Diastereoselective hydroformylation of 2,5-cyclohexadienyl-1-carbinols with catalytic amounts of a reversibly bound directing group

Article abstract of DOI:10.1021/ol1028546

A phosphinite plays a role as a reversibly bound directing group for the regio-and diastereoselective hydroformylation of 2,5-cyclohexadienyl-1- carbinols. Of the two alkene functions only one was functionalized through hydroformylation to form a syntheti

Full text of DOI:10.1021/ol1028546

ORGANIC
LETTERS
2011
Vol. 13, No. 4
612–615
Diastereoselective Hydroformylation
of 2,5-Cyclohexadienyl-1-carbinols with
Catalytic Amounts of a Reversibly Bound
Directing Group
Ippei Usui, Kenichi Nomura, and Bernhard Breit*
Institut fu€r Organische Chemie und Biochemie, Freiburg Institute for Advanced Studies
€
(FRIAS), Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21, 79104 Freiburg i. Bg.,
Germany
bernhard.breit@chemie.uni-freiburg.de
Received November 25, 2010
ABSTRACT
A phosphinite plays a role as a reversibly bound directing group for the regio- and diastereoselective hydroformylation of 2,5-cyclohexadienyl-
1-carbinols. Of the two alkene functions only one was functionalized through hydroformylation to form a synthetically attractive quaternary
carbon center leaving the second alkene function for potential further functionalization.
Hydroformylation of alkenes has contributed to industrial
chemistry and academic research for several decades.1
In spite of its utility, the control of regio- and stereoselec-
tivity is still a challenging problem. The selectivity can be
controlled by a substrate and/or a ligand. Due to an
electronic effect or a directing effect, branched aldehydes
are provided selectively from some families of monosub-
stituted olefins regardless of a choice of ligand.2 However,
simple alkenes generally provide a mixture of linear and
branched aldehydes. We have investigated methods to
change the selectivity by employing a catalyst-directing
group (CDG). Employing o-diphenylphosphinobenzoic
acid (o-DPPBA) as a stoichiometric CDG connected to
allylic alcohols and homoallylic alcohols via an ester
linkage, the double bond was functionalized in a regio-
and diastereoselective manner under hydroformylation
conditions.3 With the chiral derivative o-DPPFA, we have
studied hydroformylative desymmetrization of bisalkenyl
carbinols and bishomoallylic carbinols.4 The methodology
(3) (a) Breit, B. Angew. Chem. 1996, 108, 3021; Angew. Chem., Int. Ed.
1996, 35, 2835. (b) Breit, B. Liebigs Ann. 1997, 1841. (c) Breit, B. Eur. J.
Org. Chem. 1998, 1123. (d) Breit, B.; Heckmann, G.; Zahn, S. K.
(1) (a) Breit, B.; Seiche, W. Synthesis 2001, 1, 1–36. (b) Breit, B. Top.
Curr. Chem. 2007, 279, 139. (c) Van Leeuwen, P. W. N. M.; Claver, C.
Rhodium Catalyzed Hydroformylation; Springer-Verlag: New York, 2002;
Vol. 22. (d) Applied Homogeneous Catalysis with Organometallic Com-
pounds; Cornils, B., Herrmann, W. A., Eds.; Wiley: Weinheim, 2002; Vol. 1,
Chapter 2.
(2) (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am. Chem.
Soc. 1993, 115, 7033. (b) Nozaki, K.; Takaya, H.; Hiyama, T. Top. Catal.
1997, 4, 175. (c) Klosin, J.; Landis, C. R. Acc. Chem. Res. 2007, 40, 1251
and references cited therein. (d) McDonald, R. I.; Wong, G. W.;
Neupane, R. P.; Stahl, S. S.; Landis, C. R. J. Am. Chem. Soc. 2010,
132, 14027.
€
Chem.;Eur. J. 2003, 9, 425. (e) Breit, B.; Grunanger, C. U.; Abillard,
O. Eur. J. Org. Chem. 2007, 2497. (f) Rein, C.; Demel, P.; Outten, R. A.;
Netscher, T.; Breit, B. Angew. Chem., Int. Ed. 2007, 46, 8670. (g) Bruch,
A.; Breit, B. Synthesis2008, 2169. (h) Laemmerhold, K.; Breit, B. Angew.
Chem., Int. Ed. 2010, 49, 2367.
(4) (a) Breit, B.; Breuninger, D. J. Am. Chem. Soc. 2004, 126, 10244.
(b) Breit, B.; Breuninger, D. Eur. J. Org. Chem. 2005, 3916. (c) Breit, B.;
Breuninger, D. Eur. J. Org. Chem. 2005, 3930. (d) Breit, B.; Bigot, A.
Chem. Commun 2008, 6498. (e) Bigot, A.; Breuninger, D.; Breit, B. Org.
Lett. 2008, 10, 5321.
r
10.1021/ol1028546
Published on Web 01/13/2011
2011 American Chemical Society

