The Goldilocks Principle in Phase Labeling. Minimalist and Orthogonal Phase Tagging for Chromatography-Free Mitsunobu Reaction

Article abstract of DOI:10.1021/acs.joc.8b00014

An inexpensive and chromatography-free Mitsunobu methodology has been developed using low molecular weight and orthogonally phase-tagged reagents, a tert-butyl-tagged highly apolar phosphine, and a water-soluble DIAD analogue. The byproduct of the Mitsunobu reactions can be removed by sequential liquid-liquid extractions using traditional solvents such as hexanes, MeOH, water, and EtOAc. Owing to the orthogonal phase labeling, the spent reagents can be regenerated. This new variant of the Mitsunobu reaction promises to provide an alternative and complementary solution for the well-known separation problem of the Mitsunobu reaction without having to resort to expensive, large molecular weight reagents and chromatography.

Full text of DOI:10.1021/acs.joc.8b00014

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Article
The Goldilocks Principle in Phase Labeling. Minimalist and Orthogonal
Phase Tagging for Chromatography-free Mitsunobu Reaction
Mariann Szigeti, Zoltán Dobi, and Tibor Soós
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00014 • Publication Date (Web): 29 Jan 2018
Downloaded from http://pubs.acs.org on January 31, 2018
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The Goldilocks Principle in Phase Labeling. Minimalist and Orthogonal
Phase Tagging for Chromatography-free Mitsunobu Reaction
Mariann Szigeti, Zoltán Dobi, Tibor Soós*
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Institute of Organic Chemistry, Research Centre of Natural Sciences, Hungarian Academy of Sciences
Magyar tudósok körútja 2., H-1117, Budapest, Hungary
Supporting Information Placeholder
[
]
ABSTRACT: An inexpensive and chromatography-free Mitsunobu methodology has been developed using low molecular
weight and orthogonally phase tagged reagents, a t-butyl-tagged highly apolar phosphine and a water-soluble DIAD ana-
logue. The by-product of the Mitsunobu reactions can be removed by sequential liquid-liquid extractions using traditional
solvents such as hexanes, MeOH, water and EtOAc. Owing to the orthogonal phase labeling, the spent reagents can be re-
generated. This new variant of Mitsunobu reaction promises to provide an alternative and complementary solution for the
well-known separation problem of Mitsunobu reaction without having to resort to expensive, large molecular weight rea-
gents and chromatography.
1. INTRODUCTION
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The Mitsunobu reaction has a privileged position within current toolbox of synthetic organic chemists owing to its scope,
reliability, stereospecificity and mild reaction conditions. Employing azocarboxylate and phosphine reagents (Figure 1),
convenient synthesis of C-O, C-S, C-N, or even C-C bonds become possible from primary or secondary alcohols.1 However,
despite its many attractive features, the use of Mitsunobu reaction is inherently associated with serious practical concerns.
Because of the applied redox activation mode, vast amount of triphenylphosphine oxide and dicarboethoxyhydrazine by-
products are generated and their removal is not only an idiosyncratic problem, but also often require column chromatog-
raphy. Defined by the polarity and solubility of the employed Mitsunobu reagents and their by-products, there is
a“polarity/solubility-window” for product separation. Thus, using classical reagents, chromatography-free and large-scale
Mitsunobu reactions are viable for synthesizing highly apolar or highly polar products.2 However, Mitsunobu reaction af-
fording medium polarity “common organic molecules”, that are often the target of medicinal chemistry programs, often im-
pose significant hurdles on purification and those methods are less amenable for scale-up. These shortcomings have provided
impetus for the development of creative modifications in Mitsunobu reagents and methods. To improve the stoichiometry of
the reagents, various catalytic version of Mitsunobu reactions were described.3 Typically, one of the reagents was regenerated
in a parallel reaction. Even, a fully catalytic system for both reagents has been reported,4 nevertheless, this advancement was
recently challenged.5 Alternatively, efforts have been made to modify both the azocarboxylate and phosphine reactants with
phase labels to facilitate the removal of the excess and spent reagents in the purification process.6 Various approaches have
been explored, including soluble and insoluble supports, fluorous, and ionic tagging.7,8,9 Despite promising advances in
chromatography-free Mitsunobu methods, the relatively high cost of the modified reagents and/or their often tedious synthe-
sis limit their widespread utility both at laboratory and industrial scales. The work we report herein was prompted by the
desire to address this gap in practicality, thus, inexpensive and easily accessible phase labeled Mitsunobu reagents were tar-
geted.
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As part of our interest to develop new methodology for catalyst and reagent immobilization,10 we have embarked upon de-
veloping an operational simple and cost-effective methodology for Mitsunobu reaction purification. We wish to extend the
“polarity/solubility window” of the reagents toward both ends of the polarity scale leaving a large window for common or-
ganic molecules. We also envisioned that the ”Goldilocks Principle” should be employed at the design of the phase labels.
Thus, instead of following the widely explored practice of appending large molecular weight phase labels, we aimed to uti-
lize minimal-size phase tags which still ensure the effective separation of the reagents from a “common organic molecule”
without compromising their molecular weight, complexity and reagent cost. Additionally, a parallel use of polar and apolar
phase labels was conceived for the azocarboxylate and phosphine reagents to offer the potential of regeneration.
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Figure 1. Classical and minimally phase tagged Mitsunobu reagents
We began our investigation to select appropriate reagents for the envisioned low molecular weight and orthogonal-phase-
labeled Mitsunobu methodology. For the DEAD analog, we built upon a recently developed water soluble low-molecular
weight (dimethylamino)methylazocarbonamide carboxylate DMAM (E, Figure 1). As Furkert and Brimble reported, their
modified azomonocarboxylate E has a similar reactivity to DEAD and it is easily prepared from commercially available
starting materials9f in a scalable manner. Regarding the phosphine reagent, a highly apolar one was targeted which enables its
binary separation from a “common organic molecule”. As we have recently reported that trifluoromethyl groups (essentially
6 of them) render triphenylphosphine so apolar that the immobilization of its Pd(0) complex is possible,10a we set out our
investigation with this phosphine B (Figure 1).
