Modular 1,1′-Ferrocenediyl-cored P-Stereogenic Diphosphines: ′′JDayPhos′′ Series and its Use in Rhodium(I)-Catalyzed Hydrogenation

Article abstract of DOI:10.1002/adsc.201800255

A novel ferrocene-based P-stereogenic diphospine ligand series dubbed JDayPhos was developed, which rhodium(I) complexes of some of its members exhibited excellent enantioselectivity (up to >99% ee) and high activity in asymmetric hydrogenation of β-unsubstituted or -substituted itaconates and α-methylene-γ-oxo-carboxylates. (Figure presented.).

Full text of DOI:10.1002/adsc.201800255

Title: Modular 1,1’-Ferrocenediyl-cored P-Stereogenic Diphosphines:
''JDayPhos'' Series and its Use in Rhodium(I)-Catalyzed
Hydrogenation
Authors: Gasper Poklukar, Michel Stephan, and Barbara Mohar
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800255
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Modular 1,1’-Ferrocenediyl-cored P-Stereogenic Diphosphines:
''JDayPhos'' Series and its Use in Rhodium(I)-Catalyzed
Hydrogenation
Gašper Poklukar, Michel Stephan,a,* and Barbara Mohar*
National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
Phone: +386 14760250; e-mail: mstephan@phosphoenix.com; barbara.mohar@ki.si
Current address: PhosPhoenix SARL, 115, rue de l’Abbé Groult, 75015 Paris, France
a
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
novel ferrocene-based P-stereogenic
diphospine ligand series dubbed JDayPhos was developed,
which rhodium(I) complexes of some of its members
exhibited excellent enantioselectivity (up to >99% ee) and
high activity in asymmetric hydrogenation of -
unsubstituted or -substituted itaconates and -methylene--
oxo-carboxylates.
R1
Me
Me
PR1
R2
PR2
PR2
R2
X
2
PR2
PPh2
PPh2
2
Fe
Fe
Fe
Josiphos
series
Mandyphos
& Ferriphos
series
BPPFA: X= NMe2
BPPFOH: X= OH
R1
Keywords: Asymmetric catalysis; Carboxylic acids;
PPh2
R
Hydrogenation; P-ligands; Rhodium
PCy2
PPh2
O
P
P
Me
Me
H
Me
PPh2
Fe
Fe
Fe
NMe2
NMe2
Taniaphos series
Following the introduction in the ‘80s of
interesting first ferrocene-based type chiral
diphosphine ligands such as BPPFA and
BPPFOH, proliferation of variants occurred in
the ‘90s starting as well from Ugi’s amine
(Figure 1).[1] In fact, both planar- and carbon-
centered chiralities are present in some of these
designs. Josiphos, MandyPhos, Walphos,
Taniaphos, BoPhoz, and TRAP figure amongst
the prominent series of this type, and some found
Wudaphos
SPO-Wudaphos
Ph
Ar
Me
Me
R
N
P
R
Fe
PPh2
P
Ph
P
P
Ar
Fe
Fe
Ar
P
Ph
Ar= o-An: 1b
R
BoPhoz-type
series
Ar= 1-Nap, 2-Nap,
9-phenanthryl
R
R-FerroTANE series
Figure 1. Selected ferrocene-based chiral diphosphine
ligands.
Particularly relevant to this study, a short
ligand series of C2-symmetric P,P’-distereogenic
1,1’-bis[(aryl)(phenyl)phosphino]ferrocenes has
been prepared and the ligand having an aryl= o-
anisyl (1b) displayed 85−96% ee in the Rh(I)-
catalyzed asymmetric hydrogenation of methyl
application
in
industrial
asymmetric
hydrogenation processes.[2] These ferrocene-
cored phospine ligands are optionally modular
and can be sterically and electronically tuned by
the proper choice of the phosphino group.