was successfully applied in total synthesis.3f,h,4d An ob-
vious drawback of this approach is the requirement of a
stoichiometric amount of the directing group and addi-
tional steps for its connection and removal.
Table 1. Optimization of Reaction Conditions
entry
x mol %
y mol %
z bar
convna
1b
2
1
1
1
2
2
2
10
10
10
20
20
20
40
20
40
40
40
40
0c
25
3
50
4
100
100d
23e
5
6
a The conversions were determined by 1H NMR. b The reaction was
carried out without distillation of the substrate. c The starting material
was recovered completely. d Overreaction proceeded, and 2a was not
obtained, 72 h reaction time. e Three aldehydes and 2a was observed.
substrate (Table 1). Surprisingly, employing 1a without
prior distillative purification, and treating it with a catalyst
prepared from Rh(CO)2acac (1 mol %) and Ph2POMe
Figure 1. Hydroformylation with a catalyst-directing group
(CDG) needed only in catalytic amounts through reversible
covalent substrate binding.
˚
˚
(10 mol %), in the presence of molecular sieves 4 A (MS4 A)
under 40 bar of CO/H2 gas at 80 °C for 18 h resulted in the
complete recovery of the starting material (entry 1). This
proved the necessity of predistillation to remove traces of
water or peroxide which could deactivate the catalyst.
Although the reaction with the distilled substrate 1a under
20 bar gave the desired lactol 2a, the conversion was only
25% (entry 2). The conversion was improved to 50% at
40 bar (entry 3). The reaction with 2 mol % Rh catalyst
and 20 mol % ligand at 40 bar provided 2a in 100%
conversion (entry 4). When the reaction was performed
under the same conditions for 72 h, overreaction also
proceeded, and 2a was not observed (entry 5). A catalyst
prepared from 1 mol % of Rh(CO)2(acac) and 10 mol %
of PPh3 provided a mixture of 2a and the other three
diastereomers in a stereorandom fashion in 23% con-
version, proving the directing role of the phosphinite
system.
Recently, Tan’s group5 and we6 independently reported
the study of catalytic amounts of covalently but reversibly
bound catalyst-directing groups for hydroformylation re-
actions (Figure 1). These studies proved that the employed
ligands are required in catalytic amounts and enable us to
perform hydroformylation of homoallylic and bishomoallylic
alcohols under mild conditions to afford branched alde-
hydes selectively through a chelated transition state in an
intramolecular manner. Herein, we report the diastereose-
lective hydroformylation of cyclic dienes,7 known as chal-
lenging substrates for hydroformylation, employing a
phosphinite ligand bound covalently but reversibly on
the substrates.
Scheme 1. Synthesis of 1-Methyl-2,5-cyclohexadienyl-1-
methanol 1a
In comparison to the previous result obtained with a
simple homoallylic alcohol,6 this substrate needs harsher
conditions(higheramount of catalyst, higherpressure, and
higher temperature). Generally, cyclic alkenes are less
reactive to hydroformylation catalysts than both trans-
and cis-1,2-disubstituted alkenes. Additionally, formation
of a covalent bond between the ligand and 1a bearing
1,4-Cyclohexadienes have been employed for several
desymmetrization reactions.8 The substrate, 1-methyl-2,5-
cyclohexadienyl-1-methanol 1a bearing a hydroxy group in
an appropriate homoallylic position, was easily prepared
from benzoic acid and methyl iodide via Birch alkylation
and followed by lithium aluminum hydride (LAH) reduc-
tion to provide 1a in 67% yield over 2 steps (Scheme 1).
First, the reaction conditions were optimized with
1-methyl-2,5-cyclohexadienyl-1-methanol1aas a standard
(5) (a) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. J. Am.
Chem. Soc. 2008, 130, 9210. (b) Worthy, A. D.; Gagnon, M. M.;
Dombrowski, M. T.; Tan, K. L. Org. Lett. 2009, 11, 2764. (c) Sun, X.;
Frimpong, K.; Tan, K. L. J. Am. Chem. Soc. 2010, 132, 11841.
(d) Worthy, A. D.; Joe, C. L.; Lightburn, T. E.; Tan, K. L. J. Am.
Chem. Soc. 2010, 132, 14757.
€
(6) (a) Grunanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2010, 49,
€
967–970. (b) Grunanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2008, 47,
7346.
(7) Spencer, A. J. Organomet. Chem. 1977, 124, 85.
(8) (a) Studer, A.; Schleth, F. Synlett 2005, 20, 3033. (b) Nakahara,
K.; Fujioka, H. Symmetry 2010, 2, 437 and references therein.
Org. Lett., Vol. 13, No. 4, 2011
613

