Impact of incorporating substituents onto the P-o-anisyl groups of DiPAMP ligand on the rhodium(I)-catalyzed asymmetric hydrogenation of olefins

Article abstract of DOI:10.1002/adsc.200800363

The introduction of 1,2-bis[(o-anisyl)-(phenyl)phosphino]ethane (DiPAMP) as a P-stereogenic ligand for rhodium(I)-catalyzed hydrogenation by Knowles et al. came after their evaluation of several diphosphines. However, no in-depth study was carried out on incorporating various substituents on its P-o-anisyl groups. In this work, we have prepared a large series of enantiopure and closely related DiPAMP analogues possessing various substituents (MeO, TMS, t-Bu, Ph, fused benzene ring) on the o-anisyl rings. The new ligands were evaluated in rhodium-catalyzed hydrogenation of several model substrates: methyl α-acetamidoacrylate, methyl (Z)-α-acetamidocinnamate, methyl (Z)-β-acetamidocrotonate, dimethyl itaconate, and atropic acid. They displayed enhanced activities and increased enantioselectivities, particularly the P-(2,3,4,5-tetra-MeO-C₆H)-substituted ligand (4MeBigFUS). Interestingly enough, 88% ee was obtained in the hydrogenation of atropic acid using the Rh-(4MeBigFUS) catalyst under mild conditions (10 bar H₂, room temperature) versus 7% ee using Rh-DiPAMP. Conversely, the ligand possessing P-(2,6-di-MeO-C₆H₃) groups proved to slow down considerably the hydrogenation. X-Ray structures of their corresponding Rh complexes are presented and discussed.

Full text of DOI:10.1002/adsc.200800363

FULL PAPERS
DOI: 10.1002/adsc.200800363
Impact of Incorporating Substituents onto the P-o-Anisyl Groups
of DiPAMP Ligand on the Rhodium(I)-Catalyzed Asymmetric
Hydrogenation of Olefins
a
a,
a,b,
ˇ ˇ
Borut Zupancic, Barbara Mohar, * and Michel Stephan *
a
Laboratory of Organic and Medicinal Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana,
Slovenia
Fax : (+386)-1-476-0300; e-mail: michel.stephan@ki.si
PhosPhoenix SARL, 115, rue de l’AbbØ Groult, 75015 Paris, France
b
E-mail: mstephan@phosphoenix.com
Received: June 11, 2008; Published online: August 19, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800363.
Abstract: The introduction of 1,2-bis
A
ACHTREUNG
genic ligand for rhodium(I)-catalyzed hydrogenation C6H)-substituted ligand (4MeBigFUS). Interestingly
by Knowles et al. came after their evaluation of sev- enough, 88% ee was obtained in the hydrogenation
eral diphosphines. However, no in-depth study was of atropic acid using the Rh-(4MeBigFUS) catalyst
carried out on incorporating various substituents on under mild conditions (10 bar H2, room temperature)
its P-o-anisyl groups. In this work, we have prepared versus 7% ee using Rh-DiPAMP. Conversely, the
a large series of enantiopure and closely related ligand possessing P-(2,6-di-MeO-C6H3) groups
DiPAMP analogues possessing various substituents proved to slow down considerably the hydrogena-
(MeO, TMS, t-Bu, Ph, fused benzene ring) on the o- tion. X-Ray structures of their corresponding Rh
anisyl rings. The new ligands were evaluated in rho- complexes are presented and discussed.
dium-catalyzed hydrogenation of several model sub-
strates: methyl a-acetamidoacrylate, methyl (Z)-a-
acetamidocinnamate, methyl (Z)-b-acetamidocroto- Keywords: asymmetric catalysis; enantioselectivity;
nate, dimethyl itaconate, and atropic acid. They dis- hydrogenation; P ligands; rhodium
Introduction
spawned a myriad of C2-symmetrical diphosphines.
Nevertheless, since then diphosphines with a stereo-
Ecological and readily scalable asymmetric hydroge- genic hydrocarbon backbone continue to constitute
nations catalyzed by soluble transition-metal com- the larger pool of available chiral phosphines com-
plexes have been proven to be a key technology. pared to P-stereogenic ligands.
Mediated by Rh-, Ru- or Ir-based catalysts, they
enable the effective preparation of the desired enan- for phosphine ligands with boosted efficiency,[4] we
tiomers of bioactive ingredients.[1]
were interested in optimizing existing privileged phos-
Spurred on by an economic stimulus in our quest
After the inspiring achievement of Dang and phines for practical use instead of devising brand new
Kagan employing the l-tartaric acid-derived cis-che- ones. Hence, we were prompted to investigate further
lating 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(di- the key findings reported by Knowles et al. since mid-
phenylphosphino)butane
ligand,[2] Nobel co-laureate Knowlesꢀ and co-workersꢀ Located in close proximity to the substrate coordinat-
P-stereogenic 1,2-bis[(o-anisyl)(phenyl)phosphino]- ed to Rh, P-chirality is an ideal point to tackle. As a
(DIOP)
diphosphine 1970s as there appeared to be potential for tuning.