Nonetheless, little attention has been paid to P-
stereogenic ones,[3−6] though BoPhoz- and
Wudaphos-type series,[4,5] proved to be efficient
in Rh(I)-catalyzed asymmetric hydrogenation.
-acetamidocinnamate
(MAC).[7]
Also
noteworthy, Et-FerroTANE ligand was excellent
for the Rh(I)-catalyzed hydrogenation of
itaconates (ex. 98% ee for dimethyl itaconate).[8]
In our ongoing research focused on P-
stereogenic diphosphine ligands, we have
previously shown that the replacement of the
methyl groups of the ethane-based DIPAMP
especially with branched alkyls (or some
1
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
functionalized groups) culminated in an tetramethylethylenediamine)[13]
yielded
the
advantageous ligand series dubbed R-SMS-Phos (RP,RP)-1,1'-bis[(o-
(Figure 2).[9,10] This judicious modification hydroxyphenyl)(phenyl)phosphino-P-
sharply boosted reaction rates by several times borane]ferrocene [(RP,RP)-3a] with meso-(RP,SP)-
1
and increased enantioselectivities in the Rh(I)- 3a in a 93:7 ratio (by H NMR), along with a
catalyzed asymmetric hydrogenation of a wide trace of the corresponding mono-substituted
range of functionalized olefins. Herein, we ferrocene.[14] The stereopure (RP,RP)-3a was
present an extension of this concept to the obtained in 34% yield after
a
single
ferrocene-based P,P’-distereogenic 1,1-bis{[o- recrystallization of the crude. Another crop of
(O-branched or heteroatom-substituted alkyl or (RP,RP)-3a was obtained following column
acyl)phenyl](phenyl)phosphino}ferrocene series chromatography leading to 58% total yield. Both
1 dubbed R-JDayPhos, and its assessment in the P-configurations can be attained starting either
Rh(I)-mediated hydrogenation of itaconates and
-methylene--oxo-carboxylates.
from (+)- or ()-ephedrine.
The stereopure key-intermediate 3a permits a
general access within two steps to a variety of
enantiomerically pure R-JDayPhos ligands 1c−1e
and to 1b. Notably, the decomplexation of 3
(step c) with Et2NH afforded the ligands 1 with
preservation of the configurational purity. Hence,
the present approach offers an added flexibility
in terms of synthesis of a large series of various
analogs, and an excellent opportunity for the
fine-tuning of the features of the design.
a) Key-preparation of the 1,2-ethylene-based R-SMS-Phos series:
H3B
Ph
RO
P
P
OR
BH3
Ph
R= H: (R,R)-SMS-Phos.BH3
1. O-functionalization
2. BH3 decomplexation
R= Me: (R,R)-DiPAMP
R= iPr, cPen, Cy, Piv, etc: (R,R)-R-SMS-Phos
b) The novel 1,1'-ferrocenediyl-based R-JDayPhos series:
Ph
BH3
BH3
P
Ph
Me
2 steps
(87%)
RO
P
P
O
N
Me
Ph
OMe
Fe
Ph
OR
P
(SP)-2
OH
>99.9% ee
()-OxazaPB
Ph
(R,R)-R-JDayPhos (1)
a)
R= branched or heteroatom-substituted alkyl or acyl group
Ph
H3B
HO
P
R
Me
iPr
TIPS
Piv
Fe
Figure 2. Our ethane-based R-SMS-Phos diphosphine
series and the novel ferrocene-based R-JDayPhos series 1.
