Synthesis of new chiral monodentate phosphines and their use in asymmetric hydrogenation

Article abstract of DOI:10.1016/S0040-4039(02)00943-7

A general synthesis of chiral 4,5-dihydro-3H-dinaphthophosphepines 1a-g is described. The resulting ligands represent a new class of monodentate chiral phosphines. First applications of 1a-g in the rhodium-catalyzed asymmetric hydrogenation of unsaturated

Full text of DOI:10.1016/S0040-4039(02)00943-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4977–4980
Synthesis of new chiral monodentate phosphines and their use in
asymmetric hydrogenation
Kathrin Junge,a Gu¨nther Oehme,a Axel Monsees,b Thomas Riermeier,b Uwe Dingerdissenb and
Matthias Bellera,*
aInstitut fu¨r Organische Katalyseforschung an der Universita¨t Rostock e.V. (IfOK), Buchbinderstraße 5-6, D-18055 Rostock,
Germany
bDegussa AG, Projecthouse Catalysis, Industriepark Ho¨chst, D-65296 Frankfurt am Main, Germany
Received 27 March 2002; accepted 14 May 2002
Abstract—A general synthesis of chiral 4,5-dihydro-3H-dinaphthophosphepines 1a–g is described. The resulting ligands represent
a new class of monodentate chiral phosphines. First applications of 1a–g in the rhodium-catalyzed asymmetric hydrogenation of
unsaturated carboxylic acid derivatives demonstrate the usefulness of our ligands. Enantioselectivities up to 95% ee for the
hydrogenation of methyl a-acetamidocinnamate were obtained in the presence of 1d. This result represents one of the highest
enantioselectivities reported for asymmetric hydrogenation in the presence of monodentate phosphines. © 2002 Elsevier Science
Ltd. All rights reserved.
The synthesis of new chiral phosphines is of major
importance for organic synthesis. In general, bidentate
phosphine ligands have been found to give excellent
control in a number of catalytic asymmetric reactions.
Nevertheless, there is a continuing interest in new,
simpler phosphine ligands, which can be modularly
designed.
enantioselectivities were reported by Reetz et al.,7 by
Orpen and Pringle8 and by Helmchen et al.9
Due to the often easier synthesis of monophosphines
compared to diphosphines as well as the possibility of a
simple biphasic recycling of chiral phosphines by intro-
ducing water-soluble groups we became interested in
the synthesis of chiral monodentate phosphines, which
are easily accessible, and would give improved enan-
tioselectivities in asymmetric hydrogenation reactions.
Among the different transition metal-catalyzed reac-
tions enantioselective hydrogenations are probably the
most important class of catalytic asymmetric reactions
in industry.1 In the past optically active diphosphines
were essential as chiral ligands in order to achieve high
selectivities in these reactions.2 Attempts to develop
chiral monodentate phosphine ligands for asymmetric
hydrogenation reactions which would afford high enan-
tioselectivities met only with limited success.3 To the
best of our knowledge the highest enantioselectivity
(90% ee) has been reported already in 1972 with CAMP
(R1R2R3P, R1=c-Hex, R2=o-Anisyl, R3=Me) as lig-
and for the hydrogenation of (Z)-a-acetamidocinnamic
acid derivatives.3c,4 Very recently however, more
efficient monodentate phosphoramidates were intro-
duced by de Vries and Feringa et al.5 as well as by
Zhou et al.6 for asymmetric hydrogenation reactions.
Monodentate phosphites and phosphines giving high
At the start of our investigations we envisioned the use
of different 4,5-dihydro-3H-dinaphtho[2,1-c;1%,2%-e]-
phosphepine ligands 1. Surprisingly, these monodentate
atropisomeric ligands have been only scarcely investi-
gated.10,11 With the exception of a more complicated
resolution reaction by Gladiali and co-workers,
there has been no synthesis of enantiomerically pure
ligands 1 described.10 As shown in Scheme 1, seven
different 4,5-dihydro-3H-dinaphtho[2,1-c;1%,2%-e]phos-
phepine ligands 1 were synthesized in a simple and
straightforward manner from homochiral 2,2%-
dimethylbinaphthyl.12
On the one hand double metallation of 2,2%-dimethylbi-
naphthyl with n-butyl lithium in the presence of
TMEDA (tetramethylethylendiamine) and quenching
with commercially available dichlorophosphines gives
ligands 1a–d in 60–83% yield.13 On the other hand
Keywords: chiral P ligands; asymmetric hydrogenation; rhodium.
* Corresponding author.
double
metallation,
quenching
with
diethyl-
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00943-7

