized olefins
carrying a coordinating group near the C=C bond. Alkenes lacking a coordinating group that binds to the catalyst generally show poor
reactivity and low enantioselectivity. This limitation has been overcome with the development of iridium catalysts based on chiral P,N
ligands.
The design of these catalysts was inspired by the Crabtree catalyst,[5] an achiral cationic IrI(tricyclohexylphosphine)(pyridine) complex,
which is known for its high reactivity in the hydrogenation of unfunctionalized tri- and even tetrasubstituted olefins. The first highly
enantioselective Ir-catalyzed hydrogenations were reported in 1998 for complexes with phosphino-oxazoline (PHOX) ligands, which mimic
the P,N core of the Crabtree catalyst.[6] As the substrate scope of Ir(PHOX) catalysts was limited, we subsequently explored many other
oxazoline-based P,N ligands (Figure 1). Among them, NeoPHOX[7,8] and ThrePHOX[9] emerged as particularly effective ligands for several
substrate classes. Meanwhile, two ThrePHOX complexes have also become commercially available.[10] In addition, we developed a series of
Ir catalysts with pyridine- and quinoline-derived P,N ligands because of their close structural relationship to the Crabtree catalyst.[11] From
this ligand class, the conformationally restricted pyridophos derivatives, with an annelated pyridine framework linked to a phosphinite
group, stand out for their exceptionally broad substrate scope.[12] The same type of ligands was also reported independently by Yong-Gui
Zhou and coworkers.[13]
Other groups as well have developed efficient ligand systems for Ir-catalyzed asymmetric hydrogenation.[14-21 ] Selected examples are
shown in Figure 1. In addition to chiral P,N ligands, also other heterodonor ligands were successfully applied, such as P-thioether ligands[22-
24] and C,N ligands derived from N-heterocyclic carbenes.[25,26] Overall, iridium catalysts based on chiral heterodonor ligands have greatly
1
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10.1002/hlca.202000181
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enhanced the scope of asymmetric hydrogenation. Except for strongly coordinating substituents such as free carboxy groups or amines,
which deactivate the catalyst, they tolerate just about any substitution pattern in the substrate.
Ir-PHOX and related catalysts
BArF
Bn Bn
BArF
BArF
BArF
n
O
O
O
O
R'2P
O
N
N
R'2P
N
N
R2P
R'2P
Ir
Ir
Ir
Ir
R
R
R
Ar
PHOX
ThrePHOX
NeoPHOX
Pyridophos
OR'''
Catalysts developed by other groups
BArF
BArF
BArF
BArF
Ar
N
O
R''2P
O
O
N
N
R'''2P
Ir
S
S
N
R'
N
R'2P
N
Ir
iPr
R
iPr
Ir
Ir
R''
Ph
R'
Andersson
Burgess
Diéguez & Pàmies
Figure 1. Selected iridium catalysts successfully applied in the asymmetric hydrogenation of C-C double bonds (BArF = tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate).
Over the years, two pyridophos complexes, catA and catB (Scheme 1), were successfully applied to an impressive range of different
substrate classes. They enabled for the first time asymmetric hydrogenations of purely alkyl-substituted alkenes with high
stereoselectivities. A striking example is the highly diastereoselective, catalyst-controlled hydrogenation of hexadehydro-g-tocopheryl
acetate leading to the natural stereoisomer of the vitamin E derivative (R,R,R)-g-tocopheryl acetate.[27] Moreover, a large variety of olefins
with non-coordinating functional groups, such as alkenylboranes[28] and -silanes[29], or weakly coordinating substituents such as allylic
alcohols[12] or a,b-unsaturated esters,[12] were successfully hydrogenated with these catalysts. In addition, high enantioselectivities were
also achieved in the hydrogenation of furans, benzofurans and indoles. [30-31] Furthermore, numerous applications in the synthesis of
complex natural products have demonstrated the potential of these catalysts. [32-35]
Selected test substrates and substrate classes
O
OEt
n
BArF
O
catA, B: >99% conv. catA, B: >99% conv.