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2. RESULTS AND DISCUSSION
First, we sought to examine the utility of modified reagents, thus, we explored the Mitsunobu reaction of m-anisic acid (1)
and (S)-methyl lactate (2). In control experiments, we performed the Mitsunobu reaction with the most common PPh3/DIAD
reagents in THF and Me-THF (Table 1, entries 1, 2). Then the applicability of the selected CF3 tagged phosphine (B) with
combination of DIAD (D) (Table 1, Entry 3) was investigated. The reaction was found to be sluggish, after 24 hours, the
product was isolated with rather poor yield. We reasoned that the nucleophilicity of the phosphine should be enhanced via
replacing the CF3 groups with electron donating and highly lipophilic alkyl tags. To minimize the steric and electronic inter-
ference with the nucleophilic site, we envisaged an alkylated analogue C that has t-butyl tags in all meta positions of the
phenyl residue.11a Then, we were pleased to observe that the modified phosphine C exhibited activity parallel to that of PPh3
in Mitsunobu esterification (Table 1, Entry 4). Finally, the water-soluble azocarboxylate compound DMAM (E) was tested in
combination with the alkylated phosphine C. Gratifyingly, this combination afforded the expected Mitsunobu product in
yields close to previous test reaction (Table 1, entry 4 vs. 5). It is worth mentioning that phosphine C has received enhanced
interest in cross-coupling reactions,11b although it is not yet commercially available. Nevertheless, it is readily prepared from
inexpensive starting materials in 40 g scale without having to resort to chromatography.
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Table 1. Screening of the Mitsunobu reagentsa
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Entry Phosphine Azo
Solvent
Yield
(%)b
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compound
DIAD (D)
DIAD (D)
DIAD (D)
DIAD (D)
DMAM (E)
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PPh3(A)
THF
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87
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80
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PPh3(A)
Me-THF
Me-THF
Me-THF
Me-THF
3c
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B
C
C
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a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol, 1.0 equiv), triaryl phosphine (1.0 mmol, 1.0 equiv), azocarboxylate com-
pound (1.0 mmol, 1.0 equiv), solvent (2.0 mL), 2 h reaction time. b Isolated yield after chromatography. c 24 h reaction time.
Encouraged by the above results, we next sought to examine the feasibility of the chromatography-free and orthogonal sepa-
ration of the minimally decorated Mitsunobu reagents C/E from the product. Among the possible separation methodologies,
we wished to employ the liquid–liquid extraction. Thus, using traditional solvents, the separation would be not only inexpen-
sive and simple but also more amenable to scale up.12 To assess the possibility of binary separation of tagged phosphine C
from a “common organic molecule”, its polarity and solubility was evaluated. The t-butylated phosphine C and surprisingly
its oxide are such highly apolar compounds that they travel near the solvent front when they are subjected to thin layer chro-
matography (silica/hexanes). Furthermore, they are soluble in hexanes and insoluble in methanol-water (3:2) mixture. Im-
portantly, this aqueous-organic blended solvent is able to dissolve common organic molecules positioned across a broad
polarity range.10c Based on this, a sequential extractive procedure could be developed (Figure 2). The Mitsunobu reaction was
performed in Me-THF and the reaction mixture was diluted with hexanes and extracted with water to remove the excess of
the water-soluble azocarboxylate E and its spent hydrazine derivative (DMAM-H2). Then, the hexanes solution was extract-
ed with methanol-water (3:2). Owing to the unrivaled hydrophobicity of the water, the t-butyl tagged phosphine C and its
oxide remained in the hexanes phase and the Mitsunobu product moved to the aqueous-organic phase. Finally, the aqueous
phase was diluted with brine and then extracted with ethyl acetate. After evaporation of the organic phase, the Mitsunobu
product was obtained.
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Figure 2. Flowchart of the work-up process for low molecular weight and orthogonally tagged Mitsunobu methodology.
After identification of the minimally decorated azocarboxylate E and phosphine C as easily and orthogonally removable
reagents for Mitsunobu reaction, their utility was explored using various pro-nucleophiles and alcohols. It was also an objec-
tive to use the above extractive method for work-up to demonstrate its broad utility. Additionally, within the product, the
hydrazine by-product and the phosphine oxide residue were also determined. To gain comparable results, the reactions were
also performed with the traditional PPh3/DIAD reagent combination and in those cases, the products were isolated by chro-
matography (Scheme 1). First, the model substrates m-anisic acid (1) and (S)-methyl lactate (2) were coupled. We found that
the Mitsunobu reaction with DEAD/PPh3 reagent afforded the ester 3 in Me-THF with 87% isolated yield. With the tagged
reagents, the above extractive protocol provided the ester 3 with 76% yield, however, the product contained only 0.6% phos-
phine oxide impurity and no traces of hydrazine by-product could be detected. Next, the extension of the reaction scope to-
ward (S)-Methyl lactate (2) esterification and amidation were explored (Scheme 1). We were pleased to find that the esterifi-
cation of o-anisic acid (4), p-anisic acid (10), trimethylgallic acid (7) and the amidation with phtalimide (9) were more effi-
cient with C/E than with the classical PPh3/DIAD reagents. Using modified reagents, the esterification of 2-furoic acid with
allyl alcohol and propargyl alcohol also afforded esters 14 and 15 in excellent yields, even better yields than with traditional
reagent combination after chromatography. The reaction of m- or p-anisic acid, 2-furoic acid and p-cianophenol with (S)-
methyl lactate provided esters 3, 5, 8, 11 and the benzylation with benzyl alcohol or with p-anisyl alcohol of 2-furoic acid
delivered esters 12, 13 with yields comparable to those of non-tagged DIAD/PPh3 reagents. Alkylations of trimethylgallic
acid proceed smoothly by using allyl alcohol or phenylethanol (17, 19), although a slightly lower isolated yield was observed
with modified reagents. It was also established that this minimalist phase tagging method has its own limitations. When the
Mitsunobu products have low solubility in aqueous methanol (typically nitro and halogenated compounds), the extraction of
the desired compounds was less efficient which lowered the isolated yields (6, 16). Nevertheless, for highly apolar or highly
polar products, the classical reagents often enable chromatography-free Mitsunobu reaction.2 Finally, it is important to note
that desired products could be isolated with purities higher than 95% (with high stereoselectivity when chiral lactic ester was
used as a substrate), the phosphine oxide residue in the isolated products was in the range of 0.5-3% and the hydrazine by-
product was under the detection limit in every case.