A
ACHTREUNG
ethane (DiPAMP) ligand exhibited superior enantio- matter of fact, their initial investigation pointed to the
selectivities and activities in the Rh(I)-catalyzed hy- marked effect of the environment around the Rh
drogenation of b-substituted dehydro-a-alanines, and core, which was ascribed to the influence of the
a-substituted enol esters, etc.[3] These discoveries ortho-substituents of the P-aryl groups. They high-
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Impact of Incorporating Substituents onto the P-o-Anisyl Groups of DiPAMP Ligand
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lighted that ꢂthe power of the systemꢀ resides in the OMe groups of 1,2-bis(phosphinito-P-borane)ethane
presence of P-o-anisyl (P-o-An) groups leading to (Route B)[6d,e] yielding the opposite P-configuration.
high TOFs and ees. However, no in-depth study was
Following the expedient Route A, enantiomerically
conducted by systematically modifying the P-o-An pure (R,R)-DiPAMP [(R,R)-6a] and its new analogues
rings either by incorporating substituents onto the (R,R)-6b, d–m were obtained in 12–64% overall yield
ring or by altering the methyl of its methoxy group.[3,5] starting from (ꢀ)-1 and the corresponding aryllithium
Following later breakthroughs in access routes to reagent.[12] An alternate methodology to obtain a
P-stereogenic phosphines,[6] a number of research functionalized P-o-An ring from the aminophosphine-
groups prepared various C2-symmetrical DiPAMP- P-borane 2a was explored as well. Exploiting the di-
like ligands, wherein Knowlesꢀ ꢂtacitly recommendedꢀ rected ortho-lithiation property of the arylic MeO
P-o-An group is always present.[7a–g] Dissymmetrical group, the (O-methyl)-protected 2fa was easily
hybrid P-stereogenic diphosphines or specially tail- formed through s-BuLi metallation of (O-methyl)-
ored monophosphines were synthesized as well.[7h–k] protected 2aa followed by TMSCl quench; the struc-
In rare cases one can find P-stereogenic ethane-bridg- ture of 2fa was confirmed independently by O-meth-
ed tetraaryl diphosphines wherein the phosphorus ylation of 2f. Next, H+-catalyzed methanolysis of
atom bears a Ph group and an aryl group other than either 2f or 2fa furnished the methyl phosphinite-P-
an o-An.[6b–e,8]
borane 3f with identical optical purities. We reverted
Some X-ray crystal structures[9] or mechanistic to Route B for the synthesis of 6c [yielding the (S,S)-
NMR studies[10] by the groups of Heller and Brown enantiomer] as when following Route A, the by-prod-
demonstrated that a methoxy substituent on DiPAMP uct[13] formed during the P-OMe-displacement stage
could coordinate with the Rh or intervene at a late (step c) hampered the purification. Moreover, we pre-
stage in the hydrogenation cycle. However, although pared enantiomerically pure (S,S)-DiPAMP [(S,S)-6a]
the role or effect of the P-o-An methoxy group in the via Route B.
(Rh-DiPAMP)-catalyzed hydrogenation has not been
decisively clarified, Imamoto et al. suggested that a
steric factor rather than a weak coordinative interac- Hydrogenation Results
tion of the oxygen atom is most likely behind the
asymmetric induction.[8a]
The assessment of the efficiency of the DiPAMP ex-
We undertook the task of investigating extensively tended family members 6b–m in comparison with
the effect of electronic and steric alterations to the P- DiPAMP (6a) in Rh(I)-catalyzed hydrogenation, was
o-An groups of DiPAMP on Rh(I)-catalyzed asym- performed on the following conventional benchmark
metric hydrogenations viz. by incorporating substitu- substrates: methyl a-acetamidoacrylate (MAA),
ents onto the P-o-An rings.[11] We targeted the synthe- methyl (Z)-b-acetamidocinnamate (MAC), methyl
sis of a series of closely related analogues of DiPAMP (Z)-b-acetamidocrotonate (Z-MAB), dimethyl itaco-
with different substitution patterns on the P-o-An nate (DMI), and atropic acid (AA) (Table 1; results
groups with substituents such as: MeO, TMS, t-Bu, correspond to unoptimized reaction conditions).
Ph, or a fused benzene ring.
The sense of stereoselection in hydrogenation using
the DiPAMP analogues 6b–m is the same as observed
with DiPAMP for all the tested substrates. The pro-
posed empirical ꢂquadrant ruleꢀ is valid: (S)-a-amino
acids were obtained using (R,R)-6 ligands.[3b,8a,c] How-
ever, the overall performance of the new ligands was
in general appreciably better than the original parent
DiPAMP:[14] enhanced activities and increased enan-
Results and Discussion
Ligand Synthesis
The targeted ligands were prepared via the JugØ–Ste- tioselectivities were obtained in almost all cases, par-
phan phosphine-P-borane asymmetric route starting ticularly with the P-(2,3,4,5-tetra-MeO-C6H)-substitut-
from the enantiomerically pure 1,3,2-oxazaphospholi- ed ligand 6j which we dubbed ꢂ4MeBigFUSꢀ. Excep-
dine-2-borane complex (1).[6b,c,e] This synthon has al- tionally, the P-(2,6-di-MeO-C6H3)-substituted ligand
ready been applied in the asymmetric synthesis of 6e furnished the most sluggish catalyst and yielded
DiPAMP. The adopted synthetic strategy relies upon low ee values.
