New phosphorus self-assembling ligands for the tandem hydroformylation- Wittig olefination reaction of homoallylic alcohols - A key step for stereoselective pyran synthesis

Article abstract of DOI:10.1016/j.catcom.2014.04.022

New self-assembled phosphorus ligands are synthesized and used in the rhodium complex catalyzed hydroformylation-Wittig reaction of homoallylic olefins under optimized condition. A subsequent oxa-Michael intramolecular reaction yields β-pyran derivatives (conversion and diastereoselectivity up to 99%).

Full text of DOI:10.1016/j.catcom.2014.04.022

New phosphorus self-assembling ligands for the tandem hydroformylation-
Wittig olefination reaction of homoallylic alcohols – a key step for stereose-
lective pyran synthesis
Qiao Ruan, Le Zhou, Bernhard Breit
PII:
DOI:
Reference:
S1566-7367(14)00168-X
doi: 10.1016/j.catcom.2014.04.022
CATCOM 3890
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
7 March 2014
23 April 2014
28 April 2014
Please cite this article as: Qiao Ruan, Le Zhou, Bernhard Breit, New phosphorus self-
assembling ligands for the tandem hydroformylation-Wittig olefination reaction of ho-
moallylic alcohols – a key step for stereoselective pyran synthesis, Catalysis Communica-
tions (2014), doi: 10.1016/j.catcom.2014.04.022
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Title:
New
phosphorus
self-assembling ligands
for
the
tandem
hydroformylation-Wittig olefination reaction of homoallylic alcohols – a key step
for stereoselective pyran synthesis
Authors: Qiao Ruan1, 2, Le Zhou1,*, Bernhard Breit2, *
1 College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China
2 Institute for Organic Chemistry, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, Freiburg,
79104,Germany
*Corresponding author:
Fax: +86 29 87092226 (L.Z.), +49 761 2038715(B.B.)
E-mail: zhoulechem@nwsuaf.edu.cn (L.Z.), bernhard.breit@organik.chemie.uni-freiburg.de (B.B.)
Key words: phosphorus self-assembling ligand; homoallylic olefin; Wittig reagent; hydrofor
mylation-Wittig reaction; oxa-Michael reaction; β-pyran
Abstract:
New self-assembled phosphorus ligands are synthesized and used in the rhodium complex
catalyzed hydroformylation-Wittig reaction of homoallylic olefins under optimized condition. A
subsequent Oxa-Michael intramolecular reaction yields β-pyran derivatives (conversion and
diastereoselectivity up to 99%).
1. Introduction
Tandem reactions are suited to generate molecular complexity in a single step starting from simple
starting materials without isolating intermediates, changing reaction conditions, or adding reagents
[1-7]. In this regard the tandem hydroformylation-Wittig olefination reaction developed in our
group is a useful tool to extended carbon skeletons starting from simple alkenes [8]. In our
previous work, 1,1-substituted allylic alcohol derivatives were applied using a directed region and
stereoselective hydroformylation based upon the use of ortho-diphenylphosphanylbenzoate
(o-DPPB) as a catalyst-directing group [9]. Helmchen and co-workers investigated the tandem
hydroformylation-Wittig olefination of chiral allylamines and the subsequent intramolecular
aza-Michael reaction to furnish proline derivatives [10]. Wong and Landis described a one-pot
sequence with stabilized Wittig ylides to produce γ-chiral α,β-unsaturated carbonyl products [11].
To our best knowledge, that the tandem hydroformylation-Wittig olefination of homoallylic
alcohols furnish 7-hydroxy functionalized enoates is well-suited for a subsequent oxa-Michael
addition. This could provide a rapid and interesting entry to the preparation of pyrans, a structural
motif found in numerous natural products [12-16].
The realization of this tandem reaction would request the use of ester-substituted phosphorus
ylides. However, in the previous studies of our directed tandem hydroformylation-Wittig
olefination reactions, we observed hydrogenation of the enoates to form the saturated esters as a
side reaction limiting its utility. In order to solve this problem we thought that the development of
new ligands based on our concept of self-assembling (see Scheme 1) through complementary
hydrogen-bonding might solve this chemoselectivity issue. Based on our previous work of
self-assembling phosphine ligand rhodium (I) catalyst systems, we designed and synthesized four
new ligands depicted in Scheme 2 [17-21].

