Formation of quaternary carbon centers by highly regioselective hydroformylation with catalytic amounts of a reversibly bound directing group

Article abstract of DOI:10.1002/chem.201101186

Directly opposing Keulemans rule! Phosphinites work as reversibly bound directing groups allowing for the first highly regioselective hydroformylation of 3-substituted homoallylic alcohols to construct quaternary carbon centers. This method enables the at

Full text of DOI:10.1002/chem.201101186

COMMUNICATION
DOI: 10.1002/chem.201101186
Formation of Quaternary Carbon Centers by Highly Regioselective
Hydroformylation with Catalytic Amounts of a Reversibly Bound Directing
Group
Yusuke Ueki,[b] Hideto Ito,[c] Ippei Usui,[a] and Bernhard Breit*[a]
With nine million tons of oxoproducts produced world-
wide per year, the hydroformylation of olefins is the largest
volume application of homogeneous catalysis in industry.[1,2]
Thus, in the presence of a suitable transition-metal catalyst,
CO and hydrogen are added across the carbon–carbon
double bond of an alkene to give the homologated alde-
hydes in complete accord with the criteria of atom econo-
my.[3] The aldehydes formed are useful functional groups al-
lowing for further skeleton-expanding transformations,
which may be performed even as tandem processes.[4] De-
spite great progress in recent years, the control of regio- and
stereoselectivity in hydroformylation is still a difficult sub-
ject. As a solution to this problem we have been studying
the use of removable catalyst-directing groups (CDG) allow-
ing for both regiocontrol as well as acyclic stereocontrol em-
ploying allylic and homoallylic alcohol systems.[5] However,
the obvious drawbacks of this approach are the need for sto-
ichiometric amounts of the directing group and the necessity
for additional synthetic steps for introduction and removal.
A more preferable option would be the use of catalytic
amounts of the directing group, as we have recently shown
using a supramolecular approach based on complementary
hydrogen-bonding between substrate and the catalyst
system.[6] Alternatively, both our group and the Tan group
have reported on the use of catalytic directing groups that
bind covalently but reversibly to the substrate.[7–10] We iden-
tified diphenylphosphinites as ideal systems that allow for a
reversible transesterification of alcohols under hydroformy-
lation conditions (Scheme 1). Hence, a highly branched, re-
gioselective hydroformlyation of homoallylic and bis-homo-
allylic alcohols could be realized using this catalyst systems
to give g- and d-lactols in excellent yields (Scheme 2, reac-
tion (1)).[7]
Scheme 1. Hydroformylation with
a catalyst-directing group (CDG)
needed only in catalytic amounts through reversible covalent substrate
binding.
[a] Dr. I. Usui, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie und Biochemie
Freiburg Institute for Advanced Studies (FRIAS)
Albert-Ludwigs-Universitꢁt Freiburg, Albertstrasse 21
9104 Freiburg i.Br. (Germany)
Fax : (+49)761-203-8715
E-mail: bernhard.breit@chemie.uni-freiburg.de
[b] Y. Ueki
Department of Chemistry, Faculty of Science
Nagoya University, Furo-cho B2-3
Nagoya 464-8603 (Japan)
ACHTUNGTREN(NUNG 611) Chikusa
Scheme 2. Construction of quaternary carbon centers by hydroformyla-
tion employing a covalent but reversibly bound directing group.
[c] H. Ito
Department of Applied Chemistry
Graduate School of Engineering, Hokkaido University,
Sapporo 060-0810 (Japan)
One of the remaining tasks in hydroformylation is the
construction of quaternary carbon centers. It is so unfavora-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101186.
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8555

