Ligand-Controlled Direct Hydroformylation of Trisubstituted Olefins

Article abstract of DOI:10.1021/acs.orglett.9b01639

The direct hydroformylation of trisubstituted olefins has been achieved with a combination of a Rh(I) catalyst and a π-acceptor phosphorus (briphos) ligand. A sterically bulky briphos ligand with a large cone angle that forms a 1:1 complex with Rh(I) is found to be reactive for the hydroformylation of trisubstituted olefins. The aldehyde products were obtained with high diastereoselectivity (>99:1) and regioselectivity (49%-81%).

Full text of DOI:10.1021/acs.orglett.9b01639

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ligand-Controlled Direct Hydroformylation of Trisubstituted Olefins
Taeil Shin, Hyungsoo Kim, Sungmin Kim, Ansoo Lee, Min-Seob Seo, Jonghoon Choi, Hyungjun Kim,
and Hyunwoo Kim*
Department of Chemistry, KAIST, Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: The direct hydroformylation of trisubstituted
olefins has been achieved with a combination of a Rh(I)
catalyst and a π-acceptor phosphorus (briphos) ligand. A
sterically bulky briphos ligand with a large cone angle that
forms a 1:1 complex with Rh(I) is found to be reactive for the
hydroformylation of trisubstituted olefins. The aldehyde
products were obtained with high diastereoselectivity
(>99:1) and regioselectivity (49%−81%).
isomerization to terminal olefins followed by hydroformylation
to give linear aldehyde products have been developed with
various transition-metal catalysts5 such as Co, Rh, Ru, Pd, and
Pt (Scheme 1b). For the direct hydroformylation of internal
olefins without involving the isomerization process, the
substrate scope has only been extended to 1,1- or 1,2-
disubstituted olefins,6 whereas more-substituted olefins, such
as trisubstituted or tetrasubstituted olefins, have rarely been
used.7 Although regioselective hydroformylation of trisubsti-
tuted allyl alcohols or acetates has been reported,8 it has been a
challenge to utilize trisubstituted olefins without any other
functional groups. Given the importance of hydroformylation
in industry, it is highly desirable to expand the utility of
hydroformylation to more-substituted olefins. Here, we report
Rh-catalyzed direct hydroformylation of trisubstituted olefins
by ligand modification of bicyclic bridgehead phosphoramidite
(briphos) ligands (Scheme 1c).
Since the discovery of ligand effects on Rh-catalyzed
hydroformylation, various phosphorus ligands have been
creatively developed and applied to hydroformylation to
control the regioselectivity and stereoselectivity. Bidentate
phosphorus ligands with larger bite angles favor the formation
of linear isomers.9 Phosphorus ligands of π-acceptor properties
enhanced the reactivity,1c,10 and those with sterically bulky
groups favored the formation of branched isomers.11 On the
basis of the reported ligand effects, the ligand choice for the
hydroformylation of highly substituted olefins can be
monodentate, sterically bulky, or π-acceptor phosphorus
ligands.
ydroformylation is a highly atom-economical synthetic
Hreaction to prepare aldehydes by the addition of CO and
H2 to olefins.1 It is an industrial process that utilizes
homogeneous catalytic reaction. The resulting aldehyde
products are used to further produce more than 10 million
tons of oxo-alcohols annually.1 Although Co-based catalysts
were initially developed for hydroformylation,2 Rh-based
catalysts have been a topic of recent research because the
regioselectivity and stereoselectivity of Rh-catalyzed hydro-
formylation can be controlled by ligand design. Monodentate
or bidentate phosphorus ligands such as phosphines,
phosphoramidites, phosphinites, and phosphites, as well as
their mixed forms, have been used.3
Industrial hydroformylation mainly utilizes substrates of C2
or monosubstituted C3−C8 olefins isolated from petroleum.1c
Considering industrial applications, research on ligand
development has been focused on controlling the branched
to linear ratio of monosubstituted olefins (Scheme 1a).4 In
cases of internal olefins, tandem approaches including
Scheme 1. Regioselective Hydroformylation
To meet the ligand requirement, we used tunable π-acceptor
phosphorus ligands, bicyclic briphos ligands.12 Because of the
geometrical constraints, the briphos ligands exhibit enhanced
π-accepting properties, which can be further modulated by
substituents.12g In order to enhance the steric repulsion, we
newly prepared briphos ligands with tert-butyl groups at the
Received: May 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01639
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ortho and para positions of the phenol rings, as shown in
Scheme 2. The three-straightforward-step reactions from
compound 1,13 imine formation, reduction, and phosphor-
amidite formation, gave briphos ligands L1−L4 in overall
yields of 23%−68%.