OH
BH3
P
b
c
d
e
b)
Ph
(RP,RP)-3a
Synthesis of Ligands
Ph
Ph
H3B
RO
The targeted ligands were prepared via the
JugéStephan phosphine-P-borane asymmetric
route starting from the enantiomerically pure
1,3,2-oxazaphospholidine-2-borane
(oxazaPB) derived from
P
RO
P
Fe
Fe
P
OR
BH3
P
OR
c)
Ph
Ph
(RP,RP)-3b3e
>99.9% ee
(R,R)-R-JDayPhos (1c1e) and 1b
>99.9% ee
complex
homochiral
ephedrine.[11] This precursor has been already
successfully applied in the asymmetric synthesis
of 1b but using the enantiopure methyl (o-
anisyl)phenylphosphinite-P-borane.[7] In the
present work the versatile methyl (SP)-(o-
hydroxyphenyl)(phenyl)phosphinite-P-borane
[(SP)-2] was prepared in enantiomerically pure
form with 87% yield also via the JugéStephan
route but resorting to o-LiO-PhLi (Scheme 1).[12]
Following, the displacement of the P-OMe of 2
with 1,1'-dilithio-ferrocene (FcLi2(TMEDA)n
wherein n=1 or 2 prepared from ferrocene and n-
BuLi in hexane in the presence of
Scheme 1. Synthesis of ligand 1b and the (R,R)-R-
JDayPhos series. Reagents and conditions: a) NaH, THF,
0°C, then FcLi2(TMEDA)n, THF, 0°C to RT (58%); b) For
3b−3d: RX (MeI, iPrI, or TIPSCl), K2CO3 or Cs2CO3,
acetone, 30°C (95−97%); for 3e: PivCl, NaH, THF, 0°C to
RT (95%); c) Et2NH, 55°C (98%).
Hydrogenation Results
The new R-JDayPhos ligand series 1 was
initially screened in the Rh(I)-catalyzed
asymmetric hydrogenation of the conventional
benchmark
acetamidocinnamate
substrates
methyl
(MAC),
(Z)--
-
2
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
acetamidostyrene (AS), and 2-methylene-
succinamic acid (S1) (Table 1).[15] This study
revealed that the overall performance of the new
ligands surpasses the one of the basic o-anisyl-
substituted ligand 1b, with the O-isopropyl-
with an S/C= 10000 a complete conversion of -
(1-naphthyl)-itaconic acid 1-methyl ester (S9)
was achieved within 4 h demonstrating the
synthetic usefulness of the ligand. These results
are, in terms of enantioselectivity and especially
catalyst activity, superior to the ones with Et-
DuPHOS or Tangphos.[17] Moreover, morpholine
amide functionality was well-tolerated and
excellent activities and enantioselectivities (99%)
were obtained for S13 and S14, representing an
improvement over the literature data for these
challenging substrates.[18]
functionalized
ligand
iPr-JDayPhos
(1c)
furnishing the top results, both in terms of
enantioselectivity and reduction rate.[16]
Table 1. Screening of the (R,R)-R-JDayPhos ligand series
1c−1e in Rh(I)-catalyzed hydrogenation of reference
substrates.[a]
Time
[min]
To our delight, the -methylene--oxo-
carboxylic esters S15 and S17 (prepared via
Baylis-Hillman reaction or Friedel-Crafts
% Ee (conf)
Substrate
Ligand
5
-
2
10
2
1b
1b
88 (S)
91 (S)
CO2Me
[7b]
acylation,
respectively)
were
efficiently
iPr-JDayPhos (1c)
TIPS-JDayPhos (1d)
Piv-JDayPhos (1e)
>99 (S)
88 (S)
>99 (S)
Ph
NHAc
(MAC)
hydrogenated under 3 bar of H2 in 99% and 94%
ee, respectively, and the latter acid form S16 in
98% ee. Noteworthy, with the (Sc,RFc,RP)-SPO-
Wudaphos ligand ester S15 was hydrogenated
under 10 bar of H2 in only 81% ee, while the acid
S16 in 99% ee.[5] Finally, a never-before-reduced
-benzylidene--oxo-carboxylic esters S18−S20
were hydrogenated in respectively 90, 95 and
99% ee, but necessitated a higher catalyst
loading (S/C= 100−200) and 20 bar of H2 for
complete conversion. The resulting chiral -
substituted -oxo-carboxylates could serve for
the preparation of oxomethylene peptide
isosteres.[19]
60
20
60
60
1b
78 (S)
97 (S)
95 (S)
80 (S)
Ph
iPr-JDayPhos (1c)
TIPS-JDayPhos (1d)
Piv-JDayPhos (1e)
NHAc
(AS)
3
2
2
2
1b
98 (R)
>99 (R)
99 (R)
CO2H
iPr-JDayPhos (1c)
TIPS-JDayPhos (1d)
Piv-JDayPhos (1e)
CONH2
>99 (R)
S1
[a]
The catalyst was preformed from [Rh(nbd)2]BF4 and (R,R)-R-
JDayPhos (S/C= 100). Runs were carried out under 1 bar of
H2 at 22°C in MeOH (0.5 mmol of substrate in 7.5 mL
MeOH) for the time indicated (100% conversion); the
reaction conditions are unoptimized. Ee’s were determined by
chiral GC (for this, see the Supporting information).