ble that even a rule was stated in 1948 (Keulemans rule),
which says that “addition of the formyl group to a tertiary C
atom does not occur, so that no quaternary C atoms are
formed”.[11] This rule is indeed valid for the majority of al-
kenic substrates. Only in special cases, such as with a,b-un-
saturated esters, which are electronically activated to form
the branched regioisomer, have violations of this rule been
observed.[12] For unactivated alkenes there are only two re-
ports in the literature. Leighton et al. employed a covalently
attached phosphine directing group.[5b] Alternatively, the
Tan group recently reported the use of their “scaffolding
ligand” to effect branched selective hydroformylation of 2-
substituted allylic alcohols.[8c] Although regioselectivities are
remarkably high, the methodology so far is restricted to the
use of 2-aryl-substituted allylic alcohol derivatives to give
the corresponding b-hydroxy-carboxylic acids after subse-
quent oxidation of the labile aldehyde function.[13]
found when using 408C as the reaction temperature and a
synthesis gas pressure of 40 bar (Table 1, entry 6). Nearly
quantitative conversion and excellent regioselectivity (96:4)
was observed in favor of the g-lactol 2, with concomitant
formation of an a quaternary carbon center.
With this information in hand we next investigated the
substrate scope of the reaction. We were pleased to find in
all cases that the reaction proceeded smoothly to give (after
oxidation) the corresponding a,a-disubstituted lactones in
good to excellent yields under the optimized conditions. A
variety of tertiary homomethallylic alcohols were hydrofor-
mylated in high yield and regioselectivity. Both primary and
even secondary alkyl substituents were tolerated at the 1-po-
sition (R2) and did not significantly affect the regioselectivi-
ty, irrespective of their steric demand (Table 2, entries 2–5).
Interestingly, introduction of aromatic and heteroaromatic
groups in that position gave the highest regioselectivities in
favor of the anti-Keulemans product (Table 2, entries 6–8).
Furthermore, the reaction tolerates functional groups such
as ester, ether, and furanyl functions (Table 2, entry 7–9).
Also, in the case of an aromatic substituent at the 3 position
of the homoallylic alcohol, the branched product was ob-
tained as the major isomer (regioisomeric ratio (r.r.)=88:12,
Table 2, entry 10). A substrate with aromatic substituents in
the 1 and 3 positions could be reacted as well but gave a
mixture of diastereomers (Table 2, entry 11).
Next, we were interested in whether we could transform
the primary lactol products to the corresponding tetrahydro-
furans instead of oxidizing to the lactones.[14] Thus, treat-
ment of the crude hydroformylation mixture with triethylsi-
lane and BF3·OEt2 resulted in the formation of the desired
tetrahydrofuran in 88% yield over two steps (Scheme 3).
Replacing the hydride nucleophile with an allylsilane afford-
ed the corresponding a-allylated tetrahydrofuran in good
yield and diastereoselectivity. These simple procedures
allow for the facile synthesis of various highly substituted
tetrahydrofurans.
We herein report that employing diphenylphosphinite as a
catalytic directing group allows for highly chemo- and regio-
selective hydroformylation of a wide range of homoallylic
alcohols to give a,a-disubstituted butyrolactones, which are
important building blocks in organic synthesis, in excellent
yields (Scheme 2, reaction (2)).
We commenced our investigations on studying the hydro-
formylation of 3-methyl-3-butene-1-ol (1) by employing the
catalyst system we have developed previously for the posi-
tion-selective hydroformylation of homoallylic alcohols
(Table 1). In preliminary experiments it was essential to in-
crease the catalyst loadings to 4 mol% to get the 1,1-disubsi-
tuted alkenes to turnover. To our delight, employing a
syngas pressure of 10 bar and using 408C as the reaction
temperature a 9:1 regioselectivity towards the branched g-
lactol 2 was observed (Table 1, entry 1). However, the cata-
lyst reactivity was too low. Increasing the syngas pressure
from 10 to 20 or to 30 bars had a beneficial effect on both
the catalyst activity and the regioselectivity (Table 1, en-
tries 2 and 5). On the other hand, increasing the reaction
temperature increased the catalyst activity but lowered the
regioselectivity. Finally, optimal reaction conditions were
Table 1. Optimization of the reaction conditions for the phosphinite-di-
rected regioselective hydroformylation of 3-methyl-3-buten-1-ol (1).
Entry
Pressure
[bar]
T
[8C]
Conv.
[%][a]
Regioselectivity
ACHTUNGTRENNUNG
[2/3][a]
N
1
2
3
4
5
6
10
20
20
20
30
40
40
40
50
60
40
40
24
38
60
71
66
98
90:10
94:6
88:16
84:16
94:6
Scheme 3. Two-step preparation of highly substituted tetrahydrofurans.
96:4
In conclusion, the first highly regioselective hydroformyla-
tion of 3-substituted homoallylic alcohols for the construc-
[a] The regioselectivity was determined by GC before oxidation.
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Chem. Eur. J. 2011, 17, 8555 – 8558