(2 mol %), two aldehyde products, 5a and 5b, were mainly
produced, together with other minor aldehydes (5c) and
reduced methylcyclohexane (5d). In the cases of monodentate
phosphorus ligands PCy3, PPh3, and P(OPh)3, the conversion
was determined to be <17% (see Table 1, entries 1−3). When
a reported sterically bulky π-accepting phosphorus ligand,
tris(2,4-di-tert-butylphenyl)phosphite (TDTBPP), was used,
an increase of the conversion (65%) and moderate selectivity
(5a/5b = 2.1) were observed, indicating that both the π-
accepting property and steric bulkiness are required for the
hydroformylation of 4 (see Table 1, entry 4). We next sought
to further optimize the reactivity and selectivity by using our
briphos ligand platform. To our delight, briphos ligands with
tert-butyl groups L1−L4 showed remarkable reactivity except
L2. Both the cyclohexyl group (L1) and the 3,5-dimethox-
yphenyl group (L4) were found to be effective, giving a high
conversion of 83%. In particular, L4 showed the highest
selectivity for the formation of aldehydes (5a/5b = 4.0)
without the formation of any side products of 5c and 5d (see
Table 1, entries 5−8). Moreover, the hydroformylation was
highly diastereoselective (>99:1) to provide 5a. Indeed, the
briphos ligands with unsubstituted phenol groups L5−L8
showed poor conversion (<11%), confirming the importance
of the sterically bulky functional groups (Table 1, entries 9−
12). In addition, bidenate phosphorus ligands (xanphos,
DPPE, and BINAP) were all inefficient (Table 1, entries
13−15).
Scheme 2. Synthesis of Briphos Ligands L1−L4 Containing
tert-Butyl Groups
As a model substrate for hydroformylation of trisubstituted
olefins, 1-methyl-1-cyclohexene (4) was selected (Table 1).
When 20 bar syngas (CO and H2) was applied to a solution of
1-methyl-1-cyclohexene (4) in toluene at 100 °C in the
presence of Rh(CO)2(acac) (1 mol %) and phosphorus ligand
Table 1. Ligand Effect on the Hydroformylation of 1-
Methylcyclohexene
In order to understand the origin of reactivity and
regioselectivity, we conducted several control experiments. In
our previous study, briphos ligand L6 and Rh(I) was found to
form the 2:1 complex, which is an active species for Rh-
catalyzed conjugate additions of aryl boronic acids.12g We
obtained a crystal structure of a dinuclear [Rh(L6)2Cl]2
complex.12g However, tert-butyl substituted briphos L4 was
found to form a 1:1 complex with Rh(CO)2(acac). The crystal
structure of Rh(CO)(acac)(L4) is shown in Figure 1. When 1
c
Selectivity (%)
a
b
cd
,
entry
ligand
PCy3
PPh3
P(OPh)3
TDTBPP
L1
L2
L3
L4
L5
L6
L7
L8
xantphos
DPPE
rac-BINAP
conversion (%)
5a
5b
5c
5d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
8
11
17
65
83
11
70
83
11
14
4
71
29
31
28
31
25
27
25
20
25
25
21
33
39
−
−
4
1
4
2
−
2
−
11
2
37
7
2
−
1
4
64
67
64
73
73
73
80
64
73
42
60
46
−
1
−
−
−
−
−
−
−
−
13
−
9
3
6
NR
6
−
2
55
34
a
Conditions: 1-methyl-1-cyclohexene (1.0 mmol) and [Rh] = 0.5
Figure 1. Crystal structure of Rh(CO)(acac)(L4) (thermal ellipsoids
at 50% probability: all hydrogen atoms are omitted for clarity).
mM in a stainless-steel pressure reactor without exclusion of air or
b
c
moisture. Determined by 1H NMR spectra. Determined by GC-MS
d
spectra. 5a was obtained with >99:1 dr (trans/cis).
mol % of Rh(CO)(acac)(L4) was used for hydroformylation
of 1-methyl-1-cyclohexene, the desired aldehyde was produced
at 32% with 80% regioselectivity, indicating that Rh(CO)-
(acac)(L4) is an active precatalyst.