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Scheme 1. Comparison of classical and low molecular weight phase tagged reagents in Mitsunobu reactions.
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O
O
O
O
O
O
O
O
O
O
O
O
OMe
O
O
OMe
OMe
O
O
OMe
OMe
O
OMe
MeO
O
O
MeO
OMe
MeO
NO2
OMe
OMe
3 76%a
0.6%b
87%c
4 88%a
0.5%b
86%c
5 71%a
1.4%b
82%c
6 39%a
2.3%b
88%c
7 84%a
1.3%b
79%c
8 66%a
0.6%b
77%c
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O
O
O
O
O
O
OMe
O
O
N
OMe
OMe
O
O
O
O
MeO
NC
OMe
O
9 86%a
0.3%b
73%c
10 78%a
1.4%b
11 69%a
1.2%b
12 64%a
1.9%b
13 78%a
1.5%b
72%c
80%c
83%c
84%c
O
O
O
O
O
O
O
O
O
O
O
O
O
MeO
OMe MeO
OMe
O
O
Cl
OMe
OMe
14 92%a
2.0%b
15 93%a
2.0%b
16 25%a
2.7%b
17 74%a
1.4%b
18 48%a
1.1%b
19 76%a
3.0%b
92%c
81%c
74%c
71%c
81%c
85%c
aReaction conditions: pro-nucleophile (1.0 mmol, red colored), alcohol (1.0 mmol, 1.0 equiv, blue colored), phase tagged
phosphine (C) (1.0 mmol, 1.0 equiv), DMAM (E) (1.0 mmol, 1.0 equiv), Me-THF (2.0 mL), 2 h reaction time. Crude prod-
uct was obtained by extraction process. Method A. Residual phosphine oxide content, determined by 1H NMR of the crude
b
c
products. Reaction conditions: nucleophile (1.0 mmol), alcohol (1.0 mmol, 1.0 equiv), triphenyl phosphine (A) (1.0 mmol,
1.0 equiv), DIAD (D) (1.0 mmol, 1.0 equiv), Me-THF (2.0 mL), 2 h reaction time. Isolated yields after chromatography.
Method B
An additional advantage of this orthogonal phase tagging approach is that it enables the regeneration of spent reagents. Ac-
cordingly, after the extractive separation, the hydrazine DMAM-H2 can be re-oxidize with Oxone according to literature
procedure9f and the phosphine oxide can be reduced with trichloro-silane in the presence of triethylamine.
3. CONCLUSIONS
In summary, we have demonstrated that a convenient and inexpensive chromatography-free Mitsunobu methodology can be
developed using minimal-size and orthogonal phase tags for the reagents. This “tag-economic” approach offers an alternative
to the widely explored large-molecular-weight phase-labeled Mitsunobu reagents. The applied reagents are either known
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(DMAM, E) or conveniently prepared in multidecagram scale from commercially available inexpensive materials. This rea-
gent combination exhibits reactivity that is similar to that of classical PPh3/DIAD in Mitsunobu reaction. Most importantly,
the hydrazine and phosphine oxide by-products formed during the Mitsunobu reactions are easily removed by liquid-liquid
extractive protocol using traditional solvents and solvent mixtures and both spent reagents can be easily regenerated due to
the orthogonal phase labeling. We anticipate that these advances might result in the further valorization of Mitsunobu reac-
tion and trigger to unlock even more of its potential in organic synthesis and medicinal chemistry. Further studies to explore
the utility of minimalist tag approach are ongoing in our laboratory and will be reported in due course.
4. EXPERIMENTAL SECTION
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4.1. Materials and Methods. NMR spectra were acquired on Varian spectrometer running at 500 MHz, 125 MHz
1
and 202 MHz for H, 13C and 31P, respectively. Chemical shifts (δ) were reported in ppm relative to residual solvent signals
1
(CHCl3, 7.26 ppm for H NMR, CDCl3, 77.00 ppm for 13C NMR). The following abbreviations were used to indicate the
1
multiplicity in H NMR spectra: s, singlet; d, doublet; t, triplet; m, multiplet. 13C NMR spectra were acquired on a broad
band decoupled mode. High resolution mass spectra were obtained on a Q-TOF Premier mass spectrometer (Waters Corpora-
tion) in positive electronspray mode or EI on a GCTOF spectrometer (Jeol AccuTOF T200GC). Melting points were deter-
mined on a SRS MPA100 apparatus and are uncorrected. Column chromatography was performed with RediSep Rf Gold
Silica Flash Chromatography Colum (20-40 µm). TLC analysis was performed on silica gel 60 F254-coated aluminium sheets
(Merck). Visualization was accomplished by means of ultraviolet (UV) irradiation at 254nm and/or by staining with potassi-
um permanganate. Enantiomeric excess (ee) of the products was determined by chiral stationary phase HPLC (Chiralpak IC
or Daicel CHIRALCEL OK columns). Optical rotation measurements were carried out with an ABL&E Jasco P-2000 auto-
matic polarimeter at λ = 589 nm, the concentration (c) expressed in g/100 mL in chloroform. Commercially available materi-
als were purchased from Sigma-Aldrich and were used without further purification. All reactions were carried out under N2
atmosphere. THF and Me-THF were distillated under nitrogen directly over sodium/benzophenone. DMAM (E) was pre-
pared according to literature procedure.9f
4.2. procedure for Mitsunobu reaction with phase tagged phosphine (C) and DMAM (E) (Method A). The
pro-nucleophile (1.0 mmol, 1.0 equiv) and tris(3,5-di-tert-butylphenyl)phosphine (1.0 mmol, 1.0 equiv) were dissolved in
Me-THF (2 mL) at room temperature. Under N2 atmosphere, the appropriate alcohol (1.0 mmol, 1.0 equiv) was added fol-
lowed by the dropwise addition of DMAM (1.0 mmol, 1.0 equiv). When the reaction was completed (monitored by TLC),
the general work-up procedure was used to obtain the corresponding product.