*
O
catA: >99% conv.
99% ee
N
R2P
99% ee
99% ee
Ir
Ph
O
(pin)B
Cy
Me
N
catA: R = t-Bu, n = 1
catB: R = o-Tol,
n = 2
Boc
catA: 89% conv.
99% ee
catA: 93% conv.
98% ee
catA: >99% conv.
97% ee
Selected applications
OH
AcO
O
OH
O
O
O
I
[Ir-cat.]
H2
[Ir-cat.]
H2
OH
AcO
O
OH
O
O
O
I
γ-Tocopheryl acetate
Macrocidin A precursor
catB: 98% RRR (<0.5% RRS; <0.5 RSR; <0.5% SRR)
catB: 97:3 ds
[Ir-cat.]
H2
OH
OH
OH
OH
H31C15
H31C15
4
4
catA: >99:1 ds
Hydroxyphthioceranic acid precursor
Scheme 1. Selected substrate classes and intermediates in total synthesis successfully hydrogenated using catalysts catA and catB.
2
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Despite their wide scope, pyridophos catalysts catA and catB have been rarely used outside our research group due to the lack of a
practical scalable synthesis. Based on the original synthetic route, these catalysts were only available on small scale because the
enantiomerically pure ligands had to be prepared by resolution of a late-stage racemic intermediate by semi-preparative HPLC on a chiral
stationary phase.[12] Over the years, we have continuously improved the original synthesis. Here we report an efficient scalable synthetic
route, which allows the production of the two catalysts in high enantiomeric purity on a multigram scale. Based on this route, catalyst catA
has recently been commercialized.[36]
Results and Discussion
The original synthesis of the two most commonly applied pyridophos catalysts, catA and catB, dates from 2006 (Scheme 2).[12] The
synthesis consists of 9 steps, including resolution of the racemic pyridyl alcohols 1a and 1b by semi-preparative HPLC on a chiral stationary
phase. In several steps the products were purified by column chromatography. Expensive reagents were used in some of the steps and
several reactions suffered from only moderate yields. These issues made the synthesis difficult on a larger scale and extremely labor- and
time-intensive. However, most steps consisted of straightforward, well established reactions that should be scalable. So we felt, it should
be possible to improve the synthesis to render it practical on a multi-gram scale by optimization of the individual steps, provided that the
chromatographic resolution of the racemic pyridyl alcohols 1a and 1b, which formed the actual bottleneck of this synthetic route, could be
replaced by a more efficient and upscalable chemical process.
Synthesis of enantiopure pyridyl alcohols
O
O
N+
H
a
+
N
Ph
5, 86%
Cl
Ph
Cl
3
4
O
O
X
n
c
d
Ph
m
O
X
Ph
N
N
n
9a, n = 1; 51%
9b, n = 2; 35%
11a, n = 1; 85%
11b, n = 2; 41%
m
b
+
N
H
n
n
e
10a, n = 1; 89%, X = O, m = 1
10b, n = 2; 94%, X = CH2, m = 0
8a, n = 1
8b, n = 2
n
n
n
n
+
Ph
g
f
N
Ph
Ph
N
N
Ph
N
HO
HO
HO
rac.