In the solution state, the ligand L4 forms only the 1:1
complex, Rh(CO)(acac)(L4), even when 4 equiv of ligand L4
was used, as determined by 31P{1H} NMR analysis (Figures 2a
and 2b). When this complex was applied to 20 bar syngas, a
B
DOI: 10.1021/acs.orglett.9b01639
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope for the Hydroformylation of
Trisubstituted Olefins
Figure 2. Stacked 31P{1H} NMR spectra showing ligation of L4 and
L6 with Rh(CO)2(acac).
new Rh complex HRh(CO)2(L4) was formed. A doublet
signal at 121.5 ppm in 31P{1H} NMR and a triplet signal at
1
−9.29 ppm in H NMR spectra support the structure of
HRh(CO)2(L4) (see the Supporting Information). Even when
1 equiv of substrate, 1 mol % of Rh(CO)(acac)2, and 4 mol %
of ligand L4 were mixed for 1 h in benzene-d6 under 20 bar
syngas at ambient temperature, the 31P{1H} NMR spectra
indicated that Rh(CO)(acac)(L4) and HRh(CO)2(L4) are
the only detectable intermediates (see the Supporting
Information). Interestingly, briphos L6 without tert-butyl
groups forms 2:1 complexes with Rh(I). Rh(acac)(L6)2 and
HRh(CO)(L6)2 are in the solution state, as determined by
31P{1H} NMR analysis (Figures 2c and 2d and the Supporting
Information). Because briphos L6 showed only 3% conversion,
the formation of a 1:2 complex of Rh and ligand appears to be
inactive for hydroformylation of trisubstituted olefins.
The steric bulkiness of the phosphorus ligands can be
evaluated by measuring ligand parameters such as cone angles
or buried volumes. Briphos L4 showed %Vbur and cone angle θ
values of 30.8 and 195°, respectively, and Briphos L6 gave
corresponding values of 28.6 and 156°, respectively. (See
Table 2.) Because ligands L4 and L6 have compatible %Vbur
We then used cyclic trisubstituted olefins. In the case of an
exocyclic olefin, the desired aldehyde 11 was produced in 89%
yield and 73% regioselectivity. For endocyclic olefins, the
desired products 5 and 12−14 were obtained in somewhat
reduced yields of 59%−72%. Our structural analysis supported
syn-addition of hydrogen and formyl group to the olefins, thus
producing all trans products (see the Supporting Information).
The regioselectivity for endocyclic olefins was higher than that
for the acyclic olefins, ranging from 60% to 81%. Considering
two or three possible isomerizations in acyclic trisubstituted
olefins, the observed regioselectivity was quite significant.
In conclusion, we have demonstrated that sterically bulky π-
acceptor phosphorus ligands, briphos ligands, can efficiently
promote the direct hydroformylation of trisubstituted olefins.
Crystallographic and NMR data support that briphos ligand
substituted with di-tert-butyl groups is found to form a 1:1
complex with Rh catalyst, likely due to the large cone angle.
The briphos ligand L4 was utilized to promote direct
hydroformylation of various trisubstituted olefins including
acyclic, exocyclic, and endocyclic forms with moderate to good
yields (50%−97%) and regioselectivity (49%−81%).
Table 2. Steric Parameters14 of L4 and L6
ligand
L4
L6
%Vbur
cone angle, θ (°)
30.8
195
28.6
156
values but different θ values, the angular steric effect expressed
by the θ value appears to be crucial to form the 1:1 Rh-ligand
complex, which is effective for the direct hydroformylation of
trisubsituted olefins.
With the optimized reaction conditions of using 1 mol % of
Rh(CO)2(acac) and 2 mol % of briphos ligand L4, we
investigated the substrate scope (Scheme 3). In the case of
acyclic trisubstituted olefins, the hydroformylation proceeded
with >99% conversion and the regioselectivity of the major
aldehyde products 6−9 was 49%−76%. An aryl-substituted
olefin gave product 10 with 97% yield and 81% regioselectivity.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01639.
C
DOI: 10.1021/acs.orglett.9b01639
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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1
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crystal data of Rh(CO)(acac)(L4) (PDF)
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
̃
■
Corresponding Author
*E-mail: hwkim@kaist.edu.
ORCID
(9) (a) Jiao, Y.; Torne, M. S.; Gracia, J.; Niemantsverdriet, J. W.; van
Leeuwen, P. W. N M. Catal. Sci. Technol. 2017, 7, 1404−1414.
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Hyungjun Kim: 0000-0001-8261-9381
Hyunwoo Kim: 0000-0001-5030-9610
Notes
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The authors declare no competing financial interest.
(11) (a) Dingwall, P.; Fuentes, J. A.; Crawford, L.; Slawin, A. M. Z.;
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The authors are grateful for the financial support provided by
the C1 Gas Refinery Program (No. 2016M3D3A1A01913256)
and the National Research Foundation of Korea (No.
2017M1A2A2049208).
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DOI: 10.1021/acs.orglett.9b01639
Org. Lett. XXXX, XXX, XXX−XXX