4978
K. Junge et al. / Tetrahedron Letters 43 (2002) 4977–4980
1. n-BuLi / TMEDA
2. Cl2PR
R = Et, tBu; Ph
CH3
1. n-BuLi / TMEDA
2. Cl2PNEt2
CH3
P R
P NEt2
1a R = Et
1b R = iPr
1c R = tBu
1d R = Ph
74 %
81 %
60 %
83 %
+ HCl
- NH2Et2Cl
P Cl
1e R = 4-CH3OC6H4 76 %
1f R = 4-CF3C6H4 70 %
1g R = 3,5-(CH3)2C6H3 62 %
+ RMgBr
R = iPr; 4-CH3OC6H4;
4-CF3C6H4;
80 %
3,5-(CH3)2C6H3
Scheme 1. Synthesis of 4,5-dihydro-3H-dinaphtho[2,1-c;1%,2%-e]phosphepine ligands 1.
(93% ee). However, the best selectivity is achieved in
aminodichlorophosphine and subsequent reaction with
HCl gives the corresponding chlorophosphepine in 80%
yield. It is worthwhile mentioning that this chlorophos-
phepine is an extremely useful building block for the
synthesis of a variety of substituted 4,5-dihydro-3H-
toluene with SDS (SDS=sodium dodecyl sulfate) as
additive (95% ee). This result seems to be one of the
highest enantioselectivities ever reported for a monoden-
tate phosphine in the hydrogenation benchmark test for
chiral ligands. While most of the hydrogenation reac-
tions were performed in the presence of 1 mol% of
catalyst, it is possible to decrease the catalyst concen-
tration to 0.1 mol% without observing a negative effect
on yield and selectivity.
dinaphtho[2,1-c;1%,2%-e]phosphepine ligands
1
by
uncomplicated Grignard reaction. Hence, ligands 1e–g
were prepared without optimization in 62–76% yield. It
is easily foreseen that the described procedure will not
only allow the preparation of other chiral monodentate
phosphepines, but is useful also for the synthesis of
bidentate phosphepines.
[Rh(COD)2]BF4/1d was also used as catalyst precursor
in asymmetric hydrogenations of substituted dehydro-
amino acid methyl esters and methyl itaconate (Table
3). In all reactions excellent yields and good
With a number of chiral monodentate ligands in hand
we were interested in their catalytic behavior. Initially
as a model reaction the asymmetric hydrogenation of
methyl (Z)-a-acetamidocinnamate 2a was studied at
ambient pressure (Table 1).14 This reaction is generally
accepted as a benchmark test for new chiral ligands.
Table 1. Asymmetric hydrogenation of methyl a-
acetamidocinnamatea
O
O
H2
Although there is
a close structural relationship
Ph
OMe
Ph
OMe
*
between ligands 1a–c and the recently synthesized
MonoPhos ligand of de Vries and Feringa5 the alkyl-
substituted phosphepine ligands give only disappointing
enantioselectivities in the model reaction. However, the
aryl-substituted phosphepines 1d–g proved to be quite
selective ligands. Using 1 mol% [Rh(COD)2]BF4 in the
presence of 2 mol% ligand in 15 ml toluene enantiose-
lectivities up to 90% ee are obtained.
NHAc
2a
NHAc
3a
Entry
Ligand
ee (%) (R)
t/2 (min)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
47
46
20
90
74
82
67
6
4
52
50
12
36
17
Next a screening of solvents and conditions was applied
to the ‘best’ ligand 1d. As shown in Table 2 the use of
ethyl acetate, THF, acetone, and methanol significantly
speeds up considerably the hydrogenation reaction.
Turnover frequencies (TOF) up to 500 h−1 were
observed at 50% conversion. Improved enantioselectivi-
ties are obtained in THF (92% ee) and ethyl acetate
1g
a Conditions: 1.0 mmol substrate; 0.01 mmol [Rh(COD)2]BF4;
cat.:ligand=1:2; 15 ml solvent; 25°C, 1 bar H2; solvent: toluene;
conversion: 100%.