O
(R)-1a, n = 1; 48%
(R)-1b, n = 2; 13%
(S)-1a, n = 1; 49%
(S)-1b, n = 2; 45%
1a, n = 1; 89%
1b, n = 2; 90%
12a, n = 1; 87%
12b, n = 2; 70%
Catalyst synthesis
n
BArF
O
n
n
i
h
N
R2P
Ph
N
Ir
Ph
N
R2PO
Ph
HO
(S)-1a, n = 1
(S)-1b, n = 2
(S)-2a, n = 1, R = t-Bu; 62% (S)-catA, n = 1, R = t-Bu; 78%
(S)-2b, n = 2, R = o-Tol; 77% (S)-catB, n = 2, R = o-Tol; 87%
Scheme 2. Original synthesis of iridium complexes catA and catB published in 2006. a) CH3CN, 1 h, reflux; b) C6H6, reflux; c) 1,4-dioxane, 16 h, reflux; d)
HONH2·HCl, EtOH, 3 h, reflux; e) MCPBA (1.8 equiv), CH2Cl2, 2 h, 0 °C to RT; f) (CF3CO)2O (2.5 equiv), 4 h, 0 °C to RT; 2M aq. LiOH, RT; g) semipreparative HPLC;
h) for (S)-2a: di-tert-butylchlorophosphane (1.0 equiv), DMF, NaH (1.3 equiv), 84 h, RT; for (S)-2b: N-(di-o-tolylmethyl)-N-ethylethanamine (2.0 equiv), 4,5-
dichloroimidazole (2.0 equiv), diisopropylamine (2.0 equiv), triethylamine (1.0 equiv), 165 h, RT; i) [Ir(COD)Cl]2 (0.5 equiv), (S)-2a or (S)-2b (1.0 equiv), CH2Cl2,
50 °C, 2 h, then NaBArF (1.3 equiv), H2O, 15 min, RT.
3
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The original synthesis started with a Mannich reaction using the preformed iminium salt 3 and acetophenone (4). Although the
hydrochloride salt of the Mannich base 5 was obtained in excellent yield, the high price N,N-dimethylmethyleneiminium chloride 3 was
disadvantageous for reactions on a large scale, especially at this early stage of the synthesis (Scheme 1, a). Therefore, paraformaldehyde
(6) and dimethylamine hydrochloride (7) were used as inexpensive starting materials to form the iminium salt in situ according to the
original procedure by Mannich.[37] While this procedure gave slightly lower yields, it readily afforded the hydrochloride salt of the Mannich
base 5 in up to 160 g quantities.
Originally, cyclopentanone (8a) and cyclohexanone (8b) were converted to the 1,5-diketo derivatives 9a and 9b by conversion to the
corresponding enamines 10a and 10b and subsequent reaction with the Mannich salt 5. This procedure suffered from low yields and
required preparation of the enamines in a separate step. A much more efficient and shorter procedure was found by deprotonating the
Mannich salt 5 and subsequent condensation with cyclopentanone or cyclohexanone,[38] avoiding the detour through the corresponding
enamines (Scheme 3). In this way, 1,5-diketones 9a and 9b were obtained in 69-79% and 89% yield (based on 5), respectively, after
distillation.
H
O
O
O
O
HO
O H
x
H
a
b
Ph
H
N
Ph
Ph
+
Cl
5, 78%
+
4
6
n
NH2
Cl
9a, n = 1; 69 - 79%
9b, n = 2; 89%
7
Scheme 3. Synthesis of 1,5-diketones 9a and 9b. a) EtOH, HCl, reflux; b) sat. aq. K2CO3, extraction with Et2O; for 9a: cyclopentanone, 120 °C, for 9b:
cyclohexanone, 145 °C.
The main drawback of the original sequence leading from diketones 9a and 9b to the corresponding pyridyl alcohols 1a and 1b was the
cumbersome purification of the products by column chromatography after each step. Thus, the primary task was to find more convenient,
scalable purification methods. We found, that the 2-phenyl substituted pyridine 11a could be obtained in 79% yield by aqueous extraction,
followed by filtration of the crude product through a short plug of silica gel and subsequent crystallization from cyclohexane. The six-
membered ring analogue 11b[39] was also purified by filtration through silica gel but, instead of crystallization, it was isolated by distillation
in 82% yield.