the sequential displacement of the ephedrine auxiliary
of 1 with organolithium reagents (Scheme 1). Both P-
configurations can be attained starting from either Hydrogenation of MAA
(+)- or (ꢀ)-ephedrine. To build the ethane bridge, we
applied two established routes, which call upon either Regardless of the added group (MeO, TMS, t-Bu, Ph,
oxidative homocoupling of P-(LiCH2)-phosphine-P- or a fused benzene ring) on the P-o-An rings, in-
boranes (Route A, step d)[6a] or displacement of the P- creased reaction rates (up to 5-fold) were observed
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Scheme 1. Synthesis of ligands 6a–m. Reagents and conditions: a) ArLi, THF or Et2O, ꢀ208C!r.t.; b) MeOH, H2SO4, r.t.;
c) MeLi (Route A) or ArLi (Route B), THF, ꢀ208C!r.t.; d) s-BuLi, THF, ꢀ308C then CuCl2, ꢀ308C; e) Et2NHor morpho-
line, 55–608C; f) NaH, MeI, THF, r.t.; g) s-BuLi, THF, ꢀ78!ꢀ208C then TMSCl, ꢀ208C!r.t.
with a significant increase in the induction (up to Hydrogenation of MAC
ꢁ99% ee) especially with ligands 6b, 6f, 6g, 6h, 6i, 6j,
and 6l. Ligands possessing R1 ¼Hfavoured an in-
Higher ees (up to 99%) as well as boosted reaction
crease in the ee; for example, 6b performed better rates (up to 6-fold) were attained with the majority of
than 6c (or 6d), but interestingly, the enantioselectivi- the screened ligands, especially with 6f, 6g, 6h, 6i, 6j,
ty was identical with 6a, 6c and 6d. Also, the ee in- and 6l. Multiplication of the MeO-substituents on the
creased with increase in the bulkiness of R1 going P-o-An led to an increase in the ee going from 6a<
from MeO<Ph=(CH=)2 <TMS<t-Bu. With ligand 6b<6i<6j. The ee was slightly affected with the in-
6k, wherein the oxygen atom of R1 is part of a fused creased steric bulk of R1: MeO<Ph=t-Bu<TMS=
dihydrofuran ring, the ee remained unchanged but the (CH=)2. With ligand 6k, a 2.5-fold faster reaction rate
rate increased by a factor of 2.5. Multiplication of the was observed compared to 6a, however with an iden-
MeO-functionality on the P-o-An rings resulted in tical ee. Interestingly, ligand 6b (R1 =MeO) led to a
both faster reaction rates and higher ees within the significantly faster reaction rate compared to 6a, 6c
series 6a<6b<6i=6j.
(R2 =MeO) or 6d (R3 =MeO).
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Impact of Incorporating Substituents onto the P-o-Anisyl Groups of DiPAMP Ligand
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Hydrogenation of Z-MAB
The inspection of hydrogenation data did not reveal
particular trends upon modification of the P-o-An
rings, but within the screened ligand set conversions
were in general inferior to the one with 6a. Converse-
ly, ligands 6b and 6j afforded the highest enantioselec-
tivity (ca. 80% ee) with the latter resulting in a com-
plete conversion.
Hydrogenation of DMI
The analysis of the overall results revealed that the
R1 substituents exert virtually no or an unfavourable
influence on the induction as was the case with 6b
and 6l. Conversely, R2 or R3 substituents seemed to
play a favourable role as was the case with ligands 6i
and 6m whereby the former led to 91% ee in a 2-fold
higher reaction rate compared to 6a. Notably, for the
best efficiency, the optimum number of MeO groups
on the P-o-An was reached in ligand 6i (3Me-
BigFUS).[17]
Hydrogenation of AA
The screening results of the new DiPAMP analogues
with this substrate revealed a pronounced and striking
improvement of the ee in the majority of cases. As
high as 88% ee was attained using 6j vs. 7% ee with
6a. Ligand 6h (R1 =R3 =t-Bu) furnishing 5% ee with
69% conversion, performed as poorly as 6a. By con-
trast, ligands 6b (R1 =MeO), 6f (R1 =TMS), and 6g
(R1 =Ph) led to 61%, 79%, and 71% ee, respectively.
Mechanistic Considerations
Chirality transfer from stereogenic DPPE-derived li-
gands (for example DiPAMP) to a-amino acids
became a textbook example of the Rh(I)-catalyzed
asymmetric hydrogenation. Some studies were con-
ducted as well on b-dehydroamino acids, itaconates
and a-arylacrylates.[18] Intimate mechanistic aspects
of the proposed operative pathways were substanti-
ated by a combination of exhaustive detailed confor-
1
mational analyses resorting to in situ H, 13C, and
31P NMR spectroscopy, X-ray crystallography, kinet-
ic methods, molecular mechanics computations, etc.
Informative data could be obtained from the single-
crystal X-ray structure analyses of the diphosphine-
Rh(I)-diene precatalyst, or from the advanced inter-
mediate diphosphine-Rh(I)-substrate adduct (pre-
dominant diastereomer). Figure 1 displays the
single-crystal X-ray diffractions of catalyst precur-
sors {Rh
N
N
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ꢀ
Figure 1. ORTEP drawings in elevation-view into the coordination-plane. Coordinated NBD and counter-anion (BF4 ) are
ꢀ
omitted for clarity. Relevant bond lengths or interatomic distances (Š) and angles (8) for {Rh
2.292(2), Rh P(2) 2.297(2), Rh···O(11) 2.850(5), Rh···O(21) 3.742(5), P(1) Rh P(2) 83.69(5) (bite angle), Rh P(1) C(2)
A
G
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
109.8(1), Rh P(1) C(11) 114.6(2), Rh P(1) C(21) 115.1(2), Rh P(2) C(1) 106.0(2), Rh P(2) C(31) 116.0(2), Rh P(2)
ꢀ
C(41) 119.3(2), g1 ꢀ72.8, g2 18.7, g3 2.7, g4 77.7; for {Rh
G
(nbd)}BF4: Rh P(1) 2.288(1), Rh P(2) 2.295(1),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
120.4(2), Rh P(1) C(21) 114.1(2), Rh P(2) C(9) 110.0(2), Rh P(2) C(31) 114.9(2), Rh P(2) C(41) 115.3(3), g1 ꢀ69.7, g2
20.0, g3 2.0, g4 81.5.