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2. Experimental
Chromatographic purification of products was accomplished using Machery-Nagel
silica gel 60® (230-400 mesh). Thin layer chromatography was performed on aluminum plates
precoated with silica gel (Merck, 60F ), which were visualized by the quenching of UV
254
fluorescence (λ
= 254 nm), and/or by staining 1% w/v KMnO in 0.5 M aqueous K CO ,
4 2 3
max
followed by heating. Nuclear magnetic resonance spectra were acquired on Bruker Avance 500
1
(500 MHz and 126 MHz for H and 13C respectively), Bruker Avance 400 (400 MHz and 100.6
1
MHz for H and 13C respectively), and Varian Mercury spectrometers (300 MHz and 75.5 MHz
1
1
for H and 13C respectively). All H NMR spectra were reported in parts per million (ppm)
downfield of TMS and were measured relative to the residual solvent signal. All 13C NMR spectra
were reported in ppm relative to the respective residual solvent signal and were obtained with H
decoupling. Data for 1H NMR are described as follows: chemical shift (δ in ppm), multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal), coupling constant (Hz),
integration. Data for 13C NMR spectra are described in terms of chemical shift (δ in ppm). High
resolution mass spectra were obtained on a Finnigan MAT 8200 instrument (CI/NH : 110 eV; EI:
3
70 eV) and on a Bruker maXis-ESI-Q-TOF (ESI-TOF-HRMS).
2.1 General procedure for ligands synthesis
To a solution of diphenylether (29.3 mmol) and 1.86 mL TMEDA (58.7mmol) in 120 mL
absolutely diethyl ether / hexane (1:2) under argon, n-BuLi (28.5 mmol, 2.5 mL in hexane) was
added slowly at 0 ºC. The mixture was stirred for 30 min, then warmed to room temperature and
stirred at this temperature for another 1.5 h. Subsequently,Cl2PNEt2 (43.9 mmol, 1.27 mL) was
slowly added to the above mixture at -78 ºC, followed by stirring at room temperature for 1 h.
After cooling to 0 ºC, HCl gas was bubbled through the solution for 1.5 h then warmed up to room
temperature. The reaction mixture was filtered under argon and washed with CH2Cl2. The
combined organic phases were evaporated to furnish the crude 10-chlorophenoxaphosphine as
yellow oil (5.8 g, 84 %).
n-BuLi (2.21 mmol, 2.5 mL in hexane) was added dropwise to
a solution of
2-bromo-6-tert-butoxy-pyridine (2.21 mmol) in diethyl ether (10 mL) at 0 ºC and then stirred at
room temperature for 30 min. Subsequently, the solution of 10-chlorophenoxaphosphine (3.02
mmol) in diethyl ether (10 mL) was added to the reaction mixture at -76 ºC and stirred for 1 h,
warmed to room temperature and stirred overnight. Subsequently the reaction was quenched with
water and extracted with CH2Cl2. The combined organic phase were dried (MgSO4) and the
solvent was evaporated in vacuo. The crude product was further purified by chromatography
(silica, petroleum ether/ CH2Cl2 = 4:1) and 1.33 g (36%) of protected compound was obtained as a
solid. The solid was dissolved in formic acid and stirred at room temperature for 2 h. After adding
water, the reaction mixture was extracted with CH2Cl2 and the collected organic phases were dried
(MgSO4) and the solvent was removed in vacuo. The crude product was washed with ethyl acetate
to furnish pure L 1 (0.89g, 68%) as yellow solid (20% total yield over all steps).
Synthesis of L 2 started from 2,2′-dibromo-4,4′-di-tert-butylbiphenyl, which was treated following