The subsequent two-step transformation leading to pyridyl alcohols 1a and 1b was simplified by omitting purification of the intermediate
N-oxides 12a and 12b and subjecting them directly to the Boekelheide rearrangement (Scheme 4). In addition, we were able to replace the
more reactive but also more expensive trifluoroacetic anhydride[40] by acetic anhydride, which required moderately higher reaction
temperatures (40 °C).[41] After careful optimization of the conditions for the rearrangement and subsequent in situ hydrolysis of the
resulting acetate, the racemic pyridyl alcohol 1a was obtained in 73% yield after filtration through a short silica gel column and
crystallization from dichloromethane. Column chromatography of the mother liquor afforded another 14% of crystallized product. A similar
procedure applied to the six-membered ring analogue 11b afforded the pyridyl alcohol 1b in 64% after crystallization from ethyl
acetate/hexane and an additional batch of 17% by column chromatography of the mother liquors. In several reactions at different scales,
the total yields ranged between 78 and 92%.
1) Ac2O
2) Base
n
n
n
MCPBA
N
Ph
N
N
O
Ph
Ph
HO
11a, n = 1
11b, n = 2
12a, n = 1, 100% crude
12b, n = 2, 100% crude
1a, n = 1; 87% from 11a
1b, n = 2; 78-92% from 11b
Scheme 4. Synthesis of the racemic pyridyl alcohols 1a and 1b.
We also considered alternative routes to pyridyl alcohols 1a and 1b such as the arylation of the N-oxides 13a and 13b, according to a
procedure reported by Fagnou and coworkers.[42, 43] Although we were able to obtain the desired arylated N-oxides 12a and 12b, high
4
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catalyst loadings (5.0 mol% palladium), moderate yields and the difficult purification by column chromatography led us to abandon this
approach (Scheme 5).
Pd(OAc)2 (5.0 mol%)
(t-Bu)3PHBF4 (5.0 mol%)
n
n
+
K2CO3 (2.0 eq.)
toluene (0.15 M)
110 °C, 12-18 h
N
N
O
Ph
Br
O
13a, n = 1
13b, n = 2
12a, n = 1; 55%
12b, n = 2; 33%
Scheme 5. Alternative approach to the synthesis of N-oxides 12a and 12b.
In order to make the synthesis amenable to a larger scale, we had to replace the semi-preparative chromatographic resolution step in the
original synthesis by a more practical, scalable chemical method for the production of pyridyl alcohols 1a and 1b in high enantiomeric
purity. We evaluated several approaches based on resolution or enantioselective synthesis (Scheme 6). Kinetic resolution of racemic
pyridyl alcohols 1a and 1b by Cu(II)(borabox)-catalyzed acylation gave unsatisfactory results.[44] Better results were achieved by conversion
to diastereomeric esters with (1S)-(-)-camphanic acid chloride, followed by chromatographic separation and subsequent hydrolysis.
Although gram quantities of enantiopure pyridyl alcohols could be prepared in this way, the method suffered from the difficult
chromatographic separation, generation of a large amount of waste, and the high price of the chiral reagent. As an alternative, we also
studied the enantioselective reduction of the corresponding ketones.[45, 46] However, the various reduction methods that we evaluated gave
only moderate enantioselectivities. In addition, the extra oxidation step lengthens the synthesis. Therefore, we decided to focus on kinetic
resolution methods. In the meantime, a highly enantioselective Rh-catalyzed hydrogenation of the keto analogue of pyridyl alcohol 1b was
reported by Xumu Zhang’s group, indicating that the detour via the corresponding ketones could indeed be an option.[47]
separation by enzymatic
kinetic resolution
n
semi-preparative HPLC
Ph
N
on chiral stationary phase
HO
HO
n
(R)-1a, n = 1
(R)-1b, n = 2
Ph
N
separation by copper
catalyzed kinetic resolution
HO
n
rac-1a, n = 1
rac-1b, n = 2
Ph
N
n
(S)-1a, n = 1
(S)-1b, n = 2
Ph
N
O
O
O
separation as diastereomers
Scheme 6. Different approaches to the resolution of racemic pyridyl alcohols 1a and 1b.