4.3. General work-up procedure for Mitsunobu reaction: orthogonal phase tagging approach. The crude reac-
tion mixture was transferred to a separatory funnel and 20 mL of hexanes were added. The mixture was washed with water
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(3x5 mL) then the hexanes solution was extracted with methanol-water (3:2) mixture. The combined methanol-water mixture
was diluted with brine (50 mL) and was extracted with ethyl acetate (3x20 mL). The combined ethyl acetate phase was dried
over Na2SO4 and the solvent was evaporated at reduced pressure. In several cases, DCM was used to transfer the products to
a 4 mL vial.
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4.4. General procedure for Mitsunobu reaction with PPh3 and DIAD (Method B). The appropriate pro-
nucleophile (1.0 mmol) and PPh3 (1.0 mmol, 1.0 equiv) were dissolved in Me-THF (2 mL) at room temperature, under N2
atmosphere. The appropriate alcohol (1.0 mmol, 1.0 equiv) was added to the mixture followed by the dropwise addition of
DIAD (1.0 mmol, 1.0 equiv). When the reaction was completed (monitored by TLC), the solvent was evaporated and the
residue was purified by column chromatography (SiO2, hexanes: ethyl acetate mixture).
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Tris(3,5-di-tert-butylphenyl)phosphine11a (C). An oven dried, 2l, 4-necked round-bottom flask was equipped with
KPG stirrer, gas inlet, outlet, thermometer and dropping funnel. Under continuous N2 flush, 1-bromo-3,5-di-tert-
butylbenzene (134.62 g, 0.50 mol, 5 equiv) was dissolved in dry THF (600 mL) and the resulting solution was cooled to -
78°C. The dropping funnel was charged with 200 mL BuLi solution (2.5M in Hexanes, 0.5 mol, 5 equiv) and the solution
was introduced to the reaction mixture dropwise to maintain the temperature below -70°C. The formation of aryllithium
compound was monitored by GC (small sample was quenched with water). When the reaction was completed, 8.72 mL
(13.73 g, 0.10 mol, 1 equiv) of freshly distillated PCl3 was dissolved in dry THF (50 mL) and was added to the suspension at
-70°C. After stirring at that temperature, the reaction mixture was warmed to room temperature while becoming a yellowish
solution. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2x500 mL). The separated organic
layer was washed with saturated NaHCO3 (300 mL) and brine (300 mL) then dried over Na2SO4 and concentrated. The re-
sulting crude mixture was purified by crystallization from cold methanol to give the product (47.80 g, 80%) as a white pow-
der. 1H NMR (500 MHz, CDCl3) δ 7.37 (s, 3H), 7.09 (d, J=8.2, 6H), 1.23 (s, 54H); 13C NMR (125 MHz, CDCl3) δ 150.4 (d,
J=6.7 Hz), 136.7 (d, J=7.9 Hz), 128.0 (d, J=19.2 Hz), 122.3, 34.8, 31.4; 31P NMR (202 MHz, CDCl3) δ -3.24 (s)
Tris(3,5-di-tert-butylphenyl)phosphine oxide (C-oxide). Synthesized according to literature procedure.13 1H NMR
(500 MHz, CDCl3) δ 7.59 (s, 3H), 7.48 (d, J=14.8, 6H), 1.26 (s, 54H); 13C NMR (125 MHz, CDCl3) δ 150.9 (d, J=12.1 Hz),
130.2 (d, J=105.1 Hz), 126.6 (d, J=10.9 Hz), 126.2, 35.0, 31.3; 31P NMR (202 MHz, CDCl3) δ 32.97 (s); HRMS (ESI) calcd
for C42H64OP [M+H]+ 615.4695, found: 615.4680
Reduction of Tris(3,5-di-tert-butylphenyl)phosphine oxide.14 Tris(3,5-di-tert-butylphenyl)phosphine oxide (10.76 g,
17.5 mmol) and triethylamine (24.4 mL, 175 mmol, 10 equiv) were dissolved in dry toluene (100 mL) and under N2 atmos-
phere at 0°C, HSiCl3 (5.30 mL, 52.5 mmol, 3 equiv) was added. After stirring at 0°C for 30 minutes, the reaction mixture
was refluxed and the formation of triarylphosphine was monitored by TLC (Hexanes: Ethyl acetate 3:1). When the reaction
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was completed (within 2 hours), the mixture was cooled to 0°C and was quenched with sat. Na2CO3 solution (10 mL) then
was filtered through a plug of Celite and washed with toluene. The organic layer was separated and dried over Na2SO4 and
concentrated. The resulting crude mixture was crystallized from cold methanol to afford 9.17 g (87%) of Tris(3,5-di-tert-
butylphenyl)phosphine.
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1-methoxy-1-oxopropan-2-yl 3-methoxybenzoate (3). Method A: 181 mg (76%); Method B Hexanes: Ethyl acetate
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5:1): 207 mg (87%); Rf (Hexanes:Ethyl acetate 5:1)= 0.24; colorless liquid; H NMR (500 MHz, CDCl3) δ 7.67-7.69 (m,
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1H), 7.59 (s, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.10-7.13 (m, 1H), 5.33 (q, J=7.0 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 1.62 (d, J=7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 165.8, 159.6, 130.7, 129.4, 122.3, 119.8, 114.3, 69.1, 55.4, 52.3, 17.0;
HRMS (ESI) calcd for C12H14O5Na [M+Na]+ 261.0739, found: 261.0735; 99% ee (3) Enantioselectivity was determined by
HPLC analysis with Chiralpak IC column, 10% ethanol in heptane, 1 mL/min, λ=296.4 nm, retention times: minor: 6.623
min, major: 7.328 min; [α]D20-24.6 (c 0.88, CHCl3).