a sterically hindered quaternary center adjacent to the
hydroxy group might be difficult. Moreover, rhodium
could coordinate too tightly with the substrate having
two coordinative moieties, phosphinite and diene. To
dissociate the coordination after the desired reaction, a
higher temperature could be required.
After the hydroformylation, the resulting lactol 2a
was oxidized to lactone 3a for the ease of characteriza-
tion. The relative configuration of 3a was confirmed by
an NOE experiment and an X-ray structure analysis (see
Figure 2). The relationship between the R-proton and
methyl group of lactone 3a was a cis configuration. As
expected, syn-hydrorhodation took place to provide the
lactol 2a as a single diastereomer and PCC oxidation
afforded bicyclic lactone 3a without epimerization. The
product has an attractive carbon quaternary center and
a double bond which can be functionalized at a later
stage.
In order to determine the generality of the reaction, we
employed various substrates 1 under the optimized condi-
tions (Table 2). These substrates could be prepared easily
over two steps by Birch alkylation and LAH reduction in
good to moderate yield. Employing substrates with alkyl
substituents, the reaction furnished desired products as a
single diastereomer in good yield except one with an
isopropyl group (entry 1-5). Employing 1c as a substrate,
higher temperature and higher pressure did not improve
conversion at all. Presumably, the secondary alkyl group is
Figure 2. Determination of relative configuration; PLATON
plot of the molecular structure of lactone 3a in the crystal state.
Table 2. Scope of Substratesa
a
˚
The solution of diene 1 (0.6 mmol) with MS4 A in THF (3 mL) was stirred in the presence of 2 mol % Rh(CO)2(acac) and 20 mol % PPh2OMe at
80 °C at 40 bar for 18 h. b The lactone 3 was isolated after hydroformylation followed by PCC oxidation.
614
Org. Lett., Vol. 13, No. 4, 2011

too sterically hindered to allow exchange of the directing
group from the product to the next substrate. A substrate
with three alkene functions furnished the desired product
without touching the other two double bonds (entry 6).
Several heteroatoms were tolerated under the reaction
conditions. A substrate bearing a protected hydroxy group
provided the product in good yield without deprotection of
a benzyl ether (entry 7). A nitrile group is known to direct a
rhodium catalyst in hydroformylation reactions, though
the phosphinite ligand bound to the alcohol overruled this
effect (entry 8).9 An alkyl chloride moiety was not deha-
logenated under the reaction conditions, and the desired
product was obtained (entry 9). An additional methyl
group on one of the double bonds led to hydroformylation
of the less substituted double bond (entry 10).10
obtained bicyclic lactones are interesting building blocks
with an attractive carbon quaternary center and an addi-
tional alkene functions which can be subsequently func-
tionalized. Investigation of a chiral phosphorus ligand
leading to hydroformylative desymetrization reaction with
the substrates is ongoing.4d
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie, the DFG via the Inter-
national Research Training Group “Catalysts and Cataly-
tic Reactions for Organic Synthesis” (GRK 1038), and the
Alfried Krupp Award for young university teachers of the
€
Krupp Foundation (to B.B.). We acknowledge M. Kahny
(Albert-Ludwigs-Universitat Freiburg) for preliminary
€
work. K.N. acknowledges the Research Fellowships of
the Japan Society for the Promotion of Science for Young
Scientists for financial support.
In summary, we have demonstrated diastereoselective
hydroformylation of 2,5-cyclohexadienyl-1-methanol
employing a catalytic amount of a directing group. The
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Lambers-Verstappen, M.; de Vries, J. G. Adv. Synth. Catal. 2003,
345, 478.
(10) Relative configuration of some products was determined by
NOE experiments. See Supporting Information.
Org. Lett., Vol. 13, No. 4, 2011
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