Based on the work of Uenishi et al.,[48] we investigated the kinetic resolution by lipase-catalyzed enantioselective esterification of the
racemic pyridyl alcohols 1a and 1b with vinyl acetate. Initial experiments indicated that heating to 60 °C led to full conversion of one of the
enantiomers using commercial immobilized Candida antarctica lipase B (CALB). Both, the remaining alcohol and the corresponding acetate
were formed in high enantiomeric purity. Yet, separation of the alcohol and ester by column chromatography proved to be difficult,
hampering scale-up of the reaction. However, we were able to avoid the cumbersome chromatographic separation by in situ esterification
of the remaining (S)-pyridyl alcohol with phthalic anhydride.[49] The polar phthalic acid half esters (S)-14a and (S)-14b could be separated
from the corresponding (R)-acetates (R)-15a and (R)-15b, respectively, by simple precipitation and filtration. Subsequent hydrolysis of the
separated esters afforded the (S)- and the (R)-pyridyl alcohols (S)-1a and (R)-1b in excellent yields and very high enantiomeric purities of 98
to >99% ee (Scheme 7). This procedure proved to be easily scalable and allowed access to both enantiomers of pyridyl alcohols 1a and 1b
in multi-gram quantities.
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n
2 M NaOH, MeOH
n
40 °C (1a), 50 °C (1b)
Ph
N
Ph
N
O
5 h
O
HO
O
(S)-1a, n = 1: 47% yield*), ≥98% ee
(S)-1b, n = 2: 47% yield*) ≥98% ee
*) yield over both steps
(S)-14a, n = 1
(S)-14b, n = 2
OH
1) CALB, (iPr)2O, vinyl
n
acetate
Ph
N
2) Solvent change to
CHCl3, phthalic
HO
rac-1a, n = 1
rac-1b, n = 2
anhydride, Et3N
n
n
2 M NaOH, MeOH
RT, 15 h
Ph
Ph
N
N
O
O
HO
(R)-15a, n = 1
(R)-15b, n = 2
(R)-1a, n = 1: 42% yield*), >99.9% ee
(R)-1b, n = 2: 33% yield*), >99.9% ee
*) yield over both steps
Scheme 7. Enzymatic kinetic resolution of racemic pyridyl alcohols 1a and 1b.
With the enantiopure pyridyl alcohols in hand, we focused on the optimization of the final steps of the catalyst synthesis (Scheme 8). In the
original route, the phosphinites 2a and 2b were isolated and in case of the di-o-tolyl derivatives, even purified by column chromatography
under inert conditions using degassed solvents. Furthermore, the formation of the phosphinites required long reaction times of up to 165 h
and for the di-o-tolyl-phosphinites, the preparation of N,N-diethyl-1,1-di-o-tolylphosphanamine as phosphination reagent was necessary to
achieve satisfactory yields. These issues made the procedure cumbersome and impractical on larger scale. Ideally, these labile oxygen-
sensitive intermediates should be converted fast, without further purification, to the corresponding oxygen-stable iridium complexes.
Therefore, we examined an alternative method for this critical step that was based on a procedure reported by Knochel and co-workers for
the formation of P-O-bonds.[50, 51] They observed rapid phosphinite formation within 30 minutes at room temperature by using equimolar
amounts of an alcohol, chlorodiphenylphosphine and 4-(N,N-dimethylamino)pyridine in diethyl ether.
Since the pyridyl alcohols are poorly soluble in diethyl ether, exact implementation of this protocol was not possible. Fortunately, CH2Cl2
proved to be a suitable alternative solvent. Furthermore, we also tried to simplify this step by in-situ complexation of the formed
phosphinite 2b with [Ir(COD)Cl]2. Although phosphinite formation proceeded well in CH2Cl2, direct complexation without prior purification
resulted in low yields of the Ir complex. However, a practical solution was found by filtration of the reaction solution through a plug of basic
aluminum oxide directly into a solution of [Ir(COD)Cl]2 and NaBArF. As a further advantage, this simple purification protocol allowed the use
of a slight excess of (o-Tol)2PCl and 4-(N,N-dimethylamino)pyridine to ensure complete conversion. After complexation at 40 °C, the air-
stable Ir complex was purified by column chromatography on silica gel to afford catalyst catB as an orange solid in 88% yield. The complex
could be crystallized from CH2Cl2/pentane, yet test hydrogenations showed no difference in enantioselectivity and yield between the non-
crystallized and the crystallized catalyst.