1-methoxy-1-oxopropan-2-yl 2-methoxybenzoate (4). Method A: 209 mg (88%); Method B (Hexanes: Ethyl acetate
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5:1): 204 mg (86%); Rf (Hexanes:Ethyl acetate 5:1) = 0.18; colorless liquid; H NMR (500 MHz, CDCl3) δ 7.89-7.91 (m,
1H), 7.45-7.49 (m, 1H), 6.98 (t, J=7.6 Hz, 2H), 5.33 (q, J=7.0 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 1.59 (d, J=7.1 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 171.4, 165.0, 159.6, 133.9, 132.0, 120.1, 119.1, 112.1, 68.7, 56.0, 52.3, 17.0; HRMS (ESI) calcd
for C12H14O5Na [M+Na]+ 261.0739, found: 261.0741; 99% ee (4) Enantioselectivity was determined by HPLC analysis with
Chiralpak IC column, 50% ethanol in heptane, 1 mL/min, λ= 296.4 nm, retention times: minor: 4.958 min, major: 5.755 min;
[α]D20-3.3 (c 1.01, CHCl3).
1-methoxy-1-oxopropan-2-yl 4-methoxybenzoate (5). Method A: 169 mg (71%); Method B (Hexanes: Ethyl acetate
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3:1): 195 mg (82%); Rf (Hexanes:Ethyl acetate 3:1) = 0.40; H NMR (500 MHz, CDCl3) δ 8.03 (d, J=8.9 Hz, 2H), 6.92 (d,
J=8.9 Hz, 2H), 5.30 (q, J=7.0 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 1.60 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
171.4, 165.6, 163.7, 131.9, 121.8, 113.6, 68.8, 55.4, 52.3, 17.1; HRMS (ESI) calcd for C12H14O5Na [M+Na]+ 261.0739,
found: 261.0734; 99% ee (5) Enantioselectivity was determined by HPLC analysis with Chiralpak IC column, 50% ethanol
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in heptane, 1 mL/min, λ= 256.4 nm, retention times: minor: 4.583 min, major: 5.410 min; mp.: 61-62°C (EtOAc); [α]D
-
36.4 (c 1.02, CHCl3).
1-methoxy-1-oxopropan-2-yl 4-nitrobenzoate (6). Method A: 99 mg (39%); Method B (Hexanes: Ethyl acetate 3:1):
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222 mg (88%); Rf (Hexanes:Ethyl acetate 3:1) = 0.52; yellowish liquid; H NMR (500 MHz, CDCl3) δ 8.23-8.29 (m, 4H),
5.37 (q, J=7.0 Hz, 1H), 3.78 (s, 3H), 1.65 (d, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.6, 164.0, 150.8, 134.8,
130.9, 123.5, 69.8, 52.5, 17.0; HRMS (EI) calcd for C11H11NO6 [M]+ 253.0586, found: 253.0578; 98% ee (6) Enantioselec-
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tivity was determined by HPLC analysis with Chiralpak IC column, 50% ethanol in heptane, 1 mL/min, λ= 258.4 nm, reten-
tion times: minor: 5.433 min, major: 6.941 min; [α]D20-23.3 (c 1.01, CHCl3).
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1-methoxy-1-oxopropan-2-yl 3,4,5-trimethoxybenzoate (7). Method A: 250 mg (84%); Method B (Hexanes: Ethyl
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acetate 3:1): 235 mg (79%); Rf (Hexanes:Ethyl acetate 3:1) = 0.19; H NMR (500 MHz, CDCl3) δ 7.32 (s, 2H), 5.31 (q,
J=7.0 Hz, 1H), 3.90 (s, 9H), 3.76 (s, 3H), 1.62 (d, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 165.5, 152.9, 142.7,
124.3, 107.2, 69.2, 60.9, 56.2, 52.3, 17.0; HRMS (ESI) calcd for C14H18O7Na [M+Na]+ 321.0950, found: 321.0956; 98% ee
(7) Enantioselectivity was determined by HPLC analysis with Chiralpak IC column, 100% ethanol, 1 mL/min, λ= 268.4 nm,
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retention times: minor: 4.512 min, major: 5.581 min; mp.: 78-79°C (EtOAc); [α]D20-23.8 (c 1.01, CHCl3).
1-methoxy-1-oxopropan-2-yl furan-2-carboxylate (8). Method A: 131 mg (66%); Method B (Hexanes: Ethyl acetate
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3:1): 152 mg (77%); Rf (Hexanes:Ethyl acetate 3:1) = 0.28; colorless liquid; H NMR (500 MHz, CDCl3) δ 7.58-7.59 (m,
1H), 7.24-7.26 (m, 1H), 6.50-6.51 (m, 1H), 5.31 (q, J=7.0 Hz, 1H), 3.75 (s, 3H), 1.59 (d, J=7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 170.8, 157.7, 146.7, 143.9, 118.8, 111.9, 68.8, 52.4, 17.0; HRMS (ESI) calcd for C9H10O5Na [M+Na]+
221.0426, found: 221.0422; 99% ee (8) Enantioselectivity was determined by HPLC analysis with Chiralpak IC column,
50% ethanol in heptane, 1 mL/min, λ= 252.4 nm, retention times: minor: 4.758 min, major: 6.360 min; [α]D20-28.2 (c 0.83,
CHCl3).