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the same procedure as for L1. L2 was also obtained as yellow solid (32% total yield).
Synthesis of ligands
3
and
4
was similar to
L
2
and commenced from
N-(6-bromopyridin-2-yl)pivalamide and 3-bromo-1-(tert-butoxy)isoquinoline, respectively. The
desired ligands were obtained as yellow solids (50 % (L3) and 18% (L4) total yield).
2.2 General procedure for rhodium catalyzed Tandem Hydroformylation-Wittig Olefination
Under the conditions shown in table 1 and 2, a mixture of Rh(acac)(CO)2(0.00078 mmol), L 2
(0.016 mmol), homoallylic alcohol (0.78 mmol), Wittig reagent(1.16 mmol), and toluene (10 mL)
were subjected to an autoclave under argon. The autoclave was pressurized with synthesis gas (10
bar) and stirred for 20 h at 80 °C. After cooling to room temperature the autoclave was
depressurized and the reaction mixture was filtered with dichloromethane through a plug of silica
and evaporated under vacuum. The residue was purified by flash column chromatography
(cyclohexane/ethyl acetate) to afford the corresponding enoates products.
3. Results and discussions
The new ligands have the backbone of self-assembling ligands, which can form bidentate ligands
in the coordination sphere of rhodium(I) center. The new L 1 - 4 incorporate the phosphorus donor
into cyclic structures such as phosphaphenoxazine (L1) or a dibenzophosphol system (L2 - 4). We
speculated that such more bulky and rigid substituents at phosphorus might slow down the
undesired hydrogenation reaction of the enoate products.
In a first series of experiments homoallylic alcohol was subjected to the conditions of a tandem
hydroformylation-Wittig olefination reaction under the conditions indicated in table 1. While L1
was most chemoselective in suppressing the undesired enoate hydrogenation, its activity was
rather low (table 1, entry 1). Furthermore a low activity was observed when our standard 6-DPPon
(L5) and its fluorinated derivative were applied (entries 4, 5).The best result in terms of activity in
combination with chemo- and regioselectivity was observed with the self-assembling
dibenzophosphole ligands (entries 2 and 3).
With the optimized catalyst (Rh(I)/L2) in hand, we investigated the influence of syngas pressure
and reaction time (table 2). Hence, better yields were obtained under longer reaction time, but the
difference was not obvious any more after 16 hours. As to the pressure, the yield was poor under 2
bars, and relatively high under 3 bars, but there was no improvement with higher pressure.
Furthermore with the similar conversion, the regioselectivity is the highest under 3 bars. To study
the effect of water on the reaction, the molecular sieve (4Å) was used comparing with the reaction
with additional water. We found that molecular sieve had not obviously effect of improving
conversion, while water in the reaction system inhibited the reaction.
Next, scope and limitations of this tandem reaction with various substituted homoallylic alcohol
derivatives was explored (Table 3). Good yields were obtained for the non-substituted system
(entry 1) and 1-alkyl-substituted derivatives (entries 2-4). However, in case of 1-aryl, alkenyl and
benzyl substituents the yields were lower.
Addition of potassium tert-butoxide to the enoates obtained through the tandem
hydroformylation-Wittig olefination reaction led to a clean and rapid formation of the