This protocol was not suited for the synthesis of the sterically more demanding di-tert-butylphosphinite complex catA due to poor yields.
However, we succeeded in optimizing and simplifying the procedure used in the original synthesis. By increasing the concentration of the
reactants by a factor of 10, the reaction time was considerably shortened from 84 h to 14 h. In this case, phosphinite 2a could be obtained
in sufficient purity for the subsequent complexation step by simple filtration of a toluene solution through celite. After complexation and
anion exchange with NaBArF, the reaction mixture was adsorbed on silica gel and subjected to column chromatography. The fractions
containing the Ir complex were diluted with hexane and upon concentration, the product crystallized. After separation from the mother
liquor and washing with hexane, complex catA was obtained in analytically pure form in 79% yield.
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BArF
1) [Ir(COD)Cl]2 (0.5 equiv)
CH2Cl2, reflux, 1 h
NaH, t-Bu2PCl
THF/DMF(9:1), RT, 14 h
O
O
tBu2P
N
tBu2P
N
Ir
2) NaBArF (1.1 equiv)
CH2Cl2, RT, 30 min
Ph
Ph
(S)-2a
n
(S)-catA , 79%
(not isolated)
HO
N
Ph
BArF
(S)-1a, n = 1
(S)-1b, n = 2
O
[Ir(COD)Cl]2 (0.5 equiv)
NaBArF (1.1 equiv)
(o-Tol)2PCl (1.2 equiv)
DMAP (1.2 equiv)
O
oTol2P
N
oTol2P
N
Ir
CH2Cl2, 40 °C, 1 h
CH2Cl2, RT, 1 h
Ph
(S)-catB, 88%
Ph
(S)-2b
(not isolated)
Scheme 8. Phosphinite formation followed by direct complexation to afford catalysts catA and catB.
The optimized procedures summarized in Scheme 8 greatly simplify the transformation of pyridyl alcohols 1a and 1b into the Ir complexes
catA and catB. The procedures proved to be easily scalable and were readily performed on a multi-gram scale. Samples of these catalysts,
prepared via the new optimized synthesis, were tested in the hydrogenation of (E)-methylstilbene. The enantioselectivities and yields were
identical to those observed with the corresponding catalysts synthesized by the original procedures, confirming the high product quality
achievable by the new procedures.