Methyl 2-(1,3-dioxoisoindolin-2-yl)propanoate (9). Method A: 200 mg (86%); Method B (Hexanes: Ethyl acetate
1
3:1): 170 mg (73%); Rf (Hexanes:Ethyl acetate 3:1) = 0.37; colorless liquid; H NMR (500 MHz, CDCl3) δ 7.84-7.86 (m,
2H), 7.72-7.73 (m, 2H), 4.96 (q, J=7.3 Hz, 1H), 3.73 (s, 3H), 1.69 (d, J=7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.1,
167.3, 134.1, 131.9, 123.4, 52.7, 47.4, 15.2; HRMS (ESI) calcd for C12H11NO4Na [M+Na]+256.0586, found: 256.0584; 99%
ee (9) Enantioselectivity was determined by HPLC analysis with Daicel CHIRALCEL OKcolumn, 50% ethanol in heptane, 1
mL/min, λ= 240.4 nm, retention times: major: 9.057 min, minor: 10.176 min; [α]D20+8.2 (c 0.98, CHCl3).
Methyl 2-(4-methoxyphenoxy)propanoate (10). Method A: 164 mg (78%); Method B (Hexanes: Ethyl acetate 3:1):
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151 mg (72%); Rf (Hexanes:Ethyl acetate 3:1) = 0.36; yellowish liquid; H NMR (500 MHz, CDCl3) δ 6.79-6.84 (m, 4H),
4.67 (q, J=6.8 Hz, 1H), 3.74 (s, 6H), 1.58 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.8, 154.5, 151.6, 116.5,
114.6, 73.6, 55.6, 52.1, 18.6; HRMS (ESI) calcd for C11H14O4Na [M+Na]+ 233.0790, found: 233.0800; 96% ee (10) Enanti-
oselectivity was determined by HPLC analysis with Daicel CHIRALCEL OK column, ethanol, 1 mL/min, λ= 240.4 nm,
retention times: major: 6.127 min, minor: 7.666 min; [α]D20+29.7 (c 1.02, CHCl3).
Methyl 2-(4-cyanophenoxy)propanoate (11). Method A: 141 mg (69%); Method B (Hexanes: Ethyl acetate 3:1) :
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164 mg (80%); Rf (Hexanes:Ethyl acetate 3:1) = 0.26; yellowish liquid; H NMR (500 MHz, CDCl3) δ 7.57 (d, J=9.0 Hz,
2H), 6.91 (d, J=9.0 Hz, 2H), 4.81 (q, J=6.8 Hz, 1H), 3.77 (s, 3H), 1.65 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
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171.5, 160.7, 134.0, 118.9, 115.5, 104.8, 72.4, 52.5, 18.3; HRMS (ESI) calc. for C11H12NO3 [M+H]+ 206.0817, found:
206.0811; 96% ee (11) Enantioselectivity was determined by HPLC analysis with Daicel CHIRALCEL OK column, ethanol,
1 mL/min, λ= 246.4 nm, retention times: major: 5.451 min, minor: 7.414 min; [α]D20+42.3 (c 1.02, CHCl3).
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Benzyl furan-2-carboxylate15 (12). Method A: 129 mg (64%); Method B (Hexanes: Ethyl acetate 5:1): 168 mg
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(83%); Rf (Hexanes:Ethyl acetate 5:1) = 0.40; colorless liquid; H NMR (500 MHz, CDCl3) δ 7.57 (d, J=0.7 Hz, 1H), 7.43-
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7.44 (m, 2H), 7.32-7.39 (m, 3H), 7.20 (dd, J=3.4, 0.7 Hz, 1H), 6.49 (dd, J=3.4, 1.7Hz, 1H), 5.35 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 158.5, 146.4, 144.6, 135.6, 128.6, 128.3, 128.3, 118.1, 111.8, 66.5; HRMS (ESI) calcd for C12H10O3Na
[M+Na]+ 225.0528, found: 225.0529.
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4-methoxybenzyl furan-2-carboxylate (13). Method A: 181 mg (78%); Method B (Hexanes: Ethyl acetate 5:1): 195
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mg (84%); Rf (Hexanes:Ethyl acetate 5:1) = 0.29; yellowish liquid; H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.37 (d,
J=8.4 Hz, 2H), 7.17-7.18 (m, 1H), 6.90 (d, J=8.5 Hz, 2H), 6.48-6.49 (m, 1H), 5.28 (s, 2H), 3.81 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 159.8, 158.6, 146.3, 144.7, 130.3, 127.8, 118.0, 114.0, 111.8, 66.4, 55.3; HRMS (ESI) calcd for C13H12O4Na
[M+Na]+ 255.0633, found: 255.0635.
Allyl furan-2-carboxylate16 (14). Method A: 140 mg (92%); Method B (Hexanes: Ethyl acetate 5:1): 123 mg (81%);
Rf (Hexanes:Ethyl acetate 5:1) = 0.48; yellowish liquid; 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.18 (d, J=2.9 Hz, 1H),
6.48-6.49 (m, 1H), 5.96-6.01 (m, 1H), 5.38 (dd, J=17.2, 1.3 Hz, 1H), 5.26 (dd, J=10.4, 1.0 Hz, 1H), 4.78 (d, J=5.8 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 158.2, 146.3, 144.5, 131.8, 118.6, 117.9, 111.7, 65.3; HRMS (ESI) calcd for C8H8O3Na
[M+Na]+ 175.0371, found: 175.0371.
Prop-2-yn-1-yl furan-2-carboxylate16 (15). Method A: 139 mg (93%); Method B (Hexanes: Ethyl acetate 3:1): 111
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mg (74%); Rf (Hexanes:Ethyl acetate 3:1) = 0.42; yellowish liquid; H NMR (500 MHz, CDCl3) δ 7.57-7.58 (m, 1H), 7.21
(d, J=3.5, 1H), 6.50 (dd, J=3.4, 1.7 Hz, 1H), 4.87 (d, J=2.4Hz, 2H), 2.51 (t, J=2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
157.6, 146.7, 143.9, 118.8, 111.9, 77.3, 75.3, 52.2; HRMS (ESI) calcd for C8H6O3Na [M+Na]+ 173.0215, found: 173.0214.