cases, wherein P*P*=6e (left) or 4MeBigFUS (6j, 2.850(5) Š. This explanation is supported by the fact
right).
that the pale-yellow colored [Rh(6e)(MeOH)2]BF4
A
The analysis of these complexes reveals profound solvate solution did not yield the typical red-brown
similarities in terms of dissymmetry in the chelate colour upon addition to MAC. Moreover, the
cycles of these C2-symmetrical (R,R)-P*P* ligands.[19] 31P NMR spectrum of [Rh(6e)
(MeOH)2]BF4 in the
G
It shows the 5-membered chelate ring in an envelope absence or presence of MAC was almost unchanged,
with l-conformation where one backbone CH2 is at contrary to the spectra relative to ligand 6j.
the flap of the envelope, and the other CH2 is situated
The steric requirements of the P-aryls and the fav-
slightly out-of-plane. Also, the bulky P-(o-substitut- oured puckered-conformation of the 5-membered
ed)-phenyl and the P-phenyl at the fold of the enve- chelate ring induce a preferential chiral P-aryls array
lope occupy equatorial (face/out) and axial (edge) po- around the Rh(I). This in turn affects the coordina-
sitions, respectively. This arrangement places the sub- tion of the prochiral substrate. In the distorted
stituents on the other phosphorus atom in less differ- square-planar Rh(I) complex, the coordinated enam-
entiated positions. The aryls are in a face-edge-edge- ide (a bidentate substrate) is orthogonal to the coor-
face disposition in accordance with the averaged tor- dination-plane ligated via p-bonding of the alkene
ꢀ ꢀ
ꢀ
sion angles g1-4 [Rh P Cipso
top left to top right. This is in sharp contrast with the nearly in-plane. The [Rh
C
ortho] of aryls going from and s-bonding of the amide oxygen atom which is
ACHTREUNG
envelope d-conformation encountered in the rare exists in two diastereomeric interchangeable forms
[18f]
cases of {Rh
A
G
and {Rh- arising from the binding of either Ca-si or Ca-re enan-
tiotopic olefin faces. A major:minor ratio of ~10:1 for
A
N
ACHTREUNG
Ligand (R,R)-6e with its P-(2,6-di-MeO-C6H3) sub- DiPAMP is formed with MAC at room temperature
stituents performed noticeably worse than (R,R)- [(R,R)-DiPAMP yields the (S)-enantiomer]. Landis
DiPAMP, but still gave a predominance of the (S)-en- et al.[18f] have shown that, in solution, the chiral P-
antiomer. Ensuing the atypical hydrogenation out- aryls orientations in [Rh
come obtained with this ligand, an X-ray structure de- sponse to the steric requirements imposed by the in-
termination of its [Rh(6e)(nbd)]BF4 complex con- coming substrate, conformational changes occur
(dipamp)]+ are supple. In re-
AHCTREUNG
ꢀ
firmed our presumption that the ꢂforcedꢀ favoured po- through rotation of P Cipso bonds (variation of torsion
sitioning of one oxygen atom of a methoxy in this angles), half-chair to envelope or l to d interconver-
case hindered the appropriate binding of the substrate sions, etc. Also, the chiral P-aryls array changes on
(e.g., enamide) to the Rh atom. The Rh, P(1), C(21), going from the major diastereomer (more favourable
C(26), O(11) atoms are coplanar with a Rh···O(11)= conformation of the chelate ring) to the minor diaste-
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Impact of Incorporating Substituents onto the P-o-Anisyl Groups of DiPAMP Ligand
FULL PAPERS
reomer (less favourable conformation). And the flux as: MeO, TMS, t-Bu, Ph, or a fused benzene ring.
of catalysis is born by the minor species by its virtue This also included the DiPAMP analogue 6e having
of exceeding the reactivity of the major one toward an extra MeO in positon 6 of the P-o-An rings. The
the H2 oxidative cis-addition. This shift towards an oc- overall performance of the new ligands rivals the orig-
tahedral Rh(III)-dihydrido complex constitutes the inal parent DiPAMP ligand in the Rh(I)-catalyzed
G
rate- and enantio-determining step, and the main asymmetric hydrogenation. Increased activity and
enantioselectivity occurs between the (enamide) sub- enantioselectivity were accomplished on the model
strate and the proximal P-phenyl Hortho. Thus, the re- substrates: MAA, MAC, Z-MAB, DMI, and AA.