H
O
O
O
HO
O H
x
O
n
a
b
H
Ph
H
N
Ph
Ph
+
4
Cl
5, 78%
6
NH2 Cl
9a, n = 1; 69 - 79%
9b, n = 2; 89%
7
c
e
d
n
n
n
Ph
N
Ph
N
O
Ph
N
HO
12a, n = 1; 100% (crude)
12b, n = 2; 100% (crude)
11a, n = 1; 79%
11b, n = 2; 82%
1a, n = 1; 87%
1b, n = 2; 78-92%
f
n
BArF
O
g
+
n
n
N
R2P
Ir
Ph
N
Ph
N
Ph
HO
HO
(R)-1a, n = 1
42%, >99.9% ee
(S)-1a, n = 1
47%, ≥98% ee
catA, n = 1; R = t-Bu; 79%
catB, n = 2; R = o-Tol; 88%
(R)-1b, n = 2
(S)-1b n = 2
33%, >99.9% ee
47%, ≥98% ee
Scheme 9. Optimized syntheses of Ir-pyridophos catalysts catA and catB. a) Conc. HCl, ethanol, 16 h, reflux; b) sat. aq. K2CO3, extraction with Et2O;
cyclopentanone (2.8 equiv), 15 h, 120 °C or cyclohexanone (2.8 equiv), 4 h, 145 °C; c) hydroxylamine hydrochloride (2.0 equiv), EtOH, 85 °C, 15 h; d) MCPBA
(1.5 equiv), CH2Cl2, 4 h, RT (12a) or reflux (12b); e) Ac2O (8.5 equiv), 40 °C, 15 h (12a) or 60 °C, 5 h (12b), then NaOH, MeOH; f) CALB, vinyl acetate (2.5 equiv),
iPr2O, 60 °C, 9-18 h, then phthalic anhydride (0.9 equiv), Et3N (2.5 equiv), CH3Cl, reflux, 15 h; separation and saponification of the phthalic ester and the
acetate; g) for catA: P(t-Bu)2Cl (1.0 equiv), NaH (2.5 equiv), THF/DMF (4:1), 14 h, RT, then [Ir(COD)Cl]2 (0.5 equiv), CH2Cl2, 1 h, reflux, then NaBArF (1.1 equiv),
30 min, RT; for catB: P(o-Tol)2Cl (1.2 equiv), DMAP (1.2 equiv), CH2Cl2, 1 h, RT, filtration, then [Ir(COD)Cl]2 (0.5 equiv), NaBArF (1.1 equiv), 1 h, 40 °C.
Conclusions
By continuous modification and optimization of the original synthetic route, we have developed two efficient scalable syntheses for Ir-
pyridophos catalysts catA and catB, which have been successfully used in the asymmetric hydrogenation of a wide range of functionalized
7
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and unfunctionalized olefins as well as furans, benzofurans, and indoles. By the optimized synthetic routes summarized in Scheme 9 both
catalysts are readily accessible in multi-gram quantities in analytically pure form in overall yields of 26-30% (catA) and 31-37% (catB),
starting from acetophenone and cyclopentanone or cyclohexanone, respectively. A major advantage of the new syntheses is the efficient
and practical kinetic resolution of the late-stage pyridyl alcohol intermediates 1a and 1b with commercial, immobilized Candida antarctica
lipase B, giving access to both enantiomers of these catalysts as essentially enantiopure compounds. Several steps have been considerably
simplified by eliminating labor-intensive purification procedures such as chromatography. Only the final products, catA and catB, have to
be purified by column chromatography. However, the chromatographic procedures are straightforward and can be easily carried out on a
multi-gram scale. The catalysts are obtained as crystalline solids, which are air-stable and can be stored for years at –20 °C without notable
decomposition. Based on the procedures described herein, catalyst catA has recently been commercialized.[36] The synthetic protocols
developed for the synthesis of catA and catB should also be adaptable for the preparation of other, differently substituted Ir-pyridophos
complexes. In summary, the optimized synthetic routes should foster further application of these versatile catalysts.
Experimental Section
All manipulations, expect for the purification of the catalysts after the complexation step, were performed under an inert atmosphere
using standard Schlenk techniques and dry degassed CH2Cl2.