Following, iPr-JDayPhos ligand 1c was
In conclusion, we have prepared a new
enantiopure P-stereogenic R-JDayPhos ligand
considered for the asymmetric hydrogenation of
diverse series of itaconates (R2= CO2H, CO2Me,
C(O)NR’2) and -methylene--oxo-carboxylates
(R2= C(O)R’) (Table 2). Under our adopted
standard screening protocol (S/C= 1000, MeOH,
22°C), the corresponding chiral hydrogenation
products were obtained in good to excellent ee’s
and reaction rates. Thus, 99 to >99% ee was
obtained for itaconic acid (S2) and its 4-methyl
mono or dimethyl esters (S3 and S4,
respectively). Also, -substituted itaconic acids
and their mono esters S5−S12 (prepared by
Stobbe condensation) having an alkyl (R3= iPr)
or a (het)aryl (R3= 1-Nap, 2-Nap, 2-thienyl, 3,4-
methylenedioxy-phenyl) were hydrogenated
equally well (98 to >99% ee) with or without
adding a base (e.g. Et3N, CyNH2). Importantly,
series
1
from
1,1’-bis{[o-
hydroxyphenyl](phenyl)phosphino-P-
borane}ferrocene (3a) precursor. The seemingly
trivial alteration of the methyl groups of the P-o-
anisyl substituents of 1b to a higher isopropyl
homolog turned out to lead, as for DiPAMP, to a
more efficient ligand for the Rh(I)-catalyzed
asymmetric hydrogenation. A range of -
substituted itaconates and -methylene--oxo-
carboxylates were reduced with up to >99% ee.
These chiral -substituted -dicarboxylates and
-oxo-carboxylates are highly valuable building
blocks and can be further elaborated into
synthetically useful products.
3
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
Table 2. [Rh((R,R)-iPr-JDayPhos)(MeOH)2]BF4-catalyzed hydrogenation of itaconates and -methylene--oxo
carboxylates.[a]
CO2R1
R2
CO2R1
R2
[Rh((R,R)-iPr-JDayPhos)]+
110 bar H2/MeOH/22°C
Ph
R3
R3
*
iPrO
P
Fe
S1S21
OiPr
P
R1 = H, Me
Ph
(R,R)-iPr-JDayPhos (1c)
R2 = CO H, CO Me, CONH ,
-C(O)N
2
O
2
C(O)Me, C2(O)Ph
O
R3 = H, iPr, Ph, 1-Nap, 2-Nap, 2-thienyl,
O
p(H2)
[bar]
p(H2)
[bar]
% Ee
(conf)
% Ee
(conf)
Substrate
CO2H
S/C
Time
Substrate
S/C
Time
5 min
>99 (R)
S1
S2
S3
S4
S5
S6
1000
1
1
1
1
3
3
7 min
CO2H
S13
S14
1000
1000
3
3
99 (R)
99 (R)
Ph
Ph
CONH2
CO2H
C
O
N
O
O
>99 (R)
99 (R)
1000
1000
1000
1000
1000
13 min
2 h
CO2H
CO2H
5 min
CO2Me
C
O
N
CO2H
CO2Me
2 h
99 (R)
99 (R)
99 (R)
CO2Me
O
S15
S16
S17
1000
1000
200
3
3
3
30 min
20 min
20 min
99 (R)
CO2Me
CO2H
30 min
30 min
Me
CO2H
CO2H
O
CO2Me
98 (R)
94 (R)
CO2H
Ph
CO2Me
99 (R)
98 (R)
S7
S8
S9
1000
1000
3
3
35 min
60 min
Ph
1-Nap
1-Nap
CO2Me
O
CO2H
CO2H
Ph
CO2H
CO2Me
O
S18
200
20
36 h
90 (R)
CO2Me
>99 (R)
>99 (R)
1000
10000
3
3
15 min
4h
CO2H
Me
CO2Me