K. Junge et al. / Tetrahedron Letters 43 (2002) 4977–4980
4979
Table 2. Solvent screening in asymmetric hydrogenation of
methyl a-acetamidocinnamate for ligand 1d
ligand structure and the synthesis of water-soluble lig-
ands are currently explored.
O
O
H2
Acknowledgements
Ph
OMe
Ph
OMe
*
NHAc
2a
NHAc
3a
We thank Mrs. A. Lehmann and Mrs. M. Heyken for
excellent technical assistance. We are grateful to the
Fonds der Chemischen Industrie and the Bundesminis-
terium fu¨r Bildung und Forschung (BMBF), Degussa
AG, and the State Mecklenburg-Western Pommerania
for funding of this project. Mrs. S. Buchholz and Dr.
C. Fischer (both IfOK) are thanked for their excellent
analytical service.
Entry
Solvent
ee (%) (R)
t/2 (min)
1a
2b
3c
4d
5a
6a
7a
8a
9e
Ethyl acetate
Ethyl acetate
Ethyl acetate
Ethyl acetate
THF
Methanol
Acetone
CH2Cl2
Toluene/SDS
90
90
93
92
92
89
88
86
95
5
8
8
77
15
2
3
4
36
References
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a Conditions: 1.0 mmol substrate; 0.01 mmol [Rh(COD)2]BF4;
cat.:ligand=1:2; 15 ml solvent; 25°C, 1 bar H2.
b Rh:1d=1:1.
c Rh:1d=1:4.
d Rh:1d=0.1:1.
e Conditions like +0.2 mmol SDS; conversion: 100%.
a
Table 3. Substrate screening in asymmetric hydrogenation
for ligand 1d in toluene
O
O
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H2
R
OMe
R
OMe
*
R´
2
R´
3
Entry
Substrate
ee (%)
1a
2a
3a
4b
R=4-CH3-C6H4; R%=NHAc
R=4-Br-C6H4; R%=NHAc
R=4-NO2-C6H4; R%=NHAc
R=H; R%=CH2COOMe
90
84
90
78
a Substrate:Rh:1d=2 mmol:0.01 mmol:0.02 mmol; 5 bar H2; toluene
as solvent.
b Substrate:Rh:1d=1 mmol:0.01 mmol:0.02 mmol; solvent: ethyl ace-
tate; yield: >99%.
enantioselectivities (78–90% ee) are obtained using the
standard reaction protocol in toluene as solvent.
In conclusion, a general synthesis of optically pure
monodentate dinaphthophosphepine ligands is pre-
sented. A variety of new chiral ligands are now avail-
able on g-scale. Aryl-substituted dinaphthophosphepine
ligands lead to very good enantioselectivities in the
rhodium-catalyzed hydrogenation of (Z)-a-acetami-
docinnamic acid derivatives. Even though more selec-
tive bidentate phosphines are known for the shown
asymmetric hydrogenation reactions, the here presented
ligands demonstrate that simple monodentate phosphi-
nes are close to the selectivity level of the more promi-
nent chiral diphosphines. Further optimization of the
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4980
K. Junge et al. / Tetrahedron Letters 43 (2002) 4977–4980
13. Metallation15 of enantiomerically pure 2,2%-dimethylbi-
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naphthyl with n-BuLi/TMEDA affords the crystalline
dilithio species in 70–80% yield. Starting from 12 mmol
dilithium salt of homochiral 2,2%-dimethylbinaphthyl in
35 ml hexane 13.6 mmol phenyl dichlorophosphine in 15
ml hexane was added at 0°C. After 2 h refluxing, the
reaction mixture was quenched with water/toluene. The
organic layer was separated and dried over MgSO4. The
ligand 1d was purified by column chromatography (83%).
4 - Phenyl - 4,5 - dihydro - 3H - dinaphtho[2,1 - c;1%,2% - e]phos-
phepin (1d): 1H NMR (25°C, CD2Cl2): l 2.81–2.87 (m,
CH2, 3H), 3.05 (dd, CH2, 1H, J=16.8 Hz), 6.93 (d, 1H),
7.18–7.30 (m, 9H), 7.43 (m, 2H), 7.71 (t, 1H), 7.87–7.98
(m, 4H). 13C NMR (25°C, CD2Cl2): l 31.5 (J=17.2 Hz),
32.6 (J=22.9 Hz), 125.2, 125.4, 125.7, 126.2, 126.4, 126.8,
127.7, 128.2, 128.5, 128.6, 128.7, 129.3, 131.6, 132.3,
132.7, 133.1, 133.2, 134.0, 134.1, 134.8, 136.9, 138.3,
138.5.). 31P NMR (25°C, CD2Cl2): l 7.8. MS (ES, 70 eV):
m/z=388 [M+], 282 [M+−P−C6H5], 265, 183, 153, 107, 77;
[h]23=−14.2 (c 1, toluene).
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pure
1,1%-dimethylbinaphthyl
is
obtained in 92% overall yield from optically pure 1,1%-
binaphthol via esterification with trifluoromethanesul-
fonic acid anhydride in pyridine and subsequent
Ni-catalyzed Grignard reaction with MeMgBr.