Formation of Quaternary Carbon Centers
COMMUNICATION
Table 2. Results of the phosphinite-directed branched regioselective hydroformylation of substituted homo-
allylic alcohols.
Experimental Section
The oven dried glass inlet of an auto-
clave was equipped with molecular
sieves (4 ꢃ) and put into the oven
dried stainless steel autoclave. To pre-
vent loss of solvent from evaporation
and condensation outside the glass
inlet, a small funnel was put on top of
the inlet. This funnel allows for pres-
surization but the solvent condenses
there and drops back into the reaction
mixture. The autoclave was closed and
washed with argon. The pre-dried
(over molecular sieves and triphenyl-
Entry
Substrate
Major product
T
[8C]
Yield
[%][a]
r.r.[b]
96:4
97:3
1
2
40
40
91
99
phosphine)
unsaturated
alcohol
(1 equiv) was weighed into an oven
dried Schlenk-flask. In another oven
dried Schlenk flask a solution of the
ligand Ph2PACTHNUTRGNEU(GN OMe) (20 mol%) in THF
(0.2m) was prepared. [Rh(CO)2acac]
(4.0 mol%) was added to this solution
and the mixture was stirred for 5 min.
This mixture was transferred into the
Schlenk flask with the substrate and
stirred for another 2–3 min. The whole
reaction mixture was transferred
through a cannula into the Steel auto-
clave. The autoclave was sealed and
purged three times with 5 bar of the
CO/H2 gas mixture (1:1). The auto-
clave was pressurized with 40 bar of
CO/H2 (1:1) and placed into a pre-
heated oil bath (40–808C). The reac-
tion mixture was stirred for 16–18 h.
After pressure release, a sample was
taken for GC analysis. The solvent of
the crude reaction mixture (0.6 mmol
scale) was evaporated. The residue
was dissolved in CH2Cl2 (5 mL, 0.12m)
and the reaction mixture was cooled
to 08C and saturated NaHCO3 solu-
tion (5 mL), KBr (spatula tip, ꢀ10 mg,
ꢀ0.15 equiv) and 2,2,6,6-tetramethyl-
piperidine 1-oxyl (TEMPO, spatula
tip, ꢀ5 mg, ꢀ0.05 equiv) were added.
A NaOCl solution (ꢀ1.2m in H2O,
1 mL, 1.2 mmol, 2.0 equiv) was added
dropwise and the reaction mixture was
stirred at 08C for 30 min. The reaction
mixture was quenched with concen-
trated Na2S2O3 solution and the phases
were separated. The aqueous phase
was extracted with CH2Cl2 (3ꢄ20 mL)
and the combined organic phases were
dried over MgSO4. The solvent was
evaporated and the crude product was
purified by column chromatography.
3
4
5
6
7
50
50
50
40
60
90
85
67
92
92
95:5
95:5
96:4
99:1
99:1
8
40
97
99:1
9
50
80
60
99
95:5
10
11
85
88:12
86:14[c]
99 (d.r.=2:1)[d]
[a] Yield of the isolated product after purification by column chromatography. [b] The regioselectivity was de-
termined by GC before oxidation. [c] The regioselectivity was determined by NMR spectroscopy before oxida-
tion. [d] The relative configuration and diastereoselectivity was determined by NOE experiments.
tion of quaternary carbon centers has been presented. This
method enables the atom-economical synthesis of a wide
range of a,a-disubstituted g-lactones and highly substituted
tetrahydrofurans. Further studies will address the problem
of enantioselectivity as well as the application of similar di-
recting systems to other catalytic reactions.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie, the
DFG (“Catalysts and Catalytic Reactions for Organic Synthesis”, IRTG
1038), and the Krupp Foundation (Alfried Krupp Award for young uni-
versity teachers to B.B.). Y.U. and H.I. are grateful to the Japan Society
for the Promotion of Science for Young Scientists for the Research Fel-
lowships.
Chem. Eur. J. 2011, 17, 8555 – 8558
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Keywords: directing groups
hydroformylation · regioselectivity · synthetic methods
· homogeneous catalysis ·
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Received: April 18, 2011
Published online: July 4, 2011
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Chem. Eur. J. 2011, 17, 8555 – 8558