Rh-catalyzed asymmetric hydroformylation of functionalized 1,1-disubstituted olefins

Article abstract of DOI:10.1021/ja2092689

The first method for the highly enantioselective rhodium-catalyzed hydroformylation of 1,1-disubstituted olefins has been developed. By employing either of the P-chirogenic phosphine ligands BenzP* and QuinoxP*, linear aldehydes with β-chirality can be prepared in a highly enantioselective fashion with good chemo- and regioselectivities.

Full text of DOI:10.1021/ja2092689

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pubs.acs.org/JACS
Rh-Catalyzed Asymmetric Hydroformylation of Functionalized
1,1-Disubstituted Olefins
Xiao Wang and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
Scheme 1. AHF of Olefins To Produce Enantioenriched
Aldehydes
ABSTRACT: The first method for the highly enantioselec-
tive rhodium-catalyzed hydroformylation of 1,1-disubstitut-
ed olefins has been developed. By employing either of
the P-chirogenic phosphine ligands BenzP* and QuinoxP*,
linear aldehydes with β-chirality can be prepared in a
highly enantioselective fashion with good chemo- and
regioselectivities.
ydroformylation is one of the most important homoge-
H
neously catalyzed processes in industry, as it directly con-
verts inexpensive olefin precursors into their corresponding
aldehydes. Of particular interest for the synthesis of fine chemi-
cals is asymmetric hydroformylation (AHF), which allows for the
conversion of olefins into optically active aldehydes in a single
step.1 Since the introduction of the Binaphos ligand by Takaya in
1993,2 the development of chiral phosphorus ligands has sig-
nificantly facilitated enhanced regio- and enantioselectivity in
rhodium-catalyzed AHF.3À5 Notably, several important applica-
tions of olefin hydroformylation to the synthesis of complex
molecules have been demonstrated.6,7b However, most of the
reported methods have been limited to monosubstituted2À5 and
1,2-disubstituted olefins.8 In these cases, α-chiral branched
aldehydes are formed (Scheme 1). In contrast, AHF of 1,1-
disubstituted olefins to provide β-chiral linear aldehydes (as
indicated by Keulemans' rule)9 has been much less extensively
investigated and has proven to be a formidable challenge in terms
of enantioselectivity.7,10 In fact, this substrate class has proven
to be extremely difficult for a variety of transformations,
including asymmetric hydrogenation,11a,b epoxidation,11c,d and
hydroboration.11e,f In these reactions, it is often difficult for the
chiral catalyst to differentiate between the two enantiotopic faces,
so good enantioselectivities are observed only when there is a
significant size difference between the two substituents. The
AHF of α-alkylacrylate was previously reported by Kollꢀar in the
1980s. However, the reaction employed a PtCl2ÀSnCl2 catalyst,
which required high syngas pressures (200À250 bar) and
long reaction times (90 h) to provide the chiral products with
low to modest enantioselectivity in conjunction with sig-
nificant amounts of hydrogenated side products.12 In addi-
tion, the substrate scope was limited to methacrylate and
itaconate. Herein we disclose the first example of a general,
highly enantioselective process for the rhodium-catalyzed
hydroformylation of α-alkylacrylates that operates under
mild conditions.
Table 1. Ligand Evaluation for the AHF of Ethyl 2-Benzyla-
crylate (1)a,b
2a
yield (%)
entry ligand conv (%) yield (%) ee (%)c
2b
2c
2d
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
100
100
100
100
100
100
100
12
55
11
18
60
43
31
16 (R)
3 (S)
0
5
82
40
71
63
34
12
5
6
0
26 (S)
4 (R)
2
16
0
16
6
8 (R)
0
75 (R)
82 (R)
37
22
10
42
a All reactions were performed at 90 °C in toluene with 10 bar 1:1 CO/
H2, 2.0 mol % Rh(CO)2acac, 2.4 mol % ligand, and 20 h reaction time.
b GC yields are reported. c The ee values were determined by chiral GC.
The absolute configurations of 2a (shown in parentheses) were deter-
mined by converting 2a to the known diethyl ester (see the Supporting
Information).
hopes of discovering not only a highly enantioselective and
regioselective transformation but also one that would minimize
the formation of undesired side products such as the olefin
isomerization product 2c and the hydrogenation product 2d.
Our initial studies focused on the AHF of ethyl 2-benzylacry-
late (1) to give the desired chiral aldehyde product 2a, with the
Received: October 1, 2011
Published: October 28, 2011
r
2011 American Chemical Society
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|