action rate and stereoselectivity are regulated by the
relative concentration and reactivity of the two diaste- and yielded low ee values. Conversely, swapping the
reomeric adducts in their resting state.[21]
P-o-An groups with P-(2,3,4,5-tetra-MeO-C6H)
Ligand 6e furnished an extremely sluggish catalyst
The mechanism of asymmetric hydrogenation of a- groups led to the optimum ligand in the series, 4Me-
and b-dehydroamino acids or itaconates (at the low BigFUS. Faster reaction rates (from 2- to 5-fold) were
H2 pressure applied) could be different from the case obtained, and up to 99% and 88% ees were attained
of AA.[18] The striking enhancement of ee using the in the hydrogenation of dehydroamino acids and
new analogues compared to DiPAMP in the hydroge- atropic acid, respectively. These results are bound to
nation of AA, attests the spectacular effect of judi- broaden the scope of the application of [Rh(P*P*)]
A
cious changes in ligand design on catalysis.[22] Up to which was limited to the hydrogenation of dehydroa-
88% ee was attained with 4MeBigFUS vs. 7% ee with mino acids and closely related alkenes under mild
DiPAMP under mild conditions. Such a level of enan- conditions.
tioselectivity constitutes a particularly respectable
Despite current works based on the search for a ra-
result in the Rh(I)-catalyzed hydrogenation of this tional manner of matching substrates with catalysts,
substrate.[1a] It is quite noticeable how ligand 6h (Ar= the empirical design of ligands and catalysts still re-
4,6-di-t-Bu-2-An) furnished the same order of low ee mains a must. Although DiPAMP was once the opti-
value as DiPAMP unlike ligand 6f (Ar=6-TMS-2- mum design for P-stereogenic tetraaryl ligands, the
An), which afforded 79% ee. A stringent explanation overall outperformance of these new easily accessible
of these results is not available at the moment.
analogues is evident. Ongoing progress in our group
Overall, ligand 4MeBigFUS turned out to be the in this area shall be communicated shortly.
optimum ligand affording the highest ee values and
rates. The P-(2,3,4,5-tetra-MeO-C6H) groups increase
the steric requirements of the phosphine and may Experimental Section
favour increase in affinity of its Rh(I) complex to H2
For full chemical names related to phosphine and diene ac-
ronyms, see the Supporting Information.
or facilitate the H2 oxidative addition, which is the
turnover-limiting and enantio-determining step (for
enamides under 1 atm H2 at room temperature). With
MAC at room temperature, 4MeBigFUS yielded a
major:minor ratio of ~3:1 influencing the observed
enhanced reaction rate. Further mechanistic studies
are in progress.
From all precedent investigations in the area in-
cluding the present one, it transpires that the prime
role of the (oxygen-containing or not) substituents of
the P-(o-substituted)-phenyls is to induce a well pro-
nounced chiral environment. Although in the solid
state the oxygen atoms of P-o-An groups in Rh(I)-
DiPAMP complexes (except the ones in ref.[9]) are
not within a close interaction distance with the Rh
center, this situation could be different during cataly-
sis (in solution); the MeO group could serve an addi-
tional role.
General Procedure for the Synthesis of (Aryl)(N-
ephedrino)(phenyl)phosphine-P-Boranes (2b–m)
A
To a cold (08C) solution of the corresponding bromome-
thoxyarene (or methoxyarene) (1.3 mol equiv.) in an appro-
priate solvent (ether, cyclohexane or THF) is added under
stirring the appropriate BuLi (n, s or t) (1.3 mol equiv.). The
mixture is left at room temperatuere until the transmetalla-
tion is complete. To this mixture at ꢀ308C, a THF (100 mL)
solution of (ꢀ)-1 (1 mol equiv.) is slowly added and the re-
sulting mixture left to warm up to room temperature. After
overnight stirring, the reaction is quenched with H2O
(5 mL). The concentrated residue is partitioned between
CH2Cl2 (30 mL) and H2O (100 mL), and the organic layer is
dried over Na2SO4 then concentrated. The crude is purified
on silica gel.
General Procedure for the Synthesis of Methyl
(Aryl)-(phenyl)phosphinite-P-Boranes (3b–m)
Conclusions
To the (aryl)(N-ephedrino)(phenyl)phosphine-P-borane
A
We have prepared a large series of optically pure
DiPAMP analogues possessing various substitution
(2b–m) in MeOH(or MeOH/CH 2Cl2) is added under stir-
ring H2SO4 (96%, ꢂ 1 equiv.) at room temperature and the
patterns on the P-o-An rings with substituents such mixture is left overnight. The reaction mixture is filtered
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through a short bed of silica gel and concentrated. To the
residue H2O (100 mL) is added and extracted with CH2Cl2
(3”30 mL). The organic layer is dried over Na2SO4 and con-
centrated. Purification on silica gel eluting with toluene (3j:
toluene/EtOAc 95:5) and/or by recrystallization afforded
products 3.
MeOH(0.5 mL) or CH Cl2 (0.5 mL) is added dropwise at
2
room temperature. The resulting solution is hydrogenated
under 1 bar of H2 for ca. 15 min. Elimination of metallic
rhodium by filtration through a No. 3 sintered-glass filter af-
forded a clear brown solution of [Rh(6)(MeOH)2]BF4.
A
Procedure for the Hydrogenation of the Substrates in
Table 1
General Procedure for the Synthesis of (Aryl)-
(methyl)(phenyl)phosphine-P-Boranes (4b, d–m)
A
To a solution of the substrate (0.5 mmol) in MeOH(7 mL),
three freeze-pump-thaw cycles are applied and the system is
filled with Ar. Then to the substrate solution is added under
To
a
cold (ꢀ208C) solution of methyl (aryl)-
ACHTREUNG
argon a solution of the preformed [Rh(6)(MeOH)2]BF4 cat-
A
MeLi (1.2–2.0 mol equiv.). The resulting mixture is left to
warm up to room temperature. After stirring overnight, the
reaction is hydrolyzed with H2O (5 mL) and concentrated.