Synthesis of catalyst catA
A flame dried Schlenk tube was charged under a constant argon flow with 2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (900 mg,
4.26 mmol, 1.00 equiv) followed by addition of THF (4 mL) and DMF (1 mL). To this solution was added di-tert-butylchlorophosphine
(770 mg, 4.26 mmol, 1.00 equiv), THF (5 mL) and NaH (100%, 250 mg, 10.4 mmol, 2.45 equiv). The reaction mixture was stirred for 14 h at
room temperature and the solvent was removed under reduced pressure, using a cooling trap connected to high vacuum. The residue was
suspended in toluene (2 mL), filtered through a plug of Celite® (3 × 2 cm) and rinsed with toluene (3 × 2 mL). The solvent was removed
under reduced pressure and the residue was dissolved in CH2Cl2 (8 mL). This solution was transferred to a two-necked round bottom flask,
equipped with a reflux condenser and a two-tap Schlenk adapter connected to a bubbler and an argon/vacuum manifold,[52] and charged
with a solution of [Ir(COD)Cl]2 (1.43 g, 2.13 mmol, 0.50 equiv) in CH2Cl2 (10 mL). The solution was stirred at reflux for 1 h followed by
addition of NaBArF (4.16 g, 4.69 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred for 30 min at room
temperature. The reaction mixture was adsorbed on silica gel (10 g) followed by purification by column chromatography (SiO2, d × h: 20 ×
6.5 cm, 1. diethyl ether ~250 mL, 2. CH2Cl2 400 mL). Hexane (~200 mL) was added to the orange fraction containing the iridium complex
and the solution was slowly concentrated to a volume of ~25 mL on a rotary evaporator. During this process, the complex started to
crystallize. The mother liquor was decanted, and the residue was washed with hexane (10 mL) and dried under vacuum (10−1 mbar) for one
hour to yield the product as an orange solid (5.11 g, 79%). For analytical data see the original synthesis;[12] for spectra, see the supporting
information.
Synthesis of catalyst catB
A flame dried Schlenk tube was charged under a constant argon flow with 2-phenyl-5,6,7,8-tetrahydroquinolin-8-ol (898 mg, 3.99 mmol,
1.00 equiv) and 4-dimethylaminopyridine (585 mg, 1.20 equiv) followed by addition of CH2Cl2 (10 mL). A solution of chlorodi(o-
tolyl)phosphine (1.19 g, 1.20 equiv) in CH2Cl2 (12 mL) was added and the solution was stirred for 1 h at room temperature. The solution was
filtered through a plug of heat-dried (drying oven, 120 °C, overnight) basic aluminum oxide (activated, Brockmann I, 150 mesh; d × h: 2 ×
~
7 cm), which was then rinsed with CH2Cl2 (4 × 20 mL). This solution was added slowly (30 min) through a transfer cannula to a suspension of
NaBArF (3.89 g, 1.10 equiv) and [Ir(COD)Cl]2 (1.34 g, 0.50 equiv) in CH2Cl2 (4 mL). The transfer cannula was rinsed with CH2Cl2 (12 mL) and
the reaction mixture stirred for 1 h at 40 °C, cooled to room temperature and washed with H2O (60 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 45 mL). The combined organic layers were dried over MgSO4, filtered through a sintered glass frit and all volatiles
evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, d × h: 7 ×15 cm) with pentane:CH2Cl2 (4:1,
500 mL), (7:3, 250 mL), (3:2, 750 mL), (1:1, 250 mL), (2:3, 250 mL), (3:7, 250 mL), and finally pure CH2Cl2 until the orange band on the
8
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column had been completely eluted. After concentration of the orange fractions containing the product and drying under high vacuum,
catalyst catB was obtained as an orange solid (5.59 g, 88%). Crystals suitable for X-ray analysis could be obtained by the layering a solution
of the Ir complex in CH2Cl2 with pentane. For analytical data see the original synthesis;[12] for spectra, see the supporting information. Test
hydrogenations showed no difference in enantioselectivity and conversion between non-crystallized and crystallized catalyst samples.
Supplementary Material
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/MS-number.
Acknowledgements
Support of this work by the Swiss National Science Foundation and the Federal Commission for Technology and Innovation (KTI) is
gratefully acknowledged. We thank Dr. Sigmund Gunzenhauser for his help with difficult chromatographic separations. We also thank one
of the reviewers for bringing references [38], [41], and [51] to our attention.
Author Contribution Statement
M.-A. M, A. G., S. K., M. M., S. J. R., M. G. S., A. S. and D. W. studied new approaches to the catalyst syntheses and developed the synthetic
procedures. E. H. developed the optimized large-scale procedures. A. P. supervised the work and wrote the manuscript together with M.-A.
M.
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