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Table 2. Effect of Reaction Conditions on the Yield
and Enantioselectivity of the AHF of Ethyl
2-Benzylacrylate (1)a,b
2a
yield (%)
P (bar)
T
[Rh] conv
entry (CO:H2) (°C) (%) (%) yield (%) ee (%)c 2b 2c 2d
1
2
3
4
5
6
10 (1:1) 100 2.0 100
10 (1:1) 100 2.0 100
9 (9:1) 100 4.0 100
10 (1:5) 100 1.0 100
35
37
46
63
23
37
81
85
84
84
83
81
14
13
7
8
43
43
11 10 32
4
3
4
16 16
13 23
24 36
Figure 1. Typical chiral ligands for asymmetric hydroformylation.
6 (1:5) 100 1.0
62
10 (1:5) 90 1.0 100
The results of an evaluation of ligands for this process are
described in Table 1. Among various chiral ligands tested were
those previously demonstrated to be successful in AHF, such as
Binaphos (L1),2 diazaphospholane (L2),3 Kelliphite (L3),5 Ph-
BPE (L4),4 and BPPM (L5)12d (Figure 1). Not surprisingly,
given that 1,1-disubstituted olefins typically display poor reactiv-
ity, a 2% loading of the rhodium catalyst and a reaction
temperature of 90 °C were required for full conversion of 1 in
all cases.13 The use of Binaphos and Ph-BPE (Table 1, entries 1
and 4), while efficient for the AHF of monosubstituted olefins,
gave 2a in poor yield and with negligible ee. The diazapho-
spholane- and BPPM-derived catalysts, while displaying excellent
reactivity for the desired product, nonetheless failed to exert
efficient enantiocontrol (entries 2 and 5). Similarly, application
of the diphosphite ligand Kelliphite provided 2a in poor yield
with merely 26% ee (entry 3). We discovered, however, that by
moving to ligands bearing chiral information directly on phos-
phorus, such as the P-chirogenic diphosphine QuinoxP* (L6),
the desired product 2a could be obtained with 75% ee (entry 6).
Furthermore, the structurally related P-chirogenic ligand BenzP*
(L7) gave 2a in even greater enantiomeric excess (82%; entry 7).
It is hypothesized that these structurally rigid P-chirogenic
ligands are able to bring chiral information closer to the reaction
site, rendering them uniquely effective in differentiating between
the two olefin substituents.14
With these promising results in hand, we sought to optimize
the reaction by examining a variety of reaction conditions, as
summarized in Table 2. We found that by employing dodecane as
the solvent, we could increase the enantioselectivity of product
2a to 85% (entry 2). However, a considerable amount of
hydrogenation product 2d was still observed. This is presumably
a consequence of the electron-withdrawing effect of the
phenyl group, which decreases the rate of CO migratory
insertion (to afford 2a), thus enabling the reductive elimina-
tion (to afford 2d) and β-hydride elimination (to afford 2c) to
become competitive. We next focused on varying the total gas
pressure and the CO/H2 ratio in an effort to enhance the rate
of formation of 2a and thus to minimize the side reactions. It is
known that an increase in the CO partial pressure corresponds
to a decrease in the reaction rate with regard to Rh catalysis,15
and we indeed observed that by increasing the CO/H2 ratio to
9:1, a 4% loading of the Rh catalyst was needed for full
conversion (entry 3). However, under the same total pressure
(10 bar) but with less CO and more H2 (1:5), the reaction
afforded the desired product 2a in a yield of 63% with 84% ee
(entry 4). Under these conditions, only 1% Rh catalyst was
needed for full conversion of the starting material. The use of a
lower overall pressure (6 bar) of the same 1:5 CO/H2 mixture
a Reactions were performed in toluene (entry 1) or dodecane (entries
2À6) with 1À4 mol % Rh(CO)2acac and (R,R)-BenzP* (L/Rh = 1.2).
b GC yields are reported. c Determined by chiral GC.
led to incomplete conversion (entry 5). Lower reaction
temperatures were also explored, but both the product yield
and ee suffered in this case (entry 6).
With the reaction conditions in hand, we next set out to
investigate the substrate scope. In the presence of 1.0%
Rh(CO)2acac and 1.2% BenzP*, a variety of α-alkylacrylates
were found to be successful substrates, affording the corre-
sponding linear aldehydes in good to excellent yields with an
unprecedented lead of enantioselectivity (Table 3). The
AHF of methyl methacrylate provided the corresponding
product with 83% ee (entry 1). In the cases of more sterically
demanding substrates bearing ethyl, n-propyl, benzyl, and
the silyloxyalkyl groups, higher ee’s of up to 89% could be
realized (entries 2À5). The reaction worked particularly well
for olefins with secondary alkyl substituents, such as iso-
propyl, cyclohexyl, and cyclopentyl groups, providing the
desired aldehydes in excellent yields with enantioselectivities
of 92À94% (entries 6À8). The high yields realized in the
examples in entries 6À8 are due to the better regio- and
chemoselectivities in comparison with those in entries 1À5.
The effect of the bulkier secondary alkyl groups significantly
retards the formation of the branched RhÀalkyl inter-
mediate, which would lead to the undesired branched alde-
hyde and olefin isomer. The 2-isopropyl- and 2-cyclohexyl-
1,4-dicarbonyl structures are particularly interesting in that
they can be found in many biologically active compounds and active
pharmaceutical ingredients (Figure 2).16 Traditionally, these moi-
eties have been prepared via asymmetric alkylation facilitated by a
chiral oxazolidinone auxiliary17 or via asymmetric hydrogenation
with a multistep sequence from 2-isopropylidenesuccinic acid
1-methyl ester.18 To the best of our knowledge, no synthetic
method has been developed to install the stereogenic center
catalytically in a single step.
In summary, we have developed the first effective and
facile rhodium-catalyzed enantioselective hydroformylation of
functionalized 1,1-disubstituted alkenes under mild conditions.
In this transformation, the P-chirogenic ligands BenzP* and
QuinoxP* demonstrated unprecedented stereochemical control
in the AHF of α-alkylacrylates. Notably, we were able to
minimize the long-standing problem of side reactions by fine-
tuning the partial pressures of CO and H2. In particular, the
ability to perform this transformation at acceptably low gas
pressure makes it safe for general laboratory use. We expect this
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Table 3. Asymmetric Hydroformylation of α-Alkylacrylatesa
’ AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
’ ACKNOWLEDGMENT
We thank Novartis International AG (Basel, Switzerland) for
financial support of this project. We thank Drs. Thierry Schlama,
Meredeth McGowan, Andrew Parsons, and Timothy No€el for
helpful discussions.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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