To the residue H2O (100 mL) is added and extracted with
CH2Cl2 (3”30 mL). The organic layer is dried over Na2SO4
and concentrated. Purification on silica gel eluting with tolu-
ene (4j: toluene/EtOAc 95:5) and/or by recrystallization af-
forded products 4.
alyst (substrate/catalyst molar ratio of 100 for MAC, Z-
MAB, DMI, AA, and 200 for MAA) in MeOH(prepared
as above). A vacuum is applied to this system then it is
backfilled with H2. The mixture is stirred at room tempera-
ture under 1 bar of H2 (10 bar for AA). The progress of the
hydrogenation is monitored by the diminution of the
volume of the closed reaction system at 1 bar (until H2
uptake ceased). In case of Z-MAB, the reaction mixture is
analyzed after 16 h, and with AA analysis is carried out
after 3 h. The reaction mixture is analyzed by chiral GC (H2
as carrier gas). Absolute configurations were assigned by
comparison of optical rotation of isolated products with the
literature data.
General Procedure According to Route A for the
Synthesis of (RP,RP)-1,2-Bis
N
N
P-borane]ethanes (5b, d–m)
To
a
cold (ꢀ308C) solution of (aryl)
A
ACHTREUNG
BuLi (1.0 mol equiv.). After stirring at ꢀ308C for 1 h, anhy-
drous CuCl2 (1.05 equiv.) is added. The reaction is left at
ꢀ308C for an additional hour then quenched with H2O
(20 mL). The mixture is extracted with EtOAc (3”10 mL),
dried over Na2SO4, and concentrated. Purification on silica
gel and/or by recrystallization afforded products 5.
Acknowledgements
This work was supported by the Ministry of Higher Educa-
tion, Science, and Technology of the Republic of Slovenia
through grants P1-242 and J1-9806, and by the Ministry of
National Education, Research, and Technology of France
through grant 00P141 to PhosPhoenix SARL. We thank Dr.
Barbara Modec, University of Ljubljana, for X-ray crystal
structure analyses.
General Procedure for the Synthesis of 1,2-Bis-
[(aryl)(phenyl)phosphino]ethane (6a–m)
U
The 1,2-bis
N
N
m) in Et2NHis refluxed for 2 h under an inert atmosphere.
After concentration, purification on silica gel and/or by re-
crystallization under an inert atmosphere afforded products
6.
References
A
N
[1] a) R. Noyori, Asymmetric Catalysis in Organic Synthe-
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phosphino]ethane (6j): Purification on silica gel eluting with
CH2Cl2, then with toluene/EtOAc 8:2 (Rf =0.6) afforded a
white powder; yield: 99%; mp 78–818C; [a]2D5: ꢀ44.8
1
degcm3 gꢀ1dmꢀ1 (c 1.0 gdcLꢀ1 in CHCl3); HNMR: d=2.01
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[m, 2H; (PCHaHb)2], 2.20 [m, 2H; (PCHaHb)2], 3.63 (s, 6H;
2 OMe), 3.67 (s, 6H; 2 OMe), 3.87 (s, 6H; 2 OMe), 3.88 (s,
6H; 2 OMe), 6.32 (m, 2H; Ar-H), 7.28–7.34 (m, 6H; Ar-H),
7.36–7.43 (m, 4H; Ar-H); 13C NMR: d=22.9 (m), 56.1, 60.5,
60.8, 61.0, 109.1 (m), 125.9 (m), 128.3 (m), 128.7, 133.1 (m),
137.5 (m), 143.7, 146.6 (m), 149.3 (m), 149.6 (m); 31P NMR:
d=ꢀ21.5 (s); MS (EI): m/z (%)=638 (20) [M+]; HR-MS
(EI): m/z=638.221, calcd. for C34H40O8P2 [M+]: 638.220;
anal. calcd. for C34H40O8P2, (638.62): C 63.94, H6.31; found:
C 64.03, H6.40.
[4] M. Stephan, B. Mohar, (PhosPhoenix SARL, Nat. Inst.
Preparation of the Solvated [Rh(6)
Catalysts
(MeOH)2]BF4
of
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of
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FR2887253,
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WO2006136695, 2006.
To a solution of [Rh
A
[5] Knowles et al. have reported their results for the hy-
a solution of the ligand 6a–m (0.8 equiv. to Rh atom) in
drogenation of (Z)-a-acetamidocinnamic acid (AAC)
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Impact of Incorporating Substituents onto the P-o-Anisyl Groups of DiPAMP Ligand
FULL PAPERS
with various Rh
G
G
nished surprisingly the (S)-enantiomer in 98.6% ee.
[9] H.-J. Drexler, W. Baumann, T. Schmidt, S. Zhang, A.
Sun, A. Spannenberg, C. Fischer, H. Buschmann, D.
Heller, Angew. Chem. 2005, 117, 1208–1212; Angew.
Chem. Int. Ed. 2005, 44, 1184–1188; X-ray of major
ethane} catalysts (conditions: S/C=1000 under 3 atm
of H2 in i-PrOH(88%) at 50 8C for 0.8–1 h): 96% ee
(S) with Ar=2-MeO-C6H4 (DiPAMP), 85% ee with 2-
MeO-4-NaOSO2-C6H3, 79% ee with 2-MeO-4-
Me2NSO2-C6H3, 84% ee with 2-HO-C6H4, 63% ee with
diastereomers of {Rh
N
N
2-AcO-C6H4; noteworthy, 1,2-bis[(o-An)(Cy)phosphi-
A
no]ethane (DiCAMP) led to 64% ee.[3c]
amido)-b-aryl-acrylate]}BF4 complexes controlling the
stereochemistry of the final compound showed Rh···O
~2.3 Š.