4-chlorobenzyl furan-2-carboxylate17 (16). Method A: 59 mg (25%); Method B (Hexanes: Ethyl acetate 3:1): 168
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mg (71%); Rf (Hexanes:Ethyl acetate 3:1) = 0.43; yellowish liquid; H NMR (500 MHz, CDCl3) δ 7.58-7.59 (m, 1H), 7.34-
7.38 (m, 4H), 7.20-7.21 (m, 1H), 6.50-6.51 (m, 1H), 5.30 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 158.4, 146.5, 144.4, 134.3,
134.1, 129.7, 128.8, 118.3, 111.9, 65.7; HRMS (ESI) calcd for C12H9ClO3Na [M+Na]+ 259.0138, found: 259.0138.
Allyl benzoate18 (17). Method A: 120 mg (74%); Method B (Hexanes: Ethyl acetate 5:1): 131 mg (81%); Rf (Hex-
anes:Ethyl acetate 5:1) = 0.53; colorless liquid;1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz, 2H), 7.56 (t, J=7.4 Hz,
1H), 7.44 (t, J = 7.7 Hz, 2H), 6.01-6.09 (m, 1H), 5.42 (dd, J = 17.2, 1.4 Hz, 1H), 5.29 (dd, J = 10.5, 1.2 Hz, 1H), 4.83 (d,
J=5.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 166.2, 132.9, 132.2, 130.2, 129.6, 128.3, 118.1, 65.5
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Allyl 3,4,5-trimethoxybenzoate19 (18). Method A: 121 mg (48%); Method B (Hexanes: Ethyl acetate 5:1): 214 mg
(85%); Rf (Hexanes:Ethyl acetate 5:1) = 0.37; white solid;1H NMR (500 MHz, CDCl3) δ 7.31 (s, 2H), 6.04 (ddd, J=16.1,
10.9, 5.7 Hz, 1H), 5.41 (dd, J=17.2, 1.4 Hz, 1H), 5.28 (dd, J=10.4, 1.1 Hz, 1H), 4.81 (d, J=5.7 Hz, 2H), 3.90 (s, 9H);13C
NMR (125 MHz, CDCl3) δ165.8, 152.9, 142.3, 132.3, 125.1, 118.2, 106.9, 65.7, 60.9, 56.2.
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Phenethyl 3,4,5-trimethoxybenzoate20 (19). Method A: 240 mg (76%); Method B (Hexanes: Ethyl acetate 3:1): 291
mg (92%); Rf (Hexanes:Ethyl acetate 3:1) = 0.37; colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.24-7.33 (m, 7H), 4.52 (t,
J=6.9Hz, 2H), 3.90 (s, 3H), 3.88 (s, 6H), 3.07 (t, J=6.9Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 166.0, 152.9, 142.2, 137.9,
129.0, 128.5, 126.6, 125.3, 106.8, 65.4, 60.8, 56.2, 35.3.
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ASSOCIATED CONTENT
Supporting Information
Supporting Information: Copies of NMR spectra and HPLC chromatograms
AUTHOR INFORMATION
Corresponding Author
* e-mail: soos.tibor@ttk.mta.hu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Research, Development and Innovation Office (K-116150).
REFERENCES
(1) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380-2382. (b) Mitsunobu, O. Synthesis, 1981, 1-28. (c)
Huges, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164.
(2) Recent examples for large-scale Mitsunobu reactions using classical reagents: (a) Li, X.; Reuman, M.; Russell, R. K.;
Youells, S.; Beish, S.; Hu, Z.; Branum, S.; Jain, N.; Sui, Z. Org. Process Res. Dev. 2007, 11, 731-738. (b) Busacca, C. A.;
Cerreta, M.; Dong, Y.; Eriksson, M. C.; Farina, V.; Feng, X. W.; Kim, J.; Lorenz, J. C.; Sarvestani, M.; Simpson, R.; Varsolo-
na, R.; Vitous, J.; Campbell, S. J.; Davis, M. S.; Jones, P-J.; Norwood, D.; Qiu, F.; Beaulieu, P. L.; Duceppe, J-S.; Haché, B.;
Brong, J.; Chiu, F-T.; Curtis, T.; Kelley, J.; Lo, Y. S.; Powner, T. H. Org. Process Res. Dev. 2008, 12, 603-613. (c) Palmer, A.
M.; Webel, M.; Scheufler, C.; Haag, D.; Müller, B. Org. Process Res. Dev. 2008, 12, 1170-1182. (d) Connolly, T. J.; Au-
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guscinski,W.; Fung, P.; Galante, R.; Liu, W.; McGovern, L.; Sebastian, A.; Shen, X.; Shi, X.; Wilk, B.; Varsalona, R.; Zhong,
H. Org. Process Res. Dev. 2010, 14, 868-877. (e) Ford, J. G.; Pointon, S. M.; Powell, L.; Siedlecki, P. S. Org. Process Res.
Dev. 2010, 14, 1078-1087. (f) de Koning, P. D.; McAndrew, D.; Moore, R.; Moses, I. B.; Boyles, D. C.; Kissick, K.;
Stanchina, C. L.; Cuthbertson, T.; Kamatani, A.; Rahman, L.; Rodriguez, R.; Urbina, A.; Sandoval, A.; Rose, P. R. Org. Pro-
cess Res. Dev. 2011, 15, 1018-1026. (g) Lukin, K.; Kishore, V.; Gordon, T. Org. Process Res. Dev. 2013, 17, 666-671. (h) Yu,
J.; Wang, J. Org. Process Res. Dev. 2017, 21, 133-137. (i) Wang, Y.; Milkiewicz, K. L.; Kaufman, M. L.; He, L.; Landmesser,
N. G.; Levy, D.V.; Allwein, S.P.; Christie, Olsen, M. A.; Neville, C. J.; Muthukumaran, K. Org. Process Res. Dev. 2017, 21,
408-413.