>99 (R)
98 (S)
S10 1000
S11 1000
3
3
15 min
50 min
CO2Me
O
S19
S20
100
200
20
20
48 h
3 h
95 (R)
99 (R)
2-Nap
S
Ph
CO2H
Me
CO2Me
CO2Me
O
CO2H
1-Nap
CO2Me
O
O
>99 (R)
S12 1000
3
2 h
Me
CO2H
[a]
The catalyst was preformed from [Rh(nbd)2]BF4 and (R,R)-iPr-JDayPhos. Runs were carried out at 22°C in MeOH (0.5 mmol of
substrate in 7.5 mL MeOH) for the time indicated (100% conversion). Ee’s were determined by chiral GC or HPLC (for this, see the
Supporting information).
[Rh(nbd)2]BF4 (0.982 mg, 2.6 μmol) in MeOH (2.5 mL) at
room temperature under argon atmosphere. After stirring
Experimental Section
for 60 min, the resulting solution was hydrogenated under 1
bar of H2 for 30 min. Filtration through a No. 3 sintered-
glass frit afforded a clear reddish-brown solution which
was taken by a gas-tight syringe. This was divided into 5
portions for tests with an S/C= 1000.
General procedure for asymmetric hydrogenation at 1
bar H2 (S/C= 1000)
Preparation of catalyst (absolute MeOH degassed with
three freeze-pump-thaw cycles was used): A solution of
(R,R)-iPr-JDayPhos (1.68 mg, 2.5 μmol) in MeOH (2.5
mL) was added dropwise to a vigorously stirred solution of
Hydrogenation: The solution of substrate (0.5 mmol) in
MeOH (6.5 mL) was degassed with three freeze-pump-
thaw cycles. When frozen during the third cycle, the above
4
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
Acknowledgements
pre-formed catalyst solution was added under argon via
syringe. The system was then thawed under vacuum and
backfilled with H2. The mixture was stirred vigorously at
22°C under 1 bar of H2. The progress of the reaction was
monitored by H2 uptake.
The authors acknowledge the financial support from the
Slovenian Research Agency (research core funding No. P1-242).
We thank Dr. Damjan Šterk and Dr. Slavko Rast for the
preparation of some ligands.
For hydrogenation at 3 bar of H2, the solution was
cannulated to an argon-filled autoclave, the system purged
ten-times with H2 then charged with H2. The solution was
stirred at 22°C for the time indicated.
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1991; WO9214739, 1992.
[12] M. Stephan, B. Modec, B. Mohar, Tetrahedron Lett.
2011, 52, 1086−1089.
[13] J. J. Bishop, A. Davison, M. L. Katcher, D. W.
Lichtenberg, R. E. Merrill, J. C. Smart, J. Organomet.
Chem. 1971, 27, 241–249.
[14] For a synthetic route wherein 1,1'-dilithio-ferrocene
(FcLi2(TMEDA)n) reacted with oxazaPB, leading to the
corresponding (RP,RP)/meso products in a 82:18 ratio,
see: M. Stephan, D. Šterk, B. Modec, B. Mohar, J. Org.