[6] a) T. Imamoto, T. Oshiki, T. Onozawa, T. Kusumoto, K.
Sato, J. Am. Chem. Soc. 1990, 112, 5244–5252; b) S.
JugØ, M. Stephan, J. A. Laffitte, J.-P. GenÞt, Tetrahe-
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(SociØtØ Nationale Elf Aquitaine), WO9100286, 1991;
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ØtØ Nationale Elf Aquitaine), FR2672603, 1991;
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[10] J. A. Ramsden, T. D. W. Claridge, J. M. Brown, J.
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[11] For modification of the methyl of methoxy groups, see
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ˇ
[12] M. M. S. Stephan, D. Sterk, B. Modec, B. Mohar, J.
Org. Chem. 2007, 72, 8010–8018; therein, related (RP)-
(aryl)
N
N
anes, where aryl=2,6-dimethoxyphenyl, 2,4,6-trime-
thoxyphenyl, and 2-methoxy-1-naphthyl, were pre-
pared.
[7] a) For DPPP/DiPAMP hybrid, see: C. R. Johnson, T.
1
[13] According to HNMR of the mixture of the insepara-
Imamoto, J. Org. Chem. 1987, 52, 2170–2174; b) for
DPPB/DiPAMP hybrid, see ref.[6a]; c) for Me2Si
ACHTREUNG
ble products, we believe that the by-product is most
likely (ethyl)(5-methoxy-2-anisyl)
borane.
N
ACHTREUNG
Spindler, C. Malan, A. Mezzetti, Tetrahedron: Asym-
metry 2002, 13, 1817–1824; d) for PYRPHOS/DiPAMP
hybrid, see: U. Nagel, T. Krink, Chem. Ber. 1995, 128,
309–316; e) for DIOP/DiPAMP hybrid, see: K. Bur-
gess, M. J. Ohlmeyer, K. H. Whitmire, Organometallics
1992, 11, 3588–3600; f) X. Zhang, (The Penn State Re-
search Foundation), WO9713763, 1997; g) for DPPF/
DiPAMP hybrid, see: U. Nettekoven, P. C. J. Kamer,
P. W. N. M. van Leeuwen, M. Widhalm, A. L. Spek, M.
Lutz, J. Org. Chem. 1999, 64, 3996–4004; F. Maienza,
M. Wçrle, P. Steffanut, A. Mezzetti, Organometallics
1999, 18, 1041–1049; h) for dissymmetric DPPE/
DiPAMP hybrid, see: J. A. Ramsden, J. M. Brown,
M. B. Hursthouse, A. I. Karalulov, Tetrahedron: Asym-
metry 1994, 5, 2033–2044; i) for dissymmetric Me-BPE/
DiPAMP and RoPHOS/DiPAMP hybrids, see: D. Car-
michael, H. Doucet, J. M. Brown, Chem. Commun.
1999, 261–262; j) for MOP/PAMP hybrid, see: L. J.
Higham, E. F. Clarke, H. Müller-Bunz, D. G. Gilheany,
J. Organomet. Chem. 2005, 690, 211–219; k) for a
PAMP derivative with a b-sp2 N donor group, see: H.
Yang, N. Lugan, R. Mathieu, An. Quim. Int. Ed. 1997,
93, 28–38.
A
the literature data for MAA (see: J. W. Scott, D. D.
Keith, G. Nix Jr. , D. R. Parrish, S. Remington, G. P.
Roth, J. M. Townsend, D. Valentine Jr. , R. Yang, J.
Org. Chem. 1981, 46, 5086–5093), MAC,[3b] Z-MAB,[18h]
and DMI;[18j] with DiPAMP an increase in temperature
leads to an increase in ee, and an increase in pressure
leads to a decrease in ee.
[15] J. M. Brown, P. A. Chaloner, J. Am. Chem. Soc. 1980,
102, 3040–3048.
[16] Evolution of H2 was monitored by the diminution of
the volume of the closed reaction system under 1 bar
(until uptake ceased). In the case of Z-MAB, the reac-
tion mixture was analyzed only after 16 h, and with AA
after 3 h. Reported results correspond to the average
of duplicate independent runs.
[17] Under identical conditions, hydrogenation of itaconic
acid with [Rh(4Mebigfus)(MeOH)2]BF4 led to 85% ee
G
with total conversion in 35 minutes, while with
DiPAMP, 11% ee was obtained and up to 40% conver-
sion in 1 hour.
[18] a) B. Bosnich, N. K. Roberts, Adv. Chem. Ser. Ameri-
can Chemical Society, Washington D.C. 1982, Vol. 196,
pp 337–354; b) J. M. Brown, P. A. Chaloner, in: Homo-
geneous Catalysis with Metal Phosphine Complexes,
(Ed.: L. H. Pignolet), Plenum Press, New York, 1983,
pp 137–165; c) J. Halpern, in: Asymmetric Synthesis,
Vol. 5, (Ed.: J. D. Morrison), Academic Press, New
York, 1985, pp 41–69; d) C. R. Landis, J. Halpern, J.