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(3) (a) But, T. Y. S.; Toy, P. H. J. Am. Chem. Soc. 2006, 128, 9636-9637. (b) But, T. Y. S.; Toy, P. H. Synlett 2010, 7, 1115-
1117. (c) Hirose, D.; Taniguchi, T.; Ishibashi, H. Angew. Chem. Int. Ed. 2013, 52, 4613-5617. (d) Hirose, D.; Gazvode, M.;
Košmrlj, J.; Taniguchi, T. Chem. Sci. 2016, 7, 5148-5159. (e) März, M.; Chudoba, J.; Kohouta, M.; Cibulka, R. Org. Biomol.
Chem. 2017, 15, 1970-1975.
(4) Buonomo, J. A.; Aldrich, C. C. Angew. Chem. Int. Ed. 2015, 54, 13041-13044.
(5) Hirose, D.; Gazvoda, M.; Košmrlj, J.; Taniguchi, T. Org. Lett. 2016, 18, 4036-4039.
(6) Selected reviews on Mitsunobu reaction: (a) Dandapani, S.; Curran, D. P. Chem. Eur. J. 2004, 10, 3130-3138. (b)
Dembinski, R. Eur. J. Org. Chem. 2004, 2763-2772 (c) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340-1355. (d) Swa-
my, K. C. K.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551-2651. (e) Fletcher, S. Org. Chem. Front. 2015, 2, 739-752.
(7) Polymer supported reagents: (a) Arnold, L. D.; Assil, H. I.; Vederas, J. C.; J. Am. Chem. Soc. 1989, 111, 3973-3976. (b)
Harned, A.M.; Song He, H.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. J. Am. Chem. Soc. 2005, 127, 52-53. (c) Bergbreiter, D.
E.; Yang, Y.-C.; Hobbs, C. E. J. Org. Chem. 2011, 76, 6912–6917.
(8) Apolar and fluorous tags in Mistunobu: (a) Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org. Lett. 2006, 8, 5069-
5072. (b) Yang, J.; Dai, L.; Wang, X.; Chen, Y. Tetrahedron 2011, 67,1456-1462. (c) Dandapani, S.; Curran, D. P. Tetrahe-
dron 2002, 58, 3855-3864. (d) Markowicz, M. W.; Dembinski, R. Org. Lett. 2002, 4, 3785-3787. (e) Curran, D. P.; Wang, X.;
Zhang, Q. J. Org. Chem. 2005, 70, 3716-3719. (f) Chu, Q.; Henry, C.; Curran, D. P. Org. Lett. 2008, 10, 2453-2456.
(9) Polarity based separation (a) Camp, D.; Jenkins, I. D. Aust. J. Chem. 1988, 41, 1835-1839. (b) Kiankarimi, M.; Lowe, R.;
McCarthy J. R.; Whitten, J. P. Tetrahedron Letters 1999, 40, 4497-4500. (c) Hagiya, K.; Muramoto, N.; Misaki, T.; Sugi-
mura, T. Tetrahedron 2009, 65, 6109-6114. (d) Lanning, M. E.; Fletcher, S. Tetrahedron Letters 2013, 54, 4624-4628. (e)
Muramoto, N.; Yoshino, K.; Misaki, T.; Sugimura, T. Synthesis 2013, 45, 931-935. (f) Furkert, D. P.; Breitenbach, B.; Juen,
L.; Sroka, I.; Pantin, M.; Brimble, M. A. Eur. J. Org. Chem. 2014, 7806-7809.
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The Journal of Organic Chemistry
Page 14 of 14
(10) (a) Jakab, A.; Dalicsek, Z.; Holczbauer, T.; Hamza, A.; Pápai, I.; Finta, Z.; Timári, G.; Soós, T. Eur. J. Org. Chem. 2015,
60-66. (b) Jakab, A.; Dalicsek, Z.; Soós, T. Eur. J. Org. Chem. 2015, 56-59. The concept of minimal tagging for catalyst
separation: (c) Dalicsek, Z.; Pollreisz, F.; Soós T. Chem. Commun. 2009, 4587-4589.
1
2
3
4
5
6
7
8
(11) (a) Manabe, K. Tetrahedron 1998, 54, 14465-14476. (b) Cinderella, A. P.; Vulovic, B.; Watson, D. A. J. Am. Chem. Soc.
2017, 139, 7741-7744.
9
(12) Prat, D.; Pardigon, O.; Flemming, H.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senac, T.; Ruisseau, S.; Cru-
ciani, P.; Hosek, P. Org. Process Res. Dev. 2013, 17, 1517-1525.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13) Dubován, L.; Pöllnitz, A.; Silvestru, C. Eur. J. Inorg. Chem. 2016, 1521-1527.
(14) RajanBabu, T.V.; Nomura, N.; Jin, J.; Nandi, M.; Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431-8446.
(15) Li, Y.; Du, W.; Deng, W-P. Tetrahedron, 2012, 68, 3611-3615.
(16) Chakraborti, A. K.; Singh, B.; Chankeshwara, S. V.; Patel, A. R. J. Org. Chem. 2009, 74, 5967-5974.
(17) Liu, H.; Dong, C.; Zhang, Z.; Wu, P.; Jiang, X. Angew. Chem. Int. Ed. 2012, 51, 12570-12574.
(18) Jakob, U.; Mundinger, S.; Bannwarth, W. Eur. J. Org. Chem. 2014, 6963-6974.
(19) Upadhyaya, K.; Hamidullah; Singh, K.; Arun, A.; Shukla, M.; Srivastava, N.; Ashraf, R.; Sharma, A.; Mahar, R.;
Shukla, S. K.; Sarkar, J.; Ramachandran, R.; Lal, J.; Konwar, R.; Tripathi, R. P. Org. Biomol. Chem. 2016, 14, 1338-1358.
(20) Huang, X.; Li, X.; Zou, M.; Song, S.; Tang, C.; Yuan, Y.; Jiao, N. J. Am. Chem. Soc. 2014, 136, 14858-14865.
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