Chem. 2007, 72, 8010−8018.
[4] a) W. Chen, W. Mbafor, S. M. Roberts, J. Whittall, J.
Am. Chem. Soc. 2006, 128, 3922−3923; b) J. Deng, X.-
P. Hu, J.-D. Huang, S.-B. Yu, D.-Y. Wang, Z.-C. Duan,
Z. Zheng, J. Org. Chem. 2008, 73, 2015−2017; c) Z.-C.
Duan, X.-P. Hu, C. Zhang, Z. Zheng, J. Org. Chem.
2010, 75, 8319−8321.
[15] For an optimal comparison of catalysts’ activities, the
induction period was eliminated by preforming the
5
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
catalyst from [Rh(nbd)2]BF4 and (R,R)-R-JDayPhos.
Thus, the cationic solvate [Rh(R-
respectively. For this, see: M. J. Burk, F. Bienewald, M.
Harris, A. Zanotti-Gerosa. Angew. Chem. Int. Ed. 1998,
37, 1931−1933; b) Rh(I)-(Tangphos) (S/C= 200, 20 psi
H2, THF, 24 h) gave 99% ee for both S9 and S10. For
this, see: W. Tang, D. Liu, X. Zhang, Org. Lett. 2003, 5,
205−207.
JDayPhos)(MeOH)2]BF4 catalyst was generated from a
mixture of [Rh(nbd)2]BF4 catalyst precursor (1.05
equiv.) and R-JDayPhos (1.0 equiv.) following
prehydrogenation until metallic Rh precipitated (10-15
min under 1 bar of H2 in MeOH at 22°C). The
preformed solution of complex was filtered and the
requisite amount was transferred by syringe to the
prochiral substrate.
[18] Rh(I)-(Et-FerroTane) (S/C= 1000, 5.5 bar H2, MeOH,
1 h) gave 98% ee (100% conversion) for S13, while
Rh(I)-(Et-DuPHOS) (S/C= 1000, 5.5 bar H2, MeOH, 12
h) resulted in only 5% conversion and 85% ee.[7]
[16] Noteworthy, AH with our Rh(I)-(iPr-SMS-Phos)
(S/C= 100, 1 bar H2, MeOH) led to 99.7% ee (2 min)
for MAC, 97.8% ee (3 min) for AS, and 99.0% ee (3
min) for S1,[9b] while Rh(I)-(tBu-SMS-Phos) resulted in
99.9% ee (2 min) for S1.[9c]
[19] For synthesis of -alkyl--oxo-carboxylic acids as
oxomethylene peptide isostere core units via
enantioselective alkylation, see: R. V. Hoffman, H.-O.
Kim, J. Org. Chem. 1995, 60, 5107−5113.
[17] a) Rh(I)-(Et-DuPHOS) (S/C= 3000, 5.5 bar H2, MeOH,
12 h) gave 98% ee and 97% ee for S9 and S10,
6
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10.1002/adsc.201800255
Advanced Synthesis & Catalysis
Modular 1,1’-Ferrocenediyl-cored P-Stereogenic
Diphosphines: ''JDayPhos'' Series and its Use in
Rhodium(I)-Catalyzed Hydrogenation
CO2R1 [Rh(iPr-JDay-Phos)]+
13 bar H2, 22°C
CO2R1
R3
R3
*
R2
R2
MeOH
R1 = H, Me
up to >99% ee
100% conv
R2 = CO2H, CO2Me, CONH2,
C(O)Me, C(O)Ph
-C(O)N
O
Adv. Synth. Catal. Year, Volume, Page – Page
O
R3 = H, iPr, Ph, 1-Nap, 2-Nap, 2-thienyl,
O
Ph
23 examples
(R,R)-R-JDayPhos:
RO
P
Fe
OR
P
Gašper Poklukar, Michel Stephan,* and Barbara
Mohar*
R = iPr, TIPS, Piv
Ph
7
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