Am. Chem. Soc. 1987, 109, 1746–1754; e) B. McCul-
loch, J. Halpern, M. R. Thompson, C. R. Landis, Orga-
nometallics 1990, 9, 1392–1395; f) J. S. Giovannetti,
C. M. Kelly, C. R. Landis, J. Am. Chem. Soc. 1993, 115,
4040–4057; g) M. Yasutake, I. D. Gridnev, N. Higashi,
T. Imamoto, Org. Lett. 2001, 3, 1701–1704; h) D.
Heller, H.-J. Drexler, J. You, W. Baumann, K. Drauz,
H.-P. Krimmer, A. Bçrner, Chem. Eur. J. 2002, 8,
5196–5203; i) ref.[9]; j) W. C. Christopfel, B. D. Vine-
[8] a) Y. Wada, T. Imamoto, H. Tsuruta, K. Yamaguchi,
I. D. Gridnev, Adv. Synth. Catal. 2004, 346, 777–788;
therein the hydrogenation of MAC under 3 atm H2 in
i-PrOHat 50 8C with Rh{1,2-bis[(Ar)(Ph)phosphino]-
G
ethane} where Ar=o-Tol, o-EtC6H4, and a-(5’,6’,7’,8’-
tetrahydronaphthyl) (WadaPHOS), furnished 92, 97,
and >99% ee, respectively, demonstrating that such
groups can simulate the enantiodifferentiation of o-An
groups of DiPAMP; b) M. Gómez, S. Jansat, G. Muller,
D. Panyella, P. W. N. M. van Leeuwen, P. C. J. Kamer,
K. Goubitz, J. Fraanje, Organometallics 1999, 18, 4970–
4981; c) F. Maienza, F. Spindler, M. Thommen, B.
Pugin, C. Malan, A. Mezzetti, J. Org. Chem. 2002, 67,
5239–5249; therein hydrogenation of MAC with (Rh-
A
N
Adv. Synth. Catal. 2008, 350, 2024 – 2032
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asc.wiley-vch.de
2031

ˇ ˇ
Borut Zupancic et al.
FULL PAPERS
yard, J. Am. Chem. Soc. 1979, 101, 4406–4408; k) J. M.
Brown, D. Parker, J. Chem. Soc. Chem. Commun. 1980,
342–344; l) J. M. Brown, D. Parker, J. Org. Chem.
1982, 47, 2722–2730; m) H.-J. Drexler, S. Zhang, A.
Sun, A. Spannenberg, A. Arrieta, A. Preetz, D. Heller,
Tetrahedron: Asymmetry 2004, 15, 2139–2150.
positioned face-on (occupying the pseudoequatorial
sites), and the P-phenyls are positioned edge-on (occu-
pying the pseudoaxial sites). Moreover, the P-(o-substi-
tuted)-phenyls could adopt an ꢂinꢀ (as in {Rh
ACHTREUNG
dipamp]
dipamp]
C
ACHTREUNG
[19] CCDC 694160 {Rh
N
G
[20] H. Tsuruta, T. Imamoto, K. Yamaguchi, I. D. Gridnev,
694161 {Rh[(R,R)-4Mebigfus]
A
ACHTREUNG
Tetrahedron Lett. 2005, 46, 2879–2882; therein, an en-
supplementary crystallographic data (excluding struc-
ture factors) for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
or on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax.: +44–1223–336–033; e-mail:
deposit@ccdc.cam.ac.uk]. X-Ray crystal structure anal-
ysis of the few known Rh complexes of C2-symmetrical
velope
Tol)PCH2)2]
l-conformation
for
{Rh
G
E
AHCTREUNG
[21] For enantioselectivity and reaction rate versus confor-
mation of 5-membered chelate rings of the type
[Rh(PP)
(diene)]+ wherein PP is a stereogenic DPPE-
G
derived ligand with chirality on the ethane-bridge, see:
a) J. D. Oliver, D. P. Riley, Organometallics 1983, 2,
1032–1038; b) J. M. Brown, P. L. Evans, Tetrahedron
1988, 44, 4905–4916; c) H. Brunner, A. Winter, J. Breu,
J. Organomet. Chem. 1998, 553, 285–306.
tetraaryldiphosphines of the type [Rh
like {Rh[(S,S)-dipamp]
(nbd)}BF4,[18m]
dipamp] and {Rh[(S,S)-wadaphos]-
(cod)}BF4,[18m]
(cod)}BF4,[8a] shows a rather symmetrical half-chair l-
A
ACHTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
[22] The first proof of concept using chiral phosphines in
catalysis to transfer chirality was applied in hydrogena-
tion of a-ethylstyrene and atropic acid leading to 5–
15% ee by the use of (Me)(Pr)PPh. For this, see: a) L.
Horner, H. Siegel, H. Büthe, Angew. Chem. 1968, 80,
1034–1035; Angew. Chem. Int. Ed. Engl. 1968, 7, 942;
b) W. S. Knowles, M. J. Sabacky, Chem. Commun.
(London) 1968, 1445–1446.
ACHTREUNG
or d-conformation for the saturated 5-membered che-
late ring of (RP,RP)-P*P* and (SP,SP)-P*P*, respectively.
These complexes possess an alternating ꢂ’edge-face ex-
posed’ꢀ disposition of the four P-aryls and the backbone
CH2 groups are situated out-of-plane, one above and
ꢀ
ꢀ
one below the P Rh P coordination-plane. In this ar-
rangement, the bulky P-(o-substituted)-phenyls are
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