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corresponding cis-pyrans according to a thermodynamically controlled oxa-Michael reaction [2].
TLC control showed that the reaction is finished after 20 min. The electron donating group
promoted the cyclization of the hydroxgenoates (Table 4). The hydroxgenoates without electron
donating group (Table 3, entry 6 and 7) gave no conversion even stirred over night under the same
conditions.
4. Conclusions
Four new self-assembling phosphine ligands were prepared and evaluated in comparison with
known 6-DPPon ligands in the tandem rhodium catalyzed hydroformylation-Wittig olefination
reaction of homoallylic alcohol. L2 was identified as the best ligand in terms of activity, chemo-
and regioselectivity. The obtained 7-hydroxy enoates could be cyclized by way of an oxa-Michael
reaction to deliver the corresponding cis-pyrans in excellent yields and diastereoselectivities.
Acknowledgement
This work was financially supported by China Scholarship Council as well as the DFG (German
National Science foundation) IRTG 1038.
Appendices
1
Supplementary data for this article include H and 13C NMR data and MS data of all synthesized
products in this article.
References
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Scheme 1. Self-assembling ligands 6-DPPon [17, 18] .
Scheme 2. Structure of screened ligands
Table1. Influence of ligands in hydroformylation-Wittig reaction catalyzed by rhodium complexa

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Entry
Ligand
Conversionb
1:2:3:4c
%
%
52
1
2
3
4
5
L1
L2
75:8:14:3
70:8:10:12
73:6:14:6
59:9:15:16
67:9:13:11
>99
87
L3+L4
L5
46
L6
60
a
Reaction condition: Rh:L:homoallylic alcohol :Wittig reagent (1:20:1000:1500), Rh(CO)2acac (7.75x10-4mmol), 10 mL toluene, 10 bar
CO/H2(1:1), 80°C,20 h.
b
Determined by GC analysis of the crude reaction mixture.
c
Isolated yield. Isolated by preparative HPLC and determined by MS.
Table 2. Influence of pressure and reaction time on the conversion and yield in the
hydroformylation-Wittig reaction catalyzed by rhodium complex with L2.a
Pressure
Time
(h)
5
Conversionb
Yieldc
[%]
32
Entry
(bar)
10
10
10
10
5
[%]
38
1
2
6
50
40
3
16
20
16
16
16
16
16
16
84
70
4
>99
>99
91
70
5
75
6d
7e
8
5
77
5
0
0
4
93
79
9
3
87
76
10
2
44
37
a
b
c
d
e
Reaction conditions: Rh:L2:homoallylic alcohol:Wittig reagent (1:20:1000:1500), Rh(co)2acac (7.75x10-4mmol), 10 mL toluene, 80°C.
Determined by GC analysis of crude reaction mixture after 16h.
Isolated yield of compound 1 in table 1.
With additional adduct of molecular caves (4Å).
With additional adduct of H2O (1%).
Table 3. Scope of different substituenta

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HF and Wittig
Conversionb
Yieldc
(%)
Number
Substrate
Product
(%)
HO
1
2
87
76
83
HO
HO
>99
3
4
85
13
83
HO
HO
>99
5
6
30
32
63
25
28
43
7
a
Reaction conditions: Rh:L2:homoallylic alcohol:Wittig reagent (1:20:1000:1500), Rh(CO)2acac (7.75x10-4mmol), 10 mL toluene, 3 bar
CO/H2(1:1), 80 °C, 16h.
b
Determined by GC analysis of crude reaction mixture after appropriate reaction time.
C
The isolated yield of trans-isomer of the lineared product. Determined by GC analysis of isolated yield.

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Table 4. Internal Michael reactiona
Conversion Yieldb
Number
1
Substrate
Product
(%)
(%)
0
0
2
3
>99
>99
91
89
4
5
>99
>99
93
87
aReaction conditions:7-hydroxy enoate (0.25mmol) t-BuOK (0.2mmol), 10 mL toluene, 25°C, 20min.
bIsolated yield

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Graphical abstract

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Highlights
Four new self-assembled phosphorus ligands were synthesized.
Homo-allylic olefin was directly used in tandem hydroformylation - Wittig reaction.
Two more carbon 7-hydroxy enoates were formed in one step.
The diastereoselectivity of β-pyran produced by oxa-Michael reaction was up to 99%.